TWI730032B - 作為ｒｏｃｋ抑制劑之螺庚烷水楊酸醯胺及相關化合物 - Google Patents
作為ｒｏｃｋ抑制劑之螺庚烷水楊酸醯胺及相關化合物 Download PDFInfo
- Publication number
- TWI730032B TWI730032B TW106101072A TW106101072A TWI730032B TW I730032 B TWI730032 B TW I730032B TW 106101072 A TW106101072 A TW 106101072A TW 106101072 A TW106101072 A TW 106101072A TW I730032 B TWI730032 B TW I730032B
- Authority
- TW
- Taiwan
- Prior art keywords
- alkyl
- spiro
- oxy
- pyridine
- carboxamide
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 103
- -1 Spiroheptane salicylamides Chemical class 0.000 title claims description 228
- 239000011435 rock Substances 0.000 title abstract description 35
- 239000003112 inhibitor Substances 0.000 title abstract description 10
- 150000003839 salts Chemical class 0.000 claims abstract description 65
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 7
- 210000002460 smooth muscle Anatomy 0.000 claims abstract description 6
- 230000003176 fibrotic effect Effects 0.000 claims abstract description 5
- 208000027866 inflammatory disease Diseases 0.000 claims abstract 2
- 125000000217 alkyl group Chemical group 0.000 claims description 1933
- 125000003003 spiro group Chemical group 0.000 claims description 637
- 125000000623 heterocyclic group Chemical group 0.000 claims description 583
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 claims description 488
- 125000003545 alkoxy group Chemical group 0.000 claims description 345
- 125000002837 carbocyclic group Chemical group 0.000 claims description 290
- 235000005152 nicotinamide Nutrition 0.000 claims description 254
- 239000011570 nicotinamide Substances 0.000 claims description 254
- 229910052739 hydrogen Inorganic materials 0.000 claims description 194
- 229910052799 carbon Inorganic materials 0.000 claims description 178
- 229910052757 nitrogen Inorganic materials 0.000 claims description 167
- 229910052736 halogen Inorganic materials 0.000 claims description 164
- 150000002367 halogens Chemical class 0.000 claims description 164
- 229910052760 oxygen Inorganic materials 0.000 claims description 148
- 125000004432 carbon atom Chemical group C* 0.000 claims description 128
- 125000005842 heteroatom Chemical group 0.000 claims description 113
- 229910004013 NO 2 Inorganic materials 0.000 claims description 101
- 125000002947 alkylene group Chemical group 0.000 claims description 95
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 91
- 125000003342 alkenyl group Chemical group 0.000 claims description 79
- JVOGPCAZHXALIS-UHFFFAOYSA-N pyrazolo[1,5-a]pyridine-3-carboxamide Chemical compound C1=CC=CC2=C(C(=O)N)C=NN21 JVOGPCAZHXALIS-UHFFFAOYSA-N 0.000 claims description 73
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 69
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 68
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 53
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 52
- 125000000304 alkynyl group Chemical group 0.000 claims description 50
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 45
- ZHNUHDYFZUAESO-UHFFFAOYSA-N formamide Substances NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims description 45
- 229910002091 carbon monoxide Inorganic materials 0.000 claims description 44
- 235000010290 biphenyl Nutrition 0.000 claims description 34
- 125000006367 bivalent amino carbonyl group Chemical group [H]N([*:1])C([*:2])=O 0.000 claims description 34
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 34
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 33
- 238000006467 substitution reaction Methods 0.000 claims description 30
- 150000001335 aliphatic alkanes Chemical group 0.000 claims description 29
- 125000001188 haloalkyl group Chemical group 0.000 claims description 29
- 201000010099 disease Diseases 0.000 claims description 28
- ZMBYQTGAXZOMOO-UHFFFAOYSA-N imidazo[1,2-a]pyridine-3-carboxamide Chemical compound C1=CC=CN2C(C(=O)N)=CN=C21 ZMBYQTGAXZOMOO-UHFFFAOYSA-N 0.000 claims description 24
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 20
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 20
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 17
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 15
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 15
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 15
- 229910052801 chlorine Inorganic materials 0.000 claims description 14
- 229910052731 fluorine Inorganic materials 0.000 claims description 14
- 125000001424 substituent group Chemical group 0.000 claims description 14
- 229910052717 sulfur Inorganic materials 0.000 claims description 13
- 125000004429 atom Chemical group 0.000 claims description 12
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 11
- 206010020772 Hypertension Diseases 0.000 claims description 11
- 239000004202 carbamide Substances 0.000 claims description 11
- 125000001072 heteroaryl group Chemical group 0.000 claims description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 11
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 11
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 10
- 239000003814 drug Substances 0.000 claims description 9
- 230000000694 effects Effects 0.000 claims description 9
- CUKKPJJAMSZCEC-UHFFFAOYSA-N pyrazolo[1,5-a]pyridin-3-ylmethanamine Chemical compound C1=CC=CC2=C(CN)C=NN21 CUKKPJJAMSZCEC-UHFFFAOYSA-N 0.000 claims description 9
- 208000006011 Stroke Diseases 0.000 claims description 8
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 8
- 108010041788 rho-Associated Kinases Proteins 0.000 claims description 8
- 102000000568 rho-Associated Kinases Human genes 0.000 claims description 8
- 239000001301 oxygen Substances 0.000 claims description 7
- 125000004939 6-pyridyl group Chemical group N1=CC=CC=C1* 0.000 claims description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- 206010019280 Heart failures Diseases 0.000 claims description 5
- 206010028980 Neoplasm Diseases 0.000 claims description 5
