JPH0564150B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the general formula "In the formula, R ¹ and R ⁵ are the same or different and represent a lower alkyl group; R ² is a pyridyl, imidazolyl, imidazopyridyl or tetrahydroimidazopyridyl group; R ³ is a phenyl group substituted with a nitro group. ; R ⁴ represents an esterified carboxyl group; A represents an alkylene or alkyleneoxyalkylene group; X represents an oxygen or sulfur atom; and n represents an integer from 4 to 10, respectively. The present invention relates to novel 1,4-dihydropyridine derivatives and salts thereof. [Objective of the Invention] The object of the invention is to provide a novel drug which has not only a vasodilating effect but also a platelet aggregation inhibiting effect and is useful as a vasodilator, an antihypertensive agent, an antithrombotic agent, and a therapeutic agent for cerebral and cardiac circulation disorders. The objective is to provide compounds that are [Prior art] Conventionally, 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-
Dicarboxylic acid-dimethyl ester (generic name: nifedipine, U.S. Pat. No. 3,644,627) and 2,6
-dimethyl-4-(3-nitrophenyl)-1,4
-dihydropyridine-3,5-dicarboxylic acid-3
-1,4-dihydropyridine derivatives such as [2-(N-benzyl-N-methylamino)ethyl] ester-5-methyl ester hydrochloride (generic name: nicardipine, Japanese Patent Publication No. 55-45075) cause cerebral circulation disorders. It was known to be useful as a therapeutic agent for cardiovascular disorders. [Problems to be Solved by the Invention] However, although all of these have a strong vasodilatory effect, their effect on blood clots, which is a cause of cerebral and cardiac circulation disorders, cannot be said to be sufficient. [Means for Solving the Problems] Under such circumstances, the present inventors added the general formula -A-X-(CH ₂ ) _o - to the carboxyl group of a conventionally known 1,4-dihydropyridine derivative. R ² [wherein R ² , A, X and n have the meanings described above. ] A compound into which a group represented by is introduced, that is, a novel 1,4-dihydropyridine derivative represented by the general formula () and its salt, has not only a vasodilatory effect but also an excellent platelet aggregation inhibiting effect,
The inventors have discovered that the intended purpose can be achieved and have completed the present invention. The compounds of the present invention will be explained below. In this specification, lower alkyl groups include, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,
C _1-4 alkyl groups such as tert-butyl; aryl groups include, for example, phenyl, naphthyl; alkylene groups include, for example, methylene, ethylene, propylene, trimethylene, tetramethylene, pentamethylene, hexamethylene; A C _1-6 alkylene group such as methylene, 1-methyltrimethylene; an alkyleneoxyalkylene group is a C _1-6 alkylene group having an oxygen atom in the chain, such as methyleneoxyethylene, ethyleneoxyethylene, propyleneoxyethylene, etc. Alkyleneoxy C _1-6 alkylene group; halogen atom means, for example, fluorine atom, chlorine atom, bromine atom, iodine atom, etc. Examples of the ester-forming group in the esterified carboxyl group of R ⁴ include ester-forming groups commonly known in the art, such as lower alkyl groups; methoxyethyl, methoxypropyl, Lower alkoxy-lower alkyl groups such as ethoxyethyl, propoxyethyl, butoxyethyl; lower alkylthio-lower alkyl groups such as methylthioethyl, ethylthioethyl, propylthioethyl, butylthioethyl; N,N-dimethylaminoethyl, N,
N,N-di(lower alkyl) such as N-diethylaminoethyl, N,N-dipropylaminoethyl
Amino-lower alkyl group; N-benzyl-N-methylaminoethyl, N-(4-chlorobenzyl)-
N-aralkyl-N such as N-methylaminoethyl, N-benzyl-N-methylaminopropyl
-lower alkylamino-lower alkyl group; N-aryl-N-lower alkylamino-lower alkyl group such as N-phenyl-N-methylaminoethyl; N, such as N,N-dibenzylaminoethyl;
Examples include groups such as N-dialkylamino-lower alkyl groups. The salt of the 1,4-dihydropyridine derivative of general formula () may be any pharmaceutically acceptable salt, such as salts with mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, fumaric acid,
Salts with organic carboxylic acids such as maleic acid, malic acid, tartaric acid, aspartic acid, methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid,
