JPH0212228B2 - - Google Patents
Info
- Publication number
- JPH0212228B2 JPH0212228B2 JP13912080A JP13912080A JPH0212228B2 JP H0212228 B2 JPH0212228 B2 JP H0212228B2 JP 13912080 A JP13912080 A JP 13912080A JP 13912080 A JP13912080 A JP 13912080A JP H0212228 B2 JPH0212228 B2 JP H0212228B2
- Authority
- JP
- Japan
- Prior art keywords
- thio
- thiophene
- butyryl
- methyl
- 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
Links
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000002947 alkylene group Chemical group 0.000 claims description 4
- 125000000623 heterocyclic group Chemical group 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 125000001376 1,2,4-triazolyl group Chemical group N1N=C(N=C1)* 0.000 claims description 2
- 125000004520 1,3,4-thiadiazolyl group Chemical group 0.000 claims description 2
- 125000003277 amino group Chemical group 0.000 claims description 2
- 125000002883 imidazolyl group Chemical group 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- 125000000335 thiazolyl group Chemical group 0.000 claims description 2
- 150000003577 thiophenes Chemical class 0.000 claims description 2
- -1 methylene, Ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, methylethylene Chemical group 0.000 description 96
- 150000001875 compounds Chemical class 0.000 description 84
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 80
- 238000006243 chemical reaction Methods 0.000 description 76
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 68
- 238000002844 melting Methods 0.000 description 61
- 230000008018 melting Effects 0.000 description 61
- 239000000243 solution Substances 0.000 description 51
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 44
- 239000013078 crystal Substances 0.000 description 39
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 36
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 35
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 34
- 229930192474 thiophene Natural products 0.000 description 34
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 34
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 33
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 24
- 235000019441 ethanol Nutrition 0.000 description 23
- ZKQFHRVKCYFVCN-UHFFFAOYSA-N ethoxyethane;hexane Chemical compound CCOCC.CCCCCC ZKQFHRVKCYFVCN-UHFFFAOYSA-N 0.000 description 23
- 239000002904 solvent Substances 0.000 description 21
- 238000003756 stirring Methods 0.000 description 21
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 19
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 17
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 239000000203 mixture Substances 0.000 description 15
- 238000000921 elemental analysis Methods 0.000 description 14
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 13
- 239000007788 liquid Substances 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- 239000003826 tablet Substances 0.000 description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 12
- 238000000034 method Methods 0.000 description 11
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 9
- 229920001223 polyethylene glycol Polymers 0.000 description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- 239000002253 acid Substances 0.000 description 8
- 238000004440 column chromatography Methods 0.000 description 8
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 8
- 235000019341 magnesium sulphate Nutrition 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 7
- 229920002472 Starch Polymers 0.000 description 7
- 239000003699 antiulcer agent Substances 0.000 description 7
- 239000003795 chemical substances by application Substances 0.000 description 7
- 239000000843 powder Substances 0.000 description 7
- 239000008107 starch Substances 0.000 description 7
- 235000019698 starch Nutrition 0.000 description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 6
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 6
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 6
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 6
- 239000002202 Polyethylene glycol Substances 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 150000001298 alcohols Chemical class 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 6
- 239000003480 eluent Substances 0.000 description 6
- 150000002170 ethers Chemical class 0.000 description 6
- 150000004795 grignard reagents Chemical class 0.000 description 6
- 239000012442 inert solvent Substances 0.000 description 6
- 239000007924 injection Substances 0.000 description 6
- 238000002347 injection Methods 0.000 description 6
- 239000008101 lactose Substances 0.000 description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 6
- 229910052938 sodium sulfate Inorganic materials 0.000 description 6
- 235000011152 sodium sulphate Nutrition 0.000 description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 5
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 5
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 5
- 235000011054 acetic acid Nutrition 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 239000008103 glucose Substances 0.000 description 5
- 125000005843 halogen group Chemical group 0.000 description 5
- 229910052749 magnesium Inorganic materials 0.000 description 5
- 239000011777 magnesium Substances 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 235000011121 sodium hydroxide Nutrition 0.000 description 5
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- 229920002261 Corn starch Polymers 0.000 description 4
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 4
- 239000007818 Grignard reagent Substances 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 4
- 150000007513 acids Chemical class 0.000 description 4
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 4
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 4
- 239000008120 corn starch Substances 0.000 description 4
- 229940099112 cornstarch Drugs 0.000 description 4
- 150000002576 ketones Chemical class 0.000 description 4
- 235000019359 magnesium stearate Nutrition 0.000 description 4
- 150000007524 organic acids Chemical class 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 235000011181 potassium carbonates Nutrition 0.000 description 4
- 125000006239 protecting group Chemical group 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 4
- WNWHHMBRJJOGFJ-UHFFFAOYSA-N 16-methylheptadecan-1-ol Chemical class CC(C)CCCCCCCCCCCCCCCO WNWHHMBRJJOGFJ-UHFFFAOYSA-N 0.000 description 3
- 239000005995 Aluminium silicate Substances 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 108010010803 Gelatin Proteins 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 235000012211 aluminium silicate Nutrition 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 3
- 239000011230 binding agent Substances 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 238000000576 coating method Methods 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 3
- 239000007884 disintegrant Substances 0.000 description 3
- 239000012153 distilled water Substances 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 239000000499 gel Substances 0.000 description 3
- 239000008273 gelatin Substances 0.000 description 3
- 229920000159 gelatin Polymers 0.000 description 3
- 235000019322 gelatine Nutrition 0.000 description 3
- 235000011852 gelatine desserts Nutrition 0.000 description 3
- 230000002140 halogenating effect Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 3
- PMRYVIKBURPHAH-UHFFFAOYSA-N methimazole Chemical compound CN1C=CNC1=S PMRYVIKBURPHAH-UHFFFAOYSA-N 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 235000005985 organic acids Nutrition 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 3
- 239000006187 pill Substances 0.000 description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 3
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 3
- 235000011118 potassium hydroxide Nutrition 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 235000019260 propionic acid Nutrition 0.000 description 3
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 239000000829 suppository Substances 0.000 description 3
- MEKOFIRRDATTAG-UHFFFAOYSA-N 2,2,5,8-tetramethyl-3,4-dihydrochromen-6-ol Chemical compound C1CC(C)(C)OC2=C1C(C)=C(O)C=C2C MEKOFIRRDATTAG-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- NPFQPHILVMHTKP-UHFFFAOYSA-N 4-chloro-1-thiophen-2-ylbutan-1-one Chemical compound ClCCCC(=O)C1=CC=CS1 NPFQPHILVMHTKP-UHFFFAOYSA-N 0.000 description 2
- 229920001817 Agar Polymers 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 2
- 229920001543 Laminarin Polymers 0.000 description 2
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 2
- 229920002584 Polyethylene Glycol 6000 Polymers 0.000 description 2
- 229920001214 Polysorbate 60 Polymers 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-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
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000003377 acid catalyst Substances 0.000 description 2
- 239000008272 agar Substances 0.000 description 2
- 235000010419 agar Nutrition 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 150000007514 bases Chemical class 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N beta-monoglyceryl stearate Natural products CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 description 2
- 239000001506 calcium phosphate Substances 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 239000004359 castor oil Substances 0.000 description 2
- 235000019438 castor oil Nutrition 0.000 description 2
- 229940110456 cocoa butter Drugs 0.000 description 2
- 235000019868 cocoa butter Nutrition 0.000 description 2
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 2
- 229940038472 dicalcium phosphate Drugs 0.000 description 2
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
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- 238000005498 polishing Methods 0.000 description 1
- 229920000137 polyphosphoric acid Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 235000007686 potassium Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000012746 preparative thin layer chromatography Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- ZJLMKPKYJBQJNH-UHFFFAOYSA-N propane-1,3-dithiol Chemical compound SCCCS ZJLMKPKYJBQJNH-UHFFFAOYSA-N 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- WHMDPDGBKYUEMW-UHFFFAOYSA-N pyridine-2-thiol Chemical compound SC1=CC=CC=N1 WHMDPDGBKYUEMW-UHFFFAOYSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- LKZMBDSASOBTPN-UHFFFAOYSA-L silver carbonate Substances [Ag].[O-]C([O-])=O LKZMBDSASOBTPN-UHFFFAOYSA-L 0.000 description 1
- 229910001958 silver carbonate Inorganic materials 0.000 description 1
- HKZLPVFGJNLROG-UHFFFAOYSA-M silver monochloride Chemical compound [Cl-].[Ag+] HKZLPVFGJNLROG-UHFFFAOYSA-M 0.000 description 1
- 229910001961 silver nitrate Inorganic materials 0.000 description 1
- AUJFUOQIUSJHPF-UHFFFAOYSA-N silver;1-chloropyrrolidine-2,5-dione;nitrate Chemical compound [Ag+].[O-][N+]([O-])=O.ClN1C(=O)CCC1=O AUJFUOQIUSJHPF-UHFFFAOYSA-N 0.000 description 1
- 235000020374 simple syrup Nutrition 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 239000007940 sugar coated tablet Substances 0.000 description 1
- 238000009495 sugar coating Methods 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- CUPOOAWTRIURFT-UHFFFAOYSA-N thiophene-2-carbonitrile Chemical compound N#CC1=CC=CS1 CUPOOAWTRIURFT-UHFFFAOYSA-N 0.000 description 1
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 1
- XJVIPPHGDPEDJL-UHFFFAOYSA-N thiourea;hydrochloride Chemical compound Cl.NC(N)=S XJVIPPHGDPEDJL-UHFFFAOYSA-N 0.000 description 1
- 229910052718 tin Inorganic materials 0.000 description 1
- 239000011135 tin Substances 0.000 description 1
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 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
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 1
- 238000007794 visualization technique Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Landscapes
