TW205546B - - Google Patents
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- Publication number
- TW205546B TW205546B TW081103382A TW81103382A TW205546B TW 205546 B TW205546 B TW 205546B TW 081103382 A TW081103382 A TW 081103382A TW 81103382 A TW81103382 A TW 81103382A TW 205546 B TW205546 B TW 205546B
- Authority
- TW
- Taiwan
- Prior art keywords
- group
- carbonylquinoline
- alkyl
- item
- phenyl
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 claims description 111
- -1 carbonyl quinoline derivative Chemical class 0.000 claims description 106
- 125000000217 alkyl group Chemical group 0.000 claims description 27
- PBBBVRMFQSDGTP-UHFFFAOYSA-N 1h-quinolin-2-ylidenemethanone Chemical class C1=CC=C2C=CC(=C=O)NC2=C1 PBBBVRMFQSDGTP-UHFFFAOYSA-N 0.000 claims description 24
- 238000000034 method Methods 0.000 claims description 24
- 238000006243 chemical reaction Methods 0.000 claims description 23
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 23
- 239000000203 mixture Substances 0.000 claims description 17
- 125000005843 halogen group Chemical group 0.000 claims description 14
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 14
- 125000001424 substituent group Chemical group 0.000 claims description 13
- 125000003545 alkoxy group Chemical group 0.000 claims description 12
- 239000003795 chemical substances by application Substances 0.000 claims description 11
- 150000003839 salts Chemical class 0.000 claims description 11
- 125000003277 amino group Chemical group 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 9
- 230000000694 effects Effects 0.000 claims description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 125000003282 alkyl amino group Chemical group 0.000 claims description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 5
- 125000002947 alkylene group Chemical group 0.000 claims description 4
- 125000003368 amide group Chemical group 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 3
- 230000002079 cooperative effect Effects 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 108010085082 sigma receptors Proteins 0.000 claims description 3
- 239000011701 zinc Substances 0.000 claims description 3
- 229910052725 zinc Inorganic materials 0.000 claims description 3
- 150000001412 amines Chemical class 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 claims description 2
- 239000002023 wood Substances 0.000 claims 3
- 241000723353 Chrysanthemum Species 0.000 claims 2
- 235000007516 Chrysanthemum Nutrition 0.000 claims 2
- 150000001335 aliphatic alkanes Chemical class 0.000 claims 2
- 125000001930 alkyl chloride group Chemical group 0.000 claims 2
- CREMABGTGYGIQB-UHFFFAOYSA-N carbon carbon Chemical compound C.C CREMABGTGYGIQB-UHFFFAOYSA-N 0.000 claims 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 claims 2
- 150000003248 quinolines Chemical class 0.000 claims 2
- 241001415830 Bubo Species 0.000 claims 1
- 229910014585 C2-Ce Inorganic materials 0.000 claims 1
- BUGBHKTXTAQXES-UHFFFAOYSA-N Selenium Chemical compound [Se] BUGBHKTXTAQXES-UHFFFAOYSA-N 0.000 claims 1
- 125000003342 alkenyl group Chemical group 0.000 claims 1
- 125000004422 alkyl sulphonamide group Chemical group 0.000 claims 1
- 229940027991 antiseptic and disinfectant quinoline derivative Drugs 0.000 claims 1
- 208000016335 bubo Diseases 0.000 claims 1
- 125000004802 cyanophenyl group Chemical group 0.000 claims 1
- 230000014759 maintenance of location Effects 0.000 claims 1
- GASFVSRUEBGMDI-UHFFFAOYSA-N n-aminohydroxylamine Chemical compound NNO GASFVSRUEBGMDI-UHFFFAOYSA-N 0.000 claims 1
- 230000000926 neurological effect Effects 0.000 claims 1
- 229910052711 selenium Inorganic materials 0.000 claims 1
- 239000011669 selenium Substances 0.000 claims 1
- 235000012976 tarts Nutrition 0.000 claims 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 207
- 235000019441 ethanol Nutrition 0.000 description 74
- 239000013078 crystal Substances 0.000 description 31
- 239000000243 solution Substances 0.000 description 25
- 239000002904 solvent Substances 0.000 description 22
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 239000007858 starting material Substances 0.000 description 18
- 241000699670 Mus sp. Species 0.000 description 16
- 239000000460 chlorine Substances 0.000 description 16
- 239000000843 powder Substances 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- 125000004429 atom Chemical group 0.000 description 12
- 230000027455 binding Effects 0.000 description 12
- 239000004480 active ingredient Substances 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 10
- 239000002253 acid Substances 0.000 description 10
- 229920001223 polyethylene glycol Polymers 0.000 description 10
- 239000003826 tablet Substances 0.000 description 10
- 206010002091 Anaesthesia Diseases 0.000 description 9
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 230000037005 anaesthesia Effects 0.000 description 9
- 230000000875 corresponding effect Effects 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- 238000005481 NMR spectroscopy Methods 0.000 description 8
- 229920002472 Starch Polymers 0.000 description 8
