OA11742A - 5HT1 antagonists for antidepressant therapy. - Google Patents
5HT1 antagonists for antidepressant therapy. Download PDFInfo
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- OA11742A OA11742A OA1200100172A OA1200100172A OA11742A OA 11742 A OA11742 A OA 11742A OA 1200100172 A OA1200100172 A OA 1200100172A OA 1200100172 A OA1200100172 A OA 1200100172A OA 11742 A OA11742 A OA 11742A
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- octahydro
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Classifications
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Landscapes
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Claims (20)
1. 10 15 20 -31- CLAIMS
11742 (l) wherein R1, R2, R3 and R4 are selected, independently, from hydrogen, (C,-C4) alkyloptionally substituted with from one to three fluorine atoms, (C,-C4)alkoxy optionallysubstituted with from one to three fluorine atoms, and (C1-C4)alkoxy-(C1-C4)alkyl wherein eachof the alkyl moieties may optionally be substituted with from one to three fluorine atoms; and X is CH or N; or a pharmaceutically acceptable sait thereof.
2. A compound according to claim 1, wherein having an absolute sterochemistryof (7R, 9aS)-trans or (7S, 9aS)-cis.
3. A compound according to claim 1 that is selected from: (7R,9aS)-trans-f2-(5-Fluoro-benzo[d1isoxazol-3-yl)-octahydro-pvridoff ,2-alpyrazin-7- ylmethyl]-(5-fluoro-pyrirnidin-2-yl)-amine; (7R,9aS)-trans-f2-(5-Fluoro-benzo[d1isoxazol-3-yl)-octahydro-pyridof1,2-a]pyrazin-7-ylmethy!]-pyrimidin-2-yl)-amine; (7S,9aS)-çis-[2-(5-Fluoro-benzo[d]isoxazol-3-yI-ocîahydro-pyrido[1,2-a]pyrazin-7- ylmethyi-(5-fluoro-pyridin-2-yl)-amine; (7S,9aS)-cis-(2-Benzo[d]isoxazol-3-yi)-octahydro-pyrido[1,2-a]pyrazin-7-ylmethyl)- pyrimidin-2-yl-amine; (7S,9aS)-cis-(2-Benzo[d]isoxazo!-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethyl)-(5- fluoro-pyrimidin-2-yl)-amine; (7R,9aS)-trans-(2-Benzofdlisoxazol-3-yl-octahydro-pyridof1.2-alpvrazin-7-vlmethvl)- (5-methyl-pyrimÎdin-2-yl)-amine; (7S,9aS)-cis-(2-Benzo[d]isoxazol-3-yi-octahydro-pyrido[1,2-a]pyrazin-7-ylmethyl)-(5- methyl-pyrimidin-2-yl)-amine; 117 4 2 -32- (7R,9aS)-trans-(2-Benzo[d1isoxazol-3-yl-octahydre-pyridof1,2-ajpyrazin-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; 5 (7R,9aS)-trans-(5-C.hloro-pyrimidin-2-yl)-[2-(5-fluoro-benzo[d]isoxazol-3-yl)- octahydro-pyrido[1,2-a]pyrazin-7-ylmethyl]-amine; (7S,9aS)-cis-(5-Chloro-pyrimidin-2-yi)-[2-(5-fiuoro-benzo[d]isoxazol-3-yl)-octahydro-pyrido[1,2-a]pyrazin-7-ylmethylJ-amine; (7R,9aS)-trans-[2-(5-Fluoro-benzo[d]isoxazol-3-yl)-octahydro-pyrido[1,2-alpyrazin-7-10 ylmethyl]-(5-methyl-pyrimÎdin-2-yl)-amÎne; (7S,9aS)-cis-[2-(5-Fluoro-benzo{d]isoxazol-3-yl)-octahydro-pyrido[1,2-a]pyrazin-7- ylrnethyl]-(5-methyl-pyrirnidin-2-yl)-amine; (7R,9aS)-trans-(2-Benzo[djisoxazoi-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethyl)-(5-fiuoro-pyridin-2-yl)-amine; 15 (7S,9aS)-cis-(2-Benzo[d]isoxazol-3-yi-octahydro-pyrido[1,2-a]pyrazin-7-ylmethyl)-(5- fluoro-pyridin-2-yl)-amine; (7R,9aS)-trans-[2-(5-Fluoro-benzo[d1isoxazol-3-yl)-octahydro-pyridot1,2-a1pyrazin-7- ylmethyl]-{5-fiuoro-pyndin-2-yl)-amine; (7S,9aS)-cis-I2-(5-Fluoro-benzo[dlisoxazol-3-yl)-octahydro-pyridof1.2-a]pvrazin-7-20 ylmethyl]-(5-fluoro-pyridin-2-yl)-amine; (7R,9aS)-trans-(2-Benzofd]isoxazol-3-yl-octahydro-pyridof1,2-a]pyrazin-7-ylmethyl)-(5-fluoro-3-methyl-pyridin-2-yl)-amine; (7S,9aS)-cis-(2-Benzo[d1isoxazol-3-yl-octahydro-pyrido[1,2-a1pyrazin-7-ylmethyl)-(5- fiuoro-3-methyi-pyridin-2-yl)-amine; 25 (7R,9aS)-trans-[2-(5-Fluoro-benzojdlisoxazol-3-yl)-octahydro-pyridof1,2-a1pyrazin-7- ylmethyl]-pyridin-2-yl)-amine; (7R,93S)-trans-[2-(5-Fluoro-benzofd1isoxazoi-3-vl)-octahydro-pvridoi1.2-a1pyrazin-7- ylmethyl]-(5-fiuoro-3-methyl-pyridin-2-yl)-amine; (7S,9aS)-cis-[2-(5-Fluoro-benzo[d3isoxazoi-3-yl)-octahydro-pyridof1,2-a]pyrazin-7-30 ylmethyi)-(5-fluoro-3-methyI-pyridin-2-yl)-amine; and (7R,9aS)-trans-(2-Benzo[d]isoxazo1-3yl-octahydro-pyrido[1,2-a3pyrazin-7-yl- methyl)-(5-fluoro-pyrimidin-2-yl)-amine.
