JPS6338353B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides general formulas useful as pharmaceuticals. 1,4-dihydropyridine-3,5-
This invention relates to dicarboxylic acid ester derivatives, salts thereof, and methods for producing them.

In the above formula, each symbol is as follows.
X is pyridyl, furyl, thienyl, methyl-substituted furyl or chloro-substituted thienyl, Y is phenyl, R ¹ is lower alkyl, R ² and R ³ are the same or different lower alkyl, R ⁴ is methyl, R ⁵ represents benzyl, and n represents 1.

To explain the above definition in more detail, lower alkyl includes methyl, ethyl, propyl, isopropyl, butyl, and the like.

The compound of the present invention () has strong vasodilating and hypotensive effects, and is useful as an antihypertensive agent and a therapeutic agent for cardiac or cerebral circulation disorders.

The present invention was completed based on the new finding that when a phenyl group is introduced into the α-position of the side chain aminoalkyl ester moiety, its efficacy is enhanced and its duration is significantly prolonged.

According to the present invention, the compound of general formula () is produced, for example, by the method shown below.

Method 1 General formula (In the formula, each symbol has the same meaning as above) A compound represented by the formula X-CHO () (wherein X has the same meaning as above) A compound represented by the formula X-CHO and the general formula (In the formula, each symbol has the same meaning as above.) A method of reacting a compound represented by:

This reaction involves mixing compounds represented by the general formulas (), (), and () and using an appropriate solvent (methanol,
ethanol, propanol, isopropanol,
This is done by heating in the presence of dioxane, benzene, toluene, acetonitrile, dimethylformamide, dimethyl sulfoxide, etc.). Note that the compound () is, for example, R ² −
It can be obtained by reacting a compound represented by COCH ₂ COOR ¹ with ammonia. This product can be isolated once or directly reacted with compounds () and () to obtain the target product ().

Method 2 General formula (In the formula, each symbol has the same meaning as above) A compound represented by the general formula () and a compound represented by the general formula R ² COOCH ₂ COOR ¹ () (In the formula, each symbol has the same meaning as above) How to react.

This reaction involves mixing the compounds represented by the general formulas (), (), and (), and using an appropriate solvent (same as above).
This is done by heating in the presence of. In addition,
Compound () can be obtained, for example, by reacting a compound of general formula () with ammonia in advance. This product can be isolated once or directly reacted with compounds () and () to obtain the desired product ().

Method 3 General formula obtained by reacting the compound represented by the general formula () and the compound represented by the general formula () in advance (In the formula, each symbol has the same meaning as above.) A method of reacting a compound represented by the following with a compound represented by the general formula ().

This reaction is carried out by heating in the presence of a suitable solvent (as defined above). The compound represented by the general formula () may be isolated once or may be directly reacted with the compound represented by the formula () without being isolated.

Method 4 General formula obtained by reacting a compound represented by general formula () and a compound represented by general formula () in advance (In the formula, each symbol has the same meaning as above.) A method of reacting a compound represented by the following with a compound represented by the general formula ().

This reaction is carried out by heating in the presence of a suitable solvent (as defined above). The compound represented by the general formula () may be isolated once or may be directly reacted with the compound represented by the formula () without being isolated.

Method 5 General formula [In the formula, Z is the acid residue of the active ester (chlorine, bromine,
halogen atoms such as iodine, or alkyl or arylsulfonyloxy such as methylsulfonyloxy, ethylsulfonyloxy, benzenesulfonyloxy, para-toluenesulfonyloxy, etc.), and other symbols are as defined above. ] Compounds and general formulas represented by (In the formula, each symbol has the same meaning as above.) A method of reacting a compound represented by:

This reaction is carried out in a suitable solvent (as defined above) in the presence of a deoxidizing agent (an inorganic alkali such as an alkali carbonate, an alkali bicarbonate, an alkali alcoholate, or an organic base such as trimethylamine, dimethylaniline, pyridine). The reaction is usually carried out at around room temperature to around the boiling point of the solvent for several hours to several tens of hours. In addition, the compound represented by the general formula () is the general formula (In the formula, each symbol has the same meaning as above.) It can be easily obtained using, for example, methods 1 to 4 described above, using a compound represented by the following as a raw material.

