AP997A

AP997A - Novel erythromycin derivatives, method for preparing them and their use as medicine.

Info

Publication number: AP997A
Application number: APAP/P/1999/001513A
Authority: AP
Inventors: Jean-Michael Auger; Constantin Agouridas; Jean-Francis Chantot (Deceased); Alexis Denis
Original assignee: Aventis Pharma Sa
Priority date: 1996-12-12
Filing date: 1997-12-01
Publication date: 2001-08-09
Also published as: ATE217008T1; JP4363666B2; ES2174323T3; NO992859D0; BG63124B1; CZ208299A3; NO314040B1; KR100490074B1; CA2273985C; FR2757168B1; CZ292403B6; HUP0001180A3; SK75099A3; FR2757168A1; YU25699A; WO1998025942A1; KR20000057517A; ZA9711101B; AU5487798A; GEP20012518B

Abstract

A subject of the invention is the compounds of formula in .which R represents an optionally substituted alkyl or (CH2)nAr radical, n representing an integer ranging from 0 to 6 and Ar representing an optionally substituted aryl or heteroaryl radical, and Z represents a hydrogen atom or the remainder of a carboxylic acid. The compounds of formula (I) have useful antibiotic properties.

Description

Novel Erythromycin Derivatives, Method for Preparing them and their use as Medicine

The present invention relates to new derivatives of erythromycin, their preparation process and their use as medicaments.

A subject of the invention is the compounds of formula (I) :

AP/P/ 9 9/01513 in which R represents:

either a linear, branched or cyclic alkyl, alkenyl or alkynyl 25 radical, containing up to 18 carbon atoms, optionally substituted by one or more substituents chosen from halogen atoms, linear, branched or cyclic O-alkyl, O-alkenyl or 0alkynyl, S-alkyl, S-alkenyl or S-alkynyl radicals, containing up to 12 carbon atoms, the NO₂ radicals, the ON radicals, the following radicals:

Ra /

N \

Rb in which Ra and Rb, identical or different, represent a hydrogen atom, a linear or branched alkyl radical containing up to 4 carbon atoms, the following radicals:

AP 00997

Rc /

Si-Rd \

Rf in which Rc, Rd and Rf, identical or different, represent a linear, branched or cyclic alkyl radical containing up to 4 carbon atoms, optionally substituted by one or more halogen atoms, or a (CH₂)_nAr radical in which n represents an integer ranging from 0. to 6 and Ar represents an aryl or heteroaryl radical, optionally substituted by one or more of the j substituents indicated above,

Z represents a hydrogen atom or the remainder of an acyl radical, containing up to 12 carbon atoms, as well as their addition salts with acids.

The aryl radical can be a phenyl or naphthyl radical.

The aryl radical can also be a heterocyclic radical substituted or not such as the thienyl, furyl, pyrolyl, thiazolyl, oxazolyl, imidazolyl, thiadiazolyl, pyrazolyl or isopyrazolyl radical, a pyridyl, pyrimidyl, pyridazinyl or pyrazinyl radical, or also an indolyl benzofuranyl, benzothiazyl or guinolinyl radical.

These aryl radicals can contain one or more groups • 25 chosen from the group constituted by hydroxyl radical, halogen atoms, NH₂ radical, NO₂ radical, C=N radical, alkyl, alkenyl or alkynyl, 0-alkyl, 0-alkenyl or 0-alkynyl, Salkyl, S-alkenyl or S-alkynyl and N-alkyl, N-alkenyl or Nalkynyl radicals, containing up to 12 carbon atoms optionally substituted by one or more halogen' atoms, the Ra

N radical, Ra and Rb identical or different \

Rb

AP/P/ 9 9/01513 representing a hydrogen atom or an alkyl radical containing up to 12 carbon atoms, the

AP 00997

Ο

II

-C-R₃ radical, R^ representing an alkyl radical containing up to 12 carbon atoms, or an optionally substituted aryl or .5 heteroaryl radical, the carboxylic aryl, 0-aryl or S-aryl radicals, the heterocyclic aryl, O-aryl or S-aryl radicals with 5 or 6 members containing one or more heteroatoms, optionally substituted by one or more of the substituents mentioned below.

