NO316912B1 - Indolderivater som inhibitorer av faktor Xa - Google Patents

Info

Publication number

NO316912B1

NO316912B1 NO20003057A NO20003057A NO316912B1 NO 316912 B1 NO316912 B1 NO 316912B1 NO 20003057 A NO20003057 A NO 20003057A NO 20003057 A NO20003057 A NO 20003057A NO 316912 B1 NO316912 B1 NO 316912B1

Authority

NO

Norway

Prior art keywords

indole

benzyl

formula

residue

carboxylic acid

Prior art date

1997-12-24

Links

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• 108010074860 Factor Xa Proteins 0.000 title claims description 64
• 239000003112 inhibitor Substances 0.000 title claims description 15
• 150000002475 indoles Chemical class 0.000 title description 22
• 229940054051 antipsychotic indole derivative Drugs 0.000 title description 13
• 150000001875 compounds Chemical class 0.000 claims description 375
• 239000000203 mixture Substances 0.000 claims description 146
• 150000003839 salts Chemical class 0.000 claims description 61
• 238000000034 method Methods 0.000 claims description 57
• 239000001257 hydrogen Substances 0.000 claims description 51
• 229910052739 hydrogen Inorganic materials 0.000 claims description 51
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 37
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 36
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 32
• 125000000217 alkyl group Chemical group 0.000 claims description 30
• 229910052757 nitrogen Inorganic materials 0.000 claims description 28
• 238000002360 preparation method Methods 0.000 claims description 23
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 22
• 229910052794 bromium Inorganic materials 0.000 claims description 19
• 239000000825 pharmaceutical preparation Substances 0.000 claims description 18
• 238000004519 manufacturing process Methods 0.000 claims description 17
• 229910052801 chlorine Inorganic materials 0.000 claims description 16
• 229910052731 fluorine Inorganic materials 0.000 claims description 16
• 238000011282 treatment Methods 0.000 claims description 16
• 125000000524 functional group Chemical group 0.000 claims description 15
• 125000001624 naphthyl group Chemical group 0.000 claims description 15
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 14
• 150000002431 hydrogen Chemical class 0.000 claims description 14
• 230000023555 blood coagulation Effects 0.000 claims description 13
• 239000002243 precursor Substances 0.000 claims description 13
• 208000007536 Thrombosis Diseases 0.000 claims description 12
• 229920006395 saturated elastomer Polymers 0.000 claims description 12
• 229910052740 iodine Inorganic materials 0.000 claims description 11
• 238000011321 prophylaxis Methods 0.000 claims description 10
• 125000004076 pyridyl group Chemical group 0.000 claims description 10
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 9
• 239000003937 drug carrier Substances 0.000 claims description 9
• 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 9
• 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 9
• 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 8
• 150000001450 anions Chemical class 0.000 claims description 8
• 238000006467 substitution reaction Methods 0.000 claims description 8
• 125000002843 carboxylic acid group Chemical group 0.000 claims description 7
• 229940126601 medicinal product Drugs 0.000 claims description 7
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
• 230000008569 process Effects 0.000 claims description 5
• 125000000623 heterocyclic group Chemical group 0.000 claims description 4
• 125000000369 oxido group Chemical group [*]=O 0.000 claims description 4
• 125000006728 (C1-C6) alkynyl group Chemical group 0.000 claims description 3
• 208000024172 Cardiovascular disease Diseases 0.000 claims description 3
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 3
• 206010038563 Reocclusion Diseases 0.000 claims description 3
• 239000011737 fluorine Substances 0.000 claims description 3
• 208000010125 myocardial infarction Diseases 0.000 claims description 3
• 208000037803 restenosis Diseases 0.000 claims description 3
• 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 2
• 206010002383 Angina Pectoris Diseases 0.000 claims description 2
• 150000001204 N-oxides Chemical class 0.000 claims description 2
• 125000005047 dihydroimidazolyl group Chemical group N1(CNC=C1)* 0.000 claims description 2
• 125000003386 piperidinyl group Chemical group 0.000 claims description 2
• 125000004356 hydroxy functional group Chemical group O* 0.000 claims 4
• 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims 4
• 230000009424 thromboembolic effect Effects 0.000 claims 1
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 330
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 294
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 219
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 216
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 157
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 141
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 123
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 123
