JP4261639B2 - Phenylimidazole antihyperlipidemic drug - Google Patents
Phenylimidazole antihyperlipidemic drug Download PDFInfo
- Publication number
- JP4261639B2 JP4261639B2 JP22215898A JP22215898A JP4261639B2 JP 4261639 B2 JP4261639 B2 JP 4261639B2 JP 22215898 A JP22215898 A JP 22215898A JP 22215898 A JP22215898 A JP 22215898A JP 4261639 B2 JP4261639 B2 JP 4261639B2
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- Japan
- Prior art keywords
- group
- hydrogen atom
- independently
- optionally substituted
- alkyl group
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
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- 239000003524 antilipemic agent Substances 0.000 title claims description 7
- SEULWJSKCVACTH-UHFFFAOYSA-N 1-phenylimidazole Chemical compound C1=NC=CN1C1=CC=CC=C1 SEULWJSKCVACTH-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 33
- -1 phenylimidazole compound Chemical class 0.000 claims description 32
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 17
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 11
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 8
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 8
- 125000005843 halogen group Chemical group 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- 125000001624 naphthyl group Chemical group 0.000 claims description 5
- 239000004480 active ingredient Substances 0.000 claims description 4
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 claims description 4
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 claims description 4
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 3
- 125000003320 C2-C6 alkenyloxy group Chemical group 0.000 claims description 3
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 3
- 125000005133 alkynyloxy group Chemical group 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- 229910052717 sulfur Inorganic materials 0.000 claims description 3
- 125000003342 alkenyl group Chemical group 0.000 claims 1
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- 239000003814 drug Substances 0.000 description 11
- 238000006243 chemical reaction Methods 0.000 description 10
- 125000001424 substituent group Chemical group 0.000 description 10
- 229940079593 drug Drugs 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
- 238000004519 manufacturing process Methods 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 7
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 7
- 239000000243 solution 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
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 210000004369 blood Anatomy 0.000 description 6
- 239000008280 blood Substances 0.000 description 6
- 235000012000 cholesterol Nutrition 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 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
- 238000000034 method Methods 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 6
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 5
- 210000002966 serum Anatomy 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 5
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 208000031226 Hyperlipidaemia Diseases 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 150000002170 ethers Chemical class 0.000 description 4
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 4
- 208000010125 myocardial infarction Diseases 0.000 description 4
- 239000008107 starch Substances 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 206010003210 Arteriosclerosis Diseases 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 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 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 230000001315 anti-hyperlipaemic effect Effects 0.000 description 3
- 208000011775 arteriosclerosis disease Diseases 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 239000011737 fluorine Substances 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 150000002632 lipids Chemical class 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 239000000829 suppository Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 125000004738 (C1-C6) alkyl sulfinyl group Chemical group 0.000 description 2
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 description 2
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 description 2
- 125000004737 (C1-C6) haloalkoxy group Chemical group 0.000 description 2
- 125000006002 1,1-difluoroethyl group Chemical group 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 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 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
