CA2319494A1 - Heterocycles benzo condenses a 5 chainons utilises comme agents antithrombotiques - Google Patents
Heterocycles benzo condenses a 5 chainons utilises comme agents antithrombotiques Download PDFInfo
- Publication number
- CA2319494A1 CA2319494A1 CA002319494A CA2319494A CA2319494A1 CA 2319494 A1 CA2319494 A1 CA 2319494A1 CA 002319494 A CA002319494 A CA 002319494A CA 2319494 A CA2319494 A CA 2319494A CA 2319494 A1 CA2319494 A1 CA 2319494A1
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- CA
- Canada
- Prior art keywords
- group
- alkyl
- methyl
- substituted
- denotes
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
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- 125000002373 5 membered heterocyclic group Chemical group 0.000 title claims description 11
- 238000002360 preparation method Methods 0.000 title description 6
- 239000003814 drug Substances 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 131
- 239000000203 mixture Substances 0.000 claims abstract description 43
- 150000003839 salts Chemical class 0.000 claims abstract description 37
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 claims abstract description 33
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 28
- 150000007522 mineralic acids Chemical class 0.000 claims abstract description 4
- 150000007524 organic acids Chemical class 0.000 claims abstract description 4
- 238000004519 manufacturing process Methods 0.000 claims abstract 3
- -1 sulphinyl Chemical group 0.000 claims description 287
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 136
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 80
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 78
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 69
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 60
- 229910052757 nitrogen Inorganic materials 0.000 claims description 40
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 38
- 239000002253 acid Substances 0.000 claims description 36
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 34
- 125000006698 (C1-C3) dialkylamino group Chemical group 0.000 claims description 33
- 125000000217 alkyl group Chemical group 0.000 claims description 32
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 31
- 239000001257 hydrogen Substances 0.000 claims description 28
- 229910052739 hydrogen Inorganic materials 0.000 claims description 28
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 27
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 26
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 24
- 239000011541 reaction mixture Substances 0.000 claims description 23
- 238000006243 chemical reaction Methods 0.000 claims description 22
- 125000002112 pyrrolidino group Chemical group [*]N1C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 22
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 20
- 125000004432 carbon atom Chemical group C* 0.000 claims description 20
- 125000005493 quinolyl group Chemical group 0.000 claims description 20
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 19
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 18
- 125000005956 isoquinolyl group Chemical group 0.000 claims description 18
- 125000001624 naphthyl group Chemical group 0.000 claims description 18
- 125000004076 pyridyl group Chemical group 0.000 claims description 18
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 16
- 125000005328 phosphinyl group Chemical group [PH2](=O)* 0.000 claims description 16
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 15
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 14
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 14
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims description 14
- 239000001301 oxygen Substances 0.000 claims description 14
- 229910052760 oxygen Inorganic materials 0.000 claims description 14
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 14
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 13
- 125000002883 imidazolyl group Chemical group 0.000 claims description 12
- 125000001841 imino group Chemical group [H]N=* 0.000 claims description 12
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims description 11
- 239000000460 chlorine Substances 0.000 claims description 11
- 229910052801 chlorine Inorganic materials 0.000 claims description 11
- 125000006576 di-(C1-C3-alkyl)-aminocarbonyl group Chemical group 0.000 claims description 11
- 230000007062 hydrolysis Effects 0.000 claims description 11
- 238000006460 hydrolysis reaction Methods 0.000 claims description 11
- 150000002148 esters Chemical class 0.000 claims description 10
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 10
- 125000006518 morpholino carbonyl group Chemical group [H]C1([H])OC([H])([H])C([H])([H])N(C(*)=O)C1([H])[H] 0.000 claims description 10
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 10
- 125000006559 (C1-C3) alkylamino group Chemical group 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 9
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 8
- 150000001412 amines Chemical class 0.000 claims description 8
- 125000003277 amino group Chemical group 0.000 claims description 8
- 229910052794 bromium Inorganic materials 0.000 claims description 8
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 8
