CS219343B2 - Method of preparation of the pleuromutiline glycoside - Google Patents

Description

The novel glycosides of pleuromutilin are useful as agents against Gram-positive and Gram-negative bacteria, anaerobic bacteria and mycoplasmas. They are prepared by reacting an acetylated glycosyl derivative with pleuromutilin or a derivative thereof or a glycosyl derivative of pleuromutilin.

The antibiotic pleuromutilin was isolated in 1951 by Kavanagh et al., Proc. Acad. Soc. 37, 570-574 (1951). The structure of pleuromutilin determined later corresponds to the formula

to obtain a compound known as mutilin. The mutilin has the structure of formula II

OH

Furthermore, a large number of pleuromutilin derivatives have been prepared (Swiss Patent No. 572,894 (Derwent No. 26,553X); Dutch Patent No. 69, 11083 (Derwent No. 40,642); Knauseder et al., U.S. Patent No. 3,716,579; Egger et al., U.S. Patent No. 3,919,290; Brandl et al., U.S. Patent No. 3,949,079; Riedl, U.S. Patent No. 3,979,423; Baughn et al., U.S. Patent No. 3,987,194; Egger et al., U.S. Patent No. 4,032,530; K. Riedl, "Studies on Pleuromutilin and Some of Its Derivatives", J. Antibiotics 29: 132-139 (1976); H. Egger and H. Reinshagen, "New

The alkaline hydrolysis of pleuromutilin is

Pleuromutilin Derivatives with Enhaced Antimicrobial Activity. I. Synthesis ", J. Antibiotics, 29, 915-922 (1976) and" II. Structure-Activity Correlations ", J. Antibiotics 29, 923-927 (1976); F. Knauseder and E. Brandl," Pleuromutilins: Fermentitation, Structure and Biosynthesis ", J. Antibiotics 29: 125-131 (1976); J. Drews et al.," Antimicrobial Activities of 81,723 hfu, and New Pleuromutilin Derivative ", Antimicrob. Agents and Chemotherapy 7: 507-615 (1975).

Recently, Michel and Higgens have found antibiotic A-40104, factor A, a new member of the pleuromutilin family of antibiotics. The structure of antibiotic A-40104 factor A corresponds to formula III

OH

wherein the D-xylopyran group is in the β-configuration.

The compounds prepared according to the present invention are novel glycosides of pleuromutilin, which are active not only against Gram-positive and Gram-negative bacteria and anaerobic bacteria, but also mycoplasmas. Thus, physicians and veterinarians have an additional agent that can be used to treat infectious diseases in humans or pets.

An object of the present invention is a process for the preparation of the glycosides of pleuromutilin of formula IV

wherein R is vinyl; R ¹ is selected from the group consisting of

a] «- and β-anomers of the following hexopyranoses:

D- and L-glucose; 1-thio-D- and L-glucose, 1-thio-D- and L-galactose,

b] α- and β-anomers of the following pentopyranoses and pentofurans: 1-thio-D- and L-ribose, cis β-anomers of the following pentofuranoses: 1-thio-D- and L-xylose, dj α- and β- anomers of the pentopyranose forms of 1-thio-D- and L-xylose, the α- and β-anomers of the following pyranose amino sugars: 2-deoxy-2-amino-D- and L-glucose, N-monoalkyl and Ν, Ν-dialkyl derivatives these C 1 -C 4 amino sugars in each of the alkyls,

(f) .alpha .- and .alpha.-isomers of disaccharides:

(g) 2-deoxy-2- (hydroxyimino) -? - D-galactopyranosyl;

R ² is a hydrogen atom, characterized in that the glycosyl derivative is hydrolyzed, wherein the glycosyl moiety is selected from per-O-acylated or benzylated α- or β-anomers selected from groups a) to gj above in the presence of a base.

Compounds where R ² is a hydrogen atom are prepared by reacting pleuromutilin with the appropriate sugar moiety using conventional glycoside formation methods. For example, glycosites that are β-anomers are generally prepared by the Koenigs-Knorr method (see H. Krauch and W. Kunz, "Organic Name Reactions", John Wiley and Sons, New York, NY, 1964, p. 269). Glycosides, which are α-anomers, are generally prepared by halogen-catalyzed glycosidation. Bromo derivatives are particularly preferred for these reactions.

Yet another glycosidation method useful for preparing some of the compounds of the present invention involves the use of mercury catalysis such as mercuric cyanide.

It is understood that in these methods the per-O-acylglycosyl halide is the appropriate starting saccharide. The preparation of these per-O-acylglycosyl halides is known. For a review of the chemistry of these compounds, see Advan. Carbohyd. Chem. 10, 207-256 (1955). Per-O-acetylglycolsyl halides are the most commonly used starting carbohydrate moieties. Other acylglycosyl halides, such as per-O- (C2 to C8 alkanoyl) glycosyl halides, are also useful. Bromides and chlorides are the most commonly used derivatives of halides since iodides are easier to degrade and fluorides are less reactive.

Another method for preparing compounds of the present invention involves reacting pleuromutilin with a nitrosyl chloride adduct of the per-O-acylglycol derivative of the corresponding sugar to give the corresponding 2- (hydroxyimino) derivative, then converting the derivative to the desired aminoglycoside.

Thioglykosidové derivatives of the present invention wherein R ² is hydrogen are prepared by reacting 14-deoxy-14- (monojodacetoxyjmutilinu, hereinafter called iodopleuromutilin, with the appropriate per-O-acylmercapto sugar derivative. Iodopleuromutilin is prepared as described in U.S. Pat. No. 3,979,423 Per-O-acyl mercaptoderivatives of saccharides can be prepared from the corresponding halogen-substituted per-O-acylated analogs of carbohydrates by conventional methods. Ferrier and RH Furneaux Carbohydrate Research 52, 63-68 (1976).

2-Amino-1-thio-β-D-glycosides are preferably prepared by condensing 14-deoxy-14- (mercaptoacetoxy) mutilin, hereinafter called pleuromutilinthiol, with the corresponding 2-deoxy-2- (hydroxyimino) -per-O-acyl α-D-glycosyl chloride to give the corresponding 2- (hydroxyimino) derivative and then reduction of the oximino derivative to give the desired 2-amino compound.

Dialkylamino-1-thio- [beta] -D-glycopyranosyl derivatives are prepared by converting dialkylamino-per-O-acyl-1-bromo-D-glycopyranosides [for preparation see J. Am. Chem. Soc. 99, 5826 (1977)] to the corresponding dialkylamino-per-O-acyl-1-mercapto- [beta] -D-glycopyranosides and then reaction with iodpleuromutilin.

Compounds of the present invention wherein R is ethyl can be prepared from the corresponding compounds wherein R is vinyl by standard reduction such as hydrogenation using a palladium on carbon catalyst. These compounds can also be prepared by reacting 19,20-dihydropleuromutilin with the appropriate sugar moiety as described above.

