JPH03173876A - New diphenylthiazole derivative - Google Patents
New diphenylthiazole derivativeInfo
- Publication number
- JPH03173876A JPH03173876A JP24299490A JP24299490A JPH03173876A JP H03173876 A JPH03173876 A JP H03173876A JP 24299490 A JP24299490 A JP 24299490A JP 24299490 A JP24299490 A JP 24299490A JP H03173876 A JPH03173876 A JP H03173876A
- Authority
- JP
- Japan
- Prior art keywords
- group
- formula
- halo
- diphenylthiazole
- alkanesulfonyl
- 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.)
- Granted
Links
- MIECVJDZXBUVSN-UHFFFAOYSA-N 2,4-diphenyl-1,3-thiazole Chemical class C=1SC(C=2C=CC=CC=2)=NC=1C1=CC=CC=C1 MIECVJDZXBUVSN-UHFFFAOYSA-N 0.000 title claims description 9
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims abstract description 16
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 8
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 6
- 125000004647 alkyl sulfenyl group Chemical group 0.000 claims abstract description 5
- 125000005948 methanesulfonyloxy group Chemical group 0.000 claims abstract description 3
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims abstract description 3
- 125000005843 halogen group Chemical group 0.000 claims description 11
- 125000002252 acyl group Chemical group 0.000 claims description 4
- 125000003277 amino group Chemical group 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 26
- 239000002904 solvent Substances 0.000 abstract description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 abstract description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 abstract description 6
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 abstract description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 abstract description 4
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 abstract description 4
- 238000002360 preparation method Methods 0.000 abstract description 2
- JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical compound O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 abstract 1
- MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 abstract 1
- 229910052736 halogen Inorganic materials 0.000 abstract 1
- 150000002367 halogens Chemical class 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 16
- 229910052757 nitrogen Inorganic materials 0.000 description 16
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 14
- 229910052739 hydrogen Inorganic materials 0.000 description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 13
- 230000000694 effects Effects 0.000 description 13
- 238000002474 experimental method Methods 0.000 description 13
- -1 1so-propyl Chemical group 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- 239000013078 crystal Substances 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 238000000921 elemental analysis Methods 0.000 description 9
- 238000002844 melting Methods 0.000 description 9
- 230000008018 melting Effects 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- 230000000144 pharmacologic effect Effects 0.000 description 8
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 241000700159 Rattus Species 0.000 description 7
- 210000002683 foot Anatomy 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- 230000003110 anti-inflammatory effect Effects 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 235000010418 carrageenan Nutrition 0.000 description 5
- 229920001525 carrageenan Polymers 0.000 description 5
- 239000012299 nitrogen atmosphere Substances 0.000 description 5
- 150000003839 salts Chemical class 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- XDWGEGZDMFHZBL-UHFFFAOYSA-N 4,5-diphenyl-1,3-thiazol-2-amine Chemical compound S1C(N)=NC(C=2C=CC=CC=2)=C1C1=CC=CC=C1 XDWGEGZDMFHZBL-UHFFFAOYSA-N 0.000 description 4
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 208000009386 Experimental Arthritis Diseases 0.000 description 4
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 4
- 239000002260 anti-inflammatory agent Substances 0.000 description 4
- 229940121363 anti-inflammatory agent Drugs 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 239000005457 ice water Substances 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 4
- 206010030113 Oedema Diseases 0.000 description 3
- LEHOTFFKMJEONL-UHFFFAOYSA-N Uric Acid Chemical compound N1C(=O)NC(=O)C2=C1NC(=O)N2 LEHOTFFKMJEONL-UHFFFAOYSA-N 0.000 description 3
- TVWHNULVHGKJHS-UHFFFAOYSA-N Uric acid Natural products N1C(=O)NC(=O)C2NC(=O)NC21 TVWHNULVHGKJHS-UHFFFAOYSA-N 0.000 description 3
- 230000000202 analgesic effect Effects 0.000 description 3
- 230000003266 anti-allergic effect Effects 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 239000000679 carrageenan Substances 0.000 description 3
- 229940113118 carrageenan Drugs 0.000 description 3
- WDCDAAMJNUHOIY-UHFFFAOYSA-N ethyl acetate;2-propan-2-yloxypropane Chemical compound CCOC(C)=O.CC(C)OC(C)C WDCDAAMJNUHOIY-UHFFFAOYSA-N 0.000 description 3
- 230000029142 excretion Effects 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 230000001737 promoting effect Effects 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- 229940116269 uric acid Drugs 0.000 description 3
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 3
- CJUDGAVRXMGRLN-UHFFFAOYSA-N 4,5-bis(4-fluorophenyl)-1,3-thiazol-2-amine Chemical compound S1C(N)=NC(C=2C=CC(F)=CC=2)=C1C1=CC=C(F)C=C1 CJUDGAVRXMGRLN-UHFFFAOYSA-N 0.000 description 2
- VUQJYRXMLSGBKQ-UHFFFAOYSA-N 4,5-bis(4-methoxyphenyl)-1,3-thiazol-2-amine Chemical compound C1=CC(OC)=CC=C1C1=C(C=2C=CC(OC)=CC=2)SC(N)=N1 VUQJYRXMLSGBKQ-UHFFFAOYSA-N 0.000 description 2
- 241000186359 Mycobacterium Species 0.000 description 2
- 241000700157 Rattus norvegicus Species 0.000 description 2
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000001760 anti-analgesic effect Effects 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- SRCZQMGIVIYBBJ-UHFFFAOYSA-N ethoxyethane;ethyl acetate Chemical compound CCOCC.CCOC(C)=O SRCZQMGIVIYBBJ-UHFFFAOYSA-N 0.000 description 2
- 210000000548 hind-foot Anatomy 0.000 description 2
- 230000000871 hypocholesterolemic effect Effects 0.000 description 2
