JPH0128020B2 - - Google Patents
Info
- Publication number
- JPH0128020B2 JPH0128020B2 JP325081A JP325081A JPH0128020B2 JP H0128020 B2 JPH0128020 B2 JP H0128020B2 JP 325081 A JP325081 A JP 325081A JP 325081 A JP325081 A JP 325081A JP H0128020 B2 JPH0128020 B2 JP H0128020B2
- Authority
- JP
- Japan
- Prior art keywords
- group
- dihydropyridine
- methyl
- alkyl group
- ester
- 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.)
- Expired
Links
- -1 chlorosulfonyl Chemical group 0.000 claims description 31
- 125000000217 alkyl group Chemical group 0.000 claims description 26
- 150000001875 compounds Chemical class 0.000 claims description 26
- 238000006243 chemical reaction Methods 0.000 claims description 21
- 125000002947 alkylene group Chemical group 0.000 claims description 15
- 238000004519 manufacturing process Methods 0.000 claims description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical class C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 claims description 11
- 239000012948 isocyanate Substances 0.000 claims description 11
- 150000002513 isocyanates Chemical class 0.000 claims description 11
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 10
- 125000005843 halogen group Chemical group 0.000 claims description 10
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 230000007062 hydrolysis Effects 0.000 claims description 4
- 238000006460 hydrolysis reaction Methods 0.000 claims description 4
- 239000002220 antihypertensive agent Substances 0.000 claims description 2
- 229940030600 antihypertensive agent Drugs 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 18
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 9
- 238000001816 cooling Methods 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- ZETIVVHRRQLWFW-UHFFFAOYSA-N 3-nitrobenzaldehyde Chemical compound [O-][N+](=O)C1=CC=CC(C=O)=C1 ZETIVVHRRQLWFW-UHFFFAOYSA-N 0.000 description 7
- QUEHTJCHIQKEIB-UHFFFAOYSA-N 5-ethoxycarbonyl-6-(hydroxymethyl)-2-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid Chemical compound CCOC(=O)C1=C(CO)NC(C)=C(C(O)=O)C1C1=CC=CC([N+]([O-])=O)=C1 QUEHTJCHIQKEIB-UHFFFAOYSA-N 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- WRJWRGBVPUUDLA-UHFFFAOYSA-N chlorosulfonyl isocyanate Chemical compound ClS(=O)(=O)N=C=O WRJWRGBVPUUDLA-UHFFFAOYSA-N 0.000 description 5
- YKFZUZNJSXYIOR-UHFFFAOYSA-N ethyl 4,4-dimethoxy-3-oxobutanoate Chemical compound CCOC(=O)CC(=O)C(OC)OC YKFZUZNJSXYIOR-UHFFFAOYSA-N 0.000 description 5
- HAMGRBXTJNITHG-UHFFFAOYSA-N methyl isocyanate Chemical compound CN=C=O HAMGRBXTJNITHG-UHFFFAOYSA-N 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 230000000304 vasodilatating effect Effects 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- WETKAHLRUYEKFK-UHFFFAOYSA-N diethyl 2-(hydroxymethyl)-6-methyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound CCOC(=O)C1=C(C)NC(CO)=C(C(=O)OCC)C1C1=CC=CC=C1[N+]([O-])=O WETKAHLRUYEKFK-UHFFFAOYSA-N 0.000 description 4
- 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 4
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- XWKGWWGBIFAJOG-UHFFFAOYSA-N dimethyl 2-(hydroxymethyl)-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound COC(=O)C1=C(C)NC(CO)=C(C(=O)OC)C1C1=CC=CC([N+]([O-])=O)=C1 XWKGWWGBIFAJOG-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 229960001597 nifedipine Drugs 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- ADAKRBAJFHTIEW-UHFFFAOYSA-N 1-chloro-4-isocyanatobenzene Chemical group ClC1=CC=C(N=C=O)C=C1 ADAKRBAJFHTIEW-UHFFFAOYSA-N 0.000 description 2
- OQURWGJAWSLGQG-UHFFFAOYSA-N 1-isocyanatopropane Chemical compound CCCN=C=O OQURWGJAWSLGQG-UHFFFAOYSA-N 0.000 description 2
- KZAVVRFEOXIXSW-UHFFFAOYSA-N 2-(hydroxymethyl)-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid Chemical compound OC(=O)C1=C(CO)NC(C)=C(C(O)=O)C1C1=CC=CC([N+]([O-])=O)=C1 KZAVVRFEOXIXSW-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-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
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 239000003218 coronary vasodilator agent Substances 0.000 description 2
- KQWGXHWJMSMDJJ-UHFFFAOYSA-N cyclohexyl isocyanate Chemical group O=C=NC1CCCCC1 KQWGXHWJMSMDJJ-UHFFFAOYSA-N 0.000 description 2
- FOSKDXCWLOXIIS-UHFFFAOYSA-N diethyl 2-(carbamoyloxymethyl)-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound CCOC(=O)C1=C(C)NC(COC(N)=O)=C(C(=O)OCC)C1C1=CC=CC([N+]([O-])=O)=C1 FOSKDXCWLOXIIS-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- YPMPTULBFPFSEQ-PLNGDYQASA-N ethyl (z)-3-aminobut-2-enoate Chemical compound CCOC(=O)\C=C(\C)N YPMPTULBFPFSEQ-PLNGDYQASA-N 0.000 description 2
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- WUDNUHPRLBTKOJ-UHFFFAOYSA-N ethyl isocyanate Chemical compound CCN=C=O WUDNUHPRLBTKOJ-UHFFFAOYSA-N 0.000 description 2
- MOTRZVVGCFFABN-UHFFFAOYSA-N hexane;2-propan-2-yloxypropane Chemical compound CCCCCC.CC(C)OC(C)C MOTRZVVGCFFABN-UHFFFAOYSA-N 0.000 description 2
- 230000003301 hydrolyzing effect Effects 0.000 description 2
- 231100000053 low toxicity Toxicity 0.000 description 2
- PJYQRBMGZRVNSQ-UHFFFAOYSA-N methyl 4,4-dimethoxy-3-oxobutanoate Chemical compound COC(OC)C(=O)CC(=O)OC PJYQRBMGZRVNSQ-UHFFFAOYSA-N 0.000 description 2
- HNHVTXYLRVGMHD-UHFFFAOYSA-N n-butyl isocyanate Chemical compound CCCCN=C=O HNHVTXYLRVGMHD-UHFFFAOYSA-N 0.000 description 2
- DGTNSSLYPYDJGL-UHFFFAOYSA-N phenyl isocyanate Chemical group O=C=NC1=CC=CC=C1 DGTNSSLYPYDJGL-UHFFFAOYSA-N 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 229910001961 silver nitrate Inorganic materials 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- NNZVKALEGZPYKL-UHFFFAOYSA-N 1-isocyanato-2-methylpropane Chemical compound CC(C)CN=C=O NNZVKALEGZPYKL-UHFFFAOYSA-N 0.000 description 1
- JRVZITODZAQRQM-UHFFFAOYSA-N 1-isocyanato-2-nitrobenzene Chemical group [O-][N+](=O)C1=CC=CC=C1N=C=O JRVZITODZAQRQM-UHFFFAOYSA-N 0.000 description 1
- GFFGYTMCNVMFAJ-UHFFFAOYSA-N 1-isocyanato-3-nitrobenzene Chemical group [O-][N+](=O)C1=CC=CC(N=C=O)=C1 GFFGYTMCNVMFAJ-UHFFFAOYSA-N 0.000 description 1
- FMDGXCSMDZMDHZ-UHFFFAOYSA-N 1-isocyanato-4-methoxybenzene Chemical group COC1=CC=C(N=C=O)C=C1 FMDGXCSMDZMDHZ-UHFFFAOYSA-N 0.000 description 1
- GFNKTLQTQSALEJ-UHFFFAOYSA-N 1-isocyanato-4-nitrobenzene Chemical group [O-][N+](=O)C1=CC=C(N=C=O)C=C1 GFNKTLQTQSALEJ-UHFFFAOYSA-N 0.000 description 1
- RNSYVYVGEUGKDE-PLNGDYQASA-N 2-chloroethyl (z)-3-aminobut-2-enoate Chemical compound C\C(N)=C\C(=O)OCCCl RNSYVYVGEUGKDE-PLNGDYQASA-N 0.000 description 1
- RWKVPOCZWXIRNE-UHFFFAOYSA-N 2-isocyanato-n,n-dimethylethanamine Chemical group CN(C)CCN=C=O RWKVPOCZWXIRNE-UHFFFAOYSA-N 0.000 description 1
- GSLTVFIVJMCNBH-UHFFFAOYSA-N 2-isocyanatopropane Chemical compound CC(C)N=C=O GSLTVFIVJMCNBH-UHFFFAOYSA-N 0.000 description 1
- CMWKITSNTDAEDT-UHFFFAOYSA-N 2-nitrobenzaldehyde Chemical compound [O-][N+](=O)C1=CC=CC=C1C=O CMWKITSNTDAEDT-UHFFFAOYSA-N 0.000 description 1
- HACRKYQRZABURO-UHFFFAOYSA-N 2-phenylethyl isocyanate Chemical group O=C=NCCC1=CC=CC=C1 HACRKYQRZABURO-UHFFFAOYSA-N 0.000 description 1
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 description 1
- SBZWUHVXPDGSBA-UHFFFAOYSA-N 3-o-ethyl 5-o-propan-2-yl 2-(carbamoyloxymethyl)-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound CCOC(=O)C1=C(COC(N)=O)NC(C)=C(C(=O)OC(C)C)C1C1=CC=CC([N+]([O-])=O)=C1 SBZWUHVXPDGSBA-UHFFFAOYSA-N 0.000 description 1
- SHXLHNHBBLBLLV-UHFFFAOYSA-N 3-o-ethyl 5-o-propan-2-yl 2-(hydroxymethyl)-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound CCOC(=O)C1=C(CO)NC(C)=C(C(=O)OC(C)C)C1C1=CC=CC([N+]([O-])=O)=C1 SHXLHNHBBLBLLV-UHFFFAOYSA-N 0.000 description 1
