JPH0629245B2 - 1,4-dihydropyridine derivative - Google Patents
1,4-dihydropyridine derivativeInfo
- Publication number
- JPH0629245B2 JPH0629245B2 JP12537984A JP12537984A JPH0629245B2 JP H0629245 B2 JPH0629245 B2 JP H0629245B2 JP 12537984 A JP12537984 A JP 12537984A JP 12537984 A JP12537984 A JP 12537984A JP H0629245 B2 JPH0629245 B2 JP H0629245B2
- Authority
- JP
- Japan
- Prior art keywords
- ester
- dihydropyridine
- compound
- general formula
- dimethyl
- 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
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- Hydrogenated Pyridines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
【発明の詳細な説明】 （産業上の利用分野） 本発明は循環器系疾患に対する優れた作用を有する新規
な１，４−ジヒドロピリジン誘導体に関する。さらに詳
しくは下記一般式〔Ｉ〕 （式中、Ｒ1は炭素数１〜６を有する直鎖、分岐又は環
状の飽和又は不飽和炭化水素基を表わし、該基は随時鎖
中に１個の酸素原子を含んでいてもよく、又は、随時ア
リール基で置換されていてもよく、Ｒ2は互いに共役す
る２個の二重結合を包含する直鎖、分岐又は環状の炭化
水素基を表わし、Ｘはトリハロメチル基又はニトロ基を
意味する。）で表わされる１，４−ジヒドロピリジン誘
導体に関するものである。TECHNICAL FIELD The present invention relates to a novel 1,4-dihydropyridine derivative having an excellent action on cardiovascular diseases. More specifically, the following general formula [I] (In the formula, R 1 represents a linear, branched or cyclic saturated or unsaturated hydrocarbon group having 1 to 6 carbon atoms, and the group may optionally contain one oxygen atom in the chain, Or, optionally substituted with an aryl group, R 2 represents a linear, branched or cyclic hydrocarbon group including two double bonds conjugated to each other, and X represents a trihalomethyl group or a nitro group. Means a 1,4-dihydropyridine derivative.
（従来の技術） 従来、１，４−ジヒドロピリジン誘導体としては、４−
（２−ニトロフェニル）−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：以下ニフェジピン
と略す）あるいは４−（３−ニトロフェニル）−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５５−４
５０７５：以下ニカルジピンと略す）などが、抗狭心症
薬、脳循環改善薬あるいは高血圧治療薬として、医療に
供せられている。(Prior Art) Conventionally, as a 1,4-dihydropyridine derivative, 4-
(2-Nitrophenyl) -2,6-dimethyl-1,4-
Dihydropyridine-3,5-dicarboxylic acid dimethyl ester (U.S. Pat. No. 3,644,627; hereinafter abbreviated as nifedipine) or 4- (3-nitrophenyl) -2,6
-Dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid 3-methyl ester-5- [2- (benzylmethylamino) ethyl] ester hydrochloride (Japanese Patent Publication No. 55-4
5075: hereinafter abbreviated as nicardipine) and the like are used for medical treatment as an antianginal drug, a cerebral circulation improving drug, or a drug for treating hypertension.
（発明が解決しようとする問題点） 一般に、高血圧疾患の治療には持続性かつ緩除な血圧降
下作用を有する薬物が有効であるとされている。(Problems to be Solved by the Invention) Generally, it is considered that a drug having a sustained and slow blood pressure lowering effect is effective for treating hypertensive diseases.
しかし、前記化合物の血圧降下作用は短時間で消失し、
しかも、その作用の発現が急である。従って、これらの
化合物は高血圧治療薬として優れた薬剤であるとは言え
ない。However, the hypotensive effect of the compound disappears in a short time,
Moreover, the onset of its action is rapid. Therefore, these compounds cannot be said to be excellent drugs for treating hypertension.
（問題点を解決するための手段） 本発明者らは、これらの問題点を克服すべく研究した結
果、５位カルボン酸エステル残基中に２個の共役する２
重結合を導入することによって、血圧降下作用の持続時
間が長く、しかもその最大降圧が遅延して発現し、緩除
な血圧降下作用を示すなど、高血圧治療薬として優れた
特徴を有する一般式〔Ｉ〕で表わされる１，４−ジヒド
ロピリジン誘導体を提供することに成功した。(Means for Solving Problems) The inventors of the present invention have conducted research to overcome these problems, and as a result, two conjugating groups 2 in the 5-position carboxylic acid ester residue have been conjugated.
By introducing a heavy bond, the duration of the blood pressure lowering effect is long, and further, the maximum hypotension is delayed, and a slow blood pressure lowering effect is exhibited, and a general formula having excellent characteristics as a therapeutic agent for hypertension [ The present invention succeeded in providing a 1,4-dihydropyridine derivative represented by the formula [I].
