LU86775A1 - HETEROCYCLIC COMPOUNDS, THEIR PREPARATION AND PHARMACEUTICAL COMPOSITION - Google Patents

Description

h '1 f t

The present invention relates to novel heterocyclic derivatives which have an effect on the transmembrane influx of calcium ions into the cells of the heart and smooth muscles, processes for the preparation of these derivatives, pharmaceutical compositions containing them and their employment in the therapeutic field.

The role played by intracellular calcium ions in controlling the contraction system of the heart muscles and smooth muscles is well known. It has been found that compounds which limit the concentration of intracellular calcium ions by preventing or reducing the "influx" of transmembrane calcium ions into the cells of the contraction system of the heart muscles and smooth muscles are suitable for treatment of cardiovascular disorders.

The Applicants have now discovered a new group of compounds which reduce the concentration of intracellular calcium ions by limiting the influx of transmembrane calcium ions and, consequently, that these compounds may be of value for the treatment of 2 * disorders. cardiovascular, such as hypertension, 1 * angina pectoris, 1 * myocardial ischemia, congestive heart failure, cerebral and peripheral vascular disorders. Compounds of this kind may also be useful for the treatment of disorders characterized by reversible airway obstruction, such as asthma and chronic bronchitis.

The present invention therefore more particularly relates to compounds of general formula (I) 10 // \ • · I n • \\ A? 7. ch = cco2r6 15 Ma <\ ^ ^ OjRj

AA

r / N XAlkNR1R2 H

20 and their physiologically acceptable or compatible salts, formula in which represents a hydrogen atom or a C 1 -C 4 alkyl radical, Rg represents a hydrogen atom, a C 1 -C 6 alkyl radical or phenylalkyl (in which the phenyl nucleus may be substituted by a nitro radical, C 1 -C 4 alkyl, C 1 -C 4 alkoxy or hydroxyl, or by a halogen atom, or R 1 and R 4 may together with the nitrogen atom to which they are attached, form a pyrrolidino, piperidino, hexamethyleneimino, morpholino, thiamorpholino, thiamorpholino S-oxide, thiamorpholi-no S, S-dioxide, piperazino, N-methylpiperazino or N nucleus -phé-nylpipérazino;

Alk represents a methylene or ethylene chain; R ^ and R ^ independently represent a straight chain or branched chain alkoxyalkyl or alkyl radical

'V

x · * · * 3 in C.j-Cg; R (j represents a C 1 -C 4 alkyl radical ion;

Rg represents a C 1 -C 4 alkyl radical or m ra ~ dical cycloalkyl C, j-Cqi may be substituted by a C 1 -C 4 alkyl group and

Ry represents a halogen atom or a hydrogen atom, or a C 1 -C 4 alkyl radical.

The compounds represented by formula (I) may exist as more than one form of isomer and / or enantiomorph and, therefore, the scope of the present invention extends to all isomers, enantiomorphs and mixtures thereof. "

The term "alkyl" as a group means that this group is straight chain or branched chain.

The compounds of formula (I) form salts with inorganic and organic acids and the scope of the present invention obviously extends to these salts. Mention may be made, as more particularly advantageous salts, of those obtained with acids. physiologically acceptable or compatible inorganic and organic compounds and these salts include hydrochlorides, hydrobromides, sulfates, tosylates, methane sulfonates, acetates, maleas, fumarates, formates, succinates, phosphates, citrates, benzoates, tartrates and dibenzoyltartrates. The hydrochlorides and hydrobromides are preferred.

When R 1 represents a C 1 -C 4 alkyl radical and / or R 2 represents a C 1 -C 6 alkyl radical, they may, independently, be, for example methyl, ethyl, propyl or isopropyl radicals.

Examples of suitable radicals for R ^ and R ^ include, independently, C 1 -C 4 alkyl radicals, such as methyl, ethyl, isopropyl, isobutyl or tertiary butyl, or (C 1 -C 4) alkyl such as ethyl) substituted by C ^-C ^ alkoxy radicals (P2 ^ example metho-35 xy or propoxy) “'4

V

k

Examples of radicals which are suitable for include methyl and ethyl groups.

When the symbol Rg represents an alkyl radical, the latter may be, for example, a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, isopentyl, neopentyl, hexy-le, 2,6-dimethyl radical. -4-heptyle or octyle. When the symbol Rg represents a cycloalkyl radical, the latter is conveniently a cyclopentyl, cyclohexyl or cyclo-10-heptyl group, which may be substituted by a methyl radical.

When the symbol Ry represents a C 1 -C 3 alkyl group, the latter may be, for example, a methyl, ethyl or n-propyl radical.

When the symbol Ry represents a halogen atom, it may be, for example, a chlorine, bromine or iodine atom.

The radical -CH = CRyCO2Rg in the compounds of formula (I) can exist in the cis or trans configuration. The preferred compounds are those in which the hydrogen atom and the Rg group are present in a trans configuration with respect to each other, and these isomers will be referred to below. of this brief under the name of trans isomers.

The compounds according to the present invention have an asymmetric carbon atom at position 4 of the dihydropyridine ring and formula I encompasses both the enantio-morphs and their mixtures. The two individual enantiomorphs can be represented by the formulas (la) and (Ib) and we prefer the enantiomorph represented by the formula (1b), to which we will refer later in this memo under designation of enanfciomorph S. In the remainder of this document, reference will be made to the enantiomorph represented by the formula (1a) under the name of enan-tiomorph R.

i i "5

/ A î7 e n î7 / A

I · »// '“ C0A M2c — xx î ·, • · · · II · ”\\ / \\ / I hh \ i Rî * 02C \ / \ / C02R3 R3 ° 2C ^ ^? Ri * • * · ♦ ^ ii il nu aa, λ,, A a RS N (CH 2) NR iR 2 RiR2N (CH2) N · Rs s H ^ nw 1 Δ ^ n H s (1a) (1b)

The preferred compounds of formula (a) are those in which preferably represents a hydrogen atom or the methyl radical and R 5 preferably represents a hydrogen atom or a C 1 -C 4 alkyl radical, such as methyl, ethyl, propyl or isopropyl.

When R 1 and R 6 together with the nitrogen atom to which they are attached form a heterocyclic ring, this is preferably a pyrrolidino, piperidino, morpholino, piperazino and thiomorpholino group.

R3 independently represent preferably C 1 -C 4 alkyl radicals, for example methyl or ethyl.

R 4 preferably represents the methyl radical.

Rg represents, preferably, a Cg-Cg alkyl radical, such as an ethyl, propyl, isopropyl, tertiary bu-tyl, pentyl or octyl group, or a cycloal- radical; C1-4alkyl which may be substituted by C1-4alkyl, for example cyclohexyl;

Ry preferably represents a bromine atom or ‘6 V - h a hydrogen atom or a C 1 -C 4 alkyl radical, such as a methyl or ethyl group

A particularly preferred class of compounds according to the present invention is that formed by the substances of formula (I) in which R-jRgN represents an amino, methylamino, ethylamino, isopropylamino, dimethylamino or morpholino radical, Alk represents an ethylene chain or, more particularly, methylene, R ^ and R ^ independently represent methyl or ethyl radicals, more particularly ethyl, R ^ represents a methyl radical, Rg represents a cyclohexyl or Cg-Cg alkyl radical, for example ethyl, propyl, isopropyl, tertiary butyl, pentyl or octyl and Ry represents a hydrogen atom or a methyl or ethyl radical.

Another particularly preferred class of compounds according to the present invention is that formed by the substances of formula (I) in which R ^ RgN represents a methylamino, isopropylamino, dimethylamino or morpholino radical, Alk represents an ethylene chain, R 1 and independently represent an ethyl or methyl group, R 1 represents a methyl radical and R 6 represents an isopropyl radical or, more particularly a tert-butyl radical when Ry represents a hydrogen atom, or R 6 represents an alkyl radical in C 6 - Cg, more particularly an ethyl, isopropyl, propyl, tert-butyl or pentyl radical and Ry represents a methyl or ethyl radical.

As particularly preferred compounds according to the invention, the following substances may be mentioned: 2-dimethylaminoethyl-6-methyl-4- (2- (3- (1,1-dimethyletho-xy) -3-oxo-1 - diethyl propenyl) phenyl-1,4-dihydr opyridin-3,5-di-carboxylate; and more particularly its trans (E) isomer and their S enantiomorphs and their physiologically acceptable salts, more particularly brom-35 hydrate or hydrochloride.

i 7

, V

i.

Other preferred compounds according to the present invention are the following substances: 2-methylaminomethyl-6-methyl-4- (2- (3- (1,1-dimethylethoxy) - 3-ΟΧΟ-1-propenyl) phenyl) -1,4-dihydropyridine-3,5-dicar-5 diethyl boxylate; Diethyl 2-aminomethyl-6-methyl-4- (2- (2- (1,1-dimethylethoxy) -3-oxo-1-propenyl) phenyl) -1,4-dihydropyridine-3,5-dicarboxylate; 2-isopropylaminomethyl-6-methyl-4- (2- (3- (1,1-dimethyletho-10 xy) -3-oxo-1-propenyl) phenyl) -1,4-dihydropyridine-3,5-di diethylcarboxylate; 2-m thylaminomé thyl-6-m thyl-4- (2- (3-ethoxy-3-oxo-2-mé-thyl-1 -pr opényl) phenyl) -1,4-dihydr opyr idine-3,5 -diethyl dicarbo-xylate; Diethyl 2-methylaminomethyl-6-methyl-4- (2- (3-ethoxy-3-oxo-2-ethyl--1-propenyl) phenyl) -1,4-dihydropyridine-3,5-dicarboxylate; 2-propylaminomethyl-4- (2- (3- (1,1-dimethylethoxy) -3-oxo - 1-propenyl) phenyl) -6-methyl-1,4-dihydropyridine-3,5-di-20 carboxylate diethyl; 2-me thylaminomé thyl-4- (2- (3- (1,1-dimethylethoxy) -3-oxo - 1-propenyl) phenyl) -β-methyl-1,4-dihydropyridine-3,5-di- methyl and ethyl carboxylate; Diethyl 2-dimethylaminomethyl-6-methyl-4- (2- (3-propoxy-3-oxo-2-25 -methyl-1-propenyl) phenyl) -1,4-dihydropyridine-3,5-dicarboxylate ; 2-methylaminomethyl-6-methyl-4- (2- (3-propoxy-3-oxo-2-me-thyl-1-propenyl) phenyl) -1,4-dihydropyr idine-3,5-dicarboxy-late diethyl; 30 and, more particularly, their trans (E) isomers and their S enantiomorphs, as well as their physiologically acceptable salts.

The ability of the compounds according to the present invention to limit or inhibit the effect of calcium ions on the tone of vascular smooth muscles has been determined Λ 8

V

t ν ...

mined using a depolarized rabbit ear artery, prepared using the Towart process. R. and coli. Br. J. Pharmacol. 1982, 75, 1508.

The anti-hypertension activity of the compounds posed according to the present invention has been demonstrated by the intravenous and / or oral administration of the compound to spontaneously hypertensive male rats.

It has been found that the compounds according to the present invention tested have a particularly advantageous activity profile, including a relatively long duration of action.

The compounds according to the present invention are therefore of interest for the treatment of hypertension and of diseases characterized by a reversible obstruction of the respiratory tract, such as asthma and chronic bronchitis.

