SK283715B6 - Novel erythromycin derivatives, method for preparing them and their use as medicine - Google Patents

Abstract

The invention concerns compounds of formula (I) in which R represents an alkyl radical optionally substituted or (CH2)nAr, n representing a whole number ranging from 0 to 6 and Ar representing an aryl or heteroaryl radical optionally substituted, and Z represents a hydrogen atom or the radical of a carboxylic acid. The compounds of formula (I) have very interesting antibiotic properties.

Description

The present invention relates to erythromycin derivatives, a process and intermediates for their preparation, their use as medicaments and pharmaceutical compositions containing them.

BACKGROUND OF THE INVENTION

EP-A-680967 discloses erythromycin derivatives which are substituted at the 11 and 12 positions by a cyclic carbamate, the nitrogen atom being substituted by (CH ₂ ) _n -Ar, where n is 3, 4 or 5 and Ar is a heterocycle, for example | 4- (p-pyridyl) -1-H-imidazol-1-yl] - (CH ₂ ) ₂ -CH ₂ -CH ₂ -group.

EP-A-0487411 discloses, among other erythromycin derivatives, which are at positions 11 and 12 substituted cyclic carbamate, wherein the nitrogen is substituted with an alkyl or aralkyl group, e.g., phenyl (CH _{2) 2} CH ₂ CH ₂ or a group joining alkoxy.

EP-A-0596802 discloses among others erythromycin derivatives substituted at the 11 and 12 positions by a cyclic carbamate wherein the nitrogen atom is substituted by a (CH ₂ ) n -Ar 1 group, wherein Aij is a substituted carbocyclic or optionally substituted heterocyclic aryl group ; or X-Ar ₂ where X is an oxygen-interrupted alkyl group (among other options) and Ar ₂ is an optionally substituted heterocyclic or carbocyclic aryl group.

The present invention provides erythromycin derivatives which are substituted at the 11 and 12 positions by a cyclic carbamate wherein the nitrogen atom is substituted by a -CH ₂ -OR group which may be, inter alia, [4- (3-pyridinyl) -] - H-imidazole- 1-yl] - (CH ₂ ) ₂ -O-CH ₂ - or phenyl- (CH ₂ ) ₂ -O-CH ₂ -, and which are obtained by a synthesis process that differs from those suggested in the prior art. In addition, the compounds of the invention have antibiotic properties that are more interesting than those of the prior art compounds.

SUMMARY OF THE INVENTION

The present invention provides erythromycin derivatives of formula (D)

where

R represents either linear, branched or cyclic alkyl, alkenyl or alkynyl containing up to 18 carbon atoms, optionally substituted with at least one substituent being halogen, linear branched or cyclic O-alkyl, O-alkenyl or O-alkynyl, S-alkyl , S-alkenyl or S-alkynyl containing up to 12 carbon atoms, NO ₂ , C = N group, further groups

R ^a

wherein R ^a and R ^b , identical or differently represent a hydrogen atom, a linear or branched alkyl having up to 4 carbon atoms, the following groups

R ^c

wherein R ^c , R ^d and R ^f , identical or different, represent a linear branched or cyclic alkyl of up to 4 carbon atoms, optionally substituted with at least one halogen atom, or a (CH ₂ ) _n Ar group in which n represents an integer in the range from 0 to 6 and Ar represents aryl or heteroaryl, optionally substituted with at least one of said substituents,

Z represents a hydrogen atom or an acyl radical containing up to 12 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 such as thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, thiadiazolyl, pyrazolyl or isopyrazolyl, pyridyl, pyrimidyl, pyridazinyl or pyrazinyl, or also indolyl, benzofuranyl, benzothiazyl or benzothiazyl.

These aryl groups may contain at least one group selected from the group consisting of hydroxyl, halogen atoms, NH ₂ , NO ₂ , ON, alkyl, alkenyl or alkynyl, O-alkyl, O-alkenyl or O-alkynyl, S-alkyl, S-alkenyl or S-alkynyl, or N-alkyl, N-alkenyl or N-alkynyl. containing up to 12 carbon atoms optionally substituted by at least one halogen atom

R ^a

wherein R ^a and R ^{b are} identical or different, represent a hydrogen atom or an alkyl of up to 12 carbon atoms, a group

ABOUT

II

- C - R ³

Wherein R ³ represents alkyl of up to 12 carbon atoms or optionally substituted aryl or heteroaryl, carboxyl aryl, O-aryl or S-aryl, heterocyclic aryl, O-aryl or S-aryl of 5 or 6 members containing at least one heteroatom optionally substituted with at least one of the following substituents.

