NO327006B1 - Inhibitor av faktor XA og andre serinin proteaser involvert i koagulasjonskaskaden, samt anvendelse og fremgangsmate for fremstilling derav og farmasoytisk sammensetning - Google Patents
Inhibitor av faktor XA og andre serinin proteaser involvert i koagulasjonskaskaden, samt anvendelse og fremgangsmate for fremstilling derav og farmasoytisk sammensetning Download PDFInfo
- Publication number
- NO327006B1 NO327006B1 NO20042270A NO20042270A NO327006B1 NO 327006 B1 NO327006 B1 NO 327006B1 NO 20042270 A NO20042270 A NO 20042270A NO 20042270 A NO20042270 A NO 20042270A NO 327006 B1 NO327006 B1 NO 327006B1
- Authority
- NO
- Norway
- Prior art keywords
- amide
- phenyl
- pyrrolidine
- chloro
- dicarboxylic acid
- Prior art date
Links
- 108010074860 Factor Xa Proteins 0.000 title claims description 28
- 238000002360 preparation method Methods 0.000 title claims description 16
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 6
- 238000000034 method Methods 0.000 title description 28
- 230000015271 coagulation Effects 0.000 title description 8
- 238000005345 coagulation Methods 0.000 title description 8
- 239000003112 inhibitor Substances 0.000 title description 5
- 108091005804 Peptidases Proteins 0.000 title 1
- 102000035195 Peptidases Human genes 0.000 title 1
- 239000004365 Protease Substances 0.000 title 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 963
- -1 3-fluoro-2'-sulfamoyl-biphenyl-4-yl Chemical group 0.000 claims description 740
- QLEZWYHCXVFRKO-RFZPGFLSSA-N (2r,4r)-4-methoxypyrrolidine-1,2-dicarboxylic acid Chemical compound CO[C@@H]1C[C@H](C(O)=O)N(C(O)=O)C1 QLEZWYHCXVFRKO-RFZPGFLSSA-N 0.000 claims description 636
- 150000001875 compounds Chemical class 0.000 claims description 320
- OAWXZFGKDDFTGS-UHFFFAOYSA-N pyrrolidine-1,2-dicarboxylic acid Chemical compound OC(=O)C1CCCN1C(O)=O OAWXZFGKDDFTGS-UHFFFAOYSA-N 0.000 claims description 144
- 150000001408 amides Chemical class 0.000 claims description 141
- QLEZWYHCXVFRKO-UHFFFAOYSA-N 4-methoxypyrrolidine-1,2-dicarboxylic acid Chemical compound COC1CC(C(O)=O)N(C(O)=O)C1 QLEZWYHCXVFRKO-UHFFFAOYSA-N 0.000 claims description 135
- 238000006243 chemical reaction Methods 0.000 claims description 123
- HHDQVBSXYDRQGD-QWWZWVQMSA-N (2r,4r)-4-hydroxypyrrolidine-1,2-dicarboxylic acid Chemical compound O[C@@H]1C[C@H](C(O)=O)N(C(O)=O)C1 HHDQVBSXYDRQGD-QWWZWVQMSA-N 0.000 claims description 117
- HHDQVBSXYDRQGD-UHFFFAOYSA-N 4-hydroxypyrrolidine-1,2-dicarboxylic acid Chemical compound OC1CC(C(O)=O)N(C(O)=O)C1 HHDQVBSXYDRQGD-UHFFFAOYSA-N 0.000 claims description 54
- ZNNRVGZFHOROJG-PHDIDXHHSA-N (2r,4r)-4-ethoxypyrrolidine-1,2-dicarboxylic acid Chemical compound CCO[C@@H]1C[C@H](C(O)=O)N(C(O)=O)C1 ZNNRVGZFHOROJG-PHDIDXHHSA-N 0.000 claims description 53
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 45
- 150000003839 salts Chemical class 0.000 claims description 39
- 229910052736 halogen Inorganic materials 0.000 claims description 26
- 150000002367 halogens Chemical class 0.000 claims description 26
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 24
- PSEFWMGUIGBSMX-UHFFFAOYSA-N 3,4-dihydropyrazole-2,3-dicarboxylic acid Chemical compound OC(=O)C1CC=NN1C(O)=O PSEFWMGUIGBSMX-UHFFFAOYSA-N 0.000 claims description 23
- 229910052757 nitrogen Inorganic materials 0.000 claims description 17
- GXFAYZBQUMULJS-UHFFFAOYSA-N 4-fluoropyrrolidine-1,2-dicarboxylic acid Chemical compound OC(=O)C1CC(F)CN1C(O)=O GXFAYZBQUMULJS-UHFFFAOYSA-N 0.000 claims description 16
- 239000012948 isocyanate Substances 0.000 claims description 15
- 150000002513 isocyanates Chemical class 0.000 claims description 15
- 125000000217 alkyl group Chemical group 0.000 claims description 13
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 12
- 208000007536 Thrombosis Diseases 0.000 claims description 12
- ZNNRVGZFHOROJG-UHFFFAOYSA-N 4-ethoxypyrrolidine-1,2-dicarboxylic acid Chemical compound CCOC1CC(C(O)=O)N(C(O)=O)C1 ZNNRVGZFHOROJG-UHFFFAOYSA-N 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- DTGVTBVHWDTMBC-UHFFFAOYSA-N 5-methyl-4h-pyrazole-1,5-dicarboxylic acid Chemical compound OC(=O)C1(C)CC=NN1C(O)=O DTGVTBVHWDTMBC-UHFFFAOYSA-N 0.000 claims description 8
- 206010047249 Venous thrombosis Diseases 0.000 claims description 8
- 125000002393 azetidinyl group Chemical group 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 8
- BXOAORRUHBLISX-UHFFFAOYSA-N pyrrolidine-1,2,4-tricarboxylic acid Chemical compound OC(=O)C1CC(C(O)=O)N(C(O)=O)C1 BXOAORRUHBLISX-UHFFFAOYSA-N 0.000 claims description 8
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 8
- 230000002401 inhibitory effect Effects 0.000 claims description 7
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 7
- GXFAYZBQUMULJS-QWWZWVQMSA-N (2r,4r)-4-fluoropyrrolidine-1,2-dicarboxylic acid Chemical compound OC(=O)[C@H]1C[C@@H](F)CN1C(O)=O GXFAYZBQUMULJS-QWWZWVQMSA-N 0.000 claims description 6
- VVMGFQKRBXNUJW-RNFRBKRXSA-N (2r,4r)-4-propoxypyrrolidine-1,2-dicarboxylic acid Chemical compound CCCO[C@@H]1C[C@H](C(O)=O)N(C(O)=O)C1 VVMGFQKRBXNUJW-RNFRBKRXSA-N 0.000 claims description 6
- QLEZWYHCXVFRKO-CRCLSJGQSA-N (2r,4s)-4-methoxypyrrolidine-1,2-dicarboxylic acid Chemical compound CO[C@H]1C[C@H](C(O)=O)N(C(O)=O)C1 QLEZWYHCXVFRKO-CRCLSJGQSA-N 0.000 claims description 6
- 125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 claims description 6
- QUWVWFPFPVLXIW-UHFFFAOYSA-N 5-(hydroxymethyl)-3,4-dihydropyrazole-2,3-dicarboxylic acid Chemical compound OCC1=NN(C(O)=O)C(C(O)=O)C1 QUWVWFPFPVLXIW-UHFFFAOYSA-N 0.000 claims description 6
- 206010003178 Arterial thrombosis Diseases 0.000 claims description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- 230000001154 acute effect Effects 0.000 claims description 6
- OAWXZFGKDDFTGS-SCSAIBSYSA-N (2r)-pyrrolidine-1,2-dicarboxylic acid Chemical compound OC(=O)[C@H]1CCCN1C(O)=O OAWXZFGKDDFTGS-SCSAIBSYSA-N 0.000 claims description 5
- 241000124008 Mammalia Species 0.000 claims description 5
- 208000010378 Pulmonary Embolism Diseases 0.000 claims description 5
- 206010008118 cerebral infarction Diseases 0.000 claims description 5
- 208000026106 cerebrovascular disease Diseases 0.000 claims description 5
- 208000010125 myocardial infarction Diseases 0.000 claims description 5
- DMFOFFOEZAPORN-SCSAIBSYSA-N (2r)-4-oxopyrrolidine-1,2-dicarboxylic acid Chemical compound OC(=O)[C@H]1CC(=O)CN1C(O)=O DMFOFFOEZAPORN-SCSAIBSYSA-N 0.000 claims description 4
- JCINQOYGBLWVGB-CRCLSJGQSA-N (2r,4r)-4-cyanopyrrolidine-1,2-dicarboxylic acid Chemical compound OC(=O)[C@H]1C[C@@H](C#N)CN1C(O)=O JCINQOYGBLWVGB-CRCLSJGQSA-N 0.000 claims description 4
- SLJSRCNCQDNSEY-IUYQGCFVSA-N (2r,4s)-4-aminopyrrolidine-1,2-dicarboxylic acid Chemical compound N[C@H]1C[C@H](C(O)=O)N(C(O)=O)C1 SLJSRCNCQDNSEY-IUYQGCFVSA-N 0.000 claims description 4
- GXFAYZBQUMULJS-IUYQGCFVSA-N (2r,4s)-4-fluoropyrrolidine-1,2-dicarboxylic acid Chemical compound OC(=O)[C@H]1C[C@H](F)CN1C(O)=O GXFAYZBQUMULJS-IUYQGCFVSA-N 0.000 claims description 4
- OAWXZFGKDDFTGS-BYPYZUCNSA-N (2s)-pyrrolidine-1,2-dicarboxylic acid Chemical compound OC(=O)[C@@H]1CCCN1C(O)=O OAWXZFGKDDFTGS-BYPYZUCNSA-N 0.000 claims description 4
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 4
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims description 4
- 125000004845 (C1-C6) alkylsulfonylamino group Chemical group 0.000 claims description 4
- 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 claims description 4
- LGLWSZNPYYMBRY-UHFFFAOYSA-N 3-[4-[[1-[(4-chlorophenyl)carbamoyl]-4-methoxypyrrolidine-2-carbonyl]amino]-3-fluorophenyl]-2-oxoimidazolidine-4-carboxylic acid Chemical compound C1C(OC)CC(C(=O)NC=2C(=CC(=CC=2)N2C(NCC2C(O)=O)=O)F)N1C(=O)NC1=CC=C(Cl)C=C1 LGLWSZNPYYMBRY-UHFFFAOYSA-N 0.000 claims description 4
- LXZQZQFUSNSLMQ-UHFFFAOYSA-N 3-oxopyrazolidine-1,5-dicarboxylic acid Chemical compound OC(=O)C1CC(=O)NN1C(O)=O LXZQZQFUSNSLMQ-UHFFFAOYSA-N 0.000 claims description 4
- IYOXBCOLEAZKBF-UHFFFAOYSA-N 4,4-difluoropyrrolidine-1,2-dicarboxylic acid Chemical compound OC(=O)C1CC(F)(F)CN1C(O)=O IYOXBCOLEAZKBF-UHFFFAOYSA-N 0.000 claims description 4
- IPQLKFAHUWJGQR-UHFFFAOYSA-N 4-(aminomethyl)pyrrolidine-1,2-dicarboxylic acid Chemical compound NCC1CC(C(O)=O)N(C(O)=O)C1 IPQLKFAHUWJGQR-UHFFFAOYSA-N 0.000 claims description 4
- QMZKFOSMBYTKSY-UHFFFAOYSA-N 4-(hydroxymethyl)pyrrolidine-1,2-dicarboxylic acid Chemical compound OCC1CC(C(O)=O)N(C(O)=O)C1 QMZKFOSMBYTKSY-UHFFFAOYSA-N 0.000 claims description 4
- XFFOVQLJFXBTJC-UHFFFAOYSA-N 4-methylpyrrolidine-1,2-dicarboxylic acid Chemical compound CC1CC(C(O)=O)N(C(O)=O)C1 XFFOVQLJFXBTJC-UHFFFAOYSA-N 0.000 claims description 4
- DMFOFFOEZAPORN-UHFFFAOYSA-N 4-oxopyrrolidine-1,2-dicarboxylic acid Chemical compound OC(=O)C1CC(=O)CN1C(O)=O DMFOFFOEZAPORN-UHFFFAOYSA-N 0.000 claims description 4
- 125000004199 4-trifluoromethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C(F)(F)F 0.000 claims description 4
- FIBYOSWAIMZEKR-UHFFFAOYSA-N 5-(methoxymethyl)-3,4-dihydropyrazole-2,3-dicarboxylic acid Chemical compound COCC1=NN(C(O)=O)C(C(O)=O)C1 FIBYOSWAIMZEKR-UHFFFAOYSA-N 0.000 claims description 4
- 206010002383 Angina Pectoris Diseases 0.000 claims description 4
- 206010003658 Atrial Fibrillation Diseases 0.000 claims description 4
- 206010019280 Heart failures Diseases 0.000 claims description 4
- 206010028980 Neoplasm Diseases 0.000 claims description 4
- 125000003725 azepanyl group Chemical group 0.000 claims description 4
- 201000011510 cancer Diseases 0.000 claims description 4
- 230000001684 chronic effect Effects 0.000 claims description 4
- 206010012601 diabetes mellitus Diseases 0.000 claims description 4
- 125000005047 dihydroimidazolyl group Chemical group N1(CNC=C1)* 0.000 claims description 4
- 125000005052 dihydropyrazolyl group Chemical group N1(NCC=C1)* 0.000 claims description 4
- 125000005054 dihydropyrrolyl group Chemical group [H]C1=C([H])C([H])([H])C([H])([H])N1* 0.000 claims description 4
- 125000001475 halogen functional group Chemical group 0.000 claims description 4
- 125000002632 imidazolidinyl group Chemical group 0.000 claims description 4
- 125000002883 imidazolyl group Chemical group 0.000 claims description 4
- 125000002757 morpholinyl group Chemical group 0.000 claims description 4
- 125000000160 oxazolidinyl group Chemical group 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 4
- 125000003386 piperidinyl group Chemical group 0.000 claims description 4
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 4
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 4
- 125000004076 pyridyl group Chemical group 0.000 claims description 4
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 4
- 125000005493 quinolyl group Chemical group 0.000 claims description 4
- 208000037803 restenosis Diseases 0.000 claims description 4
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 4
- 125000001425 triazolyl group Chemical group 0.000 claims description 4
- IYOXBCOLEAZKBF-GSVOUGTGSA-N (2r)-4,4-difluoropyrrolidine-1,2-dicarboxylic acid Chemical compound OC(=O)[C@H]1CC(F)(F)CN1C(O)=O IYOXBCOLEAZKBF-GSVOUGTGSA-N 0.000 claims description 3
- GVZLWFKDTYITCE-QWWZWVQMSA-N (2r,4r)-4-(2h-tetrazol-5-yl)pyrrolidine-1,2-dicarboxylic acid Chemical compound C1N(C(O)=O)[C@@H](C(=O)O)C[C@H]1C1=NN=NN1 GVZLWFKDTYITCE-QWWZWVQMSA-N 0.000 claims description 3
- SOZZGZRWAJRTOI-RFZPGFLSSA-N (2r,4r)-4-(methanesulfonamido)pyrrolidine-1,2-dicarboxylic acid Chemical compound CS(=O)(=O)N[C@@H]1C[C@H](C(O)=O)N(C(O)=O)C1 SOZZGZRWAJRTOI-RFZPGFLSSA-N 0.000 claims description 3
- VLITYUNEECNVNB-QWWZWVQMSA-N (2r,4r)-4-(trifluoromethyl)pyrrolidine-1,2-dicarboxylic acid Chemical compound OC(=O)[C@H]1C[C@@H](C(F)(F)F)CN1C(O)=O VLITYUNEECNVNB-QWWZWVQMSA-N 0.000 claims description 3
- BPMKDLRAYMTVSR-PHDIDXHHSA-N (2r,4r)-4-acetamidopyrrolidine-1,2-dicarboxylic acid Chemical compound CC(=O)N[C@@H]1C[C@H](C(O)=O)N(C(O)=O)C1 BPMKDLRAYMTVSR-PHDIDXHHSA-N 0.000 claims description 3
- SLJSRCNCQDNSEY-QWWZWVQMSA-N (2r,4r)-4-aminopyrrolidine-1,2-dicarboxylic acid Chemical compound N[C@@H]1C[C@H](C(O)=O)N(C(O)=O)C1 SLJSRCNCQDNSEY-QWWZWVQMSA-N 0.000 claims description 3
- GVZLWFKDTYITCE-IUYQGCFVSA-N (2r,4s)-4-(2h-tetrazol-5-yl)pyrrolidine-1,2-dicarboxylic acid Chemical compound C1N(C(O)=O)[C@@H](C(=O)O)C[C@@H]1C1=NN=NN1 GVZLWFKDTYITCE-IUYQGCFVSA-N 0.000 claims description 3
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 3
- CPCLIWRBKKYRFS-UHFFFAOYSA-N 1-[4-[[1-[(4-chlorophenyl)carbamoyl]-4-methoxypyrrolidine-2-carbonyl]amino]-3-fluorophenyl]-5-oxopyrrolidine-2-carboxylic acid Chemical compound C1C(OC)CC(C(=O)NC=2C(=CC(=CC=2)N2C(CCC2C(O)=O)=O)F)N1C(=O)NC1=CC=C(Cl)C=C1 CPCLIWRBKKYRFS-UHFFFAOYSA-N 0.000 claims description 3
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 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
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 3
- VPLKQBWBFVUADA-SCSAIBSYSA-N ON=C1C[C@H](C(O)=O)N(C(O)=O)C1 Chemical compound ON=C1C[C@H](C(O)=O)N(C(O)=O)C1 VPLKQBWBFVUADA-SCSAIBSYSA-N 0.000 claims description 3
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 3
- XUWHAWMETYGRKB-UHFFFAOYSA-N delta-valerolactam Natural products O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 claims description 3
- NHBXKHSRPHSQPL-HZGVNTEJSA-N (2r,4r)-2-ethyl-4-methoxypyrrolidine-1,2-dicarboxylic acid Chemical compound CC[C@]1(C(O)=O)C[C@@H](OC)CN1C(O)=O NHBXKHSRPHSQPL-HZGVNTEJSA-N 0.000 claims description 2
- VNGXCFNFIDLEKA-PHDIDXHHSA-N (2r,4r)-4-ethylpyrrolidine-1,2-dicarboxylic acid Chemical compound CC[C@@H]1C[C@H](C(O)=O)N(C(O)=O)C1 VNGXCFNFIDLEKA-PHDIDXHHSA-N 0.000 claims description 2
- PLKSHXBKRMGXDC-SVGQVSJJSA-N (2r,4r)-4-methoxy-2-methylpyrrolidine-1,2-dicarboxylic acid Chemical compound CO[C@H]1CN(C(O)=O)[C@@](C)(C(O)=O)C1 PLKSHXBKRMGXDC-SVGQVSJJSA-N 0.000 claims description 2
- XFFOVQLJFXBTJC-RFZPGFLSSA-N (2r,4r)-4-methylpyrrolidine-1,2-dicarboxylic acid Chemical compound C[C@@H]1C[C@H](C(O)=O)N(C(O)=O)C1 XFFOVQLJFXBTJC-RFZPGFLSSA-N 0.000 claims description 2