本発明化合物〔Ｉ〕はたとえば次に示す方法によって製
造することができる。The compound [I] of the present invention can be produced, for example, by the method shown below.
製造法１ 一般式〔II〕 （式中Ｒ1は前記と同義） で表わされる化合物と一般式〔III〕 （式中Ｘは前記と同義） で表わされる化合物及び一般式〔IV〕 （式中Ｒ2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
チルホルムアミドの中で加熱することにより〔Ｉ〕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。Production method 1 General formula [II] (Wherein R 1 is as defined above) and a compound of the general formula [III] (Wherein X is as defined above) and a compound of the general formula [IV] (Wherein R 2 has the same meaning as defined above) and a solvent inert to the reaction, such as methanol, ethanol, propanol,
Isopropanol, benzene, toluene, dioxane,
[I] can be obtained by heating in tetrahydrofuran, dimethylsulfoxide or dimethylformamide. At this time, the reaction temperature is 50 ° C to 150 ° C.
Is preferred, and a reaction time of 0.5 to 15 hours is usually sufficient.
製造法２ 一般式〔Ｖ〕 で表わされる化合物と一般式〔III〕で表わされる化合
物及び一般式〔VI〕 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って、〔Ｉ〕の化合物が得られる。Production method 2 General formula [V] And a compound represented by the general formula [III] and a general formula [VI] The compound of formula (I) is obtained by reacting the compound of formula (1) with the same reaction conditions as in production method 1.
製造法３ 一般式〔VII〕 で表わされる化合物と一般式〔IV〕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方法。Production method 3 General formula [VII] A method of reacting the compound of formula (I) with the compound of formula (IV) under the same reaction conditions as in production method 1.
製造法４ 一般式〔Ｖ〕で表わされる化合物と一般式〔VIII〕 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
反応させる方法。Production Method 4 Compound represented by general formula [V] and general formula [VIII] A method of reacting the compound represented by: under the same reaction conditions as in production method 1.
製造法５ 一般式〔II〕で表わされる化合物と一般式〔VIII〕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
応条件下で反応させる方法。Production method 5 A method of reacting the compound represented by the general formula [II] with the compound represented by the general formula [VIII] and ammonia under the same reaction conditions as in Production method 1.
製造法６ 一般式〔VII〕で表わされる化合物と一般式〔VI〕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
応条件下で反応させる方法。Production method 6 A method of reacting the compound represented by the general formula [VII] with the compound represented by the general formula [VI] and ammonia under the same reaction conditions as in the production method 1.
製造法７ 一般式〔IX〕 （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、ベンゾトリアゾール−１−
オキシ基などを表わし、他の記号は前記と同義である）
で表わされる化合物と一般式〔Ｘ〕 ＨＯ−Ｒ2 〔Ｘ〕 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、三フッ化ホウソなどの存在下で行うか又は脱水縮合
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
を共存せしめて、不活性溶媒中で行うことができる。
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
下で行うことができる。Production method 7 General formula [IX] (In the formula, Z is a hydroxy group or an acid residue of an active ester, for example, a halogen atom, a methylsulfonyloxy group, a paratoluenesulfonyloxy group, a benzotriazole-1-
Represents an oxy group, etc., and other symbols have the same meanings as above)
A method of reacting the compound represented by the formula (I) with an alcohol represented by the general formula [X] HO-R 2 [X]. When Z is a hydroxy group, this reaction is carried out in the presence of an acid such as hydrogen chloride, sulfuric acid or borotrifluorotrifluoride, or in the presence of a dehydrating condensing agent such as dicyclohexylcarbodiimide or the like, and optionally 4-dimethylaminopyridine or the like. It can be carried out in an inert solvent in the presence of the base.
When Z is an active ester residue, in an inert solvent,
If desired, it can be carried out in the presence of a base such as triethylamine, 4-dimethylaminopyridine, pyridine, potassium carbonate and the like.
製造法８ 一般式〔ＸＩ〕 （式中の各記号は前記と同義） で表わされる化合物と一般式〔ＸII〕 Ｒ1−ＯＨ 〔ＸII〕 で表わされる化合物とを製造法７と同様の反応条件下で
反応させる方法。Production Method 8 General Formula [XI] (Wherein each symbol in the formula has the same meaning as defined above) and a compound represented by the general formula [XII] R 1 -OH [XII] are reacted under the same reaction conditions as in the production process 7.
〔ＸＩ〕の化合物は〔IX〕の化合物と同様に公知の方法
によって製造することができる。The compound of [XI] can be produced by a known method similarly to the compound of [IX].
このようにして得られた一般式〔Ｉ〕の化合物は通常の
化学操作によって単離精製することができる。The compound of the general formula [I] thus obtained can be isolated and purified by a usual chemical operation.
