JPH0341469B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to 1,4-dihydropyridine derivatives having vasodilatory effects such as hypotensive effects.
More specifically, it relates to a compound represented by the following general formula []. (In the formula, R ¹ is a lower alkyl group, R ² is a hydrogen atom or a halogen atom, R ³ is a halogen atom, a trifluoromethyl group, or a nitro group, R ⁴ and R ⁵ are a hydrogen atom, a lower alkyl group, a trifluoromethyl group, Fluoromethyl group, phenoxy group, phenoxymethyl group, phenylalkyl group, furyl group, thienyl group, pyrrolyl group, pyridyl group, pyrimidyl group, pyridazyl group,
A pyrazolyl group, an imidazolyl group, or a phenyl group which may have a substituent, where the substituent is a lower alkyl group, a lower alkoxy group, a trifluoromethyl group, a nitro group, an amino group, a mono-lower alkylamino group, a di- It is a lower alkylamino group, an acylamino group, a cyano group, a lower alkoxycarbonyl group, a halogen atom or a methylenedioxy group, and A represents a heptamethylene group or an octamethylene group which may be substituted with a lower alkyl group. ) 4-(2-nitrophenyl) is a 1,4-dihydropyridine derivative that has been widely used as a therapeutic agent for heart diseases, cerebral circulation disorders, hypertension, etc.
-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester (US Pat. No. 3,485,847; abbreviated as nifedipine) and 4-
(3-nitrophenyl)-2,6-dimethyl-1,
4-dihydropyridine-3,5-dicarboxylic acid 3
-Methyl ester-5-β-(N-benzyl-N
-Methylamino)ethyl ester hydrochloride (Tokukosho
No. 55-45075; abbreviated as nicardipine), etc. are known. However, when these compounds are administered intravenously at 10 μg/Kg to dogs etc., the vasodilatory and antihypertensive effects disappear in a short period of about 30 to 40 minutes, and these compounds may place a burden on cardiac function. It has been reported that it has an effect of increasing heart rate, which is one of the causes of
Forschung, Volume 22, Issue 1, Page 33, 1972;
Volume 26, No. 12, Page 2172, 1976; Journal of the Toho Medical Society,
Volume 26, No. 12, Page 48, 1979). Therefore, in order to maintain the stable effects of these compounds as therapeutic agents for hypertension and heart diseases over a long period of time, measures such as increasing the frequency of administration, creating sustained-release formulations, or using them in combination with other drugs are required. be forced to do so. The present invention has the above general formula [] which has a sustained blood pressure lowering effect and a vasodilatory effect, has a small effect on heart rate, and is therefore useful as a therapeutic drug for hypertension, cerebral and heart diseases, etc. The object of the present invention is to provide 1,4-dihydropyridine derivatives as shown below. The compound of the present invention [) is represented by the following general formula [] (In the formula, R ¹ , R ² , R ³ , R ⁴ and A have the same meanings as above.) Includes tautomers and optical isomers based on the asymmetric carbon atom at the 4-position of the 1,4-dihydropyridine ring. do. The lower alkyl groups in R ¹ , R ⁴ , R ⁵ and A in the general formula [] are methyl group, ethyl group, n-
1 or more carbon atoms such as propyl group, isopropyl group, n-butyl group, isobutyl group or tert-butyl group
Represents 4 straight or branched alkyl groups,
The halogen atoms represented by R ² and R ³ include a chlorine atom, a fluorine atom, a bromine atom, or an iodine atom, and when R ² and R ³ are both halogen atoms, it is preferable that they both be chlorine atoms. . ^R4 ,
The phenyl alkyl group in R ⁵ is a benzyl group, a chlorobenzyl group, a methoxybenzyl group,
Examples include α-phenethyl group, β-phenethyl group, and phenoxymethyl group. The phenyl group that may have a substituent for R ⁴ and R ⁵ includes an unsubstituted phenyl group, a chlorophenyl group, a bromophenyl group, a fluorophenyl group, an iodophenyl group, a dichlorophenyl group, a dibromophenyl group, a difluorophenyl group, and an unsubstituted phenyl group. enyl group, methoxyphenyl group, dimethoxyphenyl group, trimethoxyphenyl group, methylenedioxyphenyl group, tolyl group, ethyl phenyl group, propylphenyl group, butylphenyl group,
Dimethylphenyl group, diethylphenyl group, trimethylphenyl group, methoxycarbonylphenyl group, ethoxycarbonylphenyl group, propoxycarbonylphenyl group, butoxycarbonylphenyl group, aminophenyl group, N-methylaminophenyl group, N-ethylaminophenyl group, N,N
-diethylaminophenyl group, N-acetylaminophenyl group, N-benzoylaminophenyl group, etc. In addition to being unsubstituted, the heptamethylene group or octamethylene group represented by A is substituted at any of the 1st to 7th positions in the heptamethylene group, and the 1st position in the octamethylene group.
