NO302948B1 - Pyrrolidin- og piperidinderivater med antikoagulerende aktivitet, og midler inneholdende slike derivater - Google Patents
Pyrrolidin- og piperidinderivater med antikoagulerende aktivitet, og midler inneholdende slike derivater Download PDFInfo
- Publication number
- NO302948B1 NO302948B1 NO924164A NO924164A NO302948B1 NO 302948 B1 NO302948 B1 NO 302948B1 NO 924164 A NO924164 A NO 924164A NO 924164 A NO924164 A NO 924164A NO 302948 B1 NO302948 B1 NO 302948B1
- Authority
- NO
- Norway
- Prior art keywords
- nmr
- mixture
- solvent
- resulting
- solution
- Prior art date
Links
- 239000003795 chemical substances by application Substances 0.000 title claims description 18
- 230000014508 negative regulation of coagulation Effects 0.000 title description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 title 3
- 150000003053 piperidines Chemical class 0.000 title 1
- -1 aromatic amidine Chemical class 0.000 claims abstract description 248
- 150000001875 compounds Chemical class 0.000 claims abstract description 186
- 150000003839 salts Chemical class 0.000 claims abstract description 25
- 239000003146 anticoagulant agent Substances 0.000 claims abstract description 11
- 239000004480 active ingredient Substances 0.000 claims abstract description 9
- 125000001424 substituent group Chemical group 0.000 claims abstract description 8
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims abstract description 4
- 125000001624 naphthyl group Chemical group 0.000 claims abstract description 4
- 229940127090 anticoagulant agent Drugs 0.000 claims abstract description 3
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims abstract description 3
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims abstract description 3
- 125000001041 indolyl group Chemical group 0.000 claims abstract description 3
- 125000004430 oxygen atom Chemical group O* 0.000 claims abstract description 3
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 3
- 125000004434 sulfur atom Chemical group 0.000 claims abstract description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 12
- 208000007536 Thrombosis Diseases 0.000 claims description 10
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 10
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 229910052799 carbon Inorganic materials 0.000 claims description 6
- FZLDAJVXFYWRCX-UHFFFAOYSA-N 3-(7-carbamimidoylnaphthalen-2-yl)-2-[4-(1-ethanimidoylpiperidin-4-yl)oxyphenyl]propanoic acid Chemical group C1CN(C(=N)C)CCC1OC1=CC=C(C(CC=2C=C3C=C(C=CC3=CC=2)C(N)=N)C(O)=O)C=C1 FZLDAJVXFYWRCX-UHFFFAOYSA-N 0.000 claims description 4
- AGRCGQSFFMCBRE-ZEQRLZLVSA-N (2s)-3-(7-carbamimidoylnaphthalen-2-yl)-2-[4-[(3s)-1-ethanimidoylpyrrolidin-3-yl]oxyphenyl]propanoic acid Chemical group C1N(C(=N)C)CC[C@@H]1OC1=CC=C([C@H](CC=2C=C3C=C(C=CC3=CC=2)C(N)=N)C(O)=O)C=C1 AGRCGQSFFMCBRE-ZEQRLZLVSA-N 0.000 claims description 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 3
- LWVOATWCBDAHLT-YDNXMHBPSA-N 3-(5-carbamimidoyl-1-benzothiophen-2-yl)-2-[4-[[(2s)-1-ethanimidoylpyrrolidin-2-yl]methoxy]phenyl]propanoic acid Chemical group CC(=N)N1CCC[C@H]1COC1=CC=C(C(CC=2SC3=CC=C(C=C3C=2)C(N)=N)C(O)=O)C=C1 LWVOATWCBDAHLT-YDNXMHBPSA-N 0.000 claims description 3
- AGRCGQSFFMCBRE-UXMRNZNESA-N 3-(7-carbamimidoylnaphthalen-2-yl)-2-[4-[(3s)-1-ethanimidoylpyrrolidin-3-yl]oxyphenyl]propanoic acid Chemical group C1N(C(=N)C)CC[C@@H]1OC1=CC=C(C(CC=2C=C3C=C(C=CC3=CC=2)C(N)=N)C(O)=O)C=C1 AGRCGQSFFMCBRE-UXMRNZNESA-N 0.000 claims description 3
- 208000005189 Embolism Diseases 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 125000002947 alkylene group Chemical group 0.000 claims description 3
- 230000002265 prevention Effects 0.000 claims description 3
- AGRCGQSFFMCBRE-DNQXCXABSA-N (2r)-3-(7-carbamimidoylnaphthalen-2-yl)-2-[4-[(3r)-1-ethanimidoylpyrrolidin-3-yl]oxyphenyl]propanoic acid Chemical group C1N(C(=N)C)CC[C@H]1OC1=CC=C([C@@H](CC=2C=C3C=C(C=CC3=CC=2)C(N)=N)C(O)=O)C=C1 AGRCGQSFFMCBRE-DNQXCXABSA-N 0.000 claims description 2
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 2
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims 2
- LWVOATWCBDAHLT-UHFFFAOYSA-N 3-(5-carbamimidoyl-1-benzothiophen-2-yl)-2-[4-[(1-ethanimidoylpyrrolidin-2-yl)methoxy]phenyl]propanoic acid Chemical group CC(=N)N1CCCC1COC1=CC=C(C(CC=2SC3=CC=C(C=C3C=2)C(N)=N)C(O)=O)C=C1 LWVOATWCBDAHLT-UHFFFAOYSA-N 0.000 claims 1
- AGRCGQSFFMCBRE-UHFFFAOYSA-N 3-(7-carbamimidoylnaphthalen-2-yl)-2-[4-(1-ethanimidoylpyrrolidin-3-yl)oxyphenyl]propanoic acid Chemical group C1N(C(=N)C)CCC1OC1=CC=C(C(CC=2C=C3C=C(C=CC3=CC=2)C(N)=N)C(O)=O)C=C1 AGRCGQSFFMCBRE-UHFFFAOYSA-N 0.000 claims 1
- 125000003386 piperidinyl group Chemical group 0.000 claims 1
- 229920006395 saturated elastomer Polymers 0.000 abstract description 31
- 230000000694 effects Effects 0.000 abstract description 8
- 229940127219 anticoagulant drug Drugs 0.000 abstract description 7
- 230000005764 inhibitory process Effects 0.000 abstract description 6
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 abstract description 3
- 125000003277 amino group Chemical group 0.000 abstract description 2
- 125000002373 5 membered heterocyclic group Chemical group 0.000 abstract 1
- 125000004070 6 membered heterocyclic group Chemical group 0.000 abstract 1
- 125000004103 aminoalkyl group Chemical group 0.000 abstract 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 abstract 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 abstract 1
- 125000000753 cycloalkyl group Chemical group 0.000 abstract 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 abstract 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 abstract 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 436
- 239000000243 solution Substances 0.000 description 420
- 238000005160 1H NMR spectroscopy Methods 0.000 description 301
- 239000000203 mixture Substances 0.000 description 295
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 230
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 198
- 239000002904 solvent Substances 0.000 description 192
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 182
- 238000006243 chemical reaction Methods 0.000 description 177
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 162
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 156
- 238000003756 stirring Methods 0.000 description 147
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 129
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 126
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 124
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 123
- 239000007787 solid Substances 0.000 description 122
- 238000001816 cooling Methods 0.000 description 107
- 238000010898 silica gel chromatography Methods 0.000 description 104
- 239000013078 crystal Substances 0.000 description 102
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 98
- 238000001914 filtration Methods 0.000 description 91
- FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 description 87
- 239000012156 elution solvent Substances 0.000 description 83
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 81
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 78
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 76
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 72
- 238000002360 preparation method Methods 0.000 description 67
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 58
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 57
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 57
- 239000012044 organic layer Substances 0.000 description 51
- 239000003480 eluent Substances 0.000 description 49
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 44
- 238000005481 NMR spectroscopy Methods 0.000 description 44
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 43
- 238000010992 reflux Methods 0.000 description 42
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 41
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 40
- 239000003921 oil Substances 0.000 description 39
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 38
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 36
- 238000000034 method Methods 0.000 description 36
- 230000002829 reductive effect Effects 0.000 description 36
- 239000011877 solvent mixture Substances 0.000 description 32
- 239000003054 catalyst Substances 0.000 description 30
- 239000000706 filtrate Substances 0.000 description 27
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 25
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 24
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 24
- 238000001035 drying Methods 0.000 description 24
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 23
- 239000000741 silica gel Substances 0.000 description 23
- 229910002027 silica gel Inorganic materials 0.000 description 23
- TZCXTZWJZNENPQ-UHFFFAOYSA-L barium sulfate Inorganic materials [Ba+2].[O-]S([O-])(=O)=O TZCXTZWJZNENPQ-UHFFFAOYSA-L 0.000 description 22
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 22
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 22
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 21
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 21
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 21
- 239000002198 insoluble material Substances 0.000 description 21
- 239000012312 sodium hydride Substances 0.000 description 21
- 229910000104 sodium hydride Inorganic materials 0.000 description 21
- CHRJZRDFSQHIFI-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;styrene Chemical compound C=CC1=CC=CC=C1.C=CC1=CC=CC=C1C=C CHRJZRDFSQHIFI-UHFFFAOYSA-N 0.000 description 20
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 20
- 239000003463 adsorbent Substances 0.000 description 20
- 238000004440 column chromatography Methods 0.000 description 20
- 229920000642 polymer Polymers 0.000 description 20
- FXSZGKYGUFCBQY-UHFFFAOYSA-N propanoic acid;dihydrochloride Chemical compound Cl.Cl.CCC(O)=O FXSZGKYGUFCBQY-UHFFFAOYSA-N 0.000 description 19
- 235000017557 sodium bicarbonate Nutrition 0.000 description 19
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 19
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 18
- 229910021529 ammonia Inorganic materials 0.000 description 18
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 18
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 18
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 18
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 18
- 238000012360 testing method Methods 0.000 description 18
- 238000004821 distillation Methods 0.000 description 17
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 17
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 17
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 16
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 16
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 16
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 16
- 239000012046 mixed solvent Substances 0.000 description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- 238000010438 heat treatment Methods 0.000 description 15
- 238000004007 reversed phase HPLC Methods 0.000 description 15
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 14
