EA045018B1 - METHODS AND COMPOSITIONS FOR IMPROVING COGNITIVE FUNCTION - Google Patents

Description

This application claims priority to U.S. Provisional Patent Application No. 61/302,760 (filed February 9, 2010), the contents and disclosures of which are incorporated herein by reference in their entirety.

Field of technology to which the invention relates

The present invention relates to methods and compositions that improve cognitive function through the use of a combination of a synaptic vesicular protein 2A inhibitor (SV2A) and an acetocholinesterase inhibitor (AChEI). In particular, the present invention relates to the use of a combination of an SV2A inhibitor and an AChEI for the treatment of central nervous system (CNS) disorders with cognitive impairment in a subject in need thereof or at risk for a disease, including, without limitation, subjects suffering from or at risk for an age-related cognitive disorder, mild cognitive impairment (MCI), amnestic MCI, age-related memory impairment (AAMI), age-related cognitive decline (ARCD), dementia, Alzheimer's disease (AD), prodromal AD, post-traumatic stress disorder (PTSD), schizophrenia, amyotrophic lateral sclerosis (ALS) ) and cancer treatment-related cognitive impairment.

Background of the present invention

Cognitive ability may decline due to normal aging or due to a disorder of the central nervous system.

A significant population of older adults experiences cognitive decline that goes beyond what is normal with normal aging. This age-related loss of cognitive function is clinically characterized by progressive loss of memory, perception, thinking, and judgment. Mild cognitive impairment (MCI), age-related memory impairment (AAMI), age-related cognitive decline (ARCD), or similar clinical groups are among the groups that are associated with such age-related loss of cognitive function. It is estimated that there are more than 16 million people living with AAMI in the United States alone (Barker et al., 1995) and an estimated 5.5–7 million US residents over the age of 65 are affected by MCI (Plassman et al., 2008).

Other central nervous system (CNS) disorders such as dementia, Alzheimer's disease (AD), prodromal AD, post-traumatic stress disorder (PTSD), schizophrenia, amyotrophic lateral sclerosis (ALS), and cancer treatment-related cognitive impairment are also associated with cognitive impairment .

Therefore, there is a need to effectively treat central nervous system (CNS) disorders with cognitive impairment and improve cognitive function in patients diagnosed with age-related cognitive impairment, MCI, amnestic MCI, AAMI, ARCD, dementia, AD, prodromal AD, PTSD, schizophrenia, amyotrophic lateral disease sclerosis (ALS), cancer treatment-related cognitive impairment and similar central nervous system (CNS) disorders with or at risk of developing cognitive impairment.

Tacrine hydrochloride (COGNEX™), the first FDA-approved drug for Alzheimer's disease (AD), is an AChEI (Cutler et al., 1993). Other examples of AChEIs used clinically include galantamine (REMINYL™) or rivastigmine (EXELON™). However, these drugs have demonstrated limited effectiveness in improving cognitive function in patients with Alzheimer's disease and have side effect profiles that limit their use. Another AChEI, donepezil (also known as ARICEPT™), appears to be more effective than tacrine. Mild improvements in cognitive function have been observed in patients with Alzheimer's disease treated with donepezil (Barner et al., 1998; Rogers et al., 1998), but the usefulness of donepezil is limited due to its moderate effectiveness and side effects. The long-term therapeutic efficacy of donepezil is also increasingly being questioned (Maggini et al., 2006; Petersen et al., 2006). Therefore, there is a need for more effective treatment of disorders with cognitive dysfunction and, in particular, cognitive impairment in patients with AD.

Brief description of the invention

According to a first aspect, the present invention relates to a method of treating or improving cognitive function in a subject suffering from or at risk of having a central nervous system (CNS) disorder with cognitive impairment, the method comprising the step of administering to said subject a therapeutically effective amount of an SV2A inhibitor or a pharmaceutically acceptable amount thereof. salt, hydrate, solvate or polymorph in combination with a therapeutically effective amount of AChEI or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof. According to some embodiments of the present invention, the methods of the present invention prevent or slow the progression of said CNS disorder with cognitive impairment in said subject. According to other embodiments of the present invention, the methods of the present invention alleviate, reduce the intensity or slow the progression of one or more symptoms associated with said CNS disorder with cognitive impairment in said subject.

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In one embodiment of the present invention, the SV2A and/or AChEI inhibitor is administered at doses that are subtherapeutic compared to the doses at which they would be therapeutically effective when administered without the other agent.

In some embodiments of the present invention, the CNS disorder with cognitive impairment is an age-related cognitive disorder, such as mild cognitive impairment (MCI), age-related memory impairment (AAMI), age-related cognitive decline (ARCD). According to one embodiment of the present invention, the MCI is amnestic MCI. In some embodiments of the present invention, the CNS disorder with cognitive impairment is dementia, Alzheimer's disease (AD), prodromal AD, post-traumatic stress disorder (PTSD), schizophrenia, amyotrophic lateral sclerosis (ALS), or cancer treatment-related cognitive impairment. In one embodiment, the subject suffering from such a CNS disorder or such a cognitive disorder is a human patient.

The SV2A inhibitor, or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof, that is useful in the methods and compositions of the present invention includes inhibitors disclosed, for example, in US patent application 12/580464, international patent application PCT/US 2009/005647 , US Patent Application 61/105847, US Patent Application 61/152631, and US Patent Application 61/175536. However, any SV2A inhibitor or pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof can be used in the methods and compositions of the present invention. According to other embodiments, the SV2A inhibitor is selected from the SV2A inhibitors group, a link to which is given in international patent applications Wo 2010/144712, Wo 2010/002869, Wo 2007/132139, Wo 2007/065595, Wo 2006/128693, Wo 2006/128692 , WO 2005/054188, WO 2004/087658, WO 2002/094787, WO 2001/062726; US patents Nos. 7465549, 7244747, 5334720, 4696943, 4696942; Published US Patent Applications Nos. 20090312333, 20090018148, 20080081832, 2006258704; and UK Patent Nos. 1039113 and 1309692, or pharmaceutically acceptable salts, hydrates, solvates or polymorphs thereof. In other embodiments, the SV2A inhibitor is selected from the group consisting of levetiracetam, brivaracetam, and seletracetam, or derivatives, analogs, pharmaceutically acceptable salts, hydrates, solvates, or polymorphs thereof. In other embodiments, the SV2A inhibitor is levetiracetam or a derivative, analog, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.

AChEI or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof that is useful in the methods and compositions of the present invention includes inhibitors disclosed, for example, in international patent applications WO 2010/057088, WO 2009/008769, WO 2008/097546, WO 2008/074896, WO 2008/073452, WO 2007/127474, WO 2007/10784b, WO 2006/097588, WO 2006/071274, WO 2006/070394, WO 2006/060082, WO 2 006/040688, WO 2005/092009, WO 2005/079789, WO 2005/074535, WO 2005/072713, WO 2005/042475, WO 2005/039580, WO 2005/027975, WO 2004/084884, WO 2004/080393, WO 2 004/052348, WO 2004/037234, WO 2004/034963, WO 2004/032929, WO 2003/101458, WO 2003/091220, WO 2003/082820, WO 2003/082794, WO 2003/020289, WO 2002/074293, WO 2 002/032412, WO 2001/085145, WO 2001/078728, WO 2001/066114, WO 2001/066096, WO 2001/021590, WO 2001/000215, WO 2000/033840, WO 2000/03044b, WO 2000/023057, WO 2 000/015205, WO 2000/009483, WO 2000/007600, WO 2000/002549, WO 1999/047131, WO 1999/008672, WO 1999/007359, WO 1998/039000, WO 1998/030243, WO 1997/138993, WO 1 997/119059, WO

1997/038993, WO 1997/029750, WO 1997/021681, WO 1997/013754, WO 1997/008146, WO 1996/040682, WO 1994/029255, WO 1994/020476, WO 1 994/019356, WO 1993/116690, WO 1993/113100, WO

1993/007140, WO 1993/003041, WO 1993/003034, WO 1992/019238, WO 1992/017475, WO 1991/003467 and WO 1988/008708; US patents Nos. 7846930, 7732162, 7635709, 7378425, 6495700, 6479523, 6372760, 6245911, 6140321, 5985864, 5965571, 5965569, 5750542, 5744476, 5693668, 5668117, 5663448, 5622976,

5603176, 5602176, 5574046, 5455245, 5391553, 5389629, 5364864, 5338548, 5302593, 5300517, 5288758,

5246947, 5231093, 5187165, 5166181, 5106856, 5102891, 5100901, 4950658, 4948807, 4948807, 4948807,

4914102, 4895841, 4895841, 4816456, 4663318, 4663318, 4663318 and 2701225; patent applications

Japan Nos. 4-216704 and 4-187674; Canadian Patent No. 2,180,703; Published European Patent Applications Nos. 298202, 236684, 409676, 411534, 468187, 477903, 481429, 487071, 611769, 703901, 1050303, 2018874 and 2260839; Published US Patent Applications Nos. 20010036949, 20020119963, 20030078252, 2003069289, 20040082644, 20050245504, 20050124642, 20060052428, 20070 275959,20080103105, 20080261950, 20090124659, 20100152108, 20100227852 and 20100311697. However, any AChEI or its pharmaceutically acceptable salt, hydrate, solvate or the polymorph may be used in the methods and compositions of the present invention.

In other embodiments of the present invention, an SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof may be administered in dosages disclosed in, for example, US Patent Application No. 12/580464, International Patent Application PCT/US2009/005647, Application No. US Patent Application 61/105847, US Patent Application 61/152631 and US Patent Application 61/175536. In other embodiments of the present invention, an SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof is administered every 12 or 24 hours at a daily dose of about 0.001 to 5 mg/kg. In other embodiments of the present invention, the SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof is administered every 12 or 24 hours at a daily dose of about 0.1 to 5 mg/kg, or about 1 to 2 mg/kg , or about 0.1 to 0.2 mg/kg, or about 0.01 to 2.5 mg/kg, or about 0.1 to 2.5 mg/kg, or about 0.4 to 2.5 mg/kg, or about 0.6 to 1.8 mg/kg, or about 0.01 to 1 mg/kg, or about 0.001 to 1 mg/kg, or about 0.5 to 5 mg/kg, or approximately 0.05 to 0.5 mg/kg. In some embodiments, a subtherapeutic amount of an SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof is administered. Such subtherapeutic amount may be, for example, a daily dose of less than 5 mg/kg, less than 2.5 mg/kg, less than 2 mg/kg, less than 1.5 mg/kg, less than 1 mg/kg, less less than 0.5 mg/kg, less than 0.1 mg/kg, less than 0.05 mg/kg, less than 0.01 mg/kg, less than 0.005 mg/kg, or less than 0.001 mg/kg, administered every 12 or 24 hours.

In other embodiments of the present invention, AChEI or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof is administered every 12 or 24 hours at a daily dose of about 0.1 to 10 mg. In some embodiments, a subtherapeutic amount of AChEI or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof is administered. In some embodiments, the subtherapeutic amount of AChEI administered is a daily dose of less than about 10 mg, less than about 5 mg, less than about 2 mg, less than about 1 mg, less than about 0.5 mg.

In other embodiments of the present invention, the SV2A inhibitor and AChEI, or pharmaceutically acceptable salts, hydrates, solvates, or polymorphs thereof, are administered simultaneously or sequentially, either in a single dosage form or in co-packaged separate dosage forms. In other embodiments, the SV2A and AChEI inhibitor, or pharmaceutically acceptable salts, hydrates, solvates, or polymorphs thereof, are administered by different routes. As used herein, the term combination includes administration through any of the specified dosage forms or routes of administration.

In some embodiments of the present invention, the combination treatment has at least about 1.5, or 2.0, or 2.5, or 3.0, or 3.5, or 4.0, or 4.5, or 5.0, or 5.5, or 6.0, or 6.5, or 7.0, or 7.5, or 8.0, or 8, 5, or 9.0, or 9.5, or 10, or more than about 10 times a longer lasting or improved therapeutic effect in a subject than that achieved by administering AChEI or a pharmaceutically acceptable salt, hydrate, a solvate or polymorph without the SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof.

In other embodiments of the present invention, the combination treatment has at least about 1.5, or 2.0, or 2.5, or 3.0, or 3.5, or 4.0, or 4.5, or 5.0, or 5.5, or 6.0, or 6.5, or 7.0, or 7.5, or 8.0, or 8, 5, or 9.0, or 9.5, or 10, or more than about 10 times the prolonged or improved therapeutic effect in a subject that is achieved by administering an SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate or a polymorph without AChEI or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof.

According to another aspect, the present invention relates to a method of increasing the therapeutic index of AChEI or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof in a method of treating a central nervous system (CNS) disorder with cognitive impairment in a subject in need thereof or at risk of a disease, comprising administering the said a subject of an SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof in combination with AChEI or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof.

In some embodiments, an increase in the therapeutic index of AChEI or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof by at least about 1.5, or 2.0, or 2.5, or 3.0, or 3. 5, or 4.0, or 4.5, or 5.0, or 5.5, or 6.0, or 6.5, or 7.0, or 7.5, or 8.0, or 8.5, or 9.0, or 9.5, or 10, or more than about 10 times the therapeutic AChEI index when administered without an SV2A inhibitor or a pharmaceutically acceptable salt thereof, hydrate, solvate or polymorph, or a pharmaceutically acceptable salt, hydrate, solvate or polymorph of AChEI when administered without an SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof.

According to another aspect, the present invention relates to a method of increasing the therapeutic index of an SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof in a method of treating a central nervous system (CNS) disorder with cognitive impairment in a subject in need thereof or at risk of a disease, comprising administering said subject of an SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof in combination with AChEI or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof.

In some embodiments, an increase in the therapeutic index of the SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof by at least about 1.5, or 2.0, or 2.5, or 3.0, or 3 .5, or 4.0, or 4.5, or 5.0, or 5.5, or 6.0, or 6.5, or 7.0, or 7.5 , or 8.0, or 8.5, or 9.0, or 9.5, or 10, or more than approximately 10 times the therapeutic index of the SV2A inhibitor, hydrate, solvate, or polymorph when administered without AChEI or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof, or a pharmaceutically acceptable salt, hydrate, solvate or polymorph of an SV2A inhibitor when administered without AChEI or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof.

According to another aspect, the present invention provides a pharmaceutical composition for treating or improving cognitive function in a subject suffering from or at risk of developing a central nervous system (CNS) disorder with cognitive impairment, wherein the composition contains an SV2A and AChEI inhibitor or pharmaceutically acceptable salts, hydrates thereof, solvates or polymorphs. In some embodiments, the composition is in solid form. In some embodiments, the composition is in liquid form. In some embodiments, the composition is provided in the form of an aqueous solution. In some embodiments, the composition is in the form of a suspension. In some embodiments, the composition is provided in a sustained release form, a controlled release form, a delayed release form, or an extended release form. In some embodiments, the composition is provided in a single dosage form. In other embodiments, the two components of the composition are presented as co-packaged separate delivery forms.

In some embodiments of the present invention, the composition comprises levetiracetam or a derivative, analogue, pharmaceutically acceptable salt, hydrate, solvate or polymorph, and donepezil or a derivative, analogue, pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof.

In some embodiments of the present invention, the SV2A inhibitor, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, is contained in the composition in an amount of 0.07-350 mg, or 50-250 mg, or 3-50 mg. In some embodiments, the SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof is contained in an amount of less than 350 mg, less than 250 mg, less than 200 mg, less than 150 mg, less than 100 mg, less than 50 mg , less than 10 mg, less than 5 mg, less than 1 mg, less than 0.5 mg, less than 0.1 mg or less than 0.07 mg.

In some embodiments of the present invention, AChEI or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof is contained in an amount of from 0.1 to 10 mg. In some embodiments, AChEI or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof is contained in an amount of less than 10 mg, less than 5 mg, less than 2 mg, less than 1 mg, less than 0.5 mg.

Brief description of drawings

In fig. Figure 1 shows the effects of levetiracetam administration on spatial memory retention in ten age-related (AI) rats in the eight-arm radial maze (RAM) test. Six treatments were used: control with medium administration, levetiracetam (1.25 mg/kg/day), levetiracetam (2.5 mg/kg/day), levetiracetam (5 mg/kg/day), levetiracetam (10 mg/kg /day) and levetiracetam (20 mg/kg/day). In the RAM test used, there is a one-hour delay between presenting a set of arms (5 available arms and 3 blocked arms) and executing the eight-arm win-shift test (8 available arms). 30-40 minutes before the daily test, the rats are pretreated with a single drug/control treatment. The number of errors rats made during the retention phase was used as a measure of spatial memory retention. Errors were defined as instances in which rats entered an arm in which food had already been found during the pre-delay phase of the trial, or in which rats re-entered an arm that had already been visited during the post-delay phase. Paired t tests were used to compare the number of errors between different doses of levetiracetam and the vehicle control.

In fig. Figure 2 shows the effects of donepezil alone and donepezil plus levetiracetam on spatial memory retention in eight age-related (AI) rats in the eight-arm radial maze (RAM) test. Four treatments were used: vehicle control, donepezil alone (1 mg/kg/day), donepezil (2 mg/kg/day), and a combination of donepezil (1 mg/kg/day) and levetiracetam (2.5 mg/kg). /day). In the RAM test used, there is a one-hour delay between presenting a set of arms (5 available arms and 3 blocked arms) and executing the eight-arm win-shift test (8 available arms). 30-40 minutes before the daily test, rats are pre-treated with a single drug/control treatment. The number of errors rats made during the retention phase was used as a measure of spatial memory retention. Errors were defined as instances in which rats entered an arm where food had already been found during the pre-delay phase of the trial, or in which rats re-entered an arm that had already been visited during the post-delay phase. Paired t tests were used to compare the number of errors between different doses of levetiracetam and the vehicle control. Relative to the vehicle control, the combination of donepezil (1 mg/kg/day) and levetiracetam (2.5 mg/kg/day) significantly improved memory performance (t(7)=2.16, p=0.034).

In fig. Figure 3 shows the experimental design of the human trial with levetiracetam treatment.

In fig. Figure 4A depicts mean activity in left CA3 in placebo-treated aMCI subjects and placebo-treated age-matched control subjects during the presentation of lure stimuli that subjects correctly identified as similar.

In fig. Figure 4B depicts mean activity in left CA3 in subjects with aMCI treated with placebo or treated with levetiracetam (125 mg twice daily for two weeks) during the presentation of lure stimuli that subjects correctly identified as similar.

Fig. 4C is a table of the values presented in FIG. 4A and 4B.

In fig. Figure 5A depicts mean activity in left entorhinal cortex in age-matched placebo-treated control subjects and placebo-treated aMCI subjects during presentation of lure stimuli that subjects correctly identified as similar.

In fig. Figure 5B depicts mean activity in the left entorhinal cortex in the same subjects with aMCI treated with placebo or treated with levetiracetam (125 mg twice daily for two weeks) during the presentation of lure stimuli that subjects correctly identified as similar.

Fig. 5C is a table of the values shown in FIG. 5A and 5B.

In fig. 6A shows an example of a sequence of images presented to patients in the three-alternative forced choice test described in Example 2.

In fig. 6B shows samples of pairs of similar images (decoy).

In fig. Figure 7 presents the difference between subjects with aMCI (placebo) and age-matched control subjects (placebo) when they performed the three-alternative forced choice test described in Example 2. Each column represents the proportion of subjects' responses (old, similar, or new) in the process of presenting a decoy image.

In fig. Figure 8 shows the difference between the same subjects with aMCI treated with placebo or levetiracetam (125 mg twice daily for two weeks) when they performed the three-alternative forced-exact choice test described in Example 2. Each column represents the proportion of responses among subjects (old, similar or new) during the presentation of the decoy image.

Fig. 9 is a table of the values shown in FIG. 7 and 8.

In fig. 10A shows the difference between age-matched control subjects (placebo) and aMCI subjects treated with placebo or levetiracetam (125 mg twice daily for two weeks) on the Buschke Selective Memory-Delayed Recall Test.

Fig. 10B is a table of the values shown in FIG. 10A.

In fig. 11A shows the difference between subjects in the control group (placebo) and subjects with aMCI treated with placebo or levetiracetam (125 mg twice daily for two weeks) on their performance on the Benton Visual Retention Test.

Fig. 11B is a table of the values shown in FIG. 11A.

In fig. 12A shows the difference between subjects in the control group (placebo) and subjects with aMCI treated with placebo or levetiracetam (125 mg twice daily for two weeks) on their performance on the Verbal Paired Association Test - Recognition.

Fig. 12B is a table of the values shown in FIG. 12A.

In fig. 13A shows the difference between subjects in the control group (placebo) and subjects with aMCI treated with placebo or levetiracetam (125 mg twice daily for two weeks) on their performance on the Verbal Paired Association Test - Delayed Recall.

Fig. 13B is a table of the values shown in FIG. 13A.

Fig. 14A is a table showing the subject selection process for the human trials of levetiracetam described in Example 2.

Fig. 14B is a table showing the characteristics of the subjects selected for the levetiracetam human trials described in Example 2.

Detailed Description of the Present Invention

Unless otherwise defined herein, scientific and technical terms used in this application will have the meanings commonly understood by one skilled in the art.

- 5 045018 this field of technology. In general, the nomenclature and techniques described herein as applied to cell and tissue culture, molecular biology, cell and cancer biology, neurobiology, neurochemistry, virology, immunology, microbiology, pharmacology, genetics, and protein and nucleic acid chemistry are well known and widely used in the art.

Unless otherwise specifically stated, the methods and procedures of the present invention are generally carried out in accordance with conventional methods well known in the art and described in various general and more specific references that are cited and discussed throughout this specification ( see, for example, Principles of Neural Science, McGraw-Hill Medical, New York, N.Y. (2000); Motulsky, Intuitive Biostatistics, Oxford University Press, Inc. (1995); Lodish et al., Molecular Cell Biology, 4th ed. , W. H. Freeman & Co., New York (2000); Griffiths et al., Introduction to Genetic Analysis, 7th ed., W. H. Freeman & Co., N.Y. (1999); Gilbert et al., Developmental Biology, 6th ed., Sinauer Associates, Inc., Sunderland, MA (2000).

Chemical terms used herein are in accordance with generally accepted practice in the art, as exemplified by The McGrawHill Dictionary of Chemical Terms, Parker S., Ed., McGraw-Hill, San Francisco, C.A. (1985).

All of the above and any other publications, patents and published patent applications referenced in this application are specifically incorporated herein by reference. In the event of a conflict, this description, including its specific definitions, will govern.

Throughout this specification, it should be understood that the word contain, or variants such as contains or containing, implies the inclusion of a particular integer (or component) or group of integers (or components), but not the exclusion of any other integer (or component) or groups of integers (or components).

The singular forms a, an and the include the plural unless the context clearly states otherwise.

The term including is used to mean the term including without limitation. The terms including and including without limitation are used interchangeably.

The term agent is used herein to refer to a chemical compound (such as an organic or inorganic compound, a mixture of chemical compounds), a biological macromolecule (such as a nucleic acid, an antibody, including parts thereof, as well as humanized, chimeric and human antibodies and monoclonal antibodies, protein or parts thereof, e.g. peptide, lipid, hydrocarbon) or extract obtained from biological materials such as bacteria, plants, fungi or animal (particularly mammalian) cells or tissues. The means include, for example, means that are known in relation to the structure, and means that are unknown in relation to the structure.

The activity of such agents as an SV2A or AChEI inhibitor may make them useful as therapeutic agents in the methods and compositions of the present invention.

The terms patient, subject, or person are used interchangeably and refer to both human and non-human animal. These terms include mammals such as humans, primates, farm animals (including ruminants, pigs, etc.), domestic animals (eg, dogs, cats, etc.) and rodents (eg, mice and rats).

The terms cognitive function or cognitive status refer to any high-order intellectual process in the brain or state of mental abilities, respectively, involved in learning and/or memory, including, but not limited to, attention, information acquisition, information processing, working memory, short-term memory, long-term memory memory, anterograde memory, retrograde memory, memory retrieval, discrimination response learning, decision making, control of inhibitory responses, attention setting-switching, delayed reinforcement learning, skill remodeling, integration of conscious behavior over time and expression of interest in the environment and care yourself.

In humans, cognitive function may be measured by, for example and without limitation, the Clinical Global Impression of Change (CIBIC-plus scale), the Mini-Mental State Examination (MMSE), the Neuropsychiatric Inventory (NPI), the Clinical Dementia Rating Scale (CDI). CDR), Cambridge Automated Neurophysiological Test Battery (CANTAB), Sandoz Clinical Geriatric Rating Scale (SCAG), Buschke Selective Memory Test (Buschke and Fuld, 1974), Verbal Paired Association Subtest, Logical Memory Subtest, the Visual Reproduction subtest of the Wechsler Memory Scale-Revised (WMS-R) (Wechsler, 1997), the Benton Visual Retention Test, or the forced three-alternative choice test (see Folstein et al., J Psychiatric Res 12:189 -98, (1975); Robbins et al., Dementia 5:266-81, (1994); Rey, L'examen clinique en psychologie, (1964); Kluger et al., J Geriatr Psychiatry Neurol 12:168-79 , (1999); Marquis et al., 2002 and Masur et al., 1994).

In animal models, cognitive function can be measured using a variety of conventional methods known in the art, including the Morris water maze (MWM), Burns ring maze, elevated radial maze, T-maze, or any other maze in which animals use spatial information. Other tests known in the art, such as novel object recognition and odor recognition tests, can also be used to determine cognitive function.

Cognitive function can also be measured using imaging techniques such as positron emission tomography (PET), functional magnetic resonance imaging (fMRI), single photon emission computed tomography (SPECT), or any other imaging technique that measures brain function. In animals, cognitive function can also be measured using electrophysiological techniques.

The term cognitive activation refers to influencing impaired cognitive function so that it more closely matches the function of a normal, non-impaired subject. Cognitive function may be activated to any detectable degree, but in humans it is preferably activated to the extent that it allows the disordered subject to perform daily normal activities with the same level of efficiency as a normal non-disordered subject.

In some cases, the term activation of cognitive function in a subject suffering from age-related cognitive disorder refers to influencing the impaired cognitive function so that it more closely correlates with the function of an age-matched normal non-disordered subject or with the function of a young adult subject. Cognitive function in such a subject may be activated to any detectable degree, but in humans it is preferably activated to the extent that it allows the disordered subject to perform daily normal activities with the same level of efficiency as an age-matched normal non-disordered subject or young adult subject. .

The term preservation of cognitive function refers to influencing normal or impaired cognitive function so that it does not decline or fall below the value that was observed in the subject at first examination or diagnosis, or such decline is delayed.

The term improvement of cognitive function includes activation of cognitive function and/or preservation of cognitive function in a subject.

The term cognitive impairment refers to the cognitive function of a subject that is not as healthy as the expected function in a normal, non-disordered subject. In some cases, cognitive function is reduced by about 5%, about 10%, about 30%, or more, compared with the cognitive function observed in a normal, non-disordered subject. In some cases, the term cognitive impairment in subjects suffering from age-related cognitive disorder refers to the subjects' cognitive function that is not as healthy as the expected function in an age-matched normal non-disordered subject or the function of a young adult subject (i.e. subjects with average cognitive test results for a given age).

The term age-related cognitive disorder refers to a cognitive disorder in older subjects in which their cognitive function is not as healthy as predicted function in an age-matched normal non-impaired subject or predicted function in younger adult subjects. In some cases, cognitive function is reduced by approximately 5%, approximately 10%, approximately 30%, or more, compared with cognitive function expected in an age-matched normal subject. In some cases, cognitive function is consistent with that expected in an age-matched normal subject, but is reduced by about 5%, about 10%, about 30%, or more than the cognitive function expected in a young adult subject. Age-related cognitive impairment may be associated with mild cognitive impairment (MCI) (including amnestic MCI and non-amnestic MCI), age-related memory impairment (AAMI), and age-related cognitive decline (ARCD).

The term cognitive impairment associated with AD, or associated with AD, or observed in AD, refers to the cognitive function of a subject that is not as healthy as predicted function in subjects without a conventional diagnosis of AD.

The term mild cognitive impairment or MCI refers to a condition characterized by isolated memory impairment, unaccompanied by other cognitive impairment, and relatively normal functional abilities. One system of criteria for the clinical characterization of MCI establishes the following characteristics:

(1) memory complaints (according to the patient, informant or doctor),

- 7 045018 (2) normal activities of daily living (ADLs), (3) normal general cognitive function, (4) age-abnormal memory (defined as more than 1.5 standard deviations below the age-specific mean) age) and (5) absence of signs of dementia (defined by the DSM-IV manual) (see Petersen et al., Srch. Neurol. 56: 303-308 (1999); Petersen, Mild cognitive impairment: Aging to Alzheimer's Disease. Oxford University Press, N.Y. (2003)).

A diagnosis of MCI usually entails an objective assessment of cognitive impairment, which can be obtained through the use of established neurophysiological tests, including the Mini-Mental State Examination (MMSE), the Cambridge Neurophysiological Test Automated Battery (CANTAB), and individual tests such as the Rey Test of Auditory-Language. learning test (AVLT), the Logical Memory subtest of the Wechsler Memory Scale-Revised (WMS-R), and the New York University (NYU) Paragraph Reproduction Test (see Folstein et al., J Psychiatric Res 12: 189-98 (1975). ); Robbins et al., Dementia 5: 266-81 (1994); Kluger et al., J Geriatric Psychiatry Neurol 12: 168-79 (1999)).

The term age-related memory impairment (AAMI) refers to the decline in memory due to aging. A patient may be considered to have AAMI if he or she is at least 50 years of age and all of the following criteria are met: a) the patient has noticed deterioration in memory performance, b) the patient performs worse on a standard memory test compared to younger adult subjects, c) all other obvious causes of memory decline other than normal aging have been ruled out (in other words, memory decline cannot be explained by other causes such as recent heart attack or head injury, depression, abnormal drug reaction, Alzheimer's disease, etc. ).

The term age-related cognitive decline (ARCD) refers to the decline in memory and cognitive abilities that is a normal consequence of aging in humans (e.g., Craik & Salthouse, 1992). It is also found in almost all mammal species. Age-related memory loss refers to older adults with objective memory decline compared with their younger years, but with normal cognitive performance compared with their peers (Crook et al., 1986). Age-related cognitive decline is a less pessimistic diagnosis that emphasizes that it is a normal developmental change (Crook, 1993; Larrabee, 1996), not pathophysiological (Smith et al., 1991) and rarely progresses to full-blown dementia (Youngjohn & Crook, 1993). In the DSM-IV diagnostic classification (1994), a code is assigned to ARCD.

Alzheimer's disease is characterized by early-stage memory loss. Later symptoms include mental fog, disorientation, confusion, behavior changes, speech disturbances, and movement disorders. Histologically, AD is characterized by β-amyloid plaques and tau protein nodules.

Vascular dementia is caused by strokes. The symptoms are similar to those of AD, but without the emphasis on memory impairment.

Dementia with Lewy bodies is characterized by abnormal deposition of α-synuclein that occurs within neurons in the brain. Cognitive impairment may be similar to AD, including memory impairment, mental confusion, and behavior changes.

Frontotemporal dementia is characterized by gliosis, neuronal death, superficial spongy degeneration of the frontal cortex and/or anterior temporal lobes, and Pick bodies. Symptoms include changes in personality and behavior, including decreased social skills and language expression/comprehension.

The term post-traumatic stress disorder (PTSD) refers to an anxiety disorder characterized by immediate or delayed reactions to a catastrophic event, re-experiencing the trauma, mental numbness or avoidance of trauma-associated stimuli, and increased arousal. Reexperiencing phenomena include intrusive memories, flashbacks of the past, nightmares, and psychological or physiological distress in response to reminders of the trauma. Such reactions are alarming and can have a significant impact, both chronic and acute, on the patient's quality of life and physical and emotional health. PTSD is also associated with cognitive impairment, and older individuals with PTSD experience greater cognitive decline compared with controls.

The term schizophrenia refers to a chronic debilitating disorder characterized by a spectrum of psychopathology, including productive symptoms such as impaired or distorted mental representation (e.g., hallucinations, delusions), negative symptoms characterized by diminished motivation and adaptive goal-directed behavior (e.g., anhedonia, affective dullness, abulia), and cognitive impairment. Although brain abnormalities are thought to underlie the full range of psychopathology in schizophrenia, existing antipsychotic drugs are largely ineffective in treating cognitive impairment in these patients.

The term amyotrophic lateral sclerosis, also known as ALS, refers to a progressive, incurable neurodegenerative disease characterized by the degeneration of motor neurons, the nerve cells of the central nervous system that control voluntary muscle contractions. ALS is also characterized by neuronal degeneration in the entorhinal cortex and hippocampus, memory deficits, and neuronal hyperexcitability in various brain regions such as the cortex.

The term cancer treatment-related cognitive impairment refers to a cognitive impairment that develops in subjects undergoing cancer therapy, such as chemotherapy or radiation. Cytotoxicity and other harmful side effects of cancer therapy on the brain lead to cognitive impairment of functions such as memory, learning and attention.

The term treating a condition or patient refers to taking steps to obtain favorable or desired results, including clinical results. Beneficial or desired clinical outcomes include, but are not limited to, preventing or slowing the progression of a disease or disorder or alleviating, reducing the intensity or slowing the progression of one or more symptoms associated with CNS disorders with cognitive impairment, such as age-related cognitive impairment, mild cognitive impairment (MCI), amnestic MCI, dementia, Alzheimer's disease (AD), prodromal AD, PTSD, schizophrenia, amyotrophic lateral sclerosis (ALS), or cancer treatment-related cognitive impairment. Treatment of age-related cognitive impairment further includes slowing the progression of age-related cognitive impairment (including but not limited to MCI, ARCD, and AAMI) to dementia (eg, AD).

The term treatment of cognitive impairment refers to taking measures to improve cognitive function in a subject with a cognitive disorder such that the subject's performance on one or more cognitive tests improves to some detectable extent or prevents further decline. Preferably, after treatment of a cognitive disorder, the subject's cognitive function more closely approximates that of a normal non-disordered subject. Treatment of a cognitive disorder in humans may improve cognitive function to some detectable extent, but preferably improves it enough to allow the disordered subject to perform normal daily activities with the same level of efficiency as a normal non-disordered subject. In some cases, the term treating a cognitive disorder refers to taking measures to improve cognitive function in a subject with a cognitive disorder such that the subject's performance on one or more cognitive tests improves to some detectable extent or prevents further decline. Preferably, after treatment of a cognitive disorder, the subject's cognitive function more closely approximates that of a normal non-disordered subject. In some cases, the term treating a cognitive impairment in a subject suffering from age-related cognitive disorder refers to taking steps to improve the cognitive function of the subject so that, after treatment of the cognitive impairment, the subject's cognitive function more closely correlates with that of an age-matched normal non-disordered subject. or with the function of a young adult subject.

The process of administration or administration of a substance, compound or agent to a subject can be carried out using one of a number of methods known to one skilled in the art. For example, the compound or agent may be administered intravenously, arterially, intradermally, intramuscularly, intraperitoneally, intravenously, subcutaneously, intraocularly, sublingually, orally (by ingestion), intranasally (by inhalation), intraspinal, intracerebral, and transdermally (by absorption, e.g. skin pore). The compound or agent may also suitably be administered through rechargeable or biodegradable polymer devices or other devices, such as patches and pump dispensers, or dosage forms that provide sustained, slow, or controlled release of the compound or agent. Administration may also be carried out, for example, once, repeatedly, and/or over one or more extended periods of time. In some aspects, administration includes both direct administration, including self-administration, and indirect administration, including drug prescription. For example, as used herein, a physician administering a drug to a patient is considered to be a physician who instructs a patient to self-administer a drug or obtain a drug from another physician and/or who prescribes a drug to a patient.

Suitable methods of administering a substance, compound or agent to a subject will also depend, for example, on the age of the subject, whether the subject is active or inactive at the time of administration, whether the subject is cognitively impaired at the time of administration, the degree of impairment, and the chemical and biological properties of the compound or agent ( e.g. solubility, digestibility, bioavailability, stability and toxicity). In some embodiments, the connection or

- 9 045018 the agent is administered to the subject orally, for example by ingestion, or intravenously, for example by injection. In some embodiments, the orally administered compound or agent is a sustained release or slow release dosage form, or is administered using a slow or sustained release device.

As used herein, administration of an SV2A inhibitor and AChEI or pharmaceutically acceptable salts, hydrates, solvates or polymorphs thereof in combination or together includes simultaneous administration and/or administration at different times, such as sequential administration. It also includes administration in a single dosage form or in co-packaged individual dosage forms.

As used herein, coadministration means that the SV2A inhibitor and AChEI, or pharmaceutically acceptable salts, hydrates, solvates, or polymorphs thereof, are administered no more than about 15 minutes apart, and in some embodiments, no more than about 10 minutes apart. If the drugs are administered concomitantly, the SV2A inhibitor and AChEI, or salts, hydrates, solvates, or polymorphs thereof, may be contained in the same dosage form (eg, a single dosage form containing both the SV2A inhibitor and AChEI) or in separate dosage forms ( for example, an SV2A inhibitor or its salt, hydrate, solvate or polymorph is contained in one dosage form, and AChEI or its salt, hydrate, solvate or polymorph is contained in another dosage form).

As used herein, the term sequential administration means that the SV2A and AChEI inhibitor or pharmaceutically acceptable salts, hydrates, solvates, or polymorphs thereof are administered more than about 15 minutes apart, and in some embodiments, more than about one hour or within 12 hours. Both the SV2A inhibitor and the AChEI may be administered first. The SV2A and AChEI inhibitor or salts, hydrates, solvates or polymorphs thereof for sequential administration may be contained in separate dosage forms, not necessarily in the same container or package.

A therapeutically effective amount of a drug or agent is an amount of a drug or agent that, when administered to a subject, will produce the intended therapeutic effect, for example, improving cognitive function in the subject, for example, in a subject suffering from a CNS disorder with cognitive impairment. The full therapeutic effect is not necessarily achieved by a single dose and may only occur after a series of doses. Thus, a therapeutically effective amount can be administered through one or more administrations. The exact effective amount required by a subject will depend, for example, on the size, health and age of the subject, the nature and extent of the cognitive impairment, the therapeutic agents or combination of therapeutic agents selected to be administered, and the route of administration. One skilled in the art can readily determine the effective amount for a particular situation through routine testing.

The term subtherapeutic amount refers to an administered amount of an agent or compound of the present invention that is less than the therapeutic amount, i.e. is less than the amount typically used when administered alone (ie, alone and without other therapeutic agents or compounds) of said agent or compound for the treatment of disorders with cognitive dysfunction.

As used herein, the term analogue refers to a compound that is functionally similar to another chemical compound but does not have an identical chemical structure. For example, an analogue is similar to a base or parent compound such that it can replace the parent compound in therapeutic applications despite minor structural differences.

As used herein, the term derivative refers to a chemical modification of a compound. Chemical modifications of a compound may include, for example, replacement of hydrogen with an alkyl, acyl, or amino group. Many other modifications are also possible.

The term prodrug is accepted in the art and is intended to include compounds or agents that are converted under physiological conditions to an inhibitor of SV2A and AChEI. A general method for creating a prodrug is to select moieties that are hydrolyzed or metabolized under physiological conditions to produce the desired compound or agent. In other embodiments, the prodrug is converted to an SV2A and AChEI inhibitor through enzymatic activity in the host animal.

As used herein, the term pharmaceutically acceptable salts refers to an agent or compound of the present invention that is the therapeutically active, non-toxic basic and acid salt form of the agents and compounds of the present invention.

Description of methods according to the present invention

The methods of the present invention include administration of an SV2A inhibitor or a pharmaceutically acceptable salt thereof in combination with administration of AChEI or a pharmaceutically acceptable salt thereof. SV2A or AChEI inhibitor agents or compounds and pharmaceutically acceptable salts thereof also include hydrates, solvates, polymorphs, and prodrugs of these agents, compounds and salts.

Methods for assessing cognitive impairment

Animal models serve as an important resource for developing and evaluating treatments for CNS disorders with cognitive impairment. The characteristics that characterize cognitive impairment in animal models generally extend to cognitive impairment in humans. Thus, efficacy in such animal models is expected to be predictive of efficacy in humans.

The extent of cognitive impairment in an animal model of a central nervous system disorder, and the effectiveness of a method of treating said central nervous system disorder, can be tested and confirmed using a variety of cognitive tests. The sleeve radial maze (RAM) behavioral test is one example of a cognitive test, particularly testing spatial memory (Chappell et al., Neuropharmacology 37: 481-487, 1998). The RAM installation consists, for example, of eight arms spaced at regular intervals. The arm of the labyrinth is directed from each face to the center of the platform. Food is located at the far end of each sleeve. Food is used as a reward. Blocks may be installed to prevent entry into any sleeve. Numerous additional cues surrounding the maze setup may also be provided. Following the habituation and learning phase, subjects' spatial memory can be tested in RAM under control or test compound treatment conditions. As part of the test, subjects are pretreated with a vehicle control or one of a range of doses of the test compound prior to testing. At the beginning of each trial, all arms of the eight-arm maze are blocked. Subjects are given the opportunity to locate food in unlocked arms that are allowed access during this initial information phase of the test. Subjects are then removed from the maze for a delay period (e.g., 60 s delay, 15 min delay, 1 h delay, 2 h delay, 6 h delay, 24 h delay or more) between the information phase and the subsequent test. memory storage, during which the barriers from the maze are removed, thereby providing access to all eight arms. After the delay period, subjects are placed back on the central platform (barriers previously blocking the arms are removed) and given the opportunity to retrieve the food rewards remaining during the retention phase of the test. Locked sleeve numbers and configurations vary between tests. The number of errors subjects made during the memory retention test phase is monitored. A trial error occurs if the subject enters an arm in which food has already been found previously in a phase of the trial preceding the delay period, or if he re-enters an arm that has already been visited in a phase after the delay period. Fewer errors would indicate better spatial memory. The number of errors made by the test subject under different test compound treatment regimens can then be compared to evaluate the effectiveness of the test compound in treating CNS disorders with cognitive impairment.

Another cognitive test that can be used to evaluate the effect of a test compound on cognitive impairment in CNS disorders in animal models is the Morris water maze test. A water labyrinth is a pool surrounded by a new set of structures compared to a labyrinth. A training protocol for the water maze can be based on a modified water maze behavior test, which has been shown to be dependent on the hippocampus (de Hoz et al., Eur. J. Neurosci., 22:745-54, 2005; Steele and Morris, Hippocampus 9: 118-36, 1999). The subject is trained to locate a submerged escape platform hidden beneath the surface of the pool. During the learning trial, the subject is released into a maze (pool) at random starting positions around the entire perimeter of the pool. The starting position varies from trial to trial. If the subject does not find the rescue platform within the allotted time, the experimenter will guide and place the subject on the platform to teach the location of the platform. The final training test is followed by a delay, after which a memory test is administered in the absence of the rescue platform to determine spatial memory. The degree to which a subject selects the location of a rescue platform (not present in this test), measured, for example, by the time spent at that location or the number of mouse crossings of that location, indicates an improvement in spatial memory, i.e. for the treatment of cognitive impairment. The choice of rescue platform location under different treatment conditions can then be compared to evaluate the effectiveness of the test compound in treating CNS disorders with cognitive impairment.

There are various tests known in the art to assess cognitive function in humans, for example and without limitation: the Clinical Global Impression of Change scale (CIBIC-plus scale); Mini-Mental State Examination (MMSE); Neuropsychiatric Inventory (NPI); Clinical Dementia Rating (CDR); Cambridge Automated Neuropsychological Test Battery (CANTAB); Sandoz Clinical Assessment Geriatric Scale (SCAG),

- 11 045018 Buschke test for selective memory (Buschke and Fuld, 1974); verbal subtest of paired associations; logical memory subtest; the Visual Reproduction subtest of the Wechsler Memory Scale-Revised (WMS-R) (Wechsler, 1997); or the Benton visual retention test (see Folstein et al., J Psychiatric Res 12: 189-98, (1975); Robbins et al., Dementia 5: 266-81, (1994); Rey, L'examen clinique en psychologie , (1964); Kluger et al., J Geriatr Psychiatry Neurol 12: 168-79, (1999); Marquis et al., 2002 and Masur et al., 1994). Another example of a cognitive test in humans is the forced-exact choice test from three alternatives. In this test, the subject is presented with color photographs of common objects consisting of a mixture of pairs of three types of paired images: similar pairs, identical pairs, and unrelated opposites. The second of a pair of similar objects is called a decoy. Pairs of these images are completely randomized and presented individually as a series of images. Subjects are instructed to make a decision as to whether the objects seen are new, old, or similar. A similar response when presented with a lure indicates successful retrieval from the subject's memory. In contrast, calling the lure old or new indicates that correct retrieval from memory is not occurring.

In addition to assessing cognitive performance, the progression of age-related cognitive impairment and dementia, as well as the conversion of age-related cognitive impairment to dementia, can be monitored by assessing indirect changes in the patient's brain. Indirect changes include, but are not limited to, changes in brain volume, perforant path degradation, and changes observed in brain function with resting-state fMRI (R-fMRI) and fluorodeoxyglucose positron emission tomography (FDG-PET). Examples of changes in the volume of brain regions, including a decrease in the volume of the hippocampus and a decrease in the volume or thickness of the entorhinal cortex, are useful in monitoring the progression of age-related cognitive impairment and dementia. These volumes can be measured in the patient, for example, using MRI (see Aisen et al., Alzheimer's & Dementia 6:239-246 (2010)). It has been shown that degradation of the perforant tract may be associated with age as well as decline in cognitive function. For example, older adults with greater perforant path degradation tend to perform worse on hippocampus-dependent memory tests. Degradation of the perforator tract can be monitored in the patient using super-resolution diffusion tensor imaging (DTI) (see Yassa et al., PNAS 107: 12687-12691 (2010)). Resting-state fMRI (R-MRI) involves imaging of the brain at rest and recordings of spontaneous fluctuations in the fMRI signal with low frequency (<0.1 Hz) and large amplitude that are temporally correlated across functionally connected regions. Seed-based functional connectivity, independent component analysis, and/or frequency-frequency analysis are used to identify functional connectivity between brain regions, particularly those regions whose connectivity increases or decreases with age, as well as the degree of cognitive impairment and/or dementia. In FDG-PET, FDG uptake is used as a measure of the metabolic activity of a brain region. Decreased FDG uptake in areas such as the posterior lumbar cortex, temporoparietal cortex, and prefrontal association cortex has been shown to be related to the degree of cognitive decline and dementia (see Aisen et al., Alzheimer's & Dementia 6:239-246 (2010), Herholz et al., NeuroImage 17:302-316 (2002)).

Age-related cognitive impairment

The present invention provides methods and compositions for treating age-related cognitive disorder or the risk thereof using an SV2A inhibitor or a pharmaceutically acceptable salt thereof in combination with an AChEI or a pharmaceutically acceptable salt thereof. In some embodiments, treatment includes preventing or slowing the progression of age-related cognitive impairment. In some embodiments, the treatment includes alleviating, reducing the intensity, or slowing the progression of one or more symptoms associated with age-related cognitive impairment. In some embodiments, treating age-related cognitive impairment includes slowing the progression of age-related cognitive impairment (including, without limitation, MCI, ARCD, and AAMI) to dementia (eg, AD). The methods and compositions can be used in human patients in clinical use for the treatment of age-related cognitive impairment in conditions such as MCI, ARCD and AAMI, or at risk of occurrence thereof. As described herein, the dosage of the composition and dosing intervals for the method are those that are safe and effective in these applications.

In some embodiments, a patient to be treated with the methods and compositions of the present invention exhibits or is at risk of developing an age-related cognitive disorder. In some embodiments, age-related cognitive impairment includes, but is not limited to, age-related memory impairment (AAMI), mild cognitive impairment (MCI), and age-related cognitive decline (ARCD).

Animal models serve as an important resource for the development and evaluation of treatments for such age-related cognitive disorders. The characteristics that characterize age-related cognitive impairment in animal models generally extend to cognitive disorders in humans. Thus, efficacy in such animal models is expected to be predictive of efficacy in humans.

Various animal models of age-related cognitive impairment are known in the art. For example, a natural form of cognitive impairment has been identified in extensive behavioral studies in aged outbred Long-Evans rats (Charles River Laboratories; Gallagher et al., Behav. Neurosci. 107:618-626, (1993)). In the Morris water maze (MWM) behavioral test, rats learn and remember the location of an escape platform based on the configuration of spatial cues surrounding the maze. The cognitive basis of action is tested in probe trials using an assessment of the animals' spatial abilities when searching for the location of a rescue platform. Older rats in the study population do not have difficulty swimming to a visible platform, but age-related impairment is found if the platform is camouflaged, requiring the use of spatial information. The actions of individual older outbred Long-Evans rats vary considerably. For example, some rats perform actions on an equal footing with young adult rats. However, approximately 40-50% of rats act outside the range of actions of young adult rats. This variability among a population of aged rats reflects significant individual differences. Thus, within a population of aged rats, some animals have a cognitive impairment and are designated as having age-related disorders (AI), and other animals do not have the disorder and are designated as not having age-related disorders (AU) (see, for example, Colombo et al., Proc. Natl. Acad. Sci. 94:14195-14199, (1997); Gallagher and Burwell, Neurobiol. Aging 10:691-708, (1989); Gallagher and Behav. Neurosci. 107:618-626, (1993) ; Rapp and Gallagher, Proc. Natl. Acad. Sci. 93:9926-9930, (1996); Nicolle et al., Neuroscience 74:741-756, (1996) and Nicolle et al., J. Neurosci. 19: 9604-9610, (1999), international patent publication WO 2007/019312 and international patent publication WO 2004/048551). Such an animal model of age-related cognitive disorder can be used to analyze the effectiveness of the methods and compositions of the present invention in the treatment of age-related cognitive disorder.

The effectiveness of the methods and compositions of the present invention in the treatment of age-related cognitive impairment can be assessed using a variety of cognitive tests, including the Morris water maze and the radial arm maze described above.

Dementia

The present invention also provides methods and compositions for treating dementia using an SV2A inhibitor or a pharmaceutically acceptable salt thereof in combination with AChEI or a pharmaceutically acceptable salt thereof. In some embodiments, treatment includes preventing or slowing the progression of dementia. In some embodiments, treatment includes alleviating, reducing the intensity, or slowing the progression of one or more symptoms associated with dementia. In some embodiments, the symptom being treated is a cognitive disorder. In some embodiments, the dementia is Alzheimer's disease (AD), vascular dementia, dementia with Lewy bodies, or frontotemporal dementia. The methods and compositions can be used in human patients for clinical use in the treatment of dementia. As described herein, the dosage of the composition and dosing intervals for the method are those that are safe and effective in these applications.

Animal models serve as an important resource for the development and evaluation of treatments for dementia. The characteristics that characterize dementia in animal models generally extend to dementia in humans. Thus, efficacy in such animal models is expected to be predictive of efficacy in humans. Various animal models of dementia are known in the art, such as PDAPP, Tg2576, APP23, TgCRND8, J20, hPS2 Tg and APP+PS1 transgenic mice (see Sankaranarayanan, Curr. Top. Medicinal Chem. 6: 609-627, 2006 ; Kobayashi et al., Genes Brain Behav. 4: 173-196, 2005; Ashe and Zahns, Neuron. 66: 631-45, 2010). Such animal models of dementia can be used to analyze the effectiveness of the methods and compositions of the present invention in the treatment of dementia.

The effectiveness of the methods and compositions of the present invention in the treatment of dementia or cognitive impairment associated with dementia can be assessed in animal models of dementia, as well as in a human patient with dementia, using a variety of cognitive tests known in the art, discussed higher.

Post-traumatic stress disorder

The present invention also provides methods and compositions for treating post-traumatic stress disorder (PTSD) using an SV2A inhibitor or a pharmaceutically acceptable salt thereof in combination with an AChEI or a pharmaceutically acceptable salt thereof. In some embodiments, treatment includes preventing or slowing PTSD. In some embodiments, the treatment includes alleviating, reducing the intensity, or slowing the progression of one or more symptoms associated with PTSD. In some embodiments, the symptom being treated is a cognitive disorder. The methods and compositions can be used in human patients for clinical use for the treatment of PTSD. As described herein, the dosage of the composition and dosing intervals for the method are those that are safe and effective in these applications.

Patients with PTSD (and, to a lesser extent, trauma-exposed patients without PTSD) have smaller hippocampal volumes (Woon et al., Prog. Neuro-Psychopharm. & Biological Psych. 34, 1181-1188; Wang et al., Arch. Gen. Psychiatry 67:296-303, 2010). PTSD is also associated with cognitive impairment. Older individuals with PTSD show greater decline in cognitive function relative to controls (Yehuda et al., Bio. Psych. 60: 714–721, 2006) and are more likely to develop dementia (Yaffe et al., Arch. Gen. Psych. 678: 608-613, 2010).

Animal models serve as an important resource for the development and evaluation of treatments for PTSD. The characteristics that characterize PTSD in animal models generally extend to PTSD in humans. Thus, efficacy in such animal models is expected to be predictive of efficacy in humans. Various animal models of PTSD are known in the art.

One rat model of PTSD is time-dependent sensitization (TDS). TDS involves exposing an animal to an extremely stressful situation followed by a situational reminder of the stress experienced. Below is an example of TDS. The rats are placed in a restrainer, then placed in a swimming pool and forced to swim for a certain period of time, for example 20 minutes. Thereafter, each rat is immediately exposed to anesthetic gas until unconscious, and finally dried. Animals are left alone for several days, for example, one week. The rats are then subjected to a relaxation procedure involving exposure to an initial stressor, such as swimming in a swimming pool (Liberzon et al., Psychoneuroendocrinology 22:443-453, 1997; Harvery et al., Psychopharmacology 175:494-502, 2004). TDS results in an enhanced acoustic startle response (ASR) in rats that is comparable to the exaggerated acoustic startle that is a prominent symptom of PTSD (Khan and Liberzon, Psychopharmacology 172: 225-229, 2004). Such animal models of PTSD can be used to analyze the effectiveness of the methods and compositions of the present invention in the treatment of PTSD.

The effectiveness of the methods and compositions of the present invention in the treatment of PTSD or cognitive impairment associated with PTSD can be assessed in animal models of PTSD, as well as in a human patient with PTSD, using a variety of cognitive tests known in the art and described higher.

Schizophrenia

The present invention further provides methods and compositions for treating schizophrenia using an SV2A inhibitor or a pharmaceutically acceptable salt thereof in combination with AChEI or a pharmaceutically acceptable salt thereof. In some embodiments, treatment includes preventing or slowing the progression of schizophrenia. In some embodiments, the treatment includes alleviating, reducing the intensity, or slowing the progression of one or more symptoms associated with schizophrenia. In some embodiments, the symptom being treated is a cognitive disorder. The methods and compositions can be used in human patients for clinical use in the treatment of schizophrenia. As described herein, the dosage of the composition and dosing intervals for the method are those that are safe and effective in these applications.

Cognitive impairment is also associated with schizophrenia. They precede the onset of psychosis and are present in unaffected relatives. Schizophrenia-associated cognitive impairment is a good predictor of functional outcome and is a key feature of the disorder. Cognitive features in schizophrenia reflect dysfunction of frontal cortical regions and the hippocampus. Patients with schizophrenia also exhibit hippocampal pathologies such as decreased hippocampal volume, decreased neuronal size, and dysfunctional hyperactivity. Imbalances between excitation and inhibition in these brain regions have also been reported in patients with schizophrenia, suggesting that drugs targeting inhibitory mechanisms may have therapeutic effects (see, for example, Guidotti et al., Psychopharmacology, 180: 191-205, 2005; Zierhut, Psych. Res. Neuroimag, 183: 187-194, 2010; Wood et al., Neuroimage 52: 62-63, 2010; Vinkers et al., Expert Opin. Investig. Drugs 19: 1217-1233, 2009 ; Young et al., Pharmacol. Ther. 122: 150-202, 2009).

Animal models serve as an important resource for the development and evaluation of treatments for schizophrenia. The characteristics that characterize schizophrenia in animal models generally extend to schizophrenia in humans. Thus, efficacy in such animal models is expected to be predictive of efficacy in humans. Various animal models of schizophrenia are known in the art.

One animal model of schizophrenia involves chronic methionine treatment. Mice treated with methionine showed insufficient expression

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GAD67 in the frontal cortex and hippocampus, similar to that found at autopsy in the brains of patients with schizophrenia. They also exhibit prepulse inhibition of the startle response and deficits in social interaction (Tremonlizzo et al., PNAS, 99: 17095-17100, 2002). Another animal model of schizophrenia is treatment of rats with methyloxyethanol acetate (MAM). Pregnant female rats were administered MAM (20 mg/kg, i.p.) on day 17 of pregnancy. Exposure to MAM recapitulates the pathological development of offspring of the schizophrenia-like phenotype, including anatomical changes, behavioral disturbances, and impaired neural processing. More specifically, MAM-treated rats exhibit a decrease in the density of parvalbumin-positive GABAergic interneurons in the prefrontal cortex and hippocampus. In behavioral tests, MAM-treated rats exhibit reduced latent inhibition. Latent inhibition is a behavioral phenomenon in which there is attenuated learning of a stimulus to which the subject has already been exposed with some effect. This tendency to ignore previously innocuous stimuli and reduce the formation of associations with such stimuli is thought to prevent sensory overload. A low level of latent inhibition is evidence of psychosis. Latent inhibition can be tested in rats as follows. The rats are divided into two groups. One group is exposed to sound for many trials beforehand. The other group is not affected by sound. Then, in both groups, a procedure is carried out for the formation of an acoustic conditioned reflex reaction of fear, in which the same sound is simultaneously accompanied by a painful stimulus, for example, electric shock to the paw. Subsequently, both groups are exposed to a sound signal, and changes in the motor activity of the rats are monitored during the signal. After the formation of a conditioned reflex reaction of fear, rats respond to sound exposure with a strong decrease in motor activity. However, in the group exposed to sound before the formation of the conditioned reflex, obvious latent inhibition is observed: the suppression of motor activity in response to the sound signal decreases. Treated rats, in contrast, show latent inhibition. That is, exposure to sound preceding the procedure for the formation of a conditioned reflex fear reaction does not have a significant effect on the suppression of the formation of conditioned reflexes (see Lodge et al., J. Neurosci., 29:2344-2354, 2009). Such animal models of schizophrenia can be used to analyze the effectiveness of the methods and compositions of the present invention in the treatment of schizophrenia.

The effectiveness of the methods and compositions of the present invention in the treatment of schizophrenia or cognitive impairment associated with schizophrenia can be assessed in animal models of schizophrenia, as well as in a human patient with schizophrenia, using a variety of cognitive tests known in the art and described higher.

Amyotrophic lateral sclerosis (ALS)

The present invention further provides methods and compositions for treating ALS using an SV2A inhibitor or a pharmaceutically acceptable salt thereof in combination with AChEI or a pharmaceutically acceptable salt thereof. In some embodiments, treatment includes preventing or slowing the progression of ALS. In some embodiments, treatment includes alleviating, reducing the intensity, or slowing the progression of one or more symptoms associated with ALS. In some embodiments, the symptom being treated is a cognitive disorder. The methods and compositions can be used in human patients for clinical use for the treatment of ALS. As described herein, the dosage of the composition and dosing intervals for the method are those that are safe and effective for the uses described herein.

In addition to motor neuron degeneration, ALS is characterized by neuronal degeneration in the entorhinal cortex and hippocampus, memory impairment, and neuronal hyperexcitability in various brain regions such as the cortex.

The effectiveness of the methods and compositions of the present invention in the treatment of ALS or cognitive impairment associated with ALS can be assessed in animal models of ALS, as well as in a human patient with ALS, using a variety of cognitive tests known in the art and described higher.

Cancer treatment-related cognitive impairment

The present invention further provides methods and compositions for treating cancer treatment-related cognitive impairment using an SV2A inhibitor or a pharmaceutically acceptable salt thereof in combination with an AChEI or a pharmaceutically acceptable salt thereof. In some embodiments, the treatment includes preventing or slowing the progression of cancer treatment-related cognitive impairment. In some embodiments, the treatment includes alleviating, reducing the intensity, or slowing the progression of one or more symptoms associated with cancer treatment-related cognitive impairment. The methods and compositions can be used in human patients for clinical use to treat cancer treatment-related cognitive impairment. As described herein, the dosage of the composition and dosing intervals for the method are those that are safe

- 15 045018 and are effective in such applications as described herein.

Treatments used to treat cancer, including chemotherapy, radiation, or a combination of both, can cause cognitive impairment in patients with functions such as memory, learning and attention. Cytotoxicity and other harmful side effects of cancer treatment on the brain are the basis for this form of cognitive impairment, which can persist for decades (Dietrich et al., Oncologist 13: 1285-95, 2008; Soussain et al., Lancet 374: 1639- 51, 2009).

Cognitive impairment after cancer treatment reflects dysfunction in the frontal cortical regions and hippocampus, which are essential for normal cognition. In animal models, exposure to either chemotherapy or radiation has a negative effect on performance on tests of cognition that are particularly dependent on these brain systems, especially the hippocampus (Kim et al., J. Radiat. Res. 49:517-526, 2008; Yang et al., Neurobiol. Learning and Mem. 93:487–494, 2010). Therefore, drugs that target the cortical and hippocampal systems may act as neuroprotectors in patients being treated for cancer and may be effective in treating symptoms of cognitive impairment that may persist after procedures used to treat cancer.

Animal models serve as an important resource for the development and evaluation of treatments for cancer treatment-related cognitive impairment. The features that characterize cancer treatment-related cognitive impairment in animal models generally extend to cancer treatment-related cognitive impairment in humans. Thus, efficacy in such animal models is expected to be predictive of efficacy in humans. Various animal models of cancer treatment-related cognitive impairment are known in the art.

Examples of animal models of cancer treatment-related cognitive impairment include treatment of animals with antineoplastic agents, such as cyclophosphamide (CYP), or radiation, such as ⁶⁰ Co gamma rays (Kim et al., J. Radiat. Res. 49:517-526 , 2008; Yang et al., Neurobiol. Learning and Mem. 93:487-494, 2010). Cognitive performance in animal models of cancer treatment-related cognitive impairment can be tested in cognitive tests to analyze the effectiveness of the methods and compositions of the present invention in treating cancer treatment-related cognitive impairment. The effectiveness of the methods and compositions of the present invention in the treatment of cancer treatment-related cognitive impairment can be assessed in animal models of cancer treatment-related cognitive impairment, as well as in human patients with cancer treatment-related cognitive impairment, using a variety of cognitive tests known in the art. this field of technology and described above.

SV2A inhibitor

Synaptic vesicular protein 2 (SV2) is a family of synaptic vesicular proteins that consists of three members designated SV2A, SV2B, and SV2C. SV2A is the most widespread member of the family, expressed throughout the brain. The proteins are integral membrane proteins and have low levels of homology (20-30%) with twelve families of transmembrane bacterial and fungal transporter proteins that transport sugar, citrate and xenobiotics (Bajjalien et al., Science 257:1271-1273 (1992) ). SV2 family proteins are found in the brain and endocrine cells, as well as in all synaptic and endocrine vesicles. SV2 proteins have been reported to be involved in the normal functioning of synapses, and act during the maturation step of primary vesicles, in which the vesicles are converted to a Ca ²⁺ - and synaptotagmin-sensitive state ( Sudhof et al., 2009 ). Functionally, SV2 proteins have been reported to enhance synaptic currents and increase the probability of transmitter release by maintaining the size of an easily releasable pool of vesicles ( Custer et al., 2006 ).

The term SV2A inhibitor refers to any agent, substance or compound that binds to SV2A and reduces synaptic function by reducing presynaptic vesicle release (see, for example, Noyer et al. 1995; Fuks et al. 2003; Lynch et al. 2004; Gillard et al. 2006; Custer et al., 2006; Smedt et al., 2007; Yang et al. 2007; and Example 8 of WO 2001/62726, which are specifically incorporated herein by reference). A substance or compound or agent is an inhibitor of SV2A even if it does not itself bind to SV2A, provided that it causes or affects the ability of another compound or agent to bind SV2A or reduce synaptic function by reducing presynaptic vesicle release. As used herein, the term SV2A inhibitor includes pharmaceutically acceptable salts of these inhibitors. They also include hydrates, polymorphs, prodrugs, salts and solvates of these inhibitors.

Among the SV2A inhibitors or pharmaceutically acceptable salts, hydrates, solvates and polymorphs thereof that are useful in the methods and compositions of the present invention are those disclosed, for example, in US patent application 12/580464, international patent application PCT/US 2009/ 005647, US Patent Application 61/105847, US Patent Application 16 045018 61/152631, and US Patent Application 61/175536. However, any SV2A inhibitor or pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof may be used in the methods and compositions of the present invention. In some embodiments, the SV2A inhibitor is selected from the group of SV2A inhibitors or pharmaceutically acceptable salts, hydrates, solvates, or polymorphs thereof referred to in international patent applications WO 2010/144712, WO 2010/002869, WO 2008/132139, WO2007/065595 , WO 2006/128693, WO 2006/128692, WO 2005/054188, WO 2004/087658, WO 2002/094787, WO 2001/062726; US patents Nos. 7465549, 7244747, 5334720, 4696943, 4696942; Published US Patent Applications Nos. 20090312333, 20090018148, 20080081832, 2006258704; and UK Patent Nos. 1039113 and 1309692. Other SV2A inhibitors may also be used in the present invention. Applicants also refer to processes for preparing said compounds found in the documents cited above. Other synthesis methods may also be used. These methods are well known to one skilled in the art.

In some embodiments of the present invention, the SV2A inhibitor is selected from the group consisting of levetiracetam, brivaracetam and seletracetam or derivatives or analogs thereof, or pharmaceutically acceptable salts, solvates, hydrates, polymorphs or prodrugs.

In some embodiments, the SV2A inhibitor is levetiracetam or salts, solvates, hydrates, polymorphs, or prodrugs thereof. Levetiracetam refers to the International Union of Pure and Applied Chemistry (IUPAC)-named compound (2S)-2-(2-oxopyrrolidin-1-yl)butanamide.

Levetiracetam is a widely used antiepileptic drug. Levetiracetam binds to a specific site in the CNS, synaptic vesicular protein 2A (SV2A) (see, for example, Noyer et al. 1995; Fuks et al. 2003; Lynch et al. 2004; Gillard et al. 2006), and, as In addition, it has been shown to directly inhibit synaptic activity and neurotransmission by inhibiting the presynaptic release of neurotransmitters (Yang et al., 2007).

SV2A inhibitors used in the methods and compositions of the present invention include the following compounds:

i) International patent application WO 2001/062726: Compound characterized by formula I, or a pharmaceutically acceptable salt thereof _R 3a _R 4a _R 3 I--L _R 4

where X represents -CA1NR5R ⁶ or -CA1OR ⁷ or -CA1-R ⁸ or CN;

A ¹ and A ² independently represent oxygen, sulfur or -NR ⁹ ;

R ¹ is hydrogen, alkyl, aryl or -CH ₂ -R ^1a , where R ^1a is aryl, heterocycle, halogen, hydroxy, amino, nitro or cyano;

R ² , R ³ and R ⁴ are the same or different and each is independently hydrogen, halogen, hydroxy, thiol, amino, nitro, nitrooxy, cyano, azido, carboxy, amido, sulfonic acid, sulfonamide, alkyl, alkenyl, alkynyl , ester, ester, aryl, heterocycle or hydroxy derivative, thio derivative, amino derivative, acyl derivative, sulfonyl derivative or sulfinyl derivative;

R ^2a , R ^3a and R ^4a are the same or different and each independently represents hydrogen, halogen, alkyl, alkenyl, alkynyl or aryl;

R ⁵ , R ⁶ , R ⁷ and R ⁹ are the same or different and each independently represents hydrogen, hydroxy, alkyl, aryl, heterocycle or oxy derivative; And

R ⁸ represents hydrogen, hydroxy, thiol, halogen, alkyl, aryl, heterocycle or thio derivative;

with the proviso that at least one of R ² , R ³ , R ⁴ , R ^2a , R ^3a and R ^4a is other than hydrogen; and that if the compound is a mixture of all possible isomers, X is -CONR ⁵ R ⁶ , A ² is oxygen and R ¹ is hydrogen, methyl, ethyl or propyl, then the substitution on the pyrrolidine ring is other than mono-, di- or trimethyl or monoethyl; and that if R ¹ , R ² , R ⁴ , R ^2a , R ^3a and R ^4a are each hydrogen, A ² is oxygen and X is CONR ⁵ R ⁶ , then R ³ is different from carboxy, ester, amido, substituted oxopyrrolidine, hydroxy, hydroxy derivative, amino, amino derivatives, methyl, naphthyl, phenyl, optionally substituted with oxy derivatives or in the para position with a halogen atom.

As defined below, unless otherwise stated, R ¹¹ and R ¹² are the same or different and each independently represents amido, alkyl, alkenyl, alkynyl, acyl,

- 17 045018 ester, ester, aryl, aralkyl, heterocycle or hydroxy derivative, thio derivative, acyl derivative, amino derivative, sulfonyl derivative or sulfinyl derivative, each of which is optionally substituted with any suitable group, including without limitation one or more moieties selected from lower alkyl or other groups , described below, as alkyl substituents.

As used herein, the term oxy derivative is defined to include -OR ¹¹ groups, wherein R ¹¹ is as defined above, excluding oxy derivative. Non-limiting examples are alkoxy, alkenyloxy, alkynyloxy, acyloxy, oxyester, oxyamido, alkylsulfonyloxy, alkylsulfinyloxy, arylsulfonyloxy, arylsulfinyloxy, aryloxy, aralkoxy or heterocyclooxy such as pentyloxy, allyloxy, methoxy, ethoxy, phenoxy, benzyloxy, 2-naphthyloxy, 2 -pyridyloxy, methylenedioxy, carbonate.

As used herein, the term thio derivative is defined to include -SR ¹¹ groups, wherein R ¹¹ is as defined above, excluding thio derivative.

Non-limiting examples include alkylthio, alkenylthio, alkynylthio and arylthio.

As used herein, the term amino derivative is defined to include the groups -NHR ¹¹ or -NR ¹¹ R ¹² , wherein R ¹¹ and R ¹² are defined above. Non-limiting examples are mono- or dialkyl-, alkenyl-, alkynyl- and arylamino or mixed amino.

As used herein, the term acyl derivative is a radical derived from a carboxylic acid and is thus defined to include groups of the formula R ¹¹ CO-, wherein R ¹¹ is as defined above, and may also represent hydrogen. Non-limiting examples are formyl, acetyl, propionyl, isobutyryl, valeryl, lauroyl, heptanedioyl, cyclohexanecarbonyl, crotonoyl, fumaroyl, acryloyl, benzoyl, naphthoyl, furoyl, nicotinoyl, 4carboxybutanoyl, oxalyl, ethoxalyl, cysteinyl, oxamoyl.

As used herein, the term sulfonyl derivative is defined to include a group of formula -SO2-R ¹¹ , wherein R ¹¹ is as defined above, excluding sulfonyl derivative. Non-limiting examples are alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl and arylsulfonyl.

As used herein, the term sulfinyl derivative is defined to include a group of formula -SO-R ¹¹ , wherein R ¹¹ is as defined above, excluding sulfinyl derivative. Non-limiting examples are alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl and arylsulfinyl.

As used herein, the term alkyl is defined to include saturated, monovalent hydrocarbon radicals containing branched, straight-chain or cyclic moieties, or combinations thereof, and containing 1-20 carbon atoms, preferably 1-6 carbon atoms for non-cyclic alkyl and 3-6 carbon atoms for cycloalkyl (in these two preferred cases, unless otherwise specified, lower alkyl). The alkyl moieties may optionally be substituted with 1-5 substituents independently selected from the group consisting of halogen, hydroxy, thiol, amino, nitro, cyano, thiocyanato, acyl, acyloxy, sulfonyl derivative, sulfinyl derivative, alkylamino, carboxy, ester, ester, amido , azido, cycloalkyl, sulfonic acid, sulfonamide, thio derivative, oxyester, oxyamido, heterocycle, vinyl, C ₁ . ₅ αlkoxy, C ₆ . ₁₀ aryloxy and C ₆ . ₁₀ aryla.

Preferred alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, iso- or tert-butyl and 2,2,2-trimethylethyl, each of which is optionally substituted with at least one substituent selected from the group consisting of halogen , hydroxy, thiol, amino, nitro and cyano, such as trifluoromethyl, trichloromethyl, 2,2,2-trichloroethyl, 1,1-dimethyl-2,2-dibromoethyl, 1,1dimethyl-2,2,2-trichloroethyl.

As used herein, the term alkenyl is defined to include both branched and unbranched unsaturated hydrocarbon radicals containing at least one double bond, such as ethenyl (=vinyl), 1-methyl-1-ethenyl, 2,2-dimethyl -1-ethenyl, 1-propenyl, 2-propenyl (=allyl), 1-butenyl, 2-butenyl, 3-butenyl, 4-pentenyl, 1methyl-4-pentenyl, 3-methyl-1-pentenyl, 1-hexenyl , 2-hexenyl, etc., and optionally substituted with at least one substituent selected from the group consisting of halogen, hydroxy, thiol, amino, nitro, cyano, aryl and heterocycle, such as mono- and dihalogenyl, where halogen is fluorine, chlorine or bromine.

As used herein, the term alkynyl is defined to include a monovalent branched or straight-chain hydrocarbon radical containing at least one carbon-carbon triple bond, e.g., ethynyl, 2-propynyl (=propargyl), etc., and optionally substituted, at least one substituent selected from the group consisting of halogen, hydroxy, thiol, amino, nitro, cyano, aryl and a heterocycle such as haloethynyl.

When present as bridging groups, alkyl, alkenyl and alkynyl are straight or branched _C1-12 , preferably C1.4, -alkylene, or _C2 . ₁₂ , preferably C _2-4 , -alkenylene or -alkynylene fragments, respectively.

- 18 045018

Groups in which branched derivatives are traditionally identified by prefixes such as n, sec, iso, etc. (e.g. n-propyl, sec-butyl) are in the n-form unless otherwise noted.

As used herein, the term aryl is defined to include an organic radical obtained by the removal of one hydrogen atom from an aromatic hydrocarbon consisting of 1-3 rings and containing 6-30 carbon atoms, such as phenyl and naphthyl, each of which is optionally substituted with 1 - 5 substituents independently selected from halogen, hydroxy, thiol, amino, nitro, cyano, acyl, acyloxy, sulfonyl, sulfinyl, alkylamino, carboxy, ester, ester, amido, azido, sulfonic acid, sulfonamide, alkylsulfonyl, alkylsulfinyl, alkylthio, oxyester, oxyamido, aryl, C ₁ . ₆ αlkoxy, C ₆ . ₁₀ aryloxy, C ₁ . ₆ alkyl, C ₁ . ₆ haloalkyl. Aryl radicals are preferably monocyclic, containing 6-10 carbon atoms.

Preferred aryl groups are phenyl and naphthyl, each of which is optionally substituted with 1-5 substituents independently selected from halogen, nitro, amino, azido, C ₁ . ₆ αlkoxy, C ₁ . ₆ alkylthio, C ₁ . ₆ αlkyl, C ₁ . ₆ haloalkyl and phenyl.

As used herein, the term halogen includes Cl, Br, F, I.

As used herein, the term hydroxy represents a group of the formula -OH.

As used herein, the term thiol is a group of the formula -SH.

As used herein, the term cyano represents a group of the formula -CN.

As used herein, the term nitro represents a group of the formula -NO2.

As used herein, the term nitrooxy represents a group of the formula -ONO2.

As used herein, the term amino represents a group of the formula -NH2.

As used herein, the term azido is a group of the formula -N ₃ .

As used herein, the term carboxy represents a group of the formula -COOH.

As used herein, the term sulfonic acid represents a group of the formula -SO3H.

As used herein, the term sulfonamide is a group of the formula -SO2NH2.

As used herein, the term ester is defined to include a group of the formula -COO-R ¹¹ , wherein R ¹¹ is as defined above, excluding an hydroxy derivative, a thio derivative, or an amino derivative.

As used herein, the term ester is defined to include a group selected from C ₁ . ₅₀ straight or branched alkyl, or C ₂ . ₅₀ straight or branched alkenyl or alkynyl groups or combinations thereof, interrupted by one or more oxygen atoms.

As used herein, the term amido is defined to include a group of the formula -CONH2 or -CONHR ¹¹ or -CONR11R ¹² , wherein R ¹¹ and R ¹² are as defined above.

As used herein, the term heterocycle is defined to include an aromatic or non-aromatic cyclic alkyl, alkenyl or alkynyl moiety as defined above, containing at least one O, S and/or N atom interrupted by a carbocyclic ring structure, and optionally one of carbon of the carbocyclic ring structure can be replaced by carbonyl. Non-limiting examples of aromatic heterocyclic compounds include pyridyl, furyl, pyrrolyl, thienyl, isothiazolyl, imidazolyl, benzimidazolyl, tetrazolyl, quinazolinyl, quinolisinyl, naphthyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolyl, isobenzofuranyl, benzothienyl, pyrazolyl, dolyl, indolizinil, purinyl , isoindolyl, carbazolyl, thiazolyl, 1,2,4-thiadiazolyl, thieno(2,3-b)furanyl, furopyranyl, benzofuranyl, benzoxepinyl, isooxazolyl, oxazolyl, tianthrenyl, benzothiazolyl or benzoxazolyl, cinnolinyl, phthalazinyl, quinoxalinyl, phenanthridinyl, acridinyl , pyrimidinyl, phenanthrolinyl, phenothiazinyl, furazanyl, isochromanyl, indolinyl, xanthenyl, hypoxanthinyl, pteridinyl, 5azacytidinyl, 5-azauracilyl, triazolopyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl and pyrazolopyrimidinyl, optionally substituted with alkyl, or as described above for alkyl groups. Non-limiting examples of non-aromatic heterocyclic compounds include tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperidyl, piperazinyl, imidazolinyl, morpholino, morpholinyl, 1-oxaspiro-(4.5)dec-2-yl, pyrrolidinyl, 2-oxopyrrolidinyl, sugar moieties (namely glucose, pentose , hexoses, riboses, fructoses, which may also be substituted), or the same, which may be optionally substituted with any suitable group, including without limitation one or more moieties selected from lower alkyl or other groups as described above for alkyl groups . The term heterocycle also includes bicyclic, tricyclic and tetracyclic spiro groups in which any of the above heterocyclic rings is fused to one or two rings independently selected from an aryl ring, a cyclohexane ring,

- 19 045018 cyclohexene ring, cyclopentane ring, cyclopentene ring or other monocyclic heterocyclic ring, or in which the monocyclic heterocyclic group is bridged by an alkylene group, such as quinuclidinyl, 7-azabicyclo(2.2.1)heptanyl, 7-oxabicyclo(2.2.1) heptanyl, 8-azabicyclo(3.2.1)octanyl.

Based on the above definitions, it is clear that if a substituent such as R ² , R ⁴ , R ^2a , R ^3a , R ^4a , R ⁵ , R ⁶ , R ⁷ , R ⁸ is attached to the remainder of the molecule via a heteroatom or carbonyl, then between heteroatom or carbonyl and the point of attachment to the remainder of the molecule, a straight or branched C _1-12 , preferably a C _1-4 alkylene, or a C _2-12 , preferably a C _2-4 alkenylene or alkynylene bridge may optionally be inserted.

Preferred examples of X are -COOR ⁷ or -CONR5R ⁶ where R ⁵ , R ⁶ and R ⁷ are preferably hydrogen, C ₁ . ₄ alkyl, phenyl or alkylphenyl.

Preferably X is carboxy or CONR ⁵ R ⁶ where R ⁵ and R ⁶ are preferably hydrogen, C ₁ . ₄ αlkyl, phenyl or alkylphenyl, in particular -CONH2.

Preferably, A ¹ and A ² are each oxygen.

Preferably R ¹ represents hydrogen, alkyl, in particular C ₁ . ₁₂ alkyl, in particular lower alkyl or aryl, in particular phenyl.

Examples of preferred R ¹ groups are methyl, ethyl, propyl, isopropyl, butyl, iso- or tert-butyl, 2,2,2-trimethylethyl, each optionally attached via a methylene bridge, or the same, substituted by at least at least one halogen atom, such as trifluoromethyl, trichloromethyl, 2,2,2-trichloroethyl, 1,1-dimethyl-2,2-dibromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl.

Particularly preferred is R ¹ in the form of ethyl.

Preferably, R ² and R ^2a are independently hydrogen, halogen or alkyl, in particular lower alkyl.

Examples of preferred R ² and R ^2a groups are independently hydrogen, halogen or methyl, ethyl, propyl, isopropyl, butyl, iso- or tert-butyl, 2,2,2-trimethylethyl or the same, substituted by at least one halogen atom, such as trifluoromethyl, trichloromethyl, 2,2,2-trichloroethyl, 1,1-dimethyl-2,2-dibromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl.

It is particularly preferred if at least one and most preferably both of R ² and R ^2a are hydrogen.

Preferably R ^3a , R ⁴ and R ^4a are independently hydrogen, alkyl, in particular methyl or ethyl or aryl, in particular phenyl or aralkyl, in particular benzyl.

Examples of preferred R ^3a , R ⁴ and R ^4a groups are independently hydrogen, halogen or methyl, ethyl, propyl, isopropyl, butyl, iso- or tert-butyl, 2,2,2-trimethylethyl or the same, substituted at at least one halogen atom, such as trifluoromethyl, trichloromethyl, 2,2,2-trichloroethyl, 1,1-dimethyl-2,2-dibromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl.

