ES2821877T3 - Espirolactamas como inhibidores de ROCK - Google Patents

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Publication number

ES2821877T3

ES2821877T3 ES17740241T ES17740241T ES2821877T3 ES 2821877 T3 ES2821877 T3 ES 2821877T3 ES 17740241 T ES17740241 T ES 17740241T ES 17740241 T ES17740241 T ES 17740241T ES 2821877 T3 ES2821877 T3 ES 2821877T3

Authority

ES

Spain

Prior art keywords

substituted

independently selected

alkyl

pyrrolidin

phenyl

Prior art date

2016-07-07

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.)

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• 239000011435 rock Substances 0.000 title description 38
• 239000003112 inhibitor Substances 0.000 title description 12
• 150000001875 compounds Chemical class 0.000 claims abstract description 132
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract description 93
• 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 78
• 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 72
• 229910052801 chlorine Inorganic materials 0.000 claims abstract description 69
• 229910052731 fluorine Inorganic materials 0.000 claims abstract description 68
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 64
• 229910021481 rutherfordium Inorganic materials 0.000 claims abstract description 51
• 229910052794 bromium Inorganic materials 0.000 claims abstract description 50
• 150000003839 salts Chemical class 0.000 claims abstract description 50
• 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 49
• 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 42
• 125000000217 alkyl group Chemical group 0.000 claims abstract description 38
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 23
• 125000004452 carbocyclyl group Chemical group 0.000 claims abstract description 21
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 21
• 229910052702 rhenium Inorganic materials 0.000 claims abstract description 21
• 229910052701 rubidium Inorganic materials 0.000 claims abstract description 21
• 101150105130 RORB gene Proteins 0.000 claims abstract description 20
• 125000003118 aryl group Chemical group 0.000 claims abstract description 17
• 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims abstract description 13
• 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims abstract description 13
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims abstract description 11
• 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 11
• 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 9
• 125000006706 (C3-C6) carbocyclyl group Chemical group 0.000 claims abstract description 3
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 3
• 229910052700 potassium Inorganic materials 0.000 claims abstract description 3