- YZEHDFBYSOKBED-UHFFFAOYSA-N 4-isocyanato-n,n-dimethylaniline Chemical group CN(C)C1=CC=C(N=C=O)C=C1 YZEHDFBYSOKBED-UHFFFAOYSA-N 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 229940126062 Compound A Drugs 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- BWLKKFSDKDJGDZ-UHFFFAOYSA-N [isocyanato(phenyl)methyl]benzene Chemical group C=1C=CC=CC=1C(N=C=O)C1=CC=CC=C1 BWLKKFSDKDJGDZ-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 231100000215 acute (single dose) toxicity testing Toxicity 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 238000011047 acute toxicity test Methods 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- HXBPYFMVGFDZFT-UHFFFAOYSA-N allyl isocyanate Chemical group C=CCN=C=O HXBPYFMVGFDZFT-UHFFFAOYSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- LPYNWRPARGBJOL-CLFYSBASSA-N benzyl (z)-3-aminobut-2-enoate Chemical compound C\C(N)=C\C(=O)OCC1=CC=CC=C1 LPYNWRPARGBJOL-CLFYSBASSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 230000004531 blood pressure lowering effect Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000002327 cardiovascular agent Substances 0.000 description 1
- 229940125692 cardiovascular agent Drugs 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Chemical group 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- GXCONYCZOCXQEM-UHFFFAOYSA-N diethyl 2-(carbamoyloxymethyl)-6-methyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound CCOC(=O)C1=C(C)NC(COC(N)=O)=C(C(=O)OCC)C1C1=CC=CC=C1[N+]([O-])=O GXCONYCZOCXQEM-UHFFFAOYSA-N 0.000 description 1
- LWTWJBUKUVHABE-UHFFFAOYSA-N diethyl 2-(hydroxymethyl)-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound CCOC(=O)C1=C(C)NC(CO)=C(C(=O)OCC)C1C1=CC=CC([N+]([O-])=O)=C1 LWTWJBUKUVHABE-UHFFFAOYSA-N 0.000 description 1
- YFUBFBHXXMMOCX-UHFFFAOYSA-N diethyl 2-methyl-6-(methylcarbamoyloxymethyl)-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound CCOC(=O)C1=C(C)NC(COC(=O)NC)=C(C(=O)OCC)C1C1=CC=CC=C1[N+]([O-])=O YFUBFBHXXMMOCX-UHFFFAOYSA-N 0.000 description 1
- PGNHWIHDBCGMAV-UHFFFAOYSA-N diethyl 2-methyl-6-(methylcarbamoyloxymethyl)-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound CCOC(=O)C1=C(C)NC(COC(=O)NC)=C(C(=O)OCC)C1C1=CC=CC([N+]([O-])=O)=C1 PGNHWIHDBCGMAV-UHFFFAOYSA-N 0.000 description 1
- HDDAWGQZJYBRBO-UHFFFAOYSA-N dimethyl 2-(carbamoyloxymethyl)-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound COC(=O)C1=C(C)NC(COC(N)=O)=C(C(=O)OC)C1C1=CC=CC([N+]([O-])=O)=C1 HDDAWGQZJYBRBO-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000002024 ethyl acetate extract Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000001077 hypotensive effect Effects 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical group II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- CZALJDQHONFVFU-UHFFFAOYSA-N isocyanatocyclopentane Chemical group O=C=NC1CCCC1 CZALJDQHONFVFU-UHFFFAOYSA-N 0.000 description 1
- YDNLNVZZTACNJX-UHFFFAOYSA-N isocyanatomethylbenzene Chemical group O=C=NCC1=CC=CC=C1 YDNLNVZZTACNJX-UHFFFAOYSA-N 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229960002523 mercuric chloride Drugs 0.000 description 1
- LWJROJCJINYWOX-UHFFFAOYSA-L mercury dichloride Chemical compound Cl[Hg]Cl LWJROJCJINYWOX-UHFFFAOYSA-L 0.000 description 1
- XKORCTIIRYKLLG-ARJAWSKDSA-N methyl (z)-3-aminobut-2-enoate Chemical compound COC(=O)\C=C(\C)N XKORCTIIRYKLLG-ARJAWSKDSA-N 0.000 description 1
- OJURWUUOVGOHJZ-UHFFFAOYSA-N methyl 2-[(2-acetyloxyphenyl)methyl-[2-[(2-acetyloxyphenyl)methyl-(2-methoxy-2-oxoethyl)amino]ethyl]amino]acetate Chemical compound C=1C=CC=C(OC(C)=O)C=1CN(CC(=O)OC)CCN(CC(=O)OC)CC1=CC=CC=C1OC(C)=O OJURWUUOVGOHJZ-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- CHWRSCGUEQEHOH-UHFFFAOYSA-N potassium oxide Chemical compound [O-2].[K+].[K+] CHWRSCGUEQEHOH-UHFFFAOYSA-N 0.000 description 1
- 229910001950 potassium oxide Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- PPHYUEVQTFLKBA-WAYWQWQTSA-N prop-2-ynyl (z)-3-aminobut-2-enoate Chemical compound C\C(N)=C\C(=O)OCC#C PPHYUEVQTFLKBA-WAYWQWQTSA-N 0.000 description 1
- YCKAGGHNUHZKCL-XQRVVYSFSA-N propan-2-yl (z)-3-aminobut-2-enoate Chemical compound CC(C)OC(=O)\C=C(\C)N YCKAGGHNUHZKCL-XQRVVYSFSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000006190 sub-lingual tablet Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- IMCGHZIGRANKHV-AJNGGQMLSA-N tert-butyl (3s,5s)-2-oxo-5-[(2s,4s)-5-oxo-4-propan-2-yloxolan-2-yl]-3-propan-2-ylpyrrolidine-1-carboxylate Chemical compound O1C(=O)[C@H](C(C)C)C[C@H]1[C@H]1N(C(=O)OC(C)(C)C)C(=O)[C@H](C(C)C)C1 IMCGHZIGRANKHV-AJNGGQMLSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 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
- 231100000820 toxicity test Toxicity 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- 231100000691 up-and-down procedure Toxicity 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
Landscapes
- Hydrogenated Pyridines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本発明は、一般式[]
[式中、R1,R2およびR3はアルキル基、R4は
水素原子、アルキル基、シクロアルキル基、また
はハロゲン原子で置換されていてもよいフエニル
基、Aは直鎖または分岐状のアルキレン基を示
す]で表される新規な置換または未置換のカルバ
モイルオキシアルキル―1,4―ジヒドロピリジ
ン誘導体、その製造法およびその用途に関するも
のである。
本発明の該カルバモイルオキシアルキル―1,
4―ジヒドロピリジン誘導体は血管拡張作用並び
に血圧降下作用を有し、循環器用剤として期待さ
れる有用な化合物である。
本発明者らは鋭意研究の結果、前記一般式
()で表わされる該カルバモイルオキシアルキ
ル―1,4―ジヒドロピリジン誘導体が、従来よ
り知られているニフエジピン〔Nifedipine;4―
(2―ニトロフエニル)―2,6―ジメチル―1,
4―ジヒドロピリジン―3,5―ジカルボン酸ジ
メチルエステル、米国特許3485847参照〕よりも
血管拡張作用が強く、且つ毒性が極めて弱く、医
薬として有用な化合物であることを発見し、本発
明を完成した。
本発明の化合物()に含まれるものとして、
R1,R2,R3,R4およびR4aは同一または異なつ
てもよいアルキル基であり、例えばアルキル基と
しては、メチル、エチル、プロピル、イソプロピ
ル、ブチル、イソブチル、第三級ブチル、ペンチ
ル、ヘキシルなどが挙げられる。R4およびR4aの
ハロゲン原子で置換されていてもよいフエニル基
としては、フツ素、塩素、臭素もしくはヨウ素な
どで置換されていてもよいフエニル基を意味し、
好ましくはフエニル基、3―クロロフエニル基、
4―クロロフエニル基などが挙げられる。また、
R4およびR4aのシクロアルキル基としてはシクロ
プロピル、シクロブチル、シクロペンチル、シク
ロヘキシル、シクロヘブチルなどが挙げられる。
Aのアルキレン基としてはメチレン、エチレ
ン、プロピレン、テトラメチレンなどが挙げられ
る。
本発明の化合物[]は、
一般式[]
[式中、R1,R2およびR3はアルキル基、Aは
直鎖または分岐状のアルキレン基を示す]で表さ
れる1,4―ジヒドロピリジン誘導体と
一般式[]
R5NCO []
[式中、R5はクロロスルホニル基、アルキル
基、シクロアルキル基、アルケニル基、アラルキ
ル基またはハロゲン原子で置換されていてもよい
フエニル基を示す]で表されるイソシアナート、
または反応条件下で該イソシアナートを生成する
化合物を反応せしめ、次いで所望により加水分解
することによつて製造することができる。更に、
本発明化合物[]の製造法を以下の製造法A及
び製造法Bにより詳しく説明する。
製造法 A
本製造法は、一般式[]
[式中、R1,R2およびR3はアルキル基、Aは
直鎖または分岐状のアルキレン基を示す]で表さ
れる1,4―ジヒドロピリジン誘導体と、
一般式[―a]
R5a−NCO [―a]
[式中、R5aはアルキル基、シクロアルキル
基、またはハロゲン原子で置換されていてもよい
フエニル基を示す]で表されるイソシアナートま
たは反応条件下で該イソシアナートを生成する化
合物を反応させることにより
一般式[―a]
[式中、R1,R2およびR3はアルキル基、R4aは
アルキル基、シクロアルキル基、またはハロゲン
原子で置換されていてもよいフエニル基、Aは直
鎖または分岐状のアルキレン基を示す]で表され
るカルバモイルオキシアルキル―1,4―ジヒド
ロピリジン誘導体を製造するものである。
製造法 B
本製造法は、一般式[]
[式中、R1,R2およびR3はアルキル基、Aは
直鎖または分岐状のアルキレン基を示す]で表さ
れる1,4―ジヒドロピリジン誘導体と、
一般式[―b]
R5b−NCO [―b]
[式中、R5bはクロロスルホニル基を示す]で
表されるイソシアナートまたは反応条件下で該イ
ソシアナートを生成する化合物を反応させ、次い
で加水分解することにより
一般式[―b]
[式中、R1,R2およびR3はアルキル基、Aは
直鎖または分岐状のアルキレン基を示す]で表さ
れるカルバモイルオキシアルキル―1,4―ジヒ
ドロピリジン誘導体を製造するものである。
特に製造法Bは、一般式[]のR4が水素原
子である化合物を製造するものであり、イソシア
ナートまたは反応条件下で該イソシアナートを生
成する化合物との反応の終了後、反応混合物に水
を加えて加水分解処理を行う必要がある。
本発明の原料化合物()は、すでに公知化合
物であるか、または文献未載の化合物であつても
公知の方法に従つて製造することができる。例え
ば4―(2―ニトロフエニル)―2―ヒドロキシ
メチル―6―メチル―1,4―ジヒドロピリジン
―3,5―ジカルボン酸ジエチルエステルは公開
特許公報 昭52−5777に記載の方法によつて合成
できる。
本発明の一般式R5NCO[][式中、R5は前記
の意味を有する。]で表されるイソシアナートと
しては、クロロスルホニルイソシアナート、メチ
ルイソシアナート、エチルイソシアナート、プロ
ピルイソシアナート、イソプロピルイソシアナー
ト、ブチルイソシアナート、イソブチルイソシア
ナート、第三級ブチルイソシアナート、アリルイ
ソシアナート、シクロヘキシルイソシアナート、
シクロペンチルイソシアナート、フエニルイソシ
アナート、2―,3―または4―ニトロフエニル
イソシアナート、4―クロロフエニルイソシアナ
ート、4―メトキシフエニルイソシアナート、4
―ジメチルアミノフエニルイソシアナート、ベン
ジルイソシアナート、ジフエニルメチルイソシア
ナート、フエネチルイソシアナート、2―ジメチ
ルアミノエチルイソシアナートなどが挙げられ
る。
また本発明においては一般式R5NCO[][式
中、R5は前記の意味を有する。]で表されるイソ
