FR2670785A1 - 2-(4-Methoxyphenyl)-5-[2-(methylamino)ethyl]-2,3-dihydro-5H-1,5-be nzothiazepin-4-one derivatives, their preparation and their application in therapeutics - Google Patents

Abstract

Compounds corresponding to the general formula (I) in which R represents either an acetyl group or a dimethylcarbamoyl group and Y represents either a group of formula -C(:Z)-CH2- in which Z represents two hydrogen atoms or an oxygen or sulphur atom or a methylene or (C1-C4)alkoxyimino group, the -CZ- group being adjacent to the benzene ring, or a group of formula -CH=CH- or -CR1=CH- or -CH=CR2- in which R1 and R2 each represent a (C1-C4)alkyl group. Application in therapeutics.

Description

The present invention relates to derivatives of (4-methoxy-phenyl) -2 (2-methylaminoethyl) -5,5-dihydro-5H-benzothiazepine-1-one-4, their preparation and their therapeutic application. .

dans laquelle
R représente soit un groupe acétyle soit un groupe diméthylcarbamoyle, et
Y représente soit un groupe de formule générale

dans laquelle Z représente deux atomes d'hydrogène ou un atome d'oxygène ou de soufre ou un groupe méthylène ou alcoxyimino de formule générale =N-O-(C1-C4)alkyle, le groupe -CZ- étant adjacent au cycle benzénique, soit un groupe de formule -CH=CH- ou de formule générale -CR1=CH- ou -CH=CR2- dans lesquelles R1 et R2 représentent chacun un groupe (C1-C4)alkyle, l'heterocycle qui contient Y étant relié au reste de la molécule par l'une quelconque des positions 6, 7, 8 ou 9.The compounds of the invention correspond to the general formula (I)

in which
R represents either an acetyl group or a dimethylcarbamoyl group, and
Y represents either a group of general formula

in which Z represents two hydrogen atoms or an oxygen or sulfur atom or a methylene or alkoxyimino group of general formula = NO- (C1-C4) alkyl, the -CZ- group being adjacent to the benzene ring, ie a a group of formula -CH = CH- or of general formula -CR1 = CH- or -CH = CR2- in which R1 and R2 each represent a (C1-C4) alkyl group, the heterocycle which contains Y being connected to the remainder of the molecule by any of the positions 6, 7, 8 or 9.

The compounds of the invention may be in the form of free bases or addition salts with acids. The carbon atoms at the 2 and 3 positions of the benzothia zepine ring being chiral, the compounds can also exist in various forms of isomers: racemates, diastereoisomers, pure optical isomers or mixtures. These various forms are part of the invention.

According to the invention, the compounds of general formula (I) can be prepared by a process illustrated by the reaction scheme given below.

This process comprises reacting a benzothiazepinone of the general formula (II) (wherein R is as defined above) with a halogenated derivative of the general formula (III) (wherein Y is as defined above and X is an atom halogen, for example chlorine or bromine).

The reaction is carried out under well known conditions (the compound of general formula (II) being in free base or addition salt form) at the reflux temperature of an aprotic solvent such as a ketone or acetonitrile, in the presence of a base, such as potassium carbonate, for fixing the acid released (and, where appropriate, releasing the base of the starting compound), and optionally in the presence of a catalyst of phase transfer such as benzyltrimethylammonium chloride.

A compound of general formula (I) in which R represents a dimethylcarbamoyl group may also be obtained from a compound of general formula (I) in which R represents an acetyl group, firstly by hydrolysis, giving an intermediate of formula general (I) wherein R is a hydrogen atom and then esterification of the latter by means of dimethylcarbamoyl chloride.

The benzothiazepinone of general formula (II) in which R represents an acetyl group is described for example in
Chem. Pharm. Bull., 26, 2889, (1978), in J. Pharmacobio.

Dyn., -7, 24, (1978), and in J. Cardiov. Pharmacol., 2, 152, (1984).