• -1 4- (1H-pyrazol-4-yl) phenyl Chemical group 0.000 claims description 87
• 229910052799 carbon Inorganic materials 0.000 claims description 35
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 26
• 238000011282 treatment Methods 0.000 claims description 22
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 18
• 201000010099 disease Diseases 0.000 claims description 18
• 230000000694 effects Effects 0.000 claims description 16
• 239000008194 pharmaceutical composition Substances 0.000 claims description 16
• NZBBDMMHADSGAF-UHFFFAOYSA-N 1'-[4-(1H-pyrazol-4-yl)phenyl]spiro[1,3-dihydroindole-2,3'-pyrrolidine]-2'-one Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(C2(CC1)NC1=CC=CC=C1C2)=O NZBBDMMHADSGAF-UHFFFAOYSA-N 0.000 claims description 14
• 208000024172 Cardiovascular disease Diseases 0.000 claims description 12
• 239000003937 drug carrier Substances 0.000 claims description 12
• GDGXLYITRDZQAV-UHFFFAOYSA-N 5-fluoro-1'-[4-(1H-pyrazol-4-yl)phenyl]spiro[1,3-dihydroindole-2,3'-pyrrolidine]-2'-one Chemical compound N1C2=C(CC31CCN(C3=O)C1=CC=C(C3=CNN=C3)C=C1)C=C(F)C=C2 GDGXLYITRDZQAV-UHFFFAOYSA-N 0.000 claims description 10
• 206010020772 Hypertension Diseases 0.000 claims description 10
• 238000011321 prophylaxis Methods 0.000 claims description 10
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• 108010041788 rho-Associated Kinases Proteins 0.000 claims description 9
• 102000000568 rho-Associated Kinases Human genes 0.000 claims description 9
• RMVQSTDAQPRZSX-UHFFFAOYSA-N 4-fluoro-6-methoxy-1'-[4-(1H-pyrazol-4-yl)phenyl]spiro[1,3-dihydroindole-2,3'-pyrrolidine]-2'-one Chemical compound C1=2NC3(CC1=C(F)C=C(OC)C=2)CCN(C3=O)C1=CC=C(C=2C=NNC=2)C=C1 RMVQSTDAQPRZSX-UHFFFAOYSA-N 0.000 claims description 8
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• VSVFGXXQZGDKOC-UHFFFAOYSA-N 5-fluoro-1'-[6-methoxy-5-(1H-pyrazol-4-yl)pyridin-2-yl]spiro[1,3-dihydroindene-2,3'-pyrrolidine]-2'-one Chemical compound COC1=C(C=CC(=N1)N1CCC2(CC3=CC=C(F)C=C3C2)C1=O)C1=CNN=C1 VSVFGXXQZGDKOC-UHFFFAOYSA-N 0.000 claims description 7
• GFAUBMISBILPCV-UHFFFAOYSA-N 5-methoxy-1'-[4-(1H-pyrazol-4-yl)phenyl]spiro[3H-1-benzofuran-2,3'-pyrrolidine]-2'-one Chemical compound C1=2OC3(CC1=CC(OC)=CC=2)CCN(C3=O)C1=CC=C(C=2C=NNC=2)C=C1 GFAUBMISBILPCV-UHFFFAOYSA-N 0.000 claims description 7
• CZUKRUABVSLHGN-UHFFFAOYSA-N 5-methoxy-1'-[6-methoxy-5-(1H-pyrazol-4-yl)pyridin-2-yl]spiro[1,3-dihydroindene-2,3'-pyrrolidine]-2'-one Chemical compound COC=1C=C2CC3(C(N(CC3)C3=NC(=C(C=C3)C=3C=NNC=3)OC)=O)CC2=CC=1 CZUKRUABVSLHGN-UHFFFAOYSA-N 0.000 claims description 7