- JXZPCNFIWUJCIW-NKWVEPMBSA-N (2r,4r)-4-propan-2-ylpyrrolidine-1,2-dicarboxylic acid Chemical compound CC(C)[C@H]1C[C@H](C(O)=O)N(C(O)=O)C1 JXZPCNFIWUJCIW-NKWVEPMBSA-N 0.000 claims description 2
- HHDQVBSXYDRQGD-IUYQGCFVSA-N (2r,4s)-4-hydroxypyrrolidine-1,2-dicarboxylic acid Chemical compound O[C@H]1C[C@H](C(O)=O)N(C(O)=O)C1 HHDQVBSXYDRQGD-IUYQGCFVSA-N 0.000 claims description 2
- PSEFWMGUIGBSMX-GSVOUGTGSA-N (3r)-3,4-dihydropyrazole-2,3-dicarboxylic acid Chemical compound OC(=O)[C@H]1CC=NN1C(O)=O PSEFWMGUIGBSMX-GSVOUGTGSA-N 0.000 claims description 2
- KJPJLXBZWPQGKD-UHFFFAOYSA-N 1-[(4-chlorophenyl)carbamoyl]-5-[[2-fluoro-4-(2-methylsulfonylphenyl)phenyl]carbamoyl]pyrrolidine-3-carboxylic acid Chemical compound CS(=O)(=O)C1=CC=CC=C1C(C=C1F)=CC=C1NC(=O)C1N(C(=O)NC=2C=CC(Cl)=CC=2)CC(C(O)=O)C1 KJPJLXBZWPQGKD-UHFFFAOYSA-N 0.000 claims description 2
- VGXAHTYLMWWJTO-DYESRHJHSA-N 1-[4-[[(2r,4r)-1-[(4-chlorophenyl)carbamoyl]-4-methoxypyrrolidine-2-carbonyl]amino]-3-fluorophenyl]-6-oxopyridine-2-carboxylic acid Chemical compound N1([C@H](C[C@H](C1)OC)C(=O)NC=1C(=CC(=CC=1)N1C(C=CC=C1C(O)=O)=O)F)C(=O)NC1=CC=C(Cl)C=C1 VGXAHTYLMWWJTO-DYESRHJHSA-N 0.000 claims description 2
- UFMHTRMGVQGSMS-DNVCBOLYSA-N 1-[4-[[(2r,4r)-1-[(5-chloropyridin-2-yl)carbamoyl]-4-methoxypyrrolidine-2-carbonyl]amino]-3-fluorophenyl]-2-oxopyridine-3-carboxylic acid Chemical compound N1([C@H](C[C@H](C1)OC)C(=O)NC=1C(=CC(=CC=1)N1C(C(C(O)=O)=CC=C1)=O)F)C(=O)NC1=CC=C(Cl)C=N1 UFMHTRMGVQGSMS-DNVCBOLYSA-N 0.000 claims description 2
- DQGSQYIFANFTAH-DNVCBOLYSA-N 1-[4-[[(2r,4r)-1-[(5-chloropyridin-2-yl)carbamoyl]-4-methoxypyrrolidine-2-carbonyl]amino]-3-fluorophenyl]-6-oxopyridine-2-carboxylic acid Chemical compound N1([C@H](C[C@H](C1)OC)C(=O)NC=1C(=CC(=CC=1)N1C(C=CC=C1C(O)=O)=O)F)C(=O)NC1=CC=C(Cl)C=N1 DQGSQYIFANFTAH-DNVCBOLYSA-N 0.000 claims description 2
- YGSMNHKZNCRMCS-VQIMIIECSA-N 1-[4-[[(2r,4r)-1-[(5-chloropyridin-2-yl)carbamoyl]-4-methoxypyrrolidine-2-carbonyl]amino]-3-fluorophenyl]-6-oxopyridine-3-carboxylic acid Chemical compound N1([C@H](C[C@H](C1)OC)C(=O)NC=1C(=CC(=CC=1)N1C(C=CC(=C1)C(O)=O)=O)F)C(=O)NC1=CC=C(Cl)C=N1 YGSMNHKZNCRMCS-VQIMIIECSA-N 0.000 claims description 2
- PZSFPNDNNCWSPR-UHFFFAOYSA-N 1-[4-[[1-[(4-chlorophenyl)carbamoyl]-4-hydroxypyrrolidine-2-carbonyl]amino]phenyl]pyrrolidine-2-carboxylic acid Chemical compound C1C(O)CC(C(=O)NC=2C=CC(=CC=2)N2C(CCC2)C(O)=O)N1C(=O)NC1=CC=C(Cl)C=C1 PZSFPNDNNCWSPR-UHFFFAOYSA-N 0.000 claims description 2
- XJOYMNODJKLRIS-UHFFFAOYSA-N 1-[4-[[1-[(4-chlorophenyl)carbamoyl]-4-methoxypyrrolidine-2-carbonyl]amino]-3-fluorophenyl]-2-oxopiperidine-3-carboxylic acid Chemical compound C1C(OC)CC(C(=O)NC=2C(=CC(=CC=2)N2C(C(C(O)=O)CCC2)=O)F)N1C(=O)NC1=CC=C(Cl)C=C1 XJOYMNODJKLRIS-UHFFFAOYSA-N 0.000 claims description 2
- NSIPNUUCWAGVBF-UHFFFAOYSA-N 1-[4-[[1-[(4-chlorophenyl)carbamoyl]-4-methoxypyrrolidine-2-carbonyl]amino]-3-fluorophenyl]-5-oxopyrrolidine-2,2-dicarboxylic acid Chemical compound C1C(OC)CC(C(=O)NC=2C(=CC(=CC=2)N2C(CCC2=O)(C(O)=O)C(O)=O)F)N1C(=O)NC1=CC=C(Cl)C=C1 NSIPNUUCWAGVBF-UHFFFAOYSA-N 0.000 claims description 2
- RJRQLNKJVATIAJ-UHFFFAOYSA-N 1-[4-[[1-[(4-chlorophenyl)carbamoyl]-4-methoxypyrrolidine-2-carbonyl]amino]-3-fluorophenyl]imidazole-2-carboxylic acid Chemical compound C1C(OC)CC(C(=O)NC=2C(=CC(=CC=2)N2C(=NC=C2)C(O)=O)F)N1C(=O)NC1=CC=C(Cl)C=C1 RJRQLNKJVATIAJ-UHFFFAOYSA-N 0.000 claims description 2
- LYDIFOZLKWKCBD-UHFFFAOYSA-N 1-[4-[[1-[(4-chlorophenyl)carbamoyl]-4-methoxypyrrolidine-2-carbonyl]amino]-3-fluorophenyl]pyrrole-2-carboxylic acid Chemical compound C1C(OC)CC(C(=O)NC=2C(=CC(=CC=2)N2C(=CC=C2)C(O)=O)F)N1C(=O)NC1=CC=C(Cl)C=C1 LYDIFOZLKWKCBD-UHFFFAOYSA-N 0.000 claims description 2
- FJOKYRVDIZBBKP-UHFFFAOYSA-N 1-[4-[[1-[(4-chlorophenyl)carbamoyl]-4-methoxypyrrolidine-2-carbonyl]amino]phenyl]pyrrolidine-2-carboxylic acid Chemical compound C1C(OC)CC(C(=O)NC=2C=CC(=CC=2)N2C(CCC2)C(O)=O)N1C(=O)NC1=CC=C(Cl)C=C1 FJOKYRVDIZBBKP-UHFFFAOYSA-N 0.000 claims description 2
- TVHNYAFDTVZTEL-UHFFFAOYSA-N 2-(hydroxymethyl)-4-methoxypyrrolidine-1,2-dicarboxylic acid Chemical compound COC1CN(C(O)=O)C(CO)(C(O)=O)C1 TVHNYAFDTVZTEL-UHFFFAOYSA-N 0.000 claims description 2
- ALNVAFHLHROPIK-OMKBGSMGSA-N 2-[(4r)-1-[4-[[(2r)-1-[(4-chlorophenyl)carbamoyl]-4-methoxypyrrolidine-2-carbonyl]amino]phenyl]-2,5-dioxoimidazolidin-4-yl]acetic acid Chemical compound N1([C@H](CC(C1)OC)C(=O)NC=1C=CC(=CC=1)N1C([C@@H](CC(O)=O)NC1=O)=O)C(=O)NC1=CC=C(Cl)C=C1 ALNVAFHLHROPIK-OMKBGSMGSA-N 0.000 claims description 2
- UEKMPJXVWPUNCX-YJEKIOLLSA-N 2-[(4r)-1-[4-[[(2r)-1-[(5-chloropyridin-2-yl)carbamoyl]-4-methoxypyrrolidine-2-carbonyl]amino]phenyl]-2,5-dioxoimidazolidin-4-yl]acetic acid Chemical compound N1([C@H](CC(C1)OC)C(=O)NC=1C=CC(=CC=1)N1C([C@@H](CC(O)=O)NC1=O)=O)C(=O)NC1=CC=C(Cl)C=N1 UEKMPJXVWPUNCX-YJEKIOLLSA-N 0.000 claims description 2
- STDUPIADNDLYQU-UHFFFAOYSA-N 2-[1-[(4-chlorophenyl)carbamoyl]-2-[[2-fluoro-4-(2-oxopiperidin-1-yl)phenyl]carbamoyl]-4-methoxypyrrolidin-2-yl]acetic acid Chemical compound C=1C=C(N2C(CCCC2)=O)C=C(F)C=1NC(=O)C1(CC(O)=O)CC(OC)CN1C(=O)NC1=CC=C(Cl)C=C1 STDUPIADNDLYQU-UHFFFAOYSA-N 0.000 claims description 2
- RBPYHURAXHAQLL-UHFFFAOYSA-N 2-[1-[(4-chlorophenyl)carbamoyl]-5-[[2-fluoro-4-(2-oxopiperidin-1-yl)phenyl]carbamoyl]pyrrolidin-3-yl]acetic acid Chemical compound C1C(CC(=O)O)CC(C(=O)NC=2C(=CC(=CC=2)N2C(CCCC2)=O)F)N1C(=O)NC1=CC=C(Cl)C=C1 RBPYHURAXHAQLL-UHFFFAOYSA-N 0.000 claims description 2
- JLMAPPKOALEWAR-OXQOHEQNSA-N 2-[4-[[(2r,4r)-1-[(4-chlorophenyl)carbamoyl]-4-methoxypyrrolidine-2-carbonyl]amino]-3-fluorophenyl]pyrazole-3-carboxylic acid Chemical compound N1([C@H](C[C@H](C1)OC)C(=O)NC=1C(=CC(=CC=1)N1C(=CC=N1)C(O)=O)F)C(=O)NC1=CC=C(Cl)C=C1 JLMAPPKOALEWAR-OXQOHEQNSA-N 0.000 claims description 2
- JLMAPPKOALEWAR-UHFFFAOYSA-N 2-[4-[[1-[(4-chlorophenyl)carbamoyl]-4-methoxypyrrolidine-2-carbonyl]amino]-3-fluorophenyl]pyrazole-3-carboxylic acid Chemical compound C1C(OC)CC(C(=O)NC=2C(=CC(=CC=2)N2C(=CC=N2)C(O)=O)F)N1C(=O)NC1=CC=C(Cl)C=C1 JLMAPPKOALEWAR-UHFFFAOYSA-N 0.000 claims description 2
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims description 2
- NPLGZUMLQJXKJZ-PXDATVDWSA-N 2-methylpropyl 5-bromo-1-[4-[[(2r,4r)-1-[(4-chlorophenyl)carbamoyl]-4-methoxypyrrolidine-2-carbonyl]amino]-3-fluorophenyl]-2-oxopyridine-3-carboxylate Chemical compound N1([C@H](C[C@H](C1)OC)C(=O)NC=1C(=CC(=CC=1)N1C(C(C(=O)OCC(C)C)=CC(Br)=C1)=O)F)C(=O)NC1=CC=C(Cl)C=C1 NPLGZUMLQJXKJZ-PXDATVDWSA-N 0.000 claims description 2
- JFNYQZNYQLHHHB-AUSIDOKSSA-N 2-methylpropyl 5-bromo-1-[4-[[(2r,4r)-1-[(5-chloropyridin-2-yl)carbamoyl]-4-methoxypyrrolidine-2-carbonyl]amino]-3-fluorophenyl]-2-oxopyridine-3-carboxylate Chemical compound N1([C@H](C[C@H](C1)OC)C(=O)NC=1C(=CC(=CC=1)N1C(C(C(=O)OCC(C)C)=CC(Br)=C1)=O)F)C(=O)NC1=CC=C(Cl)C=N1 JFNYQZNYQLHHHB-AUSIDOKSSA-N 0.000 claims description 2
- 125000004189 3,4-dichlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(Cl)C([H])=C1* 0.000 claims description 2
- GGFPXUIJPQUKQD-DNVCBOLYSA-N 3-[4-[[(2r,4r)-1-[(4-chlorophenyl)carbamoyl]-4-methoxypyrrolidine-2-carbonyl]amino]-3-fluorophenyl]-1,2-oxazole-4-carboxylic acid Chemical compound N1([C@H](C[C@H](C1)OC)C(=O)NC=1C(=CC(=CC=1)C=1C(=CON=1)C(O)=O)F)C(=O)NC1=CC=C(Cl)C=C1 GGFPXUIJPQUKQD-DNVCBOLYSA-N 0.000 claims description 2
- CZLLJOSDIAEUCM-UHFFFAOYSA-N 3-[4-[[1-[(4-chlorophenyl)carbamoyl]-4-methoxypyrrolidine-2-carbonyl]amino]-3-fluorophenyl]-1h-pyrrole-2-carboxylic acid Chemical compound C1C(OC)CC(C(=O)NC=2C(=CC(=CC=2)C2=C(NC=C2)C(O)=O)F)N1C(=O)NC1=CC=C(Cl)C=C1 CZLLJOSDIAEUCM-UHFFFAOYSA-N 0.000 claims description 2
- WCOCGGNMEZTHDY-UHFFFAOYSA-N 3-[4-[[1-[(4-chlorophenyl)carbamoyl]-4-methoxypyrrolidine-2-carbonyl]amino]-3-fluorophenyl]furan-2-carboxylic acid Chemical compound C1C(OC)CC(C(=O)NC=2C(=CC(=CC=2)C2=C(OC=C2)C(O)=O)F)N1C(=O)NC1=CC=C(Cl)C=C1 WCOCGGNMEZTHDY-UHFFFAOYSA-N 0.000 claims description 2
- LBPNHDJWKKLZPO-UHFFFAOYSA-N 3-[4-[[1-[(4-chlorophenyl)carbamoyl]-4-methoxypyrrolidine-2-carbonyl]amino]-3-fluorophenyl]thiophene-2-carboxylic acid Chemical compound C1C(OC)CC(C(=O)NC=2C(=CC(=CC=2)C2=C(SC=C2)C(O)=O)F)N1C(=O)NC1=CC=C(Cl)C=C1 LBPNHDJWKKLZPO-UHFFFAOYSA-N 0.000 claims description 2
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims description 2
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 claims description 2
- GVZLWFKDTYITCE-UHFFFAOYSA-N 4-(2h-tetrazol-5-yl)pyrrolidine-1,2-dicarboxylic acid Chemical compound C1N(C(O)=O)C(C(=O)O)CC1C1=NN=NN1 GVZLWFKDTYITCE-UHFFFAOYSA-N 0.000 claims description 2
- SOZZGZRWAJRTOI-UHFFFAOYSA-N 4-(methanesulfonamido)pyrrolidine-1,2-dicarboxylic acid Chemical compound CS(=O)(=O)NC1CC(C(O)=O)N(C(O)=O)C1 SOZZGZRWAJRTOI-UHFFFAOYSA-N 0.000 claims description 2
- VFJIWTBLVMNGIM-UHFFFAOYSA-N 4-(methoxymethyl)pyrrolidine-1,2-dicarboxylic acid Chemical compound COCC1CC(C(O)=O)N(C(O)=O)C1 VFJIWTBLVMNGIM-UHFFFAOYSA-N 0.000 claims description 2
- MFHGRSMAIMOMED-UHFFFAOYSA-N 4-(methylamino)pyrrolidine-1,2-dicarboxylic acid Chemical compound CNC1CC(C(O)=O)N(C(O)=O)C1 MFHGRSMAIMOMED-UHFFFAOYSA-N 0.000 claims description 2
- REBBFEZJTFPBIX-UHFFFAOYSA-N 4-(methylaminomethyl)pyrrolidine-1,2-dicarboxylic acid Chemical compound CNCC1CC(C(O)=O)N(C(O)=O)C1 REBBFEZJTFPBIX-UHFFFAOYSA-N 0.000 claims description 2
- VLITYUNEECNVNB-UHFFFAOYSA-N 4-(trifluoromethyl)pyrrolidine-1,2-dicarboxylic acid Chemical compound OC(=O)C1CC(C(F)(F)F)CN1C(O)=O VLITYUNEECNVNB-UHFFFAOYSA-N 0.000 claims description 2
- RTMCNXDSXSHACI-UHFFFAOYSA-N 4-[(dimethylamino)methyl]pyrrolidine-1,2-dicarboxylic acid Chemical compound CN(C)CC1CC(C(O)=O)N(C(O)=O)C1 RTMCNXDSXSHACI-UHFFFAOYSA-N 0.000 claims description 2
- ANIBQQUCFTZYCJ-UHFFFAOYSA-N 4-[4-[[1-[(4-chlorophenyl)carbamoyl]-4-methoxypyrrolidine-2-carbonyl]amino]-3-fluorophenyl]-1h-pyrrole-3-carboxylic acid Chemical compound C1C(OC)CC(C(=O)NC=2C(=CC(=CC=2)C=2C(=CNC=2)C(O)=O)F)N1C(=O)NC1=CC=C(Cl)C=C1 ANIBQQUCFTZYCJ-UHFFFAOYSA-N 0.000 claims description 2
- UOADAZXJPZNVBE-UHFFFAOYSA-N 4-[4-[[1-[(4-chlorophenyl)carbamoyl]-4-methoxypyrrolidine-2-carbonyl]amino]-3-fluorophenyl]furan-3-carboxylic acid Chemical compound C1C(OC)CC(C(=O)NC=2C(=CC(=CC=2)C=2C(=COC=2)C(O)=O)F)N1C(=O)NC1=CC=C(Cl)C=C1 UOADAZXJPZNVBE-UHFFFAOYSA-N 0.000 claims description 2
- TVWFOCLZKWPBEV-UHFFFAOYSA-N 4-[4-[[1-[(4-chlorophenyl)carbamoyl]-4-methoxypyrrolidine-2-carbonyl]amino]-3-fluorophenyl]thiophene-3-carboxylic acid Chemical compound C1C(OC)CC(C(=O)NC=2C(=CC(=CC=2)C=2C(=CSC=2)C(O)=O)F)N1C(=O)NC1=CC=C(Cl)C=C1 TVWFOCLZKWPBEV-UHFFFAOYSA-N 0.000 claims description 2
- BPMKDLRAYMTVSR-UHFFFAOYSA-N 4-acetamidopyrrolidine-1,2-dicarboxylic acid Chemical compound CC(=O)NC1CC(C(O)=O)N(C(O)=O)C1 BPMKDLRAYMTVSR-UHFFFAOYSA-N 0.000 claims description 2
- HIOZNSQWNQNLGA-UHFFFAOYSA-N 4-acetylpyrrolidine-1,2-dicarboxylic acid Chemical compound CC(=O)C1CC(C(O)=O)N(C(O)=O)C1 HIOZNSQWNQNLGA-UHFFFAOYSA-N 0.000 claims description 2
- SLJSRCNCQDNSEY-UHFFFAOYSA-N 4-aminopyrrolidine-1,2-dicarboxylic acid Chemical compound NC1CC(C(O)=O)N(C(O)=O)C1 SLJSRCNCQDNSEY-UHFFFAOYSA-N 0.000 claims description 2
- JCINQOYGBLWVGB-UHFFFAOYSA-N 4-cyanopyrrolidine-1,2-dicarboxylic acid Chemical compound OC(=O)C1CC(C#N)CN1C(O)=O JCINQOYGBLWVGB-UHFFFAOYSA-N 0.000 claims description 2
- 125000004860 4-ethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000004861 4-isopropyl phenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- LBPDNXPDIQWRKX-UHFFFAOYSA-N 4-methoxy-2-(methoxymethyl)pyrrolidine-1,2-dicarboxylic acid Chemical compound COCC1(C(O)=O)CC(OC)CN1C(O)=O LBPDNXPDIQWRKX-UHFFFAOYSA-N 0.000 claims description 2
- ZPWSZKGQDXWSGQ-UHFFFAOYSA-N 4-methylidenepyrrolidine-1,2-dicarboxylic acid Chemical compound OC(=O)C1CC(=C)CN1C(O)=O ZPWSZKGQDXWSGQ-UHFFFAOYSA-N 0.000 claims description 2
- CJHPBOZCFOEIAO-UHFFFAOYSA-N 4-propan-2-yloxypyrrolidine-1,2-dicarboxylic acid Chemical compound CC(C)OC1CC(C(O)=O)N(C(O)=O)C1 CJHPBOZCFOEIAO-UHFFFAOYSA-N 0.000 claims description 2
- XTCRVHGRTFHROD-CRAIPNDOSA-N 5-[4-[[(2r,4r)-1-[(4-chlorophenyl)carbamoyl]-4-methoxypyrrolidine-2-carbonyl]amino]-3-fluorophenyl]-1,3-oxazole-4-carboxylic acid Chemical compound N1([C@H](C[C@H](C1)OC)C(=O)NC=1C(=CC(=CC=1)C1=C(N=CO1)C(O)=O)F)C(=O)NC1=CC=C(Cl)C=C1 XTCRVHGRTFHROD-CRAIPNDOSA-N 0.000 claims description 2
- LXZFDZBNPRZYMY-HZPDHXFCSA-N 5-[6-[[(2r,4r)-1-[(4-chlorophenyl)carbamoyl]-4-methoxypyrrolidine-2-carbonyl]amino]pyridin-3-yl]-1,3-oxazole-4-carboxylic acid Chemical compound N1([C@H](C[C@H](C1)OC)C(=O)NC=1N=CC(=CC=1)C1=C(N=CO1)C(O)=O)C(=O)NC1=CC=C(Cl)C=C1 LXZFDZBNPRZYMY-HZPDHXFCSA-N 0.000 claims description 2
- GGGAJYNPBMYSIC-DYESRHJHSA-N 5-chloro-1-[4-[[(2r,4r)-1-[(4-chlorophenyl)carbamoyl]-4-methoxypyrrolidine-2-carbonyl]amino]-3-fluorophenyl]-2-oxopyridine-3-carboxylic acid Chemical compound N1([C@H](C[C@H](C1)OC)C(=O)NC=1C(=CC(=CC=1)N1C(C(C(O)=O)=CC(Cl)=C1)=O)F)C(=O)NC1=CC=C(Cl)C=C1 GGGAJYNPBMYSIC-DYESRHJHSA-N 0.000 claims description 2
- PDTOYNIMJHUBLB-DNVCBOLYSA-N 5-chloro-1-[4-[[(2r,4r)-1-[(5-chloropyridin-2-yl)carbamoyl]-4-methoxypyrrolidine-2-carbonyl]amino]-3-fluorophenyl]-2-oxopyridine-3-carboxylic acid Chemical compound N1([C@H](C[C@H](C1)OC)C(=O)NC=1C(=CC(=CC=1)N1C(C(C(O)=O)=CC(Cl)=C1)=O)F)C(=O)NC1=CC=C(Cl)C=N1 PDTOYNIMJHUBLB-DNVCBOLYSA-N 0.000 claims description 2
- BJLLOMORJCWXON-UHFFFAOYSA-N 5-oxopyrrolidine-1,2-dicarboxylic acid Chemical compound OC(=O)C1CCC(=O)N1C(O)=O BJLLOMORJCWXON-UHFFFAOYSA-N 0.000 claims description 2
- PDVFKFREJYBDKZ-DENIHFKCSA-N N1([C@H](C[C@H](C1)OC)C(=O)NC=1C(=CC(=CC=1)N1C(C(OC(C)=O)=CC=C1)=O)F)C(=O)NC1=CC=C(Cl)C=C1 Chemical compound N1([C@H](C[C@H](C1)OC)C(=O)NC=1C(=CC(=CC=1)N1C(C(OC(C)=O)=CC=C1)=O)F)C(=O)NC1=CC=C(Cl)C=C1 PDVFKFREJYBDKZ-DENIHFKCSA-N 0.000 claims description 2
- QADCCVIARZTMAQ-YLJYHZDGSA-N N1([C@H](C[C@H](C1)OC)C(=O)NC=1C(=CC(=CC=1)N1C(C(OC(C)=O)=CC=C1)=O)F)C(=O)NC1=CC=C(Cl)C=N1 Chemical compound N1([C@H](C[C@H](C1)OC)C(=O)NC=1C(=CC(=CC=1)N1C(C(OC(C)=O)=CC=C1)=O)F)C(=O)NC1=CC=C(Cl)C=N1 QADCCVIARZTMAQ-YLJYHZDGSA-N 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- KSTOJMGYXABJEH-UHFFFAOYSA-N ethyl 1-[(4-chlorophenyl)carbamoyl]-5-[[2-fluoro-4-(2-oxopiperidin-1-yl)phenyl]carbamoyl]pyrrolidine-3-carboxylate Chemical compound C1C(C(=O)OCC)CC(C(=O)NC=2C(=CC(=CC=2)N2C(CCCC2)=O)F)N1C(=O)NC1=CC=C(Cl)C=C1 KSTOJMGYXABJEH-UHFFFAOYSA-N 0.000 claims description 2