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- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000004698 Polyethylene Substances 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- TUZYXOIXSAXUGO-UHFFFAOYSA-N Pravastatin Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(O)C=C21 TUZYXOIXSAXUGO-UHFFFAOYSA-N 0.000 description 2
- ZTHYODDOHIVTJV-UHFFFAOYSA-N Propyl gallate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 description 2
- RYMZZMVNJRMUDD-UHFFFAOYSA-N SJ000286063 Natural products C12C(OC(=O)C(C)(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 RYMZZMVNJRMUDD-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 229930006000 Sucrose Natural products 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
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 125000004442 acylamino group Chemical group 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
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- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
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- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
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- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
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- GKQLYSROISKDLL-UHFFFAOYSA-N EEDQ Chemical compound C1=CC=C2N(C(=O)OCC)C(OCC)C=CC2=C1 GKQLYSROISKDLL-UHFFFAOYSA-N 0.000 description 1
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- 229930195725 Mannitol Natural products 0.000 description 1
- 241000699673 Mesocricetus auratus Species 0.000 description 1
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- 238000005481 NMR spectroscopy Methods 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 206010058667 Oral toxicity Diseases 0.000 description 1
- 235000019482 Palm oil Nutrition 0.000 description 1
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- 206010070863 Toxicity to various agents Diseases 0.000 description 1
- 230000003187 abdominal effect Effects 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
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- 239000002253 acid Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
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- 239000003963 antioxidant agent Substances 0.000 description 1
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- 239000001506 calcium phosphate Substances 0.000 description 1
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- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 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 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 231100000517 death Toxicity 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
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- QKIUAMUSENSFQQ-UHFFFAOYSA-N dimethylazanide Chemical compound C[N-]C QKIUAMUSENSFQQ-UHFFFAOYSA-N 0.000 description 1
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- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- 125000006125 ethylsulfonyl group Chemical group 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 125000005290 ethynyloxy group Chemical group C(#C)O* 0.000 description 1
- 238000005562 fading Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 230000002140 halogenating effect Effects 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
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- 230000002401 inhibitory effect Effects 0.000 description 1
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- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
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- 238000005259 measurement Methods 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
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- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000004570 mortar (masonry) Substances 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 231100000957 no side effect Toxicity 0.000 description 1
- 231100000418 oral toxicity Toxicity 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
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- 239000006179 pH buffering agent Substances 0.000 description 1
- 239000002540 palm oil Substances 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
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- 150000004841 phenylimidazoles Chemical class 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- 229920002523 polyethylene Glycol 1000 Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
