JPS62187452A - Cyclic amine derivative - Google Patents
Cyclic amine derivativeInfo
- Publication number
- JPS62187452A JPS62187452A JP2815386A JP2815386A JPS62187452A JP S62187452 A JPS62187452 A JP S62187452A JP 2815386 A JP2815386 A JP 2815386A JP 2815386 A JP2815386 A JP 2815386A JP S62187452 A JPS62187452 A JP S62187452A
- Authority
- JP
- Japan
- Prior art keywords
- group
- hydrogen atom
- ring
- tables
- formula
- 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.)
- Granted
Links
- -1 Cyclic amine Chemical class 0.000 title claims description 19
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 14
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 9
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims abstract description 6
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 6
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 4
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 4
- 150000003839 salts Chemical class 0.000 claims description 21
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 14
- 125000003545 alkoxy group Chemical group 0.000 claims description 12
- 239000000126 substance Substances 0.000 claims description 10
- 125000004414 alkyl thio group Chemical group 0.000 claims description 6
- 125000005843 halogen group Chemical group 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 5
- 125000004423 acyloxy group Chemical group 0.000 claims description 4
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- 125000003277 amino group Chemical group 0.000 claims description 3
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims description 2
- 239000005977 Ethylene Substances 0.000 claims description 2
- 125000005098 aryl alkoxy carbonyl group Chemical group 0.000 claims description 2
- 125000002102 aryl alkyloxo group Chemical group 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 125000004043 oxo group Chemical group O=* 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 2
- 125000004442 acylamino group Chemical group 0.000 claims 1
- 125000003386 piperidinyl group Chemical group 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 53
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 abstract description 32
- 238000002360 preparation method Methods 0.000 abstract description 7
- 150000002367 halogens Chemical class 0.000 abstract description 5
- 230000002213 calciumantagonistic effect Effects 0.000 abstract description 3
- 229910052717 sulfur Inorganic materials 0.000 abstract description 2
- 239000003795 chemical substances by application Substances 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 14
- 238000002844 melting Methods 0.000 description 14
- 230000008018 melting Effects 0.000 description 14
- 239000000203 mixture Substances 0.000 description 14
- 239000002904 solvent Substances 0.000 description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 239000000047 product Substances 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- 238000004519 manufacturing process Methods 0.000 description 9
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
- 150000008065 acid anhydrides Chemical class 0.000 description 8
- 239000002585 base Substances 0.000 description 8
- 238000000034 method Methods 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
- 239000011575 calcium Substances 0.000 description 7
- 125000004432 carbon atom Chemical group C* 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 229910052791 calcium Inorganic materials 0.000 description 5
- 150000002148 esters Chemical group 0.000 description 5
- 239000003921 oil Substances 0.000 description 5
- 235000019198 oils Nutrition 0.000 description 5
- 238000005192 partition Methods 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 239000003513 alkali Substances 0.000 description 4
- 239000008187 granular material Substances 0.000 description 4
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 4
- 235000019341 magnesium sulphate Nutrition 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 235000011181 potassium carbonates Nutrition 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 3
- 229940127291 Calcium channel antagonist Drugs 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000008485 antagonism Effects 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- SKCNIGRBPJIUBQ-UHFFFAOYSA-N chloroform;ethyl acetate Chemical compound ClC(Cl)Cl.CCOC(C)=O SKCNIGRBPJIUBQ-UHFFFAOYSA-N 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 238000001819 mass spectrum Methods 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-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
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- FZFAMSAMCHXGEF-UHFFFAOYSA-N chloro formate Chemical compound ClOC=O FZFAMSAMCHXGEF-UHFFFAOYSA-N 0.000 description 2
- OQNGCCWBHLEQFN-UHFFFAOYSA-N chloroform;hexane Chemical compound ClC(Cl)Cl.CCCCCC OQNGCCWBHLEQFN-UHFFFAOYSA-N 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- HSUGRBWQSSZJOP-RTWAWAEBSA-N diltiazem Chemical class C1=CC(OC)=CC=C1[C@H]1[C@@H](OC(C)=O)C(=O)N(CCN(C)C)C2=CC=CC=C2S1 HSUGRBWQSSZJOP-RTWAWAEBSA-N 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 150000002170 ethers Chemical class 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 150000004677 hydrates Chemical class 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
- 125000005948 methanesulfonyloxy group Chemical group 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- ATYBXHSAIOKLMG-UHFFFAOYSA-N oxepin Chemical compound O1C=CC=CC=C1 ATYBXHSAIOKLMG-UHFFFAOYSA-N 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 235000009518 sodium iodide Nutrition 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- 229940124530 sulfonamide Drugs 0.000 description 2
- 150000003456 sulfonamides Chemical class 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- XYHKNCXZYYTLRG-UHFFFAOYSA-N 1h-imidazole-2-carbaldehyde Chemical compound O=CC1=NC=CN1 XYHKNCXZYYTLRG-UHFFFAOYSA-N 0.000 description 1
- SGTNSNPWRIOYBX-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-{[2-(3,4-dimethoxyphenyl)ethyl](methyl)amino}-2-(propan-2-yl)pentanenitrile Chemical compound C1=C(OC)C(OC)=CC=C1CCN(C)CCCC(C#N)(C(C)C)C1=CC=C(OC)C(OC)=C1 SGTNSNPWRIOYBX-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
- GWYFCOCPABKNJV-UHFFFAOYSA-M 3-Methylbutanoic acid Natural products CC(C)CC([O-])=O GWYFCOCPABKNJV-UHFFFAOYSA-M 0.000 description 1
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 1
- CDIIZULDSLKBKV-UHFFFAOYSA-N 4-chlorobutanoyl chloride Chemical compound ClCCCC(Cl)=O CDIIZULDSLKBKV-UHFFFAOYSA-N 0.000 description 1
- SVNNWKWHLOJLOK-UHFFFAOYSA-N 5-chloropentanoyl chloride Chemical compound ClCCCCC(Cl)=O SVNNWKWHLOJLOK-UHFFFAOYSA-N 0.000 description 1
- FWEOQOXTVHGIFQ-UHFFFAOYSA-N 8-anilinonaphthalene-1-sulfonic acid Chemical compound C=12C(S(=O)(=O)O)=CC=CC2=CC=CC=1NC1=CC=CC=C1 FWEOQOXTVHGIFQ-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 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
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 229920000858 Cyclodextrin Polymers 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
- 239000004375 Dextrin Substances 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- GKQLYSROISKDLL-UHFFFAOYSA-N EEDQ Chemical compound C1=CC=C2N(C(=O)OCC)C(OCC)C=CC2=C1 GKQLYSROISKDLL-UHFFFAOYSA-N 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical class Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- QIGBRXMKCJKVMJ-UHFFFAOYSA-N Hydroquinone Chemical compound OC1=CC=C(O)C=C1 QIGBRXMKCJKVMJ-UHFFFAOYSA-N 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 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 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 241000594009 Phoxinus phoxinus Species 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- IFFPICMESYHZPQ-UHFFFAOYSA-N Prenylamine Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)CCNC(C)CC1=CC=CC=C1 IFFPICMESYHZPQ-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 239000004373 Pullulan Substances 0.000 description 1
- 229920001218 Pullulan Polymers 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 1
- YKTSYUJCYHOUJP-UHFFFAOYSA-N [O--].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-] Chemical compound [O--].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-] YKTSYUJCYHOUJP-UHFFFAOYSA-N 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 229910001516 alkali metal iodide Inorganic materials 0.000 description 1
- 125000005278 alkyl sulfonyloxy group Chemical group 0.000 description 1
- IYABWNGZIDDRAK-UHFFFAOYSA-N allene Chemical group C=C=C IYABWNGZIDDRAK-UHFFFAOYSA-N 0.000 description 1
- 230000005260 alpha ray Effects 0.000 description 1
- WMGSQTMJHBYJMQ-UHFFFAOYSA-N aluminum;magnesium;silicate Chemical compound [Mg+2].[Al+3].[O-][Si]([O-])([O-])[O-] WMGSQTMJHBYJMQ-UHFFFAOYSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000000729 antidote Substances 0.000 description 1
- 210000002376 aorta thoracic Anatomy 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 125000005279 aryl sulfonyloxy group Chemical group 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 239000000440 bentonite Substances 0.000 description 1
- 229910000278 bentonite Inorganic materials 0.000 description 1
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 1
- 150000001558 benzoic acid derivatives Chemical class 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N beta-methyl-butyric acid Natural products CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- HRYZWHHZPQKTII-UHFFFAOYSA-N chloroethane Chemical compound CCCl HRYZWHHZPQKTII-UHFFFAOYSA-N 0.000 description 1
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid group Chemical class C(CC(O)(C(=O)O)CC(=O)O)(=O)O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- ZXIJMRYMVAMXQP-UHFFFAOYSA-N cycloheptene Chemical compound C1CCC=CCC1 ZXIJMRYMVAMXQP-UHFFFAOYSA-N 0.000 description 1
- 235000013365 dairy product Nutrition 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- UZVGSSNIUNSOFA-UHFFFAOYSA-N dibenzofuran-1-carboxylic acid Chemical compound O1C2=CC=CC=C2C2=C1C=CC=C2C(=O)O UZVGSSNIUNSOFA-UHFFFAOYSA-N 0.000 description 1
- 229960004166 diltiazem Drugs 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- PSLIMVZEAPALCD-UHFFFAOYSA-N ethanol;ethoxyethane Chemical compound CCO.CCOCC PSLIMVZEAPALCD-UHFFFAOYSA-N 0.000 description 1
- 229960003750 ethyl chloride Drugs 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical class [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 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
- 230000001939 inductive effect Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 150000003893 lactate salts Chemical class 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 1
- 229960003511 macrogol Drugs 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 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
- 239000011976 maleic acid Substances 0.000 description 1
- 150000004701 malic acid derivatives Chemical class 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 230000028161 membrane depolarization Effects 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 125000004923 naphthylmethyl group Chemical group C1(=CC=CC2=CC=CC=C12)C* 0.000 description 1
- HYIMSNHJOBLJNT-UHFFFAOYSA-N nifedipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1[N+]([O-])=O HYIMSNHJOBLJNT-UHFFFAOYSA-N 0.000 description 1
- 229960001597 nifedipine Drugs 0.000 description 1
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Substances [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- 238000007911 parenteral administration Methods 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
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 229950008882 polysorbate Drugs 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 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
- 239000002244 precipitate Substances 0.000 description 1
- 229960001989 prenylamine Drugs 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000019423 pullulan Nutrition 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000001226 reprecipitation Methods 0.000 description 1
- 230000004044 response Effects 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
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000010936 titanium Substances 0.000 description 1
- 229910052719 titanium Inorganic materials 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 125000003258 trimethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 229960001722 verapamil Drugs 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Abstract
Description
【発明の詳細な説明】
産業上の利用分野
本発明は、カルシウム拮抗作用等を有する、新規で「川
な環吠アミン誘４体及びその五−類に関する。DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to a novel ring-shaped amine derivative 4 and its penta-compounds having calcium antagonistic effects and the like.
