| 摘要 |
1. A compound of the formula wherein R<3>, R<4>, and Z are selected, independently, from hydrogen, halo (e.g., chloro, fluoro, bromo or iodo), (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 one to three fluorine atoms; W is -CH2-O-(C1-C6) alkyl wherein the alkyl moiety can be straight or branched, or W is -CH2NR<1>R<2> wherein R<1> and R<2> are independently selected from hydrogen and straight or branched (C1-C6)alkyl; or R<1> and R<2> together with the nitrogen to which they are attached, form a saturated or unsaturated nonaromatic four to seven membered monocyclic or a seven to ten membered bicyclic ring which may optionally contain one or two heteroatoms in addition to the nitrogen of NR<1>R<2>, wherein said heteroatoms are independently selected from oxygen, nitrogen and sulfur, and wherein from one to three of the ring carbon atoms or one of the ring nitrogen atoms may optionally and independently be substituted with (C1-C4) straight or branched alkyl, (C1-C4) straight or branched alkoxy, (C1-C3) straight or branched alkyl-(C3C7) cycloalkyl, hydroxy, amino, cyano, halo, aryl-(C1-C3)straight or branched alkyl or heteroaryl-(C1-C3) straight or branched alkyl, wherein said aryl is selected from phenyl and naphthyl and said heteroaryl is selected from oxazolyl, isoxazoyl, thiazolyl, isothiazolyl, furanyl, pyrazolyl, pyrrolyl, tetrazolyl, triazolyl, thienyl, imidazolyl, pyrazinyl, pyrazolyl, indolyl, isoindolyl, pyrazinyl, cinnolinyl, pyridinyl and pyrimidinyl; with the proviso that in any ring formed by NR<1>R<2>: (a) there can be no more than one ring oxygen atom; (b) there can be no hydroxy, alkoxy, alkoxymethyl, cyano, amino or alkylamino moiety bonded directly to any nitrogen atom; and (c) no ring carbon that is double bonded to another ring carbon and not part of an aromatic ring system can be bonded to a ring oxygen atom or ring nitrogen atom; and the pharmaceutically acceptable salts of such compounds. 2. A compound according to claim 1, wherein having an absolute sterochemistry of 7R,9aS-trans or 7S, 9aS-cis. 3. A compound according to claim 1 that is selected from: (7R,9aS)-trans-1-{3-[2-(5-Fluoro-benzo[d]isoxazol-3-yl)-octahydro-pyrido[1,2a]pyrazine-7-ylmethoxy]-benzyl}-azetidin-3-ol; (7R,9aS)-trans-2-(5-Fluoro-benzo[d]isoxazol-3-yl)-7-(3-morpholin-4ylmethylphenoxymethyl)-octahydro-pyrido[1,2-a]pyrazine; (7S,9aS)-cis-1-[3-(2-(benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazine-7-ylmethoxy)-benzyl]-azetidin-3-ol; (7R,9aS)-trans-2-(4-Fluoro-benzo[d]isoxazol-3-yl)-7-(3-pyrrolidin-1-ylmethylphenoxymethyl)-octahydro-pyrido[1,2-a]pyrazine; (7S,9aS)-cis-2-Benzo[d]isoxazol-3-yl-7-(3-pyrrolidin-1-ylmethyl-phenoxymethyl)-octahydro-pyrido-[1,2-a]pyrazine; (7S,9aS)-cis-1-[3-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazine-ylmethoxy)-benzyl]pyrrolidine-3,4-diol; (7R,9aS)-trans-2-(5-Fluoro-benzo[d]isoxazol-3-yl)-7-(3-pyrrolidin-1-ylmehylphenoxymethyl)-octahydro-pyrido[1,2-a]pyrazine; (7S,9aS)-cis-2-Benzo[d]isoxazol-3-yl-7-(2-methyl-5-pyrrolidin-1-ylmethylphenoxymethyl)-octahydro-pyrido[1,2-a]pyrazine; (7S,9aS)-cis-2-Benzo[d]isoxazol-3-yl-7-(3-methoxy-5-pyrrolidin-1-ylmethylphenoxymethyl)-octahydro-pyrido[1,2-a]pyrazine; (7S,9aS)-cis-2-Benzo[d]isoxazol-3-yl-7-(4-chloro-3-pyrrolidin-1-ylmethylphenoxymethyl)-octahydro-pyrido[1,2-a]pyrazine; (7S,9aS)-cis-2-Benzo[d]isoxazol-3-yl-7-(4-pyrrolidin-1-ylmethyl-phenoxymethyl)-octahydro-pyrido[1,2-a]pyrazine; (7S,9aS)-cis-7-(3-azetidin-1-ylmethyl-phenoxymethyl)-2-benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazine; (7S,9aS)-cis-[3-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7ylmethoxy)-benzyl]-cyclopropylmethyl-amine; (7S,9aS)-cis-2-Benzo[d]isoxazol-3-yl-7-[3-(2-methoxymethyl-pyrrolidin-1-ylmethyl)phenoxymethyl]-octahydro-pyrido[1,2-a]pyrazine; (7S,9aS)-cis-[3-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazine-7-ylmethoxy)-benzyl]-cyclopropyl-amine; (7S,9aS)-cis-2-Benzo[d]isoxazol-3-yl-7-[3-(4ethyl-piperazine-1-ylmethyl)-phenoxymethyl]-octahydro-pyridol[1,2-a]pyrazine; (7S,9aS)-cis-[3-(2-Benzo(d]isoxazol-3-yl- octahydro-pyrido[1,2-a]pyrazine-7-ylmethoxy)-benzyl]-cyclohexyl-amine; (7S,9aS)-cis-1-[3-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazine-7-ylmethoxy)-benzyl]-pyrrolidine-3-ol; (7S,9aS)-cis-2-Benzo[d]isoxazol-3-yl-7-[3-(2,5-dimethyl-[pyrrolidin-1ylmethyl)phenoxymethyl-octahydro-pyrido[1,2-a]pyrazine; (7S,9aS)-cis-[3-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazine-7ylmethoxy)-benzyl]-isobutyl-amine; (7S,9aS)-cis-2-Benzo[d]isoxazol-3-yl-7-(2-morpholine-4-ylmethyl-phenoxymethyl)-octahydro-pyrido[1,2-a]pyrazine; (7S,9aS)-cis-2-Benzo[d]isoxazol-3-yl-7-(2- pyrrolidin-1-ylmethyl-phenoxymethyl)-octahydro-pyrido[1,2-a]pyrazine; (7S,9aS)-cis-2-Benzo[d]isoxazol-3-yl-7-(4- morpholine-4-ylmethyl-phenoxymethyl)-octahydro-pyrido[1,2-a]pyrazine; (7S,9aS)-trans-2-(7- Fluoro-benzo[d]isoxazol-3-yl)-7-(3- pyrrolidin-1-ylmethyl-phenoxymethyl) -octahydro-pyridol[1,2-a]pyrazine; (7S,9aS)-trans-2-(6- Fluoro-benzo[d]isoxazol-3-yl)-7-(3- pyrrolidin-1-ylmethyl-phenoxymethyl)- octahydro-pyrido[1,2-a]pyrazine; (7R,9aS)-trans-2-(6,7-Fluoro-benzo[d]isoxazol-3-yl)-7-(3-pyrrolidin-1-ylmethyl-phenoxymethyl)-octahydro-pyrido[1,2-a]pyrazine; (7R,9aS)-trans-3-{3-[2-(5-Fluoro-benzo[d]isoxazol-3-yl)-octahydro-pyrido[1,2a]pyrazine-7-ylmethoxy]-benzyl}-3-aza-bicyclo[3.2.2]nonane; (7R,9aS)-trans-2-(5-Fluoro-benzo[d]isoxazol-3-yl)-7-[3-Cis-octahydro-isoindol-2-ylmethyl)-phenoxymethyl]-octahydro-pyrido[1,2-a]pyrazine and (7S,9aS)-cis-4-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido-[1,2-a]pyrazin-7-ylmethoxy)-benzylamine. 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, 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 an amount of a compound 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 a compound 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, 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 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 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, trichotillom
|
