JP3786985B2 - Pyrrolidinone derivative - Google Patents
Pyrrolidinone derivative Download PDFInfo
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- JP3786985B2 JP3786985B2 JP932895A JP932895A JP3786985B2 JP 3786985 B2 JP3786985 B2 JP 3786985B2 JP 932895 A JP932895 A JP 932895A JP 932895 A JP932895 A JP 932895A JP 3786985 B2 JP3786985 B2 JP 3786985B2
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- 150000004040 pyrrolidinones Chemical class 0.000 title claims description 14
- -1 methylenedioxy group Chemical group 0.000 claims description 114
- 150000001875 compounds Chemical class 0.000 claims description 53
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 40
- 125000005843 halogen group Chemical group 0.000 claims description 29
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 20
- 125000001424 substituent group Chemical group 0.000 claims description 20
- 125000003277 amino group Chemical group 0.000 claims description 19
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 18
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 15
- 239000003814 drug Substances 0.000 claims description 13
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 12
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 11
- 239000004480 active ingredient Substances 0.000 claims description 10
- 229940079593 drug Drugs 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 7
- YEJRWHAVMIAJKC-UHFFFAOYSA-N 4-Butyrolactone Chemical compound O=C1CCCO1 YEJRWHAVMIAJKC-UHFFFAOYSA-N 0.000 claims description 6
- 230000000561 anti-psychotic effect Effects 0.000 claims description 6
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 4
- JAHNSTQSQJOJLO-UHFFFAOYSA-N 2-(3-fluorophenyl)-1h-imidazole Chemical compound FC1=CC=CC(C=2NC=CN=2)=C1 JAHNSTQSQJOJLO-UHFFFAOYSA-N 0.000 claims description 3
- LVHBHZANLOWSRM-UHFFFAOYSA-N methylenebutanedioic acid Natural products OC(=O)CC(=C)C(O)=O LVHBHZANLOWSRM-UHFFFAOYSA-N 0.000 claims description 3
- 150000002148 esters Chemical class 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims 6
- 125000001544 thienyl group Chemical group 0.000 claims 3
- 125000000217 alkyl group Chemical group 0.000 description 47
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
- 125000004432 carbon atom Chemical group C* 0.000 description 41
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 20
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 20
- 238000006243 chemical reaction Methods 0.000 description 20
- 125000003545 alkoxy group Chemical group 0.000 description 19
- 239000000203 mixture Substances 0.000 description 19
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- 125000004414 alkyl thio group Chemical group 0.000 description 17
- 125000004103 aminoalkyl group Chemical group 0.000 description 17
- 125000004093 cyano group Chemical group *C#N 0.000 description 17
- 239000000243 solution Substances 0.000 description 17
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 16
- 125000002252 acyl group Chemical group 0.000 description 16
- 125000004442 acylamino group Chemical group 0.000 description 16
- 125000003282 alkyl amino group Chemical group 0.000 description 16
- 125000005530 alkylenedioxy group Chemical group 0.000 description 16
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 16
- 125000000753 cycloalkyl group Chemical group 0.000 description 16
- 125000005010 perfluoroalkyl group Chemical group 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- 239000003826 tablet Substances 0.000 description 14
- 150000002430 hydrocarbons Chemical group 0.000 description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 230000000694 effects Effects 0.000 description 12
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 11
- 125000003884 phenylalkyl group Chemical group 0.000 description 11
- 125000003367 polycyclic group Chemical group 0.000 description 10
- 238000012360 testing method Methods 0.000 description 10
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- 229920001223 polyethylene glycol Polymers 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 238000001816 cooling Methods 0.000 description 8
- 229910052739 hydrogen Inorganic materials 0.000 description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 235000002639 sodium chloride Nutrition 0.000 description 8
- 229910052801 chlorine Inorganic materials 0.000 description 7
- 125000004122 cyclic group Chemical group 0.000 description 7
- 239000000825 pharmaceutical preparation Substances 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- 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 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-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
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 229920002472 Starch Polymers 0.000 description 6
- 229910052731 fluorine Inorganic materials 0.000 description 6
- 239000007924 injection Substances 0.000 description 6
- 238000002347 injection Methods 0.000 description 6
- 239000008101 lactose Substances 0.000 description 6
- 239000003446 ligand Substances 0.000 description 6
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 235000019698 starch Nutrition 0.000 description 6
- 239000008107 starch Substances 0.000 description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-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
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- 239000000969 carrier Substances 0.000 description 5
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 5
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 5
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 5
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 239000008103 glucose Substances 0.000 description 5
- 239000001257 hydrogen Substances 0.000 description 5
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 5
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 5
- 229960001252 methamphetamine Drugs 0.000 description 5
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 5
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 108020003175 receptors Proteins 0.000 description 5
- 102000005962 receptors Human genes 0.000 description 5
- 108010085082 sigma receptors Proteins 0.000 description 5
- 239000012279 sodium borohydride Substances 0.000 description 5
- 229910000033 sodium borohydride Inorganic materials 0.000 description 5
- 235000019333 sodium laurylsulphate Nutrition 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 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 4
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 4
- 150000001298 alcohols Chemical class 0.000 description 4
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 4
- 150000001412 amines 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
- 239000000460 chlorine Substances 0.000 description 4
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 4
- 125000005842 heteroatom Chemical group 0.000 description 4
- 239000012442 inert solvent Substances 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 4
- 230000000144 pharmacologic effect Effects 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- SCZNXLWKYFICFV-UHFFFAOYSA-N 1,2,3,4,5,7,8,9-octahydropyrido[1,2-b]diazepine Chemical compound C1CCCNN2CCCC=C21 SCZNXLWKYFICFV-UHFFFAOYSA-N 0.000 description 3