- FBKNKRVOQGMRCR-GGFVOEBESA-N ethyl 1-[4-[[(2r,4r)-1-[(4-chlorophenyl)carbamoyl]-4-methoxypyrrolidine-2-carbonyl]amino]-3-fluorophenyl]-2-oxopiperidine-3-carboxylate Chemical compound O=C1C(C(=O)OCC)CCCN1C(C=C1F)=CC=C1NC(=O)[C@@H]1N(C(=O)NC=2C=CC(Cl)=CC=2)C[C@H](OC)C1 FBKNKRVOQGMRCR-GGFVOEBESA-N 0.000 claims description 2
- YFEUTRWLXYFNHE-NFBKMPQASA-N ethyl 1-[4-[[(2r,4r)-1-[(4-chlorophenyl)carbamoyl]-4-methoxypyrrolidine-2-carbonyl]amino]-3-fluorophenyl]-6-oxopyridine-3-carboxylate Chemical compound C1=C(C(=O)OCC)C=CC(=O)N1C(C=C1F)=CC=C1NC(=O)[C@@H]1N(C(=O)NC=2C=CC(Cl)=CC=2)C[C@H](OC)C1 YFEUTRWLXYFNHE-NFBKMPQASA-N 0.000 claims description 2
- QHOZOINOLLHGTH-WIYYLYMNSA-N ethyl 1-[4-[[(2r,4r)-1-[(5-chloropyridin-2-yl)carbamoyl]-4-methoxypyrrolidine-2-carbonyl]amino]-3-fluorophenyl]-6-oxopyridine-3-carboxylate Chemical compound C1=C(C(=O)OCC)C=CC(=O)N1C(C=C1F)=CC=C1NC(=O)[C@@H]1N(C(=O)NC=2N=CC(Cl)=CC=2)C[C@H](OC)C1 QHOZOINOLLHGTH-WIYYLYMNSA-N 0.000 claims description 2
- NBBPIEIZVXKKCH-UHFFFAOYSA-N ethyl 2-[(4-chlorophenyl)carbamoyl]-3-[[2-fluoro-4-(2-methylsulfonylphenyl)phenyl]carbamoyl]-3,4-dihydropyrazole-5-carboxylate Chemical compound C1C(C(=O)OCC)=NN(C(=O)NC=2C=CC(Cl)=CC=2)C1C(=O)NC(C(=C1)F)=CC=C1C1=CC=CC=C1S(C)(=O)=O NBBPIEIZVXKKCH-UHFFFAOYSA-N 0.000 claims description 2
- JADRUIVIEYALFE-VQIMIIECSA-N ethyl 5-[4-[[(2r,4r)-1-[(4-chlorophenyl)carbamoyl]-4-hydroxypyrrolidine-2-carbonyl]amino]-3-fluorophenyl]-1,3-oxazole-4-carboxylate Chemical compound N1=COC(C=2C=C(F)C(NC(=O)[C@@H]3N(C[C@H](O)C3)C(=O)NC=3C=CC(Cl)=CC=3)=CC=2)=C1C(=O)OCC JADRUIVIEYALFE-VQIMIIECSA-N 0.000 claims description 2
- ILIKTNXDUXMWGZ-YLJYHZDGSA-N ethyl 5-[4-[[(2r,4r)-1-[(4-chlorophenyl)carbamoyl]-4-methoxypyrrolidine-2-carbonyl]amino]-3-fluorophenyl]-1,3-oxazole-4-carboxylate Chemical compound N1=COC(C=2C=C(F)C(NC(=O)[C@@H]3N(C[C@@H](C3)OC)C(=O)NC=3C=CC(Cl)=CC=3)=CC=2)=C1C(=O)OCC ILIKTNXDUXMWGZ-YLJYHZDGSA-N 0.000 claims description 2
- RXFJCXXMRKTHKA-QZTJIDSGSA-N ethyl 5-[6-[[(2r,4r)-1-[(4-chlorophenyl)carbamoyl]-4-methoxypyrrolidine-2-carbonyl]amino]pyridin-3-yl]-1,3-oxazole-4-carboxylate Chemical compound N1=COC(C=2C=NC(NC(=O)[C@@H]3N(C[C@@H](C3)OC)C(=O)NC=3C=CC(Cl)=CC=3)=CC=2)=C1C(=O)OCC RXFJCXXMRKTHKA-QZTJIDSGSA-N 0.000 claims description 2
- XEWVCXILHAUGCV-UHFFFAOYSA-N methyl 1-[(4-chlorophenyl)carbamoyl]-5-[[2-fluoro-4-(2-methylsulfonylphenyl)phenyl]carbamoyl]pyrrolidine-3-carboxylate Chemical compound C1C(C(=O)OC)CC(C(=O)NC=2C(=CC(=CC=2)C=2C(=CC=CC=2)S(C)(=O)=O)F)N1C(=O)NC1=CC=C(Cl)C=C1 XEWVCXILHAUGCV-UHFFFAOYSA-N 0.000 claims description 2
- VCUPXGLUFKHEQP-UHFFFAOYSA-N methyl 1-[(4-chlorophenyl)carbamoyl]-5-[[2-fluoro-4-(2-oxopiperidin-1-yl)phenyl]carbamoyl]pyrrolidine-3-carboxylate Chemical compound C1C(C(=O)OC)CC(C(=O)NC=2C(=CC(=CC=2)N2C(CCCC2)=O)F)N1C(=O)NC1=CC=C(Cl)C=C1 VCUPXGLUFKHEQP-UHFFFAOYSA-N 0.000 claims description 2
- USKGFCLNMINYBF-XMSQKQJNSA-N methyl 1-[4-[[(2r,4r)-1-[(4-chlorophenyl)carbamoyl]-4-methoxypyrrolidine-2-carbonyl]amino]-3-fluorophenyl]-2-oxopyridine-3-carboxylate Chemical compound N1([C@H](C[C@H](C1)OC)C(=O)NC=1C(=CC(=CC=1)N1C(C(C(=O)OC)=CC=C1)=O)F)C(=O)NC1=CC=C(Cl)C=C1 USKGFCLNMINYBF-XMSQKQJNSA-N 0.000 claims description 2
- JRMNYBWGCDWAOK-OXQOHEQNSA-N methyl 1-[4-[[(2r,4r)-1-[(5-chloropyridin-2-yl)carbamoyl]-4-methoxypyrrolidine-2-carbonyl]amino]-3-fluorophenyl]-6-oxopyridine-2-carboxylate Chemical compound N1([C@H](C[C@H](C1)OC)C(=O)NC=1C(=CC(=CC=1)N1C(C=CC=C1C(=O)OC)=O)F)C(=O)NC1=CC=C(Cl)C=N1 JRMNYBWGCDWAOK-OXQOHEQNSA-N 0.000 claims description 2
- KSFFFIDGIKOTBP-UHFFFAOYSA-N methyl 2-[1-[(4-chlorophenyl)carbamoyl]-2-[[2-fluoro-4-(2-oxopiperidin-1-yl)phenyl]carbamoyl]-4-methoxypyrrolidin-2-yl]acetate Chemical compound C=1C=C(N2C(CCCC2)=O)C=C(F)C=1NC(=O)C1(CC(=O)OC)CC(OC)CN1C(=O)NC1=CC=C(Cl)C=C1 KSFFFIDGIKOTBP-UHFFFAOYSA-N 0.000 claims description 2
- LRKHFVRWDVXQRV-UHFFFAOYSA-N methyl 2-[1-[(4-chlorophenyl)carbamoyl]-5-[[2-fluoro-4-(2-oxopiperidin-1-yl)phenyl]carbamoyl]pyrrolidin-3-yl]acetate Chemical compound C1C(CC(=O)OC)CC(C(=O)NC=2C(=CC(=CC=2)N2C(CCCC2)=O)F)N1C(=O)NC1=CC=C(Cl)C=C1 LRKHFVRWDVXQRV-UHFFFAOYSA-N 0.000 claims description 2
- YWAIKSSOLKLFIP-NTKDMRAZSA-N methyl 2-[4-[[(2r,4r)-1-[(4-chlorophenyl)carbamoyl]-4-methoxypyrrolidine-2-carbonyl]amino]-3-fluorophenyl]benzoate Chemical compound N1([C@H](C[C@H](C1)OC)C(=O)NC=1C(=CC(=CC=1)C=1C(=CC=CC=1)C(=O)OC)F)C(=O)NC1=CC=C(Cl)C=C1 YWAIKSSOLKLFIP-NTKDMRAZSA-N 0.000 claims description 2
- QBVYNMSHKSKFLF-DYESRHJHSA-N methyl 2-[4-[[(2r,4r)-1-[(4-chlorophenyl)carbamoyl]-4-methoxypyrrolidine-2-carbonyl]amino]-3-fluorophenyl]pyrazole-3-carboxylate Chemical compound N1([C@H](C[C@H](C1)OC)C(=O)NC=1C(=CC(=CC=1)N1C(=CC=N1)C(=O)OC)F)C(=O)NC1=CC=C(Cl)C=C1 QBVYNMSHKSKFLF-DYESRHJHSA-N 0.000 claims description 2
- DNSNMEBHXMKCSU-UHFFFAOYSA-N methyl 2-[[1-[(4-chlorophenyl)carbamoyl]-4-hydroxypyrrolidine-2-carbonyl]amino]-5-(2-methylsulfonylphenyl)benzoate Chemical compound COC(=O)C1=CC(C=2C(=CC=CC=2)S(C)(=O)=O)=CC=C1NC(=O)C1CC(O)CN1C(=O)NC1=CC=C(Cl)C=C1 DNSNMEBHXMKCSU-UHFFFAOYSA-N 0.000 claims description 2
- YSJDRXBPNDLIGW-UHFFFAOYSA-N methyl 2-[[1-[(4-chlorophenyl)carbamoyl]pyrrolidine-2-carbonyl]amino]-5-(2-methylsulfonylphenyl)benzoate Chemical compound COC(=O)C1=CC(C=2C(=CC=CC=2)S(C)(=O)=O)=CC=C1NC(=O)C1CCCN1C(=O)NC1=CC=C(Cl)C=C1 YSJDRXBPNDLIGW-UHFFFAOYSA-N 0.000 claims description 2
- UXPZJMFFNMTOKH-OXQOHEQNSA-N methyl 3-[4-[[(2r,4r)-1-[(4-chlorophenyl)carbamoyl]-4-methoxypyrrolidine-2-carbonyl]amino]-3-fluorophenyl]-1,2-oxazole-4-carboxylate Chemical compound N1([C@H](C[C@H](C1)OC)C(=O)NC=1C(=CC(=CC=1)C=1C(=CON=1)C(=O)OC)F)C(=O)NC1=CC=C(Cl)C=C1 UXPZJMFFNMTOKH-OXQOHEQNSA-N 0.000 claims description 2
- OJJMHJWJGWRJOE-VQIMIIECSA-N methyl 4-[[(2r,4r)-1-[(4-chlorophenyl)carbamoyl]-4-hydroxypyrrolidine-2-carbonyl]amino]-3-(dimethylamino)benzoate Chemical compound CN(C)C1=CC(C(=O)OC)=CC=C1NC(=O)[C@@H]1N(C(=O)NC=2C=CC(Cl)=CC=2)C[C@H](O)C1 OJJMHJWJGWRJOE-VQIMIIECSA-N 0.000 claims description 2
- SAWSFOQKHXWPDP-WIYYLYMNSA-N methyl 4-[[(2r,4r)-1-[(4-chlorophenyl)carbamoyl]-4-hydroxypyrrolidine-2-carbonyl]amino]-3-pyrrolidin-1-ylbenzoate Chemical compound C([C@H](O)C[C@@H]1C(=O)NC2=CC=C(C=C2N2CCCC2)C(=O)OC)N1C(=O)NC1=CC=C(Cl)C=C1 SAWSFOQKHXWPDP-WIYYLYMNSA-N 0.000 claims description 2
- DXOXBNDJEPHRCL-XMSQKQJNSA-N methyl 5-chloro-1-[4-[[(2r,4r)-1-[(4-chlorophenyl)carbamoyl]-4-methoxypyrrolidine-2-carbonyl]amino]-3-fluorophenyl]-2-oxopyridine-3-carboxylate Chemical compound N1([C@H](C[C@H](C1)OC)C(=O)NC=1C(=CC(=CC=1)N1C(C(C(=O)OC)=CC(Cl)=C1)=O)F)C(=O)NC1=CC=C(Cl)C=C1 DXOXBNDJEPHRCL-XMSQKQJNSA-N 0.000 claims description 2
- HGFOJQDNWMFXAU-OXQOHEQNSA-N methyl 5-chloro-1-[4-[[(2r,4r)-1-[(5-chloropyridin-2-yl)carbamoyl]-4-methoxypyrrolidine-2-carbonyl]amino]-3-fluorophenyl]-2-oxopyridine-3-carboxylate Chemical compound N1([C@H](C[C@H](C1)OC)C(=O)NC=1C(=CC(=CC=1)N1C(C(C(=O)OC)=CC(Cl)=C1)=O)F)C(=O)NC1=CC=C(Cl)C=N1 HGFOJQDNWMFXAU-OXQOHEQNSA-N 0.000 claims description 2
- BDJBQJAZHHLNLK-UHFFFAOYSA-N morpholine-3,4-dicarboxylic acid Chemical compound OC(=O)C1COCCN1C(O)=O BDJBQJAZHHLNLK-UHFFFAOYSA-N 0.000 claims description 2
- IEYMNLYRGAFFMR-UHFFFAOYSA-N piperazine-1,2-dicarboxylic acid Chemical compound OC(=O)C1CNCCN1C(O)=O IEYMNLYRGAFFMR-UHFFFAOYSA-N 0.000 claims description 2
- SMCWNPAVVQIDBM-UHFFFAOYSA-N piperidine-1,2-dicarboxylic acid Chemical compound OC(=O)C1CCCCN1C(O)=O SMCWNPAVVQIDBM-UHFFFAOYSA-N 0.000 claims description 2
- NFBOGDUOBMRIIN-HYBUGGRVSA-N tert-butyl 1-[4-[[(2r,4r)-1-[(4-chlorophenyl)carbamoyl]-4-methoxypyrrolidine-2-carbonyl]amino]-3-fluorophenyl]-2-oxopyridine-3-carboxylate Chemical compound N1([C@H](C[C@H](C1)OC)C(=O)NC=1C(=CC(=CC=1)N1C(C(C(=O)OC(C)(C)C)=CC=C1)=O)F)C(=O)NC1=CC=C(Cl)C=C1 NFBOGDUOBMRIIN-HYBUGGRVSA-N 0.000 claims description 2
- GQHPHXSMTMHOQK-XMSQKQJNSA-N tert-butyl 1-[4-[[(2r,4r)-1-[(5-chloropyridin-2-yl)carbamoyl]-4-methoxypyrrolidine-2-carbonyl]amino]-3-fluorophenyl]-2-oxopyridine-3-carboxylate Chemical compound N1([C@H](C[C@H](C1)OC)C(=O)NC=1C(=CC(=CC=1)N1C(C(C(=O)OC(C)(C)C)=CC=C1)=O)F)C(=O)NC1=CC=C(Cl)C=N1 GQHPHXSMTMHOQK-XMSQKQJNSA-N 0.000 claims description 2
- 125000005236 alkanoylamino group Chemical group 0.000 claims 2
- MAHBOILFHNJLMT-UHFFFAOYSA-N 2,5-dihydropyrrole-1,2-dicarboxylic acid Chemical compound OC(=O)C1C=CCN1C(O)=O MAHBOILFHNJLMT-UHFFFAOYSA-N 0.000 claims 1
- QNJRGCLOCPIILY-OXQOHEQNSA-N methyl 1-[4-[[(2r,4r)-1-[(5-chloropyridin-2-yl)carbamoyl]-4-methoxypyrrolidine-2-carbonyl]amino]-3-fluorophenyl]-2-oxopyridine-3-carboxylate Chemical compound N1([C@H](C[C@H](C1)OC)C(=O)NC=1C(=CC(=CC=1)N1C(C(C(=O)OC)=CC=C1)=O)F)C(=O)NC1=CC=C(Cl)C=N1 QNJRGCLOCPIILY-OXQOHEQNSA-N 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 384
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 189
- 235000019439 ethyl acetate Nutrition 0.000 description 184
- NRABMCZSGNWHFX-UHFFFAOYSA-N 2-fluoro-4-(3-methylpyrazol-1-yl)aniline Chemical compound N1=C(C)C=CN1C1=CC=C(N)C(F)=C1 NRABMCZSGNWHFX-UHFFFAOYSA-N 0.000 description 175
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 156
- 239000000243 solution Substances 0.000 description 148
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 144
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 135
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 133
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 120
- 239000012267 brine Substances 0.000 description 107
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 107
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 90
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 88
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 87
- 239000007787 solid Substances 0.000 description 82
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 76
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 72
- 239000003921 oil Substances 0.000 description 65
- 235000019198 oils Nutrition 0.000 description 65
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 63
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 61
- 239000000741 silica gel Substances 0.000 description 55
- 229910002027 silica gel Inorganic materials 0.000 description 55
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 51
- 239000000203 mixture Substances 0.000 description 51
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 36
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 36
- 238000010992 reflux Methods 0.000 description 31
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 28
- ZQEBQGAAWMOMAI-UHFFFAOYSA-N 1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1CCCC1C(O)=O ZQEBQGAAWMOMAI-UHFFFAOYSA-N 0.000 description 27
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 27
- 239000000706 filtrate Substances 0.000 description 26
- 230000002829 reductive effect Effects 0.000 description 26
- 239000011734 sodium Substances 0.000 description 25
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 24
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 24
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 24
- 229920006395 saturated elastomer Polymers 0.000 description 24
- 230000015572 biosynthetic process Effects 0.000 description 23
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 22
- 239000002253 acid Substances 0.000 description 20
- 239000006260 foam Substances 0.000 description 20
- 239000002244 precipitate Substances 0.000 description 20
- 239000005457 ice water Substances 0.000 description 19
- 238000003786 synthesis reaction Methods 0.000 description 18
- ADAKRBAJFHTIEW-UHFFFAOYSA-N 1-chloro-4-isocyanatobenzene Chemical compound ClC1=CC=C(N=C=O)C=C1 ADAKRBAJFHTIEW-UHFFFAOYSA-N 0.000 description 17
- GKQLYSROISKDLL-UHFFFAOYSA-N EEDQ Chemical compound C1=CC=C2N(C(=O)OCC)C(OCC)C=CC2=C1 GKQLYSROISKDLL-UHFFFAOYSA-N 0.000 description 17
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N N-phenyl amine Natural products NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 17
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 17
- QXBWTYBCNFKURT-UHFFFAOYSA-N (2-methylsulfanylphenyl)boronic acid Chemical compound CSC1=CC=CC=C1B(O)O QXBWTYBCNFKURT-UHFFFAOYSA-N 0.000 description 16
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 16
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 16
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 15
- 239000010410 layer Substances 0.000 description 15
- 239000000843 powder Substances 0.000 description 15
- BENKAPCDIOILGV-RNFRBKRXSA-N (2r,4r)-4-hydroxy-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1C[C@H](O)C[C@@H]1C(O)=O BENKAPCDIOILGV-RNFRBKRXSA-N 0.000 description 14
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 14
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 14
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 14
- 229960002429 proline Drugs 0.000 description 14
- 239000000377 silicon dioxide Substances 0.000 description 14
- 150000002894 organic compounds Chemical class 0.000 description 13
- 238000000746 purification Methods 0.000 description 13
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 12
- 239000012298 atmosphere Substances 0.000 description 12
- COHIMMPWCAHSFN-HTQZYQBOSA-N (2r,4r)-4-methoxy-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid Chemical compound CO[C@@H]1C[C@H](C(O)=O)N(C(=O)OC(C)(C)C)C1 COHIMMPWCAHSFN-HTQZYQBOSA-N 0.000 description 11
- 239000007864 aqueous solution Substances 0.000 description 11
- 229910052786 argon Inorganic materials 0.000 description 11
- 239000007788 liquid Substances 0.000 description 11
- ODJPUYLITKOLHJ-HYBUGGRVSA-N tert-butyl (2r,4r)-4-[tert-butyl(dimethyl)silyl]oxy-2-[[2-fluoro-4-(2-methylsulfanylphenyl)phenyl]carbamoyl]pyrrolidine-1-carboxylate Chemical compound CSC1=CC=CC=C1C(C=C1F)=CC=C1NC(=O)[C@@H]1N(C(=O)OC(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)C1 ODJPUYLITKOLHJ-HYBUGGRVSA-N 0.000 description 11