Examples include salts with inorganic acids and organic acids, such as salts with sulfonic acids such as hydroxybenzenesulfonic acid, dihydroxybenzenesulfonic acid, and naphthalenesulfonic acid. The compounds of the present invention include optical isomers, geometric isomers, and tautomers, and further include all hydrates and crystal forms. The 1,4-dihydropyridine derivative of general formula () or its salt of the present invention can be produced by a method known per se, for example, by the method shown below. [In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , A, X and n have the above-mentioned meanings. ] According to this method, compounds of the general formula (), (), and () are reacted in the presence or absence of an organic solvent or water that does not usually have a negative effect on the reaction. A compound or a salt thereof is obtained. Examples of organic solvents used here include alcohols such as methanol, ethanol, isopropanol, butanol, ethylene glycol, and methyl cellosolve; aromatic hydrocarbons such as benzene and toluene; and halogenated hydrocarbons such as 1,2-dichloroethane. Hydrogens; tetrahydrofuran, dioxane,
Examples include ethers such as 1,2-dimethoxyethane; nitriles such as acetonitrile; amides such as N,N-dimethylformamide and N,N-dimethylacetamide; mixtures of two or more of these organic solvents or water You may also use it as In this reaction, the amount of the compound of general formula () and () to be used is preferably 0.5 to 2.0 times the mole of the compound of general formula (), respectively. Further, the reaction temperature is preferably 30 to 150°C and the reaction time is preferably 1 to 24 hours. The starting material for the method of the present invention can be produced, for example, by the following method or a combination of methods known per se. (i) Method for producing a compound of the general formula () The compound of the general formula () has the general formula R ⁵ COCH ₂ R ⁴ [wherein R ⁴ and R ⁵ have the above-mentioned meanings]
ammonia to the compound, for example, Journal of American Chemical Society (J. Am. Chem. Soc.), Vol.
It can be obtained by reacting under the conditions described in 2010). (ii) Method for producing the compound of general formula () The compound of general formula () can be obtained, for example, by the method shown below. [In the formula, R ⁶ represents a halogen atom or an alkylsulfonyloxy or arylsulfonyloxy group, and R ¹ , R ² , A, X and n have the meanings described above. ] Compounds of general formula () can be obtained by purchasing a compound of general formula () or a salt thereof and a compound of general formula (), for example, from Synthetic Organic Chemistry, John Wiley & Sons.
& Sons) Chapter 6, pages 226-229 (1961). Examples of the salt of the compound of general formula () include the same salts as those listed as the salt of general formula (), and this salt can be produced by a method known per se. Diketene is added to the thus obtained compound of general formula (), for example, Journal of Chemical Society (J.Chem.Soc.), Vol. 97, No.
The compound of the general formula () is produced by reacting under the conditions described in, for example, p. 1987 (1910). The compound of the general formula () thus obtained can be isolated and purified by conventional methods such as extraction, crystallization, column chromatography, etc. Salts of the compound of the general formula () can be prepared by methods known per se. obtained by the method of [Effects of the Invention] Next, the pharmacological actions of representative compounds of the present invention will be described. Test substance 1 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-[2-[4-(imidazole-
1-yl)butyloxy]ethyl]ester-
5-ethyl ester 2 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-[2-[7-(imidazole-
1-yl)heptyloxy]ethyl]ester-5-ethyl ester 3 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-[2-[9 -(imidazole-
1-yl)nonyloxy[ethyl]ester-
5-ethyl ester 4 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-[2-[9-(imidazole-
1-yl)nonylthio]ethyl]ester-5
-ethyl ester 5 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-[2-[6-(imidazo[1,
5-a]pyridin-5-yl)hexyloxy]ethyl]ester-5-ethyl ester 6 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3 -[2-[6-(5,6,7,8
-tetrahydroimidazo[1,5-a]pyridin-5-yl)hexyloxy]ethyl]ester-5-ethyl ester 7 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3, 5-dicarboxylic acid-3-[2-[2-[4-(imidazol-1-yl)butyloxy]ethyloxy]
Ethyl] ester-5-ethyl ester 8 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-[2-[2-[5-(pyridine-
3-yl)pentyloxy[ethyloxy]ethyl]ester-5-ethyl ester 9 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-[2- [9-(pyridine-3-
yl)nonyloxy]ethyl]ester-5-
Ethyl ester nicardipine: 2,6-dimethyl-4-(3-
Nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-[2-(N-benzyl-N-methylamino)ethyl] ester-
5-Methyl ester/hydrochloride OKY-1581: (E)-3-[4-(pyridine-3
-ylmethyl)phenyl]-2-methylpropenoic acid sodium sodium 1 Coronary vasodilator action [Hartley strain, male,
The hearts of 500-700 g, 3 animals per group were removed and placed in a Langendorff perfusion device. Add about 0.5% defibrinated blood and 95% _O2
The test substance was perfused with Krebs bicarbonate solution through which a mixed gas of 5% _CO2 and 5% CO2 was aerated.
