JPS58157785A - Dihydropyridine compound - Google Patents

Abstract

NEW MATERIAL:The compound of formulaI(Het is heterocyclic group; R<1> is lower alkyl; R<2> and R<3> are 1-10C alkyl; R<4> is lower alkyl or aralkyl; n is 1 or 2). EXAMPLE:2,6-Dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarbo xylic acid 3-methyl ester 5- 2-dimethylamino-1-(2-thienyl)ethyl ester. USE:A hypotensor. Useful as a remedy for cardiac and cerebral circulation disorder. PROCESS:The compound of formulaIcan be prepared by reacting the acetoacetic acid ester compound of formula II with the amino compound of formula III and nitrobenzaldehyde in a solvent such as benzene, methanol, etc., at room temperature or under heating.

Description

[Detailed description of the invention] The present invention is based on the general formula This invention relates to a novel dihydropyridine compound represented by:

In the above formula, R is a Hetli polycyclic group, R is a lower alkyl group, and R2 and R3 are the same or different and are 1.k prime numbers l to l.
O represents an alkyl group, R4 represents a lower alkyl group or an aralkyl group, and n times 1 represents 2 times.

More specifically, double H length and base are denyl, frill,
A 5- to 6-membered aromatic heterocyclic group such as pyridyl, pyrrolyl which may have a lower alkyl at the 1st position, imidazolyl, thiazolyl, oxasilyl, isoxasilyl, pyrimidinyl, etc. methyl,
Ethyl, propyl, isopropyl, butyl, etc.
Carbon & 1-10 alkyl means methyl, ethyl, propyl, isopropyl, butyl, heptyl, door, xyl,
These include octyl, decyl, etc., and the aralkyl group is benzyl, phenethyl, phenylpropyl, or mono- or di-substituted groups thereof with chloro, fluoro, methyl, methoxy, etc.

The compound (I') of the present invention has strong vasodilatory and antihypertensive effects, and can be used as an antihypertensive agent and for cardiac or cerebral circulation.
It is useful as a treatment for chapter damage.

Book 4b was completed based on the new finding that by introducing a multicyclic ring into the α-position of the side chain aminoalkyl ester moiety, the duration of its efficacy is significantly longer.

The compounds of the present invention of general formula (I) can be produced by methods well known per se for the synthesis of 1,4-dihydropyridine-3,5-dicarboxylic acid esters, but are preferably , for example, an acetoacetate compound represented by the general formula (in which each symbol has the same meaning as above) and an amino compound represented by the general formula (in the formula, each symbol has the same meaning as above), and nitrobenzaldehyde.

This reaction can be carried out without a solvent or with an appropriate solvent (such as
(such as benzene, toluene, glycylene, chloroform, carbon tetrachloride, methylene chloride, ethylene chloride, a7tonitrinohemethanol, ethanol, propatool, impropanol, butanol, water or other conventional solvents) at room temperature. Ishike heating is carried out by heating.

For example, the raw material compound represented by the general formula (■) is prepared by combining the compound represented by the general formula (in the formula, each symbol has the same meaning as above) and diketene without a solvent or in an inert solvent (
For example, it is produced by reacting at room temperature or with heating or heating in benzene, toluene, xinane, chloroform, i tetrachloride, methylene chloride, ethylene chloride, dioxane, ether, tetrahydrofuran, etc.). The reaction may also be carried out in the presence of a base catalyst (eg, pyridine, pipurine, triethylamine, etc.).

The compound represented by the general formula (III) is produced by, for example, reacting a compound represented by the general formula % (in the formula, each symbol has the same meaning as above) with ammonia or a salt thereof. Ru.

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. That is, since it has two or more -F asymmetric carbons, two or more types of cuspid diastereomers can be obtained, but
The respective stereoisomers are separated (recrystallization, column chromatography, distillation, etc.), and the racemic compound is optionally separated using an optically active acid (tartaric acid, diacetyltartaric acid, taldolanilic acid, dibenzoyltartaric acid, ditoluoyltartaric acid, etc.). etc.) to form diastereoisomers, which are then separated by crystallization and recrystallization, and optically active bases can be obtained from the separated salts. Furthermore, a compound having a desired steric configuration can also be stereoselectively produced using an optically active raw material compound.

