RU2434011C2 - Производные азабицикло [3.1.0]гексана, применимые в качестве модуляторов допаминовых рецепторов d3 - Google Patents
Производные азабицикло [3.1.0]гексана, применимые в качестве модуляторов допаминовых рецепторов d3 Download PDFInfo
- Publication number
- RU2434011C2 RU2434011C2 RU2006133909/04A RU2006133909A RU2434011C2 RU 2434011 C2 RU2434011 C2 RU 2434011C2 RU 2006133909/04 A RU2006133909/04 A RU 2006133909/04A RU 2006133909 A RU2006133909 A RU 2006133909A RU 2434011 C2 RU2434011 C2 RU 2434011C2
- Authority
- RU
- Russia
- Prior art keywords
- methyl
- azabicyclo
- thio
- propyl
- triazol
- Prior art date
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- 102000004073 Dopamine D3 Receptors Human genes 0.000 title description 2
- 108090000525 Dopamine D3 Receptors Proteins 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 380
- 150000003839 salts Chemical class 0.000 claims abstract description 76
- VLKZOEOYAKHREP-UHFFFAOYSA-N methyl pentane Natural products CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims abstract description 48
- 208000011117 substance-related disease Diseases 0.000 claims abstract description 25
- 108050004812 Dopamine receptor Proteins 0.000 claims abstract description 14
- 102000015554 Dopamine receptor Human genes 0.000 claims abstract description 14
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 7
- 238000002560 therapeutic procedure Methods 0.000 claims abstract 2
- -1 1,1-dioxo-2-isothiazolidinyl Chemical group 0.000 claims description 254
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 113
- 238000000034 method Methods 0.000 claims description 105
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 91
- 125000000217 alkyl group Chemical group 0.000 claims description 77
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 claims description 46
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 40
- 229910052736 halogen Inorganic materials 0.000 claims description 37
- 125000003545 alkoxy group Chemical group 0.000 claims description 36
- 150000002367 halogens Chemical class 0.000 claims description 36
- 229910052739 hydrogen Inorganic materials 0.000 claims description 33
- 125000000446 sulfanediyl group Chemical group *S* 0.000 claims description 31
- 208000028017 Psychotic disease Diseases 0.000 claims description 29
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 29
- 239000000460 chlorine Substances 0.000 claims description 28
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 claims description 26
- 125000002619 bicyclic group Chemical group 0.000 claims description 25
- QRDSDKAGXMWBID-UHFFFAOYSA-N 5-azabicyclo[3.1.0]hexane Chemical compound C1CCN2CC21 QRDSDKAGXMWBID-UHFFFAOYSA-N 0.000 claims description 22
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 19
- 125000001424 substituent group Chemical group 0.000 claims description 19
- 201000009032 substance abuse Diseases 0.000 claims description 18
- 125000002861 (C1-C4) alkanoyl group Chemical group 0.000 claims description 17
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims description 17
- 229910052801 chlorine Inorganic materials 0.000 claims description 17
- 125000000623 heterocyclic group Chemical group 0.000 claims description 17
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 17
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 16
- 125000001072 heteroaryl group Chemical group 0.000 claims description 16
- 102000005962 receptors Human genes 0.000 claims description 16
- 108020003175 receptors Proteins 0.000 claims description 16
