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WO2013030358A1 - Glycine b antagonists - Google Patents

Glycine b antagonists Download PDF

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Publication number
WO2013030358A1
WO2013030358A1 PCT/EP2012/066999 EP2012066999W WO2013030358A1 WO 2013030358 A1 WO2013030358 A1 WO 2013030358A1 EP 2012066999 W EP2012066999 W EP 2012066999W WO 2013030358 A1 WO2013030358 A1 WO 2013030358A1
Authority
WO
WIPO (PCT)
Prior art keywords
dichloro
amino
methyl
6alkyl
carboxylic acid
Prior art date
Application number
PCT/EP2012/066999
Other languages
French (fr)
Inventor
Ulrich Abel
Angela Hansen
Falko Ernst Wolter
Bjoern Krueger
Valerjans Kauss
Jevgenijs Rozhkovs
Irena Piskunova
Artis ZVAGULIS
Dina Trifanova
Ginta Grunsteine
Anastasija TURE
Original Assignee
Merz Pharma Gmbh & Co. Kgaa
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Merz Pharma Gmbh & Co. Kgaa filed Critical Merz Pharma Gmbh & Co. Kgaa
Publication of WO2013030358A1 publication Critical patent/WO2013030358A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/52—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
    • C07C229/68—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings being part of the same condensed ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/53—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C07C233/54—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of a saturated carbon skeleton
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    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/53—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C07C233/55—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a carbon atom of an unsaturated carbon skeleton
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    • C07C233/81—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
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    • C07C233/00—Carboxylic acid amides
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    • C07C233/92—Carboxylic acid amides having nitrogen atoms of carboxamide groups further acylated with at least one carbon atom of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
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    • C07C275/42—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by carboxyl groups
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D213/82—Amides; Imides in position 3
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    • C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/26—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Definitions

  • the present invention relates to novel 4-aminonaphthalene-2-carboxylic acids and 1 -amino-isoquinoline-3-carboxylic acids which may act as glycine B antagonists, methods for their synthesis and the treatment and/or prevention of various diseases and disorders, including neurological disorders, by administration of such substances.
  • Glutamate is a major excitatory transmitter in the central nervous system and it has become clear in recent years that it is also very important in the peripheral nervous system (PNS). Glutamate is believed to be involved in many pathological and excitotoxic processes; therefore, there is a great deal of interest in the development of glutamate antagonists for therapeutic uses. Glutamate activates three major types of ionotropic receptors: a-amino-3-hydroxy-5-methyl-4-isoazolepropionic acid (AMPA), kainate, and N-methyl-D-aspartate (NMDA) as well as several types of metabotropic receptors. Antagonism of NMDA receptors potentially has a wide range of therapeutic applications. Functional inhibition of NMDA receptors may be achieved through actions at different recognition sites, such as the primary transmitter site, the strychnine insensitive glycine site (glycine B), the polyamine site, and the phencyclidine site located inside the cation channel.
  • glycine B strychnine insensitive gly
  • Receptor desensitization may represent a physiological process serving as an endogenous control mechanism to prevent long term neurotoxic activation of glutamate receptors but allow their transient physiological activation.
  • the co-agonist glycine is an endogenous ligand inhibiting such desensitization via activation of the glycine B site. It is noteworthy that ischemia increases not only the concentration of extracellular glutamate but also that of glycine and, although this latter effect is less pronounced, it actually persists for a longer period of time.
  • glycine B antagonists may restore normal synaptic transmission under such conditions by increasing NMDA receptor desensitization to its physiological level. It has been suggested that glycine B antagonists may offer a better therapeutic window than agents acting at other recognition sites of the NMDA receptor complex.
  • glycine B antagonists may be useful for the treatment and/or prevention of pain, including acute pain, chronic pain, allodynia, hyperalgesia, visceral pain, phantom pain, post-operative pain, neuropathic pain, peripheral neuropathy including, for example neuropathy induced by nociception, inflammation, ischemia, viral infection (herpes zoster virus, HZV), traumatic and other mechanical nerve injury, cancer, chemotherapy, diabetes mellitus, HIV infection, fibromyalgia, trigeminus neuralgia, inflammatory bowel diseases (IBD), irritative bowel syndrome (IBS), complex regional pain syndrome, carpal tunnel syndrome, arthritis including rheumatoid arthritis, osteoarthritis (degenerative joint disease), multiple sclerosis (MS) and gout (metabolic arthritis).
  • pain including acute pain, chronic pain, allodynia, hyperalgesia, visceral pain, phantom pain, post-operative pain, neuropathic pain, peripheral neuropathy including,
  • Blood-brain barrier impermeable glycine B antagonists which are restricted to action in the PNS, may be particularly useful since such antagonists do not exhibit CNS side effects.
  • Glycine B antagonists may also be useful for the treatment and/or prevention of acute insults, including cerebral ischemia, cerebral infarct, brain oedema, anoxia, inner ear insult, inner ear insult in tinnitus, head or brain or spinal cord trauma, head or brain or spinal cord injuries, trauma, sound- or drug-induced inner ear insult, ischaemia resulting from cardiac arrest or stroke or bypass operations or transplants, acute pain, hypoxia, perinatal hypoxia, and ischaemia; chronic insults, such as neurodegenerative disorders, including Morbus Huntington, Alzheimer's disease Creutzfeld-Jakob ' s syndrome/disease, bovine spongiform encephalopathy (BSE) prion related infections, diseases involving mitochondrial dysfunction, diseases involving ⁇ -amyloid and/or tauopathy, Down's syndrome, motor neuron diseases, amyotrophic lateral sclerosis (ALS), olivoponto-cerebellar atrophy, Parkinson's disease, Neuronal
  • An additional object of the invention is the provision of processes for producing the 4-aminonaphthalene-2-carboxylic acid derivatives and the 1 -aminoisoquinoline-3- carboxylic acid derivatives.
  • R 1 represents halogen, C h alky!, or trifluoromethyl
  • R 2 represents hydrogen, halogen, or C h alky!
  • R 3 represents hydrogen, halogen, or C h alky!
  • R 4 represents hydrogen, Ci-6alkyl, C3-6alkenyl, C3-6alkynyl, hydroxy-Ci-6alkyl, carboxy- Ci-6alkyl, Ci-6alkoxy-Ci-6alkyl, aryl, heteroaryl, cyclo-C3-i2alkyl, cyclo-C3-i2alkyl-Ci-6alkyl, cyclo-C3-i2alkoxy-Ci-6alkyl, aryl-Ci-6alkyl, heteroaryl-Ci-6alkyl, di-
  • R 5 represents hydrogen, Chalky!, C3-6alkenyl, Cs ⁇ alkynyl, hydroxy-Ci-6alkyl, carboxy- Ci-6alkyl, Ci-6alkoxy-Ci-6alkyl, aryl, heteroaryl, cyclo-C3-i2alkyl, cyclo-C3-i2alkyl-Ci-6alkyl, cyclo-C3-i2alkoxy-Ci-6alkyl, aryl-Ci-6alkyl, heteroaryl-Ci-6alkyl, Ci-6alkylsulfonyl, arylsulfonyl, -C(O)-R 6 , or -Y-C(O)-R 7 , or R 4 and R 5 together with the nitrogen atom they are attached represent a 4-, 5-, 6- or 7-membered ring which may be saturated or unsaturated, wherein, in addition to the nitrogen atom, the ring may contain an additional heteroatom selected from sulfur, oxygen and nitrogen
  • Y represents which may be optionally substituted by Chalky!, Ci-6alkoxy- Ci-6alkyl, aryl, heteroaryl, cyclo-C3-i2alkyl, cyclo-C3-i2alkyl-Ci-6alkyl, cyclo-C3-i2alkoxy- Ci-6alkyl, aryl-Ci-6alkyl or heteroaryl-Ci-6alkyl;
  • R 7 represents OH, Ci-6alkoxy, aryl, heteroaryl, heterocyclyl or -NR 10 R 11 ;
  • R 8 represents hydrogen or Chalky!;
  • R 9 represents Ci-6alkyl, aryl, heteroaryl, cyclo-C3-i2alkyl, aryl-Ci-6alkyl, or heteroaryl- Ci -6 alkyl;
  • R 10 and R 1 1 each independently represent hydrogen, Chalky!, cyclo-C3-i2alkyl, aryl, heteroaryl, cyclo-C3-i2alkyl-Ci-6alkyl, aryl-Ci-6alkyl, or heteroaryl-Ci-6alkyl, or R 10 and R 11 together with the nitrogen atom they are attached represent a 4-, 5-, 6- or 7-membered ring which may be saturated or unsaturated, wherein, in addition to the nitrogen atom, the ring may contain an additional heteroatom selected from sulfur, oxygen and nitrogen and/or be condensed to an aromatic or heteroaromatic ring selected from benzene, thiazole, imidazole, or pyridine, and wherein the ring may be optionally substituted by one or more substituents selected from hydroxy, oxo, amino, acyl, acylamino, trifluoromethyl, Chalky!, cyclo-C3-i2alkyl, aryl, Ci
  • a further aspect of the invention relates to a compound of Formula I, wherein X represents CH.
  • Such a compound of Formula I wherein wherein R 6 represents C h alky! (e.g., methyl), aryl, heteroaryl, aryl-Ci-6alkyl, heteroaryl-Ci-6alkyl, or -NR 8 R 9 , wherein R 8 represents hydrogen or C h alky! and R 9 represents C h alky!, aryl, heteroaryl, aryl- Ci-6alkyl, or heteroaryl-Ci-6alkyl .
  • R 6 represents C h alky! (e.g., methyl), aryl, heteroaryl, aryl-Ci-6alkyl, heteroaryl-Ci-6alkyl, or -NR 8 R 9 , wherein R 8 represents hydrogen or C h alky! and R 9 represents C h alky!, aryl, heteroaryl, aryl- Ci-6alkyl, or heteroaryl-Ci-6alkyl .
  • Such a compound of Formula I wherein wherein R 6 represents aryl, heteroaryl, aryl-Ci-6alkyl, heteroaryl-Ci-6alkyl, or -NR 8 R 9 , wherein R 8 represents hydrogen or Ci-6alkyl and R 9 represents C h alky!, aryl, heteroaryl, aryl -C h alky!, or heteroaryl- Ci-6alkyl .
  • Such a compound of Formula I wherein R 6 represents phenyl, pyridyl, optionally substituted by hydroxy, thiazolyl, pyrazinyl, pyrimidinyl, benzyl, phenethyl, phenylpropyl, pyridylmethyl, thiazolylmethyl, or -NR 8 R 9 , wherein R 8 represents hydrogen and R 9 represents phenyl or benzyl .
  • R 10 and R 1 1 each independently represent hydrogen, Chalky!, cyclo-C3-i2alkyl, aryl, heteroaryl, cyclo-C3-i2alkyl-Ci-6alkyl, aryl-Ci-6alkyl, or heteroaryl-Ci-6alkyl, or R 10 and R 1 1 together with the nitrogen atom they are attached represent a 4-, 5-, 6- or 7-membered ring which may be saturated or unsaturated, wherein, in addition to the nitrogen atom, the ring may contain an additional heteroatom selected from sulfur, oxygen and nitrogen and/or be condensed to an aromatic or heteroaromatic ring selected from benzene, thiazole, imidazole, or pyridine, and wherein the ring may be optionally substituted by one or more substituents selected from hydroxy, oxo, amino, acyl, acylamino, trifluoromethyl, Chalky!, cyclo-
  • Such a compound of Formula I wherein R 10 represents hydrogen or methyl and R 1 1 represents phenyl, pyridyl, benzyl, pyridylmethyl, thiazolylmethyl, pyrimidinylmethyl, pyridazinylmethyl, or pyrazinylmethyl .
  • R 10 represents hydrogen or methyl
  • R 1 1 represents phenyl, pyridyl, benzyl, pyridylmethyl, thiazolylmethyl, pyrimidinylmethyl, pyridazinylmethyl, or pyrazinylmethyl .
  • a further aspect of the invention relates to a compound of Formula I, which is selected from those of Formula IA:
  • R 1 -R 4 and R 6 are as defined above for Formula I.
  • Such a compound of Formula IA wherein R 6 represents C h alky! (e.g., methyl), aryl, heteroaryl, aryl-Ci- 6 alkyl, heteroaryl-Ci- 6 alkyl, or -NR 8 R 9 , wherein R 8 represents hydrogen or C h alky! and R 9 represents C h alky!, aryl, heteroaryl, aryl -C h alky I, or heteroaryl-Ci- 6 alkyl.
  • R 6 represents C h alky! (e.g., methyl), aryl, heteroaryl, aryl-Ci- 6 alkyl, heteroaryl-Ci- 6 alkyl, or -NR 8 R 9 , wherein R 8 represents hydrogen or C h alky! and R 9 represents C h alky!, aryl, heteroaryl, aryl -C h alky I, or heteroaryl-Ci- 6 alkyl.
  • Such a compound of Formula IA wherein R 6 represents aryl, heteroaryl, aryl- Ci- 6 alkyl, heteroaryl-Ci- 6 alkyl, or -NR 8 R 9 , wherein R 8 represents hydrogen or C h alky! and R 9 represents Ci- 6 alkyl, aryl, heteroaryl, aryl -C h alky!, or heteroaryl-Ci- 6 alkyl.
  • a further aspect of the invention relates to a compound of Formula I, which is selected from those of formula IB: wherein R 1 -R 4 and R 7 are as defined above for Formula I and R 12 represents hydrogen, Ci- 6 alkyl or Ci- 6 alkoxy-Ci- 6 alkyl.
  • a further aspect of the invention relates to a compound of Formula I, which is selected from those of formula IC:
  • R 1 -R 4 , R 10 , and R 11 are as defined above for Formula I and R 12 represents hydrogen, C h alky! or Ci- 6 alkoxy-Ci- 6 alkyl.
  • R 1 and R 3 each represent halogen, and R 2 represents hydrogen.
  • Such a compound of Formula IC wherein R 10 and R 11 each independently represent hydrogen, Ci- 6 alkyl, cyclo-C3-i 2 alkyl, aryl, heteroaryl, cyclo-C3-i 2 alkyl-Ci- 6 alkyl, aryl-Ci- 6 alkyl, or heteroaryl-Ci- 6 alkyl, or R 10 and R 11 together with the nitrogen atom they are attached represent a 4-, 5-, 6- or 7-membered ring which may be saturated or unsaturated, wherein, in addition to the nitrogen atom, the ring may contain an additional heteroatom selected from sulfur, oxygen and nitrogen and/or be condensed to an aromatic or heteroaromatic ring selected from benzene, thiazole, imidazole, or pyridine, and wherein the ring may be optionally substituted by one or more substituents selected from hydroxy, oxo, amino, acyl, acylamino, trifluoromethyl, C h
  • Such a compound of Formula IC wherein R 10 represents hydrogen or C h alky! and R 11 represents aryl, heteroaryl, aryl-Ci- 6 alkyl, or heteroaryl-Ci- 6 alkyl.
  • Such a compound of Formula IC wherein R 10 represents hydrogen or methyl and R 11 represents phenyl, pyridyl, thiazolyl, benzyl, pyridylmethyl, thiazolylmethyl, pyrimidylmethyl, pyridazinylmethyl, or pyrazinylmethyl.
  • a further aspect of the invention relates to a compound of Formula I, which is selected from those of Formula ID:
  • R 1 -R 5 are as defined above for Formula I.
  • Such a compound of Formula ID wherein R 1 represents halogen, R 2 represents hydrogen, and R 3 represents hydrogen or halogen.
  • Such a compound of Formula ID wherein R 7 represents -NR 10 R 1 1 , wherein R 10 represents hydrogen and R 11 represents aryl-Ci-6alkyl or heteroaryl-Ci-6alkyl .
  • the invention relates to a compound of Formula I as defined above, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof for use in therapy.
  • the invention relates to a compound of Formula I as defined above, or an optical isomer, polymorph, analog, derivative, prodrug, pharmaceutically-acceptable acid or base addition salt, hydrate, or solvate thereof for the treatment or prevention of a condition associated with excitotoxicity and malfunctioning of glutamatergic neurotransmission, including for the conditions selected from those described earlier in the description.
  • Such conditions include pain, including acute pain, chronic pain, allodynia, hyperalgesia, visceral pain, phantom pain, post-operative pain, neuropathic pain, peripheral neuropathy including, for example peripheral neuropathy induced by nociception, inflammation, ischemia, viral infection (HZV), traumatic and other mechanical nerve injury, cancer, diabetes mellitus, HIV infection, fibromyalgia, trigeminus neuralgia, inflammatory bowel diseases (IBD), irritative bowel syndrome (IBS), arthritis including rheumatoid arthritis, osteoarthritis (degenerative joint disease), multiple sclerosis (MS) and gout (metabolic arthritis).
  • peripheral neuropathy including, for example peripheral neuropathy induced by nociception, inflammation, ischemia, viral infection (HZV), traumatic and other mechanical nerve injury, cancer, diabetes mellitus, HIV infection, fibromyalgia, trigeminus neuralgia, inflammatory bowel diseases (IBD), irritative bowel syndrome
  • Such conditions also include acute insults, including cerebral ischemia, cerebral infarct, brain oedema, anoxia, inner ear insult, inner ear insult in tinnitus, head or brain or spinal cord trauma, head or brain or spinal cord injuries, trauma, sound- or drug- induced inner ear insult, ischaemia resulting from cardiac arrest or stroke or bypass operations or transplants, acute pain, hypoxia, perinatal hypoxia, and ischaemia; chronic insults, such as neurodegenerative disorders, including Morbus Huntington, Alzheimer's disease Creutzfeld-Jakob ' s syndrome/disease, bovine spongiform encephalopathy (BSE) prion related infections, diseases involving mitochondrial dysfunction, diseases involving ⁇ -amyloid and/or tauopathy, Down's syndrome, motor neuron diseases, amyotrophic lateral sclerosis (ALS), olivopontocerebellar atrophy, Parkinson's disease, Neuronal Ceroid Lipofuscinosis, AIDS dementia complex,
  • the invention relates to a compound of Formula I as defined above, or an optical isomer, polymorph, analog, derivative, prodrug, pharmaceutically-acceptable acid or base addition salt, hydrate, or solvate thereof for use in the treatment or prevention of NMDA excitotoxicity or malfunctioning glutamatergic neurotransmission.
  • the invention relates to the use of a compound of Formula I as defined above or an optical isomer, polymorph, analog, derivative, prodrug, pharmaceutically- acceptable acid or base addition salt, hydrate, or solvate thereof for the manufacture of a medicament for the prevention and/or treatment of a condition associated with excitotoxicity and malfunctioning of glutamatergic neurotransmission.
  • a use includes the use of such a compound for the manufacture of a medicament for the prevention and/or treatment of a condition in an animal including a human being which condition is associated with excitotoxicity and malfunctioning of glutamatergic neurotransmission, including conditions selected from those described earlier in the description.
  • the invention relates to a method for treating or preventing a condition associated with excitotoxicity and malfunctioning of glutamatergic neurotransmission, including conditions selected from those described earlier in the description, such method comprising administering to a living animal, including a human, a therapeutically effective amount of a compound selected from those of Formula I as defined above or an optical isomer, polymorph, analog, derivative, prodrug, pharmaceutically-acceptable acid or base addition salt, hydrate, or solvate thereof.
  • a further aspect of the invention relates to such a method wherein the compound is administered in the form of a pharmaceutical composition thereof comprising at least one compound of Formula I in combination with one or more pharmaceutically- acceptable diluents, excipients, or carriers.
  • the compounds of the invention are suitable for administration in monotherapy or for combination therapy with other pharmaceutically active compounds.
  • suitable other pharmaceutically active compounds include immunomodulators and agents active against central nervous system disorders such as other NMDA agonists or antagonists including glycine B antagonists.
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising as active ingredient at least one compound of Formula I as defined above, or an optical isomer, polymorph, analog, derivative, prodrug, pharmaceutically-acceptable acid or base addition salt, hydrate, or solvate thereof, together with one or more pharmaceutically acceptable excipients or vehicles.
  • the carbon atom content of various hydrocarbon-containing moieties is indicated by a prefix designating the minimum and maximum number of carbon atoms in the moiety, i.e., the prefix C j indicates a moiety of the integer "i" to the integer "j" carbon atoms, inclusive.
  • C h alky! refers to alkyl of one to three carbon atoms, inclusive, (i.e., methyl, ethyl, propyl, and isopropyl), straight and branched forms thereof.
  • Ci-6alkyl represents straight or branched chain alkyl groups having 1 , 2, 3, 4, 5 or 6 carbon atoms
  • examples of such alkyl groups include methyl, ethyl, n-propyl, 2-propyl, n-butyl, 2-butyl, iso-butyl, tert- butyl, n-pentyl, 2-pentyl, 3-pentyl, iso-pentyl, 2-methylbutyl, tert-amyl, neopentyl, n- hexyl, 2-hexyl, 3-hexyl, 1 -methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2,3-dimethylbutyl, 2-e
  • d-zalkylene represents divalent straight or branched chain alkyl groups having 1 , 2, 3, 4, 5 , 6, or 7 carbon atoms.
  • C3-6alkenyl represents straight or branched chain alkenyl groups having 3, 4, 5 or 6 carbon atoms.
  • C3-6alkynyl represents straight or branched chain alkynyl groups having 3, 4, 5 or 6 carbon atoms.
  • cycloCs- ⁇ alkyl represents monocyclic or bicyclic, or tricyclic alkyl groups having 3, 4, 5, 6, 7, 8, 9, 10, 1 1 or 12 carbon atoms, including cydopropyl, cydobutyl, cydopentyl, cydohexyl, bicyclo[2.2.1 ]heptyl and adamantanyl, wherein the "cycloC3-i2alkyl"-ring is optionally substituted by one or more (e.g., 1 , 2, 3, or 4) fluorine, chlorine, and/or bromine atoms.
  • Ci-6alkoxy represents straight or branched chain -O-Ci-6alkyl groups. Examples of such alkoxy groups include methoxy, ethoxy, n-propoxy, and isopropoxy, sec-butoxy, terf-butoxy.
  • Ci-6alkylamino refers to an amino moiety in which the nitrogen atom of the amino group is substituted with a Chalky! group as defined above.
  • alkylamino groups include methylamino, ethylamino, propylamine isopropylamino, teff-butylamino.
  • di-(Ci-6alkyl)amino refers to an amino moiety in which the nitrogen atom of the amino group is substituted with two Chalky! groups, which may be the same or different, as defined above.
  • Examples of di-Ci-6alkylamino groups include dimethylamino, diethylamino and N-methyl-N-isopropylamino.
  • aryl represents phenyl or naphthyl, or phenyl substituted by one or more substituents selected from halogen, amino, hydroxy, nitro, cyano, COOH, CONH 2 , Ci-6alkylaminocarbonyl, phenylaminocarbonyl, heteroarylaminocarbonyl, hydroxy- Ci-6alkylaminocarbonyl, di-(Ci-6alkyl)aminocarbonyl, trifluoromethyl, Chalky!, heteroaryl, Ci-6alkoxy, difluoromethoxy, trifluoromethoxy, cyclo-Cs- ⁇ alkoxy, phenoxy, heteroaryloxy, phenyl-Ci-6alkoxy, heteroaryl-Ci-6alkoxy, amino-Ci-6alkyl, hydroxy- Ci-6alkyl, carbamoyl-Ci-6alkyl, hydroxy-Ci-6alkoxy, Ci-6alkoxycarbonyl, Ci-6alkyl
  • heteroaryl an aromatic 5-6 membered ring comprising one to four heteroatoms selected from oxygen, sulfur and nitrogen, or a bicyclic aromatic group containing a 5-6 membered ring comprising one to four heteroatoms selected from oxygen, sulfur and nitrogen fused with a benzene ring or with a 5-6 membered ring comprising one to four heteroatoms selected from oxygen, sulfur and nitrogen, wherein the heteroaryl is optionally substituted by one or more substituents selected from halogen, amino, hydroxy, nitro, cyano, COOH, CONH 2 , Ci-6alkylaminocarbonyl, di-(Ci-6alkyl)aminocarbonyl, trifluoromethyl, Chalky!, Ci-6alkoxy, difluoromethoxy, trifluoromethoxy, cyclo-Cs- ⁇ alkoxy, phenyl, pyridyl, thiazolyl, pyrazolyl, phenoxy, pyr
  • acyl represents Ci-6alkylcarbonyl, trifluoroacetyl, hydroxy- Ci-6alkylcarbonyl, carboxy-Ci-6alkylcarbonyl, Ci-6alkoxy-Ci-6alkylcarbonyl, cyclo-C3-i2alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, aryl-Ci-6alkylcarbonyl, heteroaryl-Ci-6alkylcarbonyl, heterocyclylcarbonyl and heterocyclyl-Ci-6alkylcarbonyl.
  • heterocyclyl represents a saturated 4-7 membered heterocycle containing one or two heteroatoms selected from oxygen, sulfur and nitrogen
  • heterocyclyl groups include azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, tetrahydrofuryl, thiazolidinyl, morpholinyl, thiomorpholinyl, and piperazinyl .
  • halogen represents fluorine, chlorine, bromine and iodine.
  • the compounds of the present invention are named according to the lUPAC or CAS nomenclature system. Abbreviations which are well known to one of ordinary skill in the art may be used (e.g. "Ph” for phenyl, “Me” for methyl, “Et” for ethyl, “h” for hour or hours, and “rt” for room temperature).
  • analog or “derivative” is used herein in the conventional pharmaceutical sense, to refer to a molecule that structurally resembles a reference molecule (such as 4-aminonaphthalene-2-carboxylic acid or 1 -amino-isoquinoline-3- carboxylic acid), but has been modified in a targeted and controlled manner to replace one or more specific substituents of the reference molecule with an alternate substituent, thereby generating a molecule which is structurally similar to the reference molecule.
  • reference molecule such as 4-aminonaphthalene-2-carboxylic acid or 1 -amino-isoquinoline-3- carboxylic acid
  • Synthesis and screening of analogs ⁇ e.g., using structural and/or biochemical analysis), to identify slightly modified versions of a known compound which may have improved or biased traits (such as higher potency and/or selectivity at a specific targeted receptor type, fewer side effects, etc.) is a drug design approach that is well known in pharmaceutical chemistry.
  • analogs and derivatives of the compounds of the invention can be created which have improved therapeutic efficacy, i.e., higher potency and/or selectivity at a specific targeted receptor type, either greater or lower ability to penetrate mammalian blood-brain barriers ⁇ e.g., either higher or lower blood-brain barrier permeation rate), fewer side effects, etc.
  • prodrug is used herein in the conventional pharmaceutical sense, to refer to a molecule which undergoes a transformation in vivo (e.g., an enzymatic or chemical transformation) to release an active parent drug.
  • Prodrugs of the compounds of Formula I of the present invention may be prepared by chemically modifying a functional group present in the compound of Formula I such that the chemically modified compound may undergo a transformation in vivo (e.g., enzymatic hydrolysis) to provide the compound of Formula I.
  • Examples of functional groups present in the compounds of Formula I which may be modified to produce prodrugs include carboxy, hydroxy and amino groups.
  • Prodrugs of the compounds of Formula I of the present invention may be prepared according to conventional techniques which have been described in the art (see, for example, Stella V., et al., Prodrugs: Challenges and Rewards, AAPS Press/Springer, New York, 2007).
  • compositions of the invention refers to molecular entities and other ingredients of such compositions that are physiologically tolerable and do not typically produce untoward reactions when administered to a mammal ⁇ e.g., human).
  • pharmaceutically acceptable may also mean approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in mammals, and more particularly in humans.
  • compositions of the present invention may be in the form of pharmaceutically acceptable salts.
  • “Pharmaceutically acceptable salts” refers to those salts which possess the biological effectiveness and properties of the parent compound and which are not biologically or otherwise undesirable. The nature of the salt or isomer is not critical, provided that it is non-toxic and does not substantially interfere with the desired pharmacological activity.
  • Schemes 2-5 describe the preparation of compounds of Formula I of the present invention. All of the starting materials are prepared by procedures described in Scheme 1 or following schemes, by procedures well known to one of ordinary skill in organic chemistry or can be obtained commercially. All of the final compounds of the present invention are prepared by procedures described in these charts or by procedures analogous thereto, which procedures would be well known to one of ordinary skill in organic chemistry. All of the variables used in the schemes defined below or as in the claims.
  • the compounds of general Formula IA may be prepared in two steps from an appropriately substituted ester of 4-aminonaphthalene-2- carboxylic acid 4 (Scheme 2).
  • 4-amido-2-naphthoic acid ester 6 (wherein R 6 represents C h alky!, aryl, heteroaryl, aryl-Ci-6alkyl, or heteroaryl-Ci-6alkyl) may be obtained by reacting compound 4 with compound 5 (wherein X' represents CI or Br) in the presence of an appropriate base (e.g., triethylamine) in a polar solvent (e.g., dichloromethane, acetonitrile, or DMF).
  • an appropriate base e.g., triethylamine
  • a polar solvent e.g., dichloromethane, acetonitrile, or DMF.
  • compound 6 may be prepared by reacting amine 4 with compound 5 (wherein X' represents OH) in the presence of condensing agent (e.g., EDCI and HOBT, or CDI) in an appropriate solvent (e.g., DMF).
  • condensing agent e.g., EDCI and HOBT, or CDI
  • an appropriate solvent e.g., DMF
  • the ester group of compound 6 may be hydrolyzed to yield compound IA.
  • a lower alkyl (e.g., methyl or ethyl) ester group may be hydrolyzed using reagents such as aqueous lithium hydroxide or sodium hydroxide.
  • the compounds of general Formula IA may be prepared from compound 9 by analogous procedures.
  • amine 9 may be acylated with compound 5 (wherein X' represents CI or Br) in the presence of an appropriate base (e.g., KOBu-t, or NaH) in a polar solvent (e.g., DMSO, or DMF) to give compound 10.
  • an appropriate base e.g., KOBu-t, or NaH
  • a polar solvent e.g., DMSO, or DMF
  • the ester group of compound 10 may be hydrolyzed using reagents such as aqueous lithium hydroxide or sodium hydroxide.
  • Necessary starting compounds 4 and 9 may be prepared by the cleavage of N-Boc group of compounds 3 and 8, respectively, with trifluoroacetic acid in dichloromethane.
  • Compound 8 may, in turn, be prepared by reacting compound 3 with compound 7 (wherein R 4' is C h alky!, heteroaryl-Ci- 6 alkyl, or Ci- 6 alkoxy- Ci-6alkyl) in the presence of an appropriate base (e.g., KOBu-t, or NaH) in a polar solvent (e.g., DMSO, or DMF).
  • an appropriate base e.g., KOBu-t, or NaH
  • a polar solvent e.g., DMSO, or DMF
  • Compound 3 may be synthesized in two steps from 4- hydroxy-naphthalene-2-carboxylic acid ester 1 [WO2010/139481 ], as shown in Scheme 1.
  • triflate 2 is obtained by reacting compound 1 with triflic anhydride in the presence of an appropriate base (e.g., pyridine) in a polar solvent (e.g., dichloromethane).
  • an appropriate base e.g., pyridine
  • a polar solvent e.g., dichloromethane
  • N-Boc protected alkyl 4-amino-2-naphthoate 3 may, in turn, be prepared by reacting triflate 2 with tert-butyl carbamate in the presence of an appropriate palladium catalyst (e.g., Pd 2 dba3), complexing ligand (e.g., Xantphos), and an appropriate base (e.g., cesium carbonate) in a polar solvent (e.g., THF).
  • an appropriate palladium catalyst e.g., Pd 2 dba3
  • complexing ligand e.g., Xantphos
  • an appropriate base e.g., cesium carbonate
  • the compounds of general Formula IB may be prepared in three steps from an appropriately substituted N-Boc protected alkyl 4- amino-2-naphthoate 3 (Scheme 3).
  • compound 3 may react with compound 11 (wherein R 12 represents hydrogen, C h alky! or Ci-6alkoxy-Ci-6alkyl; and wherein R 7 represents aryl, heteroaryl, or Ci-6alkoxy) to give compound 12.
  • R 12 represents hydrogen, C h alky! or Ci-6alkoxy-Ci-6alkyl; and wherein R 7 represents aryl, heteroaryl, or Ci-6alkoxy
  • the N-Boc group of compound 12 may be cleaved with trifluoroacetic acid in dichloromethane to obtain compound 13.
  • the ester group of compound 13 may be hydrolyzed using reagents such as aqueous lithium hydroxide or sodium hydroxide to yield compound IB.
  • the compounds of general Formula IB may be prepared by an analogous procedures from N-Boc protected alkyl 4-amino-2-naphthoate 3 or from compound 9.
  • compound 9 may react with compound 11 in the presence of an appropriate base (e.g., potassium carbonate) in a polar solvent (e.g., DMSO, or DMF) to give compound 14.
  • an appropriate base e.g., potassium carbonate
  • a polar solvent e.g., DMSO, or DMF
  • compound 14 may be prepared by reacting compound 13 with compound 7 in the presence of an appropriate base (e.g., potassium carbonate) in a polar solvent (e.g., DMSO, or DMF).
  • an appropriate base e.g., potassium carbonate
  • a polar solvent e.g., DMSO, or DMF.
  • the ester group of compound 14 may be hydrolyzed using aqueous lithium hydroxide or sodium hydroxide to yield compound IB.
  • the compounds of Formula IC may be prepared from compound 14, wherein R 7 represents tert-butoxy group (Scheme 4). Cleavage of tert-butoxy group of compound 14 by TFA in dichloromethane may give carboxylic acid 15 which may, in turn, react with amine 16 in the presence of condensing agent (e.g., EDCI and HOBT) and an appropriate base (e.g., triethylamine, or DIPEA) in a polar solvent (e.g., acetonitrile, or DMF) to give compound 17. Hydrolysis of ester groups of compound 17 as described above may provide compound of Formula IC.
  • condensing agent e.g., EDCI and HOBT
  • an appropriate base e.g., triethylamine, or DIPEA
  • a polar solvent e.g., acetonitrile, or DMF
  • the compounds of general Formula ID may be prepared in two steps from an appropriately substituted 1 -chloro-isoquinoline-3-carboxylic acid ester 21 (Scheme 5).
  • compound 21 may react with amine 22 (wherein R 4 and R 5 independently represent hydrogen, C h alky!, aryl-Ci- 6 alkyl, heteroaryl-Ci- 6 alkyl, Ci-6-alkoxy-Ci- 6 alkyl, and arylaminocarbonyl-Ci- 6 alkyl, heteroarylaminocarbonyl-Ci- 6 alkyl, aryl- Ci- 6 alkyaminocarbonyl-Ci-6-alkyl or heteroaryl-Ci-6-alkyaminocarbonyl-Ci- 6 alkyl) in the presence of an appropriate base (e.g., DIPEA) in a polar solvent (e.g., DMSO, or DMF) to give compound 23.
  • an appropriate base e.g., DIPEA
  • the ester group of compound 23 may be hydrolyzed using reagents such as aqueous lithium hydroxide or sodium hydroxide to yield compound I.
  • Necessary 1 -chloro-isoquinoline 21 may be prepared from corresponding 1 -oxo-1 ,2- isoquinoline-3-carboxylic acid ester 20 by a common chlorination procedure with phosphoryl chloride.
  • Compound 20 may, in turn, be prepared by condensation of 1 -oxo- 1 H-isochromene-3-carboxylic acid ester 19 with ammonium carbonate. Ester 19 may be obtained by esterification of 1 -oxo-1 H-isochromene-3-carboxylic acid 18.
  • reaction products may be isolated and purified by standard laboratory techniques, such as extraction, chromatography and crystallization.
  • Products isolated as a free base may be further converted into a hydrochloride or any other pharmaceutically acceptable salt according to known procedures.
  • Products isolated as a free carboxylic acid may be converted into sodium salt or any other pharmaceutically acceptable salt according to known procedures.
  • salts of the compounds of Formula I are those wherein the counterion is pharmaceutically acceptable.
  • salts of acids and bases which are non-pharmaceutically acceptable, may also find use, for example, in the preparation and purification of pharmaceutically acceptable compounds. All salts whether pharmaceutically acceptable or not are included within the ambit of the present invention.
  • the pharmaceutically acceptable salts as mentioned above are meant to comprise the therapeutically active non-toxic salt forms, which the compounds of Formula I are able to form. The latter can conveniently be obtained by treating the base form with such appropriate acids as inorganic acids, e.g.
  • hydrohalic acids such as hydrochloric, hydrobromic and the like; sulfuric acid; nitric acid; phosphoric acid and the like; or organic acids such as acetic, propanoic, hydroxyacetic, 2-hydroxypropanoic, oxopropanoic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, 2-hydroxy-1 ,2,3- propanetricarboxylic, methanesulfonic, ethanesulfonic, benzenesulfonic, 4- methylbenzenesulfonic, cyclohexanesulfonic, 2-hydroxybenzoic, 4-amino-2- hydroxybenzoic and like acids.
  • the salt may be converted to the free base by treatment with alkali.
  • Compounds of Formula I can form pharmaceutically acceptable salts with various basic compounds. Suitable base salts include, but are not limited to, ammonium, potassium, sodium, and choline salts.
  • compositions and unit dosages thereof may be placed into the form of pharmaceutical compositions and unit dosages thereof, and in such form may be employed as solids, such as coated or uncoated tablets or filled capsules, liquids, such as solutions, suspensions, emulsions, elixirs, or capsules filled with the same, or thin films/flash doses, all for oral use; in the form of suppositories or capsules for rectal administration or in the form of sterile injectable solutions for parenteral (including intravenous or subcutaneous) use.
  • parenteral including intravenous or subcutaneous
  • Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional or new ingredients in conventional or special proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective amount of the active ingredient of the compounds of the present invention commensurate with the intended daily dosage range to be employed.
  • Tablets containing one (1 ) to one hundred (100) milligrams of active ingredient or, more broadly, zero point five (0.5) to five hundred (500) milligrams per tablet, are accordingly suitable representative unit dosage forms.
  • excipient applied to pharmaceutical compositions of the invention refers to an adjuvant, carrier, diluent, or vehicle with which a compound of the present invention is administered.
  • Such pharmaceutical excipients may be sterile or non-sterile excipients commonly used for the formulation and production of solid, semi solid, liquid and sterile pharmaceutical compositions.
  • excipients may also be liquids, such as water, saline solutions, aqueous dextrose solutions, aqueous glycerol solutions, and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like.
  • A.R. Gennaro, 20 th Edition describes suitable pharmaceutical carriers in "Remington: The Science and Practice of Pharmacy".
  • the excipients may also be combinations of solids and liquids.
  • the active principles of the invention may be administered to a subject, e.g., a living animal (including a human) body, in need thereof, for the treatment, alleviation, or amelioration, palliation, or elimination of an indication or condition which is susceptible thereto, or representatively of an indication or condition set forth elsewhere in this application, including concurrently, simultaneously, or together with one or more pharmaceutically-acceptable excipients, carriers, or diluents, including in the form of a pharmaceutical composition thereof, whether by oral, rectal, or parental (including intravenous and subcutaneous) or in some cases even topical route, in an effective amount.
  • Suitable dosage ranges are 1 -1000 milligrams daily, optionally 10-500 milligrams daily, and optionally 50-500 milligrams daily, depending as usual upon the exact mode of administration, form in which administered, the indication toward which the administration is directed, the subject involved and the body weight of the subject involved, and the preference and experience of the physician or veterinarian in charge.
  • treat is used herein to mean to relieve or alleviate at least one symptom of a disease in a subject.
  • the term “treat” also denotes to arrest, delay the onset (i.e., the period prior to clinical manifestation of a disease) and/or reduce the risk of developing or worsening a disease.
