HU191853B - Process for prducing 1,4-dihydro-pyridine derviatives and pharmaceutical compositions containing them - Google Patents

Abstract

Compounds having the formula (I) wherein one of the two residues R1 and R2 is the methyl group and the other one is a group selected among isopropyl, n-butyl, isobutyl, cyclopentyl or isopropoxy-ethyl groups and the residue R3 is hydrogen or an optionally substituted alkyl group; these compounds are either in an optically active form when R3 is hydrogen, or in a racemic form or in an optically active form when R3 is an alkyl residue with 1 to 6 atoms of carbon, optionally substituted. Such compounds are used for the treatment of the deficiency of coronaries, cerebro-vascular deficiency, troubles of peripheral circulation, hypertension or asthma.

Description

The present invention relates to novel optically active 1,4-dihydropyridines and to pharmaceutical compositions containing them.

EP-A-150 discloses a large class of 1,4-dihydropyridine derivatives. British Patent Application No. 5,037,766 A discloses several other examples of these compounds.

We have found that it is unknown, optically active

A special class of 1,4-dihydropyridine derivatives

which are neither characterized nor suggested by the patents cited above, exhibit particularly interesting pharmacological properties.

The present invention relates to a process for the preparation of compounds of general formula (I): wherein

R, and R ₂ is methyl and the other isopropyl - η-butyl, or isobutyl and

R ₃ is for the preparation of optically active forms of H or C 1-4 alkyl optionally substituted with di (C 1-4 alkyl) amino and their acid addition salts.

The compounds of formula (I) may be referred to hereinafter as the compounds of the invention.

The two different —CO ₂ R! and the carbon atom of the 1,4-dihydropyridine ring of the compounds of formula I is chiral due to the carboxylic acid ester group of CO ₂ R ₂ .

When C 1-4 alkyl is substituted, dimethylamino is a preferred substituent. Preferred compounds of the invention wherein R and _R2 are each methyl and the other is isopropyl; even more preferred are those compounds wherein, in addition, R _{3 is} hydrogen or C 1-4 alkyl, and particularly preferred are those wherein R _{3 is} hydrogen or methyl, most preferably methyl.

The compounds of formula (I) according to the invention are prepared by: - in one of the optical isomers of a compound of formula (II): wherein R 1 and R ₃ are as defined above and R _{4 is} hydroxy, an azolid or an * a group wherein R * is a hydrocarbon group having one or more electron withdrawing groups substantially free of any chiral epimeric form - R _{4 is} replaced by -OR ₂ - wherein R ₂ is as defined above and optionally a general formula (Ia) A compound of formula I wherein R 1 and R ₂ are as defined above is alkylated on the nitrogen of the 1,4-dihydropyridine ring to give the optically active compound of formula (I), if basic, in the form of the free base or an acid addition salt thereof. separated.

The nitrogen atom of the 1,4-dihydropyridine ring is hereinafter referred to as the 1-N atom.

In the process, the 1-N-alkylated products can be prepared in a conventional manner using the appropriate alkylating agents, for example an alkyl halide, preferably in the presence of a base such as sodium hydroxide.

The 1-N-alkylated products can be isolated in the usual manner. If the 1-N-alkyl group contains a salt-forming group, such as dimethylamino, then the 1-N-alkylated product is available as an acid addition salt. Organic acids suitable for salt formation,

2 for example fumaric acid; or inorganic acids, such as halogen hydrocarbons, such as hydrochloric acid.

In accordance with the present invention, it is possible to proceed conventionally, for example, by starting from a compound of formula II wherein R 4 is a leaving group, such as a hydroxyl or azole group. A suitable azole group is, for example, the imidazolide group of formula (a). It is known that certain azolidcsoportok, especially the group of formula (b) is particularly reactive, and azolilegységük - for example, imidazol-1-yl-unit - can be easily replaced by an ester group, e.g., an _-OR2 radical of the type such that the imidazolide derivative An alcohol of the general formula R ₂ O is added and the components are reacted at elevated temperatures, for example 60-150 ° C.

Other suitable azoles which may be employed include 1,2,3-triazolidine, 1,2,4-triazolidine, benzotriazolid, benzimidazolide and tetrazolide.

