AU2012356374B2 - Pyridinone and pyrimidinone derivatives as factor XIa inhibitors - Google Patents
Pyridinone and pyrimidinone derivatives as factor XIa inhibitors Download PDFInfo
- Publication number
- AU2012356374B2 AU2012356374B2 AU2012356374A AU2012356374A AU2012356374B2 AU 2012356374 B2 AU2012356374 B2 AU 2012356374B2 AU 2012356374 A AU2012356374 A AU 2012356374A AU 2012356374 A AU2012356374 A AU 2012356374A AU 2012356374 B2 AU2012356374 B2 AU 2012356374B2
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- AU
- Australia
- Prior art keywords
- phenyl
- chloro
- oxo
- imidazol
- tetrazol
- 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.)
- Ceased
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- 108010080805 Factor XIa Proteins 0.000 title claims abstract description 24
- 239000003112 inhibitor Substances 0.000 title abstract description 20
- VTGOHKSTWXHQJK-UHFFFAOYSA-N pyrimidin-2-ol Chemical class OC1=NC=CC=N1 VTGOHKSTWXHQJK-UHFFFAOYSA-N 0.000 title description 5
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 372
- 150000003839 salts Chemical class 0.000 claims abstract description 54
- 229940002612 prodrug Drugs 0.000 claims abstract description 39
- 239000000651 prodrug Substances 0.000 claims abstract description 39
- 239000012453 solvate Substances 0.000 claims abstract description 39
- 208000001435 Thromboembolism Diseases 0.000 claims abstract description 31
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 889
- 125000000217 alkyl group Chemical group 0.000 claims description 470
- -1 cyano, oxo, amidino Chemical group 0.000 claims description 305
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 248
- 229910052736 halogen Inorganic materials 0.000 claims description 169
- 150000002367 halogens Chemical class 0.000 claims description 168
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 163
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 144
- 125000002947 alkylene group Chemical group 0.000 claims description 143
- 125000000172 C5-C10 aryl group Chemical group 0.000 claims description 125
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 121
- 229910052739 hydrogen Inorganic materials 0.000 claims description 117
- 239000001257 hydrogen Substances 0.000 claims description 117
- 125000004943 pyrimidin-6-yl group Chemical group N1=CN=CC=C1* 0.000 claims description 102
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 88
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 81
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 79
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 75
- 238000000034 method Methods 0.000 claims description 72
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 63
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 62
- 125000004648 C2-C8 alkenyl group Chemical group 0.000 claims description 61
- 125000004649 C2-C8 alkynyl group Chemical group 0.000 claims description 59
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 57
- 150000001204 N-oxides Chemical class 0.000 claims description 36
- 150000002431 hydrogen Chemical class 0.000 claims description 36
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 33
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 28
- 208000035475 disorder Diseases 0.000 claims description 27
- 230000009424 thromboembolic effect Effects 0.000 claims description 27
- 239000000460 chlorine Substances 0.000 claims description 26
- 229910052801 chlorine Inorganic materials 0.000 claims description 26
- 125000001425 triazolyl group Chemical group 0.000 claims description 26
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 25
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 25
- 125000002883 imidazolyl group Chemical group 0.000 claims description 25
- 239000003814 drug Substances 0.000 claims description 22
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 21
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 20
- 125000002971 oxazolyl group Chemical group 0.000 claims description 20
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 20
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 19
