CH660190A5 - 1,4-DIHYDROPYRIDINE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL PREPARATIONS CONTAINING THE SAME. - Google Patents

Description

The present invention relates to 1,4-dihydropyridine derivatives, processes for their preparation and pharmaceutical preparations containing them.

The invention accordingly relates to 1,4-dihydropyridine-3,5-dicarboxylic acid esters in the pyridine ring at the position adjacent to the nitrogen atom by cyan and at the position opposite the nitrogen atom by a condensed ring system which has at least two different heteroatoms and at least one optionally substituted aromatic Ring contains, are substituted and are optionally also substituted at the other positions of the pyridine ring, with the proviso that if the 1,4-di-hydropyridine-3,5-dicarboxylic acid esters are alkyl esters each having 1 to 6 carbon atoms in the alkyl part, im Dihydro-pyridine ring the nitrogen atom is unsubstituted and the other position adjacent to the nitrogen atom is substituted by methyl and the condensed ring system opposite the nitrogen atom in position 4 is bound 2,1,3-benzoxadiazolyl or 2,1,3-benzothiadiazolyl radicals, then these residues in the phenyl ring are substituted in free form or, if necessary s in salt form.

These compounds are briefly referred to below as “the compounds according to the invention”.

Those compounds according to the invention in which the nitrogen atom of the 1,4-dihydropyridinyl part is unsubstituted fall under the general disclosure of Fujisa-was German Offenlegungsschrift (DOS) No. 26 29 892. However, in this DOS there are neither specific compounds similar to the compounds according to the invention still reveals obvious. The compounds according to the invention have a particularly interesting pharmacological profile.

The prior art can be illustrated by the following disclosures:

Sandoz EP-A 150 Fujisawa DE-A 26 29 892 Fujisawa DE-A 29 40 833 Fujisawa DE-A 29 35 772 Sandoz DE-A 29 49 464

The linked ring system consists e.g. from a 2,1,3-benzoxadiazolyl or 2,1,3-benzothiadiazolyl ring.

According to the invention, preference is given to 1,4-dihydropyridine-3,5-dicarboxylic acid esters of the formula I

YOOC

COOZ

wherein

X represents oxygen or sulfur;

R for hydrogen; Alkyl of 1 to 4 carbon atoms; Alkoxy of 1 to 4 carbon atoms; Alkylthio of 1 to 4 carbon atoms; Alkylsulfonyl of 1 to 4 carbon atoms; Halogen with an atomic number from 9 to 35; Trifluoromethyl; Nitro or hydroxy;

Ri means: hydrogen; Alkyl of 1 to 6 carbon atoms; Alkenyl having 3 to 6 carbon atoms, the double bond being separated from the nitrogen atom by at least one carbon atom which is not involved in the double bond; Alkynyl having 3 to 6 carbon atoms, the triple bond being separated from the nitrogen atom by at least one carbon atom which is not involved in the triple bond; Cycloalkyl of 3 to 7 carbon atoms; Cycloalkylalkyl of 4 to 8 carbon atoms; Hydroxyalkyl of 2 to 6 carbon atoms, the hydroxy part being separated from the nitrogen atom by at least 2 carbon atoms;

Alkoxyalkyl with 2 to 6 carbon atoms or optionally substituted phenylalkyl with 7 to 9 carbon atoms or phenylalkenyl with 9 to 12 carbon atoms, the double bond being separated from the nitrogen atom by at least one carbon atom which is not involved in the double bond and the two latter radicals optionally being mono- or are identical or different di- or identical or different tri-substituted by independently of one another alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, halogen with an atomic number of 9 to 35 or hydroxy.

R2 for hydrogen; Alkyl having 1 to 6 carbon atoms or cyan and

COOY and COOZ independently of one another represent carboxylic ester residues,

with the proviso that if Y and Z are each alkyl with 1 to 6 carbon atoms, Ri is hydrogen and R: methyl and the dihydropyridinyl part is bonded to the 4-position of the condensed ring system, then R is not hydrogen.

The disclaimers in claims 1 and 2 represent a differentiation from EP application 80220 (FISONS), which was only disclosed after the filing date of the present application.

In a subset of compounds of formula I, R2 is hydrogen or alkyl. In another subgroup, R2 stands for cyan.

The 1,4-dihydropyridinyl part is preferably attached to the 2,1,3-benzoxadiazolyl or 2,1,3-benzothiadiazolyl part at a position of the benzene ring component of the latter which is adjacent to the oxadiazolyl or thiadiazolyl ring component.

X is preferably oxygen.

R preferably represents hydrogen.