Diagram

The derivatives of general formula (III) can be obtained from the corresponding acids or esters of general formula (IV) (in which Y represents a group of formula -CO-CH 2 - and R 'represents a hydrogen atom or a group lower alkyl), firstly by a reduction reaction to alcohol, the -CO- group of Y being previously protected in the form of a ketal with ethylene glycol, then by the action of a halogenation agent equivalent, preceded or followed by the conversion of ketal into ketone in acidic medium.

peut être obtenu par traitement d'un composé de formule générale (III) dans laquelle Y représente un groupe de formule -CHZ'-CH2-, dans laquelle Z' représente une fonction alcool protégée, avec un agent de sulfuration tel que le pentasulfure de phosphore (P4S1 o)
Les composés de formule générale (IV) dans laquelle Y représente un groupe de formule -CO-CH2- sont décrits dans le brevet européen N00198762. Ils sont appelés ci-après "les cétones de formule générale (IV), et peuvent servir aussi de composés de départ pour la préparation des composés de formule générale (IV) dans laquelle Y représente un autre groupe, selon des méthodes bien connues de l'homme du métier.A compound of general formula (III) in which Y represents a group of formula

can be obtained by treatment of a compound of general formula (III) in which Y represents a group of formula -CHZ'-CH2-, in which Z 'represents a protected alcohol function, with a sulphurizing agent such as pentasulfide of phosphorus (P4S1 o)
The compounds of general formula (IV) wherein Y represents a group of formula -CO-CH 2 - are described in European Patent N00198762. They are hereinafter referred to as "ketones of the general formula (IV), and may also be used as starting compounds for the preparation of the compounds of the general formula (IV) in which Y represents another group, according to methods well known in the art. skilled person.

Thus a compound of general formula (IV) in which Y represents a group of formula -CH 2 -CH 2 - can be obtained from a ketone of general formula (IV) by reduction to alcohol, for example by means of a borohydride alkali, and then by reduction of the intermediate alcohol, for example by means of sodium cyanoborohydride and zinc iodide.

Such a compound (Y = -CH 2 -CH 2 -) can also be obtained by catalytic hydrogenation of a corresponding unsaturated compound (Y = -CH = CH-), the preparation of which is described below.

These reduction and hydrogenation reactions are described in European Patent Application N00272981.

et X représente un groupement alcool peut être obtenu par réduction de l'ester en alcool, le groupe CO étant préalablement protégé comme indiqué précédemment, puis après déprotection, par réaction de Wittig avec l'ylure de phosphore correspondant.A compound of general formula (IV) wherein Y is a group of formula

and X represents an alcohol group can be obtained by reducing the ester to alcohol, the CO group being previously protected as indicated above, then after deprotection, by Wittig reaction with the corresponding phosphorus ylide.

A compound of general formula (IV) wherein Y is a group of formula

<tb> -C-CH2- <SEP> and <SEP> X <SEP> represents
<tb> NO- <SEP> (C1 <SEP> -C4) <SEP> alkyl
an alcohol group can be obtained by reducing the ester to an alcohol, the CO group being protected beforehand as indicated above, then after deprotection, by reaction with an alkylated hydroxylamine of general formula H2N-O- (C1- C4) alkyl under standard conditions.

A compound of general formula (IV) in which Y represents a group of formula -CH = CH- can be obtained by reducing a ketone of general formula (IV) to alcohol, as indicated above, and then by dehydration of the intermediate secondary alcohol, for example in the presence of para-toluenesulphonic acid. This reaction is also described in European Patent Application N00272981.

A compound of general formula (IV) in which Y represents a group of formula -CR1 = CH- can be obtained from a ketone of general formula (IV) by the action of a (C1-C4) alkylmagnesium, followed by dehydration. intermediate tertiary alcohol.

Finally, a compound of general formula (IV) in which Y represents a group of formula -CH = CR 2 - can be obtained from a ketone of general formula (IV) by silylation of the corresponding enol, alkylation by addition of a halogenated thioether of the general formula Cl-R'2-S-C6Hs (R'2 being a (C1-C4) alkyl group), reduction and dehydration of the resulting intermediate alcohol.

The esters of general formula (IV) in which Y does not represent a group of formula -CO-CH 2 - can then be reduced to alcohols and then converted into halogenated derivatives of general formula (III) under the conditions described with reference to "ketones". of general formula (IV) ".

The examples which follow illustrate in detail the preparation of some compounds according to the invention. The numbers given in parentheses in the titles of the examples correspond to those in the table given below.

The elemental microanalyses and the IR and NMR spectra confirm the structures of the products obtained.

Example 1 (Compound N01) (Acetyloxy) -3 (4-methoxyphenyl) -2 [[N - [(2,3,4,5-tetrahydro-benzo (b) oxepinnyl-7) -2-ethyl] methylamino] -2 ethyl] -5-dihydro-5H-benzothiazepine-1,5-one-4- (cis-2S, 3S) - (+) fumarate.

a) 5-Hydroxy-2,3,4,5-tetrahydro-benzo (b) oxepin-7-methyl acetate.

