KR20040007744A - 플라스미노겐 활성화제 억제제 유형-1(ｐａｉ-1)의억제제로서의 치환된 나프틸 인돌 유도체 - Google Patents
플라스미노겐 활성화제 억제제 유형-1(ｐａｉ-1)의억제제로서의 치환된 나프틸 인돌 유도체 Download PDFInfo
- Publication number
- KR20040007744A KR20040007744A KR10-2003-7016636A KR20037016636A KR20040007744A KR 20040007744 A KR20040007744 A KR 20040007744A KR 20037016636 A KR20037016636 A KR 20037016636A KR 20040007744 A KR20040007744 A KR 20040007744A
- Authority
- KR
- South Korea
- Prior art keywords
- carbon atoms
- compound
- alkyl
- pentyl
- formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
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- XEQHAEZWPZICKJ-UHFFFAOYSA-N 2-naphthalen-1-yl-1h-indole Chemical class C1=CC=C2C(C3=CC4=CC=CC=C4N3)=CC=CC2=C1 XEQHAEZWPZICKJ-UHFFFAOYSA-N 0.000 title description 9
- 239000003112 inhibitor Substances 0.000 title description 5
- 102000010752 Plasminogen Inactivators Human genes 0.000 title 1
- 108010077971 Plasminogen Inactivators Proteins 0.000 title 1
- 239000002797 plasminogen activator inhibitor Substances 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 143
- 150000003839 salts Chemical class 0.000 claims abstract description 52
- 238000000034 method Methods 0.000 claims abstract description 44
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 42
- 125000003118 aryl group Chemical group 0.000 claims abstract description 23
- 125000001589 carboacyl group Chemical group 0.000 claims abstract description 21
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 16
- 125000003435 aroyl group Chemical group 0.000 claims abstract description 15
- 239000002253 acid Chemical class 0.000 claims abstract description 14
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 14
- 125000005010 perfluoroalkyl group Chemical group 0.000 claims abstract description 14
- 150000003536 tetrazoles Chemical class 0.000 claims abstract description 14
- 238000011282 treatment Methods 0.000 claims abstract description 14
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 13
- 125000003282 alkyl amino group Chemical group 0.000 claims abstract description 12
- 229920001774 Perfluoroether Polymers 0.000 claims abstract description 11
- 125000002877 alkyl aryl group Chemical group 0.000 claims abstract description 10
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 10
- 125000004663 dialkyl amino group Chemical group 0.000 claims abstract description 9
- 125000000896 monocarboxylic acid group Chemical class 0.000 claims abstract description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 6
- PGRHXDWITVMQBC-UHFFFAOYSA-N dehydroacetic acid Natural products CC(=O)C1C(=O)OC(C)=CC1=O PGRHXDWITVMQBC-UHFFFAOYSA-N 0.000 claims abstract description 5
- PEQJBOMPGWYIRO-UHFFFAOYSA-N n-ethyl-3,4-dimethoxyaniline Chemical compound CCNC1=CC=C(OC)C(OC)=C1 PEQJBOMPGWYIRO-UHFFFAOYSA-N 0.000 claims abstract description 5
- 125000004432 carbon atom Chemical group C* 0.000 claims description 110
- 229910052739 hydrogen Inorganic materials 0.000 claims description 39
- 239000001257 hydrogen Substances 0.000 claims description 38
- -1 (2-trifluoromethyl) benzyl Chemical group 0.000 claims description 29
- 150000002431 hydrogen Chemical class 0.000 claims description 25
- 239000000203 mixture Substances 0.000 claims description 25
- 229910052736 halogen Inorganic materials 0.000 claims description 21
- 150000002367 halogens Chemical class 0.000 claims description 21
- 150000002148 esters Chemical group 0.000 claims description 19
- SIKJAQJRHWYJAI-UHFFFAOYSA-N benzopyrrole Natural products C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 15
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 14
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 13
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims description 10
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims description 10