Those compounds wherein R ¹ is a per-O-acylated sugar moiety are useful

First as intermediates to those compounds wherein R ¹ is selected from the groups listed in a) to g) and

2. as active compounds.

Those compounds wherein R ¹ is selected from substituents a) to g) are prepared from the corresponding per-O-acylated compounds by cleavage of the acyl groups in the presence of a base such as triethylamine.

In a preferred embodiment, the starting material is reacted with triethylamine in a solution of ethanol and water for several days at room temperature. The product is then evaporated to dryness in vacuo.

The preparation of the compounds of the present invention is illustrated by the following examples.

Example 1

A. Preparation of 14-deoxy-14 - [(2,3,4,6-tetra-O-acetyl- [beta] -D-glucopyranosyl) oxyacetoxy] mutilin

Pleuromutilin (1.6945 g, 4.48 mmol) was dissolved in a 1: 1 mixture of nitromethane and benzene (300 mL). About 100 ml of this solution is filtered to ensure an anhydrous environment. To this solution was added Hg (CN) 2 (1.0694 g, 4.23 mmol). A solution of acetobromoglucose (2.009 g, 4.89 mmol) in nitromethane / benzene (1: 1, 100 mL) was then added dropwise to the reaction mixture maintained at 60 ° C in an oil bath under nitrogen. The reaction mixture was stirred under these conditions for 20 hours. Additional Hg (CN) 2 (762 mg, about 3 mmol) was then added and a solution of 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide (964.2 mg, 2.34 mmol) was added dropwise. in a mixture of nitromethane and benzene (1: 1, 50 mL). After stirring for an additional 2 days, the reaction mixture was cooled in an ice bath and washed sequentially with cold saturated sodium bicarbonate solution (once) and cold saturated sodium chloride solution (twice) and after each wash the aqueous phase was back extracted with dichloromethane. The combined phases were dried over anhydrous magnesium sulfate for one hour and then evaporated to dryness in vacuo to give 4.05 g of crude product.

The crude product was further purified by silica gel column chromatography (Merck) 3 X 95 cm and eluted with a 1: 1 mixture of ethyl acetate and toluene. 8 to 10 ml fractions were collected at 45 minute intervals. The individual fractions were monitored by thin layer silica gel chromatography using a 1: 1 mixture of ethyl acetate and toluene and iodine detection. Appropriate fractions were combined and evaporated in vacuo to give 515.3 mg of purified 14-deoxy-14 - [(2,3,4,6-tetra-O-acetyl-4-D-glucopyranosyl) oxyacetoxy] mutilin in 16 yields, 24 percent. _in

B. Preparation of 14-deoxy-14 - ((β-D-glucopyranosyl} oxyacetoxy) mutilin

The 14-deoxy-14 - [(2,3,4,6-tetra-O-acetyl-4-D-glucopyranosyljoxyacetoxymutiline (1.237 g, about 1.74 mmol) prepared in Part A above was dissolved in anhydrous methanol (100 mL). To this solution was added water (100 mL) and then distilled at room temperature with stirring (CsH 2 O 5 N (30 mL)), and the resulting reaction mixture was stirred at room temperature for three days and then evaporated to dryness in vacuo. contains traces of (C2 H5) 3 N and further drying in vacuo afforded 1.7672 g of crude product.

This crude product was further purified by 2 cm silica gel column chromatography (150 g, Merck). Elution with a mixture of ethyl acetate and ethanol (4: 1) collected 2 mL fractions over a 20 minute period. Fractions were monitored by thin layer silica gel chromatography using the same solvent system and iodine detection. Fractions 98 to 130 are combined and evaporated in vacuo. There was thus obtained 278.6 mg of 14-deoxy-14 - [(O-D-glucopyranosyl-1-oxyacetoxy) mutilin.

Mass Spectrum M ⁺ + 1 = 541, NMR 4 X CH 3 0.71 (d); 0.90 (d); 1.17 (s, 1.43 (S)).

Example 2

A. Preparation of 14-deoxy-14 - [(2-deoxy-2- (hydroxyimino) -3,4,6-tri-O-acetyl-α-D-galactopyranosyl] oxyacetoxy) mutilin

Pleuromutilin (7.6342 g, 20.19 mmol) was treated with D-galactal triacetate addition product with NOCl (7.6723 g, 22.76 mmol) and purified by chromatography on silica gel using ethyl acetate / toluene (1: 1). ) yielded 14-deoxy-14 - [(2-deoxy-2- (hydroxyimino) -3,4,6-tri-O-acetyl-α-D-galactopyrahosyl] oxyacetoxy] mutilin (10.0739 g, 14.8 mol) ) in 73% yield.

B. Preparation of 14-deoxy-14 - [(2-deoxy-2- (hydroxyimino) -α-D-galactopylamino) oxyacetoxy] mutilin

14-deoxy-14 - [(2-deoxy-2- (hydroxyimino) -3,4,6-tri-O-acetyl-α-D-galactopyranosyl) oxyacetoxy] mutilin (1.5 g), prepared according to paragraph A Dissolve in methanol (50 mL) and water (50 mL). To this solution was added (CHHHsJN (50 mL)), and the resulting solution was stirred at room temperature for three days. The reaction mixture was then evaporated in vacuo. Chloroform was added and the residue was taken up in vacuo to give a foam after drying under high vacuum for one hour. 414 mg of crude product.

The crude product was dissolved in a minimum amount of methanol and loaded onto a 1.5 X X 70 cm silica gel column (Merck). Elution with ethyl acetate and ethanol (9: 1) collected 2 to 3 ml fractions at 1 hour intervals. The fractions were monitored by thin layer chromatography on silica gel using the same solvent system. The appropriate fractions were combined and evaporated to dryness in vacuo to give a total of 104.4 g of 14-deoxy-14 - [(2-deoxy-2- (hydroxyimino) -α-D-galactopyranosyl] oxyacetoxy] mutilin. = 554. NMR: 4 X CH3 0.74 (d), 0.85 (d), 1.08 (s), 1.86 (s).

Example 3

A. Preparation of 14-deoxy-14 - [(2,3,4,6-tetra-acetyl-4-D-glucopyranosyl) thioacetoxy] mutilin

A solution of iodpleuromutilin (577.3 mg), prepared according to Example 3 of U.S. Pat. No. 3,979,423, in acetone (2 mL) was added to a solution of 2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl mercaptan (428). , 8 mg) in acetone (2 mL). A solution was added to the stirred reaction mixture

K 2 CO 3 (168.4 mg) in water (1 mL) and the resulting solution was stirred at room temperature for 30 minutes. The reaction mixture was then poured into deionized water (25 ml) and the aqueous extract was extracted with dichloromethane. The dichloromethane solution was dried over sodium sulfate, filtered and evaporated to dryness in vacuo. The residue was dried under high vacuum for 1.5 hours to give 989.7 mg of 14-deoxy-14 - [(2,3,4,6-tetrahydro-3-D-glucopyranosyl) thioacetoxy] mutilin.