It is particularly preferred if at least one, and most preferably both, of R ⁴ and R ^4a are hydrogen.

In particular, R ^3a is hydrogen or alkyl, in particular lower alkyl, and most preferably hydrogen.

Preferably R ³ is hydrogen, C ₁ . ₁₂ αlkyl, in particular C ₁ . ₆ alkyl, each of which is optionally substituted by one or more substituents selected from hydroxy, halogen, cyano, thiocyanato or alkoxy, and attached to the ring either directly or via a thio, sulfinyl, sulfonyl, carbonyl or oxycarbonyl group, and optionally, C ₁ . ₄ alkylene bridge, in particular methylene; _C2 . ₆ alkenyl or -alkynyl, in particular C ₂ . ₃ alkenyl or -alkynyl, each of which is optionally substituted with one or more halogen atoms; azido; cyano; amido; carboxy; triazolyl, tetrazolyl, pyrrolidinyl, pyridyl, 1-oxidopyridyl, thiomorpholinyl, benzodioxolyl, furyl, oxazolyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl or piperazinyl, each of which is optionally substituted with one or more substituents selected from halogen, C ₁ . ₆ alkyl and phenyl, and attached to the ring either directly or via a carbonyl group or C ₁ . ₄ alkylene bridge, in particular methylene; naphthyl; or phenyl, phenylalkyl or phenylalkenyl, each of which is optionally substituted with one or more substituents selected from halogen, C ₁ . ₆ alkyl, C ₁ . ₆ haloalkyl, C ₁ . ₆ αlkox, C ₁ . ₆ alkylthio, amino, azido, phenyl and nitro, and each of which is attached to the ring either directly or through an oxy, sulfonyl, sulfonyloxy, carbonyl or carbonyloxy group and, in addition, optionally C ₁ . ₄ alkylene bridge, in particular methylene.

Also preferably, R ³ is C ₁ . ₆ alkyl, optionally substituted with one or more substituents selected from halogen, thiocyanato, azido, alkoxy, alkylthio, phenylsulfonyl; nitrooxy; _C2 . ₃ alkenyl or -alkynyl, each of which is optionally substituted with one or more halogen atoms or acetyl; tetrazolyl, pyridyl, furyl, pyrrolyl, thiazolyl or thienyl; or phenyl or phenylalkyl, each of which is optionally substituted with one or more substituents selected from halogen, C ₁ . ₆ alkyl, C ₁ . ₆ haloalkyl, C ₁ . ₆ alkoxy, amino, azido, phenyl and nitro, and each of which is attached to the ring either directly or via a sulfonyloxy and, in addition, optionally a C-alkylene bridge, in particular methylene.

Other examples of preferred R ³ groups are hydrogen, halogen or methyl, ethyl, propyl, isopropyl, butyl, iso- or tert-butyl, 2,2,2-trimethylethyl or the same substituted with at least one halogen atom, such as trifluoromethyl, trichloromethyl, 2,2,2-trichloroethyl, 1,1-dimethyl-2,2-dibromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl.

In particular, R ³ represents C _1-4 alkyl, optionally substituted with one or more substituents selected from halogen, thiocyanato or azido; C ₂ - ₅ alkenyl or -alkynyl, each of which is optionally substituted with one or more halogen atoms; thienyl; or phenyl, optionally substituted with one or more substituents selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl or azido.

Additional examples of preferred R ³ groups are C _{1 -b} alkyl and C _{2 -b} haloalkenyl.

Preferably, R ⁵ and R 6 are independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, iso- or tert-butyl, 2,2,2-trimethylethyl, in particular hydrogen or methyl.

In particular, at least one and most preferably both of R ⁵ and R 6 are hydrogen.

Preferably R ⁷ is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, iso- or tert-butyl, 2,2,2-trimethylethyl, methoxy, ethoxy, phenyl, benzyl or the same substituted with at least one atom halogen, for example trifluoromethyl, chlorophenyl.

Preferably R ⁷ is hydrogen, methyl or ethyl, in particular hydrogen.

Preferably R ⁸ is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, iso- or tert-butyl, 2,2,2-trimethylethyl, phenyl, benzyl or those substituted with at least one halogen atom, for example , trifluoromethyl, chlorobenzyl.

Preferably R ⁸ is hydrogen or methyl.

Combinations of one or more of these preferred groups of compounds are particularly preferred.

A specific group of compounds of formula I (compounds 1A) includes compounds in which

A ² represents oxygen;

X is -CONR5R6, or -COOR ⁷ , or -CO-R ⁸ , or CN;

R ¹ represents hydrogen or alkyl, aryl, halogen, hydroxy, amino, nitro, cyano;

R ² , R ³ , R ⁴ are the same or different and each independently represents hydrogen or halogen, hydroxy, amino, nitro, cyano, acyl, acyloxy, sulfonyl derivative, sulfinyl derivative, amino derivative, carboxy, ester, ester, amido, sulfonic acid, sulfonamide, alkoxycarbonyl, thio derivative, alkyl, alkoxy, hydroxy ester, oxyamido, aryl, oxy derivative, heterocycle, vinyl, and R ³ may further be C2-5alkenyl, C2-5alkynyl, or azido, each of which is optionally substituted by one or more halogen, cyano, thiocyano, azido, cyclopropyl, acyl and/or phenyl atoms; or phenylsulfonyloxy, wherein any phenyl moiety may be substituted with one or more halogen atoms, alkyls, haloalkyls, alkoxy, nitro, amino and/or phenyls; most preferably methyl, ethyl, propyl, isopropyl, butyl or isobutyl.

R ^2a , R ^3a and R ^4a represent hydrogen;

R ⁵ , R 6 , R ⁷ are the same or different and each independently represents hydrogen, hydroxy, alkyl, aryl, heterocycle or oxy derivative; And

R ⁸ represents hydrogen, hydroxy, thiol, halogen, alkyl, aryl, heterocycle, alkylthio or thio derivative.

In these compounds, IA R ¹ is preferably methyl, ethyl, propyl, isopropyl, butyl, or isobutyl; most preferably methyl, ethyl or n-propyl.

R ² and R ⁴ are preferably independently hydrogen or halogen or methyl, ethyl, propyl, isopropyl, butyl, isobutyl; and most preferably each is hydrogen.

R ³ is preferably C ₁ - ₅ alkyl, C ₂ - ₅ alkenyl, C ₂ -C ₅ -alkynyl, cyclopropyl, azido, each of which is optionally substituted with one or more halogen atoms, cyano, thiocyano, azido, alkylthio, cyclopropyl, acyl and/or phenyl; phenyl; phenylsulfonyl; phenylsulfonyloxy, tetrazole, thiazole, thienyl, furyl, pyrrole, pyridine, wherein any phenyl moiety may be substituted by one or more halogen, alkyl, haloalkyl, alkoxy, nitro, amino and/or phenyl atoms; most preferably methyl, ethyl, propyl, isopropyl, butyl or isobutyl.

X is preferably -COOH, or -COOMe, or -COOEt, or -CONH2; most preferably -CONH2.

An additional specific group of compounds of formula I (compounds IB) includes compounds in which

X is -CA ¹ NH ₂ , -CA1NHCH3 or -CA1N(CH ₃ ) ₂ ;

R ¹ represents alkyl or phenyl;

- 21 045018

R ³ represents alkyl, alkenyl, alkynyl, cyano, isothiocyanato, ether, carboxyl, amido, aryl, heterocycle; or

R ³ is CH2R ¹⁰ where R ¹⁰ is hydrogen, cycloalkyl, hydroxy ester, oxyalkylsulfonyl, oxyarylsulfonyl, aminoalkylsulfonyl, aminoarylsulfonyl, nitrooxy, cyano, isothiocyanato, azido, alkylthio, arylthio, alkylsulfinyl, alkylsulfonyl, heterocycle, aryloxy, alkoxy or trifluoroethyl ;

R ^3a is hydrogen, alkyl or aryl (particularly with the proviso that if R ^3a is hydrogen, then R ³ is other than methyl);

or R ³ R ^3a forms cycloalkyl and each of R2, R2 ^a , R ⁴ and R ^4a represents hydrogen.

In compounds of formula I

R ¹ is preferably alkyl, in particular C1-12, more particularly C1-6, alkyl and most preferably ethyl;

R ² , R ^2a , R ^3a and R ^4a are preferably hydrogen;

R ³ is preferably selected from hydrogen; C ₁ . ₁₂ αlkyl, in particular C ₁ . ₆ αlkyl, each of which is optionally substituted by one or more substituents selected from hydroxy, halogen, cyano, thiocyanato or alkoxy, and attached to the ring either directly or through a thio, sulfinyl, sulfonyl, carbonyl or oxycarbonyl group and optionally an additional C ₁ . ₄ α-alkylene bridge, in particular methylene; _C2 . ₆ alkenyl or -alkynyl, in particular C ₂ . ₃ α-alkenyl or -alkynyl, each of which is optionally substituted with one or more halogen atoms; azido; cyano; amido; carboxy; triazolyl, tetrazolyl, pyrrolidinyl, pyridyl, 1-oxidopyridyl, thiomorpholinyl, benzodioxolyl, furyl, oxazolyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl or piperazinyl, each of which is optionally substituted with one or more substituents selected from halogen, C ₁ . ₆ alkyl and phenyl, and attached to the ring either directly or via a carbonyl group or C ₁ . ₄ alkylene bridge, in particular methylene; naphthyl; or phenyl, phenylalkyl or phenylalkenyl, each of which is optionally substituted with one or more substituents selected from halogen, C ₁ . ₆ αlkylα,

C ₁ . ₆ haloalkyl, C ₁ . ₆ αlkoxy, C ₁ . ₆ alkylthio, amino, azido, phenyl and nitro, and each is attached to the ring either directly or via an oxy, sulfonyl, sulfonyloxy, carbonyl or carbonyloxy group and optionally an additional C ₁ . ₄ α-alkylene bridge, in particular methylene;

R ^3a is preferably hydrogen or C ₁ . ₄ αlkyl;

R ⁴ and R ^4a are preferably independently hydrogen, C ₁ . ₄ alkyl, phenyl or benzyl.

An additional group of compounds of formula I (compounds 1C) contain them in racemic form, where if X is -CONR5R ⁶ and R ¹ is hydrogen, methyl, ethyl or propyl, then the substitution on the pyrrolidine ring is other than mono-, di- or trimethyl or monoethyl.

An additional group of compounds of formula I (compounds 1D) contains them in racemic form, where X is -CONR5R ⁶ and R ¹ is hydrogen or C ₁ . ₆ alkyl, C2 ₆ alkenyl or -alkynyl or cycloalkyl, each of which is unsubstituted, then substitution on the ring is different from substitution with alkyl, alkenyl or alkynyl, each of which is unsubstituted.

An additional specific group of compounds of formula I (compounds 1E) includes compounds in which

X represents -CA1NH2;

R ¹ represents H;

R ³ represents azidomethyl, iodomethyl, ethyl, optionally substituted with 1-5 halogen atoms, n-propyl, optionally substituted with 1-5 halogen atoms, vinyl, optionally substituted with one or two methyls and/or 1-3 halogen atoms, acetylene, optional substituted C ₁ . ₄ alkyl, phenyl or halogen;

R ^3a is hydrogen or halogen, preferably fluorine, and R ² , R ^2a , R ⁴ and R ^4a are each hydrogen;

in the form of their racemates or in enantiomerically enriched form, preferably in the form of pure enantiomers.

An additional specific group of compounds of formula I (compounds 1F) includes compounds in which

X represents -CA1NH2;

R ¹ represents H;

R ³ represents C ₁ . ₆ alkyl, C ₂ . ₆ αlkenyl or C ₂ . ₆ alkynyl, optionally substituted with azido, oxynitro, 1-6 halogen atoms;

R ^3a is hydrogen or halogen, preferably fluorine;

and each of R ² , R ^2a , R ⁴ and R ^4a represents hydrogen;

in the form of their racemates or in enantiomerically enriched form, preferably in the form of pure enantiomers.

In all of the above embodiments, if the hydrogen atom to which R ¹ is attached is asymmetric, then it is preferably in the S configuration.

In some embodiments, the compounds useful in the methods and compositions of the present invention are selected from the group consisting of (2S)-2-[4-(bromomethyl)-2-oxo-1-pyrrolidinyl]butanamide;

(2S)-2-[(4R)-4-(iodomethyl)-2-oxopyrrolidinyl]butanamide;

(2S)-2-(2-oxo-4-phenyl-1-pyrrolidinyl)butanamide;

(2S)-2-[4-(iodomethyl)-2-oxo-1-pyrrolidinyl]butanamide;

(2S)-2-[4-(chloromethyl)-2-oxo-1-pyrrolidinyl]butanamide;

{1-[(13)-1-(aminocarbonyl)propyl]-5-oxo-Zpyrrolidinyl}methyl-4-methylbenzenesulfonate;

(2S)-2-[(4R)-4-(azidomethyl)-2-oxopyrrolidinyl]butanamide;

2-[4-(2,2-dibromovinyl)-2-oxo-1-pyrrolidinyl]butanamide;

{1-[(IS)-1-(aminocarbonyl)propyl]-5-oxo-3pyrrolidinyl}methyl nitrate;

(2S)-2-[2-OXO-4-(1H-tetrazol-1-ylmethyl)-1pyrrolidinyl]butanamide;

2-(2-oxo-4-vinyl-1-pyrrolidinyl)butanamide;

2-{2-oxo-4-[(phenylsulfonyl)methyl]-1pyrrolidinyl]butanamide;

(23)-2-((4R)-4-(2,2-dibromovinyl)-2oxopyrrolidinyl]butanamide;

(23)—2—[(43)-4-(2,2-dibromovinyl)-2oxopyrrolidinyl]butanamide;

(2S)-2-[4-(isothiocyanatomethyl)-2-oxo-1pyrrolidinyl]butanamide;

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2-[2-oxo-4-(1,3-thiazol-2-yl)-1-pyrrolidinyl]butanamide;

(2S)-2-[2-OXO-4-(2-thienyl)-1-pyrrolidinyl]butanamide;

(2S)-2-[4-(2-methoxyphenyl)-2-oxo-1pyrrolidinyl]butanamide;

(2S)-2-[4-(3-methoxyphenyl)-2-oxo-1pyrrolidinyl]butanamide;

(2S)-2-[4-(4-azidophenyl)-2-oxo-1-pyrrolidinyl]butanamide (2S)-2-[2-OXO-4-(3-thienyl)-1-pyrrolidinyl]butanamide;

(2S)-2-[4-(3-azidophenyl)-2-oxo-1-pyrrolidinyl]butanamide (2S)-2-[2-OXO-4-(3-thienyl)-1-pyrrolidinyl]butanamide;

(2S)-2-[(4S)-2-oxo-4-vinylpyrrolidinyl]butanamide;

(2S)-2-[(4R)-2-oxo-4-vinylpyrrolidinyl]butanamide;

2-[4-(2-bromophenyl)-2-oxo-1-pyrrolidinyl]butanamide;

2-[2-OXO-4-(3-pyridinyl)-1-pyrrolidinyl]butanamide;

(2S)-2-(4-[1,1'-biphenyl]-4-yl-2-oxo-1pyrrolidinyl)butanamide;

(2S)-2-{4-[(methylsulfanyl)methyl]-2-oxo-1pyrrolidinyl}butanamide;

2-[4-(iodomethyl)-2-oxo-1-pyrrolidinyl]butanamide;

(2S)-2-[(4R)-4-(iodomethyl)-2-oxo-1pyrrolidinyl]pentanamide;

(2S)-2-[(4R)-4-(iodomethyl)-2-oxopyrrolidinyl]propanamide;

2-(2-oxo-4-propyl-1-pyrrolidinyl)propanamide;

2-(2-oxo-4-propyl-1-pyrrolidinyl)butanamide;

2-(2-oxo-4-pentyl-1-pyrrolidinyl)butanamide;

(2S)-2-[(4R)-4-(iodomethyl)-2-oxopyrrolidinyl]-Nmethylbutanamide;

(2S)-2-(4-neopentyl-2-oxo-1-pyrrolidinyl)butanamide;

(2S)-2-(4-ethyl-2-oxo-1-pyrrolidinyl)butanamide;

2-[4-(2,2-difluorovinyl)-2-oxo-1-pyrrolidinyl]butanamide;

2-[4-(2,2-difluoroethyl)-2-oxo-1-pyrrolidinyl]butanamide;

(2S)-2-[(4S)-2-oxo-4-propylpyrrolidinyl]butanamide;

(2S)-2-[(4R)-2-oxo-4-propylpyrrolidinyl]butanamide;

2-{4-[(Z)-2-fluoroethenyl]-2-oxo-1-pyrrolidinyl}butanamide;

2-[4-(2-methyl-1-propenyl)-2-oxo-1pyrrolidinyl]butanamide;

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2-(4-butyl-2-oxo-1-pyrrolidinyl)butanamide;

2-[4-(cyclopropylmethyl)-2-oxo-1-pyrrolidinyl]butanamide 2-(4-isobutyl-2-oxo-1-pyrrolidinyl)butanamide;

2-[4-(4-chlorophenyl)-2-oxo-1-pyrrolidinyl]butanamide;

2-[4-(3-chlorophenyl)-2-oxo-1-pyrrolidinyl]butanamide;

2-{2-oxo-4-[2-(trifluoromethyl)phenyl]-1pyrrolidinyl}butanamide;

2-[4-(2-fluorophenyl)-2-oxo-1-pyrrolidinyl]butanamide;

2-[4-(3-methylphenyl)-2-oxo-1-pyrrolidinyl]butanamide;

(2S)-2-[2-OXO-4-(2-phenylethyl)-1-pyrrolidinyl]butanamide (2S)-2-[4-(3-bromophenyl)-2-oxo-1-pyrrolidinyl]butanamide 2- {4-[3,5-bis(trifluoromethyl)phenyl]-2-oxo-1pyrrolidinyl}butanamide;

2-[4-(3,4-dichlorophenyl)-2-oxo-1-pyrrolidinyl]butanamide;

2-[4-(2,4-dichlorophenyl)-2-oxo-1-pyrrolidinyl]butanamide;

2-[4-(2-furyl)-2-oxo-1-pyrrolidinyl]butanamide;

(23)-2-[2-oxo-4-(3-phenylpropyl)-1pyrrolidinyl]butanamide;

(23)-2-[4-(3,5-dibromophenyl)-2-oxo-1pyrrolidinyl]butanamide;

2-[4-(3,4-dichlorophenyl)-2-oxo-1-pyrrolidinyl]butanamide;

2-(2-oxo-4-propyl-1-pyrrolidinyl)butanamide;

2-[4-(3-chlorophenyl)-2-oxo-1-pyrrolidinyl]butanamide;

2-(4-ethynyl-2-oxo-1-pyrrolidinyl)butanamide;

2-[4-(2-fluorophenyl)-2-oxo-1-pyrrolidinyl]butanamide;

(23)-2-[4-(cyclopropylmethyl)-2-oxo-1pyrrolidinyl}butanamide;

(23)-2-[(4S)-4-(2,2-difluorovinyl)-2oxopyrrolidinyl]butanamide;

(23)-2-[2-oxo-4-(3,3,3-trifluoropropyl)-1pyrrolidinyl]butanamide;

2-[4-(3-methylphenyl)-2-oxo-1-pyrrolidinyl]butanamide;

(23)-2-[4-(cyclopropylmethyl)-2-oxo-1pyrrolidinyl]butanamide;

(23)-2-[(4R)-4-(2,2-difluorovinyl)-2oxopyrrolidinyl]butanamide;

- 25 045018 (2S)-2-[2-OKCO-4-(1H-pyrrol-1-yl)-1pyrrolidinyl]butanamide;

(2S)-2-(4-allyl-2-oxo-1-pyrrolidinyl)butanamide;

(2S)-2-[4-(2-iodopropyl)-2-oxo-1-pyrrolidinyl}butanamide;

(2S)-2-(4-allyl-2-oxo-1-pyrrolidinyl)butanamide;

(2S)-2-[2-oxo-4-(2-oxopropyl)-1-pyrrolidinyl]butanamide;

(2S)-2-[4-(2-bromo-1H-pyrrol-1-yl)-2-oxo-1pyrrolidinyl]butanamide;

(2S)-2-(4-methyl-2-oxo-4-propyl-1-pyrrolidinyl)butanamide;

(2R)-2-[4-2-dichlorovinyl)-2-oxo-1pyrrolidinyl]butanamide;

2-[4-(bromoethynyl)-2-oxo-1-pyrrolidinyl]butanamide;

2-[(4S)-4-(2,2-difluoropropyl)-2oxopyrrolidinyl]butanamide;

(2S)-2-[4-(bromoethynyl)-2-oxo-1-pyrrolidinyl]butanamide;

2-(2-oxo-4-propyl-1-pyrrolidinyl)pentanamide;

3-cyclopropyl-2-(2-oxo-4-propyl-1pyrrolidinyl)propanamide;

2-(2-oxo-4-propyl-1-pyrrolidinyl)-3-(1,3-thiazol-4yl)propanamide;

2-(2-oxo-4-propyl-1-pyrrolidinyl)-4-pentenamide;

(2S)-2-[(4R)-2-oxo-4-vinylpyrrolidinyl]butanamide;

including all isomeric forms and mixtures thereof, or a pharmaceutically acceptable salt thereof.

In some embodiments, the compounds useful in the methods and compositions of the present invention are selected from the group consisting of:

(2S)-2-[(4S)-4-(2,2-difluorovinyl)-2oxopyrrolidinyl]butanamide;

(2S)-2-[(4S)-2-oxo-4-propylpyrrolidinyl]butanamide;

(2S)-2-[(4R)-2-oxo-4-propylpyrrolidinyl]butanamide.

ii) International patent application WO 2002/094787:

Formula compounds

where n is 0 or 1, whereby R ¹ is not present if n=0, and R ¹ is present if n=1;

A ¹ represents an oxygen or sulfur atom;

X is -CONR ⁷ R ⁸ , -COOR ⁹ , -CO-R ¹⁰ or CN;

R ¹ (if present), R ² , R ³ , R ⁴ and R ⁵ are the same or different and each independently represents hydrogen, halogen, hydroxy, thiol, amino, nitro, nitrooxy, cyano, azido, carboxy, amido, sulfonic acid, sulfonamide, alkyl, alkenyl, alkynyl, ester, ester, aryl, heterocycle or hydroxy derivative, thio derivative, amino derivative, acyl derivative, sulfonyl derivative or sulfinyl derivative, provided that at least one of the substituents R selected from R ¹ (if present) ), R ² , R ³ , R ⁴ or R ⁵ , is not hydrogen;

R ⁶ is hydrogen, alkyl, aryl or -CH ₂ -R ^6a , where R ^6a is aryl, heterocycle, halogen, hydroxy, amino, nitro or cyano;

R ⁷ , R ⁸ and R ⁹ are the same or different and each independently represents hydrogen, hydroxy, alkyl, aryl, heterocycle or oxy derivative; And

R ¹⁰ represents hydrogen, hydroxy, thiol, halogen, alkyl, aryl, heterocycle or thio derivative;

their pharmaceutically acceptable salts, geometric isomers (including cis and trans, Z and E isomers), enantiomers, diastereoisomers and mixtures thereof (including all possible mixtures of stereoisomers).

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In the above formula, at least one substituent from R1 to ^R5 is other than hydrogen. Certain unsubstituted compounds are mentioned in US Pat. Nos. 5,468,733 and 5,516,759. US Pat. No. 5,468,733 relates to acyclic substituted 2-oxo-1-pyrrolidinyl and 2-oxo-1-piperidinyl derivatives as inhibitors of the Ras oncogene protein. In particular, these compounds block the ability of Ras to convert normal cells into cancer cells, and therefore can be included in various chemotherapeutic compositions for the treatment of cancer.

US Patent No. 5,516,759 relates to acyclic substituted 2-oxo-1-pyrrolidinyl, 2oxo-1-piperidinyl and azepanyl derivatives located at the N-terminus of dodecan peptides having LHRH (luteinizing hormone releasing factor) antagonistic activity. Such LHRH antagonists are useful in the treatment of various conditions in which suppression of sex steroid hormones plays a key role, including contraception, delayed puberty, treatment of benign prostatic hyperplasia, etc.

In the definitions set forth below, unless otherwise indicated, R ¹¹ and R ¹² are the same or different and each independently represents an amido, alkyl, alkenyl, alkynyl, acyl, ester, ester, aryl, aralkyl, heterocycle or oxy derivative, thio derivative , an acyl derivative, an amino derivative, a sulfonyl derivative, or a sulfinyl derivative, each of which is optionally substituted with any suitable group, including without limitation one or more moieties selected from lower alkyl or other groups as described below as alkyl substituents.

As used herein, the term oxy-derivative is defined to include the -OR ¹¹ group, wherein the meaning of R ¹¹ is as defined above, excluding oxy-derivative. Non-limiting examples include alkoxy, alkenyloxy, alkynyloxy, acyloxy, oxyester, oxyamido, alkylsulfonyloxy, alkylsulfinyloxy, arylsulfonyloxy, arylsulfinyloxy, aryloxy, aralkoxy or heterocyclooxy such as pentyloxy, allyloxy, methoxy, ethoxy, phenoxy, benzyloxy, 2-naphthyloxy, 2-pyridyloxy, methylenedioxy, carbonate.

As used herein, the term thio derivative is defined to include the -SR ¹¹ group, wherein R ¹¹ is as defined above, excluding thio derivative.

Non-limiting examples include alkylthio, alkenylthio, alkynylthio and arylthio.

As used herein, the term amino derivative is defined to include -NHR ¹¹ or -NR ¹¹ R ¹² groups, wherein R ¹¹ and R ¹² are defined above. Non-limiting examples are mono- or dialkyl-, alkenyl-, alkynyl- and arylamino or mixed amino.

As used herein, the term acyl derivative is a radical derived from a carboxylic acid and is therefore defined to include groups of the formula R ¹¹ -CO-, wherein R ¹¹ is as defined above and R ¹¹ may also be hydrogen. Preferred are acyl derivatives of the formula -COR ¹¹ , where R ¹¹ is selected from hydrogen, C _1-12 alkyl, C _2-12 alkenyl, C _2-12 alkenyl, heterocycle and aryl. Non-limiting examples are formyl, acetyl, propionyl, isobutyryl, valeryl, lauroyl, heptanedioyl, cyclohexanecarbonyl, crotonoyl, fumaroyl, acryloyl, benzoyl, naphthoyl, furoyl, nicotinoyl, 4-carboxybutanoyl, oxalyl, ethoxalyl, cysteinyl, oxamoyl.

As used herein, the term sulfonyl derivative is defined to include a group of formula -SO2-R ¹¹ , wherein R ¹¹ is as defined above, excluding sulfonyl derivative. Non-limiting examples are alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl and arylsulfonyl.

As used herein, the term sulfinyl derivative is defined to include a group of formula -SO-R ¹¹ , wherein R ¹¹ is as defined above, excluding sulfinyl derivative. Non-limiting examples are alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl and arylsulfinyl.

As used herein, the term alkyl is defined to include saturated, monovalent hydrocarbon radicals containing branched, straight-chain or cyclic moieties, or combinations thereof, and typically containing 1-20 carbon atoms, most commonly 112 carbon atoms, preferably 1-7 carbon atoms , for non-cyclic alkyl and 3-7 carbon atoms for cycloalkyl (unless otherwise specified, then lower alkyl in these two preferred cases), each of which is optionally substituted with preferably 1-5 substituents independently selected from the group consisting of halogen, hydroxy, thiol, amino, nitro, cyano, thiocyanato, acyl, acyloxy, sulfonyl derivative, sulfinyl derivative, alkylamino, carboxy, ester, ester, amido, azido, cycloalkyl, sulfonic acid, sulfonamide, thio derivative, alkylthio, oxyester, oxyamido, heterocycle, vinyl , alkoxy (preferably _C1-5 ) _, aryloxy (preferably _C6.io ) and aryl (preferably _C6-10 ).

Preferred are alkyl groups containing 1-7 carbon atoms, each of which is optionally substituted with one or more substituents selected from hydroxy, halogen, cyano, thiocyanato, alkoxy, azido, alkylthio, cyclopropyl, acyl and phenyl. Most preferred are _C1.4αalkyl and _C3 . ₇ cycloalkyl, each of which is optionally substituted with one or more hydroxy, halogen, lower alkyl and/or azido.

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The most preferred alkyl groups are hydroxymethyl, propyl, butyl,

2,2,2-trifluoroethyl, 2-bromo-2,2-difluoroethyl, 2-chloro-2,2-difluoroethyl, 3,3,3-trifluoropropyl, cyclopropylmethyl, iodomethyl, azidomethyl, 2,2-difluoropropyl, 2- iodine-2,2-difluoroethyl.

Unless otherwise specified, the term lower alkyl as used herein refers to a saturated straight-chain, branched or cyclic C ₁ -C ₇ hydrocarbon.

Non-limiting examples include methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, cyclopropyl, cyclopentyl, isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl, 3methylpentyl, 2,2-dimethylbutyl, each of which is optionally substituted with any suitable group, including without limitation, one or more moieties selected from the groups described above for alkyl groups. Preferably the lower alkyl is methyl.

As used herein, the term alkenyl is defined to include both branched and unbranched, unsaturated hydrocarbon radicals containing at least one double bond, and optionally substituted with at least one substituent selected from the group consisting of halogen, hydroxy, thiol, amino , thiocyanato, azido, alkylthio, cycloalkyl, acyl, nitro, cyano, aryl and heterocycle.

Preferred alkenyl groups are C ₂ -Cl ₂ alkenyls, in particular C ₂ . ₆ alkenyls such as ethenyl (=vinyl), 1-methyl-1-ethenyl, 2,2-dimethyl-1-ethenyl, 1-propenyl, 2-propenyl (=allyl), 1-butenyl, 2-butenyl, 3 -butenyl, 4-pentenyl, 1-methyl-4-pentenyl, 3-methyl-1-pentenyl, 1hexenyl, 2-hexenyl, etc., optionally substituted with one or more substituents selected from halogen, cyano, thiocyanato, azido , alkylthio, cycloalkyl, phenyl and acyl. Most preferred is vinyl, optionally substituted with one or more halogen and/or lower alkyl atoms, and in particular 2,2-difluorovinyl, 2,2-dibromovinyl and 2,2-dichlorovinyl.

As used herein, the term alkynyl is defined to include a monovalent, branched or straight-chain hydrocarbon radical containing at least one carbon-carbon triple bond, e.g., ethynyl, 2-propynyl (=propargyl), etc., and optionally substituted at least one substituent selected from the group consisting of halogen, hydroxy, thiol, amino, nitro, cyano, aryl, heterocycle, thiocyanato, azido, alkylthio, alkyl and acyl.

Preferred alkynyl groups are C ₂ . ₁₂ alkynyl, in particular C ₂ . ₆ alkynyl, optionally substituted with one or more substituents selected from halogen, cyano, thiocyanato, azido, alkylthio, acyl, aryl, such as phenyl and alkyl, preferably cycloalkyl.

Most preferred are ethynyl, propynyl and butynyl, optionally substituted with lower alkyl and/or halogen, and in particular 1-propynyl, cyclopropylethynyl, 3-methyl-1-butynyl and 3,3,3-trifluoro-1-propynyl.

When present as bridging groups, alkyl, alkenyl and alkynyl are straight or branched _C1-12 , preferably C1-4, alkylene, or _C2-12 , preferably C2-4, _alkenylene , or alkynylene moieties, respectively.

Unless otherwise noted, groups in which branched derivatives are traditionally identified by prefixes such as n, sec, iso, etc. (for example, n-propyl, sec-butyl), are in the form.

As used herein, the term aryl is defined to include an organic radical obtained by the removal of one hydrogen atom from an aromatic hydrocarbon consisting of at least one ring, most commonly 1-3 rings, and typically containing 6-30 carbon atoms, such as phenyl and naphthyl, each of which is optionally substituted with one or more substituents independently selected from halogen, hydroxy, thiol, amino, nitro, cyano, acyl, acyloxy, sulfonyl, sulfinyl, alkylamino, carboxy, ester, ester, amido, azido, sulfonic acid, sulfonamide, alkylsulfonyl, alkylsulfinyl, C ₁ . ₆ alkylthio, oxyester, oxyamido, aryl, C ₁ . ₆ alkoxy, C ₆ . ₁₀ aryloxy, C ₁ . ₆ alkyl, C ₁ . ₆ haloalkyl. Aryl radicals are preferably monocyclic or bicyclic containing 6-10 carbon atoms. Preferred aryl groups are phenyl and naphthyl, each of which is optionally substituted with one or more substituents independently selected from halogen, nitro, amino, azido, C ₁ . ₆ alkoxy, C ₁ . ₆ alkyl, C ₁ . ₆ haloalkyl, sulfonyl and phenyl.

A preferred aryl is phenyl, optionally substituted with one or more halogens, lower alkyls, azidos or nitros, such as 3-chlorophenyl and 3-azidophenyl.

As used herein, the term halogen includes Cl, Br, F, I.

As used herein, the term hydroxy represents a group of the formula -OH.

As used herein, the term thiol is a group of the formula -SH.

As used herein, the term cyano represents a group of the formula -CN.

As used herein, the term nitro represents a group of the formula -NO2.

As used herein, the term nitrooxy represents a group of the formula -ONO2.

As used herein, the term amino represents a group of the formula -NH2.

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As used herein, the term azido is a group of formula -N3.

As used herein, the term carboxy represents a group of the formula

- COOH.

As used herein, the term sulfonic acid is a group of the formula -SO ₃ H.

As used herein, the term sulfonamide is a group of the formula -SO2NH2.

As used herein, the term ester is defined to include a group of the formula -COO-R ¹¹ , wherein R ¹¹ is as defined above, excluding an hydroxy derivative, a thio derivative, or an amino derivative. Preferred are esters of the formula -COOR ¹¹ where R ¹¹ is selected from C _1-12 alkyl, C ₂ . ₁₂ alkenyl, C ₂ . ₁₂ alkynyl and aryl. Most preferred are esters where R ¹¹ represents lower alkyl, in particular methyl.

As used herein, the term ether is defined to include a group selected from C _1-50 straight or branched alkyl, or C _2-50 straight or branched alkenyl or alkynyl groups, or combinations thereof, interrupted by one or more oxygen atoms.

As used herein, the term amido is defined to include a group of formula -CONH2 or -CONHR ¹¹ or -CONR ¹¹ R ¹² , wherein R ¹¹ and R ¹² are as defined above.

As used herein, the term heterocycle is defined to include an aromatic or non-aromatic cyclic alkyl, alkenyl or alkynyl moiety as defined above, containing at least one O, S and/or N atom interrupted by a carbocyclic ring structure, and optionally one of carbon of the carbocyclic ring structure may be substituted with carbonyl, and optionally substituted with any suitable group, including without limitation one or more moieties selected from lower alkyl or other groups as described above for alkyl groups. Non-limiting examples of heterocyclic compounds include pyridyl, furyl, pyrrolyl, thienyl, isothiazolyl, triazolyl, imidazolyl, benzimidazolyl, tetrazolyl, quinazolinyl, quinolisinyl, naphthyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolyl, isobenzofuranyl, benzothienyl, pyrazole yl, indolyl, indolizinyl, purinyl, isoindolyl, carbazolyl, thiazolyl, 1,2,4-thiadiazolyl, thiomorpholinyl, thieno(2,3-b)furanyl, furopyranyl, benzofuranyl, benzoxepinyl, isooxazolyl, oxazolyl, tianthrenyl, benzothiazolyl or benzoxazolyl, cinnolinyl, phthalazinyl, quinoxalinyl, 1-oxidopyridyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenothiazinyl, furazanil, benzodioxolyl, isochromanil, indolinyl, xanthenyl, hypoxanthinyl, pteridinyl, 5-azacytidinyl, 5-azauracilyl, triazolopyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperidyl, piperazinyl, imidazolidinyl, morpholino, morpholinyl, 1-oxaspiro(4.5)dec-2-yl, pyrrolidinyl, 2-oxo-pyrrolidinyl, sugar fragments (namely glucose, pentose, hexose, ribose, fructose, which can also be substituted ), optionally substituted with alkyl, or as described above for alkyl groups. As used herein, the term heterocycle also includes bicyclic, tricyclic, and tetracyclic spiro groups in which any of the above heterocyclic rings are fused to one or two rings independently selected from an aryl ring, a cyclohexane ring, a cyclohexene ring, a cyclopentane ring, a cyclopentene ring, or another monocyclic heterocyclic ring. rings, or where the monocyclic heterocyclic group is bridged via an alkylene group, such as quinuclidinyl, 7-azabicyclo(2.2.1)heptanyl, 7-oxabicyclo(2.2.1)heptanyl, 8-azabicyclo(3.2.1)octanyl.

The heterocyclic compound is preferably selected from triazolyl, tetrazolyl, pyrrolidinyl, pyridyl, 1-oxidopyridyl, thiomorpholinyl, benzodioxolyl, furyl, oxazolyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl and piperazinyl, each of which is optionally substituted with one or more substituents selected from halogen , alkyl, substituted alkyl, alkoxy, nitro, amino, acyl and phenyl.

More preferably, the heterocycle is selected from tetrazolyl, pyrrolidinyl, pyridyl, furyl, pyrrolyl, thiazolyl and thienyl, each of which is optionally substituted with one or more substituents selected from halogen, alkyl, halogenated alkyl, acyl, alkoxy, nitro, amino and phenyl, and in in particular from 2- and 3-thienyl, optionally substituted with one or more halogen atoms, acyls such as formyl, cyano and/or lower alkyls such as methyl.

Based on the above definitions, it should be understood that if a substituent such as R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ is attached to the remainder of the molecule through a heteroatom or carbonyl, then between heteroatom or carbonyl and the point of attachment to the remainder of the molecule, a straight or branched C _1-12 , preferably C _1-4 -alkylene, or C2-12, preferably C _2-4 -alkenylene or -alkynylene bridge may optionally be inserted.

As used herein, the term substituent R independently refers to R ¹ , R ² , R ³ , R ⁴ or R ⁵ .

- 29 045018

According to a preferred embodiment, the compound of formula I is a compound as defined above, in which n is 0. The compound is a 6-ring structure (2-thioxo- or 2-oxopiperidinyl derivative) in which R ¹ is absent because n=0, and the compound is represented by formula (IA).

According to a further embodiment, the compound of formula I is a compound as defined above, in which n is 1. The compound is a 7-ring structure (2-thioxo- or 2-oxoazepanyl derivative) in which R ¹ is present because n=1 , and it is represented by formula (IB).

According to a more preferred embodiment, said compound is a compound as defined above, wherein n=0, R ³ and/or R ⁴ are other than hydrogen, and R ² and R ⁵ are hydrogen.

According to another more preferred embodiment, said compound is a compound as defined above, wherein n=1, ^R2 , ^R3 and/or ^R4 are other than hydrogen, and wherein ^R1 and ^R5 are hydrogen.

According to yet another more preferred embodiment, said compound is a compound as defined above, in which only one substituent R selected from R ³ or R ⁴ in which n=0, or from R ² , R ³ or R ⁴ in wherein n=1 is other than hydrogen, and the remaining substituent(s) R is hydrogen. Thus, the present description relates to monosubstituted 2-thioxo- or 2-oxopiperidinyl or 2-thioxo- or 2-oxoazepanyl derivatives.

According to another preferred embodiment, the compounds of formula I are a compound as defined above, in which A ¹ represents an oxygen atom. Thus, the present description relates to 2-oxopiperidinyl or 2-oxoazepanyl derivatives.

According to another preferred embodiment, the compounds of formula I are a compound as defined above, wherein X is CONR7R ⁸ , in particular CONH2. Thus, the present description relates to the amido derivatives of 2-oxo(or thioxo)piperidinyl or 2-oxo(or thioxo)azepanyl.

According to another preferred embodiment, the compounds of formula I are a compound as defined above, wherein R ⁶ is hydrogen, C1. 4alkyl or CH2-R ^6a group, where R ^6a represents a heterocycle. Most preferably, R ⁶ is C1-4 alkyl, in particular ethyl. If R ⁶ represents ethyl, then the present invention relates to 2-(2-oxo(or thioxo)-1-piperidinyl)butanamide or 2-(2-oxo(or thioxo)-1azepanyl)butanamide derivatives.

According to another preferred embodiment, the compounds of formula I are a compound as defined above in which the carbon atom to which R ⁶ is attached is in the S configuration. When R ⁶ represents ethyl, A represents oxygen, and X represents CONR7R ⁸ , the present invention relates to (2S)-2-(2-okco-1piperidinyl)butanamide or (2S)-2-(2 -oxo-1-azepanyl)butanamide derivative.

According to a preferred embodiment, the compound is as defined above, wherein R ² (if n=1), R ³ and R ⁴ are the same or different and each independently represents hydrogen, halogen, nitro, nitrooxy, cyano, carboxy, amido, sulfonic acid, sulfonamide, alkyl, alkenyl, alkynyl, ester, ether, aryl, heterocycle, acyl derivative, sulfonyl derivative or sulfinyl derivative; R ¹ (if present), R ² (if n=0) and R ⁵ are hydrogen; R ⁶ is hydrogen, alkyl, aryl or -CH ₂ -R ^6a , where R ^6a is aryl, heterocycle, halogen, hydroxy, amino, nitro or cyano;

According to this preferred embodiment, the compound is typically a compound wherein if ^R6 is benzyl, X is COOCH3, and n=1, then ^R2 is other than methyl, if both ^R3 and ^R4 are is hydrogen, and R ⁴ is different from

- 30 045018 methyl if both R ² and R ³ are hydrogen.

According to another preferred embodiment, the compound is as defined above, wherein R ² (if n=1), R ³ and R ⁴ are the same or different and each independently represents hydrogen; cyano; carboxy; amido;

C ₁ . ₁₂ alkyl, each of which is optionally substituted with one or more substituents selected from hydroxy, halogen, cyano, thiocyanato, alkoxy, azido, alkylthio, cycloalkyl, acyl, aryl and heterocycle;

_C2 . ₁₂ αlkenyl, each of which is optionally substituted with one or more substituents selected from halogen, cyano, thiocyanato, azido, alkylthio, alkyl, aryl and acyl;

_C2 . ₁₂ alkynyl, each of which is optionally substituted with one or more substituents selected from halogen, cyano, thiocyanato, azido, alkylthio, alkyl, aryl and acyl;

an acyl derivative of the formula -CO-R ¹¹ , where R ¹¹ is selected from C ₁ . ₁₂ alkyl, C ₂ . ₁₂ alkenyl, C ₂ . ₁₂ alkynyl, heterocycle and aryl;

ester of the formula -CO-OR ¹¹ , where R ¹¹ is selected from C ₁ . ₁₂ alkyl, C ₂ . ₁₂ alkenyl, C ₂ . ₁₂ alkynyl and aryl;

a heterocycle selected from triazolyl, tetrazolyl, pyrrolidinyl, pyridyl, 1-oxidopyridyl, thiomorpholinyl, benzodioxolyl, furyl, oxazolyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl and piperazinyl, each of which is optionally substituted with one or more substituents selected from halogen, alkyl, substituted alkyl, alkoxy, nitro, amino, acyl and phenyl;

aryl, each of which is optionally substituted with one or more substituents selected from _C1.6alkyl , _{C1.6haloalkyl} , _C1.6alkoxy , _C1 . ₆ αlkylthio, amino, azido, sulfonyl, aryl and nitro.

According to another preferred embodiment, the compound is as defined above, wherein R ² (if n=1), R ³ and R ⁴ are the same or different and each independently represents hydrogen;

C ₁ . ₇ alkyl, each of which is optionally substituted with one or more substituents selected from hydroxy, halogen, cyano, thiocyanato, alkoxy, azido, alkylthio, cyclopropyl, acyl and phenyl;

C ₂ .6alkenyl, each of which is optionally substituted with one or more substituents selected from halogen, cyano, thiocyanato, azido, alkylthio, cycloalkyl, phenyl and acyl;

_C2 . ₆ alkynyl, each of which is optionally substituted with one or more substituents selected from halogen, cyano, thiocyanato, azido, alkylthio, cycloalkyl, phenyl and acyl;

a heterocycle selected from tetrazolyl, pyrrolidinyl, pyridyl, furyl, pyrrolyl, thiazolyl and thienyl, each of which is optionally substituted with one or more substituents selected from halogen, alkyl, halogenated alkyl, acyl, alkoxy, nitro, amino and phenyl;

phenyl, which is optionally substituted with one or more substituents selected from C ₁ . ₆ αalkyl, halogenated alkyl, halogen, alkoxy, amino, azido, sulfonyl, phenyl and nitro.

According to another preferred embodiment, the compound is a compound as defined above, in which at least one of the substituents R is selected from the group R ² , R ³ and R ⁴ (if n=1), or from the group R ³ and R ⁴ (if n=0) independently represents C ₁ . ₄ alkyl or C ₃ . ₇ cycloalkyl, optionally substituted with one or more halogen, hydroxy, lower alkyl and/or azido.

According to another preferred embodiment, the compound is a compound as defined above, in which at least one of the substituents R is selected from the group R ² , R ³ and R ⁴ (if n=1), or from the group R ³ and R ⁴ (if n=0), independently represents vinyl, optionally substituted with one or more halogen atoms and/or lower alkyls.

According to another preferred embodiment, the compound is a compound as defined above, in which at least one of the substituents R is selected from the group R ² , R ³ and R ⁴ (if n=1), or from the group R ³ and R ⁴ (if n=0) is independently ethynyl, propynyl or butynyl, optionally substituted with one or more halogen atoms and/or lower alkyls.

According to another preferred embodiment, the compound is a compound as defined above, in which at least one of the substituents R is selected from the group R ² , R ³ and R ⁴ (if n=1), or from the group R ³ and R ⁴ (if n=0), independently represents phenyl, optionally substituted with one or more halogen atoms, lower alkyls, azidos and/or nitros.

According to another preferred embodiment, the compound is a compound as defined above, in which at least one of the substituents R is selected from the group R ² , R ³ and R ⁴ (if n=1), or from the group R ³ and R ⁴ (if n=0), independently represents 2- or 3-thienyl, optionally substituted with one or more halogen atoms, acyls,

- 31 045018 cyano and/or lower alkyls.

According to a particular preferred embodiment, the compound is a compound as defined above, in which at least one of the substituents R is selected from the group R ² , R ³ and R ⁴ (if n=1), or from the group R ³ and R ⁴ (if n=0), is hydroxymethyl, propyl, butyl, 3,3,3-trifluoropropyl, 2,2,2-trifluoroethyl, cyclopropylmethyl, iodomethyl, azidomethyl, 2-thienyl, 3-thienyl, phenyl, 3-chlorophenyl, 3-azidophenyl, 2,2-difluorovinyl, 2,2-dibromovinyl, 2,2-dichlorovinyl, 2-ethynyl, 5-methyl-2-thienyl, 5-formyl-2-ethynyl, 5-cyano- 2-thienyl, 3-bromo-2-thienyl, 4methyl-2-thienyl, 3,3,3-trifluoro-1-propynyl, 1-propynyl, cyclopropylethynyl, 3-methyl-1-butynyl, 1-butynyl, 2,2- difluoropropyl, 2-chloro-2,2-difluoroethyl, 2-bromo-2,2-difluoroethyl and 2-iodo-2,2-difluoroethyl.

According to another preferred embodiment, the compound is a compound as defined above, wherein R ¹ , R ² , R ⁴ and R ⁵ are hydrogen.

According to another preferred embodiment, the compound is a compound as defined above in which R ¹ , R ² , R ³ and R ⁵ are hydrogen.

According to another preferred embodiment, the compound is a compound as defined above, wherein n=1 and R ¹ , R ³ , R ⁴ and R ⁵ are hydrogen.

In all of the above embodiments, if the carbon atom to which R ⁶ is attached is asymmetric, then it is preferably in the S configuration.

Representative compounds useful in the above-defined methods and compositions of the present invention are selected from the group consisting of

2-[5-(hydroxymethyl)-2-oxo-1-piperidinyl]butanamide,

2-(2-oxo-5-propyl-1-piperidinyl)butanamide,

2-[2-OXO-5-(3,3,3-trifluoropropyl)-1piperidinyl]butanamide,

2-[5-(cyclopropylmethyl)-2-oxo-1-piperidinyl]butanamide,

- 32 045018

2-[5-(iodomethyl)-2-oxo-1-piperidinyl]butanamide,

2-[5-(azidomethyl)-2-oxo-1-piperidinyl]butanamide,

2-(2-oxo-5-phenyl-1-piperidinyl)butanamide,

2-[2-OXO-5-(2-thienyl)-1-piperidinyl]butanamide, 2-OXO-5-(3-thienyl)-1-piperidinyl]butanamide,

2-[5-(3-chlorophenyl)-2-oxo-1-piperidinyl]butanamide,

2-[5-(3-azidophenyl)-2-oxo-1-piperidinyl]butanamide,

2-[5-(2,2-difluorovinyl)-2-oxo-1-piperidinyl]butanamide, 2-[5-(2,2-dibromovinyl)-2-oxo-1-piperidinyl]butanamide, 2-[5 -(2,2-dichlorovinyl)-2-oxo-1-piperidinyl]butanamide,

2-5-e tinyl-2-oxo-1-piperidinyl)butane anamide,

2[5-(5-methyl-2-thienyl)-2-oxo-1-piperidinyl]butanamide, 2-5-(5-formyl-2-thienyl)-2-oxo-1-piperidinyl]butanamide, 2- 5-(5-cyano-2-thienyl)-2-oxo-1-piperidinyl]butanamide, 2-5-(3-bromo-2-thienyl)-2-oxo-1-piperidinyl]butanamide, 2-5- (4-methyl-2-thienyl)-2-oxo-1-piperidinyl]butanamide, 2-OXO-5-(3,3,3-trifluoro-1-propynyl)-1piperidinyl]butanamide,

2-OXO-5-(1-propynyl)-1-piperidinyl]butanamide,

2-5-(cyclopropylethynyl)-2-oxo-1-piperidinyl]butanamide, 2-5-(3-methyl-1-butynyl)-2-oxo-1-piperidinyl]butanamide, 2-5-(1-butynyl )-2-oxo-1-piperidinyl]butanamide,

2-[5-(2,2-difluoropropyl)-2-oxo-1-piperidinyl]butanamide, 2-[5-(2-chloro-2,2-difluoroethyl)-2-oxo-1-piperidinyl]butanamide,

2-[5-(2-bromo-2,2-difluoroethyl)-2-oxo-1piperidinyl]butanamide,

2-[4-(hydroxymethyl)-2-oxo-1-piperidinyl]butanamide,

2-(2-oxo-4-propyl-1-piperidinyl)butanamide,

2-[2-OXO-4-(3,3,3-trifluoropropyl)-1piperidinyl]butanamide,

2-[4-(cyclopropylmethyl)-2-oxo-1-piperidinyl]butanamide, 2-[4-(iodomethyl)-2-oxo-1-piperidinyl]butanamide,

2-[4-(azidomethyl)-2-oxo-1-piperidinyl]butanamide,

2-(2-oxo-4-phenyl-1-piperidinyl)butanamide,

2-[2-OXO-4-(2-thienyl)-1-piperidinyl]butanamide,

- 33 045018

2-[2-OKCO-4-(3-thienyl)-1-piperidinyl]butanamide,

2-[4-(3-chlorophenyl)-2-oxo-1-piperidinyl]butanamide,

2-[4-(3-azidophenyl)-2-oxo-1-piperidinyl]butanamide,

2-[4-(2,2-difluorovinyl)-2-oxo-1-piperidinyl]butanamide, 2-[4-(2,2-dibromovinyl)-2-oxo-1-piperidinyl]butanamide, 2-[4 - (2,2-dichlorovinyl)-2-oxo-1-piperidinyl]butanamide, 2-(4-ethynyl-2-oxo-1-piperidinyl)butanamide,

2-[4-(5-methyl-2-thienyl)-2-oxo-1-piperidinyl]butanamide, 2-[4-(5-formyl-2-thienyl)-2-oxo-1-piperidinyl]butanamide 2 -[4-(5-cyano-2-thienyl)-2-oxo-1-piperidinyl]butanamide, 2-[4-(3-bromo-2-thienyl)-2-oxo-1-piperidinyl]butanamide, 2 -[4-(4-methyl-2-thienyl)-2-oxo-1-piperidinyl]butanamide, 2-[2-OXO-4-(3,3,3-trifluoro-1-propynyl)-1piperidinyl]butanamide ,

2-[2-OXO-4-(1-propynyl)-1-piperidinyl]butanamide,

2-[4-(cyclopropylethynyl)-2-oxo-1-piperidinyl]butanamide 2-[4-(3-methyl-1-butynyl)-2-oxo-1-piperidinyl]butanamide 2-[4-(1- butynyl)-2-oxo-1-piperidinyl]butanamide,

2-[4-(2,2-difluoropropyl)-2-oxo-1-piperidinyl]butanamide, 2-[4-(2-chloro-2,2-difluoroethyl)-2-oxo-1piperidinyl]butanamide,

2-[4-(2-bromo-2,2-difluoroethyl)-2-oxo-1piperidinyl]butanamide,

2-(4-(2,2,2-trifluoroethyl)-2-oxo-1-piperidinyl]butanamide 2-[5-(hydroxymethyl)-2-oxo-1-azepanyl]butanamide,

2-(2-oxo-5-propyl-1-azepanyl)butanamide,

2-[2-OXO-5-(3,3,3-trifluoropropyl)-1-azepanyl]butanamide,

2-[5-(cyclopropylmethyl)-2-oxo-1-azepanyl]butanamide,

2-[5-(iodomethyl)-2-oxo-1-azepanyl]butanamide,

2-[5-(azidomethyl)-2-oxo-1-azepanyl]butanamide,

2-(2-oxo-5-phenyl-1-azepanyl)butanamide,

2-[2-OXO-5-(2-thienyl)-1-azepanyl]butanamide,

2-[2-OXO-5-(3-thienyl)-1-azepanyl]butanamide,

2-[5-(3-chlorophenyl)-2-oxo-1-azepanyl]butanamide,

2-[5-(3-azidophenyl)-2-oxo-1-azepanyl]butanamide,

2-[5-(2,2-difluorovinyl)-2-oxo-1-azepanyl]butanamide,

- 34 045018

2-[5-(2,2-dibromovinyl)-2-oxo-1-azepanyl]butanamide,

2-[5-(2,2-dichlorovinyl)-2-oxo-1-azepanyl]butanamide,

2-(5-ethynyl-2-oxo-1-azepanyl)butanamide,

2-[5-(5-methyl-2-thienyl)-2-oxo-1-azepanyl]butanamide,

2-[5-(5-formyl-2-thienyl)-2-oxo-1-azepanyl]butanamide,

2-[5-(5-cyano-2-thienyl)-2-oxo-1-azepanyl]butanamide,

2-[5-(3-bromo-2-thienyl)-2-oxo-1-azepanyl]butanamide,

2-[5-(4-methyl-2-thienyl)-2-oxo-1-azepanyl]butanamide,

2-[2-OXO-5-(3,3,3-trifluoro-1-propynyl)-1azepanyl]butanamide,

2-[2-OXO-5-(1-propynyl)-1-azepanyl]butanamide,

2-[5-(cyclopropylethynyl)-2-oxo-1-azepanyl]butanamide,

2-[5-(3-methyl-1-butynyl)-2-oxo-1-azepanyl]butanamide,

2-[5-(1-butynyl)-2-oxo-1-azepanyl]butanamide,

2-[5-(2,2-difluoropropyl)-2-oxo-1-azepanyl]butanamide,

2-[5-(2-chloro-2,2-difluoroethyl)-2-oxo-1-azepanyl]butanamide,

2-[5-(2-bromo-2,2-difluoroethyl)-2-oxo-1-azepanyl]butanamide,

2-[5-(2,2,2-trifluoroethyl)-2-oxo-1-azepanyl]butanamide,

2-[6-(hydroxymethyl)-2-oxo-1-azepanyl]butanamide,

2(2-oxo-6-propyl-1-azepanyl)butanamide,

2-[2-oxo-b-(3,3,3-trifluoropropyl)-1-azepanyl]butanamide,

2-[6-(cyclopropylmethyl)-2-oxo-1-azepanyl]butanamide,

2-[6-(iodomethyl)-2-oxo-1-azepanyl]butanamide,

2-[6-(azidomethyl)-2-oxo-1-azepanyl]butanamide,

2(2-oxo-6-phenyl-1-azepanyl)butanamide,

2-[2-oxo-b-(2-thienyl)-1-azepanyl]butanamide,

2-[2-oxo-b-(3-thienyl)-1-azepanyl]butanamide,

2-[b-(3-chlorophenyl)-2-oxo-1-azepanyl]butanamide,

2-[b-(3-azidophenyl)-2-oxo-1-azepanyl]butanamide,

2-[b-(2,2-fluorovinyl)-2-oxo-1-azepanyl]butanamide,

2-[b-(2,2-dibromovinyl)-2-oxo-1-azepanyl]butanamide,

2-[b-(2,2-dichlorovinyl)-2-oxo-1-azepanyl]butanamide,

2-(b-ethynyl-2-oxo-1-azepanyl)butanamide,

2-[b-(5-methyl-2-thienyl)-2-oxo-1-azepanyl]butanamide,

2-[b-(5-formyl-2-thienyl)-2-oxo-1-azepanyl1butanamide,

2-[b-(5-cyano-2-thienyl)-2-oxo-1-azepanyl]butanamide,

- 35 045018 —[6—(3-bromo-2-thienyl)-2-oxo-1-azepanyl]butanamide,

2-[6-(4-methyl-2-thienyl)-2-oxo-1-azepanyl]butanamide,

2-[2-OXO-6-(3,3,3-trifluoro-1-propynyl)-1azepanyl]butanamide,

2-[2-OXO-6-(1-propynyl)-1-azepanyl]butanamide,

2-[6-(cyclopropylethynyl)-2-oxo-1-azepanyl]butanamide,

2-[6-(3-methyl-1-butynyl)-2-oxo-1-azepanyl]butanamide,

2-[6-(1-butynyl)-2-oxo-1-azepanyl]butanamide,

2-[6-(2,2-difluoropropyl)-2-oxo-1-azepanyl]butanamide,

2-[6-(2-chloro-2,2-difluoroethyl)-2-oxo-1-azepanyl]butanamide,

2-[6-(2-bromo-2,2-difluoroethyl)-2-oxo-1-azepanyl]butanamide,

2-[6-(2,2,2-trifluoroethyl)-2-oxo-1-azepanyl]butanamide,

2-[4-(hydroxymethyl)-2-oxo-1-azepanyl]butanamide,

2-(2-oxo-4-propyl-1-azepanyl)butanamide,

2-[2-oxo-4-(3,3,3-trifluoropropyl)-1-azepanyl]butanamide,

2-[4-(cyclopropylmethyl)-2-oxo-1-azepanyl]butanamide,

2-[4-(iodomethyl)-2-oxo-1-azepanyl]butanamide,

2-[4-(azidomethyl)-2-oxo-1-azepanyl]butanamide,

2-(2-oxo-4-phenyl-1-azepanyl)butanamide,

2-[2-oxo-4-(2-thienyl)-1-azepanyl]butanamide,

2-[2-oxo-4-(3-thienyl)-1-azepanyl]butanamide,

2-[4-(3-chlorophenyl)-2-oxo-1-azepanyl]butanamide,

2-[4-(3-azidophenyl)-2-oxo-1-azepanyl]butanamide,

2-[4-(2,2-difluorovinyl)-2-oxo-1-azepanyl]butanamide,

2-[4-(2,2-dibromovinyl)-2-oxo-1-azepanyl]butanamide,

2-[4-(2,2-dichlorovinyl)-2-oxo-1-azepanyl]butanamide,

2-(4-ethynyl-2-oxo-1-azepanyl)butanamide,

2-[4-(5-methyl-2-thienyl)-2-oxo-1-azepanyl]butanamide,

2-[4-(5-formyl-2-thienyl)-2-oxo-1-azepanyl]butanamide,

2-[4-(5-cyano-2-thienyl)-2-oxo-1-azepanyl]butanamide,

2-[4-(3-bromo-2-thienyl)-2-oxo-1-azepanyl]butanamide,

2-[4-(4-methyl-2-thienyl)-2-oxo-1-azepanyl]butanamide,

2-[2-oxo-4-(3,3,3-trifluoro-1-propynyl)-1azepanyl]butanamide,

2-[2-oxo-4-(1-propynyl)-1-azepanyl]butanamide,

2-[4-(cyclopropylethynyl)-2-oxo-1-azepanyl]butanamide, 2-[4-(3-methyl-1-butynyl)-2-oxo-1-azepanyl]butanamide,

2-[4-(1-butynyl-2-oxo-1-azepanyl]butanamide,

2-[4-(2,2-difluoropropyl)-2-oxo-1-azepanyl]butanamide,

2-[4-(2-chloro-2,2-difluoroethyl)-2-oxo-1-azepanyl]butanamide,

2-[4-(2-bromo-2,2-difluoroethyl)-2-oxo-1-azepanyl]butanamide, 2-(4-(2,2,2-trifluoroethyl)-2-oxo-1-azepanyl] butanamide.

In some embodiments, compounds useful in the methods and compositions of the present invention are selected from the group consisting of (2S)-2-[5-(iodomethyl)-2-oxo-1-piperidinyl]butanamide, (2S)-2 -[5-(azidomethyl)-2-oxo-1-piperidinyl]butanamide,

2-(2-oxo-5-phenyl-1-piperidinyl]butanamide, (2S)-2-[4-(iodomethyl)-2-oxo-1-piperidinyl]butanamide,

2-[5-(iodomethyl)-2-oxo-1-azepanyl]butanamide.

ill) International patent application WO 2004/087658:

A compound characterized by formula I, or a pharmaceutically acceptable salt thereof or stereoisomeric forms thereof

- 36 045018

Where

R ¹ is hydrogen, R ² is hydrogen or C1-20alkyl, ^R3 is hydrogen, C1-20alkyl, _C4-8 cycloalkyl, _C5-8 cycloalkenyl, aryl, aromatic or non-aromatic heterocycle, _C1-20 alkoxy or a group of the formula WR ⁸ , the R ^3a group of the formula is hydrogen, C _1-20 alkyl or

or NR ³ R ^3a represents a group of the formula

R ⁴ represents hydrogen,

R ⁵ represents hydrogen; nitro; halogen; azido; cyano; -SC _1-4 alkyl; -SO-C _1-4 alkyl; -SO ₂ -C _1-4 alkyl; -SONH2; C _1-20 alkyl, unsubstituted or substituted with halogen; or C _1-20 alkoxy, unsubstituted or substituted with halogen,

R ⁶ represents hydrogen, C _1-20 alkyl or halogen,

R ⁷ represents hydrogen, C _1-20 alkyl or halogen,

W represents C _1-12 alkylene, -NH- or -NHC(=O)-,

X represents O, S or NH,

Y represents O, S, -CR12R ¹³ -, -NR ¹⁴ - or -C(=O)-,

R ⁸ represents aryl or heterocycle,

R ⁹ , R ¹⁰ , R ^10a and R ¹¹ are independently selected from hydrogen, C _1-4 alkyl, halogen, hydroxy or methoxycarbonyl, or R ¹⁰ and R ^10a together form a C _3-6 alkylene,

R ¹² represents hydrogen, C _1-4 alkyl, halogen or hydroxy,

R ¹³ represents hydrogen, or CR12R ¹³ represents dioxolanyl,

R ¹⁴ represents aryl, heterocycle or a group of the formula -VR ¹⁵ ,

V represents C _1-12 alkylene,

R ¹⁵ is aryl or heterocycle, m is 1 - 4, n is 0 or 1, and at least one of R ⁵ , R ⁶ or R ⁷ is other than hydrogen, if R ² is hydrogen, R ³ is H or 2,6-diisopropylphenyl, and R ^3a is H.

Another aspect relates to a compound characterized by formula I, a pharmaceutically acceptable salt thereof or stereoisomeric forms thereof

where R ¹ represents hydrogen,

R ² represents hydrogen or C _1-20 alkyl,

R ³ represents hydrogen, C _1-20 alkyl, C _4-8 cycloalkyl, C _5-8 cycloalkenyl, aryl, aromatic or non-aromatic heterocycle, C _1-20 alkoxy or a group of formula -WR ⁸ .

R ^3a represents hydrogen, C _1-20 alkyl or a group of the formula

or NR ³ R ^3a represents a group of the formula

R ⁴ represents hydrogen,

- 37 045018

R ⁵ represents hydrogen; nitro; halogen; C1-2oalkyl, unsubstituted or substituted with halogen; or C ₁ . ₂₀ alkoxy, unsubstituted or substituted with halogen,

R ⁶ represents hydrogen, C _1-20 alkyl or halogen,

R ⁷ represents hydrogen, C _1-20 alkyl or halogen,

W represents C _1-12 alkylene, -NH- or -NHC(=O)-,

X represents O, S or NH,

Y represents O, S, -CR ¹² R ¹³ -, -NR ¹⁴ - or -C(=O)-,

R ⁸ represents aryl or heterocycle,

R ⁹ , R ¹⁰ , R ^10a and R ¹¹ are independently selected from hydrogen, C _1-4 alkyl, halogen, hydroxy or methoxycarbonyl, or R ¹⁰ and R ^10a together form a C _3-6 alkylene,

R ¹² represents hydrogen, C _1-4 αlkyl, halogen or hydroxy,

R ¹³ represents hydrogen, or CR12R ¹³ represents dioxolanyl,

R ¹⁴ represents aryl, heterocycle or a group of the formula -VR ¹⁵ ,

V represents C _1-12 alkylene,

R ¹⁵ is aryl or heterocycle, m is 1-4, n is 0 or 1, and at least one of R ⁵ , R ⁶ or R ⁷ is other than hydrogen, if R ² is hydrogen, R ³ is H or 2,6-diisopropylphenyl, and R ^3a is H.

As used herein, the term alkyl is defined to include saturated, monovalent hydrocarbon radicals containing branched, straight-chain or cyclic moieties, or combinations thereof, and containing 1-20 carbon atoms, preferably 1-6 carbon atoms and more preferably 1-4 carbon atoms for non-cyclic alkyl and 3-8 carbon atoms for cycloalkyl. The alkyl moieties may be optionally substituted with 1-5 substituents independently selected from the group consisting of halogen, hydroxy, alkoxy, alkoxycarbonyl, ester or alkylamino. Preferred alkyl groups are methyl, ethyl, npropyl, isopropyl, trifluoromethyl, n-butyl, 2-fluoroethyl, 3-hydroxypropyl, 3-hydroxy-2,2dimethylpropyl, 1-(hydroxymethyl)propyl, 3,3,3-trifluoro- 2-hydroxypropyl, 3-ethoxypropyl, 2-ethoxy2-oxoethyl and 3-(dimethylamino)propyl.

As used herein, the term cycloalkyl refers to a monovalent group of 318 carbon atoms, preferably 4-8 carbon atoms, derived from a saturated cyclic or polycyclic hydrocarbon, which may be substituted by any suitable group, including, without limitation, one or more moieties selected from the groups, described above for alkyl groups. A preferred cycloalkyl group is cycloheptyl.

As used herein, the term alkylene refers to a divalent alkyl group containing straight or branched moieties containing 1-12 carbon atoms, preferably 1-6 carbon atoms, and optionally substituted with any suitable group, including without limitation one or more moieties selected from the groups , described above for alkyl groups. Preferred alkylene groups are methylene, ethylene, hydroxyethylene, trimethylene or propylene.

As used herein, the term cycloalkenyl is defined as a cyclic, unsaturated hydrocarbon radical containing at least one double bond containing 4-20 carbon atoms, preferably 5-8 carbon atoms, and optionally substituted with any suitable group, including without limitation one or several fragments selected from the groups described above for alkyl groups. A preferred cycloalkenyl group is 6(hydroxymethyl)cyclohex-3-en-1-yl.

As used herein, the term aryl is defined to include an organic radical obtained by the removal of one hydrogen atom from an aromatic hydrocarbon consisting of 1-3 rings and containing 6-30 carbon atoms, such as phenyl and naphthyl, each of which is optionally substituted with 1-5 substituents independently selected from halogen, hydroxy, nitro, C ₁₆ alkyl, C ₁ . ₆ alkoxy, C ₁ _ ₆ alkylsulfonyl, trifluoromethylthio or pyridinyl alkyl. Aryl radicals are preferably phenyl radicals. Preferred aryl groups are phenyl, 3-hydroxyphenyl, 3-fluorophenyl, 3-methylphenyl, 4-methylphenyl, 4-hydroxyphenyl, 4-hydroxy-3-methoxyphenyl, 3-(2-pyridin-2-ylethyl)phenyl, 3. 4-dimethylphenyl, 4-tert-butylphenyl, 4methylsulfonylphenyl, 2-nitrophenyl, 2-chloro-6-fluorophenyl, 2-[(trifluoromethyl)thio]phenyl, 2-chlorophenyl or 4-bromophenyl.

As used herein, the term halogen includes Cl, Br, F, I.

As used herein, the term nitro represents a group of the formula -NO2.

As used herein, the term hydroxy represents a group of the formula -OH.

As used herein, the term alkoxy is a group of the formula

- 38 045018

-OR ^b where R ^b represents an alkyl group as defined above.

As used herein, the term ester is a group of the formula -COOR ^c where R ^c represents an alkyl group or aryl group as defined above.

As used herein, the term alkoxycarbonyl is a group of the formula -COOR ^d where R ^d represents an alkyl group as defined above.

As used herein, the term amino represents a group of the formula -NH2.

As used herein, the term alkylamino is a group of the formula -NHR ^e or -NR ^e Rf, where R ^e and Rf represent an alkyl group as defined above.

As used herein, the term alkylsulfonyl is defined to represent a group of the formula -SO2-R ⁹ wherein R ^g is C _1-4 alkyl.

As used herein, the term heterocycle is defined to include an aromatic or non-aromatic cycloalkyl or cycloalkenyl moiety as defined above, containing at least one O, S and/or N atom interrupted by a carbocyclic ring structure, and optionally one of the carbon atoms of the carbocyclic ring structure can be replaced by carbonyl.

Non-limiting examples of aromatic heterocyclic compounds include pyrazolyl, furyl, imidazolyl, triazolyl, oxazolyl, pyridinyl, pyrrolyl, thienyl, isothiazolyl, benzimidazolyl, tetrazolyl, isooxazolyl, oxazolyl, thiazolyl, 1,2,4-thiadiazolyl, oxadiazole, pyridazinyl, pyrimidinyl, pyrazine silt , isoindolyl, triazolopyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, quinazolinyl, quinolizinyl, naphthyridinyl, quinolyl, isoquinolyl, isobenzofuranyl, benzothienyl, indolyl, indolizinyl, purinyl, carbazolyl, thieno(2,3-b)furanyl, thianthrenyl, benzothiazolyl, benzoxazolyl, cinnolinyl , quinoxalinyl, phenothiazinyl, isochromanyl and xanthenyl, optionally substituted with 1-5 substituents independently selected from halogen, hydroxy, thiol, amino, nitro, cyano, azido, C^alkoxy, _C1 . _b alkylthio, C ₁ . ₆ alkyl, C ₁ . _b haloalkyl, formyl or ester. More preferred aromatic heterocyclic compounds are pyrazolyl, furyl, imidazolyl, triazolyl, oxazolyl and pyridinyl.

Non-limiting examples of non-aromatic heterocyclic compounds include tetrahydrofuranyl, piperidinyl, piperidyl, piperazinyl, imidazolinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, thiazolidinyl, indolinyl, tetrahydrobenzazocinyl, dihydroisochromenyl, tetrahydropyranyl, oxooctahydroquinolinyl, dioxo Lanil, 1-oxaspiro(4.5)dec-2-yl, pyrrolidinyl , 2-oxopyrrolidinyl, 8-thiabicyclo[3.2.1]cyclooctanyl, 1,4-dithiepanyl, tetrahydro-2H-thiopyranyl, azepanyl and azocanyl, optionally substituted with 1-5 substituents independently selected from halogen, hydroxy, thiol, amino, nitro , cyano, azido, C ₁ . _b alkoxy, C ₁ . _b alkylthio, C ₁ . _b alkyl, C ₁ . _b haloalkyl, formyl or ester. More preferably, the non-aromatic heterocyclic compounds are tetrahydrofuranyl, piperidinyl, piperidyl, piperazinyl, imidazolinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, thiazolidinyl, indolinyl, tetrahydro-1-benzazocin-1(2H)-yl, 3,4dihydro-1H-isochromen-1- yl, tetrahydropyranyl, oxooctahydroquinolinyl and dioxolanil. As used herein, the term heterocycle also includes bicyclic, tricyclic and tetracyclic spiro groups in which any of the above heterocyclic rings are fused to one or two rings independently selected from an aryl ring, a cycloalkyl ring, a cycloalkenyl ring or other monocyclic heterocyclic ring, or wherein a monocyclic heterocyclic ring the group is bridged via an alkylene group, such as quinuclidinyl, 7-azabicyclo(2.2.1)heptanyl, 7-oxabicyclo(2.2.1)heptanyl and 8azabicyclo(3.2.1)octanyl.

As used herein, the term pyridinyl alkyl is a group of the formula ^-pyridinyl in which R ^h is C ₁ . ₄ alkylene.

As used herein, the term azido is a group of the formula -N ₃ .

As used herein, the term cyano represents a group of the formula -CN. Typically, R ² represents hydrogen or C ₁ . ₄ αlkyl.

Preferably R ² is hydrogen, methyl or ethyl. More preferably, R ² is hydrogen or methyl.

Typically, R ³ is hydrogen; C ₁ . _b alkyl, unsubstituted or substituted with 1-5 substituents selected from halogen, hydroxy, alkoxy, alkoxycarbonyl or alkylamino; _C5 . ₇ cycloalkyl; (hydroxymethyl)cyclohexenyl; phenyl, unsubstituted or substituted with 1-5 substituents selected from halogen, C ₁ . ₄ alkyl, hydroxy, methoxy, nitro, methylsulfonyl, trifluoromethylthio or pyridinyl alkyl; pyridinyl, unsubstituted or substituted with methoxy; triazolyl; C ₁ . ₄ alkoxy; or a group of the formula - WR ⁸ wherein typically W is C ₁ . ₄ alkylene, unsubstituted or substituted with halogen, hydroxy, C ₁ . ₄ alkyl or alkoxy; -NH-; or -NHC (=O)-; And

R ⁸ represents phenyl, unsubstituted or substituted with 1-5 substituents selected from halogen, C ₁ . ₄ alkyl, hydroxy, methoxy, nitro, methylsulfonyl or trifluoromethylthio; furyl, unsubstituted or substituted with methyl; pyrazolyl; pyridinyl; morpholinyl; tetrahydrobenzazocinyl; pipe- 39 045018 ridinyl, unsubstituted or substituted with methyl; dihydroisochromenyl or dihydroimoidazolyl.

Preferably R ³ is hydrogen, n-butyl, cycloheptyl, 2-fluoroethyl, 3-hydroxypropyl, 3-hydroxy-2,2-dimethylpropyl, 1-(hydroxymethyl)propyl, 3,3,3-trifluoro-2hydroxypropyl, 3-ethoxypropyl, 2-ethoxy-2-oxoethyl, 3-(dimethylamino)propyl, 6-(hydroxymethyl)cyclohex-3-en-1-yl, 3-hydroxyphenyl, 3-fluorophenyl, 3-(2-pyridin-2-ylethyl)phenyl , 3,4dimethylphenyl, 4-tert-butylphenyl, benzyl, 4-hydroxy-3-methoxybenzyl, 4-methylsulfonylbenzyl, 2nitrobenzyl, 2-chloro-6-fluorobenzyl, 2-[(trifluoromethyl)thio]benzyl, 2-hydroxy-2 -phenylethyl, 2-(3,4dimethoxyphenyl)ethyl, 2-(2-chlorophenyl)ethyl, 2-(4-methylphenyl)ethyl, (4-bromophenyl)amino, pyridin-3-yl, 6-methoxypyridin-3-yl , 4H-1,2,4-triazol-3-yl, pyridin-4-ylmethyl, (5-methyl-2-furyl)methyl, 3-(1Hpyrazol-1-yl)propyl, 2-morpholin-4-ylethyl , 2-((3,4,5,6-tetrahydro-1-benzazocin-1(2H)-yl)propyl, 2-(2methylpiperidin-1-yl)ethyl, 3,4-dihydro-1H-isochromen-1 -ylmethyl, methoxy, (4-pyridinylcarbonyl)amino or 4,5-dihydro-1H-imidazol-2-ylamino More preferably, R ³ is hydrogen.

Typically, R ^3a is hydrogen, C ₁ . ₄ alkyl or a group of the formula LJ/Ck L JmV / in which m is 1-4.

Preferably R ^3a is hydrogen, methyl or tetrahydrofuran-2-ylmethyl. More preferably, R ^3a is hydrogen.

In another embodiment, NR ³ R ^3a is piperidinyl, unsubstituted or substituted with hydroxy; thiomorpholinyl; thiazolidinyl, unsubstituted or substituted with C ₁ . ₄ alkoxycarbonyl; 2,5-dihydro-III-pyrrol-1-yl; 1,4-dioxa-8-azaspiro[4.5]dec-8-yl; 4-oxooctahydro-1(2H)-quinolinyl; or a group of the formula -f/\-R ¹⁴ in which R ¹⁴ represents pyridinyl; phenyl, unsubstituted or substituted with halogen, hydroxy, C1.4alkyl; or a group of the formula -VR ¹⁵ where V represents unsubstituted C1. ₄ alkylene, and R ¹⁵ is phenyl or morpholinyl.

In a preferred embodiment, NR ³ R ^3a is 4-pyridin-2ylpiperazin-1-yl, 4-(3-methylphenyl)piperazin-1-yl, 4-(4-hydroxyphenyl)piperazin-1-yl, 4-(2phenylethyl )piperazin-1-yl, 4-(2-morpholin-4-ylethyl)piperazin-1-yl, 3-hydroxypiperidin-1-yl, thiomorpholin-4-yl, 4-methoxycarbonyl-1,3-thiazolidin-3- yl, 2,5-dihydro-III-pyrrol-1-yl, 1,4-dioxa-8azaspiro[4.5]dec-8-yl or 4-oxooctahydro-1(2H)-quinolinyl.

Typically, R ⁵ is hydrogen, nitro, halogen, C ₁ . ₄ alkyl, unsubstituted or substituted with halogen, or C ₁ . ₄ alkoxy, unsubstituted or substituted with halogen.

Preferably R ⁵ is hydrogen, methyl, ethyl, trifluoromethyl, trifluoromethoxy, npropyl, isopropyl, nitro or halogen. More preferably, R ⁵ is halogen or trifluoromethyl.

Typically, R ⁶ is hydrogen, C ₁ . ₆ alkyl or halogen.

Preferably R ⁶ is hydrogen, methyl or Cl. More preferably, R ⁶ is hydrogen.

Typically, R ⁷ is hydrogen, methyl or halogen.

Preferably R ⁷ is hydrogen, methyl, Br, F or Cl. More preferably, R ⁷ is hydrogen, Br or F.

Combinations of one or more of these preferred groups of compounds are particularly preferred.

In a preferred embodiment, the compound is characterized by formula I, or a pharmaceutically acceptable salt thereof or a stereoisomeric form thereof

where R ¹ represents hydrogen,

R ² represents hydrogen or C ₁ . ₄ alkyl,

R ³ represents hydrogen; C ₁ . ₆ alkyl, unsubstituted or substituted with 1-5 substituents selected from halogen, hydroxy, alkoxy, alkoxycarbonyl or alkylamino; _C5 . ₇ cycloalkyl; (hydroxymethyl)cyclohexenyl; phenyl, unsubstituted or substituted with 1-5 substituents selected from

- 40 045018 halogen, C _1-4 alkyl, hydroxy, methoxy, nitro, methylsulfonyl, trifluoromethylthio or pyridinyl alkyl; pyridinyl, unsubstituted or substituted with methoxy; thiazolyl; C _1-4 alkoxy; or a group of the formula WR ⁸ ,

R ^3a represents hydrogen, C _1-4 alkyl or a group of the formula

L Jm\ 7 or NR ³ R ^3a is piperidinyl, unsubstituted or substituted with hydroxy; thiomorpholinyl; thiazolidinyl, unsubstituted or substituted with C _1-4 alkoxycarbonyl; 2,5-dihydro-1Hpyrrol-1-yl; 1,4-dioxa-8-azaspiro[4.5]dec-8-yl-; 4-oxooctahydro-1(2H)-quinolinyl; or a group of the formula -1/ \~H ¹⁴

R ⁴ represents hydrogen,

R ⁵ represents hydrogen; nitro; halogen; C _1-4 alkyl, unsubstituted or substituted with halogen; or C _1-4 alkoxy, unsubstituted or substituted with halogen,

R ⁶ represents hydrogen, C _1-6 allyl or halogen,

R ⁷ represents hydrogen, methyl or halogen,

W is C _1-4 alkylene, unsubstituted or substituted with halogen, hydroxy, C _1-4 alkyl or alkoxy; -NH-; or -NHC(=O)-,

R ⁸ is phenyl, unsubstituted or substituted with 1-5 substituents selected from halogen, C _1-4 alkyl, hydroxy, methoxy, nitro, methylsulfonyl or trifluoromethylthio; furyl, unsubstituted or substituted with methyl; pyrazolyl; pyridinyl; morpholinyl; tetrahydrobenzazocinyl; piperidinyl, unsubstituted or substituted with methyl; dihydroisochromenyl or dihydroimoidazolyl,

R ¹⁴ represents pyridinyl; phenyl, unsubstituted or substituted with halogen, hydroxy, C _1-4 alkyl; or a group of the formula -VR ¹⁵ ,

V represents unsubstituted C _1-4 alkylene,

R ¹⁵ is phenyl or morpholinyl, m is 1-4, and at least one of R ⁵ , R ⁶ or R ⁷ is other than hydrogen if R ² is hydrogen, R ³ is H or 2,6-diisopropylphenyl , and R ^3a represents H.

