RU2004112415A - Производные диазабициклических алканов с nk1-антагонистической активностью - Google Patents
Производные диазабициклических алканов с nk1-антагонистической активностью Download PDFInfo
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- RU2004112415A RU2004112415A RU2004112415/04A RU2004112415A RU2004112415A RU 2004112415 A RU2004112415 A RU 2004112415A RU 2004112415/04 A RU2004112415/04 A RU 2004112415/04A RU 2004112415 A RU2004112415 A RU 2004112415A RU 2004112415 A RU2004112415 A RU 2004112415A
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- 150000001335 aliphatic alkanes Chemical class 0.000 title 1
- 230000003042 antagnostic effect Effects 0.000 title 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims 12
- 208000035475 disorder Diseases 0.000 claims 10
- -1 2-indolyl Chemical group 0.000 claims 8
- 150000001875 compounds Chemical class 0.000 claims 7
- 125000004432 carbon atom Chemical group C* 0.000 claims 3
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims 3
- 208000019901 Anxiety disease Diseases 0.000 claims 2
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- 229910052736 halogen Inorganic materials 0.000 claims 2
- 150000002367 halogens Chemical group 0.000 claims 2
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- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims 1
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- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims 1
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- 229910052739 hydrogen Inorganic materials 0.000 claims 1
- 239000001257 hydrogen Substances 0.000 claims 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims 1
- 125000002962 imidazol-1-yl group Chemical group [*]N1C([H])=NC([H])=C1[H] 0.000 claims 1
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- 238000004519 manufacturing process Methods 0.000 claims 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims 1
- CWWARWOPSKGELM-SARDKLJWSA-N methyl (2s)-2-[[(2s)-2-[[2-[[(2s)-2-[[(2s)-2-[[(2s)-5-amino-2-[[(2s)-5-amino-2-[[(2s)-1-[(2s)-6-amino-2-[[(2s)-1-[(2s)-2-amino-5-(diaminomethylideneamino)pentanoyl]pyrrolidine-2-carbonyl]amino]hexanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-5 Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)OC)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](N)CCCN=C(N)N)C1=CC=CC=C1 CWWARWOPSKGELM-SARDKLJWSA-N 0.000 claims 1
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- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims 1
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Classifications
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Claims (7)
1. Соединения общей формулы (1):
где R1 представляет фенил, 2-индолил, 3-индолил, 3-индазолил или бензо[b]тиофен-3-ил, указанные группы могут быть замещены галогеном или алкилом(1-3С);
- R2 и R3 независимо представляют галоген, Н, ОСН3, СН3 или CF3;
- R4, R5 и R6 независимо представляют Н, ОН, О-алкил(1-4С), СН2ОН, NH2, диалкил(1-3C)N, пирролидин-1-ил, пиперидин-1-ил, морфолин-4-ил или морфолин-4-ил, замещенный одной или двумя метильными или метоксиметильными группами, морфолин-4-иламино, морфолин-4-илметил, имидазол-1-ил, тиоморфолин-4-ил, 1,1-диоксотиоморфолин-4-ил или 3-окса-8-азабицикло[3.2.1]окт-8-ил, R4 и R5 вместе могут представлять кетогруппу 1,3-диоксан-2-ил или 1,3-диоксолан-2-ил;
- X представляет O или S;
n имеет значения 1, 2 или 3;
a является асимметричным атомом углерода 8а, 9а или 10а, когда n равно 1, 2 или 3, соответственно,
и их фармацевтически приемлемые соли, включая все возможные стереоизомеры, в которых заместители у асимметричных атомов углерода 3 и "а", а также у потенциально асимметричных атомов углерода 6 и 7, находятся в R-конфигурации или в S-конфигурации, а также пролекарства.
2. Соединения по п.1, имеющие формулу (1), где R1 представляет 3-индолил, R2 и R3 являются группами CF3 в положениях 3 и 5, X представляет кетогруппу, n имеет значения 1 или 2 и "a", R4, R5 и R6 имеют значения, указанные выше, включая все возможные стереоизомеры, как определено в п.1.
3. Соединения по п.2, имеющие формулу (1), в которых R4 или R6 представляют или содержат морфолино или гидроксиметильную группу, R5 представляет водород, и стереохимией которых является 3R.
4. Соединения, имеющие формулу (2), (3) или (4):
где R1, R2 и R3 имеют значения, приведенные в п.1, А и В представляют циклический или ациклический кеталь и L представляет уходящую группу, такую как хлор, бром или метансульфонат, используемые в синтезе соединений, имеющих формулу (1).
