FR2707088A1 - New derivatives of erythromycin, process for their preparation and their application as medicinal products - Google Patents

Abstract

The subject of the invention is the compounds of the formula (I): in which, . either R represents a (CH2)nAr1 radical, n representing an integer between 1 and 6, Ar1 representing: - either a substituted carbocyclic aryl radical, - or an optionally substituted 5- or 6-membered heterocyclic aryl radical, . or R represents an XAr2 radical, in which X is an alkyl radical interrupted by O, S, . Ar2 being an optionally substituted aryl or heteroaryl radical . Z representing a hydrogen atom or the residue of an acid. The compounds of the formula (I) have valuable antibiotic properties.

Description

The present invention relates to new erythromycin derivatives,

  their preparation process and their application

  tion as drugs. The subject of the invention is the compounds of formula (I): 1I (1 oo oz in which either R represents a radical (CH2) n Ar ,, n representing an integer between 1 and 6, Ar1 representing: - either a carbocyclic aryl radical substituted by one or more radicals chosen from the group consisting of free, salified, esterified or amidified carboxyl radicals, hydroxyl radicals, halogen atoms, NO2.25 radicals CEN radicals, alkyl radicals , 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, possibly containing up to 12 carbon atoms substituted by one or more halogen atoms, the radical

R1

  N, R1 and R2 identical or different, representing

2R1 R2

  R2 a hydrogen atom or an alkyl radical containing up to 12 carbon atoms, the radical

0

  -C-R3, R3 representing an alkyl radical containing

  up to 12 carbon atoms, or an aryl or hetero radical

  optionally substituted aryl, aryl, O-aryl radicals

  or S-aryl carboxylic or aryl, O-aryl or hetero S-aryl-

  5- or 6-membered rocyclics comprising one or more heteroatoms, optionally substituted by one or more of the substituents mentioned above, 5 - either a 5 or 6-membered heterocyclic aryl radical, comprising one or more heteroatoms, optionally

  substituted by one or more of the substituents mentioned above ,. or R represents a radical X Ar2 in which X represents

  has an alkyl radical containing up to 6 carbon atoms, interrupted by an oxygen atom, a sulfur atom, an SO group, an S02 group, a C = O group, a 0 0 II II group -NH -C- or -C-NH-, and Ar2 represents an aryl or heteroaryl radical defined above unsubstituted or substituted by one or more of the possible substituents of

  Ar1 and Z represents a hydrogen atom or the remainder of a carboxylic acid containing up to 18 carbon atoms as well as the addition salts with acids of the compounds of formula (I).

  As examples of addition salts of the present derivatives with mineral or organic acids, mention may be made of the salts formed with acetic, propionic, trifluoroacetic, maleic, tartaric, methanesulfonic, benzene sulfonic, p-toluenesulfonic or hydrochloric acids. , hydrobromic, hydroiodic, sulfuric, phosphoric and especially stearic, ethylsuccinic or laurylsulfuric acids. In the definition of the substituents: - the carbocyclic aryl radical is preferably the radical

phenyl or naphthyl.

  The heterocyclic aryl radical comprises one or more heteroatoms preferably chosen from oxygen, sulfur

and nitrogen.

  - the heterocyclic 5-membered aryl radical is preferably—

  The thienyl, furyl, pyrolyl, thiazolyl, oxazolyl, imidazolyl, thiadiazolyl, pyrazolyl or iso- radical

  xazolyl, - the 6-membered heterocyclic radical is preferably a pyridyl, pyrimidinyl, pyridazinyl or pyrazinyl radical, - the 5 or 6-membered heterocyclic aryl radical can be

  also a condensed aryl radical such as for example the indolyl, benzofurannyl, benzothiazyl or quinino radical

  leinyl, or the remainder of a purine base such as adenine, the alkyl, alkenyl or alkynyl radical is preferably a methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, terbutyl, decyl or dodecyl, vinyl radical , allyl, ethynyl, propynyl, propargyl, cyclobutyl, cyclopentyl or cyclohexyl, - the halogen is preferably fluorine or chlorine, or bromine, - the alkyl radical substituted by a halogen atom is preferably a CHC12 radical, CHBr2, CHF2, CC13, CBr3, CF3,

