JPH01117860A - Benzoic acid amide derivative - Google Patents
Benzoic acid amide derivativeInfo
- Publication number
- JPH01117860A JPH01117860A JP27636987A JP27636987A JPH01117860A JP H01117860 A JPH01117860 A JP H01117860A JP 27636987 A JP27636987 A JP 27636987A JP 27636987 A JP27636987 A JP 27636987A JP H01117860 A JPH01117860 A JP H01117860A
- Authority
- JP
- Japan
- Prior art keywords
- group
- benzyl
- solvent
- amino
- 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.)
- Pending
Links
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical class NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 title claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 19
- 150000003839 salts Chemical class 0.000 claims abstract description 17
- 239000002253 acid Substances 0.000 claims abstract description 16
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 10
- 125000005843 halogen group Chemical group 0.000 claims abstract description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 6
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 5
- -1 di-substituted amino group Chemical group 0.000 claims description 62
- 239000000126 substance Substances 0.000 claims description 8
- 125000003107 substituted aryl group Chemical group 0.000 claims description 7
- 125000001424 substituent group Chemical group 0.000 claims description 6
- 125000003277 amino group Chemical group 0.000 claims description 4
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 125000004043 oxo group Chemical group O=* 0.000 claims description 3
- 125000004442 acylamino group Chemical group 0.000 claims description 2
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 2
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims 1
- 239000002904 solvent Substances 0.000 abstract description 40
- 150000001875 compounds Chemical class 0.000 abstract description 39
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 abstract description 30
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 abstract description 13
- 238000002360 preparation method Methods 0.000 abstract description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 abstract description 6
- 125000003302 alkenyloxy group Chemical group 0.000 abstract description 3
- 239000003795 chemical substances by application Substances 0.000 abstract description 3
- 125000005907 alkyl ester group Chemical group 0.000 abstract description 2
- 239000002111 antiemetic agent Substances 0.000 abstract description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract 2
- 210000001035 gastrointestinal tract Anatomy 0.000 abstract 1
- 229910052736 halogen Inorganic materials 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 230000001737 promoting 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
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 46
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 45
- 239000000243 solution Substances 0.000 description 45
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 44
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 36
- 238000006243 chemical reaction Methods 0.000 description 30
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 29
- 239000000047 product Substances 0.000 description 27
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- 238000003756 stirring Methods 0.000 description 23
- 238000004519 manufacturing process Methods 0.000 description 19
- 238000001816 cooling Methods 0.000 description 18
- 238000002844 melting Methods 0.000 description 16
- 230000008018 melting Effects 0.000 description 16
- 239000000203 mixture Substances 0.000 description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 13
- 125000004432 carbon atom Chemical group C* 0.000 description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 12
- 238000010992 reflux Methods 0.000 description 11
- 238000010898 silica gel chromatography Methods 0.000 description 11
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 9
- 150000008065 acid anhydrides Chemical class 0.000 description 9
- 238000000034 method Methods 0.000 description 9
- 239000012044 organic layer Substances 0.000 description 9
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 8
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 8
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 230000002496 gastric effect Effects 0.000 description 6
- 239000005457 ice water Substances 0.000 description 6
- 239000003921 oil Substances 0.000 description 6
- 235000019198 oils Nutrition 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 6
- 235000017557 sodium bicarbonate Nutrition 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- BYNIUBOJBWXZCC-UHFFFAOYSA-N (1-benzylpiperidin-3-yl)methanamine Chemical compound C1C(CN)CCCN1CC1=CC=CC=C1 BYNIUBOJBWXZCC-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 5
- JEDZLBFUGJTJGQ-UHFFFAOYSA-N [Na].COCCO[AlH]OCCOC Chemical compound [Na].COCCO[AlH]OCCOC JEDZLBFUGJTJGQ-UHFFFAOYSA-N 0.000 description 5
- 239000010410 layer Substances 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- 239000012419 sodium bis(2-methoxyethoxy)aluminum hydride Substances 0.000 description 5
- BELBBZDIHDAJOR-UHFFFAOYSA-N Phenolsulfonephthalein Chemical compound C1=CC(O)=CC=C1C1(C=2C=CC(O)=CC=2)C2=CC=CC=C2S(=O)(=O)O1 BELBBZDIHDAJOR-UHFFFAOYSA-N 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000010828 elution Methods 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 239000001530 fumaric acid Substances 0.000 description 4
- 230000030136 gastric emptying Effects 0.000 description 4
- 229960003531 phenolsulfonphthalein Drugs 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- RVEATKYEARPWRE-UHFFFAOYSA-N 4-amino-5-chloro-2-methoxybenzoic acid Chemical compound COC1=CC(N)=C(Cl)C=C1C(O)=O RVEATKYEARPWRE-UHFFFAOYSA-N 0.000 description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-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
- 239000003513 alkali Substances 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- AOGYCOYQMAVAFD-UHFFFAOYSA-M carbonochloridate Chemical compound [O-]C(Cl)=O AOGYCOYQMAVAFD-UHFFFAOYSA-M 0.000 description 3
- OQNGCCWBHLEQFN-UHFFFAOYSA-N chloroform;hexane Chemical compound ClC(Cl)Cl.CCCCCC OQNGCCWBHLEQFN-UHFFFAOYSA-N 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 239000012280 lithium aluminium hydride Substances 0.000 description 3
- ZDYUUBIMAGBMPY-UHFFFAOYSA-N oxalic acid;hydrate Chemical compound O.OC(=O)C(O)=O ZDYUUBIMAGBMPY-UHFFFAOYSA-N 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 210000002784 stomach Anatomy 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- SDFTVHVPMKAQAE-UHFFFAOYSA-N (1,4-dibenzylpiperazin-2-yl)methanamine Chemical compound C1CN(CC=2C=CC=CC=2)C(CN)CN1CC1=CC=CC=C1 SDFTVHVPMKAQAE-UHFFFAOYSA-N 0.000 description 2
- AUVCYEBUWFFIIO-UHFFFAOYSA-N 3-amino-5-chloro-2-ethoxybenzoic acid Chemical compound CCOC1=C(N)C=C(Cl)C=C1C(O)=O AUVCYEBUWFFIIO-UHFFFAOYSA-N 0.000 description 2
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 2
- XWGYOMHQGQZRLC-UHFFFAOYSA-N 4-amino-5-chloro-2-ethoxybenzoic acid Chemical compound CCOC1=CC(N)=C(Cl)C=C1C(O)=O XWGYOMHQGQZRLC-UHFFFAOYSA-N 0.000 description 2
- AZEIRPAUJXANCS-UHFFFAOYSA-N 4-ethoxybenzamide Chemical compound CCOC1=CC=C(C(N)=O)C=C1 AZEIRPAUJXANCS-UHFFFAOYSA-N 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-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
- 206010047700 Vomiting Diseases 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 239000012964 benzotriazole Substances 0.000 description 2
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 125000004803 chlorobenzyl group Chemical group 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 125000002946 cyanobenzyl group Chemical group 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- PSLIMVZEAPALCD-UHFFFAOYSA-N ethanol;ethoxyethane Chemical compound CCO.CCOCC PSLIMVZEAPALCD-UHFFFAOYSA-N 0.000 description 2
- NJSUFZNXBBXAAC-UHFFFAOYSA-N ethanol;toluene Chemical compound CCO.CC1=CC=CC=C1 NJSUFZNXBBXAAC-UHFFFAOYSA-N 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 125000004175 fluorobenzyl group Chemical group 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 230000007661 gastrointestinal function Effects 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- DCPMPXBYPZGNDC-UHFFFAOYSA-N hydron;methanediimine;chloride Chemical compound Cl.N=C=N DCPMPXBYPZGNDC-UHFFFAOYSA-N 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 2
- WEIORKBZXHYDMC-UHFFFAOYSA-N n-(1,4-dibenzyl-1,4-diazepan-6-yl)acetamide Chemical compound C1CN(CC=2C=CC=CC=2)CC(NC(=O)C)CN1CC1=CC=CC=C1 WEIORKBZXHYDMC-UHFFFAOYSA-N 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 125000006493 trifluoromethyl benzyl group Chemical group 0.000 description 2
- PFKFEPBMWIMCAD-UHFFFAOYSA-N (1,4-diethylpiperazin-2-yl)methanamine Chemical compound CCN1CCN(CC)C(CN)C1 PFKFEPBMWIMCAD-UHFFFAOYSA-N 0.000 description 1
- OIFNPBSEBBTVJO-UHFFFAOYSA-N (1,4-diethylpiperazin-2-yl)methanol Chemical compound CCN1CCN(CC)C(CO)C1 OIFNPBSEBBTVJO-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 1
- AEHKBYHYSYENDS-UHFFFAOYSA-N 1-ethoxy-2h-quinoline Chemical compound C1=CC=C2N(OCC)CC=CC2=C1 AEHKBYHYSYENDS-UHFFFAOYSA-N 0.000 description 1
- 125000004343 1-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C([H])([H])[H] 0.000 description 1
- XYHKNCXZYYTLRG-UHFFFAOYSA-N 1h-imidazole-2-carbaldehyde Chemical compound O=CC1=NC=CN1 XYHKNCXZYYTLRG-UHFFFAOYSA-N 0.000 description 1
- BYPXKYFXJRTUHP-UHFFFAOYSA-N 2-(chloromethyl)-1,4-diethylpiperazine Chemical compound CCN1CCN(CC)C(CCl)C1 BYPXKYFXJRTUHP-UHFFFAOYSA-N 0.000 description 1
- 125000006012 2-chloroethoxy group Chemical group 0.000 description 1
- BFSVOASYOCHEOV-UHFFFAOYSA-N 2-diethylaminoethanol Chemical group CCN(CC)CCO BFSVOASYOCHEOV-UHFFFAOYSA-N 0.000 description 1
- XDZMPRGFOOFSBL-UHFFFAOYSA-N 2-ethoxybenzoic acid Chemical compound CCOC1=CC=CC=C1C(O)=O XDZMPRGFOOFSBL-UHFFFAOYSA-N 0.000 description 1
- UBQKCCHYAOITMY-UHFFFAOYSA-N 2-hydroxy-pyridine Natural products OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- VSWICNJIUPRZIK-UHFFFAOYSA-N 2-piperideine Chemical compound C1CNC=CC1 VSWICNJIUPRZIK-UHFFFAOYSA-N 0.000 description 1
- AGIJRRREJXSQJR-UHFFFAOYSA-N 2h-thiazine Chemical compound N1SC=CC=C1 AGIJRRREJXSQJR-UHFFFAOYSA-N 0.000 description 1
- SGDYNMJTXCTTAF-UHFFFAOYSA-N 3,6-dihydro-2h-thiazine Chemical compound C1NSCC=C1 SGDYNMJTXCTTAF-UHFFFAOYSA-N 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-M 3-Methylbutanoic acid Natural products CC(C)CC([O-])=O GWYFCOCPABKNJV-UHFFFAOYSA-M 0.000 description 1
- HIZGIIULFJOEHN-UHFFFAOYSA-N 3-chloro-2-ethoxybenzamide Chemical compound ClC=1C(=C(C(=O)N)C=CC=1)OCC HIZGIIULFJOEHN-UHFFFAOYSA-N 0.000 description 1
- 125000006284 3-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C(F)=C1[H])C([H])([H])* 0.000 description 1
- HJBLUNHMOKFZQX-UHFFFAOYSA-N 3-hydroxy-1,2,3-benzotriazin-4-one Chemical compound C1=CC=C2C(=O)N(O)N=NC2=C1 HJBLUNHMOKFZQX-UHFFFAOYSA-N 0.000 description 1
- 125000006201 3-phenylpropyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- MSRCVCNYPADFER-UHFFFAOYSA-N 4-benzyl-3-(chloromethyl)morpholine Chemical compound ClCC1COCCN1CC1=CC=CC=C1 MSRCVCNYPADFER-UHFFFAOYSA-N 0.000 description 1
- 125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 description 1
- 125000004176 4-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1F)C([H])([H])* 0.000 description 1
- IVXINMFQXFEZGO-UHFFFAOYSA-N 5-chloro-2-ethoxybenzoic acid Chemical compound CCOC1=CC=C(Cl)C=C1C(O)=O IVXINMFQXFEZGO-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 239000005725 8-Hydroxyquinoline Substances 0.000 description 1
- 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 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 206010010774 Constipation Diseases 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
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- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003707 hexyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
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- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
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- 239000011630 iodine Substances 0.000 description 1
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- 125000003564 m-cyanobenzyl group Chemical group [H]C1=C([H])C(=C([H])C(C#N)=C1[H])C([H])([H])* 0.000 description 1
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- 238000001819 mass spectrum Methods 0.000 description 1
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- KJBLQGHJOCAOJP-UHFFFAOYSA-N metoclopramide hydrochloride Chemical compound O.Cl.CCN(CC)CCNC(=O)C1=CC(Cl)=C(N)C=C1OC KJBLQGHJOCAOJP-UHFFFAOYSA-N 0.000 description 1
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- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
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- 239000002356 single layer Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
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- XZPVPNZTYPUODG-UHFFFAOYSA-M sodium;chloride;dihydrate Chemical compound O.O.[Na+].[Cl-] XZPVPNZTYPUODG-UHFFFAOYSA-M 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
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- 239000000454 talc Substances 0.000 description 1
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- 235000012222 talc Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
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- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
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- 239000000052 vinegar Substances 0.000 description 1
- 235000021419 vinegar Nutrition 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Landscapes
- Plural Heterocyclic Compounds (AREA)
- Pyrrole Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
- Hydrogenated Pyridines (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
Description
【発明の詳細な説明】
産業上の利用分野
本発明は、消化管機能亢進作用を存する新規で任用な安
息香酸アミド誘導体に関する。DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention relates to novel and useful benzoic acid amide derivatives which exhibit gastrointestinal hyperactivity.
