JPH02104572A - Benzoic acid amide derivative - Google Patents
Benzoic acid amide derivativeInfo
- Publication number
- JPH02104572A JPH02104572A JP25766588A JP25766588A JPH02104572A JP H02104572 A JPH02104572 A JP H02104572A JP 25766588 A JP25766588 A JP 25766588A JP 25766588 A JP25766588 A JP 25766588A JP H02104572 A JPH02104572 A JP H02104572A
- Authority
- JP
- Japan
- Prior art keywords
- group
- benzyl
- amino
- formula
- solvent
- 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 10
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 20
- 239000002253 acid Substances 0.000 claims abstract description 18
- 150000003839 salts Chemical class 0.000 claims abstract description 15
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 9
- 125000005843 halogen group Chemical group 0.000 claims abstract description 7
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 6
- 125000004442 acylamino group Chemical group 0.000 claims abstract description 4
- 125000003302 alkenyloxy group Chemical group 0.000 claims abstract description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- 125000001424 substituent group Chemical group 0.000 claims description 8
- 125000003277 amino group Chemical group 0.000 claims description 7
- 125000003107 substituted aryl 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
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- -1 di-substituted amino Chemical group 0.000 abstract description 58
- 150000001875 compounds Chemical class 0.000 abstract description 41
- 238000002360 preparation method Methods 0.000 abstract description 15
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 abstract description 13
- 125000003118 aryl group Chemical group 0.000 abstract description 6
- 206010047700 Vomiting Diseases 0.000 abstract description 3
- 239000002111 antiemetic agent Substances 0.000 abstract description 3
- 239000002246 antineoplastic agent Substances 0.000 abstract description 2
- 229940041181 antineoplastic drug Drugs 0.000 abstract description 2
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 abstract description 2
- 229960004316 cisplatin Drugs 0.000 abstract description 2
- 229940079593 drug Drugs 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract description 2
- 230000008673 vomiting Effects 0.000 abstract description 2
- 229910052736 halogen Inorganic materials 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 230000003449 preventive effect Effects 0.000 abstract 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 60
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 52
- 239000000243 solution Substances 0.000 description 49
- 239000002904 solvent Substances 0.000 description 49
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 46
- 239000000047 product Substances 0.000 description 41
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 39
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 39
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 34
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 30
- 238000006243 chemical reaction Methods 0.000 description 28
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 27
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 27
- 238000002844 melting Methods 0.000 description 25
- 230000008018 melting Effects 0.000 description 25
- 238000003756 stirring Methods 0.000 description 25
- 238000001816 cooling Methods 0.000 description 23
- 238000004519 manufacturing process Methods 0.000 description 23
- 238000010898 silica gel chromatography Methods 0.000 description 22
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 21
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 21
- 238000001035 drying Methods 0.000 description 20
- 239000012044 organic layer Substances 0.000 description 20
- 239000000203 mixture Substances 0.000 description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 238000010992 reflux Methods 0.000 description 18
- 238000005406 washing Methods 0.000 description 17
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 15
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 14
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 12
- 125000004432 carbon atom Chemical group C* 0.000 description 10
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 10
- 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 9
- 238000000034 method Methods 0.000 description 9
- 150000008065 acid anhydrides Chemical class 0.000 description 8
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 8
- 239000003921 oil Substances 0.000 description 8
- 235000019198 oils Nutrition 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
- 238000010828 elution Methods 0.000 description 7
- 239000005457 ice water Substances 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 7
- 235000017557 sodium bicarbonate Nutrition 0.000 description 7
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- BYNIUBOJBWXZCC-UHFFFAOYSA-N (1-benzylpiperidin-3-yl)methanamine Chemical compound C1C(CN)CCCN1CC1=CC=CC=C1 BYNIUBOJBWXZCC-UHFFFAOYSA-N 0.000 description 6
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-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
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 5
- 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 4
- 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
- JEDZLBFUGJTJGQ-UHFFFAOYSA-N [Na].COCCO[AlH]OCCOC Chemical compound [Na].COCCO[AlH]OCCOC JEDZLBFUGJTJGQ-UHFFFAOYSA-N 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- PSLIMVZEAPALCD-UHFFFAOYSA-N ethanol;ethoxyethane Chemical compound CCO.CCOCC PSLIMVZEAPALCD-UHFFFAOYSA-N 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 239000001530 fumaric acid Substances 0.000 description 4
- 230000002496 gastric effect Effects 0.000 description 4
- 230000007661 gastrointestinal function Effects 0.000 description 4
- 229960003531 phenolsulfonphthalein Drugs 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 239000012419 sodium bis(2-methoxyethoxy)aluminum hydride Substances 0.000 description 4
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 230000030136 gastric emptying Effects 0.000 description 3
- 239000012280 lithium aluminium hydride Substances 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 235000011181 potassium carbonates Nutrition 0.000 description 3
- 210000002784 stomach Anatomy 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
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 2
- 125000006012 2-chloroethoxy group Chemical group 0.000 description 2
- BCFJSWISQLQWTQ-UHFFFAOYSA-N 3-amino-5-chloro-2-methoxybenzoic acid Chemical compound COC1=C(N)C=C(Cl)C=C1C(O)=O BCFJSWISQLQWTQ-UHFFFAOYSA-N 0.000 description 2
- 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 2
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 2
- 241000416162 Astragalus gummifer Species 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
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- 208000007882 Gastritis Diseases 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-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
- 229920001615 Tragacanth Polymers 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 229940125683 antiemetic agent Drugs 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
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 2
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 125000004803 chlorobenzyl group Chemical group 0.000 description 2
- OQNGCCWBHLEQFN-UHFFFAOYSA-N chloroform;hexane Chemical compound ClC(Cl)Cl.CCCCCC OQNGCCWBHLEQFN-UHFFFAOYSA-N 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
- NJSUFZNXBBXAAC-UHFFFAOYSA-N ethanol;toluene Chemical compound CCO.CC1=CC=CC=C1 NJSUFZNXBBXAAC-UHFFFAOYSA-N 0.000 description 2
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 239000000706 filtrate Substances 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
- 239000008187 granular material Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 150000004678 hydrides Chemical class 0.000 description 2
- 239000010410 layer Substances 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
- 150000002688 maleic acid derivatives Chemical class 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 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 2
- QCYNCKWLMOYESQ-UHFFFAOYSA-N n-[(1,4-dimethylpiperazin-2-yl)methyl]acetamide Chemical compound CN1CCN(C)C(CNC(C)=O)C1 QCYNCKWLMOYESQ-UHFFFAOYSA-N 0.000 description 2
- 150000003891 oxalate salts Chemical class 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 230000001737 promoting effect Effects 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 239000000196 tragacanth Substances 0.000 description 2
- 235000010487 tragacanth Nutrition 0.000 description 2
- 229940116362 tragacanth Drugs 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
- DKWRQRNCULDABS-UHFFFAOYSA-N (1-benzylpiperidin-2-yl)methanamine Chemical compound NCC1CCCCN1CC1=CC=CC=C1 DKWRQRNCULDABS-UHFFFAOYSA-N 0.000 description 1
- KHPWHJVKPZIZRG-UHFFFAOYSA-N (1-benzylpiperidin-2-yl)methanol Chemical compound OCC1CCCCN1CC1=CC=CC=C1 KHPWHJVKPZIZRG-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
- NZVZVGPYTICZBZ-UHFFFAOYSA-N 1-benzylpiperidine Chemical compound C=1C=CC=CC=1CN1CCCCC1 NZVZVGPYTICZBZ-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
- BFSVOASYOCHEOV-UHFFFAOYSA-N 2-diethylaminoethanol Chemical group CCN(CC)CCO BFSVOASYOCHEOV-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
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-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
- GWYFCOCPABKNJV-UHFFFAOYSA-M 3-Methylbutanoic acid Natural products CC(C)CC([O-])=O GWYFCOCPABKNJV-UHFFFAOYSA-M 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
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 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
- 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
- 239000005725 8-Hydroxyquinoline Substances 0.000 description 1
- 206010000060 Abdominal distension Diseases 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
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical class OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 206010010774 Constipation Diseases 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- 241000252233 Cyprinus carpio Species 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 206010018045 Gastroptosis Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
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- 125000005236 alkanoylamino group Chemical group 0.000 description 1
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- GWYFCOCPABKNJV-UHFFFAOYSA-N beta-methyl-butyric acid Natural products CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
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- 238000000605 extraction Methods 0.000 description 1
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- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
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- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
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- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
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- 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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- 229960004503 metoclopramide Drugs 0.000 description 1
- TTWJBBZEZQICBI-UHFFFAOYSA-N metoclopramide Chemical compound CCN(CC)CCNC(=O)C1=CC(Cl)=C(N)C=C1OC TTWJBBZEZQICBI-UHFFFAOYSA-N 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- ZUSSTQCWRDLYJA-UHFFFAOYSA-N n-hydroxy-5-norbornene-2,3-dicarboximide Chemical compound C1=CC2CC1C1C2C(=O)N(O)C1=O ZUSSTQCWRDLYJA-UHFFFAOYSA-N 0.000 description 1
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- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
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- AHWALFGBDFAJAI-UHFFFAOYSA-N phenyl carbonochloridate Chemical compound ClC(=O)OC1=CC=CC=C1 AHWALFGBDFAJAI-UHFFFAOYSA-N 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- NMHMNPHRMNGLLB-UHFFFAOYSA-N phloretic acid Chemical compound OC(=O)CCC1=CC=C(O)C=C1 NMHMNPHRMNGLLB-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- PRAYXGYYVXRDDW-UHFFFAOYSA-N piperidin-2-ylmethanol Chemical compound OCC1CCCCN1 PRAYXGYYVXRDDW-UHFFFAOYSA-N 0.000 description 1
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- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000001226 reprecipitation Methods 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
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- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 239000013077 target material Substances 0.000 description 1
- 239000013076 target substance Substances 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- 150000004685 tetrahydrates Chemical class 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 229910052719 titanium Inorganic materials 0.000 description 1
- 239000010936 titanium Substances 0.000 description 1
- 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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Abstract
Description
【発明の詳細な説明】
Δ菜上夏封里分■
本発明は、消化管機能亢進作用を有する新規で有用な安
息香酸アミド誘導体に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a new and useful benzoic acid amide derivative having a gastrointestinal function-enhancing effect.