- WNWHHMBRJJOGFJ-UHFFFAOYSA-N 16-methylheptadecan-1-ol Chemical class CC(C)CCCCCCCCCCCCCCCO WNWHHMBRJJOGFJ-UHFFFAOYSA-N 0.000 description 3
- KTXKWHCUYUKFOD-UHFFFAOYSA-N 4-(1,3-benzodioxol-5-yl)piperidin-4-ol;hydrochloride Chemical compound Cl.C=1C=C2OCOC2=CC=1C1(O)CCNCC1 KTXKWHCUYUKFOD-UHFFFAOYSA-N 0.000 description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 239000005995 Aluminium silicate Substances 0.000 description 3
- 0 C**(*C=O)N Chemical compound C**(*C=O)N 0.000 description 3
- 108010010803 Gelatin Proteins 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 235000012211 aluminium silicate Nutrition 0.000 description 3
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 239000011230 binding agent Substances 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 3
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
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- 238000000576 coating method Methods 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
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- 239000007884 disintegrant Substances 0.000 description 3
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- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 3
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- 235000011852 gelatine desserts Nutrition 0.000 description 3
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- 239000005457 ice water Substances 0.000 description 3
- 239000002198 insoluble material Substances 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
- 125000002510 isobutoxy group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])O* 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
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 3
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 3
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 3
- 238000000465 moulding Methods 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- PZYDAVFRVJXFHS-UHFFFAOYSA-N n-cyclohexyl-2-pyrrolidone Chemical compound O=C1CCCN1C1CCCCC1 PZYDAVFRVJXFHS-UHFFFAOYSA-N 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 3
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 3
- 125000004115 pentoxy group Chemical group [*]OC([H])([H])C([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 3
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- 238000002360 preparation method Methods 0.000 description 3
- 125000001325 propanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 3
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- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
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- 239000012312 sodium hydride Substances 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 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
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- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 3
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- 125000004417 unsaturated alkyl group Chemical group 0.000 description 3
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- 125000006219 1-ethylpentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000005917 3-methylpentyl group Chemical group 0.000 description 2
- 125000002373 5 membered heterocyclic group Chemical group 0.000 description 2
- 229920001817 Agar Polymers 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- 208000014644 Brain disease Diseases 0.000 description 2
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 2
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- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 2
- OIFBSDVPJOWBCH-UHFFFAOYSA-N Diethyl carbonate Chemical compound CCOC(=O)OCC OIFBSDVPJOWBCH-UHFFFAOYSA-N 0.000 description 2
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- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 239000007818 Grignard reagent Substances 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
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Description
【０００１】
【産業上の利用分野】
本発明は、新規なピロリジノン誘導体並びに該誘導体を含有する抗精神病薬および虚血性脳疾患治療薬に関する。
【０００２】
【従来の技術】
精神分裂病は１３０人に１人という高率で発生し、青年期に多発する。放置すれば進行性に人格が解体し、人間らしい自己発展機能が全く崩れてしまい、社会的にも大きな問題である。この病気の原因として、脳内のドーパミン伝達の異常が指摘されている。クロルプロマジンやハロペリドール等のドーパミン拮抗薬が抗精神病薬として有効なことはこの説を裏づけるものといえる。しかし、ドーパミン拮抗薬は同時に、急性ジストニア、パーキンソニズムのような錐体外路性副作用または、遅発性ディスキネジアを高率に発現させることが知られており、大きな問題となっている。
これに対して近年、従来の薬物の作用機作とは異なる側面からのアプローチが試みられている。シグマ受容体作用薬はそのひとつである。シグマ受容体作動薬であるＳＫＦ−１００４７が、ヒトに対して精神病様の作用を誘発することが明らかになっているので、このシグマ受容体の拮抗薬が、錐体外路性副作用を伴わない抗精神病薬となることが期待される。この種の薬物としてはリムカゾール（Ｒｉｍｃａｚｏｌｅ）が知られているが、シグマ受容体に対する親和性および特異性は未だ不充分である。
医薬品用途としては、式Ｉに示される化合物が特開昭５１−９５０７９号公報に記載され、鎮痛特性と制瀉特性を有すると報告されている。
【０００３】
【化１０】
他の医薬品用途としては、式ＩＩに示される化合物が抗痴呆剤として臨床研究されており、代表的文献として、Ｂｕｔｌｅｒ他，Ｊｏｕｒｎａｌ ｏｆ Ｍｅｄｉｃｉｎａｌ Ｃｈｅｍｉｓｔｒｙ，２７，６８４−６９１（１９８４）に記載されている。
【０００４】
【化１１】
【０００５】
【化１２】
が抗精神病、抗不安、鎮吐、認識力増強、抗痴呆活性を持つと報じられ、米国特許Ｎｏ．４，６６８，６８７、同Ｎｏ．３，７１７，６３４、同Ｎｏ．４，４２３，０４９、同Ｎｏ．４，５２４，２０６に記載されている。
式ＩＶで表される化合物
【０００６】
【化１３】
が鎮痛特性と同時に弱い抗炎症作用を示すことが、Ｍａｌａｗｓｋａ他の“２−ピロリジノンマンニッヒ塩基の合成と薬理特性”，Ｐｏｌｉｓｈ Ｊｏｕｒｎａｌ ｏｆ Ｐｈａｒｍａｃｏｌｏｇｙ，３４，３７３−３８２（１９８２）に述べられている。また、Ｍａｔｔｓｏｎ他，米国特許Ｎｏ．４，８２６，８４３に式Ｖの化合物が認識力および記憶増強活性を持つと示されている。
【０００７】
【化１４】
その他に、モノアミンオキシダーゼ−Ｂ阻害剤として式ＶＩの化合物がＳｉｌｖｅｒｍａｎ他（Ｊｏｕｒｎａｌ ｏｆ Ｍｅｄｉｃｉｎａｌ Ｃｈｅｍｉｓｔｒｙ，３６，３６０６−３６１０（１９９３））によって研究されている。
【０００８】
【化１５】
【０００９】
【化１６】
しかし、上記のいずれの化合物においても、シグマ受容体に高い親和性を有し、抗精神病作用を示すという記載はない。
【００１０】
【発明が解決しようとする課題】
本発明は、錐体外路性副作用を生じることなく抗精神病作用を有する化合物を提供することを目的とするものである。
【００１１】
【課題を解決するための手段】
本発明者らはこれらの課題を解決するためにピロリジノン骨格を有する化合物について鋭意検討した結果、シグマ受容体に特異的かつ高い親和性を持つ新規のピロリジノン誘導体を見いだし、本発明を完成させた。
即ち、本発明は下記一般式（１ａ）または（１ｂ）
【００１２】
【化１７】
【００１３】
【化１８】
【００１４】
【化１９】
【００１５】
好ましくは、式（１ａ）または（１ｂ）においてＲが炭素数１から１２の直鎖アルキル基、炭素数３から１２の分岐アルキル基、炭素数３から１２の環状構造を有するアルキル基、置換または無置換のフェニル基（置換基としてハロゲン原子、水酸基、カルバモイル基、アミノ基、ニトロ基、シアノ基、低級アルキル基、シクロアルキル基、低級アルコキシ基、低級アルキルアミノ基、低級アミノアルキル基、低級アルキルチオ基、低級アシル基、低級アシルアミノ基、低級アルキレンジオキシ基、低級パーフルオロアルキル基、低級パーフルオロアルキルオキシ基、フェニル基からなる群より選ばれた基を１から３個有する）、置換または無置換のフェニルアルキル基（置換基としてハロゲン原子、水酸基、カルバモイル基、アミノ基、ニトロ基、シアノ基、低級アルキル基、シクロアルキル基、低級アルコキシ基、低級アルキルアミノ基、低級アミノアルキル基、低級アルキルチオ基、低級アシル基、低級アシルアミノ基、低級アルキレンジオキシ基、低級パーフルオロアルキル基、低級パーフルオロアルキルオキシ基、フェニル基からなる群より選ばれた基を１から３個有する）あるいは炭素数９から１５の水素化縮合多環炭化水素基、ｎが１であるピロリジノン誘導体あるいはその塩である。
さらに好ましくは、下記一般式（４）
【００１６】
【化２０】
【００１７】
【化２１】
【００１８】
【化２２】
で表されるピロリジノン誘導体あるいはその塩である
または、下記一般式（７）
【００１９】
【化２３】
【００２０】
【化２４】
【００２１】
【化２５】
で表されるピロリジノン誘導体あるいはその塩である。
【００２２】
以下、本発明を詳細に説明する。 本発明において、Ｒの炭素数１から１２の直鎖アルキル基とは、メチル基、エチル基、ｎ−プロピル基、ｎ−ブチル基、ｎ−ペンチル基、ｎ−ヘキシル基、ｎ−オクチル基、ｎ−ドデシル等である。炭素数３から１２の分岐アルキル基とは、イソプロピル基、イソブチル基、ｔ−ブチル基、イソペンチル基、ネオペンチル基、イソヘキシル基、３−メチルペンチル基、１−メチルヘキシル基、１−エチルペンチル基、２，３−ジメチルブチル基、１，５−ジメチルヘキシル基、２−エチルヘキシル基、１−メチルヘプチル基、ｔ−オクチル基等である。
炭素数３から１２の環状構造を有するアルキル基とは、シクロプロピル基、シクロブチル基、シクロペンチル基、シクロヘキシル基、シクロヘプチル基、２−メチルシクロヘキシル基、３−メチルシクロヘキシル基、４−メチルシクロヘキシル基、シクロオクチル基、１−アダマンチル基、２−アダマンチル基、シクロドデシル基、シクロプロピルメチル基等である。
炭素数９から１５の水素化縮合多環炭化水素基とは１−（１，２，３，４−テトラヒドロナフチル）基、５−インダニル基、４−（１，２−シクロペンタ−１’３’−ジエノシクロオクテニル）基、７ーアセナフテニル基等である。フェニルアルキル基とはベンジル基、フェネチル基等である。
【００２３】
Ｒの置換フェニル基の置換基について詳しく述べる。ハロゲン原子とはフッ素原子、塩素原子、臭素原子、ヨウ素原子を示す。低級アルキル基とは、例えばメチル基、エチル基、ｎ−プロピル基、イソプロピル基、ｎ−ペンチル基、イソペンチル基等を示す。
シクロアルキル基とは、例えばシクロプロピル基、シクロブチル基、シクロペンチル基、シクロヘキシル基等を示す。低級アルコキシ基とは、例えばメトキシ基、エトキシ基、プロポキシ基、２−メチルエトキシ基、ブトキシ基、２−メチルプロポキシ基、ペントキシ基、２−メチルブトキシ基、２−エチルプロポキシ基等を示す。低級アルキルアミノ基とは、例えばＮ−メチルアミノ基、Ｎ，Ｎ−ジメチルアミノ基、Ｎ，Ｎ−ジエチルアミノ基、Ｎ−メチル−Ｎ−エチルアミノ基、Ｎ，Ｎ−ジイソプロピルアミノ基等を示す。
【００２４】
低級アミノアルキル基とは、例えばアミノメチル基、１−アミノエチル基、２−アミノプロピル基、２−アミノブチル基等を示す。低級アルキルチオ基とは、例えばメチルチオ基、エチルチオ基、プロピルチオ基、２−メチルエチルチオ基、ブチルチオ基等を示す。
低級アシル基とは、例えばアセチル基、プロパノイル基、ブタノイル基等を示す。低級アシルアミノ基とは、例えばアセチルアミノ基、プロパノイルアミノ基、ブタノイルアミノ基等を示す。低級アルキレンジオキシ基とは、例えばメチレンジオキシ基、エチレンジオキシ基等を示す。
