JPS6038392B2 - Naphthyridine derivatives and their production method - Google Patents
Naphthyridine derivatives and their production methodInfo
- Publication number
- JPS6038392B2 JPS6038392B2 JP59210605A JP21060584A JPS6038392B2 JP S6038392 B2 JPS6038392 B2 JP S6038392B2 JP 59210605 A JP59210605 A JP 59210605A JP 21060584 A JP21060584 A JP 21060584A JP S6038392 B2 JPS6038392 B2 JP S6038392B2
- Authority
- JP
- Japan
- Prior art keywords
- formula
- acid addition
- general formula
- tables
- formulas
- 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.)
- Expired
Links
- 150000005054 naphthyridines Chemical class 0.000 title claims description 16
- 238000004519 manufacturing process Methods 0.000 title description 2
- 150000003839 salts Chemical class 0.000 claims description 27
- 239000002253 acid Substances 0.000 claims description 19
- 238000000034 method Methods 0.000 claims description 17
- 125000004432 carbon atom Chemical group C* 0.000 claims description 13
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 12
- 150000001875 compounds Chemical class 0.000 claims description 12
- 239000000126 substance Substances 0.000 claims description 11
- 125000000217 alkyl group Chemical group 0.000 claims description 10
- 238000006243 chemical reaction Methods 0.000 claims description 8
- 125000005843 halogen group Chemical group 0.000 claims description 7
- 239000003960 organic solvent Substances 0.000 claims description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 6
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 4
- 229910052783 alkali metal Inorganic materials 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- FLBAYUMRQUHISI-UHFFFAOYSA-N 1,8-naphthyridine Chemical compound N1=CC=CC2=CC=CN=C21 FLBAYUMRQUHISI-UHFFFAOYSA-N 0.000 claims description 3
- 150000001340 alkali metals Chemical class 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 150000003512 tertiary amines Chemical class 0.000 claims description 2
- AKGSNUOZGBDODP-UHFFFAOYSA-N piperazine-1-carbonyl chloride Chemical compound ClC(=O)N1CCNCC1 AKGSNUOZGBDODP-UHFFFAOYSA-N 0.000 claims 2
- USBJISHEGKJFBS-UHFFFAOYSA-N [2-(7-chloro-1,8-naphthyridin-2-yl)-3-oxo-5-(trifluoromethyl)-1h-isoindol-1-yl] 4-methylpiperazine-1-carboxylate Chemical compound C1CN(C)CCN1C(=O)OC1C2=CC=C(C(F)(F)F)C=C2C(=O)N1C1=CC=C(C=CC(Cl)=N2)C2=N1 USBJISHEGKJFBS-UHFFFAOYSA-N 0.000 claims 1
- FLDFUIZQNROJJV-UHFFFAOYSA-N [2-(7-chloro-1,8-naphthyridin-2-yl)-3-oxo-6-(trifluoromethyl)-1h-isoindol-1-yl] 4-methylpiperazine-1-carboxylate Chemical compound C1CN(C)CCN1C(=O)OC1C2=CC(C(F)(F)F)=CC=C2C(=O)N1C1=CC=C(C=CC(Cl)=N2)C2=N1 FLDFUIZQNROJJV-UHFFFAOYSA-N 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 25
- 239000000203 mixture Substances 0.000 description 22
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- 238000001914 filtration Methods 0.000 description 9
- 239000000725 suspension Substances 0.000 description 9
- 239000002244 precipitate Substances 0.000 description 8
- WFDIJRYMOXRFFG-UHFFFAOYSA-N acetic acid anhydride Natural products CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 7
- 238000002844 melting Methods 0.000 description 7
- 230000008018 melting Effects 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 239000013543 active substance Substances 0.000 description 4
- 150000003949 imides Chemical class 0.000 description 4
- 239000003701 inert diluent Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- LUJWIDFODBQELS-UHFFFAOYSA-N 2-(7-chloro-1,8-naphthyridin-2-yl)-5-(trifluoromethyl)isoindole-1,3-dione Chemical compound C1=CC(Cl)=NC2=NC(N3C(=O)C4=CC=C(C=C4C3=O)C(F)(F)F)=CC=C21 LUJWIDFODBQELS-UHFFFAOYSA-N 0.000 description 3
- NQTLZJODEOHALT-UHFFFAOYSA-N 2-amino-4-(trifluoromethyl)benzoic acid Chemical compound NC1=CC(C(F)(F)F)=CC=C1C(O)=O NQTLZJODEOHALT-UHFFFAOYSA-N 0.000 description 3
- VNLYHYHJIXGBFX-UHFFFAOYSA-N 4-(trifluoromethyl)phthalic acid Chemical compound OC(=O)C1=CC=C(C(F)(F)F)C=C1C(O)=O VNLYHYHJIXGBFX-UHFFFAOYSA-N 0.000 description 3
- AKAAHMXNWDUFTD-UHFFFAOYSA-N 5-(trifluoromethyl)-2-benzofuran-1,3-dione Chemical compound FC(F)(F)C1=CC=C2C(=O)OC(=O)C2=C1 AKAAHMXNWDUFTD-UHFFFAOYSA-N 0.000 description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- -1 alkali metal salt Chemical class 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000008194 pharmaceutical composition Substances 0.000 description 3
- 239000008247 solid mixture Substances 0.000 description 3
- CRADWWWVIYEAFR-UHFFFAOYSA-N 1,8-naphthyridin-2-amine Chemical compound C1=CC=NC2=NC(N)=CC=C21 CRADWWWVIYEAFR-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 150000001450 anions Chemical class 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- DZICUHOFOOPVFM-UHFFFAOYSA-N methyl 2-amino-4-(trifluoromethyl)benzoate Chemical compound COC(=O)C1=CC=C(C(F)(F)F)C=C1N DZICUHOFOOPVFM-UHFFFAOYSA-N 0.000 description 2
- FVVIVIPXASZNGB-UHFFFAOYSA-N methyl 2-cyano-4-(trifluoromethyl)benzoate Chemical compound COC(=O)C1=CC=C(C(F)(F)F)C=C1C#N FVVIVIPXASZNGB-UHFFFAOYSA-N 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 239000003204 tranquilizing agent Substances 0.000 description 2
- 230000002936 tranquilizing effect Effects 0.000 description 2
- UMFCIIBZHQXRCJ-NSCUHMNNSA-N trans-anol Chemical compound C\C=C\C1=CC=C(O)C=C1 UMFCIIBZHQXRCJ-NSCUHMNNSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 239000000080 wetting agent Substances 0.000 description 2
- QNRATNLHPGXHMA-XZHTYLCXSA-N (r)-(6-ethoxyquinolin-4-yl)-[(2s,4s,5r)-5-ethyl-1-azabicyclo[2.2.2]octan-2-yl]methanol;hydrochloride Chemical compound Cl.C([C@H]([C@H](C1)CC)C2)CN1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OCC)C=C21 QNRATNLHPGXHMA-XZHTYLCXSA-N 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- VLXSIHLNPYRFFN-UHFFFAOYSA-N 1,4-dioxane;methanol Chemical compound OC.C1COCCO1 VLXSIHLNPYRFFN-UHFFFAOYSA-N 0.000 description 1
- ZQXCQTAELHSNAT-UHFFFAOYSA-N 1-chloro-3-nitro-5-(trifluoromethyl)benzene Chemical compound [O-][N+](=O)C1=CC(Cl)=CC(C(F)(F)F)=C1 ZQXCQTAELHSNAT-UHFFFAOYSA-N 0.000 description 1
- VBDNYRVQYGYKIT-UHFFFAOYSA-N 2-(7-chloro-1,8-naphthyridin-2-yl)-3-hydroxy-5-(trifluoromethyl)-3h-isoindol-1-one Chemical compound C1=CC(Cl)=NC2=NC(N3C(C4=CC(=CC=C4C3=O)C(F)(F)F)O)=CC=C21 VBDNYRVQYGYKIT-UHFFFAOYSA-N 0.000 description 1
- OJFGKHPNYXIDRK-UHFFFAOYSA-N 2-(7-chloro-1,8-naphthyridin-2-yl)-3-hydroxy-6-(trifluoromethyl)-3h-isoindol-1-one Chemical compound C1=CC(Cl)=NC2=NC(N3C(C4=CC=C(C=C4C3=O)C(F)(F)F)O)=CC=C21 OJFGKHPNYXIDRK-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 235000017166 Bambusa arundinacea Nutrition 0.000 description 1
- 235000017491 Bambusa tulda Nutrition 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-L L-tartrate(2-) Chemical compound [O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O FEWJPZIEWOKRBE-JCYAYHJZSA-L 0.000 description 1
- 231100000111 LD50 Toxicity 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 241000699660 Mus musculus Species 0.000 description 1
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- CWRVKFFCRWGWCS-UHFFFAOYSA-N Pentrazole Chemical compound C1CCCCC2=NN=NN21 CWRVKFFCRWGWCS-UHFFFAOYSA-N 0.000 description 1
- 244000082204 Phyllostachys viridis Species 0.000 description 1
- 235000015334 Phyllostachys viridis Nutrition 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 229910000831 Steel Inorganic materials 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
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- VYEYJCBEXFTGBN-UHFFFAOYSA-N acetic acid;1,3-dimethyl-7h-purine-2,6-dione Chemical compound CC(O)=O.O=C1N(C)C(=O)N(C)C2=C1NC=N2 VYEYJCBEXFTGBN-UHFFFAOYSA-N 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
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- 230000001580 bacterial effect Effects 0.000 description 1
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- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
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- 125000004093 cyano group Chemical group *C#N 0.000 description 1
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- 150000002170 ethers Chemical class 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
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- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
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- 235000008390 olive oil Nutrition 0.000 description 1
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- AHWALFGBDFAJAI-UHFFFAOYSA-N phenyl carbonochloridate Chemical compound ClC(=O)OC1=CC=CC=C1 AHWALFGBDFAJAI-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
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- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
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- 238000007363 ring formation reaction Methods 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
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- 239000010959 steel Substances 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 239000000021 stimulant Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/08—Preparation of carboxylic acids or their salts, halides or anhydrides from nitriles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/54—Preparation of carboxylic acid anhydrides
- C07C51/56—Preparation of carboxylic acid anhydrides from organic acids, their salts, their esters or their halides, e.g. by carboxylation
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Neurology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Anesthesiology (AREA)
- Pain & Pain Management (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
【発明の詳細な説明】
本発明に、治療上有用な新規ナフチリジン誘導体、その
製造方法およびそれを含有する医薬組成物に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel therapeutically useful naphthyridine derivatives, processes for their production, and pharmaceutical compositions containing them.
