JPH053468B2 - - Google Patents
Info
- Publication number
- JPH053468B2 JPH053468B2 JP7781984A JP7781984A JPH053468B2 JP H053468 B2 JPH053468 B2 JP H053468B2 JP 7781984 A JP7781984 A JP 7781984A JP 7781984 A JP7781984 A JP 7781984A JP H053468 B2 JPH053468 B2 JP H053468B2
- Authority
- JP
- Japan
- Prior art keywords
- group
- pyridyl
- substituent
- melting point
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 150000001875 compounds Chemical class 0.000 claims description 57
- -1 methylenedioxy group Chemical group 0.000 claims description 42
- 125000000217 alkyl group Chemical group 0.000 claims description 25
- 125000001424 substituent group Chemical group 0.000 claims description 22
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 20
- 125000004432 carbon atom Chemical group C* 0.000 claims description 16
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical class C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 13
- 150000003839 salts Chemical class 0.000 claims description 12
- 125000003277 amino group Chemical group 0.000 claims description 11
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 9
- 125000004076 pyridyl group Chemical group 0.000 claims description 9
- 125000003342 alkenyl group Chemical group 0.000 claims description 8
- 125000003118 aryl group Chemical group 0.000 claims description 8
- 229910052799 carbon Inorganic materials 0.000 claims description 8
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 8
- 230000000202 analgesic effect Effects 0.000 claims description 6
- 125000003258 trimethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])[*:1] 0.000 claims description 6
- 125000002541 furyl group Chemical group 0.000 claims description 5
- 125000001544 thienyl group Chemical group 0.000 claims description 5
- 239000004480 active ingredient Substances 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 239000000730 antalgic agent Substances 0.000 claims description 2
- 239000002260 anti-inflammatory agent Substances 0.000 claims description 2
- 229940121363 anti-inflammatory agent Drugs 0.000 claims description 2
- 239000003699 antiulcer agent Substances 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 66
- 238000002844 melting Methods 0.000 description 44
- 230000008018 melting Effects 0.000 description 44
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 36
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 29
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 27
- 238000003756 stirring Methods 0.000 description 27
- 239000002904 solvent Substances 0.000 description 24
- 239000000243 solution Substances 0.000 description 23
- 238000006243 chemical reaction Methods 0.000 description 20
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 9
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- 238000010992 reflux Methods 0.000 description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 8
- 238000010898 silica gel chromatography Methods 0.000 description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 7
- 239000013078 crystal Substances 0.000 description 7
- 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 7
- 238000000034 method Methods 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
- 229910052736 halogen Inorganic materials 0.000 description 6
- 150000002367 halogens Chemical class 0.000 description 6
- 239000003960 organic solvent Substances 0.000 description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 5
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 5
- 241000699670 Mus sp. Species 0.000 description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 5
- 229910052794 bromium Inorganic materials 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- ZEDZSJVLMNQCDQ-UHFFFAOYSA-N 2-bromo-1-(4-methoxyphenyl)-2-pyridin-3-ylethanone;hydrobromide Chemical compound Br.C1=CC(OC)=CC=C1C(=O)C(Br)C1=CC=CN=C1 ZEDZSJVLMNQCDQ-UHFFFAOYSA-N 0.000 description 4
- ITQTTZVARXURQS-UHFFFAOYSA-N 3-methylpyridine Chemical compound CC1=CC=CN=C1 ITQTTZVARXURQS-UHFFFAOYSA-N 0.000 description 4
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 4
- FHUODBDRWMIBQP-UHFFFAOYSA-N Ethyl p-anisate Chemical compound CCOC(=O)C1=CC=C(OC)C=C1 FHUODBDRWMIBQP-UHFFFAOYSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- 206010030113 Oedema Diseases 0.000 description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical class OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 208000025865 Ulcer Diseases 0.000 description 3
- 125000003545 alkoxy group Chemical group 0.000 description 3
- 125000003282 alkyl amino group Chemical group 0.000 description 3
- 230000003110 anti-inflammatory effect Effects 0.000 description 3
- 230000001754 anti-pyretic effect Effects 0.000 description 3
- 230000000767 anti-ulcer Effects 0.000 description 3
- 239000002221 antipyretic Substances 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 235000010418 carrageenan Nutrition 0.000 description 3
- 229920001525 carrageenan Polymers 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 125000004122 cyclic group Chemical group 0.000 description 3
- 229940043279 diisopropylamine Drugs 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 3
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- XHFLOLLMZOTPSM-UHFFFAOYSA-M sodium;hydrogen carbonate;hydrate Chemical class [OH-].[Na+].OC(O)=O XHFLOLLMZOTPSM-UHFFFAOYSA-M 0.000 description 3
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 3
- 231100000397 ulcer Toxicity 0.000 description 3
- RHBGITBPARBDPH-ZPUQHVIOSA-N (E,E)-piperic acid Chemical compound OC(=O)\C=C\C=C\C1=CC=C2OCOC2=C1 RHBGITBPARBDPH-ZPUQHVIOSA-N 0.000 description 2
- JPEZMIFKLNWZTB-UHFFFAOYSA-N 1-(2,3-dihydro-1h-inden-5-yl)-2-pyridin-3-ylethanone Chemical compound C=1C=C2CCCC2=CC=1C(=O)CC1=CC=CN=C1 JPEZMIFKLNWZTB-UHFFFAOYSA-N 0.000 description 2
- OGKXSQRUMNMIJK-UHFFFAOYSA-N 2-bromo-1-(2,3-dihydro-1h-inden-5-yl)-2-pyridin-3-ylethanone Chemical compound C=1C=C2CCCC2=CC=1C(=O)C(Br)C1=CC=CN=C1 OGKXSQRUMNMIJK-UHFFFAOYSA-N 0.000 description 2
- WXUCODGDMJORCX-UHFFFAOYSA-N 2-bromo-1-(4-methoxyphenyl)-2-pyridin-3-ylethanone Chemical compound C1=CC(OC)=CC=C1C(=O)C(Br)C1=CC=CN=C1 WXUCODGDMJORCX-UHFFFAOYSA-N 0.000 description 2
- RLQZIECDMISZHS-UHFFFAOYSA-N 2-phenylcyclohexa-2,5-diene-1,4-dione Chemical compound O=C1C=CC(=O)C(C=2C=CC=CC=2)=C1 RLQZIECDMISZHS-UHFFFAOYSA-N 0.000 description 2
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 2
- HWWYDZCSSYKIAD-UHFFFAOYSA-N 3,5-dimethylpyridine Chemical compound CC1=CN=CC(C)=C1 HWWYDZCSSYKIAD-UHFFFAOYSA-N 0.000 description 2
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 2
- NUYXENDTGLIWDX-UHFFFAOYSA-N 4-(4-methoxyphenyl)-5-pyridin-3-yl-1,3-thiazol-2-amine Chemical compound C1=CC(OC)=CC=C1C1=C(C=2C=NC=CC=2)SC(N)=N1 NUYXENDTGLIWDX-UHFFFAOYSA-N 0.000 description 2
- FKNQCJSGGFJEIZ-UHFFFAOYSA-N 4-methylpyridine Chemical compound CC1=CC=NC=C1 FKNQCJSGGFJEIZ-UHFFFAOYSA-N 0.000 description 2
- RGXHFNJJWXTYFT-UHFFFAOYSA-N 5-pyridin-2-yl-1,3-thiazole Chemical class S1C=NC=C1C1=CC=CC=N1 RGXHFNJJWXTYFT-UHFFFAOYSA-N 0.000 description 2
- REJOECPUMPPMTC-UHFFFAOYSA-N 5-pyridin-3-yl-1,3-thiazole Chemical compound S1C=NC=C1C1=CC=CN=C1 REJOECPUMPPMTC-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical group CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- UEOFNBCUGJADBM-UHFFFAOYSA-N Ethyl 3,4,5-trimethoxybenzoate Chemical compound CCOC(=O)C1=CC(OC)=C(OC)C(OC)=C1 UEOFNBCUGJADBM-UHFFFAOYSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical class CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- KQJQICVXLJTWQD-UHFFFAOYSA-N N-Methylthiourea Chemical compound CNC(N)=S KQJQICVXLJTWQD-UHFFFAOYSA-N 0.000 description 2
- XGEGHDBEHXKFPX-UHFFFAOYSA-N N-methylthiourea Natural products CNC(N)=O XGEGHDBEHXKFPX-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical class OP(O)(O)=O NBIIXXVUZAFLBC-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
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical class OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 238000005903 acid hydrolysis reaction Methods 0.000 description 2
- 238000005904 alkaline hydrolysis reaction Methods 0.000 description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- SROLLKZMNPYRBY-UHFFFAOYSA-N benzyl n-[[4-(4-methoxyphenyl)-5-pyridin-3-yl-1,3-thiazol-2-yl]methyl]carbamate Chemical compound C1=CC(OC)=CC=C1C1=C(C=2C=NC=CC=2)SC(CNC(=O)OCC=2C=CC=CC=2)=N1 SROLLKZMNPYRBY-UHFFFAOYSA-N 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 239000000679 carrageenan Substances 0.000 description 2
