MXPA00010169A - 4-benzyl piperidine alkylsulfoxide heterocycles and their use as subtype-selective nmda receptor antagonists - Google Patents

Abstract

Novel 4-Benzyl piperidine alkylsulfoxide heterocycles are disclosed and their use as subtype selective NMDA receptor antagonists, particularly for the treatment of Parkinson's disease, most preferably in combination with L-DOPA.

Description

HETEROCICLES 4-BENCIL PIPERIDINE ALKYLSULFXIDE AND ITS USE AS RECEPTOR ANTAGONISTS OF THE NMDA SELECTIVE SUBTHYPE BACKGROUND OF THE INVENTION Field of the Invention This invention relates to heterocycles 4-benzyl piperidine alkyl sulfoxide. The compounds of this invention are selectively active as antagonists of the N-methyl-D-aspartate (NMDA) receptor subtypes. The invention is also directed to the use of 4-benzyl piperidine alkyl sulfoxide heterocycles as neuroprotective agents to treat conditions such as shock, cerebral ischemia, central nervous system trauma, macular and other degenerative diseases of the retina, hypoglycemia, anxiety, psychosis , asthma, glaucoma, CMV retinitis, urinary incontinence, tinnitus, hearing loss induced by aminoglycoside antibiotics, seizures, migraine, chronic pain, depression, tolerance to opioids or neurodegenerative diseases such as lathyrism, Alzheimer's disease, Parkinson's disease and Parkinson's disease. Huntington. A particularly preferred use of the compositions of this invention is in the treatment of Parkinson's Disease.

The 4-benzyl piperidine analogues that are useful as receptor antagonists of the NMDA selective subtype are described in PCT International Publication No. WO 97/23216. However, piperidine analogues that have sulfoxide functionality are not described.

The benzylpiperidine derivatives are also described in the U.S. Patent. Do not. ,698, 553, which has the formula: in which R1 is H, Hal or nitro, R2 is a benzyl group, which is unsubstituted or substituted by Hal in the aromatic portion, in the 2-, 3- or 4- position of the piperidine ring, with the proviso that R2? 4-benzyl, that is, R2 is not in the 4 position of the piperidine ring, if X is -CO-, Y and Z are -CH2 and R1 is H, R3 is H or A, X is -O-, -S -, -NH-, -CO- or -SO2-, Y is -CH2-, -O-, -S-, -NH- or alternatively -CO- if X is -CO- and Z is -NH- or - NA-, Z is -CHr, -C (A) 2-, -CH2CH2-, -CH = CH-, -CO-, -NH-, -NA-, -O-, -S- or a bond, in where XY or YZ is not -OO-, -SS-, -NH-O-, -O-NH-, -NH-NH-, -OS- or -SO-, A is alkyl having 1-6 atoms of C, B is O or both H and OH, that is, OH I -CH- together with the carbon atom to which B is bonded, Hal is F, Cl, Br olyn is 0, 1 or 2 and its salts.

The compounds are said to be useful for the treatment of cardiovascular diseases, epilepsy, schizophrenia, Alzheimer's disease, Parkinson's disease or Huntington's disease, heart attacks or cerebral ischaemia. However, the selectivity of the subtype is not indicated and, again, the piperidine analogues having sulfoxide functionality are not followed or described.

Antagonist receptor antagonists of amino acids that block NMDA receptors are recognized for their usefulness in the treatment of diseases. The receptors are intimately involved in the phenomenon of excitotoxicity, which can be a critical determinant of the outcome of several neurological diseases. Diseases known to be responsible for blocking the NMDA receptor include acute cerebral ischemia (eg, shock or brain trauma), muscle spasm, seizure disorders, neuropathic pain and anxiety and may be a significant causative factor in chronic neurodegenerative diseases such as Parkinson's disease [T. KIockgether, L. Turski, Ann. Neurol. 34, 585-593 (1993)], neuronal damage related to the human immunodeficiency virus (HIV), amyotrophic lateral sclerosis (ALS), Alzheimer's disease [P.T. Francis, N.R. Sims, A.W. Procter, D.M. Bowen, J. Neurochem. 60 (5), 1589-1604 (1993)] and Huntington's disease. [See S. Lipton, TINS 16 (12), 527-532 (1993); S.A. Lipton, P.A. Rosenberg, New Eng. J. Med. 330 (9), 613-622 (1994); and O F. Bigge, Biochem. Pharmacol. 45, 1547-1561 (1993) and the references cited in this document]. NMDA receptor antagonists can also be used to prevent tolerance to opiate analgesia or to help control the withdrawal symptoms of adjectival drugs (European Patent Application 488 959A).

The cloning of the expression of the first NMDA receptor subunit, MMDAR1 (NR1) in the Nakanishi laboratory in 1991 provided an initial view of the molecular structure of the NMDA receptor [Nature 354, 31-37 (1991)]. There are many other structurally related subunits (NMDAR2A through NMDAR2D) that aggregate NR1 in heteromeric assemblies to form the functional ion channel complex of the receptor [Annu. Rev. Neurosci. 17, 31-108 (1994)]. The molecular homogeneity of NMDA receptors implies a future potential for agents with selective pharmacology of the subtype.

Many of the properties of NMDA receptors are observed in receptors Recombinant homomeric NR1 expressed in oocytes. These properties are altered by the NR2 subunits. The recombinant NMDA receptors expressed in Xenopus oocytes have been studied by voltage-clamp recording, as has the developmental expression and regional subunits of the NMDA receptor encoding mRNAs. The electrophysiological tests were used to characterize the actions of the compounds in the NMDA receptors expressed in the Xenopus oocytes. The compounds were tested in the four combinations of the cloned NMDA receptor subunit of rats, corresponding to three putative NMDA receptor subtypes [Moriyoshi, et al. Nature 1991, 354, 31-37; Monyer et al, Science 1992, 256, 1217-1221; Kutsuwada et al, Nature 1992, 358, 36-41; Sugihara et al, Biochem. Biophys Res. Common. 1992, 185, 826-832].

The novel 4-benzyl piperidines which have increased the selectivity of the subtype would be highly desirable, particularly for the treatment of Parkinson's disease.

SUMMARY OF THE INVENTION The invention relates to 4-benzyl piperidine alkyl sulfoxide heterocycles represented by the formula (I): or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R and R 'are independently selected from the group consisting of hydrogen, hydroxy, alkyl, halogen, nitro, cyano, carboxaldehyde, amine aldehyde, lower alkoxycarbonylmethyl, hydroxy lower alkyl, amino-carbonylmethyl, hydrazinocarbonylmethyl, acetamido, aryl, arariquilo, amino, a halogenated alkyl group, a lower aminoalkyl group or a lower alkoxy group; R "and R '" are independently selected from the group consisting of hydrogen, hydroxy, alkyl, halogen, amino, a halogenated alkyl group, a lower aminoalkyl group or a lower alkoxy group; X is hydrogen or hydroxy; Z is -CH2- or -C-; n is 2 to 4 and Y is O. NH or S.

The compounds of this invention include stereoisomers such as enantiomers as well as racemic mixtures thereof. A particularly preferred enantiomer of the present invention is (+) - 6-. { 2- [4- (4-fluorobenzyl) piperidin-1-yl] ethanesulfinyl} -3H-benzooxazol-2-one.

Examples of pharmaceutically acceptable addition salts include the organic and inorganic acid addition salts such as hydrochloride, hydrobromide, phosphate, sulfate, citrate, lactate, tartrate, maleate, fumarate, mandelate, oxalate and acetate.

Halogen is fluorine, chlorine, bromine or iodine; Preferred groups are fluorine, chlorine and bromine.

"Alkyl" means a long or branched chain of one to six atoms or a cyclic alkyl of three to seven carbon atoms including but not limited to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

"Aryl" means a carbocyclic, bicyclic or monocyclic aromatic ring system that can be substituted or unsubstituted, for example, but not limited to phenol, naphthyl or the like.

Aralkyl means any of the alkyl groups defined herein substituted by any of the aryl groups as defined herein.

