BG63124B1 - New derivatives of erythromicyn, method for their preparation and application as medicmentous forms - Google Patents

Abstract

The compounds have the formula where R is alkyl radical, optionally substituted, or (CH2)nAr, n meaning an integer from 1 to 6 and Ar is aryl or heteroaryl radical, optionally substituted, and Z means hydrogen atom or radical of a carboxylic acid. 9 claims

Description

Technical field

The present invention relates to novel erythromycin derivatives, a method for their preparation and their use as medicaments.

SUMMARY OF THE INVENTION

The invention relates to compounds of formula

wherein R or represents an alkyl, alkenyl or alkynyl radical, linear, branched or ring containing up to 18 carbon atoms, optionally substituted by one or more substituents selected from halogen atoms, the radicals O-alkyl, O-alkenyl or O -alkynyl, S-alkyl, S-alkenyl or S-alkynyl, linear, branched or ring containing up to 12 carbon atoms, NO ₂ radicals, C = N radicals, radical:

Ra N ⁴ Rb in which Ra and Rb, identical or different, denote a hydrogen atom, an alkyl radical, linear or branched, containing up to 4 carbon atoms, a radical:

in which Rc, Rd and Rf are the same or different, denote an alkyl radical, linear, branched or ring containing up to 4 carbon atoms, optionally substituted by one or more halogen atoms, or a radical (CH ₂ ) _n Ar, in which and denotes an integer from 0 to 6 and Ar represents an aryl or heteroaryl radical optionally substituted by one or more substituents mentioned above, Z represents a hydrogen atom or an acyl radical residue containing up to 12 carbon atoms, and acid addition salts.

The aryl radical may be a phenyl or naphthyl radical.

The aryl radical may also be a heterocyclic radical substituted or unsubstituted, such as thienyl, furyl, pyrrolitic, thiazolyl, oxazolyl, imidazolyl, thiazole, pyrazolyl, pyridyl, pyrimidinyl, pyrimidinyl, pyrrolidinyl

These aryl radicals may contain one or more groups selected from the group consisting of hydroxy radicals, halogen atoms, NH ₂ , NO ₂ radicals, alkyl, alkenyl or alkynyl, O-alkyl, O-alkenyl or O radicals -alkynyl, Salkyl, S-alkenyl or S-alkynyl and Nalkyl, N-alkenyl or N-alkynyl containing up to 12 carbon atoms, optionally substituted by one or more halogen atoms, a radical

where Ra and Rb equal or different denote a hydrogen atom or an alkyl radical containing up to 12 carbon atoms, a radical

as R ₃ means an alkyl radical containing up to 12 carbon atoms or an aryl or heteroaryl radical optionally substituted by aryl, O-aryl or Sarylcarboxyl or heterocyclic aryl, aryl or S-aryl radicals having 5 or 6 atoms containing one or more heteroatoms optionally substituted by one or more of the substituents mentioned below.

Preferred heterocycles may be mentioned

62124

Ο

and heterocyclic radicals contemplated in EP-A-487411, 596802, 676409 and 680967. These preferred heterocyclic radicals may be substituted by one or more functional groups.

Hal preferably represents a fluoro, chloro or bromo atom.

Acid addition salts may include the acids formed with the acids acetic, propionic, trifluoroacetic, malic, tartaric, methanesulfonic, benzenesulfonic, p-toluenesulfonic, especially the acids stearic, ethyl succinic or laurylsulfonic.

The object of the invention is generally the compounds of formula I in which Z represents a hydrogen atom, the compounds of formula I in which R represents a radical (CH ₂ ) _n Ar, in which η denotes an integer from 1 to 4 and Ar denotes aryl or heteroaryl a radical optionally substituted, in particular those in which Ar is a phenyl radical, optionally substituted, and those in which R is radicals:

optionally substituted.

In particular, it is an object of the invention to provide the compounds which are given below in the experimental part, in particular the compounds of Examples 2 and 3.

The compounds of general formula I have 25 very good antibiotic activity on gram-positive bacteria such as staphylococci, streptococci, pneumococci.

The compounds of the invention can therefore be used as medicaments for the treatment of infections with susceptible strains, namely those of staphylococci, such as septicemia with staphylococci, malignant infections with staphylococci on the face or skin, pyodermitis, septic or 35 purulent wounds, boils, boils. anthrax, phlegmon, erysipelas and acne, staphylococcal infections such as acute primary or post-influenza sore throats, bronchopneumonia, pulmonary purulent processes, streptococcal infections such as acute angi40, otitis, sinusitis, scarlet fever, pneumonia Covey infections such as pneumonia, bronchitis; brucellosis, diphtheria, gonococcal infections.