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims description 19
- 239000008194 pharmaceutical composition Substances 0.000 claims description 19
- 206010047249 Venous thrombosis Diseases 0.000 claims description 17
- 125000004450 alkenylene group Chemical group 0.000 claims description 17
- KXDAEFPNCMNJSK-UHFFFAOYSA-N benzene carboxamide Natural products NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 17
- 125000004076 pyridyl group Chemical group 0.000 claims description 15
- 125000001113 thiadiazolyl group Chemical group 0.000 claims description 14
- CVICEEPAFUYBJG-UHFFFAOYSA-N 5-chloro-2,2-difluoro-1,3-benzodioxole Chemical group C1=C(Cl)C=C2OC(F)(F)OC2=C1 CVICEEPAFUYBJG-UHFFFAOYSA-N 0.000 claims description 13
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 13
- 208000010378 Pulmonary Embolism Diseases 0.000 claims description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims description 12
- 206010051055 Deep vein thrombosis Diseases 0.000 claims description 11
- METKIMKYRPQLGS-UHFFFAOYSA-N atenolol Chemical compound CC(C)NCC(O)COC1=CC=C(CC(N)=O)C=C1 METKIMKYRPQLGS-UHFFFAOYSA-N 0.000 claims description 11
- 208000010125 myocardial infarction Diseases 0.000 claims description 11
- 230000002526 effect on cardiovascular system Effects 0.000 claims description 10
- 208000006011 Stroke Diseases 0.000 claims description 9
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 claims description 9
- 125000000335 thiazolyl group Chemical group 0.000 claims description 9
- WNWVKZTYMQWFHE-UHFFFAOYSA-N 4-ethylmorpholine Chemical group [CH2]CN1CCOCC1 WNWVKZTYMQWFHE-UHFFFAOYSA-N 0.000 claims description 8
- 206010003178 Arterial thrombosis Diseases 0.000 claims description 8
- 208000007536 Thrombosis Diseases 0.000 claims description 8
- 229910052799 carbon Inorganic materials 0.000 claims description 8
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 8
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 7
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 7
- 229910052717 sulfur Inorganic materials 0.000 claims description 7
- 206010003658 Atrial Fibrillation Diseases 0.000 claims description 6
- 206010008088 Cerebral artery embolism Diseases 0.000 claims description 6
- 208000005189 Embolism Diseases 0.000 claims description 6
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims description 6
- 102000003827 Plasma Kallikrein Human genes 0.000 claims description 6
- 108090000113 Plasma Kallikrein Proteins 0.000 claims description 6
- 208000032109 Transient ischaemic attack Diseases 0.000 claims description 6
- 208000007814 Unstable Angina Diseases 0.000 claims description 6
- 239000008280 blood Substances 0.000 claims description 6
- 210000004369 blood Anatomy 0.000 claims description 6
- 230000000302 ischemic effect Effects 0.000 claims description 6
- 201000010875 transient cerebral ischemia Diseases 0.000 claims description 6
- 208000004476 Acute Coronary Syndrome Diseases 0.000 claims description 5
- 206010002388 Angina unstable Diseases 0.000 claims description 5
- 201000001320 Atherosclerosis Diseases 0.000 claims description 5
- 206010008092 Cerebral artery thrombosis Diseases 0.000 claims description 5
- 206010014513 Embolism arterial Diseases 0.000 claims description 5
- 206010042434 Sudden death Diseases 0.000 claims description 5
- 239000007943 implant Substances 0.000 claims description 5
- 201000004332 intermediate coronary syndrome Diseases 0.000 claims description 5
- 201000010849 intracranial embolism Diseases 0.000 claims description 5
- 210000003734 kidney Anatomy 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 230000003836 peripheral circulation Effects 0.000 claims description 5
- 230000002093 peripheral effect Effects 0.000 claims description 5
- 201000005060 thrombophlebitis Diseases 0.000 claims description 5
- 200000000007 Arterial disease Diseases 0.000 claims description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 4
- 229940122036 Factor XIa inhibitor Drugs 0.000 claims description 4
- 206010037437 Pulmonary thrombosis Diseases 0.000 claims description 4
- 125000003838 furazanyl group Chemical group 0.000 claims description 4