低級パーフルオロアルキル基とは、例えばトリフルオロメチル基、ペンタフルオロエチル基等を示す。低級パーフルオロアルキルオキシ基とは、例えばトリフルオロメトキシ基、ペンタフルオロエトキシ基等を示す。
【００２５】
Ｒの置換フェニルアルキル基の置換基については、前記フェニル基の置換基と同じである。
【００２６】
Ｚの炭素数１から８の直鎖アルキル基とはメチル基、エチル基、ｎ−プロピル基、ｎ−ブチル基、ｎ−ペンチル基、ｎ−ヘキシル基、ｎ−オクチル基等である。炭素数３から８の分岐アルキル基とは、イソプロピル基、イソブチル基、ｔ−ブチル基、イソペンチル基、ネオペンチル基、イソヘキシル基、３−メチルペンチル基、１−メチルヘキシル基、１−エチルペンチル基、２，３−ジメチルブチル基、１，５−ジメチルヘキシル基、２−エチルヘキシル基、１−メチルヘプチル基、ｔ−オクチル基等である。
炭素数３から８の環状構造を有するアルキル基とは、シクロプロピル基、シクロブチル基、シクロペンチル基、シクロヘキシル基、シクロヘプチル基、２−メチルシクロヘキシル基、３−メチルシクロヘキシル基、４−メチルシクロヘキシル基、シクロオクチル基、シクロプロピルメチル基等である。炭素数２から８の不飽和アルキル基とは、ビニル基、１−プロペニル基、アリル基、イソプロペニル基、１−プロピニル基、プロパルギル基、３−ブテニル基、４−ペンテニル基、５−ヘキセニル基、２，５−ヘキサジエニル基等である。 フェニルアルキル基とは、例えばベンジル基、フェネチル基等である。
炭素数９から１５の水素化縮合多環炭化水素基とは１−（１，２，３，４−テトラヒドロナフチル）基、５−インダニル基、４−（１，２−シクロペンタ−１’３’−ジエノシクロオクテニル）基、７ーアセナフテニル基等である。ヘテロ原子を１つ含む５員環ヘテロ環基とは、例えば２−ピロリル基、２−フリル基、２−チエニル基、３−チエニル基、２−テトラヒドロフリル基等を示す。
Ｚの置換フェニル基の置換基について詳しく述べる。ハロゲン原子とはフッ素原子、塩素原子、臭素原子、ヨウ素原子を示す。低級アルキル基とは、例えばメチル基、エチル基、ｎ−プロピル基、イソプロピル基、ｎ−ペンチル基、イソペンチル基等を示す。
【００２７】
シクロアルキル基とは、例えばシクロプロピル基、シクロブチル基、シクロペンチル基、シクロヘキシル基等を示す。低級アルコキシ基とは、例えばメトキシ基、エトキシ基、プロポキシ基、２−メチルエトキシ基、ブトキシ基、２−メチルプロポキシ基、ペントキシ基、２−メチルブトキシ基、２−エチルプロポキシ基等を示す。低級アルキルアミノ基とは、例えばＮ−メチルアミノ基、Ｎ，Ｎ−ジメチルアミノ基、Ｎ，Ｎ−ジエチルアミノ基、Ｎ−メチル−Ｎ−エチルアミノ基、Ｎ，Ｎ−ジイソプロピルアミノ基等を示す。
低級アミノアルキル基とは、例えばアミノメチル基、１−アミノエチル基、２−アミノプロピル基、２−アミノブチル基等を示す。低級アルキルチオ基とは、例えばメチルチオ基、エチルチオ基、プロピルチオ基、２−メチルエチルチオ基、ブチルチオ基等を示す。
低級アシル基とは、例えばアセチル基、プロパノイル基、ブタノイル基等を示す。低級アシルアミノ基とは、例えばアセチルアミノ基、プロパノイルアミノ基、ブタノイルアミノ基等を示す。低級アルキレンジオキシ基とは、例えばメチレンジオキシ基、エチレンジオキシ基等を示す。
低級パーフルオロアルキル基とは、例えばトリフルオロメチル基、ペンタフルオロエチル基等を示す。低級パーフルオロアルキルオキシ基とは、例えばトリフルオロメトキシ基、ペンタフルオロエトキシ基等を示す。
Ｚの置換フェニルアルキル基の置換基については、前記置換フェニル基の置換基と同じである。 Ｗの炭素数９から１５の水素化縮合多環炭化水素基とは１−（１，２，３，４−テトラヒドロナフチル）基、５−インダニル基、４−（１，２−シクロペンタ−１’３’−ジエノシクロオクテニル）基、７ーアセナフテニル基等である。
【００２８】
Ｗの置換フェニル基の置換基について詳しく述べる。ハロゲン原子とはフッ素原子、塩素原子、臭素原子、ヨウ素原子を示す。低級アルキル基とは、例えばメチル基、エチル基、ｎ−プロピル基、イソプロピル基、ｎ−ペンチル基、イソペンチル基等を示す。シクロアルキル基とは、例えばシクロプロピル基、シクロブチル基、シクロペンチル基、シクロヘキシル基等を示す。
低級アルコキシ基とは、例えばメトキシ基、エトキシ基、プロポキシ基、２−メチルエトキシ基、ブトキシ基、２−メチルプロポキシ基、ペントキシ基、２−メチルブトキシ基、２−エチルプロポキシ基等を示す。低級アルキルアミノ基とは、例えばＮ−メチルアミノ基、Ｎ，Ｎ−ジメチルアミノ基、Ｎ，Ｎ−ジエチルアミノ基、Ｎ−メチル−Ｎ−エチルアミノ基、Ｎ，Ｎ−ジイソプロピルアミノ基等を示す。
低級アミノアルキル基とは、例えばアミノメチル基、１−アミノエチル基、２−アミノプロピル基、２−アミノブチル基等を示す。低級アルキルチオ基とは、例えばメチルチオ基、エチルチオ基、プロピルチオ基、２−メチルエチルチオ基、ブチルチオ基等を示す。低級アシル基とは、例えばアセチル基、プロパノイル基、ブタノイル基等を示す。低級アシルアミノ基とは、例えばアセチルアミノ基、プロパノイルアミノ基、ブタノイルアミノ基等を示す。
【００２９】
低級アルキレンジオキシ基とは、例えばメチレンジオキシ基、エチレンジオキシ基等を示す。低級パーフルオロアルキル基とは、例えばトリフルオロメチル基、ペンタフルオロエチル基等を示す。低級パーフルオロアルキルオキシ基とは、例えばトリフルオロメトキシ基、ペンタフルオロエトキシ基等を示す。
本発明の化合物は、例えば下記反応式−１に示す方法により製造できる。
反応式−１
【００３０】
【化２６】
化合物（１０）を不活性溶媒中、還元することによって化合物（１１）を得る。反応温度は−７５〜２００℃、好ましくは０〜１００℃で１〜２０時間、好ましくは５〜１５時間反応させる。用いられる不活性溶媒としては例えば、ベンゼン、トルエン等の芳香族炭化水素類、ジエチルエーテル、テトラヒドロフラン、ジオキサン、１，２−ジメトキシエタン、ジエチレングリコールジメチルエーテル等のエーテル類、ジクロロメタン、クロロホルム、１，２−ジクロロエタン等のハロゲン化炭化水素類、メタノール、エタノール等のアルコール類、もしくはこれらの混合物が挙げられる。還元の反応試剤としては例えば、水素化アルミニウム、水素化リチウムアルミニウム、水素化リチウムアルミニウムと塩化アルミニウムの組み合わせ、水素化ホウ素ナトリウム、水素化ホウ素ナトリウムと塩化カルシウムの組み合わせ、水素化ホウ素ナトリウムと塩化アルミニウムの組み合わせ等を使用できる。
【００３１】
化合物（１１）をチオニルまたはリンハライドにより相当するハロメチル化合物に、あるいはトシルまたはメシルハライドにより相当するトシルまたはメシルエステルに変換する。この反応はクロロホルム、ジクロロメタン、テトラヒドロフランまたはジメチルホルムアミドのような不活性有機溶剤をを使用して、室温から使用溶剤の沸点の間で行うのが好ましい。中間体として生成されるハロメチル化合物あるいはトシルまたはメシルエステルは単離してもよく、またはそのままさらに反応させることもできる。
【００３２】
これらの生成物をＨＸで表されるアミンと反応させると一般式（１３）の相当する目的化合物が得られる。この反応はテトラヒドロフラン、ジオキサン、アセトニトリル、ジメトキシエタンまたはジメチルホルムアミド中で実施できる。反応温度は５０〜１５０℃であり、個別の条件はアミンの塩基度および沸点によって変わる。用いられる塩基としては、例えば炭酸カリウム、炭酸ナトリウム、水酸化ナトリウム、水酸化カリウム、炭酸水素ナトリウム、ナトリウムアミド、水素化ナトリウム、等の無機塩基の他、トリエチルアミン、トリプロピルアミン、ピリジン、１，８−ジアザビシクロ〔５．４．０〕ウンデカ−７−エン（ＤＢＵ）等の有機塩基等を使用できる。また上記反応は、必要に応じて反応促進剤として、ヨウ化カリウム、ヨウ化ナトリウム等のヨウ化アルカリ金属化合物を添加することができる。上記反応におけるＨＸで表される化合物と一般式（１２）で表される化合物との使用割合は、特に限定されないが、通常前者に対し後者を等モル〜過剰量、好ましくは等モル〜５倍モルとすればよい。
ここで一般式（１０）で表される化合物は例えば以下のように合成される。
反応式−２
【００３３】
【化２７】
【００３４】
【化２８】
ピロリジノンの３位置換体（１５）は、Ｒ−ＮＨ2で表されるアミン誘導体とγ−ブチロラクトンを脱水縮合して製造される。この反応は無溶媒で、５０〜２５０℃、好ましくは１５０〜３００℃の温度条件下５時間〜２０時間、好ましくは１０〜１５時間反応させる。この時必要に応じて塩酸のような酸触媒を加えてもよい。
得られた化合物（１４）を不活性溶媒中、塩基存在下アルコキシカルボニル基導入により化合物（１５）を得る。反応温度は３０〜２００℃、好ましくは７０〜１５０℃で３〜２０時間、好ましくは５〜１５時間反応させる。用いられる不活性溶媒としては例えば、ベンゼン、トルエン、キシレン等の芳香族炭化水素類、テトラヒドロフラン、ジオキサン、ブチルエーテル、１，２−ジメトキシエタン等のエーテル類、メタノール、エタノール、プロパノール等のアルコール類あるいはジメチルホルムアミドが挙げられる。アルコキシカルボニル基導入の反応試剤としては例えば、炭酸ジメチル、炭酸ジエチル、ホスホノギ酸エチル、シュウ酸エチル、シアノギ酸エチル等のエステル類が挙げられる。塩基としては例えば、炭酸カリウム、炭酸ナトリウム、水酸化ナトリウム、水酸化カリウム、カリウム−ｔ−ブトキシド、ナトリウムメトキシド、ナトリウムエトキシド、ナトリウムアミド、水素化ナトリウム等の無機塩基等の他、トリエチルアミン、トリプロピルアミン、ピリジン、１，８−ジアザビシクロ〔５．４．０〕ウンデカ−７−エンウンデセン−７（ＤＢＵ）等の有機塩基等を使用できる。
【００３５】
ピロリジノン４位置換体（１７）は、Ｒ−ＮＨ2で表されるアミン誘導体とイタコン酸とを脱水縮合させることによって製造される。この反応は無溶媒で、５０〜２５０℃、好ましくは１５０〜２００℃の温度条件下５時間〜２０時間、好ましくは１０〜１５時間反応させる。この時必要に応じて塩酸のような酸触媒を加えてもよい。得られた化合物（１６）を、メタノールあるいはエタノールのようなアルコール溶媒中、硫酸のような触媒存在下還流することにより、化合物（１７）が得られる。
【００３６】
本発明の一般式（１３）の化合物は、通常の薬理的に許容される酸と容易に塩を形成し得る。その酸としては、例えば硫酸、硝酸、塩酸、燐酸、臭化水素酸等の無機酸、酢酸、酒石酸、フマル酸、マレイン酸、クエン酸、安息香酸、トリフルオロ酢酸、メタンスルホン酸、エタンスルホン酸、ｐ−トルエンスルホン酸等の有機酸が挙げられる。これらの塩もまたフリー体の一般式（１３）の化合物と同様に本発明の有効成分化合物として用いることができる。
なお、上記一般式で表される本発明の誘導体は、ひとつ以上の不斉炭素を有している。したがって、該誘導体は異なった立体異性形態、またはラセミ形態を含む立体異性形態の混合物の形態で存在することができる。かくして、本発明はこの様に規定したような種々の形態をも包含するが、これらも同様に有効成分化合物として用いることができる。
【００３７】
上記各反応式に示される目的とする化合物は、通常の分離手段により反応系内より分離され、さらに生成することができる。この分離および精製手段としては、例えば蒸留法、再結晶法、カラムクロマトグラフィー、イオン交換クロマトグラフィー、ゲルクロマトグラフィー、親和クロマトグラフィー、プレパラティブ薄層クロマトグラフィー、溶媒抽出法等を活用できる。
以下に本発明の化合物を具体的に（表−１）［表１−表６３］および（表−２）［表６４−表１２６］に列挙する。なお、本発明はこれらの例に何ら限定されるものではない。
【００３８】
【表１】
【表２】
【表３】
【表４】
【表５】
【表６】
【表７】
【表８】
【表９】
【表１０】
【表１１】
【表１２】
【表１３】
【表１４】
【表１５】
【表１６】
【表１７】
【表１８】
【表１９】
【表２０】
【表２１】
【表２２】
【表２３】
【表２４】
【表２５】
【表２６】
【表２７】
【表２８】
【表２９】
【表３０】
【表３１】
【表３２】
【表３３】
【表３４】
【表３５】
【表３６】
【表３７】
【表３８】
【表３９】
【表４０】
【表４１】
【表４２】
【表４３】
【表４４】
【表４５】
【表４６】
【表４７】
【表４８】
【表４９】
【表５０】
【表５１】
【表５２】
【表５３】
【表５４】
【表５５】
【表５６】
【表５７】
【表５８】
【表５９】
【表６０】
【表６１】
【表６２】
【表６３】
【表６４】
【表６５】
【表６６】
【表６７】
【表６８】
【表６９】
【表７０】
【表７１】
【表７２】
【表７３】
【表７４】
【表７５】
【表７６】
【表７７】
【表７８】
【表７９】
【表８０】
【表８１】
【表８２】
【表８３】
【表８４】
【表８５】
【表８６】
【表８７】
【表８８】
【表８９】
【表９０】
【表９１】
【表９２】
【表９３】
【表９４】
【表９５】
【表９６】
【表９７】
【表９８】
【表９９】
【表１００】
【表１０１】
【表１０２】
【表１０３】
【表１０４】
【表１０５】
【表１０６】
【表１０７】
【表１０８】
【表１０９】
【表１１０】
【表１１１】
【表１１２】
【表１１３】
【表１１４】
【表１１５】
【表１１６】
【表１１７】
【表１１８】
【表１１９】
【表１２０】
【表１２１】
【表１２２】
【表１２３】
【表１２４】
【表１２５】
【表１２６】
こうして得られる有効成分化合物は、シグマ受容体作用薬として有効であり、これらは一般的な医薬製剤の形態で用いられる。製剤は通常使用される充填剤、増量剤、結合剤、付湿剤、崩壊剤、表面活性剤、滑沢剤、等の希釈剤あるいは賦形剤を用いて調製される。この医薬製剤としては各種の形態が治療目的に応じて選択でき、その代表的なものとして錠剤、丸剤、散剤、液剤、懸濁剤、乳剤、顆粒剤、カプセル剤、坐剤、注射剤（液剤、懸濁剤等）が挙げられる。
【０１６４】
錠剤の形態に成形するに際しては、担体としてこの分野で従来よりよく知られている各種のものを広く使用することができる。その例としては、例えば乳糖、白糖、塩化ナトリウム、ブドウ糖、尿素、デンプン、炭酸カルシウム、カオリン、結晶セルロース、ケイ酸等の賦形剤、水、エタノール、プロパノール、単シロップ、ブドウ糖液、デンプン液、ゼラチン溶液、カルボキシメチルセルロース、セラック、メチルセルロース、リン酸カリウム、ポリビニルピロリドン等の結合剤、乾燥デンプン、アルギン酸ナトリウム、カンテン末、炭酸水素ナトリウム、炭酸カルシウム、ポリオキシエチレンソルビタン脂肪酸エステル類、ラウリル硫酸ナトリウム、ステアリン酸モノグリセリド、デンプン、乳糖等の崩壊剤、白糖、ステアリン酸、カカオバター、水素添加油等の崩壊抑制剤、第４級アンモニウム塩基、ラウリル硫酸ナトリウム等の吸収促進剤、グリセリン、デンプン等の保湿剤、デンプン、乳糖、カオリン、ベントナイト、コロイド状ケイ酸等の吸着剤、タルク、ステアリン酸塩、ホウ酸末、ポリエチレングリコール等の滑沢剤等を使用できる。さらに錠剤は必要に応じ通常の剤皮を施した錠剤、例えば糖衣錠、ゼラチン被包錠、腸溶被錠、フィルムコーティング錠あるいは二層錠、多層錠とすることができる。
【０１６５】
丸剤の形態に成形するに際しては、担体として従来この分野で公知のものを広く使用できる。その例としては、例えばブドウ糖、乳糖、デンプン、カカオ脂、硬化植物油、カオリン、タルク等の賦形剤、アラビアゴム末、トラガント末、ゼラチン等の結合剤、カルメロースカルシウム、カンテン等の崩壊剤を使用できる。
【０１６６】
坐剤の形態に成形するに際しては、担体として従来公知のものを広く使用できる。その例としては、例えばポリエチレングリコール、カカオ脂、高級アルコール、高級アルコールのエステル類、ゼラチン、半合成グリセライド等を挙げることができる。
カプセル剤は常法に従い通常有効成分化合物を上記で例示した各種の担体と混合して硬質ゼラチンカプセル、軟質カプセル等に充填して調製される。
注射剤として調製する場合、液剤、乳剤および懸濁剤は殺菌され、かつ血液と等張であるのが好ましく、これらの形態に成形するに際しては、希釈剤としてこの分野において慣用されているもの、例えば水、エタノール、マクロゴール、プロピレングリコール、エトキシ化イソステアリルアルコール、ポリオキシ化イソステアリルアルコール、ポリオキシエチレンソルビタン脂肪酸エステル類等を使用できる。なお、この場合等張性の溶液を調製するのに充分な量の食塩、ブドウ糖あるいはグリセリンを医薬製剤中に含有させてもよく、また通常の溶解補助剤、緩衝剤、無痛化剤等を添加してもよい。