本発明は、袴関昭４９−５２３７８号明細書に開示した
発明の改良または変更に関するものである。特閥昭４９
−５２３７８号明細書において、本出願人は一般式〔式
中、記号＝Ｘ−の１個は＝Ｎ一を表わし、そして他の３
個はそれぞれ基を表わ
し、ここでＹは水素もしくはハロゲン原子、炭素数が１
〜４のアルキル基、炭素数が１〜４のアルコキシ基、ま
たはシアノもしくはニトロ基を表わし、記号＝Ａ−およ
び＝Ａ，一は基＝ＣＨ−または＝Ｎ−を表わし、ただし
＝Ａ−がＣＨ−を表わすときは＝ＡＩ−は基＝ＣＨ−ま
たは＝Ｎ−を表わしそして＝Ａ−が＝Ｎ−を表わすとき
は＝Ａ，一は＝Ｎ−を表わし、記号Ｚは水素もしくはハ
ロゲン原子、炭素数が１〜４のアルキルもしくはアルコ
キシ基またはニトロ基を表わし、ｍは０または整数１〜
４を表わし、そして【ｉ｝ ｎは０を表わしかつＲは水
素原子、炭素数が１〜４のアルキル基、炭素数が２〜４
のアルケニル基、炭素数が２〜４のアルキニル基、炭素
数が１〜４のヒドロキシアルキル基またはフェニル基を
表わすか、或いは剛ｎは１を表わしかつＲは炭素数が１
〜４のアルキルもしくはヒドロキシアルキル基またはフ
ェニル基を表わす〕のナフチリジン誘導体およびその酸
付加塩を記載した。The present invention relates to an improvement or modification of the invention disclosed in Hakamaseki No. 49-52378. Special clique 1977
-52378, the applicant has proposed the general formula [wherein one of the symbols =X- represents =N1, and the other three
Each represents a group, where Y is a hydrogen or halogen atom, and the number of carbon atoms is 1.
~4 alkyl group, an alkoxy group having 1 to 4 carbon atoms, or a cyano or nitro group, symbols =A- and =A, one represents a group =CH- or =N-, provided that =A- When representing CH-, =AI- represents the group =CH- or =N-, and when =A- represents =N-, =A, one represents =N-, and the symbol Z is a hydrogen or halogen atom. , represents an alkyl or alkoxy group having 1 to 4 carbon atoms, or a nitro group, and m is 0 or an integer of 1 to 4.
4, and [i} n represents 0 and R is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, and 2 to 4 carbon atoms.
represents an alkenyl group, an alkynyl group having 2 to 4 carbon atoms, a hydroxyalkyl group having 1 to 4 carbon atoms, or a phenyl group, or where n represents 1 and R represents 1 carbon number.
-4 representing an alkyl or hydroxyalkyl group or a phenyl group] and acid addition salts thereof.
それらのナフチリジン誘導体は有用な薬理学的性質を有
しており、特に精神安定剤および鍵蓮剤として活性があ
る。さらに実験および研究の結果、上記一般式において
ナフチリジン後の８−位にある記号Ｘ−が＝Ｎ−を表わ
し、５−位および６一位にある記号＝Ｘ−が＝ＣＨ一を
表わしそして７−位にある記号Ｘが（Ｙはハロゲン原子
を表わす）を表
わし、記号ＡおよびＡ，がそれぞれ基＝ＣＨ一を表わし
、Ｚがトリフルオロメチル基を表わし、ｍが１を表わし
、ｎが０を表わし、そしてＲは炭素原子数１〜４のアル
キル基を表わす、該一般式を有する化合物も一般式１の
ナフチリジン譲導体と同じ有用な薬理学的性質を有する
、ということが今回見出された。These naphthyridine derivatives have useful pharmacological properties and are particularly active as tranquilizers and stimulants. Furthermore, as a result of experiments and research, the symbol X- at the 8-position after naphthyridine in the above general formula represents =N-, the symbol =X- at the 5-position and the 6-1st position represents =CH-, and the symbol The symbol X in the - position represents (Y represents a halogen atom), the symbols A and A, each represent a group=CH1, Z represents a trifluoromethyl group, m represents 1, and n represents 0 It has now been found that compounds having the general formula in which Ta.
したがって、本発明は、一般式
〔ＹＩはハロゲン原子を表わし、ＲＩは炭素原子数１〜
４のアルキル基を表わす〕の新規なナフチリジン誘導体
およびその酸付加塩を提供する。Therefore, the present invention is based on the general formula [YI represents a halogen atom, RI has 1 to 1 carbon atoms]
4 representing an alkyl group] and acid addition salts thereof.
本発明によれば、一般式０の化合物は、一般式〔式中、
ＲＩは上記に定義した通りである〕のクロロカルボニル
ピベラジンを一般式〔式中、Ｙは上記に定義した通りで
ある〕のナフチリジン誘導体と反応させることを特徴と
する方法によって製造される。According to the invention, the compound of general formula 0 is a compound of general formula [wherein,
RI is as defined above] with a naphthyridine derivative of the general formula [where Y is as defined above].
通常、一般式ｍの化合物は、一般式Ｎの化合物の随時そ
の場で製造したアルカリ金属塩と反応させ、そしてこの
反応は無水有機溶媒たとえばジメチルホルムアミドまた
はテトラヒドロフランの中で６ぴ０以下の温度にて行な
われる。Usually, a compound of general formula m is reacted with an alkali metal salt of a compound of general formula N, optionally prepared in situ, and the reaction is carried out in an anhydrous organic solvent such as dimethylformamide or tetrahydrofuran at a temperature below 60°C. It is done.
また、反応は、一般式ｍの化合物の酸付加塩好ましくは
塩酸塩をピリジン中でかつ必要に応じて第三級アミン（
たとえばトリェチルアミン）の存在下で反応させ、上記
の塩から一般式ｍの化合物を遊離させることによって行
なうこともできる。The reaction can also be carried out using an acid addition salt, preferably a hydrochloride, of a compound of general formula m in pyridine and optionally with a tertiary amine (
This can also be carried out by liberating the compound of general formula m from the above-mentioned salt by reaction in the presence of triethylamine (for example, triethylamine).
