WO1984001384A1

WO1984001384A1 - New carbothiohydroximic derivatives, preparation processes thereof and compositions containing them

Info

Publication number: WO1984001384A1
Application number: PCT/FR1982/000158
Authority: WO
Inventors: Jerome Corbiere
Original assignee: Jerome Corbiere
Priority date: 1982-09-28
Filing date: 1982-09-28
Publication date: 1984-04-12
Also published as: EP0119994A1

Abstract

New hexahydropyrimidinyl thiohydroximic acids as well as their addition salts with an organic or mineral acid or base. The invention is particularly related to hexahydropyrimidinyl carbothiohydroxymic acids having the general formula (I) wherein R1 is oxygen or sulphur, R, R2, R3 and R4 are hydrogen or a substituent, and R5 is hydrogen, an aralkyl or aryl alkyl radical. These compounds are used as active principles for drugs, particularly in the treatment of hypertension.

Description

New Carbothio hydroximic derivatives, their preparation processes and the compositions containing them.

The subject of the invention is new carbothiohyroximic acids and their methods of preparation.

It relates more particularly to carbo thiohydroximic acids whose hydrocarbon chain is linked to a diazotized heterocycle.

Its specific subject is hexahydropyri midinyl carbothiohydroximic acids of general formula I

in which R is hydrogen or a lower alkyl radical having from 1 to 6 carbon atoms in a straight or branched chain. R ₁ is oxygen or sulfur

R ₂ is hydrogen or an alkyl radical lower than 1 to 6 carbon atoms. R ₃ is hydrogen or a benzyloxycarbonyl radical.

R ₄ is hydrogen or a lower alkyl radical and R ₅ is a hydrogen atom, a lower alkyl radical, an aryl radical, or a lower aralkyl radical.

A subject of the invention is also the addition salts with a mineral or organic acid of the compounds of general formula I, preferably with a therapeutically compatible acid.

A subject of the invention is also the addition salts with a mineral or organic base of the acids of general formula I in which R ₂ is hydrogen. The invention also includes the diastereoisomers and the optical isomers thereof as well as the optically active forms of the compounds for which R ₄ is a lower alkyl radical. The hexahydropyrimidine molecule has at least one asymmetric carbon atom, two when R is a lower alkyl and one more asymmetric atom when R ₄ is a lower alkyl radical. These compounds can therefore exist in the form of threo or erythro diastereoisomers which can be split into their optically active levogyre and dextrogyre forms. The starting dihydroorotic acids can be racemic or previously split.

Among the acids used to form salts, there may be mentioned hydrochloric, hydrobromic, sulfuric, nitric, phosphoric or perchloric acids; acetic acid propionic, benzoic, methane-sulfonic, isethionic, nicotinic, naphthalene-sulfonic or glucose 1-phosphoric.

Among the bases capable of forming salts, there may be mentioned the hydroxides of alkali or alkaline-earth metals, diethylamine, amino-ethanol, dicyclohexylamine, N-methylmorpholiia or β-hydroxyethylpiperazine.

The invention also includes a process for the preparation of the compounds of general formula I, characterized in that a dihydroorotic acid of general formula II is esterified.

wherein R and R ₁ are defined as above, using an alkylating agent to obtain an alkyl dihydroorotate of general formula III.

in which R ₂ is a lower alkyl radical and R and R ₁ are defined as above, which is treated with a benzyloxy carbonyl halide in basic medium to form the N-benzyloxycarbonyl derivative corresponding to general formula IV.

in which R ₂ is a lower alkyl radical. R is hydrogen or a lower alkyl radical, and R ₃ is a benzyloxycarbonyl radical, and the latter is condensed with a cyanacetic acid of general formula V.

in which R ₄ is hydrogen or a lower alkyl radical. in the presence of a carboxyl activating agent to obtain the N-acylated derivative of general formula VI,

in which R ₄ is hydrogen or a lower alkyl radical, and the substituents R, R ₂ and R ₃ keep the previous definitions, which are oxidized using a peroxide to form nitrile oxide of general formula VII.

in which the substituents R, R ₁ , R ₂ , R ₃ and R ₄ are defined as above, then reacts the latter with a mercapitan of general formula R ₅ SH in which R ₅ is defined as above, to obtain the thiohydroximic acid of general formula I.

in which R ₃ is the benzyloxycarbonule radical R ₂ is a lower alkyl radical and R, R ₁ and R ₅ have the meanings provided above.

