FR2523128A1 - NOVEL 1,4-DIHYDROPYRIDINE DERIVATIVES, THEIR PREPARATION AND MEDICAMENTS CONTAINING THESE DERIVATIVES - Google Patents

Abstract

THE SUBJECT OF THE INVENTION IS TO ESTERS OF 1,4-DIHYDROPYRIDINE-3, 5-DICARBOXYLIC ACID WHOSE PYRIDINIC CORE IS SUBSTITUTED IN A POSITION ADJACENT TO THE NITROGEN ATOM BY A CYANO GROUP AND IN A POSITION OPPOSED TO THE CYANO GROUP. NITROGEN ATOM BY A CYCLIC SYSTEM CONTAINING AT LEAST TWO DIFFERENT HETEROATOMS AND AT LEAST ONE AROMATIC CYCLE. THESE COMPOUNDS MAY BE USED AS ACTIVE MEDICINAL SUBSTANCES.

Description

1 t. The present invention aims to

  new 1,4-dihydropyridine derivatives, their preparation

  ration and the drugs containing these derivatives.

  The invention relates in particular to esters of 1,4dihydropyridine-3,5-dicarboxylic acid, the pyridine ring of which is substituted adjacent to the nitrogen atom by a cyano group and in a position opposite to the nitrogen atom by a fused ring system containing at least two different cyclic heteroatoms and at least one aromatic ring. These compounds will be designated later

"compounds of the invention".

  The compounds of the invention in which -

  the nitrogen atom of the 1,4-dihydropyridinyl residue is unsubstituted, fall within the very broad scope of the German patent application No. 26 29 892 However, this patent application does not describe or suggest any compounds

  specific sem blable the xcomposés of the invention.

  The compounds of the invention are indicated by a

  particularly interesting pharmacological profile.

  The condensed ring system is for example

  a 2,1,3-benzoxadiazolyl or 2,1,3-benzothiazole moiety

  diazolyl. The invention relates more particularly to the compounds of formula I

R X

  Wherein X is oxygen or sulfur, R is hydrogen, halogen has an atomic number of 9 to 35 or a C 1 -C 4 alkyl group;

1 4 '

  C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, C 1 -C 4 alkylsulfonyl, CF 3, NO 2 or OH, R 1 is hydrogen or C 1 -C 6 alkyl, alkenyl at CC 6 in which the double bond is separated from the nitrogen atom by at least one carbon atom not participating in the double bond, C 3 -C 6 alkynyl in which the triple bond is atomic from the atom nitrogen by at least one carbon atom not participating in the triple bond, C 3 -C 7 cycloalkyl, C 4 -C 8 cycloalkylalkyl, C 2 -C 6 hydroxyalkyl in which the hydroxy group is separated from the nitrogen atom by at least two carbon atoms, C 2 -C 6 alkoxyalkyl, C 7 -C 9 phenylalkyl, C 9 -C 12 phenylalkenyl in which the double bond is separated from the atom

  of nitrogen by at least one carbon atom

  The benzene ring of the phenylalkyl and phenylalkenyl groups may optionally carry one, two or three substituents selected from halogens having an atomic number of from 9 to 35 and hydroxy, C 1 -C 4 alkyl and alkoxy groups. at C 1 -C 4, R is hydrogen or C 1 -C 4 alkyl

2 1 6

  or cyano, and COOY and COOZ represent identical ester groups

or different.

  In a subgroup of compounds of formula I,

  R 2 means hydrogen or an alkyl group In another sub-group

  group, R 2 means a cyano group.

  The 1,4-dihydropyridinyl residue is bound to the benzene ring of the remaining 2,1,3-benzoxadiazolyl or 2,1,3-benzothiadiazolyl, preferably on a

  adjacent to the oxadiazolyl or thiadia-

zolyle.

  X preferably means oxygen.

  R preferably means hydrogen.

  R 1 preferably means hydrogen.

  When R 1 has a meaning other than hydrogen,

  it preferably signifies an alkyl, cycloalkyl,

  alkylalkyl, optionally substituted phenylalkyl or alkoxyalkyl, especially an alkyl group or

  alkoxyalkyl, more particularly an alkyl group.

  R preferably means an alkyl group 2 -

  or cyano, especially an alkyl group.

  Preferably, COOY and COOZ mean respectively

  COOR 3 and COOR 4 in which -

  R and R 4 mean each, independently one of

3 4

  the other is a C 1 -C 12 alkyl group or a C 2 -C 12 hydroxyalkyl group in which

  the hydroxy group is separated from the carbonyl

  at least two carbon atoms, a C 3 -C 12 alkoxyalkyl group in which the alkoxy residue is separated from the carbonyloxy residue by at least two carbon atoms, a C 3 -C 6 alkenyl group in which the double bond is is separated from the carbonyloxy residue by at least one carbon atom not participating in the double bond, a C 3 -C 6 alkynyl group in which the triple bond is separated from the carbonyloxy residue by at least one carbon atom not participating in the triple bond, a C 3 -C 7 cycloalkyl group, a C 4 -C 8 cycloalkylalkyl group, a C 4 -C 8 hydroxyalkylalkyl group in which the hydroxyalkoxy residue is separated from the rest

  carbonyloxy by at least two carbon atoms

  and the hydroxy group is separated from the oxygen atom of the alkoxy residue by at least two