- 125000004076 pyridyl group Chemical group 0.000 claims description 15
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- 239000001257 hydrogen Substances 0.000 claims description 14
- 231100000736 substance abuse Toxicity 0.000 claims description 13
- 125000000335 thiazolyl group Chemical group 0.000 claims description 13
- 238000011282 treatment Methods 0.000 claims description 13
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- 125000000842 isoxazolyl group Chemical group 0.000 claims description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 11
- 125000002971 oxazolyl group Chemical group 0.000 claims description 10
- 201000000980 schizophrenia Diseases 0.000 claims description 10
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 9
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- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 9
- 125000001544 thienyl group Chemical group 0.000 claims description 9
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 8
- WGSXKYXKAARAKD-UHFFFAOYSA-N 1-fluoro-3-isocyanato-5-(trifluoromethyl)benzene Chemical group FC1=CC(N=C=O)=CC(C(F)(F)F)=C1 WGSXKYXKAARAKD-UHFFFAOYSA-N 0.000 claims description 6
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 6
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 claims description 6
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- 125000002098 pyridazinyl group Chemical group 0.000 claims description 6
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- 125000001425 triazolyl group Chemical group 0.000 claims description 6
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- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 239000011737 fluorine Substances 0.000 claims description 5
- 229910052731 fluorine Inorganic materials 0.000 claims description 5
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 5
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 5
- 125000004189 3,4-dichlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(Cl)C([H])=C1* 0.000 claims description 4
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 4
- 230000002349 favourable effect Effects 0.000 claims description 4
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims description 4
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- 125000005843 halogen group Chemical group 0.000 claims description 3
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- URICTYNITRPTLS-UZTOHYMASA-N 5-[5-[3-[(1s,5r)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl]propylsulfanyl]-4-methyl-1,2,4-triazol-3-yl]-2-methylquinoline Chemical compound C1([C@]23C[C@H]2CN(C3)CCCSC2=NN=C(N2C)C=2C3=CC=C(N=C3C=CC=2)C)=CC=C(Cl)C(Cl)=C1 URICTYNITRPTLS-UZTOHYMASA-N 0.000 claims description 2
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 2
- BCASKIBJIZNNHQ-GAJHUEQPSA-N (1s,5r)-1-(4-bromophenyl)-3-[3-[[5-(3,4-difluorophenyl)-4-methyl-1,2,4-triazol-3-yl]sulfanyl]propyl]-3-azabicyclo[3.1.0]hexane Chemical compound C1([C@]23C[C@H]2CN(C3)CCCSC=2N(C(=NN=2)C=2C=C(F)C(F)=CC=2)C)=CC=C(Br)C=C1 BCASKIBJIZNNHQ-GAJHUEQPSA-N 0.000 claims 1
- PSAASTBVOYWQMI-CJAUYULYSA-N 1-[2-methoxy-5-[(1r,5s)-3-[3-[[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-1,2,4-triazol-3-yl]sulfanyl]propyl]-3-azabicyclo[3.1.0]hexan-1-yl]phenyl]propan-1-one Chemical compound C1=C(OC)C(C(=O)CC)=CC([C@]23[C@H](C2)CN(CCCSC=2N(C(C4=C(N=CO4)C)=NN=2)C)C3)=C1 PSAASTBVOYWQMI-CJAUYULYSA-N 0.000 claims 1
- JAXBDYZJJWNOOP-UHFFFAOYSA-N 5-[5-[3-(3-azabicyclo[3.1.0]hexan-1-yl)propylsulfanyl]-4-methyl-1,2,4-triazol-3-yl]-4-methyl-1,3-oxazole Chemical compound CN1C(=NN=C1C1=C(N=CO1)C)SCCCC12CNCC2C1 JAXBDYZJJWNOOP-UHFFFAOYSA-N 0.000 claims 1