B. Preparation of 14-deoxy-14 - [(N-D-glucopyranosyl) thioacetoxy] mutilin

14-Deoxy-14 - [(2,4,4,6-tetra-O-acetyl- β-D-glucopyranosyl) thioacetoxy] -mutilirt (529.8 mg), prepared according to paragraph A, was dissolved in methanol (50 mL). ). To this solution was added water (50 mL) and (C 5 H 5 N 5 (50 mL). The resulting solution was stirred for days at room temperature and then evaporated to dryness under vacuum to dryness. The residue was re-evaporated from chloroform to give 492. mg of crude product.

This product was further purified by silica gel column chromatography (2 cm in diameter, 150 g, Merck). Elution with a mixture of ethyl acetate and ethanol (9: 1) collects 6 ml fractions at 30 minute intervals. The fractions are checked by thin layer chromatography on silica gel in the same solvent system using iodine as the detection reagent. Fractions 28-120 were combined and evaporated to give 366 mg of .alpha.-deoxy-.alpha .- (.beta. -D-glucopyranosyl] thioacetoxy] mutilin. M ⁺ -H2O = 538.

X CH3 0.70 (d); 0.91 (d); 1.13 (s); 1.40 (s).

Example 4

A. Preparation of 2,3,4-tri-O-acetyl-1-thiouronium- [beta] -D-xylopyranose hydrobromide

2,3,4-tri-O-acetyl-α-D-xylopyranosyl bromide (1.3 g, 3.83 mmol), prepared according to "Methods of Carbohydrate Chemistry", vol. 1, Academic Press, New York, NY, 1962 , p. 183, was dissolved in acetone (3 mL). To this solution was added thiourea (330 mg, 4.33 mmol). After further addition of acetone (up to 3 ml), the resulting solution is heated to boiling R (oil bath 70 ° C) for about 20 minutes. The product crystallizes by standing the reaction mixture in an ice bath. The crystals were filtered off, washed with a minimum amount of acetone and dried to give 849 mg of hydrobromide.

2,3,4-tri-O-acetyl-1-thiouronium-β-D-xylopyranose, m.p. 174-175 ° C,

B. Preparation of 2,3,4-tri-O-acetyl-1-thio-β-Dxylopyranose

To 2,3,4-tri-O-acetyl-1-thio219343 hydrobromide uronium-4-D-xylopyranose (608.4 mg, 1.466 mmol prepared according to Part A) and Na 2 S 2 O 2 (218 mg, 1.14 mmol) water (5 ml) and carbon tetrachloride (5 ml) were added and the reaction mixture was heated under reflux for 40 minutes, cooled to room temperature, the organic phase separated and the aqueous phase washed twice with 10 ml of carbon tetrachloride. The combined carbon tetrachloride fractions were dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to give 212.9 mg of 2,3,4-tri-O-acetyl-1-thio-D-xylopyranose as a yellow oil. Purification on a silica gel column yielded an oil (132.3 mg) which crystallized (mp 117-122 ° C.) In later preparations, chromatographic purification is not necessary as the product crystallizes directly after seeding.

C. Preparation of 14-deoxy-14- _{[(2,3,4-tri-O-acetyl-3-t} D-xylopyranosyl) thioacetoxy] mutilin

The 2,3,4-tri-O-acetyl-1-thio-4-D-xylopyranose (1.46 g, 5 mmol) prepared according to Part B was dissolved in acetone (10 mL). Iodpleuromutilin (2.48 g, 5.08 mmol) in acetone (10 mL) was then added. To a stirred reaction mixture was added a solution of K 2 CO 3, (721 mg, 5.19 mmol) in water (5 mL). The resulting solution was stirred at room temperature for 20 minutes and then poured into deionized water (100 mL). This solution was extracted with dichloromethane. The dichloromethane solution was dried over anhydrous sodium sulfate, filtered, evaporated to dryness in vacuo and again dried under high vacuum for 8 hours. 3.8246 g of product are obtained in the form of a white foam which is crystallized from either diethyl ether and hexane or from diethyl ether and ethyl acetate, m.p. 91 DEG-97 DEG.

D. Preparation of 14-deoxy- [(5-D-xylopyranosyl) thioacetoxy] mutilin

14-Deoxy-14 - [(2,3,4-tri-O-acetyl-4-D-xylopyranosyl) thioacetoxy] mutitlin (1.5954 g), prepared as described in paragraph C, was dissolved in methanol (60 mL). , water (50 mL) and triethylamine (55 mL) was added. The resulting reaction mixture was stirred at room temperature for two days and then evaporated to dryness in vacuo. The residue was redissolved in chloroform and redissolved four times and evaporated. The residue was dried under high vacuum for 4 hours to give 1.79 g of crude product.

This product was purified by silica gel column chromatography (2.7 cm diameter, 200 g, Merck) and eluted with a mixture of ethyl acetate and ethanol (9: 1) to collect 5 ml fractions at 20 minute intervals. Fractions were checked by thin layer silica gel chromatography using the same solvent and iodine system as the detection reagent. Fractions 38-60 are combined with evaporation in vacuo to give 1.2066 g of 14-deoxy-14 - [([beta] -D-xylopyranosyl) thioacetoxymutilin. Mass spectrum M + + 1 = 527. NMR: 4 X CH 3 0.63 (d); 0.84 (d); 1.07 (s); 1.88 (s).

Example 5

A. Preparation of 14-deoxy-14 - [(2,3,4-tri-O-acetyl- [beta] -D-arabinopyranosyl) thioacetoxymutilin

2,3,4-Tri-O-acetyl-1-thio- [5-D-arabinose (3.177 g, 0.0109 mol), prepared as described in Example 4, paragraphs A and B, was dissolved in acetone (20 mL) and iodpleuromutilin (5.31 g, 0.0109 mol) was also dissolved in acetone (20 mL) and the solutions were mixed. Potassium carbonate (1.506 g, 0.0109 mol) in water (10 mL) was then added. The resulting solution was stirred at room temperature for 30 minutes and then poured into water (100 mL). The aqueous solution was extracted three times with 50 ml portions of dichloromethane. The dichloromethane extracts were combined, dried over anhydrous sodium sulfate and filtered. The filtrates were evaporated to dryness in vacuo to give 7.1 g of crude product.