- 125000002541 furyl group Chemical group 0.000 claims description 4
- 125000001786 isothiazolyl group Chemical group 0.000 claims description 4
- 125000001715 oxadiazolyl group Chemical group 0.000 claims description 4
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 4
- 125000001544 thienyl group Chemical group 0.000 claims description 4
- IKNJDOISNRBNAB-SFHVURJKSA-N (3s)-3-[2-(6-aminopyridin-3-yl)-4-fluoro-1h-imidazol-5-yl]-7-[5-chloro-2-(tetrazol-1-yl)phenyl]-2,3-dihydro-1h-indolizin-5-one Chemical compound C1=NC(N)=CC=C1C1=NC(F)=C([C@H]2N3C(=O)C=C(C=C3CC2)C=2C(=CC=C(Cl)C=2)N2N=NN=C2)N1 IKNJDOISNRBNAB-SFHVURJKSA-N 0.000 claims description 3
- SPLMRIALVABEDR-IBGZPJMESA-N (3s)-3-[4-(6-aminopyridin-3-yl)-5-chloro-1h-imidazol-2-yl]-7-[5-methyl-2-(tetrazol-1-yl)phenyl]-2,3-dihydro-1h-indolizin-5-one Chemical compound ClC=1NC([C@@H]2CCC3=CC(=CC(=O)N32)C=2C(=CC=C(C=2)C)N2N=NN=C2)=NC=1C1=CC=C(N)N=C1 SPLMRIALVABEDR-IBGZPJMESA-N 0.000 claims description 3
- GAAMYHWRTMVMAJ-IBGZPJMESA-N (3s)-3-[5-(6-amino-2-fluoropyridin-3-yl)-1h-imidazol-2-yl]-7-[5-chloro-2-(tetrazol-1-yl)phenyl]-2,3-dihydro-1h-indolizin-5-one Chemical compound FC1=NC(N)=CC=C1C1=CN=C([C@H]2N3C(=O)C=C(C=C3CC2)C=2C(=CC=C(Cl)C=2)N2N=NN=C2)N1 GAAMYHWRTMVMAJ-IBGZPJMESA-N 0.000 claims description 3
- 125000004777 2-fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 claims description 3
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 3
- HMLYJELZUZPGSW-UHFFFAOYSA-N 6-[2-[7-[5-chloro-2-(tetrazol-1-yl)phenyl]-5-oxo-2,3-dihydro-1h-indolizin-3-yl]-1h-imidazol-5-yl]-3,4-dihydro-1h-quinolin-2-one Chemical compound C1=C2CCC(C=3NC(=CN=3)C=3C=C4CCC(=O)NC4=CC=3)N2C(=O)C=C1C1=CC(Cl)=CC=C1N1C=NN=N1 HMLYJELZUZPGSW-UHFFFAOYSA-N 0.000 claims description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 3
- MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 claims description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 3
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 3
- 229940125436 dual inhibitor Drugs 0.000 claims description 3
- HNBXYJDMZBWTRI-SFHVURJKSA-N ethyl 5-[5-chloro-2-[(3s)-7-[5-chloro-2-(tetrazol-1-yl)phenyl]-5-oxo-2,3-dihydro-1h-indolizin-3-yl]-1h-imidazol-4-yl]thiophene-2-carboxylate Chemical compound S1C(C(=O)OCC)=CC=C1C1=C(Cl)NC([C@H]2N3C(=O)C=C(C=C3CC2)C=2C(=CC=C(Cl)C=2)N2N=NN=C2)=N1 HNBXYJDMZBWTRI-SFHVURJKSA-N 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- 239000001301 oxygen Substances 0.000 claims description 3
- 239000011593 sulfur Substances 0.000 claims description 3
- DOJGBZWFAJPWJJ-SFHVURJKSA-N (3s)-3-[4-(6-aminopyridin-3-yl)-5-fluoro-1h-imidazol-2-yl]-7-[5-chloro-2-(tetrazol-1-yl)phenyl]-2,3-dihydro-1h-indolizin-5-one Chemical compound C1=NC(N)=CC=C1C1=C(F)NC([C@H]2N3C(=O)C=C(C=C3CC2)C=2C(=CC=C(Cl)C=2)N2N=NN=C2)=N1 DOJGBZWFAJPWJJ-SFHVURJKSA-N 0.000 claims description 2
- PNCKFQMSPCUDHI-QFIPXVFZSA-N (3s)-7-[5-chloro-2-(tetrazol-1-yl)phenyl]-3-[5-(4-hydroxyphenyl)-1h-imidazol-2-yl]-2,3-dihydro-1h-indolizin-5-one Chemical compound C1=CC(O)=CC=C1C1=CN=C([C@H]2N3C(=O)C=C(C=C3CC2)C=2C(=CC=C(Cl)C=2)N2N=NN=C2)N1 PNCKFQMSPCUDHI-QFIPXVFZSA-N 0.000 claims description 2
- MCYFMLHYHAVVLT-INIZCTEOSA-N (6s)-6-[4-(6-aminopyridin-3-yl)-5-fluoro-1h-imidazol-2-yl]-2-[5-chloro-2-(tetrazol-1-yl)phenyl]-7,8-dihydro-6h-pyrrolo[1,2-a]pyrimidin-4-one Chemical compound C1=NC(N)=CC=C1C1=C(F)NC([C@H]2N3C(=O)C=C(N=C3CC2)C=2C(=CC=C(Cl)C=2)N2N=NN=C2)=N1 MCYFMLHYHAVVLT-INIZCTEOSA-N 0.000 claims description 2
- XTNXFBFJEUDZCD-DEOSSOPVSA-N 2-morpholin-4-ylethyl 5-[2-[(3s)-7-[5-chloro-2-(tetrazol-1-yl)phenyl]-5-oxo-2,3-dihydro-1h-indolizin-3-yl]-1h-imidazol-5-yl]thiophene-2-carboxylate Chemical compound N1C([C@@H]2CCC3=CC(=CC(=O)N32)C=2C(=CC=C(C=2)Cl)N2N=NN=C2)=NC=C1C(S1)=CC=C1C(=O)OCCN1CCOCC1 XTNXFBFJEUDZCD-DEOSSOPVSA-N 0.000 claims description 2
- JZDGKEHJCKHFOK-UHFFFAOYSA-N 3-[5-(3-amino-1h-indazol-6-yl)-1h-imidazol-2-yl]-7-[5-chloro-2-(tetrazol-1-yl)phenyl]-2,3-dihydro-1h-indolizin-5-one Chemical compound C=1C=C2C(N)=NNC2=CC=1C(N1)=CN=C1C(N1C(=O)C=2)CCC1=CC=2C1=CC(Cl)=CC=C1N1C=NN=N1 JZDGKEHJCKHFOK-UHFFFAOYSA-N 0.000 claims description 2