  • terapéuticaally effective applied to dose or amount refers to that quantity of a compound or pharmaceutical composition that is sufficient to result in a desired activity upon administration to a living animal body in need thereof.
  • the compounds of the present invention may be administered orally, topically, parenterally, or mucosally (e.g., buccally, by inhalation, or rectally) in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers. It is usually desirable to use the oral route.
  • the compounds of the present invention may be administered orally in the form of a capsule, a tablet, or the like (see Remington: The Science and Practice of Pharmacy, 20 th Edition).
  • the orally administered medicaments may be administered in the form of a time-controlled release vehicle, including diffusion-controlled systems, osmotic devices, dissolution-controlled matrices, and erodible/degradable matrices.
  • the glycine B antagonist active component may be combined with a non-toxic, pharmaceutically acceptable excipients such as binding agents (e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, sucrose, glucose, mannitol, sorbitol and other reducing and non-reducing sugars, microcrystalline cellulose, calcium sulfate, or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc, or silica, steric acid, sodium stearyl fumarate, glyceryl behenate, calcium stearate, and the like); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulphate), coloring and flavoring agents, gelatin, sweeteners, natural and synthetic gums
  • binding agents e.g., pregelatinized maize star
  • the glycine B antagonist active components may be combined with non-toxic, pharmaceutically acceptable inert carriers ⁇ e.g., ethanol, glycerol, water), suspending agents (e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats), emulsifying agents (e.g., lecithin or acacia), non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol or fractionated vegetable oils), preservatives (e.g., methyl or propyl-p-hydroxybenzoates or sorbic acid), and the like.
  • Stabilizing agents such as antioxidants (BHA, BHT, propyl gallate, sodium ascorbate, citric acid) may also be added to stabilize the dosage forms.
  • the tablets may be coated by methods well known in the art.
  • the compounds of the present invention may be also introduced in beads, microspheres or microcapsules, e.g., fabricated from polyglycolic acid/lactic acid (PGLA).
  • Liquid preparations for oral administration may take the form of, for example, solutions, syrups, emulsions or suspensions, or they may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Preparations for oral administration may be suitably formulated to give controlled or postponed release of the active compound.
  • the compounds of the present invention may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines, as is well known.
  • the compounds of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled.
  • the instant compounds may also be coupled with soluble polymers as targetable drug carriers.
  • Such polymers include polyvinyl-pyrrolidone, pyran copolymer, polyhydroxy-propyl methacrylamide-phenol, polyhydroxy-ethyl-aspartamide-phenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues.
  • the instant compounds may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polyhydropyrans, polycyanoacrylates, and cross-linked or amphipathic block copolymers of hydrogels.
  • a drug for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polyhydropyrans, polycyanoacrylates, and cross-linked or amphipathic block copolymers of hydrogels.
  • the compounds of the present invention may be conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • Capsules and cartridges of, e.g., gelatin for use in an inhaler or insufflator can be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
  • the formulations comprising the compounds of the present invention may be delivered parenterally, i.e., by intravenous (i.v.), intracerebroventricular (i.c.v.), subcutaneous (s.c), intraperitoneal (i.p.), intramuscular (i.m.), subdermal (s.d.), or intradermal (i.d.) administration, by direct injection, via, for example, bolus injection or continuous infusion.
  • Formulations for injection can be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
  • compositions can take such forms as excipients, suspensions, solutions, or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • the active ingredient of the compounds of the present invention can be in powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • the compounds of the present invention may also be formulated for rectal administration, e.g., as suppositories or retention enemas ⁇ e.g., containing conventional suppository bases such as cocoa butter or other glycerides).
  • compositions comprising glycine B antagonists of the present invention may, if desired, be presented in a pack or dispenser device, which may contain one or more unit dosage forms containing the active ingredient and/or may contain different dosage levels to facilitate dosage titration.
  • the pack may, for example, comprise metal or plastic foil, such as a blister pack.
  • the pack or dispenser device may be accompanied by instructions for administration.
  • the glycine B antagonists of the present invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
  • the dose of the components in the compositions of the present invention is determined to ensure that the dose administered continuously or intermittently will not exceed an amount determined after consideration of the results in test animals and the individual conditions of a patient.
  • a specific dose naturally varies depending on the dosage procedure, the conditions of a patient or a subject animal such as age, body weight, sex, sensitivity, feed, dosage period, drugs used in combination, seriousness of the disease.
  • the appropriate dose and dosage times under certain conditions can be determined by the test based on the above-described indices but may be refined and ultimately decided according to the judgment of the practitioner and each patient's circumstances (age, general condition, severity of symptoms, sex, etc.) according to standard clinical techniques.
  • Toxicity and therapeutic efficacy of the compositions of the invention can be determined by standard pharmaceutical procedures in experimental animals, e.g., by determining the LD 50 (the dose lethal to 50% of the population) and the ED 50 (the dose therapeutically effective in 50% of the population).
  • the dose ratio between therapeutic and toxic effects is the therapeutic index and it may be expressed as the ratio LD 5 0/ED 5 0.
  • Compositions that exhibit large therapeutic indices are preferred.
  • the present invention provides novel and valuable applications and uses of the compounds of the present invention, which compounds comprise the active principle according to the present invention, as well as novel pharmaceutical compositions thereof and methods of preparation thereof and of treating therewith.
  • the high order of activity of the active agent of the present invention and compositions thereof, as evidenced by the tests reported, is indicative of utility based on its valuable activity in human beings as well as in lower animals. Clinical evaluation in human beings has not been completed. It will be clearly understood that the distribution and marketing of any compound or composition falling within the scope of the present invention for use in human beings will of course have to be predicated upon prior approval by governmental agencies which are responsible for and authorized to pass judgment on such questions.
  • the instant compounds of Formula I represent a novel class of glycine B antagonists. In view of their potency, they will be useful therapeutics in a wide range of disorders, including CNS disorders, which involve excessive glutamate induced excitation.
  • Use of the compounds of the present invention in the treatment of a living animal for inhibition of progression or alleviation of selected ailments or conditions, particularly ailments or conditions susceptible to treatment with a glycine B is carried out in the usual manner comprising the step of admixing an effective amount of a compound of the invention with a pharnnaceutically-acceptable diluent, excipient, or carrier, and the method-of-treating, pharmaceutical compositions, and use of a compound of the present invention in the manufacture of a medicament.
  • compositions prepared by admixing the active ingredient with a suitable pharnnaceutically-acceptable excipient, diluent, or carrier include tablets, capsules, solutions for injection, liquid oral formulations, aerosol fornnulations, TDS fornnulations, and nanopartide fornnulations, thus to produce medicaments for oral, injectable, or dermal use, also in accord with the foregoing.
  • DMF is defined as ⁇ , ⁇ -dimethylformamide, "DCM” as dichloromethane, “HCI” as hydrochloric acid, “DMSO” as dimethyl sulfoxide, “DIPEA” as ⁇ , ⁇ -diisopropylethylamine, “EDC” as 1 -ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride, ⁇ " as 1 -hydroxy-benzotriazole, “Pd2dba3 M as tris(dibenzylideneacetone)-dipalladium(0), “TBAI” as tetrabutylammonium iodide, “CDI” as 1 ,1 '-carbonyldiimidazole, “TFA” as trifluoroacetic acid, “MeCN” as acetonitrile, “THF” as tetrahydrofuran, "AcOH”
  • reaction mixture is filtered through silica gel (50 g) and the column is washed with THF. The filtrate is evaporated and the residue (8.6 g) is chromatographed on silica gel (300 g) (petroleum ether-EtOAc; gradient from 100:0 to 90:10) to give the title compound 3 (5.02 g, 83%).
  • DIPEA 43.06 mg, 0.33 mmol
  • CDI 30.62 mg, 0.19 mmol
  • the resulting mixture is stirred at 60 °C for 30 min then methyl 4-amino-5,7-dichloro-2- naphthoate, 0.43 trifluoroacetate (4) (0.036 g) is added and stirring is continued for 24 h at 60 °C.
  • the reaction mixture is allowed to cool to rt, then distilled water is added.
  • Crystallized material is filtered, washed with water and diethyl ether, and dried at 60 °C under reduced pressure to give 270 mg (63%) of the title compound.
  • Methyl 6-chloro-1 -oxo-1 ,2-dihydroisoquinoline-3-carboxylate 400 mg, 1 .68 mmol
  • POCI3 8 mL
  • 2 drops of DMF 2 drops
  • the mixture is heated at 100 °C for 7 h. Then it is allowed to cool to rt and slowly poured on ice. The precipitated solid is filtered off, washed with water and dried to give the title compound (401 mg, 93%) as a white solid.
  • the title compound is prepared from methyl 1 ,6,8-trichloroisoquinoline-3- carboxylate and 2-amino-N-(pyridin-2-ylmethyl)acetamide by analogy to the procedures described in Example 30 (i) and Example 1 (b).
  • the title compound is prepared from methyl 1 ,6,8-trichloroisoquinoline-3- carboxylate and 2-(methylamino)-N-(pyridin-3-ylmethyl)acetamide by analogy to the procedures described in Example 30 (i) and Example 1 (b).
  • reaction products can be processed into tablets, coated tablets, capsules, drip solutions, suppositories, injection and infusion preparations, and the like and can be
  • compositions follow.
  • Tablets suitable for oral administration which contain the active ingredient, may be prepared by conventional tabletting techniques.
  • any usual suppository base may be employed for incorporation thereinto by usual procedure of the active ingredient, such as a
  • polyethyleneglycol which is a solid at normal room temperature but which melts at or about body temperature.
  • a suitable formulation for a tablet containing 10 milligrams of active ingredient is as follows:
  • Another suitable formulation for a tablet containing 100 mg is as follows:
  • the film coating material consists of:
  • a suitable formulation for a capsule containing 50 milligrams of active ingredient is as follows:
  • Colloidal silicon dioxide 2 filled in a gelatin capsule.
  • a suitable formulation for an injectable solution is as follows:
  • Liquid oral formulation A suitable fornnulation for 1 liter of an oral solution containing 2 milligrams of active ingredient in one milliliter of the mixture is as follows:
  • Another suitable formulation for 1 liter of a liquid mixture containing 20 milligrams of active ingredient in one milliliter of the mixture is as follows:
  • Purified water 19.6 1 .8 ml of the solution are placed on a fleece covered by an adhesive backing foil.
  • the system is closed by a protective liner which will be removed before use.
  • Polybutylcyanoacrylate nanopartides are prepared by emulsion polymerization in a water/0.1 N HCI/ethanol mixture as polymerizsation medium. The nanopartides in the suspension are finally lyophilized under vacuum.
  • Tissue preparation is performed according to Foster & Wong (Br J
  • the homogenate is centrifuged at 1000 x g for 10 minutes, the pellet is discarded and the supernatant centrifuged at 20,000 x g for 20 minutes.
  • the resulting pellet is re- suspended in 20 volumes of distilled water and centrifuged for 20 minutes at 8000 x g.
  • the supernatant and the buffy coat are then centrifuged six times (48,000 x g for 20 minutes) in the presence of 5 mM Tris-HCI, pH 7.5. All centrifugation steps are carried out at 4°C. After resuspension in 5 volumes of 5 mM Tris-HCI, pH 7.5, the membrane suspension is frozen rapidly at -80°C.
  • the membranes are thawed, centrifuged (48,000 x g for 20 minutes) and then resuspended in 50 mM Tris-HCI, pH 7.5 (assay buffer). The amount of protein in the final membrane preparation is
  • Displacement studies [00237] A robotic system designed for 384-well format displacement studies (Tecan GmbH) is loaded with the membrane solution, test compounds, bound control (DMSO 100 %), unlabeled glycine (1 mM, Sigma-Aldrich) for evaluation of non-specific binding and radioligand.
  • protein/receptor concentration is held constant whereas the amount of specific bound radioligand is determined using increasing concentrations of ligand.
  • the measured radioactivity of the radioligand alone is set as 100 % bound control and the non-specific binding of the radioligand (which could not be displaced by glycine, 1 mM) represented the 0 % control.
  • the residual radioactivity after displacement of the test compound is then corrected with respect to the set controls. Data processing and analysis is done with the help of Pipeline Pilot software (Accelrys, Cambridge, U.K.) for IC 5 0 and Ki-value determination.
  • Antagonistic potencies of the test compounds in central and peripheral nerve cell preparations are functionally evaluated using electrophysiological whole cell patch-clamp recordings and/or fluorometric intracellular Ca 2+ -imaging by means of a Functional Drug Screening System (FDSS 7000, Hamamatsu, Herrsching, Germany).
  • FDSS 7000 Functional Drug Screening System
  • Hippocampi are pre-incubated for 8 min with a 0.66% trypsin (Sigma- Aldrich) and 0.1 % (20 U/ml) DNAase solution (Sigma-Aldrich) in Ca 2+ -free Phosphate Buffered Saline (PBS-CF, Biochrom, Berlin, Germany) and washed 3 times with HBSS- CMF. Cells are then mechanically dissociated by trituration in a PBS-CF solution containing 0.05% (10 U/ml) DNAase and 0.3% of the trypsin inhibitor ovomucoid (all from Sigma-Aldrich).
  • the cells are then centrifuged at 180 x g for 10 minutes, and the cell pellet re-suspended in basal Minimum essential medium (MEM, Invitrogen), again carefully triturated to ensure maximal dissociation and finally plated in the flexiPERM inserts (Thermo Fisher Scientific, Langenselbold, Germany) at a density of 15 x 10 3 cells/cm 2 (0.5 ml/insert) onto poly-DL-ornithine (Sigma) and mouse laminin (Invitrogen) pre-coated plastic petri dishes. After 1 hour the cells become attached to the bottom of the dish and the inserts may be removed.
  • MEM basal Minimum essential medium
  • the cells are then nourished with 2 ml MEM supplemented with 5% foetal calf serum (FCS) and 5% horse serum (all from Biochrom) and incubated at 37°C with 95% air and 5% CO 2 at 95% humidity.
  • FCS foetal calf serum
  • horse serum all from Biochrom
  • the medium is completely exchanged after an additional 2 DIV and again, but only partly (50 %), after 8 DIV.
  • the cells are used for electrophysiological recordings after 1 1 -15 DIV.
  • DRG dorsal root ganglia
  • Sprague-Dawley rats (Janvier) are anaesthetised by placing in a CO 2 - euthanasia chamber and sacrificed by decapitation.
  • the vertebral column is isolated and collected in ice cold Ca 2+ - and Mg 2+ -free Phosphate Buffered Saline.
  • the spinal cord is removed and the dorsal root ganglia are harvested bilaterally from the thoracic to lumbosacral regions. They are collected in ice- cold HBSS-CMF in a 12-well plate, transferred to 35 mm dishes with fresh ice-cold HBSS-CMF and cleared from contaminating connective tissue and the dura mater spinalis.
  • ganglia For further washing, purified ganglia are placed back in a 12 well plate containing fresh ice cold HBSS-CMF. After cutting the ganglia with small scissors, the ganglia digest is performed in 6-well plates by adding Liberase TM (Roche Diagnostics, Mannheim, Germany) dissolved in HBSS-CMF and incubating at RT and 37°C in an incubator for approximately 10 minutes, followed by a mechanical dissociation step performed with two canulaes. Enzymatic digestion is terminated by centrifugation at 180 g for 5 minutes and rinsing the cells with Neurobasal A medium (Invitrogen) without supplements but containing 10% FCS and 0.1 mg/ml DNase I (Sigma-Aldrich). After another centrifugation step at 180 g for 5 minutes, the cells are suspended in
  • the cell suspension is plated onto 35-mm culture dishes coated with poly- DL-ornithine (Sigma-Aldrich) and mouse laminin from Invitrogen containing flexiPERM inserts.
  • DRG neurons are used for electrophysiological recordings 48 hours after cell preparation.
  • borosilicate glass using a horizontal puller (P-97 Puller, Sutter Instruments, USA) and, when filled with intracellular solution, have resistances of 1 - 4 ⁇ .
  • Solutions are delivered via a home-made gravity driven very fast perfusion system ( ⁇ 10 ms) including valves to switch flow on and off in combination with a stepper motor-driven double-barrelled theta glass application pipette in order to expose cells to either agonist-free or agonist-containing solutions in presence or absence of antagonist.
  • the intracellular solution used consists of: 120 mM CsCI, 10 mM EGTA, 1 mM MgCI 2 , 200 ⁇ CaCI 2 , 10 mM glucose and 22 mM tetraethyl ammonium chloride (TEA-CI).
  • the corresponding extracellular bath solution contains: 140 mM NaCI, 3 mM KCI, 10 mM glucose, 10 mM HEPES, 1 .5 mM CaCI 2 and 4.5 mM sucrose (all from Sigma-Aldrich) pH 7.3, and is supplemented with 0.3 ⁇ tetrodotoxin (TTX, Tocris, Bristol, U.K.) to block voltage-activated sodium channels and 0.25 ⁇ bicuculline (Sigma-Aldrich) to block GABA A receptors.
  • TTX tetrodotoxin
  • rat cortical neurons Preparation and cultivation of rat cortical neurons [00254] Primary neurons are prepared from cortices of embryonal rats at day 17 of pregnancy as described by Dichter (Brain Res., 1987, 149, 279). Sprague-Dawley rat embryos (E 17, Charles River) are decapitated and neocortices are dissected, trypsinized and carefully triturated. The cell suspension is plated on poly-d-lysine pre- coated 384-well Plates (Aurora Biotechnologies, Carlsbad, USA) at a cell density of 15.000 cells /well.
  • the neurons are cultivated in Neurobasal media containing B27- Supplement (Invitrogen) and 0.5 ⁇ L-Glutamine (Biochrom) at 37°C in a humidified atmosphere of 5% CO2 / 95% air. Medium is exchanged completely at day 4 and to 50% on day 7. At the time of experiments neurons are 1 1 - 13 days in vitro.
  • Antagonists are pre- incubated with the cells for 10 min at room temperature before the addition of the agonist.
  • the fluorescence signal increase after addition of agonist reflects the increase of intracellular calcium.
  • the calcium changes in response to different concentrations of antagonist are determined using an area under the curve (AUC) calculation. All responses (RFU-values) are determined as percentage of control at agonist EC80 (12 ⁇ NMDA).
  • AUC area under the curve
  • All responses are determined as percentage of control at agonist EC80 (12 ⁇ NMDA).
  • Pipeline Pilot is used. Due to high intrinisic glycine site co-agonist concentrations within the assay system, resulting in a full activation of the receptor, K b calculations are not possible since EC 5 o's for D-serine could not be determined.
  • Example 54 4-ylmethyl)amino)-2-oxoethyl)amino)-2- 1.07 naphthoic acid 6,8-Dichloro-1 -(methyl(2-oxo-2-((pyridin-)
  • the present invention provides novel, valuable, and unpredictable applications and uses of the compounds of the present invention, which compounds comprise the active principle according to the present invention, as well as novel pharmaceutical compositions thereof and methods of preparation thereof and of treating therewith, all possessed of the foregoing more specifically-enumerated characteristics and advantages.
  • peripheral neuropathy including, for example peripheral neuropathy induced by nociception, inflammation, ischemia, viral infection (HZV), traumatic and other mechanical nerve injury, cancer, chemotherapy induced pain, diabetes mellitus, HIV infection, fibromyalgia, trigeminus neuralgia, inflammatory bowel diseases (IBD), irritative bowel syndrome (IBS), arthritis including rheumatoid arthritis, osteoarthritis (degenerative joint disease), multiple sclerosis (MS) and gout (metabolic arthritis).
  • pain including acute pain, chronic pain, allodynia, hyperalgesia, visceral pain, phantom pain, post-operative pain, neuropathic pain
  • peripheral neuropathy including, for example peripheral neuropathy induced by nociception, inflammation, ischemia, viral infection (HZV), traumatic and other mechanical nerve injury, cancer, chemotherapy induced pain, diabetes mellitus, HIV infection, fibromyalgia, trigeminus neuralgia, inflammatory bowel diseases (IBD),
  • These compounds also find application in the treatment of the following disorders of a living animal body, especially a human: acute insults, including cerebral ischemia, cerebral infarct, brain oedema, anoxia, inner ear insult, inner ear insult in tinnitus, head or brain or spinal cord trauma, head or brain or spinal cord injuries, trauma, sound- or drug-induced inner ear insult, ischaemia resulting from cardiac arrest or stroke or bypass operations or transplants, acute pain, hypoxia, perinatal hypoxia, and ischaemia; chronic insults, such as neurodegenerative disorders, including Morbus Huntington, Alzheimer's disease Creutzfeld-Jakob ' s syndrome/disease, bovine spongiform encephalopathy (BSE) prion related infections, diseases involving mitochondrial dysfunction, diseases involving ⁇ -amyloid and/or tauopathy, Down's syndrome, motor neuron diseases, amyotrophic lateral sclerosis (ALS), olivopontocerebellar atrophy, Parkinson'
  • neurological disorders including tinnitus, hearing loss, sound- or drug-induced tinnitus, haloperidol-induced dyskinesias, dopaminomimetic-induced dyskinesias, chorea, Huntington's chorea, athetosis, dystonia, stereotypy, ballism, tardive dyskinesias, tic disorder, spasmodic torticollis, blepharospasm, focal and generalized dystonia, nystagmus, Parkinson's dementia, mild cognitive impairment, cognitive deficits in various forms of mild cognitive impairment, cognitive deficits in various forms of dementia, dementia pugilistica, vascular and frontal lobe dementia, cognitive impairment, learning impairment, L-dopa-induced dykinesias, L-dopa-induced dykinesias in Parkinson's disease therapy, dyskinesias, dyskinesia in Huntington's disease, drug induced dyskinesias, neurol
  • convulsions epilepsy, temporal lobe epilepsy, myoclonic epilepsy, tremor, dementia in Alzheimer's disease, dementia in Korsakoff syndrome, dementia, hereditary cerebellar ataxias, sleep disorders, movement disorders, essential tremor, muscle spasms, and spasticity; psychological/psychiatric disorders, including generalized anxiety disorder, obsessive- compulsive disorder, panic disorder, posttraumatic stress disorder, social phobia, phobic disorders, substance-induced anxiety disorder, delusional disorder,
  • schizoaffective disorder schizophreniform disorder, substance-induced psychotic disorder, delirium, post-operative cognitive deficit (POCD), cognitive impairment, learning impairment, anxiety disorders, panic disorders, anxiety and panic disorders, social anxiety disorder (SAD), attention deficit hyperactivity disorder (ADHD), attention deficit syndrome (ADS), dementia, posttraumatic stress disorder (PTSD), schizophrenia, positive or cognitive or negative symptoms of schizophrenia, major depressive disorder, major depression, depression, bipolar manic-depressive disorder, sleep disorders, agoraphobia, bulimia nervosa, eating disorders, obesity, obesity-related disorders, obesity abuse, food addiction, binge eating disorders, and hyperactivity in children; drug/alcohol abuse, including craving (e.g., for drugs of abuse), abuse, addiction, nicotine addiction, nicotine abuse, alcohol addiction, alcohol abuse, opiate addiction, opiate abuse, cocaine addiction, cocaine abuse, amphetamine addiction, and
  • amphetamine abuse skin diseases, including atopic dermatitis, itching, skin lesions induced by severe itching or atopic dermatitis, systemic sclerosis, pruritic conditions, and pruritis; diseases of the gastro-intestinal tract and metabolic diseases, including diarrhoea, hepatic encephalopathy, hypoglycaemia, gastroesophageal reflux disease (GERD), gastrointestinal dysfunction, lower esophageal sphincter (LES) disease, functional gastrointestinal disorders, dyspepsia, vomiting, urinary incontinence, and regurgitation; diseases of the immune system, including Sjogren's syndrome, systemic lupus erythematosus, and multiple sclerosis (MS); eye diseases, including eye injuries, eye diseases, eye disorders, glaucoma,
  • retinopathy and macular degeneration
  • diseases of the respiratory tract including respiratory tract infection, chronic laryngitis, asthma, reflux-related asthma, and lung disease; migraine; autism; restless leg syndrome (RLS); Tourette syndrome; micturition disorders; neuromuscular disorder in the lower urinary tract; and drug tolerance to opioids.
  • the method-of-treating a living animal body with a compound of the invention, for the inhibition of progression or alleviation of the selected ailment therein, is as previously stated by any normally-accepted pharmaceutical route, employing the selected dosage which is effective in the alleviation of the particular ailment desired to be alleviated.
  • compositions prepared by admixing the active ingredient with a suitable pharmaceutically-acceptable excipient, diluent, or carrier include tablets, capsules, solutions for injection, liquid oral formulations, aerosol formulations, TDS formulations, and nanoparticle formulations, thus to produce medicaments for oral, injectable, or dermal use, also in accord with the foregoing.

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Abstract

The invention relates to 4-aminonaphthalene-2-carboxylic acids and 1-amino- isoquinoline-3-carboxylic acids as well as their pharmaceutically acceptable salts. The invention further relates to a process for the preparation of such compounds. The compounds of the invention are glycine B antagonists and are therefore useful for the control and prevention of various disorders, including neurological disorders.

Description

GLYCINE B ANTAGONISTS
FIELD OF THE INVENTION
[0001 ] The present invention relates to novel 4-aminonaphthalene-2-carboxylic acids and 1 -amino-isoquinoline-3-carboxylic acids which may act as glycine B antagonists, methods for their synthesis and the treatment and/or prevention of various diseases and disorders, including neurological disorders, by administration of such substances.
BACKGROUND OF THE INVENTION
[0002] Glutamate is a major excitatory transmitter in the central nervous system and it has become clear in recent years that it is also very important in the peripheral nervous system (PNS). Glutamate is believed to be involved in many pathological and excitotoxic processes; therefore, there is a great deal of interest in the development of glutamate antagonists for therapeutic uses. Glutamate activates three major types of ionotropic receptors: a-amino-3-hydroxy-5-methyl-4-isoazolepropionic acid (AMPA), kainate, and N-methyl-D-aspartate (NMDA) as well as several types of metabotropic receptors. Antagonism of NMDA receptors potentially has a wide range of therapeutic applications. Functional inhibition of NMDA receptors may be achieved through actions at different recognition sites, such as the primary transmitter site, the strychnine insensitive glycine site (glycine B), the polyamine site, and the phencyclidine site located inside the cation channel.
[0003] Receptor desensitization may represent a physiological process serving as an endogenous control mechanism to prevent long term neurotoxic activation of glutamate receptors but allow their transient physiological activation. In the case of the NMDA receptor, the co-agonist glycine is an endogenous ligand inhibiting such desensitization via activation of the glycine B site. It is noteworthy that ischemia increases not only the concentration of extracellular glutamate but also that of glycine and, although this latter effect is less pronounced, it actually persists for a longer period of time. Thus, glycine B antagonists may restore normal synaptic transmission under such conditions by increasing NMDA receptor desensitization to its physiological level. It has been suggested that glycine B antagonists may offer a better therapeutic window than agents acting at other recognition sites of the NMDA receptor complex.
[0004] Therefore, glycine B antagonists, may be useful for the treatment and/or prevention of pain, including acute pain, chronic pain, allodynia, hyperalgesia, visceral pain, phantom pain, post-operative pain, neuropathic pain, peripheral neuropathy including, for example neuropathy induced by nociception, inflammation, ischemia, viral infection (herpes zoster virus, HZV), traumatic and other mechanical nerve injury, cancer, chemotherapy, diabetes mellitus, HIV infection, fibromyalgia, trigeminus neuralgia, inflammatory bowel diseases (IBD), irritative bowel syndrome (IBS), complex regional pain syndrome, carpal tunnel syndrome, arthritis including rheumatoid arthritis, osteoarthritis (degenerative joint disease), multiple sclerosis (MS) and gout (metabolic arthritis).
[0005] Blood-brain barrier impermeable glycine B antagonists, which are restricted to action in the PNS, may be particularly useful since such antagonists do not exhibit CNS side effects.
[0006] Glycine B antagonists may also be useful for the treatment and/or prevention of acute insults, including cerebral ischemia, cerebral infarct, brain oedema, anoxia, inner ear insult, inner ear insult in tinnitus, head or brain or spinal cord trauma, head or brain or spinal cord injuries, trauma, sound- or drug-induced inner ear insult, ischaemia resulting from cardiac arrest or stroke or bypass operations or transplants, acute pain, hypoxia, perinatal hypoxia, and ischaemia; chronic insults, such as neurodegenerative disorders, including Morbus Huntington, Alzheimer's disease Creutzfeld-Jakob's syndrome/disease, bovine spongiform encephalopathy (BSE) prion related infections, diseases involving mitochondrial dysfunction, diseases involving β-amyloid and/or tauopathy, Down's syndrome, motor neuron diseases, amyotrophic lateral sclerosis (ALS), olivoponto-cerebellar atrophy, Parkinson's disease, Neuronal Ceroid Lipofuscinosis, AIDS dementia complex, AIDS- related dementia, dementia related to HIV infections, HIV-1 encephalopathy, AIDS encephalopathy, Korsakoff syndrome, vascular dementia, and corticobasal degeneration; neurological disorders, including tinnitus, hearing loss, sound- or drug-induced tinnitus, haloperidol-induced dyskinesias, dopaminomimetic-induced dyskinesias, chorea, Huntington's chorea, athetosis, dystonia, stereotypy, ballism, tardive dyskinesias, tic disorder, spasmodic torticollis, blepharospasm, focal and generalized dystonia, nystagmus, Parkinson's dementia, mild cognitive impairment, cognitive deficits in various forms of mild cognitive impairment, cognitive deficits in various forms of dementia, dementia pugilistica, vascular and frontal lobe dementia, cognitive impairment, learning impairment, L-dopa-induced dykinesias, L-dopa-induced dykinesias in Parkinson's disease therapy, dyskinesias, dyskinesia in Huntington's disease, drug induced dyskinesias, neuroleptic-induced dyskinesias, neurodegenerative cerebellar ataxias, centrally induced neuropathic pain, chronic low back pain, convulsions, epileptic convulsions, epilepsy, temporal lobe epilepsy, myoclonic epilepsy, tremor, dementia in Alzheimer's disease, dementia in Korsakoff syndrome, dementia, hereditary cerebellar ataxias, sleep disorders, movement disorders, essential tremor, muscle spasms, and spasticity; psychological/psychiatric disorders, including generalized anxiety disorder, obsessive- compulsive disorder, panic disorder, posttraumatic stress disorder, social phobia, phobic disorders, substance-induced anxiety disorder, delusional disorder, schizoaffective disorder, schizophreniform disorder, substance-induced psychotic disorder, delirium, post-operative cognitive deficit (POCD), cognitive impairment, learning impairment, anxiety disorders, panic disorders, anxiety and panic disorders, social anxiety disorder (SAD), attention deficit hyperactivity disorder (ADHD), attention deficit syndrome (ADS), dementia, posttraumatic stress disorder (PTSD), schizophrenia, positive or cognitive or negative symptoms of schizophrenia, major depressive disorder, major depression, depression, bipolar manic-depressive disorder, sleep disorders, agoraphobia, bulimia nervosa, eating disorders, obesity, obesity-related disorders, obesity abuse, food addiction, binge eating disorders, and hyperactivity in children; drug/alcohol abuse, including craving (e.g., for drugs of abuse), abuse, addiction, nicotine addiction, nicotine abuse, alcohol addiction, alcohol abuse, opiate addiction, opiate abuse, cocaine addiction, cocaine abuse, amphetamine addiction, and amphetamine abuse; skin diseases, including atopic dermatitis, itching, skin lesions induced by severe itching or atopic dermatitis, systemic sclerosis, pruritic conditions, and pruritis; diseases of the gastro-intestinal tract and metabolic diseases, including diarrhoea, hepatic encephalopathy, hypoglycaemia, gastroesophageal reflux disease (GERD), gastrointestinal dysfunction, lower esophageal sphincter (LES) disease, functional gastrointestinal disorders, dyspepsia, vomiting, urinary incontinence, and regurgitation; diseases of the immune system, including Sjogren's syndrome, systemic lupus erythematosus, and multiple sclerosis (MS); eye diseases, including eye injuries, eye diseases, eye disorders, glaucoma, retinopathy, and macular degeneration; diseases of the respiratory tract, including respiratory tract infection, chronic laryngitis, asthma, reflux-related asthma, and lung disease; migraine; autism; restless leg syndrome (RLS); Tourette syndrome; micturition disorders; neuromuscular disorder in the lower urinary tract; and drug tolerance to opioids.
THE PRESENT INVENTION
[0007] We have determined that certain 4-aminonaphthalene-2-carboxylic acids and 1 - amino-isoquinoline-3-carboxylic acids are glycine B antagonists. Therefore, these substances may be therapeutically beneficial in the treatment of conditions which involve excitotoxicity and malfunctioning of glutamatergic neurotransmission. These substances may be administered in the form of a pharmaceutical composition, wherein they are present together with one or more pharmaceutically acceptable diluents, carriers, or excipients.
OBJECTS OF THE INVENTION
[0008] It is an object of the present invention to provide novel pharmaceutical compounds which are glycine B antagonists and pharmaceutical compositions thereof. It is a further object of the invention to provide a novel method of treating, eliminating, alleviating, palliating, or ameliorating undesirable conditions, including CNS conditions, associated with excitotoxicity and malfunctioning of glutamatergic neurotransmission by employing a compound of the invention or a pharmaceutical composition containing the same.
[0009] An additional object of the invention is the provision of processes for producing the 4-aminonaphthalene-2-carboxylic acid derivatives and the 1 -aminoisoquinoline-3- carboxylic acid derivatives.
[0010] Yet additional objects will become apparent hereinafter, and still further objects will be apparent to one skilled in the art.
SUMMARY OF THE INVENTION
[001 1 ] What we therefore believe to be comprised by our invention may be summarized inter alia in the following words:
A compound selected from those of Formula I
Figure imgf000006_0001
I wherein X represents CH or N;
R1 represents halogen, Chalky!, or trifluoromethyl; R2 represents hydrogen, halogen, or Chalky!; R3 represents hydrogen, halogen, or Chalky!;
R4 represents hydrogen, Ci-6alkyl, C3-6alkenyl, C3-6alkynyl, hydroxy-Ci-6alkyl, carboxy- Ci-6alkyl, Ci-6alkoxy-Ci-6alkyl, aryl, heteroaryl, cyclo-C3-i2alkyl, cyclo-C3-i2alkyl-Ci-6alkyl, cyclo-C3-i2alkoxy-Ci-6alkyl, aryl-Ci-6alkyl, heteroaryl-Ci-6alkyl, di-
(Ci-6alkyl)aminocarbonyl-Ci-6alkyl or arylcarbonyl,
R5 represents hydrogen, Chalky!, C3-6alkenyl, Cs^alkynyl, hydroxy-Ci-6alkyl, carboxy- Ci-6alkyl, Ci-6alkoxy-Ci-6alkyl, aryl, heteroaryl, cyclo-C3-i2alkyl, cyclo-C3-i2alkyl-Ci-6alkyl, cyclo-C3-i2alkoxy-Ci-6alkyl, aryl-Ci-6alkyl, heteroaryl-Ci-6alkyl, Ci-6alkylsulfonyl, arylsulfonyl, -C(O)-R6, or -Y-C(O)-R7, or R4 and R5 together with the nitrogen atom they are attached represent a 4-, 5-, 6- or 7-membered ring which may be saturated or unsaturated, wherein, in addition to the nitrogen atom, the ring may contain an additional heteroatom selected from sulfur, oxygen and nitrogen and/or be condensed to an aromatic or heteroaromatic ring selected from benzene, furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, imidazole, pyrazole, oxadiazole, thiadiazole, triazole, pyridine, pyrimidine, pyrazine, pyridazine, and wherein the ring may be optionally substituted by one or more substituents selected from halogen, hydroxy, oxo, nitro, acyl, acylamino, trifluoromethyl, Ci-6alkyl, cyclo-C3-i2alkyl, aryl, heteroaryl, aryl -Chalky!, heteroaryl-Ci-6alkyl, Ci-6alkoxy, hydroxy-Ci-6alkyl, Ci-6alkoxy-Ci-6alkyl, COOH, CONH2, Ci-6alkylaminocarbonyl, aryl- aminocarbonyl, heteroaryl-aminocarbonyl, di-(Ci-6alkyl)aminocarbonyl, carboxy- Ci-6alkyl, and carbamoyl-Ci-6alkyl; R6 represents Chalky!, aryl, heteroaryl, cyclo-C3-i2alkyl, cyclo-C3-i2alkyl-Ci-6alkyl, aryl- Ci-6alkyl, heteroaryl-Ci-6alkyl, or -NR8R9;
Y represents
Figure imgf000008_0001
which may be optionally substituted by Chalky!, Ci-6alkoxy- Ci-6alkyl, aryl, heteroaryl, cyclo-C3-i2alkyl, cyclo-C3-i2alkyl-Ci-6alkyl, cyclo-C3-i2alkoxy- Ci-6alkyl, aryl-Ci-6alkyl or heteroaryl-Ci-6alkyl;
R7 represents OH, Ci-6alkoxy, aryl, heteroaryl, heterocyclyl or -NR10R11; R8 represents hydrogen or Chalky!;
R9 represents Ci-6alkyl, aryl, heteroaryl, cyclo-C3-i2alkyl, aryl-Ci-6alkyl, or heteroaryl- Ci-6alkyl;
R10 and R1 1 each independently represent hydrogen, Chalky!, cyclo-C3-i2alkyl, aryl, heteroaryl, cyclo-C3-i2alkyl-Ci-6alkyl, aryl-Ci-6alkyl, or heteroaryl-Ci-6alkyl, or R10 and R11 together with the nitrogen atom they are attached represent a 4-, 5-, 6- or 7-membered ring which may be saturated or unsaturated, wherein, in addition to the nitrogen atom, the ring may contain an additional heteroatom selected from sulfur, oxygen and nitrogen and/or be condensed to an aromatic or heteroaromatic ring selected from benzene, thiazole, imidazole, or pyridine, and wherein the ring may be optionally substituted by one or more substituents selected from hydroxy, oxo, amino, acyl, acylamino, trifluoromethyl, Chalky!, cyclo-C3-i2alkyl, aryl, Ci-6alkoxy, hydroxy- Ci-6alkyl, and Ci-6alkoxy-Ci-6alkyl; wherein the term "aryl" represents phenyl or naphthyl, or phenyl substituted by one or more substituents selected from halogen, amino, hydroxy, nitro, cyano, COOH, CONH2, Ci-6alkylaminocarbonyl, phenylaminocarbonyl, heteroarylaminocarbonyl, hydroxy- Ci-6alkylaminocarbonyl, di-(Ci-6alkyl)aminocarbonyl, trifluoromethyl, Chalky!, heteroaryl, Ci-6alkoxy, difluoromethoxy, trifluoromethoxy, cyclo-C3-i2alkoxy, phenoxy, heteroaryloxy, phenyl-Ci-6alkoxy, heteroaryl-Ci-6alkoxy, amino-Ci-6alkyl, hydroxy- Ci-6alkyl, carbamoyl-Ci-6alkyl, hydroxy-Ci-6alkoxy, Ci-6alkoxycarbonyl, Ci-6alkylamino, cyclo-C3-i2alkylamino, phenylamino, heteroarylamino, phenyl-Ci-6alkylamino, heteroaryl- Ci-6alkylamino, hydroxy-Ci-6alkylamino, di-(Ci-6alkyl)amino, acylamino, Ci-6alkylamino- Ci-6alkoxy, di-iCi-ealkylJamino-Ci-ealkoxy, Ci-6alkylsulfonylamino, Ci-6alkyl- aminosulfonyl, di-(Ci-6alkyl)aminosulfonyl, Ci-6alkylaminocarbonyl-Ci-6alkyl, cyclo- Cs-^alkyl-carbamoyl-Ci-ealkyl, phenylaminocarbonyl-Ci-6alkyl, heteroarylaminocarbonyl- Ci-6alkyl, hydroxy-Ci-6alkylaminocarbonyl-Ci-6alkyl, and di-(Ci-6alkyl)aminocarbonyl- Ci-6alkyl; and the term "heteroaryl" represents an aromatic 5-6 membered ring comprising one to four heteroatoms selected from oxygen, sulfur and nitrogen, or a bicyclic aromatic group containing a 5-6 membered ring comprising one to four heteroatoms selected from oxygen, sulfur and nitrogen fused with a benzene ring or with a 5-6 membered ring comprising one to four heteroatoms selected from oxygen, sulfur and nitrogen, wherein the heteroaryl is optionally substituted by one or more substituents selected from halogen, amino, hydroxy, nitro, cyano, COOH, CONH2, Ci-6alkylaminocarbonyl, di-(Ci-6alkyl)aminocarbonyl, trifluoromethyl, Chalky!, Ci-6alkoxy, difluoromethoxy, trifluoromethoxy, cyclo-C3-i2alkoxy, phenyl, pyridyl, thiazolyl, pyrazolyl, phenoxy, pyridyloxy, thiazolyloxy, pyrazolyloxy, phenyl-Ci-6alkoxy, pyridyl-Ci-6alkoxy, thiazolyl- Ci-6alkoxy, pyrazolyl-Ci-6alkoxy, amino-Ci-6alkyl, hydroxy-Ci-6alkyl, carbamoyl-Ci-6alkyl, hydroxy-Ci-6alkoxy, Ci-6alkoxycarbonyl, Ci-6alkylamino, cyclo-Cs-^alkylamino, phenylamino, pyridylamino, thiazolylamino, pyrazolylamino, phenyl-Ci-6alkylamino, pyhdyl-Ci-6alkylamino, thiazolyl-Ci-6alkylamino, pyrazolyl-Ci-6alkylamino, hydroxy- Ci-6alkylamino, di-(Ci-6alkyl)amino, acylamino, Ci-6alkylamino-Ci-6alkoxy, di-(Ci-6alkyl)amino-Ci-6alkoxy, Ci-6alkylsulfonylamino, Ci-6alkyl-aminosulfonyl, di-(Ci-6alkyl)aminosulfonyl, Ci-6alkylaminocarbonyl-Ci-6alkyl, and di-(Ci-6alkyl)aminocarbonyl-Ci-6alkyl; and optical isomers, polymorphs and pharmaceutically-acceptable acid and base addition salts and hydrates and solvates thereof.