- 239000002552 dosage form Substances 0.000 description 8
- 238000011049 filling Methods 0.000 description 8
- 239000012442 inert solvent Substances 0.000 description 8
- 230000002829 reductive effect Effects 0.000 description 8
- 239000008107 starch Substances 0.000 description 8
- 235000019698 starch Nutrition 0.000 description 8
- 239000012230 colorless oil Substances 0.000 description 7
- 239000007789 gas Substances 0.000 description 7
- 239000000825 pharmaceutical preparation Substances 0.000 description 7
- 238000011084 recovery Methods 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- 239000002202 Polyethylene glycol Substances 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 6
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 description 5
- 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 5
- 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 5
- 229920000084 Gum arabic Polymers 0.000 description 5
- 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 5
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 5
- 235000010489 acacia gum Nutrition 0.000 description 5
- 239000000205 acacia gum Substances 0.000 description 5
- 239000003638 chemical reducing agent Substances 0.000 description 5
- 150000002170 ethers Chemical class 0.000 description 5
- 239000008103 glucose Substances 0.000 description 5
- 239000008187 granular material Substances 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000008101 lactose Substances 0.000 description 5
- 238000002844 melting Methods 0.000 description 5
- 230000008018 melting Effects 0.000 description 5
- 239000003921 oil Substances 0.000 description 5
- 235000019198 oils Nutrition 0.000 description 5
- 239000002245 particle Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 230000011514 reflex Effects 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- 244000215068 Acacia senegal Species 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 4
- 206010019196 Head injury Diseases 0.000 description 4
- 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 4
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 4
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
- 150000001298 alcohols Chemical class 0.000 description 4
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- 239000000969 carrier Substances 0.000 description 4
- 238000010531 catalytic reduction reaction Methods 0.000 description 4
- 239000011248 coating agent Substances 0.000 description 4
- 238000000576 coating method Methods 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 239000012528 membrane Substances 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 229950008882 polysorbate Drugs 0.000 description 4
- 229920000136 polysorbate Polymers 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- 239000012312 sodium hydride Substances 0.000 description 4
- 229910000104 sodium hydride Inorganic materials 0.000 description 4
- 229940124597 therapeutic agent Drugs 0.000 description 4
- WNWHHMBRJJOGFJ-UHFFFAOYSA-N 16-methylheptadecan-1-ol Chemical class CC(C)CCCCCCCCCCCCCCCO WNWHHMBRJJOGFJ-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- 239000005995 Aluminium silicate Substances 0.000 description 3
- 101150041968 CDC13 gene Proteins 0.000 description 3
- 206010010071 Coma Diseases 0.000 description 3
- 208000022540 Consciousness disease Diseases 0.000 description 3
- 229920002261 Corn starch Polymers 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 235000012211 aluminium silicate Nutrition 0.000 description 3
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 229940110456 cocoa butter Drugs 0.000 description 3
- 235000019868 cocoa butter Nutrition 0.000 description 3
- 239000008120 corn starch Substances 0.000 description 3
- 229940099112 cornstarch Drugs 0.000 description 3
- 235000014113 dietary fatty acids Nutrition 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000000194 fatty acid Substances 0.000 description 3
- 229930195729 fatty acid Natural products 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- BCQZXOMGPXTTIC-UHFFFAOYSA-N halothane Chemical compound FC(F)(F)C(Cl)Br BCQZXOMGPXTTIC-UHFFFAOYSA-N 0.000 description 3
- 229960003132 halothane Drugs 0.000 description 3
- 229930195733 hydrocarbon Natural products 0.000 description 3
- 150000002430 hydrocarbons Chemical class 0.000 description 3
- 230000006872 improvement Effects 0.000 description 3
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 150000007522 mineralic acids Chemical class 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 208000020016 psychiatric disease Diseases 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 238000006722 reduction reaction Methods 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 239000000829 suppository Substances 0.000 description 3
- 239000000454 talc Substances 0.000 description 3
- 229910052623 talc Inorganic materials 0.000 description 3
- 235000012222 talc Nutrition 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- IVSZLXZYQVIEFR-UHFFFAOYSA-N 1,3-Dimethylbenzene Natural products CC1=CC=CC(C)=C1 IVSZLXZYQVIEFR-UHFFFAOYSA-N 0.000 description 2