As preferred heterocycle, the following can be mentioned amongst others:

AP/P/ 9 9/01513

AP 00997

AP/P/ 99/01513 and the heterocyclic radicals envisaged in the European Patent Applications 487411, 596802, 676409 and 680967.

These

AP 00997 preferred heterocyclic radicals being able to be substituted by one or more functional groups.

Hal preferably represents a fluorine, chlorine or bromine atom.

Among the addition salts with acids, there can be mentioned the salts formed with the following acids: acetic, propionic, trifluoroacetic, malic, tartaric, methanesulphonic, benzenesulphonic, p-toluenesulphonic, and in particular stearic, .ethylsuccinic or laurylsulphonic acids.

In particular^-a subject of the invention is the compounds of formula (I) in which Z represents a hydrogen atom, the compounds of formula (I) in which R represents a (CH₂)_nAr radical in which n represents an integer ranging from 1 to 4 and Ar represents an optionally substituted aryl or heteroaryl radical, and in particular those in which Ar is an optionally substituted phenyl radical, as well as those in which R represents an optionally substituted radical:

AP/P/ 9 9/01513

A quite particular subject of the invention is the compounds the preparation of which is given hereafter in the experimental part and in particular the products of Examples 2 and 3.

The products of general formula (I) have a very good antibiotic activity on gram ® bacteria such as staphylococci, streptococci, pneumococci.

The compounds of the invention can therefore be used as medicaments in the treatment of infections caused by susceptible germs and in particular, in that of staphylococcia, such as staphylococcal septicemias, malignant staphylococcia of the face or skin, pyodermatitis, septic or suppurating wounds, boils, anthrax, phlegmons, erysipelas and acne, staphylococcia such as acute primary or post-influenzal

AP Ο Ο 9 9 7 e

angina, bronchopneumonia, pulmonary suppuration, streptococcia such as acute angina, otitis, sinusitis, scarlet fever, pneumococcia such as pneumonia, bronchitis; brucellosis, diphtheria, gonococcal infection.

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

Therefore.a subject of the present invention is also, 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 more particular subject of the invention is, as medicaments and, in particular antibiotic medicaments, the products of Examples 2 or 3 and their pharmaceutically acceptable salts.

A subject of the invention is also the pharmaceutical compositions containing at least one of the medicaments defined above as active ingredient.

These compositions can be administered by buccal, rectal, parenteral route or by local route as a topical application on the skin and mucous membranes, but the preferred administration route is the buccal route.

These can be solid or liquid and be presented in the pharmaceutical forms currently used in human medicine, such as for example, plain or sugar-coated tablets, capsules, granules, suppositories, injectable preparations, ointments, creams, gels; they are prepared according to the usual methods. The active ingredient or ingredients can be incorporated with excipients usually employed in these pharmaceutical compositions, such as talc, gum arabic, 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, preservatives.

These compositions can also be presented in the form of

AP/P/ 9 9/01513

AP 00997 a powder intended to be dissolved extemporaneously in an appropriate vehicle, for example, apyrogenic, sterile water. ,

The administered dose is variable according to the illness treated, the patient in question, the administration route and the product considered. It can be, for example, comprised between 50 mg and 300 mg per day by oral route, for an adult for the product of Example 2.

A subject of the invention is also a preparation process for the compound of formula (I), characterized in that a compound of formula (II):

AP/P/ 99/01513 in which Z' represents the remainder of a carboxylic acid containing up to 12 carbon atoms, is subjected to the action of a blocking agent of the ketone function in position 3 in the form of an enol ether or an enol ester in order to obtain the compound of formula (III):

0 9 9 7

in which E represents the remainder of an enol ether or of an enol ester and Z' retains its previous meaning, is subjected to the action of a compound of formula (IV):

Hal-CH₂OR (IV) in which Hal represents a halogen atom, in order to obtain the corresponding compound of formula (V) :

AP/P/ 9 9/01513

AP 00997 which is subjected, if desired, to the action of an agent which releases the ketone function in position 3 and/or to the action of an agent which releases the hydroxyl in position 2', in order to obtain the corresponding compound of formula (I):

in which R and Z retain their previous meaning.