EL), manufactured by Sigma Corporation] to a concentration of 1 mg/ml, diluted with physiological saline to the desired concentration, and injected into the aorta retrogradely from a rubber tube just before the cannula. Administered in ml volume. The dilation effect is measured by perfusing the coronary blood vessels from the aorta and measuring the volume of fluid flowing out using a droplet meter (all-purpose droplet meter: manufactured by Natsume Seisakusho), and the flow rate is increased by 50% compared to before adding the test substance. The dose was determined as the ED ₅₀ value. The results are shown in Table-1.

[Table] 2 Effect of increasing blood flow in the vertebral artery Pentobarbital sodium (30 mg/Kg, i.
v.) anesthetized dogs (mongrel, 12-20 kg, 2-2 per group)
The vertebral artery blood flow was measured using an electromagnetic blood flow meter (Nihon Kohden Industries, MFV-2100). Test substance 1
It was prepared in the same manner as above and administered intravenously. Determine the dose of the test substance that shows the same activity as papaverine hydrochloride 1 mg/Kg (iv), and calculate the dose of papaverine hydrochloride (1 mg/Kg (iv)).
Kg) was calculated and expressed as efficacy ratio. The results are shown in Table-2.

[Table] 3. Thromboxane synthetase inhibitory effect on rats (Wistar strain, male,
(300-350 g, 4 animals per group) was mixed with a test substance solution [adjusted to a concentration of 5 mg/ml with an aqueous solution containing 10% (by volume) each of dimethyl sulfoxide and Cremophor EL, and then adjusted to the target concentration with water. diluted product] was administered orally, and 1 hour later, citrate blood was collected from the abdominal aorta. Preincubate 2 ml of platelet rich plasma (PRP) at 1×10 ⁹ /ml for 2 minutes at 37°C. Next, 0.1 ml of 10 mM sodium arachidonate is added and the reaction is allowed to proceed for 6 minutes, followed by the addition of indomethacin to stop the reaction. After the reaction solution was subjected to protein removal treatment and reacted with TBA (thiobarbituric acid) reagent, n-butanol 3
Extract in ml. This extract was measured colorimetrically (λ=
532nm) to measure the amount of malondialdehyde (MDA) produced. Platelet-poor plasma (PPP) obtained from the same individual is similarly operated to measure the amount of MDA produced, and the difference is taken as the MDA value. Compared with the MDA value of the control group, MDA due to the test substance
The production inhibition rate (%) was determined. The results are shown in Table-3.

[Table] 4. Antithrombotic effect (effect on mouse pulmonary infarction model) Method of G. Diminno and M.J.Silver [Journal of Pharmacology and Experimental Therapy (J. .Pharmacol.Exp.Therap.), Chapter
225 (No. 1), pp. 57-60 (1983)]. Specifically, a test substance solution prepared in the same manner as in 3 was orally administered to mice (ICR strain, male, 4 weeks old), and 1 hour later, 0.1 ml of a mixture of collagen (150 μg/ml) and epinephrine (100 μM) was intravenously administered. The effect of preventing death and cases of paralysis lasting more than 10 minutes was investigated. The results are shown in Table 4.

