HU176454B - Process for preparing 1,4-dihydro-pyridine derivatives - Google Patents

Abstract

Novel 1,4-dihydropyridine derivatives of the formula: <IMAGE> are prepared by eliminating water from compounds of the formula: <IMAGE> which, for their part, are obtained from corresponding 2-methyl-1,4-dihydropyridines by reaction with hydroxylamine or with a salt thereof. R<1> denotes cyano or lower alkoxycarbonyl, R<2> and R<3> denote esterified carboxyl and R<4> denotes lower alkyl. The compounds have vasodilatory and hypotensive effects and can be used in the form of pharmaceutical preparations for treating high blood pressure and cardiovascular diseases.

Description

Process for the preparation of 1,4-dihydropyridine derivatives

The present invention relates to novel 1,4-dihydropyridine derivatives having a vasodilator and antihypertensive activity, and to pharmaceutical compositions containing them.

The preparation of the 1,4-dihydropyridine compound (IV) which is structurally closest to the compounds of the present invention is disclosed in U.S. Patent No. 3,485,847. U.S. Pat.

The process according to the invention is novel

The 1,4-dihydropyridine derivatives have the general formula (I) wherein

R ¹ is cyano, lower alkoxycarbonyl or lower alkanesulfamoyl,

R ^{2 and} R ^{3 are C} 1 -C 7 alkoxycarbonyl optionally substituted with halogen, lower alkoxy, phenoxy, phenyl-lower alkoxy or N- (lower alkyl) -N- (phenyl) a (lower alkyl) amino group may be attached, and

R ⁴ and R ^s each represent a lower alkyl group and the other is cyano, 1-hydroxy (Cl-C3) alkyl group (preferably hydroxymethyl group), l, l-di (lower) alkoxy - (C 1 -C 3) -alkyl (preferably 1,1-di (lower) -alkoxymethyl), 1,1- (C 2 -C 4) alkylenedioxy (C 1 -C 3) -alkyl- or a C 1-3 alkyl group (preferably a formyl group) containing an oxo group at the 1-position of the carbon chain (preferably a C 1 -C 2 alkylene dioxy-methyl group).

The process of the present invention provides racemic compounds of general formula (I).

The novel compounds of formula (I) are useful in medicine for the prophylaxis or treatment of cardiovascular disorders such as coronary insufficiency, angina pectoris, myocardial infarction and hypertension.

The compounds of formula (I) according to the invention can be prepared by the following methods:

I Method 1:

Base frame design

This procedure is illustrated in Scheme (A). In the formulas, R ¹ , R ² and R ³ are as defined above, while R ⁴ and R ^{4 are} lower alkyl and the other is 1,1-di (lower) alkoxy (C 1 -C 3) alkyl. (preferably 1,1-di- (lower-alkoxymethyl) or 1,1-(lower) alkylene-dioxy (1-3C) alkyl (preferably 1,1-lower-lower alkyl-dioxy). methyl group)

Method 2:

Transformation of reactive groups

This procedure is illustrated in Scheme (B). In the formulas, R ¹ , R ² , R ³ , R f and R f are as defined above, while one of R 6 and R f is a lower alkyl group having 1 to 3 carbon atoms (preferably formyl) containing an oxo group at the 1-position of the carbon chain. group).

Method 3:

Transformation of reactive groups

This procedure is illustrated in Schemes (C) and (D). Wherein R ^1, R ² and R ³ are as defined above, R f 'and R f are each a lower alkyl group and the other is formyl group, Re and Rf are each a lower alkyl group and the other is hydroxyimino-methyl, and one of R1 and R1 represents a lower alkyl group and the other represents a cyano group.

Method 4:

Transformation of reactive groups

This procedure is illustrated in Scheme (E). In the formulas, ^{R1, R2, R3,} Rf and Rf are as defined above and R ⁴ and R f are each a lower alkyl group and the other is 1-hydroxy (C1-3) alkyl group (preferably hydroxymethyl group) represents.

If desired, the novel compounds of formula (I) prepared by any of the methods listed above can be converted into their acid addition salts or the base may be liberated from the acid addition salts of compounds of formula (I). Our patent claims also cover the preparation of their acid addition salts.

As used herein, the term "lower" refers to groups having 1 to 4 carbon atoms. For groups with different carbon numbers, the carbon number is indicated separately.

The lower alkoxycarbonyl groups at the R ¹ position correspond to the formula -CO-O-Alk where Alk is a straight or branched lower alkyl group (i.e., C 1 -C 4) as defined above. Examples of lower alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl and tert-butoxycarbonyl.

The lower alkanesulfamoyl groups at the R ¹ position correspond to the formula Alk-SO ₂ -NH-, where Alk is as defined above. Examples of lower alkanesulfamoyl groups include methanesulfamoyl, ethanesulfamoyl, propanesulfamoyl, isopropanesulfamoyl and butanesulfamoyl.

R ² and R ³ are optionally substituted with one of the groups listed above

Examples of C 1 -C 7 alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl-1-isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, neopentyloxycarbonyl, hexyloxycarbonyl, and heptyloxycarbonyl; ethoxycarbonyl, 2-chloroethoxycarbonyl, 2- or 3-chloropropoxycarbonyl, 2- or 3-bromopropoxycarbonyl, 2-methoxyethoxycarbonyl, 2-ethoxyethoxycarbonyl, 2- or 3-methoxy- propoxycarbonyl, 2- or 3-methoxypropoxycarbonyl, 2-benzyloxyethoxycarbonyl, 2- or 3-benzyloxypropoxycarbonyl, 2-phenoxyethoxycarbonyl, 2- or 3-phenoxypropoxycarbonyl or

2- (N-methyl-N-benzyl-1-amino) -ethoxycarbonyl. It is noted that R ² and R ³ may be the same or different.

Some of the compounds of formula (II) and (III) used as starting materials in the process of the present invention are known while other derivatives are novel.

Compounds of formula (II) may be prepared by reaction of the 4-substituted acetic acid ester of formula (IIA) wherein R ³ and R f are as defined above with aldehydes of formula (IIB). wherein R ¹ is as defined above.

The compounds of formula (III) may be prepared either from the acetylene derivatives of formula (IIIA) where R ² and R f are as defined above or from the substituted acetic acid ester compounds of formula (II B) where R ² and Rf are as defined above. . The reactions are illustrated in Schemes (G) and (H). In both cases, ammonium salts may be used as the reactant in place of ammonia.

In the following, the procedures leading to the 1,4-dihydropyridine derivatives of formula (1) will be described in detail.

Method 1:

According to this method, compounds of formula (II) and (III) are prepared by reaction of compounds of formula (I-1).

Both types of starting materials contain a double bond and thus exist in the form of cis and trans isomers. The compounds of formulas (II) and (III) can be used in any isomeric form for the preparation of compounds of formula (I-1). The term "compound of formula II" or "compound of formula III" refers to all possible isomers and isomer mixtures thereof.

The reaction can be carried out at room temperature with heating or heating. The reaction proceeds in the absence of a solvent, but the starting materials are usually reacted with one another in the presence of a solvent. Suitable solvents are, for example, benzene, toluene, xylene, chloroform, carbon tetrachloride, methylene chloride, ethylene chloride, methanol, propanes, butanol, water or other conventional solvents. The reaction may be accelerated using a suitable catalyst such as an acid (such as acetic acid), a base (such as pyridine or picoline) or a buffer solution. Liquid catalysts may also be used as a solvent to carry out the reaction. The reaction can also be accelerated by heating the mixture. The reaction conditions may vary depending on the nature of the reagents used.

The preparation of the starting material and the formation of the final product may be coupled together by, for example, reacting a mixture of compounds of formula (HA), (IIB) and (III) or first reacting a compound of formula (ΙΠΑ) with ammonia or an ammonium salt. product is directly reacted with a compound of formula II.

Ammonium salts include inorganic ammonium salts such as ammonium chloride or ammonium sulfate or organic ammonium salts such as ammonium acetate.

