SK282767B6 - Naftyl-substituované benzimidazolové deriváty pôsobiace ako antikoagulačné činidlá, farmaceutický prostriedok obsahujúci tieto látky a použitie týchto látok - Google Patents
Naftyl-substituované benzimidazolové deriváty pôsobiace ako antikoagulačné činidlá, farmaceutický prostriedok obsahujúci tieto látky a použitie týchto látok Download PDFInfo
- Publication number
- SK282767B6 SK282767B6 SK746-98A SK74698A SK282767B6 SK 282767 B6 SK282767 B6 SK 282767B6 SK 74698 A SK74698 A SK 74698A SK 282767 B6 SK282767 B6 SK 282767B6
- Authority
- SK
- Slovakia
- Prior art keywords
- methyl
- group
- optionally substituted
- alkyl
- piperidin
- Prior art date
Links
- 229940058303 antinematodal benzimidazole derivative Drugs 0.000 title claims abstract description 9
- 239000003146 anticoagulant agent Substances 0.000 title abstract description 7
- 229940127219 anticoagulant drug Drugs 0.000 title abstract description 6
- 125000003785 benzimidazolyl group Chemical class N1=C(NC2=C1C=CC=C2)* 0.000 title abstract description 3
- -1 benzimidazole compound Chemical class 0.000 claims abstract description 175
- 239000000203 mixture Substances 0.000 claims abstract description 62
- 108010074860 Factor Xa Proteins 0.000 claims abstract description 41
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 38
- 201000010099 disease Diseases 0.000 claims abstract description 21
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 21
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 15
- 150000001875 compounds Chemical class 0.000 claims description 435
- 229910052736 halogen Inorganic materials 0.000 claims description 149
- 150000002367 halogens Chemical group 0.000 claims description 144
- 125000000217 alkyl group Chemical group 0.000 claims description 130
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 120
- 125000004432 carbon atom Chemical group C* 0.000 claims description 76
- 125000003118 aryl group Chemical group 0.000 claims description 70
- 238000002360 preparation method Methods 0.000 claims description 64
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 62
- 238000000034 method Methods 0.000 claims description 55
- 125000001424 substituent group Chemical group 0.000 claims description 53
- 150000003839 salts Chemical class 0.000 claims description 44
- 125000002883 imidazolyl group Chemical group 0.000 claims description 31
- 125000001041 indolyl group Chemical group 0.000 claims description 31
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 claims description 29
- 125000004104 aryloxy group Chemical group 0.000 claims description 29
- 125000000262 haloalkenyl group Chemical group 0.000 claims description 29
- 229910052739 hydrogen Inorganic materials 0.000 claims description 29
- 239000001257 hydrogen Substances 0.000 claims description 27
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 26
- 125000003545 alkoxy group Chemical group 0.000 claims description 25
- 125000003342 alkenyl group Chemical group 0.000 claims description 24
- 125000005843 halogen group Chemical group 0.000 claims description 23
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 22
- 125000000623 heterocyclic group Chemical group 0.000 claims description 22
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 22
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 20
- 125000003386 piperidinyl group Chemical group 0.000 claims description 20
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 19
- 150000001556 benzimidazoles Chemical class 0.000 claims description 17
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 17
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 16
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 15
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 15
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 claims description 14
- 229910052757 nitrogen Inorganic materials 0.000 claims description 14
- 239000008194 pharmaceutical composition Substances 0.000 claims description 13
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 12
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 12
- 238000011282 treatment Methods 0.000 claims description 12
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 11
- 229910052799 carbon Inorganic materials 0.000 claims description 11
- 229920006395 saturated elastomer Polymers 0.000 claims description 10
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 9
- 125000001624 naphthyl group Chemical group 0.000 claims description 9
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 9
- 125000004429 atom Chemical group 0.000 claims description 8
- 239000001301 oxygen Chemical group 0.000 claims description 8
- 229910052760 oxygen Inorganic materials 0.000 claims description 8
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
- 125000005842 heteroatom Chemical group 0.000 claims description 7
- 229910052717 sulfur Chemical group 0.000 claims description 7
- 239000011593 sulfur Chemical group 0.000 claims description 7
- 230000001732 thrombotic effect Effects 0.000 claims description 7
- 125000006727 (C1-C6) alkenyl group Chemical group 0.000 claims description 6
- 125000002950 monocyclic group Chemical group 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 5
- 238000000338 in vitro Methods 0.000 claims description 5
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims description 4
- KAADLWVWFSABGJ-UHFFFAOYSA-N 1-[(4-carbamimidoylnaphthalen-1-yl)methyl]-6-[ethanimidoyl(piperidin-4-yl)amino]-2-propan-2-ylbenzimidazole-4-carboxamide Chemical compound C1=C2N(CC=3C4=CC=CC=C4C(C(N)=N)=CC=3)C(C(C)C)=NC2=C(C(N)=O)C=C1N(C(C)=N)C1CCNCC1 KAADLWVWFSABGJ-UHFFFAOYSA-N 0.000 claims description 4
- 125000002619 bicyclic group Chemical group 0.000 claims description 4
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 4
- YWAMXQXCSOLQOZ-UHFFFAOYSA-N 1-(4-carbamimidoylnaphthalen-1-yl)-6-[ethanimidoyl(piperidin-4-yl)amino]-5-methyl-2-propan-2-ylbenzimidazole-4-carboxylic acid Chemical compound C(N)(=N)C1=CC=C(C2=CC=CC=C12)N1C(=NC2=C1C=C(C(=C2C(=O)O)C)N(C(C)=N)C1CCNCC1)C(C)C YWAMXQXCSOLQOZ-UHFFFAOYSA-N 0.000 claims description 2
- AXYSPGHWKVUOLM-UHFFFAOYSA-N 4-(4-methyl-5-piperidin-4-yloxy-2-propan-2-ylbenzimidazol-1-yl)naphthalene-1-carboximidamide Chemical compound C(N)(=N)C1=CC=C(C2=CC=CC=C12)N1C(=NC2=C1C=CC(=C2C)OC1CCNCC1)C(C)C AXYSPGHWKVUOLM-UHFFFAOYSA-N 0.000 claims description 2
- ZWBUADCMAIKEGS-UHFFFAOYSA-N 4-[2-butyl-5-(1-ethanimidoylpiperidin-4-yl)oxy-4-methylbenzimidazol-1-yl]naphthalene-1-carboximidamide Chemical compound C(N)(=N)C1=CC=C(C2=CC=CC=C12)N1C(=NC2=C1C=CC(=C2C)OC1CCN(CC1)C(C)=N)CCCC ZWBUADCMAIKEGS-UHFFFAOYSA-N 0.000 claims description 2
- NIDKQMYDMPNKHN-UHFFFAOYSA-N 4-[2-tert-butyl-5-(1-ethanimidoylpiperidin-4-yl)oxy-4-methylbenzimidazol-1-yl]naphthalene-1-carboximidamide Chemical compound C(N)(=N)C1=CC=C(C2=CC=CC=C12)N1C(=NC2=C1C=CC(=C2C)OC1CCN(CC1)C(C)=N)C(C)(C)C NIDKQMYDMPNKHN-UHFFFAOYSA-N 0.000 claims description 2
- ATODDNVKKZMYAD-UHFFFAOYSA-N 4-[5-(1-ethanimidoylpiperidin-4-yl)oxy-2-ethyl-4-methylbenzimidazol-1-yl]naphthalene-1-carboximidamide Chemical compound C(N)(=N)C1=CC=C(C2=CC=CC=C12)N1C(=NC2=C1C=CC(=C2C)OC1CCN(CC1)C(C)=N)CC ATODDNVKKZMYAD-UHFFFAOYSA-N 0.000 claims description 2
- ZOIJYRVRYMPZRE-UHFFFAOYSA-N 4-[6-(1-ethanimidoylpiperidin-4-yl)oxy-2,4-dimethyl-7-nitrobenzimidazol-1-yl]naphthalene-1-carboximidamide Chemical compound C(N)(=N)C1=CC=C(C2=CC=CC=C12)N1C(=NC2=C1C(=C(C=C2C)OC1CCN(CC1)C(C)=N)[N+](=O)[O-])C ZOIJYRVRYMPZRE-UHFFFAOYSA-N 0.000 claims description 2
- CDTQVRWPMILIQS-UHFFFAOYSA-N 4-[6-(1-ethanimidoylpiperidin-4-yl)oxy-2,4-dimethylbenzimidazol-1-yl]naphthalene-1-carboximidamide Chemical compound C(N)(=N)C1=CC=C(C2=CC=CC=C12)N1C(=NC2=C1C=C(C=C2C)OC1CCN(CC1)C(C)=N)C CDTQVRWPMILIQS-UHFFFAOYSA-N 0.000 claims description 2
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical group [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 claims description 2
- XREWVQOSYDUXNP-UHFFFAOYSA-N C(N)(=N)C1=CC=C(C2=CC=CC=C12)N1C(=NC2=C1C=C(C(=C2C)OC2CCN(CC2)CC(=O)O)OC2CCN(CC2)C(C)=N)C Chemical compound C(N)(=N)C1=CC=C(C2=CC=CC=C12)N1C(=NC2=C1C=C(C(=C2C)OC2CCN(CC2)CC(=O)O)OC2CCN(CC2)C(C)=N)C XREWVQOSYDUXNP-UHFFFAOYSA-N 0.000 claims description 2
- OPYBLTXZCHMKSH-UHFFFAOYSA-N C(N)(=N)C1=CC=C(C2=CC=CC=C12)N1C(=NC2=C1C=C(C=C2C)OC2CCN(CC2)C(C)=N)C(C)C Chemical compound C(N)(=N)C1=CC=C(C2=CC=CC=C12)N1C(=NC2=C1C=C(C=C2C)OC2CCN(CC2)C(C)=N)C(C)C OPYBLTXZCHMKSH-UHFFFAOYSA-N 0.000 claims description 2
- WPQZKNPNLRUTIN-UHFFFAOYSA-N C(N)(=N)C1=CC=C(C2=CC=CC=C12)N1C(=NC2=C1C=C(C=C2C)OC2CCN(CC2)C(C)=N)CCC(=O)N Chemical compound C(N)(=N)C1=CC=C(C2=CC=CC=C12)N1C(=NC2=C1C=C(C=C2C)OC2CCN(CC2)C(C)=N)CCC(=O)N WPQZKNPNLRUTIN-UHFFFAOYSA-N 0.000 claims description 2
- RPHRLSYMDCNGAX-UHFFFAOYSA-N COC(=O)C=1C=C(COC=2NC3=C(N2)C=C(C=C3)OC3CCN(CC3)C(C)=N)C=CC1 Chemical compound COC(=O)C=1C=C(COC=2NC3=C(N2)C=C(C=C3)OC3CCN(CC3)C(C)=N)C=CC1 RPHRLSYMDCNGAX-UHFFFAOYSA-N 0.000 claims description 2
- 229910052796 boron Inorganic materials 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims description 2
- VLSBKKGXTZGVOQ-UHFFFAOYSA-N 1-(4-carbamimidoylnaphthalen-1-yl)-6-(1-ethanimidoylpiperidin-4-yl)oxy-4-methoxy-2,7-dimethylbenzimidazole-5-carboxylic acid Chemical compound C(N)(=N)C1=CC=C(C2=CC=CC=C12)N1C(=NC2=C1C(=C(C(=C2OC)C(=O)O)OC1CCN(CC1)C(C)=N)C)C VLSBKKGXTZGVOQ-UHFFFAOYSA-N 0.000 claims 1
- ZQNJXSVGEBWITB-UHFFFAOYSA-N 1-[4-[(4-methyl-2-propyl-1H-benzimidazol-5-yl)oxy]piperidin-1-yl]ethanimine Chemical compound CC1=C(C=CC=2N=C(NC21)CCC)OC2CCN(CC2)C(C)=N ZQNJXSVGEBWITB-UHFFFAOYSA-N 0.000 claims 1
- REKLOLKIJQGGLJ-UHFFFAOYSA-N 2-[1-(4-carbamimidoylnaphthalen-1-yl)-6-(1-ethanimidoylpiperidin-4-yl)oxy-2,4-dimethylbenzimidazol-5-yl]oxypropanoic acid Chemical compound C(N)(=N)C1=CC=C(C2=CC=CC=C12)N1C(=NC2=C1C=C(C(=C2C)OC(C)C(=O)O)OC1CCN(CC1)C(C)=N)C REKLOLKIJQGGLJ-UHFFFAOYSA-N 0.000 claims 1
- QTRASTVWXRIWGQ-UHFFFAOYSA-N 3-[1-(4-carbamimidoylnaphthalen-1-yl)-5-(1-ethanimidoylpiperidin-4-yl)oxy-4-methylbenzimidazol-2-yl]propanoic acid Chemical compound C(N)(=N)C1=CC=C(C2=CC=CC=C12)N1C(=NC2=C1C=CC(=C2C)OC1CCN(CC1)C(C)=N)CCC(=O)O QTRASTVWXRIWGQ-UHFFFAOYSA-N 0.000 claims 1
- YGUVXQFIESTCIC-UHFFFAOYSA-N 3-[1-(4-carbamimidoylnaphthalen-1-yl)-6-(1-ethanimidoylpiperidin-4-yl)oxy-4-methylbenzimidazol-2-yl]propanoic acid Chemical compound C(N)(=N)C1=CC=C(C2=CC=CC=C12)N1C(=NC2=C1C=C(C=C2C)OC1CCN(CC1)C(C)=N)CCC(=O)O YGUVXQFIESTCIC-UHFFFAOYSA-N 0.000 claims 1
- WUGNMKHJWIWUNU-UHFFFAOYSA-N 3-[[1-(4-carbamimidoylnaphthalen-1-yl)-6-(1-ethanimidoylpiperidin-4-yl)oxy-2,4-dimethylbenzimidazol-5-yl]oxymethyl]benzoic acid Chemical compound C(N)(=N)C1=CC=C(C2=CC=CC=C12)N1C(=NC2=C1C=C(C(=C2C)OCC1=CC(=CC=C1)C(=O)O)OC1CCN(CC1)C(C)=N)C WUGNMKHJWIWUNU-UHFFFAOYSA-N 0.000 claims 1
- DJLLGDCQHPNQMT-UHFFFAOYSA-N 4-(4-methyl-6-piperidin-4-yloxy-2-propylbenzimidazol-1-yl)naphthalene-1-carboximidamide Chemical compound C(N)(=N)C1=CC=C(C2=CC=CC=C12)N1C(=NC2=C1C=C(C=C2C)OC1CCNCC1)CCC DJLLGDCQHPNQMT-UHFFFAOYSA-N 0.000 claims 1
- CAHYFHICNWUAIP-UHFFFAOYSA-N 4-(7-methoxy-4-methyl-5-piperidin-4-yloxy-2-propan-2-ylbenzimidazol-1-yl)naphthalene-1-carboximidamide Chemical compound C(N)(=N)C1=CC=C(C2=CC=CC=C12)N1C(=NC2=C1C(=CC(=C2C)OC1CCNCC1)OC)C(C)C CAHYFHICNWUAIP-UHFFFAOYSA-N 0.000 claims 1
- YGHVLAPDZCAGNK-UHFFFAOYSA-N 4-[2-amino-6-(1-ethanimidoylpiperidin-4-yl)-4-methylbenzimidazol-1-yl]naphthalene-1-carboximidamide Chemical compound C(N)(=N)C1=CC=C(C2=CC=CC=C12)N1C(=NC2=C1C=C(C=C2C)C1CCN(CC1)C(C)=N)N YGHVLAPDZCAGNK-UHFFFAOYSA-N 0.000 claims 1
- GEGCGZIAPZXQFV-UHFFFAOYSA-N 4-[2-butan-2-yl-6-(1-ethanimidoylpiperidin-4-yl)oxy-4-methylbenzimidazol-1-yl]naphthalene-1-carboximidamide Chemical compound C(N)(=N)C1=CC=C(C2=CC=CC=C12)N1C(=NC2=C1C=C(C=C2C)OC1CCN(CC1)C(C)=N)C(C)CC GEGCGZIAPZXQFV-UHFFFAOYSA-N 0.000 claims 1
- LKWGHWOGKURQLZ-UHFFFAOYSA-N 4-[2-butyl-6-(1-ethanimidoylpiperidin-4-yl)oxy-4-methylbenzimidazol-1-yl]naphthalene-1-carboximidamide Chemical compound C(N)(=N)C1=CC=C(C2=CC=CC=C12)N1C(=NC2=C1C=C(C=C2C)OC1CCN(CC1)C(C)=N)CCCC LKWGHWOGKURQLZ-UHFFFAOYSA-N 0.000 claims 1
- RWUBRQKMVGMYQK-UHFFFAOYSA-N 4-[2-tert-butyl-6-(1-ethanimidoylpiperidin-4-yl)oxy-4-methylbenzimidazol-1-yl]naphthalene-1-carboximidamide Chemical compound C(N)(=N)C1=CC=C(C2=CC=CC=C12)N1C(=NC2=C1C=C(C=C2C)OC1CCN(CC1)C(C)=N)C(C)(C)C RWUBRQKMVGMYQK-UHFFFAOYSA-N 0.000 claims 1