The products of the present invention may also be prepared by starting from compounds of formula II wherein R _{4 is} -OR _S and R ₅ is a hydrocarbon group having one or more electron withdrawing groups substantially free of any chiral epimeric form, or an hydrocarbon having an amino group.

A preferred precursor is, for example, a phenylmethoxy group or a quaternary amino group. Preferred amino groups are di (C 1 -C 4 alkyl) amino groups. Preferred quaternary amino groups are tri (C 1 -C 4 alkyl) amino groups. Preferably R _{s is} an ethyl group which at the β-position has electron withdrawing groups or an amino group such as a

Substituted by 2- (R) -methoxy-2-phenylethyl or trimethylammonioethyl or dimethylaminoethyl.

The ester group -CO ₂ R _{5 is} readily convertible to the -CO ₂ R ₂ group due to electron withdrawing groups or amino group, for example, by reaction with an alcohol R ₂ OH, preferably under basic conditions. Other compounds of formula II, for example, when R ₄ is hydroxy, may be reacted in the same manner. The final products can be isolated and purified by methods known per se, if desired in the form of their acid addition salts.

In carrying out the process, for optically active compounds of formula II, R _{4 is} preferably azole or a group -OR *, wherein R * is a chiral hydrocarbon group substantially free of epimeric form and containing one or more electron withdrawing groups.

Scheme A illustrates the preparation of compounds of formula II wherein R 1 is isopropyl, R _{4 is} -OR *, R _{3 is} hydrogen, and R _{5 is} 2- (R) -methoxy-2-phenylethyl. Scheme A also indicates that the optically active two forms of formula (IIb) 1.1 can be separated by chromatography or by selective crystallization.

Scheme B illustrates the preparation of compounds of formula II wherein R 1 is isopropyl, R _{4 is} 1H-imidazol-1-yl and R _{3 is} hydrogen.

In Scheme A, the optically active compounds of formula (IIb.1.1) are separated directly from the corresponding diastereomeric ester mixtures by chromatography. The optically active compounds of formula (IIb.1.3) of Scheme B (IIb.1.3) are prepared from the diastereomeric salt mixture of formula (IIb) 1.2 by selective crystallization.

If the process is carried out on an industrial scale, crystallization for separation is preferable to chromatography.

After isolation, the compounds of formula (IIb.1.1) and (IIb.1.2) are starting materials for the preparation of the final products of formula (I).

Both the chiral ester group of compounds of formula (IIb.1.1) and the proton-dimethylaminoethyl ester group of compounds of formula (IIb.1.2) can be converted to an ester of the formula -OR ₂ . In Scheme B, this is done indirectly and this method of preparation is more preferred. 1

Although, in principle, the compounds of formula (I) may be prepared directly by esterification from the compounds of formula (IIIb.1.2) or, more preferably, of the formula (XI), it is more preferred that the compounds of formula (XI) compounds having a stronger electron withdrawing group, which allows for a second salt crystallization and purification.

Similar to compounds of formula (IIb.1.2), compounds of type (XII) can be directly transesterified to products of formula (I) *. However, it is also possible to convert the ester group by hydrolysis to a 3-carboxylic acid of formula (XIII) to form the final product of formula (I) directly or via the 3-azolid derivative of formula (IIb) 1.3. These reactions can be carried out in the usual manner to give the compounds of the formula I in good yield and in a very pure state.

The process of the invention is described in detail in the following examples, which also describe the preparation of intermediates in Schemes A and B.

Example 1 (-) - (S) - and (+) - (R) -4- (2,3,3-Benzoxadiazol-4-yl) -1,2,6-trimethyl-3- (isopropyl) -oxycarbonyl) -5- (methoxycarbonyl) -1,4-dihydropyridine (example for the preparation of antipodes of a compound of formula I).

a) (+) - (R) - and (-) - (S) -4- (2, 1,3-benzoxadiazol-4-yl) -2,6-dimethyl-3- [2- (R) - methoxy-2-phenylethyloxycarbonyl] -5- (isopropyloxycarbonyl) -1,4-dihydropyridine [(+) - (IIb.1.1) and (-) - (IIb.1.1) Compounds of Formula I].

