JPS62265270A - Novel imidazole derivative and antiulcer agent containing said derivative as active component - Google Patents
Novel imidazole derivative and antiulcer agent containing said derivative as active componentInfo
- Publication number
- JPS62265270A JPS62265270A JP10931486A JP10931486A JPS62265270A JP S62265270 A JPS62265270 A JP S62265270A JP 10931486 A JP10931486 A JP 10931486A JP 10931486 A JP10931486 A JP 10931486A JP S62265270 A JPS62265270 A JP S62265270A
- Authority
- JP
- Japan
- Prior art keywords
- group
- spectrum
- methyl
- hydrochloride
- dimethylimidazole
- 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.)
- Pending
Links
- 150000002460 imidazoles Chemical class 0.000 title claims abstract description 22
- 239000003699 antiulcer agent Substances 0.000 title claims description 5
- -1 nitro, amino Chemical group 0.000 claims abstract description 28
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 15
- 239000002253 acid Substances 0.000 claims abstract description 12
- 150000003839 salts Chemical class 0.000 claims abstract description 8
- 125000004414 alkyl thio group Chemical group 0.000 claims abstract description 5
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 5
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 4
- 125000005843 halogen group Chemical group 0.000 claims abstract description 4
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims abstract 3
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims abstract 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract 3
- 125000003258 trimethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])[*:1] 0.000 claims abstract 3
- 239000000126 substance Substances 0.000 claims description 6
- 239000004480 active ingredient Substances 0.000 claims description 4
- 229940079865 intestinal antiinfectives imidazole derivative Drugs 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims 2
- 125000003277 amino group Chemical group 0.000 claims 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims 2
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 claims 2
- 150000001875 compounds Chemical class 0.000 abstract description 74
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 abstract description 44
- 125000000446 sulfanediyl group Chemical group *S* 0.000 abstract description 35
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 abstract description 33
- 208000000718 duodenal ulcer Diseases 0.000 abstract description 10
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 abstract description 8
- 208000007107 Stomach Ulcer Diseases 0.000 abstract description 4
- 201000005917 gastric ulcer Diseases 0.000 abstract description 2
- 229910052736 halogen Inorganic materials 0.000 abstract 2
- 150000002367 halogens Chemical class 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 230000003449 preventive effect Effects 0.000 abstract 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 abstract 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 52
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 52
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 35
- 238000002844 melting Methods 0.000 description 33
- 230000008018 melting Effects 0.000 description 33
- 238000002329 infrared spectrum Methods 0.000 description 30
- 238000001819 mass spectrum Methods 0.000 description 30
- 238000001228 spectrum Methods 0.000 description 30
- 238000000034 method Methods 0.000 description 28
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 18
- 208000025865 Ulcer Diseases 0.000 description 16
- 231100000397 ulcer Toxicity 0.000 description 16
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- 239000013078 crystal Substances 0.000 description 13
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 230000000694 effects Effects 0.000 description 12
- SSOLNOMRVKKSON-UHFFFAOYSA-N proguanil Chemical compound CC(C)\N=C(/N)N=C(N)NC1=CC=C(Cl)C=C1 SSOLNOMRVKKSON-UHFFFAOYSA-N 0.000 description 12
- AXBVSRMHOPMXBA-UHFFFAOYSA-N 4-nitrothiophenol Chemical compound [O-][N+](=O)C1=CC=C(S)C=C1 AXBVSRMHOPMXBA-UHFFFAOYSA-N 0.000 description 11
- 241000700159 Rattus Species 0.000 description 10
- 210000004051 gastric juice Anatomy 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 8
- DZGCGKFAPXFTNM-UHFFFAOYSA-N ethanol;hydron;chloride Chemical compound Cl.CCO DZGCGKFAPXFTNM-UHFFFAOYSA-N 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- 125000004189 3,4-dichlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(Cl)C([H])=C1* 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- 210000002784 stomach Anatomy 0.000 description 7
- VZXOZSQDJJNBRC-UHFFFAOYSA-N 4-chlorobenzenethiol Chemical compound SC1=CC=C(Cl)C=C1 VZXOZSQDJJNBRC-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- 206010042220 Stress ulcer Diseases 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 230000000767 anti-ulcer Effects 0.000 description 6
- 238000000354 decomposition reaction Methods 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 230000005764 inhibitory process Effects 0.000 description 6
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 6
- 230000028327 secretion Effects 0.000 description 6
- 230000037396 body weight Effects 0.000 description 5
- 238000007654 immersion Methods 0.000 description 5
- HNJZDPKMMZXSKT-UHFFFAOYSA-N 3,4-dichlorobenzenethiol Chemical compound SC1=CC=C(Cl)C(Cl)=C1 HNJZDPKMMZXSKT-UHFFFAOYSA-N 0.000 description 4
- CQJDYPZUDYXHLM-UHFFFAOYSA-N 3-chlorobenzenethiol Chemical compound SC1=CC=CC(Cl)=C1 CQJDYPZUDYXHLM-UHFFFAOYSA-N 0.000 description 4
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 4
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 4
- WLHCBQAPPJAULW-UHFFFAOYSA-N 4-methylbenzenethiol Chemical compound CC1=CC=C(S)C=C1 WLHCBQAPPJAULW-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 description 4
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 4
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 4
- 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 4
- 239000001103 potassium chloride Substances 0.000 description 4
- 235000011164 potassium chloride Nutrition 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 4
- 230000001629 suppression Effects 0.000 description 4
- 238000011282 treatment Methods 0.000 description 4
- RFCQDOVPMUSZMN-UHFFFAOYSA-N 2-Naphthalenethiol Chemical compound C1=CC=CC2=CC(S)=CC=C21 RFCQDOVPMUSZMN-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- AQIXAKUUQRKLND-UHFFFAOYSA-N cimetidine Chemical compound N#C/N=C(/NC)NCCSCC=1N=CNC=1C AQIXAKUUQRKLND-UHFFFAOYSA-N 0.000 description 3
- 229960001380 cimetidine Drugs 0.000 description 3
- 210000004211 gastric acid Anatomy 0.000 description 3
- 230000002496 gastric effect Effects 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 230000002265 prevention Effects 0.000 description 3
- 230000001681 protective effect Effects 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- JDIIGWSSTNUWGK-UHFFFAOYSA-N 1h-imidazol-3-ium;chloride Chemical compound [Cl-].[NH2+]1C=CN=C1 JDIIGWSSTNUWGK-UHFFFAOYSA-N 0.000 description 2
- LXUNZSDDXMPKLP-UHFFFAOYSA-N 2-Methylbenzenethiol Chemical compound CC1=CC=CC=C1S LXUNZSDDXMPKLP-UHFFFAOYSA-N 0.000 description 2
- ZYHQGITXIJDDKC-UHFFFAOYSA-N 2-[2-(2-aminophenyl)ethyl]aniline Chemical group NC1=CC=CC=C1CCC1=CC=CC=C1N ZYHQGITXIJDDKC-UHFFFAOYSA-N 0.000 description 2
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 description 2
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 description 2
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 description 2
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 2
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 description 2
- NIFAOMSJMGEFTQ-UHFFFAOYSA-N 4-methoxybenzenethiol Chemical compound COC1=CC=C(S)C=C1 NIFAOMSJMGEFTQ-UHFFFAOYSA-N 0.000 description 2
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- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 229920000084 Gum arabic Polymers 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 208000008469 Peptic Ulcer Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 239000000205 acacia gum Substances 0.000 description 2
- 235000010489 acacia gum Nutrition 0.000 description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
- 231100000403 acute toxicity Toxicity 0.000 description 2
- 230000007059 acute toxicity Effects 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- UKJLNMAFNRKWGR-UHFFFAOYSA-N cyclohexatrienamine Chemical group NC1=CC=C=C[CH]1 UKJLNMAFNRKWGR-UHFFFAOYSA-N 0.000 description 2
- 230000001120 cytoprotective effect Effects 0.000 description 2
- IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 230000029142 excretion Effects 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 230000027119 gastric acid secretion Effects 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 208000011906 peptic ulcer disease Diseases 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 210000001187 pylorus Anatomy 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
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- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- QRVOMXNKYSBJSD-UHFFFAOYSA-N (4-sulfanylphenyl)azanium;chloride Chemical compound [Cl-].[NH3+]C1=CC=C(S)C=C1 QRVOMXNKYSBJSD-UHFFFAOYSA-N 0.000 description 1
- YNCPXBIZAPNQIJ-UHFFFAOYSA-N 1h-imidazole;sodium Chemical compound [Na].C1=CNC=N1 YNCPXBIZAPNQIJ-UHFFFAOYSA-N 0.000 description 1
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- YLZOPXRUQYQQID-UHFFFAOYSA-N 3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-1-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]propan-1-one Chemical compound N1N=NC=2CN(CCC=21)CCC(=O)N1CCN(CC1)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F YLZOPXRUQYQQID-UHFFFAOYSA-N 0.000 description 1
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- RKSANQPKBITNSO-UHFFFAOYSA-N 4,5-dimethyl-1h-imidazole;hydrochloride Chemical compound Cl.CC=1N=CNC=1C RKSANQPKBITNSO-UHFFFAOYSA-N 0.000 description 1
- MGGVALXERJRIRO-UHFFFAOYSA-N 4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]-2-[2-oxo-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethyl]-1H-pyrazol-5-one Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C=1C(=NN(C=1)CC(=O)N1CC2=C(CC1)NN=N2)O MGGVALXERJRIRO-UHFFFAOYSA-N 0.000 description 1
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- 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 1
- 229930195725 Mannitol Natural products 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- MKYBYDHXWVHEJW-UHFFFAOYSA-N N-[1-oxo-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propan-2-yl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(C(C)NC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 MKYBYDHXWVHEJW-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 231100000215 acute (single dose) toxicity testing Toxicity 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 238000011047 acute toxicity test Methods 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 230000001078 anti-cholinergic effect Effects 0.000 description 1
- 238000010009 beating Methods 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 229940127243 cholinergic drug Drugs 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 235000013365 dairy product Nutrition 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 210000001198 duodenum Anatomy 0.000 description 1
- 230000002857 effect on ulcer Effects 0.000 description 1
- 239000004210 ether based solvent Substances 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 210000001156 gastric mucosa Anatomy 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 230000000762 glandular Effects 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 210000004013 groin Anatomy 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 238000011866 long-term treatment Methods 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
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- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
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- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
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Abstract
Description
【発明の詳細な説明】
［産業上の利用分野］
本発明は、抗潰瘍作用を有する、一般式（Ｉ）で表わさ
れることを特徴とする新規イミダゾール誘導体および医
薬品として適当なその酸付加塩、およびそれらの少なく
とも一種を有効成分として含有する胃潰瘍、十二指潰瘍
等の予防、治療に有用な抗潰瘍剤に関するものである。DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention provides a novel imidazole derivative having an anti-ulcer effect and characterized by being represented by the general formula (I), and an acid addition salt thereof suitable as a pharmaceutical; The present invention also relates to an anti-ulcer agent useful for the prevention and treatment of gastric ulcer, duodenal ulcer, etc., which contains at least one of these as an active ingredient.
［従来の技術］
消化性潰瘍の発生機序は複雑であるが、胃腸粘膜に対す
る攻撃因子と防禦因子とのバランスが崩れることにより
発生するといわれている。[Prior Art] The mechanism of occurrence of peptic ulcer is complex, but it is said that peptic ulcer occurs due to disruption of the balance between factors that attack and protect the gastrointestinal mucosa.
現在使用されている治療薬は攻撃因子である胃酸の分泌
を抑制する薬剤が主であり、それらの薬剤としては抗コ
リン薬やヒスタミンＨ２受容体遮断薬（例えばシメチジ
ン）が用いられている。The therapeutic drugs currently in use are mainly drugs that suppress the secretion of gastric acid, which is an attack factor, and these drugs include anticholinergic drugs and histamine H2 receptor blockers (eg, cimetidine).
［発明が解決しようとする問題点］
しかし、攻撃因子である胃酸の分泌の抑制だけでは潰瘍
の予防や治療には不充分であり、胃酸の分泌を無酸近く
まで抑制することのできうる抗コリン薬でも潰瘍の悪化
および再発の予防には限界がある。[Problems to be solved by the invention] However, simply suppressing the secretion of gastric acid, which is an attack factor, is insufficient to prevent or treat ulcers. Even cholinergic drugs have limitations in preventing ulcer aggravation and recurrence.
またシメチジンは望ましくない中枢作用および他の副作
用を示し、特に長期治療下に認められる胃粘膜の防禦因
子の低下が問題となり、シメチジン使用中断後の再発潰
瘍の大きな原因となるといわれている。In addition, cimetidine exhibits undesirable central effects and other side effects, particularly the decrease in protective factors of the gastric mucosa observed under long-term treatment, which is said to be a major cause of recurrent ulcers after cimetidine use is discontinued.
［問題点を解決するための手段］
本発明は攻撃因子である胃酸の分泌を抑制するたけでな
く防禦因子をも増強するすぐれた抗潰瘍化合物を提供す
るものである。すなわち、本発明は一般式（Ｉ）
て表わされることを特徴とするイミダゾール誘導体、お
よびその酸付加塩と、それらの少なくとも一種を有効成
分として含有することを特徴とする抗潰瘍剤に関するも
のである。[Means for Solving the Problems] The present invention provides an excellent anti-ulcer compound that not only suppresses the secretion of gastric acid, which is an attack factor, but also enhances protective factors. Specifically, the present invention relates to an imidazole derivative represented by the general formula (I), an acid addition salt thereof, and an antiulcer agent containing at least one of them as an active ingredient. .
ここで、前記一般式（Ｉ）の各置換基の具体例は以下の
通りである。Here, specific examples of each substituent in the general formula (I) are as follows.
Ｒ１の低級アルキルチオ基は炭素原子数１〜３のアルキ
ルチオ基であり、メチルチオ基が特に好ましい。Ｒ１の
低級アルキル基は炭素原子数１〜４のアルキル基であり
、メチル基、エチル基が特に好ましい。The lower alkylthio group for R1 is an alkylthio group having 1 to 3 carbon atoms, and a methylthio group is particularly preferred. The lower alkyl group for R1 is an alkyl group having 1 to 4 carbon atoms, and methyl and ethyl groups are particularly preferred.
Ｒ２の低級アルキル基は炭素原子数１〜４のアルキル基
であり、メチル基、エチル基が好ましい。The lower alkyl group for R2 is an alkyl group having 1 to 4 carbon atoms, preferably a methyl group or an ethyl group.