- VVFVRTNNLLZXAL-UHFFFAOYSA-N 2-(2-methylphenyl)guanidine Chemical compound CC1=CC=CC=C1N=C(N)N VVFVRTNNLLZXAL-UHFFFAOYSA-N 0.000 description 2
- ZYHQGITXIJDDKC-UHFFFAOYSA-N 2-[2-(2-aminophenyl)ethyl]aniline Chemical group NC1=CC=CC=C1CCC1=CC=CC=C1N ZYHQGITXIJDDKC-UHFFFAOYSA-N 0.000 description 2
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 2
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 description 2
- LJGHYPLBDBRCRZ-UHFFFAOYSA-N 3-(3-aminophenyl)sulfonylaniline Chemical group NC1=CC=CC(S(=O)(=O)C=2C=C(N)C=CC=2)=C1 LJGHYPLBDBRCRZ-UHFFFAOYSA-N 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 206010021143 Hypoxia Diseases 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 2
- 229940094948 Sigma receptor agonist Drugs 0.000 description 2
- 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 2
- 229930006000 Sucrose Natural products 0.000 description 2
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 2
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 230000032683 aging Effects 0.000 description 2
- 125000003302 alkenyloxy group Chemical group 0.000 description 2
- 125000004414 alkyl thio group Chemical group 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- 150000003863 ammonium salts Chemical class 0.000 description 2
- 239000002269 analeptic agent Substances 0.000 description 2
- 150000008064 anhydrides Chemical class 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 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
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 239000007941 film coated tablet Substances 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
- C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
-
- 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
- A61P25/26—Psychostimulants, e.g. nicotine, cocaine
-
- 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
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/24—Oxygen atoms attached in position 8
- C07D215/26—Alcohols; Ethers thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/36—Sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/38—Nitrogen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Emergency Medicine (AREA)
- Psychiatry (AREA)
- Hospice & Palliative Care (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Quinoline Compounds (AREA)
Description
Λ 6 \\6 05546 五、發明説明() 9 本發明係閧於新穎2-羰基喹啉衍生物及含有該等化合 物之葯物組成物可用作意識紊亂改善劑,中植神經興奮劑 或σ受器促效劑者。 本發明有一目的係提供具有意識紊亂改善劑*中樞神 經条統興奮劑或〇*受器促效劑價值的2-羰基喹啉衍生物。
I 本發明之另一目的係提供可用作意識紊亂改善劑之葯 物組成物。 本發明之又一目的係提供可用作中樞神經糸統興奮劑 之葯物組成物。 本發明之又另一目的係提供可用作σ受器促效劑之葯 物組成物。 本發明之其他待點由下文之說明將顯然易明。 本發明提供具如下通式之2-羰基喹啉衍生物 (請先閲讀背而之注意事項再塡寫本頁)
經浒部屮央榣準局Α工消赀合作社印製 / \ 0 Α — Ν N - R z \_/ 〔式中R1為鹵基,羥基,低级烷氧基,低级烷基,低级烯 氧基,胺基,低级烷醢胺基或低级烷硫基;R*爲苯基。其 可任意具有1或2取代基,取代基各自獨立選自鹵基,低 级烷氧基,低级烷基,硝基,胺基,低级烷酿胺基,羥基 ,氰基,苯基-低级烷氧基及齒基-低级烷基中之任一者; A為低级烷撐基;及!!為1或2之整數;及其中介於2-羰 本紙張尺度边用中國Η家楳準(CHS) 1M規格(210x297公龙) 3 81. 4. 10,000¾ (H) 205546 五、發明説明() 基喹啉主幹之3位與4位間之碳-磺鍵可為單鍵或雙鍵〕及 其鹽。 本發明化合物具有中樞神經条統興奮劑及意識紊亂改 善活度,可用作頭部創傷,腦出血,腦梗塞,蜘蛛膜下出 血,葯物中毒*缺氧症,缺氧所導致之意外,腦手術後之 意識紊亂,及冠狀動脈繞道手術之治療劑;此等疾病之結 果,例如精神遲滯,注意力不集中,言語紊亂,認知紊亂 ,行為紊亂,意志力下降,情緒紊亂等之治療劑;又可作 為老年痴呆症狀改善劑,例如抑轡狀態,譫妄,言語紊亂 ,行為紊亂’,注意力減退*及年齡相關的記憶力受損。又 復,本發明化合物具有ir受器促效话度,因此可用作抑鬱ι ,焦廉神經官能症,精神與身體疾患,其他壓力誘發的精 神疾患,厭食性神經衰弱,腦下垂體功能不足,高濾泡榭 素血症,血管型痴呆,過動症候群,痴呆/失眠,巴金生 氏病等之治療劑。此等化合物也可用作抗抑鬱劑*抗焦慮 劑*精神與身體疾患及巴金生氏病之治療劑等。 本發明化合物之一特點為當經口投葯時其顯示中植神 經条統活化,意識紊亂改善及σ受器促效活度。 經濟部中央榣準局员工消赀合作社印製 (請先JU1讀背而之注意事項-?!-填窍本頁) 如上通式(1)中出現之各符號所代表之基更特定說明 如下。 鹵原子例如為氟,氯,溴或碘原子。 低级烷氧基包括含1至6碳原子之直鏈或支鏈垸氧基 ,例如甲氧基,乙氧基,丙氧基,丁氧基,三級丁氧基, 戊氧基及己氧基。 本紙尺度边用中ΗΒ家標準(CNS)T4規格(210X297公龙) -4 ~ 81. 4. 10,000¾ (||) 205546 經濟部屮央搮準局EX工消赀合作社印製 五、發明説明() 低级烷基包含含1至6硪原子之直鏈或支鋪烷基,如 甲基,乙基,丙基,異丙基,丁基,三级丁基,戊基及己 基。 低级烯氧基包含含2至6硕原子之直鏈或支鏈烯氧基 ,如乙烯氧基,丙烯氧基,2-丁烯氧基,3-丁烯氧基,1-甲基丙烯氧基,2-戊烯氧基及2-己烯氧基。 低级烷醢肢基包含含1至6磺原子之直鍵或支鍵烷醯 肢基,如甲醢胺基,乙酿胺基,丙酿胺基,丁醯胺基,異 丁醯胺基,戊醸肢基,三级丁基羰胺基及己基醯胺基。 低级烷硫基包含含1至6碩原子之直鋪或支鍵烷辦基 ,如甲硫基,乙硫基,丙硫基,異丙硫基,丁硫基,三级 丁硫基,戊硫基及己硫基。 苯基-低鈒烷氧基包含其中烷氧基部分爲含1至6碩 原子之直鐽或支鏈之苯基烷氧基,如苄氧基,2-苯乙氧基 ,1-苯乙氧基,3-苯丙氧基,4-苯丁氧基,1,卜二甲基-2 -苯乙氧基,5-苯戊氧基,6-苯己氧基,及2-甲基-3-苯丙 氧基。 鹵基-低级烷基包含含1至6碩原子及1至3鹵原子 之直鐽或支鍵烷基,如氯甲基,溴甲基,碘甲基,氟甲基 ,二氯甲基,二溴甲基,二氟甲基,三氯甲基,三溴甲基 ,三氟甲基,2-氯乙基,2-溴甲基,2-氟乙基,1,2_二氯 乙基,2,2-二氟乙基,卜氯-2-氟乙基,2,2,2-三氟乙基 ,2,2,2-三氯乙基,3-氟丙基,3,3,3-三氯丙基,4-氯丁 基,5-氯戊基,6-氯己基,及3-氯-2-甲基丙基。 (請先閱讀背而之注意事項洱填寫本頁) 裝 訂 線 本紙张尺度逍用中《Η家楳準(CNS)*H規格(210X297公龙) _ 5 - 81. 4. 10,000^(11) Λ 6 Η 6 05546 五、發明説明() (請先閱讀背而之注意事項#填寫本頁) 可任意有一·或二取代基且各自獨立選自齒基,低级烷 -氧基,低级烷基,硝基,胺基,低鈒烷醢胺基,羥基,氰 經濟部中央梂準局A工消#合作社印製 基,苯基-低级烷氧基及鹵基-低級烷基之苯基,包含,苯 基及一-及二-苯基取代基,其中苯環上之各取代基係獨立 選自鹵基,含1至6硪原子之直鏈或支鏈烷氧基,含1至 6硪原子之直鐽或支鐽烷基,硝基,胺基,含1至6磺原 子之直鋪或支鏈烷醯胺基,羥基,氟基;其中烷氧基部分 為含1至6碩原子之直鐽或支鍵烷氧基之苯基烷氧基,及 含1至6碳原子及含1至3齒原子之直鏈或支鍵烷基,如 2-甲氧基苯基,3-甲氧基苯基,4-甲氧基苯基,2-乙氧基 苯基,3-乙氧基苯基,4-乙氧基苯基,4-異丙氧基苯基, 4_戊氧基甲基,2,4-二甲氧基苯基,4~已氧基苯基,3,4-二甲氧基苯基,3-乙氧基-4-甲氧基苯基,2,3-二甲氧基 苯基,3,4-二乙氧基苯基,2,5-二甲氧基苯基,2,6-二甲 氧基苯基,3,5-二甲氧基苯基,3,4-二戊氣基苯基,2-氯 苯基,3-氯苯基,4-氣苯基,2-氯苯基,3-氟苯基,4-氟 苯基,2-溴苯基,3-溴苯基,4-溴苯基,2-碘苯基,3~碘 苯基,4-碘苯基,3,4-二氯苯基,3,5-二氯苯基,2,6-二 氯苯基,2,3-二氣苯基,2,4-二氯苯基,3,4_二氟苯基, 3,5-二溴苯基,2-甲氧基-3-氯苯基,2-甲基苯基,3-甲 基苯基,4-甲基苯基,2-乙基苯基,3-乙基苯基,4-乙基 苯基,4-異丙基丙基,3-丁基苯基,4-戊基苯基,4〜己基 苯基,3,4-二甲基苯基,3,4-二乙基苯基,2,4-二甲基苯· 基,2,5-二甲基苯基,2,6-二甲基苯基,3-氣-4-甲基苯 本紙張尺度逍用中國國家標準(CNS)TM規格(210x297公¢) · _ 6 — 8L 4. 10,000¾ 〇[) 05546 Λ 6 ΙΪ6 經濟部中央榀準局只工消赀合作社印製 五、發明説明() 基,2-三氟甲基苯基,3-三氟甲基苯基,4-三氟甲基苯基 ,2-氣甲基苯基* 3- (2-溴甲基)苯基,4- (3,3,3-三氯 丙基)苯基,2- (4-氯丁基)苯基,3- (5-氣戊基)苯基 ’ 4- (6-氯己基)苯基,2-硝基苯基,3-硝基苯基,4-硝 基苯基,3,.4-二硝基苯基,3,4,5-三硝基苯基,2-胺基苯 基,3-胺基苯基,4-胺基苯基,2-甲酿胺基苯基,3-乙醯 胺基苯基,2-丙醯胺基苯基,4-丁醯胺基苯基,3-戊醯胺 基苯基,4-己酿胺基笨基,2-乙醯胺基-4-甲基苯基,4-乙醯胺基-3-甲氧基苯基,2-羥基苯基,3-羥基苯基,4-羥基苯基,2,3-二羥基苯基,2,4,6-三羥基苯基,2-氛基 苯基,3-氰基苯基,4-氟基苯基-3,4-二氮基苯基,2-苄 氰基苯基,3- ( 2-苯基乙氧基)苯基,4- ( 1-苯基乙氧基 )苯基,2- (3-苯基丙氧基)苯基,3- (4-苯基丁氧基) 苯基,4- (5-苯基戊氧基)苯基及2- (6-苯基己氧基)苯 基。 低级烷撐基包含含1至6磺原子之直鏈或支鏈烷撐基 ,例如甲撐基*乙撐基,三甲撐基,2-甲基三甲撐基,1-甲基三甲撐基,四甲撐基,五甲撐基,六甲撐基,2-乙基 乙撐基,及2,2-二甲基三甲撐基。 本發明化合物可藉數種方法生成。於較佳具體例中, 可遵照下述方法生產(方法1): (請先wlift背而之注意事項#堝寫本頁) 裝 訂 線 本紙5良尺度逍用中SH家標毕(CNS)T4規格(210X2沢公徒) ~ 7 - 81. 4.】0,000張(H) 205548 Λ β Η 6 五、發明説明()