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- 239000002244 precipitate Substances 0.000 description 1
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- 229940075579 propyl gallate Drugs 0.000 description 1
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- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 229940035044 sorbitan monolaurate Drugs 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
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- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical group C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 description 1
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- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
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Description
【０００１】
【発明の属する技術分野】
本発明は、フェニルイミダゾール化合物を有効成分として含有する抗高脂血症薬に関する。
【０００２】
【従来の技術】
心筋梗塞等の重篤な心疾患は、アテローム性動脈硬化症の主要因子である高脂血症によって誘発される。心筋梗塞の予防のためには高脂血症の治療が重要であり、優れた活性と安全性を有する抗高脂血症薬の開発が求められている。
【０００３】
かかる抗高脂血症薬の代表的な薬剤として、プラバスタチン（Ｐｒａｖａｓｔａｔｉｎ），シンバスタチン（Ｓｉｍｖａｓｔａｔｉｎ），クロフィブレート系薬剤等が知られている。これらプラバスタチンやシンバスタチン等は、血中トリグリセライド及びコレステロールを低下させる薬剤であり、すでに、臨床の場で用いられている。
【０００４】
しかしながら、これらの薬剤は、血中トリグリセライドとコレステロールを同程度に強く低下させるものではない。従って、動脈硬化を原因とする虚血性心疾患，心筋梗塞，脳梗塞等の疾患の治療ならびに予防の見地から、血中トリグリセライドとコレステロールを同程度に強く低下させる薬剤の開発が特に注目されているが、いまだこれらを満足させる薬剤はない。
【０００５】
本発明に係わる化合物に類似の化合物としては、例えば、次のものが知られている。
（１）特開昭５５−６９５６７号公報には、下記の化合物（Ａ）
【０００６】
【化３】
が、抗うつ剤として記載されている。
（２）特開平２−１９７８３９号公報には、下記の化合物（Ｂ）
【０００８】
【化４】
が、有機着色物質の光褪色防止剤として記載されている。
（３）ＥＰ４５８０３７号公報には、下記の化合物（Ｃ）
【００１０】
【化５】
が、血小板活性化因子阻害剤として記載されている。
（４）ＥＰ３２４３７７号公報には、下記の化合物（Ｄ）
【００１２】
【化６】
が、降圧剤として記載されている。
（５）本発明者らによるＷＯ９５／２９１６３号公報には、化合物（Ｅ）
【００１４】
【化７】
が、コレステロール生合成阻害活性を有することが記載されている。
【００１６】
【発明が解決しようとする課題】
本発明は、優れた抗高脂血症作用、動脈硬化症の治療及び予防効果を有し、かつ、安全で副作用のない抗高脂血症薬を提供することを目的とする。
【００１７】
【課題を解決するための手段】
本発明者らは、上記課題を解決すべく鋭意研究を重ねた結果、従来の薬剤に比べて、血中トリグリセライドとコレステロールを同程度に強く低下させる化合物を見出し、本発明を完成するに至った。
【００１８】
すなわち、本発明は、一般式（１）
【００１９】
【化８】
［式中、Ｒ1 は、水素原子またはＣ1-6 アルキル基を表す。
Ｘは、Ｃ（＝Ｏ）またはＳＯ2 を表す。
Ａ，Ｂは、それぞれ、次の基
【００２１】
【化９】
（ここで、Ｒ2 ，Ｒ3 ，Ｒ6 及びＲ7 は、それぞれ独立して、水素原子，シアノ基，ヒドロキシ基，ハロゲン原子，Ｃ1-6 アルキル基，Ｃ1-6 アルコキシ基，Ｃ2-6 アルケニル基，Ｃ2-6 アルキニル基，Ｃ2-6 アルケニルオキシ基，Ｃ2-6 アルキニルオキシ基又はＣ3-6 シクロアルキル基を表し、Ｒ4 ，Ｒ5 は、それぞれ独立して、水素原子，Ｃ1-6 アルキル基またはＣ1-6 ハロアルキル基を表し、ｐは、０又は１−６の整数，ｑは、０又は１，ｒは、０又は１−６の整数を表す。）を表す。
【００２３】
Ｙは、Ｏ，Ｓ，ＳＯ，ＳＯ2 ，ＮＲ8 ，Ｃ（＝Ｏ）、ＮＲ10Ｃ（＝Ｏ）またはＣ（＝Ｏ）ＮＲ9 （ここで、Ｒ8 ，Ｒ9 及びＲ10は、それぞれ独立して、水素原子又はＣ1-6 アルキル基を表す。）を表す。
ｌは、０または１を表す。
Ｄは、置換基を有していてもよいフェニル基，置換基を有していてもよいナフチル基，置換基を有していてもよいテトラヒドロナフチル基又は置換基を有していてもよいインダニル基を表す。
Ｒ11は、ハロゲン原子，Ｃ1-6 アルキル基，Ｃ1-6 アルコキシ基又はＣ1-6 ハロアルキル基を表す。
ｍは、０または１−３の整数を表す。また、ｍが２以上のとき、Ｒ11は、同一でも相異なっていてもよい。］
で表されるフェニルイミダゾール化合物又はその薬学的に許容される塩の１種若しくはもしくは２種以上を有効成分として含有することを特徴とする、抗高脂血症薬である。
【００２４】
前記一般式（Ｉ）において、
Ｒ1 は、水素原子、又は、
メチル，エチル，プロピル，イソプロピル，ブチル，イソブチル，ｓ−ブチル，ｔ−ブチル等のＣ1-6 アルキル基を表す。
【００２５】
Ｘは、Ｃ（＝Ｏ）又はＳＯ2 を表す。
Ａ，Ｂは、それぞれ次式で示される基、
【００２６】
【化１０】
を表す。ここで、Ｒ2 ，Ｒ3 ，Ｒ6 ，Ｒ7 は、それぞれ独立して、水素原子、シアノ基、ヒドロキシ基、
塩素，フッ素，臭素，沃素等のハロゲン原子、
メチル，エチル，プロピル，イソプロピル，ブチル，イソブチル，ｓ−ブチル，ｔ−ブチル等のＣ1-6 アルキル基、
メトキシ，エトキシ，プロポキシ，イソプロポキシ，ブトキシ等のＣ1-6 アルコキシ基、
エテニル，１−プロペニル，１−メチルビニル，アリル，１−メチルアリル，２−ブテニル等のＣ2-6 アルケニルル基、
エチニル，１−プロピニル，２−プロピニル等のＣ2-6 アルキニル基、
エテニルオキシ，１−プロペニルオキシ，１−メチルビニルオキシ，アリルオキシ，１−メチルアリルオキシ，２−ブテニルオキシ等のＣ2-6 アルケニルオキシ基、
エチニルオキシ，１−プロピニルオキシ，２−プロピニルオキシ等のＣ2-6 アルキニルオキシ基、及び、
シクロプロピル，シクロブチル，シクロペンチル，シクロヘキシル等のＣ3-6 シクロアルキル基を表す。
【００２８】
Ｒ4 ，Ｒ5 は、それぞれ独立して、水素原子、
メチル、エチル、プロピル、イソプロピル、ブチル、ｓ−ブチル、ｔ−ブチル等のＣ1-6 アルキル基、
クロロメチル、ジクロロメチル、トリクロロメチル、トリフルオロメチル、トリフルオロエチル、１，１−ジフルオロエチル、ペンタフルオロエチル等のＣ1-6 ハロアルキル基を表す。
Ｙは、Ｏ，Ｓ，ＳＯ，ＳＯ2 ，ＮＲ8 ，Ｃ（＝Ｏ）、ＮＲ10Ｃ（＝Ｏ）またはＣ（＝Ｏ）ＮＲ9 を表す。
【００２９】
ここで、Ｒ8 ，Ｒ9 及びＲ10は、それぞれ独立して、水素原子、又はメチル，エチル，プロピル，イソプロピル，ブチル，イソブチル，ｓ−ブチル，ｔ−ブチル等のＣ1-6 アルキル基を表す。
【００３０】
Ｄは、ベンゼン環の任意の位置に置換基を有していてもよいフェニル基、ナフタレン環の任意の位置に置換基を有していてもよい、１−ナフチル、２−ナフチル等のナフチル基、テトラヒドロナフタレン環の任意の位置に置換基を有していてもよいテトラヒドロナフチル基又は置換基を有していてもよいインダニル基を表す。
【００３１】
前記置換基としては、ヒドロキシ基，カルボキシ基，ニトロ基，メルカプト基，ハロゲン原子，Ｃ1-6 アルキル基，Ｃ1-6 アルコキシ基，Ｃ1-6 ハロアルキル基，Ｃ1-6 ハロアルコキシ基，Ｃ1-6 アルキルチオ基，Ｃ1-6 アルキルスルフィニル基，Ｃ1-6 アルキルスルホニル基，アミノ基，Ｃ1-6 アシルアミノ基，アミド基，ジＣ1-6 アルキルアミド基，Ｃ1-6 アルコキシカルボニル基または置換されてもよいフェニル基等を例示することができる。
【００３２】
ここで、ハロゲン原子としては、塩素，フッ素，臭素，沃素等が挙げられ、Ｃ1-6 アルキル基としては、メチル，エチル，プロピル，イソプロピル，ブチル，イソブチル，ｓ−ブチル，ｔ−ブチル等が、Ｃ1-6 アルコキシ基としては、メトキシ，エトキシ，プロポキシ，イソプロポキシ，ブトキシ等が、Ｃ1-6 ハロアルキル基としては、クロロメチル，ジクロロメチル，トリクロロメチル，トリフルオロメチル，１−フルオロエチル，１，１−ジフルオロエチル，ペンタフルオロエチル等を挙げることができる。
【００３３】
Ｃ1-6 ハロアルコキシ基としては、クロロメトキシ，ジクロロメトキシ，トリクロロメトキシ，トリフルオロメトキシ，１−フルオロエトキシ，１，１−ジフルオロエトキシ，ペンタフルオロエトキシ等が、Ｃ1-6 アルキルチオ基としては、メチルチオ，エチルチオ，プロピルチオ．イソプロピルチオ，ブチルチオ，ｔ−ブチルチオ等が、Ｃ1-6 アルキルスルフィニル基としては、メチルスルフィニル，エチルスルフィニル，プロピルスルフィニル，イソプロピルスルフィニル，ブチルスルフィニル，ｔ−ブチルスルフィニル等が、Ｃ1-6 アルキルスルホニル基としては、メチルスルホニル，エチルスルホニル，プロピルスルホニル，イソプロピルスルホニル，ブチルスルホニル，ｔ−ブチルスルホニル等を挙げることができる。
【００３４】