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 14
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 13
- 239000002253 acid Substances 0.000 description 12
- 239000007864 aqueous solution Substances 0.000 description 12
- 238000002844 melting Methods 0.000 description 12
- 230000008018 melting Effects 0.000 description 12
- 229910052763 palladium Inorganic materials 0.000 description 12
- 239000011541 reaction mixture Substances 0.000 description 12
- 239000011780 sodium chloride Substances 0.000 description 12
- JIGUQPWFLRLWPJ-UHFFFAOYSA-N Ethyl acrylate Chemical compound CCOC(=O)C=C JIGUQPWFLRLWPJ-UHFFFAOYSA-N 0.000 description 11
- 229940017219 methyl propionate Drugs 0.000 description 11
- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 description 11
- 229910000027 potassium carbonate Inorganic materials 0.000 description 11
- ZFWZDHYZGCVGPP-UHFFFAOYSA-N 2-phenylpropanoic acid dihydrochloride Chemical compound Cl.Cl.C1(=CC=CC=C1)C(C(=O)O)C ZFWZDHYZGCVGPP-UHFFFAOYSA-N 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
- RJUFJBKOKNCXHH-UHFFFAOYSA-N Methyl propionate Chemical compound CCC(=O)OC RJUFJBKOKNCXHH-UHFFFAOYSA-N 0.000 description 10
- 125000004432 carbon atom Chemical group C* 0.000 description 10
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 10
- 229960004592 isopropanol Drugs 0.000 description 10
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 10
- 239000012279 sodium borohydride Substances 0.000 description 10
- 229910000033 sodium borohydride Inorganic materials 0.000 description 10
- APCBTRDHCDOPNY-SSDOTTSWSA-N tert-butyl (3r)-3-hydroxypyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC[C@@H](O)C1 APCBTRDHCDOPNY-SSDOTTSWSA-N 0.000 description 10
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 10
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 9
- CEIPQQODRKXDSB-UHFFFAOYSA-N ethyl 3-(6-hydroxynaphthalen-2-yl)-1H-indazole-5-carboximidate dihydrochloride Chemical group Cl.Cl.C1=C(O)C=CC2=CC(C3=NNC4=CC=C(C=C43)C(=N)OCC)=CC=C21 CEIPQQODRKXDSB-UHFFFAOYSA-N 0.000 description 9
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 9
- 239000005457 ice water Substances 0.000 description 9
- 239000000463 material Substances 0.000 description 9
- 230000003287 optical effect Effects 0.000 description 9
- 239000000725 suspension Substances 0.000 description 9
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 9
- VFECYOFFNUUXPX-UHFFFAOYSA-M (5-cyano-1-benzofuran-2-yl)methyl-triphenylphosphanium;chloride Chemical compound [Cl-].C=1C2=CC(C#N)=CC=C2OC=1C[P+](C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 VFECYOFFNUUXPX-UHFFFAOYSA-M 0.000 description 8
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 8
- UNMYWSMUMWPJLR-UHFFFAOYSA-L Calcium iodide Chemical compound [Ca+2].[I-].[I-] UNMYWSMUMWPJLR-UHFFFAOYSA-L 0.000 description 8
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 8
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 8
- 241000700159 Rattus Species 0.000 description 8
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 8
- 235000019270 ammonium chloride Nutrition 0.000 description 8
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 8
- 229940046413 calcium iodide Drugs 0.000 description 8
- 229910001640 calcium iodide Inorganic materials 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- 230000002401 inhibitory effect Effects 0.000 description 8
- 239000011259 mixed solution Substances 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 8
- 239000000843 powder Substances 0.000 description 8
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- 239000008096 xylene Substances 0.000 description 8
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 7
- 101150041968 CDC13 gene Proteins 0.000 description 7
- 235000019253 formic acid Nutrition 0.000 description 7
- 150000008282 halocarbons Chemical class 0.000 description 7
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- 229920000856 Amylose Polymers 0.000 description 6
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 description 6
- 108090000190 Thrombin Proteins 0.000 description 6
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 6
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 6
- BIKGMKAPPSQYQE-UHFFFAOYSA-N ethyl propanoate;dihydrochloride Chemical compound Cl.Cl.CCOC(=O)CC BIKGMKAPPSQYQE-UHFFFAOYSA-N 0.000 description 6
- 238000005755 formation reaction Methods 0.000 description 6
- 238000006460 hydrolysis reaction Methods 0.000 description 6
- 150000002825 nitriles Chemical group 0.000 description 6
- 238000000926 separation method Methods 0.000 description 6
- 229960004072 thrombin Drugs 0.000 description 6
- WGMHMVLZFAJNOT-UHFFFAOYSA-N 1-ethoxyethylideneazanium;chloride Chemical compound [Cl-].CCOC(C)=[NH2+] WGMHMVLZFAJNOT-UHFFFAOYSA-N 0.000 description 5
- FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical compound C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-N 0.000 description 5
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 5
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 5
- 210000004369 blood Anatomy 0.000 description 5
- 239000008280 blood Substances 0.000 description 5
- 238000009835 boiling Methods 0.000 description 5
- 229910000365 copper sulfate Inorganic materials 0.000 description 5
- 238000010931 ester hydrolysis Methods 0.000 description 5
- 238000005259 measurement Methods 0.000 description 5
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- 239000012047 saturated solution Substances 0.000 description 5
- HNAGHMKIPMKKBB-UHFFFAOYSA-N 1-benzylpyrrolidine-3-carboxamide Chemical compound C1C(C(=O)N)CCN1CC1=CC=CC=C1 HNAGHMKIPMKKBB-UHFFFAOYSA-N 0.000 description 4
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 4
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2,2'-azo-bis-isobutyronitrile Substances N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 4
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 4
- RGHHSNMVTDWUBI-UHFFFAOYSA-N 4-hydroxybenzaldehyde Chemical compound OC1=CC=C(C=O)C=C1 RGHHSNMVTDWUBI-UHFFFAOYSA-N 0.000 description 4
- DVFCGFDASZCOAL-UHFFFAOYSA-N 5-bromo-2-[2-(4-methoxyphenyl)ethenyl]-1-benzofuran Chemical compound C1=CC(OC)=CC=C1C=CC1=CC2=CC(Br)=CC=C2O1 DVFCGFDASZCOAL-UHFFFAOYSA-N 0.000 description 4
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 4
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 4
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 4
- 229940022663 acetate Drugs 0.000 description 4
- 239000000010 aprotic solvent Substances 0.000 description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 4
- 229910052794 bromium Inorganic materials 0.000 description 4
- OBNCKNCVKJNDBV-UHFFFAOYSA-N butanoic acid ethyl ester Natural products CCCC(=O)OCC OBNCKNCVKJNDBV-UHFFFAOYSA-N 0.000 description 4
- 239000012230 colorless oil Substances 0.000 description 4
- BOLQJTPHPSDZHR-UHFFFAOYSA-N dihydroferulic acid Chemical compound COC1=CC(CCC(O)=O)=CC=C1O BOLQJTPHPSDZHR-UHFFFAOYSA-N 0.000 description 4
- 150000002148 esters Chemical group 0.000 description 4
- PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 229910000039 hydrogen halide Inorganic materials 0.000 description 4
- 239000012433 hydrogen halide Substances 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 4
- 210000002381 plasma Anatomy 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000012264 purified product Substances 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 229920002554 vinyl polymer Polymers 0.000 description 4
- XDPCNPCKDGQBAN-BYPYZUCNSA-N (3s)-oxolan-3-ol Chemical compound O[C@H]1CCOC1 XDPCNPCKDGQBAN-BYPYZUCNSA-N 0.000 description 3
- MMGAHWANKFZZNA-UHFFFAOYSA-N (5-bromo-1-benzofuran-2-yl)-(4-methoxyphenyl)methanone Chemical compound C1=CC(OC)=CC=C1C(=O)C1=CC2=CC(Br)=CC=C2O1 MMGAHWANKFZZNA-UHFFFAOYSA-N 0.000 description 3
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 3
- UKQQKOZMHDTVCC-UHFFFAOYSA-N 2-[2-(5-cyano-1-benzofuran-2-yl)ethyl]-5-methoxybenzoic acid Chemical compound OC(=O)C1=CC(OC)=CC=C1CCC1=CC2=CC(C#N)=CC=C2O1 UKQQKOZMHDTVCC-UHFFFAOYSA-N 0.000 description 3
- GNFTZDOKVXKIBK-UHFFFAOYSA-N 3-(2-methoxyethoxy)benzohydrazide Chemical compound COCCOC1=CC=CC(C(=O)NN)=C1 GNFTZDOKVXKIBK-UHFFFAOYSA-N 0.000 description 3
- PHFUQWIZTIRSOS-UHFFFAOYSA-N 3-methyl-1-benzofuran-5-carbonitrile Chemical compound C1=C(C#N)C=C2C(C)=COC2=C1 PHFUQWIZTIRSOS-UHFFFAOYSA-N 0.000 description 3
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 3
- LHKNZMZAZVMDDA-UHFFFAOYSA-N 4-[2-(5-cyano-1-benzofuran-2-yl)ethyl]benzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1CCC1=CC2=CC(C#N)=CC=C2O1 LHKNZMZAZVMDDA-UHFFFAOYSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- OIFBSDVPJOWBCH-UHFFFAOYSA-N Diethyl carbonate Chemical compound CCOC(=O)OCC OIFBSDVPJOWBCH-UHFFFAOYSA-N 0.000 description 3
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 3
- 206010014523 Embolism and thrombosis Diseases 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 3
- 239000012346 acetyl chloride Substances 0.000 description 3
- 150000001298 alcohols Chemical class 0.000 description 3
- 125000001931 aliphatic group Chemical group 0.000 description 3
- 230000002429 anti-coagulating effect Effects 0.000 description 3
- 239000004019 antithrombin Substances 0.000 description 3
- 229910052786 argon Inorganic materials 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 239000007975 buffered saline Substances 0.000 description 3
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 description 3
- 239000007795 chemical reaction product Substances 0.000 description 3
- 238000010511 deprotection reaction Methods 0.000 description 3
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 3
- 238000005886 esterification reaction Methods 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 239000003456 ion exchange resin Substances 0.000 description 3
- 229920003303 ion-exchange polymer Polymers 0.000 description 3
- 150000007522 mineralic acids Chemical class 0.000 description 3
- 150000007524 organic acids Chemical class 0.000 description 3
- 229910003445 palladium oxide Inorganic materials 0.000 description 3
- JQPTYAILLJKUCY-UHFFFAOYSA-N palladium(ii) oxide Chemical compound [O-2].[Pd+2] JQPTYAILLJKUCY-UHFFFAOYSA-N 0.000 description 3
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 3
- 239000002504 physiological saline solution Substances 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 239000012266 salt solution Substances 0.000 description 3
- 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- 239000012258 stirred mixture Substances 0.000 description 3
- LQRGWGOFPUXNOV-SSDOTTSWSA-N tert-butyl n-[(2r)-1-hydroxybutan-2-yl]carbamate Chemical compound CC[C@H](CO)NC(=O)OC(C)(C)C LQRGWGOFPUXNOV-SSDOTTSWSA-N 0.000 description 3
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 3
- XDPCNPCKDGQBAN-SCSAIBSYSA-N (3r)-oxolan-3-ol Chemical compound O[C@@H]1CCOC1 XDPCNPCKDGQBAN-SCSAIBSYSA-N 0.000 description 2
- YQXBNCFNXOFWLR-UHFFFAOYSA-M (4-methoxyphenyl)methyl-triphenylphosphanium;chloride Chemical compound [Cl-].C1=CC(OC)=CC=C1C[P+](C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 YQXBNCFNXOFWLR-UHFFFAOYSA-M 0.000 description 2
