SK1062001A3 - Isoquinolines as urokinase inhibitors - Google Patents
Isoquinolines as urokinase inhibitors Download PDFInfo
- Publication number
- SK1062001A3 SK1062001A3 SK106-2001A SK1062001A SK1062001A3 SK 1062001 A3 SK1062001 A3 SK 1062001A3 SK 1062001 A SK1062001 A SK 1062001A SK 1062001 A3 SK1062001 A3 SK 1062001A3
- Authority
- SK
- Slovakia
- Prior art keywords
- chloro
- isoquinolyl
- mmol
- guanidine
- sulfonyl
- Prior art date
Links
- 239000002797 plasminogen activator inhibitor Substances 0.000 title description 8
- 150000002537 isoquinolines Chemical class 0.000 title description 3
- 239000000203 mixture Substances 0.000 claims description 419
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 375
- 239000000460 chlorine Substances 0.000 claims description 316
- -1 het Chemical group 0.000 claims description 205
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 145
- 150000001875 compounds Chemical class 0.000 claims description 125
- 238000002360 preparation method Methods 0.000 claims description 102
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 88
- 229910052739 hydrogen Inorganic materials 0.000 claims description 75
- 150000003839 salts Chemical class 0.000 claims description 73
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 72
- 229920006395 saturated elastomer Polymers 0.000 claims description 51
- 238000000034 method Methods 0.000 claims description 45
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 39
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 36
- 125000000217 alkyl group Chemical group 0.000 claims description 30
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 27
- ZRALSGWEFCBTJO-UHFFFAOYSA-N guanidine group Chemical group NC(=N)N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 claims description 25
- 125000001424 substituent group Chemical group 0.000 claims description 25
- 125000003118 aryl group Chemical group 0.000 claims description 24
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 23
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 claims description 22
- 239000002253 acid Substances 0.000 claims description 21
- ZSIQJIWKELUFRJ-UHFFFAOYSA-N azepane Chemical group C1CCCNCC1 ZSIQJIWKELUFRJ-UHFFFAOYSA-N 0.000 claims description 18
- 125000005842 heteroatom Chemical group 0.000 claims description 17
- 229910052717 sulfur Inorganic materials 0.000 claims description 17
- 125000003545 alkoxy group Chemical group 0.000 claims description 16
- 229910052736 halogen Inorganic materials 0.000 claims description 16
- 150000002367 halogens Chemical class 0.000 claims description 16
- 229910052760 oxygen Inorganic materials 0.000 claims description 15
- 230000008569 process Effects 0.000 claims description 14
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 13
- 229910052757 nitrogen Inorganic materials 0.000 claims description 13
- OSILBMSORKFRTB-UHFFFAOYSA-N isoquinolin-1-amine Chemical class C1=CC=C2C(N)=NC=CC2=C1 OSILBMSORKFRTB-UHFFFAOYSA-N 0.000 claims description 12
- CXDHJGCWMIOAQP-UHFFFAOYSA-N 2-pyridin-3-yl-1,4,5,6-tetrahydropyrimidine;hydrochloride Chemical compound Cl.C1CCNC(C=2C=NC=CC=2)=N1 CXDHJGCWMIOAQP-UHFFFAOYSA-N 0.000 claims description 11
- 125000002947 alkylene group Chemical group 0.000 claims description 11
- 229910052801 chlorine Inorganic materials 0.000 claims description 11
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 claims description 10
- 239000003153 chemical reaction reagent Substances 0.000 claims description 10
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 claims description 10
- 238000011282 treatment Methods 0.000 claims description 10
- 229910052794 bromium Inorganic materials 0.000 claims description 9
- 125000000623 heterocyclic group Chemical group 0.000 claims description 9
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical group O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 claims description 8
- JBDSSBMEKXHSJF-UHFFFAOYSA-N cyclopentanecarboxylic acid Chemical compound OC(=O)C1CCCC1 JBDSSBMEKXHSJF-UHFFFAOYSA-N 0.000 claims description 8
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 7
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 7
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 6
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims description 6
- 239000005977 Ethylene Substances 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
