SK83199A3 - Novel erythromycin derivatives, method of preparation and application as medicines - Google Patents

Abstract

The invention concerns compounds of formula (I) in which X represents a CH2 or NH group, R represents a (CH2)nAr, N-(CH2)nAr or N=CH(CH2)nAr radical, in which n represents a whole number ranging between 1 and 6 an Ar represents an aryl or heteroaryl, optionally substituted, the dotted lines representing an optional double bond in 2(3), and Y represents a hydrogen atom or an organic carboxylic acid radical containing up to 18 carbon atoms and their additive salts with acids. The compounds of formula (I) have antibiotic properties which enable their use as medicines.

Description

Erythromycin derivatives, process for their preparation and their use as medicaments

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

The invention relates to compounds of formula I

in. *

(I) wherein either A and B represent an OH group or B represents an OH group and A forms a double bond with the carbon carrying it and the carbon at the 10-position, or A and B together form a carbonate group, or A and B together form with the carbon atoms carrying them, the ring

wherein X represents a CH ₂ , NH or SO ₂ group,

R is (CH ₂ ) _n Ar, N- (CH ₂ ) _n Ar or N = CH (CH ₂ ) _n Ar wherein n is an integer between 1 and 6 and Ar is aryl or heteroaryl substituted when necessary by dashed lines representing an optional double bond at position 2 (3), and

Y represents a hydrogen atom or an organic carboxylic acid radical containing up to 18 carbon atoms, as well as their acid addition salts.

The aryl group may be phenyl or naphthyl.

The aryl group may also be a heterocyclic group substituted or unsubstituted with thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, thiadiazolyl, pyrazolyl or isopyrazolyl, pyridyl, pyrimidyl or pyridazinyl or pyrazinyl, or indolyl, benzofuranyl, benzoturanyl, benzoturanyl, benzoturanyl, benzoturanyl, benzoturanyl, benzoturanyl.

These aryl groups may contain at least one group selected from hydroxyl, halogen atoms, NO ₂ / NH ₂ or C = N, alkyl, alkenyl or alkynyl, O-alkyl, O-alkenyl or O-alkynyl, S-alkyl, S -alkenyl or s-alkynyl and N-alkyl, N-alkenyl or N-alkynyl containing up to 12 carbon atoms optionally substituted by at least one halogen atom, wherein R ^a and R ^{b are} identical or different, represent a hydrogen atom or an alkyl group containing up to 12 carbon atoms, group

-C-r 3 wherein R 6 represents an alkyl group

I!

containing up to 12 carbon atoms or aryl or heteroaryl, optionally substituted, aryl, O-aryl or S-aryl carboxyl or aryl, O-aryl or S-aryl heterocyclic group having 5 or 6 groups containing at least 1 heteroatom optionally substituted by at least one of the above of said substituents.

Preferred heterocycles include, but are not limited to

and heterocyclic groups disclosed in European Patent Application No. 487411, 596802, 676409 and 680967. These preferred heterocyclic groups may be substituted with at least one functional group.

Acid addition salts include salts formed with acetic, propionic, trifluoroacetic, malic, tartaric, methanesulfonic, benzenesulfonic, p-toluenesulfonic, and especially stearic, ethylsuccinic or laurylsulfonic acids.

In particular, the invention relates to compounds corresponding to formula I wherein X represents CH ₂ or NH, R represents (CH ₂ ) _n Ar, N- (CH ₂ ) _n Ar or N = CH (CH ₂ ) _n and R group wherein n represents an integer between 1 and 6 and Ar represents an aryl or heteroaryl group optionally substituted, the dotted lines represent an optional double bond at the 2 (3) position and Y represents a hydrogen atom or an organic carboxylic acid radical containing up to 18 carbon atoms as well as their addition salts with acids.

The invention especially relates to compounds of formula I wherein the dotted lines represent a double bond in 2 (3), those in which Y is H and those wherein R is (CH _{2) n} Ar group, n and Ar are as defined above .

The preferred compounds of the invention may be mentioned especially the compounds of formula I wherein R is (CH _{2) 3} Ar, (CH _{2) 4} Ar or (CH _{2) 5} Ar radical, in particular compounds in which Ar represents a group

FROM

N optionally substituted, or a group

optionally substituted, for example, compounds of formula I wherein Ar is a group

In particular, the invention relates to the compound of Example 1.

