IL124537A - History of benzimidazole converted to naphthalene and pharmaceutical preparations containing them - Google Patents

Info

Publication number

IL124537A

IL124537A IL12453796A IL12453796A IL124537A IL 124537 A IL124537 A IL 124537A IL 12453796 A IL12453796 A IL 12453796A IL 12453796 A IL12453796 A IL 12453796A IL 124537 A IL124537 A IL 124537A

Authority

IL

Israel

Prior art keywords

optionally substituted

methyl

halo

alkyl

hydroxy

Prior art date

1995-12-08

Links

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• 239000008194 pharmaceutical composition Chemical class 0.000 title claims description 13
• 229940058303 antinematodal benzimidazole derivative Drugs 0.000 title description 3
• 125000003785 benzimidazolyl group Chemical class N1=C(NC2=C1C=CC=C2)* 0.000 title description 2
• 150000001875 compounds Chemical class 0.000 claims abstract description 429
• 125000000217 alkyl group Chemical group 0.000 claims abstract description 173
• -1 hydroxy, hydroxy Chemical group 0.000 claims abstract description 127
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 125
• 239000001257 hydrogen Substances 0.000 claims abstract description 92
• 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 92
• 125000003118 aryl group Chemical group 0.000 claims abstract description 64
• 125000001424 substituent group Chemical group 0.000 claims abstract description 56
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 49
• 150000003839 salts Chemical class 0.000 claims abstract description 47
• 125000002947 alkylene group Chemical group 0.000 claims abstract description 31
• 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 claims abstract description 29
• 150000002431 hydrogen Chemical group 0.000 claims abstract description 29
• 125000003545 alkoxy group Chemical group 0.000 claims abstract description 28
• 125000002883 imidazolyl group Chemical group 0.000 claims abstract description 28
• 125000004104 aryloxy group Chemical group 0.000 claims abstract description 27
• 125000003342 alkenyl group Chemical group 0.000 claims abstract description 25
• 125000001041 indolyl group Chemical group 0.000 claims abstract description 25
• 125000000262 haloalkenyl group Chemical group 0.000 claims abstract description 23
• 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 18
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 15
• 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 14
• 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 13
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 13
• 125000001475 halogen functional group Chemical group 0.000 claims abstract 90
• 229910006069 SO3H Inorganic materials 0.000 claims abstract 9
• HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 claims description 130
• 239000000203 mixture Substances 0.000 claims description 85
• 238000000034 method Methods 0.000 claims description 40
• 108010074860 Factor Xa Proteins 0.000 claims description 37
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 28
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 22
• 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 21
• 201000010099 disease Diseases 0.000 claims description 20
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 20
• 125000003386 piperidinyl group Chemical group 0.000 claims description 13
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 8
• 238000011282 treatment Methods 0.000 claims description 8
• 230000005764 inhibitory process Effects 0.000 claims description 7
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
• 230000001732 thrombotic effect Effects 0.000 claims description 7
• 230000002401 inhibitory effect Effects 0.000 claims description 6
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 5
• JWYUFVNJZUSCSM-UHFFFAOYSA-N 2-aminobenzimidazole Chemical compound C1=CC=C2NC(N)=NC2=C1 JWYUFVNJZUSCSM-UHFFFAOYSA-N 0.000 claims description 4
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
• 238000000338 in vitro Methods 0.000 claims description 3
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 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 2
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
• 238000004519 manufacturing process Methods 0.000 claims description 2
• 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 2
• 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 2
• 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims 19
• 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 1
• 239000003814 drug Substances 0.000 claims 1
• 239000003146 anticoagulant agent Substances 0.000 abstract description 7
• 229940127219 anticoagulant drug Drugs 0.000 abstract description 7
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 197
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 162
• 239000000243 solution Substances 0.000 description 87
• 238000006243 chemical reaction Methods 0.000 description 79
• 125000005843 halogen group Chemical group 0.000 description 77
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 74
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 72
• 238000002360 preparation method Methods 0.000 description 70
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 67
• 239000011541 reaction mixture Substances 0.000 description 66
• 229940093499 ethyl acetate Drugs 0.000 description 65
• 235000019439 ethyl acetate Nutrition 0.000 description 65
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 59
• 239000002904 solvent Substances 0.000 description 45
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 39
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 36
• 238000003756 stirring Methods 0.000 description 36
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 35
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 34
• 238000003556 assay Methods 0.000 description 31
• 239000007787 solid Substances 0.000 description 30
• 239000000047 product Substances 0.000 description 29
• 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
• IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 27
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 26
• 239000003921 oil Substances 0.000 description 26
• 235000019198 oils Nutrition 0.000 description 26
• 239000012044 organic layer Substances 0.000 description 26
• 239000000010 aprotic solvent Substances 0.000 description 25
