JPH03109373A - 1,4-dihydropyridine compound - Google Patents

Abstract

NEW MATERIAL:A compound shown by formula I (A is substituent group- containing phenyl or hetero atom-containing aromatic ring; R' and R'' are alkyl or aralkyl which may be replaced; R is lower alkyl) and a salt thereof. EXAMPLE:2,6-Dimethyl-4-(2',3'-dichlorophenyl)-1,4-dihydropyridine-3,5- dicarboxylic acid 3-methyl ester-5-[1-(N-benzyl-N-methylaminomethyl)cyclohexyl]methyl ester. USE:A drug having influence of flow of Ca related to muscular contraction. PREPARATION:A compound shown by formula II (B is H or phenyl which may be replaced) is reacted with an amino-alcohol shown by formula III or an alkali metal salt thereof in a solvent such as toluene in the presence or absence of a base (e.g. potassium carbonate) at room temperature or under heating to give a compound shown by formula I.

Description

Detailed Description of the Invention (Field of Industrial Application) The present invention provides a novel 1,4-dihydropyridine compound that does not affect the flow of Ca associated with muscle contraction and is known as a drug. be.

(Prior art) Among the 1,4-dihydropyridine compounds, 4-nitro-substituted phenyl-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester has 188
It became public knowledge in 1977. (Chem, Ber, VO
l, 20)%4 known as generic name nifedipine
-(2°-nitrophenyl)-2,6,-dimethyl-1
, 4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester has a coronary vasodilatory effect, decreases total peripheral vascular resistance,
Antihypertensive effect, improved balance of myocardial oxygen demand, intracellular C
It is used in the treatment of diseases as a drug that inhibits Ca deposition on the arterial wall due to overload. Furthermore, there is a drug with a structure similar to this drug, commonly called dicardipine hydrochloride, 4-(3'-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid -Methyl ester- Mino)ethyl ester hydrochloride exhibits a dilating effect on coronary blood vessels and cerebral blood vessels, and is used to treat cerebral blood flow disorders and hypertension. However, sometimes tachycardia, sweating, headaches, hot flashes,
Undesirable side effects such as dizziness and palpitations may occur.In order to find compounds that maintain the main effect for as long as possible after administration and have fewer side effects, many compounds have been synthesized and subjected to activity tests. At present, we are creating better compounds through repeated trial and error.

(Problems to be Solved by the Present Invention) The present invention aims to provide a new 1,4-dihydropyridine compound represented by formula (I). That is, 1 represented by the formula or different alkyl group, an aralkyl group which may have a substituent, R represents a lower alkyl group,
4-dihydropyridine compounds are provided.

(Means for solving the problem) The compound represented by the above formula (T) provided by the present invention is produced as follows.

A compound represented by formula (Tl) (wherein B represents hydrogen or a phenyl group which may have a substituent, and A and R are the same as above) is added to a compound represented by formula (III) p' (wherein A is a substituted R'R'' is the same (in the formula R'
(R" is the same as above) or its alkali metal group. The reaction is performed with benzene, toluene, xylene, dioxane, tetrahydrofuran,
Potassium carbonate in a solvent that does not participate in the reaction, such as hexane,
It is carried out at room temperature or with heating in the presence or absence of sodium carbonate, sodium, potassium, etc.

The compound in which B is H in formula (n) is produced by synthesizing a compound in which B is substituted or unsubstituted phenyl, and then hydrolyzing the compound. The thus obtained carboxylic acid compound can be reacted with a compound of formula (III) using a condensing agent such as N,N-dicyclohexylcarbodiimide to obtain an esterified product in the same manner.

Further, the compound represented by formula (U) used as a raw material is produced by the reaction of substituted benzaldehyde, acetoacetic acid phenyl ester, and -monoaminocrotonic acid ester.

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.

Relaxant agent for rat thoracic aorta! Wistar rats weighing 1300-400 g were sacrificed by carotid exsanguination, and the thoracic aorta was immediately removed. This was used as a spiral strip (2 mm x 20 mm) specimen, and a nutrient solution kept at 37°C and aerated with a mixed gas consisting of 95% oxygen and 5% carbon dioxide was poured for 20 m! 1. Into the filled Magnus tube. O
It was suspended under a tension of 1.5 g.

After the specimen was contracted with a 50 mM potassium solution, the test compound was cumulatively applied to measure the degree of relaxation, and after f&, bababerine hydrochloride (to-'M) was applied to determine the maximum relaxation 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.

Example 1 0.90 g of 60% oily sodium hydride was suspended in 20 ml of dry tetrahydro 7 run, and 1-(
After adding 5.57 g of N-benzyl-N-methylamino)-t-hydroxymethylcyclohexane, the
Stir for a minute. Subsequently, 2,6-dimethyl-4- was added under water cooling.
6.69 g of (2',3'dichlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-methyl ester-5-p-methylphenyl ester was added and stirred for two days at room temperature. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in chloroform, and washed with dilute hydrochloric acid and water.

The mixture was further washed with a sodium hydrogen carbonate solution and water, dried over anhydrous magnesium sulfate, the solvent was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography. 2,6-dimethyl-4-(2',
3°-dichlorophenyl)-1,4-dihydropyridine-3°5-cicafreponic acid 3-methyl ester --(N
-benzyl-N-methylaminomethylchlorohexyl]methyl ester was obtained.

Melting point: 151-154°C. When this product was converted into a hydrochloride in isopropyl ether, a 1/2 isoglobyl ether adduct having a melting point of 138-140°C was obtained. (Compounds of Example I in the table) Compounds of Examples 2 to 12 in the table were obtained in the same manner.
child .

Example 13 2,6-cymethyl-4-(3'-pyridyl)-l.

4-dihydropyridine-3,5-dicarboxylic acid monomethyl ester 1. Og,l - (N,N-dimethylaminomethyl)-1-hydroxymethylcyclohexane 0
．． After adding 0.75 g of N,N'-dicyclohexylcarbodiimide to a mixture of 62 g and 3 ml of pyridine, 80
Stirred at ℃ for 1 hour.

After cooling, toluene was added, the pH was adjusted to 2 with dilute hydrochloric acid, the mixture was stirred for 30 minutes under water cooling, and insoluble matter was filtered off. The aqueous layer was separated, made alkaline with dilute aqueous sodium hydroxide solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried with anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure. Isopropyl ether was added to the residue and the crystals were collected by filtration to give 2,6-dimethyl-4-(3''-pyridyl)-1.

4-dihydropyridine-3.5-dicarboxylic acid 3-methylnisder-5-(1-(N-benzyl-N-methylaminomethyl)cyclohexyl)methyl ester 1.
18g was obtained.

Melting point: 170-173°C The hydrochloride of this product was a 7-ohm substance with strong hygroscopicity. (Compound of Example 13 in the table) Compounds of Examples 14 to 19 in the table were obtained in the same manner.
.

Claims (1)

[Claims] Formula ▲ Numerical formula, chemical formula, table, etc. A 1,4-dihydropyridine compound represented by the following formula (an alkyl group, an aralkyl group which may have a substituent, R represents a lower alkyl group), and a salt thereof.