It also includes those substituted with one or two lower alkyl groups at any of the to 8-positions. In this case, the lower alkyl group is most preferably a methyl group, and the bonding position is preferably at the end of each alkylene group. JP-A-56-140989 describes a compound in which an imidazolyl group is bonded to an alkylene group as the 5-position ester residue of a 1,4-dihydropyridine derivative, but this is because the alkylene group is bonded to the nitrogen atom of the imidazole ring. It is a direct combination. on the other hand,
The compound of the present invention is structurally novel in that an oxygen atom is interposed between the alkylene group and the pyrazolyl group, and it has a long-lasting and excellent pharmacological effect as described below. Next, pharmacological activity tests of representative compounds of the present invention [ ] will be explained. Measurement of blood pressure lowering effect, vasodilatory effect and heart rate Administration method: The drug was dissolved in polyethylene glycol 400 and used. Intravenous administration: The drug was administered into the right femoral vein of a mongrel dog weighing 8 to 12 kg. The results are shown in Table 1. Intraduodenal administration: Using the same animal as above, a polyethylene tube catheter was inserted into the duodenum, and after fixation, the drug was administered through the catheter. The results are shown in Table 2. Measurement method: The experimental animals were anesthetized by intravenously administering 30 mg/Kg of sodium pentobarbital, and then the drug was administered. The vasodilation effect was determined by measuring increases in blood flow in the right peristaltic artery and left femoral artery. Blood pressure was measured invasively using a pressure transducer MPU-0.5A (manufactured by Nihon Kohden).
Heart rate was measured by blood pressure pulse wave and heart rate meter AT-600G (manufactured by Nihon Kohden). In addition, the blood flow was measured non-invasively by exposing the right peristaltic artery and the left femoral artery and attaching an electromagnetic blood flow meter probe with an inner diameter of 2 to 3 mm using an electromagnetic blood flow meter MFV-1200 (manufactured by Nihon Kohden).
Measured using a pen-written oscillograph WI-681G.
(manufactured by Nihon Kohden). In Tables 1 and 2, the hypotensive effect is expressed as the change in mean blood pressure after drug administration as a percentage of the mean blood pressure before administration, and the vasodilatory effect is the increase in peristal artery blood flow and femoral artery blood flow after drug administration. The rate of change in heart rate was expressed as a percentage of the blood flow before administration of each drug, and the rate of change in heart rate was expressed as the percentage of the heart rate after administration of the drug relative to the heart rate before administration. In addition, both tables also include the test results of the above-mentioned known nicardipine as a comparative compound. In addition, in the compound display column in both tables,
Compound 1 means the compound in Example 1, which will be described later, and compound 2 means the compound in Example 2, which will be described in the same manner below.