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本発明は、新規なチオフエン誘導体、さらに詳
しくは、
一般式
〔式中、R1は、イミダゾリル、1,2,4−ト
リアゾリル、1,3,4−チアジアゾリル、1,
3,4−オキサジアゾリル、ピリジル、ピリミジ
ル、およびチアゾリル基からなる群より選ばれる
不飽和ヘテロ環基を示す。該ヘテロ環基は、アミ
ノ基および低級アルキル基からなる群から選ばれ
る1または2個の置換基を有していてもよい。A
は低級アルキレン基を示す〕
で表わされるチオフエン誘導体およびその塩に関
する。
本発明の化合物は、抗潰瘍作用および消炎作用
を有し、抗潰瘍剤および消炎剤として有用であ
る。
低級アルキル基としては、メチル、エチル、プ
ロピル、イソ−プロピル、tert−ブチル、ブチル
基など、低級アルキレン基としては、メチレン、
エチレン、トリメチレン、テトラメチレン、ペン
タメチレン、ヘキサメチレン、メチルエチレン、
2−メチル−トリエチレン、2,2−ジメチルト
リメチレン、1−メチルトリメチレン基などを例
示することができる。
本発明の代表的な化合物を以下に列挙する。
2−〔3−(2−ピリジル)チル−プロピオニ
ル〕チオフエン
2−〔4−(2−ピリジル)チオ−ブチリル〕チ
オフエン
2−〔4−(6−メチル−2−ピリジル)チオ−
ブチリル〕チオフエン
2−〔3−(3−ピリジル)チオ−プロピオニ
ル〕チオフエン
2−〔4−(3−アミノ−4−ピリジル)チオ−
ブチリル〕チオフエン
2−〔3−(4−ピリジル)チオ−プロピオニ
ル〕チオフエン
3−〔4−(2−ピリジル)チオ−ブチリル〕チ
オフエン
2−〔4−(2−ピリミジル)チオ−ブチリル〕
チオフエン
2−〔4−(4−メチル−2−ピリミジル)チオ
−ブチリル〕チオフエン
2−〔4−(4−アミノ−2−ピリミジル)チオ
−ブチリル〕チオフエン
2−〔4−(4−プロピル−5−ピリミジル)チ
オ−ブチリル〕チオフエン
3−〔4−(4−メチル−2−ピリミジル)チオ
−ブチリル〕チオフエン
2−〔4−(1−メチル−2−イミダゾリル)チ
オ−ブチリル〕チオフエン
2−〔4−(2−イミダゾリル)チオ−ブチリ
ル〕チオフエン
2−〔4−(4−tert−ブチル−2−イミダゾリ
ル)チオ−ブチリル〕チオフエン
2−〔4−(2−アミノ−4−イミダゾリル)チ
オ−ブチリル〕チオフエン
3−〔4−(1−メチル−2−イミダゾリル)チ
オ−ブチリル〕チオフエン
2−〔4−(4,5−ジメチル−1,2,4−ト
リアゾール−3−イル)チオ−ブチリル〕チオフ
エン
2−〔4−(4−エチル−5−アミノ−1,2,
4−トリアゾール−3−イル)チオ−ブチリル〕
チオフエン
2−〔3−(4H−1,2,4−トリアゾール−
3−イル)チオ−プロピオニル〕チオフエン
3−〔4−(4,5−ジメチル−1,2,4−ト
リアゾール−3−イル)チオ−ブチリル〕チオフ
エン
2−〔4−(5−メチル−1,3,4−オキサジ
アゾール−2−イル)チオ−ブチリル〕チオフエ
ン
2−〔4−(5−アミノ−1,3,4−オキサジ
アゾール−2−イル)チオ−ブチリル〕チオフエ
ン
3−〔4−(1,3,4−オキサジアゾール−2
−イル)チオ−ブチリル〕チオフエン
3−〔4−(5−メチル−1,3,4−オキサジ
アゾール−2−イル)チオ−ブチリル〕チオフエ
ン
2−〔4−(1,3,4−チアジアゾール−2−
イル)チオ−ブチリル〕チオフエン
2−〔4−(5−アミノ−1,3,4−チアジア
ゾール−2−イル)チオ−ブチリル〕チオフエン
2−〔4−(5−エチル−1,3,4−チアジア
ゾール−2−イル)チオ−ブチリル〕チオフエン
3−〔4−(5−メチル−1,3,4−チアジア
ゾール−2−イル)チオ−ブチリル〕チオフエン
2−〔5−(1−メチル−2−イミダゾリル)チ
オ−ペンタノイル〕チオフエン
2−〔5−(5−メチル−1,3,4−チアジア
ゾール−2−イル)チオ−ペンタノイル〕チオフ
エン
2−〔6−(2−ピリジル)チオ−ヘキサノイ
ル〕チオフエン
2−〔6−(4,5−ジメチル−1,2,4−ト
リアゾール−3−イル)チオ−ヘキサノイル〕チ
オフエン
2−〔4−(4−メチル−2−チアゾリル)チオ
−ブチリル〕チオフエン
2−〔4−(2−チアゾリル)チオ−ブチリル〕
チオフエン
2−〔3−(2−チアゾリル)チオ−プロピオニ
ル〕チオフエン
2−〔4−(4−アミノ−2−チアゾリル)チオ
−ブチリル〕チオフエン
本発明の化合物は、各種の方法で製造され、例
えば下記反応式−に示す方法によつて製造でき
る。
反応式−
〔式中、X1およびX2のいずれか一方はハロゲン
原子を示し、他方は基
The present invention provides novel thiophene derivatives, more specifically, the general formula: [Wherein, R 1 is imidazolyl, 1,2,4-triazolyl, 1,3,4-thiadiazolyl, 1,
It represents an unsaturated heterocyclic group selected from the group consisting of 3,4-oxadiazolyl, pyridyl, pyrimidyl, and thiazolyl groups. The heterocyclic group may have one or two substituents selected from the group consisting of an amino group and a lower alkyl group. A
represents a lower alkylene group] and its salts. The compounds of the present invention have anti-ulcer and anti-inflammatory effects and are useful as anti-ulcer agents and anti-inflammatory agents. Examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl, tert-butyl, and butyl groups; examples of lower alkylene groups include methylene,
Ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, methylethylene,
Examples include 2-methyl-triethylene, 2,2-dimethyltrimethylene, and 1-methyltrimethylene. Representative compounds of the present invention are listed below. 2-[3-(2-pyridyl)thyl-propionyl]thiophene 2-[4-(2-pyridyl)thio-butyryl]thiophene 2-[4-(6-methyl-2-pyridyl)thio-
Butyryl]thiophene 2-[3-(3-pyridyl)thio-propionyl]thiophene 2-[4-(3-amino-4-pyridyl)thio-
Butyryl]thiophene 2-[3-(4-pyridyl)thio-propionyl]thiophene 3-[4-(2-pyridyl)thio-butyryl]thiophene 2-[4-(2-pyrimidyl)thio-butyryl]
Thiophene 2-[4-(4-methyl-2-pyrimidyl)thio-butyryl]thiophene 2-[4-(4-amino-2-pyrimidyl)thio-butyryl]thiophene 2-[4-(4-propyl-5 -pyrimidyl)thio-butyryl]thiophene 3-[4-(4-methyl-2-pyrimidyl)thio-butyryl]thiophene 2-[4-(1-methyl-2-imidazolyl)thio-butyryl]thiophene 2-[4 -(2-imidazolyl)thio-butyryl]thiophene 2-[4-(4-tert-butyl-2-imidazolyl)thio-butyryl]thiophene 2-[4-(2-amino-4-imidazolyl)thio-butyryl] Thiophene 3-[4-(1-methyl-2-imidazolyl)thio-butyryl]thiophene 2-[4-(4,5-dimethyl-1,2,4-triazol-3-yl)thio-butyryl]thiophene 2 -[4-(4-ethyl-5-amino-1,2,
4-triazol-3-yl)thio-butyryl]
Thiophene 2-[3-(4H-1,2,4-triazole-
3-yl)thio-propionyl]thiophene 3-[4-(4,5-dimethyl-1,2,4-triazol-3-yl)thio-butyryl]thiophene 2-[4-(5-methyl-1, 3,4-oxadiazol-2-yl)thio-butyryl]thiophene 2-[4-(5-amino-1,3,4-oxadiazol-2-yl)thio-butyryl]thiophene 3-[4 -(1,3,4-oxadiazole-2
-yl)thio-butyryl]thiophene 3-[4-(5-methyl-1,3,4-oxadiazol-2-yl)thio-butyryl]thiophene 2-[4-(1,3,4-thiadiazole) -2-
yl)thio-butyryl]thiophene 2-[4-(5-amino-1,3,4-thiadiazol-2-yl)thio-butyryl]thiophene 2-[4-(5-ethyl-1,3,4- Thiadiazol-2-yl)thio-butyryl]thiophene 3-[4-(5-methyl-1,3,4-thiadiazol-2-yl)thio-butyryl]thiophene 2-[5-(1-methyl-2- imidazolyl)thio-pentanoyl]thiophene 2-[5-(5-methyl-1,3,4-thiadiazol-2-yl)thio-pentanoyl]thiophene 2-[6-(2-pyridyl)thio-hexanoyl]thiophene 2 -[6-(4,5-dimethyl-1,2,4-triazol-3-yl)thio-hexanoyl]thiophene 2-[4-(4-methyl-2-thiazolyl)thio-butyryl]thiophene 2-[ 4-(2-thiazolyl)thio-butyryl]
Thiophene 2-[3-(2-thiazolyl)thio-propionyl]thiophene 2-[4-(4-amino-2-thiazolyl)thio-butyryl]thiophene The compounds of the present invention can be produced by various methods, such as the following: It can be produced by the method shown in the reaction formula. Reaction formula- [In the formula, either one of X 1 and X 2 represents a halogen atom, and the other represents a group
【式】またはメ
ルカプト基を示す。R1およびAは前記と同じ〕
反応式−において、化合物(3)に変えて、化合
物(3)のカルボニル基が保護された化合物を用いて
化合物(2)と反応させて、次いで得られる化合物の
保護基を除去しても、本発明化合物(1)を製造でき
る。
反応式−において、化合物(2)および(3)は入手
容易な公知化合物であり、この反応は、通常の縮
合剤の存在下に行なわれる。この縮合剤としては
通常、塩基性化合物を広く用いることができる。
例えば水酸化ナトリウム、水酸化カリウム、炭酸
ナトリウム、炭酸カリウム、炭酸水素ナトリウ
ム、炭酸水素カリウム、炭酸銀などの無機塩基、
ナトリウム、カリウムなどのアルカリ金属、ナト
リウムメチラート、ナトリウムエチラートなどの
アルコラート、トリエチルアミン、ピリジン、
N,N−ジメチルアニリン、N−メチルモルホリ
ン、4−ジメチルアミノピリジン、1,5−ジア
ザビシクロ〔4.3.0〕ノネン−5(DBN)、1,5
−ジアザビシクロ〔5.4.0〕ウンデセン−5
(DBU)、1,4−ジアザビシクロ〔2.2.2〕オク
タン(DABCO)などの有機塩基が挙げられる。
該反応は無溶媒でもあるいは溶媒の存在下でも
行なわれ、溶媒としては反応に悪影響を与えない
不活性なものがすべて用いられ、例えば、メタノ
ール、エタノール、プロパノール、ブタノール、
エチレングリコールなどのアルコール類、ジメチ
ルエーテル、テトラヒドロフラン、ジオキサン、
モノグライム、ジグライムなどのエーテル類、ア
セトン、メチルエチルケトンなどのケトン類、ベ
ンゼン、トルエン、キシレンなどの芳香族炭化水
素類、酢酸メチル、酢酸エチルなどのエステル
類、N,N−ジメチルホルムアミド、ジメチルス
ルホキサイド、ヘキサメチルリン酸トリアミドな
どの非プロトン性極性溶媒などが挙げられる。ま
た、該反応はヨウ化ナトリウム、ヨウ化カリウム
などの金属ヨウ化物の存在下に行なうのが有利で
ある。上記方法における化合物(3)に対する化合物
(2)の使用割合はとくに限定されず、広範囲の中か
ら適宜に選択されるが、反応を無溶媒下に行なう
場合には、前者に対して後者を通常大過剰量、溶
媒中で行なう場合には、通常、前者に対して後者
を等モル〜5倍モル程度、好ましくは等モル〜2
倍モル量にて用いるのが望ましい。また、その反
応温度もとくに限定されないが、通常、−30℃〜
200℃程度、好ましくは0〜160℃で行なわれる。
反応時間は通常1〜30時間程度である。
ケトンの保護基としては、上記の反応の条件下
で安定なものであれば使用でき、例えば、メタノ
ール、エタノールなどの低級アルコール、エチレ
ングリコール、1,3−トリエチレンジオールな
どの低級アルキレンジオール、メタンチオール、
エタンチオールなどの低級アルカンチオール、
1,2−エチレンジチオール、1,3−トリメチ
レンジチオールなどの低級アルキレンジチオール
などが挙げられる。
反応後、ケトンの保護基を除去する場合は、常
法により行なわれ、例えば、上記低級アルコー
ル、低級アルキレンジオールなどで保護されたケ
タールは、酸と接触させることによつて容易にカ
ルボニル基に変換できる。この際使用される酸触
媒としては、例えば、塩酸、硫酸、硝酸、リン酸
などの無機酸、酢酸、プロピオン酸、p−トルエ
ンスルホン酸などの有機酸を挙げることができ
る。本反応で用いられる溶媒としては、例えば、
水、酢酸、プロピオン酸などの有機酸、メタノー
ル、エタノールなどのアルコール類、アセトン、
メチルエチルケトンなどのケトン類、ジオキサン
などのエーテル類、ジメチルスルホキシド、ジメ
チルホルムアミドなどの非プロトン性極性溶媒を
例示できる。この場合、溶媒として有機酸を用い
る場合には新たに酸触媒は不必要である。本反応
は通常室温〜200℃、好ましくは50〜100℃で30分
〜12時間程度で行なわれる。
また前記低級アルカンチオール、低級アルキレ
ンジチオールなどで保護されたチオケタールは、
通常のチオケタールをカルボニル基へ変換できる
反応条件を採用できる。例えば、塩化第2水銀−
酸化水銀、塩化第2水銀−炭酸カドミウム、硝酸
銀−N−クロルコハク酸イミドなどで処理するこ
とにより容易に除去される。該保護基離脱反応
は、適当な溶媒、例えば、メタノール、エタノー
ルなどの水溶性低級アルコール類、アセトン、ア
セトニトリルなどの有機溶媒と水との混合溶媒を
用い、0〜100℃、好ましくは50〜80℃にて1〜
5時間程度処理することにより行なわれる。
本発明の化合物は、また以下の反応式〜に
示す方法によつても製造できる。
反応式−
〔式中、R1,A,X1およびX2は前記に同じ、Z1
はハロゲン原子を示す〕
上記反応式−におけるメチル(2)と化合物(4)と
の反応は前記反応式−における反応と同じ反応
条件を採用できる。
化合物(5)とグリニヤ試薬(6)との反応は適当な不
活性溶媒中、−70℃〜50℃程度、好ましくは−30
℃〜室温にて、1〜6時間程度処理することによ
り達成される。不活性溶媒としては、グリニヤ反
応に慣用の溶媒を使用でき、例えば、ジメチルエ
ーテル、ジオキサン、テトラヒドロフランなどの
エーテル類、ベンゼン、トルエンなどの芳香族炭
化水素類、ペンタン、ヘキサン、ヘプタン、シク
ロヘキサンなどの飽和炭化水素類などが挙げられ
る。グリニヤ試薬(6)の使用量は、化合物(5)に対し
て少なくとも等モル量程度、好ましくは等モル〜
1.5倍モル量が用いられる。かくして製造された
化合物(5)と化合物(6)の反応生成体を通常の加水分
解して本発明の化合物(1)を得る。該加水分解反応
は、例えば、塩酸、硫酸などの鉱酸、ギ酸、酢
酸、プロピオン酸などの脂肪族カルボン酸、過塩
素酸、過沃素酸などの過ハロゲン化酸などの酸類
の存在下、適当な溶媒中、0〜100℃程度、好ま
しくは50〜80℃にて1〜5時間程度で実施でき
る。溶媒としては、例えば水と可溶なメタノー
ル、エタノールなどの低級アルコール類、テトラ
ヒドロフラン、ジオキサンなどのエーテル類、ア
セトン、アセトニトリルなどの溶媒と水との混合
溶媒を例示できる。使用される酸の量は、化合物
(5)に対して少なくとも等モル量程度が使用され
る。
上記反応式−における化合物(5)とグリニヤ試
薬(6)との反応性基を入れ替えた方法、すなわち、
下記反応式−に示す方法によつても本発明の化
合物(1)が製造される。
反応式−
〔式中、R1およびAは前記に同じ。Y1はメルカ
プト基または基[Formula] or represents a mercapto group. R 1 and A are the same as above] In reaction formula -, a compound in which the carbonyl group of compound (3) is protected is used instead of compound (3), and the compound is reacted with compound (2), and then the resulting compound is obtained. Compound (1) of the present invention can also be produced by removing the protecting group. In the reaction formula -, compounds (2) and (3) are easily available known compounds, and this reaction is carried out in the presence of a conventional condensing agent. Generally, a wide range of basic compounds can be used as this condensing agent.
Inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, silver carbonate,
Alkali metals such as sodium and potassium, alcoholates such as sodium methylate and sodium ethylate, triethylamine, pyridine,
N,N-dimethylaniline, N-methylmorpholine, 4-dimethylaminopyridine, 1,5-diazabicyclo[4.3.0]nonene-5 (DBN), 1,5
-Diazabicyclo[5.4.0]Undecene-5
(DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO), and other organic bases. The reaction is carried out without a solvent or in the presence of a solvent, and all inert solvents that do not adversely affect the reaction are used, such as methanol, ethanol, propanol, butanol,
Alcohols such as ethylene glycol, dimethyl ether, tetrahydrofuran, dioxane,
Ethers such as monoglyme and diglyme, ketones such as acetone and methyl ethyl ketone, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as methyl acetate and ethyl acetate, N,N-dimethylformamide, dimethyl sulfoxide , aprotic polar solvents such as hexamethylphosphoric triamide, and the like. Moreover, the reaction is advantageously carried out in the presence of a metal iodide such as sodium iodide or potassium iodide. Compound for compound (3) in the above method
The proportion of (2) to be used is not particularly limited and is appropriately selected from a wide range, but when the reaction is carried out without a solvent, the latter is usually used in a large excess amount relative to the former in a solvent. Usually, the latter is about 5 times the mole of the former, preferably about 2 times the mole of the former.
It is desirable to use double the molar amount. In addition, the reaction temperature is not particularly limited, but is usually -30℃~
The temperature is about 200°C, preferably 0 to 160°C.
The reaction time is usually about 1 to 30 hours. As the protecting group for the ketone, any one that is stable under the above reaction conditions can be used, such as lower alcohols such as methanol and ethanol, lower alkylene diols such as ethylene glycol and 1,3-triethylenediol, and methane. thiol,
lower alkanethiols such as ethanethiol,
Examples include lower alkylene dithiols such as 1,2-ethylene dithiol and 1,3-trimethylene dithiol. After the reaction, the protective group of the ketone is removed by a conventional method. For example, the ketal protected with the above-mentioned lower alcohol, lower alkylene diol, etc. can be easily converted into a carbonyl group by contacting with an acid. can. Examples of the acid catalyst used in this case include inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid, and organic acids such as acetic acid, propionic acid, and p-toluenesulfonic acid. Examples of the solvent used in this reaction include:
Water, organic acids such as acetic acid and propionic acid, alcohols such as methanol and ethanol, acetone,
Examples include ketones such as methyl ethyl ketone, ethers such as dioxane, and aprotic polar solvents such as dimethyl sulfoxide and dimethyl formamide. In this case, if an organic acid is used as a solvent, no additional acid catalyst is required. This reaction is usually carried out at room temperature to 200°C, preferably 50 to 100°C, for about 30 minutes to 12 hours. In addition, the thioketal protected with the lower alkanethiol, lower alkylene dithiol, etc.