さらに必要に応じて着色剤、保存剤、香料、風味剤、甘味剤等や他の医薬品を医薬製剤中に含有させることもできる。
【０１６７】
本発明のこれらの医薬製剤中に含有されるべき有効成分化合物の量としては、特に限定されずに広範囲から適宜選択されるが、通常製剤組成物中に約１〜７０重量％、好ましくは約５〜５０重量％とするのがよい。
【０１６８】
本発明のこれら医薬製剤の投与方法は特に制限はなく、各種製剤形態、患者の年齢、性別その他の条件、疾患の程度に応じた方法で投与される。例えば錠剤、丸剤、液剤、懸濁剤、乳剤、顆粒剤およびカプセル剤の場合には、経口投与される。また注射剤の場合には、単独でまたはブドウ糖、アミノ酸等の通常の補液と混合して静脈内投与され、さらに必要に応じて単独で筋肉内、皮下もしくは腹腔内投与される。坐剤の場合は直腸内投与される。
【０１６９】
本発明のこれら医薬製剤の投与量は、用法、患者の年齢、性別その他の条件、疾患の程度により適宜選択されるが、通常有効成分化合物の量が一日当たり体重１ｋｇ当たり、約０．０００１〜５０ｍｇ程度とするのがよい。また投与単位形態の製剤中には有効成分化合物が約０．００１〜１０００ｍｇの範囲で含有されるのが望ましい。
【０１７０】
【実施例】
以下に本発明の実施例として、化合物の製造例、医薬製剤の製剤例、さらに試験例を挙げて詳細に説明する。なお、本発明は以下の実施例のみに限定されるものではない。
【０１７１】
実施例１
［１−１］ イタコン酸 １７．１ｇ（１３１ｍｍｏｌ）とシクロヘキシルアミン １５．０ｍｌ（１３１ｍｍｏｌ）を混合し、１４０℃で１時間反応させた。冷却後固体をアセトンで洗浄し，１−シクロヘキシル−２−オキソ−４−ピロリジンカルボン酸（１−１） １９．６ｇを得た。
【０１７２】
［１−２］ 化合物１−１ １４．５ｇ（６８．５ｍｍｏｌ）をエタノール ２００ｍｌに懸濁させ、濃硫酸 ０．５ｍｌを加えて４時間還流した。溶媒を溜去し、残渣を酢酸エチルに溶解して飽和重曹水で洗浄し、硫酸マグネシウムで乾燥後溶媒を溜去し、１−シクロヘキシル−２−オキソ−４−ピロリジンカルボン酸エチル（１−２） １４．１ｇを得た。
【０１７３】
［１−３］ 化合物（１−２） ６．１ｇ（２５．４ｍｍｏｌ）をＴＨＦ １００ｍｌに溶解し、水素化ホウ素ナトリウム １．０ｇ（２５．４ｍｍｏｌ）を加え、還流下６時間かけて、メタノール ３ｍｌをＴＨＦ １００ｍｌに溶かした溶液を滴下した。水を加えて反応を停止し酢酸エチルで抽出後、乾燥して溶媒を溜去し、１−シクロヘキシル−４−ヒドロキシメチル−２−ピロリジノン（１−３） ３．５ｇを得た。
【０１７４】
［１−４］ 化合物（１−３） ３．０ｇ（１５．２ｍｍｏｌ）をジクロロメタン ５０ｍｌに溶かし、氷冷下メタンスルホニルクロリド ７．７ｍｌ、次いでピリジン ８．５ｍｌを加え、室温で２時間反応させた。飽和重曹水を加えて５時間攪拌し、有機層を分離して乾燥後溶媒を溜去し、シリカゲルカラムクロマトグラフィー（クロロホルム／メタノール＝４０／１）で精製し、１−シクロヘキシル−２−オキソ−４−ピロリジン−４−イル−メチルメシラート（１−４）４．２ｇを得た。
【０１７５】
［１−５］ 化合物（１−４） １．４ｇ（５．１ｍｍｏｌ）をアセトニトリル ４０ｍｌに溶かし、４−（４−クロロフェニル）−４−ヒドロキシピペリジン １．０ｇ（４．８ｍｍｏｌ）、炭酸カリウム １．０ｇ、ヨウ化カリウム ０．１ｇを加えて１０時間還流した。不溶物を濾過し溶媒を溜去後、シリカゲルカラムクロマトグラフィー（クロロホルム／メタノール＝３０／１）で精製し、４−〔４−（４−クロロフェニル）−４−ヒドロキシピペリジノメチル〕−１−シクロヘキシル−２−ピロリジノン（１−５） １．９ｇを得た。化合物（１−５）をメタノール中塩酸／ジオキサンを用い塩酸塩 ２．１ｇを得た。
ｍｐ２８０−２８１℃
1Ｈ−ＮＭＲ（ＣＤＣｌ3，δｐｐｍ）（フリー体）；１．１１（１Ｈ，ｍ）、１．３７（４Ｈ，ｍ）、１．６９（６Ｈ，ｍ）、２．２−２．８（１２Ｈ，ｍ）、３．１３（１Ｈ，ｍ）、３．４４（１Ｈ，ｍ）、３．９５（１Ｈ，ｍ）、７．２９（４Ｈ，ｍ）
【０１７６】
実施例２
［２−１］ ３７．６ｇのＮ−ブロモコハク酸イミドを１００ｍｌのクロロホルムに懸濁させ、２５．０ｇの１，３−ベンゾジオキソールを加えて３時間還流した。室温に冷却後、水、炭酸ナトリウム水、水で洗浄、乾燥濃縮し残留物を減圧蒸留して３９．６ｇの５−ブロモ−１，３−ベンゾジオキソール（２−１）を得た。
【０１７７】
［２−２］ マグネシウム細片１．３５ｇを２０ｍｌのＴＨＦと混合し（２−１）１１．０ｇのＴＨＦ５０ｍｌ溶液の内５ｍｌを加えて加温した。反応が進行したので残りの溶液を１０分間で滴下した後、１時間還流してグリニャール試薬を得た。この溶液を室温に冷却後、１−ベンジル−４−ピペリドン９．５ｇのＴＨＦ溶液を４５分かけて滴下した。１時間かき混ぜた後、５０℃でさらに１時間反応した。濃縮後、残留物を塩化アンモニウム溶液と混合してよくかき混ぜ酢酸エチルで抽出、水洗、乾燥、濃縮、残留物にＩＰＡを加えて結晶化、濾取、ＩＰＡで洗浄し１−ベンジル−４−ヒドロキシ−４−（３，４−メチレンジオキシフェニル）−ピペリジン（２−２）８．０ｇを得た。
【０１７８】
［２−３］ ８．０ｇの（２−２）を８０ｍｌのメタノールと６．１ｍｌの４Ｎ塩酸にとかし、１０％Ｐｄ／Ｃ存在下、常温常圧水素添加反応を行い、２時間後触媒を濾別、濾液を濃縮、エーテルを加えて結晶化、濾取、エーテルで洗浄して５．６ｇの４−ヒドロキシ−４−（３，４−メチレンジオキシフェニル）−ピペリジン塩酸塩（２−３）を得た。
【０１７９】
［２−４］ シクロヘキシルアミンの代わりにｍ−アミノベンゾトリフルオライド １６．１ｇ（０．１ｍｏｌ）を用いる以外は実施例１の工程［１−１、１−２、１−３］と同様の操作を行い、１−（３−トリフルオロメチル）−４−ヒドロキシメチル−２−ピロリジノン（２−４） ６．０ｇを得た。化合物（２−４）４．０ｇ（１５．４ｍｍｏｌ）と４−ヒドロキシ−４−（３，４−メチレンジオキシフェニル）−ピペリジン塩酸塩 ２．７５ｇ（１０．７ｍｍｏｌ）を用いて実施例１の工程［１−４、１−５］と同様にして４−［４−ヒドロキシ−４−（３，４−メチレンジオキシフェニル）ピペリジン−１−イルメチル］−１−（３−トリフルオロメチルフェニル）−２−ピロリジノン塩酸塩 ３．９ｇを得た。
ｍｐ２０２．５℃（分解）
1Ｈ−ＮＭＲ（ＣＤＣｌ3，δｐｐｍ）（フリー体）；１．５５−１．８（３Ｈ，ｍ）、２．０−２．２（２Ｈ，ｍ）、２．４−２．６（５Ｈ，ｍ）、２．７−２．９（４Ｈ，ｍ）、３．７−４．０５（２Ｈ，ｍ）、５．９５（２Ｈ，ｓ）、６．７５−７．０５（３Ｈ，ｍ）、７．４−８．０（４Ｈ，ｍ）
【０１８０】
実施例３
ｐ−アニシジンを用いて実施例１の工程［１−１、１−２、１−３、１−４］と同様にして１−（４−メトキシフェニル）−４−（メシルオキシメチル）−２−ピロリジノン（３−１）を合成し、この化合物（３−１） ３．２５ｇ（１０．９ｍｍｏｌ）と４−（４−クロロフェニル）−１，２，３，６−テトラヒドロピリジン塩酸塩 ２．５ｇ（１０．９ｍｍｏｌ）を実施例１の工程［１−５］と同様に操作して、４−［４−（４−クロロフェニル）−１，２，３，６−テトラヒドロピリジン−１−イルメチル］−１−（４−メトキシフェニル）−２−ピロリジノン塩酸塩 １．０ｇを得た。
【０１８１】
ｍｐ２１４−２１６℃
1Ｈ−ＮＭＲ（ＣＤＣｌ3，δｐｐｍ）（フリー体）；２．３５−２．８５（９Ｈ，ｍ）、３．１−３．２（２Ｈ，ｍ）、３．３８（３Ｈ，ｓ）、３．６５−４．０（２Ｈ，ｍ）、６．０７（１Ｈ，ｓ）、６．８５−６．９５（２Ｈ，ｍ）、７．２５−７．６（６Ｈ，ｍ）
【０１８２】
実施例４
［４−１］ アニリン ３０．１ｇ（０．３２３ｍｏｌ）とγ−ブチロラクトン ３０．６ｇ（０．３５５ｍｌ）を混合し、塩酸 ７ｍｌを加えて、４時間還流した。さらにバス温１９０−２００℃で３時間反応した。冷却後２Ｎ塩酸５０ｍｌを加えてスラッジし、濾過後水洗し乾燥した。ヘキサン／酢酸エチル（６／４）から再結晶し１−フェニル−２−ピロリジノン（４−１） ２７．２ｇを得た。
【０１８３】
［４−２］ 水素化ナトリウム（６０％ｏｉｌ） ２２．１ｇ（０．５５３ｍｏｌ）をトルエン２００ｍｌと混合し、炭酸ジエチル ６１．５ｇ（０．５２１ｍｏｌ）を加え、次いで還流下で化合物（４−１） ２５．０ｇ（０．１５５ｍｏｌ）を含むトルエン溶液 ２００ｍｌを２．５時間かけて滴下した。５．５時間還流した後、冷却し、氷水中に排出し、希塩酸で酸性にし、有機層を分離し、水層からトルエンで２回抽出、先の有機層とあわせて乾燥、濃縮後ヘキサン−エーテルを加えて洗浄後、減圧乾燥して２−オキソ−１−フェニル−３−ピロリジンカルボン酸エチル（４−２） １０．５ｇを得た。
【０１８４】
［４−３］ 化合物（４−２） １０．３ｇ（４４．５ｍｍｏｌ）をメタノール １００ｍｌに溶かし、無水塩化カルシウム １４．９５ｇ（４４．６ｍｍｏｌ）を加えて溶解させた。次いで水素化ホウ素ナトリウム ２．０６ｇ（５４．４ｍｍｏｌ）を分割装入し、氷冷下４５分攪拌した。氷水２０ｍｌと酢酸エチル２０ｍｌを加え有機層を分液し、水層を酢酸エチル、トルエン、エーテルで抽出し、先の有機層と一緒にし乾燥、濃縮後、カラムクロマトグラフィー（シリカゲル、クロロホルム／メタノール＝２０／１）で精製し、３−ヒドロキシメチル−１−フェニル−２−ピロリジノン（４−３） ３．８ｇを得た。
【０１８５】
［４−４］ 化合物（４−３） ２．１ｇ（１１．０ｍｍｏｌ）をジクロロメタン ２５ｍｌに溶かし、トリエチルアミン １．１ｇ（１０．９ｍｌ）、次いでメタンスルホニルクロリド １．２ｇ（１０．５ｍｌ）を滴下して氷冷下３０分攪拌し、室温で２．５時間反応した。トリエチルアミン０．３ｇ（３．０ｍｍｏｌ）、メタンスルホニルクロリド０．４ｇ（３．５ｍｍｏｌ）を滴下しさらに４時間反応した。水洗、乾燥、濃縮してメシル体を得た。メシル体、実施例２の工程（２−３）で得られた４−ヒドロキシ−４−（３，４−メチレンジオキシフェニル）ピペリジン塩酸塩 ２．１ｇおよび炭酸カリウム２．７ｇをアセトニトトリル３５ｍｌ中で８時間還流し、不溶物を濾別後濃縮し、シリカゲルクロマトグラフィー（クロロホルム／メタノール＝４０／１）で精製して、３−［４−ヒドロキシ−４−（３，４−メチレンジオキシフェニル）ピペリジン−１−イルメチル］−１−フェニル−２−ピロリジノン６５０ｍｇを得た。フリー体５００ｍｇをメタノールに溶かし塩酸／ジオキサンで酸性にし、濃縮し析出晶を濾取、エーテルで洗浄して３−［４−ヒドロキシ−４−（３，４−メチレンジオキシフェニル）ピペリジン−１−イルメチル］−１−フェニル−２−ピロリジノン塩酸塩４６０ｍｇｇを得た。
ｍｐ２１１−２１３℃
1Ｈ−ＮＭＲ（ＣＤＣｌ3，δｐｐｍ）（フリー体）；１．７１−１．７８（２Ｈ，ｍ）、２．０２−２．１７（３Ｈ，ｍ）、２．３４−３．０４（８Ｈ，ｍ）、３．８３（２Ｈ，ｍ）、５．９５２（２Ｈ，ｓ）、６．７７−７．１８（４Ｈ，ｍ）、７．３７（２Ｈ，ｍ）、７．６４（２Ｈ，ｍ）
【０１８６】
実施例５
［５−１］ ２．４３ｇのマグネシウムを１００ｍｌのＴＨＦと混合し１６．３ｇの２−ブロモチオフェンを滴下し、１時間還流してグリニャール試薬を調製した。室温に冷却後１７．１ｇの１−エトキシカルボニル−４−ピペリドンを滴下して１時間還流下にかき混ぜた。塩化アンモニウムを含む氷水中にあけ酢酸エチルで抽出した。この時不溶物が析出するがこれも目的物である。抽出液を濃縮すると結晶が得られた。先の析出物と混合し、メタノールより再結晶、酢酸エチルで洗浄し４−ヒドロキシ−４−（２−チエニル）−１−ピペリジンカルボキシレート（５−１）を得た。
【０１８７】
［５−２］ １２．８ｇの（５−１）を１２０ｍｌのＩＰＡに溶かし５．０ｇの水 酸化カリウムを加えて６時間還流下かき混ぜた。さらに５．０ｇの水酸化カリウムを追加して６時間還流した。冷却後、不溶物を濾取、濾液を濃縮した。残留物と先の不溶物を併せて水にあけ、クロロホルムで抽出した。水洗、乾燥濃縮後、エーテルを加えて結晶化、濾取して４−（２−チエニル）−４−ピペリジノール（５−２）６．９ｇを得た。
【０１８８】
［５−３］ 化合物（２−４）の代わりに化合物（５−２）を用いる以外は実施例２の工程［２−４］と同様にして４−（４−ヒドロキシ−４−（２−チエニル）ピペリジン−１−イルメチル）−１−（３トリフルオロメチルフェニル）−２−ピロリジノン塩酸塩を得た。
ｍｐ１９３（分解）
1Ｈ−ＮＭＲ（ＣＤＣｌ3，δｐｐｍ）（フリー体）１．９−２．１（３Ｈ，ｍ）２．１−２．２５（２Ｈ，ｍ）２．４−２．８５（９Ｈ，ｍ）３．６５−３．７５（１Ｈ，ｍ）３．９−４．０（１Ｈ，ｍ）６．９５−７．０５（２Ｈ，ｍ）７．２−７．３（１Ｈ，ｍ）７．４−７．５５（２Ｈ，２Ｈ，ｍ）
【０１８９】
実施例６〜４７
実施例１ないし５と同様にして製造し、それぞれの化合物の融点（ｍｐ）およびＭＮＲで同定し、その結果を（表−３）［表１２７−表１３５］に示す。
【０１９０】
【表１２７】
【表１２８】
【表１２９】
【表１３０】
【表１３１】
【表１３２】
【表１３３】
【表１３４】
【表１３５】
製剤例１
４−〔４−（４−クロロフェニル）−４−ヒドロキシピペリジノメチル〕−１−シクロ
ヘキシル−２−ピロリジノン塩酸塩 １３０ ｇ
クエン酸 １ ｇ
ラクトース ３５ ｇ
リン酸二カルシウム ７２ ｇ
プルロニックＦ−６８ ３０ ｇ
ラウリル硫酸ナトリウム ２０ ｇ
ポリビニルピロリドン １４ ｇ
ポリエチレングリコール（カルボワックス１５００） ５ ｇ
ポリエチレングリコール（カルボワックス６０００） ４５ ｇ
コーンスターチ ３３ ｇ
乾燥ステアリン酸ナトリウム ３ ｇ
乾燥ステアリン酸マグネシウム ３ ｇ
エタノール 適量
本発明有効成分化合物、クエン酸、ラクトース、リン酸二カルシウム、プルロニックＦ−６８およびラウリル硫酸ナトリウムを混合する。
上記混合物をＮｏ．６０スクリーンでふるい、ポリビニルピロリドン、カルボワックス１５００および同６０００を含むアルコール性溶液で湿式粒状化する。必要に応じてアルコールを添加して粉末をペースト状塊にする。コーンスターチを添加し、均一な粒子が形成されるまで混合を続ける。混合物をＮｏ．１０スクリーンを通過させ、トレイに入れ、１００℃のオーブンで１２〜１５時間乾燥する。乾燥粒子をＮｏ．１６スクリーンでふるい、乾燥ラウリル硫酸ナトリウムおよび乾燥ステアリン酸マグネシウムを加えて混合し、打錠機で所望の形状に圧縮する。
【０２００】
得られた素錠をワニスで処理し、タルクを散布し、湿気の吸収を防止する。素錠の周囲に下塗り層を被覆する。内服用のために充分な回数のワニス被覆を行う。錠剤を完全に丸くかつ平滑にするためにさらに下塗り層および平滑被覆が適用される。所望の被覆が得られるまで着色被覆を行う。乾燥後、被覆錠剤を磨いて均一な光沢の錠剤にする。
【０２０１】
製剤例２
４−［４−（４−クロロフェニル）−４−ヒドロキシピペリジノメチル］−１−シクロヘキシル−２−ピペ
リジノン塩酸塩 ５ ｇ
ポリエチレングリコール（分子量：４０００） ０．３ｇ
塩化ナトリウム １．０ｇ
ポリオキシエチレン−ソルビタンモノオレエート ０．５ｇ
メタ重亜硫酸ナトリウム ０．１ｇ
メチル−パラベン ０．２ｇ
注射用蒸留水 １０．０ｍｌ上記メチル−パラベン、メタ重亜硫酸ナトリウムおよび塩化ナトリウムを攪拌しながら８０℃で上記の約半量の蒸留水に溶解させる。得られた溶液を４０℃まで冷却し、本発明の有効成分化合物、次いでポリエチレングリコールおよびポリオキシエチレンソルビタンモノオレエートを、上記の溶液中に溶解させる。次にその溶液に注射用蒸留水を加えて最終の容量に調製し、適当なフィルターペーパーを用いて滅菌濾過することにより滅菌して、注射剤を調製する。
【０２０２】
薬理試験例１
Ｖｉｌｎｅｒらの方法（Ｂ．Ｊ．Ｖｉｌｎｅｒ ａｎｄ Ｗ．Ｄ．Ｂｏｗｅｎ，ｉｎ Ｍｕｌｔｉｐｌｅ Ｓｉｇｍａ ａｎｄ ＰＣＰ Ｒｅｃｅｐｔｏｒ Ｌｉｇａｎｄｓ： Ｍｅｃｈａｎｉｓｍｓ ｆｏｒ Ｎｅｕｒｏｍｏｄｕｌａ−ｔｉｏｎ ａｎｄ Ｎｅｕｒｏｐｒｏｔｅｃｔｉｏｎ？，ＮＰＰ Ｂｏｏｋｓ：ｐｐ ３４１（１９９２））を変更してσ1受容体に対するラジオレセプターアッセイを行った。小脳、延髄を除いたラット全脳のホモジネート（１０ｍｇ／ｍｌ）を被験薬および3Ｈ−ｌｉｇａｎｄ（５ｎＭ 3Ｈ−（＋）ｐｅｎｔａｚｏｃｉｎｅ（ＮＥＮ））とともに室温で２時間インキュベートした。脳組織をセル・ハーベスター（Ｂｒａｎｄｅｌ社、ＬＬ−１２）にてグラスファイバー濾紙（Ｗｈａｔｍａｎ，ＧＦ／Ｂ）に吸引濾過し、ｂｕｆｆｅｒで３ｍｌ、２回洗浄した。グラスファイバー濾紙をバイアルに入れ、シンチレーター（Ａｍｅｒｓｈａｍ，ＡＣＳＩＩ）を３．５ｍｌ加えて１０時間放置した後、液体シンチレーションカウンターにて受容体に結合した3Ｈ−ｌｉｇａｎｄの量を測定した。なお、ｂｌａｎｋの測定には（＋）−ｐｅｎｔａｚｏｃｉｎｅ（１０μＭ）を使用した。