- PYPOZYNQZYFJGM-UHFFFAOYSA-N 4-[5-(1-ethanimidoylpiperidin-4-yl)oxy-2-methylbenzimidazol-1-yl]naphthalene-1-carboximidamide Chemical compound C(N)(=N)C1=CC=C(C2=CC=CC=C12)N1C(=NC2=C1C=CC(=C2)OC1CCN(CC1)C(C)=N)C PYPOZYNQZYFJGM-UHFFFAOYSA-N 0.000 claims 1
- WJWHWKNMDSSCOK-UHFFFAOYSA-N 4-[5-(1-ethanimidoylpiperidin-4-yl)oxy-4-methyl-2-propan-2-ylbenzimidazol-1-yl]naphthalene-1-carboximidamide Chemical compound C(N)(=N)C1=CC=C(C2=CC=CC=C12)N1C(=NC2=C1C=CC(=C2C)OC1CCN(CC1)C(C)=N)C(C)C WJWHWKNMDSSCOK-UHFFFAOYSA-N 0.000 claims 1
- MEPWNGAQSNRCHV-UHFFFAOYSA-N 4-[5-(1-ethanimidoylpiperidin-4-yl)oxy-7-methoxy-4-methyl-2-propan-2-ylbenzimidazol-1-yl]naphthalene-1-carboximidamide Chemical compound C(N)(=N)C1=CC=C(C2=CC=CC=C12)N1C(=NC2=C1C(=CC(=C2C)OC1CCN(CC1)C(C)=N)OC)C(C)C MEPWNGAQSNRCHV-UHFFFAOYSA-N 0.000 claims 1
- JWLSGJCFHWKIKR-UHFFFAOYSA-N 4-[6-(1-ethanimidoylpiperidin-3-yl)oxy-2,4-dimethylbenzimidazol-1-yl]naphthalene-1-carboximidamide Chemical compound C(N)(=N)C1=CC=C(C2=CC=CC=C12)N1C(=NC2=C1C=C(C=C2C)OC1CN(CCC1)C(C)=N)C JWLSGJCFHWKIKR-UHFFFAOYSA-N 0.000 claims 1
- AWQZICWDJXYJLB-UHFFFAOYSA-N 4-[6-(1-ethanimidoylpiperidin-4-yl)oxy-2-ethyl-4-methylbenzimidazol-1-yl]naphthalene-1-carboximidamide Chemical compound C(N)(=N)C1=CC=C(C2=CC=CC=C12)N1C(=NC2=C1C=C(C=C2C)OC1CCN(CC1)C(C)=N)CC AWQZICWDJXYJLB-UHFFFAOYSA-N 0.000 claims 1
- BSPLSNMZGRHTLF-UHFFFAOYSA-N 4-[6-(1-ethanimidoylpiperidin-4-yl)oxy-2-methylbenzimidazol-1-yl]naphthalene-1-carboximidamide Chemical compound C(N)(=N)C1=CC=C(C2=CC=CC=C12)N1C(=NC2=C1C=C(C=C2)OC1CCN(CC1)C(C)=N)C BSPLSNMZGRHTLF-UHFFFAOYSA-N 0.000 claims 1
- ZUEWJMFFVRIKAZ-UHFFFAOYSA-N 4-[6-(1-ethanimidoylpiperidin-4-yl)oxy-4-methyl-2-propylbenzimidazol-1-yl]naphthalene-1-carboximidamide Chemical compound C(N)(=N)C1=CC=C(C2=CC=CC=C12)N1C(=NC2=C1C=C(C=C2C)OC1CCN(CC1)C(C)=N)CCC ZUEWJMFFVRIKAZ-UHFFFAOYSA-N 0.000 claims 1
- KEHSBRFPTIBGNU-UHFFFAOYSA-N 4-[6-(1-ethanimidoylpiperidin-4-yl)oxy-4-methyl-7-nitro-2-propan-2-ylbenzimidazol-1-yl]naphthalene-1-carboximidamide Chemical compound C(N)(=N)C1=CC=C(C2=CC=CC=C12)N1C(=NC2=C1C(=C(C=C2C)OC1CCN(CC1)C(C)=N)[N+](=O)[O-])C(C)C KEHSBRFPTIBGNU-UHFFFAOYSA-N 0.000 claims 1
- FONRXAUUNOHXMM-UHFFFAOYSA-N 4-[6-(1-ethanimidoylpiperidin-4-yl)oxy-5-hydroxy-2,4-dimethylbenzimidazol-1-yl]naphthalene-1-carboximidamide Chemical compound C(N)(=N)C1=CC=C(C2=CC=CC=C12)N1C(=NC2=C1C=C(C(=C2C)O)OC1CCN(CC1)C(C)=N)C FONRXAUUNOHXMM-UHFFFAOYSA-N 0.000 claims 1
- CUJBLKZRWNZHAL-UHFFFAOYSA-N 4-[[1-(4-carbamimidoylnaphthalen-1-yl)-6-(1-ethanimidoylpiperidin-4-yl)oxy-2,4-dimethylbenzimidazol-5-yl]oxymethyl]benzoic acid Chemical compound C(N)(=N)C1=CC=C(C2=CC=CC=C12)N1C(=NC2=C1C=C(C(=C2C)OCC1=CC=C(C=C1)C(=O)O)OC1CCN(CC1)C(C)=N)C CUJBLKZRWNZHAL-UHFFFAOYSA-N 0.000 claims 1
- VHDIXMNAUVOTMB-UHFFFAOYSA-N C(N)(=N)C1=CC=C(C2=CC=CC=C12)N1C(=NC2=C1C(=C(C(=C2C(=O)O)OC)OC2CCN(CC2)C(C)=N)C)C(C)C Chemical compound C(N)(=N)C1=CC=C(C2=CC=CC=C12)N1C(=NC2=C1C(=C(C(=C2C(=O)O)OC)OC2CCN(CC2)C(C)=N)C)C(C)C VHDIXMNAUVOTMB-UHFFFAOYSA-N 0.000 claims 1
- RKGSJOYGUAFQJM-UHFFFAOYSA-N C(N)(=N)C1=CC=C(C2=CC=CC=C12)N1C(=NC2=C1C(=C(C(=C2OC)C(=O)N)OC2CCN(CC2)C(C)=N)C)C Chemical compound C(N)(=N)C1=CC=C(C2=CC=CC=C12)N1C(=NC2=C1C(=C(C(=C2OC)C(=O)N)OC2CCN(CC2)C(C)=N)C)C RKGSJOYGUAFQJM-UHFFFAOYSA-N 0.000 claims 1
- CCLKEDVDXFNKRJ-UHFFFAOYSA-N C(N)(=N)C1=CC=C(C2=CC=CC=C12)N1C(=NC2=C1C=C(C(=C2C)NC(C)(C)C(=O)O)OC2CCN(CC2)C(C)=N)C(C)C Chemical compound C(N)(=N)C1=CC=C(C2=CC=CC=C12)N1C(=NC2=C1C=C(C(=C2C)NC(C)(C)C(=O)O)OC2CCN(CC2)C(C)=N)C(C)C CCLKEDVDXFNKRJ-UHFFFAOYSA-N 0.000 claims 1
- JRDLZFHPCHFVFT-UHFFFAOYSA-N C(N)(=N)C1=CC=C(C2=CC=CC=C12)N1C(=NC2=C1C=C(C(=C2C)OC(C)C(=O)N)OC2CCN(CC2)C(C)=N)C Chemical compound C(N)(=N)C1=CC=C(C2=CC=CC=C12)N1C(=NC2=C1C=C(C(=C2C)OC(C)C(=O)N)OC2CCN(CC2)C(C)=N)C JRDLZFHPCHFVFT-UHFFFAOYSA-N 0.000 claims 1
- HWNYWDFIYNOLMB-UHFFFAOYSA-N C(N)(=N)C1=CC=C(C2=CC=CC=C12)N1C(=NC2=C1C=C(C(=C2C)OC(C)C(=O)OC)OC2CCN(CC2)C(C)=N)C Chemical compound C(N)(=N)C1=CC=C(C2=CC=CC=C12)N1C(=NC2=C1C=C(C(=C2C)OC(C)C(=O)OC)OC2CCN(CC2)C(C)=N)C HWNYWDFIYNOLMB-UHFFFAOYSA-N 0.000 claims 1
- JQQVVNMHZSUHAO-UHFFFAOYSA-N C(N)(=N)C1=CC=C(C2=CC=CC=C12)N1C(=NC2=C1C=C(C(=C2N2CCC(CC2)C(=O)O)C)OC2CCN(CC2)C(C)=N)C(C)C Chemical compound C(N)(=N)C1=CC=C(C2=CC=CC=C12)N1C(=NC2=C1C=C(C(=C2N2CCC(CC2)C(=O)O)C)OC2CCN(CC2)C(C)=N)C(C)C JQQVVNMHZSUHAO-UHFFFAOYSA-N 0.000 claims 1
- CCZJOJJYIHEVFQ-UHFFFAOYSA-N C(N)(=N)C1=CC=C(C2=CC=CC=C12)N1C(=NC2=C1C=C(C(=C2OC)C)OC2CCN(CC2)C(C)=N)C(C)C Chemical compound C(N)(=N)C1=CC=C(C2=CC=CC=C12)N1C(=NC2=C1C=C(C(=C2OC)C)OC2CCN(CC2)C(C)=N)C(C)C CCZJOJJYIHEVFQ-UHFFFAOYSA-N 0.000 claims 1
- FQCDKTZLFBGDHP-UHFFFAOYSA-N C(N)(=N)C1=CC=C(C2=CC=CC=C12)N1C(=NC2=C1C=CC(=C2C)OC2CCN(CC2)C(C)=N)C Chemical compound C(N)(=N)C1=CC=C(C2=CC=CC=C12)N1C(=NC2=C1C=CC(=C2C)OC2CCN(CC2)C(C)=N)C FQCDKTZLFBGDHP-UHFFFAOYSA-N 0.000 claims 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims 1
- CREMABGTGYGIQB-UHFFFAOYSA-N carbon carbon Chemical compound C.C CREMABGTGYGIQB-UHFFFAOYSA-N 0.000 claims 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 claims 1
- 108010029144 Factor IIa Proteins 0.000 abstract description 5
- 230000001404 mediated effect Effects 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 199
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 159
- 239000011541 reaction mixture Substances 0.000 description 153
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 124
- 239000000243 solution Substances 0.000 description 123
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 72
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 65
- 238000005481 NMR spectroscopy Methods 0.000 description 64
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 61
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 55
- 238000006243 chemical reaction Methods 0.000 description 49
- 239000002904 solvent Substances 0.000 description 47
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 45
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 45
- 238000004519 manufacturing process Methods 0.000 description 45
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 43
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 39
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 39
- 238000012360 testing method Methods 0.000 description 37
- 239000000047 product Substances 0.000 description 33
- 239000007787 solid Substances 0.000 description 31
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 28
- 239000003921 oil Substances 0.000 description 28
- 235000019198 oils Nutrition 0.000 description 28
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 26
- 239000012044 organic layer Substances 0.000 description 26
- 238000003756 stirring Methods 0.000 description 26
- 239000000010 aprotic solvent Substances 0.000 description 25
- 238000000605 extraction Methods 0.000 description 23
- 238000010992 reflux Methods 0.000 description 23
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 21
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 20
- 108090000190 Thrombin Proteins 0.000 description 20
- 108010000499 Thromboplastin Proteins 0.000 description 20
- 102000002262 Thromboplastin Human genes 0.000 description 20
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 20
- 229960004072 thrombin Drugs 0.000 description 20
- 230000008569 process Effects 0.000 description 19
- 239000011550 stock solution Substances 0.000 description 19
- 239000012131 assay buffer Substances 0.000 description 18
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 18
- 238000000926 separation method Methods 0.000 description 18
- 239000002253 acid Substances 0.000 description 16
- 238000003556 assay Methods 0.000 description 16
- 238000010828 elution Methods 0.000 description 16
- 229910000104 sodium hydride Inorganic materials 0.000 description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 239000002585 base Substances 0.000 description 15
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 15
- 239000012224 working solution Substances 0.000 description 15
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 14
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 14
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 14
- 238000004587 chromatography analysis Methods 0.000 description 14
- 239000004615 ingredient Substances 0.000 description 14
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 14
- 229910052938 sodium sulfate Inorganic materials 0.000 description 14
- 235000011152 sodium sulphate Nutrition 0.000 description 14
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 13
- 102000004190 Enzymes Human genes 0.000 description 13
- 108090000790 Enzymes Proteins 0.000 description 13
- 239000012267 brine Substances 0.000 description 13
- 229940088598 enzyme Drugs 0.000 description 13
- 239000003112 inhibitor Substances 0.000 description 13
- 238000010898 silica gel chromatography Methods 0.000 description 13
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 13
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 12
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 12
- 238000007796 conventional method Methods 0.000 description 12
- 238000004128 high performance liquid chromatography Methods 0.000 description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 11
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 11
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 11
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 10
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 10
- 239000000460 chlorine Substances 0.000 description 10
- 230000015271 coagulation Effects 0.000 description 10
- 238000005345 coagulation Methods 0.000 description 10
- 239000003586 protic polar solvent Substances 0.000 description 10
- 230000002829 reductive effect Effects 0.000 description 10
- 235000017557 sodium bicarbonate Nutrition 0.000 description 10
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 10
- 239000012312 sodium hydride Substances 0.000 description 10
- 238000004440 column chromatography Methods 0.000 description 9
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 9
- 239000000543 intermediate Substances 0.000 description 9
- 229910000027 potassium carbonate Inorganic materials 0.000 description 9
- 235000011181 potassium carbonates Nutrition 0.000 description 9
- 239000000725 suspension Substances 0.000 description 9
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 8
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 8
- 208000007536 Thrombosis Diseases 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- 150000002431 hydrogen Chemical class 0.000 description 8
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 8
- 102000003978 Tissue Plasminogen Activator Human genes 0.000 description 7
- 108090000373 Tissue Plasminogen Activator Proteins 0.000 description 7
- 239000010410 layer Substances 0.000 description 7
- 239000000463 material Substances 0.000 description 7
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 7
- 150000003254 radicals Chemical class 0.000 description 7
- 229960000187 tissue plasminogen activator Drugs 0.000 description 7
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 108010094028 Prothrombin Proteins 0.000 description 6
- 229910004298 SiO 2 Inorganic materials 0.000 description 6
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 6
- 239000000872 buffer Substances 0.000 description 6
- 239000002775 capsule Substances 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 238000001704 evaporation Methods 0.000 description 6
- 230000008020 evaporation Effects 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 6
- 235000019341 magnesium sulphate Nutrition 0.000 description 6
- 239000003960 organic solvent Substances 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 239000000758 substrate Substances 0.000 description 6
- JWYUFVNJZUSCSM-UHFFFAOYSA-N 2-aminobenzimidazole Chemical compound C1=CC=C2NC(N)=NC2=C1 JWYUFVNJZUSCSM-UHFFFAOYSA-N 0.000 description 5
- YQMGMBLRHUQZMJ-UHFFFAOYSA-N 5-methoxy-6-nitro-2-propan-2-yl-1h-benzimidazole Chemical compound C1=C([N+]([O-])=O)C(OC)=CC2=C1N=C(C(C)C)N2 YQMGMBLRHUQZMJ-UHFFFAOYSA-N 0.000 description 5
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 5
- 102100027378 Prothrombin Human genes 0.000 description 5
- 230000002378 acidificating effect Effects 0.000 description 5
- BJDCWCLMFKKGEE-CMDXXVQNSA-N chembl252518 Chemical compound C([C@@](OO1)(C)O2)C[C@H]3[C@H](C)CC[C@@H]4[C@@]31[C@@H]2O[C@H](O)[C@@H]4C BJDCWCLMFKKGEE-CMDXXVQNSA-N 0.000 description 5
- 238000010790 dilution Methods 0.000 description 5