- GZRMNMGWNKSANY-UHFFFAOYSA-N 4-bromo-2-fluoroaniline Chemical compound NC1=CC=C(Br)C=C1F GZRMNMGWNKSANY-UHFFFAOYSA-N 0.000 description 10
- 239000002585 base Substances 0.000 description 10
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 10
- 150000002978 peroxides Chemical class 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- 238000010791 quenching Methods 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 9
- 150000001412 amines Chemical class 0.000 description 9
- 239000003146 anticoagulant agent Substances 0.000 description 9
- PMMYEEVYMWASQN-QWWZWVQMSA-N cis-4-hydroxy-D-proline Chemical compound O[C@H]1C[NH2+][C@@H](C([O-])=O)C1 PMMYEEVYMWASQN-QWWZWVQMSA-N 0.000 description 9
- 231100000252 nontoxic Toxicity 0.000 description 9
- 230000003000 nontoxic effect Effects 0.000 description 9
- 239000012044 organic layer Substances 0.000 description 9
- LEVCIBCTEIRAKW-HYBUGGRVSA-N tert-butyl (2r,4r)-4-[tert-butyl(dimethyl)silyl]oxy-2-[[2-fluoro-4-(2-methylsulfonylphenyl)phenyl]carbamoyl]pyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@@H]1C(=O)NC1=CC=C(C=2C(=CC=CC=2)S(C)(=O)=O)C=C1F LEVCIBCTEIRAKW-HYBUGGRVSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
- 238000003818 flash chromatography Methods 0.000 description 8
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 8
- 125000006239 protecting group Chemical group 0.000 description 8
- 125000001424 substituent group Chemical group 0.000 description 8
- JUOLQJALRNXSKA-VXGBXAGGSA-N (2r,4r)-4-[tert-butyl(dimethyl)silyl]oxy-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@@H]1C(O)=O JUOLQJALRNXSKA-VXGBXAGGSA-N 0.000 description 7
- 230000002785 anti-thrombosis Effects 0.000 description 7
- 125000004429 atom Chemical group 0.000 description 7
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 7
- 238000005859 coupling reaction Methods 0.000 description 7
- 150000002148 esters Chemical class 0.000 description 7
- 230000005764 inhibitory process Effects 0.000 description 7
- LDCWYOJSDDVVGL-UHFFFAOYSA-N n-[4-[2-(tert-butylsulfamoyl)phenyl]-2-fluorophenyl]pyrrolidine-2-carboxamide Chemical compound CC(C)(C)NS(=O)(=O)C1=CC=CC=C1C(C=C1F)=CC=C1NC(=O)C1NCCC1 LDCWYOJSDDVVGL-UHFFFAOYSA-N 0.000 description 7
- RQUNGQIRQUCJHS-CRAIPNDOSA-N tert-butyl (2r,4r)-2-[(4-bromo-2-fluorophenyl)carbamoyl]-4-[tert-butyl(dimethyl)silyl]oxypyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@@H]1C(=O)NC1=CC=C(Br)C=C1F RQUNGQIRQUCJHS-CRAIPNDOSA-N 0.000 description 7
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 7
- USFPINLPPFWTJW-UHFFFAOYSA-N tetraphenylphosphonium Chemical compound C1=CC=CC=C1[P+](C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 USFPINLPPFWTJW-UHFFFAOYSA-N 0.000 description 7
- 229940123583 Factor Xa inhibitor Drugs 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 108090000190 Thrombin Proteins 0.000 description 6
- 239000004480 active ingredient Substances 0.000 description 6
- 229940024606 amino acid Drugs 0.000 description 6
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 229910052763 palladium Inorganic materials 0.000 description 6
- LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 description 6
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 229960004072 thrombin Drugs 0.000 description 6
- ORNPJBKOARQITE-UHFFFAOYSA-N (4-nitrophenyl) n-(5-chloropyridin-2-yl)carbamate Chemical compound C1=CC([N+](=O)[O-])=CC=C1OC(=O)NC1=CC=C(Cl)C=N1 ORNPJBKOARQITE-UHFFFAOYSA-N 0.000 description 5
- QOIMFVPPCOSNBG-UHFFFAOYSA-N 2-(4-amino-3-fluorophenyl)-n-tert-butylbenzenesulfonamide Chemical compound CC(C)(C)NS(=O)(=O)C1=CC=CC=C1C1=CC=C(N)C(F)=C1 QOIMFVPPCOSNBG-UHFFFAOYSA-N 0.000 description 5
- QYLFVEJDQXSTEL-UHFFFAOYSA-N 2-fluoro-4-(5-methylpyrazol-1-yl)aniline Chemical compound CC1=CC=NN1C1=CC=C(N)C(F)=C1 QYLFVEJDQXSTEL-UHFFFAOYSA-N 0.000 description 5
- CUMTUBVTKOYYOU-UHFFFAOYSA-N 2-fluoro-4-iodoaniline Chemical compound NC1=CC=C(I)C=C1F CUMTUBVTKOYYOU-UHFFFAOYSA-N 0.000 description 5
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 5
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 5
- 239000012300 argon atmosphere Substances 0.000 description 5
- 239000000460 chlorine Substances 0.000 description 5
- 230000008878 coupling Effects 0.000 description 5
- 238000010168 coupling process Methods 0.000 description 5
- 239000013058 crude material Substances 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 125000004093 cyano group Chemical group *C#N 0.000 description 5
- 239000002552 dosage form Substances 0.000 description 5
- 239000007789 gas Substances 0.000 description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 5
- 230000037361 pathway Effects 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- UPAHQJOZYJQXQX-RKDXNWHRSA-N (2r,4r)-4-ethoxy-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid Chemical group CCO[C@@H]1C[C@H](C(O)=O)N(C(=O)OC(C)(C)C)C1 UPAHQJOZYJQXQX-RKDXNWHRSA-N 0.000 description 4
- LOTJQPHGWABBRJ-MLGOLLRUSA-N (2r,4r)-n-[2-fluoro-4-(2-methylsulfonylphenyl)phenyl]-4-hydroxypyrrolidine-2-carboxamide Chemical compound CS(=O)(=O)C1=CC=CC=C1C(C=C1F)=CC=C1NC(=O)[C@@H]1NC[C@H](O)C1 LOTJQPHGWABBRJ-MLGOLLRUSA-N 0.000 description 4
- WVBDLNWXWVQSAM-IUODEOHRSA-N (2r,4r)-n-[2-fluoro-4-(3-methylpyrazol-1-yl)phenyl]-4-methoxypyrrolidine-2-carboxamide Chemical compound C1[C@@H](OC)CN[C@H]1C(=O)NC1=CC=C(N2N=C(C)C=C2)C=C1F WVBDLNWXWVQSAM-IUODEOHRSA-N 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- QWSLTPIPEHHANA-UHFFFAOYSA-N 1-(4-amino-3-fluorophenyl)piperidin-2-one Chemical compound C1=C(F)C(N)=CC=C1N1C(=O)CCCC1 QWSLTPIPEHHANA-UHFFFAOYSA-N 0.000 description 4
- 239000005725 8-Hydroxyquinoline Substances 0.000 description 4
- HRPVXLWXLXDGHG-UHFFFAOYSA-N Acrylamide Chemical compound NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- KHBQMWCZKVMBLN-UHFFFAOYSA-N Benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1 KHBQMWCZKVMBLN-UHFFFAOYSA-N 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 150000001413 amino acids Chemical class 0.000 description 4
- 125000003277 amino group Chemical group 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 238000010511 deprotection reaction Methods 0.000 description 4
- 239000006185 dispersion Substances 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 150000004820 halides Chemical class 0.000 description 4
- 238000001802 infusion Methods 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- FJKLFKNDRHCRII-UHFFFAOYSA-N n-[2-chloro-4-(2-methylsulfonylphenyl)phenyl]pyrrolidine-2-carboxamide Chemical compound CS(=O)(=O)C1=CC=CC=C1C(C=C1Cl)=CC=C1NC(=O)C1NCCC1 FJKLFKNDRHCRII-UHFFFAOYSA-N 0.000 description 4
- FTWXPQDOELZTKY-UHFFFAOYSA-N n-[5-[2-(tert-butylsulfamoyl)phenyl]pyridin-2-yl]pyrrolidine-2-carboxamide Chemical compound CC(C)(C)NS(=O)(=O)C1=CC=CC=C1C(C=N1)=CC=C1NC(=O)C1NCCC1 FTWXPQDOELZTKY-UHFFFAOYSA-N 0.000 description 4
- 229960003540 oxyquinoline Drugs 0.000 description 4
- MCJGNVYPOGVAJF-UHFFFAOYSA-N quinolin-8-ol Chemical compound C1=CN=C2C(O)=CC=CC2=C1 MCJGNVYPOGVAJF-UHFFFAOYSA-N 0.000 description 4
- 239000011347 resin Substances 0.000 description 4
- 229920005989 resin Polymers 0.000 description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 4
- JIMLGYIFDARSKF-UHFFFAOYSA-N tert-butyl 2-[(4-bromo-2-chlorophenyl)carbamoyl]pyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCC1C(=O)NC1=CC=C(Br)C=C1Cl JIMLGYIFDARSKF-UHFFFAOYSA-N 0.000 description 4
- VFDDCJGRZZWRTO-UHFFFAOYSA-N tert-butyl 2-[(4-bromo-2-fluorophenyl)carbamoyl]pyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCC1C(=O)NC1=CC=C(Br)C=C1F VFDDCJGRZZWRTO-UHFFFAOYSA-N 0.000 description 4
- HMLVBXCRZNFHRP-UHFFFAOYSA-N tert-butyl 2-[(5-bromopyridin-2-yl)carbamoyl]pyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCC1C(=O)NC1=CC=C(Br)C=N1 HMLVBXCRZNFHRP-UHFFFAOYSA-N 0.000 description 4
- XPWZPQYSWFDSAZ-UHFFFAOYSA-N tert-butyl 2-[[2-chloro-4-(2-methylsulfonylphenyl)phenyl]carbamoyl]pyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCC1C(=O)NC1=CC=C(C=2C(=CC=CC=2)S(C)(=O)=O)C=C1Cl XPWZPQYSWFDSAZ-UHFFFAOYSA-N 0.000 description 4
- MWUZMEQAKAMVTA-UHFFFAOYSA-N tert-butyl 2-[[4-[2-(tert-butylsulfamoyl)phenyl]-2-fluorophenyl]carbamoyl]pyrrolidine-1-carboxylate Chemical compound CC(C)(C)NS(=O)(=O)C1=CC=CC=C1C(C=C1F)=CC=C1NC(=O)C1N(C(=O)OC(C)(C)C)CCC1 MWUZMEQAKAMVTA-UHFFFAOYSA-N 0.000 description 4
- KEQTWHPMSVAFDA-UHFFFAOYSA-N 2,3-dihydro-1h-pyrazole Chemical compound C1NNC=C1 KEQTWHPMSVAFDA-UHFFFAOYSA-N 0.000 description 3
- 208000024172 Cardiovascular disease Diseases 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 108010014173 Factor X Proteins 0.000 description 3
- 108010010803 Gelatin Proteins 0.000 description 3
- 239000007821 HATU Substances 0.000 description 3
- 241000282412 Homo Species 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 108010022999 Serine Proteases Proteins 0.000 description 3
- 102000012479 Serine Proteases Human genes 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 230000003197 catalytic effect Effects 0.000 description 3
- 239000003610 charcoal Substances 0.000 description 3
- 235000008504 concentrate Nutrition 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
- 229940088598 enzyme Drugs 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 229920000159 gelatin Polymers 0.000 description 3
- 239000008273 gelatin Substances 0.000 description 3
- 235000019322 gelatine Nutrition 0.000 description 3
- 235000011852 gelatine desserts Nutrition 0.000 description 3
- 230000023597 hemostasis Effects 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 150000007522 mineralic acids Chemical class 0.000 description 3
- SGOBEAZBTHBGPF-UHFFFAOYSA-N n-[2-fluoro-4-(2-methylsulfonylphenyl)phenyl]pyrrolidine-2-carboxamide Chemical compound CS(=O)(=O)C1=CC=CC=C1C(C=C1F)=CC=C1NC(=O)C1NCCC1 SGOBEAZBTHBGPF-UHFFFAOYSA-N 0.000 description 3
- 150000007524 organic acids Chemical class 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 238000002953 preparative HPLC Methods 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 150000003335 secondary amines Chemical class 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 239000004094 surface-active agent Substances 0.000 description 3
- UNOFAKDOGUZYLH-UHFFFAOYSA-N tert-butyl 2-[[2-chloro-4-(2-methylsulfanylphenyl)phenyl]carbamoyl]pyrrolidine-1-carboxylate Chemical compound CSC1=CC=CC=C1C(C=C1Cl)=CC=C1NC(=O)C1N(C(=O)OC(C)(C)C)CCC1 UNOFAKDOGUZYLH-UHFFFAOYSA-N 0.000 description 3
- WXNCJHMFVDYSHG-UHFFFAOYSA-N tert-butyl 2-[[2-fluoro-4-(2-methylsulfanylphenyl)phenyl]carbamoyl]pyrrolidine-1-carboxylate Chemical compound CSC1=CC=CC=C1C(C=C1F)=CC=C1NC(=O)C1N(C(=O)OC(C)(C)C)CCC1 WXNCJHMFVDYSHG-UHFFFAOYSA-N 0.000 description 3
- WKDWISUBYBBLBL-UHFFFAOYSA-N tert-butyl 2-[[2-fluoro-4-(2-methylsulfonylphenyl)phenyl]carbamoyl]pyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCC1C(=O)NC1=CC=C(C=2C(=CC=CC=2)S(C)(=O)=O)C=C1F WKDWISUBYBBLBL-UHFFFAOYSA-N 0.000 description 3
- YVARDIFWYMQNAF-UHFFFAOYSA-N tert-butyl 2-[[5-[2-(tert-butylsulfamoyl)phenyl]pyridin-2-yl]carbamoyl]pyrrolidine-1-carboxylate Chemical compound CC(C)(C)NS(=O)(=O)C1=CC=CC=C1C(C=N1)=CC=C1NC(=O)C1N(C(=O)OC(C)(C)C)CCC1 YVARDIFWYMQNAF-UHFFFAOYSA-N 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- SSJXIUAHEKJCMH-PHDIDXHHSA-N (1r,2r)-cyclohexane-1,2-diamine Chemical compound N[C@@H]1CCCC[C@H]1N SSJXIUAHEKJCMH-PHDIDXHHSA-N 0.000 description 2
- LDCWYOJSDDVVGL-GOSISDBHSA-N (2r)-n-[4-[2-(tert-butylsulfamoyl)phenyl]-2-fluorophenyl]pyrrolidine-2-carboxamide Chemical compound CC(C)(C)NS(=O)(=O)C1=CC=CC=C1C(C=C1F)=CC=C1NC(=O)[C@@H]1NCCC1 LDCWYOJSDDVVGL-GOSISDBHSA-N 0.000 description 2
- COHIMMPWCAHSFN-JGVFFNPUSA-N (2r,4s)-4-methoxy-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid Chemical group CO[C@H]1C[C@H](C(O)=O)N(C(=O)OC(C)(C)C)C1 COHIMMPWCAHSFN-JGVFFNPUSA-N 0.000 description 2
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 2
- UHWKBRQDSHYYOC-UHFFFAOYSA-N 1-(5-nitropyridin-2-yl)piperidin-2-one Chemical compound N1=CC([N+](=O)[O-])=CC=C1N1C(=O)CCCC1 UHWKBRQDSHYYOC-UHFFFAOYSA-N 0.000 description 2
- DSVGFKBFFICWLZ-UHFFFAOYSA-N 1-fluoro-4-isocyanatobenzene Chemical compound FC1=CC=C(N=C=O)C=C1 DSVGFKBFFICWLZ-UHFFFAOYSA-N 0.000 description 2
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 2
- INMZDDDQLHKGPF-UHFFFAOYSA-N 4-bromo-2-chloroaniline Chemical compound NC1=CC=C(Br)C=C1Cl INMZDDDQLHKGPF-UHFFFAOYSA-N 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- WGOLHUGPTDEKCF-UHFFFAOYSA-N 5-bromopyridin-2-amine Chemical compound NC1=CC=C(Br)C=N1 WGOLHUGPTDEKCF-UHFFFAOYSA-N 0.000 description 2
- CYJRNFFLTBEQSQ-UHFFFAOYSA-N 8-(3-methyl-1-benzothiophen-5-yl)-N-(4-methylsulfonylpyridin-3-yl)quinoxalin-6-amine Chemical compound CS(=O)(=O)C1=C(C=NC=C1)NC=1C=C2N=CC=NC2=C(C=1)C=1C=CC2=C(C(=CS2)C)C=1 CYJRNFFLTBEQSQ-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 241000282472 Canis lupus familiaris Species 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- 102000009123 Fibrin Human genes 0.000 description 2
- 108010073385 Fibrin Proteins 0.000 description 2
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 2
- 108010049003 Fibrinogen Proteins 0.000 description 2
- 102000008946 Fibrinogen Human genes 0.000 description 2
- 229930091371 Fructose Natural products 0.000 description 2
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 2
- 239000005715 Fructose Substances 0.000 description 2
- 230000005526 G1 to G0 transition Effects 0.000 description 2
- 241000237664 Haementeria officinalis Species 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 238000006069 Suzuki reaction reaction Methods 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 230000029936 alkylation Effects 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 150000001448 anilines Chemical class 0.000 description 2