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 229910052742 iron Inorganic materials 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- 230000008961 swelling Effects 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- WYKHSBAVLOPISI-UHFFFAOYSA-N 2-phenyl-1,3-thiazole Chemical compound C1=CSC(C=2C=CC=CC=2)=N1 WYKHSBAVLOPISI-UHFFFAOYSA-N 0.000 description 1
- UXZPFPLPTODLCU-UHFFFAOYSA-N 4,5-diphenyl-n-(2-phenylethyl)-1,3-thiazol-2-amine Chemical compound N=1C(C=2C=CC=CC=2)=C(C=2C=CC=CC=2)SC=1NCCC1=CC=CC=C1 UXZPFPLPTODLCU-UHFFFAOYSA-N 0.000 description 1
- ANFBEWMAKVJSIH-UHFFFAOYSA-N 4-(4-methylphenyl)-5-phenyl-1,3-thiazol-2-amine Chemical compound C1=CC(C)=CC=C1C1=C(C=2C=CC=CC=2)SC(N)=N1 ANFBEWMAKVJSIH-UHFFFAOYSA-N 0.000 description 1
- NTUXEUGLSZFNPX-UHFFFAOYSA-N 5-methyl-4-phenyl-n-(2-phenylethyl)-1,3-thiazol-2-amine Chemical compound N=1C(C=2C=CC=CC=2)=C(C)SC=1NCCC1=CC=CC=C1 NTUXEUGLSZFNPX-UHFFFAOYSA-N 0.000 description 1
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical class C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 208000018522 Gastrointestinal disease Diseases 0.000 description 1
- 201000005569 Gout Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- 206010030124 Oedema peripheral Diseases 0.000 description 1
- 208000025747 Rheumatic disease Diseases 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical class OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 230000036592 analgesia Effects 0.000 description 1
- HOPRXXXSABQWAV-UHFFFAOYSA-N anhydrous collidine Natural products CC1=CC=NC(C)=C1C HOPRXXXSABQWAV-UHFFFAOYSA-N 0.000 description 1
- 239000000043 antiallergic agent Substances 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 229940127218 antiplatelet drug Drugs 0.000 description 1
- 229960004676 antithrombotic agent Drugs 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000001589 carboacyl group Chemical group 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- KQDDQXNVESLJNO-UHFFFAOYSA-N chloromethanesulfonyl chloride Chemical compound ClCS(Cl)(=O)=O KQDDQXNVESLJNO-UHFFFAOYSA-N 0.000 description 1
- 208000037976 chronic inflammation Diseases 0.000 description 1
- 208000037893 chronic inflammatory disorder Diseases 0.000 description 1
- UTBIMNXEDGNJFE-UHFFFAOYSA-N collidine Natural products CC1=CC=C(C)C(C)=N1 UTBIMNXEDGNJFE-UHFFFAOYSA-N 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002169 ethanolamines Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 150000008326 guanidinothiazoles Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000002519 immonomodulatory effect Effects 0.000 description 1
- 229960000905 indomethacin Drugs 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000037356 lipid metabolism Effects 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 159000000002 lithium salts Chemical class 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- BZBWTYGKYDLIOY-UHFFFAOYSA-N n-(furan-2-ylmethyl)-5-methyl-4-phenyl-1,3-thiazol-2-amine Chemical compound N=1C(C=2C=CC=CC=2)=C(C)SC=1NCC1=CC=CO1 BZBWTYGKYDLIOY-UHFFFAOYSA-N 0.000 description 1
- SJOZGRVSGZTULY-UHFFFAOYSA-N n-[4,5-bis(4-fluorophenyl)-1,3-thiazol-2-yl]-1,1,1-trifluoromethanesulfonamide Chemical compound C1=CC(F)=CC=C1C1=C(C=2C=CC(F)=CC=2)SC(NS(=O)(=O)C(F)(F)F)=N1 SJOZGRVSGZTULY-UHFFFAOYSA-N 0.000 description 1
- VRRXTQUHOCGGDR-UHFFFAOYSA-N n-[4,5-bis(4-methoxyphenyl)-1,3-thiazol-2-yl]-1,1,1-trifluoromethanesulfonamide Chemical compound C1=CC(OC)=CC=C1C1=C(C=2C=CC(OC)=CC=2)SC(NS(=O)(=O)C(F)(F)F)=N1 VRRXTQUHOCGGDR-UHFFFAOYSA-N 0.000 description 1
- 125000006606 n-butoxy group Chemical group 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- GAAGQBXBMOGSPR-UHFFFAOYSA-N n-methyl-4,5-diphenyl-1,3-thiazol-2-amine Chemical compound S1C(NC)=NC(C=2C=CC=CC=2)=C1C1=CC=CC=C1 GAAGQBXBMOGSPR-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000002997 ophthalmic solution Substances 0.000 description 1
- 229940054534 ophthalmic solution Drugs 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000011505 plaster Substances 0.000 description 1
- 239000000106 platelet aggregation inhibitor Substances 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 150000007979 thiazole derivatives Chemical class 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Thiazole And Isothizaole Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
〔産業上の利用分野〕
本発明は、抗炎症作用、鎮痛作用、抗アレルギー作用、
尿酸排出促進作用又は血小板凝集抑制作用を有する医薬
品として有用な新規なジフェニルチアゾール誘導体に関
するものである。[Detailed Description of the Invention] [Industrial Application Field] The present invention provides anti-inflammatory effects, analgesic effects, anti-allergic effects,
The present invention relates to a novel diphenylthiazole derivative useful as a pharmaceutical having an effect of promoting uric acid excretion or inhibiting platelet aggregation.
ジフェニルチアゾール母核の２位にアミノ基又はアミノ
置換体を有する化合物は、特開昭５０−１２１２６９号
公報（以下、引例Ａと省略）、特開昭５４−１６０３６
９号公報（以下、引例Ｂと省略）および特開昭５８−２
１６１８６号公報（以下、引例Ｃと省略）に報告されて
いる。Compounds having an amino group or an amino substituent at the 2-position of the diphenylthiazole core are disclosed in JP-A-50-121269 (hereinafter abbreviated as Reference A) and JP-A-54-16036.
Publication No. 9 (hereinafter abbreviated as Reference B) and JP-A-58-2
It is reported in Publication No. 16186 (hereinafter abbreviated as Reference C).
例えば、前記引例へにおいて２−モルホリノ−４，５−
ジフェニルチアゾール、２−メチルアミノ−４，５−ジ
フェニルチアゾールおよび２−（Ｎ−メチル−Ｎ−アセ
チル）アミノ−４，５−ジフェニルチアゾール等の化合
物が記載されている。又、薬理作用においてもハイポコ
レステロレミック（ｈｙｐｏｃｈｏｌｅｓｔｅｒｏｌｅ
ｍｉｃ）作用を伴った血小板凝集抑制作用を有するが、
抗炎症作用及び鎮痛作用においては活性が弱いかほとん
ど活性を示さないことが記載されている。For example, in the above reference, 2-morpholino-4,5-
Compounds such as diphenylthiazole, 2-methylamino-4,5-diphenylthiazole and 2-(N-methyl-N-acetyl)amino-4,5-diphenylthiazole have been described. In addition, hypocholesterolemic (hypocholesterolemic)
mic) has an inhibitory effect on platelet aggregation, but
It has been described that it has weak or almost no activity in terms of anti-inflammatory and analgesic effects.
引例Ｂにおいても２−フェネチルアミノ−４，５−ジフ
ェニル−チアゾール、５−メチル−２−フェネチルアミ
ノ−４−フェニルチアゾールおよび２−フルフリルアミ
ノ−５−メチル−４−フェニル−チアゾール等の化合物
が記載されており、抗炎症や免疫調節剤として有用なこ
とが示されている。Reference B also mentions compounds such as 2-phenethylamino-4,5-diphenyl-thiazole, 5-methyl-2-phenethylamino-4-phenylthiazole, and 2-furfurylamino-5-methyl-4-phenyl-thiazole. It has been described and shown to be useful as an anti-inflammatory and immunomodulatory agent.