To a solution of 23.4 g (100 mmol) of methyl 5-oxo-3,4-dihydro-2H-benzo [b] oxepin-7-acetate in 250 ml of anhydrous methanol is added to OOC and under argon, 3.8 g (100 mmol) of sodium borohydride. The mixture is allowed to warm to room temperature, stirred for 13 hours and poured into 200 ml of ice water. The methanol is evaporated, the aqueous phase is acidified with 10% hydrochloric acid and extracted with three times 100 ml of diethyl ether.

The organic phase is dried over magnesium sulfate, filtered and the ether evaporated under reduced pressure. 22.86 g of a viscous colorless oil are obtained.

b) 2,3-Dihydro-benzo [b] oxepin-7-methyl acetate.

To a solution of 22.86 g (96.8 mmol) of 5-hydroxy-2,3,4,5-tetrahydro-benzo [b] oxepin-7-methyl acetate in 250 ml of benzene is added 1 g of acid. The mixture is refluxed for 7 hours in a flask equipped with a Dean-Stark apparatus and, after cooling, the mixture is poured into 150 ml of water and sodium carbonate is added to adjust the pH of the mixture. 8 aqueous phase, the aqueous phase is separated and extracted with 100 ml of diethyl ether, the organic phase is dried over magnesium sulfate, filtered and the ether is evaporated off under reduced pressure. 87 g of a slightly yellow oil.

c) 2,3,4,5-Tetrahydro-benzo [b] oxepin-7-methyl acetate.

To a solution of 8.22 g (37.6 mmol) of 2,3-dihydro-benzo [b] oxepin-7-methyl acetate in 190 ml of ethyl acetate is added 2 g of 5% palladium on carbon. and the mixture is hydrogenated in a Parr apparatus for 2 hours at room temperature. The catalyst is filtered off, the solvent is evaporated under reduced pressure, the residue is taken up in 20 ml of ether, the suspension is filtered through a short silica column and the filtrate is evaporated. 8.26 g of a colorless liquid are obtained.

d) 2,3,4,5-tetrahydro-benzo [F] oxepin-7-ethanol.

To a suspension of 1.42 g (37.5 mmol) of lithium aluminum hydride in 75 ml of diethyl ether, to 8.25 g (37.5 mmol) is added under argon and under argon. 2,3,4,5-tetrahydro-benzo [bloxepin-7-methyl acetate dissolved in 38 ml of ether. The mixture is allowed to return to room temperature and stirring is maintained for 1 h 30 min. 3 ml of water and then 2.4 ml of 10% aqueous sodium hydroxide are then added dropwise, the mixture is stirred for 45 minutes, 0.75 g of magnesium sulphate is added, the mixture is stirred for a further 15 minutes, the mixture is filtered, the filtrate is dried over magnesium sulfate, filtered and the solvent is evaporated off under reduced pressure. 6.52 g of a viscous colorless oil are obtained.

e) (2-Bromoethyl) -7,2,3,4,5-tetrahydro benzo [b] oxepinne.

To a solution of 3.52 g (18.3 mmol) of 2,3,4,5-tetrahydro-benzo (b) oxepin-7-ethanol and 7.89 g of tetrabromomethane in 37 ml of dichloromethane is added to OOC. and under argon, 6.72 g (25.6 mmol) of triphenylphosphine dissolved in 37 ml of dichloromethane The mixture is stirred for 4h at room temperature, the solvent is evaporated off under reduced pressure, and the residue is purified by chromatography on silica column, 4.07 g of a colorless oil is obtained.

f) (Acetyloxy) -3 (4-methoxyphenyl) -2 [[N - [(2,3,4,5-tetrahydro-benzoFb) oxepinnyl-7) -2-ethyl] methylamino] -2-ethyl] -5-dihydro-2,3 5H-benzothiazepine-1, 5-one-4- (cis-2S, 3S) - (+), fumarate.

A mixture of 4.67 g (10.7 mmol) of (acetyloxy) -3 (4-methoxy-phenyl) -2- (2-methylaminoethyl) -2,5-dihydro-5H-hydrochloride is refluxed for 5 hours. benzothiazepine-1,5-one-4- (cis-2S, 3S) - (+), 3.0 g (11.7 mmol) of (2-bromo-ethyl) -7,2,3,4,5-tetrahydro benzoate 4.43 g (32 mmol) of potassium carbonate and 55 ml of methyl isobutyl ketone are allowed to cool, the mixture is filtered, the filtrate is evaporated and the evaporation residue is purified by chromatography on a silica column. 2.86 g of crude free base are obtained, treated with one equivalent of fumaric acid in ethanol, the precipitated salt is filtered off and recrystallized in ethanol, 2.54 g of fumarate are finally isolated. .

