JPH0314307B2 - - Google Patents
Info
- Publication number
- JPH0314307B2 JPH0314307B2 JP59088411A JP8841184A JPH0314307B2 JP H0314307 B2 JPH0314307 B2 JP H0314307B2 JP 59088411 A JP59088411 A JP 59088411A JP 8841184 A JP8841184 A JP 8841184A JP H0314307 B2 JPH0314307 B2 JP H0314307B2
- Authority
- JP
- Japan
- Prior art keywords
- group
- dihydropyridine
- dimethyl
- ester
- substituted
- 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 - Lifetime
Links
- 125000004432 carbon atom Chemical group C* 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 9
- 125000002541 furyl group Chemical group 0.000 claims description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 8
- 125000001624 naphthyl group Chemical group 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
- -1 nitro-substituted phenyl group Chemical group 0.000 claims description 6
- 125000004076 pyridyl group Chemical group 0.000 claims description 6
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 6
- 125000001544 thienyl group Chemical group 0.000 claims description 6
- 229930195734 saturated hydrocarbon Natural products 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 229940085304 dihydropyridine derivative selective calcium channel blockers with mainly vascular effects Drugs 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 125000005309 thioalkoxy group Chemical group 0.000 claims description 2
- 229930195735 unsaturated hydrocarbon Natural products 0.000 claims description 2
- 125000001183 hydrocarbyl group Chemical group 0.000 claims 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 64
- 150000001875 compounds Chemical class 0.000 description 32
- 238000000921 elemental analysis Methods 0.000 description 32
- 238000002844 melting Methods 0.000 description 32
- 230000008018 melting Effects 0.000 description 32
- 150000002148 esters Chemical class 0.000 description 15
- 238000004519 manufacturing process Methods 0.000 description 13
- 238000006243 chemical reaction Methods 0.000 description 8
- 238000000034 method Methods 0.000 description 8
- JPXPPUOCSLMCHK-UHFFFAOYSA-N 5-methoxycarbonyl-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid Chemical compound COC(=O)C1=C(C)NC(C)=C(C(O)=O)C1C1=CC=CC([N+]([O-])=O)=C1 JPXPPUOCSLMCHK-UHFFFAOYSA-N 0.000 description 6
- 230000004531 blood pressure lowering effect Effects 0.000 description 6
- 230000000694 effects Effects 0.000 description 5
- 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 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- 206010020772 Hypertension Diseases 0.000 description 4
- 150000002430 hydrocarbons Chemical group 0.000 description 4
- 230000001077 hypotensive effect Effects 0.000 description 4
- 229960001597 nifedipine Drugs 0.000 description 4
- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical class C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-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
- ZBBHBTPTTSWHBA-UHFFFAOYSA-N Nicardipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN(C)CC=2C=CC=CC=2)C1C1=CC=CC([N+]([O-])=O)=C1 ZBBHBTPTTSWHBA-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 229960001783 nicardipine Drugs 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 230000003276 anti-hypertensive effect Effects 0.000 description 2
- 230000036772 blood pressure Effects 0.000 description 2
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 230000000304 vasodilatating effect Effects 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- KJEBULYHNRNJTE-UHFFFAOYSA-N 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid O3-(2-methoxyethyl) ester O5-(3-phenylprop-2-enyl) ester Chemical compound COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC=CC=2C=CC=CC=2)C1C1=CC=CC([N+]([O-])=O)=C1 KJEBULYHNRNJTE-UHFFFAOYSA-N 0.000 description 1
- QQEOWRHUXVDVJC-UHFFFAOYSA-N 2,6-dimethyl-4-(3-nitrophenyl)-5-propan-2-yloxycarbonyl-1,4-dihydropyridine-3-carboxylic acid Chemical compound CC(C)OC(=O)C1=C(C)NC(C)=C(C(O)=O)C1C1=CC=CC([N+]([O-])=O)=C1 QQEOWRHUXVDVJC-UHFFFAOYSA-N 0.000 description 1
- SGNOPIMYWCJCTF-UHFFFAOYSA-N 3-o-ethyl 5-o-(4-phenylbut-3-en-2-yl) 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound CCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C=CC=2C=CC=CC=2)C1C1=CC=CC([N+]([O-])=O)=C1 SGNOPIMYWCJCTF-UHFFFAOYSA-N 0.000 description 1
- YFKXWATZEKNNNE-UHFFFAOYSA-N 3-o-methyl 5-o-(1-phenylhex-1-en-3-yl) 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound C=1C=CC=CC=1C=CC(CCC)OC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC([N+]([O-])=O)=C1 YFKXWATZEKNNNE-UHFFFAOYSA-N 0.000 description 1
- UQYBBLVCMHECAA-UHFFFAOYSA-N 3-o-methyl 5-o-(2-methyl-4-phenylbut-3-en-2-yl) 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)(C)C=CC=2C=CC=CC=2)C1C1=CC=CC([N+]([O-])=O)=C1 UQYBBLVCMHECAA-UHFFFAOYSA-N 0.000 description 1
- VTGYIDGNWJLDOT-UHFFFAOYSA-N 3-o-methyl 5-o-(3-phenylprop-2-enyl) 2,6-dimethyl-4-(4-methylsulfanylphenyl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OCC=CC=2C=CC=CC=2)C1C1=CC=C(SC)C=C1 VTGYIDGNWJLDOT-UHFFFAOYSA-N 0.000 description 1
- XIHYNBMVKDUNED-UHFFFAOYSA-N 3-o-methyl 5-o-(3-phenylprop-2-enyl) 4-(2-cyanophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OCC=CC=2C=CC=CC=2)C1C1=CC=CC=C1C#N XIHYNBMVKDUNED-UHFFFAOYSA-N 0.000 description 1
- JAKXGEPKVUIGER-UHFFFAOYSA-N 3-o-methyl 5-o-(4-methyl-1-phenylpent-1-en-3-yl) 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC(C=CC=2C=CC=CC=2)C(C)C)C1C1=CC=CC([N+]([O-])=O)=C1 JAKXGEPKVUIGER-UHFFFAOYSA-N 0.000 description 1
- FTVJQPPBOIJVEH-UHFFFAOYSA-N 3-o-methyl 5-o-(4-naphthalen-2-ylbut-3-enyl) 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OCCC=CC=2C=C3C=CC=CC3=CC=2)C1C1=CC=CC([N+]([O-])=O)=C1 FTVJQPPBOIJVEH-UHFFFAOYSA-N 0.000 description 1
- YEDDVNQGOLMSDK-UHFFFAOYSA-N 3-o-methyl 5-o-(4-phenylbut-3-en-2-yl) 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C=CC=2C=CC=CC=2)C1C1=CC=CC([N+]([O-])=O)=C1 YEDDVNQGOLMSDK-UHFFFAOYSA-N 0.000 description 1
- WVJCYCCJJIJHDC-UHFFFAOYSA-N 3-o-methyl 5-o-[2-(2-phenylethylamino)ethyl] 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate;hydrochloride Chemical compound Cl.COC(=O)C1=C(C)NC(C)=C(C(=O)OCCNCCC=2C=CC=CC=2)C1C1=CC=CC([N+]([O-])=O)=C1 WVJCYCCJJIJHDC-UHFFFAOYSA-N 0.000 description 1
- MTLIBDLYSVXMIM-UHFFFAOYSA-N 5-(2-methoxyethoxycarbonyl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid Chemical compound COCCOC(=O)C1=C(C)NC(C)=C(C(O)=O)C1C1=CC=CC([N+]([O-])=O)=C1 MTLIBDLYSVXMIM-UHFFFAOYSA-N 0.000 description 1
