GB2026471A - Dihydropyridine compound, processes for preparation thereof and pharmaceutical composition of the same - Google Patents

Abstract

The present invention is to dihydropyridine compounds of the formula: <IMAGE> wherein R<1> is cyano or lower alkoxycarbonyl, R<2> is isopropoxycarbonyl, chloroethoxycarbonyl, benzyloxyethoxycarbonyl, or N-benzyl-N- methylaminoethoxycarbonyl, R<3> is lower alkoxycarbonyl, R<4> is lower alkyl and R<5> is di(lower)alkoxymethyl, formyl, hydroxy-iminomethyl, cyano or hydroxymethyl, to their pharmaceutically acceptable compositions and to processes for the preparation thereof. These compounds have vasodilating and anti- hypertensive activity and are useful in the treatment of cardiovascular disease and hypertension.

Description

SPECIFICATION Dihydropyridine compound, processes for preparation thereof and pharmaceutical composition of the same This invention relates to dihydropyridine compound and a salt thereof. More particularly, it relates to new dihydropyridine compound and a pharmaceutically acceptable salt thereof which have vasodilating and anti-hypertensive activity, to processes for the preparation thereof, and to pharmaceutical composition comprising the same for therapeutical treatment in cardiovascular diseases and hypertension in human being.

With regard to the states of the arts in this field, the following compound (nifedipine) is known and used as a vasodilating agent.

(U.S.P. 3,485,847) One object of this invention is to provide new and useful dihydropyridine compound and a pharmaceutically acceptable salt thereof.

Another object of this invention is to provide processes for the preparation of dihydropyridine compound and a salt thereof.

Afurtherobjectofthis invention is to provide useful pharmaceutical composition comprising said dihydropyridine compound and a pharmaceutically acceptable salt thereof as a vasodilator and antihypertensive agents.

Still further object of the present invention is to provide a therapeutical method for treating cardiovascular diseases such as coronary insufficiency, angina pectoris or myocardial infarction and hypertension.

The dihydropyridine compound of this invention can be represented by the formula:

wherein R1 is cyano or lower alkoxycarbonyl, R2 is isopropoxycarbonyl, chioroethoxycarbonyl, ethoxyethoxycarbonyl, phenoxyethoxycarbonyl, benzyloxyethoxycarbonyl or N-benzyl-N-methylamino-ethoxycarbonyl, R3 is lower alkoxycarbonyl, R4 is lower alkyl, and R5 is di (lower)alkoxymethyl, formyl, hydroxyiminomethyl, cyano or hydroxymethyl.

With regard to the object compound of the above formula (I), it is to be understood that there may be one or more optical isomers, which are due to the presence of asymmetric carbon atom(s) in the molecule of the compound (I), and these isomers are also included within the scope of the present invention.

According to this invention, the object compound (I) can be prepared by the processes as illustrated by the following schemes.

[I] Construction of fundamental structure: (1) Process

wherein R1, R2, R3 and R4 are each as defined above and R5 is di(lower)alkoxymethyl.

(2) Process 2:

wherein R1, R2, R3, R4 and Ras are each as defined above.

[II] Transformations of a functional group: (3) Process 3:

R1 . pi p3 R3 R3 Hydrolyzi'n9 Agent R2 R4 N a CHO H H ( (I-2) wherein R', R2, R3, R4 and R5 are each as defined above. (4) Process 4:

p1 D3 Hydroxylamine or R2 1 R3 a salt thereof R2 l R3 N C\\O X N CH=NOH H H (1- (1-3) wherein R1, R2, R3 and R4 are each as defined above.

(S) Process 5:

SR1 a R 1 R2AR3 Dehydrating Agent R2 R4 N CM= NOW R4 N CN H H (I - 3) (I -4) wherein R1, R2, R3 and R4 are each as defined above.

(6) Process 6:

p , p1 R2tt Reducing Agent, p3 R4 H CHO R4 H CH2OH H (1-2) (1-5) wherein R1, R2, R3 and R4 are each as defined above.

(7) Process 7:

wherein R1, R3, R4 and R5 are each as defined above.

Detailed explanation for the definitions used throughout this specification will be made and the suitable examples thereof will be illustrated in the following.

The term "lower" used in connection with all of the alkane moieties is intended to mean 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms, and more preferably 1 to 4 carbon atoms.

"Lower alkoxycarbonyl" for R1 and R3 can be also represented by the formula: -co-o(lower)alkyl, wherein the lower alkyl group includes monovalent radical of straight- and branched- chain(lower) alkanes. Suitable lower alkoxycarbonyl group may be methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, t-butyoxycarbonyl and the like, and more suitable one is methoxycarbonyl and ethoxycarbonyl.

"Lower alkyl" for R4, may include a monovalent radical of straight- and branched-chain(lower) alkanes, and suitable lower alkyl group may preferably be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, neopentyl, hexyl, heptyl, octyl and the like, more preferably C1-C4 alkyl group, and most preferably methyl.

"Di-loweralkoxymethyl"for R5and Ras may include dimethoxymethyl, diethoxymethyl, dipropoxymethyl and the like, and more preferably dimethoxymethyl or diethoxymethyl.

The starting compounds of this invention include known and new compounds, and they were prepared as follows.