CH2CF3, CH2CH2CC13, CH2CH2CF3,

  the residue of carboxylic acid is preferably the residue acetyl, propionyl, butyryl, isobutyryl, n-valeryl, isovaleryl, tert-valeryl and pivalyl. Among the preferred compounds of the invention, there may be mentioned: a) the compounds of formula (I) in which Z represents a hydrogen atom, b) the compounds of formula (I) in which R represents the radical (CH2) 4 Ar1, Ar1 being defined as above, c) the compounds of formula (I) in which Ar1 represents a phenyl radical substituted by one of the radicals listed above, for example those in which Ar1 represents a phenyl radical substituted by one or several halogen atoms, in particular one or more chlorine atoms, and very particularly the compounds of formula (I) in which Ar1 represents a 4-chlorophenyl radical, or alternatively those in which Ar1 represents a phenyl radical substituted by one or more O-alkyl radicals containing up to 4 carbon atoms, in particular those in which Ar135 represents a phenyl radical substituted by one or more methoxy radicals and very particularly the compounds s of formula (I) in which Ar1 represents a 4-methoxyphenyl radical, d) the compounds of formula (I) in which Ar1 represents

  an optionally substituted 5-membered heterocyclic aryl radical, for example an optionally substituted thienyl radical and more especially the unsubstituted thienyl radical.

  Among the preferred compounds of the invention, mention may be made of the compounds of formula (I) in which Ar1 represents

  attempt an optionally substituted biphenyl radical. By biphenyl means a radical: -o-o 30or The invention particularly relates to the compounds of formula (I) in which Ar1 represents a radical:

possibly substituted.

  Among the compounds of the invention, mention may also be made of

  the compounds of formula (I) in which R represents an XlAr2 radical in which X1 represents an alkyl radical containing up to 6 carbon atoms interrupted by

O

  a radical -NH-C-, and Ar2 retains its previous meaning-

  toothed. Among these compounds, special mention may be made of the compounds in which R represents a radical:

C H2 -CH2-N H-C

  The phenyl radical possibly being optionally substituted by one or more of the substituents indicated above.

  A subject of the invention is very particularly the compounds of formula (I), the preparation of which is given below and very particularly the compounds of Examples 1, 2, 3, 4,

11 or 15.

  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 with susceptible germs and in particular, in that of staphylococcal diseases, such as septicemia with staphylococci, malignant staphylococcal diseases of the face or pyoderma, septic or suppurative wounds, boils, anthrax, phlegmons, erysipelas and acne, staphylococcal diseases such as acute or post-acute angina influenza, bronchopneumonia,

  pulmonary suppuration, streptococcal disease such as acute angina, ear infections, sinusitis, scarlet fever, pneumococcal disease such as pneumonia, bronchitis; brucellosis, diphtheria, gonococcal disease.

  The products of the present invention are also active against infections caused by germs such as

  Haemophilus influenzae, Rickettsies, Mycoplasma pneumoniae, 30 Chlamydia, Legionella, Ureaplasma, Toxoplasma or to germs of the genus Mycobacterium, Listeria, Menincocci and Campylo-

  bacter. The present invention therefore also has for its object,

  as drugs and, in particular, antibiotic drugs

  ques, the products of formula (I) as defined above, as well as their addition salts with mineral acids or

  pharmaceutically acceptable organic.

  A more particular subject of the invention is, as medicaments and, in particular antibiotic medicaments, the preferred products of formula (I) defined above, namely the products of Examples 1, 2, 3, 4, 11 and 15, as well as their pharmaceutically acceptable salts. 5 The invention also relates to pharmaceutical compositions containing as active ingredient at least one

  of the drugs defined above. These compositions can be administered by buccal, rectal, parenteral route or by local route in application.

  topically on the skin and mucous membranes, but the preferred route of administration is the oral route.

  They can be solid or liquid and come in the pharmaceutical forms commonly used in medicine.

  human cine, such as, for example, simple or coated tablets, capsules, granules, suppositories, injections, ointments, creams, gels; they are prepared according to the usual methods. The active ingredient (s) can be incorporated therein into excipients usually employed in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, butter of

  cocoa, aqueous or non-aqueous vehicles, fatty substances of animal or vegetable origin, paraffinic derivatives, glycols, various wetting agents, dispersants or emulsifiers, preservatives.

