JPS5978186A - 1,4-dihydropyridine-3,5-dicarboxylic acid ester derivative - Google Patents

Abstract

NEW MATERIAL:The compound of formula I [R<1>, R<2> and R<3> are lower alkyl; X is CH=CH, O, S, CH=N, etc.; X<1>, X<2> and X<3> are H, halogen, nitro, etc.; R<5> and R<6> are alkyl, aralkyl or together with adjacent N form heterocyclic group (5-7-membered ring which may contain N, O, S and unsaturated bond); n is integer of 1-3] and its salt. EXAMPLE:2,6-Dimethyl-4-( 2, 1, 3-benzoxadiazol-4-yl )-1,4-dihydropyridine-3,5-dicarboxylic acid 3-methyl ester 5-(1-phenyl-2-piperidinoethyl) ester hydrochloride. USE:A hypotensor and a remedy for cardial or cerebral circulation disorder. It has strong vasodilating action. PROCESS:The compound of formula I can be prepared by reacting the compound of formula II with the compound of formula III or compound of formula IV in the presence of a solvent such as benzene under heating.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides 1, which is useful as a pharmaceutical and is represented by the general formula;
The present invention relates to 4-dihydropyridine-3,5-dicarboxylic acid ester derivatives, salts thereof, and methods for producing them.

In the above formula, each symbol is as follows.

R1 represents lower alkyl (methyl, ethyl, propinopeisoprovil, butyl, etc.), R2 and R3 are the same or different and represent lower alkyl (same as described for R1), and X represents -CI (=CH-, - 〇 −, −8−, −CH:=N−
1 spanning -N(R')-(R4 is hydrogen, lower alkyl (
(same as described for R1). ), xl.

) c 2 and x 3 are the same or different and are hydrogen, halogen (fluorine, chlorine, bromine, iodine), nitro, trifluoromethino, lower alkyl (same as described for R1)
, lower alkoxy (methoxy, ethoxy, propoxy, etc.), and R5 and R6 are the same or different, alkyl (methyl, ethyl, provinoheisoprovil, butyl, nibutyl, tert-butyl, isobutyl, pentyl, isopentyl, neopendel, tertiary pentyl, hexynopeisohexinohebutyl, octinopenoninopedecyl, etc.), aralkyl (hensyl, parafluorobenzyl,
Para'y loropendino to paramethoxypendino 3,
4-dichloropendino to phenethyl, parachlorophenetino to paramethoxyphenethyl, etc.), or R and R together with adjacent nitrogens represent a heterocycle (a 5- to 7-membered ring, nitrogen, oxygen, sulfur, unsaturated It may have a bond.

) (1-pyrrolidinyl, piperidino, hexahydroazepin-1-yl, morpholino, thiomorpholino, 1-piperazinyl, 1,2.3.6-tetrahydro-1-pyridyl, etc.), where n is 1 Indicates an integer between ~3.

The compound (I) of the present invention has a strong vasodilating effect and a blood pressure lowering effect, 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 an aromatic ring or aromatic heterocycle is introduced into the α-position of the side chain aminoalkyl ester moiety, the efficacy is enhanced and the duration is significantly longer. .

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

Method l general formula (Each symbol in the formula has the same meaning as above) Compound and general formula represented by Compounds and general formulas represented by H2 (Each symbol in the formula has the same meaning as above) A method of reacting a compound represented by

This reaction involves mixing the compounds represented by the general formulas (n), (I[I), and (W), and using a suitable solvent (methanol, ethanol/L/, 7' lovanol, impropatol, dioxane, benzene, It is carried out by heating in the presence of toluene, acetonitrinopedimethylformamide, dimethyl sulfoxide, etc.). In addition, the compound (ff)
can be obtained, for example, by reacting a compound represented by R2-C0C2C00R with ammonia in advance. This product can be isolated once or left as is (II
) and (III) to obtain the target compound (I)
It is possible to do this.

Method 2 A compound represented by the general formula (in which each symbol has the same meaning as above), a compound represented by general formula (Ill), and a compound represented by the general formula % (in which each symbol has the same meaning as above) How to react with.

7- This reaction is carried out by mixing the compounds represented by the general formulas (Y), (III), and (VD) and heating in the presence of an appropriate solvent (same definition as above). can be obtained, for example, by reacting the compound of the general formula (I[) with ammonia in advance.
The target compound (I) can be obtained by reacting with

Method 3 Compound represented by general formula (II) and general formula ([I[)
A method of reacting a compound represented by the general formula (in which each symbol has the same meaning as above) obtained by preliminarily reacting a compound represented by the formula (IV) with a compound represented by the general formula (IV).