引例Ｃにおいてもグアニジノチアゾール誘導体に関し記
載され、殊に脂質代謝に影響を及ぼす薬剤、抗血栓剤お
よび抗真菌剤として有用なことが示されている。しかし
ながら、本発明の化合物のように２位のアミノ基の一方
又は両方にハロ低級アルカノイル残基あるいは置換スル
ホニル残基でもって置換されたジフェニルチアゾール誘
導体に関しては全く開示がなく、それを示唆する記載も
ない。勿論これらの化合物において抗炎症作用、鎮痛作
用、抗アレルギー作用、尿酸排出促進作用又は血小板凝
集抑制作用の薬理活性を有していることは全く知られて
いなかった。Reference C also describes guanidinothiazole derivatives and shows that they are particularly useful as agents that affect lipid metabolism, antithrombotic agents, and antifungal agents. However, there is no disclosure whatsoever regarding diphenylthiazole derivatives in which one or both of the amino groups at the 2-position is substituted with a halo-lower alkanoyl residue or a substituted sulfonyl residue, as in the compound of the present invention, and there is no description suggesting this. do not have. Of course, it was completely unknown that these compounds had pharmacological activities such as anti-inflammatory action, analgesic action, anti-allergic action, uric acid excretion promoting action, or platelet aggregation inhibiting action.
また、アスピリン、インドメタシン等に代表される酸性
系非ステロイド消炎剤は、塩基性消炎剤に比し明確な作
用を有する反面、胃腸管障害等の副作用を併せ持ってい
る。その為、低年齢者あるいは高齢者の使用に際し、ま
た慢性炎症疾患者等の長期連用に際し、その副作用軽減
の為の対応を余儀無くされているのが現状である。Furthermore, although acidic non-steroidal anti-inflammatory agents such as aspirin and indomethacin have more distinct effects than basic anti-inflammatory agents, they also have side effects such as gastrointestinal disorders. Therefore, it is currently necessary to take measures to reduce the side effects when used by young or elderly people, or when used long-term by people with chronic inflammatory diseases.
そこで本発明は、より優れた抗炎症作用、鎮痛作用を有
すると共に、より副作用の少なく安全性の高い消炎剤の
開発、更には抗アレルギー剤、痛風治療剤又は血小板凝
集抑制剤を開発することを目的としている。Therefore, the present invention aims to develop anti-inflammatory agents that have better anti-inflammatory and analgesic effects and are highly safe with fewer side effects, as well as anti-allergic agents, gout treatment agents, and platelet aggregation inhibitors. The purpose is
本発明者は、優れた抗炎症作用、鎮痛作用、抗アレルギ
ー作用、血小板凝集抑制作用、尿酸排出促進作用を有し
、かつ副作用の少ない薬剤を得るために研究を続けたと
ころ、ある種のジフェニルチアゾール誘導体が本目的に
合致することを見い出し、本発明を完成した。The present inventor continued research to obtain a drug that has excellent anti-inflammatory, analgesic, anti-allergic, platelet aggregation-inhibiting, and uric acid excretion promoting effects, and has few side effects. The inventors have discovered that thiazole derivatives meet this purpose and have completed the present invention.
本発明のジフェニルチアゾール誘導体は、下記一般式（
Ｉ）
（式中、ｍ及びｎは１または２を、Ｒ１及びＲ２は水素
原子、低級アルキル基、低級アルコキシ基、低級アルキ
ルスルフェニル基、ニトロ基、アミノ基。The diphenylthiazole derivative of the present invention has the following general formula (
I) (wherein m and n are 1 or 2, R1 and R2 are a hydrogen atom, a lower alkyl group, a lower alkoxy group, a lower alkylsulfenyl group, a nitro group, an amino group.
メタンスルホニルオキシ基、ハロゲン原子を、Ａ１は低
級アルカンスルホニル基、ハロ低級アルカンスルホニル
基、置換ベンゼンスルホニル基、ハロ低級アルカノイル
基を、Ａ２は水素原子、低級アルカンスルホニル基、ハ
ロ低級アルカンスルホニル基、低級アルキル基を意味す
る）で表わされるジフェニルチアゾール誘導体及びその
医薬として有用な塩類に関するものである。Methanesulfonyloxy group, halogen atom, A1 is lower alkanesulfonyl group, halo lower alkanesulfonyl group, substituted benzenesulfonyl group, halo lower alkanoyl group, A2 is hydrogen atom, lower alkanesulfonyl group, halo lower alkanesulfonyl group, lower The present invention relates to diphenylthiazole derivatives represented by (meaning an alkyl group) and pharmaceutically useful salts thereof.
上記一般式について具体的に説明する。低級アルキル基
とは、メチル、エチル、ｎ−プロピル、 １ｓｏ−プ
ロピル、ｎ−ブチル、 １ｓｏ−ブチル、 ｔｅｒｔ
、−ブチル、ｎ−ペンチル、ｎ−ヘキシル等の炭素数１
〜６個のアルキル基を、低級アルコキシ基とは、メトキ
シ、エトキシ、ｎ−プロポキシ、 １ｓｏ−プロポキ
シ。The above general formula will be specifically explained. Lower alkyl groups include methyl, ethyl, n-propyl, 1so-propyl, n-butyl, 1so-butyl, tert
, -butyl, n-pentyl, n-hexyl, etc. with 1 carbon number
~6 alkyl groups, lower alkoxy groups include methoxy, ethoxy, n-propoxy, 1so-propoxy.
ｎ−ブトキシ、 １ｓｏ−ブトキシ、 ｔｅｒｔ、−
ブトキシ等の炭素数１〜６個のアルコキシ基を、低級ア
ルキルスルフェニル基とは、メチルスルフェニル基、エ
チルスルフェニル基、ｎ−プロピルスルフェニル基。n-butoxy, 1so-butoxy, tert, -
An alkoxy group having 1 to 6 carbon atoms such as butoxy, and a lower alkylsulfenyl group include a methylsulfenyl group, an ethylsulfenyl group, and an n-propylsulfenyl group.
１ｓｏ−プロピルスルフェニル基、ｎ−ブチルスルフェ
ニル基、 １ｓｏ−ブチルスルフェニル基、 ｔｅｒｔ
、−ブチルスルフェニル基等の炭素数１〜６個のアルキ
ルスルフェニル基を、低級アルカンスルホニル基とは、
メタンスルホニル、エタンスルホニル、プロパンスルホ
ニル、ブタンスルホニル等の炭素数１〜６個のアルカン
スルホニル基を、ハロ低級アルカンスルホニル基とは、
１個あるいは複数個のハロゲン原子で置換された低級ア
ルカンスルホニル基を、ハロ低級アルカノイル基とは、
１個あるいは複数個のハロゲン原子で置換された低級ア
ルカノイル基を、ハロゲン原子とは、フッ素、塩素。1so-propylsulfenyl group, n-butylsulfenyl group, 1so-butylsulfenyl group, tert
, alkylsulfenyl group having 1 to 6 carbon atoms such as -butylsulfenyl group, and lower alkanesulfonyl group,
A halo-lower alkanesulfonyl group refers to an alkanesulfonyl group having 1 to 6 carbon atoms such as methanesulfonyl, ethanesulfonyl, propanesulfonyl, butanesulfonyl, etc.
A lower alkanesulfonyl group substituted with one or more halogen atoms is called a halo-lower alkanoyl group.
A halogen atom refers to a lower alkanoyl group substituted with one or more halogen atoms, such as fluorine or chlorine.
臭素、ヨウ素の各原子を意味する。Refers to bromine and iodine atoms.