- KZLKFNFSRYRTAP-UHFFFAOYSA-N 5-o-(1,3-diphenylprop-2-enyl) 3-o-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC(C=CC=2C=CC=CC=2)C=2C=CC=CC=2)C1C1=CC=CC([N+]([O-])=O)=C1 KZLKFNFSRYRTAP-UHFFFAOYSA-N 0.000 description 1
- UFEICAJTEROYST-UHFFFAOYSA-N 5-o-(2,3-diphenylprop-2-enyl) 3-o-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OCC(=CC=2C=CC=CC=2)C=2C=CC=CC=2)C1C1=CC=CC([N+]([O-])=O)=C1 UFEICAJTEROYST-UHFFFAOYSA-N 0.000 description 1
- IFUSNPKNWGFLHX-UHFFFAOYSA-N 5-o-(4,4-dimethyl-1-phenylpent-1-en-3-yl) 3-o-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC(C=CC=2C=CC=CC=2)C(C)(C)C)C1C1=CC=CC([N+]([O-])=O)=C1 IFUSNPKNWGFLHX-UHFFFAOYSA-N 0.000 description 1
- KSSXFTLQNZRCJY-UHFFFAOYSA-N 5-o-(4,4-diphenylbut-3-enyl) 3-o-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OCCC=C(C=2C=CC=CC=2)C=2C=CC=CC=2)C1C1=CC=CC([N+]([O-])=O)=C1 KSSXFTLQNZRCJY-UHFFFAOYSA-N 0.000 description 1
- 229910015900 BF3 Inorganic materials 0.000 description 1
- LMFHGFATTGOQNO-UHFFFAOYSA-O CC(NC(C)=C(C1C2=CC([N+]([O-])=O)=CC=C2)C(OCC=CC2=C[S+](C)C=C2)=O)=C1C(OC)=O Chemical compound CC(NC(C)=C(C1C2=CC([N+]([O-])=O)=CC=C2)C(OCC=CC2=C[S+](C)C=C2)=O)=C1C(OC)=O LMFHGFATTGOQNO-UHFFFAOYSA-O 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 206010022998 Irritability Diseases 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 241000978776 Senegalia senegal Species 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 229940030600 antihypertensive agent Drugs 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 230000004872 arterial blood pressure Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 210000001198 duodenum Anatomy 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 230000001631 hypertensive effect Effects 0.000 description 1
- 230000005923 long-lasting effect Effects 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
- 150000004702 methyl esters Chemical class 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- XTFPDGZNWTZCMF-UHFFFAOYSA-N pranidipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OCC=CC=2C=CC=CC=2)C1C1=CC=CC([N+]([O-])=O)=C1 XTFPDGZNWTZCMF-UHFFFAOYSA-N 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000011699 spontaneously hypertensive rat Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
Description
〔産業上の利用分野〕
本発明は、すぐれた降圧作用を有する新規な
1,4−ジヒドロピリジン誘導体に関するもので
ある。
〔従来の技術〕
従来、血圧降下作用および冠血管拡張作用を有
する1,4−ジヒドロピリジン誘導体としては、
4−(o−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(米国特許第3644627号:以
下ニフエジピンという)あるいは4−(m−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3−メチル
エステル−5−〔2−(ベンジルメチルアミノ)エ
チル〕エステル塩酸塩(特公昭55−45075:以下
ニカルジピンという)などが医薬品として医療に
用いられている。しかし、これらはいずれも血圧
降下作用の持続時間が短かいという欠点がある。
たとえば、ニフエジピンより持続性の大きいニカ
ルジピンを犬に10μg/Kg静注した場合には、30
〜40分程度持続するにすぎないことが報告されて
いる(Arzneim−Forsch 22巻 33ページ 1976
年;同26巻 2172ページ 1982年;東邦医学会雑
誌26巻 2号 48ージ 1972年)。
〔発明が解決ようとする問題点〕
一般に、高血圧疾患の治療には持続性かつ緩徐
な血圧降下作用を有する薬物が有効であるとされ
ている。従つて、これらの化合物は、高血圧治療
剤として優れた薬剤であるということはできな
い。
〔問題点を解決するための手段〕
本発明者らは、これらの欠点を克服すべく研究
した結果、持続時間の長い血圧降下作用を有し、
しかもその血圧降下作用の最大降圧が遅延して発
現し緩徐な降下作用を有するなど、高血圧治療薬
として優れた特徴を有する一般式()で表わさ
れる1,4−ジヒドロピリジン誘導体を開発する
ことに成功した。
すなわち、本発明は、
一般式〔〕
〔式中、Rは低級アルコキシアルキル基又は炭
素数1〜3を有する直鎖もしくは分岐の飽和炭化
水素残基を表わし、Ar1はフエニル基、ナフチル
基又はフリル基を表わし、該基の水素原子は随時
ハロゲン原子、ニトロ基、シアノ基又はチオアル
コキシ基から選ばれる1個ないし2個の同一又は
相異なる基で置換されていてもよく、Aは炭素数
3〜4を有する直鎖の不飽和炭化水素残基を表わ
し、該基の水素原子は随時フエニル基で置換され
又は該基の一位の炭素原子に結合する水素原子の
少くとも1個が低級アルキル基で置換されていて
もよく、Ar2はフエニル基、ナフチル基、フリル
基、チエニル基、ピロリル基、又はピリジル基か
ら選ばれる1個の基を表わし、該基の水素原子は
随時アルキル基、ニトロ基又はシアノ基から選ば
れる1個又は2個の同一又は相異なる基で置換さ
れていてもよい。ただし、Rが炭素数1〜3を有
する直鎖もしくは分岐の飽和炭化水素残基であつ
て、Ar1がニトロ基置換フエニル基であり、Aが
無置換の炭素数3〜4を有する直鎖の不飽和炭化
水素残基であるときは、Ar2はアルキル基、ニト
ロ基、又はシアノ基から選ばれる1個又は2個の
同一又は相異なる基で置換されたフエニル基、ナ
フチル基、フリル基、チエニル基、ピロリル基又
はピリジル基もしくは無置換のナフチル基、フリ
ル基、チエニル基、ピロリル基又はピリジル基か
ら選ばれる1個の基である〕で表わされる1,4
−ジヒドロピリジン誘導体及びその酸付加塩に関
するものである。
本発明の化合物〔〕はたとえば次に示す方法
により製造することができる。
製造法 1
一般式〔〕
(式中A及びAr2は前記と同義)
で表わされる化合物と一般式〔〕
Ar1−CHO 〔〕
(式中Ar1は前記と同義)
で表わされる化合物及び一般式
(式中Rは前記と同義)
で表わされる化合物とを無溶媒もしくは反応に不
活性な溶媒、例えばメタノール、エタノール、プ
ロパノール、イソプロパノール、ベンゼン、トル
エン、ジオキサン、テトラヒドロフラン、ジメチ
ルスルホキシドまたはジメチルホルムアミド中で
加熱することによつて、〔〕を得ることができ
る。この際、反応温度は50℃〜150℃が好ましく、
反応時間は通常0.5〜15時間で十分である。
製造法 2
一般式〔〕
で表わされる化合物と一般式〔〕で表わされる
化合物及び一般式〔〕
で表わされる化合物とを製造法1と同様の反応条
件下で反応させることによつて、〔〕の化合物
を得ることができる。
製造法 3
一般式
で表わされる化合物と一般式〔〕で表わされる
化合物とを製造法1と同様の反応条件下に反応さ
せる方法。
製造法 4
一般式〔〕で表わされる化合物と一般式
〔〕
で表わされる化合物と製造法1と同様の反応条件
下で反応させる方法。
製造法 5
一般式〔〕で表わされる化合物と一般式
〔〕で表わされる化合物及びアンモニアとを反
応させる方法。
製造法 6
一般式〔〕で表わされる化合物と一般式
〔〕で表わされる化合物及びアンモニアとを製
造法1と同様の反応条件下に反応させる方法。
製造法 7
一般式〔〕
(式中、Zはヒドロキシ基又は活性エステルの
酸残基、例えば、ハロゲン原子、メチルスルホニ
ルオキシ基、パラトルエンスルホニルオキシ基、
1−ベンゾトリアジノオキシ基などを表わす。)
で表わされる化合物と一般式〔〕
HO−A−Ar2 〔〕
で表わされるアルコール類とを反応させる方法。
本反応はZがヒドロキシ基の場合、酸、例えば塩
化水素、硫酸、三フツ化ホウ素などの存在下で行
なうか又は脱水縮合剤例えばジシクロヘキシルカ
ルボジイミドなどの存在下で、所望により4−ジ
メチルアミノピリジンなどの塩基を共存せしめ、
不活性溶媒中で行なうことができる。又、Zが活
性エステル残基の場合には、不活性溶媒中、所望
により塩基、例えばトリエチルアミン、4−ジメ
チルアミノピリジン、ピリジン、炭酸カリウムな
どの存在下で行なうことができる。
製造法 8
一般式〔XI〕
で表わされる化合物と一般式〔XII〕
R−OH 〔XII〕
で表わされる化合物とを製造法9と同様の条件下
で反応させる方法。
〔XI〕の化合物は〔〕の化合物と同様に公知
の方法に依り得ることができる。
このようにして得られた一般式〔〕の化合物
は通常の化学操作によつて単離精製することがで
きる。
〔発明の効果〕
本発明の化合物は強い血管拡張作用及び血圧降
下作用を有し、既知の化合物;たとえば、ニフエ
ジピンに比べ、これらの作用が極めて優れている
と同時にその効力が著しく長く、しかもその血圧
降下作用の最大降圧が遅延して発現し、緩徐な降
圧作用を示すなどの特徴を有し、高血圧治療上極
めて有用な化合物である。
次に、本発明化合物〔〕の代表的な化合物に
ついての薬理試験結果を示す。
〔血圧降下作用〕
本発明の化合物の血圧降下作用及び該作用の持
続時間を無麻酔の自然発症高血圧ラツトを用いて
試験した。
被検化合物を5%アラビアゴム懸濁液とし予め
挿入したカニユーレを介して十二指腸内に投与
し、ラツトの尾動脈圧及び降圧効果の持続時間を
ひずみ圧力計(AP−620G、日本光電社製)を用
いて観血的に測定し、レチグラフ(8K、日本電
子三栄社製)で記録した。投与量は全化合物1
mg/Kgに統一した。
その結果を、下表に示た。
血圧降下作用は、被検化合物投与の前後におけ
る平均血圧の差で、持続時間は半減期で代用し、
分単位で表示した。さらに、最大降圧到達時間も
併せて表記した。
なお同表には、比較のため、前記と同様に試験
した、ニフエジピン及びニカルジピンの結果を併
記した。
[Industrial Application Field] The present invention relates to a novel 1,4-dihydropyridine derivative having excellent hypotensive action. [Prior Art] Conventionally, 1,4-dihydropyridine derivatives having antihypertensive and coronary vasodilating effects include:
4-(o-nitrophenyl)-2,6-dimethyl-
1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester (US Pat. No. 3,644,627; hereinafter referred to as nifedipine) or 4-(m-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5- Dicarboxylic acid 3-methyl ester-5-[2-(benzylmethylamino)ethyl] ester hydrochloride (Japanese Patent Publication No. 55-45075; hereinafter referred to as nicardipine) is used medically as a drug. However, all of these have the disadvantage that the duration of their blood pressure lowering effect is short.