  carbon atoms, a phenyl or phenyl group

  C 7 -C 10 alkyl in which the benzene ring

  It can optionally carry one or two substituents selected from halogens having an atomic number of 9 to 35 and C 1 -C 4 alkyl and C 1 -C 4 alkoxy, or a C 2 -C 6 aminoalkyl group in which the nitrogen atom is separated from the carbonyloxy residue by

  at least two carbon atoms and is possibly

  mono or independently, disubstituted with C 1 -C 4 alkyl, phenyl, C 7 -C 10 phenylalkyl or phenyl or C 7 -C 10 phenylalkyl wherein the benzene ring bears one or two substituents selected from the group consisting of halogen atoms having an atomic number of 9 to 35 and C 1 -C 4 alkyl and alkoxy groups

C 1-C 4.

  COOY and COOZ are preferably different.

  R 3 and R 4 preferably each independently of one another means an alkyl group,

  alkoxyalkyl, cycloalkylalkyl or aminoalkyl

  substituted, especially an optionally substituted alkyl or aminoalkyl group, more especially

an alkyl group.

  When R 1 is an alkyl group,

  is preferably unbranched on the carbon atom attached to the nitrogen atom. When R 1 is an alkoxyalkyl group, the alkoxy radical is preferably separated from the nitrogen atom by at least two carbon atoms. . The C 1 -C 12 alkyl group is preferably

  C 1 -C 6, especially C 1 -C 4, and in particular means

  a methyl, ethyl or isopropyl group.

  The C 1 -C 6 alkyl group is preferably C 1 -C 4, and is especially methyl or ethyl, more particularly methyl. When in the symbols R 1, R 3 and / or R 4 is a benzene group or an amino group carries a C 1 -C 4 alkyl substituent, the latter preferably containing one or two

  carbon, and in particular means a methyl group.

  When in the symbols R 1, R 3 and / or R 4 a benzene ring bears a C 1 -C 4 alkoxy substituent, the latter preferably contains one or two atoms

  of carbon and especially means a methoxy group.

  When in a symbol R 1, R 3 and / or R 4 a benzene ring

  is substituted by a halogen having an atomic number of 9 to 35, the latter is preferably

  chlorine or bromine, especially chlorine.

  The alkenyl and / or alkynyl groups preferably contain three carbon atoms. The cycloalkyl groups and / or the cycloalkyl radicals of the cycloalkylalkyl groups preferably contain 3, 5 or 6 carbon atoms, especially 5 or 6 carbon atoms. The alkylene radical of the cycloalkylalkyl and / or phenylC 7 -C 9 and / or C 7 -C 10 alkyl group preferably contains 1 or 2 carbon atoms and

  especially a methylene group.

  The alkenylene radical of the phenylalkenyl group

  preferably contains 3 carbon atoms.

  The alkyl radical 11 does not contain the C 2 -C 6 hydroxyalkyl group and / or the C 2 -C 6 alkoxyalkyl group and / or the group

  hydroxyalkoxyalkyl and / or aminoalkyl group

  replaced, preferably contains 2 or 3

  carbon atoms, especially two carbon atoms.

  The alkylene radical of the C 2 -C 12 hydroxyalkyl group preferably contains from 2 to 6 carbon atoms, especially 2 or 3 carbon atoms, more particularly 2 carbon atoms. The C 3 -C 12 alkoxyalkyl group and / or C 2 -C 6 preferably contains from 3 to 6 carbon atoms, especially

3 carbon atoms.

The hydroxy residue of the hydroxyl group

  alkyl and / or hydroxyalkoxyalkyl group and / or the amino residue of the aminoalkyl group are

  preferably at the end of the chain.

  C 2 -C 12 alkyl preferably contains 2 to 6 carbon atoms, especially 2 carbon atoms. The alkoxy residue of the hydroxyalkoxyalkyl group preferably contains 2 carbon atoms. The alkoxy residue of the alkoxyalkyl group preferably contains 1 or 2 carbon atoms. carbon, and especially means a methoxy group. When a benzene ring is present

  in a substituent, it is preferably unsubstituted.

  When substituted, it is preferably mono

  substituted, preferably in the para position When disubstituted, it is substituted preferably in ortho and para When trisubstituted,

  it is preferably substituted in meta, meta and para.

  Halogens and / or alkoxy groups are preferred as substituents of a benzene ring present as a substituent Where a benzene ring is polysubstituted

  killed, the substituents are preferably identical.

  The amino residue of the aminoalkyl group

  is preferably substituted, especially disubstituted.

  Preferred substituents of the amino group are optionally substituted alkyl and / or phenylalkyl groups. Preferably, the amino group of the aminoalkyl group is disubstituted by alkyl and / or

  optionally substituted phenylalkyl.

  A preferred group of compounds of formula I are the compounds of formula Ia / X (Ia)

R 300 C COOR

4

R H CN

R, in which

  X, R and R 1 to R 4 have the meanings given above.

  ously. In a subgroup of compounds of formula Ia, the 1,4-dihydropyridinyl moiety is attached in the 4-position.

  of the remainder 2,1,3-benzoxadiazolyl or 2,1,3-benzothiazole

  diazolyl In another subgroup, R stands for

  In another subgroup, the remaining 1,4

  dihydropyridinyl is bound in the 4-position of the remaining 2,1,3-benzoxadiazolyl or 2,1,3-benzothiadiazolyl

and R is hydrogen.

