JPH01156973A - Benzofuran derivative - Google Patents
Benzofuran derivativeInfo
- Publication number
- JPH01156973A JPH01156973A JP21211888A JP21211888A JPH01156973A JP H01156973 A JPH01156973 A JP H01156973A JP 21211888 A JP21211888 A JP 21211888A JP 21211888 A JP21211888 A JP 21211888A JP H01156973 A JPH01156973 A JP H01156973A
- Authority
- JP
- Japan
- Prior art keywords
- group
- phenyl
- lower alkyl
- atom
- benzofuran
- 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
- 150000001907 coumarones Chemical class 0.000 title claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 41
- 150000003839 salts Chemical class 0.000 claims abstract description 17
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 15
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 14
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 6
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 6
- -1 methoxyphenyl group Chemical group 0.000 claims description 15
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 6
- 125000005843 halogen group Chemical group 0.000 claims description 5
- 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 claims description 5
- 125000004434 sulfur atom Chemical group 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 3
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 3
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 3
- 125000002112 pyrrolidino group Chemical group [*]N1C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 3
- XTNMMWRMODSPMZ-UHFFFAOYSA-N 1-[2-[(2-phenyl-1-benzofuran-7-yl)methylsulfanyl]ethyl]piperidine Chemical compound C=1C=CC=2C=C(C=3C=CC=CC=3)OC=2C=1CSCCN1CCCCC1 XTNMMWRMODSPMZ-UHFFFAOYSA-N 0.000 claims description 2
- JYINXOWDSLEDQK-UHFFFAOYSA-N 1-[2-[(5-methoxy-2-phenyl-1-benzofuran-7-yl)methylsulfanyl]ethyl]piperidine Chemical compound C=12OC(C=3C=CC=CC=3)=CC2=CC(OC)=CC=1CSCCN1CCCCC1 JYINXOWDSLEDQK-UHFFFAOYSA-N 0.000 claims description 2
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- 125000000068 chlorophenyl group Chemical group 0.000 claims 1
- 125000002911 monocyclic heterocycle group Chemical group 0.000 claims 1
- 125000003944 tolyl group Chemical group 0.000 claims 1
- 230000027939 micturition Effects 0.000 abstract description 18
- 230000008602 contraction Effects 0.000 abstract description 12
- IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical compound C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 abstract description 7
- 239000003795 chemical substances by application Substances 0.000 abstract description 6
- 210000003932 urinary bladder Anatomy 0.000 abstract description 6
- 230000002401 inhibitory effect Effects 0.000 abstract description 5
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 abstract description 4
- 201000010099 disease Diseases 0.000 abstract description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 3
- 208000008967 Enuresis Diseases 0.000 abstract description 2
- 208000000693 Neurogenic Urinary Bladder Diseases 0.000 abstract description 2
- 206010029279 Neurogenic bladder Diseases 0.000 abstract description 2
- 208000005346 nocturnal enuresis Diseases 0.000 abstract description 2
- 238000002360 preparation method Methods 0.000 abstract description 2
- 230000003449 preventive effect Effects 0.000 abstract description 2
- 210000001635 urinary tract Anatomy 0.000 abstract description 2
- 206010036018 Pollakiuria Diseases 0.000 abstract 1
- 150000001412 amines Chemical class 0.000 abstract 1
- 229910052736 halogen Inorganic materials 0.000 abstract 1
- 150000002367 halogens Chemical class 0.000 abstract 1
- 125000000623 heterocyclic group Chemical group 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 229940043274 prophylactic drug Drugs 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 51
- 239000000203 mixture Substances 0.000 description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 20
- 239000002904 solvent Substances 0.000 description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 7
- 238000001035 drying Methods 0.000 description 7
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000002994 raw material Substances 0.000 description 6
- 230000002485 urinary effect Effects 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- 241000700159 Rattus Species 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- 239000002504 physiological saline solution Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- QCACXVSIJPTVSP-UHFFFAOYSA-N 7-(chloromethyl)-2-phenyl-1-benzofuran Chemical compound O1C=2C(CCl)=CC=CC=2C=C1C1=CC=CC=C1 QCACXVSIJPTVSP-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 239000012280 lithium aluminium hydride Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000004533 oil dispersion Substances 0.000 description 3
- 239000012312 sodium hydride Substances 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- CRSAYNGZMMWOFE-UHFFFAOYSA-N (2-phenyl-1-benzofuran-7-yl)methanol Chemical compound O1C=2C(CO)=CC=CC=2C=C1C1=CC=CC=C1 CRSAYNGZMMWOFE-UHFFFAOYSA-N 0.000 description 2
- VFLQQZCRHPIGJU-UHFFFAOYSA-N 1-(2-chloroethyl)piperidine;hydron;chloride Chemical compound Cl.ClCCN1CCCCC1 VFLQQZCRHPIGJU-UHFFFAOYSA-N 0.000 description 2
- IZZIWIAOVZOBLF-UHFFFAOYSA-N 5-methoxysalicylic acid Chemical compound COC1=CC=C(O)C(C(O)=O)=C1 IZZIWIAOVZOBLF-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 239000004698 Polyethylene Substances 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 2
- 210000001198 duodenum Anatomy 0.000 description 2
- 210000003191 femoral vein Anatomy 0.000 description 2
- XOEVKNFZUQEERE-UHFFFAOYSA-N flavoxate hydrochloride Chemical compound Cl.C1=CC=C2C(=O)C(C)=C(C=3C=CC=CC=3)OC2=C1C(=O)OCCN1CCCCC1 XOEVKNFZUQEERE-UHFFFAOYSA-N 0.000 description 2
- 239000003205 fragrance Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- VKYKSIONXSXAKP-UHFFFAOYSA-N hexamethylenetetramine Chemical compound C1N(C2)CN3CN1CN2C3 VKYKSIONXSXAKP-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 229920000573 polyethylene Polymers 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 230000011514 reflex Effects 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 210000005239 tubule Anatomy 0.000 description 2
- 210000000626 ureter Anatomy 0.000 description 2
- 238000003466 welding Methods 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- VFBNXNQTXQVVDG-UHFFFAOYSA-N 1-[2-[(2-phenyl-1-benzofuran-7-yl)methoxy]ethyl]piperidine;hydrochloride Chemical compound Cl.C=1C=CC=2C=C(C=3C=CC=CC=3)OC=2C=1COCCN1CCCCC1 VFBNXNQTXQVVDG-UHFFFAOYSA-N 0.000 description 1