  These compositions can also be in the form of a powder intended to be dissolved extemporaneously in an appropriate vehicle, for example pyrogen-free sterile water.30 The dose administered is variable depending on the condition treated, the subject in question, the route of administration and the

  product considered. It can be, for example, between 50 mg and 300 mg per day orally, in adults for the product of Example 2.35 The invention also relates to a process for preparing

  ration of the compounds of formula (I), characterized in that a compound of formula (II) is subjected: o HO t It ^ ........ ii ......... llllllllllll ( II) o oI lit oz in which Z represents the remainder of a carboxylic acid containing up to 18 carbon atoms, to the action of an agent capable of selectively activating the hydroxyl at 11 to obtain the compound of formula (III): oo HOOR Ill

251 4 4 (III)

  OZ in which R1 represents the remainder of an easy grouping-

  ment cleavable, which is subjected to the action of a base, to obtain the compound of formula (IV): ", .l'1lh Iil 11 ..... (IV) ll OOZ oz then submits the compound of formula (IV): - either to the action of a compound of formula (V):

R-N = C = O (V)

  in which R has the meaning defined above, to obtain the compound of formula (VI): 20 R s oH <à0

N 0

O ...... (VI)

d 0 l0

- #

  O Z which cyclizes either spontaneously by heating, or which is subjected to the action of a cyclization agent to obtain the compound of formula (IA) corresponding: T

O

  N 1j .. V Ih, ............. ll IlAllll _, "|| Nt |||| (IA)

O (10) Z

  oz in which Z does not represent a hydrogen atom, - either to the action of carbonyldiimidazole to obtain the compound of formula (VII): O s, J ......., ti: tUlllllllllllll [

N O

O. (VII)

I

OZ

  then to the action of a compound of formula (VIII):

RNH2 (VIII)

  in which R has the meaning as defined above

  above, to obtain the compound of formula (VI) defined above

  demment which spontaneously cyclizes by heating or which is subjected to the action of a cyclization agent to obtain the corresponding compound of formula (IA), then submits if necessary, the compound of formula (IA) to the action of an agent for releasing the hydroxyl function at 2 ′ and / or, where appropriate, the action of an acid to form the salt thereof. In a preferred embodiment of the method of the invention:

  the agent capable of selectively activating hydroxyl at 11 is a sulfonic anhydride such as methane anhydride;

  sulfonic, sulfonic paratoluene or sulfonic trifluoromethane,

  - the base used to create a double bond 10 (11) is a diazabicycloundecene, for example DBU (or 1.8 diazabi-

  cyclo [5-4-0] undec-7-ene), or diazabicyclononene, or 2,6-lutidine, or 2,4,6-collidine or tetramethylguanidine, - the reaction between the compound of formula (V ) and the compound of formula (VI) takes place in the presence of a base, such as pyridine, triethylamine, morpholine, N-methyl mor-20 pholine, - the reaction of the compound of formula (IV) with carbonyl - diimidazole takes place in the presence of a base such as sodium hydride, or triethylamine, or a sodium or potassium carbonate or an acid carbonate, or in the absence of a base in methylene chloride or tetrahydrofuran,

  the reaction of the compound of formula (VII) with the compound RNH2 takes place in a solvent such as for example aceto-

  nitrile, dimethylformamide or also tetrahydrofuran, dimethoxy ethane or dimethyl sulfoxide, 30 - the hydrolysis of the ester function in 2 ′ is carried out using methanol or aqueous hydrochloric acid,

  - salification is carried out using acids according to conventional methods.

  The compounds of formula (II) used as starting materials are generally known products and can be prepared as indicated in the application for

European patent 0 487 411.

  The compounds of formula RN = C = O and RNH2 are products

generally known.

  The compounds of formula RNH2 can for example be prepared according to the methods described in J. Med. Chem (1982) vol. 25 p. 947 et seq., Tetrahedron Letters vol. 32, 5 n 14, p. 1699-1702, (1991); J. Org. Chem. 54 (18) 4298, 301 (1989); J. Org. Chem. 28 (101) 2589 91 (1963 or German patent 3,406,416 .; J. Org. Chem. 6-895-901 (1941) or Synth. Commun 17 (14) 1741-8 (1987. Certain products of formula ( VIII) are new products and are in themselves an object of the present invention, their preparation is given below in the experimental section The following products are new products and are in themselves an object of the present invention : - 4- (2-thienyl) butylamine, - 4- (1,1'biphenyl) butylamine, - 4- (4-methylphenyl) butylamine, - 4- (2,4-dimethylphenyl) butylamine, - 4- (2,4,6-trimethylphenyl) butylamine,

  - 4- (2-methoxyphenyl) butylamine.