For example, if nicardipine, which is longer-lasting than nifedipine, is administered intravenously to a dog at 10 μg/Kg, 30
It has been reported that it lasts only about 40 minutes (Arzneim-Forsch vol. 22 p. 33 1976)
26th volume, 2172 pages, 1982; Journal of the Toho Medical Society, vol. 26, no. 2, page 48, 1972). [Problems to be Solved by the Invention] It is generally believed that drugs having a sustained and slow blood pressure lowering effect are effective in treating hypertensive diseases. Therefore, these compounds cannot be said to be excellent antihypertensive agents. [Means for Solving the Problems] As a result of research to overcome these drawbacks, the present inventors have found that the present inventors have a long-lasting blood pressure lowering effect,
Furthermore, we succeeded in developing a 1,4-dihydropyridine derivative represented by the general formula () that has excellent characteristics as a hypertension treatment drug, such as its maximum blood pressure lowering effect occurring with a delay and slow lowering effect. did. That is, the present invention is based on the general formula [] [In the formula, R represents a lower alkoxyalkyl group or a linear or branched saturated hydrocarbon residue having 1 to 3 carbon atoms, Ar 1 represents a phenyl group, a naphthyl group, or a furyl group, and the hydrogen atom of the group may be optionally substituted with one or two same or different groups selected from a halogen atom, a nitro group, a cyano group, or a thioalkoxy group, and A is a linear unsaturated group having 3 to 4 carbon atoms. represents a hydrocarbon residue, the hydrogen atom of the group may optionally be substituted with a phenyl group, or at least one of the hydrogen atoms bonded to the first carbon atom of the group may be substituted with a lower alkyl group, Ar 2 represents one group selected from a phenyl group, a naphthyl group, a furyl group, a thienyl group, a pyrrolyl group, or a pyridyl group, and the hydrogen atom of the group is optionally selected from an alkyl group, a nitro group, or a cyano group. may be substituted with one or two identical or different groups. However, R is a straight chain or branched saturated hydrocarbon residue having 1 to 3 carbon atoms, Ar 1 is a nitro-substituted phenyl group, and A is an unsubstituted straight chain having 3 to 4 carbon atoms. When it is an unsaturated hydrocarbon residue, Ar2 is a phenyl group, a naphthyl group, a furyl group substituted with one or two same or different groups selected from an alkyl group, a nitro group, or a cyano group. , thienyl group, pyrrolyl group, pyridyl group, or one group selected from unsubstituted naphthyl group, furyl group, thienyl group, pyrrolyl group, or pyridyl group]
- dihydropyridine derivatives and acid addition salts thereof. The compound [] of the present invention can be produced, for example, by the method shown below. Manufacturing method 1 General formula [] (In the formula, A and Ar 2 have the same meanings as above) Compounds represented by the general formula [] Ar 1 -CHO [] (In the formula, Ar 1 has the same meanings as above) and the general formula (In the formula, R has the same meaning as above) and is heated in a solvent free or inert to the reaction, such as methanol, ethanol, propanol, isopropanol, benzene, toluene, dioxane, tetrahydrofuran, dimethyl sulfoxide or dimethyl formamide. By doing so, you can obtain [ ]. At this time, the reaction temperature is preferably 50°C to 150°C,
A reaction time of 0.5 to 15 hours is usually sufficient. Manufacturing method 2 General formula [] A compound represented by a compound represented by the general formula [] and a compound represented by the general formula [] The compound [ ] can be obtained by reacting the compound represented by [ ] under the same reaction conditions as in Production Method 1. Manufacturing method 3 General formula A method of reacting a compound represented by the formula [] with a compound represented by the general formula [] under the same reaction conditions as in Production Method 1. Production method 4 Compound represented by general formula [] and general formula [] A method in which a compound represented by is reacted under the same reaction conditions as in Production Method 1. Production method 5 A method of reacting a compound represented by the general formula [] with a compound represented by the general formula [] and ammonia. Production method 6 A method of reacting a compound represented by general formula [] with a compound represented by general formula [] and ammonia under the same reaction conditions as in production method 1. Manufacturing method 7 General formula [] (In the formula, Z is a hydroxy group or an acid residue of an active ester, such as a halogen atom, a methylsulfonyloxy group, a para-toluenesulfonyloxy group,
Represents a 1-benzotriazinooxy group, etc. ) A method of reacting a compound represented by the following with an alcohol represented by the general formula [] HO-A-Ar 2 [].
When Z is a hydroxy group, this reaction is carried out in the presence of an acid such as hydrogen chloride, sulfuric acid, boron trifluoride, etc., or in the presence of a dehydration condensation agent such as dicyclohexylcarbodiimide, and optionally 4-dimethylaminopyridine. bases coexist,
It can be carried out in an inert solvent. When Z is an active ester residue, the reaction can be carried out in an inert solvent in the presence of a base, such as triethylamine, 4-dimethylaminopyridine, pyridine, potassium carbonate, etc., if desired. Manufacturing method 8 General formula [XI] A method of reacting a compound represented by the formula [XII] with a compound represented by the general formula [XII] R-OH [XII] under the same conditions as in Production Method 9. Compound [XI] can be obtained by known methods in the same manner as compound []. The compound of the general formula [] thus obtained can be isolated and purified by conventional chemical operations. [Effects of the Invention] The compound of the present invention has strong vasodilatory and antihypertensive effects, and is extremely superior in these effects to known compounds such as nifedipine. It is an extremely useful compound in the treatment of hypertension, as it has the characteristics of a delayed maximum blood pressure lowering effect and a gradual hypotensive effect. Next, pharmacological test results for representative compounds of the present invention [] will be shown. [Hypertensive lowering effect] The blood pressure lowering effect of the compounds of the present invention and the duration of this effect were tested using unanesthetized spontaneously hypertensive rats. The test compound was made into a 5% suspension of gum arabic and administered into the duodenum through a cannula inserted in advance, and the tail artery pressure of rats and the duration of the hypotensive effect were measured using a strain pressure meter (AP-620G, manufactured by Nihon Kohden). It was measured invasively using a camera, and recorded using a retigraph (8K, manufactured by JEOL Sanei Co., Ltd.). Dosage is 1 for all compounds
Standardized to mg/Kg. The results are shown in the table below. The hypotensive effect is the difference in average blood pressure before and after administration of the test compound, and the duration is substituted by the half-life.
Displayed in minutes. Furthermore, the time to reach the maximum blood pressure drop is also indicated. For comparison, the same table also shows the results of nifedipine and nicardipine, which were tested in the same manner as above.
