CH633782A5 - Derivatives of thiazolidine- and thiazanecarboxylic acids - Google Patents

Description

This invention describes new derivatives of thiazolidine-, thiazanecarboxylic acids or the like, which have the general formula:

(I)

Ri

(CH0)

2 P

and their respective salts, where R is a hydroxyl or a lower alkoxyl group, Rj and R2 are either a hydrogen atom or a lower alkyl group, Rs and R6 are either a hydrogen atom or a lower alkyl group, with the restriction that R5 and R6

cannot be simultaneously hydrogen atoms, R3 is a hydrogen atom, a short chain alkyl group or a thio-lower alkyl, R4 is either a hydrogen atom, or a lower alkanoyl or benzoyl group, or then the group:

X is either O, S, SO, SO2; when X is O, m is 2 and n is 1; m is 1.2 or 3; n is 0.1 or 2; and m + n is 2 or 3; p is 0 or 1.

The asterisks indicate asymmetric carbon atoms. The invention generally includes derivatives of carboxylic acids of the thiazolidine-, thiazane- type and the like similar to formula I above.

The compounds of this invention are characterized by the presence of a carboxylic acid which has an unsubstituted or substituted heterocycle of five or six members comprising a nitrogen atom and a sulfur or oxygen atom, the remaining members are atoms of carbon; the carboxylic acid is preferably of the thiazane-, thiazolidine- or morpholine type.

The cycle contains, as indicated, a heteroatom in addition to the nitrogen atom which is either oxygen or sulfur; the sulfur may be in oxidized form in the sulfinone groups where R is a hydroxyl and the other symbols have the same meaning as above, is combined, to carry out acetylation, with an acid of formula

F-

R4 - S - (CH2) p - CH - COOH

(III)

? ° °

He ,, \ /

_ S - or sulfone - S -

The side chain linked to the nitrogen atom of the heterocycle is a substituted or unsubstituted thioalkyl group. The compound can also be a dimer obtained by the fact that R4 is identical to its sulfur-containing substituent.

The short chain alkyl groups of the various substituents include the radicals of straight or rarefied hydrocarbons, from methyl to heptyl, for example methyl, ethyl propyl, isopropyl, isobutyl, butyl, t-butyl, pentyl, isopentyl and d 'others alike. The alkyl part of the thioalkyls is similar and contains between 1 and 7 carbon atoms. Likewise the group of alkoxyls is similar with an oxygen bond, for example the methoxyl, ethoxyl, t-butoxyl, propoxyl, iso-propoxyl, butoxyl, isobutoxyl, t-butoxyl and the like. We preferably take the members Q to C4 in each group and especially Cj and C2.

The alkanoyl groups are the radicals of lower fatty acids (comprising up to 7 carbon atoms), that is to say the acetyl, propionyl, butyryl groups and others, acetyl being preferably taken.

The symbols used in this text correspond to the description above.

The products of formula I can be obtained by different synthetic methods.

According to the preferred method, the acid of formula

40

according to one of the known methods, in which acid III is activated before reacting with acid II, this involving the formation of a mixed anhydride, a symmetrical anhydride, an acid chloride, a active ester, reagent K from Wood ward, N.N'-carbonylbisimidazole, 45 from EEDQ (N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline) or other similar compounds. When R is a lower alkoxyl group, this or other known methods of coupling such a part can be used. For a review of these methods, see "Methoden der Organischen Chemie" (Houben-50 Weyl), vol. XV, parts 1 and 2.1974.

It is obvious that the acid of formula II can be acetylated in stages. For example, a fragment of acetylating agent III can first be coupled to the acid of formula II by reacting this acid with a haloacyl halide of formula

55

f3

hai - (CH2) p -CH-CO-hal where hai represents a halogen, preferably chlorine or bromine, for example 3-bromopropionyl chloride. This gives a product of formula hai - (CH2) p

633782

4

By reacting this intermediate product with a mercaptan R4 - SH, the desired product of formula I is obtained. This stepwise acylation is described in Example 1.