Ri is preferably hydrogen. If it is not hydrogen, it preferably means alkyl having 1 to 6 carbon atoms, cycloalkylalkyl having 3 to 7 carbon atoms, optionally substituted phenylalkyl having 7 to 9 carbon atoms or

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Alkoxyalkyl with 2 to 6 carbon atoms, preferably alkyl with 1 to 6 carbon atoms or alkoxyalkyl with 2 to 6 carbon atoms, in particular alkyl with 1 to 6 carbon atoms.

R2 preferably represents alkyl or cyano, especially alkyl. COOY and COOZ are preferably COOR3 and COOR4, respectively

R3 and R.4 independently of one another are: alkyl having 1 to 12 carbon atoms; Hydroxyalkyl of 2 to 12 carbon atoms, the hydroxy part being separated from the carbonyloxy radical by at least 2 carbon atoms; Alkoxyalkyl having 3 to 12 carbon atoms, the alkoxy part being separated from the carbonyloxy radical by at least 2 carbon atoms; Alkenyl having 3 to 6 carbon atoms, the double bond being separated from the carbonyloxy radical by at least one carbon atom which is not involved in the double bond; Alkynyl having 3 to 6 carbon atoms, the triple bond being separated from the carbonyloxy radical by at least one carbon atom which is not involved in the triple bond; Cycloalkyl of 3 to 7 carbon atoms; Cycloalkylalkyl of 4 to 8 carbon atoms; Hydroxyalkoxyalkyl having 4 to 8 carbon atoms, the hydroxyalkoxy part being separated from the carbonyloxy radical by at least 2 carbon atoms and the hydroxy part being separated from the oxygen atom of the alkoxy part by at least 2 carbon atoms; Phenyl or phenylalkyl with 7 to 10 carbon atoms, optionally mono- or identically or differently disubstituted in the phenyl ring by alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms or halogen with an atomic number from 9 to 35; or aminoalkyl with 2 to 6 carbon atoms, the nitrogen atom being separated from the carbonyloxy radical by at least 2 carbon atoms and the amino part optionally being mono- or identical or differently disubstituted by alkyl having 1 to 4 carbon atoms, phenyl, phenylalkyl having 7 to 10 carbon atoms or in the phenyl ring by alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms or halogen with an atomic number from 9 to 35 mono- or identically or differently disubstituted phenyl or phenylalkyl with 7 to 10 carbon atoms.

COOY and COOZ are preferably different.

R.3 and R4 are preferably independently of one another alkyl, alkoxyalkyl, cycloalkylalkyl or optionally substituted aminoalkyl, in particular alkyl or optionally substituted aminoalkyl, in particular alkyl.

If R 1 is alkyl, it is preferably unbranched on the carbon atom which is adjacent to the nitrogen atom. If R 1 is alkoxyalkyl, its alkoxy part is preferably separated from the nitrogen atom of the 1,4-dihydropyridinyl radical by at least 2 carbon atoms.

Alkyl with 1 to 12 carbon atoms preferably contains 1 to 6, in particular 1 to 4 carbon atoms, it preferably means methyl, ethyl or isopropyl. Alkyl with 1 to 6 carbon atoms preferably contains 1 to 4, in particular 1 or 2, carbon atoms, it means in particular methyl. If alkyl having 1 to 4 carbon atoms represents a phenyl ring or amino substituent in a radical R 1, R 3 and / or R 1, it preferably contains 1 or 2 carbon atoms and in particular means methyl. If alkoxy with 1 to 4 carbon atoms represents a phenyl ring substituent in a radical R 1, R 3 and / or R 4, it preferably contains 1 or 2 carbon atoms and in particular means methoxy. If halogen with an atomic number of 9 to 35 represents a phenyl ring substituent in a radical R 1, R 3 and / or R 4, it preferably means chlorine or bromine, in particular chlorine.

Alkenyl and / or alkynyl preferably contain 3 carbon atoms. Cycloalkyl and / or the cycloalkyl part of cycloalkylalkyl preferably contain 3, 5 or 6 carbon atoms, in particular 5 or 6 carbon atoms.

The alkylene part of cycloalkylalkyl and / or of optionally substituted phenylalkyl with 7 to 9 carbon atoms or with 7 to 10 carbon atoms preferably contains 1 or 2 carbon atoms, it means in particular methylene.

The alkenylene radical of optionally substituted phenylalkenyl preferably contains 3 carbon atoms.

The alkylene part of hydroxyalkyl with 2 to 6 carbon atoms and / or of alkoxyalkyl with 2 to 6 carbon atoms and / or of hydroxyalkoxyalkyl and / or of optionally substituted aminoalkyl preferably contains 2 or 3, in particular 2, carbon atoms.