  The invention naturally extends to the products obtained during the implementation of the process of the invention, namely

  the products of formulas (III), (IV), (VI) and (VII) and very particularly to the compound of formula (IV) whose preparation is given below in the experimental part and to compound 2'- OH correspondent.

  The following examples illustrate the invention. EXAMPLE i: 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 ((4- (4-chlorophenyl) butyl) imino)) erythromycin STAGE A: 2'-acetate 3-de ((2,6-dideoxy 3-C-methyl 3-O- methyl alpha-Lribohexopyranosyl) oxy) 6-O-methyl 11-O-35 (methylsulfonyl) 3-oxo erythromycin Introduced with stirring and under nitrogen atmosphere

  17 g 3-de-2'-acetate ((2,6-dideoxy 3-C-methyl 3-O-methyl alpha-Lribohexopyranosyl) oxy) 6-O-methyl 3-oxo erythromy-

  cine in 100oo cm3 of pyridine. The mixture obtained is cooled to 10 C. 11.9 g of methane sulphonic anhydride are added. Leave to return to room temperature. Stirring is continued for 5 hours. The precipitate 5 obtained is filtered. It is concentrated, taken up in water and extracted with ethyl acetate. The organic phases are washed with water, dried,

  filters and concentrates. 20.9 g of crude desired product are thus obtained, which product is purified by salification with oxalic acid then release of the base with ammonia.

  15.16 g of the desired product are thus obtained

  (F = 210-212 C). STAGE B: 2'-11-deoxy acetate 10,11-didehydro 3de (2,6-

  dideoxy 3-C-methyl 3-O-methyl alpha-L-ribohexopyranosyl) oxy) 6-Omethyl 3-oxo erythromycin 8.26 g of product prepared in Stage A is introduced with stirring into 35 ml of acetone. Then 2.19 ml of DBU is added dropwise. Stirring is continued at room temperature for 20 hours. The reaction mixture is taken up with methylene chloride. The organic phases are washed with water, dried over sodium sulfate, filtered and concentrated. 10 g of product are obtained which is taken up in ether. It is filtered and washed with ethyl ether. 6.33 g of sought product is thus obtained (F = 230-232 C) .25 STAGE C: 2'-acetate of 11-deoxy 10,11-didehydro 3-de (2,6-dideoxy 3-C-methyl 3-O-methyl alpha-L-ribohexopyranosyl) oxy) 12-O - ((1H- imidazol-1-yl) carbonyl) 6-O-methyl 3-oxo erythromycin 96 mg of sodium hydride at 50% are introduced in oil in 15 ml of THF. The suspension obtained is cooled to 0 ° C. and a solution of 611 mg of product prepared in the preceding stage is introduced dropwise into 17 ml of THF. A solution of 486 mg of carbonyldiimidazole in 15 ml of THF is introduced at 0 ° C. Stirring is continued for 4 h 30. 35 The reaction mixture is allowed to return to room temperature, filtered and concentrated. The residue is taken up in ethyl acetate, washed with a sodium dihydrogen phosphate solution, extracted with ethyl acetate, dried, filtered and concentrated. 852 mg of sought product is obtained, which is used as it is in the following stage. STAGE D: 11,12-dideoxy 3'-acetate 3-de ((2,6-dideoxy 3-C- methyl 3-O-methyl alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 5 3-oxo 12.11- (oxycarbonyl ((4- (4-chlorophenyl) butyl) imino)) erythromycin To the 852 mg of product prepared in the preceding stage is added a solution containing 1.1 g of 4- (4-chlorophenyl)

  butylamine (prepared as indicated in J. Med. Chem. 198210 Vol. 25 no. 951), 3 ml of acetonitrile and 0.3 ml of demineralized water.

  The mixture is stirred for 4 hours at 55 C. The reaction medium is poured onto a solution of sodium dihydrogen phosphate, extracted

  with methylene chloride, wash with water, dry, filter and concentrate. 1.4 g of oil are obtained which is chromatographed on silica eluting with a methylene chloride mixture

  isopropanol (95-5). The homogeneous fractions are collected in TLC, filtered and concentrated. 0.44 g of an oil is obtained which is pasted in isopropyl ether, drained and dried at 20 70 C. This gives 0.262 g of the desired product.

