JP2002502844A - 5員複素環縮合ベンゾ誘導体、その調製及び医薬品としてのそれらの使用 - Google Patents
5員複素環縮合ベンゾ誘導体、その調製及び医薬品としてのそれらの使用Info
- Publication number
- JP2002502844A JP2002502844A JP2000530502A JP2000530502A JP2002502844A JP 2002502844 A JP2002502844 A JP 2002502844A JP 2000530502 A JP2000530502 A JP 2000530502A JP 2000530502 A JP2000530502 A JP 2000530502A JP 2002502844 A JP2002502844 A JP 2002502844A
- Authority
- JP
- Japan
- Prior art keywords
- group
- methyl
- alkyl
- substituted
- carboxy
- 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.)
- Pending
Links
- 125000002373 5 membered heterocyclic group Chemical group 0.000 title claims description 7
- 125000005605 benzo group Chemical group 0.000 title claims description 7
- 238000002360 preparation method Methods 0.000 title abstract description 8
- 239000003814 drug Substances 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 118
- 150000003839 salts Chemical class 0.000 claims abstract description 49
- 239000000203 mixture Substances 0.000 claims abstract description 43
- 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 21
- 150000007522 mineralic acids Chemical class 0.000 claims abstract description 4
- 150000007524 organic acids Chemical class 0.000 claims abstract description 4
- -1 piperazino group Chemical group 0.000 claims description 477
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Natural products OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 190
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 94
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 85
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 79
- 125000000217 alkyl group Chemical group 0.000 claims description 65
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 57
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 56
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 42
- 229910052757 nitrogen Inorganic materials 0.000 claims description 40
- 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 32
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 31
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 30
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 30
- 239000002253 acid Substances 0.000 claims description 28
- 238000006243 chemical reaction Methods 0.000 claims description 26
- 239000001257 hydrogen Substances 0.000 claims description 25
- 229910052739 hydrogen Inorganic materials 0.000 claims description 25
- 239000011541 reaction mixture Substances 0.000 claims description 25
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 23
- 238000007069 methylation reaction Methods 0.000 claims description 23
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 23
- 125000002112 pyrrolidino group Chemical group [*]N1C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 23
- 125000006698 (C1-C3) dialkylamino group Chemical group 0.000 claims description 22
- 125000003277 amino group Chemical group 0.000 claims description 22
- 125000004432 carbon atom Chemical group C* 0.000 claims description 22
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 20
- 125000005493 quinolyl group Chemical group 0.000 claims description 20
- 125000004434 sulfur atom Chemical group 0.000 claims description 20
- 229910052717 sulfur Inorganic materials 0.000 claims description 19
- 125000006705 (C5-C7) cycloalkyl group Chemical group 0.000 claims description 18
- 125000005956 isoquinolyl group Chemical group 0.000 claims description 18
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 16
- 125000001624 naphthyl group Chemical group 0.000 claims description 16
- 125000005328 phosphinyl group Chemical group [PH2](=O)* 0.000 claims description 16
- 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 16
- 125000004076 pyridyl group Chemical group 0.000 claims description 16
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims description 14
- 238000011282 treatment Methods 0.000 claims description 14
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 13
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 12
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 12
- BHELIUBJHYAEDK-OAIUPTLZSA-N Aspoxicillin Chemical group C1([C@H](C(=O)N[C@@H]2C(N3[C@H](C(C)(C)S[C@@H]32)C(O)=O)=O)NC(=O)[C@H](N)CC(=O)NC)=CC=C(O)C=C1 BHELIUBJHYAEDK-OAIUPTLZSA-N 0.000 claims description 11
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 11
- 229910052801 chlorine Inorganic materials 0.000 claims description 11
- 230000007062 hydrolysis Effects 0.000 claims description 11