The compounds of the invention are also active against infections due to 45 strains such as Haemophillus influenzae, Rickettsiae, Mycoplasma pneumoniae, Chlamydia, Legionella, Ureaplasma, Toxoplasma or strains of the genus Mycobacterium.

It is an object of the invention to use the compounds of formula I as defined above, as well as their compounds with pharmaceutically acceptable inorganic compounds

62124 Native or organic acids salts, such as medicaments, in particular as antibiotic medicines.

In particular, it is an object of the invention to use the compounds of Examples 5 2 and 3 and their pharmaceutically acceptable salts as medicaments and specifically as antibiotic medicines.

Also contemplated are pharmaceutical compositions comprising as active principle at least one of the drugs defined above.

These compositions may be administered by the oral, rectal, parenteral or topical route in topical application to the skin and mucous membranes, but the oral route of administration is the preferred route.

They can be solid or liquid and can be presented in the form of currently used in human medicine pharmaceutical forms, such as ordinary or coated tablets, gelatin capsules, granules, suppositories, injectables, lipsticks, creams, gels. They are prepared by the usual methods. The active or active substances 25 may be included therein with excipients commonly used in pharmaceutical compositions such as talc, arabic gum, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, animal or vegetable fats, paraffin derivatives, glycols, various wetting, dispersing or emulsifying agents, preservatives.

These compositions may also be presented in the form of a powder intended to be extemporaneously dissolved in a suitable carrier, for example sterile, pyrogen-free water.

The dose to be administered varies according to the disease being treated, the patient being treated, the route of administration and the product used. It may comprise, for example, between 50 mg and 300 mg per day of oral administration in adults to the compound of Example 2.

The object of the invention is also a method 45 for the preparation of the compounds of formula I, wherein the compound of formula II

in which Z 'denotes a carboxylic acid residue containing up to 12 carbon atoms, is subjected to a means of blocking the ketone function at the 3-position in the form of an ether or enol ester to give a compound of formula III

in which E denotes a residue of an ether or enol ester and Z 'retains the above meaning of reaction with a compound of formula IV

Hal - CH ₂ OR (IV) in which Hal represents a halogen atom to give the corresponding compound of formula V

which is subjected, if desired, to the action of a ketone releasing agent in the 3rd position and / or reacting with a hydroxyl group releasing agent in the 2nd position to give a compound of the corresponding formula I

OZ in which R and Z retain the above values.

The compounds of formula II used as starting materials are known and can be prepared according to the method described in EP 487411 or in WO 9321199.

Halogenomethyl ether, namely chloromethyl ether, such as MEM chloride, or 2-methoxy-ethoxy-methyl chloride, or more SEM chloride, can be used as a means of blocking ketofunction in the 3rd place, in the form of enol ether. or 2- (trimethylsilyl) ethoxy methyl chloride. Benzyloxymethyl ether (POM) may also be used as a blocking agent in the form of an enol ester.

- Hal preferably represents a chlorine atom,

- Z 'preferably represents an acetyl radical,

- the ketofunctional release agent in the third place, where:

- the release of the hydroxy group in the 2nd position is by methanolysis.

The compounds of formulas ²²² and V included in the preparation process are novel and are themselves subject to the invention.

Examples of carrying out the invention

The following examples illustrate the invention without limitation.

Example 1. 11,12-dideoxy-3-de- [(2,6-dideoxy-3-C-methyl-3-O-methyl-a-L-ribohexopyranosyl) oxy] -6-O-methyl-3- oxo-12,11- [oxy-carbonyl- [[(2-methoxyethoxy) methyl] imino]] erythromycin

Step A: 2'-acetate of 2,3-didehydro-11,12-dideoxy-3-O-de- [(2,6-dideoxy-3-C-methyl-3-methyl-a-E-ribohexopyranosyl) -6-0-methyl-

11.12- (iminocarbonyloxy) -3-0- [[(2-trimethylsilyl) ethoxy] methyl]] erythromycin

