JPH07304744A - New isoquinoline derivative and acid addition thereof salt - Google Patents
New isoquinoline derivative and acid addition thereof saltInfo
- Publication number
- JPH07304744A JPH07304744A JP6121902A JP12190294A JPH07304744A JP H07304744 A JPH07304744 A JP H07304744A JP 6121902 A JP6121902 A JP 6121902A JP 12190294 A JP12190294 A JP 12190294A JP H07304744 A JPH07304744 A JP H07304744A
- Authority
- JP
- Japan
- Prior art keywords
- acid
- compound
- formula
- acid addition
- addition salt
- 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
- 239000002253 acid Substances 0.000 title claims abstract description 17
- 150000003839 salts Chemical class 0.000 title claims abstract description 15
- 125000002183 isoquinolinyl group Chemical class C1(=NC=CC2=CC=CC=C12)* 0.000 title 1
- -1 6-substituted isoquinoline Chemical class 0.000 claims abstract description 29
- 150000001875 compounds Chemical class 0.000 claims abstract description 29
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 4
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 3
- HFHKVXKNHOPRSX-UHFFFAOYSA-N isoquinolin-6-yl 4-(diaminomethylideneamino)benzoate Chemical compound C1=CC(N=C(N)N)=CC=C1C(=O)OC1=CC=C(C=NC=C2)C2=C1 HFHKVXKNHOPRSX-UHFFFAOYSA-N 0.000 claims abstract 2
- 239000000126 substance Substances 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- RWUIBFUQTJSJJS-UHFFFAOYSA-N C1=CC(N=C(N)N)=CC=C1C(=O)OC1=CC=C(C(=NC=C2)C(O)=O)C2=C1 Chemical compound C1=CC(N=C(N)N)=CC=C1C(=O)OC1=CC=C(C(=NC=C2)C(O)=O)C2=C1 RWUIBFUQTJSJJS-UHFFFAOYSA-N 0.000 claims 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 abstract description 20
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 abstract description 10
- SXTSBZBQQRIYCU-UHFFFAOYSA-N 4-guanidinobenzoic acid Chemical compound NC(=N)NC1=CC=C(C(O)=O)C=C1 SXTSBZBQQRIYCU-UHFFFAOYSA-N 0.000 abstract description 8
- 108091005804 Peptidases Proteins 0.000 abstract description 7
- 239000003814 drug Substances 0.000 abstract description 7
- 102000035195 Peptidases Human genes 0.000 abstract description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 abstract description 6
- 230000002401 inhibitory effect Effects 0.000 abstract description 6
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 abstract description 5
- 239000003054 catalyst Substances 0.000 abstract description 5
- 239000003795 chemical substances by application Substances 0.000 abstract description 5
- 239000002904 solvent Substances 0.000 abstract description 5
- 201000010099 disease Diseases 0.000 abstract description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 3
- 101710081722 Antitrypsin Proteins 0.000 abstract description 2
- 206010033645 Pancreatitis Diseases 0.000 abstract description 2
- 230000004913 activation Effects 0.000 abstract description 2
- 230000001475 anti-trypsic effect Effects 0.000 abstract description 2
- 229940124597 therapeutic agent Drugs 0.000 abstract description 2
- 239000002753 trypsin inhibitor Substances 0.000 abstract description 2
- 230000000295 complement effect Effects 0.000 abstract 1
- 230000005494 condensation Effects 0.000 abstract 1
- 238000009833 condensation Methods 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 11
- 238000000034 method Methods 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 239000013078 crystal Substances 0.000 description 9
- 238000002844 melting Methods 0.000 description 9
- 230000008018 melting Effects 0.000 description 9
- 230000000704 physical effect Effects 0.000 description 9
- 238000000921 elemental analysis Methods 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 4
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 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 3
- AZYTZQYCOBXDGY-UHFFFAOYSA-N 2-pyrrolidin-1-ylpyridine Chemical compound C1CCCN1C1=CC=CC=N1 AZYTZQYCOBXDGY-UHFFFAOYSA-N 0.000 description 3
- FVYHJADOPOUBBA-UHFFFAOYSA-N 6-hydroxyisoquinoline-1-carboxylic acid Chemical compound OC1=CC=C2C(C(=O)O)=NC=CC2=C1 FVYHJADOPOUBBA-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 3
- 108090000631 Trypsin Proteins 0.000 description 3
- 102000004142 Trypsin Human genes 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 229940098779 methanesulfonic acid Drugs 0.000 description 3
- KRTLQDKNZAZZSH-UHFFFAOYSA-N methyl 6-hydroxyisoquinoline-1-carboxylate Chemical compound COC(=O)c1nccc2cc(O)ccc12 KRTLQDKNZAZZSH-UHFFFAOYSA-N 0.000 description 3
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- HNJUSJQIWFBNGY-UHFFFAOYSA-N OC=1C=C2C=CN=C(C2=CC1)C(=O)OCC1=CC=CC=C1 Chemical compound OC=1C=C2C=CN=C(C2=CC1)C(=O)OCC1=CC=CC=C1 HNJUSJQIWFBNGY-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 2
- FKMJXALNHKIDOD-LBPRGKRZSA-N TAMe Chemical compound NC(=N)NCCC[C@@H](C(=O)OC)NS(=O)(=O)C1=CC=C(C)C=C1 FKMJXALNHKIDOD-LBPRGKRZSA-N 0.000 description 2
- 150000008065 acid anhydrides Chemical class 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 2
- 229940092714 benzenesulfonic acid Drugs 0.000 description 2
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 2