They are also potentially useful for the treatment of other cardiovascular disorders, including angina pectoris, myocardial ischemia, congestive heart failure, cerebral and peripheral vascular disorders.

The compounds according to the present invention may be presented for use in a conventional manner, using one or more pharmaceutical excipients or carriers.

Consequently, according to one of its characteristics, the present invention also relates to compounds 1.

pharmaceutical compositions which comprise the compounds of formula (I) and / or physiologically acceptable addition salts thereof, suitable for administration by the oral, sub-lingual, transdermal, parantral or rectally, or for administration by inhalation or - insufflation.

For oral administration, the pharmaceutical composition may take the form, for example, of tablets, which may be coated with film or sugar, capsules, powders, granules, solutions including syrups, or suspensions, which are prepared by any conventional means with acceptable exci-5 pients. For administration by the sublingual route, the composition may take the form of tablets or lozenges obtained in the conventional manner.

For administration by the parenteral route, the compounds of formula (I) can be administered as by injection of a bowl or by continuous infusion. The compounds may take forms such as suspensions, solutions or emulsions in oily or aqueous vehicles and may contain composing agents, such as suspending, stabilizing and / or dispersing agents. For administration by injection, the compounds of the present invention may be presented in the form of a unit dose or in the form of multiple doses, preferably containing an additional preservative.

For administration by the parateral route, the active ingredient can also be in the form of a powder, the composition then being reconstituted by mixing the powder with an appropriate vehicle.

The compounds of formula (I) can be presented in the form of ointments and creams for transdermal administration and also in the form of sup- I.

positive or drug enema for rectal administration.

For administration by inhalation, the compounds of formula (I) may be presented in such a way that they can be inhaled as a very fine dispersion of aerosol / powder.

The proposed daily dose of active compound according to the invention for the treatment of humans varies from 10 \ 0.03 mg to 100 mg, which can conveniently be administered in one or more doses. The precise dose used depends on the age and condition of the patient, as well as the mode of administration.

For use by the oral route, the compounds according to the invention are conveniently administered to the human patient in a dose which fluctuates from 0.3 to 40 mg per day. For use by the pareral route, the compounds according to the present invention are conveniently administered in a dose which varies from 0.01 to 2 mg, preferably 0.03 to 1 mg, per day.

For use by inhalation, the compounds of the present invention are conveniently administered to the human patient in a dose ranging from 0.1 mg to 15 mg per day.

For use by the oral route, the compound is preferably administered twice or, more particularly, once a day.

Methods of preparing the compounds of formula (I) as well as intermediates are described below and in the following formulas ^ R ^ -R ^ and Alk have the meanings which have been previously assigned to them in connection with the definition of the compounds of formula (I), or else these symbols represent groups which are in a protected form, unless otherwise specified.

The compounds of formula (I) in which Alk represents the methylene radical can be prepared from compounds of formula (II) in which X represents a labyl group, such as a halogen atom 11 / Λ / Λ

î Î I II

* \\ / * \ ί7 * \\ / * \ f? - CH = cco2R6 ch = cco2r6 R, o2C \ 7co2r3 R, o2cx / Co2r3

He II II î

Rs N ch2x r 'Y \ h3 (III) and the appropriate amine The reaction is preferably carried out in an aprotic solvent, such as a halogenated hydrocarbon, for example chloroform, dichloromethane or 1, 1,1-Trichloroethane and at a temperature which fluctuates from -20 to + 20 ° C, preferably less than 0 ° C. The reaction can also conveniently be carried out in the presence of an additional base, for example py-r idine.

The compounds of formula 10 (II) are conveniently prepared in situ from the compounds of formula (III).

Thus, the compounds of formula (III) can be treated with an appropriate halogenating agent, such as chlorine, bromine, N-chlorosuccinimide or N-bromosuc-cinimide or, more particularly, brom-15 perbromide pyridine hydrate. The halogenation reaction can conveniently be carried out in a suitable aprotic solvent, such as chloroform, or, more conveniently, dichloromethane, at a temperature which varies from -20 to 40 ° C, preferably from -15 to 20 °. vs. The compounds of formula (II) in which X represents an iodine atom can be prepared by ion exchange from the corresponding bromide.

The trans isomers of the compounds of formula (I) * 12 ″ in which and / or Rg do not represent hydrogen atoms and Ry represents a hydrogen atom or an alkyl radical, can also be prepared from compounds of formula (IV) 5 # \ I li ♦ · \\ / \

Hsl 10 M2cwlwc ° 2R3 (iv) to i • t „/ \ / \ R â N Alk NRiR, 3 H 1 * 15 (in which Hal represents a bromine or iodine atom) by reaction on an acrylic ester of the formula? 7 CH2 = CC02Rg in which Ry represents a hydrogen atom or an alkyl radical.

The reaction takes place in the presence of a catalytic amount of a palladium salt, such as palladium acetate, in the presence of an organic base, such as a trial-kylamine, for example triethylamine or tri-n-butyl -25 amine. The reaction is also preferably carried out in the presence of a triarylphosphine, such as tri-o-tolylphos-phine or triphenylphosphine.

The reaction is conveniently carried out in a suitable solvent, such as xylene or t-bu-50 tyle acetate, or, more advantageously still, in dimethyl acetamide, dimethylformamide, or in a mixture of solvents, by example xylene / dimethylformamide, de = preferably under heating. The reaction mixture is preferably heated to a temperature which fluctuates from 60 ° C. to 150 ° C., preferably from 80 ° C. to 110 ° C.

13

It is also possible to prepare the compounds of formula (I) in which Alk represents the ethylene radical, starting from compounds of formula (III) by aminomethylation involving a reaction on an amine R "| R2NH, 5 or a salt of the latter and formaldehyde. The reaction can be carried out by reacting an aqueous solution of the amine with formaldehyde in aqueous solution and the compound (III), in the presence of a suitable acid, such as glacial acetic acid, under heating, of pre- 10 reference in a range which fluctuates from 80 to 100 ° C. Alternatively, when the amine is used in the form of its hydrochloride salt, the reaction can be carried out using an alkanol, such as ethanol, as solvent, in the presence of acid. hydrochloric acid, at reflux.

According to another method, the compounds according to the present invention of formula (I) can be prepared by esterifying the corresponding acid of formula (I) in which Rg represents a hydrogen atom. Thus, according to an embodiment of this process, compounds of formula (I) can be prepared by treating a compound of formula (I) in which Rg represents a hydrogen atom, with an agent for alkylation RgX in which Rg has the meanings which have been previously assigned to it with regard to the definition of formula 25 (I) and X represents a labile group, such as a halogen atom or a mesylate radical. The reaction is preferably carried out in the presence of a base, such as an alkali metal or alkaline earth metal carbonate, for example potassium carbonate, in an aprotic solvent, such as dimethylformamide or dimethyl sulfoxide, optionally under heating. Thus, for example, the reaction can be carried out at a temperature which varies from 10 to *. 100 ° C.

According to another embodiment of this process, the compounds according to the present invention can be prepared from the corresponding carboxylic acid of formula (I) in which Rg represents a hydrogen atom, via a activated derivative thereof, such as a mixed anhydride, by reaction on an appropriate alcohol of the formula RgOH in which Rg has the meanings which have been previously assigned to it in connection with the definition of formula (i), or its alcoholate .corresponding.

The compounds of formula (I) in which Rg represents a hydrogen atom can be prepared by the hydrolysis of a compound of formula (I) in which Rg represents a tertiary butyl radical. Hydrolysis can be carried out by using hydrobromic acid in acetic acid, in the presence of a solvent, such as dichloromethane. Preferably, the reaction is carried out at low temperatures, for example from -78 to -35 ° C.

The carboxylic acids represented by the compounds of formula (I) in which Rg represents a hydrogen atom are new substances and constitute chemical intermediates of interest for the preparation of the compounds of formula (I) and therefore the scope of the present invention also extends to it.

The compounds of formula (i) in which the group -CH = CRyCO2Rg occurs in the cis configuration can be prepared by irradiation of a solution of the corresponding trans isomer. Thus, when exposing a solution of the trans isomer in dichloromethane, under a nitrogen atmosphere, in daylight, a mixture of the cis and trans isomers is obtained and the latter can be separated by conventional techniques, such as fractional crystallization and / or chromatography.

The compounds of formula 5 (I) can also be prepared by the reaction of compound (VI) with phosphorane

PhjPsCRyCO ^ Rg in a suitable solvent, such as dichlo-35 romethane, tetrahydrofuran or toluene. Preferably 15 "*.

The reaction is carried out under heating, for example 40-120 ° C., conveniently at reflux.

5 Λ \ Λ \ · · · · "I il | * \ // - CH0 · \ // - CH (0Ra) 2

î! / ’XX

R | + ° 2C \ A / CQ2R3 Ri * 0 2C. ·. .C02R3 II T

V V V V V / -CH (0Re) j

10 »“ Il V

Ά / \ / '\ / \ Ln

Rs N A1KNR1R2 R 5 N 'aIKNR.R, HH 12 (wine) (VI) (VII) 15 The intermediate (VI) can be prepared by hydrolysis with acid in aqueous solution of the corresponding acetal (Vil) ( in which RQ represents an alkyl radical).

The compound of formula (VII) can be prepared from the aldehyde (VIII) by reaction with a compound of formula (XI) and / or (XIII) under the conditions described below with regard to the preparation of compounds of formula (III) from intermediate (XI). The intermediate (VIII) can be prepared from the bromobenzene derivative (IX) by reaction on butyllithium in a solvent, this reaction being followed by the addition of dimethylformamide.

/ wch (or8) 2 I î 30 \ Λ • Br (IX)

The compounds of formula (III) can be prepared by reacting the acetone a, β-unsaturated (IX) on the amino ester (X). The reaction is conveniently carried out in a solvent, such as an alkanol, for example ethanol or 1 ’isopropanol, and preferably by heating, for example, to 40-150 ° C.

5

AT

ï f f 7 / HC02R3. .-ch = cco2r6 h 2N-C ^ f ch3 1 ° rî02cx 7 / ch Γ (XI)

AT

15 0n ~ can prepare acetone a, β-unsaturated (X) by reacting the aldehyde (XII) on the ketoester (XIII), in a solvent, such as an alkanol, for example ethanol or 1 ' Isopropanol, preferably under heating, This reaction is conveniently carried out in the presence of a catalyst, such as piperidine acetate.

// \ .CH2CO2ÎU

• j ç / 25 \ / \ f7 Λ *

• CH = CC02Rs CHO

(XII) (XIII) According to a variant of this process, the aldehyde (XII) can be reacted on a mixture of the aminoester (XI) and the ketoester (XIII) under the conditions described above with regard to the reaction of the ketone α, ß— -unsaturated (X) on the aminoester (XI).

