JPH0544453B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention has a strong calcium antagonistic effect,
and to novel compounds effective in the treatment of hypertension, angina pectoris and other cardiovascular disorders. The compounds of the present invention are related to the 1,4-dihydropyridine class of calcium pathway blockers and exhibit relaxing effects on cardiac and vascular smooth muscle. Calcium pathway blockers are an important family of compounds with a variety of chemical structures that are effective in the treatment of cardiovascular disorders. Dihydropyridines are a new type of calcium antagonist with smooth muscle relaxing activity. Nifedipine (having the chemical structural formula (A) below), which is the most representative compound of this family, is already used in many countries as an antihypertensive agent and an antianginal agent. Further, nitrendipine (having the chemical structural formula (B) below) is currently under research and is a promising antihypertensive agent. The present invention relates to novel 1,4-dihydropyridines with antianginal, antihypertensive and vasodilatory properties. The compound of the present invention is represented by the following general formula (): (wherein R is 2-methoxymethoxy, 2,3-
methylenedioxy or 2,3-ethylenedioxy group, R ₁ and R ₂ are both methyl groups or are different from each other and are linear or branched C ₁ -
It is a _C4 alkyl group. ) In the general formula (), when R ₁ and R ₂ are both methyl groups, a symmetrical structure occurs. Also,
If R ₁ and R ₂ are different from each other and are straight-chain or branched C ₁ -C ₄ alkyl groups, the structure has an asymmetric center and two diastereomers are present. In the compound of general formula (), the substituent R is
Compounds that are 2,3-methylenedioxy or 2,3-ethylenedioxy groups (especially compound IQB-
837V and IQB−838V especially the compound IQB−
837V) was found to be highly active in vitro as well as in vivo. The present invention also relates to a method for producing compounds of formula () above. This method uses the general formula (): (wherein R is 2-methoxymethoxy, 2,3-
Methylenedioxy or 2,3-ethylenedioxy group. ) The substituted benzaldehyde represented by the general formula (In the formula, R ₁ is a linear or branched C ₁ to C ₄ alkyl group.) (In the formula, R and R ₁ have the same meanings as above.) α-(acetyl)-β-(substituted phenyl)
Acrylic acid ester, general formula (In the formula, R ₂ is a linear or branched C ₁ to C ₄ alkyl group. However, in relation to R ₁ , R ₁ and R ₂ are the same when R ₁ and R ₂ are both methyl groups; in other cases, R ₂ is a group different from R _1. ) Become. The present invention also relates to therapeutic compositions containing compounds of general formula () as active ingredients. The composition may be administered orally, rectally, nasally, sublingually or by injection. These pharmaceutical compositions optionally contain the active ingredient in the form of a pharmacologically acceptable salt in a solid, semisolid or liquid diluent or in a pharmacologically biodegradable capsule such as a biodegradable capsule. in combination with excipients compatible with The active ingredient generally comprises 0.1 to 99% by weight of the composition.
For example, it is 0.5 to 10% for compositions for injection, and 10 to 80% for compositions for oral administration. For preparing pharmaceutical compositions in the form of dosage units for oral use, the active ingredient is combined with solid powder excipients such as lactose, sutucarose, sorbitol, starches such as cornstarch, amylopectin, agar, cellulose derivatives, polyvinylpyrrolidone or gelatin. It may be mixed with etc. Lubricants may also be added, such as magnesium or calcium stearate, carbo waxes, or other waxes of polyethylene glycol. Tablets and sugar-coated tablets are then produced by compression of the mixture. In the case of dragee-coated tablets, the cores are coated with a concentrated solution of sugar, which may contain, for example, gum arabic, talc and/or titanium dioxide, or with a film-forming agent dissolved in a volatile organic solvent. . Coloring agents may be added to these coatings to distinguish the various active ingredients. To produce soft gelatin capsules,