また、Ｃ1-6 アシルアミノ基としては、アセチルアミノ，プロピオニルアミノ，ブチリルアミノ，ピバロイルアミノ等が、ジＣ1-6 アルキルアミド基としては、ジメチルアミド，ジエチルアミノ，ジプロピルアミノ，エチルイソプロピルアミノ，ジブチルアミノ，ジｔ−ブチルアミノ等が、Ｃ1-6 アルコキシカルボニル基としては、メトキシカルボニル，エトキシカルボニル，プロポキシカルボニル，ブトキシカルボニル等を挙げることができる。
【００３５】
これらフェニル基、ナフチル基、テトラヒドロナフチル基及びインダニル基は、同一又は相異なる複数の置換基を有していてもよい。
【００３６】
Ｒ11は、フッ素、塩素、臭素等のハロゲン原子，
メチル、エチル、プロピル、イソプロピル、ブチル等のＣ1-6 アルキル基，
メトキシ、エトキシ、プロポキシ、イソプロポキシ、ブトキシ等のＣ1-6 アルコキシ基、又は、
クロロメトキシ，ジクロロメトキシ，トリクロロメトキシ，トリフルオロメトキシ，１−フルオロエトキシ，１，１−ジフルオロエトキシ，ペンタフルオロエトキシトリフルオロメチル等のＣ1-6 ハロアルキル基を表す。
【００３７】
また、薬学的に許容される塩としては、一般式（１）で表される化合物の塩酸，硫酸，硝酸，燐酸等の無機酸の塩や、酢酸，プロピオン酸，乳酸，コハク酸，酒石酸，クエン酸，安息香酸，サリチル酸，ニコチン酸，ヘプタグルコン酸等の有機酸の塩を挙げることができる。
【００３８】
【発明の実施の形態】
前記一般式（１）で表される化合物の主な製造法を以下に説明する。
【００３９】
（製造法１）Ｘ＝Ｃ（＝Ｏ）の場合
【００４０】
【化１１】
（式中、Ａ，Ｂ，Ｄ，Ｒ1 ，Ｙ，ｌ，Ｒ11及びｍは、前記と同じ意味を表す。）
【００４２】
即ち、一般式（２）で示されるアミンと一般式（３）で示されるカルボン酸とを、常法により脱水縮合して、一般式（Ｉ−１）で示されるアミド誘導体を得る方法である。
【００４３】
この脱水縮合は、通常行われる方法により、好ましくは、縮合剤を用いる方法により行うことができる。
【００４４】
反応に用いることのできる縮合剤としては、特に限定はないが、例えば、１，３−ジシクロヘキシルカルボジイミド，１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド，２−エトキシ−１−エトキシカルボニル−１，２−ジヒドロキノリン等を挙げることができる。
【００４５】
また、この反応において、Ｎ−ヒドロキシコハク酸イミド，１−ヒドロキシベンゾトリアゾール，３，４−ジヒドロ−３−ヒドロキシ−４−オキソ−１，２，３−ベンゾトリアジンを共存させると、反応がより速やかに進行する。
【００４６】
反応溶媒としては、反応に不活性な溶媒であれば、特に限定はないが、例えば、ジエチルエーテル，テトラヒドロフラン（ＴＨＦ），１．４−ジオキサン等のエーテル類、ベンゼン，トルエン，キシレン等の芳香族炭化水素類、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、アセトニトリル，ジメチルホルムアミド（ＤＭＦ），ジメチルスルホキシド（ＤＭＳＯ），ピリジン等を用いることができる。反応温度は、−１５℃〜溶媒の沸点程度、好ましくは、０〜８０℃である。
（製造法２）
【００４７】
【化１２】
（式中、Ａ’，Ｂ’及びＤ’は、ヒドロキシ基及びアミノ基ではないＡ，Ｂ及びＤをそれぞれ表し、Ｒ1 ，Ｘ，Ｙ，ｌ，Ｒ11及びｍは、前記と同じ意味を表す。）
【００４９】
一般式（Ｉ−２）で表される化合物は、一般式（４）で表される化合物を塩化チオニル，五塩化リン等のハロゲン化剤を用いて、酸クロリドまたはスルホニルクロリド（５）に変換した後、このものを、不活性有機溶媒中、塩基存在下に、一般式（２）で表されるアミンと反応させることによって得ることができる。
【００５０】
この反応に用いることのできる溶媒としては、反応に不活性な溶媒であれば、特に限定はないが、例えば、ジエチルエーテル，ＴＨＦ，１．４−ジオキサン等のエーテル類、ベンゼン，トルエン，キシレン等の芳香族炭化水素類、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、アセトニトリル，ＤＭＦ，ＤＭＳＯ，ピリジン等を挙げることができる。
【００５１】
塩基としては、例えば、トリエチルアミン，ピリジン，１，８−ジアザビシクロ［５．４．０］ウンデセ−７−エン（ＤＢＵ）等のアミン類、炭酸水素ナトリウム，炭酸ナトリウム，炭酸カリウム，水酸化ナトリウム等の無機塩基類等を挙げることができる。反応温度は、−１５℃〜溶媒の沸点程度、好ましくは、０〜８０℃である。
【００５２】
一般式（３）及び一般式（４）で示される化合物は、文献記載の既知の方法、例えば、Ｉｎｄｉａｎ．Ｊ．Ｃｈｅｍ．，２６Ｂ，６１６−６１９（１９８７）等に記載される方法によって製造することができる。
【００５３】
本発明において、反応終了後は、通常の後処理を行うことにより目的物を得ることができる。
本発明化合物の構造は、ＩＲ，ＮＭＲ及びＭＳ等から決定した。
【００５４】
（抗高脂血症薬）
本発明化合物は、抗高脂血症薬として有用であり、その投与方法は、一般式（１）の化合物又はその薬学的に許容されている塩の純粋な形、あるいは類似の有用性を有する薬剤の投与様式として許容されている任意の様式で行うことができる。
【００５５】
例えば、経口，経鼻，非経口，局所，経皮または経直腸的に、固体，半固体，凍結乾燥粉末または液体の剤形、例えば、錠剤，坐薬，丸薬，軟質及び硬質カプセル，散薬，液剤，懸濁剤，エアゾル剤等として、好ましくは正確な投与量を処方でき、かつ、簡便に投与することができる適当な剤形として行うことができる。
【００５６】
一般的に、意図された投与様式に応じて、医薬として許容される組成物は、一般式（１）の化合物若しくはその医薬的に許容される塩の１種または２種以上を、１〜９９重量％、好ましくは５〜７５重量％含有し、残部は適当な医薬用賦形剤９９〜１重量％を含有する。
【００５７】
また、該組成物には、慣用の医薬用担体または賦形剤及び単独の又は活性成分の１種としての式（１）の化合物を含有させるが、さらに他の薬剤，製剤用成分，担体，アジュバント等を包含させることもできる。
【００５８】
好ましい投与経路は経口であり、処置される高脂血症の程度に応じて調整される簡便な１日投与量基準が用いられる。このような経口投与用の組成物は、一般式（１）の化合物もしくはその薬学的に許容される塩の１種または２種以上、及び任意の通常用いられる、例えば、医薬用のマニトール，乳糖，デンプン，ゼラチン化デンプン，ステアリン酸マグネシウム，サッカリンナトリウム，タルク，セルロースエーテル誘導体，グルコース，ゼラチン，スクロース，クエン酸塩，没食子酸プロピル等の賦形剤を加えて形成される。
【００５９】
このような組成物は、液剤，懸濁剤，錠剤，丸剤，カプセル剤，散剤，持続放出製剤，坐剤等の形態で使用される。
【００６０】
また、このような組成物の場合は、例えば、乳糖，スクロース，リン酸二カルシウム等の希釈剤、例えば、クロスカルメロースナトリウムまたはその誘導体等の崩壊剤、例えば、ステアリン酸マグネシウム等の滑沢剤、例えば、デンプン，アラビアゴム，ポリビニルピロリドン，ゼラチン，セルロースエーテル誘導体等の結合剤を含有させることができる。
【００６１】
坐剤の場合には、体内で徐々に溶解する担体、例えば、ポリオキシエチレングリコールまたはポリエチレングリコール（ＰＥＧ）、例えば、ＰＥＧ１０００（９６％）もしくはＰＥＧ４０００（４％）に、一般式（１）の化合物またはその薬学的に許容される塩０．５〜５０重量％を分散して製剤化することができる。
【００６２】
医薬として投与できる液体組成物の場合は、一般式（１）の化合物もしくはその薬学的に許容される塩の１種または２種以上を、０．５〜５０重量％、及び任意の医薬アジュバントを、水，食塩水，デキストロース水溶液，グリセロール，エタノール等の担体中に、溶解、分散させる等の処理を行い、溶液または懸濁液の形態とすることによって製造することができる。
【００６３】
本発明の医薬組成物には、所望により、少量の補助物質、例えば、湿潤剤，乳化剤，ｐＨ緩衝剤，抗酸化剤等、例えば、クエン酸，ソルビタンモノラウレート，トリエタノールアミンオレエート，ブチル化ヒドロキシトルエン等を添加することもできる。
【００６４】
このような剤形の実際の製造は、通常の方法、例えば、Ｒｅｍｉｎｇｔｏｎ’ｓ Ｐｈａｒｍａｃｅｕｔｉｃａｌ Ｓｃｉｅｎｃｅｓ，１８版，Ｍａｃｋ Ｐｕｂｌｉｓｈｉｎｇ Ｃｏｍｐａｎｙ，Ｅａｓｔｏｎ，Ｐｅｎｎｓｙｌｖａｎｉａ，１９９０に教示される方法に従って行うことができる。
【００６５】
一般的に、一般式（１）の化合物若しくはその薬学的に許容される塩の１種または２種以上は、個人及び処置される高コレステロール血症によって特徴づけられる病的状態に依存して変動する治療有効量で投与される。
【００６６】
通常、治療有効１日用量は、体重１ｋｇあたり、式（１）の化合物約０．１４ｍｇ〜約１４．３ｍｇ／日であり、好ましくは、体重１ｋｇあたり約０．７ｍｇ〜約１０ｍｇ／日、最も好ましくは、体重１ｋｇあたり約１．４ｍｇ〜約７．２ｍｇ／日である。例えば、体重７０ｋｇのヒトに投与する場合、一般式（１）の化合物またはその薬学的に許容される塩の用量範囲は、１日約１０ｍｇ〜約１．０ｇ、好ましくは、１日約５０ｍｇ〜約７００ｍｇ、より好ましくは、１日約１００ｍｇ〜約５００ｍｇである。
【００６７】
【実施例】
次に、製造例及び実施例を挙げて、本発明をさらに具体的に説明する。
【００６８】
製造例１
３−［３，５−ビス（ｔ−ブチル）−４−ヒドロキシフェニル］−Ｎ−（４−イミダゾール−１−イルフェニル）−２−プロペンアミド（化合物番号１−９９）の製造
【００６９】
【化１３】
３，５−ビス（ｔ−ブチル）−４−ヒドロキシ桂皮酸２．２１ｇ、４−アミノフェニルイミダゾール１．４１ｇ、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド塩酸塩１．７０ｇ、１−ヒドロキシベンゾトリアゾール１．３６ｇ及びトリエチルアミン１．２５ｍｌをＤＭＦ１５ｍｌに加え、室温で２０時間攪拌した。反応液を氷水中に注ぎ、析出物を濾取した。得られた結晶をクロロホルム−メタノールで抽出し、有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した後、溶媒を減圧留去し、残渣を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＝１００：３）で精製して、目的物０．７２ｇを得た。ｍ．ｐ．２７０℃以上。