Η Α - X1 (請先閲讀背而之注患事項再填筠本頁) (2 ) ‘ ( 4 )
A - N N - R £ \_/ C 1 ) 如上反應式中R1,R3,A,η及介於2-羰基喹啉主幹之3位 及4位間之磺-碳鍵之定義如上,及X1與X8各自為豳原子。 經濟部屮央標準局Α工消t合作社印製 如上方法1中,通式(2)化合物可方便地與通式(3)化 合物,於適當惰性溶劑内,於鹵化氫接受劑存在下反應。 通式(2)化合物與通式(3)化合物間之數量比並無特殊限制 ,但可適當地於廣泛#範圍内選用。然而,士略而言,後者 用量相對於每1其耳前者為不少於1其耳*更好1至3冥 耳。鹵化氫接受劑,例如為鹸金颶如鈉或鉀,鹺金屬醯胺 如納醯胺或鉀醯胺,或氫化鈉。至於惰性溶劑,值得一提 者包括芳香烴類如苯,甲苯及二甲苯;醚類如四氫呋喃, 二氧陸國及乙二醇二甲基醚;二甲亞礙,二甲基甲醯胺及 六甲基磷酸三醢胺。該反應通常係於0°至150Ό,較好0。 本紙張尺度边用中«Η家猱芈(CNS)T4規格(210X297公龙) 8 81. 4. ]0,000張(il) Λ 6 η 6 ^05546 五、發明説明() (請先間誚背而之注意事項洱塡窍本頁) 至ΐοου下進行,通常係於約1至12小時内完成。如此獲 得通式<4)化合物。 通式(4>化合物與通式(5>化合物間之反應進行時未使 用任何溶劑、或可於習知惰性溶劑内於室溫至200¾,較 好60°至1201C間之溫度進行,於約1至1〇小時內完成。 可用作惰性溶劑者為例如前述之芳番烴類,例如前述之醚 類,低級醇如甲醇,乙醇及異丙醇;乙腈,二甲基甲酿胺 ,二甲亞風等極性溶劑。更有利地於驗性化合物如齒化氫 接受劑存在下進行前逑反應。所述鹼性化合物例如為碳酸 鉀*碩酸鈉,氫氧化鈉,碩酸氫鈉,納醯胺,氫化鈉*三 乙胺,三丙胺,Ptt啶* 1,8-二吖雙環[5.4.0]十一烯-7_ (DBIO,等有機鹼。若有所需*可經由加入鹾金屬碘化物 (例如碘化鉀,碘化鈉)作反應促進劑加速反應。進行前 述反應之通式(4)化合物與通式(5>化合物間之數量比並無 特殊限制,但通常後者之用量相對於每其耳前者為1莫耳 或Μ上,較好1至5其耳。 如上通式(1)所代表之本發明化合物也可藉如下方法 (方法2 )生產: 經濟部屮央榀準局κχ工消费合作社印製 本紙張尺度边用中國明家猱準(CNS)*F4規格(210x297公¢) 9 81. 4. 10,0005^(1!) ^ 05546 Λ 6 Π 6 五、發明説明()
經浒部屮央榣準局貝工消t合作社印製 / \ 〇 A - N N - R \_/ (1)_ 如上反應式中R1,Ra,A,η及2-羰基喹啉主幹之3位與4 位間之碩-硕鍵之定義如上,而X3為鹵原子。 如上方法2中,通式(2)化合物與通式(6>化合物間之 反應,可Μ前述對通式(2)化合物及通式(3)化合物間之反 應之相同方式進行。通式(6)化合物例如可方便地藉由令 前述通式(5)化合物與通式(3)化合物反應而製備。通式 (3) 化合物與通式(5)化合物間之反應,可以如前就通式 (4) 與通式<5>化合物間之反應之相同方式進行。 如上通式(1〉所代表之本發明化合物中,其中為低 级烷醢胺基之該等化合物,及其中R2為苯環上具有至少一 個低级烷醯胺基作取代基之苯基之該等化合物,可經由將 其中R1為胺基對應化合物,及其中Ra為苯瓌上具有至少一 胺基作取代基之苯基的該等化合物,分別進行低级烷醯基 化而生產。 (請先閲讀背而之注意事項再填寫本頁) 裝_ 訂 線 本紙尺度遇用中國ffl家標华(CNS) TM規格(210X297公址) 81. 4. 10,000張 <Ιί) 五、發明説明() 前述低級烷醢基化反應之進行方式,例如藉由令起始 化合物與低鈒烷酸酐,於未使用任何溶劑内或於適當惰性 溶覿内於齡性化合物存在下反應;或藉由令起始化合物與 低级烷酸酐或低級烷醯鹵化物,於適當惰性溶劑内反應而 進行。至於使用鹸性化合物,值得一提者有機鹼如毗啶, 4-二甲胺基吡啶及三乙胺;及無機鹼如碩酸鈉及硕酸鉀。 至於惰性.溶劑*值得一提者有例如乙酸,吡啶,醚類如二 氧陸醒,芳香烴類如苯,及齒化烴類如二氯甲烷及氯仿。 母级烷酸酐或低级烷醢鹵化物之用量至少為等其耳量,通 常係於等莫耳量至大為過量之範圍。所述反應有利地可於 室溫至約150TC進行,且通常於約0.5至約5小時内完成。 由如上通式<1〉所代表之本發明化合物中,其中I為 胺基之該等化合物,或其中Ra爲苯環上具有至少一胺基作 取代基之苯基的該等化合物,可經由将其中R1為低级烷醯 胺基之對應化合物,及其中114為苯環上具有至少一低级烷 醯胺基作取代基之苯基的對應.化合物,分別水解而生成。
經濟部中央榣準局E3C工消#合作社印M 前述水解係於適當惰性溶劑内,或未使用任何溶劑於酸 之存在下進行。溶劑可為對反應無不利影锻之習知者,例 如包含水*齒化烴類如二氣乙烷及氣仿*低级醇類如甲醇 ,乙醇及異丙醇,·銅類如丙酮及甲基乙基甲酮,醚類如二 氧陸國,四氫呋喃,乙二醇一甲醚及乙.二醇二甲醚,脂肪 酸類如甲酸,及由此等溶劑所組成之混合溶剤。至於酸, 值得一提者有例如無機酸,如氫氯酸,硫酸,氫溴酸;及 有機酸如甲酸,三氟乙酸,乙酸及芳香族磺酸。酸之用量 11 (請先閲讀背而之注意事項#場寫本頁) 81. 4. 10,000張(II) 205546 Λ 6 Μ 6 經濟部屮央楳準而β工消赀合作社印製 五、發明説明() · 並無特殊限制,.但可於廣泛範圍内選用。然而,一般而言 ,其用量相對於每其耳各別起始化合物為約1至10莫耳。 槪略而言,,所逑反應於室溫至約200¾之溫度,較好於室 溫至約150¾之溫度進行,且通常於約0.5至約5小時内完 成0 如上通式(1)所代表之本發明化合物中,其中R*爲苯 環上具有至少一胺基作取代基之苯基的該等化合物,可經 由將其中為於苯環上具有至少一硝基作取代基之苯基的 對應化合物還原而生產。 前逑還原反應之進行方式,例如有(1〉使用觸媒於適 當溶劑内藉催化還原法進行;或(2)使用還原劑如金颶或 金羼鹽舆酸或舆鹺金属氫氧化物,硫化物或銨鹽之混合物 *於適當惰性溶劑内進行。 以如上(υ所述之催化還原反應為例,所用溶劑包含 水,乙睃;醇類如甲醇*乙醇及異丙醇;烴類如己烷及環 己烷;醚類如二氧陸園,四氫呋喃,二乙醚及二乙二醇二 甲醚;酯類如乙酸乙酯及乙酸甲酯;質子惰性極性溶劑如 Ν,Ν-二甲基甲醸胺;及由此等溶劑所組成之混合溶劑。所 用催化還原反應‘之觸媒例如耙,鈀黑,耙硝,鉑,氧化鉑 *亞鉻酸銅,或丹尼銳。較好,所述觸媒之用量相對於每 份起始化合物為約0.02至1重量份。反應溫度通常為約 -20°至約150*C,較好0°至約200*0 *而氫壓較好爲1至 約10大氣壓。所逑反應通常係於約0.5至約10小時内完成 。酸如氫氯酸可加入所述反應糸統内〇 (請先間讀背而之注意事項再填寫木頁) 裝_ 訂 線 本ftUfk尺度边用中國Η家標準(CNS)T4規格(210X297公tf) 81. A. 10,0005fc (II) 2〇δδ^6 Λ 6 ΙΪ6 五、發明説明() (請先閲讀背而之注意事項洱填寫本頁) 當使用如上.(2)所逑之方法時,所用還原劑例如有鐵 *鋅,錫或亞鐵氯化物與無機酸如氩氯酸或硫酸之混合物 :或鐵,硫酸亞鐵,鋅或錫,及齡金靥氩氧化物如氫氧化 鈉*硫化物如硫化銨*含水銨或銨鹽如氣化銨。所用惰性 溶劑例如爲水,乙酸,甲醇,乙醇或二氧陸國。前述還原 反應之條件可依所用還原劑適當選用。如此,舉例言之, 當還原劑包括氯化亞錫及氫氯酸時*反應推麓於約0C至 室溫進行約+0.5至約10小時。還原劑之用量相對於每其耳 起始化合物至少為等其耳暈,通常爲每其耳起始化合物1 至5莫耳之數量。 .如上通式(1)所代表之本發明化合物中*其中2-羰基 喹啉主幹之3位與4位問之碩-硪鍵為雙鍵之該等化合物 ,可經由將其中該鍵為單鍵之對應化合物,以本身習知之 方式脫氫化而生成。通式(1>所代表之本發明化合物中* 其中2-羰基喹啉主幹之3位與4位間之硝-碩鍵爲單鍵之 該等化合物,也可藉由令其中該鍵為雙鍵之對應化合物, 以本身習知之方式進行催化還原反應而生成。
經濟部屮央槛準而只工消仲合作社印M 依本發明可作為活性成分之通式(1>化合物可方便地 與葯理可接受性習知酸生成鹽。至於此等酸,值得一提者 有無機酸如硫酸,硝酸,氫氯酸,及氫溴酸;及有機酸如 乙酸,對-甲苯磺酸,乙烷磺酸,草酸,順丁烯二酸,反 丁烯二酸,掙樺酸,丁二酸*及苯甲酸。此等鹽恰如同通 式(1)游雔化合物般,也可用作本發明之活性成分化合物 。前述通式(1>化合物於其範圍内包含所有可能之立體異 本紙張尺度边用中S國家標準(CNS)T4規格(210X297公龙) 13 81. 4.〗0,000張(H) Λ 6 Η6 205546 五、發明説明() 構物及其光學異構物。此等異構物也可用作活性成分化合 物。 由如上反應式所示例說明之方法所得之期望化合物, 可藉習知分離手段及進一步純化,而與反應条统分離。有 用之分雔及純化手段有,例如蒸餾,再結晶,柱式層析* 離子交換層析,凝膠層析,親和層析,製備性薄層層析, 及溶劑抽取。 如此所得之活性成分化合物可有效用作中植神經条統 興奮劑,意識紊亂改善劑,及σ受器促效劑;及可Μ習知 葯物製劑形式使用。此等製劑可使兩習知镇充剤,增暈劑 ,黏合劑,濕潤劑,崩散劑,界面活性劑,潤滑劑,等稀 釋劑或賦形剤製備。此等葯物製劑可具有依據治療目的所 選用之各種劑型,而劑型之例有錠劑,丸劑,散劑,溶液 劑,懸浮液劑》乳液劑,粒劑,膠囊劑,栓劑,及注射劑 (溶液劑,懸浮液劑等)。欲製成錠劑,可使用業界至今 為止眾所周知之廣泛多種載劑。如此*例如可使用載媒劑 或賦形劑如乳糖,蔗糖,氯化鈉,葡萄糖,尿素,澱粉, 碳酸鈣,高嶺土,結晶纖維素及矽酸,黏合劑如水,乙醇 ,丙醇,單純糖漿,葡萄糖溶液,澱粉溶液,凝膠溶液* 羧甲基维維素,蟲膠,甲基纖維素,磷酸鉀及聚乙烯吡咯 酮;崩散劑如乾澱粉,藻蛋白酸鈉,粉狀璜脂,粉狀昆布 糖,硕酸氫鈉,硕酸鈣,聚氧乙烯聚山梨糖醇脂肪酸酯, 月桂基硫酸鈉*硬脂酸-甘油酯,澱粉及乳糖;崩散抑制 劑如蔗糖,甘油三硬脂酸酯,可可脂及氫化油;吸收促進 (請先閲讀背而之注意事項存填筠本頁〕 訂 線 經濟部中央標準局Μ工消f合作社印製 本紙張尺度边用中《國家標毕(CNS)TM規格(210x297公址) -14 - 81. 4. 10,000張(11) 205546 Λ 6 Η 6