- KBHHPDJPUXWKRE-UHFFFAOYSA-N 2-(4-methoxyphenyl)-1-benzofuran-7-carboxylic acid Chemical compound C1=CC(OC)=CC=C1C1=CC2=CC=CC(C(O)=O)=C2O1 KBHHPDJPUXWKRE-UHFFFAOYSA-N 0.000 description 1
- SQHQPORREDQNBH-UHFFFAOYSA-N 2-(4-methylphenyl)-1-benzofuran-7-carboxylic acid Chemical compound C1=CC(C)=CC=C1C1=CC2=CC=CC(C(O)=O)=C2O1 SQHQPORREDQNBH-UHFFFAOYSA-N 0.000 description 1
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 1
- AAUQLHHARJUJEH-UHFFFAOYSA-N 2-hydroxy-5-methoxybenzoic acid Natural products COC1=CC=CC(O)=C1C(O)=O AAUQLHHARJUJEH-UHFFFAOYSA-N 0.000 description 1
- RCBWMXHRGVANAW-UHFFFAOYSA-N 2-phenyl-1-benzofuran-7-carboxylic acid Chemical compound O1C=2C(C(=O)O)=CC=CC=2C=C1C1=CC=CC=C1 RCBWMXHRGVANAW-UHFFFAOYSA-N 0.000 description 1
- KMMBBZOSQNLLMN-UHFFFAOYSA-N 3-methylflavone-8-carboxylic acid Chemical compound O1C2=C(C(O)=O)C=CC=C2C(=O)C(C)=C1C1=CC=CC=C1 KMMBBZOSQNLLMN-UHFFFAOYSA-N 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- LALPLAOLAOORPI-UHFFFAOYSA-N 5-chloro-2-phenyl-1-benzofuran-7-carboxylic acid Chemical compound O1C=2C(C(=O)O)=CC(Cl)=CC=2C=C1C1=CC=CC=C1 LALPLAOLAOORPI-UHFFFAOYSA-N 0.000 description 1
- WLGGJFMFRKYMDF-UHFFFAOYSA-N 5-chloro-3-formyl-2-hydroxybenzoic acid Chemical compound OC(=O)C1=CC(Cl)=CC(C=O)=C1O WLGGJFMFRKYMDF-UHFFFAOYSA-N 0.000 description 1
- NKBASRXWGAGQDP-UHFFFAOYSA-N 5-chlorosalicylic acid Chemical compound OC(=O)C1=CC(Cl)=CC=C1O NKBASRXWGAGQDP-UHFFFAOYSA-N 0.000 description 1
- LAMZJYOMAGOZGH-UHFFFAOYSA-N 5-methoxy-2-phenyl-1-benzofuran-7-carboxylic acid Chemical compound C=1C2=CC(OC)=CC(C(O)=O)=C2OC=1C1=CC=CC=C1 LAMZJYOMAGOZGH-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 239000005973 Carvone Substances 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 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
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
- 150000008041 alkali metal carbonates Chemical class 0.000 description 1
- 229910000102 alkali metal hydride Inorganic materials 0.000 description 1
- 150000008046 alkali metal hydrides Chemical class 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 125000005278 alkyl sulfonyloxy group Chemical group 0.000 description 1
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 1
- NZUPCNDJBJXXRF-UHFFFAOYSA-O bethanechol Chemical compound C[N+](C)(C)CC(C)OC(N)=O NZUPCNDJBJXXRF-UHFFFAOYSA-O 0.000 description 1
- 229960000910 bethanechol Drugs 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 238000010531 catalytic reduction reaction Methods 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 230000008828 contractile function Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000006806 disease prevention Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 235000012438 extruded product Nutrition 0.000 description 1
- 229960000855 flavoxate Drugs 0.000 description 1
- 229960003064 flavoxate hydrochloride Drugs 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 239000004312 hexamethylene tetramine Substances 0.000 description 1
- 235000010299 hexamethylene tetramine Nutrition 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 230000036724 intravesical pressure Effects 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- FBBDOOHMGLLEGJ-UHFFFAOYSA-N methane;hydrochloride Chemical compound C.Cl FBBDOOHMGLLEGJ-UHFFFAOYSA-N 0.000 description 1
- 125000005948 methanesulfonyloxy group Chemical group 0.000 description 1
- LWQLLIVTGSMSCT-UHFFFAOYSA-N methyl 2-bromo-2-(4-chlorophenyl)acetate Chemical compound COC(=O)C(Br)C1=CC=C(Cl)C=C1 LWQLLIVTGSMSCT-UHFFFAOYSA-N 0.000 description 1
- KIGMFKZMNIHLSU-UHFFFAOYSA-N methyl 3-formyl-2-hydroxybenzoate Chemical compound COC(=O)C1=CC=CC(C=O)=C1O KIGMFKZMNIHLSU-UHFFFAOYSA-N 0.000 description 1
- BKMPCMXOQXGTJN-UHFFFAOYSA-N methyl 5-chloro-3-formyl-2-hydroxybenzoate Chemical compound COC(=O)C1=CC(Cl)=CC(C=O)=C1O BKMPCMXOQXGTJN-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- AGPIRUVUGBJHMU-UHFFFAOYSA-N oxalic acid;1-[2-[(2-phenyl-1-benzofuran-7-yl)methylsulfanyl]ethyl]piperidine Chemical compound OC(=O)C(O)=O.C=1C=CC=2C=C(C=3C=CC=CC=3)OC=2C=1CSCCN1CCCCC1 AGPIRUVUGBJHMU-UHFFFAOYSA-N 0.000 description 1
- WWRUFBWWHJODKK-UHFFFAOYSA-K oxolane;trichlorovanadium Chemical compound Cl[V](Cl)Cl.C1CCOC1.C1CCOC1.C1CCOC1 WWRUFBWWHJODKK-UHFFFAOYSA-K 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000001020 rhythmical effect Effects 0.000 description 1
- 238000009738 saturating Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- IIACRCGMVDHOTQ-UHFFFAOYSA-M sulfamate Chemical compound NS([O-])(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-M 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- 239000005051 trimethylchlorosilane Substances 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Landscapes
- Furan Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
（産業上の利用分野）
本発明は頻尿の治療・予防剤として有用なベンゾフラン
誘導体に関する。DETAILED DESCRIPTION OF THE INVENTION (Industrial Field of Application) The present invention relates to benzofuran derivatives useful as therapeutic and preventive agents for frequent urination.
（従来技術）
頻尿患者においては、−昼夜の排尿回数は健康人のそれ
よりも多くなり、この結果、日常生活に支障をきたすこ
とも少なくない。一方、排尿は反射性の排尿収縮によっ
て引き起こされるため、この排尿収縮を抑制する作用は
頻尿の治療にとって有用である。(Prior Art) In patients with frequent urination, the number of times they urinate during the day and night is greater than that of healthy people, and as a result, their daily life is often disturbed. On the other hand, since urination is caused by reflex urinary contractions, the effect of suppressing urinary contractions is useful for the treatment of frequent urination.
従来、反射性排尿収縮抑制作用を有する頻尿治療剤とし
ては、例えばフラボキセート（Ｆｌａｖｏｘａｔｅ：化
学名：３−メチル−４−オキソ−２−フェニル−４Ｈ−
１−ベンゾピラン−８−カルボン酸２−ピペリジノエチ
ルエステル〕が知られている（基礎と臨床、Ｖｏｌ、１
８、Ｎｏ、 ６．１２１〜１２７ （１９８４））。Conventionally, as a therapeutic agent for frequent urination having an effect of suppressing reflex micturition contraction, for example, flavoxate (chemical name: 3-methyl-4-oxo-2-phenyl-4H-
1-Benzopyran-8-carboxylic acid 2-piperidinoethyl ester] is known (Basic and Clinical Studies, Vol. 1).
8, No. 6.121-127 (1984)).
（発明の構成及び効果）
本発明は次の一般式（１）で示されるベンゾフラン誘導
体又はその薬理的に許容しうる塩に関する。(Structure and Effects of the Invention) The present invention relates to a benzofuran derivative represented by the following general formula (1) or a pharmacologically acceptable salt thereof.