- UQWLBVSYKUTWRG-DEOSSOPVSA-N 3-methylbutyl 4-[2-[(3s)-7-[5-chloro-2-(tetrazol-1-yl)phenyl]-5-oxo-2,3-dihydro-1h-indolizin-3-yl]-1h-imidazol-5-yl]thiophene-2-carboxylate Chemical compound S1C(C(=O)OCCC(C)C)=CC(C=2NC(=NC=2)[C@H]2N3C(=O)C=C(C=C3CC2)C=2C(=CC=C(Cl)C=2)N2N=NN=C2)=C1 UQWLBVSYKUTWRG-DEOSSOPVSA-N 0.000 claims description 2
- AARCNTLPYLQRKZ-QFIPXVFZSA-N 4-[2-[(3s)-7-[5-chloro-2-(tetrazol-1-yl)phenyl]-5-oxo-2,3-dihydro-1h-indolizin-3-yl]-1h-imidazol-5-yl]benzamide Chemical compound C1=CC(C(=O)N)=CC=C1C1=CN=C([C@H]2N3C(=O)C=C(C=C3CC2)C=2C(=CC=C(Cl)C=2)N2N=NN=C2)N1 AARCNTLPYLQRKZ-QFIPXVFZSA-N 0.000 claims description 2
- WGQINNNHNLPKLE-UHFFFAOYSA-N 4-[5-[7-[5-chloro-2-(tetrazol-1-yl)phenyl]-5-oxo-2,3-dihydro-1h-indolizin-3-yl]-4-fluoro-1h-imidazol-2-yl]thiophene-2-carboxylic acid Chemical compound S1C(C(=O)O)=CC(C=2NC(=C(F)N=2)C2N3C(=O)C=C(C=C3CC2)C=2C(=CC=C(Cl)C=2)N2N=NN=C2)=C1 WGQINNNHNLPKLE-UHFFFAOYSA-N 0.000 claims description 2
- IINHILDDQNODJN-INIZCTEOSA-N 5-[5-chloro-2-[(3s)-7-[5-chloro-2-(tetrazol-1-yl)phenyl]-5-oxo-2,3-dihydro-1h-indolizin-3-yl]-1h-imidazol-4-yl]thiophene-2-carboxylic acid Chemical compound S1C(C(=O)O)=CC=C1C1=C(Cl)NC([C@H]2N3C(=O)C=C(C=C3CC2)C=2C(=CC=C(Cl)C=2)N2N=NN=C2)=N1 IINHILDDQNODJN-INIZCTEOSA-N 0.000 claims description 2
- HMLYJELZUZPGSW-DEOSSOPVSA-N 6-[2-[(3s)-7-[5-chloro-2-(tetrazol-1-yl)phenyl]-5-oxo-2,3-dihydro-1h-indolizin-3-yl]-1h-imidazol-5-yl]-3,4-dihydro-1h-quinolin-2-one Chemical compound N1([C@H](C=2NC(=CN=2)C=2C=C3CCC(=O)NC3=CC=2)CCC1=C1)C(=O)C=C1C1=CC(Cl)=CC=C1N1C=NN=N1 HMLYJELZUZPGSW-DEOSSOPVSA-N 0.000 claims description 2
- 125000002933 cyclohexyloxy group Chemical group C1(CCCCC1)O* 0.000 claims description 2
- QUYMUPIVQIHGBM-FQEVSTJZSA-N methyl 4-[2-[(3s)-7-[5-chloro-2-(tetrazol-1-yl)phenyl]-5-oxo-2,3-dihydro-1h-indolizin-3-yl]-1h-imidazol-5-yl]thiophene-2-carboxylate Chemical compound S1C(C(=O)OC)=CC(C=2NC(=NC=2)[C@H]2N3C(=O)C=C(C=C3CC2)C=2C(=CC=C(Cl)C=2)N2N=NN=C2)=C1 QUYMUPIVQIHGBM-FQEVSTJZSA-N 0.000 claims description 2
- ASPBAMYIRWSFEM-QFIPXVFZSA-N propan-2-yl 4-[2-[(3s)-7-[5-chloro-2-(tetrazol-1-yl)phenyl]-5-oxo-2,3-dihydro-1h-indolizin-3-yl]-1h-imidazol-5-yl]thiophene-2-carboxylate Chemical compound S1C(C(=O)OC(C)C)=CC(C=2NC(=NC=2)[C@H]2N3C(=O)C=C(C=C3CC2)C=2C(=CC=C(Cl)C=2)N2N=NN=C2)=C1 ASPBAMYIRWSFEM-QFIPXVFZSA-N 0.000 claims description 2
- CCDWNZCTOKIPFF-QHCPKHFHSA-N methyl n-[4-[2-[(3s)-7-[5-chloro-2-(tetrazol-1-yl)phenyl]-5-oxo-2,3-dihydro-1h-indolizin-3-yl]-5-methyl-1h-imidazol-4-yl]phenyl]carbamate Chemical compound C1=CC(NC(=O)OC)=CC=C1C1=C(C)NC([C@H]2N3C(=O)C=C(C=C3CC2)C=2C(=CC=C(Cl)C=2)N2N=NN=C2)=N1 CCDWNZCTOKIPFF-QHCPKHFHSA-N 0.000 claims 2
- BDLJPBNCXKFIEH-NRFANRHFSA-N (3s)-3-[5-chloro-4-[6-(1,3-oxazol-2-ylmethylamino)pyridin-3-yl]-1h-imidazol-2-yl]-7-[5-chloro-2-(tetrazol-1-yl)phenyl]-2,3-dihydro-1h-indolizin-5-one Chemical compound ClC=1NC([C@H]2N3C(=O)C=C(C=C3CC2)C=2C(=CC=C(Cl)C=2)N2N=NN=C2)=NC=1C(C=N1)=CC=C1NCC1=NC=CO1 BDLJPBNCXKFIEH-NRFANRHFSA-N 0.000 claims 1
- CZHIHAHCJCNHLP-KRWDZBQOSA-N (6s)-6-[5-(6-amino-2-chloropyridin-3-yl)-1h-imidazol-2-yl]-2-[5-chloro-2-(tetrazol-1-yl)phenyl]-7,8-dihydro-6h-pyrrolo[1,2-a]pyrimidin-4-one Chemical compound ClC1=NC(N)=CC=C1C1=CN=C([C@H]2N3C(=O)C=C(N=C3CC2)C=2C(=CC=C(Cl)C=2)N2N=NN=C2)N1 CZHIHAHCJCNHLP-KRWDZBQOSA-N 0.000 claims 1
- PXYBTDUOASPPSQ-QHCPKHFHSA-N 2,2-dimethylpropanoyloxymethyl 4-[2-[(3s)-7-[5-chloro-2-(tetrazol-1-yl)phenyl]-5-oxo-2,3-dihydro-1h-indolizin-3-yl]-1h-imidazol-5-yl]thiophene-2-carboxylate Chemical compound S1C(C(=O)OCOC(=O)C(C)(C)C)=CC(C=2NC(=NC=2)[C@H]2N3C(=O)C=C(C=C3CC2)C=2C(=CC=C(Cl)C=2)N2N=NN=C2)=C1 PXYBTDUOASPPSQ-QHCPKHFHSA-N 0.000 claims 1
- QELCTAVSAASVRR-MHZLTWQESA-N 2-(2-methoxyethoxy)ethyl n-[4-[2-[(3s)-7-[5-chloro-2-(tetrazol-1-yl)phenyl]-5-oxo-2,3-dihydro-1h-indolizin-3-yl]-1h-imidazol-5-yl]phenyl]carbamate Chemical compound C1=CC(NC(=O)OCCOCCOC)=CC=C1C1=CN=C([C@H]2N3C(=O)C=C(C=C3CC2)C=2C(=CC=C(Cl)C=2)N2N=NN=C2)N1 QELCTAVSAASVRR-MHZLTWQESA-N 0.000 claims 1
- KFHOGJSFPOYJQH-IBGZPJMESA-N 4-[2-[(3s)-7-[5-chloro-2-(tetrazol-1-yl)phenyl]-5-oxo-2,3-dihydro-1h-indolizin-3-yl]-1h-imidazol-5-yl]thiophene-2-carboxylic acid Chemical compound S1C(C(=O)O)=CC(C=2NC(=NC=2)[C@H]2N3C(=O)C=C(C=C3CC2)C=2C(=CC=C(Cl)C=2)N2N=NN=C2)=C1 KFHOGJSFPOYJQH-IBGZPJMESA-N 0.000 claims 1