1. 10.5 g of 2,6-dimethyl-4- (2,3,3-benzoxadiazol-4-yl) -3- (1H-imidazol-1-ylcarbonyl) -5- (isopropyloxy) carbonyl) -1,4-dihydropyridine (compound of formula III) and 35.0 g of (R) - ^! A mixture of -2-methoxy-2-phenylethanol (prepared by W. Kirmse et al. (Chem. Bér. 108, 79, 1975)) was heated at 120 ° C for 7 hours, followed by excess optically active alcohol. distill in very good vacuum at 80-110 ° C. A ^! The residue was dissolved in dichloromethane and extracted with cold 2N hydrochloric acid. The organic layer was dried and concentrated in vacuo.

2. Isopropyl ester of 2-acetyl-3- (2,3,3-benzoxadiazol-4-yl) -2-propenoic acid (3.5 g) (Compound VII); (Z) or ¹ (E) isomer or a mixture thereof], 3.0 g of 3-aminocrotonic acid [2- (R) -methoxy-2-phenylethyl] ester (compound of formula VIII) and 100 ml the dioxane mixture was refluxed for 20 hours and then evaporated to dryness in vacuo.

The diastereomeric mixture of diastereoisomeric 853 2 obtained by Method 1 or 2 is chromatographed on silica gel at 5 atmospheres using 1.5 L of hexane / ether.

The first eluted compound was crystallized from a mixture of ethyl acetate and hexane, m.p. 89 ° C, [ _α ] _{25 D} = -92 ° (in ethanol). Yield: 80%.

| The second eluted compound was crystallized from ether and hexane or a mixture of methanol and water, m.p .: 127 ° C, ^l]? 46 ^{= +} 77 ° (EtOH). Yield: 80%.

) (ii) (+) - (S) -4- (2, 1, 3-benzoxadiazol-4-yl) -2,6-dimethyl-3- (isopropyloxycarbonyl) -5- (methoxycarbonyl) ) Preparation of -1,4-dihydropyridine [Example of preparation of an antipode of a compound of formula (Ia)]

5.3 g of (-) - (S) -4- (2, 1, 3-benzoxadiazol-4-yl) -2,6-dimethyl-3 - [(-) - (R) -methoxy-2-phenylethyl] oxycarbonyl] -5- (isopropyloxycarbonyl) -1,4-dihydropyridine [(II.b.1.1) (-) isomer] in a solution of 03 g of sodium in 100 ml of methanol under reflux for 50 hours under nitrogen After boiling, evaporate in vacuo to half and add '00 ml of ice water. The mixture was extracted with dichloromethane and the organic phase was dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by flash chromatography on silica gel eluting with hexane: ether (1: 4). After recrystallization from a mixture of ether and hexane, the pure (+) - (4S) -enantiomer ((Ia) (+) isomer) had a melting point of 142 ° C, [α] D ₂₅ = + 9.9 ° (ethanol, c = 1). , 5 g / 100 ml), [α] D 20 = + 6.7 ° (ethanol, c = 1.5 g / 100 ml). Yield: 70%.

^O :) - (-) - (S) -4- (2,3-Benzoxadiazol-4-yl) -1,2,6-trimethyl-3- (isopropyloxycarbonyl) -5- (methoxy) preparation of carbonyl) _T 1,4-dilddropyridine [Example of preparation of a veg / excess antipode of formula (I)]

0.7 g of (+) - (4S) - (2,3,3-benzoxadiazol-4-yl) -2,6-dimethyl-3- (isopropyloxycarbonyl) -5- (methoxycarbonyl) To a solution of -1,4-dihydropyridine in 10 ml of dimethylsulfoxide was added 0.43 g of potassium hydroxide, followed by 0.23 ml of methyl iodide, and the mixture was stirred under nitrogen for 1 hour. The mixture was poured into ice water and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by low pressure chromatography on silica gel using dichloromethane / ether (49 L) as eluent. After recrystallization from ether-hexane to give the title compound, melting at 92 ° C, [a] 54 ₆ = -3 ° (ethanol, c = 0.67 g / lOOml), [a]; ₄₆ = -25 ° (chloroform, c = 1.0 g / 100 ml). Yield: 50%.

