IL124537A

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

History of benzimidazole converted to naphthalene and pharmaceutical preparations containing them

Info

Publication number: IL124537A
Authority: IL; Israel
Prior art keywords: optionally substituted; methyl; halo; alkyl; hydroxy
Prior art date: 1995-12-08

Application number

IL12453796A

Other languages

English (en)

Hebrew (he)

Other versions

IL124537A0 (en

Original Assignee

Berlex Lab

Priority date

1995-12-08

Filing date

1996-12-05

Publication date

2002-04-21

1996-12-05 Application filed by Berlex Lab filed Critical Berlex Lab

1998-12-06 Publication of IL124537A0 publication Critical patent/IL124537A0/xx

2002-04-21 Publication of IL124537A publication Critical patent/IL124537A/en

Links

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
102100027378 Prothrombin Human genes 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
230000015572 biosynthetic process Effects 0.000 description 4
230000037396 body weight Effects 0.000 description 4
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