- 239000011737 fluorine Substances 0.000 claims description 8
- 229910052731 fluorine Inorganic materials 0.000 claims description 8
- 239000000126 substance Substances 0.000 claims description 8
- 125000001424 substituent group Chemical group 0.000 claims description 8
- 125000006563 (C1-3) alkylaminocarbonyl group Chemical group 0.000 claims description 7
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 7
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 7
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 238000001727 in vivo Methods 0.000 claims description 7
- 229910052740 iodine Inorganic materials 0.000 claims description 7
- 125000006239 protecting group Chemical group 0.000 claims description 7
- 238000001149 thermolysis Methods 0.000 claims description 7
- 125000002252 acyl group Chemical group 0.000 claims description 6
- 125000003282 alkyl amino group Chemical group 0.000 claims description 6
- 125000002619 bicyclic group Chemical group 0.000 claims description 6
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 6
- 125000006639 cyclohexyl carbonyl group Chemical group 0.000 claims description 6
- 230000000694 effects Effects 0.000 claims description 6
- 238000007327 hydrogenolysis reaction Methods 0.000 claims description 6
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 6
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 5
- 125000005843 halogen group Chemical group 0.000 claims description 5
- 230000002401 inhibitory effect Effects 0.000 claims description 5
- 125000004173 1-benzimidazolyl group Chemical group [H]C1=NC2=C([H])C([H])=C([H])C([H])=C2N1* 0.000 claims description 4
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 4
- 150000001721 carbon Chemical group 0.000 claims description 4
- 125000004458 methylaminocarbonyl group Chemical group [H]N(C(*)=O)C([H])([H])[H] 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 229910052727 yttrium Inorganic materials 0.000 claims description 4
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 3
- 125000006555 (C3-C5) cycloalkyl group Chemical group 0.000 claims description 3
- HCZOYKGCPREUFP-UHFFFAOYSA-N 4-[[5-[benzenesulfonyl-[2-(dimethylamino)ethyl]amino]-1-benzylbenzimidazol-2-yl]methyl]benzenecarboximidamide Chemical compound C=1C=CC=CC=1S(=O)(=O)N(CCN(C)C)C(C=C1N=C2CC=3C=CC(=CC=3)C(N)=N)=CC=C1N2CC1=CC=CC=C1 HCZOYKGCPREUFP-UHFFFAOYSA-N 0.000 claims description 3
- 108090000190 Thrombin Proteins 0.000 claims description 3
- 125000005619 boric acid group Chemical group 0.000 claims description 3
- 239000000969 carrier Substances 0.000 claims description 3
- 238000006114 decarboxylation reaction Methods 0.000 claims description 3
- 238000005695 dehalogenation reaction Methods 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 3
- 230000032050 esterification Effects 0.000 claims description 3
- 238000005886 esterification reaction Methods 0.000 claims description 3
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 3
- 150000002825 nitriles Chemical class 0.000 claims description 3
- 229960004072 thrombin Drugs 0.000 claims description 3
- 125000001140 1,4-phenylene group Chemical group [H]C1=C([H])C([*:2])=C([H])C([H])=C1[*:1] 0.000 claims description 2
- XGRGRMFILCCAMJ-UHFFFAOYSA-N 2-[[2-[[2-[(4-carbamimidoylphenyl)methyl]-1-methylbenzimidazol-5-yl]-quinolin-8-ylsulfonylamino]-2-oxoethyl]amino]acetic acid Chemical compound N=1C2=CC(N(C(=O)CNCC(O)=O)S(=O)(=O)C=3C4=NC=CC=C4C=CC=3)=CC=C2N(C)C=1CC1=CC=C(C(N)=N)C=C1 XGRGRMFILCCAMJ-UHFFFAOYSA-N 0.000 claims description 2
- UBGVJTGBDCGIFL-UHFFFAOYSA-N 2-[[5-[benzenesulfonyl-[2-(diethylamino)ethyl]amino]-2-[(4-carbamimidoylphenyl)methyl]-4-methylbenzimidazole-1-carbonyl]amino]acetic acid Chemical compound C=1C=CC=CC=1S(=O)(=O)N(CCN(CC)CC)C(C(=C1N=2)C)=CC=C1N(C(=O)NCC(O)=O)C=2CC1=CC=C(C(N)=N)C=C1 UBGVJTGBDCGIFL-UHFFFAOYSA-N 0.000 claims description 2
- DVXBYTXVYTUSLX-UHFFFAOYSA-N 4-[(1-methyl-5-pyrrolidin-1-ylsulfonylbenzimidazol-2-yl)methyl]benzenecarboximidamide Chemical compound N=1C2=CC(S(=O)(=O)N3CCCC3)=CC=C2N(C)C=1CC1=CC=C(C(N)=N)C=C1 DVXBYTXVYTUSLX-UHFFFAOYSA-N 0.000 claims description 2
- VTDOZSUVQUKQHR-UHFFFAOYSA-N 4-[[2-[(4-carbamimidoylphenyl)methyl]-1-methylbenzimidazol-5-yl]-cyclopentylamino]-4-oxobutanoic acid Chemical compound N=1C2=CC(N(C3CCCC3)C(=O)CCC(O)=O)=CC=C2N(C)C=1CC1=CC=C(C(N)=N)C=C1 VTDOZSUVQUKQHR-UHFFFAOYSA-N 0.000 claims description 2
- QEERHKYTEJZHPM-UHFFFAOYSA-N 4-[[5-[cyclopentyl(methylsulfonyl)amino]-1-methylbenzimidazol-2-yl]methyl]benzenecarboximidamide Chemical compound N=1C2=CC(N(C3CCCC3)S(C)(=O)=O)=CC=C2N(C)C=1CC1=CC=C(C(N)=N)C=C1 QEERHKYTEJZHPM-UHFFFAOYSA-N 0.000 claims description 2
- 108010022999 Serine Proteases Proteins 0.000 claims description 2
- 102000012479 Serine Proteases Human genes 0.000 claims description 2
- 125000004414 alkyl thio group Chemical group 0.000 claims description 2
- 125000005530 alkylenedioxy group Chemical group 0.000 claims description 2
- 125000004659 aryl alkyl thio group Chemical group 0.000 claims description 2
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 2
- 229910002091 carbon monoxide Inorganic materials 0.000 claims description 2
- 125000004122 cyclic group Chemical group 0.000 claims description 2
- 150000002576 ketones Chemical class 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 2