"Halogenated alkyl" means any of the alkyl groups defined herein substituted by one or more halogens as defined herein.

"Lower aminoalkyl" means any of the alkyl groups defined herein substituted by an amino group.

"Lower alkoxy" means an alkoxy group containing an alkyl group as defined herein.

The present invention also relates to a pharmaceutical composition containing the compound of this invention in an amount effective to treat chronic neurodegenerative diseases or cerebrovascular diseases responsible for the selective blockade of the NMDA receptor subtypes and a pharmaceutically acceptable carrier. Examples of diseases responsible for such treatment include cerebral ischemia caused by brain trauma, shock, hypoglycemia, heart attack and surgery, anxiety-psychosis, schizophrenia, glaucoma, CMV retinitis, antibiotic-induced hearing loss, asthma, urinary incontinence , tolerance to opioids and chronic neurodegenerative diseases such as Huntington's disease, ALS, Parkinson's disease and Alzheimer's disease. The pharmaceutical composition of this invention can also be used as an analgesic or for the treatment of seizures, i.e., epilepsy or migraine. The pharmaceutical composition of this invention could be used to treat otological diseases including, for example, tinnitus, hearing loss induced by aminoglycoside antibiotics and sound induced hearing loss. Eye diseases such as, for example, glaucoma, CMV retinitis, age-related macular degeneration (AMD) and other degenerative retinal diseases can also be treated with the pharmaceutical composition of this invention.

A particularly preferred composition of this invention includes the compound of this invention in combination with dopamine agonists or precursors, i.e., L-DOPA and a pharmaceutically acceptable carrier. The 4-benzyl piperidine alkylsulfoxide heterocycle and L-DOPA are present in an effective amount of this invention for treating Parkinson's disease. The composition of this invention may also include other agents used to treat Parkinson's disease, such as, for example, pergolide, bromocriptine, pramipexole (mirapas), depreral, apomorphine and the like.

The invention furthermore relates to a method for treating diseases responsible for the selective blockade of the N-methyl-D-aspartate receptor subtypes in an animal suffering therefrom comprising administration in a unit dose form of at least one Composite of the invention. A particularly preferred embodiment includes the method for the treatment of Parkinson's disease with an alkyl sulfoxide heterocycle of 4-benzyl piperidine and L-DOPA.

DETAILED DESCRIPTION OF THE INVENTION The alkyl-sulfoxide heterocycles of the 4-benzyl piperidine of this invention are represented by the formula (I). Preferably Z is -CH2-, R "is hydrogen and R '" is hydrogen. More preferably X is hydrogen and R is selected from the group consisting of hydrogen, fluorine, chlorine, bromine and alkyl. More preferably n is 2 and Y is 0. The compounds of this invention are selective for the NMDA subtype and more particularly the selective NR1A / 2B.

Illustrative examples of this invention include 6 { 2- [4- (4-chloro-benzyl) -piperidin-1-yl] -etanosulfinyl} -3H-benzooxazol-2-one; 6- { 2- [4- (4-Fluoro-benzyl) -piperidin-1-yl] -etanosulfinyl} -3H-benzooxazol-2-one; 6- { 2- [4- (4-methyl-benzyl) -piperidin-1-yl] ethanesulfonyl} 3H-benzooxazol-2-one; 6- [2- (4-benzyl-piperidin-1-yl) -etanosulfinyl] -3H-benzooxazol-2-one; 6- { 2- [4- (4-methoxybenzyl) -piperidin-1-yl] -etanosulfinyl} -3H-benzooxazol-2-one; 6- { 2- [4- (3,4-dichlorobenzyl) -piperidin-1-yl] -etanosulfinyl} -3H-benzooxazol-2-one; 6- { 2- [4- (2-fluorobenzyl) -piperidin-1-yl) -etanosulfinyl} -3H-benzooxazol-2-one; 6- [2- (4-benzyl-4-hydroxypiperidin-1-yl) -etanosulfinyl] -3H-benzooxazol-2-one; 6- { 2- [4- (4-fluorobenzyl) -4-hydroxy-piperidin-1-yl] -etanosulfinyl} -3H-benzooxazol-2-one; 6- [2- (4-benzoylpiperidin-1-yl) -etanosulfinyl] -3H-benzooxazol-2-one; 6- { 2- [4- (2,3-difluorobenzyl) -piperidin-1-yl] -etanosulfinyl} -3H-benoxooxazol-2-one; 6- { 2- [4- (2,4-difluorobenzyl) -piperidin-1-yl] -etanosulfinyl} -3H-benzooxazol-2-one; 6- { 2- [4- (4-trifluoromethylbenzyl) -piperidin-1-yl} -3H-benzooxazol-2-one; 6- { 2- [4- (2,6-difluorobenzyl) -piperidin-1-yl] -etanosulfinyl} -3H-benzooxazol-2-one; 6- { 2- [4- (2,4-dichlorobenzyl) -piperidin-1-yl] -etanosulfinyl} -3H-benzooxazol-2-one; N- (4- { 1 - [2- (2-oxo-2,3-dihydrobenzooxazol-6-sulfyl) ethyl] piperidin-4-ylmethyl} phenyl) acetamide; 6- [2- (4-benzylpiperidin-1-yl) ethanesulfinyl] -5-chloro-3H-benzooxazol-2-one; 5-Chloro-6-. { 2- [4- (4-fluorobenzyl) piperidin-1-yl] ethanesulfinyl} -3H-benzooxazol-2-one; (+) - 6-. { 2- [4- (4-fluorobenzyl) piperidin-1-yl] ethanesulfinyl} -3H-benzooxazol-2-one; (-) - 6-. { 2- [4, (4-fluorobenzyl) piperdin-1 -yl] ethanesulfinyl} -3H-benzooxazol-2-one and pharmaceutically acceptable salts thereof.

The compounds of the present invention are useful in the treatment or prevention of neuronal loss, neurodegenerative diseases and chronic pain. They are also useful as anticonvulsants, as well as for the treatment of epilepsy and psychosis. The profiles of the therapeutic and collateral effect of the NMDA receptor subtype antagonists of the selective subtype should be markedly different from most of the NMDA receptor inhibitors of the non-selective subtype. It is expected that the analogs of the selective subtype of the present invention exhibit few or none of the side effects from non-specific binding to other sites, particularly PCP and the glutamate binding sites associated with the NMDA receptor. In addition, selectivity for the different NMDA receptor subtypes will reduce side effects such as sedation that is common for NMDA receptor antagonists of the non-selective subtype. The compounds of the present invention are effective in the treatment or prevention of the adverse consequences of the hyperactivity of the excitatory amino acids, ie, those that are involved in the NMDA receptor system, by preventing the channels of the ligand cation. blocked from the opening and allowing excessive Ca flow in the neurons, as occurs during ischemia.

Neurodegenerative diseases that can be treated with the compounds of the present invention include those selected from the group consisting of Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease and Down syndrome. Particularly preferred is the treatment of Parkinson's disease in combination with L-DOPA therapy.

The compounds of the present invention are particularly useful in the treatment or prevention of neuronal loss associated with multiple shock that causes dementia. After a patient has been diagnosed as suffering from shock, the compounds of the present invention can be administered to ameliorate immediate ischemia and further prevent the neuronal damage that can occur from recurrent shocks.

The compounds of the invention are particularly useful in the treatment or prevention of the adverse neurological consequences of surgery. For example, coronary bypass surgery requires the use of heart-lung machines that tend to introduce air bubbles into the circulatory system that can be deposited in the brain. The presence of said oxygen air bubbles to the neuronal tissue, resulting in anoxia and ischemia. The pre- or post-surgical administration of the compounds of the present invention will treat or anticipate the resultant ischemia. In a preferred embodiment, the compounds of the invention are administered to patients undergoing cardiopulmonary bypass surgery or carotid endarterectomy surgery.

