JPS634535B2 - - Google Patents
Info
- Publication number
- JPS634535B2 JPS634535B2 JP55079290A JP7929080A JPS634535B2 JP S634535 B2 JPS634535 B2 JP S634535B2 JP 55079290 A JP55079290 A JP 55079290A JP 7929080 A JP7929080 A JP 7929080A JP S634535 B2 JPS634535 B2 JP S634535B2
- Authority
- JP
- Japan
- Prior art keywords
- dihydrocarbostyryl
- carbonylmethyl
- piperazin
- hydroxyethyl
- compound
- 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
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical class C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 claims description 5
- 125000005236 alkanoylamino group Chemical group 0.000 claims description 4
- 125000003277 amino group Chemical group 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 125000002947 alkylene group Chemical group 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 description 49
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 32
- 238000006243 chemical reaction Methods 0.000 description 32
- -1 methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy groups Chemical group 0.000 description 23
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 22
- 238000000034 method Methods 0.000 description 21
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 150000001412 amines Chemical class 0.000 description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- 239000002253 acid Substances 0.000 description 15
- 239000002904 solvent Substances 0.000 description 15
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 14
- 239000013078 crystal Substances 0.000 description 13
- 238000002844 melting Methods 0.000 description 13
- 230000008018 melting Effects 0.000 description 13
- 239000000243 solution Substances 0.000 description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- 150000007514 bases Chemical class 0.000 description 11
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 150000008065 acid anhydrides Chemical class 0.000 description 8
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 7
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- 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
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000002260 anti-inflammatory agent Substances 0.000 description 6
- 229940121363 anti-inflammatory agent Drugs 0.000 description 6
- 125000005606 carbostyryl group Chemical group 0.000 description 6
- 239000003158 myorelaxant agent Substances 0.000 description 6
- 239000003921 oil Substances 0.000 description 6
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 5
- WFCSWCVEJLETKA-UHFFFAOYSA-N 2-piperazin-1-ylethanol Chemical compound OCCN1CCNCC1 WFCSWCVEJLETKA-UHFFFAOYSA-N 0.000 description 5
- 238000003436 Schotten-Baumann reaction Methods 0.000 description 5
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 5
- 150000007513 acids Chemical class 0.000 description 5
- 229940035676 analgesics Drugs 0.000 description 5
- 239000003054 catalyst Substances 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- 229940035363 muscle relaxants Drugs 0.000 description 5
- 239000012312 sodium hydride Substances 0.000 description 5
- 229910000104 sodium hydride Inorganic materials 0.000 description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 235000011054 acetic acid Nutrition 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- VEUUMBGHMNQHGO-UHFFFAOYSA-N ethyl chloroacetate Chemical compound CCOC(=O)CCl VEUUMBGHMNQHGO-UHFFFAOYSA-N 0.000 description 4
- 229910052751 metal Inorganic materials 0.000 description 4
- 239000002184 metal Substances 0.000 description 4
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 4
- 125000005504 styryl group Chemical group 0.000 description 4
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000006664 bond formation reaction Methods 0.000 description 3
- 238000010531 catalytic reduction reaction Methods 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 3
- 239000012442 inert solvent Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 2
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 239000000730 antalgic agent Substances 0.000 description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- OQNGCCWBHLEQFN-UHFFFAOYSA-N chloroform;hexane Chemical compound ClC(Cl)Cl.CCCCCC OQNGCCWBHLEQFN-UHFFFAOYSA-N 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 150000002170 ethers Chemical class 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 150000008282 halocarbons Chemical class 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 235000006408 oxalic acid Nutrition 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 239000002798 polar solvent Substances 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 235000011181 potassium carbonates Nutrition 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000012746 preparative thin layer chromatography Methods 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 235000017550 sodium carbonate Nutrition 0.000 description 2
- 235000010288 sodium nitrite Nutrition 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-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
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-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