従来の技術
４−アミノ−５−クロロ−Ｎ−［（２−ジエチルアミノ
）エチル］−２−メトキシベンズアミド［−船名 メト
クロプラミド；例えばＭｅｒｃｋ Ｉｎｄｅに。PRIOR ART 4-Amino-5-chloro-N-[(2-diethylamino)ethyl]-2-methoxybenzamide [-Ship name Metoclopramide; for example on Merck Inde.
第１０版、 ＧＯ＋９ （＋９８３）参照］が１９６０
年代の半ばに制吐剤あるいは消化管機能亢進剤として開
発されて以来、種々の置換安息香酸アミド誘導体が合成
され、その薬理学的性質が研究されてきた（例えば特公
昭４４−２３４９８号、特開昭５２−３１０４１号、同
５２−８３３０４号、同５２−８３７３７号など参照）
。しかしながら、本発明者らの知る限りにおいて、後記
一般式（Ｉ）で表される安息香酸アミド誘導体は文献未
記峨の新規化合物である。10th edition, GO+9 (+983)] was published in 1960.
Various substituted benzoic acid amide derivatives have been synthesized and their pharmacological properties have been studied (for example, Japanese Patent Publication No. 44-23498; (See No. 52-31041, No. 52-83304, No. 52-83737, etc.)
. However, as far as the present inventors know, the benzoic acid amide derivative represented by the general formula (I) below is a novel compound that has not been described in any literature.
本発明の目的
本発明は、優れた消化管機゛能冗進作用を有する安息香
酸アミド誘導体を提供するものである。OBJECTS OF THE INVENTION The present invention provides benzoic acid amide derivatives having excellent gastrointestinal function enhancing effects.
本発明の構成及び効果
本発明によれば、一般式（Ｉ）
口１
［式中、ＲＩは低級アルキル基又は非置換もしくは置換
アリール（低級）アルキル基を意味し、Ｒ２はヒドロキ
シ基、アルコキシ基、アルケニルオキシ基、ンクロアル
キルオキシ基又は置換基を有するアルコキシ基（該置換
基はハロゲン原子、ヒドロキシ基又はオキソ基である）
を意味し％Ｒ３はアミ７基、ジ置換アミン基又はアシル
アミノ基を意味し、Ｒ４はハロゲン原子を意味するか、
あるいはＲ３とＲ４が一緒になって−Ｎｉｌ−Ｎ＝Ｎ−
を形成してもよ＜、Ｒ５は水素原子又は低級アルキル基
を意味し、Ｘは単結合又は低級アルキレン基を意味し、
Ｙは単結合、 −Ｃｉ＋２− 。Structure and effect of the present invention According to the present invention, the general formula (I) 1 [wherein RI means a lower alkyl group or an unsubstituted or substituted aryl (lower) alkyl group, and R2 is a hydroxy group or an alkoxy group] , an alkenyloxy group, a cycloalkyloxy group, or an alkoxy group having a substituent (the substituent is a halogen atom, a hydroxy group, or an oxo group)
%R3 means an amine group, a di-substituted amine group or an acylamino group, R4 means a halogen atom,
Or R3 and R4 together -Nil-N=N-
may be formed, R5 means a hydrogen atom or a lower alkyl group, X means a single bond or a lower alkylene group,
Y is a single bond, -Ci+2-.
級アルキル基又は非置換もしくは置換アリール（低級）
アルキル基を意味するか、あるいはＲ１と一緒になって
エチレン基を形成してもよい）を意味し、ｎは０又は１
を意味し、破線はＹが−ＣＨ２−でｎが０であるときに
場合により存在する二重結合を意味する。但し、（ｉ）
Ｙが単結合であるとき、ｎは０を意味し、（目）Ｙが
一〇−であるとき、ｎは１を意味し、（＋ｉｉ） Ｙが
単結合又は−ＣＨ２−であるとき、ＲＩは非置換もしく
は置換アリール（低級）アルキル基を意味し、 （ｉＶ
）ｎが０であるとき、Ｘは低級アルキレン基を意味する
。］
で表される安息香酸アミド誘導体及びその酸付加塩類が
提供さ−れる。alkyl group or unsubstituted or substituted aryl (lower)
an alkyl group or may be taken together with R1 to form an ethylene group), where n is 0 or 1
, and the broken line indicates a double bond that may be present when Y is -CH2- and n is 0. However, (i)
When Y is a single bond, n means 0, (th) When Y is 10-, n means 1, (+ii) When Y is a single bond or -CH2-, RI means an unsubstituted or substituted aryl(lower)alkyl group, (iV
) When n is 0, X means a lower alkylene group. ] Benzoic acid amide derivatives and acid addition salts thereof are provided.
式（１）で表される化合物の酸付加塩としては、生理的
に許容される塩類が好ましく、例えば塩酸塩、臭化水素
酸塩、ヨウ化水素酸塩、硫酸塩、υノ酸塩等の無ａｍ塩
、及びシュウ酸塩、マレイン酸塩、フマル酸塩、乳酸塩
、リンゴ酸塩、クエン酸塩、酒石酸塩、安息香酸塩、メ
タンスルホン酸塩等の仔機酸塩が挙げられる。The acid addition salt of the compound represented by formula (1) is preferably a physiologically acceptable salt, such as hydrochloride, hydrobromide, hydroiodide, sulfate, υnoate, etc. , and acid salts such as oxalate, maleate, fumarate, lactate, malate, citrate, tartrate, benzoate, methanesulfonate, and the like.
式（Ｉ）の化合物は、少なくとも１個の不斉炭素原子を
有するので、数種の立体異性体が存在し得る。これらの
立体異性体、それらの混合物及びラセミ体は本発明の化
合物に包含される。Since the compounds of formula (I) have at least one asymmetric carbon atom, several stereoisomers may exist. These stereoisomers, mixtures and racemates thereof are included in the compounds of the present invention.
本明細書における用伍を以下に説明する。The usage in this specification will be explained below.
「低級」とは、特にことわらない限り、１〜６個の炭素
原子を意味する。低級アルキル基、低級アルキル部分又
は低級アルキレフ基は、直鎖状でも分枝鎖状でもよい。"Lower" means 1 to 6 carbon atoms unless otherwise specified. The lower alkyl group, lower alkyl moiety, or lower alkylev group may be linear or branched.
「低級アルキル基」の具体例としては、メチル、エチル
、プロピル、イソプロピル、ブチル、インブチル、ペン
チル、ヘキシル等が挙げられる。「非置換アリール（低
級）アルキル基」の具体例としては、べ／ジル、１−フ
ェニルエチル、２−フェニルエチル、３−フェニルプロ
ピル、４−フェニルブチル、２−ナフチルメチル等が挙
げられる。「置・換アリール（低級）アルキル基」とは
、アリール部分が１〜３個のハロゲン原子、低級アルキ
ル基、トリフルオロメチル基、低級アルコキシ基、シア
ノ基又はニトロ風で置換されているものを意味し、例え
゛ば２−．３−もしくは４−フルオロベンジル、２−、
３１）しくは４−クロ自ベンジル、３−＋リフルオ口メ
チルベンジル、２−．３−もしくは４−シアノベンジル
、４−クロロ−２−二トロベンジル等が挙げられる。「
アルコキシ基」とは、炭素原子１〜１２のものを意味し
、例えばメトキシ、エトキシ、プロポキシ、インプロポ
キシ、ブトキシ、インブトキシ、 ５ｅｃ−ブトキシ、
ベアチルオキシ、イソペンチルオキ７、ヘキシルオキシ
、インへキシルオキン、ヘプチルオキシ、オクチルオキ
シ、ノニルオキシ、デシルオキシ、つブテニルオキシ、
ドデシルオキシ等が挙げられるが、炭素原子数１〜７の
ものが特に好ましい。「アルケニルオキシ基」とは、酸
素原子に隣接する炭素原子以外の位置に二重結合を１〜
２個存する、炭素原子数３〜８のものを意味し、例えば
アリルオキシ、２−ブテニルオキシ、３−ブテニルオキ
シ、３−メチル−２−ブテニルオキシ、３−もしくは４
−べブテニルオキシ、４−もしくは５−へキセニルオキ
シ、６−へブテニルオキシ等が挙げられる。「シクロア
ルキルオキシ基」とは、炭素原子数３〜６のものを意味
し、例えばシクロペンチルオキシ、シクロヘキシルオキ
シ等が挙げられる。「置換基を有するアルコキシ基」と
は、任意の位置にハロゲン原子。Specific examples of the "lower alkyl group" include methyl, ethyl, propyl, isopropyl, butyl, inbutyl, pentyl, hexyl, and the like. Specific examples of the "unsubstituted aryl (lower) alkyl group" include be/zyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 2-naphthylmethyl, and the like. "Substituted/substituted aryl (lower) alkyl group" refers to a group in which the aryl moiety is substituted with 1 to 3 halogen atoms, lower alkyl group, trifluoromethyl group, lower alkoxy group, cyano group, or nitro group. For example, 2-. 3- or 4-fluorobenzyl, 2-,
31) or 4-chlorobenzyl, 3-+refluoromethylbenzyl, 2-. Examples include 3- or 4-cyanobenzyl, 4-chloro-2-nitrobenzyl, and the like. "
"Alkoxy group" means one having 1 to 12 carbon atoms, such as methoxy, ethoxy, propoxy, impropoxy, butoxy, imbutoxy, 5ec-butoxy,
Beartyloxy, isopentyloxy7, hexyloxy, inhexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy, butenyloxy,
Examples include dodecyloxy, and those having 1 to 7 carbon atoms are particularly preferred. "Alkenyloxy group" means 1 to 1 double bond at a position other than the carbon atom adjacent to the oxygen atom.
3 to 8 carbon atoms, such as allyloxy, 2-butenyloxy, 3-butenyloxy, 3-methyl-2-butenyloxy, 3- or 4
-bebutenyloxy, 4- or 5-hexenyloxy, 6-hebutenyloxy and the like. The term "cycloalkyloxy group" means a group having 3 to 6 carbon atoms, such as cyclopentyloxy, cyclohexyloxy, and the like. "Alkoxy group having a substituent" means a halogen atom at any position.
ヒドロキシ基又はオキソ基を１個存するアルコキシ基（
好ましくは炭素原子数６以下のもの）を意味するが、置
換基がヒドロキシ基であるとき、このノ又は１位以外の
炭素原子に結合している。具体例としては、２−クロロ
エトキシ、２−ヒドロキシプロポキシ、３−ヒドロキシ
プロポキン、２−オキンプロボキシ、３−オキソブトキ
シ等が挙げられる。「ジ置換アミ７基」の具体例として
は、ジメチルアミノ、ジエチルアミノ、メチルエチルア
ミノ、メチルプロピルアミノ、モルホリノ、１−ピロリ
ジニル、ピペリジノ、４−メチル−１−ピペラジニル等
が挙げられる。「アシルアミ７基」の具体例としては、
アセチルアミノ、プロピオニルアミ／、ブチリルアミ／
、インブチリルアミ７等が挙げられる。「ハロゲン原子
」とは、フッ素。Alkoxy group containing one hydroxy group or oxo group (
(preferably 6 or less carbon atoms), but when the substituent is a hydroxy group, it is bonded to a carbon atom other than this or 1-position. Specific examples include 2-chloroethoxy, 2-hydroxypropoxy, 3-hydroxypropoquine, 2-oxyneproboxy, 3-oxobutoxy, and the like. Specific examples of the "di-substituted amine 7 group" include dimethylamino, diethylamino, methylethylamino, methylpropylamino, morpholino, 1-pyrrolidinyl, piperidino, 4-methyl-1-piperazinyl, and the like. As a specific example of “acylami 7 groups”,
Acetylamino, propionyl amine/, butyryl amine/
, imbutyrylamide 7, and the like. "Halogen atom" is fluorine.
