FR2528431A1 - NOVEL 1,4-DIHYDROPYRIDINE DERIVATIVES, THEIR PREPARATION AND THEIR USE AS MEDICAMENTS - Google Patents

Abstract

THE INVENTION CONCERNS THE DERIVATIVES OF 1,4-DIHYDROPYRIDINE OF FORMULA: (CF DRAWING IN BOPI) IN WHICH ONE OF THE R AND R SUBSTITUENTS MEANS METHYL AND THE OTHER ISOPROPYL, N-BUTYL, ISOBUTYL, CYCLOPENTYL OR ISOPROPROXYL R MEANS HYDROGEN OR ALKYL, OPTIALLY SUBSTITUTED, IN OPTICALLY ACTIVE FORM WHEN R IS HYDROGEN OR IN RACEMIC FORM OR IN OPTICALLY ACTIVE FORM WHEN R IS OTHER THAN HYDROGEN. THESE COMPOUNDS CAN BE USED AS A MEDICINAL PRODUCT.

Description

The subject of the present invention is new derivatives of 1,4-

  dihydropyridine in optically active form or in racemic form, their preparation and their therapeutic use as active ingredients of medicaments. European Patent No. 150 discloses a broad class of 1,4-dihydropyridine derivatives. British Patent Application No. 2,037,766 A describes

other examples of this class.

  The Applicant has now found that a particular group of optically active and racemic unknown 1,4-dihydropyridine derivatives hitherto, which are not specifically described or suggested in these documents, exhibit a pharmacological profile.

particularly interesting.

  The present invention relates more particularly to

  1,4-dihydropyridine derivatives of the formula I

1

R 100 C COOR, {I)

  CH 3 in which one of the substituents R and R is methyl and

  the other isopropyl, n-butyl, isobutyl, cyclopropyl

  pentyl or isopropoxyethyl and R 3 denotes hydrogen or an optionally substituted C 1 -C 6 alkyl group, either in optically active form when R 3 is hydrogen, or in racemic or optically active form when R 3 has 0 1 signifcation other than hydrogen,

  in the form of free bases or acid addition salts.

  These compounds will be designated subsequently as compounds of the invention. The compounds of formula I contain an asymmetric carbon atom at the 4-position of the 1,4-dihydropyridine ring, because of the existence

  different ester groups COOR 1 and COOR 2.

  When the C 1 -C 6 alkyl group is substituted, the

  substituent is preferably a hydroxy group, acetyl

  oxy, methoxy, ethynyl, dimethylamino or morpholino.

  Preferred compounds are those in which one of the substituents R 1 and R 2 is methyl and the other isopropyl, especially those in which R 3 is C 1 -C 6 alkyl or hydrogen, especially methyl or

  hydrogen, in particular methyl.

  The invention also relates to a process for the preparation of the compounds of the invention, wherein (a) a compound of the formula Ia R 1 OOC (Ia) H 3 C is alkylated on the nitrogen atom in position 1, in which R 1 and R 2 have the meanings given above, or b) in an optical isomer of a compound of formula II

R 1 OOC

  (I) in which R 1 and R 3 have the meanings given above, and R 4 denotes a removable group, the radical R 4 is exchanged with a radical OR 2 o R 2 -a the meaning given above, and, when the compound of formula I is basic, such a compound is recovered in free base form

  or as an acid addition salt.

  The N-alkylation process a) can be carried out by conventional methods, using

  suitable alkylating agents, for example a halogenated

  alkyl genide, preferably in the presence of a base such as sodium hydroxide.

  alkyl is substituted and the substituent is

  to react with the halogen, the substituent is preferably protected and the protecting group is

  then removed after alkylation.

  The alkylation product can be recovered in a conventional manner When the alkyl group on the nitrogen atom in the 1-position contains a group capable of forming a salt, such as the group

  dimethylamino or morpholino, the product of N-alkyl

  It can be obtained in the form of an acid addition salt, for example in the form of a salt with an organic acid such as fumaric acid, or of a salt with a mineral acid such as a halogenoacetic acid. The starting materials in process a) are known or can be prepared according to known methods from known starting materials. The starting materials used in process a) can be prepared in a manner analogous to method b), as long as they are optically active. The process b) can be carried out in a conventional manner. In the compound of formula II, the removable group R 4 is, for example, an OH group or an azolyl radical. Suitable azolyl radicals comprise, for example, the imidazolyl radical of formula "7". that especially the azolide groups, such as the group of formula N g are very reactive and easily exchange their azolyl residue, for example the residue 1 H-imidazol-1-yl, speaking remains derived from an ester group like the rest of the type OR 2, for example by adding an alcohol R 20 H 10 O and reacting the products to a tenimparature

  high, for example between 60 and 1500.

  Other azolyl radicals suitable for forming an azole group are, for example, 1,2,3-triazolyl, 1,2,4-triazolyl and benzotriazolyl radicals.

benzirlidazolyl and tetrazolyl.

