JP2528899B2 - 3-Aminocarbonyl-1,4-dihydropyridine-5-carboxylic acid ester derivative - Google Patents

Description

TECHNICAL FIELD The present invention relates to a novel 3-aminocarbonyl-1,4-dihydropyridine-5 useful as a medicine for cardiovascular diseases.
It relates to a carboxylic acid ester derivative.

BACKGROUND ART Many studies have been conducted on 1,4-dihydropyridine derivatives, especially their 3,5-dicarboxylic acid esters, and it is known that certain compounds have interesting coronary artery dilating action and blood pressure lowering action. . For example, nifedipine [chemical name: 1,4-sihydro-2,6-dimethyl-4- (2-
Nitrophenyl) -3,5-pyridinedicarboxylic acid dimethyl ester] is used as a prophylactic / therapeutic agent for angina attacks, and also nicardipine hydrochloride [Chemical name: 1,4-dihydro-2,6-dimethyl-4- (3- [Nitrophenyl) -3,5-pyridinedicarboxylic acid methyl, N-benzyl-N-methylaminoethyl ester hydrochloride] is commonly used as a hypotensive agent and a cerebral circulation improving agent. Further, regarding 1,4-dihydropyridine-3,5-asymmetric dicarboxylic acid esters, JP-B-55-29989
And JP-A-58-146565 and JP-A-61-7255.

On the other hand, as a 3-aminocarbonyl-1,4-dihydropyridine-5-carboxylic acid ester derivative having a skeleton similar to that of the compound of the present invention, German Published Patent No. 2,228,37
7, JP-B-57-20953 and JP-A-59-116267,
Further, 1,4-dihydropyridine-3-nitro-5-carboxylic acid cycloalkylamide is described in JP-A-59-227860. However, these known compounds differ from the compounds of the present invention in their amide substituents and alkyl ester groups, and their pharmacological activity has not been sufficiently disclosed.

Further, the present inventors have studied 4- (2- or 3-nitrophenyl) -3-aminocarbonyl-1,4-dihydropyridine-5-carboxylic acid ester derivatives, and as a result, have found that the mono-substituent of 3-aminocarbonyl As an alkyl group having 3 to 5 carbon atoms, an alkenyl group having 2 to 5 carbon atoms, an alkynyl group having 3 to 5 carbon atoms, or 3 to 5 carbon atoms.
It has been found that a compound in which an alkyl ester group of 5-carboxylic acid has an alkyl group having 1 to 10 carbon atoms has an excellent action particularly on cardiovascular diseases, and has already applied for a patent ( JP-A-62-174050).

OBJECT OF THE INVENTION As a result of continuous research, the present inventors have found that other 1,4-
It was found that the dihydropyridinecarboxylic acid ester derivative has excellent pharmacological activity, and the present invention has been completed. That is, the present invention provides a novel 3-aminocarbonyl-1,4-dihydropyridine-5-carboxylic acid ester derivative having excellent pharmacological activity.

Structure and Effect of the Invention The novel 3-aminocarbonyl-1,4-dihydropyridine-5-carboxylic acid ester derivative of the present invention has a structure represented by the following general formula.

[In the formula, R ¹ is hydrogen, an alkyl group having 1 to 5 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, an alkenyl group having 3 to 5 carbon atoms, or an alkynyl group having 3 to 5 carbon atoms. , R ² is an alkyl group having 1 to 10 carbon atoms, a cycloalkylalkyl group having 4 to 10 carbon atoms, an alkenyl group having 3 to 5 carbon atoms, or an alkylcarbonyl group having 3 to 5 carbon atoms,
R ³ represents NO ₂ , chlorine, fluorine or difluoromethoxy group. However, when R ¹ is hydrogen and R ² is an alkyl group having 1 to 10 carbon atoms, R ³ is chlorine or fluorine and R ¹ is ¹ carbon atom.
~ 5 alkyl groups, C3-5 alkenyl groups,
Alternatively, it is an alkynyl group having 3 to 5 carbon atoms and R ² has 1 carbon atom
In the case of 10 to 10 alkyl groups, R ³ represents chlorine, fluorine or difluoromethoxy group.] In the general formula [I], the alkyl group for R ¹ is, for example, methyl, ethyl, n-propyl, isopropyl or n.
-Butyl, isobutyl, sec-butyl, tert-butyl,
A straight-chain or branched-chain alkyl group having 1 to 5 carbon atoms such as n-pentyl and isopentyl is included, but an alkyl group having 3 to 5 carbon atoms is preferable, and an isopropyl group is particularly preferable. The cycloalkyl group represented by R ^{1 is} a cycloalkyl group having 3 to 8 carbon atoms such as cyclopropyl, cyclopentyl, cyclohexyl, and cyclooctyl, an alkenyl group is an allyl group, and an alkynyl group is a propargyl group. Can be mentioned.