【表】【table】
以下の実施例の化合物は、原料及び試薬を適宜
変えて、後記する参考例とほぼ同様の条件下で操
作して製造した。
実施例 1
4−(4−メチルチオフエニル)−2,6−ジ
メチル−1,4−ジヒドロピリジン−3,5−
ジカルボン酸3−メチルエステル5−シンナミ
ルエステル
融点 164.2〜170.8℃
元素分析値 C26H27NO4S
計算値(%) C:69.46,H:6.05,N:3.12
実測値(%) C:69.51,H:5.94,N:3.07
IR(cm-1) νNH3330,νCO1680
NMR δCDCl3 2.26(s,3H)2.28(s,3H)2.35
(s,3H)
3.61(s,3H)4.6〜4.82(m,2H)
500(s,1H)5.87〜6.69(m,2H)
6.17(s,1H)6.7〜7.8(m,9H)
実施例 2
4−(2−シアノフエニル)−2,6−ジメチ
ル−1,4−ジヒドロピリジン−3,5−ジカ
ルボン酸3−メチルエステル5−シンナミルエ
ステル
融点 油状
元素分析値 C26H24N2O4
計算値(%) C:72.88,H:5.65,N:6.54
実測値(%) C:72.75,H:5.79,N:6.48
IR(cm-1) νNH3330,νCN2230,νCO1700
NMR δCDCl3 2.32(s,6H),3.61(s,3H),
4.56〜4.86(m,2H),5.35(s,1H),
5.9〜6.3(m,2H),6.74(s,1H),
6.94〜7.62(m,9H)
実施例 3
4−(3−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3−メチルエステル−5−(1−t−
ブチル−3−フエニル−2−プロペニル)エス
テル
融点 166.5〜168℃
元素分析値 C29H32N2O6
計算値(%) C:69.03,H:6.39,N:5.55
実測値(%) C:69.06,H:6.43,N:5.51
IR(cm-1) νNH3340,νCO1700,1670,
νNO21530,1350
NMR δCDCl3 1.00(s,9H),2.34(s,6H),
3.62(s,3H)
5.10(m,1H),5.18(s,1H)
5.9〜6.6(m,3H),7.1〜8.2(m,9H)
実施例 4
4−(3−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3−メチルエステル−5−〔3−(2−
フリール)−2−プロペニル)エステル
融点 157〜159.5℃
元素分析値 C23H22N2O7
計算値(%) C:63.01,H:5.06,N:6.39
実測値(%) C:63.05,H:5.01,N:6.36
IR(cm-1) νNH3320,νCO1680,νNO21530,
1350
NMR δCDCl3 2.34(s,6H),3.62(s,3H),
4.64(d,2H)
5.12(s,1H)6.20(m,5H)
7.1〜8.1(m,5H)
実施例 5
4−(3−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3−メチルエステル−5−(1−イソ
プロピル−3−フエニル−2−プロペニル)エ
ステル
融点 油状
元素分析値 C28H30N2O6
計算値(%) C:68.56,H:6.16,N:5.71
実測値(%) C:68.58,H:6.13,N:5.69
IR(cm-1) νNH3320,νCO1680,νNO21530,
1350
NMR δCDCl3 1.00(d,6H),2.36(s,6H)
3.64(s,3H),5.16(s,1H),5.18
(m,1H)
5.9〜6.8(m,3H),7.0〜8.2(m,9H)
実施例 6
4−(3−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3−メチルエステル5−(3,3−ジ
フエニル−2−プロペニル)エステル
融点 油状
元素分析値 C31H28N2O6
計算値(%) C:70.97,H:5.38,N:5.34
実測値(%) C:71.04,H:5.32,N:5.28
IR(cm-1) νNH3330,νCO1705,νNO21530,
1350
NMR δCDCl3 2.30(s,6H),3.61(s,3H),
4.57(d,2H)
5.10(s,1H),5.90(d,1H)
6.9〜8.05(m,14H),6.18(s,1H)
実施例 7
4−(3−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3−メチルエステル5−(1−プロピ
ル−3−フエニル−2−プロペニル)エステル
融点 油状
元素分析値 C28H30N2O6
計算値(%) C:68.56,H:6.18,N:5.71
実測値(%) C:68.60,H:6.12,N:5.68
IR(cm-1) νNH3330,νCO1680,νNO21530,
1350
NMR δCDCl3 0.7〜2.0(m,7H),2.32(s,6H),
3.60(s,3H),5.10(s,1H),5.35
(m,1H),
5.9〜6.8(m,3H),7.1〜8.2(m,9H)
実施例 8
4−(3−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3−メチルエステル5−(4−α−チ
エニル−3−ブテニル)エステル
融点 油状
元素分析値 C24H24N2O6S
計算値(%) C:61.53,H:5.16,N:5.98
実測値(%) C:61.57,H:5.13,N:5.79
IR(cm-1) νNH3330,νCO1690,νNO21530,
1350
NMR δCDCl3 2.33(s,6H),2.52(t,2H),
3.58(s,3H)
4.16(t,3H),5.11(s,1H)
5.5〜8.1(m,8H)
実施例 9
4−(3−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3−メチルエステル5−(4−β−ナ
フチル−3−ブテニル)エステル
融点 151.4〜153.0℃
元素分析値 C30H28N2O6
計算値(%) C:70.30,H:5.51,N:5.47
実測値(%) C:70.34,H:5.47,N:5.42
IR(cm-1) νNH3370,νCO1700,1660,
νNO21535,1355
NMR δCDCl3 2.30(s,6H),2.4〜2.8(m,2H),
3.52(d,3H),4.0〜4.35(m,2H),
5.10(s,1H),5.7〜8.15(m,14H),
実施例 10
4−(3−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3−(2−メトキシエチル)エステル
5−シンナミルエステル
融点 115.5〜116.5℃
元素分析値 C27H28N2O7
計算値(%) C:65.84,H:5.73,N:5.69
実測値(%) C:65.88,H:5.70,N:5.66
IR(cm-1) νNH3380,νCO1710,1680,
νNO21530,1350
NMR δCDCl3 2.34(s,6H),3.25(s,3H),
3.50(t,2H)
4.15(t,2H),4.68(d,2H),5.15
(s,1H)
5.9〜6.9(m,3H),7.1〜8.2(m,9H)
実施例 11
4−(3−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3−メチルエステル5−〔4−(4−シ
アノフエニル)−3−ブテニル)エステル
融点 161.3〜164.8℃
元素分析値 C27H25N3O6
計算値(%) C:66.52,H:5.17,N:8.62
実測値(%) C:66.50,H:5.19,N:8.59
IR(cm-1) νNH3330,νCO1690,νNO21530,
1350
NMR δCDCl3 2.35(s,6H),2.58(t,2H)3.58
(s,3H)
4.20(t,2H),5.08(s,1H),
6.15〜6.40(m,3H),7.2〜8.1(m,
8H)
実施例 12
4−(3−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3−メチルエステル−5−〔4−(N−
メチル−2−ピロリル)−3−ブテニル)エス
テル
融点 油状
元素分析値 C25H27N3O6
計算値(%) C:64.51,H:5.85,N:9.03
実測値(%) C:64.58,H:5.80,N:8.97
IR(cm-1) νNH3330,νCO1690,νNO21530,
1350
NMR δCDCl3 2.30(s,6H),2.60(m,2H)3.53
(s,3H)
3.60(s,3H),4.15(t,2H),5.06
(s,1H)
5.1〜6.6(m,6H),7.1〜8.1(m,4H)
実施例 13
4−(3−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3−メチルエステル5−〔4−(p−メ
チルフエニル)−3−3−ブテニル)エステル
融点 油状
元素分析値 C27H28N2O6
計算値(%) C:68.05,H:5.92,N:5.88
実測値(%) C:68.11,H:5.83,N:5.82
IR(cm-1) νNH3330,νCO1690,νNO21530,
1350
NMR δCDCl3 2.30(d,9H),2.52(t,2H),
3.55(s,3H)
4.13(t,2H),5.07(s,1H)
6.0〜8.1(m,11H)
実施例 14
4−(3−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3−メチルエステル5−〔4−(p−ニ
トロフエニル)−3−ブテニル〕エステル
融点 111〜113.5℃
元素分析値 C26H25N3O8
計算値(%) C:61.53,H:4.97,N:8.28
実測値(%) C:61.59,H:4.79,N:8.16
IR(cm-1) νNH3340,νCO1690,1650,
νNO21525,1350
NMR δCDCl3 2.32(s,6H),2.65(m,2H),
3.60(s,3H)
4.15(m,2H),5.04(s,1H),
5.5〜6.6(m,3H),7.1〜8.2(m,8H)
実施例 15
4−(3−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3−メチルエステル5−(1,1−ジ
メチル−3−フエニル−2−プロペニル)エス
テル
融点 油状
元素分析値 C27H28N2O6
計算値(%) C:68.05,H:5.92,N:5.88
実測値(%) C:68.10,H:5.88,N:5.83
IR(cm-1) νNH3330,νCO1690,νNO21530,
1350
NMR δCDCl3 1.60(d,6H),2.30(s,6H),
3.51(s,3H)
5.05(s,1H),5.98(s,1H),6.30
(s,2H)
7.1〜8.2(m,9H)
実施例 16
4−(3−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3−メチルエステル5−(4−エチル
−3−フエニル−2−プロペニル)エステル
融点 油状
元素分析値 C27H28N2O6
計算値(%) C:68.05,H:5.92,N:5.88
実測値(%) C:68.09,H:5.90,N:5.85
IR(cm-1) νNH3330,νCO1690,νNO21530,
1350
NMR δCDCl3 1.83(m,3H),1.70(q,2H),
2.30(d,6H)
3.59(s,3H),5.09(s,1H),5.30
(t,1H)
5.8〜6.6(m,3H),7.0〜8.1(m,9H)
実施例 17
4−(3−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3−メチルエステル5−(4−(3−チ
エニル)−3−ブテニル)エステル
融点 122.1〜127.7℃
元素分析値 C24H24N2O6
計算値(%) C:61.53,H:5.16,N:5.98
実測値(%) C:61.55,H:5.13,N:5.89
IR(cm-1) νNH3340,νCO1690,νNO21530,
1350
NMR δCDCl3 2.30(s,6H),2.4〜2.8(m,2H),
3.57(d,3H),4.12(t,2H),5.07
(s,1H)
5.2〜8.1(m,10H)
実施例 18
4−(3−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3−メチルエステル5−(1,3−ジ
フエニル−2−プロペニル)エステル
融点 431〜145.5℃
元素分析値 C31H28N2O6
計算値(%) C:70.97,H:5.38,N:5.34
実測値(%) C:70.94,H:5.49,N:5.32
IR(cm-1) νNH3380,νCO1695,νNO21525,
1350
NMR δCDCl3 2.26(s,6H),3.60(s,3H),
5.16(s,1H)
6.2〜6.5(m,4H),7.0〜8.2(m,
14H)
実施例 19
4−(3−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3−メチルエステル5−〔4−(2−ピ