The products of formula I have a very good antibiotic activity against Gram positive bacteria such as staphylococci, streptococci and pneumococci.

The compounds of the invention can therefore be used as medicaments in the treatment of germ-sensitive infections and, in particular, in the treatment of staphylococcidiases such as staphylococcal septicemia, malignant facial or skin staphylococcidiasis, pyodermatitis, septic or septic ulcers, furunkle, carbunculus, eriphycoccases, phlegemones is original or influenza pharyngitis, bronchopneumonia, pulmonary supuration, streptococcidiasis such as acute pharyngitis, otitis, sinusitis, brucellosis, diphtheria, gonorrhea.

The products of the present invention are also active against infections caused by microorganisms such as Haemophilus influenzae, Rickettsie, Mycoplasma pneumoniae, Chlamydia, Legionella, Ureaplasma, Toxoplasma or microorganisms of the genus Mycobacterium.

The present invention also has, by its nature as medicaments and in particular as antibiotics, the products of formula I as defined above, as well as their addition salts with organic acids or inorganic acids, which are pharmaceutically acceptable.

In particular, the invention relates to medicaments and, in particular, to antibiotic medicaments, the products of Example 1 and pharmaceutically acceptable salts thereof.

The invention also relates to pharmaceutical compositions comprising, as an active principle, at least one medicament as defined above.

The compositions may be administered orally, rectally or parenterally, or topically by application to the skin and mucous membranes, but the oral route is the preferred route of administration.

They may be solid or liquid and may take the pharmaceutical forms commonly used in human medicine, for example, plain or coated tablets, capsules, granules, suppositories, injectables, ointments, creams and gels, which are prepared by conventional methods. The active base or bases may be incorporated therein with excipients commonly used in pharmaceutical compositions such as talk, acacia, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, fatty substances of animal or vegetable origin, paraffin derivatives, glycols, various wetting, dispersing or emulsifying agents and preservatives.

These compositions may also be in the form of a powder to be dissolved at the time of use in a suitable vehicle, for example pyrogen-free sterile water.

The dose administered varies according to the disorder to be treated, the subject, the route of administration and the product. For example, it may be between 50 mg and 30 mg per day orally for an adult for the product of Example 1.

The invention also relates to a process characterized in that the compound of formula II

wherein A and B are as previously defined, are treated with a cleavage agent of the glycosidic linkage to release the hydroxyl at the 3-position to give a compound of formula III

(III) blocking the hydroxyl at the 3-position in the form of the mesylate to give the compound of formula IV

(IV)

which is treated with a base to give a compound of formula V

(V) which is subjected, if necessary, to a hydroxyl cleavage agent at the 2 'position to give the corresponding compound of formula I.

In particular, the invention relates to a process for the preparation of a compound of formula I, characterized in that the compound of formula IIA

(HA) is treated with a glycosidic bond cleavage agent to release the hydroxyl at the 3-position to give a compound of formula IIIA

(IIIA)

Ao blocks the hydroxyl at the 3-position in the form of the mesylate to give the compound of formula IVA which is subjected to

(IVA) treatment with a base to give a compound of formula VA

(VA)

which is treated with carbonyldiimidazole to give a compound of formula VI

(VI)

(VII) which is treated with a compound of formula VII rxnh ₂ wherein R and X have their earlier meanings to give a compound of formula IA

(IA) releasing, if necessary, the hydroxyl at the 2 'position to give a compound of formula IB

(IB) which is subjected, if necessary, to a hydroxyl esterifying agent at the 2 'position and / or a double bond reducing agent at the 2 (3) position and / or to an acid to form a salt thereof.

The products of formula I used as starting products are known products which can be prepared as described by Baker et al. in J. Org. Chem. 1988, 53, 2340, 2345.

In a preferred embodiment of the invention, the hydrolysis of cladinose at the 3-position is carried out with concentrated hydrochloric acid, mesylation is performed with methanesulfonic acid or one of its derivatives, for example methanesulfonic anhydride, the base used during conversion of IV to V is diazabicycloundecen (or 1,8-diazabicyclo [5.4.0] undec-7-ene) or diazabicyclononene, or 2,6-lutidine or 2,4,6-collidine or tetramethylguanidine, the conversion of the compound of formula V to the compound of formula VI is carried out with carbonyldiimidazole, the reaction of the compound of formula IV with the compound of formula VII RXNH ₂ is carried out in the presence of a base, for example diazabicycloundecene such as DBU, or diazabicyclononene or 2,6-glutidine or 2,4,6-collidine or tetramethylguanidine.

