JPS58159462A - 1,4-dihydropyridine-3,5-dicarboxylic acid ester derivative - Google Patents

Abstract

NEW MATERIAL:The compound of formulaI(W is -CH= or -N=; Y is -CH= CH-, -O-, -S-, etc.; X<1>-X<3> are H, halogen, nitro, trifluoromethyl, etc.; Z is aryl, 5-6-membered aromatic heterocyclic group, etc.; the group of formula II is a 5-7-membered heterocyclic group containing N, S, etc. and lower alkyl, etc.) and its acid addition salt. EXAMPLE:(4S)-2, 6-Dimethyl-4-( m-nitrophenyl)-1, 4-dihydropyridine-3,5-dicarboxylic acid 3-methyl ester 5- (1R)-1-phenyl-2-piperidinoethyl ester. USE:Hypotensor and remedy for cardiac and cerebral circulation disorder. It has strong and extremely long-acting vasodilating and hypotensive activities. PROCESS:The compound of formulaIcan be prepared e.g. by reacting the compound of formula II with the compound of formula III and the compound of formula IV in a solvent such as methanol under heating.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel 1,4-dihydropyridine-3,5-dicarboxylic acid ester derivatives represented by the general formula, salts thereof, and processes for producing them, which are useful as pharmaceuticals.

In the above formula, each symbol is as follows.

W represents -CH- or -N-, Y represents -CH=CH-
.

-O-, -5-, -CH=N(0) p- (p is 0.1
is -N(R)- (R is hydrogen, lower alkyl (methyl, ethyl, propyl, isopropyl, glutyl, etc.)), and X 1 , x 2 , x 3
are the same or different, hydrogen, halogen (fluorine, bromine,
chlorine, iodine), nitro, trifluoromethyl, cyanide, lower alkylthio (methylthio, ethylthio, propylthio, isopropylthio, butylthio, etc.),
2 represents an aryl (such as phenyl) or a 5- to 6-ring aromatic complex ring (such as chenyl, furyl, pyridyl, thiazolinohoxasilyl, pyrimidinyl, inxazolinopeviloryl, and imidazolyl); 1 to 3 different halogens (fluorine, bromine, chlorine, iodine), lower alkyl (methyl, ethyl, propyl, isopropyl, butyl, etc.), lower alkoxy (methoxy, ethoxy, propoxy, impropoxy, butoxy, etc.), lower Alkanoylamino (acetylamino, propionylamino, butyrylamino, etc.), cyano, nitro, lower alkylthio (methylthio, ethylthio, propylthio, isopropylthio, butylthio, etc.), trifluoromethyl, sulfamoyl, di-lower alkylsulfamoyl (dimethylsulfamoyl) , diethylsulfamoyl, dipropylsulfamoyl, diisopropylsulfamoyl, dibutylsulfamoyl, etc.), amino, di-lower alkylamino (dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino), 5-7 It is a membered ring with nitrogen, oxygen,
Sulfur, a heterocycle which may have an unsaturated bond (1-pyrrolidinyl, piperidino, hexahydroazepin-1-yl, morpholino, thiomorpholino, 1-piperazinyl,
1.2.3.6-tetrahydro-1-pyridyl, etc.), which are lower alkyl (methyl, ethyl, propyl, isopropyl, butyl), lower alkoxycarbonyl (methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, propoxycarbonyl, methoxycarbonyl, etc.), lower alkanoylamino (acetylamino, propionylamino, butyrylamino, etc.), ethylenedioxy, -(CH2)m-OR (R hydrogen, lower alkyl (methyl, ethyl, propyl, isopropyl, butyl) ), lower alkanoyl (acetyl,
propionyl, butyryl, etc.), m is 0.1.2. ] as a substituent, R and R are the same or different and represent lower alkyl (methyl, ethyl, propyl, isopropyl, butyl, etc.), and R is lower alkyl (methyl, ethyl, propyl, isopropyl, etc.). , butyl), aralkyl (benzyl, phenethinopephenylpropyl or these mono- or di-substituted with chloro, fluoro, methyl, methoxy, etc.), heteroaralkyl (furylmethinobechenylmethyl, pyridylmethyl, etc.) and n represents an integer of 1 to 5.

The compound (i) 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 an aromatic ring or an aromatic heterocycle is introduced into the α-position of the side chain cyclic aminoalkyl ester moiety, its efficacy is enhanced and its duration becomes significantly longer. .

