NO312673B1 - Naftylsubstituerte benzimidazolderivater som antikoagulanter, farmasöytisk preparat inneholdende disse, og anvendelse avforbindelsene for fremstilling av et medikament - Google Patents

Info

Publication number

NO312673B1

NO312673B1 NO19982606A NO982606A NO312673B1 NO 312673 B1 NO312673 B1 NO 312673B1 NO 19982606 A NO19982606 A NO 19982606A NO 982606 A NO982606 A NO 982606A NO 312673 B1 NO312673 B1 NO 312673B1

Authority

NO

Norway

Prior art keywords

methyl

piperidin

amidinonaphth

benzimidazole

iminoethyl

Prior art date

1995-12-08

Links

• Espacenet
• Global Dossier
• Discuss

• 150000001875 compounds Chemical class 0.000 title claims description 405
• 238000004519 manufacturing process Methods 0.000 title claims description 48
• 239000003814 drug Substances 0.000 title claims description 3
• 239000003146 anticoagulant agent Substances 0.000 title description 7
• 229940127219 anticoagulant drug Drugs 0.000 title description 7
• 239000000825 pharmaceutical preparation Substances 0.000 title description 6
• 229940058303 antinematodal benzimidazole derivative Drugs 0.000 title description 2
• 125000003785 benzimidazolyl group Chemical class N1=C(NC2=C1C=CC=C2)* 0.000 title 1
• 125000001624 naphthyl group Chemical group 0.000 title 1
• 239000000203 mixture Substances 0.000 claims description 72
• 229910052736 halogen Inorganic materials 0.000 claims description 69
• 150000002367 halogens Chemical group 0.000 claims description 69
• 239000001257 hydrogen Substances 0.000 claims description 68
• 229910052739 hydrogen Inorganic materials 0.000 claims description 68
• 125000000217 alkyl group Chemical group 0.000 claims description 63
• -1 nitro, methyl Chemical group 0.000 claims description 50
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 49
• 150000003839 salts Chemical class 0.000 claims description 42
• 108010074860 Factor Xa Proteins 0.000 claims description 36
• 238000000034 method Methods 0.000 claims description 36
• HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 claims description 33
• 125000002947 alkylene group Chemical group 0.000 claims description 27
• 125000003386 piperidinyl group Chemical group 0.000 claims description 24
• 125000001424 substituent group Chemical group 0.000 claims description 23
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 21
• 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 20
• 201000010099 disease Diseases 0.000 claims description 19
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 19
• 150000002431 hydrogen Chemical class 0.000 claims description 16
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 16
• 238000011282 treatment Methods 0.000 claims description 11
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 9
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 8
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 8
• 230000001732 thrombotic effect Effects 0.000 claims description 8
• 230000002401 inhibitory effect Effects 0.000 claims description 6
• 230000005764 inhibitory process Effects 0.000 claims description 6
• 239000008194 pharmaceutical composition Substances 0.000 claims description 6
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
• 238000000338 in vitro Methods 0.000 claims description 5
• 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
• VLGDARRLBRYNIB-UHFFFAOYSA-N 4-[[2-tert-butyl-5-(1-ethanimidoylpiperidin-4-yl)oxybenzimidazol-1-yl]methyl]naphthalene-1-carboximidamide Chemical compound C1CN(C(=N)C)CCC1OC1=CC=C(N(CC=2C3=CC=CC=C3C(C(N)=N)=CC=2)C(=N2)C(C)(C)C)C2=C1 VLGDARRLBRYNIB-UHFFFAOYSA-N 0.000 claims description 4
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
• XESKREHIDQRXFC-UHFFFAOYSA-N methyl 2-[1-[(4-carbamimidoylnaphthalen-1-yl)methyl]-6-(1-ethanimidoylpiperidin-4-yl)oxy-2-methylbenzimidazol-5-yl]oxypropanoate Chemical compound COC(=O)C(C)OC1=CC=2N=C(C)N(CC=3C4=CC=CC=C4C(C(N)=N)=CC=3)C=2C=C1OC1CCN(C(C)=N)CC1 XESKREHIDQRXFC-UHFFFAOYSA-N 0.000 claims description 4
• UJIXNWWXFXRFNF-UHFFFAOYSA-N 1-[(4-carbamimidoylnaphthalen-1-yl)methyl]-6-(1-ethanimidoylpiperidin-4-yl)oxy-2-methylbenzimidazole-5-carboxylic acid Chemical compound C1CN(C(=N)C)CCC1OC(C(=C1)C(O)=O)=CC2=C1N=C(C)N2CC1=CC=C(C(N)=N)C2=CC=CC=C12 UJIXNWWXFXRFNF-UHFFFAOYSA-N 0.000 claims description 3
• XWKWKRAKNCBCRB-UHFFFAOYSA-N 1-[1-[(4-carbamimidoylnaphthalen-1-yl)methyl]-6-(1-ethanimidoylpiperidin-4-yl)oxy-2-propan-2-ylbenzimidazol-4-yl]piperidine-4-carboxylic acid Chemical compound C1=C2N(CC=3C4=CC=CC=C4C(C(N)=N)=CC=3)C(C(C)C)=NC2=C(N2CCC(CC2)C(O)=O)C=C1OC1CCN(C(C)=N)CC1 XWKWKRAKNCBCRB-UHFFFAOYSA-N 0.000 claims description 3
• PEVUBACYGIHBTK-UHFFFAOYSA-N 2-[1-[(4-carbamimidoylnaphthalen-1-yl)methyl]-6-(1-ethanimidoylpiperidin-4-yl)oxy-2-methylbenzimidazol-5-yl]oxyacetamide Chemical compound C1CN(C(=N)C)CCC1OC(C(=C1)OCC(N)=O)=CC2=C1N=C(C)N2CC1=CC=C(C(N)=N)C2=CC=CC=C12 PEVUBACYGIHBTK-UHFFFAOYSA-N 0.000 claims description 3
• ZRSUWCYQGNCXHE-UHFFFAOYSA-N 2-[1-[(4-carbamimidoylnaphthalen-1-yl)methyl]-6-(1-ethanimidoylpiperidin-4-yl)oxy-2-methylbenzimidazol-5-yl]oxypropanamide Chemical compound NC(=O)C(C)OC1=CC=2N=C(C)N(CC=3C4=CC=CC=C4C(C(N)=N)=CC=3)C=2C=C1OC1CCN(C(C)=N)CC1 ZRSUWCYQGNCXHE-UHFFFAOYSA-N 0.000 claims description 3
• SJLUQFZCJKQRFL-UHFFFAOYSA-N 2-[1-[(4-carbamimidoylnaphthalen-1-yl)methyl]-6-(1-ethanimidoylpiperidin-4-yl)oxy-2-methylbenzimidazol-5-yl]oxypropanoic acid Chemical compound OC(=O)C(C)OC1=CC=2N=C(C)N(CC=3C4=CC=CC=C4C(C(N)=N)=CC=3)C=2C=C1OC1CCN(C(C)=N)CC1 SJLUQFZCJKQRFL-UHFFFAOYSA-N 0.000 claims description 3
• WOIFVFVZWDDEAL-UHFFFAOYSA-N 2-[4-[1-[(4-carbamimidoylnaphthalen-1-yl)methyl]-6-(1-ethanimidoylpiperidin-4-yl)oxy-2-methylbenzimidazol-5-yl]oxypiperidin-1-yl]acetic acid Chemical compound C1CN(C(=N)C)CCC1OC(C(=C1)OC2CCN(CC(O)=O)CC2)=CC2=C1N=C(C)N2CC1=CC=C(C(N)=N)C2=CC=CC=C12 WOIFVFVZWDDEAL-UHFFFAOYSA-N 0.000 claims description 3
• YMXRBCXRAZRJGP-UHFFFAOYSA-N 2-[[1-[(4-carbamimidoylnaphthalen-1-yl)methyl]-6-(1-ethanimidoylpiperidin-4-yl)oxy-2-propan-2-ylbenzimidazol-5-yl]amino]-2-methylpropanoic acid Chemical compound C1=C2N(CC=3C4=CC=CC=C4C(C(N)=N)=CC=3)C(C(C)C)=NC2=CC(NC(C)(C)C(O)=O)=C1OC1CCN(C(C)=N)CC1 YMXRBCXRAZRJGP-UHFFFAOYSA-N 0.000 claims description 3
• APLWJNRXSCYHRI-UHFFFAOYSA-N 3-[1-[(4-carbamimidoylnaphthalen-1-yl)methyl]-5-(1-ethanimidoylpiperidin-4-yl)oxybenzimidazol-2-yl]propanoic acid Chemical compound C1CN(C(=N)C)CCC1OC1=CC=C(N(CC=2C3=CC=CC=C3C(C(N)=N)=CC=2)C(CCC(O)=O)=N2)C2=C1 APLWJNRXSCYHRI-UHFFFAOYSA-N 0.000 claims description 3
• OPOMWAAEDJNJBW-UHFFFAOYSA-N 3-[1-[(4-carbamimidoylnaphthalen-1-yl)methyl]-6-(1-ethanimidoylpiperidin-4-yl)oxybenzimidazol-2-yl]propanamide Chemical compound C1CN(C(=N)C)CCC1OC1=CC=C(N=C(CCC(N)=O)N2CC=3C4=CC=CC=C4C(C(N)=N)=CC=3)C2=C1 OPOMWAAEDJNJBW-UHFFFAOYSA-N 0.000 claims description 3
• LYFOUDKMUVVLSA-UHFFFAOYSA-N 3-[1-[(4-carbamimidoylnaphthalen-1-yl)methyl]-6-(1-ethanimidoylpiperidin-4-yl)oxybenzimidazol-2-yl]propanoic acid Chemical compound C1CN(C(=N)C)CCC1OC1=CC=C(N=C(CCC(O)=O)N2CC=3C4=CC=CC=C4C(C(N)=N)=CC=3)C2=C1 LYFOUDKMUVVLSA-UHFFFAOYSA-N 0.000 claims description 3