Method 2

According to this method, compounds of formula (I) are hydrolyzed to give compounds of formula (1-2).

The compounds of formula (I-1) may be prepared according to method 1.

In this process, the C 1 -C 3 alkyl group of the formula (I-1) in which R 1 or R 9 is substituted is hydrolytically converted to the oxo group by a 11-di (lower) alkoxy-1, 1-lower alkylene dioxide substituent.

The hydrolysis may be carried out under conditions generally used for the cleavage of the acetal and ketal groups and formation of the corresponding carbonyl group. Preferably, the geminal di- (lower) alkoxy and geminal lower alkylenedioxy groups are cleaved by acid hydrolysis, such as inorganic acids such as hydrochloric or sulfuric acid, or organic acids such as formic acid, acetic acid, trifluoroacetic acid or p-toluenesulfonic acid.

Hydrolysis in a suitable solvent such as water, acetone, methylethylketone, dioxane, ethanol, methanol, Ν, Ν-dimethylformamide, N-methylmorpholine or dimethylsulfoxide, as well as in a mixture of the listed solvents and a buffered finally. The reaction temperature is not critical. In many cases, the reaction is carried out under cooling to room temperature or with slight heating.

Method 3:

In the first step of this method, the compounds of formula (I-2 ') are reacted with hydroxylamine or a hydroxylamine salt. Yield: Compounds of formula (1-3). During the reaction, the oxo group in the Rg 'or Rb' substituent of the compound (1-2 ') is converted to the hydroxyimino group.

The compounds of formula (1-2 ') used as starting materials can be prepared by Method 2.

Preferred hydroxylamine salts are salts with an acid such as an inorganic acid (e.g. hydrochloric acid or sulfuric acid) or an organic acid such as acetic acid.

The reaction is carried out in a manner known per se, for example by adding a catalyst (such as an acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, formic acid, acetic acid, p-toluenesulfonic acid, boron trifluoride, silicon tetrachloride or titanium tetrachloride) to the reaction mixture. using free hydroxylamine under alkaline conditions. The reaction may also be carried out in the presence of a conventional acidic or basic buffer solution. The reaction is usually carried out in a solvent medium such as water, dioxane, ethanol, methanol, dimethylformamide, or optionally mixtures of the solvents listed.

The reaction temperature is not critical. In many cases, the reaction is carried out under cooling to room temperature or with slight heating.

In the next step, the compounds of formula (1-3) are prepared by dehydration of the compounds of formula (1-4).

Organic or inorganic dehydrating agents may be used in the process. Examples of dehydrating agents include inorganic acids such as sulfuric acid, phosphoric acid and polyphosphoric acid, organic acids such as formic acid, acetic acid, ethanesulfonic acid and p-toluenesulfonic acid, organic acid anhydrides such as acetic anhydride, benzoic anhydride, -chloride, trichloroacetyl chloride, mesyl chloride, tosyl chloride, ethyl chloroformate and phenyl chloroformate, inorganic halogen compounds such as thionyl chloride, phosphorus pentachloride, phosphorus oxychloride, phosphorus tribromide, tin (IV) chloride, titanium tetrachloride, dicyclohexylcarbodiimide and N-cyclohexyl-N'-morpholinoethylcarbodiimide, Ν, Ν'-carbonyldiimidazole, pentamethylene ketene-N-cyclohexylimine, ethoxyacetylene, 2-yl-7-hydroxyisoxazolium salts, other phosphorus salts , such as phosphorus pentoxide, ethyl polyphosphoric acid, triethyl phosphate and phenyl phosphate, and the aforesaid dehydrating agents. various solvents mentioned. When an acid is used as a dehydrating agent, the acid may also be added in the form of a salt (such as an alkali metal salt, such as a sodium or potassium salt) to the reaction mixture.

The reaction is usually carried out in a solvent such as diethyl ether, dimethylformamide, pyridine, acetic acid, formic acid, benzene, carbon tetrachloride, chloroform, methylene chloride, tetrahydrofuran or dioxane. The reaction temperature is not critical, but generally the reaction is carried out at room temperature or under heating.

Alternatively, the compounds of formula (1-3) are not isolated but directly subjected to the above dehydration step.

Method 4:

According to this method, the reduction of oxo compounds (1-2) gives compounds (1-5).

The oxo compounds (1-2) can be formed by Method 2.

The reduction may be carried out under conventional conditions for the conversion of aldehydes or ketones to hydroxy compounds. The compounds of formula (1-2) may be reduced using chemical reducing agents, such as alkali metal borohydrides (such as lithium borohydride, sodium borohydride, potassium borohydride or sodium cyanoborohydride), or by catalytic reduction. In the latter case, palladium on charcoal, palladium chloride or radium on charcoal are preferably used as catalysts. The reaction is usually carried out in a solvent such as water, methanol, ethanol, isopropanol, dimethylformamide or tetrahydrofuran. The reaction temperature is not critical and, in many cases, the reaction is carried out under cooling to room temperature or with slight heating. Depending on the nature of the compounds (1-2) used as starting materials, the reduction may be carried out by other known methods.

The products obtained by the methods listed above may be isolated or purified by conventional techniques, such as solvent extraction, chromatography, precipitation or recrystallization.

The novel compounds of formula I and their acid addition salts have vasodilating properties and are useful in the treatment of hypertension and certain cardiovascular diseases such as coronary insufficiency, angina pectoris and myocardial infarction.

Particularly beneficial are the compounds of formula (I) wherein R ⁴ or R ^{5 is} cyano, lower alkyl, 1-hydroxy (C 1-3) alkyl, or a compound of formula (I). is a C 1-3 alkyl group containing an oxo group. It will be appreciated that certain of the compounds of 45 formula (I) - especially those compounds in which R ⁴ or R ^s, 1,1-di (lower alkoxy) - (C1-3) alkyl group, a formyl group or L 1- (lower) alkylenedioxy (C1-C3) -alkyl can also be used to prepare other compounds of formula (I).

they may generally contain from about 0.01 mg to about 500 mg, preferably from about 0.1 mg to about 250 mg, of the active ingredient. The exact amount of active ingredient in the dosage unit will vary depending on the biological activity of the compound used and the size of the individual being treated.

The pharmaceutical compositions will usually be in the form of tablets, granules, powder mixes, capsule formulations, suppositories, suspensions or solutions.

The pharmaceutical compositions may contain, in addition to the active ingredient, solid or liquid, non-toxic, pharmaceutically acceptable carriers. Examples of excipients are lactose, magnesium stearate, sucrose, corn starch, talc, stearic acid, gelatin, agar, pectin, acacia gum, peanut oil, olive oil, sesame oil and cocoa butter. The pharmaceutical compositions may optionally contain adjuvants such as glyceryl monostearate, glyceryl distearate or wax, for example.

The pharmaceutical compositions may be marketed in a wide variety of forms. When a solid carrier is used in the preparation of the compositions, the compositions may be tabletted, filled into hard gelatin capsules or made into chewable tablets.

Pharmacological assays and their results for the biological activity of the compounds of formula (I) are described below.

In the studies, the drug was administered intravenously to dogs previously anesthetized with pentobarbital and the coronary blood flow of the animals was measured. The following active ingredients were used:

Compound A: 2,6-Dimethyl-4- (2-nitrophenyl) -3,5-dicarboxylic acid dimethyl ester (known as a coronary vasodilator, marketed as "Nifedipine") Compound B: 2-Methyl-4 - (2-Cyanophenyl) -6-cyano-3,5-dicarboxylic acid dimethyl ester (compound of formula I).

The results in% relative to the control (29.5 + 5.5 ml / min) are shown in Table 1.

Table 1

For therapeutic purposes, the 1,4-dihydropyridine compounds of formula (I) or their pharmaceutically acceptable acid addition salts are generally administered in a daily oral dosage of 0.1 to 500 mg, preferably 1 to 50 mg.