The active ingredient may be dissolved in an oil such as olive oil, sesame oil or peanut oil. Hard gelatin capsules may contain granulated and powdered solid excipients of the active ingredient, such as lactose, sugarose, starch, cellulose derivatives, polyvinylpyrrolidone or gelatin. Lubricants such as magnesium stearate or stearic acid may also be added. The compounds of the invention may also be made into sustained active forms by selecting suitable excipients. Various controlled release methods are used. That is, those coated with fine particles or powder, those coated with the active ingredient GaMatrix, or those that are hardly soluble. Liquid compositions for oral administration may be in the form of elixirs, syrups or suspensions. The solution may contain, for example, about 0.1 to 10% by weight of the active ingredient and a mixture of sugars and alcohols, water, glycerol and propylene glycol and optionally saccharin and/or carboxymethyl cellulose or pectin as flavoring agents and dispersants. May contain. In compositions for parenteral administration, some of the compounds of the invention may form salts with, for example, hydrochloric acid, phosphoric acid, tartaric acid or other inorganic or organic acids, these salts containing about 0.1-0.5%. may be prepared in an aqueous solution at a concentration of Optionally stabilizers and/or buffers may also be added. The dosage unit may be in the form of, for example, an ampoule or a vial. Dosage varies and depends on various factors. It especially depends on the patient's individual requirements. Orally, the preferred daily dose is 1
~10-50 mg in 3 doses. For parenteral administration, the preferred dose is 1-10 mg
It is. The examples below describe methods for making compounds of the invention. Comparative Example 1 1,4-dihydro-2,6-dimethyl-4-
(3',4',5'-trimethoxyphenyl)-3,5
-Production of pyridinedicarboxylic acid methyl ethyl ester (IQB-831-V) (a) Ethyl α-acetyl-β-(3,4,5-
(trimethoxyphenyl) acrylate 19.6 g of trimethoxybenzaldehyde was placed in a flask connected to a Dean-Stark separator containing 100 ml of benzene.
(0.11 mol) and 7 ml of benzene were introduced,
Then 13 g (0.1 mol) of ethyl acetoacetate was added. The mixture was stirred at 60-70° C. until complete dissolution, then 0.4 ml piperidine and 1.2 ml acetic acid were added. The mixture was refluxed for 2-3 hours until no water separated. After cooling, 11 g of crystals were filtered off. Dilute the filtrate with ether, then add 5% hydrochloric acid.
ml, 50 ml of 5% sodium bicarbonate and 50 ml of water. The organic phase was dried over anhydrous magnesium sulphate, filtered and evaporated in vacuo. An additional 13 g was obtained. Both parts were recrystallized in ethanol. Yield: 75%, melting point: 113.4°C. (b) 1,4-dihydro-2,6-dimethyl-4-
(3',4',5'-trimethoxyphenyl)-3,5
-Pyridinedicarboxylic acid methyl ethyl ester Ethyl α-acetyl-β-(3,4,5-
8 g of (trimethoxyphenyl) acrylate are dissolved in 50 ml of isopropanol with gentle heating, followed by 2.98 g of methyl aminocrotonate.
was added. The mixture was stirred at room temperature for 48 hours, then the resulting solid was filtered off. When the filtrate is evaporated in vacuum,
An oily semi-solid formed which was recrystallized in methanol. Yield: 5g (50%), melting point = 186°C. Comparative Example 2 1,4-dihydro-2,6-dimethyl-4-
Production of (3',4'-dimethoxyphenyl)-3,5-pyridinedicarboxylic acid methyl ethyl ester (IQB-834V) (a) Ethyl α-acetyl-β-(3,4-dimethoxyphenyl) ) Acrylate 4.1 g (0.025 mol) of 3,4-dimethoxy benzaldehyde was placed in a flask connected to a Dean-Stark separator containing anhydrous benzene.
and ethyl acetoacetate in 5 ml of anhydrous benzene.