Examples of the alkyl group for R ² include methyl, ethyl, n
-Propyl, isopropyl, n-butyl, isobutyl,
sec-butyl, tert-butyl, 3-methyl-2-butyl, n-pentyl, isopentyl, 2-pentyl, 3-
Preferable examples include linear or branched alkyl groups having 1 to 10 carbon atoms such as pentyl, tert-pentyl, n-hexyl, isohexyl, n-heptyl, n-octyl, n-nonyl and n-decyl. Is 1 to 3 carbon atoms or 6
~ 9 alkyl groups, especially n-hexyl, n-heptyl, n-octyl and n-nonyl groups. The cycloalkylalkyl group for R ² includes cyclopropylmethyl, α-methylcyclopropylmethyl, α-phenylcyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, α-methylcyclohexylmethyl, cyclooctylmethyl, cyclopentylethyl. , Cyclohexylethyl, cyclopentylpropyl, cyclohexylpropyl, cyclohexylbutyl and the like, which is a cycloalkylalkyl group having 4 to 10 carbon atoms, and examples of the alkenyl group include allyl, α-methylallyl, 2-butenyl, 3-butenyl and 4-pentenyl. An alkenyl group having 3 to 5 carbon atoms, such as an allyl group, or an alkylcarbonyl group such as 2-methyl-
Examples thereof include an alkylcarbonyl group having 3 to 5 carbon atoms such as 3-carbonylbutyl and 4-carbonylpentyl.

The substitution position of NO ₂ , fluorine and difluoromethoxy group of R ³ is the 2nd or 3rd position, but the 2nd position is preferable.

The novel 3-aminocarbonyl-1,4-dihydropyridine-5-carboxylic acid ester derivative of the present invention further comprises
Those having a structure represented by the following general formula are included.

[Wherein R ¹ is an isopropyl, propargyl, cyclopropyl or propenyl group, R ² is methyl, n-hexyl,
n-heptyl, n-octyl or n-nonyl group, ring A
Represents a 2,3-dichlorophenyl or 2,6-dichlorophenyl group].

The compounds of the present invention can be made by a variety of methods,
For example, it can be advantageously produced by the following method.

[Method A] Reaction Formula-1 [Wherein R ¹ , R ² and R ³ and their substitution positions are the same as described above] As shown in the above reaction formula-1, benzylideneacetoacetic acid alkyl ester [II] and 3-aminocrotonic acid amide [III] The desired compound [I] can be produced by subjecting and to a ring closure reaction in a suitable solvent.

This reaction is usually carried out at room temperature to about 160 ° C, preferably about 50 ° C.
~ 130 ° C, particularly preferably at the boiling temperature of the solvent. The solvent used may be any solvent that is inert to the reaction, for example, aromatic hydrocarbons such as benzene, toluene, xylene, methanol, ethanol, propanol, isopropanol, n-butanol, sec-butanol. Alcohols such as, diethyl ether, dioxane, tetrahydrofuran, ethers such as ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, acetic acid, pyridine,
N, N-dimethylformamide, dimethyl sulfoxide,
Acetonitrile etc. are mentioned. The reaction is preferably carried out using a non-polar solvent (benzene, toluene, xylene, etc.) while removing water produced by azeotropic distillation. In this case, the end point of the reaction is when the calculated amount of water is distilled. According to such a method, the target compound [I] can be obtained in a good yield with a much smaller amount of by-products than in the case of using other solvents, which is extremely advantageous. The above reaction is usually completed in about 1 to 7 hours, and the ratio of the raw materials used is [II]: [III] = 1: 1.5 mol to 1.5: 1 mol.

One of the starting materials [II] used in the above method is known, or the following reaction formula-
Easily manufactured by the method shown in 2 [Organic
See Organic Reactions, 15 , p. 204-599 (1967)].

Reaction formula-2 [Wherein, R ² and R ³ and the substitution positions thereof are the same as above] That is, the compound [II] is produced by reacting the substituted benzaldehyde [IV] and acetoacetic acid alkyl ester [V] in a suitable solvent. To be done. This reaction can be carried out under the same conditions using the same solvent as the reaction in the above Reaction formula-1. In addition, the compound [II] obtained by this reaction may be subjected to the reaction with the compound [III] in the above Reaction Scheme-1 after isolation, or may be directly subjected to the reaction with the compound [III] without isolation. May be offered. Then, this reaction formula-2 and reaction formula-1 can be continuously performed in the same reaction system. That is, substituted benzaldehyde [IV], acetoacetic acid alkyl ester [V] and 3-aminocrotonic acid amide [II]
By reacting I] with the same conditions as in Reaction scheme-1, the target compound [I] can be obtained all at once. In this case, the amount of the starting material used is compound [IV]: compound [V]: compound [III] = 1 to 1.5 mol: 1 to 1.5 mol: 1 to
It is in the range of 1.5 moles.

In addition, the substituted benzaldehyde [IV] which is a raw material of reaction formula-2 is a known compound, and the acetoacetic acid alkyl ester [V] which is another raw material is also a known compound, or by a known method such as the following reaction formula- It is easily manufactured by the method shown in 3 (see US Pat. No. 2,351,366).

Reaction formula-3 [Wherein R ² is the same as above] That is, diketene [VI] and alcohol [VII] in the presence of a basic catalyst in an inert solvent or without solvent,
Compound [V] is obtained by reacting at about 40 to 130 ° C.