The compounds obtained during the application of this process are novel products and themselves are the subject of the present invention.

The invention therefore has as its essence as regards the new chemical compounds the compounds of formulas III, IV, V and VI.

In particular, the invention, as far as new chemical products are concerned, are products whose preparation is given in the experimental section below.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

2,3-Didehydro-11,12-dideoxy-3-de [(2,6-dideoxy-3-C-methyl-

3-O-methyl-alpha-L-ribohexopyranosyl) oxy] -6-O-methyl-12,11 [oxycarbonyl [[4- [4- (3-pyridinyl) -1H-imidazol-1-yl] butyl] imino] ]] erythromycin

Grade A

Cyclic 11,12-carbonate-2'-acetate 3-O-de- (2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexopyranosyl) -6-O-methylerythro-

leucomycin ·

I i

A mixture of 17.9 g of cyclic 11,12-1 carbonate-2'-acetate-4- (phenylmethyl carbonate) 6-O-methylerythromycin and 360 ml of methanol is cooled to 5 ° C. 90 ml of concentrated hydrochloric acid solution are added. The temperature was allowed to rise to room temperature and the solution was allowed to stir for hours. The reaction medium is poured onto an ice-ammonia mixture, extracted with ethyl acetate, washed with water, dried and concentrated under reduced pressure. 11.62 g of product are isolated and crystallized in diethyl ether. The crystals are drained, washed and dried in vacuo at 70 ^e C give 70.83 g of the expected product, mp = 226-228 C. ^e

NMR-CDCl ₃ ppm

0.87 (t): CH ₃ -CO ₂ ; 0.95 (d) 4-Me; 1.11 (d) 8-Me; 1.19 (d):

10-Me; 1.23 (d) 2-Me; 1.27 (d): 5 '-Me; 1.28-1.49: 6 and 12-Me; 1.34 and 1.73: _CH2 in 4; 1.49 and 1.63: _CH2 in the 7; '1.59 and 1.90: _CH2 at position 14; 1.86 (d): 3-OH; 1.98 (dq): H ₄ ; 2.07 (s): OAc; 2.26 (s): N (Me) ₂ ; 2.58 (m): θ; 2.71 (m): H ₂ and H ₃ '; 2.92 (s): 6-OMe; 2.95 (q): _H10; 3.48 (m): H ₃ and H ₅ '; 3.70 (d): _H5; 4.58 (d): _Η Σ '; 4.75 (s): H _{] L} ; 4.75 (dd): H ₂ '; 5.13 (dd): H ₁₃ .

Grade B

Cyclic 11,12-carbonate-2'-acetate-3- (methanesulfonate) 3-O-de (2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexapyranosyl) -

6-0-methylerythromycin

Cool the mixture containing 9.20 g of the product obtained in Step A, 60 ml of methylene chloride and 7.9 g of DMAP to 10 ° C. 5.99 g of methanesulfonic anhydride are added. The reaction mixture was stirred at room temperature for 17 hours and 30 minutes. The reaction mixture was poured onto ice, extracted with methylene chloride, washed with water, then brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. 11.078 g of the expected product are isolated, m.p. = 194-196’C.

NMR CDCl ₃ ppm

0.89 (t): CH ₃ -CH ₂ ; 1.00 (d): 4-Me; 1.12 (d) 8-Me; 1.19 (d): 10-Me; 1.21 (d): 5-Me; 1.27 (d) 2-Me; 1.48-1.34: 6 and 12-Me; '1.48 and 1.57: _CH2 in the 7; 1.25 and 1.70: _CH2 in 4 '; 1.62 and 1.91: _CH2 at position 14; 2.02 (dq): _H4; 2.06 (s): OAc; 2.25 (s): N (Me) ₂ ; 2.63 (m): θ; 2.72 (m): H ₃ '; 2.93 (ql): _H10; 2.99: 6-OMe; 2.99 (mask.): _H2; 3.13 (s): OSO ₂ Me; 3.57 (m): H ₅ '; 4.01 (d, J = 5): H ₅ ; 4.50 (d): H +; 468 (sl): 1H _{: 1} ; 4.71 (dd): H ₂ '; 4.74 (d): _H3; 5.10 (dd): H ^ ₃ ·