- 229940113118 carrageenan Drugs 0.000 description 2
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 2
- UREBWPXBXRYXRJ-UHFFFAOYSA-N ethyl acetate;methanol Chemical compound OC.CCOC(C)=O UREBWPXBXRYXRJ-UHFFFAOYSA-N 0.000 description 2
- MTZQAGJQAFMTAQ-UHFFFAOYSA-N ethyl benzoate Chemical compound CCOC(=O)C1=CC=CC=C1 MTZQAGJQAFMTAQ-UHFFFAOYSA-N 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 238000007654 immersion Methods 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 150000002611 lead compounds Chemical class 0.000 description 2
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 2
- QMBOGHRCVUZBIR-UHFFFAOYSA-N methyl 2,3-dihydro-1h-indene-5-carboxylate Chemical compound COC(=O)C1=CC=C2CCCC2=C1 QMBOGHRCVUZBIR-UHFFFAOYSA-N 0.000 description 2
- 125000003506 n-propoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 125000002112 pyrrolidino group Chemical group [*]N1C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 2
- DSNBHJFQCNUKMA-SCKDECHMSA-N thromboxane A2 Chemical compound OC(=O)CCC\C=C/C[C@@H]1[C@@H](/C=C/[C@@H](O)CCCCC)O[C@@H]2O[C@H]1C2 DSNBHJFQCNUKMA-SCKDECHMSA-N 0.000 description 2
- 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 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- TWRFUNKGACNVQD-UHFFFAOYSA-N 1-(1,3-benzodioxol-5-yl)-2-bromo-2-pyridin-3-ylethanone Chemical compound C=1C=C2OCOC2=CC=1C(=O)C(Br)C1=CC=CN=C1 TWRFUNKGACNVQD-UHFFFAOYSA-N 0.000 description 1
- VWDDEIVOSXIFOB-UHFFFAOYSA-N 1-(1,3-benzodioxol-5-yl)-2-pyridin-3-ylethanone Chemical compound C=1C=C2OCOC2=CC=1C(=O)CC1=CC=CN=C1 VWDDEIVOSXIFOB-UHFFFAOYSA-N 0.000 description 1
- CYLUJNVQHKFWTG-UHFFFAOYSA-N 1-(1,3-benzodioxol-5-yl)-3-pyridin-3-ylpropan-2-one Chemical compound C=1C=C2OCOC2=CC=1CC(=O)CC1=CC=CN=C1 CYLUJNVQHKFWTG-UHFFFAOYSA-N 0.000 description 1
- RRYFWOWLIAHFTF-UHFFFAOYSA-N 1-(3,4-dimethoxyphenyl)-2-pyridin-3-ylethanone Chemical compound C1=C(OC)C(OC)=CC=C1C(=O)CC1=CC=CN=C1 RRYFWOWLIAHFTF-UHFFFAOYSA-N 0.000 description 1
- SNRXHZHOTNCTNN-UHFFFAOYSA-N 1-(4-ethylphenyl)-2-pyridin-3-ylethanone Chemical compound C1=CC(CC)=CC=C1C(=O)CC1=CC=CN=C1 SNRXHZHOTNCTNN-UHFFFAOYSA-N 0.000 description 1
- DNOLYZHTKURJIV-UHFFFAOYSA-N 1-(4-fluorophenyl)-2-pyridin-3-ylethanone Chemical compound C1=CC(F)=CC=C1C(=O)CC1=CC=CN=C1 DNOLYZHTKURJIV-UHFFFAOYSA-N 0.000 description 1
- YDDIGUFGIDJEEM-UHFFFAOYSA-N 1-(4-methoxyphenyl)-2-pyridin-2-ylethanone Chemical compound C1=CC(OC)=CC=C1C(=O)CC1=CC=CC=N1 YDDIGUFGIDJEEM-UHFFFAOYSA-N 0.000 description 1
- NDBVHXUNBUTGKJ-UHFFFAOYSA-N 1-(4-methoxyphenyl)-2-pyridin-3-ylethanone Chemical compound C1=CC(OC)=CC=C1C(=O)CC1=CC=CN=C1 NDBVHXUNBUTGKJ-UHFFFAOYSA-N 0.000 description 1
- FQOSOMYMMDPZAA-UHFFFAOYSA-N 1-(4-methoxyphenyl)-2-pyridin-4-ylethanone Chemical compound C1=CC(OC)=CC=C1C(=O)CC1=CC=NC=C1 FQOSOMYMMDPZAA-UHFFFAOYSA-N 0.000 description 1
- HQFISWJGKRAAFU-UHFFFAOYSA-N 1-[4-(methoxymethoxy)phenyl]-2-pyridin-3-ylethanone Chemical compound C1=CC(OCOC)=CC=C1C(=O)CC1=CC=CN=C1 HQFISWJGKRAAFU-UHFFFAOYSA-N 0.000 description 1
- BHTURNCRHPDYCF-UHFFFAOYSA-N 1-naphthalen-2-yl-2-pyridin-3-ylethanone Chemical compound C=1C=C2C=CC=CC2=CC=1C(=O)CC1=CC=CN=C1 BHTURNCRHPDYCF-UHFFFAOYSA-N 0.000 description 1
- CMOXTMGJZNCXEI-UHFFFAOYSA-N 1-phenyl-2-pyridin-2-ylethanone Chemical compound C=1C=CC=CC=1C(=O)CC1=CC=CC=N1 CMOXTMGJZNCXEI-UHFFFAOYSA-N 0.000 description 1
- DDEBMFBOWGAMAX-UHFFFAOYSA-N 1-phenyl-2-pyridin-3-ylethanone Chemical compound C=1C=CC=CC=1C(=O)CC1=CC=CN=C1 DDEBMFBOWGAMAX-UHFFFAOYSA-N 0.000 description 1
- ACULMSXMKICJIS-UHFFFAOYSA-N 1-phenyl-2-pyridin-4-ylethanone Chemical compound C=1C=CC=CC=1C(=O)CC1=CC=NC=C1 ACULMSXMKICJIS-UHFFFAOYSA-N 0.000 description 1
- NVGPNJNFXRISQH-UHFFFAOYSA-N 1-pyridin-1-ium-3-ylethanone;bromide Chemical compound [Br-].CC(=O)C1=CC=C[NH+]=C1 NVGPNJNFXRISQH-UHFFFAOYSA-N 0.000 description 1
- UPUWMQZUXFAUCJ-UHFFFAOYSA-N 2,5-dihydro-1,2-thiazole Chemical compound C1SNC=C1 UPUWMQZUXFAUCJ-UHFFFAOYSA-N 0.000 description 1
- SFLKCYWGQJJTAL-UHFFFAOYSA-N 2-(5-methylpyridin-3-yl)-1-phenylethanone Chemical compound CC1=CN=CC(CC(=O)C=2C=CC=CC=2)=C1 SFLKCYWGQJJTAL-UHFFFAOYSA-N 0.000 description 1
- OZDGMOYKSFPLSE-UHFFFAOYSA-N 2-Methylaziridine Chemical compound CC1CN1 OZDGMOYKSFPLSE-UHFFFAOYSA-N 0.000 description 1
- 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
- ZYKJENJDMYBNJP-UHFFFAOYSA-N 2-bromo-1-(3,4-dimethoxyphenyl)-2-pyridin-3-ylethanone Chemical compound C1=C(OC)C(OC)=CC=C1C(=O)C(Br)C1=CC=CN=C1 ZYKJENJDMYBNJP-UHFFFAOYSA-N 0.000 description 1
- PZPXCQUSBYKWLE-UHFFFAOYSA-N 2-bromo-1-(4-ethylphenyl)-2-pyridin-3-ylethanone Chemical compound C1=CC(CC)=CC=C1C(=O)C(Br)C1=CC=CN=C1 PZPXCQUSBYKWLE-UHFFFAOYSA-N 0.000 description 1
- JBYXKOGEXFSTSP-UHFFFAOYSA-N 2-bromo-1-(4-fluorophenyl)-2-pyridin-3-ylethanone Chemical compound C1=CC(F)=CC=C1C(=O)C(Br)C1=CC=CN=C1 JBYXKOGEXFSTSP-UHFFFAOYSA-N 0.000 description 1
- COYCTTRTOHFCQY-UHFFFAOYSA-N 2-bromo-1-(4-hydroxyphenyl)-2-pyridin-3-ylethanone Chemical compound C1=CC(O)=CC=C1C(=O)C(Br)C1=CC=CN=C1 COYCTTRTOHFCQY-UHFFFAOYSA-N 0.000 description 1
- NEZRNMJDEVSTRB-UHFFFAOYSA-N 2-bromo-1-(4-methoxyphenyl)-2-pyridin-2-ylethanone Chemical compound C1=CC(OC)=CC=C1C(=O)C(Br)C1=CC=CC=N1 NEZRNMJDEVSTRB-UHFFFAOYSA-N 0.000 description 1
- MSQHIFUAMYWZMN-UHFFFAOYSA-N 2-bromo-1-(4-methoxyphenyl)-2-pyridin-4-ylethanone Chemical compound C1=CC(OC)=CC=C1C(=O)C(Br)C1=CC=NC=C1 MSQHIFUAMYWZMN-UHFFFAOYSA-N 0.000 description 1
- FYSKSZILWCRHNL-UHFFFAOYSA-N 2-bromo-1-phenyl-2-pyridin-2-ylethanone Chemical compound C=1C=CC=NC=1C(Br)C(=O)C1=CC=CC=C1 FYSKSZILWCRHNL-UHFFFAOYSA-N 0.000 description 1
- VNVGJDKHFJLKSU-UHFFFAOYSA-N 2-bromo-1-phenyl-2-pyridin-3-ylethanone Chemical compound C=1C=CN=CC=1C(Br)C(=O)C1=CC=CC=C1 VNVGJDKHFJLKSU-UHFFFAOYSA-N 0.000 description 1
- HCXDYMDEHQTSJH-UHFFFAOYSA-N 2-bromo-1-phenyl-2-pyridin-4-ylethanone Chemical compound C=1C=NC=CC=1C(Br)C(=O)C1=CC=CC=C1 HCXDYMDEHQTSJH-UHFFFAOYSA-N 0.000 description 1
- QCFVKNXEWKLYMY-UHFFFAOYSA-N 2-bromo-2-(5-methylpyridin-3-yl)-1-phenylethanone Chemical compound CC1=CN=CC(C(Br)C(=O)C=2C=CC=CC=2)=C1 QCFVKNXEWKLYMY-UHFFFAOYSA-N 0.000 description 1
- LSLAAJZAYBJRSU-UHFFFAOYSA-N 2-bromo-2-pyridin-3-yl-1-(3,4,5-trimethoxyphenyl)ethanone Chemical compound COC1=C(OC)C(OC)=CC(C(=O)C(Br)C=2C=NC=CC=2)=C1 LSLAAJZAYBJRSU-UHFFFAOYSA-N 0.000 description 1
- SMHAPCQDIOZYPZ-UHFFFAOYSA-N 2-cyclohexyl-4-(4-methoxyphenyl)-5-pyridin-3-yl-1,3-thiazole Chemical compound C1=CC(OC)=CC=C1C1=C(C=2C=NC=CC=2)SC(C2CCCCC2)=N1 SMHAPCQDIOZYPZ-UHFFFAOYSA-N 0.000 description 1
- ROGFAYBYBRPGNJ-UHFFFAOYSA-N 2-cyclohexyl-4-phenyl-5-pyridin-3-yl-1,3-thiazole Chemical compound C1CCCCC1C1=NC(C=2C=CC=CC=2)=C(C=2C=NC=CC=2)S1 ROGFAYBYBRPGNJ-UHFFFAOYSA-N 0.000 description 1
- ABUJRBHPDLEQJL-UHFFFAOYSA-N 2-ethyl-4-(4-methoxyphenyl)-5-pyridin-3-yl-1,3-thiazole Chemical compound S1C(CC)=NC(C=2C=CC(OC)=CC=2)=C1C1=CC=CN=C1 ABUJRBHPDLEQJL-UHFFFAOYSA-N 0.000 description 1
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- WPCSNGBKVXKBPU-UHFFFAOYSA-N 2-pyridin-3-yl-1,3-thiazole Chemical compound C1=CSC(C=2C=NC=CC=2)=N1 WPCSNGBKVXKBPU-UHFFFAOYSA-N 0.000 description 1
- VKLVBJCIOOUXOQ-UHFFFAOYSA-N 2-pyridin-3-yl-1-(3,4,5-trimethoxyphenyl)ethanone Chemical compound COC1=C(OC)C(OC)=CC(C(=O)CC=2C=NC=CC=2)=C1 VKLVBJCIOOUXOQ-UHFFFAOYSA-N 0.000 description 1
- MDKGFCIBBDLSNM-UHFFFAOYSA-N 2-pyridin-3-yl-1-(5,6,7,8-tetrahydronaphthalen-2-yl)ethanone Chemical compound C=1C=C2CCCCC2=CC=1C(=O)CC1=CC=CN=C1 MDKGFCIBBDLSNM-UHFFFAOYSA-N 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical class NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- CYQPBVXPBLGHMU-UHFFFAOYSA-N 4-(1,3-benzodioxol-5-yl)-n-methyl-5-pyridin-3-yl-1,3-thiazol-2-amine Chemical compound S1C(NC)=NC(C=2C=C3OCOC3=CC=2)=C1C1=CC=CN=C1 CYQPBVXPBLGHMU-UHFFFAOYSA-N 0.000 description 1
- NLGAFPPIDFYIAE-UHFFFAOYSA-N 4-(2,3-dihydro-1h-inden-5-yl)-n-methyl-5-pyridin-3-yl-1,3-thiazol-2-amine Chemical compound S1C(NC)=NC(C=2C=C3CCCC3=CC=2)=C1C1=CC=CN=C1 NLGAFPPIDFYIAE-UHFFFAOYSA-N 0.000 description 1
- USDPJLQQSGAMIJ-UHFFFAOYSA-N 4-(4-methoxyphenyl)-2-phenyl-5-pyridin-3-yl-1,3-thiazole Chemical compound C1=CC(OC)=CC=C1C1=C(C=2C=NC=CC=2)SC(C=2C=CC=CC=2)=N1 USDPJLQQSGAMIJ-UHFFFAOYSA-N 0.000 description 1
- PKDDDTJJMPPYMB-UHFFFAOYSA-N 4-(4-methoxyphenyl)-n-methyl-5-pyridin-3-yl-1,3-thiazol-2-amine Chemical compound S1C(NC)=NC(C=2C=CC(OC)=CC=2)=C1C1=CC=CN=C1 PKDDDTJJMPPYMB-UHFFFAOYSA-N 0.000 description 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 206010061459 Gastrointestinal ulcer Diseases 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 208000025747 Rheumatic disease Diseases 0.000 description 1