- IVRDOLPDFBPIMW-UHFFFAOYSA-M (5-cyano-1-benzothiophen-2-yl)methyl-triphenylphosphanium;chloride Chemical compound [Cl-].C=1C2=CC(C#N)=CC=C2SC=1C[P+](C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 IVRDOLPDFBPIMW-UHFFFAOYSA-M 0.000 description 2
- IOMBDBRFLRVNML-UHFFFAOYSA-N (6-cyano-1,2,3,4-tetrahydronaphthalen-2-yl)methyl 4-methylbenzenesulfonate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)OCC1CC2=CC=C(C#N)C=C2CC1 IOMBDBRFLRVNML-UHFFFAOYSA-N 0.000 description 2
- FQQBNIWOOXIDEP-UHFFFAOYSA-N 1-(5-bromo-7-methoxy-1-benzofuran-2-yl)ethanone Chemical compound COC1=CC(Br)=CC2=C1OC(C(C)=O)=C2 FQQBNIWOOXIDEP-UHFFFAOYSA-N 0.000 description 2
- PLPLIFZNSGTTCK-UHFFFAOYSA-N 1-[5-bromo-2-[2-(4-methoxyphenyl)ethenyl]-1-benzofuran-3-yl]ethanone Chemical compound C1=CC(OC)=CC=C1C=CC1=C(C(C)=O)C2=CC(Br)=CC=C2O1 PLPLIFZNSGTTCK-UHFFFAOYSA-N 0.000 description 2
- RRZNKZFHUPGMJM-UHFFFAOYSA-N 1-[5-bromo-2-[2-(4-methoxyphenyl)ethyl]-1-benzofuran-3-yl]ethanone Chemical compound C1=CC(OC)=CC=C1CCC1=C(C(C)=O)C2=CC(Br)=CC=C2O1 RRZNKZFHUPGMJM-UHFFFAOYSA-N 0.000 description 2
- IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical compound C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 description 2
- MEKOFIRRDATTAG-UHFFFAOYSA-N 2,2,5,8-tetramethyl-3,4-dihydrochromen-6-ol Chemical compound C1CC(C)(C)OC2=C1C(C)=C(O)C=C2C MEKOFIRRDATTAG-UHFFFAOYSA-N 0.000 description 2
- AZASUXLDHBRIKX-UHFFFAOYSA-N 2-(2-bromoacetyl)-1-benzofuran-5-carbonitrile Chemical compound N#CC1=CC=C2OC(C(=O)CBr)=CC2=C1 AZASUXLDHBRIKX-UHFFFAOYSA-N 0.000 description 2
- UUAOXJZNRQDRGG-UHFFFAOYSA-N 2-(4-hydroxyphenyl)-3-oxopropanoic acid Chemical compound OC(=O)C(C=O)C1=CC=C(O)C=C1 UUAOXJZNRQDRGG-UHFFFAOYSA-N 0.000 description 2
- VSXBRRBPPUKEAC-UHFFFAOYSA-N 2-(4-methoxybenzoyl)-1-benzofuran-5-carbonitrile Chemical compound C1=CC(OC)=CC=C1C(=O)C1=CC2=CC(C#N)=CC=C2O1 VSXBRRBPPUKEAC-UHFFFAOYSA-N 0.000 description 2
- XRVJDLPGGJHWLC-UHFFFAOYSA-N 2-(5-bromo-1-benzothiophen-2-yl)acetonitrile Chemical compound BrC1=CC=C2SC(CC#N)=CC2=C1 XRVJDLPGGJHWLC-UHFFFAOYSA-N 0.000 description 2
- TYQFPOCJHOKFIR-UHFFFAOYSA-N 2-(bromomethyl)-1-benzothiophene-5-carbonitrile Chemical compound N#CC1=CC=C2SC(CBr)=CC2=C1 TYQFPOCJHOKFIR-UHFFFAOYSA-N 0.000 description 2
- QYXBSKYCEPSRAE-UHFFFAOYSA-N 2-(chloromethyl)-3-methyl-1-benzofuran-5-carbonitrile Chemical compound C1=C(C#N)C=C2C(C)=C(CCl)OC2=C1 QYXBSKYCEPSRAE-UHFFFAOYSA-N 0.000 description 2
- XAMQWUSDVFFTGA-UHFFFAOYSA-N 2-(chloromethyl)-3h-benzimidazole-5-carbonitrile Chemical compound N#CC1=CC=C2NC(CCl)=NC2=C1 XAMQWUSDVFFTGA-UHFFFAOYSA-N 0.000 description 2
- TUQCQABNZRVQEX-UHFFFAOYSA-N 2-(hydroxymethyl)-1-benzothiophene-5-carbonitrile Chemical compound N#CC1=CC=C2SC(CO)=CC2=C1 TUQCQABNZRVQEX-UHFFFAOYSA-N 0.000 description 2
- JRPBJJOGDOHJDR-UHFFFAOYSA-N 2-(hydroxymethyl)-3-methyl-1-benzofuran-5-carbonitrile Chemical compound C1=C(C#N)C=C2C(C)=C(CO)OC2=C1 JRPBJJOGDOHJDR-UHFFFAOYSA-N 0.000 description 2
- UYGTXDOWVDYQJK-UHFFFAOYSA-N 2-(hydroxymethyl)-7-methoxy-1-benzofuran-5-carbonitrile Chemical compound COC1=CC(C#N)=CC2=C1OC(CO)=C2 UYGTXDOWVDYQJK-UHFFFAOYSA-N 0.000 description 2
- IVGRSZXLSFWLQF-UHFFFAOYSA-N 2-[(4-hydroxyphenyl)methyl]-1-benzofuran-5-carbonitrile Chemical compound C1=CC(O)=CC=C1CC1=CC2=CC(C#N)=CC=C2O1 IVGRSZXLSFWLQF-UHFFFAOYSA-N 0.000 description 2
- FCFHSTIGTGQALA-UHFFFAOYSA-N 2-[(4-methoxyphenyl)methyl]-1-benzofuran-5-carbonitrile Chemical compound C1=CC(OC)=CC=C1CC1=CC2=CC(C#N)=CC=C2O1 FCFHSTIGTGQALA-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
- HERKXNHYQRTKGN-UHFFFAOYSA-N 2-[2-[4-(hydroxymethyl)phenyl]ethyl]-1-benzofuran-5-carbonitrile Chemical compound C1=CC(CO)=CC=C1CCC1=CC2=CC(C#N)=CC=C2O1 HERKXNHYQRTKGN-UHFFFAOYSA-N 0.000 description 2
- PAEVFFPDCMMDJV-FQEVSTJZSA-N 2-[2-[4-[(3s)-1-acetylpyrrolidin-3-yl]oxy-3-hydroxyphenyl]ethenyl]-1-benzofuran-5-carbonitrile Chemical compound C1N(C(=O)C)CC[C@@H]1OC(C(=C1)O)=CC=C1C=CC1=CC2=CC(C#N)=CC=C2O1 PAEVFFPDCMMDJV-FQEVSTJZSA-N 0.000 description 2
- JBYIRQLKRQKPLY-TXEPZDRESA-N 2-[2-[4-[(3s)-pyrrolidin-3-yl]oxyphenyl]ethyl]-1-benzofuran-5-carboximidamide;dihydrochloride Chemical compound Cl.Cl.C=1C2=CC(C(=N)N)=CC=C2OC=1CCC(C=C1)=CC=C1O[C@H]1CCNC1 JBYIRQLKRQKPLY-TXEPZDRESA-N 0.000 description 2
- LMGBAGZYSFICDQ-UHFFFAOYSA-N 2-methyl-1,3-benzothiazole-5-carbonitrile Chemical compound N#CC1=CC=C2SC(C)=NC2=C1 LMGBAGZYSFICDQ-UHFFFAOYSA-N 0.000 description 2
- BKHIEHSQVBKDPG-UHFFFAOYSA-N 3-(5-bromo-1-benzothiophen-2-yl)-2-(4-methoxyphenyl)propan-1-ol Chemical compound C1=CC(OC)=CC=C1C(CO)CC1=CC2=CC(Br)=CC=C2S1 BKHIEHSQVBKDPG-UHFFFAOYSA-N 0.000 description 2
- XONMOTAIFYYLQV-UHFFFAOYSA-N 3-[3-(4-hydroxyphenyl)propyl]-1-benzofuran-5-carbonitrile Chemical compound C1=CC(O)=CC=C1CCCC1=COC2=CC=C(C#N)C=C12 XONMOTAIFYYLQV-UHFFFAOYSA-N 0.000 description 2
- PJWBCBXVKYTEFS-UHFFFAOYSA-N 3-acetyl-2-[2-(4-methoxyphenyl)ethenyl]-1-benzofuran-5-carbonitrile Chemical compound C1=CC(OC)=CC=C1C=CC1=C(C(C)=O)C2=CC(C#N)=CC=C2O1 PJWBCBXVKYTEFS-UHFFFAOYSA-N 0.000 description 2
- LGZIQMGORGODPK-UHFFFAOYSA-N 3-acetyl-2-[2-(4-methoxyphenyl)ethyl]-1-benzofuran-5-carbonitrile Chemical compound C1=CC(OC)=CC=C1CCC1=C(C(C)=O)C2=CC(C#N)=CC=C2O1 LGZIQMGORGODPK-UHFFFAOYSA-N 0.000 description 2
- VUFWFUDFBGKNPO-UHFFFAOYSA-N 3-ethoxy-7-methoxy-1,2-dihydronaphthalene Chemical compound C1=C(OC)C=C2CCC(OCC)=CC2=C1 VUFWFUDFBGKNPO-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- ZSWZQVYDVCUCGB-NSHDSACASA-N 4-[(3s)-1-acetylpyrrolidin-3-yl]oxy-3-hydroxybenzaldehyde Chemical compound C1N(C(=O)C)CC[C@@H]1OC1=CC=C(C=O)C=C1O ZSWZQVYDVCUCGB-NSHDSACASA-N 0.000 description 2
- WMIZDIPTWWVDKZ-LBPRGKRZSA-N 4-[(3s)-1-acetylpyrrolidin-3-yl]oxy-3-methoxybenzaldehyde Chemical compound COC1=CC(C=O)=CC=C1O[C@@H]1CN(C(C)=O)CC1 WMIZDIPTWWVDKZ-LBPRGKRZSA-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
- ONNFNEFYXIPHCA-UHFFFAOYSA-N 5-bromo-1-benzothiophene-2-carboxylic acid Chemical compound BrC1=CC=C2SC(C(=O)O)=CC2=C1 ONNFNEFYXIPHCA-UHFFFAOYSA-N 0.000 description 2
- IKKGJXUMIYADBT-UHFFFAOYSA-N 5-bromo-2-[(4-methoxyphenyl)methyl]-1-benzofuran Chemical compound C1=CC(OC)=CC=C1CC1=CC2=CC(Br)=CC=C2O1 IKKGJXUMIYADBT-UHFFFAOYSA-N 0.000 description 2
- ZBKVPRAOSMEETR-UHFFFAOYSA-N 5-bromo-2-[2-(4-methoxyphenyl)ethyl]-1-benzofuran Chemical compound C1=CC(OC)=CC=C1CCC1=CC2=CC(Br)=CC=C2O1 ZBKVPRAOSMEETR-UHFFFAOYSA-N 0.000 description 2
- KQUYOXBASKPCLC-UHFFFAOYSA-N 5-bromo-2-[2-(4-methoxyphenyl)ethyl]-1-benzofuran-3-carboxylic acid Chemical compound C1=CC(OC)=CC=C1CCC1=C(C(O)=O)C2=CC(Br)=CC=C2O1 KQUYOXBASKPCLC-UHFFFAOYSA-N 0.000 description 2
- MKKSTJKBKNCMRV-UHFFFAOYSA-N 5-bromo-2-hydroxybenzaldehyde Chemical compound OC1=CC=C(Br)C=C1C=O MKKSTJKBKNCMRV-UHFFFAOYSA-N 0.000 description 2
- ILDKIOGQJZYWDY-UHFFFAOYSA-N 5-cyano-2-[2-(4-methoxyphenyl)ethyl]-1-benzofuran-3-carboxylic acid Chemical compound C1=CC(OC)=CC=C1CCC1=C(C(O)=O)C2=CC(C#N)=CC=C2O1 ILDKIOGQJZYWDY-UHFFFAOYSA-N 0.000 description 2
- INIGGLKTCYLLMV-UHFFFAOYSA-N 5-cyano-3-methyl-1-benzofuran-2-carboxylic acid Chemical compound C1=C(C#N)C=C2C(C)=C(C(O)=O)OC2=C1 INIGGLKTCYLLMV-UHFFFAOYSA-N 0.000 description 2
- ORUYTMCMDRSBEU-UHFFFAOYSA-N 6-(bromomethyl)naphthalene-2-carbonitrile Chemical compound C1=C(C#N)C=CC2=CC(CBr)=CC=C21 ORUYTMCMDRSBEU-UHFFFAOYSA-N 0.000 description 2
- HYOCUTZBFHXLKW-UHFFFAOYSA-N 6-(hydroxymethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile Chemical compound N#CC1=CC=C2CC(CO)CCC2=C1 HYOCUTZBFHXLKW-UHFFFAOYSA-N 0.000 description 2
- GLSBYJBDFOVJAG-UHFFFAOYSA-N 6-(oxan-2-yloxymethyl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile Chemical compound C1CC2=CC(C#N)=CC=C2CC1COC1CCCCO1 GLSBYJBDFOVJAG-UHFFFAOYSA-N 0.000 description 2
- YQFQLUOIJFQJJM-UHFFFAOYSA-N 6-(oxan-2-yloxymethyl)-5,6,7,8-tetrahydronaphthalene-2-carboxamide Chemical compound C1CC2=CC(C(=O)N)=CC=C2CC1COC1CCCCO1 YQFQLUOIJFQJJM-UHFFFAOYSA-N 0.000 description 2
- IUDAMQRUOZOBJJ-UHFFFAOYSA-N 6-(oxan-2-yloxymethyl)-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid Chemical compound C1CC2=CC(C(=O)O)=CC=C2CC1COC1CCCCO1 IUDAMQRUOZOBJJ-UHFFFAOYSA-N 0.000 description 2
- VMWIZZARXXSROL-UHFFFAOYSA-N 7-(bromomethyl)naphthalene-2-carbonitrile Chemical compound C1=CC(C#N)=CC2=CC(CBr)=CC=C21 VMWIZZARXXSROL-UHFFFAOYSA-N 0.000 description 2
- XEJYIXSQJAMFDO-UHFFFAOYSA-N 7-methylnaphthalene-2-carbonitrile Chemical compound C1=CC(C#N)=CC2=CC(C)=CC=C21 XEJYIXSQJAMFDO-UHFFFAOYSA-N 0.000 description 2
- JSMDPPRREJWULR-UHFFFAOYSA-N 7-methylnaphthalene-2-carboxamide Chemical compound C1=CC(C(N)=O)=CC2=CC(C)=CC=C21 JSMDPPRREJWULR-UHFFFAOYSA-N 0.000 description 2
- VVNCNSJFMMFHPL-VKHMYHEASA-N D-penicillamine Chemical compound CC(C)(S)[C@@H](N)C(O)=O VVNCNSJFMMFHPL-VKHMYHEASA-N 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 2
- 108010074860 Factor Xa Proteins 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 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
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- YNPNZTXNASCQKK-UHFFFAOYSA-N Phenanthrene Natural products C1=CC=C2C3=CC=CC=C3C=CC2=C1 YNPNZTXNASCQKK-UHFFFAOYSA-N 0.000 description 2
- 239000004698 Polyethylene Substances 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 description 2
- UYGKCTFMRDCXJL-UHFFFAOYSA-N [2-(4-acetyloxyphenyl)-2-oxoethyl] acetate Chemical compound CC(=O)OCC(=O)C1=CC=C(OC(C)=O)C=C1 UYGKCTFMRDCXJL-UHFFFAOYSA-N 0.000 description 2
- XGIARGRDHVLYGD-UHFFFAOYSA-N [2-(4-hydroxyphenyl)-2-oxoethyl] acetate Chemical compound CC(=O)OCC(=O)C1=CC=C(O)C=C1 XGIARGRDHVLYGD-UHFFFAOYSA-N 0.000 description 2
- QVAMVWKWDQMHIN-UHFFFAOYSA-N [3-(5-bromo-1-benzothiophen-2-yl)-2-(4-methoxyphenyl)propyl] methanesulfonate Chemical compound C1=CC(OC)=CC=C1C(COS(C)(=O)=O)CC1=CC2=CC(Br)=CC=C2S1 QVAMVWKWDQMHIN-UHFFFAOYSA-N 0.000 description 2
- XBCIWLDUWWZGGL-UHFFFAOYSA-N [5-bromo-2-[2-(4-methoxyphenyl)ethyl]-1-benzofuran-3-yl]methanol Chemical compound C1=CC(OC)=CC=C1CCC1=C(CO)C2=CC(Br)=CC=C2O1 XBCIWLDUWWZGGL-UHFFFAOYSA-N 0.000 description 2
- CIIMINJBNNEBOC-UHFFFAOYSA-M [5-ethoxy-2-(3-ethoxy-3-oxopropyl)-4-methoxyphenyl]methyl-triphenylphosphanium;chloride Chemical compound [Cl-].CCOC(=O)CCC1=CC(OC)=C(OCC)C=C1C[P+](C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 CIIMINJBNNEBOC-UHFFFAOYSA-M 0.000 description 2
- 125000005078 alkoxycarbonylalkyl group Chemical group 0.000 description 2
- QUMXDOLUJCHOAY-UHFFFAOYSA-N alpha-methylbenzyl acetate Natural products CC(=O)OC(C)C1=CC=CC=C1 QUMXDOLUJCHOAY-UHFFFAOYSA-N 0.000 description 2
- 150000001409 amidines Chemical class 0.000 description 2
- 230000002785 anti-thrombosis Effects 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- OFULEGMRNRXCCQ-UHFFFAOYSA-N benzotriazol-1-yl 4-[2-(5-cyano-1-benzofuran-2-yl)ethyl]benzoate Chemical compound N#CC1=CC=C2OC(CCC3=CC=C(C=C3)C(ON3C4=CC=CC=C4N=N3)=O)=CC2=C1 OFULEGMRNRXCCQ-UHFFFAOYSA-N 0.000 description 2
- MDHYEMXUFSJLGV-UHFFFAOYSA-N beta-phenethyl acetate Natural products CC(=O)OCCC1=CC=CC=C1 MDHYEMXUFSJLGV-UHFFFAOYSA-N 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
- 125000004181 carboxyalkyl group Chemical group 0.000 description 2
- 150000007942 carboxylates Chemical class 0.000 description 2
- 238000010531 catalytic reduction reaction Methods 0.000 description 2
- BULLHNJGPPOUOX-UHFFFAOYSA-N chloroacetone Chemical compound CC(=O)CCl BULLHNJGPPOUOX-UHFFFAOYSA-N 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 230000032050 esterification Effects 0.000 description 2