- 239000012895 dilution Substances 0.000 description 5
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 5
- 150000007529 inorganic bases Chemical class 0.000 description 5
- 229910052500 inorganic mineral Inorganic materials 0.000 description 5
- 239000008101 lactose Substances 0.000 description 5
- 235000010755 mineral Nutrition 0.000 description 5
- 239000011707 mineral Substances 0.000 description 5
- 229910017604 nitric acid Inorganic materials 0.000 description 5
- 235000015497 potassium bicarbonate Nutrition 0.000 description 5
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 5
- 239000011736 potassium bicarbonate Substances 0.000 description 5
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 5
- 229940039716 prothrombin Drugs 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 5
- 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 4
- NAWXUBYGYWOOIX-SFHVURJKSA-N (2s)-2-[[4-[2-(2,4-diaminoquinazolin-6-yl)ethyl]benzoyl]amino]-4-methylidenepentanedioic acid Chemical compound C1=CC2=NC(N)=NC(N)=C2C=C1CCC1=CC=C(C(=O)N[C@@H](CC(=C)C(O)=O)C(O)=O)C=C1 NAWXUBYGYWOOIX-SFHVURJKSA-N 0.000 description 4
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 4
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 4
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 4
- 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 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 4
- 108010074105 Factor Va Proteins 0.000 description 4
- 108010054964 H-hexahydrotyrosyl-alanyl-arginine-4-nitroanilide Proteins 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 102100030951 Tissue factor pathway inhibitor Human genes 0.000 description 4
- 230000009471 action Effects 0.000 description 4
- 229910021529 ammonia Inorganic materials 0.000 description 4
- 150000007514 bases Chemical class 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 239000003638 chemical reducing agent Substances 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 108010013555 lipoprotein-associated coagulation inhibitor Proteins 0.000 description 4
- 235000019359 magnesium stearate Nutrition 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 239000012299 nitrogen atmosphere Substances 0.000 description 4
- 150000007524 organic acids Chemical class 0.000 description 4
- 229910052763 palladium Inorganic materials 0.000 description 4
- 230000037361 pathway Effects 0.000 description 4
- 229940068918 polyethylene glycol 400 Drugs 0.000 description 4
- 238000011321 prophylaxis Methods 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 238000010561 standard procedure Methods 0.000 description 4
- 239000008107 starch Substances 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- 238000001356 surgical procedure Methods 0.000 description 4
- 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 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 3
- LDZYRENCLPUXAX-UHFFFAOYSA-N 2-methyl-1h-benzimidazole Chemical compound C1=CC=C2NC(C)=NC2=C1 LDZYRENCLPUXAX-UHFFFAOYSA-N 0.000 description 3
- DGMOBVGABMBZSB-UHFFFAOYSA-N 2-methylpropanoyl chloride Chemical compound CC(C)C(Cl)=O DGMOBVGABMBZSB-UHFFFAOYSA-N 0.000 description 3
- OVOZYARDXPHRDL-UHFFFAOYSA-N 3,4-diaminophenol Chemical compound NC1=CC=C(O)C=C1N OVOZYARDXPHRDL-UHFFFAOYSA-N 0.000 description 3
- JLAKCHGEEBPDQI-UHFFFAOYSA-N 4-(4-fluorobenzyl)piperidine Chemical compound C1=CC(F)=CC=C1CC1CCNCC1 JLAKCHGEEBPDQI-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 3
- 206010051055 Deep vein thrombosis Diseases 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 206010047249 Venous thrombosis Diseases 0.000 description 3
- 230000003187 abdominal effect Effects 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 239000000443 aerosol Substances 0.000 description 3
- 150000004703 alkoxides Chemical class 0.000 description 3
- 230000001668 ameliorated effect Effects 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 239000012298 atmosphere Substances 0.000 description 3
- 238000004166 bioassay Methods 0.000 description 3
- 235000011089 carbon dioxide Nutrition 0.000 description 3
- 235000019994 cava Nutrition 0.000 description 3
- 239000001913 cellulose Substances 0.000 description 3
- 229920002678 cellulose Polymers 0.000 description 3
- 239000003610 charcoal Substances 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 description 3
- 239000006260 foam Substances 0.000 description 3
- 238000004108 freeze drying Methods 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 238000001802 infusion Methods 0.000 description 3
- YDCHPLOFQATIDS-UHFFFAOYSA-N methyl 2-bromoacetate Chemical compound COC(=O)CBr YDCHPLOFQATIDS-UHFFFAOYSA-N 0.000 description 3
- 150000007530 organic bases Chemical class 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 108010014806 prothrombinase complex Proteins 0.000 description 3
- 238000004007 reversed phase HPLC Methods 0.000 description 3
- 239000000829 suppository Substances 0.000 description 3
- 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 3
- 238000004809 thin layer chromatography Methods 0.000 description 3
- 210000003462 vein Anatomy 0.000 description 3
- 238000010626 work up procedure Methods 0.000 description 3
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 2
- AOXAUVDUIYKISO-UHFFFAOYSA-N 1-(6-methoxy-2-propan-2-yl-1h-benzimidazol-4-yl)piperidine-4-carboxylic acid Chemical compound C=12NC(C(C)C)=NC2=CC(OC)=CC=1N1CCC(C(O)=O)CC1 AOXAUVDUIYKISO-UHFFFAOYSA-N 0.000 description 2
- UQXXMEMKGVVIRR-UHFFFAOYSA-N 1-[(4-carbamimidoylnaphthalen-1-yl)methyl]-6-(piperidin-4-ylamino)-2-propan-2-ylbenzimidazole-4-carboxamide Chemical compound C1=C2N(CC=3C4=CC=CC=C4C(C(N)=N)=CC=3)C(C(C)C)=NC2=C(C(N)=O)C=C1NC1CCNCC1 UQXXMEMKGVVIRR-UHFFFAOYSA-N 0.000 description 2
- HRFSIOYYRNFYQM-UHFFFAOYSA-N 1-o-tert-butyl 5-o-methyl 6-hydroxy-2-methylbenzimidazole-1,5-dicarboxylate Chemical compound C1=C(O)C(C(=O)OC)=CC2=C1N(C(=O)OC(C)(C)C)C(C)=N2 HRFSIOYYRNFYQM-UHFFFAOYSA-N 0.000 description 2
- YWOQCQYHRASAMG-UHFFFAOYSA-N 1-o-tert-butyl 6-o-methyl 2-methyl-5-[1-[(2-methylpropan-2-yl)oxycarbonyl]piperidin-4-yl]oxybenzimidazole-1,6-dicarboxylate Chemical compound COC(=O)C1=CC=2N(C(=O)OC(C)(C)C)C(C)=NC=2C=C1OC1CCN(C(=O)OC(C)(C)C)CC1 YWOQCQYHRASAMG-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 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
- UCVJHROVJNZWQY-UHFFFAOYSA-N 2-propan-2-yl-1h-benzimidazole-4,6-diol Chemical compound OC1=CC(O)=C2NC(C(C)C)=NC2=C1 UCVJHROVJNZWQY-UHFFFAOYSA-N 0.000 description 2
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 2
- GWHSFLQGVWEJAY-UHFFFAOYSA-N 3,5-dimethoxy-2-nitroaniline Chemical compound COC1=CC(N)=C([N+]([O-])=O)C(OC)=C1 GWHSFLQGVWEJAY-UHFFFAOYSA-N 0.000 description 2
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 2
- URHZCTFNFFUCMX-UHFFFAOYSA-N 5-methoxy-4-nitro-2-propan-2-yl-1h-benzimidazole Chemical compound COC1=CC=C2N=C(C(C)C)NC2=C1[N+]([O-])=O URHZCTFNFFUCMX-UHFFFAOYSA-N 0.000 description 2
- IAIIVKQZTWAAHF-UHFFFAOYSA-N 6-methoxy-2-propan-2-yl-1h-benzimidazole Chemical compound COC1=CC=C2N=C(C(C)C)NC2=C1 IAIIVKQZTWAAHF-UHFFFAOYSA-N 0.000 description 2
- DCNXFTOZCUBAIC-UHFFFAOYSA-N 6-nitro-2-propan-2-yl-1h-benzimidazol-5-ol Chemical compound OC1=C([N+]([O-])=O)C=C2NC(C(C)C)=NC2=C1 DCNXFTOZCUBAIC-UHFFFAOYSA-N 0.000 description 2
- DALVDMMOCXINKP-UHFFFAOYSA-N 7-methoxy-2-propan-2-yl-3h-benzimidazol-5-ol Chemical compound COC1=CC(O)=CC2=C1NC(C(C)C)=N2 DALVDMMOCXINKP-UHFFFAOYSA-N 0.000 description 2
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- SJZJYPSEHQDCBM-UHFFFAOYSA-N C(#N)C1=CC=C(C2=CC=CC=C12)N1C(=NC2=C1C=C(C(=C2C)OC1CCN(CC1)C(=O)OC(C)(C)C)[N+](=O)[O-])C(C)C Chemical compound C(#N)C1=CC=C(C2=CC=CC=C12)N1C(=NC2=C1C=C(C(=C2C)OC1CCN(CC1)C(=O)OC(C)(C)C)[N+](=O)[O-])C(C)C SJZJYPSEHQDCBM-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- 206010053567 Coagulopathies Diseases 0.000 description 2
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 2
- 108010054265 Factor VIIa Proteins 0.000 description 2
- 102000009123 Fibrin Human genes 0.000 description 2
- 108010073385 Fibrin Proteins 0.000 description 2
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- 101000651439 Homo sapiens Prothrombin Proteins 0.000 description 2
- LPHGQDQBBGAPDZ-UHFFFAOYSA-N Isocaffeine Natural products CN1C(=O)N(C)C(=O)C2=C1N(C)C=N2 LPHGQDQBBGAPDZ-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 239000005642 Oleic acid Substances 0.000 description 2
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 2
- 235000019502 Orange oil Nutrition 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- QQONPFPTGQHPMA-UHFFFAOYSA-N Propene Chemical group CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 2
- ZTHYODDOHIVTJV-UHFFFAOYSA-N Propyl gallate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- 102000012479 Serine Proteases Human genes 0.000 description 2
- 108010022999 Serine Proteases Proteins 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 150000003863 ammonium salts Chemical class 0.000 description 2
- 150000008064 anhydrides Chemical class 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 229960001948 caffeine Drugs 0.000 description 2
- VJEONQKOZGKCAK-UHFFFAOYSA-N caffeine Natural products CN1C(=O)N(C)C(=O)C2=C1C=CN2C VJEONQKOZGKCAK-UHFFFAOYSA-N 0.000 description 2
- 159000000007 calcium salts Chemical class 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 2
- 229960001231 choline Drugs 0.000 description 2
- 235000015165 citric acid Nutrition 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 230000035602 clotting Effects 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 2
- 238000007865 diluting Methods 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 229940012414 factor viia Drugs 0.000 description 2
- 229950003499 fibrin Drugs 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 239000007903 gelatin capsule Substances 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- KWIUHFFTVRNATP-UHFFFAOYSA-N glycine betaine Chemical compound C[N+](C)(C)CC([O-])=O KWIUHFFTVRNATP-UHFFFAOYSA-N 0.000 description 2
- 150000004820 halides Chemical class 0.000 description 2
- 229940039715 human prothrombin Drugs 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-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
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 159000000003 magnesium salts Chemical class 0.000 description 2
- HYKHFPZLVXVUHF-UHFFFAOYSA-N methyl 1-(6-hydroxy-2-propan-2-yl-1h-benzimidazol-4-yl)piperidine-4-carboxylate Chemical compound C1CC(C(=O)OC)CCN1C1=CC(O)=CC2=C1NC(C(C)C)=N2 HYKHFPZLVXVUHF-UHFFFAOYSA-N 0.000 description 2
- STQLRWBYYGWCCY-UHFFFAOYSA-N methyl 4-acetamido-2-acetyloxybenzoate Chemical compound COC(=O)C1=CC=C(NC(C)=O)C=C1OC(C)=O STQLRWBYYGWCCY-UHFFFAOYSA-N 0.000 description 2
- ZALKAXMVDJLEHC-UHFFFAOYSA-N methyl 4-acetamido-2-hydroxy-3-nitrobenzoate Chemical compound COC(=O)C1=CC=C(NC(C)=O)C([N+]([O-])=O)=C1O ZALKAXMVDJLEHC-UHFFFAOYSA-N 0.000 description 2
- JEJJIGFNMPUSSF-UHFFFAOYSA-N methyl 4-acetamido-2-hydroxy-5-nitrobenzoate Chemical compound COC(=O)C1=CC([N+]([O-])=O)=C(NC(C)=O)C=C1O JEJJIGFNMPUSSF-UHFFFAOYSA-N 0.000 description 2
- HZTZKCWGJKAUHD-UHFFFAOYSA-N methyl 4-hydroxy-2-methyl-1h-benzimidazole-5-carboxylate Chemical compound COC(=O)C1=CC=C2N=C(C)NC2=C1O HZTZKCWGJKAUHD-UHFFFAOYSA-N 0.000 description 2
- GRGLXAJGSKTUSA-UHFFFAOYSA-N methyl 6-[(2-methylpropan-2-yl)oxycarbonyl-piperidin-4-ylamino]-2-propan-2-yl-1h-benzimidazole-4-carboxylate Chemical compound C=1C=2N=C(C(C)C)NC=2C(C(=O)OC)=CC=1N(C(=O)OC(C)(C)C)C1CCNCC1 GRGLXAJGSKTUSA-UHFFFAOYSA-N 0.000 description 2
- INSJJRUXTAXZDP-UHFFFAOYSA-N methyl 6-amino-2-propan-2-yl-1h-benzimidazole-4-carboxylate Chemical compound COC(=O)C1=CC(N)=CC2=C1NC(C(C)C)=N2 INSJJRUXTAXZDP-UHFFFAOYSA-N 0.000 description 2
- ULOQAYHFTWKNBB-UHFFFAOYSA-N methyl 6-hydroxy-2-methyl-3h-benzimidazole-5-carboxylate Chemical compound C1=C(O)C(C(=O)OC)=CC2=C1N=C(C)N2 ULOQAYHFTWKNBB-UHFFFAOYSA-N 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 239000006199 nebulizer Substances 0.000 description 2
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 2
- 239000010502 orange oil Substances 0.000 description 2
- 230000036961 partial effect Effects 0.000 description 2
- 229940124531 pharmaceutical excipient Drugs 0.000 description 2
- 150000003904 phospholipids Chemical group 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 229940093429 polyethylene glycol 6000 Drugs 0.000 description 2