- 206010042220 Stress ulcer Diseases 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 231100000215 acute (single dose) toxicity testing Toxicity 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 238000011047 acute toxicity test Methods 0.000 description 1
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 229940090012 bentyl Drugs 0.000 description 1
- 238000004166 bioassay Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- SXDBWCPKPHAZSM-UHFFFAOYSA-M bromate Chemical class [O-]Br(=O)=O SXDBWCPKPHAZSM-UHFFFAOYSA-M 0.000 description 1
- SXDBWCPKPHAZSM-UHFFFAOYSA-N bromic acid Chemical compound OBr(=O)=O SXDBWCPKPHAZSM-UHFFFAOYSA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 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
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 208000000718 duodenal ulcer Diseases 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- DQYBDCGIPTYXML-UHFFFAOYSA-N ethoxyethane;hydrate Chemical compound O.CCOCC DQYBDCGIPTYXML-UHFFFAOYSA-N 0.000 description 1
- AYYNUGSDPRDVCH-UHFFFAOYSA-N ethyl 3,4-dimethoxybenzoate Chemical compound CCOC(=O)C1=CC=C(OC)C(OC)=C1 AYYNUGSDPRDVCH-UHFFFAOYSA-N 0.000 description 1
- KWFADUNOPOSMIJ-UHFFFAOYSA-N ethyl 3-chloro-3-oxopropanoate Chemical compound CCOC(=O)CC(Cl)=O KWFADUNOPOSMIJ-UHFFFAOYSA-N 0.000 description 1
- PEGFAXXBTQVMSY-UHFFFAOYSA-N ethyl 4-(methoxymethoxy)benzoate Chemical compound CCOC(=O)C1=CC=C(OCOC)C=C1 PEGFAXXBTQVMSY-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- OMRRUNXAWXNVFW-UHFFFAOYSA-N fluoridochlorine Chemical compound ClF OMRRUNXAWXNVFW-UHFFFAOYSA-N 0.000 description 1
- 238000005755 formation reaction Methods 0.000 description 1
- 210000001156 gastric mucosa Anatomy 0.000 description 1
- 230000000762 glandular Effects 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 229910000037 hydrogen sulfide Inorganic materials 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 125000000555 isopropenyl group Chemical group [H]\C([H])=C(\*)C([H])([H])[H] 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- OVEHNNQXLPJPPL-UHFFFAOYSA-N lithium;n-propan-2-ylpropan-2-amine Chemical compound [Li].CC(C)NC(C)C OVEHNNQXLPJPPL-UHFFFAOYSA-N 0.000 description 1
- 210000003141 lower extremity Anatomy 0.000 description 1
- 230000002934 lysing effect Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- GYUXWAIDEGEMEE-UHFFFAOYSA-N methyl 2,3-dihydro-1,4-benzodioxine-6-carboxylate Chemical compound O1CCOC2=CC(C(=O)OC)=CC=C21 GYUXWAIDEGEMEE-UHFFFAOYSA-N 0.000 description 1
- MSEBQGULDWDIRW-UHFFFAOYSA-N methyl 4-fluorobenzoate Chemical compound COC(=O)C1=CC=C(F)C=C1 MSEBQGULDWDIRW-UHFFFAOYSA-N 0.000 description 1
- GKKIDGUCTHRVRV-UHFFFAOYSA-N methyl 5-amino-5-sulfanylidenepentanoate Chemical compound COC(=O)CCCC(N)=S GKKIDGUCTHRVRV-UHFFFAOYSA-N 0.000 description 1
- IODOXLXFXNATGI-UHFFFAOYSA-N methyl naphthalene-2-carboxylate Chemical compound C1=CC=CC2=CC(C(=O)OC)=CC=C21 IODOXLXFXNATGI-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- XZAISPXDCGRJJO-UHFFFAOYSA-N n-[2-(methylamino)-2-sulfanylideneethyl]benzamide Chemical compound CNC(=S)CNC(=O)C1=CC=CC=C1 XZAISPXDCGRJJO-UHFFFAOYSA-N 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- DBFZMOWIKUYQAP-UHFFFAOYSA-N n-methyl-5-pyridin-3-yl-1,3-thiazol-2-amine Chemical compound S1C(NC)=NC=C1C1=CC=CN=C1 DBFZMOWIKUYQAP-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000003431 oxalo group Chemical group 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- CYQAYERJWZKYML-UHFFFAOYSA-N phosphorus pentasulfide Chemical compound S1P(S2)(=S)SP3(=S)SP1(=S)SP2(=S)S3 CYQAYERJWZKYML-UHFFFAOYSA-N 0.000 description 1
- PVIJLUXKGBJNNI-UHFFFAOYSA-N piperazine-1-carbothioamide Chemical compound NC(=S)N1CCNCC1 PVIJLUXKGBJNNI-UHFFFAOYSA-N 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- WPZSAUFQHYFIPG-UHFFFAOYSA-N propanethioamide Chemical compound CCC(N)=S WPZSAUFQHYFIPG-UHFFFAOYSA-N 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000006308 propyl amino group Chemical group 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000000452 restraining effect Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 210000000115 thoracic cavity Anatomy 0.000 description 1
- RZWIIPASKMUIAC-VQTJNVASSA-N thromboxane Chemical compound CCCCCCCC[C@H]1OCCC[C@@H]1CCCCCCC RZWIIPASKMUIAC-VQTJNVASSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 210000002417 xiphoid bone Anatomy 0.000 description 1
Landscapes
- Pyridine Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本発明は、鎮痛、解熱、抗炎症、抗潰瘍、トロ
ンボキサンA2（TXA2）合成酵素阻害、血小板凝
集抑制などの作用を有する新規な５−ピリジル−
１，３−チアゾール誘導体、その製造法およびそ
れを含んでなる医薬組成物に関する。
従来、５−ピリジル−１，３−チアゾール誘導
体は殆んど知られていない。本発明者らは新規な
５−ピリジル−１，３−チアゾール誘導体を種々
合成し、生物検定系で検索した結果、これらの化
合物が優れた鎮痛、解熱、抗炎症、抗潰瘍、トロ
ンボキサンA2（TXA2）合成酵素阻害、血小板凝
集抑制などの薬理作用を有することを見いだし
た。
すなわち本発明は、
(1) 一般式
〔式中、R1は置換基を有していてもよいアル
キル基、アルケニル基、アリール基、アラルキル
基、シクロアルキル基、チエニル基、フリール基
またはアミノ基を、R2はアルキル基で置換され
ていてもよいピリジル基を示す。R3は置換基を
有していてもよいフエニル基を示すが、ベンゼン
環上の隣接する任意の位置にメチレンジオキシ基
またはトリメチレン基を有してこれらの基がそれ
ぞれベンゼン環上の炭素原子と共に環を形成して
いてもよい。〕で表わされる１，３−チアゾール
誘導体またはその塩、
(2) 一般式
〔式中、R2およびR3前記と同意義であり、Ｘ
はハロゲン原子を示す。〕で表わされる化合物と、
一般式
〔式中、R1は前記と同意義である。〕で表わさ
れる化合物とを反応させることを特徴とする一般
式〔〕で表わされる化合物およびその塩の製造
法、
(3) 一般式（）で表わされる化合物またはその
塩を有効成分として含んでなる鎮痛または抗炎症
剤、および(4)一般式（）で表わされる化合物ま
たはその塩を有効成分として含んでなる抗潰瘍
剤、である。
前記一般式（）、（）中、R1で示されるア
ルキル基としてはたとえばメチル、エチル、ｎ−
プロピル、ｉ−プロピル、ｎ−ブチル、ｉ−ブチ
ル、ｎ−ベンチル、ｎ−ヘキシル、ｎ−オクチ
ル、ｎ−ノニル、ｎ−デシルなど炭素数１〜10の
ものが、アルケニル基としてはたとえばビニル、
アリル、２−プテニル、イソプロペニルなど炭素
数２〜４のものが、アリール基としてはたとえば
フエニル、ナフチルなどが、アラルキル基として
は、たとえばベンジル、フエネチルなど炭素数７
〜12のものが、シクロアルキル基としては、たと
えばシクロプロピル、シクロブチル、シクロベン
チル、シクロヘキシルなど炭素数３〜７のものが
あげられる。R1で示されるアルキル基、アルケ
ニル基、アリール基、アラルキル基、シクロアル
キル基、炭素を結合手とする異項環基、アミノ基
はいずれも置換基を有していてもよい。アルキル
基の置換基としてはたとえばヒドロキシル、アミ
ノ、低級アルキルアミノ（たとえばメチルアミ
ノ、エチルアミノ、プロピルアミノなど炭素数１
〜４のもの）、カルボキシ、低級アルコキシカル
ボニル（たとえばメトキシカルボニル、エトキシ
カルボニル、ｎ−プロポキシカルボニルなど炭素
数２〜５のもの）があげられる。アルケニル基の
置換基としてはたとえばヒドロキシル、低級アル
キルアミノ（たとえばメチルアミノ、エチルアミ
ノ、プロピルアミノなど炭素数１〜４のもの）、
カルボキシルなどがあげられる。アリール基の置
換基としては、たとえばカルボキシル、ハロゲン
（たとえばフツ素、塩素、臭素など）、２−カルボ
キシエテニル、２−カルボキシ−１−プロペニ
ル、アセトキシ、低級アルキル（たとえばメチ
ル、エチル、プロピル、ｉ−プロピル、ｎ−ブチ
ル、ｉ−ブチル、ｔ−ブチルなど炭素数１〜４の
もの）があげられ、これらは環上の任意の位置に
置換しうる。アラルキル基の置換基としてはたと
えばメトキシ、ハロゲン（クロル、フロルなど）
などがあげられ、これらは環上の任意の位置に置
換しうる。シクロアルキル基の置換基としてはた
とえばメチル、イソプロピル、ジメチルなど炭素
数１〜３のアルキル基があげられ、これらは環上
の任意の位置に１〜３個置換しうる。炭素を結合
手とする異項環基の置換基としてはたとえばメチ
ル、アセトキシ、ベンゾイル、ニコチノイルなど
があげられ、これらは環上の任意の位置に置換し
うる。アミノ基の置換基としては、たとえば低級
アルキル（たとえばメチル、エチル、ｎ−プロピ
ル、ｉ−プロピル、ｎ−ブチルなど炭素数１〜４
のもの）、アラルキル（たとえばベンジル、フエ
ネチルなど）、フエニル、ピリジル（たとえば２
−ピリジン、３−ピリジル、４−ピリジル、５−
メチル−３−ピリジル、４−メチル−２−ピリジ
ル、２−メチル−３−ピリジルなど）、低級アル
コキシカルボニルアセチル（たとえばメトキシカ
ルボニルアセチル、エトキシカルボニルアセチル
など）、低級アルキルカルボニル（たとえばアセ
チル、プロピオニル、ブチロイルなど）、カルボ
キシカルボニル、低級アルコキシカルボニルカル
ボニル（たとえばメトキシカルボニルカルボニ
ル、エトキシカルボニルカルボニルなど）、低級
アルコキシカルボニル（たとえばメトキシカルボ
ニル、エトキシカルボニルなど）、ハロゲノアル
キルオキシカルボニル（トリクロロエトキシカル
ボニル、ペンタフロロエトキシカルボニルなど）
などがあげられ、これらは１個または２個置換し
うる。またアミノ基が２個の置換基を有すると
き、２個の置換基が互いに結合して環状アミノ基
を形成していてもよく、環状アミノ基の例として
はたとえばピペリジノ、モルホリノ、Ｎ−アセチ
ルピペラジノ、ピロリジノなどがあげられる。
一般式（）、（）中、R2で示されるピリジ
ル基としては２−ピリジル、３−ピリジル、４−
ピリジルのいずれでもよく、これらは環上の任意
の位置に置換基としてアルキル基（たとえばメチ
ル、エチル、ｎ−プロピル、ｉ−プロピル、ｎ−
ブチル、ｉ−ブチル、ｔ−ブチルなど炭素数１〜
４のもの）を有してもよい。
一般式（）、（）中、R3で示されるフエニ
ル基は環上の任意の位置に低級アルコキシ、低級
アルキル、ヒドロキシルまたはハロゲンの１〜３
個を置換基として有していてもよく、その低級ア
ルコキシとしてはたとえばメトキシ、エトキシ、
ｎ−プロポキシなどの炭素数１〜４のものが、低
級アルキルとしてはたとえばメチル、エチル、ｎ
−プロピルなどの炭素数１〜４のものが、またハ
ロゲンとしてはフツ素、塩素、臭素、ヨウ素があ
げられる。またR3で示されるフエニル基は環上
の隣り合う任意の位置にメチレンジオキシまたは
トリメチレンを置換していてもよい。
一般式（）で表わされる化合物は、薬理学的
に許容される有機酸又は無機酸の付加塩であつて
もよく、このような塩としては、たとえば塩酸、
臭化水素酸、リン酸、硫酸、蓚酸、メタンスルホ
ン酸などの塩があげられる。
一般式（）で表わされる化合物は、一般式
（）で表わされる化合物と一般式（）で表わ
される化合物とを塩基性物質の存在下に反応させ
ることによつて製造することができる。この反応
は通常たとえば水、アルコール、アセトニトリ
ル、テトラヒドロフラン、ジメチルホルムアミ
ド、１，２−ジメトキシエタンなどの溶媒中で行
なわれる。化合物（）と化合物（）の接触割
合は化合物（）１モルに対し化合物（）１〜
1.2モルが好ましい。塩基性物質としてはたとえ
ばトリエチルアミン、水酸化ナトリウム、炭酸ナ
トリウム、炭酸カリウムなどがあげられる。塩基
性物質の添加量は化合物（）１モルに対し、通
常2.0〜3.0モル、好ましくは2.0〜2.5モルである。
反応温度は通常０℃〜溶媒の沸点の範囲内で行な
われる。この反応においては化合物（）と化合
物（）が反応してまず一般式
〔式中、R1、R2およびR3前記と同意義であ
る。〕で表わされる化合物が生成し、ついでこれ
が閉環して化合物（）が生成する。これらの反
応をより有利に行なうためには、まず化合物
（）と化合物（）を室温以下の温度で接触さ
せ、ついで室温以上に加温もしくは加熱するのが
よい。
このようにして得られる化合物（）はたとえ
ばクロマトグラフイー、溶媒抽出、結晶化、再結
晶など公知の分離精製手段により分離精製するこ
とができる。
本発明の化合物（）およびその塩は人を含む
哺乳動物に対し優れた解熱作用、鎮痛作用、抗炎
症作用、抗潰瘍作用、血小板凝集抑制作用、トロ
ンボキサンA2合成阻害作用を示し、毒性は極め
て弱く、安全域が高い。したがつて本発明の化合
物は哺乳動物に対し疼痛、炎症性疾患、リウマチ
性慢性疾患、消化器潰瘍性疾患、血小板血栓に基
づく虚血性循環器障害などの治療のために用いる
ことができる。投与方法は、たとえば錠剤、カプ
セル剤、散剤、顆粒剤などとして経口的に用いら
れるほか、注射剤、ペレツトとして非経口的に投
与することができる。投与量は成人１人につき通
常１日50〜500mgを経口的に、50〜200mgを非経口
的に１〜３回に分けて投与される。
一般式（）で表わされる化合物の中でも、４
−〔４−フエニル−５−（３−ピリジル）−１，３
−チアゾール〕酪酸、４−〔４−（４−メトキシフ
エニル）−５−（３−ピリジル）−１，３−チアゾ
ール〕酪酸は特に優れたトロンボキサン合成酵素
阻害作用を有し、２−フエニル−４−（４−メト