In a more preferred embodiment, the compound is characterized by formula I or a pharmaceutically acceptable salt or stereoisomeric form thereof

Where

R ¹ represents hydrogen,

R ² represents hydrogen, methyl or ethyl,

R ³ is hydrogen, n-butyl, cycloheptyl, 2-fluoroethyl, 3-hydroxypropyl, 3-hydroxy2,2-dimethylpropyl, 1-(hydroxymethyl)propyl, 3,3,3-trifluoro-2-hydroxypropyl, 3-ethoxypropyl , 2-ethoxy-2-oxoethyl, 3-(dimethylamino)propyl, 6-(hydroxymethyl)cyclohex-3-en-1-yl, 3-hydroxyphenyl, 3-fluorophenyl, 3-(2-pyridin-2-ylethyl)phenyl, 3,4-dimethylphenyl, 4-tert-butylphenyl, benzyl, 4-hydroxy3-methoxybenzyl, 4-methylsulfonylbenzyl, 2-nitrobenzyl, 2-chloro-6-fluorobenzyl, 2-[(trifluoromethyl)thio]benzyl, 2-hydroxy- 2-phenylethyl, 2-(3,4-dimethoxyphenyl)ethyl, 2-(2-chlorophenyl)ethyl, 2-(4methylphenyl)ethyl, (4-bromophenyl)amino, pyridin-3-yl, 6-methoxypyridin-3- yl, 4H-1,2,4-triazol-3-yl, pyridin-4-ylmethyl, (5-methyl-2-furyl)methyl, 3-(1H-pyrazol-1-yl)propyl, 2-morpholine- 4-ylethyl, 2((3,4,5,6-tetrahydro-1-benzazocin-1 (2H)-yl)propyl, 2-(2-methylpiperidin-1 -yl)ethyl, 3,4-dihydro-1Hisochromene -1-ylmethyl, methoxy, (4-pyridinylcarbonyl)amino or 4,5-dihydro-1H-imidazol-2-ylamino, R ^3a is hydrogen, methyl or tetrahydrofuran-2-ylmethyl or NR ³ R ^3a 4-pyridin- 2ylpiperazin-1-yl, 4-(3-methylphenyl)piperazin-1-yl, 4-(4-hydroxyphenyl)piperazin-1-yl, 4-(2phenylethyl)piperazin-1-yl, 4-(2-morpholine- 4-ylethyl)piperazin-1-yl, 3-hydroxypiperidin-1-yl, thiomorpholin-4-yl, 4-methoxycarbonyl-1,3-thiazolidin-3-yl, 2,5-dihydro-1H-pyrrol-1- yl, 1,4-dioxa-8azaspiro[4.5]dec-8-yl or 4-oxooctahydro-1(2H)-quinolinyl,

R ⁴ represents hydrogen,

R ⁵ is hydrogen, methyl, ethyl, trifluoromethyl, trifluoromethoxy, n-propyl, isopropyl, nitro or halogen,

R ⁶ is hydrogen, methyl or Cl,

R ⁷ is hydrogen, methyl, Br, F or Cl,

- 41 045018 and at least one of R ⁵ , R ⁶ or R ⁷ is other than hydrogen, if R ² is hydrogen,

R ³ is H or 2,6-diisopropylphenyl, and R ^3a is H.

More preferably, R ² is hydrogen or methyl, R ³ is hydrogen,

R ^3a is hydrogen, R ⁵ is halogen or trifluoromethyl, R ⁶ is hydrogen and R ⁷ is hydrogen, Br or F.

In all of the above embodiments, if R ² represents C ₁ . ₂₀ alkyl, the carbon atom to which R ² is attached is preferably in the S configuration.

In some embodiments, compounds useful in the methods and compositions of the present invention are selected from the group consisting of:

2-(5-iodo-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide; 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1yl)acetamide; 2-(5,7-dibromo-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide; 2-(5-nitro-2-oxo-2,3dihydro-III-indol-1 -yl)acetamide; 2-(5-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide; 2-(5-chloro2-oxo-2,3-dihydro-III-indol-1 -yl)propanamide; (2R)-2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1yl)propanamide; (2S)-2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)propanamide; 2-[2-oxo-5(trifluoromethoxy)-2,3-dihydro-1H-indol-1-yl]acetamide; 2-(5-isopropyl-2-oxo-2,3-dihydro-1H-indol1 -yl)acetamide; 2-(5-ethyl-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide; 2-(5-fluoro-2-oxo-2,3-dihydro1 H-indol-1 -yl)acetamide; 2-(5,7-dimethyl-2-oxo-2,3-dihydro-1H-indol-1 -yl)acetamide; 2-(5-bromo-2oxo-2,3-dihydro-1H-indol-1-yl)acetamide; 2-(2-oxo-5-propyl-2,3-dihydro-1H-indol-1-yl)acetamide; 2-[2-oxo-5-(trifluoromethyl)-2,3-dihydro-1H-indol-1-yl]acetamide; 2-(5,6-dimethyl-2-oxo-2,3-dihydro1H-indol-1-yl)acetamide; 2-(7-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide; 2-(6-chloro-2-oxo-2,3 dihydro-1H-indol-1-yl)acetamide; 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)butanamide; (+)-2-(5chloro-2-oxo-2,3-dihydro-1 H-indol-1 -yl)butanamide; (-)-2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1yl)butanamide; 2-(5-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl)propanamide; (+)-2-(5-methyl-2-oxo-2,3dihydro-III-indol-1 -yl)propanamide; (-)-2-(5-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl)propanamide; 2(5-bromo-2-oxo-2,3-dihydro-1H-indol-1-yl)propanamide; (-)-2-(5-bromo-2-oxo-2,3-dihydro-1H-indol-1yl)propanamide; (+)-2-(5-bromo-2-oxo-2,3-dihydro-1H-indol-1-yl)propanamide; 2-(5-chloro-7-fluoro-2oxo-2,3-dihydro-1H-indol-1-yl)acetamide; 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(3-hydroxyphenyl)acetamide; 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(3-fluorophenyl)acetamide; 2-(5chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-[3-(2-pyridin-2-ylethyl)phenylacetamide; 2-(5-chloro-2-oxo2,3-dihydro-1H-indol-1-yl)-N-[6-(hydroxymethyl)cyclohex-3-en-1-yl]acetamide; 5-chloro-1-[2-oxo-2-(4pyridin-2-ylpiperazin-1 -yl)ethyl]-1,3-dihydro-2H-indol-2-one; 5-chloro-1-{2-[4-(3-methylphenyl)piperazin-1-yl]-2-oxoethyl}-1,3-dihydro-2H-indol-2-one; 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N(4hydroxy-3-methoxybenzyl)acetamide; 2-(5-chloro-2-oxo-2,3-dihydro-N-indol-1-yl)-N-(pyridin-4ylmethyl)-N-(tetrahydrofuran-2-ylmethyl)acetamide; 5-chloro-1-[2-(3-hydroxypiperidin-1-yl)-2oxoethyl]-1,3-dihydro-2H-indol-2-one; 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-isonicotinylacetohydrazide; 5-chloro-1-(2-oxo-2-thiomorpholin-4-ylethyl)-1,3-dihydro-2H-indol-2-one; 2-(5-chloro-2oxo-2,3-dihydro-1H-indol-1-yl)-N-(4H-1,2,4-triazol-3-yl)acetamide; 2-(5-chloro-2-oxo-2,3-dihydro-1Hindol-1-yl)-N-[4-(methylsulfonyl)benzyl]acetamide; 1-[(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)acetyl]octahydroquinolin-4(1H)-one; N'-(4-bromophenyl)-2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1yl)acetohydrazide; 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1 -yl)-N-(6-methoxypyridin-3 -yl)acetamide; H-6util-2-(5-chloro-2-oxo-2,3-dihydro-1 H-indol-1 -yl)acetamide; 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(3-hydroxypropyl)acetamide; 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-[3-(dimethylamino)propyl]acetamide; 5-chloro-1-{2-oxo-2[4-(2-phenylethyl)piperazin-1-yl]ethyl}-1,3-dihydro-2Nindol-2-one; ethyl{[(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)acetyl]amino}acetate; 2-(5-chloro-2-oxo2,3-dihydro-1H-indol-1-yl)-N-(3-ethoxypropyl)acetamide; 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1yl)-N(2-fluoroethyl)acetamide; 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-methoxy-N-methylacetamide; 2-(5-chloro-2-oxo-2,3-dihydro-1H-indole-1-ul)-N-(3,4-dimethylphenyl)acetamide; N-(4-tert-butylphenyl)-2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide; 2-(5-chloro-2-oxo-2,3-dihydro-1 Nindol-1-yl)-N-(3-hydroxy-2,2-dimethylpropyl)acetamide; 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)N-[1-(hydroxymethyl)propyl]acetamide; 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(3,3,3-trifluoro2-hydroxypropyl)acetamide; 2-(5-chloro-2-oxo-2,3-dihydro-1H-indole-1-yI)-N-(2-hydroxy-2-phenylethyl)acetamide; 5-chloro-1 - {2-[4-(4-hydroxyphenyl)piperazin-1 -yl]-2-oxoethyl}-1,3-dihydro-2H-indol-2one; 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(pyridin-4-ylmethyl)acetamide; 2-(5-chloro-2-oxo2,3-dihydro-1H-indol-1-yl)-N-[(5-methyl-2-furyl)methyl]acetamide; 2-(5-chloro-2-oxo-2,3-dihydro-1Nindol-1-yl)-N-[3-(1H-pyrazol-1-yl)propyl]acetamide; methyl 3-[(5-chloro-2-oxo-2,3-dihydro-1H-indol-1yl]acetyl]-1,3-thiazolidine-4-carboxylate; 5-chloro-1 -[2-(2 ,5-dihydro-1H-pyrrol-1-yl)-2-oxoethyl]-1,3dihydro-2H-indol-2-one;2-(5-chloro-2-oxo-2,3-dihydro-1 H-indol-1-yl)-N'-(4,5-dihydro-1H-imidazol-2yl)acetohydrazide; 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1- yl)-N-[2-(3,4-dimethoxyphenyl)ethyl]acetamide; 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-[2- (2-chlorophenyl)ethyl]acetamide; 2-(5-chloro-2oxo-2,3-dihydro-1H-indol-1-yl)-N-[2-(4-methylphenyl)ethyl]acetamide; 2-( 5-chloro-2-oxo-2,3-dihydro-1Nindol-1-yl)-N-(2-morpholin-4-ylethyl)acetamide; 2-(5-chloro-2-oxo-2,3-dihydro -1H-indol-1-yl)-N-[2(3,4,5,6-tetrahydro-1-benzazocin-1 (2H)-yl)propyl]acetamide; 2-(5-chloro-2-oxo -2,3-dihydro-1H-indol-1 - 42 045018 yl)-N-[2-(2-methylpiperidin-1-yl)ethyl]acetamide; 2-(5-chloro-2-oxo-2,3 -dihydro-1H-indol-1-yl)-N-(2nitrobenzyl)acetamide;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(3 N-(2-chloro-6-fluorobenzyl)-2-(5-chloro-2-oxo-2,3-dihydro-1H-indole-1- yl)acetamide; N-benzyl-2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-methylacetamide; 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-{2-[(trifluoromethyl)thio]benzyl}acetamide; 5-chloro-1-[2-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-2-oxoethyl]-1,3-dihydro-2H-indol-2-one; 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)N-cycloheptylacetamide; 5-chloro-1-{2-[4-(2-morpholin-4-ylethyl)piperazin-1-yl]-2-oxoethyl}-1,3-dihydro-2H-indol-2-one and 2-( 5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-pyridin-3-ylacetamide.

In some embodiments, the compounds useful in the methods and compositions of the present invention are selected from the group consisting of 2-(5-iodo-2-oxo-2,3-dihydro-N-indol1-yl)acetamide; 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide; 2-(5,7-dibromo-2-oxo-2,3 dihydro-1H-indol-1-yl)acetamide; (2S)-2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)propanamide; 2-[2oxo-5-(trifluoromethyl)-2,3-dihydro-1H-indol-1-yl]acetαmide and 2-(5-chloro-7-fluoro-2-oxo-2,3-dihydro1H-indole -1-yl)acetamide.

In another embodiment, the compounds useful in the methods and compositions of the present invention are selected from the group consisting of 2-(5-chloro-2-oxo-2,3-dihydro-Shindol-1-yl)acetamide and (2S)- 2-(5-chloro-2-oxo-2,3-dihydro-1 H-indol-1 -yl)propanamide.

iv) US Patent No. 7244747:

A compound characterized by formula I, or a pharmaceutically acceptable salt thereof

P)

where R ¹ represents hydrogen, C ₁ . ₂₀ alkyl, C ₃ . ₈ cycloalkyl, halogen, hydroxy, alkoxy, aryloxy, ester, amido, cyano, nitro, amino, guanidine, amino derivative, alkylthio, arylthio, alkylsulfonyl, arylsulfonyl, alkylsulfinyl, arylsulfinyl, aryl or heterocycle;

R ² represents hydrogen, C ₁ . ₂₀ αlkyl, alkoxy, amino, halogen, hydroxy, ester, amido, nitro, cyano, carbamate, or aryl;

R ³ represents hydrogen, C ₁ . ₂ oalkyl, alkoxy, amino, halogen, hydroxy, ester, amido, nitro, cyano, carbamate, or aryl;

or R ² and R ³ can form together with the imidazole ring the following 1H-benzimidazole ring

R ⁴ represents hydrogen, C ₁ . ₂₀ alkyl, C ₂ . ₁₂ alkenyl, C ₂ . ₁₂ alkynyl, aryl, azido, alkoxycarbonylamino, arylsulfonyloxy or heterocycle;

R ^4a represents hydrogen or C ₁ . ₂₀ alkyl;

or R ⁴ and R ^4a may together form C ₃ . ₈ cycloalkyl;

R ⁵ represents hydrogen; or R ⁴ , R ^4a and R ⁵ can form together with the 2-oxo-1-pyrrolidine ring the following 1,3-dihydro-2H-indol-2-one ring

R ⁷ represents hydrogen;

or R ⁶ and R ⁷ are linked together to form C ₃ . ₆ cycloalkyl;

R ⁸ represents hydrogen, halogen, nitro, cyano, C ₁ . ₂₀ alkyl or alkoxy;

R ⁹ represents hydrogen, C ₁ . ₂₀ alkyl, halogen, hydroxy, alkoxy, aryloxy, ester, amido, cyano, nitro, amino, amino derivative, alkylthio, arylthio, alkylsulfonyl, arylsulfonyl, alkylsulfinyl or arylsulfinyl;

R ¹⁰ represents hydrogen, C ₁ . ₂₀ alkyl, halogen, hydroxy, alkoxy, aryloxy, ester, amido, cyano, nitro, amino, amino derivative, alkylthio, arylthio, alkylsulfonyl, arylsulfonyl,

- 43 045018 alkylsulfinyl or arylsulfinyl;

R ¹¹ represents hydrogen, halogen, nitro, cyano, _C1-20 alkyl or alkoxy;

R ¹² represents hydrogen or halogen;

R ¹³ represents hydrogen, nitro, halogen, heterocycle, amino, aryl, C _1-20 alkyl, unsubstituted or substituted with halogen, or alkoxy, unsubstituted or substituted with halogen;

R ¹⁴ represents hydrogen, C _1-20 alkyl or halogen;

R ¹⁵ represents hydrogen, C _1-20 alkyl or halogen;

with the proviso that R ⁴ is other than hydrogen if it is a group of the formula

An asterisk * indicates the point of substituent addition.

In a preferred embodiment, the compounds are characterized by formula I, their tautomers, geometric isomers (including cis and trans, Z and E isomers), enantiomers, diastereoisomers and mixtures thereof (including all possible mixtures of stereoisomers), or pharmaceutically acceptable salts thereof (I)

R ⁴

R-' where R ¹ represents hydrogen, C _1-20 alkyl, C _3-8 cycloalkyl, halogen, hydroxy, ester, amido, cyano, nitro, amino, guanidine, alkylthio, alkylsulfonyl, alkylsulfinyl, aryl or heterocycle;

R ² is hydrogen, C _1-20 alkyl, halogen, cyano, ester, carbamate or amido;

R ³ is hydrogen, cyano, C _1-20 alkyl, halogen or ester; or R ² and R ³ can form together with the imidazole ring the following 1H-benzimidazole ring

R ⁴ represents hydrogen, C _1-20 alkyl, C _2-12 alkenyl or aryl;

R ^4a represents hydrogen;

R ⁵ represents hydrogen;

or R ⁴ , R ^4a and R ⁵ can form together with the 2-oxo-1-pyrrolidine ring the following 1,3dihydro-2H-indol-2-one ring

R ⁶ represents hydrogen or C _1-20 alkyl;

R ⁷ represents hydrogen; or R ⁶ and R ⁷ are linked together to form a C _3-6 cycloalkyl;

R ⁸ represents hydrogen;

R ⁹ represents hydrogen, C _1-20 alkyl, halogen or alkoxy;

R ¹⁰ represents hydrogen, C _1-20 alkyl, halogen or cyano;

R ¹¹ represents hydrogen;

R ¹² represents hydrogen or halogen;

R ¹³ represents hydrogen, halogen, heterocycle or C _1-20 alkyl;

R ¹⁴ represents hydrogen;

R ¹⁵ represents hydrogen;

provided that ^R4 is other than hydrogen if

- 44 045018

R-

represents a group of the formula

As used herein, the term alkyl represents saturated, monovalent hydrocarbon radicals containing straight (branched) or branched or cyclic moieties or combinations thereof and containing 1-20 carbon atoms, preferably 1-10 carbon atoms, more preferably alkyl groups containing 1- 3 carbon atoms. The alkyl moieties may optionally be substituted with 1 to 5 substituents independently selected from the group consisting of halogen, hydroxy, cyano, azido, aryloxy, alkoxy, alkylthio, alkanoylamino, arylcarbonylamino, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, or aryl. In this case, alkyl groups are usually methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, 1-ethylpropyl, n-heptyl, 2,4,4-trimethylpentyl, n-decyl, chloromethyl, trifluoromethyl, 2-bromo2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, hydroxymethyl, cyanomethyl, azidomethyl, (acetylamino)methyl, (propionylamino)methyl, (benzoylamino)methyl, (4- chlorophenoxy)methyl, benzyl, 2phenylethyl or 2-(methylthio)ethyl.

Preferred alkyl groups are methyl, ethyl, n-propyl, isopropyl, nbutyl, isobutyl, tert-butyl, 1-ethylpropyl, 2,4,4-trimethylpentyl, chloromethyl, trifluoromethyl, 2,2,2trifluoroethyl, hydroxymethyl, cyanomethyl, azidomethyl , (acetylamino)methyl, (propionylamino)methyl, (benzoylamino)methyl or 2-(methylthio)ethyl. More preferred alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, azidomethyl or trifluoromethyl. The most preferred alkyl groups are methyl or n-propyl.

As used herein, the term cycloalkyl is a monovalent group of 3-8 carbon atoms, typically 3-6 carbon atoms, derived from a saturated cyclic hydrocarbon, which may be substituted by any suitable group, including, without limitation, one or more moieties selected from the groups, as described above for alkyl groups. Preferred cycloalkyl groups are cyclopropyl and cyclohexyl.

As used herein, the term alkenyl represents straight, branched or cyclic unsaturated hydrocarbon radicals or combinations thereof, containing at least one carbon-carbon double bond, and containing 2-12 carbon atoms, preferably typically 2-4 carbon atoms. Alkenyl groups are optionally substituted with any suitable group, including, without limitation, one or more moieties selected from the groups described above for alkyl groups. Typically the alkenyl group is ethenyl (vinyl), optionally substituted with 1-3 halogen atoms. In the present case, preferred alkenyl groups are 2,2-difluorovinyl.

As used herein, the term alkynyl represents straight, branched or cyclic hydrocarbon radicals or combinations thereof containing at least one carbon-carbon triple bond, containing 2-12 carbon atoms, preferably 2-6 carbon atoms, and optionally substituted with any suitable group including, without limitation, one or more moieties selected from the groups described above for alkyl groups. Preferably, the alkynyl group is a haloalkynyl group (haloalkynyl group).

Groups containing prefixes such as second, iso, tert, etc. (for example, isopropyl, sec-butyl), are branched derivatives.

As used herein, the term aryl is defined as phenyl optionally substituted with 1-4 substituents independently selected from halogen, cyano, alkoxy, alkylthio, C ₁ -alkyl or azido, preferably halogen or azido. In this case, the alkyl groups are usually phenyl, 3-chlorophenyl, 3-fluorophenyl, 4-chlorophenyl, 4-fluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 3-chloro-4-fluorophenyl, 2,3,4- trifluorophenyl, 2,4,5-trifluorophenyl, 2,3,5-trifluorophenyl, 3,4,5-trifluorophenyl, 3-azido-2,4-difluorophenyl or 3-azido-2,4,6-trifluorophenyl. Preferably, the aryl groups are phenyl, 3-chlorophenyl, 3-fluorophenyl, 4-chlorophenyl, 4-fluorophenyl, 3,4difluorophenyl, 3,5-difluorophenyl, 3-chloro-4-fluorophenyl, 2,3,4-trifluorophenyl, 2 ,4,5-trifluorophenyl, 2,3,5-trifluorophenyl, 3,4,5-trifluorophenyl or 3-azido-2,4-difluorophenyl. Most preferably aryl

- 45 045018 groups are phenyl, 3-chlorophenyl, 3-fluorophenyl, 3,5-difluorophenyl, 2,3,4-trifluorophenyl,

2,4,5-trifluorophenyl, 2,3,5-trifluorophenyl, 3,4,5-trifluorophenyl or 3-azido-2,4-difluorophenyl.

As used herein, the term heterocycle is defined to include an aromatic or non-aromatic cycloalkyl moiety as defined above and containing at least one O, S and/or N atom interrupting the carbocyclic ring structure. The heterocyclic ring moieties may optionally be replaced by alkyl groups or halogen atoms, and optionally one of the carbon atoms of the carbocyclic ring structure may be replaced by a carbonyl. Typically, heterocyclic compounds are 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-tetrahydrofuranyl, N-pyrrol-2-yl, 1-methyl-Spyrrol- 2-yl, 1H-pyrazol-2-yl, 1H-pyrazol-3-yl, 4-chloro-1-methyl-1H-pyrazol-3-yl, 5-chloro-1,3-dimethyl1H-pyrazol-4- yl, 1,2,3-thiadiazol-4-yl, 3,5-dimethyl-4-isothiazyl, 1H-imidazol-2-yl, 1-methyl-Shimidazol-2-yl, 4-methyl-1H-imidazol- 5-yl or 2-methyl-1,3-thiazol-4-yl. Preferred heterocyclic compounds are 1H-imidazol-2-yl, 1,2,3-thiadiazol-4-yl, 1H-pyrazol-3-yl, 2furyl, 3-furyl, 2-thienyl, 1-methyl-1H-pyrrole -2-yl, Sh-pyrrol-2-yl.

As used herein, the term halogen includes chlorine, bromine, fluorine, iodine. Typically, halogens are chlorine, bromine and fluorine. Preferred halogens are fluorine, bromine and chlorine.

As used herein, the term hydroxy represents a group of the formula OH.

As used herein, the term alkoxy is a group of the formula -OR ^a where R ^a represents an alkyl group as defined above. A preferred alkoxy group is methoxy.

As used herein, the term aryloxy represents a group of the formula OR ^b , where R ^b represents an aryl group as defined above. A preferred aryloxy group is phenoxy.

As used herein, the term ester is a group of the formula -COORc, where R ^c represents an alkyl group or aryl group as defined above. A preferred ester group is methoxycarbonyl.

As used herein, the term amido represents a group of the formula -CONH2.

As used herein, the term amino represents a group of the formula -NH2.

As used herein, the term amino derivative is an alkylamino or arylamino group, wherein the terms alkyl and aryl are as defined above.

As used herein, the term cyano represents a group of the formula -CN.

As used herein, the term nitro represents a group of the formula -NO2.

As used herein, the term azido is a group of formula -N3.

As used herein, the term guanidine represents a group of the formula NHC(=NH)NH2.

As used herein, the term alkylthio is a group of the formula SR ^d where R ^d represents an alkyl group as defined above. A preferred alkylthio group is methylthio.

As used herein, the term alkylsulfonyl is a group of the formula -S(=O)2R ^e where R ^e represents an alkyl group as defined above. A preferred alkylsulfonyl group is methylsulfonyl.

As used herein, the term alkylsulfinyl is a group of the formula -S(=O)R ^f , where R ^f represents an alkyl group as defined above. A preferred alkylsulfonyl group is methylsulfinyl.

As used herein, the term arylthio is a group of the formula -SR ^g , where R ^g is an aryl group as defined above.

As used herein, the term arylsulfonyl is a group of the formula -S(=O)2R ^h where R ^h is an aryl group as defined above.

As used herein, the term arylsulfinyl is a group of formula -S(=O)R', where R ¹ represents an aryl group as defined above.

As used herein, the term carbamate is a group of the formula -N(H)C(O)ORj, wherein Rj is alkyl or aryl as defined above. Typically, carbamate groups are (propoxycarbonyl)amino or (benzyloxycarbonyl)amino. A preferred carbamate group is (benzyloxycarbonyl)amino.

As used herein, the term alkanoylamino represents a group of the formula -NHC(=O)R ^k where R ^k represents an alkyl group as defined above.

As used herein, the term (arylcarbonyl)amino represents a group of the formula NHC(=O)R ^m where R ^m represents an aryl group as defined above. A preferred (arylcarbonyl)amino is benzoylamino.

- 46 045018

Typically R ¹ is hydrogen; C _1-10 alkyl, unsubstituted or substituted with halogen, hydroxy, cyano, methylthio, phenyl or 4-chlorophenoxy; hydroxy; C _3-6 cycloalkyl; halogen; ester; amido; nitro; cyano; amino; phenyl; alkylthio; alkylsulfonyl; alkylsulfinyl; heterocycle, unsubstituted or substituted with alkyl groups; or guanidine. Preferably R ¹ represents hydrogen; methyl; ethyl; isopropyl; n-propyl; cyclopropyl; n-butyl; isobutyl; tert-butyl; 1ethylpropyl; 2,4,4-trimethylpentyl; hydroxymethyl; chloromethyl; trifluoromethyl; 2,2,2-trifluoroethyl; cyanomethyl; 2-(methylthio)ethyl; chlorine; bromine; nitro; cyano; amino; aminocarbonyl; methoxycarbonyl; methylthio; methylsulfinyl; methylsulfonyl; phenyl; 2-furyl; 3-furyl; Sh-pyrrol-2-yl; 1-methyl-1H-pyrrol2-yl; 2-thienyl; 1H-pyrazol-3-yl; 1,2,3-thiadiazol-4-yl or 1H-imidαzol-2-yl. More preferably, Rl is hydrogen; methyl; ethyl; isopropyl; n-propyl; n-butyl; methylthio; nitro; cyano; amino; chlorine or Ш-pyrrol-2-yl. Most preferably, Rl is hydrogen; methyl; methylthio; nitro; cyano; amino or chlorine.

Typically R ² is hydrogen; C ₁ . ₁₀ alkyl, unsubstituted or substituted hydroxy, alkanoylamino or benzoylamino; halogen; ester; cyano; alkylcarbamate; [(N-methoxy-Nmethyl)amino]carbonyl. Preferably R ² represents hydrogen; methyl; hydroxymethyl; (acetylamino)methyl; (propionylamino)methyl; (benzoylamino)methyl; [(benzyloxy)carbonyl]amino; chlorine or cyano. More preferably, R ² is hydrogen; chlorine or cyano.

Typically R ³ is hydrogen; C _{1_4} alkyl, unsubstituted or substituted hydroxy _; halogen; ester or cyano. Preferably R ³ is hydrogen; hydroxymethyl; chlorine; cyano. More preferably, R ³ is hydrogen or cyano. Most preferably, R ³ is hydrogen.

Typically R ⁴ is hydrogen; C ₁ . ₄ alkyl, unsubstituted or substituted with halogen atoms; _C2 . ₄ alkenyl substituted with halogen atoms; or a phenyl group, unsubstituted or substituted with azido and/or halogen atoms. Preferably R ⁴ is hydrogen; n-propyl; 2,2difluorovinyl; phenyl; 3-chlorophenyl; 3-fluorophenyl; 4-chlorophenyl; 4-fluorophenyl; 3,5-difluorophenyl; 3,4difluorophenyl; 3-chloro-4-fluorophenyl; 2,3,4-trifluorophenyl; 2,4,5-trifluorophenyl; 2,3,5-trifluorophenyl; 3,4,5trifluorophenyl; 3-azido-2,4-difluorophenyl or 3-azido-2,4,6-trifluorophenyl. More preferably, R ⁴ is hydrogen; n-propyl; 2,2-difluorovinyl; phenyl; 3-chlorophenyl; 3-fluorophenyl; 4chlorophenyl; 4-fluorophenyl; 3,5-difluorophenyl; 3,4-difluorophenyl; 3-chloro-4-fluorophenyl; 2,3,4-trifluorophenyl; 2,4,5-trifluorophenyl; 2,3,5-trifluorophenyl; 3,4,5-trifluorophenyl or 3-azido-2,4-difluorophenyl. Most preferably, R ⁴ is n-propyl; 2,2-difluorovinyl; phenyl; 3-chlorophenyl; 3-fluorophenyl; 3,5-difluorophenyl; 2,3,4-trifluorophenyl; 2,4,5-trifluorophenyl; 2,3,5-trifluorophenyl; 3,4,5-trifluorophenyl or 3-azido-2,4-difluorophenyl.

Typically R ^4a is hydrogen.

Typically R ⁵ is hydrogen.

Typically R ⁶ is hydrogen or C1_ ₁₀ alkyl, unsubstituted or substituted by hydroxy or azido.

Preferably R ⁶ is hydrogen or azidomethyl. More preferably, R ⁶ is hydrogen.

Typically R ⁷ is hydrogen.

In other preferred embodiments, ^R6 and ^R7 are coupled to form cyclopropyl.

In other preferred embodiments, R ² and R ³ may form together with the imidazole ring the following 1H-benzimidazole ring

Typically R ⁸ is hydrogen.

Typically R ⁹ is hydrogen; halogen; C _1-3 alkyl or alkoxy. Preferably R ⁹ is hydrogen; methyl; chlorine or methoxy. More preferably, R ⁹ is hydrogen.

Typically R ¹⁰ is hydrogen; halogen; cyano; C1. ₃ alkyl, unsubstituted or substituted with halogen atoms; or alkoxy. Preferably R ¹⁰ is methyl; hydrogen; trifluoromethyl; fluorine; cyano or methoxy. More preferably, R ¹⁰ is hydrogen; trifluoromethyl; fluorine or cyano.

Typically R ¹¹ is hydrogen.

In other preferred embodiments, R ⁴ , R ^4a and R ⁵ may form together with the 2oxo-1-pyrrolidine ring the following 1,3-dihydro-2H-indol-2-one ring

- 47 045018

Typically R ¹² is hydrogen or halogen. Preferably R ¹² represents hydrogen; chlorine or fluorine. More preferably, R ¹² is hydrogen.

Typically R ¹³ is hydrogen; O _1-3 alkyl; halogen or thiazolyl, unsubstituted or substituted with alkyl groups, such as methylthiazolyl. Preferably R ¹³ is hydrogen; chlorine; bromine or methyl. Most preferably, R ¹³ is chlorine; bromine or methyl.

Typically R ¹⁴ is hydrogen.

Typically R ¹⁵ is hydrogen.

Combinations of one or more of these preferred groups of compounds are particularly preferred.

In general, embodiments of the compounds of Formula I or pharmaceutically acceptable salts thereof include compounds in which

R ¹ is selected from hydrogen; O _1-10 alkyl, unsubstituted or substituted with halogen, hydroxy, cyano, methylthio, phenyl or 4-chlorophenoxy; C _3-6 cycloalkyl; halogen; ester; amido; nitro; cyano; amino; phenyl; alkylthio; alkylsulfonyl; alkylsulfinyl; heterocycle, unsubstituted or substituted with an alkyl group; or guanidine;

R ² is selected from hydrogen; C _1-4 alkyl, unsubstituted or substituted with hydroxy, alkanoylamino or benzoylamino; halogen; ester; cyano; alkylcarbamate or [(N-methoxy-Nmethyl)amino]carbonyl;

R ³ is selected from hydrogen; O _1-4 alkyl, unsubstituted or substituted with hydroxy; halogen; ester or cyano;

R ⁴ is selected from hydrogen; C _1-4 alkyl, unsubstituted or substituted with halogen atoms; C ₂₄ alkenyl substituted with halogen atoms, or phenyl group, unsubstituted or substituted with azido and/or halogen atoms;

R ^4a represents hydrogen;

R ⁵ represents hydrogen;

R ⁶ is selected from hydrogen or C _1-10 alkyl, unsubstituted or substituted hydroxy or azido;

R ⁷ represents hydrogen;

or R ⁶ and R ⁷ can be combined to form cyclopropyl;

or R ² and R ³ can form together with the imidazole ring the following 1H-benzimidazole ring

R ⁸ represents hydrogen;

R ⁹ is selected from hydrogen; halogen; C _1-3 alkyl; alkoxy;

R ¹⁰ is selected from hydrogen; halogen; cyano or C _1-3 alkyl, unsubstituted or substituted with halogen atoms; or alkoxy;

R ¹¹ represents hydrogen;

or R ⁴ , R ^4a and R ⁵ can form together with the 2-oxo-1-pyrrolidine ring the following 1,3dihydro-2H-indol-2-one ring

R ¹² is selected from hydrogen or halogen;

R ¹³ is selected from hydrogen; C _1-3 alkyl; halogen; thiazolyl, unsubstituted or substituted with alkyl groups, such as methylthiazolyl;

R ¹⁴ represents hydrogen;

R ¹⁵ represents hydrogen;

provided that ^R4 is other than hydrogen if

- 48 045018

R ²

represents a group of the formula

According to a preferred embodiment, the compounds of formula I, or pharmaceutically acceptable salts thereof, are compounds in which

R ¹ is selected from hydrogen; methyl; ethyl; isopropyl; n-cut; cyclopropyl; n-butyl; isobutyl; tert-butyl; 1-ethylpropyl; 2,4,4-trimethylpentyl; trifluoromethyl; 2,2,2-trifluoroethyl; hydroxymethyl; chloromethyl; cyanomethyl; 2-(methylthio)ethyl; chlorine; bromine; nitro; cyano; amino; aminocarbonyl; methoxycarbonyl; methylthio; methylsulfinyl; methylsulfonyl; phenyl; 2-furyl; 3-furyl; 1H-pyrrol-2-yl; 1-methyl-1H-pyrrol-2-yl; 2-thienyl; 1H-pyrazol-3-yl; 1,2,3-thiadiazol-4-yl; or 1 H-imidazol-2-yl;

R ² is selected from hydrogen; methyl; hydroxymethyl; (acetylamino)methyl; (propionylamino)methyl; (benzoylamino)methyl; (benzyloxycarbonyl)amine; chlorine or cyano;

R ³ is selected from hydrogen; hydroxymethyl; chlorine; cyano; or R ² and R ³ can form together with the imidazole ring the following III-benzimidazole ring

R ⁸ represents hydrogen;

R ⁹ is selected from hydrogen; methyl; chlorine; methoxy;

R ¹⁰ is selected from methyl; hydrogen; trifluoromethyl; fluorine; cyano or methoxy;

R ¹¹ represents hydrogen;

R ⁴ is selected from hydrogen; n-cut; 2,2-difluorovinyl; phenyl; 3-chlorophenyl; 3-fluorophenyl; 4chlorophenyl; 4-fluorophenyl; 3,5-difluorophenyl; 3,4-difluorophenyl; 3-chloro-4-fluorophenyl; 2,3,4trifluorophenyl; 2,4,5-trifluorophenyl; 2,3,5-trifluorophenyl; 3,4,5-trifluorophenyl; 3-azido-2,4difluorophenyl or 3-azido-2,4,6-trifluorophenyl;

R ^4a represents hydrogen;

R ⁵ represents hydrogen;

or R ⁴ , R ^4a and R ⁵ can form together with the 2-oxo-1-pyrrolidine ring the following 1,3dihydro-2H-indol-2-one ring

R ¹

R ¹² is selected from hydrogen; chlorine; fluorine;

R ¹³ is selected from hydrogen; chlorine; bromine; methyl;

R ¹⁴ represents hydrogen;

R ¹⁵ represents hydrogen;

R ⁶ is selected from hydrogen; azidomethyl;

R ⁷ represents hydrogen;

or R ⁶ and R ⁷ are associated to form cyclopropyl;

provided that ^R4 is other than hydrogen if

R ²

represents a group of the formula

- 49 045018

According to a more preferred embodiment, the compounds of formula I or a pharmaceutically acceptable salt thereof are compounds in which

R ¹ is selected from hydrogen; methyl; ethyl; isopropyl; n-cut; n-butyl; methylthio; nitro; cyano; amino; chlorine or 1H-πpyrrol-2-yl;

R ² is selected from hydrogen; chlorine; cyano;

R ³ is selected from hydrogen; cyano;

or R ² and R ³ can form together with the imidazole ring the following 1H-benzimidazole ring

R ⁸ represents hydrogen;

R ⁹ represents hydrogen;

R ¹⁰ is selected from hydrogen; trifluoromethyl; fluorine; cyano;

R ¹¹ represents hydrogen;

R ⁴ is selected from hydrogen; n-cut; 2,2-difluorovinyl; phenyl; 3-chlorophenyl; 3-fluorophenyl; 4chlorophenyl; 4-fluorophenyl; 3,5-difluorophenyl; 3,4-difluorophenyl; 3-chloro-4-fluorophenyl; 2,3,4trifluorophenyl; 2,4,5-trifluorophenyl; 2,3,5-trifluorophenyl; 3,4,5-trifluorophenyl or 3-azido-2,4difluorophenyl;

R ^4a represents hydrogen;

R ⁵ represents hydrogen;

or R ⁴ , R ^4a and R ⁵ can form together with the 2-oxo-1-pyrrolidine ring the following 1,3dihydro-2H-indol-2-one ring

Where

R ¹² represents hydrogen;

R ¹³ is selected from methyl; chlorine; bromine;

R ¹⁴ represents hydrogen;

R ¹⁵ represents hydrogen;

R ⁶ represents hydrogen;

R ⁷ represents hydrogen;

with the proviso that R ⁴ is other than hydrogen if it is a group of the formula

In a most preferred embodiment, the compounds of formula I or a pharmaceutically acceptable salt thereof are compounds in which

R ¹ is selected from hydrogen; methyl; methylthio; nitro; cyano; amino; chlorine;

R ² is selected from hydrogen; chlorine; cyano;

- 50 045018

R ³ represents hydrogen;

R ⁴ is selected from n-propyl; 2,2-difluorovinyl; phenyl; 3-chlorophenyl; 3-fluorophenyl; 3,5difluorophenyl; 2,3,4-trifluorophenyl; 2,4,5-trifluorophenyl; 2,3,5-trifluorophenyl; 3,4,5-trifluorophenyl;

3-azido-2,4-difluorophenyl;

R ^4a represents hydrogen;

R ⁵ represents hydrogen;

or R ⁴ , R ^4a and R ⁵ can form together with the 2-oxo-1-pyrrolidine ring the following 1,3dihydro-2H-indol-2-one ring

R ¹² represents hydrogen;

R ¹³ is selected from chlorine; bromine; methyl;

R ¹⁴ represents hydrogen;

R ¹⁵ represents hydrogen;

R ⁶ represents hydrogen;

R ⁷ represents hydrogen.

In some embodiments, the compounds useful in the methods and compositions of the present invention are selected from the group consisting of 1-(1H-imidazol-1ylmethyl)pyrrolidin-2-one; 1-(1H-imidazol-1-ylmethyl)-4-phenylpyrrolidin-2-one; 4-(3-azido-2,4,6trifluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 1-(1H-imidazol-1-ylmethyl)-4-propylpyrrolidin-2-one; (-)-4-(3-azido-2,4-difluorophenyl)-1-(1 H-imidazol-1 -ylmethyl)pyrrolidin-2-one; (+)-4-(3azido-2,4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 1-[(2-ethyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(2-isopropyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(2-methyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(2-phenyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 4-propyl-1-[(2-propyl-1H-imidazol-1-yl)methyl]pyrrolidin-2-one; (+)-1 -(1 H-imidazol-1 -ylmethyl)-4-propylpyrrolidin-2-one; (-)-1-(1 H-imidazol-1 -ylmethyl)-4-propylpyrrolidin-2-one; 4-(2,2-difluorovinyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 4-(3-chlorophenyl)1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 1-{[2-(methylthio)-1H-imidazol-1-yl}methyl}-4-propylpyrrolidin-2-one; 1-{[2-(methylsulfinyl)-1H-imidazol-1-yl]methyl}-4-propylpyrrolidin-2-one; 1-[(2tert-butyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-[1-(1H-imidazol-1-yl)cyclopropyl]pyrrolidin-2-one; 1-[(2-methyl-1H-imidazol-1-yl)methyl]-4-phenylpyrrolidin-2-one; 1-{[2-(methylsulfonyl)-1H-imidazol-1-yl]methyl}propylpyrrolidin-2-one; 1-[(2-oxo-4-propylpyrrolidin-1yl)methyl]-1 H-imidazol-2-carboxamide, 4-(4-fluorophenyl)-1-(1 H-imidazol-1 -ylmethyl)pyrrolidin-2- she; 1-(1H-imidazol-1-ylmethyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one; 4-(3-fluorophenyl)-1-(1H-imidazol1 -ylmethyl)pyrrolidin-2-one; 4-(3,5-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 4-(3,4difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 4-(3-chloro-4-fluorophenyl)-1-(1H-imidazol-1 ylmethyl)pyrrolidin-2-one; 4-(4-chlorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 1-(1Himidazol-1-ylmethyl)-4-(2,3,4-trifluorophenyl)pyrrolidin-2-one; 1-(1H-imidazol-1-ylmethyl)-4-(2,3,5trifluorophenyl)pyrrolidin-2-one; 1-(1H-imidazol-1-ylmethyl)-4-(2,4,5-trifluorophenyl)pyrrolidin-2-one; 1-{[2-(hydroxymethyl)-1H-imidazol-1-yl]methyl}-4-propylpyrrolidin-2-one; methyl-1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazole-2-carboxylate; 1-[(2-nitro-1H-imidazol-1-yl)methyl]-4(3,4,5-trifluorophenyl)pyrrolidin-2-one; 1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1Nimidazole-2-carbonitrile; 1-[(2-amino-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(2,4dichloro-1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one; 1-[(5-chloro-1H-imidazol-1 yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one; 1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1yl]methyl}-1H-imidazole-4-carbonitrile; 1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}1 H-imidazole-5-carbonitrile; (+)-1-(1H-imidazol-1-ylmethyl)-4-phenylpyrrolidin-2-one; (-)-1-(1Himidazol-1-ylmethyl)-4-phenylpyrrolidin-2-one; 1-{[2-oxo-4-(2,3,5-trifluorophenyl)pyrrolidin-1 -yl]methyl}-1 H-imidazole-5-carbonitrile; (-)-1-{[2-oxo-4-(2,3,4-trifluorophenyl)pyrrolidin-1-yl]methyl}-1Himidazole-5-carbonitrile; (+)-1-{[2-oxo-4-(2,3,4-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole5-carbonitrile; (-)-1-{[2-oxo-4-(2,3,4-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-4-carbonitrile; (+)-1-{[2-oxo-4-(2,3,4-trifluorophenyl)-1-pyrrolidinyl]methyl}-1 H-imidazole-4-carbonitrile; (-)-1-{ [2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1 -yl]methyl} -1 H-imidazole-4-carbonitrile; (+)-1 {[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1 -yl]methyl }-1 H-imidazole-4-carbonitrile; (+)-1-{[2-oxo4-(2,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-4-carbonitrile; (-)-1-{[2-oxo-4-(2,4,5trifluorophenylpyrrolidin-1-yl]methyl}-1H-imidazole-4-carbonitrile; (-)-1-{[2oxo-4-(2 ,3,5-trifluorophenyl)pyrrolidin-1-yl]methyl }-1 H-imidazole-4-carbonitrile; (-)-1-{ [2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidine- 1-yl]methyl}-1 H-imidazol-5-carbonitrile; 5-carbonitrile; 1-{[2-oxo-4-(2,3,5-trifluorophenyl)pyrrolidin-1-yl]methyl}1H-imidazol-5-carbonitrile; 1-[(5-methyl-2-phenyl -1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2one; 1 -[(5-methyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1 -[( 5-phenyl-1H-imidazol-1yl)methyl]-4-propylpyrrolidin-2-one;1-[(2-ethyl-5-methyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin- 2-one; 1-[(2,5-dimethyl-1 H-imidazol-1 -yl)methyl]-4-propylpyrrolidin-2-one; 1 -[(2-chloro-1Himidazol-1 -yl)methyl] -4-(3,4,5-trifluorophenyl)pyrrolidin-2-one; 1 -[2-azido-1-(1 H-imidazol-1 -yl)ethyl] 4-propylpyrrolidin-2-one; 1-[ (4-chloro-1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2one; 1-[(2-bromo-4,5-dichloro-III-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(2-chloro-1H-imidazol-1 -yl)methyl]-4-propylpyrrolidin-2-one; (+)-1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1 yl]methyl}-1H-imidazole-5-carbonitrile; 1-{[5-(hydroxymethyl)-1H-imidazol-1-yl]methyl}-4-propylpyrrolidin-2-one; 1-{[4-(hydroxymethyl)-1 H-imidazol-1 -yl]methyl}-4-propylpyrrolidin-2-one; benzyl-1 [(2-oxo-4-propylpyrrolidin-1 -yl)methyl]-1 H-imidazol-5 -ylcarbamate; N-[(1-{ [2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1 -yl]methyl} - 1H-imidazol-5-yl)methyl]acetamide; N-[(1-{ [2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1 -yl]methyl} - 1H-imidazol-5-yl)methyl]benzamide; N-[(1-{ [2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1 -yl]methyl} - 1H-imidazol-5-yl)methyl]propanamide; 1-(1H-benzimidazol-1 -ylmethyl)4-propylpyrrolidin-2-one; 1 -[(2-methyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 4propyl-1-[(2-propyl-1H-benzimidazol-1-yl)methyl]pyrrolidin-2-one; 1 -[(2-isopropyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 4-propyl-1-{[2-(trifluoromethyl)-1 H-benzimidazol-1 yl]methyl}pyrrolidin-2-one; 1-{[2-(methylthio)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2one; 1 -[(2-amino-1 H-benzimidazol-1 -yl)methyl]-4-propylpyrrolidin-2-one; 1-{[2-(chloromethyl)-1Hbenzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one; {1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]1 H-benzimidazol-2-yl} acetonitrile; 1 -[(5-methoxy-1 H-benzimidazol-1 -yl)methyl]-4-propylpyrrolidin-2-one; 1-[(5-methyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(5,6-dimethyl-1Hbenzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-{[2-isopropyl-5-(trifluoromethyl)-1H-benzimidazol-1 -yl]methyl}-4-propylpyrrolidin-2-one; 1 -[(6-chloro-1 H-benzimidazol-1 -yl)methyl]-4-propylpyrrolidin-2-one; 1 -[(2-oxo-4-propylpyrrolidin-1 -yl)methyl]-2-propyl-1 H-benzimidazole-5-carbonitrile; 1-{[2-ethyl-5-(trifluoromethyl)-1 H-benzimidazol-1 -yl]methyl}-4-propylpyrrolidin-2-one; 4-propyl-1-{[2(1H-pyrrol-2-yl)-1H-benzimidazol-1-yl]methyl}pyrrolidin-2-one; 1 -[(5-fluoro-2-propyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1 - {[6-methyl-2-(1H-pyrrol-2-yl)-1H-benzimidazol-1yl]methyl}-4-propylpyrrolidin-2-one; 1-[(6-methoxy-2-propyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 2-butyl-1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1 H-benzimidazole-5-carbonitrile; 1-{[2-[2-(methylthio)ethyl]-5-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one; 1 -[(5-fluoro-2-isobutyl-1H-benzimidazol-1 -yl)methyl]-4-propylpyrrolidin-2-one; 1-{[5fluoro-2-(2,4,4-trimethylpentyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one; 2-cyclopropyl-1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-benzimidazole-5-carbonitrile; 1-[(2-oxo-4-propylpyrrolidin-1 -yl)methyl]-2-(1 H-pyrazol-3 -yl)-1 H-benzimidazol-5-carbonitrile; 1 -[(2-cyclopropyl-5fluoro-1 H-benzimidazol-1 -yl)methyl]-4-propylpyrrolidin-2-one; 1-[(5-fluoro-2-isopropyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-{[2-(3-furyl)-6-methoxy-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one; 1 -[(2-cyclopropyl-6-methoxy-1 H-benzimidazol-1 -yl)methyl]-4-propylpyrrolidin-2-one; 1 -[(2-isopropyl-6-methoxy-1 H-benzimidazol-1 -yl)methyl]-4-propylpyrrolidin-2one; 1-[(2-oxo-4-propylpyrrolidin-1 -yl)methyl]-2-(1,2,3-thiadiazol-4-yl-)-1 H-benzimidazol-5-carbonitrile; 1-{[2-(1H-imidazol-2-yl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one; 1-{[5-fluoro-2-(2,2,2-trifluoroethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2one; 1-{[2-(1-ethylpropyl)-6-methoxy-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one; 1-{[6methoxy-2-(1 -methyl-1 H-pyrrol-2-yl)-1 H-benzimidazol-1 -yl]methyl}-4-propylpyrrolidin-2-one; 1-{[2(2-furyl)-5-(trifluoromethyl)-1 H-benzimidazol-1 -yl]methyl}-4-propylpyrrolidin-2-one; 4-propyl-1-{[2thien-2-yl-5-(trifluoromethyl)-1 H-benzimidazol-1 -yl]methyl}pyrrolidin-2-one; 1-{[2-(3-furyl)-5 -(trifluoromethyl)-1 H-benzimidazol-1 -yl]methyl}-4-propylpyrrolidin-2-one; 1-{[2-cyclopropyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one; 4-propyl-1-{[2-(1H-pyrrol-2-yl)-5(trifluoromethyl)-1 H-benzimidazol-1 -yl]-methyl}pyrrolidin-2-one; 1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one; 5-bromo-1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one; 5-chloro-1 -(1Himidazol-1 -ylmethyl)-1,3-dihydro-2H-indol-2-one; 4-fluoro-1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2Nindol-2-one; 4-chloro-1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one; 1-(1H-imidazol-1-ylmethyl)-5-methyl-1,3-dihydro-2H-indol-2-one; 1 -[(2-oxo-2,3-dihydro-1 H-indol-1 -yl)methyl]-1 H-imidazole-5-carbonitrile and 1-[(5-chloro-2-oxo-2,3 -dihydro-1H-indol-1-yl)methyl]-1H-imidazole-5-carbonitrile.

In some embodiments, the compounds useful in the methods and compositions of the present invention are selected from the group consisting of 1-(1H-imidazol-1ylmethyl)pyrrolidin-2-one, 1-(1H-imidazol-1-ylmethyl)-4 -phenylpyrrolidin-2-one; 1-(1H-imidazol-1ylmethyl)-4-propylpyrrolidin-2-one; (-)-4-(3 -azido-2,4-difluorophenyl)-1 -(1 H-imidazol-1 -ylmethyl)pyrrolidin-2-one; (+)-4-(3 -azido-2,4-difluorophenyl)-1 -(1 H-imidazol-1 -ylmethyl)pyrrolidin-2-one; 1-[(2ethyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(2-isopropyl-1 H-imidazol-1 -yl)methyl]-4- 52 045018 propylpyrrolidin-2-one; 1 -[(2-methyl-1 H-imidazol-1 -yl)methyl]-4-propylpyrrolidin-2-one; 4-propyl1-[(2-propyl-1H-imidazol-1-yl)methyl]pyrrolidin-2-one; (+)-1 -(1 H-imidazol-1 -ylmethyl)-4-propylpyrrolidin-2-one; (-)-1 -(1 H-imidazol-1 -ylmethyl)-4-propylpyrrolidin-2-one; 4-(2,2-difluorovinyl)-1-(1Himidazol-1-ylmethyl)pyrrolidin-2-one; 4-(3-chlorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;

1-{[2-(methylthio)-1H-imidazol-1-yl]methyl}-4-propylpyrrolidin-2-one; 1 -[(2-methyl-1 H-imidazol-1 yl)methyl]-4-phenylpyrrolidin-2-one; 4-(4-fluorophenyl)-1 -(1 H-imidazol-1 -ylmethyl)pyrrolidin-2-one; 1 (1 H-imidazol-1 -ylmethyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one; 4-(3-fluorophenyl)-1-(1H-imidazol-1 ylmethyl)pyrrolidin-2-one; 4-(3,5-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 4-(3,4difluorophenyl)-1 -(1H-imidazol-1 -ylmethyl)pyrrolidin-2-one; 4-(3-chloro-4-fluorophenyl)-1-(1H-imidazol-1 ylmethyl)pyrrolidin-2-one; 4-(4-chlorophenyl)-1 -(1 H-imidazol-1 -ylmethyl)pyrrolidin-2-one; 1-(1Himidazol-1-ylmethyl)-4-(2,3,4-trifluorophenyl)pyrrolidin-2-one; 1-(11 H-imidazol-1 -ylmethyl)-4-(2,3,5trifluorophenyl)pyrrolidin-2-one; 1-(1H-imidazol-1-ylmethyl)-4-(2,4,5-trifluorophenyl)pyrrolidin-2-one; 1-[(2-nitro-1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one; 1-{[2-oxo-4-(3,4,5trifluorophenyl)pyrrolidin-1 -yl]methyl}-1 H-imidazole-2-carbonitrile; 1-[(2-amino-1H-imidazol-1 yl)methyl]-4-propylpyrrolidin-2-one; 1-[(5-chloro-1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one; 1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-4-carbonitrile; 1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile; (+)-1(1H-imidazol-1-ylmethyl)-4-phenylpyrrolidin-2-one; (-)-1-(1H-imidazol-1-ylmethyl)-4-phenylpyrrolidin-2-one; (+)-1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-4-carbonitrile; 1 -[(2-chloro-1 H-imidazol-1 -yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one; 1 -[2-azido-1 (1 H-imidazol-1 -yl)ethyl]-4-propylpyrrolidin-2-one; 1-[(2-chloro-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; (+)-1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5carbonitrile; 1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-2-propyl-1H-benzimidazole-5-carbonitrile; 1-{[2-ethyl-5-(trifluoromethyl)-1 H-benzimidazol-1 -yl]methyl}-4-propylpyrrolidin-2-one; 4-propyl-1-{[2(1H-pyrrol-2-yl)-1H-benzimidazol-1-yl]methyl}pyrrolidin-2-one; 1 -[(5-fluoro-2-propyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 2-butyl-1-[(2-oxo-4-propylpyrrolidin-1 -yl)methyl]-1Hbenzimidazole-5-carbonitrile; 1-[(5-fluoro-2-isopropyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one; 5-bromo-1-(1H-imidazol-1ylmethyl)-1,3-dihydro-2H-indol-2-one; 5-chloro-1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one; 1-(1H-imidazol-1-ylmethyl)-5-methyl-1,3-dihydro-2H-indol-2-one; 1-[(5-chloro-2-oxo-2,3-dihydro-1Nindol-1-yl)methyl]-1H-imidazole-5-carbonitrile.

In some embodiments, the compounds useful in the methods and compositions of the present invention are selected from the group consisting of 1-(1H-imidazol-1-ylmethyl)-4phenylpyrrolidin-2-one; 1-(1H-imidazol-1-ylmethyl)-4-propylpyrrolidin-2-one; (-)-4-(3 -azido-2,4difluorophenyl)-1 -(1H-imidazol-1 -ylmethyl)pyrrolidin-2-one; (+)-4-(3-azido-2,4-difluorophenyl)-1-(1Himidazol-1-ylmethyl)pyrrolidin-2-one; 4-(2,2-difluorovinyl)-1 -(1 H-imidazol-1 -ylmethyl)pyrrolidin-2one; 4-(3-chlorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 1-{[2-(methylthio)-1 H-imidazol-1 yl]methyl}-4-propylpyrrolidin-2-one; 1-[(2-methyl-1H-imidazol-1-yl)methyl]-4-phenylpyrrolidin-2-one; 1-(1H-imidazol-1-ylmethyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one; 4-(3-fluorophenyl)-1-(1H-imidazol1 -ylmethyl)pyrrolidin-2-one; 4-(3,5-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 1-(1Himidazol-1-ylmethyl)-4-(2,3,4-trifluorophenyl)pyrrolidin-2-one; 1-(1H-imidazol-1-ylmethyl)-4-(2,3,5trifluorophenyl)pyrrolidin-2-one; 1-(1H-imidazol-1-ylmethyl)-4-(2,4,5-trifluorophenyl)pyrrolidin-2-one; 1-[(2-nitro-1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one; 1-{[2-oxo-4-(3,4,5trifluorophenyl)pyrrolidin-1 -yl]methyl} -1 H-imidazole-2-carbonitrile; 1-[(2-amino-1H-imidazol-1 yl)methyl]-4-propylpyrrolidin-2-one; 1-[(5-chloro-1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one; (+)-1-(1H-imidazol-1-ylmethyl)-4-phenylpyrrolidin-2-one; (-)-1 -(1H-imidazol-1 ylmethyl)-4-phenylpyrrolidin-2-one; 1-[(2-chloro-1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one; 1-[(2-chloro-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; (+)-1-{ [2-oxo-4-(3,4,5trifluorophenyl)pyrrolidin-1 -yl]methyl} -1 H-imidazole-5-carbonitrile; 5-bromo-1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one; 5 -chloro-1 -(1 H-imidazol-1 -ylmethyl)-1,3-dihydro-2H-indol-2-one; 1 (1 H-imidazol-1 -ylmethyl)-5-methyl-1,3-dihydro-2H-indol-2-one; 1-[(5-chloro-2-oxo-2,3-dihydro-1Hindol-1-yl)methyl]-1H-imidazole-5-carbonitrile.

In some embodiments, the compounds useful in the methods and compositions of the present invention are selected from the group consisting of (-)-4-(3-azido-2,4difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidine -2-she; (+)-4-(3-azido-2,4-difluorophenyl)-1-(1Himidazol-1-ylmethyl)pyrrolidin-2-one; 4-(3 -azido-2,4-difluorophenyl)-1 -(1 H-imidazol-1 -ylmethyl)pyrrolidin-2-one.

v) International patent application WO 2007/065595: Compounds characterized by formula I, their enantiomers, diastereoisomers and mixtures thereof (including all possible mixtures of stereoisomers), or pharmaceutically acceptable salts thereof

- 53 045018

Where

R ¹ represents hydrogen or C1-6alkyl;

R ² represents hydrogen or C _1-4 alkyl;

R ³ represents a group of the formula -CHR ⁵ R6 or a benzyl group;

R ⁴ represents C _1-8 alkyl, optionally substituted with alkoxycarbonyl, C _3-6 cycloalkyl, aryl or heterocycle;

R ⁵ represents C _2-4 alkyl;

R ⁶ represents C _2-4 alkyl, amido or -COOR ⁷ ;

R ⁷ represents C _1-4 alkyl;

Typically, if R ³ represents a benzyl group, then R ⁴ represents C _1-8 alkyl, optionally substituted with alkoxycarbonyl.

In general, if R ³ is a group of formula -CHR ⁵ R ⁶ , then R ⁴ is C _1-8 alkyl, optionally substituted with C _3-6 cycloalkyl, aryl or heterocycle.

As used herein, the term alkyl is a group that represents saturated, monovalent hydrocarbon radicals containing straight or branched moieties, or combinations thereof, and containing 1-8 carbon atoms, preferably 1-6 carbon atoms; more preferably alkyl groups containing 1 to 4 carbon atoms. The alkyl moieties may optionally be substituted with 1-5 substituents independently selected from the group consisting of hydroxy, alkoxy, cyano, ethynyl, alkoxycarbonyl, acyl, aryl or heterocycle. Alkyl moieties may be optionally substituted with cycloalkyl, as defined below. Preferred alkyl groups are methyl, cyanomethyl, ethyl, 2-ethoxy-2oxoethyl, 2-methoxyethyl, n-propyl, 2-oxopropyl, 3-hydroxypropyl, 2-propynyl, n-butyl, isobutyl, npentyl, 3-pentyl, n -hexyl, cyclohexylmethyl, benzyl, 2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, 3-methoxybenzyl, 3-nitrobenzyl, 3-aminobenzyl, 4-(aminosulfonyl)benzyl, 1-phenylethyl, 2-phenylethyl, (3,5-dimethylisoxazole -4-yl)methyl or (5-nitro-2-furyl)methyl. More preferred alkyl groups are methyl, ethyl, cyanomethyl, 2-methoxyethyl, n-propyl, 3-hydroxypropyl, 2-propynyl, n-butyl, 3-pentyl, n-hexyl, benzyl, 3-bromobenzyl, 3-methoxybenzyl, 3- nitrobenzyl, 3-aminobenzyl, (3,5-dimethylisoxazol-4-yl)methyl or (5-nitro-2-furyl)methyl. The most preferred alkyl groups are methyl, ethyl, 3-methoxybenzyl, 3-nitrobenzyl or (5-nitro2-furyl)methyl.

As used herein, the term cycloalkyl is a monovalent group of 3-8, preferably 3-6, carbon atoms derived from a saturated cyclic hydrocarbon, which may be substituted by any suitable group, including without limitation one or more moieties selected from the groups described higher for alkyl groups. A preferred cycloalkyl group is cyclohexyl.

As used herein, the term aryl is defined as a phenyl group optionally substituted with 1-4 substituents independently selected from halogen, amino, nitro, alkoxy or aminosulfonyl. Preferred aryl groups are phenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 3-methoxyphenyl, 3-nitrophenyl, 3-aminophenyl or 4-(aminosulfonyl)phenyl.

As used herein, the term phenyl is an aromatic hydrocarbon group of the formula -C6H5.

As used herein, the term benzyl group is a group of the formula -CH ₂ -aryl. Preferred benzyl groups are benzyl, 2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, 3-methoxybenzyl, 3-nitrobenzyl, 3-aminobenzyl or 4-(aminosulfonyl)benzyl. More preferably, the benzyl groups are benzyl, 3-bromobenzyl, 3-methoxybenzyl, 3-nitrobenzyl or 3-aminobenzyl.

The most preferred alkyl groups are 3-methoxybenzyl or 3-nitrobenzyl.

As used herein, the term halogen represents a fluorine, chlorine, bromine or iodine atom. The preferred halogen is bromine.

As used herein, the term hydroxy represents a group of the formula -OH.

As used herein, the term cyano represents a group of the formula -CN.

As used herein, the term amino represents a group of the formula -NH ₂ .

As used herein, the term ethynyl represents a group of the formula -C CH.

As used herein, the term alkoxy is a group of the formula -OR ^a ,

- 54 045018 where R ^a represents an alkyl group as defined above. A preferred alkoxy group is methoxy.

As used herein, the term nitro represents a group of the formula -NO2.

As used herein, the term amido represents a group of the formula -C(=O)NH ₂ .

As used herein, the term acyl is a group of the formula -C(=O)R ^b where R ^b is an alkyl group as defined above. The preferred acyl group is acetyl (-C(=O)Me).

As used herein, the term alkoxycarbonyl (or ester) is a group of the formula -COOR ^c wherein R ^c is an alkyl group; with the proviso that R ^c is not alkyl, α-substituted hydroxy. A preferred alkoxycarbonyl group is ethoxycarbonyl.

As used herein, the term heterocycle is a 5-membered ring containing one or two heteroatoms selected from O or N. The heterocyclic compound may be substituted with one or two C _1-4 alkyls or nitro. Preferred heterocyclic compounds are (3,5-dimethylisoxazol-4-yl) or (5-nitro-2-furyl). The most preferred heterocyclic compound is (5-nitro-2-furyl).

Typically, R ¹ represents hydrogen or C1_6alkyl. Typically R ¹ is hydrogen or C1_ ₆ alkyl, optionally substituted with hydroxy, alkoxy, cyano, ethynyl, alkoxycarbonyl or acyl. Preferably, R ¹ is hydrogen, methyl, cyanomethyl, 2-ethoxy-2-oxoethyl, 2-methoxyethyl, n-propyl, 2-oxopropyl, 3-hydroxypropyl, 2-propynyl, n-pentyl or n-hexyl. More preferably, R ¹ is hydrogen, methyl, cyanomethyl, 2-methoxyethyl, n-propyl, 3hydroxypropyl or 2-propynyl. Most preferably, R ¹ is hydrogen.

Typically, R ² is hydrogen or C1_4alkyl. Typically ^R2 is hydrogen or unsubstituted _{C1_4} alkyl. Preferably R ² is hydrogen, methyl or n-butyl. More preferably, R ² is methyl.

Typically, R ³ is a group of the formula -CHR5R ⁶ or a benzyl group. Preferably, R ³ is 3-pentyl, 1-(aminocarbonyl)propyl, 1-(ethoxycarbonyl)propyl or 3-bromobenzyl. Most preferably, R ³ is 1-(ethoxycarbonyl)propyl.

Typically, R ⁴ is C1_8alkyl, optionally substituted with alkoxycarbonyl, C3_6cycloalkyl, aryl or heterocycle. Typically, R ⁴ is C1_ ₈ αlkyl, optionally substituted with cyclohexyl, phenyl, bromophenyl, aminophenyl, methoxyphenyl, nitrophenyl, aminosulfonylphenyl, 3,5-dimethylisoxazol-4-yl, 5-nitro-2-furyl or ethoxycarbonyl. Preferably, R ⁴ is n-butyl, isobutyl, n-pentyl, n-hexyl, cyclohexylmethyl, benzyl, 2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, 3-methoxybenzyl, 3-nitrobenzyl, 3-aminobenzyl, 4( aminosulfonyl)benzyl, 1-phenylethyl, 2-phenylethyl, (3,5-dimethylisoxazol-4-yl)methyl, (5-nitro-2furyl)methyl or 1-(ethoxycarbonyl)propyl. More preferably, R ⁴ is n-butyl, ngexyl, benzyl, 3-bromobenzyl, 3-methoxybenzyl, 3-nitrobenzyl, 3-aminobenzyl, (3,5-dimethylisoxazol4-yl)methyl, (5-nitro-2-furyl) methyl or 1-(ethoxycarbonyl)propyl. Most preferably, R ⁴ is 3-methoxybenzyl, 3-nitrobenzyl or (5-nitro-2-furyl)methyl.

Typically, R ⁵ is C2_4alkyl. Typically ^R5 is unsubstituted C24alkyl. Preferably R ⁵ is ethyl.

Typically, R ⁶ is C2_4alkyl, amido or -COOR ⁷ . Typically R ⁶ is unsubstituted C2_ ₄ alkyl, amido or -COOR ⁷ . Preferably R ⁶ is ethyl, amido or ethoxycarbonyl. Most preferably, R ⁶ is ethoxycarbonyl.

Typically, R ⁷ is C1_4alkyl. Typically R ⁷ is unsubstituted C1_ ₄ alkyl. Preferably R ⁷ is ethyl.

In some embodiments, the compounds are compounds characterized by Formula I, and their enantiomers, diastereoisomers, and mixtures thereof (including all possible mixtures of stereoisomers), or pharmaceutically acceptable salts thereof where

R ¹ represents hydrogen, C _{1_6} alkyl, optionally substituted with hydroxy, alkoxy, cyano, ethynyl, alkoxycarbonyl or acyl _;

R ² represents hydrogen or _{unsubstituted} C _{1_4} alkyl;

R ³ represents a group of the formula -CHR ⁵ R ⁶ or a benzyl group;

R ⁴ represents C ₁ _ ₈ alkyl, optionally substituted with cyclohexyl, phenyl, bromophenyl, aminophenyl, methoxyphenyl, nitrophenyl, aminosulfonylphenyl, 3,5-dimethylisoxazole-55 045018

4-yl, 5-nitro-2-furyl or ethoxycarbonyl;

R ⁵ represents unsubstituted C _2-4 alkyl;

R ⁶ represents unsubstituted C ₂ . ₄ alkyl, amido or -COOR ⁷ ;

R ⁷ represents unsubstituted C ₁ . ₄ alkyl;

with the proviso that if R ¹ is hydrogen, R ² is methyl, R ³ is -CHR5R ⁶ , R ⁶ is ethoxycarbonyl, and R ⁵ is ethyl, then R ⁴ is other than n-propyl, isopropyl, n -pentyl, n-heptyl, 3-bromobenzyl, 4-chlorobenzyl, 4-methylbenzyl or 2phenylethyl.

According to the above embodiment, it is preferable that if R ³ represents a benzyl group, then R ⁴ represents C^alkyl, optionally substituted with alkoxycarbonyl.

According to the above embodiment, it is preferable that if R ³ represents a group of the formula -CHR5R ⁶ , then R ⁴ represents C ₁ . ₈ alkyl, optionally substituted with C ₃ . ₆ cycloalkyl, aryl or heterocycle.

In a preferred embodiment, R ¹ is hydrogen, methyl, cyanomethyl, 2-ethoxy-2-oxoethyl, 2-methoxyethyl, n-propyl, 2-oxopropyl, 3-hydroxypropyl, 2-propynyl, n-pentyl or n-hexyl;

R ² represents hydrogen, methyl or n-butyl;

R ³ is 3-pentyl, 1-(aminocarbonyl)propyl, 1-(ethoxycarbonyl)propyl or 3-bromobenzyl;

R ⁴ is n-butyl, isobutyl, n-pentyl, n-hexyl, cyclohexylmethyl, benzyl, 2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, 3-methoxybenzyl, 3-nitrobenzyl, 3-aminobenzyl, 4(aminosulfonyl)benzyl, 1-phenylethyl, 2-phenylethyl, (3,5-dimethylisoxazol-4-yl)methyl, (5-nitro-2furyl)methyl or 1-(ethoxycarbonyl)propyl;

with the proviso that if R ¹ is hydrogen, R ² is methyl and R ³ is 1-(ethoxycarbonyl)propyl, then R ⁴ is other than n-pentyl, 3-bromobenzyl or 2-phenylethyl.

According to the above embodiment, it is preferable that if R ³ represents 3-bromobenzyl, then R ⁴ represents C ₁ . ₈ alkyl, optionally substituted with alkoxycarbonyl.

According to the above embodiment, it is preferable that if R ³ is 3-pentyl, 1-(aminocarbonyl)propyl or 1-(ethoxycarbonyl)propyl, then R ⁴ is other than 1(ethoxycarbonyl)propyl.

In a more preferred embodiment, R ¹ is hydrogen, methyl, cyanomethyl, 2-methoxyethyl, n-propyl, 3-hydroxypropyl or 2-propynyl;

R ² represents methyl;

R ³ is 3-pentyl, 1-(aminocarbonyl)propyl, 1-(ethoxycarbonyl)propyl or 3-bromobenzyl;

R ⁴ is n-butyl, n-hexyl, benzyl, 3-bromobenzyl, 3-methoxybenzyl, 3-nitrobenzyl, 3-aminobenzyl, (3,5-dimethylisoxazol-4-yl)methyl, (5-nitro-2-furyl) methyl or 1-(ethoxycarbonyl)propyl;

with the proviso that if R ¹ is hydrogen, R ² is methyl and R ³ is 1-(ethoxycarbonyl)propyl, then R ⁴ is other than 3-bromobenzyl.

According to the above embodiment, it is preferable that if R ³ represents 3-bromobenzyl, then R ⁴ represents 1-(ethoxycarbonyl)propyl.

According to the above embodiment, it is preferable that if R ³ is 3-pentyl, 1-(aminocarbonyl)propyl or 1-(ethoxycarbonyl)propyl, then R ⁴ is other than 1(ethoxycarbonyl)propyl.

In a most preferred embodiment, R ¹ is hydrogen; R ² represents methyl; R ³ is 1-(ethoxycarbonyl)propyl and R ⁴ is 3-methoxybenzyl, 3-nitrobenzyl or (5-nitro-2-furyl)methyl.

In a further embodiment, a compound is provided wherein R ² is methyl, R ³ is a group of the formula -CHR ⁵ R ⁶ wherein R ⁵ is C ₂ . ₄ αlkyl, R ⁶ is amido or -COOR ⁷ and R ⁷ is methyl or ethyl.

In some embodiments, the compounds useful in the methods and compositions of the present invention are selected from the group consisting of ethyl-2-[(7-benzyl-1,3-dimethyl2,6-dioxo-2,3,6,7-tetrahydro -1H-purin-8-yl)thio]butanoate; ethyl-2-{[7-(3-bromobenzyl)-1-(2-ethoxy-2oxoethyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8- yl]thio}butanoate; ethyl-2-{[7-(3-bromobenzyl)-1-(2-methoxyethyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl] thio}butanoate; ethyl 2-{[7(3-bromobenzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio} butanoate; ethyl 2-{[7-(3-bromobenzyl)1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate; ethyl 2-{[7-(2-bromobenzyl)-1,3dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate; ethyl 2-{[7-(3-bromobenzyl)-1-(cyanomethyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio} butanoate; ethyl 2-{[7-(3-bromobenzyl)-3-methyl-2,6-dioxo-1-propyl-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate; ethyl-2-{[7-(3-bromo-56 045018 benzyl)-3-methyl-2,6-dioxo-1-(2-oxopropyl)-2,3,6,7-tetrahydro-III-purine- 8-yl]thio}butanoate; ethyl-2{[7-(3-bromobenzyl)-1-(3-hydroxypropyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio }butanoate; ethyl 2-{[7-(3-bromobenzyl)-3-methyl-2,6-dioxo-1-(2-propynyl)-2,3,6,7-tetrahydro-1H-purin-8yl]thio} butanoate; ethyl 2-{[7-(3-methoxybenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8yl]thio}butanoate; ethyl 2-{[3-methyl-7-(3-nitrobenzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate; ethyl 2-{[7-(3-aminobenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio} butanoate; ethyl 2-({7-[4-(aminosulfonyl)benzyl]-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl}thio)butanoate;

ethyl 2-{[7-(4-bromobenzyl)-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate; ethyl 2{[7-(cyclohexylmethyl)-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate; ethyl 2-{[1,3-dimethyl-2,6-dioxo-7-(1-phenylethyl)-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate; ethyl 2{[1,3-dimethyl-2,6-dioxo-7-(2-phenylethyl)-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate; ethyl-2-({7[(3,5-dimethylisoxazol-4-yl)methyl]-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-III-purin-8-yl} thio)butanoate; ethyl-2-({3-methyl-7-[(5-nitro-2-furyl)methyl]-2,6-dioxo-2,3,6,7-tetrahydro-III-purin-8-yl}thio )butanoate; ethyl 2-[(7-butyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate; ethyl 2{[7-(3-bromobenzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate; ethyl 2-[(1,7-dihexyl-3methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate; ethyl 2-[(7-hexyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate; ethyl 2-[(3-methyl-2,6-dioxo-1,7-dipentyl-2,3,6,7tetrahydro-1H-purin-8-yl)thio]butanoate; 2-{[7-(3-bromobenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro1H-purin-8-yl]thio}butanamide; 2-[(7-butyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8yl)thio]butanamide; 7-(3-bromobenzyl)-8-[(1-ethylpropyl)thio]-3-methyl-3,7-dihydro-1H-purine-2,6-dione; ethyl 2-{8-[(3-bromobenzyl)thio]-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl}butanoate and ethyl- 2-[(7-isobutyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate.

In some embodiments, the compounds useful in the methods and compositions of the present invention are selected from the group consisting of ethyl-2-[(7-benzyl-1,3-dimethyl2,6-dioxo-2,3,6,7-tetrahydro -1H-purin-8-yl)thio]butanoate; ethyl 2-{[7-(3-bromobenzyl)-1-(2-methoxyethyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl] thio}butanoate; ethyl 2-{[7-(3-bromobenzyl)1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate; ethyl 2-{[7-(3-bromobenzyl)-1(cyanomethyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate ; ethyl 2-{[7-(3-bromobenzyl)-3-methyl-2,6-dioxo-1-propyl-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate; ethyl-2-{[7-(3bromobenzyl)-1-(3-hydroxypropyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio} butanoate; ethyl 2-{[7-(3-bromobenzyl)-3-methyl-2,6-dioxo-1-(2-propynyl)-2,3,6,7-tetrahydro-1H-purin-8-yl] thio}butanoate; ethyl 2-{[7-(3-methoxybenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate; ethyl 2-{[3-methyl-7-(3-nitrobenzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate; ethyl 2-{[7-(3-aminobenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate; ethyl-2-({7-[(3,5-dimethylisoxazol-4-yl)methyl]-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8yl}thio )butanoate; ethyl-2-({3-methyl-7-[(5-nitro-2-furyl)methyl]-2,6-duoxo-2,3,6,7-tetrahydro-1H-purin-8-yl}thio )butanoate; ethyl 2-[(7-butyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate; ethyl 2-[(7-hexyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate; 2-{[7-(3bromobenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanamide; 7-(3-bromobenzyl)-8[(1-ethylpropyl)thio]-3-methyl-3,7-dihydro-1H-purine-2,6-dione and ethyl 2-{8-[(3-bromobenzyl )thiol-1,3dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl} butanoate.

In some embodiments, the compounds useful in the methods and compositions of the present invention are selected from the group consisting of ethyl-2-{[7-(3-methoxybenzyl)-3methyl-2,6-dioxo-2,3,6,7 -tetrahydro-1H-purin-8-yl]thio}butanoate; ethyl 2-{[3-methyl-7-(3-nitrobenzyl)2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate and ethyl 2-( {3-methyl-7-[(5-nitro-2-furyl)methyl]-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl}thio)butanoate.

In some embodiments, the compounds are compounds characterized by Formula II, enantiomers, diastereoisomers, and mixtures thereof (including all possible mixtures of stereoisomers), or pharmaceutically acceptable salts:

R ^2,п >

!

where R ¹ represents hydrogen or C ₁ _ ₆ alkul;

_R ² represents hydrogen or C _{1_4} alkyl;

R ³ represents a group of the formula -CHR5R ⁶ or a benzyl group;

R ⁴ represents C ₁ - ₈ alkyl, optionally substituted with alkoxycarbonyl, C ₃ - ₆ cycloalkyl, aryl or heterocycle;

R ⁵ represents hydrogen or _C1-4 alkyl;

- 57 045018

R ⁶ represents C _1-4 alkyl, amido or -COOR ⁷ ;

R ⁷ represents C _1-4 alkyl;

According to the above embodiments, in some cases, if R ³ represents a benzyl group, then R ⁴ represents C _1-8 alkyl, optionally substituted with alkoxycarbonyl.

According to the above embodiments, in some cases, if R ³ represents a group of formula -CHR5R ⁶ , then R ⁴ represents C _1-8 alkyl, optionally substituted with C _3-6 cycloalkyl, aryl or heterocycle.

In some embodiments, the compounds are compounds of Formula II, enantiomers, diastereoisomers, and mixtures thereof (including all possible mixtures of stereoisomers), or pharmaceutically acceptable salts

Where

R ¹ represents hydrogen or C _1-6 alkyl;

R ² represents hydrogen or C _1-4 alkyl;

R ³ represents a group of the formula - CHR5R ⁶ or a benzyl group;

R ⁴ represents C _1-8 alkyl, optionally substituted with alkoxycarbonyl, C _3-6 cycloalkyl, aryl or heterocyclic compound;

R ⁵ represents hydrogen or C _1-4 alkyl;

R ⁶ represents C _1-4 alkyl, amido or -COOR ⁷ ;

R ⁷ represents C _1-4 alkyl.

In some embodiments, the compounds are compounds of Formula II selected from ethyl-2-[(7-heptyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8yl)thio ]butanoate; 7-(3-bromobenzyl)-3-methyl-8-(propylthio)-3,7-dihydro-1H-purine-2,-6-dione; ethyl 2-[(3methyl-2,6-dioxo-7-pentyl-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate; ethyl 2-{[7-(3-bromobenzyl)3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl-]thio}butanoate; ethyl 2-[(3-methyl-2,6-dioxo-7propyl-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate; 7-(3-bromobenzyl)-8-[(3-chloro-2-hydroxypropyl)thio]-3-methyl-3,7-dihydro-1H-purine-2,6-dione and ethyl 2-{[7 -(3-bromobenzyl)-3-methyl-2,6-dioxo2,3,6,7-tetrahydro-1H-purin-8-yl]thio} propanoate.