【００７１】
上記製造例を含め、本発明に係わる化合物の代表例を第１表に示した。
【００７２】
【表１０１】
【表１０２】
【表１０３】
【表１０４】
【表１０５】
【表１０６】
【表１０７】
【表１０８】
表中の化合物の 1Ｈ−ＮＭＲデータを次に示す。
ＮＭＲ−１（ｄ6-ＤＭＳＯ，δｐｐｍ）：7.10(s,1H),7.45-7.8(m,7H),7.95(d,2H),8.05(m,1H),8.10(d,1H),8.2(m,2H)
ＮＭＲ−２（ＣＤＣｌ3,δｐｐｍ）：1.2(t,3H),2.6(q,2H),6.95(s,1H),7.05(s,1H),7.25(d,2H),7.45-7.60(m,3H),7.80(d,2H),7.95(d,2H),8.80(s,1H)
ＮＭＲ−３（ＣＤＣｌ3,δｐｐｍ）：3.55(s,3H),7.15-7.35(m,11H),7.8(s,1H)
【００８１】
次に、本発明化合物の医薬製剤としての製造例を挙げる。
【００８２】
上記組成になるように、前記第１表中の化合物番号１２０の化合物５０ｇ，乳糖４０７ｇ及びコンスターチ１００ｇを流動造粒コーティング装置（大川原製作所（株）製）を使用して均一に混合した。これに、１０％ヒドロキシプロピルセルロース水溶液２００ｇを噴霧して造粒した。乾燥後、２０メッシュの篩を通し、これに、カルボキシメチルセルロースカルシウム２０ｇ，ステアリン酸マグネシウム３ｇを加え、ロータリー打錠機（畑鉄工所（株）製）で７ｍｍ×８．４Ｒの臼杵を使用して、一錠当たり１２０ｍｇの錠剤とした。
【００８４】
次に、本発明化合物が優れた薬理活性を有することを示す。
実施例１ コレステロール負荷ハムスターの血清脂質に及ぼす影響
１％コレステロール及び１０％やし油含有粉末飼料をシリアンハムスター（Ｓｔｄ：Ｓｙｒｉａｎ、雄、４週齢）に３週間自由摂取させた。
【００８５】
次に、０．１％塩酸溶液あるいは１％ポリエチレン硬化ヒマシ油（ＮＩＫＫＯＬ ＨＣＯ−６０）溶液に試験化合物を溶解あるいは懸濁し、最終週に１日１回５日間経口投与した。対照群に対しては、上記溶媒を経口投与した。次いで、最終投与２〜４時間後にペントバルビタール麻酔下腹部大静脈より採血し、血清を分離した。
【００８６】
測定キットを用い、自動生化学測定装置で血清総コレステロール値及び血清トリグリセライド値を測定し、各群の測定値から下式に従い、血清脂質低下率を算出した。
【００８７】
【数１】
【００８８】
【表２０１】
【表２０２】
【表２０３】
実施例２ 反復経口投与毒性
１％ポリエチレン硬化ヒマシ油（ＮＩＫＫＯＬＨＣＯ−６０）溶液に化合物番号１２０の化合物を懸濁し、１群６匹のラット（雄性ＳＤ系）に、１日量１００ｍｇ／ｋｇの割合で７日間経口投与した。その結果、死亡及びその他の毒性症状は、何ら観察されなかった。
【００９２】
【発明の効果】
以上説明したように、本発明に係わる化合物は、血中脂質低下作用を有し、高脂血症，動脈硬化症，心筋梗塞，脳梗塞等の治療薬として有用である。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to an antihyperlipidemic drug containing a phenylimidazole compound as an active ingredient.
[0002]
[Prior art]
Serious heart diseases such as myocardial infarction are induced by hyperlipidemia, which is a major factor in atherosclerosis. Treatment of hyperlipidemia is important for the prevention of myocardial infarction, and the development of antihyperlipidemic drugs having excellent activity and safety is required.
[0003]
As typical antihyperlipidemic drugs, pravastatin, simvastatin, clofibrate, and the like are known. Pravastatin, simvastatin, and the like are drugs that lower blood triglyceride and cholesterol, and are already used in clinical settings.
[0004]
However, these drugs do not reduce blood triglycerides and cholesterol to the same extent. Therefore, from the viewpoint of treatment and prevention of diseases such as ischemic heart disease, myocardial infarction, and cerebral infarction caused by arteriosclerosis, the development of a drug that lowers blood triglyceride and cholesterol to the same extent has attracted particular attention. However, there are still no drugs that satisfy these requirements.
[0005]
As compounds similar to the compounds according to the present invention, for example, the following are known.
(1) JP-A-55-69567 discloses the following compound (A)
[0006]
[Chemical 3]
Is described as an antidepressant.
(2) JP-A-2-197839 discloses the following compound (B)
[0008]
[Formula 4]
Is described as an anti-fading agent for organic coloring substances.
(3) EP 458037 discloses the following compound (C)
[0010]
[Chemical formula 5]
Has been described as a platelet activating factor inhibitor.
(4) In EP324377, the following compound (D)
[0012]
[Chemical 6]
Are described as antihypertensive agents.
(5) WO95 / 29163 by the present inventors discloses compound (E)
[0014]
[Chemical 7]
Are described to have cholesterol biosynthesis inhibitory activity.
[0016]
[Problems to be solved by the invention]
An object of the present invention is to provide an antihyperlipidemic agent which has an excellent antihyperlipidemic action, an effect of treating and preventing arteriosclerosis, and which is safe and has no side effects.
[0017]
[Means for Solving the Problems]
As a result of intensive studies to solve the above problems, the present inventors have found a compound that lowers blood triglyceride and cholesterol to the same extent as compared with conventional drugs, and have completed the present invention. .
[0018]
That is, the present invention relates to the general formula (1)
[0019]
[Chemical 8]
[Wherein, R 1 represents a hydrogen atom or a C 1-6 alkyl group.
X represents C (═O) or SO 2 .
A and B are respectively the following groups:
[Chemical 9]
(Wherein R 2 , R 3 , R 6 and R 7 are each independently a hydrogen atom, cyano group, hydroxy group, halogen atom, C 1-6 alkyl group, C 1-6 alkoxy group, C 2 -6 alkenyl group, C 2-6 alkynyl group, C 2-6 alkenyloxy group, C 2-6 alkynyloxy group or C 3-6 cycloalkyl group, R 4 and R 5 are each independently A hydrogen atom, a C 1-6 alkyl group or a C 1-6 haloalkyl group is represented, p is an integer of 0 or 1-6, q is 0 or 1, and r is an integer of 0 or 1-6. ).