- 238000006460 hydrolysis reaction Methods 0.000 claims description 11
- 125000002883 imidazolyl group Chemical group 0.000 claims description 11
- 125000001841 imino group Chemical group [H]N=* 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 11
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 11
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 11
- 125000003545 alkoxy group Chemical group 0.000 claims description 10
- 125000006576 di-(C1-C3-alkyl)-aminocarbonyl group Chemical group 0.000 claims description 10
- 230000011987 methylation Effects 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
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 9
- 238000007327 hydrogenolysis reaction Methods 0.000 claims description 9
- 125000002252 acyl group Chemical group 0.000 claims description 8
- 125000003282 alkyl amino group Chemical group 0.000 claims description 8
- 229910052731 fluorine Inorganic materials 0.000 claims description 8
- 125000001424 substituent group Chemical group 0.000 claims description 8
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 8
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 7
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 7
- 125000001153 fluoro group Chemical group F* 0.000 claims description 7
- 229910052740 iodine Inorganic materials 0.000 claims description 7
- 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 7
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 7
- 125000006239 protecting group Chemical group 0.000 claims description 7
- 238000005979 thermal decomposition reaction Methods 0.000 claims description 7
- 125000002619 bicyclic group Chemical group 0.000 claims description 6
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 6
- 230000000269 nucleophilic effect Effects 0.000 claims description 6
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 6
- 125000006563 (C1-3) alkylaminocarbonyl group Chemical group 0.000 claims description 5
- 125000006639 cyclohexyl carbonyl group Chemical group 0.000 claims description 5
- 125000005843 halogen group Chemical group 0.000 claims description 5
- 238000001727 in vivo Methods 0.000 claims description 5
- 230000002401 inhibitory effect Effects 0.000 claims description 5
- 125000004458 methylaminocarbonyl group Chemical group [H]N(C(*)=O)C([H])([H])[H] 0.000 claims description 5
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 4
- 125000006555 (C3-C5) cycloalkyl group Chemical group 0.000 claims description 4
- 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 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 4
- 108090000190 Thrombin Proteins 0.000 claims description 4
- 150000007513 acids Chemical class 0.000 claims description 4
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 4
- 125000005167 cycloalkylaminocarbonyl group Chemical group 0.000 claims description 4
- 125000002993 cycloalkylene group Chemical group 0.000 claims description 4
- 238000005661 deetherification reaction Methods 0.000 claims description 4
- 238000005695 dehalogenation reaction Methods 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
- 229960004072 thrombin Drugs 0.000 claims description 4
- 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 3
- 125000004466 alkoxycarbonylamino group Chemical group 0.000 claims description 3
- 150000001412 amines Chemical class 0.000 claims description 3
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 239000000969 carrier Substances 0.000 claims description 3
- 238000006114 decarboxylation reaction Methods 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 3
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 3
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 3
- 150000002825 nitriles Chemical class 0.000 claims description 3
- 125000005951 trifluoromethanesulfonyloxy group Chemical group 0.000 claims description 3
- BNJMRELGMDUDDB-UHFFFAOYSA-N $l^{1}-sulfanylbenzene Chemical compound [S]C1=CC=CC=C1 BNJMRELGMDUDDB-UHFFFAOYSA-N 0.000 claims description 2
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 2
- 125000001140 1,4-phenylene group Chemical group [H]C1=C([H])C([*:2])=C([H])C([H])=C1[*:1] 0.000 claims description 2
- 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 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
- QUYSOYJNGMHQDQ-UHFFFAOYSA-N 4-[[4-cyclopropyl-1-methyl-5-(pyrrolidine-1-carbonyl)benzimidazol-2-yl]methyl]benzenecarboximidamide Chemical compound N=1C2=C(C3CC3)C(C(=O)N3CCCC3)=CC=C2N(C)C=1CC1=CC=C(C(N)=N)C=C1 QUYSOYJNGMHQDQ-UHFFFAOYSA-N 0.000 claims description 2