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[Manufacturing method A]

The compound of the present invention [] has the following general formula [] (In the formula, R ² and R ³ represent the same meanings as above, and R ⁶ is the above R ¹ or the following general formula [] represents a substituted pyrazolyloxyheptyl group or a substituted pyrazolyloxyoctyl group represented by ) Benzylidene acetoacetate derivative represented by
1.0 mol and the following general formula [] In the formula, R ⁷ represents the above R ¹ or a substituted pyrazolyloxyheptyl group or a substituted pyrazolyloxyoctyl group represented by the above general formula []. However, when R ⁶ in the general formula [] represents R ¹ , R ⁷
is a substituted pyrazolyloxyheptyl group or a substituted pyrazolyloxyoctyl group represented by the general formula [], and when R ⁶ represents a group represented by the general formula [], R ⁷ represents R ¹ . ) in the presence or absence of a reaction solvent with 1.0 to 2.0 mol, preferably 1.0 mol, of the enaminocarboxylic acid ester derivative represented by
It can be produced by reacting at a reaction temperature of 50 to 150°C. Reaction solvents include alcohols such as methanol, ethanol, n-propanol, isopropanol, butanol, diols such as ethylene glycol and propylene glycol, methyl cellosolve,
Cellosolves such as ethyl cellosolve, nitrobenzene, N,N-dimethylacetamide, N,N-
One or more mixed solvents selected from dimethylformamide, hexamethylphosphoric triamide, and acetic acid are used. [Manufacturing method B] Furthermore, the compound of the present invention [] has the following general formula [] (In the formula, R ¹ , R ² , R ³ and A have the same meanings as above, and R ⁸ represents a tosyloxy group or a halogen atom.) Dihydropyridine derivative 1.0
mol and 1.0 to 6.0 mol, preferably 1.0 to 2.0 mol of a pyrazolone derivative represented by the following general formula []. In the reaction solvent in the presence of an anionizing reagent and optionally an alkali metal iodide, at a reaction temperature of 0 to 0.
It can also be produced by reacting at 180°C, preferably 15-100°C. The reaction of [Production method B] proceeds advantageously by reacting the pyrazolone derivative [] with an anionizing reagent in advance, and adding the dihydropyridine derivative [] and, if necessary, an alkali metal iodide to the reaction mixture. Examples of anionizing reagents include alkali metals such as sodium metal and potassium metal, alkaline earth metals such as calcium metal and magnesium metal, alkali metal hydrides such as sodium hydride and potassium hydride, and carbonates such as sodium carbonate and potassium carbonate. , hydroxides such as sodium hydroxide and potassium hydroxide, and sodium or potassium alkoxides of alcohols such as methanol, ethanol, propanol and butanol. When an alkoxide is used as an anionizing reagent, it is advantageous to remove as much alcohol as possible during the reaction process, and when a hydroxide is used, water is preferably removed as much as possible. The amount of anionizing reagent used is preferably 1.0~
It is appropriate that the amount is set at 2.0 mol, and within this range, the amount used is always equal to or less than the amount of the pyrazolone derivative []. Further, examples of the alkali metal iodide include potassium iodide and sodium iodide. Dimethyl sulfoxide is used as a reaction solvent,
One or a mixed solvent of two or more of N,N-dimethylacetamide, N,N-dimethylformamide, pyridine, dioxane, hexamethylphosphoric triamide, N-methylmorpholine, 1,2-dimethoxyethane, etc. is used. In this production method, compounds represented by the following general formula [] are produced as by-products, and these also have sustained blood pressure lowering and vasodilatory effects. (In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and A have the same meanings as above.) [Production method of main raw material compounds used in production methods A and B] Γ Compound of general formula [] Using an acetoacetate derivative represented by the general formula below and ammonia, (In the formula, R ⁷ has the same meaning as above.) Known methods for producing enaminocarboxylic acid ester derivatives, such as Journal of the American
It can be produced according to the method described in Chemical Society, Vol. 67, p. 1017, 1945. Γ Compound of general formula [] Benzaldehyde derivative represented by the following general formula and (In the formula, R ² and R ³ have the same meanings as above.) An acetoacetate derivative represented by the following general formula (In the formula, R ⁶ has the same meaning as defined above.)
It can be produced according to the method described in Collective Volume, Volume 4, Page 408, 1963. Γ Compound of general formula [] (In each formula, R ¹ , R ² , R ³ and A have the same meanings as above.) The compound [] is synthesized by the steps shown in the above reaction formula. That is, the dihydropyridine derivative of the general formula [] is obtained by a chemically similar method to the above-mentioned [Production Method A], and then the compound [] is obtained by a conventional halogenation reaction or tosylation reaction. In the general formula ['], R ⁶ of the general formula [] is replaced with R ¹ , and in the general formula ['], R ⁷ of the general formula [] is replaced with a group represented by -A-OH. Here, it is preferable to use thionyl chloride, thionyl bromide, etc. for the usual halogenation reaction, and tosyl chloride for the tosylation reaction. The compounds represented by the general formulas [] and [] are not only useful as intermediates for the production of the compounds of the present invention [], but also have unique and useful pharmacological activities, such as hypotensive action,
Vasodilatory effects and platelet aggregation inhibitory effects were observed. Γ Compound of general formula [ ] Known methods for producing pyrazolone derivatives, e.g.