鉋米少栽藷
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［一般名 メト
クロプラミド；例えばＭｅｒｃｋＩｎｄｅｘ、第１Ｏ版
、 ｔｉ０１９ （１９８３）参照］が１９Ｅｉｏ年代
の半ばに制吐剤あるいは消化管機能元進剤として開発さ
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く例えば特公昭４
４−２３４９６号、特開昭５２−３１０４１号。4-amino-5-chloro-N-[(2-diethylamino)ethyl]-2-methoxybenzamide [generic name metoclopramide; see for example Merck Index, 1st O edition, ti019 (1983)] was introduced in the 19Eio Since they were developed as antiemetics or gastrointestinal function promoters in the mid-1990s, various substituted benzoic acid amide derivatives have been synthesized and their pharmacological properties have been studied.
No. 4-23496, JP-A-52-31041.
同５２−８３３６４号、同５２−８３７３７号参照）。(See Nos. 52-83364 and 52-83737).
本２１Ｂ欠は的
本発明は、優れた消化管機能亢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。DISCLOSURE OF THE INVENTION The present invention provides benzoic acid amide derivatives having an excellent effect of enhancing gastrointestinal function.
本発明によれば、−数式（Ｉ）
［式中、Ｒ８は低級アルキル基又は非置換もしくは置換
基を有するアリール（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、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。According to the present invention - formula (I) [wherein R8 means a lower alkyl group or an unsubstituted or substituted aryl (lower) alkyl group, R2 is a hydroxy group, an alkoxy group, an alkenyloxy group, It means a cycloalkyloxy group or an alkoxy group having a substituent (the substituent is a halogen atom, a hydroxy group, or an oxo group).
Ｒ３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、
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−ＮＨ−Ｎ＝Ｎ−を形成してもよく、
Ｒ５は水素原子又は低級アルキル基を意味し、Ｘは単結
合または低級アルキレン基を意味し、Ｙは単結合、−Ｃ
Ｈ２−、−０−、−８−。R3 means an amino group, a di-substituted amino group or an acylamino group, and R4 means a halogen atom, or R3 and R4
may be taken together to form -NH-N=N-, 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, -C
H2-, -0-, -8-.
−５ｏ−、−５ｏ２−又は−ＮＲ，−で表される基ヲ意
味し、ここにおいてＲ６は低級アルキル基又は非置換も
し、くは置換基を有するアリール（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
形成していてもよく、
ｎはＯ又は１を意味し、
破線はＹが−ＣＨ２−でｎが０であるときは場合により
存在する二重結合を意味する。-5o-, -5o2- or -NR,-, in which R6 refers to a lower alkyl group or an unsubstituted or substituted aryl (lower) alkyl group; Alternatively, it may be combined with R1 to form an ethylene group, n means O or 1, and the broken line means a double bond that may exist when Y is -CH2- and n is 0. do.
但し、（ｉ）Ｙが−ＮＲ，−又は単結合であるとき、ｎ
は０を意味し、（ｉｉ） Ｙが一〇−であるとき、ｎは
１を意味し、（ｉｉｉ）Ｙが単結合又は−ＣＨ２−であ
り、ｎが０であるとき、Ｒ１は非置換もしくは置換基を
有するアリール（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。However, (i) when Y is -NR, - or a single bond, n
means 0, (ii) when Y is 10-, n means 1, (iii) when Y is a single bond or -CH2- and n is 0, R1 is unsubstituted or an aryl (lower) alkyl group having a substituent, (iv)
When n is 0, X means a lower alkylene group.
］
で表される安息香酸アミド誘導体及びその付加塩類が提
供される。] Benzoic acid amide derivatives and 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、リン酸塩等の無機酸
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有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, phosphate, etc. inorganic acid salts of, and oxalates, maleates, fumarates, lactates, malates, citrates, tartrates, benzoates,
Examples include organic acid salts such as methanesulfonate.
式（１）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。また、化合物（Ｉ）は水和物として
存在し得るので、その水和物も本発明の化合物に包含さ
れる。Since the compound of formula (1) has 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. Moreover, since compound (I) can exist as a hydrate, the hydrate is also included in the compounds of the present invention.
本明細書における用語を以下に説明する。Terms used 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
は低級アルキレン基は、直鎖状でも分枝鎖状でもよい、
「非置換アリール（低級）アルキル基」の具体例として
は、ベンジル、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。「置換基を有するアリ
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。"Lower" means 1 to 6 carbon atoms unless otherwise specified. The lower alkyl group, lower alkyl moiety or lower alkylene group may be linear or branched,
Specific examples of the "unsubstituted aryl (lower) alkyl group" include benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 2-
Examples include naphthylmethyl. "Aryl (lower) alkyl group having a substituent" means that the aryl moiety is 1 to 3
halogen atoms, lower alkyl groups, trifluoromethyl groups, lower alkoxy groups, cyano groups.
水酸基、アミノ基、カルボキシ基又はニトロ基で置換さ
れているものを意味する。「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個有する、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−ペンテニルオキシ、４−もしくは５−へキセニル
オキシ、６−ヘブテニルオキシ等が挙げられる。It means one substituted with a hydroxyl group, an amino group, a carboxy group, or a nitro group. "Alkenyloxy group" means a group having 1 to 2 double bonds at a position other than the carbon atom adjacent to the oxygen atom and having 3 to 8 carbon atoms, such as allyloxy, 2-butenyloxy, 3- Examples include butenyloxy, 3-methyl-2-butenyloxy, 3- or 4-pentenyloxy, 4- or 5-hexenyloxy, 6-hebutenyloxy and the like.
「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、シクロへ
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、ヒドロキシ
基又はオキソ基を１個有するアルコキシ基（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、この基は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。The term "cycloalkyloxy group" means a group having 3 to 6 carbon atoms, and includes, for example, cyclopentyloxy, cyclohexyloxy, and the like. "Alkoxy group having a substituent" means an alkoxy group (preferably one having 6 or less carbon atoms) having one halogen atom, hydroxy group, or oxo group at any position, but the substituent is a hydroxy group. When , this group is bonded to a carbon atom other than the 1-position. A specific example is 2-chloroethoxy.
２−ヒドロキシプロポキシ、３−ヒドロキシプロポキシ
、２−オキソプロポキシ、３−オキソブトキシ等が挙げ
られる。「ジ置換アミノ基」とはジ低級アルキルアミノ
基又は環状アミノ基を意味し、例えば、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
シルアミノ基」の具体例としては、アセチルアミノ。Examples include 2-hydroxypropoxy, 3-hydroxypropoxy, 2-oxopropoxy, 3-oxobutoxy, and the like. "Di-substituted amino group" means a di-lower alkylamino group or a cyclic amino group, such as dimethylamino, diethylamino, methylethylamino, methylpropylamino, morpholino, 1-pyrrolidinyl, piperidino, 4-methyl-1- Examples include piperazinyl. A specific example of the "acylamino group" is acetylamino.
プロピオニルアミノ、ブチリルアミノ、イソブチリルア
ミノ等が挙げられる。Examples include propionylamino, butyrylamino, isobutyrylamino, and the like.
本発明の化合物のうちで好適なものとして。Preferred among the compounds of the present invention.
−数式（Ｉ”）
（式中、Ｒ□゛はベンジル基、フルオロベンジル基、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。- Formula (I'') (wherein R□゛ means a benzyl group, a fluorobenzyl group, a chlorobenzyl group, a trifluoromethylbenzyl group, or a cyanobenzyl group, and R2' is an 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、シクロペンチルオキシ基。3-butenyloxy group, 3-methyl-2-butenyloxy group, cyclopentyloxy group.
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、Ｒ３′はアミノ基
、ジメチルアミノ基又は炭素原子数２〜４のアルカノイ
ルアミノ基、を意味し、ＲＩ）Ｉ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。2-chloroethoxy group, 2-hydroxypropoxy group or 2-oxopropoxy group, R3' means amino group, dimethylamino group or alkanoylamino group having 2 to 4 carbon atoms, RI)I It means a hydrogen atom or a methyl group. Examples include compounds represented by the following and physiologically acceptable acid addition salts thereof.
好適な別の本発明化合物として、−数式（Ｉ”）（式中
、Ｒｌｏ、 Ｒ２°及びＲ３°は前掲に同じものを意味
し、Ｙ゛は一〇−又は−８−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。、
好適な更に別の本発明化合物として、−数式％式％）
Ｒ８’
（式中、Ｒ２’及びＲ３’は前掲に同じものを意味し
Ｒ、Ｉ ？及びＲ６゛は同−又は異なって、炭素原子数
１〜４のアルキル基、ベンジル基。Another suitable compound of the present invention is represented by formula (I'') (wherein Rlo, R2° and R3° mean the same as defined above, and Y' means 10- or -8-). Other preferred compounds of the present invention include compounds represented by the following formula and physiologically acceptable acid addition salts thereof. mean the same thing as
R, I? and R6' are the same or different and are an alkyl group having 1 to 4 carbon atoms or a benzyl group.
フルオロベンジル基、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。It means a fluorobenzyl group, a chlorobenzyl group, a trifluoromethylbenzyl group or a cyanobenzyl group. ) 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）
（以下余白）
（式中、Ｒ２，Ｒ３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、下記−数式
（ＩＩＩ）
誕
（式中、Ｒ，、Ｒ５，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反応させることにより、式（Ｉ）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) (hereinafter referred to as the blank) (in the formula, R2, R3 and R4 have the same meanings as above) or a reactive derivative thereof, and the following - formula (III) (in the formula , R,, R5, X, Y, n and the broken line have the same meanings as mentioned above.) By reacting with a compound represented by formula (I), a compound represented by formula (I) can be obtained.
式（ＩＩ）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
、２，４．５−トリクロロフェニルエステル、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
シビペリジンエステル、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、２−ヒドロキシ
−４，５−ジクロロフェニルエステル、２−ヒドロキシ
ピリジンエステル。Examples of reactive derivatives of the compound of formula (II) 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, 2,4.5-trichlorophenyl ester, pentachlorophenyl ester, cyanomethyl ester, N-hydroxysuccinimide ester, N-hydroxyphthalimide ester, N-hydroxy-5 -norbornene-2,3-dicarboximide ester, N-hydroxybiperidine ester, 8-hydroxyquinoline ester, 2-hydroxyphenyl ester, 2-hydroxy-4,5-dichlorophenyl ester, 2-hydroxypyridine ester.
２−ピリジルチオールエステル等が挙げられる。Examples include 2-pyridylthiol ester.