- NGJROWIAIGCUGO-UHFFFAOYSA-N ethyl 2-(2-acetyl-4-bromophenoxy)acetate Chemical compound CCOC(=O)COC1=CC=C(Br)C=C1C(C)=O NGJROWIAIGCUGO-UHFFFAOYSA-N 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 2
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- HSZCZNFXUDYRKD-UHFFFAOYSA-M lithium iodide Chemical compound [Li+].[I-] HSZCZNFXUDYRKD-UHFFFAOYSA-M 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 2
- LSEFCHWGJNHZNT-UHFFFAOYSA-M methyl(triphenyl)phosphanium;bromide Chemical compound [Br-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(C)C1=CC=CC=C1 LSEFCHWGJNHZNT-UHFFFAOYSA-M 0.000 description 2
- ZRSNZINYAWTAHE-UHFFFAOYSA-N p-methoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C=C1 ZRSNZINYAWTAHE-UHFFFAOYSA-N 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 229960001639 penicillamine Drugs 0.000 description 2
- BGAXCPSNMHVHJC-UHFFFAOYSA-N phenacyl acetate Chemical compound CC(=O)OCC(=O)C1=CC=CC=C1 BGAXCPSNMHVHJC-UHFFFAOYSA-N 0.000 description 2
- 229920000573 polyethylene Polymers 0.000 description 2
- 235000019260 propionic acid Nutrition 0.000 description 2
- 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- RKZDIVDEKBPOOV-UHFFFAOYSA-N s-(4-bromo-2-formylphenyl) n,n-dimethylcarbamothioate Chemical compound CN(C)C(=O)SC1=CC=C(Br)C=C1C=O RKZDIVDEKBPOOV-UHFFFAOYSA-N 0.000 description 2
- JPJALAQPGMAKDF-UHFFFAOYSA-N selenium dioxide Chemical compound O=[Se]=O JPJALAQPGMAKDF-UHFFFAOYSA-N 0.000 description 2
- BFFLLBPMZCIGRM-QMMMGPOBSA-N tert-butyl (2s)-2-(hydroxymethyl)pyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC[C@H]1CO BFFLLBPMZCIGRM-QMMMGPOBSA-N 0.000 description 2
- XMLFYOVUGZNFRH-ZDUSSCGKSA-N tert-butyl (3s)-3-(4-formyl-3-hydroxyphenoxy)pyrrolidine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CC[C@@H]1OC1=CC=C(C=O)C(O)=C1 XMLFYOVUGZNFRH-ZDUSSCGKSA-N 0.000 description 2
- GVBXZOXXZYCGSC-QHCPKHFHSA-N tert-butyl (3s)-3-[4-[2-(5-cyano-1-benzofuran-2-yl)ethyl]phenoxy]pyrrolidine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CC[C@@H]1OC(C=C1)=CC=C1CCC1=CC2=CC(C#N)=CC=C2O1 GVBXZOXXZYCGSC-QHCPKHFHSA-N 0.000 description 2
- FPWSVALUFXHANF-QHCPKHFHSA-N tert-butyl (3s)-3-[4-[2-(6-cyano-1h-indol-2-yl)ethyl]phenoxy]pyrrolidine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CC[C@@H]1OC(C=C1)=CC=C1CCC1=CC2=CC=C(C#N)C=C2N1 FPWSVALUFXHANF-QHCPKHFHSA-N 0.000 description 2
- JOPBFJXCSWTKOO-YZSHGGLSSA-N tert-butyl (3s)-3-[4-[3-(6-cyano-1h-indol-2-yl)-1-[[(2s)-1-(4-methylphenyl)sulfonylpyrrolidin-2-yl]methoxy]-1-oxopropan-2-yl]phenoxy]pyrrolidine-1-carboxylate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)N1[C@H](COC(=O)C(CC=2NC3=CC(=CC=C3C=2)C#N)C=2C=CC(O[C@@H]3CN(CC3)C(=O)OC(C)(C)C)=CC=2)CCC1 JOPBFJXCSWTKOO-YZSHGGLSSA-N 0.000 description 2
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 231100000820 toxicity test Toxicity 0.000 description 2
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-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
- 238000010792 warming Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- VCGRFBXVSFAGGA-UHFFFAOYSA-N (1,1-dioxo-1,4-thiazinan-4-yl)-[6-[[3-(4-fluorophenyl)-5-methyl-1,2-oxazol-4-yl]methoxy]pyridin-3-yl]methanone Chemical compound CC=1ON=C(C=2C=CC(F)=CC=2)C=1COC(N=C1)=CC=C1C(=O)N1CCS(=O)(=O)CC1 VCGRFBXVSFAGGA-UHFFFAOYSA-N 0.000 description 1
- BZAOTHRLLDGSDG-UHFFFAOYSA-N (1-hydroxy-2-oxo-2-phenylethyl) acetate Chemical compound C(C)(=O)OC(C(C1=CC=CC=C1)=O)O BZAOTHRLLDGSDG-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
- BOTREHHXSQGWTR-BYPYZUCNSA-N (3s)-oxolane-3-carboxylic acid Chemical compound OC(=O)[C@H]1CCOC1 BOTREHHXSQGWTR-BYPYZUCNSA-N 0.000 description 1
- MHSGOABISYIYKP-UHFFFAOYSA-N (4-nitrophenyl)methyl carbonochloridate Chemical compound [O-][N+](=O)C1=CC=C(COC(Cl)=O)C=C1 MHSGOABISYIYKP-UHFFFAOYSA-N 0.000 description 1
- PYHGKAFYVXRYMJ-UHFFFAOYSA-M (5-bromo-1-benzofuran-2-yl)methyl-triphenylphosphanium;chloride Chemical compound [Cl-].C=1C2=CC(Br)=CC=C2OC=1C[P+](C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 PYHGKAFYVXRYMJ-UHFFFAOYSA-M 0.000 description 1
- KAKXAXVTXCGICU-UHFFFAOYSA-N (5-bromo-1-benzothiophen-2-yl)methanol Chemical compound BrC1=CC=C2SC(CO)=CC2=C1 KAKXAXVTXCGICU-UHFFFAOYSA-N 0.000 description 1
- HCYGOAPIBMWCHT-UHFFFAOYSA-M (5-cyano-1-benzofuran-3-yl)methyl-triphenylphosphanium;bromide Chemical compound [Br-].C12=CC(C#N)=CC=C2OC=C1C[P+](C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 HCYGOAPIBMWCHT-UHFFFAOYSA-M 0.000 description 1
- GASADEFQADIKCF-UHFFFAOYSA-M (5-cyano-1-benzofuran-3-yl)methyl-triphenylphosphanium;chloride Chemical compound [Cl-].C12=CC(C#N)=CC=C2OC=C1C[P+](C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 GASADEFQADIKCF-UHFFFAOYSA-M 0.000 description 1
- SQMPXPVOFLGOLK-UHFFFAOYSA-M (5-cyano-1h-indol-2-yl)methyl-triphenylphosphanium;bromide Chemical compound [Br-].C=1C2=CC(C#N)=CC=C2NC=1C[P+](C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 SQMPXPVOFLGOLK-UHFFFAOYSA-M 0.000 description 1
- QTZNQELWWDSPJF-UHFFFAOYSA-M (5-cyano-3-methyl-1-benzofuran-2-yl)methyl-triphenylphosphanium;chloride Chemical compound [Cl-].O1C2=CC=C(C#N)C=C2C(C)=C1C[P+](C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 QTZNQELWWDSPJF-UHFFFAOYSA-M 0.000 description 1
- VYDLFSHOYOXCSO-UHFFFAOYSA-M (5-cyano-7-methoxy-1-benzofuran-2-yl)methyl-triphenylphosphanium;chloride Chemical compound [Cl-].O1C=2C(OC)=CC(C#N)=CC=2C=C1C[P+](C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 VYDLFSHOYOXCSO-UHFFFAOYSA-M 0.000 description 1
- UMZXNHUGTVRBCU-UHFFFAOYSA-M (6-cyano-1,2,3,4-tetrahydronaphthalen-2-yl)methyl-triphenylphosphanium;4-methylbenzenesulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1.C1CC2=CC(C#N)=CC=C2CC1C[P+](C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 UMZXNHUGTVRBCU-UHFFFAOYSA-M 0.000 description 1
- XDWQIXNKLDISIA-UHFFFAOYSA-M (6-cyano-1-methylindol-2-yl)methyl-triphenylphosphanium;bromide Chemical compound [Br-].C=1C2=CC=C(C#N)C=C2N(C)C=1C[P+](C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 XDWQIXNKLDISIA-UHFFFAOYSA-M 0.000 description 1
- LVRCRZNKWDFOHH-UHFFFAOYSA-M (6-cyanonaphthalen-2-yl)methyl-triphenylphosphanium;bromide Chemical compound [Br-].C1=CC2=CC(C#N)=CC=C2C=C1C[P+](C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 LVRCRZNKWDFOHH-UHFFFAOYSA-M 0.000 description 1
- CSDXGEYFAIVGSH-UHFFFAOYSA-M (7-cyanonaphthalen-2-yl)methyl-triphenylphosphanium;bromide Chemical compound [Br-].C=1C2=CC(C#N)=CC=C2C=CC=1C[P+](C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 CSDXGEYFAIVGSH-UHFFFAOYSA-M 0.000 description 1
- KSEBMYQBYZTDHS-HWKANZROSA-M (E)-Ferulic acid Natural products COC1=CC(\C=C\C([O-])=O)=CC=C1O KSEBMYQBYZTDHS-HWKANZROSA-M 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- UAFOHXXTHOBOHP-UHFFFAOYSA-N 1-(5-bromo-1-benzothiophen-2-yl)ethanone Chemical compound BrC1=CC=C2SC(C(=O)C)=CC2=C1 UAFOHXXTHOBOHP-UHFFFAOYSA-N 0.000 description 1
- HQCCNFFIOWYINW-UHFFFAOYSA-N 1-(5-bromo-2-hydroxyphenyl)ethanone Chemical compound CC(=O)C1=CC(Br)=CC=C1O HQCCNFFIOWYINW-UHFFFAOYSA-N 0.000 description 1
- MOHYOXXOKFQHDC-UHFFFAOYSA-N 1-(chloromethyl)-4-methoxybenzene Chemical compound COC1=CC=C(CCl)C=C1 MOHYOXXOKFQHDC-UHFFFAOYSA-N 0.000 description 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 1
- MCZHWLPIAJZSMQ-UHFFFAOYSA-N 1-benzothiophene propanoic acid Chemical compound S1C=CC2=C1C=CC=C2.C(CC)(=O)O MCZHWLPIAJZSMQ-UHFFFAOYSA-N 0.000 description 1
- XEZNGIUYQVAUSS-UHFFFAOYSA-N 18-crown-6 Chemical compound C1COCCOCCOCCOCCOCCO1 XEZNGIUYQVAUSS-UHFFFAOYSA-N 0.000 description 1
- IUNJCFABHJZSKB-UHFFFAOYSA-N 2,4-dihydroxybenzaldehyde Chemical compound OC1=CC=C(C=O)C(O)=C1 IUNJCFABHJZSKB-UHFFFAOYSA-N 0.000 description 1
- NRIVMXXOUOBRAG-UHFFFAOYSA-N 2-(4-methoxyphenyl)acetaldehyde Chemical compound COC1=CC=C(CC=O)C=C1 NRIVMXXOUOBRAG-UHFFFAOYSA-N 0.000 description 1
- OBGXWJYYWCNXIT-UHFFFAOYSA-N 2-(4-methoxyphenyl)ethyl acetate Chemical compound COC1=CC=C(CCOC(C)=O)C=C1 OBGXWJYYWCNXIT-UHFFFAOYSA-N 0.000 description 1
- CUEDZQMJARHDAK-UHFFFAOYSA-N 2-(4-sulfanylphenyl)ethyl acetate Chemical compound CC(=O)OCCC1=CC=C(C=C1)S CUEDZQMJARHDAK-UHFFFAOYSA-N 0.000 description 1
- KEJXWCGXWMGIPJ-UHFFFAOYSA-N 2-(bromomethyl)-1,3-benzothiazole-5-carbonitrile Chemical compound N#CC1=CC=C2SC(CBr)=NC2=C1 KEJXWCGXWMGIPJ-UHFFFAOYSA-N 0.000 description 1
- FQEOEQYILBYTRT-UHFFFAOYSA-N 2-(chloromethyl)-7-methoxy-1-benzofuran-5-carbonitrile Chemical compound COC1=CC(C#N)=CC2=C1OC(CCl)=C2 FQEOEQYILBYTRT-UHFFFAOYSA-N 0.000 description 1
- MWDUSMREGVJVIZ-UHFFFAOYSA-N 2-[(5-bromo-1-benzothiophen-2-yl)methyl]-3-ethoxy-2-(4-methoxyphenyl)-3-oxopropanoic acid Chemical compound C=1C2=CC(Br)=CC=C2SC=1CC(C(=O)OCC)(C(O)=O)C1=CC=C(OC)C=C1 MWDUSMREGVJVIZ-UHFFFAOYSA-N 0.000 description 1
- YMOFSDWBUFAIRB-UHFFFAOYSA-N 2-[2-(5-carbamimidoyl-1-benzofuran-2-yl)ethyl]-1-benzofuran-5-carboximidamide Chemical compound NC(=N)C1=CC=C2OC(CCC=3OC4=CC=C(C=C4C=3)C(=N)N)=CC2=C1 YMOFSDWBUFAIRB-UHFFFAOYSA-N 0.000 description 1
- ZNHCMDCXIWIELR-TXEPZDRESA-N 2-[2-[2-(5-carbamimidoyl-1-benzofuran-2-yl)ethyl]-5-[(3s)-pyrrolidin-3-yl]oxyphenoxy]acetic acid;dihydrochloride Chemical compound Cl.Cl.C=1C2=CC(C(=N)N)=CC=C2OC=1CCC(C(=C1)OCC(O)=O)=CC=C1O[C@H]1CCNC1 ZNHCMDCXIWIELR-TXEPZDRESA-N 0.000 description 1
- MVIOOINSMHBMOW-UHFFFAOYSA-N 2-[2-[4-(hydroxymethyl)phenyl]ethenyl]-1-benzofuran-5-carbonitrile Chemical compound C1=CC(CO)=CC=C1C=CC1=CC2=CC(C#N)=CC=C2O1 MVIOOINSMHBMOW-UHFFFAOYSA-N 0.000 description 1
- RBIVRNWDVMKMMJ-UHFFFAOYSA-N 2-[2-[4-[(1-tritylimidazol-4-yl)methoxy]phenyl]ethyl]-1-benzofuran-5-carbonitrile Chemical compound C=1C2=CC(C#N)=CC=C2OC=1CCC(C=C1)=CC=C1OCC(N=C1)=CN1C(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 RBIVRNWDVMKMMJ-UHFFFAOYSA-N 0.000 description 1
- HLDWIXRUQVSIBU-FYZYNONXSA-N 2-[2-[4-[(3s)-1-acetylpyrrolidin-3-yl]oxy-3-hydroxyphenyl]ethyl]-1-benzofuran-5-carboximidamide;hydrochloride Chemical compound Cl.C1N(C(=O)C)CC[C@@H]1OC(C(=C1)O)=CC=C1CCC1=CC2=CC(C(N)=N)=CC=C2O1 HLDWIXRUQVSIBU-FYZYNONXSA-N 0.000 description 1
- IHCCLXNEEPMSIO-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperidin-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C1CCN(CC1)CC(=O)N1CC2=C(CC1)NN=N2 IHCCLXNEEPMSIO-UHFFFAOYSA-N 0.000 description 1
- DEBJBXAQOJKFHG-UHFFFAOYSA-N 2-[5-bromo-2-[2-(4-methoxyphenyl)ethyl]-1-benzofuran-3-yl]acetonitrile Chemical compound C1=CC(OC)=CC=C1CCC1=C(CC#N)C2=CC(Br)=CC=C2O1 DEBJBXAQOJKFHG-UHFFFAOYSA-N 0.000 description 1
- VNCNZKCYQHBSKA-UHFFFAOYSA-N 2-acetyl-1-benzofuran-5-carbonitrile Chemical compound N#CC1=CC=C2OC(C(=O)C)=CC2=C1 VNCNZKCYQHBSKA-UHFFFAOYSA-N 0.000 description 1
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 description 1
- REXUYBKPWIPONM-UHFFFAOYSA-N 2-bromoacetonitrile Chemical compound BrCC#N REXUYBKPWIPONM-UHFFFAOYSA-N 0.000 description 1
- ARXKVVRQIIOZGF-BYPYZUCNSA-N 2-deoxyerythritol Chemical compound OCC[C@H](O)CO ARXKVVRQIIOZGF-BYPYZUCNSA-N 0.000 description 1
- TUJWGDXCTRWVDC-UHFFFAOYSA-N 2-diethoxyphosphorylethyl acetate Chemical compound CCOP(=O)(OCC)CCOC(C)=O TUJWGDXCTRWVDC-UHFFFAOYSA-N 0.000 description 1
- QYTHAMLZLLHABK-UHFFFAOYSA-N 2-ethyl-1h-indole-6-carbonitrile Chemical compound C1=C(C#N)C=C2NC(CC)=CC2=C1 QYTHAMLZLLHABK-UHFFFAOYSA-N 0.000 description 1