Berichte Der Deutchen Chemischen
It can be produced according to the method described in Gesellschaft, Vol. 29, p. 253. Hereinafter, the method for producing the compound of the present invention [] will be specifically explained with reference to Examples. The silica gel for column chromatography used in the Examples was Wako Gel C-200 (manufactured by Wako Pure Chemical Industries, Ltd.). Example 1 3-nitrobenzylideneacetoacetic acid methyl ester 4.98 g (20 mmol), 3-aminocrotonic acid 7-(5-phenyl-3-pyrazolyloxy)
7.15 g (20 mmol) of heptyl ester and 7 ml of ethanol were mixed and heated under reflux for 5 hours. This reaction solution was concentrated under reduced pressure to obtain a yellow oily residue. This residue was subjected to silica gel column chromatography using a chloroform-methanol mixture (volume ratio 150:1) as the eluent, and the eluate containing the target product was concentrated under reduced pressure. 2 ml of ethanol was added to the yellow oil obtained. When the mixture was added and left overnight, yellow crystals were precipitated. The crystals were collected and recrystallized from ethanol to form a 1,4-dihydro-
2,6-dimethyl-4-(3-nitrophenyl)-
3-methoxycarbonyl-pyridine-5-carboxylic acid 7-(5-phenyl-3-pyrazolyloxy)
5.10 g of pale yellow crystals of heptyl ester (yield: 43.3
%) was obtained. Melting point 123-127℃ IR (CHCl ₃ ) cm ^-1 3500, 3470, 1700, 1525, 1355 PMR (DMSO-d ₆ ) δ: 0.90-2.00 (10H, m) 2.30 (6H, s) 3.54 (3H, s ) 3.94 (2H, t) 4.04 (2H, t) 4.96 (1H, s) 6.05 (1H, s) 7.10~8.07 (9H, m) 8.90 (1H, broad) 12.20 (1H, broad) Elemental analysis value (C ₃₂ H ₃₆ N ₄ O ₇ ) C H N Theoretical value % 65.29 6.16 9.52 Experimental value % 65.03 6.27 9.73 Example 2 (a) Acetoacetic acid 7-hydroxyheptyl ester
64.9 g (0.30 mol), 45.3 g (0.30 mol) of 2-nitrobenzaldehyde, and 34.5 g (0.30 mol) of β-aminocrotonic acid methyl ester were dissolved in 200 ml of ethanol and heated under reflux for 5 hours. After cooling, ethanol was distilled off under reduced pressure, the resulting residue was dissolved in 500 ml of ethyl acetate, and this was dissolved in 200 ml of water.
and dried over anhydrous sodium sulfate. The yellow oily residue obtained by concentrating this solution under reduced pressure was subjected to silica gel column chromatography using a chloroform-methanol mixture (volume ratio 50:1) as the eluent, and the eluate containing the target product was concentrated under reduced pressure. and 1,4-dihydro-2,
6-dimethyl-4-(2-nitrophenyl)-3
64.3 g (yield: 48.0%) of -methoxycarbonyl-pyridine-5-carboxylic acid 7-hydroxyheptyl ester was obtained as a yellow oil. (b) 1,4-dihydro-2,6- obtained by method (a)
Dimethyl-4-(2-nitrophenyl)-3-methoxycarbonyl-pyridine-5-carboxylic acid 7-hydroxyheptyl ester 62.5 g (0.14
mol) and tosyl chloride (53.4 g (0.28 mol)) were dissolved in 300 ml of chloroform, and 50 g (0.63 mol) of pyridine was added dropwise to this solution under ice cooling.
Stir for a minute. After adding 500 ml of ice water to this reaction solution and stirring for 1 hour, the chloroform layer was separated.