The compounds of the present invention are also useful in the treatment or prevention of chronic pain. Such chronic pain can be the result of surgery, trauma, headache, arthritis, pain from terminal cancer or degenerative diseases. The compounds of the present invention are also particularly useful in the treatment of reflex pain resulting from the amputation of a limb. In addition to pain treatment, the compounds of the invention are also expected to be useful in the induction of anesthesia, either general or local anesthesia, for example, during surgery.

Antagonists of the selective NMDA receptor subtype and modulators can be tested for anticonvulsant activity in vivo after intravenous or intraperitoneal injection using a number of anticonvulsant tests in mice (audiogenic access model in DBA-2 mice, pentylenetetrazol accesses induced in mice, test access with maximum electroshock (MES) or induced NMDA death). The compounds they can also be tested in drug discrimination tests in trained rats to discriminate the PCP from saline. It is expected that most of the compounds of the present invention do not generalize PCP at any dose. It is expected that such results will suggest that antagonists of the NMDA selective receptor subtype of the present invention do not show the side effects of behavior such as PCP that are common for NMDA channel blockers such as MK-801 and PCP or for NMDA competitive antagonists such as the CGS 19755.

Antagonists of the selective NMDA receptor subtype are also expected to show potent in vivo activity after intraperitoneal or intravenous injection suggesting that these compounds can penetrate the brain / blood barrier.

Elevated levels of glutamate have been associated with glaucoma. Furthermore, it has been described that the management of glaucoma, particularly the protection of retinal ganglion cells, can be increased by administering to a patient a compound capable of reducing the excitotoxicity induced by glutamate at an effective concentration to reduce excitotoxicity. See WO94 / 13275. Thus, the compounds of the present invention, which are expected to cross the blood-retinal barrier, are also expected to be useful in the treatment of glaucoma. Preferably, the invention is directed to the treatment of patients having primary open angle glaucoma, acute narrow angle glaucoma, pseudo-exfoliation or other types of glaucoma or ocular hypertension. Preferably, the compound is administered for a prolonged period (i.e., at least six months and preferably at least one year), without considering changes in intraocular pressure of the patient during the period of administration. The compounds of the present invention are also useful in the treatment of CMV retinitis, particularly in combination with antiviral agents. CMV afflicts the ganglion cell layer that can result in high levels of glutamate. Thus, NMDA receptor antagonists can block retinitis by blocking the toxicity effect of high levels of glutamate. The compounds of this invention may also be useful in the treatment of other ocular diseases such as AMD and other degenerative diseases of the retina.

Aminoglycoside antibiotics have been successfully used in the treatment of serious gram-negative bacterial infections. However, prolonged treatment with these antibiotics will result in the destruction of the sensory auditory cells of the inner ear and, consequently, induce permanent hearing loss. A recent study by Basile et al. (Nature Medicine, 2: 1338-1344, 1996) indicated that aminoglycosides produce an increase as polyamine in the excitotoxicity of glutamate through its interaction with the NMDA receptor. Thus, the compounds of the present invention with the activity of the NMDA receptor antagonist will be useful in the prevention of hearing loss induced by aminoglycoside antibiotics by antagonizing their interaction with the receptor. The compounds of this invention may also be useful in the treatment of other otological diseases such as tinnitus and sound-induced hearing loss.

The compounds of the present invention are useful in the treatment of headaches, in particular migraine. During the migraine attack, a sensory disturbance with unique changes in blood flow in the brain will result in the development of the characteristic phosphenes of migraine. Since this unique phenomenon has been replicated in animal experiments with cortical depression (CSD) from Leaó, A.A.P.J., Neurophysiol. 7: 359-390 (1944), CSD is considered an important phenomenon in the pathophysiology of migraine with aureoles (Tepley et al., In: Biomagnetism, eds S. Williamson, L. Kaufmann, pp. 327-330, Plenum Press, New York (1990)). CSD is associated with the propagation (2-6 mm / s) of transient changes in electrical activity that is related to the failure of ion homeostasis in the brain, emanation of excitatory amino acids from neurons and metabolism of the Increased energy (Lauritzen, M., Acta Neurol., Scand. 76 (Suppl 113): 4-40 (1987)). It has been shown that the initiation of CSD in a variety of animals, including humans, involves the release of glutamate and could be associated by NMDA (Curtis et al., Nature 191: 1010-1011 (1961) and Lauritzen et al. , Brain Res. 475: 317-327 (1988)). Antagonists of the NMDA selective subtype will be therapeutically useful for migraine due to their low expected side effects, their ability to cross the blood brain barrier and their systemic bioavailability.

The activity of the bladder is controlled by parasympathetic preganglionic neurons in the sacral spinal cord (DeGroat et al., J. Auton. Nerv. Sys. 3: 135-160 (1981)). In humans, it has been shown that the highest density of NMDA receptors in the spinal cord is localized at the sacral level, including those areas that putatively contain the parasympathetic preganglionic neurons of the bladder (Shaw et al., Brain Research 539: 164 -168 (1991)). Because NMDA receptors are excitatory in nature, drug blocking of these receptors would suppress bladder activity. It has been shown that the non-competitive NMDA receptor antagonist MK801 increased the frequency of urination in rats (Vera and Nadelhaft, Neuroscience Letters 134: 135-138 (1991)). In addition, competitive NMDA receptor antagonists have also been shown to produce a dose-dependent inhibition of the bladder and urethral sphincter activity (US Patent 5,192,751). Thus, it is anticipated that receptor antagonists of the NMDA selective subtype will be effective in the treatment of urinary incontinence mediated by its modulation in the activity of the receptor channel.

The non-competitive NMDA receptor antagonist MK801 has been shown to be effective in a wide variety of animal models whose anxiety is considerably similar to human anxiety (Clineschmidt, B.V. et al., Drug Dev. Res. 2: 147-163 (1982)). In addition, the NMDA receptor antagonists of the glycine site are shown to be effective in the enhanced alarm test in rats (Anthony, EW, Eur. J. Pharmacol., 250: 317-324 (1993)) as well as in several other anxiolytic models in animals ( Winslow, J. et al., Eur. J. Pharmacol., 190: 11-22 (1990), Dunn, R. et al., Eur. J. Pharmacol., 214: 207-214 (1992) and Kehne, JH et al. al, Eur. J. Pharmacol., 193: 283-292 (1981)). Antagonists of the glycine site, (+) HA-966 and 5,7-dichlorocinurienic acid were found to selectively oppose the stimulation induced by d-amphetamine when injected into the central planar area but not in the striated part of the rats (Hutson, PH et al., Br. J. Pharmacol. 103: 2037-2044 (1991)). Interestingly, it has been found that (+) HA-966 has also blocked PCP and MK801 induced excited behavior (Bristow, L. J. et al., Br. J. Pharmacol, 108: 1156-163 (1993)). These findings suggest that a potential use of modulators of the NMDA receptor channel, but not channel blockers, as atypical neuroleptics.

It has been shown that in an animal model of Parkinson's disease -MPP + or damage induced by methamphetamine in dopaminergic neurons can be inhibited by NMDA receptor antagonists (Rojas et al., Drug Dev. Res. 29: 222-226 (1993) and Sonsalla et al, Science 243; 398-400 (1989)). In addition, NMDA receptor antagonists have been shown to inhibit haloperidol-induced catalepsy (Schmidt, WJ et al., Amino Acids 1: 225-237 (1991)), they increase activity in rodents lacking monoamines (Carlsson et al. , Trends Neurosci 13: 272-276 (1990)) and increases ipsilateral rotation after unilateral injury of the nigra substance in rats (Shell, LD et al., J. Pharmacol. Exp. Ther. 235: 50-57 (1985)). There are also experimental animal models of Parkinson's disease. In animal studies, the antiparkinsonian agents amantadine and memantine showed activity as antiparkinsonians in animals at plasma levels leading to antagonism of the NMDA receptor (Danysz, W. et al., J. Neural Trans. 7: 155-166, ( 1944)). Thus, it is possible that these antiparkinsonian agents act therapeutically through antagonism of an NMDA receptor. Therefore, the balance of NMDA receptor activity could be important for the regulation of extrapyramity function in relation to the appearance of parkinsonian symptoms.