塩素、臭素、ヨウ素を意味する。「低級アルキレフ基」
の具体例としては、メチレン、エチレン。Means chlorine, bromine, and iodine. "Lower Alkylev group"
Specific examples include methylene and ethylene.
メヂルメチレ／、トリメチレン、プロピレン、ジメチル
メチレ／、テトラメチレ／、ペンタメチレン、ヘキサメ
チレフ等が挙げられる。Examples thereof include medylmethylene/, trimethylene, propylene, dimethylmethylene/, tetramethylene/, pentamethylene, and hexamethylene.
本発明の化合物のうちで好適なものとして、−般式（■
′）
（式中、ＲＩ′はベンジル基、フルオロベンジル基。Among the compounds of the present invention, preferred are compounds of the general formula (■
') (wherein, RI' is a benzyl group or a fluorobenzyl group.
クロロベンジルＭ、）リフルオロメチルベンジル基又は
シアノベンジル基を意味し、Ｒ２′は炭素原子数１〜７
のアルコキシ基、３−ブテニルオキシ基、３−メチル−
２−ブテニルオキシ基。Chlorobenzyl M,) means a trifluoromethylbenzyl group or a cyanobenzyl group, and R2' has 1 to 7 carbon atoms.
alkoxy group, 3-butenyloxy group, 3-methyl-
2-butenyloxy group.
シクロペンチルオキシ基、２−りｐロエトキシ基、２−
ヒドロキシプロポキシ基又は２−オキンプロボキシ基を
意味し、Ｒ３′はアミ７基、ジメチルアミ７基又は炭素
原子数２〜４のアルカノイルアミ７基を意味し、Ｒｓ′
は水素原子又はメチル基を意味する。）
で表される化合物及びその生理的に許容される酸付加塩
類が挙げられる。Cyclopentyloxy group, 2-triproethoxy group, 2-
means a hydroxypropoxy group or a 2-okyneproboxy group, R3' means 7 amide groups, 7 dimethyl amine groups or 7 alkanoyl amine groups having 2 to 4 carbon atoms, Rs'
means a hydrogen atom or a methyl group. ) and their physiologically acceptable acid addition salts.
好適な別の本発明化合物として、一般式（■＃）（式中
、Ｒ＋’、 Ｒ２’及びＲ３′は前掲に同じものを意味
し、Ｙ′は一〇−又は−Ｓ−を意味する。）で表される
化合物及びその生理的に許容される酸付加塩類が挙げら
れる。Another suitable compound of the present invention is represented by the general formula (■#) (wherein R+', R2' and R3' have the same meanings as defined above, and Y' means 10- or -S-). ) and their physiologically acceptable acid addition salts.
好適な更に別の本発明化合物として、一般式（式中、Ｒ
ｌＺ Ｒ１’及びｎは前掲に同じものを意味し、Ｒ１＃
及びＲＩＩ′は同−又は異なって、炭素原子数１〜４の
アルキル基、べ／ジル基、フルオロベ／ジル基、クロロ
ベンジル基、トリフルオロメチルベンジル基又はシアノ
ベンジル基を意味し、Ｒ２′は炭素原子数１〜７のアル
コキシ基。Further suitable compounds of the present invention include general formula (wherein R
lZ R1' and n mean the same as above, R1#
and RII' are the same or different and mean an alkyl group having 1 to 4 carbon atoms, a be/zyl group, a fluorobenzyl group, a chlorobenzyl group, a trifluoromethylbenzyl group, or a cyanobenzyl group, and R2' is Alkoxy group having 1 to 7 carbon atoms.
３−ブテニルオキシ基、３−メチル−２−ブテニルオキ
シ基、シクロベ／チルオキシ基、２−クロロエトキシ基
、２−ヒドロキシプロポキシ基又は２−オキソプロポキ
シ基を意味し、Ｘ′はｎが０のときメチレン基を、ｎが
１のとき単結合を意味する。）
で表される化合物及びその生理的に許容される酸付加塩
類が挙げられる。3-butenyloxy group, 3-methyl-2-butenyloxy group, cyclobe/thyloxy group, 2-chloroethoxy group, 2-hydroxypropoxy group or 2-oxopropoxy group, and X' is a methylene group when n is 0. , when n is 1, it means a single bond. ) and their physiologically acceptable acid addition salts.
本発明の化合物は、例えば以下の方法により製造するこ
とができる。The compound of the present invention can be produced, for example, by the following method.
一般式（ＩＩ）
（式中、Ｒｚ、 Ｒａ及びＲ４は前掲に同じものを意味
する。）
で表される化合物又はその反応性誘導体と、一般式（Ｉ
ＩＩ）
（式中、Ｒ＋、 Ｒｓ、 Ｘ、 Ｙ、 ｎ及び破線は
前掲に同じものを意味する。）
で表される化合物とを反応させることにより、式（１）
で表される化合物を得ることができる。A compound represented by the general formula (II) (wherein Rz, Ra and R4 have the same meanings as defined above) or a reactive derivative thereof, and a compound represented by the general formula (I
II) (In the formula, R+, Rs, X, Y, n and the broken line mean the same as above.) By reacting with a compound represented by
A compound represented by can be obtained.
式（１１）の化合物の反応性誘導体としては、例えば低
級アルキルエステル、活性エステル、酸無水物、酸ハラ
イド（特に酸クロリド）等を挙げることができる。活性
エステルの具体例としてはｐ−ニトロフェニルエステル
、＾４，５−）リクロ口フェニルエステル、ペンタクロ
ロフェニルエステル、シアノメチルエステル、Ｎ−ヒド
ロキシコハク酸イミドエステル、Ｎ−ヒドロキシフタル
イミドエステル、Ｎ−ヒドロキシ−５−ノルボルネン−
２，３−ジカルボキシイミドエステル、Ｎ−ヒドロキシ
ピペリジンエステル、８−ヒドロキシキノリンエステル
、２−ヒドロキシフェニルエステル。Examples of reactive derivatives of the compound of formula (11) include lower alkyl esters, active esters, acid anhydrides, acid halides (especially acid chlorides), and the like. Specific examples of active esters include p-nitrophenyl ester, 4,5-)cyclophenyl ester, pentachlorophenyl ester, cyanomethyl ester, N-hydroxysuccinimide ester, N-hydroxyphthalimide ester, N-hydroxy- 5-Norbornene-
2,3-dicarboximide ester, N-hydroxypiperidine ester, 8-hydroxyquinoline ester, 2-hydroxyphenyl ester.
２−ヒドロキシ−４，５−ジクーロフェニルエステル、
２−ヒドロキシピリジンエステル、２−ピリジルチオー
ルエステル等が挙げられる。酸無水物としては、対称酸
無水物又は混合酸無水物が用いられ、混合酸無水物の具
体例としてはクロル炭酸エチル、クロル炭酸インブチル
のようなりロル炭酸アルキルエステルとの混合酸無水物
、クロル炭酸べエチルのようなりロル炭酸アラルキルエ
ステルとの混合酸無水物、クロル炭酸フェニルのような
りロル炭酸アリールエステルとの混合酸無水物、イソ吉
草酸、ピバリン酸のようなアルカン酸との混合酸無水物
等が挙げられる。2-hydroxy-4,5-dichlorophenyl ester,
Examples include 2-hydroxypyridine ester and 2-pyridylthiol ester. As the acid anhydride, a symmetrical acid anhydride or a mixed acid anhydride is used. Specific examples of the mixed acid anhydride include mixed acid anhydrides with chloroalkyl esters such as ethyl chlorocarbonate and inbutyl chlorocarbonate; Mixed acid anhydrides with aralkyl esters of chlorocarbonate such as bethyl carbonate, mixed acid anhydrides with aryl esters of chlorocarbonate such as phenyl chlorocarbonate, mixed acid anhydrides with alkanoic acids such as isovaleric acid and pivalic acid. Examples include things.
式（■）の化合物を用いる場合には、ジシクロへキシル
カルボジイミド、１−エチル−３−（３−ジメチルアミ
／プロピル）カルボジイミド塩酸ｌｕ、Ｎ＋Ｎ’−カル
ボニルジイミダゾール、１−エトキシカルボニル−２−
エトキシ−１，２−ジヒドロキノリンのような縮合剤の
存在下に反応させることができる。縮合剤としてジシク
ロへキシルカルボジイミド又は１−エチル−３−（３−
ジメチル７ミノプロビル）カルボジイミド塩酸塩を用い
る場合には、Ｎ−ヒドロキシコハク酸イミド、１−ヒド
ロキシベンゾトリアゾール、３−ヒドロキシ−４−オキ
ソ−３，４−ジヒドロ−１，２，３−ベンゾトリアジン
、Ｎ−ヒドロキシ−５−ノルボルネン−Ｚ３−ジカルボ
キシイミド等を添加して反応させてもよい。When using the compound of formula (■), dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylami/propyl)carbodiimide hydrochloride lu, N+N'-carbonyldiimidazole, 1-ethoxycarbonyl-2-
The reaction can be carried out in the presence of a condensing agent such as ethoxy-1,2-dihydroquinoline. Dicyclohexylcarbodiimide or 1-ethyl-3-(3-
When using dimethyl 7minoprovir) carbodiimide hydrochloride, N-hydroxysuccinimide, 1-hydroxybenzotriazole, 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine, N -Hydroxy-5-norbornene-Z3-dicarboximide or the like may be added and reacted.
式（ＩＩ）の化合物又はその反応性ｖ＃誘導体式（Ｉｌ
ｌ）の化合物との反応は、溶媒中又は無溶媒下に行われ
る。使用する溶媒は、原料化合物のＵ類等に従って適宜
選択されるべきであるが、例えばベンゼン、トルエン、
キシレンのような芳香族炭化水素、類、ジエチルエーテ
ル、テトラヒドロフラン、ジオキサンのようなエーテル
類、塩化メチレン、クロロホルムのようなハロゲン化炭
化水素類、酢酸エチル、アセトニトリル、ジメチルホル
ムアミド、ジメチルスルホキシド、エチレングリコール
、水等が挙げられ、これらの溶媒はそれぞれ単独で、あ
るいは２種以上混合して用いられる。本反応は必要に応
じて塩基の存在下に行われ、塩基の具体例としては、重
炭酸ナトリウム＋ｆｆｒ炭酸カリウムのような重炭酸ア
ルカリ、炭酸ナトリウム、炭酸カリウムのような炭酸ア
ルカリあるいはトリエチルアミン、トリブチルアミ／ｌ
ジイソプロピルエチルアミン、Ｎ−メチルモルホリン
のような「機塩基が挙げられるが、式（Ｉｌｌ）の化合
物の過剰■で兼ねることもできる。反応温度は用いる原
料化合物のａ類等により異なるが、通常約−３０℃ない
し約２００℃、好ましくは約〜ｌＯ℃ないし約１５０℃
である。A compound of formula (II) or its reactive v# derivative formula (Il
The reaction with the compound l) is carried out in a solvent or without a solvent. The solvent to be used should be appropriately selected according to the U class of the raw material compound, and examples include benzene, toluene,
Aromatic hydrocarbons such as xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane, halogenated hydrocarbons such as methylene chloride, chloroform, ethyl acetate, acetonitrile, dimethylformamide, dimethyl sulfoxide, ethylene glycol, Examples include water, and these solvents may be used alone or in a mixture of two or more. This reaction is carried out in the presence of a base if necessary. Specific examples of the base include alkali bicarbonate such as sodium bicarbonate + ffr potassium carbonate, alkali carbonate such as sodium carbonate and potassium carbonate, triethylamine, tributylamine, etc. /l
Examples include organic bases such as diisopropylethylamine and N-methylmorpholine, but they can also be used in excess of the compound of formula (Ill).The reaction temperature varies depending on the class a of the raw material compound used, but is usually about - 30°C to about 200°C, preferably about ~10°C to about 150°C
It is.
上記製法により生成する化合物は、クロマトグラフィー
、再結晶、再沈殿等の常法により単層。The compound produced by the above production method is made into a single layer by conventional methods such as chromatography, recrystallization, and reprecipitation.
精製される。Refined.
式（Ｉ）の化合物は、原料化合物の選定１反応・処理条
件等により、遊離塩基又は酸付加塩の形で得られる。酸
付加塩は、常法、例えば炭酸アルカリ、水酸化アルカリ
のような塩基で処理することにより、遊離塩基に変える
ことができる。一方、遊離塩基は、常法に従って各種の
酸と処理することにより酸付加塩に埠（ことができる。The compound of formula (I) can be obtained in the form of a free base or an acid addition salt depending on the selection of raw material compounds, 1 reaction and treatment conditions, etc. Acid addition salts can be converted to the free base in a conventional manner, eg, by treatment with a base such as an alkali carbonate or an alkali hydroxide. On the other hand, free bases can be converted into acid addition salts by treatment with various acids according to conventional methods.