This was washed successively with 200 ml of 1.0N sulfuric acid, 200 ml of water, and 300 ml of saturated sodium bicarbonate solution. This chloroform solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a yellow oily residue. This residue was subjected to silica gel column chromatography using a benzene-ethyl acetate mixture (volume ratio 5:1) as an eluent, and the eluate containing the target product was concentrated under reduced pressure. ,6-dimethyl-
4-(2-nitrophenyl)-3-methoxycarbonyl-pyridine-5-carboxylic acid 7-tosyloxyheptyl ester as yellow oil
72.3g (yield 85.7%) was obtained. PMR (CDCl ₃ ) δ: 1.00 to 2.00 (10H, m) 2.25 (3H, s) 2.30 (3H, s) 2.42 (3H, s) 3.75 to 4.22 (4H, m) 5.68 (1H, s) 6.30 (1H , broad) 7.00-8.05 (9H, m) (c) Suspend 0.24 g (10 mmol) of sodium hydride in 5 ml of N,N-dimethylformamide,
Add to this 2.45 g of 3-phenyl-5-pyrazolone
(12 mmol) was added and stirred at room temperature until hydrogen evolution had ceased. This solution was obtained by the method described in (b) above. 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3-methoxycarbonyl-pyridine-5-carboxylic acid 7-
A solution of 6.01 g (10 mmol) of tosyloxyheptyl ester dissolved in 10 ml of N,N-dimethylformamide was added, and the mixture was heated and stirred at 90°C for 1 hour. After the reaction is complete, pour the reaction solution into 200ml of ice water,
The target product was extracted with 50 ml of ethyl acetate. This ethyl acetate solution was washed three times with 50 ml of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a brown oily residue. This residue was subjected to silica gel column chromatography using a benzene-ethyl acetate mixture (volume ratio 1:1) as an eluent, and the eluate containing the target product was concentrated under reduced pressure to obtain crystals. The crystals were recrystallized from ethanol to give 1,4-dihydro-
2,6-dimethyl-4-(2-nitrophenyl)
3.55 g of yellow crystals of -3-methoxycarbonyl-pyridine-5-carboxylic acid 7-(5-phenyl-3-pyrazolyloxy)heptyl ester
(yield 60.3%). Melting point 151.0-154℃ IR (KBr) cm ^-1 : 3320, 1675, 1680, 1345, 1, 1210 PMR (DMSO-d ₆ ) δ: 0.88-2.00 (10H, m) 2.18 (3H, s) 2.25 (3H , s) 3.40 (3H, s) 3.67-4.23 (4H, m) 5.51 (1H, s) 6.03 (1H, s) 7.00-7.77 (9H, m) 8.77 (1H, broad) 12.20 (1H, broad) Element Analytical value (as C ₃₂ H ₃₆ N ₄ O ₇ ) C H N Theoretical value % 65.29 6.16 9.52 Experimental value % 65.23 6.34 9.44 Example 3 0.24 g (10 mmol) of sodium hydride in N,
Suspended in 5 ml of N-dimethylformamide, 1.0 g of 3-methyl-5-pyrazolone was added to this under stirring at room temperature.
(10 mmol) was added. After hydrogen generation has finished,
Add 4.65 g (10 mmol) of 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3-methoxycarbonyl-pyridine-5-carboxylic acid 7-chloroheptyl ester to this solution.
Add 10ml of dimethylformamide solution and heat for 1 hour.
The mixture was heated and stirred at ℃. After the reaction is complete, pour the reaction solution into ice water.
The target product was extracted with 50 ml of ethyl acetate. This ethyl acetate solution was washed three times with 50 ml of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a brown oil. This oil was dissolved in chloroform.