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 2
- 125000004957 naphthylene group Chemical group 0.000 claims description 2
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 claims description 2
- 125000005550 pyrazinylene group Chemical group 0.000 claims description 2
- 125000005551 pyridylene group Chemical group 0.000 claims description 2
- 125000005576 pyrimidinylene group Chemical group 0.000 claims description 2
- 125000005557 thiazolylene group Chemical group 0.000 claims description 2
- 125000005556 thienylene group Chemical group 0.000 claims description 2
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 2
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 claims 23
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims 10
- 125000006705 (C5-C7) cycloalkyl group Chemical group 0.000 claims 6
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 1
- SAMMRXPDTIIEMS-UHFFFAOYSA-N 2-[[2-[(4-carbamimidoylphenyl)methyl]-1-methylbenzimidazol-5-yl]-quinolin-8-ylsulfonylamino]acetic acid Chemical compound N=1C2=CC(N(CC(O)=O)S(=O)(=O)C=3C4=NC=CC=C4C=CC=3)=CC=C2N(C)C=1CC1=CC=C(C(N)=N)C=C1 SAMMRXPDTIIEMS-UHFFFAOYSA-N 0.000 claims 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims 1
- 125000006501 nitrophenyl group Chemical group 0.000 claims 1
- 230000001681 protective effect Effects 0.000 claims 1
- 230000002785 anti-thrombosis Effects 0.000 abstract description 4
- 230000000144 pharmacologic effect Effects 0.000 abstract description 4
- 235000005985 organic acids Nutrition 0.000 abstract description 3
- 125000000623 heterocyclic group Chemical group 0.000 abstract description 2
- 239000013067 intermediate product Substances 0.000 abstract description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 818
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 463
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 317
- 235000019441 ethanol Nutrition 0.000 description 276
- 229960004756 ethanol Drugs 0.000 description 271
- 238000001819 mass spectrum Methods 0.000 description 228
- 235000011167 hydrochloric acid Nutrition 0.000 description 182
- 229960000443 hydrochloric acid Drugs 0.000 description 182
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 162
- 239000001099 ammonium carbonate Substances 0.000 description 157
- 229940059913 ammonium carbonate Drugs 0.000 description 157
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 148
- 235000012501 ammonium carbonate Nutrition 0.000 description 148
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 147
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 147
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Substances N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 122
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 114
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 108
- 229940073584 methylene chloride Drugs 0.000 description 106
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 99
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 99
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 95
- 239000000741 silica gel Substances 0.000 description 95
- 229910002027 silica gel Inorganic materials 0.000 description 95
- 235000013350 formula milk Nutrition 0.000 description 83
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 78
- 239000002904 solvent Substances 0.000 description 65
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 58
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 57
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 52
- 239000000243 solution Substances 0.000 description 50
- 235000019439 ethyl acetate Nutrition 0.000 description 49
- 229940093499 ethyl acetate Drugs 0.000 description 49
- 235000011121 sodium hydroxide Nutrition 0.000 description 49
- 229940083608 sodium hydroxide Drugs 0.000 description 49
- 238000001704 evaporation Methods 0.000 description 41
- 230000008020 evaporation Effects 0.000 description 41
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 39
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 36
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 34
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 33
- 238000007792 addition Methods 0.000 description 30
- 229960000583 acetic acid Drugs 0.000 description 29
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 29
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 28
- 230000000875 corresponding effect Effects 0.000 description 25
- 239000012362 glacial acetic acid Substances 0.000 description 25
- 235000002639 sodium chloride Nutrition 0.000 description 25
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 24
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 22
- 239000011734 sodium Substances 0.000 description 21
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 20
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 20
- 239000002585 base Substances 0.000 description 20
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 19
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 18
- 239000000284 extract Substances 0.000 description 17
- 239000003208 petroleum Substances 0.000 description 17
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- 229910052763 palladium Inorganic materials 0.000 description 15