Reaction conditions that can convert ordinary thioketals to carbonyl groups can be adopted. For example, mercuric chloride-
It is easily removed by treatment with mercury oxide, mercuric chloride-cadmium carbonate, silver nitrate-N-chlorosuccinimide, or the like. The protecting group removal reaction is carried out using a suitable solvent, for example, a mixed solvent of water and a water-soluble lower alcohol such as methanol or ethanol, or an organic solvent such as acetone or acetonitrile, at a temperature of 0 to 100°C, preferably 50 to 80°C. 1~ at °C
This is done by processing for about 5 hours. The compound of the present invention can also be produced by the method shown in the following reaction formula. Reaction formula- [In the formula, R 1 , A, X 1 and X 2 are the same as above, Z 1
represents a halogen atom] The reaction between methyl (2) and compound (4) in the above reaction formula - can employ the same reaction conditions as the reaction in the above reaction formula -. The reaction between compound (5) and Grignard reagent (6) is carried out in a suitable inert solvent at about -70°C to 50°C, preferably at -30°C.
This can be achieved by processing for about 1 to 6 hours at a temperature of .degree. C. to room temperature. As the inert solvent, solvents customary for Grignard reactions can be used, such as ethers such as dimethyl ether, dioxane, and tetrahydrofuran, aromatic hydrocarbons such as benzene and toluene, and saturated carbonates such as pentane, hexane, heptane, and cyclohexane. Examples include hydrogens. The amount of Grignard reagent (6) to be used is at least equimolar, preferably equimolar to compound (5).
A 1.5-fold molar amount is used. The reaction product of compound (5) and compound (6) thus produced is subjected to conventional hydrolysis to obtain compound (1) of the present invention. The hydrolysis reaction is carried out in an appropriate manner in the presence of acids such as mineral acids such as hydrochloric acid and sulfuric acid, aliphatic carboxylic acids such as formic acid, acetic acid, and propionic acid, and perhalogenated acids such as perchloric acid and periodic acid. The reaction can be carried out in a suitable solvent at a temperature of about 0 to 100°C, preferably 50 to 80°C, for about 1 to 5 hours. Examples of the solvent include lower alcohols such as methanol and ethanol that are soluble in water, ethers such as tetrahydrofuran and dioxane, and mixed solvents of water and solvents such as acetone and acetonitrile. The amount of acid used is
It is used in at least an equimolar amount to (5). A method in which the reactive groups of compound (5) and Grignard reagent (6) in the above reaction formula - are exchanged, that is,
Compound (1) of the present invention can also be produced by the method shown in the following reaction formula. Reaction formula- [In the formula, R 1 and A are the same as above. Y 1 is a mercapto group or group
【式】を示す。Z2およ
びZ3は同一または異なつてハロゲン原子を示す〕
上記化合物(2a)と化合物(7)との反応は前記
反応式−における化合物(2)と化合物(3)との反応
と同じ反応条件が採用でき、また得られた化合物
(8)に、通常のグリニヤ試薬製造に用いられる反応
条件にしたがつて、例えば適当な溶媒中、室温〜
100℃にて、30分〜数時間マグネシウムを作用さ
せることにより、容易に化合物(9)に導くことがで
きる。この場合、用いられるマグネシウムは、化
合物(8)に対して少なくとも等モル量、好ましくは
等モル〜1.5倍モル量が使用される。また、化合
物(9)と化合物(10)の反応は前記反応式−における
化合物(5)と化合物(6)との反応と同じ反応条件が採
用される。
反応式−
〔式中、R1,A,X1およびX2は前記に同じ、R3
は低級アルキル基を示す〕
上記反応式−における化合物(2)と化合物(11)と
の反応は、前述の反応式−における化合物(2)と
化合物(3)と同じ反応条件を採用できる。
化合物(12)の加水分解反応は、適当な不活性溶媒
中、通常の触媒、例えば、水酸化ナトリウム、水
酸化カリウムなどの塩基性化合物、塩酸、硫酸な
どの鉱酸の存在下、50℃〜110℃にて30分〜数時
間程度で有利に実施できる。該溶媒としては、例
えば水を例示できる。
化合物(13)と化合物(14)との反応は適当な
不活性溶媒中、−70℃〜室温程度、好ましくは−
30℃〜室温にて1〜6時間程度で実施できる。用
いられる溶媒としては、例えば、ジエチルエーテ
ル、ジオキサン、テトラヒドロフランなどのエー
テル類、ベンゼン、トルエンなどの芳香族炭化水
素類、ヘキサン、ヘプタン、ペンタン、シクロヘ
キサンなどの飽和炭化水素類などが挙げられる。
この反応における化合物(10)の使用量は化合物(9)に
対して、少なくとも2倍モル量程度、好ましくは
2〜3倍モル量である。
反応式−
〔式中、R1およびAは、前記に同じ。Mは亜鉛、
カドミユウム、マグネシウムなどの金属原子を示
す。Z4およびZ5は各々ハロゲン原子を示す〕
上記反応式−における化合物(13)とハロゲ
ン化剤との反応は、無溶媒でも、あるいは適当な
不活性溶媒中、室温〜100℃程度、好ましくは、
50〜80℃にて、30分〜6時間程度で行なわれる。
該ハロゲン化剤としては、例えば、塩化チオニ
ル、オキシ塩化リン、オキシ臭化リン、五塩化リ
ン、五臭化リンなどを例示でき、また溶媒として
は、例えば、クロロホルム、塩化メチレン、四塩
化炭素などのハロゲン化炭化水素類、ジオキサ
ン、テトラヒドロフラン、ジエチルエーテルなど
のエーテル類などが挙げられる。このハロゲン化
剤の使用量は、化合物(13)に対して、無溶媒下
で反応を行なう場合には、通常大過剰量、または
溶媒中で行なう場合には、少なくとも等モル量程
度、好ましくは2〜4倍モル量である。
化合物(15)と化合物(16)または化合物
(17)との反応は、前記反応式−における化合
物(13)と化合物(14)との反応と同じ反応条件
を採用できる。この場合、化合物(16)および化
合物(17)の使用量は、化合物(15)に対して、
少なくとも等モル量程度、好ましくは、等モル〜
1.5倍モル量である。
反応式−
〔式中、R1、AおよびZ3は前記と同じ。Bは低
級アルキレン基を示す〕
上記反応式−において、化合物(8)と化合物
(18)との反応は前記反応式−における化合物
(15)と化合物(16)または化合物(17)との反
応と同じ反応条件を採用できる。また、化合物
(19)から化合物(1)への反応は、前述の反応式−
における低級アルカンチオール、低級アルキレ
ンジチオールなどで保護されたチオケタールをカ
ルボニル基に変換する反応と同じ反応条件が採用
できる。
反応式
〔式中、R1およびAは前記に同じ。Z5はハロゲ
ン原子、水酸基または基−OCO−A−S−R1を
示す〕
上記反応式−におけるチオフエン(20)と酸
クロリド(15)の反応は、化合物(20)を化合物
(15)に対して当量〜過剰量用い好ましくは、1
〜3倍モル量が用いられ、0〜150℃程度、好ま
しくは0〜室温にて、1〜5時間程度で行われ
る。溶媒としては、ニトロベンゼン、二硫化炭
素、ジクロロメタン、四塩化炭素、1,2−ジク
ロロエタンなどを例示できる。さらに上記反応
は、フリーデルクラフト反応に慣用の触媒の存在
下有利に進行し、該触媒としては、塩化アルミニ
ウム、五塩化アンチモン、塩化第二鉄、四塩化チ
タン、三フツ化ホウ素、塩化第二スズ、塩化亜
鉛、塩化第二銀、フツ化水素、硫酸、ポリリン
酸、五酸化リンなどが例示できる。中でも塩化ア
ルミニウム、塩化第二スズ、塩化亜鉛、五酸化リ
ンが好ましく用いられる。
触媒の使用量は、化合物(15)に対して当量〜
過剰量、好ましくは1〜3倍モル量が用いられ
る。
また、一般式(1)で表わされる化合物のうち、塩
基性基を有する化合物は通常の薬理的に許容し得
る酸と容易に塩を形成し得る。かかる酸として
は、例えば、硫酸、硝酸、塩酸、臭化水素酸など
の無機酸、酢酸、p−トルエンスルホン酸、エタ
ンスルホン酸、シユウ酸、マレイン酸、コハク
酸、安息香酸などの有機酸が挙げられる。
かくして得られる本発明の化合物は、通常用い
られている分離手段により容易に単離、精製され
る。かかる分離手段としては沈殿法、描出法、再
結晶法、蒸留法、カラムクロマトグラフイまたは
プレパラテイブ薄層クロマトグラフイーなどを例
示できる。
本発明化合物は抗潰瘍剤として有用であり、通
常、一般的な医薬製剤の形態で用いられる。製剤
は通常使用される充填剤、増量剤、結合剤、付湿
剤、崩壊剤、表面活性剤、滑沢剤などの稀釈剤あ
るいは賦形剤を用いて調製される。この医薬製剤
としては各種の形態が治療目的に応じて選択で
き、その代表的なものとして錠剤、丸剤、散剤、
液剤、懸濁剤、乳剤、顆粒剤、カプセル剤、坐
剤、注射剤(液剤、懸濁剤等)などが挙げられ
る。錠剤の形態に成形するに際しては、担体とし
てこの分野で従来公知のものを広く使用でき、例
えば乳糖、白糖、塩化ナトリウム、ブドウ糖、尿
素、デンプン、炭酸カルシウム、カオリン、結晶
セルロース、ケイ酸などの賦形剤、水、エタノー
ル、プロパノール、単シロツプ、ブドウ糖液、デ
ンプン液、ゼラチン溶液、カルボキシメチルセル
ロース、セラツク、メチルセルロース、リン酸カ
リウム、ポリビニルピロリドンなどの結合剤、乾
燥デンプン、アルギン酸ナトリウム、カンテン
末、ラミナラン末、炭酸水素ナトリウム、炭酸カ
ルシウム、ポリオキシエチレンソルビタン脂肪酸
エステル類、ラウリン硫酸ナトリウム、ステアリ
ン酸モノグリセリド、デンプン、乳糖などの崩壊
剤、白糖、ステアリン、カカオバター、水素添加
油などの崩壊抑制剤、第四級アンモニウム塩基、
ラウリル硫酸ナトリウムなどの吸収促進剤、グリ
セリン、デンプンなどの保湿剤、デンプン、乳
糖、カオリン、ベントナイト、コロイド状ケイ酸
などの吸着剤、精製タルク、ステアリン酸塩、ホ
ウ酸末、ポリエチレングリコールなどの滑沢剤な
どが例示できる。さらに、錠剤は必要に応じ通常
の剤皮を施した錠剤、例えば糖衣錠、ゼラチン被
包錠、腸溶被錠、フイルムコーテイング錠あるい
は二重錠、多層錠とすることができる。丸剤の形
態に成形するに際しては、担体としてこの分野で
従来公知のものを広く使用でき、例えば、ブドウ
糖、乳糖、デンプン、カカオ脂、硬化植物油、カ
オリン、タルクなどの賦形剤、アラビアゴム末、
トラガント末、ゼラチン、エタノールなどの結合
剤、ラミナラン、カンテンなどの崩壊剤などが例
示できる。坐剤の形態に成形するに際しては、担
体として従来公知のものを広く使用でき、例えば
ポリエチレングリコール、カカオ脂、高級アルコ
ール、高級アルコールのエステル類、ゼラチン、
半合成グリセライドなどを挙げることができる。
注射剤として調製される場合には、液剤および懸
濁剤は殺菌され、かつ血液と等張であるのが好ま
しく、これら液剤、乳剤および懸濁剤の形態に成
形するのに際しては、稀釈剤としてこの分野にお
いて慣用されているものをすべて使用でき、例え
ば水、エチルアルコール、プロピレングリコー
ル、エトキシ化イソステアリルアルコール、ポリ
オキシ化イソステアリルアルコール、ポリオキシ
エチレンソルビタン脂肪酸エステル類などを挙げ
ることができる。なお、この場合等張性の溶液を
調製するに充分な量の食塩、ブドウ糖あるいはグ
リセリンを抗潰瘍剤中に含有せしめてもよく、ま
た通常の溶解補助剤、緩衝剤、無痛化剤などを、
更に必要に応じて着色剤、保存剤、香料、風味
剤、甘味剤などや他の医薬品を該治療剤中に含有
せしめてもよい。
本発明の抗潰瘍剤中に含有されるべき本発明の
化合物の量はとくに限定されず広範囲に選択され
るが、通常全組成物中1〜70重量%、好ましくは
5〜50重量%である。
本発明の抗潰瘍剤の投与方法にはとくに制限は
なく、各種製剤形態、患者の年令、性別その他の
条件、疾患の程度などに応じた方法で投与され
る。例えば錠剤、丸剤、液剤、懸濁剤、乳剤、顆
粒剤およびカプセル剤の場合には経口投与され
る。また注射剤の場合には単独であるいはブドウ
糖、アミノ酸などの通常の補液と混合して静脈内
投与され、さらには必要に応じて単独で筋肉内、
皮内、皮下もしくは腹腔内投与される。坐剤の場
合には直腸内投与される。
本発明の抗潰瘍剤の投与量は用法、患者の年
令、性別その他の条件、疾患の程度などにより適
宜選択されるが、通常本発明化合物の量は1日当
り体重1Kg当り0.6〜50mgとするのがよい。また、
投与単位形態中に有効成分を10〜1000mg含有せし
めるのがよい。
薬理試験
一般式(1)で表わされる化合物の薬理活性を、胃
液分泌抑制作用を検定する最も一般的な試験法で
あるシエイ・ラツトの幽門結紮法に従つて試験し
た。この試験には体重170g前後のウイスター系
雄性ラツトを使用した。該ラツトを24時間絶食さ
せ、幽門結紮30分前に試験されるべき化合物100
mg/Kgを十二脂腸内投与し、結紮4時間後に胃液
量、総酸度およびペプシン活性を測定した。生理
食塩水投与群を0として抑制率を%で求めた。そ
の結果を下記第1表に示す。
なお、表中における抑制率(%)の評価は下記
のとおりである。
+:10〜50%未満
++:50%以上
供試化合物No.