The process also includes the additional step of debenzyloxycarbonylation of the compounds of general formula I which consists in subjecting the N-benzyloxycarbonylated compound to the action of a hydrogenating agent in the presence of a catalyst of the platinum family such as for example , platinum, paladium or rhodium. or the action of boron trifluoride.

The process also includes the additional step of saponification of alkyl esters of general formula I by the action of trifluoroacetic acid to form an acid derivative of for general mule

that one can, if desired, salify by adding a mineral or organic base, or split by salification using a chiral base or using a physical agent.

The invention also comprises another method for obtaining the compounds of general formula I, which consists in condensing the compound of general formula IV.

in which R ₂ is a lower alkyl radical and R ₃ is a benzyloxycarbonyl radical with a blocked malonaldehydic acid of general formula VIII.

wherein R ₄ is hydrogen or a lower alkyl radical and R ₆ is a lower alkyl radical in the presence of a carboxyl activating agent, to form an N-acylated derivative of general formula IX.

in which the substituents R, R ₁ , R ₂ , R ₃ , R ₄ and R ₆ have the definitions given above, which are condensed with the hydroxylamine in acid medium to form a carbaldoxime of general formula X.

in which the substituents R, R ₁ , R ₂ , R ₃ and R ₄ are defined as above, then word the latter in contact with chlorine or a chlorinating agent to form an α -chloro carbaldoxime of general formula XI .

in which the substituents R, R ₁ , R ₂ , R ₃ and R ₄ are defined as above, and reacts the latter with a sodium mercaptan of general formula:

R ₅ SNa in which R ₅ is hydrogen, a lower alkyl radical, an aryl radical or a lower aralkyl radical, to obtain the corresponding compound of general formula I.

The compounds of general formula VI can also be obtained by condensation of a compound of general formula IV with a functional derivative of haloacetic acid of general formula XII, in which Z is a reactive group R ₄ is hydrogen or a lower alkyl radical and Hal is a halogen other than fluorine, to form an N- derivative (cetylated haloa) which is reacted with a metal cyanide alkaline or alkaline earth and forms the corresponding nitrile of general formula VI.

The compounds of the invention have interesting pharmacological properties and in particular a selective inhibitory action on the enzyme converting angiotensin I into hypertensive angiotensin II. They are therefore particularly useful for the treatment of hypertension induced by an excess of circulating angiotensin II.

To this end, they will be used in the form of pharmaceutical compositions containing, as active principle, at least one compound of general formula I or one of its salts in combination or in mixture with an inert, non-toxic excipient or a pharmaceutically acceptable vehicle.

They can also be added with another active principle of similar, synergistic or complementary action, such as, for example, a thiazide or sulfonamide diuretic, a peripheral vasodilator like hydrallazine or a hypotensive like Minoxidil.

The pharmaceutical compositions are preferably those which are suitable for administration by the buccal, parenteral, rectal, sublingual or mucous route.

It contains from 0.050 to 0.500 g of active principle per unit dose and preferably from 0.100 to 0.250 g.

Dosage in adults vario according to age and weight from subject. It is generally from 0.200 to 0.800 g per day.

The following examples illustrate the invention. They do not limit it in any way.