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- FUKUFMFMCZIRNT-UHFFFAOYSA-N hydron;methanol;chloride Chemical class Cl.OC FUKUFMFMCZIRNT-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- CATWEXRJGNBIJD-UHFFFAOYSA-N n-tert-butyl-2-methylpropan-2-amine Chemical compound CC(C)(C)NC(C)(C)C CATWEXRJGNBIJD-UHFFFAOYSA-N 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 229940024999 proteolytic enzymes for treatment of wounds and ulcers Drugs 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 239000012588 trypsin Substances 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- YETFLAUJROGBMC-UHFFFAOYSA-N (4-carboxyphenyl)-(diaminomethylidene)azanium;chloride Chemical compound Cl.NC(N)=NC1=CC=C(C(O)=O)C=C1 YETFLAUJROGBMC-UHFFFAOYSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- BWKAYBPLDRWMCJ-UHFFFAOYSA-N 1,1-diethoxy-n,n-dimethylmethanamine Chemical compound CCOC(N(C)C)OCC BWKAYBPLDRWMCJ-UHFFFAOYSA-N 0.000 description 1
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 1
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 1
- FCEQRBOTYXIORK-UHFFFAOYSA-N 2-(diaminomethylideneamino)benzoic acid Chemical class NC(=N)NC1=CC=CC=C1C(O)=O FCEQRBOTYXIORK-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- LCJQUJLWSPPYFN-UHFFFAOYSA-N 2-bromopyridin-1-ium;iodide Chemical compound [I-].BrC1=CC=CC=[NH+]1 LCJQUJLWSPPYFN-UHFFFAOYSA-N 0.000 description 1
- ABFPKTQEQNICFT-UHFFFAOYSA-M 2-chloro-1-methylpyridin-1-ium;iodide Chemical compound [I-].C[N+]1=CC=CC=C1Cl ABFPKTQEQNICFT-UHFFFAOYSA-M 0.000 description 1
- QLHVJBXAQWPEDI-UHFFFAOYSA-N 2-chloro-3,5-dinitropyridine Chemical compound [O-][N+](=O)C1=CN=C(Cl)C([N+]([O-])=O)=C1 QLHVJBXAQWPEDI-UHFFFAOYSA-N 0.000 description 1
- QRAFJHXNLQTXQW-UHFFFAOYSA-N 2-methylpropyl hydrogen carbonate Chemical compound CC(C)COC(O)=O QRAFJHXNLQTXQW-UHFFFAOYSA-N 0.000 description 1
- VLWZBLANHZIGMV-UHFFFAOYSA-N 4-(diaminomethylideneamino)benzoic acid hydrate Chemical compound O.NC(N)=NC1=CC=C(C(O)=O)C=C1 VLWZBLANHZIGMV-UHFFFAOYSA-N 0.000 description 1
- JBSRWFDTGDGNLG-UHFFFAOYSA-N 4-(diaminomethylideneamino)benzoyl chloride;hydrochloride Chemical compound Cl.NC(=N)NC1=CC=C(C(Cl)=O)C=C1 JBSRWFDTGDGNLG-UHFFFAOYSA-N 0.000 description 1
- 229910015900 BF3 Inorganic materials 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- YRXBOTBUEGOYGH-UHFFFAOYSA-N C1=NC=CC2=CC(=CC=C12)O.COC=1C=C2C=CN=CC2=CC1 Chemical compound C1=NC=CC2=CC(=CC=C12)O.COC=1C=C2C=CN=CC2=CC1 YRXBOTBUEGOYGH-UHFFFAOYSA-N 0.000 description 1
- PZDJISFKGLNERX-UHFFFAOYSA-N CCC1=CC2=CC(O)=CC=C2C(C(O)=O)=N1 Chemical compound CCC1=CC2=CC(O)=CC=C2C(C(O)=O)=N1 PZDJISFKGLNERX-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 108010088842 Fibrinolysin Proteins 0.000 description 1
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- 239000004365 Protease Substances 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
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- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 108090000190 Thrombin Proteins 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- MNZMECMQTYGSOI-UHFFFAOYSA-N acetic acid;hydron;bromide Chemical compound Br.CC(O)=O MNZMECMQTYGSOI-UHFFFAOYSA-N 0.000 description 1
- 239000003377 acid catalyst Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
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- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
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- 239000002775 capsule Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- JYYOBHFYCIDXHH-UHFFFAOYSA-N carbonic acid;hydrate Chemical compound O.OC(O)=O JYYOBHFYCIDXHH-UHFFFAOYSA-N 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000000593 degrading effect Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- TXFOLHZMICYNRM-UHFFFAOYSA-N dichlorophosphoryloxybenzene Chemical compound ClP(Cl)(=O)OC1=CC=CC=C1 TXFOLHZMICYNRM-UHFFFAOYSA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- MKRTXPORKIRPDG-UHFFFAOYSA-N diphenylphosphoryl azide Chemical compound C=1C=CC=CC=1P(=O)(N=[N+]=[N-])C1=CC=CC=C1 MKRTXPORKIRPDG-UHFFFAOYSA-N 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- GPVPDRHTRGTSIH-UHFFFAOYSA-N isoquinolin-6-ol Chemical compound C1=NC=CC2=CC(O)=CC=C21 GPVPDRHTRGTSIH-UHFFFAOYSA-N 0.000 description 1
- 150000002537 isoquinolines Chemical class 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229940012957 plasmin Drugs 0.000 description 1
- 229920000137 polyphosphoric acid Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229960004072 thrombin Drugs 0.000 description 1
Landscapes
- Other In-Based Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【０００１】[0001]
【産業上の利用分野】本発明は、新規な６−置換イソキ
ノリン誘導体及びその薬理学的に許容できる酸付加塩に
関する。本発明の化合物は、医薬品として有用である。TECHNICAL FIELD The present invention relates to a novel 6-substituted isoquinoline derivative and a pharmaceutically acceptable acid addition salt thereof. The compounds of the present invention are useful as pharmaceuticals.
【０００２】[0002]
【従来の技術】従来、種々のグアニジノ安息香酸誘導体
が、蛋白分解酵素トリプシン、プラスミン、トロンビン
等の活性を阻害する作用を有し、医薬として使用されて
いる（特公昭49- 2107号公報、特開昭52-89640号公報、
特公昭61- 1063号公報等）。しかし、その効果は必ずし
も充分なものではなく、しかも、さらに安全性が高い蛋
白分解酵素阻害剤の開発が望まれていた。2. Description of the Related Art Conventionally, various guanidinobenzoic acid derivatives have been used as pharmaceuticals because they have the activity of inhibiting the activities of proteolytic enzymes trypsin, plasmin, thrombin and the like (Japanese Examined Patent Publication No. 49-2107). Japanese Laid-Open Publication No. 52-89640,
Japanese Patent Publication No. 61-1063, etc.). However, the effect is not always sufficient, and further development of a highly safe protease inhibitor has been desired.
【０００３】[0003]
【発明が解決しようとする課題】本発明は、従来の蛋白
分解酵素阻害剤よりもさらに優れた蛋白分解酵素阻害活
性を有する物質の提供を目的とする。DISCLOSURE OF THE INVENTION An object of the present invention is to provide a substance having a proteolytic enzyme inhibitory activity which is superior to that of conventional proteolytic enzyme inhibitors.