シアナートの代わりに、下記反応条件下でそれを
生成しうる化合物、例えば加熱下における式中、
R4は前記の意味を有する]で表わされる酸アジ
ド、加熱条件下における又はトリアルキルアミン
と重金属(例えば硝酸銀もしくは塩化水銀)の存
在下における式R4NHCOSR[式中、R4は前記の
意味を有し、Rは低級アルキル基を示す]で表わ
されるチオールカルバメートを用いることもでき
る。
本発明の化合物()を製造する際の反応条件
は、用いられる反応試薬の種類により適当に選択
されるが、一般式()の1,4―ジヒドロピリ
ジン誘導体1モルに対し一般式R5NCO[][式
中、R5は前記の意味を有する]で表されるイソ
シアナートを1〜5モル、好ましくは1〜2モル
の割合で用い、通常冷却下、室温または加温乃至
加熱下で実施される。反応溶媒としてはベンゼ
ン、トルエン、クロロホルム、ジクロロメタン、
クロロベンゼン、ジオキサン、テトラヒドロフラ
ン、ジエチルエーテル、アセトニトリル、ピリジ
ン、ジメチルホルムアミドなどが用いられる。
反応は触媒の存在下で行うのが有利であり、触
媒としてはトリエチルアミン、トリメチルアミ
ン、N―アルキルピペリジン、N―アルキルモル
ホリン並びにN,N―ジアルキルアニリンなどの
三級アミン、ピリジン、水酸化ナトリウム、水酸
化カリウム、炭酸ナトリウム、炭酸水素ナトリウ
ムなどを使用することができる。
本発明の方法により合成された目的化合物
()は、いずれも抽出処理、カラムクロマトグ
ラフイー処理、並びに結晶化処理などの常法の操
作により精製、単離し採取することができる。
また所望により無機酸または有機酸の付加塩と
することもできる。
本発明の化合物()は血管拡張作用並びに血
圧降下作用を有し、特に冠血管拡張作用が強く且
つ毒性が極めて弱いので高血圧症、心不全、狭心
症、心筋梗塞並びに脳血管障害などの循環器系疾
病の治療に期待される医薬品である。
本発明で提供される化合物()のうち、次に
挙げる化合物(B〜N)について公知化合物であ
るニフエジピン(A)と比較した薬効試験並びに毒性
試験の結果を次に示す。
1 試験化合物
A:4―(2―ニトロフエニル)―2,6―ジ
メチル―1,4―ジヒドロピリジン―3,
5―ジカルボン酸ジメチルエステル〔ニフ
エジピン〕
B:4―(3―ニトロフエニル)―2―カルバ
モイルオキシメチル―6―メチル―1,4
―ジヒドロピリジン―3,5―ジカルボン
酸ジエチルエステル
C:4―(3―ニトロフエニル)―2―(N―
メチルカルバモイル)オキシメチル―6―
メチル―1,4―ジヒドロピリジン―3,
5―ジカルボン酸ジエチルエステル
D:4―(3―ニトロフエニル)―2―カルバ
モイルオキシメチル―6―メチル―1,4
―ジヒドロピリジン―3,5―ジカルボン
酸ジメチルエステル
E:4―(3―ニトロフエニル)―2―(N―
メチルカルバモイル)オキシメチル―6―
メチル―1,4―ジヒドロピリジン―3,
5―ジカルボン酸ジメチルエステル
F:4―(2―ニトロフエニル)―2―カルバ
モイルオキシメチル―6―メチル―1,4
―ジヒドロピリジン―3,5―ジカルボン
酸ジメチルエステル
G:4―(2―ニトロフエニル)―2―(N―
メチルカルバモイル)オキシメチル―6―
メチル―1,4―ジヒドロピリジン―3,
5―ジカルボン酸ジエチルエステル
H:4―(3―ニトロフエニル)―2―カルバ
モイルオキシメチル―6―メチル―1,4
―ジヒドロピリジン―3,5―ジカルボン
酸 3―エチルエステル―5―イソプロピ
ルエステル
I:4―(3―ニトロフエニル)―2―(N―
メチルカルバモイル)オキシメチル―6―
メチル―1,4―ジヒドロピリジン―3,
5―ジカルボン酸 3―エチルエステル―
5―イソプロピルエステル
J:4―(3―ニトロフエニル)―2―(N―
エチルカルバモイル)オキシメチル―6―
メチル―1,4―ジヒドロピリジン―3,
5―ジカルボン酸 3―エチルエステル
5―イソプロピルエステル
K:4―(3―ニトロフエニル)―2―(N―
プロピルカルバモイル)オキシメチル―6
―メチル―1,4―ジヒドロピリジン―
3,5―ジカルボン酸 3―エチルエステ
ル 5―イソプロピルエステル
L:4―(3―ニトロフエニル)―2―(N―
シクロヘキシルカルバモイル)オキシメチ
ル―6―メチル―1,4―ジヒドロピリジ
ン―3,5―ジカルボン酸 3―エチルエ
ステル 5―イソプロピルエステル
M:4―(3―ニトロフエニル)―2―(N―
フエニルカルバモイル)オキシメチル―6
―メチル―1,4―ジヒドロピリジン―
3,5―ジカルボン酸 3―エチルエステ
ル 5―イソプロピルエステル
N:4―(3―ニトロフエニル)―2―{N―
(4―クロロフエニル)カルバモイル}オ
キシメチル―6―メチル―1,4―ジヒド
ロピリジン―3,5―ジカルボン酸 3エ
チルエステル 5―イソプロピルエステル
2 試験結果
ランゲンドルフの方法によるウサギの冠血管拡
張作用並びにマウス急性毒性は次の表に示す通り
である。
The present invention is based on the general formula [] [In the formula, R 1 , R 2 and R 3 are an alkyl group, R 4 is a hydrogen atom, an alkyl group, a cycloalkyl group, or a phenyl group which may be substituted with a halogen atom, and A is a linear or branched The present invention relates to a novel substituted or unsubstituted carbamoyloxyalkyl-1,4-dihydropyridine derivative represented by [indicating an alkylene group], its production method, and its uses. The carbamoyloxyalkyl-1 of the present invention,
4-dihydropyridine derivatives have vasodilating and hypotensive effects, and are expected to be useful compounds as cardiovascular agents. As a result of intensive research, the present inventors have found that the carbamoyloxyalkyl-1,4-dihydropyridine derivative represented by the general formula () is the conventionally known Nifedipine [4-
(2-nitrophenyl)-2,6-dimethyl-1,
The present invention was completed based on the discovery that this compound has a stronger vasodilatory effect than 4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester (see US Pat. No. 3,485,847), has extremely low toxicity, and is a useful compound as a medicine. As included in the compound () of the present invention,
R 1 , R 2 , R 3 , R 4 and R 4a are alkyl groups which may be the same or different; examples of the alkyl group include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl , hexyl, etc. The phenyl group optionally substituted with a halogen atom of R 4 and R 4a means a phenyl group optionally substituted with fluorine, chlorine, bromine or iodine, etc.
Preferably phenyl group, 3-chlorophenyl group,
Examples include 4-chlorophenyl group. Also,
Examples of the cycloalkyl group for R 4 and R 4a include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclohebutyl. Examples of the alkylene group of A include methylene, ethylene, propylene, and tetramethylene. The compound [] of the present invention has the general formula [] A 1,4-dihydropyridine derivative represented by [wherein R 1 , R 2 and R 3 are an alkyl group, and A represents a linear or branched alkylene group] and the general formula [] R 5 NCO [] [ In the formula, R 5 represents a chlorosulfonyl group, an alkyl group, a cycloalkyl group, an alkenyl group, an aralkyl group, or a phenyl group optionally substituted with a halogen atom.
Alternatively, it can be produced by reacting a compound that produces the isocyanate under reaction conditions, and then optionally hydrolyzing it. Furthermore,
The method for producing the compound [] of the present invention will be explained in detail using the following production method A and production method B. Manufacturing method A This manufacturing method uses the general formula [] A 1,4-dihydropyridine derivative represented by [wherein R 1 , R 2 and R 3 are an alkyl group, and A represents a linear or branched alkylene group] and the general formula [-a] R 5a - NCO [-a] [In the formula, R 5a represents an alkyl group, a cycloalkyl group, or a phenyl group optionally substituted with a halogen atom] or the isocyanate is produced under reaction conditions By reacting a compound with the general formula [-a] [In the formula, R 1 , R 2 and R 3 are an alkyl group, R 4a is an alkyl group, a cycloalkyl group, or a phenyl group which may be substituted with a halogen atom, and A is a linear or branched alkylene group. A carbamoyloxyalkyl-1,4-dihydropyridine derivative represented by the following formula is produced. Manufacturing method B This manufacturing method is based on the general formula [] A 1,4-dihydropyridine derivative represented by [wherein R 1 , R 2 and R 3 are an alkyl group, and A represents a linear or branched alkylene group] and the general formula [-b] R 5b - By reacting an isocyanate represented by NCO [-b] [in the formula, R 5b represents a chlorosulfonyl group] or a compound that produces the isocyanate under reaction conditions, and then hydrolyzing it, a compound of the general formula [- b] A carbamoyloxyalkyl-1,4-dihydropyridine derivative represented by the formula [wherein R 1 , R 2 and R 3 are an alkyl group, and A is a linear or branched alkylene group] is produced. In particular, production method B produces a compound in which R 4 in the general formula [ ] is a hydrogen atom, and after the reaction with the isocyanate or a compound that produces the isocyanate under the reaction conditions, the reaction mixture is It is necessary to add water and perform hydrolysis treatment. The starting compound () of the present invention is a known compound, or even if it is a compound that has not been published in any literature, it can be produced according to a known method. For example, 4-(2-nitrophenyl)-2-hydroxymethyl-6-methyl-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester can be synthesized by the method described in Japanese Patent Publication No. 52-5777. The general formula of the present invention is R 5 NCO [] [wherein R 5 has the above-mentioned meaning]. ] Examples of the isocyanate include chlorosulfonyl isocyanate, methyl isocyanate, ethyl isocyanate, propyl isocyanate, isopropyl isocyanate, butyl isocyanate, isobutyl isocyanate, tertiary butyl isocyanate, allyl isocyanate, cyclohexyl isocyanate,
Cyclopentyl isocyanate, phenyl isocyanate, 2-, 3- or 4-nitrophenyl isocyanate, 4-chlorophenyl isocyanate, 4-methoxyphenyl isocyanate, 4