  Process b) can also be carried out according to another conventional method, using starting materials of formula II in which R 4 is a group OR 5 where R 5 is a hydrocarbon radical

  Chiral of definite configuration containing one or more

  sieurs groups attracting electrons, or a radical

  hydrocarbon containing an amino group.

  Preferred electron withdrawing groups include phenyl group, methoxy group, or quaternized amino group. Preferred amino groups are di (C 1-4 alkyl) amino groups Preferred quaternized amino groups are tri (C 1-4) alkyl groups. 1-C 4) amino The radical R 5 is preferably an ethyl radical substituted by an electron-withdrawing group or an amino group, such as the radical

  2- (R) -CH 3 0-2-phenyl-ethyl or the trimethylammonium radical;

ethyl or dimethylaminoethyl.

  Given the presence of the electron withdrawing groups or the amino group, the -COOR 5 ester group is easily converted to the -COOR 2 group, for example by reaction with an R 20 H alcohol, preferably under basic conditions. wherein R 4 is OH and the other compounds of

  Formula II can be reacted in a similar way

  The final products can be isolated and purified

  according to known methods; if desired and if possible, products can be isolated

  and purified as an acid addition salt.

  In the optically active compounds of formula II used in process b), R 4 is preferably an azolyl radical or such a group OR * o R 5 is a chiral hydrocarbon radical of defined configuration containing one or more electron withdrawing groups . Representative starting materials of formula II can be prepared as indicated in the following reaction schemes I and II; these reaction schemes illustrate the production of two optically active forms (formula II compound)

  R 1 = isopropyl, R 3 = H, R 4 = OR 5 and R 5 = 2- (R) -CH 3

  2-phenylethyl) and I Ib 1 2 (compounds of formula II where R 1 = isopropyl, R 4 = 1H-imidazol-1-yl and R 3 = H) respectively by chromatographic separation and

by selective crystallization.

  (Tables see pagessuivantes) chromatography \, / (-) - (4 S) Ilb 1 1 Scheme I N \. "He,

+ O (CH 2) 2-CN

H 2 e VI

(CH 2) 2-CN _>

vii

1V -11,

V N

0 '1 _ 1

_ O, _ ph enyl

"O -CH _to

2 'H OCH 3 ki N',

2 MI

AI NH

; 1 3

1. phenyl II -O-CH 2

0) "," to H

OCH, (+) (4 Rr ", M (il r 1 l) CID

4. 1

M '

-N N 1 N N N N

-0 O (CH

> 2) 2-N

N il, 11-1 Diagram II

0 N '1-1

> -O (CH 2) 2-116

  ## STR1 ## wherein R is a di-O-O-p-toluoyl- (D) or (L) -tartric acid

11, O

vii + he

- (CH 2) 2-N "-

H 2 M 01%

1 NF 3

0 (CH

rll 2) 2-N ", Ili

(+) - (4 R)

  crystal 1 i Sati on \ -Z / (-) (4 s) 1 ib1 2 ester 3-dimethyl, -amino noethyl

(+) - (4 R) CH 1 XI

  3 "3-trimethylammonio-thyl ester (+) - (4 R) (-) - (4 s) XII Na OH 3-carboxylic acids (-) - (4 R) (+) - (4 s) XIII compounds 3 - (1H-imidazol-1-ylcarbonyl)

(4-) (4 R)

  rlla 01 - M Co M 1 Ilb 1 3 While optically active compounds

  Of reaction scheme I are obtained directly from

  by chromatographic separation of the mixture

  diastereoisomeric esters, the optimum compounds

  The active ingredients I Ib 13 of the reaction scheme II come from the mixture of diastereoisomeric salts.

  whose components can be separated by crystallization

selective selection.

  The compounds are preferably separated by crystallization rather than by chromatography

  when operating on large quantities.

  After the separation, the same treatment is applied to the compounds I Ib II and I Ib I 2 to obtain the final products of formula I. Both the chiral residue of the ester group of the compounds I Ib II and the dimethylamino-ethyl residue protonated from the group the ester of the compounds I Ib I 2 can be converted into the OR 2 residue of the final ester group;

  in reaction scheme II, these groups are, however,

  transformed by an indirect route which constitutes

the preferred method of preparation.

  Although it is possible to prepare

  the final compounds of formula I by transesteri

  cation of the compounds I Ib I 2 or, more preferably, compounds XI, a preferred mode is to create,

  passing through the XI compounds, a more electrically

  by quaternization (compounds XII), thus allowing a second crystallization and purification of the salt. Like the compounds I Ib 1 2, those of the type XII can be transesterified directly into compounds of the formula I However, it is possible to hydrolyze these compounds and to transform the 3-carboxylic acids obtained (compounds XIII), either directly or in passing through 3-azolides I Ib l 3, into final products of formula I.

  These reactions can be carried out in a

  and allow the preparation of the compounds of

  Formula I with good yields and in a very pure state.

  The following examples illustrate this

  invention without in any way limiting its scope.

  All temperatures are in degrees Celsius.