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 5
- 230000002159 abnormal effect Effects 0.000 claims description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 5
- 208000035475 disorder Diseases 0.000 claims description 5
- UTCSSFWDNNEEBH-UHFFFAOYSA-N imidazo[1,2-a]pyridine Chemical compound C1=CC=CC2=NC=CN21 UTCSSFWDNNEEBH-UHFFFAOYSA-N 0.000 claims description 5
- 206010002383 Angina Pectoris Diseases 0.000 claims description 4
- 201000001320 Atherosclerosis Diseases 0.000 claims description 4
- 125000000440 benzylamino group Chemical group [H]N(*)C([H])([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- YNBADRVTZLEFNH-UHFFFAOYSA-N methyl nicotinate Chemical compound COC(=O)C1=CC=CN=C1 YNBADRVTZLEFNH-UHFFFAOYSA-N 0.000 claims description 4
- 208000002815 pulmonary hypertension Diseases 0.000 claims description 4
- SZMPXSZRPMZQPS-UHFFFAOYSA-N 2h-1,3-oxazole-3-carboxamide Chemical compound NC(=O)N1COC=C1 SZMPXSZRPMZQPS-UHFFFAOYSA-N 0.000 claims description 3
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 3
- 208000012902 Nervous system disease Diseases 0.000 claims description 3
- 208000025966 Neurological disease Diseases 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 3
- 208000029078 coronary artery disease Diseases 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- HFZLSTDPRQSZCQ-UHFFFAOYSA-N 1-pyrrolidin-3-ylpyrrolidine Chemical group C1CCCN1C1CNCC1 HFZLSTDPRQSZCQ-UHFFFAOYSA-N 0.000 claims description 2
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 2
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 claims description 2
- 235000019260 propionic acid Nutrition 0.000 claims description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 claims 115
- 229960003966 nicotinamide Drugs 0.000 claims 79
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims 28
- XBNXGUXGBLLYCD-UHFFFAOYSA-N imidazo[1,5-a]pyridine-1-carboxamide Chemical compound C1=CC=CC2=C(C(=O)N)N=CN21 XBNXGUXGBLLYCD-UHFFFAOYSA-N 0.000 claims 14
- 239000000779 smoke Substances 0.000 claims 5
- GGNIKGLUPSHSBV-UHFFFAOYSA-N thiazole-5-carboxamide Chemical compound NC(=O)C1=CN=CS1 GGNIKGLUPSHSBV-UHFFFAOYSA-N 0.000 claims 5
- 150000001412 amines Chemical class 0.000 claims 4
- IBBMAWULFFBRKK-UHFFFAOYSA-N picolinamide Chemical compound NC(=O)C1=CC=CC=N1 IBBMAWULFFBRKK-UHFFFAOYSA-N 0.000 claims 4
- PQQRHWFRZHFGFM-UHFFFAOYSA-N 1,3-thiazole-4-carboxamide Chemical compound NC(=O)C1=CSC=N1 PQQRHWFRZHFGFM-UHFFFAOYSA-N 0.000 claims 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims 3
- 229960002715 nicotine Drugs 0.000 claims 3
- SNICXCGAKADSCV-UHFFFAOYSA-N nicotine Natural products CN1CCCC1C1=CC=CN=C1 SNICXCGAKADSCV-UHFFFAOYSA-N 0.000 claims 3
- IJKPXNZJGLKYTM-UHFFFAOYSA-N pyridin-3-ylmethanamine 2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.NCc1cccnc1 IJKPXNZJGLKYTM-UHFFFAOYSA-N 0.000 claims 3
- LGEAQEDWGDXCCO-UHFFFAOYSA-N pyridine-3-carboxamide;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.NC(=O)C1=CC=CN=C1 LGEAQEDWGDXCCO-UHFFFAOYSA-N 0.000 claims 3
- SNICXCGAKADSCV-JTQLQIEISA-N (-)-Nicotine Chemical compound CN1CCC[C@H]1C1=CC=CN=C1 SNICXCGAKADSCV-JTQLQIEISA-N 0.000 claims 2
- QWEWLLNSJDTOKH-UHFFFAOYSA-N 1,3-thiazole-2-carboxamide Chemical compound NC(=O)C1=NC=CS1 QWEWLLNSJDTOKH-UHFFFAOYSA-N 0.000 claims 2
- ZBNZAJFNDPPMDT-UHFFFAOYSA-N 1h-imidazole-5-carboxamide Chemical compound NC(=O)C1=CNC=N1 ZBNZAJFNDPPMDT-UHFFFAOYSA-N 0.000 claims 2
- QEWYKACRFQMRMB-UHFFFAOYSA-N fluoroacetic acid Chemical compound OC(=O)CF QEWYKACRFQMRMB-UHFFFAOYSA-N 0.000 claims 2
- BEHYAANJUKYBTH-UHFFFAOYSA-N imidazo[1,2-a]pyridine-2-carboxamide Chemical compound C1=CC=CC2=NC(C(=O)N)=CN21 BEHYAANJUKYBTH-UHFFFAOYSA-N 0.000 claims 2
- FOAGVMDMGHKDDA-UHFFFAOYSA-N indolizine-3-carboxamide Chemical compound C1=CC=CN2C(C(=O)N)=CC=C21 FOAGVMDMGHKDDA-UHFFFAOYSA-N 0.000 claims 2
- DITBWPUMEUDVLU-UHFFFAOYSA-N 1h-indazole-3-carboxamide Chemical compound C1=CC=C2C(C(=O)N)=NNC2=C1 DITBWPUMEUDVLU-UHFFFAOYSA-N 0.000 claims 1
- AKWIAIDKXNKXDI-UHFFFAOYSA-N 1h-pyrrole-3-carboxamide Chemical compound NC(=O)C=1C=CNC=1 AKWIAIDKXNKXDI-UHFFFAOYSA-N 0.000 claims 1
- OFLWZAHKUJNRML-UHFFFAOYSA-N 2,3-dihydroindole-1-carboxamide Chemical compound C1=CC=C2N(C(=O)N)CCC2=C1 OFLWZAHKUJNRML-UHFFFAOYSA-N 0.000 claims 1
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 claims 1
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 claims 1
- FZZMTSNZRBFGGU-UHFFFAOYSA-N 2-chloro-7-fluoroquinazolin-4-amine Chemical compound FC1=CC=C2C(N)=NC(Cl)=NC2=C1 FZZMTSNZRBFGGU-UHFFFAOYSA-N 0.000 claims 1
- BCHZICNRHXRCHY-UHFFFAOYSA-N 2h-oxazine Chemical compound N1OC=CC=C1 BCHZICNRHXRCHY-UHFFFAOYSA-N 0.000 claims 1
- BOOMHTFCWOJWFO-UHFFFAOYSA-N 3-aminopyridine-2-carboxylic acid Chemical compound NC1=CC=CN=C1C(O)=O BOOMHTFCWOJWFO-UHFFFAOYSA-N 0.000 claims 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims 1
- QGFYFOHMBDMGBZ-UHFFFAOYSA-N 5-[(7-chloroquinolin-4-yl)amino]-2-(diethylaminomethyl)phenol Chemical compound C1=C(O)C(CN(CC)CC)=CC=C1NC1=CC=NC2=CC(Cl)=CC=C12 QGFYFOHMBDMGBZ-UHFFFAOYSA-N 0.000 claims 1
- 208000023275 Autoimmune disease Diseases 0.000 claims 1
- KZZQTCMGJNWRMM-UHFFFAOYSA-N C(N)(=O)C1=C(C=C(C=C1)C1=CC(=CC=C1)C(=O)N1CCOCC1)OC1CC2(CC(C2)NC(=O)C=2C=NN3C=2C=CC(=C3)OCC(C)(C)O)C1 Chemical compound C(N)(=O)C1=C(C=C(C=C1)C1=CC(=CC=C1)C(=O)N1CCOCC1)OC1CC2(CC(C2)NC(=O)C=2C=NN3C=2C=CC(=C3)OCC(C)(C)O)C1 KZZQTCMGJNWRMM-UHFFFAOYSA-N 0.000 claims 1
- XKQWWSFDPGQRSQ-UHFFFAOYSA-N FC(C(=O)O)(F)F.O1CN(C=C1)C(=O)N Chemical compound FC(C(=O)O)(F)F.O1CN(C=C1)C(=O)N XKQWWSFDPGQRSQ-UHFFFAOYSA-N 0.000 claims 1
- BINWUTMDRMNFJN-UHFFFAOYSA-N N-[2-(2-carbamoyl-5-cyclopropylphenoxy)spiro[3.3]heptan-6-yl]-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carboxamide Chemical compound C(N)(=O)C1=C(OC2CC3(CC(C3)NC(=O)C=3C=NN4C=3C=CC(=C4)OCC(C)(C)O)C2)C=C(C=C1)C1CC1 BINWUTMDRMNFJN-UHFFFAOYSA-N 0.000 claims 1