• UFIXUBXNBHETDF-UHFFFAOYSA-N 5-fluoro-1'-[4-(1H-pyrazol-4-yl)phenyl]spiro[1,3-dihydroindene-2,3'-pyrrolidine]-2'-one Chemical compound C12(CCN(C1=O)C1=CC=C(C=3C=NNC=3)C=C1)CC1=CC=C(F)C=C1C2 UFIXUBXNBHETDF-UHFFFAOYSA-N 0.000 claims description 6
• PXBNCAPNSJKORP-UHFFFAOYSA-N 5-methoxy-1'-[4-(1H-pyrazol-4-yl)phenyl]spiro[1,3-dihydroindene-2,3'-pyrrolidine]-2'-one Chemical compound C1=2CC3(CCN(C3=O)C3=CC=C(C=4C=NNC=4)C=C3)CC1=CC=C(OC)C=2 PXBNCAPNSJKORP-UHFFFAOYSA-N 0.000 claims description 5
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• 210000002460 smooth muscle Anatomy 0.000 claims description 5
• VQFNTTVWRYLUML-UHFFFAOYSA-N 4'-(aminomethyl)-1'-[4-(1H-pyrazol-4-yl)phenyl]spiro[1,3-dihydroindole-2,3'-pyrrolidine]-2'-one Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(C2(C(C1)CN)NC1=CC=CC=C1C2)=O VQFNTTVWRYLUML-UHFFFAOYSA-N 0.000 claims description 4
• KUVFBDVJUBDKEF-UHFFFAOYSA-N 4'-(hydroxymethyl)-1'-[4-(1H-pyrazol-4-yl)phenyl]spiro[1,3-dihydroindole-2,3'-pyrrolidine]-2'-one Chemical compound C(C1CN(C(=O)C21CC1=CC=CC=C1N2)C1=CC=C(C=C1)C=1C=NNC=1)O KUVFBDVJUBDKEF-UHFFFAOYSA-N 0.000 claims description 4
• VDUBYHAYWDQMSL-UHFFFAOYSA-N 4-methyl-1'-[4-(1H-pyrazol-4-yl)phenyl]spiro[1,3-dihydroindole-2,3'-pyrrolidine]-2'-one Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(C2(CC1)NC1=CC=CC(=C1C2)C)=O VDUBYHAYWDQMSL-UHFFFAOYSA-N 0.000 claims description 4
• XESYGOKEGVLFMK-UHFFFAOYSA-N 6-(2-hydroxy-2-methylpropoxy)-1'-[4-(1H-pyrazol-4-yl)phenyl]spiro[1,3-dihydroindole-2,3'-pyrrolidine]-2'-one Chemical compound C(COC1=CC=C2C(NC3(C2)CCN(C3=O)C2=CC=C(C=3C=NNC=3)C=C2)=C1)(C)(O)C XESYGOKEGVLFMK-UHFFFAOYSA-N 0.000 claims description 4
• BVXVOSBBRKWXTM-UHFFFAOYSA-N 6-hydroxy-1'-[4-(1H-pyrazol-4-yl)phenyl]spiro[1,3-dihydroindole-2,3'-pyrrolidine]-2'-one Chemical compound N1C2=C(CC31CCN(C3=O)C1=CC=C(C=C1)C=1C=NNC=1)C=CC(O)=C2 BVXVOSBBRKWXTM-UHFFFAOYSA-N 0.000 claims description 4
• USKLRJZVISLPLA-UHFFFAOYSA-N 6-methoxy-1-methyl-1'-[4-(1H-pyrazol-4-yl)phenyl]spiro[3H-indole-2,3'-pyrrolidine]-2'-one Chemical compound N1(C2=C(CC31CCN(C3=O)C1=CC=C(C=C1)C=1C=NNC=1)C=CC(OC)=C2)C USKLRJZVISLPLA-UHFFFAOYSA-N 0.000 claims description 4
• 206010002383 Angina Pectoris Diseases 0.000 claims description 4
• 201000001320 Atherosclerosis Diseases 0.000 claims description 4
• 239000003085 diluting agent Substances 0.000 claims description 4
• 230000003176 fibrotic effect Effects 0.000 claims description 4
• 208000002815 pulmonary hypertension Diseases 0.000 claims description 4
• MHRHCSNHLAHXPI-UHFFFAOYSA-N 1'-(4-pyridin-4-ylphenyl)spiro[1,3-dihydroindole-2,3'-pyrrolidine]-2'-one Chemical compound C1=2NC3(CC1=CC=CC=2)CCN(C3=O)C1=CC=C(C2=CC=NC=C2)C=C1 MHRHCSNHLAHXPI-UHFFFAOYSA-N 0.000 claims description 3