[0012] A further aspect of the invention relates to a compound of Formula I, wherein X represents CH.
[0013] Such a compound of Formula I, wherein R1 represents halogen, R2 represents hydrogen, and R3 represents hydrogen or halogen.
[0014] Such a compound of Formula I, wherein R1 represents chloro, R2 represents hydrogen, and R3 represents hydrogen or chloro.
[0015] Such a compound of Formula I, wherein R1 and R3 each represent chloro, and R2 represents hydrogen.
[0016] Such a compound of Formula I, wherein R4 represents hydrogen, Chalky!, arylcarbonyl, Ci-6alkoxy-Ci-6alkyl, or aryl-Ci-6alkyl.
[0017] Such a compound of Formula I, wherein R4 represents hydrogen, methyl, ethyl, n-propyl, benzoyl, methoxymethyl, methoxypropyl, or benzyl, wherein the phenyl moiety may be optionally substituted by methoxy.
[0018] Such a compound of Formula I, wherein R5 represents hydrogen, -C(O)-R6, or -Y-C(O)-R7.
[0019] Such a compound of Formula I, wherein wherein R6 represents Chalky! (e.g., methyl), aryl, heteroaryl, aryl-Ci-6alkyl, heteroaryl-Ci-6alkyl, or -NR8R9, wherein R8 represents hydrogen or Chalky! and R9 represents Chalky!, aryl, heteroaryl, aryl- Ci-6alkyl, or heteroaryl-Ci-6alkyl .
[0020] Such a compound of Formula I, wherein wherein R6 represents aryl, heteroaryl, aryl-Ci-6alkyl, heteroaryl-Ci-6alkyl, or -NR8R9, wherein R8 represents hydrogen or Ci-6alkyl and R9 represents Chalky!, aryl, heteroaryl, aryl -Chalky!, or heteroaryl- Ci-6alkyl . [0021] Such a compound of Formula I, wherein R6 represents phenyl, pyridyl, optionally substituted by hydroxy, thiazolyl, pyrazinyl, pyrimidinyl, benzyl, phenethyl, phenylpropyl, pyridylmethyl, thiazolylmethyl, or -NR8R9, wherein R8 represents hydrogen and R9 represents phenyl or benzyl .
[0022] Such a compound of Formula I, wherein Y represents -CH(R12)-, wherein R12 represents hydrogen, Chalky!, Ci-6alkoxy-Ci-6alkyl, aryl, heteroaryl, cyclo-C3-i2alkyl, cyclo-C3-i2alkyl-Ci-6alkyl, cyclo-C3-i2alkoxy-Ci-6alkyl, aryl -Chalky! or heteroaryl- Ci-6alkyl .
[0023] Such a compound of Formula I, wherein wherein R7 represents OH, Ci-6alkoxy, aryl, heteroaryl, heterocyclyl, or -NR10R1 1.
[0024] Such a compound of Formula I, wherein wherein R7 represents -NR10R1 1.
[0025] Such a compound of Formula I, wherein R10 and R1 1 each independently represent hydrogen, Chalky!, cyclo-C3-i2alkyl, aryl, heteroaryl, cyclo-C3-i2alkyl-Ci-6alkyl, aryl-Ci-6alkyl, or heteroaryl-Ci-6alkyl, or R10 and R1 1 together with the nitrogen atom they are attached represent a 4-, 5-, 6- or 7-membered ring which may be saturated or unsaturated, wherein, in addition to the nitrogen atom, the ring may contain an additional heteroatom selected from sulfur, oxygen and nitrogen and/or be condensed to an aromatic or heteroaromatic ring selected from benzene, thiazole, imidazole, or pyridine, and wherein the ring may be optionally substituted by one or more substituents selected from hydroxy, oxo, amino, acyl, acylamino, trifluoromethyl, Chalky!, cyclo- C3-i2alkyl, aryl, Ci-6alkoxy, hydroxy-Ci-6alkyl, and Ci-6alkoxy-Ci-6alkyl .
[0026] Such a compound of Formula I, wherein R10 represents hydrogen or Chalky! and R1 1 represents aryl, heteroaryl, aryl-Ci-6alkyl, or heteroaryl-Ci-6alkyl.
[0027] Such a compound of Formula I, wherein R10 represents hydrogen or methyl and R1 1 represents phenyl, pyridyl, benzyl, pyridylmethyl, thiazolylmethyl, pyrimidinylmethyl, pyridazinylmethyl, or pyrazinylmethyl . [0028] A further aspect of the invention relates to a compound of Formula I, wherein X represents nitrogen.
[0029] Such a compound of Formula I, wherein wherein R1 represents halogen, R2 represents hydrogen, and R3 represents hydrogen or halogen.
[0030] Such a compound of Formula I, wherein R1 represents chloro, R2 represents hydrogen, and R3 represents hydrogen or chloro.
[0031 ] Such a compound of Formula I, wherein R1 and R3 each represent chloro, and R2 represents hydrogen.
[0032] Such a compound of Formula I, wherein R4 represents hydrogen or Ci-6alkyl.
[0033] Such a compound of Formula I, wherein R4 represents methyl.
[0034] Such a compound of Formula I, wherein R5 represents -Y-C(O)-R7.
[0035] Such a compound of Formula I, wherein Y represents CH2.
[0036] Such a compound of Formula I, wherein R7 represents -NR10R1 1, wherein R10 represents hydrogen and R11 represents aryl-Ci-6alkyl or heteroaryl-Ci-6alkyl .
[0037] Such a compound of Formula I, wherein R11 represents benzyl or pyridylmethyl.
[0038] A further aspect of the invention relates to a compound of Formula I, which is selected from those of Formula IA:
Figure imgf000012_0001
IA
wherein R1-R4 and R6 are as defined above for Formula I. [0039] Such a compound of Formula IA, wherein R1 and R3 each represent halogen, and R2 represents hydrogen.
[0040] Such a compound of Formula IA, wherein R1 and R3 each represent chloro, and R2 represents hydrogen.
[0041 ] Such a compound of Formula IA, wherein R4 represents hydrogen, Ci-6alkyl, arylcarbonyl, Ci-6alkoxy-Ci-6alkyl, or aryl-Ci-6alkyl.
[0042] Such a compound of Formula IA, wherein R4 represents hydrogen, methyl, ethyl, propyl, methoxymethyl, methoxypropyl, phenylcarbonyl, or benzyl, wherein the phenyl moiety may be optionally substituted by methoxy.
[0043] Such a compound of Formula IA, wherein R6 represents Chalky! (e.g., methyl), aryl, heteroaryl, aryl-Ci-6alkyl, heteroaryl-Ci-6alkyl, or -NR8R9, wherein R8 represents hydrogen or Chalky! and R9 represents Chalky!, aryl, heteroaryl, aryl -Chalky I, or heteroaryl-Ci-6alkyl.
[0044] Such a compound of Formula IA, wherein R6 represents aryl, heteroaryl, aryl- Ci-6alkyl, heteroaryl-Ci-6alkyl, or -NR8R9, wherein R8 represents hydrogen or Chalky! and R9 represents Ci-6alkyl, aryl, heteroaryl, aryl -Chalky!, or heteroaryl-Ci-6alkyl.
[0045] Such a compound of Formula IA, wherein R6 represents phenyl, thiazolyl, pyrazinyl, pyrimidinyl, benzyl, phenethyl, phenylpropyl, pyridyl optionally substituted by hydroxy, pyridylmethyl or thiazolyl methyl.
[0046] Such a compound of Formula IA, wherein R6 represents -NR8R9, wherein R8 represents hydrogen and R9 represents phenyl or benzyl.
[0047] A further aspect of the invention relates to a compound of Formula I, which is selected from those of formula IB:
Figure imgf000014_0001
wherein R1-R4 and R7 are as defined above for Formula I and R12 represents hydrogen, Ci-6alkyl or Ci-6alkoxy-Ci-6alkyl.
[0048] Such a compound of Formula IB, wherein R1 and R3 each represent halogen, and R2 represents hydrogen.
[0049] Such a compound of Formula IB, wherein R1 and R3 each represent chloro, and R2 represents hydrogen.
[0050] Such a compound of Formula IB, wherein R4 represents hydrogen or Chalky! .
[0051 ] Such a compound of Formula IB, wherein R7 represents OH, Ci-6alkoxy, aryl, heteroaryl, or heterocyclyl.
[0052] A further aspect of the invention relates to a compound of Formula I, which is selected from those of formula IC:
Figure imgf000014_0002
wherein R1-R4, R10, and R11 are as defined above for Formula I and R12 represents hydrogen, Chalky! or Ci-6alkoxy-Ci-6alkyl. [0053] Such a compound of Formula IC, wherein R1 and R3 each represent halogen, and R2 represents hydrogen.
[0054] Such a compound of Formula IC, wherein R1 and R3 each represent chloro, and R2 represents hydrogen.
[0055] Such a compound of Formula IC, wherein R4 represents hydrogen or Chalky! . [0056] Such a compound of Formula IC, wherein R4 represents hydrogen or methyl.
[0057] Such a compound of Formula IC, wherein R10 and R11 each independently represent hydrogen, Ci-6alkyl, cyclo-C3-i2alkyl, aryl, heteroaryl, cyclo-C3-i2alkyl-Ci-6alkyl, aryl-Ci-6alkyl, or heteroaryl-Ci-6alkyl, or R10 and R11 together with the nitrogen atom they are attached represent a 4-, 5-, 6- or 7-membered ring which may be saturated or unsaturated, wherein, in addition to the nitrogen atom, the ring may contain an additional heteroatom selected from sulfur, oxygen and nitrogen and/or be condensed to an aromatic or heteroaromatic ring selected from benzene, thiazole, imidazole, or pyridine, and wherein the ring may be optionally substituted by one or more substituents selected from hydroxy, oxo, amino, acyl, acylamino, trifluoromethyl, Chalky!, cyclo- C3-i2alkyl, aryl, Ci-6alkoxy, hydroxy-Ci-6alkyl, and Ci-6alkoxy-Ci-6alkyl.
[0058] Such a compound of Formula IC, wherein R10 represents hydrogen or Chalky! and R11 represents aryl, heteroaryl, aryl-Ci-6alkyl, or heteroaryl-Ci-6alkyl.
[0059] Such a compound of Formula IC, wherein R10 represents hydrogen or methyl and R11 represents phenyl, pyridyl, thiazolyl, benzyl, pyridylmethyl, thiazolylmethyl, pyrimidylmethyl, pyridazinylmethyl, or pyrazinylmethyl.
[0060] A further aspect of the invention relates to a compound of Formula I, which is selected from those of Formula ID:
Figure imgf000016_0001
ID
wherein R1-R5 are as defined above for Formula I.
[0061 ] Such a compound of Formula ID, wherein R1 represents halogen, R2 represents hydrogen, and R3 represents hydrogen or halogen.
[0062] Such a compound of Formula ID, wherein R1 represents chloro, R2 represents hydrogen, and R3 represents hydrogen or chloro.
[0063] Such a compound of Formula ID, wherein R1 and R3 each represent chloro, and R2 represents hydrogen.
[0064] Such a compound of Formula ID, wherein R4 represents hydrogen or Ci-6alkyl.
[0065] Such a compound of Formula ID, wherein R4 represents methyl.
[0066] Such a compound of Formula ID, wherein R5 represents -Y-C(O)-R7, wherein Y and R7 are as defined for Formula I.
[0067] Such a compound of Formula ID, wherein Y represents CH2.
[0068] Such a compound of Formula ID, wherein R7 represents -NR10R1 1, wherein R10 represents hydrogen and R11 represents aryl-Ci-6alkyl or heteroaryl-Ci-6alkyl .
[0069] Such a compound of Formula ID, wherein R11 represents benzyl or pyridyl methyl.
[0070] Specific compounds of Formula I within the present invention include but are not limited to:
4-Amino-5,7-dichloronaphthalene-2-carboxylic acid,
4-Benzoylamino-5,7-dichloro-naphthalene-2-carboxylic acid,
5,7-Dichloro-4-phenylacetylamino-naphthalene-2-carboxylic acid, 5,7-Dichloro-4-(phenylcarbamoylmethyl-amino)-naphthalene-2-carboxylic acid,
4-[(Benzylcarbamoyl-methyl)-amino]-5,7-dichloro-naphthalene-2-carboxylic acid, 5,7-Dichloro-4-({[(pyridin-2-ylmethyl)-carbamoyl]-methyl}-amino)-naphthalene-2 carboxylic acid,
5,7-Dichloro-4-({[(pyridin-3-ylmethyl)-carbamoyl]-methyl}-amino)-naphthalene-^ carboxylic acid,
5,7-Dichloro-4-[(pyridin-3-ylcarbamoylmethyl)-amino]-naphthalene-2-carboxyli acid, 5,7-Dichloro-4-({[(thiazol-2-ylmethyl)-carbamoyl]-methyl}-amino)-naph^
carboxylic acid,
5,7-Dichloro-4-({[(pyrimidin-4-ylmethyl)-carbamoyl]-methyl}-amino)^
carboxylic acid,
4-(Benzoyl-methyl-amino)-5,7-dichloro-naphthalene-2-carboxylic acid,
5,7-Dichloro-4-(3-phenyl-ureido)-naphthalene-2-carboxylic acid,
4-(3-Benzylureido)-5,7-dichloronaphthalene-2-carboxylic acid,
5,7-Dichloro-4-(methylphenylacetylamino)-naphthalene-2-carboxylic acid,
5,7-Dichloro-4-(3-phenylpropionylamino)-naphthalene-2-carboxylic acid,
5,7-Dichloro-4-(4-phenylbutyrylamino)-naphthalene-2-carboxylic acid,
5,7-Dichloro-4-dibenzoylamino-naphthalene-2-carboxylic acid,
4-(Benzoyl-propyl-amino)-5,7-dichloro-naphthalene-2-carboxylic acid,
4-(Benzoyl-ethyl-amino)-5,7-dichloro-naphthalene-2-carboxylic acid,
5,7-Dichloro-4-[(pyridine-4-carbonyl)-amino]-naphthalene-2-carboxylic acid,
5,7-Dichloro-4-[(pyridine-3-carbonyl)-amino]-naphthalene-2-carboxylic acid,
4-[Benzoyl-(methoxymethyl)-amino]-5,7-dichloro-naphthalene-2-carboxylic acid, 5,7-Dichloro-4-[methyl-(pyridine-3-carbonyl)-amino]-naphthalene-2-carboxyli acid, 5,7-Dichloro-4-[methyl-(pyridine-4-carbonyl)-amino]-naphthalene-2-carboxyli acid, 4-(Benzoyl-benzyl-amino)-5,7-dichloro-naphthalene-2-carboxylic acid,
5,7-Dichloro-4-(2-pyridin-2-yl-acetylamino)-naphthalene-2-carboxylic acid,
4-[Benzoyl-(3-methoxy-benzyl)-amino]-5,7-dichloro-naphthalene-2-carboxylic acid, 5,7-Dichloro-4-(2-pyridin-3-yl-acetylamino)-naphthalene-2-carboxylic acid,
5,7-Dichloro-4-(2-pyridin-4-yl-acetylamino)-naphthalene-2-carboxylic acid,
1 -[(Benzylcarbamoyl-methyl)-methyl-amino]-6,8-dichloro-isoquinoline-3-ca acid, 5,7-Dichloro-4-(2-thiazol-4-yl-acetylamino)-naphthalene-2-carboxylic acid, 5,7-Dichloro-4-[(pyridine-2-carbonyl)-amino]-naphthalene-2-carboxylic acid, 5,7-Dichloro-4-[methyl-(pyridine-2-carbonyl)-amino]-naphthalene-2-carboxylic acid, 5,7-Dichloro-4-(methyl-{[(pyridin-3-ylm
carboxylic acid,
5,7-Dichloro-4-(methyl-{[(pyrimidin-5-ylmethyl)-carbamoyl]-methyl}-amino)-na 2-carboxylic acid,
5,7-Dichloro-4-(methyl-{[(pyridin-2-ylmethyl)-carbamoyl]-methyl}-amino)-naphth carboxylic acid,
5,7-Dichloro-4-({[(pyrimidin-5-ylmethyl)-carbamoyl]-methyl}-amino)-n
carboxylic acid,
5,7-Dichloro-4-{[(methyl-pyridin-2-ylmethyl-carbamoyl)-methyl]-amino
carboxylic acid,
5,7-Dichloro-4-{methyl-[(methyl-pyridin-2-ylmethyl-carbamoyl)-methy^
naphthalene-2-carboxylic acid,
5,7-Dichloro-4-{[(methyl-pyridin-3-ylmethyl-carbamoyl)-methyl]-amin
carboxylic acid,
5,7-Dichloro-4-{methyl-[(methyl-pyridin-3-ylmethyl-carbamoyl)-methy^
naphthalene-2-carboxylic acid,
5,7-Dichloro-4-(methyl-{[(pyridin-4-ylmethyl)-carbamoyl]-methyl}-amin
carboxylic acid,
4-[Benzoyl-(3-methoxy-propyl)-amino]-5,7-dichloro-naphthalene-2-carboxylic acid,
5.7- Dichloro-4-({[(pyridin-4-ylmethyl)-carbamoyl]-methyl}-amino)-naph^
carboxylic acid,
1 -((2-(Benzylamino)-2-oxoethyl)amino)-6-chloroisoquinoline-3-carboxylic acid, 1 -((2-(Benzylamino)-2-oxoethyl)amino)-6,8-dichloroisoquinoline-3-carboxylic acid,
6.8- Dichloro-1 -((2-oxo-2-((pyridin-3-ylmethyl)amino)ethyl)amino)isoquin
carboxylic acid,
6,8-Dichloro-1 -((2-oxo-2-((pyridin-2-ylmethyl)amino)ethyl)amino)isoquin
carboxylic acid,
5,7-Dichloro-4-(methyl(2-oxo-2-((pyrimidin-2-ylmethyl)amino)ethyl)ami
acid,
5,7-Dichloro-4-(N-(3-methoxybenzyl)acetamido)-2-naphthoic acid, 5,7-Dichloro-4- methyl(2-oxo-2-((pyridazin-4-ylmethyl)amino)ethyl)amino)-2-naphth acid,
5,7-Dichloro-4- methyl(2-oxo-2-((pyridazin-3-ylmethyl)amino)ethyl)amino)-2-naphth acid,
5,7-Dichloro-4- methyl(2-oxo-2-((thiazol-2-ylmethyl)amino)ethyl)amino)-2-naphth acid,
5.7- Dichloro-4- methyl(2-(methyl(pyridin-4-ylmethyl)amino)-2-oxoethyl)amino)-^ naphthoic acid.
6.8- Dichloro-1 - methyl(2-oxo-2-((pyridin-3-ylmethyl)amino)ethyl)amino)isoquinoli carboxylic acid
5,7-Dichloro-4- (2-(methyl(pyridin-4-ylmethyl)amino)-2-oxoethyl)amino)-2-naphth acid,
5,7-Dichloro-4- methyl(2-(methyl(thiazol-2-ylmethyl)amino)-2-oxoethyl)amino)-2- naphthoic acid.
5,7-Dichloro-4- N-methylthiazole-4-carboxannido)-2-naphthoic acid,
5,7-dichloro-4- methyl(2-oxo-2-((pyrazin-2-ylmethyl)amino)ethyl)amino)-2-naphth acid,
5,7-Dichloro-4- 5-hydroxy-N-methylpicolinannido)-2-naphthoic acid,
5,7-Dichloro-4- N-methylthiazole-2-carboxannido)-2-naphthoic acid,
5,7-Dichloro-4- N-methylpyrazine-2-carboxannido)-2-naphthoic acid,
5,7-Dichloro-4- N-(4-methoxybenzyl)benzannido)-2-naphthoic acid,
5,7-Dichloro-4- N-methylpyrimidine-2-carboxamido)-2-naphthoic acid,
5,7-Dichloro-4- N-methylpynmidine-4-carboxamido)-2-naphthoic acid, and optical isomers, polymorphs, analogs, derivatives, prodrugs, and pharmaceutically- acceptable acid and base addition salts, hydrates, and solvates thereof.
[0071 ] In a further aspect, the invention relates to a compound of Formula I as defined above, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof for use in therapy. [0072] Moreover, the invention relates to a compound of Formula I as defined above, or an optical isomer, polymorph, analog, derivative, prodrug, pharmaceutically-acceptable acid or base addition salt, hydrate, or solvate thereof for the treatment or prevention of a condition associated with excitotoxicity and malfunctioning of glutamatergic neurotransmission, including for the conditions selected from those described earlier in the description.
[0073] Such conditions include pain, including acute pain, chronic pain, allodynia, hyperalgesia, visceral pain, phantom pain, post-operative pain, neuropathic pain, peripheral neuropathy including, for example peripheral neuropathy induced by nociception, inflammation, ischemia, viral infection (HZV), traumatic and other mechanical nerve injury, cancer, diabetes mellitus, HIV infection, fibromyalgia, trigeminus neuralgia, inflammatory bowel diseases (IBD), irritative bowel syndrome (IBS), arthritis including rheumatoid arthritis, osteoarthritis (degenerative joint disease), multiple sclerosis (MS) and gout (metabolic arthritis).
[0074] Such conditions also include acute insults, including cerebral ischemia, cerebral infarct, brain oedema, anoxia, inner ear insult, inner ear insult in tinnitus, head or brain or spinal cord trauma, head or brain or spinal cord injuries, trauma, sound- or drug- induced inner ear insult, ischaemia resulting from cardiac arrest or stroke or bypass operations or transplants, acute pain, hypoxia, perinatal hypoxia, and ischaemia; chronic insults, such as neurodegenerative disorders, including Morbus Huntington, Alzheimer's disease Creutzfeld-Jakob's syndrome/disease, bovine spongiform encephalopathy (BSE) prion related infections, diseases involving mitochondrial dysfunction, diseases involving β-amyloid and/or tauopathy, Down's syndrome, motor neuron diseases, amyotrophic lateral sclerosis (ALS), olivopontocerebellar atrophy, Parkinson's disease, Neuronal Ceroid Lipofuscinosis, AIDS dementia complex, AIDS- related dementia, dementia related to HIV infections, HIV-1 encephalopathy, AIDS encephalopathy, Korsakoff syndrome, vascular dementia, and corticobasal degeneration; neurological disorders, including tinnitus, hearing loss, sound- or drug-induced tinnitus, haloperidol-induced dyskinesias, dopaminominnetic-induced dyskinesias, chorea, Huntington's chorea, athetosis, dystonia, stereotypy, ballism, tardive dyskinesias, tic disorder, spasmodic torticollis, blepharospasm, focal and generalized dystonia, nystagmus, Parkinson's dementia, mild cognitive impairment, cognitive deficits in various forms of mild cognitive impairment, cognitive deficits in various forms of dementia, dementia pugilistica, vascular and frontal lobe dementia, cognitive impairment, learning impairment, L-dopa-induced dykinesias, L-dopa-induced dykinesias in Parkinson's disease therapy, dyskinesias, dyskinesia in Huntington's disease, drug induced dyskinesias, neuroleptic-induced dyskinesias, neurodegenerative cerebellar ataxias, centrally induced neuropathic pain, convulsions, epileptic convulsions, epilepsy, temporal lobe epilepsy, myoclonic epilepsy, tremor, dementia in Alzheimer's disease, dementia in Korsakoff syndrome, dementia, hereditary cerebellar ataxias, sleep disorders, movement disorders, essential tremor, muscle spasms, and spasticity; psychological/psychiatric disorders, including generalized anxiety disorder, obsessive- compulsive disorder, panic disorder, posttraumatic stress disorder, social phobia, phobic disorders, substance-induced anxiety disorder, delusional disorder, schizoaffective disorder, schizophreniform disorder, substance-induced psychotic disorder, delirium, post-operative cognitive deficit (POCD), cognitive impairment, learning impairment, anxiety disorders, panic disorders, anxiety and panic disorders, social anxiety disorder (SAD), attention deficit hyperactivity disorder (ADHD), attention deficit syndrome (ADS), dementia, posttraumatic stress disorder (PTSD), schizophrenia, positive or cognitive or negative symptoms of schizophrenia, major depressive disorder, major depression, depression, bipolar manic-depressive disorder, sleep disorders, agoraphobia, bulimia nervosa, eating disorders, obesity, obesity-related disorders, obesity abuse, food addiction, binge eating disorders, and hyperactivity in children; drug/alcohol abuse, including craving (e.g., for drugs of abuse), abuse, addiction, nicotine addiction, nicotine abuse, alcohol addiction, alcohol abuse, opiate addiction, opiate abuse, cocaine addiction, cocaine abuse, amphetamine addiction, and amphetamine abuse; skin diseases, including atopic dermatitis, itching, skin lesions induced by severe itching or atopic dermatitis, systemic sclerosis, pruritic conditions, and pruritis; diseases of the gastro-intestinal tract and metabolic diseases including diarrhoea, hepatic encephalopathy, hypoglycaemia, gastroesophageal reflux disease (GERD), gastrointestinal dysfunction, lower esophageal sphincter (LES) disease, functional gastrointestinal disorders, dyspepsia, vomiting, urinary incontinence, and regurgitation; diseases of the immune system, including Sjogren's syndrome, systemic lupus erythematosus, and multiple sclerosis (MS); eye diseases, including eye injuries, eye diseases, eye disorders, glaucoma, retinopathy, and macular degeneration; diseases of the respiratory tract, including respiratory tract infection, chronic laryngitis, asthma, reflux-related asthma, and lung disease; migraine; autism; restless leg syndrome (RLS); Tourette syndrome; micturition disorders; neuromuscular disorder in the lower urinary tract; and drug tolerance to opioids.
[0075] Further, the invention relates to a compound of Formula I as defined above, or an optical isomer, polymorph, analog, derivative, prodrug, pharmaceutically-acceptable acid or base addition salt, hydrate, or solvate thereof for use in the treatment or prevention of NMDA excitotoxicity or malfunctioning glutamatergic neurotransmission.
[0076] Further, the invention relates to the use of a compound of Formula I as defined above or an optical isomer, polymorph, analog, derivative, prodrug, pharmaceutically- acceptable acid or base addition salt, hydrate, or solvate thereof for the manufacture of a medicament for the prevention and/or treatment of a condition associated with excitotoxicity and malfunctioning of glutamatergic neurotransmission. Such a use includes the use of such a compound for the manufacture of a medicament for the prevention and/or treatment of a condition in an animal including a human being which condition is associated with excitotoxicity and malfunctioning of glutamatergic neurotransmission, including conditions selected from those described earlier in the description.
[0077] Moreover, the invention relates to a method for treating or preventing a condition associated with excitotoxicity and malfunctioning of glutamatergic neurotransmission, including conditions selected from those described earlier in the description, such method comprising administering to a living animal, including a human, a therapeutically effective amount of a compound selected from those of Formula I as defined above or an optical isomer, polymorph, analog, derivative, prodrug, pharmaceutically-acceptable acid or base addition salt, hydrate, or solvate thereof.
[0078] A further aspect of the invention relates to such a method wherein the compound is administered in the form of a pharmaceutical composition thereof comprising at least one compound of Formula I in combination with one or more pharmaceutically- acceptable diluents, excipients, or carriers.
[0079] The compounds of the invention are suitable for administration in monotherapy or for combination therapy with other pharmaceutically active compounds. Examples of suitable other pharmaceutically active compounds include immunomodulators and agents active against central nervous system disorders such as other NMDA agonists or antagonists including glycine B antagonists.
[0080] Further, the invention relates to a pharmaceutical composition comprising as active ingredient at least one compound of Formula I as defined above, or an optical isomer, polymorph, analog, derivative, prodrug, pharmaceutically-acceptable acid or base addition salt, hydrate, or solvate thereof, together with one or more pharmaceutically acceptable excipients or vehicles. DETAILED DESCRIPTION OF THE INVENTION
[0081 ] For the purpose of the present invention, the carbon atom content of various hydrocarbon-containing moieties is indicated by a prefix designating the minimum and maximum number of carbon atoms in the moiety, i.e., the prefix C j indicates a moiety of the integer "i" to the integer "j" carbon atoms, inclusive. Thus, for example, Chalky! refers to alkyl of one to three carbon atoms, inclusive, (i.e., methyl, ethyl, propyl, and isopropyl), straight and branched forms thereof.
[0082] As used herein and as far as it is not defined in a different manner elsewhere in this description or the accompanying claims, the term "Ci-6alkyl" represents straight or branched chain alkyl groups having 1 , 2, 3, 4, 5 or 6 carbon atoms, examples of such alkyl groups include methyl, ethyl, n-propyl, 2-propyl, n-butyl, 2-butyl, iso-butyl, tert- butyl, n-pentyl, 2-pentyl, 3-pentyl, iso-pentyl, 2-methylbutyl, tert-amyl, neopentyl, n- hexyl, 2-hexyl, 3-hexyl, 1 -methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, and 3-methylpentyl.
[0083] The term "d-zalkylene" represents divalent straight or branched chain alkyl groups having 1 , 2, 3, 4, 5 , 6, or 7 carbon atoms.
[0084] The term "C3-6alkenyl" represents straight or branched chain alkenyl groups having 3, 4, 5 or 6 carbon atoms.
[0085] The term "C3-6alkynyl" represents straight or branched chain alkynyl groups having 3, 4, 5 or 6 carbon atoms.
[0086] The term "cycloCs-^alkyl" represents monocyclic or bicyclic, or tricyclic alkyl groups having 3, 4, 5, 6, 7, 8, 9, 10, 1 1 or 12 carbon atoms, including cydopropyl, cydobutyl, cydopentyl, cydohexyl, bicyclo[2.2.1 ]heptyl and adamantanyl, wherein the "cycloC3-i2alkyl"-ring is optionally substituted by one or more (e.g., 1 , 2, 3, or 4) fluorine, chlorine, and/or bromine atoms. [0087] The term "Ci-6alkoxy" represents straight or branched chain -O-Ci-6alkyl groups. Examples of such alkoxy groups include methoxy, ethoxy, n-propoxy, and isopropoxy, sec-butoxy, terf-butoxy.
[0088] The term "Ci-6alkylamino" refers to an amino moiety in which the nitrogen atom of the amino group is substituted with a Chalky! group as defined above. Examples of such alkylamino groups include methylamino, ethylamino, propylamine isopropylamino, teff-butylamino.
[0089] The term "di-(Ci-6alkyl)amino" refers to an amino moiety in which the nitrogen atom of the amino group is substituted with two Chalky! groups, which may be the same or different, as defined above. Examples of di-Ci-6alkylamino groups include dimethylamino, diethylamino and N-methyl-N-isopropylamino.
[0090] The term "aryl" represents phenyl or naphthyl, or phenyl substituted by one or more substituents selected from halogen, amino, hydroxy, nitro, cyano, COOH, CONH2, Ci-6alkylaminocarbonyl, phenylaminocarbonyl, heteroarylaminocarbonyl, hydroxy- Ci-6alkylaminocarbonyl, di-(Ci-6alkyl)aminocarbonyl, trifluoromethyl, Chalky!, heteroaryl, Ci-6alkoxy, difluoromethoxy, trifluoromethoxy, cyclo-Cs-^alkoxy, phenoxy, heteroaryloxy, phenyl-Ci-6alkoxy, heteroaryl-Ci-6alkoxy, amino-Ci-6alkyl, hydroxy- Ci-6alkyl, carbamoyl-Ci-6alkyl, hydroxy-Ci-6alkoxy, Ci-6alkoxycarbonyl, Ci-6alkylamino, cyclo-C3-i2alkylamino, phenylamino, heteroarylamino, phenyl-Ci-6alkylamino, heteroaryl- Ci-6alkylamino, hydroxy-Ci-6alkylamino, di-(Ci-6alkyl)amino, acylamino, Ci-6alkylamino- Ci-6alkoxy, di-(Ci-6alkyl)amino-Ci-6alkoxy, Ci-6alkylsulfonylamino, Ci-6alkyl- aminosulfonyl, di-(Ci-6alkyl)aminosulfonyl, Ci-6alkylaminocarbonyl-Ci-6alkyl, cyclo- C3-i2alkyl-carbamoyl-Ci-6alkyl, phenylaminocarbonyl-Ci-6alkyl, heteroarylaminocarbonyl- Ci-6alkyl, hydroxy-Ci-6alkylaminocarbonyl-Ci-6alkyl, and di-(Ci-6alkyl)aminocarbonyl- Ci-6alkyl .
[0091 ] The term "heteroaryl" an aromatic 5-6 membered ring comprising one to four heteroatoms selected from oxygen, sulfur and nitrogen, or a bicyclic aromatic group containing a 5-6 membered ring comprising one to four heteroatoms selected from oxygen, sulfur and nitrogen fused with a benzene ring or with a 5-6 membered ring comprising one to four heteroatoms selected from oxygen, sulfur and nitrogen, wherein the heteroaryl is optionally substituted by one or more substituents selected from halogen, amino, hydroxy, nitro, cyano, COOH, CONH2, Ci-6alkylaminocarbonyl, di-(Ci-6alkyl)aminocarbonyl, trifluoromethyl, Chalky!, Ci-6alkoxy, difluoromethoxy, trifluoromethoxy, cyclo-Cs-^alkoxy, phenyl, pyridyl, thiazolyl, pyrazolyl, phenoxy, pyridyloxy, thiazolyloxy, pyrazolyloxy, phenyl-Ci-6alkoxy, pyridyl-Ci-6alkoxy, thiazolyl- Ci-6alkoxy, pyrazolyl-Ci-6alkoxy, amino-Ci-6alkyl, hydroxy-Ci-6alkyl, carbamoyl-Ci-6alkyl, hydroxy-Ci-6alkoxy, Ci-6alkoxycarbonyl, Ci-6alkylamino, cyclo-Cs-^alkylamino, phenylamino, pyridylamino, thiazolylamino, pyrazolylamino, phenyl-Ci-6alkylamino, pyhdyl-Ci-6alkylamino, thiazolyl-Ci-6alkylamino, pyrazolyl-Ci-6alkylamino, hydroxy- Ci-6alkylamino, di-(Ci-6alkyl)amino, acylamino, Ci-6alkylamino-Ci-6alkoxy, di-(Ci-6alkyl)amino-Ci-6alkoxy, Ci-6alkylsulfonylamino, Ci-6alkyl-aminosulfonyl, di-(Ci-6alkyl)aminosulfonyl, Ci-6alkylaminocarbonyl-Ci-6alkyl, and di-(Ci-6alkyl)aminocarbonyl-Ci-6alkyl; examples of such heteroaryl groups include furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzofuryl, benzothienyl, indolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl, and quinoxalinyl.
[0092] The term "acyl" represents Ci-6alkylcarbonyl, trifluoroacetyl, hydroxy- Ci-6alkylcarbonyl, carboxy-Ci-6alkylcarbonyl, Ci-6alkoxy-Ci-6alkylcarbonyl, cyclo-C3-i2alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, aryl-Ci-6alkylcarbonyl, heteroaryl-Ci-6alkylcarbonyl, heterocyclylcarbonyl and heterocyclyl-Ci-6alkylcarbonyl.
[0093] The term "heterocyclyl" represents a saturated 4-7 membered heterocycle containing one or two heteroatoms selected from oxygen, sulfur and nitrogen, examples of such heterocyclyl groups include azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, tetrahydrofuryl, thiazolidinyl, morpholinyl, thiomorpholinyl, and piperazinyl .
[0094] The term "halogen" represents fluorine, chlorine, bromine and iodine.
[0095] The compounds of the present invention are named according to the lUPAC or CAS nomenclature system. Abbreviations which are well known to one of ordinary skill in the art may be used (e.g. "Ph" for phenyl, "Me" for methyl, "Et" for ethyl, "h" for hour or hours, and "rt" for room temperature).
[0096] The term "analog" or "derivative" is used herein in the conventional pharmaceutical sense, to refer to a molecule that structurally resembles a reference molecule (such as 4-aminonaphthalene-2-carboxylic acid or 1 -amino-isoquinoline-3- carboxylic acid), but has been modified in a targeted and controlled manner to replace one or more specific substituents of the reference molecule with an alternate substituent, thereby generating a molecule which is structurally similar to the reference molecule. Synthesis and screening of analogs {e.g., using structural and/or biochemical analysis), to identify slightly modified versions of a known compound which may have improved or biased traits (such as higher potency and/or selectivity at a specific targeted receptor type, fewer side effects, etc.) is a drug design approach that is well known in pharmaceutical chemistry.
[0097] In addition, using methods known to those skilled in the art, analogs and derivatives of the compounds of the invention can be created which have improved therapeutic efficacy, i.e., higher potency and/or selectivity at a specific targeted receptor type, either greater or lower ability to penetrate mammalian blood-brain barriers {e.g., either higher or lower blood-brain barrier permeation rate), fewer side effects, etc.
[0098] The term "prodrug" is used herein in the conventional pharmaceutical sense, to refer to a molecule which undergoes a transformation in vivo (e.g., an enzymatic or chemical transformation) to release an active parent drug. Prodrugs of the compounds of Formula I of the present invention may be prepared by chemically modifying a functional group present in the compound of Formula I such that the chemically modified compound may undergo a transformation in vivo (e.g., enzymatic hydrolysis) to provide the compound of Formula I. Examples of functional groups present in the compounds of Formula I which may be modified to produce prodrugs include carboxy, hydroxy and amino groups. Prodrugs of the compounds of Formula I of the present invention may be prepared according to conventional techniques which have been described in the art (see, for example, Stella V., et al., Prodrugs: Challenges and Rewards, AAPS Press/Springer, New York, 2007).