This product was purified by high pressure liquid chromatography (HPLC, Waters ¹ Associates Prep. LC / System 500) eluting with toluene-ethyl acetate (1: 1) at a rate of 250 mL / min. Fractions of 250 ml are collected. The individual fractions were checked by thin layer chromatography on silica gel using toluene / ethyl acetate (1: 1) and iodine as the detection reagent. Fractions 17-22 contain the maximum amount of pure product. These fractions were combined and evaporated in vacuo to give 4.989 g of 14-deoxy-14 - [(2,3,4-tri-O-acetyl-4-D-arabinopyranosyl) thioacetoxy] mutilin.

B. Preparation of 14-deoxy-14 - [(β-D-arabinopyranosyl) thioacetoxymutilin

14-deoxy-14 - [(2,3,4-tri-O-acetyl- [3-D-arabinopyranose-1) thioacetoxy] mutilin (1 g), prepared according to paragraph A, was dissolved in methanol (50 ml), water (50 mL) and then triethylamine (50 mL) was added to this solution. The resulting solution was stirred at room temperature for 48 hours. The solvent was then evaporated in vacuo to give the crude product which was further purified by high pressure liquid chromatography according to paragraph A, eluting with a solvent gradient (starting with ethyl acetate to a mixture of ethyl acetate and 95% ethanol (9: 1)) to give 0.62 g. -deoxy-14 - [(β-D-arabinopyranosyl) thioacetoxy] mutilin.

NMR: δ X CH 3, 0.65 (d); 0.70 (t); 0.87 (d); 0.92 (s) and 1.4 (s).

Example 6

A. Preparation of 14-deoxy-14 - [(2,3,4-tri-O-acetyl / 3-L-arabinopyranosyl) thioacetoxy] mutilin

Iodpleuromutilin (4.636 g, 0.0095 mol) was treated with 2,3,4-tri-O-acetyl-1-thio-L-arabinose (2.76 g, 0.0095 mol) according to the method described in the example 5A. 6.265 g of crude product are obtained, which is purified by high pressure liquid chromatography as in Example 5A using a solvent gradient of 4 liters of toluene to 4 liters of a mixture of toluene and ethyl acetate (1: 1). 3.53 g of 14-deoxy-14 - [(2,34-tri-O-acetylP / S-L-arabinopyranosyl) thioacetoxy] mutilin are obtained.

and

B. Preparation of 14-deoxy-14 - [(β-L-arabinopyranosyl) thioacetoxy] mutilin

The 14-deoxy-14 - [(2,3,4-tri-O-acetyl- [3-L-arabinopyranosyl) thioacetoxy] mutilin (1 g) prepared according to paragraph A was deacylated as described in Example 5B to give 1. , 09 g of crude product. This product was purified by high pressure liquid chromatography using a solvent gradient from 4 liters of ethyl acetate to 4 liters of a mixture of ethyl acetate and ethanol (9: 1). 0.6862 g of 14-deoxy-14 - [(<3-L-arabinopyranosyl) thioacetoxy] mutilin is obtained. Mass spectrum M @ ⁺ +1 = 527. NMR: 4.times.CH3, 0.72 (d), 0.90 (d), 1.18 (s) and 1.45 (s).

Example 7

AND.

14-Deoxy-14 - [(2,3,4-tri-O-acetyl- [3-L-xylopyranosyl) thioacetoxy] mutilin was prepared using the procedure described in Example 4 using L-xylose. as the starting material. In the final step, iodpleuromutilin (31 grams) was treated with 2,3,4-tri-O-acetyl-1-thio-5S-L-xylose (19 g) to give 39.6 g of crude product. This crude product was purified by high pressure liquid chromatography as described in Example 5 using a solvent gradient (8 L) from toluene to toluene / ethyl acetate (7: 3). The purified fractions were crystallized from toluene / ethyl acetate to give 21.05 g of 14-deoxy-14 - [(2,3,4-tri-O-acetyl- [3-L-xylopyranosyl) thioacetoxy] mutilin, mp 210-213 Deň: 32 ° C.

B.

14-Deoxy-14 - [(β-L-xylopyranosyl) thioacetoxy] mutilin, prepared from 14-deoxy-14 - [(2,3,4-tri-O-acetyl- [3-L-xylopyranosyl) thioacetoxy] mutilin (15.8 g, prepared according to paragraph A. by the procedure of Example 4D), to give 14.3 g of the product as a white foam. M ^{+ -} H ² O = 509. NMR: 4 X CH 3: 0.63 (d) , 0.82 (d), 1.16 (s), and 1.86 (s).

Example 9

A. Preparation of pleuromutilinthiouronium hydroiodide

Iodpleuromutilin (46.8 g) was dissolved in acetone (300 mL) and thiourea (7.418 g) and additional acetone (60 mL) were added. The resulting reaction mixture was heated to boiling in an oil bath at 90 ° C for 30 minutes. The reaction mixture was allowed to cool to room temperature, evaporated to dryness in vacuo to give 60 g of 14-deoxy-14- (thiouronium acetoxy) mutilin hydroiodide, hereinafter referred to as pleuromutilinthiouronium hydroiodide, as an amorphous white compound.

B. Preparation of Pleuromutilinthiol

Pleuromutilinthiouronium hydro iodide (60 grams) prepared according to Section A was dissolved in water (200 mL) and sufficient hot methanol to give a complete solution. To this solution was added a solution of Na 2 SO 4 (23 g) dissolved in water ( 100 ml) and carbon tetrachloride (150 to 200 ml), and the resulting reaction mixture is heated to boiling in an oil bath at 80 to 90 ° C for 30 minutes, the chloroform phase is separated, dried over anhydrous sodium sulfate and evaporated to dryness to give 32, 5 g of pleuromutilinthiol as a white amorphous compound.

C. Preparation of cis- and β-anomers of 14-deoxy-14 - [(2,3,4-tri-O-acetyl-D-ribopyranosyl) thioacetoxy] mutilin

The pleuromutilinthiol (7.53 g, 19.1 mmol), prepared as described in Part B, was dissolved in chloroform (100 mL) and tetra-O-acetyl-ribopyranose (6.19 g, 19.46 mmol) was added. Tortrifluoride etherate (9 mL) was added to the resulting solution. The resulting reaction mixture was stirred at room temperature for about 2½ hours and then evaporated to dryness in vacuo. The residue thus obtained is redissolved in chloroform and washed twice with an equal volume of water. The chloroform phase is separated, dried over anhydrous sodium sulphate overnight and then evaporated to dryness in vacuo. 13 g of a mixture of the α- and β-anomers of 14-deoxy-14 - [(2,3,4-tri-O-acetyl-D-ribopyranosyl) thioacetoxy] mutilin are obtained. This crude product was further purified by the high pressure liquid chromatography described in Example 5, first using a solvent gradient of 4 liters toluene to 4 liters toluene / ethyl acetate (3: 1) and then using toluene / ethyl acetate (3: 1) and finally 2 liters ethyl acetate. . The appropriate fractions were further purified from high pressure chromatography using high pressure liquid chromatography using first 4 liters of toluene and then a solvent gradient from 4 liters of toluene to 4 liters of toluene / ethyl acetate (4: 1). Again, the appropriate fractions were combined to give the purified product. This product (still anomer mixture) was further purified on a 3.5 cm silica gel column using toluene / isobutyl alcohol (9: 1), and the fractions were collected at 30 ml intervals of about 5 ml. Fractions were also checked by thin layer chromatography on silica gel. 307.3 mg of the oranomer and 1.32 g of the β-anomer are isolated.