According to the invention, compounds of general formula (I) can be prepared by method l 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) Compounds and general formulas represented by (Each symbol in the formula has the same meaning as above) A method of reacting a compound represented by

This anti-F3 is prepared by mixing the compounds represented by the general formulas (B), (1■), and (Iv)f, and using a suitable solvent (methanol, ethanolopepropanol, impropatol, dioxane, benzene, toluene, ayatonitrile, This is done by heating in the presence of dimethylformamide, dimethyl sulfoxide, etc.). Note that the compound (1v) can be obtained by, for example, reacting a compound represented by R1-COCH2COOR with ammonia in advance. This product can be isolated by -d or directly separated (b) and (II).
) can be reacted with the compound (I) to obtain the target compound (I).

Method 2 A compound represented by the general formula (each symbol in the formula has the same meaning as above) and a compound represented by the general formula (1■) and a compound represented by the general formula A method of reacting with a compound.

This reaction is carried out by mixing the compounds represented by the general formulas (1, (III), and (■)) and heating the mixture in the presence of an appropriate solvent (same as above).Compound (V)
ld can be obtained, for example, by reacting the compound of general formula (b) with ammonia in advance.

This product can be isolated or left unreacted and reacted with compounds (nl) and (■) to give the desired product (I).

Method 3 Compound represented by general formula (IT) and general formula (III
) A method of reacting a compound represented by the general formula (in the formula, each symbol has the same meaning as above) with a compound represented by the general formula (IV).

This reaction is carried out by heating in the presence of a suitable solvent or medium (as defined above). Incidentally, the compound represented by the general formula (Vl[) may be isolated once or may be directly reacted with the compound represented by 4 (■) without being isolated.

Method 4 = Compound represented by general formula (fil) and general formula (V
l) A method of reacting a compound represented by the general formula (in which each symbol has the same meaning as above) obtained by reacting a compound represented by the general formula (Vl) with a compound represented by the general formula (Vl).

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

Method 5 General formula [In the formula, ) and other records Ji! f has the same meaning as above. ] A method of reacting a compound represented by the general formula) with a compound represented by the general formula % (1) ().

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

It takes place over a period of several tens of hours. In addition, general formula (IX)
The compound represented by the general formula %) (in the formula, each symbol has the same meaning as above) is used as a raw material, for example, by the method 1 described above.
-4 can be easily obtained.

Method 6 general formula H (Each symbol in the formula has the same meaning as above) (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 Scheme 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. The racemic compound may optionally be used, for example, with an optically active acid (tartaric acid, diacetyltartaric acid, cultoranilic acid,
(dibenzoyltartaric acid, ditoluoyltartaric acid, etc.) to form diastereomers, which are then separated by crystallization, distillation, chromatography, etc., and optically active bases can be obtained from the separated salts. Furthermore, a compound having a desired stereoconfiguration 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, oxalates, maleates, fumarates, oleaginates, acetates, etc. .

It has excellent antihypertensive effects in rats and is also characterized by its extremely long action.

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 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 the disease condition to be treated. Varies depending on severity and response to treatment.

The present invention will be described in more detail with reference to Examples below.
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 chromatography analysis is the α-diastereoisomer, and the one detected at the bottom is the β-diastereoisomer. Tentatively called isomers.

Example [Acetoacetic acid/1-phenyl-2-piperidinoethyl ester 28.9 gSm-nitrobenzaldehyde I 5.
I g, β-aminocrotonic acid methyl ester11.
Dissolve 5g in 300ml of isopropyl alcohol and add 1
Heat and reflux for 7 hours. The reaction solution was concentrated under reduced pressure, and the residue was removed by silica gel column chromatography [chloroform:
methanol-1O:1 (volume ratio)]. When the eluate containing the target compound is concentrated and recrystallized from isopropyl alcohol, 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine- 3,5-dicarboxylic acid-3-methyl ester-3-(1-phenyl-2-piperidinoethyl) ester is obtained.

This product is an α-diastereoisomer, and its hydrochloride has a melting point of 238-240°C (decomposed). In addition, the 8 points of the β-diastereoisomer obtained in the same manner are 127 to 1
30°C (recrystallized from isopropyl alcohol) and the melting point of its hydrochloride salt is 222-223°C (decomposition) (recrystallized from ethanol).

Since the compound Vi of Example 1 represented by the general formula (in the formula, the umbrella symbol indicates an asymmetric carbon) has two asymmetric carbon atoms, four types of stereoisomers exist.

These isomers can be produced by optically resolving the thus obtained α-sweet or β-diastereoisomer by a conventional method, or by using One side of the asymmetric carbon is produced by using a raw material in which both sides are optically active (if diastereoisomers are obtained, they are separated).

These isomers are summarized as follows.