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
- 229940068968 polysorbate 80 Drugs 0.000 description 2
- 229920000053 polysorbate 80 Polymers 0.000 description 2
- 229920006316 polyvinylpyrrolidine Polymers 0.000 description 2
- 159000000001 potassium salts Chemical class 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 229960004063 propylene glycol Drugs 0.000 description 2
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000011347 resin Substances 0.000 description 2
- 229920005989 resin Polymers 0.000 description 2
- 230000002441 reversible effect Effects 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- 239000003001 serine protease inhibitor Substances 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 239000013589 supplement Substances 0.000 description 2
- 230000002459 sustained effect Effects 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- BVCBGEHKYFHGDD-UHFFFAOYSA-N tert-butyl 2-(piperidin-4-ylamino)benzimidazole-1-carboxylate Chemical compound C(C)(C)(C)OC(=O)N1C(=NC2=C1C=CC=C2)NC1CCNCC1 BVCBGEHKYFHGDD-UHFFFAOYSA-N 0.000 description 2
- UNEHYGTWDYEWDG-UHFFFAOYSA-N tert-butyl 4-(3h-benzimidazol-5-ylamino)piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1NC1=CC=C(N=CN2)C2=C1 UNEHYGTWDYEWDG-UHFFFAOYSA-N 0.000 description 2
- XMHYILSKQLDIAE-UHFFFAOYSA-N tert-butyl 4-[1-[(4-cyanonaphthalen-1-yl)methyl]-6-hydroxy-2-methylbenzimidazol-5-yl]oxypiperidine-1-carboxylate Chemical compound OC=1C=C2N(CC=3C4=CC=CC=C4C(C#N)=CC=3)C(C)=NC2=CC=1OC1CCN(C(=O)OC(C)(C)C)CC1 XMHYILSKQLDIAE-UHFFFAOYSA-N 0.000 description 2
- KFTKBSHBRSANEK-UHFFFAOYSA-N tert-butyl 4-[3-[(4-cyanonaphthalen-1-yl)methyl]-6-hydroxy-2-methylbenzimidazol-5-yl]oxypiperidine-1-carboxylate Chemical compound C1=C2N(CC=3C4=CC=CC=C4C(C#N)=CC=3)C(C)=NC2=CC(O)=C1OC1CCN(C(=O)OC(C)(C)C)CC1 KFTKBSHBRSANEK-UHFFFAOYSA-N 0.000 description 2
- YONAJFQTODMQRY-UHFFFAOYSA-N tert-butyl 4-[4-amino-3-[(4-cyanonaphthalen-1-yl)methyl]-2-propan-2-ylbenzimidazol-5-yl]oxypiperidine-1-carboxylate Chemical compound NC1=C2N(CC=3C4=CC=CC=C4C(C#N)=CC=3)C(C(C)C)=NC2=CC=C1OC1CCN(C(=O)OC(C)(C)C)CC1 YONAJFQTODMQRY-UHFFFAOYSA-N 0.000 description 2
- BXUVQQLGSBTLFD-UHFFFAOYSA-N tert-butyl 4-[6-[tert-butyl(dimethyl)silyl]oxy-3-[(4-cyanonaphthalen-1-yl)methyl]-2-methylbenzimidazol-5-yl]oxypiperidine-1-carboxylate Chemical compound C1=C2N(CC=3C4=CC=CC=C4C(C#N)=CC=3)C(C)=NC2=CC(O[Si](C)(C)C(C)(C)C)=C1OC1CCN(C(=O)OC(C)(C)C)CC1 BXUVQQLGSBTLFD-UHFFFAOYSA-N 0.000 description 2
- NGFQEUBOKUWNLP-UHFFFAOYSA-N tert-butyl 4-[[1-(4-methylphenyl)sulfonylbenzimidazol-5-yl]amino]piperidine-1-carboxylate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)N1C2=CC=C(NC3CCN(CC3)C(=O)OC(C)(C)C)C=C2N=C1 NGFQEUBOKUWNLP-UHFFFAOYSA-N 0.000 description 2
- JRVNQTXWXDDSLF-UHFFFAOYSA-N tert-butyl 4-[[6-[tert-butyl(dimethyl)silyl]oxy-2-methyl-1h-benzimidazol-5-yl]oxy]piperidine-1-carboxylate Chemical compound CC(C)(C)[Si](C)(C)OC=1C=C2NC(C)=NC2=CC=1OC1CCN(C(=O)OC(C)(C)C)CC1 JRVNQTXWXDDSLF-UHFFFAOYSA-N 0.000 description 2
- ROUYFJUVMYHXFJ-UHFFFAOYSA-N tert-butyl 4-oxopiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(=O)CC1 ROUYFJUVMYHXFJ-UHFFFAOYSA-N 0.000 description 2
- FCHLETFAVNRRCN-UHFFFAOYSA-N tert-butyl 5,6-dihydroxy-2-methylbenzimidazole-1-carboxylate Chemical compound OC1=C(O)C=C2N(C(=O)OC(C)(C)C)C(C)=NC2=C1 FCHLETFAVNRRCN-UHFFFAOYSA-N 0.000 description 2
- OFBGWBDHKUDNNH-UHFFFAOYSA-N tert-butyl 5-[tert-butyl(dimethyl)silyl]oxy-2-methyl-6-[1-[(2-methylpropan-2-yl)oxycarbonyl]piperidin-4-yl]oxybenzimidazole-1-carboxylate Chemical compound C1=C2N(C(=O)OC(C)(C)C)C(C)=NC2=CC(O[Si](C)(C)C(C)(C)C)=C1OC1CCN(C(=O)OC(C)(C)C)CC1 OFBGWBDHKUDNNH-UHFFFAOYSA-N 0.000 description 2
- PSHQTAVDHLTVJX-UHFFFAOYSA-N tert-butyl 6-hydroxy-2-propan-2-ylbenzimidazole-1-carboxylate Chemical compound C1=C(O)C=C2N(C(=O)OC(C)(C)C)C(C(C)C)=NC2=C1 PSHQTAVDHLTVJX-UHFFFAOYSA-N 0.000 description 2
- RQCNHUCCQJMSRG-UHFFFAOYSA-N tert-butyl piperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCCC1 RQCNHUCCQJMSRG-UHFFFAOYSA-N 0.000 description 2
- YAPQBXQYLJRXSA-UHFFFAOYSA-N theobromine Chemical compound CN1C(=O)NC(=O)C2=C1N=CN2C YAPQBXQYLJRXSA-UHFFFAOYSA-N 0.000 description 2
- 229960003766 thrombin (human) Drugs 0.000 description 2
- 108010065972 tick anticoagulant peptide Proteins 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- JNWMCBPAQCGKPE-UHFFFAOYSA-N (1,2,3,3a-tetrabutyl-2-propan-2-yl-4H-benzimidazol-4-yl)oxy-dimethylsilane Chemical compound C(CCC)C12C(N(C(N1CCCC)(C(C)C)CCCC)CCCC)=CC=CC2O[SiH](C)C JNWMCBPAQCGKPE-UHFFFAOYSA-N 0.000 description 1
- FTLYMKDSHNWQKD-UHFFFAOYSA-N (2,4,5-trichlorophenyl)boronic acid Chemical compound OB(O)C1=CC(Cl)=C(Cl)C=C1Cl FTLYMKDSHNWQKD-UHFFFAOYSA-N 0.000 description 1
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- 125000006705 (C5-C7) cycloalkyl group Chemical group 0.000 description 1
- ICLYJLBTOGPLMC-KVVVOXFISA-N (z)-octadec-9-enoate;tris(2-hydroxyethyl)azanium Chemical compound OCCN(CCO)CCO.CCCCCCCC\C=C/CCCCCCCC(O)=O ICLYJLBTOGPLMC-KVVVOXFISA-N 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- 125000004814 1,1-dimethylethylene group Chemical group [H]C([H])([H])C([*:1])(C([H])([H])[H])C([H])([H])[*:2] 0.000 description 1
- TZCPCKNHXULUIY-RGULYWFUSA-N 1,2-distearoyl-sn-glycero-3-phosphoserine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@H](N)C(O)=O)OC(=O)CCCCCCCCCCCCCCCCC TZCPCKNHXULUIY-RGULYWFUSA-N 0.000 description 1
- PWRFDGYYJWQIAB-UHFFFAOYSA-N 1,3,5-trifluoro-2-nitrobenzene Chemical compound [O-][N+](=O)C1=C(F)C=C(F)C=C1F PWRFDGYYJWQIAB-UHFFFAOYSA-N 0.000 description 1
- HPAVKBYRHWOUIR-UHFFFAOYSA-N 1,3,5-trifluoro-5-nitrocyclohexa-1,3-diene Chemical compound [O-][N+](=O)C1(F)CC(F)=CC(F)=C1 HPAVKBYRHWOUIR-UHFFFAOYSA-N 0.000 description 1
- VXNZUUAINFGPBY-UHFFFAOYSA-N 1-Butene Chemical group CCC=C VXNZUUAINFGPBY-UHFFFAOYSA-N 0.000 description 1
- FCCZYLLVOYRMGY-UHFFFAOYSA-N 1-[4-[(7-methyl-4-nitro-2-propan-2-yl-3H-benzimidazol-5-yl)oxy]piperidin-1-yl]ethanimine Chemical compound CC1=CC(=C(C=2N=C(NC21)C(C)C)[N+](=O)[O-])OC2CCN(CC2)C(C)=N FCCZYLLVOYRMGY-UHFFFAOYSA-N 0.000 description 1
- 125000004809 1-methylpropylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- OQSPSNCARQNBMU-UHFFFAOYSA-N 1-o-tert-butyl 5-o-methyl 2-methyl-6-[1-[(2-methylpropan-2-yl)oxycarbonyl]piperidin-4-yl]oxybenzimidazole-1,5-dicarboxylate Chemical compound COC(=O)C1=CC=2N=C(C)N(C(=O)OC(C)(C)C)C=2C=C1OC1CCN(C(=O)OC(C)(C)C)CC1 OQSPSNCARQNBMU-UHFFFAOYSA-N 0.000 description 1
- SWBFAJFABKJUJL-UHFFFAOYSA-N 1-o-tert-butyl 5-o-methyl 4-hydroxy-2-methylbenzimidazole-1,5-dicarboxylate Chemical compound COC(=O)C1=CC=C2N(C(=O)OC(C)(C)C)C(C)=NC2=C1O SWBFAJFABKJUJL-UHFFFAOYSA-N 0.000 description 1
- UBFAMJUONBJSHG-UHFFFAOYSA-N 1-o-tert-butyl 6-o-methyl 5-hydroxy-2-methylbenzimidazole-1,6-dicarboxylate Chemical compound C1=C(O)C(C(=O)OC)=CC2=C1N=C(C)N2C(=O)OC(C)(C)C UBFAMJUONBJSHG-UHFFFAOYSA-N 0.000 description 1
- GZGKVTXSCNPTPE-UHFFFAOYSA-N 2,3,5-triaminobenzoic acid Chemical compound NC1=CC(N)=C(N)C(C(O)=O)=C1 GZGKVTXSCNPTPE-UHFFFAOYSA-N 0.000 description 1
- LMMBCELBKIZEEP-UHFFFAOYSA-N 2,3,5-tris(2-methylpropanoylamino)benzoic acid Chemical compound CC(C)C(=O)NC1=CC(NC(=O)C(C)C)=C(NC(=O)C(C)C)C(C(O)=O)=C1 LMMBCELBKIZEEP-UHFFFAOYSA-N 0.000 description 1
- ACGHJOYWJHKWSV-UHFFFAOYSA-N 2-(benzylamino)-3,5-dinitrobenzoic acid Chemical compound OC(=O)C1=CC([N+]([O-])=O)=CC([N+]([O-])=O)=C1NCC1=CC=CC=C1 ACGHJOYWJHKWSV-UHFFFAOYSA-N 0.000 description 1
- FALRKNHUBBKYCC-UHFFFAOYSA-N 2-(chloromethyl)pyridine-3-carbonitrile Chemical compound ClCC1=NC=CC=C1C#N FALRKNHUBBKYCC-UHFFFAOYSA-N 0.000 description 1
- MSWZFWKMSRAUBD-IVMDWMLBSA-N 2-amino-2-deoxy-D-glucopyranose Chemical compound N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O MSWZFWKMSRAUBD-IVMDWMLBSA-N 0.000 description 1
- ADTKEYLCJYYHHH-UHFFFAOYSA-N 2-chloro-3,5-dinitrobenzoic acid Chemical compound OC(=O)C1=CC([N+]([O-])=O)=CC([N+]([O-])=O)=C1Cl ADTKEYLCJYYHHH-UHFFFAOYSA-N 0.000 description 1
- BFSVOASYOCHEOV-UHFFFAOYSA-N 2-diethylaminoethanol Chemical compound CCN(CC)CCO BFSVOASYOCHEOV-UHFFFAOYSA-N 0.000 description 1
- 229940013085 2-diethylaminoethanol Drugs 0.000 description 1
- XFKCVVFQGHCLIP-UHFFFAOYSA-N 2-ethylbutanedioyl dichloride Chemical compound CCC(C(Cl)=O)CC(Cl)=O XFKCVVFQGHCLIP-UHFFFAOYSA-N 0.000 description 1
- AXUDYYPUJZTLSH-UHFFFAOYSA-N 2-methyl-1h-benzimidazole-5,6-diol Chemical compound OC1=C(O)C=C2NC(C)=NC2=C1 AXUDYYPUJZTLSH-UHFFFAOYSA-N 0.000 description 1
- SOUBKSMZFMZBFH-UHFFFAOYSA-N 2-methyl-4-nitro-1h-benzimidazol-5-ol Chemical compound C1=C(O)C([N+]([O-])=O)=C2NC(C)=NC2=C1 SOUBKSMZFMZBFH-UHFFFAOYSA-N 0.000 description 1
- MJFUQZFERPSHKV-UHFFFAOYSA-N 2-methyl-6-nitro-1h-benzimidazol-5-ol Chemical compound OC1=C([N+]([O-])=O)C=C2NC(C)=NC2=C1 MJFUQZFERPSHKV-UHFFFAOYSA-N 0.000 description 1
- 125000006088 2-oxoazepinyl group Chemical group 0.000 description 1
- 125000004638 2-oxopiperazinyl group Chemical group O=C1N(CCNC1)* 0.000 description 1
- 125000004637 2-oxopiperidinyl group Chemical group O=C1N(CCCC1)* 0.000 description 1
- WFRXSXUDWCVSPI-UHFFFAOYSA-N 3h-benzimidazol-5-amine Chemical compound NC1=CC=C2NC=NC2=C1 WFRXSXUDWCVSPI-UHFFFAOYSA-N 0.000 description 1
- COYPLDIXZODDDL-UHFFFAOYSA-N 3h-benzimidazole-5-carboxylic acid Chemical compound OC(=O)C1=CC=C2N=CNC2=C1 COYPLDIXZODDDL-UHFFFAOYSA-N 0.000 description 1
- YRDLQYSDSSPINJ-UHFFFAOYSA-N 4,6-dimethoxy-2-propan-2-yl-1h-benzimidazole Chemical compound COC1=CC(OC)=C2NC(C(C)C)=NC2=C1 YRDLQYSDSSPINJ-UHFFFAOYSA-N 0.000 description 1
- NOYMIMUIXNHSCY-UHFFFAOYSA-N 4-(1H-benzimidazol-2-ylmethyl)naphthalene-1-carbonitrile Chemical compound C(#N)C1=CC=C(C2=CC=CC=C12)CC=1NC2=C(N=1)C=CC=C2 NOYMIMUIXNHSCY-UHFFFAOYSA-N 0.000 description 1
- ZJPMTNUXNRGDDY-UHFFFAOYSA-N 4-(2-ethyl-4-methyl-6-piperidin-4-yloxybenzimidazol-1-yl)naphthalene-1-carboximidamide Chemical compound C(N)(=N)C1=CC=C(C2=CC=CC=C12)N1C(=NC2=C1C=C(C=C2C)OC1CCNCC1)CC ZJPMTNUXNRGDDY-UHFFFAOYSA-N 0.000 description 1
- WMOUAIRAWCRBGU-UHFFFAOYSA-N 4-(4-methyl-6-piperidin-4-yloxy-2-propan-2-ylbenzimidazol-1-yl)naphthalene-1-carboximidamide Chemical compound C(N)(=N)C1=CC=C(C2=CC=CC=C12)N1C(=NC2=C1C=C(C=C2C)OC1CCNCC1)C(C)C WMOUAIRAWCRBGU-UHFFFAOYSA-N 0.000 description 1
- JZVWJRSOYOPBFL-UHFFFAOYSA-N 4-[5-(1-ethanimidoylpiperidin-4-yl)oxy-4-methyl-2-propylbenzimidazol-1-yl]naphthalene-1-carboximidamide Chemical compound C(N)(=N)C1=CC=C(C2=CC=CC=C12)N1C(=NC2=C1C=CC(=C2C)OC1CCN(CC1)C(C)=N)CCC JZVWJRSOYOPBFL-UHFFFAOYSA-N 0.000 description 1
- IQXUIDYRTHQTET-UHFFFAOYSA-N 4-amino-3-nitrophenol Chemical compound NC1=CC=C(O)C=C1[N+]([O-])=O IQXUIDYRTHQTET-UHFFFAOYSA-N 0.000 description 1
- AGAHETWGCFCMDK-UHFFFAOYSA-N 4-methoxybenzene-1,2-diamine Chemical compound COC1=CC=C(N)C(N)=C1 AGAHETWGCFCMDK-UHFFFAOYSA-N 0.000 description 1
- SQWCYFILTQQWMU-UHFFFAOYSA-N 4-nitro-2-propan-2-yl-1h-benzimidazol-5-ol Chemical compound C1=C(O)C([N+]([O-])=O)=C2NC(C(C)C)=NC2=C1 SQWCYFILTQQWMU-UHFFFAOYSA-N 0.000 description 1
- TYMLOMAKGOJONV-UHFFFAOYSA-N 4-nitroaniline Chemical compound NC1=CC=C([N+]([O-])=O)C=C1 TYMLOMAKGOJONV-UHFFFAOYSA-N 0.000 description 1
- 125000005986 4-piperidonyl group Chemical group 0.000 description 1
- XZIIFPSPUDAGJM-UHFFFAOYSA-N 6-chloro-2-n,2-n-diethylpyrimidine-2,4-diamine Chemical compound CCN(CC)C1=NC(N)=CC(Cl)=N1 XZIIFPSPUDAGJM-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 241000220479 Acacia Species 0.000 description 1
- 208000036762 Acute promyelocytic leukaemia Diseases 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 239000004322 Butylated hydroxytoluene Substances 0.000 description 1
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 1
- LEJWZOKOMDYCTK-UHFFFAOYSA-N C(#N)C1=CC=C(C2=CC=CC=C12)N1C(=NC2=C1C=C(C(=C2C)N)OC2CCN(CC2)C(=O)OC(C)(C)C)C(C)C Chemical compound C(#N)C1=CC=C(C2=CC=CC=C12)N1C(=NC2=C1C=C(C(=C2C)N)OC2CCN(CC2)C(=O)OC(C)(C)C)C(C)C LEJWZOKOMDYCTK-UHFFFAOYSA-N 0.000 description 1
- JHRMPOLZROWPSU-UHFFFAOYSA-N CC(C)(C)OC(=O)N1CCC(CC1)C2=CC3=C(C=C2)N=C(N3C4=CC=C(C5=CC=CC=C54)C#N)N Chemical compound CC(C)(C)OC(=O)N1CCC(CC1)C2=CC3=C(C=C2)N=C(N3C4=CC=C(C5=CC=CC=C54)C#N)N JHRMPOLZROWPSU-UHFFFAOYSA-N 0.000 description 1
- AFDFYSYBKJHMHF-UHFFFAOYSA-N CC(C)C1=NC(C=C(C(OCC(OC(C)(C)C)=O)=C2C(O)=O)O)=C2N1 Chemical compound CC(C)C1=NC(C=C(C(OCC(OC(C)(C)C)=O)=C2C(O)=O)O)=C2N1 AFDFYSYBKJHMHF-UHFFFAOYSA-N 0.000 description 1
- IAMZRTOPYWWGIP-UHFFFAOYSA-N CC1=C(C=C2C(=C1C(=O)O)N=C(N2C3=CC=C(C4=CC=CC=C43)C(=N)N)C(C)C)OC5CCN(CC5)C(=N)C Chemical compound CC1=C(C=C2C(=C1C(=O)O)N=C(N2C3=CC=C(C4=CC=CC=C43)C(=N)N)C(C)C)OC5CCN(CC5)C(=N)C IAMZRTOPYWWGIP-UHFFFAOYSA-N 0.000 description 1