EXAMPLE I:

Acid (2,4-dioxo 6-carboxy hexahydropyrimidinyl-1) 3-oxo 2-methyl propyl 1-thiohydroximique. Stage A: Methyl Dihydro Orotate 15.8 g of dihydro orotic acid are dissolved in 125 ml of methylene chloride and 50 ml of a 10% solution of diazomethane in chloroform prepared at the time of addition are added in small portions. 'employment. Once the addition is complete, the solution is kept under stirring while cooling in a mixture of water and ice. After 15 min, the e of diazomethane is destroyed by the addition of a few drops of acetic acid. Once the evolution of gas is complete, the medium is diluted with 5 ml of water and the mixture is vigorously stirred and then the aqueous phase is drawn off. The organic phase is again exhausted with 15 ml of water, then dried over sodium sulfate, filtered and brought to dryness.

14.12 g of methyl dihydro orotate are thus collected in the form of a viscous product. By trituration in ethyl acetate, methyl dihydro orotate crystallizes. After standing overnight in a cooler, the crystals are separated by filtration, rinsed with a little cold ethyl acetate, then dried under vacuum. Finally, 10.74 g of methyl dihydro orotate are obtained.

Stage B: N-carbobenzyloxy dihydro methyl orotate.

8.7 g of methyl dihydro orotate are dissolved in 100 ml of chloroform. The solution is cooled to 0 ° and then 20 ml of triethylamine and then 15 g of carbobenzoxybethyl chloride are added. The mixture is kept under stirring at ordinary temperature for 2 hours. The chloroform solution is washed with water until the washings are neutral, then dried and evaporated to dryness under reduced pressure. The residue is recrystallized from an ether-methanol mixture. N-carbobenzyloxy dihydro methyl orotate is thus obtained with a yield of 87 Stage C:

(N-carbobenzyloxy 2,4-dioxo 6-methoxycarbomyl hexahydropy rimidinyl-1) 3-oxo 2-methylpropionitrile.

10 g of ed-methylcyanacetic acid are suspended in 45 ml of dioxane. 5 ml of triethylamine are added and

1.1 g of dicyclohexylcarbodiimide. The mixture is kept stirring at a temperature of approximately 5 ° for 2 hours. To this suspension is added a solution of 11.5 g of N-carboben zyloxy dihydro methyl orotate in 55 ml of methylene chloride. It is left under stirring for 2 hours at ordinary temperature, then the excess carbodiimide is destroyed by addition of acetic acid. Filtered to separate the insoluble dicyclohexyl urea, then washed with water and dried the organic phase. After evaporation of the solvent, 18.4 g of (N-carbo benzyloxy 2,4-dioxo 6-methoxycarbonyl hexahydropyrimidinyl-1) 3-oxo 2-methylpropionitrile are collected, which are purified by recrystallization from acetonitrile. The pure product melts at 127-128 °.

Stage D: N-oxide of (N-carbobenzyloxy 2,4-dioxo 6-methoxycarbonyl hexahydropyrimidinyl-1) 3-oxo 2-methylpropionitrile.

7.2 g of propionitrile obtained in stage C are dissolved in 50 ml of dimethylformamide, then the solution is cooled to 0º ^. 10 ml of 30% hydrogen peroxide are then gradually added. Stirring is continued for one hour and then the medium is diluted with 25 ml of ice water. The propionitri N-oxide precipitate is rapidly separated by filtration, washed with ice water and dried at ordinary temperature under vacuum. The product is used as is for the next step of the synthesis.

Stage E:

Acid (N-carbobenzyloxy 2,4-dioxo 6-methoxycarbonyl hexahydropyrimidinyl-1) 3-oxo 2-methyl propinyl 1-thiohydroximique.