This reaction is carried out by heating in the presence of a suitable solvent (as defined above). In addition, the compound represented by the general formula (■) may be isolated once or may be directly used (
It may also be reacted with a compound represented by W).

Method 4 The compound represented by the general formula (III) is obtained by reacting the compound represented by the general formula (W) in advance with the compound represented by the general formula (in the formula, each symbol has the same meaning as above) and the general formula (V). A method of reacting a compound represented by

This reaction is carried out by heating in the presence of a suitable solvent (as defined above). In addition, the compound represented by the general formula (■) may be isolated once or may be directly used (
It may be reacted with a compound represented by V).

Method 5 General formula [In the formula, Z is an acid residue of an active ester (a halogen atom such as chlorine, bromine, or iodine, or an alkyl or arylsulfonyloxy such as methylsulfonyloxy, ethylsulfonyloxy, benzenesulfonyloxy, or valatoluenesulfonyloxy) ), and other symbols have the same meanings as above. ] A method of reacting a compound represented by the formula with a compound represented by the monofunctional formula.

This reaction is carried out in a suitable solvent (as defined above) in the presence of a deoxidizing agent (an inorganic alkali such as alkali carbonate, alkali bicarbonate, alkali alflate, or an organic base such as triethylamine, dimethylaniline, diethylaniline, hyridine). It is done.

The reaction usually takes place from around room temperature to around the boiling point of the solvent for several hours to several tens of hours.The compound represented by the general formula (■) is represented by the general formula (in which each symbol has the same meaning as above). Using the represented compound as a raw material, for example, the above-mentioned method 1
-4 can be easily obtained.

Method 6 general formula (Each symbol in the formula has the same meaning as above) Compound and general formula represented by (Each symbol in the formula 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 (I) 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. Racemic compounds can be prepared, if desired, by reacting with optically active acids (tartaric acid, diacetyltartaric acid, taldolanilic acid, dibenzoyltartaric acid, ditoluoyltartaric acid, etc.) to form diastereomers, and then 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 present invention can be in the form of inorganic or organic salts such as hydrochlorides, hydrobromides, phosphates, sulfates, succinates, maleates, fumarates, tartrates, acetates, and the like.

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

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

In addition, when two types of diastereoisomers are obtained in the following examples, the isomer detected at the top in thin layer chromatographic analysis is the α-diastereoisomer, and the one detected at the bottom is the β-diastereoisomer. Tentatively called diastereoisomers.

Example 1 1-phenyl-2-piperidinoethyl acetoacetate 2.0 g of oxadiazole, β-aminocrotonic acid methyl ester 1. After dissolving 6 g in 30 mt' of isopropyl alcohol, the solution was heated under reflux for 10 hours. Concentrate the reaction solution under reduced pressure. Dissolve the residue in benzene. When the benzene solution is washed with dilute hydrochloric acid, a candy-like substance is separated. The benzene layer and water layer are decanted and removed. The separated syrup is made alkaline by adding an aqueous potassium carbonate solution, and then extracted with ethyl acetate. After washing the ethyl acetate layer with water and drying over anhydrous magnesium sulfate, the solution is concentrated under reduced pressure. The residue is separated and purified by silica gel chromatography [chloroform:methanol-to:1 (volume/volume ratio)]. Concentrate the eluent that elutes first. After dissolving the residue in acetone, a hydrogen chloride ethanol solution is added. When the precipitated crystals are separated and recrystallized from ethanol, 2,6-trimethyl-4-(2,1.3-benzoxadiazol-4-yl)-1 with a melting point of 224-225°C (decomposition) is obtained. 4-dihydropyridine-3,
5-dicarboxylic acid-3-methyl ester-5 = (,
1-phenyl-2-piperidinoethyl) ester m
A salt (α-diastereoisomer) of A is obtained. Also,
When the eluent to be eluted later is treated in the same way, the melting point is 234.
The β-diastereoisomer (hydrochloride) is obtained at ~235° C. (decomposition) (recrystallized from ethanol).

Example 2 4.4 g of acetoacetic acid 2-(N-benzyl-IT-methylamino)-1-phenylethyl ester.