一般式Ｗのナフチリジン誘導体は、一般式〔式中、ＹＩ
は上記に定義した通りである〕のィミドを部分還元して
カルボニル基の１つをヒドロキシメチレン基に変えるこ
とによって得られる。The naphthyridine derivative of the general formula W has the general formula [wherein YI
is as defined above] by partial reduction of the imide to convert one of the carbonyl groups into a hydroxymethylene group.
還元は一般に有機溶液または水性−有機溶液たとえばジ
オキサンとメタノールとの濠液またはジオキサンと水と
の混液またはメタノールと水との混液またはエタノール
と水との混液の中でアルカリ金属ホゥ水素化物を用いて
行なわれる。The reduction is generally carried out using an alkali metal borohydride in an organic solution or an aqueous-organic solution such as a dioxane and methanol solution or a mixture of dioxane and water or a mixture of methanol and water or a mixture of ethanol and water. It is done.
一般式Ｖのィミドの部分還元によって異性体生成物を得
、これをたとえば分別結晶化またはクロマトグラフィー
のような物理−化学的方法によって分離することができ
る。Partial reduction of imides of general formula V gives isomeric products which can be separated by physico-chemical methods, such as fractional crystallization or chromatography.
一般式Ｖのィミドは、一般式
〔式中、ＹＩは上記に定義した通りである〕の２−アミ
ノナフチリジンを一般式の熱水物と反応させ、その際随
時に中間体として一般式〔式中、ＹＩは上記に定義した
通りである〕の生成物を生成させることにより、製造す
ることができる。Imides of the general formula V are prepared by reacting 2-aminonaphthyridine of the general formula [wherein YI is as defined above] with a hydrothermal product of the general formula, optionally using intermediates as intermediates of the general formula [formula wherein YI is as defined above.
一般式打の２−アミノナフチリジンと一般式肌の無水物
との反応は一般に、たとえば酢酸、ジメチルホルムアミ
ド、アセトニトリルまたはジフエニルェーテルのような
有機溶媒の中で加熱して行なわれる。The reaction of the general formula 2-aminonaphthyridine with the general formula anhydride is generally carried out by heating in an organic solvent such as acetic acid, dimethylformamide, acetonitrile or diphenyl ether.
一般式風の中間生成物を環化して一般式Ｖのィミド生成
物を生成せしめる工程は、酢酸または無水酢酸中で塩化
アセチルと一緒に加熱するか或いは１０ぴ０以下の温度
においてジメチルホルムアミド中でたとえばＮ，Ｎ′ー
ジシクロヘキシルカルポジイミドのような縮合剤を作用
させることによって一般に行なうことができる。Cyclization of the intermediate product of general formula V to form an imide product of general formula V can be carried out by heating with acetyl chloride in acetic acid or acetic anhydride, or in dimethylformamide at a temperature below 10°C. For example, this can generally be carried out by using a condensing agent such as N,N'-dicyclohexylcarposiimide.
本発明の別の特徴によれば、一般式Ｄの化合物は、一般
式〔式中、ＲＩは上記に定義した通りである〕のピベラ
ジンを一般式〔式中、ＹＩは上記に定義した遜りであり
、そしてＡｒは炭素数１〜４のアルキル基もしくはニト
ロ基で畳襖されていてもよいフェニル基を表わす〕の混
成カーボネートと反応させることを特徴とする方法によ
って製造される。According to another feature of the invention, the compound of the general formula D comprises a piperazine of the general formula [wherein RI is as defined above] a compound of the general formula and Ar represents a phenyl group optionally surrounded by an alkyl group having 1 to 4 carbon atoms or a nitro group].
反応は一般に約２０℃たとえば１５〜２９０の溢度にお
いてたとえばアセトニトリルのような無水の有機溶媒中
で行なわれる。一般式Ｘの混成カーボネートは、一般式
ＣＩ一ＣＯ−○一Ａ止 幻
〔式中、〜は上記に定義した通りである〕のクロロホル
メートを一般式Ｗのナフチリジン誘導体と反応させて作
ることができる。The reaction is generally carried out in an anhydrous organic solvent such as acetonitrile at a temperature of about 20 DEG C., e.g. Hybrid carbonates of general formula I can do it.
反応は、０〜２０℃の温度においてたとえばピリジンの
ような塩基性有機溶媒の中で一般に行なわれる。上記の
方法で得られる一般式０のナフチリジン誘導体は、たと
えば蒸留、結晶化またはクロマトグラフィーのような物
理的方法、或いはたとえば塩の生成、該塩の結晶化およ
びアルカリ性媒体中における該塩の分解のような化学的
方法によって精製することができる。The reaction is generally carried out in a basic organic solvent such as pyridine at a temperature of 0 to 20<0>C. The naphthyridine derivatives of general formula 0 obtained by the above process can be prepared by physical methods such as distillation, crystallization or chromatography or by e.g. formation of the salt, crystallization of the salt and decomposition of the salt in an alkaline medium. It can be purified by chemical methods such as
化学的方法を行なう場合、該塩のァニオンの性質は重要
でなく、唯一の必要とすることは塩が明確かつ容易に再
結晶しうるものでなければならないということである。
一般式ロのナフチリジン誘導体は、それ自体公知の方法
によって酸付加塩に変えることができる。酸付加塩は、
適当な溶媒中でナフチリジン誘導体に酸を作用させて得
ることができる。有機溶媒としては、アルコール、エー
テル、ケトンまたは塩素化炭化水素を挙げることができ
る。生成した塩は、必要に応じて溶液を濃縮した後に、
沈殿せしめそして炉過または煩斜によって単離する。上
述したように、一般式０のナフチリジン誘導体およびそ
れらの酸付加塩は価値ある薬理学的性質を有している。
それらは特に精神安定剤および鍵塵剤として活性がある
。動物（ハツカネズミ）中では特に下記の試験で経口的
に０．１〜１００のｏ′ｋｇ・動物体重の投薬量でその
まま投与したときにそれらは活性であることが証明され
ている：‘ｉー テデシ（Ｔｅｄｅｓｃｈｉ）他０．Ｐ
ｈａｒｍａｃｏｌ．１２５２８（１９５９）の方法と同
様な方法に従う電気的バットル試験｛ｉｉ｝ エベレツ
ト（Ｅｖｅｒｅｔｔ）およびリチヤーズ（Ｒｉｃｈａｒ
船）〔Ｊ．ＰＭてｍａｃｏｌ．８１、４０２（１拠４）
〕の方法と同様な方法に従うペンテトラゾールを用いて
の塵鰹。When carrying out chemical methods, the anionic nature of the salt is not important; the only requirement is that the salt must be clearly and easily recrystallizable.
The naphthyridine derivative of general formula (b) can be converted into an acid addition salt by a method known per se. Acid addition salts are
It can be obtained by reacting a naphthyridine derivative with an acid in a suitable solvent. As organic solvents, mention may be made of alcohols, ethers, ketones or chlorinated hydrocarbons. After concentrating the solution as necessary, the generated salt is
Precipitate and isolate by filtration or filtration. As mentioned above, naphthyridine derivatives of general formula 0 and their acid addition salts have valuable pharmacological properties.
They are particularly active as tranquilizers and locksmiths. They have been shown to be active in animals (Mus musculus), especially when administered neat orally at doses of 0.1 to 100 o'kg/animal body weight in the following tests: Tedeschi et al.0. P
harmacol. 12528 (1959) {ii} Everett and Richards
ship) [J. PM macol. 81, 402 (1 basis 4)
] using pentetrazole according to a method similar to that of [1].
｛ｉｉｉ｝ スインヤード（ＳＭｎ協てｄ）他〔Ｊ．
Ｐｈａｒｍａｃｏｌ．１０６．３１９（１９５２）〕の
方法に従う超最大電撃ショック。{iii} Swinyard (SMn cooperation d) et al. [J.
Pharmacol. 106.319 (1952)].
肋 クールボアージエ（ＣｏｕＷｏｉｓｉｅｒ）〔Ｃｏ
ｎｇｅｓｄｅＳ Ｍｅｄ≦ＣｉｎＳ，ＡＩｉ≦ｎｉＳに
ＳｅｔＮｅｕｒ。Rib CouWoisier [Co
Set Neur for ngesdeS Med≦CinS, AIi≦niS.