- 241000124008 Mammalia Species 0.000 claims description 9
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 9
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- 230000003480 fibrinolytic effect Effects 0.000 claims description 8
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- 206010047249 Venous thrombosis Diseases 0.000 claims description 7
- 239000000126 substance Substances 0.000 claims description 7
- 206010051055 Deep vein thrombosis Diseases 0.000 claims description 5
- 230000006378 damage Effects 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- SRZKBYNNCQFTFV-UHFFFAOYSA-N 1-[(4-tert-butylphenyl)methyl]-3-pentyl-2-[6-(2h-tetrazol-5-ylmethoxy)naphthalen-2-yl]indole Chemical compound C=1C=C(C(C)(C)C)C=CC=1CN1C2=CC=CC=C2C(CCCCC)=C1C(C=C1C=C2)=CC=C1C=C2OCC1=NN=NN1 SRZKBYNNCQFTFV-UHFFFAOYSA-N 0.000 claims description 4
- OPHHMFYPCBMHNT-UHFFFAOYSA-N 1-[2-[5-bromo-6-(2h-tetrazol-5-ylmethoxy)naphthalen-2-yl]-3-pentylindol-1-yl]ethanone Chemical compound CC(=O)N1C2=CC=CC=C2C(CCCCC)=C1C(C=C1C=C2)=CC=C1C(Br)=C2OCC1=NN=NN1 OPHHMFYPCBMHNT-UHFFFAOYSA-N 0.000 claims description 4
- OUFFKANICABSLH-UHFFFAOYSA-N 1-[3-pentyl-2-[6-(2h-tetrazol-5-ylmethoxy)naphthalen-2-yl]indol-1-yl]ethanone Chemical compound CC(=O)N1C2=CC=CC=C2C(CCCCC)=C1C(C=C1C=C2)=CC=C1C=C2OCC1=NN=NN1 OUFFKANICABSLH-UHFFFAOYSA-N 0.000 claims description 4
- BDPXZFKVHDEPIQ-UHFFFAOYSA-N 1-benzyl-3-pentyl-2-[6-(2h-tetrazol-5-ylmethoxy)naphthalen-2-yl]indole Chemical compound C=1C=CC=CC=1CN1C2=CC=CC=C2C(CCCCC)=C1C(C=C1C=C2)=CC=C1C=C2OCC=1N=NNN=1 BDPXZFKVHDEPIQ-UHFFFAOYSA-N 0.000 claims description 4
- BUMHVJNXFPVEMO-UHFFFAOYSA-N 1-methyl-3-pentyl-2-[6-(2h-tetrazol-5-ylmethoxy)naphthalen-2-yl]indole Chemical compound CN1C2=CC=CC=C2C(CCCCC)=C1C(C=C1C=C2)=CC=C1C=C2OCC1=NN=NN1 BUMHVJNXFPVEMO-UHFFFAOYSA-N 0.000 claims description 4
- XVZQHCZCEZTSKR-UHFFFAOYSA-N 2-[1-bromo-6-(1-methyl-3-pentylindol-2-yl)naphthalen-2-yl]oxyacetic acid Chemical compound CN1C2=CC=CC=C2C(CCCCC)=C1C1=CC=C(C(Br)=C(OCC(O)=O)C=C2)C2=C1 XVZQHCZCEZTSKR-UHFFFAOYSA-N 0.000 claims description 4
- AAWAZICAXDCTFO-UHFFFAOYSA-N 2-[5-bromo-6-(2h-tetrazol-5-ylmethoxy)naphthalen-2-yl]-1-methyl-3-pentylindole Chemical compound CN1C2=CC=CC=C2C(CCCCC)=C1C(C=C1C=C2)=CC=C1C(Br)=C2OCC1=NN=NN1 AAWAZICAXDCTFO-UHFFFAOYSA-N 0.000 claims description 4
- NJGPFBJGXYWQGI-UHFFFAOYSA-N 2-[5-bromo-6-(2h-tetrazol-5-ylmethoxy)naphthalen-2-yl]-3-pentyl-1-[[2-(trifluoromethyl)phenyl]methyl]indole Chemical compound C=1C=CC=C(C(F)(F)F)C=1CN1C2=CC=CC=C2C(CCCCC)=C1C(C=C1C=C2)=CC=C1C(Br)=C2OCC1=NN=NN1 NJGPFBJGXYWQGI-UHFFFAOYSA-N 0.000 claims description 4
- SJDRBMZDCCSQEB-UHFFFAOYSA-N 3-pentyl-2-[6-(2h-tetrazol-5-ylmethoxy)naphthalen-2-yl]-1-[[2-(trifluoromethyl)phenyl]methyl]indole Chemical compound C=1C=CC=C(C(F)(F)F)C=1CN1C2=CC=CC=C2C(CCCCC)=C1C(C=C1C=C2)=CC=C1C=C2OCC1=NN=NN1 SJDRBMZDCCSQEB-UHFFFAOYSA-N 0.000 claims description 4
- 208000027418 Wounds and injury Diseases 0.000 claims description 4
- 230000015572 biosynthetic process Effects 0.000 claims description 4
- 230000015271 coagulation Effects 0.000 claims description 4
- 238000005345 coagulation Methods 0.000 claims description 4
- 125000001041 indolyl group Chemical group 0.000 claims description 4
- 208000014674 injury Diseases 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 208000011580 syndromic disease Diseases 0.000 claims description 4
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 4
- 206010003178 Arterial thrombosis Diseases 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- 125000002252 acyl group Chemical group 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 3
- 230000002093 peripheral effect Effects 0.000 claims description 3
- 208000037260 Atherosclerotic Plaque Diseases 0.000 claims description 2
- 206010003658 Atrial Fibrillation Diseases 0.000 claims description 2