- 150000005347 biaryls Chemical group 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 230000005587 bubbling Effects 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000007958 cherry flavor Substances 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- 238000013375 chromatographic separation Methods 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 230000003013 cytotoxicity Effects 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- WQBOWGPMMLEVOY-IUYQGCFVSA-N diazonio-[(3s,5r)-1,5-dicarboxypyrrolidin-3-yl]azanide Chemical compound OC(=O)[C@H]1C[C@H](N=[N+]=[N-])CN1C(O)=O WQBOWGPMMLEVOY-IUYQGCFVSA-N 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 238000007865 diluting Methods 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 229950003499 fibrin Drugs 0.000 description 2
- 229940012952 fibrinogen Drugs 0.000 description 2
- 235000003599 food sweetener Nutrition 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 230000002439 hemostatic effect Effects 0.000 description 2
- 125000001072 heteroaryl group Chemical group 0.000 description 2
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 150000002739 metals Chemical class 0.000 description 2
- HZCWALJOVVPETG-DHIUTWEWSA-N methyl (2r,4r)-4-hydroxy-1-tritylpyrrolidine-2-carboxylate Chemical compound COC(=O)[C@H]1C[C@@H](O)CN1C(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 HZCWALJOVVPETG-DHIUTWEWSA-N 0.000 description 2
- ZORHSASAYVIBLY-RFZPGFLSSA-N methyl (2r,4r)-4-hydroxypyrrolidine-2-carboxylate Chemical compound COC(=O)[C@H]1C[C@@H](O)CN1 ZORHSASAYVIBLY-RFZPGFLSSA-N 0.000 description 2
- BCGJNQHCRXFFMV-DNQXCXABSA-N methyl (2r,4r)-4-methoxy-1-tritylpyrrolidine-2-carboxylate Chemical compound C1[C@H](OC)C[C@H](C(=O)OC)N1C(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 BCGJNQHCRXFFMV-DNQXCXABSA-N 0.000 description 2
- XEDZRASYGGJQCQ-PHDIDXHHSA-N methyl (2r,4r)-4-methoxypyrrolidine-2-carboxylate Chemical compound CO[C@H]1CN[C@@H](C(=O)OC)C1 XEDZRASYGGJQCQ-PHDIDXHHSA-N 0.000 description 2
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 2
- 244000005700 microbiome Species 0.000 description 2
- XJBMWUGGAYYYPO-UHFFFAOYSA-N n-[2-methyl-4-(2-methylsulfonylphenyl)phenyl]pyrrolidine-2-carboxamide Chemical compound CC1=CC(C=2C(=CC=CC=2)S(C)(=O)=O)=CC=C1NC(=O)C1CCCN1 XJBMWUGGAYYYPO-UHFFFAOYSA-N 0.000 description 2
- SSMSWXTVAQQQEB-UHFFFAOYSA-N n-[4-(2-methylsulfonylphenyl)-2-(trifluoromethyl)phenyl]pyrrolidine-2-carboxamide Chemical compound CS(=O)(=O)C1=CC=CC=C1C(C=C1C(F)(F)F)=CC=C1NC(=O)C1NCCC1 SSMSWXTVAQQQEB-UHFFFAOYSA-N 0.000 description 2
- PINZDTQLMQWFOP-UHFFFAOYSA-N n-tert-butyl-4-fluorobenzenesulfonamide Chemical compound CC(C)(C)NS(=O)(=O)C1=CC=C(F)C=C1 PINZDTQLMQWFOP-UHFFFAOYSA-N 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- LBKJNHPKYFYCLL-UHFFFAOYSA-N potassium;trimethyl(oxido)silane Chemical compound [K+].C[Si](C)(C)[O-] LBKJNHPKYFYCLL-UHFFFAOYSA-N 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 125000002924 primary amino group Chemical class [H]N([H])* 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000004007 reversed phase HPLC Methods 0.000 description 2
- 150000003334 secondary amides Chemical class 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 230000002459 sustained effect Effects 0.000 description 2
- 239000003765 sweetening agent Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- UMTQNDYEPQWLND-UHFFFAOYSA-N tert-butyl 2-[(4-bromo-2-methylphenyl)carbamoyl]pyrrolidine-1-carboxylate Chemical compound CC1=CC(Br)=CC=C1NC(=O)C1N(C(=O)OC(C)(C)C)CCC1 UMTQNDYEPQWLND-UHFFFAOYSA-N 0.000 description 2
- ILBTUQAFJMLVKX-UHFFFAOYSA-N tert-butyl 2-[(4-bromophenyl)carbamoyl]pyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCC1C(=O)NC1=CC=C(Br)C=C1 ILBTUQAFJMLVKX-UHFFFAOYSA-N 0.000 description 2
- YWVODCSKERKVRQ-UHFFFAOYSA-N tert-butyl 2-[[4-(2-methylsulfanylphenyl)-2-(trifluoromethyl)phenyl]carbamoyl]pyrrolidine-1-carboxylate Chemical compound CSC1=CC=CC=C1C(C=C1C(F)(F)F)=CC=C1NC(=O)C1N(C(=O)OC(C)(C)C)CCC1 YWVODCSKERKVRQ-UHFFFAOYSA-N 0.000 description 2
- OINXTVIBJSEWEL-UHFFFAOYSA-N tert-butyl 2-[[4-(2-methylsulfanylphenyl)phenyl]carbamoyl]pyrrolidine-1-carboxylate Chemical compound CSC1=CC=CC=C1C(C=C1)=CC=C1NC(=O)C1N(C(=O)OC(C)(C)C)CCC1 OINXTVIBJSEWEL-UHFFFAOYSA-N 0.000 description 2
- YTTLCWUIRZOOMQ-UHFFFAOYSA-N tert-butyl 2-[[4-(2-methylsulfonylphenyl)-2-(trifluoromethyl)phenyl]carbamoyl]pyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCC1C(=O)NC1=CC=C(C=2C(=CC=CC=2)S(C)(=O)=O)C=C1C(F)(F)F YTTLCWUIRZOOMQ-UHFFFAOYSA-N 0.000 description 2
- DWHRSLDBICKBOY-UHFFFAOYSA-N tert-butyl 2-[[4-bromo-2-(trifluoromethyl)phenyl]carbamoyl]pyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCC1C(=O)NC1=CC=C(Br)C=C1C(F)(F)F DWHRSLDBICKBOY-UHFFFAOYSA-N 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 description 2
- ONDSBJMLAHVLMI-UHFFFAOYSA-N trimethylsilyldiazomethane Chemical compound C[Si](C)(C)[CH-][N+]#N ONDSBJMLAHVLMI-UHFFFAOYSA-N 0.000 description 2
- JBWKIWSBJXDJDT-UHFFFAOYSA-N triphenylmethyl chloride Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 JBWKIWSBJXDJDT-UHFFFAOYSA-N 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- 229910000404 tripotassium phosphate Inorganic materials 0.000 description 2
- 235000019798 tripotassium phosphate Nutrition 0.000 description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
- 229960000281 trometamol Drugs 0.000 description 2
- 235000015112 vegetable and seed oil Nutrition 0.000 description 2
- 239000008158 vegetable oil Substances 0.000 description 2
- NPLZNDDFVCGRAG-UHFFFAOYSA-N (2-cyanophenyl)boronic acid Chemical group OB(O)C1=CC=CC=C1C#N NPLZNDDFVCGRAG-UHFFFAOYSA-N 0.000 description 1
- PGOHTUIFYSHAQG-LJSDBVFPSA-N (2S)-6-amino-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-4-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-1-[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2R)-2-[[(2S)-2-[[(2S)-2-[[2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-1-[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-amino-4-methylsulfanylbutanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-5-carbamimidamidopentanoyl]amino]propanoyl]pyrrolidine-2-carbonyl]amino]-3-methylbutanoyl]amino]-4-methylpentanoyl]amino]-4-methylpentanoyl]amino]acetyl]amino]-3-hydroxypropanoyl]amino]-4-methylpentanoyl]amino]-3-sulfanylpropanoyl]amino]-4-methylsulfanylbutanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-hydroxybutanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-3-hydroxypropanoyl]amino]-3-hydroxypropanoyl]amino]-3-(1H-imidazol-5-yl)propanoyl]amino]-4-methylpentanoyl]amino]-3-hydroxybutanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-oxopentanoyl]amino]-3-hydroxybutanoyl]amino]-3-hydroxypropanoyl]amino]-3-carboxypropanoyl]amino]-3-hydroxypropanoyl]amino]-5-oxopentanoyl]amino]-5-oxopentanoyl]amino]-3-phenylpropanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-methylbutanoyl]amino]-4-methylpentanoyl]amino]-4-oxobutanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-4-carboxybutanoyl]amino]-5-oxopentanoyl]amino]hexanoic acid Chemical compound CSCC[C@H](N)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](Cc1cnc[nH]1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(O)=O PGOHTUIFYSHAQG-LJSDBVFPSA-N 0.000 description 1
- OHIYKPXMNWXZQH-RNFRBKRXSA-N (2r,4r)-1-[(2-methylpropan-2-yl)oxycarbonyl]-4-(trifluoromethyl)pyrrolidine-2-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1C[C@H](C(F)(F)F)C[C@@H]1C(O)=O OHIYKPXMNWXZQH-RNFRBKRXSA-N 0.000 description 1
- MIVXQYMYEMUMKK-JGVFFNPUSA-N (2r,4r)-4-cyano-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid Chemical group CC(C)(C)OC(=O)N1C[C@H](C#N)C[C@@H]1C(O)=O MIVXQYMYEMUMKK-JGVFFNPUSA-N 0.000 description 1
- DTXUXTISZVZLOB-IUODEOHRSA-N (2r,4r)-n-[2-fluoro-4-(2-oxopiperidin-1-yl)phenyl]-4-methoxypyrrolidine-2-carboxamide Chemical compound C1[C@@H](OC)CN[C@H]1C(=O)NC1=CC=C(N2C(CCCC2)=O)C=C1F DTXUXTISZVZLOB-IUODEOHRSA-N 0.000 description 1
- NXLNNXIXOYSCMB-UHFFFAOYSA-N (4-nitrophenyl) carbonochloridate Chemical compound [O-][N+](=O)C1=CC=C(OC(Cl)=O)C=C1 NXLNNXIXOYSCMB-UHFFFAOYSA-N 0.000 description 1
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- 125000006824 (C1-C6) dialkyl amine group Chemical group 0.000 description 1
- YBWJVFMNWMLZEN-UHFFFAOYSA-N 1,2-difluoro-4-isocyanatobenzene Chemical group FC1=CC=C(N=C=O)C=C1F YBWJVFMNWMLZEN-UHFFFAOYSA-N 0.000 description 1
- FEBPTQSSHLOHEK-UHFFFAOYSA-N 1-(4-amino-3-fluorophenyl)pyridin-2-one Chemical compound C1=C(F)C(N)=CC=C1N1C(=O)C=CC=C1 FEBPTQSSHLOHEK-UHFFFAOYSA-N 0.000 description 1
- ZSLFOJJFCSKUJS-UHFFFAOYSA-N 1-(5-aminopyridin-2-yl)piperidin-2-one Chemical compound N1=CC(N)=CC=C1N1C(=O)CCCC1 ZSLFOJJFCSKUJS-UHFFFAOYSA-N 0.000 description 1
- DGWJBVUZRPJEHQ-UHFFFAOYSA-N 1-(6-aminopyridin-3-yl)pyridin-2-one Chemical compound C1=NC(N)=CC=C1N1C(=O)C=CC=C1 DGWJBVUZRPJEHQ-UHFFFAOYSA-N 0.000 description 1
- CZQIJQFTRGDODI-UHFFFAOYSA-N 1-bromo-4-isocyanatobenzene Chemical group BrC1=CC=C(N=C=O)C=C1 CZQIJQFTRGDODI-UHFFFAOYSA-N 0.000 description 1
- 125000004973 1-butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000006039 1-hexenyl group Chemical group 0.000 description 1
- FMDGXCSMDZMDHZ-UHFFFAOYSA-N 1-isocyanato-4-methoxybenzene Chemical group COC1=CC=C(N=C=O)C=C1 FMDGXCSMDZMDHZ-UHFFFAOYSA-N 0.000 description 1
- NZGOSPJWFBSVFT-RKDXNWHRSA-N 1-o-tert-butyl 2-o-methyl (2r,4r)-4-methoxypyrrolidine-1,2-dicarboxylate Chemical compound CO[C@@H]1C[C@H](C(=O)OC)N(C(=O)OC(C)(C)C)C1 NZGOSPJWFBSVFT-RKDXNWHRSA-N 0.000 description 1
- 125000006023 1-pentenyl group Chemical group 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- AAILEWXSEQLMNI-UHFFFAOYSA-N 1h-pyridazin-6-one Chemical compound OC1=CC=CN=N1 AAILEWXSEQLMNI-UHFFFAOYSA-N 0.000 description 1
- HCSBTDBGTNZOAB-UHFFFAOYSA-N 2,3-dinitrobenzoic acid Chemical compound OC(=O)C1=CC=CC([N+]([O-])=O)=C1[N+]([O-])=O HCSBTDBGTNZOAB-UHFFFAOYSA-N 0.000 description 1
- HNENEALJPWJWJY-UHFFFAOYSA-N 2,4-difluoro-1-isocyanatobenzene Chemical compound FC1=CC=C(N=C=O)C(F)=C1 HNENEALJPWJWJY-UHFFFAOYSA-N 0.000 description 1
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 1
- OZWXXJYHMXGRCA-UHFFFAOYSA-N 2-(4-amino-3-fluorophenyl)pyridazin-3-one Chemical compound C1=C(F)C(N)=CC=C1N1C(=O)C=CC=N1 OZWXXJYHMXGRCA-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- KAICSOAXLOGTRQ-UHFFFAOYSA-N 2-[1-[4-[[1-[(4-chlorophenyl)carbamoyl]-4-methoxypyrrolidine-2-carbonyl]amino]-3-fluorophenyl]-2,5-dioxoimidazolidin-4-yl]acetic acid Chemical compound C1C(OC)CC(C(=O)NC=2C(=CC(=CC=2)N2C(C(CC(O)=O)NC2=O)=O)F)N1C(=O)NC1=CC=C(Cl)C=C1 KAICSOAXLOGTRQ-UHFFFAOYSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- FYPWCYYDNHFMPL-UHFFFAOYSA-N 2-fluoro-4-(2-methylimidazol-1-yl)aniline Chemical group CC1=NC=CN1C1=CC=C(N)C(F)=C1 FYPWCYYDNHFMPL-UHFFFAOYSA-N 0.000 description 1
- WCSZDMUTWBSGAW-UHFFFAOYSA-N 2-fluoro-4-(2-methylsulfonylphenyl)aniline Chemical group CS(=O)(=O)C1=CC=CC=C1C1=CC=C(N)C(F)=C1 WCSZDMUTWBSGAW-UHFFFAOYSA-N 0.000 description 1
- FWRCOINKYLERQL-UHFFFAOYSA-N 2-fluoro-4-isocyanato-1-methylbenzene Chemical group CC1=CC=C(N=C=O)C=C1F FWRCOINKYLERQL-UHFFFAOYSA-N 0.000 description 1
- 125000006040 2-hexenyl group Chemical group 0.000 description 1
- APOYTRAZFJURPB-UHFFFAOYSA-N 2-methoxy-n-(2-methoxyethyl)-n-(trifluoro-$l^{4}-sulfanyl)ethanamine Chemical compound COCCN(S(F)(F)F)CCOC APOYTRAZFJURPB-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-M 2-methylbenzenesulfonate Chemical compound CC1=CC=CC=C1S([O-])(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-M 0.000 description 1
- GWJSQKNYHPYZRN-UHFFFAOYSA-N 2-methylpropane-2-sulfonamide Chemical compound CC(C)(C)S(N)(=O)=O GWJSQKNYHPYZRN-UHFFFAOYSA-N 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
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 125000006041 3-hexenyl group Chemical group 0.000 description 1
- 125000006032 3-methyl-3-butenyl group Chemical group 0.000 description 1
- JUOLQJALRNXSKA-UHFFFAOYSA-N 4-[tert-butyl(dimethyl)silyl]oxy-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1CC(O[Si](C)(C)C(C)(C)C)CC1C(O)=O JUOLQJALRNXSKA-UHFFFAOYSA-N 0.000 description 1
- YBAZINRZQSAIAY-UHFFFAOYSA-N 4-aminobenzonitrile Chemical compound NC1=CC=C(C#N)C=C1 YBAZINRZQSAIAY-UHFFFAOYSA-N 0.000 description 1
- PHXGKHTWEOPCEW-UHFFFAOYSA-N 4-bromo-2-(trifluoromethyl)aniline Chemical compound NC1=CC=C(Br)C=C1C(F)(F)F PHXGKHTWEOPCEW-UHFFFAOYSA-N 0.000 description 1
- PCHYYOCUCGCSBU-UHFFFAOYSA-N 4-bromo-2-methylaniline Chemical compound CC1=CC(Br)=CC=C1N PCHYYOCUCGCSBU-UHFFFAOYSA-N 0.000 description 1
- WDFQBORIUYODSI-UHFFFAOYSA-N 4-bromoaniline Chemical compound NC1=CC=C(Br)C=C1 WDFQBORIUYODSI-UHFFFAOYSA-N 0.000 description 1
- JVVRCYWZTJLJSG-UHFFFAOYSA-N 4-dimethylaminophenol Chemical compound CN(C)C1=CC=C(O)C=C1 JVVRCYWZTJLJSG-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-dimethylaminopyridine Substances CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 1
- BFXHJFKKRGVUMU-UHFFFAOYSA-N 4-fluorobenzenesulfonyl chloride Chemical compound FC1=CC=C(S(Cl)(=O)=O)C=C1 BFXHJFKKRGVUMU-UHFFFAOYSA-N 0.000 description 1
- 125000002373 5 membered heterocyclic group Chemical class 0.000 description 1
- OKRUMSWHDWKGHA-UHFFFAOYSA-N 5-bromopentanoyl chloride Chemical compound ClC(=O)CCCCBr OKRUMSWHDWKGHA-UHFFFAOYSA-N 0.000 description 1
- BPVZXWMPAJBYRY-UHFFFAOYSA-N 5-chloropyridin-2-amine;(4-nitrophenyl) n-(5-chloropyridin-2-yl)carbamate Chemical compound NC1=CC=C(Cl)C=N1.C1=CC([N+](=O)[O-])=CC=C1OC(=O)NC1=CC=C(Cl)C=N1 BPVZXWMPAJBYRY-UHFFFAOYSA-N 0.000 description 1
- IVILGUFRMDBUEQ-UHFFFAOYSA-N 5-iodopyridin-2-amine Chemical compound NC1=CC=C(I)C=N1 IVILGUFRMDBUEQ-UHFFFAOYSA-N 0.000 description 1
- XKVUYEYANWFIJX-UHFFFAOYSA-N 5-methyl-1h-pyrazole Chemical compound CC1=CC=NN1 XKVUYEYANWFIJX-UHFFFAOYSA-N 0.000 description 1
- UGSBCCAHDVCHGI-UHFFFAOYSA-N 5-nitropyridin-2-amine Chemical compound NC1=CC=C([N+]([O-])=O)C=N1 UGSBCCAHDVCHGI-UHFFFAOYSA-N 0.000 description 1
- 125000004070 6 membered heterocyclic group Chemical class 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 206010002388 Angina unstable Diseases 0.000 description 1