各被験薬濃度における3Ｈ−ｌｉｇａｎｄの受容体に対する結合率を、被験薬無添加の時を１００％、ｂｌａｎｋ物質の時を０％としてグラフを作成し、結合率が５０％になる被験薬濃度を求めてＩＣ50値とした。これよりＫｉ値を次式より求めた。
【０２０３】
抗精神病活性をマウスを使用してｍｅｔｈａｍｐｈｅｔａｍｉｎｅ誘発運動亢進により調べた。実験には５週齢のｄｄｙ系雄性マウス（日本ｓｌｃ）を１群１０匹使用した。被験薬（すべて１０ｍｇ／ｋｇ）腹腔内投与後直ちに測定用ｐｈｏｔｏｃｅｌｌケージにマウスを入れ、３０分間運動量を測定した（これを被験薬の自発運動に与える作用とした）。その後一度ケージから出し、ｍｅｔｈａｍｐｈｅｔａｍｉｎｅ １．５ｍｇ／ｋｇを皮下投与して、元のケージに戻し３０分間運動量を測定した。ｍｅｔｈａｍｐｈｅｔａｍｉｎｅの運動亢進抑制％は次式より算出した。
抑制％＝１００−［｛（被験薬投与群−正常群）／（コントロール群−正常 群）｝×１００］
被験薬投与群 ：サンプル＋ｍｅｔｈａｍｐｈｅｔａｍｉｎｅ
コントロール群：ベヒクル＋ｍｅｔｈａｍｐｈｅｔａｍｉｎｅ
正 常 群 ：ベヒクル＋ｓａｌｉｎｅ
結果を（表−５）に示す。
【０２０４】
【０２０５】
【発明の効果】
本発明により、従来問題であった錐体外路系症状の副作用を誘発することのない、抗精神病薬を提供することが期待できる。また、本発明化合物には虚血性脳疾患治療薬の効果も期待される。[0001]
[Industrial application fields]
The present invention relates to a novel pyrrolidinone derivative and an antipsychotic agent and an ischemic brain disease therapeutic agent containing the derivative.
[0002]
[Prior art]
Schizophrenia occurs at a high rate of 1 in 130 and occurs frequently in adolescence. If left unattended, the personality will be dismantled progressively, and the human-like self-development function will be completely destroyed, which is a big social problem. Abnormalities in dopamine transmission in the brain have been pointed out as the cause of this disease. Supporting this theory is that dopamine antagonists such as chlorpromazine and haloperidol are effective as antipsychotics. However, dopamine antagonists are also known to cause high rates of extrapyramidal side effects such as acute dystonia and parkinsonism, or late-onset dyskinesia, which is a major problem.
On the other hand, in recent years, an approach from a different aspect from the conventional mechanism of action of drugs has been attempted. One example is a sigma receptor agonist. Since SKF-10047, a sigma receptor agonist, has been shown to induce psychotic-like effects on humans, this sigma receptor antagonist is an anti-pyramidal side effect that is not associated with antipyramidal side effects. Expected to be a psychotic drug. Rimcazole is known as this type of drug, but the affinity and specificity for sigma receptors are still insufficient.
For pharmaceutical use, the compound represented by Formula I is described in JP-A No. 51-95079 and reported to have analgesic properties and antifungal properties.
[0003]
[Chemical Formula 10]
As other pharmaceutical applications, the compound represented by Formula II has been clinically studied as an anti-dementia agent, and as representative literature, Butler et al., Journal of Medicinal Chemistry, 27 684-691 (1984).
[0004]
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[0005]
Embedded image
Is reported to have antipsychotic, anti-anxiety, anti-emetic, cognitive enhancement, and anti-dementia activities. 4,668,687, No. 3,717,634, the same No. No. 4,423,049, the same No. 4; 4,524,206.
Compound represented by Formula IV
[0006]
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Show a weak anti-inflammatory effect simultaneously with analgesic properties, Malawska et al., “Synthesis and pharmacological properties of 2-pyrrolidinone Mannich base”, Polish Journal of Pharmacology, 34 373-382 (1982). Mattson et al., US Pat. 4,826,843 shows that compounds of formula V have cognitive and memory enhancing activity.
[0007]
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In addition, compounds of formula VI as monoamine oxidase-B inhibitors are described by Silverman et al. (Journal of Medicinal Chemistry, 36 3606-3610 (1993)).
[0008]
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[0009]
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However, there is no description that any of the above compounds has a high affinity for the sigma receptor and exhibits an antipsychotic action.
[0010]
[Problems to be solved by the invention]
The object of the present invention is to provide a compound having an antipsychotic action without causing extrapyramidal side effects.
[0011]
[Means for Solving the Problems]
In order to solve these problems, the present inventors diligently studied a compound having a pyrrolidinone skeleton, and as a result, found a novel pyrrolidinone derivative having a specific and high affinity for a sigma receptor and completed the present invention.
That is, the present invention provides the following general formula (1a) or (1b)
[0012]
Embedded image
[0013]
Embedded image
[0014]
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[0015]
Preferably, in the formula (1a) or (1b), R is a linear alkyl group having 1 to 12 carbon atoms, a branched alkyl group having 3 to 12 carbon atoms, an alkyl group having a cyclic structure having 3 to 12 carbon atoms, a substituted or Unsubstituted phenyl group (substituents are halogen atom, hydroxyl group, carbamoyl group, amino group, nitro group, cyano group, lower alkyl group, cycloalkyl group, lower alkoxy group, lower alkylamino group, lower aminoalkyl group, lower alkylthio group) 1 to 3 groups selected from the group consisting of a group, a lower acyl group, a lower acylamino group, a lower alkylenedioxy group, a lower perfluoroalkyl group, a lower perfluoroalkyloxy group, and a phenyl group), substituted or unsubstituted Substituted phenylalkyl groups (halogen atoms, hydroxyl groups, carbamoyl groups, amino groups, B, cyano group, lower alkyl group, cycloalkyl group, lower alkoxy group, lower alkylamino group, lower aminoalkyl group, lower alkylthio group, lower acyl group, lower acylamino group, lower alkylenedioxy group, lower perfluoroalkyl 1 to 3 groups selected from the group consisting of a group, a lower perfluoroalkyloxy group, and a phenyl group), a hydrogenated condensed polycyclic hydrocarbon group having 9 to 15 carbon atoms, a pyrrolidinone derivative having n of 1 or Its salt.
More preferably, the following general formula (4)
[0016]
Embedded image
[0017]
Embedded image
[0018]
Embedded image
Is a pyrrolidinone derivative represented by
Or the following general formula (7)
[0019]
Embedded image
[0020]
Embedded image
[0021]
Embedded image
Or a salt thereof.
[0022]
Hereinafter, the present invention will be described in detail. In the present invention, the straight-chain alkyl group having 1 to 12 carbon atoms of R is a methyl group, an ethyl group, an n-propyl group, an n-butyl group, an n-pentyl group, an n-hexyl group, an n-octyl group, n-dodecyl and the like. The branched alkyl group having 3 to 12 carbon atoms is isopropyl group, isobutyl group, t-butyl group, isopentyl group, neopentyl group, isohexyl group, 3-methylpentyl group, 1-methylhexyl group, 1-ethylpentyl group, 2,3-dimethylbutyl group, 1,5-dimethylhexyl group, 2-ethylhexyl group, 1-methylheptyl group, t-octyl group and the like.
The alkyl group having a cyclic structure having 3 to 12 carbon atoms includes a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a 2-methylcyclohexyl group, a 3-methylcyclohexyl group, a 4-methylcyclohexyl group, A cyclooctyl group, a 1-adamantyl group, a 2-adamantyl group, a cyclododecyl group, a cyclopropylmethyl group, and the like.
The hydrogenated condensed polycyclic hydrocarbon group having 9 to 15 carbon atoms is 1- (1,2,3,4-tetrahydronaphthyl) group, 5-indanyl group, 4- (1,2-cyclopenta-1′3 ′). -Dienocyclooctenyl) group, 7-acenaphthenyl group and the like. A phenylalkyl group is a benzyl group, a phenethyl group, or the like.