- 229910052799 carbon Inorganic materials 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- 125000005843 halogen group Chemical group 0.000 claims description 6
- 230000001404 mediated effect Effects 0.000 claims description 6
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 6
- 229910052698 phosphorus Inorganic materials 0.000 claims description 6
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 4
- VXNZUUAINFGPBY-UHFFFAOYSA-N 1-Butene Chemical group CCC=C VXNZUUAINFGPBY-UHFFFAOYSA-N 0.000 claims description 4
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- 125000000732 arylene group Chemical group 0.000 claims description 4
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 4
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 4
- 239000012458 free base Substances 0.000 claims description 4
- 125000001072 heteroaryl group Chemical group 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 claims description 4
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 4
- 125000003386 piperidinyl group Chemical group 0.000 claims description 4
- 125000006513 pyridinyl methyl group Chemical group 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- 150000001409 amidines Chemical class 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 125000001246 bromo group Chemical group Br* 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 3
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 3
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 3
- XZMCDFZZKTWFGF-UHFFFAOYSA-N Cyanamide Chemical compound NC#N XZMCDFZZKTWFGF-UHFFFAOYSA-N 0.000 claims description 2
- NZNMSOFKMUBTKW-UHFFFAOYSA-N Cyclohexanecarboxylic acid Natural products OC(=O)C1CCCCC1 NZNMSOFKMUBTKW-UHFFFAOYSA-N 0.000 claims description 2
- 229910002091 carbon monoxide Inorganic materials 0.000 claims description 2
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 2
- 125000004976 cyclobutylene group Chemical group 0.000 claims description 2
- VZFUCHSFHOYXIS-UHFFFAOYSA-N cycloheptane carboxylic acid Natural products OC(=O)C1CCCCCC1 VZFUCHSFHOYXIS-UHFFFAOYSA-N 0.000 claims description 2
- 125000004956 cyclohexylene group Chemical group 0.000 claims description 2
- 125000004979 cyclopentylene group Chemical group 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- 125000004187 tetrahydropyran-2-yl group Chemical group [H]C1([H])OC([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000005710 tetrahydropyranylene group Chemical group 0.000 claims description 2
- MWEYSFQTTAFUFL-GFCCVEGCSA-N (2r)-1-[4-chloro-1-(diaminomethylideneamino)isoquinolin-7-yl]sulfonylpyrrolidine-2-carboxylic acid Chemical compound C1=C2C(NC(=N)N)=NC=C(Cl)C2=CC=C1S(=O)(=O)N1CCC[C@@H]1C(O)=O MWEYSFQTTAFUFL-GFCCVEGCSA-N 0.000 claims 1
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims 1
- FKLXTEJVWZKEGC-UHFFFAOYSA-N 1-[[4-chloro-1-(diaminomethylideneamino)isoquinolin-7-yl]sulfonylamino]cyclopentane-1-carboxylic acid Chemical compound C1=C2C(NC(=N)N)=NC=C(Cl)C2=CC=C1S(=O)(=O)NC1(C(O)=O)CCCC1 FKLXTEJVWZKEGC-UHFFFAOYSA-N 0.000 claims 1
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims 1
- TXWOGHSRPAYOML-UHFFFAOYSA-N cyclobutanecarboxylic acid Chemical compound OC(=O)C1CCC1 TXWOGHSRPAYOML-UHFFFAOYSA-N 0.000 claims 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 385
- 239000000243 solution Substances 0.000 description 362
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 229
- 239000007787 solid Substances 0.000 description 194
- 235000019439 ethyl acetate Nutrition 0.000 description 187
- 238000004458 analytical method Methods 0.000 description 169
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 169
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 133
- 238000010898 silica gel chromatography Methods 0.000 description 127
- 239000003480 eluent Substances 0.000 description 116
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 111
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 105
- 239000002904 solvent Substances 0.000 description 100
- 239000012267 brine Substances 0.000 description 98
- 239000011734 sodium Substances 0.000 description 95
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 86
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 80
- PJJJBBJSCAKJQF-UHFFFAOYSA-N guanidinium chloride Chemical compound [Cl-].NC(N)=[NH2+] PJJJBBJSCAKJQF-UHFFFAOYSA-N 0.000 description 78
