RU2162470C2 - 2,7-замещенные производные октагидропирроло[1,2-а]пиразина, способ лечения, фармацевтическая композиция, промежуточные соединения - Google Patents
2,7-замещенные производные октагидропирроло[1,2-а]пиразина, способ лечения, фармацевтическая композиция, промежуточные соединения Download PDFInfo
- Publication number
- RU2162470C2 RU2162470C2 RU98111742/04A RU98111742A RU2162470C2 RU 2162470 C2 RU2162470 C2 RU 2162470C2 RU 98111742/04 A RU98111742/04 A RU 98111742/04A RU 98111742 A RU98111742 A RU 98111742A RU 2162470 C2 RU2162470 C2 RU 2162470C2
- Authority
- RU
- Russia
- Prior art keywords
- octahydropyrrolo
- pyrazine
- pharmaceutically acceptable
- acceptable salt
- fluoropyrimidin
- Prior art date
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- 238000000034 method Methods 0.000 title claims abstract description 58
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 15
- 238000011282 treatment Methods 0.000 title abstract description 37
- FTTATHOUSOIFOQ-UHFFFAOYSA-N 1,2,3,4,6,7,8,8a-octahydropyrrolo[1,2-a]pyrazine Chemical class C1NCCN2CCCC21 FTTATHOUSOIFOQ-UHFFFAOYSA-N 0.000 title description 2
- 239000012450 pharmaceutical intermediate Substances 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 212
- -1 benzoxazolonyl Chemical group 0.000 claims abstract description 103
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 claims abstract description 74
- 150000003839 salts Chemical class 0.000 claims abstract description 66
- 229960003638 dopamine Drugs 0.000 claims abstract description 37
- 239000000126 substance Substances 0.000 claims abstract description 16
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 15
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 14
- 230000000694 effects Effects 0.000 claims abstract description 14
- 239000000460 chlorine Substances 0.000 claims abstract description 10
- 125000005843 halogen group Chemical group 0.000 claims abstract description 10
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims abstract description 9
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 9
- 125000001424 substituent group Chemical group 0.000 claims abstract description 9
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 5
- 125000004076 pyridyl group Chemical group 0.000 claims abstract description 5
- 125000000714 pyrimidinyl group Chemical group 0.000 claims abstract description 5
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims abstract description 5
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims abstract description 4
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims abstract description 4
- 239000011737 fluorine Substances 0.000 claims abstract description 4
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- 125000001041 indolyl group Chemical group 0.000 claims abstract description 4
- 125000001624 naphthyl group Chemical group 0.000 claims abstract description 4
- 125000005493 quinolyl group Chemical group 0.000 claims abstract description 4
- 125000003373 pyrazinyl group Chemical group 0.000 claims abstract description 3
- 125000002098 pyridazinyl group Chemical group 0.000 claims abstract description 3
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- LOTBYPQQWICYBB-UHFFFAOYSA-N methyl n-hexyl-n-[2-(hexylamino)ethyl]carbamate Chemical compound CCCCCCNCCN(C(=O)OC)CCCCCC LOTBYPQQWICYBB-UHFFFAOYSA-N 0.000 claims description 7
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- JGRLEYKBYBFXAU-SQJZIBIZSA-N 3-[[(7S,8aS)-2-(5-chloropyridin-2-yl)-1-methyl-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazin-7-yl]oxy]benzonitrile Chemical compound C(#N)C=1C=C(O[C@H]2C[C@@H]3N(CCN(C3C)C3=NC=C(C=C3)Cl)C2)C=CC=1 JGRLEYKBYBFXAU-SQJZIBIZSA-N 0.000 claims description 2
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- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
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| US898895P | 1995-12-21 | 1995-12-21 | |
| US60/008,988 | 1995-12-21 |
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| RU98111742A RU98111742A (ru) | 2000-03-27 |
| RU2162470C2 true RU2162470C2 (ru) | 2001-01-27 |
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| RU98111742/04A RU2162470C2 (ru) | 1995-12-21 | 1996-11-06 | 2,7-замещенные производные октагидропирроло[1,2-а]пиразина, способ лечения, фармацевтическая композиция, промежуточные соединения |
Country Status (33)
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2322443C2 (ru) * | 2001-09-19 | 2008-04-20 | Мерк Патент Гмбх | Новое применение замещенных аминометилхроманов |