In some embodiments, the compounds are compounds of Formula I, enantiomers, diastereoisomers, and mixtures thereof (including all possible mixtures of stereoisomers), or pharmaceutically acceptable salts

Where

R ¹ represents hydrogen or C _1-6 alkyl;

R ² represents hydrogen or C _1-4 alkyl;

R ³ represents a group of the formula -CHR5R ⁶ or a benzyl group;

R ⁴ represents C _1-8 alkyl, optionally substituted with alkoxycarbonyl, C _3-6 cycloalkyl, aryl or heterocycle;

R ⁵ represents C _2-4 alkyl;

R ⁶ represents C _2-4 alkyl, amido or -COOR ⁷ ;

R ⁷ represents C _1-4 alkyl;

In another embodiment, the compounds are compounds characterized by formula II, their enantiomers, diastereoisomers and mixtures thereof (including all possible mixtures of stereoisomers), or pharmaceutically acceptable salts thereof

- 58 045018 where

R ¹ represents hydrogen or O^alkyl;

R ² represents hydrogen or C ₁ . ₄ alkyl;

R ³ represents a group of the formula -CHR5R ⁶ or a benzyl group;

R ⁴ represents C ₁ . ₈ alkyl, optionally substituted with alkoxycarbonyl, C ₃ . ₆ cycloalkyl, aryl or heterocycle;

R ⁵ represents hydrogen or C ₁ . ₄ alkyl;

R ⁶ represents C ₁ . ₄ alkyl, amido or -COOR ⁷ ;

R ⁷ represents C ₁ . ₄ alkyl;

vi) Published international patent application WO 2010/144712

According to one embodiment, a chemical composition is disclosed that contains an LEV derivative of Formula 1 or Formula 2.

The n values of Formula 2 and L, X and Y of Formulas 1 and 2 are defined as follows:

a) n is an integer with values from 0 to 8;

b) L represent one of the groups consisting of CH ₂ , CO, NHCO, NHCOO, CONH, NH, O or S and combinations thereof;

c) X represents a terminal group, an aromatic group, an aryl group or an aliphatic group with a saturated, unsaturated, substituted, unsubstituted, straight or branched chain containing 1-10 carbon and/or heteroatoms in the chain, wherein the heteroatoms contained in the chain are selected from the group consisting of oxygen, nitrogen, sulfur or phosphorus, and their combination; And

d) Y is optional and, if present, represents one of the functional groups selected from the group consisting of amino alcohol, amide, carboxylic acid, aldehyde, ester, iminoester, isocyanate, isothiocyanate, anhydride, thiol, thiolacetone, diazonium, NHS, CO-NHS, O-NHS, maleimido; or

e) Y is Yi-Z, where Yi is selected from the group consisting of COO, CO, O, CONH, NHCO or NH, and Z is an active group.

In one embodiment of the method, the active group Z is selected from the group consisting of detectable tags, antigenic carriers, binding agents, end groups, proteins, lipoproteins, glycoproteins, polypeptides, polysaccharides, nucleic acids, polynucleotides, teichoic acids, radioactive isotopes, enzymes, enzyme fragments , enzyme donor fragments, enzyme acceptor fragments, enzyme substrates, enzyme inhibitors, coenzymes, fluorescent fragments, phosphorescent fragments, anti-Stokes luminescence activator fragments, chemiluminescent fragments, luminescent fragments, dyes, sensitizers, particles, microparticles, magnetic particles, solid-phase substrates, liposomes , ligands, receptors, hapten-radioactive isotopes and their combinations.

vii) Published international patent application WO 2010/002869

The present invention relates to a compound of formula I

or a pharmaceutically acceptable salt thereof, wherein each Z is independently selected from hydrogen and deuterium; R ¹ represents an n-propyl group containing from 0 to 7 deuterium atoms; R ² is an ethyl group containing from 0 to 5 deuterium atoms, and if each R contains 0 deuterium atoms, then at least one of the Zs is deuterium.

In one embodiment, the present invention provides compounds of Formula I wherein R ¹ is selected from CD3CH2CH2-, CD3CD2CH2-, CD3CH2CD2-, CH3CH2CD2-, CH3CD2CD2-, CD3CD2CD2- or CH3CH2CH2-. In a more specific embodiment, R ¹ is CD3CD ₂ CD ₂ - or CD ₃ CD ₂ CH ₂ -. In one aspect of these embodiments, both Z ¹ and Z ² are hydrogen. According to another aspect of these embodiments, both Z ¹ and Z ² are deuterium.

In another embodiment, R ² is selected from CH3CH2-, CD3CH2-, CH3CD2- or CD3CD2-. In a more specific embodiment, R ² is selected from CH3CH ₂ - or CD ₃ CD ₂ -.

- 59 045018

In one aspect of these embodiments, both Z ¹ and Z ² are hydrogen. According to another aspect of these embodiments, both Z ¹ and Z ² are deuterium.

The R and Z variables described above can be selected and taken together to form more specific embodiments of the present invention. For example, in one embodiment, R ¹ is CD3CH2CH2-, CD3CD2CH2-, CD3CH2CD2-, CH3CH2CD2-, CH3CD2CD2-, CD3CD2CD2-, or CH3CH2CH2-; and R ² is selected from CH3CH ₂ -, CD ₃ CH ₂ -, CH ₃ CD ₂ - or CD ₃ CD ₂ -. In one aspect of this embodiment, R ² is CH3CH2- or CD3CD2-. In another embodiment, R ¹ is CD3CD ₂ CD ₂ - or CD ₃ CD ₂ CH ₂ -; and R ² is selected from CH3CH2-, CD3CH2-, CH3CD2- or CD3CD2-. In one aspect of this embodiment, R ² is CH3CH2- or CD3CD2-.

Examples of specific compounds of this invention include the following:

viii) 20090312333

The compounds of the present invention are those characterized by formula (I), diastereoisomers and mixtures thereof, or a pharmaceutically acceptable salt thereof.

ω

R ⁴

and ² .

R ¹ represents hydrogen, substituted or unsubstituted with C ₁ . ₁₂ alkyl, substituted or unsubstituted aryl or substituted or unsubstituted 3-8 membered heterocycle.

R ² represents hydrogen. Alternatively, R ¹ and R ² can be combined together to thereby form C ₃ . ₆ cycloalkyl.

R ³ is either (a) a substituted or unsubstituted heterocycle linked to the remainder of the molecule through one of its C atoms, said heterocycle being selected from the group consisting of

1H-benzimidazol-6-yl;

1H-benzimidazol-7-yl;

imidazo[1,2-a]pyridin-3-yl;

imidazo[1,2-a]pyrimidin-3-yl;

imidazo[1 _g 2 -b][1,2,4]triazin-7-yl;

imidazo[1,2-b]pyridazin-3-yl;

5,6,7,8-tetrahydroimidazo[1,2 -b]pyridazin-3-yl;

imidazo[2,1-b][1,3,4]thiadiazol-5-yl;

- 60 045018 imidazo[2,1-b][1,3]thiazol-5-yl;

3H-imidazo[4,5-b]pyridin-7-yl;

1H-imidazol-4-yl;

1H-imidazol-5-yl;

1H-indol-2-yl;

1H-indol-3-yl;

1H-indol-4-yl;

1H-indol-7-yl;

isoxazol-4-yl;

1H-pyrazol-4-yl;

1H-pyrazol-5-yl;

1H-pyrazolo[1,5-a]pyrimidin-3-yl;

1H-pyrazolo[3,4-b]pyridin-3-yl;

pyridazin-4-yl;

pyridin-2-yl;

pyridin-3-yl;

pyridin-4-yl;

1H-pyrrolo[2,3-b]pyridin-3-yl;

1H-pyrrolo[2,3-b]pyridin-4-yl;

1H-pyrrolo[2,3-b]pyridin-5-yl;

1H-pyrrolo[2,3-c]pyridin-2-yl;

1H-pyrrolo[2,3-c]pyridin-3-yl;

1H-pyrrolo[3,2-b]pyridin-3-yl;

1H-pyrrolo[3,2-c]pyridin-2-yl;

1H-pyrrolo[3,2-c]pyridin-3-yl;

1,3,4-thiadiazol-2-yl;

1,3-thiazol-5-yl;

[1,2,4]tr iazolo[4,3-b]pyridazin-7-yl;

[1,2,4]tr iazolo[4,3-b]pyridazin-8-yl;

indolizin-3-yl;

or R ³ represents (b) a substituted or unsubstituted heterocycle linked to the remainder of the molecule through one of its N atoms, said heterocycle being selected from the group consisting of

1H-1,2,3-benzotriazol-1-yl;

1H-imidazo[4,5-b]pyridin-1-yl;

- 61 045018

3H-imidazo[4,5-b]pyridin-3-yl;

7H-imidazo[4,5-c]pyridazin-7-yl;

1H-indol-1-yl;

2,3-dihydro-1H-indol-1-yl;

9H-purin-9-yl;

1H-pyrazolo[3,4-b]pyridin-1-yl;

2H-pyrazolo[3,4-b]pyridin-2-yl;

1H-pyrrolo[2,3-b]pyridin-1-yl;

1H-pyrrolo[3,2-b]pyridin-1-yl;

3,4-dihydroquinolin-1-(2H)-yl;

8H-isothiazolo[5,4-b]indol-8-yl;

1H-1,2,4-triazol-1-yl;

1H-pyrrol-1-yl;

2-chloro-1H-benzimidazol-1-yl.

R ⁴ in formula (I) is selected from the group containing or consisting of hydrogen; C _1-12 alkyl, optionally substituted with halogen, C _1-4 alkoxy, C _1-4 alkylthio, azido, nitrooxy or aryl; C _2-12 alkenyl, optionally substituted with halogen; C _2-12 alkynyl, optionally substituted with halogen; azido; alkoxycarbonylamino; arylsulfonyloxy; substituted or unsubstituted aryl; or a 3-8 membered substituted or unsubstituted heterocycle.

In a specific embodiment, R ⁴ is hydrogen; or R ⁴ is C1-12alkyl or C1-6alkyl, optionally substituted with halogen, C1-4alkoxy, C1-4alkylthio, azido or nitrooxy; or R ⁴ is C2-12 alkenyl or C _1-6 alkenyl, optionally substituted with halogen; or R ⁴ is C _2-12 alkynyl or C _1-6 alkynyl, optionally substituted with halogen; or R ⁴ is alkoxycarbonylamino.

R ⁵ represents hydrogen.

Alternatively, ^R4 can form, together with ^R5 and the 2-oxo-1-pyrrolidine ring, a 1,3-dihydro-2H-indol-2-one ring with the following structure:

An asterisk * denotes the point of substituent addition.

R ⁶ represents hydrogen or halogen.

R ⁷ in formula (I) is selected from the group consisting of hydrogen; nitro; halogen; heterocycle; amino; arila; C _1-12 alkyl, optionally substituted with at least one halogen atom; or C _1-12 alkoxy, optionally substituted with at least one halogen atom.

R ⁸ in formula (I) is selected from the group consisting of hydrogen, C _1-12 alkyl, optionally substituted with halogen, or halogen.

R ⁹ in formula (I) is selected from the group consisting of hydrogen, C _1-12 alkyl optionally substituted with halogen, or halogen.

According to a further aspect, the present invention relates to compounds of formula (I) wherein both R ¹ and R ² are hydrogen;

R ³ represents:

(a) a substituted or unsubstituted heterocycle linked to the remainder of the molecule through one of its C atoms, selected from the group consisting of

1H-benzimidazol-6-yl;

1H-benzimidazol-7-yl;

imidazo[1,2-a]pyridin-3-yl;

imidazo[1,2-a]pyrimidin-3-yl;

imidazo[1,2-b][1,2,4]triazin-7-yl;

imidazo[1,2-b]pyridazin-3-yl;

5,6,7,8-tetrahydroimidazo[1,2-b]pyridazin-3-yl;

imidazo[2,1-b][1,3,4]thiadiazol-5-yl;

imidazo[2,1-b][1,3]thiazol-5-yl;

3H-imidazo[4,5-b]pyridin-7-yl;

- 62 045018

1H-imidazol-4-yl;

1H-imidazol-5-yl;

1H-indol-2-yl;

1H-indol-3-yl;

1H-indol-4-yl;

1H-indol-7-yl;

isoxazol-4-yl;

1H-pyrazol-4-yl;

1H-pyrazol-5-yl;

1H-pyrazolo[1,5-a]pyrimidin-3-yl;

1H-pyrazolo[3,4-b]pyridin-3-yl;

pyridazin-4-yl;

pyridin-2-yl;

pyridin-3-yl;

pyridin-4-yl;

1H-pyrrolo[2,3-b]pyridin-3-yl;

1H-pyrrolo[2,3-b]pyridin-4-yl;

1H-pyrrolo[2,3-b]pyridin-5-yl;

1H-pyrrolo[2,3-c]pyridin-2-yl;

1H-pyrrolo[2,3-c]pyridin-3-yl;

1H-pyrrolo[3,2-b]pyridin-3-yl;

1H-pyrrolo[3,2-c]pyridin-2-yl;

1H-pyrrolo[3,2-c]pyridin-3-yl;

1,3,4-thiadiazol-2-yl;

1,3-thiazol-5-yl;

[1,2,4]tr iazolo[4,3-b]pyridazin-7-yl;

[1,2,4]tr iazolo[4,3-b]pyridazin-8-yl; indolizin-3-yl.

Alternatively, R ³ is:

(b) a substituted or unsubstituted heterocycle linked to the remainder of the molecule through one of its N atoms, selected from the group consisting of

1H-1,2,3-benzotriazol-1-yl;

1H-imidazo[4,5-b]pyridin-1-yl;

3H-imidazo[4,5-b]pyridin-3-yl;

7H-imidazo[4,5-c]pyridazin-7-yl; 1H-indol-1-yl;

2,3-dihydro-1H-indol-1-yl;

9H-purin-9-yl;

1H-pyrazolo[3,4-b]pyridin-1-yl;

2H-pyrazolo[3,4-b]pyridin-2-yl;

1H-pyrrolo[2,3-b]pyridin-1-yl;

1H-pyrrolo[3,2-b]pyridin-1-yl;

3,4-dihydroquinolin-1-(2H)-yl;

8H-isothiazolo[5,4-b]indol-8-yl;

1H-1,2,4-triazol-1-yl;

1H-pyrrol-1-yl;

2-chloro-1H-benzimidazol-1-yl.

R ⁴ in formula (1) is selected from the group consisting of and hydrogen; C ₁ . ₁₂ alkyl, optionally substituted with halogen, or C ₁ . ₄ alkoxy; _C2 . ₁₂ alkenyl, optionally substituted with halogen; _C2 . ₁₂ alkynyl, optionally substituted with halogen.

- 63 045018

In a further specific embodiment, R ⁴ is n-propyl,

2,2,2-trifluoroethyl, 2-chloro-2,2-difluoroethyl, 2-bromo-2,2-difluoroethyl, 2,2-difluorovinyl.

In another specific embodiment, R ⁴ is phenyl, 2,3,5-trifluorophenyl, or 3-chloro-4-fluorophenyl.

R ⁵ represents hydrogen.

According to a further embodiment, the present invention relates to compounds of formula (I) in which R ⁴ forms, together with R ^5a , a 1,3-dihydro-2H-indol-2-one ring

R ⁶

The asterisk * denotes the point of attachment of the heteroaryl alkylenyl substituent, and where

R ⁶ represents hydrogen;

R ⁷ represents chlorine;

R ⁸ represents hydrogen;

R ⁹ represents hydrogen.

According to a further embodiment, the present invention relates to compounds of formula (I) in which R ³ represents a substituted or unsubstituted heterocycle linked to the remainder of the molecule through one of its C atoms and selected from the group consisting of imidazo[1,2-a] pyrimidin-3-yl;

imidazo[1,2-b][1,2,4]triazin-7-yl;

imidazo[1,2-b]pyridazin-3-yl;

5,6,7,8-tetrahydroimidazo[1,2-b]pyridazin-3-yl;

imidazo[2,1-b][1,3,4]thiadiazol-5-yl;

imidazo[2,1-b][1,3]thiazol-5-yl;

3H-imidazo[4,5-b]pyridin-7-yl;

1H-imidazol-4-yl;

1H-imidazol-5-yl;

isoxazol-4-yl;

1H-pyrazol-4-yl;

1H-pyrazol-5-yl;

1H-pyrazolo[1,5-a]pyrimidin-3-yl;

1H-pyrazolo[3,4-b]pyridin-3-yl;

pyridin-3-yl;

1H-pyrrolo[2,3-b]pyridin-3-yl;

1H-pyrrolo[2,3-b]pyridin-4-yl;

1H-pyrrolo[2,3-b]pyridin-5-yl;

1H-pyrrolo[2,3-c]pyridin-2-yl;

1H-pyrrolo[2,3-c]pyridin-3-yl;

1,3-thiazol-5-yl;

[1,2,4]triazolo[4,3-b]pyridazin-8-yl;

indolizin-3-yl.

In a further specific embodiment, R ³ is a heterocycle linked to the remainder of the molecule through one of its C atoms and selected from the group consisting of

- 64 045018 imidazo[1,2-b]pyridazin-3-yl;

imidazo[2,1-b][1,3,4]thiadiazol-5-yl;

imidazo[2,1-b][1,3]thiazol-5-yl;

3H-imidazo[4,5-b]pyridin-7-yl;

1H-imidazol-4-yl;

1H-imidazol-5-yl;

1H-pyrazol-4-yl;

1H-pyrazolo[1,5-a]pyrimidin-3-yl;

pyridin-3-yl;

1H-pyrrolo[2,3-b]pyridin-3-yl;

1H-pyrrolo[2,3-b]pyridin-4-yl;

1,3-thiazol-5-yl;

Said heterocycles are optionally substituted, for example, with methyl, n-propyl, trifluoromethyl, cyclopropyl, bromine, chlorine, fluorine, iodine, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclopropylmethoxy, cyclobutylmethoxy, amino, methylamino, cyclopropylamino, cyclobutylamino, 1-pyrrolidinyl ohm , cyano, phenyl, benzyl or 3-thienyl.

In a further specific embodiment, R ³ is a heterocycle linked to the remainder of the molecule through one of its C atoms and selected from the group consisting of 6-chloro-2-cyclopropylimidazo[1,2-b]pyridazin-3-yl, 6- (cyclopropyloxy)-2(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl, 6-propoxy-2-(trifluoromethyl)imidazo[1,2-b]pyridazin3-yl, 6-chloroimidazo[2,1 -b][1,3]thiazol-5-yl, 2,6-dichloroimidazo[2,1-b][1,3]thiazol-5-yl, 5-chloro-1Nimidazol-4-yl, 5-bromo -1H-imidazol-4-yl, 4-bromo-1H-imidazol-5-yl, 4-chloro-1H-imidazol-5-yl, 1Himidazol-5-yl, 1-methyl-1H-imidazol-5-yl , 4-chloro-1-methyl-1H-imidazol-5-yl, 1H-pyrazol-4-yl, 1Hpyrrolo[2,3-b]pyridin-3-yl.

According to a further embodiment, the present invention relates to compounds of formula (I) in which R ³ represents a heterocycle linked to the remainder of the molecule through one of its C atoms and is a substituted or unsubstituted imidazo[1,2a]pyridin-3-yl.

Said imidazo[1,2-a]pyridin-3-yl is optionally substituted, for example, with methyl, cyclopropyl, bromine, chlorine, fluorine, iodine.

In a further specific embodiment, R ³ is a heterocycle linked to the remainder of the molecule through one of its C atoms and selected from the group consisting of: imidazo[1,2-a]pyridin-3-yl, 6-methylimidazo[1,2 -a]pyridin-3-yl, 2-chloroimidazo[1,2a]pyridin-3-yl.

According to a further embodiment, the present invention relates to compounds of formula (I) wherein R ³ is a substituted or unsubstituted heterocycle linked to the remainder of the molecule through one of its N atoms and selected from the group consisting of

3H-imidazo[4,5-b]pyridin-3-yl;

IH-indol-1-yl;

1H-pyrrolo[2,3-b]pyridin-1-yl;

1H-pyrrolo[3,2-b]pyridin-1-yl;

1H-pyrrol-1-yl;

2-chloro-1H-benzimidazol-1-yl.

According to a specific additional embodiment, the present invention relates to compounds of formula (I) in which R ³ represents a heterocycle linked to the remainder of the molecule through one of its N atoms and selected from the group consisting of

3H-imidazo[4,5-b]pyridin-3-yl;

1H-pyrrolo[3,2-b]pyridin-1-yl;

1H-pyrrol-1-yl;

2-chloro-1H-benzimidazol-1-yl;

Said heterocycles may optionally be substituted with trifluoromethyl, cyclopropyl, bromine, chlorine, fluorine, methoxy or cyano.

In a further specific embodiment, R ³ is a heterocycle linked to the remainder of the molecule through one of its C atoms and selected from the group consisting of 6-bromo-2-chloro-3H-imidazo[4,5-b]pyridine-3- yl, 6-bromo-2-cyclopropyl-3H-imidazo[4,5b]pyridin-3-yl, 1 H-pyrrolo[3,2-b]pyridin-1 -yl, 2,5-dichloro-1 H- pyrrol-1-yl, 2-chloro-5-methoxy-1H- 65 045018 benzimidazol-1-yl, 5-bromo-2-chloro-1H-benzimidazol-1-yl or 2,5-dichloro-1H-benzimidazol- 1-ila.

According to a further embodiment, the present invention relates to compounds of formula (I) wherein R ¹ , R ² and R ⁵ are hydrogen.

R ⁴ represents C ₁ . ₆ alkyl, optionally substituted with halogen, C ₂ . ₆ alkenyl, optionally substituted with halogen, or C ₂ . ₁₂ alkynyl, optionally substituted with halogen.

R ³ is selected from the group consisting of imidazo[1,2-b]pyridazin-3-yl;

imidazo[2,1-b][1,3,4]thiadiazol-5-yl;

imidazo[2,1-b][1,3]thiazol-5-yl;

3H-imidazo[4,5-b]pyridin-7-yl;

1H-imidazol-4-yl;

1H-imidazol-5-yl;

1H-pyrazol-4-yl;

1H-pyrazolo[1,5-a]pyrimidin-3-yl;

pyridin-3-yl;

1H-pyrrolo[2,3-b]pyridin-3-yl;

1H-pyrrolo[2,3-b]pyridin-4-yl;

1,3-thiazol-5-yl;

and optionally substituted with methyl, n-propyl, trifluoromethyl, cyclopropyl, bromine, chlorine, fluorine, iodine, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclopropylmethoxy, cyclobutylmethoxy, amino, methylamino, cyclopropylamino, cyclobutylamino, 1-pyrrolidinyl, cyano, phenyl , benzyl or 3-thienyl.

According to a further embodiment, the present invention relates to compounds of formula (I) wherein R ¹ , R ² and R ⁵ are hydrogen.

R ⁴ represents C ₁ . ₆ alkyl, optionally substituted with halogen, C ₂ . ₆ alkenyl, optionally substituted with halogen, or C ₂ . ₁₂ alkynyl, optionally substituted with halogen.

R ³ is selected from the group consisting of

3H-imidazo[4,5-b]pyridin-3-yl;

1H-pyrrolo[3,2-b]pyridin-1-yl;

1H-pyrrol-1-yl;

2-chloro-1H-benzimidazol-1-yl;

optionally substituted with trifluoromethyl, cyclopropyl, bromine, chlorine, fluorine, methoxy or cyano.

According to a further embodiment, the present invention relates to compounds of formula (1), diastereoisomers and mixtures thereof, or a pharmaceutically acceptable salt thereof

R ¹ , R ² and R ⁵ represent hydrogen;

R ³ represents a substituted or unsubstituted heterocycle linked to the remainder of the molecule through one of its C atoms, said heterocycle being selected from the group consisting of

- 66 045018

1H-benzimidazol-6-yl;

1H-benzimidazol-7-yl;

imidazo[1,2-a]pyridin-3-yl;

imidazo[1,2-a]pyrimidin-3-yl;

imidazo[1,2-b][1,2,4]triazin-7-yl;

imidazo[1,2-b]pyridazin-3-yl;

5,6,7,8-tetrahydroimidazo[1,2-b]pyridazin-3-yl;

imidazo[2,1-b][1,3,4]thiadiazol-5-yl;

imidazo[2,1-b][1,3]thiazol-5-yl;

3H-imidazo[4,5-b]pyridin-7-yl;

1H-imidazol-4-yl;

1H-imidazol-5-yl;

1H-indol-2-yl;

1H-indol-3-yl;

1H-indol-4-yl;

1H-indol-7-yl;

isoxazol-4-yl;

1H-pyrazol-4-yl;

1H-pyrazol-5-yl;

1H-pyrazolo[1,5-a]pyrimidin-3-yl;

1H-pyrazolo[3,4-b]pyridin-3-yl;

pyridazin-4-yl;

pyridin-2-yl;

pyridin-3-yl;

pyridin-4-yl;

1H-pyrrolo[2,3-b]pyridin-3-yl;

1H-pyrrolo[2,3-b]pyridin-4-yl;

1H-pyrrolo[2,3-b]pyridin-5-yl;

1H-pyrrolo[2,3-c]pyridin-2-yl;

1H-pyrrolo[2,3-c]pyridin-3-yl;

1H-pyrrolo[3,2-b]pyridin-3-yl;

1H-pyrrolo[3,2-c]pyridin-2-yl;

1H-pyrrolo[3,2-c]pyridin-3-yl;

1,3,4-thiadiazol-2-yl;

1,3-thiazol-5-yl;

[1,2,4]triazolo[4,3-b]pyridazin-7-yl;

[1,2,4]triazolo[4,3-b]pyridazin-8-yl;

indolizin-3-yl;

Particularly preferred are imidazo[1,2-a]pyridin-3-yl; imidazo[1,2-a]pyrimidin-3yl; imidazo[1,2-b]pyridazin-3-yl; Sh-imidazol-4-yl; 1I-imidazol-5-yl;

R ⁴ represents a substituted or unsubstituted phenyl moiety.

According to a further embodiment, the present invention relates to compounds of formula (I) wherein R ¹ represents hydrogen or C _1-12 alkyl;

R ² represents hydrogen;

R ³ is an aromatic 5-membered heterocycle linked to the rest of the molecule through one of its C atoms;

R ⁴ represents hydrogen, C _1-12 alkyl or aryl;

R ⁵ represents hydrogen;

Alternatively, R ⁴ can form together with R ⁵ and the 2-oxo-1-pyrrolidine ring the following 1,3-dihydro-2H-indol-2-one ring

R ⁶

- 67 045018 where the asterisk * indicates the point of attachment of substituents;

R ⁶ represents hydrogen or halogen.

In this embodiment, R ⁴ may not be hydrogen if R ³ is substituted with 1Hpyrazol-5-yl. Moreover, the present invention does not relate to 5-(2'-oxo-1'-pyrrolidinyl)methyl1,3,4-tricarbomethoxypyrazole disclosed in A. Padwa et al., J. Org. Chem. 2000, 65, 5223-5232, and does not have any biological activity.

In this embodiment, if R ³ is an aromatic 5-membered heterocycle linked to the remainder of the molecule through one of its C atoms, the specific R ³ moieties may be selected from 1,3-thiazol-5-yl, 1H-imidazol-4 -ulα, 1I-imidazol-5-yl, III-pyrazol-4yl, 1H-pyrazol-5-yl, 2-oxo-2,3-dihydro-1,3-thiazol-5-yl, each of which is optionally substituted 1-3 substituents independently selected from methyl, chloro, bromine, amino, methylamino, dimethylamino, (2-oxo-4-propyl-pyrrolidin-1-yl)methyl, 1-pyrrolidinyl, amido, cyano, methoxy, phenyl, 4methylphenylsulfonyl , benzyl or 2-(benzylamino)-2-oxoethyl. In this embodiment, more specific R ³ moieties are selected from 2-(methylamino)-1,3-thiazol-5-yl; 2-pyrrolidin-1yl-1,3-thiazol-5-yl; 5-bromo-1H-imidazol-4-yl; 5-chloro-1H-imidazol-4-yl; 1H-imidazol-5-yl; 1methyl-1H-umidazol-5-yl; 4-bromo-1-methyl-1H-umidazol-5-yl; 4-chloro-1H-imidazol-5-yl; 4-chloro-1methyl-1H-imidazol-5-yl; 4-cyano-1-methyl-1H-imidazol-5-yl; 1H-pyrazol-4-yl; 3,5-dimethyl-1Hpyrazol-4-yl; 3-methyl-1 H-pyrazol-4-yl.

In this embodiment, the most specific R ³ moieties are selected from 5-bromo1 H-imidazol-4-yl; 5-chloro-1 H-imidazol-4-yl; 1 I-imidazol-5-yl; 4-bromo-1 -methyl-1 I-imidazol-5 -yl; 4-chloro-1 -methyl-1 H-imidazol-5 -yl; 1 H-pyrazol-4-yl.

Also in this embodiment, the particular R ¹ moiety is selected from hydrogen or ethyl.

Also in this embodiment, the specific R ⁴ moiety is selected from hydrogen, npropyl, 2,3,5-trifluorophenyl, or phenyl.

According to a further embodiment, the present invention relates to compounds characterized by the specific formula (Ia).

(Ta)

In formula (Ia), the substituent R ¹⁰ represents hydrogen; halogen; C ₁ . ₄ alkyl, optionally substituted with at least one halogen atom; C ₁ . ₄ alkoxy; methoxycarbonyl; nitro; amino; alkylamino; amido; or alkanoylamino. Preferably R ¹⁰ is hydrogen.

R ¹¹ represents hydrogen; halogen; C ₁ . ₄ alkyl, optionally substituted with at least one halogen atom; C ₁ . ₄ alkoxy; methoxycarbonyl; nitro; amino; alkylamino; amido; or alkanoylamino. Preferably R ¹¹ is hydrogen.

R ⁴ represents C ₁ . ₄ alkyl, optionally substituted with at least one halogen atom; or C ₂ . ₄ alkenyl, optionally substituted with at least one halogen atom. Preferably R ⁴ is n-propyl. Moreover, according to this aspect of the present invention, a specific embodiment relates to an embodiment wherein R ¹⁰ is selected from hydrogen; methyl; fluorine; chlorine; bromine; methoxy; methoxycarbonyl; nitro or trifluoromethyl, while R ¹¹ is selected from hydrogen; methyl; fluorine; chlorine; bromine; methoxy; methoxycarbonyl; nitro or trifluoromethyl; and R ³ is n-propyl.

The particular compounds of the present invention are selected from the group consisting of

- 68 045018

1-[(1-methyl-1H-benzimidazol-6-yl)methyl]-4propylpyrrolidin-2-one;

1-(1H-benzimidazol-7-ylmethyl)-4-propylpyrrolidin-2-one;

1-(imidazo[1,2-a]pyridin-3-ylmethyl)-4-propylpyrrolidin-2one;

1-{[6-chloro-2-(4-methylphenyl)imidazo[1,2-a]pyridin-3yl]methyl]-4-propylpyrrolidin-2-one;

1-{[2-(4-chlorophenyl)-6-methylimidazo[1,2-a]pyridin-3yl]methyl]-4-propylpyrrolidin-2-one;

1-[(5-methylimidazo[1,2-a]pyridin-3-yl)methyl]-4phenylpyrrolidin-2-one;

1-(imidazo[1,2-a]pyridin-3-ylmethyl)-4-phenylpyrrolidin-2one;

1-[(6-methylimidazo[1,2-a]pyridin-3-yl)methyl]-4propylpyrrolidin-2-one;

1-[(6-bromimidazo[1,2-a]pyridin-3-yl)methyl]-4propylpyrrolidin-2-one;

1-[(8-methylimidazo[1,2-a]pyridin-3-yl)methyl]-4propylpyrrolidin-2-one;

1-[(6-iodimidazo[1,2-a]pyridin-3-yl)methyl]-4propylpyrrolidin-2-one;

1-{[8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-3yl]methyl}-4-propylpyrrolidin-2-one;

1-[(7-methylimidazo[1,2-a]pyridin-3-yl)methyl]-4propylpyrrolidin-2-one;

1-[(6,8-dibromimidazo[1,2-a]pyridin-3-yl)methyl]-4propylpyrrolidin-2-one;

1-[(6,8-dichloroimidazo[1,2-a]pyridin-3-yl)methyl]-4propylpyrrolidin-2-one;

1-[(6-chloroimidazo[1,2-a]pyridin-3-yl)methyl]-4-69 045018 propylpyrrolidin-2-one;

1-[(2-chloroimidazo[1,2-a]pyridin-3-yl)methyl]-4propylpyrrolidin-2-one;

1-[(2-cyclopropyl-6-fluoromidazo[1,2-a]pyridin-3-yl)methyl] 4-(2,2-difluorovinyl)pyrrolidin-2-one;

1-[(6-chloro-2-cyclopropylimidazo[1,2-a]pyridin-3-yl)methyl] 4-(2,2-difluorovinyl)pyrrolidin-2-one;

1-(imidazo[1,2-a]pyrimidin-3-ylmethyl)-4-propylpyrrolidin2-one;

1-{[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-4propylpyrrolidin-2-one;

1-(imidazo[1,2-a]pyrimidin-3-ylmethyl)-4-phenylpyrrolidin-2 one;

1-[(6-chloroimidazo[1,2-a]pyrimidin-3-yl)methyl]-4propylpyrrolidin-2-one;

1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-a]pyrimidin-3yl]methyl}-4-propylpyrrolidin-2-one;

1-[(6-phenylimidazo[1,2-b][1,2,4]triazin-7-yl)methyl]-4propylpyrrolidin-2-one;

1-{[6-chloro-2-(4-methylphenyl)imidazo[1,2 -b]pyridazin-3yl]methyl}-4-propylpyrrolidin-2-one;

1-{[6-chloro-2-(4-chlorophenyl)imidazo[1,2 -b]pyridazin-3yl]methyl}-4-propylpyrrolidin-2-one;

1-[(6-chloroimidazo[1,2 -b]pyridazin-3-yl)methyl]-4propylpyrrolidin-2-one;

1-[(6-chloroimidazo[1,2 -b]pyridazin-3-yl)methyl]-4phenylpyrrolidin-2-one;

1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2 -b]pyridazin-3yl]methyl}-4-propylpyrrolidin-2-one;

1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2 -b]pyridazin-3yl]methyl}-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;

1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2 -b]pyridazin-3yl]methyl}pyrrolidin-2-one;

1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2 -b]pyridazin-3yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one;

1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2 -b]pyridazin-3-70 045018 yl]methyl}-4-phenylpyrrolidin-2-one;

5-chloro-1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2 -b]pyridazin·3-yl]methyl}-1,3-dihydro-2H-indol-2-one;

— {[6-methoxy-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3yl]methyl}-4-propylpyrrolidin-2-one;

— [(6-chloro-2-cyclopropylimidazo[1,2-b]pyridazin-3yl)methyl]-4-propylpyrrolidin-2-one;

— {[6-isopropoxy-2-(trifluoromethyl)imidazo[1,2-b]pyridazin·3-yl]methyl]-4-propylpyrrolidin-2-one;

1-{[6-(benzyloxy)-2-(trifluoromethyl)imidazo[1,2b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one;

1-{[6-cyclopropyl-2-(trifluoromethyl)imidazo[1,2-b]pyridazin·3-yl]methyl]-4-propylpyrrolidin-2-one;

1-{[6-(dimethylamino)-2-(trifluoromethyl)imidazo[1,2b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one;

4-(2,2-difluorovinyl)-1-{[6-methoxy-2(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2one;

4-(2-chloro-2,2-difluoroethyl)-1-{[6-chloro-2(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2one;

1-{[6-(methylamino)-2-(trifluoromethyl)imidazo[1,2b]pyridazin-3-yl]methyl]-4-propylpyrrolidin-2-one;

1-{[6-hydroxy-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3yl]methyl}-4-propylpyrrolidin-2-one;

1-{[6-(methylthio)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin3-yl]methyl}-4-propylpyrrolidin-2-one;

4-(2-bromo-2,2-difluoroethyl)-1-{[6-chloro-2(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2one;

1-{[6-(methylsulfonyl)-2-(trifluoromethyl)imidazo[1,2—

b]pyridazin-3-yl]methyl]-4-propylpyrrolidin-2-one;

1-{[6-(methylsulfinyl)-2-(trifluoromethyl)imidazo[1,2—

b]pyridazin-3-yl]methyl]-4-propylpyrrolidin-2-one;

1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3yl]methyl}-4-(2,2,2-trifluoroethyl)pyrrolidin-2-one;

- 71 045018 - [(6-chloro-2-cyclobutylimidazo[1,2-b]pyridazin-3yl)methyl]-4-propylpyrrolidin-2-one;

— {[6-chloro-2-(4-methylphenyl)imidazo[1,2-b]pyridazin-3yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one;

1-{[6-amino-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3yl]methyl}-4-propylpyrrolidin-2-one;

1-{[6-(ethylamino)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin·3-yl]methyl]-4-propylpyrrolidin-2-one;

4-propyl-1-{[6-(propylamino)-2-(trifluoromethyl)imidazo[1,2b]pyridazin-3-yl]methyl}pyrrolidin-2-one;

4-(2-bromo-2,2-difluoroethyl)-1-{[6-(propylamino)-2(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2one;

4-(2,2-difluorovinyl)-1-{[6-(propylamino)-2(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2one;

4-(2,2-difluorovinyl)-1-{[6-methoxy-2-(4methylphenyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one 4-propyl-1- {[6-pyrrolidin-1-yl-2(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2one;

4-(2-bromo-2,2-difluoroethyl)-1-{[6-methoxy-2(trifluoromethyl)imidazo[1,2-b]pyrizazin-3-yl]methyl}pyrrolidin-2one;

1-{[6-(cyclopropylamino)-2-(trifluoromethyl)imidazo[1,2b]pyridazin-3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one;

1-[(6-chloro-2-cyclopropylimidazo[1,2-b]pyridazin-3yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one;

4-(2,2-difluorovinyl)-1-{[6-(isopropylamino)-2(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2one;

4-(2,2-difluorovinyl)-1-{[2-(trifluoromethyl)imidazo[1,2—

b]pyridazin-3-yl]methyl}pyrrolidin-2-one;

1-{[2-cyclopropyl-6-(propylamino)imidazo[1,2-b]pyridazin3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one;

1-({2-cyclopropyl-6-[(2-fluoroethyl)amino]imidazo[1,2—

- 72 045018

b]pyridazin-3-yl}methyl)-4-(2,2-difluorovinyl)pyrrolidin-2-one;

1-({2-cyclopropyl-6-[(2,2-difluoroethyl)amino]imidazo[1,2b]pyridazin-3-yl}methyl)-4-(2,2-difluorovinyl)pyrrolidin-2-one;

1-({2-cyclopropyl-6-[(2,2,2-trifluoroethyl)amino]imidazo[1,2 b]pyridazin-3-yl}methyl)-4-(2,2-difluorovinyl)pyrrolidine-2 -she;

4-(2,2-difluoroethyl)-1-{[2-(trifluoromethyl)imidazo[1,2—

b]pyridazin-3-yl]methyl}pyrrolidin-2-one;

1-{[2-cyclopropyl-6-(cyclopropylamino)imidazo[1,2—

b]pyridazin-3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one;

1-[(6-chloro-2-cyclobutylimidazo[1,2 -b]pyridazin-Zyl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one;

1-[(6-chloro-2-cyclopropylimidazo[1,2 -b]pyridazin-Zyl)methyl]-4-(3-chloro-4-fluorophenyl)pyrrolidin-2-one;

1-{[6-(butylamino)-2-(trifluoromethyl)imidazo[1,2—

b]pyridazin-3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one;

1-{[6-(cyclobutylamino)-2-(trifluoromethyl)imidazo[1,2—

b]pyridazin-3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one;

1-[(2-cyclopropyl-6-methoxyimidazo[1,2 -b]pyridazin-Zyl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one;

4-(2,2-difluorovinyl)-1-{[6-ethoxy-2(trifluoromethyl)imidazo[1,2 -b]pyridazin-3-yl]methyl}pyrrolidin-2one;

4-(2,2-difluorovinyl)-1-{[6-isopropoxy-2(trifluoromethyl)imidazo[1,2 -b]pyridazin-3-yl]methyl}pyrrolidin-2one;

1-{[6-(cyclopropylmethoxy)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one;

1-{[6-(cyclobutylmethoxy)-2-(trifluoromethyl)imidazo[1,2—

b]pyridazin-3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one;

1-{[6-(cyclopropyloxy)-2-(trifluoromethyl)imidazo[1,2—

b]pyridazin-3-yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one;

4-(2,2-difluorovinyl)-1-{[6-propoxy-2(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2one;

3-{[4-(2,2-difluorovinyl)-2-oxopyrrolidin-1-yl]methyl}-2(trifluoromethyl)imidazo[1,2-b]pyridazin-6-carbonitrile;

- 73 045018

4-(2,2-difluorovinyl)-1-{[6-thien-3-yl-2(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2one;

4-(2,2-difluorovinyl)-1-{[6-phenyl-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2one;

4-(2,2-difluorovinyl)-1-{[6-methyl-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2one;

4-(2,2-difluorovinyl)-1-{[6-pyridin-3-yl-2(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2one;

4-propyl-1-{[2-(trifluoromethyl)-5,6,7,8tetrahydroimidazo[1,2-b]pyridazin-3-yl]methyl}pyrrolidin-2-one;

1-[(6-methylimidazo[2,1-b][1,3,4]thiadiazol-5-yl)methyl]-4propylpyrrolidin-2-one;

1- {[6-(4-methylphenyl)imidazo[2,1-b][1,3,4]thiadiazol-5yl]methyl]-4-propylpyrrolidin-2-one;

1-[(2-cyclopropyl-6-phenylimidazo[2,1-b][1,3,4]thiadiazol-5·yl)methyl]-4-propylpyrrolidin-2-one;

1-[(6-methylimidazo[2,1-b][1,3]thiazol-5-yl)methyl]-4propylpyrrolidin-2-one;

1-[(6-chloroimidazo[2,1-b][1,3]thiazol-5-yl)methyl]-4propylpyrrolidin-2-one;

1-[(2,6-dichloroimidazo[2,1-b][1,3]thiazol-5-yl)methyl]-4propylpyrrolidin-2-one;

1-(3H-imidazo[4,5-b]pyridin-7-ylmethyl)-4-propylpyrrolidin 2-one;

1-(3H-imidazo[4,5-b]pyridin-7-ylmethyl)-4-phenylpyrrolidin2-one;

4-phenyl-1-[(5-phenyl-3H-imidazo[4,5-b]pyridin-7yl)methyl]pyrrolidin-2-one;

4-phenyl-1-{[5-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-7yl]methyl}pyrrolidin-2-one;

1-[(6-bromo-3H-imidazo[4,5-b]pyridin-7-yl)methyl]-4propylpyrrolidin-2-one;

- 74 045018

1-[(2-phenyl-3H-imidazo[4,5-b]pyridin-7-yl)methyl]-4propylpyrrolidin-2-one;

1-[(5-methyl-3H-imidazo[4,5-b]pyridin-7-yl)methyl]-4propylpyrrolidin-2-one;

1-[(2-methyl-3H-imidazo[4,5-b]pyridin-7-yl)methyl]-4propylpyrrolidin-2-one;

4-propyl-1-{[5-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-7yl]methyl}pyrrolidin-2-one;

1-[(6-methyl-3H-imidazo[4,5-b]pyridin-7-yl)methyl]-4propylpyrrolidin-2-one;

1-[(6-phenyl-3H-imidazo[4,5-b]pyridin-7-yl)methyl]-4propylpyrrolidin-2-one;

1-[1-(1H-imidazol-4-yl)propyl]pyrrolidin-2-one;

1-[(5-methyl-1H-imidazol-4-yl)methyl]pyrrolidin-2-one;

1-[(2-methyl-1H-imidazol-4-yl)methyl]pyrrolidin-2-one;

1-(1H-imidazol-4-ylmethyl)-4-propylpyrrolidin-2-one;

1-({1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazol 4-yl}methyl)-4-propylpyrrolidin-2-one;

1-[(5-chloro-1H-imidazol-4-yl)methyl]-4-(2,3,5trifluorophenyl)pyrrolidin-2-one;

1-[(5-bromo-1H-imidazol-4-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;

— [(5-bromo-1H-imidazol-4-yl)methyl]-5-chloro-1,3-dihydro-2Nindol-2-one;

1-(1H-imidazol-5-ylamethyl)pyrrolidin-2-one;

1-[(1-methyl-1H-imidazol-5-yl)methyl]pyrrolidin-2-one;

1-methyl-5-[(2-oxopyrrolidin-1-yl)methyl]-1H-imidazole-4carbonitrile;

1-(1H-imidazol-5-ylamethyl)-4-phenylpyrrolidin-2-one;

1-[(1-methyl-1H-imidazol-5-yl)methyl]-4-phenylpyrrolidin-2one;

1-[(4-methoxy-1-methyl-1H-imidazol-5-yl)methyl]pyrrolidin2-one;

1-[(1-methyl-1H-imidazol-5-yl)methyl]-4-propylpyrrolidin-2·one;

1-methyl-5-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H- 75 045018 imidazole-4-carbonitrile;

1-methyl-5-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1Nimidazole-4-carboxamide;

N-benzyl-2-{5-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1Nimidazol-1-yl]acetamide;

1-methyl-5-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1Nimidazole-2-carbonitrile;

1-[(4-chloro-1H-imidazol-5-yl)methyl]-4-propylpyrrolidin-2one;

1-methyl-5-{[2-OXO-4-(2,3,5-trifluorophenyl)pyrrolidin-1yl]methyl}-1H-imidazole-4-carbonitrile;

1-[(4-bromo-1-methyl-1H-imidazol-5-yl)methyl]-4propylpyrrolidin-2-one;

1-[(2,4-dichloro-1-methyl-1H-imidazol-5-yl)methyl]-4propylpyrrolidin-2-one;

benzyl-1-methyl-5-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]1H-imidazol-2-ylcarbamate;

1-[(4-chloro-1-methyl-1H-imidazol-5-yl)methyl]-4propylpyrrolidin-2-one;

1-[(2-chloro-1-methyl-1H-imidazol-5-yl)methyl]-4propylpyrrolidin-2-one;

5-chloro-1-(1H-imidazol-5-ylamethyl)-1,3-dihydro-2H-indol-2one;

1-[(2,4-dichloro-1H-imidazol-5-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;

1-[(2,4-dichloro-1-methyl-1H-imidazol-5-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;

1-[(2-chloro-1-methyl-1H-imidazol-5-yl)methyl]-4-(2,3,5trifluorophenyl)pyrrolidin-2-one;

1-[(4-bromo-1-methyl-1H-imidazol-5-yl)methyl]-4-(2,3,5trifluorophenyl)pyrrolidin-2-one;

5-chloro-1-[(1-methyl-1H-imidazol-5-yl)methyl]-1,3-dihydro-2H indol-2-one;

1-[(4-chloro-1-methyl-1H-imidazol-5-yl)methyl]-4-(2,3,5trifluorophenyl)pyrrolidin-2-one;

1-(1H-indol-2-ylmethyl)-4-propylpyrrolidin-2-one;

- 76 045018

1-(1H-indol-3-ylmethyl)-4-propylpyrrolidin-2-one;

3-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-indole-5carbonitrile;

1-[(2-methyl-1H-indol-3-yl)methyl]-4-propylpyrrolidin-2-one

1-[(7-methoxy-1H-indol-3-yl)methyl]-4-propylpyrrolidin-2one;

1-[(6-nitro-1H-indol-3-yl)methyl]-4-propylpyrrolidin-2-one

4-propyl-1-{[6-(trifluoromethyl)-1H-indol-3yl]methyl}pyrrolidin-2-one;

1-[(5-nitro-1H-indol-3-yl)methyl]-4-propylpyrrolidin-2-one;

1-[(7-fluoro-1H-indol-3-yl)methyl]-4-propylpyrrolidin-2-one;

1-[(5-chloro-2-methyl-1H-indol-3-yl)methyl]-4propylpyrrolidin-2-one;

1-[ΙΗ-indol-3-yl(phenyl)methyl]-4-propylpyrrolidin-2-one;

1-[1-(ΙΗ-indol-3-yl)propyl]-4-propylpyrrolidin-2-one;

1-[2-furyl(ΙΗ-indol-3-yl)methyl]-4-propylpyrrolidin-2-one;

3-[(2-oxo-4-propylpyrrolidin-1-yl)(phenyl)methyl]-1H-indole 5-carbonitrile;

1-(1H-indol-4-ylmethyl)-4-propylpyrrolidin-2-one;

1-(1H-indol-7-ylmethyl)-4-propylpyrrolidin-2-one;

1-(isoxazol-4-ylmethyl)-4-propylpyrrolidin-2-one;

— [(1-phenyl-1H-pyrazol-4-yl)methyl]-4-(2,3,5trifluorophenyl)pyrrolidin-2-one;

1-[(1-methyl-1H-pyrazol-4-yl)methyl]-4-(2,3,5trifluorophenyl)pyrrolidin-2-one;

1-[(1-benzyl-1H-pyrazol-4-yl)methyl]-4-(2,3,5trifluorophenyl)pyrrolidin-2-one;

4-(2,3,5-trifluorophenyl)-1(1,3,5-trimethyl-1H-pyrazol-4yl)methyl]pyrrolidin-2-one;

4-phenyl-1-(1H-pyrazol-4-ylmethyl)pyrrolidin-2-one;

1-({1-[(4-methylphenyl)sulfonyl]-1H-pyrazol-4-yl}methyl)-4(2,3,5-trifluorophenyl)pyrrolidin-2-one;

1-(1H-pyrazol-4-ylmethyl)-4-(2,3,5-trifluorophenyl)pyrrolidin 2-one;

1-[(5-chloro-1,3-dimethyl-1H-pyrazol-4-yl)methyl]-4-(2,3,5trifluorophenyl)pyrrolidin-2-one;

- 77 045018

1-[(1-chloro-1H-pyrazol-4-yl)methyl]-4-(2,3,5trifluorophenyl)pyrrolidin-2-one;

1-[(3,5-dimethyl-1H-pyrazol-4-yl)methyl]-4-(2,3,5trifluorophenyl)pyrrolidin-2-one;

1-[(3-methyl-1H-pyrazol-4-yl)methyl]-4-(2,3,5trifluorophenyl)pyrrolidin-2-one;

— [(5-amino-1,3-dimethyl-1H-pyrazol-4-yl)methyl]-4-(2,3,5trifluorophenyl)pyrrolidin-2-one;

1-[(5-amino-1-methyl-1H-pyrazol-4-yl)methyl]-4propylpyrrolidin-2-one;

(-)-1-(1H-pyrazol-4-ylmethyl)-4-(2,3,5trifluorophenyl)pyrrolidin-2-one;

(+)-1-(1H-pyrazol-4-ylmethyl)-4-(2,3,5trifluorophenyl)pyrrolidin-2-one;

1-(1H-pyrazol-4-ylmethyl)-1,3-dihydro-2H-indol-2-one;

5-chloro-1-(1H-pyrazol-4-ylmethyl)-1,3-dihydro-2H-indol-2one;

5-chloro-1-({1-[(4-methylphenyl)sulfonyl]-1H-pyrazol-4yl}methyl)-1,3-dihydro-2H-indol-2-one;

1-{[5-chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4yl]methyl]-4-propylpyrrolidin-2-one;

1-[(5-amino-1H-pyrazol-4-yl)methyl]-4-(2,3,5trifluorophenyl)pyrrolidin-2-one;

1-[(1-benzyl-5-chloro-1H-pyrazol-4-yl)methyl]-4propylpyrrolidin-2-one;

1-[(1,3-dimethyl-1H-pyrazol-5-yl)methyl]-4-(2,3,5trifluorophenyl)pyrrolidin-2-one;

1-(1H-pyrazol-5-ylmethyl)-4-(2,3,5-trifluorophenyl)pyrrolidin 2-one;

1-[(4-bromo-1-methyl-1H-pyrazol-5-yl)methyl]-4-(2,3,5trifluorophenyl)pyrrolidin-2-one;

1-[(1-methyl-1H-pyrazol-5-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one;

1-[(6-bromo-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4propylpyrrolidin-2-one;

1-[(2-methylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-78 045018 propylpyrrolidin-2-one;

1-[(6-bromo-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4propylpyrrolidin-2-one;

1-[(6-bromo-2-thien-2-ylpyrazolo[1,5-a]pyrimidin-3yl)methyl]-4-propylpyrrolidin-2-one;

4-propyl-1-[(2-thien-2-ylpyrazolo[1,5-a]pyrimidin-3yl)methyl]pyrrolidin-2-one;

1-[(6-bromo-2-cyclopropylpyrazolo[1,5-a]pyrimidin-3yl)methyl]-4-propylpyrrolidin-2-one;

1-[(6-bromo-2-tert-butylpyrazolo[1,5-a]pyrimidin-3yl)methyl]-4-propylpyrrolidin-2-one;

1-[(2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4propylpyrrolidin-2-one;

1-[(2-tert-butyl-6-cyclopropylpyrazolo[1,5-a]pyrimidin-3yl)methyl]-4-propylpyrrolidin-2-one;

1-{[2-(2-furyl)pyrazolo[1,5-a]pyrimidin-3-yl]methyl}-4propylpyrrolidin-2-one;

1-[(2-methyl-6-thien-2-ylpyrazolo[1,5-a]pyrimidin-3yl)methyl]-4-propylpyrrolidin-2-one;

1-[(2-methyl-6-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4 propylpyrrolidin-2-one;

1-{[2-methyl-6-(1H-pyrrol-2-yl)pyrazolo[1,5-a]pyrimidin-3yl]methyl]-4-propylpyrrolidin-2-one;

1-({6-[(1E)-hex-1-enyl]-2-methylpyrazolo[1,5-a]pyrimidin3-yl}methyl)-4-propylpyrrolidin-2-one;

1-[(b-chloro-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4propylpyrrolidin-2-one;

1-{[2-methyl-b-(phenylethynyl)pyrazolo[1,5-a]pyrimidin-3yl]methyl]-4-propylpyrrolidin-2-one;

1-[(b-bromo-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4(2,2-difluorovinyl)pyrrolidin-2-one;

— [(b-hydroxy-2-methylpyrazolo[1,5-a]pyrimidin-3yl)methyl]-4-propylpyrrolidin-2-one;

1-[(b-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4 propylpyrrolidin-2-one;

4-(2,2-difluorovinyl)-1-[(2-phenylpyrazolo[1,5-a]pyrimidine-3

- 79 045018 yl)methyl]pyrrolidin-2-one;

1-[(6-methoxy-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]4-propylpyrrolidin-2-one;

1-[(5-chloropyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4propylpyrrolidin-2-one;

4-(2,2-difluorovinyl)-1-[(5,6-dimethyl-2-phenylpyrazolo[1,5a]pyrimidin-3-yl)methyl]pyrrolidin-2-one;

4-(2,2-difluorovinyl)-1-[(6-fluoro-5-methyl-2phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]pyrrolidin-2-one;

1-[(5-methoxypyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4propylpyrrolidin-2-one;

1-{[2-(4-bromophenyl)pyrazolo[1,5-a]pyrimidin-3-yl]methyl}-4 (2,2-difluorovinyl)pyrrolidin-2-one;

1-{[2-(4-fluorophenyl)pyrazolo[1,5-a]pyrimidin-3-yl]methyl}-4 propylpyrrolidin-2-one;

4-(2,2-difluorovinyl)-1-[(6-methyl-2-phenylpyrazolo[1,5a]pyrimidin-3-yl)methyl]pyrrolidin-2-one;

4-(2,2-difluorovinyl)-1-[(5-methyl-2-phenylpyrazolo[1,5—

a]pyrimidin-3-yl)methyl]pyrrolidin-2-one;

4-(2,2-difluorovinyl)-1-[(2-thien-2-ylpyrazolo[1,5—

a]pyrimidin-3-yl)methyl]pyrrolidin-2-one;

1-{[2-(4-chlorophenyl)-6-methylpyrazolo[1,5-a]pyrimidin-3yl]methyl}-4-propylpyrrolidin-2-one;

1-{[2-(4-chlorophenyl)pyrazolo[1,5-a]pyrimidin-3-yl]methyl}-4 (2,2-difluorovinyl)pyrrolidin-2-one;

1-[(6-chloro-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4(2,2-difluorovinyl)pyrrolidin-2-one;

1-{[6-chloro-2-(4-chlorophenyl)pyrazolo[1,5-a]pyrimidin-3yl]methyl}-4-(2,2-difluorovinyl)pyrrolidin-2-one;

1-[(2-cyclopropyl-5-methylpyrazolo[1,5-a]pyrimidin-3yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one;

1-[(5-chloro-2-cyclopropylpyrazolo[1,5-a]pyrimidin-3yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one;

1-[(5-chloro-2,6-dimethylpyrazolo[1,5-a]pyrimidin-3yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one;

1-[(5-bromo-1H-pyrazolo[3,4-b]pyridin-3-yl)methyl]-4-(2,2—

- 80 045018 difluorovinyl)pyrrolidin-2-one;

4-propyl-1-(pyridin-3-ylmethyl)pyrrolidin-2-one;

(-)-1-(1-pyridin-3-ylpropyl)pyrrolidin-2-one;

5-chloro-1-[(2-fluoropyridin-3-yl)methyl]-1,3-dihydro-2H-indol·2-one;

1-[(6-chloropyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;

1-{[6-(benzylamino)pyridin-3-yl]methyl}-4-propylpyrrolidin·2-one;

1-[(2-aminopyridin-3-yl)methyl]-4-propylpyrrolidin-2-one;

4-propyl-1-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)pyrrolidin 2-one;

1-[(2-isopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-4propylpyrrolidin-2-one;

1-[(2-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-4propylpyrrolidin-2-one;

4-propyl-1-[(2-propyl-1H-pyrrolo[2,3-b]pyridin-3yl)methyl]pyrrolidin-2-one;

1-[(6-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-4propylpyrrolidin-2-one;

1-[(1-benzoyl-6-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]4-propylpyrrolidin-2-one;

1-[(6-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-4propylpyrrolidin-2-one;

1-[(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-4-(2,2difluorovinyl)pyrrolidin-2-one;

1-[(7-oxido-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-4propylpyrrolidin-2-one;

4-propyl-1-(1H-pyrrolo[2,3-b]pyridin-4-ylmethyl)pyrrolidin 2-one;

4-propyl-1-(1H-pyrrolo[2,3-b]pyridin-5-ylmethyl)pyrrolidin 2-one;

4-propyl-1-(1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)pyrrolidin 2-one;

4-propyl-1-(1H-pyrrolo[2,3-c]pyridin-3-ylmethyl)pyrrolidin 2-one;

4-propyl-1-(1H-pyrrolo[3,2-b]pyridin-3-ylmethyl)pyrrolidine

- 81 045018

2-she;

4-propyl-1-(1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)pyrrolidin 2-one;

4-propyl-1-(1H-pyrrolo[3,2-c]pyridin-3-ylmethyl)pyrrolidin 2-one;

4-propyl-1-(1,3,4-thiadiazol-2-ylmethyl)pyrrolidin-2-one;

1-[(2-amino-1,3-thiazol-5-yl)methyl]pyrrolidin-2-one;

1-(1,3-thiazol-5-ylmethyl)pyrrolidin-2-one;

1-[(2-chloro-1,3-thiazol-5-yl)methyl]-4-(2,3,5trifluorophenyl)pyrrolidin-2-one;

1-{[2-(dimethylamino)-1,3-thiazol-5-yl]methyl}-4-(2,3,5trifluorophenyl)pyrrolidin-2-one;

1-{[2-(methylamino)-1,3-thiazol-5-yl]methyl}-4-(2,3,5trifluorophenyl)pyrrolidin-2-one;

1-[(2-pyrrolidin-1-yl-1,3-thiazol-5-yl)methyl]-4-(2,3,5trifluorophenyl)pyrrolidin-2-one;

5-{[2-OXO-4-(2,3,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-

1,3-thiazol-2(3N)-one;

4-phenyl-1-{[3-(trifluoromethyl)[1,2,4]triazolo[4,3—

b]pyridazin-7-yl]methyl}pyrrolidin-2-one;

4-phenyl-1-[(3-phenyl[1,2,4]triazolo[4,3-b]pyridazin-7yl)methyl]pyrrolidin-2-one;

4-phenyl-1-{[3-(trifluoromethyl)[1,2,4]triazolo[4,3b]pyridazin-8-yl]methyl}pyrrolidin-2-one;

4-propyl-1-{[3-(trifluoromethyl)[1,2,4]triazolo[4,3—

b]pyridazin-8-yl]methyl}pyrrolidin-2-one;

4-phenyl-1-[(3-phenyl[1,2,4]triazolo[4,3-b]pyridazin-8yl)methyl]pyrrolidin-2-one;

1-[(6-chloro-3-phenyl[1,2,4]triazolo[4,3-b]pyridazin-8yl)methyl]-4-propylpyrrolidin-2-one;

1-[(6-chloro[1,2,4]triazolo[4,3-b]pyridazin-8-yl)methyl]-4phenylpyrrolidin-2-one;

1-{[6-chloro-3-(trifluoromethyl)[1,2,4]triazolo[4,3b]pyridazin-8-yl]methyl}-4-phenylpyrrolidin-2-one;

1-[(6-chloro-3-phenyl[1,2,4]triazolo[4,3-b]pyridazin-8yl)methyl]-4-phenylpyrrolidin-2-one;

- 82 045018

1-[(2-fluorindolyzin-3-yl)methyl]-4-propylpyrrolidin-2-one

1-(1H-1,2,3-benzotriazol-1-ylmethyl)-4-propylpyrrolidin-2·one

1-[(6-bromo-2-chloro-1H-imidazo[4,5-b]pyridin-1-yl)methyl]-4propylpyrrolidin-2-one;

1-[(6-bromo-2-phenyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl]-4 propylpyrrolidin-2-one;

1-(3H-imidazo[4,5-b]pyridin-3-ylmethyl)-4-propylpyrrolidine

2-she

1-[(6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl]-4propylpyrrolidin-2-one;

1-[(6-bromo-2-chloro-3H-imidazo[4,5-b]pyridin-3-yl)methyl]-4propylpyrrolidin-2-one;

1-[(b-bromo-2-phenyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl]-4 propylpyrrolidin-2-one;

1-[(6-bromo-2-cyclopropyl-3H-imidazo[4,5-b]pyridin-3yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one;

1-[(3-chloro-7H-IMIDazo[4,5-c]pyridazin-7-yl)methyl]-4propylpyrrolidin-2-one;

1-[(2-chloro-1H-indol-1-yl)methyl]-4-propylpyrrolidin-2-one;

1-[(5-methyl-1H-indol-1-yl)methyl]-4-propylpyrrolidin-2-one

1-[(6-methyl-1H-indol-1-yl)methyl]-4-propylpyrrolidin-2-one

1-[(2-phenyl-1H-indol-1-yl)methyl]-4-propylpyrrolidin-2-one

1-[(5-fluoro-1H-indol-1-yl)methyl]-4-propylpyrrolidin-2-one;

1-[(5-bromo-1H-indol-1-yl)methyl]-4-propylpyrrolidin-2-one;

1-[(5-chloro-1H-indol-1-yl)methyl]-4-propylpyrrolidin-2-one;

1-(2,3-dihydro-1H-indol-1-ylmethyl)-4-propylpyrrolidin-2one

1-[(5-fluoro-2-phenyl-1H-indol-1-yl)methyl]-4propylpyrrolidin-2-one;

1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-indole-2carbonitrile;

1-[(2-bromo-1H-indol-1-yl)methyl]-4-propylpyrrolidin-2-one 1-[(2,5-dichloro-1H-indol-1-yl)methyl]-4-propylpyrrolidine -2 she

1-[(6-amino-9H-purin-9-yl)methyl]-4-propylpyrrolidin-2-one

- 83 045018

4-propyl-1-(9H-purin-9-ylmethyl)pyrrolidin-2-one;

1-{[6-(cyclopropylamino)-9H-purin-9-yl]methyl}-4propylpyrrolidin-2-one;

1-{[6-(benzylamino)-9H-purin-9-yl]methyl}-4propylpyrrolidin-2-one;

4-propyl-1-{[6-(propylamino)-9H-purin-9yl]methyl}pyrrolidin-2-one;

1-({6-[(cyclopropylmethyl)amino]-9H-purin-9-yl}methyl)-4propylpyrrolidin-2-one;

4-propyl-1-[(6-pyrrolidin-1-yl-9H-purin-9yl)methyl]pyrrolidin-2-one;

1-[(5-bromo-3-phenyl-1H-pyrazolo[3,4-b]pyridin-1-yl)methyl]4-propylpyrrolidin-2-one;

1-[(5-bromo-2H-pyrazolo[3,4-b]pyridin-2-yl)methyl]-4propylpyrrolidin-2-one;

1-[(5-bromo-3-phenyl-2H-pyrazolo[3,4-b]pyridin-2-yl)methyl]4-propylpyrrolidin-2-one;

1-[(2-chloro-1H-pyrrolo[2,3-b]pyridin-1-yl)methyl]-4propylpyrrolidin-2-one;

4-propyl-1-(1H-pyrrolo[3,2-b]pyridin-1-ylmethyl)pyrrolidin 2-one;

1-(3,4-dihydroquinolin-1(2H)-ylmethyl)-4-propylpyrrolidin-2one;

1-(8H-isothiazolo[5,4-b]indol-8-ylmethyl)-4propylpyrrolidin-2-one;

1-(1H-1,2,4-triazol-1-ylmethyl)pyrrolidin-2-one;

1-[(2,5-dichloro-1H-pyrrol-1-yl)methyl]-4-propylpyrrolidin-2one;

1-[(2-chloro-1H-pyrrol-1-yl)methyl]-4-propylpyrrolidin-2-one

1-[(2-chloro-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin 2-one;

1-[(2-chloro-1H-benzimidazol-1-yl)methyl]-4-phenylpyrrolidin2-one;

2-chloro-1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1Hbenzimidazole-5-carbonitrile;

2-chloro-1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H- 84 045018 benzimidazole-6-carbonitrile;

4-propyl-1-[(2,5,b-trichloro-1H-benzimidazol-1yl)methyl]pyrrolidin-2-one;

1-[(2-chloro-6-methoxy-1H-benzimidazol-1-yl)methyl]-4propylpyrrolidin-2-one;

1-[(2-chloro-5-methoxy-1H-benzimidazol-1-yl)methyl]-4propylpyrrolidin-2-one;

1-[(2-chloro-6-nitro-1H-benzimidazol-1-yl)methyl]-4propylpyrrolidin-2-one;

1-[(2-chloro-5-nitro-1H-benzimidazol-1-yl)methyl]-4propylpyrrolidin-2-one;

1-[(2-chloro-6-methyl-1H-benzimidazol-1-yl)methyl]-4propylpyrrolidin-2-one;

1-[(2-chloro-1H-benzimidazol-1-yl)methyl]-4-(2,2difluorovinyl)pyrrolidin-2-one;

1-[(6-bromo-2-chloro-1H-benzimidazol-1-yl)methyl]-4propylpyrrolidin-2-one;

1-[(5-bromo-2-chloro-1H-benzimidazol-1-yl)methyl]-4propylpyrrolidin-2-one;

1-[(2-chloro-6-fluoro-1H-benzimidazol-1-yl)methyl]-4propylpyrrolidin-2-one;

1-[(2-chloro-5-fluoro-1H-benzimidazol-1-yl)methyl]-4propylpyrrolidin-2-one;

1-[(2,6-dichloro-1H-benzimidazol-1-yl)methyl]-4propylpyrrolidin-2-one;

1-[(2,5-dichloro-1H-benzimidazol-1-yl)methyl]-4propylpyrrolidin-2-one;

1-{[2-chloro-b-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}-4propylpyrrolidin-2-one;

1-{[2-chloro-5-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}-4propylpyrrolidin-2-one;

1-[(2-chloro-1H-benzimidazol-1-yl)methyl]pyrrolidin-2-one;

1-[(2-chloro-b-hydroxy-1H-benzimidazol-1-yl)methyl]-4propylpyrrolidin-2-one;

1-(pyridin-4-ylmethyl)pyrrolidin-2-one and

1-[(2-chloro-5-hydroxy-1H-benzimidazol-1-yl)methyl]-4propylpyrrolidin-2-one.

viii) US Patent No. 4696943

The present invention relates to a new compound, (S)-α-ethyl-2-oxo-1-pyrrolidine acetamide.

ix) US Patent No. 4696942

The present invention relates to a new compound, (R)-α-ethyl-2-oxo-1-pyrrolidine acetamide.

x) US Patent No. 5334720

According to the present invention, it relates to new compounds of formula I

R ₆ in which R ¹ , R ² , R ³ and R ⁴ , which may be the same or different, are independently hydrogen, C ₁ . ₆ alkyl, phenyl or phenyl substituted with one or more halogen atoms, hydroxyls, nitro, amino, C ₁ . ₆ alkyls or C ₁ -C ₆ -alkoxy groups;

- 85 045018

R ⁵ and R ⁶ independently represent hydrogen, C 1 -C ₆ -alkyl or C 3 -C ₆ -cycloalkyl, or R ⁵ and R ⁶ together with nitrogen form a C _4-6 N heterocycle;

m is an integer from 1 to 2 and n is an integer from 1 to 3;

with the proviso that two of R ¹ , R ² , R ³ and R ⁴ are independently phenyl or substituted phenyl and the other _two are independently hydrogen or C _{1_6} alkyl;

or pharmaceutically acceptable acid addition salts thereof.

Pharmaceutically acceptable acid addition salts of the compounds of formula I include salts of inorganic acids, for example, hydrohalic acids, such as hydrochloric acid or hydrobromic acid; or organic acids, such as formic, acetic or lactic acids. The acid may be polyhydric, such as sulfuric, fumaric, maleic or citric acid.

The present invention also applies to all stereoisomeric forms and optical enantiomeric forms of the compounds of formula I.

In the compounds of formula I, the alkyl groups, which are R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ , may include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl and sec-butyl;

cycloalkyl groups, which are R ⁵ and R ⁶ , may include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl;

C ₁ . ₆ alkoxy groups include methoxy, ethoxy and propoxy;

halogens include fluorine, chlorine, bromine or iodine;

Preferred are the compounds of formula I or their pharmaceutically acceptable acid addition salts, in which

R ¹ represents hydrogen, phenyl or substituted phenyl, preferably phenyl;

R ² represents hydrogen, phenyl or substituted phenyl, preferably phenyl;

R ³ is hydrogen, phenyl or substituted phenyl, preferably hydrogen;

R ⁴ is hydrogen, phenyl or substituted phenyl, preferably hydrogen;

R ⁵ represents hydrogen, C ₁ . ₃ alkyl or cyclopropyl, preferably hydrogen or methyl;

R ⁶ represents hydrogen, C ₁ . ₃ alkyl or cyclopropyl, preferably hydrogen or methyl;

m is an integer from 1 to 2, preferably 2;

n is an integer from 1 to 2, preferably 1.

Particularly preferred are compounds of formula I in which both R ¹ and R ² are phenyl.

Particularly preferred are compounds of formula I in which one of R ⁵ and R ⁶ is hydrogen and the other is hydrogen or methyl.

xi) Published international patent application WO2005/054188

According to one aspect, the invention relates to a compound characterized by Formula I, or a pharmaceutically acceptable salt thereof

Where

R ¹ represents hydrogen, C ₁ . ₂₀ alkyl, C ₃ . ₂₃ cycloalkyl, halogen, hydroxy, alkoxy, aryloxy, ester, amido, cyano, nitro, amino, guanidine, amino derivative, alkylthio, arylthio, alkylsulfonyl, arylsulfonyl, alkylsulfinyl, arylsulfinyl, aryl or heterocycle;

R ² represents hydrogen, C ₁ . ₂₀ alkyl, alkoxy, amino, halogen, hydroxy, ester, amido, nitro, cyano, carbamate, or aryl;

R ³ represents hydrogen, C ₁ . ₂₀ alkyl, alkoxy, amino, halogen, hydroxy, ester, amido, nitro, cyano, carbamate, or aryl;

or R ² and R ³ can form together with the imidazole ring the following 1H-benzimidazole ring

R ⁴ represents hydrogen, C ₁ . ₂₀ alkyl, C ₂ . ₁₂ alkenyl, C ₂ . ₁₂ alkynyl, aryl, azido, alkoxycarbonylamino, arylsulfonyloxy or heterocycle;

R ^4a represents hydrogen or C1.20alkyl; or R ⁴ and R ^4a may together form C3. ₈ ci- 86 045018 cloalkyl;

R ⁵ represents hydrogen; or R ⁴ , R ^4a and R ⁵ can form together with the 2-oxo-1-pyrrolidine ring the following 1,3-dihydro-2H-indol-2-one ring

R ⁶ represents hydrogen or C _1-20 alkyl;

R ⁷ represents hydrogen or R ⁶ and R ⁷ are linked together to form a C _3-6 cycloalkyl;

R ⁸ is hydrogen, halogen, nitro, cyano, C _1-20 alkyl or alkoxy;

R ⁹ is hydrogen, C _1-20 alkyl, halogen, hydroxy, alkoxy, aryloxy, ester, amido, cyano, nitro, amino, amino derivative, alkylthio, arylthio, alkylsulfonyl, arylsulfonyl, alkylsulfinyl or arylsulfinyl;

R ¹⁰ is hydrogen, C _1-20 alkyl, halogen, hydroxy, alkoxy, aryloxy, ester, amido, cyano, nitro, amino, amino derivative, alkylthio, arylthio, alkylsulfonyl, arylsulfonyl, alkylsulfinyl or arylsulfinyl;

R ¹¹ is hydrogen, halogen, nitro, cyano, C _1-20 alkyl or alkoxy;

R ¹² represents hydrogen or halogen;

R ¹³ represents hydrogen, nitro, halogen, heterocycle, amino, aryl, C _1-20 alkyl, unsubstituted or substituted with halogen, or alkoxy, unsubstituted or substituted with halogen;

R ¹⁴ represents hydrogen, C _1-20 alkyl or halogen;

R ¹⁵ represents hydrogen, C _1-20 alkyl or halogen;

with the proviso that R ⁴ is other than hydrogen if it is a group of the formula

An asterisk * denotes the point of substituent addition.

According to a preferred embodiment, the invention relates to the compound characterized by formula 1, its tautomers, geometric isomers (including cis- and trans-, Z and E isomers), enantiomers, diastereoisomers and mixtures thereof (including all possible mixtures of stereoisomers), or pharmaceutically acceptable salts

Rt ^r4 /—V

R ⁵ X Λο ϊ / ' (I)

^R3 ,

Where

R ¹ is hydrogen, C1-20alkyl, C3-8cycloalkyl, halogen, hydroxy, ester, amido, cyano, nitro, amino, guanidine, alkylthio, alkylsulfonyl, alkylsulfinyl, aryl or heterocycle; R ² is hydrogen, C1-20alkyl, halogen, cyano, ester, carbamate or amido; R ³ is hydrogen, cyano, C _1-20 alkyl, halogen or ester; or R ² and R ³ can form together with the imidazole ring the following 1H-benzimidazole ring

R ⁴ represents hydrogen, C _1-20 alkyl, C _2-12 alkenyl or aryl; R ^4a represents hydrogen; R ⁵ represents hydrogen; or R ⁴ , R ^4a and R ⁵ can form together with the 2-oxo-1-pyrrolidine ring the following 1,3-dihydro-2H-indol-2-one ring

- 87 045018

R ⁶ represents hydrogen or C1-20alkyl; R ⁷ represents hydrogen; or R ⁶ and R ⁷ are linked together to form a C3-6 cycloalkyl; R ⁸ represents hydrogen; R ⁹ is hydrogen, C1-20alkyl, halogen or alkoxy; R ¹⁰ is hydrogen, C1-20alkyl, halogen or cyano; R ¹¹ represents hydrogen; R ¹² represents hydrogen or halogen; R ¹³ represents hydrogen, halogen, heterocycle or C _1-20 alkyl; R ¹⁴ represents hydrogen; R ¹⁵ represents hydrogen; provided that ^R4 is other than hydrogen if

represents a group of the formula

As used herein, the term alkyl represents saturated, monovalent hydrocarbon radicals containing straight (branched) or branched or cyclic moieties or combinations thereof, and containing 1-20 carbon atoms, preferably 1-10 carbon atoms, more preferably 1-4 carbon atoms ; most preferably alkyl groups contain 1-3 carbon atoms. The alkyl moieties may optionally be substituted with 1 to 5 substituents independently selected from the group consisting of halogen, hydroxy, cyano, azido, aryloxy, alkoxy, alkylthio, alkanoylamino, arylcarbonylamino, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, or aryl. In this case, alkyl groups are usually methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, 1-ethylpropyl, n-heptyl, 2,4,4-trimethylpentyl, ndecyl, chloromethyl, trifluoromethyl , 2-bromo-2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, hydroxymethyl, cyanomethyl, azidomethyl, (acetylamino)methyl, (propionylamino)methyl, (benzoylamino)methyl, (4 -chlorophenoxy)methyl, benzyl, 2-phenylethyl or 2-(methylthio)ethyl. Preferred alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, 1ethylpropyl, 2,4,4-trimethylpentyl, chloromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, hydroxymethyl, cyanomethyl , azidomethyl, (acetylamino)methyl, (propionylamino)methyl, (benzoylamino)methyl or 2(methylthio)ethyl. More preferred alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, azidomethyl or trifluoromethyl. The most preferred alkyl groups are methyl or n-propyl.

As used herein, the term cycloalkyl refers to a monovalent group with 38 carbon atoms, typically 3-6 carbon atoms, derived from a saturated cyclic hydrocarbon, which may be substituted by any suitable group, including without limitation one or more moieties selected from the groups described above for alkyl groups. Preferred cycloalkyl groups are cyclopropyl and cyclohexyl.

As used herein, the term alkenyl represents straight, branched or cyclic unsaturated hydrocarbon radicals or combinations thereof, containing at least one carbon-carbon double bond, and containing 2-12 carbon atoms, preferably typically 2-4 carbon atoms. Alkenyl groups are optionally substituted with any suitable group, including, without limitation, one or more moieties selected from the groups described above for alkyl groups. Typically, the alkenyl group is ethenyl (vinyl), optionally substituted with 1-3 halogen atoms. In the present case, preferred alkenyl groups are 2,2-difluorovinyl.

As used herein, the term alkynyl represents straight, branched or cyclic hydrocarbon radicals or combinations thereof, containing at least one carbon-carbon triple bond, containing 2-12 carbon atoms, preferably 2-6 carbon atoms, and which are optionally substituted any suitable group, including without limitation one or more moieties selected from the groups described above for alkyl groups. Preferably, the alkynyl group is a haloalkynyl group (haloalkynyl group).

Groups containing prefixes such as second, iso, tert, etc. (for example, isopropyl,

- 88 045018 sec-butyl) are branched derivatives.

As used herein, the term aryl is defined as phenyl optionally substituted with 1-4 substituents independently selected from halogen, cyano, alkoxy, alkylthio, C ₁ . ₃ alkyl or azido, preferably halogen or azido. In the present case, generally aryl groups are phenyl, 3-chlorophenyl, 3-fluorophenyl, 4-chlorophenyl, 4-fluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 3-chloro-4-fluorophenyl, 2,3,4- trifluorophenyl, 2,4,5-trifluorophenyl, 2,3,5-trifluorophenyl, 3,4,5-trifluorophenyl, 3-azido-2,4-difluorophenyl or 3-azido-2,4,6-trifluorophenyl. Preferably, the aryl groups are phenyl, 3-chlorophenyl, 3-fluorophenyl, 4-chlorophenyl, 4-fluorophenyl, 3,4difluorophenyl, 3,5-difluorophenyl, 3-chloro-4-fluorophenyl, 2,3,4-trifluorophenyl, 2 ,4,5-trifluorophenyl, 2,3,5-trifluorophenyl, 3,4,5-trifluorophenyl or 3-azido-2,4-difluorophenyl. Most preferably, aryl groups are phenyl, 3-chlorophenyl, 3-fluorophenyl, 3,5-difluorophenyl, 2,3,4-trifluorophenyl, 2,4,5-trifluorophenyl, 2,3,5-trifluorophenyl, 3,4, 5-trifluorophenyl or 3-azido-2,4-difluorophenyl.

As used herein, the term heterocycle is defined to include an aromatic or non-aromatic cycloalkyl moiety as defined above and containing at least one O, S and/or N atom interrupting the carbocyclic ring structure. The heterocyclic ring moieties may optionally be replaced by alkyl groups or halogen atoms, and optionally one of the carbon atoms of the carbocyclic ring structure may be replaced by a carbonyl. Typically heterocycles are 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-tetrahydrofuranyl, N-pyrrol-2-yl, 1-methyl-1H-pyrrol- 2-yl, 1 H-pyrazol-2-yl, 1 H-pyrazol-3-yl, 4-chloro-1-methyl-1 H-pyrazol-3-yl, 5-chloro-1,3-dimethyl-1 H-pyrazol-4yl, 1,2,3-thiadiazol-4-yl, 3,5-dimethyl-4-isothiazyl, 1H-imidazol-2-yl, 1-methyl-1H-imidazol-2-yl, 4methyl- Sh-imidazol-5-yl or 2-methyl-1,3-thiazol-4-yl. Preferred heterocycles are 1H-imidazol-2-yl, 1,2,3-thiadiazol-4-yl, 1H-pyrazol-3-yl, 2-furyl, 3-furyl, 2-thienyl, 1-methylIII-pyrrol- 2-yl, Sh-pyrrol-2-yl.