1 2−〔4−(1−メチル−2−イミダゾリル)
チオ−ブチリル〕チオフエン
2 2−〔4−(2−ピリジル)チオ−ブチリル〕
チオフエン
3 2−〔4−(5−メチル−1,3,4−オキサ
ジアゾール−2−イル)チオ−ブチリル〕チオ
フエン
4 2−〔4−(4,5−ジメチル−1,2,4−
トリアゾール−3−イル)チオ−ブチリル〕チ
オフエン[Formula] is shown. Z 2 and Z 3 are the same or different and represent a halogen atom] The reaction between the above compound (2a) and the compound (7) is carried out under the same reaction conditions as the reaction between the compound (2) and the compound (3) in the above reaction formula -. can be adopted and the obtained compound
(8), according to the reaction conditions used for the production of Grignard reagents, for example, in an appropriate solvent from room temperature to
Compound (9) can be easily led to compound (9) by acting with magnesium at 100°C for 30 minutes to several hours. In this case, the amount of magnesium used is at least equimolar, preferably equimolar to 1.5 times the molar amount of compound (8). Furthermore, the same reaction conditions as for the reaction between compound (5) and compound (6) in the above reaction formula - are employed for the reaction between compound (9) and compound (10). Reaction formula- [In the formula, R 1 , A, X 1 and X 2 are the same as above, R 3
represents a lower alkyl group] For the reaction of compound (2) and compound (11) in the above reaction formula -, the same reaction conditions as for compound (2) and compound (3) in the above reaction formula - can be adopted. The hydrolysis reaction of compound (12) is carried out in a suitable inert solvent in the presence of a conventional catalyst such as a basic compound such as sodium hydroxide or potassium hydroxide, or a mineral acid such as hydrochloric acid or sulfuric acid at 50°C or more. This can be advantageously carried out at 110°C for about 30 minutes to several hours. An example of the solvent is water. The reaction between compound (13) and compound (14) is carried out in a suitable inert solvent at about -70°C to room temperature, preferably -
It can be carried out in about 1 to 6 hours at 30°C to room temperature. Examples of the solvent used include ethers such as diethyl ether, dioxane, and tetrahydrofuran, aromatic hydrocarbons such as benzene and toluene, and saturated hydrocarbons such as hexane, heptane, pentane, and cyclohexane.
The amount of compound (10) used in this reaction is at least twice the molar amount of compound (9), preferably 2 to 3 times the molar amount. Reaction formula- [In the formula, R 1 and A are the same as above. M is zinc;
Indicates metal atoms such as cadmium and magnesium. Z 4 and Z 5 each represent a halogen atom] The reaction between compound (13) and the halogenating agent in the above reaction formula - can be carried out without a solvent or in a suitable inert solvent at room temperature to about 100°C, preferably ,
It is carried out at 50 to 80°C for about 30 minutes to 6 hours.
Examples of the halogenating agent include thionyl chloride, phosphorus oxychloride, phosphorus oxybromide, phosphorus pentachloride, and phosphorus pentabromide, and examples of the solvent include chloroform, methylene chloride, carbon tetrachloride, etc. Examples include halogenated hydrocarbons, dioxane, tetrahydrofuran, ethers such as diethyl ether, and the like. The amount of the halogenating agent to be used is usually a large excess of compound (13) when the reaction is carried out without a solvent, or at least an equimolar amount when the reaction is carried out in a solvent, preferably at least an equimolar amount. It is 2 to 4 times the molar amount. For the reaction between compound (15) and compound (16) or compound (17), the same reaction conditions as for the reaction between compound (13) and compound (14) in the reaction formula - can be employed. In this case, the usage amounts of compound (16) and compound (17) are as follows:
At least equimolar amount, preferably equimolar to
1.5 times the molar amount. Reaction formula- [In the formula, R 1 , A and Z 3 are the same as above. B represents a lower alkylene group] In the above reaction formula -, the reaction between compound (8) and compound (18) is the same as the reaction between compound (15) and compound (16) or compound (17) in the above reaction formula -. The same reaction conditions can be adopted. In addition, the reaction from compound (19) to compound (1) is expressed by the above reaction formula -
The same reaction conditions as in the reaction for converting a thioketal protected with a lower alkanethiol, lower alkylene dithiol, etc. into a carbonyl group can be adopted. reaction formula [In the formula, R 1 and A are the same as above. Z 5 represents a halogen atom, a hydroxyl group, or a group -OCO-A-S-R 1 ] The reaction between thiophene (20) and acid chloride (15) in the above reaction formula converts compound (20) into compound (15). Used in an equivalent to excess amount, preferably 1
~3 times the molar amount is used, and the reaction is carried out at about 0 to 150°C, preferably at 0 to room temperature, for about 1 to 5 hours. Examples of the solvent include nitrobenzene, carbon disulfide, dichloromethane, carbon tetrachloride, and 1,2-dichloroethane. Furthermore, the above reaction proceeds advantageously in the presence of catalysts commonly used in Friedel-Crafts reactions, such as aluminum chloride, antimony pentachloride, ferric chloride, titanium tetrachloride, boron trifluoride, and ferric chloride. Examples include tin, zinc chloride, silver chloride, hydrogen fluoride, sulfuric acid, polyphosphoric acid, and phosphorus pentoxide. Among them, aluminum chloride, stannic chloride, zinc chloride, and phosphorus pentoxide are preferably used. The amount of catalyst used is equivalent to compound (15).
Excess amounts are used, preferably 1 to 3 times the molar amount. Further, among the compounds represented by the general formula (1), those having a basic group can easily form a salt with a common pharmacologically acceptable acid. Examples of such acids include inorganic acids such as sulfuric acid, nitric acid, hydrochloric acid, and hydrobromic acid, and organic acids such as acetic acid, p-toluenesulfonic acid, ethanesulfonic acid, oxalic acid, maleic acid, succinic acid, and benzoic acid. Can be mentioned. The compound of the present invention thus obtained can be easily isolated and purified by commonly used separation means. Examples of such separation means include precipitation methods, visualization methods, recrystallization methods, distillation methods, column chromatography, and preparative thin layer chromatography. The compounds of the present invention are useful as anti-ulcer agents and are usually used in the form of common pharmaceutical preparations. The formulation is prepared using commonly used diluents or excipients such as fillers, fillers, binders, wetting agents, disintegrants, surfactants, and lubricants. Various forms of this pharmaceutical preparation can be selected depending on the therapeutic purpose, and typical examples include tablets, pills, powders,
Examples include solutions, suspensions, emulsions, granules, capsules, suppositories, and injections (solutions, suspensions, etc.). When forming tablets, a wide variety of carriers conventionally known in this field can be used, such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, etc. Excipients, water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, binders such as polyvinylpyrrolidone, dry starch, sodium alginate, agar powder, laminaran powder , disintegrants such as sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium laurine sulfate, stearic acid monoglyceride, starch, lactose, disintegration inhibitors such as sucrose, stearin, cocoa butter, hydrogenated oil, etc. class ammonium base,
Absorption enhancers such as sodium lauryl sulfate, humectants such as glycerin and starch, adsorbents such as starch, lactose, kaolin, bentonite, and colloidal silicic acid, and lubricants such as purified talc, stearate, boric acid powder, and polyethylene glycol. Examples include brighteners. Furthermore, the tablets may be coated with a conventional coating, if necessary, such as sugar-coated tablets, gelatin-encapsulated tablets, enteric-coated tablets, film-coated tablets, double tablets, or multilayer tablets. When forming into a pill form, a wide variety of carriers conventionally known in this field can be used, such as excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, talc, gum arabic powder, etc. ,