As a preferred heterocycle, the following may be mentioned:

N- 1 CXT υο 1 P b ³ % 1 CC Oó what C

and heterocyclic groups disclosed in European Patent Application 487411, 596802, 676409 and 680967. These preferred heterocyclic groups are capable of being substituted with one or more functional groups.

Hal preferably represents a fluorine, chlorine or bromine atom.

Among the acid addition salts, mention may be made of salts formed with the following acids: acetic, propionic, trifluoroacetic, malic, tartaric, methanesulfonic, benzenesulfonic, p-toluenesulfonic, and in particular stearic, ethylsuccinic or laurylsulfonic acid.

In particular, the present invention provides compounds of formula (I) wherein Z represents a hydrogen atom, compounds of formula (I) wherein R represents a (CH ₂ ) _n Ar group in which n represents an integer ranging from 1 to 4 and Ar represents an optionally substituted aryl or heteroaryl, and especially those in which Ar is optionally substituted phenyl, as well as those in which R represents an optionally substituted group

A very particular subject of the invention are the compounds whose preparation is given below in the experimental part, and in particular the products of embodiments 2 and 3.

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

The compounds of the invention can therefore be used as medicaments in infections caused by susceptible germs and in particular in staphylococci such as staphylococcal septicemia, malignant staphylococcus of the face or skin, pyodermatitis, septic or purulent wounds, ulcers, anthrax, erythelemias, erociples and erysipelgias, acute primary or influenza angina, bronchopneumonia, pulmonary supuration, streptococia such as acute angina, otitis, sinusitis, sleep, pneumococia such as pneumonia, bronchitis, brucellosis, diphtheria and gonococcal infection.

The products of the present invention are also effective against infections caused by germs such as Haemophiltus influenzae, Rickettsia, Mycoplasnia pneumoniae, Chlamydia, Legionella, Ureaplasma, Toxoplasma or Mycobacterium.

Accordingly, the present invention also provides, as medicaments and in particular antibiotic medicaments, the products of formula (I) as defined above, as well as their addition salts with pharmaceutically acceptable mineral or organic acids.

A particular object of the invention are, as medicaments and in particular antibiotic medicaments, the products of Examples 2 or 3 and pharmaceutically acceptable salts thereof.

The present invention also provides pharmaceutical compositions comprising at least one of the defined drugs as an active ingredient.

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

The compositions may be solid or liquid and may be presented in pharmaceutical forms commonly used in human medicine, such as, for example, plain or sugar-coated tablets, capsules, granules, suppositories, injectables, ointments, creams, gels. They can be prepared by conventional methods.

The active ingredient (s) may be incorporated with excipients commonly used in these pharmaceutical compositions such as talk, acacia, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles,

286 fatty substances of animal or vegetable origin, paraffin derivatives, glycols, various wetting, dispersing or emulsifying agents and preservatives.

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

The agent to be administered is variable according to the patient's disease to be treated, the mode of administration and the product contemplated. For example, it may be included between 50 mg and 300 mg per day in an adult oral route for the product of Example 2.

The invention also provides a process for the preparation of compounds of formula (1), characterized in that the compound of formula (11)

wherein Z 'is a carboxylic acid residue of up to 12 carbon atoms, is treated with a ketone protecting group at the 3-position in the form of an enol ether or an enol ester to provide a compound of formula (III)

wherein E represents a residue of an enol ether or an enol ester and Z 'is as defined above, is treated with a compound of formula (IV)

Hal-CH ₂ OR (IV) wherein Hal represents a halogen atom to obtain the corresponding compound of formula (V)

which is subjected, if necessary, to a composition which 'releases the ketone group at the 3-position and / or a composition which releases the hydroxyl at the 2' position to give the corresponding compound of formula (I)

where R and Z retain their earlier meaning.

The products of formula (II) used as starting products are known products which can be prepared as described in EP 487411 or WO 9321199.