3.25 g (0.025 mol) was introduced. The mixture was heated until completely dissolved, then 0.1 ml piperidine and 0.3 ml glacial acetic acid were added. The mixture was refluxed until no more water separated. After cooling, the mixture was diluted with benzene and then washed twice with 25 ml of 5% hydrochloric acid, 25 ml of 5% sodium bicarbonate and water. The organic phase was dried over anhydrous magnesium sulfate,
Evaporation under vacuum gave an oil. This was used in the next step without purification. Yield: 5.8g
(85%). (b) 1,4-dihydro-2,6-dimethyl-4-
(3',4'-dimethoxyphenyl)-3,5-pyridinedicarboxylic acid methyl ethyl ester 4.8 g of ethyl α-acetyl-β-(3,4-dimethoxyphenyl) acrylate in 25 ml of isopropanol. Dissolve and then add 2 g of methyl aminocrotonate. The mixture was stirred for 48 hours at room temperature and then the solvent was removed under vacuum. An oily product was obtained which was recrystallized in ethanol. Yield: 5g (77%), melting point = 169°C. Comparative Example 3 1,4-dihydro-2,6-dimethyl-4-
(3',5'-dimethoxy-4'-hydroxyphenyl)-3,5-pyridinedicarboxylic acid methyl
Preparation of ethyl ester (IQB-832V) (a) Ethyl α-acetyl-β-(3,5-dimethoxy-4-hydroxyphenyl) acrylate connected to a Dean-Stark separator containing anhydrous benzene. In the flask, add 3,5-dimethoxy-4-hydroxy benzaldehyde.
9.1g (0.05mol), ethyl acetoacetate 6.5g
(0.05 mol) and 5 ml of benzene were introduced.
The mixture was heated until completely dissolved, then 0.2 ml piperidine and 0.7 ml glacial acetic acid were added.
The solution was refluxed for 2 hours. After cooling, white crystals precipitated from the reaction mixture. The precipitate that formed was collected by filtration and then recrystallized in ethanol. Yield: 11g (75%). (b) 1,4-dihydro-2,6-dimethyl-4-
(3',5'-dimethoxy-4'-hydroxyphenyl)-3,5-pyridinedicarboxylic acid methyl
Ethyl ester Dissolve 11 g of ethyl α-acetyl-β-(3,5-dimethoxy-4-hydroxyphenyl) acrylate in 100 ml of isopropanol.
Then 3.9 g of methyl aminocrotonate was added. The mixture was stirred for 48 hours at room temperature. The solvent was evaporated under vacuum and the oily compound obtained was then washed three times with 15 ml of n-hexane. The resulting solid was recrystallized in isopropanol. Yield: 8g (55%), melting point = 186°C. Comparative Example 4 1,4-dihydro-2,6-dimethyl-4-
Production of (2',3'-dimethoxyphenyl)-3,5-pyridinedicarboxylic acid methyl ethyl ester (IQB-835V) (a) Ethyl α-acetyl-β-(2,3-dimethoxyphenyl) ) Acrylate The manufacturing method for this compound is the Organic Synthesis Collective (Organic Synthesis Collective).
Synthesis, Coll.) Volume 408. (b) 1,4-dihydro-2,6-dimethyl-4-
(2',3'-Dimethoxyphenyl)-3,5-pyridinedicarboxylic acid methyl ethyl ester Dissolve 14 g of ethyl α-acetyl-β-(2,3-dimethoxyphenyl) acrylate in 50 ml of isopropanol. Then, 5.8 g of methyl aminocrotonate was added. The mixture was stirred for 48 hours at room temperature, then the resulting solid was filtered off. Another portion of product was obtained after removing the solvent in vacuo. These two parts were recrystallized in isopropanol. Yield: 11.5g (61%), melting point = 175
℃. Comparative Example 5 1,4-dihydro-2,6-dimethyl-4-
Production of (3',5'-dimethoxyphenyl)-3,5-pyridinedicarboxylic acid methyl ethyl ester (IQB-833V) (a) Ethyl α-acetyl-β-(3,5-dimethoxyphenyl) ) Acrylate In a flask connected to a Dean-Stark separator containing benzene, 4.1 g of 3,5-dimethoxy benzaldehyde and 5 g of anhydrous benzene were added.
3.25 g of ethyl acetoacetate per ml were introduced. The mixture was heated gently until dissolution, then 0.1 ml piperidine and 0.3 ml glacial acetic acid were added. The solution was refluxed for 2 hours until no more water separated. After cooling, the resulting precipitate was filtered off. The filtrate was diluted with 5% hydrochloric acid, 5% sodium bicarbonate and water.
The solution was washed twice and the solvent was removed in vacuo. An oily semi-solid formed which was recrystallized in ethanol. Total yield: 3.8g (55%), melting point = 73
~75℃. (b) 1,4-dihydro-2,6-dimethyl-4-
Methyl ethyl (3',5'-dimethoxyphenyl)-3,5-pyridinedicarboxylic acid ester Ethyl α-acetyl-β-(3,5-dimethoxyphenyl).