- WCTIDZVDTNFABJ-UHFFFAOYSA-N 2-formyl-1-benzothiophene-5-carbonitrile Chemical compound N#CC1=CC=C2SC(C=O)=CC2=C1 WCTIDZVDTNFABJ-UHFFFAOYSA-N 0.000 description 1
- LMWSIQGMRIVDCJ-UHFFFAOYSA-N 2-formyl-5-methoxybenzoic acid Chemical compound COC1=CC=C(C=O)C(C(O)=O)=C1 LMWSIQGMRIVDCJ-UHFFFAOYSA-N 0.000 description 1
- PGVVKQANLPHXOW-UHFFFAOYSA-N 2-methoxy-2-phenylpropanoic acid Chemical compound COC(C)(C(O)=O)C1=CC=CC=C1 PGVVKQANLPHXOW-UHFFFAOYSA-N 0.000 description 1
- GUPGZURVZDIQPM-UHFFFAOYSA-N 2-oxoethyl acetate Chemical compound CC(=O)OCC=O GUPGZURVZDIQPM-UHFFFAOYSA-N 0.000 description 1
- KNSLGPATJQAECH-UHFFFAOYSA-N 2-phenylacetamide;hydrochloride Chemical compound Cl.NC(=O)CC1=CC=CC=C1 KNSLGPATJQAECH-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- VWLLPPSBBHDXHK-UHFFFAOYSA-N 3,4-diaminobenzonitrile Chemical compound NC1=CC=C(C#N)C=C1N VWLLPPSBBHDXHK-UHFFFAOYSA-N 0.000 description 1
- HCDMJFOHIXMBOV-UHFFFAOYSA-N 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-4,7-dihydropyrrolo[4,5]pyrido[1,2-d]pyrimidin-2-one Chemical compound C=1C2=C3N(CC)C(=O)N(C=4C(=C(OC)C=C(OC)C=4F)F)CC3=CN=C2NC=1CN1CCOCC1 HCDMJFOHIXMBOV-UHFFFAOYSA-N 0.000 description 1
- AGWTYTJJTDWING-UHFFFAOYSA-N 3-(5-bromo-1-benzothiophen-2-yl)-2-(4-methoxyphenyl)butanenitrile Chemical compound C1=CC(OC)=CC=C1C(C#N)C(C)C1=CC2=CC(Br)=CC=C2S1 AGWTYTJJTDWING-UHFFFAOYSA-N 0.000 description 1
- AULXNXHTXKVGCY-DXGWAKCESA-N 3-(5-carbamimidoyl-1-benzofuran-2-yl)-2-[4-[(3s)-pyrrolidin-3-yl]oxyphenyl]propanoic acid;dihydrochloride Chemical compound Cl.Cl.C=1C2=CC(C(=N)N)=CC=C2OC=1CC(C(O)=O)C(C=C1)=CC=C1O[C@H]1CCNC1 AULXNXHTXKVGCY-DXGWAKCESA-N 0.000 description 1
- BUCCNVBFFYXTIE-UHFFFAOYSA-N 3-(5-carbamimidoyl-1-benzothiophen-2-yl)-2-[4-(1-ethanimidoylpiperidin-4-yl)oxyphenyl]propanoic acid Chemical compound C1CN(C(=N)C)CCC1OC1=CC=C(C(CC=2SC3=CC=C(C=C3C=2)C(N)=N)C(O)=O)C=C1 BUCCNVBFFYXTIE-UHFFFAOYSA-N 0.000 description 1
- WCVKYTQHVZFLSY-XEGCMXMBSA-N 3-(5-cyano-1-benzothiophen-2-yl)-2-[4-[[(2S)-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidin-2-yl]methoxy]phenyl]propanoic acid Chemical compound CC(C)(C)OC(=O)N1CCC[C@H]1COC1=CC=C(C(CC=2SC3=CC=C(C=C3C=2)C#N)C(O)=O)C=C1 WCVKYTQHVZFLSY-XEGCMXMBSA-N 0.000 description 1
- NPVAODXPKNGMTM-UHFFFAOYSA-N 3-(6-carbamimidoyl-1-ethylindol-2-yl)-2-[4-(1-ethanimidoylpiperidin-4-yl)oxyphenyl]propanoic acid Chemical compound C=1C2=CC=C(C(N)=N)C=C2N(CC)C=1CC(C(O)=O)C(C=C1)=CC=C1OC1CCN(C(C)=N)CC1 NPVAODXPKNGMTM-UHFFFAOYSA-N 0.000 description 1
- VZMXULILDCTQDZ-WTQRLHSKSA-N 3-(6-carbamimidoyl-1-ethylindol-2-yl)-2-[4-[(3r)-1-ethanimidoylpyrrolidin-3-yl]oxyphenyl]propanoic acid Chemical compound C=1C2=CC=C(C(N)=N)C=C2N(CC)C=1CC(C(O)=O)C(C=C1)=CC=C1O[C@@H]1CCN(C(C)=N)C1 VZMXULILDCTQDZ-WTQRLHSKSA-N 0.000 description 1
- VZMXULILDCTQDZ-NQCNTLBGSA-N 3-(6-carbamimidoyl-1-ethylindol-2-yl)-2-[4-[(3s)-1-ethanimidoylpyrrolidin-3-yl]oxyphenyl]propanoic acid Chemical compound C=1C2=CC=C(C(N)=N)C=C2N(CC)C=1CC(C(O)=O)C(C=C1)=CC=C1O[C@H]1CCN(C(C)=N)C1 VZMXULILDCTQDZ-NQCNTLBGSA-N 0.000 description 1
- ITRZFSJSNAHWDY-NQCNTLBGSA-N 3-(6-cyano-1h-indol-2-yl)-2-[4-[(3s)-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidin-3-yl]oxyphenyl]propanoic acid Chemical compound C1N(C(=O)OC(C)(C)C)CC[C@@H]1OC1=CC=C(C(CC=2NC3=CC(=CC=C3C=2)C#N)C(O)=O)C=C1 ITRZFSJSNAHWDY-NQCNTLBGSA-N 0.000 description 1
- MVNXETBTTGVOLO-VZBZPWRVSA-N 3-(7-carbamimidoylnaphthalen-2-yl)-2-[4-[(3s)-1-ethanimidoylpyrrolidin-3-yl]oxyphenyl]propanoic acid;dihydrochloride Chemical compound Cl.Cl.C1N(C(=N)C)CC[C@@H]1OC1=CC=C(C(CC=2C=C3C=C(C=CC3=CC=2)C(N)=N)C(O)=O)C=C1 MVNXETBTTGVOLO-VZBZPWRVSA-N 0.000 description 1
- FGYKYCWUKYGHGY-UHFFFAOYSA-N 3-(bromomethyl)-1-benzofuran-5-carbonitrile Chemical compound C1=C(C#N)C=C2C(CBr)=COC2=C1 FGYKYCWUKYGHGY-UHFFFAOYSA-N 0.000 description 1
- YUAJUZKHQUNRLB-UHFFFAOYSA-N 3-[3-(4-methoxyphenyl)propyl]-1-benzofuran-5-carbonitrile Chemical compound C1=CC(OC)=CC=C1CCCC1=COC2=CC=C(C#N)C=C12 YUAJUZKHQUNRLB-UHFFFAOYSA-N 0.000 description 1
- XDPCNPCKDGQBAN-UHFFFAOYSA-N 3-hydroxytetrahydrofuran Chemical compound OC1CCOC1 XDPCNPCKDGQBAN-UHFFFAOYSA-N 0.000 description 1
- FJCWTZOHDRAUCV-UHFFFAOYSA-N 4-(2-oxoethyl)benzoic acid Chemical compound OC(=O)C1=CC=C(CC=O)C=C1 FJCWTZOHDRAUCV-UHFFFAOYSA-N 0.000 description 1
- MRSIFRCMKFRWGI-ZYZRXSCRSA-N 4-(5-carbamimidoyl-1-benzothiophen-2-yl)-3-[4-[(3s)-1-ethanimidoylpyrrolidin-3-yl]oxyphenyl]butanoic acid Chemical compound C1N(C(=N)C)CC[C@@H]1OC1=CC=C(C(CC(O)=O)CC=2SC3=CC=C(C=C3C=2)C(N)=N)C=C1 MRSIFRCMKFRWGI-ZYZRXSCRSA-N 0.000 description 1
- YRYGATDCJVKXBF-CXNAUCHYSA-N 4-(5-carbamimidoyl-1-benzothiophen-2-yl)-3-[4-[(3s)-pyrrolidin-3-yl]oxyphenyl]butanoic acid;dihydrochloride Chemical compound Cl.Cl.C=1C2=CC(C(=N)N)=CC=C2SC=1CC(CC(O)=O)C(C=C1)=CC=C1O[C@H]1CCNC1 YRYGATDCJVKXBF-CXNAUCHYSA-N 0.000 description 1
- ADCUCAMWCWNHJA-UHFFFAOYSA-N 4-(chloromethyl)-1-tritylimidazole Chemical compound C1=NC(CCl)=CN1C(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 ADCUCAMWCWNHJA-UHFFFAOYSA-N 0.000 description 1
- ZFHUHPNDGVGXMS-UHFFFAOYSA-N 4-(hydroxymethyl)benzaldehyde Chemical compound OCC1=CC=C(C=O)C=C1 ZFHUHPNDGVGXMS-UHFFFAOYSA-N 0.000 description 1
- BQQFAIYYSNRMAN-UHFFFAOYSA-N 4-[(1-tritylimidazol-4-yl)methoxy]benzaldehyde Chemical compound C1=CC(C=O)=CC=C1OCC1=CN(C(C=2C=CC=CC=2)(C=2C=CC=CC=2)C=2C=CC=CC=2)C=N1 BQQFAIYYSNRMAN-UHFFFAOYSA-N 0.000 description 1
- KVCQTKNUUQOELD-UHFFFAOYSA-N 4-amino-n-[1-(3-chloro-2-fluoroanilino)-6-methylisoquinolin-5-yl]thieno[3,2-d]pyrimidine-7-carboxamide Chemical compound N=1C=CC2=C(NC(=O)C=3C4=NC=NC(N)=C4SC=3)C(C)=CC=C2C=1NC1=CC=CC(Cl)=C1F KVCQTKNUUQOELD-UHFFFAOYSA-N 0.000 description 1
- JQQIWBPHESZYNN-UHFFFAOYSA-N 5-(4-hydroxy-3-methoxyphenyl)pentanoic acid Chemical compound COC1=CC(CCCCC(O)=O)=CC=C1O JQQIWBPHESZYNN-UHFFFAOYSA-N 0.000 description 1
- ZIYHWMODTVOWAT-UHFFFAOYSA-N 5-bromo-2-(bromomethyl)-1-benzothiophene Chemical compound BrC1=CC=C2SC(CBr)=CC2=C1 ZIYHWMODTVOWAT-UHFFFAOYSA-N 0.000 description 1
- MMFKBTPDEVLIOR-UHFFFAOYSA-N 5-bromo-2-hydroxy-3-methoxybenzaldehyde Chemical compound COC1=CC(Br)=CC(C=O)=C1O MMFKBTPDEVLIOR-UHFFFAOYSA-N 0.000 description 1
- OLQKNZNXLBILDD-UHFFFAOYSA-N 5-bromo-2-methyl-1,3-benzothiazole Chemical compound BrC1=CC=C2SC(C)=NC2=C1 OLQKNZNXLBILDD-UHFFFAOYSA-N 0.000 description 1
- YXIAIYNVVOJVAS-UHFFFAOYSA-N 5-bromo-3-(chloromethyl)-2-[2-(4-methoxyphenyl)ethyl]-1-benzofuran Chemical compound C1=CC(OC)=CC=C1CCC1=C(CCl)C2=CC(Br)=CC=C2O1 YXIAIYNVVOJVAS-UHFFFAOYSA-N 0.000 description 1
- OEICZFFUNDGUEF-UHFFFAOYSA-N 5-bromo-7-methoxy-1-benzofuran-2-carboxylic acid Chemical compound COC1=CC(Br)=CC2=C1OC(C(O)=O)=C2 OEICZFFUNDGUEF-UHFFFAOYSA-N 0.000 description 1
- PNDRDNIFVDEDDI-UHFFFAOYSA-N 5-ethoxy-3,4-dihydro-2h-pyrrole Chemical compound CCOC1=NCCC1 PNDRDNIFVDEDDI-UHFFFAOYSA-N 0.000 description 1
- RMRKDYNVZWKAFP-UHFFFAOYSA-N 6-methoxy-3,4-dihydro-1h-naphthalen-2-one Chemical compound C1C(=O)CCC2=CC(OC)=CC=C21 RMRKDYNVZWKAFP-UHFFFAOYSA-N 0.000 description 1
- YYQROUFJRZIQNQ-UHFFFAOYSA-N 6-methylnaphthalene-2-carbonitrile Chemical compound C1=C(C#N)C=CC2=CC(C)=CC=C21 YYQROUFJRZIQNQ-UHFFFAOYSA-N 0.000 description 1
- WBCZIZCMFWRDIJ-UHFFFAOYSA-N 7-methylnaphthalene-2-carboxylic acid Chemical compound C1=CC(C(O)=O)=CC2=CC(C)=CC=C21 WBCZIZCMFWRDIJ-UHFFFAOYSA-N 0.000 description 1
- 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 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 206010002388 Angina unstable Diseases 0.000 description 1
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 206010008088 Cerebral artery embolism Diseases 0.000 description 1
- 206010008132 Cerebral thrombosis Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- XJUZRXYOEPSWMB-UHFFFAOYSA-N Chloromethyl methyl ether Chemical compound COCCl XJUZRXYOEPSWMB-UHFFFAOYSA-N 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
- YIIMEMSDCNDGTB-UHFFFAOYSA-N Dimethylcarbamoyl chloride Chemical compound CN(C)C(Cl)=O YIIMEMSDCNDGTB-UHFFFAOYSA-N 0.000 description 1
- 108010049003 Fibrinogen Proteins 0.000 description 1
- 102000008946 Fibrinogen Human genes 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- LELOWRISYMNNSU-UHFFFAOYSA-N Hydrocyanic acid Natural products N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 208000010159 IgA glomerulonephritis Diseases 0.000 description 1
- 206010021263 IgA nephropathy 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
- 201000001429 Intracranial Thrombosis Diseases 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- AYCPARAPKDAOEN-LJQANCHMSA-N N-[(1S)-2-(dimethylamino)-1-phenylethyl]-6,6-dimethyl-3-[(2-methyl-4-thieno[3,2-d]pyrimidinyl)amino]-1,4-dihydropyrrolo[3,4-c]pyrazole-5-carboxamide Chemical compound C1([C@H](NC(=O)N2C(C=3NN=C(NC=4C=5SC=CC=5N=C(C)N=4)C=3C2)(C)C)CN(C)C)=CC=CC=C1 AYCPARAPKDAOEN-LJQANCHMSA-N 0.000 description 1
- VIHYIVKEECZGOU-UHFFFAOYSA-N N-acetylimidazole Chemical compound CC(=O)N1C=CN=C1 VIHYIVKEECZGOU-UHFFFAOYSA-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
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 108010051508 Preconativ Proteins 0.000 description 1
- 208000010378 Pulmonary Embolism Diseases 0.000 description 1
- 208000006193 Pulmonary infarction Diseases 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 108010000499 Thromboplastin Proteins 0.000 description 1
- 102000002262 Thromboplastin Human genes 0.000 description 1
- 208000007814 Unstable Angina Diseases 0.000 description 1
- 206010047249 Venous thrombosis Diseases 0.000 description 1
- KOQBUFCBHFDVOV-UHFFFAOYSA-M [2-(6-cyano-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]-methyl-diphenylphosphanium;4-methylbenzenesulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1.C=1C=CC=CC=1[P+](C=1C(=CC=CC=1)C1CC2=CC=C(C=C2CC1)C#N)(C)C1=CC=CC=C1 KOQBUFCBHFDVOV-UHFFFAOYSA-M 0.000 description 1
- YNXRIAHCPAXENU-ZDUSSCGKSA-N [2-[(3s)-1-acetylpyrrolidin-3-yl]oxy-5-formylphenyl] acetate Chemical compound CC(=O)OC1=CC(C=O)=CC=C1O[C@@H]1CN(C(C)=O)CC1 YNXRIAHCPAXENU-ZDUSSCGKSA-N 0.000 description 1
- ITLHXEGAYQFOHJ-UHFFFAOYSA-N [diazo(phenyl)methyl]benzene Chemical compound C=1C=CC=CC=1C(=[N+]=[N-])C1=CC=CC=C1 ITLHXEGAYQFOHJ-UHFFFAOYSA-N 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000001252 acrylic acid derivatives Chemical class 0.000 description 1
- YKIOKAURTKXMSB-UHFFFAOYSA-N adams's catalyst Chemical compound O=[Pt]=O YKIOKAURTKXMSB-UHFFFAOYSA-N 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- WNLRTRBMVRJNCN-UHFFFAOYSA-L adipate(2-) Chemical compound [O-]C(=O)CCCCC([O-])=O WNLRTRBMVRJNCN-UHFFFAOYSA-L 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 125000005085 alkoxycarbonylalkoxy group Chemical group 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- HOPRXXXSABQWAV-UHFFFAOYSA-N anhydrous collidine Natural products CC1=CC=NC(C)=C1C HOPRXXXSABQWAV-UHFFFAOYSA-N 0.000 description 1
- 229960004676 antithrombotic agent Drugs 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 150000001491 aromatic compounds Chemical class 0.000 description 1
- 239000002473 artificial blood Substances 0.000 description 1
- 229910052788 barium Inorganic materials 0.000 description 1
- MTZQAGJQAFMTAQ-UHFFFAOYSA-N benzoic acid ethyl ester Natural products CCOC(=O)C1=CC=CC=C1 MTZQAGJQAFMTAQ-UHFFFAOYSA-N 0.000 description 1