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

As a blocking agent of the ketone function in position

3, in the form of an enol ether, a halogenomethylether can be used and in particular a chioromethethylether, such as for example MEM chloride, or 2-methoxy ethoxy methyl chloride or also SEM chloride or 2-(trimethylsilyl) ethoxymethyl chloride; as a blocking agent of the ketone function in the form of an enol ester, benzyloxymethylether (BOM) can also be used,

- Hal preferably represents a chlorine atom,

- Z' preferably represents an acetyl radical or

- the agent for releasing the ketone function in position 3,

- the release of the hydroxyl in position 2’ is carried out by methanolysis.

The compounds of formulae (III) and (V) used during the

AP/P/ 9 9/01513

AP Ο Ο 9 9 7 preparation process are new and in themselves are a subject of the present invention.

The following examples illustrate the invention without however limiting it.

EXAMPLE 1; 11,12-dideoxy-3-de[(2,6-dideoxy-3-C-methyl-3-0methyl-alpha-L-ribo-hexopyranosyl) oxy]-6-0-methyl-3-oxo12.11- [oxycarbonyl [[(2-methoxyethoxy)methyl]imino]] erythromycin

Stage A: 2,3-didehydro-ll,12-dideoxy-3-O-de[(2,6-dideoxy-3-C10 methyl-3-O-methyl-alpha-L-ribo-hexopyranosyl)-6-0-methyl11.12- (iminocarbonyloxy)-3-0-[[(2-trimethylsilyl) ethoxy] methyl]-erythromycin 2'-acetate

A solution containing 6 ml of DMF, 0.654 g of 11,12dideoxy-3-de [ (2,6-dideoxy-3-C-methyl-alpha-L-ribo15 hexopyranosyl) oxy]-6-0-methyl-3-oxo-11,12-(iminocarbonyloxy) -erythromycin 2'-acetate and 0.57 g of sodium hydride at 50% in oil is agitated for 10 minutes. The reaction mixture is heated to 40°C. After cooling down to -5°C, 0.177 μΐ of C1SEM in 5 ml of DMF is introduced dropwise. Agitation is carried out at 0°C for 30 minutes (pH 9). The medium is poured on ice, following by extracting with ethyl acetate, washing with water, drying, filtering and concentrating.

0.785 g of product is obtained which is dissolved in isopropyl ether. Crystallization is initiated, followed by separating, washing and drying at 70°C. The sought product is obtained melting at 100°C.

NMR CDCl-j ppm

Possible structure

0.07 (s): Si(Me)₃; 0.87 (t): CH₃-CH₂; _1.03: CH₂-Si; 1.10 (d)-1.12 (d)-1.14 (d)-1.24 (d) CH₃; 1.24 (s)-1.43 (s): 6 and 12 CH₃; 1.95 (s): 2-Me; 2.08 (s): OAc; 2.27 (s): N(Me)2; 2.47 (m) : Hg; 2.68 (m) : H'₃; 2.82 (s) : 6-OMe; 3.04 (q) : H₁₀; 3.31 (dq) : H₄; 3.48 (m) : H'₅; 3.73 (d, J = 2.5): H₅; 3.80-3.92: OCH₂; 3.89 (s) : H^; 4.69 (d) : ; 4.78 (dd) : H₂; 4.99 (d) 35 5.04 (d) : OCH₂O; 5.29 (dd) : H₁₃.