またＲ’、Ｒ’、Ｒ５、Ｒ６のハロゲン原子としてはフ
ッ素原子、クロル原子、ブロム原子が好ましい。低級ア
ルキル基としては炭素原子数１〜４のアルキル基が好ま
しく、低級アルコキシ基としてはメトキシ基、エトキシ
基が好ましい。Further, as the halogen atoms for R', R', R5, and R6, fluorine atoms, chlorine atoms, and bromine atoms are preferable. The lower alkyl group is preferably an alkyl group having 1 to 4 carbon atoms, and the lower alkoxy group is preferably a methoxy group or an ethoxy group.
更に本発明の新規イミダゾール誘導体の具体例としては
、以下の化合物が挙げられる。Further, specific examples of the novel imidazole derivatives of the present invention include the following compounds.
−５（４）−メチル−２−メチルチオ−４（５）−［［
（２−ナフチル）チオ〕メチル］イミダゾール０２゜５
（４）−ジメチル−４（５）−（（フェニルチオ）メチ
ルコイミダゾール
’ ４（５）−［［（３−フルオロフェニル）チオコメ
チル］−２，５（４）−ジメチルイミダゾールＱ４（５
）−［［（３−クロロフェニル）チオコメチル］−２，
５（４）−ジメチルイミダゾール’ ４（５）−［［（
４−クロロフェニル）チオコメチル］−２，５（４）−
ジメチルイミダゾール’ ４（５）−［［（３，４−ジ
クロロフェニル）チオコメチル］−２，５（４）−ジメ
チルイミダゾール口４（５）−［［（２，６−ジクロロ
フェニル）チオコメチル］−２，５（４）−ジメチルイ
ミダゾール−２，５（４）−ジメチル−４（５）−［［
（２，４，５−トリクロロフェニル）チオ〕メチル］イ
ミダゾール０４（５）−［（（４−ブロモフェニル）チ
オコメチル］−２，５（４）−ジメチルイミダゾール０
４（５）−［（（３−クロロ−４−メチルフェニル）チ
オコメチル］−２，５（４）−ジメチルイミダゾール０
２．５（４）−ジメチル−４（５）−［［（２−メチル
フェニル）チオ〕メチル］イミダゾール
−２，５（４）−ジメチル−４（５）−［（（ａ−メチ
ルフェニル）チオ〕メチル］イミダゾール
−２，５（４）−ジメチル−４（５）−［（（４−メチ
ルフェニル）チオ〕メチル］イミダゾール
’ ４（５）−［（（３，５−ジメチルフェニル）千オ
］メチル］−２，５（４）−ジメチルイミダゾール０４
（５）−［［（４−ｔｅｒｔ−ブチルフェニル）チオコ
メチル］−２，５（４）−ジメチルイミダゾール０４（
５）−［（（３−メトキシフェニル）チオコメチル］−
２，５（４）−ジメチルイミダゾール０４（５）−［［
（４−メトキシフェニル）チオコメチル］−２，５（４
）−ジメチルイミダゾール−２，５（４）−ジメチル−
４（５）−［（（４−ニトロフェニル）チオ］メチル］
イミダゾール
−４（５）−［［（２−アミノフェニル）チオコメチル
］−２，５（４）−ジメチルイミダゾール−４（５）−
［［（４−アミノフェニル）チオ］メチルコ−２，５（
４）−ジメチルイミダゾール０２．５（４）−ジメチル
−４（５）−［［（３−トリフルオロメチルフェニル）
チオコメチルコイミダゾール
−２，５（４）−ジメチル−４（５）−［、（（２−ナ
フチル）チオ〕メチル］イミダゾール
０４（５）−［（（４−クロロフェニル）チオ〕メチル
コー２−エチル−５（４）−メチルイミダゾール０４（
５）−［（（３，４−ジクロロフェニル）千オ〕メチル
］−２−エチル−５（４）−メチルイミダゾール０２−
エチル−５（４）−メチル−４（５）−［（（３−メチ
ルフェニル）チオ〕メチル］イミダゾール’ ４（５）
−［［（３，５−ジメチルフェニル）チオ］メチル］−
２−エチル−５（４）−メチルイミダゾール０５（４）
−メチル−２−フェニル−４（５）−（（フェニルチオ
）メチルコイミダゾール
−４（５）−［［（４−クロロフェニル）チオ］メチル
コ−５（４）−メチル−２−フェニルイミダゾール０５
（４）−メチル−２−フェニル−４（５）−［（（２，
４，５−トリクロロフェニル）チオ〕メチル］イミダゾ
ール
０５（４）−メチル−４（５）−［（（４−メチルフェ
ニル）チオ〕メチル］−２−フェニルイミダゾール０４
（５）−［［（４−メトキシフェニル）チオ〕メチル］
−５（４）−メチル−２−フェニルイミダゾール０５（
４）−メチル−４（５）−［［（４−ニトロフェニル）
チオ］メチル］−２−フェニルイミダゾール０５（４）
−メチル−４（５）−［［（２−ナフチル）チオ］メチ
ル］−２−フェニルイミダゾール
０２．５（４）−ジメチル−４（５）−（＜フェニルス
ルフィニル）メチルコイミダゾール
０４（５）−［［（３，４−ジクロロフェニル）スルフ
ィニルコメチル］−２，５（４）−ジメチルイミダゾー
ル
０２．５（４）−ジメチル−４（５）−［［（３−メチ
ルフェニル）スルフィニル］メチル］イミダゾール０２
．５（４）−ジメチル−４（５）−［（（２−ナフチル
）スルフィニル〕メチル］イミダゾール
次に本発明に係る一般式（Ｉ’）で表わされる化合物の
製造方法について述べる。-5(4)-methyl-2-methylthio-4(5)-[[
(2-naphthyl)thio]methyl]imidazole 02゜5
(4)-Dimethyl-4(5)-((phenylthio)methylcoimidazole' 4(5)-[[(3-fluorophenyl)thiocomethyl]-2,5(4)-dimethylimidazole Q4(5
)-[[(3-chlorophenyl)thiocomethyl]-2,
5(4)-dimethylimidazole' 4(5)-[[(
4-chlorophenyl)thiocomethyl]-2,5(4)-
Dimethylimidazole' 4(5)-[[(3,4-dichlorophenyl)thiocomethyl]-2,5(4)-dimethylimidazole 4(5)-[[(2,6-dichlorophenyl)thiocomethyl]-2,5 (4)-Dimethylimidazole-2,5(4)-dimethyl-4(5)-[[
(2,4,5-trichlorophenyl)thio]methyl]imidazole 04(5)-[((4-bromophenyl)thiocomethyl]-2,5(4)-dimethylimidazole 0
4(5)-[((3-chloro-4-methylphenyl)thiocomethyl]-2,5(4)-dimethylimidazole0
2.5(4)-dimethyl-4(5)-[[(2-methylphenyl)thio]methyl]imidazole-2,5(4)-dimethyl-4(5)-[((a-methylphenyl) thio]methyl]imidazole-2,5(4)-dimethyl-4(5)-[((4-methylphenyl)thio]methyl]imidazole' 4(5)-[((3,5-dimethylphenyl)thousand [o]methyl]-2,5(4)-dimethylimidazole 04
(5)-[[(4-tert-butylphenyl)thiocomethyl]-2,5(4)-dimethylimidazole 04(
5) -[((3-methoxyphenyl)thiocomethyl]-
2,5(4)-dimethylimidazole 04(5)-[[
(4-methoxyphenyl)thiocomethyl]-2,5(4
)-dimethylimidazole-2,5(4)-dimethyl-
4(5)-[((4-nitrophenyl)thio]methyl]
Imidazole-4(5)-[[(2-aminophenyl)thiocomethyl]-2,5(4)-dimethylimidazole-4(5)-
[[(4-aminophenyl)thio]methylco-2,5(
4)-Dimethylimidazole 02.5(4)-dimethyl-4(5)-[[(3-trifluoromethylphenyl)
Thiocomethylcoimidazole-2,5(4)-dimethyl-4(5)-[,(2-naphthyl)thio]methyl]imidazole 04(5)-[((4-chlorophenyl)thio]methylco-2-ethyl -5(4)-methylimidazole 04(
5)-[((3,4-dichlorophenyl)thousand]methyl]-2-ethyl-5(4)-methylimidazole 02-
Ethyl-5(4)-methyl-4(5)-[((3-methylphenyl)thio]methyl]imidazole' 4(5)
-[[(3,5-dimethylphenyl)thio]methyl]-
2-ethyl-5(4)-methylimidazole 05(4)
-Methyl-2-phenyl-4(5)-((phenylthio)methylcoimidazole-4(5)-[[(4-chlorophenyl)thio]methylco-5(4)-methyl-2-phenylimidazole 05
(4)-Methyl-2-phenyl-4(5)-[((2,
4,5-Trichlorophenyl)thio]methyl]imidazole 05(4)-Methyl-4(5)-[((4-methylphenyl)thio]methyl]-2-phenylimidazole 04
(5)-[[(4-methoxyphenyl)thio]methyl]
-5(4)-Methyl-2-phenylimidazole 05(
4)-Methyl-4(5)-[[(4-nitrophenyl)
thio]methyl]-2-phenylimidazole 05(4)
-Methyl-4(5)-[[(2-naphthyl)thio]methyl]-2-phenylimidazole 02.5(4)-dimethyl-4(5)-(<phenylsulfinyl)methylcoimidazole 04(5) -[[(3,4-dichlorophenyl)sulfinylcomethyl]-2,5(4)-dimethylimidazole02.5(4)-dimethyl-4(5)-[[(3-methylphenyl)sulfinyl]methyl] imidazole 02
．． 5(4)-Dimethyl-4(5)-[((2-naphthyl)sulfinyl]methyl]imidazole Next, a method for producing the compound represented by the general formula (I') according to the present invention will be described.
前記一般式（Ｉ）のＸがＳである場合の一般式（Ｉａ）
ＩＩ
の化合物は一般式（ＩＩ）
で表わされる化合物と一般式（Ｉ［［）で表わされる化
合物とを塩基の存在下もしくは非存在下に反応させるこ
とにより製造することができる。When X in the general formula (I) is S, the compound of the general formula (Ia) II is prepared by combining the compound represented by the general formula (II) and the compound represented by the general formula (I[[) in the presence of a base. Alternatively, it can be produced by reacting in the absence of the compound.
反応溶媒としては、水、メタノール、エタノール、イソ
プロピルアルコール等のプロトン性溶媒、クロロホルム
、塩化メチレン、■、２−ジクロルエタン等のハロゲン
化炭化水素系溶媒、エチルエーテル、テトラヒドロフラ
ン等のエーテル系溶媒、ピリジン、トリエチルアミン等
の塩基性溶媒、ジメチルアセトアミド、ジメチルホルム
アミド、ジメチルスルホキンド等の非プロトン性極性溶
媒を挙げることができる。これらの溶媒は単独で用いて
もあるいは２種以上の混合溶媒として用いてもよい。Reaction solvents include water, protic solvents such as methanol, ethanol, and isopropyl alcohol, halogenated hydrocarbon solvents such as chloroform, methylene chloride, and 2-dichloroethane, ether solvents such as ethyl ether and tetrahydrofuran, pyridine, Examples include basic solvents such as triethylamine, and aprotic polar solvents such as dimethylacetamide, dimethylformamide, and dimethylsulfoquine. These solvents may be used alone or as a mixed solvent of two or more.
また塩基の例としては、水酸化ナトリウム、水酸化カリ
ウム、炭酸カリウム等の無機塩基やナトリウムアルコキ
シド、ピリジン、トリエチルアミン等の有機塩基を挙げ
ることができる。Examples of the base include inorganic bases such as sodium hydroxide, potassium hydroxide, and potassium carbonate, and organic bases such as sodium alkoxide, pyridine, and triethylamine.
本反応をおこなうにあたって、通常は加熱あるいは冷却
等の温度制御は必要とせず、室温で充分に進行させるこ
とかできる。In carrying out this reaction, temperature control such as heating or cooling is usually not required, and it can proceed satisfactorily at room temperature.
また、前記一般式（Ｉ）のＸがＳ−〇である場合の一般
式（Ｉｂ）
■
の化合物は一般式（Ｉａ）で表わされる化合物を酸化す
ることにより製造することができる。Further, the compound of general formula (Ib) (1) in which X in general formula (I) is S-- can be produced by oxidizing the compound represented by general formula (Ia).
その際使用する酸化剤の例としては、３−クロロ過安息
香酸、過酸化水素等を挙げることができる。Examples of the oxidizing agent used in this case include 3-chloroperbenzoic acid and hydrogen peroxide.
これらの反応をおこなうのに必要な出発原料、すなわち
、一般式（ｎ）、（ＩＩＩ）の式で表わされる化合物は
、それらが文献記載の既知物質である場合には、いずれ
も既知方法により製造することができ、あるいはそれ自
体市販の物質として入手可能であるが、もしそれらが文
献未記載の新規物質である場合には以下の如き方法によ
り製造することができる。即ち、一般式（ｎ）で表わさ
れる化合物は一般式（ＩＶ）
で表わされる化合物から文献記載の方法（オーガニック
シンセシス ３巻８０９ページ）に準拠して製造する
ことができる。また一般式（ｍ）で表わされる化合物は
、一般式（Ｖ）
（式中、Ｒ１とＲ２は前記と同じ意味を有する。）で表
わされる化合物を塩化チオニル、トルエンスルホニルク
ロリドと反応させることにより製造することができる。The starting materials necessary for carrying out these reactions, that is, the compounds represented by the general formulas (n) and (III), are known substances described in the literature, and can be produced by known methods. Alternatively, they can be obtained as commercially available substances, but if they are new substances that have not been described in literature, they can be produced by the following method. That is, the compound represented by the general formula (n) can be produced from the compound represented by the general formula (IV) according to the method described in the literature (Organic Synthesis, Vol. 3, p. 809). Further, the compound represented by the general formula (m) is produced by reacting the compound represented by the general formula (V) (wherein R1 and R2 have the same meanings as above) with thionyl chloride and toluenesulfonyl chloride. can do.
また、一般式（Ｉ）で表わされる化合物の酸付加塩は、
前述した方法により製造した遊離塩基を酸により中和す
ることによって容易に製造することができる。この場合
の好ましい酸としては、ハロゲン化水素酸、スルホン酸
、燐酸、メタンスルホン酸、トルエンスルホン酸、マレ
イン酸、酢酸などを挙げることかできる。Furthermore, acid addition salts of the compound represented by general formula (I) are:
It can be easily produced by neutralizing the free base produced by the method described above with an acid. Preferred acids in this case include hydrohalic acid, sulfonic acid, phosphoric acid, methanesulfonic acid, toluenesulfonic acid, maleic acid, and acetic acid.