- FTTATHOUSOIFOQ-UHFFFAOYSA-N 1,2,3,4,6,7,8,8a-octahydropyrrolo[1,2-a]pyrazine Chemical compound C1NCCN2CCCC21 FTTATHOUSOIFOQ-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 125000004066 1-hydroxyethyl group Chemical group [H]OC([H])([*])C([H])([H])[H] 0.000 description 1
- LQGIKCCIECNYHT-UHFFFAOYSA-N 2-(2-oxo-3,4-dihydroquinolin-1-yl)acetic acid Chemical compound C1=CC=C2N(CC(=O)O)C(=O)CCC2=C1 LQGIKCCIECNYHT-UHFFFAOYSA-N 0.000 description 1
- WZFUQSJFWNHZHM-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)CC(=O)N1CC2=C(CC1)NN=N2 WZFUQSJFWNHZHM-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical group [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 description 1
- SXIFAEWFOJETOA-UHFFFAOYSA-N 4-hydroxy-butyl Chemical group [CH2]CCCO SXIFAEWFOJETOA-UHFFFAOYSA-N 0.000 description 1
- JQJPBYFTQAANLE-UHFFFAOYSA-N Butyl nitrite Chemical compound CCCCON=O JQJPBYFTQAANLE-UHFFFAOYSA-N 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-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
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 239000004157 Nitrosyl chloride Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-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
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 229910052783 alkali metal Inorganic materials 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
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000002973 anti-dopamine Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 description 1
- 229910001863 barium hydroxide Inorganic materials 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 235000011116 calcium hydroxide Nutrition 0.000 description 1
- 150000001718 carbodiimides Chemical class 0.000 description 1
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000001244 carboxylic acid anhydrides Chemical class 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000010779 crude oil Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 239000012024 dehydrating agentsâ Substances 0.000 description 1
- 239000012973 diazabicyclooctane Substances 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- ZYBWTEQKHIADDQ-UHFFFAOYSA-N ethanol;methanol Chemical compound OC.CCO ZYBWTEQKHIADDQ-UHFFFAOYSA-N 0.000 description 1
- XCPXPFNKTCFWTA-UHFFFAOYSA-N ethyl carbonobromidate Chemical compound CCOC(Br)=O XCPXPFNKTCFWTA-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- VGGRCVDNFAQIKO-UHFFFAOYSA-N formic anhydride Chemical compound O=COC=O VGGRCVDNFAQIKO-UHFFFAOYSA-N 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- YWGHUJQYGPDNKT-UHFFFAOYSA-N hexanoyl chloride Chemical compound CCCCCC(Cl)=O YWGHUJQYGPDNKT-UHFFFAOYSA-N 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 238000002955 isolation Methods 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
- 239000000314 lubricant Substances 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- VPCDQGACGWYTMC-UHFFFAOYSA-N nitrosyl chloride Chemical compound ClN=O VPCDQGACGWYTMC-UHFFFAOYSA-N 0.000 description 1
- 235000019392 nitrosyl chloride Nutrition 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- NMHMNPHRMNGLLB-UHFFFAOYSA-N phloretic acid Chemical compound OC(=O)CCC1=CC=C(O)C=C1 NMHMNPHRMNGLLB-UHFFFAOYSA-N 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229960003975 potassium Drugs 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
- 229910000105 potassium hydride Inorganic materials 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 229910052718 tin Inorganic materials 0.000 description 1
- 239000011135 tin Substances 0.000 description 1
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Landscapes
- Quinoline Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
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The present invention relates to novel carbostyril derivatives. The carbostyril derivative of the present invention is a novel compound that has not been described in any literature, and is represented by the following general formula (1). [In the formula, R 1 is a hydroxyl group, a lower alkoxy group, or a group
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[Formula] (R 3 is a hydroxy lower alkyl group), R 2 is a hydrogen atom, a lower alkoxy group,
A represents a nitro group, an amino group or a lower alkanoylamino group, and A represents a lower alkylene group. ] The compounds of the present invention have anti-inflammatory, analgesic, muscle-relaxing, and anti-dopamine effects, and are useful as, for example, anti-inflammatory agents, analgesics, muscle relaxants, and the like. More specifically, each group represented by R 1 , R 2 , R 3 and A in this specification is as follows. Lower alkoxy groups: methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy groups, etc. Hydroxy lower alkyl group: hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 2-hydroxyisopropyl, 2-hydroxybutyl, 4-hydroxybutyl, 2-hydroxy-1, 1-dimethylethyl, 2-hydroxypentyl, 5-hydroxypentyl, 3-hydroxyhexyl, 6-hydroxyhexyl groups, etc. Lower alkanoylamino group: formylamino, acetylamino, propionylamino, butyrylamino, isobutyrylamino, pentanoylamino, tert-butylcarbonylamino, hexanoylamino, etc. Lower alkylene group...methylene, ethylene, trimethylene, 2-methyltrimethylene, 2,2-