- 229910000104 sodium hydride Inorganic materials 0.000 description 78
- 229960000789 guanidine hydrochloride Drugs 0.000 description 77
- 239000000284 extract Substances 0.000 description 73
- 239000006185 dispersion Substances 0.000 description 71
- 239000002480 mineral oil Substances 0.000 description 70
- 235000010446 mineral oil Nutrition 0.000 description 70
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 60
- 239000011541 reaction mixture Substances 0.000 description 60
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 59
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 56
- 239000002244 precipitate Substances 0.000 description 53
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 49
- SJMDMGHPMLKLHQ-UHFFFAOYSA-N tert-butyl 2-aminoacetate Chemical compound CC(C)(C)OC(=O)CN SJMDMGHPMLKLHQ-UHFFFAOYSA-N 0.000 description 47
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 46
- 239000000725 suspension Substances 0.000 description 46
- 239000011343 solid material Substances 0.000 description 41
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- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 37
- UVTOICZCRRXFKE-UHFFFAOYSA-N 1,4-dichloroisoquinoline-7-sulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=C2C(Cl)=CN=C(Cl)C2=C1 UVTOICZCRRXFKE-UHFFFAOYSA-N 0.000 description 36
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 36
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 36
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 35
- 239000000843 powder Substances 0.000 description 33
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 32
- 238000000354 decomposition reaction Methods 0.000 description 31
- QVDYYQXUNAQSNI-UHFFFAOYSA-N ethyl acetate;pentane Chemical compound CCCCC.CCOC(C)=O QVDYYQXUNAQSNI-UHFFFAOYSA-N 0.000 description 31
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 30
- 108090000435 Urokinase-type plasminogen activator Proteins 0.000 description 29
- 239000004471 Glycine Substances 0.000 description 28
- 238000006243 chemical reaction Methods 0.000 description 28
- 229960002449 glycine Drugs 0.000 description 28
- 239000003921 oil Substances 0.000 description 28
- 235000019198 oils Nutrition 0.000 description 28
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 24
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 24
- 238000010992 reflux Methods 0.000 description 24
- DTQVDTLACAAQTR-DYCDLGHISA-N trifluoroacetic acid-d1 Chemical compound [2H]OC(=O)C(F)(F)F DTQVDTLACAAQTR-DYCDLGHISA-N 0.000 description 24
- 238000001914 filtration Methods 0.000 description 21
- 239000006260 foam Substances 0.000 description 19
- 238000003756 stirring Methods 0.000 description 19
- 229960003767 alanine Drugs 0.000 description 18
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 18
- 229960004198 guanidine Drugs 0.000 description 18
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 18
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 17
- 229960001269 glycine hydrochloride Drugs 0.000 description 17
- NILQLFBWTXNUOE-UHFFFAOYSA-N 1-aminocyclopentanecarboxylic acid Chemical compound OC(=O)C1(N)CCCC1 NILQLFBWTXNUOE-UHFFFAOYSA-N 0.000 description 16
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 16
- 239000006196 drop Substances 0.000 description 15
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 14
- 239000002585 base Substances 0.000 description 14
- 210000004027 cell Anatomy 0.000 description 14
- 238000001665 trituration Methods 0.000 description 14
- 102000003990 Urokinase-type plasminogen activator Human genes 0.000 description 13
- 239000012074 organic phase Substances 0.000 description 13
- 229940012957 plasmin Drugs 0.000 description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 12
- 229960005356 urokinase Drugs 0.000 description 12
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 11
- 125000006179 2-methyl benzyl group Chemical group [H]C1=C([H])C(=C(C([H])=C1[H])C([H])([H])*)C([H])([H])[H] 0.000 description 10
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- 238000002425 crystallisation Methods 0.000 description 10
- 230000008025 crystallization Effects 0.000 description 10
- NLLGKNYQDQBMFW-UHFFFAOYSA-N ethyl 1-aminocyclopentane-1-carboxylate Chemical compound CCOC(=O)C1(N)CCCC1 NLLGKNYQDQBMFW-UHFFFAOYSA-N 0.000 description 10
- 238000001704 evaporation Methods 0.000 description 10