[0099] The phrase "pharmaceutically acceptable", as used in connection with compositions of the invention, refers to molecular entities and other ingredients of such compositions that are physiologically tolerable and do not typically produce untoward reactions when administered to a mammal {e.g., human). The term "pharmaceutically acceptable" may also mean approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in mammals, and more particularly in humans.
[00100] Compounds of the present invention may be in the form of pharmaceutically acceptable salts. "Pharmaceutically acceptable salts" refers to those salts which possess the biological effectiveness and properties of the parent compound and which are not biologically or otherwise undesirable. The nature of the salt or isomer is not critical, provided that it is non-toxic and does not substantially interfere with the desired pharmacological activity.
[00101 ] It will be appreciated by those skilled in the art that compounds of the invention having a chiral center may exist in and be isolated in optically active and racemic forms. Some compounds may exhibit polymorphism. It is to be understood that the present invention ecompasses any racemic, optically-active, polymorphic, tautomeric, or stereoisomeric form, or mixture thereof, of a compound of the invention, which possesses the useful properties described herein.
[00102] Schemes 2-5 describe the preparation of compounds of Formula I of the present invention. All of the starting materials are prepared by procedures described in Scheme 1 or following schemes, by procedures well known to one of ordinary skill in organic chemistry or can be obtained commercially. All of the final compounds of the present invention are prepared by procedures described in these charts or by procedures analogous thereto, which procedures would be well known to one of ordinary skill in organic chemistry. All of the variables used in the schemes defined below or as in the claims.
Scheme 1 Synthesis of starting material 3
Figure imgf000029_0001
R=Me, Et
[00103] The compounds of general Formula IA (wherein R4 is hydrogen) may be prepared in two steps from an appropriately substituted ester of 4-aminonaphthalene-2- carboxylic acid 4 (Scheme 2). Thus, 4-amido-2-naphthoic acid ester 6 (wherein R6 represents Chalky!, aryl, heteroaryl, aryl-Ci-6alkyl, or heteroaryl-Ci-6alkyl) may be obtained by reacting compound 4 with compound 5 (wherein X' represents CI or Br) in the presence of an appropriate base (e.g., triethylamine) in a polar solvent (e.g., dichloromethane, acetonitrile, or DMF). Alternatively, compound 6 may be prepared by reacting amine 4 with compound 5 (wherein X' represents OH) in the presence of condensing agent (e.g., EDCI and HOBT, or CDI) in an appropriate solvent (e.g., DMF). The ester group of compound 6 may be hydrolyzed to yield compound IA. For example, a lower alkyl (e.g., methyl or ethyl) ester group may be hydrolyzed using reagents such as aqueous lithium hydroxide or sodium hydroxide.
[00104] The compounds of general Formula IA (wherein R4 is Chalky!, aryl-Ci- 6alkyl, heteroaryl-Ci-6alkyl, or Ci-6alkoxy-Ci-6alkyl) may be prepared from compound 9 by analogous procedures. Thus, amine 9 may be acylated with compound 5 (wherein X' represents CI or Br) in the presence of an appropriate base (e.g., KOBu-t, or NaH) in a polar solvent (e.g., DMSO, or DMF) to give compound 10. To obtain the compound of Formula IA, the ester group of compound 10 may be hydrolyzed using reagents such as aqueous lithium hydroxide or sodium hydroxide. [00105] Necessary starting compounds 4 and 9, may be prepared by the cleavage of N-Boc group of compounds 3 and 8, respectively, with trifluoroacetic acid in dichloromethane. Compound 8 may, in turn, be prepared by reacting compound 3 with compound 7 (wherein R4' is Chalky!,
Figure imgf000030_0001
heteroaryl-Ci-6alkyl, or Ci-6alkoxy- Ci-6alkyl) in the presence of an appropriate base (e.g., KOBu-t, or NaH) in a polar solvent (e.g., DMSO, or DMF). Compound 3 may be synthesized in two steps from 4- hydroxy-naphthalene-2-carboxylic acid ester 1 [WO2010/139481 ], as shown in Scheme 1. Thus, triflate 2 is obtained by reacting compound 1 with triflic anhydride in the presence of an appropriate base (e.g., pyridine) in a polar solvent (e.g., dichloromethane). N-Boc protected alkyl 4-amino-2-naphthoate 3 may, in turn, be prepared by reacting triflate 2 with tert-butyl carbamate in the presence of an appropriate palladium catalyst (e.g., Pd2dba3), complexing ligand (e.g., Xantphos), and an appropriate base (e.g., cesium carbonate) in a polar solvent (e.g., THF).
Scheme 2 Synthesis of compounds of Formula IA
Figure imgf000030_0002
[00106] The compounds of general Formula IB (wherein R4 is hydrogen) may be prepared in three steps from an appropriately substituted N-Boc protected alkyl 4- amino-2-naphthoate 3 (Scheme 3). Thus, compound 3 may react with compound 11 (wherein R12 represents hydrogen, Chalky! or Ci-6alkoxy-Ci-6alkyl; and wherein R7 represents aryl, heteroaryl, or Ci-6alkoxy) to give compound 12. The N-Boc group of compound 12 may be cleaved with trifluoroacetic acid in dichloromethane to obtain compound 13. The ester group of compound 13 may be hydrolyzed using reagents such as aqueous lithium hydroxide or sodium hydroxide to yield compound IB.
[00107] The compounds of general Formula IB (wherein R4 is Chalky!, aryl- Ci-6alkyl, heteroaryl-Ci-6alkyl, or Ci-6-alkoxy-Ci-6alkyl) may be prepared by an analogous procedures from N-Boc protected alkyl 4-amino-2-naphthoate 3 or from compound 9. Thus, compound 9 may react with compound 11 in the presence of an appropriate base (e.g., potassium carbonate) in a polar solvent (e.g., DMSO, or DMF) to give compound 14. Alternatively, compound 14 may be prepared by reacting compound 13 with compound 7 in the presence of an appropriate base (e.g., potassium carbonate) in a polar solvent (e.g., DMSO, or DMF). The ester group of compound 14 may be hydrolyzed using aqueous lithium hydroxide or sodium hydroxide to yield compound IB.
Figure imgf000032_0001
[00108] The compounds of Formula IC, may be prepared from compound 14, wherein R7 represents tert-butoxy group (Scheme 4). Cleavage of tert-butoxy group of compound 14 by TFA in dichloromethane may give carboxylic acid 15 which may, in turn, react with amine 16 in the presence of condensing agent (e.g., EDCI and HOBT) and an appropriate base (e.g., triethylamine, or DIPEA) in a polar solvent (e.g., acetonitrile, or DMF) to give compound 17. Hydrolysis of ester groups of compound 17 as described above may provide compound of Formula IC.
Scheme 4 Synthesis of compounds of formula IC
Figure imgf000033_0001
[00109] The compounds of general Formula ID may be prepared in two steps from an appropriately substituted 1 -chloro-isoquinoline-3-carboxylic acid ester 21 (Scheme 5). Thus, compound 21 may react with amine 22 (wherein R4 and R5 independently represent hydrogen, Chalky!, aryl-Ci-6alkyl, heteroaryl-Ci-6alkyl, Ci-6-alkoxy-Ci-6alkyl, and arylaminocarbonyl-Ci-6alkyl, heteroarylaminocarbonyl-Ci-6alkyl, aryl- Ci-6alkyaminocarbonyl-Ci-6-alkyl or heteroaryl-Ci-6-alkyaminocarbonyl-Ci-6alkyl) in the presence of an appropriate base (e.g., DIPEA) in a polar solvent (e.g., DMSO, or DMF) to give compound 23. The ester group of compound 23 may be hydrolyzed using reagents such as aqueous lithium hydroxide or sodium hydroxide to yield compound I. Necessary 1 -chloro-isoquinoline 21 may be prepared from corresponding 1 -oxo-1 ,2- isoquinoline-3-carboxylic acid ester 20 by a common chlorination procedure with phosphoryl chloride. Compound 20 may, in turn, be prepared by condensation of 1 -oxo- 1 H-isochromene-3-carboxylic acid ester 19 with ammonium carbonate. Ester 19 may be obtained by esterification of 1 -oxo-1 H-isochromene-3-carboxylic acid 18. There are many well known procedures for the synthesis of appropriately substituted 1 -oxo-1 H- isochromene-3-carboxylic acid 18 (For example, US Patent No 3,975,535 and Nakamura, Y.; Ukita, T., Org. Lett. 2002, 4, 2317.).
Scheme 5 Synthesis of compounds of formula ID
Figure imgf000034_0001
Figure imgf000034_0002
[001 10] It will be appreciated that in the above transformations it may be necessary or desirable to protect any sensitive groups in the molecule of the compound in question in order to avoid undesirable side reactions. The reaction products may be isolated and purified by standard laboratory techniques, such as extraction, chromatography and crystallization. Products isolated as a free base may be further converted into a hydrochloride or any other pharmaceutically acceptable salt according to known procedures. Products isolated as a free carboxylic acid may be converted into sodium salt or any other pharmaceutically acceptable salt according to known procedures.
[001 1 1 ] It will be apparent to those skilled in the art that the described synthetic procedures are merely representative in nature and that alternative synthetic processes are known to one of ordinary skill in organic chemistry.
[001 12] Pure stereoisomeric forms of the compounds and the intermediates of this invention may be obtained by the application of art-known procedures. Diastereomers may be separated by physical separation methods such as selective crystallization and chromatographic techniques, e.g. liquid chromatography using chiral stationary phases. Enantiomers may be separated from each other by selective crystallization of their diastereomeric salts with optically active acids. Alternatively, enantiomers may be separated by chromatographic techniques using chiral stationary phases. [001 13] Pure stereoisomeric forms may also be derived from the corresponding pure stereoisomeric form of appropriate starting materials, provided that the reaction occurs stereoselective^. Stereoisomeric forms of Formula I are obviously intended to be included within the scope of this invention.
ADDITION SALTS
[001 14] For therapeutic use, salts of the compounds of Formula I are those wherein the counterion is pharmaceutically acceptable. However, salts of acids and bases, which are non-pharmaceutically acceptable, may also find use, for example, in the preparation and purification of pharmaceutically acceptable compounds. All salts whether pharmaceutically acceptable or not are included within the ambit of the present invention. The pharmaceutically acceptable salts as mentioned above are meant to comprise the therapeutically active non-toxic salt forms, which the compounds of Formula I are able to form. The latter can conveniently be obtained by treating the base form with such appropriate acids as inorganic acids, e.g. hydrohalic acids such as hydrochloric, hydrobromic and the like; sulfuric acid; nitric acid; phosphoric acid and the like; or organic acids such as acetic, propanoic, hydroxyacetic, 2-hydroxypropanoic, oxopropanoic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, 2-hydroxy-1 ,2,3- propanetricarboxylic, methanesulfonic, ethanesulfonic, benzenesulfonic, 4- methylbenzenesulfonic, cyclohexanesulfonic, 2-hydroxybenzoic, 4-amino-2- hydroxybenzoic and like acids. Conversely, the salt may be converted to the free base by treatment with alkali. Compounds of Formula I can form pharmaceutically acceptable salts with various basic compounds. Suitable base salts include, but are not limited to, ammonium, potassium, sodium, and choline salts.
PHARMACEUTICAL COMPOSITIONS
[001 15] The active ingredients of the compounds of the present invention, together with one or more conventional adjuvants, carriers, or diluents, may be placed into the form of pharmaceutical compositions and unit dosages thereof, and in such form may be employed as solids, such as coated or uncoated tablets or filled capsules, liquids, such as solutions, suspensions, emulsions, elixirs, or capsules filled with the same, or thin films/flash doses, all for oral use; in the form of suppositories or capsules for rectal administration or in the form of sterile injectable solutions for parenteral (including intravenous or subcutaneous) use. Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional or new ingredients in conventional or special proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective amount of the active ingredient of the compounds of the present invention commensurate with the intended daily dosage range to be employed. Tablets containing one (1 ) to one hundred (100) milligrams of active ingredient or, more broadly, zero point five (0.5) to five hundred (500) milligrams per tablet, are accordingly suitable representative unit dosage forms.
[001 16] The term "excipient" applied to pharmaceutical compositions of the invention refers to an adjuvant, carrier, diluent, or vehicle with which a compound of the present invention is administered. Such pharmaceutical excipients may be sterile or non-sterile excipients commonly used for the formulation and production of solid, semi solid, liquid and sterile pharmaceutical compositions. These excipients may also be liquids, such as water, saline solutions, aqueous dextrose solutions, aqueous glycerol solutions, and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. A.R. Gennaro, 20th Edition, describes suitable pharmaceutical carriers in "Remington: The Science and Practice of Pharmacy". The excipients may also be combinations of solids and liquids.
METHOD OF TREATING
[001 17] Due to their high degree of activity and their low toxicity, together presenting a most favorable therapeutic index, the active principles of the invention may be administered to a subject, e.g., a living animal (including a human) body, in need thereof, for the treatment, alleviation, or amelioration, palliation, or elimination of an indication or condition which is susceptible thereto, or representatively of an indication or condition set forth elsewhere in this application, including concurrently, simultaneously, or together with one or more pharmaceutically-acceptable excipients, carriers, or diluents, including in the form of a pharmaceutical composition thereof, whether by oral, rectal, or parental (including intravenous and subcutaneous) or in some cases even topical route, in an effective amount. Suitable dosage ranges are 1 -1000 milligrams daily, optionally 10-500 milligrams daily, and optionally 50-500 milligrams daily, depending as usual upon the exact mode of administration, form in which administered, the indication toward which the administration is directed, the subject involved and the body weight of the subject involved, and the preference and experience of the physician or veterinarian in charge.
[001 18] The term "treat" is used herein to mean to relieve or alleviate at least one symptom of a disease in a subject. Within the meaning of the present invention, the term "treat" also denotes to arrest, delay the onset (i.e., the period prior to clinical manifestation of a disease) and/or reduce the risk of developing or worsening a disease.
[001 19] The term "therapeutically effective" applied to dose or amount refers to that quantity of a compound or pharmaceutical composition that is sufficient to result in a desired activity upon administration to a living animal body in need thereof.
[00120] The compounds of the present invention may be administered orally, topically, parenterally, or mucosally (e.g., buccally, by inhalation, or rectally) in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers. It is usually desirable to use the oral route. The compounds of the present invention may be administered orally in the form of a capsule, a tablet, or the like (see Remington: The Science and Practice of Pharmacy, 20th Edition). The orally administered medicaments may be administered in the form of a time-controlled release vehicle, including diffusion-controlled systems, osmotic devices, dissolution-controlled matrices, and erodible/degradable matrices.
[00121 ] For oral administration in the form of a tablet or capsule, the glycine B antagonist active component may be combined with a non-toxic, pharmaceutically acceptable excipients such as binding agents (e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, sucrose, glucose, mannitol, sorbitol and other reducing and non-reducing sugars, microcrystalline cellulose, calcium sulfate, or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc, or silica, steric acid, sodium stearyl fumarate, glyceryl behenate, calcium stearate, and the like); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulphate), coloring and flavoring agents, gelatin, sweeteners, natural and synthetic gums (such as acacia, tragacanth or alginates), buffer salts, carboxymethylcellulose, polyethyleneglycol, waxes, and the like. For oral administration in liquid form, the glycine B antagonist active components may be combined with non-toxic, pharmaceutically acceptable inert carriers {e.g., ethanol, glycerol, water), suspending agents (e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats), emulsifying agents (e.g., lecithin or acacia), non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol or fractionated vegetable oils), preservatives (e.g., methyl or propyl-p-hydroxybenzoates or sorbic acid), and the like. Stabilizing agents such as antioxidants (BHA, BHT, propyl gallate, sodium ascorbate, citric acid) may also be added to stabilize the dosage forms.
[00122] The tablets may be coated by methods well known in the art. The compounds of the present invention may be also introduced in beads, microspheres or microcapsules, e.g., fabricated from polyglycolic acid/lactic acid (PGLA). Liquid preparations for oral administration may take the form of, for example, solutions, syrups, emulsions or suspensions, or they may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Preparations for oral administration may be suitably formulated to give controlled or postponed release of the active compound.
[00123] The compounds of the present invention may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines, as is well known.
[00124] The compounds of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled. The instant compounds may also be coupled with soluble polymers as targetable drug carriers. Such polymers include polyvinyl-pyrrolidone, pyran copolymer, polyhydroxy-propyl methacrylamide-phenol, polyhydroxy-ethyl-aspartamide-phenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, the instant compounds may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polyhydropyrans, polycyanoacrylates, and cross-linked or amphipathic block copolymers of hydrogels.
[00125] For administration by inhalation, the compounds of the present invention may be conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, e.g., gelatin for use in an inhaler or insufflator can be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
[00126] The formulations comprising the compounds of the present invention may be delivered parenterally, i.e., by intravenous (i.v.), intracerebroventricular (i.c.v.), subcutaneous (s.c), intraperitoneal (i.p.), intramuscular (i.m.), subdermal (s.d.), or intradermal (i.d.) administration, by direct injection, via, for example, bolus injection or continuous infusion. Formulations for injection can be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions can take such forms as excipients, suspensions, solutions, or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient of the compounds of the present invention can be in powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
[00127] The compounds of the present invention may also be formulated for rectal administration, e.g., as suppositories or retention enemas {e.g., containing conventional suppository bases such as cocoa butter or other glycerides).
[00128] The compositions comprising glycine B antagonists of the present invention may, if desired, be presented in a pack or dispenser device, which may contain one or more unit dosage forms containing the active ingredient and/or may contain different dosage levels to facilitate dosage titration. The pack may, for example, comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The glycine B antagonists of the present invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
[00129] As disclosed herein, the dose of the components in the compositions of the present invention is determined to ensure that the dose administered continuously or intermittently will not exceed an amount determined after consideration of the results in test animals and the individual conditions of a patient. A specific dose naturally varies depending on the dosage procedure, the conditions of a patient or a subject animal such as age, body weight, sex, sensitivity, feed, dosage period, drugs used in combination, seriousness of the disease. The appropriate dose and dosage times under certain conditions can be determined by the test based on the above-described indices but may be refined and ultimately decided according to the judgment of the practitioner and each patient's circumstances (age, general condition, severity of symptoms, sex, etc.) according to standard clinical techniques.
[00130] Toxicity and therapeutic efficacy of the compositions of the invention can be determined by standard pharmaceutical procedures in experimental animals, e.g., by determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between therapeutic and toxic effects is the therapeutic index and it may be expressed as the ratio LD50/ED50. Compositions that exhibit large therapeutic indices are preferred.
[00131 ] From the Examples described herein below, it is apparent that the present invention provides novel and valuable applications and uses of the compounds of the present invention, which compounds comprise the active principle according to the present invention, as well as novel pharmaceutical compositions thereof and methods of preparation thereof and of treating therewith. [00132] The high order of activity of the active agent of the present invention and compositions thereof, as evidenced by the tests reported, is indicative of utility based on its valuable activity in human beings as well as in lower animals. Clinical evaluation in human beings has not been completed. It will be clearly understood that the distribution and marketing of any compound or composition falling within the scope of the present invention for use in human beings will of course have to be predicated upon prior approval by governmental agencies which are responsible for and authorized to pass judgment on such questions.
[00133] The instant compounds of Formula I represent a novel class of glycine B antagonists. In view of their potency, they will be useful therapeutics in a wide range of disorders, including CNS disorders, which involve excessive glutamate induced excitation.
[00134] These compounds accordingly find application in the treatment of the disorders of a living animal body, especially a human, as listed earlier in the description.
[00135] The method-of-treating a living animal body with a compound of the invention, for the inhibition of progression or alleviation of the selected ailment therein, is as previously stated by any normally-accepted pharmaceutical route, employing the selected dosage which is effective in the alleviation of the particular ailment desired to be alleviated. Use of the compounds of the present invention in the treatment of a living animal for inhibition of progression or alleviation of selected ailments or conditions, particularly ailments or conditions susceptible to treatment with a glycine B is carried out in the usual manner comprising the step of admixing an effective amount of a compound of the invention with a pharnnaceutically-acceptable diluent, excipient, or carrier, and the method-of-treating, pharmaceutical compositions, and use of a compound of the present invention in the manufacture of a medicament.
[00136] Representative pharmaceutical compositions prepared by admixing the active ingredient with a suitable pharnnaceutically-acceptable excipient, diluent, or carrier, include tablets, capsules, solutions for injection, liquid oral formulations, aerosol fornnulations, TDS fornnulations, and nanopartide fornnulations, thus to produce medicaments for oral, injectable, or dermal use, also in accord with the foregoing.
EXPERIMENTAL PART
[00137] The compounds and their preparation of the present invention will be better understood in connection with the following examples, which are intended as an illustration of and not a limitation upon the scope of the invention.
[00138] Hereinafter, "DMF" is defined as Ν,Ν-dimethylformamide, "DCM" as dichloromethane, "HCI" as hydrochloric acid, "DMSO" as dimethyl sulfoxide, "DIPEA" as Ν,Ν-diisopropylethylamine, "EDC" as 1 -ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride, ΉΟΒΤ" as 1 -hydroxy-benzotriazole, "Pd2dba3M as tris(dibenzylideneacetone)-dipalladium(0), "TBAI" as tetrabutylammonium iodide, "CDI" as 1 ,1 '-carbonyldiimidazole, "TFA" as trifluoroacetic acid, "MeCN" as acetonitrile, "THF" as tetrahydrofuran, "AcOH" as acetic acid, "EtOH" as ethanol, "EtOAc" as ethyl acetate, "MeOH" as methanol.
Preparation 1
Methyl 5,7-dichloro-4-{[(trifluoromethyl)sulfonyl]oxy}-2-naphthoate (2)
[00139] To a mixture of methyl 5,7-dichloro-4-hydroxy-2-naphthoate (1 ) (4.5 g, 16.6 mmol) and pyridine (2.7 mL, 33.4 mmol) in dry DCM (200 mL) under argon atmosphere at ice bath temperature is added triflic anhydride (3.3 mL, 19.9 mmol). The mixture is stirred at ice bath temperature for 1 h, then ice bath is removed and the mixture is stirred at ambient temperature overnight. The reaction mixture is poured into ice water (120 mL), the organic layer is separated and the aqueous phase is extracted with DCM (100 mL). The organic extracts are combined and washed successively with 5% HCI (150 mL), water (150 mL), brine (100 mL), and dried (Na2SO4). The solvent is evaporated and the residue is dried in vacuo to give the title compound 2 (6.64 g, 99%) as a white solid. Mp 1 18.5-120 °C. 1H NMR (400 MHz, CDCI3) δ: 4.01 (s, 3H); 7.76 (d, 2.0 Hz, 1 H); 7.92 (dd, 2.0 and 0.4 Hz, 1 H); 8.06 (d, 1 .5 Hz, 1 H); 8.52 (dd, 1 .5 and 0.4 Hz, 1 H). 19F-NMR (CDCI3) δ: -72.09. LC-MS (m/z): 401 [M-H]" (35CI). Preparation 2
Methyl 4-[(tert-butoxycarbonyl)amino]-5,7-dichloro-2-naphthoate (3)
[00140] A mixture of methyl 5,7-dichloro-4-{[(trifluoromethyl)sulfonyl]oxy}-2- naphthoate (2) (6.60 g, 16.4 mmol), pre-dried Cs2CO3 (9.07 g, 27.8 mmol), tert-butyl carbamate (2.68 g, 22.9 mmol), Xantphos (1 .14 g, 1 .96 mmol), and Pd2dba3 (0.60 g, 0.65 mmol) in THF (200 mL) is stirred under argon atmosphere at 70 °C overnight (ca. 15 h). The reaction mixture is filtered through silica gel (50 g) and the column is washed with THF. The filtrate is evaporated and the residue (8.6 g) is chromatographed on silica gel (300 g) (petroleum ether-EtOAc; gradient from 100:0 to 90:10) to give the title compound 3 (5.02 g, 83%). 1H NMR (400 MHz, CDCI3) δ: 1 .54 (s, 9H); 3.97 (s, 3H); 7.58 (d, 2.1 Hz, 1 H); 7.83 (d, 2.1 Hz, 1 H); 8.17 (b s, 1 H); 8.24 (d, 1 .6 Hz, 1 H); 8.51 (d, 1 .6 Hz, 1 H).
Example 1
4-Amino-5,7-dichloronaphthalene-2-carboxylic acid a) Methyl 4-amino-5,7-dichloro-2-naphthoate, trifluoroacetate (4)
[00141 ] To a solution of methyl 4-[(tert-butoxycarbonyl)amino]-5,7-dichloro-2- naphthoate (3) (5.00 g, 13.5 mmol) in DCM (50 mL) TFA (50 mL) is added and the mixture is stirred at rt for 2 h. The volatiles are evaporated and the residue is azeotropically dried successively with toluene, DCM, and petroleum ether, then dried in vacuo at 70 °C/2 mm Hg for 26 h to give the title compound (4.31 g, 100%) as a yellow solid with Mp 155 °C. 1H NMR (400 MHz, CDCI3) δ: 3.95 (s, 3H); 5.44 (br s, 3H); 7.30 (d, 1 .6 Hz, 1 H); 7.45 (d, 2.2 Hz, 1 H); 7.73 (d, 2.2 Hz, 1 H); 7.85 (d, 1 .6 Hz, 1 H). LC ESI- MS (m/z): 270 [M+H] (for 35CI). Anal. Calcd for Ci2H9CI2NO2 *0.43 CF3CO2H: C 48.40, H 2.98, N 4.39. Found: C 48.42, H 3.13, N 4.18. b) 4-Amino-5,7-dichloronaphthalene-2-carboxylic acid
[00142] To a suspension of methyl 4-amino-5,7-dichloro-2-naphthoate, trifluoroacetate (4) (0.03 g, 0.09 mmol) in THF (2 mL) is added LiOH monohydrate (7.77 .g, 0.19 mmol, 2 equiv.) and water (2 mL). The mixture is stirred at rt for 8 h (TLC control). THF is removed under reduced pressure and remaining suspension is diluted with distilled water (-10 mL), and slightly acidified with 10% HCI. Precipitate is filtered, washed with distilled water and small amount of MeCN, and dried in vacuo over P2O5. The title compound is obtained in 55% yield as a pale yellow solid.
1H NMR (400 MHz, DMSO-d6) δ: 6.30 (br s, 2H); 7.32 (d, 1 .6 Hz, 1 H); 7.56 (d, 2 Hz, 1 H); 7.74 (d, 1 .6 Hz, 1 H); 8.04 (d, 1 .6 Hz, 1 H).
Example 2
4-Benzoylamino-5,7-dichloro-naphthalene-2-carboxylic acid a) Methyl 4-benzoylamino-5,7-dichloro-naphthoate
[00143] To a solution of methyl 4-amino-5,7-dichloro-2-naphthoate, trifluoroacetate (0.1 g, 0.26 mmol) in DCM (10 mL) is added Et3N (0.78 mmol, 0.1 mL) and benzoyl chloride (0.04 mL, 0.39 mmol). The mixture is stirred overnight at rt. The reaction mixure is diluted with water, extracted with DCM (3 x 10 mL). The organic phase is washed with brine and dried over sodium sulfate. Solvent is evaporated and the residue is purified on silica gel (CHCI3). The title compound is obtained (83 mg, 85%) as white solid. b) 4-Benzoylamino-5,7-dichloro-naphthalene-2-carboxylic acid
[00144] To a stirring mixture of methyl 4-benzoylamino-5,7-dichloro-naphthoate (0.083 g, 0.22 mmol) in THF/water was added LiOH*H2O (0.01 1 g, 0.27 mmol, 1 .2 equiv.) reaction mixture is stirred at rt for 3 h (TLC control). The mixture is slightly acidified by addition of 1 N HCI and concentrated under reduced pressure. Solid residue is filtered off, washed with water and dried under vacuum at 65 °C. The title compound is obtained (22 mg, 28%) as white solid.
1H NMR (400 MHz, DMSO-d6) δ: 7.55-7.65 (m, 3H); 7.86 (d, 2 Hz, 1 H); 7.97 (d, 1 .6 Hz, 1 H); 8.03-8.05 (m, 2H); 8.42 (d, 2 Hz,1 H); 8.64 (d, 1 .6 Hz, 1 H); 10.61 (s, 1 H). LC-MS: 358.0 [M-H] (35CI).
Example 3
5,7-Dichloro-4-phenylacetylamino-naphthalene-2-carboxylic acid [00145] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 2(a), acylation of methyl 4-amino- 5,7-dichloro-2-naphthoate with phenylacetyl chloride gives methyl 5,7-dichloro-4- phenylacetylamino-2-naphthoate in 75% yield;
b) in analogy to the procedure described in Example 1(b), hydrolysis of methyl 5,7- dichloro-4-phenylacetylamino-2-naphthoate with LiOH gives the title compound in 25% yield as a light brown solid.
1H NMR (400 MHz, DMSO-d6) δ: 3.74 (s, 2H); 7.24-7.38 (m, 5H); 7.82 (d, 2.4 Hz, 1 H); 7.86 (d, 1 .6 Hz, 1 H); 8.36 (d, 2 Hz, 1 H); 8.56 (d, 1 .6 Hz, 1 H); 10.24 (s, 1 H). LC-MS: 372.2 [M-H] (35CI).
Example 4
5,7-Dichloro-4-(phenylcarbamoylmethyl-amino)-naphthalene-2-carboxylic acid a) Methyl 4-{(ferf-butoxycarbonyl)[2-(ferf-butoxy)-2-oxoethyl]amino}-5,7-dichloro- 2-naphthoate
[00146] To a solution of methyl 4-[(tert-butoxycarbonyl)amino]-5,7-dichloro-2- naphthoate (3) (1 .8 g, 4.86 mmol) in DMF (25 mL) at ice bath temperature 60% NaH (0.21 g, 5.25 mmol) in mineral oil is added and the mixture is stirred for 10 min. Then terf-butyl bromoacetate (0.86 mL, 5.83 mmol) is added to the mixture, then after 5 min ice bath is removed and the reaction mixture is stirred at ambient temperature for 3 h. The mixture is poured into ice water (200 mL), extracted with ether (3 x 100 mL), and the extracts are washed with brine (100 mL), and dried (Na2SO4). The solvent is evaporated and the residue is dried in vacuo over P2O5 to give the title compound (2.49 g, quant.) as a white solid. 1H NMR (400 MHz, CDCI3) δ: (rotamers, 1 :1 ) 1 .20 (s, 9H); 1 .47 (s, 9H); 1 .49 (s, 9H); 1 .53 (s, 9H); 3.49 (d, 17.4 Hz, 1 H), 3.55 (d, 17.8 Hz, 1 H); 3.92 (s, 3H); 3.94 (s, 3H); 4.48 (d, 17.8 Hz, 1 H); 4.63 (d, 17.4 Hz, 1 H); 7.61 (d, 2.1 Hz,1 H); 7.62 (d, 2.1 Hz,1 H); 7.84 (d, 2.1 Hz,1 H); 7.84 (d, 2.1 Hz,1 H); 8.28 (d, 1 .8 Hz, 1 H); 8.36 (d, 1 .8 Hz, 1 H); 8.41 (d, 1 .8 Hz, 1 H); 8.43 (d, 1 .8 Hz, 1 H). b) {[6,8-Dichloro-3-(methoxycarbonyl)-1 -naphthyl]amino}acetic acid [00147] To a solution of methyl 4-{(terf-butoxycarbonyl)[2-(terf-butoxy)-2- oxoethyl]amino}-5,7-dichloro-2-naphthoate (2.49 g, 5.14 mmol) in DCM (35 mL) TFA (15 mL) is added and the mixture is stirred at ambient temperature for 3 h. The volatiles are evaporated and the residue is azeotropically dried with toluene and DCM, and dried in vacuo to give the title compound (1 .595 g, 82%) as a yellowish solid with m.p. >220°C (dec). 1H NMR (400 MHz, DMSO-d6) δ: (a mixture of free base and TFA salt), free base - 3.89 (s, 3H); 4.05 (br s, 2H); 6.87 (d, 1 .5 Hz, 1 H); 7.30 (br s, 1 H); 7.70 (d, 2.2 Hz, 1 H); 7.87 (d, 1 .5 Hz, 1 H); 8.16 (d, 2.2 Hz, 1 H); -12.5 (br s, 1 H), TFA salt - 3.88 (d, 17.9 Hz, 1 H); 3.93 (s, 3H); 4.45 (d, 17.9 Hz, 1 H); 7.93 (d, 2.2 Hz, 1 H); 8.27 (d, 1 .8 Hz, 1 H); 8.43 (d, 2.2 Hz, 1 H); 8.69 (d, 1 .8 Hz, 1 H); -12.5 (br s, 1 H). LC ESI-MS (m/z): 328 [M+H], 350 [M+Na] (for 35CI); 326 [M-H] (35CI). Anal. Calcd for Ci4HnCI2NO4 *0.44 CF3CO2H: C 47.24, H 3.05, N 3.70. Found: C 47.24, H 2.83, N 3.55. c) Methyl 5,7-dichloro-4-(phenylcarbamoylmethyl-amino)-2-naphthoate
[00148] To a solution of {[6,8-dichloro-3-(methoxycarbonyl)-1 - naphthyl]amino}acetic acid (120 mg, 0.31 mmol) in DMF (2 mL) is added HOBT (61 .42 mg, 0.41 mmol, 1 .3 equiv.), EDC (77.67 mg, 0.41 mmol) and DIPEA (101 .09 mg, 0.78 mmol). After 5 min aniline (38.6 mg, 0.41 mmol, 1 .3 equiv.) is added and the reaction mixture is stirred at rt for 6 days (reaction is monitored by LCMS). The mixture is diluted with water and precipitate is filtered, washed with water and dried to give the title compound (44 mg, 34.9%) as a yellow powder. LCMS 403.2 [M+H] (35CI). d) 5,7-Dichloro-4-(phenylcarbamoylmethyl-amino)-naphthalene-2-carboxylic acid
[00149] In analogy to the procedure described in Example 1(b), hydrolysis of methyl 5,7-dichloro-4-(phenylcarbamoylmethyl-amino)-2-naphthoate with LiOH gives the title compound I-4 in 65% yield as a light yellow solid. Mp 225-226 °C.
1H NMR (400 MHz, DMSO-d6) δ: 4.14 (d, 4.4 Hz, 2H); 6.98 (s, 1 H); 7.06-7.10 (m, 1 H); 7.32-7.36 (m, 2H); 7.51 -7.54 (m, 1 H); 7.62 (d, 8 Hz, 2H); 7.70 (d, 2.4 Hz, 1 H); 7.86 (s, 1 H); 8.15 (d, 2.4 Hz, 1 H); 10.33 (s, 1 H). LC-MS: 387.0 [M-H] (35CI).
Example 5
4-[(Benzylcarbamoyl-methyl)-amino]-5,7-dichloro-naphthalene-2-carboxylic acid [00150] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 4(c), condensation of {[6,8- dichloro-3-(methoxycarbonyl)-1 -naphthyl]annino}acetic acid with benzylamine gives methyl 4-[(benzylcarbamoyl-methyl)-amino]-5,7-dichloro-2-naphthoate in 69% yield, LC/MS 417 M+H] (35CI);
b) in analogy to the procedure described in Example 1(b), hydrolysis of methyl 4- [(benzylcarbamoyl-methyl)-amino]-5,7-dichloro-2-naphthoate with LiOH gives the title compound in 28% yield. Mp 226-227 °C.
1H NMR (400 MHz, DMSO-d6) δ: 3.99 (d, 4 Hz, 2H); 4.36 (d, 5.6 Hz, 2H); 6.95 (s, 1 H); 7.21 -7.31 (m, 5H); 7.44 (br s, 1 H); 7.65 (s, 1 H); 7.83 (s, 1 H); 8.1 1 (s, 1 H); 8.70 (br s, 1 H). LC-MS: 401 .2 [M-H] (35CI).
Example 6
5,7-Dichloro-4-({[(pyridin-2-ylmethyl)-carbamoyl]-methyl}-amino)-naphthalene-2- carboxylic acid
[00151 ] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 4(c), condensation of {[6,8- dichloro-3-(methoxycarbonyl)-1 -naphthyl]amino}acetic acid with pyridin-2-ylmethylamine gives methyl 5,7-dichloro-4-({[(pyridin-2-ylmethyl)-carbamoyl]-methyl}-amino)-2- naphthoate in 82% yield;
b) in analogy to the procedure described in Example 1(b), hydrolysis of methyl 5,7- dichloro-4-({[(pyridin-2-ylmethyl)-carbamoyl]-methyl}-amino)-2-naphthoate with LiOH gives the title compound in 61 % yield.
1H NMR (400 MHz, DMSO-d6) δ: 4.03 (d, 4.4 Hz, 2H); 4.45 (d, 6 Hz, 2H); 6.94 (s, 1 H); 7.24-7.31 (m, 2H); 7.46-7.49 (m, 1 H); 7.68-7.72 (m, 2H); 7.86 (s, 1 H); 8.14 (d, 2 Hz, 1 H); 8.48 (d, 6 Hz, 1 H); 8.80 (t, 6 Hz, 1 H); 13.16 (br s, 1 H). LC-MS: 402.2 [M-H] (35CI).
Example 7
5 -Dichloro-4-({[(pyridin-3-ylmethyl)-carbamoyl]-methyl}-amino)-naphthalene-2- carboxylic acid [00152] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 4(c), condensation of {[6,8- dichloro-3-(methoxycarbonyl)-1 -naphthyl]annino}acetic acid with pyridin-3-ylmethylamine gives methyl 5,7-dichloro-4-({[(pyridin-3-ylmethyl)-carbamoyl]-methyl}-amino)-2- naphthoate in 79% yield;
b) in analogy to the procedure described in Example 1(b), hydrolysis of methyl 5,7- dichloro-4-({[(pyridin-3-ylmethyl)-carbamoyl]-methyl}-amino)-2-naphthoate with LiOH gives the title compound in 37% yield as a yellow powder.
1H NMR (400 MHz, DMSO-d6) δ: 3.99 (d, 4.4 Hz, 2H); 4.39 (d, 6 Hz, 2H); 6.90 (s, 1 H); 7.29-7.32 (m, 1 H); 7.45 (br s, 1 H); 7.65-7.68 (m, 2H); 7.85 (s, 1 H); 8.14 (d, 2 Hz, 1 H); 8.44 (d, 3.6 Hz, 1 H); 8.49 (s, 1 H); 8.76 (t, 6 Hz, 1 H). LC-MS: 402.2 [M-H] (35CI).
Example 8
5,7-Dichloro-4-[(pyridin-3-ylcarbamoylmethyl)-amino]-naphthalene-2-carboxylic acid
[00153] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 4(c), condensation of {[6,8- dichloro-3-(methoxycarbonyl)-1 -naphthyl]amino}acetic acid with pyridin-3-ylamine gives methyl 5,7-dichloro-4-[(pyridin-3-ylcarbamoylmethyl)-amino]-2-naphthoate in 33% yield; b) in analogy to the procedure described in Example 1(b), hydrolysis of methyl 5,7- dichloro-4-[(pyridin-3-ylcarbamoylmethyl)-amino]-2-naphthoate with LiOH gives the title compound in 34% yield as a grey powder. Mp >250 °C.