従来の技術
近年、生体内カルシウムの生理が解明されるにつれ、種
々の化学構造を存するカルシウム拮抗剤が市販あるいは
研究されてきた。代表的なものとして、プレニラミン系
、ベラパミル系。BACKGROUND OF THE INVENTION In recent years, as the physiology of calcium in living bodies has been elucidated, calcium antagonists having various chemical structures have been commercially available or studied. Representative examples include prenylamine and verapamil.
ニフェジピン系あるいはジルチアゼム系の化合物が知ら
れている。Nifedipine and diltiazem compounds are known.
発明の目的
本発明は、従来のカルシウム拮抗剤のいずれの系統にも
属さない、新しいタイプのカルシウム７５抗剤を提供す
るものである。OBJECTS OF THE INVENTION The present invention provides a new type of calcium-75 antidote that does not belong to any family of conventional calcium antagonists.
ＲＩ−Ｎ−Ｗ Ｘ Ｒａ （Ｉ）（式中
、ＲＩは
で示される基を意味し、Ａ環はベンゼン環又はシクロへ
牛サン環を意味し、Ｙ及びＺは共に水素原子を意味する
か、あるいはＹ、！：Ｚが一緒になって、単結合、
−０−、−Ｓ−、−Ｃ）（＝ＣＨ−。RI-N-W X Ra (I) (in the formula, RI means a group represented by , or Y,!:Z together to form a single bond,
-0-, -S-, -C) (=CH-.
低級アルコキシ基を意味しＮＲ３は下記（ａ）。NR3 means a lower alkoxy group as shown in (a) below.
（ｂ）、（ｃ）又は（ｄ）で示される基を意味し、０環
はべ／ゼン瑚又はシクロヘキサン環を意味し、Ｒａは同
−又は異なって水素原子、ハロゲン原子、低級アルキル
基、トリフルオロメチル基。means a group represented by (b), (c) or (d), 0 ring means a be/zengo or cyclohexane ring, Ra is the same or different and a hydrogen atom, a halogen atom, a lower alkyl group, Trifluoromethyl group.
低級アルコキシ基、低級アルキルチオ基又はシアノ基を
意味し、Ｒｓは同−又は異なって水Ｎ部子、ハロゲン４
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、低級アルキルチオ基又はシアノ基を意味し、
Ｒａは水素原子、低級アルキル基、ヒドロキシ基、アシ
ルオキシ基又は低級アルコキシカルボニル基を意味し、
Ｒ７は同−又は異なって水素原子、ハロゲンわ子、ヒド
ロキシ基、低級アルコキシ基、アラルキルオキシ基、ア
シルオキシ基、ニトロ基。means a lower alkoxy group, a lower alkylthio group, or a cyano group, and Rs are the same or different and represent a water N moiety, a halogen 4
a lower alkyl group, a trifluoromethyl group, a lower alkoxy group, a lower alkylthio group or a cyano group,
Ra means a hydrogen atom, a lower alkyl group, a hydroxy group, an acyloxy group or a lower alkoxycarbonyl group,
R7 are the same or different and are a hydrogen atom, a halogen group, a hydroxy group, a lower alkoxy group, an aralkyloxy group, an acyloxy group, or a nitro group.
アミ７基又はアシルアミ／基を意味し、Ｒａは水素原子
又はヒドロキシ基を意味し、Ｒｅは低級アルコキシカル
ボニル基、アラルキルオキシカルボニル基、フェニル基
、２２換フエニル基（Ｌｆ ｎ換基はハロゲン、低級ア
ルキル又は低級アルコキシである）又はアラルキル基を
意味するか、あるいはＲ９がピペリジ／環の４位にある
ときはＲ８−緒になってエチレンケタール基又はオキソ
基を形成してもよく、Ｗはカルボニル基又はスルホニル
基を意味し、Ｘはアルキレン基を意味し、ａ及びｂはそ
れぞれ１〜４の整数を意味し、ＣはＯ〜２の整数を意味
し、ｄはｉ〜３の整数を意味し、ｅは０又は１をα線す
るが、ｄとｅの和は２以上の整数であり、ｒは１〜３の
整数を意味する。但し、（ｉ） Ｒ３が（Ｃ）又は（ｄ
）で示される基であるとき、Ｗはカルボニル基を意味し
、（ｉｉ）Ａ環がシクロヘキサン環のとき、Ｙ及び２は
共に水素ね子を意味するか、あるいはＹとＺ原子を意味
する。］
で表される環状アミン誘４体及びその塩類を提供するも
のである。ami7 group or acylami/group, Ra means a hydrogen atom or a hydroxyl group, Re means a lower alkoxycarbonyl group, an aralkyloxycarbonyl group, a phenyl group, a 22-substituted phenyl group (Lfn substituent is a halogen, a lower alkyl or lower alkoxy) or an aralkyl group, or when R9 is in the 4-position of the piperidi/ring, R8- may be taken together to form an ethylene ketal group or an oxo group, W is carbonyl group or sulfonyl group, X means an alkylene group, a and b each mean an integer of 1 to 4, C means an integer of O to 2, d means an integer of i to 3 However, e represents 0 or 1 as an alpha ray, the sum of d and e is an integer of 2 or more, and r means an integer of 1 to 3. However, (i) R3 is (C) or (d
), W means a carbonyl group, and (ii) when A ring is a cyclohexane ring, Y and 2 both mean hydrogen atoms, or Y and Z atoms. ] The present invention provides a cyclic amine derivative represented by the following and salts thereof.
式（Ｉ）で表される化合物の塩類とは、式（Ｉ）におい
てＲ３が前記（ａ）又は（ｂ）で示される基である化合
物の塩類及びＲ３が前、？２（ｃ）又は（ｄ）で示され
る基で、Ｒフがアミノ基である化合物の塩類を意味する
。塩類としては、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、ジウ化水素酸塩、硫酸塩
、リン酸塩等の無機酸塩、及びシュウ酸塩、マレイア酸
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７Ｗａ塩等のａ機酸
塩が挙げられる。式（Ｉ）の化合物及びその塩は水和物
又は溶媒和物の形で存在することもあるので、これらの
水和物及び溶媒和物もまた本発明の化合物に包含される
。The salts of the compound represented by the formula (I) are the salts of the compound in which R3 is a group represented by (a) or (b) above, and the salts of the compound represented by the formula (I), and the salts of the compound represented by the formula (I), in which R3 is a group represented by The group represented by 2(c) or (d) refers to the salts of a compound in which R is an amino group. As the salts, physiologically acceptable salts are preferred;
For example, inorganic acid salts such as hydrochlorides, hydrobromides, dihydrogenates, sulfates, phosphates, and oxalates, maleates, fumarates, lactates, malates, citric acids. Salts, tartrates, benzoates, methanesulfo 7Wa salts, and other a-organic acid salts are mentioned. Since the compound of formula (I) and its salts may exist in the form of hydrates or solvates, these hydrates and solvates are also included in the compounds of the present invention.
式（１）の化合物は、場合によっては１個以上の不斉炭
素原子を存し、更に場合によっては１個の不斉イオウ原
子を存するので、立体異性体として存在し得る。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。The compound of formula (1) may exist as stereoisomers since it may contain one or more asymmetric carbon atoms and further may contain one asymmetric sulfur atom. These stereoisomers, mixtures and racemates thereof are 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.