The 1,4-dihydropyridine compounds of formula (I), or pharmaceutically acceptable acid addition salts thereof, may be formulated into pharmaceutical compositions in known manner. Preferably, the pharmaceutical compositions are those for oral or parenteral administration, which are in dosage unit form.

Increased blood flow,

Active ingredient in the following doses is 64 µg / kg 250 µg / kg 1000 µg / kg

"A" 169 118 the animal is dead "B" 173 159 156 According to the invention process the scope of protection

but not limited to the following examples.

Example 1

1st step:

80.5 g of metal sodium are dissolved in 960 ml of methanol and the solution is concentrated to a final volume of 470 ml. 129 g of 2,2-dichloroacetic acid were added dropwise to the resulting methanolic sodium methoxide suspension at such a rate that the solvent was slightly boiling. After the addition, the reaction mixture was stirred at reflux for 3.5 hours, cooled to less than 10 ° C, and treated with 200 ml of methanol / 100 g of aqueous hydrochloric acid dropwise over half an hour. The reaction mixture was stirred at room temperature for 18 hours and then neutralized with cooling (<10 ° C). Neutralization is carried out with sodium methoxide in methanol (32 g) and sodium methoxide (400 ml). The precipitate was filtered off and washed with 150 ml of methanol. The filtrate was combined with the washings and the mixture was evaporated to dryness under reduced pressure below 30 ° C. The residue was extracted with 1 x 200 mL, then 2 x 100 mL benzene while decanting. The benzene solutions were combined, the solvent was removed under reduced pressure and the residue was subjected to fractional distillation under reduced pressure. 89.5 g of methyl 2,2-dimethoxyacetic acid are obtained in the form of an oil, m.p. 68-69 ° C / 20 mmHg.

In a further step, 18.28 g of metal sodium are dissolved in 300 ml of methanol and the methanol is evaporated under reduced pressure. The residue was suspended in anhydrous toluene (about 700 mL) and the suspension was concentrated at atmospheric pressure to a final volume of 200 mL. To the resulting slurry of methanol-free sodium methoxide at 50-60 ° C over about 50 minutes was 88.8 g of the 2,2-dimethoxyacetic acid methyl ester prepared above and 58.8 g of acetic acid. methyl ester mixture is added dropwise. After the addition, the reaction mixture was heated under reflux for 2.5 hours. The reaction mixture was cooled, poured into a mixture of acetic acid and ice water, and the acid mixture was stirred. The organic layer was separated, washed with aqueous sodium bicarbonate solution, dried over magnesium sulfate and freed of solvent under reduced pressure. The oily residue is distilled under reduced pressure. 82.27 g as an oil

Methyl 4,4-dimethoxyacetate, m.p. 88-91 ° C / 5 mmHg.

Step 2:

To a mixture of 5.0 g of 2-cyanobenzaldehyde, 7.39 g of 4,4-dimethoxyacetacetic acid methyl ester, 0.458 g of acetic acid and 15 ml of benzene are added in three equal portions a solution of 390 mg of piperidine in 5 ml of benzene. The reaction mixture is refluxed for 2 hours while the resulting water is removed by azeotropic distillation. The reaction mixture was cooled, shaken with a mixture of 50 mL of benzene and 30 mL of water, and the organic layer was separated. The organic phase was washed with dilute aqueous sodium bicarbonate solution and the washings were extracted with benzene (ml). The benzene solutions were combined, washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The resulting oily residue weighed 14.8 g

It was chromatographed on a silica gel column (200 g), eluting with 25: 1 benzene: ethyl acetate. Obtained as an oil, 6.90 g of methyl 2- (2-cyanobenzylidene) -4,4-dimethoxyacetacetate, which was a mixture of two stereoisomers by TLC and NMR.

NMR (CDC1 _3): δ = 3.4 (3H, s), 5 3.48 (3H, s), 3.78 and 3.90 (3H, each s), 4.83 to 5, 09 (1H, both s), 7.43-7.8 (4H, m), 8.0 and 8.15 (1H, both s) ppm.

Step 3:

A mixture of 6.8 g of methyl 2- (2-cyanobenzylidene) -4,4-dimethoxyacetate, prepared as described above, and 2.98 g of methyl 3-aminocrotonic acid methyl ester for 2 hours at about 60 ° C. After stirring, the reaction mixture is gradually heated to 100-103 ° C and maintained at this temperature for 10 hours. During the reaction, 3 ml of n-propanol are added to dissolve the resulting crystal mass. The reaction mixture was dissolved in a mixture of diisopropyl ether (9 mL) and methanol (3 mL) and allowed to stand. 6.39 g of 2-methyl-4- (2-cyanophenyl) -6-dimethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester are obtained in the form of fine, light brown crystals. Part of the precipitated product was recrystallized from a 1: 1 v / v mixture of diisopropyl ether and methanol (5). A pure crystalline product having a melting point of 134.5 ° C is obtained.

Nuclear Magnetic Resonance Spectrum (CDCl3) δ = 3.4 (3H, s), 3.48 (3H, s), 3.78 and 3.9 (3H, s), 4.83 and 5.09 ( 1H, s), 7.43-7.8 (4H, m), 8.0 and 8.15 (1H, s) ppm.

Example 2

1st step:

4.92 g of methyl 2-formylbenzoic acid, 7.2 g

To a mixture of ethyl 4,4-diethoxyacetacetic acid, 0.36 g of acetic acid and 15 ml of benzene is added a solution of 306 mg of piperidine in 5 ml of benzene in three equal portions. The reaction mixture is refluxed for 3 hours, during which time the water formed is removed by azeotropic distillation. The reaction mixture was cooled, diluted with benzene (25 mL), washed with water (3x), and washed successively with dilute aqueous sodium bicarbonate, water, and saturated aqueous sodium chloride. The solution was dried over magnesium sulfate and the solvent was evaporated under reduced pressure. 12.7 g of crude 2- (2-methoxycarbonylbenzylidene) -4,4-diethoxyacetacetic acid ethyl ester are obtained as a reddish oily residue which is used directly in the next step.

Step 2:

A mixture of 12.7 g of ethyl 2- (2-methoxycarbonylbenzylidene) -4,4-diethoxyacetic acid and 5.03 g of ethyl 3-aminocrotonic acid is stirred at 60-70 ° C for 1.5 hours, then the temperature of the reaction mixture is gradually increased. The mixture was heated at 90 ° C for 3.5 hours and then at 110 ° C for 4.5 hours. The reaction mixture was cooled, dissolved in ethyl acetate (50 mL), washed twice with water, dried over magnesium sulfate and the solvent evaporated under reduced pressure. The resulting reddish oily residue (12.8 g) was treated with a 1:10 (v / v) mixture of diisopropyl ether and n-hexane. 3.5 g of 2-methyl-4- (2-methoxycarbonylphenyl) -6-diethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester are obtained in the form of a pale brown crystalline powder. An additional 0.33 g of product was isolated from the mother liquor. The oily residue (8.0 g), obtained by evaporation of the mother liquor, was chromatographed on a silica gel column (240 g) eluting with benzene: ethyl acetate (15: 1 and 10: 1). An additional 1.6 g of product was isolated, thus totaling

5.43 g of product are obtained. A 300 mg portion of the first generation product was recrystallized from 3 mL of n-hexane. 290 mg of pure crystalline product are obtained, m.p. 94-95 ° C.

NMR (CDC1 _3): δ = 1.25 (6H, t, J = 7Hz), 1.15 (6H, t, J = Hz), 2.33 (3H, s), 3.92 (3H, s), 3.42-4.23 (8H, m), 6.04 (1H, s), 6.11 (1H, s), 6.6 (1H, broad s), 7.0 -7.8 (4H, m) ppm.

Example 3

1st step:

To a mixture of 6.62 g of sodium hydroxide, 25 ml of water and 10 ml of acetone is added 7.34 g of N, N-dimethylamine hydrochloride. A solution of 14.41 g of o-toluenesulfonyl chloride in 10 ml of acetone was added dropwise at 0 ° C over half an hour, and the reaction mixture was stirred at 0-4 ° C for an additional 15 minutes. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2 x 70 mL). The extracts were combined, washed with dilute aqueous hydrochloric acid, water, and brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. 14.95 g of N, N-dimethyl-o-toluenesulfonamide are obtained as an oily residue.