1H NMR (400 MHz, DMSO-d6) δ: 4.19 (d, 2,8 Hz, 2H); 6.97 (s, 1 H); 7.36-7.39 (m, 1 H); 7.50 (s, 1 H); 7.70 (s, 1 H); 7.87 (s, 1 H); 8.07 (d, 8.4 Hz, 1 H); 8.15 (s, 1 H); 8.30 (d, 4 Hz, 1 H); 8.76 (s, 1 H); 10.55 (s, 1 H); 12.80-13.60 (br s, 1 H). LC-MS: 388.1 [M-H] (35CI).
Example 9
5,7-Dichloro-4-({[(thiazol-2-ylmethyl)-carbamoyl]-methyl}-amino)-naphthalene-2- carboxylic acid [00154] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 4(c), condensation of {[6,8- dichloro-3-(methoxycarbonyl)-1 -naphthyl]-annino}acetic acid with 2-aminomethylthiazole gives methyl 5,7-dichloro-4-({[(thiazol-2-ylmethyl)-carbamoyl]-methyl}-amino)-2- naphthoate in 86% yield; LC/MS 424 [M+H];
b) in analogy to the procedure described in Example 1(b), hydrolysis of methyl 5,7- dichloro-4-({[(thiazol-2-ylmethyl)-carbamoyl]-methyl}-amino)-2-naphthoate with LiOH gives the title compound in 68% yield as a yellow powder.
Mp 231 -232 °C. 1H NMR (400 MHz, DMSO-d6) δ: 4.00 (d, 4 Hz, 2H); 4.64 (d, 5.6 Hz, 2H); 6.91 (s, 1 H); 7.44 (s, 1 H); 7.61 (d, 2.4 Hz, 1 H); 7.68-7.72 (m, 3H); 8.14 (s, 1 H); 9.07 (t, 5.6 Hz, 1 H); 12.80-13.40 (br s, 1 H). LC-MS: 408.1 [M-H] (35CI).
Example 10
5,7-Dichloro-4-({[(pyrimidin-4-ylmethyl)-carbamoyl]-methyl}-amino)-naphthalene- 2-carboxylic acid
[00155] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 4(c), condensation of {[6,8- dichloro-3-(methoxycarbonyl)-1 -naphthyl]-amino}acetic acid with 4- (aminomethyl)pyrimidine gives methyl 5,7-dichloro-4-({[(pyrimidin-4-ylmethyl)- carbamoyl]-methyl}-amino)-2-naphthoate in 96% yield;
b) in analogy to the procedure described in Example 1(b), hydrolysis of methyl 5,7- dichloro-4-({[(pyrimidin-4-ylmethyl)-carbamoyl]-methyl}-amino)-2-naphthoate with LiOH gives the title compound in 68% yield as a yellow powder.
Mp 208-209 °C. 1H NMR (400 MHz, DMSO-d6): δ 4.07 (d, 4.4 Hz, 2H); 4.43 (d, 5.6 Hz, 2H); 6.95 (s, 1 H); 7.42-7.45 (m, 2H); 7.68 (d, 1 .6 Hz, 1 H); 7.86 (s, 1 H); 8.14 (d, 2 Hz, 1 H); 8.68 (d, 5.2 Hz, 1 H); 8.88 (t, 5.6 Hz, 1 H); 9.08 (s, 1 H). LC-MS: 403.2 [M-H] (35CI).
Example 11
4-(Benzoyl-methyl-amino)-5,7-dichloro-naphthalene-2-carboxylic acid a) Methyl 4-(benzoyl-methyl-amino)-5,7-dichloro-2-naphthoate [00156] To a solution of methyl 4-benzoylamino-5,7-dichloro-2-naphthoate (Example 2a) (0.1 g, 0.27 mmol) in DMSO (1 .5 mL) is added KOfBu (30.29 mg, 0.27 mmol) (reaction mixture immediately turned into bright green-yellow solution) and stirred for 30 min at ambient temperature. Then iodomethane (0.06 g, 0.43 mmol, 1 .6 equiv.) is added and stirring is continued for another 3 h at rt.
The reaction mixture is quenched with brine (15 mL) and extracted with EtOAc (3x25 mL). The organic phase is collected, dried over sodium sulphate, filtered and evaporated. The residue is purified on silica gel column using petroleum ether and EtOAc gradient (TLC - Hexane : EtOAc, 2:1 ; Rf=0.36). The title compound is obtained as colourless solid in 53% yield. b) 4-(Benzoyl-methyl-amino)-5,7-dichloro-naphthalene-2-carboxylic acid
[00157] In analogy to the procedure described in Example 1(b), hydrolysis of methyl 4-(benzoyl-methyl-amino)-5,7-dichloro-naphthoate with LiOH gives the title compound in 96% yield as a white solid. 1H NMR (400 MHz, DMSO-d6) δ: 3.36 (s, 3H); 7.04-7.14 (m, 4H); 7.52-7.54 and 7.68-7.71 (both m, total 1 H); 7.89 (d, 1 .6 Hz, 1 H); 7.95 and 8.16 (both d, 2 Hz, total 1 H); 8.34 and 8.47 (both d, 2 Hz, total 1 H); 8.55 and 8.72 (both d, 1 .6 Hz, total 1 H). LC-MS: 372.1 [M-H] (35CI).
Example 12
5,7-Dichloro-4-(3-phenyl-ureido)-naphthalene-2-carboxylic acid a) Methyl 4-(3-phenyl-ureido)-5,7-dichloro-2-naphthoate.
[00158] Methyl 4-amino-5,7-dichloro-2-naphthoate, 0.22 trifluoroacetate 4 (66 mg) was dissolved in DCM (12 mL). Then Et3N 6.32 mg, 0.24 mmol) is added and after 5 min phenyl isocyanate (0.03 g, 0.24 mmol) is added. The reaction mixture is stirred for 3 days at rt. (Starting material and product has the same retention time in LC-MS and the same Rf when controlled by TLC (in all common eluents). Control by 1H-NMR (DMSO- d6) is preferable.) Product is poorly soluble in DCM, so the reaction mixture is concentrated to ~5 mL volume, filtered and washed with DCM to give the title compound as a white solid in 69 % yield. b) 5,7-Dichloro-4-(3-phenyl-ureido)-naphthalene-2-carboxylic acid
[00159] In analogy to the procedure described in Example 1(b), hydrolysis of methyl 4-(3-phenyl-ureido)-5,7-dichloro-2-naphthoate with LiOH gives the title compound as a light-brown solid, Mp 180 °C (decomposition starts).
1H NMR (400 MHz, DMSO-d6) δ: 6.96 (t, 7.4 Hz, 1 H); 7.27 (t, 8 Hz, 2H); 7.48 (d, 7,6 Hz, 2H); 7.84 (d, 2 Hz, 1 H); 8.04 (d, 1 Hz, 1 H); 8.36 (d, 2 Hz, 1 H); 8.50 (d, 1 Hz, 1 H); 8.63 (s, 1 H); 9.13 (s, 1 H); 13.40 (br s, 1 H). LC-MS: 373.1 [M-H] (35CI).
Example 13
4-(3-Benzylureido)-5,7-dichloronaphthalene-2-carboxylic acid
[00160] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 12(a), methyl 4-amino-5,7- dichloro-2-naphthoate, trifluoroacetate is reacted with benzyl isocyanate in the presence of DIPEA to give methyl 4-(3-benzylureido)-5,7-dichloro-2-naphthoate in 57% yield; b) in analogy to the procedure described in Example 1(b), hydrolysis of methyl 4-(3- benzylureido)-5,7-dichloro-2-naphthoate with LiOH for 2 days at 40 °C gives the title compound in 90% yield as a pale beige solid with Mp 220 °C (decomposition starts).
1H NMR (400 MHz, DMSO-d6) δ: 4.33 (d, 5.6 Hz, 2H); 7.12-7.15 (m, 1 H); 7.22-7.28 (m, 1 H); 7.33-7.36 (m, 4H); 7.80 (d, 2.4 Hz, 1 H); 8.03 (d, 2 Hz, 1 H); 8.32 (d, 2.4 Hz, 1 H); 8.43 (d, 2 Hz, 1 H); 8.50 (s, 1 H). LC-MS: 387.4 [M-H] (35CI).
Example 14
5,7-Dichloro-4-(methylphenylacetylamino)-naphthalene-2-carboxylic acid
[00161 ] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 11(a), alkylation of methyl 5,7- dichloro-4-phenylacetylamino-2-naphthoate with iodomethane gives methyl 5,7- dichloro-4-(methylphenylacetylamino)-2-naphthoate in 60% yield;
b) in analogy to the procedure described in Example 1(b), hydrolysis of methyl 5,7- dichloro-4-(methylphenylacetylamino)-2-naphthoate with LiOH at rt for 10 h gives the title compound in 59% yield. Mp 100-1 15 °C. 1H NMR (400 MHz, DMSO-d6) δ: 3.17 and 3.43 (both s, total 3H); 3.15, 3.24, 3.89 and 3.97 (all d, 16 Hz, total 2H); 6.88-6.91 (m, 2H); 7.1 1 -7.18 (m, 2H), 7.30- 7.36 (m, 1 H); 7.84-7.87 (m, 1 H); 7.98 (d, 2.4 Hz, 1 H); 8.41 and 8.50 (both d, 2 Hz, total 1 H); 8.64 and 8.74 (both d, 1 .6 Hz, total 1 H). LC-MS: 386.1 [M-H] (35CI).
Example 15
5,7-Dichloro-4-(3-phenylpropionylamino)-naphthalene-2-carboxylic acid
[00162] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 2(a), acylation of methyl 4-amino- 5,7-dichloro-2-naphthoate with 3-phenylpropionyl chloride gives methyl 5,7-dichloro-4- (3-phenylpropionylamino)-2-naphthoate in 73% yield;
b) in analogy to the procedure described in Example 1(b), hydrolysis of methyl 5,7- dichloro-4-(3-phenylpropionylamino)-2-naphthoate with LiOH gives the title compound in 76% yield as a white solid.
1H NMR (400 MHz, DMSO-d6) δ: 2.71 (t, 7.6 Hz, 2H); 2.96 (t, 7.6 Hz, 2H); 7.18-7.33 (m, 5H); 7.82 (d, 2 Hz, 2H); 8.36 (d, 2.4 Hz, 1 H); 8.55 (d, 1 .2 Hz,1 H); 10.05 (s, 1 H). LC-MS: 386.1 [M-H] (35CI).
Example 16
5,7-Dichloro-4-(4-phenylbutyrylamino)-naphthalene-2-carboxylic acid
[00163] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 2(a), acylation of methyl 4-amino- 5,7-dichloro-2-naphthoate with 4-phenylbutyryl chloride gives methyl 5,7-dichloro-4-(4- phenylbutyrylamino)-2-naphthoate in 84% yield;
b) in analogy to the procedure described in Example 1(b), hydrolysis of methyl 5,7- dichloro-4-(4-phenylbutyrylamino)-2-naphthoate with LiOH for 3 h at 40 °C gives the title compound in 79% yield as white solid.
1H NMR (400 MHz, DMSO-d6) δ: 1 .87-1 .94 (m, 2H); 2.38 (d, 7.4 Hz, 2H); 2.63 (d, 7.4 Hz, 2H); 7.14-7.29 (m, 5H); 7.80-7.82 (m, 2H); 8.33 (d, 2 Hz, 1 H); 8.52 (d, 1 .6 Hz, 1 H); 9.98 (s, 1 H). LC-MS: 400.1 [M-H] (35CI). Example 17
5,7-Dichloro-4-dibenzoylamino-naphthalene-2-carboxylic acid
[00164] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 2(a), acylation of methyl 4-amino- 5,7-dichloro-2-naphthoate with an excess of benzoyl chloride in the presence of DIPEA gives methyl 5,7-dichloro-4-dibenzoylamino-2-naphthoate;
b) in analogy to the procedure described in Example 1(b), hydrolysis of methyl 5,7- dichloro-4-dibenzoylamino-2-naphthoate with LiOH for 16 h gives the title compound in 17% yield.
1H NMR (400 MHz, DMSO-d6) δ: 7.37-7.41 (m, 4H); 7.45-7.49 (m, 2H); 7.85-7.89 (m, 5H); 7.92 (s, 1 H); 8.27 (s, 1 H); 8.63 (s, 1 H). LC-MS: 462.3 [M-H] (35CI).
Example 18
4-(Benzoyl-propyl-amino)-5,7-dichloro-naphthalene-2-carboxylic acid
[00165] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 11(a), alkylation of methyl 4- benzoylamino-5,7-dichloro-naphthoate with 1 -iodopropane gives methyl 4-(benzoyl- propyl-amino)-5,7-dichloro-2-naphthoate in 34% yield;
b) in analogy to the procedure described in Example 1(b), hydrolysis of gives methyl 4- (benzoyl-propyl-amino)-5,7-dichloro-2-naphthoate with LiOH gives the title compound in 86% yield as a white solid.
1H NMR (400 MHz, DMSO-d6) δ: 0.62 and 0.89 (both t, 7.4 Hz, total 3H); 1 .48-1 .58 (m, 1 H); 1 .67-1 .78 (m, 1 H); 2.99-3.06 (m, 1 H); 4.30-4.38 (m, 1 H); 7.06-7.17 (m, 5H); 7.53- 7.54 and 7.64-7.66 (both m, total 1 H); 7.96 and 8.00 (both d, 2 Hz, total 1 H); 8.37 and 8.48 (both d, 2 Hz, total 1 H); 8.55 and 8.73 (both d, 1 .6 Hz, total 1 H). LC-MS: 400.0 [M- H] (35CI).
Example 19
4-(Benzoyl-ethyl-amino)-5,7-dichloro-naphthalene-2-carboxylic acid [00166] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 11(a), alkylation of methyl 4- benzoylamino-5,7-dichloro-naphthoate with iodoethane gives methyl 4-(benzoyl-ethyl- amino)-5,7-dichloro-2-naphthoate in 40% yield;
b) in analogy to the procedure described in Example 1(b), hydrolysis of gives methyl 4- (benzoyl-ethyl-amino)-5,7-dichloro-2-naphthoate with LiOH gives the title compound in 90% yield as a white solid.
1H NMR (400 MHz, DMSO-d6) δ: 1 .06 and 1 .16 (both t, 7.2 Hz, total 3H); 3.12-3.20 and 3.40-3.47 (both m, total 1 H); 3.76-3.81 and 4.38-4.47 (both m, total 1 H); 7.07-7.18 (m, 5H); 7.53-7.59 and 7.64-7.67 (both m, total 1 H); 7.96 and 8.00 (both d, 2 Hz, total 1 H); 8.38 and 8.48 (both d, 2 Hz, total 1 H); 8.56 and 8.74 (both d, 1 .6 Hz, total 1 H). LC-MS: 386.3 [M-H] (35CI).
Example 20
5,7-Dichloro-4-[(pyridine-4-carbonyl)-amino]-naphthalene-2-carboxylic acid
[00167] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 2(a), acylation of methyl 4-amino- 5,7-dichloro-2-naphthoate with pyridine-4-carbonyl chloride gives methyl 5,7-dichloro-4- [(pyridine-4-carbonyl)-amino]-2-naphthoate in 58% yield;
b) in analogy to the procedure described in Example 1(b), hydrolysis of methyl 5,7- dichloro-4-[(pyridine-4-carbonyl)-amino]-2-naphthoate with LiOH gives the title
compound in 83% yield as a white solid.
1H NMR (400 MHz, DMSO-d6) δ: 7.89 (d, 1 .6 Hz, 1 H); 7.94 (d, 5.6 Hz, 2H); 7.99-8.00 (m, 1 H); 8.44 (d, 2.4 Hz, 1 H); 8.66 (d, 1 .6 Hz, 1 H); 8.83 (d, 6 Hz, 2H); 10.91 (s, 1 H). LC- MS: 359.3 [M-H] (35CI).
Example 21
5,7-Dichloro-4-[(pyridine-3-carbonyl)-amino]-naphthalene-2-carboxylic acid
[00168] The title compound is prepared by the following reaction sequence: a) in analogy to the procedure described in Example 2(a), acylation of methyl 4-amino- 5,7-dichloro-2-naphthoate with pyridine-3-carbonyl chloride gives methyl 5,7-dichloro-4- [(pyridine-3-carbonyl)-amino]-2-naphthoate in 62% yield;
b) in analogy to the procedure described in Example 1(b), hydrolysis of methyl 5,7- dichloro-4-[(pyridine-3-carbonyl)-amino]-2-naphthoate with LiOH gives the title compound in 62% yield as a light brown solid.
1H NMR (400 MHz, DMSO-d6) δ: 7.60-7.63 (m, 1 H); 7.89 (d, 1 .6 Hz, 1 H); 7.99-8.01 (m, 1 H); 8.36-8.39 (m, 1 H); 8.44 (d, 2.4 Hz, 1 H); 8.66 (d, 1 .6 Hz, 1 H); 8.79-8.81 (m, 1 H); 9.20 (d, 2 Hz, 1 H); 10.82 (s, 1 H). LC-MS: 359.1 [M-H] (35CI).
Example 22
4-[Benzoyl-(methoxymethyl)-amino]-5,7-dichloro-naphthalene-2-carboxylic acid
[00169] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 11(a), alkylation of methyl 4- benzoylamino-5,7-dichloro-naphthoate with methomethyl chloride gives methyl 4- [benzoyl-(methoxymethyl)-amino]-5,7-dichloro-2-naphthoate in 85% yield;
b) in analogy to the procedure described in Example 1(b), hydrolysis of methyl 4- [benzoyl-(methoxymethyl)-amino]-5,7-dichloro-2-naphthoate with LiOH gives the title compound in 88% yield. as a white solid.
1H NMR (400 MHz, DMSO-d6) δ: 3.15 and 3.45 (both s, total 3H); 4.54 and 4.70 (both d, 10.4 Hz, total 1 H); 4.92 and 5.78 (both d, 10.4 Hz, total 1 H); 7.07-7.18 (m, 3H); 7.54- 7.59 (m, 1 H); 7.73-7.78 and 7.96-8.02 (both m, total 3H); 8.36 and 8.49 (both d, 2 Hz, total 1 H); 8.57 and 8.75 (both d, 1 .6 Hz, total 1 H).
LC-MS: 402.2 [M-H] (35CI).
Example 23
5,7-Dichloro-4-[methyl-(pyridine-3-carbonyl)-amino]-naphthalene-2-carboxylic acid
[00170] The title compound is prepared by the following reaction sequence: a) in analogy to the procedure described in Example 11(a), alkylation of methyl 3- (pyridine-4-carbonyl)-amino-5,7-dichloro-naphthoate with iodomethane gives methyl 5,7-dichloro-4-[methyl-(pyridine-3-carbonyl)-amino]-2-naphthoate;
b) in analogy to the procedure described in Example 1(b), hydrolysis of methyl 5,7- dichloro-4-[methyl-(pyridine-3-carbonyl)-amino]-2-naphthoate with LiOH gives the title compound in good yield.
1H NMR (400 MHz, CDCI3) δ: 3.57 (s, 3H); 7.22-7.25 (m, 1 H); 7.64 (d, 2 Hz, 1 H); 7.80 (d, 2 Hz, 1 H); 7.94-7.96 (m, 1 H); 8.29-8.31 (m, 2H); 8.39 (d, 1 .2 Hz, 1 H); 8.71 (s, 1 H). LC-MS: 373.4 [M-H] (35CI).
Example 24
5,7-Dichloro-4-[methyl-(pyridine-4-carbonyl)-amino]-naphthalene-2-carboxylic acid
[00171 ] In analogy to the procedure described in Example 11(a), alkylation of methyl 4-(pyridine-4-carbonyl)-amino-5,7-dichloro-naphthoate with iodomethane gives methyl 5,7-dichloro-4-[methyl-(pyridine-4-carbonyl)-amino]-2-naphthoate;
b) in analogy to the procedure described in Example 1(b), hydrolysis of methyl 5,7- dichloro-4-[methyl-(pyridine-4-carbonyl)-amino]-2-naphthoate with LiOH gives the title compound in 51 % yield.
1H NMR (200 MHz, CDCI3) δ: 3.48 and 3.50 (both s, total 3H); 7.30-7.40 (m, 2H); 7.75- 7.85 (m, 2H); 7.85-7.92 (m, 1 H); 8.35-8.50 (m, 3H). LC-MS: 373.2 [M-H] (35CI).
Example 25
4-(Benzoyl-benzyl-amino)-5,7-dichloro-naphthalene-2-carboxylic acid
[00172] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 11(a), alkylation of methyl 4- benzoylamino-5,7-dichloro-naphthoate with benzyl chloride gives methyl 4-(benzoyl- benzyl-amino)-5,7-dichloro-2-naphthoate in good yield; b) in analogy to the procedure described in Example 1(b), hydrolysis of methyl 4- (benzoyl-benzyl-amino)-5,7-dichloro-2-naphthoate with LiOH at rt for 2.5 h gives the title compound in 92% yield as a white solid.
1H NMR (400 MHz, DMSO-d6) δ: 4.16 and 4.56 (both d, 15.6 Hz, total 1 H); 5.17 and 5.83 (both d, 15.6 Hz, total 1 H); 7.04-7.18 (m, 6H); 7.22-7.31 (m, 5H); 7.94 and 8.00 (both d, 2.4 Hz, total 1 H); 8.32 and 8.40 (both d, 2.4 Hz, total 1 H); 8.47 and 8.59 (both d, 1 .6 Hz, total 1 H). LC-MS: 448.4 [M-H] (35CI).
Example 26
5,7-Dichloro-4-(2-pyridin-2-yl-acetylamino)-naphthalene-2-carboxylic acid
[00173] The title compound is prepared by the following reaction sequence:
a) DIPEA (43.06 mg, 0.33 mmol) and CDI (30.62 mg, 0.19 mmol) are added to a solution of 2-pyridineacetic acid hydrochloride (0.03 g, 0.18 mmol) in DMF (1 mL). The resulting mixture is stirred at 60 °C for 30 min then methyl 4-amino-5,7-dichloro-2- naphthoate, 0.43 trifluoroacetate (4) (0.036 g) is added and stirring is continued for 24 h at 60 °C. The reaction mixture is allowed to cool to rt, then distilled water is added. Precipitate is filtered and washed with distilled water and with small amount of MeOH (MeOH helps to remove some small impurities detected by LC-MS. Product partly dissolves in MeOH!) to give methyl 5,7-dichloro-4-(2-pyridin-2-yl-acetylamino)-2- naphthoate as beige solid in 41 % yield;
b) in analogy to the procedure described in Example 1(b), hydrolysis of methyl 5,7- dichloro-4-(2-pyridin-2-yl-acetylamino)-2-naphthoate with LiOH gives the title compound in 80% yield.
1H NMR (400 MHz, DMSO-d6) δ: 3.94 (s, 2H); 7.28-7.31 (m, 1 H); 7.46 (d, 8 Hz, 1 H); 7.76-7.81 (m, 1 H); 7.83 (d, 1 .6 Hz, 1 H); 7.88 (d, 1 .6 Hz, 1 H); 8.37 (d, 2 Hz, 1 H); 8.54 (d, 4 Hz, 1 H); 8.57 (s, 1 H); 10.33 (s, 1 H). LC-MS: 373 [M-H].
Example 27
4-[Benzoyl-(3-methoxy-benzyl)-amino]-5,7-dichloro-naphthalene-2-carboxylic acid
[00174] The title compound is prepared by the following reaction sequence: a) in analogy to the procedure described in Example 11(a), alkylation of methyl 4- benzoylamino-5,7-dichloro-naphthoate with 3-methoxybenzyl chloride gives methyl 4- [benzoyl-(3-methoxy-benzyl)-amino]-5,7-dichloro-2-naphthoate in 37% yield;
b) in analogy to the procedure described in Example 1(b), hydrolysis of methyl 4- [benzoyl-(3-methoxy-benzyl)-amino]-5,7-dichloro-2-naphthoate with LiOH gives the title compound in 99% yield.
1H NMR (400 MHz, DMSO-d6) δ: 3.61 and 3.68 (both s, total 3H); 4.15 (d, 15 Hz, 1 H); 5.78 (d, 15 Hz, 1 H); 6.84-6.88 (m, 3H); 7.07-7.18 (m, 5H); 7.22-7.28 (m, 2H); 8.00 and 8.03 (both d, 2 Hz, total 1 H); 8.36 and 8.44 (both d, 2 Hz, total 1 H); 8.51 and 8.64 (both d, 1 .6 Hz, total 1 H). LC-MS: 478.4 [M-H].
Example 28
5,7-Dichloro-4-(2-pyridin-3-yl-acetylamino)-naphthalene-2-carboxylic acid
[00175] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 26(a), condensation of methyl 4- amino-5,7-dichloro-2-naphthoate with pyridin-3-ylacetic acid gives methyl 5,7-dichloro- 4-(2-pyridin-3-yl-acetylamino)-2-naphthoate in 48% yield;
b) in analogy to the procedure described in Example 1(b), hydrolysis of methyl 5,7- dichloro-4-(2-pyridin-3-yl-acetylamino)-2-naphthoate with LiOH gives the title compound in 88% yield.
1H NMR (400 MHz, DMSO-d6) δ: 3.79 (s, 2H); 7.36-7.39 (m, 1 H); 7.77 (d, 8 Hz, 1 H); 7.83-7.86 (m, 2H); 8.37 (d, 1 .6 Hz, 1 H); 8.47 (d, 4.4 Hz, 1 H); 8.57 (d, 1 .6 Hz, 2H); 10.33 (s, 1 H). LC-MS: 373.3 [M-H].
Example 29
5,7-Dichloro-4-(2-pyridin-4-yl-acetylamino)-naphthalene-2-carboxylic acid
[00176] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 26(a), condensation of methyl 4- amino-5,7-dichloro-2-naphthoate with pyridin-4-ylacetic acid gives methyl 5,7-dichloro- 4-(2-pyridin-4-yl-acetylamino)-2-naphthoate in 27.7% yield; b) in analogy to the procedure described in Example 1(b), hydrolysis of methyl 5,7- dichloro-4-(2-pyridin-4-yl-acetylamino)-2-naphthoate with LiOH gives the title compound in 80% yield as pale yellow solid.
1H NMR (400 MHz, DMSO-d6) δ: 3.79 (s, 2H); 7.39 (d, 5.2 Hz, 2H); 7.79 (d, 2 Hz, 1 H); 7.84-7.86 (m, 1 H); 8.33 (d, 2 Hz, 1 H); 8.50-8.55 (m, 3H); 10.33 (s, 1 H). LC-MS: 373.3 [M-H].
Example 30
1 -[(Benzylcarbamoyl-methyl)-methyl-amino]-6,8-dichloro-isoquinoline-3- carboxylic acid a) 2,4-Dichloro-6-methyl-benzamide
[00177] To a solution of 2,4-dichloro-6-methyl-benzonitrile (500 mg, 2.69 mmol) in EtOH (7 mL) is added KOH (702 mg, 12.5 mmol) and water (0.1 mL). The mixture is stirred in a pressure bottle for 45 h at 1 10 °C temperature, then it is cooled to rt, diluted with water (20 mL) and stirred at rt for 20 h. Precipitated solid is filtered, washed with water and dried to give the title compound (300 mg, 56%) as orange solid. LC-MS: 203.9 [M+H]; 1H-NMR (DMSO-d6, 200 MHz), δ: 2.28 (s, 3H); 7.35 (s,1 H); 7.46 (s,1 H); 7.73 (br s, 1 H); 7.94 (br s, 1 H). b) 2,4-Dichloro-6-methyl-benzoic acid
[00178] Sulfuric acid (aqueous 50%, 2 mL) is added to 2,4-dichloro-6-methyl- benzamide (300 mg, 1 .47 mmol). The mixture is cooled in an ice bath till 0 °C temperature, then a solution of NaNO2 (1 1 1 mg, 1 .62 mmol) in water (1 mL) is added dropwise at stirring. The mixture is allowed to warm up till rt, then it is stirred at 100 °C for 2 h (LC-MS control). After cooling the mixture is diluted with water (10 mL), neutralized by addition of 1 M aqueous NaOH till pH~10, and extracted with EtOAc (2x). The aqueous phase is acidified by addition of 3N HCI till pH~1 and extracted with EtOAc (2x). The organic extracts are washed with water, dried over Na2SO4, filtered and evaporated to give the title compound (140 mg, 46%) as a pale brown solid. LC-MS: 203.1 [M-H]; 1H-NMR (DMSO-d6, 200 MHz), δ: 2.29 (s, 3H); 7.41 (s, 1 H); 7.53 (s, 1 H). c) 3-Bromo-5,7-dichloro-3H-isobenzofuran-1 -one
[00179] To a solution of 2,4-dichloro-6-methyl-benzoic acid (1442 mg, 7.03 mmol) in dry CCI4 (50 mL) are added NBS (3756 mg, 21 .10 mmol) and (BzO)2 (197 mg, 0.70 mmol). The mixture is stirred at reflux for 17 h (LC-MS control), then it is cooled to rt and filtered. The filtrate is evaporated and the crude product is purified by column chromatography (eluent-CHCIs) to give the title compound as oil (1668 mg, 84%). LC- MS: 279.2 [M-H]; 1H-NMR (CDCI3, 200 MHz), δ: 6.87 (s, 1 H); 7.43 (d, 2 Hz, 1 H); 7.96 (d, 2 Hz, 1 H). d) Lithium 2,4-dichloro-6-formyl-benzoate
[00180] To a suspension of 3-bromo-5,7-dichloro-3H-isobenzofuran-1 -one (446 mg, 1 .58 mmol) in water (15 mL) LiOH*H2O (132 mg, 3.16 mmol) is added. The mixture is stirred at reflux for 4 h and evaporated with MeCN to give a white solid (492 mg: contains 137 mg LiBr and 355 mg of the title compound, -100%). 1H-NMR (DMSO-d6, 200 MHz), δ: 7.54 (d, 1 .9 Hz, 1 H); 7.73 (d, 1 .9 Hz, 1 H); 9.99 (s, 1 H). e) 6,8-Dichloro-1-oxo-1H-isochromene-3-carboxylic acid
[00181 ] To a solution of crude lithium 2,4-dichloro-6-formyl-benzoate in DMPU (5 mL) is added diethyl 2-bromomalonate (754 mg, 3.15 mmol). The mixture is stirred at rt for 24 h (LC-MS control), diluted with water (20 mL) and extracted with Et2O (3 x 15 mL). The organic phase is washed with sat. NaCI solution, dried over Na2SO4 and filtered. The filtrate is evaporated to give crude intermediate as an oil (LC-MS: 376.9 [M+H]). To this is added a mixture of cone. HCI-AcOH-H2O (3:5:2, 6 mL). The mixture is stirred at 100 °C for 3 h (LC-MS control), then it is cooled to rt. Precipitated solid is filtered, washed with water (20-30 mL) and dried to give the title compound (260 mg, 49%) as white solid. LC-MS: 257.1 [M-H]; 1H-NMR (DMSO-d6, 200 MHz), δ: 7.62 (s, 1 H); 7.95 (s, 1 H); 8.02 (s, 1 H); 14.06 (br s, 1 H). f) Methyl 6,8-dichloro-1 -oxo-1H-isochromene-3-carboxylate
[00182] A solution of 6,8-dichloro-1 -oxo-1 H-isochromene-3-carboxylic acid (260 mg, 1 .01 mmol) in MeOH (5 mL) is cooled in an ice-water bath and SOCI2 (0.07 mL) is added. The mixture is allowed to warm up till rt, then it is stirred at rt for 2.5 h and at 40 °C for 0.5 h. The mixture is cooled to rt, precipitated solid is filtered and dried to give the title compound (240 mg, 88%) as a white solid. LC-MS: 272.7 [M+H]; 1H-NMR (DMSO- d6, 200 MHz), δ: 3.91 (s, 3H); 7.59 (s, 1 H); 7.69 (s, 1 H); 8.01 s, 1 H). g) Methyl 6,8-dichloro-1 -oxo-1 ,2-dihydro-isoquinoline-3-carboxylate
[00183] To a mixture of methyl 6,8-dichloro-1 -okso-1 H-isochromene-3-carboxylate (1 15 mg, 0.42 mmol) and AcOH (40 mL) under argon (NH4)2CO3 (202 mg, 2 mmol) is added in small portions. The mixture is stirred at 95 °C for 14 h, then it is cooled to rt. Precipitated solid is filtered, washed with water, MeCN, MeOH and dried to give the title compound (95 mg, 84%) as a white solid. Mp >240 °C; 1H-NMR (DMSO-d6, 600 MHz), δ: 3.85 (s, 3H); 7.33 (s, 1 H); 7.73 (d, 1 .9 Hz, 1 H); 8.00 (d, 1 .9 Hz, 1 H); 1 1 .30 (br s, 1 H); 13C-NMR (DMSO-de, 150.9 MHz), δ: 53.5, 109.1 , 123.2, 127.5, 131 .3, 131 .4, 135.9, 137.5 140.7; 159.7; 161 .5. h) Methyl 1,6,8-trichloro-isoquinoline-3-carboxylate
[00184] A mixture of methyl 6,8-dichloro-1 -oxo-1 ,2-dihydro-isoquinoline-3- carboxylate (102 mg, 0.45 mmol) and POCI3 (5 mL) is heated at 100 °C for 8 h under argon. Then it is allowed to cool to rt and slowly poured on ice. Precipitated solid is filtered and purified by flash chromatography on silica (eluent - CHCI3, Rf=0.56) to give the title compound (1 14 mg, 87%) as white solid. LC-MS: 289.9 [M+H]; 1 H-NMR (DMSO-de, 200 MHz), δ: 3.94 (s, 3H); 8.22 (d, 2.2 Hz, 1 H); 8.54 (d, 2.2 Hz, 1 H); 8.71 (s, 1 H). i) Methyl 1 -[(benzylcarbamoylmethyl)-methylamino]-6,8-dichloro-isoquinoline-3- carboxylate
(General procedure for the synthesis of /V -substituted 1 -(carbamoylmethyl- amino)-isoquinoline-3-carboxylic acids)
[00185] To a solution of N-benzyl-2-methylamino-acetamide trifluoroacetate (71 .93 mg, 0.25 mmol; 1 .25 equiv.) in DMSO (10 mL) is added (/'-Pr)2NEt (2.5 equiv.). Methyl 1 ,6,8-trichloro-isoquinoline-3-carboxylate (1 equiv.) is added after 2 min and the mixture is stirred at 95 °C for 20 h (LC-MS control). The mixtute is cooled to rt, diluted with water (50 mL) and extracted (if product is not precipitated) with ar EtOAc (3x). The organic extracts are combined, washed with water (4x), dried over Na2SO4, filtered and evaporated. The residue is purified by flash chromatography on silica (eluent - EtOAc:hexane or CHCI3) to give the title compound (51 mg, 57%) as a white crystalline solid. LC-MS: 432.4 [M+H]; 1H-NMR (CDCI3, 200 MHz), δ: 3.01 (s, 3H); 3.80 (s, 3H); 4.25-4.55 (m, 4H); 7.26 (s, 5H); 7.59 (s, 1 H): 7.73 (s, 1 H); 7.92 (s, 1 H); 8.38 (br s, 1 H). j) 1 -[(Benzylcarbamoylmethyl)-methylamino]-6,8-dichloro-isoquinoline-3- carboxylic acid
[00186] In analogy to the procedure described in Example 1(b), hydrolysis of methyl 1 -[(benzylcarbamoylmethyl)-methylamino]-6,8-dichloro-isoquinoline-3- carboxylate with LiOH gives the title compound in 77% yield as a white crystalline solid. LC-MS: 416.5 [M-H]; 1H-NMR (DMSO-d6, 200 MHz), δ: 3.01 (s, 3H); 4.14 (br s, 2H); 4.25 (d, 5.8 Hz, 2H); 7.18-7.30 (m, 5H); 7.82 (s, 1 H): 7.97 (s, 1 H); 8.17 (s, 1 H); 8.43 (br s, 1 H).
[00187] All compounds represented by following examples are prepared by procedures described above and according to Schemes 2, 3, 4 and 5, or by procedures analogous thereto. All of the starting materials can be obtained commercially or are prepared by procedures well known to one of ordinary skill in organic chemistry.
Example 31
5,7-Dichloro-4-(2-thiazol-4-yl-acetylamino)-naphthalene-2-carboxylic acid
[00188] 1H NMR (200 MHz, DMSO-d6) δ: 3.96 (s, 2H); 7.58 (d, 0.8 Hz, 1 H); 7.84 (d, 0.8 Hz, 1 H); 7.88 (s, 1 H); 8.37 (d, 0.8 Hz, 1 H); 8.57 (s, 1 H); 9.09 (d, 0.8 Hz, 1 H); 10.28 (s, 1 H). LC-MS: 379 [M-H].
Example 32
5,7-Dichloro-4-[(pyridine-2-carbonyl)-amino]-naphthalene-2-carboxylic acid
[00189] 1H NMR (200 MHz, DMSO-d6) δ: 7.68-7.75 (m, 1 H); 7.88 (d, 2.4 Hz, 1 H); 8.06-8.22 (m, 2H); 8.39-8.42 (m, 2H); 8.57 (s, 1 H); 8.79 (d, 4.6 Hz, 1 H); 1 1 .40 (s, 1 H). LC-MS: 359 [M-H]. Example 33
5,7-Dichloro-4-[methyl-(pyridine-2-carbonyl)-amino]-naphthalene-2-carboxylic acid
[00190] 1H NMR (200 MHz, DMSO-d6) δ: 3.36 and 3.39 (both s, total 3H); 7.07- 7.13 (m, 1 H); 7.55-7.76 (m, 3H); 7.88-8.03 (m, 2H); 8.35 and 8.48 (both d, 2 Hz, total 1 H); 8.54 and 8.73 (both d, 1 .2 Hz, total 1 H). LC-MS: 373 [M-H].
Example 34
5,7-Dichloro-4-(methyl-{[(pyridin-3-ylmethyl)-carbamoyl]-methyl}-amino)- naphthalene-2-carboxylic acid a) 2-((6,8-Dichloro-3-(methoxycarbonyl)naphthalen-1 -yl)(methyl)amino)acetic acid
[00191 ] 2-((6,8-Dichloro-3-(methoxycarbonyl)naphthalen-1 -yl)(methyl)amino)acetic acid trifluoroacetate salt (480 mg, 1 .25 mmol), 37% aqueous formaldehyde (4.7 mL, 62.5 mmol) and acetic acid (1 .5 mL) are mixed in acetonitrile (30 mL). Then NaBH3CN (95%) (330 mg, 5 mmol) is added portion wise during 40 min. After completion of the reaction (1 h, TLC control) the mixture is concentrated under reduced pressure. The oily residue is treated with cold water and pale yellow substance is slowly crystallized.
Crystallized material is filtered, washed with water and diethyl ether, and dried at 60 °C under reduced pressure to give 270 mg (63%) of the title compound.
Mp 180-183 °C; 1H-NMR (CDCI3, 400 MHz), δ: 2.87 (s, 3H); 3.87 (d, 16.9 Hz, 1 H); 3.99 (s, 3H); 4.07 (d, 16.9 Hz, 1 H); 7.68 (d, 2.1 Hz, 1 H); 7.84 (d, 1 .4 Hz, 1 H); 7.87 ( d, 2.1 Hz, 1 H); 8.29 (d, 1 .4 Hz, 1 H). LC-MS: 342 [M+H]. b) Methyl 5,7-dichloro-4-(methyl(2-oxo-2-((pyridin-3-ylmethyl)amino)ethyl)amino)- 2-naphthoate
[00192] To a solution of 2-((6,8-dichloro-3-(methoxycarbonyl)naphthalen-1 - yl)(methyl)amino)acetic acid (0.06 g, 0.18 mmol) in DMF (1 mL) is added CDI (0.03 g, 0.21 mmol). The mixture is heated at 50 °C for 30 min. Then pyridin-3-ylmethanamine (0.2 g, 0.21 mmol) is added and the reaction mixture is heated at 50 °C for 18 h (LC-MS control), then at 60 °C for additional 25 h. The mixture is cooled to rt, water (15 mL) is added and the mixture is extracted with EtOAc (3x15 mL). The combined organic layers are washed with brine (20 mL), dried over Na2SO4 and concentrated. The residue is purified by flash chromatography on silica gel (CH2Cl2:MeOH, 20:1 ) to give the title compound (56 mg, 73%) as yellow oil. LC/MS: 432.3 [M+H]. c) 5 -Dichloro-4-(methyl(2-oxo-2-((pyridin-3-ylmethyl)amino)ethyl)amino)-2- naphthoic acid
[00193] In analogy to the procedure described in Example 1(b), hydrolysis of methyl 5,7-dichloro-4-(methyl(2-oxo-2-((pyridin-3-ylmethyl)amino)ethyl)amino)-2- naphthoate with LiOH gives the title compound in 64% yield as a yellow solid.