The starting compounds (Il-i) and (11-2) used in Processes 1 and 2 can be prepared by reacting 4-substituted-acetoacetate (IIA) or (lIA') and an aldehyde (ilk) as shown in the following reaction schema.

wherein R1, R3 and Ras are each as defined before.

wherein R', R2 and R4 are each as defined above.

The other starting compounds (111-1) and (lli-2) used in Processes 1 and 2 can be prepared from a 4-substituted acetoacetate compound (lily) or (1I1A') and ammonia or a salt thereof as shown in the following reaction schema.

wherein R2 and R4 are each as defined before.

wherein R3 and Ras are each as defined before.

Processes for preparation of dihydropyridine compound (I) will be explained in details below.

(1) Process 1: This process relates to a method for preparing a compound (I-i) by reacting a compound (11-1) with an amino compound (111-1).

Each of the starting compounds (11-1) and (111-1) includes cis and trans isomers due to the double bond in their molecules, and both of such cis and trans isomers are equivalent in view of the compound (1-1), and therefore, each isomer and optional mixtures of the isomers of these starting compounds (11-1) and (111-1) are to be included within the scope of this process.

The reaction can be carried out at ambient temperature or under warming or heating. The reaction can be conducted in the absence of a solvent, but may be conducted in a suitable solvent such as benzene, toluene, xylene, chloroform, carbon tetrachloride, methylene chloride, ethylene chloride, methanol, propanol, butanol, water or other conventional solvents. The reaction can be preferably accelerated in the presence of an agent such as an acid (e.g. acetic acid), a base (e.g. pyridine or picoline) or in a conventional buffer solution. These agents act as a reaction accelerator and may also be used as a solvent when they are in liquid. The reactions can be also accelerated by warming or heating. The reaction condition may vary according to the kind of the reactants, solvent and/or other agent as mentioned above to be used.

As to the reaction mode of this Process, the process can also be conducted, for example, by reacting a mixture of the 4-substituted acetoacetate compound (I IA), the aldehyde (IIB) and the amino compound (111-1).

(2) Process 2: This process relates to a method for preparing a compound (1-1) by reacting a compound (11-2) with an amino compound (111-2).

This process is substantially the same as Process I, and accordingly can be conducted by reacting the compounds (11-2) and (111-2) in the same manner to those for the Process I. That is, the same reaction conditions (e.g. reaction temperature, solvent, accelerator, etc.) and the same alternative reaction procedure as mentioned in the Process I are also applied to this process, provided that the compound (11-2) or alternative reactants (I IA') and (ll-2B), and the compound (111-2) are used in this process instead of using the compound (ll-l) or alternative reactants (I 1A) and (lIB), and the compound (111-1) for the Process 1, respectively.

(3) Process 3: This process relates to a method for preparing a compound (1-2) by hydrolysing a compound (1-1).

The compound (1-1) can be prepared as illustrated in the above (Processes 1 and 2).

In this process, the di(lower)alkoxymethyl group for R5a of the compound (1-1) is transformed by hydrolysis into a formyl group.

Hydrolysis may be carried out in a conventional manner which is conventionally applied for cleavage of so-called an acetal function into the corresponding carbonyl function and preferably, for example, hydrolysis is carried out by an acidic hydrolysis, i.e. in the presence of an acid such as an inorganic acid (e.g.

hydrochloric acid, sulfuric acid, etc.) or an organic acid (e.g. formic acid, acetic acid, trifluroracetic acid, p-toluenesulfonic acid, etc.).

This hydrolysis may be carried out in a suitable conventional solvent such as water, acetone, methyl ethyl ketone, dioxane, ethanol, methanol, N,N-dimethylformamide, N-methylmorpholine or dimethylsulfoxide, an optional mixture thereof or a buffer solution thereof. The reaction temperature is not restrictive, and the reaction is usually conducted under cooling, at room temperature or under somewhat elevated temperature.

(4) Process 4; This process relates to a method for preparing a compound (1-3) by reacting the compound (1-2) with hydroxylamine or a salt thereof.

According to this process, the formyl group of the starting compound (1-2) is transformed into the hydroxyiminomethyl group.

The compound (1-2) can be obtained by the above Process 3.

Preferable salt of hydroxylamine may be a salt with an acid such as an inorganic acid (e.g. Hydrochloric acid, sulfuric acid, etc) or an organic acid (e.g. acetic acid, etc.).

The reaction is carried out in the usual manner, for example, in the presence of a catalyst such as an acid (e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, formic acid, acetic acid, p-toluenesulfonic acid, borom trifluoride, silicon tetrachloride or titanium tetrachloride); in a basic condition brought about by a base, for example free hydroxylamine; or in an acidic or basic conventional buffer solution. The reaction is usually conducted in a suitable conventional solvent such as water, dioxane, ethanol, methanol or dimethylformamide or an optional mixture thereof.

The reaction temperature is not restricitive, and the reaction is usually carried out under cooling, at room temperature or under somewhat elevated temperature.

(5) Process 5: This process relates to a method for preparing a compound (1-4) by reacting the compound (1-3) with a dehydrating agent.

The oxime compound (1-3) can be obtained by the above Process 4.