1) (-) - (R) -4- (2,1,3-Benzoxadiazol-4-yl) -2,6-dimethyl-3- (isopropyloxycarbonyl) -5- (methoxycarbonyl) Preparation of -1,4-dihydropyridine (example for the preparation of an antipode of a compound of formula Ia). This compound was prepared from the (+) - (4R) enantiomer of formula (III.b1.1) prepared in (a) in a similar manner to that described in (b): after recrystallization from ether / hexane, m.p. ₄₆ = -10.1 ° (ethanol, c = 1.67 gj / 103 mL), [α] ° ~ ⁼ -6.7 ° (ethanol, c = g / 100 mL). Yield: 70%.

-) (+) - (R) -4- (2, 1, 3-benzoxadiazol-4-yl) -1,2,6-tri-methyl-3- (isopropyloxycarbonyl) -5- (methoxy) -carbonyl) 1,4-dihydropyridine (example for the preparation of an antipode of a compound of formula I). This compound was prepared from the (-) - (4R) -enantiomer of (d) in a similar manner to that described in (c): after recrystallization from ether / 'hexane, m.p.

-3,191 853 ίαΐίθβ ⁼ + 3.1 ° (ethanol, c = 0.83 g / 100 mL), [α] ^ = _β = + 23 ° (chloroform, c = 1.1 g / 100 ml). Yield: 50%.

The imidazolide of formula (III), used in (a) (1), m.p. -3-Carboxylic acid is reacted with a slight excess of 1,1-carbonyldiimidazole at 50 ° C in a solution of dioxane.

The acid of formula (IV) having a melting point of 213 [deg.] C. is prepared by dissolving the (2-cyanoethyl) ester of the compound of formula (IV) in a solution of 3 molar sodium hydroxide in water / 1,2-dimethoxyethane (2.1). , hydrolyze at room temperature.

The ester of formula (V) having a melting point of 125 ° C, the (2-cyanoethyl) -aminocrotonic acid ester of formula (VI) and the 2-acetyl-3- (2,1,1,3) of formula (VII) benzoxadiazol-4-yl) -2-propenoic acid by reaction with isopropyl ester in dioxane solution.

The ester (VI), m.p. 88 ° C, is prepared by reacting the corresponding acetic acid (2-cyanoethyl) ester with gaseous ammonia in a benzene solution.

The ester (VII) is prepared by reacting the 2,1,3-benzoxadiazole-4-aldehyde with the corresponding acetic acid ester in the presence of a catalytic amount of piperidine and acetic acid at the boiling point of their benzene solution. The ester (VII) crystallizes as a mixture from which the E-isomer with a melting point of 75 ° C and the Z-isomer with a melting point of 55 ° C can be separated.

Example 2 (+) - (S) -4- (2,1,3-Benzoxadiazol-4-yl) -2,6-dimethyl-3- (isopropyloxycarbonyl) -5- (methoxycarbonyl) - Preparation of 1,4-dihydropyridine (Example for the preparation of a compound of formula I)

a) 2,6-Dimethyl-4- (2,1,3-benzoxa-diazol-4-yl) -3- (2-dimethylamino-ethoxycarbonyl) -5- (isopropyloxycarbonyl) ) -1,4-dihydropyridine (Compound IX).

a) 1. 5.0 g of 2,6-dimethyl-4- (2,3,3-benzoxadiazol-4-yl) -3- (isopropyloxycarbonyl-5- (1H-imidazol-1-yl) carbonyl) -1,4-dihydropyridine (compound of formula III), 2-dimethylaminoethanol (24.5 ml) and dioxane (20 ml) were heated at reflux for 5 hours, and ice-water was added and The organic layer was dried over anhydrous magnesium sulfate, evaporated to dryness in vacuo, and the residue purified by chromatography on silica gel using dichloromethane: ether (4: 1) as the eluent. Mp 150 [deg.] C. Yield: 80%.

a) 2. 182.6 g of isopropyl ester of 2-acetyl-3- (2,1,3-benzoxadiazol-4-yl) -2-propenoic acid (Compound VII, mixture of Z and E isomers), 114 A mixture of 3-aminocrotonic acid 2-dimethylaminoethyl ester (1 g) and dioxane (1 L) was refluxed for 16 hours, evaporated to dryness in vacuo, and the residue converted to hydrochloric acid and recrystallized from ethanol / ether. . Yield: 80%.

b) (-) - (S) -4- (2,3-Benzoxadiazol-4-yl) -2,6-dimethyl-3- (2-dimethylaminoethoxycarbonyl) -5- (isopropyl) - oxycarbonyl) -1,4-dihydropyridine (compound of formula XI).