When the product obtained is an ester, that is to say when R is are obtained by

Z-p by an alcoholic solution of iodine.

The products of formula I have at least one asymmetric carbon, but can have up to 4. These carbon atoms are indicated by an asterisk in formula I. Consequently, the products exist in the form of diastereoisomers or mixtures racemic of these. All of these compounds are included in this invention. The synthesis described above can use a racemic mixture or one of the enantiomorphs as starting material. When a racemic mixture is used as starting material for the above synthesis, the isomers obtained can be separated by traditional methods of chromatography or fractional crystallization. In general, the L— isomer relative to the carbon of the amino acid constitutes the preferred isomeric form.

The compounds of this invention form basic salts with numerous organic and mineral bases; these salts are also included in this invention. Such salts include ammonium salts, alkali metal salts such as sodium and potassium salts (which are preferably taken), alkaline earth metal salts such as calcium and magnesium salts, salts of organic bases, for example the salts of dicyclohexylamine, benzathine, N-methyl-D-glucamine, hydrabamine, and the salts of amino acids such as arginine, lysine and others. The non-toxic salts which are physiologically accepted are preferably chosen, although other salts are also useful in the isolation or purification of the product, as in the case of the dicyclohexylamine salt for example.

The salts are obtained in the usual way by reacting the product in acid-free form with one or more equivalents of the appropriate base which provides the desired cation, this in a solvent or a medium in which the salt is insoluble, then by filtering, or in water which is removed by lyophilization. By neutralizing the salt with an insoluble acid, such as a cationic ion exchange resin in acid form (ie a polystyrene-based sulfonic resin (Dowex 50; Mikes, "Laboratory Handbook of Chromatographie Methods", Van Nostrand, 19bl, p. 256) or with an acid in an aqueous medium and by extracting, in an organic solvent for example, ethyl acetate, dichloromethane or the like, the free form of the acid is obtained and, if desired, another salt can then be produced.

Additional experimental details can be found in the examples of preferential conditioning which serve as preparation models for the other members of the group.

The compounds of this invention inhibit the conversion of the decapeptide angiotensin I to angiotensin II and, therefore, are effective in reducing or eliminating hypertension related to angiotensin. The action of the enzyme renin on angiotensinogen,

a short-chain alkoxyl group, the ester can be converted to the free acid by alkaline hydrolysis or by treatment with trifluoroacetic acid and anisole. Conversely, the free acid can be esterified by traditional methods.

Disulfides, i.e. when R4 is a pseudo-globulin from blood plasma, produces angiotensin I. Angiotensin I is converted to angiotensin II by a converting enzyme. This final product acts on blood pressure and is responsible for many forms of hypertension found in various species of mammals such as rats, dogs, etc.

The compounds of this invention are involved in the angiotensinogen- * angiotensin I-> angiotensin II sequence by inhibiting the converting enzyme and thereby reducing or eliminating the formation of angiotensin II, responsible for increasing the pressure. blood.

The inhibition of the converting enzyme can be measured by the compounds of formula I by using in vitro converting enzyme taken from rabbit lungs and by applying the method described by Cushman and Cheung ("Biochem. Pharmacol . ”, 20,1637 1971) and, on the other hand, using an excised smooth muscle (E. O'Keefe et al.“ Fédération Proc. ”, 31,1972, 511). In these trials, these products demonstrated a potent action of inhibitors of contractile activity 40 of angiotensin I and enhancers of contractile activity of bradykinin.

Administration of a preparation of one or more compounds of formula I or their physiologically acceptable salts to a hypertensive mammal eliminates or reduces hypertension due to angiotensin. A single dose or, better still, the same dose distributed over 1 d and administered between two and four times, supplied on the basis of 5 to 1000 mg / kg / d, but preferably around 10 to 500 mg / kg / d , is suitable for the reduction of blood pressure. The animal experiments described by S.L. Engel, T.R. Schaeffer, M.H. Waugh and 50 B. Rubin, “Proc. Soc. Exp. Biol. Med. ”, 143 (1973) 483, may serve as a reference.