Suitable example of the dehydrating agent includes conventional organic or inorganic ones such as an inorganic acid (e.g. sulfuric acid, phosphoric acid, polyphosphoric acid, etc.), an organic acid (e.g. formic acid, acetic acid, ethanesulfonic acid, p-toluenesulfonic acid, etc.), an organic acid anhydride (e.g. acetic anhydride, benzoic an hydride, phthalic anhydride, etc.), an organic acid halide (e.g. acetyl chloride, benzoyl chloride trichloroacetyl chloride, mesyl chloride, tosyl chloride, ethyl chloroformate, phenyl-chloroformate, etc.); an inorganic halogen compound (e.g. thionyl chloride, phosphorus pentachloride, phosphorus oxychloride, phosphorus tribromide, stannic chloride, titanium tetrachloride, etc.); a carbodiimide (e.g.

N,N'-dicyclohexylcarbodiimide, N-cyclohexy-N'-morpholinoethylcarbodiimide, etc.), N,N'carbonyldiimidazole; pentamethyleneketene-N-cyclohexyl i mine; ethoxyacetylene; 2-ethyl-7-hydroxyisoxazolium salt; other phosphorus compound (e.g. phosphorus pentoxide, polyphosphoric acid ethyl ester, triethylphosphate or phenylphosphate) and the like or an mixture thereof. When an acid is used as the dehydrating agent, the reaction can also be conducted in the presence of its salt such as an alkali metal salt (e.g. sodium salt or potassium salt), or the like.

This reaction is usually carried out in a conventional solvent such as diethyl ether, dimethylformamide, pyridine, acetic acid, formic acid, benzene, carbon tetrachloride, chloroform, methylene chloride, tetrahydrofuran, dioxane, and the like, and usually carried out at room temperature or under heating, and the reaction temperature is not restrictive to the above.

This dehydration process can also be conducted successively to the foregoing Process 4 without any isolation of the oxime compound (1-3). This case is also included in the scope of this invention.

(6) Process 6: This process relates to a method for preparing a compound (1-5) by reducing the compound (1-2).

The compound (1-2) can be prepared by the above Process 3.

The reduction can be carried out in a conventional manner which can be applied for reduction of formyl group into hydroxy methyl group, and particularly, the reduction is conducted by reduction using a reducing agent such as an alkali metal borohydride (e.g. lithium borohydride, sodium borohydride, potassium borohydride, sodium cyanoborohydride, etc.) or by catalytic reduction for which preferable catalyst may be palladium carbon, palladium chloride or rhodium carbon and the like. The reduction is usually carried out in a conventional solvent such as water, methanol, ethanol, isopropanol, dimethylformamide, tetrahydrofuran, etc., and the like. The reaction temperature is not restrictive and the reaction is usually carried out under cooling, at room temperature or at somewhat elevated temperature.And, the method of reduction may be optionally selected according to the kind of the compound (1-2).

(7) Process 7: This process relates to a method for preparing a compound (1-6) by reacting a compound (IV) with N-benzyl-N-methylamine.

This reaction can preferably be carried out in the presence of a base, suitable examples of which may include an inorganic base such as an alkali metal hydroxide, carbonate, bicarbonate, hydride or amide (e.g.

sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, sodium hydride, sodium amide, etc.) or an organic base such as an alkali metal alkoxide (e.g. sodium, methoxide, sodium ethoxide, potassium ethoxide, lithium methoxide, etc.), a salt of an organic acid (e.g.

sodium acetate, potassium acetate, etc.), an amine or imine base (e.g. triethylamine, pyridine, picoline, N,N-dimethylaniline, N-methylpyrolidine, N-methylmorpholine, etc.) and the like.

Further, the reaction is usually carried out in a suitable solvent such as chloroform, methylene chloride, benzene, acetone, diethyl ether, tetrahydrofuran, dimethylformamide, methanol, ethanol and other conventional solvent or an optional mixture thereof.

The reaction temperature is not restrictive, and reaction is usually carried out at room temperature, or under warming or heating.

In accordance with the present invention, the reaction product can be separated and isolated from the reaction mixture and purified by methods commonly used for this purpose, for instance, extraction with suitable solvent, chromatography, precipitation, recrystallization and so on.

Suitable examples of a salt of the dihydropyridine compound include a pharmaceutically acceptable salt such as an inorganic acid salt (e.g. hydrochloride, hydrobromide, phosphate, sulfate, etc.) and an organic acid salt (e.g. formate, acetate, fumarate, maleate, aspartate, glutamate, etc.).

The compound (I) thus obtained frequently includes at least one pair of optical isomers due to the presence of an asymmetric carbon atom at the fourth position of the 1,4-dihydropyridine nucleus and can exist as each optical isomer or a mixture thereof. A racemic compound can be resolved into each optical isomer by a conventional method for recemic resolution, such as a chemical resolution of the salts of the diastereomerwith a conventional optically active acid (e.g. tartaric acid or camphor sulfonic acid, etc.).

The compound (I) according to this invention is structurally characterized in third position (i.e. R2) of its molecule, namely characterised in the specific radical (e.g. isopropoxycarbonyl, etc.) of the symbol R2 of the compound (I).

As to utility of thus characterised, it is to be noted that the compound (I) and a pharmaceutically acceptable salt thereof are possessed of strong vasodilating activity and useful for therapeutical treatment in hypertension and cardiovascular diseases such as coronary insufficiency, angina pectoris or myocardial infarction.