ｌｏｇｉＳｔｅＳ−Ｔｏ川ｓ−（１９５ｇ手６月８〜１
３日）〕およびジユル（Ｊｕｌｏｕ）〔Ｂｕｌｌｅｔｉ
ｎ ｄｅ ｌａ ＳＭｉｅに ｄｅＰｈａｒｍａｃｉｅ
ｄｅＬｉｌｌｅ，Ｍ．２．１９６７年１月、７頁〕の方
法に従う運動活性。さらに、それらは低い毒性しか示さ
ず、ハツカネズミの場合のそれらの５０％致死量（ＬＤ
５ｏ）は経口没与のときには一般に３００の９／ｋ９・
動物体重より多量である。logiSteS-Tokawas-(195g hand June 8-1
3rd)] and Julou [Bulleti
n de la SMie de Pharmacie
deLille, M. 2. Motor activity according to the method of [January 1967, p. 7]. Moreover, they exhibit low toxicity, with their 50% lethal dose (LD
5o) is generally 9/k9 of 300 when given orally.
The amount is greater than the animal's weight.
特に重要なものは、一般式０においてＹＩが塩素原子を
表わすようなナフチリジン誘導体、特に２−（７ークロ
ロー１，８−ナフチリジンー２ーイル）一３一（４ーメ
チルピベラジン−１ーイル）力ルボニルオキシ−５ート
リフルオロメチルーィソィンドリン−１ーオンおよびそ
の酸付加塩である。Of particular importance are naphthyridine derivatives in which YI represents a chlorine atom in the general formula 0, especially 2-(7-chloro-1,8-naphthyridin-2-yl)-(4-methylpiverazin-1-yl) Rubonyloxy-5-trifluoromethylisoindolin-1-one and its acid addition salt.
沿療目的のためには一般式１のナフチリジン誘導体をそ
のまま使用することもでき又は非菱性の酸付加塩、すな
わち塩の治療量では動物有機体に対して比較的無害であ
る陰イオンを含有している塩（例えば塩酸塩、硫酸塩、
硝酸塩、リン酸塩、酢酸塩、プロピオン酸塩、こはく酸
塩、安息香酸塩、フマール酸塩、マレィン酸塩、酒石酸
塩、テオフイリン酢酸塩、サリチル酸塩、フェノールフ
タリネートおよびメチレンーピスー３ーヒドロキシナフ
トェ酸塩）の形でも使用でき、その結果塩基中で固有な
有利な生理学的性質は陰イオンに帰因する副作用により
損なわれることはない。For therapeutic purposes, the naphthyridine derivatives of general formula 1 can be used as such or as non-rhombic acid addition salts, i.e. containing anions which are relatively harmless to animal organisms in therapeutic doses of the salts. (e.g. hydrochloride, sulfate,
Nitrate, phosphate, acetate, propionate, succinate, benzoate, fumarate, maleate, tartrate, theophylline acetate, salicylate, phenolphthalinate and methylene-pi-3-hydroxynaphthoic acid It can also be used in the form of a salt), so that the advantageous physiological properties inherent in the base are not compromised by the side effects attributable to the anion.
以下の実施例により、本発明の方法による−★史式０の
ナフチリジン譲導体の製造を説明する。実施例 １１ー
クロロカルボニルー４−メチルピベラジン塩酸塩（７．
５夕）を、塩化メチレン（偽ｏｃｃ）、トリエチルアミ
ン（１０．２夕；１４．２ｃｃ）およびピリジン（６６
ｃｃ）の中の２一（７ークロロ−１，８ーナフチリジン
−２ーイル）一３−ヒドロキシー５−トリフルオロメチ
ルーイソインドリン−１ーオン（４．８夕）の懸濁物に
２０〜２１℃にて加えた。The following examples illustrate the preparation of naphthyridine derivatives of formula 0 by the method of the present invention. Example 11-Chlorocarbonyl-4-methylpiverazine hydrochloride (7.
5 cc), methylene chloride (pseudo-occ), triethylamine (10.2 cc; 14.2 cc) and pyridine (66 cc).
cc) in a suspension of 2-(7-chloro-1,8-naphthyridin-2-yl)-13-hydroxy-5-trifluoromethyl-isoindolin-1-one (4.8 pm) at 20-21°C. added.
５時間後、さらに１ークロロカルボニルー４ーメチルピ
ベラジン塩酸塩（７．６夕）を加えた。After 5 hours, further 1-chlorocarbonyl-4-methylpiverazine hydrochloride (7.6 night) was added.
縄拝を１虫時間続け、次いで混合物を水（４８０ｃｃ）
で加水分解させた。有機相を頃斜し去り、そして水層を
塩化メチレン（３００ｃｃ）で抽出した。有機層を合し
、水（１５０ｃｃ）で洗浄し、次いで無水硫酸ナトリウ
ム（１５夕）で脱水した。炉過しそして濃縮乾固させた
後、残燈（９．５夕）を水（１００ｃｃ）でトリチル化
した。炉過後、生成物を水（６０ｃｃ）で洗浄し、次い
でジクロルェタン（４２ｃｃ）から再結晶された。乾い
た沈殿を水（３７ｃｃ）と一緒に１時間燈拝し、炉過し
、洗浄しそして乾燥した。これにより、融点２２が○の
２一（７ークロロ−１，８ーナフチリジンー２−イル）
−３一（４ーメチルピベラジン−１ーイル）−力ルボニ
ルオキシ−５ートリフルオロメチルーイソインドリン−
１ーオン（３．３夕）が得られた。２一（７−クロロー
１，８ーナフチリジンー２−イル）一３ーヒドロキシー
５−トリフルオロメチルーィソィンドリン−１ーオンお
よびその異性体、２−（７−クロ。Continue the rope prayer for 1 hour, then pour the mixture into water (480cc)
was hydrolyzed with. The organic phase was decanted and the aqueous layer was extracted with methylene chloride (300 cc). The organic layers were combined, washed with water (150 cc), and then dried over anhydrous sodium sulfate (15 cc). After filtration and concentration to dryness, the residual light (9.5 pm) was tritylated with water (100 cc). After filtration, the product was washed with water (60 cc) and then recrystallized from dichloroethane (42 cc). The dry precipitate was soaked with water (37 cc) for 1 hour, filtered, washed and dried. As a result, 2-(7-chloro-1,8-naphthyridin-2-yl) with a melting point of 22
-3-(4-methylpiverazin-1-yl)-carbonyloxy-5-trifluoromethyl-isoindoline-
1-on (3.3 hours) was obtained. 2-(7-chloro-1,8-naphthyridin-2-yl)-1-3-hydroxy-5-trifluoromethylisoindolin-1-one and its isomers, 2-(7-chloro.
一１，８ーナフチリジンー２ーイル）一３ーヒド。キシ
ー６ートリフルオロメチルーイソインドリン−１ーオン
は次のようにして製造することができた。ホウ水素化カ
リウム（１２夕）をメタノール（４２０ｃｃ）およびジ
オキサン（４２０ｃｃ）の中の５−トリフルオロメチル
ーＮ一（７−クロロー１，８ーナフチリジン−２ーイル
）フタルイミド（８３６夕）の温度１５〜１８つ０の懸
濁液に温度１５〜１が○で加えた。-1,8 naphthyridin-2-yl) -13-hydro. X-6-trifluoromethyl-isoindolin-1-one could be produced as follows. Potassium borohydride (12 cc) and 5-trifluoromethyl-N-(7-chloro-1,8-naphthyridin-2-yl)phthalimide (836 cc) in methanol (420 cc) and dioxane (420 cc) at a temperature of 15-18 1 was added to the suspension at a temperature of 15 to 1.