• 238000000605 extraction Methods 0.000 description 25
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 21
• 238000002955 isolation Methods 0.000 description 21
• 238000005160 1H NMR spectroscopy Methods 0.000 description 20
• 238000005481 NMR spectroscopy Methods 0.000 description 20
• 108090000190 Thrombin Proteins 0.000 description 20
• 239000012131 assay buffer Substances 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
• 238000004587 chromatography analysis Methods 0.000 description 19
• QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 18
• CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 18
• 238000012360 testing method Methods 0.000 description 18
• 239000012224 working solution Substances 0.000 description 18
• 239000002253 acid Substances 0.000 description 17
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 16
• 239000002585 base Substances 0.000 description 16
• 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 16
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
• RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 15
• 229910052757 nitrogen Inorganic materials 0.000 description 15
• 102000004190 Enzymes Human genes 0.000 description 14
• 108090000790 Enzymes Proteins 0.000 description 14
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 14
• 229940088598 enzyme Drugs 0.000 description 14
• 239000004615 ingredient Substances 0.000 description 14
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 14
• 239000012267 brine Substances 0.000 description 13
• 239000003112 inhibitor Substances 0.000 description 13
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 13
• DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 12
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 12
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 12
• 229910000104 sodium hydride Inorganic materials 0.000 description 12
• 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 12
• 230000000694 effects Effects 0.000 description 11
• 239000003586 protic polar solvent Substances 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
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 10
• 230000015271 coagulation Effects 0.000 description 10
• 238000005345 coagulation Methods 0.000 description 10
• 238000004440 column chromatography Methods 0.000 description 10
• HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 10
• 238000010898 silica gel chromatography Methods 0.000 description 10
• FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 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
• 239000000543 intermediate Substances 0.000 description 9
• 230000002829 reductive effect Effects 0.000 description 9
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 9
• FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 9
• WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 8
• 208000007536 Thrombosis Diseases 0.000 description 8
• 102000003978 Tissue Plasminogen Activator Human genes 0.000 description 8
• 108090000373 Tissue Plasminogen Activator Proteins 0.000 description 8
• 239000000706 filtrate Substances 0.000 description 8
• 150000003254 radicals Chemical class 0.000 description 8
• 229960000187 tissue plasminogen activator Drugs 0.000 description 8
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
• 238000007796 conventional method Methods 0.000 description 7
• 238000001704 evaporation Methods 0.000 description 7
• 230000008020 evaporation Effects 0.000 description 7
• 150000007529 inorganic bases Chemical class 0.000 description 7
• 239000010410 layer Substances 0.000 description 7
• 229910000027 potassium carbonate Inorganic materials 0.000 description 7
• 125000006239 protecting group Chemical group 0.000 description 7
• 229920006395 saturated elastomer Polymers 0.000 description 7
• 229910052938 sodium sulfate Inorganic materials 0.000 description 7
• 235000011152 sodium sulphate Nutrition 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
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
• 229910021529 ammonia Inorganic materials 0.000 description 6
• WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 6
• 229910052799 carbon Inorganic materials 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
• 238000001914 filtration Methods 0.000 description 6
• 238000004128 high performance liquid chromatography Methods 0.000 description 6
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 6
• 239000000463 material Substances 0.000 description 6
• 239000003960 organic solvent Substances 0.000 description 6
• 230000037361 pathway Effects 0.000 description 6
• 235000011181 potassium carbonates Nutrition 0.000 description 6
• 239000002002 slurry Substances 0.000 description 6
• 235000017557 sodium bicarbonate Nutrition 0.000 description 6
• 238000010561 standard procedure Methods 0.000 description 6
• 239000000758 substrate Substances 0.000 description 6
• CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 5
• GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 5
• 108010094028 Prothrombin Proteins 0.000 description 5
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
• 230000002378 acidificating effect Effects 0.000 description 5
• 125000004432 carbon atom Chemical group C* 0.000 description 5
• 235000011089 carbon dioxide Nutrition 0.000 description 5
• BJDCWCLMFKKGEE-CMDXXVQNSA-N chembl252518 Chemical compound C([C@@](OO1)(C)O2)C[C@H]3[C@H](C)CC[C@@H]4[C@@]31[C@@H]2O[C@H](O)[C@@H]4C BJDCWCLMFKKGEE-CMDXXVQNSA-N 0.000 description 5
• 229910052500 inorganic mineral Inorganic materials 0.000 description 5
• 239000008101 lactose Substances 0.000 description 5
• 235000019359 magnesium stearate Nutrition 0.000 description 5
• 235000010755 mineral Nutrition 0.000 description 5
• 239000011707 mineral Substances 0.000 description 5
• 239000000725 suspension Substances 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
• YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 4
• 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 4
• 108010074105 Factor Va Proteins 0.000 description 4
• 108010054964 H-hexahydrotyrosyl-alanyl-arginine-4-nitroanilide Proteins 0.000 description 4
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 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
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