低級アルキル基、低級アルコキシ基、低級アルキルチオ
基又はアルキレン基は、直鎖状でも分枝鎖状でもよいが
、直鎖状のものが好ましい、ハロゲン顛子とは、フッ素
、塩素、臭素、ヨウ素を意味するが、フッ素、塩素、Ｑ
素が好ましい、低級アルキル基とは、炭素原子数１〜Ｂ
のものを意味し、例えばメチル、エチル、プロピル、イ
ンプロピル、ブチル等が挙げられる。低級アルコキシ基
とは、炭素Ｕ子数１〜６のものを意味し、例えばメトキ
シ、エトキシ、プロポキシ、インプロポキシ等が挙げら
れる。低級アルキルチオ基とは、炭素原子数１〜６のも
のを意味し、例えばメチルチオ。The lower alkyl group, lower alkoxy group, lower alkylthio group, or alkylene group may be linear or branched, but linear ones are preferable. Meaning, fluorine, chlorine, Q
The lower alkyl group, which is preferably a carbon atom group, has 1 to B carbon atoms.
Examples include methyl, ethyl, propyl, inpropyl, butyl, and the like. The lower alkoxy group means a group having 1 to 6 carbon atoms, and includes, for example, methoxy, ethoxy, propoxy, impropoxy, and the like. A lower alkylthio group means one having 1 to 6 carbon atoms, such as methylthio.
エチルチオ、プロピルチオ、インプロピルチオ等が挙げ
られる。アシル基とは、炭ｉｏ子数１〜７の脂肪族カル
ボンｉ！Ｉａ基を意味し、例えばホルミル、アセチル、
プロピオニル、ブチリル等が挙げられる。アラルキル基
とは、アルキル部分が炭素原子数１〜４のものを意味し
、例えばベンジル。Examples include ethylthio, propylthio, inpropylthio, and the like. An acyl group is an aliphatic carbon i! having 1 to 7 carbon atoms. Ia group, such as formyl, acetyl,
Examples include propionyl and butyryl. Aralkyl group means an alkyl moiety having 1 to 4 carbon atoms, such as benzyl.
フェネチル、ナフチルメチル等が挙げられる。アルキレ
フ基とは、炭素原子数１〜ＩＯのものを意味し、例えば
メチレン、エチレ／、トリメチレン。Examples include phenethyl and naphthylmethyl. Alkylev group means one having 1 to 10 carbon atoms, such as methylene, ethylene/, trimethylene.
テトラメチレン、ペンクメチレン、ヘキサメチレン、ヘ
プタメチレン等が挙げられる。Examples include tetramethylene, pencumethylene, hexamethylene, heptamethylene and the like.
本発明化合物は例えば以下の方法により製造することか
できる。The compound of the present invention can be produced, for example, by the following method.
Ｒ＋−Ｎ−Ｗ Ｘ Ｖ （ＩＴ）（式
中、Ｒ１，Ｒ２，Ｗ及びＸは前掲に同じものを意味し、
■はアルコールの反応性エステル残基を意味する。）
で表される化合物と、一般式（ＩＩＩ）■Ｒ１１’
（ＩＩＩ）［式中、Ｒ３′は前記Ｒ３
の定義における（ａ）又は（ｂ）で示されるμを意味す
る。］
で表される化合物とを反応させることにより、式（Ｉ）
においてＲ３が前！ｃ！ （ａ ）又は（ｂ）で示され
る基である化合物を得ることができる。R+-N-W X V (IT) (wherein R1, R2, W and X mean the same as above,
■ means a reactive ester residue of alcohol. ) and the compound represented by the general formula (III) ■R11'
(III) [In the formula, R3' is the above-mentioned R3
means μ shown in (a) or (b) in the definition. ] By reacting with a compound represented by formula (I)
R3 is in front! c! A compound which is a group represented by (a) or (b) can be obtained.
式（ＩＩ）においてＶで表されるアルコールの反応性エ
ステル残基としては、例えば塩素、臭素。Examples of the reactive ester residue of alcohol represented by V in formula (II) include chlorine and bromine.
ヨウ索のようなハロゲン卵子、メタンスルホニルオキシ
、メタンスルホニルオキシのような低級アルキルスルホ
ニルオキシ基、ぺ／ゼンスルホニルオキシ、ｐ−）ルエ
ンスルホニルオキシ１ｍ−二トロベンゼ／スルホニルオ
キシのようなアリールスルホニルオキシ基が挙げられる
。Halogen ova such as methanesulfonyloxy, lower alkylsulfonyloxy groups such as methanesulfonyloxy, arylsulfonyloxy groups such as p/zenesulfonyloxy, p-)luenesulfonyloxy, 1m-nitrobenzene/sulfonyloxy can be mentioned.
式（ＩＩ）の化合物と式（Ｉｌｌ）の化合物との反応は
、無ＴＢ楳下、又は適当な溶媒中で行われ、溶媒の具体
例としては、べ７ゼ／、トルエ／、キシ１／ンのような
芳香族炭化水ｉ類、メチルエチルケトンのようなケトン
類、テトラヒドロフラン、ジオキサ／のようなエーテル
類、エタノール、インプロピルアルコールのようなアル
コール類、アセトニトリル、ジメチルホルムアミド等が
挙げられる。The reaction between the compound of formula (II) and the compound of formula (Ill) is carried out without TB or in an appropriate solvent. Specific examples of the solvent include benzene/, toluene/, Examples include aromatic hydrocarbons such as alcohol, ketones such as methyl ethyl ketone, ethers such as tetrahydrofuran and dioxa, alcohols such as ethanol and inpropyl alcohol, acetonitrile, and dimethylformamide.
これらの溶媒はそれぞれ単独で、又は２種以上を混合し
て使用できる０本反応は塩基の存在下に行うのが好まし
く、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／、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（Ｉｌｌ）の化合物の過刺量で兼ねることも
できる。These solvents can be used alone or in a mixture of two or more.The reaction is preferably carried out in the presence of a base, and specific examples of the base include heavy solvents such as sodium bicarbonate and potassium bicarbonate. Examples include alkali carbonates, alkali carbonates such as sodium carbonate and potassium carbonate, and organic bases such as triethylamine/N-methylmorpholine, but they can also be used in an excessive amount of the compound of formula (Ill).
また、式（■）においてＶが塩素又は臭素である化合物
を用いるときは、ヨウ化ナトリウム、ヨウ化カリウムの
ようなアルカリ金属ヨウ化物を添加すると反応は円滑に
進行する。反応温度は通常的０℃ないし約２００℃、好
ましくは約４０℃゛ないし約１５０℃である。Further, when using a compound in which V is chlorine or bromine in formula (■), the reaction proceeds smoothly by adding an alkali metal iodide such as sodium iodide or potassium iodide. The reaction temperature is generally 0°C to about 200°C, preferably about 40°C to about 150°C.
方法（ｉ＋）ニ
一般式（ＩＶ）
ＲＩ−ＮＨ（ＩＶ ）
（式中、ＲＩ及びＲ２は前掲に同じものを意味する。）
で表される化合物と、一般式（Ｖ）
ＩＯ−Ｃｏ −Ｘ Ｒ３（Ｖ ）
（式中％Ｒ３及びＸ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を反応させるこ
とにより、式（［）においてＷがカルボニル基である化
合物を得ることができる。Method (i+) General formula (IV) RI-NH(IV) (wherein RI and R2 have the same meanings as above)
and a compound represented by the general formula (V) IO-Co-X R3(V) (in the formula, %R3 and X have the same meanings as above) or a reactive derivative thereof. By reacting, a compound in formula ([) in which W is a carbonyl group can be obtained.
式（Ｖ）の化合物の反応性誘導体としては、例えば活性
エステル、酸無水物、ｌ！！ハライド（特に酸クロリド
）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。Reactive derivatives of the compound of formula (V) include, for example, active esters, acid anhydrides, l! ! Mention may be made of halides, especially acid chlorides. A specific example of the active ester is p-nitrophenyl ester.
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。2, 4.5. -Trichlorophenyl ester, pentachlorophenyl ester, cyanomethyl ester.
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等が挙げられる。Examples include N-hydroxysuccinimide ester and N-hydroxyphthalimide 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、混合酸無水物の具体例としてはクロルギ酸エチ
ル、クロルギ酸インブチルのようなりロルギ酸アルキル
エステルとの混合酸無水物、クロルギ酸フェニルのよう
なりロルギ酸アリールエステルとの混合酸無水物、イソ
吉草酸、ピバリン酸のようなアルカ／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 acid anhydride include ethyl chloroformate, inbutyl chloroformate, mixed acid anhydride with an alkyl lorformate, and chloroformate. Examples include mixed acid anhydrides with aryl lorformic acid such as phenyl acid, mixed acid anhydrides with alkali/acids such as isovaleric acid and pivalic acid, and the like.
式（Ｖ）の化合物を用いる場合には、シンクロへキシル
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、カルボニルジイミ
ダゾール、１−エトキシカルボニル−２−エトキシ−１
，２−ジヒドロキノリンのような縮合剤の存在下に反応
させることができる。When using the compound of formula (V), synchhexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, carbonyldiimidazole, 1-ethoxycarbonyl-2-ethoxy-1
, 2-dihydroquinoline.