（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、例えば、ニフェジピンに比べて、
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、緩除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。(Effect of the invention) The compound of the present invention has a strong vasodilatory action and hypotensive action, and compared with known compounds such as nifedipine,
These effects are extremely excellent, and at the same time, their efficacy is remarkably long, and further, the maximum hypotension of their antihypertensive effect is delayed, and has a characteristic of showing a gradual antihypertensive effect.
It is a very useful compound for treating hypertension.
〈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ットを用いて試験した。<Hypertensive action> The hypotensive action of the compound of the present invention and the duration of the action were tested using spontaneously hypertensive rats without anesthesia.
被検化合物を５％アラビアゴム懸濁液としてあらかじめ
挿入したカニューレを介して、十二指腸内に１mg／kgを
投与し、ラッ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。1 mg / kg was administered into the duodenum via a cannula in which the test compound was pre-inserted as a 5% gum arabic suspension, and the tail pressure of rats and the duration of the blood pressure-lowering effect were measured with a strain pressure gauge (AP-620G, It was measured invasively using Nihon Kohden Co., Ltd. and recorded on a retigraph (8K, manufactured by JEOL Sanei Co., Ltd.).
その結果を、表−１に示す。The results are shown in Table-1.
血圧降下作用は、被検化合物の投与前後における平均血
圧の差であり、持続時間は作用の半減期で代用し、分単
位で表示した。さらに作用の緩除性を示すために、最大
降圧到達時間を併せて表記した。なお、同表には、比較
のために、前記と同様に試験したニフェジピン及びニカ
ルジピンの結果を併記した。The antihypertensive effect is the difference in mean blood pressure before and after administration of the test compound, and the duration is represented by the half-life of the effect, which is expressed in minutes. Furthermore, in order to show the gradual release of the action, the time required for reaching the maximum hypotension is also shown. For comparison, the same table also shows the results of nifedipine and nicardipine tested in the same manner as above.
表から明らかなように、本発明の化合物は、ニフェジピ
ンあるいはニカルジピンに比べ、降圧作用が強くしかも
長く接続し、さらに最大降圧到達時間が遅延して発現す
ることが認められた。 As is clear from the table, it was confirmed that the compound of the present invention has a stronger antihypertensive action and a longer connection time than that of nifedipine or nicardipine, and further, the maximum hypotensive arrival time is delayed and expressed.
（実施例） 次に、本発明化合物〔Ｉ〕の具体的製造法について例を
あげて詳細に説明する。(Example) Next, a specific method for producing the compound [I] of the present invention will be described in detail with reference to examples.
実施例−１ ４−（３−ニトロフェニル）−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−（２，４−ヘキサジエニル）エステル ４−（３−ニトロフェニル）−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０．６６４ｇ（２ｍＭ）と２，４−ヘキサジ
エン−１−オール０．２０６ｇ（２．１ｍＭ）とジシク
ロヘキシルカルボジイミド０．４３３ｇ（２．１Ｍｍ）
と４−ジメチルアミノピリジン０．２５７ｇ（２．１ｍ
Ｍ）とをジクロロエタン２０ｍ中に、加熱して溶か
し、２時間還流した。不溶物を濾過した後、溶媒を減圧
留去し、残留物をシリカゲルカラムクロマトグラフィー
で精製し、標記化合物０．７３４ｇ（収率８９％）を得
た。Example-1 4- (3-nitrophenyl) -2,6-dimethyl-1,
4-Dihydropyridine-3,5-dicarboxylic acid 3-methyl ester 5- (2,4-hexadienyl) ester 4- (3-nitrophenyl) -2,6-dimethyl-1,
4-Dihydropyridine-3,5-dicarboxylic acid 3-methyl ester 0.664 g (2 mM), 2,4-hexadiene-1-ol 0.206 g (2.1 mM) and dicyclohexylcarbodiimide 0.433 g (2.1 Mm)
And 4-dimethylaminopyridine 0.257 g (2.1 m
M) and were dissolved by heating in 20 m of dichloroethane and refluxed for 2 hours. The insoluble material was filtered off, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 0.734 g (yield 89%) of the title compound.