Dimethyltrimethylene, 1-methyltrimethylene, methylmethylene, ethylmethylene, tetramethylene, pentamethylene, hexamethylene groups, etc. Representative compounds of the present invention represented by the above general formula (1) are listed below. Î 1-carboxymethyl-5-ethoxy-3,
4-dihydrocarbostyryl Î 1-carboxymethyl-8-methoxy-3,
4-dihydrocarbostyryl Î 1-carboxymethyl-6-methoxy-3,
4-dihydrocarbostyryl Î 1-carboxymethyl-7-methoxy-3,
4-dihydrocarbostyryl Î 1-carboxymethyl-3,4-dihydrocarbostyryl Î 1-carboxymethyl-7-ethoxy-3,
4-dihydrocarbostyryl Î 1-carboxymethyl-5-propoxy-
3,4-dihydrocarbostyryl Î 1-carboxymethyl-6-hexyloxy-3,4-dihydrocarbostyryl Î 1-carboxymethyl-5-nitro-3,4
-dihydrocarbostyryl Î 1-carboxymethyl-5-butoxy-3,
4-dihydrocarbostyryl Î 1-carboxymethyl-6-formylamino-3,4-dihydrocarbostyryl Î 1-carboxymethyl-7-nitro-3,4
-dihydrocarbostyryl Î 1-carboxymethyl-5-amino-3,4
-dihydrocarbostyryl Î 1-carboxymethyl-6-amino-3,4
-dihydrocarbostyryl Î 1-carboxymethyl-5-acetylamino-3,4-dihydrocarbostyryl Î 1-carboxymethyl-8-acetylamino-3,4-dihydrocarbostyryl Î 1-carboxymethyl-6-butyrylamino- 3,4-dihydrocarbostyryl Î 1-carboxymethyl-7-propionylamino-3,4-dihydrocarbostyryl Î 1-(2-carboxyethyl)-5-methoxy-3,4-dihydrocarbostyryl Î 1-( 2-carboxyethyl)-3,4-dihydrocarbostyryl Î 1-(2-carboxyethyl)-6-methoxy-3,4-dihydrocarbostyryl Î 1-(2-carboxyethyl)-5-nitro-3, 4-dihydrocarbostyryl Î 1-(2-carboxyethyl)-6-nitro-3,4-dihydrocarbostyryl Î 1-(2-carboxyethyl)-5-amino-3,4-dihydrocarbostyryl Î 1- (2-carboxyethyl)-5-acetylamino-3,4-dihydrocarbostyryl Î 1-(2-carboxyethyl)-6-acetylamino-3,4-dihydrocarbostyryl Î 1-(3-carboxypropyl) -5-methoxy-3,4-dihydrocarbostyryl Î 1-(3-carboxypropyl)-3,4-
Dihydrocarbostyryl Î 1-(3-carboxypropyl)-8-methoxy-3,4-dihydrocarbostyryl Î 1-(3-carboxypropyl)-5-nitro-3,4-dihydrocarbostyryl Î 1-(3 -carboxypropyl)-7-nitro-3,4-dihydrocarbostyryl Î 1-(3-carboxypropyl)-6-amino-3,4-dihydrocarbostyryl Î 1-(3-carboxypropyl)-6-acetyl Amino-3,4-dihydrocarbostyryl Î 1-(4-carboxybutyl)-3,4-dihydrocarbostyryl Î 1-(4-carboxybutyl)-6-nitro-3,4-dihydrocarbostyryl Î 1- (4-Carboxybutyl)-6-amino-3,4-dihydrocarbostyryl Î 1-methoxycarbonylmethyl-5-methoxy-3,4-dihydrocarbostyryl Î 1-methoxycarbonylmethyl-8-methoxy-3,4 -dihydrocarbostyryl Î 1-methoxycarbonylmethyl-6-methoxy-3,4-dihydrocarbostyryl Î 1-methoxycarbonylmethyl-7-methoxy-3,4-dihydrocarbostyryl Î 1-methoxycarbonylmethyl-5-hexyl Oxy-3,4-dihydrocarbostyryl Î 1-methoxycarbonylmethyl-3,4-dihydrocarbostyryl Î 1-methoxycarbonylmethyl-5-nitro-3,4-dihydrocarbostyryl Î 1-methoxycarbonylmethyl-6- Nitro-3,4-dihydrocarbostyryl Î 1-methoxycarbonylmethyl-7-nitro-3,4-dihydrocarbostyryl Î 1-methoxycarbonylmethyl-8-nitro-3,4-dihydrocarbostyryl Î 1-methoxycarbonyl Methyl-5-amino-3,4-dihydrocarbostyryl Î 1-methoxycarbonylmethyl-6-amino-3,4-dihydrocarbostyryl Î 1-methoxycarbonylmethyl-5-acetyl-amino-3,4-dihydrocarbo Styryl Î 1-methoxycarbonylmethyl-6-acetylamino-3,4-dihydrocarbostyryl Î 1-methoxycarbonylmethyl-7-acetylamino-3,4-dihydrocarbostyryl Î 1-methoxycarbonylmethyl-8-acetylamino -3,4-dihydrocarbostyryl Î 1-methoxycarbonylmethyl-8-propionylamino-3,4-dihydrocarbostyryl Î 1-methoxycarbonylmethyl-8-hexanoylamino-3,4-dihydrocarbostyryl Î 1- Methoxycarbonylmethyl-8-isobutyrylamino-3,4-dihydrocarbostyryl Î 1-ethoxycarbonylmethyl-5-ethoxy-3,4-dihydrocarbostyryl Î 1-ethoxycarbonylmethyl-8-methoxy-3,4 -dihydrocarbostyryl Î 1-methoxycarbonylmethyl-7-amino-3,4-dihydrocarbostyryl Î 1-methoxycarbonylmethyl-8-amino-3,4-dihydrocarbostyryl Î 1-ethoxycarbonylmethyl-6-ethoxy -3,4-dihydrocarbostyryl Î 1-ethoxycarbonylmethyl-3,4-dihydrocarbostyryl Î 1-ethoxycarbonylmethyl-5-nitro-3,4-dihydrocarbostyryl Î 1-ethoxycarbonylmethyl-5-amino -3,4-dihydrocarbostyryl Î 1-ethoxycarbonylmethyl-6-acetylamino-3,4-dihydrocarbostyryl Î 1-propoxycarbonylmethyl-5-methoxy-3,4-dihydrocarbostyryl Î 1-isopropoxy Carbonylmethyl-6-
Ethoxy-3,4-dihydrocarbostyryl Î 1-butoxycarbonylmethyl-7-amino-3,4-dihydrocarbostyryl Î 1-tert-butoxycarbonylmethyl-6-
Acetylamino-3,4-dihydrocarbostyryl Î 1-(2-ethoxycarbonylethyl)-
3,4-dihydrocarbostyryl Î 1-(3-ethoxycarbonylpropyl)-
3,4-dihydrocarbostyryl Î 1-(4-ethoxycarbonylbutyl)-
3,4-dihydrocarbostyryl Î 1-(6-ethoxycarbonylhexyl)-
3,4-dihydrocarbostyryl Î 1-(4-hydroxymethylpiperazine-1
-yl-carbonylmethyl)-5-methoxy-
3,4-dihydrocarbostyryl Î 1-(4-hydroxymethylpiperazine-1
-yl-carbonylmethyl)-8-methoxy-
3,4-dihydrocarbostyryl Î 1-(4-hydroxymethylpiperazine-1
-yl-carbonylmethyl)-6-methoxy-
3,4-dihydrocarbostyryl Î 1-(4-hydroxymethylpiperazine-1
-yl-carbonylmethyl)-7-acetylamino-3,4-dihydrocarbostyryl Î 1-(4-hydroxymethylpiperazine-1
1-[4-(2-hydroxyethyl)piperazin-1-yl-carbonylmethyl]-5-methoxy-3,4-dihydro Carbostyryl Î 1-[4-(2-hydroxyethyl)piperazin-1-yl-carbonylmethyl]-5-ethoxy-3,4-dihydrocarbostyryl Î 1-[4-(2-hydroxyethyl)piperazine-1 -yl-carbonylmethyl)-8-methoxy-3,4-dihydrocarbostyryl Î 1-[4-(2-hydroxyethyl)piperazin-1-yl-carbonylmethyl]-6-methoxy-3,4-dihydrocarbo Styryl Î 1-[4-(2-hydroxyethyl)piperazin-1-yl-carbonylmethyl]-7-methoxy-3,4-dihydrocarbostyryl Î 1-[4-(2-hydroxyethyl)piperazine-1- yl-carbonylmethyl]-6-ethoxy-3,4-dihydrocarbostyryl Î 1-[4-(2-hydroxyethyl)piperazin-1-yl-carbonylmethyl]-3,4