- GHCQIJCRQPKLTP-UHFFFAOYSA-N CC1=C2C(=CC(=C1OC(C)C(=O)OC)OC3CCN(CC3)C(=O)OC(C)(C)C)N(C(=N2)C)C4=CC=C(C5=CC=CC=C54)C#N Chemical compound CC1=C2C(=CC(=C1OC(C)C(=O)OC)OC3CCN(CC3)C(=O)OC(C)(C)C)N(C(=N2)C)C4=CC=C(C5=CC=CC=C54)C#N GHCQIJCRQPKLTP-UHFFFAOYSA-N 0.000 description 1
- AMRWJYBHDNXVQP-UHFFFAOYSA-N CC1=C2C(=CC(=C1OCC3=CC=C(C=C3)C(=O)OC)OC4CCN(CC4)C(=O)OC(C)(C)C)N(C(=N2)C)C5=CC=C(C6=CC=CC=C65)C#N Chemical compound CC1=C2C(=CC(=C1OCC3=CC=C(C=C3)C(=O)OC)OC4CCN(CC4)C(=O)OC(C)(C)C)N(C(=N2)C)C5=CC=C(C6=CC=CC=C65)C#N AMRWJYBHDNXVQP-UHFFFAOYSA-N 0.000 description 1
- ZQEJTAAWOGUOBP-UHFFFAOYSA-N CC1=CC=C(C=C1)S(=O)(=O)N2C(=NC3=C2C=C(C(=C3N)C4CCN(CC4)C(=O)OC(C)(C)C)CC(C)C(=O)OC)C Chemical compound CC1=CC=C(C=C1)S(=O)(=O)N2C(=NC3=C2C=C(C(=C3N)C4CCN(CC4)C(=O)OC(C)(C)C)CC(C)C(=O)OC)C ZQEJTAAWOGUOBP-UHFFFAOYSA-N 0.000 description 1
- RGZXAOFIEUWVKV-UHFFFAOYSA-N CC1=CC=C(C=C1)S(=O)(=O)N2C(=NC3=C2C=CC(=C3N)C4CCN(CC4)C(=O)OC(C)(C)C)C Chemical compound CC1=CC=C(C=C1)S(=O)(=O)N2C(=NC3=C2C=CC(=C3N)C4CCN(CC4)C(=O)OC(C)(C)C)C RGZXAOFIEUWVKV-UHFFFAOYSA-N 0.000 description 1
- GQIURDCBARAENJ-UHFFFAOYSA-N CC1=NC2=C(N1)C=C(C(=C2N)C3CCN(CC3)C(=O)OC(C)(C)C)CCCC(=O)OC Chemical compound CC1=NC2=C(N1)C=C(C(=C2N)C3CCN(CC3)C(=O)OC(C)(C)C)CCCC(=O)OC GQIURDCBARAENJ-UHFFFAOYSA-N 0.000 description 1
- QDEZVWRDCLCUJH-UHFFFAOYSA-N CC1=NC2=C(N1C3=CC=C(C4=CC=CC=C43)C#N)C=C(C(=C2N)C5CCN(CC5)C(=O)OC(C)(C)C)CC(C)C(=O)OC Chemical compound CC1=NC2=C(N1C3=CC=C(C4=CC=CC=C43)C#N)C=C(C(=C2N)C5CCN(CC5)C(=O)OC(C)(C)C)CC(C)C(=O)OC QDEZVWRDCLCUJH-UHFFFAOYSA-N 0.000 description 1
- JCPOENBSQFRMCN-UHFFFAOYSA-N CC1=NC2=C(N1C3=CC=C(C4=CC=CC=C43)C#N)C=C(C(=C2N)CC(C)C(=O)OC)C5CCN(CC5)C(=O)OC(C)(C)C Chemical compound CC1=NC2=C(N1C3=CC=C(C4=CC=CC=C43)C#N)C=C(C(=C2N)CC(C)C(=O)OC)C5CCN(CC5)C(=O)OC(C)(C)C JCPOENBSQFRMCN-UHFFFAOYSA-N 0.000 description 1
- HYAVNMKXNKLFDL-UHFFFAOYSA-N CC1=NC2=C(N1C3=CC=C(C4=CC=CC=C43)C#N)C=C(C(=C2N)CCCC(=O)OC)C5CCN(CC5)C(=O)OC(C)(C)C Chemical compound CC1=NC2=C(N1C3=CC=C(C4=CC=CC=C43)C#N)C=C(C(=C2N)CCCC(=O)OC)C5CCN(CC5)C(=O)OC(C)(C)C HYAVNMKXNKLFDL-UHFFFAOYSA-N 0.000 description 1
- XFGIRCDGDJBPED-UHFFFAOYSA-N CC1=NC2=C(N1C3=CC=C(C4=CC=CC=C43)C#N)C=C(C(=C2N)[N+](=O)[O-])C5CCN(CC5)C(=O)OC(C)(C)C Chemical compound CC1=NC2=C(N1C3=CC=C(C4=CC=CC=C43)C#N)C=C(C(=C2N)[N+](=O)[O-])C5CCN(CC5)C(=O)OC(C)(C)C XFGIRCDGDJBPED-UHFFFAOYSA-N 0.000 description 1
- HQWSILUVFVIXNL-UHFFFAOYSA-N CC1=NC2=C(N1C3=CC=C(C4=CC=CC=C43)C(=N)N)C=C(C=C2)N(CC5=CC=C(C=C5)C(=O)O)C6CCNCC6 Chemical compound CC1=NC2=C(N1C3=CC=C(C4=CC=CC=C43)C(=N)N)C=C(C=C2)N(CC5=CC=C(C=C5)C(=O)O)C6CCNCC6 HQWSILUVFVIXNL-UHFFFAOYSA-N 0.000 description 1
- CMMUNIJQUXNICW-UHFFFAOYSA-N CCOC(=O)C1CCCCN1C2(CC(=C(C=C2)[N+](=O)[O-])F)F Chemical compound CCOC(=O)C1CCCCN1C2(CC(=C(C=C2)[N+](=O)[O-])F)F CMMUNIJQUXNICW-UHFFFAOYSA-N 0.000 description 1
- CJDZWASRBUOLJB-UHFFFAOYSA-N CCOC(=O)CCC(=O)C1=CC2=C(C(=C1C3CCN(CC3)C(=O)OC(C)(C)C)N)N=C(N2)C Chemical compound CCOC(=O)CCC(=O)C1=CC2=C(C(=C1C3CCN(CC3)C(=O)OC(C)(C)C)N)N=C(N2)C CJDZWASRBUOLJB-UHFFFAOYSA-N 0.000 description 1
- RMHHSCYLPIHBJF-UHFFFAOYSA-N COC(=O)C(=C)CC1=C2C(=CC=C1)NC(=N2)N Chemical compound COC(=O)C(=C)CC1=C2C(=CC=C1)NC(=N2)N RMHHSCYLPIHBJF-UHFFFAOYSA-N 0.000 description 1
- GBEHCIKZZWEOMV-UHFFFAOYSA-N COC(=O)c1c(N)ccc(c1O)[N+]([O-])=O Chemical compound COC(=O)c1c(N)ccc(c1O)[N+]([O-])=O GBEHCIKZZWEOMV-UHFFFAOYSA-N 0.000 description 1
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 1
- CKDWPUIZGOQOOM-UHFFFAOYSA-N Carbamyl chloride Chemical compound NC(Cl)=O CKDWPUIZGOQOOM-UHFFFAOYSA-N 0.000 description 1
- 241000700199 Cavia porcellus Species 0.000 description 1
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- 108010048049 Factor IXa Proteins 0.000 description 1
- 229940123583 Factor Xa inhibitor Drugs 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- ZWZWYGMENQVNFU-UHFFFAOYSA-N Glycerophosphorylserin Natural products OC(=O)C(N)COP(O)(=O)OCC(O)CO ZWZWYGMENQVNFU-UHFFFAOYSA-N 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 208000034578 Multiple myelomas Diseases 0.000 description 1
- UEEJHVSXFDXPFK-UHFFFAOYSA-N N-dimethylaminoethanol Chemical compound CN(C)CCO UEEJHVSXFDXPFK-UHFFFAOYSA-N 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 239000008118 PEG 6000 Substances 0.000 description 1
- QGMRQYFBGABWDR-UHFFFAOYSA-M Pentobarbital sodium Chemical compound [Na+].CCCC(C)C1(CC)C(=O)NC(=O)[N-]C1=O QGMRQYFBGABWDR-UHFFFAOYSA-M 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 229920001030 Polyethylene Glycol 4000 Polymers 0.000 description 1
- 229920002584 Polyethylene Glycol 6000 Polymers 0.000 description 1
- 208000033826 Promyelocytic Acute Leukemia Diseases 0.000 description 1
- 241000867233 Prosodes Species 0.000 description 1
- 206010037549 Purpura Diseases 0.000 description 1
- 241001672981 Purpura Species 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 206010040070 Septic Shock Diseases 0.000 description 1
- 229940122055 Serine protease inhibitor Drugs 0.000 description 1
- 101710102218 Serine protease inhibitor Proteins 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- HVUMOYIDDBPOLL-XWVZOOPGSA-N Sorbitan monostearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O HVUMOYIDDBPOLL-XWVZOOPGSA-N 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 229940122388 Thrombin inhibitor Drugs 0.000 description 1
- 208000032109 Transient ischaemic attack Diseases 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- IYABWNGZIDDRAK-UHFFFAOYSA-N allene Chemical group C=C=C IYABWNGZIDDRAK-UHFFFAOYSA-N 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 125000000320 amidine group Chemical group 0.000 description 1
- 238000005915 ammonolysis reaction Methods 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000002429 anti-coagulating effect Effects 0.000 description 1
- 229940127090 anticoagulant agent Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 210000001765 aortic valve Anatomy 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 229960003121 arginine Drugs 0.000 description 1
- 125000002785 azepinyl group Chemical group 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 125000004619 benzopyranyl group Chemical group O1C(C=CC2=C1C=CC=C2)* 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- NNAGWTFGSAGUGR-UHFFFAOYSA-N benzyl 4-[3-[(4-cyanonaphthalen-1-yl)methyl]-2-methyl-6-[1-[(2-methylpropan-2-yl)oxycarbonyl]piperidin-4-yl]oxybenzimidazol-5-yl]oxypiperidine-1-carboxylate Chemical compound C1CN(C(=O)OCC=2C=CC=CC=2)CCC1OC=1C=C2N(CC=3C4=CC=CC=C4C(C#N)=CC=3)C(C)=NC2=CC=1OC1CCN(C(=O)OC(C)(C)C)CC1 NNAGWTFGSAGUGR-UHFFFAOYSA-N 0.000 description 1
- JKIUUDJOCYHIGY-UHFFFAOYSA-N benzyl 4-hydroxypiperidine-1-carboxylate Chemical compound C1CC(O)CCN1C(=O)OCC1=CC=CC=C1 JKIUUDJOCYHIGY-UHFFFAOYSA-N 0.000 description 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 229960003237 betaine Drugs 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000008033 biological extinction Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000023555 blood coagulation Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- WOBLPDAWNVAVAS-UHFFFAOYSA-N butyl carboxy carbonate Chemical compound CCCCOC(=O)OC(O)=O WOBLPDAWNVAVAS-UHFFFAOYSA-N 0.000 description 1
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 1
- 229940095259 butylated hydroxytoluene Drugs 0.000 description 1
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 1
- 229910001424 calcium ion Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 108090001015 cancer procoagulant Proteins 0.000 description 1
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 210000001715 carotid artery Anatomy 0.000 description 1
- 239000012876 carrier material Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003593 chromogenic compound Substances 0.000 description 1
- 235000013985 cinnamic acid Nutrition 0.000 description 1
- 229930016911 cinnamic acid Natural products 0.000 description 1
- 229960004106 citric acid Drugs 0.000 description 1
- 238000007820 coagulation assay Methods 0.000 description 1
- AGVAZMGAQJOSFJ-WZHZPDAFSA-M cobalt(2+);[(2r,3s,4r,5s)-5-(5,6-dimethylbenzimidazol-1-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] [(2r)-1-[3-[(1r,2r,3r,4z,7s,9z,12s,13s,14z,17s,18s,19r)-2,13,18-tris(2-amino-2-oxoethyl)-7,12,17-tris(3-amino-3-oxopropyl)-3,5,8,8,13,15,18,19-octamethyl-2 Chemical compound [Co+2].N#[C-].[N-]([C@@H]1[C@H](CC(N)=O)[C@@]2(C)CCC(=O)NC[C@@H](C)OP(O)(=O)O[C@H]3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)\C2=C(C)/C([C@H](C\2(C)C)CCC(N)=O)=N/C/2=C\C([C@H]([C@@]/2(CC(N)=O)C)CCC(N)=O)=N\C\2=C(C)/C2=N[C@]1(C)[C@@](C)(CC(N)=O)[C@@H]2CCC(N)=O AGVAZMGAQJOSFJ-WZHZPDAFSA-M 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 238000007887 coronary angioplasty Methods 0.000 description 1
- 210000004351 coronary vessel Anatomy 0.000 description 1
- 229960001681 croscarmellose sodium Drugs 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 239000010779 crude oil Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000005507 decahydroisoquinolyl group Chemical group 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- AQEFLFZSWDEAIP-UHFFFAOYSA-N di-tert-butyl ether Chemical compound CC(C)(C)OC(C)(C)C AQEFLFZSWDEAIP-UHFFFAOYSA-N 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 150000004985 diamines Chemical class 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 208000009190 disseminated intravascular coagulation Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000001952 enzyme assay Methods 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 229940125532 enzyme inhibitor Drugs 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- IBPKCIKRWOAXAZ-UHFFFAOYSA-N ethyl 1-(3,5-difluoro-2-nitrophenyl)piperidine-4-carboxylate Chemical compound C1CC(C(=O)OCC)CCN1C1=CC(F)=CC(F)=C1[N+]([O-])=O IBPKCIKRWOAXAZ-UHFFFAOYSA-N 0.000 description 1
- FCZCIXQGZOUIDN-UHFFFAOYSA-N ethyl 2-diethoxyphosphinothioyloxyacetate Chemical compound CCOC(=O)COP(=S)(OCC)OCC FCZCIXQGZOUIDN-UHFFFAOYSA-N 0.000 description 1
- CEIPQQODRKXDSB-UHFFFAOYSA-N ethyl 3-(6-hydroxynaphthalen-2-yl)-1H-indazole-5-carboximidate dihydrochloride Chemical compound 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 1
- 239000002038 ethyl acetate fraction Substances 0.000 description 1
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- JMIAPORGEDIDLT-UHFFFAOYSA-N ethyl ethanimidate Chemical compound CCOC(C)=N JMIAPORGEDIDLT-UHFFFAOYSA-N 0.000 description 1
- RUJPPJYDHHAEEK-UHFFFAOYSA-N ethyl piperidine-4-carboxylate Chemical compound CCOC(=O)C1CCNCC1 RUJPPJYDHHAEEK-UHFFFAOYSA-N 0.000 description 1
- 229940012017 ethylenediamine Drugs 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000003527 fibrinolytic agent Substances 0.000 description 1
- 230000003480 fibrinolytic effect Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 230000009969 flowable effect Effects 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 229960002442 glucosamine Drugs 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 150000002357 guanidines Chemical class 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000023597 hemostasis Effects 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 229960002885 histidine Drugs 0.000 description 1
- XGIHQYAWBCFNPY-AZOCGYLKSA-N hydrabamine Chemical compound C([C@@H]12)CC3=CC(C(C)C)=CC=C3[C@@]2(C)CCC[C@@]1(C)CNCCNC[C@@]1(C)[C@@H]2CCC3=CC(C(C)C)=CC=C3[C@@]2(C)CCC1 XGIHQYAWBCFNPY-AZOCGYLKSA-N 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 125000002636 imidazolinyl group Chemical group 0.000 description 1
- 238000000099 in vitro assay Methods 0.000 description 1
- 238000005462 in vivo assay Methods 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- VQTUBCCKSQIDNK-UHFFFAOYSA-N iso-butene Natural products CC(C)=C VQTUBCCKSQIDNK-UHFFFAOYSA-N 0.000 description 1
- LSACYLWPPQLVSM-UHFFFAOYSA-N isobutyric acid anhydride Chemical compound CC(C)C(=O)OC(=O)C(C)C LSACYLWPPQLVSM-UHFFFAOYSA-N 0.000 description 1
- 125000004594 isoindolinyl group Chemical group C1(NCC2=CC=CC=C12)* 0.000 description 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 125000004628 isothiazolidinyl group Chemical group S1N(CCC1)* 0.000 description 1
- 125000003971 isoxazolinyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 239000008297 liquid dosage form Substances 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 159000000002 lithium salts Chemical class 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000008176 lyophilized powder Substances 0.000 description 1