リジル)−3−ブテニル)エステル
融点 油状
元素分析値 C25H25N3O6
計算値(%) C:64.79,H:5.44,N:9.07
実測値(%) C:64.85,H:5.39,N:9.06
IR(cm-1) νNH3330,νCO1700,νNO21530,
1350
NMR δCDCl3 2.31(s,6H),2.60(t,2H),
3.57(s,3H)
4.20(t,2H),5.09(s,1H)
6.4〜8.6(m,9H)
実施例 20
4−(3−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3−メチルエステル5−〔3−(2−ナ
フチル)−2−プロペニル)エステル
融点 149.4〜154.3℃
元素分析値 C29H26N2O6
計算値(%) C:69.87,H:5.26,N:5.62
実測値(%) C:69.99,H:5.22,N:5.57
IR(cm-1) νNH3330,νCO1700,νNO21530,
1350
NMR δCDCl3 2.30(s,3H),2.34(s,3H),
3.60(s,3H)
4.74(d,2H),5.15(s,1H)
6.0〜6.85(m,3H),7.1〜8.2(m,
11H)
実施例 21
4−(3−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3−メチルエステル5−(1−メチル
−3−フエニル−2−プロペニル)エステル
元素分析値 C26H26N2O6
融点 油状
計算値(%) C:67.52,H:5.67,N:6.06
実測値(%) C:67.71,H:5.66,N:6.01
IR(cm-1) νNH3330,νCO1690,νNO21530,
1350
NMR δCDCl3 1.35(m,3H),2.30(s,6H),
3.60(s,3H)
5.12(s,1H),5.45(m,1H)
6.0〜6.8(m,3H),7.1〜8.2(m,9H)
実施例 22
4−(3−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3−エチルエステル5−(1−メチル
−3−フエニル−2−プロペニル)エステル
融点 油状
元素分析値 C27H28N2O6
計算値(%) C:68.05,H:5.92,N:5.88
実測値(%) C:68.11,H:5.88,N:5.83
IR(cm-1) νNH3330,νCO1690,νNO21530,
1350
NMR δCDCl3 1.25(d,3H),1.26(q,3H),
2.30(s,6H)
4.05(q,2H),5.08(s,1H),5.37
(q,1H)
5.9〜6.7(m,3H),7.0〜8.15(m,
9H)
実施例 23
4−(3−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3−イソプロピルエステル5−(1−
メニル−3−フエニル−2−プロペニル))エ
ステル
融点 油状
元素分析値 C28H30N2O6
計算値(%) C:68.56,H:6.16,N:5.71
実測値(%) C:68.60,H:6.14,N:5
IR(cm-1) νNH3330,νCO1690,νNO21530,
1350
NMR δCDCl3 1.10(d,3H),1.25(d,6H),
2.32(s,6H)
4.7〜5.2(m,1H),5.10(s,1H)
5.40(q,1H),5.9〜6.7(m,3H)
7.1〜8.2(m,9H)
実施例 24
4−(3−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3−メチルエステル5−(1−メチル
−3−フリル−2−プロペニル)エステル
融点 油状
元素分析値 C24H24N2O7
計算値(%) C:63.71,H:5.35,N:6.19
実測値(%) C:63.07,H:5.24,N:6.11
IR(cm-1) νNH3330,νCO1680,νNO21530,
1350
NMR δCDCl3 1.33(dd,3H),2.33(s,6H),
3.62(s,3H)
5.11(s,1H),5.23〜5.73(m,1H),
5.73〜6.60(m,5H),7.22〜8.23(m,
5H)
実施例 25
4−(3−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3−(2−メトキシエチル)エステル
5−(1−メチル−3−フエニル−2−プロペ
ニル)エステル
融点 油状
元素分析値 C28H30N2O7
計算値(%) C:66.39,H:5.97,N:5.53
実測値(%) C:66.44,H:5.92,N:5.47
IR(cm-1) νNH3330,νCO1690,νNO21530,
1350
NMR δCDCl3 1.30(d,3H),2.30(s,6H),
3.29(d,3H)
3.48(t,2H),4.15(t,2H),5.10
(s,1H)
5.50(q,1H),5.9〜6.7(m,3H),
7.05〜8.15(,9H)
実施例 26
4−(3−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3−メチルエステル5−(2,3−ジ
フエニル−2−プロペニル)エステル
融点 油状
元素分析値 C31H58N2O6
計算値(%) C:70.98,H:5.38,N:5.34
実測値(%) C:71.03,H:5.37,N:5.30
IR(cm-1) νNH3330,νCO1690,νNO21530,
1350
NMR δCDCl3 2.23(s,3H),2.29(s,3H),
3.60(s,3H)
4.89(s,2H),5.02(s,1H),6.30
(s,1H)
6.50(s,1H),6.7〜8.05(m,15H)
実施例 27
4−(3−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3−メチルエステル5−(1−メチル
−3−チエニル−2−プロペニル)エステル
融点 油状
元素分析値 C24H24N2O6
計算値(%) C:61.53,H:5.16,N:5.98
実測値(%) C:61.55,H:5.08,N:5.79
IR(cm-1) νNH3330,νCO1680,νNO21525,
1345
NMR δCDCl3 1.37(dd,3H),2.33(s,6H),
3.62(s,3H)
5.11(s,1H),5.23〜5.76(m,1H)
6.48(s,1H),5.78〜8.18(m,9H)
実施例 28
4−(2−フリール)−2,6−ジメチル−
1,4−ジヒドロピリジン−3,5−ジカルボ
ン酸3−メチルエステル5−シンナミルエステ
ル
融点 油状
元素分析値 C23H23NO5
計算値(%) C:70.21,H:5.89,N:3.56
実測値(%) C:70.27,H:5.84,N:3.50
IR(cm-1) νNH3340,νCO1690
NMR δCDCl3 2.28(s,6H),3.65(s,3H),
4.75(dd,2H)
5.23(s,1H),5.88〜6.60(m,5H),
7.1〜7.4(m,6H)
実施例 29
4−(2−ナフチル)−2,6−ジメチル−
1,4−ジヒドロピリジン−3,5−ジカルボ
ン酸3−メチルエステル5−シンナミルエステ
ル
融点 油状
元素分析値 C29H27NO4
計算値(%) C:76.80,H:6.00,N:3.09
実測値(%) C:76.92,H:5.88,N:3.01
IR(cm-1) νNH3330,νCO1690
NMR δCDCl3 2.23(s,3H),3.54(s,3H)
4.65(dd,2H),5.20(s,1H),
6.0〜6.6(m,3H),7.0〜7.8(m,
12H)
実施例 30
4−(3−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3−メチルエステル5−(4,4−ジ
フエル−3−ブテニル)エステル
融点 油状
元素分析値 C32H30N2O6
計算値(%) C:71.36,H:5.61,N:5.20
実測値(%) C:71.42,H:5.53,N:5.12
IR(cm-1) νNH3330,νCO1690,νNO21530,
1350
NMR δCDCl3 2.31(s,6H),2.48(m,2H),
3.59(s,3H)
4.10(t,2H),5.10(s,1H),5.83
(t,1H)
6.18(s,1H),7.03〜8.10(m,14H)
実施例 31
4−(2−フルオロフエニル)−2,6−ジメ
チル−1,4−ジヒドロピリジン−3,5−ジ
カルボン酸3メチルエステル5−シンナミルエ
ステル
融点 89.5℃
元素分析値 C25H24FNO4
計算値(%) C:71.25,H:5.74,N:3.32
実測値(%) C:71.29,H:5.70,N:3.28
IR(cm-1) νNH3340,νCO1695
NMR δCDCl3 2.62(s,6H),3.56(s,3H),
4.54〜4.78(m,2H),5.28(s,1H)
6.14(s,1H),6.06〜7.76(m,11H)
参考例
4−(3−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3−メチルエステル5−シンナミルエ
ステルの合成
2−(3−ニトロベンジリデン)アセト酢酸シ
ンナミルエステル3.15g(10mM)及び3−アミ
ノクロトン酸メチル1.38g(12mM)の混合物を
120℃で3時間反応後シリカゲルカラムクロマト
グラフイーで精製し、標記化合物3.00g(収率67
%)を得た。
融点 101〜102℃
元素分析値 C25H24N2O6
計算値(%) C:66.95,H:5.39,N:6.25
実測値(%) C:67.03,H:5.31,N:6.20
NMR δCDCl3 2.34(s,6H),3.60(s,3H),
4.69(d,2H),5.13(s,1H),
5.9〜6.7(m,3H),
7.0〜8.1(m,9H)
The compounds of the following examples were produced by changing the raw materials and reagents as appropriate and operating under substantially the same conditions as in the reference examples described later. Example 1 4-(4-methylthiophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-
Dicarboxylic acid 3-methyl ester 5-cinnamyl ester Melting point 164.2-170.8℃ Elemental analysis value C 26 H 27 NO 4 S Calculated value (%) C: 69.46, H: 6.05, N: 3.12 Actual value (%) C: 69.51 , H: 5.94, N: 3.07 IR (cm -1 ) νNH3330, νCO1680 NMR δ CDCl3 2.26 (s, 3H) 2.28 (s, 3H) 2.35
(s, 3H) 3.61 (s, 3H) 4.6 to 4.82 (m, 2H) 500 (s, 1H) 5.87 to 6.69 (m, 2H) 6.17 (s, 1H) 6.7 to 7.8 (m, 9H) Example 2 4-(2-Cyanophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid 3-methyl ester 5-cinnamyl ester Melting point Oil elemental analysis value C 26 H 24 N 2 O 4 Calculated value (%) C: 72.88, H: 5.65, N: 6.54 Actual value (%) C: 72.75, H: 5.79, N: 6.48 IR (cm -1 ) νNH3330, νCN2230, νCO1700 NMR δ CDCl3 2.32 (s, 6H) , 3.61 (s, 3H), 4.56-4.86 (m, 2H), 5.35 (s, 1H), 5.9-6.3 (m, 2H), 6.74 (s, 1H), 6.94-7.62 (m, 9H) Examples 3 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid 3-methyl ester-5-(1-t-
Butyl-3-phenyl-2-propenyl) ester melting point 166.5-168℃ Elemental analysis value C 29 H 32 N 2 O 6 Calculated value (%) C: 69.03, H: 6.39, N: 5.55 Actual value (%) C: 69.06, H: 6.43, N: 5.51 IR (cm -1 ) νNH3340, νCO1700, 1670,