（但し、Ｒ１は水素原子、低級アルコキシ基又はハロゲ
ン原子、Ｒ２及びＩ？３は一方が低級アルキル基であり
、他方が低級アルキル基又はフェニル低級アルキル基で
あるか、或いは両者が末端で結合して隣接する窒素原子
とともに複素単環式基を形成していることを表し、項八
は置換又は非置換フェニル基、Ｙは酸素原子又は硫黄原
子、ｎは２又は３を表す。）
本発明のベンゾフラン誘導体（Ｉ）又はその塩は新規化
合物であり、頻尿治療・予防剤として有用な医薬化合物
である。(However, R1 is a hydrogen atom, a lower alkoxy group, or a halogen atom, and one of R2 and I-3 is a lower alkyl group and the other is a lower alkyl group or a phenyl lower alkyl group, or both are bonded at the terminal. Term 8 represents a substituted or unsubstituted phenyl group, Y represents an oxygen atom or a sulfur atom, and n represents 2 or 3.) of the present invention. Benzofuran derivative (I) or a salt thereof is a new compound, and is a useful pharmaceutical compound as an agent for treating and preventing frequent urination.
例えば、雌性ラットに検体を十二指腸内投与してラット
の排尿収縮抑制作用を調べたところ、本発明の２−フェ
ニル−５−メトキシ−７−（２−ピペリジノエチルチオ
メチル）ベンゾフランはフラポキセートに比べ１０倍以
上強い排尿収縮抑制作用を示す。For example, when a sample was intraduodenally administered to female rats to examine its effect on suppressing urinary contractions in rats, it was found that 2-phenyl-5-methoxy-7-(2-piperidinoethylthiomethyl)benzofuran of the present invention was more effective than frapoxate. It exhibits a urinary contraction inhibitory effect that is more than 10 times stronger than that of other drugs.
本発明の目的化合物の具体例としては、一般式（１）に
おいて、環Ａがフェニル基；又は低級アルキル基、低級
アルコキシ基もしくはハロゲン原子で置換されたフェニ
ル基である化合物があげられる。Specific examples of the target compounds of the present invention include compounds in general formula (1) in which ring A is a phenyl group; or a phenyl group substituted with a lower alkyl group, a lower alkoxy group, or a halogen atom.
またＲ２及びＲ３の一方が低級アルキル基であり、他方
が低級アルキル基又はフェニル低級アルキル基であるか
、或いはＲ２及びＲ３が末端で結合して隣接する窒素原
子と共にピロリジノ基、ピペリジノ基又はモルホリノ基
を形成している化合物があげられる。In addition, one of R2 and R3 is a lower alkyl group and the other is a lower alkyl group or a phenyl lower alkyl group, or R2 and R3 are bonded at the terminal and together with the adjacent nitrogen atom, a pyrrolidino group, piperidino group, or morpholino group. Examples include compounds that form
この内、治療上より好ましい化合物は、低級アルキル基
及び低級アルコキシ基が炭素数１〜４のアルキル基及び
アルコキシ基の化合物である。Among these, therapeutically more preferred compounds are those in which the lower alkyl group and the lower alkoxy group have 1 to 4 carbon atoms.
治療上特に好ましい化合物としては、一般式（■）にお
いて、Ｒ１が水素原子、メトキシ基又は塩素原子であり
、Ｒ２がメチル基又はエチル基でありＲ３がメチル基、
エチル基又はベンジル基であるか、或いはＲ２及びＲ３
が末端で結合して隣接する窒素原子と共にピロリジノ基
、ピペリジノ基又はモルホリノ基を形成しており、環Ａ
がフェニル基、４−メチルフェニル基、４−メトキシフ
ェニル基又は４−クロロフェニル基である化合物があげ
られる。Particularly preferable compounds for treatment include general formula (■) in which R1 is a hydrogen atom, a methoxy group or a chlorine atom, R2 is a methyl group or an ethyl group, and R3 is a methyl group;
Ethyl group or benzyl group, or R2 and R3
is bonded at the terminal to form a pyrrolidino group, piperidino group, or morpholino group with the adjacent nitrogen atom, and ring A
is a phenyl group, 4-methylphenyl group, 4-methoxyphenyl group or 4-chlorophenyl group.
更に好ましい化合物はＲ１が水素原子又はメトキシ基で
あり、Ｒ２及びＲ３が末端で結合して隣接する窒素原子
と共にピペリジノ基を形成しており、Ｙが硫黄原子であ
り、ｎが２である化合物があげられる。A more preferred compound is a compound in which R1 is a hydrogen atom or a methoxy group, R2 and R3 are bonded at the terminal to form a piperidino group with the adjacent nitrogen atom, Y is a sulfur atom, and n is 2. can give.
本発明によれば、目的化合物（１）は、例えば一般式
ＣＨ２−Ｘ’
（但し、×１は反応性残基を表し、Ｒ１及び環Ａは前記
と同一意味を有する。）
で示されるベンゾフラン化合物と一般式（但し、Ｒ２、
Ｒ３、Ｙ及びｎは前記と同一意味を有する。）
で示されるアミン化合物又はその塩とを反応させるか、
或いは一般式
％式％
（但し、Ｒ１、環Ａ及びＹは前記と同一意味を有する。According to the present invention, the target compound (1) is, for example, a benzofuran represented by the general formula CH2-X' (wherein x1 represents a reactive residue, and R1 and ring A have the same meanings as above). Compound and general formula (however, R2,
R3, Y and n have the same meanings as above. ) with an amine compound or its salt, or
Or the general formula % formula % (However, R1, ring A and Y have the same meanings as above.
）
で示されるベンゾフラン化合物と一般式（但し、Ｘ２は
反応性残基を表し、Ｒ２、Ｒ３及びｎは前記と同一意味
を有する。）
で示されるアミン化合物又はその塩とを反応させること
により製造することができる。) Produced by reacting a benzofuran compound represented by the formula with an amine compound represented by the general formula (wherein, X2 represents a reactive residue, and R2, R3 and n have the same meanings as above) or a salt thereof. can do.
上記反応に用いられる原料化合物（［）及び（Ｖ）にお
ける反応性残基ＸＩ及びＸ２としては、例えばフッ素原
子、塩素原子、臭素原子の如きハロゲン原子、メタンス
ルホニルオキシ基の如き低級アルキルスルホニルオキシ
基、トルエンスルホニルオキシ基の如き置換又は非置換
アリルスルホニルオキシ基等が好適にあげられる。また
、原料化合物（［［Ｉ）又は（Ｖ）の塩としては、例え
ば塩酸塩、臭化水素酸塩、硫酸塩等が好適にあげられる
。The reactive residues XI and X2 in the raw material compounds ([) and (V) used in the above reaction include, for example, halogen atoms such as fluorine atom, chlorine atom, and bromine atom, and lower alkylsulfonyloxy groups such as methanesulfonyloxy group. , a substituted or unsubstituted allylsulfonyloxy group such as a toluenesulfonyloxy group, and the like. Further, as the salt of the raw material compound ([[I) or (V)], for example, hydrochloride, hydrobromide, sulfate, etc. are preferably mentioned.
化合物（ＩＩ）と化合物（ＩＩＩ）又はその塩との反応
及び化合物（ＩＶ）と化合物（Ｖ）又はその塩との反応
は、脱酸剤の存在もしくは非存在下に実施することがで
きる。脱酸剤としては、例えば水酸化アルカリ金属、炭
酸アルカリ金属、炭酸水素アルカリ金属、水素化アルカ
リ金属、アルカリ金属アルコキシド、トリアルキルアミ
ン、ピリジンなどが好適にあげられる。これら反応は適
当な溶媒（例えば、低級アルカノール、テトラヒドロフ
ラン、ジオキサン、ジメチルホルムアミド、ジメチルス
ルホキシド等）中冷却〜加熱下に実施するのが好ましい
。The reaction between compound (II) and compound (III) or a salt thereof and the reaction between compound (IV) and compound (V) or a salt thereof can be carried out in the presence or absence of a deoxidizing agent. Preferred examples of the deoxidizing agent include alkali metal hydroxide, alkali metal carbonate, alkali metal hydrogen carbonate, alkali metal hydride, alkali metal alkoxide, trialkylamine, and pyridine. These reactions are preferably carried out in a suitable solvent (eg, lower alkanol, tetrahydrofuran, dioxane, dimethylformamide, dimethyl sulfoxide, etc.) under cooling to heating.