- JIFPPNQZQXPJJC-UHFFFAOYSA-N N-[2-(2-carbamoyl-5-methylphenoxy)spiro[3.3]heptan-6-yl]-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carboxamide Chemical compound C(N)(=O)C1=C(OC2CC3(CC(C3)NC(=O)C=3C=NN4C=3C=CC(=C4)OCC(C)(C)O)C2)C=C(C=C1)C JIFPPNQZQXPJJC-UHFFFAOYSA-N 0.000 claims 1
- 208000031481 Pathologic Constriction Diseases 0.000 claims 1
- 208000018262 Peripheral vascular disease Diseases 0.000 claims 1
- 206010047163 Vasospasm Diseases 0.000 claims 1
- PUJDIJCNWFYVJX-UHFFFAOYSA-N benzyl carbamate Chemical compound NC(=O)OCC1=CC=CC=C1 PUJDIJCNWFYVJX-UHFFFAOYSA-N 0.000 claims 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims 1
- 208000026106 cerebrovascular disease Diseases 0.000 claims 1
- 150000001924 cycloalkanes Chemical class 0.000 claims 1
- 239000003085 diluting agent Substances 0.000 claims 1
- MLXWMEFKFOSOCP-UHFFFAOYSA-N imidazo[1,5-a]pyridine Chemical compound C1=CC=CC2=C=N[CH]N21 MLXWMEFKFOSOCP-UHFFFAOYSA-N 0.000 claims 1
- 208000010125 myocardial infarction Diseases 0.000 claims 1
- WDBQDZRKKFDOQF-UHFFFAOYSA-N pyrazolo[1,5-a]pyridine Chemical compound C1=CC=CC2=C=C[N]N21 WDBQDZRKKFDOQF-UHFFFAOYSA-N 0.000 claims 1
- HDOUGSFASVGDCS-UHFFFAOYSA-N pyridin-3-ylmethanamine Chemical compound NCC1=CC=CN=C1 HDOUGSFASVGDCS-UHFFFAOYSA-N 0.000 claims 1
- 208000037804 stenosis Diseases 0.000 claims 1
- 230000036262 stenosis Effects 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 14
- 230000002526 effect on cardiovascular system Effects 0.000 abstract description 2
- 230000001363 autoimmune Effects 0.000 abstract 1
- 230000002981 neuropathic effect Effects 0.000 abstract 1
- 230000000771 oncological effect Effects 0.000 abstract 1
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 175
- 229920000728 polyester Polymers 0.000 description 52
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 37
- 239000012453 solvate Substances 0.000 description 36
- 229940002612 prodrug Drugs 0.000 description 30
- 239000000651 prodrug Substances 0.000 description 30
- 206010007559 Cardiac failure congestive Diseases 0.000 description 27
- 238000011282 treatment Methods 0.000 description 13
- 125000004414 alkyl thio group Chemical group 0.000 description 11
- 239000000460 chlorine Substances 0.000 description 11
- 239000000203 mixture Substances 0.000 description 10
- 241000700159 Rattus Species 0.000 description 7
- 101100356682 Caenorhabditis elegans rho-1 gene Proteins 0.000 description 6
- 101150111584 RHOA gene Proteins 0.000 description 6
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 6
- 230000019491 signal transduction Effects 0.000 description 6
- 208000010228 Erectile Dysfunction Diseases 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- 201000001881 impotence Diseases 0.000 description 5
- 230000002265 prevention Effects 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- NGOGFTYYXHNFQH-UHFFFAOYSA-N fasudil Chemical compound C=1C=CC2=CN=CC=C2C=1S(=O)(=O)N1CCCNCC1 NGOGFTYYXHNFQH-UHFFFAOYSA-N 0.000 description 4
- 229960002435 fasudil Drugs 0.000 description 4
- 230000001631 hypertensive effect Effects 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 208000001286 intracranial vasospasm Diseases 0.000 description 4
- 208000017169 kidney disease Diseases 0.000 description 4
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 3
- IDDDVXIUIXWAGJ-DDSAHXNVSA-N 4-[(1r)-1-aminoethyl]-n-pyridin-4-ylcyclohexane-1-carboxamide;dihydrochloride Chemical compound Cl.Cl.C1CC([C@H](N)C)CCC1C(=O)NC1=CC=NC=C1 IDDDVXIUIXWAGJ-DDSAHXNVSA-N 0.000 description 3
- 208000024827 Alzheimer disease Diseases 0.000 description 3
- 206010003225 Arteriospasm coronary Diseases 0.000 description 3
- 208000003890 Coronary Vasospasm Diseases 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 208000010412 Glaucoma Diseases 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 150000001350 alkyl halides Chemical class 0.000 description 3
- 208000006673 asthma Diseases 0.000 description 3
- 230000036772 blood pressure Effects 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 201000011634 coronary artery vasospasm Diseases 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 125000005843 halogen group Chemical group 0.000 description 3
- 230000004047 hyperresponsiveness Effects 0.000 description 3
- 208000028867 ischemia Diseases 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 229940124597 therapeutic agent Drugs 0.000 description 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 2
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- 125000004575 3-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 201000000057 Coronary Stenosis Diseases 0.000 description 2
- 206010011089 Coronary artery stenosis Diseases 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 102000010780 Platelet-Derived Growth Factor Human genes 0.000 description 2
- 108010038512 Platelet-Derived Growth Factor Proteins 0.000 description 2
- 201000004681 Psoriasis Diseases 0.000 description 2
- 206010063837 Reperfusion injury Diseases 0.000 description 2
- 208000027418 Wounds and injury Diseases 0.000 description 2
- 125000004419 alkynylene group Chemical group 0.000 description 2
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 230000012292 cell migration Effects 0.000 description 2
- 230000008602 contraction Effects 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 231100000517 death Toxicity 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 208000014674 injury Diseases 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- 201000006417 multiple sclerosis Diseases 0.000 description 2
- 230000008692 neointimal formation Effects 0.000 description 2
- 208000004296 neuralgia Diseases 0.000 description 2
- 208000021722 neuropathic pain Diseases 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000009117 preventive therapy Methods 0.000 description 2