- LXJRGJSVLKAPND-SFHVURJKSA-N 4-[2-[(3s)-8-bromo-7-[5-chloro-2-(tetrazol-1-yl)phenyl]-5-oxo-2,3-dihydro-1h-indolizin-3-yl]-1h-imidazol-5-yl]thiophene-2-carboxylic acid Chemical compound S1C(C(=O)O)=CC(C=2NC(=NC=2)[C@H]2N3C(=O)C=C(C(Br)=C3CC2)C=2C(=CC=C(Cl)C=2)N2N=NN=C2)=C1 LXJRGJSVLKAPND-SFHVURJKSA-N 0.000 claims 1
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- QYGZGFFENZUOAB-FQEVSTJZSA-N ethyl 5-[2-[(3s)-7-[5-chloro-2-(tetrazol-1-yl)phenyl]-5-oxo-2,3-dihydro-1h-indolizin-3-yl]-1h-imidazol-5-yl]thiophene-2-carboxylate Chemical compound S1C(C(=O)OCC)=CC=C1C1=CN=C([C@H]2N3C(=O)C=C(C=C3CC2)C=2C(=CC=C(Cl)C=2)N2N=NN=C2)N1 QYGZGFFENZUOAB-FQEVSTJZSA-N 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 201000007219 factor XI deficiency Diseases 0.000 description 1
- 229960004222 factor ix Drugs 0.000 description 1
- 229940012952 fibrinogen Drugs 0.000 description 1
- 239000007888 film coating Substances 0.000 description 1
- 238000009501 film coating Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 239000012025 fluorinating agent Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 210000004211 gastric acid Anatomy 0.000 description 1
- 208000021302 gastroesophageal reflux disease Diseases 0.000 description 1
- 238000002682 general surgery Methods 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229960001031 glucose Drugs 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 229940097042 glucuronate Drugs 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000000122 growth hormone Substances 0.000 description 1
- 239000003324 growth hormone secretagogue Substances 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 208000031169 hemorrhagic disease Diseases 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000006038 hexenyl group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000005980 hexynyl group Chemical group 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000011540 hip replacement Methods 0.000 description 1
- 238000002657 hormone replacement therapy Methods 0.000 description 1
- 150000002429 hydrazines Chemical class 0.000 description 1
- BNRNAKTVFSZAFA-UHFFFAOYSA-N hydrindane Chemical compound C1CCCC2CCCC21 BNRNAKTVFSZAFA-UHFFFAOYSA-N 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 description 1
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 description 1
- 150000002463 imidates Chemical class 0.000 description 1
- 125000003037 imidazol-2-yl group Chemical group [H]N1C([*])=NC([H])=C1[H] 0.000 description 1
- QNLOWBMKUIXCOW-UHFFFAOYSA-N indol-2-one Chemical compound C1=CC=CC2=NC(=O)C=C21 QNLOWBMKUIXCOW-UHFFFAOYSA-N 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- FGFUBBNNYLNVLJ-UHFFFAOYSA-N indolone Natural products C1=CC=C2C(=O)C=NC2=C1 FGFUBBNNYLNVLJ-UHFFFAOYSA-N 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 238000007917 intracranial administration Methods 0.000 description 1
- 201000007272 intracranial sinus thrombosis Diseases 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 230000002530 ischemic preconditioning effect Effects 0.000 description 1
- 238000013150 knee replacement Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229960001375 lactose Drugs 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 229960004393 lidocaine hydrochloride Drugs 0.000 description 1
- YECIFGHRMFEPJK-UHFFFAOYSA-N lidocaine hydrochloride monohydrate Chemical compound O.[Cl-].CC[NH+](CC)CC(=O)NC1=C(C)C=CC=C1C YECIFGHRMFEPJK-UHFFFAOYSA-N 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 125000005647 linker group Chemical group 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- HCWCAKKEBCNQJP-UHFFFAOYSA-N magnesium orthosilicate Chemical compound [Mg+2].[Mg+2].[O-][Si]([O-])([O-])[O-] HCWCAKKEBCNQJP-UHFFFAOYSA-N 0.000 description 1
- 239000000391 magnesium silicate Substances 0.000 description 1
- 229910052919 magnesium silicate Inorganic materials 0.000 description 1
- 235000019792 magnesium silicate Nutrition 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L magnesium sulphate Substances [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 150000002690 malonic acid derivatives Chemical class 0.000 description 1