また、医薬として許容される塩類は、リチウム塩、ナト
リウム塩、カリウム塩等のアルカリ金属塩、カルシウム
塩、マグネシウム塩等のアルカリ土類金属塩、アンモニ
ウム塩等の無機塩及びトリエチルアミン塩、エタノール
アミン塩、トリエタノールアミン塩、ジシクロヘキシル
アミン塩、グルタミン酸塩等の有機塩であるが、これら
に限定されるものではない。Pharmaceutically acceptable salts include alkali metal salts such as lithium salts, sodium salts, and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, inorganic salts such as ammonium salts, and triethylamine salts and ethanolamine salts. , triethanolamine salt, dicyclohexylamine salt, glutamate, and the like, but are not limited to these.
一般式（Ｉ）で表わされる化合物あるいはその塩類を医
薬として用いる場合、そのままもしくは公知の賦形剤と
共に錠剤、カプセル剤、注射剤、坐剤、軟膏剤、クリー
ム剤、ゲル剤、ローション剤。When the compound represented by general formula (I) or its salts is used as a medicine, it can be used as it is or together with known excipients in tablets, capsules, injections, suppositories, ointments, creams, gels, and lotions.
エアゾール剤２口腔剤、硬膏剤、シップ剤９点眼剤など
、適宜の剤形として経口的または非経口的に安定に投与
することができる。投与量は、投与対象の症状１年齢、
性別等に応じて適宜決定されるが、通常成人に対して経
口投与する場合、化合物（Ｉ）あるいはそれらの塩類を
１同量１〜３００ｍｇ程度１日約１〜３回程度投与する
のが好ましい。It can be stably administered orally or parenterally in an appropriate dosage form such as an aerosol 2 oral preparation, plaster, or ophthalmic solution. The dosage is based on the symptoms of the subject, 1 age,
Although it is determined as appropriate depending on gender etc., when orally administered to adults, it is preferable to administer the same amount of Compound (I) or its salts at an amount of 1 to 300 mg about 1 to 3 times a day. .
次に、本発明化合物の製造法について述べる。Next, a method for producing the compound of the present invention will be described.
本発明化合物は、以下に記載する方法によって収率よく
得ることができるが、本発明の範囲はこれらに限定され
るものではない。The compound of the present invention can be obtained in good yield by the method described below, but the scope of the present invention is not limited thereto.
製造法ｌ
（式中、ｍ＋ ｎ＋ Ｒ’＋ Ｒ２＋ Ａ’は前記と
同じ意味を有し、Ｈａｔはハロゲン原子を意味する。）
反応は、一般式（ＩＩ）で表わされる化合物と一般式（
Ｉ）または（ＩＶ）で表わされる化合物を適当な溶媒中
塩基触媒の存在下で冷却下あるいは室温下あるいは加熱
下０．５〜３０時間余り反応させることにより、一般式
（Ｉ）又は（１’）で表わされる化合物を得ることがで
きる。ここで、反応溶媒としては、例えばジクロロメタ
ン、クロロホルム、四塩化炭素、テトラヒドロフラン、
、 Ｎ、 Ｎ−ジメチルホルムアミド、Ｎ、Ｎ−ジメ
チルアセトアミド、ジメチルスルホキシド等の反応に関
与しない有機溶媒であれば特に限定されない。又、塩基
触媒としては、ピリジン、コリジン、トリエチルアミン
、トリーｎ−プロピルアミン、トリーｎ−ブチルアミン
等の脱酸反応を促進する塩基性のものが用いられるが、
これらに限定されるものではない。Production method 1 (In the formula, m+ n+ R'+ R2+ A' has the same meaning as above, and Hat means a halogen atom.)
The reaction is carried out between a compound represented by general formula (II) and general formula (
The compound represented by formula (I) or (1' ) can be obtained. Here, examples of the reaction solvent include dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran,
, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and the like, which are not particularly limited as long as they do not participate in the reaction. In addition, as the base catalyst, a basic catalyst that promotes the deoxidation reaction, such as pyridine, collidine, triethylamine, tri-n-propylamine, tri-n-butylamine, etc., is used.
It is not limited to these.
製造法２ （式中、 ｌ ｎ。Manufacturing method 2 (In the formula, l n.
Ｒ２゜ ＡＩ。R2゜ A.I.
Ａ２は前記と同じ意
味を有する。）
反応は、一般式（Ｖ）で表わされる化合物と一般式（Ｗ
）で表わされる化合物を適当な溶媒中室温下あるいは加
熱下に混合することにより、一般式（Ｉ）で表わされる
化合物を得ることができる。ここで反応溶媒としては、
メタノール、エタノール。A2 has the same meaning as above. ) The reaction is carried out between a compound represented by general formula (V) and general formula (W
) can be mixed in a suitable solvent at room temperature or under heating to obtain a compound represented by general formula (I). Here, the reaction solvent is
methanol, ethanol.
テトラヒドロフラン、Ｎ、Ｎ−ジメチルホルムアミド。Tetrahydrofuran, N,N-dimethylformamide.
ジメチルスルホキシド等が用いられるが、これらに限定
されるものではない。Dimethyl sulfoxide and the like are used, but are not limited thereto.
以下に実施例を示し、本発明を更に詳細に説明する。た
だし、本発明はこれら実施例に限定されるものではない
。EXAMPLES The present invention will be explained in more detail by showing examples below. However, the present invention is not limited to these examples.
実施例１
２−アミノ−４，５−ジフェニルチアゾール３０ｇ、ト
リエチルアミン１５．６ ｇをクロロホルム中−２０〜
−１５°Ｃで撹拌しながら、無水トリフルオロメタンス
ルホン酸５３．７ ｇをゆっくり滴下、そのまま１．５
時間撹拌した。これを氷水に注ぎ抽出後、ＩＮ塩酸、飽
和炭酸水素ナトリウム水溶液。Example 1 30 g of 2-amino-4,5-diphenylthiazole and 15.6 g of triethylamine were dissolved in chloroform at -20 to
While stirring at -15°C, 53.7 g of trifluoromethanesulfonic anhydride was slowly added dropwise to 1.5 g of trifluoromethanesulfonic anhydride.
Stir for hours. This was poured into ice water and extracted, followed by IN hydrochloric acid and saturated aqueous sodium bicarbonate solution.
水の順で洗浄し、無水硫酸マグネシウムにて乾燥した。It was washed successively with water and dried over anhydrous magnesium sulfate.
溶媒を減圧下に留去し、生じた結晶をろ取、イソプロピ
ルエーテル−酢酸エチルから再結晶することにより、２
−トリフルオロメタンスルホニルアミノ−４，５−ジフ
ェニルチアゾール１８．２ ｇを得た。融点は２１２〜
２１４°Ｃであった。The solvent was distilled off under reduced pressure, the resulting crystals were collected by filtration, and recrystallized from isopropyl ether-ethyl acetate.
18.2 g of -trifluoromethanesulfonylamino-4,5-diphenylthiazole was obtained. Melting point is 212~
The temperature was 214°C.