Particularly, the compound (I), wherein R1 is 2-cyano or 2-methoxycarbonyl, R3 is methoxycarbonyl or ethoxycarbonyl, R4 is methyl and R5 is cyano or hydroxymethyl, is preferable as a compound having such therapeutical effects as mentioned above, and more particularly, said compound is possessed of stronger vasodilating activity than those of the prior Patent Application in United Kingdom No.52720/1976 (filing date: December 1976), and more useful for anti-hypertensive agents.

In addition to the above utility, it is further to be noted that the compound (I), wherein R1 is 2-cyano or 2-methoxycarbonyl, R3 is methoxycarbonyl or ethoxycarbonyl, R4 is methyl and R5 is dimethoxymethyl, diethoxymethyl, formyl or hydroxyiminomethyl, has vasodilating and anti-hypertensive activities as well as can be used as an intermediate for preparing the more preferable vasodilating and anti-hypertensive agent of this invention as illustrated hereinabove.

For therapeutical purpose, the dihydropyridine compound (I) is administered in oral daily dose of 0.1 to 500 mg, preferably 1 to 50 mg.

The pharmaceutical compositions of this invention comprise, as an active ingredient, the dihydropyridine compound (I) or pharmaceutically acceptable salt thereof in an amount of about 0.01 mg. to about 500 mg., preferably about 0.1 mg. to about 250 mg. per dosage unit for oral and parenteral use.

One skilled in the art will recognize that in determining the amount of the active ingredient in the dosage unit form, the activity of the ingredient as well as the size of the host animal must be considered. For administration purpose of this pharmaceutical composition, the active ingredient may be usually formulated in a solid form such as tablet, granule, powder, capsule, troche, lozenge or suppository, or a suspension or solution form such as syrup, injection, emulsion, lemonade, etc. and the like. A pharmaceutical carrier or diluent includes solid or liquid non-toxic pharmaceutically acceptable substances. Exemplar of solid or liquid carriers or diluents are lactose, magnesium stearate, terra alba, sucrose, corn starch, talc, stearic acid, gelatin, agar, pectin, acacia, peanut oil, olive oil or sesame oil, cacao butter, ethyleneglycol or the other conventional ones. Similarly, the carrier or diluent may include a time delay material such as glyceryl monostearate, glyceryl disterarate, a wax and the like.

For the purpose of showing the utility of the compound (1), the pharmaceutical tests were conducted on the represented compounds as follows.

Hypotensive effect: Test Method; Five Wistar rates were used per group. Each animal was immobilized in a cage sized to the body. Blood pressure was measured at the femoral artery by means of a pressure transducer and recorded as electrically integrated values of mean arterial pressure, and heat rate was determined by a pulse wave detector.

Operation for the catheterization was performed under light anesthesia with ether. The test compound was administered intravenously 3 hrs after completion of the operation.

Test Compound; Compound A: Nifedipine Compound B: isopropyl 2-methyl-4-(2-methoxycarbonylphenyl)-5 methoxycarbonyl-6-hydroxymethyl-1 ,4-dihydropyridine- 3-carboxylate Compound: isopropyl 2-methyl-4-(2-methoxycarbonylphenyl)-5 methoxycarbonyl-6-cyano-1 ,4-dihydropyridine-3 carboxylate Compound D: isopropyl 2-methyl-4-(2-cyanophenyl)-5 methoxycarbonyl-6-hydroxymethyl-1 4 dihyd ropyridine-3-carboxylate Compound E: isopropyl 2-methyl-4-(2-cyanophenyl)-5 methoxycarbonyl-6-cyano-1 ,4-dihydropyridine-3 carboxylate Test Result; Values of A Maximum Decrease of blood pressure (mmHg) were shown in the following table.

Table Dose 1 mg/kg 10 mg/kg Compound A -25615 -44 6 + 1.2 B -12.2 + 1.6 -47.2 -1- 1.6 C -25.6 + 3.0 -47.8 t 2.7 D -19.2 + 3.3 -46.8 + 2.2 E -46.6 + 3.6 -56.0 + 1.9 The following Examples are given for the purpose of illustrating the syntheses of some specific object compounds of the present invention.

Preparation of starting compounds of this invention Preparation (1) A solution of 2-cyanobenzaldehyde (6.56 g), methyl 4,4-dimethoxyacetoacetate (7.93 g), acetic acid (0.18 g) and piperidine (0.17 g) in benzene (40 ml) was refluxed for 5 hours with stirring underazeotropic dehydration. After cooling, the reaction mixture was diluted with benzene, washed with water, an aqueous solution of sodium bicarbonate, and then dried over magnesium sulfate. After removal of the solvent, the residual oil (13.75 g) was subjected to column chromatography on silica gel (420 g) with a mixture of benzene and ethyl acetate (20:1 VN) as an eluent.The fractions containing a desired compound were collected and the solvent was removed by distillation under reduced pressure to give a yellowish oil of methyl 2-(2-cyanobenzylidene)-4,4-dimethoxy acetoacetate (a mixture of cis and trans isomers) (10.11 g).

N.M.R.

bppm (CDCl3) : 3.41(s) 3.79 (s) )(6H), } (3H), 3.49 (s) 3.92 (s) 4.83 (s) 8.07 (s) } (1 H),7.5 ~ 8.0 (4H, m), )(1H) 5.11 (s) 8.16(s) The following starting compounds (2) ~ (6) were obtained in the similar manner to that of Preparation 1-(1).