Examples include binders such as tragacanth powder, gelatin, and ethanol, and disintegrants such as laminaran and agar. When forming into a suppository, a wide variety of conventionally known carriers can be used, such as polyethylene glycol, cacao butter, higher alcohols, esters of higher alcohols, gelatin,
Examples include semi-synthetic glycerides.
When prepared as injections, solutions and suspensions are preferably sterile and isotonic with blood, and when formed into solutions, emulsions, and suspensions, diluents are used. All those commonly used in this field can be used, including water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters, and the like. In this case, the anti-ulcer agent may contain a sufficient amount of salt, glucose or glycerin to prepare an isotonic solution, and the anti-ulcer agent may also contain conventional solubilizing agents, buffers, soothing agents, etc.
Furthermore, coloring agents, preservatives, perfumes, flavoring agents, sweeteners, and other pharmaceutical agents may be included in the therapeutic agent, if necessary. The amount of the compound of the present invention to be contained in the anti-ulcer agent of the present invention is not particularly limited and can be selected within a wide range, but is usually 1 to 70% by weight, preferably 5 to 50% by weight based on the total composition. . There are no particular restrictions on the method of administering the anti-ulcer agent of the present invention, and it can be administered in a manner depending on various formulation forms, age, sex and other conditions of the patient, degree of disease, etc. For example, tablets, pills, solutions, suspensions, emulsions, granules and capsules are administered orally. In the case of injections, they are administered intravenously alone or mixed with normal replacement fluids such as glucose and amino acids, and if necessary, they can also be administered intramuscularly alone.
Administered intradermally, subcutaneously, or intraperitoneally. Suppositories are administered rectally. The dosage of the anti-ulcer agent of the present invention is appropriately selected depending on the usage, age, sex and other conditions of the patient, degree of disease, etc., but the amount of the compound of the present invention is usually 0.6 to 50 mg/kg body weight per day. It is better. Also,
The dosage unit form preferably contains 10 to 1000 mg of the active ingredient. Pharmacological Test The pharmacological activity of the compound represented by the general formula (1) was tested according to the pylorus ligation method of Shei-Rat, which is the most common test method for testing gastric juice secretion suppressive action. Male Wistar rats weighing approximately 170 g were used in this test. The rats were fasted for 24 hours and the compound to be tested 100 minutes before pylorus ligation.
mg/Kg of duodenal fat was administered into the intestine, and 4 hours after ligation, the gastric juice volume, total acidity, and pepsin activity were measured. The inhibition rate was determined in %, setting the physiological saline administration group as 0. The results are shown in Table 1 below. In addition, the evaluation of the inhibition rate (%) in the table is as follows. +: 10 to less than 50% ++: 50% or more Test compound No. 1 2-[4-(1-methyl-2-imidazolyl)
Thio-butyryl]thiophene 2 2-[4-(2-pyridyl)thio-butyryl]
Thiophene 3 2-[4-(5-methyl-1,3,4-oxadiazol-2-yl)thio-butyryl]thiophene 4 2-[4-(4,5-dimethyl-1,2,4-
triazol-3-yl)thio-butyryl]thiophene
【表】
つぎに参考例および実施例をあげて本発明の化
合物およびその製造法をさらに具体的に説明す
る。
参考例 1
2−メルカプトピリジン4.4gと1−ブロム−
3−クロルプロパン9.4gとをアセトン100mlに溶
解する。これに炭酸カリウム6.8gを加えて3時
間還流する。アセトンを留去し、残渣に水を加え
て、クロロホルムで抽出する。クロロホルム溶液
を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥
する。クロロホルムを留去して残渣をカラムクロ
マトグラフイ(メルフ社製、キーゼルゲル60、溶
出液クロロホルム)で精製して2−(3−クロル
プロピル)チオ−ピリジン7.9gを得る。無色液
体、NMR(90MHz、CDCl3)、2.00〜2.40(2H、
m)、3.30(2H、t、J=6Hz)、3.66(2H、t、
J=6Hz)、6.80〜8.50(5H、m)
参考例 2
1−メチル−2−メルカプトイミダゾール2.33
gをアセトン50mlに溶解する。これに4−ブロム
酪酸メチルエステル4.3gと炭酸カリウム3gと
を加えて、3時間還流を行なう。アセトンを留去
し、残渣に水を加え、クロロホルムで抽出する。
クロロホルム溶液を飽和食塩水で洗浄し、硫酸マ
グネシウムで乾燥する。クロロホルムを留去し、
残渣をカラムクロマトグラフイ(メルク社製、キ
ーゼルゲル60)で精製する。クロロホルムで溶出
後、減圧蒸留して無色液体の4−(1−メチル−
2−イミダゾリル)チオ−酪酸メチルエステル
2.1gを得る。沸点140〜141℃(0.5mmHg)、n14 D=
1.5300
元素分析値:C9H14N2O2Sとして
計算値(%):
C、50.45;H、6.59;N、13.07
実測値(%):
C、50.40;H、6.57;N、13.05
参考例 3
4−(1−メチル−2−イミダゾリル)チオ−
酪酸メチルエステル13.1gに20%塩酸150mlを加
え、90〜95℃で1時間撹拌する。塩酸を留去し、
残渣にベンゼンを加えて水分を共沸除去する。残
留物をカラムクロマトグラフイ(ワコウゲルC−
200)で精製する。クロロホルム−メタノール
(20:1)で溶出して無色液体の4−(1−メチル
−2−イミダゾリル)チオ−酪酸塩酸塩13gを得
る。
NMR(60MHz、DMSO)1.60〜2.10(2H、m)、
2.43(2H、t、J=6Hz)、3.38(2H、t、J=6
Hz)、3.90(3H、s)、7.76(1H、br、s)、7.90
(1H、br、s)
元素分析値:C8H13N2SO2Clとして
計算値(%):
C、40.59;H、5.54;N、11.83
分析値(%):
C、40.54;H、5.51;N、11.80
参考例 4
2−メルカプト−1−メチルイミダゾール1.4
gと4−ブロムブチロニトリル3.6gとをアセト
ン50mlに溶解する。これに炭酸カリウム3gを加
えて3時間還流を行う。アセトンを留去後、残渣
に水を加え、クロロホルムで抽出する。クロロホ
ルム溶液を飽和食塩水で洗浄し、硫酸マグネシウ
ムで乾燥する。クロロホルムを留去し、残留物を
シリカゲルクロマトグラフイ(溶出液クロロホル
ム)で単離して、4−(1−メチル−2−イミダ
ゾリル)チオ−ブチロニトリル2.6gを得る。
元素分析値:C8H11N3Sとして
計算値(%):
C、53.01;H、6.12;N、23.18
分析値(%):
C、53.12;H、6.17;N、23.21
実施例 1
2−(4−クロルブチリル)チオフエン21g
(0.11モル)、ヨウ化ナトリウム22.5g(0.15モル)
をアセトンに溶解し、3時間還流する。アセトン
を留去し、残渣をジメチルホルムアミドに溶解
し、水酸化カリウム6.7g(0.12モル)および1
−メチル−2−メルカプトイミダゾール11.4g
(0.1モル)を加え、浴温80℃で8時間撹拌する。
ジメチルホルムアミドを留去し、クロロホルムで
抽出する。クロロホルム層を水、飽和重曹水、
水、飽和食塩水で洗浄後、無水硫酸マグネシウム
で乾燥する。溶媒を留去後、ヘキサン−酢酸エチ
ルより再結晶して2−〔4−(1−メチル−2−イ
ミダゾリル)チオ−ブチリル〕チオフエン11gを
得る。淡黄色針状晶、融点57〜58℃
元素分析値:C12H14N2OS2として
計算値(%):
C、54.10;H、5.30;N、10.51
分析値(%):
C、53.78;H、5.32;N、10.44
実施例 2
実施例1と同様にして下記の化合物を得る。
2−〔4−(5−アミノ−1,3,4−チアジア
ゾール−2−イル)チオ−ブチリル〕チオフエ
ン、無色針状晶(エタノール−水)、融点145〜
147℃
2−〔4−(2−ピリジル)チオ−ブチリル〕チ
オフエン、無色液体、n26.5 D=1.6222
2−〔4−(4,5−ジメチル−1,2,4−ト
リアゾール−3−イル)チオ−ブチリル〕チオフ
エン、無色プリズム状晶(ヘキサン−酢酸エチ
ル)、融点69〜70℃
2−〔4−(5−メチル−1,3,4−オキサジ
アゾール−2−イル)チオ−ブチリル〕チオフエ
ン無色プリズム状晶(ヘキサン−エーテル)、融
点60〜61℃
2−〔4−(4−メチル−2−ピリミジル)チオ
−ブチリル〕チオフエン、無色プリズム状晶(ヘ
キサン−エーテル)、融点46〜47℃
2−〔4−(4−メチル−2−チアゾリル)−チ
オ−ブチリル〕チオフエン、淡黄色板状晶(ヘキ
サン)、融点73〜75℃
実施例 3
5−〔3−(2−テノイル)プロピル〕イソチオ
尿素塩酸塩2.6gをエタノール50mlに溶解する。
これに2−アミノ−5−クロル−1,3,4−チ
アジアゾール1.6gと10%水酸化ナトリウム水溶
液10mlを加えて3時間還流を行なう。エタノール
を減圧留去後、残渣に水を加え、クロロホルムで
抽出する。クロロホルム溶液を飽和食塩水で洗浄
し、硫酸ナトリウムで乾燥する。クロロホルムを
留去し、残留物をカラムクロマトグラフイ(ワコ
ウゲルC−200、溶出液クロロホルム:メタノー
ル=50:1)で精製後、エタノール、水から再結
晶して無色針状晶の2−〔4−(5−アミノ−1,
3,4−チアジアゾール−2−イル)チオ−ブチ
リル〕チオフエン0.4gを得る。融点145〜147℃
元素分析値:C10H11N3OS3として
計算値(%):
C、42.08;H、3.89;N、14.72
実測値(%):
C、41.97;H、3.84;N、14.78
実施例 4
実施例3と同様にして下記の化合物を得る。
2−〔4−(2−ピリジル)チオ−ブチリル〕チ
オフエン、無色液体、n26.5 D=1.6222
2−〔4−(4,5−ジメチル−1,2,4−ト
リアゾール−3−イル)チオ−ブチリル〕チオフ
エン、無色プリズム状晶(ヘキサン−酢酸エチ
ル)、融点69〜70℃
2−〔4−(5−メチル−1,3,4−オキサジ
アゾール−2−イル)チオ−ブチリル〕チオフエ
ン、無色プリズム状晶(ヘキサン−エーテル)、
融点60〜61℃
2−〔4−(4−メチル−2−ピリミジル)チオ
−ブチリル〕チオフエン、無色プリズム状晶(ヘ
キサン−エーテル)、融点46〜47℃
2−〔4−(1−メチル−2−イミダゾリル)チ
オ−ブチリル〕チオフエン、淡黄色針状晶(ヘキ
サン−酢酸エチル)、融点57〜58℃
2−〔4−(4−メチル−2−チアゾリル)チオ
−ブチリル〕チオフエン、淡黄色板状晶(ヘキサ
ン)、融点73〜75℃
実施例 5
2−(4−クロルブチリル)チオフエン1.9gと
5−(2−ピリジル)イソチオ尿素塩酸塩1.9gと
をエタノール50mlに溶解する。これに10%水酸化
ナトリウム水溶液10mlを加えて、2時間還流を行
なう。エタノールを留去後、残留物に水を加えて
クロロホルムで抽出する。クロロホルム溶液を飽
和食塩水で洗浄して硫酸ナトリウムで乾燥する。
クロロホルムを留去し、残渣をカラムクロマトグ
ラフイ(ワコウゲルC−200、溶出液クロロホル
ム)で精製して無色液体の2−〔4−(2−ピリジ
ル)チオ−ブチリル〕チオフエン1.5gを得る。
n26.5 D=1.6222
元素分析値:C13H13NOS2として
計算値(%):
C、59.29;H、4.98;N、5.32
実測値(%):
C、59.34;H、4.95;N、5.37
実施例 6
実施例5と同様にして下記の化合物を得る。
2−〔4−(5−アミノ−1,3,4−チアジア
ゾール−2−イル)チオ−ブチリル〕チオフエ
ン、無色針状晶(エタノール−水)、融点145〜
147℃
2−〔4−(4,5−ジメチル−1,2,4−ト
リアゾール−3−イル)チオ−ブチリル〕チオフ
エン、無色プリズム状晶(ヘキサン−酢酸エチ
ル)、融点69〜70℃
2−〔4−(5−メチル−1,3,4−オキサジ
アゾール−2−イル)チオ−ブチリル〕チオフエ
ン、無色プリズム状晶(ヘキサン−エーテル)、
融点60〜61℃
2−〔4−(4−メチル−2−ピリミジル)チオ
−ブチリル〕チオフエン、無色プリズム状晶(ヘ
キサン−エーテル)、融点46〜47℃
2−〔4−(1−メチル−2−イミダゾリル)チ
オ−ブチリル〕チオフエン、淡黄色針状晶(ヘキ
サン−酢酸エチル)、融点57〜58℃
2−〔4−(4−メチル−2−チアゾリル)チオ
−ブチリル〕チオフエン、淡黄色板状晶(ヘキサ
ン)、融点73〜75℃
実施例 7
2−(4−メルカプトブチリル)チオフエン3.7
gを10%水酸化ナトリウム水溶液10mlに溶解す
る。これに2−クロル−4−メチルピリミジン
2.6gのメタノール10ml溶液を滴下し、室温で5
時間撹拌し、さらに60〜70℃で5時間撹拌する。
メタノールを留去後、残留物に水を加えて、クロ
ロホルムで抽出する。クロロホルム溶液を飽和食
塩水で洗浄して、硫酸ナトリウムで乾燥する。ク
ロロホルムを留去し、残渣をカラムクロマトグラ
フイ(ワコウゲルC−200、溶出液クロロホルム)
で精製後、ヘキサン−エーテルから再結晶して無
色プリズム状晶の2−〔4−(4−メチル−2−ピ
リミジル)チオ−ブチリル〕チオフエン1.2gを
得る。融点46〜47℃
元素分析値:C13H14N2OS2として
計算値(%):
C、56.08;H、5.07;N、10.06
実測値(%):
C、56.34;H、5.11;N、9.98
実施例 8
実施例7と同様にして下記の化合物を得る。
2−〔4−(5−アミノ−1,3,4−チアジア
ゾール−2−イル)チオ−ブチリル〕チオフエ
ン、無色針状晶(エタノール−水)、融点145〜
147℃
2−〔4−(2−ピリジル)チオ−ブチリル〕チ
オフエン、無色液体、n26.5 D=1.6222
2−〔4−(4,5−ジメチル−1,2,4−ト
リアゾール−3−イル)チオ−ブチリル〕チオフ
エン、無色プリズム状晶(ヘキサン−酢酸エチ
ル)、融点69〜70℃
2−〔4−(5−メチル−1,3,4−オキサジ
アゾール−2−イル)チオ−ブチリル〕チオフエ
ン、無色プリズム状晶(ヘキサン−エーテル)、
融点60〜61℃
2−〔4−(1−メチル−2−イミダゾリル)−
チオ−ブチリル〕チオフエン、淡黄色針状晶(ヘ
キサン−酢酸エチル)、融点57〜58℃
2−〔4−(4−メチル−2−チアゾリル)チオ
−ブチリル〕チオフエン、淡黄色板状晶(ヘキサ
ン)、融点73〜75℃
実施例 9
マグネシウム0.25g、2−ブロムチオフエン
1.4gおよび乾燥テトラヒドロフラン10mlとから、
臭化2−チエニルマグネシウムをつくる。これに
氷冷撹拌下に4−(1−メチル−2−イミダゾリ
ル)チオ−ブチロニトリル1.8gの乾燥テトラヒ
ドロフラン10ml溶液を滴下する。滴下後、室温で
3時間撹拌する。氷冷下1N塩酸50mlを加え、1
時間撹拌する。反応液を水でうすめてクロロホル
ムで抽出する。クロロホルム溶液を飽和重曹水お
よび飽和食塩水で洗浄し、硫酸ナトリウムで乾燥
する。クロロホルムを留去し、残渣をヘキサン−
エーテルより再結晶して2−〔4−(1−メチル−
2−イミダゾリル)チオ−ブチリル〕チオフエン
0.6gを得る。淡黄色針状晶、融点57〜58℃
元素分析値:C12H14N2OS2として