以下に、本発明の代表的化合物並びに市販の消化管機能
亢進剤であるメトクロプラミド塩酸塩１永和物について
の薬理試験の結果を示し、本発明の化合物の薬理作用を
説明する。Below, the results of pharmacological tests on representative compounds of the present invention and metoclopramide hydrochloride monohydrate, a commercially available gastrointestinal function enhancer, will be shown, and the pharmacological action of the compounds of the present invention will be explained.
試験例１ 胃排出能冗進作用
本試験は、Ｓｃａｒｐｉｇｎａｔｏらの方法［＾ｒｃｈ
、 ！ｎｔ。Test Example 1 Effect on gastric emptying This test was conducted using the method of Scarpignato et al. [^rch
, ! nt.
Ｐｈａｒｍａｃｏｄｙｎ、、 ２４０．２８８〜２９４
（＋９８０）参照］に準じて行った。ウィスター系雄
性ラット（体ｆｒｌ１３０〜１５０ｇ）を１８時間絶食
した後、フェノールレッドを０．０５％の割合で含有す
る１、５Ｘメチルセルロース溶液１．５■１を経口投与
した。投与１５分後に胃を摘出し、胃内に残存するフェ
ノールレッド量を測、定した。なお、試験化合物は０．
５％トラガ／ト溶液に演解又はＦ！濁し、フェノールレ
ッド投与の６０分前に経口投与した。胃内残存フェノー
ルレッド量に基づいて胃排出率を算出し、更に対照群の
胃排出率と比較して亢進率を求めた。使用した動物数は
対照・群及びメトクロプロマミド塩酸塩ｌ水和物投与群
についでは５匹、それ以外は４匹である。Pharmacodyn, 240.288-294
(+980)]. After fasting for 18 hours, male Wistar rats (body weight 130-150 g) were orally administered with 1.5 ml of a 1,5X methylcellulose solution containing phenol red at a rate of 0.05%. The stomach was removed 15 minutes after administration, and the amount of phenol red remaining in the stomach was measured. In addition, the test compound was 0.
Dilute or F! in 5% TRAG/TO solution. The solution was turbid and administered orally 60 minutes before administration of phenol red. The gastric emptying rate was calculated based on the amount of phenol red remaining in the stomach, and the rate of enhancement was determined by comparing it with the gastric emptying rate of the control group. The number of animals used was 5 for the control group and the metoclopromamide hydrochloride l hydrate administration group, and 4 for the others.
結果を表１に示す。The results are shown in Table 1.
表 １ 胃排出能冗進作用 ０） 実施例１の化合物を意味する（以下同じ）。Table 1: Increased effect on gastric emptying 0) means the compound of Example 1 (the same applies hereinafter).
上記試験結果から明らかなように、式（Ｉ）の化合物及
びその生理的に許容される酸付加塩類は、優れた消化管
機能亢進作用を有するので、制吐剤あるいは消化管機能
亢進剤として、急・慢性胃炎。As is clear from the above test results, the compound of formula (I) and its physiologically acceptable acid addition salts have excellent gastrointestinal function-enhancing effects, and therefore are used as acute antiemetics or gastrointestinal function-enhancing agents. ·Chronic gastritis.
胃・十二指腸ｉｎ瘍、胃神軽症、胃下垂などの疾患にお
ける食欲不振、悪心、嘔吐、腹部膨膚感等の治療及び予
防に、また食道・胆道系疾患２便秘症の治療及び予防に
用いることができる。更にまた、シスプラチンのような
抗癌剤投与時の悪心、嘔吐の治療及び予防にも用いるこ
とができる。その投与経路としては、経口投与、非経口
投与あるいは直腸内投与のいずれでもよい。投与量は、
化合物の８１類、投与方法、患者の症状・年令等により
異なるが、通常０．００１〜２０＊ ／ｋｓ ７日、好
ましくは０．００４〜５■／ｈｇ／日である１式（■）
°の化合物又はその塩は通常、製剤用担体と混合して調
製した製剤の形で投与される。製剤用担体としては、製
剤分野において常用され、かつ式（りの化合物又はその
塩と反応しない物質が用いられる。具体的には、例えば
乳糖、ブドウ糖、マンニット、シクロデキストリ／ｌデ
７ブン、白糖、結晶セルロース、ゼラヂン、アラビアゴ
ム、ヒドロ牛ジプロピルセルロース、ヒドロキシプロピ
ルメチルセルロース。It can be used for the treatment and prevention of anorexia, nausea, vomiting, abdominal swelling, etc. in diseases such as gastric/duodenal ulcers, mild gastrointestinal symptoms, and gastric ptosis, and for the treatment and prevention of esophageal/biliary system disease 2 constipation. can. Furthermore, it can be used to treat and prevent nausea and vomiting during administration of anticancer drugs such as cisplatin. The route of administration may be oral, parenteral or rectal. The dosage is
Although it varies depending on the class 81 compound, administration method, patient's symptoms and age, etc., it is usually 0.001 to 20*/ks 7 days, preferably 0.004 to 5 ■/hg/day (1 formula)
The compound or a salt thereof is usually administered in the form of a preparation prepared by mixing it with a pharmaceutical carrier. As a pharmaceutical carrier, a substance that is commonly used in the pharmaceutical field and does not react with the compound of formula (2) or its salt is used.Specifically, for example, lactose, glucose, mannitol, cyclodextrin , white sugar, crystalline cellulose, geladine, gum arabic, hydrobovine dipropyl cellulose, hydroxypropyl methylcellulose.
軽質無水ケイ酸、ステアリン酸マグネシウム、タルク、
トラガント、酸化チタン、ソルビタン脂肪酸エステル、
植物油、水等が挙げられる。剤型としては、錠剤、カプ
セル剤、顆粒剤、細粒剤、散剤、シロップ剤、懸濁剤、
注射剤、串刺等が挙げられる。これらの製剤は常法に従
って調製される。Light silicic anhydride, magnesium stearate, talc,
tragacanth, titanium oxide, sorbitan fatty acid ester,
Examples include vegetable oil and water. Dosage forms include tablets, capsules, granules, fine granules, powders, syrups, suspensions,
Examples include injections and skewers. These formulations are prepared according to conventional methods.
これらの製剤はまた、治療上価値ある他の成分を含存し
ていてもよい、。These formulations may also contain other ingredients of therapeutic value.
本発明を更に具体的に説明するために、以下に参考例及
び実施例を挙げるが、本発明はこれら実施例に限定され
るものではない。なお、化合物の同定は元素分析値、マ
ス・スペクトル、 ＩＲスペクトル、ＮＭＲスペクト
ル等により行った。In order to explain the present invention more specifically, reference examples and examples are given below, but the present invention is not limited to these examples. The compounds were identified using elemental analysis values, mass spectra, IR spectra, NMR spectra, etc.
参考例１
４−ベンジル−２−エトキシカルボニル−５，６−シヒ
ドロー１．４−チアジンの製造：水素化ナトリウム８．
１ ｇの無水テトラヒドロフラフ３３０１１ｊｊ濁液中
に室温下、５ｙｎｔｈｅＳ＋ｓ、 ０８８〜０９０ （
＋９８４）に記αの方法に従って合成した、２−エトキ
シカルボニル−
４−チアジン３２．１ｇを滴下する。室温で３０分撹拌
した後、水冷しながら臭化ベンジル３１．７ｇを滴下す
る。反応液を室温に戻して３時間撹拌した後、テトラヒ
ドロフランを留去する，残渣を酢酸エチルに溶解し、水
洗し、無水硫酸マグネシウムで乾燥したのち溶媒を留去
する。残渣をシリカゲルのカラムクロマトグラフィーに
付し、クロロホルムで溶出・精製して目的物４９ｇを得
る。Reference Example 1 Production of 4-benzyl-2-ethoxycarbonyl-5,6-sihydro1.4-thiazine: Sodium hydride 8.
5yntheS+s, 088-090 (
32.1 g of 2-ethoxycarbonyl-4-thiazine, which was synthesized according to the method described in (a) above, is added dropwise. After stirring at room temperature for 30 minutes, 31.7 g of benzyl bromide was added dropwise while cooling with water. After the reaction solution was returned to room temperature and stirred for 3 hours, the tetrahydrofuran was distilled off. The residue was dissolved in ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The residue was purified by silica gel column chromatography and eluted with chloroform to obtain 49 g of the desired product.
参考例２
４−ベンジル−２−ヒドロキシメチル−１，４−チオモ
ルホリンの製造：
水素化アルミニウムリチウム７、２ｇを無水テトラヒド
ロフラ：／２００ｍｌに懸濁し、水冷下４ーベンジルー
２ーエトキシカルボニル−５，６−ジヒドロ−１，４−
チアジン２５ｇの無水テトラヒドロフラン５０−１溶液
を滴下する。滴下終了後、室温で１８時間撹拌した後、
氷玲しながら酢酸エチル、続いて水。Reference Example 2 Production of 4-benzyl-2-hydroxymethyl-1,4-thiomorpholine: 7.2 g of lithium aluminum hydride was suspended in 200 ml of anhydrous tetrahydrofura, and 4-benzyl-2-ethoxycarbonyl-5,6 was added under water cooling. -dihydro-1,4-
A solution of 25 g of thiazine in anhydrous tetrahydrofuran 50-1 is added dropwise. After completing the dropwise addition and stirring at room temperature for 18 hours,
Add ethyl acetate, followed by water.
水酸化ナトリウム水溶液を加え、酢酸エチルで抽出する
。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウム
で乾燥したのち溶媒を留去する。残渣をシリカゲルのカ
ラムクロマトグラフィーに付し、クロロホルム−メタノ
ール（５０：１）で溶出・精製して目的物５．８ｇを得
る。Add aqueous sodium hydroxide solution and extract with ethyl acetate. The organic layer is washed with saturated brine, dried over anhydrous magnesium sulfate, and then the solvent is distilled off. The residue was purified by silica gel column chromatography and eluted with chloroform-methanol (50:1) to obtain 5.8 g of the desired product.
参考例３
４−ベンジル−２−クロロメチル−１，４−チオモルホ
リンの製造：
４−ベアジル−２−ヒドロキシメチル−１．４−チオモ
ルホリン１０．０ｇをクロロホルム１００■１に溶解し
、水冷しながら塩化チオニルＩ１ｇを加え、２０分加熱
還流する。溶媒を留去し、残渣を飽和重炭酸す）リウム
水溶液で中和し、クロロホルムで抽出する。有機層を水
洗し、無水硫酸マグネシウムで乾燥したのち溶媒を留去
する。残渣をシリカゲルのカラムクロマトグラフィーに
付し、ヘキサン−クロロホルム（１ ： １）で溶出・
精製して目的物０．８ ｇを得る。Reference Example 3 Production of 4-benzyl-2-chloromethyl-1,4-thiomorpholine: 10.0 g of 4-bearzyl-2-hydroxymethyl-1,4-thiomorpholine was dissolved in 100 x 1 chloroform, and cooled with water. While stirring, add 1 g of thionyl chloride and heat to reflux for 20 minutes. The solvent is evaporated and the residue is neutralized with saturated aqueous sodium bicarbonate solution and extracted with chloroform. The organic layer is washed with water, dried over anhydrous magnesium sulfate, and then the solvent is distilled off. The residue was subjected to silica gel column chromatography and eluted with hexane-chloroform (1:1).
Purify to obtain 0.8 g of the target product.
参考例４ ２−アセチルアミノメチル−４−べ／ジルー１。Reference example 4 2-acetylaminomethyl-4-be/girou 1.
４−チオモルホリンの製造：
ｉ） ４−ベンジル−２−クロロメチル−１，４ーチ
オモルホリン６．８ｇをアセトニトリル１００１に溶解
し、ナトリウムアジド３．７ｇを加えたのち２時間加熱
還流する。冷浸、溶媒を留去し、残渣をクロロホルムに
溶解する。クロロホルム溶液を水洗し、無水硫酸マグネ
シウムで乾燥したのち濃縮して、２−アジドメチル−４
−ベンジル−１．４−チオモルホリフ７、０ｇｔｌ−得
る。Production of 4-thiomorpholine: i) 6.8 g of 4-benzyl-2-chloromethyl-1,4-thiomorpholine is dissolved in 100 ml of acetonitrile, and after adding 3.7 g of sodium azide, the mixture is heated under reflux for 2 hours. Cool, evaporate the solvent, and dissolve the residue in chloroform. The chloroform solution was washed with water, dried over anhydrous magnesium sulfate, and concentrated to give 2-azidomethyl-4
-benzyl-1,4-thiomorpholif 7,0 gtl- is obtained.