融点 135〜136.5℃ 元素分析値 Ｃ22Ｈ24Ｎ2Ｏ6 計算値（％）Ｃ：64.07,H：5.87,N：6.79 実測値（％）Ｃ：64.14,H：5.82,N：6.76 NMRσCDCl3 1.72(d,3H),2.34(s,6H) 3.62(s,3H),4.52(d,2H) 5.3〜6.4(m,5H),7.2〜8.1(m,4H) 実施例−２ ４−（３−ニトロフェニル）−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−（２，４−ヘキサジエニル）エステル ４−（３−ニトロフェニル）−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０．６９２ｇ（２ｍＭ）と２，４−ヘキサジ
エン−１−オール０．２０６ｇ（２．１ｍＭ）とジシク
ロヘキシルカルボジイミド０．４３３ｇ（２．１ｍＭ）
と４ジメチルアミノピリジン０．２５７ｇ（２．１ｍ
Ｍ）とをジクロロエタン２０ｍ中に、加熱して溶か
し、２時間還流した。不溶物を濾過した後、溶媒を減圧
留去し、残留物をシリカゲルカラムクロマトグラフィー
で精製し、標記化合物０．７３４ｇ（収率８６．１％）
を得た。Mp 135 to 136.5 ° C. Elemental analysis C 22 H 24 N 2 O 6 Calculated (%) C: 64.07, H : 5.87, N: 6.79 Found (%) C: 64.14, H : 5.82, N: 6.76 NMRσ CDCl3 1.72 (d, 3H), 2.34 (s, 6H) 3.62 (s, 3H), 4.52 (d, 2H) 5.3 to 6.4 (m, 5H), 7.2 to 8.1 (m, 4H) Example-2 4- ( 3-nitrophenyl) -2,6-dimethyl-1,
4-Dihydropyridine-3,5-dicarboxylic acid 3-ethyl ester 5- (2,4-hexadienyl) ester 4- (3-nitrophenyl) -2,6-dimethyl-1,
4-Dihydropyridine-3,5-dicarboxylic acid 3-ethyl ester 0.692 g (2 mM), 2,4-hexadiene-1-ol 0.206 g (2.1 mM) and dicyclohexylcarbodiimide 0.433 g (2.1 mM)
And 4 dimethylaminopyridine 0.257g (2.1m
M) and were dissolved by heating in 20 m of dichloroethane and refluxed for 2 hours. The insoluble material was filtered off, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound 0.734 g (yield 86.1%).
Got
融点 114.7〜115.6℃ 元素分析値 Ｃ23Ｈ26Ｎ2Ｏ6 計算値（％）Ｃ：64.78,H：6.15,N：6.57 実測値（％）Ｃ：64.89,H：6.03,N：6.76 NMRσCDCl3 1.20(t,3H),1.72(d,3H) 2.32(s,3H),4.06(q,2H) 4.51(d,2H),5.07(s,1H) 5.2〜6.4(m,5H),7.1〜8.1(m,4H) 実施例−３ ４−（３−ニトロフェニル）−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−（２，４−ヘキサジエニル）エス
テル ４−（３−ニトロフェニル）−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０．７２１ｇ（２ｍＭ）と２，４−ヘ
キサジエン−１−オール０．２０６ｇ（２．１ｍＭ）と
ジシクロヘキシルカルボジイミド０．４３３ｇ（２．１
ｍＭ）と４−ジメチルアミノピリジン０．２５７ｇ
（２．１ｍＭ）とをジクロロエタン２０ｍ中に、加熱
して溶かし、２時間還流した。不溶物を濾過した後、溶
媒を減圧留去し、残留物をシリカゲルカラムクロマトグ
ラフィーで精製し、標記化合物０．８０１ｇ（収率９１
％）を得た 融点 102.8〜104.3℃ 元素分析値 Ｃ24Ｈ28Ｎ2Ｏ6 計算値（％）Ｃ：65.44,H：6.41,N：6.36 実測値（％）Ｃ：65.61,H：6.28,N：6.26 NMRσCDCl3 1.08(d,3H),1.25(d,3H) 1.75(d,3H),2.33(s,6H) 4.54(d,2H),5.00(q,1H) 5.08(s,1H),5.2〜6.4(m,5H) 7.2〜8.2(m,4H) 実施例−４ ４−（３−ニトロフェニル）−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−（２，４−ヘキサジエ
ニル）エステル ４−（３−ニトロフェニル）−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０．７５３ｇ（２ｍＭ）と
２，４−ヘキサジエン−１−オール０．２０６ｇ（２．
１ｍＭ）とジシクロヘキシルカルボジイミド０．４３３
ｇ（２．１ｍＭ）と４−ジメチルアミノピリジン０．２
５７ｇ（２．１ｍＭ）とをジクロロエタン２０ｍ中
に、加熱して溶かし、２時間還流した。不溶物を濾過し
た後、溶媒を減圧留去し、残留物をシリカゲルカラムク
ロマトグラフィーで精製し、標記化合物０．７５４ｇ
（収率８２．６％）を得た。Mp 114.7 to 115.6 ° C. Elemental analysis C 23 H 26 N 2 O 6 Calculated (%) C: 64.78, H : 6.15, N: 6.57 Found (%) C: 64.89, H : 6.03, N: 6.76 NMRσ CDCl3 1.20 (t, 3H), 1.72 (d, 3H) 2.32 (s, 3H), 4.06 (q, 2H) 4.51 (d, 2H), 5.07 (s, 1H) 5.2〜6.4 (m, 5H), 7.1〜 8.1 (m, 4H) Example-3 4- (3-nitrophenyl) -2,6-dimethyl-1,