4. A pharmaceutical composition for treating a disorder or condition seiectedfrom hypertension, dépréssion, generalized anxiety disorder, phobias, posttraumatic stress 35 syndrome, avoidant personality disorder, prématuré éjaculation, eating disorders, obesity,Chemical dependencies, cluster headache, migraine, pain, Alzheimer’s disease, obsessive- 117 4 2 -33- compulsive disorder, panic disorder, memory disorders, Parkinson's diseases, endocrinedisorders, vasospasm, cerebellar ataxia, gastrointestinal tract disorders, négative symptomsof schizophrénie, premenstrual syndrome, fibromyalgia syndrome, stress incontinence,Tourette’s syndrome, trichotillomania, kleptomania, male impotence, cancer, chronic 5 paroxysmal hemicrania and headache in a mammal, comprising an amount of a compoundaccording to claim 1 that is effective in treating such disorder or condition and apharmaceütically acceptable carrier.
5. A pharmaceutical composition for treating a disorder or condition that can betreated by moduiati.ng serotonergic neurotransmission in a mammal, comprising an amount of 10 a compound according to claim 1 that is effective in treating such disorder or condition and apharmaceütically acceptable carrier.
6. Use of a compound according to claim 1 in the manufacture of a médicament' for the treatment of a disorder or condition selected from hypertension, dépréssion,generalized anxiety disorder, phobias, posttraumatic stress syndrome, avoidant 15 personality disorder, prématuré éjaculation, eating disorders, obesity, Chemical dependencies,cluster headache, migraine, pain, Alzheimer’s disease, obsessive-compulsive disorder, panicdisorder, memory disorders, Parkinson's diseases, endocrine disorders, vasospasm,cerebellar ataxia, gastrointestinal tract disorders, négative symptoms of schizophrénie,premenstrual syndrome, fibromyalgia syndrome, stress incontinence, Tourette’s syndrome, 20 trichotillomania, kleptomania, male impotence, cancer, chronic paroxysmal hemicrania andheadache in a mammal
7. Use of a compound according to claim 1 in the manufacture of a médicamentfor the treatment of a disorder or condition that can be treated or prevented by modulatingserotonergic neurotransmission in a mammal. 25
8. A pharmaceutical composition for treating a disorder or condition selected from hypertension, dépréssion, generalized anxiety disorder, phobias, posttraumatic stresssyndrome, avoidant personality disorder, prématuré éjaculation, eating disorders, obesity,Chemical dependencies, cluster headache, migraine, pain, Alzheimer's disease, obsessive-compulsive disorder, panic disorder, memory disorders, Parkinson's diseases, endocrine 30 disorders, vasospasm, cerebellar ataxia, gastrointestinal tract disorders, négative symptomsof schizophrenia, premenstrual syndrome, fibromyalgia syndrome, stress incontinence,Tourette’s syndrome, trichotillomania, kleptomania, male impotence, cancer, chronicparoxysmal hemicrania and headache in a mammal, comprising a serotonin receptor 11742 -34- antagonizing or agonizing effective amount of a compound according to claim 1 and apharmaceutically acceptable carrier.