Stage B: 12,ll-dideoxy-3-de[(2,6-dideoxy-3-C-methyl-3-0methyl-alpha-L-ribo-hexopyranosyl) oxy]-6-O-methyl-3-oxoIl, 12- (oxycarbonyl [ [ (methoxymethyl) ] imino] erythromycin

AP/P/ 99/01513

AP 00997

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

The reaction mixture is cooled down to +10°C and 14 mg of sodium hydride at 50% in oil is added. The reaction

5. mixture is cooled down to 0°C and 2 6 μ.1 of MEM chloride in solution in 0.5 ml of DMF is introduced. Agitation is carried out for 25 minutes at 0°C, followed by pouring the mixture onto ice, concentrating, taking up in ethyl acetate, washing with water, extracting with ethyl acetate, drying, filtering and concentrating. A product is obtained which is diluted in 4 ml of -methanol. The solution is taken to reflux i for 2 hours, then' returned to ambient temperature. 1 ml of a

6.5 M solution of hydrochloric acid in methanol is added.

The methanol is evaporated off, followed by taking up in ethyl acetate, washing with ammonium hydroxide, diluting, extracting with ethyl acetate, drying, filtering and concentrating. 0.11 g of product is obtained which crystallizes. After purification, the crude sought product is obtained. M.p. = 238_240°C.

NMR CDCI3 ppm

0.88 (t): CH₃-CH₂; 1.03 (d): 10-Me; 1.16 (d): 8Me; 1.25 (d): 5’Me; 1.32 (d): 4Me; 1.38 (d): 2Me; 1.34 and 1.51: 0 and

12Me; ~1.57 and 1.38 CH₂ in position 14; _1.60 and 1.84:

CH₂ in position 7; _1.67 and 1.25: CH₂ in position 4'; 2.27 (s): N(Me)₂; 2.44 (m): H'₃; 2.62 (m): Hg; 2.67 (s): 6-OMe;

£15 10/66 /d/dV

3.09 (ql): H₁₀; 3.12	(m) :	H₄;	3.18	(dd): H'₂;	3.36 (s): OMe;
„3.47: OH; 3.86 (q) :	H₂;	3.87	(s) :	H_i;l; 4.24	(d): H'_i; 4.93
(d)-5.27 (d): NCH₂O;	5.05	(dd)	: H₁₃	•

EXAMPLE 2: 11,12-dideoxy-3-de[(2,6-dideoxy-3-C-methyl-3-030 methyl-alpha-L-ribo-hexopyranosyl) oxy]-6-O-methyl-3-oxo12,11-[oxycarbonyl [[[2-[4-(3-pyridinyl)-IH-imidazol-1-yl] ethoxy] methyl] imino]]-erythromycin

Stage A: 2,3-didehydro-11,12-dideoxy-3-O-de (2,6-dideoxy-3-Cmethy1- 3 -0-methyl-alpha-L-ribo-hexopyranosyl) - 6 -0-methyl35 12,11- [oxycarbonyl [[(2-bromoethoxy) methyl] imino]]-3-0-[[2(trimethylsilyl) ethoxy] methyl]-erythromycin 2'-acetate

0.278 g of sodium hydride at 50% in oil is agitated in 2 ml of THF. The mixture is cooled down to 0°C and 510 mg of

AP 00997

Stage A of Example 1, in solution in 8 ml of THF is added.

The reaction medium is returned to ambient temperature and 100 μΐ of ClCH₂OCH₂CH₂Br in solution in 4 ml of THF is introduced. The reaction medium is returned to 0°C, poured onto ice, extracted with ethyl acetate, washed with salt water, dried, filtered and concentrated. 0.709 g of sought product is obtained.

Stage B: 2,3-didehydro-11,12-dideoxy-3-O-de (2,6-dideoxy-3-Cme thy 1 - 3 - 0-methyl - alpha - L - r ibo - hexopyranosyl )-6- 0-methyl 10 12,11-[oxycarbony [[[2-[4-(3-pyridinyl)-IH-imidazoi-1-yl] ethoxy] methyl] imino] ] -3-0-[[2-(trimethylsilyl) ethoxy] methyl]-erythromycin 2’-acetate