(2) Methyl 2-(2-methoxyCarbonylbenzylidene)-4,4-dimethoxyacetoacetate (a mixture of cis and trans isomers) N.M.R.

bppm (CDCl3) : 3.26 (5) } (6H) 3.43 (s) 3.56 (s)

3.83 (5) F (6H) 3.87 (s)J 3.89 (s) 4.67 (s) }(1H) 5.13 (s) 7.2 ~ 8.1 (4H, m) 8.39 (s) } (1 H) 8.46 (s) (3) 2-Chloroethyl 2-(2-cyanobenzylidene)acetoacetate (a mixture of cis and trans isomers).

N.M.R.

#ppm (CDCl3) : 2.34 (s) } (3H) 2.50 (s) 3.6 ~ 3.9 (2H, m) 4.3 ~ 4.6 (2H, m) 7.25 ~ 7.9 (4H, m) 8.00 (s) }(1H) 7.88 (s) (4) 2-Ethoxyethyl 2-(2-cyanobenzylidene)acetoacetate (a mixture of cis and trans isomers).

N.M.R.

bppm (CDCI3): : 1.15(t,J=6.5Hz) } (3H) 1.23 (t, J=6.5 Hz) 2.35 (s) } (3H) 2.48 (s) 3.58 (2H, q, J=6.5 Hz) 3.7 ~ 3.8 (2H, m) 4.3 ~ 4.5 (2H, m) 7.30 ~ 8.05 (4H, m) 7.95 (s) } (1 H) 7.91 (s) (5) 2-Phenoxyethyl 2-(2-cyanobenzylidene)acetoacetate (one of cis and trans isomers), mp 102.5 ~ 104"C.

(6) 2-Benzyloxyethyl 2-(2-cyanobenzylidene(acetoacetate (a mixture of cis and trans isomers).

N.M.R.

5ppm (CDC13) : 2.29 (s) } (3H), 2.43 (s) 3.50 ~ 3.85 (2H, m) 4.20 ~ 4.60 (2H, m) 4.55 (s) } (2H) 4.44 (s) 7.15 ~ 7.85 (9H, m) 7.96 (s) }(1H) 7.83 (s) Preparation of the object of this invention Example 1 (1) A mixture of methyl 2-(2-cyanobenzylidene)-4,4-dimethoxyacetoacetate (10.1 g) and isopropyl 3 aminocrotonate (5.51 g) was heated for 40 minutes at 78"C and for 5.5 hours at 120 C with stirring, followed by heating for an hour at 125 C without the stirring. After the reaction mixture was allowed to stand overnight, it was dissolved in ethyl acetate.This solution was washed twice with water, dried and then evaporated to dryness under reduced pressure to give a residue, which was crystallized from ethyl ether. The crystals were collected by filtration and washed with a small amount of ethyl ether to give crude powder of isopropyl ester of 4-(2-cyanophenyl )-5-methoxyCarbonyl-6-dimethoxymethyl-2-methyl-1,4-dihydropyridine- 3-carboxylic acid (8.96 g). Further, the crude product (0.77 g) was recovered from the filtrate. 0.5 g of this crude product was recrystallized from isopropyl ether to give purified white powder of the same product (0.37 g), mp 171 - 172.50C.

The following compound was obtained in the similar manner to that of Example 1-(1).

(2) Isopropyl ester of 5-methoxycarbonyl-4-(2-methoxycarbonyl phenyl)-6-dimethoxymethyl-2-methyl-1 4- dihydropyridine-3-carboxylic acid.

N.M.R.

bppm (CDC13) : 0.95 (3H, d, J=7 Hz), 1.19 (3H, d, J=7 Hz), 2.37 (3H, s), 3.40 (3H, s), 3.46 (3H, s), 3.61 (3H, s), 3.97 (3H, s), 4.97 (1 H, heptet, J=7 Hz), 5.93 (1 H, s), 6.05 (1 H, s), 6.59 (1 H, broad s), 7.0 - 7.9 (4H, m).

Example 2 (1) A mixture of 2-chloroethyl 2-(2-cyanobenzylidene)acetoacetate (4.72 g) and ethyl 3-amino-4,4diethoxycrotonate (4.06 g) was heated for 3 hours at 100 105 C with stirring. After cooling, the reaction mixture was dissolved in ethyl acetate, and the solution was washed twice with an aqueous solution of sodium chloride and then dried over magnesium sulfate. After removal of the solvent under reduced pressure, the residual oil was chromatographed over silica gel with a mixture of benzene and ethyl acetate (5 : 1 VN) to give 2-chloroethyl ester of 4-(2-cyanophenyl)-5-ethoxy-carbonyl-6-diethoxymethyl-2-methyl-1,4- dihyrdopyridine-3-carboxylic acid (5.81 g).

N.M.R.

bppm (CDCl3):1.1 to 1.4 (9H, m), 2.37 (3H, s), 3.4 ~ 3.95 (6H, m), 4.0 ~ 4.4 4.4 (4H, m), 5.39 (1H, s), 6.24(1 H, s), 6.90 (1 H, broad s), 7.1 ~ 7.6 7.6 (4H, m) The following compounds (2) - (5) were obtained in the similar manner to that of Example 2-(1).