| RU2492172C2 (ru) * | 2006-02-24 | 2013-09-10 | Абботт Лаборэтриз | ПРОИЗВОДНЫЕ ОКТАГИДРОПИРРОЛО[3,4-b]ПИРРОЛА (ВАРИАНТЫ), СПОСОБ ПОЛУЧЕНИЯ ПРОИЗВОДНЫХ ОКТАГИДРОПИРРОЛО[3,4-b]ПИРРОЛА (ВАРИАНТЫ), ФАРМАЦЕВТИЧЕСКАЯ КОМПОЗИЦИЯ НА ИХ ОСНОВЕ И СПОСОБ ЛЕЧЕНИЯ ЗАБОЛЕВАНИЯ ИЛИ НАРУШЕНИЯ СОСТОЯНИЯ ОРГАНИЗМА, ЧУВСТВИТЕЛЬНОГО К МОДУЛЯЦИИ АКТИВНОСТИ РЕЦЕПТОРА ГИСТАМИНА-3 |
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| US6281216B1 (en) * | 1998-02-09 | 2001-08-28 | Duphar International Research B.V. | 2-aminoquinoline derivatives having d4-agonistic activity |
| EP0982030A3 (en) * | 1998-08-17 | 2000-05-10 | Pfizer Products Inc. | 2,7-substituted octahydro-pyrrolo 1,2-a]pyrazine derivatives as 5ht 1a ligands |
| PL349912A1 (en) * | 1999-02-05 | 2002-10-07 | Upjohn Co | Process to prepare (5r)-(methylamino)-5,6-dihydro-4h-imidazo[4,5,1-ij]-quinolin-2(1h)-one |
| EP1083369B1 (en) | 1999-09-10 | 2004-06-30 | Mitsubishi Jidosha Kogyo Kabushiki Kaisha | Continuously variable transmission |
| HUP0202706A3 (en) * | 1999-09-14 | 2004-12-28 | Aventis Pharmaceuticals Inc Br | Benzisoxazolyl-, pyridoisoxazolyl- and benzthienyl-phenoxy derivatives useful as d4 antagonists, their intermediates, process for their preparation and pharmaceutical compositions containing them |
| US7253165B2 (en) | 1999-09-14 | 2007-08-07 | Aventis Pharmaceuticals Inc. | Benzisoxazolyl-, pyridoisoxazolyl-and benzthienyl-phenoxy derivatives useful as D4 antagonists |
| US7091199B1 (en) | 1999-09-14 | 2006-08-15 | Aventis Pharmaceuticals Inc. | Thienoisoxazole phenoxy unsubstituted ethyl and propyl derivatives useful as d4 antagonists |
| US7125903B1 (en) | 1999-09-14 | 2006-10-24 | Aventis Pharmaceuticals Inc. | Thienoisoxazolyl-and thienylpyrrazolyl-phenoxy substituted propyl derivatives useful as D4 antagonists |
| TW200801005A (en) * | 2005-08-15 | 2008-01-01 | Astrazeneca Ab | Acetylenic piperazines as metabotropic glutamate receptor antagonists |
| US8669255B2 (en) * | 2011-09-29 | 2014-03-11 | Abbvie Inc. | Substituted octahydropyrrolo[1,2-a]pyrazines as calcium channel blockers |
| WO2020051153A1 (en) | 2018-09-04 | 2020-03-12 | Pipeline Therapeutics, Inc. | Muscarinic acetylcholine m1 receptor antagonists |
| US11752149B2 (en) | 2019-12-02 | 2023-09-12 | Pipeline Therapeutics, Inc. | Muscarinic acetylcholine M1 receptor antagonists |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0380217A1 (en) * | 1989-01-23 | 1990-08-01 | Pfizer Inc. | Bis-aza-bicyclic anxiolytic agents and antidepressants |
| WO1996010571A1 (en) * | 1994-09-30 | 1996-04-11 | Pfizer Inc. | 2,7-SUBSTITUTED OCTAHYDRO-1H-PYRIDO[1,2-a]PYRAZINE DERIVATIVES |
| WO1996018630A1 (en) * | 1994-12-12 | 1996-06-20 | Allelix Biopharmaceuticals Inc. | Bicyclic nonane and decane compounds having dopamine receptor affinity |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4400511A (en) * | 1982-05-07 | 1983-08-23 | American Home Products Corporation | 2-Substituted octahydropyrrolo(1,2-A)-pyrazine-3-carboxylic acids |
| US5122515A (en) * | 1990-06-19 | 1992-06-16 | Smith Ross C | Nutrient composition containing dipeptides and method for administering the same |
| JP3058945B2 (ja) * | 1990-10-26 | 2000-07-04 | 三共株式会社 | Ｎ−（３，３−ジ置換アクリロイル）ピペラジン誘導体 |
| AU678186B2 (en) * | 1992-10-23 | 1997-05-22 | Merck Sharp & Dohme Limited | Dopamine receptor subtype ligands |
| US5670522A (en) * | 1992-10-23 | 1997-09-23 | Merck Sharp & Dohme Limited | Dopamine receptor subtype ligands |
| KR970704698A (ko) * | 1994-08-05 | 1997-09-06 | 스피겔 알렌 제이 | 도파민 작용 활성을 갖는 벤즈이미다졸 유도체(benzimidazole derivatives having dopaminergic activity) |
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1996
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0380217A1 (en) * | 1989-01-23 | 1990-08-01 | Pfizer Inc. | Bis-aza-bicyclic anxiolytic agents and antidepressants |
| WO1996010571A1 (en) * | 1994-09-30 | 1996-04-11 | Pfizer Inc. | 2,7-SUBSTITUTED OCTAHYDRO-1H-PYRIDO[1,2-a]PYRAZINE DERIVATIVES |
| WO1996018630A1 (en) * | 1994-12-12 | 1996-06-20 | Allelix Biopharmaceuticals Inc. | Bicyclic nonane and decane compounds having dopamine receptor affinity |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2322443C2 (ru) * | 2001-09-19 | 2008-04-20 | Мерк Патент Гмбх | Новое применение замещенных аминометилхроманов |
| RU2492172C2 (ru) * | 2006-02-24 | 2013-09-10 | Абботт Лаборэтриз | ПРОИЗВОДНЫЕ ОКТАГИДРОПИРРОЛО[3,4-b]ПИРРОЛА (ВАРИАНТЫ), СПОСОБ ПОЛУЧЕНИЯ ПРОИЗВОДНЫХ ОКТАГИДРОПИРРОЛО[3,4-b]ПИРРОЛА (ВАРИАНТЫ), ФАРМАЦЕВТИЧЕСКАЯ КОМПОЗИЦИЯ НА ИХ ОСНОВЕ И СПОСОБ ЛЕЧЕНИЯ ЗАБОЛЕВАНИЯ ИЛИ НАРУШЕНИЯ СОСТОЯНИЯ ОРГАНИЗМА, ЧУВСТВИТЕЛЬНОГО К МОДУЛЯЦИИ АКТИВНОСТИ РЕЦЕПТОРА ГИСТАМИНА-3 |
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