ｉｉ）上Ｊ己アジドメチル体７．０ｇをトルエン７０１
に溶解し、水冷下７０％水素化ビス（２−メトキシエト
キシ）アルミニウムナトリウム１８ｇを少しずつ加える
。水冷下２．５時間撹拌したのち反応液を氷水中にあけ
、４８％水酸化ナトリウム水溶液を加え、クロロホルム
で抽出する。育ｖＡ層を水洗し、無水硫酸マグネシウム
で乾燥したのち無水酢ａ１５．７ｇを加え、室温で３時
間撹拌する．反応液を４８％水酸化ナトリウム水溶液、
次いで飽和食塩水で洗浄し、無水硫酸マグネシウムで乾
燥したのち溶媒を留去する。残渣をシリカゲルのカラム
クロマトグラフィーに付し、クロロホルム−メタノール
（２０：１）で溶出・精製して目的物５．８ｇを得る。ii) Add 7.0 g of the above J azidomethyl compound to 701 g of toluene.
18 g of 70% sodium bis(2-methoxyethoxy)hydride is added little by little while cooling with water. After stirring for 2.5 hours under water cooling, the reaction solution was poured into ice water, a 48% aqueous sodium hydroxide solution was added, and the mixture was extracted with chloroform. After washing the growth layer A with water and drying it over anhydrous magnesium sulfate, add 15.7 g of anhydrous vinegar and stir at room temperature for 3 hours. The reaction solution was mixed with 48% sodium hydroxide aqueous solution,
Next, the mixture is washed with saturated brine, dried over anhydrous magnesium sulfate, and then the solvent is distilled off. The residue was purified by silica gel column chromatography and eluted with chloroform-methanol (20:1) to obtain 5.8 g of the desired product.
参考例５
３−アミノメチル−１−ベンジルピペリジンの製造：
水素化リチウムアルミニウム４．０ｇの無水Ｔトラヒド
ロフラ’２００１１！！濁液中に、１−ベンジル−３−
力ルバモイルビベリジン１１．４ｇの無水テトラヒドロ
フラノ２００■Ｉ溶液を少しずつ滴下する。Reference Example 5 Production of 3-aminomethyl-1-benzylpiperidine: 4.0 g of lithium aluminum hydride anhydrous T-trahydrofura'20011! ! In the suspension, 1-benzyl-3-
A solution of 11.4 g of rubamoyl biveridine in anhydrous tetrahydrofurano 200 I was added dropwise little by little.
ｌ４下終了後、４．５時間撹拌しながら加熱還流する。After 14 hours, the mixture was heated to reflux with stirring for 4.5 hours.
室温まで戻した後、反応液に希水酸化ナトリウム水溶液
を注意深く加えて過剰の水素化リチウムアルミニウムを
分解する。不溶物を濾去し、溶媒を留去したのちクロロ
ホルムで抽出する。有機層を水、次いで飽和食塩水で洗
浄し、無水硫酸マグネシウムで乾燥した後、溶媒を留去
して油状の目的物８．０ｇを得る。After returning to room temperature, a dilute aqueous sodium hydroxide solution is carefully added to the reaction solution to decompose excess lithium aluminum hydride. Insoluble materials are filtered off, the solvent is distilled off, and the mixture is extracted with chloroform. The organic layer is washed with water and then with saturated brine, dried over anhydrous magnesium sulfate, and then the solvent is distilled off to obtain 8.0 g of the desired product as an oil.
参考例６
３−アミノメチル−１−ベンジル−１，ス５，６−チト
ラヒドロピリジンの製造：
■）３−アセチルアミノメチル−１−ベンジルピリジニ
ウム クロリド１０．Ｏｇをメタノール３０１と水８０
１の混液に加え、水冷下撹拌しながら水素化ホウ素ナト
リウム６．３ｇを少しずつ加える。還元剤を加え終わっ
た後、室温で１８時間撹拌する。Reference Example 6 Production of 3-aminomethyl-1-benzyl-1,5,6-titrahydropyridine: ■) 3-acetylaminomethyl-1-benzylpyridinium chloride 10. Og to 301 parts methanol and 80 parts water
In addition to the mixed solution in step 1, 6.3 g of sodium borohydride is added little by little while stirring under water cooling. After adding the reducing agent, stir at room temperature for 18 hours.
反応液に希塩酸を少しずつ加えて過剰の水素化ホウ素ナ
トリウームを分解した後、希水酸化ナトリウム水溶液で
アルカリ性とし、クロロホルムで抽出する。を機層を水
洗し、無水硫酸マグネシウムで乾燥したのち溶媒を留去
する。残渣をシリカゲルのカラムクロマトグラフィーに
付し、クロロホルム−メタノール（５０：１）で６出・
精製して、油状の３−アセチルアミノメチル−１−ベン
ジル−１、２，５，Ｇ−テトラヒドロピリジン５．０ｇ
を得る。Dilute hydrochloric acid is added little by little to the reaction solution to decompose excess sodium borohydride, then the mixture is made alkaline with a dilute aqueous sodium hydroxide solution and extracted with chloroform. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was subjected to column chromatography on silica gel and chromatographed with chloroform-methanol (50:1) for 6 times.
5.0 g of purified oily 3-acetylaminomethyl-1-benzyl-1,2,5,G-tetrahydropyridine
get.
■）上記テトラヒドロピリジン体５．０ｇに１０％塩＃
７５ｍ１を加え、撹拌しながら５時間加熱還流する。冷
浸、反応液を２０％水酸化ナトリウム水溶液でアルカリ
性とし、クロロホルムで抽出する。有機層を水洗し、無
水硫酸マグネシウムで乾燥した後、溶媒を留去して油状
の目的物３．８ｇを得る。■) 5.0g of the above tetrahydropyridine with 10% salt #
Add 75ml and heat to reflux for 5 hours while stirring. After cooling, the reaction solution was made alkaline with a 20% aqueous sodium hydroxide solution and extracted with chloroform. After washing the organic layer with water and drying over anhydrous magnesium sulfate, the solvent was distilled off to obtain 3.8 g of the desired product as an oil.
これを常法によりマレイン酸で処理して目的物のシマレ
イン酸塩を得る。融点１５５〜１５７℃（エタノールか
ら再結晶）
参考例７
２−アジドメチル−１，４−ジエチルピペラジンの製造
：
１１ｅｌｖ、 Ｃｈｉｎ、＾ｃｔａ、 ４５．２３８３
〜２４０２ （１９Ｇ２）に記載の方法に従って合成し
た、１，４−ジエチル−２−ヒドロキシメチルピペラジ
ン２７ｇをクロロホルム２７０■１に溶解し、水冷上塩
化チオニル２７ｇを加えた後、撹拌しながら３０分加熱
還流する。冷浸、溶媒を留去し、飽和重炭酸ナトリウム
水溶液で中和したのちクロロホルムで抽出する。有機層
を水洗し、無水硫酸マグネシウムで乾燥したのち溶媒を
留去して、２−クロロメチル−１，４−ジエチルピペラ
ジンを得る。これをアセトニトリル２７０■１に溶解し
、ナトリウムアジド２０ｇを加え、撹拌しながら２時間
加熱還流する。冷浸、溶媒を留去し、残渣をクロロホル
ムに溶解する。クロロホルム溶液を水洗し、無水硫酸マ
グネシウムで乾燥した後、溶媒を留去して油状の目的物
１５ｇを得る。This is treated with maleic acid in a conventional manner to obtain the desired simalate salt. Melting point: 155-157°C (recrystallized from ethanol) Reference Example 7 Production of 2-azidomethyl-1,4-diethylpiperazine: 11elv, Chin, ^cta, 45.2383
~2402 (19G2) 27 g of 1,4-diethyl-2-hydroxymethylpiperazine synthesized according to the method described in 2402 (19G2) was dissolved in 270 x 1 chloroform, and after cooling with water, 27 g of thionyl chloride was added, and then heated for 30 minutes with stirring. Reflux. Cool, evaporate the solvent, neutralize with saturated aqueous sodium bicarbonate solution, and extract with chloroform. The organic layer is washed with water, dried over anhydrous magnesium sulfate, and then the solvent is distilled off to obtain 2-chloromethyl-1,4-diethylpiperazine. This was dissolved in 270 ml of acetonitrile, 20 g of sodium azide was added, and the mixture was heated under reflux for 2 hours with stirring. Cool, evaporate the solvent, and dissolve the residue in chloroform. After washing the chloroform solution with water and drying over anhydrous magnesium sulfate, the solvent was distilled off to obtain 15 g of the desired product as an oil.
参考例８
２−アミノメチル−１，４−ジエチルピペラジンの製造
：
２−アジドメチル−１，４−ジエチルピペラジン１５ｇ
をトルエン１５０■Ｉに溶解し、水冷下７０％水素化ビ
ス（２−メトキシエトキシ）アルミニウムナトリウム３
４ｇを少しずつ加える。水冷しながら５時間撹拌後、反
応液を氷水中にあけ、４８％水酸化ナトリウム水溶液を
加えたのち有機層を分離する。Reference Example 8 Production of 2-aminomethyl-1,4-diethylpiperazine: 15 g of 2-azidomethyl-1,4-diethylpiperazine
was dissolved in 150 μl of toluene, and 70% sodium bis(2-methoxyethoxy)aluminum hydride was added under water cooling.
Add 4g little by little. After stirring for 5 hours while cooling with water, the reaction solution was poured into ice water, and after adding a 48% aqueous sodium hydroxide solution, the organic layer was separated.
存ａ届を水洗し、無水硫酸マグネシウムで乾燥したのち
溶媒を留去して油状の目的物１１ｇを得る。The sample was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain 11 g of the desired product as an oil.
参考例９
６−アセチルアミノ−４−ベンジル−ヘキサヒドロ−１
，４−チアゼピンの製造：
＋） Ｊ、 Ｍｅｄ、 Ｐｈａｒｍ、 Ｃ
ｈｅｗ、、 ２． ５５３〜５Ｇ２ （１９６０）
に記αの方法に従って合成した、３−エトキシカルボニ
ル−１，４−チオモルホリン１８．０ｇをメチルエチル
ケトン１７０１に溶解し、臭化ベンジル１７．８ｇと炭
酸カリウム１１．０．ｇを加え、撹拌しながら１．５時
間加０還流する。不溶物を濾去しｄ液を濃縮し、残渣に
酢酸エチルを加える。この溶液を水洗し、無水硫酸マグ
ネシウムで乾燥したのち溶媒を留去する。残渣をシリカ
ゲルのカラムクロマトグラフィーに付し、ヘキサン−ク
ロロホルム（１： １）で溶出・精製して４−ベンジル
−３−エトキシカルボニル−１，４−チオモルホリン２
０．５ｇを得る。Reference example 9 6-acetylamino-4-benzyl-hexahydro-1
, 4-thiazepine production: +) J, Med, Pharm, C
hew,, 2. 553~5G2 (1960)
18.0 g of 3-ethoxycarbonyl-1,4-thiomorpholine synthesized according to method α described above was dissolved in methyl ethyl ketone 1701, and 17.8 g of benzyl bromide and 11.0 g of potassium carbonate were dissolved. g and refluxed for 1.5 hours while stirring. Insoluble matters are removed by filtration, liquid d is concentrated, and ethyl acetate is added to the residue. This solution is washed with water, dried over anhydrous magnesium sulfate, and then the solvent is distilled off. The residue was purified by silica gel column chromatography and eluted with hexane-chloroform (1:1) to give 4-benzyl-3-ethoxycarbonyl-1,4-thiomorpholine 2.
Obtain 0.5 g.
ｉｔ）上３己ベンジル体２０．５ｇをトルエフ２００ｍ
１に溶解し、水冷下７０％水素化ビス（２−メトキシエ
トキシ）アルミニウムナトリウム４４．０ｇを少しずつ
加え、室墨に戻して一夜撹拌する。反応液を氷水中にあ
け、４８％水酸化ナトリウム水溶液を加え、トルエンで
抽出する。ＷａＳを水洗し、無水硫酸マグネシウムで乾
燥したのち溶媒を留去する。残渣をシリカゲルのカラム
クロマトグラフィーに付し、クロ四ホルムーメタノール
（５０：１）で溶出・精製して４−ベンジル−３−ヒド
ロキシメチル−！、４−チオモルホリン１３．９ｇを得
る。it) 20.5g of the upper three benzylic derivatives in Toluev 200m
1, add 44.0 g of 70% sodium bis(2-methoxyethoxy)aluminum hydride little by little while cooling with water, return to room black, and stir overnight. The reaction solution was poured into ice water, a 48% aqueous sodium hydroxide solution was added, and the mixture was extracted with toluene. The WaS is washed with water, dried over anhydrous magnesium sulfate, and then the solvent is distilled off. The residue was purified by silica gel column chromatography and eluted with chlorotetraform-methanol (50:1) to give 4-benzyl-3-hydroxymethyl-! , 13.9 g of 4-thiomorpholine are obtained.