(2) 2-(N-Benzyl-N-methylamino)ethyl ester of 4-(2-cyanophenyl-5-ethoxycarbonyl-6-diethoxymethyl-2methyl- 1 ,4-dihydropyridine-3-carboxylic acid.

N.M.R.

bppm (CDCI3): 1.1 : 1.5 (9H, m), 2.21 (3H, s), 2.40 (3H, s), 2.72 (2H, t, J=6 Hz), 3.53 (2H, s), 3.5 ~ 4.5 4.5 (8H, m), 5.44(1 H, s), 6.30 (1 H, s), 6.87 (1 H, broad s), 7.2 ~ 7.8 (9H, m) (3) 2-Ethoxyethyl ester of 4-(2cyanophenyl)-5-ethoxywarbonyl-6-diethoxymethyl-2-methyl-1,4- dihydropyridine-3-carboxylic acid.

N.M.R.

bppm (CDCl3):1.0 1.5 (12H, m), 2.42 (3H, 5)3.3 - 4.4 (12H, m), 5.45 (1H, 5), 6.30 (1H, s), 6.87 (1H, 5), 7.1 ~ 7.7 (4H, m) (4) 2-Phenoxyethyl ester of 4-(2-cyanophenyl-5-ethoxycarbonyl-6-diethoxymethyl-2-methyl-1,4- dihydropyridine-3-carboxylic acid, mp 94 ~ 95 C.

(5) 2-Benzyloxyethyl ester of 4-(2-cyanophenyl)-5-ethoxycarbonyl-6-diethoxymethyl-2-methyl-1 ,4- dihydropyridine-3-carboxylic acid, mp 97.5 ~ 98.5 C.

Example 3 (1) A solution of isopropyl ester of 4-(2-cyanophenyl)-5-methoxy-carbonyl-6-dimethoxymethyl-2-methyl- 1 ,4-dihydropyridine-3-carboxylic acid (9.32 g) in 6N hydrochloric acid (11 ml) and acetone (95 ml) was stirred for 5 hours at ambient temperature. The reaction mixture was neutralized with sodium bicarbonate and then the acetone was removed by distillation therefrom. To the resultant solution were poured water and ethyl acetate, and the ethyl acetate layer was separated, washed with water and an aqueous solution of sodium chloride, and then dried over magnesium sulfate. The ethyl acetate was removed by distillation under reduced pressure to give a solid, which was washed with a mixture of ethyl ether and hexane to provide crude yellowish-orange powder (7.65 g) of isopropyl ester of 4-(2-cyanophenyl)-6-formyl-5methoxycarbonyl-2-methyl-1 ,4-dihydropyridine-3-carboxylic acid. 0.5 g of this powder was recrystallized from isopropyl ether to give the purified yellowish-orange powder of the same product (0.34 g), mp 132 134 C.

The following compounds (2) ~ (6) were obtained in the similar manner to that of Example 3-(1).

(2) Isopropyl ester of 6-formyl-5-methoxywarbonyl-4-(2-methoxy-carbonylphenyl)-2-methyl-1,4- dihydropyridine-3-carboxylic acid N.M.R.

oppm (CDC13) : 0.94 (d, J=6.5 Hz) )(6H) 1.19 (d, J=6.5 Hz) 2.41 (3H, s), 3.70 (3H, s), 3.97 (3H, s), 4.96 (1 H, heptet, J=6.5 Hz), 6.21 H, 5), 6.82 (1 H, broad s), 7.0 ~ 7.9 (4H, m), 10.23 (1H, s) (3) 2-(N-Benzyl-N-methylamino)ethyl ester of 4-(2-cyanophenyl)-5-ethoxycarbonyl-6-formyl-2-methyl- 1,4- dihydropyridine-3-carboxylic acid.

N.M.R.

bppm (CDCI3): 1.29 (3H, t, J=7.5 Hz), 2.21 (3H, s), 2.44 (3H, s), 2.71 (2H, t, J=6 Hz), 3.51 (2H, s), 4.1 ~ 4.44.4 (4H, m), 5.51 H, s), 7.04 (1 H, broad s), 7.2 ~ 7.75 (9H, m), 10.57 (1H, s) (4) 2-Ethoxyethyl ester of 4-(2-cyanophenyl )-5-ethoxycarbonyl-64ormyl-2-methyl-1 ,4-dihydropyridi ne-3 carboxylicacid,mp 115 ~ 116 C.

(5) 2-Phenoxyethyl ester of 4-(2-cyanophenyl)-5-ethoxywarbonyl-6-formyl-2-methyl-1,4-dihydropyridine-3- carboxylicacid mp 104 - 105 C.

(6) 2-Benzyloxyethyl ester of 4-(2-cyanophenyl)-5-ethoxywarbonyl-6-formyl-2-methyl-1,4-dihydropyridine-3- carboxylic acid.

N.M.R.