In addition, 3 which is another starting material in the reaction formula-1
-Aminocrotonic acid amide [III] is also known, or easily produced by a known method, for example, the method shown in the following Reaction Scheme-4 [J.Am.Chem. Soc.), 67 , 1017 (1945)].

Reaction formula-4 [Wherein R ¹ is the same as above] That is, acetoacetic amide [VIII] is dissolved in a suitable solvent (eg, methanol, ethanol, diethyl ether, dioxane, tetrahydrofuran, etc.),
Compound [III] is obtained by passing excess ammonia gas at about 0 to 60 ° C. or by adding the above solvent solution of ammonia and reacting at about 0 to 60 ° C. in a closed container.

[Method B] Reaction Formula-5 [Wherein R ¹ , R ² and R ³ and their substitution positions are the same as described above] The compound [I] of the present invention can also be produced by the method shown in the above Reaction Scheme-5. That is, the target compound [I] is produced by subjecting benzylidene acetoacetic acid amide [IX] and 3-aminocrotonic acid alkyl ester [X] to a ring closure reaction in a suitable solvent. This reaction is carried out under substantially the same conditions as in the case of the reaction formula-1.

One of the starting materials [IX] used in the above method is known, or the following reaction formula-
Easily manufactured by the method shown in [6]
See Organic Reactions, 15 , p. 204-599 (1967)].

Reaction formula-6 [Wherein R ¹ and R ³ and their substitution positions are the same as above] That is, the compound [IX] is produced by reacting the substituted benzaldehyde [IV] and acetoacetamide [VIII] in a suitable solvent. It This reaction can be carried out under the same conditions using the same solvent as in the reaction in the above Reaction Formula-5. In addition, the compound [IX] obtained by this reaction may be subjected to the reaction with the compound [X] in the above Reaction Scheme-5 after isolation, or may be directly used for the reaction with the compound [X] without isolation. However, the reaction formula-6 and the reaction formula-5 can be continuously performed in the same reaction system. That is, the substituted benzaldehyde [IV], acetoacetic acid amide [VIII], and 3-aminocrotonic acid alkyl ester [X] are reacted under the same conditions as in Reaction scheme-5 to give the target compound [I] at once. be able to. In this case, the amount of the starting material used is in the range of compound [IV]: compound [VIII]: compound [X] = 1 to 1.5 mol: 1 to 1.5 mol: 1 to 1.5 mol.

In addition, acetoacetic acid amide [VI
II] is also a known compound, or by a known method,
For example, it can be easily produced by the method shown in the following reaction formula-7 (see German Patent 1,142,859).

Reaction formula-7 [Wherein R ¹ is the same as above] That is, the compound [VIII] can be obtained by reacting diketene [VI] and amine [XI] in an inert solvent at about −10 to 30 ° C.
Is obtained.

In addition, 3 which is another starting material in the above reaction formula-5
-Aminocrotonic acid alkyl ester [X] is also known, or by a known method, for example, the following reaction formula-8
It is easily manufactured by the method shown in [J. Am Chem.
Sock (J. Am. Chem. Soc.), 67 , 1017 (1945)].

Reaction formula-8 [Wherein R ² is the same as above] The reaction represented by the reaction formula-8 is carried out under substantially the same conditions as the reaction represented by the reaction formula-4.

The compound [I] of the present invention obtained by the above method can be isolated and purified by a conventional means such as concentration, extraction, chromatography,
It can be isolated and purified from the reaction mixture by reprecipitation, recrystallization and the like.

The experimental results regarding the pharmacological action of the compound of the present invention are shown below.

Experimental Example 1 Action on the isolated heart [Method] A Japanese white rabbit weighing 2.2 to 2.5 kg was lightly anesthetized by intravenous administration of 20 mg / kg Nembutal, then exsanguinated from the common carotid artery, and the heart was immediately removed to remove Langendorff. It was attached to a heart perfusion device (KN-206 type, manufactured by Natsume Seisakusho). Next, Krebs-Henseleite nutrient solution (32 ° ± 0.5
The heart was perfused under constant pressure of 45 cmH ₂ O at 95 ° C., 95% O ₂ + 5% CO ₂ ), the specimen was stabilized for 90 minutes, then the test compound was administered, and the perfusion rate (ET-600G titration meter was measured). , Nihon Kohden), cardiac contraction force (SB-IT type FD pickup, Nihon Kohden) and heart rate (AT-601G type heart rate meter, Nihon Kohden) changes were measured. The time required for the increased perfusion rate to recover to the level before administration by administration of the test compound was defined as the duration.

The test compound was dissolved in ethanol and used as a stock solution. 0.1 ml of the stock solution diluted 100 times with purified water
/ heart (3 μg / heart) was administered.

[Results] Table 1 shows the results of the test using the excised heart specimen.