The alkylene part of hydroxyalkyl with 2 to 12 carbon atoms preferably contains 2 to 6, in particular 2 or 3, in particular 2 carbon atoms. Alkoxyalkyl having 3 to 12 carbon atoms and / or having 2 to 6 carbon atoms preferably contains 3 to 6, in particular 3, carbon atoms.

The hydroxy part of hydroxyalkyl and / or hydroxyalkoxyalkyl and / or the amino part of aminoalkyl are preferably attached to the most distant, end-chain carbon atom. Hydroxyalkyl with 2 to 12 carbon atoms preferably contains 2 to 6, in particular 2, carbon atoms. The alkoxy part of hydroxyalkoxyalkyl preferably contains 2 carbon atoms. The alkoxy part of alkoxyalkyl preferably contains 1 or 2 carbon atoms, it means in particular methoxy.

If a phenyl ring occurs in a substituent, it is preferably unsubstituted. If it is substituted, it is preferably monosubstituted, preferably in the para position. If it is disubstituted, it is preferably substituted in the ortho and para positions. If it is trisubstituted, it is preferably substituted in the meta, meta and para positions. Alkoxy and / or halogen are preferred substituents of a phenyl ring substituent. If the phenyl ring is polysubstituted, the substituents are preferably identical.

The amino part of aminoalkyl is preferably substituted, in particular disubstituted. Preferred substituents of the amino part of aminoalkyl are alkyl and / or optionally substituted phenylalkyl. The amino part of aminoalkyl is preferably disubstituted by alkyl and optionally substituted phenylalkyl.

A preferred group of compounds of the formula I consists of the compounds of the formula Ia,

: or where X, R and Ri to R4 have the above meaning.

In a subgroup of compounds of the formula Ia, the 1,4-dihydropyridinyl part is bonded to the 4-position of the 2,1,3-benzoxadiazolyl or 2,1,3-benzothiadiazolyl part. In another subgroup, R is hydrogen. In a further subgroup, the 1,4-dihydropyridinyl part is bonded to the 4-position of the 2,1,3-benzoxadiazolyl or 2,1,3-benzothiadiazolyl part and R is hydrogen.

Another group of compounds of the formula I consists of the compounds of the formula Ip,

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IP

bonds, corresponding unsubstituted compounds N-substituted.

In particular, the compounds of the formula I are obtained by 5 a ') on the nitrogen atom of the 1,4-dihydropyridinyl residue adjacent position in compounds of the formula II,

wherein COOY and COOZ have the above meaning;

Rf means: hydrogen; Alkyl of 1 to 6 carbon atoms; Alkenyl having 3 to 6 carbon atoms, the double bond being separated from the nitrogen atom by at least one carbon atom which is not involved in the double bond; Hydroxyalkyl of 2 to 6 carbon atoms, the hydroxy part being separated from the nitrogen atom by at least 2 carbon atoms; Alkoxyalkyl having 2 to 6 carbon atoms or phenylalkyl having 7 to 9 carbon atoms or phenylalkyl having 9 to 11 carbon atoms, the double bond being separated from the nitrogen atom by at least one carbon atom which is not involved in the double bond; and

Rf represents hydrogen or alkyl having 1 to 4 carbon atoms.

In a subgroup of compounds of the formula Ip, Y and Z independently of one another denote alkyl having 1 to 12 carbon atoms; Hydroxyalkyl of 2 to 12 carbon atoms, the hydroxy part being separated from the carbonyloxy radical by at least 2 carbon atoms; or alkoxyalkyl having 3 to 12 carbon atoms, the alkoxy part being separated from the carbonyloxy radical by at least 2 carbon atoms.

Another group of compounds of the formula I consists of the compounds of the formula I

YOOC

II

wherein

2Q X, R, Ri, COOY and COOZ have the above meaning, Q stands for the oxime radical and

Q 'represents the oxime radical or has the meaning given for R2 above,

a cyano group from the oxime residue by elimination of water

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forms or b ') for the preparation of compounds of the formula I',

rN v

YOOC

X

R, 00C

40

xroRi

Is what

X, R, R2, COOY and COOZ have the above meaning and

R ', with the exception of hydrogen having the meaning given above for Ri, corresponding compounds of the formula I ",

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1

wherein

R® is hydrogen or alkyl of 1 to 4 carbon atoms;

R | represents alkyl having 1 to 4 carbon atoms and

RJand R | independently of one another means alkyl having 1 to 4 carbon atoms or aminoalkyl having 1 to 4 carbon atoms, the nitrogen atom being separated from the carbonyloxy radical by at least 2 carbon atoms and the amino part being identical or differently disubstituted by alkyl having 1 to 4 carbon atoms or phenylalkyl having 7 to 10 carbon atoms .