Example 1

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

  lracemic isopropylcarbonyl-l, 2,6-trimethylpyridine-3-carboxylate, a)

  To a solution of 2.5 g of 4- (2,1,3-benzoxa)

  diazol-4-yl) -l, 4-dihydro-5-methoxycarbonyl-2,6

  isopropyl dimethyl pyrimidine-3-carboxylate in 40 ml of dimethylsulfoxide, 1.5 g of powdered solid potassium hydroxide and 0.84 ml of methyl iodide are added under a nitrogen atmosphere. The mixture is stirred at room temperature. After one hour and a half, the mixture is poured into ice-cold water and extracted with methylene chloride. The methylene chloride solution is dried over magnesium sulphate and

it is evaporated under vacuum.

  The title compound is purified by chroma-

  silica gel chromatography using methylene chloride as eluent, and is crystallized in a

  mixture of ether and petroleum ether F = 125.

Example 2

  (-) - (S) and (+) - (R) -4- (2,1,3-benzoxadiazol-4-yl) -1,4

  dihydro-5-methoxycarbonyl-1,2,5-trimethyl-pyridine

  Isopropyl 3-carboxylate (compounds of formula I, enantiomers) a) {+ :: R) and-2- (1 S-4-: 2,1-1,3-benzoxadiazol-4: v 1: 1,4 :

  dihydro-5-iso-2-oxycarbonyl-2,6-dimethyl-2-ridine-3-

  2- (R) -methoxy-2-ehenylethyl carboxylate compound (+) I Ib 1 I and compound (-) I Ib I ll 1) A solution is heated for 7 hours at 120 ° C.

  10.5 g of 4- (2,1,3-benzoxadiazol-4-yl) -1,4-

  dihydro-5- (1H-imidazol-1-ylcarbonyl) -2,6-dimethyl

  isopropyl thyl-pyridine-3-carboxylate

  III) in 35.0 g of (R) -2-methoxy-2-phenyl-

  ethanol prepared as described by Kirmse et al in Chem Ber 108, 79 (1975) The excess of optically active alcohol is distilled off under high vacuum at 80-110. The residue is dissolved in methylene chloride.

  and the solution is washed with hydrochloric acid

  drique 2 N cold, dry and evaporate at

dryness under vacuum.

  2) A solution was heated for 20 hours under reflux.

  3.5 g of 2-acetyl-3- (2,1,3-benzoxadiazole)

  Isopropyl 4-yl) -2-propenoate (compound VII) lisomer (Z) or (E) or mixture of isomers (Z) and (E) 1 and 3.0 g of 3-amino-crotonate 2 - (R) methoxy-2-phenylethyl (compound VIII) in 100 ml of dioxane and evaporated to dryness

under vacuum.

  The mixture of diastereoisomers obtained according to method 1) or 2) is separated by chromatography on silica gel at 5 atmospheres with a 1.5: 1 mixture

hexane and ether as eluent.

  The first eluted compound is crystallized

  in a mixture of ethyl acetate and hexane.

  F = 89; lal 546 = -920 (in ethanol) (compound S).

  The second eluted compound is crystallized from a mixture of ether and hexane or methanol and water F = 127; lal 25406 = + 77 (in ethanol)

(compose).

  b) +> -: S> -4: {2,1,3-benzoxadiazol-4-y 12-1,4-dihydro-5-

  The compound of the formula Ia, enantiomer, method b) I was heated for 50 hours at reflux and

  under a nitrogen atmosphere 5.3 g of (-) - <S) -4- (2,1,3-

  benzoxadiazol-4-yl) -11,4-dihydro-5-isopropoxycarbonyl

  2- (R) -methoxy-2,6-dimethyl-pyridine-3-carboxylate

  2-phenylethylcomposition I Ib l 1 (-) l in a solution

  0.3 g of sodium in 100 ml of methanol. The volume of the solution is reduced to 50% under vacuum.

  100 ml of ice water are added. The mixture is extracted

  After mixing with methylene chloride, the methylene chloride solution is dried over magnesium sulfate and evaporated in vacuo. The residue is purified by low pressure silica gel chromatography using a 1: 4 mixture of hexane and magnesium chloride. ether as eluent The pure enantiomer (+) - (45) melts at 142 after crystallization in a mixture

ether and hexane.

  lal 546 = + 9.9 (ethanol, c = 1.5 g / dl)

  lal = + 6.70 (ethanol, c = 1.5 g / dl).