目ｉ）上記ヒドロキシメチル体１３．９ｇをクロロホル
ム１５０■１に溶解し、水冷下、塩化チオニル１４ｇを
加える。２０分加熱還流した後、溶媒を留去し、残渣を
飽和重炭酸ナトリウム水溶液で中和し、クロロホルムで
抽出する。育機居を水洗し、無水硫酸マグネシウムで乾
燥したのち溶媒を留去する。Item i) Dissolve 13.9 g of the above hydroxymethyl compound in 150 parts of chloroform, and add 14 g of thionyl chloride while cooling with water. After heating at reflux for 20 minutes, the solvent is evaporated and the residue is neutralized with saturated aqueous sodium bicarbonate solution and extracted with chloroform. After washing the ikukai with water and drying it with anhydrous magnesium sulfate, the solvent is distilled off.
残渣をシリカゲルのカラムクロマトグラフィーに付シ、
ヘキサン−クロロホルム（１： １）で溶出・精製して
、４−ベンジル−３−クロロメチル−１゜４−チオモル
ホリン１４．６ｇを得る。The residue was subjected to silica gel column chromatography.
Elution and purification with hexane-chloroform (1:1) yields 14.6 g of 4-benzyl-3-chloromethyl-1°4-thiomorpholine.
＋Ｖ）上記クロロメチル体８．０ｇをアセトニトリル８
０１に溶解し、ナトリウムアジド４．３ｇを加え、１ｊ
２ｒ′Ｐ、シながら２時間加熱還流する。溶媒を留去し
、残渣に酢酸エチルを加え、水洗し、無水硫酸マグネシ
ウムで乾燥したのち溶媒を留去する。残渣にトルエン５
０１を加え、水冷下、７０％水素化ビス（２−メトキシ
エトキシ）アルミニウムナトリウム９．８ｇを少しずつ
加えたのち３時間撹拌する。反応液を氷水中にあけ、４
８％水酸化ナトリウム水溶液を加え、クロロホルムで抽
出する。有ｖＡ層を水洗し、無水硫酸マグネシウムで乾
燥した後無水酢酸４．９ｇを加え、室温で１時間撹拌す
る０反応液を４８％水酸化ナトリウム水溶液、次いで水
で洗浄し、無水硫酸マグネシウムで乾燥したのち溶媒を
留去する。+V) 8.0 g of the above chloromethyl compound was mixed with 8.0 g of acetonitrile.
01, add 4.3g of sodium azide, and add 1j
Heat and reflux for 2 hours while stirring at 2r'P. The solvent was distilled off, ethyl acetate was added to the residue, washed with water, dried over anhydrous magnesium sulfate, and then the solvent was distilled off. Toluene 5 to the residue
01 was added thereto, 9.8 g of 70% sodium bis(2-methoxyethoxy)aluminum hydride was added little by little under water cooling, and the mixture was stirred for 3 hours. Pour the reaction solution into ice water and
Add 8% aqueous sodium hydroxide solution and extract with chloroform. After washing the aqueous A layer with water and drying it over anhydrous magnesium sulfate, add 4.9 g of acetic anhydride and stir at room temperature for 1 hour.The reaction solution is washed with a 48% aqueous sodium hydroxide solution, then with water, and dried over anhydrous magnesium sulfate. Afterwards, the solvent is distilled off.
残渣をシリカゲルのカラムクロマトグラフィーに付し、
クロロホルム−メタノール（４０：１）で溶出・精製し
て、目的物２．６ｇと３−アセチルアミノメチル−４−
べ／ジルー１，４−チオモルホリフ３．１ｇを得る。The residue was subjected to silica gel column chromatography,
Elution and purification with chloroform-methanol (40:1) yielded 2.6 g of the target product and 3-acetylaminomethyl-4-
3.1 g of Be/Giro-1,4-thiomorpholif are obtained.
参考例１０
６−アセチルアミノ−４−ベンジル−ヘキサヒドロ−１
，４−オキサゼピンの製造：
Ｊ、 Ｃｈｅｗ、 Ｓｏｃ、、 Ｐｅｒｋｉｎ Ｔｒａ
ｎｓ、 Ｉ 、 ５４７〜５５１（１９８７）に記Ｕの
方法に従って合成した、４−ベンジル−３−クロロメチ
ルモルホリン５．１ ｇをアセトニトリル５０１に溶解
し、ナトリウムアジド３．Ｏｇを加え、撹拌しな、がら
３時間加熱還流する。溶媒を留去し、残渣にクロロホル
ムを加え、水洗し、無水硫酸マグネシウムで乾燥したの
ち溶媒を留去する。残渣にトルエン５０１を加え、水冷
下、７０％水素化ビス（２−メトキシエトキシ）アルミ
ニウムナトリウム１１．５ｇを少しずつ加えたのち水冷
下に３時間撹拌する０反応液にエタノール、次いで氷水
と４８％水酸化ナトリウム水溶液を加える。トルエン層
を分離し、飽和食塩水で洗浄し、無水硫酸マグネシウム
で乾燥したのち溶媒を留去する。Reference example 10 6-acetylamino-4-benzyl-hexahydro-1
, 4-oxazepine production: J. Chew, Soc., Perkin Tra.
ns, I, 547-551 (1987), 5.1 g of 4-benzyl-3-chloromethylmorpholine, which was synthesized according to the method described in U. Add Og and heat to reflux for 3 hours while stirring. The solvent was distilled off, chloroform was added to the residue, washed with water, dried over anhydrous magnesium sulfate, and then the solvent was distilled off. Add 501 toluene to the residue, add 11.5 g of 70% sodium bis(2-methoxyethoxy)aluminum hydride little by little under water cooling, and stir for 3 hours under water cooling.To the reaction solution, add ethanol, then ice water and 48% Add aqueous sodium hydroxide solution. The toluene layer is separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and then the solvent is distilled off.
残渣をクロロホルム５０１１に溶解し、無水酢酸番、Ｏ
ｇを加え、室温で１４時間撹拌する。反応液に氷水と４
８％水酸化ナトリウム水溶液を加えてｕｉ丑し、を機巧
を分離する。これを飽和食塩水で洗浄し、無水硫酸マグ
ネシウムで乾燥したのち溶媒を留去する。残渣を中圧シ
リカゲルカラムクロマトクラフィーに付し、酢酸エチル
−ヘキサン（５：１）で溶出・精製して、目的物１．２
ｇと３−アセチルアミノメチル−４−ベンジルモルホリ
ン２．８ｇを得る。The residue was dissolved in chloroform 5011, acetic anhydride, O
g and stirred at room temperature for 14 hours. Add ice water and 4 to the reaction solution.
Add 8% aqueous sodium hydroxide solution and separate the filtrate. This is washed with saturated brine, dried over anhydrous magnesium sulfate, and then the solvent is distilled off. The residue was subjected to medium pressure silica gel column chromatography and purified by elution with ethyl acetate-hexane (5:1) to obtain the target product 1.2.
g and 2.8 g of 3-acetylaminomethyl-4-benzylmorpholine are obtained.
参考例１１
２−７セチルアミノメチルー１，４−ジベンジル゛ ピ
ペラジン及び６−アセチルアミノ−１，４−ジベンジル
−へキサヒドロ−１，４−ジアゼピンの製造：１１ｅｌ
ｖ、 Ｃｈｉｌ、 ＾ｃｔａ、 ４５． ２
３１１３〜２４０２ （１９０２） に ３己社の
方法に従って合成した、２−クロロメチル−１，４−ジ
ベンジルピペラジｙ７．５ｇをアセトニトリル７５１に
溶解し、ナトリウムアジド３．１ ｇを加え、撹拌しな
がら３時間加熱還流する。冷浸、不溶物を濾去し濾液を
濃縮する。残渣を酢酸エチルに溶解し、水洗し、無水硫
酸マグネシウムを乾燥した後、溶媒を留去して油状物６
．８ｇを得る。これをトールエン７０１に溶解し、水冷
下撹拌しながら７０％水素化ビス（２−メトキシエトキ
シ）アルミニウムナトリウム１２．５ ｇを少しずつ加
える。室温で１時間撹拌した後、エタノールと４８％水
ｆｉ 化ナトリウム水ｒＢ液を加える。トルエン層を分
子ｌｉシ、飽和食塩水で洗浄し、無水硫酸マグネシウム
で乾燥したのち溶媒を留去する。残渣をクロロホルム５
０１に溶解し、無水酢酸↓、４ｇを加えて室温で８時間
撹拌する。反応液を２０％水酸化ナトリウム水、ｉ８液
で洗浄し、無水硫酸マグネシウムで乾燥した後、溶媒を
留去して油状物６．５ｇを得る。これを中圧シリカゲル
カラムクロマトグラフィーに付し、酢酸エチル−へ牛サ
ン（５：１）で溶出・精製して、６−アセヂルアミノー
１．４−ジベンジル−へキサヒドロ−１，４−ジアゼピ
ン１．３ｇと２−アセチルアミノメチル−１，４−ジベ
ンジルピペラジン３．５ｇを得る。Reference Example 11 Production of 2-7cetylaminomethyl-1,4-dibenzyl-piperazine and 6-acetylamino-1,4-dibenzyl-hexahydro-1,4-diazepine: 11el
v, Chil, ^cta, 45. 2
3113-2402 (1902), 7.5 g of 2-chloromethyl-1,4-dibenzylpiperaziy, synthesized according to the method of 3rd company, was dissolved in 751 acetonitrile, 3.1 g of sodium azide was added, and the mixture was stirred. While heating under reflux for 3 hours. After cooling, insoluble matters are removed by filtration and the filtrate is concentrated. The residue was dissolved in ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off to give an oily substance 6.
．． Obtain 8g. This was dissolved in toluene 701, and 12.5 g of 70% sodium bis(2-methoxyethoxy)aluminum hydride was added little by little while stirring under water cooling. After stirring at room temperature for 1 hour, ethanol and 48% sodium hydride aqueous rB solution were added. The toluene layer was washed with molecular weight, saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off. Distill the residue in chloroform 5
01, add 4 g of acetic anhydride↓, and stir at room temperature for 8 hours. The reaction solution was washed with 20% sodium hydroxide solution and i8 solution, dried over anhydrous magnesium sulfate, and then the solvent was distilled off to obtain 6.5 g of an oily substance. This was subjected to medium pressure silica gel column chromatography, eluted and purified with ethyl acetate-to-beef sanitation (5:1), and 1.3 g of 6-acedylamino-1,4-dibenzyl-hexahydro-1,4-diazepine was obtained. and 3.5 g of 2-acetylaminomethyl-1,4-dibenzylpiperazine are obtained.