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 14
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 14
- 229940023032 activated charcoal Drugs 0.000 description 14
- 229910000027 potassium carbonate Inorganic materials 0.000 description 14
- 229940093956 potassium carbonate Drugs 0.000 description 14
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 14
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 13
- 235000011181 potassium carbonates Nutrition 0.000 description 13
- WEBXRQONNWEETE-UHFFFAOYSA-N 2-(4-cyanophenyl)acetic acid Chemical compound OC(=O)CC1=CC=C(C#N)C=C1 WEBXRQONNWEETE-UHFFFAOYSA-N 0.000 description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 12
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 12
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 12
- 229940076134 benzene Drugs 0.000 description 12
- 239000005457 ice water Substances 0.000 description 11
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
- 229960000510 ammonia Drugs 0.000 description 10
- 229910021529 ammonia Inorganic materials 0.000 description 10
- 229960001760 dimethyl sulfoxide Drugs 0.000 description 10
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 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
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 9
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 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 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
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- SRUPWCSFAHAVQW-UHFFFAOYSA-N ethyl 2-[[2-[(4-carbamimidoylphenyl)methyl]-1-methylbenzimidazol-5-yl]-quinolin-8-ylsulfonylamino]acetate;hydrochloride Chemical compound Cl.C=1C=CC2=CC=CN=C2C=1S(=O)(=O)N(CC(=O)OCC)C(C=C1N=2)=CC=C1N(C)C=2CC1=CC=C(C(N)=N)C=C1 SRUPWCSFAHAVQW-UHFFFAOYSA-N 0.000 description 1
- DIQIXBORCXEQCJ-UHFFFAOYSA-N ethyl 2-[[2-[5-(benzenesulfonamido)-2-[(4-cyanophenyl)methyl]benzimidazol-1-yl]acetyl]amino]acetate Chemical compound N=1C2=CC(NS(=O)(=O)C=3C=CC=CC=3)=CC=C2N(CC(=O)NCC(=O)OCC)C=1CC1=CC=C(C#N)C=C1 DIQIXBORCXEQCJ-UHFFFAOYSA-N 0.000 description 1
- QQAXXGLODZWWDL-UHFFFAOYSA-N ethyl 2-[[2-[5-[benzenesulfonyl-[2-(diethylamino)ethyl]amino]-2-[(4-carbamimidoylphenyl)methyl]benzimidazol-1-yl]acetyl]amino]acetate;dihydrochloride Chemical compound Cl.Cl.N=1C2=CC(N(CCN(CC)CC)S(=O)(=O)C=3C=CC=CC=3)=CC=C2N(CC(=O)NCC(=O)OCC)C=1CC1=CC=C(C(N)=N)C=C1 QQAXXGLODZWWDL-UHFFFAOYSA-N 0.000 description 1
- CUTHSSIEDWTVCZ-UHFFFAOYSA-N ethyl 2-[[2-[[2-[[4-(n'-cyclohexyloxycarbonylcarbamimidoyl)phenyl]methyl]-1-methylbenzimidazol-5-yl]-quinolin-8-ylsulfonylamino]acetyl]amino]acetate Chemical compound C=1C=CC2=CC=CN=C2C=1S(=O)(=O)N(CC(=O)NCC(=O)OCC)C(C=C1N=2)=CC=C1N(C)C=2CC(C=C1)=CC=C1C(N)=NC(=O)OC1CCCCC1 CUTHSSIEDWTVCZ-UHFFFAOYSA-N 0.000 description 1
- VRIHKHXKUAMVTF-UHFFFAOYSA-N ethyl 2-[[2-[[4-(n'-ethoxycarbonylcarbamimidoyl)phenyl]methyl]-1-methylbenzimidazol-5-yl]-quinolin-8-ylsulfonylamino]acetate Chemical compound C=1C=CC2=CC=CN=C2C=1S(=O)(=O)N(CC(=O)OCC)C(C=C1N=2)=CC=C1N(C)C=2CC1=CC=C(C(N)=NC(=O)OCC)C=C1 VRIHKHXKUAMVTF-UHFFFAOYSA-N 0.000 description 1
- HIGUMNPHXLSBIU-UHFFFAOYSA-N ethyl 2-[[2-[[4-(n'-ethoxycarbonylcarbamimidoyl)phenyl]methyl]-1-methylbenzimidazol-5-yl]-quinolin-8-ylsulfonylamino]acetate;hydrochloride Chemical compound Cl.C=1C=CC2=CC=CN=C2C=1S(=O)(=O)N(CC(=O)OCC)C(C=C1N=2)=CC=C1N(C)C=2CC1=CC=C(C(N)=NC(=O)OCC)C=C1 HIGUMNPHXLSBIU-UHFFFAOYSA-N 0.000 description 1
- PIZGGCRACXGWEE-UHFFFAOYSA-N ethyl 2-[benzenesulfonyl-[1-benzyl-2-[(4-carbamimidoylphenyl)methyl]benzimidazol-5-yl]amino]acetate;hydrochloride Chemical compound Cl.C=1C=CC=CC=1S(=O)(=O)N(CC(=O)OCC)C(C=C1N=C2CC=3C=CC(=CC=3)C(N)=N)=CC=C1N2CC1=CC=CC=C1 PIZGGCRACXGWEE-UHFFFAOYSA-N 0.000 description 1
- CUSBCXHGWHTKSM-UHFFFAOYSA-N ethyl 2-[benzenesulfonyl-[1-benzyl-2-[(4-cyanophenyl)methyl]benzimidazol-5-yl]amino]acetate Chemical compound C=1C=CC=CC=1S(=O)(=O)N(CC(=O)OCC)C(C=C1N=C2CC=3C=CC(=CC=3)C#N)=CC=C1N2CC1=CC=CC=C1 CUSBCXHGWHTKSM-UHFFFAOYSA-N 0.000 description 1
- IQNRTWXVNKBCDJ-UHFFFAOYSA-N ethyl 2-[benzenesulfonyl-[2-[(4-carbamimidoylphenyl)methyl]-1-propylbenzimidazol-5-yl]amino]acetate;hydrochloride Chemical compound Cl.N=1C2=CC(N(CC(=O)OCC)S(=O)(=O)C=3C=CC=CC=3)=CC=C2N(CCC)C=1CC1=CC=C(C(N)=N)C=C1 IQNRTWXVNKBCDJ-UHFFFAOYSA-N 0.000 description 1
- HMYGSGNWWUHSRG-UHFFFAOYSA-N ethyl 2-[benzoyl-[2-[(4-carbamimidoylphenyl)methyl]-1-methylbenzimidazol-5-yl]amino]acetate;hydrochloride Chemical compound Cl.C=1C=C2N(C)C(CC=3C=CC(=CC=3)C(N)=N)=NC2=CC=1N(CC(=O)OCC)C(=O)C1=CC=CC=C1 HMYGSGNWWUHSRG-UHFFFAOYSA-N 0.000 description 1
- NQGOUWYVKRAJRR-UHFFFAOYSA-N ethyl 3-(4-carbamimidoylphenyl)-3-(1-methyl-5-pyrrolidin-1-ylsulfonylbenzimidazol-2-yl)propanoate;hydrochloride Chemical compound Cl.C=1C=C(C(N)=N)C=CC=1C(CC(=O)OCC)C(N(C1=CC=2)C)=NC1=CC=2S(=O)(=O)N1CCCC1 NQGOUWYVKRAJRR-UHFFFAOYSA-N 0.000 description 1
- VZHCXYIBQUEWOD-UHFFFAOYSA-N ethyl 3-[2-[(4-carbamimidoylphenyl)methyl]-5-[2-(dimethylamino)ethyl-methylsulfonylamino]benzimidazol-1-yl]propanoate;dihydrochloride Chemical compound Cl.Cl.N=1C2=CC(N(CCN(C)C)S(C)(=O)=O)=CC=C2N(CCC(=O)OCC)C=1CC1=CC=C(C(N)=N)C=C1 VZHCXYIBQUEWOD-UHFFFAOYSA-N 0.000 description 1
- AKEGHZAMSARFRG-UHFFFAOYSA-N ethyl 3-[2-[(4-carbamimidoylphenyl)methyl]-5-[4-(dimethylamino)piperidin-1-yl]benzimidazol-1-yl]propanoate;dihydrochloride Chemical compound Cl.Cl.N=1C2=CC(N3CCC(CC3)N(C)C)=CC=C2N(CCC(=O)OCC)C=1CC1=CC=C(C(N)=N)C=C1 AKEGHZAMSARFRG-UHFFFAOYSA-N 0.000 description 1