ＩＲ： ３２４８．１３２３ｃｍ−’ＭＡＳＳ （ｍ
／ｅ） ： ３８４（Ｍ”）元素分析値（Ｃ＋５Ｈ
ｚＦｓＮＪ□Ｓｔとして）計算値 Ｃ：４９．９９％
Ｈ：２．８８％ Ｎニア、２９％実測値 Ｃ：４９．９
８％ Ｈ：２．９２％ Ｎニア、３７％実施例２
２−アミノ−４−（４−メチルフェニル）−５−フェニ
ルチアゾール５．０ｇ、トリエチルアミン５．２ｍｌを
クロロホルム中窒素雰囲気下−２０〜−１５°Ｃで撹拌
しながら、無水トリフルオロメタンスルホン酸１５．９
ｇをゆっくりと滴下、そのまま２時間撹拌した。反応
溶液を希塩酸、飽和炭酸水素ナトリウム水溶液、水の順
で洗浄し、無水硫酸マグネシウムにより乾燥した。溶媒
を減圧下に留去し、クロロホルム／酢酸エチルを展開溶
媒とするシリカゲルカラムにて分離を行った。得られた
結晶をｎ−ヘキサン−イソプロピルエーテル−酢酸エチ
ルから再結晶することにより、２−トリフルオロメタン
スルホニルアミノ−４−（４−メチルフェニル）−５−
フェニルチアゾール２．８ｇを得た。融点は１８６．５
〜１８８．５°Ｃであった。IR: 3248.1323cm-'MASS (m
/e): 384 (M”) elemental analysis value (C+5H
zFsNJ□St) Calculated value C: 49.99%
H: 2.88% N near, 29% actual value C: 49.9
8% H: 2.92% Nia, 37% Example 2 5.0 g of 2-amino-4-(4-methylphenyl)-5-phenylthiazole and 5.2 ml of triethylamine were heated in chloroform under a nitrogen atmosphere at -20~ While stirring at -15 °C, trifluoromethanesulfonic anhydride 15.9
g was slowly added dropwise, and the mixture was stirred for 2 hours. The reaction solution was washed with dilute hydrochloric acid, a saturated aqueous sodium bicarbonate solution, and water in this order, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and separation was performed using a silica gel column using chloroform/ethyl acetate as a developing solvent. By recrystallizing the obtained crystals from n-hexane-isopropyl ether-ethyl acetate, 2-trifluoromethanesulfonylamino-4-(4-methylphenyl)-5-
2.8 g of phenylthiazole was obtained. Melting point is 186.5
~188.5°C.
ＩＲ： ３１８８．１３２５ｃｍ−’ＭＡＳＳ （ｍ
／ｅ） ： ３９８（Ｍ”）元素分析値（Ｃ＋□Ｈ
＋ ｚＦｓＮｚＯ＊ｓｚとして）計算値 Ｃ：５１．２
５％ Ｈ：３．２９％ Ｎニア、０３％実測値 Ｃ：
５１．３５％ Ｈ：３．４２％ Ｎニア、０８％実施例
３
２−アミノ−４，５−ビス（４−メトキシフェニル）チ
アゾール５．０ｇ、トリエチルアミン５．０ ｍｌをク
ロロホルム中窒素雰囲気下−２０〜−１５°Ｃで撹拌し
ながら、無水トリフルオロメタンスルホン酸１３．５
ｇをゆっくりと滴下、そのまま２時間撹拌した。反応溶
液を希塩酸、飽和炭酸水素ナトリウム水溶液、水の順で
洗浄し、無水硫酸マグネシウムで乾燥した。溶媒を減圧
下に留去し、クロロホルム／酢酸エチルを展開溶媒とす
るシリカゲルカラムにて分離を行った。得られた結晶を
イソプロピルエーテル−酢酸エチルから再結晶すること
により、２−トリフルオロメタンスルホニルアミノ−４
，５−ビス（４−メトキシフェニル）チアゾール１．９
ｇを得た。融点は２４０〜２４２°Ｃであった。IR: 3188.1325cm-'MASS (m
/e): 398 (M”) elemental analysis value (C+□H
+ zFsNzO*sz) Calculated value C: 51.2
5% H: 3.29% N near, 03% actual value C:
51.35% H: 3.42% Nia, 08% Example 3 5.0 g of 2-amino-4,5-bis(4-methoxyphenyl)thiazole and 5.0 ml of triethylamine were added in chloroform under a nitrogen atmosphere. Trifluoromethanesulfonic anhydride 13.5 with stirring at 20 to -15 °C.
g was slowly added dropwise, and the mixture was stirred for 2 hours. The reaction solution was washed successively with dilute hydrochloric acid, saturated aqueous sodium bicarbonate solution, and water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and separation was performed using a silica gel column using chloroform/ethyl acetate as a developing solvent. By recrystallizing the obtained crystals from isopropyl ether-ethyl acetate, 2-trifluoromethanesulfonylamino-4
,5-bis(4-methoxyphenyl)thiazole 1.9
I got g. The melting point was 240-242°C.
ＩＲ： ３３００〜２９００．１３４４ｃｍ−’ＭＡ
ＳＳ （ｍ／ｅ） ： ４４４（Ｍ”）元素分析値
（Ｃ＋＊Ｈ＋５Ｆ２Ｎ２０４Ｓｚとして）計算値 Ｃ：
４８．６４％ Ｈ：３．４０％ Ｎ：６．３０％実測値
Ｃ：４８．６６％ Ｈ：３．４２％ Ｎ：６．３４％
実施例４
２−アミノ−４，５−ビス（４−フル才ロフエニル）チ
アゾール２．８８ｇ、トリエチルアミン１．８ｍｌをク
ロロホルム中窒素雰囲気下−２０〜−１５°Ｃて撹拌し
ながら、無水トリフルオロメタンスルホン酸２．６８ｍ
１をゆっくりと滴下、そのまま１時間撹拌した。反応溶
液をＩＮ塩酸、５％炭酸水素ナトリウム水溶液、水の順
で洗浄、無水硫酸マグネシウムにて乾燥した。溶媒を減
圧下に留去し、イソプロピルエーテルを展開溶媒とする
シリカゲルカラムにて分離を行った。得られた結晶を石
油エーテル−ジエチルエーテルから再結晶することによ
り、２−トリフルオロメタンスルホニルアミノ−４，５
−ビス（４−フルオロフェニル）チアゾール０．４７
ｇを得た。融点は１９３〜１９５℃であった。IR: 3300~2900.1344cm-'MA
SS (m/e): 444 (M”) Elemental analysis value (as C++H+5F2N204Sz) Calculated value C:
48.64% H: 3.40% N: 6.30% Actual value C: 48.66% H: 3.42% N: 6.34%
Example 4 2.88 g of 2-amino-4,5-bis(4-fluorophenyl)thiazole and 1.8 ml of triethylamine were added to anhydrous trifluoromethanesulfone while stirring at -20 to -15°C under a nitrogen atmosphere in chloroform. acid 2.68m
1 was slowly added dropwise, and the mixture was stirred for 1 hour. The reaction solution was washed in this order with IN hydrochloric acid, 5% aqueous sodium bicarbonate solution, and water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and separation was performed using a silica gel column using isopropyl ether as a developing solvent. By recrystallizing the obtained crystals from petroleum ether-diethyl ether, 2-trifluoromethanesulfonylamino-4,5
-bis(4-fluorophenyl)thiazole 0.47
I got g. The melting point was 193-195°C.