• KGWXYFHZSKMWRV-UHFFFAOYSA-N 3-[[1-[(4-carbamimidoylnaphthalen-1-yl)methyl]-6-(1-ethanimidoylpiperidin-4-yl)oxy-2-methylbenzimidazol-5-yl]oxymethyl]benzoic acid Chemical compound C1CN(C(=N)C)CCC1OC(C(=C1)OCC=2C=C(C=CC=2)C(O)=O)=CC2=C1N=C(C)N2CC1=CC=C(C(N)=N)C2=CC=CC=C12 KGWXYFHZSKMWRV-UHFFFAOYSA-N 0.000 claims description 3
• VTIRYTRSFFRWGM-UHFFFAOYSA-N 3-[[1-[(4-carbamimidoylnaphthalen-1-yl)methyl]-6-(1-ethanimidoylpiperidin-4-yl)oxy-2-propan-2-ylbenzimidazol-5-yl]amino]propanoic acid Chemical compound C1=C2N(CC=3C4=CC=CC=C4C(C(N)=N)=CC=3)C(C(C)C)=NC2=CC(NCCC(O)=O)=C1OC1CCN(C(C)=N)CC1 VTIRYTRSFFRWGM-UHFFFAOYSA-N 0.000 claims description 3
• UYZPAFVZOMVONX-UHFFFAOYSA-N 4-[(5-piperidin-4-yloxy-2-propan-2-ylbenzimidazol-1-yl)methyl]naphthalene-1-carboximidamide Chemical compound C=1C=C2N(CC=3C4=CC=CC=C4C(C(N)=N)=CC=3)C(C(C)C)=NC2=CC=1OC1CCNCC1 UYZPAFVZOMVONX-UHFFFAOYSA-N 0.000 claims description 3
• DBJCIYZRRZXNGF-UHFFFAOYSA-N 4-[(5-piperidin-4-yloxy-2-propylbenzimidazol-1-yl)methyl]naphthalene-1-carboximidamide Chemical compound C=1C=C2N(CC=3C4=CC=CC=C4C(C(N)=N)=CC=3)C(CCC)=NC2=CC=1OC1CCNCC1 DBJCIYZRRZXNGF-UHFFFAOYSA-N 0.000 claims description 3
• MVNUCAJGONRXES-UHFFFAOYSA-N 4-[(6-piperidin-4-yloxy-2-propan-2-ylbenzimidazol-1-yl)methyl]naphthalene-1-carboximidamide Chemical compound C1=C2N(CC=3C4=CC=CC=C4C(C(N)=N)=CC=3)C(C(C)C)=NC2=CC=C1OC1CCNCC1 MVNUCAJGONRXES-UHFFFAOYSA-N 0.000 claims description 3
• ZLOHGPAIOSLETO-UHFFFAOYSA-N 4-[(6-piperidin-4-yloxy-2-propylbenzimidazol-1-yl)methyl]naphthalene-1-carboximidamide Chemical compound C1=C2N(CC=3C4=CC=CC=C4C(C(N)=N)=CC=3)C(CCC)=NC2=CC=C1OC1CCNCC1 ZLOHGPAIOSLETO-UHFFFAOYSA-N 0.000 claims description 3
• LMOZLYRESOJKJL-UHFFFAOYSA-N 4-[(7-methoxy-5-piperidin-4-yloxy-2-propan-2-ylbenzimidazol-1-yl)methyl]naphthalene-1-carboximidamide Chemical compound C=1C=2N=C(C(C)C)N(CC=3C4=CC=CC=C4C(C(N)=N)=CC=3)C=2C(OC)=CC=1OC1CCNCC1 LMOZLYRESOJKJL-UHFFFAOYSA-N 0.000 claims description 3
• ACUGMFALGNHAGW-UHFFFAOYSA-N 4-[[1-[(4-carbamimidoylnaphthalen-1-yl)methyl]-6-(1-ethanimidoylpiperidin-4-yl)oxy-2-methylbenzimidazol-5-yl]oxymethyl]benzoic acid Chemical compound C1CN(C(=N)C)CCC1OC(C(=C1)OCC=2C=CC(=CC=2)C(O)=O)=CC2=C1N=C(C)N2CC1=CC=C(C(N)=N)C2=CC=CC=C12 ACUGMFALGNHAGW-UHFFFAOYSA-N 0.000 claims description 3
• GINWCUJCICISPZ-UHFFFAOYSA-N 4-[[2-butan-2-yl-5-(1-ethanimidoylpiperidin-4-yl)oxybenzimidazol-1-yl]methyl]naphthalene-1-carboximidamide Chemical compound C=1C=C2N(CC=3C4=CC=CC=C4C(C(N)=N)=CC=3)C(C(C)CC)=NC2=CC=1OC1CCN(C(C)=N)CC1 GINWCUJCICISPZ-UHFFFAOYSA-N 0.000 claims description 3
• JBJXIQXSFOPQIW-UHFFFAOYSA-N 4-[[2-butan-2-yl-6-(1-ethanimidoylpiperidin-4-yl)oxybenzimidazol-1-yl]methyl]naphthalene-1-carboximidamide Chemical compound C1=C2N(CC=3C4=CC=CC=C4C(C(N)=N)=CC=3)C(C(C)CC)=NC2=CC=C1OC1CCN(C(C)=N)CC1 JBJXIQXSFOPQIW-UHFFFAOYSA-N 0.000 claims description 3
• UNWSQSAUXWODSU-UHFFFAOYSA-N 4-[[2-butyl-5-(1-ethanimidoylpiperidin-4-yl)oxybenzimidazol-1-yl]methyl]naphthalene-1-carboximidamide Chemical compound C=1C=C2N(CC=3C4=CC=CC=C4C(C(N)=N)=CC=3)C(CCCC)=NC2=CC=1OC1CCN(C(C)=N)CC1 UNWSQSAUXWODSU-UHFFFAOYSA-N 0.000 claims description 3
• VKZWWAMXUDZAHN-UHFFFAOYSA-N 4-[[2-butyl-6-(1-ethanimidoylpiperidin-4-yl)oxybenzimidazol-1-yl]methyl]naphthalene-1-carboximidamide Chemical compound C1=C2N(CC=3C4=CC=CC=C4C(C(N)=N)=CC=3)C(CCCC)=NC2=CC=C1OC1CCN(C(C)=N)CC1 VKZWWAMXUDZAHN-UHFFFAOYSA-N 0.000 claims description 3
• ORAZLAVXXXNCIG-UHFFFAOYSA-N 4-[[5-(1-ethanimidoylpiperidin-4-yl)oxy-2-propan-2-ylbenzimidazol-1-yl]methyl]naphthalene-1-carboximidamide Chemical compound C=1C=C2N(CC=3C4=CC=CC=C4C(C(N)=N)=CC=3)C(C(C)C)=NC2=CC=1OC1CCN(C(C)=N)CC1 ORAZLAVXXXNCIG-UHFFFAOYSA-N 0.000 claims description 3
• QEJJQEKMAVKROI-UHFFFAOYSA-N 4-[[5-(1-ethanimidoylpiperidin-4-yl)oxybenzimidazol-1-yl]methyl]naphthalene-1-carboximidamide Chemical compound C1CN(C(=N)C)CCC1OC1=CC=C(N(CC=2C3=CC=CC=C3C(C(N)=N)=CC=2)C=N2)C2=C1 QEJJQEKMAVKROI-UHFFFAOYSA-N 0.000 claims description 3
• YFDYMLYCZBOPGA-UHFFFAOYSA-N 4-[[6-(1-ethanimidoylpiperidin-4-yl)oxy-2-methyl-7-nitrobenzimidazol-1-yl]methyl]naphthalene-1-carboximidamide Chemical compound C1CN(C(=N)C)CCC1OC1=CC=C(N=C(C)N2CC=3C4=CC=CC=C4C(C(N)=N)=CC=3)C2=C1[N+]([O-])=O YFDYMLYCZBOPGA-UHFFFAOYSA-N 0.000 claims description 3
• SGXRIRUGIXZLOD-UHFFFAOYSA-N 4-[[6-(1-ethanimidoylpiperidin-4-yl)oxy-2-propylbenzimidazol-1-yl]methyl]naphthalene-1-carboximidamide Chemical compound C1=C2N(CC=3C4=CC=CC=C4C(C(N)=N)=CC=3)C(CCC)=NC2=CC=C1OC1CCN(C(C)=N)CC1 SGXRIRUGIXZLOD-UHFFFAOYSA-N 0.000 claims description 3
• FQLFSVGLRSGMPG-UHFFFAOYSA-N 4-[[6-(1-ethanimidoylpiperidin-4-yl)oxy-4-methoxy-2-propan-2-ylbenzimidazol-1-yl]methyl]naphthalene-1-carboximidamide Chemical compound C=1C=2N(CC=3C4=CC=CC=C4C(C(N)=N)=CC=3)C(C(C)C)=NC=2C(OC)=CC=1OC1CCN(C(C)=N)CC1 FQLFSVGLRSGMPG-UHFFFAOYSA-N 0.000 claims description 3
• KZRKIVPOSKEPLQ-UHFFFAOYSA-N 4-[[6-(1-ethanimidoylpiperidin-4-yl)oxy-5-hydroxy-2-methylbenzimidazol-1-yl]methyl]naphthalene-1-carboximidamide Chemical compound C1CN(C(=N)C)CCC1OC(C(=C1)O)=CC2=C1N=C(C)N2CC1=CC=C(C(N)=N)C2=CC=CC=C12 KZRKIVPOSKEPLQ-UHFFFAOYSA-N 0.000 claims description 3
• SQPCFPWMXDOHII-UHFFFAOYSA-N 4-[[6-(1-ethanimidoylpiperidin-4-yl)oxy-7-nitro-2-propan-2-ylbenzimidazol-1-yl]methyl]naphthalene-1-carboximidamide Chemical compound [O-][N+](=O)C1=C2N(CC=3C4=CC=CC=C4C(C(N)=N)=CC=3)C(C(C)C)=NC2=CC=C1OC1CCN(C(C)=N)CC1 SQPCFPWMXDOHII-UHFFFAOYSA-N 0.000 claims description 3
• UFCPAJPUCFYONA-UHFFFAOYSA-N 4-[[6-(1-ethanimidoylpiperidin-4-yl)oxybenzimidazol-1-yl]methyl]naphthalene-1-carboximidamide Chemical compound C1CN(C(=N)C)CCC1OC1=CC=C(N=CN2CC=3C4=CC=CC=C4C(C(N)=N)=CC=3)C2=C1 UFCPAJPUCFYONA-UHFFFAOYSA-N 0.000 claims description 3
• POMQHOHOVQGEPT-UHFFFAOYSA-N 4-[[6-[(1-ethanimidoylpiperidin-4-yl)amino]benzimidazol-1-yl]methyl]naphthalene-1-carboximidamide Chemical compound C1CN(C(=N)C)CCC1NC1=CC=C(N=CN2CC=3C4=CC=CC=C4C(C(N)=N)=CC=3)C2=C1 POMQHOHOVQGEPT-UHFFFAOYSA-N 0.000 claims description 3
• XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 3
• TYBAIVGCYYTRAA-UHFFFAOYSA-N methyl 2-[1-[(4-carbamimidoylnaphthalen-1-yl)methyl]-6-(1-ethanimidoylpiperidin-4-yl)oxy-2-methylbenzimidazol-5-yl]oxyacetate Chemical compound COC(=O)COC1=CC=2N=C(C)N(CC=3C4=CC=CC=C4C(C(N)=N)=CC=3)C=2C=C1OC1CCN(C(C)=N)CC1 TYBAIVGCYYTRAA-UHFFFAOYSA-N 0.000 claims description 3
• BHIIOTKOSZOEBY-UHFFFAOYSA-N methyl 3-[[1-[(4-carbamimidoylnaphthalen-1-yl)methyl]-6-(1-ethanimidoylpiperidin-4-yl)oxy-2-methylbenzimidazol-5-yl]oxymethyl]benzoate Chemical compound COC(=O)C1=CC=CC(COC=2C(=CC=3N(CC=4C5=CC=CC=C5C(C(N)=N)=CC=4)C(C)=NC=3C=2)OC2CCN(CC2)C(C)=N)=C1 BHIIOTKOSZOEBY-UHFFFAOYSA-N 0.000 claims description 3
• RQMDPZDIMVCXLF-UHFFFAOYSA-N methyl 4-[[1-[(4-carbamimidoylnaphthalen-1-yl)methyl]-6-(1-ethanimidoylpiperidin-4-yl)oxy-2-methylbenzimidazol-5-yl]oxymethyl]benzoate Chemical compound C1=CC(C(=O)OC)=CC=C1COC(C(=C1)OC2CCN(CC2)C(C)=N)=CC2=C1N(CC=1C3=CC=CC=C3C(C(N)=N)=CC=1)C(C)=N2 RQMDPZDIMVCXLF-UHFFFAOYSA-N 0.000 claims description 3
• IMRMVBFTVQAXGC-UHFFFAOYSA-N 1-[(4-carbamimidoylnaphthalen-1-yl)methyl]-6-[ethanimidoyl(piperidin-4-yl)amino]-2-propan-2-ylbenzimidazole-4-carboxylic acid Chemical compound C1=C2N(CC=3C4=CC=CC=C4C(C(N)=N)=CC=3)C(C(C)C)=NC2=C(C(O)=O)C=C1N(C(C)=N)C1CCNCC1 IMRMVBFTVQAXGC-UHFFFAOYSA-N 0.000 claims description 2