- 229960001855 mannitol Drugs 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- GXHFUVWIGNLZSC-UHFFFAOYSA-N meldrum's acid Chemical class CC1(C)OC(=O)CC(=O)O1 GXHFUVWIGNLZSC-UHFFFAOYSA-N 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- FOGDAYBTFWGEHM-IBGZPJMESA-N methyl 2-[5-[5-chloro-2-[(3S)-7-[5-chloro-2-(tetrazol-1-yl)phenyl]-5-oxo-2,3-dihydro-1H-indolizin-3-yl]-1H-imidazol-4-yl]thiophen-2-yl]acetate Chemical compound COC(CC=1SC(=CC=1)C1=C(N=C(N1)[C@@H]1CCC2=CC(=CC(N12)=O)C1=C(C=CC(=C1)Cl)N1N=NN=C1)Cl)=O FOGDAYBTFWGEHM-IBGZPJMESA-N 0.000 description 1
- GIMPQQOFLICHON-PMERELPUSA-N methyl N-[4-[2-[(1S)-1-[4-[5-chloro-2-(4-fluoropyrazol-1-yl)phenyl]-2-oxopyridin-1-yl]-2-phenylethyl]-1H-imidazol-5-yl]phenyl]carbamate Chemical compound COC(NC1=CC=C(C=C1)C1=CN=C(N1)[C@H](CC1=CC=CC=C1)N1C(C=C(C=C1)C1=C(C=CC(=C1)Cl)N1N=CC(=C1)F)=O)=O GIMPQQOFLICHON-PMERELPUSA-N 0.000 description 1
- LFVAGDYDLVOWRH-QHCPKHFHSA-N methyl N-[4-[2-[(3S)-7-[5-chloro-2-(tetrazol-1-yl)phenyl]-5-oxo-2,3-dihydro-1H-indolizin-3-yl]-1H-imidazol-5-yl]-3-methoxyphenyl]carbamate Chemical compound COC(NC1=CC(=C(C=C1)C1=CN=C(N1)[C@@H]1CCC2=CC(=CC(N12)=O)C1=C(C=CC(=C1)Cl)N1N=NN=C1)OC)=O LFVAGDYDLVOWRH-QHCPKHFHSA-N 0.000 description 1
- GXFQCXSDTIYETL-NRFANRHFSA-N methyl N-[4-[2-[(6S)-2-[5-chloro-2-(tetrazol-1-yl)phenyl]-4-oxo-7,8-dihydro-6H-pyrrolo[1,2-a]pyrimidin-6-yl]-5-methyl-1H-imidazol-4-yl]phenyl]carbamate Chemical compound COC(=O)Nc1ccc(cc1)-c1[nH]c(nc1C)[C@@H]1CCc2nc(cc(=O)n12)-c1cc(Cl)ccc1-n1cnnn1 GXFQCXSDTIYETL-NRFANRHFSA-N 0.000 description 1
- DYLKDJJAGMGQSO-UHFFFAOYSA-N methyl N-[4-[2-[1-[4-[5-chloro-2-(diaminomethylideneamino)phenyl]-2-oxopyridin-1-yl]-2-phenylethyl]-1H-imidazol-5-yl]phenyl]carbamate Chemical compound COC(NC1=CC=C(C=C1)C=1N=C(NC=1)C(CC1=CC=CC=C1)N1C(C=C(C=C1)C1=C(C=CC(=C1)Cl)NC(=N)N)=O)=O DYLKDJJAGMGQSO-UHFFFAOYSA-N 0.000 description 1
- TZCSCVMBIQWABF-UHFFFAOYSA-N methyl N-[4-[2-[1-[4-[5-chloro-2-(tetrazol-1-yl)phenyl]-2-methyl-6-oxopyridin-1-yl]ethyl]-1H-imidazol-5-yl]phenyl]carbamate Chemical compound COC(NC1=CC=C(C=C1)C1=CN=C(N1)C(C)N1C(C=C(C=C1C)C1=C(C=CC(=C1)Cl)N1N=NN=C1)=O)=O TZCSCVMBIQWABF-UHFFFAOYSA-N 0.000 description 1
- JVGQBWMDRKCOFU-QHCPKHFHSA-N methyl N-[4-[5-[(3S)-7-[5-chloro-2-(tetrazol-1-yl)phenyl]-5-oxo-2,3-dihydro-1H-indolizin-3-yl]-3-oxo-1H-pyrazol-2-yl]phenyl]carbamate Chemical compound COC(=O)Nc1ccc(cc1)-n1[nH]c(cc1=O)[C@@H]1CCc2cc(cc(=O)n12)-c1cc(Cl)ccc1-n1cnnn1 JVGQBWMDRKCOFU-QHCPKHFHSA-N 0.000 description 1
- BWFUHDBHFUBYGX-NRFANRHFSA-N methyl N-[4-[5-[(3S)-7-[5-chloro-2-(tetrazol-1-yl)phenyl]-5-oxo-2,3-dihydro-1H-indolizin-3-yl]-4-fluoro-1H-imidazol-2-yl]phenyl]carbamate Chemical compound COC(NC1=CC=C(C=C1)C=1NC(=C(N=1)F)[C@@H]1CCC2=CC(=CC(N12)=O)C1=C(C=CC(=C1)Cl)N1N=NN=C1)=O BWFUHDBHFUBYGX-NRFANRHFSA-N 0.000 description 1
- CHOBMXVJHNBIFF-NRFANRHFSA-N methyl N-[4-[5-bromo-2-[(3S)-7-[5-chloro-2-(tetrazol-1-yl)phenyl]-5-oxo-2,3-dihydro-1H-indolizin-3-yl]-1H-imidazol-4-yl]phenyl]carbamate Chemical compound COC(NC1=CC=C(C=C1)C1=C(N=C(N1)[C@@H]1CCC2=CC(=CC(N12)=O)C1=C(C=CC(=C1)Cl)N1N=NN=C1)Br)=O CHOBMXVJHNBIFF-NRFANRHFSA-N 0.000 description 1
- UBIXICNQLJLUFN-UHFFFAOYSA-N methyl N-[4-[5-chloro-2-[1-[4-(2,5-dichlorophenyl)-2-oxopyridin-1-yl]-2-phenylethyl]-1H-imidazol-4-yl]phenyl]carbamate Chemical compound COC(NC1=CC=C(C=C1)C=1N=C(NC=1Cl)C(CC1=CC=CC=C1)N1C(C=C(C=C1)C1=C(C=CC(=C1)Cl)Cl)=O)=O UBIXICNQLJLUFN-UHFFFAOYSA-N 0.000 description 1
- XFUROVALYLEUNC-UHFFFAOYSA-N methyl N-[4-[5-chloro-2-[1-[4-[5-chloro-2-(tetrazol-1-yl)phenyl]-2-oxopyridin-1-yl]-2-pyridin-3-ylethyl]-1H-imidazol-4-yl]phenyl]carbamate Chemical compound COC(NC1=CC=C(C=C1)C1=C(N=C(N1)C(CC=1C=NC=CC=1)N1C(C=C(C=C1)C1=C(C=CC(=C1)Cl)N1N=NN=C1)=O)Cl)=O XFUROVALYLEUNC-UHFFFAOYSA-N 0.000 description 1
- CUMJVOYNJDEVEE-UHFFFAOYSA-N methyl N-[4-[5-chloro-2-[7-[5-chloro-2-(tetrazol-1-yl)phenyl]-5-oxo-2,3-dihydro-1H-indolizin-3-yl]-1H-imidazol-4-yl]-3-ethylphenyl]carbamate Chemical compound COC(NC1=CC(=C(C=C1)C1=C(N=C(N1)C1CCC2=CC(=CC(N12)=O)C1=C(C=CC(=C1)Cl)N1N=NN=C1)Cl)CC)=O CUMJVOYNJDEVEE-UHFFFAOYSA-N 0.000 description 1