本発明の目的化合物（１）を医薬として使用する場合、
遊離化合物としても、またその薬理的に許容しうる塩の
形ででも使用することができる。When using the object compound (1) of the present invention as a medicine,
It can be used both as the free compound and in the form of its pharmacologically acceptable salts.
薬理的に許容しうる塩としては、例えば塩酸塩、臭化水
素酸塩、硫酸塩の如き無機酸付加塩、シュウ酸塩、スル
ファミン酸塩、酢酸塩、フマール酸塩、マレイン酸塩、
クエン酸塩、メタンスルホン酸塩等の如き有機酸付加塩
などがあげられる。Examples of pharmacologically acceptable salts include inorganic acid addition salts such as hydrochloride, hydrobromide, sulfate, oxalate, sulfamate, acetate, fumarate, maleate,
Examples include organic acid addition salts such as citrate, methanesulfonate, and the like.
本発明の目的化合物（１）又はその塩は前述の通り、優
れた排尿収縮抑制作用を有するため、膀胱ならびに尿管
等の尿路系収縮機能に関する疾患、例えば頻尿、夜尿症
、神経因性膀胱等の疾患の治療・予防に使用することが
できる。As mentioned above, the object compound (1) of the present invention or a salt thereof has an excellent effect of suppressing urinary contraction, so it can be used to treat diseases related to the contractile function of the urinary tract such as the bladder and ureter, such as frequent urination, nocturnal enuresis, and neurogenic bladder. It can be used for the treatment and prevention of diseases such as.
本発明の目的化合物（１）又はその塩は、経口的にも非
経口的（例えば、静脈内、筋肉内、皮下）にも投与する
ことができる。また１日当りの投与量は、投与方法、患
者の年齢、体重、状態及び疾患の種類によっても異なる
が、通常０．０１〜１００■／ｋｇであるのが好ましく
、とりわけ経口投与の場合には０．１〜３０■／ ｋｇ
、非経口投与の場合には０．０５〜１０■／ ｋｇであ
るのが好ましい。投与に際しては、常法により例えば錠
剤、なお、原料化合物（ＩＩ）及び（ＩＶ）は、例えば
次のようにして製造することができる。即ち、−般式
（但し、Ｒ１及び環Ａは前記と同一意味を有する。）で
示されるベンゾフラン−７−カルボン酸化合物又はその
低級アルキルエステルを還元剤（例えば、リチウムアル
ミニウムヒドリド）で還元することにより、化合物（Ｉ
Ｖ） （Ｙ＝酸素原子）を製造することができ、また
該化合物の水酸基部位をそれ自体公知の方法で反応性残
基に変換すれば、原料化合物（ＩＩ）とすることができ
る。更に該化合物（ＩＩ）を千オ尿素で処理することに
より化合物（ＩＶ） （Ｙ＝硫黄原子）を製造するこ
とができる。The object compound (1) of the present invention or a salt thereof can be administered orally or parenterally (eg, intravenously, intramuscularly, subcutaneously). Although the daily dosage varies depending on the administration method, patient's age, weight, condition, and type of disease, it is usually preferably 0.01 to 100 μg/kg, especially in the case of oral administration. .1~30■/kg
In the case of parenteral administration, the amount is preferably 0.05 to 10 μ/kg. For administration, for example, tablets can be prepared by a conventional method.The starting compounds (II) and (IV) can be manufactured, for example, as follows. That is, reducing the benzofuran-7-carboxylic acid compound represented by the general formula (wherein R1 and ring A have the same meanings as above) or its lower alkyl ester with a reducing agent (for example, lithium aluminum hydride). Accordingly, the compound (I
V) (Y=oxygen atom) can be produced, and the starting compound (II) can be obtained by converting the hydroxyl group of the compound into a reactive residue by a method known per se. Furthermore, compound (IV) (Y=sulfur atom) can be produced by treating compound (II) with 1,000 urea.
実験例１
〔静脈内投与〕
ＳＤ系雌性ラット（体重２００〜３００ ｇ ）をウレ
タン（１，１ｇ／ｋｇ、 ｓ、ｃ、）で麻酔し、下腹部
を切開して膀胱尖部にカテーテルを挿入した。カテーテ
ルの他端を三方活栓を介して持続注入器と圧トランスジ
ューサに接続した。持続注入器から一定速度で生理食塩
水を持続注入し、圧トランスジューサで膀胱の内圧変化
と各排尿間の間隔を連続して測定した。検体（投与ｉｔ
： ２ ｍｇ／ｋｇ）は生理食塩水溶液として大腿静
脈より投与し、検体投与前後の排尿間隔の比を次式より
求め、検体の排尿収縮抑制作用を判定した。Experimental Example 1 [Intravenous administration] An SD female rat (body weight 200-300 g) was anesthetized with urethane (1.1 g/kg, s, c,), and a catheter was inserted into the apex of the bladder through an incision in the lower abdomen. did. The other end of the catheter was connected to a continuous infuser and pressure transducer via a three-way stopcock. Physiological saline was continuously infused at a constant rate from a continuous injector, and changes in the internal pressure of the bladder and the interval between each micturition were continuously measured using a pressure transducer. Specimen (administration it)
: 2 mg/kg) was administered through the femoral vein as a physiological saline solution, and the ratio of the micturition interval before and after administration of the sample was determined using the following formula to determine the micturition contraction inhibitory effect of the sample.
（結果）
下記第１表の化合物はいずれも排尿間隔の比が１．４以
上であった。(Results) All of the compounds in Table 1 below had a micturition interval ratio of 1.4 or more.
第１表 ＊Ｂｚは−ＣＩｌ□（＝〉を表す。Table 1 *Bz represents -CIl□(=>).
実験例２
（−二指腸内投与）
ＳＯ系系外性ラット体重２００〜３００ｇ）をウレタン
（１，１ｇ／Ｊ、 ｓ、ｃ、）で麻酔し、大腿静脈より
５％マンニト−ル水溶液を０．０６ｍ１／分の容量で持
続的に注入し、排尿の間隔（分）を測定した。Experimental Example 2 (Intra-duodenal administration) SO rats weighing 200 to 300 g were anesthetized with urethane (1.1 g/J, s, c,), and a 5% mannitol aqueous solution was administered through the femoral vein. Continuous infusion was performed at a volume of 0.06 ml/min, and the interval between urination (minutes) was measured.
検体は水溶液として十二指腸に挿入したカテーテルを介
して投与し、検体投与前後の最大排尿間隔の比を次式よ
り求め、検体の排尿収縮抑制作用を判定した。The specimen was administered as an aqueous solution through a catheter inserted into the duodenum, and the ratio of the maximum micturition interval before and after administration of the specimen was determined using the following formula to determine the micturition contraction inhibitory effect of the specimen.