-dihydrocarbostyryl Î 1-[4-(2-hydroxyethyl)piperazin-1-yl-carbonylmethyl]-7-ethoxy-3,4-dihydrocarbostyryl Î 1-[4-(2-hydroxyethyl)piperazine -1-yl-carbonylmethyl]-8-ethoxy-3,4-dihydrocarbostyryl Î 1-[4-(2-hydroxyethyl)piperazin-1-yl-carbonylmethyl]-5-propoxy-3,4- Dihydrocarbostyryl Î 1-[4-(2-hydroxyethyl)piperazin-1-yl-carbonylmethyl]-5-nitro-3,4-dihydrocarbostyryl Î 1-[4-(2-hydroxyethyl)piperazine- 1-yl-carbonylmethyl]-6-nitro-3,4-dihydrocarbostyryl Î 1-[4-(2-hydroxyethyl)piperazin-1-yl-carbonylmethyl]-7-nitro-3,4-dihydro Carbostyryl Î 1-[4-(2-hydroxyethyl)piperazin-1-yl-carbonylmethyl]-8-nitro-3,4-dihydrocarbostyryl Î 1-[4-(2-hydroxyethyl)piperazine-1 -yl-carbonylmethyl]-5-amino-3,4-dihydrocarbostyryl Î 1-[4-(2-hydroxyethyl)piperazin-1-yl-carbonylmethyl]-6-amino-3,4-dihydrocarbo Styryl Î 1-[4-(2-hydroxyethyl)piperazin-1-yl-carbonylmethyl]-7-amino-3,4-dihydrocarbostyryl Î 1-[4-(2-hydroxyethyl)piperazine-1- yl-carbonylmethyl]-8-amino-3,4-dihydrocarbostyryl Î 1-[4-(2-hydroxyethyl)piperazin-1-yl-carbonylmethyl]-5-acetylamino-3,4-dihydrocarbo Styryl Î 1-[4-(2-hydroxyethyl)piperazin-1-yl-carbonylmethyl]-6-acetylamino-3,4-dihydrocarbostyryl Î 1-[4-(2-hydroxyethyl)piperazine-1 -yl-carbonylmethyl]-7-acetylamino-3,4-dihydrocarbostyryl Î 1-[4-(2-hydroxyethyl)piperazin-1-yl-carbonylmethyl]-8-acetylamino-3,4- Dihydrocarbostyryl Î 1-[4-(2-hydroxyethyl)piperazin-1-yl-carbonylmethyl]-5-propionylamino-3,4-dihydrocarbostyryl Î 1-[4-(2-hydroxyethyl)piperazine -1-yl-carbonylmethyl]-6-propionylamino-3,4-dihydrocarbostyryl Î 1-[4-(3-hydroxypropyl)piperazin-1-yl-carbonylmethyl]-5-
Methoxy-3,4-dihydrocarbostyryl Î 1-[4-(3-hydroxypropyl)piperazin-1-yl-carbonylmethyl]-3,
4-dihydrocarbostyryl Î 1-[4-(3-hydroxypropyl)piperazin-1-yl-carbonylmethyl]-7-
Methoxy-3,4-dihydrocarbostyryl Î 1-[4-(3-hydroxypropyl)piperazin-1-yl-carbonylmethyl]-8-
Nitro-3,4-dihydrocarbostyryl Î 1-[4-(3-hydroxypropyl)piperazin-1-yl-carbonylmethyl]-5-
Amino-3,4-dihydrocarbostyryl Î 1-[4-(3-hydroxypropyl)piperazin-1-yl-carbonylmethyl]-6-
Amino-3,4-dihydrocarbostyryl Î 1-[4-(3-hydroxypropyl)piperazin-1-yl-carbonylmethyl]-8-
Acetylamino-3,4-dihydrocarbostyryl Î 1-[4-(3-hydroxypropyl)piperazin-1-yl-carbonylmethyl]-6-
Nitro-3,4-dihydrocarbostyryl Î 1-[4-(3-hydroxypropyl)piperazin-1-yl-carbonylmethyl]-6-
Acetylamino-3,4-dihydrocarbostyryl Î 1-[4-(4-hydroxybutyl)piperazin-1-yl-carbonylmethyl]-5-methoxy-3,4-dihydrocarbostyryl Î 1-[4-( 4-hydroxybutyl)piperazin-1-yl-carbonylmethyl]-3,4
-dihydrocarbostyryl Î 1-[4-(4-hydroxybutyl)piperazin-1-yl-carbonylmethyl]-6-nitro-3,4-dihydrocarbostyryl Î 1-[4-(4-hydroxybutyl)piperazine -1-yl-carbonylmethyl]-7-nitro-3,4-dihydrocarbostyryl Î 1-[4-(4-hydroxybutyl)piperazin-1-yl-carbonylmethyl]-8-amino-3,4- Dihydrocarbostyryl Î 1-[4-(4-hydroxybutyl)piperazin-1-yl-carbonylmethyl]-6-acetylamino-3,4-dihydrocarbostyryl Î 1-[4-(4-hydroxybutyl)piperazine -1-yl-carbonylmethyl]-8-acetylamino-3,4-dihydrocarbostyryl Î 1-[4-(6-hydroxyhexyl)piperazin-1-yl-carbonylmethyl]-3,
4-dihydrocarbostyryl Î 1-[4-(6-hydroxyhexyl)piperazin-1-yl-carbonylmethyl]-7-
Amino-3,4-dihydrocarbostyryl Î 1-[4-(5-hydroxypentyl)piperazin-1-yl-carbonylmethyl]-6-
Nitro-3,4-dihydrocarbostyryl Î 1-[4-(5-hydroxypentyl)piperazin-1-yl-carbonylmethyl]-6-
Acetylamino-3,4-dihydrocarbostyryl Î 1-(2-methoxycarbonylethyl)-5
-Methoxy-3,4-dihydrocarbostyryl Î 1-(2-ethoxycarbonylethyl)-5
-Ethoxy-3,4-dihydrocarbostyryl Î 1-{2-[4-(2-hydroxyethyl)
Piperazin-1-yl-carbonyl]ethyl}
-3,4-dihydrocarbostyryl Î 1-{2-[4-(6-hydroxyhexyl)piperazin-1-yl-carbonyl]ethyl}-7-ethoxy-3,4-dihydrocarbostyryl Î 1-{2 -[4-(3-hydroxypropyl)piperazin-1-yl-carbonyl]ethyl}-8-ethoxy-3,4-dihydrocarbostyryl Î 1-[2-(4-hydroxymethylpiperazin-1-yl-carbonyl) ) Ethyl]-5-propoxy-3,4-dihydrocarbostyryl Î 1-{3-[4-(5-hydroxypentyl)piperazin-1-yl-carbonyl]propyl}-5-methoxy-3,4-dihydro Carbostyryl Î 1-{3-[4-(2-hydroxyethyl)
Piperazin-1-yl-carbonyl]propyl}-6-methoxy-3,4-dihydrocarbostyryl Î 1-[3-(4-hydroxymethylpiperazin-1-yl-carbonyl)propyl]-7-
Methoxy-3,4-dihydrocarbostyryl Î 1-{4-[4-(2-hydroxyethyl)
piperazin-1-yl-carbonyl]butyl}
-6-amino-3,4-dihydrocarbostyryl Î 1-{4-[4-(2-hydroxyethyl)
piperazin-1-yl-carbonyl]butyl}
-6-acetylamino-3,4-dihydrocarbostyryl Î 1-{4-[4-(2-hydroxyethyl)
piperazin-1-yl-carbonyl]hexyl}-3,4-dihydrocarbostyryl Î 1-ethoxycarbonylmethyl-6-hexyloxy-3,4-dihydrocarbostyryl Î 1-(4-hydroxymethylpiperazine-1
-yl-carbonylmethyl)-7-methoxy-
3,4-dihydrocarbostyryl Î 1-(4-hydroxymethylpiperazine-1
-yl-carbonylmethyl)-3,4-dihydrocarbostyryl Î 1-(4-hydroxymethylpiperazine-1
-yl-carbonylmethyl)-6-nitro-
3,4-dihydrocarbostyryl Î 1-(4-hydroxymethylpiperazine-1
-yl-carbonylmethyl)-7-nitro-
3,4-dihydrocarbostyryl Î 1-(4-hydroxymethylpiperazine-1
-yl-carbonylmethyl)-6-amino-
3,4-dihydrocarbostyryl Î 1-(4-hydroxymethylpiperazine-1
-yl-carbonylmethyl)-8-amino-
3,4-dihydrocarbostyryl Î 1-(4-hydroxymethylpiperazine-1
-yl-carbonylmethyl)-5-acetylamino-3,4-dihydrocarbostyryl Î 1-(4-hydroxymethylpiperazine-1
-yl-carbonylmethyl)-6-acetylamino-3,4-dihydrocarbostyryl The compound of the present invention can be produced by various methods, but a preferred example is the following reaction scheme 1.