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-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
- 125000005619 boric acid group Chemical group 0.000 claims description 2
- 229910002091 carbon monoxide Inorganic materials 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 125000004122 cyclic group Chemical group 0.000 claims description 2
- 125000003588 lysine group Chemical group [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 claims description 2
- 125000004957 naphthylene group Chemical group 0.000 claims description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 239000001301 oxygen Substances 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
- 238000006268 reductive amination reaction Methods 0.000 claims description 2
- 125000005650 substituted phenylene group Chemical group 0.000 claims description 2
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 2
- 125000005557 thiazolylene group Chemical group 0.000 claims description 2
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 2
- 229910052727 yttrium Inorganic materials 0.000 claims description 2
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 claims 6
- 125000005079 alkoxycarbonylmethyl group Chemical group 0.000 claims 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 1
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 claims 1
- 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 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical group [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims 1
- 125000003710 aryl alkyl group Chemical group 0.000 claims 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims 1
- 150000001721 carbon Chemical group 0.000 claims 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 claims 1
- LPIQUOYDBNQMRZ-UHFFFAOYSA-N cyclopentenylidene Chemical group C1CC=CC1 LPIQUOYDBNQMRZ-UHFFFAOYSA-N 0.000 claims 1
- 239000011737 fluorine Substances 0.000 claims 1
- 230000001965 increasing effect Effects 0.000 claims 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims 1
- 230000003647 oxidation Effects 0.000 claims 1
- 238000007254 oxidation reaction Methods 0.000 claims 1
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Chemical group C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 claims 1
- 229910052710 silicon Inorganic materials 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
- 230000009286 beneficial effect Effects 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 734
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 673
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 342
- 238000001819 mass spectrum Methods 0.000 description 237
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 210
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 210
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Substances N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 172
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 166
- 239000001099 ammonium carbonate Substances 0.000 description 166
- 235000012501 ammonium carbonate Nutrition 0.000 description 166
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 156
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 150
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 113
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 106
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 104
- 239000000741 silica gel Substances 0.000 description 104
- 229910002027 silica gel Inorganic materials 0.000 description 104
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 75
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 74
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 65
- 239000002904 solvent Substances 0.000 description 64
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 54
- 239000000243 solution Substances 0.000 description 54
- 238000001704 evaporation Methods 0.000 description 46
- 230000008020 evaporation Effects 0.000 description 46
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 39
- 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 39
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 37
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 34
- 229960000583 acetic acid Drugs 0.000 description 32
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 30
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 26