- 230000009862 primary prevention Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- 208000037803 restenosis Diseases 0.000 description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 description 2
- 230000009863 secondary prevention Effects 0.000 description 2
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 2
- 208000020431 spinal cord injury Diseases 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 1
- JHHZLHWJQPUNKB-SCSAIBSYSA-N (3r)-pyrrolidin-3-ol Chemical compound O[C@@H]1CCNC1 JHHZLHWJQPUNKB-SCSAIBSYSA-N 0.000 description 1
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 description 1
- 125000006017 1-propenyl group Chemical group 0.000 description 1
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 1
- 125000004778 2,2-difluoroethyl group Chemical group [H]C([H])(*)C([H])(F)F 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- 125000006040 2-hexenyl group Chemical group 0.000 description 1
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 1
- 125000006022 2-methyl-2-propenyl group Chemical group 0.000 description 1
- 125000006024 2-pentenyl group Chemical group 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- NYCJLKMTNDLDGK-UHFFFAOYSA-N 3-bromo-5-(trifluoromethyl)benzamide Chemical compound NC(=O)C1=CC(Br)=CC(C(F)(F)F)=C1 NYCJLKMTNDLDGK-UHFFFAOYSA-N 0.000 description 1
- 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 description 1
- 125000006041 3-hexenyl group Chemical group 0.000 description 1
- 125000006042 4-hexenyl group Chemical group 0.000 description 1
- CNPURSDMOWDNOQ-UHFFFAOYSA-N 4-methoxy-7h-pyrrolo[2,3-d]pyrimidin-2-amine Chemical compound COC1=NC(N)=NC2=C1C=CN2 CNPURSDMOWDNOQ-UHFFFAOYSA-N 0.000 description 1
- 125000003119 4-methyl-3-pentenyl group Chemical group [H]\C(=C(/C([H])([H])[H])C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- PGVWJHYYJKVAKH-UHFFFAOYSA-N 4-pyrazol-1-ylbenzamide Chemical compound C1=CC(C(=O)N)=CC=C1N1N=CC=C1 PGVWJHYYJKVAKH-UHFFFAOYSA-N 0.000 description 1
- 125000006043 5-hexenyl group Chemical group 0.000 description 1
- XRAJRCMNTNSGAK-UHFFFAOYSA-N 6-(2-hydroxy-2-methylpropoxy)-N-[2-[4-(3,4,5-trifluorophenyl)phenoxy]spiro[3.3]heptan-6-yl]pyrazolo[1,5-a]pyridine-3-carboxamide Chemical compound OC(COC=1C=CC=2N(C=1)N=CC=2C(=O)NC1CC2(C1)CC(C2)OC1=CC=C(C=C1)C1=CC(=C(C(=C1)F)F)F)(C)C XRAJRCMNTNSGAK-UHFFFAOYSA-N 0.000 description 1
- KEHDPKKMEGBYBX-UHFFFAOYSA-N 6-(2-hydroxy-2-methylpropoxy)-N-[2-[4-(3-methoxyphenyl)phenoxy]spiro[3.3]heptan-6-yl]pyrazolo[1,5-a]pyridine-3-carboxamide Chemical compound OC(COC=1C=CC=2N(C=1)N=CC=2C(=O)NC1CC2(C1)CC(C2)OC1=CC=C(C=C1)C1=CC(=CC=C1)OC)(C)C KEHDPKKMEGBYBX-UHFFFAOYSA-N 0.000 description 1
- HWNVKXBBNKWDPR-UHFFFAOYSA-N 6-(2-hydroxy-2-methylpropoxy)-N-[2-[4-(3-sulfamoylphenyl)phenoxy]spiro[3.3]heptan-6-yl]pyrazolo[1,5-a]pyridine-3-carboxamide Chemical compound OC(COC=1C=CC=2N(C=1)N=CC=2C(=O)NC1CC2(C1)CC(C2)OC1=CC=C(C=C1)C1=CC(=CC=C1)S(N)(=O)=O)(C)C HWNVKXBBNKWDPR-UHFFFAOYSA-N 0.000 description 1
- FOTIPNHRXPYKJE-UHFFFAOYSA-N 6-(2-hydroxy-2-methylpropoxy)-N-[2-[4-(4-methylsulfonylphenyl)phenoxy]spiro[3.3]heptan-6-yl]pyrazolo[1,5-a]pyridine-3-carboxamide Chemical compound OC(COC=1C=CC=2N(C=1)N=CC=2C(=O)NC1CC2(C1)CC(C2)OC1=CC=C(C=C1)C1=CC=C(C=C1)S(=O)(=O)C)(C)C FOTIPNHRXPYKJE-UHFFFAOYSA-N 0.000 description 1
- JQPASOCWHULEEB-UHFFFAOYSA-N 6-(2-hydroxy-2-methylpropoxy)-N-[2-[4-[2-(trifluoromethyl)phenyl]phenoxy]spiro[3.3]heptan-6-yl]pyrazolo[1,5-a]pyridine-3-carboxamide Chemical compound OC(COC=1C=CC=2N(C=1)N=CC=2C(=O)NC1CC2(C1)CC(C2)OC1=CC=C(C=C1)C1=C(C=CC=C1)C(F)(F)F)(C)C JQPASOCWHULEEB-UHFFFAOYSA-N 0.000 description 1
- YXROUCNLNCHYKP-UHFFFAOYSA-N 6-(2-hydroxy-2-methylpropoxy)-N-[2-[4-[3-(2,2,2-trifluoroethoxy)phenyl]phenoxy]spiro[3.3]heptan-6-yl]pyrazolo[1,5-a]pyridine-3-carboxamide Chemical compound OC(COC=1C=CC=2N(C=1)N=CC=2C(=O)NC1CC2(C1)CC(C2)OC1=CC=C(C=C1)C1=CC(=CC=C1)OCC(F)(F)F)(C)C YXROUCNLNCHYKP-UHFFFAOYSA-N 0.000 description 1
- LJYNOQKIIZGJRD-UHFFFAOYSA-N 6-(2-hydroxy-2-methylpropoxy)-N-[2-[4-[3-(methoxymethyl)phenyl]phenoxy]spiro[3.3]heptan-6-yl]pyrazolo[1,5-a]pyridine-3-carboxamide Chemical compound OC(COC=1C=CC=2N(C=1)N=CC=2C(=O)NC1CC2(C1)CC(C2)OC1=CC=C(C=C1)C1=CC(=CC=C1)COC)(C)C LJYNOQKIIZGJRD-UHFFFAOYSA-N 0.000 description 1
- GHDPXCXEWNCRMV-UHFFFAOYSA-N 6-(2-hydroxy-2-methylpropoxy)-N-[2-[4-[3-(morpholine-4-carbonyl)phenyl]phenoxy]spiro[3.3]heptan-6-yl]pyrazolo[1,5-a]pyridine-3-carboxamide Chemical compound OC(COC=1C=CC=2N(C=1)N=CC=2C(=O)NC1CC2(C1)CC(C2)OC1=CC=C(C=C1)C1=CC(=CC=C1)C(=O)N1CCOCC1)(C)C GHDPXCXEWNCRMV-UHFFFAOYSA-N 0.000 description 1
- PSTQVWFQODDXII-UHFFFAOYSA-N 6-(2-hydroxy-2-methylpropoxy)-N-[2-[4-[3-(trifluoromethyl)phenyl]phenoxy]spiro[3.3]heptan-6-yl]pyrazolo[1,5-a]pyridine-3-carboxamide Chemical compound OC(COC=1C=CC=2N(C=1)N=CC=2C(=O)NC1CC2(C1)CC(C2)OC1=CC=C(C=C1)C1=CC(=CC=C1)C(F)(F)F)(C)C PSTQVWFQODDXII-UHFFFAOYSA-N 0.000 description 1
- 239000005541 ACE inhibitor Substances 0.000 description 1
- 102100023818 ADP-ribosylation factor 3 Human genes 0.000 description 1
- 102000007469 Actins Human genes 0.000 description 1
- 108010085238 Actins Proteins 0.000 description 1
- 102400000345 Angiotensin-2 Human genes 0.000 description 1
- 101800000733 Angiotensin-2 Proteins 0.000 description 1
- 102000015427 Angiotensins Human genes 0.000 description 1
- 108010064733 Angiotensins Proteins 0.000 description 1
- 102100021943 C-C motif chemokine 2 Human genes 0.000 description 1
- 101710155857 C-C motif chemokine 2 Proteins 0.000 description 1
- MFFGMKGGPRAPCR-UHFFFAOYSA-N CC(C)(COC1(CC(C2)(CC2N2N=CC=C2)C1)OC(C=C1)=CC=C1C1=CC(S(C)(=O)=O)=CC=C1)O Chemical compound CC(C)(COC1(CC(C2)(CC2N2N=CC=C2)C1)OC(C=C1)=CC=C1C1=CC(S(C)(=O)=O)=CC=C1)O MFFGMKGGPRAPCR-UHFFFAOYSA-N 0.000 description 1
- 229940127291 Calcium channel antagonist Drugs 0.000 description 1
- VPGRYOFKCNULNK-ACXQXYJUSA-N Deoxycorticosterone acetate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)COC(=O)C)[C@@]1(C)CC2 VPGRYOFKCNULNK-ACXQXYJUSA-N 0.000 description 1