As the protecting agent of the ketone group at the 3-position in the form of an enol ether, the halomethyl ether may in particular be a chloromethyl ether, such as MEM-chloride or 2-methoxyethoxy chloride, or SEM-chloride, or 2- (trimethylsilyjetoxymethyl chloride). benzyloxymethyl ether (BOM) may also be used, wherein Hal preferably represents a chlorine atom, Z 'preferably represents an acetyl group or a means for releasing the ketone group at the 3-position, the release of the hydroxyl at the 2-position is performed by methanolysis.

The compounds of formulas (III) and (V) used in the preparation process are novel and are themselves subject to the present invention.

DETAILED DESCRIPTION OF THE INVENTION

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

Grade A

2,3-didehydro-11,12-dideoxy-3-0-de [(2,6-dideoxy-3-C-methyl-3-0-methyl-.alpha.-L-ribo-hexopyranosyl) -6-0-methyl- 11,12 (iminokarbonyloxy) -3-O - [[(2-trimethylsilyl) ethoxy] methyl] erythromycin 2'-acetate

Solution containing 6 ml DMF, 0.654 g 11,12-dideoxy-3-de [(2,6-dideoxy-3-C-methyl-alpha-L-ribohexopyranosyl) oxy] -6-O-methyl-3-oxo- 11,12- (Iminocarbonyloxy) erythromycin-2'-acetate and 0.57 g of sodium hydride at 50% oil concentration are stirred for 10 minutes. The reaction mixture was heated to 40 ° C. After cooling to -5 ° C, 0.177 microliter of CISEM in 5 ml of DMF is introduced dropwise. Stirring is performed at 0 ° C for 30 minutes (pH 9).

The medium is poured onto ice, then extracted with ethyl acetate, washed with water, dried, filtered and concentrated. 0.785 g of product is obtained, which is dissolved in isopropyl ether.

Crystallization is initiated, followed by separation, washing and drying at 70 ° C. The desired product is obtained by melting at 100 ° C.

NMR CDCl 3 ppm possible structure:

0.07 (s): Si (Me) ₃ ; 0.87 (t): CH ₃ -CH ₂ ; J, 03: _CH2 -Si; 1.10 (d) - 1.12 (d) - 1.14 (d) - 1.24 (d) CH ₃ ; 1.24 (s) - 1.43 (s): 6 and 12 CH ₃ ; 1.95 (s): 2-Me; 2.08 (s): OAc; 2.27 (s): N (Me) 2; 2.47 (m): _H8; 2.68 (m): H- ₃ ; 2.82 (s): 6-OMe; 3.04 (q): _H1o ; 3.31 (dq): _H4; 3.48 (m): H- ₅ ; 3.73 (d, J = 2.5): _H5; 3.80 to 3.92: _OCH2; 3.89 (s): H _n ; 4.69 (d): H1 _; 4.78 (dd): _H2; 4.99 (d) - 5.04, (d) OCH ₂ O; 5.29 (dd): H ₁₃ .

Grade B

12,1 1-dideoxy-3-de [(2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexapyranosyl) oxy-6-O-methyl-3-oxo-11 12- (oxycarbonyl [[methoxymethyl)] imino] erythromycin

0.150 g of a mixture containing 0.150 g of the product of step 11 is dissolved in 1.5 ml of DMF.

The reaction mixture was cooled to + 10 ° C and 14 mg of sodium hydride at 50% oil concentration was added. The reaction mixture was cooled to 0 ° C and 26 µL of MEM-chloride in solution in 0.5 mL of DMF was introduced. Stirring is carried out for 25 minutes at 0 ° C, followed by pouring the mixture on ice, concentration, collection in ethyl acetate, washing with water, extraction with ethyl acetate, drying, filtration and concentration. The product is diluted with 4 ml of methanol.

The solution is refluxed for 2 hours, then returned to ambient temperature. Add 1 ml of a 6.5 M solution of hydrochloric acid in methanol. The methanol was evaporated, followed by collection in ethyl acetate, washing with ammonium hydroxide, dilution, extraction with ethyl acetate, drying, filtration and concentration. 0.11 g of product is obtained, which crystallizes. After purification, the crude desired product is obtained. MP: Mp = 238-240 ° C.