Another object of the invention is a method according to which the compounds according to the invention are obtained by a) at the nitrogen atom of the 1,4-dihydropyridinyl ring adjacent position in compounds which have an oxime residue at the corresponding position, from the oxime residue by elimination of water a cyano group forms, or b) for the preparation of compounds according to the invention substituted on the nitrogen atom of the 1,4-di-hydropyridinyl part

YOOC

50

I "

wherein X, R, R2, COOY and COOZ have the above meaning, N-substituted.

Process variants a and b can be carried out analogously to known methods.

Process variant a represents a conversion to nitrii.

If in the starting material both ring positions adjacent to the nitrogen atom of the 1,4-dihydropyridinyl part are substituted by a radical capable of conversion into a cyano group, a cyano group can be formed at both positions at the same time. Preferably, both residues capable of conversion are identical.

The radical capable of conversion into a cyano group represents the oxime radical -CH = NOH. The conversion to

660190

6

Nitrii is an elimination of water from an oxime. A preferred water elimination agent is acetic anhydride. The reaction is preferably carried out at elevated temperature, e.g. from about 80 to about 160 ° C, preferably from about 100 to about 140 ° C.

Process variant b represents a substitution of a secondary amine.

It can be used under the reaction conditions of N-alkylation of a secondary amine, e.g. be carried out with a suitable halide, or reductively. One can expediently proceed in more than one stage.

If there are potentially reactive groups such as hydroxy or primary or secondary amino, it may be appropriate to initially carry out process variants a and / or b with these groups in a protected form, e.g. for phenolic hydroxy in the form of a benzyloxy group, or for aliphatic hydroxy in the form of a tetrahydropyranyloxy group or for amino in the form of an acylamino or phthalimido group and then converting the protected groups into the desired substituents, e.g. Bonzyloxy in hydroxy, e.g. hydrogenolytic; Tetrahydropyranyloxy in hydroxy, e.g. by acid hydrolysis; and protected amino in unprotected amino, e.g. by acidic hydrolysis or hydrazinolysis.

The compounds according to the invention can be isolated and purified from the reaction mixture in a known manner.

The compounds according to the invention can be in free form or optionally in salt form. The free forms are normally neutral, unless there are ionizable substituents. Salts can exist e.g. if ionizable substituents, such as amino or phenolic hydroxy, are present. Salts can be obtained in a known manner from the compounds in free form and vice versa. Suitable acids for the formation of acid addition salts are e.g. Hydrogen chloride, malonic, p-toluenesulfonic and methanesulfonic acid. Suitable bases for the formation of anionic salts are e.g. Sodium and potassium hydroxide.

If the radicals in positions 2 and 6 and / or in positions 3 and 5 of the 1,4-dihydropyridinyl radical are different, the carbon atom in the 4-position is asymmetrically substituted. The corresponding compounds according to the invention can therefore occur in racemic form or in the form of the individual enantiomers.

The individual enantiomers can be obtained analogously to known methods, e.g.

1. by chromatography using optically active adsorbents, e.g. acylated cellulose derivatives or polymeric amino acid derivatives;

2. by fractional crystallization of salts using optically active acids or bases for salt formation, if appropriate after prior hydrolysis to give corresponding carboxylic acids and with subsequent appropriate esterification; or

3. using appropriate optically active starting products. In this case the fractionation can be carried out on intermediate products, e.g. on corresponding compounds which are substituted in the pyridine ring on the nitrogen atom of the 1,4-dihydropyridine skeleton adjacent by an acetal group -CH (OCH3) 2 or -CH (OCH2CH3) 2 or by a formyl group. Expediently, acetal or formyl compounds in the form of a corresponding mixture of diastereoisomers are used for the fractionation. Mixtures of diastereoisomers can be prepared analogously to known methods, e.g. using compounds bearing a substituent that contains another, but uniformly configured asymmetry center, e.g. as part of one of the carboxylic ester residues. Preferred as asymmetric, uniformly configured carboxylic acid ester residues are residues with electron-withdrawing substituents, e.g. [2- (R) -methoxy-2-phenylethyl] oxycarbonyl. After performing the fractionation, existing asymmetric auxiliary residues can be replaced by known methods, e.g. by transesterification.

Fractionation variant 3 using dia-stereoisomeric esters with subsequent transesterification is particularly preferred if the chiral ester residues to be used in the transesterification are more reactive than the other carboxylic ester residue on the 1,4-dihydropyridine skeleton, e.g. if it is desired to introduce the remainder of a primary or secondary alcohol by transesterification and the other carboxylic ester residue on the 1,4-dihydropyridine skeleton represents the remainder of a secondary or tertiary alcohol.