3.5 g of acrylate was dissolved and then 2.25 g of methyl aminocrotonate was added. 48 mixture
Heated at 40°C for an hour, then the solvent was removed in vacuo. The resulting oily compound was heated to boiling in n-hexane. Upon cooling, a solid precipitate was obtained. Yield: 4g (85%), melting point = 122
℃. Example 1 1,4-dihydro-2,6-dimethyl-4-
Production of (2'-methoxymethoxyphenyl)-3,5-pyridinedicarboxylic acid methyl ethyl ester (IQB-836V) (a) 2-methoxymethoxy benzaldehyde 36.6 g (0.3 mol) of salicylaldehyde and 7.3 g of sodium was dissolved in a mixture of 72 ml of absolute toluene and 18 ml of absolute ethanol. 100 ml of toluene was added again to dissolve the copious yellow precipitate of the corresponding sodium salt and the mixture was stirred for 1 hour. After cooling the mixture in an ice-salt bath, 24.7 g of freshly distilled monochloromethyl ether were slowly added with vigorous stirring. The mixture was then stirred for 24 hours at room temperature. The extent of reaction progress was evidenced by the formation of a white precipitate of sodium chloride. The sodium chloride was filtered off and the filtrate was washed several times with dilute sodium hydroxide solution to remove any remaining salicylaldehyde. After washing with water, the filtrate was dried over anhydrous magnesium sulfate and
Evaporation of the solvent in vacuo gave an oily product.
This was used in the next step without further purification. Yield: 23g (46%). (b) Ethyl α-acetyl-β-(2-methoxyphenyl) acrylate In a flask connected to a Dean-Stark separator containing benzene, 23 g of 2-methoxymethoxybenzaldehyde and ethyl acetoacetate were added.
18 g and 10 ml of anhydrous benzene were introduced. Heat until completely dissolved, then piperidine 0.55
ml and 1.6 ml of glacial acetic acid were added. The solution was then refluxed for 2 hours until no more water separated. After cooling, the mixture was diluted with diethyl ether,
Washed with 100 ml of 5% hydrochloric acid, 100 ml of sodium bicarbonate and water. The organic phase was dried over anhydrous magnesium sulfate,
The solvent was then removed in vacuo, yielding an oily compound. This was purified by distillation under 2 mmHg. The 135-145°C portion was used in the next step. Yield: 21g (55%). (c) 1,4-dihydro-2,6-dimethyl-4-
(2'-methoxymethoxyphenyl)-3,5-pyridinedicarboxylic acid methyl ethyl ester Dissolve 21 g of ethyl α-acetyl-β-(2-methoxymethoxyphenyl) acrylate in 50 ml of isopropanol, 8.6 g of methyl crotonate were added and the mixture was stirred for 48 hours at room temperature. Evaporation of the solvent in vacuo yielded an oily compound. This was crystallized in diisopropyl ether. The product was then recrystallized in ethyl acetate-cyclohexane (10:90). Yield: 17g
(60%), melting point = 129.6°C. Example 2 1,4-dihydro-2,6-dimethyl-4-
(2',3'-methylenedioxyphenyl)-3,5
-Production of pyridinedicarboxylic acid methyl ethyl ester (IQV-837V) (a) 2,3-methylenedioxybenzaldehyde 2,3-dihydroxybenzaldehyde 69g
(0.5 mol) was dissolved in 825 ml of dimethylformamide and then 144.9 g of potassium fluoride was added. The mixture was cooled in an ice bath and then 96 g of dibromomethane was slowly added with vigorous stirring. The mixture was then heated at 110-120°C for 2 hours.