A solution containing 6 ml of DMF, 0.654 g of 2'acetate of 11,12-dideoxy-3-de- [(2,6-dideoxy-3C-methyl-a-1-ribohexopyranosyl) was stirred for 10 min. oxy] -6-O-methyl-3-oxo-11,12- (iminocarbonyloxy) erythromycin and 0.057 g of sodium hydride in 50% by weight. The reaction mixture was adjusted to 40 ° C. Cool to -5 ° C and add 0,177 μΐ C1SEM dropwise. Dilute with 5 ml of DMF and bring to pH 7. 3 drops of water are added, brought to room temperature and the DMF is evaporated. The residue was taken up in 15 ml of ethyl acetate, washed with aqueous ammonia, extracted with ethyl acetate, washed with water, dried, filtered and concentrated. 0.785 g of the compound are obtained which is dissolved in isopropyl ether. Crystallization is initiated, moisture is removed, washed and dried at 70 ° C. The desired product is obtained which melts at 100 ° C.

NMR (CDC1 ₃₎ ppm

Possible structure

0.07 (s): Si (Me) ₃ ; 0.87 (t); CH ₃ -CH ₂ ; 1.03: CH ₂ -Si; 1.10 (d) -l, 12 (d) -I, 14 (d) -l, 24 (d): CH ₃ groups; 1.24 (s) -l, 43 (s): 6 and 12 CH ₃ ; 1.95 (s): 2-Me; 2.08 (s): OAc; 2.27 (s): N (Me) ₂ ; 2.47 (m): H '; 2.68 (m): H '₃; 2.82 (s): 6-OMe; 3.04 (q): H, _o ; 3.31 (dq): H ₄ ; 3.48 (m): H '₃; 3.73 (d.> 2.5): H ₃ ; 3.80-3.92: OCH ₂ ; 3.89 (s): H "; 4.69 (d): H ,; 4.78 (dd): H ₂ ; 4.99 (d) -5.04 (d): OCH ₂ O; 5.29 (dd): H ₁₃ .

Step B: 11,12-dideoxy-3-de- [(2,6-dideoxy-3-C-methyl-3-O-methyl-a-L-ribohexopyranosyl) oxy] -6-O-methyl-3- oxo-12,11- [oxycarbonyl- [[(methoxymethyl) imino]] erythromycin

0.150 g of a mixture containing 0.150 g of the Step A product is dissolved in 1.5 ml of DMF.

The reaction mixture was cooled to + 10 ° C and 14 mg of sodium hydride 50% in oil was added. The reaction mixture was cooled to 0 ° C and 26 μΐ MEM chloride dissolved in 0.5 ml DMF was added. It was stirred for 25 min at 0 ° C, poured onto ice, concentrated, mixed with ethyl acetate, washed with water, extracted with ethyl acetate, dried, filtered and concentrated. A product is obtained which is diluted in 4 ml of methanol. The solution is heated at reflux in pro

62124 for 2 h, brought to room temperature. A 1 ml solution of 6.5 M hydrochloric acid in methanol was added. The methanol was evaporated, the residue was dissolved in ethyl acetate, washed with ammonia, diluted, extracted with ethyl acetate, dried, filtered and concentrated. 0.11 g of product were obtained which crystallized. Purification yields the desired crude product. M.P. = 238-240 ° C.

NMR (CDC1 ₃₎ ppm

0.88 (t): CH ₃ -CH ₂ ; 1.03 (d): 10-Me; 1.16 (d): 8 Me; 1.25 (d): 5'Me; 1.32 (d): 4Me; 1.38 (d): 2Me; 1.34 and 1.51: O and 12Me; -1.57 and 1.38 CH ₂ at 14; -1.60 and 1.84: CH ₂ at 7; -1.67 and 1.25: CH ₂ at 4 '; 2.27 (s): N (Me) ₂ ; 2.44 (m): H '₃; 2.62 (m): H ₈ ; 2.67 (s): 6-OMe; 3.09 (ql): H ₁₀ ; 3.12 (m): H ₄ ; 3.18 (dd): H '₂; 3.36 (s): OMe; 3.47: OH; 3.86 (q): H ₂ ; 3.87 (s): H '; 4.24 (d): ',; 4.93 (d) -5.27 (d): NCH ₂ O; 5,05 (dd): H _l3.