[0023]
The substituent of the substituted phenyl group of R will be described in detail. The halogen atom is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. Examples of the lower alkyl group include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-pentyl group, and an isopentyl group.
The cycloalkyl group represents, for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group or the like. Examples of the lower alkoxy group include a methoxy group, an ethoxy group, a propoxy group, a 2-methylethoxy group, a butoxy group, a 2-methylpropoxy group, a pentoxy group, a 2-methylbutoxy group, and a 2-ethylpropoxy group. The lower alkylamino group represents, for example, an N-methylamino group, an N, N-dimethylamino group, an N, N-diethylamino group, an N-methyl-N-ethylamino group, an N, N-diisopropylamino group or the like.
[0024]
The lower aminoalkyl group represents, for example, an aminomethyl group, 1-aminoethyl group, 2-aminopropyl group, 2-aminobutyl group and the like. Examples of the lower alkylthio group include a methylthio group, an ethylthio group, a propylthio group, a 2-methylethylthio group, and a butylthio group.
Examples of the lower acyl group include an acetyl group, a propanoyl group, and a butanoyl group. Examples of the lower acylamino group include an acetylamino group, a propanoylamino group, and a butanoylamino group. Examples of the lower alkylenedioxy group include a methylenedioxy group and an ethylenedioxy group.
Examples of the lower perfluoroalkyl group include a trifluoromethyl group and a pentafluoroethyl group. Examples of the lower perfluoroalkyloxy group include a trifluoromethoxy group and a pentafluoroethoxy group.
[0025]
The substituent of the substituted phenylalkyl group of R is the same as the substituent of the phenyl group.
[0026]
Examples of the linear alkyl group having 1 to 8 carbon atoms of Z include a methyl group, an ethyl group, an n-propyl group, an n-butyl group, an n-pentyl group, an n-hexyl group, and an n-octyl group. The branched alkyl group having 3 to 8 carbon atoms is isopropyl group, isobutyl group, t-butyl group, isopentyl group, neopentyl group, isohexyl group, 3-methylpentyl group, 1-methylhexyl group, 1-ethylpentyl group, 2,3-dimethylbutyl group, 1,5-dimethylhexyl group, 2-ethylhexyl group, 1-methylheptyl group, t-octyl group and the like.
The alkyl group having a cyclic structure having 3 to 8 carbon atoms is cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, 2-methylcyclohexyl group, 3-methylcyclohexyl group, 4-methylcyclohexyl group, A cyclooctyl group, a cyclopropylmethyl group, and the like. The unsaturated alkyl group having 2 to 8 carbon atoms is vinyl group, 1-propenyl group, allyl group, isopropenyl group, 1-propynyl group, propargyl group, 3-butenyl group, 4-pentenyl group, and 5-hexenyl group. 2,5-hexadienyl group and the like. Examples of the phenylalkyl group include a benzyl group and a phenethyl group.
The hydrogenated condensed polycyclic hydrocarbon group having 9 to 15 carbon atoms is 1- (1,2,3,4-tetrahydronaphthyl) group, 5-indanyl group, 4- (1,2-cyclopenta-1′3 ′). -Dienocyclooctenyl) group, 7-acenaphthenyl group and the like. Examples of the 5-membered ring heterocyclic group containing one hetero atom include a 2-pyrrolyl group, a 2-furyl group, a 2-thienyl group, a 3-thienyl group, a 2-tetrahydrofuryl group, and the like.
The substituent of the substituted phenyl group of Z will be described in detail. The halogen atom is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. Examples of the lower alkyl group include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-pentyl group, and an isopentyl group.
[0027]
The cycloalkyl group represents, for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group or the like. Examples of the lower alkoxy group include a methoxy group, an ethoxy group, a propoxy group, a 2-methylethoxy group, a butoxy group, a 2-methylpropoxy group, a pentoxy group, a 2-methylbutoxy group, and a 2-ethylpropoxy group. The lower alkylamino group represents, for example, an N-methylamino group, an N, N-dimethylamino group, an N, N-diethylamino group, an N-methyl-N-ethylamino group, an N, N-diisopropylamino group or the like.
The lower aminoalkyl group represents, for example, an aminomethyl group, 1-aminoethyl group, 2-aminopropyl group, 2-aminobutyl group and the like. Examples of the lower alkylthio group include a methylthio group, an ethylthio group, a propylthio group, a 2-methylethylthio group, and a butylthio group.
Examples of the lower acyl group include an acetyl group, a propanoyl group, and a butanoyl group. Examples of the lower acylamino group include an acetylamino group, a propanoylamino group, and a butanoylamino group. Examples of the lower alkylenedioxy group include a methylenedioxy group and an ethylenedioxy group.
Examples of the lower perfluoroalkyl group include a trifluoromethyl group and a pentafluoroethyl group. Examples of the lower perfluoroalkyloxy group include a trifluoromethoxy group and a pentafluoroethoxy group.
The substituent of the substituted phenylalkyl group of Z is the same as the substituent of the substituted phenyl group. The hydrogenated condensed polycyclic hydrocarbon group having 9 to 15 carbon atoms of W is 1- (1,2,3,4-tetrahydronaphthyl) group, 5-indanyl group, 4- (1,2-cyclopenta-1 ′ 3'-dienocyclooctenyl) group, 7-acenaphthenyl group and the like.
[0028]
The substituent of the substituted phenyl group of W will be described in detail. The halogen atom is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. Examples of the lower alkyl group include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-pentyl group, and an isopentyl group. The cycloalkyl group represents, for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group or the like.
Examples of the lower alkoxy group include a methoxy group, an ethoxy group, a propoxy group, a 2-methylethoxy group, a butoxy group, a 2-methylpropoxy group, a pentoxy group, a 2-methylbutoxy group, and a 2-ethylpropoxy group. The lower alkylamino group represents, for example, an N-methylamino group, an N, N-dimethylamino group, an N, N-diethylamino group, an N-methyl-N-ethylamino group, an N, N-diisopropylamino group or the like.
The lower aminoalkyl group represents, for example, an aminomethyl group, 1-aminoethyl group, 2-aminopropyl group, 2-aminobutyl group and the like. Examples of the lower alkylthio group include a methylthio group, an ethylthio group, a propylthio group, a 2-methylethylthio group, and a butylthio group. Examples of the lower acyl group include an acetyl group, a propanoyl group, and a butanoyl group. Examples of the lower acylamino group include an acetylamino group, a propanoylamino group, and a butanoylamino group.
[0029]
Examples of the lower alkylenedioxy group include a methylenedioxy group and an ethylenedioxy group. Examples of the lower perfluoroalkyl group include a trifluoromethyl group and a pentafluoroethyl group. Examples of the lower perfluoroalkyloxy group include a trifluoromethoxy group and a pentafluoroethoxy group.
The compound of the present invention can be produced, for example, by the method shown in the following reaction formula-1.
Reaction Formula-1
[0030]
Embedded image
Compound (11) is obtained by reducing compound (10) in an inert solvent. The reaction temperature is -75 to 200 ° C., preferably 0 to 100 ° C., for 1 to 20 hours, preferably 5 to 15 hours. Examples of the inert solvent used include aromatic hydrocarbons such as benzene and toluene, ethers such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, and diethylene glycol dimethyl ether, dichloromethane, chloroform, and 1,2-dichloroethane. And halogenated hydrocarbons such as methanol, alcohols such as methanol and ethanol, and mixtures thereof. Examples of the reaction reagent for reduction include aluminum hydride, lithium aluminum hydride, a combination of lithium aluminum hydride and aluminum chloride, sodium borohydride, a combination of sodium borohydride and calcium chloride, sodium borohydride and aluminum chloride. Combinations can be used.
[0031]
Compound (11) is converted to the corresponding halomethyl compound by thionyl or phosphorus halide, or to the corresponding tosyl or mesyl ester by tosyl or mesyl halide. This reaction is preferably carried out using an inert organic solvent such as chloroform, dichloromethane, tetrahydrofuran or dimethylformamide between room temperature and the boiling point of the solvent used. The halomethyl compound or tosyl or mesyl ester produced as an intermediate may be isolated or further reacted as it is.
[0032]
When these products are reacted with an amine represented by HX, the corresponding target compound of the general formula (13) is obtained. This reaction can be carried out in tetrahydrofuran, dioxane, acetonitrile, dimethoxyethane or dimethylformamide. The reaction temperature is 50-150 ° C., and individual conditions vary depending on the basicity and boiling point of the amine. Examples of the base used include, for example, inorganic bases such as potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, sodium amide, sodium hydride, triethylamine, tripropylamine, pyridine, 1,8 Organic bases such as diazabicyclo [5.4.0] undec-7-ene (DBU) can be used. In the above reaction, an alkali metal iodide compound such as potassium iodide or sodium iodide can be added as a reaction accelerator if necessary. The ratio of the compound represented by HX and the compound represented by the general formula (12) in the above reaction is not particularly limited, but the latter is usually equimolar to excess, preferably equimolar to 5 times the former. What is necessary is just mol.
Here, the compound represented by the general formula (10) is synthesized, for example, as follows.
Reaction formula-2
[0033]
Embedded image
[0034]
Embedded image
Pyrrolidinone 3-substituted (15) is R-NH 2 It is produced by dehydration condensation of an amine derivative represented by the formula and γ-butyrolactone. This reaction is carried out in the absence of a solvent at 50 to 250 ° C., preferably 150 to 300 ° C. for 5 hours to 20 hours, preferably 10 to 15 hours. At this time, if necessary, an acid catalyst such as hydrochloric acid may be added.
Compound (15) is obtained by introducing alkoxycarbonyl group of the obtained compound (14) in an inert solvent in the presence of a base. The reaction temperature is 30 to 200 ° C., preferably 70 to 150 ° C., for 3 to 20 hours, preferably 5 to 15 hours. Examples of the inert solvent used include aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as tetrahydrofuran, dioxane, butyl ether and 1,2-dimethoxyethane, alcohols such as methanol, ethanol and propanol, and dimethyl. And formamide. Examples of the reaction reagent for introducing an alkoxycarbonyl group include esters such as dimethyl carbonate, diethyl carbonate, ethyl phosphonoformate, ethyl oxalate, and ethyl cyanoformate. Examples of the base include inorganic bases such as potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, potassium t-butoxide, sodium methoxide, sodium ethoxide, sodium amide, sodium hydride, triethylamine, An organic base such as propylamine, pyridine, 1,8-diazabicyclo [5.4.0] undec-7-eneundecene-7 (DBU) can be used.
[0035]
Pyrrolidinone 4-position substitute (17) is R-NH 2 It is produced by dehydrating condensation of an amine derivative represented by the formula and itaconic acid. This reaction is carried out without a solvent, at a temperature of 50 to 250 ° C., preferably 150 to 200 ° C., for 5 to 20 hours, preferably 10 to 15 hours. At this time, if necessary, an acid catalyst such as hydrochloric acid may be added. The obtained compound (16) is refluxed in the presence of a catalyst such as sulfuric acid in an alcohol solvent such as methanol or ethanol to obtain the compound (17).
[0036]
The compound of the general formula (13) of the present invention can easily form a salt with a normal pharmacologically acceptable acid. Examples of the acid include inorganic acids such as sulfuric acid, nitric acid, hydrochloric acid, phosphoric acid and hydrobromic acid, acetic acid, tartaric acid, fumaric acid, maleic acid, citric acid, benzoic acid, trifluoroacetic acid, methanesulfonic acid, and ethanesulfonic acid. And organic acids such as p-toluenesulfonic acid. These salts can also be used as the active ingredient compound of the present invention in the same manner as the free compound of the general formula (13).
The derivative of the present invention represented by the above general formula has one or more asymmetric carbons. Thus, the derivatives can exist in different stereoisomeric forms or in the form of a mixture of stereoisomeric forms including racemic forms. Thus, the present invention includes various forms as defined above, and these can also be used as active ingredient compounds.
[0037]
The target compound shown in each of the above reaction formulas can be further produced by being separated from the reaction system by ordinary separation means. As the separation and purification means, for example, distillation method, recrystallization method, column chromatography, ion exchange chromatography, gel chromatography, affinity chromatography, preparative thin layer chromatography, solvent extraction method and the like can be used.
The compounds of the present invention are specifically listed in (Table-1) [Table 1-Table 63] and (Table-2) [Table 64-Table 126]. The present invention is not limited to these examples.