After cooling, the solution was filtered through a glass filter and the residue was washed with 300 ml of chloroform. Removal of the solvent in vacuo yields an oily product,
This was distilled under reduced pressure (5 mmHg). 54.5 g (73%) of viscous oil was obtained (melting point = 109 °C,
5mmHg). This was slowly solidified. (b) Ethyl α-acetyl-β-(2,3-methylenedioxyphenyl) acrylate Method 1: In a flask connected to a Dean-Stark separator, add 36 g of 2,3-methylenedioxy benzaldehyde. and 31.2 g of ethyl acetoacetate in 17 ml of benzene were introduced. The mixture was heated to 60-70<0>C, then 0.96 ml of piveridine and 3.84 ml of glacial acetic acid were added. The resulting solution was refluxed for 2 hours until no water separated. Removal of the solvent in vacuo yielded an oily compound. This was solidified and recrystallized in ethanol. Yield: 55g (85%), melting point: 97-100°C. Method 2: 5 g of 2,3-methylenedioxybenzaldehyde, 4.5 g of ethyl acetoacetate, piperidine
0.13ml and 0.39ml of glacial acetic acid, anhydrous ethanol
Dissolved in 50ml. The mixture was refluxed for 2 hours, then the solvent was evaporated to almost dryness. ethanol
50ml was added again and then refluxed again for 2 hours. The solvent was removed in vacuo. The resulting oily product was allowed to solidify on standing at 4°C and was recrystallized in ethanol. Yield: 7.3g (83%), melting point = 97
~100℃. (c) 1,4-dihydro-2,6-dimethyl-4-
(2',3'-methylenedioxyphenyl)-3,5
-Pyridinedicarboxylic acid methyl ethyl ester 56 g of ethyl α-acetyl-β-(2,3-methylenedioxyphenyl) acrylate were dissolved in 250 ml of hot isopropanol and then 24 g of methyl aminocrotonate were added. The mixture was stirred for 48 hours at 40°C, then the solvent was removed in vacuo. The resulting solid was washed with diisopropyl ether and then recrystallized twice in ethanol. Yield: 55g (72%), melting point = 166.5°C. Example 3 1,4-dihydro-2,6-dimethyl-4-
(2',3'-ethylenedioxyphenyl)-3,5
-Production of pyridinedicarboxylic acid methyl ethyl ester (IQB-838V) (a) 2,3-ethylenedioxybenzaldehyde 2,3-dihydroxybenzaldehyde 5.52
g (0.04 mol), dimethylformamide 75 ml
Then, 11.6 g of potassium fluoride was added. The mixture was cooled in an ice bath and then 7.5 g of 1,2-dibromoethane was slowly added with vigorous stirring. The mixture was then heated at 110-120°C for 2 hours.
After cooling, the solution was filtered through a glass filter. The solid residue was washed with chloroform and the filtrate was washed with water.
It was diluted with 100ml and then extracted with chloroform. The organic phase was decanted, washed with a dilute solution of sodium hydroxide (IN) and water, dried over anhydrous magnesium sulfate and then evaporated in vacuo. The oily product obtained was used in the next step without further purification. Yield: 4.5g (70%). (b) Ethyl α-acetyl-β-(2,3-ethylenedioxyphenyl) acrylate 2,3-ethylenedioxybenzaldehyde was added to a flask connected to a Dean-Stark separator containing anhydrous benzene. 4.5 g, 3.5 g of ethyl acetoacetate and 10 ml of benzene were introduced. Heat the mixture gently until completely dissolved,
Then 0.12 ml of piperidine and 0.4 ml of glacial acetic acid were added. The solution was refluxed for 2 hours. After cooling, the mixture was diluted with benzene, then 25 ml of 5% hydrochloric acid, 5%
Washed three times with sodium bicarbonate and water. The organic phase was decanted and dried over anhydrous magnesium sulfate, then the solvent was evaporated in vacuo. The oily product obtained was slowly solidified and recrystallized in ethanol. Yield: 6.5g (85
%). (c) 1,4-dihydro-2,6-dimethyl-4-
(2',3'-ethylenedioxyphenyl)-3,5
- Pyridinedicarboxylic acid methyl ethyl ester 6.5 g of ethyl α-acetyl-β-(2,3-ethylenedioxyphenyl) acrylate are dissolved in 50 ml of hot isopropanol and then 2.7 g of methyl aminocrotonate are added. did. The mixture was stirred for 48 hours at 40°C, then the solvent was removed in vacuo, yielding an oily product. This was recrystallized in ethanol. Yield: 6.8g
(77%), melting point = 169°C. Example 4 1,4-dihydro-2,6-dimethyl-4-
(2',3'-methylenedioxyphenyl)-3,5
-Production of pyridinedicarboxylic acid methyl ester (IQB-841) (a) Methyl α-acetyl-β-(2,3-methylenedioxyphenyl) acrylate in a flask connected to a Dean-Stark separator. , 28 g of 2,3-methylenedioxybenzaldehyde and 21.6 g of methyl acetoacetate in 13 ml of anhydrous benzene were introduced. The mixture was heated until dissolved, then 0.74 ml piperidine and 2.24 ml glacial acetic acid were added. The resulting solution was refluxed for 2 hours until no water separated. After cooling, the mixture was diluted with benzene to 5%
Washed with 20 ml of hydrochloric acid, 5% sodium bicarbonate and water. The organic phase was decanted, dried over anhydrous magnesium sulfate and evaporated in vacuo to yield an oily product.