キシフエニル）−５−（３−ピリジル）−１，３−
チアゾール、２−シクロヘキシル−４−（４−メ
トキシフエニル）−５−（３−ピリジル）−１，３
−チアゾール、２−シクロヘキシル−４−フエニ
ル−５−（３−ピリジル）−１，３−チアゾールは
特に優れた血小板凝集作用を有し、また２−アミ
ノ−４−（４−メトキシフエニル）−５−（３−ピ
リジル）−１，３−チアゾール、２−メチルアミ
ノ−４−（４−メトキシフエニル）−５−（３−ピ
リジル）−１，３−チアゾール、２−エチル−４
−（４−メトキシフエニル）−５−（３−ピリジル）
−１，３−チアゾール、２−メチルアミノ−４−
（３，４−メチレンジオキシフエニル）−５−（３
−ピリジル）−１，３−チアゾール、２−メチル
アミノ−４−（３，４−トリメチレンフエニル）−
５−（３−ピリジル）−１，３−チアゾールは特に
優れた鎮痛、解熱、抗潰瘍作用を有している。
一般式（）で表わされる化合物は、たとえば
つぎの方法により製造することができる。
R2−CH3
（）リチウムジイソプロピルアミン
―――――――――――――――――→
R2
−CH2
（）
Li
R3COR4（）
―――――――→
R2
−CH2
（）COR3X2
―――――→
酢酸（）
〔式中、R2，R3およびＸは前記と同意義であ
り、R4はたとえばメトキシ、エトキシなど炭素
数１〜４の低級アルコキシ基またはジメチルアミ
ノ、ジエチルアミノ、Ｎ−フエニル−Ｎ−メチル
アミノ、Ｎ−メトキシ−メチルアミノ、ピロリジ
ノ、モノホリノ、メチルアジリジノを示す。〕
化合物（）を化合物（）へ導びく反応は、
化合物（）とリチウムジイソプロピルアミンを
反応させることによつて行なわれる。この反応は
通常たとえば無水テトラヒドロフラン、無水ジエ
チルエーテルなどの溶媒中、−70°〜10℃で行なわ
れる。
化合物（）を化合物（）に導びく反応は化
合物（）と化合物（）を反応させることによ
つて行なわれる。この反応は通常たとえば上述と
同様に無水テトラヒドロフランまたは無水ジエチ
ルエーテルなどの溶媒中0°〜20℃で行なわれる。
化合物（）にハロゲンを反応させることによ
り化合物（）を得ることができる。この反応は
たとえば酢酸などの溶媒中、化合物（）に塩
素、臭素などのハロゲンを作用させることにより
行なわれる。反応温度は通常10〜100℃で反応時
間は通常１〜10時間である。生成物は、反応液に
エーテル、イソプロピルエーテルなどを加えて不
溶性の塩として沈殿させ、溶媒を除去後、残査を
エタノール、酢酸エチル、メタノールなどから結
晶化して精製することができる。
また一般式（）で表わされる化合物はたとえ
ばつぎのようにして製造することができる。
〔式中、R1は前記と同意義であり、R5はメト
キシあるいはエトキシ基またはフエニル基を、
R6は環状アミノ基、２置換低級アルキルアミノ
またはジフエニルアミノ基を、R7はR1で示され
る置換基のうちジ置換アミノ以外の基を示す。〕
化合物（）を化合物（）に導びくには化
合物（）と化合物（）を反応させることによ
り行なわれる。この反応は有機溶媒中で行なわ
れ、溶媒としてはたとえばメチレンクロライド、
クロロホルムなどがあげられる。化合物（）と
化合物（）の接触割合は通常化合物（）１モ
ルに対し化合物（）1.0〜1.5モルである。反応
温度は通常０℃〜50℃で、反応時間は通常１〜５
時間である。
化合物（）を化合物（）に導びくには、
常法公知のアルカリ性または酸性加水分解反応が
行われる。アルカリ性加水分解には水酸化ナトリ
ウム、水酸化カリウムがまた、酸性加水分解には
塩酸、臭素酸が使用される。溶媒としては水また
は含水有機溶媒（エタノール、メタノール、ジオ
キサンなど）が用いられる。
化合物（）を化合物（）に導びくに
は、化合物（）に硫化水素を塩基性条件下に反
応させることにより行なわれる。塩基としてトリ
エチルアミン、ピリジンが好適であり、反応溶媒
としてメチレンクロライド、クロロホルム、トリ
エチルアミン、ピリジンなどが使用される。反応
は通常−10℃〜30℃で常圧または加圧下に行われ
る。
化合物（）を化合物（）に導びくには、
化合物（）にP4S10を反応させればよい。こ
の反応はエーテル、テトラヒドロフラン、メチレ
ンクロライド、クロロホルムなどの有機溶媒中
で、室温から溶媒の沸点までの温度範囲内で行わ
れる。化合物（）に対して五硫化リン（P4
S10として）は、0.5モルから1.2モル使用される。
以下に実施例、実験例および参考例を記載して
本発明をより具体的に説明する。
実施例 １
Ｎ−メチルチオウレア242mgのアセトニトリル
18ml溶液に、２−ブロム−１−（４−メトキシフ
エニル）−２−（３−ピリジル）−エタノンハイド
ロブロミド1.0ｇを懸濁し、かき混ぜながらトリ
エチルアミン0.4mlをゆつくり滴下する。滴下終
了後、還流温度で３時間かきまぜ、溶媒を留去す
る。残渣に飽和炭酸水素ナトリウム水を加え、酢
酸エチルで抽出し、乾燥後、溶媒を留去する。生
成物を酢酸エチル−イソプロピルエーテルから再
結晶すると、４−（４−メトキシフエニル）−２−
メチルアミノ−５−（３−ピリジル）−１，３−チ
アゾール650mg（85％）が得られる。融点158−
159℃。
実施例 ２
チオウレア516mgのアセトニトリル40ml溶液に
２−ブロム−１−（４−メトキシフエニル）−２−
（３−ピリジル）−エタノンハイドロブロミド2.5
ｇを懸濁し、かき混ぜながらトリエチルアミン
0.95mlをゆつくり滴下する。滴下終了後、還流温
度で３時間かきまぜ、放冷後、析出結晶を取す
る。結晶を飽和炭酸水素ナトリウム水、水、エタ
ノール、エチルエーテルの順で洗い、乾燥する。
THFより再結晶し、２−アミノ−４−（４−メト
キシフエニル）−５−（３−ピリジル）−１，３−
チアゾール1.5ｇ（90％）を得る。融点265−266
℃。
実施例 ３
チオプロピオン酸アミド493mgのアセトニトリ
ル40ml溶液に２−ブロム−１−（４−メトキシフ
エニル）−２−（３−ピリジル）−エタノン2.15ｇ
を懸濁し、かき混ぜながらトリエチルアミン0.78
mlをゆつくり滴下する。滴下終了後、還流温度で
３時間かきまぜ、溶媒を留去する。飽和炭酸水素
ナトリウム水を加え、酢酸エチルで抽出し、乾燥
後、溶媒を留去する。酢酸エチル−イソプロピル
エーテルから再結晶すると２−エチル−４−（４
−メトキシフエニル）−５−（３−ピリジル）−１，
３−チアゾール1.38ｇ（91％）が得られる。融点
59−60℃。
実施例 ４
２−ブロム−１−（４−メトキシフエニル）−２
−（３−ピリジル）エタノンハイドロブロミド
2.26ｇをアセトニトリル40mlに懸濁し、４−メト
キシカルボニルブタンチオアミド1.0ｇを加え、
かきまぜながらトリエチルアミン0.8mlを滴下す
る。還流温度で３時間かきまぜ、溶媒を留去して
飽和炭酸水素ナトリウム水を加える。生成物を酢
酸エチルで抽出し、水洗、乾燥後、濃縮し、シリ
カゲルカラムクロマトグラフイー（酢酸エチル−
イソプロピルエーテル（１：１）で精製して、２
−（３−メトキシカルボニルプロピル）−４−（４
−メトキシフエニル）−５−ピリジル）−１，３−
チアゾール1.5ｇ（収率72.6％）を得る。油状物
質。
実施例 ５
実施例４で得られる２−（３−メトキシカルボ
ニルプロピル）−４−（４−メトキシフエニル）−
５−（３−ピリジル）−１，３−チアゾール1.5ｇ
をメタノール５mlに溶かし、水酸化ナトリウム
1.5ｇの水５ml溶液を加えて、80℃で２時間かき
まぜる。水を加えてＮ−塩酸でPH6.0に調整し、
酢酸エチルで生成物を抽出する。有機層を水洗、
乾燥後濃縮し、結晶を酢酸エチルから再結晶する
と２−（３−カルボキシプロピル）−４−（４−メ
トキシフエニル）−５−（３−ピリジル）−１，３
−チアゾール1.2ｇ（収率83％）が得られる。融
点163−164℃。
実施例 ６
実施例４で得られる２−（３−メトキシカルボ
ニルプロピル）−４−（４−メトキシフエニル）−
５−（３−ピリジル）−１，３−チアゾール770mg
をTHF10mlに溶かし氷冷する。水素化リチウム
アルミニウム100mgを少しずつ加え１時間かきま
ぜた後、水を加えて酢酸エチルで抽出する。有機
層を水洗、乾燥後、濃縮し、シリカゲルカラムク
ロマトグラフイー（クロロホルム−メタノール
（９：１））で精製すると２−（４−ヒドロキシブ
チル）−４−（４−メトキシフエニル）−５−（３−
ピリジル）−１，３−チアゾール576mg（収率81
％）が得られる。油状物質。
実施例 ７
２−アミノ−４−（４−メトキシフエニル）−５
−（３−ピリジル）−１，３−チアゾール１ｇを
DMF5mlに溶かし氷冷下エトキシカルボニルアセ
チルクロリド580mgを加えてかきまぜる。30分後、
飽和炭酸水素ナトリウム水を加えて生成物を酢酸
エチルで抽出する。有機層を水洗、乾燥後、濃縮
し、テトラヒドロフランから再結晶して、２−エ
トキシカルボニルアセチルアミノ−４−（４−メ
トキシフエニル）−５−（３−ピリジル）−１，３
−チアゾール850mg（収率61％）を得る。融点202
−203℃。
実施例 ８
２−ブロム−１−（４−メトキシフエニル）−２
−（３−ピリジル）−エタノンハイドロブロミド
1.0ｇと１−ピペラジンカルボチオアミド387mgを
アセトニトリル15ml中に加え、かき混ぜながらト
リエチルアミン0.4mlをゆつくり加える。滴下終
了後、還流温度で２時間かき混ぜ、溶媒を留去す
る。残渣に飽和炭酸水素ナトリウム水を加え酢酸
エチルで抽出し、乾燥後、溶媒を留去する。残渣
をピリジン２mlに溶かし、氷冷してアセチルクロ
リド0.3mlを加え、室温で１時間放置する。反応
液を氷水中にあけて酢酸エチルで抽出し、抽出液
は水洗、乾燥、濃縮する。残渣をシリカゲルカラ
ムクロマトグラフイー（酢酸エチル−メタノール
（９：１）で溶出）で精製して、２−（４−アセチ
ル−１−ピペラジニル）−４−（４−メトキシフエ
ニル）−５−（３−ピリジル）−１，３−チアゾー
ル300mg（収率28％）を得る。
実施例 ９
２−アミノ−４−（４−メトキシフエニル）−５
−（３−ピリジル）−１，３−チアゾール200mgを
１％塩酸メタノール3.2mlに溶解し、溶媒を留去
する。残渣をメタノール−酢酸エチルから再結晶
して、２−アミノ−４−（４−メトキシフエニル）
−５−（３−ピリジル）−１，３−チアゾール塩酸
塩180mg（収率80％）を得る。融点145−150℃。
実施例 10
Ｎ−メチルチオウレア661mgのアセトニトリル
40ml溶液に、２−ブロム−１−（５−インダニル）
−２−（３−ピリジル）−エタノン ハイドロブロ
ミド2.9ｇを懸濁し、かきまぜながらトリエチル
アミン１mlをゆつくり滴下する。滴下終了後、還
流温度で２時間かき混ぜ、放冷後溶媒を留去す
る。残渣に飽和炭酸水素ナトリウム水を加え酢酸
エチルで抽出し、水洗、乾燥後、溶媒を留去す
る。酢酸エチル−イソプロピルエーテルから再結
晶すると、４−（５−インダニル）−２−メチルア
ミノ−５−（３−ピリジル）−１，３−チアゾール
1.8ｇ（収率80％）が得られる。融点169−170°。
実施例 11
ベンジルオキシカルボニルアミノチオアセトア
ミド1.12ｇのアセトニトリル40ml溶液に、２−ブ
ロム−１−（４−メトキシフエニル）−２−（３−
ピリジル）−エタノン ハイドロブロミド2.0ｇを
懸濁し、かき混ぜながら、トリエチルアミン0.8
mlを加える。還流温度で２時間かき混ぜ放冷後、
溶媒を留去する。残渣に飽和炭酸水素ナトリウム
水を加え、酢酸エチルで抽出し、乾燥後溶媒を留
去する。残渣を酢酸エチル−イソプロピルエーテ
ルから再結晶すると、２−（ベンジルオキシカル
ボニルアミノメチル）−４−（４−メトキシフエニ
ル）−５−（３−ピリジル）−１，３−チアゾール
1.3ｇ（収率56％）が得られる。融点93−94°。
実施例 12
実施例11で得られた２−（ベンジルオキシカル
ボニルアミノメチル）−４−（４−メトキシフエニ
ル）−５−（３−ピリジル）−１，３−チアゾール
1.2ｇをテトラヒドロフラン10mlに溶かし5N−塩
酸10mlを加えて80°で２時間かき混ぜる。テトラ
ヒドロフランを減圧で留去し、水層を2N−
NaOHでアルカリ性とし、酢酸エチルで抽出す
る。水洗、乾燥後、溶媒を留去し、残渣をシリカ
ゲルカラムクロマトグラフイー〔クロロホルム−
メタノール（９：１）で溶出〕で精製して、２−
（アミノメチル）−４−（４−メトキシフエニル）−
５−（３−ピリジン）−１，３−チアゾール0.5ｇ
（収率60％）を得る。
実施例 13
Ｎ−メチルベンゾイルアミノチオアセトアミド
2.3ｇのアセトニトリル50ml溶液に、２−ブロム
−１−（４−メトキシフエニル）−２−（３−ピリ
ジル）−エタノン ハイドロブロミド4.0ｇを懸濁
し、かき混ぜながらトリエチルアミン1.5mlを加
える。還流温度で２時間かき混ぜ、放冷後、溶媒
を留去する。残渣に飽和炭酸水素ナトリウム水を
加え、酢酸エチルで抽出し、乾燥後、溶媒を留去
する。残渣をシリカゲルカラムクロマトグラフイ
ーで精製（酢酸エチルで溶出）し、２−（Ｎ−メ
チルベンゾイルアミノメチル）−４−（４−メトキ
シフエニル）−５−（３−ピリジル）−１，３−チ
アゾール3.2ｇ（収率72％）を得る。
実施例 14
実施例13で得られた２−（Ｎ−メチルベンゾイ
ルアミノメチル）−４−（４−メトキシフエニル）
−５−（３−ピリジル）−１，３−チアゾールに
5N−塩酸20mlを加え、80°で２時間かき混ぜる。
反応液は放冷後、2N−NaOHでアルカリ性にし、
酢酸エチルで抽出する。抽出液を水洗、乾燥後、
減圧で濃縮し、シリカゲルカラムクロマトグラフ
イー〔クロロホルム−メタノール（９：１）で溶
出〕で精製して、４−（４−メトキシフエニル）−
２−メチルアミノメチル−５−（３−ピリジル）−
１，３−チアゾール2.1ｇ（収率91％）を得る。
上記実施例１〜９に準拠し製造した化合物の例
を表１に示す。なお融点は未補正である。
The present invention provides a novel 5- pyridyl-
The present invention relates to a 1,3-thiazole derivative, a method for producing the same, and a pharmaceutical composition comprising the same. Hitherto, 5-pyridyl-1,3-thiazole derivatives have hardly been known. The present inventors synthesized various novel 5-pyridyl-1,3-thiazole derivatives and conducted a search using a bioassay system. As a result, these compounds were found to have excellent analgesic, antipyretic, antiinflammatory, antiulcer, and thromboxane A 2 (TXA 2 ) was found to have pharmacological effects such as inhibition of synthetic enzymes and inhibition of platelet aggregation. That is, the present invention provides: (1) General formula [In the formula, R 1 is an alkyl group, alkenyl group, aryl group, aralkyl group, cycloalkyl group, thienyl group, furyl group, or amino group that may have a substituent, and R 2 is an alkyl group substituted with an alkyl group. Indicates a pyridyl group which may be R 3 represents a phenyl group which may have a substituent, but it has a methylenedioxy group or a trimethylene group at any adjacent position on the benzene ring, and these groups each have a carbon atom on the benzene ring. They may form a ring together. ] A 1,3-thiazole derivative or a salt thereof, (2) General formula [In the formula, R 2 and R 3 have the same meanings as above, and X
indicates a halogen atom. ] and a compound represented by
general formula [In the formula, R 1 has the same meaning as above. A method for producing a compound represented by the general formula [ ] and a salt thereof, which comprises reacting the compound represented by the general formula [ ] with a compound represented by the formula (3) a compound represented by the general formula ( ) or a salt thereof as an active ingredient. An analgesic or anti-inflammatory agent, and (4) an antiulcer agent comprising a compound represented by the general formula () or a salt thereof as an active ingredient. In the general formulas () and (), examples of the alkyl group represented by R 1 include methyl, ethyl, n-
Propyl, i-propyl, n-butyl, i-butyl, n-bentyl, n-hexyl, n-octyl, n-nonyl, n-decyl, etc. have 1 to 10 carbon atoms, and alkenyl groups include vinyl,
Those with 2 to 4 carbon atoms such as allyl, 2-putenyl, and isopropenyl, aryl groups such as phenyl and naphthyl, and aralkyl groups with 7 carbon atoms such as benzyl and phenethyl.