混合物をさらに２時間燈拝し次いで氷格により外部から
冷却した。生成した沈殿を炉別し、次いでメタノール−
ジオキサン渡液（容量で１：１；４０ｃｃ）で洗浄した
。沈殿を再び炉別し、乾燥させ、次いで同じ演液（２０
０ｃｃ）と一緒に３０分間縄拝し、次いで炉別しそして
還流下にエタノール（２００ｃｃ）と一緒に加熱した。
懸濁液を冷却しそして炉過すると、３０び○以上の温度
で溶融する２−（７ークロロ−１，８−ナフチリジン−
２ーイル）−３−ヒドロキシー５ートリフルオロメチル
−ィソィンドリンー１ーオン（２１．９夕）が得られた
。反応混合物を炉過した後に縛られる溶液と、メタノー
ル−ジオキサン混液による洗浄からの液体とを合し、水
（２５００ｃｃ）を加えた。The mixture was allowed to stand for an additional 2 hours and then cooled externally using an ice rack. The generated precipitate was separated by furnace, and then methanol-
Washed with a dioxane flow (1:1 by volume; 40 cc). The precipitate was filtered again, dried and then soaked in the same working liquid (20
0 cc) for 30 minutes, then furnaced and heated under reflux with ethanol (200 cc).
When the suspension is cooled and filtered, the 2-(7-chloro-1,8-naphthyridine-
2-yl)-3-hydroxy-5-trifluoromethyl-isoindolin-1-one (21.9 pm) was obtained. The solution bound after filtering the reaction mixture and the liquid from the methanol-dioxane wash were combined and water (2500 cc) was added.
生成した沈殿を炉別し、水（６００ｃｃ）で洗浄し、次
いでメタ／ールージオキサン鶴液（容量で５：５）から
２回再結晶させた。これにより、融点２６５ｑｏの２−
（７ークロロー１．８ーナフチリジンー２ーイル）一３
−ヒドロキシ−６ートリフルオロメチル−イソインドリ
ン−１−オン（１５．３夕）が得られた。５ートリフル
オロメチル一Ｎ−（７ークロロ−１，８ーナフチリジン
ー２ーイル）ーフタルイミドは次のようにして製造する
ことができた。The resulting precipitate was filtered out, washed with water (600 cc), and then recrystallized twice from m/- dioxane solution (5:5 by volume). As a result, 2- with a melting point of 265 qo
(7-chloro-1.8-naphthyridine-2-yl)-3
-Hydroxy-6-trifluoromethyl-isoindolin-1-one (15.3 evenings) was obtained. 5-trifluoromethyl-N-(7-chloro-1,8-naphthyridin-2-yl)-phthalimide could be produced as follows.
ジメチルホルムアミド（１５００ｃｃ）中の無水４ート
リフルオロメチルーフタル酸（７３．５夕）およびＮー
ヒドロキシスクシンイミド（５０．２夕）ご７５〜７８
ｑｏに１糊時間加熱した。次いで、２−アミノー７ーク
ロロ−１，８ーナフチリジン−（６１．４夕）およびＮ
，Ｎ′−ジシク。へシキルカルボジイミド（１４０夕）
を加え、そして混合物を同温度にてさらに３時間加熱し
た。冷却後、生成した沈殿を炉刻しそしてジメチルホル
ムアミド（１００ｃｃ）次いでジィソプロピルェーテル
（２００ｃｃ）で洗浄した。この反応混合物に水（１５
００ｃｃ）を加えた。生成した沈殿を炉別しそして塩化
メチレン（１５００ｃｃ）で洗浄した。これら２つの沈
殿を合し、塩化メチレン（８リットル）中に溶解させた
。不溶の物質を炉去し、次いで炉液を濃縮乾固させた。
これにより、融点２６ｙｏの５ートリフルオロメチル−
Ｎ−（７ークロロー１，８−ナフチリジンー２ーイル）
ーフタルイミド（８３６夕）が得られた。無水４ートリ
フルオロメチルーフタル酸は次のようにして製造するこ
とができた。４−トリフルオロメチルーフタル酸（１０
６．６夕）および無水酢酸（２１５ｃｃ）を還流下に３
０分間加熱した。4-trifluoromethylphthalic anhydride (73.5 min) and N-hydroxysuccinimide (50.2 min) in dimethylformamide (1500 cc) 75-78
qo for 1 hour. Then 2-amino-7-chloro-1,8-naphthyridine- (61.4 m) and N
, N′-Jishik. Hesykylcarbodiimide (140 yen)
was added and the mixture was heated at the same temperature for a further 3 hours. After cooling, the precipitate formed was chopped and washed with dimethylformamide (100 cc) and then diisopropyl ether (200 cc). This reaction mixture was added with water (15
00cc) was added. The resulting precipitate was filtered out and washed with methylene chloride (1500 cc). These two precipitates were combined and dissolved in methylene chloride (8 liters). Insoluble material was removed from the oven, and the oven liquor was then concentrated to dryness.
As a result, 5-trifluoromethyl-
N-(7-chloro-1,8-naphthyridin-2-yl)
-phthalimide (836 units) was obtained. 4-trifluoromethylphthalic anhydride could be produced as follows. 4-Trifluoromethylphthalic acid (10
6.6) and acetic anhydride (215 cc) under reflux.
Heated for 0 minutes.
減圧下（３０風Ｈｇ）で濃縮した後、磯笹をシクロヘキ
サン（４２０ｃｃ）と一緒に婿拝した。炉過おっび乾燥
すると、融点５４℃の無水４ートリフルオロメチルーフ
タル酸（７３．５夕）が得られた。４−トリフルオロメ
チルーフタル酸は次のようにして製造することができた
。After concentrating under reduced pressure (30 atmospheres of Hg), the isosasa was mixed with cyclohexane (420 cc). After drying in an oven, 4-trifluoromethylphthalic anhydride (73.5 min) having a melting point of 54°C was obtained. 4-Trifluoromethylphthalic acid could be produced as follows.
メチル２ーシアノ−４ートリフルオロメチルーベンゾェ
ート（１０２．３夕）、水酸化ナトリウムベレツト（１
０８夕）、水（９００ｃｃ）およびメタノール（１９０
０ｃｃ）を還流下に１幼時間加熱した。Methyl 2-cyano-4-trifluoromethyl-benzoate (102.3 evenings), sodium hydroxide beret (1
08 evening), water (900cc) and methanol (190cc)
0 cc) was heated under reflux for 1 hour.
この溶液を動物性骨炭（０．６夕）で脱色した。炉過後
、塩酸（ｄ＝１．１９：１００ｃｃ）を加え、そしてこ
の混合物をジェチルェーテル（２．２５〆）で抽出した
。有機層を無水硫酸マグネシウム（４０夕）で脱水した
。炉過しそして炉液を濃縮すると、融点１７８℃の４ー
トリフルオロメチルーフタル酸（９９．１夕）が得られ
た。メチル２ーシアノー４ートリフルオロメチル−ペン
ゾェートは次のようにして製造することができた。This solution was decolorized with animal bone charcoal (0.6 mm). After filtration, hydrochloric acid (d=1.19:100 cc) was added, and the mixture was extracted with diethyl ether (2.25 cc). The organic layer was dehydrated with anhydrous magnesium sulfate (40 min). Filtration and concentration of the filtrate yielded 4-trifluoromethylphthalic acid (99.1 min.) with a melting point of 178°C. Methyl 2-cyano 4-trifluoromethyl-penzoate could be produced as follows.
メチル２−アミノ−４−トリフルオロメチルーベンゾェ
ート（１４４．６夕）を氷（１．３ｋ９）、水（７３０
ｃｃ）および塩酸（ｄ＝１．１９：１７１．５ｃｃ）の
混合物の中に懸濁させた。Methyl 2-amino-4-trifluoromethyl-benzoate (144.6 evening) was added to ice (1.3k9) and water (730
cc) and hydrochloric acid (d=1.19:171.5cc).
水（１７２ｃｃ）中の亜硝酸ナトリウム（４９．９のの
溶液を、上記懸濁液に１度に全部加えた。反応混合物を
０〜１℃で２時間半縄拝し、炉過し、次いでこれを水（
１３２０ｃｃ）中の硫酸鋼（２２６夕）とシアン化カリ
ウム（２６１夕）の４〜５℃に保たれた溶液〔ガプリェ
ル（Ｇａｂｒｉｅｌ）にしたがって調製した溶液、Ｂｅ
ｒ．，５２，１雌９（１９１９）〕に１時間２０分かけ
て滴加した。A solution of sodium nitrite (49.9 g) in water (172 cc) was added all at once to the above suspension. The reaction mixture was heated at 0-1° C. for 2.5 hours, filtered, and then Mix this with water (
A solution of steel sulfate (226 mm) and potassium cyanide (261 mm) in 1320 cc) kept at 4-5 °C (solution prepared according to Gabriel, Be
r. , 52, 1 female 9 (1919)] over a period of 1 hour and 20 minutes.