D

  c)): - S: 24 :? 2,1,3-benzoxadiazol-4 :: 4 dhdro-5-

  Methoxy-carbonyl-1,2,6-trimethyl-pyridine-3-carboxy: isoester 2-terminal The compound of formula I, enantiomer, process a)

  To a solution of 0.7 g of (+) - (4 S) - (2,1,3-

  benzoxadiazol-4-yl) -1,4-dihydro-5-methoxycarbonyl-

  Isopropyl 2,6-dimethyl-pyridine-3-carboxylate in 10 ml of dimethylsulfoxide was added 0.43 g of powdered potassium hydroxide. After addition of 0.23 ml of methyl hard, the mixture was shaken. for 1 hour under a nitrogen atmosphere and then

28431

  The mixture is extracted with ice water. The mixture is extracted with methylene chloride, the methylene chloride solution is dried over magnesium sulphate and evaporated in vacuo. The residue is purified by low pressure silica gel chromatography.

  using a 49: 1 mixture of methyl chloride

  ether and ether as eluent After crystallization from a mixture of ether and hexane, the title compound melts at 92 lal 546 = -3 (ethanol, c = 0.67 9 / dl), lal 06 = -25 (chloroform,

c = 1.0 g / dl).

  d) 1: 1-13-: 1: ja 1,3: benzoxadiazol-4: yl) y, 4: dihydro-methoxy-carbonyl-2,6-dimethyl: ridin-3-carboxylate

  _ _ _ _ _ __ _ ___-__ _ _-__-__ _ _ _ _

  22 'isoer 29 py lcomposé of formula Ia, enantiomer, process b) l

  This compound is prepared from iso-

  mother (+) - (4 R) obtained under a), proceeding in a manner analogous to that described under b) It melts at 140 after crystallization in a mixture of ether

  and hexane Ia 206 = -10.1 (ethanol, c = 1.67 g / dl).

the 546

  lalD = -6.7 (ethanol, c = 1.67 g / dl).

  e) (±: (R 124 :( 2,1,3-benzoxadiazole: 4-y 1: 2,4-dihydro-5-

  methoxy-1,2,6-trimethyl-trimethyl-pyridine-3-carboxy:

  iso 2 ropyl late compound of formula I, enantiomer, process a)

  This compound is prepared from iso-

  (-) - (4 R) obtained under (d), in a manner similar to that described under (c) after crystallization in

  a mixture of ether and hexane, it melts at 93.

  lal 26 = + 3.1 (ethanol, c = 0.83 g / dl).

546 + 30 (0.3 cc)

  lal 5046 = + 23 (chloroform, c = 1.1 g / dl).

546 ''

  The imidazolide (III) used under a) 1) has a boiling point of 166 and is prepared by reaction

    4- (2,1,3-benzoxadiazol-4-yl) -1,4-acid

  dihydro-5-isopropoxycarbonyl-2,6-dimethyl-pyridine-3-

  carboxylic acid (compound IV) with a slight excess of 1.1 '-

  carbonyldiimidazole in dioxane.

  IV acid (F = 213) is obtained by

  hydrolysis at room temperature of 4- (2,1,3-benzoxamide)

  diazol-4-yl) - 11,4-dihydro-5-isopropoxycarbonyl-2,6-

  2-cyanoethyl dimethyl pyridine-3-carboxylate

  V) with 3 moles of NaOH in a 2: 1 mixture of water

and 1,2-dimethoxyethane.

  Ester V (F = 125) is prepared by reaction of 2-cyanoethyl aminocrotonate (compound VI) with 2-acetyl-3- (2,1,3-benzoxadiazol-4-yl) -2-propenoate

  isopropyl (compound VII) in dioxane.

  The ester VI (F = 88) is obtained by reaction of 2-cyanoethyl acetoacetate

  benzene solution with gaseous ammonia.

  Ester VII is prepared by condensation

  of 2,1,3-benzoxadiazole 4-carbaldehyde with acetone

  corresponding acetate in benzene at boiling, in the presence of catalytic amounts of piperidine

and acetic acid.

  Ester VII crystallizes as a mixture which can be separated into the E isomer (F = 75) and

Z isomer (F = 55).

Example 3

  (+) - (S) -4- (2,1,3-benzoxadiazol-4-yl) -1,4-dihydro-

  isopropylmethoxycarbonyl-2,6-dimethyl-pyridine-3-carboxylate lprocessed b) l

  a) 4 2,1,3-benzoxadiazol-4-yl) -1,4-dihydro-5-isopropoxy

  2-dimethylaminoethylcarbonyl-2,6-dimethylpyridine-3-carboxylate (compound IX) a.l The mixture is heated for 5 hours at room temperature.

  of boiling 5.0 g of 4- (2,1,3-benzoxadiazole)

  4-yl) R, 4-dihydro-5- (1H-imidazol-1-ylcarbonyl) -

  Isopropyl 2,6-dimethyl-pyridine-3-carboxylate

  (Compound III) and 24.5 ml of 2-dimethylamino-

  ethanol in 20 ml of dioxane The mixture is extracted with ice-water and acetate

  The organic phase is dried over sodium

  Magnesium fate is evaporated to dryness in vacuo and the residue is purified by silica gel chromatography. A 4: 1 mixture of methylene chloride and ether is used as the eluent. The hydrochloride is crystallized from a silica gel. mixture of ethanol and ether; He melts

at 150.

  a.2. It is heated for 16 hours at room temperature

  of boiling 182.6 g of 2-acetyl-3- (2,1,3-

  isopropyl benzoxadiazol-4-yl) -2-propenoate (compound VII) (mixture of Z and E isomers) and