[0023]
Y is O, S, SO, SO 2 , NR 8 , C (═O), NR 10 C (═O) or C (═O) NR 9 (where R 8 , R 9 and R 10 are Each independently represents a hydrogen atom or a C 1-6 alkyl group.
l represents 0 or 1;
D is a phenyl group which may have a substituent, a naphthyl group which may have a substituent, a tetrahydronaphthyl group which may have a substituent or an indanyl which may have a substituent. Represents a group.
R 11 represents a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group or a C 1-6 haloalkyl group.
m represents 0 or an integer of 1-3. When m is 2 or more, R 11 may be the same or different. ]
An antihyperlipidemic agent characterized by containing one or more of the phenylimidazole compounds represented by the formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.
[0024]
In the general formula (I),
R 1 is a hydrogen atom or
C 1-6 alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl and the like are represented.
[0025]
X represents C (═O) or SO 2 .
A and B are groups represented by the following formulae,
[0026]
[Chemical Formula 10]
Represents. Here, R 2 , R 3 , R 6 and R 7 are each independently a hydrogen atom, a cyano group, a hydroxy group,
Halogen atoms such as chlorine, fluorine, bromine and iodine,
C 1-6 alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl,
C 1-6 alkoxy groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy,
C 2-6 alkenyl groups such as ethenyl, 1-propenyl, 1-methylvinyl, allyl, 1-methylallyl, 2-butenyl,
C 2-6 alkynyl groups such as ethynyl, 1-propynyl, 2-propynyl,
C 2-6 alkenyloxy groups such as ethenyloxy, 1-propenyloxy, 1-methylvinyloxy, allyloxy, 1-methylallyloxy, 2-butenyloxy,
C 2-6 alkynyloxy groups such as ethynyloxy, 1-propynyloxy, 2-propynyloxy and the like, and
Represents a C 3-6 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like;
[0028]
R 4 and R 5 are each independently a hydrogen atom,
A C 1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl,
C 1-6 haloalkyl groups such as chloromethyl, dichloromethyl, trichloromethyl, trifluoromethyl, trifluoroethyl, 1,1-difluoroethyl, pentafluoroethyl and the like are represented.
Y represents O, S, SO, SO 2 , NR 8 , C (═O), NR 10 C (═O) or C (═O) NR 9 .
[0029]
Here, R 8 , R 9 and R 10 are each independently a hydrogen atom or a C 1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl or the like. To express.
[0030]
D is a phenyl group which may have a substituent at an arbitrary position of the benzene ring, or a naphthyl group such as 1-naphthyl or 2-naphthyl which may have a substituent at an arbitrary position of the naphthalene ring. Represents a tetrahydronaphthyl group which may have a substituent or an indanyl group which may have a substituent at any position of the tetrahydronaphthalene ring.
[0031]
Examples of the substituent include hydroxy group, carboxy group, nitro group, mercapto group, halogen atom, C 1-6 alkyl group, C 1-6 alkoxy group, C 1-6 haloalkyl group, C 1-6 haloalkoxy group, C 1-6 alkylthio group, C 1-6 alkylsulfinyl group, C 1-6 alkylsulfonyl group, amino group, C 1-6 acylamino group, amide group, di-C 1-6 alkylamide group, C 1-6 alkoxy Examples thereof include a carbonyl group or a phenyl group which may be substituted.
[0032]
Here, examples of the halogen atom include chlorine, fluorine, bromine, iodine and the like, and examples of the C 1-6 alkyl group include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl and the like. C 1-6 alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy and the like, and C 1-6 haloalkyl groups include chloromethyl, dichloromethyl, trichloromethyl, trifluoromethyl, 1-fluoroethyl, Examples thereof include 1,1-difluoroethyl and pentafluoroethyl.
[0033]
As the C 1-6 haloalkoxy group, chloromethoxy, dichloromethoxy, trichloromethoxy, trifluoromethoxy, 1-fluoroethoxy, 1,1-difluoroethoxy, pentafluoroethoxy, etc., as the C 1-6 alkylthio group, Methylthio, ethylthio, propylthio. Isopropylthio, butylthio, t-butylthio and the like are C 1-6 alkylsulfinyl groups, and methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl, butylsulfinyl, t-butylsulfinyl and the like are C 1-6 alkylsulfonyl groups. Examples thereof include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, t-butylsulfonyl and the like.
[0034]
Examples of the C 1-6 acylamino group include acetylamino, propionylamino, butyrylamino, pivaloylamino, and examples of the diC 1-6 alkylamide group include dimethylamide, diethylamino, dipropylamino, ethylisopropylamino, dibutylamino, Examples of the C 1-6 alkoxycarbonyl group for di-t-butylamino and the like include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and the like.
[0035]
These phenyl group, naphthyl group, tetrahydronaphthyl group and indanyl group may have a plurality of the same or different substituents.
[0036]
R 11 is a halogen atom such as fluorine, chlorine or bromine,
C 1-6 alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl,
A C 1-6 alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, or
C 1-6 haloalkyl groups such as chloromethoxy, dichloromethoxy, trichloromethoxy, trifluoromethoxy, 1-fluoroethoxy, 1,1-difluoroethoxy, pentafluoroethoxytrifluoromethyl and the like are represented.
[0037]
Examples of the pharmaceutically acceptable salt include salts of inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid of the compound represented by the general formula (1), acetic acid, propionic acid, lactic acid, succinic acid, tartaric acid, Mention may be made of organic acid salts such as citric acid, benzoic acid, salicylic acid, nicotinic acid and heptagluconic acid.
[0038]
DETAILED DESCRIPTION OF THE INVENTION
The main production methods of the compound represented by the general formula (1) will be described below.
[0039]
(Production Method 1) When X = C (= O)
Embedded image
(In the formula, A, B, D, R 1 , Y, 1, R 11 and m have the same meaning as described above.)
[0042]
That is, it is a method for obtaining an amide derivative represented by the general formula (I-1) by dehydrating and condensing an amine represented by the general formula (2) and a carboxylic acid represented by the general formula (3) by a conventional method. .
[0043]
This dehydration condensation can be carried out by a usual method, preferably by a method using a condensing agent.
[0044]
The condensing agent that can be used in the reaction is not particularly limited. For example, 1,3-dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, 2-ethoxy-1-ethoxycarbonyl- 1,2-dihydroquinoline and the like can be mentioned.
[0045]
In this reaction, when N-hydroxysuccinimide, 1-hydroxybenzotriazole, and 3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine coexist, the reaction becomes faster. Proceed to.
[0046]
The reaction solvent is not particularly limited as long as it is inert to the reaction. For example, ethers such as diethyl ether, tetrahydrofuran (THF), and 1.4-dioxane, and aromatics such as benzene, toluene, and xylene. Hydrocarbons, halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), pyridine and the like can be used. The reaction temperature is −15 ° C. to the boiling point of the solvent, preferably 0 to 80 ° C.
(Production method 2)
[0047]
Embedded image
(In the formula, A ′, B ′ and D ′ respectively represent A, B and D which are not a hydroxy group and an amino group, and R 1 , X, Y, 1, R 11 and m have the same meaning as described above. To express.)