35 The compounds of formula (III) in which and 9 ί.

17 R ^ are identical and represents the methyl radical, can be prepared by reacting the aldehyde (XII) on the aminoester (XI), in the presence of a suitable acid catalyst. Examples of suitable acid catalysts include organic acids, such as oxalic acid, alkanoic acids, for example acetic acid, or haloalkanoic acids, such as trichloroacetic acid or acid. trifluoroacetic acid, or their pyridimium salts, or a sulfonic acid, such as an alkane sulfonic acid, for example methane sulfonic acid, or an arylsulfonic acid, for example benzene sulfonic acid or p-toluene acid sulfonic, or a tetrahaloboric acid, such as tetrafluoroboric acid. The reaction can be carried out in the presence of a solvent and preferably at a temperature which fluctuates from -70 ° C to 30 ° C, more preferably from -30 ° C to 20 ° C. Mention may be made, as solvents suitable for carrying out the reaction, of aprotic solvents, such as hydrocarbons, for example hexane or cyclohexane, acetonitrile or ethers, such as tert-butyl ether - methyl, dioxane or tetrahydrofuran, or protic solvents, such as an alkanol, for example methanol, ethanol, propanol, isopropanol or butanol · Compounds of the formula ( XII) in which Ry has the meanings which were previously assigned to it, other than a halogen atom, by reacting a 2-halobenzaldehyde (XIV)

/AT

• ·

I II

• · \ al (XIV)

CHQ

5 18 (in which Hal represents a bromine or iodine atom) L7 on an acrylic ester of the formula CHgsCCOgRg, under the conditions described with regard to the reaction between the 'compounds of formula (IV). on the acrylic ester of F7 formula CHgsCCO ^ Rg.

The compounds of formula (XII) can also be prepared by reacting the bisaldehyde (XV) with the triphenylphosphorane Ph ^ P ^ RyCOgRg in a solvent, such as chloromethane, dichloromethane or toluene.

/ Λ

I II

• "\\ / \

15CHQ

CHO

(XV)

The compounds of formula (IV) can be prepared from compounds of formula (XVI) 20 / Λ I lî • · \\ / \ • Hal 25 M2 <\ 7 · χ / C0-2R3 r.

• · II. It • · D / \ I \ R 5 fj CH 3 (XVI) using the amination and aminomethylation processes previously described in connection with the preparation of compounds of formula (I).

.30

V

19

Compounds of formula (i) can also be prepared by the reaction of the ketone a, β-unsaturated (X) on the diaminoester (XVII). The reaction is conveniently carried out in a solvent, such as a suitable alkanol, for example ethanol or isopropanol and, preferably, under heating, for example at a temperature of 40 to 150 ° C.

10 A

• · 1 "\\ A i7 ♦ ch = c-co2r6 M2Cw / CH fJH CO 2R 3 'c, c λ ei / \ D, C .. H2N (ch2) -nr, r2 R 5 0 (X) (XVII ) In order to prepare the compounds of formula (I) in which R 1 and / or R 2 represent hydrogen atoms, it is necessary to use a diaminoester of the formula (XVII) in which R 1 and R 2 represent a group which can be removed, so as to obtain a hydrogen atom. Thus, it is possible to prepare the compounds of formula (I) in which R ^ and R2 both represent hydrogen atoms, using a diaminoester (XVII) in which the radical NR ^ Rg represents a phthalimido group . The compound resulting from formula (I) in which R ,, R2N represents a phthalimido group can then be converted into the compound in which Rj and R2 represent hydrogen atoms, by treatment with hydrazine in an appropriate solvent , like an alkanol.

The intermediates of formula (XVI) can be prepared from compounds of formulas (XI), (XIII) and * 20 * (XIV) according to a reaction analogous to that which was previously described with regard to the preparation of the compounds of formula (III) from the compounds of formulas (XI), (XII) and (XIII).

The compounds of formula (I) in which one of the symbols and represents a hydrogen atom can be prepared by treating the corresponding compound of formula (I) in which the appropriate symbol R ^ or Rg represents a radical benzyl, with a suitable ester of chloroformic acid and then hydrolyzing the carbamate derivative thus obtained. As suitable esters of chloroformic acid, mention may be made of haloethyl chloroforms, such as trichlorethyl chbrotofate, and this reaction step is conveniently carried out in a solvent, such as a hydrocarbon, for example toluene. and preferably under heating. Hydrolysis of the carbamate thus obtained, for example trichlorethyl carbamate, can be carried out using zinc and the appropriate acid, such as formic acid or acetic acid, and this is optionally carried out. hydrolysis in a solvent, such as dimethylformamide.

In the general processes for the preparation of the compounds of formula (I) described above, the desired product can be obtained and / or isolated in the form of a salt, conveniently in the form of a physiologically acceptable salt. or compatible. When desired, such salts can be converted to the corresponding free base of formula (I) by use of conventional methods.

Physiologically acceptable or compatible salts of the compounds of formula (I) can be prepared by reacting a compound of formula (I) with a suitable acid, in a suitable solvent, such as acetone, acetate, ethyl, or an alkanol, for example ethanol. When it is necessary to obtain a specific enantiomorph of the formula (1a) or (1b), this can be obtained by solving a mixture of enantiomorphs of the corresponding compound of the general formula (I ) using conventional methods. Thus, according to example 5, an optically active acid suitable for forming salts with a mixture of enantiomorphs of a compound of the general formula (I) can be used. The mixture of isomeric salts thus obtained can be separated, for example, by fractional crystallization, into the individual diastereoisomeric salts, from which the desired enantiomorph of formula (1a) or (1b) can be isolated, whatever either in the form of the free base or in the form of a salt.

The compounds of formulas (V), (IX), (XI), (XIII), (XIV), (XIV) and (XVII) are known compounds, or else they can be prepared according to methods analogous to those used. works for obtaining known substances.

The following examples illustrate the present invention. In these examples, temperatures are given in degrees Celsius. In all of the following examples, the abbreviation c.c.m. denotes thin layer chromatography on silica plates and, unless otherwise specified, using ethyl acetate / cyclohexane / methanol (7: 3: 2) as solvent. Column chromatography was carried out on silica gel by eluting with ethyl acetate / cyclohexane / methanol (7: 5: 2), unless otherwise specified.

Intermediate 1 4- (2-BromoT) hénvl) -1.4-dihvdro-2.6-dimé thvl-5.5-nvr diethyl idine-carboxylate Intermediate 2 (s) -3- (2-Formvlnhénvl) -2-T> ronenoate 1 “1-dimethyl and ethyl” ♦ 22

Intermediate 5 (E) -4- (2- (3- (1,1-Dimethylethoxv) -5-oxo-1 -propenvl) phenyl) --1,4-diethyl-2,6-dimethyl-3 "5-pyridinedicarboxvlate 5 Intermediate 4 (a) (S) -3- (2-Formvlphénvl) -2-methvl-2-ethyl propenoate

A solution of ethyl 2- (triphenylphosphoran-ylidene) propanoate (8 g) in dry dichloromethane was added to a solution of ortho-phthalaldehyde (2.9 g) in dry dichloromethane (10 ml) at 0 ° C. The solvent was evaporated and the oil was taken up in diethyl ether. The solid triphenylphosphine oxide was filtered, washed with ether and the solution was evaporated to dryness so as to obtain a colorless oil which was eluted on a column of silica gel (diethyl ether / petroleum ether, 1: 1) so as to obtain the compound indicated in the title in the form of a colorless oil (4.3 g).

Similarly, the following compound was prepared: (b) (S) -5- (2-Formylphenyl) -2-methyl-2-propenoate of 1,1-dimethyl methyl From 2- (triphenylphosphoranylidene) 1,1-Dimethylethyl prophylate and ortho-phthalaldehyde (c) (S) -3- (2-Formylphenyl) -2-ethyl-2-propenoate A solution of 2- (triphenylphosphoran- ylidene) ethyl butanoate (5.6 g) in dry dichloromethane (10 ml) to a solution of ortho-phthalaldehyde (2 g) in dry dichloromethane (10 ml) at 0 ° C. The solvent was evaporated and the oil was taken up in diethyl ether. The solid triphenylphosphine oxide was separated by filtration, washed with ether and the 23 \ t solution obtained was evaporated to dryness so as to collect a colorless oil which was eluted on a silica gel column (petroleum ether / ethyl acetate gradient, 9: 1 - 8: 2), so as to obtain the title compound in the form of a colorless oil (3 g).

Similarly, the following compounds were prepared: (d) (S) -3- (2-f ormvlphénvl) -2-nro, pvl-2-ethyl pro-penoate as a colorless oil 10 From o-phthalaldehyde and 2- (triphenylphosphoranylidene)-1,1-dimethylethylpentanoate.

Intermediate 5 (a) (B) -4- (2- (3-Sthoxv-3-oxo-2-methvl-1-propenvl) phenyl- -1.4-dihydro-2.6-dimethyl-3.5-Pvridinedicarboxvlate 15

Ethyl 3-araino-2-butenoate was dissolved in acetic acid (3 ml) and this solution was treated with a solution of intermediate 4 (a) (3 g) in acid acetic acid (5 ml) at room temperature. The solution thus obtained was stirred at room temperature for 2 hours, then poured into water and extracted with ethyl acetate. The organic phase was washed with 5% NaHCO 4 and then with water and dried over 4 SO 4. Evaporation of the solvent gave a yellow oil which was eluted twice on a column of silica gel (petroleum ether / ethyl acetate, 7: 3), so as to obtain a color solid yellow. This solid was recrystallized from a mixture of petroleum ether and diethyl ether (1: 1) so as to obtain the compound indicated in the title in the form of a pale yellow solid (0.45 g), having a melting point of 105-106 ° C.

The following compound was prepared similarly: (b) (B) -4 (2- (3- (1.1-Dimethvlethoxy) -3-oxo-2-methyl-1-prop-

V

♦ X .......

24 nyl) phenyl) -1,4-dihydro-2t 6-dimethyl-3 "5-pyridinecarboxyla-te of diethyl PF 130-131 ° From 1 * intermediate 4 (b) and 3-amino-2-butenoate ethyl.

5 (c) (B) -4- (2- (3-Ethoxy-3-oxo-2-ethvl-1-propenyl) phenyl) - 1 * 4-dihydro-2,6-dimethvl-3.5-pvtidinecarboxvlate de diethyl

A solution of intermediate 4 (c) (6 g) in ethanol (50 ml) was cooled to -10 ° C and thereto was added trifluoroacetic acid (4 ml) , this addition being followed by that of a solution of ethyl 3-amino-2-butenoate (17 g) in ethanol (50 ml).

The mixture was stirred at -10 ° C for one hour, evaporated in vacuo and the residue was taken up in ethyl acetate, then washed with 10% HCl Vî (3 x 50 ml), then washing with water and drying over NagSO ^. Evaporation of the solvent gave an oil which was purified by chromatography on silica (petroleum ether / diethyl ether) gradient 7: 3 - 3: 7), so as to obtain the compound indicated in the title as a white solid with a melting point of 92-94 °.

The following compounds were obtained similarly: (d) (B) -4- (2- (3-Bthoxv-5-oxo-2-propyl-1-propenyl) phenvl) - -1,4-dihydro -2t diethyl 6-dimethyl-3.5-pyridinecarboxylate P, F. 93-95 ° • From intermediate 4 (d) and ethyl 3-amino-2-butenoate.