The use of opioids is well known, that is to say, morphine, in the medical field to relieve pain. (As used herein, the term "opioids" means any preparation or derivative of opium, especially the alkaloids naturally contained therein, of which there are approximately twenty, ie, morphine, noscapine, codeine, papaverine and thebaine and Their derivatives). Unfortunately, with continued use, the body creates a tolerance to opioids and in this way, for continued relief, the patient must be subject to progressively higher doses. Tolerance develops after chronic and acute morphine administration (Kornetsky et al., Science 162: 1011-1012 (1968)).; Way et al., J. Pharmacol. Exp Ther. 167: 1-8 (1969); Huidobro et al., J. Pharmacol. Exp Ther. 198: 318-329 (1976); Lutfy et al., J. Pharmacol. Exp Ther. 256: 575-580 (1991)). This, by itself, can harm the patient's health. In addition, it is possible that over time there is a substantially complete tolerance and the properties of the drug to eliminate pain are no longer effective. Additionally, administration of high doses of morphine can lead to respiratory depression, causing the patient to no longer breathe. The search for alternative drugs to produce analgesia without development or tolerance or as adjunctive therapy to block tolerance without interfering with analgesia is an active area of search.

Recent studies have suggested a modulatory role for the NMDA receptor in the tolerance of morphine (Trujillo et al., Science 251: 85-87 (1991); Marek et al., Brain Res. 547: 77-81 (1991); Tiseo et al., J. Pharmacol. Exp Ther. 264: 1090-1096 (1993); Lufty et al., Brain Res. 616: 83-88 (1993); Herman et al., Neuropsychopharmacology 12: 269-294 (1995).). On the other hand, it has been reported that NMDA receptor antagonists are useful for inhibiting opioid tolerance and some of the symptoms of opioid withdrawal. Thus, the present invention is also directed to the administration of the compounds described herein to inhibit opioid tolerance and to treat or ameliorate the symptoms of opioid withdrawal by blocking the glycine co-agonist site associated with opioids. the NMDA receptor.

It has been suggested that peripheral NMDA receptor activation may be an important mechanism in airway inflammation and hyper-activity exhibited in branchial asthma. According to S.J. Trends in Pharmacol. Sci., 20: 132-34 (1999). It was reported that this may explain the observations that acute asthmatic attacks may be triggered by food containing glutamate and ketamine's ability to relax the smooth muscle of the airline, possibly due to the NMDA receptor blocking activity of ketamine . Thus, the compounds of this invention may also be useful in the treatment of asthma.

Thus, the present invention is directed to compounds having high affinity for a particular subtype of the NMDA receptor and low affinity for other sites such as dopamine and other catecholamine receptors. In accordance with the present invention, those compounds that bind substantially to a particular NMDA subunit exhibit an IC50 of about 100 μM or less in an NMDA subunit binding assay. Preferably, the compounds of the present invention exhibit a selective IC50 subunit of 10 μM or less. More preferably, the compounds of the present invention exhibit a selective IC50 subunit of about 1.0 μM or less.

The compositions within the scope of this invention include all compositions wherein the compounds of the present invention are contained in an amount that is effective to achieve the intended purpose. While the individual needs vary, the determination of optimal proportions of the effective amounts of each of the components is found in the prior art. Typically, the compounds can be administered to mammals, i.e., humans, orally in a dose of 0.0025 to 50 mg / kg or an equivalent amount of the pharmaceutically acceptable salt thereof, per day according to the body weight of the mammal being treated. for anxiety disease, that is, generalized anxiety disease, phobic diseases, obsessive compulsive disease, panic disorder and post-traumatic stress illnesses. Preferably, about 0.01 to about 10 mg / kg are orally administered to treat or prevent such diseases for schizophrenia or other psychoses. For intramuscular injection, the dose is generally about half the oral dose. For example, for the treatment or prevention of anxiety, an appropriate intramuscular dose should be from about 0.0025 to about 15 mg / kg and more preferably, from about 0.01 to about 10 mg / kg.

In the method of treatment or prevention of neuronal loss in ischemia, trauma to the bone marrow or brain, hypoxia, hypoglycemia and surgery, to treat or prevent glaucoma or urinary incontinence, as well as for the treatment of Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease and Down syndrome or in a method for the treatment of a disease in which the pathophysiology of the disease involves the hyperactivity of excitatory amino acids or Neurotoxicity related to the NMDA receptor ion channel, the pharmaceutical compositions of the invention may comprise the compounds of the present invention at a unit dose level of from about 0.01 to about 50 mg / kg per body weight or an equivalent amount of the pharmaceutically acceptable salt thereof, at a rate of 1. -4 times per day. Of course, it is understood that the exact treatment level will depend on the history of the animal, that is, the human being being treated. The level of precise treatment can be determined by one skilled in the art without undue experimentation.

The oral unit dose may comprise from about 0.01 to about 50 mg, preferably about 0.01 to about 10 mg of the compound. The unit dose may be administered one or more times daily as one or more tablets, each containing from about 0.1 to about 10, conveniently about 0.25 to 50 mg of the compound or its solvates.

In addition to administering the compound as a natural chemical, the compounds of the invention can be administered as part of a pharmaceutical preparation containing pharmaceutically acceptable carriers comprising excipients and auxiliaries that facilitate the processing of the compounds into preparations that can be used pharmaceutically. Preferably, the preparations, particularly those preparations which can be administered orally and which can be used for the preferred type of administration, such as tablets, troches and capsules and also preparations that can be administered rectally, such as suppositories, as well as appropriate solutions for administration by injection or orally, containing from about 0.01 to 99 percent, preferably from about 0.25 to 75 percent of the active compound (s), together with the excipient.

The pharmaceutically acceptable non-toxic salts of the compounds of the present invention are also included within the scope of the present invention. Acid addition salts are formed by mixing a solution of the particular selective NMDA receptor subtype antagonist of the present invention with a solution of a pharmaceutically acceptable non-toxic acid, such as hydrochloric acid, fumaric acid, maleic acid, succinic acid , acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid, oxalic acid and the like.

The pharmaceutical compositions of the invention can be administered to any animal that experiences the beneficial effects of the compounds of the invention. Primarily within such animals are mammals, ie, humans, although the invention is not so limited.

The pharmaceutical compositions of the present invention can be administered by any means that achieves its intended purpose. For example, administration may be parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, or buccal. Alternatively, or concurrently, the administration may be oral. The dose administered will depend on the age, health and weight of the recipient, the type of concurrent treatment, if any, the frequency of treatment and the nature of the desired effect.

The pharmaceutical preparations of the present invention are prepared in a manner well known in the art, for example, conventional mixing, granulating, troducing, dissolving or lyophilizing processes. Thus, pharmaceutical preparations for oral use can be obtained by combining the active compounds with solid excipients, optionally grinding the resulting mixture and processing the mixture of granules, after adding the appropriate auxiliaries, if desired or necessary, to get tablets or troches.

Suitable excipients are, in particular, filling agents such as saccharides, for example, lactose or sucrose, mannitol or sorbitol, cellulose preparations and / or calcium phosphates, for example tricalcium phosphate or hydrogenated calcium phosphate, as well as binders such as starch paste, using for example, corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and / or polyvinyl pyrrolidone. If desired, disintegrating agents such as the starches mendionados previously and also carboxymethyl starch, cross-linked polyvinyl pyrrolidone can be added., agar or alginic acid or a salt thereof, such as sodium alginate. Auxiliaries include, without limitation, flow regulating agents and lubricants, for example, silica, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate and / or polyethylene glycol. The troches are provided with appropriate coatings which, if desired, are resistant to gastric juices. For this purpose, concentrated saccharide solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol and / or titanium dioxide, lacquer solutions and appropriate organic solvents or solvent mixtures. To produce coatings resistant to gastric juices, solutions of appropriate cellulose preparations such as acetyl cellulose phthalate or hydroxypropylmethyl cellulose phthalate are used. Dye materials or pigments can be added to the tablets or to the coatings of the troches, for example, for the identification or to characterize the combinations of the doses of the active compounds.