  (F = 179-181 C). STAGE E: 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 ((4- (4-chlorophenyl) butyl) imino)) ery-

  thromycin A mixture of 0.23 g of product prepared in the preceding stage and 6 ml of methanol is kept under stirring. Stirring is continued at room temperature for 15 hours. The methanol is evaporated, chromatography on silica, eluting with an ethyl methanol-ammonium acetate mixture (9-1-0.01). We bring together the homogeneous phases in CCM,

  filters and concentrates. 0.14 g of oil is obtained which is pasted in isopropyl ether, drained and dried at 80 ° C. under reduced pressure. 0.094 g of product is obtained (F = 35 194-196 C). aD: +23 CHCl3 (1%).

  EXAMPLE 2: 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 ((4 (4-methoxyphenyl) butyl) imino))

  erythromycin STAGE A: 2'-11,12-dideoxy acetate 3-de ((2,6-dideoxy 3- C-

  methyl 3-0-methyl alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 5 3-oxo 12, 11- (oxycarbonyl ((4- (4-methoxyphenyl) butyl) imino)) erythromycin Operating as in Example 1, Stage D, from 0.8 g of 11'-deoxy-10,11-didehydro 3-de-acetate 3-de ((2,6-dideoxy 3-C-methyl 3-0-methyl alpha-L -ribohexopyranosyl) oxy) 12-O - ((1H-imidazol-1-yl) carbonyl) 6-Omethyl 3-oxo erythromycin, 3 ml of acetonitrile and 1.0 g of 4- (4-methoxyphenyl) butylamine prepared according to Tetrahedron Letters 32,

  1699-1702, (1991) 0.8 g of the desired product is obtained in the form of a mixture of acetylated and deacetylated product in 2 '.

  Chromatography on silica methylene chloride-methanol

  (9-1). rf = 0.47. STAGE B: 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 ((4- (4-methoxyphenyl) butyl) imino)) erythromycin By operating as in Example 1, stage E, at starting from 0.8 g of the crude product obtained in the previous stage, we obtain

  0.237 g of the desired product (F = 193-195 C). aD: +2203 (C = 1% CHCl3).

  EXAMPLE 3 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 ((4- (2-thienyl) butyl) imino))) erythromy-

cine

  STAGE A: 2'-11,12-dideoxy 3-acetate ((2,6-dideoxy 3-C-

  methyl 3-0-methyl alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo 12.11 (oxycarbonyl ((4- (2-thienyl) butyl) imino)) erythromycin Operating as in Example 1 , stage D, from

  0.85 g of 11'-deoxy 10,11-didehydroxy 3'-acetate 3-de ((2,6-

  dideoxy 3-C-methyl 3-0-methyl alpha-L-ribohexopyranosyl) 12-

  O - ((1H-imidazol-1-yl) carbonyl) 6-O-methyl 3-oxo erythromyci-

  ne, 3 ml acetonitrile, 0.3 ml water and 0.822 g 4- (2-

  thienyl) butylamine (the preparation of which is given below)

  0.212 g of sought product is obtained (F = 218-2200C).

  STAGE B: 11,12-dideoxy 3-de ((2,6-dideoxy 3-C-methyl 3-O- methyl alphaL-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo 12,11- (oxycarbonyl (( 4- (2thienyl) butyl) imino)) erythromycin By operating as in Example 1, stage E, starting from 0.182 g of product prepared in the preceding stage and 6 ml of methanol, 0.085 g of sought product is obtained

(F = 188-190 C).

  aD: + 24 (C = 1% CDCl3). EXAMPLE 4 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 ((4- (1,1'-biphenyl) 4-yl) butyl) imino)) erythromycin Heat at 55'C for 5 hours, a mixture containing 3.5 ml of acetonitrile, 0.7 g of 2'-acetate of 11-deoxy, 11-didehydro 3-de ((2,6dideoxy 3-C-methyl 3-O -methyl alpha-L-ribohexopyranosyl) oxy) 12-O ((1H-imidazol-1-yl)

  carbonyl) 6-O-methyl 3-oxo erythromycin, 0.3 ml of water, 1.1 g20 of biphenylbutylamine (preparation given below).