52.6 g of compound of formula IX prepared according to a) and 49.6 g of (-) -di-0,0 '- (4-methylbenzoyl) - (L)-tartaric acid

Dissolve in 200 mL of hot isopropanol and allow to stand. After cooling to room temperature, the precipitated di-0,0 '- (4-methylbenzoyl) - (L)-tartaric acid salt (compound of formula X) is filtered off and isopropanol is added. recrystallize twice and the resulting salt is dried under high vacuum at 90 ° C. The salt thus obtained (m.p .: 146 ° C [αβ ° = -122 ° (ethanol, c = 1 g / 100 mL), [a] D = $ ₆ = - 156 ° (ethanol, c = 1 g / 100 ml)] is converted to compound the title compound (XI) to a dilute sodium hydroxide solution was added and extracted with ether. the thus produced base oil, [cif _n ° = -45 ° (ethanol, c = 1 g / 100 ml ), [α] D 20 = -58 ° (ethanol, c = 1 g / 100 mL) Yield: 40%.

c) (-) - (S) -4- (2,3-Benzoxadiazol-4-yl) -2,6-dimethyl-3- (2-trimethylammonioethoxycarbonyl) -5- (iso) opropyloxy-15 carbonyl) -1,4-dihydropyridine iodide (compound of formula XII).

To a solution of 12.4 g of the compound of formula XI prepared in b) in 120 ml of methanol is added 2.34 ml of methyl iodide and the solution is stirred at room temperature for 15 hours.

Let 2C stand. The crystalline precipitate is filtered and recrystallized from methanol-ether to give the title compound, mp .: 2221, [?] D = -75 ° (ethanol, c = 1 g / / 100 mL), [a] = _é ° j -99 ° (ethanol, c = 1 g / 100 ml). Yield: 95%

d) (+) - (S) -4- (2,3-Benzoxadiazol-4-yl) -2,6-dimethyl-5- (isopropyloxycarbonyl) -1,4-dihydropyridine-3 carboxylic acid] (compound of formula XIH).

The quaternary compound (XII) prepared in (gc) is dissolved in 150 ml of dioxane and after adding 300 ml of 2N aqueous sodium hydroxide solution, it is allowed to stand at room temperature for 16 hours. stir chilled. The crystalline precipitate is filtered off, washed with ice-water and dried under high vacuum at 80 ° C. to yield the title compound, m.p .: 168 ° C [α] θ ° = + 17 ° (ethanol, c = 1 g / 100 mL), [a] s4 ₆ = + 27 ° (ethanol, c = 1 g / 100 mL). Yield: 95%.

^e ) (-) - (S) -4- (2,1,3-Benzoxadiazol-4-yl) -2,6-dimethyl-3-isopropyloxycarbonyl-5- (1H-imidazole-1 ylcarbonyl) 1,4-dihydropyridine (IIb.1.3).

A mixture of the compound of formula XIII prepared according to 8.6 gd, 9.75 g of l'-carbonyldiimidazole and 190 g of dioxane was added in ⁴ ml ^. After heating for 2 hours in a 50 ° C bath with stirring, the mixture is evaporated to dryness in vacuo and the residue is purified by low pressure chromatography on silica gel. Elution was carried out with a 19: 1 mixture of dichloromethane and ethanol. After recrystallization from dichloromethane / ether, the title compound melted at 182 ° C, [α] D = -50 ° (ethanol, c = 1 g / 100 ml), [α] D ₂₀ = -71 ° ethanol, c = 1 g / 100 ml). Yield: 80%.