As shown in Table 1, in the coronary vasodilatory action, the compounds of the present invention have equivalent or higher potency than known 1,4-dihydropyridine derivatives (nifedipine, nicardipine hydrochloride). Example number 27,
The compounds of 79, 82, 83 and 109 are also useful as therapeutic agents for coronary artery diseases such as myocardial infarction and angina pectoris and arrhythmias because they also have moderate cardiac contractile force and heart rate suppressing action.

Experimental Example 2 Antihypertensive Action [Method] Male spontaneously hypertensive rats (3 to 10 animals per group) aged 13 to 15 weeks were used. Blood pressure is the maximum blood pressure (systolic pressure)
The blood pressure was around 200 mmHg, and the average blood pressure was around 180 mmHg. The rat was semi-fixed in a Hallman cage under non-fasting conditions, and a femoral artery pressure was applied to the femoral artery by a blood transfusion method under a non-anesthetized condition via a pressure transducer (MPU-0.5, manufactured by Nihon Kohden Co., Ltd.) from a cannula previously inserted into the femoral artery. It was measured.

The test compound was orally administered as a 0.5% methylcellulose suspension. The dose was 1 mg / kg and 1 part was 3 mg / kg. Blood pressure was measured up to 8 hours after administration of the test compound.

[Results] Table 2 shows the hypotensive action (blood pressure after administration-blood pressure before administration) of the test compound.

As shown in Table 2, the compound of the present invention also has an antihypertensive effect, and in particular, the compound of Example No. 9 exhibits a stronger antihypertensive effect as compared to the control known compound nicardipine hydrochloride, and also has a prolonged effect. It was longer.

When the compound of the present invention is used as a medicine, it is mixed with a usual pharmaceutically acceptable carrier, excipient and diluent to give a pharmaceutical preparation. Such pharmaceutical formulations include powders,
It includes solid preparations such as granules, fine granules, tablets, capsules and suppositories, and liquid preparations such as solutions, suspensions, emulsions and injections, and is orally or parenterally administered. The dose varies depending on the administration route, symptoms, sex of the patient, age, body weight, etc., but when orally administered to an adult hypertensive patient, for example, 0.5 to 500 mg / day, preferably 1.0 to 150 mg / day per day It is desirable to administer it in 1 to several divided doses.

Next, the present invention will be described more specifically with reference to Reference Examples, Examples and Experimental Examples. The melting points of the compounds shown were measured (uncorrected) by the hot plate method (using Yanagimoto MP-S2 type).

Reference Example 1 Production of o-nitrobenzylidene acetoacetic acid methyl ester: 7.6 g (0.05 mol) of o-nitrobenzaldehyde and 5.8 g (0.05 mol) of acetoacetic acid methyl ester were added to 40 ml of benzene.
And 0.2 ml of piperidine and 0.6 ml of acetic acid are added thereto, and the mixture is heated under reflux for 5 hours. The reaction is terminated when the produced water is removed and a theoretical amount of water is distilled off.
After completion of the reaction, the reaction solution is washed with 5% hydrochloric acid and then with water, and the solvent is distilled off under reduced pressure to obtain 12.2 g (yield 98%) of a brown oily target product.

Reference Example 2 Production of acetoacetic acid cyclopropylamide: 42.2 g (0.74 mol) of cyclopropylamine was dissolved in 300 ml of chloroform, and diketene 62.1 was stirred while cooling with ice.
g (0.74 mol) is added dropwise over 1 to 1.5 hours. After dropping, the mixture was stirred at 40 ° C for 1 hour, the solvent was distilled off under reduced pressure, and the residue was treated with benzene.
Recrystallized from n-hexane to obtain 83.4g of the target compound as colorless needles.
(Yield 80%) is obtained. Melting point 65-66 ° C.

Elemental analysis value (as C ₇ H ₁₁ NO ₂ ) Calculated value (%): C59.55, H7.85, N9.92 Measured value (%): C59.37, H7.99, N9.68 Reference example 3 3 Preparation of aminocrotonic acid methylamide: 175.4 g (1.58 mol) of acetoacetic acid methylamide are dissolved in 55 ml of ethanol and ammonia gas is passed through this solution. Cool in a water bath so that the reaction temperature does not exceed 30 ° C. When ammonia gas is passed for about 3 hours, yellow crystals are deposited. This is left overnight at 0 ° C. and then filtered, and the resulting crystals are washed with diethyl ether to obtain 115.2 g (yield 66%) of the desired product as colorless prism crystals. Melting point 102-107 ° C.

 Various compounds shown in Table 1 are obtained in the same manner as above.

Reference Example 14 Preparation of 3-aminocrotonic acid allylamide: 111.4 g (0.79 mol) of acetoacetic acid allylamide is dissolved in 80 ml of ethanol, and ammonia gas is passed through this solution. Cool in a water bath so that the reaction temperature does not exceed 30 ° C. When conducting ammonia gas for about 3 hours, colorless crystals are precipitated. This is left overnight at 0 ° C. and then filtered, and the resulting crystals are washed with diethyl ether to obtain 91.5 g (yield 82.7%) of the desired product as colorless prism crystals. Melting point 143-144 ° C.