It is manufactured by the method shown in ~4. Reaction formula 1 [In the formula, R 1 ] is a lower alkoxy group or a group
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R 1 is a lower alkoxy group or a group
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R1ãåº[Formula] (R 3 is a hydroxy lower alkyl group) Compounds (compounds of general formula (1 a ))
is produced by reacting a carbostyryl derivative represented by the known general formula (2) with a compound represented by the known general formula (3). The reaction between the carbostyril derivative represented by the general formula (2) and the compound represented by the general formula (3) is carried out in a conventional inert solvent in the presence of a basic compound. As the above-mentioned inert solvent, any inert solvent that does not adversely affect the reaction can be used, such as ethers such as diethyl ether, tetrahydrofuran, and dioxane, aromatic hydrocarbons such as benzene, toluene, and xylene, methyl acetate, and acetic acid. Examples include esters such as ethyl, aprotic polar solvents such as N,N-dimethylformamide, dimethyl sulfoxide, and hexamethylphosphoric triamide. A wide variety of known basic compounds can be used, including alkali metal hydrogen compounds such as sodium hydride and potassium hydride, alkyllithium compounds such as butyllithium, and inorganic basic compounds such as sodium and potassium. The ratio of the carbostyryl derivative represented by the general formula (2) and the compound represented by the general formula (3) is not particularly limited and can be appropriately selected within a wide range, but usually the latter is at least equimolar to the former. Preferably equimolar to 2
It is sufficient to use twice the molar amount. The reaction may be carried out under cooling, at room temperature, or under heating, but usually -
It is carried out at a temperature of about 30 to 100°C, preferably 0 to 50°C,
Generally, the reaction is completed in about 30 minutes to 12 hours. Reaction scheme 2 [In the formula, R 1 ', R 2 and A are the same as above. ] According to reaction scheme 2, among the compounds of the present invention
The compound in which R 1 represents a hydroxyl group (compound of general formula (1 b )) is produced by hydrolyzing the compound of general formula (1 a ) obtained above. The hydrolysis reaction of the compound of general formula ( 1a ) is carried out using a catalyst in the presence of a solvent. As the solvent used at this time, a wide range of solvents that do not participate in the reaction can be used.
Examples include water, methanol, ethanol, isopropanol, diethylene glycol, acetonitrile, acetic acid, and pyridine. In addition, as the catalyst used, both acids and basic compounds used in ordinary hydrolysis reactions can be used, such as basic compounds such as sodium hydroxide, potassium hydroxide, barium hydroxide, sulfuric acid, hydrochloric acid, nitric acid, Mention may be made of acids such as phosphoric acid, sodium nitrite, nitrosyltetrafluoroborate, n-butyl nitrite, nitrosyl chloride, sodium nitrite, and ion exchange resins. The reaction may be carried out under cooling, at room temperature, or under heating, but is usually carried out at about 0 to 170°C, preferably at room temperature to 150°C, and the reaction is generally completed in about 0.5 to 12 hours. do. Reaction scheme 3 [In the formula, R 2 , R 3 and A are the same as above. ] According to reaction scheme 3, among the compounds of the present invention
R 1 is the base
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èç¹ 217.5ã218.5âãThe compound represented by [Formula] (compound of general formula ( 1c )) is produced by reacting the compound of general formula ( 1b ) obtained above with the known compound represented by general formula (4). Ru. The method shown in Reaction Scheme 3 is a method in which a carboxyalkoxycarbostyryl derivative represented by general formula (1 b ) and an amine represented by general formula (4) are reacted in a conventional amide bond forming reaction.
In the present invention, a compound whose carboxyl group is activated may be used instead of the compound of general formula ( 1b ). As the amide bond forming reaction, conditions for known amide bond forming reactions can be easily applied. For example, (a) mixed acid anhydride method, that is, a method in which carboxylic acid (1b) is reacted with an alkylhalocarboxylic acid to form a mixed acid anhydride, which is then reacted with amine (4), (b) active ester method, that is, carboxylic acid A method in which (1b) is converted into an active ester such as p-nitrophenyl ester, N-hydroxysuccinimide ester, 1-hydroxybenzotriazole ester, etc. and reacted with amine (4); (3) carbodiimide method, i.e., carboxylic acid A method of condensing amine (4) to (1b) in the presence of an activator such as dicyclohexylcarbodiimide or carbonyldiimidazole, (d)
Other methods include converting carboxylic acid (1b) to carboxylic anhydride using a dehydrating agent such as acetic anhydride and reacting this with amine (4);
A method of reacting an amine (4) with an ester of a carboxylic acid (1b) and a lower alcohol under high pressure and high temperature.