- 102400000686 Endothelin-1 Human genes 0.000 description 1
- 101800004490 Endothelin-1 Proteins 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 239000004606 Fillers/Extenders Substances 0.000 description 1
- 108091006027 G proteins Proteins 0.000 description 1
- 102000030782 GTP binding Human genes 0.000 description 1
- 108091000058 GTP-Binding Proteins 0.000 description 1
- 101000684275 Homo sapiens ADP-ribosylation factor 3 Proteins 0.000 description 1
- 101001000061 Homo sapiens Protein phosphatase 1 regulatory subunit 12A Proteins 0.000 description 1
- 101001130437 Homo sapiens Ras-related protein Rap-2b Proteins 0.000 description 1
- 101000669917 Homo sapiens Rho-associated protein kinase 1 Proteins 0.000 description 1
- 101000669921 Homo sapiens Rho-associated protein kinase 2 Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- CZGUSIXMZVURDU-JZXHSEFVSA-N Ile(5)-angiotensin II Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C([O-])=O)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(N)=[NH2+])NC(=O)[C@@H]([NH3+])CC([O-])=O)C(C)C)C1=CC=C(O)C=C1 CZGUSIXMZVURDU-JZXHSEFVSA-N 0.000 description 1
- 206010061216 Infarction Diseases 0.000 description 1
- 108010037801 Myosin-Light-Chain Phosphatase Proteins 0.000 description 1
- 102000011131 Myosin-Light-Chain Phosphatase Human genes 0.000 description 1
- BXZCGMHIXJQIOO-UHFFFAOYSA-N N-[2-[4-(3-cyano-5-fluorophenyl)phenoxy]spiro[3.3]heptan-6-yl]-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carboxamide Chemical compound C(#N)C=1C=C(C=C(C=1)F)C1=CC=C(C=C1)OC1CC2(CC(C2)NC(=O)C=2C=NN3C=2C=CC(=C3)OCC(C)(C)O)C1 BXZCGMHIXJQIOO-UHFFFAOYSA-N 0.000 description 1
- GORWVVFMQZACDT-UHFFFAOYSA-N N-[2-[4-(3-cyano-5-nitrophenyl)phenoxy]spiro[3.3]heptan-6-yl]-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carboxamide Chemical compound C(#N)C=1C=C(C=C(C=1)[N+](=O)[O-])C1=CC=C(C=C1)OC1CC2(CC(C2)NC(=O)C=2C=NN3C=2C=CC(=C3)OCC(C)(C)O)C1 GORWVVFMQZACDT-UHFFFAOYSA-N 0.000 description 1
- NOAZWTCGEHCCRC-UHFFFAOYSA-N N-[2-[4-(3-cyanophenyl)phenoxy]spiro[3.3]heptan-6-yl]-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carboxamide Chemical compound C(#N)C=1C=C(C=CC=1)C1=CC=C(C=C1)OC1CC2(CC(C2)NC(=O)C=2C=NN3C=2C=CC(=C3)OCC(C)(C)O)C1 NOAZWTCGEHCCRC-UHFFFAOYSA-N 0.000 description 1
- LXZRFBBCCSMJLT-UHFFFAOYSA-N N-[2-[4-(3-fluorophenyl)phenoxy]spiro[3.3]heptan-6-yl]-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carboxamide Chemical compound FC=1C=C(C=CC=1)C1=CC=C(C=C1)OC1CC2(CC(C2)NC(=O)C=2C=NN3C=2C=CC(=C3)OCC(C)(C)O)C1 LXZRFBBCCSMJLT-UHFFFAOYSA-N 0.000 description 1
- VFFZLOFCNYRYDP-UHFFFAOYSA-N N-[2-[4-[3,5-bis(hydroxymethyl)phenyl]phenoxy]spiro[3.3]heptan-6-yl]-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carboxamide Chemical compound OCC=1C=C(C=C(C=1)CO)C1=CC=C(C=C1)OC1CC2(CC(C2)NC(=O)C=2C=NN3C=2C=CC(=C3)OCC(C)(C)O)C1 VFFZLOFCNYRYDP-UHFFFAOYSA-N 0.000 description 1
- CKZBYHMKONZSIP-UHFFFAOYSA-N N-[2-[4-[3-(2-aminoethyl)phenyl]phenoxy]spiro[3.3]heptan-6-yl]-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carboxamide Chemical compound NCCC=1C=C(C=CC=1)C1=CC=C(C=C1)OC1CC2(CC(C2)NC(=O)C=2C=NN3C=2C=CC(=C3)OCC(C)(C)O)C1 CKZBYHMKONZSIP-UHFFFAOYSA-N 0.000 description 1
- DBWOXLWCCWFRIP-UHFFFAOYSA-N N-[2-[4-[3-(3-aminopropoxy)phenyl]phenoxy]spiro[3.3]heptan-6-yl]-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carboxamide Chemical compound NCCCOC=1C=C(C=CC=1)C1=CC=C(C=C1)OC1CC2(CC(C2)NC(=O)C=2C=NN3C=2C=CC(=C3)OCC(C)(C)O)C1 DBWOXLWCCWFRIP-UHFFFAOYSA-N 0.000 description 1
- YPPRMWFUAWLDOW-UHFFFAOYSA-N N-[2-[4-[3-(5-amino-4-cyano-3-methylpyrazol-1-yl)phenyl]phenoxy]spiro[3.3]heptan-6-yl]-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carboxamide Chemical compound NC1=C(C(=NN1C=1C=C(C=CC=1)C1=CC=C(C=C1)OC1CC2(CC(C2)NC(=O)C=2C=NN3C=2C=CC(=C3)OCC(C)(C)O)C1)C)C#N YPPRMWFUAWLDOW-UHFFFAOYSA-N 0.000 description 1
- VRAZGPIGBNKNQY-UHFFFAOYSA-N N-[2-[4-[3-(aminomethyl)phenyl]phenoxy]spiro[3.3]heptan-6-yl]-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carboxamide Chemical compound NCC=1C=C(C=CC=1)C1=CC=C(C=C1)OC1CC2(CC(C2)NC(=O)C=2C=NN3C=2C=CC(=C3)OCC(C)(C)O)C1 VRAZGPIGBNKNQY-UHFFFAOYSA-N 0.000 description 1
- HVSRECXESAGUIV-UHFFFAOYSA-N N-[2-[4-[3-(hydroxymethyl)phenyl]phenoxy]spiro[3.3]heptan-6-yl]-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carboxamide Chemical compound OC(COC=1C=CC=2N(C=1)N=CC=2C(=O)NC1CC2(C1)CC(C2)OC1=CC=C(C=C1)C1=CC(=CC=C1)CO)(C)C HVSRECXESAGUIV-UHFFFAOYSA-N 0.000 description 1
- LCEHHRWQVJVBPT-UHFFFAOYSA-N N-[2-[4-[4-fluoro-3-(2H-tetrazol-5-yl)phenyl]phenoxy]spiro[3.3]heptan-6-yl]-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carboxamide Chemical compound FC1=C(C=C(C=C1)C1=CC=C(C=C1)OC1CC2(CC(C2)NC(=O)C=2C=NN3C=2C=CC(=C3)OCC(C)(C)O)C1)C1=NN=NN1 LCEHHRWQVJVBPT-UHFFFAOYSA-N 0.000 description 1
- 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 description 1
- 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 description 1
- 102000009516 Protein Serine-Threonine Kinases Human genes 0.000 description 1
- 108010009341 Protein Serine-Threonine Kinases Proteins 0.000 description 1
- 102100036547 Protein phosphatase 1 regulatory subunit 12A Human genes 0.000 description 1
- 208000001647 Renal Insufficiency Diseases 0.000 description 1
- 208000002200 Respiratory Hypersensitivity Diseases 0.000 description 1
- 102100039313 Rho-associated protein kinase 1 Human genes 0.000 description 1
- 102100039314 Rho-associated protein kinase 2 Human genes 0.000 description 1
- 102100027609 Rho-related GTP-binding protein RhoD Human genes 0.000 description 1
- 229940124639 Selective inhibitor Drugs 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- 101001076390 Sus scrofa Interleukin-1 beta Proteins 0.000 description 1
- 206010047295 Ventricular hypertrophy Diseases 0.000 description 1