Elemental analysis value (as C ₇ H ₁₂ N ₂ O) Calculated value (%): C59.97, H8.63, N19.99 Measured value (%): C59.78, H8.76, N20.08 Reference example 15 Production of 3-aminocrotonic acid propargylamide: 73.4 g of acetoacetic acid propargylamide 93.4 g (0.67 mol)
Dissolve in 0 ml ethanol and pass ammonia gas through this solution. Cool in a water bath so that the reaction temperature does not exceed 30 ° C. When conducting ammonia gas for about 3 hours, colorless crystals are precipitated. This is left overnight at 0 ° C. and then filtered, and the obtained crystals are washed with diethyl ether to obtain 87.7 g (yield 94.6%) of the desired product as colorless needle crystals. Melting point 137-138 ° C.

Elemental analysis value (as C ₇ H ₁₀ N ₂ O) Calculated value (%): C60.85, H7.30, N20.28 Measured value (%): C60.80, H7.34, N20.56 Reference example 16 Preparation of 3-aminocrotonic acid cyclopropylamide: Acetoacetic acid cyclopropylamide 209.4 g (1.48 mol)
Is dissolved in 160 ml of ethanol and ammonia gas is passed through this solution. Cool in a water bath so that the reaction temperature does not exceed 30 ° C. When ammonia gas is passed for about 3 hours, yellow crystals are deposited. This is left overnight at 0 ° C. and then filtered, and the resulting crystals are washed with diethyl ether to obtain 172.2 g (yield 82.8%) of the desired product as colorless prismatic crystals. Melting point 169-1
71 ° C.

Elemental analysis value (as C ₇ H ₁₂ N ₂ O) Calculated value (%): C59.97, H8.63, N19.99 Measured value (%): C59.71, H8.77, N20.17 Reference example 17 Preparation of 3-aminocrotonic acid cyclopentylamide: 169.1 g (1.00 mol) of acetoacetic acid cyclopentylamide
Is dissolved in 100 ml of ethanol and ammonia gas is passed through this solution. Cool in a water bath so that the reaction temperature does not exceed 30 ° C. When conducting ammonia gas for about 3 hours, colorless crystals are precipitated. This is left overnight at 0 ° C. and then filtered, and the obtained crystals are washed with diethyl ether to obtain 140.4 g (yield 85.6%) of the target compound as colorless needles. Melting point 138-139 ° C.

Elemental analysis value (as C ₉ H ₁₆ N ₂ O) Calculated value (%): C64.25, H9.59, N16.65 Measured value (%): C64.03, H9.79, N16.53 Example 1 Production of 2,6-dimethyl-3-aminocarbonyl-4- (2-nitrophenyl) -1,4-dihydropyridine-5-carboxylic acid cyclohexylethyl ester: 2-nitrobenzylideneacetoacetic acid cyclohexylethyl ester 17.5 g (0.05 mol) ) And 3-aminocrotonamide 5 g (0.05 mol) are dissolved in 100 ml of ethanol,
After heating the mixture under reflux for 7 hours, the solvent was distilled off,
The residue is dissolved in 30 ml of an elution solvent [chloroform: hydrogen tetrachloride: ethyl formate: formic acid: ethanol (10: 10: 8: 1: 2)] and subjected to column chromatography [silica gel 60 Art.
9385 (Merck) 600g, φ40mm x 100cm]. The target fraction
The pH is adjusted to 10 with 28% aqueous ammonia, the organic layer is separated, washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is recrystallized from methanol to obtain 15.8 g (yield 74.0%) of the desired product as yellow prism-like crystals. Melting point 209-211 [deg.] C.

IR (KBr, cm ^-1 ): 1685, 1520, 1360 NMR (DMSO, δ: ppm): 0.40-1.80 (13H, m), 2.15 (3H,
s), 2.20 (3H, s), 3.70-4.10 (2H, m), 5.40 (1H,
s), 6.85 (2H, s), 7.10-7.80 (4H, m), 8.50 (1H,
s) Elemental analysis (C ₂₃ H ₂₉ N ₃ as O ₅₎ Calculated (%): C64.65, H6.84, N9.76 Found (%): C64.76, H7.20, N9.76 Example 2 Preparation of 2,6-dimethyl-3-aminocarbonyl-4- (2-nitrophenyl) -1,4-dihydropyridine-5-carboxylic acid cyclooctyl methyl ester: 2-nitrobenzylidene acetoacetic acid cyclooctyl methyl ester 18.0 g (0.05 mol) and 3-aminocrotonic acid amide 5.0 g (0.05 mol) were dissolved in 100 ml of ethanol, the mixture was heated under reflux for 7 hours, the solvent was distilled off, and the residue was eluted with chloroform [chloroform: Carbon tetrachloride: ethyl formate: formic acid: ethanol (10: 10: 8: 1: 2)] dissolved in 30 ml and subjected to column chromatography [silica gel 60
Art.9385 (Merck) 600g, φ40mm × 100cm. The target fraction is adjusted to pH 10 with 28% aqueous ammonia, the organic layer is separated, washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is recrystallized from methanol to obtain 10.7 g (yield 48.3%) of the target product as pale yellow prismatic crystals. 228-230 ° C.