4-formyl-2,1,3-benzoxadiazole 2. Ogs β-aminocrotonic acid methyl ester 1
．． After dissolving 6 g in 30 Tnl of isopropyl alcohol, the solution was heated under reflux for 10 hours. After the reaction is completed, 2,6-trimethyl-4 is produced by the same treatment as in Example 1.
- (2, 1. 3-benzoxadiazole-
4-yl) = 1,4-dihydropyridine-3,5
-dicarboxylic acid-3-methyl ester-5-( 2-(
N-benzyl-1-methylamino)-1-phenylethyl ester hydrochloride is obtained. The melting point of the α-diastereoisomer (hydrochloride) is 190-191°C (decomposed) (recrystallized from ethanol), and the β-diastereoisomer (
The melting point of the hydrochloride salt is 234-235°C (decomposed) (recrystallized from ethanol).

Example 3 Acetoacetic acid [2-piperidino-1-(2-chenyl)
Ethyl] ester 4.0 g, 4-formyl-2, L
2.0 g of 3-benzoxadiazole and 1.6 g of β-aminocrotonic acid methyl ester were dissolved in 30 me of isopropyl alcohol and heated under reflux for 10 hours. After the reaction, 2,6-dimethyl-4-(2,1.3-benzoxadiazol-4-yl)-1,4-dihydropyridine-3,5-dicarvone was obtained by the same treatment as in Example 1. acid-3-methyl ester-5-
C2-piperidino-1-(2-thenyl)ethyl]ester hydrochloride is obtained. The melting point of the α-diastereoisomer (hydrochloride) is 184-186 °C (decomposed) (recrystallized from ethanol), and the melting point of the β-diastereoisomer (hydrochloride) is 205-208 °C (min # U) (recrystallized from ethanol).

Example 4 7-1=)Vinegar Ae・(2-(N-benzyl-N-vthylamino)-1-(2-allyl)ethyl]ester 4.3
g, 4-formyl-2,1,3-benzoxadiazole 2.0 g, β-aminocrotonic acid methyl ester 1.
After dissolving 6 g in 30 me of isopropyl alcohol, the solution was heated under reflux for 10 hours. After the reaction is completed, 2,6-dimethyl-4 is produced by the same treatment as in Example 1.
-(2,1,3-benzoxathiazol-4-yl)
-1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-5-[2-(N-benzyl-N
-methylamino)-17-(2-furyl)ethyl] ester hydrochloric acid i is obtained. The melting point of the α-diastereoisomer (hydrochloride) is 188-189°C (decomposed) (recrystallized from ethanol), and the melting point of the β-diastereoisomer (hydrochloride) is 186~! 88°C (decomposed) (recrystallized from ethanol).

Example 5 3.9 g of acetoacetic acid/1-phenyl-2-piperidinoethyl ester 55-formyl-2,l 2.0 g of 3-benzoxadiazole, 1.6 g of β-aminocrotonic acid methyl ester and 30 ml of isopropyl alcohol '
After dissolving in the solution, the mixture was heated under reflux for 10 hours. After the reaction, 2,6-dimethyl-4-(2,1,3-benzoxadiazole-
5-yl)-L4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-5-(1-phenyl-2
-piperidinoethyl) ester hydrochloride is obtained. α
-The melting point of the diastereoisomer (hydrochloride) is 242-24
3-diastereoisomer (1/2 fumarate salt)).