Example 2. 11,12-dideoxy-3-de [(2,6-dideoxy-3-C-methyl-3-O-methyl-a-L-ribohexopyranosyl) oxy] -6-O-methyl-3-oxo -12,11- [oxycarbonyl- [[[2- [4- (3-pyridinyl) -1H-imidazol-1-yl] ethoxy] methyl] imino]] erythromycin

Step A: 2'-acetate of 2,3-didehydro-11,12-dideoxy-3-O-de- (2,6-dideoxy-3-C-methyl-30-methyl-a-E-ribohexopyranosyl) - 6-0-methyl12,11- [oxycarbonyl- [[(2-bromo-ethoxy) methyl] imino]] -3-O- [[2- (trimethylsilyl) ethoxy] methyl] -erythromycin

0.278 g of sodium hydride 50% in oil are stirred in 2 ml of THF. Cool to 0 ° C and add 510 mg of the product of Step A of Example 1 dissolved in 8 ml of THF. The temperature was adjusted to 0 ° C, poured onto ice, extracted with ethyl acetate, washed with sodium chloride solution, dried, filtered and concentrated. 0.709 g of the desired product is obtained.

Step B: 2'-acetate of 2,3-didehydro-11,12-dideoxy-3-O-de- (2,6-dideoxy-3-C-methyl-30-methyl-a-L-ribohexopyranosyl-6 -O-methyl12,11 - [oxycarbonyl- [[[2- (4- (3-pyridinyl) -1Nimidazol-1-1-yl] ethoxy] methyl] imino]] -3-O [[2- (3 -trimethylsilyl (ethoxy] methyl] erythromycin A solution of 3 ml DMF and 0.377 g 4- (3-pyridinyl) -1H-imidazole was added to a solution containing 2 ml DMF and 0.162 g sodium hydride 50% in oil. for a quarter of an hour, and 0.709 g of the product of Step A of Example 2 was added as a solution in 8 ml of DMF, stirred for 3 h at room temperature and for 15 min at 60 ° C. was extracted with ethyl acetate, washed with sodium chloride solution, then with water, dried, filtered and concentrated to give 0.644 g of product.

Step C: 11,12-dideoxy-3-de- [(2,6-dideoxy-3-C-methyl-3-O-methyl-a-L-ribohexopyranosoxy) -6-O-methyl-3-oxo- 12,11- [oxycarbonyl- [[[2- [4- (3-pyridinyl) -1H-imidazol-1-yl] -ethoxy] methyl] imino]] erythromycin

A solution containing 0.644 g of the product from step B and 8 ml of methanol was stirred at room temperature for 48 h, then 0.565 g of the resulting product was diluted in 5 ml of ethyl acetate. Cool to 0 ° C and add 2.5 ml of a 2.1 N hydrochloric acid solution in methanol and bring to room temperature. Stirred at room temperature for 1 hour. The solvents were evaporated, diluted with water, poured into saturated aqueous sodium carbonate solution, filtered and concentrated. 0.508 g of an oil is obtained, which is chromatographed on silica gel. CH ₂ Cl ₂ / MeOH (93-7) then CH ₂ Cl ₂ / MeOH / NH ₄ OH (93-7-0.5). The fractions that were homogeneous by TLC were concentrated, the residue was taken up in ethyl acetate, washed with ammonia, diluted, extracted with ethyl acetate, water, dried, filtered and concentrated. 66 mg of the desired product are obtained.

NMR (CDC1 ₃₎ ppm

0.85 (t): CH ₃ -CH ₂ ; 1.00 (d) -l, 15 (d) -l, 25 (d) 1.31 (d) -l, 40 (d): CH ₃ -CH groups; 1.34 and 1.51: 6 and 12 Me; 2.26 (s): N (Me) ₂ ; 2.44 (m): H ''; 2.60 (m): H ₈ ; 2.68 (s): 6-OMe; 3.03 (m): H ₄ and H ₁₀ ; 3.18 (dd): H '₂; 3.55 (m): H '₅; 3.76 (s) -3.92 (m) -4.38 (m): OCH ₂ CH ₂ N; 3.87 (s): H '; 3.83 (q): H ₂ ; 4,24 (d): H _5; 4.31 (d): H ',; 4.96 (dd): H, ₃ ; 4.99 (d) -5.37 (d): NCH ₂ O; 7.36 (d) -7.54 (d): H imidazole; 7.30 (ddd): H ₃ ; 8,08 (dt): H _4; 8.45 (dd): H ₆ ; 8.95 (ddd): pyridine.