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
、クロル炭酸イソ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、クロル炭酸ベンジルのような
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ロ炭酸アリールエステルと
の混合酸無水物、イソ吉草酸、ピバリン酸のよりなアル
カン酸との混合酸無水物等が挙げられる。As the acid anhydride, a symmetrical acid anhydride or a mixed acid anhydride is used. Specific examples of the mixed anhydride include ethyl chlorocarbonate, isobutyl chlorocarbonate, mixed acid anhydride with an alkyl chlorocarbonate, and chlorocarbonate. Mixed acid anhydrides with aralkyl rorocarbonates such as benzyl, mixed acid anhydrides with aryl rorocarbonates such as phenyl chlorocarbonate, mixed acid anhydrides with alkanoic acids such as isovaleric acid and pivalic acid, etc. can be mentioned.
式（ＩＩ）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
ミノプロピル）カルボジイミド塩酸塩、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−１ｅ２−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−
ジメチルアミノプロピル）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。When using the compound of formula (II), dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, N,N'-carbonyldiimidazole, 1-ethoxycarbonyl-2-
The reaction can be carried out in the presence of a condensing agent such as ethoxy-1e2-dihydroquinoline. Dicyclohexylcarbodiimide or 1-ethyl-3-(3-
N-hydroxysuccinimide when dimethylaminopropyl)carbodiimide hydrochloride is used.
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−２，３
−ジカルボキシイミド等を添加して反応させてもよい。1-hydroxybenzotriazole, 3-hydroxy-
4-oxo-3,4-dihydro-1,2゜3-benzotriazine, N-hydroxy-5-norbornene-2,3
-Dicarboximide or the like may be added and reacted.
式（ＩＩ）の化合物又はその反応性誘導体と式（ｉ Ｉ
Ｉ ）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、原料化合物の種類等に従って
適宜選択・されるべきであるが１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。A compound of formula (II) or a reactive derivative thereof and a compound of formula (i I
The reaction with the compound I) is carried out in a solvent or without a solvent. The solvent to be used should be appropriately selected according to the type of raw material compound, etc. 1 For example, aromatic hydrocarbons such as benzene, toluene, xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane, methylene chloride , halogenated hydrocarbons such as chloroform, ethyl acetate, acetonitrile, dimethylformamide, dimethyl sulfoxide, ethylene glycol, water, etc., and these solvents may be used alone or in combination of two or more.
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、重炭酸カリウムのよ
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
チルアミン、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有機塩基が挙げられるが、式（ＩＩ
Ｉ）の化合物の過剰量で兼ねることもできる。反応温度
は用いる原料化合物の種類等により異なるが、通常−３
０°Ｃないし約２０口°Ｃ１好ましくは約−１Ｏ°Ｃな
いし約１５０°Ｃである。This reaction is carried out in the presence of a base if necessary. Specific examples of the base include alkali bicarbonates such as sodium bicarbonate and potassium bicarbonate, alkali carbonates such as sodium carbonate and potassium carbonate, triethylamine, and triethylamine. Organic bases such as butylamine, diisopropylethylamine, N-methylmorpholine, and
An excess amount of the compound I) can also serve as the compound. The reaction temperature varies depending on the type of raw material compound used, but is usually -3
0°C to about 20°C, preferably about -10°C to about 150°C.
上記製法により生成する化合物（Ｉ）は、クロマトグラ
フィー、再結晶、再沈澱等の常法により単離、精製され
る。Compound (I) produced by the above production method is isolated and purified by conventional methods such as chromatography, recrystallization, and reprecipitation.
式（１）の化合物は、原料化合物の選定９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５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導くことができる。The compound of formula (1) can be obtained in the form of a free base or an acid addition salt depending on the selection of raw material compounds, reaction and treatment conditions, etc. Acid addition salts can be converted to the free base by conventional methods5, 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１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水和物について
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。The results of pharmacological tests on a representative compound of the present invention and metoclopramide hydrochloride monohydrate, a commercially available gastrointestinal function enhancer, will be shown below, and the pharmacological action of the compound of the present invention will be explained.
評ツ丸例」ヨ 胃排出能冗進作用
本試験は、５ｃａｒｐ ｉｇｎａｔｏらの方法［Ａｒｃ
ｈ、 Ｉｎｔ。This test was performed using the method of Carp Ignato et al [Arc
h, Int.
Ｐｈａｒｍａｃｏｄｙｎ、、 ２４６．２８６〜２９４
（１９８０）参照］に準じて行った。ウィスター系雄
性ラット（体重１３０〜１５０ ｇ）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、５％メチルセルロース溶液１．５ ｍｌ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
％トラガント溶液に溶解又は懸濁し、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
群及びメトクロプラミド塩酸塩１水和物投与群について
は５匹、それ以外は４匹である。結果を表１に示す。Pharmacodyn, 246.286-294
(1980)]. After fasting male Wistar rats (body weight 130-150 g) for 18 hours, 1.5 ml of a 1.5% methylcellulose solution containing phenol red at a rate of 0.05% was orally administered. 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 is 0.5
% tragacanth solution and orally administered 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 metoclopramide hydrochloride monohydrate administration group, and 4 for the others. The results are shown in Table 1.
（以下余白） 表 １ 胃排出能元進作用 零）実施例１の化合物を意味する（以下同じ）。(Margin below) Table 1: Effect on promoting gastric emptying capacity Zero) means the compound of Example 1 (the same applies hereinafter).
（以下余白）
上記試験結果から明らかなように１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。(Left space below) As is clear from the above test results, the compound of Formula 1 (I) and its physiologically acceptable acid addition salts have an excellent effect on promoting gastrointestinal function, so they can be used as anti-emetic agents or as gastrointestinal function-enhancing agents. As a drug, acute and chronic gastritis.
胃・十二指腸潰瘍、胃神経症、胃下垂などの疾患におけ
る食欲不振、悪心、嘔吐、腹部膨満感等の治療及び予防
に、また食道・胆道系疾患９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
物の種類、投与方法、患者の症状・年齢等により異なる
が１通常０．００１〜２０ ｍｇ／ｋｇ７日、好ましく
は０．００４〜５ ｍｇ／ｋｇ／日である。式（Ｉ）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（Ｉ）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、シクロデキストリン、デン
プン、白糖、結晶セルロース、ゼラチン、アラビアゴム
、ヒドロキシ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、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。It can be used for the treatment and prevention of anorexia, nausea, vomiting, abdominal bloating, etc. in diseases such as gastric/duodenal ulcers, gastric neurosis, and gastroptosis, and for the treatment and prevention of esophageal/biliary system diseases 9 and constipation. 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 dose varies depending on the type of compound, administration method, patient's symptoms, age, etc., but is usually 0.001 to 20 mg/dose. kg/7 days, preferably 0.004-5 mg/kg/day. The compound of formula (I) or a salt thereof is usually administered in the form of a preparation prepared by mixing it with a pharmaceutical carrier. As the pharmaceutical carrier, a substance commonly used in the pharmaceutical field and which does not react with the compound of formula (I) or its salt is used. Specifically, for example, lactose, glucose, mannitol, cyclodextrin, starch, white sugar, crystalline cellulose, gelatin, gum arabic, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, light silicic anhydride, magnesium stearate, talc, tragacanth, oxidized Examples include titanium, sorbitan fatty acid ester, vegetable oil, and water.
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、坐剤等が挙げられる
。これらの製剤は常法に従って調製される。これらの製
剤はまた、治療上価値ある他の成分を含有していてもよ
い。Examples of dosage forms include tablets, capsules, granules, fine granules, powders, syrups, suspensions, injections, and suppositories. These formulations are prepared according to conventional methods. 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 by elemental analysis, mass spectra, IR spectra, NMR spectra, etc.
（以下余白）
参」」（−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．
１ｇの無水テトラヒドロフラン３３０ ｍｌ懸濁液中に
室温下、５ｙｎｔｈｅｓｉｓ、 ８８８〜６９０ （１
９８４）に記載の方法に従って合成した、２−エトキシ
カルボニル−５，６−シヒドロー１．４−チアジン３２
．１ｇを滴下する。室温で３０分攪拌した後、氷冷しな
がら臭化ベンジル３１．７ ｇを滴下する０反応液を室
温に戻して３時間攪拌した後、テトラヒドロフランを減
圧で留去する。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後、溶媒を減圧で留去す
る。残渣をシル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４９ ｇを得
る。(Left below) "(-1) 4-benzyl-2-ethoxycarbonyl-5゜6-sihydro1. Production of 4-thiazine: Sodium hydride 8.
1 g of anhydrous tetrahydrofuran in 330 ml at room temperature, 888-690 (1
2-ethoxycarbonyl-5,6-sihydro-1,4-thiazine 32, synthesized according to the method described in 984)
．． Drop 1 g. After stirring at room temperature for 30 minutes, 31.7 g of benzyl bromide was added dropwise while cooling with ice.The reaction solution was returned to room temperature and stirred for 3 hours, then tetrahydrofuran was distilled off under reduced pressure. The residue is dissolved in ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. The residue was purified by silica gel column chromatography and eluted with chloroform to obtain 49 g of the desired product.
象煮■−ユ
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
ロフラン２００ ｍｌに懸濁し、水冷下４−ベンジルー
２−エトキシカルボニル−５，６−シヒドロー１．４−
チアジン２５ ｇの無水テトラヒドロフラン５０ ｍｌ
溶液を滴下する０滴下終了後、室温で１８時間攪拌した
後、氷冷しながら酢酸エチル、続いて水、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後
、溶媒を減圧で留去する。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：ｌ）で溶出・精製して目的物５．８ｇを得る。Production of 4-benzyl-2-hydroxymethyl-1,4-thiomorpholine: 7.2 g of lithium aluminum hydride was suspended in 200 ml of anhydrous tetrahydrofuran, and 4-benzyl-2-ethoxycarbonyl-5 was added under water cooling. ,6-Sihydro1.4-
25 g of thiazine in 50 ml of anhydrous tetrahydrofuran
After the solution was added dropwise, the mixture was stirred at room temperature for 18 hours, and then ethyl acetate was added, followed by water and an aqueous sodium hydroxide solution, followed by extraction with ethyl acetate. The organic layer is washed with saturated brine, dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. The residue was subjected to silica gel column chromatography using chloroform-methanol (
50:l) to obtain 5.8 g of the target product.
