Patent EA-003099-B1 (EA)
Title: 3-(pyrido[1,2-a]pyrazinyl)benzioxazol derivatives as antidepressants
Inventor: BRIGHT GENE MICHAEL
IPC: C07D471/04
Filed: 1999-11-03
Abstract: 1. A compound of the formula:   wherein R<1>, R<2>, R<3> and R<4> are selected, independently, from hydrogen, (C1-C4) alkyl optionally substituted with from one to three fluorine atoms, (C1-C4) alkoxy optionally substituted with from one to three fluorine atoms, and (C1-C4) alkoxy- (C1-C4) alkyl wherein each of the alkyl moieties may optionally be substituted with from 1 to 3 fluorine atoms; and X is CH or N; or a pharmaceutically acceptable salt thereof. 2. The compound or salt according to claim 1, wherein the compound has an absolute stereochemistry of (7R,9aS)-trans or (7S, 9aS) -cis. 3. (7R, 9aS)-trans-[2-(5-Fluorobenzo [d] isoxazol-3-yl)-octahydro-pyrido[1,2-a]pyrazin-7-ylmethyl]-(5-fluoro-pyrimidin-2-yl)-amine; (7R, 9aS)-trans-[2-(5-Fluorobenzo[d]isoxazol-3-yl)-octahydro-pyrido[1,2-a]pyrazin-7-ylmethyl]-pyrimidin-2-yl)-amine; (7S, 9aS)-cis-[2-(5-Fluorobenzo[d]isoxazol-3-yl)-octahydro-pyrido[1,2-a]pyrazin-7-ylmethyl-(5-fluoro-pyridin-2-yl)-amine; (7S, 9aS)-cis-(2-Benzo[d]isoxazol-3-yl) -octahydro-pyrido [1,2-a] pyrazin-7-ylmethyl) -pyrimidin-2-yl-amine; (7S, 9aS)-cis-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido [1,2-a] pyrazin-7-ylmethyl)-(5-fluoro-pyrimidin-2-yl) amine; (7R, 9aS)-trans-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethyl)-(5-methyl-pyrimidin-2-yl)-amine; (7S,9aS)-cis-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido [1,2-a] pyrazin-7-ylmethyl)-(5-methyl-pyrimidin-2-yl) amine; (7R, 9aS)-trans-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethyl)-(5-chloro-pyrimidin-2-yl)-amine; (7S, 9aS)-cis-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethyl)-(5-chloro-pyrimidin-2-yl)-amine; (7R, 9aS)-trans-(5-Chloro-pyrirnidin-2-yl)-[2-(5fluoro-benzo[d]isoxazol-3-yl)octahydro-pyrido[1,2-a]pyrazin-7-ylmethyl]-amine; (7S, 9aS)-cis-(5-Chloro-pyrimidin-2-yl)-[2-(5-fluoro-benzo[d]isoxazol-3-yl) octahydro-pyrido [1,2-a] pyrazin-7-ylmethyl]-amine; (7R,9aS)-trans-[2-(5-Fluorobenzo[d]isoxazol-3-yl)-octahydro-pyrido[1,2-a]pyrazin-7-ylmethyl]-(5-methyl-pyrimidin-2-yl)-amine; (7S,9aS)-cis-[2-(5-Fluorobenzo[d]isoxazol-3-yl)-octahydro-pyrido[1,2-a]pyrazin-7-ylmethyl]-(5-methyl-pyrimidin-2-yl)-amine; (7R,9aS)-trans-(2-benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethyl)-(5-fluoro-pyridin-2-yl)-amine; (7S,9aS)-cis-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethyl)-(5-fluoro-pyridin-2-yl)-amine; (7R,9aS)-trans-[2-(5-Fluorobenzo[d]isoxazol-3-yl)-octahydro-pyrido[1,2-a]pyrazin-7-ylmethyl]-(5-fluoro-pyridin-2-yl)-amine; (7S,9aS)-cis-[2-(5-Fluorobenzo[d]isoxazol-3-yl)-octahydro-pyrido[1,2-a]pyrazin-7-ylmethyl]-(5-fluoro-pyridin-2-yl)-amine; (7R,9aS)-trans-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethyl)-(5-fluoro-3-methyl-pyridin-2-yl)-amine; (7S,9aS)-cis-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethyl)-(5-fluoro-3-methyl-pyridin-2-yl)-amine; (7R,9aS)-trans-[2-(5-Fluorobenzo[d]isoxazol-3-yl)-octahydro-pyrido[1,2-a]pyrazin-7-ylmethyl]-(pyridin-2-yl)-amine; (7R,9aS)-trans-[2-(5-Fluorobenzo[d]isoxazol-3-yl)-octahydro-pyrido[1,2-a]pyrazin-7-ylmethyl]-(5-fluoro-3-methyl-pyridin-2-yl)-amine; (7S, 9aS)-cis-[2-(5-Fluorobenzo[d]isoxazol-3-yl) octahydro-pyrido [1,2-a] pyrazin-7-ylmethyl]-(5-fluoro-3-methyl-pyridin-2-yl)-amine; (7R, 9aS)-trans-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethyl)-(5-fluoro-pyrimidin-2-yl)-amine. 4. A pharmaceutical composition for treating a disorder or condition selected from hypertension, depression, generalized anxiety disorder, phobias, posttraumatic stress syndrome, avoidant personality disorder, premature ejaculation, eating disorders, obesity, chemical dependencies, cluster headache, migraine, pain, Alzeimer's disease, obsessivecompulsive disorder, panic disorder, memory disorders, Parkinson's diseases, endocrine disorders, vasospasm, cerebellar ataxia, gastrointestinal tract disorders, negative symptoms of schizophrenia, premenstrual syndrome, fibromyalgia syndrome, stress incontinence, Tourette's syndrome, trichotillomania, kleptomania, male impotence, cancer, chronic paroxysmal hemicrania and headache in a mammal, comprising an amount of the compound or salt according to claim 1 that is effective in treating such disorder or condition, and a pharmaceutically acceptable carrier. 5. A pharmaceutical composition for treating a disorder or condition that can be treated by modulating serotonergic neurotransmission in a mammal, comprising an amount of the compound or salt according to claim 1 that is effective in treating such disorder or condition, and a pharmaceutically acceptable carrier. 