• NJYJCZUCPKVVSC-UHFFFAOYSA-N 4-[(4-methoxy-6-piperidin-4-yloxy-2-propan-2-ylbenzimidazol-1-yl)methyl]naphthalene-1-carboximidamide Chemical compound C=1C=2N(CC=3C4=CC=CC=C4C(C(N)=N)=CC=3)C(C(C)C)=NC=2C(OC)=CC=1OC1CCNCC1 NJYJCZUCPKVVSC-UHFFFAOYSA-N 0.000 claims description 2
• CHYWWWTXUICNMD-UHFFFAOYSA-N 4-[[2-tert-butyl-6-(1-ethanimidoylpiperidin-4-yl)oxybenzimidazol-1-yl]methyl]naphthalene-1-carboximidamide Chemical compound C1CN(C(=N)C)CCC1OC1=CC=C(N=C(N2CC=3C4=CC=CC=C4C(C(N)=N)=CC=3)C(C)(C)C)C2=C1 CHYWWWTXUICNMD-UHFFFAOYSA-N 0.000 claims description 2
• ZLDZCDYTQMQNNC-UHFFFAOYSA-N 4-[[5-(1-ethanimidoylpiperidin-4-yl)oxy-7-methoxy-2-propan-2-ylbenzimidazol-1-yl]methyl]naphthalene-1-carboximidamide Chemical compound C=1C=2N=C(C(C)C)N(CC=3C4=CC=CC=C4C(C(N)=N)=CC=3)C=2C(OC)=CC=1OC1CCN(C(C)=N)CC1 ZLDZCDYTQMQNNC-UHFFFAOYSA-N 0.000 claims description 2
• 229940079593 drug Drugs 0.000 claims description 2
• 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims 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 claims 1
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 203
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 156
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 136
• 239000011541 reaction mixture Substances 0.000 description 92
• 239000000243 solution Substances 0.000 description 85
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 74
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 67
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 59
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 54
• 125000002887 hydroxy group Chemical group [H]O* 0.000 description 43
• 239000002904 solvent Substances 0.000 description 43
• 238000006243 chemical reaction Methods 0.000 description 40
• 238000002360 preparation method Methods 0.000 description 38
• 238000003756 stirring Methods 0.000 description 35
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 33
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 33
• 239000007787 solid Substances 0.000 description 31
• 229910001868 water Inorganic materials 0.000 description 31
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 28
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 28
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 27
• 239000000047 product Substances 0.000 description 27
• 238000012360 testing method Methods 0.000 description 27
• 239000003921 oil Substances 0.000 description 26
• 235000019198 oils Nutrition 0.000 description 26
• 239000012044 organic layer Substances 0.000 description 26
• 238000002474 experimental method Methods 0.000 description 25
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 24
• 239000000010 aprotic solvent Substances 0.000 description 24
• 238000000605 extraction Methods 0.000 description 23
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 22
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 21
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 20
• 108090000190 Thrombin Proteins 0.000 description 20
• 238000002955 isolation Methods 0.000 description 20
• 229960004072 thrombin Drugs 0.000 description 20
• 108010000499 Thromboplastin Proteins 0.000 description 19
• 102000002262 Thromboplastin Human genes 0.000 description 19
• 239000002253 acid Substances 0.000 description 19
• CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 18
• 238000004587 chromatography analysis Methods 0.000 description 18
• 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 18
• 125000003118 aryl group Chemical group 0.000 description 17
• 239000012224 working solution Substances 0.000 description 17
• 239000002585 base Substances 0.000 description 16
• RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 15
• QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 14
• 102000004190 Enzymes Human genes 0.000 description 14
• 108090000790 Enzymes Proteins 0.000 description 14
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 14
• 229940088598 enzyme Drugs 0.000 description 14
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 14
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 13
• 230000015271 coagulation Effects 0.000 description 13
• 238000005345 coagulation Methods 0.000 description 13
• 239000003112 inhibitor Substances 0.000 description 13
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
• 239000012131 assay buffer Substances 0.000 description 12
• 239000012267 brine Substances 0.000 description 12
• 239000000872 buffer Substances 0.000 description 12
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 12
• 239000003586 protic polar solvent Substances 0.000 description 12
• 229910000104 sodium hydride Inorganic materials 0.000 description 12
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 12
• 238000010898 silica gel chromatography Methods 0.000 description 11
• 239000011550 stock solution Substances 0.000 description 11
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 11
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 10
• 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 10
• 125000003342 alkenyl group Chemical group 0.000 description 10
• 125000003545 alkoxy group Chemical group 0.000 description 10
• 125000004104 aryloxy group Chemical group 0.000 description 10
• 238000004440 column chromatography Methods 0.000 description 10
• 125000000753 cycloalkyl group Chemical group 0.000 description 10
• 125000000262 haloalkenyl group Chemical group 0.000 description 10
• 125000002883 imidazolyl group Chemical group 0.000 description 10
• 125000001041 indolyl group Chemical group 0.000 description 10
• 229910052757 nitrogen Inorganic materials 0.000 description 10
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 10
• 239000011734 sodium Substances 0.000 description 10
• 239000000725 suspension Substances 0.000 description 10
• 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 10
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
• 208000007536 Thrombosis Diseases 0.000 description 9
• 125000002102 aryl alkyloxo group Chemical group 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
• 229910000042 hydrogen bromide Inorganic materials 0.000 description 9
• 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 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
• 125000003710 aryl alkyl group Chemical group 0.000 description 8
• 239000000543 intermediate Substances 0.000 description 8
• HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical class [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 8
• 230000002829 reductive effect Effects 0.000 description 8
• FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 8
• 229910004298 SiO 2 Inorganic materials 0.000 description 7
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
• 102000003978 Tissue Plasminogen Activator Human genes 0.000 description 7
• 108090000373 Tissue Plasminogen Activator Proteins 0.000 description 7
• 238000001704 evaporation Methods 0.000 description 7
• 230000008020 evaporation Effects 0.000 description 7
• 239000000706 filtrate Substances 0.000 description 7
• 238000004128 high performance liquid chromatography Methods 0.000 description 7
• 239000010410 layer Substances 0.000 description 7
• 235000017557 sodium bicarbonate Nutrition 0.000 description 7