The starting products can be obtained analogously to known methods.

Suitable starting compounds in which the oxime group -CH = NOH represents the radical capable of conversion into a cyano group are obtained, for example by cyclization of corresponding 2-acyl-3-aryl-2-propenoic esters with corresponding 3-amino-3-dimethoxymethyl- (or -3-diethoxymethyl) -2-propenoic esters, subsequent hydrolysis of the acetal compounds thus obtained and subsequent reaction of the so Formyl compounds obtained with hydroxyamine.

Analogously to that set out above for the compounds according to the invention, the starting products, in particular the acetal, formyl and oxime intermediates, can also be present in free form and, if appropriate, in salt form.

Insofar as the production of the required starting materials is not described, they are known or can be produced by methods known per se or analogously to the methods described here or analogously to methods known per se.

In the following examples, all temperatures are given in degrees Celsius without corrections.

Example 1: 4- (2, 1,3-benzoxadiazol-4-yl) -6-cyan-1,4-dihydro-5-methoxycarbonyl-2-methyl-3-pyridinecarboxylic acid isopropyl ester (process variant a)

(Formula I: Y = isopropyl; Z = methyl)

To the solution of the crude 4- (2,1,3-benzoxadiazol-4-yl) -6-hydroxyiminomethyl-l, 4-dihydro-5-methoxycarbonyl-2-methyl-3-pyridinecarboxylic acid isopropyl ester prepared as described below is added Without further purification, 5 ml of acetic anhydride, the solution is heated to a bath temperature of 120 ° for 4 hours, allowed to cool, diluted with ice water and extracted with methylene chloride. The organic phase is washed with saturated aqueous sodium bicarbonate solution, dried with magnesium sulfate and evaporated under vacuum. The title compound is obtained (mp. 196 ° from ether).

The starting material is obtained as follows:

a) A solution of 22.8 g of 2-acetyl-3- (2, l, 3-benzoxadia-zol-4-yl) -2-propenoic acid isopropyl ester and 14.6 g of 3-amino-3-dimethoxymethyl-2 methyl propenate in 500 ml of dioxane is heated to reflux for 48 hours and the solution obtained is evaporated in vacuo. This gives the isopropyl 4- (2, 1,3-benzoxadiazol-4-yl) -6-dimethoxymethyl-1,4-dihydro-5-methoxycarbonyl-2-methyl-3-pyridinecarbonate (mp. 99 ° - from hexane / ether).

b) A solution of 18 g of the acetal obtained as described under a in 360 ml of dioxane is mixed with 54 ml of 6N aqueous hydrochloric acid and the mixture thus obtained is stirred for 4 hours at room temperature. Then it is poured onto ice-water, extracted with methylene chloride, the organic phase is dried with magnesium sulfate and concentrated in vacuo

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steamed. This gives the isopropyl 4- (2, 1,3-benzoxadiazol-4-yl) -6-formyl-1,4-dihydro-5-methoxycarbonyl-2-methyl-3-pyridinecarboxylic acid (mp. 127 ° - from ether / hexane).

The same formyl compound is obtained if the procedure is carried out starting from the corresponding diethoxymethyl compound (prepared as described above under a), using methyl 3-amino-3-diethoxymethyl-2-propenate instead of 3-amino-3-dimethoxymethyl-2- propenoic acid methyl ester).

c) 1.0 g of hydroxylamine hydrochloride and 3.2 g of sodium acetate are added to a solution of 5 g of the formyl compound obtained as described under b above in 150 ml of glacial acetic acid and the mixture is stirred for 90 minutes at room temperature. The 4- (2, l, 3-benzoxadiazol-4-yl) -6-hydroxy-iminomethyl-l, 4-dihydro-5-methoxycarbonyl-2-methyl-3-pyridinecarboxylic acid isopropyl ester (processed raw) is obtained.

Example 2: (+) -4- (2, 1, 4-Benzoxadiazol-4-yl) -6-cyan-1, 4-di-hydro-5-methoxycarbonyl-2-methyl-3-pyridinecarboxylic acid isopropyl ester

(Right-hand enantiomer of the title compound of Example 1)

The title compound is obtained analogously to Example 1, starting from the corresponding optically active oxime compound and with an additional final chromatography on silica gel using methylene chloride / ether (49: 1) as eluent (mp. 157 ° from ether) ; [cc] b ° = + 215 °, [a] 546 + 300 ° (ethanol, c = 0.42 g / dl).