ＩＲ： ３２１０．１３４０ｃｍ−’ＭＡＳＳ （ｍ
ｌｅ） ： ４２０（Ｍ”）元素分析値（Ｃ＋ ５
ＨｓＦｓＮ２０２ｓｔとして）計算値 Ｃ：４５．７２
％ Ｈ＋２．１６％ Ｎ：６．６６％実測値 Ｃ：４５
．６９％ Ｈ：２．２４％ Ｎ：６．４８％実施例５
２−アミノ−４，５−ジフェニルチアゾール５．０ｇ、
ピリジン３．２ ｍｌをジクロロメタン中室温で撹拌し
ながら、メタンスルホン酸塩化物２．５ｇを滴下、その
まま−晩撹拌した。反応溶液を希塩酸。IR: 3210.1340cm-'MASS (m
le): 420 (M”) elemental analysis value (C+ 5
HsFsN202st) Calculated value C: 45.72
% H+2.16% N: 6.66% Actual value C: 45
．． 69% H: 2.24% N: 6.48% Example 5 5.0 g of 2-amino-4,5-diphenylthiazole,
While stirring 3.2 ml of pyridine in dichloromethane at room temperature, 2.5 g of methanesulfonic acid chloride was added dropwise, and the mixture was stirred overnight. Dilute the reaction solution with dilute hydrochloric acid.
飽和炭酸水素ナトリウム水溶液、水の順で洗浄し、無水
硫酸マグネシウムで乾燥した。溶媒を減圧下に留去し、
イソプロピルエーテル、酢酸エチルを展開溶媒とするシ
リカゲルカラムにて分離を行った。得られた結晶をイソ
プロピルエーテルよりろ取、ジエチルエーテルで洗浄す
ることにより、２−メタンスルホニルアミノ−４，５−
ジフェニルチアゾール１．６ ｇを得た。融点は２２５
〜２２７°Ｃてあった。It was washed successively with a saturated aqueous sodium hydrogen carbonate solution and water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure,
Separation was performed using a silica gel column using isopropyl ether and ethyl acetate as developing solvents. The obtained crystals were filtered from isopropyl ether and washed with diethyl ether to give 2-methanesulfonylamino-4,5-
1.6 g of diphenylthiazole was obtained. Melting point is 225
It was ~227°C.
［Ｒ： ３２０６． １２７８ｃｍ−ＭＡＳＳ （ｍ
ｌｅ） ： ３３０（Ｍ”）元素分析値（Ｃ，ｇＨ
，、Ｎ２０□Ｓ２として）計算値 Ｃ：５８’、１６％
Ｈ：４．２７％ Ｎ：８．４８％実測値 Ｃ：５７．
９６％ Ｈ：４．３３％ Ｎ：８．４１％実施例６
２−アミノ−４，５−ジフェニルチアゾール２．２７ｇ
をピリジン中窒素雰囲気下室温で撹拌しながら、クロロ
メタンスルホン酸塩化物２．７０ｇを滴下、そのまま２
時間撹拌した。反応溶液を氷水に注ぎ、析出した結晶を
ろ取、イソプロピルエーテル、酢酸エチルを展開溶媒と
するシリカゲルカラムにて分離を行った。得られた結晶
をイソプロピルエーテル−酢酸エチルから再結晶するこ
とにより、２−クロロメタンスルホニルアミノ−４，５
−ジフェニルチアゾール１．４５ ｇを得た。融点は２
０１〜２０３°Ｃであった。[R: 3206. 1278cm-MASS (m
le): 330 (M”) elemental analysis value (C, gH
,, N20□S2) Calculated value C: 58', 16%
H: 4.27% N: 8.48% Actual value C: 57.
96% H: 4.33% N: 8.41% Example 6 2-amino-4,5-diphenylthiazole 2.27 g
While stirring the mixture in pyridine under a nitrogen atmosphere at room temperature, 2.70 g of chloromethane sulfonic acid chloride was added dropwise to the mixture.
Stir for hours. The reaction solution was poured into ice water, and the precipitated crystals were collected by filtration and separated using a silica gel column using isopropyl ether and ethyl acetate as developing solvents. By recrystallizing the obtained crystals from isopropyl ether-ethyl acetate, 2-chloromethanesulfonylamino-4,5
1.45 g of -diphenylthiazole was obtained. The melting point is 2
The temperature was 01-203°C.
ＩＲ： ３２１５．１３０５．１２９０ｃｍ−’ＭＡ
ＳＳ （ｍｌｅ） 二 ３６４（Ｍ”）元素分
析値（ＣＩ＝Ｈ，２ＣＩＮ２０２Ｓ２として）計算値
Ｃ：５２．６７％ Ｈ：３．５９％ Ｎニア、６８％実
測値 Ｃ：５２．６７％ Ｈ：３．４９％ Ｎニア、５
８％実施例７
２−アミノ−４，５−ビス（４−メトキシフェニル）チ
アゾール１．５６ ｇをピリジン中室温で窒素雰囲気下
に撹拌しながら、２．２．２−１リフルオロエタンスル
ホン酸塩化物０．９２ ｇを滴下、そのまま１時間撹拌
した。これを氷水に注ぎ析出した結晶をろ取、ジエチル
エーテル−酢酸エチルから再結晶することにより、２−
（２，２，２−１リフルオロエタンスルホニル）アミノ
−４，５−ビス（４−メトキシフェニル）チアゾール０
．８０ ｇを得た。IR: 3215.1305.1290cm-'MA
SS (mle) 2 364 (M”) Elemental analysis value (CI=H, 2CIN202S2) Calculated value
C: 52.67% H: 3.59% N near, 68% actual value C: 52.67% H: 3.49% N near, 5
8% Example 7 1.56 g of 2-amino-4,5-bis(4-methoxyphenyl)thiazole was dissolved in pyridine at room temperature with stirring under a nitrogen atmosphere to 2.2.2-1-lifluoroethanesulfonic acid. 0.92 g of chloride was added dropwise, and the mixture was stirred for 1 hour. This was poured into ice water and the precipitated crystals were collected by filtration and recrystallized from diethyl ether-ethyl acetate.
(2,2,2-1lifluoroethanesulfonyl)amino-4,5-bis(4-methoxyphenyl)thiazole 0
．． 80 g was obtained.
融点は２５９〜２６１°Ｃであった。The melting point was 259-261°C.