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 7
• 229910052938 sodium sulfate Inorganic materials 0.000 description 7
• 235000011152 sodium sulphate Nutrition 0.000 description 7
• 229960000187 tissue plasminogen activator Drugs 0.000 description 7
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
• 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
• DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
• 108010094028 Prothrombin Proteins 0.000 description 6
• WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 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
• 238000007796 conventional method Methods 0.000 description 6
• 238000001914 filtration Methods 0.000 description 6
• 150000007529 inorganic bases Chemical class 0.000 description 6
• 239000003960 organic solvent Substances 0.000 description 6
• 230000037361 pathway Effects 0.000 description 6
• 229910000027 potassium carbonate Inorganic materials 0.000 description 6
• 235000011181 potassium carbonates Nutrition 0.000 description 6
• 238000010992 reflux Methods 0.000 description 6
• 239000000758 substrate Substances 0.000 description 6
• 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
• 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 5
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
• 108010029144 Factor IIa Proteins 0.000 description 5
• 102100027378 Prothrombin Human genes 0.000 description 5
• 230000002378 acidificating effect Effects 0.000 description 5
• 229910021529 ammonia Inorganic materials 0.000 description 5
• 239000004615 ingredient Substances 0.000 description 5
• 229910052500 inorganic mineral Inorganic materials 0.000 description 5
• 239000000463 material Substances 0.000 description 5
• 235000010755 mineral Nutrition 0.000 description 5
• 239000011707 mineral Substances 0.000 description 5
• 229940039716 prothrombin Drugs 0.000 description 5
• 229920006395 saturated elastomer Polymers 0.000 description 5
• 239000000741 silica gel Substances 0.000 description 5
• 229910002027 silica gel Inorganic materials 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
• JWYUFVNJZUSCSM-UHFFFAOYSA-N 2-aminobenzimidazole Chemical compound C1=CC=C2NC(N)=NC2=C1 JWYUFVNJZUSCSM-UHFFFAOYSA-N 0.000 description 4
• LDZYRENCLPUXAX-UHFFFAOYSA-N 2-methyl-1h-benzimidazole Chemical compound C1=CC=C2NC(C)=NC2=C1 LDZYRENCLPUXAX-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
• XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
• CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-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
• 101100030361 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pph-3 gene Proteins 0.000 description 4
• GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 4
• KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 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
• 238000003556 assay Methods 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
• 239000002775 capsule Substances 0.000 description 4
• 235000011089 carbon dioxide Nutrition 0.000 description 4
• 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 4
• 239000003153 chemical reaction reagent Substances 0.000 description 4
• 239000003638 chemical reducing agent Substances 0.000 description 4
• 238000010790 dilution Methods 0.000 description 4
• 239000012895 dilution Substances 0.000 description 4
• JMIAPORGEDIDLT-UHFFFAOYSA-N ethyl ethanimidate Chemical compound CCOC(C)=N JMIAPORGEDIDLT-UHFFFAOYSA-N 0.000 description 4
• 108010013555 lipoprotein-associated coagulation inhibitor Proteins 0.000 description 4
• 235000019359 magnesium stearate Nutrition 0.000 description 4
• 229910017604 nitric acid Inorganic materials 0.000 description 4
• 150000007524 organic acids Chemical class 0.000 description 4
• 150000007530 organic bases Chemical class 0.000 description 4
• 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 description 4
• 229910000028 potassium bicarbonate Inorganic materials 0.000 description 4
• 239000011780 sodium chloride Substances 0.000 description 4
• 239000012312 sodium hydride Substances 0.000 description 4
• 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 4
• 238000004809 thin layer chromatography Methods 0.000 description 4
• FWPIDFUJEMBDLS-UHFFFAOYSA-L tin(II) chloride dihydrate Chemical compound O.O.Cl[Sn]Cl FWPIDFUJEMBDLS-UHFFFAOYSA-L 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
• 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
• OFERXYONSRMYRP-UHFFFAOYSA-N 4-[[5-(1-ethanimidoylpiperidin-4-yl)oxy-2-propylbenzimidazol-1-yl]methyl]naphthalene-1-carboximidamide Chemical compound C=1C=C2N(CC=3C4=CC=CC=C4C(C(N)=N)=CC=3)C(CCC)=NC2=CC=1OC1CCN(C(C)=N)CC1 OFERXYONSRMYRP-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
• UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 3
• 206010051055 Deep vein thrombosis Diseases 0.000 description 3
• DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 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
• 102000012479 Serine Proteases Human genes 0.000 description 3
• 108010022999 Serine Proteases Proteins 0.000 description 3
• 206010047249 Venous thrombosis Diseases 0.000 description 3
• 230000003187 abdominal effect Effects 0.000 description 3
• 230000009471 action Effects 0.000 description 3
• 239000000443 aerosol Substances 0.000 description 3
• 150000004703 alkoxides Chemical class 0.000 description 3
• 150000001408 amides Chemical class 0.000 description 3
• 150000001412 amines Chemical class 0.000 description 3
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
• 238000004166 bioassay Methods 0.000 description 3
• 239000001110 calcium chloride Substances 0.000 description 3
• 235000011148 calcium chloride Nutrition 0.000 description 3
• 229910001628 calcium chloride Inorganic materials 0.000 description 3
• 239000003795 chemical substances by application Substances 0.000 description 3
• 239000000460 chlorine Substances 0.000 description 3
• 239000012043 crude product Substances 0.000 description 3
• 238000001035 drying Methods 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
• 238000009472 formulation Methods 0.000 description 3
• 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
• 238000001802 infusion Methods 0.000 description 3
• 230000007246 mechanism Effects 0.000 description 3
• YDCHPLOFQATIDS-UHFFFAOYSA-N methyl 2-bromoacetate Chemical compound COC(=O)CBr YDCHPLOFQATIDS-UHFFFAOYSA-N 0.000 description 3
• 150000007522 mineralic acids Chemical class 0.000 description 3
• 229940124531 pharmaceutical excipient Drugs 0.000 description 3
• 235000015497 potassium bicarbonate Nutrition 0.000 description 3
• 239000011736 potassium bicarbonate Substances 0.000 description 3
• TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 3
• 230000003389 potentiating effect Effects 0.000 description 3
• 230000002265 prevention Effects 0.000 description 3
• 108010014806 prothrombinase complex Proteins 0.000 description 3
• 239000012266 salt solution Substances 0.000 description 3
• 229910052708 sodium Inorganic materials 0.000 description 3
• 239000000829 suppository Substances 0.000 description 3
• 238000001356 surgical procedure Methods 0.000 description 3