• KCYPZRNQRHBHRS-UHFFFAOYSA-N 1'-(4-pyridin-4-ylphenyl)spiro[3H-1-benzofuran-2,3'-pyrrolidine]-2'-one Chemical compound O1C2=C(CC31CCN(C3=O)C1=CC=C(C3=CC=NC=C3)C=C1)C=CC=C2 KCYPZRNQRHBHRS-UHFFFAOYSA-N 0.000 claims description 3
• BCKCDMOENWEOTR-UHFFFAOYSA-N 1'-[3-methoxy-4-(1H-pyrazol-4-yl)phenyl]spiro[1,3-dihydroindene-2,3'-pyrrolidine]-2'-one Chemical compound C1=2CC3(CCN(C3=O)C3=CC=C(C(OC)=C3)C=3C=NNC=3)CC1=CC=CC=2 BCKCDMOENWEOTR-UHFFFAOYSA-N 0.000 claims description 3
• GVRNNYOHGGGEEX-UHFFFAOYSA-N 1'-[4-(1H-indazol-5-yl)phenyl]spiro[1,3-dihydroindole-2,3'-pyrrolidine]-2'-one Chemical compound C1=2NC3(CC1=CC=CC=2)CCN(C3=O)C1=CC=C(C=C1)C1=CC=2C=NNC=2C=C1 GVRNNYOHGGGEEX-UHFFFAOYSA-N 0.000 claims description 3
• YWXBSRRUYFCTFK-UHFFFAOYSA-N 1'-[4-(1H-pyrazol-4-yl)phenyl]spiro[1,3-dihydroindene-2,3'-pyrrolidine]-2'-one Chemical compound N1(CCC2(C1=O)CC1=CC=CC=C1C2)C1=CC=C(C2=CNN=C2)C=C1 YWXBSRRUYFCTFK-UHFFFAOYSA-N 0.000 claims description 3
• KXFCSULEXHNDMS-UHFFFAOYSA-N 1'-[6-methoxy-5-(1H-pyrazol-4-yl)pyridin-2-yl]spiro[1,3-dihydroindene-2,3'-pyrrolidine]-2'-one Chemical compound C1=2CC3(CCN(C3=O)C3=NC(=C(C=4C=NNC=4)C=C3)OC)CC1=CC=CC=2 KXFCSULEXHNDMS-UHFFFAOYSA-N 0.000 claims description 3
• RJXLYIPFCSEPIV-UHFFFAOYSA-N 1'-[6-methoxy-5-(1H-pyrazol-4-yl)pyridin-2-yl]spiro[1,3-dihydroindole-2,3'-pyrrolidine]-2'-one Chemical compound C1=2NC3(CC1=CC=CC=2)CCN(C3=O)C1=NC(=C(C2=CNN=C2)C=C1)OC RJXLYIPFCSEPIV-UHFFFAOYSA-N 0.000 claims description 3
• RSNXWZHLOZFELL-UHFFFAOYSA-N 5-methoxy-1'-[4-(1H-pyrazol-4-yl)phenyl]spiro[1,3-dihydroindole-2,3'-pyrrolidine]-2'-one Chemical compound C1=2NC3(CCN(C3=O)C3=CC=C(C=C3)C3=CNN=C3)CC1=CC(OC)=CC=2 RSNXWZHLOZFELL-UHFFFAOYSA-N 0.000 claims description 3
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• KUVFBDVJUBDKEF-FBLFFUNLSA-N (2R)-4'-(hydroxymethyl)-1'-[4-(1H-pyrazol-4-yl)phenyl]spiro[1,3-dihydroindole-2,3'-pyrrolidine]-2'-one Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C([C@@]2(C(C1)CO)NC1=CC=CC=C1C2)=O KUVFBDVJUBDKEF-FBLFFUNLSA-N 0.000 claims description 2
• KUVFBDVJUBDKEF-LFABVHOISA-N (2S)-4'-(hydroxymethyl)-1'-[4-(1H-pyrazol-4-yl)phenyl]spiro[1,3-dihydroindole-2,3'-pyrrolidine]-2'-one Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C([C@]2(C(C1)CO)NC1=CC=CC=C1C2)=O KUVFBDVJUBDKEF-LFABVHOISA-N 0.000 claims description 2
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• MEFGTSSAPBMNDT-UHFFFAOYSA-N 1'-[5-(1H-pyrazol-4-yl)pyridin-2-yl]spiro[1,3-dihydroindole-2,3'-pyrrolidine]-2'-one Chemical compound C1=2NC3(CC1=CC=CC=2)CCN(C3=O)C1=NC=C(C=2C=NNC=2)C=C1 MEFGTSSAPBMNDT-UHFFFAOYSA-N 0.000 claims description 2
• AYRXESUXLWHBCL-UHFFFAOYSA-N spiro[1,3-dihydroindole-2,3'-pyrrolidine]-2'-one Chemical compound N1C(C2(CC1)NC1=CC=CC=C1C2)=O AYRXESUXLWHBCL-UHFFFAOYSA-N 0.000 claims description 2
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