-dimethylaminophenyl isocyanate, benzyl isocyanate, diphenylmethyl isocyanate, phenethyl isocyanate, 2-dimethylaminoethyl isocyanate and the like. Further, in the present invention, the general formula R 5 NCO [] [wherein R 5 has the above-mentioned meaning] is used. ] Instead of the isocyanate represented by
An acid azide of the formula R 4 NHCOSR [wherein R 4 has the meaning given above ] under heating conditions or in the presence of a trialkylamine and a heavy metal (e.g. silver nitrate or mercuric chloride); and R represents a lower alkyl group] can also be used. The reaction conditions for producing the compound () of the present invention are appropriately selected depending on the type of reaction reagent used, but the reaction conditions for producing the compound () of the general formula R 5 NCO[ ] [In the formula, R 5 has the above-mentioned meaning] is used at a ratio of 1 to 5 mol, preferably 1 to 2 mol, and carried out usually under cooling, room temperature, or heating. be done. Reaction solvents include benzene, toluene, chloroform, dichloromethane,
Chlorobenzene, dioxane, tetrahydrofuran, diethyl ether, acetonitrile, pyridine, dimethylformamide, etc. are used. The reaction is advantageously carried out in the presence of catalysts, such as tertiary amines such as triethylamine, trimethylamine, N-alkylpiperidines, N-alkylmorpholines and N,N-dialkylanilines, pyridine, sodium hydroxide, water, etc. Potassium oxide, sodium carbonate, sodium hydrogen carbonate, etc. can be used. The target compound () synthesized by the method of the present invention can be purified, isolated, and collected by conventional operations such as extraction treatment, column chromatography treatment, and crystallization treatment. It can also be used as an addition salt of an inorganic or organic acid, if desired. The compound () of the present invention has a vasodilatory effect and a blood pressure lowering effect, and has a particularly strong coronary vasodilatory effect and extremely low toxicity, so it can be used to treat cardiovascular disorders such as hypertension, heart failure, angina pectoris, myocardial infarction, and cerebrovascular disorders. It is a drug that is expected to treat certain types of diseases. Among the compounds () provided by the present invention, the results of efficacy tests and toxicity tests for the following compounds (BN) compared with the known compound nifedipine (A) are shown below. 1 Test compound A: 4-(2-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,
5-dicarboxylic acid dimethyl ester [nifedipine] B: 4-(3-nitrophenyl)-2-carbamoyloxymethyl-6-methyl-1,4
-dihydropyridine-3,5-dicarboxylic acid diethyl ester C:4-(3-nitrophenyl)-2-(N-
Methylcarbamoyl)oxymethyl-6-
Methyl-1,4-dihydropyridine-3,
5-dicarboxylic acid diethyl ester D: 4-(3-nitrophenyl)-2-carbamoyloxymethyl-6-methyl-1,4
-dihydropyridine-3,5-dicarboxylic acid dimethyl ester E:4-(3-nitrophenyl)-2-(N-
Methylcarbamoyl)oxymethyl-6-
Methyl-1,4-dihydropyridine-3,
5-dicarboxylic acid dimethyl ester F: 4-(2-nitrophenyl)-2-carbamoyloxymethyl-6-methyl-1,4
-dihydropyridine-3,5-dicarboxylic acid dimethyl ester G:4-(2-nitrophenyl)-2-(N-
Methylcarbamoyl)oxymethyl-6-
Methyl-1,4-dihydropyridine-3,
5-dicarboxylic acid diethyl ester H: 4-(3-nitrophenyl)-2-carbamoyloxymethyl-6-methyl-1,4
-dihydropyridine-3,5-dicarboxylic acid 3-ethyl ester-5-isopropyl ester I: 4-(3-nitrophenyl)-2-(N-
Methylcarbamoyl)oxymethyl-6-
Methyl-1,4-dihydropyridine-3,
5-dicarboxylic acid 3-ethyl ester-
5-isopropyl ester J: 4-(3-nitrophenyl)-2-(N-
ethylcarbamoyl)oxymethyl-6-
Methyl-1,4-dihydropyridine-3,
5-dicarboxylic acid 3-ethyl ester
5-isopropyl ester K: 4-(3-nitrophenyl)-2-(N-
Propylcarbamoyl)oxymethyl-6
-Methyl-1,4-dihydropyridine-
3,5-dicarboxylic acid 3-ethyl ester 5-isopropyl ester L: 4-(3-nitrophenyl)-2-(N-
cyclohexylcarbamoyl)oxymethyl-6-methyl-1,4-dihydropyridine-3,5-dicarboxylic acid 3-ethyl ester 5-isopropyl ester M: 4-(3-nitrophenyl)-2-(N-
phenylcarbamoyl)oxymethyl-6
-Methyl-1,4-dihydropyridine-
3,5-dicarboxylic acid 3-ethyl ester 5-isopropyl ester N: 4-(3-nitrophenyl)-2-{N-
(4-chlorophenyl)carbamoyl}oxymethyl-6-methyl-1,4-dihydropyridine-3,5-dicarboxylic acid 3 ethyl ester 5-isopropyl ester 2 Test results Coronary vasodilator effect in rabbits and acute toxicity in mice by Langendorff's method is shown in the table below.
【表】
3 試験方法
a 冠血管拡張作用
ランゲンドルフ※
の方法に従い摘出ウサギ心蔵
の潅流標本に対する冠動脈内投与効果を求めた。
冠血管拡張作用の強さは冠動脈血流量を50%増加
させるサンプル投与量;pl50により評価した。
※ O.Langendorff;Pflu¨gers arch.ges.
Phisiol.,61,291―332(1895)
b 急性毒性試験
DM系雄マウス(18〜22g)を用い、静脈内投
与法においてアツプアンドダウン法によりLD50
値を算出した。
本発明の化合物()は血管拡張剤並びに血圧
降下剤として有用であることが期待され、その目
的のための投与形態としては一般に静脈内、皮下
または筋肉内注射、または直腸投与などによる非
経口投与、あるいは錠剤、散剤、顆粒剤、カプセ
ル剤、舌下錠またはシロツプ剤などによる経口投
与などが挙げられる。
投与量としては患者の症状、年令、体重並びに
投与形態によつて異るが、通常は成人に対して1
日量0.1乃至1000mg、好ましくは1〜100mgであ
る。
前記の各製剤はそれぞれ周知の方法により製造
することができる。
次に本発明の化合物()およびその製造法を
実施例を挙げて詳しく説明するが、本発明はこれ
により特に限定されるものではない。
参考例
原料化合物()の合成例
3―ニトロベンズアルデヒド(3.4g)、4,4
―ジメトキシアセト酢酸メチル(4g)およびピ
ペリジン(0.3ml)をベンゼン(30ml)に混合し、
共沸脱水条件下、4時間加熱還流する。冷却後、
反応混合物を水洗並びに乾燥処理し、減圧蒸留に
より溶媒を留去する。残渣の油状物に3―アミノ
クロトン酸メチルエステル(2.6g)を加えて混
合し、100℃、1.5時間次いで120℃、8時間加熱
撹拌する。反応混合物を冷却後、酢酸エチルで抽
出し、抽出液を水洗並びに乾燥したあと減圧蒸留
により溶媒を留去する。残渣の油状物を展開溶媒
(ヘキサン:酢酸エチル=2:1)を用いてシリ
カゲルカラムクロマトグラフイーにより分離、精
製して黄色油状の4―(3―ニトロフエニル)―
2―ジメトキシメチル―6―メチル―1,4―ジ
ヒドロピリジン―3,5―ジカルボン酸ジメチル
エステル(4,8g)を得る。
この黄色油状物をアセトン(100ml)と6規定
塩酸(4ml)の混液に溶解し、室温、1時間撹拌
反応する。反応混合物を減圧濃縮し残渣(アルデ
ヒド)をエタノール(60ml)に溶解し、冷却下、
これに水素化ホウ素ナトリウム(418mg)を加え、
1時間撹拌反応する。反応混合物をPH4(1規定
塩酸)に修正したあと減圧濃縮し、残渣の油状物
を酢酸エチルで抽出し、抽出液を減圧濃縮する。
残渣を展開溶媒(ベンゼン:酢酸エチル=9:
1)を用いてシリカゲルカラムクロマトグラフイ
ーにより精製処理して結晶状の4―(3―ニトロ
フエニル)―2―ヒドロキシメチル―6―メチル
―1,4―ジヒドロピリジン―3,5―ジカルボ
ン酸ジメチルエステル(12g)を得る。
mp 144―146℃
IR(KBr):3550,3360,2970,1695,1660,
1530,1475,1350,1220,1120,1095,
1020,900,830,785,750,700cm-1
UV(in MeOH):λnax=235,355nm
NMR(90MHz,in DMSO―d6):δ2.4(S,
3H),3.55(s,6H),4.6(d,J=5Hz,
2H),5.0(s,1H),5.5(t,J=5Hz,
1H),7.3―8.0(m,4H),8.5(br.s.1H).
同様の方法により、原料化合物()として例
えば、
3―ニトロベンズアルデヒド、4,4―ジメト
キシアセト酢酸エチルおよび3―アミノクロトン
酸エチルエステルから4―(3―ニトロフエニ
ル)―2―ヒドロキシメチル―6―メチル―1,
4―ジヒドロピリジン―3,5―ジカルボン酸ジ
エチルエステルが、
2―ニトロベンズアルデヒド、4,4―ジメト
キシアセト酢酸エチルおよび3―アミノクロトン
酸エチルエステルから4―(2―ニトロフエニ
ル)―2―ヒドロキシメチル―6―メチル―1,
4―ジヒドロピリジン―3,5―ジカルボン酸ジ
エチルエステルが、
3―ニトロベンズアルデヒド、4,4―ジメト
キシアセト酢酸エチルおよび3―アミノクロトン
酸イソプロピルエステルから4―(3―ニトロフ
エニル)―2―ヒドロキシメチル―6―メチル―
1,4―ジヒドロピリジン―3,5―ジカルボン
酸 3―エチルエステル―5―イソプロピルエス
テルが、
3―ニトロベンズアルデヒド、4,4―ジメト
キシアセト酢酸メチルおよび3―アミノクロトン
酸(2―クロロエチル)エステルから4―(3―
ニトロフエニル)―2―ヒドロキシメチル―6―
メチル―1,4―ジヒドロピリジン―3,5―ジ
カルボン酸 3―メチルエステル―5―(2―ク
ロロエチル)エステルが、
3―ニトロベンズアルデヒド、4,4―ジメト
キシアセト酢酸エチルおよび3―アミノクロトン
酸アリルエステルから4―(3―ニトロフエニ
ル)―2―ヒドロキシメチル―6―メチル―1,
4―ジヒドロピリジン―3,5―ジカルボン酸
3―エチルエステル―5―アリルエステルが、
3―ニトロベンズアルデヒド、4,4―メトキ
シアセト酢酸エチルおよび3―アミノクロトン酸
2―プロピニルエステルから4―(3―ニトロフ
エニル)―2―ヒドロキシメチル―6―メチル―
1,4―ジヒドロピリジン―3,5―ジカルボン
酸 3―エチルエステル―5―(2―プロピニ
ル)エステルが、
3―ニトロベンズアルデヒド、4,4―ジメト
キシアセト酢酸エチルおよび3―アミノクロトン
酸ベンジルエステルから4―(3―ニトロフエニ
ル)―2―ヒドロキシメチル―6―メチル―1,
4―ジヒドロピリジン―3,5―ジカルボン酸
3―エチルエステル―5―ベンジルエステルが、
それぞれ合成される。
実施例 1
4―(2―ニトロフエニル)―2―ヒドロキシ
メチル―6―メチル―1,4―ジヒドロピリジン
―3,5―ジカルボン酸ジエチルエステル(390
mg)をベンセン(10ml)に溶解し、これにクロロ
スルホニルイソシアナート(0.2ml)を加え、室
温、30分間撹拌して反応する。反応混合物に冷却
下、水(10ml)を加え、室温、30分間撹拌して加
水分解処理する。この反応混合物を酢酸エチルで
抽出し酢酸エチル抽出液を減圧濃縮する。残渣を
酢酸エチル―ヘキサンから再結晶処理すると、結
晶状の4―(2―ニトロフエニル)―2―カルバ
モイルオキシメチル―6―メチル―1,4―ジヒ
ドロピリジン―3,5―ジカルボン酸ジエチルエ
ステル(210mg)を得る。
mp 128―132℃
IR(KBr):3540,3400,3000,1710,1690,
1535,1495,1340,1205,1120,1100,
1095,780,755,715 cm-1
UV(in MeOH):λnax=235,350 nm
NMR(90MHz,in CDC13):δ1.18(t,J=7
Hz,6H),2.35(s,3H),4.15(m,4H),
5.38(br.s,4H),5.96(s,1H) 7.1―8.0
(m,5H).