IR (KBr, cm ^-1 ): 1680, 1520, 1360 NMR (DMSO, δ: ppm): 1.45 (15H, s), 2.15 (3H, s), 2.
25 (3H, s), 3.50-3.90 (2H, m), 5.45 (1H, s), 6.90
(2H, s), 7.20-7.90 (4H, m), 8.55 (1H, s) Elemental analysis value (as C ₂₄ H ₃₁ N ₃ O ₅ ) Calculated value (%): C65.28, H7.08, N9 .52 Found (%): C65.30, H7.27, N9.52 Example 3 2,6-Dimethyl-3-cyclopropylaminocarbonyl-4- (2-nitrophenyl) -1,4-dihydropyridine- Preparation of 5-carboxylic acid cyclohexylethyl ester: 2-nitrobenzylideneacetoacetic acid cyclohexylethyl ester 17.3 g (0.05 mol) and 3-aminocrotonic acid cyclopropylamide 7.0 g (0.05 mol) were added to benzene 10
Dissolve in 0 ml and heat the mixture to reflux for 7 hours. The produced water is azeotropically separated by a water content meter, and the point at which a theoretical amount of water is collected is taken as the end point of the reaction. After the reaction was completed, the solvent was distilled off under reduced pressure, diethyl ether was added to the residue, and the precipitated crystals were collected by filtration and recrystallized from 80% ethanol to give 18.1 g of the desired product as pale yellow prismatic crystals (yield 77.3 %). Melting point 186-188 [deg.] C.

IR (KBr, cm ^-1 ): 1680, 1530, 1350 NMR (DMSO, δ: ppm): 0.30-2.00 (17H, m), 2.20 (3H,
s), 2.40 (3H, s), 2.50-2.90 (1H, m), 3.50 to 4.00
(2H, m), 5.30 (1H, s), 6.90 (1H, s), 7.00 to 7.60
(4H, m) Elemental analysis (C ₂₆ H ₃₃ N ₃ as O ₅₎ Calculated (%): C66.79, H7.11, N8.99 Found (%): C67.01, H7.21, N9.10 Example 4 2,6-Dimethyl-3-isopropylaminocarbonyl-
Preparation of 4- (2,6-dichlorophenyl) -1,4-dihydropyridine-5-carboxylic acid n-octyl ester: 2,6-dichlorobenzylideneacetoacetic acid n-octyl ester 18.6 g (0.05 mol) and 3-aminocroton 7.1 g (0.05 mol) of acid isopropylamide is dissolved in 60 ml of benzene, and this mixture is heated under reflux for 7 hours. The produced water is azeotropically separated by a water content meter, and the point at which a theoretical amount of water is collected is taken as the end point of the reaction. After the reaction was completed, the solvent was distilled off under reduced pressure, isopropyl ether was added to the residue, and the precipitated crystals were collected by filtration and recrystallized from 80% ethanol to give 4.5 g of the desired product as pale yellow prismatic crystals (yield 18.2). %). Melting point
197-199 ° C.

IR (KBr, cm ^-1 ): 1670 NMR (DMSO, δ: ppm): 0.90-1.10 (6H, m), 1.20 (15H,
s), 1.90 (3H, s), 2.20 (3H, s), 3.60 to 4.10 (3H, s)
m), 5.40 (1H, d), 5.80 (1H, s), 6.50 (1H, s), 6.80
−7.40 (3H, m) Elemental analysis value (as C ₂₆ H ₃₆ Cl ₂ N ₂ O ₅ ) Calculated value (%): C63.02, H7.32, N5.65 Measured value (%): C63.13, H7.33, N5.81 Example 5 2,6-Dimethyl-3-propargylaminocarbonyl-
Preparation of 4- (2,3-dichlorophenyl) -1,4-dihydropyridine-5-carboxylic acid methyl ester: 13.7 g (0.05 mol) of 2,3-dichlorobenzylidene acetoacetic acid methyl ester and 3-aminocrotonic acid propargylamide 6.9 g (0.05 mol) is dissolved in 60 ml of benzene,
The mixture is heated to reflux for 7 hours. The produced water is azeotropically separated by a water content meter, and the point at which a theoretical amount of water is collected is taken as the end point of the reaction. After completion of the reaction, diethyl ether is added to the reaction mixture, and the precipitated crystals are collected by filtration and recrystallized from ethanol to obtain 17.1 g (yield 87.0%) of the desired product as yellow prism-like crystals. Melting point 199-201 ° C.