f) (+) - (S) -4- (2,1,3-Benzoxadiazol-4-yl) -2,6-dimethyl-3- (isopropyloxycarbonyl) -5- (methoxycarbonyl) - Preparation of 1,455-dihydropyridine (Example for the preparation of a compound of the formula I) A solution of the imidazolide IIb.1.3 (50) in methanol (50 g) is refluxed for 16 hours and then evaporated to dryness in vacuo. The residue was purified by low pressure chromatography on silica gel eluting with hexane: ether (1: 3). After recrystallization from a mixture of ether and hexane, m.p. 141 DEG C., [.alpha.] D @ ₂₀ = + 8 DEG (ethanol, c = Ig / 100 ml), [.alpha.] D @ ₂₀ = + 12 DEG (ethanol, c = 1 g / 100 mL). Yield: 85%.

191,853

In a similar manner to that described in Example 1, the following compounds were prepared:

The serial number of the example Ri r ₂ r ₃ Rtcema or antipode Physical constants Month- zam, % Third methyl- isopropyl 2-dimethylamino -ethyl- + m.p. = 92 ° C [a] ³⁰ = + 15 ° [a] IS ₆ = + 20 ° 20 (methanol, c = g / 100 mL), HBr salt mp .: 243 ° C [a] £ ° = + 5 ° C, [a] ₆ = + 8 S ° (methanol, c = 0.6 g / 100 ml ) 4th methyl- isopropyl 2-dimethyl- aminoethyl op.:92°C [a] ³⁰ = -15 [a] l $ ₆ = -20 ° (methanol, c = 1 g / 100 mL), HBr salt mp .: 243 ° C [a] '° = -5 °, [a] i? _Δ = -8 ° (methanol, c = 0.6 g / 100 ml) 20

The compounds of the invention have pharmacological activity.

In particular, the compounds of the present invention exhibit the characteristic effects of calcium antagonists: they have a pronounced muscle relaxant effect, particularly on the smooth muscle, and are expressed in vasodilator and antihypertensive activity using standard assays. For example, in anesthetized cats using the microsphere tracking method [R. Hof et al., Basic Slit. Cardiol. 75, 747 (1980) and 76, 630 (1981), by R. Hof et al., J.Car- diovasc. Pharmacol. 4, 352 (1982)], dilation of coronary arteries is observed when intravenous administration of 1-N-alkylated compounds of formula (I), or from about 5 to about 50 mg / kg. Up to Mg / kg is administered intraduodenally a compound of formula I wherein R ³ is hydrogen. An antihypertensive effect can be observed when 1 to N-alkylated compounds of formula (I) is administered intravenously in an amount of about 5 to about 250 mg / kg, or intravenously in an amount of about 5 to about 50 mg / kg. wherein R ³ is hydrogen.

In alert, genetically hypertonic rats [Gerold and Tschirki method, Arzneimittelforsch. 18, 1285 (1968)], an antihypertensive effect can be observed when from about 0.1 to about 50 mg / kg subcutaneously the 1-N-alkylated compounds of formula (I), or from about 0.1 to about 50 mg / kg. Up to 10 mg / kg is administered subcutaneously to compounds of formula I wherein R ³ is hydrogen.

It is therefore appropriate to use the compounds of the invention as calcium antagonists for the prevention and treatment of the following pathological conditions:

- coronary insufficiency, such as angina pectoris;

- cerebrovascular failure, cerebrovascular accidents such as cerebral haemorrhage, cerebral vasospasm:

Peripheral circulatory disorders such as limb blood supply failure, consequent claudicatio intermittens and convulsions such as colonic cramps;

- asthma, such as asthma breathing difficulties due to exercise; and - hypertension.

The recommended daily dose is from about 5 mg to about 400 mg of the 1-N-alkylated compounds of formula (I), or from about 5 mg to compounds of formula (I) wherein R ³ is hydrogen. up to about 200 mg terje45 de amount. This amount is about 1.25 mg for 1-N-alkylated compounds of formula (I) ^; divided into doses of about 200 mg, or, for compounds of formula I wherein R ₃ is hydrogen, at doses of about 50 1.25 mg to about 100 mg, 2 to 4 times daily, or the active ingredient is administered in a slow release form, preferably orally. A recommended daily dose is, for example, from about 5 mg to about 200 mg, preferably from about 10 mg to about 50 mg, of the compounds of Example le).