(A) (4S) -2,6-dimethy; L/ -4
-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-3-C
(IR)-■-7enyl-2-piperidinoethyl] ester, melting point 169-17oC (decomposition), [α]25+
201.9° (C=-+, O, methanol) (B)
(4R)-2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-1-phenyl-2-piperidinoethyl] ester, melting point 169~ 17 pC (decomposition), [α] 9 -201, 2
°(C=1.0, methanol) (C) (4S
) −2. 6-dimethy/L/-4-(m
−=l−.

phenyl) - 1. 4-dihydropyridine-3.5
-dicarboxylic acid-3-methyl ester-5-1m(I
s)-1-phenyl-2-hyperidinoethyl]ester, melting point 143°C, [α)]D-5.09° (c=2.5
.

Chloroform) (D) (4R) -2. 6-dimethy/L
/−4” (m−=).

phenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-5-[(IR
)-1-phenyl-2-piperidinoethyl] ester,
Melting point 143℃, [α), +5.42° (c=-2.5
.

chloroform) Example 2 2,6-dimethyl-4-(m-nitrophenyl)-1,
5.4 g of 4-dihydropyridine-3,5-dicarboxylic acid-7nomethyl ester are added to chloroform 90-.

3. Phosphorus pentachloride at 0-5''C while cooling with ice water.
Add 7g at once. The reaction solution was kept at 0-5°C and stirred for 1 hour. Without isolating the acid chloride produced, it was cooled to -40°C on a dry ice-methanol bath and
-Phenyl-2-(4-ethoxycarbonyl-1-piperazinyl)ethanol 1 3. 6 g in 30 ml of chloroform. A solution dissolved in is added dropwise in 30 minutes. After cooling to 0°C, the mixture was cooled with ice water and stirred for 2 hours. The chloroform layer is washed with a 5% aqueous sodium carbonate solution, a 5% aqueous hydrochloric acid solution, and a 5% aqueous solution of sodium carbonate. The chloroform layer was dried over magnesium sulfate, and the chloroform was distilled off under reduced pressure. Dissolve the residue in acetone, add hydrogen chloride ethanol solution, and leave in the refrigerator overnight. The precipitated crystals were collected and recrystallized from a mixed solvent of methanol and ether to give 2,6-dimethyl-4-(2,6-dimethyl-4-(
m-nitrophenyl)-1,4-dihydropyridine-3
,5-dicarboxylic acid-3-methyl ester-3-CI-
-yeny#-C2-Cl-(4-,:r-toxycarbonyl)hyperazinyl]]ethyl]ester -jul(β
- diastereoisomers) are obtained. Also, concentrate the crystal mother liquor, add acetone to the residue, and leave it in the refrigerator.

When the precipitated crystals are separated and recrystallized from a mixed solvent of methanol and ether, the α-diastereoisomer (hydrochloride, 1/2
hydrate) is obtained.

Example 3 Acetoacetic acid/l-phenyl-2-piperidinoethyl ester 9.87 g, β-aminocrotonic acid methyl ester 3.9 g 12.3-dichlorobenzaldehyde 6.0 g
was added to ethanol 55- and heated under reflux for 19 hours. The reaction solution was concentrated under reduced pressure, and the residue was dried. Chloroform was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [chloroform:ethyl acetate-95:5 (volume tJt)]. Concentrate the eluent and dissolve the residue in acetone. Add hydrogen chloride ethanol solution to make hydrochloride. When the precipitated crystals are collected by F and recrystallized from methanol, the melting point is 24.
2,6-cymethyl-4 as colorless crystals at 6°C (decomposition)
-(2,3-dichlorophenyl)-1,4-cyhydrohyricine-3.5=dicarboxylic acid-3-methyl ester-
-phenyl-2-piperidinoethyl) ester hydrochloride (β-diastereoisomer) is obtained.

After concentrating the crystal mother liquor to the free form, it is purified by column chromatography, the eluent is concentrated and the residue is dissolved in acetone. Add hydrogen chloride ethanol solution,
Make into hydrochloride. Furthermore, ether is added to precipitate crystals. The precipitated crystals are separated and recrystallized from a mixed solvent of methanol-ether to obtain the α-diastereoisomer (hydrochloride) as pale yellow crystals with a melting point of 205-206°C (decomposed).

Example 4 Acetoacetic acid/l-phenyl-3-piperidinopropyl ester 20.8 g, β-aminocrotonic acid methyl ester 7.9 g, m-nitrobenzaldehyde I O. 3
g was added to 100 me of ethanol, and the mixture was heated and refluxed for 16 hours. Concentrate the reaction solution and dissolve the residue in chloroform. Chloroform (Mi5% hydrochloric acid, 5% carbonic acid)
Wash with IJum water and dry with magnesium sulfate. After drying, chloroform was distilled off and the residue was purified by silica gel column chromatography [chloroform:methanol-95
:5 (volume ratio)]. The eluent that is eluted first is concentrated, and the residue is dissolved in acetone. A hydrogen chloride ethanol solution is added to precipitate crystals. The precipitated crystals were collected and the crude crystals were recrystallized from a mixed solvent of methanol and ether to give 2,6-dimethyl-4-(m-nitrophenyl)- as yellow crystals with a melting point of 245-246°C (decomposition). 1,4-,dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-3-(1-phenyl-3-
piperidinopropyl) ester hydrochloride (α-diastereoisomer) is obtained. In addition, by treating the subsequent eluate in the same manner, the β-diastereoisomer (hydrochloride-172
hydrate) is obtained.