Melting point: 159-1570C. [&alpha;] D20 = + 83.1 (c = 0.2, MeOH).

Example 2 (Compound N07) (Acetyloxy) -3 (4-methoxyphenyl) -2- (FN-F (5-oxo-tetrahydro2,3,4,5-benzoFb) oxepinnyl-8) -2-ethyl-methylamino] -2-ethyl] -5 2,3-dihydro-5H-benzothiazepine-1, 5-one-4- (cis-2S, 3S) - (+), oxalate.

a) 3,4-Dihydro-spiro [2H-benzo [b] oxepin-5 (2H): 2'-dioxolane-1,3] -8-methyl acetate.

A mixture of 10 g (41 mmol) of 5-oxo-3,4-dihydro-2H-benzo-C0-oxepin-8-methyl acetate, 0.2 g of para-toluenesulphonic acid and 23 ml (41 mmol) is refluxed for 8 hours. ethylene glycol in 100 ml of benzene. The benzene phase is separated, washed with 50 ml of water, dried over magnesium sulfate and the solvent is evaporated under reduced pressure. 9 g of colorless oil are obtained.

b) Dihydro-3,4-spiro [2H-benzo [b] oxepin-5 (2H): 2'-dioxolan-1,3] -8-ethanol.

A solution of 9 g (32 mmol) of 3,4-dihydro-spiro [2H-benzo [b] oxepin-5 (2H): 2'-dioxolan-1,3] -8-methyl acetate was slowly added in 50 ml of sodium hydroxide. diethyl ether to a suspension of 1.5 g (39 mmol) of lithium aluminum hydride in 100 ml of diethyl ether. The mixture is stirred at room temperature for 30 minutes, cooled, 3 ml of 10% aqueous sodium hydroxide and then 2 ml of water are added with stirring for 40 minutes. 1 g of magnesium sulphate is then added, the mixture is filtered and the filtrate is evaporated. 6.8 g of colorless viscous oil are obtained.

c) (2-Hydroxyethyl) -3,4-dihydro-2H-benzo [Fb] oxepinnone-5.

To a solution of 6.8 g (27 mmol) of 3,4-dihydro-spiro [2H-benzo [b] oxepin-5 (2H): 2'-dioxolan-1,3] -8-ethynol in 100 ml of acetone is added 60 ml of 2N aqueous hydrochloric acid. Stirring is maintained at room temperature for 30 minutes, then the mixture is extracted with dichloromethane. The organic phase is dried over magnesium sulfate, filtered and the solvent evaporated under reduced pressure. 4.8 g of colorless viscous oil are obtained.

d) (2-Bromoethyl) -8-dihydro-3,4H-benzo [bb] oxepin-5-one.

8.5 g (32.5 mmol) of triphenylphosphine are added slowly to a solution of 4.8 g (25 mmol) of (2-hydroxyethyl) -3,4-dihydro-2H-benzo [b] oxepinnone-5 and 10.8 g (32.5 mmol) of tetrabromomethane in 200 ml of OOC acetonitrile. The mixture is stirred at this temperature for 30 minutes, then at room temperature for 1 hour. The mixture is filtered, the filtrate is evaporated, and the oily residue is purified by chromatography on a silica column, eluting with an 80/20 mixture of hexane / ethyl ether. 5.1 g of colorless oil are obtained.

e) (Acetyloxy) -3 (4-methoxyphenyl) -2 [FN-F (5-oxo-2,3,4,5-tetrahydro-benzo [2- (oxepinnyl) -2-ethyl] methylamino] -2 ethyl] - 2,3-dihydro-1H-benzothiazepine-1,5-a-4- (cis2S, 3S) - (+), oxalate.

A mixture of 3.5 g (8.4 mmol) of (acetyloxy) -3 (4-methoxy-phenyl) -2 (methylamino) -2-ethyl) -5-dihydro-5H hydrochloride is refluxed for 20 hours. benzothiazepine-1,5-one-4- (cis-2S, 3S) - (+), 2.5 g (9.5 mmol) of (2-bromo-ethyl) -8-dihydro-2H-benzold] oxepinnone-5 and 8.6 g (67 mmol) of potassium carbonate in 100 ml of butanone-2.