D.

14-Deoxy-14 - [(β-D-ribopyranosyl) thio acetoxy] mutilin is prepared from 14-deoxy-14 - [(2,3,4-tri-O-acetyl- / 3-D-ribopyranosyl) thioacetoxy] mutilin (prepared according to the procedure of paragraph C. following the procedure of Example 4D).

M ⁺ 526 mass spectrum. NMR .delta.

Example 10

A. Preparation of 14-deoxy-14 - [(2,3,5-tri-O-acetyl-D-ribopyranosyl) thioacetoxy] mutilin α- and β-anomers

The pleuromutilinthiol (6.5 g, 16.49 mmol) prepared as described in Example 9, Part B, was dissolved in chloroform (150 mL) and tetra-O-acetyl-4-D-ribofuranose (6.9 g, 21.69 mmol). To the resulting solution was gradually added borontrifluoroetherate (10 mL). The reaction was carried out as in Example 9, paragraph C, to give 10 g of a crude product which was a mixture of anomers.

This mixture was separated by high pressure liquid chromatography as described in Example 5 using a first 8 liters gradient from toluene to toluene / ethyl acetate (3: 1) and an additional 8 liters gradient from toluene / ethyl acetate (3: 1) to toluene and ethyl acetate (1: 3). There was obtained 1.5859 g of purified crude product. This product is chromatographed on a silica gel column (2.5 cm in diameter, 225 g, Merck) eluting with toluene / isobutyl alcohol (9: 1). Fractions of about 3 ml are collected at 30 minute intervals. Fractions 205-250 were combined and evaporated in vacuo to give 0.494 g of further purified material. This material was rechromatographed on another silica gel column using the same conditions. Fractions 209-215 were combined and evaporated in vacuo to give 56 mg of 14-deoxy-14 - [(2,3,5-tri-O-acetyl-N-D-ribofuranosyl) thioacetoxy] mutilin. Fractions 248-260 were also pooled to give 28 mg of 14-deoxy-14 - [(2,3,5-tri-O-acetyl-4-dibofuranosyl) thioacetoxy] mutilin.

B.

14-Deoxy-14 - [(α-D-ribofuranosyl) thioacetoxy] mutilin is prepared from 14-deoxy-14 - [(2,3,5-tri-O-acetyl-α-D-ribofuranosyl) thioacetoxy] mutilin (prepared according to of paragraph A. following the procedure of Example 4D.

Example 11

14-Deoxy-14 - [(β-D-ribofuranosyl) -thioacetoxy] mutilin, prepared from 14-deoxy-14 - [(2,3,5-tri-O-acetyl-4-D-ribofuranosyl) thioacetoxy] mutilin (prepared according to Example 10) according to the procedure of Example 4D.

Example 12

A. Preparation of 14-deoxy-14 - [(2-deoxy-2- (N, N-dimethylamino) -3,4,6-tri-O-acetyl- [3-D-lucopyranosyl) thioacetoxy] mutilin

To a solution of D-glucosamine hydrochloride (10.8 g, 0.05 mol) in water (250 mL) was added 250 mL of a 37% aqueous formaldehyde solution and 5 g of 10% palladium on carbon. The resulting mixture was hydrogenated until the theoretical amount was consumed to convert to 2-deoxy-2- (Ν, Ν-dimethylamino) -D-glucosamine. The catalyst was filtered off and the filtrate was lyophilized. The product obtained is acetylated with acetic anhydride and pyridine to give the corresponding tetra-O-acetyl derivative. This was then converted to the 2-deoxy-2- (Ν, Ν-dimethylamino) -3,4,6-tri-O-acetyl-D-glucopyranosyl bromide which was then converted to the corresponding 1-mercaptoderivative as described in Example 4. Reaction 2-Deoxy-2- (Ν, Ν-dimethylamino) -3,4,6-tri-O-acetyl-1-thio-D-glucopyranose with iodpleuromutilin following the procedure of Example 4, paragraph C, afforded the desired product.

B.

14-Deoxy-14 - [(2-deoxy-2- (Ν, Ν-dimethylamino) -β-D-glucopyranosyl) thioacetoxy] mutilin is prepared from 14-deoxy-14 - [(2-deoxy-2- ( (Ν, Ν-dimethylamino) -3,4,6-tri-O-acetyl- (2-D-glucopyranosyl) thioacetoxy] mutilin (prepared according to paragraph A. by the procedure of Example 4D.) Mass spectrum M ⁺ - | - 1 = 598 NMR: 4 X CH 3 0.64 (d), 0.84 (d), 1.07 (s) and 1.88 (s); CH (CH ₃ ) 2 0.96 (d).

Example 13

A. Preparation of 14-deoxy-14 - [(4-O- (2,3,4,6-tetra-O-acetyl-4-D-glucopyranosyl) -2,3,6-tri-O-acetyl] -. (D-glucopyranosyl) thioacetoxy] mutilin

This compound, hereinafter referred to as the heptaacetylthiomaltose derivative, was prepared according to the procedure of Example 4 except that octa-O-maltose acetate was used as the starting material. Maltose octa-O-acetate is prepared as described in Methods, Volume 1, p. 334; prepared from this compound as described by Finam and Warren, J. Chem. Soc. 1982 2823 hepta-O-acetylmaltose bromide. Iodpleuromutilin (8.6 g) was then reacted with hepta-O-acetylmaltose thiol (11.8 g, prepared according to Example 4, section A and B) according to Example 4, section C to give 17 g of product form of white foam. This product was further purified by high pressure liquid chromatography using a gradient of ethyl acetate to ethyl acetate / ethanol (1: 1) as eluent. 1.12 g of a heptaacetylthlomaltose derivative is obtained.

B.

14-Deoxy-14 - [(4-O- (α-glucopyranosyl) - S-D-glucopyranosyl) thioacetoxy] -mutilin, hereinafter referred to as thiomaltose derivative, was prepared by deacetylation of a heptaacetylthiomaltose derivative (1.1 grams) as described in Example 4D. 1.1 g of crude product are obtained in the form of a yellow residue. This product was further purified by high pressure liquid chromatography as described in Example 5. 732.6 mg of thiomaltose derivative were obtained.

