FR2505333A1 - Antihypertensive hexa:hydro-pyrimidine thio:hydroximic acid derivs. - are 2-2-oxo or thio-4-oxo-6-carboxy hexa:hydro-1-pyrimidinyl-carbonyl-ethyl 1-thio-hydroximic acid which inhibit angiotensin I conversion - Google Patents

Abstract

1-R5S-C(=NOH)-CHR4-CO-2-R1= -3-R3-4-oxo-5-R-6-R2OOC hexahydropyrimidine of formula (I) and their acid addn. salts, salts with bases and diastereoisomers and optically active forms are new. (R is H or opt. branched 1-6C alkyl; R1 is O or S; R2 is H or 1-6C alkyl; R3 is H or benzyloxycarbonyl; R4 is H or lower alkyl and R5 is H, lower alkyl, aryl or lower aralkyl). (I) selectively inhibit the enzyme which converts angiotensin I to the hypertensive angiotensin II and is used to treat hypertension. (I) is administered orally, parenterally, rectally, sub-liagually or by permucous route. Unit doses comprise 50-500 mg, pref. 100-250 mg, to give daily doses of about 200-800 mg. (I) may be used in association with substances having complementary, synergestic or similar activity e.g. sulphamide or thiazide diuretics, peripheral vasodilators, such as hydralazine, or a hypotensive, such as Minoxidil.

Description

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

 It more particularly relates to carbothiohydroximic acids, the hydrocarbon chain of which is linked to a diazotized heterocycle.

It specifically relates to the hexahydropyrimidinyl carbothiohydroximic acids of general formula I

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

R1 is oxygen or sulfur
R2 is hydrogen or a lower alkyl radical having from 1 to 6 carbon atoms.

 R3 is hydrogen or a benzyloxycarbonyl radical.

R4 is hydrogen or a lower alkyl radical
and R5 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.

The subject of the invention is also the addition salts with a mineral or organic base of the acids of general formula
I in which R2 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 R4 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 R4 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, nitric sulfuric, phosphoric or perchloric acids; acetic acids propionic, benzoic, methane-sulfonic, nicotinic isethionic, naphthalene-sulfonic or glucose l ~ phcEphorique.

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

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

in which R and R1 are defined as above,
using an alkylating agent to obtain an alkyl dihydroorotate of general formula III.

in which R2 is a lower alkyl radical
and R and R1 are defined as above,
which is treated with a halogenated benzyloxy carbonyl in basic medium to form the N-benzyloxycarbonyl derivative corresponding to the general formula Iv.

in which R2 is a lower alkyl radical,
R is hydrogen or a lower alkyl radical, and 3 is a benzyloxycarbonyl radical,
and the latter is condensed with a cyanacetic acid of general formula V.

 in which R4 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 R4 is hydrogen or a lower alkyl radical,
and the substituents R, R2 and R3 keep the previous definitions,
which is oxidized using a peroxide to form the nitrile oxide of general formula VII.

in which the substituents R, R1, R2, R3 and R4 are defined as above,
then reacts it with a mercaptan of general formula R5SH in which R5 is defined as above, to obtain the thiohydroximic acid of general formula I.

in which
R3 is the benzyloxycarbonyl radical
R2 is a lower alkyl radical
and R, R1 and R5 have the meanings provided above.

 The process also comprises 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 to the action of boron trifluoride.

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

which can, if desired, be salified 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 R2 is a lower alkyl radical and R3 is a benzyloxycarbonyl radical with a blocked malonaldéhyique acid of general formula VIII.

wherein R4 is hydrogen or a lower alkyl radical and R6 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, R1, R2 R3, R4 and R6 have the definitions given above,
which is condensed with hydroxylamine in an acid medium to form a carbaldoxime of formula. general X.

in which the substituents R, R1, R2, R3 and R4 are defined as above,
then puts it in contact with chlorine or a chlorinating agent to form an oL-chloro carbaldoxime of general formula

in which the substituents R, R1, R2, R3 and R4 are defined as above,
and reacts the latter with a sodium mercaptan of general formula
R5 SNa
in which R5 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
R4 is hydrogen or a lower alkyl radical
and Hal is a halogen other than fluorine,
to form an N- (haloacetylated) derivative which is reacted with an alkali or alkaline earth metal cyanide 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 agent like Minoxidil.

 The pharmaceutical compositions are preferably those which are suitable for administration by the oral, 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.

 The dosage in adults varies according to the age and weight of the 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-diox-o 6-carboxy hexahydropyrimidinyl-1) 3-oxo
2-methyl propyl l-thiohydroximique.

Stage A: Dihydro methyl orotate
15.8 g of dihydroorotic acid are dissolved in 125 ml of methylene chloride and 50 ml of a 10 × diazomethane solution in chloroform prepared at the time of use are added in small portions. Once the addition is complete, the solution is kept under stirring while cooling in a mixture of water and ice. After 15 min, the excess diazomethane is destroyed by adding a few drops of acetic acid.