ジアゾ化合物の添加の間、炭酸ナトリウムの１０％（Ｗ
／Ｖ）溶液を加えてｐＨを６〜７に保った。縄梓を続け
、その間温度を上昇させた。次いで、混合物をジェチル
ェーテル（３ク）で抽出した。エーテル層を水（１５０
ｃｃ）で洗浄し、次いで無水硫酸マグネシウム（３０の
で脱水した。炉過および濃縮すると、融点５２０の メ
チル２ーシアノー４−トリフルオロメチルーベンゾヱー
ト（９４．９のが得られた。メチル２−アミノー４ート
リフルオロメチルーベンゾェートは次のようにして製造
できた。During the addition of the diazo compound, 10% of sodium carbonate (W
/V) solution was added to keep the pH at 6-7. The rope was continued, and the temperature was increased during that time. The mixture was then extracted with diethyl ether (3 kg). The ether layer is mixed with water (150
cc) and then dehydrated with anhydrous magnesium sulfate (30°C). Filtration and concentration gave methyl 2-cyano-4-trifluoromethyl-benzoate (94.9°C), melting point 520. Amino-4-trifluoromethyl-benzoate could be produced as follows.
２ーアミノ−４−トリフルオロメチルー安息香酸（１４
１．２夕）、メタノール（１．５１夕）および三弗化棚
素ェテレート（５０６ｃｃ）を還流下に９餌時間加熱し
た。2-Amino-4-trifluoromethyl-benzoic acid (14
1.2 pm), methanol (1.51 pm) and trifluoride sheranesate (506 cc) were heated under reflux for 9 hours.
得られた溶液を氷水（２．８Ｘ９）中の炭酸ナトリウム
（３５０夕）に加えた。・混合物を１５分間鷹押し、次
いでジェチルエーテル（３そ）で抽出した。エーテル層
を水（２５０ｃｃ）で洗浄し、次いで無水硫酸マグネシ
ウム（３０夕）で脱水した。炉週および濃縮すると、融
点６４ｑ○のメチル２ーアミノー４ートリフルオロメチ
ルーベンゾエート（１３７夕）が得られた。２−アミノ
ー４−トリフルオロメチルー安息香酸は、／・ゥプトシ
ャィン等（也ｕｐｔｓｃｈｅｉｎｅｔａｌ）〔Ｊ．Ａ．
Ｃ．Ｓ．，７０ １０５１（１９５４）〕にしたがって
製造できる。The resulting solution was added to sodium carbonate (350 ml) in ice water (2.8×9). - The mixture was pressed for 15 minutes and then extracted with diethyl ether (3 portions). The ether layer was washed with water (250 cc) and then dehydrated over anhydrous magnesium sulfate (30 cc). After heating and concentrating, methyl 2-amino-4-trifluoromethyl-benzoate (137 ml) was obtained with a melting point of 64 ml. 2-Amino-4-trifluoromethyl-benzoic acid is described by Uptscheinetal [J. A.
C. S. , 70 1051 (1954)].
実施例 ２
実施例１の手順にしたがうが、塩化メチレン（２５０ｃ
ｃ）中の２−（７−クロロー１，８ーナフチリジンー２
ーイル）−３ーヒドロキシ−６ートリフルオロメチルー
イソインドリン−１−オン（４．８夕）、１ークロロカ
ルボニル−４ーメチルピベラジン塩酸塩（１５．１夕）
、トリェチルアミン（１０．２夕）：１４．２ｃｃ）お
よびピリジン（６６ｃｃ）から出発して、粗生成物（７
．８夕）を得、そしてこれを水（５０ｃｃ）でトリチル
化した。Example 2 The procedure of Example 1 was followed but methylene chloride (250c
c) 2-(7-chloro-1,8-naphthyridine-2)
-yl)-3-hydroxy-6-trifluoromethyl-isoindolin-1-one (4.8 evening), 1-chlorocarbonyl-4-methylpiverazine hydrochloride (15.1 evening)
, triethylamine (10.2 min): 14.2 cc) and pyridine (66 cc), the crude product (7
．． 8 ml) was obtained, and this was tritylated with water (50 cc).
得られた固体を炉別しそして水（３０ｃｃ）で洗浄した
。ィソプ。パノール（２４０ｃｃ）から再結晶させると
、融点２１９℃の２一（７−クロロー１，８ーナフチリ
ジン−２−イル）一３−（４ーメチルピベラジン−１ー
イル）力ルボニルオキシー６ートリフルオロメチルーィ
ソインドリンー１ーオン（４．７夕）が得られた。２一
（７ークロロー１，８−ナフチリジン−２−イル）一８
ーヒドロキシー６ートリフルオロメチルーィソインドリ
ンー１ーオンは、実施例１に記載したようにして製造で
きる。The resulting solid was filtered out and washed with water (30 cc). Aesop. Recrystallization from Panol (240 cc) yields 2-(7-chloro-1,8-naphthyridin-2-yl)-3-(4-methylpiverazin-1-yl)-carbonyloxy-6-trifluoromethane with a melting point of 219°C. Thiruisoindolin-1-one (4.7 hours) was obtained. 2-(7-chloro-1,8-naphthyridin-2-yl)-8
-Hydroxy-6-trifluoromethylisoindolin-1-one can be prepared as described in Example 1.
実施例 ３
２−（７−クロロー１，８ーナフチリジンー２−イル）
一３−フエノキシカルボニルオキシー５ートリフルオロ
メチルーイソインドリン−１ーオン（１４．２夕）のア
セトニトリル（２８０ｃｃ）中の懸濁物中に約２ぴ○の
温度においてＮ−メチルピベラジン（８５ｃｃ）を添加
した。Example 3 2-(7-chloro-1,8-naphthyridin-2-yl)
N-Methylpiverazine (85 cc) was added to a suspension of 1-3-phenoxycarbonyloxy-5-trifluoromethyl-isoindolin-1-one (14.2 mL) in acetonitrile (280 cc) at a temperature of about 2 psi. Added.
２０〜２１００で２時間瀦梓後、反応混合物を水（１０
００ｃｃ）で稀釈し、次いで懸濁物をジェチルェーテル
（１１００ｃｃ）で抽出した。After heating at 20-2100 for 2 hours, the reaction mixture was diluted with water (10
00 cc) and then the suspension was extracted with diethyl ether (1100 cc).
無水炭酸加里（１００夕）上で乾燥後炉過して、溶媒を
約３０午○で減圧下（２０肋日ｇ）留去した。残笹は沸
騰するアセトニトリル（７０ｃｃ）により再結晶し、ｍ
．ｐ．２１９〜松１℃の２一（７ークロロー１，８ーナ
フチリジンー２−イル）一３一（４ーメチルピベラジン
ー１−イル）力ルボニルオキシー５ートリフルオロメチ
ルーイソインドリンー１ーオン（９．２夕）を得た。２
一（７ークロロー１，８ーナフチリジンー２−イル）一
３ーフエノキシカルボニルオキシ−５ートリフルオロメ
チル−イソインドリンー１ーオンは次の様にして得られ
た：２−（７ークロロー１，８ーナフチリジンー２−イ
ル）−３ーヒドロキシー５ートリフルオロメチルーイソ
インドリンー１ーオン（１１．２夕）のピリジン（１０
０ｃｃ）中の懸濁物に、約１がＣで、フェニルクロロホ
ルメート（１４．１夕）を２４分かかって添加した。After drying over anhydrous potassium carbonate (100 g), it was filtered and the solvent was distilled off under reduced pressure (20 g) at about 30 p.m. The remaining bamboo was recrystallized with boiling acetonitrile (70cc), and m
．． p. 219-pine 2-(7-chloro-1,8-naphthyridin-2-yl)-131(4-methylpiverazin-1-yl)-carbonyloxy-5-trifluoromethyl-isoindolin-1-one (9. 2 evenings). 2
1-(7-chloro-1,8-naphthyridin-2-yl)-13-phenoxycarbonyloxy-5-trifluoromethyl-isoindolin-1-one was obtained as follows: 2-(7-chloro-1,8-naphthyridin-2-yl) -yl)-3-hydroxy-5-trifluoromethyl-isoindolin-1-one (11.2) of pyridine (10
To the suspension in 0 cc) phenyl chloroformate (14.1 cc) was added over 24 min.