（結果）
本発明の２−フェニル−７−（２−ピペリジノエチルチ
オメチル）ベンゾフラン・シュウ酸塩は投与量３０ｎ＋
ｇ／ｋｇで最大排尿間隔の比が２．７であった。ちなみ
に、フラボキセート・塩酸塩は投与量１００ ｍｇ／ｋ
ｇで最大排尿間隔の比が１．３であった。(Results) The dose of 2-phenyl-7-(2-piperidinoethylthiomethyl)benzofuran oxalate of the present invention was 30n+
g/kg and the ratio of maximum micturition interval was 2.7. By the way, the dosage for flavoxate hydrochloride is 100 mg/k.
g and the ratio of maximum micturition interval was 1.3.
実験例３
ＳＯ系雌性ラット（体重２００〜３００ｇ）をウレタン
（１１ｇ／ｋｇ、 ｓ、ｃ、）で麻酔後、両側の輸尿管
にポリエチレン細管を挿入し、実験中に腎臓で生成され
る尿を体外へ排出させた。膀胱にポリエチレン細管を外
尿道口より挿入し、その他端を低圧トランスジューサー
に接続して膀胱内圧の変化を測定した。膀胱に０．５ｍ
ｌの生理食塩水を負荷し、塩酸ベタネコールの生理食塩
水溶液を静脈内に持続注入（５３ｇｇ／ｋｇ／分）した
。安定した律動性収縮が３０分以上発現することを１１
１１Ｉ認した後、検体の蒸留水溶液（０，１ｍｌ／１０
０ｇ）を十二指腸内へ投与し、検体投与前後の収縮回数
を調べた。検体の排尿収縮抑制作用は次式から算出され
る抑制率（％（結果）
本発明の２−フェニル−５−メトキシ−７−（２−ピペ
リジノエチルチオメチル）ベンゾフラン・シュウ酸塩は
投与量３０ｍｇ／ｋｇで抑制率が６７％であった。ちな
みに、フラボキセ−１−・塩酸塩は投与ｆｉｔ ３００
ｍｇ／ｋｇで抑制率が２８％であった。Experimental Example 3 After anesthetizing SO female rats (weight 200-300 g) with urethane (11 g/kg, s, c,), polyethylene tubules were inserted into the ureters on both sides, and urine produced in the kidneys during the experiment was collected outside the body. It was discharged to. A polyethylene tubule was inserted into the bladder through the external urethral orifice, and the other end was connected to a low-pressure transducer to measure changes in intravesical pressure. 0.5m to the bladder
l of physiological saline was loaded, and a physiological saline solution of bethanechol hydrochloride was continuously infused intravenously (53 gg/kg/min). 11. Stable rhythmic contractions must occur for 30 minutes or more.
After 11I recognition, a distilled aqueous solution of the specimen (0.1 ml/10
0g) was administered into the duodenum, and the number of contractions before and after administration of the sample was examined. The inhibitory effect of the sample on urinary contraction is the inhibition rate (% (result)) calculated from the following formula. The inhibition rate was 67% at a dose of 30 mg/kg.Incidentally, flavoxe-1-hydrochloride was administered at a dose of 300 mg/kg.
The inhibition rate was 28% at mg/kg.
実施例１
（１） ２−フェニルベンゾフラン−７−カルボン酸
４０ｇをテトラヒドロフラン３００ｍ１に溶解し、この
溶液を水冷下リチウムアルミニウムヒドリド１９．１２
ｇのテトラヒドロフラン１３０ｍ１懸濁液に滴下する。Example 1 (1) 40 g of 2-phenylbenzofuran-7-carboxylic acid was dissolved in 300 ml of tetrahydrofuran, and the solution was dissolved in 19.12 g of lithium aluminum hydride under water cooling.
g into 130 ml of tetrahydrofuran suspension.
混合物を７０°Ｃで２時間撹拌後、水を加えて過剰のリ
チウムアルミニウムヒドリド及びその複合体を分解する
。不溶物をろ別し、ろ液を減圧下に濃縮する。残香を酢
酸エチルに溶解し、水洗、乾燥後減圧下に溶媒を留去す
る。After stirring the mixture at 70° C. for 2 hours, water is added to decompose excess lithium aluminum hydride and its complexes. Insoluble matter is filtered off, and the filtrate is concentrated under reduced pressure. Dissolve the residual aroma in ethyl acetate, wash with water, dry, and then evaporate the solvent under reduced pressure.
残香を酢酸エチルとｎ−ヘキサンとの混液から再結晶す
ることにより、７−ヒドロキシメチル−２＝フェニルベ
ンゾフラン３４．４ｇを得る。 収率：９１％
ｍ、ｐ、 １１７． ５〜１１８． ５°Ｃ（２） ７
−ヒドロキシメチル−２−フェニルベンゾフラン１．０
ｇ、ピリジン０．３８ｍ１及び塩化メチレン８ｍｌの混
合物に塩化チオニル０．６５ｍ１を氷水冷却下加え室温
で３０分間撹拌する。混合物を減圧下に濃縮する。残香
を酢酸エチルに溶解し、水洗、乾燥後減圧下に溶媒を留
去する。残香をｎ−ヘキサンから再結晶することにより
、７−クロロメチル−２−フェニルベンゾフラン０゜９
ｇを得る。 収率：８３％
ｍ、ｐ、７２〜７３°Ｃ
（３） ６０％水素化ナトリウム（油状分散物）０．
２ｇのテトラヒドロフラン３ｍ１ＦＡ濁液にＮ−（２−
メルカプトエチル）ピペリジン０．７３ｇを加え、この
混合物に７−クロロメチル−２−フェニルベンゾフラン
１．２１ｇのテトラヒドロフラン３ｍｌ溶液を加える。By recrystallizing the residual aroma from a mixture of ethyl acetate and n-hexane, 34.4 g of 7-hydroxymethyl-2=phenylbenzofuran is obtained. Yield: 91% m, p, 117. 5-118. 5°C (2) 7
-Hydroxymethyl-2-phenylbenzofuran 1.0
g, 0.38 ml of pyridine, and 8 ml of methylene chloride were added with 0.65 ml of thionyl chloride under cooling with ice water, and the mixture was stirred at room temperature for 30 minutes. The mixture is concentrated under reduced pressure. Dissolve the residual aroma in ethyl acetate, wash with water, dry, and then evaporate the solvent under reduced pressure. By recrystallizing the residual aroma from n-hexane, 7-chloromethyl-2-phenylbenzofuran 0.9
get g. Yield: 83% m, p, 72-73°C (3) 60% sodium hydride (oil dispersion) 0.
N-(2-
0.73 g of mercaptoethyl)piperidine is added, and a solution of 1.21 g of 7-chloromethyl-2-phenylbenzofuran in 3 ml of tetrahydrofuran is added to the mixture.
混合物を室温で２時間撹拌後１時間還流する。冷後、混
合物を水で希釈し、酢酸エチルで抽出する。抽出液を水
洗、乾燥後減圧下に溶媒を留去する。残香をシュウ酸塩
とし、エタノールから再結晶することにより、２−フェ
ニ／Ｌｚ−７−（２−ピペリジノエチルチオメチル）ベ
ンゾフラン・シュウ酸塩１．８ｇを得る。The mixture is stirred at room temperature for 2 hours and then refluxed for 1 hour. After cooling, the mixture is diluted with water and extracted with ethyl acetate. After washing the extract with water and drying, the solvent was distilled off under reduced pressure. The residual aroma is converted into oxalate and recrystallized from ethanol to obtain 1.8 g of 2-pheny/Lz-7-(2-piperidinoethylthiomethyl)benzofuran oxalate.