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- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 9
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- NYYSTELLMIKOJD-UHFFFAOYSA-N 1,4-dichloroisoquinoline-7-carbonyl chloride Chemical compound ClC1=CN=C(Cl)C2=CC(C(=O)Cl)=CC=C21 NYYSTELLMIKOJD-UHFFFAOYSA-N 0.000 description 6
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 6
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 6
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 6
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- RNLQHMIDSCYLAK-UHFFFAOYSA-N tert-butyl 2-(methylamino)acetate;hydron;chloride Chemical compound Cl.CNCC(=O)OC(C)(C)C RNLQHMIDSCYLAK-UHFFFAOYSA-N 0.000 description 1
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- JCIAOAWEMURZPR-UHFFFAOYSA-N tert-butyl 3-[(1,4-dichloroisoquinolin-7-yl)sulfonylamino]propanoate Chemical compound ClC1=CN=C(Cl)C2=CC(S(=O)(=O)NCCC(=O)OC(C)(C)C)=CC=C21 JCIAOAWEMURZPR-UHFFFAOYSA-N 0.000 description 1
- XOBTVGBENYKVOJ-UHFFFAOYSA-N tert-butyl 3-[(1,4-dichloroisoquinoline-7-carbonyl)amino]propanoate Chemical compound ClC1=CN=C(Cl)C2=CC(C(=O)NCCC(=O)OC(C)(C)C)=CC=C21 XOBTVGBENYKVOJ-UHFFFAOYSA-N 0.000 description 1
- CSOJECDGWHHWRS-UHFFFAOYSA-N tert-butyl n-[(2-methylpropan-2-yl)oxycarbonylcarbamothioyl]carbamate Chemical compound CC(C)(C)OC(=O)NC(=S)NC(=O)OC(C)(C)C CSOJECDGWHHWRS-UHFFFAOYSA-N 0.000 description 1
- IUUYANMOEMBTBV-UHFFFAOYSA-N tert-butyl pyrrolidin-1-ium-2-carboxylate;chloride Chemical compound Cl.CC(C)(C)OC(=O)C1CCCN1 IUUYANMOEMBTBV-UHFFFAOYSA-N 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
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- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
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- A—HUMAN NECESSITIES
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- A61P17/06—Antipsoriatics
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- A—HUMAN NECESSITIES
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- A61P19/00—Drugs for skeletal disorders
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/16—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
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/46—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with hetero atoms directly attached to the ring nitrogen atom
- C07D207/48—Sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/60—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
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/92—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with a hetero atom directly attached to the ring nitrogen atom
- C07D211/96—Sulfur atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
- C07D213/42—Radicals substituted by singly-bound nitrogen atoms having hetero atoms attached to the substituent nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
- C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring 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
- C07D401/06—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
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Rheumatology (AREA)
- Reproductive Health (AREA)
- Dermatology (AREA)
- Physical Education & Sports Medicine (AREA)
- Endocrinology (AREA)
- Immunology (AREA)
- Ophthalmology & Optometry (AREA)
- Gynecology & Obstetrics (AREA)
- Pregnancy & Childbirth (AREA)
- Pain & Pain Management (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Enzymes And Modification Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Hydrogenated Pyridines (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB9816228.2A GB9816228D0 (en) | 1998-07-24 | 1998-07-24 | Isoquinolines |
| GBGB9908829.6A GB9908829D0 (en) | 1998-07-24 | 1999-04-16 | Isoquinolines |
| PCT/IB1999/001289 WO2000005214A2 (fr) | 1998-07-24 | 1999-07-15 | Isoquinoleines utilisees en tant qu'inhibiteurs de l'urokinase |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| SK1062001A3 true SK1062001A3 (en) | 2001-11-06 |
Family
ID=10836172
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| SK106-2001A SK1062001A3 (en) | 1998-07-24 | 1999-07-15 | Isoquinolines as urokinase inhibitors |
Country Status (39)
| Country | Link |
|---|---|
| EP (1) | EP1077945B1 (fr) |
| JP (1) | JP2002521367A (fr) |
| KR (1) | KR20010083137A (fr) |
| CN (1) | CN1318059A (fr) |
| AR (1) | AR018960A1 (fr) |
| AT (1) | ATE230730T1 (fr) |
| AU (1) | AU745545B2 (fr) |
| BG (1) | BG105252A (fr) |