經濟部中央梂半局A工消#合作社印M 五、發明説明() 劑如四级銨鹾及.月桂基硫酸納;濕潤剤或保濕劑如甘油及 澱粉;吸附劑如澱粉,乳糖,高嶺土,皂土及膠醱氧化矽 ;及潤滑剤如細分滑石,硬脂酸鹽,粉狀硼酸及聚乙二醇 。若有所需,錠劑又可帶有習知塗膜,因而獲得糖衣錠, * 凝膠衣錠,腸衣錠,膜衣錠,或雙衣錠或多層錠。欲製造 九劑,可使用桊界眾所周知之廣泛多種載劑。其範例有載 媒劑及賦形劑如葡萄糖,乳糖*澱粉,可可脂,硬化植物 油,高嶺土及滑石;黏合劑如粉狀阿拉伯膠*粉狀西黃養 膠,明膠及乙醇;及崩散劑如昆帝糖及瓊脂。欲製造栓劑 可用至今已知之廣泛多種載劑。值得一提者之例有聚乙二 醇,可可脂,高级醇類,高级酯類*明膠*及半合成甘油 酯類。膠囊係藉習知方式製備,概略而言,係將各活性成 分化合物與各種載劑,例如前述者混合,及填充入硬明膠 膠囊及軟膠囊内等。注射劑之製備中,溶液剤,乳液劑或 懸浮液劑較好經滅菌,且較好與血液成等張;以及欲製備 此等劑型*可用業界習用之各種稀釋劑。如此,舉例言之 ,值得一提者有水,乙醇,macro gol,丙二醇,乙氧基化 異硬脂醇,多氧基化異硬脂醇,及聚氧乙烯聚山梨糖醇脂 肪酸酯。此例中,葯物製劑可含其數量足夠獲得等張溶液 之氣化鈉;葡萄糖或甘油。可加入任一種習知增溶劑,緩 衝劑,緩和劑或局部麻醉劑等。又復,若有所需,葯物製 劑可含有色料,保藏剤,番料*矯味劑,增甜劑等及其他 齡物。 本發明之此等葯物製劑內之活性成分化合物之比例並 (請先閲誚背而之注意事項#填穷本頁) 裝_ 訂 線 本紙張尺度边用中国Η家樣準(CNS)TM規怙(210X297公龙) —15 - 81. 4. 10,000¾ (II) 205546
Λ 6 HG
經濟部屮央梂準局A工消t合作社印M 五、發明説明() 無特殊限制,但適合選自廣泛範圍。然而,概略而言,其 比例推薦選用約1至約70%重量比,較好約5至50%重量 比之範圍。 本發明之葯物製劑之投葯途徑並無特殊限制,但可依 據劑型,病人年齡,性別及其他因素,及有待治療之疾病 駸重度而選用。如此,例如當以錠劑,丸劑,溶液劑.,懸 浮液劑,粒劑或膠囊劑形式提供時,此等製劑可經口投葯 。注射溶液劑可單獨,或與習知含葡萄糖,胺基酸等非經 腸道輪注液混合經靜脈投葯。若有所需,此等溶液劑也可 就此藉肌肉,皮内》皮下或腹内途徑投葯。栓劑可經直腸 投葯。 本發明之此等葯物製劑之劑量可依投葯方法*病人年 齡,性別及其他因素,病情廉重度及其他因素適當選用。 然而,概略而言,各活性化合物之每日劑童推薦係於0.0001 至約50 mg/kg體重之範圍。期望各單位劑塑所含活性化 合物之數量由約0.001至約1,000 mg。 示例說明本發明之進一步細節,於下文列舉若干劑型 例,劑型例後,接著為賁施例供示例說明前逑活性成分化 合物之生產,又接箸為使用典型活性成分化合物之試驗例 0 劑型例1 5-甲氧基-1-〔3-〔4~(3-氯苯基)-1-哌畊基〕 丙基〕-3, 4二氫2-羰基喹啉 150 g Αν i cel (商品名,旭化成工業公司產品) 40 g 4 (請先閲讀背而之注意事項再塡寫本頁) 裝 訂 線 本紙张尺度遑用中Η Η家標準(CNS)TM規枯(210x297公龙) 81. 4. 10,000¾ (H) 205541 Λ 6 Π 6 五、發明説明() 玉米澱粉 30 g 硬脂酸鎂 2 g 羥丙基甲基灌維素 10 g 聚乙二醇6000 3 g 苠麻油 40 g 乙醇 40 g 經濟部十央槛準局cx工消t合作社印製 將本發明之活性成分化合物,Αν i cel,玉米澱粉及硬 脂酸鎂合併,一起硏磨,及所得混合物使用糖衣RlOmm衝 頭打錠。所得錠劑塗上由羥丙基甲基绻維素,聚乙二醇 6000,Μ麻油及乙醇所組成之膜衣組成物而得膜衣錠。 割型例2 5-甲氧基-卜〔3-〔4- (3-三氟甲基苯基)-卜 _阱基〕丙基〕_3, 4 -二氣2 -销基唾咐 150g 檸檬酸 乳糖 磷酸二鈣 Pluronic F-68 月桂基硫酸鈉 聚乙烯吡咯酮 聚乙二醇(Carbowax 1 500) 聚乙二醇(Carbowax 6000) 玉张澱粉 乾硬脂酸納 乾硬脂酸鎂 1.0 g 33.5 g 70.0 g 30.0 g 15.0 g 15.0 g 4.5 g 45. 0 g 30.0 g 3.0 g 3.0 g (請先閲讀背而之注意事項#硯窍本頁) 裝 訂 線 本紙張尺度边用中Η明家搮準(CNS)*IM規格(210X297公龙) 17 81. 4.】0,000張(II) Λ 6 It 6 205546 五、發明説明() 乙醇 q . S . (請先閲讀背而之注意事項孙填寫本頁) 將本發明之活性成分化合物,檸樺酸,乳糖,磷酸二 鈣,Pluronic F-6S及月桂基硫酸鈉混合。 使用60號篩篩選尺寸後,混合物使用f聚乙烯毗咯嗣 * Carbowax 1500及Carbowax 6000之醇糸溶液利用濕法造 粒。若有所需,可加醇將混合物調整為糊狀物質。然後加 入玉米澱粉*持續摻混至生成均勻顆粒為止。然後混合物 通過10號筛,置於托盤上*及於維持於ιοου之烘箱内乾 燥12至14小時。乾顆粒通過16號篩,加入乾月桂基硫酸鈉 及乾硬脂酸鎂;摻混後,使用打錠機將混合物壓縮成期望 之尺寸及形狀。 前述心錠使用清漆處理,及Μ滑石撒粉,預防吸收水 分,然後提供底塗層。清漆之塗覆重覆儘可能多次俾可供 内服使用。錠劑藉施加又一底塗層及一光滑塗層而變成完 全圓形光滑塗層。進行箸色塗層直到獲得期望的色彩為止 。乾燥後*加衣錠經拋光而得均勻拋光錠。 劑型例2 5 -氛-1-〔3-〔4- (3 -甲氧基苯基)-卜哌哄基〕 經濟部屮央槛準历Μ工消#合作社印製 丙基〕~3,4~二氫2-羰基喹啉 5 g 聚乙二醇(分子量:4,000) 0.3 g 氯化納 0.9 g 聚氧乙烯聚山梨糖醇一油酸酯 0.4 g 偏亞硫酸氫鈉 ^ 0. 1 g 對羥基苯甲酸甲酯 0. 18 g 本紙張尺度边用中S S家楳準(CNS)f 4規格(210X297公址) ~ 18 - 81. 4.】0,000張(11) 203546 Λ 6 Η6 經濟部屮央榀準局A工消货合作杜印製 五、發明説明() 對羥基苯甲酸丙酯 〇.〇2 g 注射用蒸餾水 10.0 ml 前述各對羥基苯甲酸酯,偏亞硫酸氫鈉及氯化鈉於80 t藉攪拌溶解於如上規定蒸餾水體積之約半量内。所得溶 液冷卻至40C *本發明之活性成分化合物溶解於該溶液内 ,然後*將聚乙二醇及聚氧乙烯聚山梨糖醇一油酸醋溶解 於其中。然後,將其餘注射用蒸箱水加入溶液中調整爲最 終體積,及所得溶液使用適當瀘紙藉細菌性過漶滅菌而得 注射用溶液劑。 參者例1 於5-甲氧基-3,4-二氫2-羰基喹啉(53.18,0.3!〇〇1 )於200ml二甲基甲醯胺(DMF)之溶液内,於室溫逐分加入 60%氫化鈉於油(19.2 P 0.4 mol ),及將混合物攪拌 30分鐘。於如此所得之5-甲氧基-3,4-二氫2-羰基喹啉之 鈉鹽於DMF之溶液内加入卜溴-3-氯丙烷(94 ml,0.6mol )。混合物於80-90t:攪拌8小時。減壓蒸餾之DMF,殘渣 Μ氣彷抽取。抽取物Μ水洗及乾燥(無水硫酸鎂),於減 壓下蒸餾去除氯仿,及殘渣由乙醇中再結晶而得59g 1-( 3-氯丙基)-5-甲氧基'3,4-二氫2-羰基喹啉,呈無色針晶 〇 熔點 103- 1051C。 ^-NMR (CDC1 3 , δ ppm): 2.09-2.28 (2H, m) , 2.57^2.62 (2H, πι) , 2.90 (2Η, t, J=7.5 Hz), 3.47 (1H, t, J-7.5 Hz), 3.62 (1H, t. (請先閲讀背而之注意事項孙填寫本頁) 裝- 訂 線 本紙张尺度边用中國ffl家楳华(CNS>1M規格(210X297公货) 81. 4_ 10,000張(II) ί:0δ548 Λ 6 Η 6_ 五、發明説明() J = 7.5 Hz) , 3.8-5 (3Hr s) , 4.05-4.12 (2H, m) , 6.64 (請先閲讀背而之注意事項#堝筠本頁) , (1H, d, J=9 Hz). 6.72 (1H, d, J=9 Hz), 7.22 (1H, t, J=9 Hz) 參者俐2 以參考例1之相同方式,將60%氫化鈉於油逐分加入 5-氯-3,4-二氫2-羰基喹啉於DMF之溶液內,所得混合物攢 择30分鐘,然後加入卜溴-3-氣丙烷,所生成之混合物又 於80-90tl攪拌8小時。減壓蒸餾去除DMF,及Μ氯仿抽取 殘渣。抽取物以水洗及乾燥(無水硫酸鎂),減壓蒸餾去 除氯仿,及殘渣藉矽膠柱式層析純化而得5-氯-卜(3-氨 丙基)-3,4-二氫2_羰基喹啉呈淡黃色油。 ΑΗ-ΝΜΚ (CDCU, 5ppm); 2.15-2.25 (2H, m), 2.65 (2H, t, J=7.5 Hz), 3.04 ( 2H, t, J=7.5 Hz), 3.48 (2H, t, J=7.5 Hz), 4.08 (2H, t, J=7.5 Hz), 6.99 (1H, d, J-9 Hz), 7.10 (1HP d, J=9 Hz), 7.20 (1H, tt J=9 Hz) 使用適當起始物料,遵照參考例1之程序*可得如下 所界定之參考例3至10之化合物。 經浒部中央櫺準局员工消货合作社印姐 袞者例3 1-(3-氯丙基)-5_乙氧基-3,4-二氫2-羰基喹啉,無色油。 ^-NMR (CDC13 , δρρπι); 1.42 (3Hf t, 3=7.5 Hz), 2.08-2.28 (2H, m), 2.57-2.65 (2H, m), 2.91 (2H, t, J=7.5 Hz), 3.42 (1H, t, J = 7.5 Hz), 3.62 (1H, t, J = 7.5 Hz), 4.01~4.11 (4Hf 81. 4. Κ),ϋυ〇張(H) 本*Ufc尺度边用中a s家楳毕(CHS)TM規格(210x297公Λ) :05546 五、發明説明() m), 6.62 (1H, d, J=9 Hz), 6.71 (1H, d, J=9 Hz), 7.20 (1H, t, J=9 Hz) 兹者例4 1- (3-氯丙基)-5-異丙氧基-3,4-二氫2-羰基喹啉,無色 油。 ^-NMR (CDC13i appii); 1.34 (6H, d, J=7.5 Hz), 2.01-2.29 (2H, m), 2.58-2.62 (2H, a), 2.89 (2H, t, J=7.5 Hz), 3.48 (1H, t, J=7.5,Hz), 3.63 (1H, t, J=7.5 Hz), 4.08 (2H, t, J=7.5 Hz), 4.50-4.60 (1H, m), 6.65 (1H, d, J=9 Hz), 6.69 (1H, d, J=9 Hz), 7.18 (1H, t, J=9 Hz)
兹老例fS 1- (3-氯丙基)_5-甲基-3,4-二氫2-羰基喹啉,無色油。 ^-NMR (CDC13, appm); . 2.15-2.25 (2H, m), 2. 30 (3H, s), 2.62 (2H,· t, J = 7.5 Hz), 2.84 (2H, t, J-7.5 Hz), 3.47 (2H, t ( J = 7.5 Hz), 4.08 (2H, t, J = 7. 5 Hz), 6.90 (1H, d, J = 經濟部屮央楛準而β工消f合作社印製 9 Hz), 6.94 (1HP d, J=9 Hz), 7.16 (1H, t, J=9 Hz) 參者例6 卜(3-氯丙基卜5-甲硫基-3,4-二氫2~羰基喹啉,黃色油。 ^-NMR (CDC13i δρρπι); 2.09-2.25 (2Η, in), 2.47 (3H, s) , 2.59-2.70 (2H, m), 2,91-2.99 (2H, m), 3.36 (1H, t, J-7.5 Hz), 3.47 ( 1H, t, J-7.5 Hz), 4.08 (2H, t, J=7.5 Hz), 6.90 (1H, 81.乂 ι(),ϋϋ〇張(η) (請先閲讀背而之注意事項再堝寫本頁) 本紙張尺度逍用中a ffl家樣準(CNS)甲4規格(210X297公Λ) 2〇ϋ546 A 6 U6_ 五、發明説明() (請先閱讀背而之注意事項再填寫本頁) d,J = 9 Hz), 6..94 (1H, d, J = 9 Hz〉,7.24 (1H, t, J = 9 Hz) 參者例7 1-(3-氯丙基)-8-甲氣基-3,4-二氳2-羰基喹啉,無色油。 ^-NMR (CDC13, δρρπι); 2.10- 2,30 (2Η, m), 2.55-2.65 (2Η, m), 2.70-2,80 ( 2H, m), 3.55 (2H, t, J-7.5 Hz), 3.85 (3H, t, J-7.5