9. A pharmaceutical composition for treating a disorder or condition that can betreated by modulating serotonergic neurotransmission in a mammal, comprising a serotonin 5 receptor antagonizing or agonizing effective amount of a compound of according to claim 1and a pharmaceutically acceptable carrier.
10. Use according to Claim 6 wherein the compound is used in a serotonin IAreceptor antagonizing or agonizing effective amount, or a serotonin 1D receptor antagonizingeffective amount, _ 1®
11· Use according to Claim 7 wherein the compound is used in a serotonin IA receptor antagonizing or agonizing effective amount, or a serotonin 1D receptor antagonizingeffective amount. 20
12. A pharmaceutical composition for treating disorder or condition that can betreated or prevented by modulating serotonergic neurotransmission in a mammal, comprising: a) a pharmaceutically acceptable carrier, b) a compound of according to ciaim 1 ; and c) a 5-HT re-uptake inhibitor or a pharmaceutically acceptable sait thereof;wherein the amount of the active compounds are such that the combination is effective in treating such disorder or condition.
13. Use of (a) a compound according to claim 1 ; and (b) a 5-HT re-uptake inhibitor or a pharmaceutically acceptable sait thereof, in the manufacture of a médicament for the treatment of a disorder or a condition that can betreated by modulating serotonergic neurotransmission in a mammal. 25
14. A pharmaceutical composition according to ciaim 12, wherein the 5-KT re- uptake inhibitor is sertraline or a pharmaceutically acceptable sait thereof. 117 4 2 -35-
15. Use according to claim 13, wherein the 5-HT re-uptake inhibitor is sertralineor a pharmaceutically acceptable sait thereof.
16. Use of (a) a compound according to claim 1; and 5 (b) a 5-HT re-uptake inhibitor or a pharmaceutically acceptable sait thereof in the manufacture of a médicament for the treatment of a disorder or condition selected fromhypertension, dépréssion, generalized anxïety disorder, phobias, posttraumatic stresssyndrome, avoidant personality disorder, sexual dysfunction, eating disorders, obesity, Chemical dependencies, cluster headache, migraine, pain, Alzheimer’s disease, obsessive- Wcompulsive disorder, panic~disorder, memory disorders, Parkinson's diseases, endocrinedisorders, vasospasm, cerebellar ataxia, gastrointestinal tract disorders, négative symptomsof schizophrénie, premenstrual syndrome, fibromyalgia syndrome, stress incontinence,Tourette’s syndrome,’ trichotillomania, kleptomanie, male impotence, cancer, chronicparoxysmal hemicrania and· headache in a mammai *5
17. Use of (a) a 5-HT IA antagonist or agonist or a pharmaceutically acceptable saitthereof; and (b) a 5-HT 1D antagonizing compound according to claim 1; for the manufacture of a médicament for the treatment of a disorder or condition that 2Q:an be treated or prevented by modulating serotonergic neurotransmission in a mammai.
18. Use of (a) a 5-HT1A agonist or antagonist or a pharmaceutically acceptable sait thereof;and (b) a 5-HT 1D antagonizing compound according to claim 1; 25for the manufacture of a médicament for the treatment of a disorder or condition selectedfrom: hypertension dépréssion, generalized anxiety disorder, phobias, posttraumatic stresssyndrome, avoidant personality disorder, sexual dysfunction, eating disorders, obesity, Chemical dependencies, cluster headache, migraine, pain, Alzheimer’s disease, obsessive-·compuisive disorder, partie disorder, memory disorders, Parkinson’s diseases, endocrine 3° disorders, vasospasm, cerebellar ataxia, gastrointestinal tr3ct disorders, négative 11742 -36- symptoms of schizophrenia, premenstruai syndrome, fibromyalgia syndrome,stress incontinence,· Tourette’s syndrome, trichotiiiomania, kleptomania, maleimpotence, cancer, chronic paroxysmal hemicransa and headache in a mammal
19. A pharmaceutica! composition for treating a disorder or condition that can betreated by modulating serotonergic neurotransmission in a mammai, comprising: a) a 5-HT1A agonist or antagonist or a pharmaceutically acceptable sait thereof;and b) a 5-HT1D antagonizing compound according to claim 1; wherein the amounts of the active compounds are such that the combination iseffective in treating such disorder or condition.
20. A pharmaceutical composition for treating a disorder or condition selectedfrom hypertension, dépréssion, generalized anxiety disorder, phobias, posttraumatic stresssyndrome, avoidant personaiity disorder, sexuai dysfunction, eating disorders, obesity,Chemical dependencies, cluster headache, migraine, pain, Alzheimer's disease, obsessive-compulsive disorder, panic disorder, memory disorders, Parkinson's diseases, endocrinedisorders, vasospasm, cerebellar ataxia, gastrointestinal tract disorders, négative symptomsof schizophrenia, premenstruai syndrome, fibromyalgia syndrome, stress incontinence,Tourette’s syndrome, trichotiiiomania, kieptomania, male impotence, cancer, chronicparoxysmal hemicrania and headache in a mammal, comprising: a) a 5-HT1A agonist or antagonist or a pharmaceutically acceptable sait thereof;and b) a 5-HT1D antagonizing compound according to claim 1 ; wherein the amounts of the active compounds are such that the combination iseffective in treating such disorderor condition.