Examples include a method of reacting (4). Among these, the mixed acid anhydride method is preferred. Examples of the alkylhalocarboxylic acids used in the mixed acid anhydride method include methyl chloroformate, ethyl bromoformate, and isobutyl chloroformate. Mixed acid anhydrides are obtained by the usual Schotten-Baumann reaction, and by reacting them with amines (4) without isolation, the general formula ( 1c ) is obtained.
of compounds are produced. The Schotten-Baumann reaction is carried out in the presence of a basic compound. Examples of such basic compounds include triethylamine, trimethylamine, pyridine, dimethylaniline, N-methylmorpholine, 1,5-diazabicyclo[4,3,0]nonene-5 (DBN), 1,
5-diazabicyclo[5,4,0]undecene-
5 (DBU), 1,4-diazabicyclo[2,2,
2] Organic bases such as octane (DABCO), potassium carbonate, sodium carbonate, potassium hydrogen carbonate,
Examples include inorganic bases such as sodium bicarbonate. The amount of the alkylhalocarboxylic acid used in the Schotten-Baumann reaction is not particularly limited and can be appropriately selected within a wide range, but it is usually at least an equimolar amount, preferably at least an equimolar amount relative to the compound of general formula ( 1b ). It is preferable to use equimolar to 1.5 times the molar amount. The reaction is generally carried out in a suitable solvent. Examples of such solvents include halogenated hydrocarbons such as methylene chloride, chloroform, and dichloroethane, aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as diethyl ether, tetrahydrofuran, and dimethoxyethane, methyl acetate, and ethyl acetate. esters such as
dimethylformacide, dimethyl sulfoxide,
Examples include aprotic polar solvents such as hexamethylphosphoric triamide. The above reaction is usually carried out at about -20 to 100°C, preferably 0 to 50°C, and is generally completed in about 5 minutes to 10 hours. The reaction between the mixed acid anhydride produced by the Schotten-Baumann reaction and the amine (4) is generally carried out in a suitable solvent. As the solvent, any of the solvents used in the above Schotten-Baumann reaction can be used. The amount of amine (4) to be used is not particularly limited and may be appropriately selected within a wide range, but it is preferably used in an amount of at least equimolar, preferably equimolar to 1.5 times the molar amount of the mixed acid anhydride. The above reaction is usually carried out at about -20 to 100°C, preferably 0 to 50°C, and is generally completed in about 5 minutes to 10 hours. Reaction scheme 4 [In the formula, R 4 represents a lower alkyl group. R1 and A
is the same as above. ] According to reaction scheme 4, among the compounds of the present invention
A compound in which R 2 represents an amino group (compound of general formula (1 e )) is produced by reducing a compound in which R 2 represents a nitro group (compound of general formula (1 d )),
Further, a compound in which R 2 represents a lower alkanoylamino group (compound of general formula (1 f )) is produced by acylating a compound of general formula (1 e ). For the reduction of the compound of general formula (1 d ), any usual conditions for reducing an aromatic nitro group to an amino group can be employed. The typical method is catalytic reduction method,
A method using a metal and an acid can be mentioned.
In the catalytic reduction method, examples of catalysts used include palladium, platinum, Raney-nickel, etc., and it is preferable to use such catalysts in normal catalytic amounts. This catalytic reduction can be carried out either under normal pressure or under increased pressure, but is usually carried out within the range of normal pressure to 10 kg/cm 2 , preferably normal pressure to 3 kg/cm 2 , and the reaction temperature is usually 0. ~100â,
Preferably, the temperature is within the range of room temperature to 50°C.
In the method using a metal and an acid, examples of the metal used include zinc, tin, iron, etc., and examples of the acid used include hydrochloric acid, acetic acid, etc. The amounts of the metal and acid to be used are not particularly limited and may be appropriately selected within a wide range as necessary. The method is generally carried out in a solvent such as water, lower alcohols such as methanol, ethanol, and isopropanol. Acylation of the compound of general formula ( 1e ) is usually carried out using an acylating agent in a suitable solvent. Examples of the solvent used include water, lower alcohols such as methanol, ethanol, and isopropanol, halogenated hydrocarbons such as chloroform, methylene chloride, and dichloroethane, pyridine, dimethylformamide, and dimethyl sulfoxide. Examples of the acylating agent include acid anhydrides or acid halides of lower alkanoic acids such as formic anhydride, acetic anhydride, acetyl chloride, propionyl chloride, and hexanoyl chloride. The reaction is usually carried out at a temperature of about -10° to 70°C, preferably 20° to 40°C, and the reaction is generally carried out at a temperature of about 30°C.
It takes about 5 minutes to 5 hours to complete. The amount of the acylating agent to be used is usually at least equimolar, preferably equimolar to 1.5 times the molar amount of the compound of general formula ( 1e ). A compound having a basic group among the carbostyryl derivatives represented by the general formula (1) of the present invention can be easily converted into an acid addition salt by reacting with a pharmaceutically acceptable acid. Examples of the acid include hydrohalic acids such as hydrochloric acid, hydrobromic acid, and hydroiodic acid; inorganic acids such as sulfuric acid and phosphoric acid; acetic acid, lactic acid,
Organic acids such as oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, mandelic acid, and methanesulfonic acid can be mentioned. Further, among the carbostyril derivatives represented by the general formula (1) of the present invention, the compound having an acidic group can be easily converted into a salt by the action of a pharmaceutically acceptable basic compound. Examples of the basic compound include inorganic basic compounds such as sodium hydroxide, potassium hydroxide, aluminum hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, and sodium hydrogen carbonate, and organic basic compounds such as morpholine, piperazine, and piperidine. can be mentioned. The target compounds obtained in each step can be easily isolated and purified by conventional separation means. Examples of the separation means include solvent extraction, dilution, recrystallization, column chromatography, preparative thin layer chromatography, and the like. Incidentally, the present invention naturally also includes optical isomers. When the compound of general formula (1) and its salts are used as anti-inflammatory agents, analgesics, and muscle relaxants, they are usually formulated into a pharmaceutical composition together with a pharmaceutical carrier. As carriers, diluents or excipients such as fillers, fillers, binders, wetting agents, disintegrants, surfactants, lubricants, etc., which are commonly used to prepare drugs according to the usage form, can be used. I can give an example. Various dosage forms for anti-inflammatory agents, analgesics, and muscle relaxants can be selected depending on the therapeutic purpose, and representative examples include tablets, liquids, suspensions, emulsions, powders, capsules, and suppositories. Examples include preparations, injections, and ointments. The amount of the compound of general formula (1) or its salt to be contained in anti-inflammatory agents, analgesics and muscle relaxants is not particularly limited and can be appropriately selected within a wide range, but usually 1% of the total composition.