Step C 1 -Acetate 11-deoxy-3-de ([2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexopyranosyl) oxy] -6-O-ethyl-2,3,10, 11-tetradehydroerytromycínu

A mixture of 9.56 g of the product obtained in Step B, 95 ml of acetone and 15.5 ml of DBU is maintained under reflux for 6 hours and 30 minutes. Pour the reaction mixture over ice-water. The precipitate was filtered, dissolved in ethyl acetate, dried over sodium sulfate and concentrated under reduced pressure. 5.45 g of the crude expected product is isolated and this is transferred into a paste using diethyl ether. Filter and dry at 70 ° C under vacuum. 2,781 g of the expected product is isolated.

mp = 156-158'C.

NMR CDCl ₃ ppm

1.02 (t): _{CH3 --CH2;} 1.14 (d): 4-Me; 1.23 (d) 8-Me; 1.27 (d): 5'Me; 1.30-1.34: 6 and 12-Me; 1.78-2.02-2.04: 2-Me-10-Me and 2'-EtOAc; 1.35 and 1.75: _CH2 in 4 '; 1.49 and 1.99; CH ₂ V 7; 1.62 and 1.83; _CH2 at position 14; 2.70: H ₃ 'and H ₄ ; 2.27 (s): N (Me) ₂ ; 3.01 (m): _H8; 3.07 (s) 6-OMe; 3.52 (m): H ₅ '; 3.70 (d): _H3; 4.44 (d): _Η Σ '; 4.76 (dd): H ₂ '; 4.81 (dd): H ₁₃ ; 6.28 (s, l) H _{i; l;} 7.01 (d): H ₃ .

t Grade D

2,3-Didehydro-11,12-dideoxy-3-de [(2,6-dideoxy-3-C-methyl-

3-O-methyl-alpha-L-ribohexapyranosyl) oxy] -6-O-methyl-12,11 [oxycarbonyl- [[4- [4- (3-pyridinyl) -1H-imidazol-1-yl] butyl] imino]] erythromycin

507 mg of the product obtained in step C, 6 ml of THF, 22.4 µl of DBU and 243 mg of CDI are mixed together. A solution is obtained which is added to a mixture of 345 mg of aminobutylimidazole-17 pyridine and 4 ml of methylene chloride. 1 drop of DBU was added and the reaction mixture was stirred at 0C for 8.5 days.

Add a little ethyl acetate to the reaction medium, allow the temperature to rise to room temperature, wash with water, ammonia water, then water. The aqueous phases are extracted with ethyl acetate, the organic phases are combined, dried over anhydrous sodium sulfate, then concentrated under reduced pressure. 694 mg of product are isolated and dissolved in 7 ml of methanol. The solution is kept under reflux and concentrated under reduced pressure. 639 mg of crude expected product is isolated and chromatographed on silica gel, eluting with 90:10 ethyl acetate / triethylamine.

292 mg of crystals were isolated and converted into a slurry with diethyl ether. The product obtained is drained, washed and dried at 50 DEG C. under reduced pressure. 170 mg of product are obtained, which is dissolved in ethyl acetate, washed with aqueous ammonia solution, dried over anhydrous sodium sulfate and concentrated. 140 mg of crystals were isolated and slurried in ethyl acetate, washed and dried under reduced pressure at 60 ° C. 94 mg of the expected product are obtained, m.p. = 196-198C.

NMR CDCl ₃ ppm

0.98 (t): _CH2-CH2; 1.01 (d): 10-Me; 1.15 (d) 8-Me; 1.25 (d): 5 '-Me; 1.28 (d): 4-Me; 1.30 and 1.48: 6 and 12-Me; 1.89 (bs): 2-Me; 2.27 (s): N _{(CH3) 2;} 2.47 (m): H ₃ '; 2,64 (m): θ; 2.76 (m): _H4; 2.76 (s): 6-OMe; 3.00 (q): _H10; 3.16 (dd): H ₂ '; 3.52: _H5; 3.60: _H5; 3.27: Η _1χ ; 3.52 (m), 4.04 (m): CH ₂ -NC = buy up .; 4.41 (d): H, t; 4.71 (dd): H ₁₃ ; 6.69 (d): H ₃ ; 7.27 (dm): H _5-8.10 (dt): H _4-8.45 (dd): H _g 9.01 (dd): H ₂ (pyridine); 7.40 (d) - 7.56 (d) (H imidazoles).