This was used as it was in the next step. Yield: 25
g (54%). Purification of the sample by recrystallization in 90% ethanol resulted in a yellow-white solid.
Melting point: 73-74℃. (b) 1,4-dihydro-2,6-dimethyl-4-
(2',3'-methylenedioxyphenyl)-3,5
- Preparation of pyridinedicarboxylic acid dimethyl ester 10 g of methyl α-acetyl-β-(2,3 methylenedioxyphenyl)-acrylate were dissolved in 50 ml of hot isopropanol and then 4.3 g of methyl aminocrotonate were added. The mixture was stirred for 48 hours at room temperature. The solid precipitate was filtered off and the filtrate was evaporated in vacuo to give an oily product. This was recrystallized twice in hot methanol. Yield: 6g (43%), melting point = 202°C. Example 5 1,4-dihydro-2,6-dimethyl-4-
(2',3'-methylenedioxyphenyl)-3,5
-Methyl isobutyl pyridinedicarboxylate
Production of ester (IQB-842) (a) Isobutyl α-acetyl-β-(2,3-
Methylenedioxyphenyl) acrylate 10 g of 2,3-methylenedioxybenzaldehyde, 10.5 g of isobutyl acetoacetate and 5 ml of benzene were introduced into a flask connected to a Dean-Stark separator containing anhydrous benzene. The mixture was heated until dissolved and 0.26 ml piperidine and 0.80 ml glacial acetic acid were added. The resulting solution was refluxed for 2 hours, then the mixture was diluted with benzene and washed three times with 20 ml of 5% hydrochloric acid, 5% sodium bicarbonate and water. Drying the organic phase over anhydrous magnesium sulfate and then removing the solvent in vacuo yields an oily product. This was recrystallized in n-hexane. The product was purified by recrystallization in isopropanol/n-hexane. Yield: 13.3g (69
%), melting point = 62-64°C. (b) 1,4-dihydro-2,6-dimethyl-4-
(2',3'-methylenedioxyphenyl)-3,5
-Methyl isobutyl pyridinedicarboxylate
Ester isobutyl α-acetyl-β-(2,3-
methylenedioxyphenyl) acrylate 10
g was dissolved in 50 ml of hot isopropanol and then 4 g of methyl aminocrotonate were added.
