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

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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

1998-02-03

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.)

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• 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
• ALCFAGHHQUTFIL-UHFFFAOYSA-N ethyl 5-[2-[(4-cyanophenyl)methyl]-5-(cyclohexanecarbonylamino)benzimidazol-1-yl]pentanoate Chemical compound N=1C2=CC(NC(=O)C3CCCCC3)=CC=C2N(CCCCC(=O)OCC)C=1CC1=CC=C(C#N)C=C1 ALCFAGHHQUTFIL-UHFFFAOYSA-N 0.000 description 1
• ULZBBFLXVIMJQR-UHFFFAOYSA-N ethyl 5-[[2-[(4-carbamimidoylphenyl)methyl]-1-methylbenzimidazol-5-yl]sulfonyl-(2-methylpropyl)amino]pentanoate;hydrochloride Chemical compound Cl.N=1C2=CC(S(=O)(=O)N(CC(C)C)CCCCC(=O)OCC)=CC=C2N(C)C=1CC1=CC=C(C(N)=N)C=C1 ULZBBFLXVIMJQR-UHFFFAOYSA-N 0.000 description 1
• RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
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• FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 1
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• 239000004220 glutamic acid Substances 0.000 description 1
• 235000013922 glutamic acid Nutrition 0.000 description 1
• 230000026030 halogenation Effects 0.000 description 1
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• 125000000623 heterocyclic group Chemical group 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
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• 238000005984 hydrogenation reaction Methods 0.000 description 1
• WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
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• 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
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• 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
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