- 229940007550 benzyl acetate Drugs 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 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
- QUKGYYKBILRGFE-UHFFFAOYSA-N benzyloxyacetoaldehyde Natural products CC(=O)OCC1=CC=CC=C1 QUKGYYKBILRGFE-UHFFFAOYSA-N 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 230000023555 blood coagulation Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- KDPAWGWELVVRCH-UHFFFAOYSA-M bromoacetate Chemical compound [O-]C(=O)CBr KDPAWGWELVVRCH-UHFFFAOYSA-M 0.000 description 1
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 1
- KVNRLNFWIYMESJ-UHFFFAOYSA-N butyronitrile Chemical compound CCCC#N KVNRLNFWIYMESJ-UHFFFAOYSA-N 0.000 description 1
- 238000011088 calibration curve Methods 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001734 carboxylic acid salts Chemical class 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 210000001715 carotid artery Anatomy 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 206010008118 cerebral infarction Diseases 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 229920001429 chelating resin Polymers 0.000 description 1
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 1
- 229940061627 chloromethyl methyl ether Drugs 0.000 description 1
- 230000004087 circulation Effects 0.000 description 1
- GKTWGGQPFAXNFI-HNNXBMFYSA-N clopidogrel Chemical compound C1([C@H](N2CC=3C=CSC=3CC2)C(=O)OC)=CC=CC=C1Cl GKTWGGQPFAXNFI-HNNXBMFYSA-N 0.000 description 1
- UTBIMNXEDGNJFE-UHFFFAOYSA-N collidine Natural products CC1=CC=C(C)C(C)=N1 UTBIMNXEDGNJFE-UHFFFAOYSA-N 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000007887 coronary angioplasty Methods 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 231100000517 death Toxicity 0.000 description 1
- 238000010908 decantation Methods 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- 238000010612 desalination reaction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 208000009190 disseminated intravascular coagulation Diseases 0.000 description 1
- CJYQQUPRURWLOW-YDLUHMIOSA-M dmsc Chemical compound [Na+].OP(=O)=O.OP(=O)=O.OP(=O)=O.[O-]P(=O)=O.O=C1C2=C(O)C=CC=C2[C@H](C)[C@@H]2C1=C(O)[C@]1(O)C(=O)C(C(N)=O)=C(O)[C@@H](N(C)C)[C@@H]1[C@H]2O CJYQQUPRURWLOW-YDLUHMIOSA-M 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- BGWMHFKCAUBYJJ-UHFFFAOYSA-N ethyl 2-chloroethanimidate;hydrochloride Chemical compound Cl.CCOC(=N)CCl BGWMHFKCAUBYJJ-UHFFFAOYSA-N 0.000 description 1
- MODZVIMSNXSQIH-UHFFFAOYSA-N ethyl benzenecarboximidate;hydron;chloride Chemical compound Cl.CCOC(=N)C1=CC=CC=C1 MODZVIMSNXSQIH-UHFFFAOYSA-N 0.000 description 1
- XITIPHRDUYXQRM-UHFFFAOYSA-N ethyl n-methylethanimidate;hydrochloride Chemical compound Cl.CCOC(C)=NC XITIPHRDUYXQRM-UHFFFAOYSA-N 0.000 description 1
- KSEBMYQBYZTDHS-HWKANZROSA-N ferulic acid Chemical compound COC1=CC(\C=C\C(O)=O)=CC=C1O KSEBMYQBYZTDHS-HWKANZROSA-N 0.000 description 1
- 229940114124 ferulic acid Drugs 0.000 description 1
- KSEBMYQBYZTDHS-UHFFFAOYSA-N ferulic acid Natural products COC1=CC(C=CC(O)=O)=CC=C1O KSEBMYQBYZTDHS-UHFFFAOYSA-N 0.000 description 1
- 235000001785 ferulic acid Nutrition 0.000 description 1
- 229940012952 fibrinogen Drugs 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- JFCQEDHGNNZCLN-UHFFFAOYSA-N glutaric acid Chemical compound OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000023597 hemostasis Effects 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- DKAGJZJALZXOOV-UHFFFAOYSA-N hydrate;hydrochloride Chemical compound O.Cl DKAGJZJALZXOOV-UHFFFAOYSA-N 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 201000004332 intermediate coronary syndrome Diseases 0.000 description 1
- 201000010849 intracranial embolism Diseases 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 1
- 210000004731 jugular vein Anatomy 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 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
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- SFGOUECCROBXPW-UHFFFAOYSA-N methyl 2-acetyloxy-2-phenylacetate Chemical compound COC(=O)C(OC(C)=O)C1=CC=CC=C1 SFGOUECCROBXPW-UHFFFAOYSA-N 0.000 description 1
- 229940095102 methyl benzoate Drugs 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- PHWISQNXPLXQRU-UHFFFAOYSA-N n,n-dimethylcarbamothioyl chloride Chemical compound CN(C)C(Cl)=S PHWISQNXPLXQRU-UHFFFAOYSA-N 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- ISTNTWNUUVRSBR-UHFFFAOYSA-N o-(4-bromo-2-formylphenyl) n,n-dimethylcarbamothioate Chemical compound CN(C)C(=S)OC1=CC=C(Br)C=C1C=O ISTNTWNUUVRSBR-UHFFFAOYSA-N 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- ORWKVZNEPHTCQE-VQEHIDDOSA-N oxomethyl acetate Chemical compound CC(=O)O[13CH]=O ORWKVZNEPHTCQE-VQEHIDDOSA-N 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical class CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- WSDQIHATCCOMLH-UHFFFAOYSA-N phenyl n-(3,5-dichlorophenyl)carbamate Chemical compound ClC1=CC(Cl)=CC(NC(=O)OC=2C=CC=CC=2)=C1 WSDQIHATCCOMLH-UHFFFAOYSA-N 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-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
- 229920001296 polysiloxane Polymers 0.000 description 1
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 1
- ZNNZYHKDIALBAK-UHFFFAOYSA-M potassium thiocyanate Chemical compound [K+].[S-]C#N ZNNZYHKDIALBAK-UHFFFAOYSA-M 0.000 description 1
- 229940116357 potassium thiocyanate Drugs 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 230000003449 preventive 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
- 125000004742 propyloxycarbonyl group Chemical group 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000007575 pulmonary infarction Effects 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- XFTQRUTUGRCSGO-UHFFFAOYSA-N pyrazin-2-amine Chemical compound NC1=CN=CC=N1 XFTQRUTUGRCSGO-UHFFFAOYSA-N 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 230000006965 reversible inhibition Effects 0.000 description 1
- 125000005920 sec-butoxy group Chemical group 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
- 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
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000000859 sublimation Methods 0.000 description 1
- 230000008022 sublimation Effects 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YAUZPGGLENQLNI-ZDUSSCGKSA-N tert-butyl (3s)-3-(4-formyl-2-methoxyphenoxy)pyrrolidine-1-carboxylate Chemical compound COC1=CC(C=O)=CC=C1O[C@@H]1CN(C(=O)OC(C)(C)C)CC1 YAUZPGGLENQLNI-ZDUSSCGKSA-N 0.000 description 1
- MEQOYLKEHIWPOZ-AWEZNQCLSA-N tert-butyl (3s)-3-(4-formylphenoxy)pyrrolidine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CC[C@@H]1OC1=CC=C(C=O)C=C1 MEQOYLKEHIWPOZ-AWEZNQCLSA-N 0.000 description 1
- PWQLFIKTGRINFF-UHFFFAOYSA-N tert-butyl 4-hydroxypiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(O)CC1 PWQLFIKTGRINFF-UHFFFAOYSA-N 0.000 description 1
- QQWYQAQQADNEIC-UHFFFAOYSA-N tert-butyl [[cyano(phenyl)methylidene]amino] carbonate Chemical compound CC(C)(C)OC(=O)ON=C(C#N)C1=CC=CC=C1 QQWYQAQQADNEIC-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- LQRGWGOFPUXNOV-ZETCQYMHSA-N tert-butyl n-[(2s)-1-hydroxybutan-2-yl]carbamate Chemical compound CC[C@@H](CO)NC(=O)OC(C)(C)C LQRGWGOFPUXNOV-ZETCQYMHSA-N 0.000 description 1
- FXMNVYBROILAKU-UHFFFAOYSA-N tert-butyl n-[cyano(phenyl)methylidene]carbamate Chemical compound CC(C)(C)OC(=O)N=C(C#N)C1=CC=CC=C1 FXMNVYBROILAKU-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- HFRXJVQOXRXOPP-UHFFFAOYSA-N thionyl bromide Chemical compound BrS(Br)=O HFRXJVQOXRXOPP-UHFFFAOYSA-N 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- QURCVMIEKCOAJU-UHFFFAOYSA-N trans-isoferulic acid Natural products COC1=CC=C(C=CC(O)=O)C=C1O QURCVMIEKCOAJU-UHFFFAOYSA-N 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 238000003828 vacuum filtration Methods 0.000 description 1
- MWOOGOJBHIARFG-UHFFFAOYSA-N vanillin Chemical compound COC1=CC(C=O)=CC=C1O MWOOGOJBHIARFG-UHFFFAOYSA-N 0.000 description 1
- FGQOOHJZONJGDT-UHFFFAOYSA-N vanillin Natural products COC1=CC(O)=CC(C=O)=C1 FGQOOHJZONJGDT-UHFFFAOYSA-N 0.000 description 1
- 235000012141 vanillin Nutrition 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C257/00—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines
- C07C257/10—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines
- C07C257/18—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines having carbon atoms of amidino groups bound to carbon atoms of six-membered aromatic rings
-
- 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
- C07D207/12—Oxygen or sulfur atoms
-
- 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
- C07D211/06—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 no double bonds between ring members or between ring members and non-ring members
- C07D211/08—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 no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—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 no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/20—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 no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
- C07D211/22—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 no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
-
- 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
- C07D211/06—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 no double bonds between ring members or between ring members and non-ring members
- C07D211/36—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 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
- C07D211/40—Oxygen atoms
- C07D211/44—Oxygen atoms attached in position 4
- C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- 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
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
- C07D307/80—Radicals substituted by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
- C07D307/81—Radicals substituted by nitrogen atoms not forming part of a nitro radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
- C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
- C07D333/60—Radicals substituted by 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
- 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
- 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
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 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)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Plural Heterocyclic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Hydrogenated Pyridines (AREA)
- Furan Compounds (AREA)
- Pyrrole Compounds (AREA)
- Materials For Medical Uses (AREA)
- Solid-Sorbent Or Filter-Aiding Compositions (AREA)
- Medicinal Preparation (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Cultivation Of Plants (AREA)
- Seasonings (AREA)
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP28608891 | 1991-10-31 |
Publications (3)
Publication Number | Publication Date |
---|---|
NO924164D0 NO924164D0 (no) | 1992-10-29 |
NO924164L NO924164L (no) | 1993-05-03 |
NO302948B1 true NO302948B1 (no) | 1998-05-11 |
Family
ID=17699787