| BR (1) | BR9912374A (fr) |
| CA (1) | CA2337247A1 (fr) |
| CO (1) | CO5080787A1 (fr) |
| DE (1) | DE69904814T2 (fr) |
| DK (1) | DK1077945T3 (fr) |
| DZ (1) | DZ2852A1 (fr) |
| EA (1) | EA200100073A1 (fr) |
| EE (1) | EE200100049A (fr) |
| ES (1) | ES2189434T3 (fr) |
| GB (2) | GB9816228D0 (fr) |
| GT (1) | GT199900116A (fr) |
| HK (1) | HK1040996A1 (fr) |
| HN (1) | HN1999000116A (fr) |
| HR (1) | HRP20010059A2 (fr) |
| HU (1) | HUP0103665A3 (fr) |
| ID (1) | ID26993A (fr) |
| IS (1) | IS5789A (fr) |
| MA (1) | MA26664A1 (fr) |
| NO (1) | NO20010400L (fr) |
| OA (1) | OA11578A (fr) |
| PA (1) | PA8478901A1 (fr) |
| PE (1) | PE20000937A1 (fr) |
| PL (1) | PL346022A1 (fr) |
| PT (1) | PT1077945E (fr) |
| SI (1) | SI1077945T1 (fr) |
| SK (1) | SK1062001A3 (fr) |
| TN (1) | TNSN99149A1 (fr) |
| TR (1) | TR200100222T2 (fr) |
| TW (1) | TW530049B (fr) |
| UY (1) | UY25663A1 (fr) |
| ZA (1) | ZA200100230B (fr) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2003219039A1 (en) * | 2002-03-11 | 2003-09-22 | Curacyte Ag | Urokinase inhibitors, production and use thereof |
| JP4664924B2 (ja) | 2003-12-02 | 2011-04-06 | ウーツェーベー ファルマ ゲーエムベーハー | 中枢神経因性疼痛の治療のためのペプチド化合物の新規使用 |
| EP1604655A1 (fr) | 2004-06-09 | 2005-12-14 | Schwarz Pharma Ag | Utilisation nouvelle de peptides pour le traitement de neuralgies trigeminales |
| EP1604656A1 (fr) | 2004-06-09 | 2005-12-14 | Schwarz Pharma Ag | Utilisation nouvelle de peptides pour le traitement de la sclérose amytrophique latérale (ALS) |
| WO2007144195A2 (fr) | 2006-06-15 | 2007-12-21 | Schwarz Pharma Ag | Composition pharmaceutique ayant un effet anticonvulsivant synergique |
-
1998
- 1998-07-24 GB GBGB9816228.2A patent/GB9816228D0/en not_active Ceased
-
1999
- 1999-04-16 GB GBGB9908829.6A patent/GB9908829D0/en not_active Ceased
- 1999-07-15 HR HR20010059A patent/HRP20010059A2/hr not_active Application Discontinuation
- 1999-07-15 EA EA200100073A patent/EA200100073A1/ru unknown
- 1999-07-15 BR BR9912374-6A patent/BR9912374A/pt not_active IP Right Cessation
- 1999-07-15 TR TR2001/00222T patent/TR200100222T2/xx unknown
- 1999-07-15 HK HK02102712.1A patent/HK1040996A1/zh unknown
- 1999-07-15 HU HU0103665A patent/HUP0103665A3/hu unknown
- 1999-07-15 SK SK106-2001A patent/SK1062001A3/sk unknown
- 1999-07-15 PT PT99928177T patent/PT1077945E/pt unknown
- 1999-07-15 KR KR1020017000956A patent/KR20010083137A/ko not_active Ceased
- 1999-07-15 CA CA002337247A patent/CA2337247A1/fr not_active Abandoned
- 1999-07-15 DE DE69904814T patent/DE69904814T2/de not_active Expired - Fee Related
- 1999-07-15 AT AT99928177T patent/ATE230730T1/de not_active IP Right Cessation
- 1999-07-15 ID IDW20010169D patent/ID26993A/id unknown
- 1999-07-15 EP EP99928177A patent/EP1077945B1/fr not_active Expired - Lifetime
- 1999-07-15 AU AU45289/99A patent/AU745545B2/en not_active Ceased
- 1999-07-15 EE EEP200100049A patent/EE200100049A/xx unknown
- 1999-07-15 OA OA1200100002A patent/OA11578A/en unknown
- 1999-07-15 DK DK99928177T patent/DK1077945T3/da active
- 1999-07-15 CN CN99809025A patent/CN1318059A/zh active Pending
- 1999-07-15 ES ES99928177T patent/ES2189434T3/es not_active Expired - Lifetime
- 1999-07-15 SI SI9930178T patent/SI1077945T1/xx unknown
- 1999-07-15 PL PL99346022A patent/PL346022A1/xx not_active Application Discontinuation
- 1999-07-15 JP JP2000561170A patent/JP2002521367A/ja active Pending
- 1999-07-16 HN HN1999000116A patent/HN1999000116A/es unknown
- 1999-07-21 DZ DZ990152A patent/DZ2852A1/fr active
- 1999-07-21 TN TNTNSN99149A patent/TNSN99149A1/fr unknown
- 1999-07-21 PE PE1999000733A patent/PE20000937A1/es not_active Application Discontinuation
- 1999-07-21 MA MA25695A patent/MA26664A1/fr unknown
- 1999-07-22 AR ARP990103614A patent/AR018960A1/es not_active Application Discontinuation
- 1999-07-23 TW TW088112548A patent/TW530049B/zh active
- 1999-07-23 PA PA19998478901A patent/PA8478901A1/es unknown
- 1999-07-23 GT GT199900116A patent/GT199900116A/es unknown
- 1999-07-26 CO CO99047012A patent/CO5080787A1/es unknown
- 1999-08-16 UY UY25663A patent/UY25663A1/es unknown
-
2000
- 2000-12-22 IS IS5789A patent/IS5789A/is unknown
-
2001
- 2001-01-09 ZA ZA200100230A patent/ZA200100230B/en unknown
- 2001-01-23 NO NO20010400A patent/NO20010400L/no not_active Application Discontinuation
- 2001-02-14 BG BG105252A patent/BG105252A/xx unknown
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