象考拠−１
４−ベンジル−２−クロロメチル−１，４−−／−オモ
ルホリンの製造：
４−ベンジフレー２−ヒドロキシメチル−１，４−チオ
モルホリン１０．８ ｇをクロロホルムｌ口Ｏｍｌに溶
解し、氷冷しながら塩化チオニル１１ ｇを加え、２０
分間加熱還流する。溶媒を減圧で留去し、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。有機層を水洗し、無水硫酸マグネシウムで乾燥した
後、溶媒を減圧で留去する。Concept-1 Production of 4-benzyl-2-chloromethyl-1,4-/-omorpholine: Dissolve 10.8 g of 4-benzifury 2-hydroxymethyl-1,4-thiomorpholine in 1 Oml of chloroform. Then, while cooling on ice, add 11 g of thionyl chloride, and add 20 g of thionyl chloride.
Heat to reflux for minutes. The solvent is removed under reduced pressure and the residue is neutralized with saturated aqueous sodium bicarbonate solution and extracted with chloroform. After washing the organic layer with water and drying over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure.
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ｆ！、８ ｇｔｅ得る。The residue was subjected to silica gel column chromatography,
Elute and purify with hexane-chloroform (1:1) to obtain the target f! , get 8 gte.
参考１
２−アセチルアミノメチル−４−ベンジル−１゜４−チ
オモルホリンの製造：
（１）４−ベンジル−２−クロロメチル−１，４−チオ
モルホリン６．８ｇをアセトニトリル１００ ｍｌに溶
解し、ナトリウムアジド３．７ｇを加えた後。Reference 1 Production of 2-acetylaminomethyl-4-benzyl-1゜4-thiomorpholine: (1) Dissolve 6.8 g of 4-benzyl-2-chloromethyl-1,4-thiomorpholine in 100 ml of acetonitrile, After adding 3.7 g of sodium azide.
２時間加熱還流する。冷後、溶媒を減圧で留去し、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、濃縮して、２−
アジドメチル−４−ベンジル−１゜４−チオモルホリン
７、Ｏｇを得る。Heat to reflux for 2 hours. After cooling, the solvent is distilled off under reduced pressure and the residue is dissolved in chloroform. The chloroform solution was washed with water, dried over anhydrous magnesium sulfate, and concentrated to give 2-
Azidomethyl-4-benzyl-1°4-thiomorpholine 7, Og is obtained.
（２）上記アジドメチル体７．０ｇをトルエン７０ ｍ
ｌ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１６ ｇを少しずつ加
える。水冷下２．５時間攪拌した後、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、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、無水酢酸５．７ｇを加え、室温で３時
間攪拌する。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
燥した後、溶媒を減圧で留去する。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。(2) 7.0 g of the above azidomethyl compound was added to 70 m of toluene.
16 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 organic layer with water and drying over anhydrous magnesium sulfate, 5.7 g of acetic anhydride is added and stirred at room temperature for 3 hours. The reaction solution was mixed with 48% sodium hydroxide aqueous solution,
After washing with saturated brine and drying over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure. 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.
象考冊〜ｊ
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の無水テトラヒド
ロフラン２００１ＩＩｌ懸濁液中に、１−ベンジル−３
−カルバモイルピペリジン１１．４ ｇの無水テトラヒ
ドロフラン２００ ｍｌ溶液を少しずつ滴下する。Elephant Book ~ j Production of 3-aminomethyl-1-benzylpiperidine: In a suspension of 4.0 g of lithium aluminum hydride in 2001III anhydrous tetrahydrofuran, 1-benzyl-3
- A solution of 11.4 g of carbamoylpiperidine in 200 ml of anhydrous tetrahydrofuran is added dropwise.
滴下終了後、４．５時間攪拌しながら加熱還流する。After completion of the dropwise addition, the mixture was heated to reflux while 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、溶媒を減圧で留去した後、
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
を減圧で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. After filtering off the insoluble matter and distilling off the solvent under reduced pressure,
Extract 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 under reduced pressure to obtain 8.0 g of the desired product as an oil.
参考１
３−アミノメチル−１−ベンジル−１，２，５゜６−チ
トラヒドロビリジンの製造：
（１）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ｉｏ、ｏ ｇをメタノール３０ｍ１と
水８００１１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。Reference 1 Production of 3-aminomethyl-1-benzyl-1,2,5゜6-titrahydrobiridine: (1) 3-acetylaminomethyl-1-benzylpyridinium chloride io, og was mixed with 30ml of methanol and 800ml of water. In addition to the mixed solution, 6.3 g of sodium borohydride is added little by little while stirring under water cooling.
還元剤を加え終わった後、室温で１８時間攪拌する。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。有機層を水洗
し、無水硫酸マグネシウムで乾燥した後、溶媒を減圧で
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、油状の３−アセチルアミノメチル−１−
ベンジル−１，２，５，６−チトラヒドロビリジン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. After washing the organic layer with water and drying over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure. The residue was purified by silica gel column chromatography and eluted with chloroform-methanol (50:1) to obtain oily 3-acetylaminomethyl-1-
Benzyl-1,2,5,6-titrahydrobiridine5.
Obtain 0g.
（２）上記テトラヒドロピリジン体５．０ｇに１０％塩
酸７５ ｍｌを加え、攪拌しながら５時間加熱還流する
。冷後、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。(2) Add 75 ml of 10% hydrochloric acid to 5.0 g of the above tetrahydropyridine, and heat under reflux for 5 hours while stirring. After cooling, the reaction solution is made alkaline with a 20% aqueous sodium hydroxide solution and extracted with chloroform.
有機層を水洗し、無水硫酸マグネシウムで乾燥した後、
溶媒を減圧で留去して油状の目的物３．８ｇを得る。こ
れを常法によ′リマレイン酸で処理して目的物のシマレ
イン酸塩を得る。After washing the organic layer with water and drying with anhydrous magnesium sulfate,
The solvent was distilled off under reduced pressure to obtain 3.8 g of the target product as an oil. This is treated with limaleic acid in a conventional manner to obtain the desired simalate salt.
融点１５５〜１５７℃（エタノールから再結晶）象考旦
−ユ
２−アジドメチル−１，４−ジエチルピペラジンの製造
：
■ｅｌｖ、 ＣｈｉＩｌ、 Ａｃｔａ、 ４５．２３８
３〜２４０２ （１９６２）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２７ ｇをクロロホルム２７０ ｍｌに溶解し、水
冷上塩化チオニル２７ ｇを加えた後、攪拌しながら３
０分間加熱還流する。Melting point: 155-157°C (recrystallized from ethanol) Production of 2-azidomethyl-1,4-diethylpiperazine: ■elv, ChiIl, Acta, 45.238
3-2402 (1962) was dissolved in 270 ml of chloroform, and after adding 27 g of thionyl chloride on a water-cooled solution, the solution was dissolved with stirring.
Heat to reflux for 0 minutes.
冷後、溶媒を減圧で留去し、飽和重炭酸ナトリウム水溶
液で中和した後、クロロホルムで抽出する。After cooling, the solvent is distilled off under reduced pressure, neutralized with saturated aqueous sodium bicarbonate solution, and extracted with chloroform.
有機層を水洗し、無水硫酸マグネシウムで乾燥した後、
溶媒を減圧で留去して、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
ｍｌに溶解し、ナトリウムアジド２０ ｇを加え、攪
拌しながら２時間加熱還流する。After washing the organic layer with water and drying with anhydrous magnesium sulfate,
The solvent is distilled off under reduced pressure to obtain 2-chloromethyl-1,4-diethylpiperazine. Add this to acetonitrile 270
ml, add 20 g of sodium azide, and heat under reflux for 2 hours while stirring.
冷後、溶媒を減圧で留去し、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、溶媒を減圧で留去して油状の目的物１
５ ｇを得る。After cooling, the solvent is distilled off under reduced pressure and the residue is dissolved in chloroform. After washing the chloroform solution with water and drying with anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain the oily target product 1.
Obtain 5 g.
１毀拠−１
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１５
ｇをトルエン１５０ ｍｌ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３４ ｇを少しずつ加える。氷冷しながら５時間攪拌
後、反応液を氷水中にあけ、４８％水酸化ナトリウム水
溶液を加えた後、有機層を分離する。有機層を水洗し、
無水硫酸マグネシウムで乾燥した後、溶媒を減圧で留去
して目的物１１ ｇを得る。1 Evidence-1 Production of 2-aminomethyl-1,4-diethylpiperazine: 2-azidomethyl-1,4-diethylpiperazine 15
g was dissolved in 150 ml of toluene, and 34 g of 70% sodium bis(2-methoxyethoxy)hydride was added little by little while cooling with water. After stirring for 5 hours while cooling with ice, the reaction solution was poured into ice water, and after adding a 48% aqueous sodium hydroxide solution, the organic layer was separated. Wash the organic layer with water,
After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 11 g of the desired product.
１考拠−遣
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：
（１） Ｊ、 Ｍｅｄ、 Ｐｈａｒｍ、 ＣｈｅＩＩ
ｌ、、 ２．５５３〜５６２（１９［３０）に記載の方
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１６．６ ｇをメチルエチルケトン１
７０ ｍｌに溶解し、臭化ベンジル１７．８ ｇと炭酸
カリウム１７．０ｇを加え、攪拌しながら１．５時間加
熱還流する。不溶物を濾去し濾液を濃縮し、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
ウムで乾燥した後、溶媒を減圧で留去する。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
０．５ ｇを得る。1 Evidence - 6-acetylamino-4-benzyl-hexahydro-1
,4-thiazepine production: (1) J, Med, Pharm, CheII
3-ethoxycarbonyl-1,4, synthesized according to the method described in 1,, 2.553-562 (19[30)
-16.6 g of thiomorpholine to 1 part of methyl ethyl ketone
Dissolve in 70 ml, add 17.8 g of benzyl bromide and 17.0 g of potassium carbonate, and heat under reflux for 1.5 hours while stirring. Insoluble matters are removed by filtration, the filtrate 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 under reduced pressure. The residue was subjected to silica gel column chromatography, and hexane-
Elute and purify with chloroform (1:1) to obtain 4-benzyl-3-ethoxycarbonyl-1,4-thiomorpholine 2.
Obtain 0.5 g.