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO924164A NO302948B1 (no) | 1991-10-31 | 1992-10-29 | Pyrrolidin- og piperidinderivater med antikoagulerende aktivitet, og midler inneholdende slike derivater |
Country Status (29)
Country | Link |
---|---|
US (4) | US5576343A (xx) |
EP (1) | EP0540051B1 (xx) |
JP (2) | JP2879718B2 (xx) |
KR (1) | KR100205152B1 (xx) |
CN (3) | CN1049434C (xx) |
AT (1) | ATE136293T1 (xx) |
AU (1) | AU666137B2 (xx) |
BG (1) | BG63237B2 (xx) |
CA (1) | CA2081836C (xx) |
CZ (1) | CZ284381B6 (xx) |
DE (1) | DE69209615T2 (xx) |
DK (1) | DK0540051T3 (xx) |
EE (1) | EE03024B1 (xx) |
ES (1) | ES2088073T3 (xx) |
FI (1) | FI107923B (xx) |
GR (1) | GR3019832T3 (xx) |
HK (1) | HK1002999A1 (xx) |
HR (1) | HRP921147B1 (xx) |
HU (1) | HU221976B1 (xx) |
IL (1) | IL103564A (xx) |
MX (1) | MX9206295A (xx) |
NO (1) | NO302948B1 (xx) |
NZ (1) | NZ244936A (xx) |
PL (1) | PL170312B1 (xx) |
RU (1) | RU2139851C1 (xx) |
SG (1) | SG78251A1 (xx) |
SK (1) | SK327692A3 (xx) |
TW (1) | TW210998B (xx) |
ZA (1) | ZA928276B (xx) |
Families Citing this family (126)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6087380A (en) * | 1949-11-24 | 2000-07-11 | Boehringer Ingelheim Pharma Kg | Disubstituted bicyclic heterocycles, the preparations and the use thereof as pharmaceutical compositions |
US5731324A (en) * | 1993-07-22 | 1998-03-24 | Eli Lilly And Company | Glycoprotein IIb/IIIa antagonists |
US6448269B1 (en) | 1993-07-22 | 2002-09-10 | Eli Lilly And Company | Glycoprotein IIb/IIIa antagonists |
US6137002A (en) * | 1993-07-22 | 2000-10-24 | Eli Lilly And Company | Glycoprotein IIb/IIIa antagonists |
IL110172A (en) * | 1993-07-22 | 2001-10-31 | Lilly Co Eli | Bicycle compounds and pharmaceuticals containing them |
CA2134192A1 (en) * | 1993-11-12 | 1995-05-13 | Michael L. Denney | 5, 6-bicyclic glycoprotein iib/iiia antagonists |
EP0712844A4 (en) * | 1994-06-06 | 1996-11-06 | Green Cross Corp | NOVEL CARBOXYLIC ACID COMPOUND WITH FUSED CORE OR SALT THEREOF, AND ITS USE IN MEDICINE |
MX9704059A (es) * | 1994-12-02 | 1997-08-30 | Yamanouchi Pharma Co Ltd | Derivado de amidinonaftilo novedoso o sal del mismo. |
ES2208737T3 (es) * | 1995-03-10 | 2004-06-16 | Berlex Laboratories, Inc. | Derivados de benzamidina, su preparacion y su utilizacion como anticoagulantes. |
US5691364A (en) * | 1995-03-10 | 1997-11-25 | Berlex Laboratories, Inc. | Benzamidine derivatives and their use as anti-coagulants |
US5612363A (en) * | 1995-06-02 | 1997-03-18 | Berlex Laboratories, Inc. | N,N-di(aryl) cyclic urea derivatives as anti-coagulants |
DE19530996A1 (de) * | 1995-08-23 | 1997-02-27 | Boehringer Mannheim Gmbh | Cyclische Guanidine, Verfahren zu ihrer Herstellung und Arzneimittel |
US5849759A (en) * | 1995-12-08 | 1998-12-15 | Berlex Laboratories, Inc. | Naphthyl-substituted benzimidazole derivatives as anti-coagulants |
US5939418A (en) * | 1995-12-21 | 1999-08-17 | The Dupont Merck Pharmaceutical Company | Isoxazoline, isothiazoline and pyrazoline factor Xa inhibitors |
US5994375A (en) * | 1996-02-12 | 1999-11-30 | Berlex Laboratories, Inc. | Benzamidine derivatives substituted by amino acid and hydroxy acid derivatives and their use as anti-coagulants |
DE19612828C1 (de) * | 1996-03-30 | 1997-02-27 | Boehringer Mannheim Gmbh | Verfahren zur Herstellung von Naphthonitrilderivaten und deren Verwendung zur Herstellung von Faktor-Xa-Inhibitoren |
ES2171945T3 (es) * | 1996-05-31 | 2002-09-16 | C & C Res Lab | Derivados aromaticos de amidina que sirven de inhibidores selectivos de la trombina. |
NZ333696A (en) * | 1996-07-08 | 2000-06-23 | Du Pont Pharm Co | Amidinoindoles, amidinoazoles, and analogs thereof as inhibitors of trypsin like protease enzymes like thrombin and Xa factor |
US5977138A (en) * | 1996-08-15 | 1999-11-02 | Schering Corporation | Ether muscarinic antagonists |
US5693641A (en) * | 1996-08-16 | 1997-12-02 | Berlex Laboratories Inc. | Bicyclic pyrimidine derivatives and their use as anti-coagulants |
US5753635A (en) * | 1996-08-16 | 1998-05-19 | Berlex Laboratories, Inc. | Purine derivatives and their use as anti-coagulants |
TW430652B (en) | 1996-09-06 | 2001-04-21 | Daiichi Seiyaku Co | Process for preparing 2-phenyl-3-naphthyl propionic acid derivatives |
US6008234A (en) * | 1996-09-12 | 1999-12-28 | Berlex Laboratories, Inc. | Benzamidine derivatives substituted by cyclic amino acid and cyclic hydroxy acid derivatives and their use as anti-coagulants |
EP0929547B1 (en) | 1996-09-12 | 2002-11-27 | Schering Aktiengesellschaft | Benzamidine derivatives substituted by cyclic amino acid or cycl ic hydroxy acid derivatives and their use as anti-coagulants |
US6004985A (en) * | 1996-10-09 | 1999-12-21 | Berlex Laboratories, Inc. | Thio acid derived monocylic N-heterocyclics as anticoagulants |
EP0842941A1 (de) | 1996-11-16 | 1998-05-20 | Roche Diagnostics GmbH | Neue Phosphonate, Verfahren zu ihrer Herstellung und Arzneimittel |
CA2275475A1 (en) * | 1996-12-19 | 1998-06-25 | Hiroshi Kikuchi | Pharmaceutical composition for oral administration |
SE9604744D0 (sv) * | 1996-12-20 | 1996-12-20 | Pharmacia & Upjohn Ab | A modified coagulation agent |
PE121699A1 (es) * | 1997-02-18 | 1999-12-08 | Boehringer Ingelheim Pharma | Heterociclos biciclicos disustituidos como inhibidores de la trombina |
US7109326B2 (en) | 1997-04-15 | 2006-09-19 | Genentech, Inc. | Halo-alkoxycarbonyl prodrugs |
DE69828522T2 (de) | 1997-04-30 | 2005-12-15 | Eli Lilly And Co., Indianapolis | Antithrombotische mittel |
CA2288144A1 (en) | 1997-04-30 | 1998-11-05 | Eli Lilly And Company | Antithrombotic agents |
US6350774B1 (en) | 1997-04-30 | 2002-02-26 | Eli Lilly And Company | Antithrombotic agents |
CA2287980A1 (en) * | 1997-04-30 | 1998-11-05 | Daniel Jon Sall | Antithrombotic agents |
WO1998048798A1 (en) * | 1997-04-30 | 1998-11-05 | Eli Lilly And Company | Antithrombotic agents |
EP0980366B1 (en) | 1997-04-30 | 2004-06-09 | Eli Lilly And Company | Antithrombotic agents |
EP1019047B1 (en) | 1997-05-01 | 2003-11-05 | Eli Lilly And Company | Antithrombotic agents |
TW513402B (en) * | 1997-05-30 | 2002-12-11 | Daiichi Seiyaku Co | Process for preparing 3-(7-amidino-2-naphthyl)-2-phenylpropionic acid derivatives |
FR2764511B1 (fr) | 1997-06-13 | 2000-09-08 | Sanofi Sa | Compositions pour le traitement et la prevention de la thrombose arterielle et utilisation d'un inhibiteur du facteur xa seul et/ou en combinaison avec un antiagregant plaquettaire |
IL133623A0 (en) * | 1997-06-26 | 2001-04-30 | Lilly Co Eli | Antithrombotic agents |
AU735144B2 (en) | 1997-07-23 | 2001-07-05 | Yamanouchi Pharmaceutical Co., Ltd. | Novel hexahydro-1,4-diazepine derivatives or their salts |
ZA986594B (en) * | 1997-07-25 | 1999-01-27 | Abbott Lab | Urokinase inhibitors |
US6258822B1 (en) | 1997-08-06 | 2001-07-10 | Abbott Laboratories | Urokinase inhibitors |
US5886191A (en) * | 1997-08-18 | 1999-03-23 | Dupont Pharmaceuticals Company | Amidinoindoles, amidinoazoles, and analogs thereof |
US6740682B2 (en) | 1997-08-29 | 2004-05-25 | Tularik Limited | Meta-benzamidine derivatives as serine protease inhibitors |
AU8886698A (en) * | 1997-09-01 | 1999-03-22 | Yamanouchi Pharmaceutical Co., Ltd. | Novel naphthamide derivatives or salts thereof |
CA2303438A1 (en) | 1997-09-09 | 1999-03-18 | Bristol-Myers Squibb Pharma Company | Benzimidazolinones, benzoxazolinones, benzopiperazinones, indanones, and derivatives thereof as inhibitors of factor xa |
DE19743435A1 (de) * | 1997-10-01 | 1999-04-08 | Merck Patent Gmbh | Benzamidinderivate |
EP1030844A1 (en) * | 1997-11-10 | 2000-08-30 | Array Biopharma Inc. | Compounds which inhibit tryptase activity |
US6150379A (en) * | 1997-11-26 | 2000-11-21 | Axys Pharmaceuticals, Inc. | Compounds and compositions as anticoagulants |
AU1608399A (en) * | 1997-11-26 | 1999-06-15 | Axys Pharmaceuticals, Inc. | Substituted amidinoaryl derivatives and their use as anticoagulants |
WO1999026932A1 (en) * | 1997-11-26 | 1999-06-03 | Axys Pharmaceuticals, Inc. | By amidino group substituted heterocyclic derivatives and their use as anticoagulants |
KR19990043605A (ko) * | 1997-11-29 | 1999-06-15 | 이경하 | 선택적 트롬빈 억제제로 유용한 방향족 아미딘유도체 |
US6686364B2 (en) | 1997-12-08 | 2004-02-03 | Berlex Laboratories, Inc. | Benzamidine derivatives and their use as anti-coagulants |
US6140351A (en) * | 1997-12-19 | 2000-10-31 | Berlex Laboratories, Inc. | Ortho-anthranilamide derivatives as anti-coagulants |
ES2215337T3 (es) | 1997-12-19 | 2004-10-01 | Schering Aktiengesellschaft | Derivados de orto-antranilamida como anticoagulantes. |
US6114532A (en) * | 1998-02-03 | 2000-09-05 | Boehringer Ingelheim Pharma Kg | Bicyclic heterocycles, the preparation thereof, and their use as pharmaceuticals |
EP1060166A1 (de) * | 1998-02-03 | 2000-12-20 | Boehringer Ingelheim Pharma KG | 5-gliedrige benzokondensierte heterocyclen als antithrombotika |
EP0937723A1 (de) * | 1998-02-18 | 1999-08-25 | Roche Diagnostics GmbH | Neue Sulfonamide, Verfahren zu ihrer Herstellung sowie diese enthaltende Arzneimittel |
KR19990074598A (ko) * | 1998-03-12 | 1999-10-05 | 성재갑 | 고체상 반응을 이용한 벤즈아미딘 유도체의 신규한 제조방법 |
EP2332522A3 (en) | 1998-03-19 | 2011-12-07 | Bristol-Myers Squibb Company | Biphasic controlled release delivery system for high solubility pharmaceuticals and method |
AR015269A1 (es) | 1998-04-10 | 2001-04-18 | Japan Tobacco Inc | Compuesto amidinico y composicion farmaceutica, inhibidor de la coagulacion sanguinea e inhibidor del factor xa que lo comprenden |
US6284756B1 (en) | 1998-04-30 | 2001-09-04 | Eli Lilly And Company | Antithrombotic agents |
DE19834751A1 (de) * | 1998-08-01 | 2000-02-03 | Boehringer Ingelheim Pharma | Disubstituierte bicyclische Heterocyclen, ihre Herstellung und ihre Verwendung als Arzneimittel |
US6504031B1 (en) | 1998-08-06 | 2003-01-07 | Milan Bruncko | Naphthamidine urokinase inhibitors |
US6284796B1 (en) | 1998-08-06 | 2001-09-04 | Abbott Laboratories | Ukokinase inhibitors |
DE19839499A1 (de) * | 1998-08-29 | 2000-03-02 | Merck Patent Gmbh | 2-Oxo-2H-chinolinderivate |
JP2000080046A (ja) | 1998-09-03 | 2000-03-21 | Dai Ichi Seiyaku Co Ltd | 多臓器障害の予防・治療剤 |
US6362216B1 (en) | 1998-10-27 | 2002-03-26 | Array Biopharma Inc. | Compounds which inhibit tryptase activity |
ATE229520T1 (de) * | 1998-10-28 | 2002-12-15 | Lilly Co Eli | Benzothiophenderivate als antithrombotische mitteln und zwischenprodukte |
US6262088B1 (en) | 1998-11-19 | 2001-07-17 | Berlex Laboratories, Inc. | Polyhydroxylated monocyclic N-heterocyclic derivatives as anti-coagulants |
US6127376A (en) | 1998-12-04 | 2000-10-03 | Berlex Laboratories, Inc. | Aryl and heterocyclyl substituted pyrimidine derivatives as anti-coagulants |
ES2230909T3 (es) | 1998-12-14 | 2005-05-01 | F. Hoffmann-La Roche Ag | Derivados de fenilglicina. |
AU3127900A (en) * | 1998-12-23 | 2000-07-31 | Du Pont Pharmaceuticals Company | Thrombin or factor xa inhibitors |
US6689780B1 (en) | 1998-12-23 | 2004-02-10 | Eli Lilly And Company | Heteroroaromatic amides as inhibitor of factor Xa |
CA2358095A1 (en) * | 1998-12-23 | 2000-07-06 | Eli Lilly And Company | Heteroroaromatic amides as inhibitor of factor xa |
CA2356934A1 (en) | 1999-01-13 | 2000-07-20 | Genentech, Inc. | Serine protease inhibitors |
FR2793687B1 (fr) * | 1999-04-26 | 2001-08-24 | Sanofi Sa | Nouvelle composition injectable d'un anticoagulant |