前記一般式（Ｉ）の化合物は胃潰瘍、十二指腸潰瘍の予
防ならびに治療用の医薬として、化合物自体をそのまま
人間を含む補乳動物に投与することもできるが、一般に
は医薬として許容され得る種々の製剤組成物として、経
口的あるいは非経口的に投与することができる。The compound of the general formula (I) can be administered as it is to dairy animals including humans as a medicine for the prevention and treatment of gastric ulcers and duodenal ulcers, but in general, various pharmaceutically acceptable formulations can be used. The composition can be administered orally or parenterally.
処方にあたっては、前記一般式（Ｉ）の化合物を薬学的
に許容し得る塩の形で用いることができる。これらの化
合物は、それを単独でもしくは二種以上を適宜組み合せ
て用いることができる。また、これらの化合物は、他の
医薬活性成分と配合して用いても良い。For formulation, the compound of general formula (I) can be used in the form of a pharmaceutically acceptable salt. These compounds can be used alone or in an appropriate combination of two or more. Moreover, these compounds may be used in combination with other pharmaceutically active ingredients.
経口での投与形態としては、上記化合物を適当な添加剤
、例えば乳糖、マンニット、トウモロコシデンプン、バ
レイショデンブン、結晶セルロース等の賦形剤、セルロ
ース誘導体、アラビアゴム、ゼラチン等の結合剤、バレ
イショデンプン、カルボキシメチルセルロースナトリウ
ム等の滑沢剤等と組み合せることにより錠剤、散剤、カ
プセル剤とすることができる。For oral administration, the above compound may be mixed with suitable additives, such as excipients such as lactose, mannitol, corn starch, potato starch, crystalline cellulose, binders such as cellulose derivatives, gum arabic, gelatin, etc. By combining it with a lubricant such as starch or sodium carboxymethylcellulose, it can be made into tablets, powders, or capsules.
非経口的投与の形態としては、例えば水、アルコール、
ポリオール、グリセリン等と組み合せることにより注射
用液剤とすることができる。Examples of parenteral administration include water, alcohol,
By combining with polyol, glycerin, etc., it can be made into an injectable solution.
投与量は年齢、症状、治療効果、投与方法、投与期間に
より異なるが、通常、経口投与の場合には０．４〜１５
ａ＋ｇ／ｋｇ／日の投与範囲で１日１〜３回の範囲で投
与するのが好適である。The dosage varies depending on age, symptoms, therapeutic effects, administration method, and administration period, but is usually 0.4-15 for oral administration.
It is preferable to administer the drug once to three times a day within the dosage range of a+g/kg/day.
［作 用コ
次に、本発明の一般式（Ｉ）で表わされる各化合物の抗
潰瘍作用について、水浸拘束ストレス潰瘍試験、幽門結
紮ラットの胃液分泌抑制試験および塩酸−エタノール潰
瘍試験の方法および結果により説明する。[Effect]Next, the anti-ulcer effect of each compound represented by the general formula (I) of the present invention will be examined using the water immersion stress ulcer test, the gastric juice secretion suppression test in pylorus-ligated rats, and the hydrochloric acid-ethanol ulcer test. This will be explained based on the results.
水浸拘束ストレス潰瘍試験は以下のように行なった。The water immersion restraint stress ulcer test was conducted as follows.
２４時間絶食した雄性ＳＤクラット体重２１０〜２４０
ｇ）をストレスケージ（東大薬作型）に入れ、２３℃の
水槽内に胸部まで浸し、ストレスを負荷した。７時間後
に水槽よりラットを引き揚げ直ちに撲殺し胃を取り出し
た。２％ホルマリン液ｌＯν！を胃内に注入し、さらに
固液で１０分間固定した。大切に沿って胃を開き、実体
顕微鏡下（Ｘ １０）て腺胃部に発生する潰瘍の長さく
ｎ＋ｍ）を測定し、−匹当りの合計を潰瘍係数とした。24-hour fasted male SD rat body weight 210-240
g) was placed in a stress cage (Tokyo University Yakusaku type) and immersed up to the chest in a water tank at 23°C to apply stress. After 7 hours, the rat was taken out of the water tank and immediately beaten to death, and its stomach was removed. 2% formalin solution lOν! was injected into the stomach and further fixed with solid liquid for 10 minutes. The stomach was opened along the groin, and the length (n+m) of the ulcer occurring in the glandular stomach was measured under a stereoscopic microscope (X 10), and the sum per animal was taken as the ulcer coefficient.
被験化合物あるいはコントロールとしての１％カルボキ
シメチルセルロースナトリウム（Ｎａ−ＣＭＣ）は０．
５１７／１００ｇ体重の割合でストレス負荷１０分前に
強制経口投与した。The test compound or 1% sodium carboxymethyl cellulose (Na-CMC) as a control was 0.
The mice were forcibly administered orally at a ratio of 517/100 g body weight 10 minutes before stress loading.
潰瘍形成抑制率（％）は下記の式により計算した。結果
を表−１に示す。The ulcer formation inhibition rate (%) was calculated using the following formula. The results are shown in Table-1.
潰瘍形成抑制率（％）
表−１水浸拘束ストレス潰瘍に対する効果全ての化合物
は３０ｍｇ／ｋｇ経ロ投与＊：Ｐ（０，０５＊ネ：
Ｐ（０，０１ｉｔ ： Ｐ（０，００５本発明の化合
物はいずれも水浸拘束ストレス潰瘍試験に於いて強い抗
潰瘍作用を示した。Ulcer formation inhibition rate (%) Table 1 Effect on water immersion restraint stress ulcer All compounds were administered orally at 30 mg/kg*:P(0,05*N:
P(0,01it: P(0,005) All compounds of the present invention exhibited strong anti-ulcer activity in the water immersion restraint stress ulcer test.
幽門結紮ラットの胃液分泌抑制試験は以下のように行っ
た。A gastric juice secretion suppression test in pylorus-ligated rats was conducted as follows.
雄性ＳＤクラット体重ｉａｏ〜２２０ｇ ）を２４時間
絶食し、常法に従いエーテル軽麻酔下に胃幽門部を結紮
した。４時間放置（絶食、絶水）後にエーテル致死せし
め、胃を取り出し、胃内に貯留した胃液を採取した。胃
液を３０００ｒｐｍ 、 １０分間遠沈し、胃液量、酸
度−，ｉｌＩ＋定した。酸度は自動滴定装置を使用して
、０．１ＮＮａＯＨでｐＨ７，０まで滴定して求めた。A male SD rat (body weight iao ~ 220 g) was fasted for 24 hours, and the gastric pylorus was ligated under light anesthesia with ether according to a conventional method. After being left for 4 hours (no food or water), the animals were sacrificed with ether, the stomach was removed, and the gastric juice stored in the stomach was collected. The gastric juice was centrifuged at 3000 rpm for 10 minutes, and the gastric juice volume and acidity -, IL+ were determined. Acidity was determined by titrating to pH 7.0 with 0.1N NaOH using an automatic titrator.
また胃液量と酸度との積から１時間当りの酸排出量（μ
Ｅｑ／ｈｒ）を算出した。被験化合物あるいはコントロ
ールとしての１％Ｎａ−ＣＭＣは、０．５ｉｆ／２００
ｇの割合で幽門結紮直後に十二指腸内投与した。In addition, the amount of acid excreted per hour (μ
Eq/hr) was calculated. 1% Na-CMC as a test compound or control is 0.5if/200
It was administered into the duodenum immediately after pylorus ligation at a rate of 1.5 g.
胃液量の抑制率（％）および酸排出量の抑制率（％）は
下記の式によりそれぞれ計算した。The suppression rate (%) of gastric juice volume and the suppression rate (%) of acid excretion were calculated using the following formulas.
結果を表−２に示す。The results are shown in Table-2.
胃液量の抑制率（％）
酸排出量の抑制率（％）
表−２幽門結紮したラットにおける胃液分泌に対する効
果
本発明の化合物は幽門結紮ラットに於いて胃液および胃
酸の分泌を強力に抑制した。Inhibition rate of gastric juice volume (%) Inhibition rate of acid excretion rate (%) Table 2 Effect on gastric juice secretion in pylorus-ligated rats The compound of the present invention strongly inhibited gastric juice and gastric acid secretion in pylorus-ligated rats. .
塩酸−エタノール潰瘍試験は以下のように行なった。The hydrochloric acid-ethanol ulcer test was conducted as follows.
雄性ＳＤクラット体重１７０〜１９０ｇ）を２４時間絶
食後、１５０ｍＭ塩酸−６０％エタノールを１ ｘｌ経
口投与した。１時間後、ラットを撲殺し胃を取り出した
。ストレス潰瘍の場合と同様に処理し、潰瘍係数を求め
た。被験化合物あるいはコントロールとしての１％Ｎａ
−ＣＭＣは、０．５ｙｌ／１００ｇの割合で塩酸−エタ
ノール投与３０分前に経口投与した。After fasting for 24 hours, male SD rats (body weight 170 to 190 g) were orally administered 1 x l of 150 mM hydrochloric acid-60% ethanol. One hour later, the rat was killed by beating and the stomach was removed. The treatment was performed in the same manner as for stress ulcers, and the ulcer coefficient was determined. Test compound or 1% Na as control
-CMC was orally administered at a rate of 0.5yl/100g 30 minutes before hydrochloric acid-ethanol administration.
潰瘍形成抑制率を下記の式により計算した。The ulcer formation inhibition rate was calculated using the following formula.
結果を表−３に示す。The results are shown in Table-3.
潰瘍形成抑制率（％）
表−３塩酸−エタノールで惹起した潰瘍形成に対する効
果
本発明の化合物は塩酸エタノールで惹起した潰瘍モデル
に於いて潰瘍の形成を強力に抑制し、細胞保護作用を有
することが判明した。Ulcer formation inhibition rate (%) Table 3: Effect on ulcer formation induced by hydrochloric acid and ethanol The compound of the present invention strongly inhibits ulcer formation in the ulcer model induced by hydrochloric acid and ethanol, and has a cytoprotective effect. There was found.
次に、本発明の化合物の急性毒性について説明する。Next, the acute toxicity of the compounds of the present invention will be explained.
後記実施例６及び実施例２６で得た被験化合物を３％ア
ラビアゴム溶媒に投与液量が２ 、０ ’１１／ ｌｏ
ｏｇ体重となるように懸濁し、５週令ＩＣＲ：ＪＣ４雄
性マウス５匹に単回強制投与し、５日間観察した。結果
を下記表−４に示す。The test compounds obtained in Examples 6 and 26 below were administered in a 3% gum arabic solvent at a liquid volume of 2.0'11/lo.
The suspension was suspended to give a body weight of 0.05 oz, and was forcibly administered once to 5 5-week-old ICR:JC4 male mice, and observed for 5 days. The results are shown in Table 4 below.
表−４急性毒性試験結果
［実 施 例コ
以下に、実施例により本発明に係る化合物を具体的に詳
述するが、本発明はこれら実施例により限定されるもの
ではない。Table 4 Acute Toxicity Test Results [Example] The compounds according to the present invention will be specifically described in detail below using Examples, but the present invention is not limited by these Examples.
実施例１
４（５）−［（（４−クロロフェニル）チオ〕メチル］
−２−エチル−５（４）−メチルイミダゾール８５％水
酸化カリウム１．９７８ｇ（３０ＩＩＩＭ）をメタノー
ル３０１１に溶解し、次いで４−クロロベンゼンチオー
ル２．１８９ｇ（Ｉ５ｍＭ）と４（５）−クロロメチル
−２−エチル−５（４）−メチルイミダゾール塩酸塩２
．９３１ｇ（Ｉ５＋ｎＭ）を加え、室温で２時間攪拌の
後、析出した塩化カリウムを）戸去し、メタノールを減
圧留去した。得られた残留物をシリカゲルカラムクロマ
トグラフィー（メルク社シリカゲル６０）に付し題記化
合物を１．４１０ｇ （収率３５％）得た。Example 1 4(5)-[((4-chlorophenyl)thio]methyl]
-2-Ethyl-5(4)-methylimidazole 1.978g (30IIIM) of 85% potassium hydroxide was dissolved in methanol 3011, and then 2.189g (I5mM) of 4-chlorobenzenethiol and 4(5)-chloromethyl- 2-Ethyl-5(4)-methylimidazole hydrochloride 2
．． After adding 931 g (I5+nM) and stirring at room temperature for 2 hours, the precipitated potassium chloride was removed and methanol was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (Merck Silica Gel 60) to obtain 1.410 g (yield 35%) of the title compound.
融 点：１■８〜１１９℃（酢酸エチル）ＮＭＲスペ
クトル（ＤＭＳＯ−ｄ６ ） δ：１．１６（３Ｈ１ｔ
、ＣＨ２Ｃｔｈ ） １．９７（３Ｈ，Ｓ、Ｃ）ｌ：
り２．５７（２１１，Ｑ、ＣＨ２Ｃｌ１３ ） ４．
００（２１１，ｓ、５ＣＩｂ ）７．２８（４Ｈ，ｓ、
Ａｒ）
ＩＲスペクトル（ＫＢ「）ｃＩｌｌ−１：１Ｂ１０．１
５３０．１４７５．１４３０． ＬＧ９５．１０Ｂ０゜
１０３５、１００５． ８０５
実施例２
４（５）−［［（３，４−ジクロロフェニル）チオ］メ
チルコー２−エチル−５（４）−メチルイミダゾール上
記実施例１に於ける４−クロロベンゼンチオールに代え
て３．４−ジクロロベンゼンチオールと４（５）−クロ
ロメチル−２−エチル−５（４）−メチルイミダゾール
塩酸塩を用い実施例１に準拠した方法により題記化合物
を得、エタノール−塩酸により塩酸塩とした（収率２０
％）。Melting point: 1.8~119°C (ethyl acetate) NMR spectrum (DMSO-d6) δ: 1.16 (3H1t
, CH2Cth) 1.97(3H,S,C)l:
2.57 (211,Q, CH2Cl13) 4.
00(211,s,5CIb)7.28(4H,s,
Ar) IR spectrum (KB")cIll-1:1B10.1
530.1475.1430. LG95.10B0゜1035, 1005. 805 Example 2 4(5)-[[(3,4-dichlorophenyl)thio]methylco-2-ethyl-5(4)-methylimidazole 3.4- in place of 4-chlorobenzenethiol in Example 1 above The title compound was obtained according to the method of Example 1 using dichlorobenzenethiol and 4(5)-chloromethyl-2-ethyl-5(4)-methylimidazole hydrochloride, and converted into a hydrochloride with ethanol-hydrochloric acid. rate 20
%).