実施例 2
4―(2―ニトロフエニル)―2―ヒドロキシ
メチル―6―メチル―1,4―ジヒドロピリジン
―3,5―ジカルボン酸ジエチルエステル(220
mg)をベンゼン(10ml)に溶解し、これにメチル
イソシアナート(0.1ml)およびトリエチルアミ
ン(0.3ml)を加え、還流下、1時間反応する。
冷却後、反応混合液中に析出した結晶を濾取し、
ジイソプロピルエーテル―ヘキサンから再結晶処
理して4―(2―ニトロフエニル)―2―(N―
メチルカルバモイル)オキシメチル―6―メチル
―1,4―ジヒドロピリジン―3,5―ジカルボ
ン酸ジエチルエステル(140mg)を得る。
mp 165―169℃
IR(KBr):3380,3000,1690,1680,1535,
1495,1355,1280,1205,1100,785,
760,715 cm-1
UV(in MeOH):λnax=235,350 nm
NMR(90MHz,in CDC13):δ 1.2(t,J=
7Hz,6H),2.38(s,3H)2.91(d,J=
6Hz,3H),4.18(m,4H),5.15(m,
1H),5.38(s,2H),5.98(s,1H),7.2
―8.0(m,5H)。
実施例 3
クロロスルホニルイソシアナート(0.57g)の
ベンセン溶液(10ml)に4―(3―ニトロフエニ
ル)―2―ヒドロキシメチル―6―メチル―1,
4―ジヒドロピリジン―3,5―ジカルボン酸ジ
エチルエステル(1.56g)を加え、室温、30分間
撹拌して反応する。反応混合物に冷却下、水(10
ml)を加え、室温、30分間撹拌して加水分解処理
する。この反応混合物を酢酸エチルで抽出処理し
抽出液を水洗および乾燥したあと減圧濃縮する。
残渣を酢酸エチル―ヘキサンにより結晶化処理す
ると、結晶状の4―(3―ニトロフエニル)―2
―カルバモイルオキシメチル―6―メチル―1,
4―ジヒドロピリジン―3,5―ジカルボン酸ジ
エチルエステル(1.07g)を得る。
mp 144―148℃
IR(KBr):3540,3380,3000,1710,1690,
1490,1355,1335,1210,1105,1090,
790,760,720cm -1
UV(in MeOH):λnax=235,355 nm
NMR(90MHz,in CDC13):δ 1.23(t,J
=7Hz,6H),24(s,3H),4.18(q,J
=7Hz,4H),5.2(s,1H),5.3(s,
2H),5.4(s,2H),7.2―8.2(m,5H).
実施例 4
4―(3―ニトロフエニル)―2―ヒドロキシ
メチル―6―メチル―1,4―ジヒドロピリジン
―3,5―ジカルボン酸ジエチルエステル(560
mg)とメチルイソシアナート(0.1ml)を用い、
実施例2と同様の方法により反応および処理を実
施して、結晶状の4―(3―ニトロフエニル)―
2―(N―メチルカルバモイル)オキシメチル―
6―メチル―1,4―ジヒドロピリジン―3,5
―ジカルボン酸ジエチルエステル(260mg)を得
る。
mp 192―193℃
IR(KBr):3400,3300,3000,1690,1685,
1480,1355,1280,1205,1105,790,
760,720 cm-1
UV(in MeOH):λnax=235,355 nm
NMR(90MHz,in DMSO―d6):δ 1.18(t,
J=7Hz,6H),2.38(s,3H),2.67(d,
J=5Hz,3H),4.12(q,J=7Hz,
4H),5.13(s,3H),7.22(m,1H),7.5
―8.3(m,4H),9.13(s,1H).
実施例 5
4―(3―ニトロフエニル)―2―ヒドロキシ
メチル―6―メチル―1,4―ジヒドロピリジン
―3,5―ジカルボン酸ジメチルエステル(420
mg)とクロロスルホニルイソシアナート(0.2ml)
を用い、実施例1と同様の方法により反応および
処理を実施して、結晶状の4―(3―ニトロフエ
ニル)―2―カルバモイルオキシメチル―6―メ
チル―1,4―ジヒドロピリジン―3,5―ジカ
ルボン酸メチルエステル(150mg)を得る。
mp 110〜114℃
IR(KBr):3540,3360,2980,1715,1690,
1495,1355,1340,1210,1105,1090,
830,805,790,755,710 cm-1
UV(in MeOH):λnax=235,355 nm
NMR(90MHz,in CDC13):δ 2.38(s,
3H),3.72(s,6H),5.2(s,1H),5.35
(s,2H),5.4(s,2H),7.3―8.25(m,
5H).
実施例 6
4―(3―ニトロフエニル)―2―ヒドロキシ
メチル―6―メチル―1,4―ジヒドロピリジン
―3,5―ジカルボン酸ジメチルエステル(450
mg)とメチルイソシアナート(0.1ml)を用い、
実施例2と同様の方法により反応および処理を実
施して、結晶状の4―(3―ニトロフエニル)―
2―(N―メチルカルバモイル)オキシメチル―
6―メチル―1,4―ジヒドロピリジン―3,5
―ジカルボン酸ジメチルエステル(200mg)を得
る。
mp 151〜153℃
IR(KBr):3350,2950,1700,1685,1530,
1480,1350,1210,1095,780,705 cm-1
UV(in MeOH):λnax=235,355 nm
NMR(90MHz,in CDC13):δ 2.38(s,
3H),2.88(d,J=5Hz,3H),3.72(s,
6H),5.2(s,2H),5.4(s,2H),7.35―
8.3(m,5H).
実施例 7
4―(3―ニトロフエニル)―2―ヒドロキシ
メチル―6―メチル―1,4―ジヒドロピリジン
―3,5―ジカルボン酸 3―エチルエステル―
5―イソプロピルエステル(850mg)とクロロス
ルホニルイソシアナート(0.4ml)を用い、実施
例1と同様の方法により反応および処理を実施し
て、結晶状の4―(3―ニトロフエニル)―2―
カルバモイルオキシメチル―6―メチル―1,4
―ジヒドロピリジン―3,5―ジカルボン酸 3
―エチルエステル―5―イソプロピルエステル
(210mg)を得る。
mp 130―132℃
IR(KBr):3450,3350,2980,1705,1685,
1530,1485,1350,1205,1100,1080,
780,715cm-1
UV(in MeOH):λnax=235,355 nm
NMR(90MHz,in CDC13):δ 1.14(t,J
=8Hz,3H),1.27(d,J=6Hz,6H),
1.42(s,3H),4.15(q,J=8Hz,2H),
5.0(m,J=6Hz,1H),5.14(s,1H),
5.3(s,2H),6.1(m,2H),7.5―8.4(m,
5H).
実施例 8
4―(3―ニトロフエニル)―2―ヒドロキシ
メチル―6―メチル―1,4―ジヒドロピリジン
―3,5―ジカルボン酸 3―エチルエステル―
5―イソプロピルエステル(850mg)とメチルイ
ソシアナート(0.15ml)を用い、実施例2と同様
の反応および処理を実施して、結晶状の4―(3
―ニトロフエニル)―2―(N―メチルカルバモ
イル)オキシメチル―6―メチル―1,4―ジヒ
ドロピリジン―3,5―ジカルボン酸 3―エチ
ルエステル―5―イソプロピルエステル(250mg)
を得る。
mp 194―196℃
IR(KBr):3380,3290,3980,1680,1525,
1480,1350,1275,1250,1205,1100,
780,715 cm-1
UV(in MeOH):λnax=235,355 nm
NMR(90MHz,in DMSO―d6):δ 1.0―1.3
(m,9H),2.38(s,3H),2.67(m,
3H),4.1(q,J=7Hz,2H),4.93(sep,
J=6Hz,1H),5.1(s,3H),7.2(m,
1H),7.4―8.2(m,4H),9.1(s,1H).
実施例 9
4―(3―ニトロフエニル)―2―ヒドロキシ
メチル―6―メチル―1,4―ジヒドロピリジン
―3,5―ジカルボン酸 3―エチルエステル―
5―イソプロピルエステル(404mg)とエチルイ
ソシアナート(0.4ml)を用い、実施例2と同様
の反応および処理を実施して、結晶状の4―(3
―ニトロフエニル)―2(N―エチルカルバモイ
ル)オキシメチル―6―メチル―1,4―ジヒド
ロピリジン―3,5―ジカルボン酸 3―エチル
エステル―5―イソプロピルエステル(370mg)
を得る。
mp 153―154.5℃
IR(KBr):3350,2980,1685,1530,1480,
1350,1275,1250,1205,1095,780,715
cm-1
UV(in MeOH):λnax=235,355 nm
NMR(90MHz,in DMSO―d6):δ 0.9―1.3
(m,12H),2.34(s,3H),3.07(q,J
=7Hz,2H),4.07(q,J=8Hz,2H),
4.9(m,1H),5.06(s,3H),7.28(t,
J=7Hz,1H),7.5―8.2(m,4H),9.05
(br.s,1H).
実施例 10
4―(3―ニトロフエニル)―2―ヒドロキシ
メチル―6―メチル―1,4―ジヒドロピリジン
―3,5―ジカルボン酸 3―エチルエステル―
5―イソプロピルエステル(404mg)とプロピル
イソシアナート(0.4ml)を用い、実施例2と同
様の反応および処理を実施して、結晶状の4―
(3―ニトロフエニル)―2―(N―プロピルカ
ルバモイル)オキシメチル―6―メチル―1,4
―ジヒドロピリジン―3,5―ジカルボン酸 3
―エチルエステル―5―イソプロピルエステル
(440mg)を得る。
mp 150.5―152℃
IR(KBr):3350,2980,1685,1530,1480,
1355,1270,1240,1207,1100,780,715
cm-1
UV(in MeOH):λnax=235,355 nm
NMR(90MHz,in DMSO―d6):δ 0.88(t,
J=8Hz,3H),1.0―1.3(m,9H),1.48
(m,2H),2.38(s,3H),3.04(q,J=
7Hz,2H),4.12(q,J=8Hz,2H),
4.14(m,1H),5.1(s,3H),7.36(t,
J=7Hz,1H),7.6―8.3(m,4H),9.1
(s,1H).