Once the evolution of gas has ended, 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 in vacuo. 10.74 g of methyl dihydro orotate are finally obtained.

 Stage B: N-carbobenzvloxv dihvdro 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 carbobenzoxyl 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 X.

Stage C
(N-carbobenzyloxy 2,4-dioxo 6-methoxycarbomyl hexahydropyrimidinyl-1) 3-oxo 2-methylpropionitrile.

 10 g of or methylcyanacetic acid are suspended in 45 ml of dioxane. 5 ml of triethylamine and then 1.1 g of dicyclohexylcarbodiimide are added. The mixture is kept stirring at a temperature of approximately 50 for 2 hours. A solution of 11.5 g of methyl N-carbobenzyloxy dihydro orotate in 55 ml of methylene chloride is added to this suspension. The mixture is left stirring for 2 hours at room temperature, then the excess carbodiimide is destroyed by adding acetic acid. Filtered to separate the insoluble dicyclohexylurea, then washed with water and dried the organic phase.

After evaporation of the solvent, 18.4 g of (N-carbobenzyloxy 2,4-dioxo 6-methoxycarbonyl hexahydropyrimidinyl-1) 3-oxo 2-methylpropionitrile are collected, which is purified by recrystallization from acetonitrile. The pure product melts at 127-1289.

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

 7.2 g of propionitrile obtained in stage C are dissolved in 50 ml of dimethylformamide, then the solution is cooled to 0.

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 propionitrile 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 propyl 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 it is maintained at a temperature close to + 5 to + 100 while a solution of 36 g of N-oxide of (N-carbobenzyloxy 2,4-dioxo 6) is poured in one hour -methoxycarbonyl hexahydropyrimidinyl-1) l-oxo 2-methyl propionitrile in 200 ml of methanol. At the end of the addition, the reaction mixture is kept at 100 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. is purified by redissolution in a solution of sodium carbonate at 10 X, 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-methylpropylg thiohydroximic acid are thus obtained.

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

 A mixture of 9 g of acid (N-carbobenzyaxy 2,4 dioxo 6-methoxycarbonyl hexahydropyrimidinyl-1) 3-oxo 2methylpropyl-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 OO 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 cut under vacuum.

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

Stage G
Acid (2,4-dioxo 6-carboxyhexahydropyrimidinyl-1) 3-oxo 2-methylpropyl l-thiohydroximique.

 The acid (2,4-dioxo 6-methoxycarbonyl hexahydropyrimidinyl-1) 3-oxo 2-methyl propyl thiohydroximique is dissolved in 50 ml of hot methanol. 25 ml of methanolic potassium hydroxide are then added and the mixture is left in contact for one hour at ordinary 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-carboxyhexahydropyrimidinyl-l) 3-oxo 2-methyl propyl l-thiohydroximique melts at 1700-1720 (with decomposition).

EXAMPLE II
Acid (2-thio 4-oxo 6-carboxy hexahydropyrimidinyl-1) 3-oxopropyl l-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-methoxyear-
bonyl hexahydropyrimidinyl-1) 3-oxo propionitrile
- acid (N-carbobenzyloxy 2-thio 4-oxo 6-methoxycarbonyl
hexahydropyrimidinyl-l) 3-oxo propyl-l thiohydroximique
- 2-thio 4-oxo 6-methoxycarbonyl hexahydropyrimidi acid
ny-l) 3-oxo propyl l-thio hydroximique
- acid (2-thio 4-oxo 6-carboxyhexahydropyrimidinyl-1)
3-oxopropyl 1-thiohydroximique which melts at 148 - 1500.

EXAMPLE III
Acid (2,4-dioxo 5-methyl 6-carboxyhexahydropyrimidinyl-1) 3-oxo 2-methyl propyl l-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-methyldihydro orotate methyl
- (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
- acid (N-carbobenzyloxy 2,4-dioxo 5-methyl 6-methoxy
carbonyl hexahydropyrimidinyl-1) 3-oxo 2-methyl propyl
l-thiohydroximique
- acid (2,4-dioxo 5-methyl 6-methoxycarbonyl hexahydro
pyrimidinyl-1) 3-oxo 2-methyl propyl l-thiohydroximique
- 2,4-dioxo 5-methyl 6-carboxy hexahydropyrimidi acid
nyl-1) 3-oxo 2-methyl propyl 1-thiohydroximique which melts
at 167 - 168.

EXAMPLE IV
(N-carbobenzyloxy 2,4-dioxo 6-methoxycarbonyl hexahydropyrimidinyl-1) 3-oxo 2-methyl propyl l-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 from
N-carbobenzyloxy dihydro methyl orotate and 2-methyl 3,3-diethoxypropionic acid, the (N-carbobenzyloxy 2,4dioxo 6-methoxycarbonyl hexahydropyrimidinyl-1) 3-oxo 2-methyl 1,1-diethoxypropane is obtained.

Stage B
(N-carbobenzyloxy 2 4-dioxo 6-methoxycarbonyl hexahydropyrimidinyl-1) 3-oxo 2-methyl 1-oximidopropane.