融 点＝１５２〜１５４℃（塩酸塩）Ｍａｓｓスペク
トル（ｍ／ｅ）：
３００（Ｍ” ）、 １７８．１２３
ＮＭＲスペクトル（ＤＭＳＯ−ｄ６） δ：４．３２（
２Ｈ，Ｓ、５ＣＨ２）
ＩＲスペクトル（ＫＢｒ） ｃｍ’ ：１６９０、１
６４０．１５８５．１５００．１４Ｂ０．１１００゜実
施例３
４（５）−［［（３，５−ジメチルフェニル）チオ］メ
チル］−２−エチル−５（４）−メチルイミダゾール上
記実施例１に於ける４−クロロベンゼンチオールに代え
て３．５−ジメチルベンゼンチオールと４（５）−クロ
ロメチル−２−エチル−５（４）−メチルイミダゾール
塩酸塩を用い実施例１に準拠した方法により題記化合物
を得、エタノール−塩酸により塩酸塩とした（収率１１
％）。Melting point = 152-154°C (hydrochloride) Mass spectrum (m/e): 300 (M"), 178.123 NMR spectrum (DMSO-d6) δ: 4.32 (
2H,S,5CH2) IR spectrum (KBr) cm': 1690, 1
640.1585.1500.14B0.1100° Example 3 4(5)-[[(3,5-dimethylphenyl)thio]methyl]-2-ethyl-5(4)-methylimidazole In Example 1 above The title compound was prepared by a method based on Example 1 using 3,5-dimethylbenzenethiol and 4(5)-chloromethyl-2-ethyl-5(4)-methylimidazole hydrochloride in place of 4-chlorobenzenethiol. was converted into hydrochloride with ethanol-hydrochloric acid (yield: 11
%).
融 点：１２４〜１２５℃（塩酸塩）Ｍａｓｓスペク
トル（ａ＋／ｅ）：
２６０（Ｍ” ）、 １３８． １２３ＮＭＲスペク
トル（ＤＭＳＯ−ｄ６）δ：４．１０（２１１，ｓ、５
ＣＩＩｒ ）ＩＲスペクトル（ＫＢｒ） ｃｒ’ ：
１［ｉ５ｇ、 １８００． １５８０． １５０５．
１４２０． １０７０実施例４
２−エチル−５（４）−メチル−４（５）−［［（３−
メチルフェニル）チオコメチルコイミダゾール上記実施
例１に於ける４−クロロベンゼンチオールに代えて３−
メチルベンゼンチオールと４（５）−クロロメチル−２
−エチル−５（４）−メチルイミダゾール塩酸塩を用い
実施例１に準拠した方法により題記化合物を得、エタノ
ール−塩酸により塩酸塩としたく収率５３％）。Melting point: 124-125°C (hydrochloride) Mass spectrum (a+/e): 260 (M”), 138.123 NMR spectrum (DMSO-d6) δ: 4.10 (211, s, 5
CIIr) IR spectrum (KBr) cr':
1[i5g, 1800. 1580. 1505.
1420. 1070 Example 4 2-ethyl-5(4)-methyl-4(5)-[[(3-
3-methylphenyl)thiocomethylcoimidazole in place of 4-chlorobenzenethiol in Example 1 above
Methylbenzenethiol and 4(5)-chloromethyl-2
The title compound was obtained by the method of Example 1 using -ethyl-5(4)-methylimidazole hydrochloride, and converted into a hydrochloride salt with ethanol-hydrochloric acid (yield: 53%).
融 点：９４〜９６℃（塩酸塩）
Ｍａｓｓスペクトル（ＩＩｌ／ｅ）：
２４Ｂ（Ｍ” ）、 １４９．１２３
ＮＭＲスペクトル（ＤＭＳＯ−ｄ６ ）δ：４．１６（
２＋１．８，５Ｃ１１２）
ＩＲスペクトル（ＫＢｒ） ｃｒ’ ：１６５０．１
５９５．１４７０
実施例５
４（５）−［（（３−クロロフェニル）チオコメチル］
−２，５（４）−ジメチルイミダゾール塩酸塩８５％水
酸化カリウム５４２ｍｇをメタノール３０１１に溶解し
、次いで３−クロロベンゼンチオール８０４ｍｇと４（
５）−クロロメチル−２，５（４）−ジメチルイミダゾ
ール塩酸塩７３８Ｂを加え、室温で３時間攪拌の後、析
出塩をＰ去し、ｐ液に塩酸のエタノール溶液を加え、塩
酸塩となし溶媒を減圧留去した。残留物をアセトン−メ
タノール−エーテルにて晶出し、無色結晶の題記化合物
を３８０＋ｎｇ （収率３３％）得た。Melting point: 94-96°C (hydrochloride) Mass spectrum (IIl/e): 24B (M”), 149.123 NMR spectrum (DMSO-d6) δ: 4.16 (
2+1.8,5C112) IR spectrum (KBr) cr': 1650.1
595.1470 Example 5 4(5)-[((3-chlorophenyl)thiocomethyl]
-2,5(4)-dimethylimidazole hydrochloride 542 mg of 85% potassium hydroxide was dissolved in methanol 3011, and then 804 mg of 3-chlorobenzenethiol and 4(
5) -Chloromethyl-2,5(4)-dimethylimidazole hydrochloride 738B was added, and after stirring at room temperature for 3 hours, the precipitated salt was removed, and an ethanol solution of hydrochloric acid was added to the P solution to form the hydrochloride. The solvent was removed under reduced pressure. The residue was crystallized from acetone-methanol-ether to obtain 380+ng (yield 33%) of the title compound as colorless crystals.
融 点＝ １７９〜１８０℃
Ｍａｓｓスペクトル（ｍ／ｅ）：
２５４（Ｍ” ＞、 ２５２（Ｍ” ）、 １４１１ｉ
、 １４４ＮＭＲスペクトル（ＤＭＳＯ−ｄ６ ）δ：
２．１０（３１１，ｓ、ＣＨ３） ２．５３（３１
１，ｓ、ＣＨｇ）４．３３（２Ｈ，Ｓ、５ＣＨ２）
７．１６〜７．８６（４Ｈ，ｌＩｌ、Ａｒ）ＩＲスペク
トル（ＫＢｒ） ａｎ−’ ：１８５０、 １５Ｂ０
． １４５５． １４３５． １３９０゜８７５、 ７
６０
実施例６
４（５）−［（（３−フルオロフェニル）チオコメチル
］−２，５（４）−ジメチルイミダゾール塩酸塩上記実
施例５に於ける３−クロロベンゼンチオールに代えて３
−フルオロベンゼンチオールと４（５）−クロロメチル
−２，５（４）−ジメチルイミダゾール塩酸塩を用い実
施例５に準拠した方法により題記化合物を得た（収率３
７％）。Melting point = 179-180°C Mass spectrum (m/e): 254 (M”>, 252 (M”), 1411i
, 144 NMR spectrum (DMSO-d6) δ:
2.10 (311,s, CH3) 2.53 (31
1, s, CHg) 4.33 (2H, S, 5CH2) 7.16-7.86 (4H, lIl, Ar) IR spectrum (KBr) an-': 1850, 15B0
．． 1455. 1435. 1390°875, 7
60 Example 6 4(5)-[((3-fluorophenyl)thiocomethyl]-2,5(4)-dimethylimidazole hydrochloride 3 in place of 3-chlorobenzenethiol in Example 5 above)
The title compound was obtained in accordance with Example 5 using -fluorobenzenethiol and 4(5)-chloromethyl-2,5(4)-dimethylimidazole hydrochloride (yield: 3
7%).
融 点；１９３〜１９４℃（塩酸塩）Ｍａｓｓスペク
トル（Ｉｌ／ｅ）：
２３Ｂ（Ｍ” ）、 １２８．１０１
０９Ｎスペクトル（ＤＭＳＯ−ｄ６）６＝４．２３（２
Ｈ，ｓ、５ｃｉ１２）
ＩＲスペクトル（ＫＢｒ） ｃｒ’ ：１６５８、１
６００．１５８０．１４ｇ０．１２０８．１０４０実施
例７
４（５）−［［（３，５−ジメチルフェニル）チオ］メ
チル］−２，５（４）−ジメチルイミダゾール塩酸塩上
記実施例５に於ける３−クロロベンゼンチオールに代え
て３．５−ジメチルベンゼンチオールと４（５）−クロ
ロメチル−２，５＜４）−ジメチルイミダゾール塩酸塩
を用い実施例５に準拠した方法により題記化合物を得た
（収率３５％）。Melting point: 193-194°C (hydrochloride) Mass spectrum (Il/e): 23B (M”), 128.101 09N spectrum (DMSO-d6) 6 = 4.23 (2
H, s, 5ci12) IR spectrum (KBr) cr': 1658, 1
600.1580.14g0.1208.1040Example 7 4(5)-[[(3,5-dimethylphenyl)thio]methyl]-2,5(4)-dimethylimidazole hydrochloride In Example 5 above The title compound was obtained by a method based on Example 5 using 3.5-dimethylbenzenethiol and 4(5)-chloromethyl-2,5<4)-dimethylimidazole hydrochloride in place of 3-chlorobenzenethiol ( yield 35%).
融 点：２４７〜２４８℃（塩酸塩）（分解）Ｍａｓ
ｓスペクトル（ｍ／ｅ）：
２４８（Ｍ” ）、 １３８．１０１
０９Ｎスペクトル（ＤＭＳＯ−ｄｓ ）δ：４．０７（
２）１．Ｓ、５ＣＨ２）
ＩＲスペクトル（ＫＢｒ） ｃａ＋−’ ：１６９０
、１６５８．１８００．１４４０．１０３８実施例８
２．５（４）−ジメチル−４（５）−［［（３−トリフ
ルオロメチルフェニル）チオ］メチル］イミダゾール塩
酸塩
上記実施例５に於ける３−クロロベンゼンチオールに代
えて３−トリフルオロメチルベンゼンチオールと４（５
）−クロロメチル−２，５（４）−ジメチルイミダゾー
ル塩酸塩を用い実施例５に準拠した方法により題記化合
物を得た（収率４５％）。Melting point: 247-248℃ (hydrochloride) (decomposition) Mas
s spectrum (m/e): 248 (M”), 138.101 09N spectrum (DMSO-ds) δ: 4.07 (
2)1. S, 5CH2) IR spectrum (KBr) ca+-': 1690
, 1658.1800.1440.1038 Example 8 2.5(4)-dimethyl-4(5)-[[(3-trifluoromethylphenyl)thio]methyl]imidazole hydrochloride 3 in Example 5 above -3-trifluoromethylbenzenethiol and 4(5) instead of chlorobenzenethiol
)-chloromethyl-2,5(4)-dimethylimidazole hydrochloride and the method according to Example 5 to obtain the title compound (yield: 45%).
融 点：２０２〜２０３．５℃（塩酸塩）（分解）Ｍ
ａｓｓスペクトル（ｍ／ｅ）：
２８Ｂ（Ｍ” ）、 １７８．１０１
０９Ｎスペクトル（ＤＭＳＯ−ｄｓ ）δ：４．３０（
２Ｈ，Ｓ、ＳＣＩ＋２ ＞
ＩＲスペクトル（ＫＢｒ） ｃｒ’ ：１Ｂ９０．１
６５８．１６００．１４８０．１３００゜１１２５．１
０４０
実施例９
４（５）−［［（３−クロロ−４−メチルフェニル）チ
オコメチル］−２，５（４）−ジメチルイミダゾール塩
酸塩
上記実施例５に於ける３−クロロベンゼンチオールに代
えて３−クロロ−４−メチルベンゼンチオールと４（５
）−クロロメチル−２，５（４）−ジメチルイミダゾー
ル塩酸塩を用い実施例５に準拠した方法により題記化合
物を得た（収率３８％）。Melting point: 202-203.5℃ (hydrochloride) (decomposition) M
ass spectrum (m/e): 28B (M”), 178.101 09N spectrum (DMSO-ds) δ: 4.30 (
2H, S, SCI+2 > IR spectrum (KBr) cr': 1B90.1
658.1600.1480.1300゜1125.1
040 Example 9 4(5)-[[(3-chloro-4-methylphenyl)thiocomethyl]-2,5(4)-dimethylimidazole hydrochloride 3 in place of 3-chlorobenzenethiol in Example 5 above -chloro-4-methylbenzenethiol and 4(5
)-Chloromethyl-2,5(4)-dimethylimidazole hydrochloride and the method according to Example 5 to obtain the title compound (yield: 38%).
融 点＝２０３〜２０５℃（塩酸塩）（分解）Ｍａｓ
ｓスペクトル（ｍ／ｅ）：
２６６（Ｍ” ）、 １５８． １０１０９Ｎスペク
トル（ＤＭＳＯ−ｄ６ ）δ：４．２３（２１Ｌｓ、５
ＣＨｚ ）
ＩＲスペクトル（ＫＢｒ） ａｍ−’ ：１７００．
１Ｂ５８，１５７０，１４７０，１４４０．１０５０実
施例１０
５（４）−メチル−２−メチルチオ−４（５）−［（（
２−ナフチル）チオ〕メチル］イミダゾール８５％水酸
化カリウム２１０ｇ（３，２＋ｎＭ）をメタノール２０
１！に溶解し、次いで２−ナフタレンチオール２５５Ｂ
（Ｉ，６ｍＭ） と４（５）−クロロメチル−５（４
）−メチル−２−メチルチオイミダゾール塩酸塩３６０
Ｂ（Ｉ、６＋ｎＭ）を加え、室温で１７時間攪拌の後、
析出した塩化カリウムを）戸去し、メタノールを減圧留
去した。得られた残留物をシリカゲルカラムクロマトグ
ラフィー（メルク社シリカゲル６０）に付し無色油状物
の題記化合物を２２８ｍｇ （収率７６％）得た。Melting point = 203-205℃ (hydrochloride) (decomposition) Mas
s spectrum (m/e): 266 (M”), 158. 10109N spectrum (DMSO-d6) δ: 4.23 (21Ls, 5
CHz) IR spectrum (KBr) am-': 1700.
1B58,1570,1470,1440.1050 Example 10 5(4)-Methyl-2-methylthio-4(5)-[((
2-naphthyl)thio]methyl]imidazole 85% potassium hydroxide 210g (3,2+nM) was dissolved in methanol 20g.
1! and then 2-naphthalenethiol 255B
(I, 6mM) and 4(5)-chloromethyl-5(4
)-Methyl-2-methylthioimidazole hydrochloride 360
After adding B(I, 6+nM) and stirring at room temperature for 17 hours,
The precipitated potassium chloride was removed, and methanol was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (Merck Silica Gel 60) to obtain 228 mg (yield 76%) of the title compound as a colorless oil.