As used herein, the term halogen includes chlorine, bromine, fluorine, iodine. Typically, halogens are chlorine, bromine and fluorine. Preferred halogens are fluorine, bromine and chlorine.

As used herein, the term hydroxy represents a group of the formula -OH.

As used herein, the term alkoxy is a group of the formula -OR ^a where R ^a represents an alkyl group as defined above. A preferred alkoxy group is methoxy.

As used herein, the term aryloxy represents a group of the formula OR ^b , where R ^b represents an aryl group as defined above. A preferred aryloxy group is phenoxy.

As used herein, the term ester is a group of the formula -COOR ^c where R ^c represents an alkyl group or aryl group as defined above. A preferred ester group is methoxycarbonyl.

As used herein, the term amido represents a group of the formula -CONH ₂ .

As used herein, the term amino represents a group of the formula -NH ₂ .

As used herein, the term amino derivative is an alkylamino or arylamino group, the terms alkyl and aryl as used herein being defined above.

As used herein, the term cyano represents a group of the formula -CN.

As used herein, the term nitro represents a group of the formula -NO2.

As used herein, the term azido is a group of the formula -N ₃ .

As used herein, the term guanidine represents a group of the formula -NHC(=NH)NH ₂ .

As used herein, the term alkylthio is a group of formula SR ^d where R ^d represents an alkyl group as defined above. One alkylthio group is methylthio.

As used herein, the term alkylsulfonyl is a group of the formula -S(=O) ₂ R ^e , where R ^e represents an alkyl group as defined above. One alkylsulfonyl group is methylsulfonyl.

As used herein, the term alkylsulfinyl is a group of the formula -S(=O)R ^f , where R ^f represents an alkyl group as defined above. One alkylsulfinyl group is methylsulfinyl.

As used herein, the term arylthio is a group of the formula -SR ^g , where R ^g is an aryl group as defined above.

As used herein, the term arylsulfonyl is a group of the formula -S(=O) ₂ R ^h where R ^h is an aryl group as defined above.

- 89 045018

As used herein, the term arylsulfinyl is a group of the formula -S(=O)R ⁱ where R ⁱ is an aryl group as defined above.

As used herein, the term carbamate is a group of the formula N(H)C(O)OR ^j where R ^j is alkyl or aryl as defined above. Typically, carbamate groups are (propoxycarbonyl)amino or (benzyloxycarbonyl)amino. One carbamate group is (benzyloxycarbonyl)amino.

As used herein, the term alkanoylamino represents a group of the formula -NHC(=O)R ^k where R ^k represents an alkyl group as defined above.

As used herein, the term (arylcarbonyl)amino represents a group of the formula NHC(=O)R ^m where R ^m represents an aryl group as defined above. One (arylcarbonyl)amino is benzoylamino.

Typically Rl is hydrogen; C ₁ . ₁₀ alkyl, unsubstituted or substituted with halogen, hydroxy, cyano, methylthio, phenyl or 4-chlorophenoxy; hydroxy; C ₃ . ₆ cycloalkyl; halogen; ester; amido; nitro; cyano; amino; phenyl; alkylthio; alkylsulfonyl; alkylsulfinyl; heterocycle, unsubstituted or substituted with alkyl groups; or guanidine.

In some embodiments, R ¹ is hydrogen; methyl; ethyl; isopropyl; n-propyl; cyclopropyl; n-butyl; isobutyl; tert-butyl; 1-ethylpropyl; 2,4,4-trimethylpentyl; hydroxymethyl; chloromethyl; trifluoromethyl; 2,2,2-trifluoroethyl; cyanomethyl; 2-(methylthio)ethyl; chlorine; bromine; nitro; cyano; amino; aminocarbonyl; methoxycarbonyl; methylthio; methylsulfinyl; methylsulfonyl; phenyl; 2-furyl; 3-furyl; Sh-pyrrol-2-yl; 1-methyl-1H-pyrrol-2-yl; 2-thienyl; 1H-pyrazol-3-yl; 1,2,3-thiadiazol-4-yl or 1H-imidazol-2-yl. More preferably, Rl is hydrogen; methyl; ethyl; isopropyl; n-propyl; n-butyl; methylthio; nitro; cyano; amino; chlorine or Ш-pyrrol-2-yl. Most preferably, R ¹ is hydrogen; methyl; methylthio; nitro; cyano; amino or chlorine.

Typically, R ² is hydrogen; C ₁ . ₄ alkyl, unsubstituted or substituted hydroxy, alkanoylamino or benzoylamino; halogen; ester; cyano; alkylcarbamate; [(N-methoxy-Nmethyl)amino]carbonyl. Preferably R ² represents hydrogen; methyl; hydroxymethyl; (acetylamino)methyl; (propionylamino)methyl; (benzoylamino)methyl; [(benzyloxy)carbonyl]amino; chlorine or cyano. In some embodiments, R ² is hydrogen; chlorine or cyano.

Typically R ³ is hydrogen; C ₁ . ₄ alkyl, unsubstituted or substituted hydroxy; halogen; ester or cyano. In some embodiments, R ³ is hydrogen; hydroxymethyl; chlorine; cyano. In some embodiments, R ³ is hydrogen or cyano. In some embodiments, R ³ is hydrogen.

Typically R ⁴ is hydrogen; C ₁ . ₄ alkyl, unsubstituted or substituted with halogen atoms; _C2 . ₄ alkenyl, substituted with halogen atoms, or a phenyl group, unsubstituted or substituted with azido and/or halogen atoms. Preferably R ⁴ is hydrogen; n-propyl; 2,2difluorovinyl; phenyl; 3-chlorophenyl; 3-fluorophenyl; 4-chlorophenyl; 4-fluorophenyl; 3,5-difluorophenyl; 3,4difluorophenyl; 3-chloro-4-fluorophenyl; 2,3,4-trifluorophenyl; 2,4,5-trifluorophenyl; 2,3,5-trifluorophenyl; 3,4,5trifluorophenyl; 3-azido-2,4-difluorophenyl or 3-azido-2,4,6-trifluorophenyl. More preferably, R ⁴ is hydrogen; n-propyl; 2,2-difluorovinyl; phenyl; 3-chlorophenyl; 3-fluorophenyl; 4chlorophenyl; 4-fluorophenyl; 3,5-difluorophenyl; 3,4-difluorophenyl; 3-chloro-4-fluorophenyl; 2,3,4-trifluorophenyl; 2,4,5-trifluorophenyl; 2,3,5-trifluorophenyl; 3,4,5-trifluorophenyl or 3-azido-2,4-difluorophenyl. Most preferably, R ⁴ is n-propyl; 2,2-difluorovinyl; phenyl; 3-chlorophenyl; 3-fluorophenyl; 3,5-difluorophenyl; 2,3,4-trifluorophenyl; 2,4,5-trifluorophenyl; 2,3,5-trifluorophenyl; 3,4,5-trifluorophenyl or 3-azido-2,4-difluorophenyl.

Typically R ^4a is hydrogen.

Typically R ⁵ is hydrogen.

Typically ^R6 is hydrogen or _C1 . ₁₀ αlkyl, unsubstituted or substituted with hydroxy or azido.

Preferably R ⁶ is hydrogen or azidomethyl. More preferably, R ⁶ is hydrogen.

Typically R ⁷ is hydrogen.

In other embodiments, R ⁶ and R ⁷ are coupled to form cyclopropyl.

In other embodiments, R ² and R ³ may form, together with the imidazole ring, the following 1 H-benzimidazole ring

Typically R ⁸ is hydrogen.

- 90 045018

Typically R ⁹ is hydrogen; halogen; C _1-3 alkyl or alkoxy. In some embodiments, R ⁹ is hydrogen; methyl; chlorine or methoxy. In some embodiments, R ⁹ is hydrogen.

Typically R ¹⁰ is hydrogen; halogen; cyano; C _1-3 alkyl, unsubstituted or substituted with halogen atoms; or alkoxy. In some embodiments, R ¹⁰ is methyl; hydrogen; trifluoromethyl; fluorine; cyano or methoxy. In some embodiments, R ¹⁰ is hydrogen; trifluoromethyl; fluorine or cyano.

Typically R ¹¹ is hydrogen.

In other embodiments, R ⁴ , R ^4a and R ⁵ may form together with the 2-oxo-1-pyrrolidine ring the following 1,3-dihydro-2H-indol-2-one ring

Typically R ¹² is hydrogen or halogen. In some embodiments, R ¹² is hydrogen, chlorine, or fluorine. In some embodiments, R ¹² is hydrogen.

Typically R ¹³ is hydrogen; C _1-3 alkyl; halogen or thiazolyl, unsubstituted or substituted with alkyl groups, such as methylthiazolyl. In some embodiments, R ¹³ is hydrogen; chlorine; bromine or methyl. In some embodiments, R ¹³ is chlorine, bromine, or methyl.

Typically R ¹⁴ is hydrogen.

Typically R ¹⁵ is hydrogen.

According to a general embodiment of the present invention, the compounds of formula I or pharmaceutically acceptable salts thereof are compounds in which

R ¹ is selected from hydrogen; C _1-10 αlkyl, unsubstituted or substituted with halogen, hydroxy, cyano, methylthio, phenyl or 4-chlorophenoxy; C _3-6 cycloalkyl; halogen; ester; amido; nitro; cyano; amino; phenyl; alkylthio; alkylsulfonyl; alkylsulfinyl; heterocycle, unsubstituted or substituted with an alkyl group; or guanidine;

R ² is selected from hydrogen; C _1-4 alkyl, unsubstituted or substituted with hydroxy, alkanoylamino or benzoylamino; halogen; ester; cyano; alkylcarbamate or [(N-methoxy-Nmethyl)amino]carbonyl;

R ³ is selected from hydrogen; C _1-4 alkyl, unsubstituted or substituted hydroxy; halogen; ester or cyano;

R ⁴ is selected from hydrogen; C _1-4 alkyl, unsubstituted or substituted with halogen atoms; C _2-4 alkenyl substituted with halogen atoms, or a phenyl group, unsubstituted or substituted with azido and/or halogen atoms;

R ^4a represents hydrogen;

R ⁵ represents hydrogen;

R ⁶ is selected from hydrogen or C _1-10 alkyl, unsubstituted or substituted hydroxy or azido;

R ⁷ is hydrogen or R ⁶ and R ⁷ can be combined to form cyclopropyl; or R ² and R ³ can form together with the imidazole ring the following 1H-benzimidazole ring

R ⁸ represents hydrogen;

R ⁹ is selected from hydrogen; halogen; C _1-3 alkyl; alkoxy;

R ¹⁰ is selected from hydrogen; halogen; cyano or Cil alkyl, unsubstituted or substituted with halogen atoms; or alkoxy;

R ¹ represents hydrogen; or R ⁴ , R ^4a and R ⁵ can form together with the 2-oxo-1-pyrrolidine ring the following 1,3-dihydro-2H-indol-2-one ring

R ¹² is selected from hydrogen or halogen;

R ¹³ is selected from hydrogen; C _1-3 alkyl; halogen; thiazolyl, unsubstituted or substituted with alkyl groups, such as methylthiazolyl;

R ¹⁴ represents hydrogen;

- 91 045018

R ¹⁵ represents hydrogen; with the proviso that R ⁴ is other than hydrogen if it is a group of the formula

According to some embodiment of the invention, compounds of Formula I, or a pharmaceutically acceptable salt thereof, are compounds in which

R ¹ is selected from hydrogen; methyl; ethyl; isopropyl; n-cut; cyclopropyl; n-butyl; isobutyl; tert-butyl; 1-ethylpropyl; 2,4,4-trimethylpentyl; trifluoromethyl; 2,2,2-trifluoroethyl; hydroxymethyl; chloromethyl; cyanomethyl; 2-(methylthio)ethyl; chlorine; bromine; nitro; cyano; amino; aminocarbonyl; methoxycarbonyl; methylthio; methylsulfinyl; methylsulfonyl; phenyl; 2-furyl; 3-furyl; 1H-pyrrol-2-yl; 1-methyl-1H-pyrrol-2-yl; 2-thienyl; 1H-pyrazol-3-yl; 1,2,3-thiadiazol-4-yl or 1Himidazol-2-yl;

R ² is selected from hydrogen; methyl; hydroxymethyl; (acetylamino)methyl; (propionylamino)methyl; (benzoylamino)methyl; (benzyloxycarbonyl)amino; chlorine or cyano;

R ³ is selected from hydrogen; hydroxymethyl; chlorine; cyano; or R ² and R ³ can form together with the imidazole ring the following III-benzimidazole ring

R ⁸ represents hydrogen;

R ⁹ is selected from hydrogen; methyl; chlorine; methoxy;

R ¹⁰ is selected from methyl; hydrogen; trifluoromethyl; fluorine; cyano; or methoxy; R represents hydrogen; R ⁴ is selected from hydrogen; n-cut; 2,2-difluorovinyl; phenyl; 3-chlorophenyl; 3fluorophenyl; 4-chlorophenyl; 4-fluorophenyl; 3,5-difluorophenyl; 3,4-difluorophenyl; 3-chloro-4-fluorophenyl2,3,4-trifluorophenyl; 2,4,5-trifluorophenyl; 2,3,5-trifluorophenyl; 3,4,5-trifluorophenyl; 3-azido-2,4difluorophenyl or 3-azido-2,4,6-trifluorophenyl; R ^4a represents hydrogen; R ⁵ represents hydrogen; or R ⁴ , R ^4a and R ⁵ can form together with the 2-oxo-1-pyrrolidine ring the following 1,3-dihydro-2H-indol-2-one ring

R ¹² is selected from hydrogen; chlorine; fluorine; R ¹³ is selected from hydrogen; chlorine; bromine; methyl; R ¹⁴ represents hydrogen; R ¹⁵ represents hydrogen; R ⁶ is selected from hydrogen; azidomethyl; R ⁷ represents hydrogen; or R ⁶ and R ⁷ are combined to form cyclopropyl, provided that R ⁴ is other than hydrogen if it is a group of the formula

According to one embodiment of the invention, the compounds of formula I or pharmaceutically acceptable salts thereof are compounds in which

R ¹ is selected from hydrogen; methyl; ethyl; isopropyl; n-cut; n-butyl; methylthio; nitro; cyano;

- 92 045018 amino; chlorine or 1H-pyrrol-2-yl; R ² is selected from hydrogen; chlorine; cyano; R ³ is selected from hydrogen;

cyano; or R ² and R ³ can form together with the imidazole ring the following 1Hbenzimidazole ring

R ⁸ represents hydrogen;

R ⁹ represents hydrogen;

R ¹⁰ is selected from hydrogen; trifluoromethyl; fluorine; cyano;

R ¹¹ represents hydrogen;

R ⁴ is selected from hydrogen; n-cut; 2,2-difluorovinyl; phenyl; 3-chlorophenyl; 3-fluorophenyl; 4chlorophenyl; 4-fluorophenyl; 3,5-difluorophenyl; 3,4-difluorophenyl; 3-chloro-4-fluorophenyl; 2,3,4trifluorophenyl; 2,4,5-trifluorophenyl; 2,3,5-trifluorophenyl; 3,4,5-trifluorophenyl or 3-azido-2,4difluorophenyl;

R ^4a represents hydrogen;

R ⁵ represents hydrogen; or R ⁴ , R ^4a and R ⁵ can form together with the 2-oxo-1-pyrrolidine ring the following 1,3-dihydro-2H-indol-2-one ring

in which R ¹² represents hydrogen;

R ¹³ is selected from methyl; chlorine; bromine;

R ¹⁴ represents hydrogen;

R ¹⁵ represents hydrogen; R ⁶ represents hydrogen;

R ⁷ represents hydrogen; provided that ^R4 is other than hydrogen if

R ¹¹ represents a group of the formula

According to one embodiment of the invention, the compounds of formula I or pharmaceutically acceptable salts thereof are compounds in which

R ¹ is selected from hydrogen; methyl; methylthio; nitro; cyano; amino; chlorine;

R ² is selected from hydrogen; chlorine; cyano;

R ³ represents hydrogen;

R ⁴ is selected from n-propyl; 2,2-difluorovinyl; phenyl; 3-chlorophenyl; 3-fluorophenyl; 3,5difluorophenyl; 2,3,4-trifluorophenyl; 2,4,5-trifluorophenyl; 2,3,5-trifluorophenyl; 3,4,5-trifluorophenyl; 3-azido-2,4-difluorophenyl;

R ^4a represents hydrogen;

R ⁵ represents hydrogen; or R ⁴ , R ^4a and R ⁵ can form together with the 2-oxo-1-pyrrolidine ring the following 1,3-dihydro-2H-indol-2-one ring

R ¹² represents hydrogen;

R ¹³ is selected from chlorine; bromine; methyl;

R ¹⁴ represents hydrogen; R ¹⁵ represents hydrogen;

R ⁶ represents hydrogen;

R ⁷ represents hydrogen.

- 93 045018

In some embodiments, the compounds are 1-(1H-imidazol-1ylmethyl)pyrrolidin-2-one; 1-(1H-imidazol-1-ylmethyl)-4-phenylpyrrolidin-2-one; 4-(3 -azido-2,4,6trifluorophenyl)-1 -(1H-imidazol-1 -ylmethyl)pyrrolidin-2-one; 1-(1H-imidazol-1-ylmethyl)-4-propylpyrrolidin-2-one; (-)-4-(3 -azido-2,4-difluorophenyl)-1 -(1 H-imidazol-1 -ylmethyl)pyrrolidin-2-one; (+)-4-(3 azido-2,4-difluorophenyl)-1-(1 H-imidazol-1 -ylmethyl)pyrrolidin-2-one; 1-[(2-ethyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1 -[(2-isopropyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1 [(2-methyl-III-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(2-phenyl-1H-imidazol-1-yl)methyl]-4propylpyrrolidin-2-one; 4-propyl-1-[(2-propyl-1 H-imidazol-1 -yl)methyl]pyrrolidin-2-one; (+)-1 -(1Himidazol-1 -ylmethyl)-4-propylpyrrolidin-2-one; (-)-1-(1 H-imidazol-1 -ylmethyl)-4-propylpyrrolidin-2one; 4-(2,2-difluorovinyl)-1-(1 H-imidazol-1 -ylmethyl)pyrrolidin-2-one; 4-(3-chlorophenyl)-1 -(1 H-imidazol1 -ylmethyl)pyrrolidin-2-one; 1 -{[2-(methylthio)-1H-imidazol-1 -yl]methyl}-4-propylpyrrolidin-2-one; 1 {[2-(methylsulfinyl)-1 H-imidazol-1 -yl]methyl}-4-propylpyrrolidin-2-one; 1 -[(2-tert-butyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-[1-(III-imidazol-1-yl)cyclopropyl]pyrrolidin-2-one; 1 [(2-methyl-III-imidazol-1-yl)methyl]-4-phenylpyrrolidin-2-one; 1-{[2-(methylsulfonyl)-1 H-imidazol-1 yl]methyl}-4-propylpyrrolidin-2-one; 1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-III-imidazole-2carboxamide; 4-(4-fluorophenyl)-1 -(1 H-imidazol-1 -ylmethyl)pyrrolidin-2-one; 1-(1H-imidazol-1ylmethyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one; 4-(3-fluorophenyl)-1-(III-imidazol-1-ylmethyl)pyrrolidin-2-one; 4-(3,5-difluorophenyl)-1 -(III-imidazol-1 -ylmethyl)pyrrolidin-2-one; 4-(3,4-difluorophenyl)1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 4-(3-chloro-4-fluorophenyl)-1-(1 H-imidazol-1 -ylmethyl)pyrrolidin-2-one; 4-(4-chlorophenyl)-1 -(1 H-imidazol-1 -ylmethyl)pyrrolidin-2-one; 1-(1H-imidazol-1ylmethyl)-4-(2,3,4-trifluorophenyl)pyrrolidin-2-one; 1-(1H-imidazol-1-ylmethyl)-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one; 1-(III-imidazol-1-ylmethyl)-4-(2,4,5-trifluorophenyl)pyrrolidin-2-one; 1-{[2(hydroxymethyl)-III-imidazol-1-yl]methyl}-4-propylpyrrolidin-2-one; methyl 1-[(2-oxo-4-propylpyrrolidin-1 -yl)methyl]-1H-imidazole-2-carboxylate; 1-[(2-nitro-1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one; 1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole2-carbonitrile; 1-[(2-amino-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(2,4-dichloro-Shimidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one; 1 -[(5-chloro-1 H-imidazol-1 -yl)methyl]-4(3,4,5-trifluorophenyl)pyrrolidin-2-one; 1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1Himidazole-4-carbonitrile; 1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5carbonitrile; (+)-1 -(1 H-imidazol-1 -ylmethyl)-4-phenylpyrrolidin-2-one; (-)-1-(1 H-imidazol-1 -ylmethyl)4-phenylpyrrolidin-2-one; 1-{[2-oxo-4-(2,3,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5carbonitrile; (-)-1-{[2-oxo-4-(2,3,4-trifluorophenyl)pyrrolidin-1-yl]methyl}-III-imidazole-5-carbonitrile; (+)-1-{[2-oxo-4-(2,3,4-trifluorophenyl)pyrrolidin-1-yl]methyl}-III-imidazole-5-carbonitrile; (-)1-{[2-oxo-4-(2,3,4-trifluorophenyl)pyrrolidin-1-yl]methyl}-III-imidazole-4-carbonitrile; (+)-1-{[2-oxo4-(2,3,4-trifluorophenyl)-1-pyrrolidinyl]methyl}-III-imidazole-4-carbonitrile; (-)-1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-III-imidazole-4-carbonitrile; (+)-1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-4-carbonitrile; (+)-1-{[2-oxo-4-(2,4,5-trifluorophenyl)pyrrolidin-1 -yl]methyl} -1 H-imidazole-4-carbonitrile; (-)-1-{[2-oxo-4-(2,4,5-trifluorophenyl)pyrrolidin-1 yl]methyl}-1H-imidazole-4-carbonitrile; (-)-1-{[2-oxo-4-(2,3,5-trifluorophenyl)pyrrolidin-1-ylmethyl}1 H-imidazol-4-carbonitrile; (-)-1-{ [2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1 -yl]methyl} -1 H-imidazole-5-carbonitrile; 1-{[2-oxo-4-(2,3,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5carbonitrile; 1-{[2-oxo-4-(2,3,5-trifluorophenyl)pyrrolidine-methyl}-III-imidazole-5-carbonitrile; 1-[(5methyl-2-phenyl-III-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1 -[(5-methyl-1 H-imidazol-1 -yl)methyl]-4-propylpyrrolidin-2-one; 1-[(5-phenyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(2ethyl-5-methyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(2,5-dimethyl-1H-imidazol-1 yl)methyl]-4-propylpyrrolidin-2-one; 1 -[(2-chloro-1 H-imidazol-1 -yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one; 1 -[2-azido-1 -(1 H-imidazol-1 -yl)ethyl]-4-propylpyrrolidin-2-one; 1 -[(4-chloro-1Himidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one; 1-[(2-bromo-4,5-dichloro-1H-imidazol-1yl)methyl]-4-propylpyrrolidin-2-one; 1 -[(2-chloro-1 H-imidazol-1 -yl)methyl]-4-propylpyrrolidin-2-one; (+)-1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile; 1-{[5-(hydroxymethyl)-1H-imidazoiso-1-yl]methyl}-4-propylpyrrolidin-2-one; 1-{[4-(hydroxymethyl)-1H-imidazol-1 -yl]methyl}-4-propylpyrrolidin-2-one; benzyl-1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1Himidazol-5-ylcarbamate; N-[(1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazol-5yl)methyl]acetamide; N-[(1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazol-5yl)methyl]benzamide; N-1-{(1-1[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazol-5yl)methyl]propanamide; 1-(1H-benzimidazol-1-ylmethyl)-4-propylpyrrolidin-2-one; 1 -[(2-methyl-1Hbenzimidazol-1 -yl)methyl]-4-propylpyrrolidin-2-one; 4-propyl-1-[(2-propyl-III-benzimidazol-1-yl)methyl]pyrrolidin-2-one; 1-[(2-isopropyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 4propyl-1-{ [2-(trifluoromethyl)-1H-benzimidazol-1 -yl]methyl} pyrrolidin-2-one; 1-{[2-(methylthio)-1Hbenzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one; 1 -[(2-amino-1 H-benzimidazol-1 -yl)methyl]-4-propylpyrrolidin-2-one; 1-{[2-(chloromethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one; {1[(2-oxo-4-propylpyrrolidin-1 -yl)methyl]-1 H-benzimidazol-2-yl} acetonitrile; 1-[(5-methoxy-1H-ben

- 94 045018 zimidazol-1 -yl)methyl]-4-propylpyrrolidin-2-one; 1 -[(5-methyl-1 H-benzimidazol-1 -yl)methyl]-4-propylpyrrolidin-2-one; 1-[(5,6-dimethyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-{[2isopropyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one; 1-[(6-chloro-1Hbenzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-2propyl-1H-benzimidazole-5-carbonitrile; 1-{[2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}-4propylpyrrolidin-2-one; 4-propyl-1-{[2-(1 H-pyrrol-2-yl)-1 H-benzimidazol-1 -yl]methyl}pyrrolidin-2one; 1 -[(5-fluoro-2-propyl-1 H-benzimidazol-1 -yl)methyl]-4-propylpyrrolidin-2-one; 1 - {[6-methyl-2-(1 Hpyrrol-2-yl)-1 H-benzimidazol-1 -yl]methyl}-4-propylpyrrolidin-2-one; 1 -[(6-methoxy-2-propyl-1 H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 2-butyl-1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]1 H-benzimidazole-5-carbonitrile; 1-{[2-[2-(methylthio)ethyl]-5-(trifluoromethyl)-1H-benzimidazol-1 -yl]methyl}-4-propylpyrrolidin-2-one; 1-[(5-fluoro-2-isobutyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-{[5-fluoro-2-(2,4,4-trimethylpentyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin2-one; 2-cyclopropyl-1-[(2-oxo-4-propylpyrrolidin-1 -yl)methyl]-1 H-benzimidazole-5-carbonitrile; 1 [(2-oxo-4-propylpyrrolidin-1 -yl)methyl]-2-(1 H-pyrazol-3 -yl)-1 H-benzimidazol-5-carbonitrile; 1-[(2cyclopropyl-5-fluoro-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(5-fluoro-2-isopropyl1 H-benzimidazol-1 -yl)methyl]-4-propylpyrrolidin-2-one; 1-{[2-(3-furyl)-6-methoxy-1H-benzimidazol1-ylmethyl}-4-propylpyrrolidin-2-one; 1-[(2-cyclopropyl-6-methoxy-1H-benzimidazol-1-yl)methyl]-4propylpyrrolidin-2-one; 1 -[(2-isopropyl-6-methoxy-1 H-benzimidazol-1 -yl)methyl]-4-propylpyrrolidin-2-one; 1 -[(2-oxo-4-propylpyrrolidin-1 -yl)methyl]-2-(1,2,3-thiadiazol-4-yl)-1 H-benzimidazol-5carbonitrile; 1-{[2-(1H-imidazol-2-yl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one; 1-{[5-fluoro-2-(2,2,2-trifluoroethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin2-one; 1-{[2-(1-ethylpropyl)-6-methoxy-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one; 1-{[6methoxy-2-(1 -methyl-1 H-pyrrol-2-yl)-1 H-benzimidazol-1 -yl]methyl}-4-propylpyrrolidin-2-one; 1-{[2-(2furyl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one; 4-propyl-1-{[2thien-2-yl-5-(trifluoromethyl)-1 H-benzimidazol-1 -yl]methyl}pyrrolidin-2-one; 1-{[2-(3-furyl)-5 -(trifluoromethyl)-1 H-benzimidazol-1 -yl]methyl}-4-propylpyrrolidin-2-one; 1-{[2-cyclopropyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one; 4-propyl-1-{[2-(1H-pyrrol-2-yl)-5(trifluoromethyl)-1 H-benzimidazol-1 -yl]methyl}pyrrolidin-2-one; 1-(1H-imidazol-1-ylmethyl)-1,3-dihydrO-2H-indol-2-one; 5-bromo-1 -(1 H-imidazol-1 -ylmethyl)-1,3-dihydro-2H-indol-2-one; 5-chloro-1 -(1Himidazol-1 -ylmethyl)-1,3-dihydro-2H-indol-2-one; 4-fluoro-1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2Nindol-2-one; 4-chloro-1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one; 1-(1H-imidazol-1-ylmethyl)5-methyl-1,3-dihydro-2H-indol-2-one; 1-[(2-oxo-2,3-dihydro-1H-indol-1 -yl)methyl]-1H-imidazol-5-carbonitrile and 1-[(5-chloro-2-oxo-2,3- Dihydro-1H-indol-1-yl)methyl]-1H-imidazole-5-carbonitrile.

In some embodiments, the compounds are 1-(1H-imidazol-1ylmethyl)pyrrolidin-2-one, 1-(1H-imidazol-1 -ylmethyl)-4-phenylpyrrolidin-2-one; 1-(1H-imidazol-1ylmethyl)-4-propylpyrrolidin-2-one; (-)-4-(3 -azido-2,4-difluorophenyl)-1 -(1 H-imidazol-1 -ylmethyl)pyrrolidin-2-one; (+)-4-(3 -azido-2,4-difluorophenyl)-1-(1 H-imidazol-1 -ylmethyl)pyrrolidin-2-one; 1-[(2-ethyl1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1 -[(2-isopropyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1 -[(2-methyl-1 H-imidazol-1 -yl)methyl]-4-propylpyrrolidin-2-one; 4-propyl-1-[(2propyl-1 H-imidazol-1 -yl)methyl]pyrrolidin-2-one; (+)-1-(1H-imidazol-1-ylmethyl)-4-propylpyrrolidin-2-one; (-)-1-(1 H-imidazol-1 -ylmethyl)-4-propylpyrrolidin-2-one; 4-(2,2-difluorovinyl)-1-(1Himidazol-1-ylmethyl)pyrrolidin-2-one; 4-(3-chlorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 1 {[2-(methylthio)-1 H-imidazol-1 -yl]methyl}-4-propylpyrrolidin-2-one; 1 -[(2-methyl-1 H-imidazol-1 -yl)methyl]-4-phenylpyrrolidin-2-one; 4-(4-fluorophenyl)-1 -(1 H-imidazol-1 -ylmethyl)pyrrolidin-2-one; 1-(1Himidazol-1 -ylmethyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one; 4-(3-fluorophenyl)-1-(1H-imidazol-1 ylmethyl)pyrrolidin-2-one; 4-(3,5-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 4-(3,4difluorophenyl)-1 -(1H-imidazol-1 -ylmethyl)pyrrolidin-2-one; 4-(3-chloro-4-fluorophenyl)-1-(1H-imidazol-1 ylmethyl)pyrrolidin-2-one; 4-(4-chlorophenyl)-1 -(1 H-imidazol-1 -ylmethyl)pyrrolidin-2-one; 1-(1Himidazol-1 -ylmethyl)-4-(2,3,4-trifluorophenyl)pyrrolidin-2-one; 1-(1H-imidazol-1-ylmethyl)-4-(2,3,5trifluorophenyl)pyrrolidin-2-one; 1-(1H-imidazol-1-ylmethyl)-4-(2,4,5-trifluorophenyl)pyrrolidin-2-one; 1-[(2-nitro-1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one; 1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1 -yl]methyl} -1 H-imidazole-2-carbonitrile; 1 -[(2-amino-1 H-imidazol-1 -yl)methyl]-4-propylpyrrolidin-2-one; 1-[(5-chloro-1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one; 1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-4-carbonitrile; 1{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1 -yl]methyl} -1 H-imidazole-5-carbonitrile; (+)-1-(1H-imidazol-1-ylmethyl)-4-phenylpyrrolidin-2-one; (-)-1-(1H-imidazol-1-ylmethyl)-4-phenylpyrrolidin-2-one; (+)-1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-4-carbonitrile; 1-[(2-chloro1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one; 1 -[2-azido-1 -(1H-imidazol-1 yl)ethyl]-4-propylpyrrolidin-2-one; 1 -[(2-chloro-1 H-imidazol-1 -yl)methyl]-4-propylpyrrolidin-2-one; (+)1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile; 1-[(2-oxo-4propylpyrrolidin-1 -yl)methyl]-2-propyl-1 H-benzimidazole-5-carbonitrile; 1-{[2-ethyl-5-(trifluoromethyl)-1 H-benzimidazol-1 -yl]methyl}-4-propylpyrrolidin-2-one; 4-propyl-1-{[2-(1 H-pyrrol-2-yl)-1 H-ben- 95 045018 zimidazol-1-yl]methyl}pyrrolidin-2-one; 1-[(5-fluoro-2-propyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 2-butyl-1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-benzimidazole-5-carbonitrile; 1-[(5-fluoro-2-isopropyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-(1Himidazol-1 -ylmethyl)-1,3-dihydro-2H-indol-2-one; 5-bromo-1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2Nindol-2-one; 5-chloro-1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one; 1-(1H-imidazol-1-ylmethyl)5-methyl-1,3-dihydro-2H-indol-2-one; 1 -[(5-chloro-2-oxo-2,3-dihydro-1H-indol-1 -yl)methyl]-1 H-imidazole5-carbonitrile.

In some embodiments, the compounds are: 1-(1H-imidazol-1ylmethyl)-4-phenylpyrrolidin-2-one; 1-(1H-imidazol-1-ylmethyl)-4-propylpyrrolidin-2-one; (-)-4-(3azido-2,4-difluorophenyl)-1-(1 H-imidazol-1 -ylmethyl)pyrrolidin-2-one; (+)-4-(3 -azido-2,4-difluorophenyl)1-(1 H-imidazol-1 -ylmethyl)pyrrolidin-2-one; 4-(2,2-difluorovinyl)-1-(1 H-imidazol-1 -ylmethyl)pyrrolidin-2-one; 4-(3-chlorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 1-{[2-(methylthio)-1 H-imidazol1-yl]methyl}-4-propylpyrrolidin-2-one; 1-[(2-methyl-1H-imidazol-1-yl)methyl]-4-phenylpyrrolidin-2-one; 1-(1H-imidazol-1-ylmethyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one; 4-(3-fluorophenyl)-1-(1 H-imidazol1 -ylmethyl)pyrrolidin-2-one; 4-(3,5-difluoromethyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 1-(1Himidazol-1 -ylmethyl)-4-(2,3,4-trifluorophenyl)pyrrolidin-2-one; 1-(1H-imidazol-1-ylmethyl)-4-(2,3,5trifluorophenyl)pyrrolidin-2-one; 1-(1H-imidazol-1-ylmethyl)-4-(2,4,5-trifluorophenyl)pyrrolidin-2-one; 1-[(2-nitro-1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one; 1-{[2-oxo-4-(3,4,5trifluorophenyl)pyrrolidin-1 -yl]methyl} -1 H-imidazole-2-carbonitrile; 1-[(2-amino-1H-imidazol-1 yl)methyl]-4-propylpyrrolidin-2-one; 1-[(5-chloro-1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one; (+)-1 -(1 H-imidazol-1 -ylmethyl)-4-phenylpyrrolidin-2-one; (-)-1-(1 H-imidazol-1 -ylmethyl)4-phenylpyrrolidin-2-one; 1-[(2-chloro-1H-imidazol-1 -yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one; 1-[(2-chloro-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; (+)-1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile; 5-bromo-1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one; 5-chloro-1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one; 1-(1H-imidazol-1ylmethyl)-5-methyl-1,3-dihydro-2H-indol-2-one; 1-[(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)methyl]-1Nimidazole-5-carbonitrile.

Some of the compounds are: (-)-4-(3-azido-2,4-difluorophenyl)-1-(1H-imidazol-1ylmethyl)pyrrolidin-2-one; (+)-4-(3 -azido-2,4-difluorophenyl)-1-(1 H-imidazol-1 -ylmethyl)pyrrolidin-2one; 4-(3 -azido-2,4-difluorophenyl)-1 -(1 H-imidazol-1 -ylmethyl)pyrrolidin-2-one.

The acid addition salt form of the compound of formula I, which occurs in its free form as a base, can be prepared by treating the free base with an appropriate acid, for example an inorganic acid such as a hydrohalic acid, for example hydrochloric or hydrobromic, sulfuric, nitric, phosphoric and etc.; or an organic acid such as, for example, acetic, trifluoroacetic, hydroxyacetic, propanoic, lactic, pyruvic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, para-toluenesulfonic, cyclamic, salicylic, para -aminosalicylic, pamic, etc.

Compounds of formula I containing acid protons can be converted to their therapeutically active non-toxic base addition salt forms, for example metal or amine salts, by treatment with appropriate organic and inorganic bases. Suitable forms of base salts include, for example, ammonium salts, alkali and alkaline earth metal salts, for example, lithium, sodium, potassium, magnesium, calcium and the like salts, salts with organic bases, for example, N-methylN-glucamine, hydrabamine salts and salts with amino acids such as, for example, arginine, lysine and the like.

Conversely, these salt forms can be converted to free forms by treatment with an appropriate base or acid.

The compounds of formula I and their salts may be in the form of a solvate, which is included within the scope of the present invention. Such solvates include, for example, hydrates, alcoholates, and the like.

Many of the compounds of formula I and some of their intermediates contain at least one stereogenic center in their structure. This stereogenic center may be present in an R or S configuration, with the symbols R and S being used in accordance with the rules described in Pure Appl. Chem., 45 (1976) 11-30.

The present invention also relates to all stereoisomeric forms, such as enentiomeric and diastereoisomeric forms of the compounds of formula I, or mixtures thereof (including all possible mixtures of stereoisomers).

Some of the compounds of formula I may also exist in tautomeric forms. Such forms, even if not specifically indicated in the above formula, are to be included within the scope of the present invention.

According to another preferred embodiment, the present invention also relates to compounds of formula IA and their tautomeric form IB

- 96 045018

References herein to a compound or compounds are intended to include such compound in each of its possible isomeric forms and mixtures thereof, unless specifically referred to as a specific isomeric form.

The compounds of the present invention may exist in various polymorphic forms. Even if not specifically indicated in the above formula, such forms are to be included within the scope of the present invention.

Also included within the scope of the present invention are prodrug forms of the compounds of formula I and their various subvariants and subgroups.

xii) U.S. Patent Application Published No. 20090018148. In one aspect, the present invention relates to the compounds of Formula I, enantiomers, diastereoisomers, and mixtures thereof (including all possible mixtures of stereoisomers), or pharmaceutically acceptable salts thereof

Where

R ¹ represents hydrogen or C _1-6 alkyl;

R ² represents hydrogen or C _1-4 alkyl;

R ³ represents a group of the formula -CHR5R ⁶ or a benzyl group;

R ⁴ represents C _1-8 alkyl, optionally substituted with alkoxycarbonyl, C _3-6 cycloalkyl, aryl or heterocycle;

R ⁵ represents C _2-4 alkyl;

R ⁶ represents C _2-4 alkyl, amido or -COOR ⁷ ;

R ⁷ represents C _1-4 alkyl;

In one aspect, the present invention provides compounds wherein if R ¹ is hydrogen, R ² is methyl, R ³ is -CHR5R ⁶ , R ⁶ is ethoxycarbonyl, and R ⁵ is ethyl, then R ⁴ is other than methyl, npropyl, isopropyl, n-pentyl, n-heptyl, 3-bromobenzyl, 4-chlorobenzyl, 4-methylbenzyl or 2phenylethyl;

if R ¹ is hydrogen, R ² is methyl, R ³ is benzyl, then R ⁴ is other than isopropyl, n-butyl, 3-methylbutyl, benzyl, phenylethyl or 3-phenylpropyl;

if R ¹ and R ² are methyl, R ³ is benzyl, then R ⁴ is other than methyl, 3methylbutyl, benzyl, 3-phenylpropyl or 4-chlorophenylmethyl;

Finally, 8-(2-chloro-benzylsulfanyl)-3-methyl-7-octyl-3,7-dihydropurine-2,6dione is considered.

Typically, if R ³ is a benzyl group, then R ⁴ is C _1-8 alkyl, optionally substituted with alkoxycarbonyl.

Generally, if R ³ is a group of formula -CHR5R ⁶ then R ⁴ is C _1-8 alkyl, optionally substituted with C _3-6 cycloalkyl, aryl or heterocycle.

As used herein, the term alkyl is a group that represents saturated, monovalent hydrocarbon radicals containing straight or branched moieties, or combinations thereof, and containing 1-8 carbon atoms, preferably 1-6 carbon atoms; more preferably, alkyl groups contain 1-4 carbon atoms. The alkyl moieties may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of hydroxy, alkoxy, cyano, ethynyl, alkoxycarbonyl, acyl, aryl or heterocycle. Alkyl moieties may be optionally substituted with cycloalkyl, as defined below. Preferred alkyl groups according to the present invention are methyl, cyanomethyl, ethyl, 2-ethoxy-2-oxoethyl, 2-methoxyethyl, n-propyl, 2-oxopropyl, 3-hydroxypropyl, 2-propynyl, n-butyl, isobutyl, n-pentyl, 3-pentyl, n-hexyl, cyclohexylmethyl, benzyl, 2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, 3-methoxybenzyl, 3-nitrobenzyl, 3-aminobenzyl, 4-(aminosulfonyl)benzyl, 1-phenylethyl, 2-phenylethyl, ( 3,5-dimethylisoxazol-4-yl)methyl or (5-nitro-2-furyl)methyl. More preferred alkyl groups are methyl, ethyl, cyanomethyl, 2-methoxyethyl, n-propyl, 3-hydroxypropyl, 2-propynyl, n-butyl, 3-pentyl, n-hexyl, benzyl, 3-bromobenzyl, 3methoxybenzyl, 3-nitrobenzyl, 3-aminobenzyl, (3,5-dimethylisoxazol-4-yl)methyl or (5-nitro-2furyl)methyl. The most preferred alkyl groups are methyl, ethyl, 3methoxybenzyl, 3-nitrobenzyl or (5-nitro-2-furyl)methyl.

As used herein, the term cycloalkyl is a monovalent group of 3-8, preferably 3-6, carbon atoms derived from a saturated cyclic hydrocarbon, which may be substituted by any suitable group, including without limitation one or more moieties selected from the groups described higher for alkyl groups. A preferred cycloalkyl group according to the present invention is cyclohexyl.

As used herein, the term aryl is defined as a phenyl group optionally substituted with 1-4 substituents independently selected from halogen, amino, nitro, alkoxy or aminosulfonyl. Preferred aryl groups are phenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 3-methoxyphenyl, 3-nitrophenyl, 3-aminophenyl or 4-(aminosulfonyl)phenyl.

As used herein, the term phenyl is an aromatic hydrocarbon group of the formula -C ₆ H ₅ .

As used herein, the term benzyl group is a group of the formula -CH ₂ -aryl. Preferred benzyl groups are benzyl, 2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, 3-methoxybenzyl, 3-nitrobenzyl, 3-aminobenzyl or 4-(aminosulfonyl)benzyl. More preferably, the benzyl groups are benzyl, 3-bromobenzyl, 3-methoxybenzyl, 3-nitrobenzyl or 3-aminobenzyl. In some embodiments, the benzyl groups are 3-methoxybenzyl or 3-nitrobenzyl.

As used herein, the term halogen represents a fluorine, chlorine, bromine or iodine atom. In some embodiments, the halogen is bromine.

As used herein, the term hydroxy represents a group of the formula -OH.

As used herein, the term cyano represents a group of the formula -CN.

As used herein, the term amino represents a group of the formula -NH ₂ .

As used herein, the term ethynyl represents a group of the formula -C CH.

As used herein, the term alkoxy is a group of the formula -OR ^a where R ^a represents an alkyl group as defined above. In some embodiments, the alkoxy group is methoxy.

As used herein, the term nitro represents a group of the formula -NO2.

As used herein, the term amido represents a group of the formula -C(=O)NH2.

As used herein, the term acyl is a group of the formula -C(=O)R ^b where R ^b is an alkyl group as defined above. In some embodiments, the acyl group is acetyl (-C(=O)Me).

As used herein, the term alkoxycarbonyl (or ester) is a group of the formula -COOR ^c wherein R ^c is an alkyl group; with the proviso that R ^c is not alkyl, α-substituted hydroxy. In some embodiments, the alkoxycarbonyl group is ethoxycarbonyl.

As used herein, the term heterocycle is a 5-membered ring containing one or two heteroatoms selected from O or N. The heterocycle may be substituted with one or two C ₁ .4 alkyls or nitro. In some embodiments, the heterocycles are (3,5-dimethylisoxazol-4-yl) or (5-nitro-2-furyl).

Most preferably, the heterocycle is (5-nitro-2-furyl).

Typically, R ¹ is hydrogen or C1.6alkyl. Typically, R ¹ is hydrogen or C1. ₆ αlkyl, optionally substituted with hydroxy alkoxy, cyano, ethynyl, alkoxycarbonyl or acyl. In some embodiments, R ¹ is hydrogen, methyl, cyanomethyl, 2-ethoxy-2-oxoethyl, 2-methoxyethyl, n-propyl, 2-oxopropyl, 3-hydroxypropyl, 2-propynyl, npentyl, or n-hexyl. In some embodiments, R ¹ is hydrogen, methyl, cyanomethyl, 2-methoxyethyl, n-propyl, 3-hydroxypropyl, or 2-propynyl. In some embodiments, R ¹ is hydrogen.

Typically, R ² is hydrogen or C1.4alkyl. Typically R ² is hydrogen or unsubstituted C1.4 alkyl. In some embodiments, R ² is hydrogen, methyl, or n-butyl. In some embodiments, R ² is methyl.

Typically, R ³ is a group of the formula -CHR5R ⁶ or a benzyl group. In some embodiments, R ³ is 3-pentyl, 1-(aminocarbonyl)propyl, 1(ethoxycarbonyl)propyl, or 3-bromobenzyl. In some embodiments, R ³ is 1-(ethoxycarbonyl)propyl.

- 98 045018

Typically, R ⁴ is C _1-8 alkyl, optionally substituted with alkoxycarbonyl, C ₃ 6 cycloalkyl, aryl or heterocycle. Typically, R ⁴ is alkyl, optionally substituted with cyclohexyl, phenyl, bromophenyl, aminophenyl, methoxyphenyl, nitrophenyl, aminosulfonylphenyl, 3,5-dimethylisoxazol-4-yl, 5-nitro-2-furyl or ethoxycarbonyl. In some embodiments, R ⁴ is n-butyl, isobutyl, n-pentyl, nhexyl, cyclohexylmethyl, benzyl, 2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, 3-methoxybenzyl, 3-nitrobenzyl, 3-aminobenzyl, 4-( aminosulfonyl)benzyl, 1-phenylethyl, 2-phenylethyl, (3,5dimethylisoxazol-4-yl)methyl, (5-nitro-2-furyl)methyl or 1-(ethoxycarbonyl)propyl. In some embodiments, R ⁴ is n-butyl, n-hexyl, benzyl, 3-bromobenzyl, 3-methoxybenzyl, 3-nitrobenzyl, 3-aminobenzyl, (3,5-dimethylisoxazol-4-yl)methyl, (5-nitro- 2furyl)methyl or 1-(ethoxycarbonyl)propyl. In some embodiments, R ⁴ is 3-methoxybenzyl, 3-nitrobenzyl, or (5-nitro-2-furyl)methyl.

Typically, R ⁵ is C2-4 alkyl. Typically ^R5 is unsubstituted C24alkyl. In some embodiments, R ⁵ is ethyl.

Typically, R6 is C _2-4 alkyl, amido or -COOR ⁷ . Typically R6 is unsubstituted C _2-4 alkyl, amido or -COOR ⁷ . In some embodiments, R6 is ethyl, amido, or ethoxycarbonyl. In some embodiments, R ⁶ is ethoxycarbonyl.

Typically, R ⁷ is C1-4 alkyl. Typically R ⁷ is unsubstituted C1-4 alkyl. In some embodiments, R ⁷ is ethyl.

Generally, the invention relates to compounds characterized by formula I, their enantiomers, diastereoisomers and mixtures thereof (including all possible mixtures of stereoisomers), or pharmaceutically acceptable salts thereof

R ² where

R ¹ represents hydrogen, C _1-6 αlkyl, optionally substituted with hydroxy, alkoxy, cyano, ethynyl, alkoxycarbonyl or acyl;

R ² represents hydrogen or unsubstituted C _1-4 alkyl;

R ³ represents a group of the formula -CHR5R ⁶ or a benzyl group;

R ⁴ is C _1-8 alkyl, optionally substituted with cyclohexyl, phenyl, bromophenyl, aminophenyl, methoxyphenyl, nitrophenyl, aminosulfonylphenyl, 3,5-dimethylisoxazol4-yl, 5-nitro-2-furyl or ethoxycarbonyl;

R ⁵ represents unsubstituted C _2-4 alkyl;

R ⁶ represents unsubstituted C _2-4 alkyl, amido or -COOR ⁷ ;

R ⁷ represents unsubstituted C _1-4 alkyl;

provided that if R ¹ is hydrogen, R ² is methyl, R ³ is -CHR ⁵ R ⁶ , R ⁶ is ethoxycarbonyl and R ⁵ is ethyl, then R ⁴ is other than n-propyl, isopropyl, n-pentyl, n-heptyl, 3-bromobenzyl, 4-chlorobenzyl, 4-methylbenzyl or 2phenylethyl.

According to the above embodiment, in the case where R ³ represents a benzyl group, then R ⁴ represents C1-8 alkyl, optionally substituted with alkoxycarbonyl. According to the above embodiment, when R ³ represents a group of formula -CHR5R ⁶ , then R ⁴ represents C1-8alkyl, optionally substituted with _C3-6 cycloalkyl, aryl or heterocycle.

In one embodiment, R ¹ is hydrogen, methyl, cyanomethyl, 2-ethoxy-2-oxoethyl, 2-methoxyethyl, n-propyl, 2-oxopropyl, 3-hydroxypropyl, 2-propynyl, n-pentyl, or n-hexyl;

R ² represents hydrogen, methyl or n-butyl;

R ³ is 3-pentyl, 1-(aminocarbonyl)propyl, 1-(ethoxycarbonyl)propyl or 3-bromobenzyl;

R ⁴ is n-butyl, isobutyl, n-pentyl, n-hexyl, cyclohexylmethyl, benzyl, 2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, 3-methoxybenzyl, 3-nitrobenzyl, 3-aminobenzyl, 4(aminosulfonyl)benzyl, 1-phenylethyl, 2-phenylethyl, (3,5-dimethylisoxazol-4-yl)methyl, (5-nitro-2furyl)methyl or 1-(ethoxycarbonyl)propyl;

provided that if R ¹ is hydrogen, R ² is methyl and R ³ is 1-(ethoxycarbonyl)propyl, then R ⁴ is other than n-pentyl, 3-bromobenzyl or 2-phenylethyl.

According to the above embodiment, in the case where R ³ is 3-bromobenzyl, then R ⁴ is C ₁ . ₈ αlkyl, optionally substituted with alkoxycarbonyl.

According to the above embodiment, in case R ³ is 3-pentyl,

1-(aminocarbonyl)propyl or 1-(ethoxycarbonyl)propyl, then R ⁴ is different from 1-(ethoxycarbonyl)propyl.

In a more preferred embodiment, R ¹ is hydrogen, methyl, cyanomethyl, 2-methoxyethyl, n-propyl, 3-hydroxypropyl or 2-propynyl;

R ² represents methyl;

R ³ is 3-pentyl, 1-(aminocarbonyl)propyl, 1-(ethoxycarbonyl)propyl or 3-bromobenzyl;

R ⁴ is n-butyl, n-hexyl, benzyl, 3-bromobenzyl, 3-methoxybenzyl, 3-nitrobenzyl, 3-aminobenzyl, (3,5-dimethylisoxazol-4-yl)methyl, (5-nitro-2-furyl) methyl or 1-(ethoxycarbonyl)propyl;

with the proviso that if R ¹ is hydrogen, R ² is methyl and R ³ is 1-(ethoxycarbonyl)propyl, then R ⁴ is other than 3-bromobenzyl.

According to the above embodiment, in the case where R ³ is 3-bromobenzyl, then R ⁴ is 1-(ethoxycarbonyl)propyl.

According to the above embodiment, in the case where R ³ is 3-pentyl, 1-(aminocarbonyl)propyl or 1-(ethoxycarbonyl)propyl, then R ⁴ is other than 1-(ethoxycarbonyl)propyl.

In one embodiment, R ¹ is hydrogen; R ² represents methyl; R ³ represents 1-(ethoxycarbonyl)propyl; and R ⁴ is 3-methoxybenzyl, 3-nitrobenzyl or (5-nitro-2-furyl)methyl.

A further embodiment of the invention relates to compounds in which R ² represents methyl, R ³ represents a group of formula -CHR5R ⁶ where R ⁵ represents C ₂ . ₄ αlkyl, R ⁶ is amido or -COOR ⁷ , and R ⁷ is methyl or ethyl.

In some embodiments, the compounds are ethyl 2-[(7-benzyl-1,3dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate; ethyl-2-{[7-(3-bromobenzyl)-1 -(2-ethoxy-2oxoethyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1 H-purine-8 -yl]thio} butanoate; ethyl-2-{[7-(3-bromobenzyl)-1 (2-methoxyethyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1 H-purin-8 -yl] thio} butanoate; ethyl 2-{[7-(3-bromobenzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate; ethyl 2-{[7-(3-bromobenzyl)-1,3-dimethyl2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate; ethyl 2-{[7-(2-bromobenzyl)-1,3-dimethyl-2,6dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate; ethyl 2-{[7-(3-bromobenzyl)-1-(cyanomethyl)-3-methyl2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate; ethyl 2-{[7-(3-bromobenzyl)-3-methyl-2,6-dioxo1-propyl-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate; ethyl-2-{[7-(3-bromobenzyl)-3-methyl-2,6-dioxo-1-(2-oxopropyl)-2,3,6,7-tetrahydro-1H-purin-8-yl] thio}butanoate; ethyl-2-{[7-(3-bromobenzyl)-1-(3hydroxypropyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio} butanoate; ethyl-2-{[7-(3bromobenzyl)-3-methyl-2,6-dioxo-1-(2-propynyl)-2,3,6,7-tetrahydro-1H-purin-8-yl]thio } butanoate; ethyl 2{[7-(3-methoxybenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio} butanoate; ethyl 2-{[3-methyl7-(3-nitrobenzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate; ethyl 2-{[7-(3-aminobenzyl)-3methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate; ethyl 2-({7-[4-(aminosulfonyl)benzyl]-3methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl}thio)butanoate; ethyl 2-{[7-(4-bromobenzyl)-1,3-dimethyl2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate; ethyl 2-{[7-(cyclohexylmethyl)-1,3-dimethyl-2,6dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate; ethyl 2-{[1,3-dimethyl-2,6-dioxo-7-(1-phenylethyl)2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate; ethyl 2-{[1,3-dimethyl-2,6-dioxo-7-(2-phenylethyl)-2,3,6,7tetrahydro-1H-purin-8-yl]thio}butanoate; ethyl-2-({7-[(3,5-dimethylisoxazol-4-yl)methyl]-3-methyl-2,6-dioxo2,3,6,7-tetrahydro-1H-purin-8-yl}thio )butanoate; ethyl 2-({3-methyl-7-[(5-nitro-2-furyl)methyl]-2,6-dioxo2,3,6,7-tetrahydro-1H-purin-8-yl}thio)butanoate ; ethyl 2-[(7-butyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro1H-purin-8-yl)thio]butanoate; ethyl 2-{[7-(3-bromobenzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8yl]thio}butanoate; ethyl 2-[(1,7-dihexyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate; ethyl 2-[(7-hexyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate; ethyl 2-[(3methyl-2,6-dioxo-1,7-dipentyl-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate; 2-{[7-(3-bromobenzyl)-3methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanamide; 2-[(7-butyl-3-methyl-2,6-dioxo2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanamide; 7-(3-bromobenzyl)-8-[(1-ethylpropyl)thio]-3-methyl-3,7dihydro-1H-purine-2,6-dione; ethyl 2-{8-[(3-bromobenzyl)thio]-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro7H-purin-7-yl]butanoate and ethyl 2- [(7-isobutyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8yl)thio]butanoate. In some embodiments, the compounds are: ethyl 2-[(7benzyl-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio] butanoate; ethyl-2-{[7-(3-bromobenzyl)-1 (2-methoxyethyl)-3 -methyl-2,6-dioxo-2,3,6,7-tetrahydro-1 H-purin-8 -yl] thio} butanoate; ethyl 2-{[7-(3-bromobenzyl)-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate; ethyl 2-{[7-(3-bromobenzyl)-1(cyanomethyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate ; ethyl 2-{[7-(3-bromobenzyl)3-methyl-2,6-dioxo-1-propyl-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate; ethyl 2-{[7-(3-bromobenzyl)-1(3-hydroxypropyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio }butanoate; ethyl-2-{[7-(3- 100 045018 bromobenzyl)-3 -methyl-2,6-dioxo-1 -(2-propynyl)-2,3,6,7-tetrahydro-1 H-purine-8 -yl]thio} butanoate; ethyl 2{[7-(3-methoxybenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio} butanoate; ethyl 2-{[3-methyl7-(3-nitrobenzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate; ethyl 2-{[7-(3-aminobenzyl)-3methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate; ethyl-2-({7-[(3,5-dimethylisoxazol-4yl)methyl]-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl}thio )butanoate; ethyl 2-({3-methyl-7-[(5-nitro2-furyl)methyl]-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl}thio)butanoate ; ethyl 2-[(7-butyl-3-methyl-2,6dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate; ethyl 2-[(7-hexyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate; 2-{[7-(3-bromobenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8yl]thio}butanamide; 7-(3-bromobenzyl)-8-[(1-ethylpropyl)thio]-3-methyl-3,7-dihydro-1H-purine-2,6-dione and ethyl2-{8-[(3-bromobenzyl) thio]-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl}butanoate.

In some embodiments, the compounds are: ethyl-2-{[7-(3methoxybenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-III-purin-8-yl]thio} butanoate; ethyl 2-{[3-methyl-7(3-nitrobenzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate and ethyl 2-( {3-methyl-7-[(5nitro-2-furyl)methyl]-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl}thio)butanoate.

The acid addition salt form of a compound of formula I which occurs in its free form as a base can be prepared by treating the free base with an appropriate acid, for example an inorganic acid such as a hydrohalic acid, for example hydrochloric or hydrobromic, sulfuric, nitric, phosphoric and etc.; or an organic acid such as, for example, acetic, trifluoroacetic, hydroxyacetic, propanoic, lactic, pyruvic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, para-toluenesulfonic, cyclamic, salicylic, para -aminosalicylic, pamic, etc.

Compounds of formula I containing acid protons can be converted to their therapeutically active non-toxic base addition salt forms, for example metal or amine salts, by treatment with appropriate organic and inorganic bases. Suitable forms of base salts include, for example, ammonium salts, alkali and alkaline earth metal salts, for example, lithium, sodium, potassium, magnesium, calcium and the like salts, salts with organic bases, for example, N-methyl-D-glucamine salts , hydrabamine and salts with amino acids such as, for example, arginine, lysine and the like.

Conversely, these salt forms can be converted to free forms by treatment with an appropriate base or acid.

The compounds of formula I and their salts may be in the form of a solvate, which is included within the scope of the present invention. Such solvates include, for example, hydrates, alcoholates, and the like.

Many of the compounds of formula I and some of their intermediates contain at least one stereogenic center in their structure. This stereogenic center may be present in an R or S configuration, with the symbols R and S being used in accordance with the rules described in Pure Appl. Chem., 45 (1976) 11-30.

The present invention also relates to all stereoisomeric forms, such as enantiomeric and diastereoisomeric forms of the compounds of formula I, or mixtures thereof (including all possible mixtures of stereoisomers).

References herein to a compound or compounds are intended to include such compound in each of its possible isomeric forms and mixtures thereof, unless specifically referred to as a specific isomeric form.

The compounds of the present invention may exist in various polymorphic forms. Even if not specifically indicated in the above formula, such forms are to be included within the scope of the present invention.

xiii) US Patent No. 7465549

In some embodiments, the compound comprises optionally substituted N-alkylated 2-oxopyrrolidine derivatives. In some embodiments, the compounds are alkylamide derivatives substituted at the 4th and/or 5th positions of the pyrrolidone ring. Examples of optionally substituted N-alkylated 2oxopyrrolidine derivatives include, but are not limited to, compounds such as (2S)-2-[(4S)-4-(2,2difluorovinyl)-2-oxopyrrolidinyl]butanamide, (2S)-2-[(4R) -2-oxo-4-propylpyrrolidinyl]butanamide, (2S)-2-[(4S)-2-oxo-4-propylpyrrolidinyl]butanamide and (2S)-2-[4-(3-azidophenyl)-2-oxopyrrolidine -1yl]butanamide.

In some embodiments, the compounds further include optionally substituted N-alkylated 2-oxopiperidinyl derivatives. In some embodiments, the compounds are alkylamide derivatives substituted at the 4th and/or 5th and/or 6th positions of the 2-oxopiperidinyl ring. Examples of optionally substituted N-alkylated 2-oxopyrrolidine derivatives include, but are not limited to, compounds such as those listed in international patent application PCT/EP 02/05503, such as (2S)-2-[5-(iodomethyl)-2-oxo- 1-piperidinyl]butanamide, (2S)-2-[5-(azidomethyl)-2-oxo-1-pipe- 101 045018 ridinyl]butanamide, 2-(2-oxo-5-phenyl-1-piperidinyl]butanamide, (2S)-2-[4-(iodomethyl)-2-oxo-1-piperidinyl]butanamide and (2S)-2-[4-(2-fluoro-2-methylpropyl)-2-oxo-1-pyrrolidinyl] butanamide

In some embodiments, the compounds include any acetam compound of Formula I in racemic or isomeric form, or a pharmaceutically acceptable salt thereof

Where

R represents hydrogen or hydroxy;

R ¹ and R ² independently represent hydrogen or an alkyl group of 1-4 carbon atoms; And

R ³ and R ⁴ are independently hydrogen, an alkyl group of 1-4 carbon atoms or (CH ₂ )n-NR ⁵ R ⁶ where n is 1, 2 or 3, and R ⁵ and R ⁶ are independently hydrogen or an alkyl group of 1-4 carbon atoms.

An example of such an acetam compound includes, without limitation, a compound of formula I wherein R, R ¹ , R ² , R ³ and R ⁴ are hydrogen, 2-oxopyrrolidineacetamide, known by the generic name piracetam, described in UK Patent Nos. 1039113 and 1309692.

In some embodiments, the compounds also include optionally substituted N-alkylated 2-oxoazepanyl derivatives. Preferably, such compounds are alkylamide derivatives substituted at the 4th and/or 5th and/or 6th and/or 7th positions of the 2-oxoazepanyl ring. Examples of optionally substituted N-alkylated 2oxoazepanyl derivatives include, but are not limited to, those listed in international patent application PCT/EP 02/05503, such as 2-[5-(iodomethyl)-2-oxo-1-azepanyl]butanamide.

xiv) Published US Patent Application No. 2006258704

The present invention relates to new compounds of formula I

where n is 0 or 1, resulting in R ¹ being absent if n=0 and R ¹ present if n=1;

A ¹ represents an oxygen or sulfur atom;

X is -COR ⁷ R ⁸ , -COOR ⁹ , -CO-R ¹⁰ or CN;

R ¹ (if present), R ² , R ³ , R ⁴ and R ⁵ are the same or different, and each independently represents hydrogen, halogen, hydroxy, thiol, amino, nitro, nitrooxy, cyano, azido, carboxy, amido, sulfonic acid, sulfonamide, alkyl, alkenyl, alkynyl, ester, ether, aryl, heterocycle or hydroxy derivative, thio derivative, amino derivative, acyl derivative, sulfonyl derivative or sulfinyl derivative, provided that at least one of the substituents R selected from R ¹ (if available), R ² , R ³ , R ⁴ or R ⁵ , is not hydrogen;

R ⁶ is hydrogen, alkyl, aryl or -CH ₂ -R ^6a , where R ^6a is aryl, heterocycle, halogen, hydroxy, amino, nitro or cyano;

R ⁷ , R ⁸ and R ⁹ are the same or different and each independently represents hydrogen, hydroxy, alkyl, aryl, heterocycle or oxy derivative; And

R ¹⁰ represents hydrogen, hydroxy, thiol, halogen, alkyl, aryl, heterocycle or thio derivative;

their pharmaceutically acceptable salts, geometric isomers (including cis and trans, Z and E isomers), enantiomers, diastereoisomers and mixtures thereof (including all possible mixtures of stereoisomers).

In the above formula, at least one of the substituents R1 to ^R5 is other than hydrogen. Certain unsubstituted compounds are listed in US Pat. Nos. 54,68733 and 5,516,759. US Pat. No. 5,468,733 discloses non-cyclic derivatives of substituted 2-oxo-1-pyrrolidinyl and 2-oxo-1-piperidinyl as inhibitors of the Ras oncogene protein. In particular, these compounds block the ability of Ras to convert normal cells into cancer cells, and therefore can be included in various chemotherapeutic compositions for the treatment of cancer.

- 102 045018

US Patent No. 5,516,759 relates to acyclic substituted 2-oxo-1-pyrrolidinyl, 2oxo-1-piperidinyl and azepanyl derivatives present at the N-terminus of dodecan peptides having LHRH (luteinizing hormone releasing factor) antagonistic activity. Such LHRH antagonists are useful in the treatment of various conditions in which suppression of sex steroid hormones plays a key role, including contraception, delayed puberty, treatment of benign prostatic hyperplasia, etc.

In the definitions set forth below, unless otherwise indicated, R ¹¹ and R ¹² are the same or different and each independently represents an amido, alkyl, alkenyl, alkynyl, acyl, ester, ester, aryl, aralkyl, heterocycle or oxy derivative, thio derivative , an acyl derivative, an amino derivative, a sulfonyl derivative, or a sulfinyl derivative, each of which is optionally substituted with any suitable group, including without limitation one or more moieties selected from lower alkyl or other groups described below as alkyl substituents.

As used herein, the term oxy-derivative is defined to include the -OR ¹¹ group, wherein the meaning of R ¹¹ is as defined above, excluding oxy-derivative. Non-limiting examples include alkoxy, alkenyloxy, alkynyloxy, acyloxy, oxyester, oxyamido, alkylsulfonyloxy, alkylsulfinyloxy, arylsulfonyloxy, arylsulfinyloxy, aryloxy, aralkoxy or heterocyclooxy such as pentyloxy, allyloxy, methoxy, ethoxy, phenoxy, benzyloxy, 2-naphthyloxy, 2-pyridyloxy, methylenedioxy, carbonate.

As used herein, the term thio derivative is defined to include the -SR ¹¹ group, wherein R ¹¹ is as defined above, excluding thio derivative.

Non-limiting examples include alkylthio, alkenylthio, alkynylthio and arylthio.

As used herein, the term amino derivative is defined to include the -NHR ¹¹ or -NR11R ¹² group, wherein R ¹¹ and R ¹² are defined above. Non-limiting examples are mono- or dialkyl-, alkenyl-, alkynyl- and arylamino or mixed amino.

As used herein, the term acyl derivative is a radical derived from a carboxylic acid and is therefore defined to include groups of the formula R11-CO-, wherein ^R11 is as defined above, and may also represent hydrogen. Preferred are acyl derivatives of the formula -COR ¹¹ , where R ¹¹ is selected from hydrogen, C _1-12 alkyl, C _2-12 alkenyl, C ₂₁₂ alkenyl, heterocycle and aryl. Non-limiting examples are formyl, acetyl, propionyl, isobutyryl, valeryl, lauroyl, heptanedioyl, cyclohexanecarbonyl, crotonoyl, fumaroyl, acryloyl, benzoyl, naphthoyl, furoyl, nicotinoyl, 4-carboxybutanoyl, oxalyl, ethoxalyl, cysteinyl, oxamoyl.

As used herein, the term sulfonyl derivative is defined to include a group of formula -SO2-R ¹¹ , wherein R ¹¹ is as defined above, excluding sulfonyl derivative. Non-limiting examples are alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl and arylsulfonyl.

As used herein, the term sulfinyl derivative is defined to include a group of formula -SO-R ¹¹ , wherein R ¹¹ is as defined above, excluding sulfinyl derivative. Non-limiting examples are alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl and arylsulfinyl.

As used herein, the term alkyl is defined to include saturated, monovalent hydrocarbon radicals containing branched, straight-chain or cyclic moieties, or combinations thereof, and typically containing 1-20 carbon atoms, most commonly 112 carbon atoms, preferably 1-7 carbon atoms for non-cyclic alkyl and 3-7 carbon atoms for cycloalkyl (unless otherwise specified, then lower alkyl in the two preferred cases), each of which is optionally substituted with preferably 1-5 substituents independently selected from the group consisting of halogen, hydroxy, thiol , amino, nitro, cyano, thiocyanato, acyl, acyloxy, sulfonyl derivative, sulfinyl derivative, alkylamino, carboxy, ester, ether, amido, azido, cycloalkyl, sulfonic acid, sulfonamide, thio derivative, alkylthio, oxyester, oxyamido, heterocycle, vinyl, alkoxy (preferably _C1-5 ), _aryloxy (preferably _C6 -io) and aryl (preferably _{C6_10} ).

In some embodiments, alkyl groups containing 1-7 carbon atoms are provided, each of which is optionally substituted with one or more substituents selected from hydroxy, halogen, cyano, thiocyanato, alkoxy, azido, alkylthio, cyclopropyl, acyl, and phenyl. Most preferred are C ₁ . ₄ αlkyl and C ₃ . ₇ cycloalkyl, each of which is optionally substituted with one or more hydroxy, halogen, lower alkyl and/or azido.

In some embodiments, the alkyl groups are hydroxymethyl, propyl, butyl, 2,2,2-trifluoroethyl, 2-bromo-2,2-difluoroethyl, 2-chloro-2,2-difluoroethyl, 3,3,3trifluoropropyl, cyclopropylmethyl , iodomethyl, azidomethyl, 2,2-difluoropropyl, 2-iodo-2,2-difluoroethyl.

Unless otherwise specified, the term lower alkyl as used herein refers to a C ₁ -C ₇ saturated straight, branched or cyclic hydrocarbon. Non-limiting examples include methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, cyclopropyl, cyclopentyl, isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl, 3-methylpentyl, 2,2dimethylbutyl, optionally substituted with any suitable group, including without limitation one or more moieties selected from the groups described above for alkyl groups. Preferably, the lower alkyl is methyl.

As used herein, the term alkenyl is defined to include both branched and unbranched, unsaturated hydrocarbon radicals containing at least one double bond, and optionally substituted with at least one substituent selected from the group consisting of halogen, hydroxy, thiol, amino , thiocyanato, azido, alkylthio, cycloalkyl, acyl, nitro, cyano, aryl and heterocycle.

In some embodiments, the alkenyl groups are C2-C12 alkenyls, particularly _C2 . ₆ alkenyls such as ethenyl (=vinyl), 1-methyl-1-ethenyl, 2,2-dimethyl-1-ethenyl, 1-propenyl, 2-propenyl (=allyl), 1-butenyl, 2-butenyl, 3 -butenyl, 4-pentenyl, 1-methyl-4-pentenyl, 3methyl-1-pentenyl, 1-hexenyl, 2-hexenyl, etc., optionally substituted with one or more substituents selected from halogen, cyano, thiocyanato, azido , alkylthio, cycloalkyl, phenyl and acyl. Most preferred is vinyl, optionally substituted with one or more halogen atoms, and/or lower alkyl, and in particular 2,2-difluorovinyl, 2,2-dibromovinyl and 2,2dichlorovinyl.

As used herein, the term alkynyl is defined to include a monovalent, branched or straight-chain hydrocarbon radical containing at least one carbon-carbon triple bond, e.g., ethynyl, 2-propynyl (=propargyl), etc., and optionally substituted at least one substituent selected from the group consisting of halogen, hydroxy, thiol, amino, nitro, cyano, aryl, heterocycle, thiocyanato, azido, alkylthio, alkyl and acyl.

In some embodiments, preferred alkynyl groups are _C2 . ₁₂ alkynyl, in particular C ₂ . ₆ alkynyl, optionally substituted with one or more substituents selected from halogen, cyano, thiocyanato, azido, alkylthio, acyl, aryl, such as phenyl and alkyl, preferably cycloalkyl.

In some embodiments, ethynyl, propynyl, and butynyl, optionally substituted with lower alkyl and/or halogen, are preferred, and in particular 1-propynyl, cyclopropylethynyl, 3-methyl-1-butynyl, and 3,3,3-trifluoro-1-propynyl.

When present as bridging groups, alkyl, alkenyl and alkynyl are straight-chain or branched C1-12, preferably C1.4-alkylene or C2-12, preferably _{C2_4 -} alkenylene or alkynylene moieties, respectively.

Unless otherwise noted, groups in which branched derivatives traditionally contain prefixes such as n, sec, iso, etc. (for example, n-propyl, sec-butyl), are in the n-form.

As used herein, the term aryl is defined to include an organic radical obtained by the removal of one hydrogen atom from an aromatic hydrocarbon consisting of at least one ring, most commonly 1-3 rings, and typically containing 6-30 carbon atoms, such as phenyl and naphthyl, each of which is optionally substituted with one or more substituents independently selected from halogen, hydroxy, thiol, amino, nitro, cyano, acyl, acyloxy, sulfonyl, sulfinyl, alkylamino, carboxy, ester, ether, amido, azido, sulfonic acid, sulfonamide, alkylsulfonyl, alkylsulfinyl, C ₁ . ₆ alkylthio, oxyester, oxyamido, aryl, C ₁ . ₆ αlkoxy, C ₆ . ₁₀ aryloxy, C ₁ . ₆ αlkyl, C ₁ . ₆ haloalkyl. Aryl radicals are preferably monocyclic or bicyclic containing 6-10 carbon atoms. Preferred aryl groups are phenyl and naphthyl, each of which is optionally substituted with one or more substituents independently selected from halogen, nitro, amino, azido, Cl. ₆ αlkox, C ₁ . ₆ alkyl, C ₁ . ₆ haloalkyl, sulfonyl and phenyl.

In some embodiments, aryl is phenyl, optionally substituted with one or more halogens, lower alkyls, azidos, or nitros, such as 3-chlorophenyl and 3-azidophenyl.

As used herein, the term halogen includes Cl, Br, F, I.

As used herein, the term hydroxy represents a group of the formula -OH.

As used herein, the term thiol is a group of the formula -SH.

As used herein, the term cyano represents a group of the formula -CN.

As used herein, the term nitro represents a group of the formula -NO2.

As used herein, the term nitrooxy represents a group of the formula -ONO2.

As used herein, the term amino represents a group of the formula -NH2.

As used herein, the term azido is a group of formula -N3.

As used herein, the term carboxy represents a group of the formula -COOH.

As used herein, the term sulfonic acid represents the group

- 104 045018 formula -SO ₃ H.

As used herein, the term sulfonamide is a group of the formula

-SO2NH2.

As used herein, the term ester is defined to include a group of the formula -COO-R ¹¹ , wherein R ¹¹ is as defined above, excluding an hydroxy derivative, a thio derivative, or an amino derivative. Preferred are esters of the formula -COOR ¹¹ , where R ¹¹ is selected from C ₁ . ₁₂ alkyl, C ₂ . ₁₂ αlkenyl, C ₂ . ₁₂ alkynyl and aryl. Most preferred are esters where R ¹¹ represents lower alkyl, in particular methyl.

As used herein, the term ether is defined to include a group selected from C ₁ . ₅ straight or branched alkyl, or C ₂ . ₅₀ straight or branched alkenyl or alkynyl groups, or combinations thereof, interrupted by one or more oxygen atoms.

As used herein, the term amido is defined to include a group of formula -CONH2 or -CONHR ¹¹ or -CONR ¹¹ R ¹² , wherein R ¹¹ and R ¹² are as defined above.

As used herein, the term heterocycle is defined to include an aromatic or non-aromatic cyclic alkyl, alkenyl or alkynyl moiety as defined above, containing at least one O, S and/or N atom interrupted by a carbocyclic ring structure, and one of the carbon atoms of the carbocyclic ring structure. ring structure may optionally be replaced by carbonyl, and it is optionally substituted by any suitable group, including without limitation one or more moieties selected from lower alkyl or other groups as described above for alkyl groups. Non-limiting examples of heterocyclic compounds include pyridyl, furyl, pyrrolyl, thienyl, isothiazolyl, triazolyl, imidazolyl, benzimidazolyl, tetrazolyl, quinazolinyl, quinolisinyl, naphthyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolyl, isobenzofuranyl, benzothienyl, pyrazole yl, indolyl, indolizinyl, purinyl, isoindolyl, carbazolyl, thiazolyl, 1,2,4-thiadiazolyl, thiomorpholinyl, thieno(2,3-b)furanyl, furopyranyl, benzofuranyl, benzoxepinyl, isooxazolyl, oxazolyl, tianthrenyl, benzothiazolyl or benzoxazolyl, cinnolinyl, phthalazinyl, quinoxalinyl, 1-oxidopyridyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenothiazinyl, furazanil, benzodioxolyl, isochromanil, indolinyl, xanthenyl, hypoxanthinyl, pteridinyl, 5-azacytidinyl, 5-azauracilyl, triazolopyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperidyl, piperazinyl, imidazolinyl, morpholino, morpholinyl, 1-oxaspiro(4.5)dec-2-yl, pyrrolidinyl, 2-oxo-pyrrolidinyl, sugar fragments (namely glucose, pentose, hexose, ribose, fructose, which can also be substituted ), optionally substituted with alkyl or as described above for alkyl groups. The term heterocycle also includes bicyclic, tricyclic and tetracyclic spiro groups in which any of the above heterocyclic rings are fused to one or two rings independently selected from an aryl ring, a cyclohexane ring, a cyclohexene ring, a cyclopentane ring, a cyclopentene ring or another monocyclic heterocyclic ring, or wherein a monocyclic heterocyclic group is bridged via an alkylene group, such as quinuclidinyl, 7-azabicyclo(2.2.1)heptanyl, 7-oxabicyclo(2.2.1)heptanyl, 8-azabicyclo(3.2.1)octanyl.

The heterocyclic compound may be selected from triazolyl, tetrazolyl, pyrrolidinyl, pyridyl, 1-oxidopyridyl, thiomorpholinyl, benzodioxolyl, furyl, oxazolyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl and piperazinyl, each of which is optionally substituted with one or more substituents selected from halogen, alkyl, substituted alkyl, alkoxy, nitro, amino, acyl and phenyl. In some embodiments, the heterocycle is selected from tetrazolyl, pyrrolidinyl, pyridyl, furyl, pyrrolyl, thiazolyl, and thienyl, each of which is optionally substituted with one or more substituents selected from halogen, alkyl, halogenated alkyl, acyl, alkoxy, nitro, amino, and phenyl, and in particular from 2- and 3-thienyl, optionally substituted with one or more halogen atoms, acyl such as formyl, cyano and/or lower alkyl such as methyl.

Based on the above definitions, it should be understood that if a substituent such as R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ is attached to the remainder of the molecule through a heteroatom or carbonyl, then a straight or branched C _1-12 , preferably Cm, -alkylene or C _2-12 , preferably C ₂ - ₄ -alkenylene or -alkynylene bridge may optionally be inserted between the heteroatom or carbonyl and the point of attachment to the remainder of the molecule.

The acid addition salt form of a compound of formula I which occurs in its free form as a base can be prepared by treating the free base with an appropriate acid, for example an inorganic acid such as a hydrohalic acid, for example hydrochloric or hydrobromic, sulfuric, nitric, phosphoric and etc.; or an organic acid such as, for example, acetic, trifluoroacetic, hydroxyacetic, propanoic, lactic, pyruvic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, para-toluenesulfonic, cyclamic, salicylic, para -aminosalicylic, pamo

- 105 045018 wai, etc.

Compounds of formula I containing acid protons can be converted to their therapeutically active non-toxic base addition salt forms, for example metal or amine salts, by treatment with appropriate organic and inorganic bases. Suitable forms of basic salts include, for example, ammonium salts, alkali and alkaline earth metal salts, for example, lithium, sodium, potassium, magnesium, calcium and the like salts, salts with organic bases, for example, K-methyl-O salts -glucamine, hydrabamine and salts with amino acids such as, for example, arginine, lysine, etc.

Conversely, these salt forms can be converted to free forms by treatment with an appropriate base or acid.

The compounds of formula I and their salts may be in the form of a solvate, which is included within the scope of the present invention. Such solvates include, for example, hydrates, alcoholates, and the like.

Many of the compounds of formula I and some of their intermediates contain at least one stereogenic center in their structure. This stereogenic center may be present in an R or S configuration, with the symbols R and S being used in accordance with the rules described in Pure Appl. Chem., 45 (1976) 11-30.

The present invention also relates to all stereoisomeric forms, such as enentiomeric and diastereoisomeric forms of the compounds of formula I, or mixtures thereof (including all possible mixtures of stereoisomers).

In addition, some compounds of formula I that contain alkenyl groups may exist as Z (together) or E (opposite) isomers. In each case, the present invention includes both mixtures and individual isomers.

Many substituents on the piperidinyl or azepanyl ring may also be in the cis or trans position relative to each other relative to the area of the piperidinyl or azepanyl ring.

Some of the compounds of formula I may also exist in tautomeric forms. Such forms, even if not specifically indicated in the above formula, are to be included within the scope of the present invention.