The mixture is filtered, the filtrate is evaporated, the residue is taken up in 80 ml of chloroform, the solution is washed with 50 ml of water, dried over magnesium sulphate, the solvent is evaporated off under reduced pressure and the residue is purified. residual oil by chromatography on a silica column. 1.85 g of free base is obtained which is taken up in ethanol and treated with one equivalent of oxalic acid. The precipitated salt is filtered and recrystallized from ethanol. Finally, 1.62 g of oxalate are finally isolated.

Melting point: 1100C. [&alpha;] D20 = + 76.3 (c = 0.5, MeOH).

Example 3 (Compound N08) (Dimethylcabamoyloxy) -3 (4-methoxyphenyl) [[N - [(5-oxo-2,3,4,5-tetrahydro-benzo [b] oxepinnyl-8) -2-ethylmethylamino] 2 ethyl] -5-dihydro-2,3,5H-benzothiazepne-1,5-one-4- (cis2S, 3S) - (+), oxalate.

a) 3-Hydroxy-4- (4-methoxyphenyl) - (FN-F (5-oxo-tetrahydro-2,3,4,5-benzo-2,6-oxepinnyl-8) -2-ethyl] methylamino] -2-ethyl] -5-dihydro-5H benzothiazepine-1,5-one-4- (cis-2S, 3S) - (+).

To a solution of 3.18 g (5.40 mmol) of (acetyloxy) -3 (4-methoxyphenyl) -2 [[N - [(oxo-5-tetrahydro-2,3,4,5 benzo [b]] 8-oxepinnyl) -2-ethyl] methylamino] ethyl] -5-dihydro-5H-benzothiazepine-1,5-one-4- (cis-2S, 3S) - (+) in 40 ml of methanol is added , under argon and OOC, 0.23 ml (73.3 mmol) sodium methoxide 5.9N solution in methanol. The mixture is stirred for 1 hour at 0 ° C. and then for 3 hours at room temperature, the solvent is evaporated off under reduced pressure and the residue is taken up with 150 ml of chloroform. The resulting solution is washed with 80 ml of saturated aqueous sodium bicarbonate solution and then with 80 ml of water, dried over magnesium sulfate, filtered and the filtrate evaporated. 2.87 g of highly viscous oil are obtained.

b) (dimethylcarbamoyloxy) -3 (4-methoxyphenyl) -2 [(N - [(oxo-5-tetrahydro-2,3,4,5-benzo [b] oxepinnyl-8) -2ethyl] methylamino] -2-ethyl ] -5-dihydro-5H-benzothiazepine-1,5-one-4- (cis2S, 3S) - (+), oxalate.

To a solution of 2.87 g (5.25 mmol) of 3-hydroxy-4-methoxy-phenyl-2 [[N - [(oxo-5-tetrahydro-2,3,4,5-benzo [b] oxepinnyl) 8) -2-ethyl] methylamino] -2-ethyl-5-dihydro-5H-benzothiazepine-1,5-one-4- (cis-2S, 3S) - (+) in 70 ml of benzene is added under at room temperature, 0.67 g (16.8 mmol) of 50% sodium hydride in mineral oil.

The mixture is refluxed for 1 hour, allowed to cool and at about 30 ° C. 0.58 ml (6.3 mmol) of dimethylcarbamoyl chloride is added. Stirring is continued at room temperature for 15 hours, then the excess sodium hydride is hydrolyzed by adding, dropwise, 30 ml of 10% aqueous potassium carbonate, and the mixture is diluted with 50 ml of sodium hydroxide. diethyl ether. The organic phase is separated, dried over magnesium sulfate, filtered, the filtrate is evaporated and the residue is purified by chromatography on a silica column. 1.82 g of free base are obtained, treated with one equivalent of oxalic acid in ethanol. The precipitated salt is filtered and recrystallized from ethanol. 1.58 g of oxalate are finally isolated.

Melting point: 163-164. Fa = 20 = + 29.60 (c = 0.2, MeOH).

Example 4 (Compound NO9) (Acetyloxy) -3 (4-methoxyphenyl) -2 [[N - [(2,3,4,5-dihydro-benzo [bb] oxepinnyl-7) -2-ethyl] methylamino] -2-ethyl 5-dihydro-2,3H-benzothiazepine-1,5-one-4- (cis-2S, 3S) - (+), oxalate.

a) (2-bromo-ethyl) -7-dihydro-2,3-benzo [b] oxepinne.