計算値(%):
C、54.10;H、5.30;N、10.51
実測値(%):
C、53.78;H、5.32;N、10.44
実施例 10
実施例9と同様にして下記の化合物を得る。
2−〔4−(5−アミノ−1,3,4−チアジア
ゾール−2−イル)チオ−ブチリル〕チオフエ
ン、無色針状晶(エタノール−水)、融点145〜
147℃
2−〔4−(2−ピリジル)チオ−ブチリル〕チ
オフエン、無色液体、n26.5 D=1.6222
2−〔4−(4,5−ジメチル−1,2,4−ト
リアゾール−3−イル)チオ−ブチリル〕チオフ
エン、無色プリズム状晶(ヘキサン−酢酸エチ
ル)、融点69〜70℃
2−〔4−(5−メチル−1,3,4−オキサジ
アゾール−2−イル)チオ−ブチリル〕チオフエ
ン、無色プリズム状晶(ヘキサン−エーテル)、
融点60〜61℃
2−〔4−(4−メチル−2−ピリミジル)チオ
−ブチリル〕チオフエン、無色プリズム状晶(ヘ
キサン−エーテル)、融点46〜47℃
2−〔4−(4−メチル−2−チアゾリル)チオ
−ブチリル〕チオフエン、淡黄色板状晶(ヘキサ
ン)融点73〜75℃
実施例 11
マグネシウム0.3gを乾燥テトラヒドロフラン
5mlに懸濁する。これに窒素気流中撹拌下に沃素
の少片を加え、さらに4,5−ジメチル−3−
(3−クロルプロピル)チオ−1,2,4−トリ
アゾール0.3gを加える。臭化エチル0,1mlを
加え、外部から加熱して反応を開始させる。残り
の4,5−ジメチル−3−(3−クロルプロピル)
チオ−1,2,4−トリアゾール2.0gの乾燥テ
トラヒドロフラン15ml溶液を滴下する。滴下後、
1時間還流を行なう。得られたグリニヤ試薬に氷
冷撹拌下、2−シアノチオフエン1.0gの乾燥テ
トラヒドロフラン5ml溶液を滴下する。室温で3
時間撹拌する。氷冷下1N塩酸20mlを加えて、1
時間撹拌する。反応液を水でうすめてクロロホル
ムで抽出する。クロロホルム溶液を飽和重曹水お
よび飽和食塩水で洗浄後、硫酸ナトリウムで乾燥
する。エーテルを留去し、残渣をヘキサン−酢酸
エチルより再結晶して2−〔4−(4,5−ジメチ
ル−1,2,4−トリアゾール−3−イル)チオ
−ブチリル〕チオフエン0.7gを得る。無色プリ
ズム状晶、融点69〜70℃
元素分析値:C12H15N3OS2として
計算値(%):
C、51.22;H、5.37;N、14.93
実測値(%):
C、50.98;H、5.43;N、14.87
実施例 12
実施例11と同様にして下記の化合物を得る。
2−〔4−(2−ピリジル)チオ−ブチリル〕チ
オフエン、無色液体、n26.5 D=1.6222
2−〔4−(5−メチル−1,3,4−オキサジ
アゾール−2−イル)チオ−ブチリル〕チオフエ
ン、無色プリズム状晶(ヘキサン−エーテル)、
融点60〜61℃
2−〔4−(4−メチル−2−ピリミジル)チオ
−ブチリル〕チオフエン、無色プリズム状晶(ヘ
キサン−エーテル)、融点46〜47℃
2−〔4−(1−メチル−2−イミダゾリル)チ
オ−ブチリル〕チオフエン、淡黄色針状晶(ヘキ
サン−酢酸エチル)、融点57〜58℃
2−〔4−(4−メチル−2−チアゾリル)チオ
−ブチリル〕チオフエン、淡黄色板状晶(ヘキサ
ン)、融点73〜75℃
実施例 13
4−(5−メチル−1,3,4−オキサジアゾ
ール−2−イル)チオ−酪酸2gを無水ベンゼン
20mlに溶解する。アルゴン気流下−70℃で撹拌下
に1.5規定2−チエニルリチウムのエーテル溶液
13.3mlを滴下する。徐々に室温まで温度を上げな
がら3時間撹拌する。さらに室温で一晩撹拌し、
反応液を氷水にあけてエーテルで抽出する。エー
テル溶液を飽和重曹水および飽和食塩水で洗浄
後、硫酸マグネシウムで乾燥する。エーテルを留
去し、残渣をヘキサン−エーテルより再結晶し
て、2−〔4−(5−メチル−1,3,4−オキサ
ジアゾール−2−イル)チオ−ブチリル〕チオフ
エン0.6gを得る。無色プリズム状晶(ヘキサン
−エーテル)、融点60〜61℃
元素分析値:C11H12N2O2S2として
計算値(%):
C、49.23;H、4.51;N、10.44
実測値(%):
C、49.48;H、4.59;N、10.36
実施例 14
実施例13と同様にして企記の化合物を得る。
2−〔4−(5−アミノ−1,3,4−チアジア
ゾール−2−イル)チオ−ブチリル〕チオフエ
ン、無色針状晶(エタノール−水)、融点145〜
147℃
2−〔4−(2−ピリジル)チオ−ブチリル〕チ
オフエン、無色液体、n26.5 D=1.6222
2−〔4−(4,5−ジメチル−1,2,4−ト
リアゾール−3−イル)チオ−ブチリル〕チオフ
エン、無色プリズム状晶(ヘキサン−酢酸エチ
ル)、融点69〜70℃
2−〔4−(4−メチル−2−ピリミジル)チオ
−ブチリル〕チオフエン、無色プリズム状晶(ヘ
キサン−エーテル)、融点46〜47℃
2−〔4−(1−メチル−2−イミダゾリル)−
チオ−ブチリル〕チオフエン、淡黄色針状晶(ヘ
キサン−酢酸メチル)、融点57〜58℃
2−〔4−(4−メチル−2−チアゾリル)チオ
−ブチリル〕チオフエン、淡黄色板状晶(ヘキサ
ン)、融点73〜75℃
実施例 15
2−(2−チエニル)−1,3−ジチアン2.2g
を乾燥テトラヒドロフラン20mlに溶解し、−78℃
に冷却する。これにアルゴン気流中、撹拌下に、
1.6規定n−ブチルリチウムのn−ヘキサン溶液
6.5mlを滴下する。−78℃で30分間撹拌する。これ
に4,5−ジメチル−3−(3−クロルプロピル)
チオ−1,2,4−トリアゾール2gの乾燥テト
ラヒドロフラン5ml溶液を滴下する。−78℃で1
時間撹拌後、徐々に0℃まで温度を上げながら4
時間撹拌する。反応液を氷水にあけてエーテルを
抽出する。エーテル溶液を水および飽和食塩水で
洗浄後、硫酸マグネシウムで乾燥する。エーテル
を留去し、残渣をアセトニトリル20mlに溶解す
る。
別に硝酸銀7gおよびN−クロルこはく酸イミ
ド4.9gを水40mlとアセトニトリル100mlに溶解す
る。これに窒素気流中0℃で撹拌しながら上記ジ
チアン溶液を滴下する。0℃で30分間撹拌したの
ち室温まで温め、さらに30分間撹拌する。水でう
すめて、クロロホルムで抽出する。クロロホルム
溶液を水および飽和食塩水で洗浄し、硫酸マグネ
シウムで乾燥する。クロロホルムを留去し、残渣
をヘキサン−酢酸エチルより再結晶して2−〔4
−(4,5−ジメチル−1,2,4−トリアゾー
ル−3−イル)チオ−ブチリル〕チオフエン0.4
gを得る。無色プリズム状晶、融点69〜70℃
元素分析値:C12H15N3OS2として
計算値(%):
C、51.22;H、5.37;N、14.93
実測値(%):
C、50.98;H、5.43;N、14.87
実施例 16
実施例15と同様にして下記の化合物を得る。
2−〔4−(5−アミノ−1,3,4−チアジア
ゾール−2−イル)チオ−ブチリル〕チオフエ
ン、無色針状晶(エタノール−水)、融点145〜
147℃
2−〔4−(2−ピリジル)チオ−ブチリル〕チ
オフエン、無色液体、n26.5 D=1.6222
2−〔4−(5−メチル−1,3,4−オキサジ
アゾール−2−イル)チオ−ブチリル〕チオフエ
ン、無色プリズム状晶(ヘキサン−エーテル)、
融点60〜61℃
2−〔4−(4−メチル−2−ピリミジル)チオ
−ブチリル〕チオフエン、無色プリズム状晶(ヘ
キサン−エーテル)、融点46〜47℃
2−〔4−(1−メチル−2−イミダゾリル)チ
オ−ブチリル〕チオフエン、淡黄色針状晶(ヘキ
サン−酢酸エチル)、融点57〜58℃
2−〔4−(4−メチル−2−チアゾリル〕チオ
−ブチリル〕チオフエン、淡黄色板状晶(ヘキサ
ン)、融点73〜75℃
実施例 17
4−(4−メチル−2−ピリミジル)チオ−酪
酸2.1gに塩化チオニル5mlを加え、40〜50℃で
1時間撹拌する。過剰の塩化チオニルを減圧留去
する。乾燥ベンゼンを加えて共沸して水分を除去
し、えられた混合液より4−(4−メチル−2−
ピリミジル)チオ−酪酸クロリドを得る。密閉し
た2口フラスコに沃化銅571mgを加え、減圧脱気
後窒素を満たす。これに無水エーテル10mlを注入
し、全体を−40℃に冷やす。これに1.332M2−チ
エニルリチウムのエーテル溶液5mlを加え、−40
℃で5分間撹拌したのち、−78℃に冷やす。これ
に上記で得られた4−(4−メチル−2−ピリミ
ジル)チオ−酪酸クロリド0.25gの冷無水エーテ
ル溶液5mlを注入し、−78℃で15分間撹拌する。
この反応液に無水メタノール35mlを注入し、フラ
スコを室温に戻す。反応液を飽和塩化アンモニウ
ム水溶液にあけ、エーテルで抽出する。エーテル
溶液を硫酸マグネシウムで乾燥し、エーテルを留
去する。残渣をヘキサン−エーテルより再結晶し
て、2−〔4−(4−メチル−2−ピリミジル)チ
オ−ブチリル〕チオフエン0.1gを得る。無色プ
リズム状晶、融点46〜47℃
元素分析値:C13H14N2OS2として
計算値(%):
C、56.08;H、5.07;N、10.06
実測値(%):
C、56.34;H、5.11;N、9.98
実施例 18
実施例17と同様にして下記の化合物を得る。
2−〔4−(5−アミノ−1,3,4−チアジア
ゾール−2−イル)チオ−ブチリル〕チオフエ
ン、無色針状晶(エタノール−水)、融点145〜
147℃
2−〔4−(2−ピリジル)チオ−ブチリル〕チ
オフエン、無色液体、n26.5 D=1.6222
2−〔4−(4,5−ジメチル−1,2,4−ト
リアゾール−3−イル)チオ−ブチリル〕チオフ
エン、無色プリズム状晶(ヘキサン−酢酸エチ
ル)、融点69〜70℃
2−〔4−(5−メチル−1,3,4−オキサジ
アゾール−2−イル)チオ−ブチリル〕チオフエ
ン、無色プリズム状晶(ヘキサン−エーテル)、
融点60〜61℃
2−〔4−(1−メチル−2−イミダゾリル)チ
オ−ブチリル〕チオフエン、淡黄色針状晶(ヘキ
サン−酢酸エチル)、融点57〜58℃
2−〔4−(4−メチル−2−チアゾリル)チオ
−ブチリル〕チオフエン、淡黄色板状晶(ヘキサ
ン)、融点73〜75℃
実施例 19
五酸化リン1.6gを無水ベンゼン20mlに懸濁さ
せる。これに、チオフエン1.34gと4−(2−ピ
リジル)チオ−酪酸2gとを加えて、4時間還流
させる。ベンゼン溶液を分離し、残渣はさらにベ
ンゼンで洗浄する。ベンゼン溶液をあわせて硫酸
ナトリウムで乾燥する。ベンゼンを留去後、残留
物をカラムクロマトグラフイ(ワコウゲルC−
200、溶出液クロロホルム)で精製して、無色液
体の2−〔4−(2−ピリジル)チオ−ブチリル〕
チオフエン0.5gを得る。n26.5 D=1.6222
元素分析値:C13H13NOS2として
計算値(%):
C、59.29;H、4.98;N、5.32
実測値(%):
C、59.19;H、4.96;N、5.29
実施例 20
実施例19と同様にして下記の化合物を得る。
2−〔4−(1−メチル−2−イミダゾリル)チ
オ−ブチリル〕チオフエン、淡黄色針状晶(ヘキ
サン−酢酸エチル)、融点57〜58℃
2−〔4−(5−アミノ−1,3,4−チアジア
ゾール−2−イル)チオ−ブチリル〕チオフエ
ン、無色針状晶(エタノール−水)、融点145〜
147℃
2−〔4−(4,5−ジメチル−1,2,4−ト
リアゾール−3−イル)チオ−ブチリル〕チオフ
エン、無色プリズム状晶(ヘキサン−酢酸エチ
ル)、融点69〜70℃
2−〔4−(5−メチル−1,3,4−オキサジ
アゾール−2−イル)チオ−ブチリル〕チオフエ
ン、無色プリズム状晶(ヘキサン−エーテル)、
融点60〜61℃
2−〔4−(4−メチル−2−ピリミジル)チオ
−ブチリル〕チオフエン、無色プリズム状晶(ヘ
キサン−エーテル)、融点46〜47℃
2−〔4−(4−メチル−2−チアゾリル〕チオ
−ブチリル〕チオフエン、淡黄色板状晶(ヘキサ
ン)、融点73〜75℃
実施例 21
2−〔1,1−エチレンジオキシ−4−(2−ピ
リジル)チオ−ブチリル〕チオフエン0.4gを酢
酸5mlに溶解する。これに水2.5mlと濃塩酸0.5ml
とを加えて水浴上で1時間加熱する。反応液に水
を加えてクロロホルムで抽出する。クロロホルム
液を水、飽和重曹水および飽和食塩水で洗浄し、
硫酸マグネシウムで乾燥する。クロロホルムを留
去し、残渣をシリカゲルカラムクロマトグラフイ
(メルク社製、キーゼルゲル60)で精製する。ク
ロロホルムで溶出して2−〔4−(2−ピリジル)
チオ−ブチリル〕チオフエン0.2gを得る。無色
液体、n26.5 D=1.6222
元素分析値:C13H13NOS2として
計算値(%):
C、59.29;H、4.98;N、5.32
実測値(%):
C、59.25;H、4.95;N、5.35
実施例 22
実施例21と同様にして下記の化合物を得る。
2−〔4−(1−メチル−2−イミダゾリル)チ
オ−ブチリル〕チオフエン、淡黄色針状晶(ヘキ
サン−酢酸エチル)、融点57〜58℃
2−〔4−(5−アミノ−1,3,4−チアジア
ゾール−2−イル)チオ−ブチリル〕チオフエ
ン、無色針状晶(エタノール−水)、融点145〜
147℃
2−〔4−(4,5−ジメチル−1,2,4−ト
リアゾール−3−イル)チオ−ブチリル〕チオフ
エン、無色プリズム状晶(ヘキサン−酢酸エチ
ル)、融点69〜70℃
2−〔4−(5−メチル−1,3,4−オキサジ
アゾール−2−イル)チオ−ブチリル〕チオフエ
ン、無色プリズム状晶(ヘキサン−エーテル)、
融点60〜61℃
2−〔4−(4−メチル−2−ピリミジル)チオ
−ブチリル〕チオフエン、無色プリズム状晶(ヘ
キサン−エーテル)、融点46〜47℃
2−〔4−(4−メチル−2−チアゾリル)チオ
−ブチリル〕チオフエン、淡黄色板状晶(ヘキサ
ン)、融点73〜75℃
製剤例 1
2−〔4−(5−アミノ−1,3,4−チアジア
ゾール−2−イル)チオ−ブチリル〕チオフエン
150g
アビセル(商標名 旭化成(株)製) 40g
コーンスターチ 30g
ステアリン酸マグネシウム 2g
ヒドロキシプロピルメチルセルロース 10g
ポリエチレングリコール−6000 3g
ヒマシ油 40g
メタノール 40g
本発明化合物、アビセル、コーンスターチおよ
びステアリン酸マグネシウムを混合研磨後、糖衣
R10mmのキネで打錠する。得られた錠剤をヒドロ
キシプロピルメチルセルロース、ポリエチレング
リコール−6000、ヒマシ油およびメタノールから
なるフイルムコーテイング剤で被覆を行ないフイ
ルムコーテイング錠を製造する。
製剤例 2
2−〔4−(4,5−ジメチル−1,2,4−ト
リアゾール−3−イル)チオ−ブチリル〕チオフ
エン 150g
クエン酸 1.0g
ラクトース 33.5g
リン酸二カルシウム 70.0g
プルロニツクF−68 30.0g
ラウリル硫酸ナトリウム 15.0g
ポリビニルピロリドン 15.0g
ポリエチレングリコール(カルボワツクス
1500) 4.5g
ポリエチレングリコール(カルボワツクス
6000) 45.0g
コーンスターチ 30.0g
乾燥ラウリル硫酸ナトリウム 3.0g
乾燥ステアリン酸マグネシウム 3.0g
エタノール 適量
本発明化合物、クエン酸、ラクトース、リン酸
二カルシウム、プルロニツクF−68およびラウリ
ル硫酸ナトリウムを混合する。
上記混合物をNo.60スクリーンでふるい、ポリビ
ニルピロリドン、カルボワツクス1500および6000
を含むアルコール性溶液で湿式粒状化する。必要
に応じてアルコールを添加して粉末をペーースト
状塊にする。コーンスターチを添加し、均一な粒
子が形成されるまで混合を続ける。No.10スクリー
ンを通過させ、トレイに入れ100℃のオーブンで
12〜14時間乾燥する。乾燥粒子をNo.16スクリーン
でふるい、乾燥ラウリル硫酸ナトリウムおよび乾
燥ステアリン酸マグネシウムを加え混合し、打錠
機で所望の形状に圧縮する。
上記の芯部をワニスで処理し、タルクを散布し
湿気の吸収を防止する。芯部の周囲に下塗り層を
被覆する。内服用のために十分な回数のワニス被
覆を行なう。錠剤を完全に丸くかつ滑かにするた
めに、さらに下塗層および平滑被覆が適用され
る。所望の色合が得られるまで着色被覆を行な
う。乾燥後、被覆錠剤を磨いて均一な光沢の錠剤
にする。
製剤例 3
2−〔4−(4−メチル−2−ピリミジル)チオ
−ブチリル〕チオフエン 5g
ポリエチレングリコール(分子量:4000)
0.3g
塩化ナトリウム 0.9g
ポリオキシエチレンソルビタンモノオレエート
0.4g
メタ重亜硫酸ナトリウム 0.1g
メチル−パラベン 0.18g
プロピル−パラベン 0.02g
注射用蒸留水 100ml
上記パラベン類、メタ重亜硫酸ナトリウムおよ
び塩化ナトリウムを撹拌しながら80℃で上記の約
半量の蒸留水に溶解する。得られた溶液を40℃ま
で冷却し、本発明化合物、つぎにポリエチレング
リコールおよびポリオキシエチレンソルビタンモ
ノオレエートをその溶液中に溶解した。次にその
溶液に注射用蒸留水を加えて最終の容量に調製
し、適当なフイルターペーパーを用いて滅菌過
することにより滅菌して、注射剤を調製する。[Table] Next, the compound of the present invention and the method for producing the same will be explained in more detail with reference to Reference Examples and Examples. Reference example 1 4.4g of 2-mercaptopyridine and 1-bromo-
Dissolve 9.4 g of 3-chloropropane in 100 ml of acetone. Add 6.8 g of potassium carbonate to this and reflux for 3 hours. Acetone is distilled off, water is added to the residue, and the mixture is extracted with chloroform. The chloroform solution is washed with saturated brine and dried over magnesium sulfate. Chloroform was distilled off, and the residue was purified by column chromatography (Kieselgel 60, manufactured by Melf, eluent: chloroform) to obtain 7.9 g of 2-(3-chloropropyl)thio-pyridine. Colorless liquid, NMR (90MHz, CDCl3 ), 2.00-2.40 (2H,
m), 3.30 (2H, t, J=6Hz), 3.66 (2H, t,
J=6Hz), 6.80-8.50 (5H, m) Reference example 2 1-Methyl-2-mercaptoimidazole 2.33
Dissolve g in 50 ml of acetone. To this were added 4.3 g of 4-bromobutyric acid methyl ester and 3 g of potassium carbonate, and the mixture was refluxed for 3 hours. Acetone is distilled off, water is added to the residue, and the mixture is extracted with chloroform.