FR2793247B1 (fr) * | 1999-05-04 | 2001-06-22 | Synthelabo | Derives de 6-[[(aryl et heteroaryl)oxy]methyl]naphtalene-2- carboximidamide, leur preparation et leur application en therapeutique |
WO2000073270A1 (fr) * | 1999-05-31 | 2000-12-07 | Daiichi Pharmaceutical Co., Ltd. | Remedes traitant les maladies paradontales |
WO2001002356A1 (fr) * | 1999-07-01 | 2001-01-11 | Sankyo Company, Limited | Dérivés d'indoline ou tétrahydroquinoline |
US6350761B1 (en) | 1999-07-30 | 2002-02-26 | Berlex Laboratories, Inc. | Benzenamine derivatives as anti-coagulants |
GB9924155D0 (en) * | 1999-10-12 | 1999-12-15 | Rhone Poulenc Rorer Pharma | Chemical compounds |
DE60024120T2 (de) * | 1999-08-26 | 2006-07-27 | Aventis Pharmaceuticals Inc. | Substituierte (aminoiminomethyl oder aminomethyl) dihydrobenzofurane und benozopyrane |
US6844367B1 (en) | 1999-09-17 | 2005-01-18 | Millennium Pharmaceuticals, Inc. | Benzamides and related inhibitors of factor Xa |
CZ20021432A3 (cs) | 1999-10-28 | 2002-10-16 | Sankyo Company Limited | Benzamidové deriváty |
EP1242366A1 (en) * | 1999-12-15 | 2002-09-25 | Axys Pharmaceuticals, Inc. | Salicylamides as serine protease and factor xa inhibitors |
AU2001227122A1 (en) * | 2000-01-29 | 2001-08-07 | Lg Chem Investment Ltd. | Factor xa inhibitors with aryl-amidines and derivatives, and prodrugs thereof |
AU2001234689A1 (en) * | 2000-02-01 | 2001-08-14 | Cor Therapeutics, Inc. | Bivalent phenylene inhibitors of factor xa |
WO2001057020A1 (en) * | 2000-02-01 | 2001-08-09 | Cor Therapeutics, Inc. | INDOLE AND BENZIMIDAZOLE INHIBITORS OF FACTOR Xa |
WO2001064642A2 (en) | 2000-02-29 | 2001-09-07 | Cor Therapeutics, Inc. | Benzamides and related inhibitors of factor xa |
AU2001247589A1 (en) * | 2000-03-20 | 2001-10-03 | Axys Pharmaceuticals, Inc. | Non-amidine containing protease inhibitors |
JP2001261674A (ja) * | 2000-03-22 | 2001-09-26 | Mitsui Chemicals Inc | ベンゾチオフェン誘導体およびそれを有効成分として含有する核内レセプター作動薬 |
DE10014645A1 (de) | 2000-03-24 | 2001-09-27 | Merck Patent Gmbh | Substituierte Biphenylderivate |
WO2001081314A1 (en) * | 2000-04-25 | 2001-11-01 | Abbott Laboratories | Naphthamidine urokinase inhibitors |
US6495562B1 (en) | 2000-04-25 | 2002-12-17 | Abbott Laboratories | Naphthamidine urokinase inhibitors |
US20020037912A1 (en) * | 2000-08-11 | 2002-03-28 | Leahy Ellen M. | Factor viia inhibitors |
CZ20032728A3 (cs) | 2001-04-05 | 2004-02-18 | Sankyo Company, Limited | Benzamidinové deriváty |
TWI240723B (en) | 2001-06-20 | 2005-10-01 | Wyeth Corp | Substituted naphthyl benzofuran derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-1) |
DE10130718A1 (de) * | 2001-06-26 | 2003-01-02 | Merck Patent Gmbh | Kohlenhydratderivate |
EP1408963A1 (en) * | 2001-07-09 | 2004-04-21 | Axys Pharmaceuticals, Inc. | 2- 5-(5-CARBAMIMIDOYL-1 i H /i -HETEROARYL)-6-HYDROXYBIPHENYL-3-YL]-SUCCINIC ACID DERIVATIVES AS FACTOR VIIA INHIBITORS |
DE10139060A1 (de) | 2001-08-08 | 2003-02-20 | Merck Patent Gmbh | Phenylderivate |
CA2464763A1 (en) * | 2001-11-09 | 2003-05-15 | Kissei Pharmaceutical Co., Ltd. | 5-amidino-2-hydroxybenzenesulfonamide derivatives, medicinal compositions containing the same, medicinal use thereof and intermediates in the production thereof |
US20030181488A1 (en) | 2002-03-07 | 2003-09-25 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Administration form for the oral application of 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1H-benzimidazol-5-carbonyl)-pyridin-2-yl-amino]-propionic acid ethyl ester and the salts thereof |
WO2003099805A1 (en) * | 2002-05-28 | 2003-12-04 | 3-Dimensional Pharmaceuticals, Inc. | Novel thiophene amidines, compositions thereof, and methods of treating complement-mediated diseases and conditions |
JP2006096668A (ja) * | 2002-11-08 | 2006-04-13 | Ono Pharmaceut Co Ltd | エラスターゼ阻害剤と血液凝固系および/または線溶系酵素阻害剤との組み合わせからなる医薬 |
EP2982668A3 (en) | 2002-12-03 | 2016-04-13 | Pharmacyclics LLC | 2-(2-hydroxybiphenyl-3-yl)-1h-benzoimidazole-5-carboxamidine derivatives as factor viia inhibitors for the treatment of thromboembolic disorders |
DE10302500A1 (de) | 2003-01-23 | 2004-07-29 | Merck Patent Gmbh | Carbonsäureamidderivate |
DE10308907A1 (de) | 2003-02-28 | 2004-09-09 | Merck Patent Gmbh | Ethynylderivate |
DE10339862A1 (de) | 2003-08-29 | 2005-03-24 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | 3-[(2-{[4-(Hexyloxycarbonylamino-imino-methyl)- phenylamino]-methyl}-1-methyl-1H-benzimidazol-5-carbonyl)-pyridin-2-yl-amino]-propionsäure-ethylester-Methansulfonat und dessen Verwendung als Arzneimittel |
BRPI0415051A (pt) | 2003-10-01 | 2006-11-28 | Procter & Gamble | compostos antagonistas do hormÈnio concentrador de melanina e suas composições farmacêuticas |
CN1605336A (zh) | 2003-10-10 | 2005-04-13 | 中国医学科学院药物研究所 | 左旋丁基苯酞在制备预防和治疗脑梗塞的药物中的应用 |
TWI396686B (zh) | 2004-05-21 | 2013-05-21 | Takeda Pharmaceutical | 環狀醯胺衍生物、以及其製品和用法 |
JP2006036710A (ja) * | 2004-07-28 | 2006-02-09 | Mitsui Chemicals Inc | 光学活性な3−ヒドロキシテトラヒドロフランの製造法 |
GB2431927B (en) | 2005-11-04 | 2010-03-17 | Amira Pharmaceuticals Inc | 5-Lipoxygenase-activating protein (FLAP) inhibitors |
US8399666B2 (en) | 2005-11-04 | 2013-03-19 | Panmira Pharmaceuticals, Llc | 5-lipoxygenase-activating protein (FLAP) inhibitors |
US7977359B2 (en) | 2005-11-04 | 2011-07-12 | Amira Pharmaceuticals, Inc. | 5-lipdxygenase-activating protein (FLAP) inhibitors |
EP1800727A1 (en) * | 2005-12-20 | 2007-06-27 | DSMIP Assets B.V. | Process for the treatment of an aqueous mixture comprising a dipolar aprotic compound |
PT2077995E (pt) | 2006-11-02 | 2012-05-10 | Millennium Pharm Inc | Métodos de sintetizar sais farmacêuticos de um inibidor de fator xa |
US8227492B2 (en) * | 2007-08-07 | 2012-07-24 | Cadila Healthcare Limited | Sulfoxamine derivatives as factor Xa inhibitors |
TW200920369A (en) | 2007-10-26 | 2009-05-16 | Amira Pharmaceuticals Inc | 5-lipoxygenase activating protein (flap) inhibitor |
JP5791500B2 (ja) | 2008-05-23 | 2015-10-07 | パンミラ ファーマシューティカルズ,エルエルシー. | 5−リポキシゲナーゼ活性化タンパク質阻害剤 |
KR101126080B1 (ko) * | 2008-06-12 | 2012-04-12 | 한미홀딩스 주식회사 | 베타-아밀로이드 피브릴 형성 저해 효능을 갖는 스티릴벤조퓨란 화합물 및 이의 제조 방법 |
US8546431B2 (en) | 2008-10-01 | 2013-10-01 | Panmira Pharmaceuticals, Llc | 5-lipoxygenase-activating protein (FLAP) inhibitors |
EP2590634B1 (en) | 2010-07-09 | 2016-03-09 | BHV Pharma, Inc. | Combination immediate/delayed release delivery system for short half-life pharmaceuticals including remogliflozin |
WO2016200851A1 (en) | 2015-06-09 | 2016-12-15 | Abbvie Inc. | Nuclear receptor modulators |
Family Cites Families (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1050302A (xx) * | 1964-02-19 | |||
AU527371B2 (en) * | 1980-09-16 | 1983-03-03 | Torii & Co., Ltd. | Amidine |
US4681886A (en) * | 1982-04-30 | 1987-07-21 | E. R. Squibb & Sons, Inc. | Substituted 4-phenoxy or 4-phenylthio prolines |
JPS59139357A (ja) * | 1983-01-28 | 1984-08-10 | Torii Yakuhin Kk | アミジン誘導体 |
US4563527A (en) * | 1984-07-19 | 1986-01-07 | Torii & Co., Ltd. | Amidine compounds |
DE3882894T2 (de) * | 1987-10-20 | 1994-03-17 | Mitsui Toatsu Chemicals | 1,2-Naphtalocyanine, Infrarotabsorber und sie verwendende Aufzeichnungsmaterialien. |
US5256812A (en) * | 1989-01-31 | 1993-10-26 | Hoffmann-La Roche Inc. | Carboxamides and sulfonamides |
US4952562A (en) * | 1989-09-29 | 1990-08-28 | Rorer Pharmaceutical Corporation | Anti-thrombotic peptides and pseudopeptides |
US5258398A (en) * | 1991-12-16 | 1993-11-02 | Rhone-Poulenc Rorer Pharmaceuticals Inc. | Antithrombotic diaminoalkanoic acid derivatives |
JPH08176139A (ja) * | 1994-12-20 | 1996-07-09 | Tokuyama Corp | クロメン化合物 |
-
1992
- 1992-10-26 ZA ZA928276A patent/ZA928276B/xx unknown
- 1992-10-27 IL IL10356492A patent/IL103564A/en not_active IP Right Cessation
- 1992-10-28 TW TW081108599A patent/TW210998B/zh active
- 1992-10-29 NZ NZ244936A patent/NZ244936A/en not_active IP Right Cessation
- 1992-10-29 HR HRHEI-3-286088A patent/HRP921147B1/xx not_active IP Right Cessation
- 1992-10-29 NO NO924164A patent/NO302948B1/no unknown
- 1992-10-30 CZ CS923276A patent/CZ284381B6/cs not_active IP Right Cessation
- 1992-10-30 AU AU27470/92A patent/AU666137B2/en not_active Ceased
- 1992-10-30 MX MX9206295A patent/MX9206295A/es not_active IP Right Cessation
- 1992-10-30 CA CA002081836A patent/CA2081836C/en not_active Expired - Fee Related
- 1992-10-30 ES ES92118705T patent/ES2088073T3/es not_active Expired - Lifetime
- 1992-10-30 EP EP92118705A patent/EP0540051B1/en not_active Expired - Lifetime
- 1992-10-30 JP JP4292892A patent/JP2879718B2/ja not_active Expired - Fee Related
- 1992-10-30 SK SK3276-92A patent/SK327692A3/sk unknown
- 1992-10-30 DK DK92118705.0T patent/DK0540051T3/da active
- 1992-10-30 HU HU9203433A patent/HU221976B1/hu not_active IP Right Cessation
- 1992-10-30 AT AT92118705T patent/ATE136293T1/de not_active IP Right Cessation
- 1992-10-30 FI FI924932A patent/FI107923B/fi not_active IP Right Cessation
- 1992-10-30 RU RU92004542A patent/RU2139851C1/ru not_active IP Right Cessation
- 1992-10-30 DE DE69209615T patent/DE69209615T2/de not_active Expired - Fee Related
- 1992-10-30 PL PL92296439A patent/PL170312B1/pl not_active IP Right Cessation
- 1992-10-30 SG SG1996006031A patent/SG78251A1/en unknown
- 1992-10-31 CN CN92114304A patent/CN1049434C/zh not_active Expired - Fee Related
- 1992-10-31 KR KR1019920020309A patent/KR100205152B1/ko not_active IP Right Cessation
-
1994
- 1994-02-25 BG BG098594A patent/BG63237B2/bg unknown
- 1994-11-22 EE EE9400407A patent/EE03024B1/xx not_active IP Right Cessation
-
1995
- 1995-06-06 US US08/468,304 patent/US5576343A/en not_active Expired - Fee Related
- 1995-06-06 US US08/471,173 patent/US5620991A/en not_active Expired - Fee Related
-
1996
- 1996-05-06 GR GR960401207T patent/GR3019832T3/el unknown
-
1997
- 1997-04-16 CN CN97110745A patent/CN1097052C/zh not_active Expired - Fee Related
- 1997-04-16 CN CN97110748A patent/CN1062865C/zh not_active Expired - Fee Related
- 1997-09-05 US US08/924,504 patent/US5866577A/en not_active Expired - Fee Related
-
1998
- 1998-03-12 HK HK98102072A patent/HK1002999A1/xx not_active IP Right Cessation
- 1998-03-31 JP JP08545498A patent/JP3461441B2/ja not_active Expired - Fee Related
- 1998-08-07 US US09/131,235 patent/US5962695A/en not_active Expired - Fee Related
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
NO302948B1 (no) | Pyrrolidin- og piperidinderivater med antikoagulerende aktivitet, og midler inneholdende slike derivater | |
EP0456835B1 (en) | Quinazoline-3-alkanoic acid derivative, salt thereof, and production thereof | |
JP3457694B2 (ja) | インフルエンザ感染予防・治療薬 | |
US5786355A (en) | 4,6-diarylpyrimidine derivatives and salts thereof | |
KR20110073580A (ko) | 스핑고신-1-포스페이트 수용체 길항제 | |
JP3202994B2 (ja) | 選却的トロンビン抑制剤として有用な芳香族アミジン誘導体 | |
US8119673B2 (en) | Compounds 148 | |
CA2036516A1 (en) | Optically active 8-methoxyouinolonecarboxylic acid derivatives, their preparative processes and their intermediates | |
EP0579059B1 (en) | Pyridazinone derivatives and processes for preparing the same | |
KR20130122361A (ko) | 베타-세크리테아제 활성을 억제하는 4-(벤즈이미다졸-2-일아미노)피롤리딘 유도체 및 이를 유효성분으로 함유하는 약제학적 조성물 | |
US5112841A (en) | Imidazole derivatives and antiepileptics comprising said imidazole derivatives as effective ingredients | |
JPS62148481A (ja) | 新規な1,4−ジヒドロピリジン誘導体およびその塩 |