A sodium sulfide solution is prepared cold from 59.5 g of sodium hydroxide, 51 g of hydrogen sulfide and 600 ml of water, avoiding any heating. It is diluted with 400 ml of methanol, then maintained at a temperature close to from + 5 to + 10 ° while pouring in one hour a solution of 36 g of N-oxide of (N-carbobenzyloxy 2,4-dioxo 6-methoxycarbonyl hexahydropyrimidinyl-1) 1-oxo 2-methyl propionitrile in 200 ml of methanol. At the end of the addition, the reaction mixture is kept at 10 ° for 30 minutes, then the methanol is evaporated under reduced pressure. The aqueous phase is exhausted with ether, then acidified to pH 4.5 by addition of a 10N hydrochloric acid solution. The thiohydroximic acid which precipitates is drained, washed with water, then dried. The product is purified by redissolving in a 10% sodium carbonate solution, then reprecipitation at pH 4.5 by addition of acid. 17.3 g of N-carbobenzyloxy 2,4-dioxo 6-methoxycarbonyl hexahydropyrimidinyl-1) 3-oxo 2-methylproρyl_1 thiohydroximic acid are thus obtained.

Stage F: Acid (2,4-dioxo 6-methoxycarbonylhexahydropyrimidinyl-1) 3-oxo 2-methyl propyl i-thiohydroximique.

A mixture of 9 g of acid (N-carbobenzyloxy 2,4 dioxo 6-methoxycarbony] hexahydropyrimidinyl-1) 3-oxo 2-methylpropyl-1 thiohydroximique in 40 ml of benzene and 0.4 ml of boron trifluoride is prepared. The suspension is stirred at ordinary temperature for one hour, then 5 ml of methanol are added, and the mixture is stirred at 0 ° for 30 min. The methanol and the volatile fractions are removed by distillation under high vacuum at ordinary temperature. The dry residue is taken up in 25 ml of hot methanol and kept under boiling at reflux for 10 min. By cooling (2,4-dioxo 6-methoxycarbonyl hexahydropyrimidinyl-1) 3-oxo 2-methyl propyl-1 thiohydroximique precipitates. It is separated by filtration, rinsed with a little methanol and dried under vacuum.

The acid (2,4-dioxo 6- ”methoxycarbonyl hexahydropyrimidinyl-1) 3-oxo 2-methyl propyl-1 thiohydroximic is used as it is for the next stage of the synthesis.

Stage G:

Acid (2, 4-dioxo 6-carboxyhexahydropyrimidinyl-1) 3-oxo 2-met hylpropyl 1 --thiohydroximique. The acid (2,4-dioxo 6-methoxycarbonyl hexahydro pyrimidinyl-1) 3-oxo 2-methyl propyl thiohydroximique is dissolved in 50 ml of hot methanol. 25 ml of methanoli potassium are then added and left in contact for one hour at standard temperature. The medium is then acidified by adding acetic acid. The thiohydroximic acid precipitates, it is separated, washed with water and then dried under vacuum. It is recrystallized from ethanol by hot and cold. The acid (2,4-dioxo 6-carboxyhexa hydropyrimidinyl-1) 3-oxo 2-methyl propyl 1-thiohydroximique melts at 170 ° -172 ° (with decomposition).

EXAMPLE II:

Acid (2-thio 4-oxo 6-carboxy hexahydropyrimidinyl-1) 3-σxopropyl 1-thiohydroximique. By operating according to the same procedure as in Example I, starting from dihydrothio-orotic acid, one successively obtains:

- methyl dihydrothio orotate

- methyl N-carbobenzyloxy dihydro thio orotate - (N-carbobenzyloxy 2-thio 4-oxo 6-methoxycarbonyl hexa hydropyrimidinyl-1) 3-oxo propionitrile

- N-oxide of (N-carbobenzyloxy 2-thio 4-oxo 6-methoxycar bonyl hexahydropyrimidinyl-1) 3-oxo propionitrile

- (N-carbobenzyloxy 2-thio 4-oxo 6-methoxycarbonyl hexahydropyrimidinyl-1) 3-oxo propyl-1 thiohydroximique

- 2-thio 4-oxo 6-methoxycarbonyl hexahydropyrimidi nyl-1) 3-oxo propyl 1-thio hydroximique

- acid (2-thio 4-oxo 6-carboxyhexahydropyrimidinyl-1) 3-oxopropyl 1- thiohydroximiqxie which melts at 148 - 150º.