Hz), 4.05 (2H, t, J=7.5 Hz), 6.80 (1H, d, J-9 Hz), 6.90 (1H, d, J=9 Hz). 7.05 (1H, t, J=9 Hz) 參者例ft 卜(3-氯丙基)-5,6_二氯-3,4-二氫2-羰基喹啉,無色油。 ^H-NMR (CDC1 3 , ,βρρπϊ); 2.10- 2.25 (2Η, m), 2.64-2.70 (2Η, m), 3.08-3.15 ( 2Η, in), 3.47 (2Η, t, J = 7.5 Hz), 4.05 (2 H, t, J = 7.5
Hz), 6.95 (1H, d, J=9 Hz), 7.36 (1H, d, J-9 Hz) 袞者例9 5-乙醯胺基-1- (3-氯丙基)-3,4-二氫2-羰基喹啉,無色 油。 經濟部中央榡準而β工消费合作杜印製 ^-NMR (CDC1 □ , δρριη); 2.10- 2,25 (2Η, m), 2.15 (3Η, s), 2.64-2.70 (2Η, m), 3.08-3.15 (2H, m), 3.48 {2Hf tf J-7.5 Hz), 4.05 ( 2H, t, J-7.5 Hz), 6.62 (1H, d, J=7.5 Hz), 6.75 (1H, d, J-9 Hz), 7.25 (1H, t, J=9 Hz) 袞者例1 0 81. 4. ιο,ϋυο張(il) 本紙張尺度通用中Η國家標毕(CNS) ΤΜ規格(210X297公:it) 05546 五、發明説明() 1- (3-氣丙基)-5-甲氧基2-羰基喹啉,無色油。 ^-NMR (CDCla, 5ppm); 2.15-2.38 (2H, m), 3·55 (2H, t, j=7_5 Hz), 3_96 ( 3H, s), 4.42 (2H, t, J=7.5 Hz), 6.62 (1H, d, J=l〇 Hz), 6.65 (1H, d, J=9 Hz), 7.〇5 (1H, t, J=9 Hz), 7.50 (1H, t, J=9 Hz), 8.15 (1H, d, J=l〇 Hz) 蓳.施例1 由1-(3-氯丙基)-5-甲氧基-3,4-二氫2-羰基喹啉( 3.91 g,0.15 mol),碘化鈉(33.5 g, 0.23 mol)及乙 睛(200 ml)所組成之溶液回流加熱1小時,然後後冷卻 至室溫。此溶液内又加入卜(3-氯苯基)哌畊(39. 3 g, 0.2 mol)及碩酸鈉(21 g,0_2 mol)。混合物又攪拌4 小時,然後趁熱過濾。濾液經減壓濃縮。殘渣藉矽膠柱式 層析純化,Μ鹽酸調整為酸性,然後由乙醇中再結晶而得 31.2 S 1-〔3-〔4- (3-氯苯基)-卜哌畊基〕丙基〕-5-甲氧基-3,4-二氫2-羰基喹啉鹽酸,呈無色片晶。 熔點239-242π (分解)。 奮旃例?荃 經濟部屮央楛準局只工消1V合作社印製 (請先閲讀背而之注意事項冉塡寫本頁) 使用適當起始物料,遵照實施例1之程序,獲得下表 1所列舉之各化合物。表1中,溶劑代表再結晶用之溶 劑〇 本紙張尺*度近用中國Η家標準(CNS)TM規格(210x297公龙) 81. 10,000¾ (1!) 05546 五、發明説明() 表1 Λ 6 η 6 經撕部屮央梂準局A工消t合作社印製 實施例 結構式 結晶形 (溶劑) mp(eC) 2 όα0 · ^ 〇 2HCI 〇CH3 無色針晶 (甲醇) 212-213 (dec.) 3 och3 όςχ0 1 ° HCI Br 無色針晶 (乙醇) 228-231 (dec.) 4 och3 .6a〇 HCI CF 無色針晶 (乙醇) 207-208 5 och3 6^hci C1 CL 白色粉末 (乙醇) 226-228 (dec.) (請先閱讀背而之注意事項再塡寫本頁) 本紙張尺度逍用中ffl®家標準(CHS)甲4規格(2〗0χ2ί)7公;it) 81. 4. ΙΟ,ϋΟΟ張(Η)
^〇554G 五、發明説明() 表1 (繙) 經澌部屮央榀準灼貝工消t合作杜印製 實施例 結構式 結晶形 (溶劑) mp(°C) 6 OCH2CH3 * • όςχ0 1 ° HCI Cl 白色粉末 (乙醇) 226-228 (dec.) 7 OCH(CH3)2 ' όα〇 〇 HCI Cl ^nCn-^ 無色Η晶 (乙醇) 218-229 (dec.) 8 ch3 6α0 HCI ci ! 無色針晶 (乙醇) 196-198 9 och3 όςι0 I 0 HCI CH3 無色針晶 (乙醇) 220-228 (dec.) 10 och3 daG 1 ° HCI 〇CH2CH3 無色針晶 (乙醇) \ 168-173 (dec.) (請先閒請背而之注意事項#项筠本頁) 本紙5fc尺度逍用中BIS家標毕(CHS)IM規格(210X297公度) -25 - 81. 4.〗0,000張<]{) 05546 Λ 6 I? 6 五、發明説明() 表1 (續) 經濟部中央榀準局β工消#合作社印製 實施例 結構式 結晶彤 (溶劑) mp ( β〇 11 sch3 όςχ0 1 ° HCI Cl 無色針晶 (乙醇) 221-224 (dec.) 12 och3 , όςχ0 1 0 HCI Cl 無色針晶 (乙醇) 214-215 (dec.) 13 och3 όζλ0 ^nCn^^ci 無色針晶 (乙醇) 124-125 14 och3 όα〇 1 0 HCI F 無色針晶 (乙醇) 236-240 (dec.) 15 och3 NwN-Q 無色針晶 (乙醇) 132-132.5 本紙張尺度边用中B1H家樣準(CNS)T4規格(210X297公;it) - 26 - 81. 4. 10,000¾ (Η) (請先閲讀背而之注意事項洱项寫本頁) Λ 6 1^6 £05546 .表1 (續) 經濟部中央櫺準局员工消赀合作杜印51 五、發明説明() 實施例 結構式 結晶形 (溶劑) mp(eC) 16 〇ch3 όα〇 ^ 〇 HCi Cl 無色針晶 (乙醇) 128-129 (dec.) 17 och3 . όςι0 V 〇 HCI 無色針晶 (乙醇) 226-229 (dec.) 18 och3 ; όςχ γ Ο HCI OCH3 無色針晶 (乙醇) 176-177 19 0CH3 to0 1 0 HCI CH3 ch3 無色針晶 (乙醇) 223-226 ' (dec.) 20 och3 όςι0 I ◦ HCI CH3 CH3 U〇-e 無色針晶 (乙醇) 228-230 (dec.) 本紙張尺度边用中Hffl家楳準(CNS)甲4規格(2】0x297公龙) -27 - 81. 4. i(),⑽3張⑻ (請先間讀背而之注意事項#填寫本頁) 裝- 訂 線 :05546 Λβ 五、發明説明() 表1 (續) 經濟部中央梂準局员工消贽合作社印製 實施例 結構式 結晶形 (溶劑) mp ( °〇 21 och3 όςχ Ν 〇 2HCI ch3 q uo-^ 無色針晶 (乙醇) 232-234 (dec.) 22 och3 ' όςχ HCI ch3 無色針晶 (乙醇) 212-216 23 Cl όζν f 〇 2HCI Cl 無色針晶 (乙醇) 217-218 (dec.) 24 OH 6ςι0 1 0 CH3/C1 ^0-0 無色稜晶 (乙醇) 185.5-186.5 25 ch3 6cx 1 〇 HC! 〇CH3 * 無色針晶 ‘(乙醇) 145-146 . 本紙張尺度逍用中國困家搮毕(CNS)TM規格(210x297公:a:) 81. 4. ίΜϋϋ張(Η) (請先閱讀背而之注意事項#填寫本頁) 裝 訂 線 05546 Λ 6 ΙΪ6 五、發明説明() 經濟部中央梂準而Μ工消许合作社印製 表1 (續) i實施例 結構式 結晶形 (溶劑) rnp ( °〇 26 CH3〇to0 ci uo^ 白色粉末 (乙醇) 159-161 27 * j〇^l ch3o^^n^〇 hci , C1 無色針晶 (乙醇) 224-229 (dec.) 28 Χ)ζΧ CH3X^^ hc, c •白色粉末 (乙醇) 136-137 \ 29 OCH2CH=CH2 0 HCI Cl 無色針晶 (乙醇> 180-185 30 JOCX 0 HCI Cl 無色針晶 (乙醇) 172-173 (請先間讀背而之注意事項再填艿本頁) 本紙張尺度通用中圏®家楳毕(CNS)TM規格(210X297公龙) -29 - 81. 4 . ΙΟ,ΟϋΟ張(Π) 6 4 5 ο Γίν 6 6 ΛΠ 五、發明説明() 經濟部屮央榀準局Μ工消t合作社印製 表1 (續) 、實施例 結構式 .結晶形 (溶劑) mp(〇C) 31 χςι α γ o hci 〇ch3 無色針晶 (乙醇) 185-187 32 OH ' i Cl 無色稜晶 (乙醇) 200-201.5 (dec.) 33 όα〇 1 0 HCI N〇2 黃色針晶 (乙醇) 204-21Ϊ (dec.) 34 6ζΐ〇 1 nh2 無色針晶 (乙醇) 16X-X63 35 Cl όζλ | 〇 HCI NHCOCH3 無色針晶 (乙醇) 177-178 本紙張尺度边用中a困家標準(CNS)甲4規格(210x297公;it) 81. 4. ΙΟ,ϋΟΟ張(Η) (請先閲讀背而之注意亊項#塥寫本頁) 205546 五、發明説明() A 6 Π 6 經濟部屮央梂準局Μ工消份合作杜印Μ 表1 (續) 實施例 結構式 結晶形 (溶劑) mp(〇C) 36 .άλ i 0 PH 丨 nr 1 pc c 無色顆粒 二甲基甲 醯胺-甲醇 236-239 37 Cl ' 6ζχ V ° HCI CKCH2)2CH3 無色顆粒 (乙醇) 186-188 38 Cl ^^0 HCi 〇CH20 無色顆拉 (乙醇) 181-183 39 och3 d〇0 Y 〇 HCI Cl uo^ · 無色針晶 (乙醇) 232-236 (dec.) 40 och3 uo-d 無色針晶 (乙醇) 222-232 (dec.) 本紙張尺度边用中闺®家垛毕(CNS)IM規格(210Χ2ΪΠ公;¢) - 31 - 81. 4. ΙΟ,ϋϋϋ張(|丨) (請先閲請背而之注意事項#塥窍本頁) 5rj ο 2 6 4 6 6 ΛΠ 五、發明説明()表1 (續) 經濟部屮央櫺準局A工消t合作杜印11 實施例 結構式 結晶彤 (溶劑) mp ( °〇 41 OCH3 ί όςχοΗ〇, cp 無色顆粒 (乙醇) 221-228 (dec.) 42 : HCI 'CH30 /—n /-=< 白色粉末 (乙醇) 196-201 43 NHCOCH3 hci C1 無色顆粒 (乙醇) 177-183 (dec.) 44 nh2 6a . 2HCI p| 白色粉末 (乙醇) 2X8-240 (dec.) 45 α"όζχ0 1 0 HCI 〇ch3 無色片晶 (乙醇) 212-216 (請先閱讀背而之注意事項#碣裒本頁) 裝 線 本紙张尺度逍用中國ffi家標準(CHS)甲4規格(210X297公龙) -32 - 81.个ΙΟ,ϋϋΟ張(Π) Λ 6 1^6 五、發明説明() 表1 (薄) 經濟部屮央桴準历贷工消t合作杜印製 實施例 結構式 ι[ * 結晶彤 (溶劑) mp(*C) 46 och3 όζΧ〇 Γ CY 白色粉末 (乙醇) 215-221 (dec.) 47 〇ch3 . 6ςι0 Υ 〇 HCI Cl ^〇-^α 白色粉末 (乙醇) 228-234 48 och3 όα0 V 〇 2HCI ν〇2 無色片晶 (乙醇) 221-222 (dec.) 49 〇ch3 άχ . 1 ° 褐色顆粒 (乙醇) 132-133 50 och3 6cx0 0 2HCI NHCOCH3 淺黃色粉末 (乙醇) r 198-201 (請先閲讀背而之注意事項洱项寫本頁) 本紙張尺度边用中Η困家標準([:Μ5)Ή規格(210X297公釐) -33 - 81.个ΙΟ,Ουϋ張<Η) r Λ 6 U6 五、發明説明()