- 239000002585 base Substances 0.000 description 26
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 24
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 24
- 230000000875 corresponding effect Effects 0.000 description 24
- 239000012362 glacial acetic acid Substances 0.000 description 24
- 239000011734 sodium Substances 0.000 description 24
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 23
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 21
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 20
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 20
- 239000000284 extract Substances 0.000 description 20
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 18
- 239000003208 petroleum Substances 0.000 description 18
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 17
- 229910052763 palladium Inorganic materials 0.000 description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 15
- 229910000027 potassium carbonate 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
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 14
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 14
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- FGRNQCUULDGKSB-UHFFFAOYSA-N ethyl 3-[[2-[(4-carbamimidoylphenyl)methyl]-1-methylbenzimidazol-5-yl]sulfonyl-ethylamino]propanoate;hydrochloride Chemical compound Cl.N=1C2=CC(S(=O)(=O)N(CC)CCC(=O)OCC)=CC=C2N(C)C=1CC1=CC=C(C(N)=N)C=C1 FGRNQCUULDGKSB-UHFFFAOYSA-N 0.000 description 1
- UVPVDNJJPKJPCX-UHFFFAOYSA-N ethyl 4-(n-[2-[(4-carbamimidoylphenyl)methyl]-1-methylbenzimidazol-5-yl]sulfonylanilino)butanoate;hydrochloride Chemical compound Cl.C=1C=C2N(C)C(CC=3C=CC(=CC=3)C(N)=N)=NC2=CC=1S(=O)(=O)N(CCCC(=O)OCC)C1=CC=CC=C1 UVPVDNJJPKJPCX-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
- VQSMQDVPCWCPTL-UHFFFAOYSA-N ethyl 4-[2-[(4-carbamimidoylphenyl)methyl]-5-(cyclohexanecarbonylamino)benzimidazol-1-yl]butanoate;hydrochloride Chemical compound Cl.N=1C2=CC(NC(=O)C3CCCCC3)=CC=C2N(CCCC(=O)OCC)C=1CC1=CC=C(C(N)=N)C=C1 VQSMQDVPCWCPTL-UHFFFAOYSA-N 0.000 description 1
- QSIWHIZYXWEABY-UHFFFAOYSA-N ethyl 4-[2-[(4-carbamimidoylphenyl)methyl]-5-[cyclohexanecarbonyl(methyl)amino]benzimidazol-1-yl]butanoate Chemical compound N=1C2=CC(N(C)C(=O)C3CCCCC3)=CC=C2N(CCCC(=O)OCC)C=1CC1=CC=C(C(N)=N)C=C1 QSIWHIZYXWEABY-UHFFFAOYSA-N 0.000 description 1
- AJVLZGZQNGCJJG-UHFFFAOYSA-N ethyl 4-[2-[(4-carbamimidoylphenyl)methyl]-5-[methyl(piperidine-1-carbonyl)amino]benzimidazol-1-yl]butanoate;hydrochloride Chemical compound Cl.N=1C2=CC(N(C)C(=O)N3CCCCC3)=CC=C2N(CCCC(=O)OCC)C=1CC1=CC=C(C(N)=N)C=C1 AJVLZGZQNGCJJG-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
- WVHSNPNRZTUDQD-UHFFFAOYSA-N ethyl 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)OCC)C1CCCC1 WVHSNPNRZTUDQD-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
- WTCPRONTWHTOKN-UHFFFAOYSA-N ethyl 5-[2-[(4-carbamimidoylphenyl)methyl]-5-[cyclohexanecarbonyl(methyl)amino]benzimidazol-1-yl]pentanoate;hydrochloride Chemical compound Cl.N=1C2=CC(N(C)C(=O)C3CCCCC3)=CC=C2N(CCCCC(=O)OCC)C=1CC1=CC=C(C(N)=N)C=C1 WTCPRONTWHTOKN-UHFFFAOYSA-N 0.000 description 1
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- 229940014800 succinic anhydride Drugs 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- 125000001273 sulfonato group Chemical group [O-]S(*)(=O)=O 0.000 description 1
- 230000006103 sulfonylation Effects 0.000 description 1
- 238000005694 sulfonylation reaction Methods 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
- 238000001356 surgical procedure Methods 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
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000005556 thienylene group Chemical group 0.000 description 1
- 150000007970 thio esters Chemical class 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 1
- DWCSXQCXXITVKE-UHFFFAOYSA-N triethyloxidanium Chemical compound CC[O+](CC)CC DWCSXQCXXITVKE-UHFFFAOYSA-N 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 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
Classifications
-
- 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
-
- 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
-
- 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
-
- 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
-
- 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
-
- 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
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Vascular Medicine (AREA)