EXAMPLE III:

Acid (2,4-dioxo 5-methyl 6-carboxyhexahydropyrimidinyl-1) 3-oxo 2-methyl propyl 1-thiohydroximique.

By operating according to the procedure of Example I starting from 5-methyl dihydroorotic acid, one obtains successively:

- methyl 5-methyldihydro orotate

- N-carbobenzyloxy 5-methyl methyldihydro orotate - (N-carbobenzyloxy 2,4-dioxo 5-methyl 6-methoxycarbo nyl hexahydropyrimidinyl-1) 3-oxo 2-methyl propionitrile

- N-oxide of (N-carbobenzyloxy 2,4-dioxo 5-methyl 6-metho xycarbonyl hexahydropyrimidinyl-1) 3-oxo 2-methyl propio nitrile

- (N-carbobenzyloxy 2,4-dioxo 5-methyl 6-methoxy carbonyl hexahydropyrimidinyl-1) 3-oxo 2-methyl propyl 1-thiohydroximique

- acid (2,4-dioxo 5-methyl 6-methoxycarbonyl hexahydropyrimidinyl-1) 3-oxo 2-methyl propyl thiohydroximique

- 2, 4-dioxo 5-methyl 6-carboxy hexahydropyrimidi nyl-1) 3-oxo 2-methyl propyl 1-thiohydroximique which melts at 167 - 168º.

EXAMPLE IV:

(Methyl N-carbobenzyloxy 2,4-dioxo 6-methoxycarbonyl hexahydropyrimιdinyl-1) 3-oxo 2-methyl propyl 1-thiohydroximate.

Stage A: (N-carbobenzyloxy 2,4-dioxo 6-methoxycarbonyl hexahydropyrimidinyl-1) 3-oxo 2-methyl 1,1 diethoxypropane.

By operating as in Stage C of Example I starting from N-carbobenzyloxy dihydro methyl orotate and 2-methyl 3, 3-diethoxypropionic acid, the (N-carbobenzyloxy 2,4-dioxo 6-methoxycarbonyl hexahydropyrimidinyl is obtained -1) 3-oxo 2-methyl 1,1-diethoxypropane.

Stage B:

(N-carbobenzyloxy 2,4-dioxo 6-methoxycarbonyl hexahydropyrimidinyl-1) 3-oxo 2-methyl 1-oximidoρropane.

6 g of N-carbobenzyloxy 2,4-dioxo 6-methoxycarbonyl hexahydropyrimidinyl-1) 3-oxo 2-methyl 1,1-diethoxypropane are dissolved in 125 ml of ethanol. 0.84 g of carbaldoxime is added, then a solution of 0.2 g of hydroxylamine hydrochloride in 20 ml of ethanol. The medium is acidified with a few drops of concentrated hydrochloric acid and the mixture is heated to reflux for 4 hours. Then allowed to cool and added 1.25 ml of 50% sodium hydroxide. The mixture is cooled by addition of ice to maintain the temperature at + 10 ° with stirring. The mixture is then exhausted with 50 ml of ether to remove neutral impurities, then acidified to pH 6 and then extracted twice with dichloromethane. The chloro-methane extracts are combined, washed with water, dried, filtered, then evaporated to dryness. The oxime thus obtained is pure enough to be able to be directly converted into imidoyl chloride.

Stage C: (N-carbobenzyloxy 2,4-dioxo 6-methoxycarbonyl hexahydropyrimidinyl-1) 3-oxo 2-methylpropio imiooyl chloride.

3.8 g of oxime obtained in Stage B are dissolved in 250 ml of dimethylformamide previously warmed to 25-30 °. 2 g of N-chlorosuccinimide are carefully added and left in contact for 10 minutes. The reaction then starts and the temperature of the solvent is brought to 25 °. 8 g of N-chlorosuccinimide are then added in small portions and the temperature of the reaction medium is maintained at this temperature by cooling in an ice bath whenever necessary.