Example 5 30.9 g of acetoacetic acid I-(2-chenyl)-2-piperidinoethyl ester, 5.4 g of m-nitrobenzaldehyde I, and 11.7 g of β-aminocrotonic acid methyl ester were mixed with 350 g of isopropyl alcohol. The mixture was dissolved in water and heated under reflux for 20 hours.

The reaction solution was concentrated under reduced pressure, and the growth was purified by silica gel chromatography [chloroform:methanol=10:■, 2 (volume ratio)]. Concentrate the eluent that elutes first,
When recrystallized from ethanol, 2,6-dimedy-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-3- CI-(2-chenyl)-2-piperidinoethyl ester is obtained. It is a crystalline α-diastereoisomer, and its hydrochloride has a melting point of 215-218°C (decomposed). In addition, when the eluent was washed and recrystallized from ethanol, the melting point was 12.
The β-diastereoisomer is obtained as crystals at 8-134°C. The melting point of ice crystal hydrochloride is 188-190℃ (
decomposition).

Example 6 14.7 g of 1-phenyl-2-piperidinoethanol,
7. tg, triethylamine Irn
Add to ef benzene 130d. Heat the mixture for 3 hours,
Reflux. By concentrating the reaction solution under reduced pressure, acetoacetic acid/l-phenyl-2-piperidinoethyl ester 2
2g is obtained.

22 g of acetoacetic acid/1-phenyl-2-piperidinoethyl ester, 10.6 g of m-nitrobenzaldehyde
, 12.7 g of β-aminocrotonic acid (2-furyl)methyl ester are added to 130 g of isopropyl alcohol. The mixture is heated to reflux for 12 hours. Concentrate the reaction solution under reduced pressure. After adding hydrogen chloride ethanol solution to the viscous candy-like part, concentrate. A mixed solvent of acetone and ether is added to the viscous candy-like residue to crystallize it. When the crystals are separated and recrystallized from a mixed solvent of acetone and methanol,
2. As yellow crystals with a melting point of 219-221°C (decomposition).
6-Simethyl-4-(m-nitrophenyl)-1,4-
Dihydropyridine-3,5-dicarboxylic acid-5-(2-
Furyl) methyl ester-3-(1-phenyl-2-piperidinoethyl) ester hydrochloride (α-diastereoisomer) is obtained. The crystal mother liquor is concentrated, converted back to base, and purified by silica gel chromatography. Concentrate the eluate and add hydrogen chloride ethanol solution to the growth for crystallization. When the crystals are collected and recrystallized from a mixed solvent of acetone and methanol, the β-diastereoisomer (hydrochloride) is obtained as yellow crystals with a melting point of 211-214°C (decomposition).

Example 7 Phenacyl bromide 53g, 3-methylpiperidine 2
5 g and 37 g of potassium carbonate, 300 g of methanol.
me and react at room temperature for 2 hours.

Insoluble matter in the reaction solution was removed, and 7.1 g of sodium borohydride was added to the p solution at room temperature, followed by stirring for 2 hours.

The reaction solution was concentrated under reduced pressure, and the obtained oil was dissolved in ethyl acetate. After washing with water, extract with 1N hydrochloric acid. Wash the aqueous layer with ethyl acetate. The aqueous layer was adjusted to pH 10 with potassium carbonate.
Make it. The oil that separates is extracted with ethyl acetate. After washing the extracted layer with water, it is dried with magnesium sulfate. The ethyl acetate layer was concentrated under reduced pressure and recrystallized from isopropyl ether three times to obtain 2-( with a melting point of 70°C).
3-Methylpiperidino)-1-phenylethanol is obtained. Furthermore, collect the recrystallization mother liquor and reduce the pressure? ! Tritify by 1% and dissolve the remainder in isopropyl alcohol. Add hydrogen chloride ethanol solution to make hydrochloride. P the precipitated crystals
By recrystallizing twice with isopropyl alcohol, the other diastereoisomer hydrochloride having a melting point of 195-196°C is obtained.

9.5 g of 2-(3-methylpiperidino)-1-phenylethanol with a melting point of 70°C, 5 g of diketene and 0.1 me of triethylamine were mixed with benzene I O0rnI! and heat under reflux for 2 hours. When the reaction solution was concentrated under reduced pressure, oily acetoacetic acid/2-(3-methylpiperidino) was obtained.
14 g of -1-phenylethyl ester are obtained.