To a mixture of 20.0 g of N, N-dimethyl-o-toluenesulphonamide, 163 g of acetic anhydride and 170 ml of acetic acid is added dropwise 40.2 g of 1.84 g / ml of sulfuric acid at 5-8 ° C over a period of 15 minutes. At a temperature of less than 10 ° C, 28 g of chromium trioxide were added portionwise over a period of 1.33 hours. The reaction mixture was stirred for 1 hour then allowed to stand overnight at room temperature. The reaction mixture was poured into a mixture of 1 kg of ice and 200 ml of water with stirring, neutralized with sodium bicarbonate and extracted with 2 x 400 ml of ethyl acetate. The extracts were combined, washed with an aqueous solution of sodium bicarbonate, with an aqueous solution of sodium chloride, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure.

The resulting oily residue (25.8 g) was chromatographed on a silica gel column (516 g), eluting with benzene: ethyl acetate (15: 1). 8.36 g of N-methyl-o- (1,1-diacetoxymethyl) benzenesulfonamide are obtained as an oil.

A mixture of 8.3 g of N-methyl-o- (1,1-diacetoxymethyl) benzenesulfonamide, 33 ml of concentrated hydrochloric acid, 11 ml of ethanol and 55 ml of water is refluxed for 45 minutes. The reaction mixture was cooled, diluted with water (100 mL) and shaken with ethyl acetate (100 mL). The ethyl acetate layer was separated and the aqueous layer was extracted with 50 mL of ethyl acetate. The ethyl acetate solutions were combined, washed with aqueous sodium bicarbonate solution, water, and finally aqueous sodium chloride solution, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting oily residue (1.99 g) was crystallized by trituration with diethyl ether and the precipitated crystals were filtered off. Yield: 570 mg of N-methyl-o-formylbenzenesulfonamide, m.p. 110-112 ° C. The mother liquor was chromatographed on a silica gel column (40 g) eluting with 10: 3 benzene: ethyl acetate. An additional 1.1 g of product was isolated to give the product in a total yield of 1.67 g.

Step 2:

To a solution of 1.75 g of 2- (N-methylsulfamoyl) -benzaldehyde, 1.70 g of 4,4-dimethoxyacetacetic acid methyl ester and 0.1 g of acetic acid in 5 ml of benzene is added a solution of 1 (i) and 2 ( A solution of piperidine (90 mg) in benzene (3 ml) was added as described in step (i). The reaction mixture is refluxed for 2 hours while the water formed is removed by azeotropic distillation. The reaction mixture was cooled, diluted with benzene (15 mL), washed twice with dilute aqueous sodium bicarbonate solution, once with water, and once with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and the solvent was evaporated. The resulting red-yellow oily residue (3.46 g) was chromatographed on a silica gel column (69 g) eluting with benzene: ethyl acetate (3.5: 1). 1.12 g of 2- (2- (N-methylsulfamoyl) -benzylidene) -4,4-dimethoxyacetacetic acid methyl ester are obtained as an oil.

A mixture of 1.0 g of methyl 2- (2- (N-methylsulfamoyl / benzylidene) -4,4-dimethoxyacetate, prepared as above, and 355 mg of 3-aminocrotonic acid methyl ester for 3 hours at 60 ° C. We keep C. The mixture was then heated to 100 ° C over 1.5 hours and

Keep at this temperature for 5.5 hours. The reaction mixture was chromatographed on a column of silica gel (33 g), eluting with 5: 1 benzene: ethyl acetate. 840 mg of dimethyl 2-methyl-4- (2- (N-methylsulfamoyl) -phenyl) -6-dimethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate are obtained as an oil.

NMR (CDC1 _3): δ = 2.37 (3H, s), 2.65 (3H, d, J = 3Hz), 3.40 (3H, s), 3.45 (3H, s) , 3.63 (3H, s), 3.65 (3H, s), 4.77 (1H, q, J = 3Hz), 5.11 (1H, s), 6.01 (1H, s) , 6.88 (1H, broad s), 7.35-7.75 (4H, m) ppm.

Example 4

To a solution of 6.0 g of 2-methyl-4- (2-cyanophenyl) -6-dimethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester in 60 ml of acetone was added 6 ml of 6N aqueous hydrochloric acid, and the reaction mixture is stirred for 3 hours at room temperature. The reaction mixture was diluted with water (30 mL), basified to pH 7.5 with aqueous sodium bicarbonate, and the acetone was evaporated under reduced pressure. The resulting crystalline mass is crushed to the smallest possible size with a glass rod, mixed with 100 ml of water, removed, washed thoroughly with additional water and finally air-dried. 5.19 g of dimethyl 2-methyl-4- (2-cyanophenyl) -6-formyl-1,4-dihydropyridine-3,5-dicarboxylate are obtained as a powdery crystalline material.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ) δ = 2.41 (3H, s), 3.65 (3H, s), 3.75 (3H, s), 5.5 (1H, s), 7.0 ( 1H, s), 7.25-7.66 (4H, m), 10.53 (1H, s) ppm.

Example 5

5.0 To a solution of 3 g of 2-methyl-4- (2-methoxycarbonylphenyl) -6-diethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester in 50 ml of acetone was added 5 ml of aqueous hydrochloric acid was added and the reaction mixture was stirred for 2 hours at room temperature. Water (30 ml) was added, the mixture was neutralized with aqueous sodium bicarbonate solution and the acetone was evaporated under reduced pressure. The resulting oily residue was extracted with ethyl acetate. The ethyl acetate extracts were combined, washed with water and brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The crude 2-methyl-4- (2-methoxycarbonylphenyl) -6-phenyl-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester (4.26 g) was obtained as a reddish oily residue. in the next step.

NMR (CDC1 _3): δ = 1.1 (3H, t, J = 7Hz), 1.8 (3H, t, J = 7Hz), 2.37 (3H, s), 3, 93 (3H, s), 3.9-4.28 (4H, m), 6.2 (1H, s), 6.98 (1H, s), 7.1-7.8 (4H, m) , 10.2 (1H, s) ppm.

Example 6

To a solution of 600 mg of 2-methyl-4- (2- (N-methylsulfamoyl) -phenyl) -6-dimethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester in 6 ml of acetone was added 0.6 ml. 6N aqueous hydrochloric acid was added and the mixture was added

Stir at room temperature for 2.5 hours. The mixture was neutralized to pH 7-8 with dilute aqueous sodium bicarbonate solution and the acetone was evaporated under reduced pressure. The resulting oily precipitate was triturated with water. 380 mg of dimethyl 2-methyl-4- (2- (N-methylsulfanyl) phenyl) -6-formyl-1,4-dihydropyridine-3,5-dicarboxylate are obtained as a powdery crystalline material.

NMR (CDC1 _3): δ = 2.45 (3H, s), 2.65 βΗ, d, J = 3Hz), 3.65 (3H, s), 3.76 (3H, s); 4.6 (1H, q, J = 3Hz), 5.22 (1H, s), 7.09 (1H, broad s), 7.35-7.85 (4H, m), 10.49 (1H , s) ppm.

Example 7

2.4g of 2-methyl-4- (2-cyanophenyl) -6-formyl-1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester, 539.3 mg of hydroxylamine hydrochloride, 752.3 mg of sodium acetate and Acetic acid (15 mL) was stirred at room temperature for 55 minutes to give dimethyl ester of 2-methyl-4- (2-cyanophenyl) -6-hydroxyiminomethyl-1,4-dihydropyridine-3,5-dicarboxylic acid (2,375). Acetic anhydride (g) was added and the mixture was stirred for 4 hours at 110 [deg.] C. The reaction mixture was concentrated and water (30 ml) was added to the residue. The resulting acidic solution was basified to pH 7.5-8 with aqueous sodium hydrogen carbonate. The organic layer was washed with water and saturated brine, dried and concentrated under reduced pressure, the residue was stored overnight in a refrigerator, the precipitated crystals were filtered off and washed with a little cold methanol, 1.71 g of crystalline 2-methanol. 4- (2-cyanophenyl) -6-cyano-l, 4-dihydro-pyridyl An additional 0.9 g of product is isolated from the mother liquor. The product fractions were combined and recrystallized from methanol.