  Another group of compounds of formula I is the compounds of formula Ip NYC wherein R COOY and COOZ have the meanings given above, R is the hydrogen or alkyl group. C 1 -C 6, C 3 -C 6 alkenyl wherein the double bond is separated from the nitrogen atom by at least one carbon atom not participating in the C 2 -C 6 hydroxyalkyl double bond in wherein the hydroxy group is separated from the nitrogen atom by at least two carbon atoms, C 2 -C 6 alkoxyalkyl, C 7 -C 9 phenylalkyl or C -C 11 phenylalkenyl in which the double bond is separated of the nitrogen atom by at least one carbon atom not participating in the double bond, and P

  R 2 is hydrogen or C 1 -C 6 alkyl.

  In a subgroup of compounds of formula Ip, Y and Z each signify, independently of each other, a C 1 -C 12 alkyl, C 2 -C 12 hydroxyalkyl group in which the hydroxy group is separated. from the remainder carbonyloxy by at least two carbon atoms, or C 3 -C 12 alkoxyalkyl in which the alkoxy residue is separated from the carbonyloxy residue by at least two

carbon atoms.

  Another group of compounds of the invention consists of the compounds of formula Is

NOT

R 3 COORS (Is)

RO 4

I I

RS N CN

  R 1 wherein Rs is hydrogen or C 1 -C 4 alkyl R 14 R s is cyano or C 1 -C 4 alkyl, and and RS are each independently of one another, a C 1 -C 4 alkyl or C 2 -C 6 aminoalkyl group in which the nitrogen atom is separated from the carbonyloxy residue by at least two carbon atoms and is independently disubstituted by

  C 1 -C 4 alkyl and / or C 7 -C 10 phenylalkyl groups.

  According to the process of the invention, to prepare the compounds of the invention a) a cyano group is formed adjacent to the nitrogen atom of the 1,4-dihydropyridinyl residue in an appropriate compound having a group capable of at this position, or b) to prepare a substituted compound of the invention on the nitrogen atom of the 1,4-dihydropyridinyl radical, the nitrogen is appropriately substituted for

  corresponding unsubstituted compound.

  In particular, to prepare a compound of formula I a ') a cyano group is formed adjacent to the nitrogen atom of the 1,4-dihydropyridinyl residue in a compound of formula II

NOT

  Wherein X, R, R1, COOY and COOZ have the meanings

previously data -

  Q is a group capable of being converted to a cyano group and Q 'means a group capable of being converted into a cyano group or has the meaning given above for R 2, or b') to prepare a compound of formula I 'N \ x Stil YOQC oz (I ')

R N N

  in which X, R, R 2, COOY and COO 2 have the previously given sigations and R 'has the meaning given above for R 11 except for hydrogen, the appropriate nitrogen is substituted for a corresponding compound of formula I "

R __NR

I ")

OOC COOZ

R P 7 CN

H

  in which X, R, R 2 COOY and COOZ have the meanings

previously.

  Processes a) and b) can be performed

  killed analogously to known methods.

  Process a) is a nitrile transformation. Where the starting material has a group that can be converted into a cyano group on

  each of the two positions adjacent to the azo atom

  In the case of the remaining 1,4-dihydropyridinyl, it is possible in this case to simultaneously form a cyano group at these two positions. When it is desired to prepare a compound in which the two positions adjacent to the nitrogen atom of the remaining 1,4 dihydropyridinyl are substituted with a cyano group, in this case a starting material is preferably used in which these two positions are substituted by a group capable of being converted into a cyano group.

preferably identical.

  A group that can be transformed into

  cyano group is for example an oxime-CH = NOH residue.

  In this case, the conversion to nitrile is a

  hydration of an oxime The dehydrating agent is

  preferably acetic anhydride.

  The reaction is preferably carried out at

  high temperature, for example at a

  between about 80 and about 160, preferably

  from about 100 to about 1400.

  Process b) is a substitute reaction

  secondary amine It can be carried out

  under the conditions of a-N-alkylation of a secondary amine

  re, for example with a suitable halide, or with

  It is also possible to operate more

several steps.

  When potentially reactive groups are present, such as hydroxy or amino groups

  primary or secondary education, it may be

  kill the process a) and / or b) with these groups in protected form, for example for the phenolic hydroxy groups as benzyloxy groups, for the aliphatic hydroxy groups as a tetrahydropyranyloxy residue and for the amino groups under

  form of an acylamino or phthalimido group, and of

  then forming any protecting group present by the desired substituent, for example the benzyloxy group to hydroxy group, for example by hydrogenolysis, the tetrahydropyranyloxy group to hydroxy group, for example by acid hydrolysis, and the amino group protected to unprotected amino group, for example by hydrolysis

acid or hydrazinolysis.

  The compounds of the invention can then be isolated from the reaction mixture and purified

according to known methods.

  The compounds of the invention may exist

  in free form or optionally in the form of salts.