5ppm (CDCl3): 1.28(3H,tJ=7Hz),2.41 (3H, s), 3.5 ~ 3.8 (2H, m), 4.0 ~ 4.54.5 (4H, m), 4.48 (2H, s), 5.48(1H, 5)6.9 ~ 7.5 (10H, m), 10.51 (1H,s) Example 4 (1) To a solution of isopropyl ester of 4-(2-cyanophenyl )-6-formyl-5-methoxycarbonyl-2-methyl-l ,4- dihydropyridine-3-carboxylic acid (3.90 g) in acetic acid (20 ml) were added hydroxylamine hydrochloride (0.88 g) and sodium acetate (1.30 g), and the mixture was stirred for an hour at ambient temperature.

To the reaction mixture was added acetic anhydride (3.97 g) with stirring, and the stirring was continued for an hour at ambient temperature and for additional 4 hours at 95 ~ 100 C. After the reaction mixture was allowed to stand at ambient temperature, the acetic acid was removed by distillation under reduced pressure. The resultant residue was diluted with water, neutralized with an aqueous solution of sodium bicarbonate and then extracted twice with ethyl acetate. After the combined extract was washed twice with water and dried, the solvent was removed by distillation under reduced pressure to give an oil, which was allowed to stand overnight and pulverized with a small amount of ethyl ether.The powder was washed with isopropyl ether and recrystallized from methanol to give yellowish-orange crystals of isopropyl ester of 6-cyano-4-(2-cyanophenyl)-5-methoxycarbonyl-2-methyl-1 ,4-dihydropyridine-3-carboxylic acid (1.99 g), mp 198 ~ 200 C.

The following compounds (2) ~ (6) were obtained in the similar manner to that of Example 4-(1).

(2) Isopropyl ester of 6-cyano-5-methoxycarbonyl-4-(2-methoxy-carbonylphenyl)-2-methyl-1,4- dihydropyridine-3-carboxylic acid, mp 121.5 ~ 123"C.

(3) 2-(N-Benzyl-N-methyla mino)ethyl ester of 6-cyano-4-(2-cyanophenyl )-5-ethoxycarbonyl-2-methyl-1 ,4- dihydropyridine-3-carboxylic acid hydrochloride, mp 230"C (dec.).

(4) 2-Ethoxyethyl ester of 6-cyano-4-(2-cyanophenyl)-5-ethoxy-carbonyl-2-methyl-1 ,4-diphydropyridine-3- carboxylic acid, mp 135 ~ 136 C.

(5) 2-Phenoxyethyl ester of 6-cyano-4-(2-cyanophenyl )-5-ethoxy-ca rbonyl-2-methyl-1 ,4-dihydropyridine-3carboxylic acid, mp 170.5 ~ 172 C.

(6) 2-Benzyloxyethyl ester of 6-cyano-4-(2-cyanophenyl)-5-ethoxycarbonyl-2-methyl-1 ,4-dihyd ropyridine-3carboxylic acid, mp 132 ~ 133 C.

Example 5 (1) To a solution of isopropyl ester of 4-(2-cyanophenyl )-6-formyl-5-methoxycarbonyl-2-methyl-l ,4- dihydropyridine-3-carboxylic acid (3.2 g) in ethanol (65 ml) was added dropwise sodium borohydride (0.33 g) over a period of 10 minutes under cooling at 0 C with stirring, and the stirring was continued for an hour at the same temperature. After the reaction mixture was slightly acidified with 50% aqueous acetic acid under cooling at 0 C, the ethanol was removed by distillation under pressure. The resultant residue was diluted with water, neutralized with sodium bicarbonate and extracted twice with ethyl acetate. The combined extract was washed with water, an aqueous solution of sodium chloride, and then dried.The solvent was removed by distillation under reduced pressure give a viscous yellowish oil (3.75 g), which was pulverized with a mixture of ethyl ether and hexane. This powder (3.19 g) was recrystallized from isopropyl ether containing a small amount of methanol to give pale-yellowish crystals of isopropyl ester of 4-(2 cyanophenyl)-6-hydroxymethyl-5-methoxycarbonyl-2-methyl-1 ,4-dihydropyridine-3-carboxylic acid (1.97 g), mp 135 - 137"C.

The following compounds (2) - (5) were obtained in the similar manner to that of Example 5-(1).

(2) Isopropyl ester of 6-hydroxymethyl-5-methoxycarbonyl-4-(2-methoxycarbonylphenyl)-2-methyl-1 ,4- dihydropyridine-3-carboxylic acid, mp 144 - 145"C.

(3) 2-Ethoxyethyl ester of 4-(2cyanophenyl )-5-ethoxycarbonyl-6-hydroxymethyl-2-methyi-1,4- dihydropyridine-3-carboxylic acid, mp 127.5 ~ 128.5"C.

(4) 2-Phenoxyethyl ester of 4-(2-cya nophenyl )-5-ethoxycarbonyl-6-hydroxymethyl-2-methyl-1 ,4- dihydropyridine-3-carboxylic acid, mp 116 1 117"C.

(5) 2-Benzyloxyethyl ester of 4-(2-cyanophenyl)-5-ethoxycarbonyl-6-hydroxymethyl-2-methyl-1 4 dihydropyridine-3-carboxylicacid, mp 109 - 110 C.

Example 6 To a mixture of 2-chloroethyl ester of 5-ethoxycarbonyl-4-(2-cyanophenyl)-6-diethoxymethyl-2-methyl-1 ,4- dihydropyridine-3-carboxylic acid (5.81 g) and N-benzyl-N-methylamine (5.78 g) in n-propyl alcohol (10 ml) was added a catalytic amount of sodium iodide (0.2 g), and the mixture was refluxed for 4 hours under heating with stirring. After cooling, the solvent was removed by distillation form the reaction mixture under reduced pressure to give a residue, which was dissolved in a mixture of ethyl acetate and water.