經濟部中央榀準而货工消f合作社印M 表1 (繙) 實施例 結構式 結晶形 (溶剤) mp(eC) * 51 〇CH3 6d 1 〇 HCj OH 白色粉末 (乙醇) 205-208 (dec.) 52 och3 όα 0 2HCI 〇-(CH2)3CH3 白色粉末 (乙醇) 176-179 53 〇ch3 〇Ci0 . | 〇 2HCI 0CH(CH3)2 白色粉末 (乙醇) 170-173 54 〇ch3 όςχ0 〇 白色粉末 (乙醇) 184-186 (dec.) 55 och3 όζχ〇 | ° HCi CN 無色片晶 (乙醇) 235-236 (請先閲讀背而之注意事項寫本頁) 裝- 訂 線 本紙張尺度边用中ΒΙΗ家標準(CNS)IM規格(210X297公;it) - 34 - 8丨.4.丨0,000張(Η) 嫩·_ 五、發明説明() Λ 6 116 表1 (續)
啻旃俐57 (請先閲讀背而之注意事項再填寫本頁) 裝- 5-氯-1-〔3-〔4_ (3_硝基苯基)-1-赠哄基〕丙基〕 -3,4-二氫2-羰基喹啉(3 g)溶解於1〇〇 ml乙醇内,加入 2 ml濃鹽睃及於3大氣壓於1.5 g 5%耙-碳存在下進行催 化澤原反應。然後過濾去除辑媒*濾液經減壓濃縮,及殘 渣由乙醇中再結晶而得2.5 g卜〔3-〔4- (3-胺苯基) -哌阱基〕丙基〕-5-氣-3,4-二氫2-羰基喹啉,呈無色針 晶。 .溶點16卜163*0。 窗施例58 1-〔3-〔4- (3-胺苯基)-卜峤畊基〕丙基〕-5-氣 -3,4-二氫2~羰基喹啉(1 g)溶解於10 ml氣仿内,加入 5 mi乙酐及0.1 g 4-二甲基胺基吡啶,且混合物回流加熱 30分鐘。反應混合物經減壓濃縮*及殘渣藉矽膠柱式層析 本紙張尺度边用中明Η家標毕(CNS)甲4規格(210X297公;Ϊ) 線 經濟部屮央橾準局民工消#合作杜印製 ai. 4. ιο,οϋο張⑻ £〇5δ46 經濟部+央桴準局A工消货合作社印製 Λ 6 Π 6 五、發明説明() 純化,然後轉成鹽酸盏形式,此化合物由乙醇中再結晶而 得900 mg 1-〔3-〔4- (3-乙醯胺基苯基)-卜哌畊基〕丙 基〕-5-氯-3,4-二氫2-羰基喹啉鹽酸,呈無色針晶。 熔點 177-1781C。 音掄捥59 5-乙醢胺基1-〔3-〔4- (3-氯苯基)-1-哌畊基〕丙 基〕-3,4-二氫2-羰基喹啉( 800 mg)溶解於20 ml 6N鹽 酸内*混合物經回流加熱1小時。反應混合物經減壓濃縮 ,殘渣由乙醇中再結晶而得4&0 mg 5-胺基1-〔 3-〔 4-( 3-氯苯基)-卜哌畊基〕丙基〕-3,4-二氫2-羰基喹啉,呈 白色粉末。 熔點218-240C (分解)。
審飾例ftO 使用對應之起始物料,遵照例57之程序,生產例49之 化合物。 奮掄例Μ 使用對應之起始物料,道照例58之程序,生產例43及 例50之化合物。 啻掄例62 使用對應之起始物料,遵照例59之程序,生產例44及 例49之化合物。 葯理試驗撊1 由halothane麻醉中恢復之加速 (加速恢復功效) (請先閲讀背而之注意事項#填寫本頁) 裝 線 本紙張尺度遴用中國困家楳华(CHS) 規格(210 X 297公*) 81. 4. 10,000張(J1) 2〇5:θ46 五、發明説明() 試驗係使用小鼠,依據英國葯理期刊5丘,27-35 (1976) 所逑之方法進行。如此,將空腹18-20小時之4到5周齡· 雄小鼠(重20-29 g)置於隔間內,隔間M2 L/min之速 率供應含4% halothane之空氣。小鼠於隔間內立刻喪失 直立反射。即使由隔間内取出後,小鼠仍持縷顳示喪失直 立反射經歴一段時間,然後再度恢復反射。由喪失直立反 •射至恢復反射之時間經測定,及用作haiothane-誘生麻醉 作用之持鏞時間。試驗葯物,或懸浮或溶解於5%阿拉伯 膠鹽水溶液内,於麻醉負荷前1小時經口投葯。對照小鼠 接受5郑阿拉伯膠於鹽水。試驗葯物之加速恢復功效係K 給予試驗葯物之小鼠之麻醉時間相對於對照小鼠之比(對 照組之%)表示。結果示於表2。 (請先間誚背而之注意事項#蜞寫本頁) 裝 訂 線 經濟部中央榣準屈员工消#合作杜印製 81. 4. ΙΟ,ϋΟΟ張(H) 本紙張尺度逍用中SH家樣準(CNS)T4規格(210><297公;》:) 205¾46 Λ 6 Π6 五、發明説明() 表2 試驗化合物 投葯途徑之劑量 (mg/ kg) ha 1 othane-誘生 麻醉之持續時間 (%對照〉 實施例1化合物 經口 100 52 實施例2化合物 經口 100 51 實施例3化合物 經口 100 54 實施例4化合物 經口 100 66 實施例5化合物 經口 100 85 實施例6化合物 經口 100 68 實施例7化合物 經口 100 86 實施例8化合物 經口 100 74 實施例32化合物 經口 100 88 實施例35化合物 經口 30 85 實施例36化合物 經口 30 65 實施例38化合物 經口 30 86 實施例48化合物 經口 100 61 實施例55化合物 經口 30 83 (請先閲誚背而之注意事項再填窍本頁) 本紙尺度边用中 家標 1MCNS)1M規格(210x297公:《:) - 38 - 81. 4. 10,000張(H) 205546 Λ 6 η 6 五、發明説明() 表2中,顯示使用各試驗化合物處理之小鼠麻醉持鏞 時間,係Μ對照小鼠藉halothane-誘生之麻醉持續時間當 100%表示。發現本發明化合物可缩短麻醉時間,如表2 所示,代表本發明化合物具有中樞神經糸統興奮活度。 好理試驗例2 使用頭部受傷後昏迷之小鼠模式評估意識紊亂改善功效。 試驗係依日本意外》療學會期刊202 (1977>及 Igaku no Ayumi, 867-869 (1977)所述之方法進行 。如此將4至5周齡雄小鼠(重20-29 g)空腹18-20小時 。然後,將各小鼠頭固定於聚苯乙烯發泡體枕上*經由透 明塑膠管放下一根圓柱形丙烯酸樹脂桿而對壁區一擊。就 下列兩項觀察意識受損:由撞擊後,至直立反射恢復時間 (RR時間),及至自發活動恢復時間(SM時間)。各試驗 化合物或懸浮或溶解於5%阿拉伯膠溶液於生理鹽水之溶 液內,於麻醉負荷之前1小時經口投葯。對照小鼠接受5 %阿拉伯膠於鹽水。試驗化合物之意識紊亂改善功效係K 使用試驗化合物處理小鼠之RR或SM時間對對照小鼠之RR或 SM時間之比表示(佔對照之%)。結果示於表3。 (請先閲讀背而之注意事項#堝窍本頁) 裝 訂 線 經濟部屮央櫺準而员工消费合作社印製 81. U),⑻0張(II) 本紙張尺度逍用中Η «家標毕(CNS)T4規格(210x297公放) 205546 Λ 6ne 表3 試驗化合物 投葯途徑及剤置 {mg/ kg) “時間佔 對照之% SM時間佔 對照之% 實施例1之化合物 口服30 20 20 實施例2化合物 口服30 28 28 實施例4化合物 口服30 36 48 實施例41化合物 口服30 51 58 實施例4 8化合物 口服30 52 52 (請先閲讀背而之注意事項#填寫本頁) 丁 經濟部屮央橾準局A工消t合作社印製 表3中,作為由頭部受傷後昏迷的恢復之指檫,使用 各試驗化合物處理之小鼠的RR時間或SM時間係以百分率表 示,而對照小鼠之RR或SM時間取作100%。本發明化合物 用於此模式可明顯縮短RR時間與SM時間二者,代表此化合 物可加速頭部受傷的昏迷中恢復,且對受損的意識具有改 善功效。 玆理試驗锎3 對σ受器之結合親和力 製備一膜段及進行[3Η]-1,3-二〔2-甲苯基〕胍(DTG) .結合試驗,二者皆利用Wettstein等人〔Wettstein, J.F., Romman, F.J·, Rocher, M.N·及 Junien, J.L.,精神薇理 學,104,157-163 (1991>〕之方法進行。如此,將威斯 本紙張尺度逍用中SB家樣毕(CNS)TM規格(210X297公徒) -40 - 8丨.4. 1(),〇υΰ張(H) 經濟部屮央榀準而cx工消#合作社印製 五、發明説明() 達品条雄大鼠斬首,取出全腦,於30倍體積之冰冷50 mM ,Tris邇酸經衝液(pH 7.4)均化。然後,均化物於4 及 " 50,000 s均化15分鐘。所得沈锻懸浮於1倍體積之如前述 縷衝液内,經由於37Χ:培育45分鐘後,再度離心懋浮液 。所得沈殺懸浮於1倍體積之相同緩衝液內*及懸浮液於 -80Ό冷凍儲存至使用前為止.。 結合實驗係如下述進行。冷凍組鏃製品於4t:及 50,000 g解凍並離心15分鐘,所得沈澱懸浮於10倍體積 之5 mM Tris鹽酸緩衝液内(pH 7.4)。懸浮液用作膜製 品。於試管内放置各棰稀釋度之試驗化合物(50 μΐ), [3H]-DTG (50 ,最終濃度3 ηΜ)及膜製品(150 ill) (總體積250 Ml/管)。膜裂品之添加後開始進行反應。 管於25它培育60分鐘,及使用細胞收穫機(Brandel))藉著 抽吸過濾通過事先使用0.5%聚乙撐亞胺飽和的Whatman GF/B過濾器终止反應,過漶器立刻使用3 ml部分冰冷 5 mM Tris鹽酸緩衝液洗滌。 過濾器移至小瓶內,加人5 mi液體閃爍《雜尾酒”( Aquasol 2)後,令小瓶於暗處靜置一段預定時間。然 後使用閃爍計數器测量放射活度。由緦結合量中扣除有10 <iM haloperidol共存下之結合量,測知特異性結合量。使 用非線性最小平方法,藉電腦分析算出I C e 值。 結果示於表4。 本紙张尺度逍用中國®家標率(CNS)T4規格(210x297公龙) 81. 4. 1(),_張⑻ (請先閲請背而之注意事項典蜞寫本頁) 裝 線 205〇4£ Λ 6 Π 6 經濟部屮央標準XOM工消t合作社印製 試驗化合物 抑制活度ICe。 (ίΐΜ士 SED) 實施例1之化合物 0.34土 0_ 11 實施例2之化合物 0.13土 0016 實施例4之化合物 0.49士(K 032 實施例39之化合物 0.98土 0. 13 $施例41之化合物 0.82±0.11 實施例48之化合物 0.87土 0 14 實施例49之化合物 1.21 士 0· 14 實施例53之化合物 0.49± 0.048 實施例56之化合物 0.71 土 0.066 (請先閲讀背而之注意事項洱艰寫本頁) 訂 線 本紙it尺度逍用中国困家搮準(CNS)甲4規格(210X297公龙) 81. 4. I0,0U0張(H)
Claims (1)