Method 6 General formula (Each symbol in the formula has the same meaning as above) Compounds represented by and general formula (In the formula, each symbol has the same meaning as above.) A method of reacting with a compound represented by:

This reaction is carried out in the same manner as described in Method 5 above. The compound of general formula () thus obtained can be isolated and purified by conventional chemical operations.

Although the compound of the present invention has an asymmetric carbon, all optically active forms and mixtures thereof are included within the scope of the present invention. If desired, the racemic compound may be prepared by reacting with an optically active acid (tartaric acid, diacetyltartaric acid, tartoranilic acid, dibenzoyltartaric acid, ditoluoyltartaric acid, etc.) to form a diastereomer, followed by crystallization, distillation, chromatography, etc. The optically active base can be obtained from the separated salt. Furthermore, a compound having a desired steric configuration can also be stereoselectively produced using an optically active raw material compound.

The compounds of the invention can be inorganic or organic salts such as hydrochlorides, hydrobromides, phosphates, sulfates, oxalates, maleates, fumarates, tartrates, acetates, and the like.

The compounds of the present invention are excellent in, for example, vertebral artery blood flow-increasing effects and coronary blood flow-increasing effects in dogs, cerebral blood flow-increasing effects in domestic rabbits, and antihypertensive effects in spontaneously hypertensive rats; It is characterized by being extremely long.

When the compound of the present invention is used as a medicine, the compound itself or a suitable pharmacologically acceptable excipient, carrier,
Mix with diluent etc. to form tablets, capsules, granules,
It can be administered orally or parenterally in the form of powder or injection. In the case of oral administration, the dose is usually about 1 mg to 50 mg per day for adults, and is administered once or in several doses, depending on age, body weight, and/or severity of the disease to be treated. May vary depending on severity and response to treatment.

The present invention will be described in more detail with reference to Examples below, but the present invention is not limited thereto.

In addition, when two types of diastereoisomers are obtained in the following examples, the isomer detected in the upper part in thin layer chromatography analysis is referred to as the α-diastereoisomer, and the one detected in the lower part is referred to as the β-diastereoisomer. Tentatively called diastereoisomers.

Example 1 Acetoacetic acid [1-phenyl-2-(N-benzyl-N-methylamino)ethyl]ester 10.4
g, 3.1 g of furfural, and 3.7 g of β-aminocrotonic acid methyl ester in isopropyl alcohol.
After dissolving in 100ml, heat and reflux for 10 hours.
The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel chromatography [dichloromethane: ethyl acetate = 98:
2 (volume ratio)]. Concentrate the eluent that elutes first. After dissolving the residual oil in acetone, an alcoholic solution of hydrogen chloride is added.
The precipitated crystals are collected and recrystallized from a methanol-ether mixed solvent to give 2,6-dimethyl-4-(2-furyl)- with a melting point of 172-173°C (decomposition).
1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-5-[1-phenyl-
2-(N-benzyl-N-methylamino)ethyl]
Ester/hydrochloride/hemihydrate (α-diastereoisomer) is obtained. In addition, if the eluent to be eluted later is treated in the same way, β-
Diastereoisomers (hydrochloride) are obtained.

Example 2 2,6-dimethyl-4-(2-thienyl)-1,
4-dihydropyridine-3,5-dicarboxylic acid-
8.8g of monomethyl ester in 100ml of dichloromethane
While cooling with ice water, add 6.9 g of phosphorus pentachloride at 0 to 5°C all at once. The reaction solution is kept at 0-5°C and stirred for 1 hour. Cool to −40° C. on a dry ice-methanol bath without isolating the acid chloride formed. 1-phenyl-2-(N-
A solution prepared by dissolving 23.1 g of (benzyl-methylamino) ethanol in 50 ml of dichloromethane was added dropwise over 30 minutes. After cooling to 0°C, the mixture was stirred for 2 hours while cooling with ice water. 5% dichloromethane layer
Wash with aqueous sodium carbonate solution, 5% aqueous hydrochloric acid, and 5% aqueous sodium carbonate solution. The dichloromethane layer is dried over anhydrous magnesium sulfate, and dichloromethane is distilled off under reduced pressure. The residue is subjected to column chromatography and treated in the same manner as in Example 1. From the eluent that elutes first, melting point 219-221°C (decomposition) (recrystallized from methanol-ether) 2,6-dimethyl-4-(2-thienyl)-1,4-dihydropyridine-3,5-dicarboxylic acid -3-Methyl ester-5-[1-phenyl-2-(N-benzyl-N-
methylamino)ethyl] ester hydrochloride (α-
diastereoisomers) are obtained. In addition, from the eluent that is eluted later, the melting point is 204-206℃ (decomposition).
The α-diastereoisomer (hydrochloride) of (recrystallized from isopropyl alcohol) is obtained.