- 101710163968 Antistasin Proteins 0.000 description 1
- 108010011485 Aspartame Proteins 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- 102000004506 Blood Proteins Human genes 0.000 description 1
- 108010017384 Blood Proteins Proteins 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 241000167854 Bourreria succulenta Species 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- WYMGIGWOPVSUSI-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1C(CCC1)C(NC1=CC=C(C=C1)C#N)=O.C(#N)C1=CC=C(C=C1)NC(=O)C1NCCC1 Chemical compound C(C)(C)(C)OC(=O)N1C(CCC1)C(NC1=CC=C(C=C1)C#N)=O.C(#N)C1=CC=C(C=C1)NC(=O)C1NCCC1 WYMGIGWOPVSUSI-UHFFFAOYSA-N 0.000 description 1
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 1
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 206010065559 Cerebral arteriosclerosis Diseases 0.000 description 1
- 206010008088 Cerebral artery embolism Diseases 0.000 description 1
- 206010008092 Cerebral artery thrombosis Diseases 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 206010011091 Coronary artery thrombosis Diseases 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- 206010051055 Deep vein thrombosis Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
- 206010014513 Embolism arterial Diseases 0.000 description 1
- 108010062466 Enzyme Precursors Proteins 0.000 description 1
- 102000010911 Enzyme Precursors Human genes 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- 108010074105 Factor Va Proteins 0.000 description 1
- 108010071289 Factor XIII Proteins 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 229910004373 HOAc Inorganic materials 0.000 description 1
- 206010062713 Haemorrhagic diathesis Diseases 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- 238000003820 Medium-pressure liquid chromatography Methods 0.000 description 1
- 244000246386 Mentha pulegium Species 0.000 description 1
- 235000016257 Mentha pulegium Nutrition 0.000 description 1
- 235000004357 Mentha x piperita Nutrition 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- BXEFQPCKQSTMKA-UHFFFAOYSA-N OC(=O)C=[N+]=[N-] Chemical compound OC(=O)C=[N+]=[N-] BXEFQPCKQSTMKA-UHFFFAOYSA-N 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-L Phosphate ion(2-) Chemical compound OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 108010094028 Prothrombin Proteins 0.000 description 1
- 102100027378 Prothrombin Human genes 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- 206010063544 Renal embolism Diseases 0.000 description 1
- 206010038563 Reocclusion Diseases 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 1
- 108090000373 Tissue Plasminogen Activator Proteins 0.000 description 1
- 102000003978 Tissue Plasminogen Activator Human genes 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- 208000007814 Unstable Angina Diseases 0.000 description 1
- 208000024248 Vascular System injury Diseases 0.000 description 1
- 208000012339 Vascular injury Diseases 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 239000002250 absorbent Substances 0.000 description 1
- 230000002745 absorbent Effects 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- IPBVNPXQWQGGJP-UHFFFAOYSA-N acetic acid phenyl ester Natural products CC(=O)OC1=CC=CC=C1 IPBVNPXQWQGGJP-UHFFFAOYSA-N 0.000 description 1
- HFBMWMNUJJDEQZ-UHFFFAOYSA-N acryloyl chloride Chemical compound ClC(=O)C=C HFBMWMNUJJDEQZ-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 125000002015 acyclic group Chemical group 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 150000003973 alkyl amines Chemical group 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- AEMOLEFTQBMNLQ-BKBMJHBISA-N alpha-D-galacturonic acid Chemical compound O[C@H]1O[C@H](C(O)=O)[C@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-BKBMJHBISA-N 0.000 description 1
- 230000006229 amino acid addition Effects 0.000 description 1
- 125000005214 aminoheteroaryl group Chemical class 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 229960004676 antithrombotic agent Drugs 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 159000000032 aromatic acids Chemical class 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 1
- 239000000605 aspartame Substances 0.000 description 1
- 229960003438 aspartame Drugs 0.000 description 1
- 235000010357 aspartame Nutrition 0.000 description 1
- 238000000065 atmospheric pressure chemical ionisation Methods 0.000 description 1
- 150000007514 bases Chemical class 0.000 description 1
- JUHORIMYRDESRB-UHFFFAOYSA-N benzathine Chemical compound C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 JUHORIMYRDESRB-UHFFFAOYSA-N 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 230000036765 blood level Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000006189 buccal tablet Substances 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 201000002676 cerebral atherosclerosis Diseases 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 235000019693 cherries Nutrition 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- KVSASDOGYIBWTA-UHFFFAOYSA-N chloro benzoate Chemical compound ClOC(=O)C1=CC=CC=C1 KVSASDOGYIBWTA-UHFFFAOYSA-N 0.000 description 1
- FZFAMSAMCHXGEF-UHFFFAOYSA-N chloro formate Chemical compound ClOC=O FZFAMSAMCHXGEF-UHFFFAOYSA-N 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- VDANGULDQQJODZ-UHFFFAOYSA-N chloroprocaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1Cl VDANGULDQQJODZ-UHFFFAOYSA-N 0.000 description 1
- 229960002023 chloroprocaine Drugs 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- 239000003593 chromogenic compound Substances 0.000 description 1
- 239000004927 clay Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- JNGZXGGOCLZBFB-IVCQMTBJSA-N compound E Chemical compound N([C@@H](C)C(=O)N[C@@H]1C(N(C)C2=CC=CC=C2C(C=2C=CC=CC=2)=N1)=O)C(=O)CC1=CC(F)=CC(F)=C1 JNGZXGGOCLZBFB-IVCQMTBJSA-N 0.000 description 1
- 208000002528 coronary thrombosis Diseases 0.000 description 1
- 210000004351 coronary vessel Anatomy 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 239000003405 delayed action preparation Substances 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 150000008049 diazo compounds Chemical class 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- 150000001991 dicarboxylic acids Chemical class 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 229940043237 diethanolamine Drugs 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-M dihydrogenphosphate Chemical compound OP(O)([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-M 0.000 description 1
- UGMCXQCYOVCMTB-UHFFFAOYSA-K dihydroxy(stearato)aluminium Chemical compound CCCCCCCCCCCCCCCCCC(=O)O[Al](O)O UGMCXQCYOVCMTB-UHFFFAOYSA-K 0.000 description 1
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 1
- 235000011180 diphosphates Nutrition 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000002612 dispersion medium Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- YVPJCJLMRRTDMQ-UHFFFAOYSA-N ethyl diazoacetate Chemical compound CCOC(=O)C=[N+]=[N-] YVPJCJLMRRTDMQ-UHFFFAOYSA-N 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 238000013213 extrapolation Methods 0.000 description 1
- 239000004744 fabric Substances 0.000 description 1
- 229940012444 factor xiii Drugs 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 150000002191 fatty alcohols Chemical class 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 230000020764 fibrinolysis Effects 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- FVIZARNDLVOMSU-UHFFFAOYSA-N ginsenoside K Natural products C1CC(C2(CCC3C(C)(C)C(O)CCC3(C)C2CC2O)C)(C)C2C1C(C)(CCC=C(C)C)OC1OC(CO)C(O)C(O)C1O FVIZARNDLVOMSU-UHFFFAOYSA-N 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 125000005908 glyceryl ester group Chemical group 0.000 description 1
- 239000001087 glyceryl triacetate Substances 0.000 description 1
- 235000013773 glyceryl triacetate Nutrition 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 230000000004 hemodynamic effect Effects 0.000 description 1
- 208000031169 hemorrhagic disease Diseases 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 235000001050 hortel pimenta Nutrition 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 150000002462 imidazolines Chemical class 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 201000004332 intermediate coronary syndrome Diseases 0.000 description 1
- 201000005851 intracranial arteriosclerosis Diseases 0.000 description 1
- 201000010849 intracranial embolism Diseases 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 230000007794 irritation 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
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 1
- QRXWMOHMRWLFEY-UHFFFAOYSA-N isoniazide Chemical compound NNC(=O)C1=CC=NC=C1 QRXWMOHMRWLFEY-UHFFFAOYSA-N 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- XMGQYMWWDOXHJM-UHFFFAOYSA-N limonene Chemical compound CC(=C)C1CCC(C)=CC1 XMGQYMWWDOXHJM-UHFFFAOYSA-N 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 239000006210 lotion 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
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 125000005341 metaphosphate group Chemical group 0.000 description 1
- TWXDDNPPQUTEOV-FVGYRXGTSA-N methamphetamine hydrochloride Chemical compound Cl.CN[C@@H](C)CC1=CC=CC=C1 TWXDDNPPQUTEOV-FVGYRXGTSA-N 0.000 description 1
- 229940095102 methyl benzoate Drugs 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- OSWPMRLSEDHDFF-UHFFFAOYSA-N methyl salicylate Chemical compound COC(=O)C1=CC=CC=C1O OSWPMRLSEDHDFF-UHFFFAOYSA-N 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- KFIGICHILYTCJF-UHFFFAOYSA-N n'-methylethane-1,2-diamine Chemical compound CNCCN KFIGICHILYTCJF-UHFFFAOYSA-N 0.000 description 1
- NOKGYCHGXQQITG-UHFFFAOYSA-N n-(4-cyanophenyl)pyrrolidine-2-carboxamide Chemical compound C1CCNC1C(=O)NC1=CC=C(C#N)C=C1 NOKGYCHGXQQITG-UHFFFAOYSA-N 0.000 description 1
- SEDMCVCCUYHFOF-UHFFFAOYSA-N n-[4-(2-methylsulfonylphenyl)phenyl]pyrrolidine-2-carboxamide Chemical compound CS(=O)(=O)C1=CC=CC=C1C(C=C1)=CC=C1NC(=O)C1NCCC1 SEDMCVCCUYHFOF-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
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 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
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-M octanoate Chemical compound CCCCCCCC([O-])=O WWZKQHOCKIZLMA-UHFFFAOYSA-M 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000007968 orange flavor Substances 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 239000012026 peptide coupling reagents Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229960003742 phenol Drugs 0.000 description 1
- DGTNSSLYPYDJGL-UHFFFAOYSA-N phenyl isocyanate Chemical group O=C=NC1=CC=CC=C1 DGTNSSLYPYDJGL-UHFFFAOYSA-N 0.000 description 1
- 229940049953 phenylacetate Drugs 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 230000009124 positive feedback regulation Effects 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 230000002947 procoagulating effect Effects 0.000 description 1
- 150000003147 proline derivatives Chemical class 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 230000002797 proteolythic effect Effects 0.000 description 1
- 229940039716 prothrombin Drugs 0.000 description 1
- 108010014806 prothrombinase complex Proteins 0.000 description 1
- 238000006862 quantum yield reaction Methods 0.000 description 1
- 238000011555 rabbit model Methods 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 238000011552 rat model Methods 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 108091006091 regulatory enzymes Proteins 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 229940116351 sebacate Drugs 0.000 description 1
- CXMXRPHRNRROMY-UHFFFAOYSA-L sebacate(2-) Chemical compound [O-]C(=O)CCCCCCCCC([O-])=O CXMXRPHRNRROMY-UHFFFAOYSA-L 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- XGVXKJKTISMIOW-ZDUSSCGKSA-N simurosertib Chemical compound N1N=CC(C=2SC=3C(=O)NC(=NC=3C=2)[C@H]2N3CCC(CC3)C2)=C1C XGVXKJKTISMIOW-ZDUSSCGKSA-N 0.000 description 1
- 239000000344 soap Substances 0.000 description 1
- 229940083542 sodium Drugs 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 239000007892 solid unit dosage form Substances 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 238000012289 standard assay Methods 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- QEJYMLJTWPHESG-CRAIPNDOSA-N tert-butyl (2r,4r)-2-[[2-fluoro-4-(2-oxopiperidin-1-yl)phenyl]carbamoyl]-4-methoxypyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1C[C@H](OC)C[C@@H]1C(=O)NC1=CC=C(N2C(CCCC2)=O)C=C1F QEJYMLJTWPHESG-CRAIPNDOSA-N 0.000 description 1
- PHPUYKMSWQZLQH-CRAIPNDOSA-N tert-butyl (2r,4r)-2-[[2-fluoro-4-(3-methylpyrazol-1-yl)phenyl]carbamoyl]-4-methoxypyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1C[C@H](OC)C[C@@H]1C(=O)NC1=CC=C(N2N=C(C)C=C2)C=C1F PHPUYKMSWQZLQH-CRAIPNDOSA-N 0.000 description 1
- UXQKXLREJKIIKO-CRAIPNDOSA-N tert-butyl (2r,4r)-4-[tert-butyl(dimethyl)silyl]oxy-2-[(2-fluoro-4-iodophenyl)carbamoyl]pyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@@H]1C(=O)NC1=CC=C(I)C=C1F UXQKXLREJKIIKO-CRAIPNDOSA-N 0.000 description 1
- URZGEDXCEIOBPR-ATIYNZHBSA-N tert-butyl (2r,4r)-4-[tert-butyl(dimethyl)silyl]oxy-2-[[4-[2-(tert-butylsulfamoyl)-5-fluorophenyl]-2-fluorophenyl]carbamoyl]pyrrolidine-1-carboxylate Chemical compound CC(C)(C)NS(=O)(=O)C1=CC=C(F)C=C1C(C=C1F)=CC=C1NC(=O)[C@@H]1N(C(=O)OC(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)C1 URZGEDXCEIOBPR-ATIYNZHBSA-N 0.000 description 1
- XSMPFSIHOGPCFT-UHFFFAOYSA-N tert-butyl 2-[(4-cyanophenyl)carbamoyl]pyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCC1C(=O)NC1=CC=C(C#N)C=C1 XSMPFSIHOGPCFT-UHFFFAOYSA-N 0.000 description 1
- BAYSFDWZTCAJQW-UHFFFAOYSA-N tert-butyl 2-[[2-fluoro-4-(2-methylsulfonylphenyl)phenyl]carbamoyl]pyrrolidine-1-carboxylate N-[2-fluoro-4-(2-methylsulfonylphenyl)phenyl]pyrrolidine-2-carboxamide Chemical compound C(C)(C)(C)OC(=O)N1C(CCC1)C(NC1=C(C=C(C=C1)C1=C(C=CC=C1)S(=O)(=O)C)F)=O.FC=1C=C(C=CC1NC(=O)C1NCCC1)C1=C(C=CC=C1)S(=O)(=O)C BAYSFDWZTCAJQW-UHFFFAOYSA-N 0.000 description 1