Examples of the cycloalkyl group include those having 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclobentyl, and cyclohexyl. Any of the alkyl group, alkenyl group, aryl group, aralkyl group, cycloalkyl group, heterocyclic group having a carbon bond, and amino group represented by R 1 may have a substituent. Substituents for alkyl groups include, for example, hydroxyl, amino, lower alkylamino (for example, methylamino, ethylamino, propylamino, etc. having 1 carbon number)
-4), carboxy, and lower alkoxycarbonyl (for example, those having 2 to 5 carbon atoms, such as methoxycarbonyl, ethoxycarbonyl, and n-propoxycarbonyl). Examples of substituents for alkenyl groups include hydroxyl, lower alkylamino (for example, those having 1 to 4 carbon atoms such as methylamino, ethylamino, and propylamino),
Examples include carboxyl. Substituents for the aryl group include, for example, carboxyl, halogen (e.g., fluorine, chlorine, bromine, etc.), 2-carboxyethenyl, 2-carboxy-1-propenyl, acetoxy, lower alkyl (e.g., methyl, ethyl, propyl, i -propyl, n-butyl, i-butyl, t-butyl, etc. having 1 to 4 carbon atoms), and these can be substituted at any position on the ring. Examples of substituents for aralkyl groups include methoxy, halogen (chloro, fluor, etc.)
These can be substituted at any position on the ring. Examples of substituents for the cycloalkyl group include alkyl groups having 1 to 3 carbon atoms such as methyl, isopropyl, and dimethyl, and 1 to 3 of these can be substituted at any position on the ring. Examples of the substituent of the heterocyclic group having carbon as a bond include methyl, acetoxy, benzoyl, nicotinoyl, etc., and these can be substituted at any position on the ring. Examples of substituents for the amino group include lower alkyl (for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, etc. having 1 to 4 carbon atoms)
), aralkyl (e.g. benzyl, phenethyl, etc.), phenyl, pyridyl (e.g. 2
-pyridine, 3-pyridyl, 4-pyridyl, 5-
methyl-3-pyridyl, 4-methyl-2-pyridyl, 2-methyl-3-pyridyl, etc.), lower alkoxycarbonylacetyl (e.g. methoxycarbonylacetyl, ethoxycarbonylacetyl, etc.), lower alkylcarbonyl (e.g. acetyl, propionyl, butyroyl) ), carboxycarbonyl, lower alkoxycarbonylcarbonyl (e.g. methoxycarbonylcarbonyl, ethoxycarbonylcarbonyl, etc.), lower alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, etc.), halogenoalkyloxycarbonyl (trichloroethoxycarbonyl, pentafluoroethoxycarbonyl, etc.)
etc., and one or two of these may be substituted. Further, when the amino group has two substituents, the two substituents may be bonded to each other to form a cyclic amino group, and examples of the cyclic amino group include piperidino, morpholino, and N-acetylpipe. Examples include radino and pyrrolidino. In the general formulas () and (), the pyridyl group represented by R 2 is 2-pyridyl, 3-pyridyl, 4-
Any pyridyl may be used as a substituent at any position on the ring, such as an alkyl group (e.g. methyl, ethyl, n-propyl, i-propyl, n-
Butyl, i-butyl, t-butyl, etc. with 1 or more carbon atoms
4). In the general formulas () and (), the phenyl group represented by R 3 has 1 to 3 lower alkoxy, lower alkyl, hydroxyl or halogen at any position on the ring.
The lower alkoxy may have, for example, methoxy, ethoxy,
Those having 1 to 4 carbon atoms such as n-propoxy, lower alkyl such as methyl, ethyl, n-propoxy, etc.
-Those having 1 to 4 carbon atoms such as propyl, and halogens include fluorine, chlorine, bromine, and iodine. Furthermore, the phenyl group represented by R 3 may be substituted with methylenedioxy or trimethylene at any adjacent position on the ring. The compound represented by the general formula () may be an addition salt of a pharmacologically acceptable organic or inorganic acid, such as hydrochloric acid,
Examples include salts of hydrobromic acid, phosphoric acid, sulfuric acid, oxalic acid, and methanesulfonic acid. The compound represented by the general formula () can be produced by reacting the compound represented by the general formula () with the compound represented by the general formula () in the presence of a basic substance. This reaction is usually carried out in a solvent such as water, alcohol, acetonitrile, tetrahydrofuran, dimethylformamide, 1,2-dimethoxyethane, or the like. The contact ratio between compound () and compound () is 1 to 1 mol of compound () to 1 mole of compound ().
1.2 mol is preferred. Examples of basic substances include triethylamine, sodium hydroxide, sodium carbonate, and potassium carbonate. The amount of the basic substance added is usually 2.0 to 3.0 mol, preferably 2.0 to 2.5 mol, per 1 mol of compound ().
The reaction temperature is usually within the range of 0°C to the boiling point of the solvent. In this reaction, compound () and compound () react and first the general formula [In the formula, R 1 , R 2 and R 3 have the same meanings as above. ] is produced, which is then ring-closed to produce the compound ( ). In order to carry out these reactions more advantageously, it is preferable to first bring the compound () into contact with the compound () at a temperature below room temperature, and then warm or heat the mixture to above room temperature. The compound () thus obtained can be separated and purified by known separation and purification means such as chromatography, solvent extraction, crystallization, and recrystallization. The compound () of the present invention and its salts exhibit excellent antipyretic, analgesic, anti-inflammatory, anti-ulcer, platelet aggregation-inhibiting, and thromboxane A2 synthesis inhibitory effects on mammals including humans, and are nontoxic. Extremely weak and has a high margin of safety. Therefore, the compounds of the present invention can be used in mammals to treat pain, inflammatory diseases, chronic rheumatic diseases, gastrointestinal ulcer diseases, ischemic circulatory disorders based on platelet thrombosis, and the like. For example, the drug can be administered orally in the form of tablets, capsules, powders, granules, etc., or parenterally in the form of injections or pellets. The dosage for each adult is usually 50 to 500 mg orally and 50 to 200 mg parenterally in 1 to 3 divided doses per day. Among the compounds represented by the general formula (), 4
-[4-phenyl-5-(3-pyridyl)-1,3
-thiazole]butyric acid, 4-[4-(4-methoxyphenyl)-5-(3-pyridyl)-1,3-thiazole]butyric acid has a particularly excellent thromboxane synthase inhibitory effect, and 2-phenyl -4-(4-methoxyphenyl)-5-(3-pyridyl)-1,3-
Thiazole, 2-cyclohexyl-4-(4-methoxyphenyl)-5-(3-pyridyl)-1,3
-thiazole, 2-cyclohexyl-4-phenyl-5-(3-pyridyl)-1,3-thiazole has particularly excellent platelet aggregation activity, and 2-amino-4-(4-methoxyphenyl)- 5-(3-pyridyl)-1,3-thiazole, 2-methylamino-4-(4-methoxyphenyl)-5-(3-pyridyl)-1,3-thiazole, 2-ethyl-4
-(4-methoxyphenyl)-5-(3-pyridyl)
-1,3-thiazole, 2-methylamino-4-
(3,4-methylenedioxyphenyl)-5-(3
-pyridyl)-1,3-thiazole, 2-methylamino-4-(3,4-trimethylenephenyl)-
5-(3-pyridyl)-1,3-thiazole has particularly excellent analgesic, antipyretic, and antiulcer effects. The compound represented by the general formula () can be produced, for example, by the following method. R 2 −CH 3 () Lithium diisopropylamine――――――――――――――――→ R 2 −CH 2 () Li R 3 COR 4 () ――――――――→ R 2 −CH 2 ( ) COR 3 ~4 lower alkoxy groups or dimethylamino, diethylamino, N-phenyl-N-methylamino, N-methoxy-methylamino, pyrrolidino, monophorino, and methylaziridino. ] The reaction that leads compound () to compound () is
It is carried out by reacting the compound () with lithium diisopropylamine. This reaction is usually carried out in a solvent such as anhydrous tetrahydrofuran or anhydrous diethyl ether at -70° to 10°C. The reaction of leading compound () to compound () is carried out by reacting compound () with compound (). This reaction is usually carried out at 0° to 20°C in a solvent such as anhydrous tetrahydrofuran or anhydrous diethyl ether, for example as described above. Compound () can be obtained by reacting compound () with a halogen. This reaction is carried out, for example, by allowing a halogen such as chlorine or bromine to act on the compound () in a solvent such as acetic acid. The reaction temperature is usually 10 to 100°C and the reaction time is usually 1 to 10 hours. The product can be purified by adding ether, isopropyl ether, etc. to the reaction solution to precipitate it as an insoluble salt, removing the solvent, and crystallizing the residue from ethanol, ethyl acetate, methanol, etc. Further, the compound represented by the general formula () can be produced, for example, in the following manner. [In the formula, R 1 has the same meaning as above, R 5 represents a methoxy or ethoxy group, or a phenyl group,
R 6 represents a cyclic amino group, a disubstituted lower alkylamino group or a diphenylamino group, and R 7 represents a group other than di-substituted amino among the substituents represented by R 1 . ] Compound () is introduced into compound () by reacting compound () with compound (). This reaction is carried out in an organic solvent, such as methylene chloride,
Examples include chloroform. The contact ratio between compound () and compound () is usually 1.0 to 1.5 moles of compound () per 1 mole of compound (). The reaction temperature is usually 0℃~50℃, and the reaction time is usually 1~5℃.
It's time. To lead compound () to compound (),
A conventional alkaline or acidic hydrolysis reaction is carried out. Sodium hydroxide and potassium hydroxide are used for alkaline hydrolysis, and hydrochloric acid and bromic acid are used for acidic hydrolysis. As the solvent, water or a water-containing organic solvent (ethanol, methanol, dioxane, etc.) is used. Compound () is introduced into compound () by reacting compound () with hydrogen sulfide under basic conditions. Triethylamine and pyridine are suitable as the base, and methylene chloride, chloroform, triethylamine, pyridine and the like are used as the reaction solvent. The reaction is usually carried out at -10°C to 30°C under normal pressure or increased pressure. To lead compound () to compound (),
What is necessary is to react compound () with P 4 S 10 . This reaction is carried out in an organic solvent such as ether, tetrahydrofuran, methylene chloride, or chloroform at a temperature ranging from room temperature to the boiling point of the solvent. Phosphorus pentasulfide (P 4
S 10 ) is used from 0.5 mol to 1.2 mol. The present invention will be explained in more detail by describing Examples, Experimental Examples, and Reference Examples below. Example 1 242 mg of N-methylthiourea in acetonitrile
1.0 g of 2-bromo-1-(4-methoxyphenyl)-2-(3-pyridyl)-ethanone hydrobromide is suspended in a 18 ml solution, and 0.4 ml of triethylamine is slowly added dropwise while stirring. After completion of the dropwise addition, the mixture was stirred at reflux temperature for 3 hours and the solvent was distilled off. Saturated sodium hydrogen carbonate water is added to the residue, extracted with ethyl acetate, dried, and the solvent is distilled off. The product was recrystallized from ethyl acetate-isopropyl ether to give 4-(4-methoxyphenyl)-2-
650 mg (85%) of methylamino-5-(3-pyridyl)-1,3-thiazole are obtained. Melting point 158−
159℃. Example 2 2-bromo-1-(4-methoxyphenyl)-2- was added to a solution of 516 mg of thiourea in 40 ml of acetonitrile.