【０００４】[0004]
【課題を解決するための手段】本発明者らは、新規な蛋
白分解酵素阻害剤を研究する過程において、次の一般式
（Ｉ）で表される新規な６−置換イソキノリン誘導体が
優れた蛋白分解酵素阻害活性を有することを見出し、本
発明を完成するに至った。Means for Solving the Problems In the process of studying a novel protease inhibitor, the present inventors have found that a novel 6-substituted isoquinoline derivative represented by the following general formula (I) is an excellent protein. The inventors have found that they have a degrading enzyme inhibitory activity and have completed the present invention.
【０００５】すなわち、本発明は、次の一般式（Ｉ）で
表される６−置換イソキノリン誘導体またはその薬理学
的に許容できる酸付加塩に関する。That is, the present invention relates to a 6-substituted isoquinoline derivative represented by the following general formula (I) or a pharmaceutically acceptable acid addition salt thereof.
【０００６】[0006]
【化２】 〔式中、Ｒは水素または COOR1基を示す。ただし、Ｒ1
は水素、炭素数１〜４の直鎖または分枝鎖アルキル基、
フェニル基及びベンジル基よりなる群から選択される基
を示す。〕[Chemical 2] [In the formula, R represents hydrogen or a COOR 1 group. However, R 1
Is hydrogen, a linear or branched alkyl group having 1 to 4 carbon atoms,
A group selected from the group consisting of a phenyl group and a benzyl group is shown. ]
【０００７】本発明化合物（Ｉ）は、式（II）で表され
る４−グアニジノ安息香酸またはその反応性誘導体と、The compound (I) of the present invention comprises 4-guanidinobenzoic acid represented by the formula (II) or a reactive derivative thereof,
【化３】 次式(III) で表される６−ヒドロキシイソキノリン化合
物またはその反応性誘導体とを反応させることにより得
ることができる。[Chemical 3] It can be obtained by reacting with a 6-hydroxyisoquinoline compound represented by the following formula (III) or a reactive derivative thereof.
【化４】 〔式中、Ｒ及びＲ中に示されるＲ1 は前記と同様の意味
で用いられる〕[Chemical 4] [In the formula, R and R 1 shown in R are used in the same meaning as above]
【０００８】また、４−グアニジノ安息香酸（II）また
はその反応性誘導体と６−ヒドロキシイソキノリン化合
物 (III)またはその反応性誘導体との反応は、一般の脱
水反応を適用することができる。例えば、（ａ）触媒、
縮合剤等の存在下に遊離の４−グアニジノ安息香酸（I
I）またはその酸付加塩と６−ヒドロキシイソキノリン
化合物(III) またはその酸付加塩とを反応させる方法、
（ｂ）４−グアニジノ安息香酸（II）の反応性誘導体と
６−ヒドロキシイソキノリン化合物(III) とを反応させ
る方法、（ｃ）遊離の４−グアニジノ安息香酸（II）と
６−ヒドロキシイソキノリン化合物(III) の反応性誘導
体とを反応させる方法などを適用できる。For the reaction of 4-guanidinobenzoic acid (II) or its reactive derivative with 6-hydroxyisoquinoline compound (III) or its reactive derivative, a general dehydration reaction can be applied. For example, (a) catalyst,
In the presence of a condensing agent, etc., free 4-guanidinobenzoic acid (I
I) or an acid addition salt thereof and a method for reacting a 6-hydroxyisoquinoline compound (III) or an acid addition salt thereof,
(B) a method of reacting a reactive derivative of 4-guanidinobenzoic acid (II) with a 6-hydroxyisoquinoline compound (III), (c) free 4-guanidinobenzoic acid (II) and a 6-hydroxyisoquinoline compound (II) A method of reacting with the reactive derivative of III) can be applied.
【０００９】方法（ａ）における触媒としては、例え
ば、硫酸、塩酸、ｐ−トルエンスルホン酸、オキシ塩化
リン、ポリリン酸、三フッ化ホウ素等の酸触媒を挙げる
ことができる。縮合剤としては、例えば、ジフェニルホ
スホリルアジド、ジシクロヘキシルカルボジイミド、
Ｎ，Ｎ'-カルボジイミダゾール、Ｎ，Ｎ'-ジスクシンイ
ミジルカルボネート、１−（３−ジメチルアミノプロピ
ル）−３−エチルカルボジイミド、ジメチルホルムアミ
ドジエチルアセタール、Ｎ，Ｎ'-ジメチルホスホリルア
ミジックジクロライド、ジクロルリン酸フェニル等を利
用できる。このとき、ジメチルアミノピリジン、ピロリ
ジノピリジン等の塩基触媒を併用することもできる。Examples of the catalyst in the method (a) include acid catalysts such as sulfuric acid, hydrochloric acid, p-toluenesulfonic acid, phosphorus oxychloride, polyphosphoric acid and boron trifluoride. Examples of the condensing agent include diphenylphosphoryl azide, dicyclohexylcarbodiimide,
N, N'-carbodiimidazole, N, N'-disuccinimidyl carbonate, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, dimethylformamide diethyl acetal, N, N'-dimethylphosphorylamidic Dichloride, phenyl dichlorophosphate, etc. can be used. At this time, a base catalyst such as dimethylaminopyridine or pyrrolidinopyridine may be used in combination.
【００１０】反応条件は、用いる触媒または縮合剤によ
って異なるが、例えば、縮合剤であるジシクロヘキシル
カルボジイミドを用いる場合には、溶媒中で４−グアニ
ジノ安息香酸（II）とジシクロヘキシルカルボジイミド
とを反応させ、これに６−ヒドロキシイソキノリン化合
物(III) の溶液を加えて塩基の存在下または不存在下に
−30乃至 100℃で、数時間ないし数日間攪拌することに
よって反応は終了する。The reaction conditions differ depending on the catalyst or condensing agent used. For example, when dicondensing agent dicyclohexylcarbodiimide is used, 4-guanidinobenzoic acid (II) is reacted with dicyclohexylcarbodiimide in a solvent, The reaction is terminated by adding a solution of 6-hydroxyisoquinoline compound (III) to the above and stirring at -30 to 100 ° C for several hours to several days in the presence or absence of a base.