ＩＲ： ３２１０．１３３０ｃｍ−’ＭＡＳＳ（ｍｌ
ｅ） ： ４５８（Ｍ＋）元素分析値（Ｃ＋−Ｈｌ
７ＦＪｚ０４Ｓ２として）計算値 Ｃ：４９．７８％
Ｈ：３．７４％ Ｎ：６．１１％実測値 Ｃ：４９．５
２％ Ｈ：３．５９％ Ｎ：５．９３％実施例８
２−アミノ−４，５−ジフェニルチアゾール３．１２ｇ
、４−）リフルオロメチルベンゼンスルホン酸塩化物２
．４４ ｇをピリジン中室温で４．５時間撹拌した。こ
れを氷水に注ぎ析出した結晶をろ取、イソブロビルエー
テルー酢酸エチルから再結晶することにより、２−（４
−）リフルオロメチルベンゼンスルホニル）アミノ−４
，５−ジフェニルチアゾール０．５５ ｇを得た。融点
は２４８〜２４９°Ｃであった。IR: 3210.1330cm-'MASS(ml
e): 458 (M+) elemental analysis value (C+-Hl
7FJz04S2) Calculated value C: 49.78%
H: 3.74% N: 6.11% Actual value C: 49.5
2% H: 3.59% N: 5.93% Example 8 3.12 g of 2-amino-4,5-diphenylthiazole
, 4-) Lifluoromethylbenzenesulfonic acid chloride 2
．． 44 g was stirred in pyridine at room temperature for 4.5 hours. This was poured into ice water and the precipitated crystals were collected by filtration and recrystallized from isobrobyl ether-ethyl acetate.
-)lifluoromethylbenzenesulfonyl)amino-4
, 0.55 g of 5-diphenylthiazole was obtained. The melting point was 248-249°C.
ＩＲ： ３１９５．１３２０ｃｍ−’ＭＡＳＳ （ｍ
／ｅ） ： ４６０（Ｍ”）元素分析値（Ｃ２２＋
１１６Ｆ３Ｎ２０２Ｓ２として）計算値 Ｃ：５７．３
８％ Ｈ：３．２８％ Ｎ：６．０８％実測値 Ｃ：５
７．３１％ Ｈ：３．３９％ Ｎ：５゜９５％実施例９
２−アミノ−４，５−ビス（４−フルオロフェニル）チ
アゾール２．８８ｇを無水トリフルオロ酢酸中１時間加
熱還流した。これを減圧下に蒸発乾固し、生じた結晶を
ｎ−ヘキサンよりろ取・洗浄することにより、２−トリ
フルオロアセトアミノ−４，５−ビス（４−フルオロフ
ェニル）チアゾール３、５６ ｇを得た。融点は２１４
〜２１６°Ｃであった。IR: 3195.1320cm-'MASS (m
/e): 460 (M”) elemental analysis value (C22+
116F3N202S2) Calculated value C: 57.3
8% H: 3.28% N: 6.08% Actual value C: 5
7.31% H: 3.39% N: 5°95% Example 9 2.88 g of 2-amino-4,5-bis(4-fluorophenyl)thiazole was heated under reflux in trifluoroacetic anhydride for 1 hour. This was evaporated to dryness under reduced pressure, and the resulting crystals were filtered and washed with n-hexane to obtain 3.56 g of 2-trifluoroacetamino-4,5-bis(4-fluorophenyl)thiazole. Obtained. Melting point is 214
~216°C.
ＩＲ： ２８７８． １６４４ｃｍ−ＭＡＳＳ （ｍ
／ｅ） ： ３８４（Ｍつ元素分析値（ＣＩ□Ｈ，
Ｆ、Ｎ２Ｏ５として）計算値 Ｃ：５３．１３％ Ｈ：
２．３６％ Ｎニア、２９％実測値 Ｃ：５２．９８％
Ｈ：２．４４％ Ｎニア、０５％実施例１Ｏ〜４６
実施例１〜９の方法に準じて次表の本発明化合物を合成
した。IR: 2878. 1644cm-MASS (m
/e): 384 (M elemental analysis value (CI□H,
Calculated value (as F, N2O5) C: 53.13% H:
2.36% N near, 29% actual value C: 52.98%
H: 2.44% N near, 05% Examples 1O to 46 The compounds of the present invention shown in the following table were synthesized according to the methods of Examples 1 to 9.
以下に、本発明の化合物の薬効を実証するために本発明
の化合物を用いた薬理実験法および薬理データを示す。Below, pharmacological experimental methods and pharmacological data using the compounds of the present invention are shown in order to demonstrate the medicinal efficacy of the compounds of the present invention.
薬理実験１
（ラットでのカラゲニン足踏浮腫実験）体重１４０〜１
６０ｇのウィスター系雄性ラットを１群６匹として使用
した。１％カラゲニン（ピクニンＡ、逗子化学）０．１
ｍｌをラット右後肢足跋皮下に注射し、腫脹を足浮腫測
定装置を用いて経時的に測定した。被験化合物は０．５
％トラガント溶液あるいは０．５％ＣＭＣ溶液に懸濁し
、カラゲニン注射の１時間前に経口投与した。結果は、
反応惹起から３時間後における対照群（化合物を経口投
与しなかったもの）に対する抑制率（平均値）を以下の
表に示した。Pharmacological experiment 1 (Carrageenan paw edema experiment in rats) Body weight 140-1
Six Og male Wistar rats were used in each group. 1% carrageenin (Pykunin A, Zushi Kagaku) 0.1
ml was injected subcutaneously into the right hind paw of the rat, and the swelling was measured over time using a paw edema measuring device. Test compound is 0.5
% tragacanth solution or 0.5% CMC solution and orally administered 1 hour before carrageenin injection. Result is,
The inhibition rate (average value) relative to the control group (to which the compound was not orally administered) 3 hours after induction of the reaction is shown in the table below.
薬理実験２
（ラットでのアジュバント関節炎実験）流動パラフィン
に懸濁させたマイコバクテリウムブチリコム（Ｍｙｃｏ
ｂａｃｔｅｒｉｕｍ ｂｕｔｙｒｉｃｕｍ ： ６ｍ
ｇ／ １ ｍｌ）Ｏ−１ｍｌを体重２００ｇ前後のウィ
スター系雄性ラットの尾根部に皮肉投与し、２０日後に
後肢足に明らかに関節炎が発症したラットを１群７匹と
して使用した。被験化合物を以下に示す用量で１日１回
ずつ７日間縁口投与し、それによる後肢足の腫脹の抑制
率を指標としてアジュバント関節炎に対する効果を調べ
た。なお、抑制率は次の式により算出し、その結果を以
下の表に示した。Pharmacological experiment 2 (Adjuvant arthritis experiment in rats) Mycobacterium butyricum (Mycobacterium butyricum) suspended in liquid paraffin
bacterium butyricum: 6m
g/1 ml) was subcutaneously administered to the base of the tail of male Wistar rats weighing approximately 200 g, and 20 days later, rats with obvious arthritis in their hind legs were used as a group of 7 rats. The test compound was administered via the verge once a day for 7 days at the doses shown below, and the effect on adjuvant arthritis was investigated using the inhibition rate of swelling of the hind paw as an index. The inhibition rate was calculated using the following formula, and the results are shown in the table below.
抑制率＝（（皮肉投与後２７日後の足容積−健常足容積
）／（皮肉投与後２０日後の足容積−健常足容積））Ｘ
１００
薬理実験３
（マウスでの酢酸ライジング実験）
体重２３ｇ前後のｄｄＹ系雄性マウスを１群７〜９匹と
して使用した。被験化合物を経口投与し、その３０分後
に０．６％酢酸・生理食塩溶液を体重１０ｇ当り０．１
ｍｌ腹腔内投与した。その５分後から１０分間のライジ
ング症状の発現回数を数え、対照群のライジング数と比
較して抑制率を求めて以下の表に示した。Suppression rate = ((paw volume 27 days after iron administration - healthy foot volume)/(foot volume 20 days after iron administration - healthy foot volume))
100 Pharmacology Experiment 3 (Acetic acid writhing experiment in mice) Male ddY mice weighing around 23 g were used in groups of 7 to 9 mice. The test compound was orally administered, and 30 minutes later, 0.6% acetic acid/physiological saline solution was administered at 0.1% per 10g body weight.
ml was administered intraperitoneally. The number of occurrences of writhing symptoms for 10 minutes from 5 minutes later was counted and compared with the number of writhing symptoms in the control group to determine the suppression rate, which is shown in the table below.