NMR CDCl3 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): 4 Me; 1.38 (d): 2 Me; 1.34 and 1.51: 0 and 12Me; J, 57, and 1.38 _CH2 at position 4; .1,60 and 1.84: _CH2 in position 7; J, 67 and 1.25: _CH2 in position 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): _H10; 3.12 (m): H ₄ ; 3.18 (dd): H- ₂ ; 3.36 (s): OMe; 3.47: OH; 3.86 (q): _H2; 3.87 (s): H1; 4.24 (d): H '; 4.93 (d) - 5.27 (d): H ₂ NCH; 5.05 (dd): H ₁₃ .

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

Grade A

2,3-didehydro-1,1,12-dideoxy-3-O-de (2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexapyranosyl) -6-O-methyl- 12,11- [oxycarbonyl [[(2-bromoethoxy) methyl] imino]] - 3-O - [[2- (trimethylsilyl) ethoxy] methyl] erythromycin-2'-acetate

0.278 g of sodium hydride at 50% concentration in oil was stirred in 2 ml of THF. The mixture was cooled to 0 ° C and 510 mg of the product of Step A of Example 1 in solution in 8 mL of THF was added. The reaction medium is returned to room temperature and introduced into 100 microliters of ClCH ₂ OCH ₂ CH ₂ Br in solution in 4 mL of THF. The reaction medium is returned to 0 ° C, poured onto ice, extracted with ethyl acetate, washed with brine, dried, filtered and concentrated. 0.709 g of the expected product is obtained.

Grade B

2,3-Didehydro-11,12-dideoxy-3-O-de (2,6-dideoxy-3TC-methyl-3-O-methyl-alpha-L-ribohexopyranosyl) -6-O-methyl-12,11 - [ oxycarbonyl [[2- [4- (3-pyridinyl) -1H-imidazol-1-yl] ethoxy] methyl] imino]] - 3-O - [[2- (trimethylsilyl) ethoxy] methyl] erythromycin-2 'acetate

A solution of 3 ml of DMF and 0.377 g of de-4- (3-pyridinyl) -1H-imidazole is introduced into a solution containing 2 ml of DMF and 0.162 g of sodium hydride at 50% concentration in oil. Stirring is carried out for 1/4 hour and 0.709 g of the product from Step A, Example 2 are introduced in solution in 8 ml of DMF. Stir 3 hours at ambient temperature and for 15 minutes at 60 ° C. The reaction medium is poured onto ice, extracted with ethyl acetate, washed with brine, then water, dried, filtered and concentrated. 0.644 g of product is obtained.

Grade C

11,12-Dideoxy-3-de [(2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexopyranosyl) oxy] -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 of Step B and 8 ml of methanol is stirred for 48 hours at ambient temperature, then 0.565 g of the product obtained is diluted in 5 ml of ethyl acetate. The reaction medium is cooled to 0 DEG C. and 2.5 ml of a 2.0N hydrochloric acid / methanol solution are introduced and the whole is returned to ambient temperature. Stirring is maintained at ambient temperature for 1 hour.

The solvent was evaporated, followed by dilution with water, pouring into saturated aqueous sodium carbonate solution, extraction with ethyl acetate, washing with water, drying, filtration and concentration. To give 0.508 g of an oil which was chromatographed on silica gel using CH ₂ Cl ₂ / MeOH (93-7), and CH ₂ Cl ₂ / MeOH / NH ₄ OH (93-7-0,5). The homogeneous fractions were concentrated by thin layer chromatography followed by collection in ethyl acetate, washing with ammonium hydroxide, dilution, extraction with ethyl acetate and water, drying, filtration and concentration. 66 mg of the expected product are obtained. CDCl ₃ ppm

0.85 (t): _{CH3 --CH2;} 1.00 (d) - 1.15 (d) - 1.25 (d) 1.31 (H) - 1.40 (d): the _CH3 --CH; 1.34 and 1.51: 6 and 12 Me; 2.26 (s): N (Me) 2; 2.44 (m): H- ₄ ; 2.60 (m): _H8; 2.68 (s): 6-OMe; 3.03 (m): H ₄ and H _lo; 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 _n ; 3.83 (q): _H2; 4.24 (d): _H5; 4.31 (d): H '; 4.96 (dd): H ₁₃ ; 4.99 (d) - 5.37 (d): H ₂ NCH; 7.36 (d) - 7.54 (d): H imidazole; 7.30 (ddd): _H5; 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-alpha-L-ribohexapyranosyl) oxy] -6-O-methyl-3-oxo-12, 11- [oxycarbonyl - [[(2-phenylethoxy) methyl] imino]] erythromycin

Grade A

2,3-Didehydro-1,1,12-dideoxy-3-O-de (2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexapyranosyl) -6-O-methyl-12; 11- [oxycarbonyl [[(2-phenylethoxy) methyl] imino]] - 3-O - [[2- (trimethylsilyl-ethoxy) methyl] erythromycin-2'-acatate mg sodium hydride at 50% concentration in oil is added at 10 ° C to a solution containing 2 ml DMF and 203 mg of the product obtained in Step A, Example 1.