5. Фармацевтические композиции, содержащие фармакологически активное количество по меньшей мере одного соединения по любому из пп.1-3 в качестве активного ингредиента.
6. Применение соединения по одному из пп.1-3 для изготовления фармацевтической композиции для лечения заболеваний, в которые вовлечены нейрокинины, которые взаимодействуют с рецепторами NK1, например, вещество Р, или которые могут лечиться путем манипуляций с такими рецепторами.
7. Применение по п.6, отличающееся тем, что указанными заболеваниями являются острые и хронические боли, рвота, воспалительные заболевания, такие как менингит, артрит, астма, псориаз и (солнечные) ожоги; желудочно-кишечные расстройства, в частности, синдром раздраженной толстой кишки, воспалительные заболевания желудка (болезнь Крона), язвенный колит; расстройства, связанные с чрезмерной подвижностью мочевого пузыря или желудочно-кишечного тракта, воспаление мочевых путей; аллергические реакции, такие как экзема и ринит; сердечно-сосудистые расстройства, такие как гипертония, атеросклероз, отек, стенокардия, гистаминовая головная боль и мигрень; кожные заболевания, такие как крапивница, красная волчанка и зуд; респираторные расстройства, включая хроническую обструктивную болезнь легких, спазмы бронхов, бронхопневмонию, бронхит, респираторный дистресс-синдром и синдром фиброзно-кистозной дегенерации; различные опухолевые заболевания; психиатрические и/или неврологические расстройства, такие как шизофрения и другие психотические расстройства; расстройства настроения, такие как биполярные I, биполярные II и униполярные депрессивные расстройства, подобные легкой депрессии, сезонному аффективному расстройству, посленочной депрессивной дистимии и сильной депрессии; расстройства, связанные с беспокойством, включая паническое нарушение (с агорафобией или без нее), социальные фобии, навязчиво-компульсивное расстройство (со связанным с заболеванием тиком или без него или с шизотипальным расстройством), посттравматический стресс и общее состояние беспокойства; нарушения, расстройства, связанные с веществами, включая расстройства, обусловленные приемом лекарств (подобные зависимости и злоупотреблению) и вызванные лекарствами расстройства (подобные синдрому отмены лекарства); расстройства общего развития, включая аутизм и болезнь Ретта; расстройства, связанные с дефицитом внимания и разрушительным поведением, такие как дефицит внимания и гиперактивность; нарушения контроля импульсов, подобные агрессии, патологической привязанности к игре; расстройства питания, подобные нервной анорексии и нервной булимии, тучности; нарушения сна, подобные бессоннице; тиковые нарушения, подобные синдрому Туретта, синдрому беспокойства ног; расстройства, характеризуемые ослаблением познавательной способности и памяти, такие как болезнь Альцгеймера, болезнь Крейтцфельда-Якоба, болезнь Хантингтона, болезнь Паркинсона и нейрореабилитация (посттравматические повреждения мозга).
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| WO2003101459A1 (en) * | 2002-05-29 | 2003-12-11 | The Regents Of The University Of California | Antagonizing nk1 receptors inhibits consumption of substances of abuse |
| TW200514785A (en) | 2003-09-26 | 2005-05-01 | Solvay Pharm Bv | Hexa- and octahydro-pyrido[1,2-a]pyrazine derivatives with NK1 antagonistic activity |
| WO2006013205A1 (en) * | 2004-08-04 | 2006-02-09 | Solvay Pharmaceuticals B.V. | Neurokinin-1 receptor antagonists for the treatment of conditions responsive to testosterone elevation |
| DE102006049452A1 (de) | 2006-10-17 | 2008-05-08 | Grünenthal GmbH | Substituierte Tetrahydropyrolopiperazin-Verbindungen und deren Verwendung in Arzneimitteln |