- 229960003646 lysine 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
- 239000011976 maleic acid Substances 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- WAPWDAQAEJHERT-UHFFFAOYSA-N methyl 1-(2,3-diamino-5-methoxyphenyl)piperidine-4-carboxylate Chemical compound C1CC(C(=O)OC)CCN1C1=CC(OC)=CC(N)=C1N WAPWDAQAEJHERT-UHFFFAOYSA-N 0.000 description 1
- XBPUYHPTTAZLFX-UHFFFAOYSA-N methyl 1-(2,3-diamino-5-methoxyphenyl)piperidine-4-carboxylate;dihydrochloride Chemical compound Cl.Cl.C1CC(C(=O)OC)CCN1C1=CC(OC)=CC(N)=C1N XBPUYHPTTAZLFX-UHFFFAOYSA-N 0.000 description 1
- ISKROWAGCCWXPO-UHFFFAOYSA-N methyl 1-[4-amino-5-methoxy-2,3-bis(2-methylpropanoyl)phenyl]piperidine-4-carboxylate Chemical compound C1CC(C(=O)OC)CCN1C1=CC(OC)=C(N)C(C(=O)C(C)C)=C1C(=O)C(C)C ISKROWAGCCWXPO-UHFFFAOYSA-N 0.000 description 1
- LVSONODYIJYOQV-UHFFFAOYSA-N methyl 2-amino-6-hydroxy-4-(2-methylpropanoyl)-3-nitrobenzoate Chemical compound COC(=O)c1c(O)cc(C(=O)C(C)C)c(c1N)[N+]([O-])=O LVSONODYIJYOQV-UHFFFAOYSA-N 0.000 description 1
- WKSSGYDGEBDKKR-UHFFFAOYSA-N methyl 2-methyl-6-[1-[(2-methylpropan-2-yl)oxycarbonyl]piperidin-4-yl]oxy-3h-benzimidazole-5-carboxylate Chemical compound COC(=O)C1=CC=2NC(C)=NC=2C=C1OC1CCN(C(=O)OC(C)(C)C)CC1 WKSSGYDGEBDKKR-UHFFFAOYSA-N 0.000 description 1
- BZHKYTORCRHYDY-UHFFFAOYSA-N methyl 3-[(4-cyanonaphthalen-1-yl)methyl]-6-[(2-methylpropan-2-yl)oxycarbonyl-piperidin-4-ylamino]-2-propan-2-ylbenzimidazole-4-carboxylate Chemical compound C=1C=2N=C(C(C)C)N(CC=3C4=CC=CC=C4C(C#N)=CC=3)C=2C(C(=O)OC)=CC=1N(C(=O)OC(C)(C)C)C1CCNCC1 BZHKYTORCRHYDY-UHFFFAOYSA-N 0.000 description 1
- FKWNAVCXZSQYTA-UHFFFAOYSA-N methyl 3-bromo-2-methylpropanoate Chemical compound COC(=O)C(C)CBr FKWNAVCXZSQYTA-UHFFFAOYSA-N 0.000 description 1
- NLWBJPPMPLPZIE-UHFFFAOYSA-N methyl 4-(bromomethyl)benzoate Chemical compound COC(=O)C1=CC=C(CBr)C=C1 NLWBJPPMPLPZIE-UHFFFAOYSA-N 0.000 description 1
- ZBJBWCUKWKHMBO-UHFFFAOYSA-N methyl 4-acetamido-3-amino-2-hydroxybenzoate Chemical compound COC(=O)C1=CC=C(NC(C)=O)C(N)=C1O ZBJBWCUKWKHMBO-UHFFFAOYSA-N 0.000 description 1
- KEZGTKDKXNPULT-UHFFFAOYSA-N methyl 4-acetamido-5-amino-2-hydroxybenzoate Chemical compound COC(=O)C1=CC(N)=C(NC(C)=O)C=C1O KEZGTKDKXNPULT-UHFFFAOYSA-N 0.000 description 1
- BHKXPWBZGXDSES-UHFFFAOYSA-N methyl 6-hydroxy-2-propan-2-yl-3h-benzimidazole-5-carboxylate Chemical compound C1=C(O)C(C(=O)OC)=CC2=C1N=C(C(C)C)N2 BHKXPWBZGXDSES-UHFFFAOYSA-N 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- YJMNOKOLADGBKA-UHFFFAOYSA-N naphthalene-1-carbonitrile Chemical compound C1=CC=C2C(C#N)=CC=CC2=C1 YJMNOKOLADGBKA-UHFFFAOYSA-N 0.000 description 1
- 230000014508 negative regulation of coagulation Effects 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 239000012434 nucleophilic reagent Substances 0.000 description 1
- 125000005060 octahydroindolyl group Chemical group N1(CCC2CCCCC12)* 0.000 description 1
- 125000005061 octahydroisoindolyl group Chemical group C1(NCC2CCCCC12)* 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 238000006053 organic reaction Methods 0.000 description 1
- 230000000399 orthopedic effect Effects 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000000160 oxazolidinyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000005476 oxopyrrolidinyl group Chemical group 0.000 description 1
- QQOXBFUTRLDXDP-UHFFFAOYSA-N p-Aminosalicylic acid methyl ester Chemical compound COC(=O)C1=CC=C(N)C=C1O QQOXBFUTRLDXDP-UHFFFAOYSA-N 0.000 description 1
- 239000006179 pH buffering agent Substances 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 229960001412 pentobarbital Drugs 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 239000002831 pharmacologic agent Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 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
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 description 1
- 229920002523 polyethylene Glycol 1000 Polymers 0.000 description 1
- 229940113116 polyethylene glycol 1000 Drugs 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 239000000473 propyl gallate Substances 0.000 description 1
- 235000010388 propyl gallate Nutrition 0.000 description 1
- 229940075579 propyl gallate Drugs 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 239000003223 protective agent Substances 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- 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 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 125000004621 quinuclidinyl group Chemical group N12C(CC(CC1)CC2)* 0.000 description 1
- 210000002796 renal vein Anatomy 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 229940085605 saccharin sodium Drugs 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 238000009738 saturating Methods 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 230000036303 septic shock Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
- KYITYFHKDODNCQ-UHFFFAOYSA-M sodium;2-oxo-3-(3-oxo-1-phenylbutyl)chromen-4-olate Chemical compound [Na+].[O-]C=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 KYITYFHKDODNCQ-UHFFFAOYSA-M 0.000 description 1
- 238000000935 solvent evaporation Methods 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 229940035044 sorbitan monolaurate Drugs 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 229940014800 succinic anhydride Drugs 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- YJXUDIIGRVWDMJ-UHFFFAOYSA-N tert-butyl 2-butyl-6-[1-[(2-methylpropan-2-yl)oxycarbonyl]piperidin-4-yl]oxybenzimidazole-1-carboxylate Chemical compound C1=C2N(C(=O)OC(C)(C)C)C(CCCC)=NC2=CC=C1OC1CCN(C(=O)OC(C)(C)C)CC1 YJXUDIIGRVWDMJ-UHFFFAOYSA-N 0.000 description 1
- PDCBPPZKJMFSQO-UHFFFAOYSA-N tert-butyl 2-butyl-6-hydroxybenzimidazole-1-carboxylate Chemical compound C1=C(O)C=C2N(C(=O)OC(C)(C)C)C(CCCC)=NC2=C1 PDCBPPZKJMFSQO-UHFFFAOYSA-N 0.000 description 1
- IOLLMRCVSJHBAE-UHFFFAOYSA-N tert-butyl 2-ethyl-6-[1-[(2-methylpropan-2-yl)oxycarbonyl]piperidin-4-yl]oxybenzimidazole-1-carboxylate Chemical compound C1=C2N(C(=O)OC(C)(C)C)C(CC)=NC2=CC=C1OC1CCN(C(=O)OC(C)(C)C)CC1 IOLLMRCVSJHBAE-UHFFFAOYSA-N 0.000 description 1
- CZYMULBIXSISJZ-UHFFFAOYSA-N tert-butyl 2-ethyl-6-hydroxybenzimidazole-1-carboxylate Chemical compound C1=C(O)C=C2N(C(=O)OC(C)(C)C)C(CC)=NC2=C1 CZYMULBIXSISJZ-UHFFFAOYSA-N 0.000 description 1
- KOSBBADXDQAWHT-UHFFFAOYSA-N tert-butyl 2-methyl-6-[1-[(2-methylpropan-2-yl)oxycarbonyl]piperidin-4-yl]oxybenzimidazole-1-carboxylate Chemical compound C1=C2N(C(=O)OC(C)(C)C)C(C)=NC2=CC=C1OC1CCN(C(=O)OC(C)(C)C)CC1 KOSBBADXDQAWHT-UHFFFAOYSA-N 0.000 description 1
- OAJSZPZUQGXUCL-UHFFFAOYSA-N tert-butyl 2-tert-butyl-6-[1-[(2-methylpropan-2-yl)oxycarbonyl]piperidin-4-yl]oxybenzimidazole-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1OC1=CC=C(N=C(N2C(=O)OC(C)(C)C)C(C)(C)C)C2=C1 OAJSZPZUQGXUCL-UHFFFAOYSA-N 0.000 description 1
- WRLKZKGXDSJSOF-UHFFFAOYSA-N tert-butyl 2-tert-butyl-6-hydroxybenzimidazole-1-carboxylate Chemical compound C1=C(O)C=C2N(C(=O)OC(C)(C)C)C(C(C)(C)C)=NC2=C1 WRLKZKGXDSJSOF-UHFFFAOYSA-N 0.000 description 1
- SXVRLUNXZZPCTC-UHFFFAOYSA-N tert-butyl 4-[(2-methyl-4-nitro-1h-benzimidazol-5-yl)oxy]piperidine-1-carboxylate Chemical compound [O-][N+](=O)C1=C2NC(C)=NC2=CC=C1OC1CCN(C(=O)OC(C)(C)C)CC1 SXVRLUNXZZPCTC-UHFFFAOYSA-N 0.000 description 1
- XGWGYZJWMVFKQU-UHFFFAOYSA-N tert-butyl 4-[(2-methyl-6-nitro-1h-benzimidazol-5-yl)oxy]piperidine-1-carboxylate Chemical compound [O-][N+](=O)C=1C=C2NC(C)=NC2=CC=1OC1CCN(C(=O)OC(C)(C)C)CC1 XGWGYZJWMVFKQU-UHFFFAOYSA-N 0.000 description 1
- YOMYNUANIDAZGY-UHFFFAOYSA-N tert-butyl 4-[(4-methyl-2-propan-2-yl-1H-benzimidazol-5-yl)oxy]piperidine-1-carboxylate Chemical compound CC1=C(C=CC2=C1N=C(N2)C(C)C)OC3CCN(CC3)C(=O)OC(C)(C)C YOMYNUANIDAZGY-UHFFFAOYSA-N 0.000 description 1
- CMJUISRJLWBTHZ-UHFFFAOYSA-N tert-butyl 4-[(4-nitro-2-propan-2-yl-1h-benzimidazol-5-yl)oxy]piperidine-1-carboxylate Chemical compound C=1C=C2NC(C(C)C)=NC2=C([N+]([O-])=O)C=1OC1CCN(C(=O)OC(C)(C)C)CC1 CMJUISRJLWBTHZ-UHFFFAOYSA-N 0.000 description 1
- UGDMXXJDZSWZPS-UHFFFAOYSA-N tert-butyl 4-[(7-methyl-6-nitro-2-propan-2-yl-3H-benzimidazol-5-yl)oxy]piperidine-1-carboxylate Chemical compound CC1=C2C(=CC(=C1[N+](=O)[O-])OC3CCN(CC3)C(=O)OC(C)(C)C)NC(=N2)C(C)C UGDMXXJDZSWZPS-UHFFFAOYSA-N 0.000 description 1
- WHEMAFMDCGPQJL-UHFFFAOYSA-N tert-butyl 4-[1-(4-cyanonaphthalen-1-yl)-2-(2-methylpropyl)benzimidazol-5-yl]oxypiperidine-1-carboxylate Chemical compound C=1C=C2N(C=3C4=CC=CC=C4C(C#N)=CC=3)C(CC(C)C)=NC2=CC=1OC1CCN(C(=O)OC(C)(C)C)CC1 WHEMAFMDCGPQJL-UHFFFAOYSA-N 0.000 description 1
- FGHQGNJLFLPODS-UHFFFAOYSA-N tert-butyl 4-[1-(4-cyanonaphthalen-1-yl)-2-(trifluoromethyl)benzimidazol-5-yl]oxypiperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1OC1=CC=C(N(C(=N2)C(F)(F)F)C=3C4=CC=CC=C4C(C#N)=CC=3)C2=C1 FGHQGNJLFLPODS-UHFFFAOYSA-N 0.000 description 1
- DMLVTAHWIZMFDN-UHFFFAOYSA-N tert-butyl 4-[1-(4-cyanonaphthalen-1-yl)-2-ethylbenzimidazol-5-yl]oxypiperidine-1-carboxylate Chemical compound C=1C=C2N(C=3C4=CC=CC=C4C(C#N)=CC=3)C(CC)=NC2=CC=1OC1CCN(C(=O)OC(C)(C)C)CC1 DMLVTAHWIZMFDN-UHFFFAOYSA-N 0.000 description 1
- RIFGJIWPMFZRAI-UHFFFAOYSA-N tert-butyl 4-[1-(4-cyanonaphthalen-1-yl)-2-methylbenzimidazol-5-yl]oxypiperidine-1-carboxylate Chemical compound C=1C=C2N(C=3C4=CC=CC=C4C(C#N)=CC=3)C(C)=NC2=CC=1OC1CCN(C(=O)OC(C)(C)C)CC1 RIFGJIWPMFZRAI-UHFFFAOYSA-N 0.000 description 1
- KJXKEHVAWLZDKS-UHFFFAOYSA-N tert-butyl 4-[1-(4-cyanonaphthalen-1-yl)-2-propylbenzimidazol-5-yl]oxypiperidine-1-carboxylate Chemical compound C=1C=C2N(C=3C4=CC=CC=C4C(C#N)=CC=3)C(CCC)=NC2=CC=1OC1CCN(C(=O)OC(C)(C)C)CC1 KJXKEHVAWLZDKS-UHFFFAOYSA-N 0.000 description 1
- QNSYMDOUWYRCRL-UHFFFAOYSA-N tert-butyl 4-[1-(4-cyanonaphthalen-1-yl)-4-methoxy-2-propan-2-ylbenzimidazol-5-yl]oxypiperidine-1-carboxylate Chemical compound C1=CC=2N(C=3C4=CC=CC=C4C(C#N)=CC=3)C(C(C)C)=NC=2C(OC)=C1OC1CCN(C(=O)OC(C)(C)C)CC1 QNSYMDOUWYRCRL-UHFFFAOYSA-N 0.000 description 1
- RMRYRIZOZHWWGI-UHFFFAOYSA-N tert-butyl 4-[1-(4-cyanonaphthalen-1-yl)benzimidazol-5-yl]oxypiperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1OC1=CC=C(N(C=N2)C=3C4=CC=CC=C4C(C#N)=CC=3)C2=C1 RMRYRIZOZHWWGI-UHFFFAOYSA-N 0.000 description 1
- CRXSTGGCTDTMNK-UHFFFAOYSA-N tert-butyl 4-[2-butyl-1-(4-cyanonaphthalen-1-yl)benzimidazol-5-yl]oxypiperidine-1-carboxylate Chemical compound C=1C=C2N(C=3C4=CC=CC=C4C(C#N)=CC=3)C(CCCC)=NC2=CC=1OC1CCN(C(=O)OC(C)(C)C)CC1 CRXSTGGCTDTMNK-UHFFFAOYSA-N 0.000 description 1
- LHJBVGXDKJHKGW-UHFFFAOYSA-N tert-butyl 4-[2-butyl-3-(4-cyanonaphthalen-1-yl)benzimidazol-5-yl]oxypiperidine-1-carboxylate Chemical compound C1=C2N(C=3C4=CC=CC=C4C(C#N)=CC=3)C(CCCC)=NC2=CC=C1OC1CCN(C(=O)OC(C)(C)C)CC1 LHJBVGXDKJHKGW-UHFFFAOYSA-N 0.000 description 1
- JFGJDPLXHCBYOI-UHFFFAOYSA-N tert-butyl 4-[2-tert-butyl-1-(4-cyanonaphthalen-1-yl)benzimidazol-5-yl]oxypiperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1OC1=CC=C(N(C(=N2)C(C)(C)C)C=3C4=CC=CC=C4C(C#N)=CC=3)C2=C1 JFGJDPLXHCBYOI-UHFFFAOYSA-N 0.000 description 1
- BKTAAUQIUXFRPV-UHFFFAOYSA-N tert-butyl 4-[2-tert-butyl-3-(4-cyanonaphthalen-1-yl)benzimidazol-5-yl]oxypiperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1OC1=CC=C(N=C(N2C=3C4=CC=CC=C4C(C#N)=CC=3)C(C)(C)C)C2=C1 BKTAAUQIUXFRPV-UHFFFAOYSA-N 0.000 description 1
- GJRWHSXJPDBTLC-UHFFFAOYSA-N tert-butyl 4-[3-(4-cyanonaphthalen-1-yl)-2-(2-methylpropyl)benzimidazol-5-yl]oxypiperidine-1-carboxylate Chemical compound C1=C2N(C=3C4=CC=CC=C4C(C#N)=CC=3)C(CC(C)C)=NC2=CC=C1OC1CCN(C(=O)OC(C)(C)C)CC1 GJRWHSXJPDBTLC-UHFFFAOYSA-N 0.000 description 1
- IONVDOLWZBAKQW-UHFFFAOYSA-N tert-butyl 4-[3-(4-cyanonaphthalen-1-yl)-2-(trifluoromethyl)benzimidazol-5-yl]oxypiperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1OC1=CC=C(N=C(N2C=3C4=CC=CC=C4C(C#N)=CC=3)C(F)(F)F)C2=C1 IONVDOLWZBAKQW-UHFFFAOYSA-N 0.000 description 1
- IJLRLJFHSPVTPU-UHFFFAOYSA-N tert-butyl 4-[3-(4-cyanonaphthalen-1-yl)-2-ethylbenzimidazol-5-yl]oxypiperidine-1-carboxylate Chemical compound C1=C2N(C=3C4=CC=CC=C4C(C#N)=CC=3)C(CC)=NC2=CC=C1OC1CCN(C(=O)OC(C)(C)C)CC1 IJLRLJFHSPVTPU-UHFFFAOYSA-N 0.000 description 1
- GSGSEESIFPVHBC-UHFFFAOYSA-N tert-butyl 4-[3-(4-cyanonaphthalen-1-yl)-2-methylbenzimidazol-5-yl]oxypiperidine-1-carboxylate Chemical compound C1=C2N(C=3C4=CC=CC=C4C(C#N)=CC=3)C(C)=NC2=CC=C1OC1CCN(C(=O)OC(C)(C)C)CC1 GSGSEESIFPVHBC-UHFFFAOYSA-N 0.000 description 1