更に３０分縄梓後、反応混合物を氷水（７２０ｃｃ）中
へ注入した。生成した沈毅を炉別し、炉過器上で水（２
５０ｃｃ）で洗浄した。このようにしてｍ．ｐ．２１４
〜２１が０の２−（７ークロロー１，８−ナフチリジン
−２−イル）一３−フエノキシカルボニルオキシ−５ー
トリフルオロメチルーイソインドリンー１−オン（１５
夕）が得られた。本発明は、その範囲内に、活性成分と
して少なくとも１種の一般式ロのナフチリジン誘導体ま
たはその無毒性酸付加塩を製薬上の担体またはコーチン
グと一緒に含んでなる医薬組成物を包含する。本発明は
、特に経口投与用、非経口投与用もしくはレクタル投与
用または局部塗布（たとえば軟膏）用として作り上げた
製剤を包含する。経口投与用の固形組成物は錠剤、丸薬
、粉末および頚粒を包含する。そのような固形組成物に
おいては、活性化合物をたとえば蕗糖、乳糖または殿粉
のような少なくとも１種の不活性希釈剤と混合する。該
組成物はまた、通常の槍列にしたがって不活性希釈剤以
外の追加物質たとえば滑沢剤（たとえばステアリン酸マ
グネシウム）を含むこともできる。経口投与用の液体組
成物は、当タ料野で一般的に使用される不活性希釈剤（
たとえば水および液体パラフィン）を含有する製薬上許
容しうる乳液、溶液、懸濁液、シラップおよびェリキシ
ルを包含する。そのような組成物は、不活性希釈剤の他
に補助剤たとえば湿潤剤、乳化剤および懸濁剤、ならび
に甘味料、香料および芳香物質を含むこともできる。経
口投与用の本発明の組成物は、希釈剤または補形薬を添
加してまたは添加せずに活性物資を含有する可吸収性物
質（たとえばゼラチン）のカプセルをも包含する。非経
口投与用の本発明の組成物は無菌の水性もしくは非水性
の溶液、懸濁液または乳液を包含する。After stirring for an additional 30 minutes, the reaction mixture was poured into ice water (720 cc). The generated sediment is separated into a furnace and poured with water (2
50cc). In this way m. p. 214
2-(7-chloro-1,8-naphthyridin-2-yl)-13-phenoxycarbonyloxy-5-trifluoromethyl-isoindolin-1-one (15
evening) was obtained. The present invention includes within its scope pharmaceutical compositions comprising as active ingredient at least one naphthyridine derivative of general formula I or a non-toxic acid addition salt thereof together with a pharmaceutical carrier or coating. The present invention encompasses formulations specifically formulated for oral, parenteral or rectal administration or for topical application (eg, ointment). Solid compositions for oral administration include tablets, pills, powders and granules. In such solid compositions, the active compound is mixed with at least one inert diluent, such as sucrose, lactose or starch. The compositions may also contain additional substances other than inert diluents, such as lubricants (eg magnesium stearate), in accordance with the usual sequence. Liquid compositions for oral administration are prepared using inert diluents (
These include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing, for example, water and liquid paraffin. Besides inert diluents, such compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring and perfuming substances. Compositions of the invention for oral administration also include capsules of absorbable material (eg, gelatin) containing the active substance with or without the addition of diluents or excipients. Compositions of the invention for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, or emulsions.
非水性溶媒もしくはべヒクルの例はプロピレングリコー
ル、ポリエチレングリコール、たとえばオリーブ油のよ
うな植物油、およびたとえばオレィン酸エチルのような
注射可能の有機ェステルである。これら組成物はまた、
たとえば保存料、湿潤剤、乳化剤および分散剤のような
補助剤を含有することもできる。それらは、たとえば細
菌捕獲用７戸過器を通しての炉過、組成物に対する殺菌
剤の配合、照射、または加熱によって無菌化することが
できる。それらはまた無菌の固形組成物の形態で製造す
ることもでき、これらは使用直前に無菌水またはその注
射可能な無菌媒体に溶解させることができる。レクタル
投与用の組成物は坐薬であり、これは活性物質の他にた
とえばカカオバターまたは適当なワックスベースのよう
な補形薬を含有する。Examples of non-aqueous solvents or vehicles are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. These compositions also
It may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. They can be sterilized, for example, by filtration through a seven-door strainer for bacterial capture, by incorporating a disinfectant into the composition, by irradiation, or by heating. They can also be prepared in the form of sterile solid compositions which can be dissolved in sterile water or injectable medium immediately before use. Compositions for rectal administration are suppositories, which contain, in addition to the active substance, excipients such as, for example, cocoa butter or a suitable wax base.
本発明組成物中の活性成分の比率は変えることができる
が、適した投薬量が得られるような比率を構成すること
が必要である。投薬量は所望の治療効果、投与経路およ
び処置の持続期間に依存する。人間治療の場合、成人に
対して経口投与する組成物は、一般に１日当り活性物質
１０奴乃至５００奴の投薬量を与えるべきである。一般
に、医者は、処理すべき患者の年令、体量および患者の
本質的なその他因を考慮に入れて、適当と考えられる薬
量を決定するであろう。下記の実施例によって、本発明
の医薬組成物を例示する。実施例 ４
活性物質２５のｏを含有しかつ下記組成を有する錠剤を
通常の技術にしたがって製造した。The proportions of active ingredients in the compositions of the invention may vary, but it is necessary to construct the proportions such that a suitable dosage will be obtained. The dosage depends on the desired therapeutic effect, route of administration and duration of treatment. For human therapy, compositions for oral administration to adults should generally provide a dosage of 10 to 500 mg of active substance per day. Generally, the physician will determine the dosage that is considered appropriate, taking into account the age, body mass, and other factors inherent in the patient to be treated. The following examples illustrate the pharmaceutical compositions of the invention. Example 4 Tablets containing 25 o of active substance and having the following composition were prepared according to conventional techniques.