[0049]
The compound represented by general formula (I-2) is converted into acid chloride or sulfonyl chloride (5) using a halogenating agent such as thionyl chloride or phosphorus pentachloride. Then, this can be obtained by reacting with an amine represented by the general formula (2) in the presence of a base in an inert organic solvent.
[0050]
The solvent that can be used in this reaction is not particularly limited as long as it is inert to the reaction. Examples thereof include ethers such as diethyl ether, THF, and 1.4-dioxane, benzene, toluene, xylene, and the like. Aromatic hydrocarbons, halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, DMF, DMSO, pyridine and the like.
[0051]
Examples of the base include amines such as triethylamine, pyridine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), sodium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide and the like. Examples thereof include inorganic bases. The reaction temperature is −15 ° C. to the boiling point of the solvent, preferably 0 to 80 ° C.
[0052]
The compounds represented by the general formula (3) and the general formula (4) can be prepared by known methods described in literatures, for example, Indian. J. et al. Chem. , 26B , 616-619 (1987) and the like.
[0053]
In the present invention, after completion of the reaction, the desired product can be obtained by carrying out usual post-treatment.
The structure of the compound of the present invention was determined from IR, NMR, MS and the like.
[0054]
(Antihyperlipidemic drug)
The compound of the present invention is useful as an antihyperlipidemic agent, and its administration method has a pure form of the compound of the general formula (1) or a pharmaceutically acceptable salt thereof, or similar utility. It can be performed in any manner acceptable as a mode of administration of the drug.
[0055]
For example, oral, nasal, parenteral, topical, transdermal or rectal, solid, semi-solid, lyophilized powder or liquid dosage forms such as tablets, suppositories, pills, soft and hard capsules, powders, solutions , Suspensions, aerosols and the like, preferably in an appropriate dosage form that can be formulated accurately and can be easily administered.
[0056]
In general, depending on the intended mode of administration, the pharmaceutically acceptable composition comprises one or more of the compounds of general formula (1) or pharmaceutically acceptable salts thereof in an amount of 1 to 99. % By weight, preferably 5 to 75% by weight, the balance containing 99 to 1% by weight of a suitable pharmaceutical excipient.
[0057]
The composition also contains a conventional pharmaceutical carrier or excipient and a compound of formula (1), alone or as one of the active ingredients, but also other drugs, pharmaceutical ingredients, carriers, An adjuvant or the like can also be included.
[0058]
The preferred route of administration is oral, and a simple daily dosage standard adjusted according to the degree of hyperlipidemia being treated is used. Such a composition for oral administration comprises one or more compounds of the general formula (1) or pharmaceutically acceptable salts thereof, and any commonly used, for example, pharmaceutical mannitol, lactose , Starch, gelatinized starch, magnesium stearate, sodium saccharin, talc, cellulose ether derivatives, glucose, gelatin, sucrose, citrate, propyl gallate and the like.
[0059]
Such compositions are used in the form of solutions, suspensions, tablets, pills, capsules, powders, sustained release formulations, suppositories, and the like.
[0060]
In the case of such a composition, for example, a diluent such as lactose, sucrose, or dicalcium phosphate, a disintegrant such as croscarmellose sodium or a derivative thereof, and a lubricant such as magnesium stearate, for example. For example, binders such as starch, gum arabic, polyvinyl pyrrolidone, gelatin, cellulose ether derivatives and the like can be contained.
[0061]
In the case of suppositories, a compound of general formula (1) is dissolved in a carrier that dissolves slowly in the body, such as polyoxyethylene glycol or polyethylene glycol (PEG), such as PEG 1000 (96%) or PEG 4000 (4%). Alternatively, it can be formulated by dispersing 0.5 to 50% by weight of a pharmaceutically acceptable salt thereof.
[0062]
In the case of a liquid composition that can be administered as a medicament, 0.5 to 50% by weight of one or more compounds of the general formula (1) or a pharmaceutically acceptable salt thereof, and an optional pharmaceutical adjuvant It can be produced by carrying out treatment such as dissolution and dispersion in a carrier such as water, saline, dextrose aqueous solution, glycerol, ethanol and the like to form a solution or suspension.
[0063]
The pharmaceutical composition of the present invention may optionally contain small amounts of auxiliary substances such as wetting agents, emulsifiers, pH buffering agents, antioxidants, etc. such as citric acid, sorbitan monolaurate, triethanolamine oleate, butyl. Hydroxytoluene or the like can also be added.
[0064]
The actual manufacture of such dosage forms can be performed according to conventional methods, for example, the methods taught in Remington's Pharmaceutical Sciences, 18th edition, Mack Publishing Company, Easton, Pennsylvania, 1990.
[0065]
Generally, one or more of the compounds of general formula (1) or pharmaceutically acceptable salts thereof will vary depending on the individual and the pathological condition characterized by the hypercholesterolemia being treated. Administered in a therapeutically effective amount.
[0066]
Usually, the therapeutically effective daily dose is about 0.14 mg to about 14.3 mg / day of the compound of formula (1) per kg body weight, preferably about 0.7 mg to about 10 mg / day, most preferably Preferably, it is about 1.4 mg / kg to about 7.2 mg / kg body weight. For example, when administered to a human weighing 70 kg, the dose range of the compound of general formula (1) or a pharmaceutically acceptable salt thereof is about 10 mg to about 1.0 g per day, preferably about 50 mg per day About 700 mg, more preferably about 100 mg to about 500 mg per day.
[0067]
【Example】
Next, the present invention will be described more specifically with reference to production examples and examples.
[0068]
Production Example 1
Preparation of 3- [3,5-bis (t-butyl) -4-hydroxyphenyl] -N- (4-imidazol-1-ylphenyl) -2-propenamide (Compound No. 1-99)
Embedded image
3,5-bis (t-butyl) -4-hydroxycinnamic acid 2.21 g, 4-aminophenylimidazole 1.41 g, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride 1.70 g, -1.36 g of hydroxybenzotriazole and 1.25 ml of triethylamine were added to 15 ml of DMF and stirred at room temperature for 20 hours. The reaction solution was poured into ice water, and the precipitate was collected by filtration. The obtained crystals were extracted with chloroform-methanol, the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform: methanol = 100: Purification in 3) gave 0.72 g of the desired product. m. p. 270 ° C or higher.
[0071]
Table 1 shows representative examples of the compounds according to the present invention including the above production examples.
[0072]
[Table 101]
[Table 102]
[Table 103]
[Table 104]
[Table 105]
[Table 106]
[Table 107]
[Table 108]
The 1 H-NMR data of the compounds in the table are shown below.