収率：８２％
ｍ、ｐ、 １８７〜１８８°Ｃ
実施例２
７−クロロメチル−２−フェニルベンゾフラン７．０ｇ
、チオ尿素２．５ｇ、水２ｍｌ及びエタノール３８ｍ１
の混合物を１．５時間加熱還流し、次いで水酸化ナトリ
ウム１．７３ｇの水１８ｍ１溶液を加え更に１．５時間
還流する。冷後、混合物を１０％硫酸でｐＨ３とし、酢
酸エチルで抽出する。Yield: 82% m, p, 187-188°C Example 2 7-chloromethyl-2-phenylbenzofuran 7.0 g
, thiourea 2.5g, water 2ml and ethanol 38ml
The mixture was heated under reflux for 1.5 hours, then a solution of 1.73 g of sodium hydroxide in 18 ml of water was added, and the mixture was further refluxed for 1.5 hours. After cooling, the mixture is brought to pH 3 with 10% sulfuric acid and extracted with ethyl acetate.
抽出液を水洗、乾燥後減圧下に溶媒を留去する。After washing the extract with water and drying, the solvent was distilled off under reduced pressure.
残香（７−メルカブトメチルー２−フェニルベンゾフラ
ン）をエタノール１５ｍ１に溶解し、この溶液に４．７
％水酸化カリウム／エタノール溶液１００ｍ１及びＮ−
（２−クロロエチル）ピペリジン塩酸塩５．５ｇを加え
６０°Ｃで１時間撹拌する。Dissolve residual fragrance (7-mercabutomethyl-2-phenylbenzofuran) in 15 ml of ethanol, and add 4.7 mL to this solution.
% potassium hydroxide/ethanol solution 100 ml and N-
Add 5.5 g of (2-chloroethyl)piperidine hydrochloride and stir at 60°C for 1 hour.
反応混合物を減圧下に濃縮して、液量を約１／３とする
。濃縮物を水で希釈し、酢酸エチルで抽出する。抽出液
を水洗、乾燥後減圧下に溶媒を留去する。残香をイソロ
バノールから再結晶することにより、２−フェニル−７
−（２−ピペリジノエチルチオメチル）ベンゾフラン８
．４３ｇを得る。The reaction mixture is concentrated under reduced pressure to reduce the liquid volume to about ⅓. Dilute the concentrate with water and extract with ethyl acetate. After washing the extract with water and drying, the solvent was distilled off under reduced pressure. By recrystallizing the residual aroma from isolobanol, 2-phenyl-7
-(2-piperidinoethylthiomethyl)benzofuran 8
．． Obtain 43g.
収率：８３％
ｍ、ｐ、６４．５〜６５．５°Ｃ
本品の塩酸塩
ｍ、ｐ、 １９６〜１９７°Ｃ（エタノールから再結晶
）実施例３〜９
対応原料化合物を実施例２と同様に処理することにより
、下記第２表記載の化合物を得る。Yield: 83% m, p, 64.5-65.5°C Hydrochloride of this product m, p, 196-197°C (recrystallized from ethanol) Examples 3-9 Corresponding raw material compounds in Example 2 By treating in the same manner as above, the compounds listed in Table 2 below are obtained.
第２表 ＊ＢＺは−ＣＩｌ□◎ を表す。Table 2 *BZ represents -CIl□◎.
実施例１０〜１４
（１） 対応原料化合物を実施例１−（１）と同様に処
理することにより、下記第３表記載化合物を得る。Examples 10 to 14 (1) Compounds listed in Table 3 below are obtained by treating the corresponding raw material compounds in the same manner as in Example 1-(1).
第 ３ 表
（２） 対応原料化合物を実施例１−（２）と同様に処
理することにより、下記第４表記載化合物を得る。Table 3 (2) The corresponding starting compounds were treated in the same manner as in Example 1-(2) to obtain the compounds listed in Table 4 below.
第４表
（３） 対応原料化合物を実施例２と同様に処理するこ
とにより、下記第５表記載の化合物を得る。Table 4 (3) By treating the corresponding starting compounds in the same manner as in Example 2, the compounds listed in Table 5 below are obtained.
第５表
実施例１５
７〜ヒドロキシメチル−２−フェニルベンゾフラン１．
５７ｇをジメチルスルホキシド１０ｍ１に溶解し、この
溶液に６０％水素化ナトリウム（油状分散物）０．５７
ｇを加え１０分間撹拌する。Table 5 Example 15 7-Hydroxymethyl-2-phenylbenzofuran 1.
57 g was dissolved in 10 ml of dimethyl sulfoxide, and 0.57 g of 60% sodium hydride (oil dispersion) was added to this solution.
g and stir for 10 minutes.
混合物にＮ−（２−クロロエチル）ピペリジン塩酸塩１
．３５ｇを加え室温で４時間撹拌する。混合物を水で希
釈し、酢酸エチルで抽出する。抽出液を水洗、乾燥後減
圧下に溶媒を留去する。残香を塩酸塩とし、酢酸エチル
から再結晶することにより、７−（２−ピペリジノエト
キシ）メチル−２−フェニルベンゾフラン・塩酸塩１．
３２ｇを得る。 収率：５１％
ｍ、ｐ、 １３５〜１３６°Ｃ
実施例１６
ツーヒドロキシメチル−２−ツエニルベンゾフラン１．
５７ｇ、６０％水素化ナトリウム（油状分散物）０．５
７ｇ及びＮ−（３−クロロプロピル）ヒ：ペリジン・塩
酸塩１．４７ｇを実施例１５と同様に処理することによ
り、７−（３−とベリジノプロビルオキシ）メチル−２
〜フエニルベンゾフラン・シュウ酸塩２．０９ｇを得る
収率：６８％
ｍ、１．１７８．５〜１７９．５℃（メタノールから再
結晶）
〔原料化合物の調製〕
製造例１
（Ｉ） ５−クロロ−２−ヒドロキシ安息香酸１０２ｇ
とへキサメチレンテトラミン１６６ｇのトリフルオロ酢
酸溶液を一夜加熱後、希塩酸を加え加熱する。冷接、押
出品をろ取して、５−クロロ−３−ホルミル−２−ヒド
ロキシ安息香酸９６゜９ｇを得る。 ｍ、ｐ、 ２１８
°Ｃ
（２） 本市１９３ｇのメタノール溶液を塩化水素で飽
和させた後、チオニルクロリド１００ ｍｆｔを加え還
流する。冷接、押出品をろ取、乾燥して５−クロロ−３
−ホルミル−２−ヒドロキシ安息香酸メチルエステル１
９０ｇを得る。 ｍ、ｐ、 １３２〜１３４℃
（３）本市３．０ｇ、α−ブロモフェニル酢酸メチルエ
ステル３．４４ｇ、炭酸カリウム８．２８ｇのジメチル
ホルムアミド混液を加熱する。反応後、塩酸酸性下で酢
酸エチル抽出し、抽出液を洗浄、乾燥後、溶媒を留去す
る。残香をエタノールに溶解し、水酸化カリウム４．５
ｇを加えて還流後、溶媒を留去する。残香に水を加え、
塩酸酸性上酢酸エチルで抽出する。抽出液を乾燥後、溶
媒を留去し、残香にキシレン及びｐ−）ルエンスルホン
酸を加えて還流する。反応後、溶媒を留去し、残香を酢
酸エチルに熔解して、洗浄、乾燥後、溶媒を留去する。Add 1 part of N-(2-chloroethyl)piperidine hydrochloride to the mixture.