1.2 g of pure crystalline product are obtained, m.p. 166-166.5 ° C.

NMR (CDC1 _3): δ = 2.4 (3H, s), 3.67 (3H, s), 3.75 (3H, s), 5.42 (1H, s), 7.2 -7.62 (4H, m), 7.9 (1H, s) ppm.

Example 8

2.6 g of 2-methyl-4- (2-methoxycarbonylphenyl) -6-formyl-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester, 495 mg of hydroxylamine hydrochloride, 691 mg of sodium acetate and 20 ml the mixture was stirred for 1 hour at room temperature. The reaction gives 2-methyl-4- (2-methoxycarbonylphenyl) -6-hydroxyiminomethyl-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester. To the reaction mixture was added 2.18 g of acetic anhydride and the mixture was stirred at 110 ° C for 3.5 hours. The acetic acid was evaporated under reduced pressure and the residue was basified to pH 8 with aqueous sodium bicarbonate. The resulting solution was extracted with ethyl acetate. The aqueous extracts were combined, washed with water and brine, dried over magnesium sulfate and the solvent was evaporated. The oily residue (2.88 g) was chromatographed on a silica gel column (72 g), eluting with 10: 1 benzene: ethyl acetate. The received

The oily material (1.6 g) was triturated with diisopropyl ether (3 mL) and the resulting crystalline powder (1.3 g) was recrystallized from diisopropyl ether: ethanol (15: 1, v / v). 1.03 g of pure crystalline 2-methyl-4- (2-methoxycarbonylphenyl) -6-cyano-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester are obtained, m.p. 126-127 ° C. .

NMR (CDC1 _3): δ = 1.15 (3H, t, J = 7Hz), 1.24 (3H, t, J = 7Hz), 2.33 (3H, s), 3, 98 (3H, s), 3.90-4.38 (4H, q, J = 7Hz), 6.22 (1H, s), 7.2-7.88 (4H, m) ppm.

IS

Example 9

To a solution of 2.3 g of dimethyl 2-methyl-4- (2-cyanophenyl) -6-formyl-1,4-dihydropyridine-3,5-dicarboxylic acid in 46 ml of methanol at -5 ° C in portions 140.7 mg of sodium borohydride are added over 10 minutes. During the addition, the reaction mixture is stirred at a temperature of -4 ° C to -5 ° C. The reaction mixture was stirred for an additional 15 minutes at -6 ° C, then diluted with water (20 mL) and acidified to about pH 5 with 50% aqueous acetic acid. The reaction mixture was concentrated under reduced pressure to crystallize. Water (30 mL) was added to the crystalline material, and the crystals were filtered, washed well with water and dried. The resulting crystalline product (2.05 g) was recrystallized from methanol (15 mL). 1.67 g of 2-methyl-4- (2-cyanophenyl) -6-hydroxymethyl-1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester are obtained as a pure crystalline product, m.p. 178 ° C.

NMR (CDC1 _3): δ = 2.4 (3H, s), 3.63 (3H, s), 3.66 (3H, s), 4.8 (2H, br s), 3, 52 (1H, m), 5.35 (1H, s), 7.1-7.63 (4H, m) ppm.

Example 10

To a solution of 1.2 g of 2-methyl-4- (2-methoxycarbonylphenyl) -6-phenyl-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester in 15 ml of ethanol with stirring at 0 ° C 62.3 mg of sodium borohydride are added portionwise over 30 minutes. The mixture was stirred for an additional 20 minutes at 0 ° C, acidified to pH = 6 with 50% aqueous acetic acid, and the ethanol was evaporated under reduced pressure. The resulting solution was shaken with a mixture of water and ethyl acetate. The organic layer was separated, washed with water, aqueous sodium bicarbonate solution and water again, dried over magnesium sulfate and the solvent was evaporated under reduced pressure. The oily residue (1.0 g) was triturated with diethyl ether (2 mL) and the resulting crude crystalline material was purified. In our experience, the product cannot be sufficiently purified by recrystallization. Therefore, 0.9 g of the product is chromatographed on a column of 27 g of silica gel, eluting with 7: 1 benzene: ethyl acetate. 800 mg of purified diethyl 2- (2-methoxycarbonylphenyl) -6-hydroxymethyl-1,4-dihydropyridine-3,5-dicarboxylate are obtained in the form of an oil. The product was crystallized from a mixture of diethyl ether and n-hexane and recrystallized from the same solvent mixture. 500 mg of pure crystalline product are obtained, m.p. 106-108 ° C.

NMR (CDC1 _3): δ = 1.05 (3H, t, J = 7Hz), 1.1 (3H, t, J = 7Hz), 2.25 (3H, s), 3, 90 (3H, s), 3.85-4.13 (2H, m), 4.71 (2H, broad s), 5.98 (1H, s), 7-7.6 (5H, m) ppm .

Example 11

350 mg of dimethyl 2-methyl-4- (2- (N-methylsulfamoyl) -phenyl) -6-formyl-1,4-dihydropyridine-3,5-dicarboxylic acid in 7 ml of methanol at -2 ° C. To this suspension was added 17.85 mg of sodium borohydride in three equal portions with stirring over a minute. The mixture was stirred for an additional 1 hour and 40 minutes at -5 ° C to -4 ° C. At the same time, methanol (3 ml) was added after 30 minutes, methanol (4 ml) was added after 1 hour, and, after stirring for 1 hour and 20 minutes, another 9 mg of sodium borohydride was added. The mixture was diluted with water (30 mL) and cooled for 1 hour. The precipitated crystals are filtered off and the crystalline product (260 mg) is recrystallized from 3 ml of methanol. M.p. 210-212 DEG C., yields 2-methyl-4- (2- (N-methylsulfamoyl) phenyl) -6-hydroxymethyl-1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester.

NMR _(DMSO-d6): δ = 2.39 (3H, s), 3.33 (3H, s), 3.59 (6H, s), 4.66 (2H, br d, J = 5 Hz), 5.03 (1H, s), 5.59 (1H, broad t, J = 5 Hz), 7.3-7.78 (5H, m), 7.34 (1H, s) , 8.6 (1H, broad s). ppm.

Example 12

2- (2-Methoxycarbonyl-benzylidene) -4,4-ethylenedioxy-acetacetic acid methyl ester was reacted with 3-aminocrotonic acid isopropyl ester as described in Example 2, Step 2. The product isopropyl ester of 2-methyl-4- (2-methoxycarbonylphenyl) -5-methoxycarbonyl-1-6-ethylenedioxy-methyl-1,4-dihydropyridine-3-carboxylic acid, m.p. 129-129.5 ° C. .

Example 13

A mixture of 10.1 g of methyl 2- (2-cyanobenzylidene) -4,4-dimethoxyacetate and 5.51 g of isopropyl 3-aminocrotonic acid was heated at 78 ° C for 40 minutes and then for 5.5 hours. Stir at 120 ° C. The reaction mixture was then heated at 125 ° C without stirring for 1 hour. After standing overnight, the reaction mixture was dissolved in ethyl acetate, washed twice with water, dried and evaporated to dryness under reduced pressure. The resulting residue was crystallized from ethyl ether. The crystals were filtered off and washed with a little ethyl ether. 8.96 g of crude powdery isopropyl ester of 4- (2-cyanophenyl / 5-methoxycarbonyl-6-dimethoxymethyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid are obtained. 0.77 g of crude product are isolated. The crude product was recrystallized from isopropyl ether to give 0.37 g of a white powdery pure product, mp 171-172.5 ° C.