（２）上記ベンジル体２０．５ ｇをトルエン２００
ｍｌ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４４．６ ｇを少し
ずつ加え、室温に戻して一夜攪拌する。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。有機層を水洗し、無水硫酸マグネシウム
で乾燥した後、溶媒を減圧で留去する。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、４−ベンジ
ル−３−ヒドロキシメチル−１，４−チオモルホリン１
３．９ ｇを得る。(2) 20.5 g of the above benzyl compound was added to 200 g of toluene.
ml, add 44.6 g of 70% sodium bis(2-methoxyethoxy)aluminum hydride little by little while cooling with water, return to room temperature, 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. After washing the organic layer with water and drying over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure. The residue was subjected to silica gel column chromatography and chloroform-
Elution and purification with methanol (50:1) yielded 4-benzyl-3-hydroxymethyl-1,4-thiomorpholine 1.
Obtain 3.9 g.
（３）上記ヒドロキシメチル体１３．９ ｇをクロロホ
ルム１５０ ｍｌに溶解し、水冷下、塩化チオニル１４
ｇを加える。２０分間加熱還流した後、溶媒を減圧で
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。有機層を水洗し、無水硫酸マ
グネシウムで乾燥した後、溶媒を減圧で留去する。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−クロロメチル−１，４−チオモルホリン
１４．６ ｇを得る。(3) Dissolve 13.9 g of the above hydroxymethyl compound in 150 ml of chloroform, and add thionyl chloride (14 g) under water cooling.
Add g. After heating to reflux for 20 minutes, the solvent was removed under reduced pressure and the residue was neutralized with saturated aqueous sodium bicarbonate solution.
Extract with chloroform. After washing the organic layer with water and drying over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure. The residue was purified by silica gel column chromatography and eluted with hexane-chloroform (1:1) to obtain 4-
14.6 g of benzyl-3-chloromethyl-1,4-thiomorpholine are obtained.
（４）上記クロロメチル体８．０ｇをアセトニトリル８
０ ｍｌに溶解し、ナトリウムアジド４．３ｇを加え。(4) 8.0 g of the above chloromethyl compound was added to 8.0 g of acetonitrile.
0 ml and added 4.3 g of sodium azide.
攪拌しながら２時間加熱還流する。溶媒を減圧で留去し
、残渣に酢酸エチルを加え、水洗し、無水硫酸マグネシ
ウムで乾燥した後、溶媒を減圧で留去する。残渣にトル
エン５０ ｍｌ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
を少しずつ加えた後、３時間攪拌する。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、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、無水酢酸４．９ｇを加え、室温で１
時間攪拌する０反応液を４８％水酸化ナトリウム水溶液
１次いで水で洗浄し、無水硫酸マグネシウムで乾燥した
後、溶媒を減圧で留去する。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
（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−ベンジル−１，４−チオモ
ルホリン３．１ｇを得る。Heat to reflux for 2 hours while stirring. The solvent was distilled off under reduced pressure, and ethyl acetate was added to the residue, washed with water, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. Add 50 ml of toluene to the residue, and add 70% bishydride (2
-methoxyethoxy)aluminum sodium 9.8g
After adding little by little, stir for 3 hours. 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 organic layer with water and drying with anhydrous magnesium sulfate, 4.9 g of acetic anhydride was added and the mixture was stirred at room temperature for 1
The reaction mixture, which was stirred for an hour, was washed with a 48% aqueous sodium hydroxide solution, then with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography and eluted with chloroform-methanol (40:1) to obtain 2.6 g of the target product and 3-
3.1 g of acetylaminomethyl-4-benzyl-1,4-thiomorpholine are obtained.
１号冊−１没
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、 Ｓａｃ、、 Ｐｅｒｋｉｎ Ｔｒａ
ｎｓ、 Ｉ、 ５４７〜５５１（１９８７）に記載の方
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５．１ｇをアセトニトリル５０ ｍｌに溶解
し、ナトリウムアジド３．Ｏｇを加え、攪拌しながら３
時間加熱還流する。溶媒を減圧で留去し、残渣にクロロ
ホルムを加え。Volume 1 - 1-6-acetylamino-4-benzyl-hexahydro-1
, 4-oxazepine production: J. Chew, Sac, Perkin Tra.
NS, I, 547-551 (1987), 5.1 g of 4-benzyl-3-chloromethylmorpholine was dissolved in 50 ml of acetonitrile, and sodium azide 3. Add Og and add 3 while stirring.
Heat to reflux for an hour. The solvent was distilled off under reduced pressure, and chloroform was added to the residue.
水洗し、無水硫酸マグネシウムで乾燥した後、溶媒を減
圧で留去する。残渣にトルエン５０ ｍｌ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１１．５ ｇを少しずつ加えた後、水
冷下で３時間攪拌する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
ムで乾燥した後、溶媒を減圧で留去する。残渣をクロロ
ホルム５０ｍ１に溶解し、無水酢酸４．０ｇ加え、室温
で１４時間攪拌する０反応液に氷水と４８％水酸化ナト
リウム水溶液を加えて振酪し、有機層を分離する。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
た後、溶媒を減圧で留去する。残渣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−ヘキサン
（５：１）で溶出・精製して。After washing with water and drying over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure. Add 50 ml of 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 mixture, add ethanol and then ice water. and 48% 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 under reduced pressure. Dissolve the residue in 50 ml of chloroform, add 4.0 g of acetic anhydride, and stir at room temperature for 14 hours. Ice water and a 48% aqueous sodium hydroxide solution are added to the reaction mixture and shaken, and the organic layer is separated. After washing this with saturated brine and drying over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure. The residue was purified by medium pressure silica gel column chromatography and eluted with ethyl acetate-hexane (5:1).
目的物１．２ｇ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。1.2 g of the target product and 2.8 g of 3-acetylaminomethyl-4-benzylmorpholine are obtained.
１号１１
２−アセチルアミノメチル−１，４−ジベンジルピペラ
ジンの製造：
■ｅｌｙ、 Ｃｈｉｍ、 Ａｃｔａ、 ４５．２３８３
〜２４０２ （１９６２）に記載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ン
７．５ｇをアセトニトリル７５ ｍｌに溶解し、ナトリ
ウムアジド３．１ｇを加え、攪拌しながら３時間加熱還
流する。冷後、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で
乾燥した後、溶媒を減圧で留去して油状物６．８ｇを得
る。これをトルエン７０ ｍｌ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１２．５ｇを少しずつ加える。室温
で１時間攪拌した後、エタノールと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後、溶媒を
減圧で留去する。残渣をクロロホルム５［１ｍｌに溶解
し、無水酢酸４．４ｇを加えて室温で３時間攪拌する０
反応液を２０％水酸化ナトリウム水溶液で洗浄し、無水
硫酸マグネシウムで乾燥した後、溶媒を減圧で留去して
油状物６．５ｇを得る。これをシリカゲルのカラムクロ
マトグラフィーに付し、酢酸エチル−ヘキサン（５：１
）で溶出・精製して、目的物３．５ｇを得る。No. 1 11 Production of 2-acetylaminomethyl-1,4-dibenzylpiperazine: ■ely, Chim, Acta, 45.2383
2402 (1962) was dissolved in 75 ml of acetonitrile, 3.1 g of sodium azide was added, and the mixture was heated for 3 hours with stirring. Reflux. 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 under reduced pressure to obtain 6.8 g of an oil. Dissolve this in 70 ml of toluene, and add 12.5 g of 70% sodium bis(2-methoxyethoxy)aluminum hydride little by little while stirring under water cooling. After stirring for 1 hour at room temperature, ethanol and 48% aqueous sodium hydroxide solution are added. The toluene layer is separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. Dissolve the residue in 5 [1 ml of chloroform], add 4.4 g of acetic anhydride, and stir at room temperature for 3 hours.
The reaction solution was washed with a 20% aqueous sodium hydroxide solution and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain 6.5 g of an oil. This was subjected to silica gel column chromatography, and ethyl acetate-hexane (5:1
) to obtain 3.5 g of the target product.
参渚１又
３−アセチルアミノ−１−ベンジル−１Ｈ−へキサヒド
ロアゼピンの製造：
（１）２−ピペリジンメタノール１０ ｇを、メチルエ
チルケトン２０Ｏｍｌに溶かし、炭酸カリウム２４ ｇ
と塩化ベンジル１１ ｇを加え、１８時間加熱還流する
。Production of Sangi 1mata 3-acetylamino-1-benzyl-1H-hexahydroazepine: (1) Dissolve 10 g of 2-piperidine methanol in 20 Oml of methyl ethyl ketone, and dissolve 24 g of potassium carbonate.
and 11 g of benzyl chloride were added, and the mixture was heated under reflux for 18 hours.
冷後、不溶物を濾過して除き、溶媒を減圧で留去する。After cooling, insoluble matters are removed by filtration, and the solvent is distilled off under reduced pressure.
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、１−ベンジル−２−ヒドロキシメチルピペリジン１
２ ｇを得る。The residue was subjected to silica gel column chromatography,
Elution and purification with chloroform-methanol (20:1) yielded 1-benzyl-2-hydroxymethylpiperidine 1.
Obtain 2 g.
（２）上記ヒドロキシ体ｌｏｇを塩化メチレン１［１（
１ａ＋１に溶がし、Ｎ、Ｎ−ジメチルホルムアミド３滴
と塩化チオニル１０ ｍｌを加える。２時間加熱還流し
た後、溶媒を減圧で留去し、残渣を飽和重炭酸ナトリウ
ム水溶液で中和し、酢酸エチルで抽出する。有機層を水
洗し、無水硫酸マグネシウムで乾燥した後、溶媒を減圧
で留去する。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、ｌ−ベン
ジル−２−クロロメチルピペリジン１０ ｇを得る。(2) The above hydroxyl log is converted into methylene chloride 1[1(
1a+1 and add 3 drops of N,N-dimethylformamide and 10 ml of thionyl chloride. After heating at reflux for 2 hours, the solvent is removed under reduced pressure and the residue is neutralized with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. After washing the organic layer with water and drying over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure. The residue is purified by silica gel column chromatography, eluted with chloroform, to obtain 10 g of l-benzyl-2-chloromethylpiperidine.