- PHOYQXNYVNYDOX-UHFFFAOYSA-N C(#N)Cl(O)OC(F)(F)F Chemical compound C(#N)Cl(O)OC(F)(F)F PHOYQXNYVNYDOX-UHFFFAOYSA-N 0.000 claims 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims 1
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Applications Claiming Priority (7)
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| PCT/EP2005/001940 WO2005080382A1 (en) | 2004-02-23 | 2005-02-21 | Azabicyclo (3.1.0) hexane derivatives useful as modulators of dopamine d3 receptors |
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| PT1745040E (pt) * | 2004-02-23 | 2010-03-08 | Glaxo Group Ltd | Derivados do azabiciclo3.1.0-hexano úteis como moduladores dos receptores d3 da dopamina |
| US20070043100A1 (en) | 2005-08-16 | 2007-02-22 | Hagen Eric J | Novel polymorphs of azabicyclohexane |
| GB0507601D0 (en) * | 2005-04-14 | 2005-05-18 | Glaxo Group Ltd | Compounds |
| GB0507602D0 (en) | 2005-04-14 | 2005-05-18 | Glaxo Group Ltd | Compounds |
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| GB0512099D0 (en) * | 2005-06-14 | 2005-07-20 | Glaxo Group Ltd | Compounds |
| EP1891056B1 (en) | 2005-06-14 | 2010-10-13 | Glaxo Group Limited | Novel compounds |
| WO2007006117A1 (en) * | 2005-07-13 | 2007-01-18 | Nicogen Inc. | Novel cyp2a6 inhibitors |
| EP1915146A4 (en) | 2005-07-27 | 2010-06-02 | Dov Pharmaceutical Inc | NOVEL 1-ARYL-3-AZABICYCLO [3.1.0] HEXANEES. PREPARATION AND USE FOR THE TREATMENT OF NEUROPSYCHIATRIC DISEASES |
| GB0517175D0 (en) * | 2005-08-22 | 2005-09-28 | Glaxo Group Ltd | Compounds |
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| GB0517193D0 (en) * | 2005-08-22 | 2005-09-28 | Glaxo Group Ltd | Novel use |
| US7799815B2 (en) * | 2005-08-22 | 2010-09-21 | Glaxo Group Limited | Triazole derivatives as modulators of dopamine D3 receptors |
| GB0517191D0 (en) | 2005-08-22 | 2005-09-28 | Glaxo Group Ltd | Compounds |
| EA200870404A1 (ru) | 2006-04-03 | 2009-04-28 | Глэксо Груп Лимитед | Производные азабицикло[3.1.0.]гексила в качестве модуляторов рецепторов допамина d3 |
| GB0607899D0 (en) * | 2006-04-03 | 2006-05-31 | Glaxo Group Ltd | Process for preparing heterocyclic derivatives |
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| WO2007113258A1 (en) * | 2006-04-03 | 2007-10-11 | Glaxo Group Limited | Azabicyclo [3. 1. o] hexane derivatives as modulators of dopamine d3 receptors |
| EP2007751B1 (en) * | 2006-04-03 | 2013-08-21 | Glaxo Group Limited | Azabicyclo [3. 1. o] hexyl derivatives as modulators of dopamine d3 receptors |
| GB0608452D0 (en) * | 2006-04-27 | 2006-06-07 | Glaxo Group Ltd | Novel compounds |
| US20080045725A1 (en) | 2006-04-28 | 2008-02-21 | Murry Jerry A | Process For The Synthesis of (+) And (-)-1-(3,4-Dichlorophenyl)-3-Azabicyclo[3.1.0]Hexane |
| GB0616574D0 (en) * | 2006-08-21 | 2006-09-27 | Glaxo Group Ltd | Compounds |
| US8138377B2 (en) | 2006-11-07 | 2012-03-20 | Dov Pharmaceutical, Inc. | Arylbicyclo[3.1.0]hexylamines and methods and compositions for their preparation and use |
| EP2167083B1 (en) * | 2007-06-06 | 2015-10-28 | Euthymics Bioscience, Inc. | 1- heteroaryl-3-azabicyclo[3.1.0]hexanes, methods for their preparation and their use as medicaments |
| US9133159B2 (en) | 2007-06-06 | 2015-09-15 | Neurovance, Inc. | 1-heteroaryl-3-azabicyclo[3.1.0]hexanes, methods for their preparation and their use as medicaments |
| GB0719235D0 (en) | 2007-10-02 | 2007-11-14 | Glaxo Group Ltd | Novel compounds |
| GB0719234D0 (en) * | 2007-10-02 | 2007-11-14 | Glaxo Group Ltd | Novel compounds |