The substance is preferably administered orally, but parenteral routes such as subcutaneous, intramuscular, intravenous or intraperitoneal routes can also be used.

The compounds of this invention can be used to obtain a reduction in blood pressure, in preparations of tablets, capsules or elixirs for oral administration or in the form of sterile solutions or suspensions for administration parenteral. An amount of about 10 to 500 mg of the compound or of a mixture of compounds of formula I or of a physiologically accepted salt is mixed with a physiologically acceptable support such as excipient, binder, stabilizer, preservative, flavor, etc., to form a traditional dose in accordance with usual pharmaceutical practice.

The amount of active substance in these preparations is such that the dose supplied is within the indicated range.

The following examples describe this invention and the conditions. X R

R3 VR2 "=» m <? - Rl n

/)

-S (CH9) - CH CO N CH CO R

/. p oxidation of a compound of formula / R X R

6 / \ / 5 \

R- vR9-C) (C-R, ^

• 3 £, m> ln

HS (CH „) CH CO N CH CO R

5

633782

preferential payments. All temperatures are in degrees centigrade.

Example 1:

3- (3-acetylthiopropionyl) -2,2-dimethyl-4-L-thiazolidine-carboxylic acid.

5.74 g of 2,2-dimethylthiazolidine-4-carboxylic acid are dissolved hot in 58 ml of anhydrous pyridine. The solution is cooled on an ice bath, stirring; 4.814 g of 3-acetylthiopropionyl chloride are added dropwise. The bath is removed, and the reaction mixture is left at room temperature overnight. The precipitate is filtered and the filtrate is evaporated to dryness under vacuum. The residue is recovered in ethyl acetate and washed with a 10% solution of potassium bisulfate and water. The ethyl acetate extract is dried over magnesium sulfate and evaporated to dryness in vacuo. The residue is triturated with ether, filtered, and the filtrate is evaporated to dryness, then crystallized from acetonitrile. Yield: 2.63 g of 3- (3-acetylthiopropionyl) -2,2-dimethyl-4-L-thiazolidinecarboxylic acid, mp 126-127 °.

Example 2:

3- (3-Mercaptopropionyl) -1-oxopropyl-2,2-dimethyl-4-L-thia-zolidinecarboxylic acid.

5.82 g of 3- (acetylpropionyl) -2,2-dimethyl-4-L-thiazolidine-carboxylic acid are dissolved cold in a solution of 15 ml of water and 15 ml of concentrated ammonium hydroxide under argon protection and left for 30 min at room temperature, the reaction mixture is cooled and acidified with concentrated hydrochloric acid. The crystals are cooled, filtered and washed with water, yield 4.79 g, mp 132-136 ° (cloudy). This is taken up in hot acetonitrile and the cloudiness is filtered. The filtrate gives 3.4 g of 3- (3-mercaptopropionyl) -1-oxopropyl-2,2-dimethyl-4-L-thiazolidinecarboxylic acid, mp 135-136 °.

Example 3:

A cide 3-f 3-acetylthio-2-methylpropionylJ -2,2-dimethyl-4-L-thiazolidinecarboxylic, isomer A.

19.8 g of 2,2-dimethyl-4-thiazolidine-carboxylic acid hydrochloride are dissolved in 200 ml of anhydrous pyridine while stirring on an ice bath. To this is added dropwise 18.0 g of 3-acetylthio-2-methylpropionyl chloride. The reaction mixture is stirred overnight at room temperature. The precipitate is filtered and the filtrate is evaporated to dryness under vacuum. The residue is dissolved in ethyl acetate, washed with a 10% solution of potassium bisulfate, with water, then dried over magnesium sulfate and evaporated to dryness under vacuum to obtain 31 g of 3- (3-acetylthio-2-methylpropionyl) -2,2-dimethyl-4-L-thiazolidine-carboxylic acid, A-isomer, crude. The dicyclohexylamine salt is obtained by adding free acid to dicyclohexylamine in acetonitrile, yield 24 g. The salt is recrystallized from 700 ml of acetonitrile, yield 18.2 g, m.p. 197-198 °. The salt is reconverted in the form of free acid by dissolution in ethyl acetate and 10% potassium bisulfate, then recrystallized from acetonitrile, yield 8.9 g, m.p. 171-172 °.