The mixture was subjected to silica gel column chromatography using a methanol mixture (volume ratio 100:1) as an eluent, and the eluate containing the target product was concentrated under reduced pressure to obtain crystals. This crystal was recrystallized from benzene to give 1,4-dihydro-2,6-
Dimethyl-4-(3-nitrophenyl)-3-methoxycarbonyl-pyridine-5-carboxylic acid 7-
2.10 g (yield 39.9%) of yellow crystals of (5-methyl-3-pyrazolyloxy)heptyl ester were obtained. Melting point 122.0-124.0℃ IR (CHCl ₃ ) cm ^-1 3500, 3465, 2950, 1695, 1520, 1345 PMR (CDCl ₃ ) δ: 1.09-1.97 (10H, m) 2.17 (3H, s) 2.30 (6H, s ) 3.65 (3H, s) 4.00 (2H, t) 4.03 (2H, t) 5.03 (1H, s) 5.40 (1H, s) 6.18 (1H, s) PMR (CDCl ₃ + DMSO・d ₆ ) δ: 11.07 ( 1H,
Broad) Elemental analysis value (as C ₂₇ H ₃₄ N ₄ O ₇ ) C H N Theoretical value % 61.58 6.51 10.64 Experimental value % 61.61 6.78 10.37 Examples 4 to 33 Produced by applying the above production method A or B as appropriate . Table 3 lists the names of the compounds produced, their melting points, and IR.
The spectrum, PMR spectrum and elemental analysis values are shown.

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[Table] In addition to the compounds described in the examples, the following compounds were also synthesized. 1,4-dihydro-2,6-dimethyl-4-
(3-Nitrophenyl)-3-methoxycarbonyl-pyridine-5-carboxylic acid 7-[5-(2-pyrrolyl)-3-pyrazolyloxy]heptyl ester 1,4-dihydro-2,6-dimethyl-4-
(3-Nitrophenyl)-3-methoxycarbonyl-pyridine-5-carboxylic acid 7-[5-(2-pyridyl)-3-pyrazolyloxy]-1-methyl-heptyl ester 1,4-dihydro-2,6-dimethyl -4-
(3-Nitrophenyl)-3-methoxycarbonyl-pyridine-5-carboxylic acid 7-[5-(3-pyridyl)-3-pyrazolyloxy]-7-methyl-heptyl ester 1,4-dihydro-2,6-dimethyl -4-
(3-Nitrophenyl)-3-methoxycarbonyl-pyridine-5-carboxylic acid 7-[5-(4-pyridyl)-3-pyrazolyloxy]heptyl ester 1,4-dihydro-2,6-dimethyl-4-
(3-Nitrophenyl)-3-methoxycarbonyl-pyridine-5-carboxylic acid 7-[5-(4-pyrimidyl)-3-pyrazolyloxy]heptyl ester 1,4-dihydro-2,6-dimethyl-4-
(3-Nitrophenyl)-3-methoxycarbonyl-pyridine-5-carboxylic acid 7-[5-(4-pyridazyl)-3-pyrazolyloxy]heptyl ester 1,4-dihydro-2,6-dimethyl-4-
(3-Nitrophenyl)-3-methoxycarbonyl-pyridine-5-carboxylic acid 8-[5-(4-pyridazyl)-3-pyrazolyloxy]-1,8-dimethyl-octyl ester 1,4-dihydro-2,6 -dimethyl-4-
(2,3-dichlorophenyl)-3-methoxycarbonyl-pyridine-5-carboxylic acid 7-[5-(4
-pyridazyl)-3-pyrazolyloxy]heptyl ester 1,4-dihydro-2,6-dimethyl-4-
(2-trifluorophenyl)-3-methoxycarbonyl-pyridine-5-carboxylic acid 7-[5-(4
-pyridazyl)-3-pyrazolyloxy]heptyl ester 1,4-dihydro-2,6-dimethyl-4-
(3-Nitrophenyl)-3-methoxycarbonyl-pyridine-5-carboxylic acid 7-[5-(3-pyrazolyl)-3-pyrazolyloxy]heptyl ester 1,4-dihydro-2,6-dimethyl-4-
(3-Nitrophenyl)-3-methoxycarbonyl-pyridine-5-carboxylic acid 7-[5-(4-imidazolyl)-3-pyrazolyloxy]heptyl ester 1,4-dihydro-2,6-dimethyl-4-