- HHAOMEDBCCBQKZ-UHFFFAOYSA-N tert-butyl 4-[3-(4-cyanonaphthalen-1-yl)-2-propylbenzimidazol-5-yl]oxypiperidine-1-carboxylate Chemical compound C1=C2N(C=3C4=CC=CC=C4C(C#N)=CC=3)C(CCC)=NC2=CC=C1OC1CCN(C(=O)OC(C)(C)C)CC1 HHAOMEDBCCBQKZ-UHFFFAOYSA-N 0.000 description 1
- VGCSVHVBZRSEIF-UHFFFAOYSA-N tert-butyl 4-[3-(4-cyanonaphthalen-1-yl)-7-methoxy-2-propan-2-ylbenzimidazol-5-yl]oxypiperidine-1-carboxylate Chemical compound C=1C=2N(C=3C4=CC=CC=C4C(C#N)=CC=3)C(C(C)C)=NC=2C(OC)=CC=1OC1CCN(C(=O)OC(C)(C)C)CC1 VGCSVHVBZRSEIF-UHFFFAOYSA-N 0.000 description 1
- KRGSJNHNEVJPPG-UHFFFAOYSA-N tert-butyl 4-[3-(4-cyanonaphthalen-1-yl)-7-methyl-2-propan-2-ylbenzimidazol-5-yl]oxypiperidine-1-carboxylate Chemical compound C(C)(C)(C)OC(=O)N1CCC(CC1)OC=1C=C(C2=C(N(C(=N2)C(C)C)C2=CC=C(C3=CC=CC=C23)C#N)C=1)C KRGSJNHNEVJPPG-UHFFFAOYSA-N 0.000 description 1
- JAHAZMAHHPPSAW-UHFFFAOYSA-N tert-butyl 4-[3-(4-cyanonaphthalen-1-yl)-7-methyl-6-nitro-2-propan-2-ylbenzimidazol-5-yl]oxypiperidine-1-carboxylate Chemical compound C(#N)C1=CC=C(C2=CC=CC=C12)N1C(=NC2=C1C=C(C(=C2C)[N+](=O)[O-])OC1CCN(CC1)C(=O)OC(C)(C)C)C(C)C JAHAZMAHHPPSAW-UHFFFAOYSA-N 0.000 description 1
- MEOGYZFOCNBWSH-UHFFFAOYSA-N tert-butyl 4-[3-(4-cyanonaphthalen-1-yl)benzimidazol-5-yl]oxypiperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1OC1=CC=C(N=CN2C=3C4=CC=CC=C4C(C#N)=CC=3)C2=C1 MEOGYZFOCNBWSH-UHFFFAOYSA-N 0.000 description 1
- JSQYFKFQPPGDKB-UHFFFAOYSA-N tert-butyl 4-[3-[(4-cyanonaphthalen-1-yl)methyl]-4-nitro-2-propan-2-ylbenzimidazol-5-yl]oxypiperidine-1-carboxylate Chemical compound [O-][N+](=O)C1=C2N(CC=3C4=CC=CC=C4C(C#N)=CC=3)C(C(C)C)=NC2=CC=C1OC1CCN(C(=O)OC(C)(C)C)CC1 JSQYFKFQPPGDKB-UHFFFAOYSA-N 0.000 description 1
- WISMFFWIKVHUTD-UHFFFAOYSA-N tert-butyl 4-[3h-benzimidazol-5-yl(methyl)amino]piperidine-1-carboxylate Chemical compound C=1C=C2N=CNC2=CC=1N(C)C1CCN(C(=O)OC(C)(C)C)CC1 WISMFFWIKVHUTD-UHFFFAOYSA-N 0.000 description 1
- ZOKLIFQGPPCXTA-UHFFFAOYSA-N tert-butyl 4-[6-[tert-butyl(dimethyl)silyl]oxy-1-[(4-cyanonaphthalen-1-yl)methyl]-2-methylbenzimidazol-5-yl]oxypiperidine-1-carboxylate Chemical compound CC(C)(C)[Si](C)(C)OC=1C=C2N(CC=3C4=CC=CC=C4C(C#N)=CC=3)C(C)=NC2=CC=1OC1CCN(C(=O)OC(C)(C)C)CC1 ZOKLIFQGPPCXTA-UHFFFAOYSA-N 0.000 description 1
- MAWCRHAECOSYGW-UHFFFAOYSA-N tert-butyl 4-[[2-methyl-1-(4-methylphenyl)sulfonylbenzimidazol-5-yl]amino]piperidine-1-carboxylate Chemical compound C=1C=C2N(S(=O)(=O)C=3C=CC(C)=CC=3)C(C)=NC2=CC=1NC1CCN(C(=O)OC(C)(C)C)CC1 MAWCRHAECOSYGW-UHFFFAOYSA-N 0.000 description 1
- BBJIGBROUGRMGO-UHFFFAOYSA-N tert-butyl 4-[[3-(4-methylphenyl)sulfonylbenzimidazol-5-yl]amino]piperidine-1-carboxylate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)N1C2=CC(NC3CCN(CC3)C(=O)OC(C)(C)C)=CC=C2N=C1 BBJIGBROUGRMGO-UHFFFAOYSA-N 0.000 description 1
- IKYSCPCXKNZFJP-UHFFFAOYSA-N tert-butyl 4-methoxy-6-[1-[(2-methylpropan-2-yl)oxycarbonyl]piperidin-4-yl]oxy-2-propan-2-ylbenzimidazole-1-carboxylate Chemical compound C=1C=2N(C(=O)OC(C)(C)C)C(C(C)C)=NC=2C(OC)=CC=1OC1CCN(C(=O)OC(C)(C)C)CC1 IKYSCPCXKNZFJP-UHFFFAOYSA-N 0.000 description 1
- BWGZMMUMHVKFLN-UHFFFAOYSA-N tert-butyl 5,6-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylbenzimidazole-1-carboxylate Chemical compound CC(C)(C)[Si](C)(C)OC1=C(O[Si](C)(C)C(C)(C)C)C=C2N(C(=O)OC(C)(C)C)C(C)=NC2=C1 BWGZMMUMHVKFLN-UHFFFAOYSA-N 0.000 description 1
- ZZSQIEATPYWSOK-UHFFFAOYSA-N tert-butyl 5-[tert-butyl(dimethyl)silyl]oxy-6-hydroxy-2-methylbenzimidazole-1-carboxylate Chemical compound CC(C)(C)[Si](C)(C)OC1=C(O)C=C2N(C(=O)OC(C)(C)C)C(C)=NC2=C1 ZZSQIEATPYWSOK-UHFFFAOYSA-N 0.000 description 1
- VOGPCKAYIWTYKY-UHFFFAOYSA-N tert-butyl 6-[1-[(2-methylpropan-2-yl)oxycarbonyl]piperidin-4-yl]oxy-2-(2-methylpropyl)benzimidazole-1-carboxylate Chemical compound C1=C2N(C(=O)OC(C)(C)C)C(CC(C)C)=NC2=CC=C1OC1CCN(C(=O)OC(C)(C)C)CC1 VOGPCKAYIWTYKY-UHFFFAOYSA-N 0.000 description 1
- KYPVUNRLLOMVBB-UHFFFAOYSA-N tert-butyl 6-[1-[(2-methylpropan-2-yl)oxycarbonyl]piperidin-4-yl]oxy-2-(trifluoromethyl)benzimidazole-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1OC1=CC=C(N=C(N2C(=O)OC(C)(C)C)C(F)(F)F)C2=C1 KYPVUNRLLOMVBB-UHFFFAOYSA-N 0.000 description 1
- HKUZVJHETHAAAR-UHFFFAOYSA-N tert-butyl 6-[1-[(2-methylpropan-2-yl)oxycarbonyl]piperidin-4-yl]oxy-2-propan-2-ylbenzimidazole-1-carboxylate Chemical compound C1=C2N(C(=O)OC(C)(C)C)C(C(C)C)=NC2=CC=C1OC1CCN(C(=O)OC(C)(C)C)CC1 HKUZVJHETHAAAR-UHFFFAOYSA-N 0.000 description 1
- FKTUHIDTMLLZJS-UHFFFAOYSA-N tert-butyl 6-[1-[(2-methylpropan-2-yl)oxycarbonyl]piperidin-4-yl]oxybenzimidazole-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1OC1=CC=C(N=CN2C(=O)OC(C)(C)C)C2=C1 FKTUHIDTMLLZJS-UHFFFAOYSA-N 0.000 description 1
- DPDWQTSKNSJUTD-UHFFFAOYSA-N tert-butyl 6-[tert-butyl(dimethyl)silyl]oxy-5-hydroxy-2-methylbenzimidazole-1-carboxylate Chemical compound OC1=C(O[Si](C)(C)C(C)(C)C)C=C2N(C(=O)OC(C)(C)C)C(C)=NC2=C1 DPDWQTSKNSJUTD-UHFFFAOYSA-N 0.000 description 1
- RGIVDRJXTZAETK-UHFFFAOYSA-N tert-butyl 6-hydroxy-2-(3-methoxy-3-oxopropyl)benzimidazole-1-carboxylate Chemical compound C1=C(O)C=C2N(C(=O)OC(C)(C)C)C(CCC(=O)OC)=NC2=C1 RGIVDRJXTZAETK-UHFFFAOYSA-N 0.000 description 1
- ZUFQITYZGHTZPY-UHFFFAOYSA-N tert-butyl 6-hydroxy-2-(trifluoromethyl)benzimidazole-1-carboxylate Chemical compound C1=C(O)C=C2N(C(=O)OC(C)(C)C)C(C(F)(F)F)=NC2=C1 ZUFQITYZGHTZPY-UHFFFAOYSA-N 0.000 description 1
- PJUWDNHXZGNVGP-UHFFFAOYSA-N tert-butyl 6-hydroxy-2-methylbenzimidazole-1-carboxylate Chemical compound C1=C(O)C=C2N(C(=O)OC(C)(C)C)C(C)=NC2=C1 PJUWDNHXZGNVGP-UHFFFAOYSA-N 0.000 description 1
- NQSHQOOBVRVTEX-UHFFFAOYSA-N tert-butyl 6-hydroxy-2-propylbenzimidazole-1-carboxylate Chemical compound C1=C(O)C=C2N(C(=O)OC(C)(C)C)C(CCC)=NC2=C1 NQSHQOOBVRVTEX-UHFFFAOYSA-N 0.000 description 1
- DQAHLMUNFSYNMT-UHFFFAOYSA-N tert-butyl 6-hydroxy-4-(4-methoxycarbonylpiperidin-1-yl)-2-propan-2-ylbenzimidazole-1-carboxylate Chemical compound C1CC(C(=O)OC)CCN1C1=CC(O)=CC2=C1N=C(C(C)C)N2C(=O)OC(C)(C)C DQAHLMUNFSYNMT-UHFFFAOYSA-N 0.000 description 1
- KBQQKBJSBCQAKI-UHFFFAOYSA-N tert-butyl 6-hydroxy-4-methoxy-2-propan-2-ylbenzimidazole-1-carboxylate Chemical compound COC1=CC(O)=CC2=C1N=C(C(C)C)N2C(=O)OC(C)(C)C KBQQKBJSBCQAKI-UHFFFAOYSA-N 0.000 description 1
- RSDVPMNYCRZLCN-UHFFFAOYSA-N tert-butyl 6-hydroxybenzimidazole-1-carboxylate Chemical compound C1=C(O)C=C2N(C(=O)OC(C)(C)C)C=NC2=C1 RSDVPMNYCRZLCN-UHFFFAOYSA-N 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- YJBKVPRVZAQTPY-UHFFFAOYSA-J tetrachlorostannane;dihydrate Chemical compound O.O.Cl[Sn](Cl)(Cl)Cl YJBKVPRVZAQTPY-UHFFFAOYSA-J 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 229960004559 theobromine Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 239000003868 thrombin inhibitor Substances 0.000 description 1
- GZNAASVAJNXPPW-UHFFFAOYSA-M tin(4+) chloride dihydrate Chemical compound O.O.[Cl-].[Sn+4] GZNAASVAJNXPPW-UHFFFAOYSA-M 0.000 description 1
- FWPIDFUJEMBDLS-UHFFFAOYSA-L tin(II) chloride dihydrate Substances O.O.Cl[Sn]Cl FWPIDFUJEMBDLS-UHFFFAOYSA-L 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 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
- 201000010875 transient cerebral ischemia Diseases 0.000 description 1
- 229940117013 triethanolamine oleate Drugs 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 108010036927 trypsin-like serine protease Proteins 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 230000003966 vascular damage Effects 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Preventing Corrosion Or Incrustation Of Metals (AREA)
- Separation Of Suspended Particles By Flocculating Agents (AREA)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08/570,057 US5849759A (en) | 1995-12-08 | 1995-12-08 | Naphthyl-substituted benzimidazole derivatives as anti-coagulants |
PCT/IB1996/001496 WO1997021437A1 (en) | 1995-12-08 | 1996-12-05 | Naphthyl-substituted benzimidazole derivatives as anticoagulants |
Publications (2)
Publication Number | Publication Date |
---|---|
SK74698A3 SK74698A3 (en) | 1998-12-02 |
SK282767B6 true SK282767B6 (sk) | 2002-12-03 |
Family
ID=24278023
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
SK746-98A SK282767B6 (sk) | 1995-12-08 | 1996-12-05 | Naftyl-substituované benzimidazolové deriváty pôsobiace ako antikoagulačné činidlá, farmaceutický prostriedok obsahujúci tieto látky a použitie týchto látok |
Country Status (23)
Country | Link |
---|---|
US (1) | US5849759A (xx) |
EP (1) | EP0865281B1 (xx) |
JP (1) | JP2000502082A (xx) |
KR (1) | KR19990071974A (xx) |
CN (1) | CN1110305C (xx) |
AT (1) | ATE215371T1 (xx) |
CZ (1) | CZ177698A3 (xx) |
DE (1) | DE69620443T2 (xx) |
DK (1) | DK0865281T3 (xx) |
ES (1) | ES2175179T3 (xx) |
HK (1) | HK1018208A1 (xx) |
HU (1) | HUP9904066A3 (xx) |
IL (1) | IL124537A (xx) |
MX (1) | MX9804597A (xx) |
NO (1) | NO312673B1 (xx) |
NZ (1) | NZ325449A (xx) |
PL (1) | PL327169A1 (xx) |
PT (1) | PT865281E (xx) |
RU (1) | RU98112597A (xx) |
SK (1) | SK282767B6 (xx) |
UA (1) | UA49869C2 (xx) |
WO (1) | WO1997021437A1 (xx) |
ZA (1) | ZA9610315B (xx) |
Families Citing this family (80)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ATE251141T1 (de) | 1995-03-10 | 2003-10-15 | Berlex Lab | Benzamidin-derivate, deren herstellung und deren verwendung als anti-koagulantien |
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 |
CZ86199A3 (cs) | 1996-09-12 | 1999-08-11 | Schering Aktiengesellschaft | Benzamidinové deriváty substituované cyklickou aminokyselinou a cyklické hydrokyselinové deriváty, farmaceutický prostředek obsahující tyto látky a jejich použití jako protisrážecích činidel |
US6004985A (en) * | 1996-10-09 | 1999-12-21 | Berlex Laboratories, Inc. | Thio acid derived monocylic N-heterocyclics as anticoagulants |
DE69830504T2 (de) * | 1997-06-26 | 2006-03-16 | Eli Lilly And Co., Indianapolis | Antithrombotische mitteln |
US6150379A (en) * | 1997-11-26 | 2000-11-21 | Axys Pharmaceuticals, Inc. | Compounds and compositions as anticoagulants |
DE19753522A1 (de) * | 1997-12-03 | 1999-06-10 | Boehringer Ingelheim Pharma | Substituierte Indole, ihre Herstellung und ihre Verwendung als Arzneimittel |
US6686364B2 (en) | 1997-12-08 | 2004-02-03 | Berlex Laboratories, Inc. | Benzamidine derivatives and their use as anti-coagulants |
WO1999032477A1 (en) | 1997-12-19 | 1999-07-01 | Schering Aktiengesellschaft | Ortho-anthranilamide derivatives as anti-coagulants |
US6140351A (en) * | 1997-12-19 | 2000-10-31 | Berlex Laboratories, Inc. | Ortho-anthranilamide derivatives as anti-coagulants |
PL195682B1 (pl) | 1997-12-24 | 2007-10-31 | Sanofi Aventis Deutschland | Pochodne indolu, sposób ich wytwarzania, środek farmaceutyczny oraz zastosowanie pochodnych indolu |
US6200976B1 (en) | 1998-04-17 | 2001-03-13 | Boehringer Ingelheim Pharma Kg | Antithrombotic quinoxazolines |
DE19816983A1 (de) * | 1998-04-17 | 1999-10-21 | Boehringer Ingelheim Pharma | Bicyclen, deren Herstellung und deren Verwendung als Arzneimittel |
TWI248435B (en) * | 1998-07-04 | 2006-02-01 | Boehringer Ingelheim Pharma | Benzimidazoles, the preparation thereof and their use as pharmaceutical compositions |
US6248770B1 (en) | 1998-07-09 | 2001-06-19 | Boehringer Ingelheim Pharma Kg | Benzimidazoles having antithrombotic activity |
DE19834751A1 (de) * | 1998-08-01 | 2000-02-03 | Boehringer Ingelheim Pharma | Disubstituierte bicyclische Heterocyclen, ihre Herstellung und ihre Verwendung als Arzneimittel |
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 |
US6350761B1 (en) | 1999-07-30 | 2002-02-26 | Berlex Laboratories, Inc. | Benzenamine derivatives as anti-coagulants |
AU6762400A (en) * | 1999-08-12 | 2001-03-13 | Cor Therapeutics, Inc. | Inhibitors of factor xa |
US6451832B2 (en) | 1999-12-23 | 2002-09-17 | Boehringer Ingelheim Pharma Kg | Benzimidazoles with antithrombotic activity |
WO2001051484A1 (de) * | 2000-01-12 | 2001-07-19 | Merck Patent Gmbh | Benzimidazolderivate und inre verwendung als faktor xa inhibitorem |
WO2001057020A1 (en) * | 2000-02-01 | 2001-08-09 | Cor Therapeutics, Inc. | INDOLE AND BENZIMIDAZOLE INHIBITORS OF FACTOR Xa |
CA2401778C (en) | 2000-02-29 | 2010-12-21 | Cor Therapeutics, Inc. | Benzamides and related inhibitors of factor xa |
HU230302B1 (hu) | 2000-10-20 | 2015-12-28 | Eisai R&D Management Co., Ltd. | Nitrogéntartalmú aromás származékok és ezeket tartalmazó gyógyászati készítmények |
EA006205B1 (ru) * | 2000-11-02 | 2005-10-27 | Уайт | 1-арил- или 1-алкилсульфонилгетероциклилбензазолы в качестве лигандов 5-гидрокситриптамина-6 |