Other pharmaceutical preparations that can be used orally include closed capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. Closed capsules can contain the active compounds in the form of granules which can be mixed with filling agents such as lactose, binders such as starches and / or lubricants such as talc or magnesium stearate and optionally stabilizers. In soft capsules, the active compounds are preferably dissolved or suspended in suitable liquids, such as fatty oils or liquid paraffin. In addition, stabilizers are added.

Possible pharmaceutical preparations that can be used rectally include, for example, suppositories, which consist of a combination of one or more of the active compounds with a suppository base. Suitable suppository bases are, for example, synthetic or natural triglycerides or paraffin hydrocarbons. In addition, it is possible to use rectal gelatin capsules consisting of a combination of the active compounds with a base. Possible base materials include, for example, liquid triglycerides, polyethylene glycols or paraffin hydrocarbons.

Formulations suitable for parenteral administration include aqueous solutions of the active compounds in water-soluble form, for example, water soluble salts and alkaline solutions. In addition, suspensions of the active compounds as appropriate suspensions of oily injection can be administered. Suitable lipophilic solvents or vehicles include fatty oils, for example, sesame oil or synthetic fatty acid esters, for example, ethyl oleate or triglycerides or polyethylene glycol-400 (the compounds are soluble in PEG-400). Aqueous injection suspensions may contain substances that increase the viscosity of the suspension include, for example, sodium carboxymethyl cellulose, sorbitol and / or dextran. Optionally, the suspension may also contain stabilizers.

The characterization of the binding sites of the NMDA subunit in vitro has been difficult due to the lack of selective drug ligands. Thus, the compounds of the present invention can be used to characterize the NMDA subunits and their distribution. Particularly preferred selective NMDA subtype receptor antagonists that can be used for this purpose are isotopically labeled derivatives, ie, wherein one or more atoms are replaced with 3 H, 11 C, 14 C, 16 N or 18 F.

EXAMPLE 1 6- [2- [4- (4-Fluor-benzyl) -piperidin-1-yl] -etanosulfinyl] -3H-benzooxazol-2-one Stage A: Preparation of 4- (4-fluorobenzyl) -1-piperidineethanethiol A mixture of 4- (4-fluorobenzyl) piperidine (5.9 g, 30.5 mmol) and ethyl 2-mechaptoethyl carbonate (4.8 g, 32 mmol) was heated to reflux in toluene (250 ml) for 18 hours under a nitrogen atmosphere. The toluene was removed in vacuo and the resulting oil was used without purification in the next step.

Step B: Preparation of 5- [2- [4-fluorobenzyl] piperidin-1-yl] ethanesulfanyl] -2-nitroanisole A mixture of 4- (4-fluorobenzyl) -1-piperidineethanethiol (7.7 g, 30.4 mmol), 5-bromo-2-nitroanisole (7 g, 30.4 mmol) and K2CO2 (4.8 g, 35 mmol) in acetonitrile (250 ml) ) was heated to reflux for 18 hours under nitrogen. After the mixture was cooled, the salts were removed by filtration and the filtrate was concentrated in an oil. The compound was purified by chromatography to provide 6 g of an oil.

Step C: Preparation of 5- [2- [4- (4-fluorobenzyl) piperidin-1-yl] ethanesulfanyl] -2-nitrophenol - [2- [4- (4-fluorobenzyl) piperidin-1-yl] ethanesulfanyl] -2-nitroanisole (6 g) was heated to reflux for 2.5 hours in 48% hydrobromic acid (100 ml), the HBr The mixture was distilled and the residue was partitioned between 2N Na2CO3 and chloroform (200 ml each). The organic layer was dried (MgSO4) and concentrated to a solid. Trituration in ethyl ether yielded 4.3 g of 5- [2- [4- (4-fluorobenzyl) piperidin-1-yl] ethanesulfanyl] -2-notrophenol, mp 130-133 ° C.

Stage D: Preparation of 6-. { 2- [4- (4-Fluoro-benzyl) -piperidin-1-yl] -ethanesulfanyl} -3H-benzooxazol-2-one - [2- [4- (4-Fluorobenzyl) piperidin-1-yl) ethanesulfanyl] -2-nitrophenol (0.62 g, 1.59 mmol) was dissolved in a 50:50 mixture of tetrahydrofuran and methanol (100 mL). After Raney nickel (0.5 g) was added, the reaction mixture was hydrogen (50 psi) for 2 hours. The catalysis was removed by filtration and the solvents were distilled to provide the aminophenol which was used immediately. The aminophenol (1.59 mmol) was treated with 1, 1'-carbonyldiimidazole (0.5 g, 3 mmol) in tetrahydrofuran (100 ml) and stirred at room temperature for 18 hours. Removal of the solvent and purification of the residue by chromatography on silica gel eluted with 5% 1 N methanolic ammonia in chloroform gave a crude product. Trituration in ethyl ether gave 0.42 g of 6-. { 2- [4- (4-Fluoro-benzyl) -piperidin-1-yl] -ethanesulfanyl} -3H-benzooxazol-2-one, mp 177-179 ° C.

Stage E: Preparation of 6-. { 2- [4- (4-Fluoro-benzyl) -piperidin-1-yl] -etanosulfinyl} -3H-benzooxazol-2-one A solution of 6-. { 2- [4- (4-Fluoro-benzyl) -piperidin-1-yl] -ethanesulfanyl} -3H-benzooxazol-2-one (1.80 g, 4.55 mmol) in glacial acetic acid (120 mL) was treated with 30% hydrogen peroxide (1 mL, 9 mmol) and stirred at room temperature for 18 hours. After no peroxide remained, the reaction mixture was concentrated in vacuo and the residue was neutralized with aqueous ammonia. The resulting solid was collected by filtration, dried and chromatographed on silica gel by diluting with 20% 2N methanolic ammonia in chloroform. The homogeneous fractions were combined, concentrated in a solid and triturated in ethyl ether to provide 1.25 g of 6-. { 2- [4- (4-fluoro-encyl) -piperidin-1-yl] -etanosulfinyl} -3H-benzooxazol-2-one, mp 202-204 ° O EXAMPLE 2 6-. { 2- [4- (4-chloro-benzyl) -piperidin-1-yl} -etanosulfinil} -3H-benzooxazol-2-one The title compound was prepared using a process analogous to Example 1, with the exception that 4- (4-chlorobenzyl) piperidine was used as an initial material, (mp 213-214 ° C).

EXAMPLE 3 6-. { 2- [4- (4-methyl-benzyl) -piperidin-1-yl] -etanosulfinyl} -3H-benzooxazol-2-one The title compound was prepared using a process analogous to Example 1, with the exception that 4- (4-methylbenzyl) piperidine was used as an initial material, (mp 177-179 ° C).

EXAMPLE 4 6- [2- (4-Benzyl-piperidin-1-yl) -etanosulfinyl] -3H-benzooxazol-2-one The title compound was prepared using a process analogous to Example 1, with the exception that 4-benzyl piperidine was used as an initial material, (mp 176-178 ° C).

EXAMPLE 5 6-. { 2- [4- (4-methoxybenzyl) -piperidin-1-yl] -etanosulfinyl} -3H-benzooxazol-2-one The title compound was prepared using a process analogous to Example 1, with the exception that 4- (4-methoxybenzyl) -piperidine was used as an initial material, (mp 169-170 ° C).

EXAMPLE 6 6-. { 2- [4- (3,4-dichlorobenzyl) -piperidin-1-yl] -etanosulfinyl} -3H-benzooxazol-2-one The title compound was prepared using a process analogous to Example 1, with the exception that 4- (3,4-dichlorobenzyl) -piperidine was used as an initial material, (mp 189-191 ° C).

EXAMPLE 7 6-. { 2- [4- (2-fluorobenzyl) -piperidin-1-yl] -ethanesulfonyl} -3H-benzooxazol-2-one The title compound was prepared using a process analogous to Example 1, with the exception that 4- (2-fluorobenzyl) -piperidine was used as an initial material, (mp 179-181 ° C).