A solution of 3 ml of DMF and 0.377 g de 4-(3pyridinyl)-IH-imidazole are introduced into a solution containing 2 ml of DMF and 0.162 g of sodium hydride at 50% in oil. Agitation is carried out for a quarter of an hour and 0.709 g of the product of Stage A of Example 2 in solution in 8 ml of DMF is introduced. Agitation is carried out for 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 salt water then with water, dried, filtered and concentrated. 0.644 g of product is obtained. Stage C: 11,12-dideoxy-3-de[(2,6-dideoxy-3-C-methyl-3-0methyl-alpha-L-ribo-hexopyranosyl) oxy] -6-0-methyl-3-oxo25 12,11-[oxycarbonyl [[[2-[4-(3-pyridinyl)-IH-imidazoi-1-yl] ethoxy] methyl] imino] ]-erythromycin

A solution containing 0.644 g of the product of Stage B and 8 ml of methanol are agitated for 48 hours at ambient temperature, then 0.565 g of the product obtained is diluted

0 in 5 ml of ethyl acetate. The reaction medium is cooled down to 0°C and 2.5 ml of a 2. IN solution of hydrochloric acid in methanol is introduced and the whole is returned to ambient temperature. Agitation is maintained at ambient temperature for 1 hour. The solvents are evaporated off, followed by diluting with water, pouring into a saturated aqueous solution of sodium carbonate extracting with ethyl acetate washing with water, drying, filtering and concentrating.

0.508 g of an oil is obtained which is chromatographed on

AP/P/ 9 9/01513

ΑΡ ΟΟ997 silica CH₂Cl₂/MeOH (93-7) then CH₂Cl₂/MeOH/NH₄OH (93-7-0.5). The homogeneous fractions are concentrated by TLC, followed by taking up in ethyl acetate, washing with ammonium hydroxide, diluting, extracting with ethyl acetate, with water, drying, filtering and concentrating. 66 mg of sought product is obtained.

NMR CDC1₂ ppm

0.85 (t): CH₃-CH₂; 1.00 (d) - 1.15 (d) - 1.25 (d) 1.31 (d) 1.40 (d) 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): Η_θ; 2.68 (s): 6-OMe; 3.03 (m): H₄ and H₁₀; 3,18 (dd): H’₂; 3.55 (m): H'₅; 3.76 (s) 3.92 (m) -4.38 (m) : OCH₂CH₂N; 3.87 (s) : H_11;· 3.83 (q) : H₂; 4.24 (d) : H₅; 4.31 (d) : H'-jj 4.96 (dd) : H₁₃; 4.99 (d) - 5.37 (d): NCH₂O. 7.36 (d) - 7.54 (d): H imidazole; 7.30 (ddd): H₅;

8.08 (dt): H₄ - 8.45 (dd): Hg - 8.95 (ddd): pyridine.

EXAMPLE 3: 11,12 -dideoxy-3 -de[(2,6 -dideoxy-3 -C-methyl-3-0methyl-alpha-L-ribo-hexopyranosyl) oxy]-6-O-methyl-3-oxo12.11- [oxycarbonyl [[(2-phenylethoxy) methyl] imino]]erythromycin

Stage A: 2,3-didehydro-ll,12-dideoxy-3-0-de(2,6-dideoxy-3-Cmethyl-3-0-methyl-alpha-L-ribo-hexopyranosyl)-6-O-methyl12.11- [oxycarbony [[ (2-phenylethoxy) methyl] imino]]-3-0-[[2(trimethylsilyl) ethoxy] methyl]-erythromycin 2'-acetate mg of sodium hydride at 50% in oil is added at 10°C to a solution containing 2 ml of DMF and 203 mg of the product obtained in Stage A of Example 1.

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

The DMF is evaporated off, followed by taking up in ethyl acetate, washing with water, drying, filtering and concentrating. 0.277 g of sought product is obtained.