- 205546 82,1U 本年 9 成方----六、中請專ή範a 第81 103382號申請案申請專利範圍修正本 修正日期:S 3年4月 ~ 1,—種如下通式之2-羰基喹啉衍生物〔式中Ria為齒基,Ct-Cs烷氯基,Ct-C6烷基* C2-Ce烯氯基,胺基,(^-“烷胺基或“-匕烷硫基_ ;R*為苯基其可任意具有1或2取代基*取代基各自 獨立選自鹵基,L-Cs烷氣基,C/Cs烷基,硝基,胺 基,Ci-“烷韹胺基,羥基,氰基,苯基-Ct-C6烷氯 (琦先.¾^背*之:ni意事項再填艿本7Γ -打· 經濟部十央標芈局只工消许合作社印製 基及鹵基-Ct-CB烷基中之任一者;A為^-(:6烷撑基 ;及〇為1或2之整數;及其中介於2-羰基喹啉主幹 之3位與4位間之鸱-碳踺可為單越或雙踺]或其監: 2.如申請專利範園第1項之2_羰基喹啉衍生物或其鹽, 其中Ria為囱蕋或[^-“烷基 3 _如φ胪逛利箝圃第1頃之2_坡越吱啉衍生物或其傾, 其中R 1 a為C i - C r.1 院:丛:,C丨-C “締氣盛,极沾,C丨-C 烷鼯胺茲或c ^ -C ,烷硫越。 4.如申詰專利範圃第2項之2-琺莛嘧啉衍生物或其谠,205546 b;Γ4先3?碛背面之i±意事項再填穹本頁} 其中ρ為苯基其具有各自獨立選自鹵基,Ci-Cs烷氧 、 碁,硝基及鹵基-Ci-Ce烷基中之任一或二取代基。 5 .如申請專利範圍第2項之2-羰基喹啉衍生物或其鹽, 其中Rs為苯基其可任意具有各自獨立選自L-“烷基 ’胺基,(^-(:6烷醯胺基,羥基,氰基及苯基-c,-cs 烷氧基中之任一或二取代基。 S .如申請專利範圍第3項之2-羰基喹琳衍生物或其鹽, 其中R2為‘苯基其具有各自獨立選自鹵基,Ct -C6烷氯 基,硝基及鹵基-CrCe烷基中之任一或二职代基。 •訂. 7 .如申謓專利範圍第3項之2-羰基喹啉衍生物或其鹽, 其中R*為苯基其可任意具有各自濁立選自C^Cs烷基 ,胺基,C:-“烷韹胺基,羥基,氣基及苯基-Κ6 烷氯基中之任一或二収代基。 δ ,如申請專利範圍第4項之2-羰基喹啉衍生物·其中介 於2-羰基喹啉主幹之3與4位間之硪-頃躂為單键。 9 .如申請專利範圍第4項之2-羰基喹啉衍生物,其中介 於2-羰基喹啉主幹之3與4位間之磺-碳鐽為雙鍵。 經濟部屮央楛芈局只工消費合作杜印製 1 0 .如申請專利範圍第5、6或7項之2-羰基喹啉衍生物 ,其中介於2-羰越喹啉主幹之3與4位間之碳-碳挞 為犁01。 1 1 .如申玷孬利範圆第Ϊ3、6或7項之2-彼驻喹啉衍生物 ,其中介於2 -羰褪喹啉主锌之3與4位問之碳-碳ίϋ 木紙張尺度延川屮阴闲家坊平(CMS)VM规格(210χ29*^ϋ· SI. 4. 5.000 (H) 205546 Βτ L i . DT 六、申讣專刊範31 12.如申請專利範圍第8項之2-羰基喹啉衍生物,其中η 為1而取代基Ria位在2-辕基喹啉主幹之5位。 13.5- 甲氧基-1-〔3-〔4-(3-氮苯基)-:1-哌[1弁基〕丙基〕 -3, 4-二氫2-羰基喹啉。 14.5- 甲氧基-卜〔3-〔4-(3-溴苯基)-:1-呢.卩弁基〕丙基〕 -3,4-二氫2-羰基喹啉。 15.5- 甲氣基-1-〔3-〔4-(3-硝苯基)-;1-哌!1幷基〕丙基〕 -3,4-二氫2-羰基喹啉。 16. 5-乙氧基-1-〔 3-〔 4-(3-氣苯基)-卜哌哄基〕丙基〕 -3,4-二氫2-羰基喹啉。 17.5- 氯-1-〔3-〔4-(3-甲氧苯基卜卜崤11井基〕丙基〕-3, A二氫2-羰基喹啉。 1δ. —種可改善意議紊亂之II藥組合物,其包含具有下列 .通式之2-羰基喹啉衍生物 (請先5?請背面之注意事項再填穽本頁} -打·經濟部中央標爭局R工消费合作社印製 / \ 2 Α — Ν N — R \_/ 式中R1為齒基,羥莛,C,-C。烷氣茲,(:丨-CM基,Ct -Cs^氣基,胺蕋,C^-“烷醯胺基或“-“烷硫挂; 木紙诅尺度適/M屮fSI W家捃平(CNS)UjMiK 210 X 29?公^) 81. 4. 5.000 (H) 205546 A. Β· c D: 六、 中苑園 R 3 ’ A,n及介於2-羰基喹啉主幹之3與4位間之碩-碩键之定義如上,或其鹽以及一可接受之載髏。 1 9 .—種可用作中揠神經糸統劑之藥學組合物,其包 含如申請專利範圍第1 2.-羰基喹啉衍生物 或其鹽與一可接受之載體。 20 . —種可作為σ受器i足效劑之藥學組合物,其包含如申 請專利範圍第1 #镳之2 -羰基喹啉衍生物或其諉-與 —可接受之載體> 2 1 ·—種可製備如申請專利範圍第1項之2-羰基喹啉衍生 物或其留之方法,其之待歡為令如下通式化合物(4) (锜先聞讀背面之a意事項再填艿本百 k. A - X 〔式中R 1 a .* A,η及介於2-羰基喹啉主幹之3與4位 間之頊-硝踺定義如上;X1代表鹵原子〕與如下通式 化合物反蛵 -打- 經濟部中央標芈局@工消費合作社印製 Η Ν Ν - R % (5 ) 〔式中R2定雜如I申請專利範圍第1項〕· 22 ·—種製備如申譆專利範圍第1.項之2 -戡基喹啉衍生物 木紙張尺度適』丨】屮阳HmpTKCNS)MM规格(2丨0χ29、;ί^Γ SI. 4. 5,000 ⑻(6 ) Λ' Β· C Ο' 或其鹽之方法,其之持歡為令如下通式化合物 (2 ) 〔式中R 1 a,η及介於2-羰基喹啉主,幹之3與4位間之 磺-碳鐽定義如淖請專利範圍第1項〕和如下通式反 應 X j - A - N N_R 〔式中R2及A定義虻宇請專利範圍第1項;'X3代表鹵 原子〕· {锜先聞話背面之注意事項再填艿本百 訂 ♦ 經濟部屮夬標準局Π工消费合作社印製 木紙張尺度適川屮ff! W Ϊ:榀平(CNS广[M规格(210 X 297公竑) 81. 4. 5.000 (H)
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JPS574974A (en) * | 1980-06-11 | 1982-01-11 | Otsuka Pharmaceut Co Ltd | Carbostyril derivative |
DK588486A (da) * | 1985-12-09 | 1987-06-10 | Otsuka Pharma Co Ltd | Anvendelse af en forbindelse til behandling af hypoxi |
DK111387A (da) * | 1986-03-05 | 1987-09-06 | Otsuka Pharma Co Ltd | Carbostyrilderivater og salte deraf, laegemiddel indeholdende saadanne derivater samt fremgangsmaade til fremstilling af derivaterne |
JPS63146872A (ja) * | 1986-07-08 | 1988-06-18 | Yoshitomi Pharmaceut Ind Ltd | ピリミジニルピペラジン化合物 |
AU639529B2 (en) * | 1987-03-04 | 1993-07-29 | Higuchi, Yoshinari | Carbostyril derivatives and salts thereof and anti-arrhythmic agents containing the carbostyril derivatives |
US5028610A (en) * | 1987-03-18 | 1991-07-02 | Sankyo Company Limited | N-benzhydryl-substituted heterocyclic derivatives, their preparation and their use |
FI95572C (fi) * | 1987-06-22 | 1996-02-26 | Eisai Co Ltd | Menetelmä lääkeaineena käyttökelpoisen piperidiinijohdannaisten tai sen farmaseuttisen suolan valmistamiseksi |
JP2718127B2 (ja) * | 1988-01-06 | 1998-02-25 | 武田薬品工業株式会社 | 複素環カルボン酸エステルの誘導体 |
JPH01272524A (ja) * | 1988-04-21 | 1989-10-31 | Japan Found Cancer Res | 癌化学療法剤 |
JPH02102568A (ja) * | 1988-10-11 | 1990-04-16 | Nec Corp | 半導体集積回路装置 |
EP0507863A4 (en) * | 1989-12-28 | 1993-07-07 | Virginia Commonwealth University | Sigma receptor ligands and the use thereof |
-
1992
- 1992-04-28 CA CA002067475A patent/CA2067475C/en not_active Expired - Lifetime
- 1992-04-29 AU AU15262/92A patent/AU648890B2/en not_active Expired
- 1992-04-29 TW TW081103382A patent/TW205546B/zh not_active IP Right Cessation
- 1992-05-07 EP EP92107681A patent/EP0512525B1/en not_active Expired - Lifetime
- 1992-05-07 DE DE69200739T patent/DE69200739T2/de not_active Expired - Lifetime
- 1992-05-07 ES ES92107681T patent/ES2065723T3/es not_active Expired - Lifetime
- 1992-05-07 DK DK92107681.6T patent/DK0512525T3/da active
- 1992-05-08 JP JP4115037A patent/JP2579263B2/ja not_active Expired - Lifetime
- 1992-05-08 CN CN92104551A patent/CN1042531C/zh not_active Expired - Lifetime
- 1992-05-08 MX MX9202151A patent/MX9202151A/es unknown
- 1992-05-08 KR KR1019920007840A patent/KR0145337B1/ko not_active IP Right Cessation
-
1995
- 1995-06-05 US US08/465,579 patent/US5656633A/en not_active Expired - Lifetime
-
1998
- 1998-04-29 HK HK98103666A patent/HK1004549A1/xx not_active IP Right Cessation
Also Published As
Publication number | Publication date |
---|---|
KR920021532A (ko) | 1992-12-18 |
JPH05125053A (ja) | 1993-05-21 |
CN1042531C (zh) | 1999-03-17 |
MX9202151A (es) | 1993-08-01 |
EP0512525B1 (en) | 1994-11-30 |
HK1004549A1 (en) | 1998-11-27 |
CA2067475C (en) | 2000-10-10 |
AU648890B2 (en) | 1994-05-05 |
DK0512525T3 (da) | 1995-04-24 |
CA2067475A1 (en) | 1992-11-09 |
ES2065723T3 (es) | 1995-02-16 |
AU1526292A (en) | 1992-11-12 |
JP2579263B2 (ja) | 1997-02-05 |
US5656633A (en) | 1997-08-12 |
EP0512525A1 (en) | 1992-11-11 |
DE69200739D1 (de) | 1995-01-12 |
CN1069973A (zh) | 1993-03-17 |
KR0145337B1 (ko) | 1998-07-15 |
DE69200739T2 (de) | 1995-05-11 |
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