[0038]
[Table 1]
[Table 2]
[Table 3]
[Table 4]
[Table 5]
[Table 6]
[Table 7]
[Table 8]
[Table 9]
[Table 10]
[Table 11]
[Table 12]
[Table 13]
[Table 14]
[Table 15]
[Table 16]
[Table 17]
[Table 18]
[Table 19]
[Table 20]
[Table 21]
[Table 22]
[Table 23]
[Table 24]
[Table 25]
[Table 26]
[Table 27]
[Table 28]
[Table 29]
[Table 30]
[Table 31]
[Table 32]
[Table 33]
[Table 34]
[Table 35]
[Table 36]
[Table 37]
[Table 38]
[Table 39]
[Table 40]
[Table 41]
[Table 42]
[Table 43]
[Table 44]
[Table 45]
[Table 46]
[Table 47]
[Table 48]
[Table 49]
[Table 50]
[Table 51]
[Table 52]
[Table 53]
[Table 54]
[Table 55]
[Table 56]
[Table 57]
[Table 58]
[Table 59]
[Table 60]
[Table 61]
[Table 62]
[Table 63]
[Table 64]
[Table 65]
[Table 66]
[Table 67]
[Table 68]
[Table 69]
[Table 70]
[Table 71]
[Table 72]
[Table 73]
[Table 74]
[Table 75]
[Table 76]
[Table 77]
[Table 78]
[Table 79]
[Table 80]
[Table 81]
[Table 82]
[Table 83]
[Table 84]
[Table 85]
[Table 86]
[Table 87]
[Table 88]
[Table 89]
[Table 90]
[Table 91]
[Table 92]
[Table 93]
[Table 94]
[Table 95]
[Table 96]
[Table 97]
[Table 98]
[Table 99]
[Table 100]
[Table 101]
[Table 102]
[Table 103]
[Table 104]
[Table 105]
[Table 106]
[Table 107]
[Table 108]
[Table 109]
[Table 110]
[Table 111]
[Table 112]
[Table 113]
[Table 114]
[Table 115]
[Table 116]
[Table 117]
[Table 118]
[Table 119]
[Table 120]
[Table 121]
[Table 122]
[Table 123]
[Table 124]
[Table 125]
[Table 126]
The active ingredient compounds thus obtained are effective as sigma receptor agonists, and these are used in the form of general pharmaceutical preparations. The preparation is prepared using diluents or excipients such as fillers, extenders, binders, moisturizers, disintegrants, surfactants, lubricants and the like that are usually used. Various forms of this pharmaceutical preparation can be selected according to the purpose of treatment. Representative examples thereof include tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, injections ( Liquid, suspension, etc.).
[0164]
In molding into a tablet form, various carriers well known in the art can be widely used as carriers. Examples thereof include excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, water, ethanol, propanol, simple syrup, glucose solution, starch solution, Gelatin solution, binder such as carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone, dry starch, sodium alginate, agar powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearin Disintegrants such as acid monoglycerides, starch and lactose, disintegration inhibitors such as sucrose, stearic acid, cocoa butter, hydrogenated oil, quaternary ammonium base, absorption accelerators such as sodium lauryl sulfate, glycerin, den Humectants such emissions, starch, lactose, kaolin, bentonite, adsorbent such as colloidal silicic acid, talc, stearic acid salts, boric acid powder, a lubricant such as a polyethylene glycol may be used. Further, the tablets can be made into tablets with ordinary coatings as necessary, for example, sugar-coated tablets, gelatin-encapsulated tablets, enteric-coated tablets, film-coated tablets, bilayer tablets, and multilayer tablets.
[0165]
In molding into a pill form, a wide variety of carriers conventionally known in this field can be used. Examples thereof include excipients such as glucose, lactose, starch, cacao butter, hydrogenated vegetable oil, kaolin and talc, binders such as gum arabic powder, tragacanth powder and gelatin, and disintegrants such as carmellose calcium and agar. Can be used.
[0166]
In molding into a suppository form, conventionally known carriers can be widely used. Examples thereof include polyethylene glycol, cocoa butter, higher alcohols, higher alcohol esters, gelatin, semi-synthetic glycerides and the like.
Capsules are usually prepared by mixing the active ingredient compound with the various carriers exemplified above and filling them into hard gelatin capsules, soft capsules and the like according to conventional methods.
When prepared as injections, solutions, emulsions and suspensions are preferably sterilized and isotonic with blood, and when formed into these forms, those commonly used in this field as diluents, For example, water, ethanol, macrogol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters and the like can be used. In this case, a sufficient amount of sodium chloride, glucose or glycerin may be contained in the pharmaceutical preparation to prepare an isotonic solution, and usual solubilizing agents, buffers, soothing agents, etc. are added. May be.
Furthermore, a coloring agent, a preservative, a fragrance | flavor, a flavoring agent, a sweetening agent, etc. and other pharmaceuticals can also be contained in a pharmaceutical formulation as needed.
[0167]
The amount of the active ingredient compound to be contained in these pharmaceutical preparations of the present invention is not particularly limited and is appropriately selected from a wide range, but is usually about 1 to 70% by weight in the preparation composition, preferably about It is good to set it as 5 to 50 weight%.
[0168]
The administration method of these pharmaceutical preparations of the present invention is not particularly limited, and it is administered by a method according to various preparation forms, patient age, sex and other conditions, and the degree of disease. For example, in the case of tablets, pills, solutions, suspensions, emulsions, granules and capsules, they are administered orally. In the case of an injection, it is administered intravenously alone or mixed with a normal fluid such as glucose and amino acids, and further administered alone intramuscularly, subcutaneously or intraperitoneally as necessary. In the case of a suppository, it is administered intrarectally.
[0169]
The dosage of these pharmaceutical preparations of the present invention is appropriately selected depending on the usage, patient age, sex and other conditions, and the degree of the disease. Usually, the amount of the active ingredient compound is about 0.0001 to 1 kg per body weight per day. It should be about 50 mg. In addition, it is desirable that the active ingredient compound is contained in a dosage unit form in a range of about 0.001 to 1000 mg.
[0170]
【Example】
Examples of the present invention will be described in detail below with reference to compound production examples, pharmaceutical preparation examples, and test examples. In addition, this invention is not limited only to a following example.
[0171]
Example 1
[1-1] Itaconic acid 17.1 g (131 mmol) and cyclohexylamine 15.0 ml (131 mmol) were mixed and reacted at 140 ° C. for 1 hour. After cooling, the solid was washed with acetone to obtain 19.6 g of 1-cyclohexyl-2-oxo-4-pyrrolidinecarboxylic acid (1-1).
[0172]
[1-2] 14.5 g (68.5 mmol) of Compound 1-1 was suspended in 200 ml of ethanol, 0.5 ml of concentrated sulfuric acid was added, and the mixture was refluxed for 4 hours. The solvent was distilled off, the residue was dissolved in ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, dried over magnesium sulfate, the solvent was distilled off, and ethyl 1-cyclohexyl-2-oxo-4-pyrrolidinecarboxylate (1-2 ) 14.1 g was obtained.
[0173]
[1-3] 6.1 g (25.4 mmol) of compound (1-2) was dissolved in 100 ml of THF, 1.0 g (25.4 mmol) of sodium borohydride was added, and 3 ml of methanol was added over 6 hours under reflux. Was added dropwise in 100 ml of THF. Water was added to stop the reaction, and the mixture was extracted with ethyl acetate, dried and evaporated to obtain 3.5 g of 1-cyclohexyl-4-hydroxymethyl-2-pyrrolidinone (1-3).
[0174]
[1-4] 3.0 g (15.2 mmol) of compound (1-3) was dissolved in 50 ml of dichloromethane, 7.7 ml of methanesulfonyl chloride and 8.5 ml of pyridine were added under ice cooling, and the mixture was reacted at room temperature for 2 hours. . Saturated aqueous sodium hydrogen carbonate was added and the mixture was stirred for 5 hours. The organic layer was separated and dried, the solvent was distilled off, and the residue was purified by silica gel column chromatography (chloroform / methanol = 40/1) to give 1-cyclohexyl-2-oxo- 4.2 g of 4-pyrrolidin-4-yl-methyl mesylate (1-4) was obtained.
[0175]
[1-5] Compound (1-4) 1.4 g (5.1 mmol) was dissolved in acetonitrile 40 ml, and 4- (4-chlorophenyl) -4-hydroxypiperidine 1.0 g (4.8 mmol), potassium carbonate. 0 g and 0.1 g of potassium iodide were added and refluxed for 10 hours. The insoluble material was filtered off, the solvent was distilled off, and the residue was purified by silica gel column chromatography (chloroform / methanol = 30/1) to give 4- [4- (4-chlorophenyl) -4-hydroxypiperidinomethyl] -1- 1.9 g of cyclohexyl-2-pyrrolidinone (1-5) was obtained. 2.1g of hydrochloride was obtained for the compound (1-5) using hydrochloric acid / dioxane in methanol.
mp 280-281 ° C
1 H-NMR (CDCl Three , Δ ppm) (free form); 1.11 (1H, m), 1.37 (4H, m), 1.69 (6H, m), 2.2-2.8 (12H, m), 3. 13 (1H, m), 3.44 (1H, m), 3.95 (1H, m), 7.29 (4H, m)
[0176]
Example 2
[2-1] 37.6 g of N-bromosuccinimide was suspended in 100 ml of chloroform, 25.0 g of 1,3-benzodioxole was added, and the mixture was refluxed for 3 hours. After cooling to room temperature, it was washed with water, aqueous sodium carbonate and water, dried and concentrated, and the residue was distilled under reduced pressure to obtain 39.6 g of 5-bromo-1,3-benzodioxole (2-1).
[0177]
[2-2] 1.35 g of magnesium fine pieces were mixed with 20 ml of THF (2-1) 5 ml of a solution of 11.0 g of 50 ml of THF was added and heated. Since the reaction proceeded, the remaining solution was added dropwise over 10 minutes and then refluxed for 1 hour to obtain a Grignard reagent. After this solution was cooled to room temperature, a THF solution of 9.5 g of 1-benzyl-4-piperidone was added dropwise over 45 minutes. After stirring for 1 hour, the mixture was reacted at 50 ° C. for another hour. After concentration, the residue is mixed well with ammonium chloride solution, extracted with ethyl acetate, washed with water, dried, concentrated, crystallized by adding IPA to the residue, filtered, washed with IPA, and washed with 1-benzyl-4-hydroxy. 8.0 g of -4- (3,4-methylenedioxyphenyl) -piperidine (2-2) was obtained.
[0178]
[2-3] 8.0 g of (2-2) was dissolved in 80 ml of methanol and 6.1 ml of 4N hydrochloric acid, followed by hydrogenation reaction at room temperature and pressure in the presence of 10% Pd / C. Filtration, concentration of the filtrate, crystallization with addition of ether, filtration, washing with ether and 5.6 g of 4-hydroxy-4- (3,4-methylenedioxyphenyl) -piperidine hydrochloride (2-3 )
[0179]
[2-4] The same operation as in Step [1-1, 1-2, 1-3] of Example 1 except that 16.1 g (0.1 mol) of m-aminobenzotrifluoride is used instead of cyclohexylamine. And 6.0 g of 1- (3-trifluoromethyl) -4-hydroxymethyl-2-pyrrolidinone (2-4) was obtained. Using 4.0 g (15.4 mmol) of compound (2-4) and 2.75 g (10.7 mmol) of 4-hydroxy-4- (3,4-methylenedioxyphenyl) -piperidine hydrochloride, Example 1 4- [4-Hydroxy-4- (3,4-methylenedioxyphenyl) piperidin-1-ylmethyl] -1- (3-trifluoromethylphenyl) in the same manner as in Step [1-4, 1-5] 3.9 g of 2-pyrrolidinone hydrochloride was obtained.
mp202.5 ° C (decomposition)
1 H-NMR (CDCl Three , Δ ppm) (free form); 1.55-1.8 (3H, m), 2.0-2.2 (2H, m), 2.4-2.6 (5H, m), 2.7 -2.9 (4H, m), 3.7-4.05 (2H, m), 5.95 (2H, s), 6.75-7.05 (3H, m), 7.4-8 .0 (4H, m)
[0180]
Example 3
1- (4-Methoxyphenyl) -4- (mesyloxymethyl) -2 in the same manner as in Step [1-1, 1-2, 1-3, 1-4] of Example 1 using p-anisidine. -Pyrrolidinone (3-1) was synthesized, and 3.25 g (10.9 mmol) of this compound (3-1) and 2.5 g of 4- (4-chlorophenyl) -1,2,3,6-tetrahydropyridine hydrochloride (10.9 mmol) was treated in the same manner as in step [1-5] of Example 1 to give 4- [4- (4-chlorophenyl) -1,2,3,6-tetrahydropyridin-1-ylmethyl]- 1.0 g of 1- (4-methoxyphenyl) -2-pyrrolidinone hydrochloride was obtained.
[0181]
mp214-216 ° C
1 H-NMR (CDCl Three , Δ ppm) (free form); 2.35-2.85 (9H, m), 3.1-3.2 (2H, m), 3.38 (3H, s), 3.65-4.0 (2H, m), 6.07 (1H, s), 6.85-6.95 (2H, m), 7.25-7.6 (6H, m)
[0182]
Example 4
[4-1] 30.1 g (0.323 mol) of aniline and 30.6 g (0.355 ml) of γ-butyrolactone were mixed, 7 ml of hydrochloric acid was added, and the mixture was refluxed for 4 hours. Furthermore, it reacted for 3 hours at bath temperature 190-200 degreeC. After cooling, 50 ml of 2N hydrochloric acid was added to sludge, filtered, washed with water and dried. Recrystallization from hexane / ethyl acetate (6/4) gave 17.2 g of 1-phenyl-2-pyrrolidinone (4-1).