式（ＩＶ）の化合物と式（Ｖ）の化合物又はその反応性
誘導体との反応は通常、溶媒中で行われる。The reaction between the compound of formula (IV) and the compound of formula (V) or a reactive derivative thereof is usually carried out in a solvent.
使用する溶媒は、原料化合物のａ類等に従って適宜選択
されるべきであるが、例えばベンゼン、トルエン、キシ
レンのような芳香族炭化水素類、ジエチルエーテル、テ
トラヒドロフラン、ジオキサンのようなエーテル類、塩
化メチレン、クロロホルムのようなハロゲン化炭化水素
類、酢酸エチル、アセトニトリル、ジメチルホルムアミ
ド、ジメチルスルホキシド、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！Ｉｔ以上混合して
用いられる。本反応は必要に応じて塩基の存在下に行わ
れ、塩基の具体例としては、（ｉ）法の部分で述べた塩
基の具体例をそのまま挙げることができる。反応温度は
用いる部将化合物の種類等により異なるが、通常約−２
０℃ないし約１５０℃、好ましくは約０℃ないし約８０
℃である。The solvent to be used should be appropriately selected according to class a of the raw material compound, and examples thereof include aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as diethyl ether, tetrahydrofuran, and dioxane, and methylene chloride. , halogenated hydrocarbons such as chloroform, ethyl acetate, acetonitrile, dimethylformamide, dimethyl sulfoxide, water, etc. These solvents may be used alone or in combination of 2! It is used in a mixture of more than It. This reaction is carried out in the presence of a base if necessary, and as specific examples of the base, the specific examples of the base mentioned in the section (i) of method can be cited as they are. The reaction temperature varies depending on the type of general compound used, but is usually about -2
0°C to about 150°C, preferably about 0°C to about 80°C
It is ℃.
上記各製法により生成する式（Ｉ）の化合物は、クロマ
トグラフィー、再結晶又は再沈殿等の常法により単離、
精製される。The compound of formula (I) produced by each of the above production methods can be isolated by conventional methods such as chromatography, recrystallization, or reprecipitation.
Refined.
式（ｒ）に右いてｆｈが上記（ａ）又は（ｂ）で示され
る基である化合物及びＲ３が上記（Ｃ）又は（ｄ）で示
される基で％Ｒ７がアミノ基である化合物は、わ科化合
物の選定９反応・処理条件等により、遊離塩基又は塩の
形で得られる。塩は、常法、例えばＡ２２ｆｆｉ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、塩に導くことができる。Compounds in which fh is a group represented by the above (a) or (b) in formula (r) and compounds in which R3 is a group represented by the above (C) or (d) and %R7 is an amino group are: Selection of Robinaceous Compounds 9 Depending on the reaction and processing conditions, etc., compounds can be obtained in the form of free bases or salts. Salts can be converted to the free base in conventional manner, for example by treatment with a base such as an A22ffi alkali. On the other hand, free bases can be converted into salts by treatment with various acids according to conventional methods.
式（Ｉ）の化合物及びその生理的に許容される塩類は、
優れたカルシウム拮抗作用を有するので、高血圧症及び
／又は虚血性循環器障害の予防並びに治療にを用である
。The compound of formula (I) and its physiologically acceptable salts are:
Since it has an excellent calcium antagonistic effect, it is used for the prevention and treatment of hypertension and/or ischemic circulatory disorders.
以下に、本発明の代表的化合物並びに市販のカルシウム
拮抗剤であるエロ酸ジルチアゼム及びニフェジピ７につ
いての薬理試験の結果を示し、本発明の化合物の薬理作
用を説明する。Below, the results of pharmacological tests on representative compounds of the present invention and commercially available calcium antagonists diltiazem eroate and nifedipi 7 will be shown, and the pharmacological action of the compounds of the present invention will be explained.
試験例 カルシウム拮抗作用
本試験は、Ｇｏｄｒｒａｉｎｄらの方法［［１ｒ、 Ｊ
、 ’Ｐｈａｒｍａｃ、。Test Example Calcium antagonism This test was performed using the method of Godrraind et al. [[1r, J
, 'Pharmac,.
姐、５４９〜５００ （１９０９）］に準じて行った。549-500 (1909)].
体ｍ ２５０〜３００ ｇの雄性ウィスター（ＩＨｓｔ
ａｒ）系ラットの摘出胸部大動脈を螺旋吠に切間し、幅
３〜４ｍｍ、Ｉｋさ約３０−の動脈切片標本を作製した
。Male Wistar (IHst) with body m 250-300 g
The isolated thoracic aorta of the ar) type rat was cut into a spiral shape to prepare an artery section specimen with a width of 3 to 4 mm and an Ik of about 30 mm.
９５％ ０２ ＋ ５９Ａ Ｃｏｔの混合ガスを通気し
、３７℃に保温した！θ園１のクレプス・ビカーボネー
ト液中に標本を懸垂し、１ｇの張力を加えた。標本の収
縮反応は張力−変位トランスジューサーを介してインク
書きオシログラフで記録した。A mixed gas of 95% 02 + 59A Cot was aerated and the temperature was kept at 37°C! The specimen was suspended in Kreps bicarbonate solution in θ Garden 1, and a tension of 1 g was applied. The contraction response of the specimen was recorded with an ink-writing oscillograph via a tension-displacement transducer.
まず、標本を！！垂したマグヌス槽内の溶液をＣａ”を
含まない高に＋クレプス・ビカーボネート液に交換し、
脱分極を惹起させた後に、ＣａＣｌ＊を累積的に添加し
、ｃｈ”による用量−収縮曲線を求めた。次に試験化合
物存在下に同様の実験を行い、Ｃａ”による用量−収縮
曲線を求め、 Ｖａｎ Ｒｏｓｓｕ■の方法［＾ｒｃｈ
、 ＋ｎｔ、 Ｐｈａｒｍａｃｏｄｙｎ、、 １４３．
２９９〜３３Ｇ（＋９０３＞］に準じてカルシウム拮抗
作用のＰｈ３を算出した。なお、ｐＡ＊とは、σｅによ
る用量−収縮曲１ａ（試験化合物非存在下）を２倍だけ
高０度側へ平行移動させるのに必要な試験化合物のモル
ロ度の逆対数で定義される数値である。First, the specimen! ! Replace the dripping solution in the Magnus tank with Ca''-free solution + Kreps bicarbonate solution,
After inducing depolarization, CaCl* was added cumulatively, and a dose-contraction curve due to ch'' was determined. Next, a similar experiment was conducted in the presence of the test compound, and a dose-contraction curve due to Ca'' was determined. , Van Rossu's method [^rch
, +nt, Pharmacodyn, 143.
Ph3 of calcium antagonism was calculated according to 299-33G (+903>). Note that pA* is the dose-contraction curve 1a (in the absence of test compound) by σe parallel to the high 0 degree side by twice. It is a number defined as the inverse logarithm of the molarity of the test compound required to migrate.
結果を表１に示す。表中の数値は、３〜６標本について
の平均値上標準誤差を表す。The results are shown in Table 1. The numbers in the table represent the standard error above the mean for 3 to 6 samples.
（以下余白） 表 １ カルシウム拮抗作用 １ 実施例１の化合物をΩ味する（以下同じ）。(Margin below) Table 1 Calcium antagonism 1 Taste the compound of Example 1 (the same applies below).
式（１）の化合物及びその生理的に許容される塩類の投
与経路としては、経口投与、非経口投与あるいはにｆ腸
内投与のいずれでもよいが、経口投与が好ましい。その
投与口は、化合物の種類、投与方法１ｍ者の症伏・年令
等により異なるが、通常０．００５〜２０ｇ／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、デキス
トリ／ｌ シクロデキストリ／、デンプン、白糖。The compound of formula (1) and its physiologically acceptable salts may be administered by oral administration, parenteral administration or intestinal administration, but oral administration is preferred. The administration dose varies depending on the type of compound, the method of administration, the patient's symptoms, age, etc., but is usually 0.005 to 20 g/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 a pharmaceutical carrier, it is commonly used in the pharmaceutical field and has the formula (I).
A substance that does not react with the compound or its salt is used. Specifically, for example, lactose, glucose, mannitol, dextrin/l cyclodextrin/, starch, and white sugar.
メタケイ酸アルミン酸マグネシウム、合成ケイ酸アルミ
ニウム、結晶セルロース、カルボキシメチルセルロース
ナトリウム、ヒドロキシプロピルデ／プ７１ カルボキ
シメチルセルロースカルシウム。Magnesium aluminate metasilicate, synthetic aluminum silicate, crystalline cellulose, sodium carboxymethylcellulose, hydroxypropyl de/p71 calcium carboxymethylcellulose.
イオン交換樹脂、メチルセルロース、ゼラチン。Ion exchange resin, methylcellulose, gelatin.
アラビアゴム、プルラン、ヒドロキシプロピルセルロー
ス、低置換度ヒドロキク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、ポリビニルピロリドン、
ポリビニルアルコール、軽質無水ケイ酸、ステアリン酸
マグネクウム、タルク。Gum arabic, pullulan, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone,
Polyvinyl alcohol, light silicic anhydride, magnesium stearate, talc.