IR (KBr, cm ^-1 ): 1670 NMR (DMSO, δ: ppm): 1.90 (3H, s), 2.25 (3H, s), 2.8
0-3.00 (2H, m), 3.40 (1H, s), 3.70-4.00 (3H, m)
m), 5.20 (1H, s), 7.20 (3H, s), 8.00 (1H, t), 8.3
0 (1H, s) Elemental analysis value (as C ₁₉ H ₁₈ Cl ₂ N ₂ O ₃ ) Calculated value (%): C58.03, H4.61, N7.13 Measured value (%): C58.05, H4 .58, N7.10 Example 6 2,6-Dimethyl-3-isopropylaminocarbonyl-
Preparation of 4- (2-fluorophenyl) -1,4-dihydropyridine-5-carboxylic acid n-octyl ester: 2-fluorobenzylideneacetoacetic acid n-octyl ester 16.0 g (0.05 mol) and 3-aminocrotonic acid isopropylamide 7.0 g (0.05 mol) is dissolved in 60 ml of benzene and the mixture is heated under reflux for 7 hours. The produced water is azeotropically separated by a water content meter, and the point at which a theoretical amount of water is collected is taken as the end point of the reaction. After completion of the reaction, the solvent was distilled off under reduced pressure, and iropropyl ether was added to the residue, and the precipitated crystals were collected by filtration and recrystallized from 80% ethanol to obtain 9.20 g of the desired product as colorless prism crystals (yield 41.6 %). Melting point 166
~ 168 ° C IR (KBr, cm ^-1 ): 1720 NMR (DMSO, δ: ppm): 0.60-1.50 (21H, m), 1.85 (3H,
s), 2.20 (3H, s), 3.50-4.00 (3H, m), 4.95 (1H,
s), 6.70-7.30 (5H, s ), 8.60 (1H, s) Elemental analysis (C ₂₆ H ₃₇ FN as ₂ O ₃₎ Calcd (%): C70.24, H8.39, N6.30 Found Value (%): C70.48, H8.58, N6.45 Example 7 2,6-Dimethyl-3-isopropylaminocarbonyl-
Preparation of 4- (2-difluoromethoxyphenyl) -1,4-dihydropyridine-5-carboxylic acid ethyl ester: 2-difluoromethoxybenzylidene acetoacetic acid methyl ester 13.5 g (0.05 mol) and 3-aminocrotonic acid isopropylamide 7.1 g (0.05 mol) is dissolved in 60 ml of benzene and the mixture is heated to reflux for 7 hours. The produced water is azeotropically separated by a water content meter, and the point at which a theoretical amount of water is collected is taken as the end point of the reaction. After completion of the reaction, diethyl ether was added to the reaction mixture, and the precipitated crystals were collected by filtration and
Recrystallization from% ethanol gives 13.6 g (yield 68.9%) of the desired product as colorless prismatic crystals. Melting point 201-203 ° C IR (KBr, cm ^-1 ): 1690 NMR (DMSO, δ: ppm): 1.00 (6H, d), 2.00 (3H, s), 2.2
0 (3H, s), 3.30 (3H, s), 3.50-4.00 (1H, m), 4.90
(1H, s), 6.50-7.30 ( 5H, m), 8.00-8.20 (1H, m) Elemental analysis _{(C 20 H 24 F 2 N} 2 as O ₄₎ Calculated (%): C60.90, H6 .13, N7.10 Found (%): C61.19, H6.14, N7.06 Example 8 2,6-Dimethyl-3-aminocarbonyl-4- (2-nitrophenyl) -1,4- Preparation of dihydropyridine-5-carboxylic acid allyl ester: 2-nitrobenzylideneacetoacetic acid allyl ester 1
3.8 g (0.05 mol) and 3-aminocrotonic acid amide 5.1 g
(0.05 mol) is dissolved in 100 ml of ethanol and the mixture is heated under reflux for 7 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, diethyl ether was added to the residue, and the precipitated crystals were collected by filtration and recrystallized from ethanol to give 4.3 g (yield 24.2%) of the desired product as yellow prism-like crystals. obtain. Melting point 190-192 ° C IR (KBr, cm ^-1 ): 1680, 1520, 1360 NMR (DMSO, δ: ppm): 2.23 (3H, s), 2.25 (3H, s), 4.5
0 (2H, m), 5.30 (1H, s), 5.57-6.30 (3H, m), 7.50
(2H, s), 7.35-7.98 ( 4H, m), 8.74 (1H, s) Elemental analysis (C ₁₈ H ₁₉ N ₃ as O ₅₎ Calculated (%): C60.50, H5.36, N11 .76 found (%): C60.78, H5.41, N11.72 Example 9 2,6-Dimethyl-3-isopropylaminocarbonyl-
Preparation of 4- (2-nitrophenyl) -1,4-dihydropyridine-5-carboxylic acid allyl ester: 2-nitrobenzylidene acetoacetic acid allyl ester 7.
0 g (0.025 mol) and 3-aminocrotonic acid isopropylamide (3.5 g, 0.025 mol) are dissolved in 50 ml of benzene, and the mixture is heated under reflux for 3 hours. The produced water is azeotropically separated by a water content meter, and the point at which a theoretical amount of water is collected is taken as the end point of the reaction. After the reaction was completed, the solvent was distilled off under reduced pressure, diethyl ether was added to the residue, and the precipitated crystals were collected by filtration and recrystallized from ethanol to obtain 2.0 g of the target product as yellow prism-like crystals (yield 61.2%). obtain. Melting point 195-197 ° C.