The compounds of the present invention can be converted into inorganic salts or +1-organic salts such as hydrochlorides, hydrobromides, phosphates, sulfates, oxalates, maleates, fumarates, tartrates, and salts. Can be done.

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 hypotensive effects in spontaneously hypertensive rats; It has the characteristic of being extremely long-lasting.

When the compound of the present invention is used as a medicine, it can be administered by itself or mixed with pharmaceutically acceptable excipients, carriers, diluents, etc., and administered orally in the form of tablets, capsules, granules, powders, or injections. It can be administered intravenously or parenterally. In the case of oral administration, the dosage is usually 1 mg to 5 per day for adults.
The culm strength is 0 fng, and these doses may be administered once or in several divided doses, but this may vary depending on the age of the equipment, body weight, and/or severity of the disease to be treated and response to treatment.

Example: 33 g of acetate 2-diethylamino-1-(2-thenyl)ethyl ester, 17 g of m-nitrobenzaldehyde, 13 g of methyl β-aminocrotonate, and 200 ml of isopropanol. Dissolve and heat under reflux for 17 hours. The reaction solution was concentrated under reduced pressure, the residue was dissolved in toluene, and 2N hydrochloric acid was added.

The oil that separates is neutralized with potassium carbonate and extracted with ethyl acetate. After drying the extract over sodium sulfate, the solvent is distilled off under reduced pressure. The residue is separated by silica gel column chromatography using a mixed solvent of chloroform and ethyl acetate as eluent. Concentrate the eluent that elutes first, and convert it into a hydrochloride with a hydrogen chloride ethanol solution. When the obtained crystals are recrystallized from ethanol, 2,6-dimethyl-4-(m-nitrophenyl)-1,4-cyhydrohyridine-3,5-dicarboxylic acid-3-methyl ester-
One diastereoisomer of 3-(2-diethylamino-1-(2-thenyl)ethyl)ester φ hydrochloride is obtained with a melting point of 208° C. (decomposition).

In addition, by crystallizing the subsequent eluate in the same manner and recrystallizing it from methanol, the other diastereoisomer was obtained at a temperature of 208°C (decomposed) at the Showa 1 point.

For example, the following compounds are further produced in the same manner as in the above examples.

◎ 2,6-simethyl-4-(m-nitrophenyl)-
1,4-cyhydrohyricin-3,5-dicarboxylic acid-3
-Methyl ester-5-[2-dimethylamino-1-(
2-furyl)ethyl]ester◎ 2,6-silf-4-(m-nitrophenyl)-L4-dihydrobiricin-3,5-dicarboxylic acid-3-methyl ester-5
-[2-dimethylamino-1-(5-pyridyl)ethyl]ester ◎ 2,6-silityl-4-(m-nitrophenyl)-1,4-cyhydrohyricin-3,5-dicarboxylic acid -3-Methyl ester-3C2-schif'thylamino-1-(2-chenyl)ethyl]ester ◎ 2,6
-Simethyl-4-(m-nitrophenyl) -1,4-
Dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-3-(2-dibentylamino-1-(2-chenyl)ethyl) ester ◎ 2,6-siltino L/-
4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-3
-C2-dihexylamino-1-(5-pyridyl)ethyl]ester o 2,6-dimedy11/ -4-(ln
-nitrophenyl)-1,4-dihydropyridine-3,
5-dicarboxylic acid-3-isopropyl ester-5-[
3-dimethylamine-1-(2-chenyl)ethyl]ester 11-

Claims (1)

[Claims] General formula (wherein, Hat represents a heterocyclic group, R represents a lower alkyl group,
R2 and R3 are the same or different and represent an alkyl group having 1 to IO carbon atoms, R4 represents a lower alkyl group or an aralkyl group, and n represents 1 or 2. ) A dihydropyridine compound represented by