【table】

[Table] 5 Acute Toxicity The LD ₅₀ values of test substances 3, 4, 5, and 9 administered intravenously to mice (ICR strain, male, 4 weeks old, 5 mice per group) were 30 mg/Kg or higher. From the above results, it can be easily understood that the compound of the present invention has an excellent vasodilatory effect and a platelet aggregation inhibiting effect, that is, an antithrombotic effect based on an inhibitory effect on thromboxane synthase, and has low toxicity. Therefore, the compound of the present invention is a vasodilator, an antihypertensive agent,
It is a useful compound as an antithrombotic agent and a therapeutic agent for cerebral and cardiac circulation disorders. When the compound of the present invention is used as a medicine, it can be prepared by itself or mixed with appropriate additives such as pharmaceutically acceptable excipients, carriers, and diluents, and in the form of tablets, capsules, granules, powders, injections, etc. It can be administered orally or parenterally. In the case of oral administration, the dosage is usually about 10 to 600 mg per day for adults.
The dose is administered once or in several doses, and the dose is appropriately selected depending on age, body weight, and symptoms. Reference Examples, Examples, and Formulation Examples will be given below to explain the present invention in more detail, but the present invention is not limited thereto. Reference Example 1 0.50 g of 9-(imidazol-1-yl)nonyl alcohol was dissolved in 5 ml of methylene chloride, 0.52 ml of thionyl chloride was added under ice-cooling, and the solution was dissolved under heating under reflux.
Allow time to react. The solvent and excess thionyl chloride were distilled off under reduced pressure, and the resulting residue was dissolved in ethyl acetate.
Dissolve in a mixed solvent of 20 ml and 20 ml of water, and adjust the pH to 7.5 with a saturated aqueous sodium bicarbonate solution. The organic layer was separated, washed sequentially with 20 ml of water and 10 ml of saturated saline, and dried over anhydrous sodium sulfate.
By distilling off the solvent under reduced pressure, crude 9-(imidazol-1-yl)nonyl chloride hydrochloride is obtained.
This compound, 0.31 ml of 2-mercaptoethanol and 0.18 g of sodium hydroxide are dissolved in 4 ml of ethanol and reacted at room temperature for 30 minutes and then at 50°C for 1 hour. Then, the solvent is distilled off under reduced pressure, and the resulting residue is dissolved in a mixed solvent of 20 ml of ethyl acetate and 20 ml of water. The organic layer is separated, washed successively with 20 ml of water and 10 ml of saturated saline, and dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure, and the resulting residue is crystallized with a mixed solvent of ethanol and diethyl ether to form 2-[9-(imidazole-1) as colorless needle-like crystals with a melting point of 48-50°C. -yl)nonylthio]ethanol 0.42g (yield, 70.0
%). IR (KBr) cm ^-1 : 3150 NMR (CDCl ₃ ) δ value: 1.05 to 2.00 (14H, m), 2.55 (2H, t, J = 7Hz), 2.74 (2H, t, J = 6.5Hz), 3.78 (2H, t, J=6.5Hz), 3.97 (2H, t, J=6.5Hz), 4.20 (1H, s), 7.00 (1H, bs), 7.12 (1H, bs), 7.57 (1H, bs) Reference example 2 (1) 0.28g of metallic sodium is mixed with ethylene glycol
