JPH02240060A - 1,4-dihydropyridine compound - Google Patents

Abstract

NEW MATERIAL:A compound of formula I (A is substituted phenyl; R<2> is H, 1-5C alkyl, alkyl divided with an oxygen atom, halogen-substituted alkyl, etc.; R<3> and R<5> are lower alkyl) and a salt thereof. EXAMPLE:3,5-Dimethoxycarbonyl-2-methoxycarbonylmethyl-6-methyl-4-(3'- nitrophenyl)-1,4-dihydropyridine. USE:A hyertensive drug. PREPARATION:A combination of an aldehyde of formula: A-CHO and a compound of compound II or III or a combination of the compound of the formula: A-CHO and a compound of formula IV or V is reacted with each other to provide the compound of formula I. The reaction is carried out in the presence or absence of dioxane, THF, benzene, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Application Field) The present invention provides a novel 1,4-dihydropyridine compound known as a drug that affects Ca flow related to muscle contraction. , the compound has the effect of lowering blood pressure.

(Prior art v#) Among the 1,4-dihydrobiridine compounds, 4-nitro-substituted phenyl-2,6-dimethyl-1,4-dihydrobiridine-3,5-dicarboxylic acid diethyl ester is 1887
It became publicly known in . (Chern.Bar.Vol.
．． 20) 4-(2-nito-phenyl)-2,6-dimethyl-1,4-dihydrobiridine-3,5-dicarboxylic acid dimethyl ester, commonly known as difedipine, has a coronary vasodilatory effect and a peripheral vasodilatory effect. It is used in the treatment of diseases as a drug that reduces vascular resistance, antihypertensive action, improves the balance of myocardial oxygen demand, and suppresses Ca deposition on arterial walls due to intracellular Ca overload. Furthermore, there is a compound similar to this drug, 4-(3nitrophenyl)-2,6-dimethyl-1,4-dihydrobiridine-3,5-dicarbonate, which is commonly called dicardipine hydrochloride. 3-Methyl ester-5-β-(N-benzyl-N-methylamino)ethyl ester hydrochloride exhibits a dilating effect on cerebral blood vessels and is used to treat cerebral blood flow disorders and hypertension. There is.

However, sometimes undesirable side effects such as tachycardia, nausea, headaches, hot flashes, dizziness, and palpitations can be a curse, so we are trying to find compounds that maintain the main effect for as long as possible after administration and have fewer side effects. At present, many compounds have been synthesized and subjected to activity measurement tests, and through repeated trial and error, more excellent compounds are being created.

(Problems to be Solved by the Present Invention) The present invention aims to provide a new 1,4-dihydrobiridine compound represented by formula (1). That is, Formula A (wherein A is a phenyl group having a substituent, R2 is H,
C to C alkyl groups, alkyl groups separated by a bond, halogen-substituted alkyl groups, cyclic aliphatic hydrocarbons or alkyl groups containing them, aralkyl groups that may have substituents. phenyl group which may have a substituent,
or -B-N-R' R7 (B is an optionally branched alkylene group of C. to Cs, R'', R7 is the same or different and is an alkyl group, an aralkyl group that may have a substituent) or one is B
Does it form a ring? or may be combined with N to form pyrrolidine, piperidine, morpholine, or aralkyl-substituted piperazine) R3, R'' are the same or different and represent a lower alkyl group) A 1,4-dihydrobiridine compound represented by provided.

(Means for Solving the Problems) The compound represented by the above formula (1) provided by the present invention is produced as follows.

It is produced by reacting an aldehyde compound represented by A-C I{ 0 with a combination of NH2 〇l-1, C=CHCOOR' O [CH3CCH2COOR'.

(In the formula, A, R", R', R' are the same as above.) The reaction is carried out by heating and stirring in the presence or absence of a solvent. The solvents used include lower alcohols, dioxane, and dioxane. - Hydrofuran, benzene, toluene, xylene, hexane, hebutane, octane, etc., which are not involved in the reaction, may be used as appropriate.

Here, the compound in which R1 is }-I in formula (1) is produced by synthesizing a compound in which R1 is methyl or ethyl, and then hydrolyzing the compound. The thus obtained carboxylic acid compound can be used for the synthesis of many different esters by esterification. Such esters can also be produced by transesterifying a compound in which R2 is methyl or ethyl with various alcohol compounds in the presence of an acid or alkali.

Examples will be described below to further specifically explain the present invention.

The pharmacological activity of the compounds obtained in each example was measured by the method described below.

(1) Relaxation effect on rat thoracic aorta Male Wista strain rats weighing 300 to 400 g were killed by carotid-femoral exsanguination, and the thoracic aorta was immediately removed.

This was used as a spiral strip (2 mrtt x 20 mm) specimen, and 3
The specimen was suspended under a tension of 0.015 in a Magnus tube filled with 20 ml of nutrient solution kept at 7° C. and aerated with a mixed gas of 95% oxygen and 5% carbon dioxide.

After the specimen was contracted with a 40 mM potassium solution, the test compound was applied cumulatively to measure the degree of relaxation, and finally papaverine hydrochloride (IOM) was applied to determine the maximum relaxation 4i value. Taking the maximum relaxation value as 100%, the concentration of the test compound required to induce 50% relaxation (IC, .) was calculated from the cumulative dose-response curve.