Stirring is carried out for 15 minutes, followed by cooling to -5 ° C, and 46 microliters of chloromethylphenyl ether in solution in 0.5 ml of DMF is added.

The DMF was evaporated, followed by collection in ethyl acetate, washing with water, drying, filtration and concentration. 0.277 g of the expected product is obtained.

Step B 1,12-Dideoxy-3-de [(2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexapyranosyl) oxy] -6-O-methyl-3-oxo 12,1- [oxycarbonyl - [[(2-phenylethoxy) methyl] imino]] erythromycin

0.227 g of the product obtained in Step A is introduced in one portion into 0.33 ml of a 0.19N solution of hydrochloric acid in ethyl acetate cooled to + 5 ° C. The reaction medium is returned to ambient temperature and stirring is performed for 2 hours. After cooling to 0 ° C, water is added, the pH is adjusted to 9-10 with concentrated ammonium hydroxide solution, followed by extraction with ethyl acetate, washing with water, drying, filtration and concentration. 0.201 g of product is obtained, which is diluted in 2.5 ml of methanol. The whole is brought to reflux for 2 hours 30 minutes. Methanol was evaporated to give 0.88 mg of product which was chromatographed on silica gel eluting with methylene chloride-isopropanol-ammonium hydroxide (95-5-0.5). After concentration, the residue is taken up in methylene chloride, a drop of concentrated ammonium hydroxide is added, followed by stirring, drying, filtration and concentration. 55 mg of product are obtained, which product is separated and dried at 80 ° C. 36 mg of product are obtained.

MP: MP 210-212 ° C.

NMR CDCl ₃ ppm

0.88 (t): CH ₃ -CH ₂ ; 1.02 (d) - 1.15 (d) - 1.25 (d) - 1.31 (d) - 1.39 (d): the _CH3 --CH; 1.33-1.51: 6 and 12 Me; 2.27 (s): N (Me) ₂ ; 2.45 (m): H '; 2.62 (m): H _s ; 2.70 (s): 6-OMe; 2.91 (m): _CH2 lake; 3.08 (ql): _H10 ; -3.15 (m): H ₄ ; 3.18 (dd) H '₂; -3.58 (m): H- ₅ ; -3.58 and 3.77: OCH ₂ ; 3.87 (q): _H2; 3.91 (s): H _n ; 4.25 (d): _H5; 4.32 (d): H1; 5.00 (d) - 5.33 (d): NCH ₂ O; 5.05 (dd): H ₁₃ ; 7.13 to, 7.30: phenyl, ether (-0.3 mol).

Working up as described gave the following product.

Example 4

11,12-dideoxy-3-de [(2,6-dideoxy-3-C-methyl-3-0-methyl-.alpha.-L-ribohexopyranosyl) oxy] -6-0-methyl-3-oxo-12, 11 - [oxycarbonyl - [[(2- (trimethylsilyl) ethoxy] methyl] imino]] erythromycin

T. t. = 141-143 ° C, R f = 0.38 (AcOEt-TEA 95-5).

An example of a pharmaceutical composition

A composition containing the product of Example 21 of 150 mg excipient s.q.f. was prepared. 1 g excipient component: starch, talk, magnesium stearate. Pharmacological Study of Products of the Invention Dilution method in liquid medium

A series of tubes are prepared in which an equal amount of sterile nutrient medium is distributed. Spread an increasing amount of the product to be studied in each tube, then inoculate each tube with a bacterial strain. After incubation for 24 hours in a thermostate at 37 ° C, growth inhibition is evaluated by transilumination, which makes it possible to determine the minimum inhibitory concentrations (MIC), expressed in micrograms / cm ³ .

The following results were obtained.