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 114
• 239000000047 product Substances 0.000 description 113
• -1 m-amidino phenyl Chemical class 0.000 description 108
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 108
• 238000001819 mass spectrum Methods 0.000 description 104
• 239000000243 solution Substances 0.000 description 103
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 102
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 95
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 70
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 66
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 66
• 239000002904 solvent Substances 0.000 description 58
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 57
• 239000011347 resin Substances 0.000 description 56
• 229920005989 resin Polymers 0.000 description 56
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 54
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 51
• 239000000741 silica gel Substances 0.000 description 50
• 229910002027 silica gel Inorganic materials 0.000 description 50
• 238000006243 chemical reaction Methods 0.000 description 49
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 46
• 235000011054 acetic acid Nutrition 0.000 description 45
• 239000013078 crystal Substances 0.000 description 44
• 238000003818 flash chromatography Methods 0.000 description 43
• SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 42
• 239000000463 material Substances 0.000 description 42
• 230000000694 effects Effects 0.000 description 39
• CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 38
• INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 38
• USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 36
• 239000005695 Ammonium acetate Substances 0.000 description 36
• 235000019257 ammonium acetate Nutrition 0.000 description 36
• 229940043376 ammonium acetate Drugs 0.000 description 36
• RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 35
• 239000007858 starting material Substances 0.000 description 35
• 239000011541 reaction mixture Substances 0.000 description 33
• 230000014759 maintenance of location Effects 0.000 description 32
• 239000002994 raw material Substances 0.000 description 32
• QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 31
• 230000015572 biosynthetic process Effects 0.000 description 30
• 238000000746 purification Methods 0.000 description 30
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 28
• MKRTXPORKIRPDG-UHFFFAOYSA-N diphenylphosphoryl azide Chemical compound C=1C=CC=CC=1P(=O)(N=[N+]=[N-])C1=CC=CC=C1 MKRTXPORKIRPDG-UHFFFAOYSA-N 0.000 description 27
• IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 26
• 229910000041 hydrogen chloride Inorganic materials 0.000 description 26
• 238000003786 synthesis reaction Methods 0.000 description 25
• 239000002253 acid Substances 0.000 description 24
• 239000007787 solid Substances 0.000 description 24
• 125000001424 substituent group Chemical group 0.000 description 24
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 23
• PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 22
• RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 22
• 230000002401 inhibitory effect Effects 0.000 description 22
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 22
• CVKOOKPNCVYHNY-UHFFFAOYSA-N 3-(bromomethyl)benzonitrile Chemical compound BrCC1=CC=CC(C#N)=C1 CVKOOKPNCVYHNY-UHFFFAOYSA-N 0.000 description 21
• 125000003118 aryl group Chemical group 0.000 description 21
• 230000015271 coagulation Effects 0.000 description 21
• 238000005345 coagulation Methods 0.000 description 21
• 239000012044 organic layer Substances 0.000 description 21
• GETOHMIIRHERDB-UHFFFAOYSA-N 1-[(3-cyanophenyl)methyl]indole-2-carboxylic acid Chemical compound OC(=O)C1=CC2=CC=CC=C2N1CC1=CC=CC(C#N)=C1 GETOHMIIRHERDB-UHFFFAOYSA-N 0.000 description 20
• 239000003814 drug Substances 0.000 description 20
• 229910000037 hydrogen sulfide Inorganic materials 0.000 description 20
• 238000003556 assay Methods 0.000 description 19
• 239000003153 chemical reaction reagent Substances 0.000 description 19
• 108010000499 Thromboplastin Proteins 0.000 description 18
• 102000002262 Thromboplastin Human genes 0.000 description 18
• 238000002425 crystallisation Methods 0.000 description 18
• 230000008025 crystallization Effects 0.000 description 18
• 230000005764 inhibitory process Effects 0.000 description 18
• 229910000029 sodium carbonate Inorganic materials 0.000 description 18
• 108090000190 Thrombin Proteins 0.000 description 17
• 229960004072 thrombin Drugs 0.000 description 17
• 102000004190 Enzymes Human genes 0.000 description 16
• 108090000790 Enzymes Proteins 0.000 description 16
• 239000003795 chemical substances by application Substances 0.000 description 16
• 229940088598 enzyme Drugs 0.000 description 16
• 238000003756 stirring Methods 0.000 description 16
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 15
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 15
• 239000000758 substrate Substances 0.000 description 15
• 150000001412 amines Chemical class 0.000 description 14