Preferred active ingredients are the title compound of Examples 1b and le.

Preferably, the 1-N-alkylated compounds of formula (I) and θθ, particularly when administered intravenously, have a slow onset of action and a longer duration than h; administered intraduodenally. These compounds have approximately the same activity (approximately equipotent) when administered intraduodenally or intravenously. Because of their slow onset and persistence, and thus fewer side effects, these compounds are safer for intravenous administration than other 1,4-dihydropyridine derivatives.

Compounds of the present invention having the S configuration, such as the title compounds of Examples 1b) and le), exhibit a more favorable pharmacological profile than their corresponding R configuration compounds.

The compounds of the invention are administered in free form or, where possible and appropriate, in the form of their pharmaceutically acceptable acid addition salts. The effect of such salts is of the same magnitude as that of the free bases and is readily prepared by conventional means.

The invention also relates to pharmaceutical compositions comprising a compound of the invention in the form of the free base or, where possible and appropriate, in the form of a pharmaceutically acceptable acid addition salt thereof, together with a pharmaceutically acceptable carrier or diluent.

These pharmaceutical compositions may be prepared, for example, in the form of a solution or tablet.

Claims (6)

Claims A process for the preparation of an optically active compound of formula (I) wherein: One of R ₁ and R ₂ is methyl, the other is isopropyl, η-butyl, or isobutyl, and; R ₃ is hydrogen or optionally di (C 1 -C 4 alkyl) and their acid addition salts, characterized in that one of the optical isomers of a compound of formula (II) - wherein R 1 and R ₃ are as defined above , and R ₄ is hydroxy, an azolide, or an OR * group wherein R * is a hydrocarbon group containing one or more electron withdrawing groups substantially free of any chiral epimeric form - the R ₄ group is replaced by an OR ₂ group wherein R ₂ is as defined above in 191 853 and, if desired, the resulting optically active compound of formula (I) wherein R 1 and R ₂ are as defined above and R _{3 is} hydrogen is a 1,4-dihydropyridine ring nitro The compound of formula (I) thus obtained is optionally converted into an acid addition salt. 2. A process according to claim 1 wherein the starting material is a compound of formula II wherein R ₄ is - OR * and R ₂ 1C represents methyl or isopropyl. The process according to claim 1, which is (-) - (S) -4- (2,1,3-benzoxadiazol-4-yl) -1,4-dihydro-5-methoxycarbonyl 1,2,6-trimethyl For the preparation of isopropyl ester of -3-pyridine carboxylic acid, characterized in that (+) - (4S) - (2,1,3-benzo [15] oxadiazol-4-yl) -1,4-dihydro-5-methoxycarbonyl N-methylated to -2,6-dimethyl-3-pyridine carboxylic acid isopropyl ester. 4. A process according to claim 1 (I) - wherein R ¹ and R ² substituents kö20 zul represents a methyl group, the other is isopropyl, and R ³ is hydrogen - Preparation antipodes, characterized in that a Starting from the compound of formula (II) wherein R ¹ and R ³ are as defined above, R ⁴ is -OR ^{5 K} and the dihydropyridine The configuration of the asymmetric carbon atoms of the 25 rings corresponds to the desired antipode. The process according to claim 1, wherein the compounds of formula I are one of the substituents R ¹ and R ² being a methyl group and the other being an isopropyl group, 30 and R ³ are for the preparation of antipodes of C 1 -C 4 alkyl, characterized by starting from a compound of formula II wherein R ¹ and R ³ are as defined above, R ⁴ is -OR ^SK , and the dihydro- The configuration of the asymmetric carbon atom of the pyridine ring corresponds to the desired antipode. 6. A process for the preparation of a medicament for the prevention and treatment of coronary artery, cerebral vascular dysfunction, peripheral circulatory disorders, hypertension or asthma, comprising: or a pharmaceutically acceptable acid addition salt thereof, in admixture with customary diluents, carriers and excipients, in the form of pharmaceutical compositions.