Ｍａｓｓスペクトル（ＩＩｌ／ｅ）；
３００（Ｍ” ）、 ２５４． １６０．
１４１ＮＭＲスペクトル（ＣＤＣｆ３）δ：
１．９６（３１（、ｓ、ＣＨ３） ２．３６（３＋１
．Ｓ、５Ｃ１１３）４．１８（２Ｈ，Ｓ、５ＣＨ２）
７．１３〜７．８３（７１１，ａ＋、Ａｒ）１１．０（
ＩＩＬｓ、ＮＨ）
ＩＲスペクトル（ＫＢｒ） ｃｒ’ ：１５９０、
１４２０． １１４０． ８８２．８２０． ７５０実
施例１１
４（５）−［［（４−アミノフェニル）チオコメチル］
−２，５（４）−ジメチルイミダゾール塩酸塩４−アミ
ノベンゼンチオールと４（５）−クロロメチル−２，５
（４）−ジメチルイミダゾール塩酸塩を用い実施例１０
に準拠した方法により題記化合物を得た（収率６％）
Ｍａｓｓスペクトル（ｍ／ ｅ） ：
２３３、１２５．１０１
０９Ｎスペクトル（ＤＭＳＯ−ｄ６． ＣＤ３００）δ
：２．００（３１１，９，Ｃ）１３） ２．５０（
３Ｈ，ｓ、Ｃ１ｈ）４．１３（２ｉ（、ｓ、’５Ｃｌ１
２） ７．３３（４Ｈ，ｓ、Ａｒ）ＩＲスペクトル（
ＫＢｒ） ｃｍ−’ ：３４５０、 １５Ｂ０． １
４９０． １０１５．８７０．８１５実施例１２
２．５（４）−ジメチル−４（５）−［［（４−メチル
フェニル）チオ］メチル］イミダゾール
ナトリウム２３０ｍｇ（Ｉ０ａ＋ｇａｔｏ１１）と無水
エタノール４０’１１より調製されたナトリウムエトキ
シド溶液に、４−メチルベンゼンチオール６２１ｍｇ（
５ａ＋Ｍ）と４（５）−クロロメチル−２，５（４）−
ジメチルイミダゾール塩酸塩９０５ｍ（５ａＭ）を加え
、室温で２．５時間攪拌し、析出した塩化ナトリウムを
）戸別後、溶媒を減圧留去した。この残査にアセトンを
加え、析出した結晶をアセトニリルがら再結晶し無色結
晶の題記化合物を３８５ｍｇ （収率３３％）得た。Mass spectrum (IIl/e); 300 (M”), 254. 160.
141NMR spectrum (CDCf3) δ: 1.96(31(,s,CH3) 2.36(3+1
．． S, 5C113) 4.18 (2H, S, 5CH2) 7.13-7.83 (711, a+, Ar) 11.0 (
IILs, NH) IR spectrum (KBr) cr': 1590,
1420. 1140. 882.820. 750 Example 11 4(5)-[[(4-aminophenyl)thiocomethyl]
-2,5(4)-dimethylimidazole hydrochloride 4-aminobenzenethiol and 4(5)-chloromethyl-2,5
Example 10 using (4)-dimethylimidazole hydrochloride
The title compound was obtained by a method based on (yield 6%) Mass spectrum (m/e): 233, 125.101 09N spectrum (DMSO-d6.CD300) δ
:2.00(311,9,C)13) 2.50(
3H,s,C1h)4.13(2i(,s,'5Cl1
2) 7.33 (4H, s, Ar) IR spectrum (
KBr) cm-': 3450, 15B0. 1
490. 1015.870.815 Example 12 2.5(4)-dimethyl-4(5)-[[(4-methylphenyl)thio]methyl]imidazole sodium 230 mg (I0a+gato11) and absolute ethanol 40'11 621 mg of 4-methylbenzenethiol (
5a+M) and 4(5)-chloromethyl-2,5(4)-
905 m (5 aM) of dimethylimidazole hydrochloride was added, stirred at room temperature for 2.5 hours, the precipitated sodium chloride was separated, and the solvent was distilled off under reduced pressure. Acetone was added to this residue, and the precipitated crystals were recrystallized from acetonitrile to obtain 385 mg (yield: 33%) of the title compound as colorless crystals.
融 点：１１４〜１１９℃
Ｍａｓｓスペクトル（ａ＋／ｅ） ：
２３２（Ｍ” ）、 １０１
０９Ｎスペクトル（ＤＭＳＯ−ｄ６）δ：１．９２（３
Ｈ，Ｓ、Ｃ）１２） ２．１８（３Ｈ，Ｓ、Ｃ）１
３）２．２５（３＋１．Ｓ、ＣＨ２） ３．９３（
２Ｈ，Ｓ、５Ｃ１１２）８．９０〜７．３０Ｃ４１１，
ｍ、Ａｒ’）ＩＲスペクトル（ＫＢｒ） ｃｒ’ ：
２９５０、 １４９０． １４５０． １０５０． ８
１０． ８００実施例１３
２．５（４）−ジメチル−４（５）−［（（２−ナフチ
ル）チオ〕メチル］イミダゾール
上記実施例１２に於ける４−メチルベンゼンチオールに
代えて２−ナフタレンチオールと４（５）−クロロメチ
ル−２，５（４）−ジメチルイミダゾール塩酸塩を用い
実施例１２に準拠した方法により題記化合物を得た（収
率６４．６％）。Melting point: 114-119°C Mass spectrum (a+/e): 232 (M”), 10109N spectrum (DMSO-d6) δ: 1.92 (3
H, S, C) 12) 2.18 (3H, S, C) 1
3) 2.25 (3+1.S, CH2) 3.93 (
2H, S, 5C112) 8.90-7.30C411,
m, Ar') IR spectrum (KBr) cr':
2950, 1490. 1450. 1050. 8
10. 800 Example 13 2.5(4)-dimethyl-4(5)-[((2-naphthyl)thio]methyl]imidazole 2-naphthalenethiol in place of 4-methylbenzenethiol in Example 12 above) The title compound was obtained by a method based on Example 12 using 4(5)-chloromethyl-2,5(4)-dimethylimidazole hydrochloride (yield 64.6%).
融 点＝６８〜７０℃
Ｍａｓｓスペクトル（ｌＩｌ／ｅ）：
２８８（Ｍ” ）、 ｌＩｌｉＯ
ＮＭＩ？スペクトル（ＤＭＳＯ−ｄ６ ）δ：４．１２
（２Ｈ，Ｓ、５ＣＨ２）
ＩＲスペクトル（ＫＢｒ） ｃｍ−’ ：１６５ｇ、
１５９３．１４１０．１０４０．８１０．７３５実施
例１４
２．５（４）−ジメチル−４（５）−［［（３−メチル
フェニル）チオ〕メチル］イミダゾール
上記実施例１２に於ける４−メチルベンゼンチオールに
代えて３−メチルベンゼンチオールと４（５）−クロロ
メチル−２，５（４）−ジメチルイミダゾール塩酸塩を
用い実施例１２に準拠した方法により題記化合物を得た
（収率８６．２％）。Melting point = 68-70°C Mass spectrum (lIl/e): 288 (M"), lIliO NMI? spectrum (DMSO-d6) δ: 4.12
(2H,S,5CH2) IR spectrum (KBr) cm-': 165g,
1593.1410.1040.810.735 Example 14 2.5(4)-dimethyl-4(5)-[[(3-methylphenyl)thio]methyl]imidazole 4-methylbenzene in Example 12 above The title compound was obtained by a method based on Example 12 using 3-methylbenzenethiol and 4(5)-chloromethyl-2,5(4)-dimethylimidazole hydrochloride in place of thiol (yield: 86.2 %).
融 点＝１７４〜１７６℃
Ｍａｓｓスペクトル（ｍ／ｅ）：
２３２（Ｍ” ）、１２３．１０１
０９Ｎスペクトル（ＤＭＳＯ−ｄも） ６ ：４．００
（２Ｈ，Ｓ、ＳＣＩ＋２ ）
ＩＲスペクトル（ＫＢｒ） ａｍ” ：１Ｂ５５．１
５９５．１４４１．１０４０．８４９．７６２実施例１
５
４（５）−［（（４−クロロフェニル）チオコメチル］
−２，５（４）−ジメチルイミダゾール上記実施例１２
に於ける４−メチルベンゼンチオールに代えて４〜クロ
ロベンゼンチオールと４（５）−クロロメチル−２，５
（４）−ジメチルイミダゾール塩酸塩を用い実施例１２
に準拠した方法により題記化合物を得た（収率３７．０
％）。Melting point = 174-176°C Mass spectrum (m/e): 232 (M”), 123.101 09N spectrum (also DMSO-d) 6:4.00
(2H, S, SCI+2) IR spectrum (KBr) am”: 1B55.1
595.1441.1040.849.762 Example 1
5 4(5)-[((4-chlorophenyl)thiocomethyl]
-2,5(4)-dimethylimidazole Above Example 12
4-chlorobenzenethiol and 4(5)-chloromethyl-2,5 instead of 4-methylbenzenethiol in
Example 12 using (4)-dimethylimidazole hydrochloride
The title compound was obtained by a method based on (yield: 37.0
%).
融 点： １１４〜１１５℃
Ｍａｓｓスペクトル（ａ＋／ｅ）：
２５２（Ｍ” ）、 １４３
ＮＭＲスペクトル（ＤＭＳＯ−ｄ６ ）δ：３．９８（
２Ｈ，ｓ、５ｃｔ１２）
ＩＲスペクトル（ＫＢｒ） ｃｒ’ ：１Ｂ２２．１
５４０．１４８０．１１００．８１３実施例１６
４（５）−［（（４−メトキシフェニル）チオコメチル
］−２，５（４）−ジメチルイミダゾール上記実施例１
２に於ける４−メチルベンゼンチオールに代えて４−メ
トキシベンゼンチオールと４（５）−クロロメチル−２
，５（４）−ジメチルイミダゾール塩酸塩を用い実施例
１２に準拠した方法により題記化合物を得た（収率５７
．３％）。Melting point: 114-115°C Mass spectrum (a+/e): 252 (M”), 143 NMR spectrum (DMSO-d6) δ: 3.98 (
2H, s, 5ct12) IR spectrum (KBr) cr': 1B22.1
540.1480.1100.813 Example 16 4(5)-[((4-Methoxyphenyl)thiocomethyl]-2,5(4)-dimethylimidazole Above Example 1
4-methoxybenzenethiol and 4(5)-chloromethyl-2 in place of 4-methylbenzenethiol in 2.
, 5(4)-dimethylimidazole hydrochloride in accordance with Example 12 to obtain the title compound (yield 57
．． 3%).
融 点、８９〜９１℃
Ｍａｓｓスペクトル（ｆｆｌ／ｅ）：
２４８．１３９，１０１
０９Ｎスペクトル（ＤＭＳＯ−ｄ６）δ：３．８９（２
ｔｌ、ｓ、５ＣＨ２）
ＩＲスペクトル（ＫＢｒ） ａｍ−’ ：１６５３、
１５９０． １４９５． １２４８． １０３４．
８２９実施例１７
２．５（４）−ジメチル−４（５）−［（（２，４，５
−）リクロロフェニル）チオ］メチル］イミダゾール９
５％水酸化ナトリウム４２１ａ＋ｇ（Ｉ０ａ＋Ｍ）を水
１１！に溶解し、テトラヒドロフラン３０１１を加えた
溶液に、２，４．５−トリクロロベンゼンチオール１０
８７ｍｇ（５ｍＭ）と４（５）−クロロメチル−２，５
（４）−ジメチルイミダゾール塩酸塩９０５ａ＋ｇ（５
ｉＭ）を加え、室温で１時間攪拌し、析出した塩化ナト
リウムをｐ別後、溶媒を減圧留去した。この残香にエチ
ルエーテルを加え、析出した結晶をアセトニリルから再
結晶し、微黄色針状結晶の題記化合物を９１０ｍｇ （
収率５７％）得た。Melting point, 89-91°C Mass spectrum (ffl/e): 248.139,10109N spectrum (DMSO-d6) δ: 3.89 (2
tl, s, 5CH2) IR spectrum (KBr) am-': 1653,
1590. 1495. 1248. 1034.
829 Example 17 2.5(4)-dimethyl-4(5)-[((2,4,5
-)lichlorophenyl)thio]methyl]imidazole 9
5% sodium hydroxide 421a+g (I0a+M) in water 11! 2,4.5-trichlorobenzenethiol 10
87mg (5mM) and 4(5)-chloromethyl-2,5
(4)-Dimethylimidazole hydrochloride 905a+g(5
iM) and stirred at room temperature for 1 hour. After separating the precipitated sodium chloride, the solvent was distilled off under reduced pressure. Ethyl ether was added to this residual aroma, and the precipitated crystals were recrystallized from acetonitrile to give 910 mg of the title compound in the form of pale yellow needle-like crystals (
Yield: 57%).
融 点＝１３８〜１４４℃
Ｍａｓｓスペクトル（ＩＩｌ／ｅ）：
３２２（Ｍ” ）、 １０１
０９Ｎスペクトル（ＤＭＳＯ−ｄ６） δ：２．１２（
３Ｈ，ｓ、ＣＨ２）
２．２２（３１１，Ｓ、ＣＨ２）
４．１５（２Ｈ，ｓ、５ｃＨ２）
７．８８．７．７３ （いずれもＩＩ、ｓ、Ａｒ）ＩＲ
スペクトル（ＫＢｒ）ａｍ−’ ：１４５０．１４３
０．１３２０，１１２０．１０８０．８７０実施例１８
２．５（４）−ジメチル−４（５）−［（（４−ニトロ
フェニル）チオ〕メチルコイミダゾー／Ｉ／
９５％水酸化ナトリウム４２１ｎｇ（ｌｏｉＭ）を９５
％エタノール４０１！に溶解し、次いで４−ニトロベン
ゼンチオール７７６ａ＋ｇ（５ｍＭ）と４（５）−クロ
ロメチル−２゜５（４）−ジメチルイミダゾール塩酸塩
９０５ｍｇ＜５ｍＭ）を加え、室温で３時間攪拌し、析
出した塩化ナトリウムをｐ別後、溶媒を減圧留去した。Melting point = 138-144°C Mass spectrum (IIl/e): 322 (M”), 10109N spectrum (DMSO-d6) δ: 2.12 (
3H, s, CH2) 2.22 (311, S, CH2) 4.15 (2H, s, 5cH2) 7.88.7.73 (all II, s, Ar) IR
Spectrum (KBr) am-': 1450.143
0.1320,1120.1080.870 Example 18 2.5(4)-dimethyl-4(5)-[((4-nitrophenyl)thio]methylcoimidazo/I/ 421 ng of 95% sodium hydroxide ( loiM)95
%ethanol 401! Then, 776a+g (5mM) of 4-nitrobenzenethiol and 905mg (5mM) of 4(5)-chloromethyl-2°5(4)-dimethylimidazole hydrochloride were added, and the mixture was stirred at room temperature for 3 hours to dissolve the precipitated chloride. After removing the sodium, the solvent was distilled off under reduced pressure.