Biological activity of pleuromutilin glycosides

The compounds of the present invention inhibit the growth of certain pathogenic organisms, particularly gram-positive bacteria. The compounds are preferably tested against typical Gram positive organisms such as Staphylococcus aureus using a turbidometric assay on a semi-automatic instrument (Autoturb Microbiological Assay System, Elanco) described by NR Kužel and FW Kavanagh in J. Pharmaceut. ScL, 60, (5), 764 and 767 (1971). The following parameters were used to test these compounds: Staphylococcus aureus (H-Heatley) NRRL B-314 in nutrient medium (pH 7) incubated for 4 hours at 37 ° C. Test samples and A-40104 factor A, which were used as standards, were dissolved in water. Standards were present in the Autoturb instrument at concentrations of 1.25; 2.50; 3.75; 5.00 and 6.25 / zg / ml. Test compounds were diluted to contain approximately 2.5 to 5.0 µg of activity per ml. The units of activity of some typical compounds of the present invention (R ² - H in group tested) in this in vitro assay are summarized in Table 1.

Table 1

Test compound R

R ¹ /3-D-xylopyranosyl (standard) / 5-D-glucopyranosyl 1-thio- / 3-D-xylopyranosyl 1-thio-R-D-glucopyranosyl

1-thio-4-D-ribopyranosyl 1-thio-α-D-ribopyranosyl

1-thio-4-D-arabinopyranosyl

Units of activity (µg / mg)

446 to 452 12 to 13 995 to 1003 36

1070

350

380

The pleuromutilin glycosides of the present invention are relatively nontoxic. For example, LD 50 values of 14-deoxy-14 - [(β-D-xylopyranosyl) thioacetoxy] mutilin and 14-deoxy-14 - [(β-D-xylopyranosyl) thioacetoxy] -19,20-dihydromutilin, by intraperitoneal injection the mice are greater than 1500 mg / kg; The LD 50 of 14-deoxy-14 - [(3,4,6-tri-O-acetyl-2-deoxy-2- (hydroxyimino) -4-D-glucopyranosyl) oxyacetoxy] -19,20-dihydromutilin are also intraperitoneal injection to mice greater than 300 mg / kg.

Typical compounds of the present invention exhibit in vivo antimicrobial activity against experimental bacterial infections. When two doses of these compounds are administered to mice with the respective infection, the activity found is reported as ED 50 values (effective dose in mg / kg that protects 50% of the test animals. See Warren Wick et al. J. Bacteriol. 81, 233-235). The ED 50 values observed for these compounds are shown in Tables II and III.

Table II

In vivo activity of 14-deoxy- [(β-D-xylopyranosyl) thioacetoxy] mutilin

Tested organism application ED50 X 2 degree of infection Staphylococcus aureus 3055 subcutaneously 1.85 82 X LD50 (ip) Staphylococcus aureus 3055 orally 44 3400 X LD50 (ip) Staphylococcus aureus 3055 orally 32.4 500 X LD50 (ip) Streptococcus pyogenes C203 subcutaneously 11.4 370 X LD50 Streptococcus pneumoniae Park I subcutaneously 65 42 X LD50 Streptococcus pneumoniae B1492 subcutaneously 15.3 340 X LD50 (ip)

Table III

In vivo activity of 14-deoxy-14 - [(1S-D-xylopyranosyl) thioacetoxy] -19,20-dihydromutilin

Tested organism application EDaO X 2 degree of infection Staphylococcus aureus 3055 subcutaneously 1.6 400 X LD50 Staphylococcus aureus 3055 orally 29 3400 X LD50 Staphylococcus aureus 3055 orally 21 .500 X LD50 (ip) Streptococcus pyogenes C203 subcutaneously 7.0 500 X LD50 Streptococcus pneumoniae Park I subcutaneously 58.5 42 X LDoo Streptococcus pneumoniae B1343 subcutaneously 16.3 30 X LD50 Streptococcus pneumoniae B1492 subcutaneously 13.25 340 X LDoO The compounds of the present invention invention compounds according to of the present invention, how also inhibit the growth of various anaerobic bac- was determined standard dilution

terií. Table IV summarizes the activity of typical agar assays.

Table IV

MIC ((Ug / ml) * Compound Number

1 2 3 4 5 6 Actinomyces israelii á 0,5 á 0,5 0.5 <0.5 <0.5 2,0 Clostridium perfringéhs 16.0 2,0 2,0 > 128 δ, Ο > 128 Clostridium septicum <0.5 2,0 1.0 4.0 32.0 1.0 Eubacterium aerofaciens 16.0 1.0 0.5 > 128 4.0 16.0 Peptococcus ááaccharolyticus <0.5 g 0,5 0.5 <0.5 4.0 4.0 Peptococcus prevoti <0.5 g 0,5 g 0.125 8.0 2,0 2,0 Peptosterptococcus anaerobius Ě 0,5 g 0,5 g 0.125 1.0 8.0 g 0,5 Peptostreptococcus interme- dius <0.5 <0.5 0.5 2,0 2,0 4.0 Bacteroides fřagilis 111 8.0 1.0 2,0 32.0 64.0 2,0 Bacteroides fagilis 1877 4.0 1.0 1.0 32.0 64.0 2,0 Bacteroides fagilis 1936B 8.0 1.0 1.0 64.0 128 8.0 Bacteroides thetaiotaomicron 8.0 1.0 0.5 64.0 64.0 8.0 Bacteroides melaninogenicus > 128 > 128 0.25 8.0 2,0 2,0 1865/28 Bacteroides melaninogenicus 2,0 1.0 0.5 4.0 4.0 4.0 2736 Bacteroides vulgatis 4.0 1.0 1.0 32.0 32.0 4.0 Bacteroides corrodens 4.0 1.0 1.0 32.0 64.0 4.0 Fusobacterium symbiosum 4.0 2,0 1.0 128 16.0 4.0 Fusobacterium neerophorum <0.5 g 0,5 1.0 <0.5 8.0 4.0

MIC (µg / ml) * Compound Number

Actinomyces israelii 64.0

Clostridium perfringens> 128

Clostridium septicum> 128

Eubacterin aerofaciens> 128

Peptococcus asaccharolyticus 64.0

Peptococcus prevoti 128

Peptostreptococcus anaerobius 64.0

Peptostreptococcus intermedius> 128

Bacteroides fragilis 111> 128

Bacteroides fragilis 1877> 128

Bacteroides fragilis 1936B> 128

Bacteroides thetaiotaomicron> 128

Bacteroides melaninogenicus 1856/28> 128

Bacteroides melaninogenicus

2736 32

Bacteroides vulgatis> 128

Bacteroides corrodens> 128

Fusobacterium symbiosum 4.0

Fusobacterium necrophorum> 128 * terminated after 24-hour incubation Table IV - continued

Compound Name

C.