【００１１】このとき用いられる溶媒としては、一般の
有機溶媒、例えば、ピリジン、ジメチルホルムアミド、
クロロホルム、ジクロロメタン、四塩化炭素、ベンゼ
ン、トルエン、キシレン、ジエチルエーテル、ジオキサ
ン、テトラヒドロフラン、アセトニトリル、酢酸エチ
ル、ジメチルスルホキシドの他、水等を挙げることがで
きる。また、塩基としては、ピリジン、トリエチルアミ
ン、ジイソプロピルエチルアミン、ジ−ｔ−ブチルアミ
ン、ジメチルアミノピリジン、ピロリジノピリジン、Ｎ
−メチルモルホリン、１，８−ジアザビシクロ〔５，
４，０〕−７−ウンデセン等を挙げることができる。The solvent used at this time is a common organic solvent such as pyridine, dimethylformamide,
In addition to chloroform, dichloromethane, carbon tetrachloride, benzene, toluene, xylene, diethyl ether, dioxane, tetrahydrofuran, acetonitrile, ethyl acetate, dimethyl sulfoxide, water and the like can be mentioned. Further, as the base, pyridine, triethylamine, diisopropylethylamine, di-t-butylamine, dimethylaminopyridine, pyrrolidinopyridine, N
-Methylmorpholine, 1,8-diazabicyclo [5,5
4,0] -7-undecene and the like can be mentioned.
【００１２】方法（ｂ）におけるカルボン酸（II）の反
応性誘導体としては、酸ハライド、例えば、酸クロライ
ド、酸ブロマイド等；混合酸無水物、例えば、トリフロ
ロ酢酸、メタンスルホン酸、ベンゼンスルホン酸、イソ
ブトキシギ酸等との混合酸無水物；オニウム塩、例え
ば、２−ブロモ−１−ピリジニウムアイオダイド、２−
クロロ−３，５−ジニトロピリジン、２−クロロ−１−
メチルピリジニウムアイオダイド；活性エステル、例え
ば、ｐ−ニトロフェニルエステル、Ｎ−Ｏ−スクシンイ
ミドエステル等を挙げることができる。Examples of the reactive derivative of carboxylic acid (II) in the method (b) include acid halides such as acid chloride and acid bromide; mixed acid anhydrides such as trifluoroacetic acid, methanesulfonic acid and benzenesulfonic acid. Mixed acid anhydrides such as isobutoxyformic acid; onium salts such as 2-bromo-1-pyridinium iodide, 2-
Chloro-3,5-dinitropyridine, 2-chloro-1-
Methylpyridinium iodide; active esters such as p-nitrophenyl ester, N-O-succinimide ester and the like can be mentioned.
【００１３】反応条件は用いる反応性誘導体によって異
なるが、例えば、酸クロライドを用いる場合には、溶媒
中で酸クロライドと６−ヒドロキシイソキノリン化合物
(III) とを塩基の存在下または不存在下に−30乃至 100
℃で、数時間ないし数日間攪拌することによって反応は
終了する。The reaction conditions vary depending on the reactive derivative used. For example, when an acid chloride is used, the acid chloride and the 6-hydroxyisoquinoline compound are used in a solvent.
(III) in the presence or absence of a base -30 to 100
The reaction is completed by stirring at 0 ° C for several hours to several days.
【００１４】このとき用いられる溶媒としては、一般の
有機溶媒、例えば、ピリジン、クロロホルム、ジクロロ
メタン、ベンゼン、トルエン、キシレン、ジオキサン、
テトラヒドロフラン、アセトニトリル、酢酸エチル、ジ
メチルホルムアミド、ジメチルスルホキシド等を挙げる
ことができる。また、塩基としては、トリエチルアミ
ン、ジイソプロピルエチルアミン、ジ−ｔ−ブチルアミ
ン、ピリジン、ジメチルアミノピリジン、ピロリジノピ
リジン、Ｎ−メチルモルホリン、１，８−ジアザビシク
ロ〔５，４，０〕−７−ウンデセン等を利用できる。The solvent used at this time is a general organic solvent such as pyridine, chloroform, dichloromethane, benzene, toluene, xylene, dioxane,
Tetrahydrofuran, acetonitrile, ethyl acetate, dimethylformamide, dimethylsulfoxide and the like can be mentioned. As the base, triethylamine, diisopropylethylamine, di-t-butylamine, pyridine, dimethylaminopyridine, pyrrolidinopyridine, N-methylmorpholine, 1,8-diazabicyclo [5,4,0] -7-undecene, etc. Available.
【００１５】また、方法（ｃ）における６−ヒドロキシ
イソキノリン化合物(III) の反応性誘導体としては、例
えば、そのトリフロロ酢酸エステル、あるいは式(IV)The reactive derivative of the 6-hydroxyisoquinoline compound (III) in the method (c) is, for example, its trifluoroacetic acid ester or the formula (IV).
【化５】 〔式中、III ′は前記(III) で表される６−ヒドロキシ
イソキノリン化合物のヒドロキシル残基を表す〕で表さ
れる化合物等が利用できる。[Chemical 5] A compound represented by the formula [III 'represents a hydroxyl residue of the 6-hydroxyisoquinoline compound represented by the formula (III)] can be used.
【００１６】また、反応液から本発明化合物（Ｉ）を単
離精製するには、抽出、濃縮、結晶化、濾過、再結晶、
各種クロマトグラフィー等、通常の単離精製に用いられ
る化学操作を適用して行うことができる。In order to isolate and purify the compound (I) of the present invention from the reaction solution, extraction, concentration, crystallization, filtration, recrystallization,
It can be performed by applying chemical operations commonly used for isolation and purification such as various chromatography.
【００１７】以上のごとくして得られる本発明化合物
（Ｉ）は、必要に応じ、常法により酸付加塩とすること
ができる。酸としては、硫酸、塩酸、硝酸、リン酸、臭
化水素酸、炭酸等の無機酸、また、酢酸、乳酸、コハク
酸、酒石酸、リンゴ酸、クエン酸、メタンスルホン酸、
トルエンスルホン酸、ベンゼンスルホン酸等の有機酸が
利用できる。The compound (I) of the present invention obtained as described above can be converted into an acid addition salt by a conventional method, if necessary. Examples of the acid include inorganic acids such as sulfuric acid, hydrochloric acid, nitric acid, phosphoric acid, hydrobromic acid and carbonic acid, and acetic acid, lactic acid, succinic acid, tartaric acid, malic acid, citric acid, methanesulfonic acid,
Organic acids such as toluenesulfonic acid and benzenesulfonic acid can be used.