5.74 g of 2,3-dihydro-benzo [b] oxepin-7-methyl acetate are reduced by means of lithium aluminum hydride under the conditions described in Example 1b and the dihydro-2 is treated. , 3 benzolb] oxepin-7-ethanol obtained with a mixture of triphenylphosphine tetrabromomethane and under the conditions described in Example 2d, and gives 6.6 g of colorless oil.

b) (Acetyloxy) -3 (4-methoxyphenyl) -2 [[N - [(2,3,4,5-dihydro-benzo [b] oxepinnyl-7) -2-ethyl] methylamino] -2-ethyl] -5-dihydro- 2,3 5H-benzothiazepine-1,5-one-4- (cis-2S, 3S) - (+), oxalate.

A mixture of 6.27 g (14.3 mmol) of (acetyloxy) -3 (4-methoxy-phenyl) -2 (methylamino) -2-ethyl) -5-dihydro-5H hydrochloride is refluxed for 6 hours. benzothiazepine-1,5-one-4- (cis-2S, 3S) - (+), 4.0 g (15.8 mmol) of (2-bromo-ethyl) -7-dihydro-benzo [b] oxepinne, 5.95 g (43 mmol) of potassium carbonate and 72 ml of methyl isobutyl ketone. The mixture is allowed to cool, it is filtered, the filtrate is evaporated, the oily residue is taken up in 100 ml of dichloromethane, the solution is washed with 100 ml of water, dried over magnesium sulphate, filtered and filtered. The solvent is evaporated under reduced pressure and the residue is purified by chromatography on a silica column. 3.83 g of crude free base are obtained, treated with one equivalent of oxalic acid in ethanol. The salt which precipitates is filtered and recrystallized from ethanol. Finally, 3.75 g of oxalate are finally isolated.

Melting point: 158-1900C. [α] 20 = + 77.0 O (c = 0.2; MeOH).

The following table illustrates the structures and physical properties of some compounds according to the invention.

Board

<tb><SEP> Position <SEP> of <SEP> Salt <SEP>[&alpha;] D20 <SEP>
<tb> N <SEP> R <SEP> Y
<tb><SEP> the <SEP> bond <SEP> (*) <SEP> (c, MeOH) <SEP> F (0C)
<tb><SEP> 1 <SEP> COCH3 <SEP> -CH2-CH2- <SEP> 7 <SEP> Smoke <SEP> +83.1 <SEP> 156-157
<tb><SEP> (0,2)
<tb><SEP> 2 <SEP> CON (CH3) 2 <SEP> -CH2-CH2- <SEP> 7 <SEP> OX <SEP> +26.5 <SEQ> 165.8-166.3
<tb><SEP> (0,2)
<tb><SEP> 3 <SEP> COCH3 <SEP> -CH2-CH2- <SEP> 8 <SEP> OX <SEP> +76.7 <SEP> 126
<tb><SEP> (0,1)
<tb><SEP> 4 <SEP> CON (CH3) 2 <SEP> -CH2-CH2- <SEP> 8 <SEP> HCl <SEP> +31.7 <SEP> 122
<tb><SEP> (0,5)
<tb><SEP> 5 <SEP> COCH3 <SEP> -CO-CH2- <SEP> 7 <SEP> OX <SEP> +80.6 <SEP> 100
<tb><SEP> (0,5)
<tb><SEP> 6 <SEP> CON (CH3) 2 <SEP> -CO2-CH2- <SEP> 7 <SEP> OX <SEP> +30.0 <SEP> 106
<tb><SEP> (0,5)
<tb><SEP> 7 <SEP> COCH3 <SEP> -CO-CH2- <SEP> 8 <SEP> OX <SEP> +76.3 <SEP> 110
<tb><SEP> (0,5)
<tb><SEP> 8 <SEP> CON (CH3) 2 <SEP> -CH2-CH2- <SEP> 8 <SEP> OX <SEP> +29.6 <SEQ> 163-164
<tb><SEP> (0,2)
<tb><SEP> 9 <SEP> COCH3 <SEP> -CH = CH- <SEP> 7 <SEP> OX <SEP> +77.0 <SEP> 158-160
<tb><SEP> (0,2)
<tb> 10 <SEP> CON (CH3) 2 <SEP> -CH = CH- <SEP> 7 <SEP> OX <SEP> +28.8 <SEP> 169.7-170.2
<tb><SEP> (0,2)
<tb> 11 <SEP> COCH3 <SEP> -CH = CH- <SEP> 8 <SEP> OX <SEP> +78.3 <SEP> 148
<tb><SEP> (0,5)
<Tb>
Table (continuation and end)