1H NMR (200 MHz, DMSO-d6) δ: 2.86 (s, 3H); 3.72 (d, 15 Hz, 1 H); 3.90 (d, 15 Hz, 1 H); 4.26 (d, 6.6 Hz, 2H); 7.22-7.28 (m, 1 H); 7.47 (d, 8 Hz, 1 H); 7.72-7.75 (m, 2H); 8.19-8.28 (m, 3H); 8.38-8.41 (m, 2H). LC-MS: 416 [M-H].
Example 35
5,7-Dichloro-4-(methyl-{[(pyrimidin-5-ylmethyl)-carbamoyl]-methyl}-amino)- naphthalene-2-carboxylic acid
[00194] 1H NMR (200 MHz, DMSO-d6) δ: 2.84 (s, 3H); 3.72 (d, 15 Hz, 1 H); 3.90 (d, 15 Hz, 1 H); 4.28 (d, 5.6 Hz, 2H); 7.72-7.75 (m, 2H); 8.25-8.32 (m, 3H); 8.58 (s, 2H); 9.02 (s, 1 H). LC-MS: 417 [M-H].
Example 36
5,7-Dichloro-4-(methyl-{[(pyridin-2-ylmethyl)-carbamoyl]-methyl}-amino)- naphthalene-2-carboxylic acid
[00195] 1H NMR (200 MHz, DMSO-d6) δ: 2.84 (s, 3H); 3.75 (d, 15 Hz, 1 H); 3.97 (d, 15 Hz, 1 H); 4.36 (d, 6 Hz, 2H); 7.10 (d, 7.8 Hz, 1 H); 7.20-7.26 (m, 1 H); 7.62-7.79 (m, 3H); 8.27-8.31 (m, 3H); 8.43 (d, 5 Hz, 1 H). LC-MS: 416 [M-H]. Example 37
5,7-Dichloro-4-({[(pyrimidin-5-ylmethyl)-carbamoyl]-methyl}-amino)-naphthal^ 2-carboxylic acid
[00196] 1H NMR (200 MHz, DMSO-d6) δ: 4.00 (d, 3.6 Hz, 2H); 4.39 (d, 4.8 Hz, 2H); 6.88 (s, 1 H); 7.45 (t, 3.6 Hz, 1 H); 7.69 (s, 1 H); 7.85 (s, 1 H); 8.15 (s, 1 H); 8.70 (s, 2H); 8.81 (t, 4.8 Hz, 1 H); 9.06 (s, 1 H). LC-MS: 403 [M-H].
Example 38
5,7-Dichloro-4-{[(methyl-pyridin-2-ylmethyl-carbamoyl)-methyl]-amino}- naphthalene-2-carboxylic acid
[00197] 1H NMR (200 MHz, DMSO-d6) δ: 2.89 and 3.14 (both s, total 3H); 4.23 (br s, 2H); 4.69 and 4.77 (both s, total 2H); 6.92 and 7.01 (both s, total 1 H); 7.24-7.40 (m, 2H); 7.67-7.82 (m, 4H); 8.12 (br s, 1 H); 8.50-8.57 (m, 1 H). LC-MS: 416 [M-H].
Example 39
5,7-Dichloro-4-{methyl-[(methyl-pyridin-2-ylmethyl-carbamoyl)-methyl]-amino}- naphthalene-2-carboxylic acid
[00198] 1H NMR (200 MHz, CDCI3) δ: 2.99 and 3.05 (both s, total 6H); 3.95-4.07 and 4.21 -4.28 (both m, total 2H); 4.61 -4.72 and 4.80-4.91 (both m, total 2H); 7.07-7.25 (m, 2H); 7.49-7.81 (m, 3H); 7.93 (s, 1 H); 8.14 and 8.20 (both s, total 1 H); 8.57 and 8.59 (both s, total 1 H).
LC-MS: 430 [M-H].
Example 40
5,7-Dichloro-4-{[(methyl-pyridin-3-ylmethyl-carbamoyl)-methyl]-amino}- naphthalene-2-carboxylic acid
[00199] 1H NMR (400 MHz, DMSO-d6) δ: 2.88 and 3.09 (both s, total 3H); 4.22 (s, 2H); 4.66 and 4.76 (both s, total 2H); 7.00 (s, 1 H); 7.36-7.43 (m, 1 H); 7.68-7.74 (m, 2H); 7.82-7.84 (m, 2H); 8.14 (d, 2.4 Hz, 1 H); 8.49-8.56 (m, 2H); 13.00-13.40 (br s, 1 H). LC- MS: 415 [M-H].
Example 41
5 -Dichloro-4-{methyl-[(methyl^yridin-3-ylmethyl-carbamoyl)-methyl]-amino}- naphthalene-2-carboxylic acid
[00200] 1H NMR (400 MHz, DMSO-d6) δ: 2.76, 2.88 and 2.90 (all s, total 6H); 3.85- 3.95 and 4.20-4.25 (both m, total 2H); 4.35-4.45 and 4.50-4.65 (both m, total 2H); 7.31 (br s, 1 H); 7.48-7.59 (m, 1 H); 7.69 and 7.80 (both br s, total 2H); 8.15-8.30 (m, 2H); 8.37-8.50 (m, 2H). LC-MS: 430 [M-H].
Example 42
5,7-Dichloro-4-(methyl-{[(pyridin-4-ylmethyl)-carbamoyl]-methyl}-amino)- naphthalene-2-carboxylic acid
[00201 ] 1H NMR (400 MHz, DMSO-d6) δ: 2.90 (s, 3H); 3.78 (d, 16 Hz, 1 H); 3.93 (d, 16 Hz, 1 H); 4.20-4.32 (m, 2H); 7.06 (d, 5.6 Hz, 2H); 7.75 (s, 2H); 8.24-8.31 (m, 3H); 8.40 (d, 5.6 Hz, 2H); 13.00-13.60 (br s, 1 H). LC-MS: 416 [M-H].
Example 43
4-[Benzoyl-(3-methoxy-propyl)-amino]-5,7-dichloro-naphthalene-2-carboxylic acid
[00202] 1H NMR (400 MHz, DMSO-d6) δ: 1 .70-1 .80 (m, 1 H); 1 .95-2.05 (m, 1 H); 3.00 and 3.18 (both s, total 3H); 3.08-3.15 (m, 1 H); 3.37-3.40 (m, 2H); 3.75-3.85 and 4.40-4.50 (both m, total 1 H); 7.07-7.17, 7.52-7.54 and 7.64-7.67 (all m, total 5H); 7.69 and 7.96 (both d, 2.4 Hz, total 1 H); 8.00-8.05 (both d, 2 Hz, total 1 H); 8.37 and 8.48 (both d, 2 Hz, total 1 H); 8.55 and 8.73 (both d, 2.4 Hz, total 1 H). LC-MS: 430 [M-H].
Example 44
5,7-Dichloro-4-({[(pyridin-4-ylmethyl)-carbamoyl]-methyl}-amino)-naphthalene-2- carboxylic acid [00203] 1H NMR (400 MHz, DMSO-d6) δ: 4.04 (d, 4.8 Hz, 2H); 4.37 (d, 6 Hz, 2H); 6.94 (s, 1 H); 7.25 (d, 5.6 Hz, 2H); 7.45 (t, 4.8 Hz, 1 H); 7.68 (d, 2.4 Hz, 1 H); 7.86 (s, 1 H); 8.14 (d, 2.4 Hz, 1 H); 8.45 (d, 5.6 Hz, 2H); 8.78 (t, 6 Hz, 1 H). LC-MS: 402 [M-H].
Example 45
1 -((2-(Benzylamino)-2-oxoethyl)amino)-6-chloroisoquinoline-3-carboxylic acid a) Methyl 6-chloro-1 -oxo-1 ,2-dihydroisoquinoline-3-carboxylate
[00204] Methyl 4-chloro-2-iodobenzoate (284 mg, 0.96 mmol) is dissolved in DMF (2 mL) then methyl 2-acetamidoacrylate (205 mg, 1 .44 mmol), tetrabutylammonium bromide (308 mg, 0.96 mmol), NaHCO3 (201 mg, 2.39 mmol) and palladium (II) acetate (1 1 mg, 0.05 mmol) are added. The reaction mixture is heated at 85-90 °C for 20 h under argon atmosphere. At the begining the reaction mixture is red, but after 10 min turned to dark red. After 20 h the reaction mixture is cooled to rt and 25 mL of water are added. The heterogenous solution is filtered, washed with small portions of water and dried to give the title compound (157 mg, 69%) as a brown solid. 1H-NMR (200 MHz, DMSO-de), δ: 3.86 (s, 3H); 7.41 (s, 1 H); 7.64 (d, 8.8 Hz, 1 H); 8.05 (s, 1 H); 8.20 (d, 8.8 Hz, 1 H). LC-MS: 238 [M+H]. b) Methyl 1 ,6-dichloroisoquinoline-3-carboxylate
[00205] Methyl 6-chloro-1 -oxo-1 ,2-dihydroisoquinoline-3-carboxylate (400 mg, 1 .68 mmol) is mixed with POCI3 (8 mL) and 2 drops of DMF are added. The mixture is heated at 100 °C for 7 h. Then it is allowed to cool to rt and slowly poured on ice. The precipitated solid is filtered off, washed with water and dried to give the title compound (401 mg, 93%) as a white solid. 1H-NMR (200 MHz, DMSO-d6), δ: 3.94 (s, 3H); 7.99 (dd, 2.2 Hz, 9.2 Hz, 1 H); 8.37 (d, 9.2 Hz, 1 H); 8.52 (d, 2.2 Hz, 1 H); 8.69 (s, 1 H). LC-MS: 256 [M+H]. c) Methyl 1 -((2-(tert-butoxy)-2-oxoethyl)amino)-6-chloroisoquinoline-3-carboxylate
[00206] To a solution of terf-butyl 2-aminoacetate hydrochloride (131 mg, 0.78 mmol) in DMSO (5 mL) DIPEA (151 mg, 1 .17 mmol) is added. After 2 min methyl 1 ,6- dichloroisoquinoline-3-carboxylate (100 mg, 0.39 mmol) is added and the reaction mixture is heated at 100 °C for 55 h. After the reaction mixture is cooled to rt, water (50 mL) is added, and the mixture is extracted with EtOAc (2x40 mL). The organic extracts are dried over Na2SO4 and concentrated under reduced pressure. The residue is purified by column chromatography (EtOAc:Hexane, 1 :4), to give the title compound (45 mg, 33%) as a yellow solid. 1H-NMR (200 MHz, CDCI3), δ: 1 .52 (s, 9H); 3.97 (s, 3H); 4.36 (d, 4.8 Hz, 2H); 5.96 (br s, 1 H); 7.52 (dd, 2.2 Hz, 9 Hz, 1 H); 7.76-7.85 (m, 3H). LC- MS: 351 .1 [M+H]. d) 2-((6-Chloro-3-(methoxycarbonyl)isoquinolin-1 -yl)amino)acetic acid
[00207] To a solution of methyl 1 -((2-(terf-butoxy)-2-oxoethyl)amino)-6- chloroisoquinoline-3-carboxylate (245 mg, 0.64 mmol) in CH2CI2 (10 mL), TFA (1 mL) is added. After 24 h the solvent is evaporated to give the title compound (200 mg, 95%) as a purple solid. 1H-NMR (200 MHz , CDCI3), δ: 3.97 (s, 3H); 4.42 (d, 4.8 Hz, 2H); 7.58 (dd, 2.2 Hz, 9 Hz, 1 H); 7.82-7.96 (m, 3H); 8.14 (br s, 1 H). LC-MS: 295.2 [M+H]. e) Methyl 1 -((2-benzylamino)-2-oxoethyl)amino)-6-chloroisoquinoline-3- carboxylate
[00208] 2-((6-Chloro-3-(methoxycarbonyl)isoquinolin-1 -yl)amino)acetic acid (60 mg, 0.20 mmol) is dissolved in DMF (2 mL). HOBT (30 mg, 0.22 mmol) and 1 -ethyl-3- (3-dimethylaminopropyl)carbodiimide) (42 mg, 0.22 mmol) and DIPEA (61 mg, 0.47 mmol) are added. After 5 min benzylamine (24 mg, 0.22 mmol) is added. The reaction mixture is stirred at rt for 3 days. Water is added (10 mL), the precipitate is filtred off and washed with water, dried on air. The solid obtained is washed with Et2O (2x5 mL) and dried under reduced pressure to give the title compound (26 mg, 33 %) as a grey solid. 1H-NMR (200 MHz , DMSO-d6), δ: 3.85 (s, 3H); 4.17 (d, 5.2 Hz, 2H); 4.29 (d, 5.6 Hz, 2H); 7.19-7.34 (m, 5H); 7.72 (d, 7.4 Hz, 1 H); 7.79 (s, 1 H); 8.1 1 (d, 1 .2 Hz, 1 H); 8.21 (t, 5.2 Hz, 1 H); 8.34 (d, 8.8 Hz, 1 H); 8.51 (t, 5.6 Hz, 1 H). LC-MS: 384.2 [M+H]. f) 1 -((2-(Benzylamino)-2-oxoethyl)amino)-6-chloroisoquinoline-3-carboxylic acid
[00209] In analogy to the procedure described in Example 1(b), hydrolysis of methyl 1 -((2-(benzylamino)-2-oxoethyl)amino)-6-chloroisoquinoline-3-carboxylate with LiOH gives the title compound as a white crystalline solid. Mp >207 °C (decomp.); 1H- NMR (400 MHz , DMSO-d6), δ: 4.21 (d, 5.5 Hz, 2H); 4.28 (d, 6.3Hz, 2H); 7.16-7.24 (m, 5H); 7.70 (dd, 1 .9 Hz, 9 Hz, 1 H); 7.77 (s, 1 H); 8.09 (d, 1 .9 Hz, 1 H); 8.23 (t, 5.5 Hz; 1 H); 8.36 (d, 9 Hz, 1 H); 8.50 (t, 6.3 Hz, 1 H); 12.51 (br s, 1 H). LC-MS: 368.2 [M-H].
Example 46
1 -((2-(Benzylamino)-2-oxoethyl)amino)-6,8-dichloroisoquinoline-3-carboxylic acid
[00210] The title compound is prepared from methyl 1 ,6,8-trichloroisoquinoline-3- carboxylate and 2-amino-N-benzylacetamide by analogy to the procedures described in Example 30 (i) and Example 1 (b). Mp >190 °C (decomp.); 1H-NMR (400 MHz, DMSO- d6), δ: 4.26 (d, 4.6 Hz, 2H); 4.32 (d, 6 Hz, 2H); 7.18-7.29 (m, 5H); 7.76 (s, 1 H); 7.84 (d, 1 .9 Hz, 1 H); 8.09-8.13 (m, 2H); 8.65 (t, 6 Hz, 1 H). LC-MS: 404.2 [M-H].
Example 47
6,8-Dichloro-1 -((2-oxo-2-((pyridin-3-ylmethyl)amino)ethyl)amino)isoquinoline-3- carboxylic acid
[0021 1 ] The title compound is prepared from methyl 1 ,6,8-trichloroisoquinoline-3- carboxylate and 2-amino-N-(pyridin-3-ylmethyl)acetamide by analogy to the procedures described in Example 30 (i) and Example 1 (b). Mp >179 °C (decomp.); 1H-NMR (200 MHz, DMSO-de), δ: 4.25 (d, 4.4 Hz, 2H); 4.33 (d, 5.8 Hz, 2H); 7.25-7.31 (m, 1 H); 7.64 (d, 7.3 Hz, 1 H); 7.77 (s, 1 H); 7.84 (d, 2.2 Hz, 1 H); 8.10-8.13 (m, 2H); 8.41 (m, 2H); 8.69 (t, 5.8 Hz, 1 H). LC-MS: 403.4 [M-H].
Example 48
6,8-Dichloro-1 -((2-oxo-2-((pyridin-2-ylmethyl)amino)ethyl)amino)isoquinoline-3- carboxylic acid
[00212] The title compound is prepared from methyl 1 ,6,8-trichloroisoquinoline-3- carboxylate and 2-amino-N-(pyridin-2-ylmethyl)acetamide by analogy to the procedures described in Example 30 (i) and Example 1 (b). Mp >185 °C (decomp.); 1H-NMR (400 MHz, DMSO-de), δ: 4.29 (d, 4.7 Hz, 2H); 4.39 (d, 5.8 Hz, 2H); 7.20-7.24 (m, 1 H); 7.32 (d, 7.8 Hz, 1 H); 7.64-7.69 (m, 1 H); 7.77 (s, 1 H); 7.84 (d, 1 .9 Hz, 1 H); 8.09-8.13 (m, 2H); 8.44 (d, 4.8 Hz, 1 H); 8.72 (t, 5.8 Hz, 1 H). LC-MS: 403.4 [M-H].
Example 49
5,7-Dichloro-4-(methyl(2-oxo-2-((pyrimidin-2-ylmethyl)amino)ethyl)amino)-2- naphthoic acid a) Methyl 5,7-dichloro-4-(methyl(2-oxo-2-((pyrimidin-2- ylmethyl)amino)ethyl)amino)-2-naphthoate
(General procedure for the synthesis of Λ -substituted 4-(carbamoylmethyl- amino)- 5,7-dichloro-2-naphthoic acids)
[00213] To a solution of 2-((6,8-dichloro-3-(methoxycarbonyl)naphthalen-1 - yl)(methyl)annino)acetic acid (60 mg, 0.18 mmol) in DMF (1 ml_) is added CDI (40 mg, 0.25 mmol), and the mixture is heated at 50 °C for 30 min. Then pyrimidin-2- ylmethanamine hydrochloride (36 mg, 0.25 mmol) and DIPEA (34 mg, 0.26 mmol) are added, and the reaction mixture is stirred at 50 °C for 3 days (LC-MS control). The mixture is allowed to cool to rt, diluted with water (5 mL) and brine (6 mL), and extracted with EtOAc (4x). The organic extracts are combined, dried over Na2SO4, filtered and evaporated. The residue is purified by flash chromatography on silica (eluent - EtOAc:hexane or DCM:MeOH) to give the title compound in 72% yield as a yellow oil. b) 5,7-Dichloro-4-(methyl(2-oxo-2-((pyrimidin-2-ylmethyl)amino)ethyl)amino)-2- naphthoic acid
[00214] In analogy to the procedure described in Example 1(b), hydrolysis of methyl 5,7-dichloro-4-(methyl(2-oxo-2-((pyrimidin-2-ylmethyl)amino)ethyl)amino)-2- naphthoate with LiOH at rt for 4 h gives the title compound in 49% yield as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ: 2.84 (s, 3H); 3.73 (d, 16 Hz, 1 H); 4.00 (d, 16 Hz, 1 H); 4.47 and 4.55 (both dd, 17 and 5.6 Hz, both 1 H); 7.39 (t, 5 Hz, 1 H); 7.75 (d, 1 .6 Hz, 1 H); 7.79 (d, 2 Hz, 1 H); 8.25 (t, 6 Hz, 1 H); 8.27 (d, 2 Hz, 1 H); 8.31 (d, 1 .6 Hz, 1 H); 8.71 (d, 5 Hz, 2H) and 13.33 (br s, 1 H). LC-MS: 417 [M-H] (35CI).
Example 50 5,7-Dichloro-4-(N-(3-methoxybenzyl)acetamido)-2-naphthoic acid
[00215] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 2(a), acylation of methyl 4-amino- 5,7-dichloro-2-naphthoate with acetyl chloride in the presence of DIPEA gives methyl 4- acetamido-5,7-dichloro-2-naphthoate in 98% yield;
b) in analogy to the procedure described in Example 11(a), alkylation of methyl 4- acetamido-5,7-dichloro-2-naphthoate with 3-methoxybenzylbromide gives methyl 5,7- dichloro-4-(N-(3-methoxybenzyl)acetamido)-2-naphthoate in 61 % yield;
c) in analogy to the procedure described in Example 1(b), hydrolysis of methyl 5,7- dichloro-4-(/V-(3-methoxybenzyl)acetamido)-2-naphthoate with LiOH at rt for 5 h gives the title compound in 86% yield as a white solid. 1H NMR (400 MHz, DMSO-d6) δ: 1 .71 and 2.31 (both s, total 3H); 3.67 and 3.70 (both s, total 3H); 3.82 and 4.48 (both d, 15 Hz, total 1 H); 5.27 and 5.54 (both d, 15 Hz, total 1 H); 6.70-6.95 (m, 3H); 7.20 and 7.28 (both t, 8 Hz, total 1 H); 7.44 and 7.55 (both d, 1 .6 Hz, total 1 H); 7.92 and 8.03 (both d, 2 Hz, total 1 H); 8.40 and 8.48 (both d, 2 Hz, total 1 H); 8.60 and 8.69 (both d, 1 .6 Hz, total 1 H) and 13.50 (br s, 1 H). LC-MS: 416 [M-H] (35CI).
Example 51
5,7-Dichloro-4-(methyl(2-oxo-2-((pyridazin-4-ylmethyl)amino)ethyl)amino)-2- naphthoic acid
[00216] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 49(a), condensation of 2-((6,8- dichloro-3-(methoxycarbonyl)naphthalen-1 -yl)(methyl)amino)acetic acid with pyridazin- 4-ylmethanamine gives methyl 5,7-dichloro-4-(methyl(2-oxo-2-((pyridazin-4- ylmethyl)amino)ethyl)amino)-2-naphthoate in 74% yield as a yellow oil;
b) in analogy to the procedure described in Example 1(b), hydrolysis of methyl 5,7- dichloro-4-(methyl(2-oxo-2-((pyridazin-4-ylmethyl)amino)ethyl)amino)-2-naphthoate with LiOH at rt for 4 h gives the title compound in 65% yield as a pale yellow solid.
1H NMR (400 MHz, DMSO-d6) δ: 2.89 (s, 3H); 3.79 (d, 16 Hz, 1 H); 3.95 (d, 16 Hz, 1 H); 4.28 and 4.34 (both dd, 17 and 6 Hz, both 1 H); 7.32 (dd, 6 and 2 Hz, 1 H); 7.74 (d, 1 .6 Hz, 1 H); 7.76 (d, 2 Hz, 1 H); 8.27 (d, 2 Hz, 1 H); 8.29 (d, 1 .6 Hz, 1 H); 8.35 (t, 6 Hz, 1 H); 9.00-9.05 (m, 1 H); 9.05 (dd, 5.5 and 1 .2 Hz, 1 H) and 13.32 (br s, 1 H). LC-MS: 417 [M- H] (35CI).
Example 52
5,7-Dichloro-4-(methyl(2-oxo-2-((pyridazin-3-ylmethyl)amino)ethyl)amino)-2- naphthoic acid
[00217] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 49(a), condensation of 2-((6,8- dichloro-3-(methoxycarbonyl)naphthalen-1 -yl)(nnethyl)annino)acetic acid with pyridazin- 3-ylmethanannine gives methyl 5,7-dichloro-4-(methyl(2-oxo-2-((pyridazin-3- ylmethyl)amino)ethyl)amino)-2-naphthoate in 80% yield as a yellow oil;
b) in analogy to the procedure described in Example 1(b), hydrolysis of methyl 5,7- dichloro-4-(methyl(2-oxo-2-((pyridazin-3-ylmethyl)amino)ethyl)amino)-2-naphthoate with LiOH at rt for 4 h gives the title compound in 83% yield as a pale yellow solid.
1H NMR (400 MHz, DMSO-d6) δ: 2.87 (s, 3H); 3.76 (d, 16 Hz, 1 H); 3.96 (d, 16 Hz, 1 H); 4.56 (d, 6 Hz, 2H); 7.39 (dd, 8.6 and 1 .6 Hz, 1 H); 7.55-7.60 (m, 1 H); 7.73 (d, 1 .6 Hz, 1 H); 7.76 (d, 2 Hz, 1 H); 8.26 (d, 2 Hz, 1 H); 8.29 (d, 1 .6 Hz, 1 H); 8.44 (t, 6 Hz, 1 H); 9.10 (dd, 4.7 and 1 .6 Hz, 1 H) and 13.33 (br s, 1 H). LC-MS: 417 [M-H] (35CI).
Example 53
5,7-Dichloro-4-(methyl(2-oxo-2-((thiazol-2-ylmethyl)amino)ethyl)amino)-2- naphthoic acid
[00218] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 49(a), amidation of 2-((6,8- dichloro-3-(methoxycarbonyl)naphthalen-1 -yl)(methyl)amino)acetic acid with thiazol-2- ylmethanamine gives methyl 5,7-dichloro-4-(methyl(2-oxo-2-((thiazol-2- ylmethyl)amino)ethyl)amino)-2-naphthoate in 66% yield as a yellow oil; b) in analogy to the procedure described in Example 1(b), hydrolysis of methyl 5,7- dichloro-4-(methyl(2-oxo-2-((thiazol-2-ylmethyl)amino)ethyl)amino)-2-naphthoate with LiOH at rt for 2 h gives the title compound in 91 % yield as a pale yellow solid.
1H NMR (400 MHz, DMSO-d6) δ: 2.87 (s, 3H); 3.73 (d, 16 Hz, 1 H); 3.93 (d, 16 Hz, 1 H); 4.45-4.65 (m, 2H); 7.57 (d, 3.5 Hz, 1 H); 7.68 (d, 3.5 Hz, 1 H); 7.70-7.80 (m, 2H); 8.23 (d, 2 Hz, 1 H); 8.26 (d, 1 .6 Hz. 1 H); 8.53 (t, 6 Hz, 1 H) and 13.30 (br s, 1 H). LC-MS: 422.0 [M-H] (35CI).
Example 54
5.7- Dichloro-4-(methyl(2-(methyl(pyridin-4-ylmethyl)amino)-2-oxoethyl)amino)-2- naphthoic acid
[00219] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 49(a), amidation of 2-((6,8- dichloro-3-(methoxycarbonyl)naphthalen-1 -yl)(methyl)amino)acetic acid with /V-methyl- 1 -(pyridin-4-yl)methanamine gives methyl 5,7-dichloro-4-(methyl(2-(methyl(pyridin-4- ylmethyl)amino)-2-oxoethyl)amino)-2-naphthoate in 51 % yield as a yellow oil;
b) in analogy to the procedure described in Example 1(b), hydrolysis of methyl 5,7- dichloro-4-(methyl(2-(methyl(pyridin-4-ylmethyl)amino)-2-oxoethyl)amino)-2-naphthoate with LiOH at rt for 4 h gives the title compound in 67% yield as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ: 2.78 and 2.91 , and 2.93 (all s, total 6H); 3.88 and 4.02 (both d, 16 Hz, total 1 H); 4.08 and 4.28 (both d, 16 Hz, total 1 H); 4.40-4.55 and 4.50- 4.70 (both m, total 2H); 7.09 and 7.12 (both d, 6 Hz, total 2H); 7.61 and 7.74 (both d, 2 Hz, total 1 H); 7.73 and 7.79 (both d, 1 .2 Hz, total 1 H); 8.20-8.25 and 8.25-8.30 (both m, total 2H); 8.40-8.50 (m, 2H) and 13.29 (br s, 1 H). LC-MS: 430 [M-H] (35CI).
Example 55
6.8- Dichloro-1 -(methyl(2-oxo-2-((pyridin-3- ylmethyl)amino)ethyl)amino)isoquinoline-3-carboxylic acid
[00220] The title compound is prepared from methyl 1 ,6,8-trichloroisoquinoline-3- carboxylate and 2-(methylamino)-N-(pyridin-3-ylmethyl)acetamide by analogy to the procedures described in Example 30 (i) and Example 1 (b). 1H-NMR (200 MHz, DMSO-de), δ: 3.02 (s, 3H); 4.14 (s, 2H); 4.28 (d, 5.4 Hz, 2H); 7.27-7.33 (m, 1 H); 7.63 (d, 8.2 Hz, 1 H); 7.84 (s, 1 H); 7.98 (s, 1 H); 8.19 (s, 1 H); 8.41 -8.52 (m, 2H); 8.55 (t, 5.4 Hz, 1 H). LC-MS: 417.4 [M-H].
Example 56
5,7-Dichloro-4-((2-(methyl(pyridin-4-ylmethyl)amino)-2-oxoethyl)amino)-2- naphthoic acid
[00221 ] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 49(a), amidation 2-((6,8-dichloro- 3-(methoxycarbonyl)naphthalen-1 -yl)amino)acetic acid with /V-methyl-1 -(pyridin-4- yl)methanannine gives methyl 5,7-dichloro-4-((2-(methyl(pyridin-4-ylmethyl)amino)-2- oxoethyl)amino)-2-naphthoate in 58% yield as a yellow oil;
b) in analogy to the procedure described in Example 1(b), hydrolysis of methyl 5,7- dichloro-4-((2-(methyl(pyridin-4-ylmethyl)amino)-2-oxoethyl)amino)-2-naphthoate with LiOH at rt for 25 h gives the title compound in 85% yield as a pale yellow solid.
1H NMR (400 MHz, DMSO-d6) δ: 2.92 and 3.12 (both s, total 3H); 4.14 and 4.27 (both d, 3.5 Hz, total 2H); 4.66 and 4.78 (both s, total 2H); 6.93 and 7.02 (both d, 1 .2 Hz, total 1 H); 7.25-7.35 (m, 2H); 7.67 and 7.79 (both d, 2 Hz, total 1 H); 7.75-7.85 (m, 2H); 8.12 and 8.14 (both d, 2 Hz, total 1 H); 8.50-8.60 (m, 2H) and 13.15 (br s, 1 H). LC-MS: 416 [M-H] (35CI).
Example 57
5,7-Dichloro-4-(methyl(2-(methyl(thiazol-2-ylmethyl)amino)-2-oxoethyl)amino)-2- naphthoic acid
[00222] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 49(a), amidation of 2-((6,8- dichloro-3-(methoxycarbonyl)naphthalen-1 -yl)(methyl)amino)acetic acid with /V-methyl- 1 -(thiazol-2-yl)methanamine gives methyl 5,7-dichloro-4-(methyl(2-(methyl(thiazol-2- ylmethyl)amino)-2-oxoethyl)amino)-2-naphthoate in 43% yield as a yellow oil; b) in analogy to the procedure described in Example 1(b), hydrolysis of methyl 5,7- dichloro-4-(methyl(2-(methyl(thiazol-2-ylmethyl)amino)-2-oxoethyl)amino)-2-naphthoate with 5 equiv. of LiOH at rt for 2 h gives the title compound in 99% yield as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ: 2.82 and 2.88 (both s, total 3H); 2.92 and 3.01 (both s, total 3H); 3.89 and 4.03 (both d, 16 Hz, total 1 H); 4.20-4.30 (m, 1 H); 4.60 (d, 16 Hz) and 4.78-4.90 (m, total 2H); 7.60-7.80 (three m, total 4H); 8.20-8.30 (m, 2H) and 13.26 (br s, 1 H). LC-MS: 436 [M-H] (35CI).
Example 58
5,7-Dichloro-4-(N-methylthiazole-4-carboxamido)-2-naphthoic acid
[00223] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 2(a), acylation of methyl 5,7- dichloro-4-(methylamino)-2-naphthoate with thiazole-4-carbonyl chloride in the presence of DIPEA gives methyl 5,7-dichloro-4-(/V-methylthiazole-4-carboxamido)-2-naphthoate in 86% yield;
b) in analogy to the procedure described in Example 1(b), hydrolysis of methyl 5,7- dichloro-4-(/V-methylthiazole-4-carboxamido)-2-naphthoate with LiOH at rt for 6 h gives the title compound in 91 % yield as white solid.
1H NMR (200 MHz, DMSO-d6) δ: 3.33 and 3.56 (both s, overlap with water residual peak, total 3H); 7.73 and 8.00 (both d, 1 .5 Hz, total 1 H); 7.90 and 7.93 (both d, 2 Hz, total 1 H); 8.09 and 8.35 (both d, 2 Hz, total 1 H); 8.40 and 8.47 (both d, 2 Hz, total 1 H); 8.53 and 8.27 (both d, 2 Hz, total 1 H) and 8.62 and 8.72 (both d, 2 Hz, total 1 H). LC- MS: 379 [M-H] (35CI).
Example 59
5,7-dichloro-4-(methyl(2-oxo-2-((pyrazin-2-ylmethyl)amino)ethyl)amino)-2- naphthoic acid
[00224] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 49(a), amidation of 2-((6,8- dichloro-3-(methoxycarbonyl)naphthalen-1 -yl)(methyl)amino)acetic acid with pyrazin-2- ylmethanamine gives methyl 5,7-dichloro-4-(methyl(2-oxo-2-((pyrazin-2- ylmethyl)annino)ethyl)annino)-2-naphthoate in 68% yield as a yellow oil;
b) in analogy to the procedure described in Example 1(b), hydrolysis of methyl 5,7- dichloro-4-(methyl(2-oxo-2-((pyrazin-2-ylmethyl)amino)ethyl)amino)-2-naphthoate with
LiOH at rt for 3 h gives the title compound in 80% yield as a yellow solid.
1H NMR (200 MHz, DMSO-d6) δ: 2.84 (s, 3H); 3.74 (d, 16 Hz, 1 H); 3.97 (d, 16 Hz, 1 H);
4.43 (d, 6 Hz, 2H); 7.70-7.80 (m, 2H); 8.25-8.40 (m, 3H) and 8.45-8.55 (m, 3H). LC-MS:
417 [M-H] (35CI).
Example 60
5,7-Dichloro-4-(5-hydroxy-N-methylpicolinamido)-2-naphthoic acid
[00225] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 2(a), acylation of methyl 5,7- dichloro-4-(methylamino)-2-naphthoate with an excess of 5-hydroxypicolinoyl chloride in the presence of DIPEA gives methyl 5,7-dichloro-4-(5-hydroxy-N-methylpicolinamido)-2- naphthoate (31 mg, 19%) as white solid. 1H-NMR (400 MHz, CDCI3), δ: 3.34 and 3.45 ( s overlaped by H2O signal and s, total 3H); 3.84 and 3.92 (both s, total 3H); 7.00-7.03 and 7.23-7.28 (both m, total 2H); 7.53-7.54 and 7.64-7.66 (both m, total 2H); 7.86 and 8.18 (both d, 2, Hz, total 1 H); 8.36 and 8.46 (both d, 2 Hz, total 1 H); 8.57 and 8.72 (both d, 2 Hz, total 1 H). LC-MS: 405.3 [M+H];
b) in analogy to the procedure described in Example 1(b), hydrolysis of methyl 5,7- dichloro-4-(5-hydroxy-N-methylpicolinamido)-2-naphthoate with LiOH for 2 h gives the title compound (13 mg, 45%) as white solid. 1H NMR (400 MHz, DMSO-d6) δ: 3.30 and 3.45 (both s, overlaped by H2O signal, total 3H); 7.00-7.03 and 7.26-7.30 (both m, total 2H); 7.58-7.63 and 7.88-7.93 (both m, total 2H); 7.83 and 8.19-8.20 (d, 2 Hz, and m, total 1 H); 8.32 and 8.43 (both d, 2 Hz, total 1 H); 8.52 and 8.67 (both s, total 1 H); 10.15 and 10.48 (both s, total 1 H). LC-MS: 389.2 [M-H].
Example 61
5,7-Dichloro-4-(N-methylthiazole-2-carboxamido)-2-naphthoic acid [00226] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 2(a), acylation of methyl 5,7- dichloro-4-(methylamino)-2-naphthoate with thiazole-2-carbonyl chloride in the presence of DIPEA gives methyl 5,7-dichloro-4-(/V-methylthiazole-2-carboxamido)-2-naphthoate in 89% yield;
b) in analogy to the procedure described in Example 1(b), hydrolysis of methyl 5,7- dichloro-4-(/V-methylthiazole-2-carboxamido)-2-naphthoate with LiOH at rt for 6 h gives the title compound in 67% yield as white solid. 1H NMR (400 MHz, DMSO-d6) δ: 3.37 and 3.90 (both s, total 3H); 7.40 and 8.1 1 (both d, 3 Hz, total 1 H); 7.79 and 8.15 (both d, 3 Hz, total 1 H); 7.88 and 7.93 (both d, 2 Hz, total 1 H); 7.92 and 8.06 (both d, 1 .6 Hz, total 1 H); 8.44 and 8.48 (both d, 2 Hz, total 1 H); 8.70 and 8.73 (both d, 1 .6 Hz, total 1 H). LC-MS: 379 [M-H] (35CI).
Example 62
5,7-Dichloro-4-(N-methylpyrazine-2-carboxamido)-2-naphthoic acid
[00227] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 2(a), acylation of methyl 5,7- dichloro-4-(methylamino)-2-naphthoate with an excess of pyrazine-2-carbonyl chloride in the presence of DIPEA gives methyl 5,7-dichloro-4-(N-methylpyrazine-2- carboxamido)-2-naphthoate (79 mg, 69%) as white solid. 1H-NMR (CDCI3, 400 MHz), δ: 3.50 and 3.60 (both s, total 3H); 3.95 and 4.00 (both s, total 3H); 7.69 and 7.71 (both d, 2 Hz, total 1 H); 7.81 and 7.96 (both d, 2 Hz, total 1 H); 7.86-7.87, (m, total 2H); 8.41 and 8.71 (both d, 2 Hz, total 1 H); 9.05 and 9.12 (both d, 2 Hz, total 1 H). LC-MS: 390.3 [M+H];
b) in analogy to the procedure described in Example 1(b), hydrolysis of methyl 5,7- dichloro-4-(N-methylpyrazine-2-carboxamido)-2-naphthoate with LiOH gives the title compound (54 mg, 88%) as white solid. 1H NMR (400 MHz, DMSO-d6) δ: 3.38 and 3.42 (both s, total 3H); 7.84 and 8.08 (both d, 2 Hz, total 1 H); 7.92 and 7.94 (both d, 2 Hz, total 1 H); 8.01 and 8.73 (both d, 2 Hz, total 1 H); 8.34-8.37 and 8.77-8.82 (both m, total 2H); 8.47 and 8.56 (both d, 2 Hz, total 1 H); 8.85 and 9.00 (s and d, 2 Hz, total 1 H). LC- MS: 374.3 [M-H]. Example 63
5,7-Dichloro-4-(N-(4-methoxybenzyl)benzamido)-2-naphthoic acid
[00228] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 11(a), alkylation of methyl 4- benzamido-5,7-dichloro-2-naphthoate (Example 2(a)) with an excess of 4- methoxybenzylbromide in the presence of potassium tert-butoxide gives methyl 5,7- dichloro-4-(N-(4-methoxybenzyl)benzamido)-2-naphthoate;
b) in analogy to the procedure described in Example 1(b), hydrolysis of methyl 5,7- dichloro-4-(N-(4-methoxybenzyl)benzamido)-2-naphthoate with with LiOH gives the title compound as white solid. 1H NMR (400 MHz, DMSO-d6) δ: 3.64 and 3.70 (both s, total 3H); 4.04 and 4.47 (both d, 14 Hz, total 1 H); 5.07 and 5.73 (both d, 14 Hz, total 1 H); 6.71 -6.90 (m, 2H); 7.05-7.17 and 7.54-7.73 (both m, total 8H); 7.92 and 7.97 (both d, 2 Hz, total 1 H); 8.30 and 8.38 (d, 2 Hz and br s, total 1 H); 8.44 and 8.58 (both s, total 1 H). LC-MS: 478 [M-H].