• 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
• 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 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
• 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
• 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
• GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical class 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
• QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
• OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
• XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 2
• 102000009123 Fibrin Human genes 0.000 description 2
• 108010073385 Fibrin Proteins 0.000 description 2
• BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 2
• VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-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
• RRHGJUQNOFWUDK-UHFFFAOYSA-N Isoprene Chemical compound CC(=C)C=C RRHGJUQNOFWUDK-UHFFFAOYSA-N 0.000 description 2
• GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Chemical class 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 2
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
• 241001465754 Metazoa Species 0.000 description 2
• 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
• 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
• GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
• NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
• ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-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
• 229920002472 Starch Chemical class 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
• 239000013543 active substance Substances 0.000 description 2
• 150000008064 anhydrides Chemical class 0.000 description 2
• 229910052786 argon Inorganic materials 0.000 description 2
• 150000001556 benzimidazoles Chemical class 0.000 description 2
• WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
• 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 2
• 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 2
• 239000008280 blood Substances 0.000 description 2
• 210000004369 blood Anatomy 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
• 239000011575 calcium Substances 0.000 description 2
• 229910052791 calcium Inorganic materials 0.000 description 2
• 238000004364 calculation method Methods 0.000 description 2
• 239000003054 catalyst Substances 0.000 description 2
• 229920003086 cellulose ether Chemical class 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
• 238000001816 cooling Methods 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
• XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
• 150000002170 ethers Chemical class 0.000 description 2
• 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 2
• 229950003499 fibrin Drugs 0.000 description 2
• 239000012458 free base Substances 0.000 description 2
• 238000004108 freeze drying 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
• 150000003840 hydrochlorides Chemical class 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
• JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 2
• 239000008101 lactose Chemical class 0.000 description 2
• 150000002632 lipids Chemical class 0.000 description 2
• 239000007788 liquid Substances 0.000 description 2
• 230000007774 longterm Effects 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
• 239000010502 orange oil Substances 0.000 description 2
• 230000036961 partial effect Effects 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
• 229940068918 polyethylene glycol 400 Drugs 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
• 229910052700 potassium Inorganic materials 0.000 description 2
• 239000011591 potassium Substances 0.000 description 2
• 239000000843 powder Substances 0.000 description 2
• 239000002244 precipitate Substances 0.000 description 2
• 108090000765 processed proteins & peptides Proteins 0.000 description 2
• 229960004063 propylene glycol Drugs 0.000 description 2
• 125000006239 protecting group Chemical group 0.000 description 2
• 238000001953 recrystallisation Methods 0.000 description 2
• 238000004007 reversed phase HPLC Methods 0.000 description 2
• 230000007017 scission Effects 0.000 description 2
• 238000013207 serial dilution Methods 0.000 description 2
• 239000003001 serine protease inhibitor Substances 0.000 description 2
• 238000000638 solvent extraction Methods 0.000 description 2
• 239000008107 starch Chemical class 0.000 description 2
• 235000019698 starch Nutrition 0.000 description 2
• 239000005720 sucrose Substances 0.000 description 2
• 230000002459 sustained effect Effects 0.000 description 2
• 238000003786 synthesis reaction Methods 0.000 description 2
• GTNBKORVTYFBAK-UHFFFAOYSA-N tert-butyl 4-[(6-nitro-2-propan-2-yl-1h-benzimidazol-5-yl)oxy]piperidine-1-carboxylate Chemical compound [O-][N+](=O)C=1C=C2NC(C(C)C)=NC2=CC=1OC1CCN(C(=O)OC(C)(C)C)CC1 GTNBKORVTYFBAK-UHFFFAOYSA-N 0.000 description 2
• HZKXXCPPZWIJTA-UHFFFAOYSA-N tert-butyl 4-[1-[(4-cyanonaphthalen-1-yl)methyl]-2-propan-2-ylbenzimidazol-5-yl]oxypiperidine-1-carboxylate Chemical compound C=1C=C2N(CC=3C4=CC=CC=C4C(C#N)=CC=3)C(C(C)C)=NC2=CC=1OC1CCN(C(=O)OC(C)(C)C)CC1 HZKXXCPPZWIJTA-UHFFFAOYSA-N 0.000 description 2
• HBEFMPWVQFKTHJ-UHFFFAOYSA-N tert-butyl 4-[1-[(4-cyanonaphthalen-1-yl)methyl]-6-nitro-2-propan-2-ylbenzimidazol-5-yl]oxypiperidine-1-carboxylate Chemical compound [O-][N+](=O)C=1C=C2N(CC=3C4=CC=CC=C4C(C#N)=CC=3)C(C(C)C)=NC2=CC=1OC1CCN(C(=O)OC(C)(C)C)CC1 HBEFMPWVQFKTHJ-UHFFFAOYSA-N 0.000 description 2
• DAKIBKCUPVZWHU-UHFFFAOYSA-N tert-butyl 4-[3-[(4-cyanonaphthalen-1-yl)methyl]-2-propan-2-ylbenzimidazol-5-yl]oxypiperidine-1-carboxylate Chemical compound 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 DAKIBKCUPVZWHU-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
• NAMAWIGSKJRCQA-UHFFFAOYSA-N tert-butyl 4-[3-[(4-cyanonaphthalen-1-yl)methyl]-6-nitro-2-propan-2-ylbenzimidazol-5-yl]oxypiperidine-1-carboxylate Chemical compound C1=C2N(CC=3C4=CC=CC=C4C(C#N)=CC=3)C(C(C)C)=NC2=CC([N+]([O-])=O)=C1OC1CCN(C(=O)OC(C)(C)C)CC1 NAMAWIGSKJRCQA-UHFFFAOYSA-N 0.000 description 2
• 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 2
• 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 2
• 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 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
• 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 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
• 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
• VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
• 238000012546 transfer Methods 0.000 description 2
• GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
• 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
• WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-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
• 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
• 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 description 1
• 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 1
• OGJSHIYACXNENZ-UHFFFAOYSA-N 1-[4-(1h-benzimidazol-2-yloxy)piperidin-1-yl]ethanimine Chemical compound C1CN(C(=N)C)CCC1OC1=NC2=CC=CC=C2N1 OGJSHIYACXNENZ-UHFFFAOYSA-N 0.000 description 1