30 (e) (B) -4- (2- (3- (1.1 -dimethvlethoxv) -3-oxo-2-éthvl-1 -pro-

pyl) phenyl) -1.4-dihydr o-2.6-dimé thyl-3 "5-pyr idinedicar-diethyl boxylate m.p. 99-101 ° C

25 From intermediate 4 (e) and ethyl 3-amino-2-butenoate.

Intermediate 6 (a) (S) -4- (2- (2-Carboxy-1-propenyl) phenyl) -1.4-dihvdro- 5 -2.6 dimethyl-3,5-pyridinedicarboxylate To a solution of intermediate 5 (b) (5 g) in dichloromethane (30 ml) at -78 °, a solution of 33% HBr / acetic acid (15 ml) was slowly added in dichloromethane (30 ml). The mixture was then heated to -30 ° and stirred at -30 ° C for 20 minutes. The mixture was poured into ice water, NaHCO 4 (5 g) was added thereto and the mixture was extracted with dichloromethane, washed with water and dried over Na ^ SO ^. Evaporation of the solvent gave a solid which was recrystallized from a mixture of petroleum ether and ethyl acetate, (1: 1), so as to obtain the title compound under the form of a white solid (3.5 g) having a melting point of 205-207 °.

(b) Di (S) -4- (2- (2-carboxv-1-butenvl) nhénvl) - 20 -1.4-dihydro-2,6-dimethvl-3.5-Pvridinedicarboxylate was similarly prepared from of intermediary 5 (e).

, Intermediate 7 (a) (2) -4- (2- (5-Propoxy-5-oxo-2-methyl “1-propenyl) phenyl-25 -1,4-dihydro-2,6-dimethyl-3, Diethyl 5-pyridlnedicarboxylate • A suspension of intermediate 6 (a) of propyl bromide and potassium carbonate in dimethylformamide was stirred at room temperature for 6 hours. The mixture was poured into water and we got it 26

V

V

. -t- '* "treated with ethyl acetate, then it was vigorously washed with water and dried over NagSO 4. Evaporation of the solvent gave an oil which was triturated with petroleum and recrystallized from petroleum ether so as to obtain the title compound, having a melting point of 108-110 °.

(b) (B) -4- (2- (5-uentvloxv-3-oxo-2-methvl-1-orooénvl) ohenyl) -1.4-dihvdro-2,6-dimethyl-3.5-Pvridinecarboxvla- te diethyl PF 126-127 ° prepared from intermediate 6 (a) and 1-bromopentane.

(c) (B) -4- (2- (5-orot> oxv-3-oxo-2-ethyl-1 -propenyl) nhenyl) - -1.4-dihydro-2 "6-dimethyl-3,5-pyridinecarboxylate prepared from intermediate 6 (b) and propyl bromide.

15 (d) (B) -4- (2- (5-pentyloxy-5-oxo-2-ethvl-1-propenvl) phenyl) -1,4-dihydro-2.6-dlmethyl-5.5-Ovridinedicarboxy-late of diethyl prepared from intermediate 6 (b) and 1-bromopentane.

Intermediate 8 20 4- (2-FormvlOhénvl) -1.4-dihvdro-2-dimethylamino-methvl-6- -methyl-3.5-T? Vridinedicarboxvlate

Pyridine hydrobromide perbromide (3.2 g) was added to a solution of diethyl 4- (2-formylphenyl) -1,4-dihydro - 2,6-dimethyl-3,5-pyridinedicarboxylate (3, 25 g) and pyridine (1.3 ml) in dichloromethane (100 ml) at 0 ° C and stirred for 0.5 hour. The mixture was then cooled to -10 ° C, treated with dimethylamine (10.6 ml) and stirred at -10 ° C for one hour. The solvent was evaporated and the residue was taken up with ethyl acetate. The solid was filtered off and the solution was evaporated to dryness so as to obtain a red oil which was eluted on a column of silica gel (ethyl acetate / petroleum ether / methanol, 7: 3: 1), so as to obtain the compound 5 indicated in the title in the form of a yellow solid (in petroleum ether) (2.3 g), mp 115-120 ° C . c.c.m. (CH ^ Clg / methanol, 95: 5), Rf. 0.38.

Intermediate 9 2-Dimé thvlaminomé t hvl-6-mé t hvl- (5) -4- (2- (2-carboxvé thénvl) -10 nhénvl) ~ 1,4-dihydro-3.5 ", Pvridinedicarboyvlate. Bromhvdrate ( 1) Method (A)

Pyridine hydrobromide perbromide was added to a solution of (E) -4 (-2 (2-carboxyethenyl) phenyl) -1,4-15 -dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (3.5 g) and pyridine (2 ml) in dichlorome-thane (100 ml) at 0 ° C and the whole was stirred at the same temperature for 30 minutes. The mixture was then cooled to -10 ° C and slowly dimed-thylamine (10.6 ml) was added thereto. The mixture was stirred at -10 ° C for one hour. The solvent was then evaporated and the residue was taken up in methanol so as to obtain the title compound in the form of a yellow solid which was recrystallized from a mixture of petroleum ether and methanol (8: 2) (2.7 g), mp 145-150 ° C (dec), ccm (CH2Cl2 / Methanol, 8: 2) Rf. = 0.50 Method (B) To a solution of the compound of Example 3 (1g) in dichloromethane (10 ml), at -70 ° C, was slowly added a hydrobromic acid solution at 33 % in acetic acid (3 ml) in dichloromethane (5 ml). The reaction mixture was then brought to -35 ° C and, after 10 minutes, poured into a mixture of ice and water. The pH was adjusted to 6 and the mixture was extracted with dichloromethane, then washed with water 5 and dried with CaCl2. Evaporation of the solvent afforded the free base of the title compound as a yellow solid (0.5 g) 5 mp 135-145 ° C (dec.).

c.c.m. (CH2Cl2 / Methanol, 8: 2) Rf. 0.50.

10 Intermediate 10 (a) Ethyl 3-amino-4-dimethylamino-2-butenoate

Pyridine hydrobromide perbromide (48 g) was added to a solution of ethyl acetoacetate (19.4 g) in anhydrous methylene chloride (500 ml) at room temperature over a period of 20 minutes. The mixture was stirred for 2 hours and then added dropwise to a solution of dimethylamine (48.8 g) in anhydrous methylene chloride (100 ml) at -15-0®, within an hour. The mixture thus obtained-20 was cooled down to -20® and ammonia was bubbled through the mixture, with stirring, for one hour and, for 2 hours at room temperature. The reaction was completed by allowing the mixture to stand overnight at about 5 ° C. After evaporation of the solvent, the residue was treated with ether, the solid was filtered off and the solution was evaporated to give a brown oil which was purified by column chromatography on silica gel so as to obtain the compound indicated in the title. (10.8 g) in the form of an orange oil, ccm Rf. = 0.4.

Similarly, methyl (3) -amino-4-dimethylamino-2-butenoate (b) was obtained in the form of a red oil (c.c.m. Rf. = 0.38) from ". ------- 29 methyl acetoacetate (16.2 ml) and dimethylamine (60 ml).

Intermediate 11 3- (2-Formylphenyl) -2-bromo-2-propenoate 5 A solution of ethyl 2-brorao-2- (triphenylphosphoranylidene) acetoate (15 g) was added in dichloro dry methane (30 ml) to a solution of ortho-phthaldehyde (4.7 g) in dry dichloromethane (.30 ml), at 0 ° C. The solvent was evaporated and the oil was taken up in diethyl ether. The solid triphenylphosphine oxide was separated by filtration, washed with ether and the solution was evaporated to dryness so as to obtain a colorless oil which is eluted on a column of silica gel (gradient; petroleum ether / ethyl acetate, 15: 2 -> 6: 4), so as to obtain the compound indicated in the title (6.2 g) in the form of a colorless oil (6, 2 g), ccm (petroleum ether / ethyl acetate, 7: 3) Rf.

= 0.41.

Intermediate 12 20 (z) -4- (2- (3-Ethoxv-3-oxo-2-bromo-1-oropenvl) phenyl) -1.4- -dlhvdro-2.6-dimethyl-3.5-pyridinedicarboxylate

A solution of intermediate 11 (5.5 g) in ethanol (50 ml) was cooled to -10 ° and thereto was added trifluoroacetic acid (4 ml), this addition being followed that of a solution of ethyl 3-amino-2-buteno-te (12.3 g) in ethanol (50 ml). The mixture was stirred at -10 ° for one hour, evaporated in vacuo and the residue was taken up in ethyl acetate, washed with 10% HCl, then with water and dried over Na2SO4. Evaporation of the solvent produced an oil. Purification of the oil by column chromatography (gradient: diethyl ether / petroleum ether, 8: 2 9: 1) gave the title compound as a white solid (3.2 g), having a melting point of 137 °. c.c.m. (petro ether / ethyl acetate, 1: 1) Rf. = 0.38o 5 Intermediate 13 (a) 2- (2- (3- (1.1-Dimethvlethoxy) -3-OXO-1-propenyl) phenyl) - -methylene-3-oxo-butenoate

A solution of piperidine (0.11 g) and acetic acid (0.078 g) in isopropanol (1 ml) was added to a solution of intermediate 2 (5.2 g) and aceto - methyl acetate (2.55 g) in isopropanol (15 ml). The mixture was stirred at 60 ° C for one hour, then the solvent was evaporated and the residue was taken up in ether (100 ml). The solution was washed with 1N hydrochloric acid 1N HCl, water, saturated bicarbonate solution, then again with water and dried over Na2SO4. Evaporation of the solvent made it possible to obtain an oil which was purified by column chromatography (gradient: petrol / ether, 7: 3 - 1: 1), so as to obtain the compound indicated in the title under the form of a pale oil (4.2 g, mixture of E / Z isomers).

The following compounds were prepared in a similar manner: (b) 2- (2- (3- (1.1 (Dimethylethoxy) -2-oxo-1-propenyl) phenyl) - *. / 25 -methylene-3 -ethyl oxo-butanoate prepared from intermediate 2 and ethyl acetoate

Example 1 Diethyl 2-Aminomethvl-6-methvl-4 (S) (2- (3- (1.1-dimethvlethoxy) - 3-ΟΧΟ-1 -propenyl) phenyl) -1.4-dihydro-3.5-pyridinedicarbo-30 xylate . hydrobromide

Pyridine hydrobromide 31 perbromide (13.5 g) was added to a solution of intermediate 3 (15.4 g) and pyridine (5 ml) in anhydrous methylene chloride (350 ml), at 0 °, in the space of 10 minutes. The mixture was stirred at 0-3 ° for 30 minutes and then added dropwise to a saturated solution of ammonia in methylene chloride (180 ml), at -10 °, in l space of 30 minutes. Ammonia was bubbled through the mixture thus obtained, with stirring, for -1-, 30 hours, at -10 to -5e and then for 2 hours at room temperature. The pyridine hydrobromide was separated by filtration and the solution was washed with 0.1N HBr and brine. After evaporation of the solvent, the residue was purified by column chromatography to obtain the title compound (4.2 g) having a melting point of 165-8 °. c.c.m. Rf. = 0.2.

Example 2 „2a 2-Isopropyllaminomethyl-6-methvl-4 (E) (2- (3- (1" 1-dimethyl - ethoxy) -5-ΟΧΟ-1 -propenyl) phenyl) -1 "4-dihydro- 3 ♦ diethyl 5-pyri-20 di-dicarboxylate, hydrobromide

Pyridine hydrobromide perbromide (4.5 g) was added to a solution of intermediate 3 (5.1 g) and pyridine (1.75 ml) in anhydrous methylene chloride (125 ml) at 0 ° C, within 10 minutes. The mixture was stirred at 0-3 ° for 30 minutes and then added dropwise to a solution of isopropylamine (6.5 ml) in methylene chloride (50 ml), 0 ° and in the space of 20 minutes. The mixture thus obtained was stirred for 2 hours at room temperature. The solid was filtered off and the solution was washed with 0.1N HBr and brine. After evaporation of the solvent, the residue was treated with ethyl acetate / ethyl ether so as to obtain a yellow precipitate of the compound 32 V ''

X

described in the title (3.1 g), having a melting point of 218-220 °, c.c.m. Rf. 0.28.