Applications Claiming Priority (1)
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| US11395798P | 1998-12-28 | 1998-12-28 |
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| WO2003065970A2 (fr) * | 2001-02-20 | 2003-08-14 | Royal College Of Surgeons Ie | Traitement de la fibromyalgie et du syndrome de fatigue associe au moyen d'antagonistes ou d'agonistes partiels de recepteurs 5ht1a |
| GB0203778D0 (en) * | 2002-02-18 | 2002-04-03 | Glaxo Group Ltd | Compounds |
| AP2005003390A0 (en) * | 2003-03-12 | 2005-09-30 | Pfizer Prod Inc | Pyridyloxymethyl and benzisoxazole azabicyclic derivatives. |
| GB0316915D0 (en) * | 2003-07-18 | 2003-08-20 | Glaxo Group Ltd | Compounds |
| WO2005082370A1 (fr) * | 2004-01-29 | 2005-09-09 | Pfizer Products Inc. | Combinaisons d'un antipsychotique atypique et de derives azabicycliques d'aminomethylpyridyloxy- methyle/benzisoxazole pour le traitement de troubles du systeme nerveux central |
| AR048112A1 (es) * | 2004-03-25 | 2006-03-29 | Solvay Pharm Bv | Derivados de 1-(2h-1-benzopiran-2-on-8-il)-piperazina para el tratamiento de dolor |
| AR049478A1 (es) | 2004-03-25 | 2006-08-09 | Solvay Pharm Bv | Un procedimiento para la preparacion de 3-amino-8-(1-piperazinil)-2h-1-benzopiran-2-ona. sales e hidratos y composiciones farmaceuticas. |
| BRPI0515143A (pt) * | 2004-09-10 | 2008-07-08 | Pfizer Prod Inc | usos de derivados azabicìclicos de piridiloximetila e benzisoxazol para a preparação de uma composição farmacêutica para o tratamento dos distúrbios de humor |
| JP2008512441A (ja) * | 2004-09-10 | 2008-04-24 | ファイザー・プロダクツ・インク | ピリジルオキシメチル、及びベンズイソオキサゾール・アザビシクロ誘導体を使用する、認知障害の治療方法 |
| DE102005026194A1 (de) * | 2005-06-06 | 2006-12-07 | Grünenthal GmbH | Substituierte N-Benzo[d]isoxazol-3-yl-amin-Derivate und deren Verwendung zur Herstellung von Arzneimitteln |
| WO2008019431A1 (fr) * | 2006-08-14 | 2008-02-21 | Brc Operations Pty Limited | Procédé et compositions pour réguler simultanément la mémoire et l'humeur |
| WO2014078568A1 (fr) | 2012-11-14 | 2014-05-22 | The Johns Hopkins University | Méthodes et compositions pour le traitement de la schizophrénie |
| WO2020183011A1 (fr) | 2019-03-14 | 2020-09-17 | Institut Curie | Inhibiteurs de htr1d et leurs utilisations dans le traitement du cancer |
| WO2021127391A1 (fr) * | 2019-12-20 | 2021-06-24 | The Jackson Laboratory | Cibles moléculaires pour la dépendance |
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| US5157034A (en) * | 1991-02-27 | 1992-10-20 | Pfizer Inc. | Neuroleptic perhydro-1H-pyrido[1,2-a]pyrazines |
| GB9410512D0 (en) * | 1994-05-25 | 1994-07-13 | Smithkline Beecham Plc | Novel treatment |
| US5756496A (en) * | 1994-05-28 | 1998-05-26 | Smithkline Beecham P.L.C. | Amide derivatives having 5HT1D-antagonist activity |
| IL132409A0 (en) * | 1997-04-18 | 2001-03-19 | Smithkline Beecham Plc | Indole derivatives having combined 5ht1a 5ht1b and 5ht1d receptor antagonist activity |
| IT1293807B1 (it) * | 1997-08-01 | 1999-03-10 | Recordati Chem Pharm | Derivati 1- (n-fenilaminoalchil) piperazinici sostituiti alla posizione 2 dell'anello fenilico |
| PA8469101A1 (es) * | 1998-04-09 | 2000-09-29 | Pfizer Prod Inc | Ligandos azabiciclicos de receptores 5ht1 |
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