(3-Nitrophenyl)-3-methoxycarbonyl-pyridine-5-carboxylic acid 7-[5-(3-chlorophenyl)-3-pyrazolyloxy]heptyl ester 1,4-dihydro-2,6-dimethyl-4-
(3-Nitrophenyl)-3-methoxycarbonyl-pyridine-5-carboxylic acid 7-[5-(4-iodophenyl)-3-pyrazolyloxy]heptyl ester 1,4-dihydro-2,6-dimethyl-4-
(3-Nitrophenyl)-3-methoxycarbonyl-pyridine-5-carboxylic acid 7-[5-(2-bromophenyl)-3-pyrazolyloxy]heptyl ester 1,4-dihydro-2,6-dimethyl-4-
(3-nitrophenyl)-3-methoxycarbonyl-pyridine-5-carboxylic acid 8-[5-(2,4-
dichlorophenyl)-3-pyrazolyloxy]octyl ester 1,4-dihydro-2,6-dimethyl-4-
(3-nitrophenyl)-3-methoxycarbonyl-pyridine-5-carboxylic acid 8-[4-(2,6-
dimethoxyphenyl)-3-pyrazolyloxy]
Octyl ester 1,4-dihydro-2,6-dimethyl-4-
(3-Nitrophenyl)-3-methoxycarbonyl-pyridine-5-carboxylic acid 7-[5-(α-phenethyl)-3-pyrazolyloxy]heptyl ester 1,4-dihydro-2,6-dimethyl-4-
(3-Nitrophenyl)-3-methoxycarbonyl-pyridine-5-carboxylic acid 7-[5-(4-isopropoxyphenyl)-3-pyrazolyloxy]
Heptyl ester 1,4-dihydro-2,6-dimethyl-4-
(3-nitrophenyl)-3-methoxycarbonyl-pyridine-5-carboxylic acid 7-[5-(3,4-
methylenedioxylbenzyl)-3-pyrazolyloxy]heptyl ester 1,4-dihydro-2,6-dimethyl-4-
(3-Nitrophenyl)-3-methoxycarbonyl-pyridine-5-carboxylic acid 7-[5-(4-N,
N-dimethylaminophenyl)-3-pyrazolyloxy]heptyl ester 1,4-dihydro-2,6-dimethyl-4-
(3-Nitrophenyl)-3-methoxycarbonyl-pyridine-5-carboxylic acid 7-[5-(4-aminophenyl)-3-pyrazolyloxy]heptyl ester 1,4-dihydro-2,6-dimethyl-4-
(3-Nitrophenyl)-3-methoxycarbonyl-pyridine-5-carboxylic acid 7-[5-(4-acetylaminophenyl)-3-pyrazolyloxy]
Heptyl ester 1,4-dihydro-2,6-dimethyl-4-
(3-Nitrophenyl)-3-methoxycarbonyl-pyridine-5-carboxylic acid 7-[5-(4-benzoylaminophenyl)-3-pyrazolyloxy]
Heptyl ester 1,4-dihydro-2,6-dimethyl-4-
(3-Nitrophenyl)-3-methoxycarbonyl-pyridine-5-carboxylic acid 7-[5-(2-chlorobenzyl)-3-pyrazolyloxy]heptyl ester 1,4-dihydro-2,6-dimethyl-4-
(3-Nitrophenyl)-3-methoxycarbonyl-pyridine-5-carboxylic acid 7-[5-(4-methoxybenzyl)-3-pyrazolyloxy]heptyl ester

Claims (1)

[Claims] 1. General formula (In the formula, R ¹ is a lower alkyl group, R ² is a hydrogen atom or a halogen atom, R ³ is a halogen atom, a trifluoromethyl group, or a nitro group, R ⁴ and R ⁵ are a hydrogen atom, a lower alkyl group, a trifluoromethyl group, Fluoromethyl group, phenoxy group, phenoxymethyl group, phenylalkyl group, furyl group, thienyl group, pyrrolyl group, pyridyl group, pyrimidyl group, pyridazyl group,
A pyrazolyl group, an imidazolyl group, or a phenyl group which may have a substituent, where the substituent is a lower alkyl group, a lower alkoxy group, a trifluoromethyl group, a nitro group, an amino group, a mono-lower alkylamino group, a di- A lower alkylamino group, acylamino group, cyano group, lower alkoxycarbonyl group, halogen atom, or methylenedioxy group, A
represents a heptamethylene group or an octamethylene group which may be substituted with a lower alkyl group. ) A 1,4-dihydropyridine derivative represented by