<tb><SEP> Position <SEP> of <SEP> Salt <SEP>[&alpha;;] D20
<tb> N <SEP> R <SEP> Y <SEP><SEP> Liasion <SEP> (*) <SEP> (c, <SEP> MeOH) <SEP> F (C)
<tb> 12 <SEP> CON (CH3) 2 <SEP> -CH = CH- <SEP> 8 <SEP> OX <SEP> +32.0 <SEP> 104
<tb><SEP> (0,1)
<tb> 13 <SEP> COCH3 <SEP> -C-CH2- <SEP> 7 <SEP> OX <SEP> +76.3 <SEP> 132.7-133.6
<tb><SEP>#<SEP> (0,4)
<tb><SEP> CH2
<tb> 14 <SEP> COCH3 <SEP> -C = CH- <SEP> 7 <SEP> OX <SEP> +77.5 <SEP> 111.5-112.9
<tb><SEP> CH3
<tb> 15 <SEP> COCH3 <SEP> -C-CH2- <SEP> 7 <SEP> OX <SEP> +76.6 <SEP> 91.6
<tb><SEP>#<SEP> (0,5)
<tb><SEP> NO-CH3
<tb> (*) fum: fumarate; ox: oxalate; HCl: hydrochloride
The compounds of the invention have been the subject of a series of pharmacological tests which have demonstrated their interest as therapeutic substances of the cardiovascular system.

Their activity as calcium antagonists was shown by an isolated rabbit aortic test. The experimental protocol used is a variant of the one used by
Godfraind and Kaba (1969), (Blockade or reversal of the contraction induced by calcium and adrenaline in depolarized arterial smooth muscle, Br. J. Pharmac., 36, 549-560).

The details of the test are described in European patent N001 03500.

The molar concentration causing 50% relaxation of the calcium response (CEso) or its antilogarithm (pCE50) is calculated.

The pCE50s of the compounds of the invention range from 4.7 to 6.75.

The compounds of the invention have also been subjected to a [3H] nitrendipine binding assay on the total rat cortex.

The details of the test are described in European Patent Application No. 0300865.

The IC 50 concentrations of the compounds of the invention (concentrations which inhibit 50% of the specific binding of 3 H) nitrendipine are between 0.01 and 0.5 μM.

The compounds of the invention have also been the subject of an inhibition test for the specific binding of "PAF", platelet activation factor.

The animals are rabbits weighing 2.5 to 3 kg, anesthetized with pentobarbital sodium (0.25 mg / kg intravenously) and maintained under artificial respiration by intubation. The blood is taken from the carotid artery and collected in tubes containing a citrate anticoagulant. The tubes were centrifuged at 100g for 15 min, and the platelet-rich plasma was diluted with 2 volumes of 10mM Tris-HCl buffer, pH 7.5, containing 150mM sodium chloride and 2mM d EDTA (buffer A). After centrifugation at 1000 g for 10 min at 40 ° C., the pellet is washed with 2 volumes of buffer A, and a new centrifugation is carried out.

The platelet-rich pellet is suspended in ice-cold buffer (10 mM Tris-HCl, pH 7.0, containing 5 mM magnesium chloride and 2 mM EDTA), homogenized and centrifuged. at 30000g and 40C for 10 minutes. This procedure is repeated, the resulting pellet is collected in the same buffer, homogenized and the membrane suspension is frozen in liquid nitrogen. For the binding inhibition assay, the suspension is released and diluted with buffer to provide about 150 μg protein per milliliter.

Aliquots (30 μg of protein) of membranes are incubated in the presence of 10 mM Tris-HCl buffer, pH 7.0, containing 10 mM magnesium chloride and 0.25% (w / v). bovine serum albumin, for 2 hours at 250C, with 1 nM tritiated PAF (13H] 1-O-hexadecyl-2-acetyl-n-glyceryl-3-phosphorylcholine), in a final volume of 1 ml. The incubation is completed by collecting the membranes and washing them rapidly with ice-cold buffer on filters
Whatman, using a Skatron cell collector connected to a vacuum pump. The filters are dried and measured by scintigraphic spectrometry. Specific binding is defined by the difference in membrane radioactivity observed in the absence and presence of 1 μM tritiated PAF.