トラガ／ト、ベントナイト、ビーガム、カルボキシビ二
ルボリマー、ａ化チタン、ンルビタン脂肪酸エステル、
ラウリル硫酸ナトリウム、カカオ脂。Toraga/T, bentonite, vegum, carboxyvinyl polymer, titanium a oxide, nrubitan fatty acid ester,
Sodium lauryl sulfate, cocoa butter.
グリセリン、脂肪酸グリセリンエステル、精製う／す／
、グリセロゼラチン、ポリソルベート、マクロゴール、
植物油、ロウ、プロピレングリコール、水等が挙げられ
る。剤型としては、錠剤、カプセル剤、顆粒剤、細粒剤
、散剤、シロップ剤。Glycerin, fatty acid glycerin ester, purified ox/su/
, glycerogelatin, polysorbate, macrogol,
Examples include vegetable oil, wax, propylene glycol, water, and the like. Dosage forms include tablets, capsules, granules, fine granules, powders, and syrups.
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。なお液体製剤にあっては、用
時、水又は他の適当な媒体に溶解又は懸濁する形であっ
てもよい。また錠剤、顆粒剤。Examples include suspensions, injections, and suppositories. These formulations are prepared according to conventional methods. In the case of a liquid preparation, it may be dissolved or suspended in water or other suitable medium before use. Also tablets and granules.
細粒剤は周知の方法でコーティングしてもよい。Granules may be coated by known methods.
これらの製剤は、式（Ｉ）の化合物又はその生理的に許
容される塩を０．５％以上、好ましくは１〜７０９１＆
の割合で含何することができる。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。These preparations contain 0.5% or more of the compound of formula (I) or a physiologically acceptable salt thereof, preferably 1-7091&
It can contain anything in the proportion of These formulations also
It may also contain other ingredients of therapeutic value.
また、以下の参考例及び実施例において記載の筒略化の
ために次の略号を使用することもある。Furthermore, in the following Reference Examples and Examples, the following abbreviations may be used to simplify the description.
Ｍｅ：メチル基
Ｅｔ：エチル基
Ｐｒ ：プロビル基
Ｐｈ：フェニル基
へ〇ニア七チル基
Ａ ：エタノール
ＡＥ：酢酸エチル
ＣＨ：クロロホルム
Ｅ ニジエチルエーテル
Ｈ：ｎ−へ牛サン
■Ｅニジイソプロピルエーテル
参考例１
１１−“（５−クロロバレリルアミノ）−ａｌｌ−ジヒ
ドロジベンゾ［ｂ、ｅ］チェピンの製造：■−アミノー
Ｑｌｌ−ジヒドロジベ／ゾ［ｂ、ｅ］チェピン８．８ｇ
、 ５−クロロ吉草酸クロリド０．０ｇ及びジオキサ
ン１００■ｌの混合物を撹拌下に１５時間加熱還流する
。溶媒を減圧で留去し、残渣をエタノールから再結晶し
て目的物１２．５ ｇを得る。Me: Methyl group Et: Ethyl group Pr: Probyl group Ph: Phenyl group 〇nia7tyl group A: Ethanol AE: Ethyl acetate CH: Chloroform E Nidiethyl ether H: N-hegyusan■E Nidiisopropyl ether reference example 1 Production of 11-“(5-chlorovalerylamino)-all-dihydrodibenzo[b,e]chepin: ■-Amino-Qll-dihydrodibe/zo[b,e]chepin 8.8 g
A mixture of 0.0 g of 5-chlorovaleric acid chloride and 100 μl of dioxane is heated under reflux for 15 hours with stirring. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethanol to obtain 12.5 g of the desired product.
融点１５５〜１５０℃
参考例２〜１２
対応する原料化合物を用い、参考例１と同様に反応・処
理して以下の化合物を得る。Melting point: 155-150°C Reference Examples 2-12 Using the corresponding raw material compounds, the following compounds were obtained by reacting and treating in the same manner as in Reference Example 1.
・１ｌ−（４−クロロブチリルアミノ）−ａｌｌ−ジヒ
ドロジベンゾ［ｂ、ｅ］オキセピン
１１ａ １０９〜１７１℃（トルエンから再結晶）・１
１− （３−クロロプロピオニルアミノ）−８，１１−
ジヒドロジベンゾ［ｂ、 ｅ］チェピン・１ ／ ５
ＥｔＯ１１融点１１７〜１７７．５℃（エタノールから
再結晶）−１１−（４−クロロブチリルアミノ）−ａｈ
−ジヒドロジベンゾ［ｂ、ｅｌｌチェピ
ッ点１８９〜１９０℃（エタノールから再結晶）−１１
−（４−クロロブチリルアミノ）−２−フルオロ−８，
Ｉｆ−ジヒドロジベ／ゾｌ：ｂ、ｅｌチェピ／融点 １
８７〜１８９℃（酢酸エチルから再結晶）・ＩＩ−（４
−クロロブチリルアミノ）−２−メチル−Ｑｌ＋−ジヒ
ドロジベンゾ［ｂ、ａｌｌチェピッ点１８８〜１９０℃
（酢酸エチルから再結晶）ｅ目−（４−クロロブチリル
アミノ）−３−メチル−８，１１−ジヒドロジベンゾ［
ｂ、ａ］チェピン融点 １７４〜１７Ｇ”Ｃ（酢酸エチ
ルから再結晶）・Ｉｆ−（４−クロロブチリルアミノ）
−３−メトキシ−８，１１−ジヒドロジベンゾ［：ｂ、
ｅ］チェピ／融点 １７０〜１７２℃（酢酸エチルから
再結晶）−５−（４−クロロブチリルアミノ）−５１１
−ジペど
／ゾ［ａ、ｄ］シクロヘプテ／ 融点２２０〜２２３℃
（トルエンから再結晶）
−５−（４−クロロブチリルアミノ）−１−クロロ−５
Ｈ−ジベンゾ［ａ、ｄ］シクロヘプテン融点２３０〜２
３３℃（クロロホルムから再結晶）−５−（４−クロロ
ブチリルアミノ）−３−プロモー５１〜■−ジベンゾ［
ａ、ｄｌｌツクヘプテンＭ４ ２１０〜２１２℃（クロ
ロホルム−酢酸エチルから再結晶）
・５−（４−クロロブチリルアミノ）−５１！−１０゜
１１−ジヒドロジベンゾ［ａ、ｄｌシクロヘプテンｍ点
２２０〜２２２℃（トルエンから再結晶）参考例１３
１１−（４−クロロブチリルアミノ）−ａｌｌ−ジヒド
ロジベンゾ［ｂ、ｅｌチェピン−５，５−ジオキシドの
製造：
１ｌ−（４−クロロブチリルアミノ）−８，１１−ジヒ
ドロジベンゾ［ｂ、ｅｌチェピン５．０ｇをクロロホル
ム１００■１に溶解し、これに水冷下ｍ−クロクロ安息
香ａ １２ｇを加えた後、０°Ｃで１時間撹拌する。・1l-(4-chlorobutyrylamino)-all-dihydrodibenzo[b,e]oxepin 11a 109-171°C (recrystallized from toluene)・1
1-(3-chloropropionylamino)-8,11-
Dihydrodibenzo[b,e]chepin・1/5
EtO11 melting point 117-177.5°C (recrystallized from ethanol) -11-(4-chlorobutyrylamino)-ah
-dihydrodibenzo [b, ell Chepi point 189-190°C (recrystallized from ethanol) -11
-(4-chlorobutyrylamino)-2-fluoro-8,
If-dihydrodibe/sol: b, el Chepi/Melting point 1
87-189°C (recrystallized from ethyl acetate) II-(4
-chlorobutyrylamino)-2-methyl-Ql+-dihydrodibenzo[b, all Chepi point 188-190°C
(Recrystallized from ethyl acetate) -(4-chlorobutyrylamino)-3-methyl-8,11-dihydrodibenzo[
b, a] Chepin Melting point 174-17G"C (recrystallized from ethyl acetate) If-(4-chlorobutyrylamino)
-3-methoxy-8,11-dihydrodibenzo[:b,
e] Chepi/Melting point 170-172°C (recrystallized from ethyl acetate) -5-(4-chlorobutyrylamino)-511
-Dipedo/zo[a,d]cyclohepte/ Melting point 220-223℃
(Recrystallized from toluene) -5-(4-chlorobutyrylamino)-1-chloro-5
H-dibenzo[a,d]cycloheptene melting point 230-2
33°C (recrystallized from chloroform) -5-(4-chlorobutyrylamino)-3-promo 51~■-dibenzo[
a, dll Tsukuheptene M4 210-212°C (recrystallized from chloroform-ethyl acetate) ・5-(4-chlorobutyrylamino)-51! -10° 11-dihydrodibenzo[a, dl cycloheptene m point 220-222°C (recrystallized from toluene) Reference example 13 11-(4-chlorobutyrylamino)-all-dihydrodibenzo[b, el Chepin-5, Production of 5-dioxide: Dissolve 5.0 g of 1l-(4-chlorobutyrylamino)-8,11-dihydrodibenzo[b,el chepine in 100 parts of chloroform, and add 12 g of m-chlorobenzoin a to this under cooling with water. After adding, stir at 0°C for 1 hour.