A variant of this preparation method according to the invention, the product of formula IV, that is, 2'-acetate 11-deoxy-3-de - [(2,6-dideoxy-

3-C-methyl-3-0-methyl-.alpha.-L-ribohexopyranosyl) oxy] -6-0-metyl18

2,3,10,11-tetrahydroerythromycin can be prepared as follows.

Grade A

3-O-de- (2,6-Dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexapyranosyl) -1-deoxy-6-O-methylerythromycin

A mixture of 5 g of 3-O-de- (2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexopyranosyl) -6-methylerythromycin, 85 cm ^{@ 1 of} ethyl acetate, 8 g of ethylene carbonate and 1.1 g of potassium carbonate and dried at 160C. Stirring is continued for 80 hours. Filter and evaporate under reduced pressure. 8.54 g of product are obtained, which is chromatographed on silica gel, eluting with 96: 4 ethyl acetate / triethylamine. 3.07 g of the expected product are obtained.

I

Grade B

2'-Acetate-3-O-de- (2,6-dideoxy-3-C-methyl-3-O-methyl-aifa-L-ribohexopyranosyl) -1-deoxy-6-O-methylerythromycin

Stir at room temperature for 1 night

1.0612 g of the product of Step A, 15 cm ^{3 of} ethyl acetate and 0.2 cm ^{3 of} acetic anhydride. 20 cm ^{3 of} water and 4 cm ^{3 of} ammonia are added. Extract with ethyl acetate, wash with water, dry and concentrate. 0.9426 g of the expected product is obtained.

Grade C

2'-Acetate-3- (methanesulfonate) 11-deoxy-3-O-de- (2,6-dideoxy-3C-methyl-3-O-methyl-alpha-2-ribohexopyranosyl) -6-O-methylerythromycin

The ^E 10 C was added 194 .mu.L of mesyl chloride to a solution of 600 mg of the product from Step B, 3 ^cm3 mety19 chloride and 404 .mu.L of pyridine. The temperature was allowed to rise to room temperature and stirring was continued for 8 hours. Pour on ice, extract with methylene chloride, wash with water, dry, filter and concentrate.

After chromatography and crystallization in ether, 0.675 g of the desired product is obtained.

Grade D

11-Deoxy-3-de - [(2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexopyranosyl) oxy] -6-O-methyl-2,3,10-acetate , 11-tetradehydroerytromycínu

100 mg of the product of the previous step, 225 microl of DBU and 6 ml of acetone are kept under reflux for 24 hours. Pour into water, extract with ethyl acetate, wash with water, dry, filter and concentrate under reduced pressure and chromatograph on silica gel eluting with 98: 2 ethyl acetate / triethylamine. 51 mg of the expected product are obtained.

An example of a pharmaceutical composition

Compositions containing:

the product of Example 1150 mg sufficient excipient for 1 g

Excipient details: starch, talk, calcium stearate

Pharmacological research of the products of the invention

Method utilizing dilution in a liquid medium

A series of tubes were prepared, each containing the same amount of sterile nutrient medium. An increasing amount of the product of interest was dispensed into each tube, then each tube was inoculated with a bacterial strain. After incubation for 24 hours in a thermostate at 37 ° C, growth inhibition by transillumination was detected, allowing the determination of the minimum inhibitory concentrations (MIC) expressed in micrograms / cm ³ .

The following results were obtained:

Strains of Gram-positive bacteria

Products Example 1

Staphylococcus aureus 011UC4 0.08 Staphylococcus epidermidis 012G011I 0.15 Streptococcus pyogenes Group A O2A1UC1 <0.02 Streptococcus agalactiae Group B 02B1HT1 <0.02 Streptococcus faecalis Group D 02D2UC1 <0HT Streptococcus fa3ium . Group G 02G0GR5 <0.02 Streptococcus mitis 02mitCB1 <0.02 Streptococcus mitis 02mitGR16I <0.02 Streptococcus agalactiae Group B 02B1SJ1 <0.08 Streptococcus pneumoniae 030ROIÍ <0.02

In addition, the product of Example 1 showed interesting activity with respect to the following strains of gram-negative bacteria:

Haemophilus influenzae 351HT3, 351CB12, 351CA1 and 351GR6.