νNO 2 1530, 1350 NMR δ CDCl3 1.00 (s, 9H), 2.34 (s, 6H),
3.62 (s, 3H) 5.10 (m, 1H), 5.18 (s, 1H) 5.9-6.6 (m, 3H), 7.1-8.2 (m, 9H) Example 4 4-(3-nitrophenyl)-2,6 -dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid 3-methyl ester -5-[3-(2-
Freel)-2-propenyl) ester Melting point 157-159.5℃ Elemental analysis value C 23 H 22 N 2 O 7 Calculated value (%) C: 63.01, H: 5.06, N: 6.39 Actual value (%) C: 63.05, H :5.01, N:6.36 IR (cm -1 ) νNH3320, νCO1680, νNO 2 1530,
1350 NMR δ CDCl3 2.34 (s, 6H), 3.62 (s, 3H),
4.64 (d, 2H) 5.12 (s, 1H) 6.20 (m, 5H) 7.1-8.1 (m, 5H) Example 5 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3 ,5-dicarboxylic acid 3-methyl ester-5-(1-isopropyl-3-phenyl-2-propenyl) ester melting point Oil elemental analysis value C 28 H 30 N 2 O 6 calculated value (%) C: 68.56, H: 6.16, N: 5.71 Actual value (%) C: 68.58, H: 6.13, N: 5.69 IR (cm -1 ) νNH3320, νCO1680, νNO 2 1530,
1350 NMR δ CDCl3 1.00 (d, 6H), 2.36 (s, 6H) 3.64 (s, 3H), 5.16 (s, 1H), 5.18
(m, 1H) 5.9-6.8 (m, 3H), 7.0-8.2 (m, 9H) Example 6 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarbonate Acid 3-methyl ester 5-(3,3-diphenyl-2-propenyl) ester Melting point Oil elemental analysis value C 31 H 28 N 2 O 6 Calculated value (%) C: 70.97, H: 5.38, N: 5.34 Actual value (%) C: 71.04, H: 5.32, N: 5.28 IR (cm -1 ) νNH3330, νCO1705, νNO 2 1530,
1350 NMR δ CDCl3 2.30 (s, 6H), 3.61 (s, 3H),
4.57 (d, 2H) 5.10 (s, 1H), 5.90 (d, 1H) 6.9-8.05 (m, 14H), 6.18 (s, 1H) Example 7 4-(3-nitrophenyl)-2,6-dimethyl -1,4-dihydropyridine-3,5-dicarboxylic acid 3-methyl ester 5-(1-propyl-3-phenyl-2-propenyl) ester Melting point Oil elemental analysis value C 28 H 30 N 2 O 6 Calculated value (% ) C: 68.56, H: 6.18, N: 5.71 Actual value (%) C: 68.60, H: 6.12, N: 5.68 IR (cm -1 ) νNH3330, νCO1680, νNO 2 1530,
1350 NMR δ CDCl3 0.7-2.0 (m, 7H), 2.32 (s, 6H), 3.60 (s, 3H), 5.10 (s, 1H), 5.35
(m, 1H), 5.9-6.8 (m, 3H), 7.1-8.2 (m, 9H) Example 8 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5- Dicarboxylic acid 3-methyl ester 5-(4-α-thienyl-3-butenyl) ester melting point Oil elemental analysis value C 24 H 24 N 2 O 6 S Calculated value (%) C: 61.53, H: 5.16, N: 5.98 Actual value (%) C: 61.57, H: 5.13, N: 5.79 IR (cm -1 ) νNH3330, νCO1690, νNO 2 1530,
1350 NMR δ CDCl3 2.33 (s, 6H), 2.52 (t, 2H),
3.58 (s, 3H) 4.16 (t, 3H), 5.11 (s, 1H) 5.5-8.1 (m, 8H) Example 9 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine- 3,5-Dicarboxylic acid 3-methyl ester 5-(4-β-naphthyl-3-butenyl) ester Melting point 151.4-153.0℃ Elemental analysis value C 30 H 28 N 2 O 6 Calculated value (%) C: 70.30, H : 5.51, N: 5.47 Actual value (%) C: 70.34, H: 5.47, N: 5.42 IR (cm -1 ) νNH3370, νCO1700, 1660,
νNO 2 1535, 1355 NMR δ CDCl3 2.30 (s, 6H), 2.4 ~ 2.8 (m, 2H), 3.52 (d, 3H), 4.0 ~ 4.35 (m, 2H), 5.10 (s, 1H), 5.7 ~ 8.15 (m, 14H), Example 10 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid 3-(2-methoxyethyl) ester 5-cinnamyl ester melting point 115.5-116.5℃ Elemental analysis value C 27 H 28 N 2 O 7 Calculated value (%) C: 65.84, H: 5.73, N: 5.69 Actual value (%) C: 65.88, H: 5.70, N: 5.66 IR (cm -1 ) νNH3380, νCO1710, 1680,
νNO 2 1530, 1350 NMR δ CDCl3 2.34 (s, 6H), 3.25 (s, 3H),
3.50 (t, 2H) 4.15 (t, 2H), 4.68 (d, 2H), 5.15
(s, 1H) 5.9-6.9 (m, 3H), 7.1-8.2 (m, 9H) Example 11 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarvone Acid 3-methyl ester 5-[4-(4-cyanophenyl)-3-butenyl) ester Melting point 161.3-164.8℃ Elemental analysis value C 27 H 25 N 3 O 6 Calculated value (%) C: 66.52, H: 5.17, N: 8.62 Actual value (%) C: 66.50, H: 5.19, N: 8.59 IR (cm -1 ) νNH3330, νCO1690, νNO 2 1530,
1350 NMR δ CDCl3 2.35 (s, 6H), 2.58 (t, 2H) 3.58
(s, 3H) 4.20 (t, 2H), 5.08 (s, 1H), 6.15~6.40 (m, 3H), 7.2~8.1 (m,
8H) Example 12 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid 3-methyl ester-5-[4-(N-
Methyl-2-pyrrolyl)-3-butenyl) ester melting point Oil elemental analysis value C 25 H 27 N 3 O 6 Calculated value (%) C: 64.51, H: 5.85, N: 9.03 Actual value (%) C: 64.58, H:5.80, N:8.97 IR (cm -1 ) νNH3330, νCO1690, νNO 2 1530,
1350 NMR δ CDCl3 2.30 (s, 6H), 2.60 (m, 2H) 3.53
(s, 3H) 3.60 (s, 3H), 4.15 (t, 2H), 5.06
(s, 1H) 5.1-6.6 (m, 6H), 7.1-8.1 (m, 4H) Example 13 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarvone Acid 3-methyl ester 5-[4-(p-methylphenyl)-3-3-butenyl) ester Melting point Oil elemental analysis value C 27 H 28 N 2 O 6 Calculated value (%) C: 68.05, H: 5.92, N :5.88 Actual value (%) C: 68.11, H: 5.83, N: 5.82 IR (cm -1 ) νNH3330, νCO1690, νNO 2 1530,
1350 NMR δ CDCl3 2.30 (d, 9H), 2.52 (t, 2H),
3.55 (s, 3H) 4.13 (t, 2H), 5.07 (s, 1H) 6.0-8.1 (m, 11H) Example 14 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine- 3,5-Dicarboxylic acid 3-methyl ester 5-[4-(p-nitrophenyl)-3-butenyl] ester Melting point 111-113.5℃ Elemental analysis value C 26 H 25 N 3 O 8 Calculated value (%) C: 61.53 , H: 4.97, N: 8.28 Actual value (%) C: 61.59, H: 4.79, N: 8.16 IR (cm -1 ) νNH3340, νCO1690, 1650,
νNO 2 1525, 1350 NMR δ CDCl3 2.32 (s, 6H), 2.65 (m, 2H),
3.60 (s, 3H) 4.15 (m, 2H), 5.04 (s, 1H), 5.5-6.6 (m, 3H), 7.1-8.2 (m, 8H) Example 15 4-(3-nitrophenyl)-2, 6-Dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid 3-methyl ester 5-(1,1-dimethyl-3-phenyl-2-propenyl) ester Melting point Oil elemental analysis value C 27 H 28 N 2 O 6 Calculated value (%) C: 68.05, H: 5.92, N: 5.88 Actual value (%) C: 68.10, H: 5.88, N: 5.83 IR (cm -1 ) νNH3330, νCO1690, νNO 2 1530,
1350 NMR δ CDCl3 1.60 (d, 6H), 2.30 (s, 6H),
3.51 (s, 3H) 5.05 (s, 1H), 5.98 (s, 1H), 6.30
(s, 2H) 7.1-8.2 (m, 9H) Example 16 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid 3-methyl ester 5-(4 -ethyl-3-phenyl-2-propenyl) ester melting point Oil elemental analysis value C 27 H 28 N 2 O 6 Calculated value (%) C: 68.05, H: 5.92, N: 5.88 Actual value (%) C: 68.09, H:5.90, N:5.85 IR (cm -1 ) νNH3330, νCO1690, νNO 2 1530,
1350 NMR δ CDCl3 1.83 (m, 3H), 1.70 (q, 2H),