- WHIWTFPBBOELOA-UHFFFAOYSA-N ethyl 3-[2-[(4-cyanophenyl)methyl]-5-[4-(dimethylamino)piperidin-1-yl]benzimidazol-1-yl]propanoate Chemical compound N=1C2=CC(N3CCC(CC3)N(C)C)=CC=C2N(CCC(=O)OCC)C=1CC1=CC=C(C#N)C=C1 WHIWTFPBBOELOA-UHFFFAOYSA-N 0.000 description 1
- ATRCTJHEDUGZKZ-UHFFFAOYSA-N ethyl 3-[5-(benzenesulfonamido)-2-[(4-carbamimidoylphenyl)methyl]benzimidazol-1-yl]propanoate;hydrochloride Chemical compound Cl.N=1C2=CC(NS(=O)(=O)C=3C=CC=CC=3)=CC=C2N(CCC(=O)OCC)C=1CC1=CC=C(C(N)=N)C=C1 ATRCTJHEDUGZKZ-UHFFFAOYSA-N 0.000 description 1
- PGMPWSVHLYWNFR-UHFFFAOYSA-N ethyl 3-[5-[benzenesulfonyl-[3-(dimethylamino)propyl]amino]-2-[(4-carbamimidoylphenyl)methyl]benzimidazol-1-yl]propanoate;dihydrochloride Chemical compound Cl.Cl.N=1C2=CC(N(CCCN(C)C)S(=O)(=O)C=3C=CC=CC=3)=CC=C2N(CCC(=O)OCC)C=1CC1=CC=C(C(N)=N)C=C1 PGMPWSVHLYWNFR-UHFFFAOYSA-N 0.000 description 1
- KOQLKDNDOICVHO-UHFFFAOYSA-N ethyl 3-[[2-[(4-cyanophenyl)methyl]-1-methylbenzimidazol-5-yl]-cyclopentylsulfamoyl]propanoate Chemical compound C=1C=C2N(C)C(CC=3C=CC(=CC=3)C#N)=NC2=CC=1N(S(=O)(=O)CCC(=O)OCC)C1CCCC1 KOQLKDNDOICVHO-UHFFFAOYSA-N 0.000 description 1
- APFUFEIDVQFZJJ-UHFFFAOYSA-N ethyl 4-(n-[2-[(4-carbamimidoylphenyl)methyl]-1-methylbenzimidazole-5-carbonyl]anilino)butanoate;hydrochloride Chemical compound Cl.C=1C=CC=CC=1N(CCCC(=O)OCC)C(=O)C(C=C1N=2)=CC=C1N(C)C=2CC1=CC=C(C(N)=N)C=C1 APFUFEIDVQFZJJ-UHFFFAOYSA-N 0.000 description 1
- UECWJJFMUGZWTL-UHFFFAOYSA-N ethyl 4-(n-[2-[(4-cyanophenyl)methyl]-1-methylbenzimidazole-5-carbonyl]anilino)butanoate Chemical compound C=1C=CC=CC=1N(CCCC(=O)OCC)C(=O)C(C=C1N=2)=CC=C1N(C)C=2CC1=CC=C(C#N)C=C1 UECWJJFMUGZWTL-UHFFFAOYSA-N 0.000 description 1
- HJDUPQHNDHJOTF-UHFFFAOYSA-N ethyl 4-[2-[(4-carbamimidoylphenyl)methyl]-5-(cyclohexylmethylcarbamoyl)benzimidazol-1-yl]butanoate;hydrochloride Chemical compound Cl.N=1C2=CC(C(=O)NCC3CCCCC3)=CC=C2N(CCCC(=O)OCC)C=1CC1=CC=C(C(N)=N)C=C1 HJDUPQHNDHJOTF-UHFFFAOYSA-N 0.000 description 1
- SODFGICPQLJKND-UHFFFAOYSA-N ethyl 4-[2-[(4-carbamimidoylphenyl)methyl]-5-[2-(dimethylamino)ethyl-ethylsulfamoyl]benzimidazol-1-yl]butanoate;dihydrochloride Chemical compound Cl.Cl.N=1C2=CC(S(=O)(=O)N(CC)CCN(C)C)=CC=C2N(CCCC(=O)OCC)C=1CC1=CC=C(C(N)=N)C=C1 SODFGICPQLJKND-UHFFFAOYSA-N 0.000 description 1
- JAAASSWNEWBYOV-UHFFFAOYSA-N ethyl 4-[2-[(4-carbamimidoylphenyl)methyl]-5-[2-(dimethylamino)ethyl-methylsulfonylamino]benzimidazol-1-yl]butanoate;dihydrochloride Chemical compound Cl.Cl.N=1C2=CC(N(CCN(C)C)S(C)(=O)=O)=CC=C2N(CCCC(=O)OCC)C=1CC1=CC=C(C(N)=N)C=C1 JAAASSWNEWBYOV-UHFFFAOYSA-N 0.000 description 1
- AQARKQVNKQSJBJ-UHFFFAOYSA-N ethyl 4-[2-[(4-carbamimidoylphenyl)methyl]-5-[2-(dimethylamino)ethylsulfamoyl]benzimidazol-1-yl]butanoate;dihydrochloride Chemical compound Cl.Cl.N=1C2=CC(S(=O)(=O)NCCN(C)C)=CC=C2N(CCCC(=O)OCC)C=1CC1=CC=C(C(N)=N)C=C1 AQARKQVNKQSJBJ-UHFFFAOYSA-N 0.000 description 1
- NVHYLBMJWYRHIB-UHFFFAOYSA-N ethyl 4-[5-[benzenesulfonyl(3-piperidin-1-ylpropyl)amino]-2-[(4-cyanophenyl)methyl]benzimidazol-1-yl]butanoate Chemical compound N=1C2=CC(N(CCCN3CCCCC3)S(=O)(=O)C=3C=CC=CC=3)=CC=C2N(CCCC(=O)OCC)C=1CC1=CC=C(C#N)C=C1 NVHYLBMJWYRHIB-UHFFFAOYSA-N 0.000 description 1
- GYEZVATZWLFNGF-UHFFFAOYSA-N ethyl 4-[5-[benzenesulfonyl-[2-(dimethylamino)ethyl]amino]-2-[(4-carbamimidoylphenyl)methyl]benzimidazol-1-yl]butanoate;dihydrochloride Chemical compound Cl.Cl.N=1C2=CC(N(CCN(C)C)S(=O)(=O)C=3C=CC=CC=3)=CC=C2N(CCCC(=O)OCC)C=1CC1=CC=C(C(N)=N)C=C1 GYEZVATZWLFNGF-UHFFFAOYSA-N 0.000 description 1
- OBTYYWGRDDHFBG-UHFFFAOYSA-N ethyl 4-[5-[benzenesulfonyl-[3-(dimethylamino)propyl]amino]-2-[(4-carbamimidoylphenyl)methyl]benzimidazol-1-yl]butanoate;dihydrochloride Chemical compound Cl.Cl.N=1C2=CC(N(CCCN(C)C)S(=O)(=O)C=3C=CC=CC=3)=CC=C2N(CCCC(=O)OCC)C=1CC1=CC=C(C(N)=N)C=C1 OBTYYWGRDDHFBG-UHFFFAOYSA-N 0.000 description 1
- LFTNQXDXDYXKPC-UHFFFAOYSA-N ethyl 4-[[2-[(4-carbamimidoylphenyl)methyl]-1-(2-ethoxy-2-oxoethyl)benzimidazol-5-yl]amino]butanoate;hydrochloride Chemical compound Cl.N=1C2=CC(NCCCC(=O)OCC)=CC=C2N(CC(=O)OCC)C=1CC1=CC=C(C(N)=N)C=C1 LFTNQXDXDYXKPC-UHFFFAOYSA-N 0.000 description 1
- VDZCHJGEAZXYLL-UHFFFAOYSA-N ethyl 4-[[2-[(4-carbamimidoylphenyl)methyl]-1-methylbenzimidazol-5-yl]-quinolin-8-ylsulfonylamino]butanoate;hydrochloride Chemical compound Cl.C=1C=CC2=CC=CN=C2C=1S(=O)(=O)N(CCCC(=O)OCC)C(C=C1N=2)=CC=C1N(C)C=2CC1=CC=C(C(N)=N)C=C1 VDZCHJGEAZXYLL-UHFFFAOYSA-N 0.000 description 1
- PQBIMCMTCROIBH-UHFFFAOYSA-N ethyl 4-[benzenesulfonyl-[2-[(4-carbamimidoylphenyl)methyl]-1-(2-ethoxy-2-oxoethyl)benzimidazol-5-yl]amino]butanoate;hydrochloride Chemical compound Cl.C=1C=CC=CC=1S(=O)(=O)N(CCCC(=O)OCC)C(C=C1N=2)=CC=C1N(CC(=O)OCC)C=2CC1=CC=C(C(N)=N)C=C1 PQBIMCMTCROIBH-UHFFFAOYSA-N 0.000 description 1
- FZOLWPZHCUIHJD-UHFFFAOYSA-N ethyl 4-amino-2-[[2-[[2-[(4-carbamimidoylphenyl)methyl]-1-methylbenzimidazol-5-yl]-quinolin-8-ylsulfonylamino]acetyl]amino]-4-oxobutanoate;hydrochloride Chemical compound Cl.C=1C=CC2=CC=CN=C2C=1S(=O)(=O)N(CC(=O)NC(CC(N)=O)C(=O)OCC)C(C=C1N=2)=CC=C1N(C)C=2CC1=CC=C(C(N)=N)C=C1 FZOLWPZHCUIHJD-UHFFFAOYSA-N 0.000 description 1