The free base of the title compound was obtained having a melting point of 135-137 ° by treating the hydrobromide with an inorganic base.

Microanalysis for C29N4qN2 ° 6 exiSe C67.94; H7.86; N5.46 found C68.21; H7.84; N5.49%

Treatment of the free base with an equimolar amount of hydrochloric acid gave the corresponding hydrochloride having a melting point of 204-205 °.

Similarly, the following compounds were obtained: 2b 2-Methvlaminomethvl-6-methvl-4 (B) (2- (3- (1.1-dimethyl-ethoxy) -3-ΟΧΟ-1 - • pro-penyl) phenvl) -1,4-dihvdro-3,5-pyridine-15 diethyl dicarboxylate. hydrobromide (5.5 g) m.p. 208-210 °, c.c.m. Rf. 0.125 from intermediate 3 (10.2 g) and methylamine (10 ml).

The free base of the title compound was obtained by treating the hydrobromide with a solution of sodium hydroxide-20 xyde. Mp 151-153 °.

2c 2-Dimethylaminomethyl-6-methyl-4 (5) (2- (5- (1.1 (dimethyl-ethoxy) -5-oxo-1 ~ pronenyl) nhenyl) -1.4-dlhydro-5.5-pyri-dine-dicarboxylate diethyl. hydrobromide (1.6 g) m.p. 192-194 °, c.c.m Rf. 0.33 from intermediate 3 (5.1 g) and dimethylamine (5 ml).

· '2d 2-Methylaminomethyl-6-methyl-4 (B) - (2- (3-ethoxy-3-oxo-2- -methyl-1-propenyl) phenyl) -1,4-dihydro-5,5- diethyl pyridinedicarboxylate (3 g). M.p. 96-98 °. c.c.m. (ethyl acetate / methanol, 1: 1) Rf. 0.22 from the intermediate 30a 5a (5.08 g) and methylamine (7 ml).

The corresponding hydrochloride 7 was obtained by treating a solution of the free base (940 mg) in a mixture of methanol and acetone (3: 1) with 0.1N HBr (20 ml).

V

\ 33

J

The mixture was dried in vacuo and treated with diethyl ether to give bromhy-drate (850 mg) having a melting point of 245-247 °.

The corresponding hydrochloride 7-5 dant was also obtained, having a melting point of 230-2.32 °.

2e 2-Isopronvlaminomethyl-6-methyl-4 (5) - (2- (3-ethoxv-3- -oxo-2-methvl-1 -or opénvl) nhenyl) -1.4-dihvro-3,5-pyri-dinedicarboxylate (850 mg) from intermediate 5a (3.15 g) and isopropylamine (4.82 ml).

The corresponding hydrochloride salt was obtained, this product having a melting point of 124-128 °.

2f 2-Dimethvlaminomethvl-6-methvl-4 (E) - (2- (3-ethoxv-3- -oxo-2-methvl-1-propenvl) phenvl) -1.4-dihydro-3.5-nvri- dethicarboxylate ( 1.15 g) from intermediate 5a (2.74 g) and dimethylamine (3.1 ml).

The corresponding hydrochloride salt was obtained, having a melting point of 208-210 °.

2g 2-Dimethylaminométhvl-6-méthvl-4 (B) - (2- (3-ethoxv-3- -oxo-2-éthvl-1-propénvDphénvl) -1.4dihydro-3.5-nvri- 20 dinedicarboxylate (1, 5 g) from intermediate 5c (3 g) and dimethylamine (3.1 ml).

The corresponding hydrochloride salt having a melting point of 185-187 ° was obtained.

2h 2-Dimé thvlaminomé thvl-6-mé thvl-4 (S) - (2- (3-é thoxv-5-oxo- 25 -2- ~ proOvl-1 - • propenyl) ohénvl) -1.4-dihydro-3.5 -nvridine- diethyl dicarboxylate. hydrochloride. Mp 118-120 °.

From intermediate 5d (2.7 g) and dimethylamine (-2.8 ml).

2i 2-Dimethylaminomethyl-6-methyl1-4 (3) -2 (2- (3-pr opoxy-3-30 -oxo-2-methyl-1 -propenyl) phenyl) -1,4-dihydro-3,5 -pyridi- 54 * diethyl nedicarboxylate. hydrochloride. M.p. 198-199 °. c.c.m. Rf. 0.50.

From intermediate 7a (2.6 g) and dimethylamine (2.7 ml).

5 2j 2-Pro-pvlaminométhvl-6-méthvl-4 (2) - (2- (5.1.1 -diméthvl- é thöxy) -5-oxo-1-or on enyl) ohényl) -1.4-dihvdro-5 " 5-nvr i-diethyl dicarboxylate (2.7 g). Mp 70-75 °. c: c.m. Rf, 0.54 From intermediate 5 (4.55 g) and propylamine 10 (5.1 ml). .

The corresponding salt hydrochloride was obtained by treating a solution of the free base (2.6 g) in acetone (50 ml) with 0.2N HCl (26 ml). The mixture was dried in vacuo and treated with diethyl ether to give the hydrochloride having a melting point of 182-184 °.

2k 2-Pyrrolidonomethvl-6-methvl-4 (E) - (2- (5- (1.1-dimethvl-ethoxy) -5-ΟΧΟ-1-propenvl) phenvl) -1 "4-dihydro-5.5-pyridinicicboxbox of diethvle. hydrochloride (1.2 g) P.F.

20 211-215 °. c.c.m. (ethyl acetate / methanol 1: 1) Rf. 0.44 From intermediate 5 (4.55 g) and pyrrolidone (4.15’ml).

21 2-Piperazinomethyl-6-methyl-4 (B) - (2-5 (-1,1-dimethyletho-xy-5-oxo-1-propenyl) phenyl) -1,4-dihydro-5,5-pyridinedi - 25 diethyl carboxylate, dihydrochloride (5.6 g) PF

195-200 °. c.c.m. (ethyl acetate / cyclohexane / methanol / NH20H 20%, 7: 5: 2: 0.5) Rf. 0.54.

From intermediate 5 (6.8 g) and piperazine (0.75 g).

jO 2m 2-methylaminomethyl-6-methvl-4 (5) - (2- (5-octyloxy-5-oxo- -1-pronenyl) phenyl) -1.4-dihvdro-5.5-pyridinedicarboxyla-te of diethvl, hydrochloride (0 , 75 g). M.p. 200-202 ° C.

35 \ λ c.c.m. as in 1 * example 21 Rf. 0.43 from methyl amine (3.1 ml) and (E) -4- (2- (3-octyloxy-3-oxo-1-propenyl) phenyl) -1, 4-dihydro-2, Diethyl 6-dimethyl-3,5-pyridinedicarbo-xylate (5.4 g).

5 2n S-methylaminométhvl-6-methyl-4 (E) - (2- (3-cyclohexyloxy- -3-0X0-1 - · ρηορέηνΐ) · ρ] ^ ην1) -1.4-dihydro-3 “5-pyridinedicar- diethyl boxylate, hydrochloride (0.40 g) PF 210-211 °.

c.c.m. (Ethyl acetate / cyclohexane / methanol / NH ^ OH 20 c / a Ί0 7: 3: 2: 0.2) Rf 0.18 From methylamine (3.45 ml) and (E) -4- (3-cyclohe-xyloxy-3-oxo-1-propenyl) phenyl) -1,4-diethyl-2,6-dimethyl-3,5-pyridinedicarboxylate (5.65 g).

2o 2-Me thylaminomethyl-6-methyl-4 (S) - (2- (3-iso, propvloxy-5-15 -oxo-1 -propenyl) phenyl) -1.4-dihvdro-3,5-pyridinedicarboxylate. hydrochloride (1.1 g) c.c.m. as in 1 * example 2n Rf 0.24.

From methylamine (3.1 ml) and (E) 4- (2- (3- (1-methylated thoxy) -3-OXO-1 -propenyl) phenyl) -1,4-dihydro-2,6 -di-20 methyl-3,5-diethyl pyridinedicarboxylate (4.66 g).

2p 2- (1 -Morpholinomethyl) -6-methvl-4 (E) -2- (3- (1 "1-dimethylethethoxy) -3-OXO-1 -propenyl) phenyl) -1,4-dihydro- Diethyl 3,5-pyridinedicarboxylate. hydrochloride (3.5 g)

M.p. 210-12 ° C

* '25 c.c.m. (Ethyl acetate / cyclohexane 7: 3) Rf 0.23.

From intermediate 3 (6.83 g) and morpholine (9.1 ml).

2q 2-Dimethylamlnomethyl-6-methyl-4 (E) - (2- (3-pentyloxy-3- -oxo-2-methyl-1-propenyl) phenyl-1,4-dihydro-3,5-pyridinedicarboxylate diethyl hydrochloride (0.38 g) FP

155-57 ° C

c.c.m. (ethyl acetate / cyclohexane / MeOH 7: 3: 1) Rf 0.33.

36 From intermediate 7b (1.3 g) and dimethylamine (1.3 ml).

2r -2- (1-Morpholinométhvl) -6-méthvl-4 (5) - (2- (3-ethoxy) - 3-oxo-2-mé thyl-1 -propényl) pérryl) —1.4-dihydro-5 "Diethyl 5-py-5 ridinedicarboxylate. hydrochloride (1.21 g) m.p. 14 ° C.

c.c.m. (Ethyl acetate / CHgClg 1: 1) Rf 0.45.

From intermediate 5a (3 g) and morpholine (4.4 ml).

Ί0 2s 2-Methylaminomethyl-6-methvl-4 (32) - (2- (3-pentyloxy-3- -oxo-2-methyl thyl-1 -propenvl) phenvl-1.4-dihydro-3.5-pyrfdine dicarboxylate. hydrochloride (3 g) FP

185-186 ° C.

c.c.m. (Ethyl acetate / cyclohexane / MeOH 7: 3: 2) Rf 0.25.

-5 from intermediate 7b (1.4 g) and methylamine (1.0 ml).

2t 2-Me thvlamionomé thyl-6-mé thvl-4 (E) - (2- (3-propoxv-3-oxo - 2-methvl-1-propenyl) phenvl-1.4-dihydro-3.5-pyridine-dlcarboxylate diethyl, hydrochloride (0.67 g) FP

20 206-208 ° C.

c.c.m. (Ethyl acetate / cyclohexane / MeOH 7: 3: 2). Rf = 0.21.

From intermediate (7a) (2.66 g) and methylamine (1.9 ml).