2.30 (d, 6H) 3.59 (s, 3H), 5.09 (s, 1H), 5.30
(t, 1H) 5.8-6.6 (m, 3H), 7.0-8.1 (m, 9H) Example 17 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarvone Acid 3-methyl ester 5-(4-(3-thienyl)-3-butenyl) ester Melting point 122.1-127.7℃ Elemental analysis value C 24 H 24 N 2 O 6 Calculated value (%) C: 61.53, H: 5.16, N: 5.98 Actual value (%) C: 61.55, H: 5.13, N: 5.89 IR (cm -1 ) νNH3340, νCO1690, νNO 2 1530,
1350 NMR δ CDCl3 2.30 (s, 6H), 2.4-2.8 (m, 2H), 3.57 (d, 3H), 4.12 (t, 2H), 5.07
(s, 1H) 5.2-8.1 (m, 10H) Example 18 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid 3-methyl ester 5-(1 , 3-diphenyl-2-propenyl) ester Melting point 431-145.5℃ Elemental analysis value C 31 H 28 N 2 O 6 Calculated value (%) C: 70.97, H: 5.38, N: 5.34 Actual value (%) C: 70.94 , H: 5.49, N: 5.32 IR (cm -1 ) νNH3380, νCO1695, νNO 2 1525,
1350 NMR δ CDCl3 2.26 (s, 6H), 3.60 (s, 3H),
5.16 (s, 1H) 6.2~6.5 (m, 4H), 7.0~8.2 (m,
14H) Example 19 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid 3-methyl ester 5-[4-(2-pyridyl)-3-butenyl) Ester melting point Oil elemental analysis value C 25 H 25 N 3 O 6 Calculated value (%) C: 64.79, H: 5.44, N: 9.07 Actual value (%) C: 64.85, H: 5.39, N: 9.06 IR (cm - 1 ) νNH3330, νCO1700, νNO 2 1530,
1350 NMR δ CDCl3 2.31 (s, 6H), 2.60 (t, 2H),
3.57 (s, 3H) 4.20 (t, 2H), 5.09 (s, 1H) 6.4-8.6 (m, 9H) Example 20 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine- 3,5-dicarboxylic acid 3-methyl ester 5-[3-(2-naphthyl)-2-propenyl) ester Melting point 149.4-154.3℃ Elemental analysis value C 29 H 26 N 2 O 6 Calculated value (%) C: 69.87 , H: 5.26, N: 5.62 Actual value (%) C: 69.99, H: 5.22, N: 5.57 IR (cm -1 ) νNH3330, νCO1700, νNO 2 1530,
1350 NMR δ CDCl3 2.30 (s, 3H), 2.34 (s, 3H),
3.60 (s, 3H) 4.74 (d, 2H), 5.15 (s, 1H) 6.0~6.85 (m, 3H), 7.1~8.2 (m,
11H) Example 21 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid 3-methyl ester 5-(1-methyl-3-phenyl-2-propenyl) Ester elemental analysis value C 26 H 26 N 2 O 6 Melting point Oil calculated value (%) C: 67.52, H: 5.67, N: 6.06 Actual value (%) C: 67.71, H: 5.66, N: 6.01 IR (cm - 1 ) νNH3330, νCO1690, νNO 2 1530,
1350 NMR δ CDCl3 1.35 (m, 3H), 2.30 (s, 6H),
3.60 (s, 3H) 5.12 (s, 1H), 5.45 (m, 1H) 6.0-6.8 (m, 3H), 7.1-8.2 (m, 9H) Example 22 4-(3-nitrophenyl)-2,6 -Dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid 3-ethyl ester 5-(1-methyl-3-phenyl-2-propenyl) ester melting point Oil elemental analysis value C 27 H 28 N 2 O 6 calculated value (%) C: 68.05, H: 5.92, N: 5.88 Actual value (%) C: 68.11, H: 5.88, N: 5.83 IR (cm -1 ) νNH3330, νCO1690, νNO 2 1530,
1350 NMR δ CDCl3 1.25 (d, 3H), 1.26 (q, 3H),
2.30 (s, 6H) 4.05 (q, 2H), 5.08 (s, 1H), 5.37
(q, 1H) 5.9~6.7 (m, 3H), 7.0~8.15 (m,
9H) Example 23 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid 3-isopropyl ester 5-(1-
Menyl-3-phenyl-2-propenyl)) Ester melting point Oil elemental analysis value C 28 H 30 N 2 O 6 Calculated value (%) C: 68.56, H: 6.16, N: 5.71 Actual value (%) C: 68.60, H:6.14, N:5 IR (cm -1 ) νNH3330, νCO1690, νNO 2 1530,
1350 NMR δ CDCl3 1.10 (d, 3H), 1.25 (d, 6H),
2.32 (s, 6H) 4.7-5.2 (m, 1H), 5.10 (s, 1H) 5.40 (q, 1H), 5.9-6.7 (m, 3H) 7.1-8.2 (m, 9H) Example 24 4-( 3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid 3-methyl ester 5-(1-methyl-3-furyl-2-propenyl) ester Melting point Oil elemental analysis value C 24 H 24 N 2 O 7 Calculated value (%) C: 63.71, H: 5.35, N: 6.19 Actual value (%) C: 63.07, H: 5.24, N: 6.11 IR (cm -1 ) νNH3330, νCO1680, νNO 2 1530,
1350 NMR δ CDCl3 1.33 (dd, 3H), 2.33 (s, 6H),
3.62 (s, 3H) 5.11 (s, 1H), 5.23-5.73 (m, 1H), 5.73-6.60 (m, 5H), 7.22-8.23 (m,
5H) Example 25 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid 3-(2-methoxyethyl) ester 5-(1-methyl-3-phenyl) -2-propenyl) ester melting point Oil elemental analysis value C 28 H 30 N 2 O 7 Calculated value (%) C: 66.39, H: 5.97, N: 5.53 Actual value (%) C: 66.44, H: 5.92, N: 5.47 IR (cm -1 ) νNH3330, νCO1690, νNO 2 1530,
1350 NMR δ CDCl3 1.30 (d, 3H), 2.30 (s, 6H),
3.29 (d, 3H) 3.48 (t, 2H), 4.15 (t, 2H), 5.10
(s, 1H) 5.50 (q, 1H), 5.9-6.7 (m, 3H), 7.05-8.15 (, 9H) Example 26 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine -3,5-Dicarboxylic acid 3-methyl ester 5-(2,3-diphenyl-2-propenyl) ester Melting point Oil elemental analysis value C 31 H 58 N 2 O 6 Calculated value (%) C: 70.98, H: 5.38 , N: 5.34 Actual value (%) C: 71.03, H: 5.37, N: 5.30 IR (cm -1 ) νNH3330, νCO1690, νNO 2 1530,
1350 NMR δ CDCl3 2.23 (s, 3H), 2.29 (s, 3H),
3.60 (s, 3H) 4.89 (s, 2H), 5.02 (s, 1H), 6.30
(s, 1H) 6.50 (s, 1H), 6.7-8.05 (m, 15H) Example 27 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid 3 -Methyl ester 5-(1-methyl-3-thienyl-2-propenyl) ester Melting point Oil elemental analysis value C 24 H 24 N 2 O 6 Calculated value (%) C: 61.53, H: 5.16, N: 5.98 Actual value (%) C: 61.55, H: 5.08, N: 5.79 IR (cm -1 ) νNH3330, νCO1680, νNO 2 1525,
1345 NMR δ CDCl3 1.37 (dd, 3H), 2.33 (s, 6H),
3.62 (s, 3H) 5.11 (s, 1H), 5.23-5.76 (m, 1H) 6.48 (s, 1H), 5.78-8.18 (m, 9H) Example 28 4-(2-Freel)-2,6 -dimethyl-
1,4-Dihydropyridine-3,5-dicarboxylic acid 3-methyl ester 5-cinnamyl ester Melting point Oil elemental analysis value C 23 H 23 NO 5 Calculated value (%) C: 70.21, H: 5.89, N: 3.56 Actual value (%) C: 70.27, H: 5.84, N: 3.50 IR (cm -1 ) νNH3340, νCO1690 NMR δ CDCl3 2.28 (s, 6H), 3.65 (s, 3H),
4.75 (dd, 2H) 5.23 (s, 1H), 5.88-6.60 (m, 5H), 7.1-7.4 (m, 6H) Example 29 4-(2-naphthyl)-2,6-dimethyl-
1,4-Dihydropyridine-3,5-dicarboxylic acid 3-methyl ester 5-cinnamyl ester Melting point Oil elemental analysis value C 29 H 27 NO 4 Calculated value (%) C: 76.80, H: 6.00, N: 3.09 Actual value (%) C: 76.92, H: 5.88, N: 3.01 IR (cm -1 ) νNH3330, νCO1690 NMR δ CDCl3 2.23 (s, 3H), 3.54 (s, 3H) 4.65 (dd, 2H), 5.20 (s, 1H), 6.0-6.6 (m, 3H), 7.0-7.8 (m,