The mixture was stirred for 48 hours at room temperature, then the solvent was removed in vacuo. The oily product obtained was solidified after boiling in n-hexane and cooling. Yield: 10g
(80%), melting point = 153°C. Example 6 1,4-dihydro-2,6-dimethyl-4-
(2',3'-methylenedioxyphenyl)-3,5
-Preparation of pyridinedicarboxylic acid isopropyl methyl ester (IQB-845) (a) Methyl α-acetyl-β-(2,3-methylenediosyphenyl) acrylate This intermediate was described in Example 9. manufactured by the method. (b) 1,4-dihydro-2,6-dimethyl-4-
2′,3′-methylenedioxyphenyl)-3,5
-Pyridinedicarboxylic acid isopropyl methyl ester 5 g of methyl α-acetyl-β-(2,3-methylenedioxy) acrylate were dissolved in 30 ml of hot isopropanol and then 2.8 g of isopropyl aminocrotonate were added. The mixture was stirred for 48 hours at room temperature, then the solvent was removed in vacuo, yielding an oily product which was solidified by the addition of n-hexane. The product was purified by recrystallization in n-hexane-isopropanol. Yield: 3g (40%). Example 7 1,4-dihydro-2,6-dimethyl-4-
(2',3'-methylenedioxyphenyl)-3,5
- Preparation of pyridinedicarboxylic acid isopropyl ethyl ester (IQB-847) (a) Ethyl α-acetyl-β-(2,3-methylenedioxyphenyl) acrylate This intermediate is described in Example 7. It was manufactured according to the method described above. (b) 1,4-dihydro-2,6-dimethyl-4-
(2',3'-methylenedioxyphenyl)-3,5
-Pyridinedicarboxylic acid isopropyl ethyl ester 5 g of ethyl α-acetyl-β-(2,3-methylenedioxyphenyl) acrylate were dissolved in 50 ml of hot isopropanol, then 2.66 g of isopropyl aminocrotonate were added. . The mixture was heated at 40° C. for 48 hours, then the solvent was evaporated in vacuo to yield a solid. This is n
- Recrystallized in hexane. Yield: 4.5g
(62%), melting point = 165°C. Each of the compounds of the present invention and comparative compounds was subjected to pharmacological tests to demonstrate calcium pathway blocking properties. These tests were performed "in vitro" and "in vivo" according to conventional methods. (1) "In vitro" test: Inhibitory effect of potassium chloride-induced contraction in rat aortas Wistar rats weighing 220-250 g were decapitated, their aortas were removed, and Krebs solution with the following composition was added at 34°C. Place in a 20ml bath. Composition (mmol/): NaCl: 137;
KCl: 2.7; MgCl ₂・6H ₂ O: 1.04; CaCl ₂・
2H ₂ O: 0.8; Na ₂ HPO ₄・H ₂ O: 0.42;
_NaHCO3 : 11.9; Glucose: 5, _O2 (95%)
+oxygenated with CO ₂ (5%) (Furchgott and Bhadakrom, 1956). After a stabilization period of 45 minutes under a tension of 2 g, maximal contraction of the artery was induced by adding potassium chloride into the bath to obtain a final concentration of 80 mmol/. After stabilization of contraction, each compound or nifedipine (used as a control compound) was administered cumulatively, separated by at least 10 minutes to allow stabilization of relaxation. Pre-solutions of approximately 1 mg/ml were prepared by dissolving each compound in ethanol. By addition of saline from these solutions
Dilutions of 10 ⁻¹⁰ M to ^{10 −6} M were obtained. Inhibitory concentration 50 (IC50) was determined by regression analysis. (2) “In-vivo” test The tail of a conscious spontaneously hypertensive (SHR) rat was tested using an inflatable rubber arm sphygmomanometer and a digital manometer LE5000 (from Barcelona, Spain).
Systolic blood pressure was measured using Letica Instruments (manufactured by Letica Instruments). Measurements were carried out before product administration and 30 minutes, 1 hour, 2 hours, 6 hours and 24 hours after administration. During the measurements, the animals were fixed in a preheated plastic cylinder. Rats with blood pressure below 160 mmHg were not included in the experiment. Each compound was tested on 5 animals. Each compound as well as nitrepine (used as a control compound)
It was administered orally in the form of a suspension in 5% gum arabic. Table 1 shows the in vitro activity of compounds of the invention against contractions induced in rat aortas by potassium chloride (80mM). Compound 2 with an IC50 of 3.5×10 ⁻⁹ M was found to be the most active of the ethyl methyl diester derivative series. In the same test, nifedipine, with an IC50 of 7.5×10 ⁻⁹ M, was found to be approximately two times less active than Compound 2. Comparative compounds 1, 2 and 3 with substituents in the para position on the phenyl group were found to have little or no activity. Compounds 1 and 3, which have an ortho-methoxymethoxy group, showed considerably better activity. Among the derivatives of compound 2, the asymmetric derivative was found to be the most active. This feature is common to all calcium inhibitors derived from 1,4-dihydropyridine, with symmetrical compounds generally being less active than asymmetrical compounds.