 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 adding ice to maintain the temperature at + 100 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 iminoyl chloride.

Stage C
(N-Carbobenzyloxy 2,4-dioxo 6-methoxycarbonyl hexahydropyrimidinyl-1) 3-oxo 2-methylpropio iminoyl chloride.

 3.8 g of oxime obtained in Stage B are dissolved in 250 ml of dimethylformamide previously warmed to 25-300. 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 250. 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 S.

Stage D
(Methyl N-carbobenzyloxy 2,4-dioxo 6-methoxycarbonyl hexahydropyrimidinyl-1) 3-oxo 2-methylpropyl l-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, is added at a temperature below 200, 8.2 dildo chloride of (Ncarbobenzyloxy 2,4-dioxo 6-methoxycarbonyl hexahydropyrimidinyl -1) 3-oxo 2-methylpropio-iminoyl. 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 215-2160.

 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 anesthetized rats at doses ranging according to the compounds between 0.5 mg and 1.5 mg (inhibition at 75%).

 Likewise, the compounds according to the invention inhibit the proteolytic activity of the angiotensin I to angiotensin II converting enzyme by using the hippuryl Lhistidyl-L-Leucine as 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-carboxyhexahydropyrimidinyl-1) 3-oxo 2-methylpropyl 1-thiohydroximique .............: 100 g
Corn starch .............. but 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 with an average weight of 0.300 g.

Claims (11)

 1) The 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,  R1 is oxygen or sulfur,  R2 is hydrogen or a lower alkyl radical having from 1 to 6 carbon atoms,  R3 is hydrogen or a benzyloxy-carbonyl radical,  R4 is hydrogen or a lower alkyl radical  and R5 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 10 with a mineral or organic acid.  3) The addition salts of the compounds of general formula I according to claim 1 with an inorganic or organic base when R2 is hydrogen.  4) The diastereoisomers of the compounds of general formula I as well as their optically active forms according to one of claims 10 to 30.  5) A process for obtaining the compounds according to one of claims 10 to 40 characterized in that one esterifies a dihydroorotic acid of general formula IIX

 wherein R and R1 are defined as above, using an alkylating agent to obtain an alkyl dihydro-orotate of general formula III.  in which R2 is a lower alkyl radical and R and R1 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, R1 and R2 are defined as above,  and R3 is a benzyloxycarbonyl radical, condenses the latter with a cyanacetic acid of general formula V.

 in which R4 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 R4 is hydrogen or an alkyl radical  inferior,  and the substituents R, R1, R2 and R3 keep the previous meanings,  which is oxidized using a peroxide to form the nitrile oxide of general formula VII

 in which the substituents R, R1, R2, R3 and R4 are defined as above,  then reacts it with a mercaptan of general formula R5SH (in which R5 is defined as above) to obtain the thiohydroximic acid of general formula I.

 in which R3 is the benzyloxy carbonyl radical  R2 is a lower alkyl radical  and R, R1 and R5 have the meanings provided above, which can, if desired, be salified by adding a mineral or organic acid.  6) A method according to claim 50 which comprises the additional step of debenzyloxy carbonylation of the compounds of general formula I which consists in subjecting an N-benzyloxycarbonylated compound to the action of boron trifluoride or of a hydrogenation agent in the presence a catalyst from the platinum family to obtain a compound of general formula I in which R3 is hydrogen.  70) A process according to claim 50 or claim 60 which comprises 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,  R1, R4 and R5 are defined as above,  that one can, if desired, salify by addition of a mineral or organic base or split by addition of a chiral base or using a physical agent.  80) A process for obtaining the compounds according to claim 10 which consists in condensing a compound of general formula IV.

 in which R2 is a lower alkyl radical,  R3 is a benzyloxycarbonyl radical,  and R and R1 are defined as above,  with blocked malonaldehyde acid of general formula VIII

 wherein R4 is hydrogen or a lower alkyl radical, and R6 is a lower alkyl radical, in the presence of a carbonyl activating agent to form an N-acylated derivative of general formula IX.

 in which the substituents R, R1, R2, R3, R4 and R6 have the definitions given above,  which is condensed with hydroxylamine in an acid medium to form a carbaldoxime of general formula X.

 in which the substituents R, R1, R2, R3 and R4 are defined as above,  puts it in contact with chlorine or an agent  of chlorination to form an oL-chlorocarbaldoxime of general formula XI.

 in which the definition of the substituents R, R1, R2,  R3 and R4 remains unchanged,  and reacts the latter with a sodium mercaptan of general formula R5SNa,  wherein R5 is hydrogen, a lower alkyl radical, 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 10 to 40 in association or in mixture with an excipient or an inert, non-toxic pharmaceutically acceptable vehicle.  10) The pharmaceutical compositions according to claim 90 characterized in that they additionally contain another active principle of similar, synergistic or complementary action.  11) A pharmaceutical composition according to one of claims 90 or 100, in which the content of active principle according to one of claims 10 to 40 ranges from 0.050 g to 0.500 g.