14-Deoxy-14 - [(2,3,4-tri-O-acetyl- [3-D-xylopyranosyl) thioacetoxy] mutilin

14-Deoxy-14 - [(β-D-xylopyranosyl) thioacetoxy] mutilin

14-deoxy-14 - [(3-D-xylopyranosyl) thioacetoxy-19,20-dihydromutilin

14-deoxy-14 - [(2,3,4,6-tetra-O-acetyl-4-D-glucopyranosyl) thioacetoxy] -19,20-dihydromutilin

14-deoxy-14 - [(N-D-glucopyranosyl) thioacetoxy] -19,20-dihydromutilin

14-deoxy-14 - [(2,3,4-tri-O-acetyl-4-D-xylopyranosyl) thioacetoxy] -19,20-dihydromutilin

14-deoxy-14 - [(3,4,6-tri-O-acetyl-2-deoxy-2- (hydroxyimino) -D-glucopyranosyl) oxyacetoxy] mutilin

14-deoxy-14 - [(3,4,6-tri-O-acetyl-2-deoxy-2- (hydroxyimino) -or-D-glucopyranosyl) oxyacetoxy] -19,20-dihydromutilin

14-deoxy-14 - [(3,4,6-tri-O-acetyl-2-deoxy-2- (hydroxyimino) -N-galactopyranosyl) oxyacetoxy] mutilin

14-deoxy-14 - [([1,2-D-glucopyranols] thioacetoxy] mutilin

9 10 11

8.0> 128> 128> 128 8.0> 128 64.0 1.0> 128> 128> 128 16.0 16.0 2,0 2.0 64.0 64.0 16.0 16.0 16.0 W 0.5 g 0.5> 128 16,0 128 á 0,5 <0,5 š 0,5 > 128 > 128 4.0 1.0 > 128 > 128 128 128 > 128 > 128 64.0 32.0 > 128 > 128 64.0 32.0 > 128 > 128 64.0 16.0 > 128 > 128 > 128 > 128 > 128 > 128 32.0 16.0 > 128 > 128 64.0 32.0 > 128 > 128 64.0 32.0 > 128 > 128 64.0 128 > 128 64.0 2,0 16.0 Compound Name

C.

14-Deoxy-14 - [(2,3,4,6-tetra-O-acetyl-4-D-glucopyranosyl) thioacetoxy] mutilin

An important feature of the activity of the compounds of the present invention is their activity against mycoplasmas. Some species of mycoplasma are pathogenic in humans and various animals. Substances active against mycoplasmas are particularly necessary for the prevention and treatment of diseases caused by mycoplasmas in poultry, pigs and cattle.

An important feature of the activity of the compounds of the present invention is their activity against mycoplasmas. Some species of mycoplasma are pathogenic in humans and various animals. Substances active against mycoplasmas are particularly necessary for the prevention and treatment of diseases caused by mycoplasmas in poultry, pigs and cattle.

For example, 14-deoxy-14 - [(β-D-xylopyranosyl) thioacetoxy] mutilin and 14-deoxy-14 - [(β-D-xylopyranosyl) thioacetoxy] -19,20-dihydromutilin are active against Ureaplasma sp in vitro assays. , Mycoplasma bovis, Mycoplasma dispar and some other bovine mycoplasmas in an amount of 0.024 µg / ml.

The minimum inhibitory concentration (MIC) of a range of typical compounds of the present invention ^(R2 = H) in the test group against various mycoplasma species, as determined in vitro dilution tests are summarized in Table V.

Table V

Test compound

R R ¹ vinyl β-D-glucopyranosyl vinyl 1-thio- (3-D-xylopyranosyl) vinyl 1-thio-1-D-glucopyranosyl vinyl Β-D-glucopyranosyl vinyl 1-thio- [3-D-xylopyranosyl] vinyl 1-thio-β-D-glucopyranosyl Compounds according to of the present invention

MIC (jug / ml)

Mycoplasma Mycoplasma gallisepticum synoviae

0.39 0.78 0.78 0.78 1.56 3.12 0.78 0.39 0.15 1.56

also show in vitro activity against Pasteurella multocida, Pasteurella hemolytica, and Pseudomonas species that are pathogenic in fish. For example, P. multocida causes respiratory infection in cattle, poultry and pigs. P. hemolytica is a major cause of respiratory disease in cattle.

For example, in in vitro assays against Pasteurella hemolytica, the average MIC value for 14-deoxy-14 - [(β-D-xylopyranosyl) thioacetoxyjmutiline and 14-deoxy-14 - [(pD-xylopyranosyl) thioacetoxy] -19,20-dihydromutilin 12 , 5 µg / ml and 10.4 (µg / ml.

The activity of representative compounds of the present invention (R ² - H in group tested) against P. multocida and the Pseudomonas sp. is included in Table VI.

Table VI

Test compound RR ¹ vinyl 1-thio-4-D-xylopyranosyl

According to another important feature, the compounds of the present invention are also active against Spiroplasmas. Spiroplasma citri causes tough citrus disease, other Spiroplasma affects corn growth. Table VII summarizes the in vitro activity of representative compounds of the present invention (R ² - H in this group) pro-

MIC (µg / ml) Pseudomonas sp · (fish) Pasteurella multocida (bovine cattle) Pasteurella multocida (cruel) 3.12 6.25 6.25

those of Spiroplasma citri. In this assay, inhibition of S. citri is determined by color reaction. Red (R) indicates complete inhibition, red-orange (RO) indicates partial inhibition, and yellow (Y) indicates no inhibition. For example, 14-deoxy-14 - [(β-D-xylopyranosyl) thioacetoxy] -19,20-dihydromutilin inhibits the growth of S. citri in an amount of 0.01 ppm.

Table VII test compound R1 R1 1-thio-5S-D-xylopyranosyl vinyl / 3-D-glucopyranosyl

An important feature of the present invention is the use of the compounds of the present invention for the treatment of dysentery in pigs. As reported by W, E. Brown et al., U.S. Patent No. 4,041,175, pleuromutilin is effective for treating dysentery in pigs. It has now been found that the glycosides of the pleuromutilins of the present invention are also effective against Treponema hyodysenteriae, the organism most associated with swine dysenteria. The activity against T. hyodysenteriae is determined by an in vitro test. The assay includes the addition of compound in an amount of 50; 5.0; 0.5; and 0.05 µg / ml trypticase soy agar plates containing 5% bovine blood.

activity - ppm

1.0 0.1 0.05 0.01

R, R, R, R, R, RO

R Y - -

The agar surface was inoculated with 0.1 ml of 10 ^-1 dilution suspension T.hyodysenteriae. The plates are incubated for 4 days under anaerobic conditions and then the presence or absence of hemolytic treponema is determined. 14-deoxy-14 - [(β-D-xylopyranosyl) thioacetoxy] -mutilin and 14-deoxy-14 - [(β-D-xylopyranosyl) thioacetoxy] -19,20-dihydromutilin inhibit growth of 50; 5.0; 0.5 (µg / ml agar concentration).