  114.7 g of 2-dimethylamino-3-aminocrotonate

  in a liter of dioxane The mixture is evaporated to dryness in vacuo,

  the residue into hydrochloride and crystallized

  in a mixture of ethanol and ether.

  b) t: 1: S) -4: {2, I, 3: benzoxadiazol-4-yl> -1,4-dihydro-5-

  iso 1 r 22 exy: carb 2 oyl-2,6-dimethyl: eyridine-3-carboxy-

  2-dimethylaminoethyl late (compound XI) 52.6 g of the compound IX obtained under

  a) and 49.6 g of (-) - di-O, O'-p-toluoyl- (L) -tar-

  in 200 ml of warm isopropanol and

  rest; it forms the di-O, O'-p-toluoyl- (L) -tar-

  (compound X) After cooling to room temperature

  ambient, we filter the crystals that have

  formed and recrystallized twice in the

  propanol di-O, O'-p-toluoyl- (L) -tartrate is dried under high vacuum at 90 It melts at 146; 20 = 122 (ethanol, c = 1 g / dl), 1al 2546 = -156 (ethanol, c = 1 g / dl) The salt is converted to the title compound XI by addition of sodium hydroxide diluted and extracted with ether I 1 is in the form of an oily product of -45 (ethanol, c = 1 g / dl), lal 546 = -58 (ethanol,

c = 1 g / dl).

  c) 2,6-Dimethylammonioetyl iodide 2: 3: benzoxadiazol: 4: yl-1-dihydro-5-iso-2-oxycarbonyl 2,6-dimethyl-2-dichloro-3-carboxylic acid iodide; (compound XII) 12.4 g of the compound XI obtained under b) are dissolved in 120 ml of methanol. After adding 2.34 ml of methyl iodide, the solution is left standing for 15 hours at room temperature. are trained and we

  recrystallized from a mixture of methanol and ether.

  The product melts at 222 ° C., lal = -75 (ethanol,

* g / dl) the 20 = D-

  c = 1 g / dl), lal 546 = -99 (ethanol, c = 1 g / dl).

  (d) 2,4-Benzyl-2-benzoxadiazol-4-yl (2,4-benzaziazol-4-yl): 1,4-

  dihydr 5-isopro 22 xylbenzyl: 256: dimethyl: eyridine

  3-carboxylic acid (compound XIII) is allowed to stand for 16 hours at

  room temperature a solution of 15 g of iodine

  Methylate XII obtained under c) in 150 ml of dioxane and 300 ml of a 2 N aqueous solution of sodium hydroxide. While stirring and cooling, the solution is acidified by adding dropwise concentrated hydrochloric acid. for 30 minutes in an ice bath, the crystals which have formed are filtered, washed with

  ice water and they are dried under high vacuum at 80.

  + 7 ehnl The product melts at 168; lalD = +17 (ethanol, l = c D

  c = 1 g / dl), lal 240 = + 270 (ethanol, c = 1 g / dl).

  e) -1 S: 4: 2, 1,3-benoxadzol-4-yl) -1,4: dihydro-

  54 H-imi dazol-carbo ny -2-diimeth Y_ 1: ey ri di ne-3-

  Sulfyl carboxate (compound I Ib 13) is stirred for 2 hours at a bath temperature of a mixture of 8.6 g of the acid.

  XIII obtained under d) and 9.75 g of 1,4-carbonyldiimide.

  dazole in 190 ml of dioxane OD evaporates the solution

  The mixture is evaporated to dryness in vacuo and the residue is purified by gentle pressure chromatography on silica gel using a 19: 1 mixture of methylene chloride and ethanol as eluent. The product is crystallized from a mixture of methylene chloride and methylene chloride. of ether It melts at 182; lalD = 50 (ethanol, c = 1 g / dl), lal 546-71 (ethanol,

c = 1 g / dl).

  f) - + 4-: ys 14: 12,1,3: benzoxadiazo 14: y-) - 1:, 4-dihydro-

  Isoxycarbonyl-2: 2,6-dimethyl-pyridine-3-carboxylate (compound of formula I)

  It is heated for 16 hours at room temperature

  refluxing a solution of 5 g of the imidazolide I Ib 1 3 obtained under e) in 50 ml of methanol and evaporated to dryness in vacuo The residue is purified by chromatography on silica gel under slight pressure, using a mixture 1: 3 hexane and

ether as eluent.

  The product is crystallized from a mixture of ether and hexane It melts at 141; lal 20 = + 8 o (ethanol, c = 1 g / dl), lal 546 = + 12 (ethanol,

c = 1 g / dl).

  By proceeding in a manner analogous to that described in Example 1, the following compounds of formula I are obtained. The starting materials are known or can be prepared according to known methods.

from known products.

  Ex r R 3 enantiomer i i i i i i i i i i F F F CH 1) CH 1) CH 1)

1 CH 1)

- (CH 2) 2-OH 2).