  Free forms are normally neutral except in

  the case where the compound contains ionic substituents

  sand It may form a salt for example when

  that an ionizable substituent is present, such as an amino or phenolic hydroxy group A free form can be converted into salt according to known methods,

  and conversely, the appropriate acids for forma-

  Examples of acid addition salts include hydrochloric, malonic, p-toluenesulfonic and methanesulphonic acid. Suitable bases for the formation of anionic salts include hydroxide

of sodium and potassium.

  When the substituent in position 2 and 6 and / or in position 3 and 5 of the 1,4-dihydropyridinyl residue are different, the carbon atom in position 4 is

  asymmetrically substituted compounds of the invention.

  The corresponding invention may therefore exist as racemic or as individual enantiomers. The individual enantiomers can be obtained according to the known methods, for example 1) by chromatography using optically active adsorbents, such as, for example, acyl derivatives of cellulose or polymeric derivatives of amino acids,

  2) by fractional crystallisation of salts using

  optically active acids or bases for the formation of salts, optionally with

  prior hydrolysis to the corresponding carboxylic acid

  subsequent appropriate esterification, or 3) using a corresponding optically active starting material; in this case, the resolution can be carried out on an intermediate, for example on a corresponding compound substituted on one or on the two positions adjacent to the nitrogen atom of the 1,4-dihydropyridinyl residue by an acetal group -CH (OCH 3) 2 or -CH (OCH 2 CH 3) 2 or by a formyl group For the resolution, it may be appropriate to use an acetal or a formyl compound

  in the form of a corresponding mixture of diastereo-

  Such a mixture of diastereoisomers can be prepared according to known methods, for example

  using a compound having a substituent comprising

  as another determined configuration asymmetry center, being part of, for example, one of the ester groups A preferred asymmetric ester group of a given configuration is a group having an electron withdrawing substituent

  such that the remainder 1 2- (R) -methoxy-2-phenylethylloxy-

  carbonyl The doubling done, the group asy? auxiliary metric may be replaced according to

  known methods, for example by transesterification

  cation. The resolving method 3) using the diastereoisomeric esters with subsequent transesterification is particularly interesting when

  the chiral residue of the ester group to be replaced during the transester-

  terification, is more reactive than the rest of the other ester group, for example when it is desired to introduce

  by transesterification the remainder of a primary or secondary alcohol

  and the other ester group on the 1,4-dihydropyridinyl radical

  is the rest of a secondary or tertiary alcohol.

  Starting materials can be obtained

according to known methods.

  Suitable starting materials containing an oxime group -CH = NOH which may be converted into the cyano group may, for example, be obtained

  by cyclization of a 2-acyl-3-aryl-2-acid ester

  propenolic corresponding with an acid ester

  3-amino-3-dimethoxymethyl (or 3-diethoxymethyl) -2-pro-

  corresponding penicula, hydrolysis of the resulting acetal

  and reactin of the resulting formylated compound with hydroxylamine. The starting materials, in particular the

  acetals, formyl compounds and intermediate oximes

  may exist in free form or under

  form of salts, as indicated above for

poses of the invention.

  When the preparation of a particular starting material is not specifically described, it will be a known compound or which may be prepared in known manner from known products, or in a manner analogous to that described herein. request.

  The following examples illustrate the

  invention without in any way limiting its scope.

  All temperatures are given in degrees Celsius

and are uncorrected.

Example 1

  4- (2,1,3-Benzoxadiazol-4-yl) -6-cyano-11,4-dihydro-5-

  isopropyl methoxycarbonyl-2-methyl-pyridine-3-carboxylate (compound of formula I wherein Y = isopropyl and Z = methyl)

  To the solution prepared as described above

  after and containing 4- (2,1,3-benzoxadiazol-4-yl) -6-

  hydroxyiminomethyl-11,4-dihydro-5-methoxycarbonyl-2-

  isopropyl methylpyridine-3-carboxylate is added without further purification 5 ml of acetic anhydride and

  the solution is heated for 4 hours at a temperature of

  After cooling, the mixture was diluted with ice water and extracted with methylene chloride. The organic phase was washed with saturated aqueous sodium bicarbonate solution and dried over magnesium sulfate. and evaporated under reduced pressure to give the title compound (F = 196 after crystallization from ether). The starting material can be obtained as follows: a) A solution is refluxed for 48 hours.

  22.8 g of 2-acetyl-3- (2,1,3-ben: oxadiazol-4-yl) -

  Isopropyl 2-propenoate and 14.6 g of 3-amino

  Methyl 3-dimethoxymethyl-2-propenoate in 500 ml of dioxane and under reduced pressure the resulting solution is evaporated to dryness.

  thus 4- (2,1,3-benzoxadiazol-4-yl) -6-dimethoxy-

  methyl-11,4-dihydro-5-methoxycarbonyl-2-methyl

  isopropyl pyridine-3-carboxylate (F = 99 after

  crystallization in a mixture of hexane and ether).

  b) To a solution of 18 g of the acetal obtained under a) in 360 ml of dioxane, 54 ml of 6 N aqueous hydrochloric acid are added and the mixture is shaken.

  resulting for 4 hours at room temperature

  The mixture is then poured into a mixture of water and ice and extracted with chloride.