Example 64
5,7-Dichloro-4-(N-methylpyrimidine-2-carboxamido)-2-naphthoic acid
[00229] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 2(a), acylation of methyl 5,7- dichloro-4-(methylamino)-2-naphthoate with an excess of pyrimidine-2-carbonyl chloride in the presence of DIPEA gives methyl 5,7-dichloro-4-(N-methylpyrimidine-2- carboxamido)-2-naphthoate (45 mg, 44%) as white solid. 1H-NMR (400 MHz, CDCI3), δ: 3.38 and 3.51 (both s, total 3H); 3.93 and 4.00 (both s, total 3H); 6.97 and 7.42 (both t, 5 Hz, total 1 H); 7.72 and 7.73 (both d, 2 Hz, total 1 H); 7.83, 7.95 and 8.18 (all d, 2 Hz, total 2H); 8.36 and 8.56 (both d, 2 Hz, total 1 H); 8.39 and 8.92 (both d, 5 Hz, total 2H). LC-MS: 390.2 [M+H];
b) in analogy to the procedure described in Example 1(b), hydrolysis of methyl 5,7- dichloro-4-(N-methylpyrimidine-2-carboxamido)-2-naphthoate with LiOH for 2 h gives the title compound (40 mg, 83%) as white solid. 1H NMR (400 MHz, DMSO-d6) δ: 3.20 and 3.36 (both s, total 3H); 7.14 and 7.65 (both t, 5 Hz, total 1 H); 7.72 and 7.93 (both d, 2 Hz, total 1 H); 7.93 and 7.96 (both d, 2 Hz, total 1 H); 8.29 and 8.48 (both d, 2 Hz, total 1 H); 8.44 and 8.98 (both d, 5 Hz, total 2H); 8.49 and 8.73 (both br s, total 1 H). LC-MS: 376.2 [M+H].
Example 65
5,7-Dichloro-4-(N-methylpyrimidine-4-carboxamido)-2-naphthoic acid
[00230] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 2(a), acylation of methyl 5,7- dichloro-4-(methylamino)-2-naphthoate with an excess of pyrimidine-4-carbonyl chloride in the presence of DIPEA gives methyl 5,7-dichloro-4-(N-methylpyrimidine-4- carboxamido)-2-naphthoate (99 mg, 62%) as white solid. 1H-NMR (400 MHz, CDCI3,), δ: 3.48 and 3.57 (both s, total 3H); 3.96 and 4.01 (both s, total 3H); 7.70 and 7.71 (both d, 2 Hz, total 1 H); 7.73 and 7.79 (both dd, 5 and 2 Hz, total 1 H); 7.82 and 7.96 (both d, 2 Hz, total 1 H); 7.88 and 8.12 (both d, 2 Hz, total 1 H); 8.42 and 8.56 (both d, 2 Hz, total 1 H); 8.57 and 9.36 (both d, 2 Hz, total 1 H); 8.67 and 8.97 (both d, 5 Hz, total 1 H). LC- MS: 390.2 [M+H];
b) in analogy to the procedure described in Example 1(b), hydrolysis of methyl 5,7- dichloro-4-(N-methylpyrimidine-4-carboxamido)-2-naphthoate with LiOH for 1 h gives the title compound (43 mg, 70%) as white solid. 1H NMR (400 MHz, DMSO-d6) δ: 3.34 and 3.36 (both s, total 3H); 7.61 and 7.84 (dd, 5 and 2 Hz, and dd overlaped by d, total 1 H); 7.83 and 8.07 (both d, 2 Hz, total 1 H); 7.93 and 7.94 (both d, 2 Hz, total 1 H); 8.34 and 8.46 (both d, 2 Hz, total 1 H); 8.55 and 8.72 (both d, 2 Hz, total 1 H); 8.62 and 9.34 (both d, 2 Hz, total 1 H); 8.71 and 9.02 (both d, 5 Hz, total 1 H). LC-MS: 376 [M+H].
Figure imgf000080_0001
Figure imgf000080_0002
Example
X R1 R2 R3 R4 R5 No.
17 CH CI H CI C(O)Ph C(O)Ph
18 CH CI H CI n-Pr C(O)Ph
19 CH CI H CI Et C(O)Ph
20 CH CI H CI H
0
21 CH CI H CI H
0
22 CH CI H CI CH2OMe C(O)Ph
23 CH CI H CI Me
0
24 CH CI H CI Me
0
25 CH CI H CI CH2Ph C(O)Ph
^ rv , N
26 CH CI H CI H
0
27 CH CI H CI C(O)Ph
28 CH CI H CI H o ^ N
29 CH CI H CI H
30 N CI H CI Me CH2C(O)NHCH2Ph
31 CH CI H CI H
32 CH CI H CI H
0
33 CH CI H CI Me
0
Figure imgf000082_0001
Figure imgf000083_0001
Example
X R1 R2 R3 R4 R5
No.
60 CH CI H CI Me
0
61 CH CI H CI Me - J3
0
62 CH CI H CI Me .,,ό
' if N
0
63 CH CI H CI C(O)Ph
64 CH CI H CI Me
0
N^ N
64 CH CI H CI Me
0
EXAMPLES OF REPRESENTATIVE PHARMACEUTICAL COMPOSITIONS
[00231 ] With the aid of commonly used solvents, auxiliary agents and carriers, the reaction products can be processed into tablets, coated tablets, capsules, drip solutions, suppositories, injection and infusion preparations, and the like and can be
therapeutically applied by the oral, rectal, parenteral, and additional routes.
Representative pharmaceutical compositions follow.
(a) Tablets suitable for oral administration, which contain the active ingredient, may be prepared by conventional tabletting techniques.
(b) For suppositories, any usual suppository base may be employed for incorporation thereinto by usual procedure of the active ingredient, such as a
polyethyleneglycol which is a solid at normal room temperature but which melts at or about body temperature.
(c) For parental (including intravenous and subcutaneous) sterile solutions, the active ingredient together with conventional ingredients in usual amounts are employed, such as for example sodium chloride and double-distilled water q.s., according to conventional procedure, such as filtration, aseptic filling into ampoules or IV-drip bottles, and autoclaving for sterility.
[00232] Other suitable pharmaceutical compositions will be immediately apparent to one skilled in the art.
FORMULATION EXAMPLES
[00233] The following examples are again given by way of illustration only and are not to be construed as limiting.
EXAMPLE 1
Tablet Formulation
A suitable formulation for a tablet containing 10 milligrams of active ingredient is as follows:
Mg
Active Ingredient 10
Lactose 61
Microcrystalline Cellulose 25
Talcum 2
Magnesium stearate 1
Colloidal silicon dioxide 1
EXAMPLE 2
Tablet Formulation
Another suitable formulation for a tablet containing 100 mg is as follows:
mg
Active Ingredient 100
Polyvinylpyrrolidone, crosslinked 10
Potato starch 20
Polyvinylpyrrolidone 19
Magnesium stearate 1 Microcrystalline Cellulose 50
Film coated and colored.
The film coating material consists of:
Hypromellose 10
Microcryst. Cellulose 5
Talcum 5
Polyethylene glycol 2
Color pigments 5
EXAMPLE 3
Capsule Formulation
A suitable formulation for a capsule containing 50 milligrams of active ingredient is as follows:
Mg
Active Ingredient 50
Corn starch 26
Dibasic calcium phosphate 50
Talcum 2
Colloidal silicon dioxide 2 filled in a gelatin capsule.
EXAMPLE 4
Solution for injection
A suitable formulation for an injectable solution is as follows:
Active Ingredient Mg 10
Sodium chloride Mg q.s.
Water for Injection mL add 1 .0
EXAMPLE 5
Liquid oral formulation A suitable fornnulation for 1 liter of an oral solution containing 2 milligrams of active ingredient in one milliliter of the mixture is as follows:
Mg
Active Ingredient 2
Saccharose 250
Glucose 300
Sorbitol 150
Orange flavor 10
Colorant q.s.
Purified water Add 1000 mL
EXAMPLE 6
Liquid oral formulation
Another suitable formulation for 1 liter of a liquid mixture containing 20 milligrams of active ingredient in one milliliter of the mixture is as follows:
G
Active Ingredient 20.00
Tragacanth 7.00
Glycerol 50.00
Saccharose 400.00
Methylparaben 0.50
Propylparaben 0.05
Black currant-flavor 10.00
Soluble Red color 0.02
Purified water Add 1000 mL
EXAMPLE 7
Liquid oral formulation
Another suitable formulation for 1 liter of a liquid mixture containing 2 milligrams of active ingredient in one milliliter of the mixture is as follows: G
Active Ingredient 2
Saccharose 400
Bitter orange peel tincture 20
Sweet orange peel tincture 15
Purified water Add 1000 mL
EXAMPLE 8
Aerosol formulation
180 g aerosol solution contain:
G
Active Ingredient 10
Oleic acid 5
Ethanol 81
Purified Water 9
Tetrafluoroethane 75
15 ml of the solution are filled into aluminum aerosol cans, capped with a dosing valve, purged with 3.0 bar.
EXAMPLE 9
TDS formulation
100 g solution contain:
Active Ingredient 10.0
Ethanol 57.5
Propyleneglycol 7.5
Dimethylsulfoxide 5.0
Hydroxyethylcellulose 0.4
Purified water 19.6 1 .8 ml of the solution are placed on a fleece covered by an adhesive backing foil. The system is closed by a protective liner which will be removed before use.
EXAMPLE 10
Nanoparticle formulation
10 g of polybutylcyanoacrylate nanopartides contain:
G
Active Ingredient 1 .00
Poloxamer 0.10
Butylcyanoacrylate 8.75
Mannitol 0.10
Sodium chloride 0.05
Polybutylcyanoacrylate nanopartides are prepared by emulsion polymerization in a water/0.1 N HCI/ethanol mixture as polymerizsation medium. The nanopartides in the suspension are finally lyophilized under vacuum.
PHARMACOLOGY
[00234] The active principles of the present invention, and pharmaceutical compositions thereof and method of treating therewith, are characterized by unique and advantageous properties, rendering the "subject matter as a whole", as claimed herein, unobvious. The compounds and pharmaceutical compositions thereof exhibit, in standard accepted reliable test procedures, the following valuable properties and characteristics:
METHODS
BINDING ASSAYS FOR THE CHARACTERIZATION OF GLYCINE B ANTAGONIST PROPERTIES
[3H]MDL-105,519 Displacement Studies [00235] For the evaluation of the binding affinity of the test compounds on the glycine binding pocket of the NMDA receptor, [3H]-MDL-105,519 (Perkin Elmer ,
Rodgau, Germany) displacement studies are performed using a 384-well plate robotic platform (Tecan Deutschland GmbH, Crailsheim, Germany). MDL-105,519 (Baron et al., J Pharmacol Exp Ther 1996, 279(1 ), 62-68; Baron et al., European Journal of
Pharmacology, 1997, 323(2-3), 181 -192; Hoffner & Wanner, Neuroscience Letters, 1997, 226(2), 79-82) is a selective, high affinity antagonist at the NMDA receptor glycine site.
Preparation of cortical membranes:
[00236] Tissue preparation is performed according to Foster & Wong (Br J
Pharmacol, 1987, 91 , 403-409) with some modifications. Anaesthetised male Sprague- Dawley rats (200-250 g, Janvier, Le Genest-lsle, France) are decapitated and their brains removed rapidly. The cortex is dissected out and processed as described by Parsons, et al. (J Pharmacol Exp Ther, 1997, 283(3), 1264-1275). For isolation of the cell membranes, the cortices are homogenized in 20 volumes of ice-cold 0.32 M sucrose (Sigma-Aldrich, Taufkirchen, Germany) using a glass-Teflon homogenizer. The homogenate is centrifuged at 1000 x g for 10 minutes, the pellet is discarded and the supernatant centrifuged at 20,000 x g for 20 minutes. The resulting pellet is re- suspended in 20 volumes of distilled water and centrifuged for 20 minutes at 8000 x g. The supernatant and the buffy coat are then centrifuged six times (48,000 x g for 20 minutes) in the presence of 5 mM Tris-HCI, pH 7.5. All centrifugation steps are carried out at 4°C. After resuspension in 5 volumes of 5 mM Tris-HCI, pH 7.5, the membrane suspension is frozen rapidly at -80°C. On the day of assay, the membranes are thawed, centrifuged (48,000 x g for 20 minutes) and then resuspended in 50 mM Tris-HCI, pH 7.5 (assay buffer). The amount of protein in the final membrane preparation is
determined according to the method of Lowry, et al. (J. Biological Chemistry, 1951 , 193, 256-275) with some modifications (Hartree, Analytical Biochemistry, 1972, 48, 422-427). The final protein concentration used for our studies is 200 g / ml.
Displacement studies [00237] A robotic system designed for 384-well format displacement studies (Tecan Deutschland GmbH) is loaded with the membrane solution, test compounds, bound control (DMSO 100 %), unlabeled glycine (1 mM, Sigma-Aldrich) for evaluation of non-specific binding and radioligand.
[00238] Before performing displacement studies, saturation experiments are performed to determine the equilibrium dissociation constant (Kd) of [3H]-MDL-105,519, which is a parameter for the affinity of the radioligand to the binding site. The
protein/receptor concentration is held constant whereas the amount of specific bound radioligand is determined using increasing concentrations of ligand.
[00239] On the basis of the saturation experiments, a final [3H]-MDL-105,519 concentration of 3 nM is selected. The Multiscreen HTS glass fibre (type B) filter 384- well assay plates (Millipore, Schwalbach, Germany) are loaded in the following order with 55 μΙ buffer (50 mM Tris-HCI, pH 7.5), 10 μΙ radioligand, 10 μΙ test compound, bound or non-specific and finally with 25 μΙ membrane solution. Compounds are tested as dose response curves (7 concentrations, n = 4, 9 compounds per plate). The final DMSO concentration is 1 %. After mixing, the reaction mix is shaken for 1 h at 4°C. The solution is then exhausted as rapidly as possible via a vacuum manifold under a constant vacuum of 450 mbar. The membranes are washed four times with cold assay buffer (100 μΙ_). 10 μΙ_ of Ultima Gold scintillation cocktail (PerkinElmer) is added to dried filter plates (1 h at 50 °C and at least 5 h at RT) and incubated at room
temperature for at least 2.5 h before counting the disintegration per minutes using a liquid scintillation counter (MicroBeta, PerkinElmer).
Analysis of data
[00240] For the evaluation of the binding affinity of the test compound to the glycine B binding site and its potency to displace [3H]-MDL-105,519, the measured radioactivity of the radioligand alone is set as 100 % bound control and the non-specific binding of the radioligand (which could not be displaced by glycine, 1 mM) represented the 0 % control. The residual radioactivity after displacement of the test compound is then corrected with respect to the set controls. Data processing and analysis is done with the help of Pipeline Pilot software (Accelrys, Cambridge, U.K.) for IC50 and Ki-value determination.
FUNCTIONAL SCREENING FOR THE CHARACTERIZATION OF GLYCINE B ANTAGONIST PROPERTIES
[00241 ] Antagonistic potencies of the test compounds in central and peripheral nerve cell preparations are functionally evaluated using electrophysiological whole cell patch-clamp recordings and/or fluorometric intracellular Ca2+-imaging by means of a Functional Drug Screening System (FDSS 7000, Hamamatsu, Herrsching, Germany).
Whole cell patch-clamp recordings
Preparation and cultivation of rat hippocampal neurons
[00242] Cell preparation is performed as described by Parsons, et al.
(Neuropharmacology, 1998, 37(6), 719-727). The anaesthetised female Sprague- Dawley rat (Charles River, Sulzfeld, Germany) is sacrificed by cervical dislocation. After opening the abdominal cavity, embryos (E20) are removed and stored in ice cold Ca2+- and Mg2+-free Hank's Buffered Salt Solution (pH 7.3), containing 4 g/l glucose (HBSS- CMF, Invitrogen, Darmstadt, Germany). Hippocampi are then isolated from the brains of at least 8 embryos after decapitation, transferred into ice cold HBSS-CMF and washed 3 to 4 times.
[00243] Hippocampi are pre-incubated for 8 min with a 0.66% trypsin (Sigma- Aldrich) and 0.1 % (20 U/ml) DNAase solution (Sigma-Aldrich) in Ca2+-free Phosphate Buffered Saline (PBS-CF, Biochrom, Berlin, Germany) and washed 3 times with HBSS- CMF. Cells are then mechanically dissociated by trituration in a PBS-CF solution containing 0.05% (10 U/ml) DNAase and 0.3% of the trypsin inhibitor ovomucoid (all from Sigma-Aldrich). The cells are then centrifuged at 180 x g for 10 minutes, and the cell pellet re-suspended in basal Minimum essential medium (MEM, Invitrogen), again carefully triturated to ensure maximal dissociation and finally plated in the flexiPERM inserts (Thermo Fisher Scientific, Langenselbold, Germany) at a density of 15 x 103 cells/cm2 (0.5 ml/insert) onto poly-DL-ornithine (Sigma) and mouse laminin (Invitrogen) pre-coated plastic petri dishes. After 1 hour the cells become attached to the bottom of the dish and the inserts may be removed. The cells are then nourished with 2 ml MEM supplemented with 5% foetal calf serum (FCS) and 5% horse serum (all from Biochrom) and incubated at 37°C with 95% air and 5% CO2 at 95% humidity. After 4 days in vitro (DIV) further glial mitosis is inhibited by adding 10 μΙ of AraC (5 μΜ endconcentration, Sigma-Aldrich). The medium is completely exchanged after an additional 2 DIV and again, but only partly (50 %), after 8 DIV. The cells are used for electrophysiological recordings after 1 1 -15 DIV.
Preparation and cultivation of rat dorsal root ganglia neurons
[00244] For the peripheral glycine B site antagonistic potency evaluation, compounds are functionally tested using dorsal root ganglia (DRG) neurons from 3 - 5 week old male rats, modified from Li et al. (Pain, 2004, 109, 443-452).
[00245] Sprague-Dawley rats (Janvier) are anaesthetised by placing in a CO2- euthanasia chamber and sacrificed by decapitation. The vertebral column is isolated and collected in ice cold Ca2+- and Mg2+-free Phosphate Buffered Saline. After opening the vertebral column, the spinal cord is removed and the dorsal root ganglia are harvested bilaterally from the thoracic to lumbosacral regions. They are collected in ice- cold HBSS-CMF in a 12-well plate, transferred to 35 mm dishes with fresh ice-cold HBSS-CMF and cleared from contaminating connective tissue and the dura mater spinalis. For further washing, purified ganglia are placed back in a 12 well plate containing fresh ice cold HBSS-CMF. After cutting the ganglia with small scissors, the ganglia digest is performed in 6-well plates by adding Liberase TM (Roche Diagnostics, Mannheim, Germany) dissolved in HBSS-CMF and incubating at RT and 37°C in an incubator for approximately 10 minutes, followed by a mechanical dissociation step performed with two canulaes. Enzymatic digestion is terminated by centrifugation at 180 g for 5 minutes and rinsing the cells with Neurobasal A medium (Invitrogen) without supplements but containing 10% FCS and 0.1 mg/ml DNase I (Sigma-Aldrich). After another centrifugation step at 180 g for 5 minutes, the cells are suspended in
Neurobasal A medium containing 2% B-27 supplement, GlutaMax (0.5 mM, both from Invitrogen), and D-AP5 (100 μΜ, Sigma-Aldrich), and then mechanically dissociated by trituration. The cell suspension is plated onto 35-mm culture dishes coated with poly- DL-ornithine (Sigma-Aldrich) and mouse laminin from Invitrogen containing flexiPERM inserts.
[00246] Two hours after seeding, when the cells had settled, the inserts are removed. After an overnight incubation a 75% medium exchange is performed. The cultures are maintained at 37°C in a humidified atmosphere of 95% air and 5% CO2.
[00247] DRG neurons are used for electrophysiological recordings 48 hours after cell preparation.
Whole cell patch-clamp recordings
[00248] Cells are visualised using an inverted microscope and selected for patching based upon their position and morphology. Voltage clamp recordings are made in the whole cell configuration of the patch clamp technique at a holding potential of -70 mV with the aid of an EPC-10 amplifier (Heka Elektronik, Lambrecht, Germany) in combination with pipette manipulator. Patch clamp pipettes are pulled from
borosilicate glass using a horizontal puller (P-97 Puller, Sutter Instruments, USA) and, when filled with intracellular solution, have resistances of 1 - 4 ΜΩ.
[00249] Solutions are delivered via a home-made gravity driven very fast perfusion system (< 10 ms) including valves to switch flow on and off in combination with a stepper motor-driven double-barrelled theta glass application pipette in order to expose cells to either agonist-free or agonist-containing solutions in presence or absence of antagonist.
[00250] The intracellular solution used consists of: 120 mM CsCI, 10 mM EGTA, 1 mM MgCI2, 200 μΜ CaCI2, 10 mM glucose and 22 mM tetraethyl ammonium chloride (TEA-CI). The corresponding extracellular bath solution contains: 140 mM NaCI, 3 mM KCI, 10 mM glucose, 10 mM HEPES, 1 .5 mM CaCI2 and 4.5 mM sucrose (all from Sigma-Aldrich) pH 7.3, and is supplemented with 0.3 μΜ tetrodotoxin (TTX, Tocris, Bristol, U.K.) to block voltage-activated sodium channels and 0.25 μΜ bicuculline (Sigma-Aldrich) to block GABAA receptors. [00251 ] For the determination of concentration-dependency of blockade, 5 control traces are recorded with application of NMDA (200 μΜ) and D-Serine (1 μΜ) or Glycine (10 μΜ, all from Sigma-Aldrich) in case of DRG neurons for 5 seconds in order to reduce the effect of rundown, then the highest concentration of the test-substance is applied for 1 minute before applying the agonists for 5 seconds in the presence of antagonist. Three recordings are made in the presence of the antagonist and 3 recovery traces are recorded after it's removal. The procedure is repeated for three to four further concentrations of antagonist with declining concentrations e.g. 10, 3, 1 , 0.3, and 0.1 μΜ. For the final recovery, agonists are again applied five times after wash-out of the test substance.
[00252] Alternatively cumulative compound application protocols could be used, in which the agonists are applied, then 5 concentrations of antagonist are sequentially coapplied before the antagonist is removed and the current is allowed to recover. The cumulative protocol enables a fast determination of the concentration-dependency of blockade - i.e. cells do not have to remain stable for long recording durations.
Analysis of data
[00253] Data are analysed using TIDA 5.0 (Heka Elektronik). With the help of Microsoft Excel, data are pooled and finally GraFit software (Erithacus Software Ltd., Surrey, U.K.) is used to fit the data e.g. with the four parameter logistic equation for determining IC5o values. For normalization of the calculated IC5o values of the tested glycine B antagonists, depending on the agonist affinity (EC5o) in the test system, the equilibrium dissociation constant (Kb) is determined according to the Cheng & Prusoff (Biochemical Pharmacology, 1973, 22, 3099-108) equation. Alternatively, Pipeline Pilot protocols are implemented for data processing and analysis. For all data points, the value given is the mean ± S.E.M. (standard error of the mean) of results from at least 4 individual cells per concentration.
Calcium FDSS 7000 studies
Preparation and cultivation of rat cortical neurons [00254] Primary neurons are prepared from cortices of embryonal rats at day 17 of pregnancy as described by Dichter (Brain Res., 1987, 149, 279). Sprague-Dawley rat embryos (E 17, Charles River) are decapitated and neocortices are dissected, trypsinized and carefully triturated. The cell suspension is plated on poly-d-lysine pre- coated 384-well Plates (Aurora Biotechnologies, Carlsbad, USA) at a cell density of 15.000 cells /well. The neurons are cultivated in Neurobasal media containing B27- Supplement (Invitrogen) and 0.5 μΜ L-Glutamine (Biochrom) at 37°C in a humidified atmosphere of 5% CO2 / 95% air. Medium is exchanged completely at day 4 and to 50% on day 7. At the time of experiments neurons are 1 1 - 13 days in vitro.
Calcium FDSS 7000 studies
[00255] The increase of intracellular calcium after stimulation with 12 μΜ NMDA (EC80) is measured using the Functional Drug Screening System (FDSS 7000,
Hamamatsu) and the Calcium-4-Kit (Molecular Devices, Ismaning, Germany) in 384- well format. No D-Serine is added, since the endogenous co-agonist concentrations are sufficient. Test compound dilution series (6 different concentrations, n = 4, 9
compounds per plate) are performed on a Tecan pipette robot. Prior to addition of agonist or antagonist the medium is aspirated before loading with 45 μΙ_ of loading buffer (1 h at room temperature), consisting of Ca-4 sensitive dye reconstituted in extracellular patch-clamp bath solution, pH 7.3. Subsequently, 384-plates are
transferred to FDSS 7000 to detect increases in intracellular calcium after the addition of agonist, measured as relative fluorescence units (RFU). Antagonists are pre- incubated with the cells for 10 min at room temperature before the addition of the agonist.
Data analysis
[00256] The fluorescence signal increase after addition of agonist reflects the increase of intracellular calcium. For the evaluation of the antagonistic potency, the calcium changes in response to different concentrations of antagonist are determined using an area under the curve (AUC) calculation. All responses (RFU-values) are determined as percentage of control at agonist EC80 (12 μΜ NMDA). For data processing and IC50 value calculations Pipeline Pilot is used. Due to high intrinisic glycine site co-agonist concentrations within the assay system, resulting in a full activation of the receptor, Kb calculations are not possible since EC5o's for D-serine could not be determined.
[00257] Results for respresentative compounds of the invention are shown in Tables 2-3.
Table 2 - [3H]-MDL-105,519 Displacement Studies
NMDA-MDL
Compound Chemical Name 105519-r-CTX
- IC50 [|JM]
4-(Benzoyl-methyl-amino)-5,7-dichloro-
Example 1 1 0.384
naphthalene-2-carboxylic acid
4-(3-Benzylureido)-5,7-dichloronaphthalene-
Example 13 2.68
2-carboxylic acid
5,7-Dichloro-4-(methylphenylacetylamino)-
Example 14 0.069
naphthalene-2-carboxylic acid
5,7-Dichloro-4-dibenzoylamino-naphthalene-
Example 17 2.12
2-carboxylic acid
4-(Benzoyl-propyl-amino)-5,7-dichloro-
Example 18 0.867
naphthalene-2-carboxylic acid
4-[Benzoyl-(methoxymethyl)-amino]-5,7-
Example 22 0.426
dichloro-naphthalene-2-carboxylic acid
4-(Benzoyl-benzyl-amino)-5,7-dichloro-
Example 25 0.316
naphthalene-2-carboxylic acid
1 -[(Benzylcarbamoyl-methyl)-methyl-amino]-
Example 30 0.144
6,8-dichloro-isoquinoline-3-carboxylic acid
5,7-Dichloro-4-[methyl-(pyridine-2-carbonyl)-
Example 33 0.036
amino]-naphthalene-2-carboxylic acid
5,7-Dichloro-4-(methyl-{[(pyridin-3-ylmethyl)-
Example 34 carbamoyl]-methyl}-amino)-naphthalene-2- 0.058
carboxylic acid
5,7-Dichloro-4-(methyl-{[(pyridin-2-ylmethyl)-
Example 36 0.458
carbamoyl]-methyl}-amino)-naphthalene-2- carboxylic acid
5,7-Dichloro-4-{methyl-[(methyl-pyridin-2-
Example 39 ylmethyl-carbamoyl)-methyl]-amino}- 0.986 naphthalene-2-carboxylic acid
1 -((2-(Benzylamino)-2-oxoethyl)amino)-
Example 46 6,8-dichloroisoquinoline-3-carboxylic 0.868 acid
6,8-Dichloro-1 -((2-oxo-2-((pyridin-3-
Example 47 ylmethyl)annino)ethyl)annino)isoquinoline- 1.38
3-carboxylic acid
5,7-Dichloro-4-(methyl(2-oxo-2-
Example 49 ((pyrimidin-2-ylmethyl)amino)ethyl)- 0.363 amino)-2-naphthoic acid
5,7-Dichloro-4-(N-(3-
Example 50 methoxybenzyl)acetamido)-2-naphthoic 0.33 acid
5,7-Dichloro-4-(methyl(2-oxo-2- ((pyridazin-4-
Example 51 0.745 ylmethyl)annino)ethyl)annino)-2-naphthoic
acid
5,7-Dichloro-4-(methyl(2-oxo-2- ((pyridazin-3-
Example 52 0.338 ylmethyl)annino)ethyl)annino)-2-naphthoic
acid
5,7-Dichloro-4-(methyl(2-oxo-2-((thiazol-
Example 53 2-ylmethyl)annino)ethyl)annino)-2- 0.1 naphthoic acid
5,7-Dichloro-4-(methyl(2-(nnethyl(pyndin-
Example 54 4-ylmethyl)amino)-2-oxoethyl)amino)-2- 1.07 naphthoic acid 6,8-Dichloro-1 -(methyl(2-oxo-2-((pyridin-
Example 55 3-ylmethyl)amino)ethyl)amino)- 0.143 isoquinoline-3-carboxylic acid
5,7-Dichloro-4-((2-(methyl(pyridin-4-
Example 56 ylmethyl)amino)-2-oxoethyl)amino)-2- 13.5 naphthoic acid
5,7-Dichloro-4-(methyl(2-(nnethyl(thiazol-
Example 57 2-ylmethyl)amino)-2-oxoethyl)amino)-2- 0.63 naphthoic acid
5,7-Dichloro-4-(N-methylthiazole-4-
Example 58 0.026 carboxamido)-2-naphthoic acid
5,7-dichloro-4-(methyl(2-oxo-2-((pyrazin-
Example 59 2-ylmethyl)amino)ethyl)amino)-2- 0.233 naphthoic acid
5,7-Dichloro-4-(5-hydroxy-N-
Example 60 0.029 methylpicolinamido)-2-naphthoic acid
5,7-Dichloro-4-(N-methylthiazole-2-
Example 61 0.039 carboxamido)-2-naphthoic acid
5,7-Dichloro-4-(N-methylpyrazine-2-
Example 62 0.032 carboxamido)-2-naphthoic acid
5,7-Dichloro-4-(N-(4-
Example 63 methoxybenzyl)benzannido)-2-naphthoic 0.527 acid
Table 3 - Functional Calcium FDSS 7000 studies in rat cortical neurons
NMDA-FDSS-
Compound Chemical Name rCTX- IC50
[μΜ]
4-[(Benzylcarbamoyl-methyl)-amino]-5,7-
Example 5 1.66 dichloro-naphthalene-2-carboxylic acid
Example 7 5,7-Dichloro-4-({[(pyridin-3-ylnnethyl)- 1.22 carbamoyl]-methyl}-amino)-naphthalene- 2-carboxylic acid
5,7-Dichloro-4-({[(thiazol-2-ylmethyl)-
Example 9 carbamoyl]-methyl}-amino)-naphthalene- 2.0
2-carboxylic acid
4-(Benzoyl-methyl-amino)-5,7-dichloro-
Example 1 1 1 .186 naphthalene-2-carboxylic acid
5,7-Dichloro-4-(methylphenylacetylamino)-
Example 14 0.273 naphthalene-2-carboxylic acid
4-(Benzoyl-propyl-amino)-5,7-dichloro-
Example 18 2.158 naphthalene-2-carboxylic acid
4-[Benzoyl-(methoxymethyl)-amino]-5,7-
Example 22 1 .13 dichloro-naphthalene-2-carboxylic acid
4-(Benzoyl-benzyl-amino)-5,7-dichloro-
Example 25 1 .1 1 naphthalene-2-carboxylic acid
1 -[(Benzylcarbamoyl-methyl)-methyl-amino]-
Example 30 0.74
6,8-dichloro-isoquinoline-3-carboxylic acid
5,7-Dichloro-4-[methyl-(pyridine-2-carbonyl)-
Example 33 0.255 amino]-naphthalene-2-carboxylic acid
5,7-Dichloro-4-(methyl-{[(pyridin-3-ylmethyl)-
Example 34 carbamoyl]-methyl}-amino)-naphthalene-2- 0.853 carboxylic acid
5,7-Dichloro-4-(methyl-{[(pyridin-2-ylmethyl)-
Example 36 carbamoyl]-methyl}-amino)-naphthalene-2- 4.67 carboxylic acid
5,7-Dichloro-4-{methyl-[(methyl-pyridin-2-
Example 39 ylmethyl-carbamoyl)-methyl]-amino}- 5.26 naphthalene-2-carboxylic acid
1 -((2-(Benzylamino)-2-oxoethyl)amino)-
Example 46 6,8-dichloroisoquinoline-3-carboxylic 4.58 acid
6,8-Dichloro-1 -((2-oxo-2-((pyridin-3-
Example 47 5.17 ylmethyl)annino)ethyl)annino)isoquinoline- 3-carboxylic acid
5,7-Dichloro-4-(methyl(2-oxo-2-
Example 49 ((pyrim id in-2-yl methyl )am ino)ethyl )- 2.88 amino)-2-naphthoic acid
5,7-Dichloro-4-(N-(3-
Example 50 methoxybenzyl)acetamido)-2-naphthoic 2.58 acid
5,7-Dichloro-4-(methyl(2-oxo-2- ((pyridazin-4-
Example 51 6.7 ylmethyl)annino)ethyl)annino)-2-naphthoic acid
5,7-Dichloro-4-(methyl(2-oxo-2- ((pyridazin-3-
Example 52 3.07 ylmethyl)annino)ethyl)annino)-2-naphthoic acid
5,7-Dichloro-4-(methyl(2-oxo-2-((thiazol-
Example 53 2-ylmethyl)amino)ethyl)amino)-2- 1.29 naphthoic acid
6,8-Dichloro-1 -(methyl(2-oxo-2-((pyridin- 3-
Example 55 1.34 ylmethyl)annino)ethyl)annino)isoquinoline- 3-carboxylic acid
5,7-Dichloro-4-(methyl(2-(nnethyl(thiazol-
Example 57 2-ylmethyl)annino)-2-oxoethyl)annino)-2- 5.33 naphthoic acid
5,7-Dichloro-4-(N-methylthiazole-4-
Example 58 0.28 carboxamido)-2-naphthoic acid
5,7-dichloro-4-(methyl(2-oxo-2-((pyrazin-
Example 59 2-ylmethyl)annino)ethyl)annino)-2- 2.28 naphthoic acid
Example 60 5,7-Dichloro-4-(5-hydroxy-N- 0.21 nnethylpicolinannido)-2-naphthoic acid
5,7-Dichloro-4-(N-methylthiazole-2-
Example 61 0.28
carboxamido)-2-naphthoic acid
CONCLUSIONS
[00258] In conclusion, from the foregoing, it is apparent that the present invention provides novel, valuable, and unpredictable applications and uses of the compounds of the present invention, which compounds comprise the active principle according to the present invention, as well as novel pharmaceutical compositions thereof and methods of preparation thereof and of treating therewith, all possessed of the foregoing more specifically-enumerated characteristics and advantages.
[00259] The high order of activity of the active agent of the present invention and compositions thereof, as evidenced by the tests reported, is indicative of utility based on its valuable activity in lower animals. Clinical evaluation in human beings has not been completed, however. It will be clearly understood that the distribution and marketing of any compound or composition falling within the scope of the present invention for use in human beings will of course have to be predicated upon prior approval by governmental agencies, such as the U.S. Federal Food and Drug Administration, which are
responsible for and authorized to pass judgment on such questions.
[00260] The instant 4-aminonaphthalene-2-carboxylic acid and 1 -amino- isoquinoline-3-carboxylic acid derivatives represent a novel class of glycine B
antagonists. In view of their potency, they will be useful therapeutics in a wide range of disorders, including CNS / PNS disorders, which involve excessive glutamate induced excitation.
[00261 ] These compounds accordingly find application in the treatment of the following disorders of a living animal body, especially a human: pain, including acute pain, chronic pain, allodynia, hyperalgesia, visceral pain, phantom pain, post-operative pain, neuropathic pain, peripheral neuropathy including, for example peripheral neuropathy induced by nociception, inflammation, ischemia, viral infection (HZV), traumatic and other mechanical nerve injury, cancer, chemotherapy induced pain, diabetes mellitus, HIV infection, fibromyalgia, trigeminus neuralgia, inflammatory bowel diseases (IBD), irritative bowel syndrome (IBS), arthritis including rheumatoid arthritis, osteoarthritis (degenerative joint disease), multiple sclerosis (MS) and gout (metabolic arthritis).
[00262] These compounds also find application in the treatment of the following disorders of a living animal body, especially a human: acute insults, including cerebral ischemia, cerebral infarct, brain oedema, anoxia, inner ear insult, inner ear insult in tinnitus, head or brain or spinal cord trauma, head or brain or spinal cord injuries, trauma, sound- or drug-induced inner ear insult, ischaemia resulting from cardiac arrest or stroke or bypass operations or transplants, acute pain, hypoxia, perinatal hypoxia, and ischaemia; chronic insults, such as neurodegenerative disorders, including Morbus Huntington, Alzheimer's disease Creutzfeld-Jakob's syndrome/disease, bovine spongiform encephalopathy (BSE) prion related infections, diseases involving mitochondrial dysfunction, diseases involving β-amyloid and/or tauopathy, Down's syndrome, motor neuron diseases, amyotrophic lateral sclerosis (ALS), olivopontocerebellar atrophy, Parkinson's disease, Neuronal Ceroid Lipofuscinosis, AIDS dementia complex, AIDS- related dementia, dementia related to HIV infections, HIV-1 encephalopathy, AIDS encephalopathy, Korsakoff syndrome, vascular dementia, and corticobasal
degeneration; neurological disorders, including tinnitus, hearing loss, sound- or drug-induced tinnitus, haloperidol-induced dyskinesias, dopaminomimetic-induced dyskinesias, chorea, Huntington's chorea, athetosis, dystonia, stereotypy, ballism, tardive dyskinesias, tic disorder, spasmodic torticollis, blepharospasm, focal and generalized dystonia, nystagmus, Parkinson's dementia, mild cognitive impairment, cognitive deficits in various forms of mild cognitive impairment, cognitive deficits in various forms of dementia, dementia pugilistica, vascular and frontal lobe dementia, cognitive impairment, learning impairment, L-dopa-induced dykinesias, L-dopa-induced dykinesias in Parkinson's disease therapy, dyskinesias, dyskinesia in Huntington's disease, drug induced dyskinesias, neuroleptic-induced dyskinesias, neurodegenerative cerebellar ataxias, centrally induced neuropathic pain, convulsions, epileptic
convulsions, epilepsy, temporal lobe epilepsy, myoclonic epilepsy, tremor, dementia in Alzheimer's disease, dementia in Korsakoff syndrome, dementia, hereditary cerebellar ataxias, sleep disorders, movement disorders, essential tremor, muscle spasms, and spasticity; psychological/psychiatric disorders, including generalized anxiety disorder, obsessive- compulsive disorder, panic disorder, posttraumatic stress disorder, social phobia, phobic disorders, substance-induced anxiety disorder, delusional disorder,
schizoaffective disorder, schizophreniform disorder, substance-induced psychotic disorder, delirium, post-operative cognitive deficit (POCD), cognitive impairment, learning impairment, anxiety disorders, panic disorders, anxiety and panic disorders, social anxiety disorder (SAD), attention deficit hyperactivity disorder (ADHD), attention deficit syndrome (ADS), dementia, posttraumatic stress disorder (PTSD), schizophrenia, positive or cognitive or negative symptoms of schizophrenia, major depressive disorder, major depression, depression, bipolar manic-depressive disorder, sleep disorders, agoraphobia, bulimia nervosa, eating disorders, obesity, obesity-related disorders, obesity abuse, food addiction, binge eating disorders, and hyperactivity in children; drug/alcohol abuse, including craving (e.g., for drugs of abuse), abuse, addiction, nicotine addiction, nicotine abuse, alcohol addiction, alcohol abuse, opiate addiction, opiate abuse, cocaine addiction, cocaine abuse, amphetamine addiction, and
amphetamine abuse; skin diseases, including atopic dermatitis, itching, skin lesions induced by severe itching or atopic dermatitis, systemic sclerosis, pruritic conditions, and pruritis; diseases of the gastro-intestinal tract and metabolic diseases, including diarrhoea, hepatic encephalopathy, hypoglycaemia, gastroesophageal reflux disease (GERD), gastrointestinal dysfunction, lower esophageal sphincter (LES) disease, functional gastrointestinal disorders, dyspepsia, vomiting, urinary incontinence, and regurgitation; diseases of the immune system, including Sjogren's syndrome, systemic lupus erythematosus, and multiple sclerosis (MS); eye diseases, including eye injuries, eye diseases, eye disorders, glaucoma,
retinopathy, and macular degeneration; diseases of the respiratory tract, including respiratory tract infection, chronic laryngitis, asthma, reflux-related asthma, and lung disease; migraine; autism; restless leg syndrome (RLS); Tourette syndrome; micturition disorders; neuromuscular disorder in the lower urinary tract; and drug tolerance to opioids.