- (CH IlCH 3)

2) 2 - (- C 3

- (CH 2) 2-0 CH 34)

  CH 3 CH 3 CH 3 CH 3 CH 3 CH 3 CH 3 CH 3 -butyl-butylcyclopentyl- (CH 2) 2 -O-propylpropyl i-propyl 'i-propyl i-propyl

= _ 117 '

= 1 33 '

= I Ao

= 106 '

4- E oil oil

F = 1060

F - = 100 "

  6) CH 2 -propyl - (-%, H) -fi -, 3

2 2 'CH

  i-propyl (CH 2) 8) CH 2 -propyl - (CH) N 3

2 2 '1 _ 1 CH

  1 F = 179% (hydrogen fumarate) CH 3

F = 162 '

  (Hydrogen fumarate) ## STR5 ## (methanol c = 1 g / d hydrobromide: m.p. = 243 ° C).

20

= + 5 c r ,, -: - + "O

10, L _J L t, -

  (methanol c = 0.6 q / d I CH 3 i t Ex R 1 R R Racemic or enantiomeric ipropyl CH

- (CH 2) 2 -N <C 3

9)

F = 92

  ## STR5 ## where: = 20 ° C = 0.65 (methanol, c = 1 g / dl), hydrobromide: mp = 243 ° C: D = 5.14, 546 = -8 (methanol, c = 0.6); g / dl)) alkylation with CH 3 I 2> alkylation with Br - (CH 2) 2 = 0-0 and cleavage of the ether linkage with HCl 3 from the compound of example 8 by reaction with acetic anhydride 4) alkylation with I- (CH 2) 2 -O-CH 3) alkylation with Br-CH 2 -C 6 -CH 6) alkylation with Cl- (CH 2) 2 -N- (CH 3) 2 7) alkylation with C- (CH 2) 2 -N alkylation with CI- (CHA) N, alkylation II of the compound of Example 3 f according to Example 12 II Il 2 d Il Il

CH 3

  8) 9) The compounds of the invention are distinguished by interesting pharmacological properties and can therefore be used therapeutically as medicaments. The compounds of the invention exert the

  characteristic effects of calcium antagonists.

  They exert a pronounced myo-relaxing effect, in parti-

  This is the case, for example, in the microsphere test carried out in the anesthetized cat according to the method described by R. Hof et al. in the case of the smooth muscles, as shown by the vasodilatation and the fall in blood pressure. Basic Res Cardiol 75, 747-756 (1980) and 76630-638 (1981) and by R Hof et al in J Cardiovasc Pharmacol 4, 352-362 (1982), dilation of the coronary vessels after intravenous administration of from about 5 to about 200 μg / kg or by intraduodenal administration from about 5 to about 400 μg / kg of N-alkylated compound of formula I and after intravenous administration of from about 5 to about 50 μg / kg or by intraduodenal route of about 10 to about 200, ug / kg of

  compound of formula I wherein R 3 is hydrogen.

  There is also a decrease in blood pressure after intravenous administration of approximately

  At about 250 pug / kg of N-alkylated compound and after

  intravenous administration of about 5 to about pg / kg of the compound of formula I wherein R 3 is hydrogen. There is also a drop in

  blood pressure in spontaneously awake awake rats

  stretched according to the method described by M. Gerold et al.

  in Arzneimittelforsch 18 1285 (1968) after administration of

  subcutaneously from about 0.1 to about 50 μg / kg of N-alkylated compound and after

2 28431

  subcutaneously from about 0.1 to about 10 mg / kg of

  compound of formula I wherein R 3 is hydrogen

  gene. Thanks to these properties, the compounds of the invention can therefore be used in therapeutics as calcium antagonists, for the prevention and the treatment.

  coronary insufficiency, such as angina pectoris

  trine, cerebrovascular insufficiency, such as stroke and stroke

  cerebrovascular, and cerebral spasm

  vascular, peripheral circulation disorders, for example in the limbs such as intermittent claudication and smooth muscle spasm, eg colon muscles, asthma, for example post-exercise asthma, and

hypertension.

  For therapeutic uses -indicated above, Nalkyl compounds will be

  given at a daily dose of between

  5 and about 400 mg and the compounds of Formula I

  wherein R 3 is hydrogen at a daily dose

  from about 5 to about 200 mg, advantageously administered, for example orally, in divided doses 2 to 4 times per day under

  form of unit doses each comprising between

  1.25 to about 100 mg of the compound of formula I wherein R 3 is hydrogen, or in delayed release form. An example of a daily dose is between about 5 mg

2 S D 28431

  and about 200 mg, preferably about 10

  and about 50 mg of the compound of Example 2c.

  The compounds of Examples 2b and 2c are

preferred compounds.

  The compounds of formula I alkylated on the nitrogen atom at the 1-position, especially the compound of Example 2c, have the advantage when administered intravenously, to have a slow onset of action and long duration of action, in comparison

  intraduodenal administration.