【００１８】式（Ｉ）の６−置換イソキノリン誘導体の
イン・ビトロ（in vitro）でのトリプシンの阻害作用
は、村松らの方法〔ザ・ジャーナル・オブ・バイオケミ
ストリー(The Journal of Biochemistry) ，58, 214 (1
965)〕に準じて行ったところ、次の表１に示す通りであ
った。37℃、10分間の反応でトリプシン 1.5μg がｐ−
トシルアルギニンメチルエステル（ＴＡＭＥ）を加水分
解する作用を50％抑制する式（Ｉ）で示される化合物の
濃度を表１に示す。本発明化合物の試験化合物番号及び
対照薬フォイパン（登録商標、小野薬品製）の構造式は
次の通りである。The in vitro inhibition of trypsin of the 6-substituted isoquinoline derivative of the formula (I) is described by Muramatsu et al. [The Journal of Biochemistry, 58. , 214 (1
965)], the results are shown in Table 1 below. Trypsin 1.5 μg was added to the p-
Table 1 shows the concentration of the compound represented by the formula (I) which suppresses the action of hydrolyzing tosylarginine methyl ester (TAME) by 50%. The test compound number of the compound of the present invention and the structural formula of the control drug Foypan (registered trademark, manufactured by Ono Yakuhin) are as follows.
【００１９】[0019]
【化６】 [Chemical 6]
【００２０】[0020]
【表１】 ───────────────────── 番号 50％阻害濃度（Ｍ） ───────────────────── １） 8.4×10-8 ２） 7.2×10-8 ３） 7.8×10-8 ４） 1.9×10-7 ５） 1.8×10-7 ───────────────────── フォイパン(FOIPAN) 6.5×10-8 ─────────────────────[Table 1] ───────────────────── Number 50% inhibitory concentration (M) ────────────────── ──── 1) 8.4 × 10 -8 2) 7.2 × 10 -8 3) 7.8 × 10 -8 4) 1.9 × 10 -7 5) 1.8 × 10 -7 ─────────── ────────── FOIPAN 6.5 × 10 -8 ─────────────────────
【００２１】このように本発明化合物（Ｉ）は、優れた
抗トリプシン作用を有しており、蛋白分解酵素または補
体の活性化により生じる疾患、例えば膵炎等の治療剤と
して有用である。Thus, the compound (I) of the present invention has an excellent antitrypsin action, and is useful as a therapeutic agent for diseases caused by activation of proteolytic enzymes or complements, such as pancreatitis.
【００２２】本発明化合物（Ｉ）を医薬として使用する
場合には、適当な賦形剤、担体、希釈剤等を用いて錠
剤、カプセル剤、顆粒、粉末又は注射剤等の剤形とし経
口または非経口的に投与することができる。When the compound (I) of the present invention is used as a medicine, it is made into a dosage form such as tablets, capsules, granules, powders or injections using an appropriate excipient, carrier, diluent or the like. It can be administered parenterally.
【００２３】次に本発明を参考例、実施例を挙げて説明
するが、これは本発明を具体例により、理解し易くする
ためのもので、本発明化合物の製造がこれにより制限さ
れるものではない。The present invention will now be described with reference to Reference Examples and Examples, which are for facilitating the understanding of the present invention by way of specific examples, and the production of the compound of the present invention is limited thereby. is not.
【参考例１】 ６−ヒドロキシイソキノリン ６−メトキシイソキノリン 510mgに48％臭化水素酸34ml
を加え、２時間加熱還流した後、反応液を減圧濃縮し
た。得られた固形物を水10mlに溶解し、炭酸水素ナトリ
ウムを加え中和した。析出した結晶を濾取し、2-プロパ
ノールから再結晶したところ、次の物性を有する標題化
合物20mg (収率 4.3％) を得た。Reference Example 1 6-Hydroxyisoquinoline 6-Methoxyisoquinoline 510 mg to 48% hydrobromic acid 34 ml
Was added and refluxed under heating for 2 hours, and then the reaction solution was concentrated under reduced pressure. The obtained solid was dissolved in 10 ml of water, and sodium hydrogen carbonate was added to neutralize it. The precipitated crystals were collected by filtration and recrystallized from 2-propanol to obtain 20 mg (yield 4.3%) of the title compound having the following physical properties.
【００２４】融点： 224〜225 ℃Melting point: 224-225 ° C.
【００２５】[0025]
【参考例２】 ６−ヒドロキシ−１−イソキノリンカルボン酸メチル ６−ヒドロキシ−１−イソキノリンカルボン酸10.00gを
メタノール50mlに懸濁し、次いで飽和塩化水素メタノー
ル溶液50mlを加え、70時間加熱還流した。反応混合物を
約半量に減圧濃縮し、析出した結晶を濾取した。得られ
た結晶は水30mlに懸濁し、飽和炭酸水素ナトリウム水溶
液で中和した後、酢酸エチル(200ml×3)で抽出し、有機
層は、水、飽和食塩水で洗浄後、無水硫酸マグネシウム
で乾燥し、減圧濃縮し、粗結晶を得た。得られた粗結晶
はエタノール−水から再結晶したところ、次の物性を有
する標題化合物 5.32g (収率49.5％）を得た。Reference Example 2 Methyl 6-hydroxy-1-isoquinolinecarboxylate 10.00 g of 6-hydroxy-1-isoquinolinecarboxylic acid was suspended in 50 ml of methanol, 50 ml of saturated hydrogen chloride methanol solution was added, and the mixture was heated under reflux for 70 hours. The reaction mixture was concentrated under reduced pressure to about half the amount, and the precipitated crystals were collected by filtration. The obtained crystals were suspended in 30 ml of water, neutralized with a saturated aqueous solution of sodium hydrogen carbonate, and extracted with ethyl acetate (200 ml × 3) .The organic layer was washed with water and saturated saline, and then dried over anhydrous magnesium sulfate. The crystals were dried and concentrated under reduced pressure to give crude crystals. The obtained crude crystals were recrystallized from ethanol-water to obtain 5.32 g (yield 49.5%) of the title compound having the following physical properties.