| MX2010014500A (es) | 2008-06-24 | 2011-05-30 | Codexis Inc | Procedimientos biocataliticos para la preparacion de compuestos de prolina biciclica fusionada sustancialmente estereomericamente puros. |
| US8536185B2 (en) * | 2008-09-22 | 2013-09-17 | Cayman Chemical Company, Incorporated | Multiheteroaryl compounds as inhibitors of H-PGDS and their use for treating prostaglandin D2 mediated diseases |
| KR20120106697A (ko) * | 2009-06-26 | 2012-09-26 | 파나세아 바이오테크 리미티드 | 신규 아자비시클로헥산 |
| US20140206740A1 (en) | 2011-07-30 | 2014-07-24 | Neurovance, Inc. | Use Of (1R,5S)-(+)-(Napthalen-2-yl)-3-Azabicyclo[3.1.0]Hexane In The Treatment Of Conditions Affected By Monoamine Neurotransmitters |
| EP3068226A4 (en) * | 2013-11-11 | 2017-05-17 | Euthymics Bioscience, Inc. | Novel methods |
| ES2821896T3 (es) | 2015-08-05 | 2021-04-28 | Indivior Uk Ltd | Antagonistas del receptor de dopamina D3 que tienen una unidad estructural biciclo |
| US11447484B2 (en) | 2018-01-26 | 2022-09-20 | Shionogi & Co., Ltd. | Cyclic compound having dopamine D3 receptor antagonistic effect |
| AU2021296163B2 (en) | 2020-06-22 | 2024-07-04 | Corcept Therapeutics Incorporated | Quaternary indazole glucocorticoid receptor antagonists |
| US12115154B2 (en) | 2020-12-16 | 2024-10-15 | Srx Cardio, Llc | Compounds for the modulation of proprotein convertase subtilisin/kexin type 9 (PCSK9) |
| IL313663A (en) | 2021-12-21 | 2024-08-01 | Corcept Therapeutics Inc | Piperazine indazole glucocorticoid receptor antagonists |
| KR20240125035A (ko) | 2021-12-21 | 2024-08-19 | 코어셉트 쎄라퓨틱스 인코포레이티드 | 이환 인다졸 글루코코르티코이드 수용체 길항제 |
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| TWI274750B (en) * | 1999-01-12 | 2007-03-01 | Abbott Gmbh & Co Kg | Triazole compounds showing high affinity to dopamine D3 receptor and pharmaceutical composition comprising the same |
| GB0015562D0 (en) * | 2000-06-23 | 2000-08-16 | Pfizer Ltd | Heterocycles |
| EP1335915B1 (en) | 2000-11-14 | 2008-01-02 | Smithkline Beecham Plc | Tetrahydrobenzazepine derivatives useful as modulators of dopamine d3 receptors (antipsychotic agents) |
| US6569887B2 (en) * | 2001-08-24 | 2003-05-27 | Dov Pharmaceuticals Inc. | (−)-1-(3,4-Dichlorophenyl)-3-azabicyclo[3.1.0]hexane, compositions thereof, and uses as a dopamine-reuptake |
| EA006708B1 (ru) * | 2001-10-22 | 2006-02-24 | Пфайзер Продактс Инк. | Производные 3-азабицикло (3.1.0) гексана в качестве антагонистов опиоидного рецептора |
| WO2004014881A2 (en) * | 2002-08-09 | 2004-02-19 | Astra Zeneca Ab | '1,2,4'oxadiazoles as modulators of metabotropic glutamate receptor-5 |
| PT1745040E (pt) * | 2004-02-23 | 2010-03-08 | Glaxo Group Ltd | Derivados do azabiciclo3.1.0-hexano úteis como moduladores dos receptores d3 da dopamina |
| GB0507601D0 (en) * | 2005-04-14 | 2005-05-18 | Glaxo Group Ltd | Compounds |
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| GB0517175D0 (en) | 2005-08-22 | 2005-09-28 | Glaxo Group Ltd | Compounds |
| US7799815B2 (en) * | 2005-08-22 | 2010-09-21 | Glaxo Group Limited | Triazole derivatives as modulators of dopamine D3 receptors |
| GB0517187D0 (en) * | 2005-08-22 | 2005-09-28 | Glaxo Group Ltd | Compounds |
| GB0517191D0 (en) | 2005-08-22 | 2005-09-28 | Glaxo Group Ltd | Compounds |
| GB0517193D0 (en) * | 2005-08-22 | 2005-09-28 | Glaxo Group Ltd | Novel use |
| EA200870404A1 (ru) | 2006-04-03 | 2009-04-28 | Глэксо Груп Лимитед | Производные азабицикло[3.1.0.]гексила в качестве модуляторов рецепторов допамина d3 |
| GB0616574D0 (en) * | 2006-08-21 | 2006-09-27 | Glaxo Group Ltd | Compounds |
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2005
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