Example 4:

3- (3-acety lthio-2-methylpropionyl) -2,2-dimethyl l-4-L-thia-zolidinecarboxylic acid, B isomer

The stock solutions of the preparation of the dicyclohexylamine salt obtained in Example 3 are evaporated to dryness under vacuum. The residue is taken up in ethyl acetate and 10% potassium bisulfate, then crystallized from 80 ml of acetonitrile to obtain 7.5 g of 3- (3-acetylthio-2-methylpropionyl) -2 , 2-dimethyl-4-L-thiazolidine-carboxylic acid, isomer B, mp 156-157 °.

Example 5:

3- (3-Mercapto-2-methylpropionyl) -2,2-dimethyl 1-4-L-thia-zolidinecarboxylic acid, A isomer

5 g of 3- (3-acetylthio-2-methylpropionyl) -2,2-dimethyl-4-L-thiazolidinecarboxylic acid, isomer A, are dissolved in a cold solution of 15 ml of water and 15 ml of hydroxide of concentrated ammonium under argon protection. After 30 min, the mixture is cooled and the mixture is acidified with concentrated hydrochloric acid. The crystalline precipitate is filtered and washed with water. The product, 3- (3-mercapto-2-methylpropionyl) -2,2-dimethyl-4-L-thiazolidinecarboxylic acid, isomer A, is recrystallized from 40 ml of acetonitrile (filtered cloudiness), yield 4.2 g, mp 174-175 °.

Example 6:

3- (3-Mercapto-2-methylpropionyl) -2,2-dimethyl-4-L-thiazolidinecarboxylic acid, B isomer

4 g of 3- (3-acetylthio-2-methylpropionyl) -2,2-dimethyl-4-L-thiazolidinecarboxylic acid, isomer B, are dissolved in a cold solution of 6 ml of water and 6 ml of hydroxide of concentrated ammonium under argon protection. After 30 min at room temperature, the mixture is cooled and acidified with concentrated hydrochloric acid. The crystalline precipitate is filtered and washed with water. The product, 3- (3-mercapto-2-methylpropionyl) -2,2-dimethyl-4-L-thiazolidinecarboxylic acid, isomer B, is recrystallized from acetonitrile, yield 3.7 g, PF 197-198 °.

Example 7:

3- (3-acetylthiopropionyl) -5,5-dimethyl-4-DL-thiazolidine-carboxylic acid.

A) 5,5-Dimethyl-4-thiazolidinecarboxylic acid

20 g (134 mmol) of D, L-penicillamine are dissolved in 134 ml of IN hydrochloric acid at room temperature and 40 ml (192 mmol) of a 37% aqueous formaldehyde solution are added. After 30 min, 11 g (134 mmol) of sodium acetate are added and the reaction mixture is stirred at room temperature overnight. After filtration, the solid is washed with ice-cold aqueous solution of 50% ethanol and dried under vacuum, and gives a yield of 14.4 g of 5,5-dimethyl-4-thiazolidinecarboxylic acid, m.p. 209-210 °.

After concentration under vacuum, the mother liquor is triturated with 95% ethanol to recover an additional 1.4 g of product, mp 212-213 °. Total yield: 15.8 g (73%).

B) 3- (3-acetylthiopropionyl) -5,5-dimethyl-4-DL-thiazolidine-carboxylic acid.