- 206010008132 Cerebral thrombosis Diseases 0.000 claims description 2
- 201000001429 Intracranial Thrombosis Diseases 0.000 claims description 2
- 150000001540 azides Chemical class 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 125000004785 fluoromethoxy group Chemical group [H]C([H])(F)O* 0.000 claims description 2
- 230000003301 hydrolyzing effect Effects 0.000 claims description 2
- 208000031225 myocardial ischemia Diseases 0.000 claims description 2
- UUEVFMOUBSLVJW-UHFFFAOYSA-N oxo-[[1-[2-[2-[2-[4-(oxoazaniumylmethylidene)pyridin-1-yl]ethoxy]ethoxy]ethyl]pyridin-4-ylidene]methyl]azanium;dibromide Chemical compound [Br-].[Br-].C1=CC(=C[NH+]=O)C=CN1CCOCCOCCN1C=CC(=C[NH+]=O)C=C1 UUEVFMOUBSLVJW-UHFFFAOYSA-N 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 230000009424 thromboembolic effect Effects 0.000 claims description 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 4
- BPYFWNGIPZCIAT-UHFFFAOYSA-N 1-benzyl-2-[5-bromo-6-(2h-tetrazol-5-ylmethoxy)naphthalen-2-yl]-3-pentylindole Chemical compound C=1C=CC=CC=1CN1C2=CC=CC=C2C(CCCCC)=C1C(C=C1C=C2)=CC=C1C(Br)=C2OCC1=NN=NN1 BPYFWNGIPZCIAT-UHFFFAOYSA-N 0.000 claims 1
- 125000006491 4-t-butyl benzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])*)C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims 1
- 206010037437 Pulmonary thrombosis Diseases 0.000 claims 1
- 210000001367 artery Anatomy 0.000 claims 1
- 102000012335 Plasminogen Activator Inhibitor 1 Human genes 0.000 abstract description 30
- 108010022233 Plasminogen Activator Inhibitor 1 Proteins 0.000 abstract description 30
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- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 43
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- 238000001819 mass spectrum Methods 0.000 description 32
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- 239000011734 sodium Substances 0.000 description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 13
- 239000012267 brine Substances 0.000 description 13
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 13
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- WEVYAHXRMPXWCK-UHFFFAOYSA-N methyl cyanide Natural products CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
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- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
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| PCT/US2002/021113 WO2003000684A1 (en) | 2001-06-20 | 2002-06-18 | Substituted naphthyl indole derivatives as inhibitors of plasminogen activator inhibitor type-1 (pai-1) |
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| US7332521B2 (en) * | 2003-09-25 | 2008-02-19 | Wyeth | Substituted indoles |
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| US7141592B2 (en) * | 2003-09-25 | 2006-11-28 | Wyeth | Substituted oxadiazolidinediones |
| US7582773B2 (en) * | 2003-09-25 | 2009-09-01 | Wyeth | Substituted phenyl indoles |
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| US7446201B2 (en) * | 2003-09-25 | 2008-11-04 | Wyeth | Substituted heteroaryl benzofuran acids |
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| US9120744B2 (en) * | 2007-04-16 | 2015-09-01 | The Regents Of The University Of Michigan | Plasminogen activator inhibitor-1 inhibitors and methods of use thereof to modulate lipid metabolism |
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| US8633245B2 (en) * | 2008-04-11 | 2014-01-21 | Institute Of Medicinal Molecular Design, Inc. | PAI-1 inhibitor |
| DK2914575T3 (da) | 2012-10-31 | 2021-01-18 | Univ Michigan Regents | Plasminogen-aktivator-1-inhibitorer og fremgangsmåder til anvendelse deraf |
| CN106890324A (zh) * | 2015-12-18 | 2017-06-27 | 深圳瑞健生命科学研究院有限公司 | 一种预防和治疗糖尿病肾病的方法 |
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