References herein to a compound or compounds are intended to include such compound in each of its possible isomeric forms and mixtures thereof, unless specifically referred to as a specific isomeric form.

Also included within the scope of the present invention are prodrug forms of the compounds of formula I and their various subvariants and subgroups.

As used herein, the term prodrug includes forms of compounds that are rapidly converted in vivo to the parent compound of the present invention, for example, by hydrolysis in the blood. Prodrugs are compounds bearing groups that are modified by biotransformation before exerting their pharmacological action. Such groups include moieties that are readily oxidized, cycled, or cleaved, and the compound remains or becomes pharmacologically active after biotransformation. For example, metabolically cleavable groups form a class of groups well known to those skilled in the art. These include, without limitation, groups such as alkanoyl (i.e., acetyl, propionyl, butyryl, etc.), unsubstituted and substituted carbocyclic aroyl (such as benzoyl, substituted benzoyl and 1- and 2-naphthoyl), alkoxycarbonyl ( such as ethoxycarbonyl), trialkylsilyl (such as trimethyl and triethylsilyl), monoesters formed with dicarboxylic acids (such as succinyl), phosphate, sulfate, sulfonate, sulfonyl, sulfinyl and the like. Compounds bearing biotransformable groups are advantageous because they may exhibit improved bioavailability as a result of the enhanced solubility and/or absorption rate of the parent compound due to the presence of the biotransformable group (see T. Higuchi and V. Stella, Pro-drugs as Novel Delivery System, Vol. 14 of the A.C.S. Symposium Series; Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987).

As used herein, the term substituent R independently refers to R ¹ , R ² , R ³ , R ⁴ or R ⁵ .

In one embodiment, the present invention provides a compound of formula I as defined above, where n is 0. The compound is a 6-ring structure (2-thioxo- or 2-oxopiperidinyl derivative), where R ¹ is absent because n=0, and is represented by the formula (IA).

- 106 045018

According to a further embodiment, the present invention relates to a compound of formula I according to the present invention as defined above, where n is 1. The compound is a 7-membered structure (2-thioxo- or 2-oxoazepanyl derivative), where R ¹ is present because n= 1, and is represented by formula (IB).

(1-B)

R·' R ⁴

In one embodiment, the present invention relates to the compound as defined above, wherein n=0, R ³ and/or R ⁴ are other than hydrogen, and R ² and R ⁵ are hydrogen.

According to another embodiment, the present invention relates to the specified compound as defined above, where n=1, R ² , R ³ and/or R ⁴ are other than hydrogen, and where R ¹ and R ⁵ represent hydrogen.

According to another embodiment, the present invention relates to the specified compound as defined above, wherein only one substituent R, selected from R ³ or R ⁴ where n=0, or from R ² , R ³ or R ⁴ where n=1, is different from hydrogen, and the remaining substituent(s) R is hydrogen. Thus, the present description relates to monosubstituted 2-thioxo- or 2oxopiperidinyl or 2-thioxo- or 2-oxoazepanyl derivatives.

According to another embodiment, the present invention relates to compounds of formula I according to the present invention as defined above, wherein A ¹ represents an oxygen atom. Thus, the present description relates to 2-oxopiperidinyl or 2-oxoazepanyl derivatives.

According to another embodiment, the present invention relates to compounds of formula I according to the present invention as defined above, wherein X represents CONR7R ⁸ , in particular CONH2. Thus, the present description relates to the amido derivatives of 2-oxo (or thioxo)-piperidinyl or 2-oxo (or thioxo)azepanil.

According to another embodiment, the present invention relates to compounds of formula I according to the present invention, as defined above, wherein R ⁶ represents hydrogen, a C14 alkyl or CH2-R ^6a group, where R ^6a represents a heterocycle. Most preferably R ⁶ is 61-4 alkyl, in particular ethyl. If R ⁶ represents ethyl, then the present invention relates to 2-(2-oxo(or thioxo)-1-piperidinyl)butanamide or 2-(2-oxo(or thioxo)-1azepanyl)butanamide derivatives.

According to another embodiment, the present invention relates to compounds of formula I according to the present invention as defined above, wherein the carbon atom to which R ⁶ is attached is in the S configuration. In case R ⁶ represents ethyl, A represents oxygen, and X represents CONR7R ⁸ , the present invention relates to (2S)-2-(2-okco-1piperidinyl)butanamide or (2S)-2-(2-oxo) -1-azepanyl)butanamide derivative.

According to another embodiment, the present invention provides a compound as defined above, wherein R ² (if n=1), R ³ and R ⁴ are the same or different and each independently represents hydrogen, halogen, nitro, nitrooxy, cyano, carboxy, amido, sulfonic acid, sulfonamide, alkyl, alkenyl, alkynyl, ester, ester, aryl, heterocycle, acyl derivative, sulfonyl derivative or sulfinyl derivative;

R ¹ (if present), R ² if n=0, and R ⁵ are hydrogen;

R ⁶ is hydrogen, alkyl, aryl or -CH ₂ -R ^6a , where R ^6a is aryl, heterocycle, halogen, hydroxy, amino, nitro or cyano;

provided that if R ⁶ is hydrogen then X is -CONR7R ⁸ and that the compound is neither methyl (2R)-2-[(6R)-6-methyl-2-oxoazepanyl]-3-phenylpropanoate , nor methyl(2S)-2-[(4R)-4-methyl-2-oxoazepanyl]-3-phenylpropanoate.

According to this embodiment, the compound is generally a compound such that if R ⁶ is benzyl, then X is -COOCH ₃ and n=1, R ² is other than methyl,

- 107 045018 if R ³ and R ⁴ are both hydrogen, and R ⁴ is other than methyl if R ² and R ³ are both hydrogen.

According to another embodiment, the present invention provides a compound as defined above, wherein R ² (if n=1), R ³ and R ⁴ are the same or different and each independently represents hydrogen; cyano; carboxy; amido;

C ₁ . ₁₂ αlkyl, each of which is optionally substituted with one or more substituents selected from hydroxy, halogen, cyano, thiocyanato, alkoxy, azido, alkylthio, cycloalkyl, acyl, aryl and heterocycle;

_C2 . ₁₂ alkenyl, each of which is optionally substituted with one or more substituents selected from halogen, cyano, thiocyanato, azido, alkylthio, alkyl, aryl and acyl;

_C2 . ₁₂ alkynyl, each of which is optionally substituted with one or more substituents selected from halogen, cyano, thiocyanato, azido, alkylthio, alkyl, aryl and acyl;

an acyl derivative of the formula -CO-R ¹¹ , where R ¹¹ is selected from C ₁ . ₁₂ alkyl, C ₂ . ₁₂ alkenyl, C ₂ . ₁₂ alkynyl, heterocycle and aryl;

ester of the formula -CO-OR ¹¹ , where R ¹¹ is selected from C ₁ . ₁₂ alkyl, C ₂ . ₁₂ alkenyl, C ₂ . ₁₂ alkynyl and aryl;

a heterocycle selected from triazolyl, tetrazolyl, pyrrolidinyl, pyridyl, 1-oxidopyridyl, thiomorpholinyl, benzodioxolyl, furyl, oxazolyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl and piperazinyl, each of which is optionally substituted with one or more substituents selected from halogen, alkyl, substituted alkyl, alkoxy, nitro, amino, acyl and phenyl;

aryl, each of which is optionally substituted with one or more substituents selected from C ₁ .6 alkyl, C ₁ .6 haloalkyl, ^^ alkoxy, C ₁ . ₆ αlkylthio, amino, azido, sulfonyl, aryl and nitro.

According to another embodiment, the present invention provides a compound as defined above, wherein R ² (if n=1), R ³ and R ⁴ are the same or different and each independently represents hydrogen;

C ₁ . ₇ alkyl, each of which is optionally substituted with one or more substituents selected from hydroxy, halogen, cyano, thiocyanato, alkoxy, azido, alkylthio, cyclopropyl, acyl and phenyl;

C ₂ .6alkenyl, each of which is optionally substituted with one or more substituents selected from halogen, cyano, thiocyanato, azido, alkylthio, cycloalkyl, phenyl and acyl;

_C2 . ₆ alkynyl, each of which is optionally substituted with one or more substituents selected from halogen, cyano, thiocyanato, azido, alkylthio, cycloalkyl, phenyl and acyl;

a heterocycle selected from tetrazolyl, pyrrolidinyl, pyridyl, furyl, pyrrolyl, thiazolyl and thienyl, each of which is optionally substituted with one or more substituents selected from halogen, alkyl, halogenated alkyl, acyl, alkoxy, nitro, amino and phenyl;

phenyl, each of which is optionally substituted with one or more substituents selected from C ₁ . ₆ alkyl, halogenated alkyl, halogen, alkoxy, amino, azido, sulfonyl, phenyl and nitro.

According to another embodiment, the present invention relates to a compound as defined above, wherein at least one of the substituents R selected from the group ^R2 , ^R3 and ^R4 , if n=1, or from the group ^R3 and ^R4 , if n=0, independently represents C ₁ . ₄ αlkyl or C ₃ . ₇ cycloalkyl, optionally substituted with one or more halogen, hydroxy, lower alkyl and/or azido.

According to another embodiment, the present invention relates to a compound as defined above, wherein at least one of the substituents R selected from the group R ² , R ³ and R ⁴ if n=1, or from the group R ³ and R ⁴ if n =0, independently represents vinyl, optionally substituted with one or more halogen atoms and/or lower alkyls.

According to another embodiment, the present invention relates to a compound as defined above, wherein at least one of the substituents R selected from the group R ² , R ³ and R ⁴ if n=1, or from the group R ³ and R ⁴ if n =0, independently represents ethynyl, propynyl or butynyl, optionally substituted with one or more halogen atoms and/or lower alkyls.

According to another embodiment, the present invention relates to a compound as defined above, wherein at least one of the substituents R selected from the group R ² , R ³ and R ⁴ if n=1, or from the group R ³ and R ⁴ if n =0, independently represents phenyl, optionally substituted with one or more halogen atoms, lower alkyls, azidos and/or nitros.

According to another embodiment, the present invention relates to a compound as defined above, wherein at least one of the substituents R selected from the group R ² , R ³ and R ⁴ if n=1, or from the group R ³ and R ⁴ if n =0, independently represents 2- or 3-thienyl, optionally substituted with one or more halogen atoms, acyls, cyanos and/or lower alkyls.

According to a specific embodiment, the present invention relates to a compound,

- 108 045018 as defined above, where at least one of the substituents R selected from the group R ³ , R ⁴ and R ² if n=1, or from the group R ³ and R ⁴ if n=0, is hydroxymethyl, propyl, butyl, 3,3,3trifluoropropyl, 2,2,2-trifluoroethyl, cyclopropylmethyl, iodomethyl, azidomethyl, 2-thienyl, 3-thienyl, phenyl, 3-chlorophenyl, 3-azidophenyl, 2,2-difluorovinyl, 2, 2-dibromovinyl, 2,2-dichlorovinyl, 2-ethynyl, 5methyl-2-thienyl, 5-formyl-2-ethynyl, 5-cyano-2-thienyl, 3-bromo-2-thienyl, 4-methyl-2- thienyl, 3,3,3trifluoro-1-propynyl, 1-propynyl, cyclopropylethynyl, 3-methyl-1-butynyl, 1-butynyl, 2,2difluoropropyl, 2-chloro-2,2-difluoroethyl, 2-bromo-2, 2-difluoroethyl and 2-iodo-2,2-difluoroethyl.

According to another embodiment, the present invention relates to a compound as defined above, wherein R ¹ , R ² , R ⁴ and R ⁵ are hydrogen.

According to another embodiment, the present invention relates to a compound as defined above, wherein R ¹ , R ² , R ³ and R ⁵ are hydrogen.

According to another embodiment, the present invention relates to a compound as defined above, where n=1 and R ¹ , R ³ , R ⁴ and R ⁵ are hydrogen.

In all of the above embodiments, if the carbon atom to which R ⁶ is attached is asymmetric, then it may be in the S configuration.

Representative compounds of the present invention as defined above are selected from the group consisting of 2-[5-(hydroxymethyl)-2-oxo-1-piperidinyl]butanamide, 2-(2-oxo-5-propyl-1piperidinyl)butanamide, 2 -[2-oxo-5-(3,3,3-trifluoropropyl)-1-piperidinyl]butanamide, 2-[5-(cyclopropylmethyl)-2-oxo-1-piperidinyl]butanamide, 2-[5-(iodomethyl )-2-oxo-1-piperidinyl]butanamide, 2[5-(azidomethyl)-2-oxo-1-piperidinyl]butanamide, 2-(2-oxo-5-phenyl-1-piperidinyl)butanamide, 2-[ 2-oxo-5-(2-thienyl)-1-piperidinyl]butanamide, 2-[2-oxo-5-(3-thienyl)-1-piperidinyl]butanamide, 2-[5(3-chlorophenyl)-2-oxo -1-piperidinyl]butanamide, 2-[5-(3-azidophenyl)-2-oxo-1-piperidinyl]butanamide, 2-[5-(2,2-difluorovinyl)-2-oxo-1-piperidinyl]butanamide , 2-[5-(2,2-dibromovinyl)-2-oxo-1piperidinyl]butanamide, 2-[5-(2,2-dichlorovinyl)-2-oxo-1-piperidinyl]butanamide, 2-(5- ethynyl-2oxo-1-piperidinyl)butanamide, 2-[5-(5-methyl-2-thienyl)-2-oxo-1-piperidinyl]butanamide, 2-[5-(5formyl-2-thienyl)-2- oxo-1-piperidinyl]butanamide, 2-[5-(5-cyano-2-thienyl)-2-oxo-1-piperidinyl]butanamide, 2-[5-(3-bromo-2-thienyl)-2- oxo-1-piperidinyl]butanamide, 2-[5-(4-methyl-2-thienyl)-2oxo-1-piperidinyl]butanamide, 2-[2-oxo-5-(3,3,3-trifluoro-1 -propynyl)-1-piperidinyl]butanamide, 2[2-oxo-5-(1-propynyl)-1-piperidinyl]butanamide, 2-[5-(cyclopropylethynyl)-2-oxo-1-piperidinyl]butanamide, 2 -[5-(3-methyl-1-butynyl)-2-oxo-1-piperidinyl]butanamide, 2-[5-(1-butynyl)-2-oxo-1piperidinyl]butanamide, 2-[5-(2 ,2-difluoropropyl)-2-oxo-1-piperidinyl]butanamide, 2-[5-(2-chloro-2,2difluoroethyl)-2-oxo-1-piperidinyl]butanamide, 2-[5-(2-bromo -2,2-difluoroethyl)-2-oxo-1-piperidinyl]butanamide, 2-[4-(hydroxymethyl)-2-oxo-1-piperidinyl]butanamide, 2-(2-oxo-4-propyl-1 piperidinyl) )butanamide, 2-[2-oxo-4-(3,3,3-trifluoropropyl)-1-piperidinyl]butanamide, 2-[4(cyclopropylmethyl)-2-oxo-1-piperidinyl]butanamide, 2-[4 -(iodomethyl)-2-oxo-1-piperidinyl]butanamide, 2-[4-(azidomethyl)-2-oxo-1-piperidinyl]butanamide, 2-(2-oxo-4-phenyl-1-piperidinyl)butanamide , 2-[2-oxo-4-(2-thienyl)-1-piperidinyl]butanamide, 2-[2-oxo-4-(3-thienyl)-1 piperidinyl]butanamide, 2-[4-(3- chlorophenyl)-2-oxo-1-piperidinyl]butanamide, 2-[4-(3-azidophenyl)-2oxo-1-piperidinyl]butanamide, 2-[4-(2,2-difluorovinyl)-2-oxo-1 -piperidinyl]butanamide, 2-[4-(2,2-dibromovinyl)-2-oxo-1-piperidinyl]butanamide, 2-[4-(2,2-dichlorovinyl)-2-oxo-1-piperidinyl]butanamide, 2 -(4-ethynyl-2-oxo-1-piperidinyl)butanamide, 2-[4-(5-methyl-2-thienyl)-2-oxo-1-piperidinyl]butanamide, 2-[4-(5-formyl) -2-thienyl)-2-oxo-1-piperidinyl]butanamide, 2-[4-(5-cyano-2thienyl)-2-oxo-1-piperidinyl]butanamide, 2-[4-(3-bromo-2 -thienyl)-2-oxo-1-piperidinyl]butanamide, 2-[4-(4-methyl-2-thienyl)-2-oxo-1-piperidinyl]butanamide, 2-[2-oxo-4-(3 ,3,3-trifluoro-1-propynyl)-1piperidinyl]butanamide, 2-[2-oxo-4-(1-propynyl)-1-piperidinyl]butanamide, 2-[4-(cyclopropylethynyl)-2-oxo- 1-piperidinyl]butanamide, 2-[4-(3-methyl-1-butynyl)-2-oxo-1-piperidinyl]butanamide, 2-[4-(1-butynyl)-2-oxo-1-piperidinyl] butanamide, 2-[4-(2,2-difluoropropyl)-2-oxo-1-piperidinyl]butanamide, 2-[4-(2-chloro-2,2-difluoroethyl)-2-oxo-1-piperidinyl]butanamide , 2-[4-(2bromo-2,2-difluoroethyl)-2-oxo-1-piperidinyl]butanamide, 2-[4-(2,2,2-trifluoroethyl)-2-oxo-1-piperidinyl]butanamide , 2-[5-(hydroxymethyl)-2-oxo-1-azepanyl]butanamide, 2-(2-oxo-5-propyl-1azepanyl)butanamide, 2-[2-oxo-5-(3,3,3 -trifluoropropyl)-1-azepanyl]butanamide, 2-(5-(cyclopropylmethyl)-2-oxo-1-azepanyl]butanamide, 2-[5-(iodomethyl)-2-oxo-1-azepanyl]butanamide, 2- [5(azidomethyl)-2-oxo-1-azepanyl]butanamide, 2-(2-oxo-5-phenyl-1-azepanyl)butanamide, 2-[2-oxo-5-(2thienyl)-1-azepanyl] butanamide, 2-[2-oxo-5-(3-thienyl)-1-azepanyl]butanamide, 2-[5-(3-chlorophenyl)-2oxo-1-azepanyl]butanamide, 2-[5-(3- azidophenyl)-2-oxo-1-azepanyl]butanamide, 2-[5-(2,2-difluorovinyl)-2-oxo-1-azepanyl]butanamide, 2-[5-(2,2-dibromovinyl)-2 -oxo-1-azepanyl]butanamide, 2-[5(2,2-dichlorovinyl)-2-oxo-1-azepanyl]butanamide, 2-(5-ethynyl-2-oxo-1-azepanyl)butanamide, 2- [5-(5methyl-2-thienyl)-2-oxo-1-azepanyl]butanamide, 2-[5-(5-formyl-2-thienyl)-2-oxo-1-azepanyl]butanamide, 2-[5 -(5-cyano-2-thienyl)-2-oxo-1-azepanyl]butanamide, 2-[5-(3-bromo-2-thienyl)-2-oxo-1azepanyl]butanamide, 2-[5-( 4-methyl-2-thienyl)-2-oxo-1-azepanyl]butanamide, 2-[2-oxo-5 -(3,3,3trifluoro-1-propynyl)-1-azepanyl]butanamide, 2-[2 -oxo-5-(1-propynyl)-1-azepanyl]butanamide, 2-[5(cyclopropylethynyl)-2-oxo-1-azepanyl]butanamide, 2-[5-(3-methyl-1-butynyl)- 2-oxo-1-azepanyl]butane

- 109 045018 amide, 2-[5-(1-butynyl)-2-oxo-1-azepanyl]butanamide, 2-[5-(2,2-difluoropropyl)-2-oxo-1-azepanyl]butanamide, 2 -[5-(2-chloro-2,2-difluoroethyl)-2-oxo-1-azepanyl]butanamide, 2-[5-(2-bromo-2,2-difluoroethyl)-2-oxo-1-azepanyl]butanamide , 2-[5-(2,2,2-trifluoroethyl)-2-oxo-1-azepanyl]butanamide, 2[6-(hydroxymethyl)-2-oxo-1-azepanyl]butanamide, 2-(2-oxo -6-propyl-1-azepanyl)butanamide, 2-[2oxo-6-(3,3,3-trifluoropropyl)-1-azepanyl)butanamide, 2-[6-(cyclopropylmethyl)-2-oxo-1-azepanyl ]butanamide, 2-[6-(iodomethyl)-2-oxo-1-azepanyl]butanamide, 2-[6-(azidomethyl)-2-oxo-1-azepanyl]butanamide, 2-(2-oxo-6- phenyl-1-azepanyl)butanamide, 2-[2-oxo-6-(2-thienyl)-1-azepanyl]butanamide, 2[2-oxo-6-(3-thienyl)-1-azepanyl]butanamide, 2 -[6-(3-chlorophenyl)-2-oxo-1-azepanyl]butanamide, 2-[6-(3azidophenyl)-2-oxo-1-azepanyl]butanamide, 2-[6-(2,2-difluorovinyl) )-2-oxo-1-azepanyl]butanamide, 2-[6(2,2-dibromovinyl)-2-oxo-1-azepanyl]butanamide, 2-[6-(2,2-dichlorovinyl)-2-oxo -1-azepanyl]butanamide, 2-(6-ethynyl-2-oxo-1-azepanyl)butanamide, 2-[6-(5-methyl-2-thienyl)-2-oxo-1-azepanyl]butanamide, 2 -[6-(5-formyl-2-thienyl)-2-oxo-1-azepanyl]butanamide, 2-[6-(5-cyano-2-thienyl)-2-oxo-1azepanyl]butanamide, 2-[ 6-(3-bromo-2-thienyl)-2-oxo-1-azepanyl]butanamide, 2-[6-(4-methyl-2-thienyl]-2oxo-1-azepanyl]butanamide, 2-[2- oxo-6-(3,3,3-trifluoro-1-propynyl)-1-azepanyl]butanamide, 2-[2-oxo6-(1-propynyl)-1-azepanyl]butanamide, 2-[6-(cyclopropylethynyl )-2-oxo-1-azepanyl]butanamide, 2-[6(3-methyl-1-butynyl)-2-oxo-1-azepanyl]butanamide, 2-[6-(1-butynyl)-2-oxo -1-azepanyl]butanamide, 2[6-(2,2-difluoropropyl)-2-oxo-1-azepanyl]butanamide, 2-[6-(2-chloro-2,2-difluoroethyl)-2-oxo- 1-azepanyl]butanamide, 2-[6-(2-bromo-2,2-difluoroethyl)-2-oxo-1-azepanyl]butanamide, 2-[6-(2,2,2-trifluoroethyl)2-oxo -1-azepanyl]butanamide, 2-[4-(hydroxymethyl)-2-oxo-1-azepanyl]butanamide, 2-(2-oxo-4-propyl1-azepanyl)butanamide, 2-[2-oxo-4- (3,3,3-trifluoropropyl)-1-azepanyl]butanamide, 2-[4-(cyclopropylmethyl)-2-oxo-1-azepanyl]butanamide, 2-[4-(iodomethyl)-2-oxo-1- azepanyl]butanamide, 2-[4(azidomethyl)-2-oxo-1-azepanyl]butanamide, 2-(2-oxo-4-phenyl-1-azepanyl)butanamide, 2-[2-oxo-4-(2thienyl )-1-azepanyl]butanamide, 2-[2-oxo-4-(3-thienyl)-1-azepanyl]butanamide, 2-[4-(3-chlorophenyl)-2oxo-1-azepanyl]butanamide, 2- [4-(3-azidophenyl)-2-oxo-1-azepanyl]butanamide, 2-[4-(2,2-difluorovinyl)-2-oxo-1-azepanyl]butanamide, 2-[4-(2, 2-dibromovinyl)-2-oxo-1-azepanyl]butanamide, 2-[4-(2,2dichlorovinyl)-2-oxo-1-azepanyl]butanamide, 2-(4-ethynyl-2-oxo-1-azepanyl )butanamide, 2-[4-(5-methyl2-thienyl)-2-oxo-1-azepanyl]butanamide, 2-[4-(5-formyl-2-thienyl)-2-oxo-1-azepanyl]butanamide , 2-[4(5-cyano-2-thienyl)-2-oxo-1-azepanyl]butanamide, 2-[4-(3-bromo-2-thienyl)-2-oxo-1-azepanyl]butanamide, 2-[4-(4-methyl-2-thienyl)-2-oxo-1-azepanyl]butanamide, 2-[2-oxo-4-(3,3,3-trifluoro-1-propynyl)-1 azepanyl ]butanamide, 2-[2-oxo-4-(1-propynyl)-1-azepanyl]butanamide, 2-[4-(cyclopropylethynyl)-2oxo-1-azepanyl]butanamide, 2-[4-(3-methyl -1-butynyl)-2-oxo-1-azepanyl]butanamide, 2-[4-(1-butynyl)2-oxo-1-azepanyl]butanamide, 2-[4-(2,2-difluoropropyl)-2 -oxo-1-azepanyl]butanamide, 2-[4-(2-chloro-2,2difluoroethyl]-2-oxo-1-azepanyl]butanamide, 2-[4-(2-bromo-2,2-difluoroethyl) -2-oxo-1-azepanyl]butanamide, 2-[4-(2,2,2-trifluoroethyl)-2-oxo-1-azepanyl]butanamide.

Results were obtained with the following compounds: (2S)-2-[5-(iodomethyl)-2-oxo-1piperidinyl]butanamide, (2S)-2-[5-(azidomethyl)-2-okCO-1-piperidinyl]butanamide , 2-(2-oxo-5-phenyl-1 piperidinyl]butanamide, (2S)-2-[4-(iodomethyl)-2-oxo-1-piperidinyl]butanamide, 2-[5-(iodomethyl)-2oxo -1-azepanil] butanamide.

xv) Published international patent application WO 2008/132139

In some embodiments, the compounds are characterized by the following formula (I):

Where

Y is O or S. In some embodiments, Y is O.

R ¹ represents hydrogen or C-|.g alkyl;

R ² represents hydrogen;

R ³ represents -CONR5R ⁶ , -COR ⁷ , imidazolyl, imidazopyridinyl, imidazopyridazinyl;

R ⁵ , R ⁶ are the same or different, and are independently selected from hydrogen and C^alkyl;

R ⁷ represents C<;[_6-alkyl;

A is a monocyclic or bicyclic heterocyclic moiety selected from the group consisting of imidazolidin-1-yl, 1,3-oxazolidin-3-yl, 2,5-dihydro-1H-pyrrol-1-yl, 1,3-thiazol -3(2H)-yl, 1,3-thiazolidin-3-yl, piperidin-1-yl, azepan-1-yl, 5, 6-dihydro-4H-thieno[3,2b]pyrrol-4-yl, hexahydro-4H-thieno[3,2-b]pyrrol-4-yl, 2,3-dihydro-1H-thieno[3,4-b]pyrrol-1-yl, 1,3benzothiazol-3(2H)-yl , 1,3-benzoxazol-3(2H)-yl, pyrazolo[1,5-a]pyridin-1(2H)-yl, 3,4-dihydroisoquinolin-2(1H)-yl, 3,4-dihydroquinoline -1 (2H)-yl, 1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl,

1,2,4,5-tetrahydro-3H-3-benzazepin-3-yl;

- 110 045018

R ⁴ is either R ^a or R ^b depending on whether A is a monocyclic or bicyclic heterocycle:

if A is a monocyclic heterocyclic moiety, then R ⁴ is R ^a which is selected from the group consisting of hydrogen; C-jg alkyl, optionally substituted with a substituent selected from halogen, C _1-4 alkoxy, C _1-4 alkylthio, azido, nitrooxy or aryl; C _2-6 alkenyl, optionally substituted with halogen; C _2-6 alkynyl, optionally substituted with halogen; azido; alkoxycarbonylamino; arylsulfonyloxy; substituted or unsubstituted aryl; or a 38-membered substituted or unsubstituted heterocycle;

if A is a bicyclic heterocyclic moiety, then R ⁴ is R ^b which is selected from the group consisting of and consisting of hydrogen; nitro; cyano; halogen; heterocycle; amino; arila; C-jg alkyl, optionally substituted with at least one halogen atom; or C-Jg alkoxy, optionally substituted with at least one halogen atom;

In some embodiments, the compounds are:

For compounds, if A=Y is selected from 2-oxo-piperidin-1-yl, 2-oxo-azepan-1-yl, 2-oxo-1,3benzothiazol-3(2H)-yl or 2-oxo-1, 3-benzoxazol-3(2H)-yl, then R ³ must be selected from imidazolyl, imidazopyridinyl or imidazopyridazinyl.

For compounds, if A=Y is 5-oxoimidazolidin-1-yl, RA and RA are hydrogen, R ³ is -CONR ⁵ R ⁶ , the meanings of R ⁵ and R ⁶ are as defined above, then R ^a cannot be alkyl , aralkyl or substituted aralkyl.

If A=Y is either 2-oxopiperidin-1-yl or 2-oxo-azepan-1-yl, R ^A , R ^A and R ^a are all hydrogen, then R ^a cannot be 2-phenylimidazo[1 ,2-a]pyridin-3-yl.

In a specific embodiment, A=Y is selected from a list consisting of

where X is O or S, according to a more specific embodiment of O; in another embodiment, X is S.

The asterisks in the above illustration indicate the attachment sites of the R ^a substituent.

In a particular embodiment, if RA is -CONR ⁵ R ⁶ and Ra is C-pg alkyl, then the carbon atom to which R-1 and RA are attached is preferably in the S'' configuration.

In a specific embodiment, RA is hydrogen, methyl, ethyl and Ra is hydrogen. In a specific embodiment, R ³ is -CONH ₂ .

In a further specific embodiment, RA is 1Himidazol-1-yl, 1H-imidazol-4-yl, 1H-imidazol-5-yl, imidazo[1,2-a]pyridin-3-yl, or imidazo-[1,2b ]pyridazin-3-yl. In a particular embodiment, R ^a is C-jg alkyl, which may optionally be substituted with halogen; or phenyl.

In another specific embodiment, R ^b is hydrogen, halogen, nitro, cyano, or C-pg alkyl, optionally substituted with halogen.

According to a further embodiment, the compounds can be used in the treatment of the above-mentioned disorders, in particular epilepsy, the compounds being characterized by the formula (I-E), as well as their geometric isomers, enantiomers, diastereoisomers and mixtures, or a pharmaceutically acceptable salt thereof,

Where

X represents O or S;

- 111 045018

R ¹ represents hydrogen or C-[.g alkyl, in a more specific embodiment hydrogen;

R ³ represents imidazolyl, imidazopyridinyl, imidazopyridazinyl; R ^b represents hydrogen; nitro;

cyano; halogen; C-|.g alkyl, optionally substituted with halogen; C-].g alkoxy, optionally substituted with halogen.

According to a further aspect, the present invention relates to novel compounds characterized by formula (IA), geometric isomers, enantiomers, diastereoisomers and mixtures thereof, or a pharmaceutically acceptable salt thereof ^R \

M (1-A) where

R ¹ represents hydrogen or Cj.g alkyl, preferably hydrogen, methyl or ethyl; in a more specific embodiment, R ^a is ethyl.

R ³ is -CONH ₂ , imidazolyl, imidazopyridinyl, imidazopyridazinyl, preferably RA is CONH2.

R ^a is either hydrogen or aryl; subject to the exclusion of 2-(5-oxoimidazolidin-1yl)acetamide.

Preferably, R ^a is aryl, for example phenyl, which may preferably be substituted with halogen, nitro, alkoxy, in particular nitro.

In a particular embodiment, if R ^A is -CONH2 and R ^A is Cj.g alkyl, the carbon atom to which R ¹ and RA are attached is preferably in the S'' configuration.

According to a further aspect, the present invention relates to novel compounds characterized by the formula (I-B1 or I-B2), geometric isomers, enantiomers, diastereoisomers and mixtures thereof, or a pharmaceutically acceptable salt thereof,

wherein X in formula (I-B2) is either S or O, according to a more specific embodiment of S;

R ¹ represents hydrogen or C-[.g alkyl, preferably hydrogen, methyl or ethyl; according to a more specific embodiment, R ¹ represents ethyl.

R ³ represents -CONH2, imidazolyl, imidazopyridinyl, imidazopyridazinyl; preferably R ³ is CONH2.

R ^a represents hydrogen; C-[.g alkyl, optionally substituted with halogen, or C1_4alkoxy; aryl; or C2.g alkenyl, optionally substituted with halogen. Preferably, R ^a is C-|.g alkyl, optionally substituted with halogen, or C2_ ₆ alkenyl, optionally substituted with halogen, or aryl. In a more specific embodiment, R ^a is C-[.g alkyl, optionally substituted with halogen, or aryl.

In a particular embodiment, if RA is -CONH ₂ and RA is Cj.g alkyl, then the carbon atom to which R ¹ and ^Ra are attached is preferably in the S configuration.

According to a further aspect, the present invention relates to novel compounds characterized by formula (I-B3), their geometric isomers, enantiomers, diastereoisomers and mixtures, or a pharmaceutically acceptable salt thereof

Where

R ¹ is either hydrogen or C ^A g alkyl, preferably hydrogen, methyl or ethyl; more preferably R ¹ is ethyl.

R ³ represents -CONH2, imidazolyl, imidazopyridinyl, imidazopyridazinyl; preferably R ³ is CONH ₂ ,

R ^a represents C- _{j_5} alkyl, optionally substituted with halogen or C _{1_4} alkoxy; aryl;

- 112 045018 or C2_g alkenyl, optionally substituted with halogen.

Preferably R ^a is Cj.g alkyl, optionally substituted with halogen, or

C2_g alkenyl, optionally substituted with halogen.

In a particular embodiment, if RA is -CONH ₂ and RA is C-|.g alkyl, then the carbon atom to which R ¹ and ^RA are attached is preferably in the S configuration.

According to a further aspect, the present invention relates to novel compounds characterized by formula (I-C), geometric isomers, enantiomers, diastereoisomers and mixtures thereof, or a pharmaceutically acceptable salt thereof

(|-C) where

R ¹ represents hydrogen or C-[.g alkyl, in particular hydrogen, methyl or ethyl.

R ³ represents -CONH2, imidazolyl, imidazopyridinyl, imidazopyridazinyl; in particular R ³ is -CONH2.

R ^a represents methyl, ethyl, butyl optionally substituted with halogen or C1-4 alkoxy, unsubstituted phenyl or phenyl substituted with halogen, C-[.g alkyl optionally substituted with halogen or C1-4 alkoxy; or R ^a is C2-6 alkenyl, optionally substituted with halogen.

Preferably, R ^a is methyl, optionally substituted with halogen, unsubstituted phenyl or phenyl substituted with halogen.

In a particular embodiment, if RA is -CONH2 and RA is C-[.g alkyl, then the carbon atom to which R ¹ and Re are attached is preferably in the S configuration.

According to a further aspect, the present invention relates to compounds characterized by formula (I-D1 or I-D2), geometric isomers, enantiomers, diastereoisomers and mixtures thereof, or a pharmaceutically acceptable salt thereof

(I-D1) (I-D2) where

R ¹ represents hydrogen or Cj.g alkyl, in particular hydrogen;

R ³ represents imidazolyl, imidazopyridinyl or imidazopyridazinyl.

In one embodiment, RA is 1H-imidazol-1-yl, 1H-imidazol4-yl, 1H-imidazol-5-yl, imidazo[1,2-a]pyridin-3-yl, or imidazo[1,2- b]pyridazin-3-yl. In a more specific embodiment, RA is 1H-imidazol-1-yl, 1H-imidazol-4-yl, N-imidazol-5-yl, imidazo[1,2-a]pyridin-3-yl; R ^a represents hydrogen, C-|.g alkyl, optionally substituted with halogen or C _1-4 alkoxy; aryl; or C2-g alkenyl, optionally substituted with halogen.

In a specific embodiment, R ^a is C-[.g alkyl, optionally substituted with halogen; aryl; or C _2-6 alkenyl, optionally substituted with halogen.

In a more specific embodiment, R ^a is C-[.g alkyl, optionally substituted with halogen; or aryl, for example propyl or phenyl;

with the proviso that if RA and R ^a are hydrogen, then RA is not 2phenylimidazo[1,2-a]pyridin-3-yl.

According to a further aspect, the present invention relates to compounds characterized by the formula (I-F1, I-F2 or I-F3), geometric isomers, enantiomers, diastereoisomers and mixtures thereof, or a pharmaceutically acceptable salt thereof

Where

R ¹ represents hydrogen or C-[.g alkyl, preferably hydrogen, methyl or ethyl; more preferably R ¹ is hydrogen.

- 113 045018

R ³ represents -CONH2, imidazolyl, imidazopyridinyl or imidazopyridazinyl; in a more specific embodiment, R ³ is -CONH2, 1H-imidazol-1-yl, 1Himidazol-4-yl, 1H-imidazol-5-yl, imidazo[1,2-a]pyridin-3-yl or imidazo [1,2-b]pyridazin-3-yl.

Rb represents hydrogen; halogen; nitro; cyano; C _1-4 alkyl, optionally substituted with halogen; C _1-4 alkoxy, optionally substituted with halogen. In a more specific embodiment, RA is hydrogen, halogen or cyano, more specifically halogen.

In a particular embodiment, if RA is -CONH2 and ^RA is C-|.g alkyl, then the carbon atom to which R ¹ and Re are attached is preferably in the S configuration.

According to a further aspect, the present invention relates to compounds characterized by formula (I-F4), their geometric isomers, enantiomers, diastereoisomers and mixtures, or a pharmaceutically acceptable salt thereof

(1-M) where

R ¹ represents hydrogen or C-[.g alkyl, preferably hydrogen;

R ³ is imidazolyl, imidazopyridinyl or imidazopyridazinyl; more specifically, R ³ is 1H-imidazol-1-yl, 1H-imidazol-4-yl, 1H-imidazol-5-yl, imidazo[1,2a]pyridin-3-yl or imidazo[1,2-b] pyridazin-3-yl. More specifically, R ³ is 1Himidazol-4-yl or imidazo[1,2-a]pyridin-3-yl.

Rb represents hydrogen; halogen; nitro; cyano; C _1-4 alkyl, optionally substituted with halogen; C _1-4 alkoxy, optionally substituted with halogen; in particular Rb is hydrogen, halogen or cyano.

In a particular embodiment, if RA is -CONH2 and Ra is C-[.g alkyl, then the carbon atom to which R ¹ and RA are attached is preferably in the S configuration.

According to a further aspect, the present invention relates to compounds characterized by any of the formulas (I-G1, I-G2 or I-G3), geometric isomers, enantiomers, diastereoisomers and mixtures thereof, or a pharmaceutically acceptable salt thereof

Where

R ¹ represents hydrogen or C-|.g alkyl; preferably hydrogen;

R ³ represents -CONH2, imidazolyl, imidazopyridinyl, imidazopyridazinyl; in a more specific embodiment, R ³ is -CONH2, 1H-imidazol-1-yl, 1Himidazol-4-yl, 1H-imidazol-5-yl, imidazo[1,2-a]pyridin-3-yl or imidazo [1,2-b]pyridazin-3-yl. In a more specific embodiment, R ³ is 1H-imidazol-4-yl or imidazo[1,2-a]pyridin-3-yl;

R ⁴ b represents hydrogen; halogen; C _1-4 alkyl, optionally substituted with halogen; Cp ₄ alkoxy, optionally substituted with halogen.

The particular compounds of the present invention are selected from the group consisting of: (2B)-2-[3-(4-nitrophenyl)-5-oxoimidazolidin-1-yl]butanamide; (2S)-2-[3-(2,4-dinitrophenyl)-5-oxoimidazolidin-1-yl]butanamide; (2S)-2-(5-oxo-3-phenylimidazolidin-1-yl)butanamide; 2-[5-(iodomethyl)2-oxo-1,3-oxazolidin-3-yl]butanamide; 2-(2-oxo-2,5-dihydro-1H-pyrrol-1-yl)butanamide; 2-(2-oxo4-phenyl-2,5-dihydro-1H-pyrrol-1-yl)butanamide; 2-(4-methyl-2-oxo-2,5-dihydro-1 H-pyrrol-1 -yl)butanamide; (2S)-2-(2-oxo-5-propyl-1,3-thiazol-3(2H)-yl)butanamide; 2-(2-oxo-5-propyl-1,3-thiazol-3(2H)yl)propanamide; 2-(5-butyl-2-oxo-1,3-thiazolidin-3-yl)butanamide; 2-(5-butyl-2-oxo-1,3-thiazolidin3-yl)propanamide; 2-(2-oxo-5-phenyl-1,3-thiazolidin-3-yl)propanamide; 2-(2-oxo-5-propyl-1,3thiazolidin-3-yl)butanamide; 2-(2-oxo-5-phenyl-1,3-thiazolidin-3-yl)butanamide; 2-(2-oxo-5-propyl1,3-thiazolidin-3-yl)propanamide; (2S)-2-[2-oxo-5-(2,2,2-trifluoroethyl)-1,3-thiazolidin-3-yl]butanamide; 1 - {[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}piperidin-2-one; 1-(1Himidazol-4-ylmethyl)-5-propylpiperidin-2-one; 1 -(1 H-imidazol-1 -ylmethyl)-5 -propylpiperidin-2-one; 1 -(imidazo[1,2-a]pyridin-3-ylmethyl)-5-propylpiperidin-2-one; 1-(1H-imidazol-1-ylmethyl)-5-phenyl

- 114 045018 piperidin-2-one; 1 -(imidazo[1,2-a]pyridin-3-ylmethyl)-5-phenylpiperidin-2-one; 1 -(imidazo[1,2a]pyridin-3-ylmethyl)-4-phenylpiperidin-2-one; 1-(1H-imidazol-1-ylmethyl)-4-phenylpiperidin-2-one;

1-(imidazo[1,2-a]pyridin-3-ylmethyl)-4-propylpiperidin-2-one; 1-(1H-imidazol-5-ylamethyl)-4-propylpiperidin-2-one; 1-(1H-imidazol-1-ylmethyl)-4-propylpiperidin-2-one; 1 - {[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}azepan-2-one; 1-(1H-imidazol-5-ylmethyl)-5-propylazepan-2one; 5-propyl-1-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl}azepan-2-one; 5-phenyl-1-{[2(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl}azepan-2-one; 1-(1H-imidazol-5-ylamethyl)-6-propylazepan-2-one; 1-(1H-imidazol-4-ylmethyl)-4-propylazepan-2-one; 4-(1H-imidazol-4-ylmethyl)-4,6dihydro-5H-thieno[3,2-b]pyrrol-5-one; 2-(5-oxo-5,6-dihydro-4H-thieno[3,2-b]pyrrol-4-yl)acetamide; 4{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl}-4,6-dihydro-5H-thieno[3,2-b]pyrrol-5-one; 4-{[2(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl}hexahydro-5H-thieno[3,2-b]pyrrol-5-one; 1-(1Himidazol-4-ylmethyl)-1H-thieno[3,4-b]pyrrol-2(3H)-one; 2-(6-chloro-2-oxo-1,3-benzothiazol-3(2H)-yl)acetamide; 6-bromo-3-(1H-imidazol-1-ylmethyl)-1,3-benzothiazol-2(3H)-one; 2-(6-bromo-2-oxo-1,3-benzothiazol-3(2H)-yl)propanamide; 2-(6-bromo-2-oxo-1,3-benzothiazol-3(2H)-ylpropanamide; 2-(6-fluoro-2oxo-1,3-benzothiazol-3(2H)-yl)acetamide; 2- (6-methyl-2-oxo-1,3-benzothiazol-3(2H)-yl)acetamide; 6fluoro-3-( 1 H-imidazol-1 -ylmethyl)-1,3-benzoxazol-2(3H)- she; 1-(1 H-imidazol-4-ylmethyl)pyrazolo[1,5a]pyridin-2(1 H)-one; 2-(6-chloro-3-oxo-3,4-dihydroisoquinoline-2(1 H)-yl)propanamide; 5-chloro-2-(1Himidazol-4-ylmethyl)-1,4-dihydroisoquinolin-3(2H)-one; 2-(6-chloro-2-oxo-3,4-dihydroquinoline -1(2H)yl)acetamide; 2-(6-bromo-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetamide; 1-(1H-imidazol-4-ylmethyl)3,4 -dihydroquinolin-2(1H)-one; 2-(6-iodo-2-oxo-3,4-dihydroquinolin-(2H)-yl)acetamide; 2-(6-cyano-2oxo-3,4-dihydroquinoline- 1 (2H)-yl)acetamide; 7-chloro-2-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3yl]methyl}-1,2,4,5-tetrahydro-3H-2 -benzazepin-3-one; 7-chloro-2-(1H-umidazol-4-ylmethyl)-1,2,4,5-tetrahydro-3H-2-benzazepin-3-one; 7-chloro-3-( 1H-imidazol-4-ylmethyl)-1,3,4,5-tetrahydro-2H-3-benzazepin-2one and 7-chloro-3-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin- 3-yl]methyl}-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one.

In some embodiments, the compounds of the present invention are selected from the group consisting of: 1-(1H-imidazol-4-ylmethyl)-5-propylpiperidin-2-one; 1-(1Himidazol-1-ylmethyl)-5-propylpiperidin-2-one; 1-(imidazo[1,2-a]pyridin-3-ylmethyl)-5-propylpiperidin-2-one; 1-(1H-imidazol-1-ylmethyl)-5-phenylpiperidin-2-one; 1 -(imidazo[1,2-a]pyridin-3 ylmethyl)-4-phenylpiperidin-2-one; 1-(1H-imidazol-1-ylmethyl)-4-phenylpiperidin-2-one; 1 -(imidazo[1,2-a]pyridin-3-ylmethyl)-4-propylpiperidin-2-one; 1-(1H-imidazol-5-ylamethyl)-4-propylpiperidin2-one; 1-(1H-imidazol-1-ylmethyl)-4-propylpiperidin-2-one; 1-(1H-imidazol-4-ylmethyl)-1H-thieno[3,4b]pyrrol-2(3H)-one; 6-bromo-3-(1H-imidazol-1-ylmethyl)-1,3-benzothiazol-2(3H)-one; 2-(6-bromo-2-oxo1,3-benzothiazol-3(2H)-yl)propanamide and 5-chloro-2-(1H-imidazol-4-ylmethyl)-1,4-dihydroisoquinoline3(2H)- she.

The following paragraphs provide designations for the various chemical moieties that constitute the compounds of the present invention and are intended to be used uniformly throughout the specification and claims unless otherwise specifically stated provides a broader definition.

C-_P alkyl refers to alkyl groups containing 1-6 or 1-4 carbon atoms. This term is illustrated by groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, n-hexyl, trifluoromethyl, and the like. Aryl refers to an unsaturated aromatic carbocyclic group of 6-14 carbon atoms containing a single ring (eg, phenyl) or multiple fused rings (eg, naphthyl). Preferred aryl includes phenyl, naphthyl, phenanthrenyl and the like.

A heterocycle refers to a saturated or unsaturated ring system containing, in addition to carbon atoms, at least one heteroatom such as nitrogen, oxygen and/or sulfur. A heterocycle includes both heteroaryl and heterocycloalkyl.

Heteroaryl refers to a monocyclic heteroaromatic, or bicyclic or tricyclic heteroaromatic group with fused rings. Specific examples of heteroaromatic groups include optionally substituted pyridyl, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3oxadiazolyl, 1 ,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,3,4-triazinyl, 1,2,3triazinyl, benzofuryl, [2,3-dihydro]benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, isobenzothienyl, indolyl, isoindolyl, 3H-indolyl, benzimidazolyl, imidazopyridinyl, benzothiazolyl, benzoxazolyl, quinolizinyl, quinazolinyl, phthalazinyl, quinoxalinyl, cinnolinyl, naphthyridinyl, pyrido[3,4-b]pyridyl, pyrido[3,2 - b]pyridyl, pyrido[4,3-b]pyridyl, quinolyl, isoquinolyl, tetrazolyl, 5,6,7,8-tetrahydroquinolyl, 5,6,7,8-tetrahydroisoquinolyl, purinyl, pteridinyl, carbazolyl, xanthenyl, benzoquinolyl, imidazopyrimidinyl, imidazopyridazinyl, imidazothiazolyl or imidazothiadiazolyl.

C ₂ . ₆ alkenyl refers to alkenyl groups, preferably containing from 2 to 6 carbon atoms and containing at least 1 or 2 alkenyl unsaturation positions. Preferred alkenyl groups include ethenyl (vinyl, -CH=CH ₂ ), n-2-propenyl (allyl,

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-CH2CH=CH2), etc.

_C2 . ₆ alkynyl refers to alkynyl groups preferably containing from 2 to 6 carbon atoms and containing at least 1-2 sites of alkynyl unsaturation, preferred alkynyl groups include ethynyl (-C^CH), propargyl (-CH ₂ C^CH), etc. .P.

C ₃ . ₈ cycloalkyl refers to a saturated carbocyclic group of 3-8 carbon atoms containing a single ring (eg cyclohexyl) or multiple fused rings (eg norbornyl). Preferred cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl and the like.

Heterocycloalkyl refers to C ₃ as defined above. ₈ cycloalkyl group in which 1-3 carbon atoms are replaced by heteroatoms selected from the group consisting of O, S, NR, and R is defined as hydrogen or Cj.g alkyl.

Alkoxy belongs to the group -OR, where R includes C ^A g alkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl, C ₃ . ₈ cycloalkyl, heterocycloalkyl, aryl, heteroaryl.

Amino refers to the group -NRR', where each R, R' independently represents hydrogen, Cj.g alkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl, C ₃ . ₈ cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and wherein R and R', together with the nitrogen atom to which they are attached, may optionally form a 38-membered heterocycloalkyl ring.

Amido belongs to the group -C(=O)NRR', where each R, R' independently represents hydrogen, C ₁ . ₅ alkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl, C ₃ . ₈ cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and where R and R', together with the nitrogen atom to which they are attached, can optionally form a 3-8 membered heterocycloalkyl ring.

Acylamino refers to the group -NRC(O)R', where the values of R and R' are defined above for amino groups.

Ureido belongs to the group -NR''C(O)NRR', where the values of R and R' are defined above for amino groups, and the value of R'' is defined above.

Sulfanyl belongs to the group -SR, where R represents Cj.g alkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl, C ₃ . ₈ cycloalkyl, heterocycloalkyl, aryl or heteroaryl.

Sulfinyl belongs to the group -S(=O)R, where R represents Cj.g alkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl, C ₃ . ₈ cycloalkyl, heterocycloalkyl, aryl or heteroaryl.

Sulfonyl belongs to the group -S(=O)2R, where R represents Cj.g alkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl, C ₃ . ₈ cycloalkyl, heterocycloalkyl, aryl or heteroaryl.

Halogen refers to fluorine, chlorine, bromine and iodine atoms.

Substituted or unsubstituted: Unless otherwise limited by the specific substituent, the above groups such as alkyl, alkenyl, alkynyl, aryl and heteroaryl and other groups may be optionally substituted with 1 to 5 substituents selected from the group consisting of Cj.g alkyl , C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl, cycloalkyl, heterocycloalkyl, amino, amido, acylamino, ureido, aryl, heteroaryl, alkoxy, halogen, cyano, hydroxy, mercapto, nitro, amido, sulfanyl, sulfinyl, sulfonyl, etc.

The acid addition salt form of a compound of formula I which occurs in its free form as a base can be prepared by treating the free base with an appropriate acid, for example an inorganic acid such as a hydrohalic acid, for example hydrochloric or hydrobromic, sulfuric, nitric, phosphoric and etc.; or an organic acid such as, for example, acetic, trifluoroacetic, hydroxyacetic, propanoic, lactic, pyruvic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, para-toluenesulfonic, cyclamic, salicylic, para -aminosalicylic, pamic, etc.

Compounds of formula I containing acid protons can be converted to their therapeutically active non-toxic base addition salt forms, for example metal or amine salts, by treatment with appropriate organic and inorganic bases. Suitable forms of base salts include, for example, ammonium salts, alkali and alkaline earth metal salts, for example, lithium, sodium, potassium, magnesium, calcium and the like salts, salts with organic bases, for example, N-methyl-D-glucamine salts , hydrabamine and salts with amino acids such as, for example, arginine, lysine and the like.

Conversely, these salt forms can be converted to free forms by treatment with an appropriate base or acid.

The compounds of formula I and their salts may be in the form of a solvate, which is included within the scope of the present invention. Such solvates include, for example, hydrates, alcoholates, and the like.

Many of the compounds of formula I and some of their intermediates contain at least one stereogenic center in their structure. This stereogenic center may be present in an R or S configuration, with the symbols R and S being used in accordance with the rules described in Pure Appl. Chem., 45 (1976) 11-30.

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The present invention also relates to all stereoisomeric forms, such as enentiomeric and diastereoisomeric forms of the compounds of formula I, or mixtures thereof (including all possible mixtures of stereoisomers). For purposes of the present invention, reference to a compound or compounds is intended to include such compound in each of its possible isomeric forms and mixtures thereof, unless specifically referenced to a particular isomeric form.

The compounds of the present invention may exist in various polymorphic forms. Even if not specifically indicated in the above formula, such forms are to be included within the scope of the present invention.

Some of the compounds of formula I may also exist in tautomeric forms. Such forms, even if not specifically indicated in the above formula, are to be included within the scope of the present invention.

Also included within the scope of the present invention are prodrug forms of the compounds of formula I and their various subvariants and subgroups.

According to a specific embodiment, the present invention relates to a compound selected from the group consisting of: (2S)-2-[3-(4-nitrophenyl)-5-oxoimidazolidin-1-yl]butanamide; (2S)-2-[3-(2,4-dinitrophenyl)-5-oxoimidazolidin-1-yl]butanamide; (2S)-2-(5-oxo-3-phenylimidazolidin-1-yl)butanamide; 2-[5-(iodomethyl)-2-oxo-1,3-oxazolidin-3-yl]butanamide; 2-(2-oxo-2,5-dihydro1H-pyrrol-1-yl)butanamide; 2-(2-oxo-4-phenyl-2,5-dihydro-1H-pyrrol-1-yl)butanamide; 2-(4-methyl-2oxo-2,5-dihydro-1H-pyrrol-1-yl)butanamide; (+)-(2S)-2-(2-oxo-4-propyl-2,5-dihydro-1H-pyrrol-1yl)butanamide; (2S)-2-(2-oxo-5-propyl-1,3-thiazol-3(2H)-yl)butanamide; 2-(2-oxo-5-propyl-1,3-thiazol3(2H)-yl)propanamide; 2-(5-butyl-2-oxo-1,3-thiazolidin-3-yl)butanamide; 2-(5-butyl-2-oxo-1,3thiazolidin-3-yl)propanamide; 2-(2-oxo-5-phenyl-1,3-thiazolidin-3-yl)propanamide; 2-(2-oxo-5propyl-1,3-thiazolidin-3-yl)butanamide; 2-(2-oxo-5-phenyl-1,3-thiazolidin-3-yl)butanamide; 2-(2-oxo5-propyl-1,3-thiazolidin-3-yl)propanamide; (2S)-2-[2-oxo-5-(2,2,2-trifluoroethyl)-1,3-thiazolidin-3yl]butanamide; 1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}piperidin-2-one; 1(1H-imidazol-4-ylmethyl)-5-propylpiperidin-2-one; 1-(1H-imidazol-1-ylmethyl)-5-propylpiperidin-2one; 1-(imidazo[1,2-a]pyridin-3-ylmethyl)-5-propylpiperidin-2-one; 1-(III-imidazol-1-ylmethyl)-5phenylpiperidin-2-one; 1 -(imidazo[1,2-a]pyridin-3-ylmethyl)-5-phenylpiperidin-2-one; 1 -(imidazo[1,2a]pyridin-3-ylmethyl)-4-phenylpiperidin-2-one; 1-(1H-imidazol-1-ylmethyl)-4-phenylpiperidin-2-one; 1-(imidazo[1,2-a]pyridin-3-ylmethyl)-4-propylpiperidin-2-one; 1-(1H-imidazol-5-ylamethyl)-4-propylpiperidin-2-one; 1-(1H-imidazol-1-ylmethyl)-4-propylpiperidin-2-one; 1 - {[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}azepan-2-one; 1-(1H-imidazol-5-ylmethyl)-5-propylazepan-2one; 5-propyl-1-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl}azepan-2-one; 1-(1H-imidazol-5ylamethyl)-5-phenylazepan-2-one; 5-phenyl-1-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl}azepan-2-one; 1 -(1H-imidazol-5-ylmethyl)-6-propylazepan-2-one; 1-(1H-imidazol-4-ylmethyl)-4propylazepan-2-one; 4-(1H-imidazol-4-ylmethyl)-4,6-dihydro-5H-thieno[3,2-b]pyrrol-5-one; 2-(5-oxo5,6-dihydro-4H-thieno[3,2-b]pyrrol-4-yl)acetamide; 4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3yl]methyl}-4,6-dihydro-5H-thieno[3,2-b]pyrrol-5-one; 4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3yl]methyl}hexahydro-5H-thieno[3,2-b]pyrrol-5-one; 1-(1H-imidazol-4-ylmethyl)-1H-thieno[3,4-b]pyrrol2(3H)-one; 2-(6-bromo-2-oxo-1,3-benzothiazol-3(2H)-yl)acetamide; 2-(2-oxo-1,3-benzothiazol-3(2H)yl)acetamide; 2-(6-chloro-2-oxo-1,3-benzothiazol-3(2H)-yl)acetamide; 6-bromo-3-(1H-imidazol-1 ylmethyl)-1,3-benzothiazol-2(3H)-one; 6-bromo-3-(2-oxopropyl)-1,3-benzothiazol-2(3H)-one; 2-(6-nitro-2oxo-1,3-benzothiazol-3(2H)-yl)acetamide; 2-(6-bromo-2-oxo-1,3-benzothiazol-3(2H)-yl)propanamide; 2-(6bromo-2-oxo-1,3-benzothiazol-3(2H)-yl)propanamide; 2-(6-fluoro-2-oxo-1,3-benzothiazol-3(2H)-yl)acetamide; 2-(6-methyl-2-oxo-1,3-benzothiazol-3(2H)-yl)acetamide; 6-fluoro-3-(1H-imidazol-1-ylmethyl)-1,3benzoxazol-2(3H)-one; 1-(1H-imidazol-4-ylmethyl)pyrazolo[1,5-a]pyridin-2(1H)-one; 2-(6-chloro-3-oxo3,4-dihydroisoquinolin-2(1H)-yl)propanamide; 5-chloro-2-(1H-imidazol-4-ylmethyl)-1,4-dihydroisoquinolin-3(2H)-one; 2-(6-chloro-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetamide; 2-(6-bromo-2-oxo-3,4dihydroquinolin-1(2H)-yl)acetamide; 1-1 H-imidazol-4-ylmethyl)-3,4-dihydroquinolin-2(1 H)-one; 2-(6iodo-2-oxo-3,4-dihydroquinolin-1 (2H)-yl)acetamide; 2-(6-cyano-2-oxo-3,4-dihydroquinolin-1(2H)yl)acetamide; 7-chloro-2-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl}-1,2,4,5-tetrahydro-3H-2benzazepin-3-one; 7-chloro-2-(1H-imidazol-4-ylmethyl)-1,2,4,5-tetrahydro-3H-2-benzazepin-3-one; 7-chloro3-(1H-imidazoiso-4-ylmethyl)-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one and 7-chloro-3 - {[2-(trifluoromethyl)imidazo[ 1,2-a]pyridin-3-yl]methyl}-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one.

xvi) UK Patent No. 1039113

The new compounds of the present invention are N-substituted lactams of the general formula in which N is an integer from 3 to 5 and

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R is a radical in which m is 0, 1 or 2, and R' is a hydrogen atom, or an alkyl, cycloalkyl, alkenyl or alkynyl radical which may contain from 3 to 6 carbon atoms, or an aryl radical, and R is a hydrogen or an alkyl radical, or both R' and R together with the nitrogen atom to which they are attached form a heterocyclic ring such as a pyrrolidine ring.

xvii) UK Patent No. 1309692

According to the present invention, new N-substituted lactams of the general formula are presented:

¹ sk-so-<; R in which X represents a hydrogen atom or an alkyl, alkenyl or alkynyl radical containing 1-6 carbon atoms, p represents an integer from 1 to 6, Y represents a hydrogen atom or an alkyl, alkenyl or alkynyl radical containing 1-6 carbon atoms, or cycloalkyl radical, and R' and R, which may be the same or different, represent hydrogen atoms or alkyl, alkenyl, alkynyl, cycloalkyl or aryl radicals, or R' and R together with the nitrogen atom to which they are attached , form a heterocyclic radical, which may contain an additional number of heteroatoms, provided that at least one of X and Y is different from a hydrogen atom.

Acetylcholinesterase inhibitor

AChEIs useful in the methods and compositions of the present invention include the following:

zanapezil, ganstigmine, phenethylnorcimserine (PENC), cymserine, thiacimserine, SPH 1371 (galantamine plus), ER 127528, RS 1259, F3796, tetrahydroaminoacridine, DFP (diisopropyl fluorophosphate), Ladostigil, Memoquin, SP-004, BGC-20-125 9, NP -0361, ZTPET-1, INM-176, pyridostigmine, ambenonium, demarcarium, edrophonium, pralidoxime, Amirin, SW-10888, MF-217, Ro 45-5934, HP-290, ENA 713, CP 118.954, ONO 1603, eptastigmine , magnolia extract, e.g. magnolol, honokiol, taspin and azimilobine, alacepril, benazepril, captopril, ceronapril, cilazapril, delapril, enalapril, enalaprilat, fosinopril, imidapril, lisinopril, moexipril, moveltipril, omapatrilat, perindopril, quinapril, ramipril, itself patrilat, spripapril, temocaptril, trandolapril, piperidinyl alkanoyl heterocyclic compounds, N-benzylpiperidine derivatives, 4-(1-benzylpiperidyl)-substituted fused quinoline derivatives, monoamine acridines and their derivatives, cyclic amide derivatives, carboxylic acid derivatives, salicylate, obidoxime, trimedoxime, diacetyl monooxime, demecarium, icopezil (5,7-dihydro-3-(2-(1-(phenylmethyl)-4-pineridinyl)ethyl)-6Hpyrrolo(3,2-f)-l,2-benzisoxazol-6-one), heptylphysostgmine , E-2020, Citicoline, wellnacrine maleate, sulfonyl fluorides such as methanesulfonyl fluoride (Moos and Hershenson, 1989) and phenylmethylsulfonyl fluoride (Ferris, 1990; Pope and Padilla, 1990), Huperzine B, Myotin, Suronacrine and its maleate, 7methoxytacrine, SM-10888 and its citrate, ENA-713, TKA-147, CP-118954, Zifrosilone, (SR,9R)-5-(r -chloro-2hydroxy-3-methoxybenzylidene-amino)-11-ethylidene-7-methyl-1,2,5,6,9,10-hexahydro-5,9-methanocycloocta[b]pyridin-2-one (ZT 1 ), stacophylline, SPH 1371, SPH 1373 and SPH 1375, tolserine, 1-(3fluorobenzyl)-4-[(2-fluoro-5,6-dimethoxy-1-indanon-2-yl)methyl]piperidine hydrochloride (ER 127528 ), thiatolserine, (-)12-amino-3-chloro-9-ethyl-6,7,10,11-tetrahydro-7,11-methanecycloocta[b]quinoline hydrochloride (huperine X), hemifumarate ester N,N -dimethylcarbamic acid 4-[l(S)-(methylamino)-3-(4nitrophenoxy)propyl]phenyl (RS 1259), 2-[2-(1-benzylpiperidin-4-yl)ethyl]-2,3- dihydro-9-methokCu-1Hpyrrolo[3,4-b]quinolin-1-one hemifumerate (T 82), 1,3-dichloro-6,7,8,9,10,12-hexahydroazepino [2,1-b ]quinazoline (CI 1002), N-heptylcarbamic acid, 2,4a,9-trimethyl-2,3,4,4a,9,9a-hexahydro-1,2oxazino[6,5-b]indol-6-yl complex ester-L-tartrate (CHF 2060), 3-(2-[1-(1,3-diocolan-2ylmethyl)piperidin-4-yl]ethyl)-3,4-dihydro-2H-1,3-benzoxazine hydrochloride -2,4-dione (E 2030), (3aS,8aR)-1,3a,8trimethyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indol-5-yl ester N-[10-(dietulamino)decyl]carbamic acid (MF 247), 5-amino-6-chloro-4-hydroxy-3,4-dihydro-1H-thionirano-[3,4b]quinoline (MF 8615), L-bitartrate hydrate of (3aS,8aR)-1,3a,8-trimethyl-1,2,3,3a,8,8ahexahydropyrrolo[2,3-b]indol-5-yl ester N-[8-(cis- 2,6-Dimethylmorpholin-4-yl)octyl]carbamic acid (MF 268), (-)N-(3-niperidinopropyl)-N-demethylgalantamine (SPH 1286), N-propargyl3R-aminoindan-5-yl-ethylmethylcarbamate ( TV 3326), cryptotanshinone, dihydrotanshinone I and tanshinone I.

Acetylcholinesterase inhibitors useful in the methods and compositions of the present invention include the compounds or agents listed in:

i) US Patent Application No. 20080103105

- 118 045018

In one embodiment, the AChEI is metrifonate, which is also known as metrifonate or trichlorophone, or its active metabolite, 2,2dimethyldichlorovinylphosphate (or dichlorvos or DDVP). Metrifonate is represented by the following formula: (CH3O)2-PO-CHON-OC13.

Echothiophate is also known as ecothiopathate, echothiophate iodide, phospholine iodide, (2-mercaptoethyl)trimethylammonium O,O'-diethylphosphorothioate S-ester, BRN 1794025, ecothiopathate or phospholine.

Ecothiophate is registered under CAS number 6736-03-4.

In other embodiments, the AChE inhibitor is an aminoacridine, such as tacrine or ipidacrine as non-limiting examples. Tacrine/COGNEX® (1,2,3,4tetrahydro-9-aminoacridine hydrochloride) is also known as tetrahydroaminoacridine or THA.

Takrine is registered under CAS number 321-64-2. Ipidacrine is also known as Amiridine.

In further embodiments, the AChE inhibitor is a carbamate, such as physostigmine, neostigmine, or rivastigmine as non-limiting examples.

Physostigmine, also known as 1,2,3,3a,8,8α-hexahydro-1,3α,8-trimethylmethylcarbamate (ester) or (3αS,8αR)-pyrrolo[2,3-b]indol-5-ol , registered under CAS number 57-47-6. It is a tertiary amine that can penetrate the blood-brain barrier.

Neostigmine or ammonium meta-hydroxyphenyltrimethyldimethylcarbamate (ester) is registered under CAS number 59-99-4.

Rivastigmine is also known as rivastigmine tartrate or (S)-N-ethyl-N-methyl-3-[1(dimethylamino)ethyl]phenylcarbamate hydro-(2R, 3R)-tartrate or SDZ ENA 713 or ENA 713. Rivastigmine is registered under no. CAS 123441-03-2.

In further embodiments, the AChE inhibitor is a carbamate-phenanthrine derivative, such as galantamine, or a hydrobromide thereof, as non-limiting examples. Galantamine is also known as (4aS,6R,8aS)-4a,5,9,10,11,12-hexahydro-3-methoxy-11-methyl6H-benzofuro(3a,3,2-ef)(2)benzazepine-6 -ol and it is often used in its hydrobromide form. Galantamine is registered under CAS number 357-70-0.

The AChE inhibitor may also be a piperidine derivative, such as donepezil as a non-limiting example. Donepezil is also known as 2,3-dihydro-5,6-dimethoxy-2((1-(phenylmethyl)-4-piperidinyl)methyl)-1H-inden-1-one and is registered under CAS number 12001406-4.

Itopride may also be an AChE inhibitor for use in the embodiments disclosed herein. Itopride HCl is registered under CAS number 122898-67-3. In one embodiment, the total daily dose for itopride-HCl is from about 25 mg to about 1000 mg, or from about 100 mg to about 300 mg. In some embodiments, the AChE inhibitor, or neurogenic agent, is an N-oxide derivative of itopride, which is the primary metabolite of itopride -HCl in humans.

Another AChE inhibitor for use in the disclosed embodiments is (-)-huperzine A, also called HupA and 1-amino-13-ethylidene-11-methyl-6-azatricyclo[7.3.1,.02,7]trideca-2 (7),3,10-trien-5-one. It is registered under CAS number 102518-79-6.

In a further embodiment, the AChE inhibitor is phenserine, the structure and synthesis of which is described in US Pat. No. 6,495,700.

Although galantamine is only an example of an acetylcholinesterase inhibitor for use in the present invention, other acetylcholinesterase inhibitors can be used equally. Examples of such compounds include galantamine derivatives, for example compounds of formula (I) (D)

R ¹ R ⁶

where the dotted line represents a single or double carbon-carbon bond;

the two symbols R ¹ are the same or different, and each represents a hydrogen atom, a hydroxy group, an alkyl group, an aryl group, an aralkyl group, a hydroxyalkyl group, a thioalkyl group, a carboxyalkyl group, a carboxyalkyl amino group, an alkylamino group, an acyl group, a cyano group, a sulfohydryl group, C ₁ -C ₆ alkoxy group, alkylthio group, aryloxy group, arylthio group, aliphatic or aromatic carbamoyl group, aralkoxy group, aralkylthio group, aryloxymethyl group, alkanoyloxy group, hydroxyalkanoyloxy group, benzoyloxy group, benzoyloxy group, substituted by one or more groups

R ³ as defined below, or an aryloxycarbonyl group;

R ² represents a hydrogen atom, a C ₁ -C ₆ alkyl group, a C ₂ -C ₆ alkenyl group (for example, an allylic group), an aralkyl group, wherein said alkyl, alkenyl and aralkyl groups are unsubstituted or substituted at least , one halogen atom, cycloalkyl group, hydroxy group, alkoxy group, nitro group, amino group, aminoalkyl group, acylamino group, aromatic or non-aromatic heterocyclic group (for example, α- or β-furyl group, α- or β-thienyl group, α- or β-thienyl group, pyridyl group, pyrazinyl group or pyrimidyl group), an alkyl group substituted with an aromatic heterocyclic group, an aryl group (eg, a phenyl group), an aralkyl group, a cyano group, an aroyl group or a cycloalkylmethyl group;

the symbols R ³ are the same or different and each represents a hydrogen atom, a hydroxy group, an alkyl group, an aryl group, an aralkyl group, a hydroxyalkyl group, a thioalkyl group, a sulfohydryl group, a C ₁ -C ₆ -alkoxy group, an aryloxy group, an arylthio group, an aralkoxy group, an aralkylthio group , nitro group, amino group, alkylamino group, arylamino group, aralkylamino group, halogen atom or trifluoromethyl group;

the symbols R ⁴ are the same or different and each represents a hydrogen atom, a halogen atom, a trifluoromethyl group or a C ₁ -C ₄ alkyl group;

the two symbols R ⁵ are the same or different, and each represents a hydrogen atom or a hydroxymethyl group;

R ⁶ represents a hydrogen atom or a C ₁ -C ₆ alkyl group, or if the symbol R ¹ is attached to the same carbon atom as R ⁶ and represents a hydrogen atom, then R ⁶ represents a group of formula (Ia)

R ^a Η

Where

R ^a represents the connecting bond and the values of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , X and Y are determined for formula (1);

or R ⁶ and R ¹ attached to the same carbon atom as R ⁶ together represent a semicarbazone;

X represents an oxygen atom or a group of the formula -R ³ wherein R ³ is as defined above;

Y represents a nitrogen atom or a phosphorus atom;

and pharmaceutically acceptable salts thereof.

In the above compounds of formula (1), unless otherwise noted, the alkyl groups may be straight or branched and preferably contain from 1 to 10 carbon atoms, and examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec. butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl and decyl groups. By analogy, alkoxy groups and other simple derivatives of alkyl groups preferably contain from 1 to 10, more preferably from 1 to 6 carbon atoms.

Aryl and heterocyclic groups may be unsubstituted, or they may be substituted by one or more substituents selected from the groups and atoms defined for R ³ , provided that any of the R ³ substituents may itself be further substituted by a substituted aryl or heterocyclic group .

Preferred halogen atoms are fluorine, chlorine, bromine and iodine.

Preferred compounds of formula (I) are compounds in which the alkyl groups contain from 1 to 8, more preferably from 1 to 6, carbon atoms, the halogen atoms are fluorine, chlorine or bromine atoms, the aryl groups are phenyl group (which may be substituted or unsubstituted, preferably unsubstituted), cycloalkyl groups contain from 3 to 7 ring carbon atoms (preferably cyclopropyl or cyclobutyl), acyl groups are lower (for example, C ₂ -C ₆ -alkanoyl groups), and heterocyclic

- 120 045018 groups are aromatic and contain from 5 to 8 ring atoms (for example thienyl, furyl, pyridyl, pyrrolyl or pyrazinyl groups).

Particularly preferred compounds for use according to the present invention are those of formula (II)

Where

R ^1a and R 2 ^a are the same or different and each represents a hydrogen atom, an acyl group (preferably a lower alkanoyl group such as an acetyl group) or a C ₁ -C ₆ alkyl group (such as a methyl, ethyl, propyl or isopropyl group) ;

R ^3a represents an alkyl, alkenyl or aralkyl group, each of which may be unsubstituted or substituted by one or more halogen atoms, or it is a cycloalkyl group, hydroxy, alkoxy, nitro, amino, aminoalkyl group, acylamino, aromatic heterocyclic group, aroyl group, aroylalkyl group or cyano group; And

R ^4a represents a hydrogen or halogen atom;

and their pharmaceutically acceptable salts, in particular hydrobromide, hydrochloride, methylsulfonyl and methyl iodide.

Of these compounds, galantamine and its salts or donepezil and its salts, in particular halides such as galantamine hydrobromide or donepezil hydrochloride, are particularly preferred.

Galantamine derivatives that can be used according to the present invention include norgalantamine, norgalantamine derivatives and epigalantamine.

Other compounds that may be used as an acetylcholinesterase inhibitor include: physostigmine, tacrine and tacrine analogues, fasciculin, metrifonate, heptylphysostigmine, norpyridostigmine, norneostigmine, neostigmine, pyridostigmine, huperzine or its prodrugs, rivastigmine or its prodrugs, gossypol or phenserine or its prodrugs.

In particular, another preferred acetylcholinesterase inhibitor is donepezil and its salts, in particular halides such as donepezil hydrochloride.

ii) US Patent Application No. 20070275959

According to one embodiment, the invention relates to a carbamoyl ester characterized by the following structure:

wherein A is selected from the group consisting of unsubstituted aryl, substituted aryl, unsubstituted heteroaryl and substituted heteroaryl; and each of R ¹ and R ² , alone or in combination, is selected from the group consisting of hydrogen, unsubstituted alkyl, substituted alkyl, unsubstituted aralkyl, substituted aralkyl, unsubstituted heteroalkyl, substituted heteroalkyl, unsubstituted heteroaralkyl, substituted heteroaralkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, substituted heteroaryl, unsubstituted cycloalkyl, substituted cycloalkyl, unsubstituted heterocycloalkyl and substituted heterocycloalkyl.

According to a further embodiment, the invention relates to a carbamoyl ester selected from the group consisting of

- 121 045018

wherein each of R ³ , R ⁴ and R ⁵ , alone or in combination, is selected from the group consisting of hydrogen, unsubstituted alkyl, substituted alkyl, unsubstituted aralkyl, substituted aralkyl, unsubstituted heteroalkyl, substituted heteroalkyl, unsubstituted heteroaralkyl, substituted heteroaralkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, substituted heteroaryl, unsubstituted cycloalkyl, substituted cycloalkyl, unsubstituted heterocycloalkyl and substituted heterocycloalkyl.

According to another embodiment, the invention relates to a carbamoyl ester selected from the group consisting of

- 122 045018

iii) European patent application EP 1050303

In some embodiments, the acetylcholinesterase inhibitor is a compound of Formula 1

wherein each of R ¹ and R ² is independently selected from the group consisting of hydrogen; (C1-C6)alkoxy; benzyloxy; phenoxy; hydroxy; phenyl; benzyl; halogen; nitro; cyano; -COR ⁵ ; COOR ⁵ ; -CONHR ⁵ ; -NR5R ⁶ ; -NR5COR ⁶ ; -OCONR5R ⁶ ; -NHCOOR ⁵ ; (^^alkyl, which may be substituted with 1-3 fluorine atoms; SOPCH ₂ -phenyl or SOp (C ₁ -C ₆ )alkyl, where p is 0, 1 or 2; pyridylmethyloxy or thienylmethyloxy; 2-oxazolyl; 2-thiazolyl and benzenesulfonamide; wherein the phenyl moieties of said phenoxy, benzyloxy, phenyl, benzyl and benzenesulfonamide groups, the pyridyl and thienyl moieties of said pyridylmethyloxy or thienylmethyloxy groups and the oxazolyl and thiazolyl moieties of said 2-oxazolyl and 2-thiazolyl groups may be substituted with 1 or 2 independently selected substituents from the group consisting of halogen, (C ₁ -C ₄ )alkyl, trifluoromethyl, (C ₁ -C ₄ )alkoxy, cyano, nitro and hydroxy;

or R ¹ and R ² are connected to adjacent carbon atoms and form, together with the carbon atoms to which they are attached, a group of formula 2 in which R ³ represents hydrogen or (C ₁ -C ₆ )alkyl;

J represents oxygen, sulfur or NR ⁴ ;

R ⁴ represents hydrogen or (C ₁ -C ₄ )alkyl and

- 123 045018

Q represents oxygen, sulfur, NH, CHCH3, C(CH3)2, -CH=CH- or (CH2) _i , where i is an integer from 1 to 3;

X represents oxygen or sulfur;

Y is -(CH2)m-, -CH=CH(CH2)n-, -NR4(CH2)m-, or -O(CH2)m-, where n is an integer from 0 to 3, and m represents an integer from 1 to 3;

each of R ⁵ and R ⁶ is independently selected from the group consisting of hydrogen, (C ₁ -C ₆ )alkyl, phenyl and benzyl, wherein the phenyl moieties of said phenyl and benzyl groups may be substituted by 1 or 2 substituents independently selected from the group, consisting of fluorine, chlorine, bromine, iodine, (C ₁ -C ₄ )alkyl, trifluoromethyl, (C ₁ -C ₄ )alkoxy, cyano, nitro and hydroxy; or NR5R ⁶ together form a 4 or 5 membered ring in which one ring atom is nitrogen and the others are carbon, oxygen or nitrogen; or NR5COR ⁶ together form a 4 or 5 membered lactam ring;

L represents phenyl, phenyl-(C ₁ -C ₆ )alkyl, cinnamyl or pyridylmethyl, wherein the phenyl moieties of said phenyl and phenyl-(C ₁ -C ₆ )alkyl may be substituted with 1-3 substituents independently selected from the group consisting of from (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, (C ₁ -C ₄ )alkoxycarbonyl, (C1C ₆ )alkylcarbonyl, OCONR5R ⁶ , -NHCOOR ⁵ and halogen; or L represents a group of formula 3 ( ^CHH 5 R”, in which b is an integer from 1 to 4; R ⁹ and R ¹⁰ are independently selected from the group consisting of hydrogen, (C ₁ -C ₄ )alkyl, halogen and phenyl; E and F are independently -CH- or nitrogen; and G is oxygen, sulfur or NR ⁴ , provided that if both E and F are nitrogen, then one of R ⁹ and R ¹⁰ is absent; and

R ⁷ and R ⁸ are independently selected from the group consisting of hydrogen, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxycarbonyl, (C ₁ -C ₆ )alkylcarbonyl and (C ₁ -C ₆ )alkoxy, with the proviso that said (C ₁ -C ₆ )alkoxy is not attached to a carbon that is adjacent to the nitrogen;

or a pharmaceutically acceptable salt or solvate thereof.