(3-pyridyl)-ethanone hydrobromide 2.5
Suspend g and add triethylamine while stirring.
Slowly drip 0.95ml. After the dropwise addition, the mixture was stirred at reflux temperature for 3 hours, left to cool, and the precipitated crystals were collected. The crystals are washed with saturated sodium bicarbonate solution, water, ethanol, and ethyl ether in this order, and dried.
Recrystallized from THF, 2-amino-4-(4-methoxyphenyl)-5-(3-pyridyl)-1,3-
1.5 g (90%) of thiazole is obtained. Melting point 265−266
℃. Example 3 2.15 g of 2-bromo-1-(4-methoxyphenyl)-2-(3-pyridyl)-ethanone in a solution of 493 mg of thiopropionic acid amide in 40 ml of acetonitrile.
Suspend the triethylamine 0.78 while stirring.
Slowly drip ml. After completion of the dropwise addition, the mixture was stirred at reflux temperature for 3 hours and the solvent was distilled off. Add saturated aqueous sodium hydrogen carbonate, extract with ethyl acetate, dry, and evaporate the solvent. Recrystallization from ethyl acetate-isopropyl ether gives 2-ethyl-4-(4
-methoxyphenyl)-5-(3-pyridyl)-1,
1.38 g (91%) of 3-thiazole are obtained. melting point
59−60℃. Example 4 2-bromo-1-(4-methoxyphenyl)-2
-(3-pyridyl)ethanone hydrobromide
Suspend 2.26g in 40ml of acetonitrile, add 1.0g of 4-methoxycarbonylbutanethioamide,
Add 0.8 ml of triethylamine dropwise while stirring. Stir at reflux temperature for 3 hours, distill off the solvent, and add saturated aqueous sodium bicarbonate. The product was extracted with ethyl acetate, washed with water, dried, concentrated, and subjected to silica gel column chromatography (ethyl acetate-
Purified with isopropyl ether (1:1) to give 2
-(3-methoxycarbonylpropyl)-4-(4
-methoxyphenyl)-5-pyridyl)-1,3-
1.5 g of thiazole (yield 72.6%) is obtained. oily substance. Example 5 2-(3-methoxycarbonylpropyl)-4-(4-methoxyphenyl)- obtained in Example 4
5-(3-pyridyl)-1,3-thiazole 1.5g
Dissolve in 5 ml of methanol and add sodium hydroxide.
Add a solution of 1.5 g in 5 ml of water and stir at 80°C for 2 hours. Add water and adjust the pH to 6.0 with N-hydrochloric acid.
Extract the product with ethyl acetate. Wash the organic layer with water,
After drying and concentrating, the crystals were recrystallized from ethyl acetate to give 2-(3-carboxypropyl)-4-(4-methoxyphenyl)-5-(3-pyridyl)-1,3
-1.2 g of thiazole (yield 83%) are obtained. Melting point 163-164℃. Example 6 2-(3-methoxycarbonylpropyl)-4-(4-methoxyphenyl)- obtained in Example 4
5-(3-pyridyl)-1,3-thiazole 770mg
Dissolve in 10ml of THF and cool on ice. Add 100 mg of lithium aluminum hydride little by little and stir for 1 hour, then add water and extract with ethyl acetate. The organic layer was washed with water, dried, concentrated, and purified by silica gel column chromatography (chloroform-methanol (9:1)) to give 2-(4-hydroxybutyl)-4-(4-methoxyphenyl)-5-. (3-
pyridyl)-1,3-thiazole 576 mg (yield 81
%) is obtained. oily substance. Example 7 2-amino-4-(4-methoxyphenyl)-5
-(3-pyridyl)-1,3-thiazole 1g
Dissolve in 5 ml of DMF, add 580 mg of ethoxycarbonylacetyl chloride under ice cooling, and stir. 30 minutes later,
Saturated aqueous sodium bicarbonate is added and the product is extracted with ethyl acetate. The organic layer was washed with water, dried, concentrated, and recrystallized from tetrahydrofuran to give 2-ethoxycarbonylacetylamino-4-(4-methoxyphenyl)-5-(3-pyridyl)-1,3
- Obtain 850 mg of thiazole (yield 61%). melting point 202
−203℃. Example 8 2-bromo-1-(4-methoxyphenyl)-2
-(3-pyridyl)-ethanone hydrobromide
Add 1.0 g and 387 mg of 1-piperazinecarbothioamide to 15 ml of acetonitrile, and slowly add 0.4 ml of triethylamine while stirring. After completion of the dropwise addition, the mixture was stirred at reflux temperature for 2 hours and the solvent was distilled off. Saturated sodium bicarbonate water was added to the residue, extracted with ethyl acetate, dried, and the solvent was distilled off. Dissolve the residue in 2 ml of pyridine, cool on ice, add 0.3 ml of acetyl chloride, and leave at room temperature for 1 hour. The reaction solution was poured into ice water and extracted with ethyl acetate, and the extract was washed with water, dried, and concentrated. The residue was purified by silica gel column chromatography (eluted with ethyl acetate-methanol (9:1)) to give 2-(4-acetyl-1-piperazinyl)-4-(4-methoxyphenyl)-5-( 300 mg (yield 28%) of 3-pyridyl)-1,3-thiazole are obtained. Example 9 2-amino-4-(4-methoxyphenyl)-5
200 mg of -(3-pyridyl)-1,3-thiazole was dissolved in 3.2 ml of 1% hydrochloric acid and methanol, and the solvent was distilled off. The residue was recrystallized from methanol-ethyl acetate to give 2-amino-4-(4-methoxyphenyl).
180 mg (yield: 80%) of -5-(3-pyridyl)-1,3-thiazole hydrochloride is obtained. Melting point 145-150℃. Example 10 661 mg of N-methylthiourea in acetonitrile
2-Bromo-1-(5-indanyl) in 40ml solution
-2-(3-Pyridyl)-ethanone 2.9 g of hydrobromide is suspended, and 1 ml of triethylamine is slowly added dropwise while stirring. After completion of the dropwise addition, the mixture was stirred at reflux temperature for 2 hours, left to cool, and the solvent was distilled off. Saturated sodium bicarbonate water is added to the residue, extracted with ethyl acetate, washed with water, dried, and the solvent is distilled off. Recrystallization from ethyl acetate-isopropyl ether yields 4-(5-indanyl)-2-methylamino-5-(3-pyridyl)-1,3-thiazole.
1.8 g (80% yield) is obtained. Melting point 169−170°. Example 11 2-bromo-1-(4-methoxyphenyl)-2-(3-
pyridyl)-ethanone Suspend 2.0 g of hydrobromide and, while stirring, add 0.8 g of triethylamine.
Add ml. After stirring at reflux temperature for 2 hours and cooling,
The solvent is distilled off. Saturated sodium bicarbonate water is added to the residue, extracted with ethyl acetate, dried, and the solvent is distilled off. The residue was recrystallized from ethyl acetate-isopropyl ether to give 2-(benzyloxycarbonylaminomethyl)-4-(4-methoxyphenyl)-5-(3-pyridyl)-1,3-thiazole.
1.3 g (yield 56%) is obtained. Melting point 93−94°. Example 12 2-(benzyloxycarbonylaminomethyl)-4-(4-methoxyphenyl)-5-(3-pyridyl)-1,3-thiazole obtained in Example 11
Dissolve 1.2 g in 10 ml of tetrahydrofuran, add 10 ml of 5N hydrochloric acid, and stir at 80° for 2 hours. Tetrahydrofuran was distilled off under reduced pressure, and the aqueous layer was diluted with 2N−
Make alkaline with NaOH and extract with ethyl acetate. After washing with water and drying, the solvent was distilled off and the residue was subjected to silica gel column chromatography [chloroform-
Elution with methanol (9:1)] to obtain 2-
(aminomethyl)-4-(4-methoxyphenyl)-
5-(3-pyridine)-1,3-thiazole 0.5g
(yield 60%). Example 13 N-methylbenzoylaminothioacetamide
Suspend 4.0 g of 2-bromo-1-(4-methoxyphenyl)-2-(3-pyridyl)-ethanone hydrobromide in a solution of 2.3 g in 50 ml of acetonitrile, and add 1.5 ml of triethylamine while stirring. The mixture was stirred at reflux temperature for 2 hours, left to cool, and then the solvent was distilled off. Saturated sodium hydrogen carbonate water is added to the residue, extracted with ethyl acetate, dried, and the solvent is distilled off. The residue was purified by silica gel column chromatography (eluted with ethyl acetate) to give 2-(N-methylbenzoylaminomethyl)-4-(4-methoxyphenyl)-5-(3-pyridyl)-1,3- 3.2 g (72% yield) of thiazole are obtained. Example 14 2-(N-methylbenzoylaminomethyl)-4-(4-methoxyphenyl) obtained in Example 13
-5-(3-pyridyl)-1,3-thiazole
Add 20ml of 5N hydrochloric acid and stir at 80° for 2 hours.
After the reaction solution was allowed to cool, it was made alkaline with 2N-NaOH.
Extract with ethyl acetate. After washing the extract with water and drying,
It was concentrated under reduced pressure and purified by silica gel column chromatography [eluted with chloroform-methanol (9:1)] to give 4-(4-methoxyphenyl)-
2-Methylaminomethyl-5-(3-pyridyl)-
2.1 g (yield 91%) of 1,3-thiazole is obtained. Table 1 shows examples of compounds produced according to Examples 1 to 9 above. Note that the melting point is uncorrected.