- OUXTYEWOOUEDIN-UHFFFAOYSA-N tert-butyl 2-[[2-methyl-4-(2-methylsulfanylphenyl)phenyl]carbamoyl]pyrrolidine-1-carboxylate Chemical compound CSC1=CC=CC=C1C(C=C1C)=CC=C1NC(=O)C1N(C(=O)OC(C)(C)C)CCC1 OUXTYEWOOUEDIN-UHFFFAOYSA-N 0.000 description 1
- ZZHJNRSJEZVOEH-UHFFFAOYSA-N tert-butyl 2-[[2-methyl-4-(2-methylsulfonylphenyl)phenyl]carbamoyl]pyrrolidine-1-carboxylate Chemical compound CC1=CC(C=2C(=CC=CC=2)S(C)(=O)=O)=CC=C1NC(=O)C1CCCN1C(=O)OC(C)(C)C ZZHJNRSJEZVOEH-UHFFFAOYSA-N 0.000 description 1
- BGWSFSNURLNMIH-UHFFFAOYSA-N tert-butyl 2-[[4-(2-methylsulfonylphenyl)phenyl]carbamoyl]pyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCC1C(=O)NC1=CC=C(C=2C(=CC=CC=2)S(C)(=O)=O)C=C1 BGWSFSNURLNMIH-UHFFFAOYSA-N 0.000 description 1
- KXMWFRHQHOKJOJ-UHFFFAOYSA-N tert-butyl 2-[[4-(2-methylsulfonylphenyl)phenyl]carbamoyl]pyrrolidine-1-carboxylate N-[4-(2-methylsulfonylphenyl)phenyl]pyrrolidine-2-carboxamide Chemical compound C(C)(C)(C)OC(=O)N1C(CCC1)C(NC1=CC=C(C=C1)C1=C(C=CC=C1)S(=O)(=O)C)=O.CS(=O)(=O)C1=C(C=CC=C1)C1=CC=C(C=C1)NC(=O)C1NCCC1 KXMWFRHQHOKJOJ-UHFFFAOYSA-N 0.000 description 1
- UXQKXLREJKIIKO-UHFFFAOYSA-N tert-butyl 4-[tert-butyl(dimethyl)silyl]oxy-2-[(2-fluoro-4-iodophenyl)carbamoyl]pyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC(O[Si](C)(C)C(C)(C)C)CC1C(=O)NC1=CC=C(I)C=C1F UXQKXLREJKIIKO-UHFFFAOYSA-N 0.000 description 1
- URZGEDXCEIOBPR-UHFFFAOYSA-N tert-butyl 4-[tert-butyl(dimethyl)silyl]oxy-2-[[4-[2-(tert-butylsulfamoyl)-5-fluorophenyl]-2-fluorophenyl]carbamoyl]pyrrolidine-1-carboxylate Chemical compound CC(C)(C)NS(=O)(=O)C1=CC=C(F)C=C1C(C=C1F)=CC=C1NC(=O)C1N(C(=O)OC(C)(C)C)CC(O[Si](C)(C)C(C)(C)C)C1 URZGEDXCEIOBPR-UHFFFAOYSA-N 0.000 description 1
- LFKDJXLFVYVEFG-UHFFFAOYSA-N tert-butyl carbamate Chemical compound CC(C)(C)OC(N)=O LFKDJXLFVYVEFG-UHFFFAOYSA-N 0.000 description 1
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 1
- CQKAPARXKPTKBK-UHFFFAOYSA-N tert-butylazanium;bromide Chemical compound Br.CC(C)(C)N CQKAPARXKPTKBK-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- 230000002537 thrombolytic effect Effects 0.000 description 1
- 201000005060 thrombophlebitis Diseases 0.000 description 1
- 108010065972 tick anticoagulant peptide Proteins 0.000 description 1
- 229960000187 tissue plasminogen activator Drugs 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 229960002622 triacetin Drugs 0.000 description 1
- NHDIQVFFNDKAQU-UHFFFAOYSA-N tripropan-2-yl borate Chemical compound CC(C)OB(OC(C)C)OC(C)C NHDIQVFFNDKAQU-UHFFFAOYSA-N 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
- 229930195735 unsaturated hydrocarbon Natural products 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 201000002282 venous insufficiency Diseases 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 235000012431 wafers Nutrition 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 239000009637 wintergreen oil Substances 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
- C07D231/02—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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
-
- 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
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- 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
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/20—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member 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
- C07D207/24—Oxygen or sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member 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
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member 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
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
- C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D211/74—Oxygen atoms
- C07D211/76—Oxygen atoms attached in position 2 or 6
-
- 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
- C07D231/06—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
- C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
- C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having 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
- C07D237/14—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
-
- 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
- C07D401/04—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 directly linked by a ring-member-to-ring-member bond
-
- 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
- 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
- C07D403/02—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 two hetero rings
- C07D403/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Hospice & Palliative Care (AREA)
- Endocrinology (AREA)
- Obesity (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Emergency Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Enzymes And Modification Thereof (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pyrrole Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Peptides Or Proteins (AREA)
- Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Hydrogenated Pyridines (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US33416801P | 2001-11-29 | 2001-11-29 | |
US38489502P | 2002-05-31 | 2002-05-31 | |
IB0233416 | 2002-11-14 |
Publications (2)
Publication Number | Publication Date |
---|---|
NO20042270L NO20042270L (no) | 2004-06-01 |
NO327006B1 true NO327006B1 (no) | 2009-04-06 |
Family
ID=26989068
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO20042270A NO327006B1 (no) | 2001-11-29 | 2004-06-01 | Inhibitor av faktor XA og andre serinin proteaser involvert i koagulasjonskaskaden, samt anvendelse og fremgangsmate for fremstilling derav og farmasoytisk sammensetning |
Country Status (42)
Families Citing this family (90)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
TWI288745B (en) | 2000-04-05 | 2007-10-21 | Daiichi Seiyaku Co | Ethylenediamine derivatives |
DE10113379B4 (de) * | 2001-03-20 | 2006-08-24 | Karl Eugen Fischer Gmbh Maschinenfabrik | Vorschubeinrichtung, insbesondere für Cordbänder |
WO2003000657A1 (fr) | 2001-06-20 | 2003-01-03 | Daiichi Pharmaceutical Co., Ltd. | Derives de diamine |
US7030141B2 (en) * | 2001-11-29 | 2006-04-18 | Christopher Franklin Bigge | Inhibitors of factor Xa and other serine proteases involved in the coagulation cascade |
KR20030080810A (ko) * | 2002-04-11 | 2003-10-17 | 주식회사 엘지생명과학 | 아미노피리도아릴 그룹을 가진 선택적 트롬빈 억제제 |
US20040138269A1 (en) * | 2002-10-11 | 2004-07-15 | Sugen, Inc. | Substituted pyrroles as kinase inhibitors |
US7205318B2 (en) | 2003-03-18 | 2007-04-17 | Bristol-Myers Squibb Company | Lactam-containing cyclic diamines and derivatives as a factor Xa inhibitors |
DE10329457A1 (de) * | 2003-04-03 | 2005-01-20 | Merck Patent Gmbh | Ethinylprolinderivate |
EP1720844B1 (fr) * | 2003-04-03 | 2009-04-29 | MERCK PATENT GmbH | Derives pyrrolidino-1,2-dicarboxy-1-(phenylamide)-2-(4-(3-oxo-morpholino-4-yl9-phenylamide) et composes similaires pour l'utilisation comme inhibiteurs du facteur xa pour le traitement de maladies thromboemboliques |
KR20060023154A (ko) * | 2003-06-18 | 2006-03-13 | 메르크 파텐트 게엠베하 | 혈전증 치료용 응고 인자 xa 및 viia의 저해제로서의피롤리딘-1,2-디카르복실산-1-[(4-에티닐-페닐)-아미드]-2-[(페닐)-아미드] 유도체 |
EP1670739A4 (fr) | 2003-10-08 | 2007-08-08 | Bristol Myers Squibb Co | Diamines cycliques et derives comme inhibiteurs du facteur xa |
DE10358814A1 (de) * | 2003-12-16 | 2005-07-21 | Merck Patent Gmbh | Prolinylarylacetamide |
WO2005085200A1 (fr) * | 2004-03-05 | 2005-09-15 | Banyu Pharmaceutical Co., Ltd. | Dérivé pyridone |
DE102004014945A1 (de) * | 2004-03-26 | 2005-10-13 | Merck Patent Gmbh | Prolinylderivate |
US7550487B2 (en) * | 2004-03-26 | 2009-06-23 | Hoffmann-La Roche Inc. | Pyrrolidine-3,4-dicarboxamide derivatives |
DE102004016605A1 (de) * | 2004-04-03 | 2005-10-20 | Merck Patent Gmbh | Thiocarbamoylproline |
TWI350168B (en) | 2004-05-07 | 2011-10-11 | Incyte Corp | Amido compounds and their use as pharmaceuticals |
EP1768954A4 (fr) | 2004-06-24 | 2008-05-28 | Incyte Corp | 2-methylpropanamides et leur utilisation en tant que pharmaceutiques |
DE102004045796A1 (de) * | 2004-09-22 | 2006-03-23 | Merck Patent Gmbh | Arzneimittel enthaltend Carbonylverbindungen sowie deren Verwendung |
DE102004047254A1 (de) * | 2004-09-29 | 2006-04-13 | Merck Patent Gmbh | Carbonylverbindungen |
DE102004047255A1 (de) * | 2004-09-29 | 2006-04-13 | Merck Patent Gmbh | Prolinderivate |
WO2006038119A1 (fr) * | 2004-10-08 | 2006-04-13 | Warner-Lambert Company Llc | Synthese stereoselective d'alcoxy-prolines n-protegees |
CA2585615C (fr) * | 2004-11-03 | 2013-11-26 | F. Hoffmann-La Roche Ag | Nouveaux derives de dicarboxamide |
CN101103003A (zh) * | 2004-11-16 | 2008-01-09 | 詹森药业有限公司 | 用作选择性雄激素受体调节剂(sarms)的新的杂环衍生物 |
EP1891044A1 (fr) | 2005-03-24 | 2008-02-27 | Warner-Lambert Company LLC | Formes cristallines d'un inhibiteur pyrrolidine connu du facteur xa |
DE102005017116A1 (de) * | 2005-04-13 | 2006-10-26 | Novartis Ag | Hemmstoffe für Inhibitoren von Apoptose Proteinen (IAP) |
SI1928454T1 (sl) | 2005-05-10 | 2015-01-30 | Intermune, Inc. | Piridonski derivati za moduliranje s stresom aktiviranega protein kinaznega sistema |
KR101083506B1 (ko) | 2005-07-15 | 2011-11-16 | 에프. 호프만-라 로슈 아게 | 신규한 헤테로아릴 융합된 환형 아민 |
US7678917B2 (en) | 2005-09-01 | 2010-03-16 | Hoffman-La Roche Inc. | Factor Xa inhibitors |
WO2007053610A2 (fr) * | 2005-11-01 | 2007-05-10 | The Regents Of The University Of California | Traitement de la fibrillation auriculaire a base de pirfenidone |
AU2006314637A1 (en) | 2005-11-16 | 2007-05-24 | F. Hoffmann-La Roche Ag | Novel pyrrolidine derivatives as inhibitors of coagulation factor Xa |
CA2633541A1 (fr) * | 2005-12-12 | 2007-06-21 | Genelabs Technologies, Inc. | Composes antiviraux n-(noyau aromatique a 6 chainons) amido |
WO2007084314A2 (fr) * | 2006-01-12 | 2007-07-26 | Incyte Corporation | MODULATEURS de la 11-ß HYDROXYSTEROIDE DESHYDROGENASE DE TYPE 1, LEURS COMPOSITIONS PHARMACEUTIQUES ET LEURS PROCEDES D'UTILISATION |
EP1847537A1 (fr) | 2006-04-21 | 2007-10-24 | F. Hoffmann-La Roche Ag | Dérivés de dicarboxamide |
EP2051975B1 (fr) * | 2006-05-16 | 2012-09-12 | Boehringer Ingelheim International GmbH | Prolinamides substitués, procédé de production et utilisation de ceux-ci comme médicaments |
WO2008044700A1 (fr) * | 2006-10-11 | 2008-04-17 | Takeda Pharmaceutical Company Limited | INHIBITEUR DE LA GSK-3β |
TW200827368A (en) * | 2006-11-21 | 2008-07-01 | Genelabs Tech Inc | Amido anti-viral compounds |
EP2086962A1 (fr) * | 2006-11-29 | 2009-08-12 | Pfizer Products Inc. | 1- [ ( 4 -chlorophényl) amide 5-{[2-fluoro-4- (2-oxo-2h-pyridin-1-yl) -phényl]amide) d'acide (r) -5-méthyl-4, 5-dihydro- pyrazole-1, 5-dicarboxylique servant d'inhibiteur du facteur xa |
EP2129660A2 (fr) | 2006-12-19 | 2009-12-09 | Pfizer Products Inc. | Dérivés de nicotinamide en tant qu'inhibiteurs de h-pgds et leur utilisation pour le traitement de maladies liées aux prostaglandines d2 |
KR101473207B1 (ko) | 2007-04-13 | 2014-12-16 | 밀레니엄 파머슈티컬스 인코퍼레이티드 | Xa 인자 억제제로서 작용하는 화합물과의 병용 항응고 요법 |
TW200911787A (en) * | 2007-07-03 | 2009-03-16 | Astrazeneca Ab | New aza-bicyclohexane compounds useful as inhibitors of thrombin |
DK2227466T3 (da) * | 2007-11-30 | 2011-08-08 | Bayer Schering Pharma Ag | Heteroaryl-substituerede piperidiner |
JP5627574B2 (ja) | 2008-06-03 | 2014-11-19 | インターミューン, インコーポレイテッド | 炎症性および線維性疾患を治療するための化合物および方法 |
US8703761B2 (en) * | 2008-07-15 | 2014-04-22 | Novartis Ag | Organic compounds |
RU2012114770A (ru) * | 2009-09-04 | 2013-10-10 | Вандербилт Юниверсити | АЛЛОСТЕРИЧЕСКИЕ СРЕДСТВА ПОТЕНЦИРОВАНИЯ mGluR4, КОМПОЗИЦИИ И СПОСОБЫ ЛЕЧЕНИЯ НЕВРОЛОГИЧЕСКИХ ДИСФУНКЦИЙ |
US8377970B2 (en) | 2009-10-08 | 2013-02-19 | Rhizen Pharmaceuticals Sa | Modulators of calcium release-activated calcium channel |
US8993612B2 (en) | 2009-10-08 | 2015-03-31 | Rhizen Pharmaceuticals Sa | Modulators of calcium release-activated calcium channel and methods for treatment of non-small cell lung cancer |
KR20140027090A (ko) | 2011-01-04 | 2014-03-06 | 노파르티스 아게 | 연령-관련 황반 변성 (amd)의 치료에 유용한 인돌 화합물 또는 그의 유사체 |
WO2013102242A1 (fr) | 2012-01-06 | 2013-07-11 | Spinifex Pharmaceuticals Pty Ltd | Composés hétérocycliques et procédés pour leur utilisation |
CN117736134A (zh) * | 2012-01-12 | 2024-03-22 | 耶鲁大学 | 通过e3泛素连接酶增强靶蛋白质及其他多肽降解的化合物和方法 |
EP2867229B1 (fr) | 2012-06-28 | 2017-07-26 | Novartis AG | Dérivés pyrrolidine et leur utilisation en tant que modulateurs de la voie du complément |
ES2647124T3 (es) | 2012-06-28 | 2017-12-19 | Novartis Ag | Derivados de pirrolidina y su uso como moduladores de la ruta del complemento |
JP6209605B2 (ja) | 2012-06-28 | 2017-10-04 | ノバルティス アーゲー | ピロリジン誘導体、および補体経路調節因子としてのその使用 |
US9487483B2 (en) | 2012-06-28 | 2016-11-08 | Novartis Ag | Complement pathway modulators and uses thereof |
JP6273274B2 (ja) | 2012-06-28 | 2018-01-31 | ノバルティス アーゲー | 補体経路モジュレーターおよびその使用 |
EP2872503B1 (fr) | 2012-07-12 | 2018-06-20 | Novartis AG | Modulateurs de trajet de complément et leurs utilisations |
MX2015000830A (es) * | 2012-07-18 | 2015-10-26 | Sunshine Lake Pharma Co Ltd | Derivados heterociclicos nitrogenosos y su aplicacion en farmacos. |
AR092742A1 (es) | 2012-10-02 | 2015-04-29 | Intermune Inc | Piridinonas antifibroticas |
EA201300843A1 (ru) * | 2013-08-01 | 2015-04-30 | Арсений Валерьевич Айбушев | Карбамоилфенильные производные для остановки, предотвращения и профилактики кровотечений или усиления системы гемостаза |
CN103570699A (zh) * | 2013-09-29 | 2014-02-12 | 北京万全德众医药生物技术有限公司 | 一种制备普卡必利的方法 |
EP3828173B1 (fr) * | 2014-03-07 | 2022-08-31 | BioCryst Pharmaceuticals, Inc. | Pyrazoles substitués en tant qu`inhibiteurs de la kallicréine plasmatique humaine |
KR102373700B1 (ko) | 2014-04-02 | 2022-03-11 | 인터뮨, 인크. | 항섬유성 피리디논 |
US20170327469A1 (en) | 2015-01-20 | 2017-11-16 | Arvinas, Inc. | Compounds and methods for the targeted degradation of androgen receptor |