IR (KBr, cm ^-1 ): 1690, 1520, 1350 NMR (DMSO, δ: ppm): 0.90-1.00 (6H, m), 2.00 (3H,
s), 2.20 (3H, s), 3.50-4.00 (1H, m), 4.80 (2H, s)
d), 4.70-6.00 (4H, m), 7.00-7.80 (4H, m), 8.40
(1H, s) Elemental analysis value (as C ₂₁ H ₂₅ N ₃ O ₅ ) Calculated value (%): C63.14, H6.31, N10.52 Measured value (%): C63.00, H6.22, N10.59 Example 10 Preparation of 2,6-dimethyl-3-aminocarbonyl-4- (2-nitrophenyl) -1,4-dihydropyridine-5-carboxylic acid-4'-carbonylpentyl ester: 2-nitrobenzylidene Acetoacetic acid-4'-carbonylpentyl ester 6.38 g (0.02 mol) and 3-aminocrotonic acid amide 2.0 g (0.02 mol) were dissolved in 50 ml of ethanol, and the mixture was heated under reflux for 7 hours, and then the solvent was distilled off. , The residue is an elution solvent [n-hexane: acetone (1:
1)] Dissolve in 30 ml and subject to column chromatography.
[Silica gel 60 Art.9385 (Merck) 300g, φ40mm x 50c
m]. The target fraction is concentrated under reduced pressure. The residue is recrystallized from ethanol + water to obtain 3.14 g (yield 39.1%) of the desired product as orange-yellow needles. 190-192 ° C.

IR (KBr, cm ^-1 ): 1680, 1530, 1350 NMR (DMSO, δ: ppm): 1.40-1.90 (2H, m), 1.95-2.50
(11H, m), 3.50-4.00 (2H, m), 5.30 (1H, s), 6.80
(2H, s), 7.00-7.80 ( 4H, s), 8.40 (1H, s) Elemental analysis (C ₂₀ H ₂₃ N ₃ as O ₆₎ Calculated (%): C59.84, H5.78, N10 .47 Found (%): C59.67, H5.73, N10.50 Examples 11 to 114 In the same manner as in Examples 1 to 10 above, the compounds shown in Tables 1 to 8 were obtained.

Continuation of the front page (56) References Arzneim-Forsch. , Vol. 35, No. 4 (1985), PP. 668-672.

Claims (6)

(57) [Claims] 1. A general formula [Wherein R ¹ is hydrogen, an alkyl group having 1 to 5 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, an alkenyl group having 3 to 5 carbon atoms, or an alkynyl group having 3 to 5 carbon atoms, R ² is an alkyl group having 1 to 10 carbon atoms, a cycloalkylalkyl group having 4 to 10 carbon atoms, an alkenyl group having 3 to 5 carbon atoms, or an alkylcarbonyl group having 3 to 5 carbon atoms, R ³
Represents NO ₂ , chlorine, fluorine or difluoromethoxy group.
However, when R ¹ is hydrogen and R ² is an alkyl group having 1 to 10 carbon atoms, R ³ is chlorine or fluorine, and R ¹ is ¹ to 5 carbon atoms.
Alkyl groups, alkenyl groups having 3 to 5 carbon atoms, or alkynyl groups having 3 to 5 carbon atoms and R ² having 1 to 10 carbon atoms
In the case of a single alkyl group, R ³ represents chlorine, fluorine, or a difluoromethoxy group], and is a 3-aminocarbonyl-1,4-dihydropyridine-5-carboxylic acid ester derivative. 2. R ¹ is hydrogen, an alkyl group having 1 to 5 carbon atoms,
An alkenyl group having 3 to 5 carbon atoms, or an alkynyl group having 3 to 5 carbon atoms, R ² is cyclopropylmethyl, α-methylcyclopropylmethyl, α-phenylcyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,
The cyclohexylmethyl, α-methylcyclohexylmethyl, cyclooctylmethyl, cyclopentylethyl, cyclohexylethyl, cyclopentylpropyl, cyclohexylpropyl, cyclohexylbutyl, and the aforementioned (1), wherein R ³ is an ortho-position or a meta-position NO ₂ group. Compound of. 3. A compound according to claim 1, wherein R ¹ is an isopropyl group, R ² is a methyl, n-hexyl, n-heptyl, n-octyl or n-nonyl group, and R ³ is fluorine at the 2-position. . 4. The above (1), wherein R ¹ is an isopropyl, cyclopropyl, allyl or propargyl group, R ² is a methyl, n-octyl or n-nonyl group, and R ³ is a difluoromethoxy group at the 2-position. Compound of. 5. R ¹ is hydrogen or an alkyl group having 1 to 5 carbon atoms, R ² is allyl, α-methylallyl, 2-butenyl,
The compound according to the above (1), wherein 3-butenyl or 4-pentenyl group and R ³ is NO ₂ group at 2-position or 3-position. 6. R ¹ is hydrogen or an isopropyl group, and R ² is 2-
The compound according to the above item (1), wherein methyl-3-carbonylbutyl or 4-carbonylpentyl group and R ³ is a NO ₂ group at the 2-position or 3-position.