- Urology & Nephrology (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Plural Heterocyclic Compounds (AREA)
- Indole Compounds (AREA)
- Furan Compounds (AREA)
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE1998104085 DE19804085A1 (de) | 1998-02-03 | 1998-02-03 | 5-Gliedrige heterocyclische kondensierte Benzoderivate, deren Herstellung und deren Verwendung als Arzneimittel |
| DE1998134325 DE19834325A1 (de) | 1998-07-30 | 1998-07-30 | 5-Gliedrige heterocyclische kondensierte Derivate, deren Herstellung und deren Verwendung als Arzneimittel |
| DE19834325.6 | 1998-07-30 | ||
| DE19804085.7 | 1998-07-30 | ||
| PCT/EP1999/000537 WO1999040072A1 (de) | 1998-02-03 | 1999-01-28 | 5-gliedrige benzokondensierte heterocyclen als antithrombotika |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2002502844A true JP2002502844A (ja) | 2002-01-29 |
| JP2002502844A5 JP2002502844A5 (enExample) | 2006-03-23 |
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| Application Number | Title | Priority Date | Filing Date |
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| JP2000530502A Pending JP2002502844A (ja) | 1998-02-03 | 1999-01-28 | 5員複素環縮合ベンゾ誘導体、その調製及び医薬品としてのそれらの使用 |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP1060166A1 (enExample) |
| JP (1) | JP2002502844A (enExample) |
| AU (1) | AU2720199A (enExample) |
| CA (1) | CA2319494A1 (enExample) |
| WO (1) | WO1999040072A1 (enExample) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2010511635A (ja) * | 2006-12-04 | 2010-04-15 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Hiv複製の阻害剤 |
| JP2011507929A (ja) * | 2007-12-28 | 2011-03-10 | アジェンデ・キミケ・リウニテ・アンジェリニ・フランチェスコ・ア・チ・エレ・ア・エフェ・ソシエタ・ペル・アチオニ | 5位置換アザインドール誘導体,それを含む医薬組成物,中間化合物及びその製造方法 |
| JP2013538800A (ja) * | 2010-08-10 | 2013-10-17 | アッヴィ・インコーポレイテッド | 新規trpv3モジュレーター |
| JP2015532916A (ja) * | 2012-09-21 | 2015-11-16 | サノフイ | Apj受容体モジュレーターとしてのベンゾイミダゾールカルボン酸アミド誘導体 |
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| US6291514B1 (en) | 1998-02-09 | 2001-09-18 | 3-Dimensional Pharmaceuticals, Inc. | Heteroaryl amidines, methylamidines and guanidines, preparation thereof, and use thereof as protease inhibitors |
| AR023510A1 (es) | 1999-04-21 | 2002-09-04 | Astrazeneca Ab | Un equipo de partes, formulacion farmaceutica y uso de un inhibidor de trombina. |
| EP1214330A1 (en) * | 1999-09-21 | 2002-06-19 | LION Bioscience AG | Benzimidazole derivatives and combinatorial libraries thereof |
| DK1220844T3 (da) * | 1999-09-24 | 2003-07-28 | Boehringer Ingelheim Pharma | Arylsulfonamid-substituerede benzimidazolderivater og deres anvendelse som tryptase-inhibitorer |
| US6407130B1 (en) | 1999-11-10 | 2002-06-18 | Boehringer Ingelheim Pharma Kg | Carboxamide-substituted benzimidazoles having tryptase-inhibiting activity |
| DE19953899A1 (de) * | 1999-11-10 | 2001-05-17 | Boehringer Ingelheim Pharma | Carboxamid-substituierte Benzimidazolderivate, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel |
| US6451832B2 (en) | 1999-12-23 | 2002-09-17 | Boehringer Ingelheim Pharma Kg | Benzimidazoles with antithrombotic activity |
| DE19962329A1 (de) * | 1999-12-23 | 2001-06-28 | Boehringer Ingelheim Pharma | Benzimidazole, deren Herstellung und deren Verwendung als Arzneimittel |
| US6448281B1 (en) * | 2000-07-06 | 2002-09-10 | Boehringer Ingelheim (Canada) Ltd. | Viral polymerase inhibitors |
| US6670364B2 (en) | 2001-01-31 | 2003-12-30 | Telik, Inc. | Antagonists of MCP-1 function and methods of use thereof |
| US6962926B2 (en) | 2001-01-31 | 2005-11-08 | Telik, Inc. | Antagonist of MCP-1 function, and compositions and methods of use thereof |
| US6656956B2 (en) | 2001-02-08 | 2003-12-02 | Boehringer Ingelheim Pharma Kg | Benzimidazole derivatives, processes for preparing them and their use as pharmaceutical compositions |
| DE10105628A1 (de) * | 2001-02-08 | 2002-08-22 | Boehringer Ingelheim Pharma | Benzimidazolderivate, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel |
| TWI245761B (en) | 2001-03-01 | 2005-12-21 | Telik Inc | Antagonists of MCP-1 function and methods of use thereof |
| TWI236474B (en) | 2001-04-03 | 2005-07-21 | Telik Inc | Antagonists of MCP-1 function and methods of use thereof |
| HUP0400467A3 (en) * | 2001-04-19 | 2012-08-28 | Eisai R & D Man Co | 2-iminopyrrolidine derivatives, pharmaceutical compositions containing them and their use |
| DE10125478A1 (de) * | 2001-05-25 | 2002-11-28 | Boehringer Ingelheim Pharma | Verwendung bicyclischer Heterocyclen zur Behandlung und Vorbeugung arterieller thrombotischer Erkrankungen |