6 g of the product from part A (37.2 mmol) are dissolved in a mixture of 3.5 g (41.4 mmol) of sodium bicarbonate in 42 ml of tetrahydrofuran and 41 ml of water. 5.5 g (41.1 mmol) of 3-acetylthiopropionyl chloride in 5.5 ml of ether are added dropwise, then titration is carried out with 2N sodium hydroxide which maintains the pH between 6 and 7. The reaction mixture is stirred for 30 min from the end of the addition, then the reaction is stopped by the addition of 100 ml of hydrochloric acid. The mixture is extracted with 2 x 250 ml of ethyl acetate and the organic extracts are washed with 100 ml portions of water and brine, dried over sodium sulfate and evaporated to dryness under vacuum. The oil obtained solidifies at room temperature to give 11.0 g of crude 3- (3-acetylthio-propionyl) -5,5-dimethyl-4-DL-thiazolidinecarboxylic acid. By recrystallization from petroleum ether, 7.9 g (73%) of the product are obtained, m.p. 99-100.5 °.

Example 8:

3- (3-Mercaptopropionylj -5,5-dimethyl-4-DL-thiazolidine-carboxylic acid.

A suspension of 2.91 g (10 mmol) of 3- (3-acetylthio-propionyl) -5,5-dimethyl-4-thiazolidinecarboxylic acid in 8 ml of water is stirred vigorously at room temperature under protection

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633782

argon. The suspension is treated with 8 ml of an approximately 58% aqueous solution of sodium hydroxide added dropwise over a period of approximately 1 min. The inhomogeneous solution is stirred under argon for 30 min, then cooled and acidified with concentrated hydrochloric acid. The aqueous solution is extracted with 40 and 30 ml portions of ethyl acetate. The combined organic solutions are washed with 5 ml of water, 10 ml of brine, dried (Na2SO4) and concentrated in vacuo to give 2.74 g of crude oil.

When the oil is treated with approximately 50 ml of a mixture (4/6) of ethyl acetate / hexane, rapid crystallization, caused by scraping, occurs and gives 1.88 g of a light white solid , 3- (3-mercaptopropionyl) -5,5-dimethyl-4-DL-thiazolidinecarboxylic acid (75%), mp 100-101.5 °. Test by thin layer chromatography, Rf = 0.46 (silica gel; 60/20/6/11, EtOAc / pyridine / -MeOH / H2O).

Example 9:

DL-3 (3-mercapto-2-methylpropionyl) -2,2,5,5-tetramethyl-4-DL-thiazolidinecarboxylic acid.

By substitution of 2,2,5,5-tetramethyl-4-thiazolidine-carboxylic acid for 2,2-dimethyl-4-thiazolidine-carboxylic acid hydrochloride in the method of Example 5, and by subjecting the product in the process of Example 5, 3- (3-acetyl-thio-2-methylpropionyl) -2,2,5,5-tetramethyl-4-DL-thiazolidine-carboxylic and 3- (3) acids are obtained -mercapto-2-methylpropionyl) -2,2,5,5-tetramethyl-4-DL-thiazolidinecarboxylic.

Example 10:

3- (3-Mercapto-2-methylpropionyl) -2-ethyl-2-methyl-4-L-thiazolidinecarboxylic acid.

By substituting 2-ethyl-2-methyl-4-L-thiazolidine-carboxylic acid for 2,2-dimethyl-4-L-thiazolidinecarboxylic acid hydrochloride in the method of Example 3, then subjecting the produced in the process of Example 5, 3- (3-acetylthio-2-methylpropionyl) -2-ethyl-2-methyl-4-L-thiazolidinecarboxylic and 3- (3-mercapto-2-methylpropionyl) acids are obtained -2-ethyl-2-methyl-4-L-thiazolidinecarboxylic.

Example 11:

3- (3-mccaptopropionyl) -2-ethyl-5,5-dimethyl-4-DL-thiazolidinecarboxylic acid.