Gram-positive bacterial strains Products Exam.2 Príkl.3 Staphyloaoccus aureus 011UC4 0.08 0.04 Staphylococcus aureus 011GO25I 0.08 0 _r 15 Staphyloaoccus epictermldis 012GO11I 0.08 0.08 Streptococcus pyogenes group A £ 0.02 £ 0.02 02A1UC1 Streptococcus agalactiae group B SO, 02 <0.02 02B1HT1 Streptococcus faecalis group D SO, 02 ÍO, 04 02D2UC1 Streptococcus faecium group D S0,02 £ 0.02 02D3HT1 Streptococcus sp. group G £ 0.02 £ 0.02 O2GOGR5 Streptococcus mitis 02mitCB1 SO, 02 £ 0.02 Streptococcus mi tis 02mitGR16I £ 0.02 £ 0.02 Streptococcus agalactiae group B 0.08 0.04 O2B1SJ1 Streptococcus pneumoniae O32UC1 0.02 £ 0.02

In addition, the product of Example 1 had useful activity on the following gram-negative bacterial strains: Haemophilus influenzae 351HT3, 351CB12, 351CA1 and 351GR6.

Claims (10)

An erythromycin derivative of formula (I) wherein R represents either linear, branched or cyclic alkyl, alkenyl or alkynyl containing up to 18 carbon atoms, optionally substituted with at least one substituent which is halogen, linear branched or cyclic δ-alkyl, O-alkenyl or O-alkynyl, S-alkyl , S-alkenyl or S-alkynyl containing up to 12 carbon atoms, NO ₂ , CsN group, further groups wherein R ^a and R ^b , identical or differently represent hydrogen, linear or branched alkyl containing up to 4 carbon atoms, the following groups R ^c / The --R ³ · ^d wherein R ^c, R ^d and R ^f, the same or different, represent a linear branched or cyclic alkyl having up to 4 carbon atoms, optionally substituted with at least one halogen atom, or (CH _{2) n} Ar radical, in wherein n is an integer ranging from 0 to 6 and Ar is aryl or heteroaryl, optionally substituted with at least one of said substituents, Z represents a hydrogen atom or an acyl radical containing up to 12 carbon atoms, as well as their acid addition salts. The erythromycin derivatives of formula (I) according to claim 1, wherein Z represents a hydrogen atom. The erythromycin derivatives of formula (I) according to claim 1 or 2, wherein R represents a (CH ₂ ) _n Ar group in which n represents an integer ranging from 1 to 4 and Ar represents an optionally substituted aryl or heteroaryl. The erythromycin derivatives of formula (I) according to claim 3, wherein Ar is optionally substituted phenyl. The erythromycin derivatives of formula (I) according to claim 3, wherein R represents an optionally substituted group or wherein Z 'represents a carboxylic acid residue containing up to 12 carbon atoms, is treated with a 3-position ketone protecting agent in the form of an enol ether or an enol ester to obtained a compound of formula (III) wherein E represents a residue of an enol ether or enol ester and Z 'retains its stated meaning which is treated with a compound of formula (IV) Hal-CH 3 OR (IV) wherein Hal represents a halogen atom to obtain the corresponding compound of formula (V) 6. The erythromycin derivatives of formula (I) which are 11,12-didexy-3-de [(2,6-dideoxy-3-C-methyl-3-O-methyl-.alpha.-L-ribohexopyranosyl) oxy] -6-O-methyl-3-oxo-12, 11- [oxycarbonyl - [[(2- [4- (3-pyridinyl) -1H-imidazol-1-yl] ethoxy) methyl] imino]] erythromycin, 1,1,12-dideoxy-3-de [(2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexopyranosyl) oxy] -6-O-methyl-3-oxo-12 1,1- [oxycarbonyl - [[(2-phenylethoxy) methyl] imino]] erythromycin. Erythromycin derivatives of formula (I) as defined in any one of claims 1 to 6 for use as medicaments. Pharmaceutical compositions comprising at least one erythromycin derivative of formula (I) according to claim 7 as an active ingredient. A process for the preparation of erythromycin derivatives of formula (I), characterized in that the compound of formula (H), which, if necessary, is treated with a agent which releases the ketone group at the 3-position and / or with a agent that releases hydroxyl at the 2 'position to give the corresponding compound of formula (I) wherein R and Z retain their stated meaning. Compounds of formulas (III) and (V) as defined in claim 9 as intermediates for the preparation of erythromycin derivatives of formula (I) according to claim 1.