（３）上記クロロメチル体１０ ｇをアセトニトリル１
００ ｍｌに溶かし、ナトリウムアジド５．８ｇを加え
、攪拌しながら２時間加熱還流する。冷後、不溶物ｔｅ
濾過して除き、溶媒を減圧で留去する。残渣にトルエン
１８０ ｍｌ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１８ ｇを加
えた後、３時間攪拌する。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
。有機層を水洗し、無水硫酸マグネシウムで乾燥した後
、溶媒を減圧で留去する。残渣をクロロホルムに溶かし
、無水酢酸９ｇを加え、室温で１８時間攪拌する。反応
液を４８％水酸化ナトリウム水溶液１次いで水で洗浄し
、無水硫酸マグネシウムで乾燥した後、溶媒を減圧で留
去する。残渣をシリカゲルのカラムクロマトに付し、ク
ロロホルム−メタノール（５０：１）で溶出・精製して
、目的物６．０ｇを得る。(3) 10 g of the above chloromethyl compound was added to 1 acetonitrile.
00 ml, add 5.8 g of sodium azide, and heat under reflux for 2 hours while stirring. After cooling, the insoluble matter
Filter off and remove the solvent under reduced pressure. 180 ml of toluene was added to the residue, and 18 g of 70% sodium bis(2-methoxyethoxy)aluminum hydride was added under water cooling, followed by stirring for 3 hours. Pour the reaction solution into ice water and
% aqueous sodium hydroxide solution and extracted with toluene. After washing the organic layer with water and drying over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure. The residue was dissolved in chloroform, 9 g of acetic anhydride was added, and the mixture was stirred at room temperature for 18 hours. The reaction solution was washed with a 48% aqueous sodium hydroxide solution and then with water, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography and eluted with chloroform-methanol (50:1) to obtain 6.0 g of the desired product.
融点 ６８−７０°Ｃ（トルエン−石油エーテル）象考
叢−Ｊユ
３−アセチルアミノ−１−メチル−ＩＨ−へキサヒドロ
アゼピンの製造：
３−アセチルアミノ−１−ベンジル−ＩＨ−へキサヒド
ロアゼピン２．８ｇを塩化メチレン３０ ｍｌに溶かし
、１−クロロエチルクロロホルメート２．８ｇを加え、
１時間加熱還流する。溶媒を減圧で留去し、メタノール
３０ ｍｌを加え、１時間加熱還流する。溶媒を減圧で
留去し、残渣に水酸化ナトリウム水溶液を加え、塩化メ
チレンで抽出する。有機層を、無水硫酸マグネシウムで
乾燥した後、溶媒を減圧で留去し、２．３ｇの油状物を
得る。このものに９０％ギ酸３．５ｇと３５％ホルマリ
ン２．９ｇを加え、９時間加熱還流する。溶媒を減圧で
留去し、残渣に水酸化ナトリウム水溶液を加え、塩化メ
チレンで抽出する。有機層を、無水硫酸マグネシウムで
乾燥した後、溶媒を減圧で留去して目的物２．５ｇを得
る。Melting point 68-70°C (toluene-petroleum ether) Quadrilateral - Jyu 3-acetylamino-1-methyl-IH-hexahydroazepine preparation: 3-acetylamino-1-benzyl-IH-hexahydro Dissolve 2.8 g of azepine in 30 ml of methylene chloride, add 2.8 g of 1-chloroethyl chloroformate,
Heat to reflux for 1 hour. The solvent is distilled off under reduced pressure, 30 ml of methanol is added, and the mixture is heated under reflux for 1 hour. The solvent was distilled off under reduced pressure, aqueous sodium hydroxide solution was added to the residue, and the mixture was extracted with methylene chloride. After drying the organic layer over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 2.3 g of an oil. 3.5 g of 90% formic acid and 2.9 g of 35% formalin are added to this mixture, and the mixture is heated under reflux for 9 hours. The solvent was distilled off under reduced pressure, aqueous sodium hydroxide solution was added to the residue, and the mixture was extracted with methylene chloride. After drying the organic layer over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 2.5 g of the desired product.
参考■−１１
６−アセチルアミノ−４−メチル−ヘキサヒドロ−１，
４−チアゼピンの製造：
参考例１３における３−アセチルアミノ−１−ベンジル
−ＩＨ−へキサヒドロアゼピンの代りに、６−アセチル
アミノ−４−ベンジル−ヘキサヒドロ−１，４−チアゼ
ピンを用い参考例１３と同様に反応・処理して目的物を
得る。Reference ■-11 6-acetylamino-4-methyl-hexahydro-1,
Production of 4-thiazepine: In place of 3-acetylamino-1-benzyl-IH-hexahydroazepine in Reference Example 13, 6-acetylamino-4-benzyl-hexahydro-1,4-thiazepine was used to produce Reference Example 13. React and process in the same manner as above to obtain the desired product.
（以下余白）
大溝４（−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３．６ ｇｔ！−
１Ｏ％塩酸３６ ｍｌに溶解し、４時間加熱還流する。(Leaving space below) Oomizo 4 (-1 Production of 4-amino-N-[(4-benzyl-1,4-thiomorpholin-2-yl)methyl]-5-chloro-2-ethoxybenzamide: 2-acetylaminomethyl -4
-Benzyl-1°4-thiomorpholine 3.6 gt! −
Dissolve in 36 ml of 10% hydrochloric acid and heat under reflux for 4 hours.
冷機、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、溶媒を減圧で留去して油状
物２．５ｇを得る。これを塩化メチレン３０ ｍｌに溶
解し、４−アミノ−５−クロロ−２−エトキシ安息香酸
２．４ｇと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２．２ｇを加え、室温で２
時間攪拌する０反応液を水洗し、無水硫酸マグネシウム
で乾燥した後、溶媒を減圧で留去する。残渣をメタノー
ルから再結晶して目的物の１７４永和物２．８ｇを得る
。 融点 １３３〜１３５°Ｃ実１１肌−１５
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−メトキ
シ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ｌ／４水和物を得る。Make alkaline with a 48% aqueous sodium hydroxide solution in a refrigerator, and extract with chloroform. After washing the organic layer with water and drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 2.5 g of an oil. This was dissolved in 30 ml of methylene chloride, 2.4 g of 4-amino-5-chloro-2-ethoxybenzoic acid and 2.2 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride were added, and the mixture was heated at room temperature. So 2
The reaction mixture, which was stirred for an hour, was washed with water, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was recrystallized from methanol to obtain 2.8 g of the desired product 174 elongate. Melting point 133-135°C Fruit 11 Skin-15 Production of 4-amino-N-[(4-benzyl-1,4-thiomorpholin-2-yl)methyl]-5-chloro-2-methoxybenzamide: Example 1 4-amino- in
Using 4-amino-5-chloro-2-methoxybenzoic acid in place of 5-chloro-2-ethoxybenzoic acid, Example 1
The reaction and treatment are carried out in the same manner as above to obtain the target product, l/4 hydrate.
融点１３２〜１３４°Ｃ（エタノール−ジエチルエーテ
ルから再結晶）
夾胤拠−１
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−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。これを常法によリフマル酸
で処理して目的物のフマル酸塩・酢酸エチル・ｌ／２水
和物を得る。Melting point: 132-134°C (recrystallized from ethanol-diethyl ether) 4-Amino-N-(4-benzyl-hexahydro-1,
Preparation of 4-thiazepin-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-thiazepine, the reaction and treatment are carried out in the same manner as in Example 1 to obtain the desired product. This is treated with rifmaric acid in a conventional manner to obtain the target fumarate/ethyl acetate/l/2 hydrate.
融点 ９２〜９５°Ｃ（酢酸エチルから再結晶）実】ｌ
１−Ａ−
４−アミノ−５−クロロ−２−エトキシ−Ｎ−（４−メ
チル−ヘキサヒドロ−１，４−チアゼピン−６−イル）
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−メチル−ヘキサヒドロ−１，４−チアゼピン
を用い、実施例１と同様に反応した後、中圧シリカゲル
クロマトグラフィーに付し、アセトンで溶出・精製して
目的物を得る。Melting point: 92-95°C (recrystallized from ethyl acetate)
1-A- 4-amino-5-chloro-2-ethoxy-N-(4-methyl-hexahydro-1,4-thiazepin-6-yl)
Production of benzamide: Using 6-acetylamino-4-methyl-hexahydro-1,4-thiazepine in place of 2-acetylaminomethyl-4-benzyl-1,4-thiomorpholine in Example 1, the same procedure as in Example 1 was carried out. After reacting in the same manner, the product is purified by medium pressure silica gel chromatography and eluted with acetone to obtain the desired product.
融点 １４５−１４７°Ｃ（アセトンから再結晶）火五
拠−五
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フマル酸塩を得る。 融点 １
３７〜１３８°Ｃ（エタノールから再結晶）火癒拠−１
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−アミノ−５−クロロ−２−エトキシ安
息香酸の代りに６−アセチルアミノ−４−ベンジル−ヘ
キサヒドロ−１，４−チアゼピンと５−カルボキシ−６
−メドキシーＩＨ−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３／２フマル酸塩・１
／４エタノール・１７４永和物を得る。Melting point 145-147°C (recrystallized from acetone) 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-oxazepine, 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. Melting point 1
37-138°C (recrystallized from ethanol) Production of pyrolysis-1 5-[N-(4-benzyl-hexahydro-1°4-thiazepin-6-yl)]]carbamoyl-6-medoxy IH benzotriazole :2 in Example 1
-6-acetylamino-4-benzyl-hexahydro-1,4-thiazepine and 5 instead of acetylaminomethyl-4-benzyl-1,4-thiomorpholine and 4-amino-5-chloro-2-ethoxybenzoic acid. -carboxy-6
Using -Medoxy IH-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 3/2 fumarate of the target product and 1
/4 ethanol/174 permanent product is obtained.
融点 １６５〜１６８°Ｃ（エタノールから再結晶）夾
旌叢−ユ
４−アミノ−Ｎ−［（１−ベンジル−３−ピペリジニル
）メチル］−５−クロロー２−エトキシベンズアミドの
製造：
３−アミノメチル−１−ベンジルピペリジン２．４ｇの
塩化メチレン５０ ｍｌ溶液に、４−アミノ−５−クロ
ロ−２−エトキシ安息香酸２．５ｇを加え、次いで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２．３ｇを加え、室温で４時間攪拌する１
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後、溶
媒を減圧で留去する。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）で溶出・精製する。得られる油状の目的物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。Melting point 165-168°C (recrystallized from ethanol) Preparation of 4-amino-N-[(1-benzyl-3-piperidinyl)methyl]-5-chloro-2-ethoxybenzamide: 3-aminomethyl -To a solution of 2.4 g of 1-benzylpiperidine in 50 ml of methylene chloride was added 2.5 g of 4-amino-5-chloro-2-ethoxybenzoic acid, and then l-
Add 2.3 g of ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and stir at room temperature for 4 hours.