| EP2312947B1 (en) * | 2008-07-25 | 2014-01-01 | GlaxoSmithKline LLC | Trpv4 antagonists |
| WO2010011912A1 (en) * | 2008-07-25 | 2010-01-28 | Smithkline Beecham Corporation | Trpv4 antagonists |
| WO2013049174A1 (en) | 2011-09-29 | 2013-04-04 | Abbvie Inc. | Substituted octahydropyrrolo[1,2-a]pyrazine sulfonamides as calcium channel blockers |
| WO2013049164A1 (en) * | 2011-09-29 | 2013-04-04 | Abbvie Inc. | SUBSTITUTED OCTAHYDROPYRROLO[1,2-a]PYRAZINES AS CALCIUM CHANNEL BLOCKERS |
| ES2568909T3 (es) * | 2012-02-22 | 2016-05-05 | Leo Pharma A/S | Novedosos compuestos antagonistas del receptor de la neuroquinina 1 |
| CN105008361A (zh) | 2012-12-12 | 2015-10-28 | 艾伯维公司 | 作为钙通道阻滞剂用于治疗疼痛的的二氮杂*衍生物 |
| RS60679B1 (sr) * | 2013-07-25 | 2020-09-30 | Neuren Pharmaceuticals Ltd | Neurozaštitna biciklična jedinjenja i postupci za njihovu upotrebu u lečenju poremećaja iz spektra autizma i neurorazvojnih poremećaja |
| WO2015024203A1 (en) * | 2013-08-20 | 2015-02-26 | Leo Pharma A/S | Novel neurokinin 1 receptor antagonist compounds ii |
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| GB1125112A (en) * | 1966-01-07 | 1968-08-28 | Science Union & Cie | New derivatives of diazabicyclo-decane and process for preparing them |
| IL111730A (en) | 1993-11-29 | 1998-12-06 | Fujisawa Pharmaceutical Co | Piperazine derivatives processes for the preparation thereof and pharmaceutical compositions containing the same |
| KR100446099B1 (ko) * | 1995-05-23 | 2004-11-10 | 얀센 파마슈티카 엔.브이. | (2-모르폴리닐메틸)벤즈아미드유도체 |
| GB9510600D0 (en) | 1995-05-25 | 1995-07-19 | Fujisawa Pharmaceutical Co | Piperazine derivatives |
| HUP9900822A3 (en) | 1995-05-25 | 1999-11-29 | Fujisawa Pharmaceutical Co | Piperazine derivatives, process for producing them, pharmaceutical compositions containing them and method for treating tachykinin-mediated diseases |
| DE69621831T2 (de) | 1995-12-18 | 2003-01-02 | Fujisawa Pharmaceutical Co., Ltd. | Piperazinderivative als tachykinin antagonisten |
| AUPO735997A0 (en) | 1997-06-17 | 1997-07-10 | Fujisawa Pharmaceutical Co., Ltd. | Piperazine derivatives |
| DE19824865A1 (de) * | 1997-08-27 | 1999-03-04 | Solvay Pharm Gmbh | Neue Harnstoffderivate |
| EP0899270B1 (de) | 1997-08-27 | 2008-05-21 | Solvay Pharmaceuticals GmbH | Indolmethyl-N,N'-bisacylpiperazine als Neurokininrezeptorantagonisten |
| 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 |
| WO2000035915A1 (en) | 1998-12-14 | 2000-06-22 | Fujisawa Pharmaceutical Co., Ltd. | Piperazine derivatives |
| DE10036818A1 (de) | 2000-07-28 | 2002-02-07 | Solvay Pharm Gmbh | Neue N-Triazolylmethyl-Piperazinderivate als Neurokininrezeptor-Antagonisten |
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| IL160943A (en) | 2008-11-03 |
| US20050119267A1 (en) | 2005-06-02 |
| MXPA04004812A (es) | 2004-08-11 |
| CN1592747A (zh) | 2005-03-09 |
| EP1495022A1 (en) | 2005-01-12 |
| DE60328272D1 (de) | 2009-08-20 |
| UA77515C2 (en) | 2006-12-15 |
| WO2003084955A1 (en) | 2003-10-16 |
| BR0306148A (pt) | 2004-10-19 |
| CA2462708A1 (en) | 2003-10-16 |
| IL160943A0 (en) | 2004-08-31 |
| CN1279041C (zh) | 2006-10-11 |
| NO20044775L (no) | 2004-12-16 |
| AR039192A1 (es) | 2005-02-09 |
| HK1070356A1 (en) | 2005-06-17 |
| RU2310656C2 (ru) | 2007-11-20 |
| HRP20040273A2 (en) | 2005-02-28 |
| KR20040095361A (ko) | 2004-11-12 |
| PL371378A1 (en) | 2005-06-13 |
| AU2003224162A1 (en) | 2003-10-20 |
| ZA200404744B (en) | 2005-09-21 |
| AU2003224162B2 (en) | 2008-06-12 |
| JP2005525395A (ja) | 2005-08-25 |
| US7202238B2 (en) | 2007-04-10 |
| ATE435863T1 (de) | 2009-07-15 |
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