Compound 7, with an IC50 of 2.1×10 ⁻⁹ M, was found to be as active as compound 2. Table 2 shows the in vivo activity of compounds of the invention on blood pressure in spontaneously hypertensive (SHR) rats. In this test, compound 2 (8 mg/Kg, P.
OS.) is night range pin (8mg/KgP.OS.)
and lowered blood pressure in SHR rats.
Reduce by 30%. Compound 3 was quite active in vitro.
showed only a slight antihypertensive effect.
On the other hand, compounds 1, 5 and 7 were shown to be active in vivo. Next, acute toxicity tests for the compounds of the present invention will be described. The LD ₅₀ value of Compound 2 of Example 2 by oral administration is 700 mg/Kg in mice and 1500 mg/Kg in rats.
It was mg/Kg. Other compounds 1, 3, 4,
The LD ₅₀ values of 5, 6 and 7 are the LD ₅₀ of compound 2.
The value was equal to or higher than the value.

[Table] Note: “Ratio” indicates a comparative compound.

【table】

【table】

Claims (1)

[Claims] 1. General formula (wherein R is 2-methoxymethoxy, 2,3-
methylenedioxy or 2,3-ethylenedioxy group, R ₁ and R ₂ are both methyl groups or are different from each other and are linear or branched C ₁ -
It is a _C4 alkyl group. ) 1,4-dihydropyridine derivatives and pharmacologically acceptable inorganic or organic acid addition salts thereof. 2 1,4-dihydro-2,6-dimethyl-4-
The compound according to claim 1, which is (2'-methoxymethoxyphenyl)-3,5-pyridinedicarboxylic acid methyl ethyl ester. 3 1,4-dihydro-2,6-dimethyl-4-
(2',3'-methylenedioxyphenyl)-3,5-
The compound according to claim 1, which is pyridinedicarboxylic acid methyl ethyl ester. 4 1,4-dihydro-2,6-dimethyl-4-
(2',3'-ethylenedioxyphenyl)-3,5-
The compound according to claim 1, which is pyridinedicarboxylic acid methyl ethyl ester. 5 1,4-dihydro-2,6-dimethyl-4-
(2',3'-methylenedioxyphenyl)-3,5-
The compound according to claim 1, which is pyridinedicarboxylic acid methyl isobutyl ester. 6 1,4-dihydro-2,6-dimethyl-4-
(2',3'-methylenedioxyphenyl)-3,5-
The compound according to claim 1, which is pyridinedicarboxylic acid methyl isopropyl ester. 7 1,4-dihydro-2,6-dimethyl-4-
(2',3'-methylenedioxyphenyl)-3,5-
The compound according to claim 1, which is ethyl isopropyl pyridinedicarboxylate ester. 8 General formula (wherein R is 2-methoxymethoxy, 2,3-
Methylenedioxy or 2,3-ethylenedioxy group. ) The substituted benzaldehyde represented by the general formula (In the formula, R ₁ is a linear or branched C ₁ to C ₄ alkyl group.) (In the formula, R and R ₁ have the same meanings as above.) α-(acetyl)-β-(substituted phenyl)
Acrylic acid ester, general formula (In the formula, R ₂ is a linear or branched C ₁ to C ₄ alkyl group. However, in relation to R ₁ , R ₁ and R ₂ are the same when R ₁ and R ₂ are both methyl groups; in other cases, R ₂ is a group different from R _1. ) general formula (In the formula, R, R ₁ and R ₂ have the same meanings as above.) A 1,4-dihydropyridine derivative represented by the above formula is obtained, and if desired, it is added to a pharmacologically acceptable inorganic or organic acid addition salt. 1. A method for producing a 1,4-dihydropyridine derivative, which is characterized by leading to the following. 9 General formula (wherein R is 2-methoxymethoxy, 2,3-
methylenedioxy or 2,3-ethylenedioxy group, R ₁ and R ₂ are both methyl groups or are different from each other and are linear or branched C ₁ -
It is a _C4 alkyl group. ) A therapeutic drug for cardiovascular disorders, which contains as an active ingredient a 1,4-dihydropyridine derivative represented by the following formula and a pharmacologically acceptable inorganic acid or organic acid addition salt thereof. 10. The therapeutic agent according to claim 9, which is combined with a pharmacologically acceptable excipient.