By substituting 2-ethyl-5,5-dimethyl-4-DL-thiazolidine-carboxylic acid for 5,5-dimethyl-4-thiazolidinecarboxylic acid in the method of Example 7, and by subjecting the product to process of Example 8, 3- (3-acetylthiopropionyl) -2-ethyl-5,5-dimethyl-4-DL-thiazolidinecarboxylic acid and 3- (3-mercapto-propionyl) -2-ethyl-5 are obtained , 5-dimethyl-4-DL-thiazolidinecarboxylic.

Example 12:

A cide 3- [2- (mercaptomethyl-3-mercaptopropionyl] -5,5-dimethyl-4-DL-thiazolidinecarboxylic.

By substituting 5,5-dimethyl-4-DL-thiazolidine- acid

4-L-thiazolidinecarboxylic acid carboxylic acid in the method of Example 9, and by subjecting the product to the method of Example 10, 3- [2- (acetylthiomethyl) -3-acetylthio-propionyl acids are obtained ] -5,5-dimethyl-4-DL-thiazolidinecarboxylic acid and 3- [2- (mercaptomethyl) -3-mercaptopropionyl] -5,5-dimethyl-4-DL-thiazolidinecarboxylic acid.

Example 13:

4- (3-Mercapto-2-methylpropionyl) -5,5-dimethyl-1,4-L-thia-zane-3-carboxylic acid.

By substituting 5,5-dimethyl-1,4-L-thiazanecarboxylic acid for 2,2-dimethyl-4-L-thiazolidinecarboxylic acid hydrochloride in the method of Example 3, and by subjecting the product to process of Example 5, 4- [3- (acetylthio) -2-methylpropionyl] -5,5-dimethyl-1,4-thiazane-3-carboxylic acid and 4- (3-mercapto-2- methylpropionyl) -5,5-dimethyl-1,4-L-thiazane-3-carboxylic.

Example 14:

Ethyl 3-carboxylate 1-2,2-dimethyl 1,1, 4-DL-thiazane.

A mixture of 1.133 mol of DL-penicillamine ethyl ester hydrochloride and 0.4 mol of triethylamine in chloroform (200 ml) is added to a solution of ethylene dibromide (0.133 mol) in 120 ml of chloroform / benzene mixture (3/5). The mixture is refluxed for 1 h, then stirred at room temperature for 16 h. The precipitate is removed by filtration and the filtrate is concentrated under vacuum, then distilled to give ethyl-2,2-dimethyl-1,4-DL-thiazane 3-carboxylate.

4- (3-Mercapto-2-methylpropionyl) -2,2-dimethyl 1-1,4-DL-thiazanecarboxylic acid.

By substituting ethyl-2,2-dimethyl-1,4-DL-thiazane 3-carboxylate for the 2-methyl ester of thiazolidinecarboxylic acid in the method of Example 4, and by subjecting the product to process of Example 5, ethyl-4- [3-acetylthio) -2-methylpropionyl] -2,2-dimethyl-1,4-DL-thiazane 3-carboxylate and 4- (3- mercapto-2-methylpropionyl) -2,2-dimethyl-1,4-DL-thiazane-3-car-boxylics are obtained.

Example 15:

1-Oxo-4- (3-mercapto-2-methylpropionyl) -5,5-dimethyl-1,4-L-thiazane-3-carboxylic acid.

By substituting l-oxo-5,5-dimethyl-1,4-L-thiazane-3-carboxylic acid for 2,2-dimethyl-4-L-thiazolidinecarboxylic acid in the method of Example 3, then by subjecting the product to the method of Example 5, the l-oxo-4- (3-acetylthio-2-methylpropionyl) -5,5-dimethyl-1,4-L-thiazane-2-carboxylic acid and are obtained 1-oxo-4- (3-mercapto-2-methylpropionyl) -5,5-dimethyl-1,4-L-thiazane-3-carboxylic.