Acetoacetic acid 2-(3-methylpiperidino)-1-phenylethyl ester 14g 1m-nitrobenzaldehyde 6.5g, β-aminocrotonic acid methyl ester 5g
was added to 150 ml of isopropyl alcohol and heated under reflux for 15 hours. The reaction solution was concentrated under reduced pressure and the oily growth was dissolved in ethyl acetate. The ethyl acetate layer is washed with 1N hydrochloric acid, potassium carbonate, and water. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. 25 g of oily growth are purified by column chromatography. Concentrate the eluent and dissolve the residue in acetone. A hydrogen chloride ethanol solution is added to precipitate crystals. When the precipitated crystals are separated and recrystallized from ethanol, the melting point is 225.
2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-3 as crystals at ~226°C (decomposition)
-(2-(3-methylpiperidino)-1-phenylethyl ester hydrochloride is obtained.

In addition, by treating other eluents in the same way, melting point 2
The other diastereoisomer (hydrochloride) is obtained as crystals at 22-223°C (decomposition).

Furthermore, starting from 2-(3-methylpiperidino)-1-phenylethanol hydrochloride with a melting point of 195 to 196°C, the melting point 1
Crystals from 95 to 196°C (decomposed), and melting point 242°C
Two diastereoisomers (hydrochloride) of the target product are obtained as crystals (decomposition).

The following compound is produced by a method similar to the above example.

(1) 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-3-(1-phenyl-2-(
l-pyrrolidinyl)ethyl] ester, α-diastereoisomer: melting point 158-159°C, melting point of hydrochloride 237
°C (decomposition); β-diastereoisomer: melting point 162-1
63°C, melting point of hydrochloride 228-2306C (decomposition) (2) 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-3- C2-(hexahydroazepin-1-yl)-1-phenylethyl] ester,
α-diastereoisomer: m point 148-151°C, hydrochloride melting point 228-230°C (decomposition); β-diastereoisomer: melting point 153-155°C, hydrochloride melting point 188-230°C
191°C (decomposition) (3) 2.6-dimethyl-4-
(m-nitrophenyl)-1,4-dihydropyridine-
3,5-dicarboxylic acid-3-methyl ester-3-(2
-MorphoIJ/-1-phenylethyl) ester, α
- Diastereoisomer: melting point 166-170 °C, hydrochloride melting point 156-160 °C (decomposition); β-diastereoisomer, melting point 130-133 °C1 hydrochloride melting point 216
~219°C (decomposition) (4) 2.6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-3-(l-phenyl-2 =thiomorpholinoethyl) ester, 0! -Diastereoisomers: melting point 166-168°C, melting point of hydrochloride 223-2
246C (decomposed); β-diastereoisomer, melting point 14
8-150°C, melting point of hydrochloride 221-222°C (decomposition) (5) 3-methyl 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate Ester-3-(2-C1-(4-)
f-ruviperazinyl)]-]1-phenylethyl] ester 2 fumarate, β-diastereoisomer: melting point 175
~180°C (decomposition) (6) 2.6-dimethyl-4-(0-chlorophenyl)-1,4-dihydropyridine-3,5-dicarbone-3-methyl ester-3-(1-phenyl-2-
piperidinoethyl) ester hydrochloride, melting point 232-2
34°C (decomposition) (7) 2.6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarbone-3-1 sopropyl ester-3-(1-phenyl- 2-piperidinoethyl) ester, α-diastereoisomer: hydrochloride/hemihydrate melting point 217-219°C
(Decomposition) iβ-diastereoisomer: Melting point of hydrochloride 16
5-167°C (decomposition) (8) 2.6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-benzyl ester-3
-(1-phenyl-2-piperidinoethyl) ester,
α-diastereoisomer: hydrochloride melting point 213-214