Once the reaction is complete, the mixture is poured into four volumes of ice water. The suspension is exhausted twice with ether. The ethereal extracts are washed with water, dried over calcium sulphate, filtered, then evaporated to dryness under vacuum. Propioiminoyl chloride is thus obtained with a yield of 65%.

Stage D:

(Methyl N-carbobenzyloxy 2,4-dioxo 6-methoxycarbonyl hexahydropyrimidinyl-1) 3-oxo 2-methylpropyl 1-thiohydroximate. A methanolic solution of sodium methyl mercaptide is prepared by reacting 5.8 g of sodium and 12 g of sodium acid sulfide in 100 ml of methanol. To this solution, 8.2 g of (N-carbobonzyloxy 2,4-dioxo 6-methoxycarbonyl hexahydropyrimidinyl-1) 3-oxo 2-methylpropio-iminoyl chloride is added at a temperature below 20º. When the addition is complete, the reaction mixture is heated at reflux for one and a half hours. After cooling, the precipitate of sodium chloride which has formed is filtered and the solvent is evaporated from the filtrate. The dry residue is taken up in water and the pH of the solution is brought to 6 by the addition of 20% hydrochloric acid. The precipitating ester is filtered, washed with water and dried. 5 g of crude product are thus obtained which, after recrystallization from methanol by hot and cold, provides 4.1 g of pure product melting at 215-216 °.

The carbobenzyloxy group is then eliminated by hydrogenolysis and then saponifies the ester function of the carbobenzyloxy group in an alkaline medium. This gives methyl (2,4-dioxo 6-carboxy hexahydropyrimidinyl-1) 3-oxo 2-methylpropyl 1-thiohydroximate.

EXAMPLE V:

Pharmacological study of the compounds according to the invention. The compounds according to the invention inhibit the vasopressor effects induced by an intravenous injection of 1000 μg / kg of angiotensin I to rats anesthetized at doses ranging according to the compounds between 0.5 mg and 1.5 mg ( 75% inhibition). Likewise, the compounds according to the invention inhibit the proteolytic activity of the angiotensin I to angiotensin II converting enzyme by using hippuryl L-histidyl-L-Leucine as a substrate. The average inhibitory dose varies from 1 to 2.5 mg depending on the compound. The acute toxicity of the compounds according to the invention was determined on batches of Rockland strain mice, weighing approximately 20 g to which the product is administered orally in suspension in gummed water. After eight days of observation, the deaths are counted and the average lethal dose is calculated by a graphical method.

The average lethal dose ranges according to the compounds between 850 mg and 1400 mg / kg.

EXAMPLE VI Preparation of 100 mg tablets (2,4 dioxo 6-carboxyhexahydropyrimidinyl-1) 3-oxo 2-methylpropyl 1-thiohydroximique.

Acid (2,4-dioxo 6-carboxyhexαhydropyrimidinyl-1) 3-oxo

2-methylpropyl 1-thiohydroximique: 100 g

Claims

R E V E N D I C A T I O N S

1) Hexahydropyrimidinyl carbothiohydroximic acids of general formula I

in which R is hydrogen or a lower alkyl radical having from 1 to 6 carbon atoms in a straight or branched chain,

R ₁ is oxygen or sulfur,

R ₂ is hydrogen or a lower alkyl radical having 1 to 6 carbon atoms, R ₃ is hydrogen or a benzyloxy bonyl radical, R ₄ is hydrogen or a lower alkyl radical and R ₅ is a hydrogen atom, a lower alkyl radical, an aryl radical or a lower aralkyl radical.

2) The addition salts of the compounds of general formula I according to claim 1 with a mineral or organic acid.

3) The addition salts of the compounds of general formula I according to claim 1º with a mineral or organic base when R ₂ is hydrogen.

4) The diastereoisomers of the compounds of general formula I as well as their optically active forms according to one of claims 1º to 3º.