[00263] The method-of-treating a living animal body with a compound of the invention, for the inhibition of progression or alleviation of the selected ailment therein, is as previously stated by any normally-accepted pharmaceutical route, employing the selected dosage which is effective in the alleviation of the particular ailment desired to be alleviated.
[00264] Use of the compounds of the present invention in the treatment of a living animal for inhibition of progression or alleviation of selected ailments or conditions, particularly ailments or conditions susceptible to treatment with a glycine B is carried out in the usual manner comprising the step of admixing an effective amount of a
compound of the invention with a pharmaceutically-acceptable diluent, excipient, or carrier, and the method-of-treating, pharmaceutical compositions, and use of a compound of the present invention in the manufacture of a medicament.
[00265] Representative pharmaceutical compositions prepared by admixing the active ingredient with a suitable pharmaceutically-acceptable excipient, diluent, or carrier, include tablets, capsules, solutions for injection, liquid oral formulations, aerosol formulations, TDS formulations, and nanoparticle formulations, thus to produce medicaments for oral, injectable, or dermal use, also in accord with the foregoing.
* * * * *
[00266] The present invention is not to be limited in scope by the specific embodiments described herein. Indeed, various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description.
[00267] All patents, applications, publications, test methods, literature, and other materials cited herein are hereby incorporated by reference.

Claims

CLAIMS compound selected from those of Formula I:
Figure imgf000107_0001
I
wherein
X represents CH or N;
R1 represents halogen, Chalky!, or trifluoromethyl; R2 represents hydrogen, halogen, or Ci-6alkyl; R3 represents hydrogen, halogen, or Ci-6alkyl;
R4 represents hydrogen, Chalky!, C3-6alkenyl, C3-6alkynyl, hydroxy-Ci-6alkyl, carboxy-Ci-6alkyl, Ci-6alkoxy-Ci-6alkyl, aryl, heteroaryl, cyclo-C3-i2alkyl, cyclo- C3-i2alkyl-Ci-6alkyl, cyclo-C3-i2alkoxy-Ci-6alkyl, aryl-Ci-6alkyl, heteroaryl-Ci-6alkyl, di-(Ci-6alkyl)aminocarbonyl-Ci-6alkyl or arylcarbonyl,
R5 represents hydrogen, Chalky!, Cs^alkenyl, Cs^alkynyl, hydroxy-Ci-6alkyl, carboxy-Ci-6alkyl, Ci-6alkoxy-Ci-6alkyl, aryl, heteroaryl, cyclo-C3-i2alkyl, cyclo- C3-i2alkyl-Ci-6alkyl, cyclo-C3-i2alkoxy-Ci-6alkyl, aryl-Ci-6alkyl, heteroaryl-Ci-6alkyl, Ci-6alkylsulfonyl, arylsulfonyl, -C(O)-R6, or -Y-C(O)-R7, or R4 and R5 together with the nitrogen atom they are attached represent a 4-, 5-, 6- or 7-membered ring which may be saturated or unsaturated, wherein, in addition to the nitrogen atom, the ring may contain an additional heteroatom selected from sulfur, oxygen and nitrogen and/or be condensed to an aromatic or heteroaromatic ring selected from benzene, furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, imidazole, pyrazole, oxadiazole, thiadiazole, triazole, pyridine, pyrimidine, pyrazine, pyridazine, and wherein the ring may be optionally substituted by one or more substituents selected from halogen, hydroxy, oxo, nitro, acyl, acylamino, trifluoromethyl, Chalky!, cyclo-C3-i2alkyl, aryl, heteroaryl, aryl-Ci-6alkyl, heteroaryl-Ci-6alkyl, Ci-6alkoxy, hydroxy-Ci-6alkyl, Ci-6alkoxy- Ci-6alkyl, COOH, CONH2, Ci-6alkylaminocarbonyl, aryl-aminocarbonyl, heteroaryl-aminocarbonyl, di-(Ci-6alkyl)aminocarbonyl, carboxy-Ci-6alkyl, and carbamoyl-Ci-6alkyl;
R6 represents Chalky!, aryl, heteroaryl, cyclo-C3-i2alkyl, cyclo-C3-i2alkyl-Ci-6alkyl, aryl-Ci-6alkyl, heteroaryl-Ci-6alkyl, or -NR8R9;
Y represents which may be optionally substituted by Chalky!, Ci-6alkoxy-Ci-6alkyl, aryl, heteroaryl, cyclo-C3-i2alkyl, cyclo-C3-i2alkyl-Ci-6alkyl, cyclo-C3-i2alkoxy-Ci-6alkyl, aryl-Ci-6alkyl or heteroaryl-Ci-6alkyl;
R7 represents -NR10R1 1, OH, Ci-6alkoxy, aryl, heteroaryl, or heterocyclyl;
R8 represents hydrogen or Chalky!;
R9 represents Chalky!, aryl, heteroaryl, cyclo-C3-i2alkyl, aryl -Chalky!, or heteroaryl-Ci-6alkyl;
R10 and R11 each independently represent hydrogen, Chalky!, cyclo-C3-i2alkyl, aryl, heteroaryl, cyclo-C3-i2alkyl-Ci-6alkyl, aryl -Chalky!, or heteroaryl-Ci-6alkyl, or R10 and R11 together with the nitrogen atom they are attached represent a 4-, 5-, 6- or 7-membered ring which may be saturated or unsaturated, wherein, in addition to the nitrogen atom, the ring may contain an additional heteroatom selected from sulfur, oxygen and nitrogen and/or be condensed to an aromatic or heteroaromatic ring selected from benzene, thiazole, imidazole, or pyridine, and wherein the ring may be optionally substituted by one or more substituents selected from hydroxy, oxo, amino, acyl, acylamino, trifluoromethyl, Chalky!, cyclo-C3-i2alkyl, aryl, Ci-6alkoxy, hydroxy-Ci-6alkyl, and Ci-6alkoxy-Ci-6alkyl; wherein the term "aryl" represents phenyl or naphthyl, or phenyl substituted by one or more substituents selected from halogen, amino, hydroxy, nitro, cyano, COOH, CONH2, Ci-6alkylaminocarbonyl, phenylaminocarbonyl, heteroarylaminocarbonyl, hydroxy-Ci-6alkylaminocarbonyl, di-(Ci-6alkyl)aminocarbonyl, trifluoromethyl, Ci-6alkyl, heteroaryl, Ci-6alkoxy, difluoromethoxy, trifluoromethoxy, cyclo- C3-i2alkoxy, phenoxy, heteroaryloxy, phenyl-Ci-6alkoxy, heteroaryl-Ci-6alkoxy, amino-Ci-6alkyl, hydroxy-Ci-6alkyl, carbamoyl-Ci-6alkyl, hydroxy-Ci-6alkoxy, Ci-6alkoxycarbonyl, Ci-6alkylamino, cyclo-Cs-^alkylamino, phenylamino, heteroarylamino, phenyl-Ci-6alkylamino, heteroaryl-Ci-6alkylamino, hydroxy- Ci-6alkylamino, di-(Ci-6alkyl)amino, acylamino, Ci-6alkylamino-Ci-6alkoxy, di-(Ci-6alkyl)amino-Ci-6alkoxy, Ci-6alkylsulfonylamino, Ci-6alkyl-aminosulfonyl, di-(Ci-6alkyl)aminosulfonyl, Ci-6alkylaminocarbonyl-Ci-6alkyl, cyclo-C3-i2alkyl- carbamoyl-Ci-6alkyl, phenylaminocarbonyl-Ci-6alkyl, heteroarylaminocarbonyl- Ci-6alkyl, hydroxy-Ci-6alkylaminocarbonyl-Ci-6alkyl, and di-(Ci-6alkyl)aminocarbonyl-Ci-6alkyl; and the term "heteroaryl" represents an aromatic 5-6 membered ring comprising one to four heteroatoms selected from oxygen, sulfur and nitrogen, or a bicyclic aromatic group containing a 5-6 membered ring comprising one to four heteroatoms selected from oxygen, sulfur and nitrogen fused with a benzene ring or with a 5-6 membered ring comprising one to four heteroatoms selected from oxygen, sulfur and nitrogen, wherein the heteroaryl is optionally substituted by one or more substituents selected from halogen, amino, hydroxy, nitro, cyano, COOH, CONH2, Ci-6alkylaminocarbonyl, di-(Ci-6alkyl)aminocarbonyl, trifluoromethyl, Chalky!, Ci-6alkoxy, difluoromethoxy, trifluoromethoxy, cyclo- C3-i2alkoxy, phenyl, pyridyl, thiazolyl, pyrazolyl, phenoxy, pyridyloxy, thiazolyloxy, pyrazolyloxy,
Figure imgf000110_0001
pyridyl-Ci-6alkoxy, thiazolyl-Ci-6alkoxy, pyrazolyl-Ci-6alkoxy, amino-Ci-6alkyl, hydroxy-Ci-6alkyl, carbamoyl-Ci-6alkyl, hydroxy-Ci-6alkoxy, Ci-6alkoxycarbonyl, Ci-6alkylamino, cyclo-Cs-^alkylamino, phenylamino, pyridylamino, thiazolylamino, pyrazolylamino, phenyl- Ci-6alkylamino, pyridyl-Ci-6alkylannino, thiazolyl-Ci-6alkylamino, pyrazolyl- Ci-6alkylamino, hydroxy-Ci-6alkylamino, di-(Ci-6alkyl)amino, acylamino, Ci-ealkylannino-Ci-ealkoxy, dKCi-ealkylJannino-Ci-ealkoxy, Ci-6alkylsulfonylamino, Ci-6alkyl-aminosulfonyl, di-(Ci-6alkyl)aminosulfonyl, Ci-6alkylaminocarbonyl- Ci-6alkyl, and di-(Ci-6alkyl)aminocarbonyl-Ci-6alkyl; and optical isomers, polymorphs, analogs, derivatives, prodrugs, and pharmaceutically- acceptable acid and base addition salts and hydrates and solvates thereof.
2. The compound as claimed in Claim 1 , wherein R4 represents hydrogen, Chalky!, arylcarbonyl, Ci-6alkoxy-Ci-6alkyl, or aryl-Ci-6alkyl.
3. The compound as claimed in Claim 1 or Claim 2, wherein R5 represents hydrogen, -C(O)-R6, or -Y-C(O)-R7.
4. The compound as claimed in Claim 3, wherein R6 represents Chalky!, aryl,
heteroaryl, aryl -Chalky!, heteroaryl-Ci-6alkyl, or -NR8R9, wherein R8 represents hydrogen or Chalky! and R9 represents Chalky!, aryl, heteroaryl, aryl -Chalky I, or heteroaryl-Ci-6alkyl.
5. The compound as claimed in Claim 3, wherein R7 represents -NR10R1 1.
6. The compound as claimed in Claim 5, wherein R10 represents hydrogen or
Ci-6alkyl and R1 1 represents aryl, heteroaryl, aryl -Chalky!, or heteroaryl-Ci-6alkyl .
7. The compound as claimed in any preceding claim, wherein R1 represents halogen, R2 represents hydrogen, and R3 represents hydrogen or halogen.
8. The compound as claimed in Claim 7, wherein R1 represents chloro, R2 represents hydrogen, and R3 represents hydrogen or chloro .
9. The compound as claimed in any of Claims 1 to 3 or 5 to 8, wherein Y represents -CH(R12)-, wherein R12 represents hydrogen, Chalky! or Ci-6alkoxy-Ci-6alkyl .
10. The compound as claimed in Claim 1 , which is selected from:
4-Amino-5,7-dichloronaphthalene-2-carboxylic acid,
4-Benzoylamino-5,7-dichloro-naphthalene-2-carboxylic acid,
5,7-Dichloro-4-phenylacetylamino-naphthalene-2-carboxylic acid,
5,7-Dichloro-4-(phenylcarbamoylmethyl-amino)-naphthalene-2-carboxylic acid, 4-[(Benzylcarbamoyl-methyl)-amino]-5,7-dichloro-naphthalene-2-carboxylic acid, 5,7-Dichloro-4-({[(pyridin-2-ylmethyl)-carbamoyl]-methyl}-amino)-naphthalene-2- carboxylic acid,
5,7-Dichloro-4-({[(pyridin-3-ylmethyl)-carbamoyl]-methyl}-amino)-naphthalene-2- carboxylic acid,
5,7-Dichloro-4-[(pyridin-3-ylcarbamoylmethyl)-amino]-naphthalene-2-carboxylic acid,
5,7-Dichloro-4-({[(thiazol-2-ylmethyl)-carbamoyl]-methyl}-amino)-naphthalene-2- carboxylic acid,
5,7-Dichloro-4-({[(pyrimidin-4-ylmethyl)-carbamoyl]-methyl}-amino)-naphthalene- 2-carboxylic acid,
4-(Benzoyl-methyl-amino)-5,7-dichloro-naphthalene-2-carboxylic acid,
5,7-Dichloro-4-(3-phenyl-ureido)-naphthalene-2-carboxylic acid,
4-(3-Benzylureido)-5,7-dichloronaphthalene-2-carboxylic acid,
5,7-Dichloro-4-(methylphenylacetylamino)-naphthalene-2-carboxylic acid, 5,7-Dichloro-4-(3-phenylpropionylamino)-naphthalene-2-carboxylic acid,
5,7-Dichloro-4-(4-phenylbutyrylamino)-naphthalene-2-carboxylic acid,
5,7-Dichloro-4-dibenzoylamino-naphthalene-2-carboxylic acid, 4-(Benzoyl-propyl-amino)-5,7-dichloro-naphthalene-2-carboxylic acid,
4-(Benzoyl-ethyl-amino)-5,7-dichloro-naphthalene-2-carboxylic acid,
5,7-Dichloro-4-[(pyridine-4-carbonyl)-annino]-naphthalene-2-carboxylic acid, 5,7-Dichloro-4-[(pyridine-3-carbonyl)-annino]-naphthalene-2-carboxylic acid, 4-[Benzoyl-(methoxymethyl)-amino]-5,7-dichloro-naphthalene-2-carboxylic acid, 5,7-Dichloro-4-[methyl-(pyridine-3-carbonyl)-amino]-naphthalene-2-carboxylic acid,
5,7-Dichloro-4-[methyl-(pyridine-4-carbonyl)-amino]-naphthalene-2- carboxylic acid,
4-(Benzoyl-benzyl-amino)-5,7-dichloro-naphthalene-2-carboxylic acid,
5,7-Dichloro-4-(2-pyridin-2-yl-acetylamino)-naphthalene-2-carboxylic acid, 4-[Benzoyl-(3-methoxy-benzyl)-amino]-5,7-dichloro-naphthalene-2-carboxylic acid,
5,7-Dichloro-4-(2-pyridin-3-yl-acetylamino)-naphthalene-2-carboxylic acid, 5,7-Dichloro-4-(2-pyridin-4-yl-acetylamino)-naphthalene-2-carboxylic acid,
1 - [(Benzylcarbamoyl-methyl)-methyl-amino]-6,8-dichloro-isoquinoline-3- carboxylic acid,
5,7-Dichloro-4-(2-thiazol-4-yl-acetylamino)-naphthalene-2-carboxylic acid, 5,7-Dichloro-4-[(pyridine-2-carbonyl)-amino]-naphthalene-2-carboxylic acid, 5,7-Dichloro-4-[methyl-(pyridine-2-carbonyl)-amino]-naphthalene-2-carboxylic acid,
5,7-Dichloro-4-(methyl-{[(pyridin-3-ylmethyl)-carbamoyl]-methyl}-amino naphthalene-2-carboxylic acid,
5,7-Dichloro-4-(methyl-{[(pyrimidin-5-ylmethyl)-carbamoyl]-methyl}-am
naphthalene-2-carboxylic acid,
5,7-Dichloro-4-(methyl-{[(pyridin-2-ylmethyl)-carbamoyl]-methyl}-amino)^ naphthalene-2-carboxylic acid,
5,7-Dichloro-4-({[(pyrimidin-5-ylmethyl)-carbamoyl]-methyl}-amino)-n
2- carboxylic acid,
5,7-Dichloro-4-{[(methyl-pyridin-2-ylmethyl-carbamoyl)-methyl]-amino}- naphthalene-2-carboxylic acid, 5,7-Dichloro-4-{methyl-[(methyl-pyridin-2-ylmethyl-carbamoyl)-methyl]-ami naphthalene-2-carboxylic acid,
5,7-Dichloro-4-{[(methyl-pyridin-3-ylmethyl-carbamoyl)-methyl]-amino}- naphthalene-2-carboxylic acid,
5,7-Dichloro-4-{methyl-[(methyl-pyridin-3-ylmethyl-carbamoyl)-methyl]-amino}^ naphthalene-2-carboxylic acid,
5,7-Dichloro-4-(methyl-{[(pyridin-4-ylmethyl)-carbamoyl]-methyl}-amino)- naphthalene-2-carboxylic acid,
4-[Benzoyl-(3-methoxy-propyl)-annino]-5,7-dichloro-naphthalene-2-carboxylic acid,
5.7- Dichloro-4-({[(pyridin-4-ylmethyl)-ca^
carboxylic acid,
1 -((2-(Benzylamino)-2-oxoethyl)amino)-6-chloroisoquinoline-3-carboxylic acid,
1 -((2-(Benzylamino)-2-oxoethyl)amino)-6,8-dichloroisoquinoline-3-carboxylic acid,
6.8- Dichloro-1 -((2-oxo-2-((pyridin-3-ylmethyl)amino)ethyl)amino)isoquinoline-3- carboxylic acid,
6,8-Dichloro-1 -((2-oxo-2-((pyridin-2-ylmethyl)amino)ethyl)amino)isoquinoline-3- carboxylic acid,
5,7-Dichloro-4-(methyl(2-oxo-2-((pyrimidin-2-ylmethyl)amino)ethyl)amino)-2- naphthoic acid,
5,7-Dichloro-4-(N-(3-methoxybenzyl)acetannido)-2-naphthoic acid,
5,7-Dichloro-4-(methyl(2-oxo-2-((pyridazin-4-ylmethyl)amino)ethyl)amino)-2- naphthoic acid,
5,7-Dichloro-4-(methyl(2-oxo-2-((pyridazin-3-ylmethyl)amino)ethyl)amino)-2- naphthoic acid,
5,7-Dichloro-4-(methyl(2-oxo-2-((thiazol-2-ylmethyl)amino)ethyl)amino)-2- naphthoic acid,
5.7- Dichloro-4-(methyl(2-(methyl(pyridin-4-ylmethyl)amino)-2-oxoethyl)amino)-2 naphthoic acid,
6.8- Dichloro-1 -(methyl(2-oxo-2-((pyridin-3- ylmethyl)annino)ethyl)annino)isoquinoline-3-carboxylic acid, 5,7-Dichloro-4-((2-(methyl(pyridin-4-ylmethyl)amino)-2-oxoethyl)am naphthoic acid,
5,7-Dichloro-4-(methyl(2-(methyl(thiazol-2-ylmethyl)amino)-2-oxoethyl)amino)-2- naphthoic acid,
5,7-Dichloro-4-(N-methylthiazole-4-carboxannido)-2-naphthoic acid,
5,7-dichloro-4-(methyl(2-oxo-2-((pyrazin-2-ylmethyl)amino)ethyl)amino)-2- naphthoic acid,
5,7-Dichloro-4-(5-hydroxy-N-methylpicolinannido)-2-naphthoic acid,
5,7-Dichloro-4-(N-methylthiazole-2-carboxannido)-2-naphthoic acid,
5,7-Dichloro-4-(N-methylpyrazine-2-carboxannido)-2-naphthoic acid,
5,7-Dichloro-4-(N-(4-methoxybenzyl)benzannido)-2-naphthoic acid,
5,7-Dichloro-4-(N-methylpyrinnidine-2-carboxannido)-2-naphthoic acid,
5,7-Dichloro-4-(N-methylpyrinnidine-4-carboxannido)-2-naphthoic acid, and optical isomers, polymorphs, analogs, derivatives, prodrugs, and
pharmaceutically-acceptable acid and base addition salts, hydrates, and solvates thereof.
1 1 . A pharmaceutical composition comprising as active ingredient a compound as claimed in any preceding claim, optionally together with one or more
pharmaceutically acceptable excipients.
12. A compound as claimed in any of Claims 1 to 10 for use in therapy.
13. A compound as claimed in any of Claims 1 to 10 for use in the prevention and/or treatment of a condition selected from: pain, including acute pain, chronic pain, allodynia, hyperalgesia, visceral pain, phantom pain, post-operative pain, neuropathic pain, peripheral neuropathy including, for example peripheral neuropathy induced by nociception, inflammation, ischemia, viral infection (HZV), traumatic and other mechanical nerve injury, cancer, chemotherapy induced pain, diabetes mellitus, HIV infection, fibromyalgia, trigeminus neuralgia, inflammatory bowel diseases (IBD), irritative bowel syndrome (IBS), arthritis including rheumatoid arthritis, osteoarthritis (degenerative joint disease), multiple sclerosis (MS) and gout (metabolic arthritis); acute insults, including cerebral ischemia, cerebral infarct, brain oedema, anoxia, inner ear insult, inner ear insult in tinnitus, head or brain or spinal cord trauma, head or brain or spinal cord injuries, trauma, sound- or drug-induced inner ear insult, ischaemia resulting from cardiac arrest or stroke or bypass operations or transplants, acute pain, hypoxia, perinatal hypoxia, and ischaemia; chronic insults, such as neurodegenerative disorders, including Morbus Huntington, Alzheimer's disease Creutzfeld-Jakob's syndrome/disease, bovine spongiform encephalopathy (BSE) prion related infections, diseases involving mitochondrial dysfunction, diseases involving β-amyloid and/or tauopathy, Down's syndrome, motor neuron diseases, amyotrophic lateral sclerosis (ALS), olivoponto-cerebellar atrophy, Parkinson's disease, Neuronal Ceroid Lipofuscinosis, AIDS dementia complex, AIDS-related dementia, dementia related to HIV infections, HIV-1 encephalopathy, AIDS encephalopathy, Korsakoff syndrome, vascular dementia, and corticobasal degeneration; neurological disorders, including tinnitus, hearing loss, sound- or drug-induced tinnitus, haloperidol-induced dyskinesias, dopaminomimetic-induced dyskinesias, chorea, Huntington's chorea, athetosis, dystonia, stereotypy, ballism, tardive dyskinesias, tic disorder, spasmodic torticollis, blepharospasm, focal and generalized dystonia, nystagmus, Parkinson's dementia, mild cognitive impairment, cognitive deficits in various forms of mild cognitive impairment, cognitive deficits in various forms of dementia, dementia pugilistica, vascular and frontal lobe dementia, cognitive impairment, learning impairment, L-dopa-induced dykinesias, L-dopa-induced dykinesias in Parkinson's disease therapy, dyskinesias, dyskinesia in Huntington's disease, drug induced dyskinesias, neuroleptic-induced dyskinesias,
neurodegenerative cerebellar ataxias, centrally induced neuropathic pain, convulsions, epileptic convulsions, epilepsy, temporal lobe epilepsy, myoclonic epilepsy, tremor, dementia in Alzheimer's disease, dementia in Korsakoff syndrome, dementia, hereditary cerebellar ataxias, sleep disorders, movement disorders, essential tremor, muscle spasms, and spasticity;
psychological/psychiatric disorders, including generalized anxiety disorder, obsessive-compulsive disorder, panic disorder, posttraumatic stress disorder, social phobia, phobic disorders, substance-induced anxiety disorder, delusional disorder, schizoaffective disorder, schizophreniform disorder, substance-induced psychotic disorder, delirium, post-operative cognitive deficit (POCD), cognitive impairment, learning impairment, anxiety disorders, panic disorders, anxiety and panic disorders, social anxiety disorder (SAD), attention deficit hyperactivity disorder (ADHD), attention deficit syndrome (ADS), dementia, posttraumatic stress disorder (PTSD), schizophrenia, positive or cognitive or negative symptoms of schizophrenia, major depressive disorder, major depression, depression, bipolar manic-depressive disorder, sleep disorders, agoraphobia, bulimia nervosa, eating disorders, obesity, obesity-related disorders, obesity abuse, food addiction, binge eating disorders, and hyperactivity in children; drug/alcohol abuse, including craving (e.g., for drugs of abuse), abuse, addiction, nicotine addiction, nicotine abuse, alcohol addiction, alcohol abuse, opiate addiction, opiate abuse, cocaine addiction, cocaine abuse, amphetamine addiction, and amphetamine abuse; skin diseases, including atopic dermatitis, itching, skin lesions induced by severe itching or atopic dermatitis, systemic sclerosis, pruritic conditions, and pruritis; diseases of the gastro-intestinal tract and metabolic diseases, including diarrhoea, hepatic encephalopathy, hypoglycaemia, gastroesophageal reflux disease
(GERD), gastrointestinal dysfunction, lower esophageal sphincter (LES) disease, functional gastrointestinal disorders, dyspepsia, vomiting, urinary incontinence, and regurgitation; diseases of the immune system, including Sjogren's syndrome, systemic lupus erythematosus, and multiple sclerosis (MS); eye diseases, including eye injuries, eye diseases, eye disorders, glaucoma, retinopathy, and macular degeneration; diseases of the respiratory tract, including respiratory tract infection, chronic laryngitis, asthma, reflux-related asthma, and lung disease; migraine; autism; restless leg syndrome (RLS); Tourette syndrome; micturition disorders; neuromuscular disorder in the lower urinary tract; and drug tolerance to opioids.
14. A compound as claimed in Claim 13, wherein the condition is selected from: pain, acute pain, chronic pain, allodynia, hyperalgesia, visceral pain, phantom pain, post-operative pain, neuropathic pain, peripheral neuropathy including, for example peripheral neuropathy induced by nociception, inflammation, ischemia, viral infection (HZV), traumatic and other mechanical nerve injury, cancer, chemotherapy induced pain, diabetes mellitus, HIV infection, fibromyalgia, trigeminus neuralgia, inflammatory bowel diseases (IBD), irritative bowel syndrome (IBS), arthritis including rheumatoid arthritis, osteoarthritis (degenerative joint disease), multiple sclerosis (MS) and gout (metabolic arthritis).
15. Use of a compound as claimed in any of Claims 1 to 10 for the manufacture of a medicament for the treatment or prevention of a condition selected from: pain, including acute pain, chronic pain, allodynia, hyperalgesia, visceral pain, phantom pain, post-operative pain, neuropathic pain, peripheral neuropathy including, for example peripheral neuropathy induced by nociception, inflammation, ischemia, viral infection (HZV), traumatic and other mechanical nerve injury, cancer, chemotherapy induced pain, diabetes mellitus, HIV infection, fibromyalgia, trigeminus neuralgia, inflammatory bowel diseases (IBD), irritative bowel syndrome (IBS), arthritis including rheumatoid arthritis, osteoarthritis (degenerative joint disease), multiple sclerosis (MS) and gout (metabolic arthritis); acute insults, including cerebral ischemia, cerebral infarct, brain oedema, anoxia, inner ear insult, inner ear insult in tinnitus, head or brain or spinal cord trauma, head or brain or spinal cord injuries, trauma, sound- or drug-induced inner ear insult, ischaemia resulting from cardiac arrest or stroke or bypass operations or transplants, acute pain, hypoxia, perinatal hypoxia, and ischaemia; chronic insults, such as neurodegenerative disorders, including Morbus Huntington, Alzheimer's disease Creutzfeld-Jakob's syndrome/disease, bovine spongiform encephalopathy (BSE) prion related infections, diseases involving mitochondrial dysfunction, diseases involving β-amyloid and/or tauopathy, Down's syndrome, motor neuron diseases, amyotrophic lateral sclerosis (ALS), olivopontocerebellar atrophy, Parkinson's disease, Neuronal Ceroid Lipofuscinosis, AIDS dementia complex, AIDS-related dementia, dementia related to HIV infections, HIV-1 encephalopathy, AIDS encephalopathy, Korsakoff syndrome, vascular dementia, and corticobasal degeneration; neurological disorders, including tinnitus, hearing loss, sound- or drug-induced tinnitus, haloperidol-induced dyskinesias, dopaminomimetic-induced dyskinesias, chorea, Huntington's chorea, athetosis, dystonia, stereotypy, ballism, tardive dyskinesias, tic disorder, spasmodic torticollis, blepharospasm, focal and generalized dystonia, nystagmus, Parkinson's dementia, mild cognitive
impairment, cognitive deficits in various forms of mild cognitive impairment, cognitive deficits in various forms of dementia, dementia pugilistica, vascular and frontal lobe dementia, cognitive impairment, learning impairment, L-dopa-induced dykinesias, L-dopa-induced dykinesias in Parkinson's disease therapy,
dyskinesias, dyskinesia in Huntington's disease, drug induced dyskinesias, neuroleptic-induced dyskinesias, neurodegenerative cerebellar ataxias, centrally induced neuropathic pain, convulsions, epileptic convulsions, epilepsy, temporal lobe epilepsy, myoclonic epilepsy, tremor, dementia in Alzheimer's disease, dementia in Korsakoff syndrome, dementia, hereditary cerebellar ataxias, sleep disorders, movement disorders, essential tremor, muscle spasms, and spasticity; psychological/psychiatric disorders, including generalized anxiety disorder, obsessive-compulsive disorder, panic disorder, posttraumatic stress disorder, social phobia, phobic disorders, substance-induced anxiety disorder, delusional disorder, schizoaffective disorder, schizophreniform disorder, substance-induced psychotic disorder, delirium, post-operative cognitive deficit (POCD), cognitive impairment, learning impairment, anxiety disorders, panic disorders, anxiety and panic disorders, social anxiety disorder (SAD), attention deficit hyperactivity disorder (ADHD), attention deficit syndrome (ADS), dementia, posttraumatic stress disorder (PTSD), schizophrenia, positive or cognitive or negative symptoms of schizophrenia, major depressive disorder, major depression, depression, bipolar manic-depressive disorder, sleep disorders, agoraphobia, bulimia nervosa, eating disorders, obesity, obesity-related disorders, obesity abuse, food addiction, binge eating disorders, and hyperactivity in children; drug/alcohol abuse, including craving (e.g., for drugs of abuse), abuse, addiction, nicotine addiction, nicotine abuse, alcohol addiction, alcohol abuse, opiate addiction, opiate abuse, cocaine addiction, cocaine abuse, amphetamine addiction, and amphetamine abuse; skin diseases, including atopic dermatitis, itching, skin lesions induced by severe itching or atopic dermatitis, systemic sclerosis, pruritic conditions, and pruritis; diseases of the gastro-intestinal tract and metabolic diseases, including diarrhoea, hepatic encephalopathy, hypoglycaemia, gastroesophageal reflux disease
(GERD), gastrointestinal dysfunction, lower esophageal sphincter (LES) disease, functional gastrointestinal disorders, dyspepsia, vomiting, urinary incontinence, and regurgitation; diseases of the immune system, including Sjogren's syndrome, systemic lupus erythematosus, and multiple sclerosis (MS); eye diseases, including eye injuries, eye diseases, eye disorders, glaucoma, retinopathy, and macular degeneration; diseases of the respiratory tract, including respiratory tract infection, chronic laryngitis, asthma, reflux-related asthma, and lung disease; migraine; autism; restless leg syndrome (RLS); Tourette syndrome; micturition disorders; neuromuscular disorder in the lower urinary tract; and drug tolerance to opioids.
16. Use as claimed in Claim 15, wherein the medicament is manufactured for the
treatment or prevention of a condition selected from: pain, acute pain, chronic pain, allodynia, hyperalgesia, visceral pain, phantom pain, post-operative pain, neuropathic pain, peripheral neuropathy including, for example peripheral neuropathy induced by nociception, inflammation, ischemia, viral infection (HZV), traumatic and other mechanical nerve injury, cancer, chemotherapy induced pain, diabetes mellitus, HIV infection, fibromyalgia, trigeminus neuralgia, inflammatory bowel diseases (IBD), irritative bowel syndrome (IBS), arthritis including
rheumatoid arthritis, osteoarthritis (degenerative joint disease), multiple sclerosis (MS) and gout (metabolic arthritis).
17. A method of treating or preventing a condition selected from pain, including acute pain, chronic pain, allodynia, hyperalgesia, visceral pain, phantom pain, postoperative pain, neuropathic pain, peripheral neuropathy including, for example peripheral neuropathy induced by nociception, inflammation, ischemia, viral infection (HZV), traumatic and other mechanical nerve injury, cancer,
chemotherapy induced pain, diabetes mellitus, HIV infection, fibromyalgia, trigeminus neuralgia, inflammatory bowel diseases (IBD), irritative bowel syndrome (IBS), arthritis including rheumatoid arthritis, osteoarthritis (degenerative joint disease), multiple sclerosis (MS) and gout (metabolic arthritis); acute insults, including cerebral ischemia, cerebral infarct, brain oedema, anoxia, inner ear insult, inner ear insult in tinnitus, head or brain or spinal cord trauma, head or brain or spinal cord injuries, trauma, sound- or drug-induced inner ear insult, ischaemia resulting from cardiac arrest or stroke or bypass operations or transplants, acute pain, hypoxia, perinatal hypoxia, and ischaemia; chronic insults, such as neurodegenerative disorders, including Morbus Huntington, Alzheimer's disease Creutzfeld-Jakob's syndrome/disease, bovine spongiform encephalopathy (BSE) prion related infections, diseases involving mitochondrial dysfunction, diseases involving β-amyloid and/or tauopathy, Down's syndrome, motor neuron diseases, amyotrophic lateral sclerosis (ALS), olivopontocerebellar atrophy, Parkinson's disease, Neuronal Ceroid Lipofuscinosis, AIDS dementia complex, AIDS-related dementia, dementia related to HIV infections, HIV-1 encephalopathy, AIDS encephalopathy, Korsakoff syndrome, vascular dementia, and corticobasal degeneration; neurological disorders, including tinnitus, hearing loss, sound- or drug-induced tinnitus, haloperidol-induced dyskinesias, dopaminomimetic-induced dyskinesias, chorea, Huntington's chorea, athetosis, dystonia, stereotypy, ballisnn, tardive dyskinesias, tic disorder, spasmodic torticollis, blepharospasm, focal and generalized dystonia, nystagmus, Parkinson's dementia, mild cognitive
impairment, cognitive deficits in various forms of mild cognitive impairment, cognitive deficits in various forms of dementia, dementia pugilistica, vascular and frontal lobe dementia, cognitive impairment, learning impairment, L-dopa-induced dykinesias, L-dopa-induced dykinesias in Parkinson's disease therapy,
dyskinesias, dyskinesia in Huntington's disease, drug induced dyskinesias, neuroleptic-induced dyskinesias, neurodegenerative cerebellar ataxias, centrally induced neuropathic pain, convulsions, epileptic convulsions, epilepsy, temporal lobe epilepsy, myoclonic epilepsy, tremor, dementia in Alzheimer's disease, dementia in Korsakoff syndrome, dementia, hereditary cerebellar ataxias, sleep disorders, movement disorders, essential tremor, muscle spasms, and spasticity; psychological/psychiatric disorders, including generalized anxiety disorder, obsessive-compulsive disorder, panic disorder, posttraumatic stress disorder, social phobia, phobic disorders, substance-induced anxiety disorder, delusional disorder, schizoaffective disorder, schizophreniform disorder, substance-induced psychotic disorder, delirium, post-operative cognitive deficit (POCD), cognitive impairment, learning impairment, anxiety disorders, panic disorders, anxiety and panic disorders, social anxiety disorder (SAD), attention deficit hyperactivity disorder (ADHD), attention deficit syndrome (ADS), dementia, posttraumatic stress disorder (PTSD), schizophrenia, positive or cognitive or negative symptoms of schizophrenia, major depressive disorder, major depression, depression, bipolar manic-depressive disorder, sleep disorders, agoraphobia, bulimia nervosa, eating disorders, obesity, obesity-related disorders, obesity abuse, food addiction, binge eating disorders, and hyperactivity in children; drug/alcohol abuse, including craving (e.g., for drugs of abuse), abuse, addiction, nicotine addiction, nicotine abuse, alcohol addiction, alcohol abuse, opiate addiction, opiate abuse, cocaine addiction, cocaine abuse, amphetamine addiction, and amphetamine abuse; skin diseases, including atopic dermatitis, itching, skin lesions induced by severe itching or atopic dermatitis, systemic sclerosis, pruritic conditions, and pruritis; diseases of the gastro-intestinal tract and metabolic diseases, including diarrhoea, hepatic encephalopathy, hypoglycaemia, gastroesophageal reflux disease
(GERD), gastrointestinal dysfunction, lower esophageal sphincter (LES) disease, functional gastrointestinal disorders, dyspepsia, vomiting, urinary incontinence, and regurgitation; diseases of the immune system, including Sjogren's syndrome, systemic lupus erythematosus, and multiple sclerosis (MS); eye diseases, including eye injuries, eye diseases, eye disorders, glaucoma, retinopathy, and macular degeneration; diseases of the respiratory tract, including respiratory tract infection, chronic laryngitis, asthma, reflux-related asthma, and lung disease; migraine; autism; restless leg syndrome (RLS); Tourette syndrome; micturition disorders; neuromuscular disorder in the lower urinary tract; and drug tolerance to opioids, such method comprising the step of administering to a living animal, including a human, a therapeutically effective amount of a compound of Claim 1 .
18. The method of Claim 18, wherein the condition is selected from pain, acute pain, chronic pain, allodynia, hyperalgesia, visceral pain, phantom pain, post-operative pain, neuropathic pain, peripheral neuropathy including, for example peripheral neuropathy induced by nociception, inflammation, ischemia, viral infection (HZV), traumatic and other mechanical nerve injury, cancer, chemotherapy induced pain, diabetes mellitus, HIV infection, fibromyalgia, trigeminus neuralgia, inflammatory bowel diseases (IBD), irritative bowel syndrome (IBS), arthritis including rheumatoid arthritis, osteoarthritis (degenerative joint disease), multiple sclerosis (MS) and gout (metabolic arthritis).
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