  The organic phase is dried over sodium

  magnesium fate and is evaporated under pressure

  The resulting 4- (2,1,3-benzoxadiazole

  4-yl) -6-formyl-11,4-dihydro-5-methoxycarbonyl-2-

  isopropyl methyl-pyridine-3-carboxylate (F = 127 after crystallization from a mixture of ether and hexane). The same formyl compound is obtained when the corresponding diethoxymethyl compound (prepared as described under a) above is used as starting material.

  using 3-amino-3-diethoxymethyl-2-propene

  methyl ester in place of 3-amino-3-dimethoxy-

methyl-2-propenoate methyl).

  c) To a solution of 5 g of the formyl compound obtained as

  described under (b) above in 150 ml of acetic acid

  1.0 g of hydrochloride hydrochloride is added

  xylamine and 3.2 g of sodium acetate and the mixture is stirred

  mixing for 90 minutes at room temperature.

  There is thus obtained 4- (2,1,3-benzoxadiazol-4-yl) -

  6-hydroxy-iminomethyl-11,4-dihydro-5-methoxycarbonyl

  Isopropyl 2-methyl-pyridine-3-carboxylate

(gross product)

Example 2

  (+) 4- (2,1,3-Benzoxadiazol-4-yl) -6-cyano-1,4-dihydro-

  isopropyl-methoxycarbonyl-2-methyl-pyridine-3-carboxylate (dextrorotatory enantiomer of the

* example 1).

  The title compound is obtained analogously to that described in Example 1, from the corresponding optically active oxime, and with additional final chromatography on silica gel using, as eluent, a 49: 1 mixture of chloride. methylene and ether (F = 107 after crystallization from ether); lal O 2 = + 2150, the O

  lal 546 = + 300 (ethanol, c = 0.42 g / dl).

  The starting oxime can be obtained as follows:

  a) 3-Amino-3-dimethoxymethyl is reacted with 100

  Methyl 2-propenoate with (-) (R) -2-methoxy-2-

  phenylethanol in the presence of sodium hydride and the resulting oil is purified by chromatography on silica gel using, as eluent, a mixture of

  2: 1 hexane and ether; 3-amino-3-dimethoxy-

  2- (R) -methoxy-2-phenylethyl methyl-2-propenoate

2320

  resulting -LalD = 38, 11 56 2 45 (methanol,

  c = 0.58 g / dl) is reacted with 2-acetyl-

  Isopropyl 3- (2,1,3-benzoxadiazol-4-yl) -2-propenoate

  in a manner similar to that described in

  example la), and the resulting mixture of diastereo-

  isomers is separated by chromatography over 100 times its amount of silica gel using as eluent a 5: 1 mixture of hexane and acetate

  of ethyl 4- (2,1,3-benzoxadiazol-4-yl) -2-dimethyl

  thoxymethyl-11,4-dihydro-5-isopropoxycarbonyl-6-

  1- (R) -2-methoxy-1-methylpyridine-3-carboxylate

  Eluted 2-phenylethylel is obtained in two separate fractions each containing a diastereoisomer: first diastereoisomer (oil): Ial O = -29 (ethanol, c = 0.86 g / dl); second diastereoisomer (oil): lal 20 = _ 2

(ethanol, c = 0.6 g / dl).

  According to a variant of the resolution method described above, the resulting diastereoisomeric mixture

  is first hydrolysed to give the dia-

  stereoisomer of the corresponding 2-formyl derivative.

  This mixture is then resolved analogously and the formylated diastereoisomers thus isolated are separately converted back into acetals.

  diastereoisomers mentioned above.

  b) For 3 hours under a nitrogen atmosphere and at a bath temperature of 100.6 g of the first diastereoisomer obtained as described under a) above, the mixture is stirred in a solution of 0.3 g of sodium in 65 g. The mixture is added to a cold solution of 1N aqueous hydrochloric acid and is extracted with methylene chloride. The organic phase is dried over magnesium sulphate and

  Evaporate the solvent under reduced pressure.

  tograph the residue on silica gel using,

  as eluent, a 19: 1 mixture of methyl chloride

  lene and ethyl acetate This gives the

  (+) - 4- (2,1,3-benzoxadiazol-4-yl) -6-dimethoxymethyl

  1,4-dihydro-5-methoxycarbonyl-2-methyl-pyridin-3-

  isopropyl carboxylate F = 93 after crystallization

  in a mixture of ether and hexane; l0 = 3 'to 20 lD l O = + 38, lal 546 = + 53 (ethanol, c = 0.47 g / dl).

  (c) The (+) - acetal obtained under (b) above is hydro-

  lysed in a manner similar to that described in the

  pIb). This gives the (+) - 4- (2,1,3-benzoxa)

  diazol-4-yl) -6-formyl-l, 4-dihydro-5-methoxycarbonyl

  isopropyl bonyl-2-methyl-pyridine-3-carboxylate. Mp = 148 after crystallization from ether;

  lal 20 = + 1530, lal 5206 = + 220 (ethanol, c = 0.7 g / dl).

  (d) The (+) - formylated compound obtained under (c) above is reacted in a manner similar to that described above.

  in example 1c), thus obtaining (+) - 4- (2,1,3-

  benzoxadiazol-4-yl) -6-hydroxyiminomethyl-l, 4-

  dihydro-5-methoxycarbonyl-2-methyl-pyridin-3-

  isopropyl carboxylate (crude product).