この残香にアセトンを加え、析出した結晶をアセトニト
リルから再結晶し、微黄色結晶の題記化合物を６７ｈ＋
ｇ （収率５１％）得た。Acetone was added to this residual aroma, and the precipitated crystals were recrystallized from acetonitrile to obtain the title compound as pale yellow crystals.
g (yield 51%) was obtained.
融 点： Ｌ４４．５〜１４６．５℃Ｍａｓｓス
ペクトル（Ｉｌｌ／ｅ）：
２６３（Ｍ” ）、 １０１
０９Ｎスペクトル（ＤＭＳＯ−ｄ６）δ：ＩＲスペクト
ル（ＫＢｒ）ｃａｂ−’ ：１５９５．１５８０．１
５０５，１３４０，１０９５．７４０実施例１９
２．５（４）−ジメチル−４（５）−（（フェニルチオ
）メチルクイミダゾール
上記実施例１８に於ける４−ニトロベンゼンチオールに
代えてベンゼンチオールと４（５）−クロロメチル−２
，５（４）−ジメチルイミダゾール塩酸塩を用い実施例
１８に準拠した方法により題記化合物を得て塩酸塩とし
た（収率４６％）。Melting point: L44.5-146.5°C Mass spectrum (Ill/e): 263 (M"), 10109N spectrum (DMSO-d6) δ: IR spectrum (KBr) cab-': 1595.1580.1
505,1340,1095.740 Example 19 2.5(4)-dimethyl-4(5)-((phenylthio)methylquimidazole In place of 4-nitrobenzenethiol in Example 18 above, benzenethiol and 4( 5)-Chloromethyl-2
, 5(4)-dimethylimidazole hydrochloride according to the method described in Example 18 to obtain the title compound as a hydrochloride (yield 46%).
融 点：１６６〜１６９℃（塩酸塩）Ｍａｓｓスペク
トル（ｍ／ｅ）：
２１８（Ｍ” ）、 １０１
０９Ｎスペクトル（ＤＭＳＯ−ｄ６ ）δ：４．１３（
２１１，ｓ、５ＣＩＩ２）
＋Ｒスペクトル（ＫＢｒ） ａｍ−’ ：１６５０．
１５７０，１４４０，１０４０，８７０，７５０実施例
２０
４（５）−［［（４−ｔｅｒｔ−ブチルフェニル）チオ
コメチル］−２，５（４）−ジメチルイミダゾール上記
実施例１８に於ける４−ニトロベンゼンチオールに代え
て４−ｔ１３ｒｔ−ブチルベンゼンチオールと４（５）
−クロロメチル−２，５（４）−ジメチルイミダゾール
塩酸塩を用い実施例１８に準拠した方法により題記化合
物を得て塩酸塩とした（収率３８％）。Melting point: 166-169°C (hydrochloride) Mass spectrum (m/e): 218 (M”), 10109N spectrum (DMSO-d6) δ: 4.13 (
211,s, 5CII2) +R spectrum (KBr) am-': 1650.
1570,1440,1040,870,750 Example 20 4(5)-[[(4-tert-butylphenyl)thiocomethyl]-2,5(4)-dimethylimidazole 4-nitrobenzenethiol in Example 18 above 4-t13rt-butylbenzenethiol and 4(5) instead of
The title compound was obtained as a hydrochloride salt using -chloromethyl-2,5(4)-dimethylimidazole hydrochloride in accordance with the method described in Example 18 (yield 38%).
融 点：２２７〜２２８℃（塩酸塩）Ｍａｓｓスペク
トル（ａ＋／ｅ）’
２７４（Ｍ” ）、 １０１
０９Ｎスペクトル（ＤＭ’３Ｏ−ａ６） δ：３．９８
（２＋１．Ｓ、５ＣＩＩ：！ ）ＩＲスペクトル（ＫＢ
ｒ） ｃｒ’ ：１Ｂ５５．１５９０．１４９０．８
９０．８３０実施例２１
４（５）−［（（２−アミノフェニル）チオコメチル］
−２，５（４）−ジメチルイミダゾール上記実施例１８
に於ける４−ニトロベンゼンチオールに代えて２−アミ
ノベンゼンチオールと４（５）−クロロメチル−２，５
（４）−ジメチルイミダゾール塩酸塩を用い実施例１８
に準拠した方法により題記化合物を得て塩酸塩とした（
収率９％）。Melting point: 227-228°C (hydrochloride) Mass spectrum (a+/e)' 274 (M"), 10109N spectrum (DM'3O-a6) δ: 3.98
(2+1.S, 5CII:!) IR spectrum (KB
r) cr': 1B55.1590.1490.8
90.830 Example 21 4(5)-[((2-aminophenyl)thiocomethyl]
-2,5(4)-dimethylimidazole Example 18 above
2-aminobenzenethiol and 4(5)-chloromethyl-2,5 instead of 4-nitrobenzenethiol in
Example 18 using (4)-dimethylimidazole hydrochloride
The title compound was obtained and made into a hydrochloride by a method according to
yield 9%).
融 点＝２１４〜２１８℃（塩酸塩）（分解）ＮＭＲ
スペクトル（ＤＭＳＯ−ｄ６）δ：４．１７（２１＋、
Ｓ、５ＣＨ２）
ＩＲスペクトル（ＫＢｒ） ｃｒ’ ：１６５５、１
５７０．１５２０．１４７０．７７５．７５５実施例２
２
２．５（４）−ジメチル−４（５）−［［（２−メチル
フェニル）チオ］メチル］イミダゾール
上記実施例１８に於ける４−ニトロベンゼンチオールに
代えて２−メチルベンゼンチオールと４（５）−クロロ
メチル−２，５（４）−ジメチルイミダゾール塩酸塩を
用い実施例１８に準拠した方法により題記化合物を得て
塩酸塩とした（収率３１％）。Melting point = 214-218℃ (hydrochloride) (decomposition) NMR
Spectrum (DMSO-d6) δ: 4.17 (21+,
S, 5CH2) IR spectrum (KBr) cr': 1655, 1
570.1520.1470.775.755 Example 2
2 2.5(4)-Dimethyl-4(5)-[[(2-methylphenyl)thio]methyl]imidazole In place of 4-nitrobenzenethiol in Example 18 above, 2-methylbenzenethiol and 4( The title compound was obtained as a hydrochloride using a method based on Example 18 using 5)-chloromethyl-2,5(4)-dimethylimidazole hydrochloride (yield 31%).
融 点；１６１〜１６４℃（塩酸塩）ＮＭＲスペクト
ル（ＤＭＳＯ−ｄ、 ）δ：４．０８（２１１，ｓ、５
ＣＩｚ ）
ＩＲスペクトル（ＫＢｒ） ａｍ” ：２８５０、２
７５０．１６６０．１４４５．１０４０．７５５実施例
２３
５（４）−メチル−４（５）−［［（４−ニトロフェニ
ル）チオ〕メチル］−２−フェニルイミダゾール８５％
水酸化カリウム５２８．１ｍｇ＜８ｍＭ）をエタノール
３０１！に溶解し、この溶液に４−ニトロベンゼンチオ
ールｅ２０．７ａ＋ｇ（４ｍＭ）と４（５）−クロロメ
チル−５（４）−メチル−２−フェニルイミダゾール塩
酸塩９７２．４Ｂ（４ｍＭ）を加え、室温で５時間攪拌
し、析出した塩化カリウムを）戸別後、エタノールを減
圧留去した。この残香にアセトンを加え、析出した結晶
をエタノールから再結晶し、微黄色針状結晶の題記化合
物を８１３．５ｍｇ （収率５６．６％）得た。Melting point: 161-164°C (hydrochloride) NMR spectrum (DMSO-d, ) δ: 4.08 (211, s, 5
CIz) IR spectrum (KBr) am”: 2850, 2
750.1660.1445.1040.755 Example 23 5(4)-Methyl-4(5)-[[(4-nitrophenyl)thio]methyl]-2-phenylimidazole 85%
Potassium hydroxide 528.1mg<8mM) and ethanol 301! To this solution were added 4-nitrobenzenethiol e20.7a+g (4mM) and 4(5)-chloromethyl-5(4)-methyl-2-phenylimidazole hydrochloride 972.4B (4mM), and the solution was stirred at room temperature. After stirring for 5 hours and removing precipitated potassium chloride, ethanol was distilled off under reduced pressure. Acetone was added to this residual aroma, and the precipitated crystals were recrystallized from ethanol to obtain 813.5 mg (yield 56.6%) of the title compound as pale yellow needle-like crystals.
Ｍａｓｓスペクトル（ｍ／ｅ）：
３２５、 １７１．１５５． １２５．１０９．９７．
７７ＮＭＲスペクトル（ＤＭＳＯ−ｄ６）δ：２．２５
（３ｉ１．ｓ、Ｃ）ｌｘ ）
４．２８（２１＋、Ｓ、５ＣＨ２）
７．０８〜８．４２（９ｔｈＩＩ１．Ａｒ）ＩＲスペク
トル（ＫＢｒ）ｃｍ−Ｉ：
１５９０、１５７０．１５００．１３１５．１０９５．
１０５０゜８５０、 ８３０． ７４０
実施例２４
５（４）−メチル−４（５）−［（（４−メチルフェニ
ル）チオ］メチル］−２−フェニルイミダゾール上記実
施例２３に於ける４−ニトロベンゼンチオールに代えて
４−メチルベンゼンチオールと４（５）−クロロメチル
−５（４）−メチル−２−フェニルイミダゾール塩酸塩
を用い実施例２３に準拠した方法により題記化合物を得
た（収率７２６３％）。Mass spectrum (m/e): 325, 171.155. 125.109.97.
77NMR spectrum (DMSO-d6) δ: 2.25
(3i1.s, C)lx) 4.28 (21+, S, 5CH2) 7.08-8.42 (9thII1.Ar) IR spectrum (KBr) cm-I: 1590, 1570.1500.1315.1095.
1050°850, 830. 740 Example 24 5(4)-Methyl-4(5)-[((4-methylphenyl)thio]methyl]-2-phenylimidazole 4-methyl in place of 4-nitrobenzenethiol in Example 23 above) The title compound was obtained by a method based on Example 23 using benzenethiol and 4(5)-chloromethyl-5(4)-methyl-2-phenylimidazole hydrochloride (yield 7263%).
融 点＝ １７８〜 ＋８１”Ｃ
Ｍａｓｓスペクトル（ｍ／ｅ）：
２９４（Ｍ” ）、 １７１． １２３ＮＭＲスペク
トル（ＤＭＳＯ−ｄ６ ） ６ ’４．２７（２０，ｓ
、５ｃｌＩ２）
！Ｒスペクトル（ＫＢｒ） ｃｒ’ ：１Ｂ５０．１４
９０，１３１０，１３０５．１０９０実施例２５
４（５）−［［（４−メトキシフェニル）チオコメチル
］−５（４）−メチル−２−フェニルイミダゾール上記
実施例２３に於ける４−ニトロベンゼンチオールに代え
て４−メトキシベンゼンチオールと４（５）−クロロメ
チル−５（４）−メチル−２−フェニルイミダゾール塩
酸塩を用い実施例２３に準拠した方法により題記化合物
を得た（収率５３．１％）。Melting point = 178 to +81"C Mass spectrum (m/e): 294 (M"), 171. 123NMR spectrum (DMSO-d6) 6'4.27 (20,s
,5clI2)! R spectrum (KBr) cr': 1B50.14
90,1310,1305.1090 Example 25 4(5)-[[(4-methoxyphenyl)thiocomethyl]-5(4)-methyl-2-phenylimidazole Substituted for 4-nitrobenzenethiol in Example 23 above The title compound was obtained in accordance with Example 23 using 4-methoxybenzenethiol and 4(5)-chloromethyl-5(4)-methyl-2-phenylimidazole hydrochloride (yield 53.1%). ).
融 点： １１３．５〜１１７．５℃Ｍａｓｓスペ
クトル（ｍ／ｅ）：
３１０（Ｍ” ）、 １７１．１４Ｏ
ＮＭＲスペクトル（ＤＭＳＯ−ｄ６）δ：４．１１（２
１１，ｓ、５ＣＩＩ２）
！Ｒスペクトル（ＫＢｒ） ｃｍ’ ：１６４８、１
５８５．１４９０．１２８２実施例２６
４（５）−［［（４−クロロフェニル）チオ〕メチル］
−５（４）−メチル−２−フェニルイミダゾール上記実
施例２３に於ける４−ニトロベンゼンチオールに代えて
４−クロロベンゼンチオールと４（５）−クロロメチル
−５（４）−メチル−２−フェニルイミダゾール塩酸塩
を用い実施例２３に準拠した方法により題記化合物を得
た（収率７０．３％）。Melting point: 113.5-117.5°C Mass spectrum (m/e): 310 (M”), 171.14O NMR spectrum (DMSO-d6) δ: 4.11 (2
11,s,5CII2)! R spectrum (KBr) cm': 1648, 1
585.1490.1282 Example 26 4(5)-[[(4-chlorophenyl)thio]methyl]
-5(4)-Methyl-2-phenylimidazole In place of 4-nitrobenzenethiol in Example 23 above, 4-chlorobenzenethiol and 4(5)-chloromethyl-5(4)-methyl-2-phenylimidazole The title compound was obtained by a method based on Example 23 using a hydrochloride (yield 70.3%).