Claims (1)
は炭素原子数１〜４のアルキル基を表わす〕のナフチリ
ジン誘導体およびその酸付加塩。 ２ Ｙ＾１が塩素原子を表わす、特許請求の範囲第１項
記載のナフチリジン誘導体およびその酸付加塩。 ３ ２−（７−クロロ−１，８−ナフチリジン−２−イ
ル）−３−（４−メチルピペラジン−１−イル）カルボ
ニルオキシ−５−トリフルオロメチル−イソインドリン
−１−オンおよびその酸付加塩である、特許請求の範囲
第１項記載の化合物。 ４ ２−（７−クロロ−１，８−ナフチリジン−２−イ
ル）−３−（４−メチルピペラジン−１−イル）カルボ
ニルオキシ−６−トリフルオロメチル−イソインドリン
−１−オンおよびその酸付加塩である、特許請求の範囲
第１項記載の化合物。 ５ 一般式 ▲数式、化学式、表等があります▼ 〔式中、Ｒ＾１は後記式Iに定義した通りである〕のク
ロロカルボニルピペラジンを一般式 ▲数式、化学式、表等があります▼ 〔式中、Ｙ＾１は後記式Iに定義した通りである〕のナ
フチリジン誘導体またはそのアルカリ金属誘導体と反応
させることを特徴とする、一般式▲数式、化学式、表等
があります▼〔式中、Ｙ＾１はハロゲン原子を表わし、
そしてＲ＾１は炭素原子１〜４個を有するアルキル基を
表わす〕のナフチリジン誘導体およびその酸付加塩の製
造方法。 ６ ナフチリジン誘導体のアルカリ金属誘導体を使用し
そして反応を無水有機溶媒中において６０℃より低い温
度で行なう、特許請求の範囲第５項記載の方法。７ ク
ロロカルボニルピペラジンの酸付加塩を使用しそして反
応をピリジン中で、必要に応じて第三級アミンの存在下
で、行なう特許請求の範囲第５項記載の方法。 ８ 特許請求の範囲第５〜７項記載の方法によつて得ら
れたナフチリジン塩基をそれ自体公知の方法で酸付加塩
に変える工程を含む、特許請求の範囲第５〜７項のいず
れかに記載の方法。 ９ 一般式 ▲数式、化学式、表等があります▼ 〔式中、Ｒ＾１は後記式Iに定義した通りである〕のピ
ペラジンを一般式 ▲数式、化学式、表等があります▼ 〔式中、Ｙ＾１は後記式Iに定義した通りであり、そし
てＡｒは炭素原子１〜４個を有するアルキル基もしくは
ニトロ基で置換されていてもよいフエニル基を表わす〕
の混成カーボネートと反応させることを特徴とする、一
般式I▲数式、化学式、表等があります▼ 〔式中、Ｙ＾１はハロゲン原子を表わし、そしてＲ＾１
は炭素原子１〜４個を有するアルキル基を表わす〕のナ
フチリジン誘導体およびその酸付加塩の製造方法。 １０ 特許請求の範囲第９項記載の方法によつて得られ
たナフチリジン塩基をそれ自体公知の方法で酸付加塩に
変える工程を含む、特許請求の範囲第９項に記載の方法
。[Claims] 1 General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, Y^1 represents a halogen atom, and R^1
represents an alkyl group having 1 to 4 carbon atoms] and acid addition salts thereof. 2. The naphthyridine derivative and acid addition salt thereof according to claim 1, wherein Y^1 represents a chlorine atom. 3 2-(7-chloro-1,8-naphthyridin-2-yl)-3-(4-methylpiperazin-1-yl)carbonyloxy-5-trifluoromethyl-isoindolin-1-one and its acid addition The compound according to claim 1, which is a salt. 4 2-(7-chloro-1,8-naphthyridin-2-yl)-3-(4-methylpiperazin-1-yl)carbonyloxy-6-trifluoromethyl-isoindolin-1-one and its acid addition The compound according to claim 1, which is a salt. 5 General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R^1 is as defined in formula I below] Chlorocarbonylpiperazine is expressed by the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [Formula There are general formulas, chemical formulas, tables, etc., characterized by reacting with a naphthyridine derivative or its alkali metal derivative, where Y^1 is as defined in formula I below] ^1 represents a halogen atom,
and R^1 represents an alkyl group having 1 to 4 carbon atoms] and an acid addition salt thereof. 6. Process according to claim 5, in which an alkali metal derivative of a naphthyridine derivative is used and the reaction is carried out in an anhydrous organic solvent at a temperature below 60°C. 7. A process according to claim 5, in which an acid addition salt of chlorocarbonylpiperazine is used and the reaction is carried out in pyridine, optionally in the presence of a tertiary amine. 8. Any one of claims 5 to 7, comprising a step of converting the naphthyridine base obtained by the method described in claims 5 to 7 into an acid addition salt by a method known per se. Method described. 9 General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R^1 is as defined in formula I below] Piperazine is expressed by the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, Y^1 is as defined in formula I below, and Ar represents a phenyl group optionally substituted with an alkyl group having 1 to 4 carbon atoms or a nitro group]
There are general formula I▲ mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, Y^1 represents a halogen atom, and R^1
represents an alkyl group having 1 to 4 carbon atoms] and an acid addition salt thereof. 10. The method according to claim 9, comprising the step of converting the naphthyridine base obtained by the method according to claim 9 into an acid addition salt by a method known per se.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR7528951A FR2324305A2 (en) | 1975-09-22 | 1975-09-22 | NEW DERIVATIVES OF ISOINDOLINE, THEIR PREPARATION AND THE COMPOSITIONS CONTAINING THEM |
| FR7528951 | 1975-09-22 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS60100579A JPS60100579A (en) | 1985-06-04 |
| JPS6038392B2 true JPS6038392B2 (en) | 1985-08-31 |
Family
ID=9160275
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP51110948A Pending JPS5239700A (en) | 1975-09-22 | 1976-09-17 | Production of naphtidine derivative |
| JP59210605A Expired JPS6038392B2 (en) | 1975-09-22 | 1984-10-09 | Naphthyridine derivatives and their production method |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP51110948A Pending JPS5239700A (en) | 1975-09-22 | 1976-09-17 | Production of naphtidine derivative |
Country Status (26)
| Country | Link |
|---|---|
| JP (2) | JPS5239700A (en) |
| AR (1) | AR209515A1 (en) |
| AT (1) | AT349024B (en) |
| AU (1) | AU502308B2 (en) |
| BE (1) | BE846409R (en) |
| CH (2) | CH617696A5 (en) |
| CS (1) | CS196323B2 (en) |
| DD (1) | DD126905A6 (en) |
| DE (1) | DE2642598A1 (en) |
| DK (1) | DK142365B (en) |
| ES (1) | ES451741A2 (en) |
| FI (1) | FI59595C (en) |
| FR (1) | FR2324305A2 (en) |
| GB (1) | GB1498348A (en) |
| HU (1) | HU176005B (en) |
| IE (1) | IE43551B1 (en) |
| LU (1) | LU75838A1 (en) |
| MX (1) | MX3641E (en) |
| NL (1) | NL7610201A (en) |
| NO (1) | NO145098C (en) |
| PH (1) | PH12289A (en) |
| PL (2) | PL111060B1 (en) |
| SE (1) | SE423391B (en) |
| SU (1) | SU671724A3 (en) |
| YU (1) | YU230476A (en) |
| ZA (1) | ZA765589B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1282532C (en) * | 1986-08-22 | 1991-04-02 | Myron Timothy Maxson | Organosiloxane inhibitors for hydrosilation reactions and polyorganosiloxane compositions containing same |
| US6739238B2 (en) | 2000-11-20 | 2004-05-25 | Nissan Motor Co., Ltd. | Sliding structure for a reciprocating internal combustion engine and a reciprocating internal combustion engine using the sliding structure |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| OA04700A (en) * | 1973-05-15 | 1980-07-31 | Rhone Poulenc Sa | New derivatives of naphthyridine and their preparation process. |
-
1975
- 1975-09-22 FR FR7528951A patent/FR2324305A2/en active Granted
-
1976
- 1976-08-24 PH PH18826A patent/PH12289A/en unknown
- 1976-09-14 NL NL7610201A patent/NL7610201A/en not_active Application Discontinuation
- 1976-09-17 SU SU762403396A patent/SU671724A3/en active
- 1976-09-17 GB GB38671/76A patent/GB1498348A/en not_active Expired
- 1976-09-17 JP JP51110948A patent/JPS5239700A/en active Pending
- 1976-09-17 AU AU17893/76A patent/AU502308B2/en not_active Expired
- 1976-09-17 ZA ZA765589A patent/ZA765589B/en unknown
- 1976-09-17 IE IE2064/76A patent/IE43551B1/en unknown
- 1976-09-20 MX MX764932U patent/MX3641E/en unknown
- 1976-09-20 PL PL1976192537A patent/PL111060B1/en unknown
- 1976-09-20 YU YU02304/76A patent/YU230476A/en unknown
- 1976-09-20 PL PL1976209687A patent/PL110655B1/en unknown
- 1976-09-20 AR AR264772A patent/AR209515A1/en active
- 1976-09-21 CH CH1196276A patent/CH617696A5/en not_active IP Right Cessation
- 1976-09-21 HU HU76RO900A patent/HU176005B/en unknown
- 1976-09-21 NO NO763225A patent/NO145098C/en unknown
- 1976-09-21 BE BE170795A patent/BE846409R/en not_active IP Right Cessation
- 1976-09-21 LU LU75838A patent/LU75838A1/xx unknown
- 1976-09-21 CS CS766117A patent/CS196323B2/en unknown
- 1976-09-21 DK DK425076AA patent/DK142365B/en not_active IP Right Cessation
- 1976-09-21 DD DD194904A patent/DD126905A6/xx unknown
- 1976-09-21 SE SE7610477-7A patent/SE423391B/en not_active IP Right Cessation
- 1976-09-22 AT AT702476A patent/AT349024B/en not_active IP Right Cessation
- 1976-09-22 FI FI762699A patent/FI59595C/en not_active IP Right Cessation
- 1976-09-22 DE DE19762642598 patent/DE2642598A1/en not_active Ceased
- 1976-09-22 ES ES451741A patent/ES451741A2/en not_active Expired
-
1979
- 1979-09-04 CH CH796279A patent/CH617935A5/en not_active IP Right Cessation
-
1984
- 1984-10-09 JP JP59210605A patent/JPS6038392B2/en not_active Expired
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