Example 3

  (-) - 4- (2,1,3-Benzoxadiazol-4-yl) -6-cyano-1,4-dihydro-5-

  isopropyl methoxycarbonyl-2-methyl-pyridine-3-carboxylate (laevorotatory enantiomer of the

example 1)

  The title compound is obtained in a manner analogous to that described in Example 2 using

  as the starting material, the corresponding oxime optimizes

actively active.

  The product melts at 157 after crystallization

  In ether; lal -212 lal 546 = -295

O 546

(ethanol, c = 0.79 g / dl).

  The starting oxime is obtained in a manner similar to that described in Example 2 using the second isolated diastereoisomer as described in Example 2 a).

Example 4

  4- (2,1,3-Benzoxadiazol-4-yl) -6-cyano-1,4-dihydro-5-

  isopropyl methoxycarbonyl-11,2-dimethyl-pyridine-3-carboxylate (compound of formula I wherein Y = isopropyl and Z = methyl)

  It is stirred for one hour at room temperature.

  ambient temperature a mixture of 1.25 9 of 4- (2,1,3-benzoxa)

  diazol-4-yl) -6-cyano-11,4-dihydro-5-methoxycarbonyl-2-

  isopropyl methylpyridine-3-carboxylate in 25 ml of methylene chloride, 25 ml of 40% aqueous sodium hydroxide solution, 0.62 ml of

  dimethyl and 0.1 g of tetrabutylammonium bromide.

  The reaction mixture is then diluted with water, extracted with methylene chloride, the organic phase is dried over magnesium sulphate and evaporated to dryness under reduced pressure. The product is chromatographed on silica gel. using methylene chloride as eluent

  thus the title compound as an oil.

  By proceeding in a manner analogous to that described in Example 1, the following compounds of formula I are obtained. T t Position of the remainder Example point R 1 R y z R 1,4-dihydropyridinyl and X fus ion

2 on the system cy-

  Tue / Wed: Me, Me, Me, E, T (CH 2) 2 N (Me) Me Bz i Pr i Pr "And Me (CH 2) 2 N (Me) Bz Me M 1.f% HHH 111 HH w-1 _1 1, 1 - j + 11 ch = in the form of hydrochloride Bz = benzyl Et = ethyl n = in free form i Pr = isopropyl Mie = methyl

  From the corresponding compound of formula II O Q and Q 'signify CH = NOH.

  o o o o o o n o 1870 n 1520 n 1150 n, 1400 ch 22205 n oil r, Ln> 1 j r ', Co H H H H in * Me I.' The compounds of the invention are distinguished by interesting pharmacological properties and

  can therefore be used in therapeutics

  as drugs The compounds of the invention exert effects characteristic of the antagonists

  They exert a pronounced myorelaxant effect

  especially in smooth muscle, as evidenced by vasodilatation and lowering of blood pressure in conventional tests. For example, in the microsphere test carried out in anesthetized cats according to the method.

  described by R Hof et al. in Basic Res Cardiol.

  747-756 (1980) and 76630-638 (1981) and by R Hof et al in J Cardiovasc Pharmacol 4, 352-362 (1982), dilation of coronary vessels, increased blood flow in skeletal muscles is observed. and a drop in blood pressure after administration of the compounds of the invention intravenously at doses of between about 3

and about 300 μg / kg.

  There is also a drop in

  blood pressure in spontaneously awake awake rats

  stretched according to the method described by G M Tschirki in

  Arzneimittelforschung 18 1285 (1968) after administration

  In one embodiment, the compounds of the invention are administered subcutaneously at doses of from about 1 to about 1 μg / kg. Thus, the compound of Example 1 causes a 40% decrease in blood pressure.

  after administration of 1 mg / kg subcutaneously.

  The compounds are more potent and have a longer duration of action than known reference substances. Thanks to these properties, the compounds of

  The invention can therefore be used in therapeutic

  as calcium antagonists, for the prevention of

  treatment and treatment of coronary insufficiency, such as, for example, angina pectoris, disorders in the cerebral circulation such as cerebrovascular insufficiency, cerebrovascular accidents such as cerebrovascular attacks, and cerebrovascular spasm,

  other disorders in peripheral traffic

  that, for example in the limbs, such as intermittent claudication and smooth muscle spasm, eg colon muscles, asthma, for example, stress-induced asthma, and

hypertension.

  The compounds of the invention also exert

  vasodilator action on the capillary vessels of the carotid area; This results in an antagonistic effect on the vasoconstrictor effect exerted by serotonin and an inhibition of the disorders associated therewith. By virtue of this property, the compounds of the invention can be used therapeutically for the prophylaxis and treatment of migraine headaches and

  vascular headaches such as vascular pain

  facial cues, especially for the long-term treatment of migraine For this indication, the

  Preferred compounds are those having a relative effect

  moderate pressure on blood pressure and

peripheral blood vessels.

  For therapeutic uses indi-

  As described above, the compounds of the invention will be administered at a daily dose of from about 5 to about 500 mg, advantageously administered, for example orally, in divided doses of 2.

  to 4 times daily in unit dose form including

  each of between about 1.25 and about 250 mg of

  active substance, or in a releasable form

  late An example of a daily dose is included

  between about 5 mg and about 100 mg.

  The compounds of Examples 1 and 2 are the preferred compounds. The (+) enantiomer of the compound of Example 1 is pharmacologically more active than

  the enantiomer (-) and the corresponding racemic.