5-Methoxycarbonyl-4- (2-methoxycarbonyl-phenyl) -6-dimethoxymethyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid isopropyl ester was prepared according to the procedure described in Example 13.

Nuclear Magnetic Resonance Spectrum: δ (CDCl ₃ ) = 0.95 (3H, d, J = 7Hz), 1.19 (3H, d, J = 7Hz), 2.37 (3H, s),

3.40 (3H, s), 3.46 (3H, s), 3.61 (3H, s), 3.97 (3H, s), 4.97 (1H, heptet, J = 7Hz), δ , 93 (1H, s), 6.05 (1H, s), 6.59 (1H, broad s), 7.0-7.9 (4H, m) ppm.

Example 14

A mixture of 2- (2-cyanobenzylidene) -acetic acid 2-chloroethyl ester (4.72 g) and 3-amino-4,4-diethoxycrotonic acid ethyl ester (4.06 g) for 3 hours at 100-105 ° C is light weight.

The reaction mixture was cooled, dissolved in ethyl acetate, and washed twice with brine. The organic phase was dried over magnesium sulfate and the solvent was evaporated under reduced pressure. The oily residue was purified kroma- _s eluant, 5: mixture of benzene / ethyl acetate 1 as eluent. 5.81 g of 4- (2-cyanophenyl) -5-ethoxycarbonyl-6-diethoxymethyl-2-methyl-1,4-diylhydropyridine-3-carboxylic acid 2-chloroethyl ester are obtained.

Nuclear Magnetic Resonance Spectrum: δ (CDCl ₃ ) = 1.1-1.4 (9H, m), 2.37 (3H, s), 3.4-3.95 (6H, m), 4.0- 4.4 (4H, m), 5.39 (1H, s), 6.24 (1H, s), 6.90 (1H, broad s), 7.1-7.6 (4H, m) ppm .

By following the procedure described in Example 14, the following compounds were prepared:

4- (2-Cyanophenyl) -5-ethoxycarbonyl-6-diethoxymethyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid 2- (N-benzyl-N-methyl-)

amino) ethyl ester.

Nuclear Magnetic Resonance Spectrum: δ (CDCl 3) = 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 (1H, s), 6.30 (1H, s), 6.87 (1H , broad s), 7.2-7.8 δ (9H, m) ppm. 4- (2-cyanophenyl) -5-ethoxycarbonyl-6-diethoxymethyl-2-methyl-l, 4-dihydro-pyridine-3-carboxylic acid 2-ethoxy ethyl ester.

Nuclear Magnetic Resonance Spectrum: δ (CDCl ₃ ) = 1.0-1.5 (12H, m), 2.42 (3H, s), 3.3-4.4 (12H, m), 5.45 (1H, s), 6.30 (1H, s), 6.87 (1H, s), 7.1-7.7 (4H, m) ppm.

4- (2-Cyanophenyl) -5-ethoxycarbonyl-6-diethoxymethyl-2-methyl-1,4-dihydro-

Pyridine-3-carboxylic acid 2-phenoxyethyl ester, m.p. 94-95 ° C. 4- (2-Cyanophenyl) -5-ethoxycarbonyl-6-diethoxymethyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid 2-benzyloxyethyl ester, m.p. 97.5-98; 5 ° C.

Example 15

9.32 g of 4- (2-cyanophenyl) -5-methoxycarbonyl-6-dimethoxymethyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid isopropyl ester with 11 ml of 6N aqueous hydrochloric acid and 95 ml acetone solution was stirred for 5 hours at room temperature. The reaction mixture was neutralized with sodium bicarbonate and the acetone was evaporated. Water and ethyl acetate were added to the resulting solution. The ethyl acetate layer was separated, washed with water and brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting solid residue was washed with a mixture of ethyl ether and hexane. 7.65 g of crude 4- (2-cyanophenyl) -6-formyl-5-methoxycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid isopropyl ester are obtained in the form of a yellow-orange powder. 0.5 g of crude product 60 is recrystallized from isopropyl ether. 0.34 g of purified product are obtained in the form of a yellow-orange powder, m.p. 132-134 ° C.

The following compounds were prepared according to the procedure of Example 15: 65

6-Formyl-5-methoxycarbonyl-4- (2-methoxycarbonyl-phenyl) -2-methyl-1,4-dihydropyridine-3-carboxylic acid isopropanol ester.

Nuclear Magnetic Resonance Spectrum: δ (CDCl ₃ ) = 0.94 (d, J = 6.5Hz) and 1.19 (d, J = 6.5Hz) (6H), 2.41 (3H, s), δ , 70 (3H, s), 3.97 (3H, s), 4.96 (1H, heptet, J = 6.5Hz), 6.21 (1H, s), 6.82 (1H, broad s) , 7.0-7.9 (4H, m), 10.23 (1H, s) ppm. 4- (2-Cyanophenyl) -5-ethoxycarbonyl-6-phenyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid 2- (N-benzyl-N-methylamino) ethyl ester .

Nuclear Magnetic Resonance Spectrum: δ (CDCl ₃ ) = 1.29 (3H, t, J = 7.5 Hz), 2.21 (3H, s), 2.44 (3H, s), 2.71 (2H) , t, J = 6Hz), 3.51 (2H, s), 4.1-4.4 (4H, m), 5.51 (1H, s), 7.04 (1H, broad s), 7 , 2-7.75 (9H, m), 10.57 (1H, s) ppm. 4- (2-Cyanophenyl) -5-ethoxycarbonyl-6-formyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid 2-ethoxyethyl ester, m.p. 115-116 ° C.

4- (2-Cyanophenyl) -5-ethoxycarbonyl-6-formyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid 2-phenoxyethyl ester, m.p. 104-105 ° C.

4- (2-cyanophenyl) -5-ethoxycarbonyl-6-formyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid 2-benzyloxy-ethyl ester.

Nuclear Magnetic Resonance Spectrum: δ (CDG ₃ ) = 1.28 (3H, t, J = 7Hz), 2.41 (3H, s), 3.5-3.8 (2H, m), 4.0 -4.5 (4H, m), 4.48 (2H, s), 5.48 (1H, s), 6.9-7.5 (10H, m), 10.51 (1H, s) ppm .

Example 16

To a solution of 3.90 g of 4- (2-cyanophenyl) -6-formyl-5-methoxycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid isopropyl ester in 20 ml of acetic acid was added 0.88 g of hydroxylamine. hydrochloride and 1.30 g of sodium acetate were added and the mixture was stirred for 1 hour at room temperature. 3.97 g of acetic anhydride are added to the reaction mixture with stirring, and the mixture is stirred for 1 hour at room temperature and finally for 4 hours at 95-100 ° C. The reaction mixture was allowed to stand at room temperature and the acetic acid was evaporated under reduced pressure. The resulting residue was diluted with water, neutralized with aqueous sodium bicarbonate solution, and extracted twice with ethyl acetate. The extracts were combined, washed twice with water, dried and the solvent evaporated under reduced pressure. The resulting oily residue was allowed to stand overnight and then triturated with a small amount of ethyl ether. The powdered product was washed with isopropyl ether and then recrystallized from methanol. Yield: 1.99 g of 6-cyano-4- (2-cyanophenyl) -5-methoxycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid isopropyl ester, m.p. 198 -200 ° C.

The following compounds were prepared according to the procedure described in Example 16. 6-Cyano-5-methoxycarbonyl-4- (2-methoxycarbonyl-phenyl) -2-methyl-1,4-dihydropyridine-3-carboxylic acid isopropyl ester, m.p. 121.5-123 ° C.

6-Cyano-4- (2-cyanophenyl) -5-ethoxycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid 2- (N-benzyl-N-methylamino) -etilészter- hydrochloride, m.p. 230 DEG C. (dec.).

6-Cyano-4- (2-cyanophenyl) -5-ethoxycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid 2-ethoxyethyl ester, m.p. 135-136 ° C.