12H) Example 30 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid 3-methyl ester 5-(4,4-diphenyl-3-butenyl) ester melting point Oil elemental analysis value C 32 H 30 N 2 O 6 Calculated value (%) C: 71.36, H: 5.61, N: 5.20 Actual value (%) C: 71.42, H: 5.53, N: 5.12 IR (cm -1 ) νNH3330, νCO1690, νNO 2 1530,
1350 NMR δ CDCl3 2.31 (s, 6H), 2.48 (m, 2H),
3.59 (s, 3H) 4.10 (t, 2H), 5.10 (s, 1H), 5.83
(t, 1H) 6.18 (s, 1H), 7.03-8.10 (m, 14H) Example 31 4-(2-fluorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarvone Acid 3 methyl ester 5-cinnamyl ester Melting point 89.5℃ Elemental analysis value C 25 H 24 FNO 4 Calculated value (%) C: 71.25, H: 5.74, N: 3.32 Actual value (%) C: 71.29, H: 5.70, N: 3.28 IR (cm -1 ) νNH3340, νCO1695 NMR δ CDCl3 2.62 (s, 6H), 3.56 (s, 3H), 4.54~4.78 (m, 2H), 5.28 (s, 1H) 6.14 (s, 1H) , 6.06-7.76 (m, 11H) Reference example Synthesis of 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid 3-methyl ester 5-cinnamyl ester 2- A mixture of 3.15g (10mM) of cinnamyl (3-nitrobenzylidene)acetoacetate and 1.38g (12mM) of methyl 3-aminocrotonate was added.
After reacting at 120°C for 3 hours, it was purified by silica gel column chromatography to obtain 3.00 g of the title compound (yield 67
%) was obtained. Melting point 101-102℃ Elemental analysis value C 25 H 24 N 2 O 6 Calculated value (%) C: 66.95, H: 5.39, N: 6.25 Actual value (%) C: 67.03, H: 5.31, N: 6.20 NMR δ CDCl3 2.34 (s, 6H), 3.60 (s, 3H), 4.69 (d, 2H), 5.13 (s, 1H), 5.9~6.7 (m, 3H), 7.0~8.1 (m, 9H)
Claims (1)
素数1〜3を有する直鎖もしくは分岐の飽和炭化
水素残基を表わし、Ar1はフエニル基、ナフチル
基又はフリル基を表わし、該基の水素原子は随時
ハロゲン原子、ニトロ基、シアノ基又はチオアル
コキシ基から選ばれる1個ないし2個の同一又は
相異なる基で置換されていてもよく、Aは炭素数
3〜4を有する直鎖の不飽和炭化水素残基を表わ
し、該基の水素原子は随時フエニル基で置換され
又は該基の一位の炭素原子に結合する水素原子の
少くとも1個が低級アルキル基で置換されていて
もよく、Ar2はフエニル基、ナフチル基、フリル
基、チエニル基、ピロリル基、又はピリジル基か
ら選ばれる1個の基を表わし、該基の水素原子は
随時アルキル基、ニトロ基又はシアノ基から選ば
れる1個又は2個の同一又は相異なる基で置換さ
れていてもよい。ただし、Rが炭素数1〜3を有
する直鎖もしくは分岐の飽和炭化水素残基であつ
て、Ar1がニトロ基置換フエニル基であり、Aが
無置換の炭素数3〜4を有する直鎖の不飽和炭化
水素残基であるときは、Ar2はアルキル基、ニト
ロ基、又はシアノ基から選ばれる1個又は2個の
同一又は相異なる基で置換されたフエニル基、ナ
フチル基、フリル基、チエニル基、ピロリル基又
はピリジル基もしくは無置換のナフチル基、フリ
ル基、チエニル基、ピロリル基又はピリジル基か
ら選ばれる1個の基である〕で表わされる1,4
−ジヒドロピリジン誘導体及びその酸付加塩。[Claims] 1. General formula [] [In the formula, R represents a lower alkoxyalkyl group or a linear or branched saturated hydrocarbon residue having 1 to 3 carbon atoms, Ar 1 represents a phenyl group, a naphthyl group, or a furyl group, and the hydrogen atom of the group may be optionally substituted with one or two same or different groups selected from a halogen atom, a nitro group, a cyano group, or a thioalkoxy group, and A is a linear unsaturated group having 3 to 4 carbon atoms. represents a hydrocarbon residue, the hydrogen atom of the group may optionally be substituted with a phenyl group, or at least one of the hydrogen atoms bonded to the first carbon atom of the group may be substituted with a lower alkyl group, Ar 2 represents one group selected from a phenyl group, a naphthyl group, a furyl group, a thienyl group, a pyrrolyl group, or a pyridyl group, and the hydrogen atom of the group is optionally selected from an alkyl group, a nitro group, or a cyano group. may be substituted with one or two identical or different groups. However, R is a straight chain or branched saturated hydrocarbon residue having 1 to 3 carbon atoms, Ar 1 is a nitro-substituted phenyl group, and A is an unsubstituted straight chain having 3 to 4 carbon atoms. When it is an unsaturated hydrocarbon residue, Ar2 is a phenyl group, a naphthyl group, a furyl group substituted with one or two same or different groups selected from an alkyl group, a nitro group, or a cyano group. , thienyl group, pyrrolyl group, pyridyl group, or one group selected from unsubstituted naphthyl group, furyl group, thienyl group, pyrrolyl group, or pyridyl group]
-Dihydropyridine derivatives and acid addition salts thereof.
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP59088411A JPS60233058A (en) | 1984-05-04 | 1984-05-04 | 1,4-dihydropyridine derivative |
US06/727,692 US4672068A (en) | 1984-05-04 | 1985-04-26 | Antihypertensive 1,4-dihydropyridines having a conjugated ester |
DE8585303141T DE3582952D1 (en) | 1984-05-04 | 1985-05-02 | DIHYDROPYRIDINE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME. |
EP85303141A EP0161877B1 (en) | 1984-05-04 | 1985-05-02 | 1,4-dihydropyridine derivatives, methods for their production and pharmaceutical compositions comprising the same |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP59088411A JPS60233058A (en) | 1984-05-04 | 1984-05-04 | 1,4-dihydropyridine derivative |
Publications (2)
Publication Number | Publication Date |
---|---|
JPS60233058A JPS60233058A (en) | 1985-11-19 |
JPH0314307B2 true JPH0314307B2 (en) | 1991-02-26 |
Family
ID=13942053
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP59088411A Granted JPS60233058A (en) | 1984-05-04 | 1984-05-04 | 1,4-dihydropyridine derivative |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPS60233058A (en) |
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EP0985667A4 (en) | 1997-04-25 | 2000-03-22 | Ajinomoto Kk | Novel dihydropyridine derivative |
AU5568300A (en) | 1999-06-23 | 2001-01-09 | Ajinomoto Co., Inc. | Novel dihydropyridine derivative |
WO2000078719A1 (en) | 1999-06-23 | 2000-12-28 | Ajinomoto Co., Inc. | Dihydropyridine derivative |
JP7333105B2 (en) * | 2019-05-31 | 2023-08-24 | アールディスカバリー エルエルシー | Drp1-filamin complex formation inhibitor |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS60120861A (en) * | 1983-12-02 | 1985-06-28 | Otsuka Pharmaceut Co Ltd | Dihydropyridine derivative |
-
1984
- 1984-05-04 JP JP59088411A patent/JPS60233058A/en active Granted
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS60120861A (en) * | 1983-12-02 | 1985-06-28 | Otsuka Pharmaceut Co Ltd | Dihydropyridine derivative |
Also Published As
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JPS60233058A (en) | 1985-11-19 |
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