実施例１
４−アミノ−Ｎ−［（４−ベンジル−１，４−チオモル
ホリン−２−イル）メチル］−５−クロロー２−エトキ
シベンズアミドの製造：
２−アセチルアミノメチル−４−ベンジル−１゜４−チ
オモルホリン３．６ｇを１０％塩酸３６１に溶解し、４
時間加熱還流する。冷暖、４８％水酸化ナトリウム水溶
液でアルカリ性とし、クロロホルムで抽出する。有機層
を水洗し、無水硫酸マグネシウムで乾燥した後、溶媒を
留去して油状物２．５ｇを得る。これを塩化メチレン３
０−１に溶解し、４−アミノ−５−クロロ−２−エトキ
シ安息香ｆｆ１２．４ｇとｌ−エチル−３−（３−ジメ
チルアミノプロピル）カルボジイミド塩酸塩２．２ｇを
加え、室温で２時間撹拌する。反応液を水洗し、無水硫
酸マグネシウムで乾燥したのち溶媒を留去する。残渣を
メタノールから再結晶して目的物の１／４水和物２．８
ｇを得る。融点１３３〜１３５℃実施例２
４−アミノ−Ｎ−［（４−ベンジル−１，４−チオモル
ホリ／−２−イル）メチル］−５−クロロー２−メトキ
ンベンズアミドの製造：
実施例１における４−アミノ−５−クロロ−２−エトキ
シ安息香酸の代りに４−アミノ−５−クロロ−２−メト
キシ安息香酸を用い、実施例１と同様に反応・処理して
目的物の１／４水和物を得る。Example 1 Preparation of 4-amino-N-[(4-benzyl-1,4-thiomorpholin-2-yl)methyl]-5-chloro-2-ethoxybenzamide: 2-acetylaminomethyl-4-benzyl-1゜Dissolve 3.6 g of 4-thiomorpholine in 10% hydrochloric acid 361,
Heat to reflux for an hour. Cool and warm, make alkaline with 48% aqueous sodium hydroxide solution, and extract with chloroform. After washing the organic layer with water and drying over anhydrous magnesium sulfate, the solvent was distilled off to obtain 2.5 g of an oily substance. Add this to methylene chloride 3
0-1, add 12.4 g of 4-amino-5-chloro-2-ethoxybenzoic ff and 2.2 g of l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, and stir at room temperature for 2 hours. do. The reaction solution was washed with water, dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The residue was recrystallized from methanol to obtain 1/4 hydrate of the target product, 2.8
get g. Melting point: 133-135°C Example 2 Preparation of 4-amino-N-[(4-benzyl-1,4-thiomorphol/-2-yl)methyl]-5-chloro-2-methquine benzamide: 4 in Example 1 - Using 4-amino-5-chloro-2-methoxybenzoic acid instead of amino-5-chloro-2-ethoxybenzoic acid, the reaction and treatment were carried out in the same manner as in Example 1 to achieve 1/4 hydration of the target product. get something
ａ点１３２〜１３４℃（メタノール−ジエチルエーテル
から再結晶）
実施例３
４−アミノ−Ｎ−（４−ベンジル−ヘキサヒドロ−１，
４−チアゼピン−６−イル）−５−クロロ−２−エトキ
シベンズアミドの製造：
実施例１における２−アセチルアミ／メチル−４−ベン
ジル−１，４−チオモルホリンの代りに６−アセチルア
ミノ−４−ベンジル−ヘキサヒドロ−１，４−チアゼピ
ンを用い、実施例１と同様に反応・処理して目的物を得
る。これを常法によりフマル酸で処理して目的物の３７
２フマル酸塩・１／２水和物を得る。融点９２〜９５℃
（酢酸エチルから再結晶）
実施例４
４−アミノ−５−クロロ−Ｎ−（１，４−ジベンジル−
へキサヒドロ−１，４−ジアゼピン−６−イル）−２−
エトキシベンズアミドの製造：実施例１における２−ア
セチルアミノメチル−４−ベンジル−１，４−チオモル
ホリンの代りに６−アセチルアミノ−１，４−ジベンジ
ル−へキサヒドロ−１，４−ジアゼピンを用い、実施例
１と同様に反応・処理して目的物の１７２水和物を得る
。Point a 132-134°C (recrystallized from methanol-diethyl ether) Example 3 4-Amino-N-(4-benzyl-hexahydro-1,
Preparation of 4-thiazepin-6-yl)-5-chloro-2-ethoxybenzamide: 6-acetylamino-4-instead of 2-acetylamino/methyl-4-benzyl-1,4-thiomorpholine in Example 1 Using benzyl-hexahydro-1,4-thiazepine, the reaction and treatment are carried out in the same manner as in Example 1 to obtain the desired product. This was treated with fumaric acid in a conventional manner to obtain the desired product, 37
Difumarate 1/2 hydrate is obtained. Melting point 92-95℃
(Recrystallized from ethyl acetate) Example 4 4-Amino-5-chloro-N-(1,4-dibenzyl-
hexahydro-1,4-diazepin-6-yl)-2-
Production of ethoxybenzamide: using 6-acetylamino-1,4-dibenzyl-hexahydro-1,4-diazepine in place of 2-acetylaminomethyl-4-benzyl-1,4-thiomorpholine in Example 1, The reaction and treatment are carried out in the same manner as in Example 1 to obtain the target product, 172-hydrate.
融点１３５〜１３７℃（エタノールから再結晶）実施例
５
４−アミノ−Ｎ−（４−ベンジル−ヘキサヒドロ−１，
４−オキサゼピン−６−イル）−５−クロロ−２−エト
キシベンズアミドの製造：実施例１における２−アセチ
ルアミノメチル−４−ベンジル−１，４−チオモルホリ
ンの代りに６−アセチルアミノ−４−ベンジル−ヘキサ
ヒドロ−１，４−オキサゼピ／を用い、実施例１と同様
に反応・処理して目的物を得る。これを常法によりフマ
ル酸で処理して目的物のフマル酸塩を得る。Melting point 135-137°C (recrystallized from ethanol) Example 5 4-Amino-N-(4-benzyl-hexahydro-1,
Preparation of 4-oxazepin-6-yl)-5-chloro-2-ethoxybenzamide: 6-acetylamino-4-in place of 2-acetylaminomethyl-4-benzyl-1,4-thiomorpholine in Example 1 Using benzyl-hexahydro-1,4-oxazepi/, the reaction and treatment are carried out in the same manner as in Example 1 to obtain the desired product. This is treated with fumaric acid in a conventional manner to obtain the target fumarate salt.
融点１３７〜１３８℃（エタノールから再結晶）実施例
６
５− ［Ｎ−（４−ベンジル−へキサヒドロ−１゜４−
チアゼピン−６−イル）］］カルバモイルー６−メドキ
シーＩＨ−ベンゾトリアゾールの製造：実施例１におけ
る２−アセチルアミノメチル−４−ベンジル−１，４−
チオモルホリンと４−７ミノー５−クロロ−２−エトキ
シ安息香酸の代りにそれぞれ、６−アセチルアミノ−４
−ベンジル−ヘキサヒドロ−１，４−チアゼピンと５−
カルボキシ−６−メドキシー１ ）１−ベンゾトリアゾ
ールを用い、実施例１と同様に反応・処理して目的物を
得る。これを常法によりフマル酸で処理して目的物の３
１２フマル酸塩・１ ／４ ＥｔＯＨ−１／４水和物を
得る。融点１６５〜１０８℃（エタノールから再結晶）
実施例７
４−アミノ−Ｎ−［（１−ベンジル−３−ピペリジル）
メチルコー５−クロロー２−エトキシベ／ズアミドの製
造：
３−アミノメチル−１−ベンジルピペリジン２．４ｇの
塩化メチレノ５０１溶液に、４−アミノ−５−クロロ−
２−エトキシ安息香酸２．５ｇ、次いで１−エチル−３
−（３−ジメチルアミノプロピル）カルボジイミド塩酸
塩２．３ｇを加え、室温で４ｒｉ１間撹拌する０反応液
を水、水酸化ナトリウム水溶液、水、飽和食塩水の順で
洗浄し、無水硫酸マグネシウムで乾燥したのち溶媒を留
去する。残渣をシリカゲルのカラムクロマトグラフィー
に付し、クロロホルム−メタノール（９： １） テ溶
出・精製する。得られる油吠の目的物３．０ｇをエタノ
ールに溶解し、シュウ酸のエタノール溶液を加えて室温
で放置すると目的物の３／２シユウ酸塩・３／４ 〜水
和物が得られる。融点１０３〜１０５℃（エタノールか
ら再結晶）
実施例８
４−アミノ−５−クロロ−Ｎ−［（１，４−ジエチル−
２−ピペラジニル）メチル］−２−エトキシベンズアミ
ドの製造：
実施例７における３−アミノメチル−１−ベンジルピペ
リジンの代りに２−アミノメチル−１，４−ジエチルビ
ベラジンを用い、実施例７と同様に反応・処理して目的
物を得る。これを常法によりフマル酸で処理して目的物
のフマル酸塩を得る。Melting point: 137-138°C (recrystallized from ethanol) Example 6 5-[N-(4-benzyl-hexahydro-1°4-
Preparation of carbamoyl-6-medoxy IH-benzotriazole: 2-acetylaminomethyl-4-benzyl-1,4- in Example 1
6-acetylamino-4 instead of thiomorpholine and 4-7minor 5-chloro-2-ethoxybenzoic acid, respectively.
-benzyl-hexahydro-1,4-thiazepine and 5-
Carboxy-6-medoxy 1) Using 1-benzotriazole, the reaction and treatment are carried out in the same manner as in Example 1 to obtain the desired product. This was treated with fumaric acid in a conventional manner to obtain the desired product, 3
12 fumarate 1/4 EtOH-1/4 hydrate is obtained. Melting point 165-108°C (recrystallized from ethanol) Example 7 4-Amino-N-[(1-benzyl-3-piperidyl)
Production of methylco-5-chloro-2-ethoxybe/zamide: 4-amino-5-chloro-
2.5 g of 2-ethoxybenzoic acid, then 1-ethyl-3
Add 2.3 g of -(3-dimethylaminopropyl)carbodiimide hydrochloride and stir at room temperature for 4 days. The reaction solution is washed with water, an aqueous sodium hydroxide solution, water, and saturated brine in that order, and dried over anhydrous magnesium sulfate. Afterwards, the solvent is distilled off. The residue was purified by column chromatography on silica gel, eluting with chloroform-methanol (9:1). When 3.0 g of the obtained oil-based target compound is dissolved in ethanol, an ethanol solution of oxalic acid is added, and the mixture is allowed to stand at room temperature, 3/2 oxalate 3/4 to 3/4 hydrate of the target compound is obtained. Melting point 103-105°C (recrystallized from ethanol) Example 8 4-Amino-5-chloro-N-[(1,4-diethyl-
Production of 2-piperazinyl)methyl]-2-ethoxybenzamide: Same as Example 7, using 2-aminomethyl-1,4-diethylbiverazine in place of 3-aminomethyl-1-benzylpiperidine in Example 7. React and process to obtain the desired product. This is treated with fumaric acid in a conventional manner to obtain the target fumarate salt.
融点２０８〜２１０℃（メタノールから再結晶）実施例
９
４−アミノ−Ｎ−［（１−ベンジル−４−メチル−２−
ピペラジニル）メチル］−５−クロロー２−エトキシベ
／ズアミドの製造：
実施例７における３−アミノメチル−１−べ／ジルピペ
リジンの代りに２−アミノメチル−１−ベンジル−４−
メチルピペラジンを用い、実施例７と同様に反応・処理
して目的物を得る。Melting point 208-210°C (recrystallized from methanol) Example 9 4-Amino-N-[(1-benzyl-4-methyl-2-
Preparation of 2-aminomethyl-1-benzyl-4-piperidine in place of 3-aminomethyl-1-be/zylpiperidine in Example 7.
Using methylpiperazine, the reaction and treatment are carried out in the same manner as in Example 7 to obtain the desired product.
融点１９９〜２０１’Ｃ（エタノールから再結晶）実施
例１０
４−アミノ−５−りＣ’０−Ｎ−［（１，４−ジベ／ジ
ル−２−ピペラジニル）メチル］−２−メトキシベンズ
アミドの製造：
実施例７における３−アミノメチル−１−ベンジルピペ
リジンと４−アミノ−５−クロロ−２−エトキシ安息香
酸の代りにそれぞれ、２−アミノメチル−１，４−ジベ
ンジルピペラジンと４−アミノ−５−クロロ−２−メト
キシ安息香酸を用い、実施例７と同様に反応・処理して
目的物のシュウ酸塩・１水和物を得る。融点１０３〜１
１０℃（エタノール−ジエチルエーテルから再結晶）実
施例１１
４−アミノ−５−クロロ−Ｎ−［（１，４−ジベンジル
−２−ピペラジニル）メチル］−２−エトキシベンズア
ミドの製造：
実施例７における３−アミノメチル−１−ベンジルピペ
リジンの代りに２−アミノメチル−１，４−ジベンジル
ピペラジ／を用い、実施例７と同様に反応・処理して目
的物のシュウ酸塩・１水和物を得る。 融点９８〜１０
２℃（エタノール−ジエチルエーテルから再結晶）
実施例１２
４−アミノ−Ｎ−［（１−ベンジル−３−ピペリジル）
メチル］−５−クロロー２−メトキシベンズアミドの製
造：
実施例７における４−アミノ−５−クロロ−２−エトキ
シ安息香酸の代りに４−アミノ−５−クロロ−２−メト
キシ安息香酸を用い、実施例７と同様に反応・処理して
目的物の３／２シユウ酸塩・１水和物を得る。融点１０
４〜１０７℃（エタノールから再結晶）
実施例１３
４−アミノ−Ｎ−［（１−ベンジル−１，２，５，８−
テトラヒドロピリジン−３−イル）メチル］−５−クロ
ロー２−エトキシベンズアミドの製造：実施例７におけ
る３−アミノメチル−１−ベンジルピペリジンの代りに
３−アミノメチル−１−ベンジル−１，２，５，８−テ
トラヒドロピリジンを用い、実施例７と同様に反応・処
理して目的物を得る。融点＋４４− ＋４７°Ｃ（エタ
ノール−トルエンから再結晶）
実施例１４
４−アミノ−Ｎ−［（１−ベンジル−１，、２，５，６
−テトラヒドロピリジン−３−イル）メチル］−５−ク
ロロー２−メトキシベンズアミドの製造：実施例７にお
ける３−アミ／メチル−１−べ／ジルピペリジンと４−
アミノ−５−クロロ−２−エトキシ安息香酸の代りにそ
れぞれ、３−アミノメチル−１−ベンジル−１，２，５
，６−テトラヒドロピリジンと４−アミノ−５−クロロ
−２−メトキシ安息香酸を用い、実施例７と同様に反応
・処理して目的物を得る。融点１４７〜１５０℃（エタ
ノール−トルエンから再結晶）
実施例１５〜１９
対応する原料化合物を用い、実施例７と同様に反応・処
理して表２に示す化合物を得る。Melting point 199-201'C (recrystallized from ethanol) Example 10 4-amino-5-riC'0-N-[(1,4-dibe/zyl-2-piperazinyl)methyl]-2-methoxybenzamide Production: 2-aminomethyl-1,4-dibenzylpiperazine and 4-amino in place of 3-aminomethyl-1-benzylpiperidine and 4-amino-5-chloro-2-ethoxybenzoic acid in Example 7, respectively. Using -5-chloro-2-methoxybenzoic acid, the reaction and treatment are carried out in the same manner as in Example 7 to obtain the desired product, oxalate monohydrate. Melting point 103~1
10°C (recrystallized from ethanol-diethyl ether) Example 11 Preparation of 4-amino-5-chloro-N-[(1,4-dibenzyl-2-piperazinyl)methyl]-2-ethoxybenzamide: In Example 7 Using 2-aminomethyl-1,4-dibenzylpiperazine in place of 3-aminomethyl-1-benzylpiperidine, the reaction and treatment were carried out in the same manner as in Example 7 to obtain the desired product, oxalate monohydrate. get something Melting point 98-10
2°C (recrystallized from ethanol-diethyl ether) Example 12 4-Amino-N-[(1-benzyl-3-piperidyl)
Production of methyl]-5-chloro-2-methoxybenzamide: Performed using 4-amino-5-chloro-2-methoxybenzoic acid in place of 4-amino-5-chloro-2-ethoxybenzoic acid in Example 7. The reaction and treatment were carried out in the same manner as in Example 7 to obtain the desired product, 3/2 oxalate monohydrate. melting point 10
4-107°C (recrystallized from ethanol) Example 13 4-Amino-N-[(1-benzyl-1,2,5,8-
Preparation of tetrahydropyridin-3-yl)methyl]-5-chloro-2-ethoxybenzamide: 3-aminomethyl-1-benzyl-1,2,5 in place of 3-aminomethyl-1-benzylpiperidine in Example 7 , 8-tetrahydropyridine and the same reaction and treatment as in Example 7 to obtain the desired product. Melting point +44- +47°C (recrystallized from ethanol-toluene) Example 14 4-Amino-N-[(1-benzyl-1,,2,5,6
-tetrahydropyridin-3-yl)methyl]-5-chloro-2-methoxybenzamide: 3-ami/methyl-1-be/zylpiperidine and 4-
3-aminomethyl-1-benzyl-1,2,5 in place of amino-5-chloro-2-ethoxybenzoic acid, respectively.