EXAMPLE 8 6- [2- (4-Benzyl-4-hydroxypiperidin-1-yl) -etanosulfinyl] -3H-benzooxazol-2-one The title compound was prepared using a process analogous to Example 1, with the exception that 4-benzyl-4-hydroxy-piperidine was used as an initial material, (mp 138-140 ° C).

EXAMPLE 9 6-. { 2- [4- (4-fluorobenzyl) -4-hydroxy-piperidin-1-yl] -etanosulfinyl} -3H-benzooxazol-2-one The title compound was prepared using a process analogous to Example 1, with the exception that 4- (4-fluorobenzyl) -4-hydroxy-piperidine was used as an initial material, (mp 153-155 ° C).

EXAMPLE 10 6- [2- (4-Benzoylpiperidin-1-yl) -etanosulfinyl] -3H-benzooxazol-2-one The title compound was prepared using a process analogous to Example 1, with the exception that 4-benzoyl-pyrpridine was used as an initial material, (mp 68-72 ° C).

EXAMPLE 11 6-. { 2- [4- (2,3-d.fluorobenzyl) -piperidin-1-yl] -etanosulfinyl} -3H-benzooxazol-2-one The title compound was prepared using a process analogous to Example 1, with the exception that 4- (2,3-difluorobenzyl) -piperidine was used as an initial material, (mp 188-190 ° C).

EXAMPLE 12 6-. { 2- [4- (2,4-difluorobenzyl) -piperidin-1-yl] -etanosulfinyl} -3H-benzooxazol-2-one The title compound was prepared using a process analogous to Example 1, with the exception that 4- (2,4-difluorobenzyl) -piperidine was used as an initial material, (mp 166-168 ° C).

EXAMPLE 13 6-. { 2- [4- (4-trifluoromethylbenzyl) -piperidin-1-yl} -3H-benzooxazol-2-one The title compound was prepared using a process analogous to Example 1, with the exception that 4- (4-trifluoromethylbenzyl) -piperidine was used as an initial material, (mp 165-166 ° C).

EXAMPLE 14 6-. { 2- [4- (2,6-dichlorobenzyl) -piperidin-1-yl] -etanosulfinyl} -3H-benzooxazol-2-one The title compound was prepared using a process analogous to Example 1, with the exception that 4- (2,6-difluorobenzyl) -piperidine was used as an initial material, (mp 187-189 ° C).

EXAMPLE 15 6-. { 2- [4- (2,4-dichlorobenzyl) -piperidin-1-yl] -etanosulfinyl} -3h-benzooxazol-2-one The title compound was prepared using a process analogous to Example 1, with the exception that 4- (2,4-dichlorobenzyl) -piperidine was used as an initial material. (mp 146-148 ° C).

EXAMPLE 16 n- (4- { 1- [2- (2-Oxo-2,3-dichlorobenzooxazol-6-sulfinyl) ethyl] piperidin-4-ylmethyl} phenyl) acetamide The title compound was prepared using a process analogous to Example 1, with the exception that (. {Piperidin-4-ylmethyl}. Phenyl) -acetamide was used as the starting material, (mp 104-105 ° C) .

EXAMPLE 17 6- [2- (4-benzylpiperidin-1-yl) ethanesulfinyl] -5-chloro-3H-benzooxazol-2-one Stage A: Preparation of 5-chloro-6-chlorosulfonyl-3H-benzooxazol-2-one -Chloro-3H-benzooxazol-2-one (10.0 g, 59 mmol) was added portionwise to chlorosulfonic acid (30 mL) at -20 ° C with stirring. The mixture was stirred at room temperature for 2.5 hours and at 70 ° C for 1.5 hours. The cooled reaction mixture was poured slowly into ice water (300 ml) and stirred for 1 hour. The precipitate was collected and washed with water. The dried precipitate was stirred in chloroform (500 ml) for 3 hours at room temperature, filtered and dried to give 12.3 g of a pale pink solid. Stage B: Preparation of 5-chloro-6-sulfanyl-3H-benzooxazol-2-one Zinc powder (14.4 g, 0.22 mol) was added to a solution of mercury chloride (2.86 g, 10.6 mmol) in water (42 ml) and concentrated hydrochloric acid (1.7 ml). The mixture was stirred for 15 minutes and the floating cream separated. The residue was washed with water (2 x 15 ml), ethanol (2 x 15 ml) and diethyl ether (2 x 15 ml). 5-Chloro-6-chlorosulfonyl-3H-benzooxazol-2-one (12.3 g, 46 mmol) and ethanol (70 ml) were added to the residue and the mixture was placed in an ice bath. The concentrated hydrochloric acid (36 ml) was added via the addition funnel for 15 min and the resulting mixture was stirred at reflux for 18 hours. The cooled reaction mixture was poured into ice water (300 ml) and stirred for 20 min. The precipitate was collected to give 9.5 g of a white powder.

Step C: Preparation of 5-chloro-. { 6-chloroethanesulfanyl} -3H-benzooxazol-2-one 1, 8-Diazabicyclo [5.4.0] undec-7-ene (7.2 ml, 48 mmol) was added to 5-chloro-6-sulfanyl-3H-benzooxazol-2-one (9.5 g, 47 mmol) and 1- Bromo-2-chloroethane (17.3 ml, 0.21 mol) in acetonitrile (80 ml) at 0 ° C with stirring. The resulting solution was stirred at room temperature overnight. The reaction mixture was poured into cold-ice water (200 ml) and the precipitate was collected. The precipitate was dissolved in ethyl acetate (350 ml), dried over magnesium sulfate, filtered and evaporated to leave 6.0 g of a grayish solid.

Step D: Preparation of 5-chloro-. { 6-chloroethanesulfinyl} -3H-benzooxazol-2-one Sodium periodate (2.49 g, 11.7 mmol) was added to 5-chloro-chloro-. { 6-chloroethanesulfanyl} -3H-benzooxazol-2-one (3.08 g, 11.7 mmol) in methanol (300 ml) and water (80 ml at 0 ° C with stirring) The resulting mixture was stirred at room temperature for 1 hour, then more periodate was added. of sodium (2.49 g, 11.7 mmol) at 0 ° C and the mixture was stirred at room temperature for 3 days, water (500 ml) was added and the mixture was extracted with chloroform (3 x 300 ml). on magnesium sulfate, filtered and evaporated to give 3.1 g of a brown solid.

Step E: Preparation of 6- [2- (4-benzylpperidin-1-yl) ethanesulfinyl] -5-chloro-3H-benzooxazol-2-one 4-benzylpiperidine (0.2 ml, 1.2 mmol) in acetonitrile (5 ml) was treated with 5-chloro-. { 6-chloroethanesulfinyl} -3H-benzooxazol-2-one (300 mg, 1.1 mmol), 2N NaOH (0.5 mL) and water (0.5 mL). The mixture was stirred at 60 ° C under argon for 30 minutes. More 2N NaOH (0.5 mL) was added and the mixture was stirred for an additional 2 hours at 60 ° O The mixture was cooled to room temperature and the pH adjusted to 6. The precipitate was filtered and dried to give 0.26 g of a dust. The powder was recrystallized from hot EtOAc (30 mL) and methanol (20 mL) to give 0.14 g of 6- [2- (4-benzylpiperidin-1-yl) ethanesulfinyl] -5-chloro-3H-benzooxazol-2-one. , a white powder, (mp 190-192 ° C).

EXAMPLE 18 5-Chloro-6-. { 2- [4- (4-fluorobenzyl) piperidin-1-yl] ethanesulfinyl} -3H-benzooxazol-2-one The title compound was prepared using a process analogous to Example 17, with the exception that 4- (4-fluorobenzyl) piperidine was used as an initial material, (mp 199-200 ° C).

EXAMPLE 19 (+) - 6-. { 2- [4- (4-Fluorobenzyl) p.peridin-1-yl] ethanesulfinyl} -3H-benzooxazol-2-one 6-Chloroethanesulfinyl-3H-benzooxazol-2-one was prepared using a process analogous to Example 17, steps A-D, with the exception that 3H-benzooxazol-2-one was used as an initial material.