KR20230175343A (ko) | 2015-03-18 | 2023-12-29 | 아비나스 오퍼레이션스, 인코포레이티드 | 타겟화된 단백질들의 향상된 분해를 위한 화합물들 및 방법들 |
EP3302482A4 (fr) | 2015-06-05 | 2018-12-19 | Arvinas, Inc. | Tank-binding kinase-1 protacs et procédés d'utilisation associés |
US10772962B2 (en) | 2015-08-19 | 2020-09-15 | Arvinas Operations, Inc. | Compounds and methods for the targeted degradation of bromodomain-containing proteins |
SI3355890T1 (sl) | 2015-10-01 | 2022-04-29 | Biocryst Pharmaceuticals, Inc. | Inhibitorji kalikreina človeške plazme |
EP3512842B1 (fr) | 2016-09-15 | 2024-01-17 | Arvinas, Inc. | Dérivés d'indole en tant qu'agents de dégradation des récepteurs de l'estrogène |
WO2018071606A1 (fr) | 2016-10-11 | 2018-04-19 | Arvinas, Inc. | Composés et procédés pour la dégradation ciblée du récepteur des androgènes |
US11458123B2 (en) | 2016-11-01 | 2022-10-04 | Arvinas Operations, Inc. | Tau-protein targeting PROTACs and associated methods of use |
EP3689868B1 (fr) | 2016-12-01 | 2023-09-27 | Arvinas Operations, Inc. | Dérivés de tétrahydronaphtalène et de tétrahydroisoquinoléine en tant qu'agents de dégradation des récepteurs des oestrogènes |
US11173211B2 (en) | 2016-12-23 | 2021-11-16 | Arvinas Operations, Inc. | Compounds and methods for the targeted degradation of rapidly accelerated Fibrosarcoma polypeptides |
BR112019012682A2 (pt) | 2016-12-23 | 2019-12-17 | Arvinas Operations Inc | moléculas quiméricas visando a proteólise de egfr e métodos associados de uso |
CA3047784A1 (fr) | 2016-12-23 | 2018-06-28 | Arvinas Operations, Inc. | Composes et methodes pour la degradation ciblee de polypeptides de fibrosarcome rapidement accelere |
EP3559006A4 (fr) | 2016-12-23 | 2021-03-03 | Arvinas Operations, Inc. | Composés et procédés pour la dégradation ciblée de polypeptides de kinase du foie f tal |
US11191741B2 (en) | 2016-12-24 | 2021-12-07 | Arvinas Operations, Inc. | Compounds and methods for the targeted degradation of enhancer of zeste homolog 2 polypeptide |
KR20230140606A (ko) | 2017-01-26 | 2023-10-06 | 아비나스 오퍼레이션스, 인코포레이티드 | 에스트로겐 수용체 단백질 분해 조절제 및 관련 사용 방법 |
CN111132673A (zh) | 2017-05-03 | 2020-05-08 | 维瓦斯治疗公司 | 非稠合三环化合物 |
US11192865B2 (en) | 2017-08-21 | 2021-12-07 | Vivace Therapeutics, Inc. | Benzosulfonyl compounds |
US11065231B2 (en) | 2017-11-17 | 2021-07-20 | Arvinas Operations, Inc. | Compounds and methods for the targeted degradation of interleukin-1 receptor- associated kinase 4 polypeptides |
CA3084648A1 (fr) | 2017-12-06 | 2019-06-13 | Vivace Therapeutics, Inc. | Composes benzocarbonyle |
CN110240591A (zh) * | 2018-03-08 | 2019-09-17 | 天津药物研究院有限公司 | 脯氨酸衍生物及其制备方法和用途 |
WO2019185868A1 (fr) * | 2018-03-29 | 2019-10-03 | Centre National De La Recherche Scientifique | Modulateurs p2rx7 utilisés en thérapie |
CN112218859A (zh) | 2018-04-04 | 2021-01-12 | 阿尔维纳斯运营股份有限公司 | 蛋白水解调节剂及相关使用方法 |
EP3793551A4 (fr) | 2018-05-16 | 2022-01-26 | Vivace Therapeutics, Inc. | Composés d'oxadiazole |
WO2020041331A1 (fr) | 2018-08-20 | 2020-02-27 | Arvinas Operations, Inc. | Composé chimère ciblant la protéolyse (protac) ayant une activité de liaison à l'ubiquitine ligase e3 et ciblant une protéine alpha-synucléine pour le traitement de maladies neurodégénératives |
EP3999182A1 (fr) | 2019-07-17 | 2022-05-25 | Arvinas Operations, Inc. | Composés ciblant la protéine tau et procédés d'utilisation associés |
US11883393B2 (en) | 2019-12-19 | 2024-01-30 | Arvinas Operations, Inc. | Compounds and methods for the targeted degradation of androgen receptor |
WO2021231174A1 (fr) | 2020-05-09 | 2021-11-18 | Arvinas Operations, Inc. | Procédés de fabrication d'un composé bifonctionnel, formes ultra-pures du composé bifonctionnel, et formes posologiques les comprenant |
WO2024054591A1 (fr) | 2022-09-07 | 2024-03-14 | Arvinas Operations, Inc. | Composés de dégradation de fibrosarcome rapidement accéléré (raf) et procédés d'utilisation associés |
Family Cites Families (37)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US91116A (en) * | 1869-06-08 | Improvement in guard for door-knobs | ||
US2947755A (en) * | 1959-02-05 | 1960-08-02 | Wallace & Tiernan Inc | Substituted 1-m-aminophenyl-2-pyridones |
US4559157A (en) * | 1983-04-21 | 1985-12-17 | Creative Products Resource Associates, Ltd. | Cosmetic applicator useful for skin moisturizing |
LU84979A1 (fr) * | 1983-08-30 | 1985-04-24 | Oreal | Composition cosmetique ou pharmaceutique sous forme aqueuse ou anhydre dont la phase grasse contient un polyether oligomere et polyethers oligomeres nouveaux |
US4820508A (en) * | 1987-06-23 | 1989-04-11 | Neutrogena Corporation | Skin protective composition |
US4992478A (en) * | 1988-04-04 | 1991-02-12 | Warner-Lambert Company | Antiinflammatory skin moisturizing composition and method of preparing same |
US4938949A (en) * | 1988-09-12 | 1990-07-03 | University Of New York | Treatment of damaged bone marrow and dosage units therefor |
US5118691A (en) * | 1990-09-20 | 1992-06-02 | Warner-Lambert Co. | Substituted tetrahydropyridines as central nervous system agents |
DE4326465A1 (de) * | 1993-01-20 | 1995-02-09 | Thomae Gmbh Dr K | Aminosäurederivate, diese Verbindungen enthaltende Arzneimittel und Verfahren zu ihrer Herstellung |
US5681844A (en) | 1994-04-18 | 1997-10-28 | Corvas International, Inc. | Methionine sulfone and s-substituted cysteine sulfone derivatives as enzyme inhibitors |
GB9515489D0 (en) | 1995-07-28 | 1995-09-27 | Sandoz Ltd | Organic compounds |
DE19544687A1 (de) | 1995-11-30 | 1997-06-05 | Thomae Gmbh Dr K | Aminosäurederivate, diese Verbindungen enthaltende Arzneimittel und Verfahren zu ihrer Herstellung |
HU224315B1 (hu) | 1996-06-05 | 2005-07-28 | Gyógyszerkutató Intézet Kft. | Véralvadásgátló hatású peptidil-arginin-aldehid-származékok és a vegyületeket tartalmazó gyógyszerkészítmények |
EP0986384B1 (fr) | 1997-05-07 | 2012-02-22 | University Of Pittsburgh | Inhibiteurs de proteines isoprenyle transferases |
WO1998052558A1 (fr) * | 1997-05-23 | 1998-11-26 | Bayer Corporation | INHIBITION DE L'ACTIVITE DE LA p38 KINASE PAR DES ARYL-UREES |
ZA985247B (en) * | 1997-06-19 | 1999-12-17 | Du Pont Merck Pharma | Guanidine mimics as factor Xa inhibitors. |
JP2001521934A (ja) * | 1997-11-03 | 2001-11-13 | ベーリンガー インゲルハイム ファーマシューティカルズ インコーポレイテッド | 抗炎症薬としての芳香族ヘテロ環式化合物 |
WO2001019788A2 (fr) | 1999-09-17 | 2001-03-22 | Cor Therapeutics, Inc. | BENZAMIDES ET INHIBITEURS CORRESPONDANTS DU FACTEUR Xa |
US6632815B2 (en) * | 1999-09-17 | 2003-10-14 | Millennium Pharmaceuticals, Inc. | Inhibitors of factor Xa |
NZ517828A (en) | 1999-09-17 | 2003-10-31 | Millennium Pharm Inc | Inhibitors having activity against mammalian factor Xa |
DE10008329A1 (de) | 2000-02-23 | 2001-08-30 | Merck Patent Gmbh | Aminosulfonylbiphenylderivate |
EP1259485B1 (fr) | 2000-02-29 | 2005-11-30 | Millennium Pharmaceuticals, Inc. | Benzamides et inhibiteurs associes du facteur xa |
WO2001074769A1 (fr) * | 2000-03-27 | 2001-10-11 | Applied Research Systems Ars Holding N.V. | Derives de la pyrrolidine pharmaceutiquement actifs comme inhibiteurs de bax |
MXPA02009382A (es) * | 2000-03-27 | 2003-01-28 | Applied Research Systems | Derivados de pirrolidina farmaceuticamente activos. |
GB0030303D0 (en) | 2000-12-13 | 2001-01-24 | Lilly Co Eli | Compounds |
WO2002000651A2 (fr) | 2000-06-27 | 2002-01-03 | Bristol-Myers Squibb Pharma Company | Inhibiteurs du facteur xa |
DE10036121A1 (de) | 2000-07-25 | 2002-02-07 | Merck Patent Gmbh | N-Substituierte-1-amino-1,1-dialkyl-carbonsäurederivate |
DE10046272A1 (de) | 2000-09-19 | 2002-03-28 | Merck Patent Gmbh | Aminoheterocyclen (Faktor Xa Inhibitoren 14) |
DE10050723A1 (de) | 2000-10-13 | 2002-04-25 | Merck Patent Gmbh | N-Substituierte Aminosäurederivate (Faktor Xa Inhibitoren 12) |
DE10063008A1 (de) | 2000-12-16 | 2002-06-20 | Merck Patent Gmbh | Carbonsäureamidderivate |
DE10102322A1 (de) | 2001-01-19 | 2002-07-25 | Merck Patent Gmbh | Phenylderivate |
US7030141B2 (en) * | 2001-11-29 | 2006-04-18 | Christopher Franklin Bigge | Inhibitors of factor Xa and other serine proteases involved in the coagulation cascade |
CA2543882A1 (fr) * | 2003-10-30 | 2005-05-19 | Merck & Co., Inc. | Aralkylamines utilisees en tant que modulateurs des recepteurs cannabinoides |
FR2864958B1 (fr) * | 2004-01-12 | 2006-02-24 | Sanofi Synthelabo | Derive de n-[(1,5-diphenyl-1h-pyrazol-3-yl)methyl] sulfonamide, leur preparation et leur application en therapeutique. |
DE102005038537A1 (de) * | 2005-08-16 | 2007-02-22 | Merck Patent Gmbh | 1-Acyldihydropyrazolderivate |
EP2096111A1 (fr) * | 2006-11-20 | 2009-09-02 | Japan Tobacco Inc. | Pyrazoles et leur utilisation en tant que médicaments |
DE102007037017A1 (de) * | 2007-08-06 | 2009-02-19 | Clariant International Ltd. | 1-Alkyl-5-oxo-pyrrolidin-3-carbonsäureester mit verbesserter biologischer Abbaubarkeit |
-
2002
- 2002-10-23 US US10/278,643 patent/US7030141B2/en not_active Expired - Fee Related
- 2002-11-14 GE GE5587A patent/GEP20063871B/en unknown
- 2002-11-14 DE DE60209944T patent/DE60209944T2/de not_active Expired - Lifetime
- 2002-11-14 AU AU2002365313A patent/AU2002365313B2/en not_active Ceased
- 2002-11-14 DK DK06110738T patent/DK1671949T3/da active
- 2002-11-14 PT PT06110738T patent/PT1671949E/pt unknown
- 2002-11-14 DE DE60227853T patent/DE60227853D1/de not_active Expired - Lifetime
- 2002-11-14 SI SI200230316T patent/SI1465864T1/sl unknown
- 2002-11-14 EP EP02803885A patent/EP1465864B1/fr not_active Expired - Lifetime
- 2002-11-14 EP EP08101927A patent/EP2085391A3/fr not_active Withdrawn
- 2002-11-14 MX MXPA04003606A patent/MXPA04003606A/es active IP Right Grant
- 2002-11-14 PL PL02370134A patent/PL370134A1/xx not_active Application Discontinuation
- 2002-11-14 CA CA2468715A patent/CA2468715C/fr not_active Expired - Fee Related
- 2002-11-14 OA OA1200400149A patent/OA13064A/en unknown
- 2002-11-14 BR BR0214519-7A patent/BR0214519A/pt not_active IP Right Cessation
- 2002-11-14 KR KR1020047008251A patent/KR100688814B1/ko not_active IP Right Cessation
- 2002-11-14 AT AT02803885T patent/ATE320414T1/de not_active IP Right Cessation
- 2002-11-14 EP EP06110738A patent/EP1671949B1/fr not_active Expired - Lifetime
- 2002-11-14 JP JP2003547364A patent/JP4238135B2/ja not_active Expired - Fee Related
- 2002-11-14 HU HU0402529A patent/HUP0402529A3/hu unknown
- 2002-11-14 WO PCT/IB2002/004757 patent/WO2003045912A1/fr active Application Filing
- 2002-11-14 SI SI200230722T patent/SI1671949T1/sl unknown
- 2002-11-14 RS YUP-436/04A patent/RS51087B/sr unknown
- 2002-11-14 PT PT02803885T patent/PT1465864E/pt unknown
- 2002-11-14 AT AT06110738T patent/ATE402148T1/de not_active IP Right Cessation
- 2002-11-14 CN CN028238370A patent/CN1582274B/zh not_active Expired - Fee Related
- 2002-11-14 KR KR1020067017890A patent/KR100712782B1/ko not_active IP Right Cessation
- 2002-11-14 ES ES02803885T patent/ES2259113T3/es not_active Expired - Lifetime
- 2002-11-14 DK DK02803885T patent/DK1465864T3/da active
- 2002-11-14 AP APAP/P/2004/003035A patent/AP1744A/en active
- 2002-11-14 ES ES06110738T patent/ES2308653T3/es not_active Expired - Lifetime
- 2002-11-14 EA EA200400606A patent/EA007579B1/ru not_active IP Right Cessation
- 2002-11-14 NZ NZ532384A patent/NZ532384A/en not_active IP Right Cessation
- 2002-11-14 IL IL16182602A patent/IL161826A0/xx unknown
- 2002-11-26 DO DO2002000525A patent/DOP2002000525A/es unknown
- 2002-11-27 AR ARP020104557A patent/AR037676A1/es active IP Right Grant
- 2002-11-27 MY MYPI20024444A patent/MY132419A/en unknown
- 2002-11-28 UY UY27558A patent/UY27558A1/es not_active Application Discontinuation
- 2002-11-28 TW TW091134659A patent/TWI324515B/zh not_active IP Right Cessation
- 2002-11-28 PE PE2002001145A patent/PE20030662A1/es not_active Application Discontinuation
- 2002-11-28 PA PA20028559101A patent/PA8559101A1/es unknown
- 2002-11-28 SV SV2002001414A patent/SV2004001414A/es not_active Application Discontinuation
- 2002-11-29 GT GT200200248A patent/GT200200248A/es unknown
- 2002-11-29 GT GT200200248AK patent/GT200200248AA/es unknown
-
2004
- 2004-04-15 IS IS7220A patent/IS2552B/is unknown
- 2004-05-04 CR CR7332A patent/CR7332A/es unknown
- 2004-05-20 MA MA27687A patent/MA27146A1/fr unknown
- 2004-05-27 HR HR20040470A patent/HRP20040470A2/hr not_active Application Discontinuation
- 2004-05-28 EC EC2004005126A patent/ECSP045126A/es unknown
- 2004-05-28 TN TNP2004000098A patent/TNSN04098A1/fr unknown
- 2004-06-01 NO NO20042270A patent/NO327006B1/no not_active IP Right Cessation
- 2004-12-20 US US11/017,598 patent/US7407972B2/en not_active Expired - Fee Related
-
2005
- 2005-04-18 US US11/108,582 patent/US7407974B2/en not_active Expired - Fee Related
-
2006
- 2006-03-30 CY CY20061100448T patent/CY1105374T1/el unknown
- 2006-08-02 US US11/461,859 patent/US20060264626A1/en not_active Abandoned
-
2008
- 2008-06-16 US US12/139,799 patent/US20090221546A1/en not_active Abandoned
- 2008-06-26 US US12/147,038 patent/US20080287674A1/en not_active Abandoned
- 2008-08-08 CR CR10190A patent/CR10190A/es not_active Application Discontinuation
- 2008-08-28 CY CY20081100928T patent/CY1109068T1/el unknown
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
NO327006B1 (no) | Inhibitor av faktor XA og andre serinin proteaser involvert i koagulasjonskaskaden, samt anvendelse og fremgangsmate for fremstilling derav og farmasoytisk sammensetning | |
AU2014204666B2 (en) | Benzylamine derivatives | |
EP3224255B1 (fr) | Composés n-((het)arylméthyl)-hétéroaryl-carboxamides en tant qu'inhibiteurs de kallikréine | |
WO2016083816A1 (fr) | Dérivés de n-((hétéroarylméthyl)-hétéroaryl-carboxamide utilisés en tant qu'inhibiteurs de la kallikréine plasmatique | |
CA2560669C (fr) | Nouveaux derives de pyrrolidine-3,4-dicarboxamide | |
US20220289727A1 (en) | Enzyme inhibitors | |
WO2021032933A1 (fr) | Inhibiteurs d'enzymes | |
AU2017224343B2 (en) | Novel pyrrolidine derivatives | |
AU2013305102A1 (en) | Novel pyridine derivatives |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
MM1K | Lapsed by not paying the annual fees |