反応液を１０％水酸化ナトリウム、水、飽和食塩水で順
次洗浄したのち硫酸マグネシウムで乾燥する。The reaction solution was washed successively with 10% sodium hydroxide, water, and saturated saline, and then dried over magnesium sulfate.
溶媒を留去し、残渣をメタノールから再結晶して目的物
５．１ｇを得る。融点２１５〜２２７℃参考例１４
■−（４−クロロブチリルアミノ）−＋３，１１−ジヒ
ドロジベンゾ［ｂ、ｅ］チェピン−５−オキシドの製造
：
＋１−（４−クロロブチリルアミノ）−＋３，１１−ジ
ヒドロジベンゾ［ｂ、ｅ］チェピ／１０ｇを塩化メチレ
ノ５００園１に溶解し、これに水冷下ｍ−クロロ過安息
香酸７．Ｏｇを加えた後、室温で３０分撹拌する。The solvent was distilled off, and the residue was recrystallized from methanol to obtain 5.1 g of the desired product. Melting point 215-227°C Reference Example 14 ■ Production of -(4-chlorobutyrylamino)-+3,11-dihydrodibenzo[b,e]chepin-5-oxide: +1-(4-chlorobutyrylamino)-+3 , 11-dihydrodibenzo[b,e]chepi/10g was dissolved in methylene chloride 500g, and 7g of m-chloroperbenzoic acid was added to the solution under water cooling. After adding Og, stir at room temperature for 30 minutes.
反応液を１０％水酸化ナトリウム、水、！２１和食塩水
で順次洗浄した後、＆！Ｅ酸マグネシウムで乾燥する。The reaction solution was mixed with 10% sodium hydroxide, water, and! 21 After sequentially washing with Japanese saline solution, &! Dry with magnesium E acid.
塩化メチレンを留去し、残渣をクロロホルム−ｎ−ヘキ
サンから再結晶して目的物８．０ｇを得る。Methylene chloride was distilled off, and the residue was recrystallized from chloroform-n-hexane to obtain 8.0 g of the desired product.
融点２１０〜２１２℃
参考例１５
トランス−１１−（４−クロロブチリルアミノ）−０，
Ｏａ、？、８．９，１０，１０ａ、１１−オクタヒドロ
ジベ７ゾ［：ｂ、ｅｌチェピンの製造：
（１）トランス−ｆｌ、（ｌａ、？、Ｌ９，１０，１０
ａ、１１−オクタヒドロ−１１−オキソジベンゾ［：ｂ
、ｅｌｌチェピッ６及びギ酸アンモニウム４０ｇの混合
物を２２０℃で２時間溶融撹拌した後、ギ酸アンモニウ
ム４０ｇを追加し、２２０℃で更に２時間撹拌する。６
後、反応混合物に水を加え、析出する油仕切をトルエン
で抽出する。抽出液を水洗したのち減圧で濃縮し、残渣
をシリカゲルカラムクロマトグラフィーに付し、クロロ
ホルムで溶出してトランス−■−ホルムアミドー〇、Ｏ
ａ、？、８，９．１０．１０ａ、１１−オクタヒドロジ
ベンゾ［ｂ、ｅ］チェピン５ｇを油仕切として得る。Melting point 210-212°C Reference example 15 trans-11-(4-chlorobutyrylamino)-0,
Oa,? , 8.9,10,10a,11-octahydrodibe7zo[:b,elChepin production: (1) trans-fl, (la, ?, L9,10,10
a, 11-octahydro-11-oxodibenzo[:b
, ELL Chepi 6, and 40 g of ammonium formate were melted and stirred at 220° C. for 2 hours, then 40 g of ammonium formate was added, and the mixture was further stirred at 220° C. for 2 hours. 6
After that, water is added to the reaction mixture, and the precipitated oil partition is extracted with toluene. After washing the extract with water, it was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography and eluted with chloroform to obtain trans-■-formamide〇, O
a,? , 8,9.10.10a, 5 g of 11-octahydrodibenzo[b,e]chepine are obtained as oil partition.
■ 上記■−ホルムアミド体５ｇ、エタノール４０１及
び製塩ｆ！ｌＩ２０ｍ１の混合物を１００℃で３０分間
加熱還流する。反応液を減圧で濃縮し、残渣に１０％炭
酸カリウムを加え、析出する油仕切を酢酸エチルで抽出
する。抽出液を水洗し、硫酸マグネシウムで乾燥した後
、減圧でｅＪ縮してトランス−■−アミノー０．Ｏａ、
？、８，９．ＩＯ，１０ａ、ＩＩ−オクタヒドロジベン
ゾ［ｂ、ｅ］チェピン４ｇを油仕切として得る。■ Above ■ - 5 g of formamide, ethanol 401 and salt production f! A mixture of 20 ml of lI is heated to reflux at 100° C. for 30 minutes. The reaction solution is concentrated under reduced pressure, 10% potassium carbonate is added to the residue, and the precipitated oil partition is extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, and then concentrated under reduced pressure to obtain trans-■-amino 0. Oa,
? , 8, 9. 4 g of IO,10a,II-octahydrodibenzo[b,e]chepine are obtained as oil partition.
（３） 上記■−アミノ体２．５０ｇ、 ）ルエノ
５０１及び４−クロロ酪酸クロリド１．９ｇの混合物を
１３０℃で１６時間加ａ還流する。溶媒を減圧で留去し
、残渣をシリカゲルカラムクロマトグラフィーに付し、
クロロホルムで溶出して目的物３．Ｏｇを油仕切として
得る。マス・スペクトルｍ／ｚ ： ３３７ （Ｍ”
）実施例１
１１− ［４−（１，２，へ４−テトラヒドロインキノ
リ／−２−イル）ブチリルアミノ］−８，１１−ジヒド
ロジベンゾ［ｂ、ｅ］チェピンの製造：１ｌ−（４−ク
ロロブチリルアミノ）−０，ＩＩ−ジヒドロジベンゾ［
ｂ、ｅ］チェピン１．０ ｇ、 １，２．３．４−テ
トラヒドロインキノリ：／１．４ｇ、Ｅｌつ化ナトリウ
ム４．０ｇ及びジメチルホルムアミド２０１の混合物を
１００℃で１時間撹拌する。６後、１０％炭酸カリウム
を加えクロロホルムで抽出する。抽出液を水、次いで飽
和食塩水で洗浄したのち硫酸マグネシウムで乾燥する。(3) A mixture of 2.50 g of the above ■-amino compound, ) Lueno 501 and 1.9 g of 4-chlorobutyric acid chloride was refluxed at 130° C. for 16 hours. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography.
Elute with chloroform to obtain the target product 3. Obtain Og as an oil partition. Mass spectrum m/z: 337 (M”
) Example 1 Preparation of 11-[4-(1,2,he4-tetrahydroinquinol/-2-yl)butyrylamino]-8,11-dihydrodibenzo[b,e]chepin: 1l-(4-chloro butyrylamino)-0,II-dihydrodibenzo[
b, e] A mixture of 1.0 g of Chepine, 1.4 g of 1,2.3.4-tetrahydroin quinol, 4.0 g of sodium elutide, and 201 g of dimethylformamide is stirred at 100° C. for 1 hour. After 6 hours, 10% potassium carbonate was added and extracted with chloroform. The extract is washed with water, then with saturated saline, and then dried over magnesium sulfate.
ｒｔＩ媒を留去し、残渣をシリカゲルカラムクロマトグ
ラフィーに付し、クロロホルム−メタノール（１００：
２＞で溶出して目的物の１／４水和物１．２ｇを得る。The rtI medium was distilled off, the residue was subjected to silica gel column chromatography, and chloroform-methanol (100:
2> to obtain 1.2 g of a quarter hydrate of the target product.
融点１４５〜１４８℃（クロロホルム−ｎ−へキサンか
ら再ＬＶ 品＞実施例２
１鳳−［［３−（１，ス３，４−テトラヒトロインキノ
リン−２−イル）プロピル］スルホンアミド］−ａ■−
ジヒドロジベンゾ［ｂ、ｅ］チェピアの製造：１１−
［（３−クロロプロピル）スルホンアミド］−ｆＬ１１
−ジヒドロジベンゾ［ｂ、ｅ］チェピン！、８ｇ、１，
２，３．４−テトラヒトロインキノリン里、２ｇ。Melting point: 145-148°C (re-LV product from chloroform-n-hexane>Example 2 1-[[3-(1,3,4-tetrahytroinquinolin-2-yl)propyl]sulfonamide]- a■-
Production of dihydrodibenzo[b,e]chepia: 11-
[(3-chloropropyl)sulfonamide]-fL11
-dihydrodibenzo[b,e]chepin! ,8g,1,
2,3,4-tetrahytroinquinoline, 2 g.