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

+61 2.6-dimethyl-4-(2,1,3-benzoxadiazol-4-yl) -1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-
5-(2-dimethylamino-1-phenylethyl) ester + 7) 2.6-trimethyl-4- (2,L 3-benzoxadiazol-4-yl)-L4-dihydropyridine-3,5-dicarboxylic acid- 3-methyl ester-
5-(2-diethylamine-1-phenylethyl) ester + 8) 2.6-dimethyl-4-(2,1,3-benzoxadiazol-4-yl) -L 4-dihydropyridine-3,5-dicarboxylic acid -3-methyl ester-5-(1-phenyl-2-dipropylaminoethyl)
Ester (9) 2,6-dimethyl-4-(2,1,3-benzoxadiazol-4-yl) -1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-
5-(2-dibutylamino-1-phenylethyl)ester++01 2.6-dimethyl-4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydropyridine-3,5-dicarvone Acid-3-methyl ester-5-(2-cyhentylamino-1-phenylethyl)
Ester (II) 2,6-tumethyl-4- (2,1,3-
Benzoxadiazol-4-yl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-5-(2-symxylamino-1-phenylethyl) ester 2,6-dimethyl-4 -(2,1,3-benzoxadiazol-4-yl) -1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-5-
(2-diheptylamino-l-phenylethyl) ester (l-2,6-trimethyl-4 = (2,1,3-benzoxadiazol-4-yl) -1,4-dihydropyridine-3,5- Dicarboxylic acid-3-methyl ester-thyl) ester 0 sets 2,6-trimethyl-4-(2, L'3-
benzoxadiazol-4-yl) -1. 4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-5-(1-phenyl-2-(1-pyrrolidinyl)ethyl) ester 0[92.6-trimethyl-4-(2, 1.3
-benzoxadiazol-4-yl) - L 4-
Dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-5-(2-morpholino-l-phenylethyl) ester (I) 2,6-dimethyl-4-(2,L3-benzoxadiazol-4-yl) ) -L 4-dihydropyridine-3,5-dicarboxylic acid-3-methylester-yl) ester θ7) 2,6-dimethyl-4-(2,1.3-benzoxadiazol-4-yl) -1. 4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-5-(2-(hexahydroazepin-1-yl)-1-phenylethyl) ester end 2,6-tumethyl-4-(2, 1. 3-
benzoxadiazol-4-yl) - 1. 4-
Dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-5-[2=(1,2,3.6-tetrahydro-1-pyridyl)-1-phenylethyl diester (112,6-dimethyl-4-(2 , 1.3-benzoxadiazol-4-yl) - 1. 4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester - 5 - ( 2 - ( N - p-fluorobenzyl-N-methylamino )-1-phenylethyl diester (fi2.6-tmethyl-4-(2, L
3-benzoxadiazol-4-yl) - L
4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-5-[2-(N-p-chlorobenzyl-
N-methylamine)-1-phenylethyl diester H
2,6-dimethyl-4-(2,1.3-benzoxadiazol-4-yl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-5
-(2-(N-p-methoxybenzyl-N
-methylamino)-1-phenylethyl diester @2
,6-tumethyl-4-(2,1.3-benzoxadiazol-4-yl)-1. 4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-5-(2-(N-(3,4-dichlorobenzyl)-
N-methylamino]-1-phenylethyl]ester (2) 2,6-tumethyl-4- (2,L 3-benzoxadiazol-4-yl) -1,4-dihydropyridine-3,5- Dicarboxylic acid-3-methyl ester-5-C2-(N-methyl-N-phenethylamino)-
1-Phenylethyl] ester e1412.6-Thmethyl-4- (2,1,3-benzoxadiazol-4-yl) -1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-5- (2-(N-1)-chlorophenethyl-N-methylamino)-1-phenylethyl] ester [2,6-
dimethyl-4-(2,L 3-benzoxadiazol-4-yl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester 5-[2-(N-p-
Methoxyphenethyl-N-methylamine)-i-phenylethyl] ester (to) 2,6-tumethyl-4- (2,1,3-benzoxadiazol-4-yl') -L 4-dihydropyridine-3, 5-Dicarboxylic acid-3-ethyl ester-5-(1-phenyl-2-piperidinoethyl) ester @2,6-dimethyl-4-(2,C3-benzoxadiazol-4-yl)-1,4-dihydropyridine −
3,5-dicarboxylic acid-3-methyl ester-5-(1
-p-chlorophenyl-2-piperidinoethyl) ester (c) 2,6-tumethyl-4- (2,1,3-benzoxadiazol-4-yl) -1,4-dihydropyridine-3,5-dicarboxylic acid- 3-Methyl ester-5-(1-p-methylphenyl-2-piperidinoethyl)ester 4 2,6-tumethyl-4- (2,L 3-benzoxadiazol-4-yl) -1,4-dihydropyridine- 3,5-dicarboxylic acid-3-methyl ester-5