The enantiomers of 6-chloroethanesulfinyl-3H-benzooxazol-2-one were separated by liquid chromatography on a 20 x 250 mm chirobiotic T column by diluting with ethanol at 2 ml / min. The fastest eluting enantiomer was coupled with 4- (4-fluoro-benzyl) piperidine using a process analogous to Example 17, step E to give the title compound, (mp 150-155 ° C). _ > [ or. \ = + 124 ° (C = 0.002, CF3CO2H at 1% in MeOH) EXAMPLE 20 (-) - 6-. { 2- [4, (4-fluorobenzyl) piperidin-1-yl] ethanesulfinyl} -3h-benzooxazol-2-one The title compound was prepared using a process analogous to Example 19, with the exception that the slower eluting enantiomer was obtained (mp 150-155 ° C). [? . = -146 ° (C = 0.002, CF3CO2H at 1% in MeOH) The compounds of this invention prepared above were tested by electrophysiological tests on the NMDA receptor subunits and were found to be antagonists of the NMDA selective subtype.

Electrophysiological tests in the NMDA receptor subunits Preparation of RNA. The cDNA clones encoding NR1A, NR2A, NR2B and NR2C of the NMDA receptor subtypes in rats. (See, Morivoshi et al., Nature (London), 354: 31-37 (1991), Kutsuwada et al., Nature (Lod., 358: 36-41 (1992) Monver et al.

Science. Whashinqton, D.C.) 256: 1217-1221 (1992); Ikeda et al .. FEBS Lett. 313: 34-38 (1992); Ishii et al. J. Biol. Chem. 268: 2836-2843 (1993) for details of these clones or their mouse counterparts). The clones were transformed into the appropriate host bacterium and the plasmid preparations were made with conventional DNA purification techniques. A sample of each clone was linearized by the digestion of the restriction enzyme and the cRNA was synthesized with the AR3 T3 polymerase. The cRNA was diluted to 400 ng / μl and stored in 1 μl of aliquots at -80 ° C until injection.

The expression system of Xenopus oocyte. Mature females Xenopus laevis (20-40 min) were synthesized using 0.15% 3-aminobenzoic acid ethyl ester (MS-222) and 2-4 ovaries of lobes were surgically removed. Oocytes in developmental stages IV-VI (Dumont, J.N., J. Morphol., 136: 153-180 (1972)), were dissected from the ovary still surrounded by the ovarian envelope tissues. The oocytes enclosed in the follicle were micro-injected with 1: 1 mixtures of NR1A: NR2A, 2Bo 2C; by injecting 1-10 ng of RNA encoding each receptor subunit. The NR1A encoding the RNA was injected only at ~20 ng. The oocytes were stored in a Barth medium containing (in mM): NaCl, 88; KC1, 1; CaCl2, 0.41; Ca (NO3) 2) 0.33; MgSO4, 0.82 NaHCO3, 2.4; HEPES 5, pH 7.4, with 0.11 mg / ml gentamicin sulfate. While oocytes still surrounded by ovarian envelope tissues, Barth's medium is supplemented with 0.1% bovine serum. The oocytes were defoliated for 1-2 days following the injections by treatment with collagenase (0.5 mg / ml Sigma Type I for 0.5-1 hour) (Miledi and Woodward, J. Physiol. (Lond) 416: 601 -621 (1989)) and subsequently stored in a serum-free medium.

Electrical readings were made using a conventional two-electrode voltage clamp (Dagan TEV-200) for periods ranging from 3-21 days following injection. (Woodward et al., Mol.Pharmacol 41: 89-103 (1992)). The oocytes were placed in a continuously flooded recording chamber (5-15 thousand min "1) with a Ringer solution containing (in mM): NaCl, 115; KCL, 2; BaCI2, 1.8; HEPES, 5; pH 7.4. Drugs were applied by perfusion bath Using oocytes expressing different combinations of NMDA receptor subunits, NMDA currents were activated by the co-application of glutamate (100 μM) and glycine (1-100 μM). of the novel antagonists were evaluated in responses emitted by fixed concentrations of glutamate and glycine, by means of the reductions of the measurement in the current induced by the progressive increase of the concentrations of the antagonist.The inhibition-concentration curves were proved with the equation 1. l / l8nt = 1 / (1 + ([antagonist] / 10-pIC50) p) Eq. 1 in which lControi is the current evoked by only the agonists, plC50 = -log IC50, IC 0 is the concentration of the antagonist that produces the maximum average inhibition and n is the tilt factor. (De Lean et al., Am. J. Phvsiol. 235: E97-102 (1978)). The analysis of incomplete curves was not reliable and the IC50 values were calculated by simple regression in the linear portions of the curves (Origin: Microcal Software).

The results of the electrophysiological test are shown in Table 1. 6-OHDA test in rats Rats injured with 6-hydroxydopamine (See Ungerstedt, U ,; Arbuthnott, G.W., Quantitative recording of rotational behavior in rats after 6-hydroxy-dopamine lesions of the nigrostraiatal dopamine system. Brain Res. 1971, 24 (3), 485-93).

Adult male Sprague-Dawley rats were anesthetized with oral hydrate, unilateral lesions of the nigrostriatal dopamine system were effected by infusion of 8 μg of 6-hydroxydopamin HBr (6-OHDA) into the right middle wrap of the brain. The rats were pretreated 30 minutes before surgery with desipramine HCl 25 mg / kg intraperitoneally (IP) to protect the noradrenergic neurons and pargilin 25 mg / kg IP to potentiate the effects of 6-OHDA. A minimum of 3 weeks after surgery, the rotational behavior induced by apomorphine HCl 50 μg / kg subcutaneously (SC) was carried out. Only the rats that demonstrated more than 100 important turns / hour to apomorphine were used for the present experiments. The rotational behavior was measured using an automatic rotameter system (Rotorat Rotational Activity System, MED Associates, Georcia, VT). The anti-parkinsonian activity was carried out as the compound's ability to potentiate the controversial rotation induced by the methyl ester L-DOPA, 10 mg / kg SC, during a period of 6 hours. The experiments were conducted using a crossover paradigm where each rat received one vehicle plus L-DOPA or the test compound plus L-DOPS, in random order. The rats were tested at 7-day intervals. In experiments in which the compound was tested orally, the rats were deprived of feed for 16 hours. Statistical analysis between the treatment groups was performed using a t-pair test. The results are reported in Table 1 as the minimum effective dose (MED) of the compound required to produce a statistically significant increase in total controversial rotations compared to rats that received only L-DOPA.

Table 1 Other variations and modifications of this invention will be obvious to those skilled in the art. This invention is not limited except as set forth in the following claims.

Claims (28)