• 125000004432 carbon atom Chemical group C* 0.000 description 14
• 125000004093 cyano group Chemical group *C#N 0.000 description 14
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 14
• 238000004366 reverse phase liquid chromatography Methods 0.000 description 14
• FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 14
• PDJZOFLRRJQYBF-UHFFFAOYSA-N 4-(aminomethyl)-n,n-dimethylaniline Chemical compound CN(C)C1=CC=C(CN)C=C1 PDJZOFLRRJQYBF-UHFFFAOYSA-N 0.000 description 13
• HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 13
• 239000000460 chlorine Substances 0.000 description 13
• 201000010099 disease Diseases 0.000 description 13
• 239000002244 precipitate Substances 0.000 description 13
• 238000010992 reflux Methods 0.000 description 13
• WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 13
• 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 12
• 229940079593 drug Drugs 0.000 description 12
• 239000005457 ice water Substances 0.000 description 12
• 239000012074 organic phase Substances 0.000 description 12
• KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 11
• QQXQAEWRSVZPJM-UHFFFAOYSA-N ethyl 1h-indole-2-carboxylate Chemical compound C1=CC=C2NC(C(=O)OCC)=CC2=C1 QQXQAEWRSVZPJM-UHFFFAOYSA-N 0.000 description 11
• 238000004108 freeze drying Methods 0.000 description 11
• 229960002897 heparin Drugs 0.000 description 11
• 229920000669 heparin Polymers 0.000 description 11
• 125000002887 hydroxy group Chemical group [H]O* 0.000 description 11
• 238000002953 preparative HPLC Methods 0.000 description 11
• 239000012312 sodium hydride Substances 0.000 description 11
• 229910000104 sodium hydride Inorganic materials 0.000 description 11
• LRXFKKPEBXIPMW-UHFFFAOYSA-N 2-(9h-fluoren-2-yl)propanoic acid Chemical compound C1=CC=C2C3=CC=C(C(C(O)=O)C)C=C3CC2=C1 LRXFKKPEBXIPMW-UHFFFAOYSA-N 0.000 description 10
• BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 10
• IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 10
• 241000700159 Rattus Species 0.000 description 10
• 210000004369 blood Anatomy 0.000 description 10
• 239000008280 blood Substances 0.000 description 10
• 150000001732 carboxylic acid derivatives Chemical class 0.000 description 10
• 238000004587 chromatography analysis Methods 0.000 description 10
• 239000000543 intermediate Substances 0.000 description 10
• 229920001223 polyethylene glycol Polymers 0.000 description 10
• 150000003254 radicals Chemical class 0.000 description 10
• CMBGGZQNJYMKRZ-UHFFFAOYSA-N 1-[(3-cyanophenyl)methyl]-5-fluoroindole-2-carboxylic acid Chemical compound OC(=O)C1=CC2=CC(F)=CC=C2N1CC1=CC=CC(C#N)=C1 CMBGGZQNJYMKRZ-UHFFFAOYSA-N 0.000 description 9
• 108010094028 Prothrombin Proteins 0.000 description 9
• 102100027378 Prothrombin Human genes 0.000 description 9
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 9
• 238000005804 alkylation reaction Methods 0.000 description 9
• 239000003146 anticoagulant agent Substances 0.000 description 9
• 229940127219 anticoagulant drug Drugs 0.000 description 9
• 150000002148 esters Chemical class 0.000 description 9
• 125000001041 indolyl group Chemical group 0.000 description 9
• 229940039716 prothrombin Drugs 0.000 description 9
• LEEZUCJXPOWXPB-UHFFFAOYSA-N 1-[(3-cyanophenyl)methyl]-4-methoxyindole-2-carboxylic acid Chemical compound OC(=O)C1=CC=2C(OC)=CC=CC=2N1CC1=CC=CC(C#N)=C1 LEEZUCJXPOWXPB-UHFFFAOYSA-N 0.000 description 8
• 208000032843 Hemorrhage Diseases 0.000 description 8
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
• 150000007513 acids Chemical class 0.000 description 8
• 230000029936 alkylation Effects 0.000 description 8
• 208000034158 bleeding Diseases 0.000 description 8
• 230000000740 bleeding effect Effects 0.000 description 8
• 239000000969 carrier Substances 0.000 description 8
• 239000012043 crude product Substances 0.000 description 8
• 125000004185 ester group Chemical group 0.000 description 8
• 238000002474 experimental method Methods 0.000 description 8
• 230000009467 reduction Effects 0.000 description 8
• 238000006722 reduction reaction Methods 0.000 description 8
• 238000012360 testing method Methods 0.000 description 8
• BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 7
• VWGUDGOGNMZVSS-UHFFFAOYSA-N 1-[(3-cyanophenyl)methyl]-4-methylindole-2-carboxylic acid Chemical compound OC(=O)C1=CC=2C(C)=CC=CC=2N1CC1=CC=CC(C#N)=C1 VWGUDGOGNMZVSS-UHFFFAOYSA-N 0.000 description 7
• 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 7
• 101710163968 Antistasin Proteins 0.000 description 7
• 229940123583 Factor Xa inhibitor Drugs 0.000 description 7
• 241000283973 Oryctolagus cuniculus Species 0.000 description 7
• 150000001409 amidines Chemical class 0.000 description 7
• 238000003776 cleavage reaction Methods 0.000 description 7
• 238000010828 elution Methods 0.000 description 7
• 238000001704 evaporation Methods 0.000 description 7
• 230000008020 evaporation Effects 0.000 description 7
• 238000000338 in vitro Methods 0.000 description 7
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 7
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