4-Dihydropyridine-3,5-dicarboxylic acid 3-isopropyl ester 5- (2,4-hexadienyl) ester 4- (3-nitrophenyl) -2,6-dimethyl-1,
4-Dihydropyridine-3,5-dicarboxylic acid 3-isopropyl ester 0.721 g (2 mM), 2,4-hexadiene-1-ol 0.206 g (2.1 mM) and dicyclohexylcarbodiimide 0.433 g (2.1
mM) and 4-dimethylaminopyridine 0.257 g
(2.1 mM) was dissolved in 20 m of dichloroethane by heating and refluxed for 2 hours. The insoluble material was filtered off, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give 0.801 g of the title compound (yield 91
%) Melting point 102.8-104.3 ° C elemental analysis value C 24 H 28 N 2 O 6 calculated value (%) C: 65.44, H: 6.41, N: 6.36 measured value (%) C: 65.61, H: 6.28, N: 6.26 NMRσ CDCl3 1.08 (d , 3H), 1.25 (d, 3H) 1.75 (d, 3H), 2.33 (s, 6H) 4.54 (d, 2H), 5.00 (q, 1H) 5.08 (s, 1H) , 5.2-6.4 (m, 5H) 7.2-8.2 (m, 4H) Example-4 4- (3-nitrophenyl) -2,6-dimethyl-1,
4-dihydropyridine-3,5-dicarboxylic acid 3- (2
-Methoxyethyl) ester 5- (2,4-hexadienyl) ester 4- (3-nitrophenyl) -2,6-dimethyl-1,
4-dihydropyridine-3,5-dicarboxylic acid 3- (2
-Methoxyethyl) ester 0.753 g (2 mM) and 2,4-hexadiene-1-ol 0.206 g (2.
1 mM) and dicyclohexylcarbodiimide 0.433
g (2.1 mM) and 4-dimethylaminopyridine 0.2
57 g (2.1 mM) was dissolved by heating in 20 m of dichloroethane and refluxed for 2 hours. The insoluble material was filtered off, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (0.754 g)
(Yield 82.6%) was obtained.
融点 97.3〜98.5℃ 計算値（％）Ｃ：63.15,H：6.18,N：6.14 実測値（％）Ｃ：63.20,H：5.98,N：6.23 NMRσCDCl3 1.71(d,3H),2.32(s,6H) 3.51(t,2H),4.16(t,2H) 4.50(d,2H),5.10(s,1H) 5.2〜6.4(m,5H),7.1〜8.2(m,4H) 実施例−５ ４−（３−ニトロフェニル）−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−シク
ロヘキシルエステル５−（２，４−ヘキサジエニル）エ
ステル ４−（３−ニトロフェニル）−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−シク
ロヘキシルエステル０．７９９ｇ（２ｍＭ）と２，４−
ヘキサジエン−１−オール０．２０６ｇ（２．１ｍＭ）
とジシクロヘキシルカルボジイミド０．４３３ｇ（２．
１ｍＭ）と４−ジメチルアミノピリジン０．２５７ｇ
（２．１ｍＭ）とをジクロロエタン２０ｍ中に、加熱
して溶かし、２時間還流した。不溶物を濾過した後、溶
媒を減圧留去し、残留物をシリカゲルカラムクロマトグ
ラフィーで精製し、油状の標記化合物０．８６８ｇ（収
率９０．３％）を得た。Melting point 97.3-98.5 ° C Calculated value (%) C: 63.15, H: 6.18, N: 6.14 Measured value (%) C: 63.20, H: 5.98, N: 6.23 NMR σCDCl3 1.71 (d, 3H), 2.32 (s, 6H ) 3.51 (t, 2H), 4.16 (t, 2H) 4.50 (d, 2H), 5.10 (s, 1H) 5.2 ~ 6.4 (m, 5H), 7.1 ~ 8.2 (m, 4H) Example-5 4- (3-nitrophenyl) -2,6-dimethyl-1,
4-Dihydropyridine-3,5-dicarboxylic acid 3-cyclohexyl ester 5- (2,4-hexadienyl) ester 4- (3-nitrophenyl) -2,6-dimethyl-1,
4-Dihydropyridine-3,5-dicarboxylic acid 3-cyclohexyl ester 0.799 g (2 mM) and 2,4-
Hexadiene-1-ol 0.206 g (2.1 mM)
And dicyclohexylcarbodiimide 0.433 g (2.
1 mM) and 4-dimethylaminopyridine 0.257 g
(2.1 mM) was dissolved in 20 m of dichloroethane by heating and refluxed for 2 hours. The insoluble material was filtered off, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 0.868 g (yield 90.3%) of the title compound as an oil.