ヨウ化ナトリウム番、Ｏｇ及びジメチルホルムアミドＩ
Ｏｍ ｌの混合物を１００℃で２．５時間撹拌する。６
後、反応液を実施例１と同様に後処理してアメ状の目的
物１．１７ｇを得る。Sodium iodide No., Og and dimethylformamide I
The Oml mixture is stirred at 100° C. for 2.5 hours. 6
Thereafter, the reaction solution was post-treated in the same manner as in Example 1 to obtain 1.17 g of a candy-like target product.
この遊離塩基をエタノール１０１に溶解し、マレイン酸
０．３ｇのエタノール３ ａｌｌ液を加えた後、エタノ
ールを留去し、残渣をエタノール−ジエチルエーテルか
ら再結晶して、目的物のマレイン酸塩・３／４水和物１
．１ ｆｆを得る。融点＋０１−１０３℃実施例３
ＩＩ−［４−（インドリン−１−イル）ブチリルアミノ
］−へ！！−ジヒドＶジベンゾ［ｂ、ｃ］オキセピンの
製造：
■−アミノーへ１！−ジヒドロジベンゾ［ｂ、ｅｌオキ
セピ：／１．Ｏｇ、 ４− （インドリ７−１−イル）
酪１！ｌ］、Ｏｇ、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１．１ｇ及びジメ
チルホルムアミド１０１の混合物を室温で２時間撹拌す
る０反応液に水５０１を加えて酢酸エチルで抽出し、抽
出液を水洗したのち無水硫酸ナトリウムで乾燥する。溶
媒を留去し、残渣を酢酸エチルから再結晶して目的物１
．０ ［を得る。This free base was dissolved in ethanol 101, and after adding 0.3 g of maleic acid in 3 all ethanol solution, the ethanol was distilled off, and the residue was recrystallized from ethanol-diethyl ether to obtain the desired maleate salt. 3/4 hydrate 1
．． 1 ff is obtained. Melting point +01-103°C Example 3 To II-[4-(indolin-1-yl)butyrylamino]-! ! -Production of dihydro V dibenzo[b,c]oxepin: ■-1 to amino! -dihydrodibenzo[b,eloxepi:/1. Og, 4-(indol-7-1-yl)
Dairy 1! A mixture of 1.1 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 101 g of dimethylformamide was stirred at room temperature for 2 hours. 501 water was added to the reaction mixture and extracted with ethyl acetate. After washing the extract with water, dry it with anhydrous sodium sulfate. The solvent was distilled off, and the residue was recrystallized from ethyl acetate to obtain the desired product 1.
．． 0 [obtain.
融点１５里〜１５３℃
実施例４
１１−［Ｎ−メチル−Ｎ−［４−（インドリ／−１−イ
ル）ブチリル］アミノ］−６．１１−ジヒドロジベンゾ
［ｂ、ｅ］チェピンの製造：
ＩＩ−メチルアミノ−ａｌｌ−ジヒドロジベンゾ［ｂ
＊ ｅ ］チェピン０．３ｇ、４−（インドリン−１−
イル）酪ｆｌＯ，３ｇ、 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０．３ｇ
及びジメチルホルムアミド６１の混合物を室温で１．５
時間撹拌する０反応液に水４Ｇ＋＋１を加えてトルエン
で抽出し、抽出液を水洗したのち無水硫酸ナトリウムで
乾燥する。溶媒を留去し、残渣をシリカゲルカラムクロ
マトグラフィーに付し、クロロホルムで溶出してアメ状
の目的物０．２ ｇを得る。Melting point 15°C to 153°C Example 4 Preparation of 11-[N-methyl-N-[4-(indol/-1-yl)butyryl]amino]-6.11-dihydrodibenzo[b,e]chepin: II -methylamino-all-dihydrodibenzo[b
*e] Chepin 0.3 g, 4-(indoline-1-
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride 0.3 g
and dimethylformamide 61 at room temperature.
4G++1 of water is added to the reaction solution which is stirred for an hour and extracted with toluene.The extract is washed with water and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was subjected to silica gel column chromatography and eluted with chloroform to obtain 0.2 g of the target product in the form of a candy.
マス・スペクトルｍ／ｚ ： ４２８ （Ｍ” ）実施
例５
１１−［４−（２−オキソインドリン−１−イル）ブチ
リルアミノ］−ａｌｌ−ジヒドロジベ／ゾ［ｂ、 ｅｌ
チェピンの製造：
■−７ミノーａｌｌ−ジヒドロジベ７ゾ［ｂ、ｅ］チェ
ピン２゜Ｏｇ、４−（２−オキソインドリン−１−イル
）酪＃２．Ｏｇ、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１．７ｇ及び塩化エ
チル１５ｏ１の混合物を室温で３時間撹拌する６反応液
にクロロホルム２００■１を加え、１０％炭酸カリウム
、水、１０％塩酸、水、飽和食塩水で順次洗浄した後、
硫酸マグネシウムで乾燥する。溶媒を留去し、ａｔｌｉ
をクロロホルム−酢酸エチルから再結晶して目的物３．
１ｇを得る。Mass spectrum m/z: 428 (M”) Example 5 11-[4-(2-oxoindolin-1-yl)butyrylamino]-all-dihydrodibe/zo[b, el
Production of Chepin: ■-7 minnow all-dihydrodibe7zo[b,e]Chepin 2°Og, 4-(2-oxoindolin-1-yl)butyric #2. A mixture of 1.7g of Og, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 15o1 of ethyl chloride is stirred at room temperature for 3 hours.6 Add 200μ1 of chloroform to the reaction mixture, and add 10% potassium carbonate, After sequentially washing with water, 10% hydrochloric acid, water, and saturated saline,
Dry with magnesium sulfate. The solvent was distilled off and atli
was recrystallized from chloroform-ethyl acetate to obtain the desired product 3.
Obtain 1g.
融点２１０〜２１７℃
実施例６
１１−［４−（フタルイミド−２−イル）ブチリルアミ
ノ］−ａｌｌ−ジヒドロジベンゾ［ｂ、ｅ］ヂエピンの
製造：
１１−アミノ−ａｌｌ−ジヒドロジベンゾ［ｂ、ｅｌチ
ェピｙ２．Ｏｇ、 ４− （フタルイミド−２−イル
）酪酸２．０ｇ 、ジシクロへキシルカルボジイミド２
．０ｇ及び塩化メチレン５０１の混合物を室温で１５時
間撹拌する。析出物を濾去し、濾液を減圧でＯｓする。Melting point 210-217°C Example 6 Preparation of 11-[4-(phthalimido-2-yl)butyrylamino]-all-dihydrodibenzo[b,e]diepine: 11-amino-all-dihydrodibenzo[b,elchepiy2 ．． Og, 2.0 g of 4-(phthalimid-2-yl)butyric acid, 2 dicyclohexylcarbodiimide
．． A mixture of 0 g and 501 methylene chloride is stirred at room temperature for 15 hours. The precipitate was filtered off and the filtrate was evaporated under reduced pressure.
残渣をクロロホルム−酢酸エチルから再結晶して目的物
２．８ｇを得る。 融点２０７〜２０９℃実施例７〜４
２
対応する原料化合物を用い、実施例１〜６と同様に反応
・処理して表２に示す化合物を得る。The residue was recrystallized from chloroform-ethyl acetate to obtain 2.8 g of the desired product. Melting point 207-209°C Examples 7-4
2 Using the corresponding raw material compounds, the compounds shown in Table 2 are obtained by reacting and treating in the same manner as in Examples 1 to 6.
表２
“ マス・スペクトルにおけるｍ／ｚ （Ｍ” ）（以
下同じ）表 ２（続き）
表２（続き）
対応する原料化合物を用い、実施例１〜Ｇと同様に反応
・処理して表３に示す化合物を得る。Table 2 "m/z in mass spectrum (M") (same hereinafter) Table 2 (Continued) Table 2 (Continued) Table 3 The compound shown in is obtained.
表３
Ｒ＋−ＮＩＩＣＯ−（ＣＩｌｔ）ｎ−Ｒ８Ｉ表 ３（続
き）
１ マス・スペクシルにおけるｍ／ｚ （Ｍ” ）実施
例６４〜６９
対応する原料化合物を用い、実施例３〜６と同様に反応
・処理して表４に示す化合物を得る。Table 3 R+-NIICO-(CIlt)n-R8I Table 3 (Continued) 1 m/z in Mass Speccil (M”) Examples 64-69 Reactions were carried out in the same manner as Examples 3-6 using the corresponding raw material compounds. - Process to obtain the compounds shown in Table 4.