- MNMAVMZWHMCADH-UHFFFAOYSA-N ethyl 5-[2-[(4-carbamimidoylphenyl)methyl]-5-(cyclohexanecarbonylamino)benzimidazol-1-yl]pentanoate;hydrochloride Chemical compound Cl.N=1C2=CC(NC(=O)C3CCCCC3)=CC=C2N(CCCCC(=O)OCC)C=1CC1=CC=C(C(N)=N)C=C1 MNMAVMZWHMCADH-UHFFFAOYSA-N 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 1
- 229960004222 factor ix Drugs 0.000 description 1
- 229940012414 factor viia Drugs 0.000 description 1
- 229950003499 fibrin Drugs 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 239000000727 fraction Substances 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 229940116364 hard fat Drugs 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 125000003104 hexanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000005935 hexyloxycarbonyl group Chemical group 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000005928 isopropyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229960004873 levomenthol Drugs 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 229940099594 manganese dioxide Drugs 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229910052987 metal hydride Inorganic materials 0.000 description 1
- 150000004681 metal hydrides Chemical class 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 1
- 229940057952 methanol Drugs 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- OHTZXQYRHDVXLJ-UHFFFAOYSA-N methyl 2-(4-cyanophenyl)acetate Chemical compound COC(=O)CC1=CC=C(C#N)C=C1 OHTZXQYRHDVXLJ-UHFFFAOYSA-N 0.000 description 1
- GTWQHMIEQNSPHA-UHFFFAOYSA-N methyl 2-[1-[3-amino-4-(methylamino)benzoyl]cyclohexyl]acetate Chemical compound C1=C(N)C(NC)=CC=C1C(=O)C1(CC(=O)OC)CCCCC1 GTWQHMIEQNSPHA-UHFFFAOYSA-N 0.000 description 1
- IFQHCWOQQOCCTP-UHFFFAOYSA-N methyl 2-[1-[4-(methylamino)-3-nitrobenzoyl]cyclohexyl]acetate Chemical compound C1=C([N+]([O-])=O)C(NC)=CC=C1C(=O)C1(CC(=O)OC)CCCCC1 IFQHCWOQQOCCTP-UHFFFAOYSA-N 0.000 description 1
- WKLCURVCLLUIRP-UHFFFAOYSA-N methyl 2-[[2-[[4-(n'-methoxycarbonylcarbamimidoyl)phenyl]methyl]-1-methylbenzimidazol-5-yl]-quinolin-8-ylsulfonylamino]acetate Chemical compound C=1C=CC2=CC=CN=C2C=1S(=O)(=O)N(CC(=O)OC)C(C=C1N=2)=CC=C1N(C)C=2CC1=CC=C(C(N)=NC(=O)OC)C=C1 WKLCURVCLLUIRP-UHFFFAOYSA-N 0.000 description 1
- KGNIHMQFAVOVES-UHFFFAOYSA-N methyl 3-[[3-amino-4-(methylamino)phenyl]-cyclopentylsulfamoyl]propanoate Chemical compound C1=C(N)C(NC)=CC=C1N(S(=O)(=O)CCC(=O)OC)C1CCCC1 KGNIHMQFAVOVES-UHFFFAOYSA-N 0.000 description 1
- RGFDLZMOTGXYDP-UHFFFAOYSA-N methyl 3-[cyclopentyl-[4-(methylamino)-3-nitrophenyl]sulfamoyl]propanoate Chemical compound C1=C([N+]([O-])=O)C(NC)=CC=C1N(S(=O)(=O)CCC(=O)OC)C1CCCC1 RGFDLZMOTGXYDP-UHFFFAOYSA-N 0.000 description 1
- BTTWXJLIQFCGPD-UHFFFAOYSA-N methyl 4-[[2-[(4-carbamimidoylphenyl)methyl]-1-methylbenzimidazol-5-yl]-cyclopentylamino]-4-oxobutanoate;hydrochloride Chemical compound Cl.C=1C=C2N(C)C(CC=3C=CC(=CC=3)C(N)=N)=NC2=CC=1N(C(=O)CCC(=O)OC)C1CCCC1 BTTWXJLIQFCGPD-UHFFFAOYSA-N 0.000 description 1
- CAEHTLHKMNBTFQ-UHFFFAOYSA-N methyl 4-[[2-[(4-cyanophenyl)methyl]-1-methylbenzimidazol-5-yl]-cyclopentylamino]-4-oxobutanoate Chemical compound C=1C=C2N(C)C(CC=3C=CC(=CC=3)C#N)=NC2=CC=1N(C(=O)CCC(=O)OC)C1CCCC1 CAEHTLHKMNBTFQ-UHFFFAOYSA-N 0.000 description 1
- SNICPLMMTLDTBF-UHFFFAOYSA-N methyl 4-[[5-[benzenesulfonyl-[2-(dimethylamino)ethyl]amino]-2-[(4-carbamimidoylphenyl)methyl]benzimidazol-1-yl]methyl]benzoate;dihydrochloride Chemical compound Cl.Cl.C1=CC(C(=O)OC)=CC=C1CN1C2=CC=C(N(CCN(C)C)S(=O)(=O)C=3C=CC=CC=3)C=C2N=C1CC1=CC=C(C(N)=N)C=C1 SNICPLMMTLDTBF-UHFFFAOYSA-N 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- RDRJJMFJQKQHGO-QCOHSWCKSA-N n-[(e)-[(3z)-3-[(3,3-dimethyl-4h-isoquinolin-1-yl)hydrazinylidene]butan-2-ylidene]amino]-3,3-dimethyl-4h-isoquinolin-1-amine Chemical compound C1=CC=C2C(N/N=C(\C)/C(=N\NC=3C4=CC=CC=C4CC(C)(C)N=3)/C)=NC(C)(C)CC2=C1 RDRJJMFJQKQHGO-QCOHSWCKSA-N 0.000 description 1
- JVWKQVMJKNVFOX-UHFFFAOYSA-N n-[1-benzyl-2-[(4-cyanophenyl)methyl]benzimidazol-5-yl]-n-(3-piperidin-1-ylpropyl)benzenesulfonamide Chemical compound C=1C=CC=CC=1S(=O)(=O)N(C=1C=C2N=C(CC=3C=CC(=CC=3)C#N)N(CC=3C=CC=CC=3)C2=CC=1)CCCN1CCCCC1 JVWKQVMJKNVFOX-UHFFFAOYSA-N 0.000 description 1
- RYZXRYOWEMLJGH-UHFFFAOYSA-N n-[2-(4-cyanoanilino)-1-methylbenzimidazol-5-yl]quinoline-8-sulfonamide Chemical compound N=1C2=CC(NS(=O)(=O)C=3C4=NC=CC=C4C=CC=3)=CC=C2N(C)C=1NC1=CC=C(C#N)C=C1 RYZXRYOWEMLJGH-UHFFFAOYSA-N 0.000 description 1
- ZWEWXOIAAFWIRO-UHFFFAOYSA-N n-[2-(4-cyanobenzoyl)-1-methylbenzimidazol-5-yl]-n-(2-morpholin-4-ylethyl)quinoline-8-sulfonamide Chemical compound C=1C=C2N(C)C(C(=O)C=3C=CC(=CC=3)C#N)=NC2=CC=1N(S(=O)(=O)C=1C2=NC=CC=C2C=CC=1)CCN1CCOCC1 ZWEWXOIAAFWIRO-UHFFFAOYSA-N 0.000 description 1
- CPMAUPRMYOVOEF-UHFFFAOYSA-N n-[2-[(4-carbamimidoylphenyl)methyl]-1-methylbenzimidazol-5-yl]-n-methyl-2,3-dihydroindole-1-carboxamide;hydrochloride Chemical compound Cl.C1CC2=CC=CC=C2N1C(=O)N(C)C(C=C1N=2)=CC=C1N(C)C=2CC1=CC=C(C(N)=N)C=C1 CPMAUPRMYOVOEF-UHFFFAOYSA-N 0.000 description 1
- XSACWQKFVNKHKQ-UHFFFAOYSA-N n-[2-[(4-carbamimidoylphenyl)methyl]-1-methylbenzimidazol-5-yl]-n-methylpiperidine-1-carboxamide;hydrochloride Chemical compound Cl.C=1C=C2N(C)C(CC=3C=CC(=CC=3)C(N)=N)=NC2=CC=1N(C)C(=O)N1CCCCC1 XSACWQKFVNKHKQ-UHFFFAOYSA-N 0.000 description 1
- DLTJBPSMOJAYIH-UHFFFAOYSA-N n-[2-[(4-cyanophenyl)methyl]-1-methylbenzimidazol-5-yl]-2,3,5,6-tetramethylbenzenesulfonamide Chemical compound CC1=CC(C)=C(C)C(S(=O)(=O)NC=2C=C3N=C(CC=4C=CC(=CC=4)C#N)N(C)C3=CC=2)=C1C DLTJBPSMOJAYIH-UHFFFAOYSA-N 0.000 description 1