°C (decomposition); melting point of β-diastereoisomeric dihydrochloride 212-213 °C (decomposition) (9) 2.6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5 -dicarbone-3-methyl ester-3-(1-phenyl-4-
piperisiptyl) ester (1o) 2,6-dimethyl-4-(m-nitrophenyl) -L 4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-3-(1-(0-chlorophenyl)-2 -Piperidinoethyl] ester, α-diastereoisomer: Melting point of hydrochloride: 218 Melting point of salt: 231
~232°C (decomposition) (n) 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-3-C1-(p-chlorophenyl )-2-piperidinoethyl] ester, α-diastereoisomer: melting point 174-176°C1 Hydrochloride melting point 205-207°C! β-diastereoisomer: melting point 128-130°C1 Hydrochloride melting point 205-207°C
(Decomposition) (12) 2.6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-3-(1-(0-methylphenyl)- 2-piperidinoethyl] ester, α-diastereoisomer: hydrochloride melting point 224-225°C (
Decomposition); Melting point of β-diastereoisomerically suspended hydrochloride: 235
~236°C (decomposition) (13) 2.6-cymethyl-4
-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-5”
(1-(p-methylphenyl)-2-piperidinoethyl) ester, α-diastereoisomer: melting point 143-1
455°C1 Melting point of hydrochloride 168-170°C (decomposition)
, β-diastereoisomer: fM11A122-124
°C, melting point of hydrochloride 209-209.5 °C (decomposition) (1
4) 2.6-dimethyl-4-(m-nitrophenyl)-],]4-dihydropyridine-3.5-'; Carboxylic acid-3-methyl ester-3-(+-(p-fluorophenyl)-2 -piperidinoethyl] ester, α-diastereoisomer: hydrochloride-1/2 hydrate melting point 186
~187 °C (decomposition), melting point of β-thia 9 stereoisomer dihydrochloride 195 °C (decomposition) (1s) 2.6-dimethyl-4-(m-nitrophenyl) -1,4-dihydropyridine- 3,5-dicarboxylic acid-3-methyl ester-3-CI-(p-methoxyphenyl)-2-piperidinoethyl] ester, α-
Diastereoisomer: melting point 162-164°C 2β-diastereoisomer: hydrochloride melting point 204-205°C (decomposition) (ls) 2.6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine -3,5-dicarboxylic acid-3-methyl ester-3-(1-(2-methylpiperidino)-1-phenylethyl diester, α-diastereoisomer; hydrochloride melting point 226-226.5°C (
decomposition); β-diastereoisomer: melting point of hydrochloride 222
°C (decomposition) (17) 2.6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-3-(2-(4-methylpiperidino)- 1-phenylethyl diester, α-diastereoisomer: hydrochloride, melting point 216-219°C (decomposition), β-diastereoisomer: hydrochloride, melting point 227-219°C
228℃ (decomposition) (18) 2.6-cymethyl-4-
(m-=to7X=ru) -1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-
3-C2-(4-hydroxypiperidino)-1-phenylethyl diester, α-diastereoisomer = l fumarate, melting point 144-147°C (decomposition); β-diastereoisomer: hydrochloride. Melting point of hemihydrate: 222-22
3°C (decomposition) (19) 2.6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-5-1: 2-(4-acetyl (oxypiperidino)-1-phenylethyl diester, α-diastereoisomer: melting point of hydrochloride 200~
202'C (decomposition), β-diastereoisomer: Melting point of hydrochloride 223-226°C (decomposition) (20) 2.6-
Dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-3-(2-(4-acetylaminopiperidino)-
1-phenylethyl] ester, β-diastereo-X form: +fumarate melting point 218-220'C (decomposition) (
21) 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-3-42-(4-methoxypiperidino)-1-phenyl ethyl] ester, α-diastereoisomer: hydrochloride, melting point 235-236°C (
decomposition), β-diastereoisomer: hydrochloride melting point 248
~249°C (decomposition) (22) 2.6-cymethyl-4
-(m-nitrophenyl) -L 4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-3-
C2-(4,4-ethylenedioxypiperidino)-1-
Phenylethyl] ester, α-diastereoisomer:
Melting point of hydrochloride monohydrate: 205-20.7°C (decomposed).