- IYOZTVGMEWJPKR-IJLUTSLNSA-N Y-27632 Chemical compound C1C[C@@H]([C@H](N)C)CC[C@@H]1C(=O)NC1=CC=NC=C1 IYOZTVGMEWJPKR-IJLUTSLNSA-N 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 208000037883 airway inflammation Diseases 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 125000004450 alkenylene group Chemical group 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 229950006323 angiotensin ii Drugs 0.000 description 1
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 125000000043 benzamido group Chemical group [H]N([*])C(=O)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
- 239000002876 beta blocker Substances 0.000 description 1
- 229940097320 beta blocking agent Drugs 0.000 description 1
- 239000000480 calcium channel blocker Substances 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 230000021164 cell adhesion Effects 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 125000003636 chemical group Chemical group 0.000 description 1
- 230000035605 chemotaxis Effects 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 230000021953 cytokinesis Effects 0.000 description 1
- 229960004486 desoxycorticosterone acetate Drugs 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 229940030606 diuretics Drugs 0.000 description 1
- 239000003596 drug target Substances 0.000 description 1
- 239000012636 effector Substances 0.000 description 1
- 230000002124 endocrine Effects 0.000 description 1
- 235000019439 ethyl acetate Nutrition 0.000 description 1
- 210000001105 femoral artery Anatomy 0.000 description 1
- 230000004761 fibrosis Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 238000013299 hypertensive rat model Methods 0.000 description 1
- 125000002962 imidazol-1-yl group Chemical group [*]N1C([H])=NC([H])=C1[H] 0.000 description 1
- 210000002865 immune cell Anatomy 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000007574 infarction Effects 0.000 description 1
- 208000030603 inherited susceptibility to asthma Diseases 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 201000006370 kidney failure Diseases 0.000 description 1
- 238000011866 long-term treatment Methods 0.000 description 1
- PCLIUMMFWRGXRK-UHFFFAOYSA-N methyl azetidine-1-carboxylate Chemical compound COC(=O)N1CCC1 PCLIUMMFWRGXRK-UHFFFAOYSA-N 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
- DXASQZJWWGZNSF-UHFFFAOYSA-N n,n-dimethylmethanamine;sulfur trioxide Chemical group CN(C)C.O=S(=O)=O DXASQZJWWGZNSF-UHFFFAOYSA-N 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000007971 neurological deficit Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 229960002748 norepinephrine Drugs 0.000 description 1
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 125000004274 oxetan-2-yl group Chemical group [H]C1([H])OC([H])(*)C1([H])[H] 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 208000030613 peripheral artery disease Diseases 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- UZFKIHMFDWGBKC-UHFFFAOYSA-N pyridine-4-carboxamide Chemical compound NC(=O)C1=CC=NC=C1.NC(=O)C1=CC=NC=C1 UZFKIHMFDWGBKC-UHFFFAOYSA-N 0.000 description 1
- QDXGKRWDQCEABB-UHFFFAOYSA-N pyrimidine-5-carboxamide Chemical compound NC(=O)C1=CN=CN=C1 QDXGKRWDQCEABB-UHFFFAOYSA-N 0.000 description 1
- BLTDCIWCFCUQCB-UHFFFAOYSA-N quionoline-3-carboxamide Natural products C1=CC=CC2=CC(C(=O)N)=CN=C21 BLTDCIWCFCUQCB-UHFFFAOYSA-N 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 230000016487 regulation of smooth muscle contraction Effects 0.000 description 1
- 238000007634 remodeling Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000003590 rho kinase inhibitor Substances 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 238000011699 spontaneously hypertensive rat Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 125000004149 thio group Chemical group *S* 0.000 description 1
- 125000000101 thioether group Chemical group 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 230000002227 vasoactive effect Effects 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/64—One oxygen atom attached in position 2 or 6
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D231/18—One oxygen or sulfur atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—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
- 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
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—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
- C07D471/12—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 three hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/06—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Reproductive Health (AREA)
- Endocrinology (AREA)
- Gynecology & Obstetrics (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pyridine Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Indole Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201662278122P | 2016-01-13 | 2016-01-13 | |
| US62/278,122 | 2016-01-13 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| TW201726619A TW201726619A (zh) | 2017-08-01 |
| TWI730032B true TWI730032B (zh) | 2021-06-11 |
Family
ID=57907009
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| TW106101072A TWI730032B (zh) | 2016-01-13 | 2017-01-12 | 作為ｒｏｃｋ抑制劑之螺庚烷水楊酸醯胺及相關化合物 |
Country Status (29)
| Country | Link |
|---|---|
| US (2) | US10611776B2 (https=) |
| EP (2) | EP3402790B1 (https=) |
| JP (2) | JP6976953B2 (https=) |
| KR (1) | KR102725741B1 (https=) |
| CN (1) | CN108699038B (https=) |
| AR (1) | AR107354A1 (https=) |
| AU (2) | AU2017206820B2 (https=) |
| BR (1) | BR112018013780B1 (https=) |
| CA (1) | CA3010900A1 (https=) |
| CL (1) | CL2018001899A1 (https=) |
| CO (1) | CO2018008173A2 (https=) |
| CY (1) | CY1124858T1 (https=) |
| EA (1) | EA036172B1 (https=) |
| ES (1) | ES2898698T3 (https=) |
| HR (1) | HRP20211888T1 (https=) |
| HU (1) | HUE057455T2 (https=) |
| IL (1) | IL260448B (https=) |
| LT (1) | LT3402790T (https=) |
| MA (2) | MA43862A (https=) |
| MX (2) | MX382434B (https=) |
| PL (1) | PL3402790T3 (https=) |
| PT (1) | PT3402790T (https=) |
| RS (1) | RS62690B1 (https=) |