- XOCDNIZQIWVGPN-UHFFFAOYSA-N methyl N-[4-[5-chloro-2-[[4-[5-chloro-2-(tetrazol-1-yl)phenyl]-2-methyl-6-oxopyrimidin-1-yl]methyl]-1H-imidazol-4-yl]phenyl]carbamate Chemical compound COC(NC1=CC=C(C=C1)C1=C(N=C(N1)CN1C(=NC(=CC1=O)C1=C(C=CC(=C1)Cl)N1N=NN=C1)C)Cl)=O XOCDNIZQIWVGPN-UHFFFAOYSA-N 0.000 description 1
- VLERCJMCGBFOCO-DEOSSOPVSA-N methyl N-[4-[5-methyl-2-[(3S)-7-[5-methyl-2-(tetrazol-1-yl)phenyl]-5-oxo-2,3-dihydro-1H-indolizin-3-yl]-1H-imidazol-4-yl]phenyl]carbamate Chemical compound COC(NC1=CC=C(C=C1)C1=C(N=C(N1)[C@@H]1CCC2=CC(=CC(N12)=O)C1=C(C=CC(=C1)C)N1N=NN=C1)C)=O VLERCJMCGBFOCO-DEOSSOPVSA-N 0.000 description 1
- JPVNQOIWBYORDM-NRFANRHFSA-N methyl N-[5-[2-[(3S)-7-[5-chloro-2-(tetrazol-1-yl)phenyl]-5-oxo-2,3-dihydro-1H-indolizin-3-yl]-1H-imidazol-5-yl]pyridin-2-yl]carbamate Chemical compound COC(NC1=NC=C(C=C1)C1=CN=C(N1)[C@@H]1CCC2=CC(=CC(N12)=O)C1=C(C=CC(=C1)Cl)N1N=NN=C1)=O JPVNQOIWBYORDM-NRFANRHFSA-N 0.000 description 1
- VLCBDDIUZYRACT-IBGZPJMESA-N methyl N-[5-[4-chloro-5-[(3S)-7-[5-chloro-2-(tetrazol-1-yl)phenyl]-5-oxo-2,3-dihydro-1H-indolizin-3-yl]-1H-imidazol-2-yl]pyridin-2-yl]carbamate Chemical compound COC(NC1=NC=C(C=C1)C=1NC(=C(N=1)Cl)[C@@H]1CCC2=CC(=CC(N12)=O)C1=C(C=CC(=C1)Cl)N1N=NN=C1)=O VLCBDDIUZYRACT-IBGZPJMESA-N 0.000 description 1
- KJIOEAJVMBCKTO-FQEVSTJZSA-N methyl N-[5-[5-chloro-2-[(3S)-7-[5-methyl-2-(tetrazol-1-yl)phenyl]-5-oxo-2,3-dihydro-1H-indolizin-3-yl]-1H-imidazol-4-yl]pyridin-2-yl]carbamate Chemical compound COC(NC1=NC=C(C=C1)C1=C(N=C(N1)[C@@H]1CCC2=CC(=CC(N12)=O)C1=C(C=CC(=C1)C)N1N=NN=C1)Cl)=O KJIOEAJVMBCKTO-FQEVSTJZSA-N 0.000 description 1
- UTVSETFYEAWWFB-QFIPXVFZSA-N methyl N-[6-[2-[(3S)-7-[5-chloro-2-(tetrazol-1-yl)phenyl]-5-oxo-2,3-dihydro-1H-indolizin-3-yl]-5-methyl-1H-imidazol-4-yl]pyridin-3-yl]carbamate Chemical compound COC(=O)Nc1ccc(nc1)-c1[nH]c(nc1C)[C@@H]1CCc2cc(cc(=O)n12)-c1cc(Cl)ccc1-n1cnnn1 UTVSETFYEAWWFB-QFIPXVFZSA-N 0.000 description 1
- DFFZLXMOSYWWQZ-UHFFFAOYSA-N methyl N-[6-[2-[7-[5-chloro-2-(tetrazol-1-yl)phenyl]-5-oxo-2,3-dihydro-1H-indolizin-3-yl]-1H-imidazol-5-yl]pyridin-3-yl]carbamate Chemical compound COC(NC=1C=NC(=CC=1)C1=CN=C(N1)C1CCC2=CC(=CC(N12)=O)C1=C(C=CC(=C1)Cl)N1N=NN=C1)=O DFFZLXMOSYWWQZ-UHFFFAOYSA-N 0.000 description 1
- LJPBWICYIUSMOB-FQEVSTJZSA-N methyl N-[6-[4-chloro-5-[(3S)-7-[5-chloro-2-(tetrazol-1-yl)phenyl]-5-oxo-2,3-dihydro-1H-indolizin-3-yl]-1H-imidazol-2-yl]pyridin-3-yl]carbamate Chemical compound COC(NC=1C=NC(=CC=1)C=1NC(=C(N=1)Cl)[C@@H]1CCC2=CC(=CC(N12)=O)C1=C(C=CC(=C1)Cl)N1N=NN=C1)=O LJPBWICYIUSMOB-FQEVSTJZSA-N 0.000 description 1
- XXAHQPHVMRKUJN-NRFANRHFSA-N methyl N-[6-[5-chloro-2-[(3S)-7-[5-methyl-2-(tetrazol-1-yl)phenyl]-5-oxo-2,3-dihydro-1H-indolizin-3-yl]-1H-imidazol-4-yl]pyridin-3-yl]carbamate Chemical compound COC(NC=1C=NC(=CC=1)C1=C(N=C(N1)[C@@H]1CCC2=CC(=CC(N12)=O)C1=C(C=CC(=C1)C)N1N=NN=C1)Cl)=O XXAHQPHVMRKUJN-NRFANRHFSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- XAFJHYBQQFKSRO-NRFANRHFSA-N methyl n-[4-[2-[(3r)-7-[5-chloro-2-(tetrazol-1-yl)phenyl]-5-oxo-2,3-dihydro-[1,3]thiazolo[3,2-a]pyridin-3-yl]-1h-imidazol-5-yl]phenyl]carbamate Chemical compound C1=CC(NC(=O)OC)=CC=C1C1=CN=C([C@H]2N3C(=O)C=C(C=C3SC2)C=2C(=CC=C(Cl)C=2)N2N=NN=C2)N1 XAFJHYBQQFKSRO-NRFANRHFSA-N 0.000 description 1
- MGJXBDMLVWIYOQ-UHFFFAOYSA-N methylazanide Chemical compound [NH-]C MGJXBDMLVWIYOQ-UHFFFAOYSA-N 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- XKBGEWXEAPTVCK-UHFFFAOYSA-M methyltrioctylammonium chloride Chemical compound [Cl-].CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC XKBGEWXEAPTVCK-UHFFFAOYSA-M 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 230000003278 mimic effect Effects 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000002394 mineralocorticoid antagonist Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 208000002089 myocardial stunning Diseases 0.000 description 1
- DUWWHGPELOTTOE-UHFFFAOYSA-N n-(5-chloro-2,4-dimethoxyphenyl)-3-oxobutanamide Chemical compound COC1=CC(OC)=C(NC(=O)CC(C)=O)C=C1Cl DUWWHGPELOTTOE-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