Dissolve 9-(pyridine-3-
A mixture of 0.69 g of nonyl chloride hydrochloride and 2.2 ml of dimethyl sulfoxide was added dropwise,
React at 110°C for 1 hour. Next, add 50 ml of water under ice cooling, adjust the pH to 7 with 2N hydrochloric acid,
Extract with 20ml of toluene. The extract is washed successively with 30 ml of water and 20 ml of saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography [Wako silica gel C-200, elution solvent: toluene:ethyl acetate (volume ratio 5:1)] to obtain 2 as a colorless oil. -[9-pyridin-3-yl)nonyloxy]ethanol 0.46 g (yield
60.5%). IR (film) cm ^-1 : 3350 NMR (CDCl ₃ ) δ value: 1.05 to 1.82 (14H, m), 2.60 (2H, t, J = 7Hz), 3.35 to 3.86 (7H, m), 7.03 to 7.62 ( 2H, m), 8.26-8.63 (2H, m) The following compound was obtained in the same manner. Γ 2-[9-(imidazol-1-yl)nonyloxy]ethanol (colorless oil) IR (film) cm ^-1 : 3420-3200 NMR ( _CDCl3 ) δ value: 0.75-2.10 (14H, m), 3.25- 4.13 (8H, m), 4.22 (1H, s), 6.98 (1H, bs), 7.09 (1H, bs), 7.53 (1H, s) Γ 2-[7-(imidazol-1-yl)hebutyloxy]ethanol (colorless oil) IR (film) cm ^-1 : 3375 Γ 2-[4-(imidazol-1-yl)butyloxy]ethanol (colorless oil) IR (film) cm ^-1 : 3400 to 3300 Γ 2- [6- (Imidazole[1,5-a]pyridin-5-yl)hexyloxy]ethanol (light brown crystals) Melting point: 67℃ IR (KBr) cm ^-1 : 3150 NMR (CDCl ₃ ) δ value: 1.02 ~ 2.15 (8H , m), 2.55-3.05 (2H, m), 3.15-3.85 (7H, m), 6.15-6.85 (2H, m), 7.15-7.45 (2H, m), 8.05 (1H, s) (2) Ethylene Using trimethylene glycol or diethylene glycol instead of glycol
The reaction was carried out in the same manner as in (1) to obtain the following compound. Γ 3-[9-(imidazol-1-yl)nonyloxy]propanol (colorless oil) IR (film) cm ^-1 : 3400-3290 Γ 2-[2-[4-(imidazol-1-yl)]
Butyloxy]ethyloxy]ethanol (colorless oil) IR (film) cm ^-1 : 3375 NMR (CDCl ₃ ) δ value: 1.23 to 2.22 (4H, m), 3.18 to 4.25 (12H, m), 4.53 (1H, s) , 7.07 (1H, bs), 7.15 (1H, bs), 7.68 (1H, s) Γ 2-[2-[5-(pyridin-3-yl)pentyloxy]ethyloxy]ethanol (colorless oil) IR (film )cm ^-1 :3350 Reference example 3 2-[6-(indazo[1,5-a]pyridine-
0.44 g of 5-yl)hexyloxy]ethanol is dissolved in a mixture of 20 ml of ethanol and 5 ml of concentrated hydrochloric acid, 0.70 g of 10% palladium on carbon is added thereto, and the mixture is stirred at room temperature under a hydrogen atmosphere (5 atm) for 8 hours. Filter the reaction solution and concentrate the solution under reduced pressure to obtain 2-[6-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-5-yl)hexyloxy]ethanol/hydrochloric acid. Salt [colorless oil,
IR (film) cm ^-1 : 3400]. This compound is dissolved in 10 ml of chloroform and ammonia gas is introduced for 20 minutes at room temperature. The precipitated ammonia chloride was removed, and the solvent was distilled off under reduced pressure. The residue was dissolved in 5 ml of anhydrous tetrahydrofuran, 1 drop of triethylamine was added thereto, and 0.11 ml of diketene was added.