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参考例 １
ジイソプロピルアミン33.2mlの無水テトラヒド
ロフラン300ml溶液を−78°に冷却し、かきまぜな
がらｎ−ブチルリチウムヘキサン溶液（1.6M）
148mlを滴下する。滴下終了後、10分間同温度で
かきまぜ、続いてβ−ピコリン20ｇを滴下する。
温度を−10°〜0°に上昇させ、20分間かきまぜた
後、ｐ−アニス酸エチル19.4ｇを無水テトラヒド
ロフラン40mlに溶かして滴下する。滴下終了後、
室温で１時間かきまぜ、水約100mlを加える。有
機溶媒を減圧で留去し、濃縮液を酢酸エチルで抽
出する。抽出液は水洗し、硫酸マグネシウム上で
乾燥した後、濃縮し、生成物を酢酸エチル−イソ
プロピルエーテルから結晶化させると、１−（４
−メトキシフエニル）−２−（３−ピリジル）−エ
タノン20.8ｇ（収率85％）が得られる。融点71−
72°
上記参考例に準じ、ｐ−アニス酸エチルの代わ
りに、安息香酸エチル、３，４−ジメトキシ安息
香酸エチル、３，４，５−トリメトキシ安息香酸
エチル、４−メトキシメトキシ安息香酸エチル、
５−インダニルカルボン酸メチル、５，６，７，
８−テトラヒドロ−２−ナフチルカルボン酸メチ
ル、１，４−ベンゾジオキサン−６−カルボン酸
メチル、２−ナフチルカルボン酸メチル、４−フ
ルオロ安息香酸メチルを用いることによつて下記
の化合物を合成することができる。
１−フエニル−２−（３−ピリジル）−エタノン
融点44.5−45.5°
１−（３，４−ジメトキシフエニル）−２−（３
−ピリジル）エタノン 融点114−115°
１−（３，４，５−トリメトキシフエニル）−２
−（３−ピリジル）エタノン 融点104−105°
１−（４−メトキシメトキシフエニル）−２−
（３−ピリジル）エタノン 融点43−44°
１−（４−フルオロフエニル）−２−（３−ピリ
ジル）エタノン 油状物
１−（５−インダニル）−２−（３−ピリジル）
エタノン 融点55−56°
１−（５，６，７，８−テトラヒドロ−２−ナ
フチル）−２−（３−ピリジル）エタノン 融点65
−66°
１−（１，４−ベンソジオキサン−６−イル）−
２−（３−ピリジル）エタノン 融点89−90°
１−（２−ナフチル）−２−（３−ピリジル）エ
タノン 融点69−70°
同様にして、またβ−ピコリンの代わりにα−
ピコリン、γ−ピコリン、３，５−ルチジンを用
いることによつて下記の化合物を合成することが
できる。
１−フエニル−２−（２−ピリジル）−エタノン
融点59−60°
１−（４−メトキシフエニル）−２−（２−ピリ
ジル）エタノン 融点77−78°
１−フエニル−２−（４−ピリジル）エタノン
融点109−110°
１−（４−メトキシフエニル）−２−（４−ピリ
ジル）エタノン 融点103−104°
１−フエニル−２−（５−メチル−３−ピリジ
ル）エタノン 融点53−54°
１−（４−エチルフエニル）−２−（３−ピリジ
ル）エタノン 融点80−81°
１−（３，４−メチレンジオキシフエニル）−２
−（３−ピリジル）エタノン 融点98−99°
参考例 ２
参考例１で得られる１−（４−メトキシフエニ
ル）−２−（３−ピリジル）エタノン6.85ｇを酢酸
36mlに溶かし、臭素1.7mlを加えて80°で３時間か
きまぜる。反応液を氷水で冷却し、析出した結晶
を過する。結晶体をエタノール、エチルエーテ
ルで洗浄後、乾燥すると２−ブロム−１−（４−
メトキシフエニル）−２−（３−ピリジル）エタノ
ンの臭化水素酸塩10.4ｇ（収率89％）が得られ
る。融点188−195°
参考例２と同様の方法で下記の化合物の臭化水
素酸塩が得られる。
２−ブロム−１−フエニル−２−（３−ピリジ
ル）エタノン 融点※１
208−215°
２−ブロム−１−（３，４−ジメトキシフエニ
ル）−２−（３−ピリジル）エタノン 融点※１
191−193°
２−ブロム−１−（３，４，５−トリメトキシ
フエニル）−２−（３−ピリジル）エタノン 融点
※１
184−186°
２−ブロム−１−（４−ヒドロキシフエニル）−
２−（３−ピリジル）エタノン※２
２−ブロム−１−（４−フルオロフエニル）−２
−（３−ピリジル）エタノン 融点※１
189−191°
２−ブロム−１−フエニル−２−（２−ピリジ
ル）エタノン 融点※１
180−181°
２−ブロム−１−（４−メトキシフエニル）−２
−（２−ピリジル）エタノン 融点※１
170−171°
２−ブロム−１−フエニル−２−（４−ピリジ
ル）エタノン 融点※１
230−232°
２−ブロム−１−（４−メトキシフエニル）−２
−（４−ピリジル）エタノン 融点※１
207−209°
２−ブロム−１−フエニル−２−（５−メチル
−３−ピリジル）エタノン 融点※１
189−193°
２−ブロム−１−（４−エチルフエニル）−２−
（３−ピリジル）エタノン 融点145−146°
２−ブロム−１−（３，４−メチレンジオキシ
フエニル）−２−（３−ピリジル）エタノン 融点
※１
174−175°
２−ブロム−１−（５−インダニル）−２−（３
−ピリジル）エタノン 融点※１
177−178°
２−ブロム−１−（５，６，７，８，−テトラヒ
ドロ−２−ナフチル）−２−（３−ピリジル）エタ
ノン 融点※１
160−162°
２−ブロム−１−（１，４−ベンゾジオキサン
−６−イル）−２−（３−ピリジル）エタノン
２−ブロム−１−（２−ナフチル）−２−（３−
ピリジル）エタノン 融点※１
197−199°
※１融点は臭化水素酸塩を示す。
※２本臭素酸塩は精製せずに直接チアゾール形
成反応に使用。
参考例 ３
ジイソプロピルアミン8.86mlの無水テトラヒド
ロフラン80ml溶液を−10°に冷却し、かき混ぜな
がらｎ−ブチルリチウムヘキサン溶液（1.6M）
39.5mlを滴下する。滴下終了後30分間同温度でか
き混ぜ、続いてβ−ピコリン5.34ｇを滴下する。
30分間かき混ぜた後、５−メトキシカルボニルイ
ンダン５ｇを無水テトラヒドロフラン10mlに溶か
して滴下する。滴下終了後、室温で１時間かき混
ぜ、水約25mlを加える。有機溶媒を減圧で留去
し、濃縮液を酢酸エチルで抽出する。抽出液は、
水洗し、硫酸マグネシウム上で乾燥した後、濃縮
し、生成物を酢酸エチル−イソプロピルエーテル
から結晶化させると、１−（５−インダニル）−２
−（３−ピリジル）−エタノン5.6ｇ（収率82％）
が得られる。融点55−56°
参考例 ４
１−（５−インダニル）−２−（３−ピリジン）−
エタノン4.3ｇを酢酸20mlに溶かし、臭素0.93ml
を加える。80°で１時間かき混ぜた後、反応液を
冷却する。エチルエーテル80mlを加えると油状物
が遊離する。上澄液を捨て、残渣をアセトニトリ
ル50mlに溶かして冷却すると２−ブロム−１−
（５−インダニル）−２−（３−ピリジル）−エタノ
ン ハイドロプロミド6.2ｇが得られる。収率86
％。融点176−177°
参考例 ５
ピペロニル酸5.0ｇを塩化チオニル６mlに懸濁
し、８時間加熱還流する。過剰の塩化チオニルを
減圧で留去し、ピペロニル酸の酸塩化物の粗結晶
を得る。この粗結晶を塩化メチレン10mlに溶か
し、プロピレンイミン1.7ｇとトリエチルアミン
3.3ｇの石油エーテル15ml溶液に、0°でかき混ぜ
ながら、ゆつくり滴下する。滴下終了後、さらに
30分間かきまぜ、溶媒を減圧で留去する。残渣に
水を加え酢酸エチルで抽出し、抽出液は水洗、乾
燥後、減圧濃縮する。粗成績体をシリカゲルカラ
ムクロマトグラフイーで精製（酢酸エチルで溶
出）してＮ−ピペロニロイルプロピレンイミン
4.37ｇ（収率69％）を得る。
参考例 ６
ジイソプロピルアミン3.2ml、ｎ−ブチルリチ
ウムヘキサン溶液（1.6M）14.5ml、テトラヒド
ロフラン60mlより、リチウムジイソプロピルアミ
ド溶液を0°で調整する。この溶液にβ−ピコリン
1.95ｇを加えて0°で30分間かき混ぜる。次にＮ−
ピペロニルプロピレンイミン4.3ｇのテトラヒド
ロフラン溶液をゆつくり滴下し、滴下終了後、１
時間かき混ぜる。Ｎ−塩酸を反応液が酸性になる
まで加え、有機溶媒を減圧で留去する。水層を重
ソウ水で弱アルカリ性にした後、酢酸エチルで抽
出し、抽出液は、水洗、乾燥後、減圧で濃縮す
る。残渣は、シリカゲルカラムクロマトグラフイ
ーで精製し（酢酸エチルで溶出）し、続いて酢酸
エチル−イソプロピルエーテルから再結晶すると
１−ピペロニル−２−（３−ピリジル）−エタノン
3.2ｇ（収率63％）が得られる。融点98−99°
実験例
Ａ カラゲニン浮腫法による抗炎症作用（C.E.
法）
Jol：SDラツト（雄性、体重180〜220ｇ）１群
６匹を用い、ウインターら（Winter et al）の方
法〔Proc.Soc.exp.Biol.Med.，111，544（1962）〕
に従つてしらべた。検体の経口投与１時間後に１
％カラゲニン生理食塩水溶液0.05mlを足蹠の皮下
に注射した。カラゲニン注射３時間後における後
肢容積と注射前容積を測定しその差から浮腫容積
を求めた。検体投与群と検体非投与対照群との浮
腫容積を比較して浮腫抑制率を求めた。
Ｂ フエニルキノン・ライシング・シンドローム
法による鎮痛作用試験（P.Q.法）
生後４週令、体重20±２ｇのSlc.ICR系雄マウ
ス１群10匹を用い、シーグムンド（Siegmund）
らの方法〔Proc.Soc.Exp.Biol.Med.，95729
（1957）〕に従つて行なつた。検体を経口投与して
30分後に0.02％フエニルキノン0.1ml／10ｇを腹
腔内投与し、20分間にわたりマウスが示すライシ
ング（writhing）またはストレツチング
（stretching）の回数を数えた。検体投与群と検
体非投与対照群との平均回数を比較し抑制率を求
めた。
Ｃ 水浸拘束ストレス潰瘍試験（W.I.法）
SD系雄性ラツト（７週令、体重190〜240ｇ）
一群６匹を用い、高木及び岡部の方法〔Jpn.J.
Pharmacol.，18，９（1968）〕に従い、24時間絶
食（但し水は自由に摂取）後、実験した。ラツト
をステンレス製拘束ケージ内に入れ、胸部剣状骨
下まで23℃に調節した水槽内に５時間浸けた。腺
胃部粘膜の潰瘍を実体顕微鏡下に各潰瘍の長径
（mm）を測り、和して潰瘍指数とした。検体は水
浸30分前に経口投与した。検体投与群と検体非投
与対照群との潰瘍指数を比較し抑制率を求めた。
Ｄ マウスでの急性毒性試験（急性毒性）
５週令のICR系雄性マウス、１群５匹とし、各
検体500mg／Kgを経口投与し、７日間の死亡例を
測定した。
以上の試験結果の代表例を表２に示す。[Table] Reference Example 1 A solution of 33.2 ml of diisopropylamine in 300 ml of anhydrous tetrahydrofuran was cooled to -78°, and while stirring was added n-butyllithium hexane solution (1.6 M).
Drop 148ml. After the addition is completed, the mixture is stirred at the same temperature for 10 minutes, and then 20 g of β-picoline is added dropwise.
After raising the temperature to -10° to 0° and stirring for 20 minutes, 19.4 g of ethyl p-anisate dissolved in 40 ml of anhydrous tetrahydrofuran is added dropwise. After the dripping is finished,
Stir at room temperature for 1 hour, then add about 100ml of water. The organic solvent was distilled off under reduced pressure, and the concentrated solution was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, concentrated, and the product was crystallized from ethyl acetate-isopropyl ether to give 1-(4
20.8 g (85% yield) of -methoxyphenyl)-2-(3-pyridyl)-ethanone are obtained. Melting point 71−
72° According to the above reference example, instead of ethyl p-anisate, ethyl benzoate, ethyl 3,4-dimethoxybenzoate, ethyl 3,4,5-trimethoxybenzoate, ethyl 4-methoxymethoxybenzoate,
Methyl 5-indanylcarboxylate, 5,6,7,
Synthesize the following compound by using methyl 8-tetrahydro-2-naphthylcarboxylate, methyl 1,4-benzodioxane-6-carboxylate, methyl 2-naphthylcarboxylate, and methyl 4-fluorobenzoate. I can do it. 1-Phenyl-2-(3-pyridyl)-ethanone Melting point 44.5-45.5° 1-(3,4-dimethoxyphenyl)-2-(3
-pyridyl)ethanone Melting point 114-115° 1-(3,4,5-trimethoxyphenyl)-2
-(3-pyridyl)ethanone Melting point 104-105° 1-(4-methoxymethoxyphenyl)-2-
(3-pyridyl)ethanone Melting point 43-44° 1-(4-fluorophenyl)-2-(3-pyridyl)ethanone Oil 1-(5-indanyl)-2-(3-pyridyl)
Ethanone Melting point 55-56° 1-(5,6,7,8-tetrahydro-2-naphthyl)-2-(3-pyridyl)ethanone Melting point 65
-66° 1-(1,4-bensodioxan-6-yl)-
2-(3-pyridyl)ethanone, melting point 89-90° 1-(2-naphthyl)-2-(3-pyridyl)ethanone, melting point 69-70° Similarly, and in place of β-picoline, α-
By using picoline, γ-picoline, and 3,5-lutidine, the following compounds can be synthesized. 1-Phenyl-2-(2-pyridyl)-ethanone Melting point 59-60° 1-(4-methoxyphenyl)-2-(2-pyridyl)ethanone Melting point 77-78° 1-Phenyl-2-(4- Pyridyl)ethanone Melting point 109-110° 1-(4-methoxyphenyl)-2-(4-pyridyl)ethanone Melting point 103-104° 1-Phenyl-2-(5-methyl-3-pyridyl)ethanone Melting point 53- 54° 1-(4-ethylphenyl)-2-(3-pyridyl)ethanone Melting point 80-81° 1-(3,4-methylenedioxyphenyl)-2
-(3-pyridyl)ethanone Melting point 98-99° Reference example 2 6.85 g of 1-(4-methoxyphenyl)-2-(3-pyridyl)ethanone obtained in Reference example 1 was added to acetic acid.
Dissolve in 36ml, add 1.7ml of bromine, and stir at 80° for 3 hours. The reaction solution was cooled with ice water, and the precipitated crystals were filtered. After washing the crystal with ethanol and ethyl ether and drying it, 2-bromo-1-(4-
10.4 g (89% yield) of hydrobromide of methoxyphenyl)-2-(3-pyridyl)ethanone are obtained. Melting point: 188-195° The hydrobromide salt of the following compound is obtained in the same manner as in Reference Example 2. 2-Bromo-1-phenyl-2-(3-pyridyl)ethanone Melting point *1 208-215° 2-Bromo-1-(3,4-dimethoxyphenyl)-2-(3-pyridyl)ethanone Melting point *1
191-193° 2-Bromo-1-(3,4,5-trimethoxyphenyl)-2-(3-pyridyl)ethanone Melting point*1 184-186° 2-Bromo-1-(4-hydroxyphenyl )−
2-(3-pyridyl)ethanone*2 2-bromo-1-(4-fluorophenyl)-2
-(3-pyridyl)ethanone Melting point *1 189-191° 2-Bromo-1-phenyl-2-(2-pyridyl)ethanone Melting point *1 180-181° 2-brom-1-(4-methoxyphenyl) -2
-(2-pyridyl)ethanone Melting point *1 170-171° 2-Bromo-1-phenyl-2-(4-pyridyl)ethanone Melting point *1 230-232° 2-Bromo-1-(4-methoxyphenyl) -2
-(4-pyridyl)ethanone Melting point *1 207-209° 2-bromo-1-phenyl-2-(5-methyl-3-pyridyl)ethanone Melting point *1 189-193° 2-brom-1-(4- ethyl phenyl)-2-
(3-pyridyl)ethanone Melting point 145-146° 2-brom-1-(3,4-methylenedioxyphenyl)-2-(3-pyridyl)ethanone Melting point*1 174-175° 2-brom-1- (5-indanyl)-2-(3
-pyridyl)ethanone Melting point *1 177-178° 2-bromo-1-(5,6,7,8,-tetrahydro-2-naphthyl)-2-(3-pyridyl)ethanone Melting point *1 160-162° 2 -Bromo-1-(1,4-benzodioxan-6-yl)-2-(3-pyridyl)ethanone 2-Bromo-1-(2-naphthyl)-2-(3-
Pyridyl) ethanone Melting point *1 197-199° *1 Melting point indicates hydrobromide. *Two bromates are used directly in the thiazole formation reaction without purification. Reference Example 3 A solution of 8.86 ml of diisopropylamine in 80 ml of anhydrous tetrahydrofuran was cooled to -10°, and while stirring, added n-butyllithium hexane solution (1.6 M).