β-diastereoisomer: hydrochloride melting point 233-235
°C (decomposition) (23) 2.6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-3-C2-111-(1
, 2,3,6-titrahydropyridyl)]-]1-phenylethyl]ester α-diastereoisomer: Melting point 1
Melting point of 68-17piC1 hydrochloride 235-237°C (decomposition); β-diastereoisomer: melting point 122-126°
Melting point of CS hydrochloride 21 o ~ 213 ° C (decomposition) (24) 2.6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-3- CI-(2-furyl)-2-piperidinoethyl] ester, α-diastereoisomer: melting point 182-185°C1 hydrochloride melting point 19
0-193°C (decomposition), β-diasteno isomer: melting point 104-107°C1 Hydrochloride melting point 138-142°
C (decomposition) (25) 2,6-dimethyl-4-(0-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-3-(1-phenyl-2
-piperidinoethyl) ester, α-diastereoisomer: hydrochloride melting point 233-234°C (decomposition) (26) 2.6-dimethyl-4-(m-nitrophenyl) -1,4-dihydropyridine-3,5 -dicarboxylic acid-3-methyl ester-5-1:1-(3-piI
J Sil) -2-hyheridinoethyl] ester dihydrochloride 1/2 hydrate, melting point 200.5-202°C (decomposition) (27) 2.6-dimethyl-4-(m-nitrophenyl) -1 ,4-dihydropyridine-3,5-dicarbone-3-methyl ester-3-C2-piperisino 1-(2-pyrrolyl)ethyl] ester (28) 2
．． 6-dimethyl-4-(m-nitrophenyl)-1,4
-dihydropyridine-3,5-dicarboxylic acid-3-methy(ruester-5-CI-(1-methyl-2-pyrrolyl)-2-piperidinoethyl) ester (29) 2,6-dimethyl-4-(m-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-5-[1-(1-methyl-
2-imidazolyl)-2-piperidinoethyl] ester (30) 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarponic acid-3-methyl ester-5-[2- piperidi/-
1-(2-thiazolyl)ethyl]ester (31)
2.6-cymethyl-4-(m-nitro-7-diyl)-1
,4-dihydropyridine-3,5-dicarboxylic acid-3-
Methyl ester-5-[1-(2-oxasilyl)-2
-piperidinoethyl]ester (32) 2.6-dimethyl-4-(2-chloro-5-nitrophenyl)-1
,4-dihydropyridine-3,5=dicarboxylic acid-3-
Methyl ester-3-(1-phenyl-2-piperidinoethyl) ester, α-diastereoisomer: hydrochloride melting point 233-234°C (decomposition); β-diastereoisomer: hydrochloride melting point 175-178°C (Decomposition) (33) 2.6-dimethyl-4-(2-chenyl)
=1.4-cyhytrohyricin-3,5-dicarboxylic acid-
3-Methyl ester-3-(1-phenyl-2-piperidinoethyl) ester, α-diastereoisomer: Hydrochloride melting point 232°C (decomposition): β-diastereoisomer: Hydrochloride melting point 233-234 °C (decomposition) (34) 2.6-dimethyl-4-(2-furyl)-
1,4-dihydropyridine-3,5-dicarboxylic acid-3
-Methyl ester-3-(1-phenyl-2-piperidinoethyl) ester, α-diastereoisomer: hydrochloride melting point 196-198°C (decomposition), β-diastereoisomer: hydrochloride melting point 216-198°C 217°C (decomposition) (35) 2.6-dimethyl-4-(0-)lifluoromethylphenyl)-1,4-cyhydrohylJsyn-3
,5-dicarboxylic acid-3-methyl ester--phenyl-2-piperidinoethyl) ester (36) 2.6
-Simethyl-4-(o-cyanophenyl) - 1.
4-dihydropyridine-3,5-dicarbonate-3-methylester-5-(1-phenyl-2-piperidinoethyl) ester (37) 2.6-dimethyl-4-(0-methylthiophenyl)-1.4- Dihydropyridine-3.5-dicarboxylic acid-3-methyl ester-5-(1-phenyl-2-piperidinoethyl) ester (38) 2.6
-Simethyl-4-(2-pyridyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-1-f-)reester-5-<1-phenyl-2-prismatic=2-hydrochloride melting point 260 ~265°C (decomposition); β-diastereoisomer: hydrochloride melting point 170-175°C (decomposition) (39) 2.6-dimethyl-4-(2-pyrrolyl)
-1,4-dihydropyridine-3,5-dicarboxylic acid-
3-Methyl ester-5-(1-phenyl-2-piperidinoethyl) ester (40) 2.6-dimethyl-4-(l-methyl-2
-pyrrolyl)-1,4-dihydropyridine-3. 5
-dicarboxylic acid-3-methyl ester-phenyl-2-piperidinoethyl) ester (41)
2.6-dimethyl-4-(2-pyrrolyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-5-(l-phenyl-2=piperidinoethyl)
Ester, β-diastereoisomer = 1 fumarate,
Melting point of hemihydrate: 141-143°C (decomposition) (42) 2.6-dimethyl-4-(3-chenyl)
-L 4-dihydropyridine-3,5-dicarboxylic acid-
3-Methyl ester-5-(l-phenyl-2-piperidinoethyl) ester, α-diastereoisomer: hydrochloride melting point 238-239°C (decomposition); β-diastereoisomer: hydrochloride @l/2 Melting point of hydrate 234-236°
C (decomposition) (43) 2.6-dimethyl-4-4: 2-(5-
methylfuryl) ') -1,4-dihydropyridine-
3,5-dicarboxylic acid-3-methyl ester-3-(1
-phenyl-2-piperidinoethyl) ester, α-cyaste V isomer: hydrochloride melting point 214-216'c
(decomposition); β-diastereoisomer: melting point of hydrochloride 22
0°C (decomposition) (44) 2.6-dimethyl-4-(2-furyl)
-1,4-dihydropyridine-3,5-dicarboxylic acid-
3-Methyl ester-5-42-piperidino-1-(2
-thenyl)ethyl] ester, α-diastereoisomer: hydrochloride melting point 205-207°C (decomposition); β-diastereoisomer: hydrochloride melting point 215-217°C (decomposition) (45) 2. 6-Simethyl-4-(3-pyridyl)
-1,4-dihydropyridine-3,5-dicarboxylic acid-
3-Methyl ester-3-(1-phenyl-2-piperidinoethyl) ester, α-diastereoisomer: hydrochloride, melting point 225-227°C (decomposed); β-diastereoisomer: maleic acid, melting point 21O ~215°C (decomposition) (46) 2.6-dimethyl-4-(2-imidazolyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-3-(1-phenyl-2- piperidinoethyl) ester, α-diastereoisomer =
Melting point of dihydrochloride e3/dihydrate: 211.5-212°C
(decomposition); β-diastereoisomer: dihydrochloride dihydrate, melting point 227-228°C (decomposition) (47) 2.6-dimethyl-4-(2-thiazolyl)-1,4-dihydropyridine- 3,5-dicarboxylic acid-3-methyl ester-3-(1-phenyl-2-piperidinoethyl) ester, α-diastereoisomer = 2
Melting point of hydrochloride/1/3 hydrate: 192°C (decomposition): β-diasteno isomer: Melting point of hydrochloride: 214-215°C (
decomposition) (48) 2.6-dimethyl-4-(pyridine-N-
oxide-3-yl)-1,4-'jhydropyridine-3,5-dicarboxylic acid-3-methyl ester-3-(
1-phenyl-2-piperidinoethyl) ester, α-
Diastereoisomer: melting point of 2 fumarates 151-15
3°C (decomposition), melting point of β-diastereoisomer: dihydrochloride 180-185°C (decomposition) Pharmaceutical formulation example 5m (1 tablet is prepared according to the following composition.