The chloroform solution is washed with saturated brine and dried over magnesium sulfate. Distill the chloroform,
The residue is purified by column chromatography (Merck Kieselgel 60). After elution with chloroform, 4-(1-methyl-
2-imidazolyl)thio-butyric acid methyl ester
Obtain 2.1g. Boiling point 140-141℃ (0.5mmHg), n 14 D =
1.5300 Elemental analysis value: C 9 H 14 N 2 O 2 S Calculated value (%):
C, 50.45; H, 6.59; N, 13.07 Actual value (%):
C, 50.40; H, 6.57; N, 13.05 Reference example 3 4-(1-methyl-2-imidazolyl)thio-
Add 150 ml of 20% hydrochloric acid to 13.1 g of butyric acid methyl ester and stir at 90-95°C for 1 hour. Distill the hydrochloric acid,
Benzene is added to the residue to remove water azeotropically. The residue was subjected to column chromatography (Wakogel C-
200). Elution with chloroform-methanol (20:1) yields 13 g of 4-(1-methyl-2-imidazolyl)thio-butyric acid hydrochloride as a colorless liquid. NMR (60MHz, DMSO) 1.60-2.10 (2H, m),
2.43 (2H, t, J = 6Hz), 3.38 (2H, t, J = 6
Hz), 3.90 (3H, s), 7.76 (1H, br, s), 7.90
(1H, br, s) Elemental analysis value: C 8 H 13 N 2 SO 2 Cl Calculated value (%):
C, 40.59; H, 5.54; N, 11.83 Analysis value (%):
C, 40.54; H, 5.51; N, 11.80 Reference example 4 2-mercapto-1-methylimidazole 1.4
g and 3.6 g of 4-brombutyronitrile are dissolved in 50 ml of acetone. Add 3 g of potassium carbonate to this and reflux for 3 hours. After distilling off the acetone, water is added to the residue and extracted with chloroform. The chloroform solution is washed with saturated brine and dried over magnesium sulfate. The chloroform is distilled off and the residue is isolated by silica gel chromatography (eluent: chloroform) to obtain 2.6 g of 4-(1-methyl-2-imidazolyl)thio-butyronitrile. Elemental analysis value: C 8 H 11 N 3 S Calculated value (%):
C, 53.01; H, 6.12; N, 23.18 Analysis value (%):
C, 53.12; H, 6.17; N, 23.21 Example 1 2-(4-chlorobutyryl)thiophene 21 g
(0.11 mol), sodium iodide 22.5g (0.15 mol)
Dissolve in acetone and reflux for 3 hours. Acetone was distilled off, the residue was dissolved in dimethylformamide, and 6.7 g (0.12 mol) of potassium hydroxide and 1
-Methyl-2-mercaptoimidazole 11.4g
(0.1 mol) and stirred for 8 hours at a bath temperature of 80°C.
Dimethylformamide is distilled off and extracted with chloroform. Add chloroform layer to water, saturated sodium bicarbonate solution,
After washing with water and saturated saline, drying with anhydrous magnesium sulfate. After distilling off the solvent, the residue was recrystallized from hexane-ethyl acetate to obtain 11 g of 2-[4-(1-methyl-2-imidazolyl)thio-butyryl]thiophene. Pale yellow needle crystals, melting point 57-58℃ Elemental analysis: C 12 H 14 N 2 OS 2 Calculated value (%):
C, 54.10; H, 5.30; N, 10.51 Analysis value (%):
C, 53.78; H, 5.32; N, 10.44 Example 2 The following compound was obtained in the same manner as in Example 1. 2-[4-(5-amino-1,3,4-thiadiazol-2-yl)thio-butyryl]thiophene, colorless needles (ethanol-water), melting point 145~
147℃ 2-[4-(2-pyridyl)thio-butyryl]thiophene, colorless liquid, n 26.5 D = 1.6222 2-[4-(4,5-dimethyl-1,2,4-triazol-3-yl) Thio-butyryl]thiophene, colorless prismatic crystals (hexane-ethyl acetate), melting point 69-70°C 2-[4-(5-methyl-1,3,4-oxadiazol-2-yl)thio-butyryl] Thiophene, colorless prismatic crystals (hexane-ether), melting point 60-61°C 2-[4-(4-methyl-2-pyrimidyl)thio-butyryl]thiophene, colorless prismatic crystals (hexane-ether), melting point 46-47 °C 2-[4-(4-methyl-2-thiazolyl)-thio-butyryl]thiophene, pale yellow platelets (hexane), melting point 73-75°C Example 3 5-[3-(2-thenoyl)propyl ] Dissolve 2.6 g of isothiourea hydrochloride in 50 ml of ethanol.
To this were added 1.6 g of 2-amino-5-chloro-1,3,4-thiadiazole and 10 ml of a 10% aqueous sodium hydroxide solution, and the mixture was refluxed for 3 hours. After evaporating ethanol under reduced pressure, water is added to the residue, and the mixture is extracted with chloroform. Wash the chloroform solution with saturated saline and dry with sodium sulfate. Chloroform was distilled off, and the residue was purified by column chromatography (Wako Gel C-200, eluent chloroform:methanol = 50:1), and then recrystallized from ethanol and water to obtain colorless needle-like crystals of 2-[4 -(5-amino-1,
0.4 g of 3,4-thiadiazol-2-yl)thio-butyryl]thiophene is obtained. Melting point 145-147℃ Elemental analysis value: C 10 H 11 N 3 OS 3 Calculated value (%):
C, 42.08; H, 3.89; N, 14.72 Actual value (%):
C, 41.97; H, 3.84; N, 14.78 Example 4 The following compound was obtained in the same manner as in Example 3. 2-[4-(2-pyridyl)thio-butyryl]thiophene, colorless liquid, n 26.5 D = 1.6222 2-[4-(4,5-dimethyl-1,2,4-triazol-3-yl)thio- Butyryl]thiophene, colorless prismatic crystals (hexane-ethyl acetate), melting point 69-70°C 2-[4-(5-methyl-1,3,4-oxadiazol-2-yl)thio-butyryl]thiophene, colorless prismatic crystals (hexane-ether),
Melting point 60-61°C 2-[4-(4-methyl-2-pyrimidyl)thio-butyryl]thiophene, colorless prismatic crystals (hexane-ether), melting point 46-47°C 2-[4-(1-methyl- 2-[4-(4-methyl-2-thiazolyl)thio-butyryl]thiophene, pale yellow needles (hexane-ethyl acetate), melting point 57-58°C. Crystalline (hexane), melting point 73-75°C Example 5 1.9 g of 2-(4-chlorobutyryl)thiophene and 1.9 g of 5-(2-pyridyl)isothiourea hydrochloride are dissolved in 50 ml of ethanol. Add 10 ml of 10% aqueous sodium hydroxide solution to this and reflux for 2 hours. After distilling off the ethanol, water is added to the residue and extracted with chloroform. The chloroform solution is washed with saturated saline and dried over sodium sulfate.
Chloroform was distilled off, and the residue was purified by column chromatography (Wako Gel C-200, eluent: chloroform) to obtain 1.5 g of 2-[4-(2-pyridyl)thio-butyryl]thiophene as a colorless liquid.
n 26.5 D = 1.6222 Elemental analysis value: C 13 H 13 NOS 2 Calculated value (%):
C, 59.29; H, 4.98; N, 5.32 Actual value (%):
C, 59.34; H, 4.95; N, 5.37 Example 6 The following compound was obtained in the same manner as in Example 5. 2-[4-(5-amino-1,3,4-thiadiazol-2-yl)thio-butyryl]thiophene, colorless needles (ethanol-water), melting point 145~
147℃ 2-[4-(4,5-dimethyl-1,2,4-triazol-3-yl)thio-butyryl]thiophene, colorless prismatic crystals (hexane-ethyl acetate), melting point 69-70℃ 2- [4-(5-methyl-1,3,4-oxadiazol-2-yl)thio-butyryl]thiophene, colorless prismatic crystals (hexane-ether),
Melting point 60-61°C 2-[4-(4-methyl-2-pyrimidyl)thio-butyryl]thiophene, colorless prismatic crystals (hexane-ether), melting point 46-47°C 2-[4-(1-methyl- 2-[4-(4-methyl-2-thiazolyl)thio-butyryl]thiophene, pale yellow needles (hexane-ethyl acetate), melting point 57-58°C. Crystalline (hexane), melting point 73-75°C Example 7 2-(4-mercaptobutyryl)thiophene 3.7
Dissolve g in 10 ml of 10% aqueous sodium hydroxide solution. To this, 2-chloro-4-methylpyrimidine
Add a solution of 2.6 g in 10 ml of methanol dropwise and let it cool for 5 minutes at room temperature.
Stir for 1 hour and further stir at 60-70°C for 5 hours.
After distilling off the methanol, water is added to the residue and extracted with chloroform. The chloroform solution is washed with saturated saline and dried over sodium sulfate. Chloroform was distilled off and the residue was subjected to column chromatography (Wako Gel C-200, eluent: chloroform)
After purification, the product was recrystallized from hexane-ether to obtain 1.2 g of 2-[4-(4-methyl-2-pyrimidyl)thio-butyryl]thiophene in colorless prismatic crystals. Melting point 46-47℃ Elemental analysis value: C 13 H 14 N 2 OS 2 Calculated value (%):
C, 56.08; H, 5.07; N, 10.06 Actual value (%):
C, 56.34; H, 5.11; N, 9.98 Example 8 The following compound was obtained in the same manner as in Example 7. 2-[4-(5-amino-1,3,4-thiadiazol-2-yl)thio-butyryl]thiophene, colorless needles (ethanol-water), melting point 145~
147℃ 2-[4-(2-pyridyl)thio-butyryl]thiophene, colorless liquid, n 26.5 D = 1.6222 2-[4-(4,5-dimethyl-1,2,4-triazol-3-yl) Thio-butyryl]thiophene, colorless prismatic crystals (hexane-ethyl acetate), melting point 69-70°C 2-[4-(5-methyl-1,3,4-oxadiazol-2-yl)thio-butyryl] Thiophene, colorless prismatic crystals (hexane-ether),
Melting point 60-61℃ 2-[4-(1-methyl-2-imidazolyl)-
2-[4-(4-methyl-2-thiazolyl)thio-butyryl]thiophene, light yellow platelets (hexane-ethyl acetate), melting point 57-58°C ), melting point 73-75°C Example 9 Magnesium 0.25g, 2-bromothiophene
From 1.4 g and 10 ml of dry tetrahydrofuran,
Produce 2-thienylmagnesium bromide. To this was added dropwise a solution of 1.8 g of 4-(1-methyl-2-imidazolyl)thio-butyronitrile in 10 ml of dry tetrahydrofuran while stirring on ice. After dropping, stir at room temperature for 3 hours. Add 50ml of 1N hydrochloric acid under ice cooling,
Stir for an hour. The reaction solution was diluted with water and extracted with chloroform. The chloroform solution is washed with saturated aqueous sodium bicarbonate and saturated brine, and dried over sodium sulfate. Chloroform was distilled off, and the residue was diluted with hexane.
Recrystallized from ether to give 2-[4-(1-methyl-
2-imidazolyl)thio-butyryl]thiophene
Obtain 0.6g. Pale yellow needle crystals, melting point 57-58℃ Elemental analysis: C 12 H 14 N 2 OS 2 Calculated value (%):
C, 54.10; H, 5.30; N, 10.51 Actual value (%):
C, 53.78; H, 5.32; N, 10.44 Example 10 The following compound was obtained in the same manner as in Example 9. 2-[4-(5-amino-1,3,4-thiadiazol-2-yl)thio-butyryl]thiophene, colorless needles (ethanol-water), melting point 145~
147℃ 2-[4-(2-pyridyl)thio-butyryl]thiophene, colorless liquid, n 26.5 D = 1.6222 2-[4-(4,5-dimethyl-1,2,4-triazol-3-yl) Thio-butyryl]thiophene, colorless prismatic crystals (hexane-ethyl acetate), melting point 69-70°C 2-[4-(5-methyl-1,3,4-oxadiazol-2-yl)thio-butyryl] Thiophene, colorless prismatic crystals (hexane-ether),
Melting point 60-61°C 2-[4-(4-methyl-2-pyrimidyl)thio-butyryl]thiophene, colorless prismatic crystals (hexane-ether), melting point 46-47°C 2-[4-(4-methyl- 2-Thiazolyl)thio-butyryl]thiophene, pale yellow platelets (hexane) mp 73-75°C Example 11 0.3 g of magnesium is suspended in 5 ml of dry tetrahydrofuran. A small piece of iodine was added to this under stirring in a nitrogen stream, and 4,5-dimethyl-3-
Add 0.3 g of (3-chloropropyl)thio-1,2,4-triazole. Add 0.1 ml of ethyl bromide and heat externally to start the reaction. remaining 4,5-dimethyl-3-(3-chloropropyl)
A solution of 2.0 g of thio-1,2,4-triazole in 15 ml of dry tetrahydrofuran is added dropwise. After dripping,
Reflux for 1 hour. A solution of 1.0 g of 2-cyanothiophene in 5 ml of dry tetrahydrofuran was added dropwise to the Grignard reagent under ice-cooling and stirring. 3 at room temperature
Stir for an hour. Add 20ml of 1N hydrochloric acid under ice cooling,
Stir for an hour. The reaction solution was diluted with water and extracted with chloroform. The chloroform solution is washed with saturated aqueous sodium bicarbonate and saturated brine, and then dried over sodium sulfate. The ether was distilled off, and the residue was recrystallized from hexane-ethyl acetate to obtain 0.7 g of 2-[4-(4,5-dimethyl-1,2,4-triazol-3-yl)thio-butyryl]thiophene. . Colorless prismatic crystals, melting point 69-70℃ Elemental analysis: C 12 H 15 N 3 OS 2 Calculated value (%):
C, 51.22; H, 5.37; N, 14.93 Actual value (%):
C, 50.98; H, 5.43; N, 14.87 Example 12 The following compound is obtained in the same manner as in Example 11. 2-[4-(2-pyridyl)thio-butyryl]thiophene, colorless liquid, n 26.5 D = 1.6222 2-[4-(5-methyl-1,3,4-oxadiazol-2-yl)thio- butyryl]thiophene, colorless prismatic crystals (hexane-ether),
Melting point 60-61°C 2-[4-(4-methyl-2-pyrimidyl)thio-butyryl]thiophene, colorless prismatic crystals (hexane-ether), melting point 46-47°C 2-[4-(1-methyl- 2-[4-(4-methyl-2-thiazolyl)thio-butyryl]thiophene, pale yellow needles (hexane-ethyl acetate), melting point 57-58°C. Example 13 2 g of 4-(5-methyl-1,3,4-oxadiazol-2-yl)thio-butyric acid was dissolved in anhydrous benzene.