• 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 1
• 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 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
• GGCFVDRFTWLKDU-UHFFFAOYSA-N 1h-benzimidazol-2-yloxymethanol Chemical compound C1=CC=C2NC(OCO)=NC2=C1 GGCFVDRFTWLKDU-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
• HZLYORKTUWEXGT-UHFFFAOYSA-N 2-[1-[(4-carbamimidoylnaphthalen-1-yl)methyl]-6-(1-ethanimidoylpiperidin-4-yl)oxy-2-methylbenzimidazol-5-yl]oxyacetic acid Chemical compound C1CN(C(=N)C)CCC1OC(C(=C1)OCC(O)=O)=CC2=C1N=C(C)N2CC1=CC=C(C(N)=N)C2=CC=CC=C12 HZLYORKTUWEXGT-UHFFFAOYSA-N 0.000 description 1
• 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 1
• XONLJQIPTUVMFS-UHFFFAOYSA-N 2-[6-hydroxy-1-[(2-methylpropan-2-yl)oxycarbonyl]-2-propan-2-ylbenzimidazol-4-yl]oxyacetic acid Chemical compound C1=C(O)C=C2N(C(=O)OC(C)(C)C)C(C(C)C)=NC2=C1OCC(O)=O XONLJQIPTUVMFS-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
• SBKRUWFIHAIXBH-UHFFFAOYSA-N 2-piperidin-4-yloxy-1h-benzimidazole Chemical compound C1CNCCC1OC1=NC2=CC=CC=C2N1 SBKRUWFIHAIXBH-UHFFFAOYSA-N 0.000 description 1
• LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
• BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
• WFRXSXUDWCVSPI-UHFFFAOYSA-N 3h-benzimidazol-5-amine Chemical compound NC1=CC=C2NC=NC2=C1 WFRXSXUDWCVSPI-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
• JLFGFORZHJVEOI-UHFFFAOYSA-N 4-[(2-ethyl-5-piperidin-4-yloxybenzimidazol-1-yl)methyl]naphthalene-1-carboximidamide Chemical compound C=1C=C2N(CC=3C4=CC=CC=C4C(C(N)=N)=CC=3)C(CC)=NC2=CC=1OC1CCNCC1 JLFGFORZHJVEOI-UHFFFAOYSA-N 0.000 description 1
• BDPUEYVBXQQEJX-UHFFFAOYSA-N 4-[(2-ethyl-6-piperidin-4-yloxybenzimidazol-1-yl)methyl]naphthalene-1-carboximidamide Chemical compound C1=C2N(CC=3C4=CC=CC=C4C(C(N)=N)=CC=3)C(CC)=NC2=CC=C1OC1CCNCC1 BDPUEYVBXQQEJX-UHFFFAOYSA-N 0.000 description 1
• SUUOMXUPMIQDJM-UHFFFAOYSA-N 4-[(2-methyl-5-piperidin-4-yloxybenzimidazol-1-yl)methyl]naphthalene-1-carboximidamide Chemical compound C=1C=C2N(CC=3C4=CC=CC=C4C(C(N)=N)=CC=3)C(C)=NC2=CC=1OC1CCNCC1 SUUOMXUPMIQDJM-UHFFFAOYSA-N 0.000 description 1
• ZAOZAVOIITTZHZ-UHFFFAOYSA-N 4-[(2-methyl-6-piperidin-4-yloxybenzimidazol-1-yl)methyl]naphthalene-1-carboximidamide Chemical compound C1=C2N(CC=3C4=CC=CC=C4C(C(N)=N)=CC=3)C(C)=NC2=CC=C1OC1CCNCC1 ZAOZAVOIITTZHZ-UHFFFAOYSA-N 0.000 description 1
• VYIRVKXEFCACPF-UHFFFAOYSA-N 4-[(5-piperidin-4-yloxy-2-propan-2-ylbenzimidazol-1-yl)methyl]naphthalene-1-carboximidamide;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F.C=1C=C2N(CC=3C4=CC=CC=C4C(C(N)=N)=CC=3)C(C(C)C)=NC2=CC=1OC1CCNCC1 VYIRVKXEFCACPF-UHFFFAOYSA-N 0.000 description 1
• VYYRBQLXIXGETL-UHFFFAOYSA-N 4-[(5-piperidin-4-yloxybenzimidazol-1-yl)methyl]naphthalene-1-carboximidamide Chemical compound C12=CC=CC=C2C(C(=N)N)=CC=C1CN(C1=CC=2)C=NC1=CC=2OC1CCNCC1 VYYRBQLXIXGETL-UHFFFAOYSA-N 0.000 description 1
• SROAICLUFWHYND-UHFFFAOYSA-N 4-[(6-piperidin-4-yloxybenzimidazol-1-yl)methyl]naphthalene-1-carboximidamide Chemical compound C12=CC=CC=C2C(C(=N)N)=CC=C1CN(C1=C2)C=NC1=CC=C2OC1CCNCC1 SROAICLUFWHYND-UHFFFAOYSA-N 0.000 description 1
• 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 description 1
• MUAYHWWOQGSJFD-UHFFFAOYSA-N 4-[[5-(1-ethanimidoylpiperidin-4-yl)oxy-2-ethylbenzimidazol-1-yl]methyl]naphthalene-1-carboximidamide Chemical compound C=1C=C2N(CC=3C4=CC=CC=C4C(C(N)=N)=CC=3)C(CC)=NC2=CC=1OC1CCN(C(C)=N)CC1 MUAYHWWOQGSJFD-UHFFFAOYSA-N 0.000 description 1
• OHSDVYINQLDSAB-UHFFFAOYSA-N 4-[[5-(1-ethanimidoylpiperidin-4-yl)oxy-2-methylbenzimidazol-1-yl]methyl]naphthalene-1-carboximidamide Chemical compound C1CN(C(=N)C)CCC1OC1=CC=C(N(CC=2C3=CC=CC=C3C(C(N)=N)=CC=2)C(C)=N2)C2=C1 OHSDVYINQLDSAB-UHFFFAOYSA-N 0.000 description 1
• AAEWIPBESFAXHJ-UHFFFAOYSA-N 4-[[5-(1-ethanimidoylpiperidin-4-yl)oxy-2-propan-2-ylbenzimidazol-1-yl]methyl]naphthalene-1-carboximidamide;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F.C=1C=C2N(CC=3C4=CC=CC=C4C(C(N)=N)=CC=3)C(C(C)C)=NC2=CC=1OC1CCN(C(C)=N)CC1 AAEWIPBESFAXHJ-UHFFFAOYSA-N 0.000 description 1
• BEVGYXKHBAZDPG-UHFFFAOYSA-N 4-[[6-(1-ethanimidoylpiperidin-3-yl)oxy-2-methylbenzimidazol-1-yl]methyl]naphthalene-1-carboximidamide Chemical compound C1N(C(=N)C)CCCC1OC1=CC=C(N=C(C)N2CC=3C4=CC=CC=C4C(C(N)=N)=CC=3)C2=C1 BEVGYXKHBAZDPG-UHFFFAOYSA-N 0.000 description 1
• FIRXNVNZNZGVHA-UHFFFAOYSA-N 4-[[6-(1-ethanimidoylpiperidin-4-yl)oxy-2-(trifluoromethyl)benzimidazol-1-yl]methyl]naphthalene-1-carboximidamide Chemical compound C1CN(C(=N)C)CCC1OC1=CC=C(N=C(N2CC=3C4=CC=CC=C4C(C(N)=N)=CC=3)C(F)(F)F)C2=C1 FIRXNVNZNZGVHA-UHFFFAOYSA-N 0.000 description 1
• JISLXEDSKDXDOA-UHFFFAOYSA-N 4-[[6-(1-ethanimidoylpiperidin-4-yl)oxy-2-ethylbenzimidazol-1-yl]methyl]naphthalene-1-carboximidamide Chemical compound C1=C2N(CC=3C4=CC=CC=C4C(C(N)=N)=CC=3)C(CC)=NC2=CC=C1OC1CCN(C(C)=N)CC1 JISLXEDSKDXDOA-UHFFFAOYSA-N 0.000 description 1
• YJVBVPPVQLNISW-UHFFFAOYSA-N 4-[[6-(1-ethanimidoylpiperidin-4-yl)oxy-2-methylbenzimidazol-1-yl]methyl]naphthalene-1-carboximidamide Chemical compound C1CN(C(=N)C)CCC1OC1=CC=C(N=C(C)N2CC=3C4=CC=CC=C4C(C(N)=N)=CC=3)C2=C1 YJVBVPPVQLNISW-UHFFFAOYSA-N 0.000 description 1
• VYZXJUJFRMPALX-UHFFFAOYSA-N 4-[[6-(1-ethanimidoylpiperidin-4-yl)oxy-2-propan-2-ylbenzimidazol-1-yl]methyl]naphthalene-1-carboximidamide Chemical compound C1=C2N(CC=3C4=CC=CC=C4C(C(N)=N)=CC=3)C(C(C)C)=NC2=CC=C1OC1CCN(C(C)=N)CC1 VYZXJUJFRMPALX-UHFFFAOYSA-N 0.000 description 1
• FFEJPGWHSZBUGI-UHFFFAOYSA-N 4-[[6-(1-ethanimidoylpiperidin-4-yl)oxy-2-propan-2-ylbenzimidazol-1-yl]methyl]naphthalene-1-carboximidamide;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F.C1=C2N(CC=3C4=CC=CC=C4C(C(N)=N)=CC=3)C(C(C)C)=NC2=CC=C1OC1CCN(C(C)=N)CC1 FFEJPGWHSZBUGI-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
• TYMLOMAKGOJONV-UHFFFAOYSA-N 4-nitroaniline Chemical compound NC1=CC=C([N+]([O-])=O)C=C1 TYMLOMAKGOJONV-UHFFFAOYSA-N 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
• QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
• 244000215068 Acacia senegal Species 0.000 description 1
• 235000006491 Acacia senegal Nutrition 0.000 description 1
• 208000036762 Acute promyelocytic leukaemia Diseases 0.000 description 1
• 206010001052 Acute respiratory distress syndrome Diseases 0.000 description 1
• 206010002388 Angina unstable Diseases 0.000 description 1
• 101710163968 Antistasin Proteins 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
• BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 1
• CKDWPUIZGOQOOM-UHFFFAOYSA-N Carbamyl chloride Chemical class NC(Cl)=O CKDWPUIZGOQOOM-UHFFFAOYSA-N 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
• 206010053567 Coagulopathies Diseases 0.000 description 1
• RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
• FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical class 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
• 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
• 229940123583 Factor Xa inhibitor Drugs 0.000 description 1
• 108010049003 Fibrinogen Proteins 0.000 description 1
• 102000008946 Fibrinogen Human genes 0.000 description 1
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-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