  They are about as active

  intraduodenally than intravenously.

  Their slow onset of action and their long duration of action make these substances, with their lesser side effects, safer than other 1,4-dihydro-pyridines for intravenous administration. Compounds having the S configuration, for example the compounds of Examples 2b and 2c, have a better pharmacological profile with respect to their activity than the R compounds and

the corresponding racemics.

  The compounds of the invention may be administered in free form or, if possible and appropriate, in the form of pharmaceutically acceptable acid addition salts. Such salts exert the same order of activity as the corresponding free forms and can be prepared according to

known methods.

  The invention thus relates to the compounds of the invention, in free form or in the form of a pharmaceutically acceptable acid addition salt, for use as medicaments, in particular for the treatment of coronary insufficiency. , cerebrovascular insufficiency,

  disorders of peripheral circulation, hyper-

tension or asthma.

  The invention also relates to a medicament

  cament containing, as active ingredient, a compound of the invention in free form or in the form of a salt

  acceptable acid addition from the pharmaceutical point of view

  ceutical. As medicaments, the compounds of the invention can be used in the form of pharmaceutical compositions containing a compound of the invention in free form or in the form of a salt.

  acceptable acid addition from the pharmaceutical point of view

  This pharmaceutical composition, which is also part of the present invention, may be prepared according to the usual methods and may for example be in the form of a pharmaceutically acceptable diluent or carrier.

  form-solutions, capsules or tablets.

Claims (11)