  For the prophylaxis and treatment of migraine and vascular headaches, the preferred compounds are those in which the condensed ring system located in position opposite the nitrogen atom on the 1,4-dihydropyridinyl residue, is a residue 2, 1

3-benzothiadiazolyl.

  The compounds of the invention can be administered in free form or in the form of a pharmaceutically acceptable salt. Such salts exert the same order of activity as the free forms.

corresponding.

  The invention also relates to a medicament comprising, as active ingredient, a compound of the invention in free form or in the form

  a pharmaceutically acceptable salt.

  The invention also includes composi-

  pharmaceutical products containing, as a

  this activates a compound according to the invention in free form or in the form of a pharmaceutically acceptable salt, in combination with acceptable vehicles or diluents.

  From the pharmaceutical point of view, such composi-

  Pharmaceutical compositions can be prepared according to known methods. The pharmaceutical compositions can be in the usual forms, for example

  in the form of solutions or tablets.

Claims (9)

1. esters of 1,4-dihydropyridine-3,5-dicarboxylic acid whose pyridine ring is substituted adjacent to the nitrogen atom by a cyano group and in the opposite position to the atom nitrogen by a condensed ring system containing at least two different cyclic heteroatoms and at least one aromatic ring.   2. The 1,4-dihydropyridine derivatives corresponding to formula I R X R 2 N N 2 I N   R 1 wherein X is oxygen or sulfur, R is hydrogen, halogen has an atomic number of 9 to 35 or C 1 -C 4 alkyl, C 1 -C 4 alkoxy, alkylthio C 1 -C 4, C 1 -C 4 alkylsulfonyl, CF 3, NO 2 or OH, R is hydrogen or C 1 -C 6 alkyl, C 3 -C 6 alkenyl wherein the double bond is separated from the nitrogen atom by at least one carbon atom not belonging to the double bond, C 3 -C 6 alkynyl in which the triple bond is separated from the nitrogen atom by at least one atom of carbon not participating in the triple bond, C 3 -C 7 cycloalkyl, C 4 -C 8 cycloalkylalkyl, C 2 -C 6 hydroxyalkyl in which the hydroxy group is separated from the nitrogen atom per minus two carbon atoms, C 2 -C 6 alkoxyalkyl C 7 -C 9 phenylalkyl, phenylalkenyl CC 12 in which the double bond is separated from the atom   of nitrogen by at least one carbon atom   The benzene ring of the phenylalkyl and phenylalkenyl groups may optionally carry one, two or three substituents selected from halogen atoms having an atomic number of from 9 to 35 and hydroxy, C 1 -C 6 alkyl groups. 4 and C 1 -C 4 alkoxy, R 2 is hydrogen or C 1 -C 6 alkyl 2 1 6   or cyano, and COOY and COOZ represent identical ester groups or different.   3. Derivatives of 1,4-dihydropyridine corresponding to the formula Ia N ^^^ X R 300 C COOR 4 (ia) I I R R 1 in which   X, R, R and R have the meanings given to the claim   * R 2 tion 2, and R 3 and R 4 each signify, independently of one another, a C 1 -C 12 alkyl group, a 2523 1 22   C 2 -C 12 hydroxyalkyl group in which   the hydroxy group is separated from the carbonyl   oxy with at least two carbon atoms, a C 3 -C 12 alkoxyalkyl group in which the alkoxy residue is separated from the carbonyloxy residue by at least two atoms of carbon, a C 3 -C 6 alkenyl group in which the double bond is separated from the carbonyloxy residue by at least one carbon atom not participating in the double bond, a C 3 -C 6 alkynyl group in which the triple bond is separated from the carbonyloxy residue by at least one carbon atom not participating in the triple bond, a C 3 -C 7 cycloalkyl group, a C 4 -C 8 cycloalkylalkyl group, a C 4 -C 8 hydroxyalkoxyalkyl group in which the hydroxyalkoxy residue is separated from the rest   carbonyloxy by at least two carbon atoms   and the hydroxy group is separated from the oxygen atom of the alkoxy residue by at least two   carbon atoms, a phenyl or phenyl group   C 7 -C 10 alkyl in which the benzene ring is   It can optionally carry one or two substituents selected from halogens having an atomic number of 9 to 35 and C 1 -C 4 alkyl and C 1 -C 4 alkoxy groups, or 1 -4 1 _'49   C 2 -C 6 aminoalkyl group in which the nitrogen atom is separated from the carbonyloxy residue by   at least two carbon atoms and is possibly   mono or independently, disubstituted with C 1 -C 4 alkyl, phenyl, C 7 -C 20 phenylalkyl phenyl or C 7 -C 10 phenylalkyl wherein the benzene ring bears one or two substituents selected from halogen atoms. having an atomic number of 9 to 35 and the C 1 -C 4 alkyl and alkoxy groups C 1 -C 4.   4 1,4-Dihydropyridine derivatives corresponding to the formula Ip N t '& lk z (Ip) YOOC COOZ R 2 NN   R 1 wherein COOY and COOZ have the meanings given in claim 2, P R 1 is hydrogen or C 1 -C 6 alkyl, 1 16   C 3 -C 6 alkenyl wherein the double bond is separated from the nitrogen atom by at least one carbon atom not participating in the C 2 -C 6 hydroxyalkyl double bond in which the hydroxy group is separated of the nitrogen atom by at least two carbon atoms, C 2 -C 6 alkoxyalkyl, C 7 -C 9 phenylalkyl or C 9 -C 13 phenylalkenyl in which the double bond is separated from the atom of nitrogen by at least one carbon atom not participating in the double bond, and P   R 2 is hydrogen or C 1 -C 6 alkyl.   