実施例 11
4―(3―ニトロフエニル)―2―ヒドロキシ
メチル―6―メチル―1,4―ジヒドロピリジン
―3,5―ジカルボン酸 3―エチルエステル―
5―イソプロピルエステル(404mg)とシクロヘ
キシルイソシアナート(0.4ml)を用い、実施例
2と同様の反応および処理を実施して、結晶状の
4―(3―ニトロフエニル)―2―(N―シクロ
ヘキシルカルバモイル)オキシメチル―6―メチ
ル―1,4―ジヒドロピリジン―3,5―ジカル
ボン酸 3―エチルエステル―5―イソプロピル
エステル(330mg)を得る。
mp 157―159.5℃
IR(KBr):3350,2940,1680,1530,1480,
1350,1275,1207,1095,780,710 cm-1
UV(in MeOH):λnax=235,355 nm
NMR(90MHz,in DMSO―d6):δ 1.0―1.4
(m,9H),1.4―2.0(m,10H),2.37(s,
3H),3.35(br.s,2H),4.1(q,J=8Hz,
2H),4.93(m,1H),5.1(s,3H),7.26
(d,J=8Hz,1H),7.5―8.3(m,4H),
9.07(s,1H).
実施例 12
4―(3―ニトロフエニル)―2―ヒドロキシ
メチル―6―メチル―1,4―ジヒドロピリジン
―3,5―ジカルボン酸 3―エチルエステル―
5―イソプロピルエステル(404mg)とフエニル
イソシアナート(0.4ml)を用い、実施例2と同
様の反応および処理を実施して、結晶状の4―
(3―ニトロフエニル)―2―(N―フエニルカ
ルバモイル)オキシ6―メチル―1,4―ジヒド
ロピリジン―3,5―ジカルボン酸 3―エチル
エステル―5―イソプロピルエステル(370mg)
を得る。
mp 134―136℃
IR(KBr):3350,2980,1685,1530,1480,
1350,1205,1100,740,710,690 cm-1
UV(in MeOH):λnax=238,356 nm
NMR(90MHz,in DMSO―d6):δ 1.0―1.4
(m,9H),2.4(s,3H),4.12(q,J=
8Hz,2H),4.93(m,1H),5.1(s,
1H),5.25(s,2H),7.0―8.3(m,9H),
9.27(s,1H),9.86(s,1H).
実施例 13
4―(3―ニトロフエニル)―2―ヒドロキシ
メチル―6―メチル―1,4―ジヒドロピリジン
―3,5―ジカルボン酸 3―エチルエステル―
5―イソプロピルエステル(404mg)と4―クロ
ロフエニルイソシアナート(0.4ml)を用い、実
施例2と同様の反応および処理を実施して、結晶
状の4―(3―ニトロフエニル)―2―(N―4
―クロロフエニルカルバモイル)オキシメチル―
6―メチル―1,4―ジヒドロピリジン―3,5
―ジカルボン酸 3―エチルエステル―5―ソプ
ロピルエステル(390mg)を得る。
mp 113―116.5℃
IR(KBr):3380,2980,1695,1530,1350,
1220,1100,825,740,705, cm-1
UV(in MeOH):λnax=235,355 nm
NMR(90MHz,in DMSO―d6):δ 0.95―
1.35(m,9H),2.37(s,3H),4.08(q,
J=8Hz,2H),4.93(m,1H),5.1(s,
1H),5.36(s,2H),7.3―8.3(m,8H),
9.27(s,1H),10.0(p,1H).
実施例 14
4―(3―ニトロフエニル)―2―ヒドロキシ
メチル―6―メチル―1,4―ジヒドロピリジン
―3,5―ジカルボン酸 3エチルエステル―5
―イソプロピルエステル(404mg),S―メチル―
N―シクロヘキシル―チオールカルバメート
(600mg)およびトリエチルアミン(0.4ml)を、
ピリジン(10ml)とアセトニトリル(2ml)の混
液に加える。この混合物に、冷却下、撹拌しなが
ら硝酸銀(220mg)のアセトニトリル溶液(2ml)
を滴下する。混合物を100℃、4時間加熱する。
冷却後、酢酸エチルを加え、沈澱物を濾去したあ
と、水洗および乾燥する。減圧濃縮により溶媒を
留去し、残渣をジイソプロピルエーテル―ヘキサ
ンから再結晶処理すると、融点157―159℃の4―
(3―ニトロフエニル)―2―(N―シクロヘキ
シルルカルバモイル)オキシメチル―6―メチル
―1,4―ジヒドロピリジン―3,5―ジカルボ
ン酸―3―エチルエステル―5―イソプロピルエ
ステル(250mg)を得る。このものの機器分析デ
ータは、実施例11の生成物のそれとよい一致を示
した。[Table] 3 Test method a Coronary vasodilatory effect The effect of intracoronary administration on a perfused specimen of isolated rabbit heart was determined according to the method of Langendorff*.
The strength of the coronary vasodilator effect was evaluated by the sample dose that increases the coronary blood flow by 50%; pl 50 . ※ O. Langendorff; Pflu¨gers arch.ges.
Physiol., 61 , 291-332 (1895) b Acute toxicity test Using DM male mice (18-22 g), LD 50 was determined by up-and-down method during intravenous administration.
The value was calculated. The compound () of the present invention is expected to be useful as a vasodilator and an antihypertensive agent, and the administration form for this purpose is generally parenteral administration such as intravenous, subcutaneous or intramuscular injection, or rectal administration. Oral administration using tablets, powders, granules, capsules, sublingual tablets or syrups. The dosage varies depending on the patient's symptoms, age, weight, and dosage form, but is usually 1 dose for adults.
The daily dose is 0.1 to 1000 mg, preferably 1 to 100 mg. Each of the above-mentioned formulations can be manufactured by a well-known method. Next, the compound () of the present invention and the method for producing the same will be explained in detail with reference to Examples, but the present invention is not particularly limited thereto. Reference example Synthesis example of raw material compound () 3-nitrobenzaldehyde (3.4g), 4,4
-Mix methyl dimethoxyacetoacetate (4 g) and piperidine (0.3 ml) in benzene (30 ml),
Heat under reflux for 4 hours under azeotropic dehydration conditions. After cooling,
The reaction mixture is washed with water and dried, and the solvent is distilled off under reduced pressure. 3-Aminocrotonic acid methyl ester (2.6 g) was added to the residual oil and mixed, followed by heating and stirring at 100°C for 1.5 hours and then at 120°C for 8 hours. After cooling the reaction mixture, it is extracted with ethyl acetate, the extract is washed with water and dried, and then the solvent is distilled off under reduced pressure. The residual oil was separated and purified by silica gel column chromatography using a developing solvent (hexane:ethyl acetate = 2:1) to obtain 4-(3-nitrophenyl)- as a yellow oil.
2-dimethoxymethyl-6-methyl-1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester (4.8 g) was obtained. This yellow oil was dissolved in a mixture of acetone (100 ml) and 6N hydrochloric acid (4 ml), and reacted with stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, the residue (aldehyde) was dissolved in ethanol (60 ml), and the solution was dissolved under cooling.
Add sodium borohydride (418mg) to this,
Stir and react for 1 hour. The reaction mixture was adjusted to pH 4 (1N hydrochloric acid), concentrated under reduced pressure, the residual oil was extracted with ethyl acetate, and the extract was concentrated under reduced pressure. The residue was dissolved in a developing solvent (benzene: ethyl acetate = 9:
1) by silica gel column chromatography to obtain crystalline 4-(3-nitrophenyl)-2-hydroxymethyl-6-methyl-1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester ( 12g). mp 144-146℃ IR (KBr): 3550, 3360, 2970, 1695, 1660,
1530, 1475, 1350, 1220, 1120, 1095,
1020, 900, 830, 785, 750, 700 cm -1 UV (in MeOH): λ nax = 235, 355 nm NMR (90 MHz, in DMSO-d 6 ): δ2.4 (S,
3H), 3.55 (s, 6H), 4.6 (d, J=5Hz,
2H), 5.0 (s, 1H), 5.5 (t, J=5Hz,
1H), 7.3-8.0 (m, 4H), 8.5 (br.s.1H). Using a similar method, starting compounds () such as 3-nitrobenzaldehyde, ethyl 4,4-dimethoxyacetoacetate and 3-aminocrotonic acid ethyl ester are converted to 4-(3-nitrophenyl)-2-hydroxymethyl-6-methyl. -1,
4-dihydropyridine-3,5-dicarboxylic acid diethyl ester is converted from 2-nitrobenzaldehyde, ethyl 4,4-dimethoxyacetoacetate and 3-aminocrotonic acid ethyl ester to 4-(2-nitrophenyl)-2-hydroxymethyl-6 -Methyl-1,
4-dihydropyridine-3,5-dicarboxylic acid diethyl ester is converted from 3-nitrobenzaldehyde, ethyl 4,4-dimethoxyacetoacetate and 3-aminocrotonic acid isopropyl ester to 4-(3-nitrophenyl)-2-hydroxymethyl-6 -Methyl-
1,4-dihydropyridine-3,5-dicarboxylic acid 3-ethyl ester-5-isopropyl ester is synthesized from 3-nitrobenzaldehyde, methyl 4,4-dimethoxyacetoacetate and 3-aminocrotonic acid (2-chloroethyl) ester. -(3-
Nitrophenyl)-2-hydroxymethyl-6-
Methyl-1,4-dihydropyridine-3,5-dicarboxylic acid 3-methyl ester-5-(2-chloroethyl) ester, 3-nitrobenzaldehyde, ethyl 4,4-dimethoxyacetoacetate, and 3-aminocrotonic acid allyl ester from 4-(3-nitrophenyl)-2-hydroxymethyl-6-methyl-1,
4-dihydropyridine-3,5-dicarboxylic acid
3-ethyl ester-5-allyl ester is converted from 3-nitrobenzaldehyde, ethyl 4,4-methoxyacetoacetate and 3-aminocrotonic acid 2-propynyl ester to 4-(3-nitrophenyl)-2-hydroxymethyl-6- Methyl
1,4-dihydropyridine-3,5-dicarboxylic acid 3-ethyl ester-5-(2-propynyl) ester is synthesized from 3-nitrobenzaldehyde, ethyl 4,4-dimethoxyacetoacetate and 3-aminocrotonic acid benzyl ester. -(3-nitrophenyl)-2-hydroxymethyl-6-methyl-1,
4-dihydropyridine-3,5-dicarboxylic acid
3-ethyl ester-5-benzyl ester is synthesized, respectively. Example 1 4-(2-nitrophenyl)-2-hydroxymethyl-6-methyl-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester (390
mg) in benzene (10 ml), add chlorosulfonyl isocyanate (0.2 ml), and react by stirring at room temperature for 30 minutes. Water (10 ml) was added to the reaction mixture under cooling, and the mixture was stirred at room temperature for 30 minutes for hydrolysis. This reaction mixture was extracted with ethyl acetate, and the ethyl acetate extract was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give crystalline 4-(2-nitrophenyl)-2-carbamoyloxymethyl-6-methyl-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester (210 mg). get. mp 128-132℃ IR (KBr): 3540, 3400, 3000, 1710, 1690,
1535, 1495, 1340, 1205, 1120, 1100,
1095, 780, 755, 715 cm -1 UV (in MeOH): λ nax = 235, 350 nm NMR (90 MHz, in CDC1 3 ): δ1.18 (t, J = 7
Hz, 6H), 2.35 (s, 3H), 4.15 (m, 4H),
5.38 (br.s, 4H), 5.96 (s, 1H) 7.1―8.0
(m, 5H). Example 2 4-(2-nitrophenyl)-2-hydroxymethyl-6-methyl-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester (220
mg) in benzene (10 ml), methyl isocyanate (0.1 ml) and triethylamine (0.3 ml) were added thereto, and the mixture was reacted under reflux for 1 hour.