The oxime compound used as the starting product is obtained as follows:

a) 3-Amino-3-dimethoxymethyl-2-propenoic acid methyl ester is reacted with (-) (R) -2-methoxy-2-phenylethanol at 100 ° C. in the presence of sodium hydride and the oil obtained is purified by chromatography on silica gel using hexane / ether (2: 1) as eluent: the 3-amino-3-dimethoxymethyl-2-propenoic acid obtained [2- (R) - methoxy-2-phenylethyl] ester {[cx] d = - 38 °, [cc] ^ = - 45 ° (methanol, c = 0.58 g / dl)} is set as described in Example 1 under a with 2-acetyl-3- (2, l, 3-benzoxadiazol-4- yl) -2-propenoic acid, and the resulting diastereoisomer mixture is separated by chromatography over a 100-fold excess of silica gel, using hexane / ethyl acetate (5: 1) as the eluent. The eluted 4- (2, 1,3-benzoxadiazol-4-yl) -2-dimethoxymethyl-1,4-dihydro-5-isopropoxycarbonyl-6-methyl-3-pyridinecarboxylic acid [2- (R) -methoxy- 2-phenylethyl] esters are obtained in two separate fractions, each containing 1 diastereoisomer:

first diastereoisomer (oil): [cc] d = - 29 ° (ethanol, c = 0.86 g / dl); second diastereoisomer (oil): [a] o = - 2 ° (ethanol, c = 0.6 g / dl).

In a variant of the above fractionation method, the diastereoisomer mixture obtained is first hydrolyzed to the diastereoisomer mixture of the corresponding 2-formyl derivative. This is then separated in an analogous manner and the isolated formyldiastereoisomers obtained are reacted separately again to give the corresponding acetal diastereoisomers above.

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b) A mixture of 6.5 g of the first diastereoisomer obtained as described under a in 0.3 g of sodium in 65 ml of methanol is stirred for 3 hours under nitrogen and at a bath temperature of 100 °. The mixture is then added to a cold IN aqueous solution of hydrochloric acid; the mixture is extracted with methylene chloride, the organic phase is dried over magnesium sulfate and the solvent is evaporated off under vacuum. The residue is chromatographed on silica gel using methylene chloride / ethyl acetate (19: 1) as eluent. The (+) -4- (2, l, 3-benzoxadiazol-4-yl) -6-dimethoxymethyl-l, 4-dihydro-5-methoxycarbonyl-2-methyM-nvridicarboxylic acid isopropyl ester (mp. 93 ° - from ether / hexane);

[cc] d = + 38 °, [a] R | 546 = + 53 ° (ethanol, c = 0.47 g / dl).

c) The (+) acetal obtained as described under b is hydrolyzed as described in Example 1 under b. The (+) -4- (2, l, 3-benzoxadiazol-4-yl) -6-formyl-l, 4-dihydro-5-methoxycarbonyl-2-methyl-3-pyridinecarboxylic acid isopropyl ester (mp 148 ° - from ether); [a] 5 ° = + 153 °, Ms46 = + 220 ° (ethanol, c = 0.7 g / dl).

d) The (+) -formyl compound obtained as described under c is reacted as described in Example 1 under c. The (+) -4- (2, l, 3-benzoxadiazol-4-yl) -6-hydroxyiminomethyl-1,4-dihydro-5-methoxycarbonyl-2-methyl-3-pyridinecarboxylic acid isopropyl ester (crude) is obtained.

Example 3: (-) -4- (2, 1, 3-Benzoxadiazol-4-yl) -6-cyano-1, 4-di-hydro-5-methoxycarbonyl-2-methyl-3-pyridinecarboxylic acid isopropyl ester

(Left-handed enantiomer of the title compound of Example 1)

The title compound is obtained ((mp. 157 ° - from ether); [a] 2D ° = -212 °, [a] 126 = -295 ° (ethanol, c = 0.79 g / dl)} analogously to Example 2 , based on the corresponding optically active oxime compound.

The oxime compound used as the starting product is obtained analogously to Example 2, using the second diastereoisomer obtained as described in Example 2 under a.

Example 4: 4- (2, l, 3-benzoxadiazol-4-yl) -6-cyan-l, 4-dihydro-

5-methoxycarbonyl-1,2-dimethyl-3-pyridinecarboxylic acid isopropyl ester

(Formula I: Y = isopropyl; Z = methyl)

A mixture of 1.25 g of 4- (2, l, 3-benzoxadiazol-4-yl) -

6-cyan-l, 4-dihydro-5-methoxycarbonyl-2-methyl-3-pyridine-carboxylic acid isopropyl ester in 25 ml of methylene chloride; 25 ml 40% sodium hydroxide solution; 0.62 ml dimethyl sulfate; and 0.1 g of tetrabutylammonium bromide is stirred at room temperature for 1 hour. Then it is diluted with ice water, extracted with methylene chloride, the organic phase is dried with magnesium sulfate and evaporated in vacuo. The product is purified by chromatography on silica gel using methylene chloride as the eluent. The title compound (oil) is obtained.