5) A process for obtaining the compounds according to one of claims 1º to 4º, characterized in that a dihydroorotic acid of general formula II is esterified, Corn starch 150 g

Gelatin 7.5 g

Microcrystalline cellulose sold under the brand AVICEL 25 g

Magnesium stearate 2.5 g

Talc 15 g

Ethylcellulose 5 g

per 1000 finished tablets at an average weight of 0.300 g.

wherein R and R ₁ are defined as above using an alkylating agent to obtain an alkyl dihydro-orotate of general formula III. in which R ₂ is a lower alkyl radical and R and R ₁ are defined as above. which is treated with a benzyloxy carbonyl halide in basic medium to form the N-benzyloxycarbonyl derivative of general formula IV.

in which R, R ₁ , and R ₂ are defined as above, and R ₃ , is a benzyloxycarbonyl radical, condenses the latter with a cyanacetic acid of general formula V.

in which R ₄ is hydrogen or a lower alkyl radical, in the presence of a carboxyl activating agent, to obtain the N-acylated derivative of general formula VI.

in which R ₄ is hydrogen or an alkyl radical lower, and the substituents R, R ₁ , R ₂ and R ₃ retain the previous meanings, which are oxidized using a peroxide to form the nitrile oxide of general formula VII

in which the substituents R, R ₁ , R ₂ , _R3 and R ₄ are defined as above, then reacted with a mercaptan of general formula R ₅ SH (in which R ₅ is defined as above) to obtain the thiohydroximic acid of general formula I.

in which R ₃ is the benzyloxy carbonyl radical R ₂ is a lower alkyl radical and R, R ₁ and R ₅ have the meanings provided above, which can be, if desired, salified by adding a mineral acid or organic.

6) A process according to claim 5 which comprises the additional step of debenzyloxy carbonylation of the compounds of general formula 1 which consists in subjecting an N-benzyloxycarbonylated compound to the action of a hydrogenation agent in the presence of a catalyst from the platinum family to obtain a compound of general formula I in which R ₃ is hydrogen.

7 °) A process according to claim 5 ° or the dream tion 6º which includes the additional step of saponification of the esters of general formula I to form an acid of general formula I

in which R is a lower alkyl radical or hydrogen, R ₁ , R ₄ and R ₅ are defined as above, which can, if desired, be salified by addition of a mineral or organic base or split by addition from a chiral base or using a physical agent.

8º) A process for obtaining compounds according to claim 1 which consists in condensing a compound of general formula IV.

in which R ₂ is a lower alkyl radical, R ₃ is a benzyloxycarbonyl radical, and R and R ₁ are defined as above, with a blocked malonaldéhyd iquc acid of general formula

VIII:

in which R ₄ is hydrogen or a lower alkyl radical, and R ₆ is an internal alkyl radical, in the presence of a carbonyl activating agent to form an N-acylated derivative of general formula IX.

wherein the substituents R, R ₁ , R ₂ , R ₃ and R ₄ are defined as above, puts the latter in contact with chlorine or with a chlorinating agent to form an α-chlorocarbaldoxime of general formula XI.

in which the definition of the substituents R, R ₁ , R ₂ , R ₃ and R ₄ remains unchanged, and reacts the latter with a sodium mercaptan of general formula R ₅ SNa, in which R ₅ is hydrogen, a radical lower alkyl, an aryl radical or a lower aralkyl radical. to obtain the corresponding compound of general formula I.

9) Pharmaceutical compositions containing as active principle at least one compound according to one of claims 1º to 4º in combination or in mixture with an excipient or an inert, non-toxic pharmaceutically acceptable vehicle.

10) The pharmaceutical compositions according to claim 9, characterized in that they also contain another active principle of similar, synergistic or complementary action.

11) A pharmaceutical composition according to one of claims 9º or 10º, in which the content of active principle according to one of claims 1 ° to 4º ranges from 0.050 g to 0, 500 g.