【００２６】融点： 180〜182 ℃ ＩＲ：νKBr cm-1: 3420, 3000, 1730, 1720, 1640, 15
90. 元素分析値：C11H9NO3として計算 Melting point: 180 to 182 ° C. IR: ν KBr cm −1 : 3420, 3000, 1730, 1720, 1640, 15
90. Elemental analysis value: Calculated as C 11 H 9 NO 3
【００２７】[0027]
【参考例３】 ６−ヒドロキシ−１−イソキノリンカルボン酸エチル ６−ヒドロキシ−１−イソキノリンカルボン酸 5.10g、
エタノール25ml、飽和塩化水素メタノール溶液25mlを用
いて、参考例２記載の方法に従って反応、後処理を行っ
たところ、次の物性を有する標題化合物 1.83g (収率3
1.2％) を得た。Reference Example 3 Ethyl 6-hydroxy-1-isoquinolinecarboxylic acid 5.10 g of 6-hydroxy-1-isoquinolinecarboxylic acid,
Using 25 ml of ethanol and 25 ml of saturated hydrogen chloride methanol solution, the reaction and post-treatment were carried out according to the method described in Reference Example 2, and 1.83 g of the title compound having the following physical properties (yield 3
1.2%).
【００２８】融点： 194〜195.5 ℃ ＩＲ：νKBr cm-1: 3420, 3000, 1720, 1640, 1600. 元素分析値：C12H11NO3 として計算 Melting point: 194 to 195.5 ° C. IR: ν KBr cm −1 : 3420, 3000, 1720, 1640, 1600. Elemental analysis value: calculated as C 12 H 11 NO 3.
【００２９】[0029]
【参考例４】 ６−ヒドロキシ−１−イソキノリンカルボン酸ベンジル ６−ヒドロキシ−１−イソキノリンカルボン酸10.00gを
ジメチルホルムアミド100mlに溶解し、炭酸水素ナトリ
ウム11.1g を加え、臭化ベンジル9.92g を10分かけて滴
下し、さらに80℃で１時間攪拌した。反応混合物を氷水
100mlに注ぎ、酢酸エチル(100ml×3)で抽出した後、有
機層を水、飽和食塩水で洗浄し、無水硫酸マグネシウム
で乾燥し、減圧濃縮したところ、赤色油状物を得た。得
られた油状物は、エタノール−水で結晶化したところ、
次の物性を有する標題化合物6.97g(収率47.2％) を得
た。Reference Example 4 Benzyl 6-hydroxy-1-isoquinolinecarboxylate 10.00 g of 6-hydroxy-1-isoquinolinecarboxylic acid was dissolved in 100 ml of dimethylformamide, 11.1 g of sodium hydrogencarbonate was added, and 9.92 g of benzyl bromide was added for 10 minutes. It dripped over, and also stirred at 80 degreeC for 1 hour. Reaction mixture with ice water
After pouring into 100 ml and extracting with ethyl acetate (100 ml × 3), the organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a red oil. The obtained oil was crystallized from ethanol-water,
The title compound (6.97 g, yield 47.2%) having the following physical properties was obtained.
【００３０】融点： 143〜144 ℃ ＩＲ：νKBr cm-1: 3420, 3020, 1720, 1640, 1590. 元素分析値：C17H13NO3 として計算 Melting point: 143-144 ° C. IR: ν KBr cm −1 : 3420, 3020, 1720, 1640, 1590. Elemental analysis value: calculated as C 17 H 13 NO 3.
【００３１】[0031]
【実施例１】 ６−（４−グアニジノベンゾイル）オキシイソキノリン
二メタンスルホン酸塩 ４−グアニジノ安息香酸塩酸塩 4.50gをピリジン90mlに
溶解し、氷冷下ジシクロヘキシルカルボジイミド 4.10g
を加え、１時間攪拌した。次いで６−ヒドロキシイソキ
ノリン 3.00gをピリジン50mlに溶解した溶液を滴下し、
氷冷下１時間さらに室温で16時間攪拌した。析出した反
応生成物を濾取し、得られた固形物は、メタノール20ml
を加え 2.5時間攪拌後、不溶物を濾去した。濾液は、減
圧濃縮し、得られた残渣にメタノール20mlを加え懸濁
し、氷冷下液性が酸性になるまでメタンスルホン酸を滴
下した後、不溶物を濾去した。濾液にエーテルを加え結
晶化したところ、次の物性を有する標題化合物 2.10g
(収率20.4％) を得た。Example 1 6- (4-guanidinobenzoyl) oxyisoquinoline dimethanesulfonate 4.50 g of 4-guanidinobenzoic acid hydrochloride was dissolved in 90 ml of pyridine, and 4.10 g of dicyclohexylcarbodiimide was cooled with ice.
Was added and stirred for 1 hour. Then, a solution of 3.00 g of 6-hydroxyisoquinoline in 50 ml of pyridine was added dropwise,
The mixture was stirred under ice cooling for 1 hour and further at room temperature for 16 hours. The precipitated reaction product was collected by filtration, and the obtained solid was 20 ml of methanol.
Was added and the mixture was stirred for 2.5 hours, and then the insoluble matter was filtered off. The filtrate was concentrated under reduced pressure, 20 ml of methanol was added to the resulting residue to suspend it, and methanesulfonic acid was added dropwise until the liquid property became acidic under ice cooling, and then the insoluble matter was filtered off. Ether was added to the filtrate for crystallization, and 2.10 g of the title compound having the following physical properties was obtained.
(Yield 20.4%) was obtained.