Analogously to Example 1, the following compounds according to the invention are obtained (based on formula I below):

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At- Ri Rî Y Z R position of the X Smp.

game 1,4-dihydropy

No ridinrestes on the linked ring system

5

H

Me

Me

6

H

Me

Et

7

H

Me

- (<

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H

Me

Me

9

Me

Me iPr

10 *

H

CN

iPr iPr H 4 On 187 °

Et H 4 On 152 °

: Me H 4 On 115 °

- (CH2) 2N (Me) BzH 4 0 n 140 °

ch 222 °

Me H 4 0 oil

Me H 4 0

Bz = benzyl, Et = ethyl, iPr = isopropyl, Me = methyl, ch = in acid addition salt form as hydrochloride, n = in free form ♦ starting from the corresponding compound of formula II, in which Q and Q 'represent -CH = NOH

The compounds according to the invention, in free form or, if appropriate, in the form of their physiologically tolerable salts, are distinguished by interesting pharmacodynamic properties. They can be used as a medicine.

They show typical effects for calcium antagonists. They have a pronounced muscle relaxant effect, especially on smooth muscles, as can be seen from the determination of vasodilating and hypotensive activity in standard tests. So they effect e.g. in the anesthetized cat test using "tracer" microspheres (R. Hof et al., Basic Res. Cardiol. 75 [1980] 747-756 and 76 [1981] 630-638; R. Hof et al., J. Cardiovasc. Pharmacol. 4 [1982] 352-362) coronary vasodilation, an increase in blood flow in the skeletal muscles and a decrease in blood pressure after intravenous administration of about 3 to about 300 .ug / kg.

A decrease in blood pressure is also seen in the awake, spontaneously hypertensive rat (method of Gerald M. Tschirki, Arzneimittelforsch. 18 [1968] 1285) after administration of approximately 1 to approximately 100 μg / kg s.c. detected. The compounds are stronger and longer effective than known standard compounds.

They are therefore suitable as calcium antagonists for the prophylaxis and therapy of

Coronary insufficiency, e.g. Angina pectoris;

- Brain circulation disorders such as cerebrovascular insufficiency; cerebrovascular insults, e.g. Stroke; and cerebrovascular spasms;

- other peripheral circulation disorders, e.g. in the limbs, such as intermittent limping and spasms, e.g. cholic;

Asthma, e.g. exercise-related asthma; and

- hypertension.

They also have a vasodilating effect on the capillary blood vessels in the carotid area; the vasoconstrictive effect of serotonin is suppressed and the associated dysregulation inhibited. They are therefore suitable for the prophylaxis and treatment of migraines and vas-

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culinary headaches, such as “cluster headache”, especially for interval treatment (prevention) of migraines. Preferred in this indication are those compounds which have a relatively modest effect on blood pressure and peripheral blood vessels.

The title compounds of Examples 1 and are preferred

2nd

The (+) enantiomer of the title compound of Example 1 is pharmacologically more active than the corresponding 3c (-) enantiomer or as the racemate.

Preferred in the prophylaxis and treatment of migraines and vascular headaches are those compounds in which the linked ring system on the nitrogen atom of the 1,4-dihydropyridine residue opposite position represents a 2,1,3-benzothiadiazolyl residue.

For the above-mentioned uses as medicaments, the dose to be used naturally varies depending on the substance used, the mode of administration and the desired treatment. In general, however, satisfactory results are obtained with a daily dose of approximately 5 mg to approximately 500 mg; if necessary, it can be administered in 2 to 4 portions or as a slow-release form. Suitable dosage forms for e.g. oral administration generally contains from about 1.25 mg to about 45 250 mg in addition to solid or liquid carriers. A suitable daily dose is e.g. about 5 mg to about 100 mg.

The compounds according to the invention in free form or, if appropriate, in the form of their physiologically tolerable salts, preferably acid addition salts, can be administered alone or in a suitable dosage form. The dosage forms, e.g. a solution or a tablet can be prepared analogously to known methods. The invention therefore also relates to pharmaceutical preparations which contain the compounds according to the invention in free form 55 or, if appropriate, in the form of their physiologically tolerable salts, and to the preparation of these pharmaceutical preparations in a manner known per se. The auxiliaries and carriers customary in pharmacy can be used for their production.