Example 3 13 g of acetoacetic acid [1-phenyl-2-(N-benzyl-N-methylamino)ethyl] ester,
After dissolving 4.3 g of pyridine-2-aldehyde and 4.6 g of β-aminocrotonic acid methyl ester in 110 ml of isopropyl alcohol, the solution was heated under reflux for 14 hours. The reaction solution was distilled off under reduced pressure. The residue is subjected to column chromatography and treated in the same manner as in Example 1. From the eluent that elutes first, the melting point is 159-161
2, °C (recrystallized from isopropyl alcohol)
6-dimethyl-4-(2-pyridyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-5-[1-phenyl-2-(N-benzyl-N-methylamino)ethyl ] Esters (α-diastereoisomers) are obtained. Also,
A β-diastereoisomer (hydrochloride monohydrate) having a melting point of 147-148°C (decomposition) (resolution from methanol) is obtained from the eluate that is eluted later.

Example 4 9.8 g of acetoacetic acid [1-phenyl-2-(N-benzyl-N-methylamino)ethyl] ester,
5-methyl-furan-2-aldehyde 3.3g, β
- After dissolving 3.5 g of aminocrotonic acid methyl ester in isopropyl alcohol, the solution is heated under reflux for 16 hours. The reaction solution is concentrated under reduced pressure, and the residue is dissolved in benzene. After washing the benzene solution with water, add 30 ml of 3N hydrochloric acid and shake. A brown oil separates. The water and benzene are decanted off and the separated oil is dissolved in chloroform. After washing the chloroform solution with an aqueous potassium carbonate solution, it is dried over anhydrous magnesium sulfate. Chloroform is distilled off under reduced pressure. The residue is subjected to column chromatography and treated in the same manner as in Example 1.
From the eluent that elutes first, 2, with a melting point of 194-195°C (decomposition) (recrystallized from methanol-ether)
6-dimethyl-4-(5-methyl-2-furyl)-
1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-5-[1-phenyl-
2-(N-benzyl-N-methylamino)ethyl]
Ester hydrochloride (α-diastereoisomer) is obtained. In addition, the β-diastereoisomer (hydrochloride) with a melting point of 178-180℃ (decomposition) (recrystallized from methanol-ether) was obtained from the eluent that was eluted later.
is obtained.

Example 5 9.8 g of acetoacetic acid [1-phenyl-2-(N-benzyl-N-methylamino)ethyl] ester,
4.4 g of 5-chloro-2-thiophenaldehyde,
After dissolving 3.5 g of β-aminocrotonic acid methyl ester in 100 ml of isopropyl alcohol,
Heat to reflux for 20 hours. After the reaction is completed, crystallization occurs in the same manner as in Example 4. The melting point is 170-172℃ from the eluent that is eluted first after column chromatography.
(decomposition) (recrystallized from methanol-ether) 2,6-dimethyl-4-(5-chloro-2-thienyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-5- [1-phenyl-2-(N-benzyl-N-methylamino)
[ethyl] ester hydrochloride (α-diastereoisomer) is obtained. In addition, a β-diastereoisomer (hydrochloride) having a melting point of 166 to 168°C (decomposition) (resolution from ethanol-ether) is obtained from the eluent that is eluted later.

Claims (1)

[Claims] 1. General formula 1,4-dihydropyridine-3,5 represented by
-Dicarboxylic acid ester derivatives or salts thereof. [In the above formula, X is pyridyl, furyl, thienyl,
methyl-substituted furyl or chloro-substituted thienyl, Y
is phenyl, R ¹ is lower alkyl, R ² and R ³ are the same or different lower alkyl, R ⁴ is methyl,
R ⁵ represents benzyl, and n represents 1. ]