The content is preferably ~70% by weight. Furthermore, the above-mentioned anti-inflammatory agents, analgesics, and muscle relaxants are not particularly limited in their use, and can be administered in a manner appropriate for various forms. For example, in the case of tablets, solutions, suspensions, emulsions, powders, and capsules, it is administered orally, and in the case of injections, it is administered alone or with glucose,
It is administered intravenously by mixing with normal replacement fluids such as amino acids, and if necessary, it is administered alone intramuscularly, intradermally, subcutaneously, or intraperitoneally. In the case of suppositories, it is administered rectally, and as ointments. applied in some cases. The dosage of the anti-inflammatory agent, analgesic agent, and muscle relaxant of the present invention is appropriately selected depending on the purpose of use, symptoms, etc.
Usually, a pharmaceutical composition containing about 5 to 40 mg/Kg of the compound of general formula (1) or a salt thereof per day may be administered in 3 to 4 divided doses. Examples are given below. Example 1 5 g of 3,4-dihydrocarbostyryl is dissolved in 40 ml of dimethylformamide, and 1.8 g of 50% sodium hydride is added. After stirring at room temperature for about 1 hour, 4.58 g of ethyl chloroacetate was added dropwise under ice cooling. After the addition, the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated to dryness and extracted with chloroform. The chloroform layer is thoroughly washed with water, dried, and then the solvent is distilled off. The residue is purified on a silica gel column to obtain an oil, which is crystallized by adding hexane. The resulting crystals were recrystallized from isopropyl ether to obtain 5.2 g of 1-ethoxycarbonylmethyl-3,4-dihydrocarbostyryl. Melting point 69.5-71.0°C Example 2 Same as Example 1 except that 5 g of 6-nitro-3,4-dihydrocarbostyryl, 50 ml of dimethylformamide, 1.37 g of 50% sodium hydride and 3.5 g of ethyl chloroacetate were used. The resulting crystals were recrystallized from isopropanol to obtain 6.24 g of 1-ethoxycarbonylmethyl-6-nitro-3,4-dihydrocarbostyryl. Melting point 110.0-111.5°C Example 3 10 g of 5-ethoxy-3,4-dihydrocarbostyryl, 100 ml of dimethylformamide, 2.76 g of 50% sodium hydride and 7.05 g of ethyl chloroacetate
1-ethoxycarbonylmethyl-5-ethoxy-3,4-
10.3 g of dihydrocarbostyril are obtained. Melting point: 93.5-95.5°C Example 4 1 g of sodium hydroxide is dissolved in 30 ml of methanol, 3.83 g of 1-ethoxycarbonylmethyl-3,4-dihydrocarbostyryl is added, and the mixture is stirred overnight at room temperature. Methanol is distilled off, the residue is dissolved in water, and the pH is adjusted to 1 with concentrated hydrochloric acid. The precipitated crystals were collected, washed with water, and further recrystallized from chloroform-hexane to obtain 2.93 g of 1-carboxymethyl-3,4-dihydrocarbostyryl. Melting point 157.0-158.0â Example 5 1-ethoxycarbonylmethyl-6-nitro-
3,4-dihydrocarbostyryl 15g, concentrated hydrochloric acid
Mix 100ml and 20ml of water and stir at 90°C for 4 hours. After the reaction is complete, add 100 ml of water to the reaction solution and cool with ice water. The precipitated crystals were collected, washed with water, and further recrystallized from isopropanol to obtain 13.1 g of 1-carboxymethyl-6-nitro-3,4-dihydrocarbostyryl. Melting point 210.5-213.5â Example 6 1-ethoxycarbonylmethyl-5-ethoxy-3,4-dihydrocarbostyryl 10g, concentrated hydrochloric acid
1-carboxymethyl-5-ethoxy- in the same manner as in Example 5 except that 80 ml and 20 ml of water were used.
8.5 g of 3,4-dihydrocarbostyryl are obtained. Melting point 186.5-187.5°C Example 7 10 g of 8-methoxy-3,4-dihydrocarbostyryl, 100 ml of dimethylformamide, 2.98 g of 50% sodium hydride and 7.61 g of ethyl chloroacetate
The reaction is carried out in the same manner as in Example 1. The reaction solution was concentrated to dryness and extracted with chloroform. The chloroform layer was thoroughly washed with water, dried, the solvent was distilled off, and 1-
ethoxycarbonylmethyl-8-methoxy-3,
16.2 g of 4-dihydrocarbostyryl was obtained as a crude oil. A portion of this oily substance was purified using a silica gel column, and confirmed to be the above compound by IR spectrum and NMR spectrum. 80 ml of concentrated hydrochloric acid and 20 ml of water are added to the crudely purified oil, and the mixture is stirred at 90°C for 2 hours. The reaction solution is neutralized with a 10N aqueous sodium hydroxide solution to pHâ1-2 (oil precipitates), and extracted with chloroform. The chloroform layer is extracted with aqueous sodium bicarbonate, then the aqueous sodium bicarbonate layer is adjusted to pHâ1 with concentrated hydrochloric acid, and extracted with chloroform again. Dry the chloroform layer and evaporate the solvent. Ether is added to the residue, and the precipitated crystals are collected and recrystallized from chloroform-hexane to obtain 7.5 g of 1-carboxymethyl-8-methoxy-3,4-dihydrocarbostyryl. Melting point 179.5-182.0°C Example 8 1-carboxymethyl-3,4-dihydrocarbostyril 6g and chloroform 60ml mixed with 1,5-
Diazabicyclo[5,4,0]undecene-5
5.34 g was added thereto, and then 4.38 g of isobutyl chlorocarbonate was added dropwise while cooling with ice water. After the dropwise addition, the mixture was stirred for 30 minutes, then 4.23 g of 2-hydroxyethylpiperazine was added, and the mixture was stirred at room temperature for 5 hours. Chloroform and 0.5N aqueous sodium hydroxide solution are added to the reaction solution for extraction. The chloroform layer is washed with water, dried, and the solvent is distilled off. The residue was purified with a silica gel column to obtain 4.2 g of 1-[4-(2-hydroxyethyl)piperazin-1-yl-carbonylmethyl]-3,4-dihydrocarbostyryl. This compound is dissolved in acetone, and an equimolar amount of an acetone solution of oxalic acid is added. Take the precipitated crystals and dry them. After the resulting crude crystals are thoroughly ground, methanol is added and stirred for a while. The crystals are taken and washed with methanol to obtain the above compound in the form of oxalate with a yield of 4.2 g. Melting point 150.5-152.0°C Example 9 1-carboxymethyl-3,4-dihydrocarbostyryl 5g, chloroform 50ml, 1,5-diazabicyclo[5,4,0]undecene-5
1-[4-(2-hydroxyethyl)piperazin-1-yl-carbonylmethyl]-6 in the same manner as in Example 8, except that 3.65 g, isobutyl chlorocarbonate, 3.00 g, and 2.9 g of 2-hydroxyethylpiperazine were used. -Nitro-3,4-dihydrocarbostyryl is obtained in the form of an oil. Add isopropanol to this to crystallize. The precipitated crystals are collected and further recrystallized from ethanol to obtain 2.1 g of the above compound. Melting point 170.5-171.5â Example 10 1-carboxymethyl-5-ethoxy-3,4
-Dihydrocarbostyril 8g, chloroform 70g
ml, 1,5-diazabicyclo[5,4,0]undecene-5 5.84g, isobutyl chlorocarbonate 4.82
1-[4-
(2-hydroxyethyl)piperazin-1-yl-carbonylmethyl]-5-ethoxy-3,4-
4.3 g of dihydrocarbostyril are obtained. Dissolve this compound in acetone, add concentrated hydrochloric acid to adjust the pH to 1, and crystallize. The crystals were collected and recrystallized from methanol to obtain the above compound in the form of hydrochloride.