．． Add 35 g and stir at room temperature for 4 hours. The mixture is diluted with water and extracted with ethyl acetate. After washing the extract with water and drying, the solvent was distilled off under reduced pressure. By converting the residual aroma into a hydrochloride salt and recrystallizing it from ethyl acetate, 7-(2-piperidinoethoxy)methyl-2-phenylbenzofuran hydrochloride 1.
Obtain 32g. Yield: 51% m, p, 135-136°C Example 16 Two-hydroxymethyl-2-zenylbenzofuran 1.
57g, 60% sodium hydride (oil dispersion) 0.5
7g and N-(3-chloropropyl)h:peridine hydrochloride 1.47g were treated in the same manner as in Example 15 to obtain 7-(3- and beridinopropyloxy)methyl-2.
~ Obtain 2.09 g of phenylbenzofuran oxalate Yield: 68% m, 1.178.5-179.5°C (recrystallized from methanol) [Preparation of raw material compound] Production example 1 (I) 5- Chloro-2-hydroxybenzoic acid 102g
After heating a solution of 166 g of hexamethylenetetramine in trifluoroacetic acid overnight, dilute hydrochloric acid was added and heated. After cold welding, the extrudate was filtered to obtain 96.9 g of 5-chloro-3-formyl-2-hydroxybenzoic acid. m, p, 218
°C (2) After saturating 193 g of Motoichi's methanol solution with hydrogen chloride, 100 mft of thionyl chloride was added and refluxed. After cold welding, the extruded product was collected by filtration and dried to give 5-chloro-3.
-Formyl-2-hydroxybenzoic acid methyl ester 1
Obtain 90g. m, p, 132-134°C (3) A dimethylformamide mixture containing 3.0 g of Motoichi, 3.44 g of α-bromophenyl acetic acid methyl ester, and 8.28 g of potassium carbonate is heated. After the reaction, the mixture is extracted with ethyl acetate under hydrochloric acid, the extract is washed and dried, and the solvent is distilled off. Dissolve the residual fragrance in ethanol and add 4.5% potassium hydroxide.
After adding g and refluxing, the solvent was distilled off. Add water to the lingering scent,
Acidified with hydrochloric acid and extracted with ethyl acetate. After drying the extract, the solvent is distilled off, xylene and p-)luenesulfonic acid are added to the residual aroma, and the mixture is refluxed. After the reaction, the solvent is distilled off, the residual aroma is dissolved in ethyl acetate, and after washing and drying, the solvent is distilled off.
残香をイソプロピルエーテルから結晶化して５−クロロ
−２−フェニルベンゾフラン−７−カルボン酸２．３２
．を得る。 ｍ、ρ。The residual aroma was crystallized from isopropyl ether to give 2.32% of 5-chloro-2-phenylbenzofuran-7-carboxylic acid.
．． get. m, ρ.
２５５〜２５８℃
２−ヒドロキシ−５−メトキシ安息香酸１５ｇを上記（
１）〜（３）と同様に処理することにより、５−メトキ
シ−２−フェニルベンゾフラン−７−カルボン酸１０．
８ｇを得る。 ｍ、ｐ、 １８５〜１８７℃
（４） 本市１．４６ ｇのエチレングリコールモノメ
チルエーテル及びメタノール混液に１０％パラジウム炭
素５００ ｔｒｙ及びギ酸アンモニウム１．６ｇを加え
加熱する。反応液をろ過し、ろ液を減圧下に濃縮する。255-258°C 15g of 2-hydroxy-5-methoxybenzoic acid was added to the above (
By treating in the same manner as in 1) to (3), 5-methoxy-2-phenylbenzofuran-7-carboxylic acid 10.
Obtain 8g. m, p, 185-187°C (4) Add 500 tries of 10% palladium on carbon and 1.6 g of ammonium formate to 1.46 g of a mixed solution of ethylene glycol monomethyl ether and methanol and heat. The reaction solution is filtered, and the filtrate is concentrated under reduced pressure.
残香を酢酸エチルに溶解し、洗浄、乾燥後、溶媒を留去
して２−フェニルベンゾフラン−７−カルボンＭ１．Ｏ
ｇを得る。ｍ、ｐ、 ２１２〜２１４℃製造例２
（１）５−クロロ−３−ホルミル−２−ヒドロキシ安息
香酸メチルエステル７３．２ｇ、エチレングリコール３
５０ｍ１及びトリメチルクロロシラン１２９ｍ１の混合
物を室温で２時間撹拌後、炭酸水素ナトリウム水溶液と
トリエチルアミンとの混合物に江別し、酢酸エチルで抽
出する。抽出液を水洗、乾燥後溶媒を留去することによ
り、５−クロロ−３−（１，３−ジオキソラン−２−イ
ル）−２−ヒドロキシ安息香酸メチルエーテル８６ｇを
黄色粉末として得る。The residual aroma was dissolved in ethyl acetate, washed and dried, and the solvent was distilled off to give 2-phenylbenzofuran-7-carvone M1. O
get g. m, p, 212-214°C Production example 2 (1) 5-chloro-3-formyl-2-hydroxybenzoic acid methyl ester 73.2 g, ethylene glycol 3
After stirring a mixture of 50 ml and 129 ml of trimethylchlorosilane at room temperature for 2 hours, it was poured into a mixture of an aqueous sodium bicarbonate solution and triethylamine, and extracted with ethyl acetate. The extract was washed with water, dried, and the solvent was distilled off to obtain 86 g of 5-chloro-3-(1,3-dioxolan-2-yl)-2-hydroxybenzoic acid methyl ether as a yellow powder.
（２）本市８６ｇをメタノール７００ｍ１とテトラヒド
ロフラン５０ｍ１との混液に溶解し、トリエチルアミン
７０ｍ１及び１０％パラジウム・炭素７ｇを加え常圧下
に接触還元する。反応混合物を濾過後溶媒を留去する。(2) Dissolve 86 g of Motoichi in a mixture of 700 ml of methanol and 50 ml of tetrahydrofuran, add 70 ml of triethylamine and 7 g of 10% palladium on carbon, and perform catalytic reduction under normal pressure. After filtering the reaction mixture, the solvent was distilled off.