融 点：１３０〜１３３℃
Ｍａｓｓスペクトル（ａ＋／ｅ）：
３１４（Ｍ” ）、 １７１．１４４
ＮＭＲスペクトル（ＤＭＳＯ−ｄａ ）δ：４．３２（
２８，Ｓ、５ＣＨ２）
！Ｒスペクトル（ＫＢｒ） ｃ「１：
１６５５、１５００．１４７０．１０９０実施例２７
５（４）−メチル−４（５）−［（（４−ナフチル）チ
オ〕メチル］−２−フェニルイミダゾール
上記実施例２３に於ける４−ニトロベンゼンチオールに
代えて２−ナフタレンチオールと４（５）−クロロメチ
ル−５（４）−メチル−２−フェニルイミダゾール塩酸
塩を用い実施例２３に準拠した方法により題記化合物を
得た（収率８７．２％）。Melting point: 130-133°C Mass spectrum (a+/e): 314 (M”), 171.144 NMR spectrum (DMSO-da) δ: 4.32 (
28, S, 5CH2)! R spectrum (KBr) c'1: 1655, 1500.1470.1090 Example 27 5(4)-Methyl-4(5)-[((4-naphthyl)thio]methyl]-2-phenylimidazole Above example The title compound was prepared by a method based on Example 23 using 2-naphthalenethiol and 4(5)-chloromethyl-5(4)-methyl-2-phenylimidazole hydrochloride in place of 4-nitrobenzenethiol in Example 23. (yield 87.2%).
融 点：１３３〜１６１”Ｃ
Ｍａｓｓスペクトル（ｍ／ｅ）：
３３０（Ｍ” ）、 １８Ｏ
ＮＭＲスペクトル（ＤＭＳＯ−ｄ６）δ：４．１８（２
ｆ１．ｓ、５ＣＩＩｚ ）！Ｒスペクトル（ＫＢｒ）
ｃｍ−’ ：１８５０、１５ｇ５．１４９３．１３１
０．１０７３．８０８実施例２８
５（４）−メチル−２−フェニル−４（５）−［（フェ
ニルチオ）メチルコイミダゾール
上記実施例２３に於ける４−ニトロベンゼンチオールに
代えてベンゼンチオールと４（５）−クロロメチル−５
（４）−メチル−２−フェニルイミダゾール塩酸塩を用
い実施例２３に準拠した方法により題記化合物を得た（
収率８４％）。Melting point: 133-161"C Mass spectrum (m/e): 330 (M"), 18O NMR spectrum (DMSO-d6) δ: 4.18 (2
f1. s, 5CIIz)! R spectrum (KBr)
cm-': 1850, 15g5.1493.131
0.1073.808 Example 28 5(4)-Methyl-2-phenyl-4(5)-[(phenylthio)methylcoimidazole In place of 4-nitrobenzenethiol in Example 23 above, benzenethiol and 4( 5)-Chloromethyl-5
(4) The title compound was obtained by a method based on Example 23 using -methyl-2-phenylimidazole hydrochloride (
yield 84%).
融 点：１７２〜１７４℃（分解）
Ｍａｓｓスペクトル（ａ＋／ｅ）：
２８０（Ｍ” ）、 １７１
ＮＭＲスペクトル（ＤＭＳＯ−ｄａ ）δ：４．２３（
２ｔｌ、ｓ、５ＣＨ２）
ＩＲスペクトル（ＫＢｒ） ｃｒ’ ：２７２０、
１Ｂ５０．１４９０． １４８０． １３０５． １０
８５゜１１１７０、 ７２５
実施例２９
５（４）−メチル−２−フェニル−４（５）−［（（２
，４，５−トリクロロフェニル）チオ〕メチル］イミダ
ゾール塩酸塩
２．４．５−トリクｏｏベンゼンチオール８５４．Ｏａ
＋ｇ（４ｔｌ１Ｍ）と４（５）−クロロメチル−５（４
）−メチル−２−フェニルイミダゾール９７２．８ωｇ
（４ｄ）を、ジメチルホルムアミド２ｏ１！に溶解し、
油浴で８５℃に加温しながら３時間攪拌した。この反応
溶液を１５０ｚｆの水にあけ、析出した結晶を）戸数し
、この結晶をエタノールがら再結晶し、題記化合物を１
１７０ｍｇ （収率６１．１％）得た。Melting point: 172-174°C (decomposition) Mass spectrum (a+/e): 280 (M”), 171 NMR spectrum (DMSO-da) δ: 4.23 (
2tl, s, 5CH2) IR spectrum (KBr) cr': 2720,
1B50.1490. 1480. 1305. 10
85°11170, 725 Example 29 5(4)-Methyl-2-phenyl-4(5)-[((2
, 4,5-trichlorophenyl)thio]methyl]imidazole hydrochloride 2.4.5-Trichlorophenyl)oobenzenethiol 854. Oa
+g(4tl1M) and 4(5)-chloromethyl-5(4
)-Methyl-2-phenylimidazole 972.8ωg
(4d) with dimethylformamide 2o1! dissolved in
The mixture was stirred for 3 hours while being heated to 85°C in an oil bath. This reaction solution was poured into 150zf water, the precipitated crystals were separated, and the crystals were recrystallized from ethanol to obtain the title compound.
170 mg (yield 61.1%) was obtained.
融 点：２４１〜２４６℃（分解）
Ｍａｓｓスペクトル（ｍ／ｅ）：
３８４、３８２．３４７．２１２．１７２．１４２．１
２９゜１０４、 ９７． ７７
ＮＭＲスペクトル（ＤＭＳＯ−ｄ６ ）δ：２．３２（
３１１，Ｓ、ＣＨ３） ４．５３（２１１，ｓ、５
Ｃｔ１２）７．４５〜７．７２，７．７２ 〜７．９ｇ
、７．９８ 〜８．３８（７１１，ｉ、Ａｒ）
ＩＲスペクトル（ＫＢｒ）ａｍ−’ ：１７００．１
Ｇ４５，１４９０，１４３０，１３１５，１１１５゜１
０５５、 ８８５． ８６５
実施例３０
４（５）−［（（３，４−ジクロロフェニル）チオコメ
チル］−２，５（４）−ジメチルイミダゾール塩酸塩８
５％水酸化カリウム１．３２ｇ＜２０ａ＋Ｍ）をエタノ
ール５０ｘ１に溶解し、この溶液に、３．４−ジクロロ
ベンゼンチオール１ 、７９ｇ （ｌ ＯｍＭ）と４（
５）−クロロメチル−２，５（４）−ジメチルイミダゾ
ール塩酸塩１．８１ｇ（ｌｏｍＭ）を加え、室温で７時
間攪拌し、析出した塩化カリウムを）戸別後、エタール
を減圧留去した。残渣をエチルエーテルに溶解し、この
溶液にエタール性塩酸を加え塩酸塩となし、無色結晶の
題記化合物を２．４０ｇ （収率７４，１％）得た。Melting point: 241-246°C (decomposition) Mass spectrum (m/e): 384, 382.347.212.172.142.1
29°104, 97. 77 NMR spectrum (DMSO-d6) δ: 2.32 (
311, S, CH3) 4.53 (211, s, 5
Ct12) 7.45-7.72, 7.72-7.9g
, 7.98 ~ 8.38 (711, i, Ar) IR spectrum (KBr) am-': 1700.1
G45, 1490, 1430, 1315, 1115゜1
055, 885. 865 Example 30 4(5)-[((3,4-dichlorophenyl)thiocomethyl]-2,5(4)-dimethylimidazole hydrochloride 8
Dissolve 1.32 g (1 OmM) of 5% potassium hydroxide in 50 x 1 ethanol and add 79 g (1 OmM) of 3,4-dichlorobenzenethiol and 4 (
5)-Chloromethyl-2,5(4)-dimethylimidazole hydrochloride (1.81 g (lomM)) was added, and the mixture was stirred at room temperature for 7 hours. After the precipitated potassium chloride was separated, the ether was distilled off under reduced pressure. The residue was dissolved in ethyl ether, and ethal hydrochloric acid was added to this solution to form a hydrochloride, to obtain 2.40 g (yield: 74, 1%) of the title compound as colorless crystals.
融 点：２１８〜２２０℃
Ｍａｓｓスペクトル（ｍ／ｅ）：
２１ｔ６，１４２．１０９． Ｉｌｉ８ＮＭＲスペク
トル（ＤＭＳＯ−ｄ６ ）δ：２．０７（３ｆ１．ｓ、
ＣＨ３） ２．４８（３Ｈ，Ｓ、ＣＨ３）４．２７
（２１１，Ｓ、５ＣＩ（２）
７．１２〜７．６８ （３Ｈ，ｍ、Ａｒ）１３．６２〜
１５．１８（２１１，ｂｒ、：Ｎｌ２）ＩＲスペクトル
（ＫＢｒ）ａｍ−’ ：１６５２．１５Ｂ５．１４４
５．１０２５．８７０，８０５実施例３１
４（５）−［（（４−ブロモフェニル）チオコメチル］
−２、５（４）−ジメチルイミダゾール上記実施例３０
に於ける３、４−ジクロロベンゼンチオールに代えて４
−ブロモベンゼンチオールと４（５）−クロロメチル−
２，５（４）−ジメチルイミダゾール塩酸塩を用い実施
例３０に準拠した方法により題記化合物を得て塩酸塩と
した（収率７４．９％）。Melting point: 218-220°C Mass spectrum (m/e): 21t6,142.109. Ili8 NMR spectrum (DMSO-d6) δ: 2.07 (3f1.s,
CH3) 2.48 (3H, S, CH3) 4.27
(211, S, 5CI(2) 7.12~7.68 (3H, m, Ar) 13.62~
15.18(211,br,:Nl2)IR spectrum (KBr)am-':1652.15B5.144
5.1025.870,805 Example 31 4(5)-[((4-bromophenyl)thiocomethyl]
-2,5(4)-dimethylimidazole Example 30 above
4 in place of 3,4-dichlorobenzenethiol in
-bromobenzenethiol and 4(5)-chloromethyl-
The title compound was obtained as a hydrochloride using a method based on Example 30 using 2,5(4)-dimethylimidazole hydrochloride (yield 74.9%).
融 点＝２３３〜２３６．５℃（塩酸塩）Ｍａｓｓス
ペクトル（ｍ／ｅ）：
２９８．２９’６，１６７．１４９，１０１０９Ｎスペ
クトル（ＤＭＳＯ−ｄ６）δ：４．１８（２１１，ｓ、
５ＣＨ２）
ＩＲスペクトル（ＫＢｒ） ｃｍ−’ 二１０５０、
１５６５． １４７０． １４４０実施例３２
４（５）−［（（２，６−ジクロロフェニル）チオコメ
チル］−２，５（４）−ジメチルイミダゾール上記実施
例３０に於ける３、４−ジクロロベンゼンチオールに代
えて２．６−ジクロロベンゼンチオールと４（５）−ク
ロロメチル−２，５（４） −ジメチルイミダゾール
塩酸塩を用い実施例３０に準拠した方法により題記化合
物を得た（収率６９．５％）。Melting point = 233-236.5°C (hydrochloride) Mass spectrum (m/e): 298.29'6, 167.149, 10109N spectrum (DMSO-d6) δ: 4.18 (211, s,
5CH2) IR spectrum (KBr) cm-'21050,
1565. 1470. 1440 Example 32 4(5)-[((2,6-dichlorophenyl)thiocomethyl]-2,5(4)-dimethylimidazole 2.6 in place of 3,4-dichlorobenzenethiol in Example 30 above) The title compound was obtained in accordance with Example 30 using -dichlorobenzenethiol and 4(5)-chloromethyl-2,5(4)-dimethylimidazole hydrochloride (yield 69.5%).
融 点：１６４〜１６５．５℃
Ｍａｓｓスペクトル（ｍ／ｅ）：
２８８、２８ｆ３．２５１．１７７、１４２．１０１０
９Ｎスペクトル（ＤＭＳＯ−ｄ６）δ：３．８７（２Ｈ
，Ｓ、５ＣＨ２）
ＩＲスペクトル（ＫＢｒ） ｃ「１：
１６１２、１５５５．１４２５．１４００実施例３３
４（５）−［（（３−メトキシフェニル）チオコメチル
］−２，５（４）−ジメチルイミダゾール上記実施例３
０に於ける３、４−ジクロロベンゼンチオールに代えて
３−メトキシベンゼンチオールと４（５）−クロロメチ
ル−２，５（４）−ジメチルイミダゾール塩酸塩を用い
実施例３０に準拠した方法により題記化合物を得た（収
率３２．５％）。Melting point: 164-165.5°C Mass spectrum (m/e): 288, 28f3.251.177, 142.1010
9N spectrum (DMSO-d6) δ: 3.87 (2H
, S, 5CH2) IR spectrum (KBr) c'1: 1612, 1555.1425.1400 Example 33 4(5)-[((3-methoxyphenyl)thiocomethyl]-2,5(4)-dimethylimidazole above Example 3
The title was prepared by a method based on Example 30 using 3-methoxybenzenethiol and 4(5)-chloromethyl-2,5(4)-dimethylimidazole hydrochloride in place of 3,4-dichlorobenzenethiol in 0. A compound was obtained (yield 32.5%).
融 点： １２３．５〜１２５．５℃Ｍａｓｓスペ
クトル（ｍ／ｅＬ
２４８（Ｍ” ）、 １４０．１０１
０９Ｎスペクトル（ＤＭＳＯ−ｄ６）δ：３．９８（２
ｔｌ、ｓ、５Ｃｌｂ ）
ＩＲスペクトル（ＫＢｒ） Ｃｍ−’ ：１５９０、
１５７０．１４７９．１４２２実施例３４
４（５）−［［（３，４−ジクロロフェニル）スルフィ
ニルコメチル］−２，５（４）−ジメチルイミダゾール
４（５）−［［（３，４−ジクロロフェニル）チオコメ
チル］−２，５（４）−ジメチルイミダゾール５７４．
４ｍｇ（２ｍＭ）をクロロホルム５ 、５ ｘｌに溶解
し、水冷した。この溶液に９５％３−クロロ過安息香酸
３Ｅｉ３．３ｍｇ（２ｍＭ）を少；ずつ加えた、水冷し
たまま３０分間攪拌した。この反応液をクロロホルム３
０厭で希釈し、飽和炭酸ナトリウム水溶液で洗浄し、さ
らに飽和食塩水で洗浄後、硫酸ナトリウム上て乾燥させ
、クロロホルムを減圧下留去した。Melting point: 123.5-125.5°C Mass spectrum (m/eL 248 (M”), 140.101 09N spectrum (DMSO-d6) δ: 3.98 (2
tl, s, 5Clb) IR spectrum (KBr) Cm-': 1590,
1570.1479.1422 Example 34 4(5)-[[(3,4-dichlorophenyl)sulfinylcomethyl]-2,5(4)-dimethylimidazole 4(5)-[[(3,4-dichlorophenyl) thiocomethyl]-2,5(4)-dimethylimidazole574.
4 mg (2 mM) was dissolved in 5.5 xl of chloroform and cooled with water. To this solution, 3.3 mg (2 mM) of 95% 3-chloroperbenzoic acid 3Ei was added little by little, and the mixture was stirred for 30 minutes while being cooled with water. This reaction solution was mixed with chloroform 3
After diluting with 0.0 ml of water and washing with saturated aqueous sodium carbonate solution and further washing with saturated brine, it was dried over sodium sulfate, and chloroform was distilled off under reduced pressure.