The inhibition of the binding tests are carried out under the conditions described, in the presence of different concentrations of test compounds. The IC50 concentration for each compound (concentration which inhibits the specific binding by 50%) is then determined by plotting the inhibition curve according to the least squares method.

The IC.sub.50 of the compounds of the invention in this test are between 0.5 and 10 .mu.M.

Finally, the compounds of the invention were the subject of an inhibition test of blood platelet aggregation induced by "PAF-acether" (1-O- (C16-Cl8-alkyl) -2- acetyl-sn-glyceryl-3-phosphorylcholine).

The assay is performed according to the method of Born (J. Physiol., (1963), 168, 178-195) on rabbit platelets. The blood is collected by cardiac puncture, and collected on trisodium citrate at 3.8% in the proportions of 1 volume of anticoagulant solution for 9 volumes of blood. It is then centrifuged at 250 g for 10 min, the platelet-rich plasma is removed and the platelets are counted.

The pellet is recentrifuged at 3600 g for 15 minutes to obtain platelet-poor plasma, and the platelet-rich plasma is diluted with the platelet-poor plasma to obtain a suspension containing from 200,000 to 300,000 platelets per tablet. ijl.

Aggregation in vitro is performed using PAF-acether at the maximum concentration necessary to obtain a maximum reversible response (normally between 1.5 and 3 ng / ml). The optical density variations are recorded by means of an aggregometer (300 μl of platelet-rich plasma per tank, 1100 rpm at 370 ° C.) until the maximum aggregation is exceeded.

For the tests, the compounds of the invention are dissolved in dimethylsulfoxide and incubated for 2 minutes at 370 ° C. before addition of the PAF-acether.

The anti-aggregating action of the compounds is expressed by the IC50 concentration, concentration which inhibits by 50% the aggregation caused by the PAF-acether.

The IC.sub.50 of the compounds of the invention in this test are between 3 and 20 .mu.M.

The results of the pharmacological tests show that the compounds of the invention are calcium antagonists and can, as such, be used for the treatment of various conditions for which this type of agent is indicated.

Thus, in particular, they can be used in cardiovascular medicine for the treatment of conditions requiring modulators of transmembrane and intracellular calcium movements, especially hyper tension, angina and cardiac arrhythmia.

They also have antiatherogenic, antiplatelet, cardiac anti-ischemic, anti-ischemic cerebral, anti-migraine, antiepileptic, anti-asthmatic and antiulcerous effects.

In the cardiovascular field they can be used alone or in combination with other known active substances such as diuretics, B-blockers, angiotensin converting enzyme inhibitors, α1-receptor antagonists, antiplatelet agents and acetylsalicylic acid.

Combined with agents intended to potentiate their effects or to reduce their toxicity, they may also be indicated for the treatment of cancer or in transplants.

The compounds of the invention may be presented in any form suitable for oral or parenteral administration, in combination with known excipients, for example in the form of tablets, capsules, dragees, capsules, solutions or suspensions drinkable or injectable.

The daily dosage may range, for example, from 10 to 400 mg orally and from 5 to 100 mg parenterally.

Claims (4)

claims 1. Compounds, in the form of pure optical isomers or mixtures thereof, of general formula (I)

 in which R represents either an acetyl group or a dimethylcarbamoyl group, and Y represents either a group of general formula

 in which Z represents two hydrogen atoms or an oxygen or sulfur atom or a methylene or alkoxyimino group of general formula = NO- (C1-C4) alkyl, the -CZ- group being adjacent to the benzene ring, ie a group of formula -CH = CH- or of general formula -CR1 = CH- or -CH = CR2- in which R1 and R2 each represent a (C1-C4) alkyl group, the heterocycle which contains Y being connected to the remainder of the molecule by any of the 6, 7, 8 or 9 positions, as well as their addition salts with pharmaceutically acceptable acids. 2. Compounds according to claim 1, characterized in that Y represents either a group of formula -CO-CH2-, a group of formula -CH2-CH2-, or a group of formula -CH = CH-. 3. Process for the preparation of the compounds according to one of claims 1 and 2, characterized in that a benzothiazepinone of general formula (II) is reacted

 (wherein R is as defined above) with a halogenated derivative of general formula (III)

 (wherein Y is as defined above and X represents a halogen atom) at the reflux temperature of an aprotic solvent, in the presence of a base, and optionally in the presence of a phase transfer catalyst . 4. Pharmaceutical composition characterized in that it contains a compound according to one of claims 1 and 2.