(2) Antihypertensive agent 71I in rats 300 to 400 male Wista strain rats were anesthetized with urethane (1.0 g/kg intraperitoneally administered). Blood pressure was set so that it could be measured via a pressure transducer from the carotid artery. Test compounds were administered through a cannula placed in the femoral vein. Dose is 1■/kg or 0.1
■/kg. Test compounds were added to PV in 1 ml of DMSO.
It was prepared by dissolving it in a solution containing 200 mg of P and diluting it with distilled water.

The antihypertensive effect was determined by measuring the blood pressure before administration, the blood pressure at the maximum drop after administration, and the blood pressure 30 minutes and 60 minutes later, and the difference was calculated.

Example 1 3-nitrobenzaldehyde l 5. A mixture consisting of l l K, 17.42 K of methyl acetonedicarboxylate, 11.51 g of methyl β-aminocrotonate, and 78 ml of isobrobyl alcohol was stirred under reflux for 16 hours. The reaction solution was concentrated under reduced pressure, and 40 ml of toluene was added to the residue. The precipitated crystals were collected by filtration, and 3,5-dimethoxycarbonyl-2-methoxycarbonylmethyl-6-methyl-4-
17.14 g of (3'-ditrophenyl)-1,4-dihydropyridine was obtained. (Compounds of Example 1 in the table) Compounds of Examples 2 to 7 in the table were obtained in the same manner.

Example 8 3,5-dimethoxylponyl-2-methoxylponylmethyl-6-methyl-4-(3'-bitrophenyl)
-1.4-dihydropyridine 20.63 g, IN aqueous sodium monohydroxide solution 5 3 ml, methanol 1
The mixture of 0 6 rn 1 was stirred at room temperature for 4 hours. The mixture was washed with chloroform, acidified with hydrochloric acid, and extracted with chloroform. The chloroform layer was cooled and the precipitated crystals were collected by filtration to give 2-hydroxylponylmethyl-3,5-dimethoxylponyl-6-methyl-4-(3'-ditrophenyl)-1.4. -dihydropyridine 1/2 chloroforno,
15.96 g of an adduct compound (compound of Example 8 in the table) was obtained.

Compounds of Examples 9 to 10 in the table were obtained in the same manner.

Example 11 3,5-dimethoxycarbonyl-2-methoxycarbonylmethyl-6-methyl-4-(3'-bitrophenyl)
-1.0 g of 4-dihydroviridine + 4 ml of n-propanol, 0.0 g of p-toluenesulfonic acid monohydrate. oag
The mixture was refluxed for 6 hours.

The reaction mixture was subjected to silica gel chromatography.
3,5-dimethoxycarbonyl-6-methynole-4-(
0.63 g of 3'1-ditrophenyl)-2-propoxycarponylmethyl-1,4-dihydropyridine (compound of Example 11 in the table) was obtained.

Compounds of Examples 12 to 14 in the table were obtained in the same manner.

Example 15 2-Hydroxycarbonylmethyl-3,5-dimethoxycarbonyl-6-methyl-4-(3-nitrophenyl)
-1.5 g of 1.4-dihydropyridine 1/2 chloroform adduct, 3 tn l of pyridine, 0.96 g of β-(N,N-dibenzylamino)ethanol, DC:CO,
-82 g of the mixture was stirred at room temperature for 3 hours. Furthermore, under water cooling, chloroform lOm1 was added, and hydrochloric acid was added to pI{
2 and stirred for 1 hour. The chloroform layer was washed with water, dried, condensed, and subjected to silica gel force column chromatography to obtain 2-
β-(N,N-dibenzylamino)ethoxylponylmethyl-3,S-dimethoxylbonyl-6-methyl-
1.04 g of 4-(3'-ditrophenyl)-1,4-dihydropyridine (compound of Example 39 in the table) was obtained.

Compounds of Examples 15 to 54 and 57 to 64 in the table were obtained in the same manner.

Example 56 4-(2',3-dichlorophenyl)-3,5-dimethoxycarbonyl-2-methoxycarbonylmethyl-6-
Methyl-1,4-dihydropyridine 1.5gy β-(
A mixture of 3.49 g of N-p-chlorobenzyl-N-methylamino) ethanol and 1 drop of 28% sodium methylate was stirred at room temperature for 5 hours. After extracting with chloroform and purifying with silica gel column chromatography, 2-β-(N.-p-
Chlorobenzyl-N-methylamino)ethoxylponylmethyl-4-(2',3-dichlorophenyl)-3,
0.68 g of 5-dimethoxycarbonyl-6-methyl-1.4-dihydropyridine (compound of Example 56 in the table) was obtained.

In the same manner, the compound of Example 55 in the table was obtained.

Claims (1)

[Claims] Formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, A is a phenyl group having a substituent, R^2 is H
, C_1 to C_5 alkyl groups, alkyl groups separated by oxygen bonds, halogen-substituted alkyl groups, cyclic aliphatic hydrocarbons or alkyl groups containing them, aralkyl groups that may have substituents, substituents. (B is an optionally branched alkylene group of C_2 to C_5, and R^6 and R^7 are the same or different alkyl base,
It is an aralkyl group which may have a substituent, or one of them may form a ring with B, or together with N, it may form pyrrolidine, piperidine, morpholine, or aralkyl-substituted piperazine) A 1,4-dihydropyridine compound and a salt thereof.