Stage B: 11,12-dideoxy-3-de[(2,6-dideoxy-3-C-methyl-3-0methyl-alpha-L-ribo-hexopyranosyl) oxy]-6-O-methyl-3-oxo35 12,11-[oxycarbonyl [[(2-phenylethoxy) methyl] imino]]erythromycin

0.227 g of the product obtained in Stage A is introduced in one go into 0.33 ml of a 0.19N solution of hydrochloric

AP/P/ 9 9/01513

AP 00997 acid in ethyl acetate cooled down to +5°C. The reaction medium is returned to ambient temperature and agitation is carried out for 2 hours. After cooling down to 0°C, water is added, the pH is adjusted to 9-10 with a concentrated solution of ammonium hydroxide, followed by extracting with ethyl acetate, washing with water, drying, filtering and concentrating. 0.201 g.of product is obtained which is diluted in 2.5 ml of methanol. The whole is taken to reflux for 2 hours 3 0 minutes'. The methanol is evaporated off and

0.188 mg of product is obtained which is chromatographed on silica eluting with a 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 agitation, drying, filtering and concentrating. 55 mg of product is obtained which is separated and dried at 80°C. 36 mg of product is obtained. M.p. = 210 _ 212°C.

NMR CDCl^ ppm

0.88 (t): CH₃-CH₂; 1.02 (d) - 1.15 (d) - 1.25 (d) - 1.31 (d)

- 1.39 (d): CH₃-CH; 1.33-1.51: 6 and 12 Me; 2.27 (s): N(Me)₂; 2.45 (m) : H'₃; 2.62 (m) : Hg; 2.70 (s) : 6-OMe; 2.91 (m) : CH₂4>; 3.08 (ql) : H₁₀; ~3.15 (m) : H₄; 3.18 (dd) : H'₂; _3.58 (m) : H'₅; _3.58 and 3.77: OCH₂; 3.87 (q) : H₂; 3.91 (s) : H·^; 4.25 (d): H₅; 4.32 (d): H’_i; 5.00 (d) - 5.33 (d): NCH₂O; 5.05 (dd) : H₁₃; 7.13 to 7.30: phenyl, ether (_0.3 mole).

By operating as indicated above, the following product was prepared:

EXAMPLE 4 ; 11,12 - dideoxy-3 - de ( (2,6-dideoxy-3 -C-methyl-3 -0methyl-alpha-L-ribohexopyranosyl) oxy) 6-0-methyl-3-oxo30 12,11-(oxycarbonyl (((2-(trimethylsilyl) ethoxy) methyl) imino)) erythromycin.

M.p. = 141-143°C; Rf = 0.38 (AcOEt-TEA 95-5).

EXAMPLE OF PHARMACEUTICAL COMPOSITION

Compounds were prepared containing:

AP/P/ «9/01513

Product of Example 2........................ 150 mg

Excipient s.q.f............................. 1 g

Detail of excipient: starch, talc, magnesium stearate

AP 00997

PHARMACOLOGICAL STUDY OF THE PRODUCTS OF THE INVENTION

Method of dilutions in liquid medium

A series of tubes are prepared in which the same quantity of sterile nutritive medium is distributed. Increasing quantities of the product to be studied are distributed into each tube; then each tube is sown with a bacterial strain. After incubation for twenty-four hours in a heating chamber at 37°C, the growth inhibition is evaluated by transillumination, which allows the minimal inhibitory I concentrations (M.I.C.) to be determined, expressed in micrograms/cm3 .

The following results were obtained:

GRAM+ bacterial strains
Products	Ex. 2	Ex. 3
Staphylococcus aureus 011UC4	0,08	0,04
Staphylococcus aureus 011G025I	0,08	0,15
Staphylococcus epidermidis 012GO11I	0,08	0,08
Streptococcus pyogenes group A	£ 0,02	£ 0,02
02A1UC1
Streptococcus agalactiae group B	£ 0,02	£ 0,02
02B1HT1
Streptococcus faecalis group D	s 0,02	£ 0,04
02D2UC1
Streptococcus faecium group D	s 0,02	£ 0,02
02D3HT1
Streptococcus sp group G	s' 0,02	£ 0,02
02G0GR5
Streptococcus mitis 02mitCBl	s 0,02	s 0,02
Streptococcus mitis 02mitGR16I	s 0,02	£ 0,02
Streptococcus agalactiae group B	0,08	0,04
02B1SJ1
Streptococcus pneumoniae 032UC1	0,02	£ 0,02