• 229920000084 Gum arabic Polymers 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
• WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 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
• FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
• 229930195725 Mannitol Natural products 0.000 description 1
• 229920000881 Modified starch Chemical class 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
• HTLZVHNRZJPSMI-UHFFFAOYSA-N N-ethylpiperidine Chemical compound CCN1CCCCC1 HTLZVHNRZJPSMI-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
• 239000005642 Oleic acid Substances 0.000 description 1
• ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
• 239000008118 PEG 6000 Substances 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
• 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
• 208000013616 Respiratory Distress Syndrome Diseases 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
• 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
• 208000032109 Transient ischaemic attack Diseases 0.000 description 1
• 208000007814 Unstable Angina Diseases 0.000 description 1
• HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
• JJZPWCVHSLZLQC-UHFFFAOYSA-N [N].C1=CC=C2NC=NC2=C1 Chemical compound [N].C1=CC=C2NC=NC2=C1 JJZPWCVHSLZLQC-UHFFFAOYSA-N 0.000 description 1
• 210000001015 abdomen Anatomy 0.000 description 1
• 235000010489 acacia gum Nutrition 0.000 description 1
• 150000008065 acid anhydrides Chemical class 0.000 description 1
• 150000007513 acids Chemical class 0.000 description 1
• 230000004913 activation Effects 0.000 description 1
• 239000004480 active ingredient Substances 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
• 229910000147 aluminium phosphate Inorganic materials 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
• 230000010100 anticoagulation Effects 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
• 239000012298 atmosphere Substances 0.000 description 1
• 235000010233 benzoic acid Nutrition 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
• 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
• 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
• 238000009530 blood pressure measurement Methods 0.000 description 1
• 238000010241 blood sampling Methods 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
• 235000010354 butylated hydroxytoluene Nutrition 0.000 description 1
• 229940095259 butylated hydroxytoluene Drugs 0.000 description 1
• 229910001424 calcium ion Inorganic materials 0.000 description 1
• 239000001506 calcium phosphate Substances 0.000 description 1
• 108090001015 cancer procoagulant Proteins 0.000 description 1
• 239000007894 caplet Substances 0.000 description 1
• 125000004432 carbon atom Chemical group C* 0.000 description 1
• 210000001715 carotid artery Anatomy 0.000 description 1
• 239000000969 carrier Substances 0.000 description 1
• 239000001913 cellulose Substances 0.000 description 1
• 229920002678 cellulose Polymers 0.000 description 1
• 239000003610 charcoal Substances 0.000 description 1
• 239000007795 chemical reaction product Substances 0.000 description 1
• 150000001805 chlorine compounds Chemical class 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
• 230000035602 clotting Effects 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
• 229910052681 coesite Inorganic materials 0.000 description 1
• 239000012141 concentrate Substances 0.000 description 1
• 239000012059 conventional drug carrier Substances 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
• 229940072645 coumadin Drugs 0.000 description 1
• 229910052906 cristobalite Inorganic materials 0.000 description 1
• 239000010779 crude oil Substances 0.000 description 1
• 230000003247 decreasing effect Effects 0.000 description 1
• 239000012351 deprotecting agent Substances 0.000 description 1
• 238000011161 development Methods 0.000 description 1
• 239000008121 dextrose Substances 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
• 238000007865 diluting Methods 0.000 description 1
• 239000003085 diluting agent Substances 0.000 description 1
• 239000007884 disintegrant Substances 0.000 description 1
• 208000009190 disseminated intravascular coagulation Diseases 0.000 description 1
• 238000004090 dissolution Methods 0.000 description 1
• 239000002552 dosage form Substances 0.000 description 1
• 230000003828 downregulation Effects 0.000 description 1
• 239000000890 drug combination Substances 0.000 description 1
• 238000010828 elution Methods 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
• 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
• 229940012017 ethylenediamine Drugs 0.000 description 1
• 230000029142 excretion Effects 0.000 description 1
• 230000001747 exhibiting effect Effects 0.000 description 1
• 229940012414 factor viia Drugs 0.000 description 1
• 229940012952 fibrinogen Drugs 0.000 description 1
• 239000003527 fibrinolytic agent Substances 0.000 description 1
• 230000003480 fibrinolytic 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
• 239000001530 fumaric acid Substances 0.000 description 1
• 235000011087 fumaric acid Nutrition 0.000 description 1
• 229940083124 ganglion-blocking antiadrenergic secondary and tertiary amines Drugs 0.000 description 1
• 239000007789 gas Substances 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
• 125000000623 heterocyclic group Chemical group 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
• XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
• 238000001727 in vivo Methods 0.000 description 1
• 208000015181 infectious disease Diseases 0.000 description 1
• 238000009413 insulation Methods 0.000 description 1
• 201000004332 intermediate coronary syndrome Diseases 0.000 description 1
• 239000013067 intermediate product Substances 0.000 description 1
• 238000001990 intravenous administration Methods 0.000 description 1
• 239000011630 iodine Substances 0.000 description 1
• 229910052740 iodine Inorganic materials 0.000 description 1
• 239000003456 ion exchange resin Substances 0.000 description 1
• 229920003303 ion-exchange polymer Polymers 0.000 description 1
• 229910052742 iron Inorganic materials 0.000 description 1
• 230000002427 irreversible effect Effects 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
• QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
• 239000008297 liquid dosage form Substances 0.000 description 1
• 229910052744 lithium Inorganic materials 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
• 239000011777 magnesium Substances 0.000 description 1
• 229910052749 magnesium Inorganic materials 0.000 description 1
• 159000000003 magnesium salts Chemical class 0.000 description 1
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
• 235000019341 magnesium sulphate Nutrition 0.000 description 1
• VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
• 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
• 108010011227 meizothrombin Proteins 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
• ILSLXHVMCZVCOY-UHFFFAOYSA-N methyl 1-[(4-cyanonaphthalen-1-yl)methyl]-2-methyl-6-[1-[(2-methylpropan-2-yl)oxycarbonyl]piperidin-4-yl]oxybenzimidazole-5-carboxylate Chemical compound COC(=O)C1=CC=2N=C(C)N(CC=3C4=CC=CC=C4C(C#N)=CC=3)C=2C=C1OC1CCN(C(=O)OC(C)(C)C)CC1 ILSLXHVMCZVCOY-UHFFFAOYSA-N 0.000 description 1