[0183]
[4-2] 22.1 g (0.553 mol) of sodium hydride (60% oil) was mixed with 200 ml of toluene, 61.5 g (0.521 mol) of diethyl carbonate was added, and then compound (4-1) was added under reflux. ) 200 ml of a toluene solution containing 25.0 g (0.155 mol) was added dropwise over 2.5 hours. After refluxing for 5.5 hours, the mixture is cooled, discharged into ice water, acidified with dilute hydrochloric acid, the organic layer is separated, extracted twice from the aqueous layer with toluene, dried together with the previous organic layer, concentrated, and then hexane- Ether was added and washed, and then dried under reduced pressure to obtain 10.5 g of ethyl 2-oxo-1-phenyl-3-pyrrolidinecarboxylate (4-2).
[0184]
[4-3] Compound (4-2) 10.3 g (44.5 mmol) was dissolved in 100 ml of methanol, and 14.95 g (44.6 mmol) of anhydrous calcium chloride was added and dissolved. Next, 2.06 g (54.4 mmol) of sodium borohydride was charged in portions and stirred for 45 minutes under ice cooling. Ice water (20 ml) and ethyl acetate (20 ml) were added to separate the organic layer. The aqueous layer was extracted with ethyl acetate, toluene and ether, dried together with the previous organic layer, concentrated, and column chromatography (silica gel, chloroform / methanol = 20/1) to obtain 3.8 g of 3-hydroxymethyl-1-phenyl-2-pyrrolidinone (4-3).
[0185]
[4-4] 2.1 g (11.0 mmol) of the compound (4-3) was dissolved in 25 ml of dichloromethane, 1.1 g (10.9 ml) of triethylamine, and then 1.2 g (10.5 ml) of methanesulfonyl chloride were added dropwise. The mixture was stirred for 30 minutes under ice cooling and reacted at room temperature for 2.5 hours. Triethylamine 0.3 g (3.0 mmol) and methanesulfonyl chloride 0.4 g (3.5 mmol) were added dropwise and reacted for another 4 hours. Washing with water, drying and concentration gave a mesyl body. Mesyl derivative, 2.1 g of 4-hydroxy-4- (3,4-methylenedioxyphenyl) piperidine hydrochloride obtained in step (2-3) of Example 2 and 2.7 g of potassium carbonate in 35 ml of acetonitotolyl After refluxing for 8 hours, the insoluble material was filtered off, concentrated, and purified by silica gel chromatography (chloroform / methanol = 40/1) to give 3- [4-hydroxy-4- (3,4-methylenedioxyphenyl). Piperidin-1-ylmethyl] -1-phenyl-2-pyrrolidinone 650 mg was obtained. 500 mg of the free compound was dissolved in methanol, acidified with hydrochloric acid / dioxane, concentrated, and the precipitated crystals were collected by filtration and washed with ether to give 3- [4-hydroxy-4- (3,4-methylenedioxyphenyl) piperidine-1- 460 mgg of ylmethyl] -1-phenyl-2-pyrrolidinone hydrochloride was obtained.
mp 211-213 ° C
1 H-NMR (CDCl Three , Δ ppm) (free form); 1.71-1.78 (2H, m), 2.02-2.17 (3H, m), 2.34-3.04 (8H, m), 3.83 (2H, m), 5.952 (2H, s), 6.77-7.18 (4H, m), 7.37 (2H, m), 7.64 (2H, m)
[0186]
Example 5
[5-1] 2.43 g of magnesium was mixed with 100 ml of THF, 16.3 g of 2-bromothiophene was added dropwise, and refluxed for 1 hour to prepare a Grignard reagent. After cooling to room temperature, 17.1 g of 1-ethoxycarbonyl-4-piperidone was added dropwise and stirred under reflux for 1 hour. The mixture was poured into ice water containing ammonium chloride and extracted with ethyl acetate. At this time, an insoluble material is precipitated, but this is also a target product. When the extract was concentrated, crystals were obtained. It was mixed with the previous precipitate, recrystallized from methanol, and washed with ethyl acetate to obtain 4-hydroxy-4- (2-thienyl) -1-piperidinecarboxylate (5-1).
[0187]
[5-2] 12.8 g of (5-1) was dissolved in 120 ml of IPA, 5.0 g of potassium hydroxide was added, and the mixture was stirred for 6 hours under reflux. An additional 5.0 g of potassium hydroxide was added and refluxed for 6 hours. After cooling, insoluble matters were collected by filtration, and the filtrate was concentrated. The residue and the insoluble matter were combined and poured into water, and extracted with chloroform. After washing with water and concentration by drying, ether was added to crystallize and collect by filtration to obtain 6.9 g of 4- (2-thienyl) -4-piperidinol (5-2).
[0188]
[5-3] 4- (4-Hydroxy-4- (2- Thienyl) piperidin-1-ylmethyl) -1- (3 trifluoromethylphenyl) -2-pyrrolidinone hydrochloride was obtained.
mp193 (decomposition)
1 H-NMR (CDCl Three , Δ ppm) (free form) 1.9-2.1 (3H, m) 2.1-2.25 (2H, m) 2.4-2.85 (9H, m) 3.65-3.75 (1H, m) 3.9-4.0 (1H, m) 6.95-7.05 (2H, m) 7.2-7.3 (1H, m) 7.4-7.55 (2H , 2H, m)
[0189]
Examples 6 to 47
The compounds were prepared in the same manner as in Examples 1 to 5 and identified by the melting point (mp) and MNR of each compound. The results are shown in (Table-3) [Table 127-Table 135].
[0190]
[Table 127]
[Table 128]
[Table 129]
[Table 130]
[Table 131]
[Table 132]
[Table 133]
[Table 134]
[Table 135]
Formulation Example 1
4- [4- (4-Chlorophenyl) -4-hydroxypiperidinomethyl] -1-cyclo
Hexyl-2-pyrrolidinone hydrochloride 130 g
Citric acid 1 g
Lactose 35 g
Dicalcium phosphate 72 g
Pluronic F-68 30 g
Sodium lauryl sulfate 20 g
Polyvinylpyrrolidone 14 g
Polyethylene glycol (Carbowax 1500) 5 g
Polyethylene glycol (Carbowax 6000) 45 g
Cornstarch 33 g
Dry sodium stearate 3 g
3 g dried magnesium stearate
Ethanol appropriate amount
The active ingredient compound of the present invention, citric acid, lactose, dicalcium phosphate, pluronic F-68 and sodium lauryl sulfate are mixed.
The above mixture is referred to as “No. Sieve through 60 screens and wet granulate with alcoholic solution containing polyvinylpyrrolidone, Carbowax 1500 and 6000. Alcohol is added as necessary to make the powder into a pasty mass. Add corn starch and continue mixing until uniform particles are formed. The mixture was No. Pass through 10 screens, put in a tray and dry in oven at 100 ° C. for 12-15 hours. The dried particles were No. Sift through 16 screens, add dry sodium lauryl sulfate and dry magnesium stearate, mix and compress to desired shape on tablet press.
[0200]
Treat the resulting uncoated tablets with varnish, spray talc and prevent moisture absorption. An undercoat layer is coated around the uncoated tablet. Apply varnish a sufficient number of times for internal use. Further subbing layers and smooth coatings are applied to make the tablet completely round and smooth. Color coating is performed until the desired coating is obtained. After drying, the coated tablet is polished to a uniform gloss tablet.
[0201]
Formulation Example 2
4- [4- (4-Chlorophenyl) -4-hydroxypiperidinomethyl] -1-cyclohexyl-2-pipe
Lydinone hydrochloride 5 g
Polyethylene glycol (molecular weight: 4000) 0.3g
Sodium chloride 1.0g
Polyoxyethylene-sorbitan monooleate 0.5g
Sodium metabisulfite 0.1g
Methyl-paraben 0.2g
Distilled water for injection 10.0 ml The above methyl-paraben, sodium metabisulfite and sodium chloride are dissolved in approximately half of the above distilled water at 80 ° C. with stirring. The resulting solution is cooled to 40 ° C., and the active ingredient compound of the present invention, and then polyethylene glycol and polyoxyethylene sorbitan monooleate are dissolved in the above solution. Next, distilled water for injection is added to the solution to prepare a final volume, and the solution is sterilized by sterile filtration using an appropriate filter paper to prepare an injection.
[0202]
Pharmacological test example 1
Vinner et al. (BJ Vilner and WD Bowen, in Multiple Sigma and PCP Receptor Ligands: Mechanisms for Neuromodulation-Neuroprotection? 1 A radioreceptor assay for the receptor was performed. Homogenate (10 mg / ml) of rat whole brain excluding cerebellum and medulla Three H-ligand (5nM Three Incubated with H-(+) pentazocine (NEN) for 2 hours at room temperature. The brain tissue was suction filtered through a cell harvester (Brandel, LL-12) onto glass fiber filter paper (Whatman, GF / B) and washed twice with buffer at 3 ml. Glass fiber filter paper was put into a vial, 3.5 ml of scintillator (Amersham, ACSII) was added and left for 10 hours, and then bound to the receptor with a liquid scintillation counter. Three The amount of H-ligand was measured. In addition, (+)-pentazocine (10 micromol) was used for the measurement of blank.
At each test drug concentration Three The H-ligand receptor binding rate is 100% when no test drug is added and 0% when the blank substance is added. The concentration of the test drug at which the binding rate is 50% is determined by IC. 50 Value. From this, the Ki value was determined from the following equation.
[0203]
Antipsychotic activity was examined by methamphetamine-induced hyperactivity using mice. In the experiment, 10 ddy male mice (Japan slc) aged 5 weeks were used. Immediately after intraperitoneal administration of the test drug (all 10 mg / kg), the mouse was placed in the photocell cage for measurement, and the amount of exercise was measured for 30 minutes (this was considered to be an effect on the spontaneous movement of the test drug). Thereafter, the drug was once removed from the cage, and 1.5 mg / kg of methamphetamine was subcutaneously administered, returned to the original cage, and the momentum was measured for 30 minutes. The percent inhibition of exercise enhancement of methamphetamine was calculated from the following equation.
% Inhibition = 100 − [{(test drug administration group−normal group) / (control group−normal group)} × 100]
Study drug administration group: Sample + methamphetamine
Control group: vehicle + methamphetamine
Normal group: vehicle + salene
The results are shown in (Table-5).
[0204]
[0205]
【The invention's effect】
The present invention can be expected to provide an antipsychotic drug that does not induce the side effects of extrapyramidal symptoms, which has been a problem in the past. In addition, the compound of the present invention is also expected to have an effect as a therapeutic agent for ischemic brain disease.
Claims (7)
Ｒは、置換されていないか、又はメトキシ基、トリフルオロメチル基、ハロゲン原子、ベンジルオキシ基、アミノ基、ニトロ基もしくはエチル基により置換されているフェニル基であり；
ｎは１の整数であり；そして
Ｘは、下記一般式（２）：
Ｚは、フェニル基（このフェニル基は、ハロゲン原子、メチレンジオキシ基、トリフルオロメチル基又はメトキシ基により置換されている）又はチエニル基を表す〕を表し；あるいは
Ｘは、下記一般式（３）：
で表されるピロリジノン誘導体、あるいはその塩。The following general formula (1a) or (1b):
R is a phenyl group which is unsubstituted or substituted by a methoxy group, trifluoromethyl group, halogen atom, benzyloxy group, amino group, nitro group or ethyl group;
n is an integer of 1; and X is the following general formula (2):
The pyrrolidinone derivative represented by these, or its salt.
Ｒは、置換されていないか、又はハロゲン原子、アミノ基、ニトロ基、エチル基、メトキシ基、トリフルオロメチル基及びベンジルオキシ基からなる群より選ばれた１〜３個の置換基により置換されたフェニル基を表し；そして
Ｘは、下記一般式（５）：
Ｘは、下記一般式（６）：
で表される、請求項２記載のピロリジノン誘導体、あるいはその塩。The following general formula (4):
R is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a halogen atom, amino group, nitro group, ethyl group, methoxy group, trifluoromethyl group and benzyloxy group. And X represents the following general formula (5):
The pyrrolidinone derivative of Claim 2 represented by these, or its salt.
Ｒは、置換されていないか、又はハロゲン原子、アミノ基、ニトロ基、エチル基、メトキシ基、トリフルオロメチル基及びベンジルオキシ基からなる群より選ばれた１〜３個の置換基により置換されているフェニル基を表し；そして
Ｘは、下記一般式（８）：
Ｘは、下記一般式（９）：
により表される、請求項２に記載のピロリジノン誘導体、あるいはその塩。The following general formula (7):
R is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a halogen atom, amino group, nitro group, ethyl group, methoxy group, trifluoromethyl group and benzyloxy group. And X represents the following general formula (8):
The pyrrolidinone derivative of Claim 2 represented by these, or its salt.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP932895A JP3786985B2 (en) | 1994-01-27 | 1995-01-24 | Pyrrolidinone derivative |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP738394 | 1994-01-27 | ||
| JP6-7383 | 1994-01-27 | ||
| JP932895A JP3786985B2 (en) | 1994-01-27 | 1995-01-24 | Pyrrolidinone derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH07252220A JPH07252220A (en) | 1995-10-03 |
| JP3786985B2 true JP3786985B2 (en) | 2006-06-21 |
Family
ID=26341667
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP932895A Expired - Fee Related JP3786985B2 (en) | 1994-01-27 | 1995-01-24 | Pyrrolidinone derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP3786985B2 (en) |
-
1995
- 1995-01-24 JP JP932895A patent/JP3786985B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| JPH07252220A (en) | 1995-10-03 |
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