AP/P/ 9 9/01513

AP 00997

In addition, the product of Example 1 has shown a useful activity on the following gram- bacterial strains:

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

Claims

1) The compounds of formula (I):

(I!

in which R represents either a linear, branched or cyclic 20 alkyl, alkenyl or alkynyl radical, containing up to 18 carbon atoms, optionally substituted by one or more substituents chosen from halogen atoms, linear, branched or cyclic 0alkyl, O-alkenyl or O-alkynyl, S-alkyl, S-alkenyl or Salkynyl radicals, containing up to 12 carbon atoms, the NC>2

25 radicals, the C=N radicals, the following radicals:

AP/P/ 9 9/01513

Ra

Rc /

Si-Rd \

Rf

AP 00997 *

in which Rc, Rd and Rf, identical or different, represent a linear, branched or cyclic alkyl radical containing up to 4 carbon atoms, optionally substituted by one or more halogen atoms,

5 or a (CH₂)_nAr radical in which n represents an integer ranging from 0 to 6 and Ar represents an aryl or heteroaryl radical, optionally substituted by one or more of the substituents indicated above,

Z represents a hydrogen atom or the remainder of an acyl

10 radical, containing up to 12 carbon atoms, as well as their addition salts with acids.

2) The compounds -of formula (I) as defined in claim 1, in which Z represents a hydrogen atom.

3) The compounds of formula (I) as defined in claim 1 or 2,

15 in which R represents a (CH₂)_nAr radical in which n represents an integer ranging from 1 to 4 and Ar represents an optionally substituted aryl or heteroaryl radical.

4) The compounds of formula (I) defined in claim 3 in which Ar is an optionally substituted phenyl radical.

20

5) The compounds of formula (I) defined in claim 3 in which R represents an optionally substituted

AP/P/ 9 9/01513 radical.

6) The compounds of formula (I) the names of which follow:

30 - ll,12-dideoxy-3-de[(2,6-dideoxy-3-C-methyl-3-0-methylalphaL-ribo-hexopyranosyl) oxy]-6-0-methyl-3-oxo-12,11[oxycarbonyl [[ (2-[4-(3-pyridinyl)-IH-imidazol-l-yl] ethoxy) methyl] imino]]-erythromycin.

- 11,12-dideoxy-3-de[(2,6-dideoxy-3-C-methyl-3-O-methylalpha35 L-ribo-hexopyranosyl) oxy]-6-0-methyl-3-oxo-12,11[oxycarbonyl [[(2-phenylethoxy) methyl] imino]]-erythromycin.

7) As medicaments, the compounds of formula (I) defined in any one of claims 1 to 6.

AP 00997

8) Pharmaceutical compositions containing at least one medicament according to claim 7 as active ingredient.

9) Preparation process for the compounds of formula (I) , characterized in that a compound of formula (II):

in which Z' represents the remainder of a carboxylic acid 20 containing up to 12 carbon atoms, is subjected to the action of a blocking agent of the ketone function in position 3 in the form of an enol ether or an enol ester in order to obtain the compound of formula (III):

AP/P/ 9 9/01513 (III)

AP 00997 in which E represents the remainder of an enol ether or of an’ enol ester and Z' retains its previous meaning·, is subjected to the action of a compound of formula (IV):

5 Hal-CH₂OR (IV) in which Hal represents a halogen atom, in order to obtain the corresponding compound of formula (V):

£ I S Λ 0 / 6 6 /d/dV which is subjected, if desired, to the action of an agent 25 which releases the ketone function in position 3 and/or to the action of an agent which releases the hydroxyl in position 2’, in order to obtain the corresponding compound of formula (I) :

AP 00997

15 in which R and Z retain their previous meaning.

10) As new chemical products, the compounds of formulae (III) and (V) defined in claim 9.