• QYVUSVUPAARBGS-UHFFFAOYSA-N methyl 1-[5-methoxy-2,3-bis(2-methylpropanoylamino)phenyl]piperidine-4-carboxylate Chemical compound C1CC(C(=O)OC)CCN1C1=CC(OC)=CC(NC(=O)C(C)C)=C1NC(=O)C(C)C QYVUSVUPAARBGS-UHFFFAOYSA-N 0.000 description 1
• CFTUQSLVERGMHL-UHFFFAOYSA-N methyl 2-(bromomethyl)prop-2-enoate Chemical compound COC(=O)C(=C)CBr CFTUQSLVERGMHL-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
• UMABGEUDMULPLQ-UHFFFAOYSA-N methyl 3-[(4-cyanonaphthalen-1-yl)methyl]-2-methyl-6-[1-[(2-methylpropan-2-yl)oxycarbonyl]piperidin-4-yl]oxybenzimidazole-5-carboxylate Chemical compound COC(=O)C1=CC=2N(CC=3C4=CC=CC=C4C(C#N)=CC=3)C(C)=NC=2C=C1OC1CCN(C(=O)OC(C)(C)C)CC1 UMABGEUDMULPLQ-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
• 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
• WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
• 238000002156 mixing Methods 0.000 description 1
• 238000012986 modification Methods 0.000 description 1
• 230000004048 modification Effects 0.000 description 1
• 208000010125 myocardial infarction Diseases 0.000 description 1
• 229910000069 nitrogen hydride Inorganic materials 0.000 description 1
• 230000000269 nucleophilic effect Effects 0.000 description 1
• ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
• 235000005985 organic acids Nutrition 0.000 description 1
• 230000000399 orthopedic effect Effects 0.000 description 1
• 235000006408 oxalic acid Nutrition 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
• 238000007911 parenteral administration Methods 0.000 description 1
• WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 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
• UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
• WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 description 1
• 229920000768 polyamine Polymers 0.000 description 1
• 229920002523 polyethylene Glycol 1000 Polymers 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
• 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
• 230000008569 process Effects 0.000 description 1
• 239000003380 propellant Substances 0.000 description 1
• 238000011321 prophylaxis Methods 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
• 150000003212 purines Chemical class 0.000 description 1
• 201000005380 purpura fulminans Diseases 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
• 210000002796 renal vein Anatomy 0.000 description 1
• 238000011160 research Methods 0.000 description 1
• 239000011347 resin Substances 0.000 description 1
• 229920005989 resin Polymers 0.000 description 1
• 230000002441 reversible effect Effects 0.000 description 1
• 230000006965 reversible inhibition Effects 0.000 description 1
• CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical class C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
• JZWFDVDETGFGFC-UHFFFAOYSA-N salacetamide Chemical group CC(=O)NC(=O)C1=CC=CC=C1O JZWFDVDETGFGFC-UHFFFAOYSA-N 0.000 description 1
• 238000009738 saturating Methods 0.000 description 1
• 230000036303 septic shock Effects 0.000 description 1
• 239000000377 silicon dioxide Substances 0.000 description 1
• 235000012239 silicon dioxide Nutrition 0.000 description 1
• BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 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
• 229910052682 stishovite Inorganic materials 0.000 description 1
• 239000000126 substance Substances 0.000 description 1
• 229940014800 succinic anhydride Drugs 0.000 description 1
• 238000011477 surgical intervention Methods 0.000 description 1
• 239000000454 talc Chemical class 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
• 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 1
• YBHLQPAFEWZDAH-UHFFFAOYSA-N tert-butyl 4-[(6-hydroxy-2-methyl-1h-benzimidazol-5-yl)oxy]piperidine-1-carboxylate Chemical compound OC=1C=C2NC(C)=NC2=CC=1OC1CCN(C(=O)OC(C)(C)C)CC1 YBHLQPAFEWZDAH-UHFFFAOYSA-N 0.000 description 1
• KDRSVDAWGYJCMU-UHFFFAOYSA-N tert-butyl 4-[1-[(4-cyanonaphthalen-1-yl)methyl]-6-[1-(2-ethoxy-2-oxoethyl)piperidin-4-yl]oxy-2-methylbenzimidazol-5-yl]oxypiperidine-1-carboxylate Chemical compound C1CN(CC(=O)OCC)CCC1OC(C(=C1)OC2CCN(CC2)C(=O)OC(C)(C)C)=CC2=C1N=C(C)N2CC1=CC=C(C#N)C2=CC=CC=C12 KDRSVDAWGYJCMU-UHFFFAOYSA-N 0.000 description 1
• 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 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
• IMZNIIRMGVYETC-UHFFFAOYSA-N tert-butyl 4-[3-[(4-cyanonaphthalen-1-yl)methyl]-6-[(4-methoxycarbonylphenyl)methylamino]-2-propan-2-ylbenzimidazol-5-yl]oxypiperidine-1-carboxylate Chemical compound C1=CC(C(=O)OC)=CC=C1CNC(C(=C1)OC2CCN(CC2)C(=O)OC(C)(C)C)=CC2=C1N(CC=1C3=CC=CC=C3C(C#N)=CC=1)C(C(C)C)=N2 IMZNIIRMGVYETC-UHFFFAOYSA-N 0.000 description 1
• IGVQHPXLHIISRB-UHFFFAOYSA-N tert-butyl 4-[4-[(3-methoxy-2-methyl-3-oxopropyl)amino]-2-methyl-1-(4-methylphenyl)sulfonylbenzimidazol-5-yl]piperidine-1-carboxylate Chemical compound CC1=NC=2C(NCC(C)C(=O)OC)=C(C3CCN(CC3)C(=O)OC(C)(C)C)C=CC=2N1S(=O)(=O)C1=CC=C(C)C=C1 IGVQHPXLHIISRB-UHFFFAOYSA-N 0.000 description 1
• 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 1
• 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 1
• CCWPRRDCCYMIBX-UHFFFAOYSA-N tert-butyl 4-[6-amino-3-[(4-cyanonaphthalen-1-yl)methyl]-2-propan-2-ylbenzimidazol-5-yl]oxypiperidine-1-carboxylate Chemical compound C1=C2N(CC=3C4=CC=CC=C4C(C#N)=CC=3)C(C(C)C)=NC2=CC(N)=C1OC1CCN(C(=O)OC(C)(C)C)CC1 CCWPRRDCCYMIBX-UHFFFAOYSA-N 0.000 description 1
• 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 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
• 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 1
• 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 1
• 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 1
• 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 1
• XYJFVOVLHZWUHU-UHFFFAOYSA-N tert-butyl 6-[tert-butyl(dimethyl)silyl]oxy-2-methyl-5-[1-[(2-methylpropan-2-yl)oxycarbonyl]piperidin-4-yl]oxybenzimidazole-1-carboxylate Chemical compound CC(C)(C)[Si](C)(C)OC=1C=C2N(C(=O)OC(C)(C)C)C(C)=NC2=CC=1OC1CCN(C(=O)OC(C)(C)C)CC1 XYJFVOVLHZWUHU-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
• 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
• RQCNHUCCQJMSRG-UHFFFAOYSA-N tert-butyl piperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCCC1 RQCNHUCCQJMSRG-UHFFFAOYSA-N 0.000 description 1
• 238000010998 test method Methods 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
• 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
• 201000010875 transient cerebral ischemia Diseases 0.000 description 1
• 229910052905 tridymite Inorganic materials 0.000 description 1
• YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
• 238000001665 trituration Methods 0.000 description 1
• 230000001810 trypsinlike Effects 0.000 description 1
• 230000003827 upregulation Effects 0.000 description 1
• 230000002792 vascular Effects 0.000 description 1
• 210000003462 vein Anatomy 0.000 description 1
• PJVWKTKQMONHTI-UHFFFAOYSA-N warfarin Chemical compound OC=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 PJVWKTKQMONHTI-UHFFFAOYSA-N 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