  1. Derivatives of 1,4-dihydropyridine of formula I N R OOC 'CR 1 COOR 2) l f v Q 2 ((I) H 3 N CH 3 R 3   wherein one of the substituents R 1 and R 2 is methyl and   the other isopropyl, n-butyl, isobutyl, cyclopropyl   pentyl or isopropoxyethyl and R 3 is hydrogen or an optionally substituted C 1 -C 6 alkyl group, or optically active lor-sque   R 3 means hydrogen, either in the form   racemic or optically active when R 3 has a meaning other than hydrogen 2. The 1,4-dihydropyridine derivatives according to claim 1, characterized in that one of the substituents R 1 and R 2 means methyl and the other isopropyl. The 1,4dihydropyridine derivatives according to claim 2, characterized in that R 3 is C 1 -C 6 alkyl.   4. The 1,4-dihydropyridine derivatives according to claim 2, characterized in that R 3 is methyl.   5. The 1,4-dihydropyridine derivatives according to claim 2, characterized in that R 3 is hydrogen.   2 z 284231 6 1,4-dihydropyrimidine derivatives,   characterized in that they are selected from 4- (2,1,3-   benzoxadiazol-4-yl) -11,4-dihydro-5-methyl-thoxycarbonyl   Isopropyl 1,2,6-trirsyryl-pyridine-3-carboxylate, (+) - (R) -4- (2,1,3-benzoxadiazol-4-yl) -1,4-dihydro-methoxy -carbonyl-11,2,6-trynethylpyrid, ne-3-carboxy-   isopropyl late, (-) (R) -4- (2,1, -3-benzoxadiazole-4-   yl) -1,4-dihydro-5-methoxycarbonyl-2,6-dimethyl-pyridine   Isopropyl 3-carboxylate, 4- (2,1,3-benzoxadiazole-4-   yl) -1,4-dihydro-5-methoxy-carbonyl-1,2,6-trimethyl-   n-butyl pyridine-3-carboxylate, 4- (2,1,3-   benzoxadiazol-4-yl) -1,4-dihydro-5-methoxy-carbonyl-   1,2,6-trimethyl-pyridine-3-carboxylic acid isobutyl ester,   4- (2,1,3-benzoxadiazol-4-yl) -1,4-dihydro-5-methoxy-   cyclic carbonyl-1,2,6-trimethylpyridine-3-carboxylate   pentyl, 4- (2,1,3-benzoxadiazol-4-yl) -1,4-dihydro-   -methoxy-carbonyl-11,2,6-trimethyl-pyridine-3-carboxy   2-isopropoxy-ethyl acetate, 4- (2,1,3-benzoxadiazole   4-yl) -1,4-dihydro-1- (2-hydroxyethyl) -5-methoxycarbonyl   Isopropyl 2,6-dimethyl-pyridine-3-carboxylate,   1- (2-acetoxyethyl) -4- (2,1,3-benzoxadiazol-4-yl) -1,4-   dihydro-5-methoxycarbonyl-2,6-dimethyl-pyridin-3-   isopropyl carboxylate, 4- (2,1,3-benzoxadiazole-4-   yl) - 11,4-dihydro-5-methoxycarbonyl-1- (2-methoxyethyl) -   2,6'-Dimethyl pyridine-3-carboxylic acid isopropyl   4- (2,1,3-Benzoxadiazol-4-yl) 1,4-dihydro-5-methoxy-   carbonyl -2,6-dimethyl-1- (2-propynyl) -pyridine-3-carboxylic acid   isopropyl late, 4- (2,1,3-benzoxadiazo-1-4-yl) -1-   (2-dimethylaminoethyl) -1,4-dihydro-5-methoxycarbonyl   Isopropyl 2,6-dimethyl-pyridine-3-carboxylate,   4- (2,1,3-Benzoxadiazol-4-yl) -11,4-dihydro-5-methoxy-   carbonyl-2,6-dimethyl-1- (2-morpholinoethyl) -pyri-   isopropyl dine-3-carboxylate, the (+) - (S) -4- (2,1,3-   benzoxadiazol-4-yl) -1- (2-dimethylaminoethyl) 11.4-   Dihydro-5-methoxycarbonyl-2,6-dilethylpyridin-3-   isopropyl carboxylate and (-) - (R) -4- (2,1,3-benzoxa)   diazol-4-yl) -1- (2-dimethylaminoethyl) -1,4-dihydro-5-   isopropyl methoxycarbonyl-2,6-dimethyl-pyridine-3-carboxylate.   7. (-) - (S) -4- (2,1,3-benzoxadiazole   4-yl) - 11,4-dihydro-5-methoxycarbonyl-1,2,6-trimethyl-   isopropyl pyridine-3-carboxylate.   8. (+) - (S) -4- (2,1,3-benzoxadiazole-4-   yl) - 11,4-dihydro-5-methoxycarbonyl-2,6-dimethylpyridine Isopropyl 3-carboxylate.   9. Derivatives of 1,4-dihydropyridine   according to any one of claims 1 to 8,   characterized in that the basic compounds are   in the form of free base or acid addition salts.   A process for the preparation of the 1,4-dihydropyridine derivatives of the formula I as claimed in claim 1, characterized in that a) a compound of the formula Ia + sN R is alkylated on the nitrogen atom in the 1-position. 100 yCR 2 (Ia) HC N CH   3 h 3 in which R 1 and R 2 have the meanings given in claim 1, or b) in an optical isomer of a compound of formula II   3 R 1 10 CO 4 - (I I) c OR 4 H 3 C CH 3 3 in which   R 1 and R 3 have the meanings given to the   1, and R 4 denotes an eliminable group, the radical R 4 is exchanged with a radical OR 2 O R 2 has the meaning given in claim 1, and when the compound of formula I is basic, such a recycle is recovered. compound in free base form   or as an acid addition salt.   11 Derivatives of 1,4-dihydropyridine   according to any one of claims 1 to 8, the   basic compounds being in free base form or in the form of a pharmaceutically acceptable acid addition salt, for use as a drugs.   12. Derivatives of 1,4-dihydropyridine   according to any one of claims 1 to 8, the   basic compounds being in free base form or in the form of a pharmaceutically acceptable acid addition salt, for use in the   treatment of coronary insufficiency, insufficiency   cerebrovascular disease, circulatory disorders   peripheral, hypertension or asthma.   13. A medicament, characterized in that it contains, as active principle, a 1,4-dihydropyridine derivative as specified in one of the following:   any of claims 1 to 8 in the form of   free base or in the form of a pharmaceutically acceptable acid addition salt when the compound is basic.   14. A pharmaceutical composition, characterized in that it contains as active substance a derivative of 1,4-dihydropyridine such as   specified in any one of claims 1 to 8,   as a free base or as an additive salt   a pharmaceutically acceptable acid when the compound is basic, in combination with pharmaceutically acceptable diluents or carriers.   15. The derivatives of 1,4-dihydro- pyridine of formula II 0 N N IN / ', R 100 C 'N OR 4 t I (He) H 3 C CH 3 3   in which R 1 and R 3 have the given meanings   in claim 1, and R 4 denotes a group eliminating nable, as optical isomers.   16. The 1,4-dihydropyridine derivatives according to claim 15, characterized in that   are selected from (-) - (S) -4- (2,1,3-benzoxadiazole-   4-yl) -1,4-dihydro-5-i-propoxycarbonyl-2,6-dimethyl -   2- (R) -methoxy-2-phenylethyl pyridine-3-carboxylate,   (+) - (R) -4- (2,1,3-benzoxadiazol-4-yl) -1,4-dihydro-.   2- (R) -methoxy-2-phenylethyl-isopropoxycarbonyl-2,6-dimethyl-pyrrole-3-carboxylate, 4- (2,1,3-   -benzoxadiazol-4-yl) -1,4-dihydro-5- (I-H-imidazol-1-   ylc arbonyl) -2,6-dimethyl-pyridine-3-carboxylic acid ester   propyl, 1 '- (-) - (S) -4- (2,1,3-benzoxadiazol-4-yl) -1,4-   dihydro-5- (1H-imidazol-1-ylcarbonyl) -2,6-dimethyl   Isopropyl pyridine-3-carboxylate and (+) - (R) -   4- (2,1,3-Benzoxadiazol-4-yl) -1,4-dihydro-5- (1H-imidazol-1-ylca) -rbonyl) -2-dmethyl-pyldi-3-arboxyl ate dl i sopropy the