The reaction solution is washed with water, an aqueous sodium hydroxide solution, water, and saturated brine in this order, dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. The residue was subjected to silica gel column chromatography using chloroform-methanol (9:
Elute and purify in step 1). 3.0g of oily target material obtained
When dissolved in ethanol, added with an ethanol solution of oxalic acid and left at room temperature, 3/2 oxalate and 3/3 of the target substance were obtained.
A tetrahydrate is obtained.
融点 １０３〜１０５℃（エタノールから再結晶）夾施
Ｕ
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
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。これを常法によリフマル酸で処理して目的
物のフマル酸塩を得る。Melting point: 103-105°C (recrystallized from ethanol) 4-amino-5-chloro-N-[(1,4-diethyl-
Production of 2-piperazinyl)methyl]-2-ethoxybenzamide: Same as Example 7, using 2-aminomethyl-1°4-diethylpiperazine instead of 3-aminomethyl-1-benzylpiperidine in Example 7. React and process to obtain the desired product. This is treated with rifmaric acid in a conventional manner to obtain the target fumarate salt.
融点 ２０８〜２１０°Ｃ（メタノールから再結晶）火
旌拠−１
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−メトキシベンズアミ
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−アセ
チルアミノメチル−１，４−ジエチルピペラジンと４−
アミノ−５−クロロ−２−メトキシ安息香酸を用い、実
施例１と同様に反応した後、中圧シリカゲルクロマトグ
ラフィーに付し、アセトンで溶出・精製して油状の目的
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３／２フマル酸塩・１／４水和物を得る。Melting point 208-210°C (recrystallized from methanol) 4-amino-5-chloro-N-[(1,4-diethyl-
Preparation of 2-piperazinyl)methyl]-2-methoxybenzamide: Replacement of 2-acetylaminomethyl-4-benzyl-1,4-thiomorpholine and 4-amino-5-chloro-2-ethoxybenzoic acid in Example 1 2-acetylaminomethyl-1,4-diethylpiperazine and 4-acetylaminomethyl-1,4-diethylpiperazine, respectively.
After reacting in the same manner as in Example 1 using amino-5-chloro-2-methoxybenzoic acid, the reaction mixture was subjected to medium pressure silica gel chromatography and purified by elution with acetone to obtain the desired product as an oil. This is treated with fumaric acid in a conventional manner to obtain the target product, 3/2 fumarate/1/4 hydrate.
融点 １７３〜１７７°Ｃ（イソブロビルアルコールー
ジエチルエーテルがら再結晶）
夾施拠−１没
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
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＝ベンジル−４
−メチルビペラジンを用い、実施例７と同様に反応・処
理して目的物を得る。Melting point: 173-177°C (recrystallized from isobrobyl alcohol-diethyl ether)
Preparation of 2-aminomethyl-1-benzylpiperidine in Example 7, 2-aminomethyl-1=benzyl-4
- Using methylbiperazine, react and treat 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）夾
五拠−上Ｊ
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−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永和物を得る。 融点 １０３
〜１１０°Ｃ（エタノール−ジエチルエーテルから再結
晶）丈族拠−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
ピペラジンを用い、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 ９８〜１
０２°Ｃ（エタノール−ジエチルエーテルから再結晶）
夾胤貯−上１
４−アミノ−５−クロロ−Ｎ−［（１，４−ジメチル−
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２−アセチルア
ミノメチル−１，４−ジメチルピペラジンを用い、実施
例１と同様に反応・処理して目的物を得る。Melting point: 199-201°C (recrystallized from ethanol) Preparation of 4-amino-5-chloro-N-[(1,4-dibenzyl-2-piperazinyl)methyl]-2-methoxybenzamide: 2-aminomethyl-1,4-dibenzylpiperazine and 4-amino-5 were used instead of 3-aminomethyl-1-benzylpiperidine and 4-amino-5-chloro-2-ethoxybenzoic acid in Example 7, respectively. Using -chloro-2-methoxybenzoic acid, the reaction and treatment are carried out in the same manner as in Example 7 to obtain the desired oxalate salt 1-elongated product. Melting point 103
~110°C (recrystallized from ethanol-diethyl ether) Preparation of 11 4-amino-5-chloro-N-[(1,4-dibenzyl-2-piperazinyl)methyl]-2-ethoxybenzamide: Using 2-aminomethyl-1.4-dibenzylpiperazine in place of 3-aminomethyl-1-benzylpiperidine in Example 7, the reaction and treatment were carried out in the same manner as in Example 7 to obtain the target oxalate. Obtain hydrate. Melting point 98-1
02°C (recrystallized from ethanol-diethyl ether) 4-Amino-5-chloro-N-[(1,4-dimethyl-
2-Piperazinyl)methyl]-2-ethoxybenzamide: 2-acetylaminomethyl-1,4-dimethylpiperazine was substituted for 2-acetylaminomethyl-4-benzyl-1,4-thiomorpholine in Example 1. The desired product is obtained by reacting and treating in the same manner as in Example 1.
融点 １６２−１６３°Ｃ（）ルエンがら再結晶）夾五
冊−１１
４−アミノ−５−クロロ−Ｎ−［（１，４−ジメチル−
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−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−アセ
チルアミノメチル−１，４−ジメチルピペラジンと４−
アミノ−５−クロロ−２−メトキシ安息香酸を用い、実
施例１と同様に反応した後、中圧シリカゲルクロマトグ
ラフィーに付し、アセトンで溶出・精製して目的物を得
る。融点 １６０〜１６３°Ｃ（アセトンから再結晶）
夾隻尉−±５
４−アミノ−Ｎ−［（１−ベンジル−４−メチル−３−
ピペラジニル）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３−アセチルア
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１と同様に反応した後、中圧シリカゲルクロマ
トグラフィーに付し、アセトンで溶出・精製して目的物
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。 融点 １８８〜１９０°Ｃ（エタ
ノールから再結晶）
夾施桝−１１
４−アミノ−Ｎ−［（１−ベンジル−３−ピペリジニル
）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。Melting point 162-163°C () recrystallized from toluene) 11 4-amino-5-chloro-N-[(1,4-dimethyl-
Preparation of 2-piperazinyl)methyl]-2-methoxybenzamide: Replacement of 2-acetylaminomethyl-4-benzyl-1,4-thiomorpholine and 4-amino-5-chloro-2-ethoxybenzoic acid in Example 1 2-acetylaminomethyl-1,4-dimethylpiperazine and 4-acetylaminomethyl-1,4-dimethylpiperazine, respectively.
After reacting in the same manner as in Example 1 using amino-5-chloro-2-methoxybenzoic acid, the product is subjected to medium pressure silica gel chromatography and purified by elution with acetone to obtain the desired product. Melting point: 160-163°C (recrystallized from acetone)
Kampai-±5 4-amino-N-[(1-benzyl-4-methyl-3-
Preparation of 2-acetylaminomethyl-4-benzyl-1,4-thiomorpholine in Example 1: 3-acetylaminomethyl-1-benzyl-4- After reacting in the same manner as in Example 1 using methylpiperazine, the product is subjected to medium pressure silica gel chromatography and purified by elution with acetone to obtain the desired product. This is treated with fumaric acid in a conventional manner to obtain the target fumarate salt. Melting point 188-190°C (recrystallized from ethanol) Production of 4-amino-N-[(1-benzyl-3-piperidinyl)methyl]-5-chloro-2-methoxybenzamide: in Example 7 Using 4-amino-5-chloro-2-methoxybenzoic acid instead of 4-amino-5-chloro-2-ethoxybenzoic acid, the reaction and treatment were carried out in the same manner as in Example 7 to obtain 3/2 of the target product. Obtain the acid salt monohydrate.
融点 １０４〜１０７℃（エタノールから再結晶）火五
桝−１ユ
４−アミノ−Ｎ−［（１−ベンジル−１，２゜５．６−
テトラヒドロビリジン−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，
２，５，６−チトラヒドロビリジンを用い、実施例７と
同様に反応・処理して目的物を得る。 融点 １４４〜
１４７°Ｃ（エタノール−トルエンから再結晶）
Ｘ旌烈−１１
４−アミノ−Ｎ−［（１−ベンジル−１，２゜５．６−
テトラヒドロビリジン−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３−アミノメチル−１−ベンジル
−１，２，５，６−チトラヒドロビリジンと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’Ｃ（エタノール−トルエンから再結晶）
１９〜２３
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: 104-107°C (recrystallized from ethanol)
Preparation of methyl]-5-chloro-2-ethoxybenzamide: 3-aminomethyl-1-benzyl-1, instead of 3-aminomethyl-1-benzylpiperidine in Example 7
Using 2,5,6-titrahydrobiridine, the reaction and treatment are carried out in the same manner as in Example 7 to obtain the desired product. Melting point 144~
147°C (recrystallized from ethanol-toluene)
Preparation of 3-aminomethyl-1-benzylpiperidine and 4-amino-5-chloro-2-ethoxybenzoic acid in Example 7 , using 3-aminomethyl-1-benzyl-1,2,5,6-titrahydrobiridine and 4-amino-5-chloro-2-methoxybenzoic acid, respectively, Example 7
React and process in the same manner as above to obtain the desired product. Melting point 147
~150'C (recrystallized from ethanol-toluene) 19-23 Using the corresponding raw material compounds, the compounds shown in Table 2 are 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：イソプロピルアルコール
Ｍ ：メタノール
（以下余白）
表２
Ｈ２Ｐｈ
（以下余白）
実肩ｊ［−支ま
４−アミノ−Ｎ−（１−ベンジル−ＩＨ−へキサヒドロ
アゼピン−３−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３−アセチルア
ミノ−１−ベンジル−ＩＨ−へキサヒドロアゼピンを用
い、実施例１と同様に反応した後、中圧シリカゲルカラ
ムクロマトグラフィーに付し、アセトンで溶出・精製し
て目的物を得る。これを常法によりマレイン酸で処理し
て目的物のマレイン酸塩を得る。 融点 １７４〜１７
Ｅｉ°Ｃ（エタノール−メタノールがら再結晶）火に冊
−１１
４−アミノ−５−クロロ−２−エトキシ−Ｎ−（１−メ
チル−’ＩＨ−へキサヒドロアゼピン−３−イル）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３−アセチルア
ミノ−１−メチル−ＩＨ−へキサヒドロアゼピンを用い
、実施例１と同様に反応した後、中圧シリカゲルカラム
クロマトグラフィーに付し、アセトンで溶出・精製して
目的物を得る。Me: Methyl group Et: Ethyl group Ph: Phenyl group A: Ethanol IP: Isopropyl alcohol M: Methanol (blank below) Table 2 H2Ph (blank below) Real shoulder j [-support 4-amino-N-(1-benzyl -IH-hexahydroazepin-3-yl)-5-chloro-2-ethoxybenzamide: 3-acetyl instead of 2-acetylaminomethyl-4-benzyl-1,4-thiomorpholine in Example 1 After reacting in the same manner as in Example 1 using amino-1-benzyl-IH-hexahydroazepine, the product is subjected to medium pressure silica gel column chromatography and purified by elution with acetone to obtain the desired product. This is treated with maleic acid in a conventional manner to obtain the desired maleate salt. Melting point 174-17
Ei°C (Recrystallization from ethanol-methanol) Tue-11 Production of 4-amino-5-chloro-2-ethoxy-N-(1-methyl-'IH-hexahydroazepin-3-yl)benzamide : The reaction was carried out in the same manner as in Example 1, using 3-acetylamino-1-methyl-IH-hexahydroazepine instead of 2-acetylaminomethyl-4-benzyl-1,4-thiomorpholine in Example 1. After that, it is subjected to medium pressure silica gel column chromatography and purified by elution with acetone to obtain the desired product.