After cooling, the crystals precipitated in the reaction mixture were collected by filtration,
Recrystallized from diisopropyl ether-hexane to give 4-(2-nitrophenyl)-2-(N-
methylcarbamoyl)oxymethyl-6-methyl-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester (140 mg) was obtained. mp 165-169℃ IR (KBr): 3380, 3000, 1690, 1680, 1535,
1495, 1355, 1280, 1205, 1100, 785,
760, 715 cm -1 UV (in MeOH): λ nax = 235, 350 nm NMR (90 MHz, in CDC1 3 ): δ 1.2 (t, J =
7Hz, 6H), 2.38 (s, 3H) 2.91 (d, J=
6Hz, 3H), 4.18 (m, 4H), 5.15 (m,
1H), 5.38 (s, 2H), 5.98 (s, 1H), 7.2
-8.0 (m, 5H). Example 3 4-(3-nitrophenyl)-2-hydroxymethyl-6-methyl-1, in a benzene solution (10 ml) of chlorosulfonyl isocyanate (0.57 g)
Add 4-dihydropyridine-3,5-dicarboxylic acid diethyl ester (1.56 g) and stir at room temperature for 30 minutes to react. Water (10
ml) and stirred at room temperature for 30 minutes for hydrolysis. This reaction mixture is extracted with ethyl acetate, and the extract is washed with water, dried, and then concentrated under reduced pressure.
When the residue is crystallized with ethyl acetate-hexane, crystalline 4-(3-nitrophenyl)-2
-carbamoyloxymethyl-6-methyl-1,
4-dihydropyridine-3,5-dicarboxylic acid diethyl ester (1.07 g) is obtained. mp 144-148℃ IR (KBr): 3540, 3380, 3000, 1710, 1690,
1490, 1355, 1335, 1210, 1105, 1090,
790, 760, 720 cm -1 UV (in MeOH): λ nax = 235, 355 nm NMR (90 MHz, in CDC1 3 ): δ 1.23 (t, J
=7Hz, 6H), 24(s, 3H), 4.18(q, J
=7Hz, 4H), 5.2(s, 1H), 5.3(s,
2H), 5.4 (s, 2H), 7.2-8.2 (m, 5H). Example 4 4-(3-nitrophenyl)-2-hydroxymethyl-6-methyl-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester (560
mg) and methyl isocyanate (0.1 ml).
The reaction and treatment were carried out in the same manner as in Example 2 to obtain crystalline 4-(3-nitrophenyl)-
2-(N-methylcarbamoyl)oxymethyl-
6-methyl-1,4-dihydropyridine-3,5
-Dicarboxylic acid diethyl ester (260mg) is obtained. mp 192-193℃ IR (KBr): 3400, 3300, 3000, 1690, 1685,
1480, 1355, 1280, 1205, 1105, 790,
760, 720 cm -1 UV (in MeOH): λ nax = 235, 355 nm NMR (90 MHz, in DMSO-d 6 ): δ 1.18 (t,
J=7Hz, 6H), 2.38 (s, 3H), 2.67 (d,
J=5Hz, 3H), 4.12(q, J=7Hz,
4H), 5.13 (s, 3H), 7.22 (m, 1H), 7.5
-8.3 (m, 4H), 9.13 (s, 1H). Example 5 4-(3-nitrophenyl)-2-hydroxymethyl-6-methyl-1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester (420
mg) and chlorosulfonyl isocyanate (0.2ml)
The reaction and treatment were carried out in the same manner as in Example 1 to obtain crystalline 4-(3-nitrophenyl)-2-carbamoyloxymethyl-6-methyl-1,4-dihydropyridine-3,5- Dicarboxylic acid methyl ester (150 mg) is obtained. mp 110~114℃ IR (KBr): 3540, 3360, 2980, 1715, 1690,
1495, 1355, 1340, 1210, 1105, 1090,
830, 805, 790, 755, 710 cm -1 UV (in MeOH): λ nax = 235, 355 nm NMR (90 MHz, in CDC1 3 ): δ 2.38 (s,
3H), 3.72 (s, 6H), 5.2 (s, 1H), 5.35
(s, 2H), 5.4 (s, 2H), 7.3-8.25 (m,
5H). Example 6 4-(3-nitrophenyl)-2-hydroxymethyl-6-methyl-1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester (450
mg) and methyl isocyanate (0.1 ml).
The reaction and treatment were carried out in the same manner as in Example 2 to obtain crystalline 4-(3-nitrophenyl)-
2-(N-methylcarbamoyl)oxymethyl-
6-methyl-1,4-dihydropyridine-3,5
- Obtain dicarboxylic acid dimethyl ester (200mg). mp 151~153℃ IR (KBr): 3350, 2950, 1700, 1685, 1530,
1480, 1350, 1210, 1095, 780, 705 cm -1 UV (in MeOH): λ nax = 235, 355 nm NMR (90 MHz, in CDC1 3 ): δ 2.38 (s,
3H), 2.88 (d, J=5Hz, 3H), 3.72 (s,
6H), 5.2 (s, 2H), 5.4 (s, 2H), 7.35―
8.3 (m, 5H). Example 7 4-(3-nitrophenyl)-2-hydroxymethyl-6-methyl-1,4-dihydropyridine-3,5-dicarboxylic acid 3-ethyl ester
Using 5-isopropyl ester (850 mg) and chlorosulfonyl isocyanate (0.4 ml), reaction and treatment were carried out in the same manner as in Example 1 to obtain crystalline 4-(3-nitrophenyl)-2-.
Carbamoyloxymethyl-6-methyl-1,4
-dihydropyridine-3,5-dicarboxylic acid 3
-Ethyl ester-5-isopropyl ester (210 mg) is obtained. mp 130-132℃ IR (KBr): 3450, 3350, 2980, 1705, 1685,
1530, 1485, 1350, 1205, 1100, 1080,
780, 715 cm -1 UV (in MeOH): λ nax = 235, 355 nm NMR (90 MHz, in CDC1 3 ): δ 1.14 (t, J
= 8Hz, 3H), 1.27 (d, J = 6Hz, 6H),
1.42 (s, 3H), 4.15 (q, J=8Hz, 2H),
5.0 (m, J=6Hz, 1H), 5.14 (s, 1H),
5.3 (s, 2H), 6.1 (m, 2H), 7.5-8.4 (m,
5H). Example 8 4-(3-nitrophenyl)-2-hydroxymethyl-6-methyl-1,4-dihydropyridine-3,5-dicarboxylic acid 3-ethyl ester
Using 5-isopropyl ester (850 mg) and methyl isocyanate (0.15 ml), the same reaction and treatment as in Example 2 were carried out to obtain crystalline 4-(3
-Nitrophenyl)-2-(N-methylcarbamoyl)oxymethyl-6-methyl-1,4-dihydropyridine-3,5-dicarboxylic acid 3-ethyl ester-5-isopropyl ester (250mg)
get. mp 194-196℃ IR (KBr): 3380, 3290, 3980, 1680, 1525,
1480, 1350, 1275, 1250, 1205, 1100,
780, 715 cm -1 UV (in MeOH): λ nax = 235, 355 nm NMR (90MHz, in DMSO- d6 ): δ 1.0-1.3
(m, 9H), 2.38 (s, 3H), 2.67 (m,
3H), 4.1 (q, J=7Hz, 2H), 4.93 (sep,
J = 6Hz, 1H), 5.1 (s, 3H), 7.2 (m,
1H), 7.4-8.2 (m, 4H), 9.1 (s, 1H). Example 9 4-(3-nitrophenyl)-2-hydroxymethyl-6-methyl-1,4-dihydropyridine-3,5-dicarboxylic acid 3-ethyl ester
Using 5-isopropyl ester (404 mg) and ethyl isocyanate (0.4 ml), the same reaction and treatment as in Example 2 were carried out to obtain crystalline 4-(3
-Nitrophenyl)-2(N-ethylcarbamoyl)oxymethyl-6-methyl-1,4-dihydropyridine-3,5-dicarboxylic acid 3-ethyl ester-5-isopropyl ester (370mg)
get. mp 153-154.5℃ IR (KBr): 3350, 2980, 1685, 1530, 1480,
1350, 1275, 1250, 1205, 1095, 780, 715
cm -1 UV (in MeOH): λ nax = 235, 355 nm NMR (90MHz, in DMSO- d6 ): δ 0.9-1.3
(m, 12H), 2.34 (s, 3H), 3.07 (q, J
= 7Hz, 2H), 4.07 (q, J = 8Hz, 2H),
4.9 (m, 1H), 5.06 (s, 3H), 7.28 (t,
J=7Hz, 1H), 7.5-8.2 (m, 4H), 9.05
(br.s, 1H). Example 10 4-(3-nitrophenyl)-2-hydroxymethyl-6-methyl-1,4-dihydropyridine-3,5-dicarboxylic acid 3-ethyl ester
Using 5-isopropyl ester (404 mg) and propyl isocyanate (0.4 ml), the same reaction and treatment as in Example 2 were carried out to obtain crystalline 4-
(3-nitrophenyl)-2-(N-propylcarbamoyl)oxymethyl-6-methyl-1,4
-dihydropyridine-3,5-dicarboxylic acid 3
-Ethyl ester-5-isopropyl ester (440mg) is obtained. mp 150.5―152℃ IR (KBr): 3350, 2980, 1685, 1530, 1480,
1355, 1270, 1240, 1207, 1100, 780, 715
cm -1 UV (in MeOH): λ nax = 235, 355 nm NMR (90 MHz, in DMSO-d 6 ): δ 0.88 (t,
J = 8Hz, 3H), 1.0-1.3 (m, 9H), 1.48
(m, 2H), 2.38 (s, 3H), 3.04 (q, J=
7Hz, 2H), 4.12 (q, J=8Hz, 2H),
4.14 (m, 1H), 5.1 (s, 3H), 7.36 (t,
J=7Hz, 1H), 7.6-8.3 (m, 4H), 9.1
(s, 1H). Example 11 4-(3-nitrophenyl)-2-hydroxymethyl-6-methyl-1,4-dihydropyridine-3,5-dicarboxylic acid 3-ethyl ester
Using 5-isopropyl ester (404 mg) and cyclohexyl isocyanate (0.4 ml), the same reaction and treatment as in Example 2 were carried out to obtain crystalline 4-(3-nitrophenyl)-2-(N-cyclohexylcarbamoyl). ) Oxymethyl-6-methyl-1,4-dihydropyridine-3,5-dicarboxylic acid 3-ethyl ester-5-isopropyl ester (330 mg) is obtained. mp 157-159.5℃ IR (KBr): 3350, 2940, 1680, 1530, 1480,
1350, 1275, 1207, 1095, 780, 710 cm -1 UV (in MeOH): λ nax = 235, 355 nm NMR (90MHz, in DMSO- d6 ): δ 1.0-1.4
(m, 9H), 1.4-2.0 (m, 10H), 2.37 (s,
3H), 3.35 (br.s, 2H), 4.1 (q, J=8Hz,
2H), 4.93 (m, 1H), 5.1 (s, 3H), 7.26
(d, J=8Hz, 1H), 7.5-8.3 (m, 4H),
9.07 (s, 1H). Example 12 4-(3-nitrophenyl)-2-hydroxymethyl-6-methyl-1,4-dihydropyridine-3,5-dicarboxylic acid 3-ethyl ester