【００３２】融点： 195〜206 ℃ ＩＲ：νKBr cm-1: 3400〜2800, 1730, 1700, 1660, 16
40, 1570. 元素分析値：C17H14N4O2・2CH3SO3Hとして計算 Ｃ (％) Ｈ (％) Ｎ (％) Ｓ (％) 理論値 45.78 4.45 11.24 12.86 実測値 45.82 4.60 11.22 12.59Melting point: 195 to 206 ° C. IR: ν KBr cm −1 : 3400 to 2800, 1730, 1700, 1660, 16
40, 1570. Elemental analysis: Calculated as C 17 H 14 N 4 O 2・ 2CH 3 SO 3 H C (%) H (%) N (%) S (%) Theoretical value 45.78 4.45 11.24 12.86 Measured value 45.82 4.60 11.22 12.59
【００３３】[0033]
【実施例２】 ６−（４−グアニジノベンゾイル）オキシ−１−イソキ
ノリンカルボン酸メチル塩酸塩 ４−グアニジノ安息香酸 1.35gに塩化チオニル12.5mlを
加え、45分間加熱還流した。反応混合物にｎ−ヘキサン
を加え結晶化し、析出した結晶を濾取して４−グアニジ
ノ安息香酸塩化物塩酸塩を得た。この化合物を６−ヒド
ロキシ−１−イソキノリンカルボン酸メチル 1.02gのピ
リジン12.5ml溶液に−５℃で加え、反応温度を室温まで
昇温し30分間攪拌した。反応混合物にアセトン12.5mlを
加え、析出した結晶を濾取した。得られた結晶はメタノ
ールから再結晶したところ、次の物性を有する標題化合
物 1.33g (収率66.4％) を得た。Example 2 Methyl 6- (4-guanidinobenzoyl) oxy-1-isoquinolinecarboxylic acid hydrochloride To 1.35 g of 4-guanidinobenzoic acid was added 12.5 ml of thionyl chloride, and the mixture was heated under reflux for 45 minutes. N-Hexane was added to the reaction mixture for crystallization, and the precipitated crystals were collected by filtration to obtain 4-guanidinobenzoic acid chloride hydrochloride. This compound was added to a solution of 1.02 g of methyl 6-hydroxy-1-isoquinolinecarboxylate in 12.5 ml of pyridine at -5 ° C, the reaction temperature was raised to room temperature, and the mixture was stirred for 30 minutes. Acetone 12.5 ml was added to the reaction mixture, and the precipitated crystals were collected by filtration. The obtained crystals were recrystallized from methanol to give 1.33 g (yield 66.4%) of the title compound having the following physical properties.
【００３４】融点： 192〜194 ℃ ＩＲ：νKBr cm-1: 3300, 3100, 1720, 1680, 1630, 16
00, 1570. 元素分析値：C19H16N4O4・HCl として計算 Melting point: 192-194 ° C. IR: ν KBr cm −1 : 3300, 3100, 1720, 1680, 1630, 16
00, 1570. Elemental analysis: Calculated as C 19 H 16 N 4 O 4 · HCl
【００３５】[0035]
【実施例３】 ６−（４−グアニジノベンゾイル）オキシ−１−イソキ
ノリンカルボン酸エチル塩酸塩 ４−グアニジノ安息香酸 0.99g、塩化チオニル10.0ml、
６−ヒドロキシ−１−イソキノリンカルボン酸メチル
0.80g、ピリジン10.0mlを用いて、実施例２記載の方法
に従って反応、後処理を行ったところ、次の物性を有す
る標題化合物1.11g(収率72.6％) を得た。Example 3 6- (4-guanidinobenzoyl) oxy-1-isoquinolinecarboxylic acid ethyl hydrochloride 4-guanidinobenzoic acid 0.99 g, thionyl chloride 10.0 ml,
Methyl 6-hydroxy-1-isoquinolinecarboxylate
Using 0.80 g and 10.0 ml of pyridine, the reaction and post-treatment were carried out according to the method described in Example 2 to obtain 1.11 g (yield 72.6%) of the title compound having the following physical properties.
【００３６】融点： 210〜211.5 ℃ ＩＲ：νKBr cm-1: 3300, 3100, 1720, 1710, 1680, 16
50, 1630, 1600. 元素分析値：C20H18N4O4・HCl として計算 Melting point: 210 to 211.5 ° C. IR: ν KBr cm −1 : 3300, 3100, 1720, 1710, 1680, 16
50, 1630, 1600. Elemental analysis value: calculated as C 20 H 18 N 4 O 4 · HCl
【００３７】[0037]
【実施例４】 ６−（４−グアニジノベンゾイル）オキシ−１−イソキ
ノリンカルボン酸ベンジル塩酸塩 1/4水和物 ４−グアニジノ安息香酸 2.70g、塩化チオニル20.0ml、
６−ヒドロキシ−１−イソキノリンカルボン酸ベンジル
2.80g、ピリジン20.0mlを用いて、実施例２記載の方法
に従って反応、後処理を行ったところ、次の物性を有す
る標題化合物 1.68g (収率35.1％) を得た。Example 4 6- (4-guanidinobenzoyl) oxy-1-isoquinolinecarboxylic acid benzyl hydrochloride 1/4 hydrate 4-guanidinobenzoic acid 2.70 g, thionyl chloride 20.0 ml,
Benzyl 6-hydroxy-1-isoquinolinecarboxylate
When 2.80 g and 20.0 ml of pyridine were used and the reaction and post-treatment were carried out according to the method described in Example 2, 1.68 g (yield 35.1%) of the title compound having the following physical properties was obtained.
【００３８】融点： 193.5〜194 ℃ ＩＲ：νKBr cm-1: 3300, 3100, 1730, 1680, 1630, 16
00, 1570. 元素分析値：C25H20N4O4・HCl ・1/4 H2O として計算 Melting point: 193.5 to 194 ° C. IR: ν KBr cm −1 : 3300, 3100, 1730, 1680, 1630, 16
00, 1570. Elemental analysis: Calculated as C 25 H 20 N 4 O 4 · HCl · 1/4 H 2 O
【００３９】[0039]
【実施例５】 ６−（４−グアニジノベンゾイル）オキシ−１−イソキ
ノリンカルボン酸塩酸塩 実施例４記載の方法に従って製造した６−（４−グアニ
ジノベンゾイル）オキシ−１−イソキノリンカルボン酸
ベンジル塩酸塩 1/4水和物 1.00gを30％臭化水素−酢酸
溶液８mlに溶解し、室温で７日間攪拌した。反応混合物
にアセトン50mlを加え、析出した固形物を濾取した。得
られた固形物は、ジメチルスルホキシド4.3mlに溶解
し、水16mlで希釈した後、氷冷下、飽和炭酸水素ナトリ
ウムで中和し、次いで水16mlを加え、析出した固形物を
濾取した。得られた固形物は、メタノール６mlに懸濁
し、２Ｎ塩酸にてpH２とした後、４℃で15時間放置し結
晶化させたところ、次の物性を有する標題化合物 0.09g
(収率10.5％) を得た。Example 5 6- (4-guanidinobenzoyl) oxy-1-isoquinolinecarboxylic acid hydrochloride 6- (4-guanidinobenzoyl) oxy-1-isoquinolinecarboxylic acid benzyl hydrochloride prepared according to the method described in Example 4 1 Tetrahydrate (1.00 g) was dissolved in 30% hydrogen bromide-acetic acid solution (8 ml), and the mixture was stirred at room temperature for 7 days. Acetone 50 ml was added to the reaction mixture, and the precipitated solid was collected by filtration. The obtained solid was dissolved in 4.3 ml of dimethyl sulfoxide, diluted with 16 ml of water, neutralized with saturated sodium hydrogen carbonate under ice cooling, 16 ml of water was added, and the precipitated solid was collected by filtration. The obtained solid was suspended in 6 ml of methanol, adjusted to pH 2 with 2N hydrochloric acid, and allowed to stand at 4 ° C for 15 hours for crystallization to give 0.09 g of the title compound having the following physical properties.