- YAPJWVHQWVLFDL-UHFFFAOYSA-N n-[2-[(4-cyanophenyl)methyl]-1-methylbenzimidazol-5-yl]-2,5-dimethoxybenzenesulfonamide Chemical compound COC1=CC=C(OC)C(S(=O)(=O)NC=2C=C3N=C(CC=4C=CC(=CC=4)C#N)N(C)C3=CC=2)=C1 YAPJWVHQWVLFDL-UHFFFAOYSA-N 0.000 description 1
- VAPRAPPUXOHPJC-UHFFFAOYSA-N n-[2-[(4-cyanophenyl)methyl]-1-methylbenzimidazol-5-yl]-3,5-bis(trifluoromethyl)benzenesulfonamide Chemical compound N=1C2=CC(NS(=O)(=O)C=3C=C(C=C(C=3)C(F)(F)F)C(F)(F)F)=CC=C2N(C)C=1CC1=CC=C(C#N)C=C1 VAPRAPPUXOHPJC-UHFFFAOYSA-N 0.000 description 1
- CWXMRYPRKSNZAW-UHFFFAOYSA-N n-[2-[(4-cyanophenyl)methyl]-1-methylbenzimidazol-5-yl]-n-(naphthalen-1-ylmethyl)methanesulfonamide Chemical compound N=1C2=CC(N(CC=3C4=CC=CC=C4C=CC=3)S(C)(=O)=O)=CC=C2N(C)C=1CC1=CC=C(C#N)C=C1 CWXMRYPRKSNZAW-UHFFFAOYSA-N 0.000 description 1
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- BVOMBQVNDKSJFQ-UHFFFAOYSA-N n-[2-[(4-cyanophenyl)methyl]-1-methylbenzimidazol-5-yl]-n-[2-(dimethylamino)ethyl]quinoline-8-sulfonamide Chemical compound C=1C=CC2=CC=CN=C2C=1S(=O)(=O)N(CCN(C)C)C(C=C1N=2)=CC=C1N(C)C=2CC1=CC=C(C#N)C=C1 BVOMBQVNDKSJFQ-UHFFFAOYSA-N 0.000 description 1
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- WHMZMMXNJPSBOA-UHFFFAOYSA-N n-[2-[(4-cyanophenyl)methyl]-1-methylbenzimidazol-5-yl]-n-methyl-2,3-dihydroindole-1-carboxamide Chemical compound C1CC2=CC=CC=C2N1C(=O)N(C)C(C=C1N=2)=CC=C1N(C)C=2CC1=CC=C(C#N)C=C1 WHMZMMXNJPSBOA-UHFFFAOYSA-N 0.000 description 1
- OXJJTEMQBAMAMX-UHFFFAOYSA-N n-[2-[(4-cyanophenyl)methyl]-1-methylbenzimidazol-5-yl]benzenesulfonamide Chemical compound N=1C2=CC(NS(=O)(=O)C=3C=CC=CC=3)=CC=C2N(C)C=1CC1=CC=C(C#N)C=C1 OXJJTEMQBAMAMX-UHFFFAOYSA-N 0.000 description 1
- PJQZBNJGBDAVBD-UHFFFAOYSA-N n-[2-[(4-cyanophenyl)methyl]-1-methylbenzimidazol-5-yl]isoquinoline-5-sulfonamide Chemical compound N=1C2=CC(NS(=O)(=O)C=3C4=CC=NC=C4C=CC=3)=CC=C2N(C)C=1CC1=CC=C(C#N)C=C1 PJQZBNJGBDAVBD-UHFFFAOYSA-N 0.000 description 1
- YTNLNGJDNIJMIE-UHFFFAOYSA-N n-[4-(benzenesulfonyl)-2-nitrophenyl]-n-methylmethanesulfonamide Chemical compound C1=C([N+]([O-])=O)C(N(C)S(C)(=O)=O)=CC=C1S(=O)(=O)C1=CC=CC=C1 YTNLNGJDNIJMIE-UHFFFAOYSA-N 0.000 description 1
- HPPDEAUJCRPOQL-UHFFFAOYSA-N n-benzyl-2-[(4-carbamimidoylphenyl)methyl]-1-methylbenzimidazole-5-carboxamide;hydrochloride Chemical compound Cl.N=1C2=CC(C(=O)NCC=3C=CC=CC=3)=CC=C2N(C)C=1CC1=CC=C(C(N)=N)C=C1 HPPDEAUJCRPOQL-UHFFFAOYSA-N 0.000 description 1
- JNJPQGQVJWKRIE-UHFFFAOYSA-N n-benzyl-2-[(4-cyanophenyl)methyl]-1-methylbenzimidazole-5-carboxamide Chemical compound N=1C2=CC(C(=O)NCC=3C=CC=CC=3)=CC=C2N(C)C=1CC1=CC=C(C#N)C=C1 JNJPQGQVJWKRIE-UHFFFAOYSA-N 0.000 description 1
- AURSLVUZRGZYRL-UHFFFAOYSA-N n-cyclopentyl-4-fluoro-3-nitroaniline Chemical compound C1=C(F)C([N+](=O)[O-])=CC(NC2CCCC2)=C1 AURSLVUZRGZYRL-UHFFFAOYSA-N 0.000 description 1
- 229940124305 n-propanol Drugs 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000002905 orthoesters Chemical class 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 1
- QJPQVXSHYBGQGM-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 QJPQVXSHYBGQGM-UHFFFAOYSA-N 0.000 description 1
- 125000001148 pentyloxycarbonyl group Chemical group 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229940069002 potassium dichromate Drugs 0.000 description 1
- RPDAUEIUDPHABB-UHFFFAOYSA-N potassium ethoxide Chemical compound [K+].CC[O-] RPDAUEIUDPHABB-UHFFFAOYSA-N 0.000 description 1
- 239000012286 potassium permanganate Substances 0.000 description 1
- 229960001841 potassium permanganate Drugs 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229960004063 propylene glycol Drugs 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 125000004742 propyloxycarbonyl group Chemical group 0.000 description 1
- JUYUYCIJACTHMK-UHFFFAOYSA-N quinoline-8-sulfonyl chloride Chemical compound C1=CN=C2C(S(=O)(=O)Cl)=CC=CC2=C1 JUYUYCIJACTHMK-UHFFFAOYSA-N 0.000 description 1
- 230000036647 reaction Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 208000037803 restenosis Diseases 0.000 description 1
- QBERHIJABFXGRZ-UHFFFAOYSA-M rhodium;triphenylphosphane;chloride Chemical compound [Cl-].[Rh].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 QBERHIJABFXGRZ-UHFFFAOYSA-M 0.000 description 1
- 102220007334 rs111033643 Human genes 0.000 description 1
- 239000011833 salt mixture Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 229960005202 streptokinase Drugs 0.000 description 1
- 230000009861 stroke prevention Effects 0.000 description 1
- 229940014800 succinic anhydride Drugs 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-N sulfonic acid Chemical compound OS(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-N 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 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 1
- BNWCETAHAJSBFG-UHFFFAOYSA-N tert-butyl 2-bromoacetate Chemical compound CC(C)(C)OC(=O)CBr BNWCETAHAJSBFG-UHFFFAOYSA-N 0.000 description 1
- 150000003509 tertiary alcohols Chemical class 0.000 description 1
- OULAJFUGPPVRBK-UHFFFAOYSA-N tetratriacontan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO OULAJFUGPPVRBK-UHFFFAOYSA-N 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 150000007970 thio esters Chemical class 0.000 description 1