Obtained in a yield of 3.9 g. Melting point 234-237â (decomposition) Example 11 1-carboxymethyl-8-methoxy-3,4
-Dihydrocarbostyril 7.1g, chloroform
50ml, 1,5-diazabicyclo[5,4,0]undecene-5 5.51g, isobutyl chlorocarbonate
4.53g and 2-hydroxyethylpiperazine 4.38
1- in the same manner as in Example 8 except for using g.
[4-(2-hydroxyethyl)piperazine-1
-yl-carbonylmethyl]-8-methoxy-
2 g of 3,4-dihydrocarbostyryl are obtained. This compound is dissolved in acetone and crystallized. The crystals are collected and further recrystallized from isopropanol to obtain 1.6 g of the above compound in the form of fumarate salt. Melting point 166.0-167.5â Example 12 1-[4-(2-hydroxyethyl)piperazin-1-yl-carbonylmethyl]-6-nitro-3,4-dihydrocarbostyryl hydrochloride 4.4g
Dissolved in 200 ml of methanol and 20 ml of water, added 500 mg of 10% palladium-carbon, and dissolved at room temperature and pressure to 1.5
Contact reduction takes time. The catalyst was removed, concentrated hydrochloric acid was added to the solution to adjust the pH to 1, and the solution was concentrated to dryness. Add a small amount of water to the residue to crystallize it, add acetone, collect the crystals, and wash with acetone. The crude crystals were recrystallized from methanol-ethanol to give 1-[4-
3.32 g of (2-hydroxyethyl)piperazin-1-yl-carbonylmethyl]-6-amino-3,4-dihydrocarbostyryl dihydrochloride is obtained. Melting point 217-220â (decomposed) Example 13 1-[4-(2-hydroxyethyl)piperazin-1-yl-carbonylmethyl]-6-amino-3,4-dihydrocarbostyryl dihydrochloride
Dissolve 900ml in 10ml of methanol and 2ml of water to make 2N
- Add 2.22 ml of a methanol solution of sodium hydroxide. Next, 250 mg of acetic anhydride is added and reacted at room temperature for 2 hours. The reaction solution was concentrated to dryness, and the residue was purified by preparative thin layer chromatography to obtain an oil. This oil was crystallized and further recrystallized from ethanol to obtain 360 mg of 1-[4-(2-hydroxyethyl)piperazin-1-yl-carbonylmethyl]-6-acetamido-3,4-dihydrocarbostyryl. Melting point 217.5-218.5â.
Claims (1)
åºãåŒãïŒR3ã¯ããããã·äœçŽã¢ã« ãã«åºïŒããR2ã¯æ°ŽçŽ ååãäœçŽã¢ã«ã³ãã·åºã
ãããåºãã¢ããåºãŸãã¯äœçŽã¢ã«ã«ãã€ã«ã¢ã
ãåºããã¯äœçŽã¢ã«ãã¬ã³åºããããã瀺ããã ã§è¡šããããã«ã«ãã¹ããªã«èªå°äœåã³ãã®å¡©ã[Claims] 1. General formula [In the formula, R 1 is a hydroxyl group, a lower alkoxy group, or a group [Formula] (R 3 is a hydroxy lower alkyl group), and R 2 is a hydrogen atom, a lower alkoxy group,
A represents a nitro group, an amino group or a lower alkanoylamino group, and A represents a lower alkylene group. ] A carbostyril derivative represented by these and its salt.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP7929080A JPS574974A (en) | 1980-06-11 | 1980-06-11 | Carbostyril derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP7929080A JPS574974A (en) | 1980-06-11 | 1980-06-11 | Carbostyril derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS574974A JPS574974A (en) | 1982-01-11 |
| JPS634535B2 true JPS634535B2 (en) | 1988-01-29 |
Family
ID=13685719
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP7929080A Granted JPS574974A (en) | 1980-06-11 | 1980-06-11 | Carbostyril derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS574974A (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4530928A (en) * | 1982-01-13 | 1985-07-23 | Merck & Co., Inc. | Quinoline carboxylic acid complexes with guanidinium carbonate |
| FI80022C (en) * | 1982-07-05 | 1990-04-10 | Otsuka Pharma Co Ltd | FOERFARANDE FOER FRAMSTAELLNING AV ETT NYTT, TERAPEUTISKT ANVAENDBART KARBOSTYRILDERIVAT. |
| CA2067475C (en) * | 1991-05-08 | 2000-10-10 | Yasuo Oshiro | Carbostyril derivatives and their use |
-
1980
- 1980-06-11 JP JP7929080A patent/JPS574974A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS574974A (en) | 1982-01-11 |
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