Claims (9)

660190 2nd PATENT CLAIMS 1. 1,4-dihydropyridine-3,5-dicarboxylic acid esters which are cyanated in the pyridine ring at the position adjacent to the nitrogen atom by cyan and at the position opposite the nitrogen atom by a condensed ring system which contains at least two different heteroatoms and at least one optionally substituted aromatic Ring contains, are substituted and optionally also substituted at the other positions of the pyridine ring, with the proviso that if the 1,4-dihydropyridine-3,5-dicarboxylic acid esters are alkyl esters each having 1 to 6 carbon atoms in the alkyl part, im Dihydropyridine ring, the nitrogen atom is unsubstituted and the other position adjacent to the nitrogen atom is substituted by methyl and the condensed ring system opposite the nitrogen atom in position 4 is 2,1,3-benzoxadiazolyl or 2,1,3-benzothiadiazo-lyl radicals, then these residues in the phenyl ring substituted in free form or optionally in salt rm, r 2. l, 4-dihydropyridine-3,5-dicarboxylic acid ester according to claim 1 of formula I. YOOC COOZ wherein X represents oxygen or sulfur; R for hydrogen; Alkyl of 1 to 4 carbon atoms; Alkoxy of 1 to 4 carbon atoms; Alkylthio of 1 to 4 carbon atoms; Alkylsulfonyl of 1 to 4 carbon atoms; Halogen with an atomic number from 9 to 35; Trifluoromethyl; Nitro or hydroxy; Ri means: hydrogen; Alkyl of 1 to 6 carbon atoms; Alkenyl having 3 to 6 carbon atoms, the double bond being separated from the nitrogen atom by at least one carbon atom which is not involved in the double bond; Alkynyl having 3 to 6 carbon atoms, the triple bond being separated from the nitrogen atom by at least one carbon atom which is not involved in the triple bond; Cycloalkyl of 3 to 7 carbon atoms; Cycloalkylalkyl of 4 to 8 carbon atoms; Hydroxy alkyl having 2 to 6 carbon atoms, the hydroxy part being separated from the nitrogen atom by at least 2 carbon atoms; Alkoxyalkyl with 2 to 6 carbon atoms or optionally substituted phenylalkyl with 7 to 9 carbon atoms or phenylalkenyl with 9 to 12 carbon atoms, the double bond being separated from the nitrogen atom by at least one carbon atom which is not involved in the double bond and the two latter radicals optionally being mono- or the same or different di- or the same or different tri-substituted by independently of one another alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, halogen with an atomic number of 9 to 35 or hydroxy; R2 for hydrogen; Alkyl of 1 to 6 carbon atoms; or cyano stands and COOY and COOZ independently of one another represent carboxylic ester residues, with the proviso that if Y and Z are each alkyl with 1 to 6 carbon atoms, R 1 is hydrogen and R 2 is methyl and the dihydropyridinyl part is bonded to the 4-position of the condensed ring system, then R is not hydrogen in free form or optionally in Salt form. 3rd 660 190 YOOC COOZ wherein X, R, R2, COOY and COOZ have the meaning given in claim 2, N-substituted. 3. Compounds according to claim 2 of formula I in the form of the individual enantiomers. 4. Compounds according to claim 2 of formula I, in free form or in pharmacologically acceptable salt form as active ingredients against cerebrovascular insults. 5 10th 15 20th 25th 30th 35 40 45 50 55 60 65 5. A process for the preparation of the compounds defined in claim 1, characterized in that at the position adjacent to the nitrogen atom of the 1,4-dihydropyridinyl ring in compounds which carry an oxime radical in the corresponding position, a cyano group is formed from the oxime radical by elimination of water, and the compounds thus obtained in free form or optionally in salt form. 6. The method according to claim 5 for the preparation of the compounds defined in claim 2, characterized in that at the position adjacent to the nitrogen atom of the 1,4-dihydropyridinyl radical in the compounds of the formula II, YOOC ■ COOZ wherein X, R, Ri, COOY and COOZ have the meaning given in claim 2, Q represents an oxime residue and Q 'represents an oxime radical or has the meaning given for R2 in claim 2, forms a cyano group from the oxime residue by elimination of water. 7. A process for the preparation of the compounds defined in claim 1 which are substituted on the nitrogen atom of the 1,4-dihydropyridinyl moiety, characterized in that corresponding unsubstituted compounds are N-substituted and the compounds thus obtained are obtained in free form or, if appropriate, in salt form. 8. The method according to claim 7 for the preparation of compounds of the formula I 'according to claim 2, : 00z YOOC wherein X, R, R2, COOY and COOZ have the meaning given in claim 2 and R'i has the meaning given for Ri with the exception of hydrogen, characterized in that corresponding compounds of the formula I ", 9. Pharmaceutical preparations, characterized in that they contain the compounds defined in claim 1 in free form or, if appropriate, in the form of their physiologically tolerable salts as an active ingredient.