6-Cyano-4- (2-cyanophenyl) -5-ethoxycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid 2-phenoxyethyl ester, m.p. 170.5-172 ° C. .

6-Cyano-4- (2-cyanophenyl) -5-ethoxycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid 2-benzyloxyethyl ester, m.p. 132-133 ° C.

Example 17

A solution of isopropyl ester of 4- (2-cyanophenyl) -6-formyl-5-methoxycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid (3.2 g) in ethanol (65 mL) over 10 minutes at 0 ° C. C. while stirring, 0.33 g of sodium borohydride was added dropwise and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was slightly acidified with 50% aqueous acetic acid with cooling (0 ° C) and the ethanol was evaporated under reduced pressure. The resulting residue was diluted with water and the solution was neutralized with sodium bicarbonate and extracted twice with ethyl acetate. The extracts were combined, washed with water and brine, dried, and the solvent was evaporated under reduced pressure. The resulting yellowish viscous oil (3.75 g) was triturated with a mixture of ethyl ether and hexane and the resulting powder (3.19 g) was recrystallized from isopropyl ether containing a small amount of methanol. 1.97 g of 4- (2-cyanophenyl) -6-hydroxymethyl-5-methoxycarbonyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid isopropyl ester are obtained in the form of pale yellow crystals, m.p. 135-137. ° C.

By following the procedure described in Example 17, 6-Hydroxymethyl-5-methoxycarbonyl-4- (2-methoxycarbonylphenyl) -2-methyl-1,4-dihydropyridine-3-carboxylic acid isopropyl ester, m.p. 144-145 ° C.

4- (2-Cyanophenyl) -5-ethoxycarbonyl-6-hydroxymethyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid 2-ethoxyethyl ester, m.p. 127.5-128.5 ° C.

4- (2-Cyanophenyl) -5-ethoxycarbonyl-6-hydroxymethyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid 2-phenoxyethyl ester, m.p. 116-117 ° C.

4- (2-Cyanophenyl) -5-ethoxycarbonyl-6-hydroxymethyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid 2-benzyloxyethyl ester, m.p. 109-110 ° C.

Example 18

This example illustrates the preparation of the starting materials used in the process of the invention.

A solution of 6.56 g of 2-cyanobenzaldehyde, 7.93 g of 4,4-dimethoxyacetacetic acid methyl ester, 0.18 g of acetic acid and 0.17 g of piperidine in 40 ml of benzene is refluxed for 5 hours while stirring. the water formed is removed by azeotropic distillation. The reaction mixture was cooled, diluted with benzene, washed with water and aqueous sodium bicarbonate solution, and dried over magnesium sulfate. The solvent was evaporated and the oily residue (13.75 g) was chromatographed on silica gel (420 g). The eluent was benzene: ethyl acetate (20: 1, v / v). The fractions containing the desired product were combined and the solvent was evaporated under reduced pressure. In the form of a yellowish oil

10.11 g of 2- (2-cyanobenzylidene) -4,4-dimethoxyacetacetic acid methyl ester (cis / trans isomer mixture) are obtained.

Nuclear Magnetic Resonance Spectrum: δ (CDCl ₃ ) = 3.41 (s) and

3.49 (s) (6H), 3.79 (s) and 3.92 (s) (3H), 4.83 (s) and

5.11 (s) (1H), 7.5-8.0 (4H, m), 8.07 (s) and 8.16 (s) (1H) ppm.

By following the procedure described in Example 18, the following compounds were prepared:

2- (2-Methoxycarbonyl-benzylidene) -4,4-dimethoxy-acetacetic acid methyl ester (cis / trans isomer mixture):

Nuclear Magnetic Resonance Spectrum: δ (CDCl ₃ = 3.26 (s) and

3.43 (s) (6H), 3.56 (s), 3.83 (s), 3.87 (s) and 3.89 (s) (6H), 4.67 (s) and 5.13 ( s) (1H), 7.2-8.1 (4H, m), 8.39 (s) and 8.46 (s) (1H) ppm.

- (2-Cyanobenzylidene) -acetic acid 2-chloroethyl ester (cis / trans mixture).

Nuclear Magnetic Resonance Spectrum: δ (CDCl ₃ ) = 2.34 (s) and

2.50 (s) (3H), 3.6-3.9 (2H, m), 4.3-4.6 (2H, m), 7.25-7.9 (4H, m), 8.00 (s) and 7.88 (s) (1H) ppm.

2- (2-Cyanobenzylidene) acetic acid 2-ethoxyethyl ester (cis / trans isomer mixture).

Nuclear Magnetic Resonance Spectrum: δ (CDCl ₃ ) = 1.15 (t, J = 6.5 Hz) and 1.23 (t, J = 6.5 Hz) (3H), 2.35 (s) and 2 , 48 (s) (3H), 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) and 7.91 (s) (1H) ppm.

- (2-Cyanobenzylidene) -acetic acid 2-phenoxyethyl ester (one of the cis and trans isomers), m.p. 102.5-104 ° C.

2- (2-Cyanobenzylidene) -acetic acid 2-benzyloxyethyl ester (cis / trans mixture).

Nuclear Magnetic Resonance Spectrum: δ (CDG ₃ ) = 2.29 (s) and

2.43 (s) (3H), 3.50-3.85 (2H, m), 4.20-4.60 (2H, m), 4.55 (s) and 4.44 (s) (2H) , 7.15-7.85 (9H, m), 7.96 (s) and 7.83 (s) (1H) ppm.

Example 19

4.29 g of 6-formyl-2-methyl-4- (2-cyanophenyl) -5-methoxycarbonyl-1,4-dihydropyridine-3-carboxylic acid n-propyl ester, 0.87 g of hydroxylamine hydrochloride, A mixture of 1.13 g of sodium acetate and 26 ml of acetic acid was stirred at room temperature for 5 hours. To the reaction mixture was added acetic anhydride (5 g) and the mixture was stirred at room temperature for 80 minutes, at 85 ° C for 2.5 hours and finally at 93 ° C for 9.5 hours. After cooling, the solvent was evaporated under reduced pressure, and aqueous sodium bicarbonate solution and methylene chloride were added to the residue. The organic layer was separated, washed with water, dried and the solvent was evaporated. The residue (3.42 g) is chromatographed on 100 g of silica gel using methylene chloride as the eluent. The eluate fractions containing the desired product were combined and evaporated. The resulting residue was recrystallized twice from methanol / water and once from methylene chloride. 2.29 g of n-propyl ester of 6-cyano-2-methyl-4- (2-cyanophenyl) -5-methoxycarbonyl-1,4-dihydropyridine-3-carboxylic acid are obtained as a pure crystalline product, m.p. 150-151.5 ° C.

NMR (CDC1 _3): 0.77 (3H, t, J = 7Hz), 1.59 (2H, sextet, J - 7 Hz), 2.37 (3H, s), 3.74 ( 3H, s), 3.98 (2H, t, J = 7Hz), 5.38 (1H, s), 6.85 (1H, m), 7.0-7.7 (4H, m) ppm.

Example 20

Example 19 was repeated except that 3.39 g of 6-fluorine-2-methyl-4- (2-cyanophenyl) -5-methoxycarbonyl-1,4-dihydropyridine were used as starting materials. -3-Carboxylic acid isobutyl ester, 0.89 g of hydroxylamine hydrochloride, 1.12 g of sodium acetate, 25 ml of acetic acid and 6.24 g of acetic anhydride are used. 1.81 g of isobutyl ester of 6-cyano-2-methyl-1- (2-cyanophenyl) -5-methoxycarbonyl-1,4-dihydropyridine-3-carboxylic acid are obtained, m.p. 196-197. , 5 ° C.

NMR (CDC1 _3): 0.75 (3H, d, J = 7Hz), 0.81 (3H, d, J = 7Hz), 1.97 (1H, m);

2.40 (3H, s), 3.78 (3H, s), 3.85 (2H, d, J = 7Hz),

5.41 (1H, s), 7.02 (1H, m), 7.19-7.68 (4H, m) ppm.