-(1-p-methoxyphenyl-2-piperidinoethyl) ester (3[*2,6-dimethyl-4-(2,1,3-benzoxadiazol-4-yl) -1,4-dihydropyridine-3, 5-Dicarboxylic acid-3-methyl ester-
5-(1-m-nitrophenyl-2-piperidinoethyl)ester@a2,6-dimethyl-4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydropyridine-3,5 -dicarboxylic acid-3-methyl ester-5
-(1-(2-furyl)-2-piperidinoethyl]ester (9) 2,6-dimethyl-4-(2,1,3-benzoxadiazol-4-yl") -1,4-dihydropyridine-3 , 5-dicarboxylic acid-3-methyl ester-5-(1-(3-7lyl)-2-piperidinoethyl)
Ester@4 2,6-dimethyl-4-(2,1,3-benzoxadiazol-4-yl) -L 4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-5
-C2-Piperidino-1-(3-chenyl)ethyl ester (3412,6-tumethyl-4- (2,L 3-benzoxadiazol-4-yl) -L 4-dihydropyridine-3,5-dicarboxylic acid- 3-Methyl ester-5-CI-(2-(5-chlorochenyl)]-2-piperidinoethyl]ester 112.6-dimethyl-4-(2,1,3-benzoxadiazol-4-yl) -1, 4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-5-
(l-C2-(5-methylfuryl)]-]2-hyhelicinoethyl]ester) 2,6-tumethyl-4- (2,L 3-benzoxadiazol-4-yl) -1,4-dihydropyridine-3 ,5-dicarbonyl-3-methyl ester-5,-(2-piperidino-1-(2-pyridyl)ethyl) ester0η 2,6-dimethyl-4-(2,1,3-benzoxathiazole-4 -yl) -1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-5
-C2-piperidino-1-(3-pyridyl)ethyl]ester (c) 2,6-dimethyl-4-(2,1,3-benzoxadiazol-4-yl) -L 4-dihydropyridine-3,5 -Dicarboxylic acid-3-methyl ester-
5-(2-piperidino-1-(4-pyridyl)ethyl)
Ester-2,6-tumethyl-4- (2,1,3-benzoxadiazol-4-yl) -1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-5-
1:2-piperidino-1-(2-pyrrolyl)ethyl]ester +41 2.6-dinithyl-4-(2,L 3-benzoxadiazol-4-yl) -1,4-dihydropyridine-3,5- Dicarboxylic acid 3-methyl ester
5-(1-phenyl-2-piperidinoethyl)ester (4η 2,6-tumethyl-4-(2,1,3-benzoxadiazol-4-yl)-L4-dihydropyridine-3,5-dicarboxylic acid-3 -Methyl ester-5
-(1-phenyl-3-piperidinoprobyl) ester (6) 2,6-tumethyl-4- (2,1,3-benzoxadiazol-4-yl') -1,4-dihydropyridine-3 ,5-dicarboxylic acid-3-methyl ester-5-(1-phenyl-4-piperisiptyl) ester +412,6-tumethyl-4-(2,1,3-benzoxadiazol-5-yl) -1,4 -dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-
5-(2-(N-benzyl-N-methylamino)-1-
Phenylethyl]ester 1442.6-Thmethyl-4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-
5-C2-(N-benzyl-■-ethylamino)-1-
Phenylethyl] Ester Agent Patent Attorney Masaru Takamiyagi Continued from page 1 ■Int, C1, 3 identification code Office reference number (C
07D 413/14 211100 7138-4C2
131007138-4C 2711007330-4C 3071006640-4C 333100) 8214-4C
O Inventor: Kazuhiko Araki 1212, Kamiikenaga, Fumima, Nakatsu City @ Inventor: Aoeiki 1-545-6 Nakadonomachi, Nakatsu City ■ Inventor: 5-6-11-16 Toshima, Kita-ku, Tokyo 0 authors: Tadayu Nakamura 2-468-1 Shimomiyaga, Nakatsu City 0 authors: Aihara Lab - 13 Hirotsu, Yoshitomi-cho, Chikjo-gun, Fukuoka Prefecture

Claims (1)

[Scope of Claims] A 1,4-dihydropyridine-3,5-dicarboxylic acid ester derivative or a salt thereof represented by the general formula. [In the above formula, R1 is lower alkyl, R2 and R3 are the same or different lower alkyl, X is -CH=CH-,
-0=, -8-, -CH=N-1 or -N(R4)(
R4 represents hydrogen or lower alkyl. ), xl. X and X are the same or different and represent lower alkyl or lower alkoxy to hydrogen, halogen, nitro, trifluoromethino, R and R are the same or different and represent alkynopearalkyl, or R and R are adjacent Together with nitrogen, a heterocycle (a 5- to 7-membered ring that may contain nitrogen, oxygen, sulfur, and an unsaturated bond) may be formed, and n is 1
Indicates an integer between ~3. ]