, 6-tetrahydropyridine and 4-amino-5-chloro-2-methoxybenzoic acid are reacted and treated in the same manner as in Example 7 to obtain the desired product. Melting point: 147-150°C (recrystallized from ethanol-toluene) Examples 15-19 Using the corresponding raw material compounds, the compounds shown in Table 2 were obtained by reacting and treating in the same manner as in Example 7.
表２において記載の簡略化のために以下の略号を使用す
る。The following abbreviations are used in Table 2 to simplify the description.
Ｍｅ ：メチル基
Ｅｔ：エチル基
Ｐｈ：フェニル基
Ａ ：エタノール
ＩＰ ：イソプロビルアルコール
Ｍ ：メタノール
（以下余白）
表２
Ｈ２Ｐｈ
′） Ｒ４の立体配！（相対）ニドランス１） マス・
スベク） ルｍ／ ｚ ： ４１５ （Ｍ” ）”’）
Ｒ４の立体配二（相対）、シス実施例２０
４−アミノ−Ｎ −［（４−ベンジル−１，４−チオモ
ルホリ／−１−オキシド−２−イル）メチル］−５−ク
ロロー２−エトキシベンズアミドの製造＝４−アミノ−
Ｎ−［（４−べ／ジルー１，４−チオモルホリンー２−
イル）メチル］−５−クロロー２−エトキンベ／ズアミ
ド１．１ ｇを塩化メチレン２０１に溶解し、食塩−水
で冷却しながら、ｍ−クロ口過安息香１１０．０２ｇを
加え、１時間撹拌する。Me: Methyl group Et: Ethyl group Ph: Phenyl group A: Ethanol IP: Isopropyl alcohol M: Methanol (blank below) Table 2 H2Ph') Configuration of R4! (Relative) Nidorance 1) Mass・
m/z: 415 (M")"')
Configuration (relative) of R4, cis Example 20 4-Amino-N-[(4-benzyl-1,4-thiomorphol/-1-oxid-2-yl)methyl]-5-chloro2-ethoxybenzamide Production of = 4-amino-
N-[(4-be/girou 1,4-thiomorpholine-2-
1.1 g of methyl]-5-chloro-2-ethquimbe/zamide is dissolved in 201 g of methylene chloride, and while cooling with brine-water, 110.02 g of m-chloroperbenzoate is added and stirred for 1 hour.
反応液に飽和重炭酸ナトリウム水溶液を加え、クロロホ
ルムで抽出する。打機層を水洗し、無水硫酸マグネシウ
ムで乾燥したのち溶媒を留去する。Add saturated aqueous sodium bicarbonate solution to the reaction mixture, and extract with chloroform. The batter layer is washed with water, dried over anhydrous magnesium sulfate, and then the solvent is distilled off.
残渣をシリカゲルのカラムクロマトグラフィーに付し、
クロロホルム−メタノール（２０：１）で溶出・精製し
、得られる油状物をイソプロピルアルコールから再結晶
して目的物０．３ｇを得る。The residue was subjected to silica gel column chromatography,
Elution and purification are performed with chloroform-methanol (20:1), and the resulting oil is recrystallized from isopropyl alcohol to obtain 0.3 g of the desired product.
融点１９３〜１９５℃
実施例２１
４−アミノ−Ｎ−［（４−ベンジル−１，４−チオモル
ホリン−１，１−ジオキシド−２−イル）メヂル］−５
−クロロー２−エトキシベンズアミドの製造：
４−アミノ−Ｎ −［（４−ベンジル−１，４−チオモ
ルホリン−２−イル）メチルゴー５−クロＩ′ｊ−２−
エトキシベンズアミド０．５ｇを塩化メチレン１０■Ｉ
に溶解し、水冷下ｍ−クロロ過安息香酸０．４５ｇを加
え、室温に戻し１７時間撹拌する。反応液に飽和重炭酸
ナトリウム水溶液を加え、クロロホルムで抽出する。有
機層を水洗し、無水硫酸マグネシウムで乾燥したのち溶
媒を留去する。残渣をアセトン−エタノールから再結晶
して目的物０．４ｇを得る。融点１９３〜１９８℃
特許出願人 大日本製薬株式会社
代 理 人 小 島 −兄弟１頁の続きMelting point 193-195°C Example 21 4-Amino-N-[(4-benzyl-1,4-thiomorpholin-1,1-dioxid-2-yl)medyl]-5
-Production of chloro-2-ethoxybenzamide: 4-amino-N-[(4-benzyl-1,4-thiomorpholin-2-yl)methylgo-5-chloroI'j-2-
0.5 g of ethoxybenzamide in 10 I of methylene chloride
0.45 g of m-chloroperbenzoic acid was added under water cooling, and the mixture was returned to room temperature and stirred for 17 hours. Add saturated aqueous sodium bicarbonate solution to the reaction mixture, and extract with chloroform. The organic layer is washed with water, dried over anhydrous magnesium sulfate, and then the solvent is distilled off. The residue is recrystallized from acetone-ethanol to obtain 0.4 g of the desired product. Melting point: 193-198℃ Patent applicant: Dainippon Pharmaceutical Co., Ltd. Representative: Kojima - Brothers Continued from page 1
Claims (1)
リール（低級）アルキル基を意味し、Ｒ＿２はヒドロキ
シ基、アルコキシ基、アルケニルオキシ基，シクロアル
キルオキシ基又は置換基を有するアルコキシ基（該置換
基はハロゲン原子、ヒドロキシ基又はオキソ基である）
を意味し、Ｒ＿３はアミノ基、ジ置換アミノ基又はアシ
ルアミノ基を意味し、Ｒ＾４はハロゲン原子を意味する
か、あるいはＲ＿３とＲ＿４が一緒になって−ＮＨ−Ｎ
＝Ｎ−を形成してもよく、Ｒ＿５は水素原子又は低級ア
ルキル基を意味し、Ｘは単結合又は低級アルキレン基を
意味し、Ｙは単結合、−ＣＨ＿２−、−Ｏ−、−Ｓ−、
▲数式、化学式、表等があります▼、▲数式、化学式、
表等があります▼又は▲数式、化学式、表等があります
▼（Ｒ＿６は低級アルキル基又は非置換もしくは置換ア
リール（低級）アルキル基を意味するか、あるいはＲ＿
１と一緒になってエチレン基を形成してもよい）を意味
し、ｎは０又は１を意味し、破線はＹが−ＣＨ＿２−で
ｎが０であるときに場合により存在する二重結合を意味
する。但し、（ｉ）Ｙが単結合であるとき、ｎは０を意
味し、（ｉｉ）Ｙが−Ｏ−であるとき、ｎは１を意味し
、（ｉｉｉ）Ｙが単結合又は−ＣＨ＿２−であるとき、
Ｒ＿１は非置換もしくは置換アリール（低級）アルキル
基を意味し、（ｉｖ）ｎが０であるとき、Ｘは低級アル
キレン基を意味する。］ で表される安息香酸アミド誘導体及びその酸付加塩類。[Claims] General formula ▲ Numerical formulas, chemical formulas, tables, etc. Oxy group, cycloalkyloxy group or alkoxy group having a substituent (the substituent is a halogen atom, hydroxy group or oxo group)
, R_3 means an amino group, a di-substituted amino group or an acylamino group, and R^4 means a halogen atom, or R_3 and R_4 together represent -NH-N
=N- may be formed, R_5 means a hydrogen atom or a lower alkyl group, X means a single bond or a lower alkylene group, Y is a single bond, -CH_2-, -O-, -S- ,
▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲Mathematical formulas, chemical formulas,
There are tables, etc. ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (R_6 means a lower alkyl group or an unsubstituted or substituted aryl (lower) alkyl group, or R_
(may be taken together with 1 to form an ethylene group), n means 0 or 1, and the dashed line indicates a double bond that is optionally present when Y is -CH_2- and n is 0. means. However, (i) when Y is a single bond, n means 0, (ii) when Y is -O-, n means 1, (iii) when Y is a single bond or -CH_2- When
R_1 means an unsubstituted or substituted aryl (lower) alkyl group, and (iv) when n is 0, X means a lower alkylene group. ] Benzoic acid amide derivatives and acid addition salts thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP27636987A JPH01117860A (en) | 1987-10-30 | 1987-10-30 | Benzoic acid amide derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP27636987A JPH01117860A (en) | 1987-10-30 | 1987-10-30 | Benzoic acid amide derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH01117860A true JPH01117860A (en) | 1989-05-10 |
Family
ID=17568472
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP27636987A Pending JPH01117860A (en) | 1987-10-30 | 1987-10-30 | Benzoic acid amide derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH01117860A (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0358903A2 (en) * | 1988-07-29 | 1990-03-21 | Dainippon Pharmaceutical Co., Ltd. | Indazole-3-carboxylic acid derivatives |
| WO1998007710A1 (en) * | 1996-08-23 | 1998-02-26 | Neurosearch A/S | Disubstituted morpholine, oxazepine or thiazepine derivatives, their preparation and their use as dopamine d4 receptor antagonists |
| EP0873990A1 (en) * | 1995-09-22 | 1998-10-28 | Yoshitomi Pharmaceutical Industries, Ltd. | Benzoic acid compounds and medicinal use thereof |
| US6166015A (en) * | 1998-11-20 | 2000-12-26 | Syntex (U.S.A.) Inc. | Pyrrolidine derivatives-CCR-3 receptor antagonists |
-
1987
- 1987-10-30 JP JP27636987A patent/JPH01117860A/en active Pending
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0358903A2 (en) * | 1988-07-29 | 1990-03-21 | Dainippon Pharmaceutical Co., Ltd. | Indazole-3-carboxylic acid derivatives |
| EP0873990A1 (en) * | 1995-09-22 | 1998-10-28 | Yoshitomi Pharmaceutical Industries, Ltd. | Benzoic acid compounds and medicinal use thereof |
| EP0873990A4 (en) * | 1995-09-22 | 1998-12-02 | ||
| WO1998007710A1 (en) * | 1996-08-23 | 1998-02-26 | Neurosearch A/S | Disubstituted morpholine, oxazepine or thiazepine derivatives, their preparation and their use as dopamine d4 receptor antagonists |
| US6207662B1 (en) | 1996-08-23 | 2001-03-27 | Neurosearch A/S | Disubstituted morpholine, oxazepine or thiazepine derivatives, their preparation and their use as dopamine D4 receptor antagonists |
| US6479491B1 (en) | 1996-08-23 | 2002-11-12 | Neurosearch A/S | Disubstituted morpholine, oxazepine or thiazepine derivatives, their preparation and their use as dopamine d4 receptor antagonists |
| US6166015A (en) * | 1998-11-20 | 2000-12-26 | Syntex (U.S.A.) Inc. | Pyrrolidine derivatives-CCR-3 receptor antagonists |
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