| US7232924B2 (en) | 2001-06-11 | 2007-06-19 | Xenoport, Inc. | Methods for synthesis of acyloxyalkyl derivatives of GABA analogs |
| US6818787B2 (en) | 2001-06-11 | 2004-11-16 | Xenoport, Inc. | Prodrugs of GABA analogs, compositions and uses thereof |
| US8048917B2 (en) | 2005-04-06 | 2011-11-01 | Xenoport, Inc. | Prodrugs of GABA analogs, compositions and uses thereof |
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| JP4628678B2 (ja) * | 2002-03-29 | 2011-02-09 | ノバルティス バクシンズ アンド ダイアグノスティックス,インコーポレーテッド | 置換ベンズアゾールおよびRafキナーゼ阻害剤としてのそれらの使用 |
| JP4334476B2 (ja) * | 2002-07-29 | 2009-09-30 | 株式会社静岡カフェイン工業所 | 1,3アゾール誘導体及び同誘導体を含む血栓症治療のための医薬組成物 |
| PE20040804A1 (es) * | 2002-12-19 | 2004-12-31 | Boehringer Ingelheim Pharma | DERIVADOS DE CARBOXAMIDAS COMO INHIBIDORES DEL FACTOR Xa |
| AU2004218187C1 (en) | 2003-02-19 | 2011-04-07 | Eisai R&D Management Co., Ltd. | Methods for producing cyclic benzamidine derivatives |
| BRPI0515522A (pt) * | 2004-09-21 | 2008-07-29 | Athersys Inc | composto, composição farmacêutica. métodos de inibir a ligação de ligandos endógenos ao receptor crth-2 em uma célula, de tratar, melhorar ou prevenir um distúrbio responsivo à inibição da ligação de ligandos endógenos ao receptor crth-2 em um animal e de preparar um composto, e, kit |
| ES2318556T3 (es) * | 2004-11-02 | 2009-05-01 | Pfizer, Inc. | Derivados de sulfonil bencimidazol. |
| US7514460B2 (en) | 2004-12-22 | 2009-04-07 | 4Sc Ag | Benzazole analogues and uses thereof |
| WO2012129491A1 (en) | 2011-03-24 | 2012-09-27 | Abbott Laboratories | Trpv3 modulators |
| CA2853097A1 (en) | 2011-10-24 | 2013-05-02 | Abbvie Inc. | Novel trpv3 modulators |
| US9056874B2 (en) | 2012-05-04 | 2015-06-16 | Novartis Ag | Complement pathway modulators and uses thereof |
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| JP6387391B2 (ja) | 2013-03-14 | 2018-09-05 | ノバルティス アーゲー | 眼科疾患の処置に有用な補体因子B阻害剤としての2−(1H−インドール−4−イルメチル)−3H−イミダゾ[4,5−b]ピリジン−6−カルボニトリル誘導体 |
| EP3089963A1 (en) | 2013-10-30 | 2016-11-09 | Novartis AG | 2-benzyl-benzimidazole complement factor b inhibitors and uses thereof |
| US9902702B2 (en) | 2014-07-15 | 2018-02-27 | Bristol-Myers Squibb Company | Spirocycloheptanes as inhibitors of rock |
| WO2016187620A2 (en) * | 2015-05-21 | 2016-11-24 | The Regents Of The University Of California | Anti-cancer compounds |
| KR102494294B1 (ko) | 2016-06-24 | 2023-01-31 | 더 리전트 오브 더 유니버시티 오브 캘리포니아 | Parp1, pap2 및/또는 튜블린의 저해제로서 암 치료에 유용한 프탈라진 유도체 |
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| DE3531658A1 (de) * | 1985-09-05 | 1987-03-12 | Boehringer Mannheim Gmbh | Heterocyclisch substituierte indole, zwischenprodukte, verfahren zu ihrer herstellung und arzneimittel |
| DE3701277A1 (de) * | 1987-01-17 | 1988-07-28 | Boehringer Mannheim Gmbh | Neue tricyclische benzimidazole, verfahren zu ihrer herstellung und verwendung als arzneimittel |
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| DE4213919A1 (de) * | 1992-04-28 | 1993-11-04 | Thomae Gmbh Dr K | Cyclische iminoderivate, verfahren zu ihrer herstellung und diese verbindungen enthaltende arzneimittel |
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| CA2134192A1 (en) * | 1993-11-12 | 1995-05-13 | Michael L. Denney | 5, 6-bicyclic glycoprotein iib/iiia antagonists |
| 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/de not_active Withdrawn
- 1999-01-28 JP JP2000530502A patent/JP2002502844A/ja active Pending
- 1999-01-28 AU AU27201/99A patent/AU2720199A/en not_active Abandoned
- 1999-01-28 WO PCT/EP1999/000537 patent/WO1999040072A1/de not_active Ceased
- 1999-01-28 CA CA002319494A patent/CA2319494A1/en not_active Abandoned
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2010511635A (ja) * | 2006-12-04 | 2010-04-15 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Hiv複製の阻害剤 |
| JP2011507929A (ja) * | 2007-12-28 | 2011-03-10 | アジェンデ・キミケ・リウニテ・アンジェリニ・フランチェスコ・ア・チ・エレ・ア・エフェ・ソシエタ・ペル・アチオニ | 5位置換アザインドール誘導体,それを含む医薬組成物,中間化合物及びその製造方法 |
| JP2013538800A (ja) * | 2010-08-10 | 2013-10-17 | アッヴィ・インコーポレイテッド | 新規trpv3モジュレーター |
| JP2015532916A (ja) * | 2012-09-21 | 2015-11-16 | サノフイ | Apj受容体モジュレーターとしてのベンゾイミダゾールカルボン酸アミド誘導体 |
Also Published As
| Publication number | Publication date |
|---|---|
| CA2319494A1 (en) | 1999-08-12 |
| AU2720199A (en) | 1999-08-23 |
| WO1999040072A1 (de) | 1999-08-12 |
| EP1060166A1 (de) | 2000-12-20 |
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