| SG (1) | SG11201805927YA (https=) |
| SI (1) | SI3402790T1 (https=) |
| SM (1) | SMT202100660T1 (https=) |
| TW (1) | TWI730032B (https=) |
| UY (1) | UY37073A (https=) |
| WO (1) | WO2017123860A1 (https=) |
Families Citing this family (40)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10123993B2 (en) | 2015-01-09 | 2018-11-13 | Bristol-Myers Squibb Company | Cyclic ureas as inhibitors of rock |
| ES2730112T3 (es) | 2015-03-09 | 2019-11-08 | Bristol Myers Squibb Co | Lactamas como inhibidores de ROCK |
| TWI730032B (zh) | 2016-01-13 | 2021-06-11 | 美商必治妥美雅史谷比公司 | 作為ｒｏｃｋ抑制劑之螺庚烷水楊酸醯胺及相關化合物 |
| US20170197947A1 (en) | 2016-01-13 | 2017-07-13 | Gruenenthal Gmbh | 3-((Hetero-)Aryl)-Alkyl-8-Amino-2-Oxo-1,3-Diaza-Spiro-[4.5]-Decane Derivatives |
| SI3402782T1 (sl) | 2016-01-13 | 2020-11-30 | Grunenthal Gmbh | 8-amino-2-okso-1,3-diaza-spiro-(4,5)-dekanski derivati |
| EP3722284B1 (en) | 2016-01-13 | 2025-01-22 | Grünenthal GmbH | 3-((hetero-)aryl)-8-amino-2-oxo-1,3-diaza-spiro-[4.5]-decane derivatives |
| JP6854823B2 (ja) | 2016-01-13 | 2021-04-07 | グリュネンタール・ゲゼルシャフト・ミト・ベシュレンクテル・ハフツング | ３−（カルボキシメチル）−８−アミノ−２−オキソ−１，３−ジアザ−スピロ−［４．５］−デカン誘導体 |
| CN109152784B (zh) | 2016-03-16 | 2021-12-28 | 库拉肿瘤学公司 | 经取代的menin-mll抑制剂及使用方法 |
| WO2017205709A1 (en) | 2016-05-27 | 2017-11-30 | Bristol-Myers Squibb Company | Triazolones and tetrazolones as inhibitors of rock |
| ES2829550T3 (es) | 2016-07-07 | 2021-06-01 | Bristol Myers Squibb Co | Ureas cíclicas espiro-condensadas como inhibidores de ROCK |
| JP7113810B2 (ja) | 2016-07-07 | 2022-08-05 | ブリストル－マイヤーズ スクイブ カンパニー | Ｒｏｃｋ阻害剤としてのスピロラクタム |
| JP6903731B2 (ja) | 2016-07-07 | 2021-07-14 | ブリストル−マイヤーズ スクイブ カンパニーＢｒｉｓｔｏｌ−Ｍｙｅｒｓ Ｓｑｕｉｂｂ Ｃｏｍｐａｎｙ | 強力で選択的なｒｏｃｋ阻害剤としてのラクタム、環状尿素、およびカルバメート、およびトリアゾロン誘導体 |
| KR102511441B1 (ko) | 2016-11-30 | 2023-03-16 | 브리스톨-마이어스 스큅 컴퍼니 | 트리시클릭 Rho 키나제 억제제 |
| US11306081B2 (en) | 2017-07-12 | 2022-04-19 | Bristol-Myers Squibb Company | Phenylacetamides as inhibitors of rock |
| US11447487B2 (en) | 2017-07-12 | 2022-09-20 | Bristol-Myers Squibb Company | Spiroheptanyl hydantoins as rock inhibitors |
| TW201908293A (zh) | 2017-07-12 | 2019-03-01 | 美商必治妥美雅史谷比公司 | 作為rock抑制劑之5員及雙環雜環醯胺 |
| JP7234201B2 (ja) * | 2017-07-12 | 2023-03-07 | ブリストル－マイヤーズ スクイブ カンパニー | 心不全の治療のためのｒｏｃｋの５員アミノヘテロ環および５，６－または６，６員二環式アミノヘテロ環の阻害剤 |
| US12060341B2 (en) | 2017-07-12 | 2024-08-13 | Bristol-Myers Squibb Company | Spiroheptanyl hydantoins as ROCK inhibitors |
| US11649251B2 (en) | 2017-09-20 | 2023-05-16 | Kura Oncology, Inc. | Substituted inhibitors of menin-MLL and methods of use |
| EP3704121B1 (en) | 2017-11-03 | 2022-12-21 | Bristol-Myers Squibb Company | Diazaspiro rock inhibitors |
| IL277963B2 (en) * | 2018-04-17 | 2024-09-01 | Tempest Therapeutics Inc | Bicyclic carboxamides and methods of use thereof |
| EP4431596A4 (en) | 2021-11-11 | 2026-01-14 | The Doshisha | CRYOCONSERVATION PREPARATION FOR CORNIAL ENDOTHELIAL CELLS AND PROCESS FOR PRODUCING SAID CRYOCONSERVATION PREPARATION |
| JP7797234B2 (ja) | 2022-02-18 | 2026-01-13 | キヤノン株式会社 | 保持装置、リソグラフィ装置、および物品製造方法 |
| WO2024013736A1 (en) * | 2022-07-12 | 2024-01-18 | Adama Makhteshim Ltd. | Process for preparing substituted benzamides |
| WO2024229439A2 (en) * | 2023-05-03 | 2024-11-07 | The University Of Chicago | Inhibitors of nsun1- and nsun2-mediated active structures |
| AU2024265078A1 (en) | 2023-05-04 | 2025-12-11 | Revolution Medicines, Inc. | Combination therapy for a ras related disease or disorder |
| IL326136A (en) | 2023-08-07 | 2026-03-01 | Revolution Medicines Inc | RMC-6291 for use in the treatment of a disease or disorder associated with the RAS protein |
| US20250154171A1 (en) | 2023-10-12 | 2025-05-15 | Revolution Medicines, Inc. | Ras inhibitors |
| WO2025171296A1 (en) | 2024-02-09 | 2025-08-14 | Revolution Medicines, Inc. | Ras inhibitors |
| WO2025240847A1 (en) | 2024-05-17 | 2025-11-20 | Revolution Medicines, Inc. | Ras inhibitors |
| WO2025247783A1 (en) | 2024-05-29 | 2025-12-04 | Syngenta Crop Protection Ag | Pesticidally active dihydro-benzoxazinone compounds |
| US20250375445A1 (en) | 2024-06-07 | 2025-12-11 | Revolution Medicines, Inc. | Methods of treating a ras protein-related disease or disorder |
| WO2025265060A1 (en) | 2024-06-21 | 2025-12-26 | Revolution Medicines, Inc. | Therapeutic compositions and methods for managing treatment-related effects |
| WO2026006747A1 (en) | 2024-06-28 | 2026-01-02 | Revolution Medicines, Inc. | Ras inhibitors |
| WO2026015825A1 (en) | 2024-07-12 | 2026-01-15 | Revolution Medicines, Inc. | Use of ras inhibitor for treating pancreatic cancer |
| WO2026015790A1 (en) | 2024-07-12 | 2026-01-15 | Revolution Medicines, Inc. | Methods of treating a ras related disease or disorder |
| WO2026015796A1 (en) | 2024-07-12 | 2026-01-15 | Revolution Medicines, Inc. | Methods of treating a ras related disease or disorder |
| WO2026015801A1 (en) | 2024-07-12 | 2026-01-15 | Revolution Medicines, Inc. | Methods of treating a ras related disease or disorder |
| WO2026050446A1 (en) | 2024-08-29 | 2026-03-05 | Revolution Medicines, Inc. | Ras inhibitors |
| WO2026072904A2 (en) | 2024-09-26 | 2026-04-02 | Revolution Medicines, Inc. | Compositions and methods for treating lung cancer |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2025676A1 (en) * | 2006-06-08 | 2009-02-18 | Ube Industries, Ltd. | Novel indazole derivative having spiro ring structure in side chain |
| TW201607933A (zh) * | 2014-07-15 | 2016-03-01 | 必治妥美雅史谷比公司 | 做為Ｒｈｏ激酶（ＲＯＣＫ）抑制劑之螺環庚烷類 |
Family Cites Families (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008036540A2 (en) | 2006-09-20 | 2008-03-27 | Boehringer Ingelheim International Gmbh | Rho kinase inhibitors |
| NZ577980A (en) * | 2006-12-27 | 2012-01-12 | Sanofi Aventis | Cycloalkylamine substituted isoquinolone derivatives |