NMR-1 (d 6 -DMSO, δ ppm): 7.10 (s, 1H), 7.45-7.8 (m, 7H), 7.95 (d, 2H), 8.05 (m, 1H), 8.10 (d, 1H), 8.2 (m, 2H)
NMR-2 (CDCl 3 , δ ppm): 1.2 (t, 3H), 2.6 (q, 2H), 6.95 (s, 1H), 7.05 (s, 1H), 7.25 (d, 2H), 7.45-7.60 (m , 3H), 7.80 (d, 2H), 7.95 (d, 2H), 8.80 (s, 1H)
NMR-3 (CDCl 3 , δ ppm): 3.55 (s, 3H), 7.15-7.35 (m, 11H), 7.8 (s, 1H)
[0081]
Next, the manufacture example as a pharmaceutical formulation of this invention compound is given.
[0082]
To achieve the above composition, 50 g of the compound No. 120 in Table 1 above, 407 g of lactose and 100 g of starch were mixed uniformly using a fluidized granulation coating apparatus (Okawara Seisakusho Co., Ltd.). This was sprayed and granulated with 200 g of a 10% hydroxypropylcellulose aqueous solution. After drying, pass through a 20 mesh sieve, add 20 g of carboxymethylcellulose calcium and 3 g of magnesium stearate, and use a 7 mm × 8.4 R mortar with a rotary tableting machine (manufactured by Hata Iron Works Co., Ltd.). The tablets were 120 mg per tablet.
[0084]
Next, it shows that this invention compound has the outstanding pharmacological activity.
Example 1 Effect of Cholesterol-Loaded Hamster on Serum Lipid Syrian hamsters (Std: Syrian, male, 4 weeks old) were allowed to freely ingest powdered diet containing 1% cholesterol and 10% palm oil for 3 weeks.
[0085]
Next, the test compound was dissolved or suspended in 0.1% hydrochloric acid solution or 1% polyethylene hydrogenated castor oil (NIKKOL HCO-60) solution, and orally administered once a day for 5 days once a week. The solvent was orally administered to the control group. Subsequently, blood was collected from the abdominal vena cava under pentobarbital anesthesia 2 to 4 hours after the final administration, and the serum was separated.
[0086]
Using the measurement kit, the serum total cholesterol value and the serum triglyceride value were measured with an automatic biochemical measuring device, and the serum lipid lowering rate was calculated from the measured value of each group according to the following formula.
[0087]
[Expression 1]
[0088]
[Table 201]
[Table 202]
[Table 203]
Example 2 Repeated Oral Toxicity Toxicity: Compound No. 120 was suspended in a 1% polyethylene hydrogenated castor oil (NIKKOLHCO-60) solution, and a daily dose of 100 mg / kg was given to 6 rats (male SD system) per group. For 7 days. As a result, no deaths or other toxic symptoms were observed.
[0092]
【The invention's effect】
As described above, the compound according to the present invention has a blood lipid lowering action and is useful as a therapeutic agent for hyperlipidemia, arteriosclerosis, myocardial infarction, cerebral infarction and the like.
Claims (1)
Ｘは、Ｃ（＝Ｏ）またはＳＯ２を表す。
Ａ、Ｂは、それぞれ独立して、次式で示される基
Ｙは、Ｏ、Ｓ、ＳＯ、ＳＯ２、ＮＲ８、Ｃ（＝Ｏ）、Ｃ（＝Ｏ）ＮＲ９またはＮＲ１０Ｃ（＝Ｏ）（ここで、Ｒ８、Ｒ９およびＲ１０は、それぞれ独立して、水素原子またはＣ１−６アルキル基を表す。）を表す。
ｌは、０または１を表す。
Ｄは、置換基を有していてもよいフェニル基、置換基を有していてもよいナフチル基、置換基を有していてもよいテトラヒドロナフチル基または置換基を有していてもよいインダニル基を表す。
Ｒ１１は、ハロゲン原子、Ｃ１−６アルキル基、Ｃ１−６アルコキシ基またはＣ１−６ハロアルキル基を表す。
ｍは、０または１−３の整数を表し、ｍが２以上のとき、Ｒ１１は、同一でも相異なっていてもよい。〕
で表されるフェニルイミダゾール化合物（但し、下記化合物を除く。）、
X represents C (═O) or SO 2 .
A and B are each independently a group represented by the following formula:
Y is O, S, SO, SO 2 , NR 8 , C (═O), C (═O) NR 9 or NR 10 C (═O) (where R 8 , R 9 and R 10 are Each independently represents a hydrogen atom or a C1-6 alkyl group).
l represents 0 or 1;
D represents an optionally substituted phenyl group, an optionally substituted naphthyl group, an optionally substituted tetrahydronaphthyl group, or an optionally substituted indanyl. Represents a group.
R 11 represents a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group or a C 1-6 haloalkyl group.
m represents 0 or an integer of 1-3, and when m is 2 or more, R 11 may be the same or different. ]
A phenylimidazole compound represented by (except the following compounds),
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| JP22215898A JP4261639B2 (en) | 1998-08-05 | 1998-08-05 | Phenylimidazole antihyperlipidemic drug |
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|---|---|---|---|
| JP22215898A JP4261639B2 (en) | 1998-08-05 | 1998-08-05 | Phenylimidazole antihyperlipidemic drug |
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| SE9901875D0 (en) * | 1999-05-25 | 1999-05-25 | Astra Pharma Prod | Novel compounds |
| BR0114657A (en) * | 2000-10-05 | 2003-09-30 | Daiso Co Ltd | Benzamide compounds and their use |
| WO2003072532A1 (en) * | 2002-02-28 | 2003-09-04 | Japan Tobacco Inc. | Ester compound and medicinal use thereof |
| EP1641759B1 (en) * | 2003-07-07 | 2014-03-12 | Merck Patent GmbH | Malonamide derivatives |
| AU2004268621C1 (en) * | 2003-08-29 | 2011-08-18 | Exelixis, Inc. | c-Kit modulators and methods of use |
| WO2006037468A1 (en) * | 2004-09-30 | 2006-04-13 | Istituto Di Ricerche Di Biologia Molecolare P Angeletti Spa | Hiv reverse transcriptase inhibitors |
| US8101774B2 (en) | 2004-10-18 | 2012-01-24 | Japan Tobacco Inc. | Ester derivatives and medicinal use thereof |
| AU2006226775A1 (en) * | 2005-03-24 | 2006-09-28 | Janssen Pharmaceutica, N.V. | Biaryl derived amide modulators of vanilloid VR1 receptor |
| KR100708613B1 (en) * | 2006-01-31 | 2007-04-18 | (주)아모레퍼시픽 | Phenyl imidazol sulfonamide derivatives and preparation method thereof and whitening cosmetic composition containing it |
| US7935715B2 (en) * | 2006-07-28 | 2011-05-03 | Boehringer Ingelheim International Gmbh | Compounds which modulate the CB2 receptor |
| EP2842938A4 (en) * | 2012-04-25 | 2015-12-23 | Korea Res Inst Chem Tech | Novel beta-alanine derivatives, pharmaceutically acceptable salts thereof, and pharmaceutical composition comprising same as active ingredient |
-
1998
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