Claims (16)

PATENT CLAIMS Compounds of formula I wherein either A and B are OH or B is OH and A forms a double bond with the carbon carrying it and the carbon at the 10-position, or A and B together form a carbonate group, or A and B together form with the carbon atoms carrying them a ring in which X represents a CH ₂ , NH or SO ₂ group, R is (CH ₂ ) _n Ar, N- (CH ₂ ) _n Ar or N = CH (CH ₂ ) _n Ar wherein n is an integer from 1 to 6 and Ar is aryl or heteroaryl, optionally substituted, intermittently the lines represent an optional double bond at the 2 (3) position, and Y represents a hydrogen atom or an organic carboxylic acid radical containing up to 18 carbon atoms, as well as their acid addition salts. Compounds of formula I according to claim 1, in which X represents a CH ₂ or NH group, R is (CH ₂ ) _n Ar, N- (CH ₂ ) _n Ar or N = CH (CH ₂ ) _n Ar wherein n is an integer from 1 to 6 and Ar is aryl or heteroaryl optionally substituted dashed lines represent an optional double bond at position 2 (3), and Y represents a hydrogen atom or an organic carboxylic acid radical containing up to 18 carbon atoms, as well as their acid addition salts. Compounds of formula I according to claims 1 or 2, wherein the dotted lines represent a double bond at position 2 (3). Compounds of formula I according to claim 1, 2 or 3, wherein Y represents a hydrogen atom. Compounds of formula I according to any one of claims 2 to 4, wherein R represents a (CH ₂ ) _n Ar group, wherein Ar is as defined in claim 1. Compounds of formula I according to any one of claims 2 to 5, wherein R represents a (CH ₂ ) ₃ Ar, (CH ₂ ) ₄ Ar or (CH ₂ ) ₅ Ar group. Compounds of formula I according to any one of claims 2 to 6, wherein Ar represents an optionally substituted group or an optionally substituted group. Compounds of formula I according to claim 7, wherein Ar represents a group Compounds of formula (I) according to claim 1 which are 2,3-didehydro-11,12-dideoxy-3-de [(2,6-dideoxy-3-C-methyl-3O-methyl-alpha-L-ribohexopyranosyl) oxy] -6-O-methyl-12, 11- [oxycarbonyl [[4- [4- (3-pyridinyl) -1H-imidazol-1-yl] butyl] imino]] erythromycin. Compounds of formula (I) according to any one of claims 1 to 8 as well as their pharmaceutically acceptable acid addition salts, as medicaments. A compound according to claim 9 as well as pharmaceutically acceptable acid addition salts thereof, as a medicament. Pharmaceutical compositions, characterized in that they contain at least one medicament according to claims 10 or 11 as an active base. 13. A process for the preparation of compounds of the formula I, characterized in that the compound of the formula II (II) In which A and B are as previously defined, they are treated with a cleavage agent of the glycosidic linkage to release the hydroxyl at the 3-position to give the compound of formula III (III), blocking the hydroxy at the 3-position as the mesylate to give the compound of the formula IV (IV) which is treated with a base to give a compound of formula V (V) which is subjected, if necessary, to a hydroxyl cleavage agent at the 2 'position to give the corresponding compound of formula I. 14. A process for the preparation of compounds of formula (I), characterized in that the compound of formula (IIA) (HA) is treated with a glycosidic bond cleavage agent to release the hydroxyl at position 3 to obtain a compound of formula (IIIA). 3 in the form of mesylate to give a compound of formula IVA (IVA) which is treated with a base to give a compound of formula VA (VA) which is treated with carbonyldiimidazole to give a compound of formula VI (VI) which is treated with a compound of formula VII rxnh ₂ (VII) wherein R and X have their earlier meaning to give a compound of formula IA (IA) is released, if necessary, hydroxy1 at the 2 'position, thereby to obtain a compound of formula IB (IB) OH which is subjected, if necessary, to a hydroxyl esterifying agent at the 2 'position and / or a double bond reducing agent at the 2 (3) position and / or to an acid to give a salt thereof. Compounds of formulas III, IV, V and VI according to claim 1 13 or 14 as new chemicals. Compounds according to claim 15 as novel chemicals which are cyclic 11,12-carbonate 2'-acetate 3- (methanesulfonate) 3-O-de (2,6-dideoxy-3-C-methyl-3-O- methyl-alpha and L-ribohexopyranosyl) 6-O-methylerythromycin, 11-deoxy-3-de - [(2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexopyranosyl) oxy] -6-O-methyl-2,3,10,11 acetate -tetrahydroerytromycínu.