Example 3: 11,12-Dideoxy-3-de- [(2,6-dideoxy-3-C-methyl-3-O-methyl-a-L-ribohexopyranosyl) oxy-6-0-methyl-3-oxo -12,11 - [oxycarbonyl [[(2-phenylethoxy) methyl] imino]] -erythromycin

Step A: 2'-acetate of 2,3-didehydro-11,12-dideoxy-3-O-de- (2,6-dideoxy-3-C-methyl-30-methyl-a-E-ribohexopyranosyl) - 6-0-methyl12,11- [oxycarbonyl- [[(2-phenylethoxy) methyl] imino]] -3-O- [[2- (trimethylsilyl) ethoxy] methyl] erythromycin

At 10 ° C, 18 mg of sodium hydride 50% in oil was added to a solution containing 2 ml of DMF and 203 mg of the product obtained in step A of Example 1.

Stirred for 15 min.

Cool to -5 ° C and add 46 μΐ chloromethylphenyl ether dissolved in 0.5 ml DMF.

The DMF was evaporated, the residue was taken up in ethyl acetate, washed with water, dried, filtered and concentrated. 0.277 g of the desired product is obtained.

Step B: 11,12-dideoxy-3-de- [(2,6-dideoxy-3-C-methyl-3-O-methyl-a-L-ribohexopyranosyl) oxy] -6-O-methyl-3- oxo-12,11- [oxycarbonyl- [[(2-phenylethoxy) methyl] imino] erythromycin

Cool to + 5 ° C and add 0.227 g of the product obtained in step A at a time to 0.33 ml of a 0.19 N hydrochloric acid solution in ethyl acetate. The temperature was brought to room and stirred for 2 h. It is cooled to 0 ° C, water is added, the pH is adjusted to 9-10 with concentrated ammonia solution, extracted with ethyl acetate, washed with water, dried, filtered and concentrated. 0.201 g of the product are obtained, which is diluted in 2.5 ml of methanol. The mixture was refluxed for 2 h. The methanol was evaporated to give 0.188 mg of the product which was chromatographed on silica gel, eluting with a mixture of methylene chloride-isopropanol-ammonia (95-5-0.5). It was concentrated, redissolved in methylene chloride, a drop of concentrated ammonia was added, stirred, dried, filtered and concentrated. 55 mg of the product is obtained which is dehydrated and dried at 80 ° C. 36 mg of product are obtained, m.p. 210-212 ° C.

NMR (CDC1 ₃₎ ppm

0.88 (t): CH ₃ -CH ₂ ; 1.02 (d) -l, 15 (d) -l, 25 (d) -l, 31 (d) -l, 39 (d): the groups CH ₃ -CH; 1,331.51: 6 and 12 Me; 2.27 (s): N (Me) ₂ ; 2.45 (m): H '₃; 2.62 (m): H _g ; 2.70 (s): 6-OMe; 2.91 (m):

GRAM ⁺ bacterial strains

CH ₂ Ph; 3.08 (ql): H ₁₀ ; -3.15 (m): H ₄ ; 3.18 (dd): H '₂; -3.58 (m): H '_s; -3.58 and 3.77: OCH ₂ ; 3.87 (q): H ₂ ; 3.91 (s): H '; 4.25 (d): H ₃ ; 4.32 (d): H ',; 5.00 (d) -5.33 (d): NCH ₂ O; 5.05 (dd): H _I3 ; 7.13 to 7.30: phenyl, ether (-0.3 mol).

By working as indicated above, the following compound is obtained:

Example 4: 11,12-Dideoxy-3-de- ((2,6-dideoxy-3-C-methyl-3-O-methyl-a-L-ribohexopyranosyl) oxy) -6-O-methyl-3- oxo-12,11- (oxycarbonyl- (((2- (trimethylsilyl) ethoxy) methyl) imino)) erythromycin

M.P. Mp 141-143 ° C; R, = 0.38 (AcOEt TEA 95-5).

An example of a pharmaceutical composition

A composition is prepared that contains: Compound of Example 2 150 mg Excipient q, s, for 1 g Excipient Details: starch, talc, magnesium stearate

Pharmacological study of the compounds of the invention

Method of dilution in liquid medium

A series of tubes is prepared in which an equal amount of sterile culture medium is distributed. Increasing amounts of the test product are distributed into each tube, then a bacterial strain is inoculated into each tube. After 24 h incubation in a thermostat at 37 ° C, growth inhibition was determined by transillumination, which allowed the minimum inhibitory concentrations (SM ² ) expressed in pg / cm ³ to be determined.