25 2u Ethylaminomethyl-6-methyl-4 (S) (2- (3-ethoxy-3-oxo-2- -ethyl-1-propenyl) phenyl) 1,4-dihydro-3,5-pyridinedicar-boxylate hydrochloride (1.7 g) mp 149-153 ° C.

c.c.m. (Ethyl acetate / cyclohexane / MeOH / NH ^ OH 20%, 30 7: 3: 2: 0.3). Rf. 0.6> 37 From intermediate (5c) (5.63 g) and ethylamine (5 ml), 2v 2-Methvlaminomethvl-6-methvl-4 (5) (2- (3-propoxv- 3-oxo- -2-ethvl-1 -propenvl) phenvl) -1.4-dlhydro-3 "5-pyridine-5 dicarboxvlate. hydrochloride (0.98 g) P, F. 189-190 ° C, c.c.m. (1,1,1, trichloroethane / Me0H / NH40H 20 Si, 8: 1: 0.5)

Rf = 0.45.

From methylamine (3.1 ml) and intermediate 7c 10 (5.0 g).

2w 2-Méthvlaminométhvl-6-méthvl-4 (S) - (2- (5- (1.1 (dimethvl- ethoxv) -3-oxo-2-éthvl-1-propénvl) phenvl ·) -1.4-dihvdro- - • 3.5-Diethyl acid, hydrochloride (1.2 g) PF 198-200 °.

15 c.c.m. (Ethyl acetate / cyclohexane / MeOH / NH ^ OH 20% 7: 3: 2: 0.3). Rf = 0.61.

From methylamine (3.1 ml) and intermediate 5e (5.1.3 g).

2x 2-Methvlaminomethvl-6-methvl-4 (E) - (2- (3-pentvloxv-3-20 -oxo-2-ethyl-1-propenvl) phenvl) -1.4-dihydro-3.5-pyri- dinedicarhoxylate , hydrochloride PF 190-200 °.

c.c.m. From intermediate 7d (1.8 g) and methylamine (3.1 ml).

'25 2y 2-Piperidinomethyl-6-methyl-4 (E) - (2- (3- (1,1-dimethylethoxy) 3-oxo-1-propenyl) phenyl) 1,4-dihydro-3,5 -pyridine- diethyl dicarboxylate, hydrochloride (2.98 g) mp 218-220 °.

c.c.m. (Cyclohexane / Acetone / MeOH 7: 2: 1) Rf = 0.42. c 50 From intermediate 3 (6.8 g) and piperidine (10.3 ml).

38

Example 3 2-Dimethvlaminométhvl-6-methyl-4 (ff) (2- (3- (1 "1-dimethyl-ethoxy) -5-oxo-1-propenyl) pheny1) -1.4-dihydro-3,5-pyridine dicarboxylate diethyl 5 (1) 2-dimethylaminomethyl-6-methyl-4- (2-bromophenyl) -1,4- -dihydro-3,5-pyridine-diethyl dicarboxylate

Pyridine hydrobromide perbromide (7.68 g) was added to a solution of intermediate 1 (6.86 g) and pyridine (2.6 ml) in methylene chloride anhy-10 dre (100 ml ) at 0 °, for 10 minutes. The mixture was stirred at 0 ° for 40 minutes and added to a solution of dimethylamine (6.3 g) in methylene chloride (50 ml) at 0 °, over 20 minutes. The mixture thus obtained was stirred for 30 minutes, the solids were filtered off and the solvent was evaporated. The residue was dissolved in ethyl acetate and washed_ with 0.1N sodium hydroxide and water. After evaporation of the ethyl acetate, the residue was eluted on a column of silica gel (ethyl acetate / cyclohexa-20 ne 3: 7), so as to obtain the compound indicated in the title (4 g ) having a melting point of 142-143 °. c.c.m. Rf 0.36.

(ii) 2-Dimethvlaminomethyl-6-methyl-6-methvl-4 (E) - (2- (3- - (1,1-dimethylethoxv) -3-oxo-1-propenvl) phenvl) -1.4- /. / 25 diethyl-5,5-pyridine-diethyl dicarboxylate

A mixture of the product from step (i) (3.71 g), tert-butyl acrylate (1.21 ml), tri-n-butylamine (3 ml), acetate was heated. palladium (0.0225 g), triphenylphosphine (0.05 g) and tetrahydrofuran (5 ml), with stirring, at 110 ° for 72 hours. The mixture was cooled, filtered and concentrated in vacuo until a brown oil was obtained which was purified by column chromatography using silica gel and proceeding to elution with a mixture of ethyl acetate and methanol 9: 1, so as to obtain the title compound in the form of a yellow solid (1.15 mg), having a melting point of 146-148 ° ccm *. (Ethyl acetate / methanol 9: 1) Rf * 0.38,

With maleic acid, the title compound gave the maleate salt having a melting point of 154-156 °, Example 4 (a) 2- (2- (N, N-Dimethylamino) ethvl) -4 (E) - (2- (3-0,1-dimethl thoxy) -5-oxo-1-propenvl) phenvl) -6-methvl-1,4-di- hydro-3,5-pyridine-dicarboxylate

A mixture of intermediate 3 (4.6 g), a 35% solution of dimethylamine (3 ml), a 40% solution of formaldehyde (1.15 ml) and acetic acid (10 ml) at reflux for 5 hours. After cooling to room temperature, water (150 ml) was added and then 10% NaOH until a pH of 9 was obtained. The solid obtained was separated by filtration, washed with water and eluted on a silica gel column (1,1,1-trichloroethane / MeOH 1: 1), so as to obtain, after crystallization from a mixture of ether diethyl and n-hexane, the compound indicated in title 25 (0.9 g). M.p. 150-151 ° c.c.m. (1,1,1-trichloroethane / MeOH, 1: 1) Rf 0.21.

(b) 2- (2- (N-morpholino) ethyl) -4 (S) - (2- (3- (1,1-dimethyletho-xy) -5-OXO-1-propenyl) phenyl) -6- methyl-1,4-dihydro-3,5 - diethyl pyridine-dicarboxylate "A mixture of intermediate 3 (9.2 g), morpholine (4.35 ml), a solution was carried 40% formaldehyde (3.8 ml) and acetic acid (20 ml) at reflux for 40 2 hours. After cooling, water (about 250 ml) was added and then 10% NaOH until a pH of 9 was obtained. The aqueous mixture was extracted with ethyl acetate and the organic layer 5 was washed with brine. After evaporation of the solvent, the residue was purified by column chromatography, so as to obtain, after crystallization from methanol, the title compound (1.6 g) having a melting point of 170-172 °. c.c.m. Rf 0.5.

10 (c) 2- (2- (NN-Dimethvlamino) ethhl) -6-me thvl-4, (E) - (2- (3- -ethoxv-5-oxo-2-methvl-1 -or ot) envi) -phenyl) -1,4-dihy- dro-5.5-pyridine dicethyl dicarboxylate

A mixture of intermediate 5 (a) (10 g), a 35% dimethylamine solution (4.55 ml), a 40% formaldehyde solution (2.34 ml) was worn. and acetic acid (20 ml) at reflux for one hour. Evaporation of the acetic acid in vacuo gave a residue which was treated with ethyl acetate, washed with 10% NaOH and water. After evaporation of the solvent, the residue was purified by column chromatography on silica gel (ethyl acetate / methanol 7: 3), so as to obtain the compound indicated in the title (3 g) having a melting point of -109 ° C. c.c.m. (1,1,1-trichlorethane / methanol 1: 1) Rf 0.46.

Example 5 5a 2-Methylaminomethyl-6-methyl-4 (S) - (2- (3-ethoxy-3-oxo - 2-ethyl-1-propenyl) -1,4-dihydro-3,5-pyridinecarboxyla diethyl

Pyridine hydrobromide perbromide (3.2 g) was slowly added to a solution of intermediate 5c (4 g) and pyridine (1.3 ml) in methylene chloride (100 ml) at 0 ° and the mixture was stirred at the same time. ”41

X

# temperature for 30 minutes. The cooled solution was then added dropwise to a solution of methylamine (5 g) in methylene chloride (30 ml), at -30 ° C, for 15 minutes. The mixture 5 was then stirred for one hour, during which time the temperature rose to 0 ° C and then poured into a mixture of ice and water. The aqueous solution was made alkaline by the addition of a 10% aqueous solution of sodium hydroxide, extracted with methylene chloride and the organic phase was dried (NagSO 4). Evaporation of the solvent made it possible to obtain an oil (4.5 g) which was eluted on a column of silica gel so as to obtain the compound indicated in the title (3 g) having a 78-80 ° fusion.

15 5b 2-Methlaminomethl-6-methvl-4 (B) - (2- (3-ethoxv-5-oxo- -2-ethyl-1-propenyl) phenyl) -1.4-dihydro-5.5-Pvridine- diethyl dicarboxylate . hydrochloride salt

The compound of Example 5a (2.7 g) was dissolved in acetone (25 ml) and the solution was treated with 1N hydrochloric acid (5.5 ml). The solution was evaporated to a small volume, then acetone was added thereto and the resulting mixture was stirred at 0 ° for 20 hours. The white solid (2.7 g) was separated by filtration and recrystallized from a mixture of ethyl acetate and methanol (8: 2), so as to obtain the title compound ( 2 g) in the form of a white solid having a melting point of 210-212 °.

5c 2-Methylaminome thyl-6-methyl-4 (5) - (2- (3-ethoxy-5-oxo- -2-ethyl-1-propenyl) phenyl) -1.4-dihydro-3 5-pyridinedi- 50 carboxylate diethyl, hydrochloride salt 42 Λ *

A mixture of the compound of Example 5a (1 g), hydrobromic acid (48 S®) (5 ml) in ethyl acetate (30 ml) and water (5 ml) was stirred in ethyl acetate (30 ml) and water (50 ml), for 10 minutes.

The mixture was filtered to obtain the title compound (0.6 g) as a packed solid with a melting point of 231-233 °.

The salts below were prepared in a similar manner, starting from the compound of Example 5a and ap-10 proprié acid.

5d 2-Methylaminomethvl-6-methyl-4 (3) - (2- (3-ethoxv-3-oxo - 2-ethyl-1 -propenyl) phenvl) -1,4-dihydro-3.5-Pvridine-dicarboxylate diethyl.tosylate. PF 160 ° 5th 2-Me thylaminomé thyl-6-methvl-4 (S) - (2- (3-ethoxv-3-oxo-15 -2-ethyl-1-propenyl) phenvl) -1.4-dihvdro-3.5- diethyl pyridine dicarboxylate. formate. Mp 184-185 °

Example 6 2- (N-benzvl-N-methyl) aminomethyl-6-methyl- (E) -4- (2- (3- - (1.1-dimethylethoxy) -5-oxo-1-propenyl) phenvl) -1.4 -dihv- 20 dro-3.5-pyridinedicarboxylate of 3-ethyl and 5-methyl

A solution of intermediate 13a (12 g) and 3-amino-4- (N-benzyl-N-methylamino) -2-ethyl butenoate (7.5 g) was heated in ethanol (100 ml), at reflux, for 22 hours. The solvent was evaporated and the crude oil was eluted on a column of silica gel (ethyl acetate / petroleum ether, 7: 3), so as to obtain the compound * indicated in the title as '' a pale yellow oil (3.7 g).

c.c.m. (Petroleum ether / ethyl acetate 7: 3), Rf = 0.27.