(Yield 10.5%) was obtained.
【００４０】融点： 175〜181 ℃ ＩＲ：νKBr cm-1: 3500〜2750, 1740, 1680, 1630, 16
00, 1570, 1520. 元素分析値：C18H14N4O4・HCl として計算 Melting point: 175 to 181 ° C. IR: ν KBr cm −1 : 3500 to 2750, 1740, 1680, 1630, 16
00, 1570, 1520. Elemental analysis value: Calculated as C 18 H 14 N 4 O 4 · HCl
【００４１】[0041]
【発明の効果】本発明の新規なイソキノリン誘導体また
はその酸付加塩は優れた蛋白分解酵素阻害作用を有し、
蛋白分解酵素の作用に基づく疾病の治療に有効である。INDUSTRIAL APPLICABILITY The novel isoquinoline derivative of the present invention or an acid addition salt thereof has an excellent protease inhibitory action,
It is effective in treating diseases caused by the action of proteolytic enzymes.
───────────────────────────────────────────────────── フロントページの続き (72)発明者 島田 信一 栃木県宇都宮市兵庫塚１−10−２ 県営住 宅211 (72)発明者 瀬谷 元秀 栃木県下都賀郡石橋町石橋773−３ ＳＫ マンション３−Ａ (72)発明者 野本 信 栃木県河内郡南河内町薬師寺325−４ グ リーンタウン112−１−５−102 (72)発明者 奥江 雅之 栃木県下都賀郡石橋町石橋405 (72)発明者 富塚 英衞 埼玉県加須市中央１−12−27 ─────────────────────────────────────────────────── ─── Continued Front Page (72) Inventor Shinichi Shimada 1-10-2 Hyogozuka, Utsunomiya City, Tochigi Prefecture 211 (72) Inventor Motohide Seya 773-3 Ishibashi, Ishibashi-cho, Shimotsuga-gun, Tochigi SK Mansion 3-A (72) Innovator Nomoto Nobu 325-4 Yakushiji, Minamikawachi-cho, Kawachi-gun, Tochigi Green Town 112-1-5-102 (72) Inventor Masayuki Okue Ishibashi, Ishibashi-cho, Shimotsuga-gun, Tochigi 405 (72) Invention Person Hidetsuka Totsuka 1-12-27 Chuo, Kazo City, Saitama Prefecture
Claims (6)
ノリン誘導体またはその薬理学的に許容できる酸付加
塩。 【化１】 〔式中、Ｒは水素または COOR1基を表す。ただし、Ｒ1
は水素、炭素数１〜４の直鎖または分枝鎖アルキル基、
フェニル基及びベンジル基よりなる群から選択される基
を表す。〕1. A 6-substituted isoquinoline derivative represented by the general formula (I) or a pharmaceutically acceptable acid addition salt thereof. [Chemical 1] [In the formula, R represents hydrogen or a COOR 1 group. However, R 1
Is hydrogen, a linear or branched alkyl group having 1 to 4 carbon atoms,
It represents a group selected from the group consisting of a phenyl group and a benzyl group. ]
シイソキノリンまたはその薬理学的に許容できる酸付加
塩である請求項１記載の化合物。2. The compound according to claim 1, which is 6- (4-guanidinobenzoyl) oxyisoquinoline or a pharmaceutically acceptable acid addition salt thereof.
シ−１−イソキノリンカルボン酸またはその薬理学的に
許容できる酸付加塩である請求項１記載の化合物。3. The compound according to claim 1, which is 6- (4-guanidinobenzoyl) oxy-1-isoquinolinecarboxylic acid or a pharmaceutically acceptable acid addition salt thereof.
シ−１−イソキノリンカルボン酸メチルまたはその薬理
学的に許容できる酸付加塩である請求項１記載の化合
物。4. The compound according to claim 1, which is methyl 6- (4-guanidinobenzoyl) oxy-1-isoquinolinecarboxylate or a pharmaceutically acceptable acid addition salt thereof.
シ−１−イソキノリンカルボン酸エチルまたはその薬理
学的に許容できる酸付加塩である請求項１記載の化合
物。5. The compound according to claim 1, which is ethyl 6- (4-guanidinobenzoyl) oxy-1-isoquinolinecarboxylate or a pharmaceutically acceptable acid addition salt thereof.
シ−１−イソキノリンカルボン酸ベンジルまたはその薬
理学的に許容できる酸付加塩である請求項１記載の化合
物。6. The compound according to claim 1, which is benzyl 6- (4-guanidinobenzoyl) oxy-1-isoquinolinecarboxylate or a pharmaceutically acceptable acid addition salt thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP6121902A JPH07304744A (en) | 1994-05-11 | 1994-05-11 | New isoquinoline derivative and acid addition thereof salt |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP6121902A JPH07304744A (en) | 1994-05-11 | 1994-05-11 | New isoquinoline derivative and acid addition thereof salt |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH07304744A true JPH07304744A (en) | 1995-11-21 |
Family
ID=14822742
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP6121902A Pending JPH07304744A (en) | 1994-05-11 | 1994-05-11 | New isoquinoline derivative and acid addition thereof salt |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH07304744A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20010112673A (en) * | 2000-06-09 | 2001-12-21 | 김환기 | Preparation of Tropisetron HCl |
-
1994
- 1994-05-11 JP JP6121902A patent/JPH07304744A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20010112673A (en) * | 2000-06-09 | 2001-12-21 | 김환기 | Preparation of Tropisetron HCl |
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