The following results are obtained:

Compounds Example 2 Example 3 Staphylococcus aureus 01IUC4 0.08 0.04 Staphylococcus aureus 011G025I 0.08 0.15 Staphylococcus epidermidis 012G011I 0.08 0.08 Streptococcus pyogenes group A 02A1UC1 £ 0.02 £ 0.02 Streptococcus agalactiae group B 02B1HT1 £ 0.02 £ 0.02 Streptococcus faecalis group D 02D2UC1 £ 0.02 £ 0.04 Streptococcus faecium group D 02D3HT1 £ 0.02 £ 0.02

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Streptococcus sp group G O2G0GR5 £ 0.02 £ 0.02 Streptococcus mitis 02mitCBJ £ 0.02 £ 0.02 Streptococcus mitis 02mitGR16I £ 0.02 £ 0.02 Streptococcus agalactiae group B 02BISJ1 0.08 0.04 Streptococcus pneumoniae 032UC1 0.02 £ 0.02

Moreover, the compound of Example 1 showed interesting activity on the following Gram negative strains: Haemophilus influenzae 351HT3, 351B12, 351CA1 and 351GR6.

branch or ring containing up to 4 carbon atoms, optionally substituted by one

Claims (9)

Compounds of formula (I) (I) in which R is either an alkyl, alkenyl or alkynyl radical, linear, branched or ring containing up to 18 carbon atoms, optionally substituted by one or more substituents selected between halogen atoms, radicals O-alkyl, O-al-5-kenyl or O-alkynyl, S-alkyl, S-alkenyl or S-alkynyl, linear, branched or ring containing up to 12 carbon atoms, NO ₂ radicals C = N, radical: 4Q or more halogen atoms, or represents a radical (CH _{2) k} -Ar, where η is an integer from 0 to 6 and A represents an aryl or heteroaryl radical optionally substituted by one or more of the above substituents. Ζ means a hydrogen atom or an acyl radical residue containing up to 12 carbon atoms and their acid addition salts. Compounds of formula I according to claim 1, characterized in that Ζ represents a hydrogen atom. Compounds of formula I according to claim 1 or 2, characterized in that R is a radical (CH ₂ ) _n Ar, in which η is an integer from 1 to 4 and Ar represents an aryl or heteroaryl radical optionally substituted with one or more of the above substituents. Compounds of formula I according to claim 3, characterized in that Ar means phenyl optionally substituted. Compounds of formula I according to claim 3, characterized in that R represents the radicals Ν 'in which Ra and Rb equal or different denote a hydrogen atom, an alkyl radical, linear or branched, containing up to 4 carbon atoms, a radical: Rc / Si-Rd # f ⁵⁰ in which Rc, Rd and Rf are the same or different, denotes an alkyl radical, linear, optionally substituted. 6. A compound of general formula I, named 11,12-dideoxy-3-de- [(2,6-dideoxy-3-methyl-3-O-methyl-α-L-ribohexopyranosyl) oxy] -6-O-methyl-3-oxo-12,11 - [oxycarbonyl- [[[[2 [4- (3-pyridinyl) -1H-imidazol-1-yl] ethoxy] -methyl] imino] erythromycin, 11,12-dideoxy-3-de- [(2,6-dideoxy-3-methyl-3-O-methyl-a-L-ribohexopyranosyl) oxy] -6-O-methyl-3-oxo-12,11 - [oxycarbonyl- [[(2-phenylethoxy) methyl] imino] erythromycin. Use of a compound of formula I according to any one of claims 1 to 6 as a medicament. A pharmaceutical composition comprising at least one drug according to claim 7 as an active principle. 9. A process for the preparation of a compound of formula I, wherein the compound of formula wherein E represents a residue of an ether or enol ester and Z 'retains the above meaning, then reacts with a compound of formula Hal - CH ₂ OR (IV) in which Hal represents a halogen atom to give the corresponding compound of formula (II) in which Z 'means a carboxylic acid residue containing up to 12 carbon atoms, reacts with a means of blocking the ketone function of 3rd place in the form of an ether or enol ester to give a compound of formula (V) which is subjected, if desired, to the action of a ketone releasing agent in the 3rd place and / or interacting with a the release of 25 hydroxy group at the 2'-position to give a compound of the corresponding formula I.