The separated organic layer was washed several times with water and then dried. Removal of the solvent gave brownish oil, which was purified by column chromatagraphy on silica gel (230 g) with a mixture of benzene and ethyl acetate (5 : 2 v/v) as an eluent to give 2-(n-benzyl-N-methylamino)ethyl ester of 4-(2-cyanophenyl )-5-ethoxyca rbonyl-6-diethoxymethyl-2-methyl-1 ,4-dihyd ropyridine-3-carboxylic acid (5.10 9).

N.M.R.

oppm (CDC13) 1.1 : 1.5 (9H, m), 2.21 (3H, s), 2.40 (3H, s), 2.72 (2H, t, J=6 Hz), 3.53 (2H, s), 3.5 4.5 (8H, m), 5.44(1 H, s), 6.30 (1 H, s), 6.87 (1 H, broad s), 7.2 ~ 7.8 7.8 (9H, m).

Claims (16)

1. Acompound oftheformula:

wherein R1 is cyano or lower alkoxycarbonyl, R2 is isopropoxycarbonyl, chloroethoxycarbonyl, ethoxyethoxycarbonyl, phenoxyethoxycarbonyl, benzyloxyethoxycarbonyl or N-benzyl-N-methylamino ethoxycarbonyl, R2 is lower alkoxycarbonyl, R4 is lower alkyl and R5 is di(lower)alkoxymethyl, formyl, hydroxyiminomethyl, cyano or hydroxymethyl.

2. A compound according to claim 1, wherein R1 is cyano or methoxycarbonyl, R2 is isopropoxycarbonyl, chloro-ethoxycarbonyl, ethoxyethoxycarbonyl, phenoxyethoxyca rbonyl, benzyloxyethoxycarbonyl or N-benzyl-N-methylaminoethoxycarbonyl, R3 is methoxycarbonyl or ethoxycarbonyl, R4 is methyl and R5 is dimethoxymethyl, diethoxymethyl, formyl, hydroxyiminomethyl, cyano or hydroxymethyl.

3. A compound according to claim 2, wherein R1 is cyano, R5 is cyano or hydroxymethyl, and R2, R3 and R4 are each as defined in claim 2.

4. A compound according to claim 3, that is isopropyl 6-cyano-4-(2-cyanophenyl )-5-methoxycarbonyl-2-methyl-1 ,4-dihydropyridine-3-carboxylate.

5. A compound according to claim 3, that is 2-(N-benzyl-N-methylamino)ethyl 6-cyano-4-(2-cyanophenyl )-5-ethoxycarbonyl-2-methyl-1 ,4- dihydropyridi ne-3-carboxylate.

6. A compound according to claim 3, that is 2-ethoxyethyl 6-cyano-4-(2-cyanophenyl )-5-ethoxycarbonyl-2-methyl-1 ,4-dihydropyridine-3-carboxylate.

7. A compound according to claim 3, that is 2-phenoxyethyl 6-cyano-4-(2-cyanophenyl)-5-ethoxycarbonyl-2-methyl-1 ,4-dihyrdopyridine-3- ca rboxylate.

8. A compound according to claim 3, that is 2-benzyloxyethyl 6-cyano-4-(2-cyanophenyl )-5-ethoxycarbonyl-2-methyl-1,4-dihyd ropyridine-3- carboxylate.

9. A compound according to claim 3, that is isopropyl 6-hyd roxymethyl-4-(2-cyanophenyl )-5-methoxycarbonyl-2-methyl-1 ,4-dihydropyridine-3carboxylate.

10. A compound according to claim 3, that is 2-ethoxyethyl 6-hydroxymethyl-4-(2-cyanophenyl )-5-ethoxycarbonyl-2-methyl-1 ,4-dihydropyridine-3- carboxylate.

11. A compound according to claim 3, that is 2-phenoxyethyl 6-hyd roxymethyl-4-(2-cyanophenyl )-5-ethoxycarbonyl-2-methyl-1 ,4-d ihyd ropyridi ne-3carboxylate.

12. A compound according to claim 3, that is 2-benzyloxyethyl 6-hyd roxymethyl-4-(2-cyano phenyl )-5-ethoxycarbonyl-2-methyl-1 ,4-dihydropyrid ine-3carboxylate.

13. A compound according to claim 2, wherein R' is methoxycarbonyl, R5is cyano or hydroxymethyl, and R2, R3 and R4 are each as defined in claim 2.

14. A compound according to claim 13, that is isopropyl 6-cyano-4-(2-methoxycarbonyl phenyl )-5-methoxycarbonyl-2-methyl-l ,4-dihydropyridi ne-3- carboxylate.

15. A compound according to claim 13, that is isopropyl 6-hydroxymethyl-4-(2-methoxycarbonyl phenyl )-5-methoxycarbonyl-2-methyl-1 ,4- dihydropyridine-3-carboxylate.

16. A pharmaceutical composition comprising, as an active ingredient, the compound of claim 1, in association with a non-toxic, pharmaceutically acceptable carrier or excipient.