According to some embodiments of the invention, the compound of formula 1 is selected from the group consisting of:

5,7-dihydro-7-methyl-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-bH-pyrrolo[4,5-f]-1,2-benzisoxazol-b-one;

5,7-dihydro-7-ethyl-3-[2[1-(phenylmethyl)-4-piperidinyl]ethyl]-bH-pyrrolo[4,5-f]-1,2-benzisoxazol-b-one;

5,7-dihydro-3-[2-[1-(2-chloro-5-thiophenemethyl)-4-piperidinyl]ethyl]bH-pyrrolo[4,5-f]-1,2-benzisoxazol-b-one ;

5,7-dihydro-3-[2-[1-(2-methyl-4-thiazolmethyl)-4-piperidinyl]ethyl]-bH-pyrrolo[4,5-f]-1,2-benzisoxazole-b- she;

3-[2-[1-(3-bromophenylmethyl)-4-piperidinyl]ethyl]-5,7dihydro-bH-pyrrolo[4,5-f]-1,2-benzisoxazol-b-one;

3-[2-[1-(4-bromophenylmethyl)-4-piperidinyl]ethyl]-5,7dihydro-bH-pyrrolo[4,5-f]-1,2-benzisoxazol-b-one;

5,7-dihydro-3-[3-[1-(phenylmethyl)-4-piperidinyl]propyl]-6Hpyrrolo[4,5-f]-1,2-benzisoxazol-b-one;

b,8-dihydro-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-7Hpyrrolo[5,4-g]-1,2-benzisoxazal-7-one and

5,7-dihydro-3-[3-[1-(phenylmethyl)-4-piperidinyl]ethyl]-6Hpyrrolo[4,5-f]-1,2-benzisoxazol-b-one;

In some embodiments of the present invention, the compound of Formula 1 is 5,7-dihydro-3-[3-[1-(phenylmethyl)-4-piperidinyl]ethyl]-6H-pyrrolo[4,5-f]-1,2benzisoxazole -6-on.

iv) Published international patent application WO 2000/030446

a) The acetylcholinesterase inhibitor is selected from the group consisting of galantamine, lycoramine and analogues of these compounds in which their methoxy group is replaced by another alkoxy group containing from one to six carbon atoms, a hydroxy group, hydrogen, an alkanoyloxy group, a benzoyloxy or substituted benzoyloxy group, a carbonate group or a carbamate group .

b) The acetylcholinesterase inhibitor is selected from the group consisting of analogs of galantamine and lycoramine in which the hydroxy group of galantamine or lycoramine is replaced by an alkoxy group containing from one to six carbon atoms, hydrogen, alkanoyloxy, benzoyloxy or substituted

- 124 045018 benzoyloxy group, carbonate group or carbamate group.

c) The acetylcholinesterase inhibitor is selected from the group consisting of galantamine and lycoramine analogues in which the N-methyl group of galantamine or lycoramine is replaced by a hydrogen, alkyl, benzyl or cyclopropylmethyl group or a substituted or unsubstituted benzoyloxy group.

d) The acetylcholinesterase inhibitor according to point a) is selected from the group consisting of galantamine, lycoramine and analogs thereof, in which the methoxy group of such compounds is replaced by hydrogen, hydroxy or an alkoxy group containing from one to six carbon atoms, or an acyloxy group containing from one to seven atoms carbon.

e) An acetylcholinesterase inhibitor according to point a), wherein said acetylcholinesterase inhibitor is selected from the group consisting of analogs of galantamine or lycoramine, where their methoxy group is replaced by a mono- and dialkylcarbamate or carbonate group, where the alkyl groups contain from 1 to 8 carbon atoms.

f) An acetylcholinesterase inhibitor according to point e), wherein the alkyl group or groups of said carbonate or carbamate groups contain from 4 to 6 carbon atoms.

g) An acetylcholinesterase inhibitor according to point a), wherein said acetylcholinesterase inhibitor is selected from the group consisting of galantamine or lycoramine analogs in which their hydroxy group is replaced by a mono- or dialkylcarbamate or carbonate group, where the alkyl groups contain from 1 to 8 carbon atoms.

h) An acetylcholinesterase inhibitor according to point f), wherein the alkyl group or groups of said carbonate or carbamate groups contain from 4 to 6 carbon atoms.

i) An acetylcholinesterase inhibitor according to point a), wherein said acetylcholinesterase inhibitor is selected from the group consisting of galantamine or lycoramine analogues in which their methoxy group is replaced by an arylcarbamate or carbonate group, wherein said aryl group is selected from phenyl, naphthyl, substituted phenyl and substituted naphthyl groups wherein said substituent is selected from alkyl and alkoxy groups containing from 1 to 6 carbon atoms, trifluoromethyl groups and halogens.

j) An acetylcholinesterase inhibitor according to point b), wherein said acetylcholinesterase inhibitor is selected from the group consisting of galantamine and lycoramine analogues in which their hydroxy group is replaced by an arylcarbamate or carbonate group, wherein said aryl group is selected from phenyl, naphthyl, substituted phenyl and substituted naphthyl groups wherein said substituent is selected from alkyl and alkoxy groups containing from 1 to 6 carbon atoms, trifluoromethyl groups and halogens.

k) An acetylcholinesterase inhibitor according to point b), wherein said acetylcholinesterase inhibitor is selected from the group consisting of galantamine, lycoramine and analogues thereof, in which the hydroxy group of said compounds is replaced by hydrogen or an alkoxy group containing from one to six carbon atoms, or an acyl group containing from one to seven carbon atoms.

l) An acetylcholinesterase inhibitor according to point a), wherein said acetylcholinesterase inhibitor is selected from the group consisting of analogues of galantamine and lycoramine, in which the hydroxy group of galantamine or lycoramine is replaced by an alkoxy group containing from one to six carbon atoms, hydrogen, an alkanoyloxy group, benzoyloxy or a substituted benzoyloxy group, carbonate group or carbamate group.

v) Published international patent application WO 2006/070394

AChEI, which is a quinoline derivative represented by formulas 1 and 2 below:

in which Ri = alkyl, aryl; R ² = H, alkyl, aralkyl.

In one embodiment, the resulting substituted carbamic acid quinolinyl esters are selected from the group consisting of:

1a) quinolin-6-yl ester of hexylcarbamic acid;

1b) heptylcarbamic acid quinolin-6-yl ester;

1c) quinolin-6-yl ester of (2-chlorophenyl)carbamic acid;

1d) quinolin-6-yl ester of (3-bromo-phenyl)carbamic acid;

2a) 1,2,3,4-tetrahydroquinolin-6-yl ester of hexylcarbamic acid;

2b) heptylcarbamic acid 1,2,3,4-tetrahydroquinolin-6-yl ester;

2c) 1,2,3,4-tetrahydroquinolin-6-yl ester (3-bromophenyl)carbamic acid;

2d) 1,2,3,4-tetrahydroquinolin-6-yl ester of (2-chlorophenyl)carbamic acid;

2e) (4-chloro-3-trifluoromethylphenyl)carbamic acid 1,2,3,4-tetrahydroquinolin-6-yl ester;

- 125 045018

2f) 1,2,3,4-tetrahydroquinolin-6-yl ester of (4-bromo-phenyl)carbamic acid;

2g) heptylcarbamic acid 1-benzyl-1,2,3,4-tetrahydroquinolin-6-yl ester;

2h) hexylcarbamic acid 1-benzyl-1,2,3,4-tetrahydroquinolin-6-yl ester;

2i) (2-chlorophenyl)carbamic acid 1-benzyl-1,2,3,4-tetrahydroquinolin-6-yl ester;

2j) 1-benzyl-1,2,3,4-tetrahydroquinolin-6-yl ester of (3-bromo-phenyl)carbamic acid;

2k) (4-chloro-3-trifluoromethylphenyl)carbamic acid 1-benzyl-1,2,3,4-tetrahydroquinolin-6-yl ester;

2l) 1-benzyl-1,2,3,4-tetrahydroquinolin-6-yl ester of (4-bromo-phenyl)carbamic acid;

2m) hexylcarbamic acid 1-methyl-1,2,3,4-tetrahydroquinolin-6-yl ester;

2n) 1-methyl-1,2,3,4-tetrahydroquinolin-6-yl ester of heptylcarbamic acid;

2o) (2-chlorophenyl)carbamic acid 1-methyl-1,2,3,4-tetrahydroquinolin-6-yl ester;

2p) 1-methyl-1,2,3,4-tetrahydroquinolin-6-yl ester of (3-bromo-phenyl)carbamic acid;

2q) 1-methyl-1,2,3,4-tetrahydroquinolin-6-yl ester (4-chloro-3-trifluoromethylphenyl)carbamic acid;

2r) 1-methyl-1,2,3,4-tetrahydroquinolin-6-yl ester of (4-bromo-phenyl)carbamic acid.

According to one embodiment of the invention, if R ¹ represents aryl, then it is selected from the group consisting of 2-chloro-, 3-bromo-, 4-bromo- and 4-chloro-3-trifluoromethylphenyl.

According to another embodiment of the present invention, R ² is selected from the group consisting of methyl and benzyl.

vi) Published international patent application WO 2004/032929

One embodiment relates to compounds represented by the general formula /g—* ₃ /\ // Vn

N Ch----N----(L)n—(L)n—(L)n—(L)n—(L)n—X

AvAs

Formula I where

X represents one of the following radicals

L is independently selected from -C(R)(R'')-, -CO-, -O- or -NR'-, n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, R and R are independently selected from hydrogen, alkyl, aryl, heteroaryl, halogen, haloalkyl, alkoxy, hydroxyl, nitro and alkylthio,

D is independently selected from -C(R ⁹ )-, =C- or -N-, A ¹ , A ² , A ³ , A ⁴ , A ⁵ , A ⁶ , A ⁷ , A ⁸ , B ¹ , B ² , B ³ , B ⁴ , B ⁵ , B ⁶ , B ⁷ , B ⁸ , G and E are independently selected from -CO-, -C(R ¹⁰ ) (R ¹¹ )-, =C(R ¹⁰ )-, -N (R ¹² )-, =N-, -O-, -S(O) _t -,

R ¹ , R ² , R ³ , R ⁴ , R ⁹ , R ¹⁰ and R ¹¹ are independently selected from hydrogen, alkyl, alkoxy, hydroxyl, alkylthio, cycloalkyl, haloalkyl, halogen, aryl, -(Z)n-, aryl, heteroaryl, -O(R ⁷ ), -C(O)R ⁷ , -C(O)OR ⁷ , -S(O) _t , cyano, nitro and mercapto, aryl substituted with alkyl, alkoxy, hydroxy, halogen, haloalkyl , nitro or alkylthio; and heteroaryl substituted with alkyl, alkoxy, hydroxy, halogen, haloalkyl, nitro or alkylthio,

R ⁵ , R ⁶ and R ¹² are independently selected from hydrogen, alkyl, alkoxy, hydroxyl, cycloalkyl, haloalkyl, aryl, heteroaryl, aryl substituted with alkyl, alkoxy, hydroxy, halogen, haloalkyl or alkylthio; and heteroaryl substituted with alkyl, alkoxy, hydroxy, halogen, haloalkyl, nitro or alkylthio,

Z is independently selected from -C(R ⁷ )(R ⁸ )-, -C (O)-, -O-, -C(=NR ⁷ )-, -S(O) _t , N(R ⁷ )-,

R ⁷ and R ⁸ are independently selected from hydrogen, alkyl, alkoxy, alkylthio, cycloalkyl, haloalkyl,

- 126 045018 halogen, aryl, heteroaryl, cyano, nitro, mercapto, aryl, substituted with alkyl, alkoxy, hydroxy, halogen, haloalkyl, nitro or alkylthio; and heteroaryl substituted with alkyl, alkoxy, hydroxy, halogen, haloalkyl, nitro or alkylthio, t is 0, 1 or 2.

In general, provided that if X is

That

a) each of the atoms in the groups A1-A ⁴ , A ⁵ -A ⁸ , B1-B ⁴ and B ⁵ -B ⁸ in no case simultaneously represents =C(R ¹⁰ )-, and

b) each of the atoms in one of the two groups A1-A ⁴ and A5-A ⁸ , and each of the atoms in one of the two groups B1-B ⁴ and B ⁵ -B ⁸ in no case simultaneously represents =C( R ¹⁰ )-.

In a related aspect, the invention relates to compounds of formula (1) and is represented by the general formulas Ia and IIa

Where

X represents -C (R ^1a ) (R ^2a )-, -CO-, -O- or -NR ^1a -;

n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

R ^1a and R ^2a are independently selected from hydrogen, alkyl, aryl, halogen, haloalkyl;

R ^3a , R ^4a and R ^5a are independently selected from hydrogen, alkyl, cycloalkyl, haloalkyl, halogen, aryl, -(Z)naphthyl, heteroaryl, OR ^3a , -C(O)R ^3a , -C(O)OR ^3a , -S(O) _t -;

t is 0, 1 or 2;

Z is independently selected from C (R ^3a ) (R ^4a )-, -C (O)-, -O-, C(=NR ^3a )-, -S(O)t-, N(R ^3a )-.

Definitions

In clause vi) the following terms have the following meanings:

The term alkyl refers to a straight or branched hydrocarbon chain containing only carbon and hydrogen atoms and containing no unsaturated bonds, containing from one to eight carbon atoms and linked to the remainder of the molecule by a single bond, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, etc. Alkyl radicals may be optionally substituted with one or more substituents independently selected from the group consisting of halogens, hydroxyl, alkoxides, carboxy, cyano, carbonyl, acyl, alkoxycarbonyl, amino, nitro, mercapto and alkylthio. Preferably, alkyl is C ₁ -C ₆ -alkyl.

The term alkoxy refers to a radical of the formula -OR ^a where R ^a is an alkyl radical as described above, for example methoxy, ethoxy, propoxy, etc.

The term alkoxycarbonyl refers to a radical of the formula -C(O)OR ^a where R ^a is an alkyl radical as described above, for example methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, etc.

The term alkylthio refers to a radical of the formula -SR ^a , where R ^a is an alkyl radical as described above, for example, methylthio, ethylthio, propylthio, etc.

The term amino refers to a radical of the formula -NH2.

The term aryl refers to a phenyl or naphthyl radical. The aryl radical may be optionally substituted with one or more substituents selected from the group consisting of hydroxy, mercapto, halogens, alkyl, phenyl, alkoxy, haloalkyl, nitro, cyano, dialkylamino, aminoalkyl, acyl and alkoxycarbonyl, as defined herein.

The term acyl refers to a radical of the formula -C(O)-R ^a and -C(O)-R ^b , where R ^a is an alkyl radical as described above, and R ^b is an aryl radical as described above, e.g. acetyl, propionyl, benzoyl and the like.

- 127 045018

The term carboxy refers to the radical of the formula -C(O)OH.

The term cyano refers to a radical of the formula -CN.

The term cycloalkyl refers to stable rings of 3-10 monocyclic or bicyclic groups that are saturated or partially saturated, and consist solely of carbon and hydrogen atoms. The term also includes cycloalkyl radicals which may be optionally substituted with one or more substituents independently selected from the group consisting of alkyl, halogen, hydroxy, amino, cyano, nitro, alkoxy, carboxy and alkoxycarbonyl.

The term halogens refers to bromine, chlorine, iodine or fluorine.

The term haloalkyl refers to an alkyl radical as defined above which is substituted with one or more halogen atoms as also defined above, for example trifluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl and the like.

The term heterocycle refers to a heterocyclic radical. A heterocycle refers to a stable ring of 3 to 15 members containing carbon atoms and one to five heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. For purposes of the present invention, the heterocycle may be a monocyclic, bicyclic or tricyclic system, which may include fused rings, and the nitrogen, carbon or sulfur atoms may optionally be oxidized, the nitrogen atom may optionally be quaternized, and the heterocycle may be partially or fully saturated or aromatic. Examples of such heterocyclic compounds include, but are not limited to, azepines, benzimidazole, benzothiazole, furan, isothiazole, imidazole, indole, piperidine, piperazine, purine, quinoline, thiadiazole, tetrahydrofuran. The heterocycle may be optionally substituted with R ³ and R ⁴ as defined in the Brief Description of the Invention.

The term mercapto refers to a radical of the formula -SH.

The term nitro refers to a radical with the formula -NO ₂ .

In the -(L)n-(L)n-(L)n-(L)n-(L)n- chain, each -(L)n- group is preferably -(CH ₂ )n (where n is not equal to zero), -CO-NH- or -NCH ₃ -.

Preferably, there are at least one or two groups -(L)n-, where n is not zero. A suitable chain corresponds to the formula - (CH ₂ )n-, - (CH ₂ )n-NR ^a - (CH2)n-, - (CH2)n-NR ^a -CO-, -(CH2)nNR ^a -CO-( CH2)n- or -(CH2)n-NR ^a - (CH2)n-NR ^a -CO-, where each n is non-zero and each R ^a is -NH- or -NCH3-, usually preferably -NH -. The total sum of integers n is preferably in the range from 2 to 15.

In the formula

N---(l)n—(L)n—(l)n—(L)n— (L)n—X

A ₇ ---Ae each group A (ie A ¹ -A ⁸ ) is preferably =CH- or -CH ₂ -, although one or both of A ² and A ⁷ may be a halogen, in particular chlorine, if the remaining A groups are =CH-.

Some AChEIs are compounds in which X is represented by the following formula:

Preferably D is -CH-, =C- or -N-. Preferably E is CO-, -CH ₂ -, =CH-, =NO- or -S-. Preferably G is -CO-, -CH ₂ -, =CH- or =N-. Preferably R ¹ -R ⁴ are hydrogen.

In some embodiments, the compounds are compounds wherein X is: phthalimidyl (1,3-dioxo-1,3-dihydroisoindol-2-yl), indol-2-yl, indanon-2-yl, benzimidazol-2 -yl, indandione-2-yl, indazol-2-yl, benzofuran-2-yl, benzothiophen-2-yl or benzotriazol-2-yl.

In some embodiments, the compounds are compounds wherein X is phthalimide (1,3-dioxo-1,3-dihydroisoindol-2-yl) and the cyclic moiety of Formula I is 9-acridinyl, 1,2,3, 4-tetrahydroacridin-9-yl or 6-chloro-1,2,3,4tetrahydroacridin-9-yl. Some compounds are 2-[6-(acridin-9-ylamino)hexyl]isoindole-1,3-dione (6), 2-[7-(acridin-9-ylamino)heptyl]isoindole-1,3-dione (7 ), 2-[8- 128 045018 (acridin-9-ylamino)octyl]isoindole-1,3-dione (8), 2-[9-(acridin-9-ylamino)nonyl]isoindole-1,3-dione (9), N-[7-(6-chloro-1,2,3,4-tetrahydroacridin-9-ylamino)heptyl]-2-(1,3-dioxo-1,3-dihydro-isoindol-2yl) acetamide (10), N-(3-{[3-(6-chloro-1,2,3,4-tetrahydroacridin-9-ylamino)propyl]methylamino}propyl)2-(1,3-dioxo-1, 3-dihydroisoindol-2-yl)acetamide (11), N-[6-(6-chloro-1,2,3,4-tetrahydroacridin-9ylamino)-exyl]-2-(1,3-dioxo-1, 3-dihydroisoindol-2-yl)acetamide (12), 2-[6-(1,2,3,4-tetrahydroacridin-9-ylamino)hexylamino]indan-1,3-dione (3), 2-[7 -(1,2,3,4-tetrahydroacridin-9-ylamino)heptyl]isoindol-1,3-dione (4) and 2-[8-(1,2,3,4-tetrahydroacridin-9-ylamino)octyl ]isoindole-1,3-dione (5).

Some compounds are those wherein X is 1indanon-2-yl and the cyclic moiety of formula 1 is 1,2,3,4-tetrahydroacridin-9-yl; such compounds include, but are not limited to, the following compounds: 5,6-dimethoxy-2-{[7(1,2,3,4-tetrahydroacridin-9-ylamino)heptylamino]methyl}indan-1-one (1) and 5,6-dimethoxy-2-{[6-( 1,2,3,4tetrahydroacridin-9-ylamino)hexylamino]methyl}indan-1-one (2).

In such compounds where X is represented by the following formula:

&--Вз Ό' /Ч ^В \ / ^Вь в?—в $ , each group B (that is, B ¹ -B ⁸ ) is preferably =CH- or -CH ₂ -, although one or both of B ² and B ⁷ may be a halogen, in particular chlorine, if the remaining B groups are =CH-. Some compounds are compounds in which X is 9-acridinyl, 6-chloro-1,2,3,4-tetrahydroacridin-9-yl and 1,2,3,4-tetrahydroacridin-9-yl. Among such compounds are those in which the cyclic part of formula I is: 9-acridinyl, 6-chloro-1,2,3,4-tetrahydroacridin-9-yl or 1,2,3,4-tetrahydroacridin-9-yl; such compounds include, but are not limited to, the following compounds: N-[2-(6-chloro-1,2,3,4,4a,9a-hexahydroacridin-9-ylamino)ethyl]-N-(6-chloro- 1,2,3,4-tetrahydroacridin-9-yl)-N-methylethane-1,2-diamine (19), Nacridin-9-yl-N'-(1,2,3,4-tetrahydroacridin-9- yl)nonane-1,9-diamine (20), N-acridin-9-yl-N'-[2(1,2,3,4,4a,9a-hexahydroacridin-9-ylamino)ethyl]-N' -methylethane-1,2-diamine (21), N-[2-(acridin-9ylamino)ethyl]-N'-(6-chloro-1,2,3,4-tetrahydroacridin-9-yl)-N- methylethane-1,2-diamine (22), N-acridin-9yl-N'-(6-chloro-1,2,3,4-tetrahydroacridin-9-yl)heptan-1,7-diamine (23) and N-acridin-9-yl-N'-(6-chloro1,2,3,4-tetrahydroacridin-9-yl)octan-1,8-diamine (24).

In such compounds where X is represented by the following formula:

the groups R ⁵ and R ⁶ represent suitable alkyl or substituted alkyl, namely alkoxycarbonylalkyl.

Preferred compounds are those in which the cyclic portion of formula I is: 9-acridinyl, 6-chloro, 1,2,3,4-tetrahydroacridin-9-yl or 1,2,3,4tetrahydroacridin-9-yl; such compounds include, but are not limited to, the following compounds: 2-ethyl-4-isopropyl-5-[7-(1,2,3,4-tetrahydroacridin-9-ylamino)heptylimino]-[1,2,4] thiadiazolidin-3-one (13), 2-ethyl-4-isopropyl-5-[9-(1,2,3,4-tetrahydroacridin-9-ylamino)nonylimino]-[1,2,4]thiadiazolidin3-one (14), 4-isopropyl-3-oxo-5-[9-(1,2,3,4-tetrahydroacridin-9ylamino)nonylimino]-[1,2,4]thiadiazolidine-2-carboxylic acid ethyl ester ( 15), 4-ethyl-2-propyl-5-[7-(1,2,3,4tetrahydroacridin-9-ylamino)heptylimino]-[1,2,4]thiadiazolidin-3-one (16), 4- ethyl 2-isopropyl-5-[8(1,2,3,4-tetrahydroacridin-9-ylamino)octylimino]-[1,2,4]thiadiazolidin-3-one (17) and 4-ethyl-2isopropyl- 5-[6-(1,2,3,4-tetrahydroacridin-9-ylamino)hexylimino]-[1,2,4]thiadiazolidin-3-one (18).

vii) US Patent Application No. 20050124642

In some embodiments, the AChEI is:

1) a (1-indanone)-(1,2,3,6-tetrahydropyridine) compound represented by the formula

- 129 045018 in formula (I) R ¹ , R ² , R ³ and R ⁴ are the same or different, and each represents a group selected from a hydrogen atom, a halogen atom, a hydroxyl group, a nitrile group, an alkyl group containing from one up to six carbon atoms which may be substituted, a cycloalkyl group containing from three to eight carbon atoms which may be substituted, an alkoxy group containing from one to six carbon atoms which may be substituted, a cycloalkoxy group containing from three to eight carbon atoms which may be substituted, an acyl group containing from one to six carbon atoms which may be substituted, a C1-C6 alkoxycarbonyl group which may be substituted, a _C1 - _C6 alkylaminocarbonyloxy group which may be substituted, a di-( _C1 -C ₆ )alkylaminocarbonyloxy group which may be substituted, nitro group, amino group which may be substituted, amide group which may be substituted, mercapto group and thioalkoxy group containing from one to six carbon atoms which may be substituted, where R ¹ and R ² , or R ² and R ³ , or R ³ and R ⁴ may together form an aliphatic ring, an aromatic ring, a heterocyclic ring or an alkylenedioxy ring;

partial structure

is a group represented by >C-CH-(CH ₂ )m- or >C(R ⁶ )-CH(R ⁶ )-(CH2)m- (where m is 0 or an integer from 1 to 5; and R ⁶ represents a hydrogen atom, a halogen atom, a hydroxyl group, an alkyl group containing one to six carbon atoms, an alkoxy group containing one to six carbon atoms, a nitrile group, a haloalkyl group containing from one to six carbon atoms, hydroxyalkyl a group containing one to six carbon atoms, a cyano-C1-C ₆ alkyl group, an aminoalkyl group containing one to six carbon atoms, a nitro group, an azide group, an amino group which may be substituted, a carbamoyl group which may be substituted , a carboxyl group which may be substituted, a mercapto group or thioalkoxy group containing from one to six carbon atoms; and R ⁵ represents a hydrogen atom, an alkyl group containing from one to six carbon atoms which may be substituted, an alkenyl group containing from two to six carbon atoms which may be substituted, an alkynyl group having from two to six carbon atoms which may be substituted, a cycloalkyl group having from three to eight carbon atoms which may be substituted, 2,2-(alkylenedioxy) an ethyl group or a group represented by the formula

wherein ring C is a benzene ring, an aliphatic ring or a heterocyclic ring; R ⁷ are the same or different, and each represents a hydrogen atom, a halogen atom, a hydroxyl group, a nitrile group, an alkyl group containing from one to six carbon atoms which may be substituted, an alkenyl group containing from two to six carbon atoms, which may be substituted, an alkynyl group containing from two to six carbon atoms which may be substituted, a cycloalkyl group containing from three to eight carbon atoms which may be substituted, an alkoxy group containing from one to six carbon atoms which may be substituted substituted, a C ₁ -C ₆ alkoxy-alkoxy group which may be substituted, an aryloxy group which may be substituted, an aralkyloxy group which may be substituted or the like, where two of the R ⁷ may together form an aliphatic ring, an aromatic ring, heterocyclic ring or alkylenedioxy ring; and n is an integer from 1 to 5, a pharmacologically acceptable salt thereof, or a hydrate thereof;

2) The compound (1-indanone)-(1,2,3,6-tetrahydropyridine) described in paragraph 1), its pharmacologically acceptable salt or hydrate thereof, where R ¹ and R ⁴ represent hydrogen atoms; and R ² and R ³ are the same or different, and each represents a hydrogen atom, a halogen atom, an alkyl group containing from one to six carbon atoms which may be substituted, a cycloalkyl group containing from three to eight carbon atoms which may be substituted, an alkoxy group containing from one to six carbon atoms which may be substituted or a cycloalkoxy group containing from three to eight carbon atoms which may be substituted, or R ² and R ³ may together form an aliphatic ring, an aromatic ring, a heterocyclic ring or an alkylenedioxy ring;

3) The compound (1-indanone)-(1,2,3,6-tetrahydropyridine) described in paragraphs 1) or 2), its pharmacologically acceptable salt or hydrate thereof, where R ⁶ represents a hydrogen atom, a halogen atom or an alkyl a group containing from one to six carbon atoms;

4) The compound (1-indanone)-(1,2,3,6-tetrahydropyridine) described in any of items 1) to 3), its

- 130 045018 pharmacologically acceptable salt or hydrate thereof, where R ⁵ represents a group represented by the formula

in which the values of ring C, R ⁷ and n are defined above;

5) The compound (1-indanone)-(1,2,3,6-tetrahydropyridine) described in paragraph 4), a pharmacologically acceptable salt thereof or a hydrate thereof, wherein ring C is a benzene ring or a cycloalkyl ring containing three to eight carbon atoms;

6) The compound (1-indanone)-(1,2,3,6-tetrahydropyridine) described in paragraph 4), a pharmacologically acceptable salt thereof or a hydrate thereof, where R ⁷ are the same or different and each represents a hydrogen atom, a halogen atom, an alkyl group containing from one to six carbon atoms which may be substituted, an alkenyl group containing from two to six carbon atoms which may be substituted, an alkynyl group containing from two to six carbon atoms which may be substituted , a cycloalkyl group containing from three to eight carbon atoms which may be substituted, or two of R ⁷ may together form an aliphatic ring, an aromatic ring, a heterocyclic ring or an alkylenedioxy ring;

7) The compound (1-indanone)-(1,2,3,6-tetrahydropyridine) described in paragraph 4), a pharmacologically acceptable salt thereof or a hydrate thereof, where n is an integer equal to 1 or 2;

8) The compound (1-indanone)-(1,2,3,6-tetrahydropyridine) described in any of items 1) to 7), a pharmacologically acceptable salt thereof or a hydrate thereof, wherein the partial structure

A~B-represents a group represented by >C(R ⁶ )-CH(R ⁶ )-(CH2)m- (where m is 0 or is an integer from 1 to 5; and R ⁶ represents a hydrogen atom) ;

9) The compound (1-indanone)-(1,2,3,6-tetrahydropyridine) described in any of items 1) to 7), a pharmacologically acceptable salt thereof or a hydrate thereof, wherein the partial structure

A-B- represents a group represented by >C(R ⁶ )-CH(R ⁶ )-(CH2)m- (where m is 0 or is an integer from 1 to 5; and R ⁶ represents a halogen atom, hydroxyl group, alkyl group containing from one to six carbon atoms, alkoxy group containing from one to six carbon atoms, nitrile group, haloalkyl group containing from one to six carbon atoms, hydroxyalkyl group containing from one to six carbon atoms, cyano -C ₁ -C ₆ -αalkyl group, aminoalkyl group containing from one to six carbon atoms, nitro group, azide group, amino group which may be substituted, carbamoyl group which may be substituted, carboxyl group which may be substituted, mercapto group or a thioalkoxy group containing from one to six carbon atoms;

10) The compound (1-indanone)-(1,2,3,6-tetrahydropyridine) described in paragraph 1), a pharmacologically acceptable salt thereof or a hydrate thereof, where the compound (1-indanone)-(1,2,3, 6-tetrahydropyridine) represented by formula (I) is selected from:

(1) 1-benzyl-4-[(5,6-dimethoxy-1-indanone)-2-yl]methyl-1,2,3,6-tetrahydropyridine, (2) 1-benzyl-4-[(5 ,6-diethoxy-1-indanone)-2-yl]methyl-1,2,3,6-tetrahydropyridine and (3) 1-benzyl-4-[(5,6-diethoxy-2-fluoro-1-indanone )-2-yl]methyl-1,2,3,6-tetrahydropyridine;

For example, see also AChEI inhibitors presented in Brufani et al, Alzheimer Disease: From Molecular Biology to Therapy, eds. Becker et al., pp. 171-177 (1996); Schmidt et al., Alzheimer's Disease: From Molecular Biology to Therapy, eds. Becker et al., pp. 217-221 (1996); Vargas et al., Alzheimer's Disease: From Molecular Biology to Therapy, eds. Becker et al., pp. 261-255 (1996); Greig et al., Alzheimer's Disease: From Molecular Biology to Therapy, eds. Becker et al., pp. 231-237 (1996); and Giacobini, Alzheimer Disease: From Molecular Biology to Therapy eds. Becker et al., pp. 187-204 (1996).

viii) US Patent No. 7378425

In some embodiments, the following compounds (1)-(4) are compounds having acetylcholinesterase inhibitor activity.

(1) A cyclic amine derivative represented by the following formula, a pharmacologically acceptable salt thereof, or a hydrate thereof

- 131 045018

where J, for example, is represented by the formula

where S, for example, represents a lower alkoxy group containing from one to six carbon atoms; and t is 0 or an integer from 1 to 4); B, for example, represents a methylene chain; K, for example, represents a benzyl group, which may be substituted; and partial structure: - represents a single bond or a double bond, subject to the exclusion of a compound in which J represents a 5,6-dimethoxy-1-indanon-2-yl group, B represents a -CH ₂ group, and K represents an unsubstituted benzyl group, a pharmacologically acceptable salt thereof or a hydrate thereof (JP-B22733203).

(2) A compound represented by the following formula:

or a pharmacologically acceptable salt thereof (JP-A 2000-319257).

(3) A 4-substituted piperidine derivative fluoride represented by the following formula:

where R ¹ , for example, represents a substituent represented by

where R ³ are the same or different, and each represents, for example, an alkoxy group containing from one to six carbon atoms; m is 0 or an integer from 1 to 6; and n is an integer from 1 to 4); and R ² represents, for example, a benzyl group, which may be substituted, provided that 1-benzyl-4-[(5,6-dimethoxy-2-fluoro1-indanone)-2-yl]methylpiperidine or a pharmacologically acceptable salt thereof is excluded ), a pharmacologically acceptable salt thereof or a hydrate thereof (JP-A 2000-319258).

(4) A 4-substituted piperidine derivative represented by the following formula:

(where R ¹ is, for example, the group represented by the formula

where R ³ are the same or different, and each represents, for example, an alkoxy group containing from one to six carbon atoms; R ⁵ , for example, represents a halogen atom other than a fluorine atom; m is 0 or an integer from 1 to 6; and n is an integer from 1 to 4; and R ² , for example, represents a benzyl group which may be substituted), a pharmacologically acceptable salt thereof or a hydrate thereof (JP-A 2001-139547).

According to some embodiments, the present invention relates to:

1) The (1-indanone)-(1,2,3,6-tetrahydropyridine) compound represented by formula (I)

R ⁴ in formula (I) R ¹ , R ² , R ³ and R ⁴ are the same or different, and each represents a group selected from a hydrogen atom, a halogen atom, a hydroxyl group, a nitrile group, an alkyl group containing from one to six carbon atoms that can be substituted, cycl

- 132 045018 loalkyl group containing from three to eight carbon atoms which may be substituted, alkoxy group containing from one to six carbon atoms which may be substituted, cycloalkoxy group containing from three to eight carbon atoms which may be substituted, acyl a group containing from one to six carbon atoms which may be substituted, a C _r C ₆ alkoxycarbonyl group which may be substituted, a C ₁ -C ₆ -alkylaminocarbonyloxy group which may be substituted, a di-(C ₁ -C ₆ )alkylaminocarbonyloxy group which may be substituted, a nitro group, an amino group which may be substituted, an amide group which may be substituted, a mercapto group and a thioalkoxy group containing from one to six carbon atoms which may be substituted, where R ¹ and R ² or R ² and R ³ or R ³ and R ⁴ may together form an aliphatic ring, an aromatic ring, a heterocyclic ring or an alkylenedioxy ring;

partial structure

is a group represented by >C-CH-(CH ₂ )m- or >C(R ⁶ )-CH(R ⁶ )-(CH2)m- (where m is 0 or an integer from 1 to 5; and R ⁶ represents a hydrogen atom, a halogen atom, a hydroxyl group, an alkyl group containing one to six carbon atoms, an alkoxy group containing one to six carbon atoms, a nitrile group, a haloalkyl group containing one to six carbon atoms, a hydroxyalkyl group containing from one to six carbon atoms, a cyano-C1-C ₆ -alkyl group, an aminoalkyl group containing from one to six carbon atoms, a nitro group, an azide group, an amino group which may be substituted, a carbamoyl group which may be substituted, a carboxyl group which may be substituted, a mercapto group or thioalkoxy group containing from one to six carbon atoms; and R ⁵ represents a hydrogen atom, an alkyl group containing from one to six carbon atoms which may be substituted, an alkenyl group containing from two up to six carbon atoms which may be substituted, an alkynyl group containing from two to six carbon atoms which may be substituted, a cycloalkyl group containing from three to eight carbon atoms which may be substituted, 2,2-(alkylenedioxy)ethyl group or group represented by the formula

wherein ring C is a benzene ring, an aliphatic ring or a heterocyclic ring; R ⁷ are the same or different, and each represents a hydrogen atom, a halogen atom, a hydroxyl group, a nitrile group, an alkyl group containing from one to six carbon atoms which may be substituted, an alkenyl group containing from two to six carbon atoms, which may be substituted, an alkynyl group containing from two to six carbon atoms which may be substituted, a cycloalkyl group containing from three to eight carbon atoms which may be substituted, an alkoxy group containing from one to six carbon atoms which may be substituted substituted, a C ₁ -C ₆ alkoxy-alkoxy group which may be substituted, an aryloxy group which may be substituted, an aralkyloxy group which may be substituted or the like, where two of the R ⁷ may together form an aliphatic ring, an aromatic ring, heterocyclic ring or alkylenedioxy ring; and n is an integer from 1 to 5, a pharmacologically acceptable salt thereof, or a hydrate thereof;

2) The compound (1-indanone)-(1,2,3,6-tetrahydropyridine) described in paragraph 1), its pharmacologically acceptable salt or hydrate thereof, where R ¹ and R ⁴ represent hydrogen atoms; and R ² and R ³ are the same or different, and each represents a hydrogen atom, a halogen atom, an alkyl group containing from one to six carbon atoms which may be substituted, a cycloalkyl group containing from three to eight carbon atoms which may be substituted, an alkoxy group containing from one to six carbon atoms which may be substituted or a cycloalkoxy group containing from three to eight carbon atoms which may be substituted, or R ² and R ³ may together form an aliphatic ring, an aromatic ring, a heterocyclic ring or an alkylenedioxy ring;

3) The compound (1-indanone)-(1,2,3,6-tetrahydropyridine) described in paragraph 1) or 2), its pharmacologically acceptable salt or hydrate thereof, where R ⁶ represents a hydrogen atom, a halogen atom or an alkyl a group containing from one to six carbon atoms;

4) The (1-indanone)-(1,2,3,6-tetrahydropyridine) compound described in any of items 1) to 3), a pharmacologically acceptable salt thereof or a hydrate thereof, wherein R ⁵ is a group represented by the formula

- 133 045018 where the values of the ring C, R ⁷ and n are defined above;

5) The compound (1-indanone)-(1,2,3,6-tetrahydropyridine) described in paragraph 4), its pharmacological

a commercially acceptable salt or hydrate thereof, wherein ring C is a benzene ring or a cycloalkyl ring containing three to eight carbon atoms;

6) The compound (1-indanone)-(1,2,3,6-tetrahydropyridine) described in paragraph 4), a pharmacologically acceptable salt thereof or a hydrate thereof, where R ⁷ are the same or different and each represents a hydrogen atom, a halogen atom, an alkyl group containing from one to six carbon atoms which may be substituted, an alkenyl group containing from two to six carbon atoms which may be substituted, an alkynyl group containing from two to six carbon atoms which may be substituted , a cycloalkyl group containing from three to eight carbon atoms, which may be substituted, or two R ⁷ may together form an aliphatic ring, an aromatic ring, a heterocyclic ring or an alkylenedioxy ring;

7) The compound (1-indanone)-(1,2,3,6-tetrahydropyridine) described in paragraph 4), a pharmacologically acceptable salt thereof or a hydrate thereof, where n is an integer equal to 1 or 2;

8) The compound (1-indanone)-(1,2,3,6-tetrahydropyridine) described in any of items 1) to 7), a pharmacologically acceptable salt thereof or a hydrate thereof, wherein the partial structure \-B represents the group represented by >C(R ⁶ )-CH(R ⁶ )-(CH ₂ )m-, where m is 0 or an integer from 1 to 5; and R ⁶ represents a hydrogen atom;

9) The compound (1-indanone)-(1,2,3,6-tetrahydropyridine) described in any of items 1) to 7), a pharmacologically acceptable salt thereof or a hydrate thereof, wherein the partial structure \—in— represents a group represented by >C(R ⁶ )-CH(R ⁶ )-(CH ₂ )m- (where m is 0 or an integer from 1 to 5); and R ⁶ represents a halogen atom, a hydroxyl group, an alkyl group containing one to six carbon atoms, an alkoxy group containing one to six carbon atoms, a nitrile group, a haloalkyl group containing one to six carbon atoms, a hydroxyalkyl group, containing from one to six carbon atoms, a cyano-C ₁ -C ₆ -alkyl group, an aminoalkyl group containing from one to six carbon atoms, a nitro group, an azide group, an amino group which may be substituted, a carbamoyl group which may be substituted, a carboxyl group, which may be substituted, a mercapto group or a thioalkoxy group containing from one to six carbon atoms;

10) The compound (1-indanone)-(1,2,3,6-tetrahydropyridine) described in paragraph 1), a pharmacologically acceptable salt thereof or a hydrate thereof, wherein the compound (1-indanone)(1, 2,3,6-tetrahydropyridine) is selected from:

(1) 1-benzyl-4-[(5,6-dimethoxy-1-indanone)-2-yl]methyl-1,2,3,6-tetrahydropyridine, (2) 1-benzyl-4-[(5 ,6-diethoxy-1-indanone)-2-yl]methyl-1,2,3,6-tetrahydropyridine and (3) 1-benzyl-4-[(5,6-diethoxy-2-fluoro-1-indanone )-2-yl]methyl-1,2,3,6-tetrahydropyridine.

ix) Published international patent application WO2 003/020289

The compounds of formula I according to the present invention are those of the following general formula 1:

s/ ^x \,CH ₂ OSO ₂ NHR ¹

R ⁵ ( X ^{2 2} )—\ ^r2

R ⁴ R ³ |, where

X represents CH2 or oxygen;

R ¹ represents hydrogen or alkyl; and R ² , R ³ , R ⁴ and R ⁵ independently represent hydrogen or lower alkyl and, if X represents CH2, then R ⁴ and R ⁵ may represent alkene groups connected to form a benzene ring, and if X represents is oxygen, then R ² and R ³ and/or R ⁴ and R ⁵ together may represent a methylenedioxy group of the following formula II:

- 134 045018

Where

R ⁶ and R ⁷ are the same or different and are hydrogen, lower alkyl, or are alkyl and joined together to form a cyclopentyl or cyclohexyl ring.

R ¹ is particularly hydrogen or alkyl of about 1 to 4 carbon atoms, such as methyl, ethyl and isopropyl. As used herein, alkyl includes straight-chain and branched-chain alkyl. The alkyl groups R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ contain approximately 1 to 3 carbon atoms and include methyl, ethyl, isopropyl and n-propyl.

If X is CH2, then ^R4 and ^R5 can be combined to form a benzene ring fused to a 6-membered X-containing ring, e.g. ^R4 and ^R5 are defined as an alkatrienyl group =C-CH=CH-CH= .

A particular group of compounds of formula 1 includes compounds in which X represents oxygen, and R ² and R ³ together with R ⁴ and R ⁵ represent a methylenedioxy group of formula II, in which R ⁶ and R ⁷ are both hydrogen, both are alkyl or combined to form a spirocyclopentyl or cyclohexyl ring, in particular when R ⁶ and R ⁷ are both alkyl, such as methyl. The second group of compounds includes compounds in which X represents CH2, and R ⁴ and R ⁵ are combined to form a benzene ring. The third group of compounds of formula I includes compounds in which R ² and R ³ are both hydrogen.

x) US Patent Application No. 2003069289

In view of the above circumstances, the inventors of the present invention have conducted extensive research in which it has been found that as the compound represented by the formula

where the fragments a are the same or different, and each represents a hydrogen atom or a C _1-6 alkoxy group; n is an integer from 1 to 4; and X' ^(-) represents a halogen ion, so does the compound represented by the formula

where b, c, d and e are the same straight or branched or different, and each is hydrogen or C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkoxycarbonyl, C _1-6 al kylaminocarbonyloxy, di-( C _1-6 alkyl)aminocarbonyloxy or halogen; and X ^(-) is an anion of chloride, bromide, iodide and sulfate, exhibit excellent acetylcholinesterase inhibitory effects. Moreover, based on the discoveries made, it was found that the 1-benzylpyridine salt represented by the formula

in which R ¹ , R 2 , R ³ and R ⁴ are the same or different and represent a hydrogen atom, a halogen atom, a hydroxyl group, a nitrile group, a C 1-6 alkyl group, a C 1-6 alkoxy group, a C 1-6 alkoxycarbonyl group, a C 1-6 alkylaminocarbonyloxy group or di -(C1-6alkyl)aminocarbonyloxy group; R ⁵ represents a hydrogen atom, a halogen atom, a C1-6 alkyl group, a C _2-6 alkenyl group or a C _2-6 alkynyl group;

partial structure:

represents a group represented by the formula >C(R6) -CH2-, where R6 represents a hydrogen atom or a halogen atom) or >C-CH-; X ^- represents a halide ion or an organic sulfonic acid ion; and m is equal to 0 or is an integer from 1 to 5, exhibit different

- 135 045018 new inhibitory effect on acetylcholinesterase, thereby forming the present invention.

That is, the first aspect of the present invention is (1) an acetylcholinesterase inhibitor containing a 1-benzylpyridinium salt represented by formula (I) above; (2) further, in the above paragraph (1), R ¹ , R ² , R ³ and R ⁴ may be the same or different from each other, and each represents a hydrogen atom or a C1-6 alkoxy group; (3) in the above paragraph (1), R ¹ , R ² , R ³ and R ⁴ may be the same or different from each other, and each represents a hydrogen atom or a methoxy group; (4) in the above paragraph (1), R ¹ and R ⁴ may represent a hydrogen atom; and R ² and R ³ may represent a methoxy group; (5) in the above paragraph (1), R ⁵ may represent a hydrogen atom; (6) in the above paragraph (1), the partial structure may be a group represented by the formula >C(R ⁶ ) -CH2-, where R ⁶ represents a hydrogen atom or a halogen atom; (7) in the above paragraph (1), m may be O, 2 or 4;

(8) in the above paragraph (1), the halide ion represented by X ^- may be a chloridion, bromide ion or iodide ion, preferably a chloride ion or bromide ion; (9) in the above paragraph (1), the organic sulfonic acid ion represented by X ^- may be a methanesulfonate ion, trifluoromethanesulfonate ion, ethanesulfonate ion, benzenesulfonate ion, toluenesulfonate ion or camphorsulfonate ion; (10) In the above paragraph (1), the 1-benzylpyridinium salt may be a compound represented by the formula

R ¹

R

R· in which the values are R ¹ , R ² , R ³ , R ⁴ 6; (11) in the above paragraph (1) represented by the formula r ¹ _g and X ^are defined above and n is an integer from 1 to 1-benzylpyridinium salt may be a compound,

R ¹

R

R-

R ⁴ in which the values of R ¹ , R ² , R ³ , R ⁴ and X ^are as defined above and p is 0 or an integer from 1 to 5; (12) in paragraph (1) above, the drug may be a drug for the treatment, prevention or improvement of senile dementia, cerebrovascular dementia or attention deficit hyperactivity disorder; and (13) in the above paragraph (12), the senile dementia may be senile dementia of the Alzheimer's type.

The second aspect of the present invention is (14) a pharmaceutical preparation containing a 1-benzylpyridinium salt represented by the formula

F

R* in which R ¹ , R ² , R ³ , R ⁴ , R ⁵ , partial structure:

The values of X ^- and m are defined above.

Moreover, the third aspect of the present invention is (15) the use of 1-benzylpyridinium salt represented by the formula

where R ¹ , R ² , R ³ , R ⁴ , R ⁵ , partial structure

- 136 045018

the values of X- and m are defined above for the preparation of an acetylcholinesterase inhibitor.

The present invention relates to a method for preventing, treating or ameliorating a disease in which acetylcholinesterase inhibitory action is effective for preventing, treating or ameliorating a disease by administering to a patient a pharmacologically effective dose of 1-benzylpyridinium salt represented by the above formula (I).

According to the present invention, the disease in which acetylcholinesterase inhibitory action is effective in preventing, treating or ameliorating includes senile dementia such as senile dementia of the Alzheimer's type and cerebrovascular dementia and attention deficit hyperactivity disorder.

Next, the meanings of symbols, terms, etc. used in the description are described, and the present description is described in detail.

In the present description, the structural formulas of compounds may, for convenience, denote a specific isomer, but the present invention covers all possible isomers that may exist in the structures of the compound, for example, geometric isomer, optical isomer based on asymmetric carbon, stereoisomer and tautomer, and mixtures of such isomers; therefore, the compound of the present invention may be any of the isomers or a mixture thereof, without limitation to the formulas presented for convenience. Accordingly, a compound of the present invention may contain an intramolecular asymmetric carbon atom and therefore exist as optically active isomers or racemic modifications, and any of such compounds are included in the present invention without limitation. In the presence of crystal polymorphism, the compound of the present invention may exist as a single crystal or as a mixed crystal without limitation. Compound (I) or its salts may be anhydrides or hydrates, each of which falls within the scope of the claims. In addition, metabolites formed by degradation of compound (I) in vivo, and prodrugs of compound (I) or salts thereof also fall within the scope of the claims.

As used herein, the term halogen atom refers to an atom such as a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, preferably a fluorine atom, a chlorine atom or a bromine atom.

The term C ₁ _ ₆ α alkyl group presented in the specification R ¹ , R ² , R ³ and R ⁴ refers to an alkyl group containing 1 to 6 carbon atoms, and examples thereof include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, 1,1-dimethylpropyl group, 1,2-dimethylpropyl group, 2,2-dimethylpropyl group, 1-ethylpropyl group, 2-ethylpropyl group , n-hexyl group, 1-methyl-2-ethylpropyl group, 1-ethyl-2-methylpropyl group, 1,1,2-trimethylpropyl group, 1-propylpropyl group, 1-methylbutyl group, 2-methylbutyl group, 1,1-dimethylbutyl group , 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 2-ethylbutyl group, 2-methylpentyl group, 3-methylpentyl group, etc., preferably methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group and tert-butyl group.

The term C ₁ _ ₆ alkoxy group presented in the description of R ¹ , R ² , R ³ and R ⁴ refers to an alkoxy group containing 1-6 carbon atoms, and examples thereof include methoxy group, ethoxy group, npropoxy group, isopropoxy group, sec-propoxy group, n -бутоксигруппу, изобутоксигруппу, вторбутоксигруппу, трет-бутоксигруппу, н-пентилоксигруппу, изопентилоксигруппу, втор-пентилоксигруппу, н-гексоксигруппу, изогексоксигруппу, 1,1-диметилпропилоксигруппу, 1,2-диметилпропоксигруппу, 2,2-диметилпропилоксигруппу, 2-этилпропоксигруппу, 1 -methyl-2-ethylpropoxy group, 1-ethyl-2-methylpropoxy group, 1,1,2-trimethylpropoxy group, 1,1,2-trimethylpropoxy group, 1,1-dimethylbutoxy group, 1,2-dimethylbutoxy group, 2,2-dimethylbutoxy group, 2,3 -dimethylbutyloxy group, 1,3-dimethylbutyloxy group, 2-ethylbutoxy group, 1,3-dimethylbutoxy group, 2methylpentoxy group, 3-methylpentoxy group, hexyloxy group, etc., preferably methoxy group, ethoxy group, n-propoxy group and isopropoxy group.

The term C ₁ _ ₆ alkoxycarbonyl group presented in the description of R ¹ , R ² , R ³ and R ⁴ is represented as a group in which a C ₁ _ ₆ alkoxy group, the meaning of which is defined above, is linked to a carbonyl group. For example, methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group, isopropoxycarbonyl group, n-butoxycarbonyl group, isobutoxycarbonyl group, tert-butoxycarbonyl group, pentyloxycarbonyl group, hexyloxycarbonyl group, etc., preferably methoxycarbonyl group, ethoxycarbonyl group, npropoxycarbonyl ary group and isopropoxycarbonyl group .

Term C ₁ . ₆ αalkylaminocarbonyloxy group, presented in the description R ¹ , R ² , R ³ and R ⁴ , refers to an aminocarbonyloxy group in which the nitrogen atom is replaced by C ₁ . ₆ alkyl group, the meaning of which is

- 137 045018 is defined above, and its examples include methylaminocarbonyloxy group, ethylaminocarbonyloxy group, n-propylaminocarbonyloxy group, isopropylaminocarbonyloxy group, n-butylaminocarbonyloxy group, isobutylaminocarbonyloxy group, tert-butylaminocarbonyloxy group, npentylaminocarbonyloxy group, isopentylamines nocarbonyloxy group, neopentylaminocarbonyloxy group, hexylaminocarbonyloxy group, 1-methylpropylaminocarbonyloxy group, 1-methylbutylaminocarbonyloxy group, 2-methylbutylaminocarbonyloxy group and etc.

The term di(C ₁ . ₆ αlkyl)aminocarbonyloxy group presented in the description of R ¹ , R ² , R ³ and R ⁴ refers to an aminocarbonyloxy group whose nitrogen atom has been replaced by two C ₁ . ₆ alkyl groups, and examples thereof include dimethylaminocarbonyloxy group, diethylaminocarbonyloxy group, di-(npropyl)aminocarbonyloxy group, di-(isopropyl)aminocarbonyloxy group, di-(n-butyl)aminocarbonyloxy group, di-(isobutyl)aminocarbonyloxy group, di-(tert-butyl)aminocarbonyloxy group , di-(n-pentyl)aminocarbonyloxy group, di-(isopentyl)aminocarbonyloxy group, di-(neopentyl)aminocarbonyloxy group, di-(n-hexyl)aminocarbonyloxy group, di-(1-methylpropyl)aminocarbonyloxy group, di-(1-methylbutyl)aminocarbonyloxy group , di-(2-methylbutyl)aminocarbonyloxy group, etc.

As preferred herein, R ¹ , R ² , R ³ and R ⁴ are the same or different and each represents a hydrogen atom, a halogen atom, a hydroxyl group, a nitrile group, a C1.6 alkyl group or a C1.6 alkoxy group; more preferably they are the same or different and each represents a hydrogen atom, a halogen atom, a hydroxyl group, a nitrile group or a C1.6αalkoxy group; more preferably they are the same or different and each represents a hydrogen atom or a C1.6alkoxy group; and most preferably, R ¹ and R ⁴ are hydrogen, while R ² and R ³ are the same or different and each is C1. ₆ alkoxy group (for example, methoxy group, ethoxy group, etc.).

The terms halogen atom and _C1 . _{The 6} alkyl group represented herein by R ⁵ refers to the halogen atom and C ₁ . ₆ alkyl group, the meaning of each being defined above.

Term _C2 . ₆ alkenyl group represented in the present specification R ⁵ refers to an alkenyl group containing 2-6 carbon atoms, and examples thereof include straight-chain or branched alkenyl groups such as vinyl group, allyl group, 1-propenyl group, isopropenyl group , 1-buten-1-yl group, 1-buten-2-yl group, 1-buten-3-yl group, 2-buten-1-yl group and 2-buten-2-yl group, preferably vinyl group, allylic group and an isopropenyl group.

Term _C2 . _{The 6} alkynyl group represented herein by R ⁵ refers to an alkynyl group containing 2 to 6 carbon atoms, and examples thereof include such straight-chain or branched C ₂ chains. ₆ alkynyl groups, such as ethynyl group, 1-propynyl group, 2-propynyl group, butynyl group, pentynyl group and hexynyl group.

Preferred examples of R ⁵ in the present specification include a hydrogen atom and a halogen atom (eg, fluorine atom, chlorine atom, bromine atom, etc.).

Partial structure

may either be a group represented by the formula >C(R ⁶ )-CH2- (where R ⁶ represents a hydrogen atom or a halogen atom) or >C-CH-, preferably a group represented by the formula >C(R ⁶ )-CH2- where R ⁶ represents a hydrogen atom or a halogen atom. As used herein, the term halogen atom represented by R ⁶ means an atom having the same meaning as a halogen atom in the above definition, and R ⁶ is preferably a hydrogen atom, a fluorine atom, a chlorine atom or a bromine atom, more preferably a hydrogen atom or fluorine atom. Thus, the group that may be represented by a partial structure is more preferably represented by the formula >CH-CH ₂ -, >C(F)-CH ₂ -, >C(Cl)-CH ₂ - or >C(Br)-CH ₂ -, more preferably with the formula >CHCH2- or >C(F)-CH2-.

The term halide ion represented herein as X ^- refers to fluoride ion, chloride ion, bromide ion, iodide ion, etc., preferably chloride ion, bromide ion and iodide ion, more preferably chloride ion and bromide ion, most preferably chloride ion. The term organic sulfonic acid ion represented by X ^- refers to methanesulfonate ion, trifluoromethanesulfonate ion, ethanesulfonate ion, benzenesulfonate ion, toluenesulfonate ion and camphorsulfonate ion, etc.

As used herein, m is 0 or an integer from 1 to 5, where the partial structure

- 138 045018

represented by (1) the formula >C(R ⁶ )-CH2- or >C-CH-, where m is 0; (2) the formula >C(R ⁶ )-(CH2)2 or >C=CH-(CH2)-, where m is 1; (3) the formula >C(R ⁶ )-(CH2) ₃ - or >C-CH-(CH ₂ ) ₂ -, where m is 2; (4) the formula >C(R ⁶ )-(CH2)4- or >C-CH-(CH2)3-, where m is 3; (5) the formula >C(R ⁶ )-(CH2) ₅ - or >C-CH(CH ₂ ) ₄ -, where m is 4; and (6) the formula >C(R ⁶ )-(CH ₂ ) ₆ - or >C-CH-(CH ₂ ) ₅ -, where m is 5, respectively (in the formula, the value of R ⁶ is defined above), m is preferably equal to 0, 2 or 4, more preferably 0 or 2.

According to one embodiment, the acetylcholinesterase inhibitor of the present invention, for example, includes such acetylcholinesterase inhibitors containing the following compounds. However, it is intended that embodiments of the present invention are not limited to these acetylcholinesterase inhibitors containing these compounds.

The acetylcholinesterase inhibitor contains one or two or more 1-benzylpyridinium salts selected from:

1-benzyl-4-(1-indanon-2-yl)methylpyridinium chloride;

1-benzyl-4-[(4-methoxy-1-indanone)-2yl]methylpyridinium chloride;

1-benzyl-4-[(5-methoxy-1-indanone)-2yl]methylpyridinium chloride;

1-benzyl-4-[(6-methoxy-1-indanone)-2yl]methylpyridinium chloride;

1-benzyl-4-[(7-methoxy-1-indanone)-2yl]methylpyridinium chloride;

1-benzyl-4-[(5,6-dimethoxy-1-indanone)-2yl]methylpyridinium chloride;

1-benzyl-4-[(5,7-dimethoxy-1-indanone)-2yl]methylpyridinium chloride;

1-benzyl-4-[(4,7-dimethoxy-1-indanone)-2yl]methylpyridinium chloride;

1-benzyl-4-[(4,5-dimethoxy-1-indanone)-2yl]methylpyridinium chloride;

1-benzyl-4-[(6,7-dimethoxy-1-indanone)-2yl]methylpyridinium chloride;

1-benzyl-4-[(5,6,7-trimethoxy-1-indanone)-2yl]methylpyridinium chloride;

1-benzyl-4-[(5,6-diethoxy-1-indanone)-2yl]methylpyridinium chloride;

1-benzyl-4-(1-indanon-2-yl)methylpyridinium bromide;

1-benzyl-4-[(4-methoxy-1-indanone)-2yl]methylpyridinium bromide;

1-benzyl-4-[(5-methoxy-1-indanone)-2yl]methylpyridinium bromide;

1-benzyl-4-[(6-methoxy-1-indanone)-2yl]methylpyridinium bromide;

1-benzyl-4-[(7-methoxy-1-indanone)-2yl]methylpyridinium bromide;

1-benzyl-4-[(5,6-dimethoxy-1-indanone)-2yl]methylpyridinium bromide;

1-benzyl-4-[(5,7-dimethoxy-1-indanone)-2yl]methylpyridinium bromide;

1-benzyl-4-[(4,7-dimethoxy-1-indanone)-2-139 045018 yl]methylpyridinium bromide;

1-benzyl-4-[(4,5-dimethoxy-1-indanone)-2yl]methylpyridinium bromide;

1-benzyl-4-[(6,7-dimethoxy-1-indanone)-2yl]methylpyridinium bromide;

1-benzyl-4-[(5,6,7-trimethoxy-1-indanone)-2yl]methylpyridinium bromide and 1-benzyl-4-[(5,6-diethoxy-1-indanone)-2yl]methylpyridinium bromide.

xi) Published international patent application WO 2000/033840

In some embodiments, the compounds include donepezil, rivastigmine, galantamine, lycoramine, and galantamine and lycoramine analogues. Suitable compounds are galantamine, lycoramine and analogues thereof, in which at least one of the methoxy, hydroxy or methyl groups of galantamine or lycoramine is substituted as follows:

methoxy group - another alkoxy group containing from one to six carbon atoms, a hydroxy group, hydrogen, an alkanoyloxy group, a benzoyloxy or substituted benzoyloxy group, a carbonate group or a carbamate group or a trialkylsilyloxy group;

hydroxy group - an alkoxy group containing from one to six carbon atoms, hydrogen, an alkanoyloxy group, a benzoyloxy or substituted benzoyloxy group, a carbonate group or a carbamate group;

N-methyl group - hydrogen, alkyl, benzyl, cyclopropylmethyl group or substituted or unsubstituted benzoyloxy group.

One or more of the methoxy, hydroxy and methyl groups of galantamine or lycoramine may be replaced by the groups noted above.

When referring to a substituent group, the group may be selected from alkyl or alkoxy groups containing from 1 to 6 carbon atoms, halogens and haloalkyl groups such as trifluoromethyl. When referring to alkyl groups, where the context permits, as used herein, the term also includes groups that are or contain cycloalkyl groups, including adamantyl. Aryl groups are usually phenyl or naphthyl, but may include heteroaryl such as morpholino.

Galantamine and lycoramine have the following formulas:

Suitable analogues are described, for example, in international patent application WO88/08708 and in Bores and Kosley, Drugs of the Future 21: 621-631 (1996).

Other useful pharmacological agents for such drugs include rivastigmine and other pharmacological agents with half-life values of 1-11 hours.

Particularly useful analogues of galantamine and lycoramine that are useful in the present invention include analogues thereof in which the methoxy group of such compounds is replaced by hydrogen, hydroxy or an alkoxy group containing from two to six carbon atoms, or an acyloxy group, for example, an alkanoyloxy group containing from one to seven carbon atoms , or benzoyl

- 140 045018 group, or in which the methoxy group is replaced by a mono- or dialkylcarbamate group, or by a mono- or dialkylcarbonate group, in which the alkyl groups contain from 1 to 8 carbon atoms, preferably from 4 to 8 carbon atoms, or in which the methoxy group is replaced by an arylcarbamate or carbonate group group, wherein said aryl group is selected from phenyl, naphthyl, substituted phenyl and substituted naphthyl groups, in which said substituent is selected from alkyl and alkoxy groups containing 1-6 carbon atoms, trifluoromethyl groups and halogens.

Other useful analogues include compounds in which, whether the methoxy group is substituted, the hydroxy group is replaced by an alkoxy group containing from one to six carbon atoms, hydrogen, an acyloxy group, for example, an alkanoyloxy group typically containing from 1 to 7 carbon atoms, benzoyloxy or substituted a benzoyloxy group, in which said substituent is selected from alkyl and alkoxy groups containing 1 to 6 carbon atoms, trifluoromethyl groups and halogens, a carbonate group or a carbamate group, which may be mono- or dialkyl or arylcarbamate or carbonate, in which the alkyl groups contain from 1 to 8 carbon atoms, preferably 4 to 6 carbon atoms, or said aryl group selected from phenyl, naphthyl, substituted phenyl and substituted naphthyl groups, wherein said substituent is selected from alkyl and alkoxy groups containing 1 to 6 carbon atoms, trifluoromethyl groups and halogens .

xii) Published International Patent Application No. WO 1999/007359

In some embodiments, cholinesterase inhibitors may include, but are not limited to, physostigmine, tacrine and tacrine analogs, phasiculin, metrifonate, heptylphysostigmine, norpyridostigmine, norneostigmine, huperazine, donepezil, and prodrugs of any of these compounds, wherein the inhibitor is modified according to prodrug design rules known in the art. in this field of technology. Examples of such modifications include the introduction of hydrophilic or lipophilic groups to enhance solubility or ability to penetrate cell membranes, respectively.

In some embodiments, the cholinesterase inhibitors are acetylcholinesterase inhibitors, particularly compounds that are capable of crossing the blood-brain barrier.

Particularly preferred cholinesterase inhibitors for use in the present invention include galantamine, epigalantamine and norgalantamine, as well as analogs, salts and derivatives of any of them. Galantamine was formerly known as galanthamine. It is a tertiary alkaloid that can be extracted from the bulbs of various snowdrops, such as the Caucasian snowdrop Galanthus woronowii (Amaryllidaceae) and related species, as well as the bulbs of the yellow narcissus, or obtained by chemical synthesis. It is highly selective for acetylcholinesterase as opposed to butyrylcholinesterase. It is substantially selectively active at nicotinic receptor sites and is substantially marginally effective at muscarinic receptor sites.

Particularly preferred cholinesterase inhibitors for use according to the present invention are galantamine and its derivatives of formula (I)

wherein the dotted line represents an optional double bond between carbon atoms 3 and 4; each R ¹ is independently selected from hydrogen, hydroxyl, straight or branched alkyl, hydroxyalkyl, carboxyalkylamine, alkylamino, acyl, lower alkanoyl, cyano, sulfhydryl, C ₁ . ₆ alkoxy, alkylthio, aryloxy, arylthio, R ³ -substituted aryloxy, R ³ -substituted arylthio, aralkoxy, optionally R ³ -substituted aliphatic or arylcarbamyl group, aralkylthio, R ³ -substituted aralkoxy, R ³ -substituted aralkylthio, aryloxymethyl, R ³ substituted aryloxymethyl, alkanoyloxy, hydroxy-substituted alkanoyloxy, benzoyloxy, R ³ -substituted benzoyloxy, aryloxycarbonyl and R ³ -substituted aryloxycarbonyl;

R ² is selected from hydrogen, straight-chain or branched C ₁ . ₆ alkyl, alkenyl or alkaryl group, optionally substituted with a halogen atom or cycloalkyl, hydroxy, alkoxy, nitro, amino, aminoalkyl, acylamino, heteroaryl, heteroarylalkyl, aryl, arylalkyl, cyano, amyl, aroyl, cycloalkylmethyl, allyl, phenyl, R ³ - substituted phenyl, alkylphenyl, R ³ -substituted alkylphenyl, heterocyclyl selected from a- or ss-furyl, a- or ss-thienyl, tenyl, pyridyl, pyrazinyl and pyrimidyl, alkylheterocyclyl or R ¹ -substituted heterocyclyl, wherein R1 is alkyl or alkoxy;

- 141 045018 each R ³ is independently selected from hydrogen, hydroxyl, sulfhydryl, alkyl, hydroxyalkyl, aryl, aralkyl, alkoxy, mercaptoalkyl, aryloxy, thiaryloxy, alkaryloxy, mercaptoalkaryl, nitro, amino, N-alkylamino, N-arylamino, N-alkarylamino , fluorine, chlorine, bromine, iodine and trifluoromethyl;

each R ⁴ is independently selected from hydrogen, halogen, trifluoromethyl or C ₁ - ₄ alkyl;

each R ⁵ is independently selected from hydrogen or hydroxymethyl;

R ⁶ is hydrogen or C ₁ _ ₆ alkyl, or, if R ¹ on the 2-position carbon atom is hydroxyl, then R ⁶ may be a fragment of formula I in which R ⁶ is hydrogen and R ¹ is constitutes a connection; or R ¹ on the carbon atom in the 2nd position and R ⁶ can together form a semicarbazone;

X represents oxygen or NR ₃ ;

Y represents nitrogen or phosphorus, as well as their methylenedioxy derivatives and their pharmaceutically acceptable acid addition salts.

Among the compounds of formula I that can be used in the method according to the present invention, some compounds are compounds in which alkyl moieties contain 1-8 carbon atoms; the halogen atoms are preferably fluorine, bromine, chlorine; the aryl moieties are preferably phenyl; the cycloalkyl groups are preferably 3-7 membered rings, in particular cyclopropyl or cyclobutyl; the acyl groups are preferably lower alkanoyl groups; and the heteroaryl moieties are preferably 5-8 membered rings, for example thienyl, furyl, pyridyl, pyrrolyl or pyrizanyl.

In some embodiments, the compounds of formula I are compounds of formula II

wherein each of R ¹ and R ² , which may be the same or different, represents a hydrogen atom or an acyl group, such as a lower alkanoyl group, such as an acetyl group, or a straight or branched alkyl group, such as methyl, ethyl, propyl or isopropyl ; R ³ represents a straight or branched alkyl, alkenyl or alkaryl group which is optionally substituted with a halogen atom or cycloalkyl, hydroxy, alkoxy, nitro, amino, aminoalkyl, acylamino, heteroaryl, heteroarylalkyl, aroyl, aroylalkyl or cyano group; and R ⁴ represents a hydrogen or halogen atom attached to at least one of the ring carbons of the tetracyclic skeleton; as well as their pharmaceutically acceptable salts, such as hydrobromide, hydrochloride, methyl sulfate or methyl iodide.

Formula II includes galantamine itself.

In some embodiments, the compound is galantamine itself and its salts, such as halides, such as galantamine hydrobromide.

xiii) Published International Patent Application No. WO 1997/038993

This application relates to compounds of the formula

in which

R represents hydrogen, (C ₁ -C ₆ )alkyl or hydroxy(C ₁ -C ₆ )alkyl;

X is hydrogen, hydroxy, (C ₁ -C ₆ )alkoxy, phenyl (C ₁ -C ₆ )alkoxy or -O (C=O)NR1R ² ; And

Y represents hydrogen or halogen;

where R ¹ is (C ₁ -C ₆ )alkyl, phenyl or phenyl(C ₁ -C ₆ )alkyl, where the phenyl group is optionally substituted with (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, halogen or trifluoromethyl;

R ² represents hydrogen or (C ₁ -C ₆ )alkyl or

R ¹ and R ² together with the nitrogen to which they are attached form a tetrahydroisoquinoline group;

and pharmaceutically acceptable acid addition salts thereof.

As used herein, the term alkyl will mean a straight-chain or branched alkyl group of a specified number of carbon atoms. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and straight and branched pentyl and hexyl.

As used herein, the term halogen will mean chlorine, fluorine, bromine and iodine.

As used herein, the term phenyl will mean phenyl containing 0, 1, 2 or 3 substituents independently selected from the group consisting of (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, halogen or trifluoromethyl.

In a specific embodiment of the present invention, the compounds are compounds of formula (I)

in which

R represents hydrogen, (C ₁ -C ₆ )alkyl or hydroxy(C ₁ -C ₆ )alkyl;

X is hydrogen, hydroxy, (C ₁ -C ₆ )alkoxy, benzyloxy, or -O(C=O)NR1R ² and

Y represents hydrogen or halogen;

where R ¹ represents (C ₁ -C ₆ )alkyl, phenethyl or benzyl, where the phenyl group is optionally substituted with (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, halogen or trifluoromethyl; And

R ² represents hydrogen or (C ₁ -C ₆ )alkyl;

and pharmaceutically acceptable acid addition salts thereof.

In one embodiment, if R ¹ is (C ₁ -C ₆ )alkyl, then R ² is hydrogen.

In one embodiment, the compounds are compounds of Formula I wherein R is (C ₁ -C ₆ )alkyl. In one embodiment, X is hydrogen, Y is hydrogen, and R is hydrogen, methyl, ethyl, or propyl.

In another embodiment, the compounds are compounds of formula I

in which

R represents hydrogen, (C ₁ -C ₆ )alkyl or hydroxy(C ₁ -C ₆ )alkyl;

X is hydrogen, hydroxy, (C ₁ -C ₆ )alkoxy, benzyloxy or -O(C=O)NR1R ² and

Y represents hydrogen or halogen;

where R ¹ and R ² together with the nitrogen to which they are attached form a tetrahydroisoquinoline group;

and pharmaceutically acceptable acid addition salts thereof.

In one embodiment, X is -O(C=O)NR1R ² and Y is hydrogen.

xiv) US Patent No. 5965569

The new aminopyridine compounds which are the object of the present invention correspond to the general formula (I) (11

I Λ χ V \/

R> in which R may represent hydrogen, alkyl, aralkyl or acyl;

R ¹ and R ² may independently represent hydrogen, alkyl, aralkyl, alkoxy, alkoxycarbonyl, amino, or amino substituted with one or two alkyl, aralkyl or acyl groups;

m and n can take the values 1, 2 or 3;

X and Y may independently represent a bond between two carbons, an oxygen or sulfur atom, an NR ³ group, or an alkylene or alkenylene bridge containing from 1 to 5 carbon atoms, and which may contain one or more R ⁴ substituents. If X represents an alkenylene group, the latter may be fused to a saturated or unsaturated carbocyclic or heterocyclic ring system, the ring being substituted by one or more R ⁵ groups; for example, X may be an orthophenylene group; And

- 143 045018 p, q and r have values equal to or greater than 1, and R ⁶ and R ⁷ represent substituents, each of which separately may be hydrogen, halogen, preferably fluorine or chlorine, lower alkoxy or lower alkyl.

In the above definitions, the term alkyl as used herein is a hydrocarbon residue containing from one to six carbon atoms with straight, branched, substituted cyclic or cycloalkyl chains, for example, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, pentyl, cyclopentyl, cyclopentylmethyl, cyclohexyl, etc.;

As used herein, the term aralkyl means phenylalkyl or phenylalkyl substituted at phenyl containing from 7 to 12 carbon atoms. As used herein, the term alkyl in phenylalkyl or phenylalkyl substituted at phenyl means an alkylene group containing a linear chain containing from one to four carbon atoms, for example, methylene, ethylene, trimethylene or tetramethylene. Substituted phenyl in phenylalkyl, substituted at phenyl, is a phenyl group containing one or more substituents selected from the group consisting of halogen, for example, fluorine, chlorine, bromine and iodine, lower alkyl, which includes straight or branched alkyl groups containing from one to four carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl and tert-butyl, and lower alkoxy, which includes a straight or branched chain alkoxy group containing from one to four carbon atoms, for example, methoxy , ethoxy, propoxy, isopropoxy, butoxy and sec-butoxy. Examples of such aralkyl groups include benzyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl, 2-(4methoxyphenyl)ethyl, 2-(2-methylphenyl)ethyl, 2-(4-fluorophenyl)ethyl and 4-(4-chlorophenyl)butyl .

As used herein, the term acyl means an alkylcarbonyl or aralkylcarbonyl group, in which alkyl and aralkyl radicals may have the meanings defined above.

In the context of R ¹ and R ² , as used herein, the terms alkyl and aralkyl have the meaning given above for R. The alkoxy substituent and the alkoxy group of the alkoxycarbonyl substituent may have the meaning given above for the lower alkoxy group. Alkyl, aralkyl and acyl substituents on the amino group may also have the meaning given above in the context of R.

The group R ³ in NR ³ can take on the values defined above for R.

The R ⁴ groups attached to an alkylene or alkenylene bridge may independently be hydrogen, straight or branched lower alkyl, alkenyl or alkylidene containing from one to four carbon atoms, phenyl, phenyl substituted by one or more lower alkyl groups containing from one up to four carbon atoms, lower alkoxy groups containing from one to four carbon atoms, or halogens (fluorine, chlorine, bromine or iodine), aralkyl as defined above in the context of R, lower alkoxy containing from one to four carbons, and hydroxyl.

The R ⁵ groups that are substituents on the ring fused to X or Y may be hydrogen, lower alkyl or lower alkoxy containing one to four carbon atoms, or halogen (fluorine, chlorine, bromine and iodine).

Since the compounds of general formula (I) contain at least two chiral centers, i.e. two asymmetric carbon atoms capable of forming optical isomerism, then the present invention applies to racemic compounds, and to all possible enantiomers of such compounds, or to mixtures thereof in various proportions. Pharmaceutically acceptable addition salts can be formed with organic or inorganic acids, such as hydrochloric, hydrobromic, sulfuric and nitric acids among inorganic acids, and tartaric, succinic, maleic, fumaric and citric acids among organic acids.

xv) US Patent No. 5663448

The compounds of the present invention are characterized by the following formula I:

- 144 045018 as well as their stereoisomers and pharmaceutically acceptable salts, in which each of Z and Z' independently represents H or F;

Q represents

Oh oh

II II

C, CH(OH), CHOCR ₄ ;

X is H, Br, Cl, F or CF3; Y represents H, Br, Cl, F, OH, _OR5 , OC(O)R4, N3, CN, NO2, SO3H, CO2R4, NH2, NHR9, NR9K9, C(R6)(R7)(V'R8) or C(O)R7, provided that if both Z and Z' are F, then Y is H or F;

V and V' are each independently CH ₂ or O;

R ¹ represents H or CH3;

R2, _R9 and _R'9 are each independently ( _C1-6 )alkyl, or R2 and V-R3 together with the carbon atom to which they are attached form a 3-6 membered ring;

_R3 , _R6 , R7 and R8 are each independently H, ( _C1-6 )alkyl or ( _C3-6 )cycloalkyl;

R4 is H, (C _1-10 )alkyl, (C _0-4 )alkylenaryl or (C _3-8 )cycloalkyl and

R ₅ represents (C _1-10 )alkyl, benzyl, phenethyl or (C _3-6 )cycloalkyl.

As used herein, the terms (C _1-6 )alkyl and (C _1-10 )alkyl mean straight-chain or branched alkyl radicals containing from 1 to 6 carbon atoms and from 1 to 10 carbon atoms, respectively, including but not limited to methyl, ethyl , n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2,2-dimethylbutyl, 2-methylpentyl, 2,2dimethylpropyl, n-hexyl, etc. . By analogy, as used herein, the term ( _C04 )alkylenaryl can mean straight or branched alkylene groups of up to 4 carbon atoms, such as ethylethylene, 2-methyltrimethylene, etc. Of course, C0 means that there is no alkylene moiety attached to the aryl.

The term hydroxy (C _1-6 )alkyl means a (C _1-6 )alkyl group containing from 1 to 3 hydroxy substituents. Preferably, there is only one hydroxy substituent at the α-position (attached to the carbon atom that is directly connected to the phenyl).

The term Ts or tosyl means ##STR5##. Tosyl derivatives mean ##STR6##, where R represents C _1-6 alkyl.

The term aryl includes both carbocyclic and heterocyclic moieties, of which phenyl, pyridyl, indolyl, indazolyl, furyl and thienyl are of primary interest; said moieties include their positional isomers, such as, for example, 2-, 3- or 4-pyridyl, 2- or 3-furyl and thienyl, 1-, 2- or 3-indolyl or 1- and 3-indazolyl, as well as Dihydro- and tetrahydroanalogues of the furyl and thienyl fragments. As used herein, the term aryl also includes fused carbocyclic moieties such as pentalenyl, indenyl, naphthalenyl, azulenyl, heptalenyl, acenaphthylenyl, fluorenyl, phenalenyl, phenanthrenyl, anthracenyl, acephenanthrlenyl, aceanthrlenyl, triphenylenyl, pyrenyl, chrysenyl, and naphthacenyl. As used herein, the term aryl also includes heterocyclic radicals such as 2- or 3-benzo[b]thienyl, 2-or 3-naphtho[2,3-b]thienyl, 2- or 3-thianthrenyl, 2H-pyran-3-( or 4- or 5-)yl, 1-isobenzofuranyl, 2Hchromenyl-3-yl, 2- or 3-phenoxathiinyl, 2- or 3-pyrrolyl, 4- or 3-pyrazolyl, 2-pyrazinyl, 2-pyrimidinyl, 3-pyridazinyl , 2-indolizinyl, 1-isoindolyl, 4H-quinolizin-2-yl, 3-isoquinolyl, 2quinolyl, 1-phthalazinyl, 1,8-naphthyridinyl, 2-quinoxalinyl, 2-quinazolinyl, 3-cinnolinyl, 2pteridinyl, 4aH-carbazole -2-yl, 2-carbazolyl, beta-carbolin-3-yl, 3-phenanthridinyl, 2-acridinyl, 2-perimidinyl, 1-phenazinyl, 3-isothiazolyl, 2-phenothiazinyl, 3-isochazolyl, 2-phenoxazinyl, 3-isochromanyl, 7 -chromanyl, 2-pyrrolin-3-yl, 2-imidazolinyl, 2-imidazolin-4-yl, 2-pyrazolidinyl, 3-pyrazolin-3-yl, 2-piperidyl, 2-piperazinyl, 1-indolinyl, 1-isoindolinyl, 3 -morpholinyl, benzo[h]isoquinolinyl and benzo[b]furanyl, including their positional isomers, except that heterocyclic moieties cannot be attached directly through their nitrogen atoms. Aryl groups may be unsubstituted or substituted with one, two or three substituents independently selected from C _1-6 alkyl, haloalkyl, alkoxy, thioalkoxy, aminoalkylamino, dialkylamino, hydroxy, halogen, mercapto, nitro, carboxaldehyde, carboxy, carboalkoxy and carboxamide.

When R ² and VR ³ are taken together, they can form a 3-membered ring that contains a carbon atom with R ² and V attached to it (if R ³ is H). Other rings formed may contain 4, 5 or 6 ring atoms. As used herein, the term 3-6 membered ring refers to the number of carbon atoms and oxygen atoms (if V is O) making up the structure of the ring.

The term stereoisomers for compounds of formula I is a general term for all isomers of individual molecules that differ only in the orientation of their atoms in space. It includes mirror image isomers (enantiomers), geometric isomers (cis/trans), and isomers of compounds with more than one chiral center that are not mirror images of each other (diastereoisomers), any forms are acceptable for the compound.

- 145 045018 xvi) European Patent Application No. EP 0611769

The compounds of the present invention are characterized by the following formula I:

z

in ₃ —si—R.

I r ₂ stereoisomers or mixtures thereof, as well as pharmaceutically acceptable salts thereof, wherein each of Z and Z' is independently H or F, provided that at least one of Z or Z' is F;

Q represents

-s-, -CH- or -CH-

II II oh he o-cr ₄

II

ABOUT ;

X is H, Br, Cl, F or CF ₃ ;

Y is H, OH, (C _1-6 )alkyl, -(CH2)mOR5, hydroxy(C _1-6 )αalkyl, (CH2)nNR ₆ R ₆ ', azido, CN, CO2R4, COR ₆ , SO3H, Br, Cl, F, NO2 or -(CH2) _n SiR ₁ 'R2'R ₃ ', provided that if Z and Z' are both F, then Y is H or F;

R1, R2, _R3 , R1', R2' and R3' are each independently ( _C1-10 )alkyl or ( _CH2 ) _naryl ;

R4 is H, (C _1-10 )alkyl, phenyl, benzyl or phenethyl;

R5 is H, (C _1-10 )alkyl, benzyl or phenethyl;

R6 and _R6 ' independently represent hydrogen or _C1-10 alkyl;

m is an integer selected from 0, 1, 2, 3 or 4; and n is an integer selected from 0, 1 or 2.

