Patent EA-003946-B1 (EA)
Title: Bicyclo[2.2.1]heptanes and related compounds
Inventor: CHENARD BERTRAND LEO
IPC: A61K31/424
Filed: 1999-03-04
Abstract: 1. A compound of the formula wherein n is 0-6, X isCH2, CH2CH2 or oxygen, Z isCHR2 or NR2 and R<1> and R<2> are selected independently from hydrogen,(C1-C6) alkyl, aryl and heteroaryl, wherein said aryl is selected from phenyl and naphthyl and said heteroaryl is selected from 5 and 6-membered aromatic heterocyclic rings that contain from one to four heteroatoms selected, independently, from nitrogen, oxygen and sulfur, and wherein said aryl and heteroaryl moieties can optionally be substituted with one or more substituents that are selected, independently, from halogen, -S (C1-C6) alkyl, -S (O) (C1-C6) alkyl, -S(O)2(C1-C6) alkyl, (C1-C6) alkyl optionally substituted with from one to seven fluorine atoms, (C1-C6) alkoxy optionally substituted with from one to seven fluorine atoms, amino, nitro, cyano, carboxy, -CO2(C1-C6) alkyl, (C1-C6) alkylamino, di-[(C1-C6)alkyl] amino phenoxy, anilino and phenylthio, with the proviso that none of said heteroaryl moieties contains more than one ring oxygen atom or more than one ring sulfur atom, or a pharmaceutical acceptable salt of such compound. 2. A compound according to claim 1, wherein Z is CH2. 3. A compound according to claim 1, wherein R<1> is selected from the group consisting of hydrogen, unsubstituted phenyl, and phenyl substituted with one or two substituents. 4. A compound according to claim 1, wherein n is zero, 1 or 2. 5. A compound according to claim 1, wherein X is CH2. 6. A compound according to claim 1 selected from the group consisting of: 2-(endo)-amino-bicyclo[2.2.1]heptane-2-(exo)-6-(exo)-dicarboxylic acid; (+)-2-(endo)-aminobicyclo[2.2.1]heptane-2-(exo)-6-(exo)-dicarboxylic acid; (-)-2-(endo)-aminobicyclo[2.2.1]heptane-2-(exo)-6-(exo)-dicarboxylic acid ; 2-(endo)-benzylamino-bicyclo[2.2.1]heptane-2-(exo)-6-(exo)-dicarboxylic acid and 2-(endo)-phenylethylamino-bicyclo[2.2.1]heptane-2-(exo)-6-(exo)-dicarboxylic acid. 7. A pharmaceutical composition for treating a disorder or condition selected from brain stroke, cerebral ischemia, spinal cord trauma, head trauma, Alzheimer's Disease, Huntington's Chorea, amyotrophic lateral sclerosis, AIDS-induced dementia, muscular spasms, migraine headaches, urinary incontinence, psychosis, convulsions, perinatal hypoxia, hypoxia, cardiac arrest, hypoglycemicneuronal damage, opiate tolerance and withdrawal, chemical dependencies and addictions, ocular damage and retinopathy, idiopathic and drug induced Parkinson's Disease, anxiety, including panic disorder, General Anxiety Disorder, Post Traumatic Stress Syndrome, simple and social phobias; schizophrenia, depression, bipolar disorder, obsessive-compulsive disorder, Tourette's syndrome, emesis, brain edema, chronic and acute pain, tardive dyskinesia and cerebral deficits subsequent to cardiac bypass surgery and grafting in a mammal, which can be effected or facilitated by modulating glutamate neurotransmission in a mammal, comprising an amount of a compound according to claim 1 that is effective in treating such disorder or condition and a pharmaceutically acceptable carrier. 8. A method for treating a disorder or condition selected from brain stroke, cerebral ischemia, spinal cord trauma, head trauma, Alzheimer's Disease, Huntington's Chorea, amyotrophic lateral sclerosis, AIDS-induced dementia, muscular spasms, migraine headaches, urinary incontinence, psychosis, convulsions, perinatal hypoxia, hypoxia, cardiac arrest, hypoglycemicneuronal damage, opiate tolerance and withdrawal, ocular damage and retinopathy, idiopathic and drug induced Parkinson's Disease, anxiety, including panic disorder, General Anxiety disorder, Post Traumatic Stress Syndrome, simple and social phobias, schizophrenia, depression, bipolar disorder, obsessive-compulsive disorder, Tourette's syndrome, emesis, brain edema, chronic and acute pain, tardive dyskinesia and cerebral deficits subsequent to cardiac bypass surgery and grafting in a mammal, which can be effected or facilitated by modulating glutamate neurotransmission comprising administering to a mammal requiring such treatment an amount of a compound according to claim 1 that is effective in treating such condition and a pharmaceutically acceptable carrier. 