| CL2007003874A1 (es) | 2007-01-03 | 2008-05-16 | Boehringer Ingelheim Int | Compuestos derivados de benzamida; composicion farmaceutica que comprende a dichos compuestos; y su uso para tratar enfermedades cardiovasculares, hipertension, aterosclerosis, reestenosis, ictus, insuficiencia cardiaca, lesion isquemica, hipertensio |
| CN101910123A (zh) * | 2007-12-26 | 2010-12-08 | 塞诺菲-安万特股份有限公司 | 6-取代的-1-(2h)-异喹啉酮的制备方法 |
| AU2011329233A1 (en) | 2010-11-15 | 2013-05-23 | Abbvie Deutschland Gmbh & Co Kg | NAMPT and ROCK inhibitors |
| JP6488239B2 (ja) | 2013-01-18 | 2019-03-20 | ブリストル−マイヤーズ スクイブ カンパニーＢｒｉｓｔｏｌ−Ｍｙｅｒｓ Ｓｑｕｉｂｂ Ｃｏｍｐａｎｙ | Ｒｏｃｋ阻害剤としてのフタラジノンおよびイソキノリノン |
| AR094929A1 (es) | 2013-02-28 | 2015-09-09 | Bristol Myers Squibb Co | Derivados de fenilpirazol como inhibidores potentes de rock1 y rock2 |
| WO2014134391A1 (en) | 2013-02-28 | 2014-09-04 | Bristol-Myers Squibb Company | Phenylpyrazole derivatives as potent rock1 and rock2 inhibitors |
| EP3016950B1 (en) | 2013-07-02 | 2017-06-07 | Bristol-Myers Squibb Company | Tricyclic pyrido-carboxamide derivatives as rock inhibitors |
| US9914740B2 (en) | 2013-07-02 | 2018-03-13 | Bristol-Myers Squibb Company | Tricyclic pyrido-carboxamide derivatives as rock inhibitors |
| WO2016028971A1 (en) | 2014-08-21 | 2016-02-25 | Bristol-Myers Squibb Company | Tied-back benzamide derivatives as potent rock inhibitors |
| US10123993B2 (en) | 2015-01-09 | 2018-11-13 | Bristol-Myers Squibb Company | Cyclic ureas as inhibitors of rock |
| ES2730112T3 (es) | 2015-03-09 | 2019-11-08 | Bristol Myers Squibb Co | Lactamas como inhibidores de ROCK |
| TWI730032B (zh) | 2016-01-13 | 2021-06-11 | 美商必治妥美雅史谷比公司 | 作為ｒｏｃｋ抑制劑之螺庚烷水楊酸醯胺及相關化合物 |
| WO2017205709A1 (en) | 2016-05-27 | 2017-11-30 | Bristol-Myers Squibb Company | Triazolones and tetrazolones as inhibitors of rock |
| JP6903731B2 (ja) | 2016-07-07 | 2021-07-14 | ブリストル−マイヤーズ スクイブ カンパニーＢｒｉｓｔｏｌ−Ｍｙｅｒｓ Ｓｑｕｉｂｂ Ｃｏｍｐａｎｙ | 強力で選択的なｒｏｃｋ阻害剤としてのラクタム、環状尿素、およびカルバメート、およびトリアゾロン誘導体 |
| ES2829550T3 (es) | 2016-07-07 | 2021-06-01 | Bristol Myers Squibb Co | Ureas cíclicas espiro-condensadas como inhibidores de ROCK |
| JP7113810B2 (ja) | 2016-07-07 | 2022-08-05 | ブリストル－マイヤーズ スクイブ カンパニー | Ｒｏｃｋ阻害剤としてのスピロラクタム |
| KR102511441B1 (ko) | 2016-11-30 | 2023-03-16 | 브리스톨-마이어스 스큅 컴퍼니 | 트리시클릭 Rho 키나제 억제제 |
-
2017
- 2017-01-12 TW TW106101072A patent/TWI730032B/zh active
- 2017-01-12 AR ARP170100088A patent/AR107354A1/es unknown
- 2017-01-12 UY UY0001037073A patent/UY37073A/es unknown
- 2017-01-13 SM SM20210660T patent/SMT202100660T1/it unknown
- 2017-01-13 MA MA043862A patent/MA43862A/fr unknown
- 2017-01-13 KR KR1020187022838A patent/KR102725741B1/ko active Active
- 2017-01-13 AU AU2017206820A patent/AU2017206820B2/en active Active
- 2017-01-13 ES ES17701785T patent/ES2898698T3/es active Active
- 2017-01-13 MA MA055633A patent/MA55633A/fr unknown
- 2017-01-13 JP JP2018536481A patent/JP6976953B2/ja active Active
- 2017-01-13 SG SG11201805927YA patent/SG11201805927YA/en unknown
- 2017-01-13 CN CN201780015453.3A patent/CN108699038B/zh active Active
- 2017-01-13 MX MX2018008219A patent/MX382434B/es unknown
- 2017-01-13 EA EA201891557A patent/EA036172B1/ru not_active IP Right Cessation
- 2017-01-13 PL PL17701785T patent/PL3402790T3/pl unknown
- 2017-01-13 US US16/067,619 patent/US10611776B2/en active Active
- 2017-01-13 WO PCT/US2017/013323 patent/WO2017123860A1/en not_active Ceased
- 2017-01-13 HU HUE17701785A patent/HUE057455T2/hu unknown
- 2017-01-13 BR BR112018013780-4A patent/BR112018013780B1/pt active IP Right Grant
- 2017-01-13 EP EP17701785.2A patent/EP3402790B1/en active Active
- 2017-01-13 CA CA3010900A patent/CA3010900A1/en active Pending
- 2017-01-13 SI SI201730984T patent/SI3402790T1/sl unknown
- 2017-01-13 LT LTEPPCT/US2017/013323T patent/LT3402790T/lt unknown
- 2017-01-13 PT PT177017852T patent/PT3402790T/pt unknown
- 2017-01-13 HR HRP20211888TT patent/HRP20211888T1/hr unknown
- 2017-01-13 RS RS20211514A patent/RS62690B1/sr unknown
- 2017-01-13 EP EP21193297.5A patent/EP3954681A1/en active Pending
-
2018
- 2018-07-02 MX MX2021005311A patent/MX2021005311A/es unknown
- 2018-07-05 IL IL260448A patent/IL260448B/en active IP Right Grant
- 2018-07-12 CL CL2018001899A patent/CL2018001899A1/es unknown
- 2018-08-01 CO CONC2018/0008173A patent/CO2018008173A2/es unknown
-
2020
- 2020-01-10 US US16/739,363 patent/US10829501B2/en active Active
-
2021
- 2021-08-26 AU AU2021221872A patent/AU2021221872A1/en not_active Abandoned
- 2021-11-10 JP JP2021182946A patent/JP7268116B2/ja active Active
- 2021-12-09 CY CY20211101084T patent/CY1124858T1/el unknown
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2025676A1 (en) * | 2006-06-08 | 2009-02-18 | Ube Industries, Ltd. | Novel indazole derivative having spiro ring structure in side chain |
| TW201607933A (zh) * | 2014-07-15 | 2016-03-01 | 必治妥美雅史谷比公司 | 做為Ｒｈｏ激酶（ＲＯＣＫ）抑制劑之螺環庚烷類 |
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| TWI730032B (zh) | 作為ｒｏｃｋ抑制劑之螺庚烷水楊酸醯胺及相關化合物 | |
| CN106817899B (zh) | 作为rock抑制剂的螺环庚烷 | |
| ES2886650T3 (es) | Derivados de indazol como antagonistas de integrina alfaV | |
| CN103998042B (zh) | Pi3k的活性或功能的抑制剂的应用 | |
| CN107108566B (zh) | 取代的2-氮杂双环化合物以及它们作为食欲素受体调节剂的用途 | |
| CN110520423A (zh) | 作为激酶抑制剂的氨基三唑并吡啶 | |
| TW201414737A (zh) | 作爲激酶抑制劑之咪唑并三□甲腈 | |
| TW201609725A (zh) | 作為抗癌劑之新穎三環化合物 | |
| JP2019537594A (ja) | アルファｖインテグリン阻害剤としての３−置換プロピオン酸 | |
| TW201443023A (zh) | 作爲ｒｏｃｋ抑制劑之酞□酮及異喹啉酮 | |
| JP2019530739A (ja) | Ｎ−（ピリジン−２−イル）ピリジン−スルホンアミド誘導体および疾患の処置におけるそれらの使用 | |
| TWI822754B (zh) | 作為crhr2拮抗劑之稠合環狀脲衍生物 | |
| CN114302886A (zh) | 三唑并哒嗪类衍生物、其制备方法、药物组合物和用途 | |
| CN114127080B (zh) | 作为激酶抑制剂的杂环化合物、包括该杂环化合物的组合物、及其使用方法 | |
| CN112135818A (zh) | 4-羟基哌啶衍生物及其作为泛素特异性蛋白酶19(usp19)的抑制剂的用途 | |
| WO2020216378A1 (zh) | 一种含杂环的化合物、其应用及含其的组合物 | |
| CN113365696A (zh) | 药物化合物和其作为泛素特异性蛋白酶19(usp19)抑制剂的用途 | |
| HK40063823A (en) | Heterocyclic compounds as kinase inhibitors, compositions comprising the heterocyclic compound, and methods of use thereof | |
| HK40037565A (en) | Fused cyclic urea derivatives as crhr2 antagonist | |
| HK1248678A1 (zh) | 核受體調節劑 |