US7034029B2 (en) * | 2000-11-02 | 2006-04-25 | Wyeth | 1-aryl- or 1-alkylsulfonyl-heterocyclylbenzazoles as 5-hydroxytryptamine-6 ligands |
US7312235B2 (en) | 2001-03-30 | 2007-12-25 | Millennium Pharmaceuticals, Inc. | Benzamide inhibitors of factor Xa |
DE10238002A1 (de) * | 2002-08-20 | 2004-03-04 | Merck Patent Gmbh | Benzimidazolderivate |
WO2004048363A1 (ja) | 2002-11-22 | 2004-06-10 | Takeda Pharmaceutical Company Limited | イミダゾール誘導体、その製造法および用途 |
CN100513398C (zh) | 2002-12-03 | 2009-07-15 | Axys药物公司 | 作为因子viia抑制剂的2-(2-羟基联苯-3-基)-1h-苯并咪唑-5-甲脒衍生物 |
EP1927594A1 (en) * | 2003-01-14 | 2008-06-04 | Arena Pharmaceuticals, Inc. | 1,2,3-Trisubstituted aryl and heteroaryl derivatives as modulators of metabolism and the prophylaxis and treatment of disorders related thereto such as diabetes and hyperglycemia |
US8293751B2 (en) * | 2003-01-14 | 2012-10-23 | Arena Pharmaceuticals, Inc. | 1,2,3-trisubstituted aryl and heteroaryl derivatives as modulators of metabolism and the prophylaxis and treatment of disorders related thereto such as diabetes and hyperglycemia |
EP1606282B1 (en) * | 2003-02-24 | 2008-11-12 | Arena Pharmaceuticals, Inc. | Phenyl- and pyridylpipereidinye-derivatives as modulators of glucose metabolism |
AR045047A1 (es) * | 2003-07-11 | 2005-10-12 | Arena Pharm Inc | Derivados arilo y heteroarilo trisustituidos como moduladores del metabolismo y de la profilaxis y tratamiento de desordenes relacionados con los mismos |
KR20060110288A (ko) | 2003-10-09 | 2006-10-24 | 밀레니엄 파머슈티컬스 인코퍼레이티드 | 인자 xa 의 저해제로서의 티오에테르-치환 벤즈아미드 |
CN101337930B (zh) | 2003-11-11 | 2010-09-08 | 卫材R&D管理有限公司 | 脲衍生物的制备方法 |
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 |
DK1756084T3 (da) * | 2004-06-04 | 2009-03-23 | Arena Pharm Inc | Substituerede aryl- og heteroarylderivater som modulatorer af metabolisme og forebyggelse og behandling af forstyrrelser beslægtet dermed |
JP5020073B2 (ja) | 2004-06-18 | 2012-09-05 | ミレニアム ファーマシューティカルズ インク. | 第Xa因子阻害剤 |
ATE428421T1 (de) | 2004-09-17 | 2009-05-15 | Eisai R&D Man Co Ltd | Medizinische zusammensetzung mit verbesserter stabilität und reduzierten gelierungseigenschaften |
CN101083993A (zh) | 2004-09-20 | 2007-12-05 | 泽农医药公司 | 杂环衍生物及其作为硬脂酰CoA去饱和酶抑制剂的用途 |
CN101084207A (zh) | 2004-09-20 | 2007-12-05 | 泽农医药公司 | 杂环衍生物及其作为硬脂酰CoA去饱和酶抑制剂的用途 |
US7612089B2 (en) | 2004-11-19 | 2009-11-03 | Portola Pharmaceuticals, Inc. | Tetrahydroisoquinolines as factor Xa inhibitors |
US7678913B2 (en) | 2004-12-07 | 2010-03-16 | Portola Pharmaceuticals, Inc. | Ureas as factor Xa inhibitors |
MY148521A (en) * | 2005-01-10 | 2013-04-30 | Arena Pharm Inc | Substituted pyridinyl and pyrimidinyl derivatives as modulators of metabolism and the treatment of disorders related thereto |
DOP2006000010A (es) | 2005-01-10 | 2006-07-31 | Arena Pharm Inc | Procedimiento para preparar eteres aromáticos |
US8541457B2 (en) | 2005-06-03 | 2013-09-24 | Xenon Pharmaceuticals Inc. | Aminothiazole derivatives as human stearoyl-CoA desaturase inhibitors |
US20090221644A1 (en) * | 2005-06-30 | 2009-09-03 | Stuart Edward Bradley | Gpcr Agonists |
WO2007015578A1 (ja) | 2005-08-02 | 2007-02-08 | Eisai R & D Management Co., Ltd. | 血管新生阻害物質の効果を検定する方法 |
NZ565898A (en) * | 2005-09-16 | 2010-07-30 | Arena Pharm Inc | Modulators of metabolism and the treatment of disorders related thereto |
PT1948608E (pt) | 2005-11-08 | 2012-05-24 | Millennium Pharm Inc | Novos sais farmacêuticos e polimorfos de um inibidor do fator xa |
RU2448708C3 (ru) | 2006-05-18 | 2017-09-28 | Эйсай Ар Энд Ди Менеджмент Ко., Лтд. | Противоопухолевое средство против рака щитовидной железы |
TW200811140A (en) * | 2006-07-06 | 2008-03-01 | Arena Pharm Inc | Modulators of metabolism and the treatment of disorders related thereto |
TW200811147A (en) * | 2006-07-06 | 2008-03-01 | Arena Pharm Inc | Modulators of metabolism and the treatment of disorders related thereto |
KR101472600B1 (ko) | 2006-08-28 | 2014-12-15 | 에자이 알앤드디 매니지먼트 가부시키가이샤 | 미분화형 위암에 대한 항종양제 |
PT2404906E (pt) | 2006-11-02 | 2015-11-02 | Millennium Pharm Inc | Métodos de sintetizar sais farmacêuticos de um inibidor de fator xa |
WO2008093855A1 (ja) | 2007-01-29 | 2008-08-07 | Eisai R & D Management Co., Ltd. | 未分化型胃癌治療用組成物 |
WO2009060945A1 (ja) | 2007-11-09 | 2009-05-14 | Eisai R & D Management Co., Ltd. | 血管新生阻害物質と抗腫瘍性白金錯体との併用 |
UA100192C2 (xx) * | 2008-11-11 | 2012-11-26 | УАЙТ ЭлЭлСи | 1-(арилсульфоніл)-4-(піперазин-1-іл)-1h-бензімідазоли як ліганди 5-гідрокситриптаміну-6$1-(арилсульфонил)-4-(пиперазин-1-ил)-1h-бензимидазолы как лиганды 5-гидрокситриптамина-6 |
JP5856980B2 (ja) | 2010-01-27 | 2016-02-10 | アリーナ ファーマシューティカルズ, インコーポレイテッド | (R)−2−(7−(4−シクロペンチル−3−(トリフルオロメチル)ベンジルオキシ)−1,2,3,4−テトラヒドロシクロペンタ[b]インドール−3−イル)酢酸およびその塩の調製のためのプロセス |
EA015918B1 (ru) | 2010-03-03 | 2011-12-30 | Дмитрий Геннадьевич ТОВБИН | УРЕТАНЫ, МОЧЕВИНЫ, АМИДЫ И РОДСТВЕННЫЕ ИНГИБИТОРЫ ФАКТОРА Xa |
BR112012032462A2 (pt) | 2010-06-25 | 2016-11-08 | Eisai R&D Man Co Ltd | agente antitumoral empregando compostos que, em combinação, têm efeito inibidor de quinase. |
KR101871011B1 (ko) | 2010-09-22 | 2018-06-25 | 아레나 파마슈티칼스, 인크. | Gpr119 수용체의 조절제 및 그와 관련된 장애의 치료 |
CN103402519B (zh) | 2011-04-18 | 2015-11-25 | 卫材R&D管理有限公司 | 肿瘤治疗剂 |
JP6038128B2 (ja) | 2011-06-03 | 2016-12-07 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | レンバチニブ化合物に対する甲状腺癌対象及び腎臓癌対象の反応性を予測及び評価するためのバイオマーカー |
CN104755463A (zh) | 2012-12-21 | 2015-07-01 | 卫材R&D管理有限公司 | 非晶态形式的喹啉衍生物及其生产方法 |
MX368099B (es) | 2013-05-14 | 2019-09-19 | Eisai R&D Man Co Ltd | Biomarcadores para predecir y evaluar el grado de respuesta de sujetos con cancer de endometrio a compuestos de tipo lenvatinib. |
KR102329681B1 (ko) | 2014-08-28 | 2021-11-23 | 에자이 알앤드디 매니지먼트 가부시키가이샤 | 고순도의 퀴놀린 유도체 및 이를 제조하는 방법 |
UA126268C2 (uk) | 2015-01-06 | 2022-09-14 | Арена Фармасьютікалз, Інк. | СПОСОБИ ЛІКУВАННЯ СТАНІВ, ПОВ'ЯЗАНИХ З РЕЦЕПТОРОМ S1P<sub>1 </sub> |
BR112017017428A2 (pt) | 2015-02-25 | 2018-04-03 | Eisai R&D Management Co., Ltd. | ?método para supressão do amargor de derivado de quinolina? |
CA2978226A1 (en) | 2015-03-04 | 2016-09-09 | Merck Sharpe & Dohme Corp. | Combination of a pd-1 antagonist and a vegfr/fgfr/ret tyrosine kinase inhibitor for treating cancer |
BR112017027227B1 (pt) | 2015-06-16 | 2023-12-12 | Eisai R&D Management Co., Ltd | Agente anti-câncer |
EA201890096A1 (ru) | 2015-06-22 | 2018-08-31 | Арена Фармасьютикалз, Инк. | КРИСТАЛЛИЧЕСКАЯ L-АРГИНИНОВАЯ СОЛЬ (R)-2-(7-(4-ЦИКЛОПЕНТИЛ-3-(ТРИФТОРМЕТИЛ)БЕНЗИЛОКСИ)-1,2,3,4-ТЕТРАГИДРОЦИКЛОПЕНТА[b]ИНДОЛ-3-ИЛ)УКСУСНОЙ КИСЛОТЫ (СОЕДИНЕНИЯ 1) ДЛЯ ПРИМЕНЕНИЯ ПРИ РАССТРОЙСТВАХ, СВЯЗАННЫХ С S1P-РЕЦЕПТОРОМ |
TW201813963A (zh) | 2016-09-23 | 2018-04-16 | 美商基利科學股份有限公司 | 磷脂醯肌醇3-激酶抑制劑 |
TW201815787A (zh) | 2016-09-23 | 2018-05-01 | 美商基利科學股份有限公司 | 磷脂醯肌醇3-激酶抑制劑 |
TW201825465A (zh) * | 2016-09-23 | 2018-07-16 | 美商基利科學股份有限公司 | 磷脂醯肌醇3-激酶抑制劑 |
US11534424B2 (en) | 2017-02-16 | 2022-12-27 | Arena Pharmaceuticals, Inc. | Compounds and methods for treatment of primary biliary cholangitis |
CA3145453A1 (en) | 2019-07-01 | 2021-01-07 | Tonix Pharma Limited | Anti-cd154 antibodies and uses thereof |
MX2023008055A (es) | 2021-01-06 | 2023-08-22 | Tonix Pharma Ltd | Métodos para inducir tolerancia inmune con anticuerpos anti-cd154 modificados. |
Family Cites Families (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS59139357A (ja) * | 1983-01-28 | 1984-08-10 | Torii Yakuhin Kk | アミジン誘導体 |
ZA928276B (en) * | 1991-10-31 | 1993-05-06 | Daiichi Seiyaku Co | Aromatic amidine derivates and salts thereof. |
WO1993015756A1 (en) * | 1992-02-14 | 1993-08-19 | Corvas International, Inc. | Inhibitors of thrombosis |
DE4213919A1 (de) * | 1992-04-28 | 1993-11-04 | Thomae Gmbh Dr K | Cyclische iminoderivate, verfahren zu ihrer herstellung und diese verbindungen enthaltende arzneimittel |
AU675981B2 (en) * | 1992-12-02 | 1997-02-27 | Bristol-Myers Squibb Company | Guanidinyl-substituted heterocyclic thrombin inhibitors |
US5883077A (en) * | 1992-12-15 | 1999-03-16 | Corvas International, Inc. | Inhibitors of factor Xa |
US5332822A (en) * | 1992-12-24 | 1994-07-26 | Bristol-Myers Squibb Company | Heteroaromatic and thioheteroaromatic substituted sulfonamide thrombin inhibitors |
CA2155931C (en) * | 1993-02-12 | 2002-11-19 | George Phillip Vlasuk | Inhibitors of thrombosis |
IL113472A0 (en) * | 1994-04-29 | 1995-07-31 | Lilly Co Eli | Non-peptidyl tachykinin receptor antogonists |
-
1995
- 1995-12-08 US US08/570,057 patent/US5849759A/en not_active Expired - Fee Related
-
1996
- 1996-12-05 WO PCT/IB1996/001496 patent/WO1997021437A1/en not_active Application Discontinuation
- 1996-12-05 HU HU9904066A patent/HUP9904066A3/hu unknown
- 1996-12-05 CZ CZ981776A patent/CZ177698A3/cs unknown
- 1996-12-05 KR KR1019980704265A patent/KR19990071974A/ko not_active Application Discontinuation
- 1996-12-05 IL IL12453796A patent/IL124537A/en not_active IP Right Cessation
- 1996-12-05 MX MX9804597A patent/MX9804597A/es not_active IP Right Cessation
- 1996-12-05 PT PT96944123T patent/PT865281E/pt unknown
- 1996-12-05 UA UA98073607A patent/UA49869C2/uk unknown
- 1996-12-05 SK SK746-98A patent/SK282767B6/sk unknown
- 1996-12-05 AT AT96944123T patent/ATE215371T1/de not_active IP Right Cessation
- 1996-12-05 CN CN96199921A patent/CN1110305C/zh not_active Expired - Fee Related
- 1996-12-05 RU RU98112597/04A patent/RU98112597A/ru not_active Application Discontinuation
- 1996-12-05 DE DE69620443T patent/DE69620443T2/de not_active Expired - Fee Related
- 1996-12-05 EP EP96944123A patent/EP0865281B1/en not_active Expired - Lifetime
- 1996-12-05 NZ NZ325449A patent/NZ325449A/xx unknown
- 1996-12-05 ES ES96944123T patent/ES2175179T3/es not_active Expired - Lifetime
- 1996-12-05 JP JP9521899A patent/JP2000502082A/ja not_active Ceased
- 1996-12-05 DK DK96944123T patent/DK0865281T3/da active
- 1996-12-05 PL PL96327169A patent/PL327169A1/xx unknown
- 1996-12-06 ZA ZA9610315A patent/ZA9610315B/xx unknown
-
1998
- 1998-06-05 NO NO19982606A patent/NO312673B1/no unknown
-
1999
- 1999-07-27 HK HK99103225A patent/HK1018208A1/xx not_active IP Right Cessation
Also Published As
Publication number | Publication date |
---|---|
US5849759A (en) | 1998-12-15 |
AU700894B2 (en) | 1999-01-14 |
PT865281E (pt) | 2002-09-30 |
CZ177698A3 (cs) | 1998-09-16 |
DK0865281T3 (da) | 2002-07-29 |
NZ325449A (en) | 2000-01-28 |
EP0865281A4 (en) | 1999-07-28 |
KR19990071974A (ko) | 1999-09-27 |
JP2000502082A (ja) | 2000-02-22 |
NO312673B1 (no) | 2002-06-17 |
PL327169A1 (en) | 1998-11-23 |
IL124537A0 (en) | 1998-12-06 |
HK1018208A1 (en) | 1999-12-17 |
DE69620443D1 (de) | 2002-05-08 |
WO1997021437A1 (en) | 1997-06-19 |
CN1209062A (zh) | 1999-02-24 |
HUP9904066A2 (hu) | 2000-03-28 |
AU1395697A (en) | 1997-07-03 |
ATE215371T1 (de) | 2002-04-15 |
NO982606D0 (no) | 1998-06-05 |
EP0865281A1 (en) | 1998-09-23 |
EP0865281B1 (en) | 2002-04-03 |
DE69620443T2 (de) | 2002-11-28 |
RU98112597A (ru) | 2000-10-20 |
NO982606L (no) | 1998-08-10 |
MX9804597A (es) | 1998-10-31 |
IL124537A (en) | 2002-04-21 |
SK74698A3 (en) | 1998-12-02 |
ZA9610315B (en) | 1997-06-17 |
CN1110305C (zh) | 2003-06-04 |
UA49869C2 (uk) | 2002-10-15 |
ES2175179T3 (es) | 2002-11-16 |
HUP9904066A3 (en) | 2001-11-28 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
SK282767B6 (sk) | Naftyl-substituované benzimidazolové deriváty pôsobiace ako antikoagulačné činidlá, farmaceutický prostriedok obsahujúci tieto látky a použitie týchto látok | |
US6008234A (en) | Benzamidine derivatives substituted by cyclic amino acid and cyclic hydroxy acid derivatives and their use as anti-coagulants | |
US6265404B1 (en) | Benzamidine derivatives substituted by cyclic amino acid and cyclic hydroxy acid derivatives and their use as anti-coagulants | |
US6552030B2 (en) | Polyhydroxylated monocyclic N-heterocyclic derivatives as anti-coagulants | |
RO120971B1 (ro) | Derivaţi de pirimidină aril şi heterociclil, substituiţi ca anticoagulanţi | |
SK283306B6 (sk) | Benzamidínové deriváty substituované aminokyselinovými alebo hydroxykyselinovými derivátmi, farmaceutický prostriedok obsahujúci tieto deriváty a ich použitie | |
US6350761B1 (en) | Benzenamine derivatives as anti-coagulants | |
AU700894C (en) | Naphthyl-substituted benzimidazole derivatives as anticoagulants | |
CA2239508A1 (en) | Naphthyl-substituted benzimidazole derivatives as anticoagulants | |
MXPA99002396A (en) | Benzamidine derivatives substituted by cyclic amino acid or cycl ic hydroxy acid derivatives and their use as anti-coagulants | |
BG106363A (bg) | Бензенаминови производни като анти-коагуланти |