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 229920001206 natural gum Polymers 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
- 125000004365 octenyl group Chemical group C(=CCCCCCC)* 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000005069 octynyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C#C* 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 229940127234 oral contraceptive Drugs 0.000 description 1
- 239000003539 oral contraceptive agent Substances 0.000 description 1
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- 235000010288 sodium nitrite Nutrition 0.000 description 1
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- 229940079832 sodium starch glycolate Drugs 0.000 description 1
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- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 description 1
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- 239000012414 tert-butyl nitrite Substances 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical compound C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- RAOIDOHSFRTOEL-UHFFFAOYSA-N tetrahydrothiophene Chemical compound C1CCSC1 RAOIDOHSFRTOEL-UHFFFAOYSA-N 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- RWXZKKKYLRFREK-UHFFFAOYSA-N thiadiazepane Chemical compound C1CCSNNC1 RWXZKKKYLRFREK-UHFFFAOYSA-N 0.000 description 1
- TVQOEGVBMRCMFR-UHFFFAOYSA-N thiadiazinane Chemical compound C1CNNSC1 TVQOEGVBMRCMFR-UHFFFAOYSA-N 0.000 description 1
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- AJZGFFKDLABHDD-UHFFFAOYSA-N thiazinane Chemical compound C1CCSNC1 AJZGFFKDLABHDD-UHFFFAOYSA-N 0.000 description 1
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- QERYCTSHXKAMIS-UHFFFAOYSA-N thiophene-2-carboxylic acid Chemical compound OC(=O)C1=CC=CS1 QERYCTSHXKAMIS-UHFFFAOYSA-N 0.000 description 1
- 230000002537 thrombolytic effect Effects 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- YEMJHNYABQHWHL-UHFFFAOYSA-N tributyl(ethynyl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C#C YEMJHNYABQHWHL-UHFFFAOYSA-N 0.000 description 1
- DBGVGMSCBYYSLD-UHFFFAOYSA-N tributylstannane Chemical compound CCCC[SnH](CCCC)CCCC DBGVGMSCBYYSLD-UHFFFAOYSA-N 0.000 description 1
- 125000006000 trichloroethyl group Chemical group 0.000 description 1
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- SEDZOYHHAIAQIW-UHFFFAOYSA-N trimethylsilyl azide Chemical compound C[Si](C)(C)N=[N+]=[N-] SEDZOYHHAIAQIW-UHFFFAOYSA-N 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- 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
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- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
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- 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
- 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
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
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- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
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- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Epidemiology (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB1122139.7A GB2497806A (en) | 2011-12-21 | 2011-12-21 | Pyridinone and pyrimidinone derivatives as factor XIa inhibitors |
| GB1122139.7 | 2011-12-21 | ||
| GB1217290.4 | 2012-09-27 | ||
| GB201217290A GB201217290D0 (en) | 2012-09-27 | 2012-09-27 | Compounds |
| PCT/GB2012/053217 WO2013093484A1 (en) | 2011-12-21 | 2012-12-20 | Pyridinone and pyrimidinone derivatives as factor xia inhibitors |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| AU2012356374A1 AU2012356374A1 (en) | 2014-07-10 |
| AU2012356374A8 AU2012356374A8 (en) | 2014-08-07 |
| AU2012356374B2 true AU2012356374B2 (en) | 2017-06-22 |
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| AU2012356374A Ceased AU2012356374B2 (en) | 2011-12-21 | 2012-12-20 | Pyridinone and pyrimidinone derivatives as factor XIa inhibitors |
Country Status (22)
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|---|---|---|---|---|
| TWI520965B (zh) | 2010-02-11 | 2016-02-11 | 必治妥美雅史谷比公司 | 作為因子ｘｉａ抑制劑之巨環類 |
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