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Claims (20)

633782 2 XR #; x Re \ \ / 5) M ^ -C) (C-R / 2 | m | ln CO N CH CO R 1. Compound of formula: R3 r S (CH2) ^ characterized in that R is a hydroxyl or a lower alkoxyl group; Rt and R2 are either a hydrogen atom or a lower alkyl group, Rs and R6 are either a hydrogen atom or a lower alkyl group, with the restriction that they cannot both be d atoms simultaneously hydrogen, R3 is a hydrogen atom, a lower alkyl group or a lower thioalkyl group, R4 is a hydrogen atom, a lower alkanoyl or benzoyl group or (\ ^ xvD Rn VR? -C> n, ÎC-R / 13 2 | m | 1 n -S (CH,) - CH CO N CH CO R £. p X is O, S, SO, or S02, m being 2 and n being 1 when X is O; Hydrogen atoms, methyl or ethyl groups; m is 1, 2 or 3; n is 0.1 or 2 and m + n is 2 or 3; p is 0 or 1; and their R4 is a hydrogen atom, an acetyl or benzoyl group; X is respective salts. sulfur; m is 1 or 2; n is 1; p is 0 or 1. 2. Compound according to Claim 1, characterized in that R 4 Compound according to Claim 1, characterized in that is a hydroxyl or a lower alkoxyl group, R! and R2 are either is a hydrogen atom. a hydrogen atom, or a lower alkyl group, R, is a 30,. ,,. ,. vs .. .. 5. A compound according to claim 1, characterized in that hydrogen atom, a lower alkyl group or a thio group _. , ....... n t t ,,,,,,. R4 is an acetyl group. lower alkyl, R4 is a hydrogen atom, a lower alkanoyl or benzoyl group, 6- Compound according to claim 1, characterized in that X is either sulfur or oxygen, m is 1 or 2, n is 1, and p is 0 or 1. R * is' benzoyl suPPe. 3. Compound according to Claim 1, characterized in that 7. A compound according to Claim 1, characterized in that R is a hydroxyl, a methoxy or ethoxy group; Rj, R2 and R3 are R4 is the group -S (CHn) 2 P 8. Compound according to claim 1, characterized in that R is a hydroxyl. 9. Compound according to claim 1, characterized in that p is 1. 10. Compound according to claim 1, characterized in that X is an oxygen atom. 11. Compound according to claim 1, characterized in that X is a sulfur atom. 12. Compound according to claim 11, characterized in that R is a hydroxyl, R ,, R2 and R3 are hydrogen atoms, R4 is a benzoyl, m and n are each 1 and p is 1. 13. Compound according to claim 11, characterized in that R is a hydroxyl, R15 R2, R3 and R4 are hydrogen atoms, n and m are each 1 and p is 1. 14. Compound according to claim 11, characterized in that R is a hydroxyl, R], R2 and R4 are hydrogen atoms, R3 is methyl, m and n are each 1 and p is 1. 15. Compound according to claim 11, characterized in that R is a hydroxyl; Rlt R2 and R3 are hydrogen atoms, R4 is an acetyl group, m is 2, n is 1 and p is 1. 16. Compound according to claim 11, characterized in that R is a hydroxyl; Rlt R2, R3 and R4 are hydrogen atoms; m is 2, n is 1 and p is 1. 17. Compound according to claim 11, characterized in that R! and R5 are hydrogen atoms, R2 and R6 are methyl and m, n and p are each 1. 18. Compound according to claim 11, characterized in that 55 R, and Rs are methyls; R2 and R6 are hydrogen atoms and m, n and p are each 1. 19. Compound according to claim 17, characterized in that R is a hydroxyl and R4 is a hydrogen atom. 20. Compound according to claim 18, characterized in that R is a hydroxyl and R4 is a hydrogen atom. 21. Compound according to claim 17, characterized in that R is a hydroxyl and R3 and R4 are hydrogen atoms. 22. Compound according to claim 17, characterized in that 65 R is a hydroxyl, R4 is a hydrogen atom and R3 is a methyl group. 60 633,782