Example 21

Example 19 was repeated except that 3.78 g of 6-formyl-2-methyl-4- (2-cyanophenyl) -5-methoxycarbonyl-1,4-dihydropyridine was used as starting material. 3-Carboxylic acid neopentyl ester, 1.19 g of sodium acetate, 0.97 g of hydroxylamine hydrochloride, 25 ml of acetic acid and 6.4 g of acetic anhydride are used. 1.69 g of 6-cyano-2-methyl-4- (2-cyanophenyl) -5-methoxycarbonyl-1,4-dihydropyridine-3-carboxylic acid neopentyl ester are obtained, m.p. 173.0-174. , 0 ° C.

NMR (CDC1 _3): 0.87 (9H, s);

2.41 (3H, s), 3.79 (3H, s), 3.84 (2H, s), 5.44 (1H, s), 6.85 (1H, m), 7.2-7.8 (4H, m) ppm.

Example 22

2.00 g of a suspension of 6-formyl-2-methyl-4- (2-cyanophenyl) -5-methoxycarbonyl-1,4-dihydropyridine-3-carboxylic acid n-propyl ester in 40 ml of ethanol over 5 minutes, while stirring at -5 ° C to -10 ° C, 0.17 g of sodium borohydride is added. After the addition of the reagent, the reaction mixture was stirred at the same temperature for a further 2 hours. To the reaction mixture was added 0.6 ml of a 50% aqueous acetic acid solution, and the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate, washed with brine, dried, and the solvent was evaporated. 2.04 g of crude crystalline residue are obtained. The crude product was recrystallized from methanol / water. 1.34 g of pure 6-hydroxymethyl-2-methyl-4- (2-cyanophenyl) -5-methoxycarbonyl-1,4-dihydropyridine-3-carboxylic acid n-propyl ester are obtained, m.p. 149.0 -152.5 ° C.

NMR (CDC1 _3): 0.77 (3H, t, J = 7Hz), 1.61 (2H, sextet, J = 7Hz), 2.38 (3H, s), 3.63 ( 3H, s), 3.99 (2H, t, J = 7Hz), 4.79 (2H, s), 5.31 (1H, s), 7.32 (1H, m), 7.1-. 7.6 (4H, m) ppm.

Example 23

Example 22 except that 2.00 g of 6-formyl-2-methyl-4- (2-cyanophenyl) -5-methoxycarbonyl-1,4-dihydropyridine-3-carboxylic acid were obtained. starting from isobutyl ester and 0.18 g of sodium borohydride. 1.49 g of isobutyl ester of 6-hydroxymethyl-2-methyl-4- (2-cyanophenyl) -5-methoxycarbonyl-1,4-dihydropyridine-3-carboxylic acid are obtained, m.p. 134.5-137. , 0 ° C.

NMR (CDC1 _3): 0.75 (3H, d, J = 7Hz), 0.81 (3H, d, J = 7Hz), 1.97 (1H, m.). 2.39 (3H, s), 2.8 (1H, m), 3.64 (3H, s), 3.86 (2H, d, J = 7Hz), 4.81 (2H, s). 5.35 (1H, s) 7.1-7.7 (5H, m) ppm.

Example 24

Example 22 was repeated except that 2.00 g of 6-formyl-2-methyl-4- (2-cyanophenyl) -5-methoxycarbonyl-1,4-dihydropyridine-3-carboxylic acid were obtained. starting from neopentyl ester and 0.16 g of sodium borohydride. 1.54 g of the neopentyl ester of 6-hydroxymethyl-2-methyl-4- (2-cyano-phenyl) -5-methoxycarbonyl-1,4-dihydropyridine-3-carboxylic acid are obtained, m.p. -179.5 ° C.

NMR (CDC1 _3): 0.87 (9H, s), 2.38 (3H, s), 3.63 (3H, s), 3.81 (2H, s), 4.78 (2H , s), 5.33 (1H, s), 7.37 (1H, m), 7.17.6 (4H, m) ppm.

Claims (5)

A process for the preparation of the novel 1,4-dihydropyridine derivatives of the formula (I) and their acid addition salts, wherein: R ¹ is cyano, lower alkoxycarbonyl or lower alkanesulfamoyl, R ² and R ^{3 are C} 1 -C 7 alkoxycarbonyl optionally substituted with halogen, lower alkoxy, phenoxy, phenyl-lower alkoxy, or N- (lower alkyl) -N- (phenyl) a lower alkyl alkylamino group; and R ⁴ and R ^s each represent a lower alkyl group and the other is cyano, 1-hydroxy (Cl-C3) alkyl group, preferably a hydroxymethyl group, l, l-di (lower) alkoxy (C 1 -C 3) -alkyl, preferably 1,1-di-lower-alkoxymethyl, 1.1- ( C 2 -C 4 alkylenedioxy) - (1- C 3 -C 3 alkyl, preferably 1,1- (2- Represents a (C 1 -C 4 alkylene dioxy) methyl group or a (C 1 -C 3) alkyl group, preferably a formyl group, containing an oxo group in the 1-position of the carbon chain, (a) for the preparation of compounds of formula (I-1) which are a narrower group of compounds of formula (I) - wherein R ¹ , R ² and R ³ are as defined in the preamble, and R ⁴ and R 1 are; one is lower alkyl and the other is 1,1-di- (lower) alkoxy (C 1 -C 3) alkyl, preferably 1,1-di (lower) alkoxymethyl, or 1,1-di (lower) alkoxymethyl; - a (C 2 -C 4) -alkylenedioxy (C 1 -C 3) -alkyl group, preferably a (C 1 -C 4) -alkylenedioxymethyl group - a parent compound of formula (II) - wherein R ¹ , R ³ and R a are as defined above - by reaction with an amino compound of formula III wherein R ² and R ⁴ are as defined above or b) for the preparation of compounds of the general formula (1-2) which are a narrower group of the compounds of the formula I - wherein R *, R ² and R ³ are as defined in the scope of the invention and R ¹ and R ¹ are; one represents a lower alkyl group and the other represents a 13-membered alkyl group containing an oxo group in the 1-position of the carbon chain, preferably a formyl group - a compound of the formula (I-1) wherein R *, R ² and R ³ and R * and R * are as defined in (a) - a hydrolyzing agent suitable for cleaving the acetal group, preferably an acid, or c) for the preparation of a compound of formula I, which is a narrower group of compounds of formula I, wherein R ¹ , R ² and R ³ are as defined in the preamble and one of R 1 and R 1 is lower alkyl and the other is cyano. represents a compound of the formula (1-2 ') wherein R *, R ² and R ³ are as defined in the preceding disclosure and one of R 1' and R 4 'is lower alkyl and the other is formyl with hydroxylamine or by reacting with a hydroxylamine salt and treating the resultant product with another dehydrating agent, preferably an inorganic or organic acid, an organic acid anhydride, an inorganic halide or a carbodiimide, to convert the oxime group to a cyano group, or d) for the preparation of compounds of general formula 1-5 which are a narrow group of compounds of general formula 1 - wherein R *, R ² and R ³ are as defined in the preceding claims and R 1 and R 1 are lower alkyl, another represents a 1-hydroxy (1-3C) alkyl group, preferably a hydroxymethyl group - a compound of formula (1-2) 0 - wherein R ¹ , R ² and R ³ are in the scope R 1]. and r6 is as defined in (b), with a reducing agent for converting the oxo group to a hydroxyl group, preferably an alkali metal borohydride or hydrogen in the presence of a catalyst and optionally converting a compound of formula (I) to an acid addition salt; optionally liberating the base of formula (I) from the acid addition salt. The further development of any method according to claim 1 for the preparation of a pharmaceutical composition having a predominantly vasodilating effect, characterized in that a compound of formula (I) - wherein R ¹ , R ² , R ³ R ⁴ and R ⁵ Or a pharmaceutically acceptable acid addition salt thereof, in a known manner using a pharmaceutical diluent, carrier and / or excipient.