元素分析値 Ｃ27Ｈ32Ｎ2Ｏ6 計算値（％） Ｃ：67.48,H：6.71,N：5.83 実測値（％） Ｃ：67.62,H：6.49,N：5.76 NMRσCDCl3 0.9〜2.1(m,10H),1,73(d,3H) 2.31(s,6H),4.4〜4.9(m,1H) 4.51(d,2H),5.08(s,1H) 5.2〜6.4(m,4H),6.77(s,1H) 7.1〜8.2(m,4H) 実施例−６ ４−（３−ニトロフェニル）−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−シン
ナミルエステル５−（２，４−ヘキサジエニル）エステ
ル ４−（３−ニトロフェニル）−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−シン
ナミルエステル０．８６８ｇ（２ｍＭ）と２，４−ヘキ
サジエン−１−オール０．２０６ｇ（２．１ｍＭ）とジ
シクロヘキシルカルボジイミド０．４３３ｇ（２．１ｍ
Ｍ）と４−ジメチルアミノピリジン０．２５７ｇ（２．
１ｍＭ）とをジクロロエタン２０ｍ中に、加熱して溶
かし、２時間還流した。不溶物を濾過した後、溶媒を減
圧留去し、残留物をシリカゲルカラムクロマトグラフィ
ーで精製し、標記化合物０．９２６ｇ（収率９０％）を
得た。Elemental analysis C 27 H 32 N 2 O 6 Calculated (%) C: 67.48, H : 6.71, N: 5.83 Found (%) C: 67.62, H : 6.49, N: 5.76 NMRσ CDCl3 0.9~2.1 (m , 10H), 1,73 (d, 3H) 2.31 (s, 6H), 4.4 ~ 4.9 (m, 1H) 4.51 (d, 2H), 5.08 (s, 1H) 5.2 ~ 6.4 (m, 4H), 6.77 (s, 1H) 7.1 to 8.2 (m, 4H) Example-6 4- (3-nitrophenyl) -2,6-dimethyl-1,
4-Dihydropyridine-3,5-dicarboxylic acid 3-cinnamyl ester 5- (2,4-hexadienyl) ester 4- (3-nitrophenyl) -2,6-dimethyl-1,
4-Dihydropyridine-3,5-dicarboxylic acid 3-cinnamyl ester 0.868 g (2 mM), 2,4-hexadiene-1-ol 0.206 g (2.1 mM) and dicyclohexylcarbodiimide 0.433 g (2.1 m)
M) and 4-dimethylaminopyridine 0.257 g (2.
1 mM) was dissolved in 20 m of dichloroethane by heating and refluxed for 2 hours. The insoluble material was filtered off, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 0.926 g (yield 90%) of the title compound.
融点 141〜142℃ 元素分析値 Ｃ30Ｈ30Ｎ2Ｏ6 計算値（％）Ｃ：70.02,H：5.88,N：5.44 実測値（％）Ｃ：70.21,H：5.68,N：5.26 NMRσCDCl3 1.67(d,3H),2.31(s,6H) 4.50(d,2H),4.68(d,2H) 5.16(s,1H),5.2〜6.9(m,7H) 7.1〜8.2(m,9H) 実施例−７ ４−（３−トリフロロメチルフェニル）−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−（２，４−ヘキサジエニル）
エステル ２−（３−トリフロロメチルベンジリデン）アセト酢酸
（２，４−ヘキサジエニル）エステル０．３３８ｇ（１
ｍＭ）と３−アミノクロトン酸メチルエステル０．１３
８ｇ（１．２ｍＭ）との混合物を１２０℃で３時間反応
せしめた。反応混合物をシリカゲルカラムクロマトグラ
フィーで精製し、標記化合物０．２７９ｇ（収率６４
％）を得た。Mp 141-142 ° C. Elemental analysis C 30 H 30 N 2 O 6 Calculated (%) C: 70.02, H : 5.88, N: 5.44 Found (%) C: 70.21, H : 5.68, N: 5.26 NMRσ CDCl3 1.67 (d, 3H), 2.31 (s, 6H) 4.50 (d, 2H), 4.68 (d, 2H) 5.16 (s, 1H), 5.2 to 6.9 (m, 7H) 7.1 to 8.2 (m, 9H) Implemented Example-7 4- (3-trifluoromethylphenyl) -2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid 3-methyl ester 5- (2,4-hexadienyl)
Ester 2- (3-trifluoromethylbenzylidene) acetoacetic acid (2,4-hexadienyl) ester 0.338 g (1
mM) and 3-aminocrotonic acid methyl ester 0.13
A mixture with 8 g (1.2 mM) was reacted at 120 ° C. for 3 hours. The reaction mixture was purified by silica gel column chromatography to give the title compound 0.279 g (yield 64
%) Was obtained.