6. A method for treating a disorder or condition selected from hypertension, depression, generalized anxiety disorder, phobias, posttraumatic stress syndrome, avoidant personality disorder, premature ejaculation, eating disorders, obesity, chemical dependencies, cluster headache, migraine, pain, Alzheimer's disease, obsessive-compulsive disorder, panic disorder, memory disorders, Parkinson's diseases, endocrine disorders, vasospasm, cerebellar ataxia, gastrointestinal tract disorders, negative symptoms of schizophrenia, premenstrual syndrome, fibromyalgia syndrome, stress incontinence, Tourette's syndrome, trichotillomania, kleptomania, male impotence, cancer, chronic paroxysmal hemicrania and headache in a mammal, comprising administering to a mammal in need of such treatment an amount of a compound according to claim 1 that is effective in treating such disorder or condition. 7. A method for treating a disorder or condition that can be treated or prevented by modulating serotonergic neurotransmission in a mammal, comprising administering to a mammal in need of such treatment an amount of a compound according to claim 1 that is effective in treating such disorder or condition. 8. A pharmaceutical composition for treating a disorder or condition selected from hypertension, depression, generalized anxiety disorder, phobias, posttraumatic stress syndrome, avoidant personality disorder, premature ejaculation, eating disorders, obesity, chemical dependencies, cluster headache, migraine, pain, Alzheimer's disease, obsessivecompulsive disorder, panic disorder, memory disorders, Parkinson's diseases, endocrine disorders, vasospasm, cerebellar ataxia, gastrointestinal tract disorders, negative symptoms of schizophrenia, premenstrual syndrome, fibromyalgia syndrome, stress incontinence, Tourette's syndrome, trichotillomania, kleptomania, male impotence, cancer, chronic paroxysmal hemicrania and headache in a mammal, comprising a serotonin receptor antagonizing or agonizing effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier. 9. A pharmaceutical composition for treating a disorder or condition that can be treated by modulating serotonergic neurotransmission in a mammal, comprising a serotonin receptor antagonizing or agonizing effective amount of a compound of according to claim 1 and a pharmaceutically acceptable carrier. 10. A method for treating a disorder or condition selected from hypertension, depression, generalized anxiety disorder, phobias, posttraumatic stress syndrome, avoidant personality disorder, sexual dysfunction, eating disorders, obesity, chemical dependencies, cluster headache, migraine, pain, Alzheimer's disease, obsessive-compulsive disorder, panic disorder, memory disorders, Parkinson's diseases, endocrine disorders, vasospasm, cerebellar ataxia, gastrointestinal tract disorders, negative symptoms of schizophrenia, premenstrual syndrome, fibromyalgia syndrome, stress incontinence, Tourette's syndrome, trichotillomania, kleptomania, male impotence, cancer, chronic paroxysmal hemicrania and headache in a mammal, comprising administering to a mammal requiring such treatment a serotonin 1A receptor antagonizing or agonizing effective amount, or a serotonin 1D receptor antagonizing effective amount, of a compound according to claim 1. 11. A method for treating a disorder or condition that can be treated by modulating serotonergic neurotransmission in a mammal, comprising administering to a mammal requiring such treatment a serotonin 1A receptor antagonizing or agonizing effective amount, or a serotonin 1D receptor antagonizing effective amount, of a compound according to claim 1. 12. A pharmaceutical composition for treating disorder or condition that can be treated or prevented by modulating serotonergic neurotransmission in a mammal, comprising: a) a pharmaceutically acceptable carrier; b) a compound of according to claim 1; and c) a 5-HT re-uptake inhibitor or a pharmaceutically acceptable salt thereof; wherein the amount of the active compounds are such that the combination is effective in treating such disorder or condition. 13. A method for treating a disorder or condition that can be treated by modulating serotonergic neurotransmission in a mammal, comprising administering to a mammal requiring such treatment or prevention: a) a compound according to claim 1; and b) a 5-HT re-uptake inhibitor or a pharmaceutically acceptable salt thereof; wherein the amounts of the active compounds are such that the combination is effective in treating such disorder or condition. 14. A pharmaceutical composition according to claim 12, wherein the 5-HT reuptake inhibitor is sertraline or a pharmaceutically acceptable salt thereof. 15. A method according to claim 13, wherein the 5-HT re-uptake inhibitor is sertraline or a pharmaceutically acceptable salt thereof. 16. A method for treating a disorder or condition selected from hypertension, depression, generalized anxiety disorder, phobias, posttraumatic stress syndrome, avoidant personality disorder, sexual dysfunction, eating disorders, obesity, chemical dependencies, cluster headache, migraine, pain, Alzheimer's disease, obsessive-compulsive disorder, panic disorder, memory disorders, Parkinson's diseases, endocrine disorders, vasospasm, cerebellar ataxia, gastrointestinal tract disorders, negative symptoms o