43

Example 7 2-Methylaminomé thvl-6-mé thyl- (B) -4- (2- (3-1.1 -dimethyl-ethoxy) -3-OXO-1 -propenyl) phenyl) -1,4-dihydro-3.5- 3-ethyl-5-methylpyridine dicarboxylate hydrochloride 5 2,2,2-trichloroethyl chloroformate (1.0 ml) was added to a solution of Example 6 (3.6 g) in dry toluene (35 ml) and the mixture was heated at 50 ° C for 45 minutes. The solvent was evaporated and the residue (3 g) was dissolved in dimethylformamide (40 ml) and 10 onTa treated with formic acid (0.7 g). Zinc (1.2 g) was then added at 0 ° G and the mixture was stirred for one hour at room temperature. Evaporation of the solvent gave an oil which was eluted on a column of silica gel (cyclohexane / ethyl acetate / me-thanol, 7: 3: 2), so as to obtain a colorless oil ( 3.2 g) which was dissolved in ethyl acetate and washed twice with water. The solvent was evaporated and the solid formed was recrystallized from ethyl ether, so as to obtain a yellow liquid which was then treated with hydrochloric acid in methanol so as to obtain the indicated compound in the title in the form of a solid of yellow hue (0.6 g) having a melting point of 208-210 ° C.

c.c.m. (Ethyl acetate / methanol, 1: 1), Rf * 0.22.

Example 8 2- (Dimethylaminomethyl-6-methyl-4 (B) - (2- (3-1,1-dimethyl-ethoxy) -5-OXO-1 -propenyl) phenyl) -1,4-dihydro-3 , Diethyl 5-pyridine-dicarboxylate, hydrochloride

Pyridine (1.7 g) and pyridinium bromide perbromide (6.68 g) were added to a solution of intermediate 3 (10 g) in methylene chloride (120 ml), cooled to 'at -20 ° C. The temperature of 44 1 * "was allowed to rise to + 4 ° C over 1.5 hours, then cooled again to -20 ° C. N, N-dimethylamine (4.9 g) was then added and the temperature allowed to rise to + 15 ° within 1 hour · The solution was poured onto a mixture of ice and water (approximately 200 ml), the organic layer was separated and concentrated in vacuo. The residue was dissolved in ethyl acetate (200 ml) and the solution was washed twice with 10-10% aqueous sodium hydroxide solution (2 x 50 ml) and water (2 x 200 ml). The aqueous phase was dried over Na 2 SO 4 and concentrated in vacuo so as to obtain a red oil which was taken up in ethyl acetate (25 ml) and treated with a solution 1, 2N hydrochloric dracid in ethyl acetate (20 ml). The mixture was allowed to stand at 0 ° C for one day, filtered and the yellow solid was washed with ethyl acetate (5 ml) and dried in vacuo to give the title compound as a yellow solid (7.6 g) having a melting point of 190-193 ° C.

c.c.m. (Ethyl acetate / methanol, 8: 2) Rf = 0.43.

Sxemnle 9 2-Dimethvlaminomethvl-6-methvl-4 (E) - (2- (3-1.1 -dimethyl-ethoxv) -5-OXO-1 -nr onénvl) nhenyl) -1.4-dihvdro-5 "5-nvr idine -25 diethylcarboxylate. hydrochloride

Intermediate 10a (6.25 g) was added to a solution of intermediate 13b (5 g) in isopropyl alcohol (50 ml) and the mixture was heated to 40-45 ° C for 48 hours. The solvent was removed by evaporation in vacuo, so as to obtain an orange residue which was dissolved in methylene chloride (100 ml) and the solution thus obtained was washed twice with acid. 4 hydrochloric acid diluted with water. The organic layer was concentrated in vacuo and the residue was eluted on a column of silica gel (ethyl acetate / methanol 9: 1), so as to obtain the title compound as a yellow solid (0.9 g), having a melting point of 190-193 ° C.

c.c.m. (Ethyl acetate / methanol, 8: 2) Rf = 0.43.

Example 10 (a) (-) (S) - (S) -4— (2- (3- (1.1-dimethvlethoxv) -3-oxo-1-propé-nvl) phenvl) -2-dimethvlaminomethvl-6-methvl -1. 4-dihv-10 dro-5.5-pyridine diethvic dicarboxvlate. chlorhy drate

(-) - dibenzoyl-L-tartaric acid monohydrate (8.0 g) was added to a solution of (E) -4- (2- (3- (1,1-dimé-thyléthoxy- 3-oxo-1-propenyl) phenyl) -2-dimethylaminomethyl-15 -6-methyl-1,4-dihydro-3,5-pyridinedicarboxylate (Example 3) (10.6 g) in 1 ' isopropanol (360 ml) and the mixture was warmed to room temperature and stirred for 20 hours The yellow crystals were collected by filtration and purified at 3 times by crystallization from Isopropanol The solid (1.50 g) was dissolved in dichlaromethane (50 ml) and treated with a solution of 10 c / o sodium hydroxide (40 ml). organic layer, the residue was dissolved in ethyl acetate (20 ml) and acidified with hydrochloric acid in ethyl acetate (1.2N) ( The solid was separated by filtration and dried to obtain the title compound (0.63 g) having a melting point of 202-203 ° C, 30 c. .c.m. (Ethyl acetate / methanol, 8: 2) Rf "0.43 - 69.2 (c = 1.04 in 95% ethanol).

Similarly, we prepared the 46

It t (b) (+) (R) - (E) -4- (2- (3- (1.1-Dimethvlethoxv) -3-oxo-1-pro-penyl) phenvl) -2-dimethvlaminomethvl-6-methvl -1.4-di-hydro-5.5-pyridinedicarboxylate of diethvle. chlorhv- t drate (0.65 g) c.c.m. (ethyl acetate / methanol, 5 8: 2) Rf = 0.43 ^ ° +0.5 (c = 1.04 in 95% EtOH) from the compound of Example 3 (10.6 g ) with (+) dibenzoyl-D-tartaric acid monohydrate (8.0 g), mp, 203 ° C.

Example 11 2-Dimé thvlaminomé thvl-6-mé thyl- (E) -4- (2- (3- (1.1 -diméthvl-10 é thoxy) -5-oxo-1 -propényl) phenyl) -1-1.4- diethyl-3 "5-pyridine-diethyl dicarboxylate

1,1-Dimethyl triphenylphosphoranylidene acetate (0.38 g) was added to a solution of intermediate 8 (2.3 g) in toluene (20 ml) and the mixture was heated at reflux for 8 hours. Additional phosphorane (0.38 g) was added and the mixture was heated at reflux for 8 hours. The solvent was evaporated and the residue was purified by column chromatography (dichloromethane / methanol, 95: 5), so as to obtain the title compound as a yellow solid (0.1 g) (from petroleum / ether, 8: 2) having a melting point of 146-148 °. c.c.m. (Dichloromethane / methanol, 95: 5) = 0.30 c.c.m. (Ethyl acetate / methanol, 9: 1) = 0.38.

Example 12 2-Dimethvlaminomethyl-6-methvl- (S) -4- (2- (5- (1,1-dimethylethoxy) -3-oxo-1 -propenyl) phenyl-1,4-dihydro- 3 ♦ 5-pyridine-diethyl dicarboxylate, hydrochloride

A suspension of intermediate 9 (0.1 30 g) and potassium carbonate (1 g) in N, N-dimethylformamide (10 ml) was treated with small fractures of tert-butyl bromide (2.74 g) under vigorous stirring, at room temperature, in 1 * space of 4 hours. The mixture was stirred at room temperature for 2 hours, then poured into water and extracted with ethyl acetate, washed thoroughly with water and dried over Na2SO4. Evaporation of the solvent gave an oil (0.07 g). A sample of the base was treated with HCl / NaOH in ethyl ether to obtain the title compound as a yellow solid with a melting point of 190-193 ° vs. c.c.m. (Ethyl acetate / methanol, 8: 2) Rf * 0.43

Example 13 (a) 2-Dimethylaminomethyl-6-methvl-4 (35) - (2- (3- (1.1 (dimethylethoxy) -3-oxo-propenyl) phenyl) -1.4-dihydro-3 ♦ 5- -pyridinedicarboxylate of 5-ethyl and 5-methyl

A mixture of intermediate 13 (a) (18.33 g) and intermediate 10 (a) (5.1 g) was brought to isopropanol, at boiling point, for 24 hours . After evaporation of the solvent, the residue was eluted on a column of silica gel (ethyl acetate / cyclohexane / MeOH 7: 3: 2).

The isolated dihydropyridine (3.5 g) was purified by crystallization from petroleum ether to give the title compound as a yellow solid (2 g) having a melting point of 126 -128 ° C.

*. /

Similarly, the following compounds were obtained: (b) 2-Dimethylaminomethyl-6-methyl-4 (S) - (2- (3 ~ (1,1-dimé-thylethoxy) -5-oxo-propenyl) phenyl) -1,4-dihydro-3,5- pyridinedicarboxylate of 3-methyl and 5-ethyl in the form of a white solid, mp 132-133 ° (1.2 g) from intermediate 13b (15.7 g) and the intermediary ”“ '48

AT

* 10b (4.2 g).

c.c.m. (ethyl acetate / cyclohexane / MeOH / ilH ^ OH 20%, 7: 3: 2: 0.3) Rf. = 0.7.

(c) 2-Dimethvlaminomethvl-6-methvl-4 (S) - (2- (3-ethoxv-3- 5 -oxo-2-é thvl-1-propenvl) phenyl) -1.4-dihydro-5.5-Pvri- 3-ethyl and 5-methyl dicarboxylate (0.51 g) in the form of a white solid, mp 98-99 ° C.

From 1 * intermediate 13c (3.9 g) and intermediate (10a) (1.9 g) 10 c.c.m. (ethyl acetate / cyclohexane / MeOH / NH ^ OH 20 7: 3: 2: 0.3) Rf. = 0.32.

Example 14 (Z) -2-Dimethvlaminomethhl-6-methvl-4- (2- (5-ethoxv-3-oxo- -2-bromo-1-propenyl) phenyl) -1,4-dihydro-3,5- pyrethylamine diethyl carboxylate. hydrochloride

Pyridine hydrochloride perbromide (1.7 g) was slowly added to a solution of intermediate 12 (2.3 g) and pyridine (0.8 ml) in dry dichloromethane (50 ml), at 0 °. The mixture was stirred at 0 ° for 30 minutes and then added dropwise to a solution of dimethylamine (2.2 ml) in dichloromethane (20 ml) at 0 °. The mixture thus obtained was stirred at 0 ° for 2 hours, the solvent was evaporated and the residue was taken up in ethyl acetate and washed with 10% HCl f of 10% MeOH % and brine. Evaporation of the solvent made it possible to obtain an oil which was eluted on a column of gsl of silica so as to obtain the compound indicated in the title (1.4 g) (in petroleum ether / diethyl ether, 8: 1), after treatment with 0.1N HCl, the product having a melting point of 193-195 °.

c.c.m. (methylene chloride / methanol, 9: 1) Rf = 0.42.

\ 49 Λ ·

In the examples which follow B.P, relates to the British pharmacopoeia.

Example 15

Pharmaceutical compositions 5 (a) TABLETS

^ mg / tablet

Active ingredient 1

Polyvinylpyrrolidone (PVP) 20

Lactose B.P. 127 10 Magnesium stearate B.P. 2

Weight after compression 150

The drug substance is granulated using a solution of PVP in ethanol, the granules are mixed with the excipients and compressed using 15 appropriate punches · mg / tablet

Active ingredient 1

BPC 40 microcrystalline cellulose

Lactose B.P. 100

Carboxymethylcellulose sodium 8 20 Magnesium stearate B.P. 1 y

Weight after compression 150

The drug substance is sieved through a suitable sieve, mixed with the excipients and compressed using suitable punches. Tablets of other active ingredient contents can be prepared by changing the weight after compression and using the appropriate punches.