融点 129.5〜131.1℃ 元素分析値 Ｃ23Ｈ24Ｆ3ＮＯ6 計算値（％）Ｃ：59.10,H：5.18,N：3.00 実測値（％）Ｃ：59.23,H：5.11,N：2.87 NMRσCDCl3 1.73(d,3H),2.30(s,6H) 4.51(d,2H),5.03(s,1H) 5.2〜6.3(m,5H),7.1〜7.6(m,4H) 実施例−８ ４−（３−ニトロフェニル）−２，６−ジメチル−１，
４−ジヒドロピリジン−３，５−ジカルボン酸３，５−
ジ（２，４−ヘキサジエニル）エステル ４−（３−ニトロフェニル）−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−
（２，４−ヘキサジエニル）エステル０．３９８ｇ（１
ｍＭ）と２，４−ヘキサジエン−１−オール０．１０８
ｇ（１．１ｍＭ）とジシクロヘキシルカルボジイミド
０．２２７ｇ（１．１ｍＭ）と４−ジメチルアミノピリ
ジン０．１３４ｇ（１．１ｍＭ）とをジクロロエタン２
０ｍ中に、加熱して溶かし、２時間還流した。不溶物
を濾過した後、溶媒を減圧留去し、残留物をシリカゲル
カラムクロマトグラフィーで精製し、標記化合物０．４
２８ｇ（収率８９．４％）を得た。Mp from 129.5 to 131.1 ° C. Elemental analysis C 23 H 24 F 3 NO 6 Calculated (%) C: 59.10, H : 5.18, N: 3.00 Found (%) C: 59.23, H : 5.11, N: 2.87 NMRσ CDCl3 1.73 (d, 3H), 2.30 (s, 6H) 4.51 (d, 2H), 5.03 (s, 1H) 5.2 to 6.3 (m, 5H), 7.1 to 7.6 (m, 4H) Example-8 4- ( 3-nitrophenyl) -2,6-dimethyl-1,
4-dihydropyridine-3,5-dicarboxylic acid 3,5-
Di (2,4-hexadienyl) ester 4- (3-nitrophenyl) -2,6-dimethyl-1,
4-dihydropyridine-3,5-dicarboxylic acid 3-
(2,4-hexadienyl) ester 0.398 g (1
mM) and 2,4-hexadiene-1-ol 0.108
g (1.1 mM), dicyclohexylcarbodiimide 0.227 g (1.1 mM) and 4-dimethylaminopyridine 0.134 g (1.1 mM) were added to dichloroethane 2
In 0 m, it was heated to dissolve and refluxed for 2 hours. The insoluble material was filtered off, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound 0.4
28 g (yield 89.4%) was obtained.
融点 145.1〜146.1℃ 元素分析値 Ｃ27Ｈ30Ｎ2Ｏ6 計算値（％）Ｃ：67.77,H：6.32,N：5.85 実測値（％）Ｃ：67.91,H：6.19,N：5.71 NMRσCDCl3 1.71(d,6H),2.30(s,6H) 4.51(d,4H),5.10(s,1H) 5.2〜6.4(m,8H),6.60(s,1H) 7.2〜8.2(m,4H) 実施例−９ ４−（３−ニトロフェニル）−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−〔４−（２，６，６−トリメチル
−１−シクロヘキセン−１−イル）−３−ブテニル〕｝
エステル ４−（３−ニトロフェニル）−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０．３３２ｇ（１ｍＭ）と４−（２，６，６
−トリメチル−１−シクロヘキセン−１−イル）−３−
ブテン−２−オール０．２１３ｇ（１．１ｍＭ）とジシ
クロヘキシルカルボジイミド０．１０３ｇ（１．１ｍ
Ｍ）と４−ジメチルアミノピリジン０．１２４ｇ（１．
１ｍＭ）とをジクロロエタン２０ｍ中に、加熱して溶
かし、そのまま２時間還流した。不溶物を濾過した後、
溶媒を減圧下で留去し、残留物をシリカゲルカラムクロ
マトグラフィーで精製し、油状の標記化合物０．４６８
ｇ（収率９２．１％）を得た。Mp from 145.1 to 146.1 ° C. Elemental analysis C 27 H 30 N 2 O 6 Calculated (%) C: 67.77, H : 6.32, N: 5.85 Found (%) C: 67.91, H : 6.19, N: 5.71 NMRσ CDCl3 1.71 (d, 6H), 2.30 (s, 6H) 4.51 (d, 4H), 5.10 (s, 1H) 5.2 to 6.4 (m, 8H), 6.60 (s, 1H) 7.2 to 8.2 (m, 4H) Example-9 4- (3-nitrophenyl) -2,6-dimethyl-1,
4-Dihydropyridine-3,5-dicarboxylic acid 3-methyl ester 5- {2- [4- (2,6,6-trimethyl-1-cyclohexen-1-yl) -3-butenyl]}
Ester 4- (3-nitrophenyl) -2,6-dimethyl-1,
4-Dihydropyridine-3,5-dicarboxylic acid 3-methyl ester 0.332 g (1 mM) and 4- (2,6,6
-Trimethyl-1-cyclohexen-1-yl) -3-
0.213 g (1.1 mM) butene-2-ol and 0.103 g (1.1 m) dicyclohexylcarbodiimide
M) and 4-dimethylaminopyridine 0.124 g (1.