Dissolve in 20ml. Ether solution of 1.5N 2-thienyllithium with stirring at -70℃ under argon stream
Drop 13.3ml. Stir for 3 hours while gradually raising the temperature to room temperature. Further stir overnight at room temperature,
Pour the reaction solution into ice water and extract with ether. The ether solution is washed with saturated aqueous sodium bicarbonate and saturated brine, and then dried over magnesium sulfate. The ether was distilled off and the residue was recrystallized from hexane-ether to obtain 0.6 g of 2-[4-(5-methyl-1,3,4-oxadiazol-2-yl)thio-butyryl]thiophene. . Colorless prismatic crystals (hexane-ether), melting point 60-61℃ Elemental analysis: C 11 H 12 N 2 O 2 S 2 Calculated value (%):
C, 49.23; H, 4.51; N, 10.44 Actual value (%):
C, 49.48; H, 4.59; N, 10.36 Example 14 Analogously to Example 13, the compound of interest is obtained. 2-[4-(5-amino-1,3,4-thiadiazol-2-yl)thio-butyryl]thiophene, colorless needles (ethanol-water), melting point 145~
147℃ 2-[4-(2-pyridyl)thio-butyryl]thiophene, colorless liquid, n 26.5 D = 1.6222 2-[4-(4,5-dimethyl-1,2,4-triazol-3-yl) Thio-butyryl]thiophene, colorless prismatic crystals (hexane-ethyl acetate), melting point 69-70°C 2-[4-(4-methyl-2-pyrimidyl)thio-butyryl]thiophene, colorless prismatic crystals (hexane-ether) ), melting point 46-47℃ 2-[4-(1-methyl-2-imidazolyl)-
2-[4-(4-methyl-2-thiazolyl)thio-butyryl]thiophene, light yellow platelets (hexane-methyl acetate), melting point 57-58°C ), melting point 73-75°C Example 15 2-(2-thienyl)-1,3-dithiane 2.2 g
Dissolved in 20 ml of dry tetrahydrofuran at -78℃
Cool to This was then stirred in a stream of argon.
1.6N n-butyllithium n-hexane solution
Drop 6.5ml. Stir for 30 minutes at -78°C. To this, 4,5-dimethyl-3-(3-chloropropyl)
A solution of 2 g of thio-1,2,4-triazole in 5 ml of dry tetrahydrofuran is added dropwise. 1 at -78℃
After stirring for 4 hours, gradually raise the temperature to 0℃
Stir for an hour. Pour the reaction solution into ice water and extract the ether. The ether solution is washed with water and saturated saline, and then dried over magnesium sulfate. The ether is distilled off and the residue is dissolved in 20 ml of acetonitrile. Separately, 7 g of silver nitrate and 4.9 g of N-chlorosuccinimide are dissolved in 40 ml of water and 100 ml of acetonitrile. The above dithiane solution was added dropwise to this while stirring at 0° C. in a nitrogen stream. After stirring at 0°C for 30 minutes, warm to room temperature and stir for an additional 30 minutes. Dilute with water and extract with chloroform. The chloroform solution is washed with water and saturated saline, and dried over magnesium sulfate. Chloroform was distilled off, and the residue was recrystallized from hexane-ethyl acetate to give 2-[4
-(4,5-dimethyl-1,2,4-triazol-3-yl)thio-butyryl]thiophene 0.4
get g. Colorless prismatic crystals, melting point 69-70℃ Elemental analysis: C 12 H 15 N 3 OS 2 Calculated value (%):
C, 51.22; H, 5.37; N, 14.93 Actual value (%):
C, 50.98; H, 5.43; N, 14.87 Example 16 The following compound was obtained in the same manner as in Example 15. 2-[4-(5-amino-1,3,4-thiadiazol-2-yl)thio-butyryl]thiophene, colorless needles (ethanol-water), melting point 145~
147℃ 2-[4-(2-pyridyl)thio-butyryl]thiophene, colorless liquid, n 26.5 D = 1.6222 2-[4-(5-methyl-1,3,4-oxadiazol-2-yl) Thio-butyryl]thiophene, colorless prismatic crystals (hexane-ether),
Melting point 60-61°C 2-[4-(4-methyl-2-pyrimidyl)thio-butyryl]thiophene, colorless prismatic crystals (hexane-ether), melting point 46-47°C 2-[4-(1-methyl- 2-[4-(4-methyl-2-thiazolyl)thio-butyryl]thiophene, pale yellow needles (hexane-ethyl acetate), melting point 57-58°C. Crystalline (hexane), melting point 73-75°C Example 17 Add 5 ml of thionyl chloride to 2.1 g of 4-(4-methyl-2-pyrimidyl)thio-butyric acid and stir at 40-50°C for 1 hour.Excess chloride Thionyl is distilled off under reduced pressure. Dry benzene is added and water is removed azeotropically, and 4-(4-methyl-2-
pyrimidyl)thio-butyric acid chloride is obtained. Add 571 mg of copper iodide to a sealed two-necked flask, and after degassing under reduced pressure, fill it with nitrogen. Pour 10 ml of anhydrous ether into this and cool the whole to -40°C. Add 5 ml of an ether solution of 1.332M2-thienyllithium to this, and -40
After stirring at ℃ for 5 minutes, cool to -78℃. 5 ml of a cold anhydrous ether solution containing 0.25 g of 4-(4-methyl-2-pyrimidyl)thio-butyric acid chloride obtained above was poured into the mixture, and the mixture was stirred at -78 DEG C. for 15 minutes.
35 ml of anhydrous methanol is poured into this reaction solution, and the flask is returned to room temperature. The reaction solution was poured into a saturated aqueous ammonium chloride solution and extracted with ether. The ether solution is dried over magnesium sulfate and the ether is distilled off. The residue is recrystallized from hexane-ether to obtain 0.1 g of 2-[4-(4-methyl-2-pyrimidyl)thio-butyryl]thiophene. Colorless prismatic crystals, melting point 46-47℃ Elemental analysis: C 13 H 14 N 2 OS 2 Calculated value (%):
C, 56.08; H, 5.07; N, 10.06 Actual value (%):
C, 56.34; H, 5.11; N, 9.98 Example 18 The following compound was obtained in the same manner as in Example 17. 2-[4-(5-amino-1,3,4-thiadiazol-2-yl)thio-butyryl]thiophene, colorless needles (ethanol-water), melting point 145~
147℃ 2-[4-(2-pyridyl)thio-butyryl]thiophene, colorless liquid, n 26.5 D = 1.6222 2-[4-(4,5-dimethyl-1,2,4-triazol-3-yl) Thio-butyryl]thiophene, colorless prismatic crystals (hexane-ethyl acetate), melting point 69-70°C 2-[4-(5-methyl-1,3,4-oxadiazol-2-yl)thio-butyryl] Thiophene, colorless prismatic crystals (hexane-ether),
Melting point 60-61℃ 2-[4-(1-methyl-2-imidazolyl)thio-butyryl]thiophene, pale yellow needles (hexane-ethyl acetate), melting point 57-58℃ 2-[4-(4- Methyl-2-thiazolyl)thio-butyryl]thiophene, pale yellow platelets (hexane), melting point 73-75°C Example 19 1.6 g of phosphorus pentoxide are suspended in 20 ml of anhydrous benzene. To this were added 1.34 g of thiophene and 2 g of 4-(2-pyridyl)thio-butyric acid, and the mixture was refluxed for 4 hours. The benzene solution is separated and the residue is further washed with benzene. Combine the benzene solutions and dry with sodium sulfate. After distilling off the benzene, the residue was subjected to column chromatography (Wakogel C-
200, eluent chloroform) to yield 2-[4-(2-pyridyl)thio-butyryl] as a colorless liquid.
Obtain 0.5 g of thiophene. n 26.5 D = 1.6222 Elemental analysis value: C 13 H 13 NOS 2 Calculated value (%):
C, 59.29; H, 4.98; N, 5.32 Actual value (%):
C, 59.19; H, 4.96; N, 5.29 Example 20 The following compound is obtained in the same manner as in Example 19. 2-[4-(1-methyl-2-imidazolyl)thio-butyryl]thiophene, pale yellow needles (hexane-ethyl acetate), mp 57-58°C 2-[4-(5-amino-1,3) ,4-thiadiazol-2-yl)thio-butyryl]thiophene, colorless needle crystals (ethanol-water), melting point 145~
147℃ 2-[4-(4,5-dimethyl-1,2,4-triazol-3-yl)thio-butyryl]thiophene, colorless prismatic crystals (hexane-ethyl acetate), melting point 69-70℃ 2- [4-(5-methyl-1,3,4-oxadiazol-2-yl)thio-butyryl]thiophene, colorless prismatic crystals (hexane-ether),
Melting point 60-61°C 2-[4-(4-methyl-2-pyrimidyl)thio-butyryl]thiophene, colorless prismatic crystals (hexane-ether), melting point 46-47°C 2-[4-(4-methyl- 2-thiazolyl]thio-butyryl]thiophene, pale yellow platelets (hexane), melting point 73-75°C Example 21 2-[1,1-ethylenedioxy-4-(2-pyridyl)thio-butyryl]thiophene Dissolve 0.4g in 5ml of acetic acid.Add 2.5ml of water and 0.5ml of concentrated hydrochloric acid to this.
Add and heat on a water bath for 1 hour. Add water to the reaction solution and extract with chloroform. Wash the chloroform solution with water, saturated sodium bicarbonate solution and saturated saline solution,
Dry with magnesium sulfate. Chloroform is distilled off, and the residue is purified by silica gel column chromatography (Merck & Co., Kieselgel 60). Elute with chloroform to obtain 2-[4-(2-pyridyl)
0.2 g of thio-butyryl]thiophene is obtained. Colorless liquid, n 26.5 D = 1.6222 Elemental analysis value: C 13 H 13 NOS 2 Calculated value (%):
C, 59.29; H, 4.98; N, 5.32 Actual value (%):
C, 59.25; H, 4.95; N, 5.35 Example 22 The following compound is obtained in the same manner as in Example 21. 2-[4-(1-methyl-2-imidazolyl)thio-butyryl]thiophene, pale yellow needles (hexane-ethyl acetate), mp 57-58°C 2-[4-(5-amino-1,3) ,4-thiadiazol-2-yl)thio-butyryl]thiophene, colorless needle crystals (ethanol-water), melting point 145~
147℃ 2-[4-(4,5-dimethyl-1,2,4-triazol-3-yl)thio-butyryl]thiophene, colorless prismatic crystals (hexane-ethyl acetate), melting point 69-70℃ 2- [4-(5-methyl-1,3,4-oxadiazol-2-yl)thio-butyryl]thiophene, colorless prismatic crystals (hexane-ether),
Melting point 60-61°C 2-[4-(4-methyl-2-pyrimidyl)thio-butyryl]thiophene, colorless prismatic crystals (hexane-ether), melting point 46-47°C 2-[4-(4-methyl- 2-thiazolyl)thio-butyryl]thiophene, pale yellow plate crystals (hexane), melting point 73-75°C Formulation example 1 2-[4-(5-amino-1,3,4-thiadiazol-2-yl)thio -Butyrylthiophene
150g Avicel (trade name: manufactured by Asahi Kasei Corporation) 40g Corn starch 30g Magnesium stearate 2g Hydroxypropyl methyl cellulose 10g Polyethylene glycol-6000 3g Castor oil 40g Methanol 40g After mixing and polishing the compound of the present invention, Avicel, cornstarch and magnesium stearate, sugar coating
Compress the tablets with an R10mm kine. The obtained tablets are coated with a film coating agent consisting of hydroxypropyl methylcellulose, polyethylene glycol-6000, castor oil, and methanol to produce film-coated tablets. Formulation example 2 2-[4-(4,5-dimethyl-1,2,4-triazol-3-yl)thio-butyryl]thiophene 150g Citric acid 1.0g Lactose 33.5g Dicalcium phosphate 70.0g Pluronic F-68 30.0g Sodium lauryl sulfate 15.0g Polyvinylpyrrolidone 15.0g Polyethylene glycol (Carbowax)
1500) 4.5g polyethylene glycol (Carbowax
6000) 45.0g Corn starch 30.0g Dry sodium lauryl sulfate 3.0g Dry magnesium stearate 3.0g Ethanol Appropriate amount The compound of the present invention, citric acid, lactose, dicalcium phosphate, Pluronic F-68, and sodium lauryl sulfate are mixed. The above mixture was sieved through a No. 60 screen, and polyvinylpyrrolidone, Carbowax 1500 and 6000 were added.
wet granulation in an alcoholic solution containing Add alcohol if necessary to make the powder into a paste-like mass. Add cornstarch and continue mixing until uniform particles are formed. Pass it through a No. 10 screen, put it in a tray and put it in an oven at 100℃.
Dry for 12-14 hours. The dry particles are sieved through a No. 16 screen, dried sodium lauryl sulfate and dry magnesium stearate are added and mixed, and compressed into the desired shape using a tablet machine. The core is treated with varnish and sprinkled with talc to prevent moisture absorption. A subbing layer is applied around the core. Apply varnish a sufficient number of times for internal use. Further subbing layers and smooth coatings are applied to make the tablet perfectly round and smooth. Pigmented coatings are applied until the desired shade is obtained. After drying, the coated tablets are polished to a uniform gloss. Formulation example 3 2-[4-(4-methyl-2-pyrimidyl)thio-butyryl]thiophene 5g Polyethylene glycol (molecular weight: 4000)
0.3g Sodium chloride 0.9g Polyoxyethylene sorbitan monooleate
0.4g Sodium metabisulfite 0.1g Methyl-paraben 0.18g Propyl-paraben 0.02g Distilled water for injection 100ml Dissolve the above parabens, sodium metabisulfite and sodium chloride in about half the amount of distilled water above at 80°C with stirring. do. The resulting solution was cooled to 40°C, and the compound of the present invention, followed by polyethylene glycol and polyoxyethylene sorbitan monooleate, were dissolved in the solution. Next, distilled water for injection is added to the solution to adjust the final volume, and the solution is sterilized by sterilization using a suitable filter paper to prepare an injection.
Claims (1)
リアゾリル、1,3,4−チアジアゾリル、1,
3,4−オキサジアゾリル、ピリジル、ピリミジ
ル、およびチアゾリルからなる群から選ばれる不
飽和ヘテロ環基を示す。該ヘテロ環基は、アミノ
基および低級アルキル基からなる群から選ばれる
1または2個の置換基を有していてもよい。Aは
低級アルキレン基を示す] で表わされるチオフエン誘導体およびその塩。[Claims] 1. General formula [Wherein, R 1 is imidazolyl, 1,2,4-triazolyl, 1,3,4-thiadiazolyl, 1,
It represents an unsaturated heterocyclic group selected from the group consisting of 3,4-oxadiazolyl, pyridyl, pyrimidyl, and thiazolyl. The heterocyclic group may have one or two substituents selected from the group consisting of an amino group and a lower alkyl group. A represents a lower alkylene group] A thiophene derivative and a salt thereof.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP13912080A JPS5764691A (en) | 1980-10-03 | 1980-10-03 | Thiophene derivative |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP13912080A JPS5764691A (en) | 1980-10-03 | 1980-10-03 | Thiophene derivative |
Publications (2)
Publication Number | Publication Date |
---|---|
JPS5764691A JPS5764691A (en) | 1982-04-19 |
JPH0212228B2 true JPH0212228B2 (en) | 1990-03-19 |
Family
ID=15237960
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP13912080A Granted JPS5764691A (en) | 1980-10-03 | 1980-10-03 | Thiophene derivative |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPS5764691A (en) |
-
1980
- 1980-10-03 JP JP13912080A patent/JPS5764691A/en active Granted
Also Published As
Publication number | Publication date |
---|---|
JPS5764691A (en) | 1982-04-19 |
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