9. A pharmaceutical composition for treating a disorder or condition selected from stroke, cerebral ischemia, spinal cord trauma, head trauma, Alzheimer's Disease, Huntington's Chorea, amyotrophiclateral lateral sclerosis, AIDS-induced dementia, muscular spasms, migraine headaches, urinary incontinence, psychosis, convulsions, perinatal hypoxia, hypoxia, cardiac arrest, hypoglycemic neuronal damage, chemical depencies and addictions, ocular damage and retinopathy, idiopathic and drug induced Parkinson's Disease, anxiety, including panic disorder, General Anxiety Disorder, Post Traumatic Stress Syndrome, simple and social phobias, schizophrenia, depression, bipolar disorder, obsessive-compulsive disorder, Tourette's syndrome, emesis, brain edema, chronic and acute pain, tardive dyskinesia and cerebral deficits subsequent to cardiac bypass surgery and grafting, in a mammal, the treatment of which can be effected or facilitated by modulating glutamate neurotransmission comprising (a) a compound of the formula 1, or a pharmaceutically acceptable salt thereof, b) a serotonin reuptake inhibitor or a serotonin-1A (5HT1A) receptor ligand, or a pharmaceutically acceptable salt of such inhibitor or ligand, and (c) a pharmaceutically acceptable carrier, wherein the amounts of the compound of formula I and the serotonin reuptake inhibitor or 5HT1A receptor ligand that are contained in such composition are such that the combination of the two active ingredients is effective in treating such disorder or condition. 10. A method for treating a disorder or condition selected from stroke, cerebral ischemia, spinal cord trauma, head trauma, Alzheimer's Disease, Huntington's Chorea, amyotrophic lateral sclerosis, AIDS-induced dementia, muscular spasms, migraine headaches, urinary incontinence, psychosis, convulsions, perinatal hypoxia, hypoxia, cardiac arrest, hypoglycemic neuronal damage, opiate tolerance and withdrawal, ocular damage and retinopathy, idiopathic and drug induced Parkinson's Disease, anxiety, including panic disorder, General Anxiety Disorder, Post Traumatic Stress Syndrome, simple phobias, and social phobia; schizophrenia, depression, bipolar disorder, obsessive-compulsive disorder, Tourette's syndrome, emesis, brain edema, chronic and acute pain, tardive dyskinesia and cerebral deficits subsequent to cardiac bypass surgery and grafting in a mammal, which can be effected or facilitated by modulating glutamate neurotransmission comprising administering to a mammal comprising administering to a mammal requiring such treatment (a) a compound according to claim 1 or a pharmaceutically acceptable salt thereof and (b) a serotonin reuptake inhibitor or a serotonin -1A (5HT1A) receptor ligand or a pharmaceutically acceptable salt of such inhibitor or ligand, wherein the compound according to formula I and a serotonin reuptake inhibitor or a serotonin -1A (5HT1A) receptor ligand that are used within such method are such that the combination of the two active ingredients is effective in treating such disorder or condition. 11. A pharmaceutical composition according to claim 9, wherein (b) is a serotonin reuptake inhibitor selected from sertraline, fluoxetine, fluvoxamine, paroxetine, citalopram, fenfluramine, and femoxetine. 12. A method according to claim 10, wherein (b) is a serotonin reuptake inhibitor selected from sertraline, fluoxetine, fluvoxamine, paroxetine, citalopram, fenfluramine, and femoxetine. 13. A compound of the formula wherein n is 0-6, X is CH2, CH2CH2 or oxygen, Z is CHR<2> or NR<2> and R<1> and R<2> are selected independently from hydrogen, (C1-C6)alkyl, aryl and heteroaryl, wherein said aryl is selected from phenyl and naphthyl and said heteroaryl is selected from 5 and 6-membered aromatic heterocyclic rings that contain from one to four heteroatoms selected, independently, from nitrogen, oxygen and sulfur, and wherein said aryl and heteroaryl moieties can optionally be substituted with one or more substituents that are selected, independently, from halogen, -S(C1-C6)alkyl, -S(O)(C1-C6)alkyl, -S(O)2(C1-C6)alkyl, (C1-C6)alkyl optionally substituted with from one to seven fluorine atoms, (C1-C6)alkoxy optionally substituted with from one to seven fluorine atoms, amino, nitro, cyano, carboxy,-CO2(C1-C6)alkyl, (C1-C6)alkylamino, di-[(C1-C6)alkyl] aminophenoxy, anilino and phenylthio, and R<7> is hydrogen, (C1-C6) alkyl or benzyl, with the proviso that none of said heteroaryl moieties contains more than one ring oxygen atom or more than one ring sulfur atom.