表４Table 4
Claims (1)
、表等があります▼ で示される基を意味し、Ａ環はベンゼン環又はシクロヘ
キサン環を意味し、Ｙ及びＺは共に水素原子を意味する
か、あるいはＹとＺが一緒になって、単結合、−Ｏ−、
−Ｓ−、 −ＣＨ＝ＣＨ−、−ＣＨ＿２ＣＨ＿２−、▲数式、化学
式、表等があります▼、−ＣＨ＿２Ｏ−又は▲数式、化
学式、表等があります▼を形成し、Ｒ＿２は水素原子、
低級アルキル基又は低級アルコキシ基を意味し、Ｒ＿３
は下記（ａ）、（ｂ）、（ｃ）又は（ｄ）で示される基
を意味し、 （ａ）▲数式、化学式、表等があります▼（ｂ）▲数式
、化学式、表等があります▼ （ｃ）▲数式、化学式、表等があります▼（ｄ）▲数式
、化学式、表等があります▼ Ｂ環はベンゼン環又はシクロヘキサン環を意味し、Ｒ＿
４は同一又は異なって水素原子、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、
低級アルキルチオ基又はシアノ基を意味し、Ｒ＿５は同
一又は異なって水素原子、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、低級ア
ルキルチオ基又はシアノ基を意味し、Ｒ＿６は水素原子
、低級アルキル基、ヒドロキシ基、アシルオキシ基又は
低級アルコキシカルボニル基を意味し、Ｒ＿７は同一又
は異なって水素原子、ハロゲン原子、ヒドロキシ基、低
級アルコキシ基、アラルキルオキシ基、アシルオキシ基
、ニトロ基、アミノ基又はアシルアミノ基を意味し、Ｒ
＿８は水素原子又はヒドロキシ基を意味し、Ｒ＿９は低
級アルコキシカルボニル基、アラルキルオキシカルボニ
ル基、フェニル基、置換フェニル基（該置換基はハロゲ
ン、低級アルキル又は低級アルコキシである）又はアラ
ルキル基を意味するか、あるいはＲ＿９がピペリジン環
の４位にあるときはＲ＿８と一緒になってエチレンケタ
ール基又はオキソ基を形成してもよく、Ｗはカルボニル
基又はスルホニル基を意味し、Ｘはアルキレン基を意味
し、ａ及びｂはそれぞれ１〜４の整数を意味し、ｃは０
〜２の整数を意味し、ｄは１〜３の整数を意味し、ｅは
０又は１を意味するが、ｄとｃの和は２以上の整数であ
り、ｆは１〜３の整数を意味する。但し、（ｉ）Ｒ＿３
が（ｃ）又は（ｄ）で示される基であるとき、Ｗはカル
ボニル基を意味し、（ｉｉ）Ａ環がシクロヘキサン環の
とき、Ｙ及びＺは共に水素原子を意味するか、あるいは
ＹとＺが一緒になって▲数式、化学式、表等があります
▼を形成し、Ｒ＿４は水素原子を意味する。］ で表される環状アミン誘導体及びその塩類。[Claims] General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R_1 is a group represented by ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ A ring means a benzene ring or a cyclohexane ring, Y and Z both represent a hydrogen atom, or Y and Z together represent a single bond, -O-,
-S-, -CH=CH-, -CH_2CH_2-, ▲There are mathematical formulas, chemical formulas, tables, etc.▼, -CH_2O-, or ▲There are mathematical formulas, chemical formulas, tables, etc.▼, and R_2 is a hydrogen atom,
means a lower alkyl group or a lower alkoxy group, R_3
means a group shown in (a), (b), (c) or (d) below. ▼ (c) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (d) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ Ring B means benzene ring or cyclohexane ring, R_
4 is the same or different and is a hydrogen atom, a halogen atom, a lower alkyl group, a trifluoromethyl group, a lower alkoxy group,
means a lower alkylthio group or a cyano group, R_5 is the same or different and means a hydrogen atom, a halogen atom, a lower alkyl group, a trifluoromethyl group, a lower alkoxy group, a lower alkylthio group or a cyano group, R_6 is a hydrogen atom, It means a lower alkyl group, a hydroxy group, an acyloxy group, or a lower alkoxycarbonyl group, and R_7 is the same or different and is a hydrogen atom, a halogen atom, a hydroxy group, a lower alkoxy group, an aralkyloxy group, an acyloxy group, a nitro group, an amino group, or means an acylamino group, R
_8 means a hydrogen atom or a hydroxy group, R_9 means a lower alkoxycarbonyl group, an aralkyloxycarbonyl group, a phenyl group, a substituted phenyl group (the substituent is halogen, lower alkyl or lower alkoxy) or an aralkyl group Alternatively, when R_9 is at the 4-position of the piperidine ring, it may be combined with R_8 to form an ethylene ketal group or an oxo group, W means a carbonyl group or a sulfonyl group, and X means an alkylene group. , a and b each mean an integer from 1 to 4, and c is 0
d means an integer of 1 to 3, e means 0 or 1, but the sum of d and c is an integer of 2 or more, and f means an integer of 1 to 3. means. However, (i) R_3
is a group represented by (c) or (d), W means a carbonyl group, and (ii) when A ring is a cyclohexane ring, Y and Z both mean a hydrogen atom, or Y and Z together form ▲There are mathematical formulas, chemical formulas, tables, etc.▼, and R_4 means a hydrogen atom. ] A cyclic amine derivative and its salts.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2815386A JPH07100688B2 (en) | 1986-02-12 | 1986-02-12 | Cyclic amine derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2815386A JPH07100688B2 (en) | 1986-02-12 | 1986-02-12 | Cyclic amine derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS62187452A true JPS62187452A (en) | 1987-08-15 |
| JPH07100688B2 JPH07100688B2 (en) | 1995-11-01 |
Family
ID=12240812
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2815386A Expired - Lifetime JPH07100688B2 (en) | 1986-02-12 | 1986-02-12 | Cyclic amine derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH07100688B2 (en) |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1996026924A1 (en) * | 1995-02-28 | 1996-09-06 | Suntory Limited | Arylpiperidine and arylpiperazine derivatives and drugs containing the same |
| JP2002519372A (en) * | 1998-06-30 | 2002-07-02 | ニューロメド テクノロジーズ， インコーポレイテッド | Calcium channel blockers |
| JP2006511500A (en) * | 2002-10-30 | 2006-04-06 | メルク エンド カムパニー インコーポレーテッド | γ-Aminoamide-based chemokine receptor activity modulator |
| EP3498701A1 (en) * | 2012-12-21 | 2019-06-19 | Epizyme Inc | Prmt5 inhibitors and uses thereof |
| US11426412B2 (en) | 2017-10-18 | 2022-08-30 | Jubilant Epipad LLC | Imidazo-pyridine compounds as PAD inhibitors |
| US11459338B2 (en) | 2017-11-24 | 2022-10-04 | Jubilant Episcribe Llc | Heterocyclic compounds as PRMT5 inhibitors |
| US11529341B2 (en) | 2018-03-13 | 2022-12-20 | Jubilant Prodel LLC | Bicyclic compounds as inhibitors of PD1/PD-L1 interaction/activation |
| US11629135B2 (en) | 2017-11-06 | 2023-04-18 | Jubilant Prodell Llc | Pyrimidine derivatives as inhibitors of PD1/PD-L1 activation |
| US11833156B2 (en) | 2017-09-22 | 2023-12-05 | Jubilant Epipad LLC | Heterocyclic compounds as pad inhibitors |
-
1986
- 1986-02-12 JP JP2815386A patent/JPH07100688B2/en not_active Expired - Lifetime
Cited By (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1996026924A1 (en) * | 1995-02-28 | 1996-09-06 | Suntory Limited | Arylpiperidine and arylpiperazine derivatives and drugs containing the same |
| EP0757986A1 (en) * | 1995-02-28 | 1997-02-12 | Suntory Limited | Arylpiperidine and arylpiperazine derivatives and drugs containing the same |
| EP0757986A4 (en) * | 1995-02-28 | 1997-04-16 | Suntory Ltd | Arylpiperidine and arylpiperazine derivatives and drugs containing the same |
| US5723475A (en) * | 1995-02-28 | 1998-03-03 | Suntory Limited | Arylpiperidine and arylpiperazine derivatives and medicament containing the same |
| JP2002519372A (en) * | 1998-06-30 | 2002-07-02 | ニューロメド テクノロジーズ， インコーポレイテッド | Calcium channel blockers |
| JP2006511500A (en) * | 2002-10-30 | 2006-04-06 | メルク エンド カムパニー インコーポレーテッド | γ-Aminoamide-based chemokine receptor activity modulator |
| EP3498701A1 (en) * | 2012-12-21 | 2019-06-19 | Epizyme Inc | Prmt5 inhibitors and uses thereof |
| US10980794B2 (en) | 2012-12-21 | 2021-04-20 | Epizyme, Inc. | PRMT5 inhibitors and uses thereof |
| EP4219465A3 (en) * | 2012-12-21 | 2023-09-27 | Epizyme, Inc. | Prmt5 inhibitors and uses thereof |
| US11833156B2 (en) | 2017-09-22 | 2023-12-05 | Jubilant Epipad LLC | Heterocyclic compounds as pad inhibitors |
| US11426412B2 (en) | 2017-10-18 | 2022-08-30 | Jubilant Epipad LLC | Imidazo-pyridine compounds as PAD inhibitors |
| US11629135B2 (en) | 2017-11-06 | 2023-04-18 | Jubilant Prodell Llc | Pyrimidine derivatives as inhibitors of PD1/PD-L1 activation |
| US11459338B2 (en) | 2017-11-24 | 2022-10-04 | Jubilant Episcribe Llc | Heterocyclic compounds as PRMT5 inhibitors |
| US11529341B2 (en) | 2018-03-13 | 2022-12-20 | Jubilant Prodel LLC | Bicyclic compounds as inhibitors of PD1/PD-L1 interaction/activation |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH07100688B2 (en) | 1995-11-01 |
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