When used for the treatment of swine dysentery, the compounds of the present invention may be administered orally to swine in the form of tablets, capsules, powders and the like. However, a preferred method of administration is to administer the compound with food.

Claims (16)

A process for the preparation of glycosides of pleuromutilin of the general formula IV wherein R is vinyl; R ¹ is selected from the group consisting of (a) the α- and β-anomers of the following hexopyranoses: D- and L-glucose; 1-thio-D- and L-glucose, 1-thio-D- and L-galactose, (b) the ^1- and β-anomers of the following pentopyranoses and pentofuranoses: 1-thio-D- and L-ribose, 1-thio-L- and D-arabinose, (c) α- and β-anomers of the following pentofuranoses: 1-thio-D- and L-xylose; d) α- and β-anomers of pentopyranose forms of 1-thio-D- and L-xylose, (e) the cu ^1- and β-anomers of the following pyranos amino sugars: 2-deoxy-2-amino-D- and L-glucose, N-monoalkyl and Ν, Ν-dialkyl derivatives of these C 1 -C 4 -amino sugars in each of alkyls, (f) α- and β-anomers of disaccharides: 1-thiomaltose, (g) 2-deoxy-2- (hydroxyimino) -cu-D-galactopyranosyl; R ² is a hydrogen atom, characterized by hydrolyzing the corresponding glykolderivát wherein the glycosyl moiety is selected from per-O-acylated or benzylated a- or 6-anomers selected from groups a] to g) above in the presence of a base. 2. A process according to claim 1 for the preparation of non-acylated pleuromutilin glycosides of the aforementioned formula (IV), characterized in that the pleuromutilin per-O-acylglycoside is hydrolyzed in the presence of triethylamine. 3. The process according to claim 2, for the preparation of 14-deoxy-14 - [(β-D-glucopyranosyl) thioacetoxy jututiline, characterized in that 14-deoxy-14 - [(2,3,4,6-tetra-O) is hydrolyzed. (acetyl-4-D-glucopyranosyl) thioacetoxyiminutilin. 4. A process according to claim 2, for the preparation of 14-deoxy-14 - [(β-D-xylopyranosyl) thioacetoxy] mutilin, characterized in that 14-deoxy-14 - [(2,3,4-tri-O-) is hydrolyzed. acetyl-D-xylopyranosyl) thioacetoxymutilin. 5. A process according to claim 2 for the preparation of 14-deoxy-14 - [(.beta.-D-arabinopyranosyl] thioacetoxy] -mutilin, characterized in that 14-deoxy-14 - [(2,3,4-tri-O - acetyl- (3-D-arabinopyranosyl) thioacetoxy] -mutilin. 6. A process according to item 2 for the preparation of 14 &apos; -deoxy-14 - [([beta] -L-arabinopyranosyl) thioacetoxy] butilin, which comprises hydrolyzing 14-deoxy-14 - [(2,3,4-tri-O)]. -acetyl- (3-L-arabinopyranosyl) thioacetoxyiminutilin. 7. A process according to claim 2 for the preparation of 14-deoxy-14 - [(β-L-xylopyranosyl) thioacetoxy] mutilin, characterized in that 14-deoxy-14 - [(2,3,4-tri-O-acetyl) is hydrolyzed - (3-L-xylopyranosyl) thioacetoxy] mutilin. 8. A process according to claim 2 for the preparation of 14-deoxy-14 - [(1'-D-ribopyranosyl) thioacetoxyjmutilin, characterized in that 14-deoxy-14 - [(2,3,4-tri-O-acetyl) is hydrolyzed. [α (D-ribopyranosyl) thioacetoxy] mutilin. 9. A process according to claim 2 for the preparation of 14-deoxy-14 - [(4-D-ribopyranosyl) thioacetoxyjmutiline, characterized in that 14-deoxy-14 - [(2,3,4-tri-O-acetyl) is hydrolyzed. - (2-D-ribopyranosyl) thioacetoxy] mutilin. 10. A process according to claim 2 for the preparation of 14-deoxy-14 - [(2-D-ribofuranosyl) thioacetoxy] -mutilin, characterized in that 14-deoxy-14 - [(2,3,5-triacetyl-α-) -hydroxy is hydrolyzed. (D-ribofuranosyl) thioacetoxy] mutilin. 11. A process according to claim 2 for the preparation of 14-deoxy-14 - [(R-D-ribofuranosyl) thioacetoxy] butilin, characterized in that 14-deoxy-14 - [(2,3,5-tri-O-) is hydrolyzed. acetyl- (3-D-ribofuranosyl) thioacetoxyiminutilin. 12. The process of item 2 for the preparation of 14-deoxy-14 - [(2-deoxy-2- (N, N-dimethylamino) -O-O-giconyranosyl] thioacetoxy) mutilin, characterized in that 14-deoxy- 14- [(2-deoxy-2- (N, N-dimethylamino) -3,4 ₅ 6-tri-O-acetyl- / 3-D-glucopyranosyl] mutilin thioacetoxy. 13. The method of item 2 for the preparation of 14-deoxy-14 - [(4-O- (α-D-glucopyranosyl) -β-D-glucopyranosyl] thioacetoxy] mutilin, characterized in that 14-deoxy-14 [ (4-O- (2,3,4, G-tetra-O-acetyl-cu-D-glucopyranosyl) -3,4,6-tri-O-acetyl- [beta] -D-glucopyranose) thioacetoxy] mutilin . 14. A process according to claim 2 for the preparation of 14- [(3-D-glucopyranosyl) oxyacetoxy] mutilin, characterized in that 14'-deoxy-14- [(2,3,4,6-tetra-O-) is hydrolyzed. acetyl-4- (D-glucopyranosyl) oxyacetoxy] mutilin. 15. A process according to item 2 for the preparation of 14-deoxy-14 - [(2-deoxy-2- (hydroxyimino) -cu-D-galactopyranosyl) oxyacetoxy] mutilin, characterized in that 14-deoxy-14 - [( 2-deoxy-2- (hydroxyimino) -3,4,6-tri-O-acetyl-N-galactopyranosyl) oxyacetoxy] mutilin. 16. A process according to claim 2 for the preparation of 14-deoxy-14 - [(.beta.-D-galactopyranosyl) thioacetoxy] -mutilin, characterized in that 14-deoxy-14 - [(2,3,4,6-tetra-O) is hydrolyzed. -acetyl- [3-D-galactopyranosyl] thioacetoxy] mutilin.