ml and anhydrous tetrahydrofuran (1 ml) was added dropwise under heating to reflux, and the mixture was allowed to react at the same temperature for 1 hour. Then, the solvent is distilled off under reduced pressure, and the resulting residue is purified by column chromatography [Wako silica gel C-200, elution solvent: chloroform:ethanol (volume ratio 30:1)] to obtain a colorless oil. 0.39 g (yield 66.5%) of acetoacetic acid-2-[6-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-5-yl)hexyloxy]ethyl ester is obtained. IR (film) cm ^-1 : 1740, 1720 NMR (CDCl ₃ ) δ value: 1.15-2.15 (14H, m), 2.24 (3H, s), 2.55-2.90 (2H, m), 3.25-3.75 (6H, m), 3.84-4.40 (3H, m), 6.62 (1H, s), 7.38 (1H, s) Example 1 (1) 0.56 g of 2-[9-(pyridin-3-yl)nonyloxy]ethanol anhydrous Dissolve in 8 ml of tetrahydrofuran and add 1 drop of triethylamine. A mixed solution of 0.20 ml of diketene and 2 ml of anhydrous tetrahydrofuran was added dropwise to this solution over 1 hour while heating under reflux, and the mixture was allowed to react at the same temperature for 1 hour. Then, the solvent is distilled off under reduced pressure, and the residue is purified by column chromatography [Wako silica gel C-200, elution solvent: toluene:ethyl acetate (volume ratio 5:1)] to obtain acetoacetic acid as a colorless oil. -2-[9-(pyridin-3-yl)nonyloxy]ethyl ester 0.71g (yield 95.9
%). IR (film) cm ^-1 : 1745, 1720 NMR (CCl ₄ ) δ value: 1.05 to 1.85 (14H, m), 2.22 (3H, s), 2.62 (2H, t, J = 7Hz), 3.20 to 3.70 ( 6H, m), 4.10-4.35 (2H, m), 7.06-7.58 (2H, m), 8.25-8.53 (2H, m) (2) Acetoacetic acid-2-[9-(pyridin-3-yl)nonyloxy ] Ethyl ester 0.71g, 3
-Aminocrotonic acid ethyl ester (0.34 g) and 3-nitrobenzaldehyde (0.29 g) are dissolved in 8 ml of ethanol and reacted under heating under reflux for 10 hours. Then, the solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography [Wako silica gel C-200, elution solvent: toluene:ethyl acetate (volume ratio 5:1)] to give a yellow oil. 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,
0.91 g (yield 75.8%) of 5-dicarboxylic acid-3-[2-[9-(pyridin-3-yl)nonyloxy]ethyl]ester-5-ethyl ester is obtained. IR (KBr) cm ^-1 : 3330, 1700, 1530, 1345 NMR (CDCl ₃ ) δ value: 1.05 to 1.85 (17H, m), 2.39 (6H, s), 2.65 (2H, t, J = 7.5Hz) , 3.28-3.73 (4H, m), 3.85-4.37 (4H, m), 5.18 (1H, s), 7.10-8.30 (7H, m), 8.35-8.61 (2H, m) Similarly, the following compounds get. Γ 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-[2-[9-(imidazole-
1-yl)nonyloxy[ethyl]ester-
5-ethyl ester (yellow oil) IR (film) cm ^-1 : 1710, 1675, 1535, 1350 NMR (CDCl ₃ ) δ value: 0.83 to 2.03 (17H, m), 2.37 (6H, s), 3.20 to 3.70 (4H, m), 3.78-4.34 (6H, m), 5.13 (1H, s), 6.92 (1H, bs), 7.05 (1H, bs), 7.14-8.28 (6H, m) Hydrochloride: Yellow crystals ( Recrystallization solvent; mixed solvent of ethanol and ethyl acetate) Melting point 143-144℃ Γ 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-[3- [9-(imidazole-
1-yl)nonyloxy]propyl]ester-5-ethyl ester (yellow oil) IR (film) cm ^-1 : 1690, 1525, 1350 NMR (CDCl ₃ ) δ value: 0.70-2.15 (19H, m), 2.45 ( 6H, s), 3.08-3.59 (4H, m), 3.70-4.60 (6H, m), 5.10 (1H, s), 7.20-8.40 (8H, m) Hydrochloride: Yellow crystals (recrystallization solvent; ethanol and Mixed solvent of ethyl acetate) Melting point 114-115℃ Γ 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-[2-[7-(imidazole-
1-yl)hebutyloxy[ethyl]ester-5-ethyl ester (yellow oil) IR (film) cm ^-1 : 1705, 1675, 1615,
1530, 1350 NMR ( _CDCl3 ) δ value: 0.96-2.04 (13H, m), 2.29 (3H, s), 2.39 (3H, s), 3.26-3.70 (4H, m), 3.77-4.34 (6H, m ), 5.15 (1H, s), 6.98 (1H, bs), 7.11 (1H, bs), 7.24-8.29 (6H, m) Hydrochloride: Yellow crystals (recrystallization solvent; mixed solvent of ethanol and ethyl acetate) Melting point 140-145℃ Γ 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-[2-[4-(imidazole-