As used herein, the terms (C _1-6 )alkyl and (C _1-10 )alkyl mean straight-chain or branched alkyl radicals containing, respectively, 1 to 6 carbon atoms and 1 to 10 carbon atoms, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2,2-dimethylbutyl, 2-methylpentyl, 2,2dimethylpropyl, n-hexyl, etc. d. By analogy, as used herein, the terms (CH ₂ ) _n or (CH ₂ ) _m can represent alkylene chains, which may be branched or unbranched.

The term hydroxy (C ₁ _ ₆ )alkyl means a (C ₁ _ ₆ )alkyl group containing from 1 to 3 hydroxy substituents. Preferably, there is only one hydroxy substituent at the α-position (attached to the carbon atom that is directly connected to the phenyl). The terms Ts or tosyl mean EMI3.1. Tosyl derivatives are EM13.2, where R is C ₁ . ₆ alkylene.

The term aryl includes both carbocyclic and heterocyclic moieties, of which phenyl, pyridyl, indolyl, indazolyl, furyl and thienyl are of primary interest; said moieties include their positional isomers, such as, for example, 2-, 3- or 4-pyridyl, 2- or 3-furyl and thienyl, 1-, 2- or 3-indolyl or 1- and 3-indazolyl, as well as Dihydro- and tetrahydroanalogues of the furyl and thienyl fragments. As used herein, the term aryl also includes fused carbocyclic moieties such as pentalenyl, indenyl, naphthalenyl, azulenyl, heptalenyl, acenaphthylenyl, fluorenyl, phenalenyl, phenanthrenyl, anthracenyl, acephenanthrlenyl, aceanthrlenyl, triphenylenyl, pyrenyl, chrysenyl, and naphthacenyl. As used herein, the term aryl also includes heterocyclic radicals such as 2- or 3-benzo[b]thienyl, 2-or 3-naphtho[2,3-b]thienyl, 2- or 3-thianthrenyl, 2H-niran-3-( or 4- or 5-)yl, 1-isobenzofuranyl, 2Hchromenyl-3-yl, 2- or 3-phenoxathiinyl, 2- or 3-pyrrolyl, 4- or 3-pyrazolyl, 2-pyrazinyl, 2-pyrimidinyl, 3-pyridazinyl , 2-indolizinyl, 1-isoindolyl, 4H-quinolizin-2-yl, 3-isoquinolyl, 2-quinolyl, 1-phthalazinyl, 1,8-naphthyridinyl, 2-quinoxalinyl, 2-quinazolinyl, 3-cinnolinyl, 2pteridinyl, 4aH-carbazole -2-yl, 2-carbazolyl, beta-carbolin-3-yl, 3-phenanthridinyl, 2-acridinyl, 2-perimidinyl, 1-phenazinyl, 3-isothiazolyl, 2-phenothiazinyl, 3-isoxazolyl, 2-phenoxazinyl, 3-isochromanyl, 7 -chromanyl, 2-pyrrolin-3-yl, 2-imidazolidinyl, 2-imidazolin-4-yl, 2-pyrazolidinyl, 3-pyrazolin-3-yl, 2-piperidyl, 2-piperazinyl, 1-indolinyl, 1-isoindolinyl, 3 -morpholinyl, benzo[h]isoquinolinyl and benzo[b]furanyl, including their positional isomers, except that heterocyclic moieties cannot be attached directly through their nitrogen atoms. Aryl groups may be unsubstituted or substituted with one, two or three substituents independently selected from C ₁ . ₆ alkyl, haloalkyl, alkoxy, thioalkoxy, aminoalkylamino, dialkylamino, hydroxy, halogen, mercapto, nitro, carboxaldehyde, carboxy, carboalkoxy and carboxy

- 146 045018 samida.

R1, R2, _R3 , R1', R2' and _R3 ' are each independently selected from _C1-10 alkyl or (CH2)n aryl, which means that, for example, ^R1 may be benzyl while R2 is methyl. In other words, none of R1, R2, _R3 , R1', R2' and _R3 ' need be the same fragment, although this is possible.

The term stereoisomers for compounds of formula I is a general term for all isomers of individual molecules that differ only in the orientation of their atoms in space. It includes mirror image isomers (enantiomers), geometric isomers (cis/trans), and isomers of compounds with more than one chiral center that are not mirror images of each other (diastereoisomers), any forms are acceptable for the compound.

xvii) Published International Patent Application No. WO 1993/03034

The present invention also includes novel compounds of formula I in which A is

where n is 1-10; P represents a bond or (CH ₂ )m, where m is 0-10; wherein nitrogen, oxygen or sulfur atoms may replace a methylene group on ring A that is not adjacent to the quinazoline moiety, and Y is attached to a carbon atom on ring A, wherein Y is hydrogen, hydroxy, halogen, carboxy, lower alkoxy , lower alkyl, aryl, heteroaryl, keto, lower alkoxycarbonyl or lower alkanoyl;

M represents =S, =NR,

where R and R' independently represent hydrogen, hydroxy, lower alkyl, lower alkoxy, lower alkenyl, lower alkynyl, aryl, aryloxy, aryl(lower)alkyl, heteroaryl or heteroaryl(lower)alkyl, and taken together can form 3-6 -membered ring, optionally containing from one to three heteroatoms selected from nitrogen, oxygen and sulfur;

and X is absent or represents one to four substituents selected from halogen, alkyl (C _1-22 ), straight or branched, saturated, or alkenyl or alkynyl, if the alkyl is of a suitable size to form a ring, saturated or unsaturated, containing (or not containing) one or more heteroatoms, such as O, S, N, Se, P, etc., or an aromatic or heteroaromatic ring containing (or not containing) one or more heteroatoms, such as O, S, N, Se, etc., primary, secondary or tertiary amino, nitro(lower alkyl)thio or aryl(or heteroaryl)thio, mercapto, hydroxy, carboxy, lower alkoxy or aryl(or heteroaryl)oxy, alkyl(C _1-22 ) or aryl (or heteroaryl) sulfinyl, alkyl(C _1-22 ), or aryl (or heteroaryl) sulfonyl, perfluoroalkyl (C _1-22 ), such as trifluoromethyl, perfluoroalkoxy(C _1-22 )r, such as trifluoromethoxy, perfluoroalkylthio(C1-22) such as trifluoromethylthio, perfluoroalkylsulfinyl( _C1-22 ) such as trifluoromethylsulfinyl, perfluoroalkylsulfonyl( _C1-22 )r such as trifluoromethylsulfonyl, alkyl( _C1-22 ) or aryl(or heteroaryl)carbamoyl , or diacylamino, including cyclic imido, such as succinimido, alkyl(C _1-22 ) or aryl(or heteroaryl)sulfinylamido, alkyl(C _1-22 ) or aryl(or heteroaryl)sulfonylamido, perfluoroalkyl(C _1-22 )sulfinylamido such as trifluoromethylsulfinylamido, perfluoroalkyl(C _1-22 )sulfonylamido such as the above trifluoromethylsulfonylamido, trialkylsilyl such as trimethylsilyl or triethylsilyl, acyl such as acetyl, benzoyl, phenylacetyl, hydrocinnamoyl and the like, perfluoroacyl such such as trifluoroacetyl, heptafluorobutyryl and the like, acyl(lower alkyl) such as acetylmethyl, benzoylmethyl, phenylacetylmethyl, hydrocinnamoylmethyl and the like, perfluoroacyl(lower alkyl) such as trifluoroacetylmethyl, heptafluorobutyrylmethyl and the like, alkyl( C _1-22 ) or aryl (or heteroaryl) carbamoyloxy, dialkyl (C _1-22 ) or diaryl (or diheteroaryl) carbamoyloxy, alkyl (C _1-22 ) or aryl (or heteroaryl) carbamoylthio, alkyl (C _1-22 ) or aryl(or heteroaryl)carbamoylalkyl or diacylaminoalkyl, including cyclic imidoalkyl such as acetamidomethyl, octanamidomethyl or succinimidomethyl, aryl or aryl(lower alkyl), including substituted aryl with groups such as halogen and

- 147 045018 the above groups, heteroaryl or heteroaryl(lower alkyl), such as furan, thiophene, pyrrole, pyridine and the like, including substituted derivatives with groups such as halogen and the groups described above;

Z is hydrogen, halogen, alkyl(C _1-12 )r, straight or branched, saturated, or alkenyl or alkynyl, if the alkyl is of a suitable size to form a ring, saturated or unsaturated, free or containing one or more heteroatoms selected from O, S and N, may also form an aromatic or heteroaromatic ring containing none or containing one or more heteroatoms selected from O, S and N, primary, secondary or tertiary amino(lower alkyl)thio-, aryl-, heteroarylthio, mercapto , hydroxy, carboxy, carbalkoxy, where alkyl is C ₁ -C ₂₂ -alkyl, lower alkoxy, aryl or heteroaryloxy, perfluoroalkyl, where alkyl is C ₁ -C ₂₂ -alkyl, perfluoroalkoxy, where the alkyl moiety is C ₁ - C ₂₂ alkyl, alkyl(C ₁ -C ₂₂ ), aryl or heteroarylcarbamoyl, diacylamino, cyclic imido or acyl, or a pharmaceutically acceptable acid addition salt thereof; provided that if A is

where n represents 1-3; m is 0; Y represents hydrogen; and M is RR', where both R and R' are hydrogen, then X may be absent or represent a single hydroxy or methoxy group; and if A has the formula IId, then X is 1,3-dihalogen or 2,4-dihalogen.

xviii) Published International Patent Application No. WO 1992/019238

The present invention relates to a number of compounds of general formula (I), which are formally derivatives of huperzine A

in which R1 represents H, (C1- _C8 )alkyl or halogen; R2 represents H or (C ₁ -C ₈ )alkyl; R3 and R4 are individually H, (C ₁ -C ₈ )alkyl, NO2, hydroxy or halogen; R5 and R6 are individually H, (C ₁ -C ₈ )alkyl, aryl or aralkyl; R7 is H, halogen or (C ₁ -C ₈ )alkyl, R8 is halogen or (C ₁ -C ₈ )alkyl, R ₉ is absent or is H; and the bonds designated -- are either absent or, together with an adjacent bond, form C.dbd.C, provided that if both bonds designated -- are present, then both R3 and _R4 cannot be H unless R ₇ or R ₈ is not halogen; and their pharmaceutically acceptable salts.

Therefore, the genus of compounds of formula I cannot include huperzine A itself or its simple N-alkylated derivatives. Preferably R1 is H, halogen (Cl, Br, I or F, most preferably F) or methyl. Preferably R2 is H, preferably R3 is nitro or halogen, preferably R4 is (C ₁ -C ₄ )alkyl or OH, and preferably R5.dbd.R6.dbd.H. Preferably, R7 and R9 represent H, and R8 represents (C ₁ -C ₄ )alkyl. Preferably, at least one of the bonds indicated by -- is absent. Therefore, preferred compounds of formula I are dihydro or bis(dihydro) analogs of huperzine A, which may also contain substituents on the pyridone ring or are analogs of huperzine A with a substituted pyridone ring.

The compounds of general formula I or II may exist in the form of optical isomers, and such isomers, as well as racemic (+/-) mixtures, are included in the present invention. The present invention also includes the 12R and 12S, as well as the 15R and 15S enantiomers of these compounds, as well as unresolved or partially resolved mixtures thereof. As used herein, the term alkyl includes linear or branched alkyl. As used herein, the terms aryl and aralkyl are fully defined below herein. In some embodiments, aryl groups include phenyl, tolyl, xylyl, anisyl, and the like. In some embodiments, aralkyl groups include aryloxy and aryl (C ₁ -C ₃ ) alkyl moieties. The C15-R1 bond is shown wavy to indicate that the R ₁ substituent (if present) may be equatorial or axial, or a mixture thereof. Although the Cl-C ₁₂ bond is located equatorially for convenience, it can be either equatorial, axial, or a mixture of both.

xix) European Patent Application No. EP0236684

Galantamine is generally considered to have the structure

- 148 045018

Compounds with similar structure in which hydroxy is replaced by methoxy, ethoxy, lower alkanoyloxy such as acetyloxy or oxy, methoxy group is replaced by hydrogen, methoxy, ethoxy or lower alkanoyloxy such as acetyloxy, methyl group substituted at nitrogen atom is replaced by other straight or branched lower alkyl groups such as ethyl, cyclopropylmethyl or cyclobutylmethyl, allyl, lower alkylphenyl or substituted lower alkylphenyl, where the substituents are fluorine, chlorine, bromine, lower alkoxy, hydroxy, nitro, amino(lower alkyl) or acylamino, containing 1-5 carbon atoms, heteroaryl(lower alkyl) in which the heteroaryl group is thienyl, furyl, pyridyl, pyrrolyl or pyrazinyl, or a cyano radical; or unsubstituted and halogen-substituted benzoyl(lower alkyl) in which the substituents are on the phenyl ring, and compounds in which the hydrogen atoms in the core structure have been replaced by fluorine or chlorine groups, or a carbon-carbon single bond between the carbons common to rings B and C, replaced by a double bond, appears to have properties similar to galantamine.

xx) US Patent No. 4895841

The invention relates to a cyclic amine compound characterized by the following formula (XXV), and to its pharmacologically acceptable salt:

-----(XXV)

Ji=Bss.T Q— K where J represents:

(a) a substituted or unsubstituted group selected from the group consisting of (1) phenyl, (2) pyridyl, (3) pyrazyl, (4) quinolyl, (5) cyclohexyl, (6) quinoxalyl and (7) furyl;

(b) a monovalent or divalent group, in which the phenyl may contain substituent(s) selected from the group consisting of (1) indanyl, (2) indanonyl, (3) indenyl, (4) indenonyl, (5) indanedionyl, (6) tetralonyl, (7) benzosuberonyl, (8) indanolyl and (9) C ₆ H ₅ --CO--CH(CH ₃ )--;

(c) a monovalent group derived from a cyclic amide compound;

(d) lower alkyl or (e) a group R ²¹ --CH.dbd.CH--, in which R ²¹ represents hydrogen or lower alkoxycarbonyl (dbd is the designation of a double bond);

B represents --(CHR ²² )r--, --CO-(CHR ²² )r--, --NR ⁴ --(CHR ²² )r--, R ⁴ represents hydrogen, lower alkyl, acyl, lower alkylsulfonyl, phenyl, substituted phenyl, benzyl or substituted benzyl, --CO--NR ⁵ --(CHR ²² )r--, R ⁵ is hydrogen, lower alkyl or phenyl, --CH.dbd.CH-( CHR ²² )r--, --OCOO--(CHR ²² )r--, --OOC--NH--(CHR ²² )r--, --NH--CO--(CHR ²² )r- -, --CH2-- CO-NH--(CHR ²² )r--, --(CH2)2--NH--(CHR ²² )r--, --CH(OH)--(CHR ²² )r--, r is 0 or an integer from 1 to 10, R ²² is hydrogen or methyl, so that one alkylene group may contain no methyl branch or may contain one or more methyl branches, .dbd.(CH -CH.dbd.CH)b--, b is an integer from 1 to 3, .dbd.CH--(CH ₂ ) _c --, c is 0 or is an integer from 1 to 9, .dbd .(CH--CH)d.dbd., d is 0 or an integer from 1 to 5; --CO--CH.dbd.CH--CH2--, --CO--CH2--CH(OH)--CH2--, --CH(CH3)-CO-NH--CH2--, --CH.dbd.CH-CO-NH-(CH ₂ ) ₂ --, --NH--, --O--, --S--, dialkylaminoalkylcarbonyl or lower alkoxycarbonyl;

T represents nitrogen or carbon;

Q represents nitrogen, carbon or ->O and

q is an integer selected from 1-3;

K represents hydrogen, phenyl, substituted phenyl, arylalkyl, where phenyl may contain a substituent, cinnamyl, lower alkyl, pyridylmethyl, cycloalkylalkyl, adamantanemethyl, furylmentyl, cycloalkyl, lower alkoxycarbonyl or acyl;

and ·=· indicates a single bond or a double bond.

In compounds of formula (XXV), J is preferably (a) or (b). In definition (b), monovalent groups (2), (3) and (5) and divalent groups (2) are preferred. In Definition B, the preferred ones are --(CHR ²² ) _r --, .dbd.(CH--CH.dbd.CH) _b --, .dbd.CH--(CH ₂ ) _c -- and .dbd.( CH--CH)d.dbd. Said preferred groups (B) may be combined with (b) of J, in particular with (2) of (b).

In formula (XXV), it is preferable if Q is nitrogen, T is carbon, q is 1 or 3, and Q is carbon; T is nitrogen and q is 2. Most preferably, Q is nitrogen, T is carbon and q is 2.

Preferably, K is phenylalkyl or phenylalkyl containing phenyl substituent(s).

Preferred compounds of the present invention include:

1-benzyl-4-((5,6-dimethoxy-1-indanone)-2-yl)methylpiperidine,

1-benzyl-4-((5,6-dimethoxy-1-indanone)-2ylidenyl)methylpiperidine,

1-benzyl-4-((5-methoxy-1-indanone)-2-yl)methylpiperidine,

1-benzyl-4-((5,6-diethoxy-1-indanone)-2-yl)methylpiperidine,

1-benzyl-4-((5,6-methylenedioxy-1-indanone)-2yl)methylpiperidine,

1-(meta-nitrobenzyl)-4-((5,6-dimethoxy-1-indanone)-2yl)methylpiperidine,

1-cyclohexymethyl-4-((5,6-dimethoxy-1-indanone)-2yl)methylpiperidine,

1-(meta-fluorobenzyl)-4-((5,6-dimethoxy-1-indanone)-2yl)methylpiperidine,

1-benzyl-4-((5,6-dimethoxy-1-indanone)-2yl)propylpiperidine,

1-benzyl-4-((5-isopropoxy-6-methoxy-1-indanone)-2yl)methylpiperidine and

1-benzyl-4-((5,6-dimethoxy-1-oxoindanone)-2yl)propenylpiperidine, characterized by the following formula

In addition, the present invention relates to a therapeutic composition that contains a pharmacologically effective amount of a cyclic amine compound of formula (XXV) or a pharmacologically acceptable salt thereof and a pharmacologically acceptable carrier, as well as a method for preventing and treating a disease caused by the activity of acetylcholinesterase by administering the compound to a sick person a cyclic amine of formula (XXV) or a pharmacologically acceptable salt thereof.

A preferred compound has the above formula in which J represents (b). Group (b) includes ten groups having the corresponding formulas below. S represents hydrogen or a substituent such as lower alkyl containing 1-6 carbon atoms and lower alkoxy containing 1-6 carbon atoms. Among the substituents, methoxy is most preferred, t is an integer selected from 1-4. Most preferred is phenyl containing 1-3 methoxy groups. (S)t can form a methylenedioxy group or ethylenedioxy group on two adjacent carbon atoms of the phenyl group.

- 150 045018

The preferred definition of B includes --(CHR ²² )r--, --CO--(CHR ²² )r--, .dbd.(CH--CH.dbd.CH)b--, .dbd.CH-- (CH ₂ ) _c -- and .dbd.(CH--CH)d.dbd. Most preferred are the -(CHR ²² ) _r -- group, in which R ²² is hydrogen and r is an integer selected from 1-3, and the .dbd.CH--(CH2)c-- group.

- 151 045018

In the above-defined cyclic amine compound according to the present invention, it is preferable if J in the formula represents (b) a monovalent or divalent group. In definition (b), indanonyl, indanedionyl and indenyl are most preferred, optionally containing phenyl substituent(s).

In Definition B, --(CHR ²² ) _r -- and .dbd.CH--(CH ₂ )c-- are preferred.

The ring containing T and Q may be a 5-, 6-, or 7-membered ring. Preferably, Q is nitrogen, T is carbon or nitrogen, and n is 2; Q represents nitrogen, T represents carbon, and n is 1 or 3; Q represents carbon, T represents nitrogen and n is 2.

In the determination of K, phenyl, arylalkyl and cinnamyl, optionally containing phenyl substituent(s), are preferred.

The present invention will be explained in detail taking into account piperidine compounds that fall within the scope of the above-defined cyclic amine compound. The explanation applies to the entire invention of the cyclic amine compound.

The piperidine compound is defined by formula (I)

in which R ¹ represents the following substituted or unsubstituted group: ring 1 phenyl group, ring 2 pyridyl group, ring 3 pyrazyl group, ring 4 quinolyl group, ring 5 indanyl group, . ring.6 is a cyclohexyl group, ring.7 is a quinoxalyl group, or ring 11.8 is a furyl group; a monovalent or divalent group derived from an indanone containing an unsubstituted or substituted phenyl ring; a monovalent group derived from a cyclic amide compound; a lower alkyl group or a group represented by the formula R ³ --CH.dbd.C-- (where R ³ is a hydrogen atom or a lower alkoxycarbonyl group),

X represents a group represented by the formula --(CH ₂ )n--, a group represented by the formula

group represented by the formula

R ⁴

I

-№(CH ₃ ) _L - where R ⁴ represents a hydrogen atom, a lower alkyl group, an acyl group, a lower alkylsulfonyl group or a substituted or unsubstituted phenyl or benzyl group, a group represented by the formula

ABOUT

II —C—N— (CH1) _I —

R" where R ⁵ represents a hydrogen atom, a lower alkyl group or a phenyl group, a group represented by the formula --CH.dbd.CH--(CH ₂ ) _n --, a group represented by the formula o

II

-о—с—О—(Снр,— group represented by the formula o

II —O—C-NH—(CH _g ) _l — group represented by the formula group represented by the formula group represented by the formula o II —NH—C—(CH ₃ )„— o

II -CH ₂ -C-NH—(CH ₃ ) _L “group represented by the formula o II —(CHg-C—NH—(CHg)" ^- group represented by the formula

- 152 045018 he —CH—fCH^

oh he

II I -s-sn ₂ -sn-sn _g -

G group represented by the formula o II -C-CH=CH-CHj- group represented by the formula o he

II I -c-cn ₂ -cn-cn _g is the group represented by the formula

CH3 -CH-C-NH-CHj- II o group represented by the formula o a -CH=CH-C-NH-(CH3) ₂ - dialkylaminoalkylcarbonyl group or lower alkoxycarbonyl group, provided that in the above definition X each of n independently represents an integer from 0 to 6,

R ² represents a substituted or unsubstituted phenyl group, a substituted or unsubstituted arylalkyl group, a cinnamyl group, a lower alkyl group, a pyridylmethyl group, a cycloalkylalkyl group, an adamantane methyl group or a furoylmethyl group, and the symbol ---- in the above general formula means a single bond or double bond.

As used herein, the term lower alkyl group used in the above definition of R ¹ , R ² , R ⁴ and R ⁵ in relation to the compound (I) of the present invention will mean a straight or branched alkyl group containing 1 to 6 carbon atoms, and examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl(amyl), isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl , hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 3,3dimethylbutyl, 1 -ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2trimethylpropyl, 1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl groups. Among them, methyl, ethyl, propyl, isopropyl groups, etc. are preferred. The methyl group is most preferred.

Examples of the substituent provided in the definition of R ¹ by the expression the following substituted or unsubstituted group: (1) phenyl group, (2) pyridyl group, (3) pyrazyl group, (4) quinolyl group, (5) indanyl group, (6) cyclohexyl group The (7) quinoxalyl group or (8) furyl group includes lower alkyl groups containing 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl groups; a lower alkoxy group corresponding to the lower alkyl groups described above, such as methoxy and ethoxy groups; nitro group; halogen atoms such as chlorine, bromine and fluorine; carboxyl group; lower alkoxycarbonyl groups corresponding to the lower alkoxy groups defined above, such as methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, npropoxycarbonyl and n-butyloxycarbonyl groups; amino group; a lower monoalkylamino group; lower dialkylamino group, carbamoyl group; acylamino groups derived from aliphatic saturated monocarboxylic acids containing 1-6 carbon atoms, such as acetylamino, propionylamino, butyrylamino, isobutyrylamino, valerylamino and pivaloylamino groups; cycloalkyloxycarbonyl groups such as a cyclohexyloxycarbonyl group; lower alkylaminocarbonyl groups such as methylaminocarbonyl and ethylaminocarbonyl groups; lower alkylcarbonyloxy groups corresponding to the lower alkyl groups defined above, such as methylcarbonyloxy, ethylcarbonyloxy and n-propylcarbonyloxy; halogenated lower alkyl groups containing a trifluoromethyl group; hydroxyl group; a formyl group and lower alkoxy (lower alkyl) groups such as ethoxymethyl, methoxymethyl and methoxyethyl groups. The terms lower alkyl groups and lower alkoxy groups in the above description of the substituent include all groups derived from the above groups. One to three substituents may be the same or different.

Additionally, if the substituent is a phenyl group, then the following group falls within the scope of the substituted phenyl group:

- 153 045018

in which G is the group represented by the formula o

I!

-C— group represented by the formula

group represented by the formula --O--, group represented by the formula o

II —CHj—NH—C— _f group represented by the formula --CH2--O--, group represented by the formula -CH2--SO2--, group represented by the formula -CH-

I is _a group represented by the formula _-CH -S-, and E represents a carbon or nitrogen atom.

Preferred examples of phenyl group substituents include, among others, lower alkyl, lower alkoxy, nitro, halogenated lower alkyl, lower alkoxycarbonyl, formyl, hydroxyl and lower alkoxy (lower alkyl), halogen atoms, and benzoyl and benzylsulfonyl groups. The two or more substituents may be the same or different.

Preferred examples of the pyridyl group substituent include lower alkyl and amino groups, as well as halogen atoms.

Preferable examples of the pyrazyl group substituent include lower alkoxycarbonyl, carboxyl, acylamino, carbamoyl and cycloalkyloxycarbonyl groups.

With respect to R ¹ , the pyridyl group is preferably a 2-pyridyl, 3-pyridyl or 4-pyridyl group; the pyrazyl group is preferably a 2-pyrazinyl group; the quinolyl group is preferably a 2-quinolyl or 3-quinolyl group; the quinoxalinyl group is preferably a 2-quinoxalinyl or 3-quinoxalinyl group; and the furyl group is preferably a 2-furyl group.

Specific examples of preferred monovalent or divalent group derived from indanone containing an unsubstituted or substituted phenyl ring include those represented by the following formulas (II) and (III):

in which each m is an integer from 1 to 4; and each of the A, which may be the same or different, represents the substituents described in paragraphs (1) to (8) of the definition of R ¹ above, or a hydrogen atom, preferably a hydrogen atom (i.e., is unsubstituted), a lower alkyl group or lower alkoxy group, and most preferably the indanone group is unsubstituted or substituted with 1-3 methoxy groups.

Examples of the monovalent group derived from the cyclic amide compound include quinazolone, tetrahydroisoquinolinone, tetrahydrobenzodiazepinone and hexahydrobenzazocinone. However, the monovalent group may be any group containing a cyclic amide group in its structural formula, and is not limited to the specific examples described above. A cyclic amide group is a group derived from a monocyclic or fused heterocyclic ring. The fused heterocyclic ring is preferably a ring formed by condensation with a phenyl ring. In this case, the phenyl ring may be replaced by a lower alkyl group containing 1 to 6 carbon atoms, preferably a methyl group, or a lower alkoxy group containing 1 to 6 carbon atoms, preferably a methoxy group.

Preferable examples of the monovalent group include the following groups:

- 154 045018

In the above formulas, each Y in formulas (i) and (l) represents a hydrogen atom or a lower alkyl group, V in formula (k) represents a hydrogen atom or a lower alkoxy group, each of W ¹ and W ² in formulas (m) and (n) represents a hydrogen atom, a lower alkyl group or a lower alkoxy group, and W ³ represents a hydrogen atom or a lower alkyl group.

The right-hand ring in each of formulas (j) and (l) is a seven-membered ring, while the right-hand ring in formula (k) is an eight-membered ring.

Some examples of R ¹ as defined above include a monovalent group derived from an indanone containing an unsubstituted or substituted phenyl group, and a monovalent group derived from a cyclic amide compound. Some examples of X as defined above include a group represented by the formula --(CH ₂ ) _n --, a group containing an amide group, and groups represented by the above formulas in which n is 2. Therefore, it is most preferred that any part of the group , represented by the formula ^{R x} ~' contains a carbonyl or amide group.

The substituents provided by the expressions substituted or unsubstituted phenyl group and substituted or unsubstituted arylalkyl group in the above definition of R ² are the same as those described in the above paragraphs (1) to (8) in the above definition of R ¹ .

As used herein, the term arylalkyl group is intended to mean an unsubstituted benzyl or phenethyl group and the like.

Specific examples of the pyridylmethyl group include 2-pyridylmethyl, 3-pyridylmethyl and 4-pyridylmethyl groups.

Preferred examples of R ² include benzyl and phenethyl groups. The designation indicates either a single or double bond. This bond is a double bond only if R ¹ is the above-described divalent group (III) derived from indanone containing an unsubstituted or substituted phenyl ring; whereas in other cases it represents a single bond. The compounds of the present invention may contain an asymmetric carbon atom depending on the type of substituent and, therefore, have stereoisomers. Stereoisomers certainly fall within the scope of the present invention.

One specific example will be described below. If R ¹ contains an indanone skeleton, then the compound of the present invention contains an asymmetric carbon atom and therefore may have stereoisomers, optical isomers, diastereoisomers and the like. All of these isomers fall within the scope of the present invention.

Method for treating CNS disorders with cognitive impairment by administering an SV2A and AChEI inhibitor or pharmaceutically acceptable salts thereof

In one aspect, the present invention provides methods and compositions for treating or improving cognitive function in a subject suffering from a central nervous system (CNS) disorder with cognitive impairment (e.g., age-related cognitive disorder, MCI, amnestic MCI, dementia, AD, prodromal AD, PTSD , schizophrenia, ALS and cancer treatment-related cognitive impairment) or at risk for the same, in a subject in need thereof by administering an SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof in combination with AChEI or a pharmaceutically acceptable salt, hydrate thereof, solvate or polymorph. In some embodiments, the SV2A inhibitor is selected from the group consisting of levetiracetam, brivaracetam, and seletracetam, or derivatives, analogs, pharmaceutically acceptable salts, solvates, hydrates, polymorphs, or prodrugs thereof. In other embodiments, the SV2A inhibitor is levetiracetam or a derivative, analog, pharmaceutically acceptable salt or solvate or hydrate or polymorph or prodrug thereof. In some embodiments, the AChEI is donepezil, tacrine, rivatigmine, physostigmine, galantamine, or metrifonate, or derivatives, analogs, pharmaceutically acceptable salts, solvates, hydrates, polymorphs, or prodrugs thereof. In other embodiments, AChEI is donepezil or a derivative, analog, pharmaceutically acceptable salt, solvate, hydrate, polymorph, or prodrug thereof. In some embodiments, the CNS disorder with cognitive impairment is an age-related cognitive disorder, such as mild cognitive impairment (MCI), age-related memory impairment (AAMI), age-related cognitive decline (ARCD). According to one embodiment of the present invention, the MCI is amnestic MCI. In some embodiments of the present invention, the CNS disorder with cognitive impairment is dementia, post-traumatic stress disorder (PTSD), schizophrenia, amyotrophic lateral sclerosis (ALS), or cancer treatment-related cognitive impairment. In one embodiment, the subject suffering from such a cognitive disorder is a human patient. The subject may be a human or another mammal, such as a non-human primate or a rodent (eg, a rat). In some embodiments, the subject is a human patient.

In clinical use, donepezil exhibits a cholinergic side effect profile and dosage administered to patients is limited by such side effects. Use of SV2A inhibitors and their pharmaceutically acceptable salts, hydrates, solvates and polymorphs in combination with donepezil or other AChEIs and their pharmaceutically acceptable salts, hydrates, solvates and polymorphs reduces the amount of donepezil or other AChEIs required for the treatment of CNS disorders with cognitive dysfunction or other mood disorders, including MCI, amnestic MCI, AAMI, ARCE, dementia, AD, PTSD, schizophrenia, amyotrophic lateral sclerosis (ALS) or cancer treatment-related cognitive impairment. In one embodiment, the subject suffering from such a cognitive disorder is a human patient and therefore reduces the side effects caused by donepezil or other AChEIs without compromising efficacy. In addition, the effectiveness of the combination of an SV2A inhibitor and donepezil or other AChEIs and their pharmaceutically acceptable salts, solvates, hydrates and polymorphs exceeds the effectiveness of each drug administered separately at its optimal dose, and therefore represents an improved treatment for CNS disorders with cognitive impairment.

It should be understood that the compounds and agents used in the compositions and methods of the present invention should preferably readily cross the blood-brain barrier when administered peripherally. Compounds that cannot cross the blood-brain barrier can nevertheless also be effectively administered directly to the central nervous system, for example, by the intraventricular or other neurocompatible route.

As used herein in relation to the administration of an SV2A inhibitor and AChEI or their pharmaceutically acceptable salts, hydrates, solvates and polymorphs, the term combination includes simultaneous administration and/or administration at different times, such as sequential administration. Co-administration of an SV2A inhibitor and AChEI or their pharmaceutically acceptable salts, hydrates, solvates and polymorphs may optionally be combined with additional doses of an SV2A inhibitor and/or AChEI and their salts, hydrates, solvates and polymorphs. Concomitant administration of drugs includes administration as a joint dosage form or, alternatively, as separate compositions.

According to the present invention, the SV2A and AChEI inhibitor and pharmaceutically acceptable salts, hydrates, solvates and polymorphs thereof can be administered to a subject by any suitable route or routes. In some embodiments, the drugs are administered orally; however, intravenous, subcutaneous, intraarterial, intramuscular, intraspinal, rectal, intrathoracic, intraperitoneal, intraventricular, transdermal, topical, or inhalation administration are also contemplated. The agents may be administered orally, for example, in the form of tablets, lozenges, capsules, elixirs, suspensions, syrups, wafers, and the like, prepared by methods known in the art. In some embodiments, the SV2A and AChEI inhibitor and pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof can be administered to a subject through various routes. For example, an SV2A inhibitor or a salt, solvate, hydrate or polymorph thereof is administered intravenously, and AChEI or a salt, solvate, hydrate or polymorph thereof is administered orally.

In some embodiments, the administration is a slow or sustained release. The term sustained release is widely known in the pharmaceutical sciences and is used herein to refer to the controlled release of an active compound or agent from a dosage form into the environment over an extended period of time, for example greater than or equal to one hour. A sustained release dosage form will release the drug at a substantially constant rate over a long period of time, or a substantially constant amount of drug will be released gradually over a long period of time. As used herein, the term sustained release includes the terms controlled release, extended release, sustained release, delayed release, or slow release as these terms are used in the pharmaceutical sciences. In some embodiments, sustained release doses are administered via a patch or pump dispenser.

If a solid carrier is used for administration, the preparation may take the form of a tablet, may be placed in a hard gelatin capsule in powder or granule form, or it may take the form of a lozenge or lozenge. If a liquid carrier is used, the preparation may take the form of a syrup, emulsion, soft gelatin capsule, or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.

Dosage regimens for the agents and compositions in accordance with the methods of the present invention will vary depending on the particular compound or compositions selected, the route of administration, the nature of the condition being treated, the age and health of the patient, the course or stage of treatment, and will ultimately be determined at the discretion of the attending physician. It should be understood that the administered amounts of the SV2A and AChEI inhibitor and their pharmaceutically acceptable salts, hydrates, solvates and polymorphs will be amounts effective to produce the desired biological effect, such as beneficial results, including clinical results (for example, an amount that increases GABA- ergic activity, reduces excitatory neurotransmission and blocks, suppresses or reduces acetylcholinesterase activity and/or amounts, which in combination lead to improved cognitive function). It should be understood that an effective amount may be administered in more than one dose and over the course of treatment.

The desired duration of administration of the SV2A inhibitor and AChEI and their pharmaceutically acceptable salts, hydrates, solvates and polymorphs can be determined by one skilled in the art through standard experimentation. For example, the SV2A and AChEI inhibitor and pharmaceutically acceptable salts, hydrates, solvates and polymorphs thereof can be administered for 1-4 weeks, 13 months, 3-6 months, 6-12 months, 1-2 years or more, throughout patient's life expectancy.

It is known in the art that normalization to body surface area is a suitable way to extrapolate doses between species. The Human Equivalent Dose (HED) for a dosage can be quantified using the following formula, which takes into account differences in body surface area (see Estimating the Safe Starting Dose in Clinical Trials for Therapeutics in Adult Healthy Volunteers, December 2002, Center for Biologies Evaluation and Research): HED = animal dose x (animal Km/human Km), in which the Km factor is body weight divided by body surface area (rat Km has been determined to be 6, and human Km is 37; see Reagan -Saw, Nihal, Ahmad, 2007). Thus, a dosage of 10 mg/kg in rats is equivalent to 1.6 mg/kg in humans (10 mg/kg x (6/37) = 1.6 mg/kg). For humans, to calculate the mg dose from the mg/kg dose, multiply the mg/kg dose by a standard adult weight of 70 kg.

In some embodiments of the present invention, an SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate, and polymorph thereof may be administered in dosages in accordance with, for example, US Patent Application 12/580464, International Patent Application PCT/US2009/005647, Application US Patent Application 61/105847, US Patent Application 61/152631 and US Patent Application 61/175536. In some embodiments of the present invention, the SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate, and polymorph thereof is administered every 12 or 24 hours at a daily dose of about 0.001 to 5 mg/kg. In some embodiments, the SV2A inhibitor, or a pharmaceutically acceptable salt, hydrate, solvate, and polymorph thereof, is administered every 12 or 24 hours at a daily dose of about 0.1 to 5 mg/kg, or about 1 to 2 mg/kg, or about 0.1 to 0.2 mg/kg, or about 0.01 to 2.5 mg/kg, or about 0.1 to 2.5 mg/kg, or about 0.4 to 2, 5 mg/kg, or about 0.6 to 1.8 mg/kg, or about 0.04 to 2.5 mg/kg, or about 0.06 to 1.8 mg/kg, or about 0.01 to 1 mg/kg, or about 0.001 to 1 mg/kg, or about 0.5 to 5 mg/kg, or about 0.05 to 0.5 mg/kg.

Repeated administration over several days or weeks or a longer period, depending on the circumstances, was continued until a sufficient level of cognitive function was achieved.

The SV2A inhibitor, or a pharmaceutically acceptable salt, hydrate, solvate, and polymorph thereof, may be administered at subtherapeutic dosages when provided in combination with an AChEI or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, due to the AChEI-dependent increase in the therapeutic index of the SV2A inhibitor. In some embodiments, due to combination with an AChEI, the therapeutic index of the SV2A inhibitor is at least about 1.5, or 2.0, or 2.5, or 3.0, or 3.5, or at 4.0, or at 4.5, or at 5.0, or at 5.5, or at 6.0, or at 6.5, or at 7.0, or at 7.5, or at 8 .0, or 8.5, or 9.0, or 9.5, or 10, or more than about 10 times the therapeutic index of the SV2A inhibitor administered without AChEI. In some embodiments, combinations of an SV2A inhibitor with an AChEI reduce the dosage of the SV2A inhibitor required for its therapeutic effect. In some embodiments, the amount of SV2A inhibitor administered in combination with the AChEI is a subtherapeutic amount. In some embodiments, the SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate, and polymorph thereof is administered every 12 or 24 hours at a daily dose of less than 5 mg/kg, less than 2.5 mg/kg, less than 2 mg/kg , less than 1.5 mg/kg, less than 1 mg/kg, less than 0.5 mg/kg, less than 0.1 mg/kg, less than 0.05 mg/kg, less than 0.01 mg /kg, less than 0.005 mg/kg or less than 0.001 mg/kg.

AChEI or its pharmaceutically acceptable salt, hydrate, solvate and polymorph can be administered in dosages within the range of conventional dosages. Appropriate dosages will depend on the specific AChEI chosen. AChEI may be administered up to twice daily, once daily, or it may be administered less frequently. For ARICEPT®, the standard daily dosage when administered individually is approximately 5 to 10 mg. In some embodiments of the present invention, the amount of ARICEPT® administered in combination with an SV2A inhibitor is from about 0.1 to 10 mg. In some embodiments, the amount of ARICEPT® administered in combination with the SV2A inhibitor is a subtherapeutic amount. According to some options

- 158 045018 implementation, the amount of ARICEPT® administered in combination with an SV2A inhibitor is less than 10 mg per day, less than 5 mg per day, less than 1 mg per day, less than 0.5 mg per day, or less than 0.1 mg per day.

AChEI or its salt, hydrate, solvate and polymorph can be administered in different dosages from conventional dosages, provided that it is administered in combination with an SV2A inhibitor, due to the SV2A inhibitor-dependent increase in the therapeutic index of AChEI. In some embodiments, due to combination with an SV2A inhibitor, a therapeutic AChEI index of at least about 1.5, or 2.0, or 2.5, or 3.0, or 3.5, or 4.0, or 4.5, or 5.0, or 5.5, or 6.0, or 6.5, or 7.0, or 7.5, or 8, 0, or 8.5, or 9.0, or 9.5, or 10, or more than about 10 times the therapeutic index of AChEI administered without the SV2A inhibitor. In some embodiments, combinations of AChEI with an SV2A inhibitor reduce the dosage of AChEI required for its therapeutic effect. In some embodiments, the amount of AChEI administered in combination with the SV2A inhibitor is from about 0.1 to 10 mg. In some embodiments, the amount of AChEI administered in combination with the SV2A inhibitor is a subtherapeutic amount. In some embodiments, the amount of AChEI administered in combination with the SV2A inhibitor is less than 10 mg per day, less than 5 mg per day, less than 1 mg per day, less than 0.5 mg per day, or less than 0 .1 mg per day.

The frequency of administration of the composition of the present invention may be adjusted during the course of treatment, based on the judgment of the attending physician. It should be understood that the SV2A and AChEI inhibitor and their salts, hydrates, solvates and polymorphs can be administered at different dosage frequencies or intervals. For example, the SV2A inhibitor may be administered daily (including multiple doses per day) or less frequently. AChEI may be administered daily (including multiple doses per day) or less frequently. In some embodiments, sustained release dosage forms may be desirable. Various dosage forms and devices for achieving sustained release are known in the art.

As described above, some AChEIs (such as donepezil) and their salts, hydrates, solvates and polymorphs may cause cholinergic side effects. The use of a combination of an SV2A inhibitor and an AChEI may reduce the amount of AChEI needed to treat CNS disorders with cognitive impairment and therefore may reduce the side effects caused by AChEI. In particular, combining an SV2A inhibitor with a reduced amount of AChEI may reduce cholinergic side effects without negatively impacting efficacy. Accordingly, in some embodiments, a subtherapeutic amount of AChEI is administered.

In some embodiments, an appropriate amount of an SV2A inhibitor is administered to reduce the dose of AChEI (e.g., the dose required to provide some degree of improvement in cognitive function or treatment of age-related cognitive impairment) by at least about 20%, by at least about 30% %, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or more, relative to the dose of AChEI typically used when administered alone (ie, alone and not in combination with other therapeutic agents or compounds). The reduction may be reflected in terms of the amount administered at a given administration and/or the amount administered over a period of time (reduced frequency).

In some embodiments of the present invention, coadministration of an SV2A inhibitor or a salt, hydrate, solvate and polymorph thereof and AChEI or a salt, hydrate, solvate and polymorph thereof in a subject can achieve at least about 1.5, or 2.0 , or 2.5, or 3.0, or 3.5, or 4.0, or 4.5, or 5.0, or 5.5, or 6.0, or 6.5, or 7.0, or 7.5, or 8.0, or 8.5, or 9.0, or 9.5, or 10, or more than approximately 10 times longer lasting or improved therapeutic effect than that obtained with AChEI alone or an SV2A inhibitor alone.

Compositions according to the present invention

In one aspect, the present invention provides compositions containing an SV2A and AChEI inhibitor and salts, hydrates, solvates and polymorphs thereof. In some embodiments, the SV2A inhibitor and AChEI may be present in a single dosage form (eg, combined together in a single capsule, tablet, powder or liquid, etc.). In some embodiments, the AChEI in the composition is donepezil. In some embodiments, the composition contains levetiracetam or seletracetam or brivaracetam, or a derivative or analog thereof, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph as an SV2A inhibitor, and contains donepezil or a derivative or analog thereof, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph. as AChEI. In some embodiments, the composition comprises levetiracetam or a derivative or analog thereof, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph, and donepezil or a derivative or analog thereof, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph. The composition described herein may contain more than one SV2A inhibitor and/or more than one AChEI. In some embodiments, the SV2A inhibitor and AChEI are co-packaged in separate dosage forms.

The composition described herein may also contain pharmaceutically acceptable excipient(s) and may contain other agents that serve to enhance and/or complement the effectiveness of the SV2A and/or AChEI inhibitor. The compositions may also contain additional agents known to be useful in the treatment of cognitive impairment.

The composition of the present invention may be in the form of a solid dosage form such as capsules, tablets, dragees, pills, lozenges, powders and granules. If necessary, they can be formulated with coatings, such as enteric coatings, or they can be formulated to provide controlled release of one or more active ingredients, such as sustained or sustained release, according to methods well known in the art. technology. In some embodiments, the composition is in a slow, controlled, or sustained release form. The term sustained release is widely known in the pharmaceutical sciences and is used herein to refer to the controlled release of an active compound or agent from a dosage form into the environment over an extended period of time, for example greater than or equal to one hour. A sustained release dosage form will release the drug at a substantially constant rate over a long period of time, or a substantially constant amount of drug will be gradually released over a long period of time. As used herein, the term sustained release includes the terms controlled release, extended release, sustained release, delayed release, or slow release as these terms are used in the pharmaceutical sciences. In some embodiments, the sustained release dose is administered via a patch or pump dispenser. The composition may also be in the form of liquid dosage forms, including solutions, emulsions, suspensions, syrups and elixirs.

The compositions may be specifically formulated for administration by any suitable route of administration described herein and known in the art. Compositions for parenteral administration contain sterile aqueous and non-aqueous injection solutions, dispersions, suspensions or emulsions, as well as sterile powders, to be reconstituted in sterile injection solutions or dispersions before use. Compositions for intraoral and oral delivery (including sublingual and buccal administration, eg, Danckwerts et al., and oral) include, but are not limited to, bioadhesive polymers, tablets, patches, liquids and semi-solid forms (see, eg, Smart et al.). Compositions for respiratory delivery (pulmonary and nasal delivery) include, but are not limited to, a variety of metered dose aerosol inhalers, dry powder inhalers, nebulizers, aqueous aerosol inhalers, drops, solutions, suspensions, sprays, powders, gels, ointments, and specialized systems such as liposomes and microspheres (see, for example, Owens et al., Alternative Routes of Insulin Delivery and Martini et al.). Compositions for transdermal delivery include, but are not limited to, colloidal systems, patches, and microemulsions. Other suitable forms of administration of the above or other compositions include injectable release dosage forms, suppositories, sprays, ointments, creams, gels, inhalations, skin patches, implants, etc.

The compositions may also contain adjuvants such as preservatives, humectants, emulsifiers and dispersants. Prevention of the action of microorganisms can be achieved by including various antibacterial and antifungal agents in the composition, for example, paraben, chlorobutanol, phenol sorbic acid, etc. It may also be desirable to include isotonic agents such as sugars, sodium chloride and the like in the compositions. In addition, prolonged absorption of the injectable pharmaceutical form can be achieved by including agents that delay absorption, such as aluminum monostearate and gelatin.

Therapeutic dosage forms can be prepared by methods well known in the field of pharmacy (see, for example, Goodman et al., 2001; Ansel, et al., 2004; Stoklosa et al., 2001; and Bustamante, et al., 1993) .

According to some embodiments of the present invention, a composition comprising an SV2A inhibitor and AChEI and their salts, hydrates, solvates and polymorphs contains an SV2A inhibitor in an amount of 0.07 to 350 mg, or 50 to 200 mg, or 3 to 50 mg. In some embodiments, the amount of SV2A inhibitor is less than 350 mg, less than 250 mg, less than 200 mg, less than 150 mg, less than 100 mg, less than 50 mg, less than 10 mg, less than 5 mg, less less than 1 mg, less than 0.5 mg, less than 0.1 mg or less than 0.07 mg. In some embodiments, the amount of AChEI in the composition is from about 0.1 to 10 mg. In some embodiments, the amount of AChEI in the composition is less than 10 mg, less than 5 mg,

- 160 045018 less than 2 mg, less than 1 mg, less than 0.5 mg or less than 0.1 mg.

One skilled in the art will understand that the compositions and methods described herein may be adapted and modified in accordance with the application in question, and that the compositions and methods described herein may be used in other suitable applications, and that such other additions and modifications will not go beyond the scope of the present invention.

The present invention will become more clear from the following Detailed Experimental Description section. However, one skilled in the art will readily understand that the specific methods and results discussed are merely illustrative of the present invention, which is more fully described in the embodiments that follow.

Examples

Introduction and models of cognitive disorders

A number of conditions characterized by cognitive impairment, such as age-related memory impairment (AAMI), mild cognitive impairment (MCI), and age-related cognitive decline (ARCD), are thought to be associated with aging. Others are associated with a disease, such as AD. Animal models serve as an important resource for developing and evaluating therapies for these age-related cognitive disorders. The characteristics that characterize age-related cognitive impairment in animal models generally extend to age-related cognitive impairment in humans. Thus, efficacy in such animal models will be predictive of efficacy in humans.

Among the available models, the Long-Evans rat model of cognitive impairment is particularly suitable for distinguishing between disease-related cognitive impairment and that associated with aging. Indeed, a natural form of cognitive impairment has been identified in extensive behavioral studies in aged Long-Evans outbred rats (Charles River Laboratories; Gallagher et al., Behav. Neurosci. 107:618626, (1993)). In the Morris water maze (MWM) behavioral test, rats learn and remember the location of an escape platform based on the configuration of spatial cues surrounding the maze. The cognitive basis of action is tested in probe trials using an assessment of the animals' spatial abilities when searching for the location of a rescue platform. Older rats in the study population do not have difficulty swimming to a visible platform, but age-related impairment is found if the platform is camouflaged, requiring the use of spatial information. The actions of individual older outbred Long-Evans rats vary considerably. For example, some rats perform actions on an equal footing with young adult rats. However, approximately 40-50% of rats act outside the range of actions of young adult rats. This variability among a population of aged rats reflects significant individual differences. Thus, within a population of aged rats, some animals have a cognitive impairment and are designated as having age-related disorders (AI), and other animals do not have the disorder and are designated as not having age-related disorders (AU) (see, for example, Colombo et al., Proc. Natl. Acad. Sci. 94: 14195-14199, (1997); Gallagher and Burwell, Neurobiol. Aging 10: 691-708, (1989); Rapp and Gallagher, Proc. Natl. Acad. Sci. 93: 99269930 , (1996); Nicolle et al., Neuroscience 74: 741-756, (1996); and Nicolle et al., J. Neurosci. 19: 9604-9610, (1999)).

Applicants used the rat model described above to identify individual AI and AU rats. Applicants then assessed the behavior of AI rats when administered various pharmacological therapies.

Example 1 Behavioral Assessment of Treatment with Levetiracetam, Donepezil, and Combination Treatment in the Radial Arm Maze Test

Aged male Long-Evans rats were obtained at 8–9 months of age from Charles River Laboratories (Raleigh, NC) and maintained in the animal facility until 24–26 months of age. All rats were housed individually at 25°C under a 12-h light/dark cycle. Unless otherwise specified, food and water were provided ad libitum. Rats were monitored for health and pathogen freedom throughout the experiment and were necropsied at sacrifice.

All rats were screened using a standardized assessment of spatial perception. The established MWM protocol described above was used for this baseline data assessment. To study the effects of drugs, elderly rats with manifestations of memory dysfunction were selected in a standardized assessment of spatial perception, that is, AI rats. Selected AI rats were tested for memory of novel spatial information in the radial arm maze (RAM) test under different drug/control conditions: vehicle control, donepezil alone, levetiracetam alone, and a combination of donepezil and levetiracetam. The RAM test also extended behavioral assessment to spatial memory using appetitive motivation. The applicants used a protocol that allows for intragroup assessment between drugs in different doses and combinations (Koh et al., Neuropsychopharmacology, epub. 1-10, (2009)).

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Radial Arm Maze Test

The radial maze consists of eight arms emanating from each side of an octagonal central platform, with a feeder located at the far end of each arm. Plexiglas™ blocks can be installed in any of the hoses to prevent entry. The room surrounding the maze provided landmarks outside the maze and provided overhead lighting. Pretraining, as detailed in Chappell et al. Neuropharmacology 37: 481–487 (1998), consisted of habituation, standard win-shift training, and win-shift training with delays between the information phase and the testing phase. Drug treatment began 2 days after completion of the preliminary training. At the beginning of each trial, three arms were blocked (information phase). The number and configuration of the blocked sleeves varied during testing. Food-deprived rats were allowed to find a food reward (Kellogg's Froot Loops™ cereal) in five unblocked arms. The rat was then removed from the maze for 60 min (memory retention time), during which time the barriers on the blocked arms were removed, allowing access to all eight arms. The rats were then placed back on the central platform and allowed to find the remaining food rewards (memory test phase).

The number of errors made by AI rats during the memory retention phase was monitored. The mistake consisted of returning to the sleeve (all four paws on the sleeve), in which food had already been found. For example, a trial error occurs if rats enter an arm in which food has already been found during the pre-delay phase of the trial, or if rats re-enter an arm that has already been visited during the post-delay phase.

Treatment with levetiracetam

An independent group of rats (n=10) were first tested with levetiracetam (Tecoland, Edison, NJ). 30-40 minutes before the daily AI test, rats were pretreated with a single intraperitoneal (i.p.) injection of one of the following six treatments: 1) vehicle control (0.9% saline); 2) levetiracetam (1.25 mg/kg/day); 3) levetiracetam (2.5 mg/kg/day); 4) levetiracetam (5 mg/kg/day); 5) levetiracetam (10 mg/kg/day); 6) levetiracetam (20 mg/kg/day). Injections were performed every other day, alternating with withdrawal days. To counterbalance any potential bias, drug effect was assessed using ascending-descending dose series, i.e. series of doses were administered first in ascending order and then repeated in descending order. Therefore, there are two measurements for each dose.

Parametric statistics (paired t-tests) were used to compare the results of the AI rats' memory retention test in the one-hour RAM version of the test under varying doses of levetiracetam and the vehicle control (see Fig. 1). The mean number of errors in trials was significantly lower when treated with levetiracetam at a dose of 5 mg/kg/day (mean number of errors ± standard error of the mean (SEM) = 0.75 ± 0.32) and at a dose of 10 mg/kg/day (mean number of errors ± SEM = 0.80 ± 0.27) than when using control with the introduction of medium (average number of errors ± SEM = 2.00 ± 0.42). Relative to the control with the introduction of the medium, levetiracetam significantly improves memory performance at doses of 5 mg/kg/day (t(9)=2.18, p=0.057) and 10 mg/kg/day (t(9)=2.37, p =0.042).

Treatment with donepezil

After completion of the levetiracetam evaluation, a new group of AI rats (n=8) were tested with donepezil. 30-40 minutes before the daily AI test, rats were pretreated with a single intraperitoneal (i.p.) injection of one of the following three options: 1) control medium (0.9% saline); 2) donepezil (1 mg/kg/day); 3) donepezil (2 mg/kg/day). Injections were performed every day. To counterbalance any potential bias, drug effect was assessed using a series of ascending descending doses, i.e. series of doses were administered first in ascending order and then repeated in descending order. Therefore, there are two measurements for each dose.

Parametric statistics (paired t-tests) were used to compare the results of the AI rats' memory retention test in the two-hour RAM version of the test at different doses of donepezil and the vehicle control (see Fig. 2). The mean number of errors across trials was not significantly different between donepezil 1 mg/kg/day (mean ± standard error of the mean (SEM)=2.88±0.46) and 2 mg/kg/day donepezil ( mean number of errors ± SEM = 2.81 ± 0.43) than when using the control with the introduction of medium (mean number of errors ± SEM = 2.88 ± 0.67). Compared to the control medium, donepezil did not lead to a significant improvement in memory performance at doses of 1 mg/kg/day (t(7)=0, p=1.00) or 2 mg/kg/day (t(7)=0, 91, p=0.930).

Combination of levetiracetam and donepezil

Applicants used the same AI rats (n=8) to test the memory-enhancing effects of the combination of levetiracetam and donepezil when administered at subtherapeutic doses. In this experiment, the subtherapeutic doses were 2.5 mg/kg/day levetiracetam and 1 mg/kg/day donepezil. As described above, when levetiracetam is administered at a dose of 2.5 mg/kg/day alone without donepezil, it does not significantly improve memory performance in AI rats (see Fig. 1). If donepezil is administered at a dose of 1 mg/kg/day alone without levetiracetam, this does not lead to a significant improvement in memory performance in AI rats (see Fig. 2).

30-40 minutes before the daily AI test, rats were pretreated with a single intraperitoneal (i.p.) injection of one of the following two options: 1) medium control (0.9% saline); 2) donepezil (1 mg/kg/day) and levetiracetam (2.5 mg/kg/day). Injections were performed every day. To counterbalance any potential bias, drug effect was assessed using a series of ascending descending doses, i.e. series of doses were administered first in ascending order and then repeated in descending order. Therefore, there are two measurements for each dose.

Parametric statistics (paired t-tests) were used to compare the results of the AI rats' memory retention test in the two-hour RAM version of the levetiracetam-donepezil combination and the vehicle control (see Fig. 2). The mean number of errors per trial was significantly lower when donepezil (1 mg/kg/day) and levetiracetam (2.5 mg/kg/day) were coadministered (mean number of errors ± standard error of the mean (SEM) = 1.69 ± 0. 53) than when using the medium control (mean number of errors ± SEM = 2.88 ± 0.67). Relative to the vehicle control, the combination of donepezil (1 mg/kg/day) and levetiracetam (2.5 mg/kg/day) significantly improved memory performance (t(7)=2.16, p=0.034).

When administered at subtherapeutic doses such as those tested in this experiment, without another drug, neither donepezil nor levetiracetam significantly improved memory performance in AI rats (see Figs. 1 and 2). However, the combination of donepezil and levetiracetam significantly improved memory performance in AI rats. These results indicate that a superadditive or synergistic interaction exists between donepezil and levetiracetam when administered together.

Example 2 Treatment of humans with levetiracetam

An 8-week intragroup trial was conducted in 17 subjects with amnestic MCI (aMCI) and 17 age-matched control subjects, treated with low-dose levetiracetam. During the course of the study, each subject with aMCI receives both drug and placebo separately for two periods of two weeks each, with the order of treatment counterbalanced across different subjects with aMCI (see Fig. 3). Age-matched placebo-treated control subjects serve as additional controls. After each two-week drug/placebo treatment period, cognitive testing data and fMRI imaging data are obtained from subjects.

Participants and clinical description

For the study, 17 right-handed patients with aMCI were recruited from the Alzheimer's Disease Research Center (ADRC) at Johns Hopkins Hospital and other referring institutions. Additionally, 17 right-handed healthy control volunteers were recruited from the ADRC and other referring organizations. All participants completed a telephone interview to assess cognitive status to determine whether they met study inclusion criteria (including criteria for MRI scanning). All participants additionally undergo neurological, psychiatric and neuropsychological examination using standardized instruments and methods. Psychiatric evaluation includes the Structured Clinical Interview for DSM-IV Axis I Disorders and the Clinical Dementia Rating (CDR) test. All patients with aMCI had a CDR of 0.5. Diagnosis of aMCI is based on criteria proposed by Petersen et al. (e.g., Mild cognitive impairment: Aging to Alzheimer's Disease, Oxford University Press, N.Y. (2003)), which include memory complaints (confirmed by the informant), impaired memory function on testing (1.5 standard deviations below normal), preserved in otherwise cognitive performance (within 1 standard deviation of normal), no functional decline, and no dementia. The final diagnosis of aMCI is made by clinical consensus. Exclusion criteria include severe neurological or psychiatric disorders, head trauma with loss of consciousness, previous drug abuse or dependence, and general contraindications to MRI examination (eg, cardiac pacemaker, aneurysm coil, claustrophobia). Each subject with aMCI is required to have a study partner (i.e., informant) who can provide information about the subject's daily activities and ensure proper medication administration (see FIGS. 14A and 14B).

Scheduled Visits: The study consists of 4 visits over 8 weeks (see Figure 3). The baseline visit serves to conduct a medical, neurological, psychiatric, and neurocognitive assessment. Visits 1 and 2 are identical to the baseline visit but include an fMRI procedure. The washout visit at the end of the 4-week washout period serves to conduct a brief clinical assessment and begin the second drug/placebo phase.

Baseline visit: At the screening visit, informed consent is obtained from the subject (and informant in the case of subjects with aMCI). The subject and the informant participate in a standardized

- 163 045018 clinical interview, which is used to determine the degree of functional impairment of the subject in daily life, based on the Clinical Dementia Rating (CDR) scale. A medical, neurological, and psychiatric history (including a review of current medications) and a family history of dementia are obtained. Conduct a brief medical, neurological, and psychiatric examination of the subject (including vital signs). Blood is collected to perform standard laboratory tests necessary to determine whether the subject meets the study inclusion criteria. The subject is re-screened for contraindications to MRI scanning using the standard form used at the Kirby Imaging Center. A brief cognitive test (described below in the section on neuropsychological assessment) is administered. Survey data is used to determine whether a subject meets study inclusion criteria. All of the above is completed using standardized forms. If the subject meets the study inclusion criteria, the subject is prescribed the test drug (drug or placebo, randomly selected) and given instructions for taking it. The subject is counseled about possible suicidal ideation and is advised, if this occurs, to stop taking the medication and immediately contact the study physician.

Visit 1: 2 weeks after the baseline visit, at the end of the first drug/placebo period, the medical, neurological, and psychiatric examination and cognitive test are repeated. The subject is also clinically assessed for suicidal ideation. Re-draw blood to repeat standard tests and determine if any drug-related changes are present; the level of levetiracetam in the subject's blood is also determined. All medications dispensed at the baseline visit (drug or placebo) are collected and subject compliance with the medication regimen is assessed. On the same day, either before or immediately after the clinical examination, the first fMRI procedure (with cognitive tests) is performed. Subjects discontinue the first period of treatment at this visit.

Withdrawal Visit: At the end of the washout period (4 weeks) following Visit 1, the subject undergoes a brief clinical evaluation, including a medical and psychiatric evaluation. Blood is drawn to measure the level of levetiracetam in the blood (to confirm elimination). The subject is given a new drug (drug or placebo changed from what was dispensed in the previous treatment period) for the final phase of the study with instructions on how to take it.

Visit 2: Approximately 2 weeks after the withdrawal visit (that is, 2 weeks after the start of the second treatment period), the medical, neurological and psychiatric examination and cognitive test are repeated. The subject is clinically assessed for suicidal ideation. Re-draw blood to repeat standard tests and determine if any drug-related changes are present; the level of levetiracetam in the subject's blood is also determined. All medications dispensed at the baseline visit (drug or placebo) are collected and subject compliance with the medication regimen is assessed. On the same day, either before or immediately after the clinical examination, a second fMRI procedure (with cognitive tests) is performed.

Neuropsychological assessment

All participants undergo neuropsychological assessments during the treatment assessment (Visits 1 and 2) as well as at the baseline visit. Assessment occurs outside the scanner and includes the Buschke Selective Memory Test (Buschke and Fuld, 1974) and the Verbal Paired Associations subtest, the Logical Memory subtest, and the Wechsler Memory Scale-Revised (WMS-R) Visual Reproduction subtest (Wechsler, 1997). and the Benton Visual Retention Test, as these tests are particularly sensitive to medial temporal lobe function and early memory problems (Marquis et al., 2002 and Masur et al., 1994). In addition, subjects are asked to complete tests of more general cognitive function, such as tests to assess general mental status, executive function, attention, and general naming ability. All neuropsychological tests are administered by a trained research assistant during a 60-minute session. Because three neuropsychological assessments occur over an 8-week period in this study, different versions of the neuropsychological tests were used to minimize test-specific training effects. Patients are given breaks if necessary.

Administration of drugs

As described above, the drug treatment period is the 2 weeks preceding Visit 1 or 2 (with a 2-week period preceding the other visit being the placebo phase). For subjects receiving drug treatment, use half a scored levetiracetam tablet (250 mg) twice daily to achieve a dose of 125 mg/kg, which is approximately 3.6 mg/kg/day (assuming an average person weight of 70 kg).

All drug and placebo preparations are carried out with a 1/1 ratio. The pharmacy randomizes patients as they sign up and keeps a list of drug prescriptions.

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Levetiracetam is rapidly and almost completely absorbed after oral administration and its bioavailability is not affected by food. The plasma half-life is approximately 7±1 hours (estimated to be 9-10 hours in the elderly due to reduced renal function).

Absorption is rapid, with peak plasma levels 1 hour after oral administration. Equilibrium levels can be achieved after 2 days of repeated dosing twice a day.

The typical starting dose of levetiracetam for the treatment of epilepsy in humans is 500 mg twice daily, which is approximately 14.3 mg/kg/day. Then, the dosage is increased to optimal effectiveness, up to 50 mg/kg/day inclusive. Thus, the dose used in the present experiment is one quarter of the lowest dose used in the treatment of epilepsy in humans.

Based on previous animal studies showing the effectiveness of low doses, even lower dosages are suggested, such as 25-60 mg twice daily. The highest effective doses of levetiracetam used in animal models were 5-10 mg/kg (acute administration). The human equivalent dose (HED) calculated as described above for the indicated dose for the treatment of age-related cognitive impairment in humans is equivalent to 0.8-1.6 mg/kg/day (or 28-56 mg twice daily).

MRI Data Acquisition

Imaging data is obtained using high-resolution methods developed by the Stark laboratory. Data are acquired on a Phillips 3 Tesla scanner (Eindhoven, The Netherlands) equipped with an 8-channel SENSE (sensitivity programming) head coil located in the F.M. Kirby Research Center for Functional Brain Imaging at the Kennedy Krieger Institute (Baltimore, MD). High-resolution echo-planar images are acquired using a 64x64 acquisition matrix, 1500 ms repetition time, 30 ms echo time, 70° vector flip angle, SENSE factor of 2, and 1.5 mm x 1.5 mm x isotropic resolution 1.5 m without gap. Nineteen oblique slices were obtained parallel to the main longitudinal axis of the hippocampus, covering the entire medial temporal lobe bilaterally. In addition to the functional runs, a structural MPRAGE image of the whole brain is acquired (parameters: 150 oblique slices, 1 mm isotropic resolution).

Image Analysis

Data analysis was performed using Analysis for Functional Neuroimages software (AFNI, release 2008_07_18_1710). The images are first recorded together to correct for head movement along and across the image. Data that exhibit significant motion (more than 3° of rotation or 2 mm of shift in any direction relative to previous data), plus or minus one repetition time within 1.5 s, are excluded from analysis. Structural anatomical data are recorded in standard stereotactic coordinates (Talairach & Tournoux, 1988) and the same parameters are subsequently applied to functional data. To model various types of research, behavioral vectors are obtained.

ROI-LDDMM (Large Deformation Diffeomorphic Metric Mapping), a multi-target targeting technique, increases the power of fMRI studies of brain regions in many subjects by focusing targeting ability directly on ROIs (regions of interest) rather than on some other brain region . First, all anatomical and functional images are normalized to the Talairach atlas using AFNI. Subregions of the medial temporal lobe and hippocampus (bilateral entorhinal cortex, perirhinal cortex, parahippocampal cortex, CA3/dentate area, CA 1 and support structure) are segmented in three dimensions in MPRAGE images. Markers to the CA3 region and the dentate gyrus (DG) are combined. The anatomically defined regions of interest are then used to calculate a 3D vector field transform ROI-LDDMM for each patient using a customized template based on the average of the entire sample tested as the target. Then, the ROI-LDDMM transformations for each patient's study area are plotted on the approximation coefficient maps.

Group data were analyzed using two-way analysis of variance (ANOVA) with study type and group as fixed factors and patient as a random factor nested within group. To define functional regions of interest, a wide peak threshold of p < 0.05 is used for all F statistics, as is a spatial extent threshold of 10 voxels. This approach, as opposed to using direct pairwise contrast, reduces the bias in voxel selection because any differences among the different conditions allow voxel selection. This threshold is then combined with the results of anatomical segmentation to include only voxels within the regions of interest. This serves to eliminate voxels that do not change with any of the model factors, effectively limiting the analysis to voxels that show any change with test or group conditions. Voxels within each functional region of interest are compressed for further analysis.

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Cognitive tests during fMRI scanning during visits 1 and 2

Activity in the subject's medial temporal lobe is measured using functional MRI while the subject participates in a three-alternative forced choice test, where participants view novel, repeated, and similar (lure) stimuli. Psychophysics Toolbox extensions in Matlab 7.0 (The MathWorks, Natick, MA) are used to present the stimulus and collect behavioral information. The stimuli are color photographs of common objects. During the functional imaging procedure, each participant undergoes a series of test trials, with each trial consisting of a mixture of three types of image pairs: similar pairs, identical pairs, and unrelated opposites. These image pairs are completely randomized throughout the trial and are presented individually as a series of images (see Fig. 6A). Participants are instructed to decide whether the seen object is new, old, or similar. Particularly important are participants' responses when presented with the second of a pair of similar objects (lures; see Fig. 6B). The subject's correct identification of lure stimuli as similar provides behavioral evidence of image separation, i.e. division of similar impressions into separate non-overlapping representations. However, misidentification of lure stimuli as old or new indicates a failure of pattern separation. Identification of lure stimuli as old indicates that the patient is focused on the similarities between the lure stimulus and the previously shown paired image. Identification of decoy stimuli as new indicates that the patient is generally unable to remember the previously shown paired image. Each trial also contains several baseline trials that use a complex perceptual discrimination test, which is known to provide a lower and more robust estimate of baseline activity in the medial temporal lobe (Stark & Squire, 2001 PNAS; Law et al., 2005).

An fMRI study of the activity levels of various subregions in the medial temporal lobe during a cognitive test shows that aMCI patients have hyperactive DG/CA3 and hypoactive entorhinal cortices when performing memory tests compared to age-matched controls.

The applicants assessed the level of activity in DG/CA3 during successful memory decision making in controls and patients with aMCI. Average activity is calculated from the average activity measured by fMRI during the presentation of lure stimuli correctly identified by the subject as similar, which is calibrated relative to baseline activity. From fig. Figure 4A shows that subjects with aMCI exhibit DG/CA3 hyperactivity when making these decisions (p=0.013). At the same time, in FIG. Figure 4B shows that levetiracetam treatment reduces DG/CA3 hyperactivity in subjects with aMCI (p=0.037). The activity level of the drug-treated aMCI subject is effectively normalized to the extent that it is statistically indistinguishable from the activity of placebo-treated control subjects (for the mean activity values presented in Figures 4A and 4B, (see Figure 4C ).

The level of EC activity during memory successful decision making was significantly lower in aMCI subjects treated with placebo compared to controls (p=0.003, see Fig. 5A). However, levetiracetam treatment also normalizes EC activity in subjects with aMCI. Levetiracetam treatment increases EC activity during decision memory in subjects with aMCI to such an extent that it is statistically indistinguishable from the activity of placebo-treated control subjects (for the mean activity values presented in Figs. 5A and 5B, see Figs. 5C).

The normalization of DG/CA3 and EC activity in decision memory by levetiracetam treatment is reflected in the change observed in cognitive test scores in subjects with aMCI. In the placebo treatment, aMCI patients performed worse on the tasks than control subjects, being less likely to correctly identify lure stimuli as similar and more likely to incorrectly identify them as old (p=0.009, see Fig. 7). However, task performance of subjects with aMCI significantly improved when treated with levetiracetam (see Fig. 8). The combination of more correct definitions of similar with fewer incorrect definitions of old during drug treatment leads to a significant improvement in the results of this memory test (p = 0.039, see Fig. 9 for the table of data presented in Figs. 7 and 8).

The performance of subjects in placebo controls and subjects with aMCI with drug or placebo treatment was also compared with other established cognitive tests, such as the Buschke Selective Memory Test - Delayed Recall (Figs. 10A and 10B), Benton Visual Retention Test (Figs. 11A and 11B), Verbal Paired Association Test - Recognition (FIGS. 12A and 12B) and Verbal Paired Association Test - Delayed Recall (FIGS. 13A and 13B). In all of these tests, placebo-treated aMCI subjects performed worse than placebo-treated control subjects, and levetiracetam treatment failed to improve performance in aMCI subjects.

There are a number of possible reasons why levetiracetam treatment did not help subjects with aMCI on these cognitive tests. The forced three-alternative choice test performed in fMRI studies is a test that is particularly sensitive to DG/CA3 function. In this capacity, subjects' performance of this test may be particularly

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Claims (30)

This is particularly consistent with changes in DG/CA3 activity resulting from levetiracetam treatment. In addition, subjects with aMCI were treated with levetiracetam for only two weeks before cognitive testing. It is expected that treatment durations greater than two weeks, such as 16 weeks or 8 months, will increase the effectiveness of drug treatment. In conclusion, comparative animal studies (see Example 1) indicate that even a lower dose would be more effective. The human dosage of 125 mg twice daily is equivalent to the rat dosage of 22.3 mg/kg/day. As shown in Example 1 and FIG. 1, the dose of 20 mg/kg levetiracetam is too high for rats, and is unable to improve the AI performance of rats in the radial maze test. Effective doses of levetiracetam used in animal models are 510 mg/kg. The human dose (HED) equivalent to the optimal dose for rats is 0.8-1.6 mg/kg/day. This dose would result in administration of 28–56 mg twice daily (which is substantially lower than the 125 mg twice daily dose used in the present study). Thus, it is expected that subjects with aMCI will experience additional normalization of DG/CA3 and EC activity, as well as additional improvement in cognitive test scores, if they are treated with lower doses equivalent to effective doses in rats, e.g. 60 mg levetiracetam twice daily. CLAIM 1. A method of treating a cognitive disorder associated with a disorder of the central nervous system (CNS) in a subject, comprising administering brivaracetam or a pharmaceutically acceptable salt, hydrate or solvate thereof and donepezil, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in doses that are subtherapeutic compared to the doses at which the compounds are therapeutically effective when administered individually. 2. The method according to claim 1, wherein said brivaracetam or a pharmaceutically acceptable salt, hydrate or solvate thereof is administered every 12 or 24 hours at a daily dose of 0.001 to 5 mg/kg. 3. The method according to claim 2, wherein said brivaracetam or a pharmaceutically acceptable salt, hydrate or solvate thereof is administered every 12 or 24 hours at a daily dose of 0.5 to 5 mg/kg. 4. The method according to claim 2, wherein said brivaracetam or a pharmaceutically acceptable salt, hydrate or solvate thereof is administered every 12 or 24 hours at a daily dose of 0.05 to 0.5 mg/kg. 5. The method according to claim 1, wherein said donepezil or a pharmaceutically acceptable salt, hydrate or solvate thereof is administered in a daily dose of 0.1 to 10 mg. 6. The method according to claim 1, wherein said brivaracetam or a pharmaceutically acceptable salt, hydrate or solvate thereof and donepezil are administered simultaneously. 7. The method of claim 6, wherein said brivaracetam or a pharmaceutically acceptable salt, hydrate or solvate thereof and said donepezil are administered in a single dosage form. 8. The method according to claim 1, wherein said brivaracetam or a pharmaceutically acceptable salt, hydrate or solvate thereof and donepezil are administered sequentially. 9. The method according to claim 6 or 8, wherein brivaracetam or a pharmaceutically acceptable salt, hydrate or solvate thereof and said donepezil or a pharmaceutically acceptable salt, hydrate or solvate thereof are administered in separate dosage forms. 10. The method according to claim 1, wherein said donepezil or a pharmaceutically acceptable salt, hydrate or solvate thereof is administered in a daily dose of less than 10 mg, less than 5 mg, less than 2 mg, less than 1 mg, less than 0 .5 mg or less than 0.1 mg. 11. The method according to claim 1, wherein said brivaracetam or a pharmaceutically acceptable salt, hydrate or solvate thereof is administered every 12 or 24 hours at a daily dose of less than 350 mg, less than 250 mg, less than 200 mg, less than 150 mg, less than 100 mg, less than 50 mg, less than 10 mg, less than 5 mg, less than 1 mg, less than 0.5 mg, less than 0.1 mg or less than 0.07 mg. 12. A method of increasing the therapeutic index of donepezil or a pharmaceutically acceptable salt, hydrate or solvate thereof in a method of treating cognitive impairment associated with a disorder of the central nervous system (CNS) in a subject in need thereof or at risk of a disease, comprising administering to said subject brivaracetam or a pharmaceutical thereof an acceptable salt, hydrate or solvate in combination with said donepezil or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the increase in the therapeutic index of said donepezil or a pharmaceutically acceptable salt, hydrate or solvate thereof is at least about 1.5, or 2, 0, or 2.5, or 3.0, or 3.5, or 4.0, or 4.5, or 5.0, or 5.5, or 6.0, or 6.5, or 7.0, or 7.5, or 8.0, or 8.5, or 9.0, or 9.5, or 10, or more than approximately 10 times the therapeutic index of donepezil or its pharmaceutically acceptable salt, hydrate or solvate when administered without brivaracetam or its pharmaceutically acceptable salt, hydrate or solvate; and wherein said brivaracetam or a pharmaceutically acceptable salt, hydrate or - 167 045018 solvate is administered every 12 or 24 hours in a daily dose of less than 350 mg, less than 250 mg, less than 200 mg, less than 150 mg, less than 100 mg, less than 50 mg, less than 10 mg, less than 5 mg, less than 1 mg, less than 0.5 mg, less than 0.1 mg or less than 0.07 mg. 13. A method of increasing the therapeutic index of brivaracetam or a pharmaceutically acceptable salt, hydrate or solvate thereof in a method of treating cognitive impairment associated with a disorder of the central nervous system (CNS) in a subject in need thereof or at risk of a disease, comprising administering to said subject brivaracetam or a pharmaceutically formulated compound thereof. an acceptable salt, hydrate or solvate in combination with donepezil or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the increase in the therapeutic index of brivaracetam or a pharmaceutically acceptable salt, hydrate or solvate thereof is at least about 1.5, or 2.0, or 2.5, or 3.0, or 3.5, or 4.0, or 4.5, or 5.0, or 5.5, or 6.0, or 6.5, or 7.0, or 7.5, or 8.0, or 8.5, or 9.0, or 9.5, or 10, or more than about 10 times the therapeutic index of brivaracetam or a pharmaceutically acceptable salt, hydrate or solvate thereof when administered without donepezil or a pharmaceutically acceptable salt, hydrate or solvate thereof; and wherein said donepezil or a pharmaceutically acceptable salt, hydrate or solvate thereof is administered in a daily dose of less than 10 mg, less than 5 mg, less than 2 mg, less than 1 mg, less than 0.5 mg or less than 0 .1 mg. 14. The method according to any one of claims 1, 12 and 13, wherein the cognitive impairment is an age-related cognitive impairment. 15. The method according to any one of claims 1, 12 and 13, wherein the cognitive impairment is associated with mild cognitive impairment. 16. The method according to any one of claims 1, 12 and 13, wherein the cognitive impairment is associated with amnestic mild cognitive impairment. 17. The method according to any one of claims 1, 12 and 13, wherein the cognitive impairment is associated with dementia. 18. The method according to claim 17, wherein the dementia is Alzheimer's disease. 19. Method according to any one of claims 1, 12 and 13, wherein the cognitive disorder is associated with schizophrenia. 20. The method according to any one of claims 1, 12 and 13, wherein the cognitive impairment is associated with amyotrophic lateral sclerosis. 21. The method according to any one of claims 1, 12 and 13, wherein the cognitive impairment is associated with post-traumatic stress disorder. 22. The method according to any one of claims 1, 12 and 13, wherein the cognitive impairment is associated with cancer therapy-related cognitive impairment. 23. The use of a pharmaceutical composition intended for carrying out a method of treating cognitive impairment associated with a disorder of the central nervous system (CNS) in a subject, containing brivaracetam and donepezil or their pharmaceutically acceptable salts, hydrates or solvates, where the composition contains brivaracetam and donepezil in doses that are subtherapeutic compared to the doses at which the compounds are therapeutically effective when administered alone. 24. Use according to claim 23, wherein the composition is in solid form, liquid form, suspension form, sustained release form, delayed release form or sustained release form. 25. Use according to claim 23, wherein said brivaracetam or a pharmaceutically acceptable salt, hydrate or solvate thereof is contained in the composition in an amount of 0.07-350 mg. 26. Use according to claim 25, wherein said brivaracetam or a pharmaceutically acceptable salt, hydrate or solvate thereof is contained in the composition in an amount of 50-250 mg. 27. Use according to claim 25, wherein said brivaracetam or a pharmaceutically acceptable salt, hydrate or solvate thereof is contained in the composition in an amount of 3-50 mg. 28. Use according to claim 23, where said brivaracetam or a pharmaceutically acceptable salt, hydrate or solvate thereof is contained in an amount of less than 350 mg, less than 250 mg, less than 200 mg, less than 150 mg, less than 100 mg, less than 50 mg, less than 10 mg, less than 5 mg, less than 1 mg, less than 0.5 mg, less than 0.1 mg or less than 0.07 mg. 29. Use according to claim 23, wherein said donepezil or a pharmaceutically acceptable salt, hydrate or solvate thereof is contained in the composition in an amount ranging from 0.1 to 10 mg. 30. Use according to claim 23, wherein said donepezil or a pharmaceutically acceptable salt, hydrate or solvate thereof is contained in an amount of less than 10 mg, less than 5 mg, less than 2 mg, less than 1 mg or less than 0.5 mg. - 168 -