Drop 39.5ml. After the addition was completed, the mixture was stirred at the same temperature for 30 minutes, and then 5.34 g of β-picoline was added dropwise.
After stirring for 30 minutes, 5 g of 5-methoxycarbonylindane dissolved in 10 ml of anhydrous tetrahydrofuran was added dropwise. After dropping, stir at room temperature for 1 hour and add approximately 25 ml of water. The organic solvent was distilled off under reduced pressure, and the concentrated solution was extracted with ethyl acetate. The extract is
After washing with water and drying over magnesium sulfate, concentration and crystallization of the product from ethyl acetate-isopropyl ether, 1-(5-indanyl)-2
-(3-pyridyl)-ethanone 5.6g (yield 82%)
is obtained. Melting point 55-56° Reference example 4 1-(5-indanyl)-2-(3-pyridine)-
Dissolve 4.3g of ethanone in 20ml of acetic acid and 0.93ml of bromine.
Add. After stirring at 80° for 1 hour, the reaction mixture is cooled. Addition of 80 ml of ethyl ether liberates an oil. Discard the supernatant liquid, dissolve the residue in 50 ml of acetonitrile and cool it to obtain 2-bromo-1-
(5-Indanyl)-2-(3-pyridyl)-ethanone 6.2 g of hydropromide are obtained. Yield 86
%. Melting point: 176-177° Reference Example 5 5.0 g of piperonic acid is suspended in 6 ml of thionyl chloride and heated under reflux for 8 hours. Excess thionyl chloride is distilled off under reduced pressure to obtain crude crystals of the acid chloride of piperonic acid. Dissolve this crude crystal in 10 ml of methylene chloride, add 1.7 g of propylene imine and triethylamine.
Add slowly dropwise to a solution of 3.3 g in 15 ml of petroleum ether while stirring at 0°. After dripping, further
Stir for 30 minutes and remove the solvent under reduced pressure. Water is added to the residue, extracted with ethyl acetate, and the extract is washed with water, dried, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluted with ethyl acetate) to obtain N-piperonyloylpropyleneimine.
Obtain 4.37 g (yield 69%). Reference Example 6 A lithium diisopropylamide solution is prepared from 3.2 ml of diisopropylamine, 14.5 ml of n-butyllithium hexane solution (1.6M), and 60 ml of tetrahydrofuran at 0°. β-picoline in this solution
Add 1.95g and stir at 0° for 30 minutes. Then N-
A solution of 4.3 g of piperonylpropyleneimine in tetrahydrofuran was slowly added dropwise, and after the addition was completed, 1
Stir for an hour. N-hydrochloric acid was added until the reaction solution became acidic, and the organic solvent was distilled off under reduced pressure. The aqueous layer is made slightly alkaline with diluted sodium chloride water, extracted with ethyl acetate, and the extract is washed with water, dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with ethyl acetate) and then recrystallized from ethyl acetate-isopropyl ether to yield 1-piperonyl-2-(3-pyridyl)-ethanone.
3.2 g (yield 63%) is obtained. Melting point 98-99° Experimental example A Anti-inflammatory effect by carrageenan edema method (CE
Jol: Method of Winter et al. [Proc.Soc.exp.Biol.Med., 111 , 544 (1962)] using 6 SD rats (male, weight 180-220g) per group.
I investigated according to the following. 1 hour after oral administration of the specimen
0.05 ml of % carrageenan saline solution was injected subcutaneously into the footpad. The hindlimb volume 3 hours after carrageenin injection and the pre-injection volume were measured, and the edema volume was calculated from the difference. The edema suppression rate was determined by comparing the edema volume between the sample-administered group and the non-specimen-administered control group. B Analgesic effect test using phenylquinone lysing syndrome method (PQ method) Using 10 Slc.ICR male mice (4 weeks old, weight 20 ± 2 g) per group, Siegmund
[Proc.Soc.Exp.Biol.Med., 95 729
(1957)]. Orally administering the specimen
After 30 minutes, 0.1 ml/10 g of 0.02% phenylquinone was administered intraperitoneally, and the number of writhing or stretching movements exhibited by the mice over 20 minutes was counted. The suppression rate was determined by comparing the average number of times between the sample administration group and the non-specimen administration control group. C Water immersion restraint stress ulcer test (WI method) SD male rats (7 weeks old, weight 190-240 g)
Using the method of Takagi and Okabe [Jpn.J.
Pharmacol., 18 , 9 (1968)], the experiment was conducted after a 24-hour fast (however, water was freely available). The rats were placed in a stainless steel restraining cage and immersed in a water tank adjusted to 23°C for 5 hours up to the thoracic region below the xiphoid bone. The long axis (mm) of each ulcer in the glandular gastric mucosa was measured under a stereomicroscope, and the sum was used as the ulcer index. The specimen was orally administered 30 minutes before water immersion. The ulcer index was compared between the sample-administered group and the non-specimen-administered control group to determine the inhibition rate. D. Acute toxicity test in mice (Acute toxicity) 5 week old ICR male mice (5 mice per group) were orally administered 500 mg/Kg of each sample, and mortality was measured for 7 days. Representative examples of the above test results are shown in Table 2.
Claims (1)
キル基、アルケニル基、アリール基、アラルキル
基、シクロアルキル基、チエニル基、フリール基
またはアミノ基を、R2はアルキル基で置換され
ていてもよいピリジル基を示す。R3は置換基を
有していてもよいフエニル基を示すが、ベンゼン
環上の隣接する任意の位置にメチレンジオキシ基
またはトリメチレン基を有してこれらの基がそれ
ぞれベンゼン環上の炭素原子と共に環を形成して
いてもよい。］で表される１，３−チアゾール誘
導体またはその塩。 ２ 一般式 ［式中、R2はアルキル基で置換されていても
よいピリジル基を示す。R3は置換基を有してい
てもよいフエニル基を示すが、ベンゼン環上の隣
接する任意の位置にメチレンジオキシ基またはト
リメチレン基を有してこれらの基がそれぞれベン
ゼン環上の炭素原子と共に環を形成していてもよ
い。Ｘはハロゲン原子を示す。］で表される化合
物と一般式 ［式中、R1は置換基を有していてもよいアル
キル基、アルケニル基、アリール基、アラルキル
基、シクロアルキル基、チエニル基、フリール基
またはアミノ基を、R2はアルキル基で置換され
ていてもよいピリジル基を示す。］で表される化
合物を反応させることを特徴とする一般式 ［式中、R1，R2およびR3は前記と同意義であ
る］で表される１，３−チアゾール誘導体または
その塩の製造法。 ３ 一般式 ［式中、R1は置換基を有していてもよいアル
キル基、アルケニル基、アリール基、アラルキル
基、シクロアルキル基、チエニル基、フリール基
またはアミノ基を、R2はアルキル基で置換され
ていてもよいピリジル基を示す。R3は置換基を
有していてもよいフエニル基を示すが、ベンゼン
環上の隣接する任意の位置にメチレンジオキシ基
またはトリメチレン基を有してこれらの基がそれ
ぞれベンゼン環上の炭素原子と共に環を形成して
いてもよい。］で表される１，３−チアゾール誘
導体またはその塩を有効成分として含んでなる鎮
痛または抗炎症剤。 ４ 一般式 ［式中、R1は置換基を有していてもよいアル
キル基、アルケニル基、アリール基、アラルキル
基、シクロアルキル基、チエニル基、フリール基
またはアミノ基を、R2はアルキル基で置換され
ていてもよいピリジル基を示す。R3は置換基を
有していてもよいフエニル基を示すが、ベンゼン
環上の隣接する任意の位置にメチレンジオキシ基
またはトリメチレン基を有してこれらの基がそれ
ぞれベンゼン環上の炭素原子と共に環を形成して
いてもよい。］で表される１，３−チアゾール誘
導体またはその塩を有効成分として含んでなる抗
潰瘍剤。[Claims] 1. General formula [In the formula, R 1 is an alkyl group, alkenyl group, aryl group, aralkyl group, cycloalkyl group, thienyl group, furyl group, or amino group that may have a substituent, and R 2 is an alkyl group substituted with an alkyl group. Indicates a pyridyl group which may be R 3 represents a phenyl group which may have a substituent, but it has a methylenedioxy group or a trimethylene group at any adjacent position on the benzene ring, and these groups each have a carbon atom on the benzene ring. They may form a ring together. ] A 1,3-thiazole derivative or a salt thereof. 2 General formula [In the formula, R 2 represents a pyridyl group which may be substituted with an alkyl group. R 3 represents a phenyl group which may have a substituent, but it has a methylenedioxy group or a trimethylene group at any adjacent position on the benzene ring, and these groups each have a carbon atom on the benzene ring. They may form a ring together. X represents a halogen atom. ] Compounds and general formulas [In the formula, R 1 is an alkyl group, alkenyl group, aryl group, aralkyl group, cycloalkyl group, thienyl group, furyl group, or amino group that may have a substituent, and R 2 is an alkyl group substituted with an alkyl group. Indicates a pyridyl group which may be ] A general formula characterized by reacting a compound represented by A method for producing a 1,3-thiazole derivative or a salt thereof represented by the formula [wherein R 1 , R 2 and R 3 have the same meanings as above]. 3 General formula [In the formula, R 1 is an alkyl group, alkenyl group, aryl group, aralkyl group, cycloalkyl group, thienyl group, furyl group, or amino group that may have a substituent, and R 2 is an alkyl group substituted with an alkyl group. Indicates a pyridyl group which may be R 3 represents a phenyl group which may have a substituent, but it has a methylenedioxy group or a trimethylene group at any adjacent position on the benzene ring, and these groups each have a carbon atom on the benzene ring. They may form a ring together. ] Analgesic or anti-inflammatory agent comprising a 1,3-thiazole derivative or a salt thereof as an active ingredient. 4 General formula [In the formula, R 1 is an alkyl group, alkenyl group, aryl group, aralkyl group, cycloalkyl group, thienyl group, furyl group, or amino group that may have a substituent, and R 2 is an alkyl group substituted with an alkyl group. Indicates a pyridyl group which may be R 3 represents a phenyl group which may have a substituent, but it has a methylenedioxy group or a trimethylene group at any adjacent position on the benzene ring, and these groups each have a carbon atom on the benzene ring. They may form a ring together. ] An anti-ulcer agent comprising a 1,3-thiazole derivative or a salt thereof as an active ingredient.
Priority Applications (9)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP7781984A JPS6110580A (en) | 1984-04-17 | 1984-04-17 | 5-pyridyl-1,3-thiazole derivative, preparation thereof and pharmaceutical composition containing same |
| AT84305789T ATE83483T1 (en) | 1983-09-09 | 1984-08-23 | 5-PYRIDYL-1,3-THIAZOLE DERIVATIVES, THEIR PREPARATION AND USE. |
| EP84305789A EP0149884B1 (en) | 1983-09-09 | 1984-08-23 | 5-pyridyl-1,3-thiazole derivatives, their production and use |
| DE8484305789T DE3486009T2 (en) | 1983-09-09 | 1984-08-23 | 5-PYRIDYL-1,3-THIAZOL DERIVATIVES, THEIR PRODUCTION AND USE. |
| AU32433/84A AU567754B2 (en) | 1983-09-09 | 1984-08-27 | 5-pyridyl-1,3-thiazoles |
| US06/647,436 US4612321A (en) | 1983-09-09 | 1984-09-05 | 5-pyridyl-1,3-thiazole derivatives |
| CA000462626A CA1255663A (en) | 1983-09-09 | 1984-09-07 | 5-pyridyl-1,3-thiazole derivatives, their production and use |
| HU843401A HU201753B (en) | 1983-09-09 | 1984-09-07 | Process for producing new 5-pyridyl-1,3-thiazole derivatives and pharmaceutical compositions comprising same as active ingredient |
| KR1019840005499A KR910004430B1 (en) | 1983-04-17 | 1984-09-08 | Process for the preparation of 5-pyridil-1,3-thiazol derivatives |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP7781984A JPS6110580A (en) | 1984-04-17 | 1984-04-17 | 5-pyridyl-1,3-thiazole derivative, preparation thereof and pharmaceutical composition containing same |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS6110580A JPS6110580A (en) | 1986-01-18 |
| JPH053468B2 true JPH053468B2 (en) | 1993-01-14 |
Family
ID=13644638
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP7781984A Granted JPS6110580A (en) | 1983-04-17 | 1984-04-17 | 5-pyridyl-1,3-thiazole derivative, preparation thereof and pharmaceutical composition containing same |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS6110580A (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1268474A2 (en) * | 2000-03-30 | 2003-01-02 | Takeda Chemical Industries, Ltd. | Substituted 1,3-thiazole compounds, their production and use |
-
1984
- 1984-04-17 JP JP7781984A patent/JPS6110580A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS6110580A (en) | 1986-01-18 |
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