α-diastereoisomer of Example 1 5.0 rng
Lactose 62.31ng Cornstarch 25. O1ng microcrystalline cellulose 6. Orng methylcellulose 1.0 memagnesium stearate 0.71nglOO0
Ornf1 1% powder is prepared with the following composition (% by weight).

α-diastereoisomer of Example 1 1.0% lactose
88.0% microcrystalline cellulose to, 0% methylcellulose to, 0%100,
0% L to stop Todorocho I upper 1 I b cup h Kuchiju no z □Continuation of 1st page 211100 7138-4C2131
00) 7138-4C (C07D
401104 211100 7138-4 C207
100) 7242-4C (C07D
401104 211100 7138-4C2331
00) 7133-4C (C07D
401/12 211100 7138-4 C207
100) 7242-4C (C07D
401/12 211100 7138-4 C233
100) 7133-4C (C07D
401/14 211100 7138-4 C213
100) 7138~4CoInt,
C1,” Identification symbol Internal office reference number (
C07D 405104 211100 7138-4C3
07100) 7043iC(C
07D 405/12 211100 7138-4 C
307100) 7043iC(
C07D 491/113 221100 6675-4 C
317100) 7432~40
(C07D 409104 211100 7138-4C3
33100) 8214-4C(
C07D 409/12 211100 7138-4 C
333100) 8214-4C
(C07D 409 /14 7
431-4 C11100 07100 333100) (C07D 4i3/12 74
31-4C11100 263100) 277100) ■Int, C1,3 identification code Internal serial number 27
7100) 0 Inventors Aoiki 1-545-645 Nakadono, Nakatsu City 0 Inventors 6-11-916' Toshima 5-6-11, Kita-ku, Tokyo 0 Inventors Aihara Lab - Yoshitomi-cho, Chikjo-gun, Fukuoka Prefecture Oaza Hirotsu 13 6 567-

Claims (1)

[Scope of Claims] A 1,4-dihydropyridine-3,5-dicarboxylic acid ester derivative represented by the general formula -3 or a pharmaceutically acceptable acid addition salt thereof. [In the above formula, W is -CH- or -N=, Y is -CH
diCH-, O-, -5-, -CH=N(0)p- (p is 0.1) or -N(R)- (R is hydrogen, lower alkyl), X and X are the same or different, and represent hydrogen, halogen, nitro, trifluoromethyl, cyan, or lower alkylthio; 2 is aryl; Even if it has halogen, lower alkyl, lower alkoxy, lower alkanoylamino, cyan, nitro, lower alkylthio, trifluoromethyl, sulfamoyl, di-lower alkylsulfamoyl, ami/, di-lower alkylamino as a substituent good), nest, oxygen,
Sulfur, which may have an unsaturated bond, t alkyl, lower alkoxy, carboni/L/. Lower alkanoylamino, ethylenedioxy, -(CH
□) m-OR'(R' represents hydrogen, lower alkyl, or lower alkanoyl, m represents 0 or 1.2) as a substituent, and R and R are the same or different and may have lower alkyl, R represents lower alkyl, aralkyl or heteroaralkyl, and n represents an integer of 1 to 5. ]