Using 5-isopropyl ester (404 mg) and phenyl isocyanate (0.4 ml), the same reaction and treatment as in Example 2 were carried out to obtain crystalline 4-
(3-Nitrophenyl)-2-(N-phenylcarbamoyl)oxy6-methyl-1,4-dihydropyridine-3,5-dicarboxylic acid 3-ethyl ester-5-isopropyl ester (370mg)
get. mp 134-136℃ IR (KBr): 3350, 2980, 1685, 1530, 1480,
1350, 1205, 1100, 740, 710, 690 cm -1 UV (in MeOH): λ nax = 238, 356 nm NMR (90MHz, in DMSO-d 6 ): δ 1.0-1.4
(m, 9H), 2.4 (s, 3H), 4.12 (q, J=
8Hz, 2H), 4.93 (m, 1H), 5.1 (s,
1H), 5.25 (s, 2H), 7.0-8.3 (m, 9H),
9.27 (s, 1H), 9.86 (s, 1H). Example 13 4-(3-nitrophenyl)-2-hydroxymethyl-6-methyl-1,4-dihydropyridine-3,5-dicarboxylic acid 3-ethyl ester
Using 5-isopropyl ester (404 mg) and 4-chlorophenyl isocyanate (0.4 ml), the same reaction and treatment as in Example 2 were carried out to obtain crystalline 4-(3-nitrophenyl)-2-(N -4
-Chlorophenylcarbamoyl)oxymethyl-
6-methyl-1,4-dihydropyridine-3,5
-Dicarboxylic acid 3-ethyl ester-5-sopropyl ester (390 mg) was obtained. mp 113-116.5℃ IR (KBr): 3380, 2980, 1695, 1530, 1350,
1220, 1100, 825, 740, 705, cm -1 UV (in MeOH): λ nax = 235, 355 nm NMR (90MHz, in DMSO―d 6 ): δ 0.95―
1.35 (m, 9H), 2.37 (s, 3H), 4.08 (q,
J = 8Hz, 2H), 4.93 (m, 1H), 5.1 (s,
1H), 5.36 (s, 2H), 7.3-8.3 (m, 8H),
9.27 (s, 1H), 10.0 (p, 1H). Example 14 4-(3-nitrophenyl)-2-hydroxymethyl-6-methyl-1,4-dihydropyridine-3,5-dicarboxylic acid 3ethyl ester-5
-Isopropyl ester (404mg), S-methyl-
N-cyclohexyl-thiol carbamate (600 mg) and triethylamine (0.4 ml),
Add to a mixture of pyridine (10 ml) and acetonitrile (2 ml). A solution of silver nitrate (220 mg) in acetonitrile (2 ml) was added to this mixture under cooling and stirring.
drip. Heat the mixture at 100°C for 4 hours.
After cooling, ethyl acetate is added and the precipitate is filtered off, washed with water and dried. The solvent was removed by concentration under reduced pressure, and the residue was recrystallized from diisopropyl ether-hexane to give 4-
(3-Nitrophenyl)-2-(N-cyclohexyllucarbamoyl)oxymethyl-6-methyl-1,4-dihydropyridine-3,5-dicarboxylic acid-3-ethyl ester-5-isopropyl ester (250 mg) was obtained. The instrumental analysis data of this showed good agreement with that of the product of Example 11.
Claims (1)
水素原子、アルキル基、シクロアルキル基、また
はハロゲン原子で置換されていてもよいフエニル
基、Aは直鎖または分岐状のアルキレン基を示
す]で表される1,4―ジヒドロピリジン誘導
体。 2 一般式[―a] [式中、R1,R2およびR3はアルキル基、R4aは
アルキル基、シクロアルキル基、またはハロゲン
原子で置換されていてもよいフエニル基、Aは直
鎖または分岐状のアルキレン基を示す]で表され
る特許請求の範囲第1項記載の1,4―ジヒドロ
ピリジン誘導体。 3 一般式[―b] [式中、R1,R2およびR3はアルキル基、Aは
直鎖または分岐状のアルキレン基を示す]で表さ
れる特許請求の範囲第1項記載の2―カルバモイ
ルオキシアルキル―1,4―ジヒドロピリジン誘
導体。 4 一般式[] [式中、R1,R2およびR3はアルキル基、Aは
直鎖または分岐状のアルキレン基を示す]で表さ
れる1,4―ジヒドロピリジン誘導体と、 一般式[―a] R4a−NCO [―a] [式中、R4aはアルキル基、シクロアルキル
基、またはハロゲン原子で置換されていてもよい
フエニル基を示す]で表されるイソシアナートま
たは反応条件下でイソシアナートを生成する化合
物を反応させることを特徴とする。 一般式[―a] [式中、R1,R2およびR3はアルキル基、R4aは
アルキル基、シクロアルキル基、またはハロゲン
原子で置換されていてもよいフエニル基、Aは直
鎖または分岐状のアルキレン基を示す]で表され
る1,4―ジヒドロピリジン誘導体の製造法。 5 一般式[] [式中、R1,R2およびR3はアルキル基、Aは
直鎖または分岐状のアルキレン基を示す]で表さ
れる1,4―ジヒドロピリジン誘導体と、 一般式[―b] R4b−NCO [―b] [式中、R4bはクロロスルホニル基を示す]で
表されるイソシアナートまたは反応条件下で該イ
ソシアナートを生成する化合物を反応させ、次い
で加水分解することを特徴とする。 一般式[―b] [式中、R1,R2およびR3はアルキル基、Aは
直鎖または分岐状のアルキレン基を示す]で表さ
れるカルバモイルオキシアルキル―1,4―ジヒ
ドロピリジン誘導体の製造法。 6 一般式[] [式中、R1,R2およびR3はアルキル基、R4は
水素原子、アルキル基、シクロアルキル基、また
はハロゲン原子で置換されていてもよいフエニル
基、Aは直鎖または分岐状のアルキレン基を示
す]で表される1,4―ジヒドロピリジン誘導体
を有効成分とする血圧降下剤。[Claims] 1. General formula [] [In the formula, R 1 , R 2 and R 3 are an alkyl group, R 4 is a hydrogen atom, an alkyl group, a cycloalkyl group, or a phenyl group which may be substituted with a halogen atom, and A is a linear or branched 1,4-dihydropyridine derivative represented by [representing an alkylene group]. 2 General formula [-a] [In the formula, R 1 , R 2 and R 3 are an alkyl group, R 4a is an alkyl group, a cycloalkyl group, or a phenyl group which may be substituted with a halogen atom, and A is a linear or branched alkylene group. 1,4-dihydropyridine derivative according to claim 1, which is represented by: 3 General formula [-b] 2-carbamoyloxyalkyl-1 according to claim 1, represented by [wherein R 1 , R 2 and R 3 are an alkyl group, and A represents a linear or branched alkylene group]; 4-dihydropyridine derivative. 4 General formula [] A 1,4-dihydropyridine derivative represented by [wherein R 1 , R 2 and R 3 are an alkyl group, and A represents a linear or branched alkylene group] and the general formula [-a] R 4a - NCO [-a] [In the formula, R 4a represents an alkyl group, a cycloalkyl group, or a phenyl group which may be substituted with a halogen atom] or an isocyanate is produced under the reaction conditions It is characterized by reacting compounds. General formula [-a] [In the formula, R 1 , R 2 and R 3 are an alkyl group, R 4a is an alkyl group, a cycloalkyl group, or a phenyl group which may be substituted with a halogen atom, and A is a linear or branched alkylene group. A method for producing a 1,4-dihydropyridine derivative represented by: 5 General formula [] A 1,4-dihydropyridine derivative represented by [wherein R 1 , R 2 and R 3 are an alkyl group, and A represents a linear or branched alkylene group] and the general formula [-b] R 4b - It is characterized by reacting an isocyanate represented by NCO [-b] [wherein R 4b represents a chlorosulfonyl group] or a compound that produces the isocyanate under reaction conditions, followed by hydrolysis. General formula [-b] A method for producing a carbamoyloxyalkyl-1,4-dihydropyridine derivative represented by the formula [wherein R 1 , R 2 and R 3 are an alkyl group, and A is a linear or branched alkylene group]. 6 General formula [] [In the formula, R 1 , R 2 and R 3 are an alkyl group, R 4 is a hydrogen atom, an alkyl group, a cycloalkyl group, or a phenyl group which may be substituted with a halogen atom, and A is a linear or branched An antihypertensive agent whose active ingredient is a 1,4-dihydropyridine derivative represented by the following alkylene group.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP325081A JPS57118565A (en) | 1981-01-14 | 1981-01-14 | Carbamoyloxyalkyl-1,4-dihydropyridine derivative and its preparation |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP325081A JPS57118565A (en) | 1981-01-14 | 1981-01-14 | Carbamoyloxyalkyl-1,4-dihydropyridine derivative and its preparation |
Publications (2)
Publication Number | Publication Date |
---|---|
JPS57118565A JPS57118565A (en) | 1982-07-23 |
JPH0128020B2 true JPH0128020B2 (en) | 1989-05-31 |
Family
ID=11552209
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP325081A Granted JPS57118565A (en) | 1981-01-14 | 1981-01-14 | Carbamoyloxyalkyl-1,4-dihydropyridine derivative and its preparation |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPS57118565A (en) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5927871A (en) * | 1982-08-06 | 1984-02-14 | Banyu Pharmaceut Co Ltd | Novel preparation of 2-carbamoyloxyalkyl-1,4- dihydropyridine derivative |
EP0311053A3 (en) * | 1987-10-06 | 1991-05-08 | Banyu Pharmaceutical Co., Ltd. | Ameliorant of cerebral circulation and optical isomer of nb-818, processes for its production and its use |
-
1981
- 1981-01-14 JP JP325081A patent/JPS57118565A/en active Granted
Also Published As
Publication number | Publication date |
---|---|
JPS57118565A (en) | 1982-07-23 |
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