残香に１０％塩酸を加えて濃縮後、水を加え、酢酸エチ
ルで抽出し、乾燥後溶媒を留去する。得られる結晶をろ
取し、冷エタノールで洗浄後乾燥することにより、３−
ホルミル−２−ヒドロキシ安息香酸メチルエステル５１
゜１ｇを無色針状晶として得る。ｍ、ｐ、 ８２〜８４
℃（３）本市２．０ｇ、α−ブロモ−ｐ−クロロフェニ
ル酢酸メチルエステル３．５１ｇ、炭酸カリウム５．５
５ｇ及びジメチルホルムアミドの混合物を７０〜８０°
Ｃで１５分間加熱し、さらに１００℃で１０分間加熱す
る。混合物を濾過し、酢酸エチルで洗浄する。ろ液と洗
液を合わせ水を加えた後１０％塩酸で酸性とする。有機
層を分取し、水層を酢酸エチルで抽出する。有機層と抽
出液を合わせ水洗、乾燥後溶媒を留去し、残香をエタノ
ールに溶解汲水酸化カリウム３．２５ｇを加え、１時間
還流する。混合物を濃縮して溶媒を留去し、残香に水を
加えた後１０％塩酸で酸性とし、酢酸エチルで抽出する
。抽出液を水洗、乾燥後溶媒を留去し、残香にキシレン
及びｐ−トルエンスルホン酸１５０ｍｇを加え１時間還
流する。冷接、混合物に酢酸エチルを加え水洗、乾燥後
溶媒を留去し、残香を酢酸エチルから再結晶することに
より、２−（４−クロロフェニル）ベンゾフラン−７−
カルボン酸１．８４ｇを無色針状晶として得る。After adding 10% hydrochloric acid to the residual aroma and concentrating it, water was added and extracted with ethyl acetate. After drying, the solvent was distilled off. The resulting crystals were collected by filtration, washed with cold ethanol, and dried to give 3-
Formyl-2-hydroxybenzoic acid methyl ester 51
Obtain 1 g of colorless needles. m, p, 82-84
°C (3) Motoichi 2.0g, α-bromo-p-chlorophenylacetic acid methyl ester 3.51g, potassium carbonate 5.5g
A mixture of 5g and dimethylformamide was heated at 70-80°
Heat at 100° C. for 15 minutes and then at 100° C. for 10 minutes. Filter the mixture and wash with ethyl acetate. Combine the filtrate and washing liquid, add water, and acidify with 10% hydrochloric acid. Separate the organic layer and extract the aqueous layer with ethyl acetate. The organic layer and extract were combined, washed with water, and dried. The solvent was distilled off, the residual aroma was dissolved in ethanol, 3.25 g of potassium hydroxide was added, and the mixture was refluxed for 1 hour. The mixture is concentrated to remove the solvent, water is added to the residual aroma, acidified with 10% hydrochloric acid, and extracted with ethyl acetate. After the extract is washed with water and dried, the solvent is distilled off, xylene and 150 mg of p-toluenesulfonic acid are added to the residual aroma, and the mixture is refluxed for 1 hour. 2-(4-chlorophenyl)benzofuran-7-
1.84 g of carboxylic acid are obtained as colorless needles.
ｍ、ｐ、 ２２８〜２３０℃
製造例３〜４
対応原料化合物を上記と同様に処理することにより、下
記化合物を得る。m, p, 228-230°C Production Examples 3-4 The following compounds are obtained by treating the corresponding raw material compounds in the same manner as above.
３）２−（４−メチルフェニル）ベンゾフラン−７−カ
ルボン酸
ｍ、ｐ、 ２２７〜２２９℃（酢酸エチル−ｎ−へキサ
ンから再結晶）
４）２−（４−メトキシフェニル）ベンゾフラン−７−
カルボン酸
ｍ、ｐ、 ２４９〜２５０．５℃（テトラヒドロフラン
−イソプロピルエーテルから再結晶）代理人 弁理士
中 嶋 正 二3) 2-(4-methylphenyl)benzofuran-7-carboxylic acid m, p, 227-229°C (recrystallized from ethyl acetate-n-hexane) 4) 2-(4-methoxyphenyl)benzofuran-7-
Carboxylic acid m, p, 249-250.5°C (recrystallized from tetrahydrofuran-isopropyl ether) Agent Patent attorney
Shoji Nakajima
Claims (7)
ゲン原子、Ｒ＾２及びＲ＾３は一方が低級アルキル基で
あり、他方が低級アルキル基又はフェニル低級アルキル
基であるか、或いは両者が末端で結合して隣接する窒素
原子とともに複素単環式基を形成していることを表し、
環Ａは置換又は非置換フェニル基、Ｙは酸素原子又は硫
黄原子、ｎは２又は３を表す。） で示されるベンゾフラン誘導体又はその薬理的に許容し
うる塩。(1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (I) (However, R^1 is a hydrogen atom, a lower alkoxy group, or a halogen atom, and one of R^2 and R^3 is a lower alkyl group. , the other is a lower alkyl group or a phenyl lower alkyl group, or both are bonded at the terminal to form a heteromonocyclic group with the adjacent nitrogen atom,
Ring A represents a substituted or unsubstituted phenyl group, Y represents an oxygen atom or a sulfur atom, and n represents 2 or 3. ) A benzofuran derivative or a pharmacologically acceptable salt thereof.
ルコキシ基又はハロゲン原子で置換されたフェニル基で
ある請求項１記載の化合物。(2) The compound according to claim 1, wherein ring A is a phenyl group; or a phenyl group substituted with a lower alkyl group, a lower alkoxy group, or a halogen atom.
フェニル基又はクロロフェニル基である請求項１記載の
化合物。(3) The compound according to claim 1, wherein ring A is a phenyl group, a methylphenyl group, a methoxyphenyl group, or a chlorophenyl group.
り、Ｒ＾２がメチル基又はエチル基であり、Ｒ＾３がメ
チル基、エチル基又はベンジル基であるか、或いはＲ＾
２及びＲ＾３が末端で結合して隣接する窒素原子と共に
ピロリジノ基、ピペリジノ基又はモルホリノ基を形成し
ており、環Ａがフェニル基、４−メチルフェニル基、４
−メトキシフェニル基又は４−クロロフェニル基である
請求項３記載の化合物。(4) R^1 is a hydrogen atom, methoxy group, or chlorine atom, R^2 is a methyl group or ethyl group, and R^3 is a methyl group, ethyl group, or benzyl group, or R^
2 and R^3 are bonded at the terminal to form a pyrrolidino group, piperidino group, or morpholino group with the adjacent nitrogen atom, and ring A is a phenyl group, 4-methylphenyl group, 4
4. The compound according to claim 3, which is a -methoxyphenyl group or a 4-chlorophenyl group.
及びＲ＾３が末端で結合して隣接する窒素原子と共にピ
ペリジノ基を形成しており、Ｙが硫黄原子であり、ｎが
２である請求項４記載の化合物。(5) R^1 is a hydrogen atom or a methoxy group, and R^2
5. The compound according to claim 4, wherein and R^3 are bonded at the terminal to form a piperidino group together with an adjacent nitrogen atom, Y is a sulfur atom, and n is 2.
ジノエチルチオメチル）ベンゾフラン又はその薬理的に
許容しうる塩。(6) 2-phenyl-5-methoxy-7-(2-piperidinoethylthiomethyl)benzofuran or a pharmacologically acceptable salt thereof.
メチル）ベンゾフラン又はその薬理的に許容しうる塩。(7) 2-phenyl-7-(2-piperidinoethylthiomethyl)benzofuran or a pharmacologically acceptable salt thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP21211888A JPH01156973A (en) | 1987-09-04 | 1988-08-25 | Benzofuran derivative |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP62-222754 | 1987-09-04 | ||
| JP22275487 | 1987-09-04 | ||
| JP21211888A JPH01156973A (en) | 1987-09-04 | 1988-08-25 | Benzofuran derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH01156973A true JPH01156973A (en) | 1989-06-20 |
Family
ID=26519007
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP21211888A Pending JPH01156973A (en) | 1987-09-04 | 1988-08-25 | Benzofuran derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH01156973A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7284739B2 (en) | 2002-04-19 | 2007-10-23 | Nakabayashi Co., Ltd. | Stand for albums, scrapbooks and the like |
| US8129535B2 (en) | 2001-10-19 | 2012-03-06 | Toyama Chemical Co., Ltd. | Alkyl ether derivatives or salts thereof |
-
1988
- 1988-08-25 JP JP21211888A patent/JPH01156973A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8129535B2 (en) | 2001-10-19 | 2012-03-06 | Toyama Chemical Co., Ltd. | Alkyl ether derivatives or salts thereof |
| USRE43676E1 (en) | 2001-10-19 | 2012-09-18 | Toyama Chemical Co., Ltd. | Alkyl ether derivatives or salts thereof |
| US7284739B2 (en) | 2002-04-19 | 2007-10-23 | Nakabayashi Co., Ltd. | Stand for albums, scrapbooks and the like |
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