1. A compound represented by the formula or stesomers or a pharmaceutically acceptable salt the, wherein R and R 'are independently selected from the group consisting of hydrogen, hydroxy, alkyl, halogen, nitro, cyano, carboxaldehyde, amino aldehyde, carbonylmethyl lower alkoxy, hydroxy lower alkyl, amino carbonylmethyl, hydrazinocarbonylmethyl, acetamido, aryl, aralkyl, amino, a halogenated alkyl group, a lower aminoalkyl group or a lower alkoxy group; R "and R '" are independently selected from the group consisting of hydrogen, hydroxy, alkyl, halogen, amino, a halogenated alkyl group, a lower aminoalkyl group or a lower alkoxy group; X is hydrogen or hydroxy; OR II Z is -CH2- or -C-; n is 2 to 4 and Y is O, NH or S.
2. 2. A compound according to claim 1, wherein Z is -CH 2 -, R "is hydrogen and R '" is hydrogen.
3. 3. A compound according to claim 2, wherein R 'is hydrogen and X is hydrogen.
4. 4. A compound according to claim 3, wherein R is selected from the group consisting of hydrogen, fluorine, chlorine, bromine and alkyl.
5. 5. A compound according to claim 4, wherein n is 2.
6. 6. A compound according to claim 5, wherein Y is 0.
7. 7. A compound according to claim 1, wherein said compound is selected from the group consisting of 6 { 2- [4- (4-chloro-benzyl) -piperidin-1-yl] -etanosulfinyl} - 3H-benzooxazol-2-one; 6- { 2- [4- (4-Fluoro-benzyl) -piperidin-1-yl] -etanosulfinyl} -3H-benzooxazol-2-one; 6- { 2- [4- (4-methyl-benzyl) -piperidin-1-yl] -etanosulfinyl} 3H-benzooxazol-2-one; 6- [2- (4-benzyl-piperidin-1-yl) -etanosulfinyl] -3H-benzooxazol-2-one; 6- { 2- [4- (4-methoxybenzyl) -piperidin-1-yl] -etanosulfinyl} -3H-benzooxazol-2-one; 6- { 2- [4- (3,4-dichlorobenzyl) -piperidin-1-yl] -etanosulfinyl} -3H-benzooxazol-2-one; 6- { 2- [4- (2-fluorobenzyl) -piperidin-1-yl) -etanosulfinyl} -3H-benzooxazol-2-one; 6- [2- (4-benzyl-4-hydroxy-piperidin-1-yl) -etanosulfinyl] -3H-benzooxazol-2-one; 6- { 2- [4- (4-fluorobenzyl) -4-hydroxy-piperidin-1-yl] -etanosulfinyl} -3H-benzooxazol-2-one; 6- [2- (4-benzoylpiperidin-1-yl) -etanosulfinyl] -3H-benzooxazol-2-one; 6- { 2- [4- (2,3-difluorobenzyl) -piperidin-1-yl] -etanosulfinyl} -3H-benzooxazol-2-one; 6- { 2- [4- (2,4-difluorobenzyl) -piperidin-1-yl] -etanosulfinyl} -3H-benzooxazol-2-one; 6- { 2- [4- (4-trifluoromethylbenzyl) -piperidin-1-yl} -3H-benzooxazol-2-one; 6- { 2- [4- (2,6-difluorobenzyl) -piperidin-1-yl] -etanosulfinyl} -3H-benzooxazol-2-one; 6- { 2- [4- (2,4-dichlorobenzyl) -piperidin-1-yl] -etanosulfinyl} -3H-benzooxazol-2-one; N- (4- { 1- [2- (2-oxo-2,3-dihydrobenzooxazol-6-sulfinyl) ethyl] piperidin-4-ylmethyl} phenyl) acetamide; 6- [2- (4-benzylpiperidin-1-yl) ethanesulfinyl] -5-chloro-3H-benzooxazol-2-one; 5-Chloro-6-. { 2- [4- (4-fluorobencll) piperidin-1-yl] ethanesulfinyl} -3H-benzooxazol-2-one; (+) - 6-. { 2- [4- (4-fluorobenzyl) piperidin-1-yl] ethanesulfinyl} -3H-benzooxazol-2-one; (-) - 6-. { 2- [4, (4-fluorobenzyl) piperidin-1-yl] ethanesulfinyl} -3H-benzooxazol-2-one and pharmaceutically acceptable salts the.
8. 8. A compound according to claim 1, wherein said compound is 6- [2 - [- (4-Fluoro-benzyl) -piperidin-1-yl] -etanosulfinyl] -3H-benzooxazol-2-one or a pharmaceutically salt acceptable of it.
9. 9. An enantiomer of 6- [2- [4- (4-Fluoro-benzyl) -piperidin-1-yl] ethanesulfinyl] -3H-benzooxazol-2-one or a pharmaceutically acceptable salt the, wherein said enantiomer is present in at least 50% of the enantiomeric excess with respect to the other enantiomer.
10. 10. An enantiomer according to claim 9, wherein said enantiomer is (+) - 6-. { 2- [4- (4-fluorobenzyl) piperidin-1-yl] ethanesulfinyl} -3H-benzooxazol-2-one.
11. 11. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a therapeutically effective amount of at least one of the compound according to claims 1 to 10.
12. 12. A pharmaceutical composition according to claim 11, wherein said composition is useful for treating diseases responsible for the selective blockade of the M-methyl-D-aspartate receptor subtypes selected from the group consisting of shock, cerebral ischemia, central nervous system, trauma, hypoglycemia, neurodegenerative diseases, anxiety, migraine, convulsions, tinnitus, hearing loss induced by aminoglycoside antibiotics, macular or retinal degeneration, psychosis, glaucoma, depression, asthma, CMV retinitis, tolerance to opioids, chronic pain or urinary incontinence.
13. 13. A pharmaceutical composition according to claim 12, wherein said neurodegenerative disease is Parkinson's disease.
14. 14. A pharmaceutical composition according to claim 13, further comprising a dopamine agonist or precursor thereof in an amount effective to treat Parkinson's disease.
15. 15. A pharmaceutical composition according to claim 14, wherein said dopamine agonist is L-DOPA.
16. 16. A pharmaceutical composition comprising (+) - 6-. { 2-4- (4-fluorobenzyl) piperidin-1-yl] ethanesulfinyl} -3H-benzooxazol-2-one or a pharmaceutically acceptable salt thereof, substantially free of (-) - 6-. { 2- [4- (4-fluorobenzyl) piperidin-1-yl] ethanesulfinyl} -3H-benzooxazol-2-one and a pharmaceutically acceptable carrier or diluent.
17. 17. A pharmaceutical composition according to claim 16, further comprising L-DOPA.
18. 18. A method for the treatment of diseases responsible for the selective blockade of the N-methyl-D-aspartate receptor subtypes in an animal suffering from them comprising the administration in unit dose form of at least one compound represented by the formula or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R is selected from the group consisting of hydrogen, hydroxy, alkyl, halogen, nitro, cyano, carboxaldehyde, amine aldehyde, lower alkoxycarbonylmethyl, hydroxy lower alkyl, amino carbonylmethyl, hydrazinocarbonylmethyl , acetamido, aryl, aralkyl, amino, a halogenated alkyl group, a lower aminoalkyl group or a lower alkoxy group; R "and R '" are independently selected from the group consisting of hydrogen, hydroxy, alkyl, halogen, amino, a halogenated alkyl group, an amino lower alkyl group or a lower alkoxy group; X is hydrogen or hydroxy; OR II Z is -CH2- or -C-; n is 2 to 4 and Y is O, NH or S.
19. 19. A method according to claim 18, wherein Z is -CH2-, R "is hydrogen and R '" is hydrogen.
20. 20. A method according to claim 18, wherein said disease is selected from the group consisting of shock, cerebral ischemia, central nervous system diseases, trauma, hypoglycemia, neurodegenerative diseases, anxiety, migraine, convulsions, tinnitus, hearing loss induced by aminoglycoside antibiotics, psychosis, macular or retinal degeneration, glaucoma, CMV retinitis, asthma, tolerance to opioids, chronic pain, depression or urinary incontinence.
21. 21. A method according to claim 18, wherein said disease is Parkinson's disease.
22. 22. A method according to claim 18, wherein said disease is chronic pain.
23. 23. A method according to claim 18, wherein said disease is depression.
24. 24. A method according to claim 18, wherein said disease is seizures.
25. 25. A method according to claim 21, further comprising administering in a unit dose form a dopamine agonist to said animal suffering from Parkinson's disease.
26. 26. A method according to claim 25, wherein said dopamine agonist is L-DOPA.
27. 27. A method for the treatment of diseases responsible for the selective blockade of the N-methyl-D-aspartate receptor subtypes in an animal suffering from them comprising the administration in unit dose form (+) - 6-. { 2- [4- (4-fluorobenzyl) piperidin-1-yl] ethanesulfinyl} -3H-benzooxazol-2-one or a pharmaceutically acceptable salt thereof, substantially free of (-) - 6-. { 2- [4- (4-fluorobenzyl) piperidin-1-yl) ethanesulfinyl} -3H-benzooxazol-2-one.
28. 28. A method according to claim 27, wherein said method further comprises administering L-DOPA in unit dosage form to said animal.