The tablets can be coated with a film by using suitable film or film-forming substances, for example methylcellulose, ethylcellulose or hydroxypropylmethylcellulose, using conventional techniques. You can also coat the sugar cubes.

(b) MOLLIS GELATIN CAPSULES

mg / capsule

Active ingredient 1 ’

Polyethylene glycol (PEG) 400 199 • f

Weight after filling 200 10 The active substance is dissolved in PSG 400 with stirring and the mixture is introduced into soft gelatin capsules using an appropriate filling machine. Other doses can be prepared by modifying the weight after filling and, if necessary, by changing the size of the capsules to adapt to the change in weight after filling.

In.iection quantity / amnoules * Active ingredient 1.0 mg

Water for injection up to 2.0 ml 20 * quantity expressed as the free base.

The active ingredient is dissolved in water for injection with stirring. The solution is sterilized by filtration and introduced into glass ampoules under sterile conditions. Other doses can be prepared by changing the filling volume or the concentration of active ingredient. In the pharmaceutical examples above, the expression "active ingredient" refers to one or more compounds of the general formula (I) but ".51 preferably designates 2-dimethylaminomethyl-6-mes-thyl-4- (2- (3- (1,1-dimethylethoxy) -3-oxo-1 -propenyl) phe-nyl) -1,4-dihydro-3,5-pyridine-diethyl dicarboxylate and, more particularly, l 'E isomer of this component 5 and their enantiomorphs S,

In general, the compounds are non-toxic at therapeutically effective doses. Thus, for example, no harmful effects are observed when the compounds of the examples are administered by seeing it orally in doses of 10 10 mg / kg to the conscious rat.

Claims (17)

1. Compounds of the general formula (i) / Λ Γ i 5 \ Λ i7 · t ch = cco2r6 R- ° A A / “*" ”• · 1 II 10. AA (I) R5 N AlkNR | _R £ and their physiologically acceptable or compatible salts, formula in which represents a hydrogen atom or a C 1 -C 4 alkyl radical, R2 represents a hydrogen atom, a radical C1-C6-alkyl or phenyl (C1-C4) alkyl where the phenyl ring may be substituted by a nitro radical, C1-C4-alkyl, alkoxy or hydroxyl, or by a halogen atom, or alternatively and R £ may form together with the nitrogen atom to which they are attached, a pyrrolidino, piperidino, hexamethyleneimino, morpholino, thiamorpholino, thiamorpholino S-oxide, thiamorpholi-no S nucleus , S-dioxide, piperazino, N-methylpiperazino or N-phe-nylpiperazino; Alk represents a methylene or ethylene chain; R ^ and R ^ independently represent a straight chain or branched chain alkyl or alkyl radical at (3 ,, - Cg; represents a C 1 -C 4 alkyl radical; Rg represents a C 1 -C alkyl radical - C 4 or a C 6 -C 10 cycloalkyl radical which may be substituted by O 8 a C 1 -C 4 alkyl group; and Ry represents a halogen atom or a hydrogen atom, or an alkyl radical in C ^ -C ^. \ 53> »* 2. Compounds according to claim 1, characterized in that R <j represents a hydrogen atom or the methyl radical and R2 represents a hydrogen atom or an alkyl radical in or else and R ^ form, with the atom nitrogen, a pyrrolidono, piperidino, morpholino, piperazino or thiomorpholino group; e-fc * ^ 4 independently represent C 1 -C 4 alkyl radicals; represents the methyl radicalj 10 Rg represents a C 2 -C 6 alkyl radical or a C 1 -C 6 cycloalkyl radical which may be substituted by a C 1 -C 4 alkyl radical Ry represents a bromine atom or a hydrogen atom j or a radical C ^ -C ^ alkyl. 3. Compound according to any one of claims 1 and 2, characterized in that R ^ and R ^ represent, independently, methyl or ethyl radicals. 4. Compounds according to any one of claims 1 to .3, characterized in that R ^ RgN represents an amino, methylamino, ethylamino, isopropylamino, dimethylamino or morpholino radical, R ^ and R ^ represent, inde! meanwhile, methyl or ethyl radicals, R ^ represents | the methyl radical, Rg represents the ethyl, propyl, isopropyl, tertiary butyl, pentyl, cyclohexyl or octyl radical and Ry represents a hydrogen atom or the methyl or ethyl radical. 5. Compounds according to any one of claims 1 to 4, characterized in that R ^ RgN represents a methylamino, isopropylamino or dimethylamino or morpholino radical, Alk represents a methylene chain, R ^ and R ^ represent methyl or ethyl radicals , R ^ represents the methyl radical, Rg represents the isopropyl radical. or tert-butyl and Ry represents a hydrogen atom, Rg represents an ethyl, isopropyl, propyl, tert-butyl or pentyl radical and Ry represents the methyl or 54 s * ethyl radical. 6. Compounds according to any one of Claims 1 to 5, characterized in that Rg represents a radical of the tertiary butyl type. 5. 2-Dimethylaminomethyl-6-methyl-4- (2- (3- (1,1-di-methylethoxy) -3-oxo-1-propenyl) phenyl) -1,4-dihydropyridi-ne-3,5-dicarboxylate diethyl; and its physiologically acceptable or compatible salts. 12. 2-Methylaminomethyl-6-methyl-4- (2- (3- (1,1-dimethyl-10 ethoxy) -3-oxo-1-propenyl) phenyl) -1,4-dihydropyridine-3,5- , diethyl dicarboxylate; Diethyl 2-aminomethyl-6-methyl-4- (2- (3- (1,1-dimethylethoxy) -3-oxo-1-propenyl) phenyl) -1,4-dihydropyridine-3,5-dicarboxylate; 15 2-isopropylaminomethyl-6-methyl-4- (2- (3- (1,1-dimethyl-etho xy) -3-OXO-1-propenyl) phenyl) -1,4-dihydro-pyridine-3,5 diethyl dicarboxylate; 2-me thylaminomé thyl-6-mé thyL-4- (2- (3-ethoxy-3-oxo-2-mé-thyl-1 -propényl) phenyl) -1,4-dihydr opyr idine -3,5- diethyl dicarboxy-late; Diethyl 2-methylaminomethyl-6-methyl-4- (2- (3-ethoxy-3-oxo-2 - ethyl-1-propenyl) phenyl) -1,4-dihydropyridine-3,5-dicarboxylate; i 2-pr opylaminomé thyl-4- (2- (3- (1,1-dimé thy1é thoxy) -3-oxo-1-25 -propényl) phenyl) -6-methyl-1,4-dihydro-pyridine- Diethyl 3,5-dicar boxylate; 2-me thylaminomé thyl-4- (2- (3- (1,1-dimé thyle thoxy) -3-oxo - 1 -propényl) phenyl) -6-methyl-1,4-dihydropyr idine-3,5 -methyl and ethyl dicarboxylate; 30 2-dimé thylaminomé thyl-6-mé thyl-4- (2- (3-propoxy-3-oxo-2- -methyl-1-propenyl) phenyl) -1,4-dihydropyridine-3,5-dicarboxylate diethyl; , 55 *. . * * „2-methylaminomethyl-6-methyl-4- (2- (3-propoxy-3-oxo-2- -methyl-1-propenyl) phenyl) -1,4-dihydropyridine-3,5-dicar-boxylate diethyl; and their physiologically acceptable or compatible salts. 9. The trans isomers of the compounds according to any one of claims 8 to 8, 10. The S-enantiomorphs of the compounds according to any one of claims 1 to 9 · 10 ίι ·. Process for the preparation of the compound of general formula (I) as defined in claim 1, characterized in that it comprises: (a) the preparation of the compound of formula (I) in which Alk represents a methylene radical, in causing Ί5 to react a compound of formula (II) in which X represents a labile group and R ^ -Ry have the meanings which were previously assigned to them in claim 1, on an amine R ^ RgNH in which R1 and R ,, have the meanings which were previously assigned to them in claim 1j // \ i II • · R - \\ / \ T7 25. CH = CC02R6 m2cn / \ / C02R3 • · il II •. · / \ / \ R s N CH, X 5 H 2 (II) 1.56 * * (b) the preparation of the trans isomers of compounds of formula (I) in which Rj and / or Rg do not represent hydrogen atoms and Ry represents an atom of hydrogen or a Cen alkyl radical reacting a compound of the formula (IV) in which Rj-R ^ have the singifications which were previously assigned to them in claim 1 and Hal represents a bromine or iodine atom, on an acrylic ester of the formula CHgsCRyCOgRg in which Rg has the meanings which were previously assigned to it in claim 1 and Ry represents a hydrogen atom or a C 1 -C 4 alkyl radical, in the presence of a palladium salt and an organic base ^ // \ Γ | î -------- \\ / \ • Hal 20 '' R4 ° 2C \ / \ / C02R3 1 'Ί / \ / \ R5 N AlkNR1R2 H CIV) 25 (c) the preparation of compounds of formula (I) in which Alk represents an ethylene radical, by reacting a compound of formula (III) in which R ^ -Ry have the meanings previously assigned to them in the claim. 1, on an amine R- ^ NH or a salt thereof and formaldehyde te »V 57%. • 1 ·; ’'/ Λ, \ A î7? CH = CCa2Rs R "° 2C \ À Z02" 3 1 'lî „/ \ / \ Rs N CH3 H (XII) (d) Esterification of the corresponding acid of formula (I) in which Rg represents an atom of hydrogen ^ (e) The reaction of a compound of formula (V) in which-5 the R "jR (j have the meanings which were previously assigned to them in claim 1, on the triphenylphosphorane of the formula Ph ^ P = CRyC02Rg in which Rg and Ry have the meanings which have been assigned to them previously in claim 1 10 // \ i iî «1 · \\ / \. CHO 15 M2 <\ / n / D! Sî ji IR / \ / N'AlkNR1R2 H (V) 20: (f) The preparation of compounds of formula (I) by reacting a compound of formula (X ) in which the symbols R ^ f R ^, Rg and R ^ have the meanings which 4. 58 V η - '*., Λ were previously assigned to them in claim 1, on the diaminoester (XVII) in which the radicals R "j, Rg ^ 3 have the meanings previously assigned to them in claim 1, 5 or are groups convertible into such radicals A '! i! 7! 0 \ / CHsC-C0 ** - ‘CO 2R 3 î CH7 M2 <\ / H I £ H2N ^ (CH2) nNRiR2 '/ \\ 15 R5 0 (X) (XVII) (g) Preparation of a cis isomer of a compound of formula (I) by irradiation of a solution of the trans isomer of formula (I) corresponding) (h) Preparation of the S and / or R enantiomorphs separated from a compound of formula (I) by solving the appropriate cis or trans isomer of a compound of formula (I) using a optically active acid; and if desired, converting the compound thus obtained of formula (I) or a salt thereof to a physiologically acceptable salt thereof · 12. Pharmaceutical compositions comprising a compound according to claim 1, in combination with a pharmaceutically acceptable diluent, vehicle or excipient. ft 1