1 mM) was dissolved in 20 m of dichloroethane by heating and the mixture was refluxed for 2 hours. After filtering the insoluble matter,
The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (0.468) as an oil.
g (yield 92.1%) was obtained.
元素分析値 Ｃ29Ｈ36Ｎ2Ｏ6 計算値（％）Ｃ：68.48,H：7.13,N：5.51 実測値（％）Ｃ：68.59,H：6.99,N：5.36 NMRσCDCl3 0.68〜2.30(m,9H),0.95(s,3H) 0.98(s,3H),1.63(s,3H) 2.34(s,6H),3.62(s,3H) 5.09(s,1H),5.20〜6.25(m,3H) 6.30(s,1H),7.10〜8.16(m,4H)Elemental analysis C 29 H 36 N 2 O 6 Calculated (%) C: 68.48, H : 7.13, N: 5.51 Found (%) C: 68.59, H : 6.99, N: 5.36 NMRσ CDCl3 0.68~2.30 (m , 9H), 0.95 (s, 3H) 0.98 (s, 3H), 1.63 (s, 3H) 2.34 (s, 6H), 3.62 (s, 3H) 5.09 (s, 1H), 5.20 ~ 6.25 (m, 3H ) 6.30 (s, 1H), 7.10 ~ 8.16 (m, 4H)
Claims (1)
状の飽和又は不飽和炭化水素基を表わし、該基は随時鎖
中に１個の酸素原子を含んでいてもよく、又は、随時ア
リール基で置換されていてもよく、Ｒ２は互いに共役す
る２個の二重結合を包含する直鎖、分岐又は環状の炭化
水素基を表わし、Ｘはトリハロメチル基又はニトロ基を
意味する。）で表わされる１，４−ジヒドロピリジン誘
導体。1. A general formula (In the formula, R 1 represents a linear, branched or cyclic saturated or unsaturated hydrocarbon group having 1 to 6 carbon atoms, and the group may optionally contain one oxygen atom in the chain, Or, optionally substituted with an aryl group, R 2 represents a linear, branched or cyclic hydrocarbon group including two double bonds conjugated to each other, and X represents a trihalomethyl group or a nitro group. 1,4-dihydropyridine derivative represented by the formula (1).
Priority Applications (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP12537984A JPH0629245B2 (en) | 1984-06-20 | 1984-06-20 | 1,4-dihydropyridine derivative |
| US06/727,692 US4672068A (en) | 1984-05-04 | 1985-04-26 | Antihypertensive 1,4-dihydropyridines having a conjugated ester |
| EP85303141A EP0161877B1 (en) | 1984-05-04 | 1985-05-02 | 1,4-dihydropyridine derivatives, methods for their production and pharmaceutical compositions comprising the same |
| DE8585303141T DE3582952D1 (en) | 1984-05-04 | 1985-05-02 | DIHYDROPYRIDINE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME. |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP12537984A JPH0629245B2 (en) | 1984-06-20 | 1984-06-20 | 1,4-dihydropyridine derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS617255A JPS617255A (en) | 1986-01-13 |
| JPH0629245B2 true JPH0629245B2 (en) | 1994-04-20 |
Family
ID=14908674
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP12537984A Expired - Lifetime JPH0629245B2 (en) | 1984-05-04 | 1984-06-20 | 1,4-dihydropyridine derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0629245B2 (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS62174050A (en) * | 1985-10-21 | 1987-07-30 | Nippon Shoji Kk | 3-aminocarbonyl-1, 4-dihydropyridine-5-carboxylic acid derivative, production thereof and drug composition |
| JPS632975A (en) * | 1986-06-24 | 1988-01-07 | Sanwa Kagaku Kenkyusho Co Ltd | 1,4-dihydropyridine derivative, salt thereof, production thereof and drug for circulatory organ comprising said compound as active ingredient |
| US10411542B2 (en) * | 2012-10-15 | 2019-09-10 | Mitsubishi Electric Corporation | Fixing structure and fixing method for wire connection plate, and rotating electrical machine |
| 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 |
-
1984
- 1984-06-20 JP JP12537984A patent/JPH0629245B2/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| JPS617255A (en) | 1986-01-13 |
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