〔発明の効果〕
本発明の化合物は前記薬理実験ｌのラットてのカラゲニ
ン足踏浮腫実験から明らかなように、用量１０■／ｋｇ
でもって顕著なカラゲニン足踏浮腫抑制作用を有する。[Effects of the Invention] As is clear from the carrageenan paw edema experiment in rats in the pharmacological experiment 1, the compound of the present invention can be used at a dose of 10 μ/kg.
Therefore, carrageenan has a remarkable effect of suppressing foot edema.
また、薬理実験２のラットでのアジュバント関節炎実験
から明らかなように、用量ｌＯ■／ｋｇでもって顕著な
アジュバント関節炎抑制作用を有する。Furthermore, as is clear from the adjuvant arthritis experiment in rats in Pharmacology Experiment 2, it has a remarkable adjuvant arthritis suppressive effect even at a dose of 1O2/kg.
さらに、薬理実験３のマウスでの酢酸ライジング実験か
ら明らかなように、用量２０■／ ｋｇでもって顕著な
抑制作用を有することが判明した。Furthermore, as is clear from the acetic acid writhing experiment in mice in Pharmacological Experiment 3, it was found that a dose of 20 μ/kg had a significant suppressive effect.
以上説明したように、本発明の化合物は従来の非ステロ
イド系抗炎症剤に代表される抗炎症剤に匹敵する顕著な
薬理作用を有し、炎症又は鎮痛を伴う諸疾患に対する非
ステロイド系の抗炎症剤として、あるいはリュウマチ性
疾患に対する抗炎症剤としての使用が期待されるもので
ある。As explained above, the compounds of the present invention have remarkable pharmacological effects comparable to anti-inflammatory agents represented by conventional non-steroidal anti-inflammatory drugs, and are non-steroidal anti-inflammatory agents for various diseases accompanied by inflammation or analgesia. It is expected to be used as an inflammatory agent or as an anti-inflammatory agent for rheumatic diseases.
従って、本発明の化合物は薬効的に優れ、かつ安全性の
高い非ステロイド系の抗炎症剤として医薬産業上極めて
有用である。Therefore, the compound of the present invention is extremely useful in the pharmaceutical industry as a non-steroidal anti-inflammatory agent that is highly effective and highly safe.
Claims (1)
水素原子、低級アルキル基、低級アルコキシ基、低級ア
ルキルスルフェニル基、ニトロ基、アミノ基、メタンス
ルホニルオキシ基、ハロゲン原子を、Ａ＾１は低級アル
カンスルホニル基、ハロ低級アルカンスルホニル基、置
換ベンゼンスルホニル基、ハロ低級アルカノイル基を、
Ａ＾２は水素原子、低級アルカンスルホニル基、ハロ低
級アルカンスルホニル基、低級アルキル基を意味する）
で表わされるジフェニルチアゾール誘導体。[Claims] 1. General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, m and n are 1 or 2, and R^1 and R^2 are hydrogen atoms, lower alkyl groups, lower alkoxy group, lower alkylsulfenyl group, nitro group, amino group, methanesulfonyloxy group, halogen atom, A^1 is lower alkanesulfonyl group, halo lower alkanesulfonyl group, substituted benzenesulfonyl group, halo lower alkanoyl group,
A^2 means a hydrogen atom, a lower alkanesulfonyl group, a halo-lower alkanesulfonyl group, or a lower alkyl group)
A diphenylthiazole derivative represented by
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1-247813 | 1989-09-21 | ||
| JP24781389 | 1989-09-21 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH03173876A true JPH03173876A (en) | 1991-07-29 |
| JPH078863B2 JPH078863B2 (en) | 1995-02-01 |
Family
ID=17169046
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2242994A Expired - Fee Related JPH078863B2 (en) | 1989-09-21 | 1990-09-12 | Novel diphenylthiazole derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH078863B2 (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5449783A (en) * | 1991-03-07 | 1995-09-12 | Hisamitsu Pharmaceutical Co., Inc. | Diphenylthiazole derivative |
| WO2001090092A1 (en) * | 2000-05-22 | 2001-11-29 | Biovitrum Ab | Inhibitors of 11-beta-hydroxy steroid dehydrogenase type 1 |
| US7094792B2 (en) | 2001-11-22 | 2006-08-22 | Biovitrum Ab | Inhibitors of 11-beta-hydroxy steroid dehydrogenase type 1 |
| US7638536B2 (en) | 2002-01-18 | 2009-12-29 | Astellas Pharma Inc. | 2-Acylaminothiazole derivative or salt thereof |
-
1990
- 1990-09-12 JP JP2242994A patent/JPH078863B2/en not_active Expired - Fee Related
Non-Patent Citations (1)
| Title |
|---|
| J.INDIAN.CHEM.SOC.=1988 * |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5449783A (en) * | 1991-03-07 | 1995-09-12 | Hisamitsu Pharmaceutical Co., Inc. | Diphenylthiazole derivative |
| WO2001090092A1 (en) * | 2000-05-22 | 2001-11-29 | Biovitrum Ab | Inhibitors of 11-beta-hydroxy steroid dehydrogenase type 1 |
| US7030135B2 (en) | 2000-05-22 | 2006-04-18 | Biovitrum Ab | Inhibitors of 11-β-hydroxy steroid dehydrogenase type 1 |
| US7132436B2 (en) | 2000-05-22 | 2006-11-07 | Biovitrum Ab | Inhibitors of 11-β-hydroxy steroid dehydrogenase type 1 |
| US7618961B2 (en) | 2000-05-22 | 2009-11-17 | Biovitrum Ab | Inhibitors of 11-beta-hydroxy steroid dehydrogenase type 1 |
| US7094792B2 (en) | 2001-11-22 | 2006-08-22 | Biovitrum Ab | Inhibitors of 11-beta-hydroxy steroid dehydrogenase type 1 |
| US7671051B2 (en) | 2001-11-22 | 2010-03-02 | Biovitrum Ab | Inhibitors of 11-β-hydroxy steroid dehydrogenase type 1 |
| US7638536B2 (en) | 2002-01-18 | 2009-12-29 | Astellas Pharma Inc. | 2-Acylaminothiazole derivative or salt thereof |
| US8338429B2 (en) | 2002-01-18 | 2012-12-25 | Astellas Pharma, Inc. | 2-acylaminothiazole derivative or salt thereof |
| US8765764B2 (en) | 2002-01-18 | 2014-07-01 | Astellas Pharma, Inc. | 2-acylaminothiazole derivative or salt thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH078863B2 (en) | 1995-02-01 |
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