融点 １２８〜１３０℃（エタノール−ジエチルエーテ
ルから再結晶）
夾胤五−又１
４−アミノ−５−クロロ−２−メトキシ−Ｎ−（１−メ
チル−ＩＨ−へキサヒドロアゼピン−３−イル）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−アセ
チルアミノ−１−メチル−ＩＨ−へキサヒドロアゼピン
と４−アミノ−５−クロロ−２−メトキシ安息香酸を用
い、実施例１と同様に反応・処理して目的物を得る。Melting point: 128-130°C (recrystallized from ethanol-diethyl ether) Preparation of benzamide: In place of 2-acetylaminomethyl-4-benzyl-1,4-thiomorpholine and 4-amino-5-chloro-2-ethoxybenzoic acid in Example 1, 3-acetylamino-1- Using methyl-IH-hexahydroazepine and 4-amino-5-chloro-2-methoxybenzoic acid, the reaction and treatment are carried out in the same manner as in Example 1 to obtain the desired product.
融点 １７０〜１７３°Ｃ（アセトンから再結晶）大溝
律Ｌ−１ｊ−
４−アミノ−Ｎ−［（４−ベンジル−１，４−チオモル
ホリン−１−才キシト−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−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ｔ、ｔｇを塩化メチレン２０ ｍｌに溶
解し、食塩−氷で冷却しながら、ｍ−クロロ過安息香酸
０．６２ ｇを加え、１時間攪拌する１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後
、溶媒を減圧で留去する。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、得られる油状物をイソプロ
ピルアルコールで結晶化して目的物０．３ｇを得る。
融点 １９３〜１９５°Ｃ
犬旌拠−１１
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−ベンジル−１，４−チオモル
ホリン−２−イル）メチル】−５−クロロ−２−エトキ
シベンズアミド０．５ｇを塩化メチレン１０ ｍｌに溶
解し、水冷下ｍ−クロロ過安息香酸０．４５ ｇを加え
、室温に戻し１７時間攪拌する０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後、溶媒
を減圧で留去する。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 １９３〜１９
８°Ｃ特許出願人 大日本製薬株式会社Melting point 170-173°C (recrystallized from acetone) Omizo Ritsu L-1j- 4-amino-N-[(4-benzyl-1,4-thiomorpholin-1-oxyt-2-yl)methyl]-5 -Production of chloro-2-ethoxybenzamide: 4-amino-N-[(4-benzyl-1,4-thiomorpholin-2-yl)methyl]-5-chloro-2-ethoxybenzamide t,tg in 20 ml of methylene chloride Add 0.62 g of m-chloroperbenzoic acid while cooling with salt-ice and stir for 1 hour. Add saturated aqueous sodium bicarbonate solution to the reaction mixture and extract with chloroform. After washing the organic layer with water and drying over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure. The residue was subjected to silica gel column chromatography using chloroform-methanol (
20:1) and the resulting oil was crystallized with isopropyl alcohol to obtain 0.3 g of the desired product.
Melting point 193-195°C Dog test-11 4-amino-N-[(4-benzyl-1,4-thiomorpholin-1,1-dioxid-2-yl)methyl]-5
-Production of chloro-2-ethoxybenzamide: 0.5 g of 4-amino-N-[(4-benzyl-1,4-thiomorpholin-2-yl)methyl]-5-chloro-2-ethoxybenzamide was added to 10 g of methylene chloride. ml, add 0.45 g of m-chloroperbenzoic acid under water cooling, return to room temperature and stir for 17 hours. To the reaction mixture, saturated aqueous sodium bicarbonate solution is added and extracted with chloroform. After washing the organic layer with water and drying over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure. The residue is recrystallized from acetone-ethanol to obtain 0.4 g of the desired product. Melting point 193-19
8°C patent applicant Dainippon Pharmaceutical Co., Ltd.
Claims (1)
換基を有するアリール（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
結合または低級アルキレン基を意味し、Ｙは単結合、−
ＣＨ＿２−、−Ｏ−、−Ｓ−、−ＳＯ−、−ＳＯ＿２−
又は−ＮＲ＿６−で表される基を意味し、ここにおいて
Ｒ＿６は低級アルキル基又は非置換もしくは置換基を有
するアリール（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いてもよ
く、 ｎは０又は１を意味し、 破線はＹが−ＣＨ＿２−でｎが０であるときは場合によ
り存在する二重結合を意味する。但し、 （ｉ）Ｙが−ＮＲ＿６−又は単結合であるとき、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−であり、ｎが０
であるとき、Ｒ＿１は非置換もしくは置換基を有するア
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 formula, chemical formula, table, etc. ▼ [In the formula, R_1 means a lower alkyl group or an unsubstituted or substituted aryl (lower) alkyl group, R_2 is a hydroxy group, It means 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), and R_3 is an amino group, a disubstituted amino group, or an acylamino group. , R_4 means a halogen atom, or R_3 and R_4 may be taken together to form -NH-N=N-, R_5 means a hydrogen atom or a lower alkyl group, and X is means a single bond or a lower alkylene group, Y is a single bond, -
CH_2-, -O-, -S-, -SO-, -SO_2-
or -NR_6-, where R_6 means a lower alkyl group or an unsubstituted or substituted aryl (lower) alkyl group, or together with R_1 forms an ethylene group. n means 0 or 1, and the broken line means a double bond that may be present when Y is -CH_2- and n is 0. However, (i) When Y is -NR_6- or a single bond, n is 0
(ii) When Y is -O-, n means 1, (iii) When Y is a single bond or -CH_2- and n is 0
(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 |
|---|---|---|---|
| JP25766588A JPH02104572A (en) | 1988-10-13 | 1988-10-13 | Benzoic acid amide derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP25766588A JPH02104572A (en) | 1988-10-13 | 1988-10-13 | Benzoic acid amide derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH02104572A true JPH02104572A (en) | 1990-04-17 |
Family
ID=17309402
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP25766588A Pending JPH02104572A (en) | 1988-10-13 | 1988-10-13 | Benzoic acid amide derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH02104572A (en) |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0774460A4 (en) * | 1994-03-30 | 1997-03-18 | Yoshitomi Pharmaceutical | Benzoic acid compound and use thereof as medicine |
| EP0794184A4 (en) * | 1994-11-21 | 1998-01-14 | Dainippon Pharmaceutical Co | 6-methoxy-1h-benzotriazole-5-carboxamide derivatives, process for producing the same, and medicinal composition containing the same |
| 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 |
| FR2819511A1 (en) * | 2001-01-18 | 2002-07-19 | Servier Lab | New N-substituted azepane or azepanone derivatives, are selective farnesyl transferase inhibitors useful for treating cancer diseases, restenosis or type I neurofibromatosis |
| EP1390034A1 (en) * | 2001-04-03 | 2004-02-25 | Merck & Co., Inc. | N-substituted nonaryl-heterocyclo amidyl nmda/nr2b antagonists |
-
1988
- 1988-10-13 JP JP25766588A patent/JPH02104572A/en active Pending
Cited By (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0774460A1 (en) * | 1994-03-30 | 1997-05-21 | Yoshitomi Pharmaceutical Industries, Ltd. | Benzoic acid compound and use thereof as medicine |
| EP0774460A4 (en) * | 1994-03-30 | 1997-03-18 | Yoshitomi Pharmaceutical | Benzoic acid compound and use thereof as medicine |
| US5932568A (en) * | 1994-11-21 | 1999-08-03 | Dainippon Pharmaceutical Co., Ltd. | 6-methoxy-1H-benzotriazole-5-carboxamide derivatives and pharmaceutical compositions containing them |
| EP0794184A4 (en) * | 1994-11-21 | 1998-01-14 | Dainippon Pharmaceutical Co | 6-methoxy-1h-benzotriazole-5-carboxamide derivatives, process for producing the same, and medicinal composition containing the same |
| 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 |
| FR2819511A1 (en) * | 2001-01-18 | 2002-07-19 | Servier Lab | New N-substituted azepane or azepanone derivatives, are selective farnesyl transferase inhibitors useful for treating cancer diseases, restenosis or type I neurofibromatosis |
| EP1390034A1 (en) * | 2001-04-03 | 2004-02-25 | Merck & Co., Inc. | N-substituted nonaryl-heterocyclo amidyl nmda/nr2b antagonists |
| EP1390034A4 (en) * | 2001-04-03 | 2005-07-13 | Merck & Co Inc | N-substituted nonaryl-heterocyclo amidyl nmda/nr2b antagonists |
| AU2002338334B2 (en) * | 2001-04-03 | 2008-08-14 | Merck & Co., Inc. | N-substituted nonaryl-heterocyclo amidyl NMDA/NR2B antagonists |
| AU2002338334B8 (en) * | 2001-04-03 | 2008-09-18 | Merck & Co., Inc. | N-substituted nonaryl-heterocyclo amidyl NMDA/NR2B antagonists |
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