1-yl)butyloxy]ethyl]ester-
5-ethyl ester Yellow crystals (recrystallization solvent: acetonitrile) Melting point 152-153℃ IR (KBr) cm ^-1 : 1690, 1630, 1350 NMR (CDCl ₃ ) δ value: 1.26 (3H, t, J = 7Hz), 1.44-2.10 (4H, m), 2.42 (6H, s), 3.39-3.80 (4H, m), 3.90-4.40 (6H, m), 5.22 (1H, s), 6.99-8.34 (8H, m) Γ 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-[2-[2-[5-(pyridine-
3-yl)bentyloxy[ethyloxy]ethyl]ester-5-ethyl ester (yellow oil) IR (film) cm ^-1 : 3310, 1690, 1520, 1345 NMR (CDCl ₃ ) δ value: 1.05-1.85 (9H, m ), 2.35 (6H, s), 2.68 (3H, t, J=7Hz), 3.30~3.82 (8H, m), 3.88~4.37 (4H, m), 5.16 (1H, s), 7.07~8.57 (9H , m) Γ 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-[2-[2-[4-(imidazol-1-yl)butyloxy] [Ethyloxy]
Ethyl] ester-5-ethyl ester (yellow oil) IR (film) cm ^-1 : 1690, 1525, 1350 NMR (CDCl ₃ ) δ value: 1.23 (t, J = 7Hz) 0.93 to 2.10 (m) (7H) , 2.33 (3H, s), 2.42 (3H, s), 3.35~3.85 (8H, m), 3.90~4.39 (6H, m), 5.18 (1H, s), 6.97~8.32 (8H, m) Γ 2 ,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-[2-[9-(imidazole-
1-yl)nonylthio]ethyl]ester-5
-Ethyl ester (yellow powder) IR (KBr) cm ^-1 : 3320, 1690, 1525, 1345 NMR (CDCl ₃ ) δ value: 1.00 to 1.98 (17H, m), 2.39 (s) 2.15 to 2.96 (m) ( 10H), 3.80-4.40 (6H, m), 5.16 (1H, s), 6.90-8.30 (8H, m) Hydrochloride: Yellow crystals (recrystallization solvent; mixed solvent of ethanol and diethyl ether) Melting point 118-120℃ Γ 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-[2-[6-(imidazo[1,
5-a]Pyridin-5-yl)hexyloxy]ethyl]ester-5-ethyl ester (yellow oil) IR (film) cm ^-1 : 1690, 1640, 1620,
1520, 1350 NMR ( _CDCl3 ) δ value: 1.20 (3H, t, J = 7Hz), 1.2 ~ 2.05 (8H, m), 2.36 (6H, s), 2.65 ~ 3.05 (2H, m), 3.16 ~ 3.70 (4H, m), 3.80 to 4.32 (4H, m), 5.10 (1H, s), 6.36 (1H, d, J = 6Hz), 6.70 (1H, q, J = 9Hz, 6Hz), 7.0 to 8.15 ( 8H, m) Γ 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-[2-[6-(5,6,7,8
-Tetrahydroimidazo[1,5-a]pyridin-5-yl)hexyloxy]ethyl]ester-5-ethyl ester (yellow oil) IR (film) cm ^-1 : 1740, 1690, 1630,
1525, 1350 NMR ( _CDCl3 ) δ value: 1.08-2.28 (17H, m), 2.38 (3H, s), 2.42 (3H, s), 2.60-3.0 (2H, m), 3.28-3.78 (4H, m) ), 3.80-4.40 (5H, m), 5.16 (1H, s), 6.75 (1H, s), 7.10-8.30 (6H, m) Formulation example 2,6-dimethyl-4-(3-nitrophenyl)
-1,4-dihydropyridine-3,5-dicarboxylic acid-3-[2-[9-(imidazol-1-yl)]
Tablets containing 25 mg of nonyloxy[ethyl]ester-5-ethyl ester are prepared using the following additives in a manner known per se. For 1000 tablets: Above compound 25g Cellulose 70g Lactose 78g Corn starch 70g Magnesium stearate 2g Water Appropriate amount

Claims (1)

[Claims] 1. General formula "In the formula, R ¹ and R ⁵ are the same or different and represent a lower alkyl group; R ² is a pyridyl, imidazolyl, imidazopyridyl or tetrahydroimidazopyridyl group; R ³ is a phenyl group substituted with a nitro group. ; R ⁴ represents an esterified carboxyl group; A represents an alkylene or alkyleneoxyalkylene group; X represents an oxygen or sulfur atom; and n represents an integer from 4 to 10, respectively. 1,4-dihydropyridine derivatives and salts thereof.