- 230000002537 thrombolytic effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 1
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 229960005356 urokinase Drugs 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
- C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
- C07D263/56—Benzoxazoles; Hydrogenated benzoxazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D209/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an alkyl or cycloalkyl radical attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D235/16—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
- C07D277/62—Benzothiazoles
- C07D277/64—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/08—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing alicyclic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/08—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing alicyclic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
- C07F9/6503—Five-membered rings
- C07F9/6506—Five-membered rings having the nitrogen atoms in positions 1 and 3
- C07F9/65068—Five-membered rings having the nitrogen atoms in positions 1 and 3 condensed with carbocyclic rings or carbocyclic ring systems
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- Chemical & Material Sciences (AREA)
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- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Cardiology (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Molecular Biology (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Biochemistry (AREA)
- Heart & Thoracic Surgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Indole Compounds (AREA)
- Furan Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
L'invention concerne de nouveaux dérivés benzo condensés hétérocycliques à 5 chaînons de la formule générale (I) dans laquelle R¿a? à R¿c?, A, Ar, X et Y ont la signification mentionnée dans la revendication 1, leurs tautomères, leurs stéréoisomères, leurs mélanges et leurs sels, notamment leurs sels physiologiquement compatibles avec des acides inorganiques ou organiques ou des bases, présentant des propriétés précieuses. Les composés de la formule générale (I) précitée, dans laquelle R¿c? représente un groupe cyano, constituent des produits intermédiaires précieux pour préparer les autres composés de la formule générale (I), et les composés de la formule générale (I) précitée, dans laquelle R¿c? représente un des groupes amidino subséquent, ainsi que leurs tautomères et leurs stéréoisomères présentent des propriétés pharmacologiques précieuses, notamment une action antithrombotique.
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19804085.7 | 1998-02-03 | ||
DE1998104085 DE19804085A1 (de) | 1998-02-03 | 1998-02-03 | 5-Gliedrige heterocyclische kondensierte Benzoderivate, deren Herstellung und deren Verwendung als Arzneimittel |
DE19834325.6 | 1998-07-30 | ||
DE1998134325 DE19834325A1 (de) | 1998-07-30 | 1998-07-30 | 5-Gliedrige heterocyclische kondensierte Derivate, deren Herstellung und deren Verwendung als Arzneimittel |
PCT/EP1999/000537 WO1999040072A1 (fr) | 1998-02-03 | 1999-01-28 | Heterocycles benzo condenses a 5 chainons utilises comme agents antithrombotiques |
Publications (1)
Publication Number | Publication Date |
---|---|
CA2319494A1 true CA2319494A1 (fr) | 1999-08-12 |
Family
ID=26043548
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA002319494A Abandoned CA2319494A1 (fr) | 1998-02-03 | 1999-01-28 | Heterocycles benzo condenses a 5 chainons utilises comme agents antithrombotiques |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP1060166A1 (fr) |
JP (1) | JP2002502844A (fr) |
AU (1) | AU2720199A (fr) |
CA (1) | CA2319494A1 (fr) |
WO (1) | WO1999040072A1 (fr) |
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CA2134192A1 (fr) * | 1993-11-12 | 1995-05-13 | Michael L. Denney | Antagonistes iib/iiia de la glycoproteine 5, 6-bicyclique |
PE121699A1 (es) * | 1997-02-18 | 1999-12-08 | Boehringer Ingelheim Pharma | Heterociclos biciclicos disustituidos como inhibidores de la trombina |
DE19718181A1 (de) * | 1997-04-30 | 1998-11-05 | Boehringer Ingelheim Pharma | Disubstituierte bicyclische Heterocyclen, ihre Herstellung und ihre Verwendung als Arzneimittel |
-
1999
- 1999-01-28 EP EP99907437A patent/EP1060166A1/fr not_active Withdrawn
- 1999-01-28 AU AU27201/99A patent/AU2720199A/en not_active Abandoned
- 1999-01-28 JP JP2000530502A patent/JP2002502844A/ja active Pending
- 1999-01-28 CA CA002319494A patent/CA2319494A1/fr not_active Abandoned
- 1999-01-28 WO PCT/EP1999/000537 patent/WO1999040072A1/fr not_active Application Discontinuation
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7326791B2 (en) | 2002-12-19 | 2008-02-05 | Boehringer Ingelheim Pharma Gmbh & Co., Kg | Carboxylic acid amides, the preparation thereof, and their use as pharmaceutical compositions |
US7514460B2 (en) | 2004-12-22 | 2009-04-07 | 4Sc Ag | Benzazole analogues and uses thereof |
US8039638B2 (en) | 2006-12-04 | 2011-10-18 | Boehringer Ingelheim International Gmbh | Inhibitors of HIV replication |
Also Published As
Publication number | Publication date |
---|---|
AU2720199A (en) | 1999-08-23 |
EP1060166A1 (fr) | 2000-12-20 |
JP2002502844A (ja) | 2002-01-29 |
WO1999040072A1 (fr) | 1999-08-12 |
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