残渣を分取ＴＬＣて精製し、無色結晶の題記化合物を５
２９．６ｍｇ （収率８７．３％）得た。The residue was purified by preparative TLC to obtain the title compound as colorless crystals.
29.6 mg (yield 87.3%) was obtained.
融 点：５３〜５４℃
Ｍａｓｓスペクトル（ｍ／ｅ）：
２９０、２８８．２８６．２８４．２５７．１９４．１
７７゜１４２、 Ｈ４，１０９，６７
ＮＭＲスペクトル（ＣＤ（４３）δ：
１．８７（３）Ｉ、ｓ、ＣＨ３） ２．３１（３１
１，ｓ、ＣＨｚ）４．００（２＋１．８．ＳＣ１＋２
）凸
７゜０７〜 ７．０８（３１１，ｍ、Ａｒ）８．８２〜
９．３２ （ｉｌｌ、ｂｒ、 二：ＮＩＩ）ＩＲ
スペクトル（ＫＢｒ）ｃｍ−’ ：＋６１０．１５４
０．１４５５，１４０５．１３Ｂ５，１２１５゜１１４
０．１０２５
実施例３５
２．５（４）−ジメチル−４（５）−［［（２−ナフチ
ル）スルフィニル］メチル］イミダゾール
上記実施例１３で合成したスルフィド化合物を３−クロ
ロ過安息香酸を用い前記実施例３４に準拠した方法によ
り酸化し、題記化合物を得た（収率８１％）。Melting point: 53-54°C Mass spectrum (m/e): 290, 288.286.284.257.194.1
77°142, H4,109,67 NMR spectrum (CD(43)δ: 1.87(3)I,s,CH3) 2.31(31
1, s, CHz) 4.00 (2+1.8.SC1+2
) Convexity 7°07~ 7.08 (311, m, Ar) 8.82~
9.32 (ill, br, 2:NII)IR
Spectrum (KBr) cm-': +610.154
0.1455, 1405.13B5, 1215°114
0.1025 Example 35 2.5(4)-dimethyl-4(5)-[[(2-naphthyl)sulfinyl]methyl]imidazole The sulfide compound synthesized in Example 13 above was synthesized using 3-chloroperbenzoic acid. Oxidation was performed according to the method described in Example 34 to obtain the title compound (yield: 81%).
融 点＝８２〜８３℃
Ｍａｓｓスペクトル（ＩＩ／ｅ） ： １７６、１８
０．１１５ＩＲスペクトル（ＫＢｒ） ｃｍ−’ ：
１Ｇ１５．１５４５．１０４３．１０１３実施例３６
２．５（４）−ジメチル−４（５）−［（（３−メチル
フェニル）スルフィニル〕メチル］イミダゾール実施例
１４で合成したスルフィド化合物を３−クロロ過安息香
酸を用い前記実施例３４に準拠した方法により酸化し、
題記化合物を得た（収率７５％）。Melting point = 82-83°C Mass spectrum (II/e): 176, 18
0.115IR spectrum (KBr) cm-':
1G15.1545.1043.1013 Example 36 2.5(4)-dimethyl-4(5)-[((3-methylphenyl)sulfinyl]methyl]imidazole The sulfide compound synthesized in Example 14 was purified by 3-chlorofiltration. Oxidation using benzoic acid according to the method described in Example 34,
The title compound was obtained (yield 75%).
融 点＝５２〜５３℃
Ｍａｓｓスペクトル（ｍ／ｅ）： １４０．１２４．
１０９１Ｒスペクトル（ＫＢｒ） ｃｍ−’ ：
１０３８．１０１９実施例３７
２．５（４）−ジメチル−４（５）−（（フェニルスル
フィニル）メチルコイミダゾール
実施例１９で合成したスルフィド化合物を３−クロロ過
安息香酸を用い前記実施例３４に準拠した方法により酸
化し、油状の題記化合物を得た（収率３Ｂ％）。Melting point = 52-53°C Mass spectrum (m/e): 140.124.
1091R spectrum (KBr) cm-':
1038.1019 Example 37 2.5(4)-Dimethyl-4(5)-((phenylsulfinyl)methylcoimidazole) The sulfide compound synthesized in Example 19 was synthesized in Example 34 using 3-chloroperbenzoic acid. Oxidation was performed according to a method according to the standard to obtain the title compound as an oil (yield: 3B%).
ＩＲスペクトル（ＫＢｒ） ａｍ−’ ：１Ｂ１０．
１５４０．１４７５．１４４０．１４００．１０１０８
ＯＮスペクトル（ＤＭＳＯ−ｄ６）δ：３．９０（２１
１，ｓ、５ＣＩ１２）
凸
［発明の効果コ
以上述べたように本発明の一般式（Ｉ）で表わされる化
合物は文献未記載の新規化合物であり、優れた抗潰瘍作
用を示すことから有用な物質である。IR spectrum (KBr) am-': 1B10.
1540.1475.1440.1400.10108
ON spectrum (DMSO-d6) δ: 3.90 (21
1, s, 5CI12) Convex [Effects of the Invention As stated above, the compound represented by the general formula (I) of the present invention is a new compound that has not been described in any literature, and is useful because it exhibits excellent antiulcer activity. It is a substance.
また、一般式（Ｉ）で表わされる化合物を含有する抗潰
瘍剤は、水浸拘束ストレス潰瘍試験に於いて強い抗潰瘍
作用を示し、幽門結紮ラットに於いて胃液および胃酸の
分泌を強力に抑制することができ、更に塩酸−エタノー
ル潰瘍試験に於いて塩酸−エタノールによる潰瘍形成を
抑制することから細胞保護作用（防禦因子増強作用）を
有する。更に又、急性毒性も低いことから、急性、慢性
の胃潰瘍、十二指腸潰瘍、胃炎、胃酸過多症に対し、そ
の予防ならびに治療用の医薬としてを用である。In addition, anti-ulcer agents containing the compound represented by general formula (I) exhibit strong anti-ulcer effects in water immersion stress ulcer tests, and strongly suppress gastric juice and gastric acid secretion in pylorus-ligated rats. Furthermore, it inhibits ulcer formation caused by hydrochloric acid-ethanol in the hydrochloric acid-ethanol ulcer test, and thus has a cytoprotective effect (protective factor-enhancing effect). Furthermore, since it has low acute toxicity, it can be used as a medicine for the prevention and treatment of acute and chronic gastric ulcers, duodenal ulcers, gastritis, and gastric hyperacidity.
Claims (1)
、あるいはフェニル基を 表わし、 Ｒ＾２は水素原子または低級アルキル 基を表わし、 ＸはＳまたはＳ＝Ｏを表わし、 Ｒ＾３、Ｒ＾４、Ｒ＾５、Ｒ＾６は任意の位置に置換し
ていて、それぞれ同一または 異なっていてもよく、水素原子、 ハロゲン原子、低級アルキル基、 低級アルコキシ基、ニトロ基、ア ミノ基、トリフルオロメチル基、 シアノ基、低級アルコキシカルボ ニル基、カルバモイル基、アセチ ル基を表わすか、あるいは隣りあ って環を形成した１，３−ブタジエン −１，４−ジイル基、トリメチレン基 テトラメチレン基またはメチレン ジオキシ基を表わす。］ で表わされることを特徴とするイミダゾール誘導体およ
びその酸付加塩。 ２）一般式（ I ） ▲数式、化学式、表等があります▼…（ I ） ［式中、Ｒ＾１は低級アルキルチオ基、低級アルキル基
、あるいはフェニル基を 表わし、 Ｒ＾２は水素原子または低級アルキル 基を表わし、 ＸはＳまたはＳ＝Ｏを表わし、 Ｒ＾３、Ｒ＾４、Ｒ＾５、Ｒ＾６は任意の位置に置換し
ていて、それぞれ同一または 異なっていてもよく、水素原子、 ハロゲン原子、低級アルキル基、 低級アルコキシ基、ニトロ基、ア ミノ基、トリフルオロメチル基、 シアノ基、低級アルコキシカルボ ニル基、カルバモイル基、アセチ ル基を表わすか、あるいは隣りあ って環を形成した１，３−ブタジエン −１，４−ジイル基、トリメチレン基 テトラメチレン基またはメチレン ジオキシ基を表わす。］ 表わされるイミダゾール誘導体もしくはそ 酸付加塩の少なくとも一種を有効成分とし 含有することを特徴とする抗潰瘍剤。[Claims] 1) General formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼...(I) [In the formula, R^1 represents a lower alkylthio group, a lower alkyl group, or a phenyl group, and R ^2 represents a hydrogen atom or a lower alkyl group, X represents S or S=O, and R^3, R^4, R^5, and R^6 are substituted at any position, and are each the same or They may be different and represent a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a nitro group, an amino group, a trifluoromethyl group, a cyano group, a lower alkoxycarbonyl group, a carbamoyl group, an acetyl group, or It represents a 1,3-butadiene-1,4-diyl group, a trimethylene group, a tetramethylene group, or a methylenedioxy group that forms a ring. ] An imidazole derivative and its acid addition salt characterized by being represented by these. 2) General formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼…(I) [In the formula, R^1 represents a lower alkylthio group, lower alkyl group, or phenyl group, and R^2 represents a hydrogen atom or represents a lower alkyl group, X represents S or S=O, and R^3, R^4, R^5, and R^6 are substituted at any position and may be the same or different, Represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a nitro group, an amino group, a trifluoromethyl group, a cyano group, a lower alkoxycarbonyl group, a carbamoyl group, an acetyl group, or is a group that forms a ring by adjoining them. It represents a 1,3-butadiene-1,4-diyl group, a trimethylene group, a tetramethylene group, or a methylenedioxy group. ] An anti-ulcer agent characterized by containing at least one of the following imidazole derivatives or sonic acid addition salts as an active ingredient.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP10931486A JPS62265270A (en) | 1986-05-13 | 1986-05-13 | Novel imidazole derivative and antiulcer agent containing said derivative as active component |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP10931486A JPS62265270A (en) | 1986-05-13 | 1986-05-13 | Novel imidazole derivative and antiulcer agent containing said derivative as active component |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPS62265270A true JPS62265270A (en) | 1987-11-18 |
Family
ID=14507067
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP10931486A Pending JPS62265270A (en) | 1986-05-13 | 1986-05-13 | Novel imidazole derivative and antiulcer agent containing said derivative as active component |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS62265270A (en) |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1994000120A1 (en) * | 1992-06-30 | 1994-01-06 | Smithkline Beecham Corporation | Chemical compounds |
| US5728842A (en) * | 1992-06-30 | 1998-03-17 | Smithkline Beecham Corporation | Substituted imidazolyl-alkylthio-alkanoic acids |
| KR100385095B1 (en) * | 1997-07-15 | 2003-08-19 | 주식회사 엘지생명과학 | 2- or 3-membered ring aromatic compound having farnesyl transferase inhibiting activity |
| EP1484322A1 (en) * | 2002-03-12 | 2004-12-08 | Takeda Pharmaceutical Company Limited | Process for producing optically active sulfoxide derivative |
| WO2008074679A3 (en) * | 2006-12-18 | 2008-10-09 | Hoffmann La Roche | 4-imidazolines as taar's ligands |
| US8183273B2 (en) | 2001-08-08 | 2012-05-22 | Tobira Therapeutics, Inc. | Bicyclic compound, production and use thereof |
| US10301287B2 (en) | 2016-08-31 | 2019-05-28 | Tobira Therapeutics, Inc. | Solid forms of cenicriviroc mesylate and processes of making solid forms of cenicriviroc mesylate |
| US10407411B2 (en) | 2016-06-21 | 2019-09-10 | Tobira Therapeutics, Inc. | Purified cenicriviroc and purified intermediates for making cenicriviroc |
| US10526349B2 (en) | 2014-12-23 | 2020-01-07 | Tobira Therapeutics, Inc. | Process of making cenicriviroc and related analogs |
-
1986
- 1986-05-13 JP JP10931486A patent/JPS62265270A/en active Pending
Cited By (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5728842A (en) * | 1992-06-30 | 1998-03-17 | Smithkline Beecham Corporation | Substituted imidazolyl-alkylthio-alkanoic acids |
| US5929249A (en) * | 1992-06-30 | 1999-07-27 | Smithkline Beecham Corporation | Substituted imidazolyl-alkyethio-aldanoic acids |
| WO1994000120A1 (en) * | 1992-06-30 | 1994-01-06 | Smithkline Beecham Corporation | Chemical compounds |
| KR100385095B1 (en) * | 1997-07-15 | 2003-08-19 | 주식회사 엘지생명과학 | 2- or 3-membered ring aromatic compound having farnesyl transferase inhibiting activity |
| US8741943B2 (en) | 2001-08-08 | 2014-06-03 | Tobira Therapeutics, Inc. | Bicyclic compound, production and use thereof |
| US8183273B2 (en) | 2001-08-08 | 2012-05-22 | Tobira Therapeutics, Inc. | Bicyclic compound, production and use thereof |
| US8362058B2 (en) | 2001-08-08 | 2013-01-29 | Tobira Therapeutics, Inc. | Bicyclic compound, production and use thereof |
| US10045968B2 (en) | 2001-08-08 | 2018-08-14 | Tobira Therapeutics, Inc. | Bicyclic compound, production and use thereof |
| EP1484322A1 (en) * | 2002-03-12 | 2004-12-08 | Takeda Pharmaceutical Company Limited | Process for producing optically active sulfoxide derivative |
| EP1484322A4 (en) * | 2002-03-12 | 2008-01-23 | Takeda Pharmaceutical | Process for producing optically active sulfoxide derivative |
| WO2008074679A3 (en) * | 2006-12-18 | 2008-10-09 | Hoffmann La Roche | 4-imidazolines as taar's ligands |
| US8399463B2 (en) | 2006-12-18 | 2013-03-19 | Hoffmann-La Roche Inc. | Imidazole derivatives |
| US10526349B2 (en) | 2014-12-23 | 2020-01-07 | Tobira Therapeutics, Inc. | Process of making cenicriviroc and related analogs |
| US10407411B2 (en) | 2016-06-21 | 2019-09-10 | Tobira Therapeutics, Inc. | Purified cenicriviroc and purified intermediates for making cenicriviroc |
| US10301287B2 (en) | 2016-08-31 | 2019-05-28 | Tobira Therapeutics, Inc. | Solid forms of cenicriviroc mesylate and processes of making solid forms of cenicriviroc mesylate |
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