5. Derivatives of 1,4-dihydropyridine corresponding to the formula Is (formula Is see next page) R 300 COO Rs s 10 3 4   R 2 N to CN s R 1 wherein R 1 is hydrogen or C 1 -C 4 alkyl, R 1 is cyano or C 1 -C 4 alkyl, and 2 C 1 C   Rs and R4 mean each, independently one of.   the other is a C 1 -C 4 alkyl or C 2 -C 6 aminoalkyl group in which the nitrogen atom is separated from the carbonyloxy residue by at least two carbon atoms and is independently disubstituted by C 1 -C 6 alkyl groups; C 1 -C 4 and / or C 7 -C 10 phenylalkyl. 6. A 1,4dihydropyridine derivative according to claim 5, characterized in that it is chosen from compounds in which Rs, R 2, Rs and Rs mean respectively 3 4   H, CH 3, CH 3 and isopropyl, H, CH 3, C 2 H 5 and C 2 H 5, H CH 3, (CH 2) 2 -N (CH 3) CH 2 C 6 H 5 and CH 3 3, H, CH 3 CH and - (CH 2) 2 -N (CH 3) CH 2 C 6 H 5, CH 3, CH 3, isopropyl and CH 3, and H, CH, isopropyl and CH 3.   7. A derivative of 1,4-dihydropyridine   according to any one of claims 1 to 6,   characterized in that it is in the form of a facemic or enantiomer when the substituents in position 2 and 6 and / or in position 3 and 5 of the remainder   1,4-dihydropyridinyl are different.   8. 4-2,1,3-benzoxadiazol-4-yl) -6-cyano-   1,4-Dihydro-5-methoxycarbonyl-2-methyl-pyridine-3-   isopropyl carboxylate, in racemic or enantiomeric form. 9. A compound according to any of   Claims 1 to 8, characterized in that   present in free form or in salt form.   10. A process for the preparation of 1,4-dihydropyridine-3,5-dicarboxylic acid esters having a pyridine ring substituted adjacent to the nitrogen atom by a cyano group and in a position opposite to the nitrogen atom by a fused ring system containing at least two different cyclic heteroatoms and at least one aromatic ring, characterized in that a) a cyano group is formed adjacent to the nitrogen atom of the remaining 1,4- dihydropyridinyl in a suitable compound having a group capable of being converted into a cyano group in this position, or b) to prepare a compound of the invention substituted on the nitrogen atom of the 1,4-dihydropyridinyl residue, is substituted for nitrogen appropriately a   corresponding unsubstituted compound.   A process for the preparation of the compounds of formula I specified in claim 2, characterized in that a ') forms a cyano group in a position adjacent to the nitrogen atom of the 1,4-dihydropyridinyl radical in a compound of formula II -   Wherein X, R, R 1, COOY and COOZ have the meanings given in claim 2, Q means a group capable of being transformed into a cyano group and Q 'means a group capable of to be converted into a cyano group or has the meaning given in claim 2 for R 2, or b ') to prepare a compound of the formula I in which X, R, R 2 , COOY and COOZ have the meanings given in claim 2, and R 'is given to the meaning of 2 for Rigenigenesis 2 except for hydrogen, the nitrogen is suitably substituted with a corresponding compound of formula I " R vooc cooz (t ") YOOC, OO FI R N r H   in which X, R, R 2 COOY and COOZ have the meanings data in claim 2.   12. A derivative of 1,4-dihydropyridine   according to any one of claims 1 to 8,   in free form or in the form of a pharmaceutical salt   acceptable for use as a medicinal product 13 A 1,4-dihydropyridine derivative   according to any one of claims 1 to 8,   in free form or in the form of a pharmaceutical salt   acceptable, for use as an antagonist calcium.   A medicament, characterized in that it contains, as active ingredient, a 1,4-dihydropyridine derivative specified in any one of   Claims 1 to 8, in free form or in   form of a pharmaceutically acceptable salt.   A pharmaceutical composition, which is   in that it contains, as active ingredient, a 1,4-dihydropyridine derivative specified in   any of claims 1 to 8, in free form   or in the form of a pharmaceutically acceptable salt, 2523 1 28   in combination with diluents or pharmaceutical vehicles ceutically acceptable.   16. The esters of 1,4-dihydro-   pyridine-3,5-dicarboxylic acid, the pyridine ring of which is substituted adjacent to the nitrogen atom by a group capable of being converted into a cyano group and in a position opposite to the nitrogen atom by a condensed ring system containing at least two different cyclic heteroatoms and at least one ring aromatic.   17. The esters of 1,4-dihydro-   pyridine-3,5-dicarboxylic acid, the pyridine ring of which is substituted adjacent to the nitrogen atom by a formyl group or a dimethoxymethyl or 1,5-diethoxymethyl group and in a position opposite to the nitrogen atom by a ring system condensed mixture containing at least two different cyclic heteroatoms and at least one aromatic cycle.