  The reaction medium is poured onto a saturated aqueous solution of sodium dihydrogen phosphate, extracted with acetate.

  ethyl tate and filter. The aqueous phase is left to settle, extracted with ethyl acetate and washed with water. Dry, filter and concentrate. 1.1 g of a product are obtained which is poured into 12 ml of methanol. The solution obtained is stirred for 15 hours at room temperature. Concentrate, dilute with 3 ml of methylene chloride, dry, filter, concentrate. A product is obtained which is recrystallized from a mixture of isopropyl ether and ethyl ether (9-1). It is filtered, dried at 80 ° C. and 0.148 g of product melts at 166-168 ° is obtained. NMR - CDCl3 1.34 (s) and 1.47 (s) - 6 and 12 CH3; 2.68 (m) - CH2-e; 3.05 to 3.25 - Ho10, H4 and H2 '; 3.60 (s) - H11; 3.67 (m) - CH2-N-C; It O - 7.26 - - 7.49 - internal phenyl; 7.31 H in para,

  - 7.42 H in meta, - 7.58 H in external ortho-phenyl.

  Microanalysis:% theoretical% found

C% 68.75 C% 68.6

H% 8.35 H% 8.5

N% 3.41 N% 3.3

  By operating as above, from the 2'-acetate of

  11-deoxy 10,11-didehydro 3-de ((2,6-dideoxy 3-C-methyl 3-O-

  methyl alpha-L-ribohexopyranosyl) oxy) 12-O - ((1H-imidazol-1-

  yl) carbonyl) 6-0-methyl 3-oxo erythromycin, and amines

  corresponding, the following products were obtained: EXAMPLE 5: 11,12dideoxy 3-de ((2,6-dideoxy 3-C-methyl 3-O-

  methyl alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo 12.11 (oxycarbonyl ((4- (2-methoxyphenyl) butyl) imino)) erythromycin

  F = 190 - 192'C. aD: + 24 (C = 1% CHCl3).

  EXAMPLE 6: 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- (phenylmethylthio) ethyl) imino))

erythromycin F = 190 - 192'C.

  aD: - 11.5 (C = 1% CHCl3). EXAMPLE 7: 11,12-dideoxy 3-de ((2,6-dideoxy 3-C-methyl 3-O- methyl alpha-L-ribohexopyranosyl) oxy) 6-O- methyl 3-oxo25 12.11- (oxycarbonyl ((4- (4-nitrophenyl) butyl) imino))

erythromycin F = 200 - 202'C.

  aD: + 15.5 (C = 1% CHCl3). EXAMPLE 8: 11,12-dideoxy 3-de ((2,6-dideoxy 3-C-methyl 3-O-30 methyl alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo 12,11- ( oxycarbonyl ((4- (2,4-dimethylphenyl) butyl) imino))

erythromycin F = 183-185'C.

  aD: + 21 (C = 1% CHCl3) .35 EXAMPLE 9: 11,12-dideoxy 3-de ((2,6-dideoxy 3C-methyl 3-0-

  methyl alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo 12.11 (oxycarbonyl ((4- (4-methylphenyl) butyl) imino)) erythromycin

F = 200 - 202'C.

  aD: + 23 (C = 1% CHCl3). EXAMPLE 10: 11,12-dideoxy 3-de ((2,6-dideoxy 3-C-miethyl 3-0- methyl alpha-L-ribohexopyranosyl) oxy) 6-0-methyl 3-oxo 5 12.11- ( oxycarbonyl ((4- (2,4,6-trimethylphenyl) butyl) imino))

erythromycin F = 188 - 190'C.

  aD: + 24 (C = 1% CHCl3). EXAMPLE 11: 11,12-dideoxy 2-de ((2,6-dideoxy 3-C-methyl 3-0-10 methyl alpha-L-ribohexopyranosyl) oxy) 6-0-methyl 3-oxo 12,11- ( oxycarbonyl ((4 - ((1H) -imidazol-1-yl) butyl) imino))

erythromycin F = 212 - 214'C.

  aD: + 26.2 (C = 0.85% CHCl3) .15 EXAMPLE 12: 11,12-dideoxy 3-de ((2,6dideoxy 3-C-methyl 3-0- methyl alpha-L-ribohexopyranosyl) oxy ) 6-0- methyl 3-oxo 12,11- (oxycarbonyl ((4- (3-methoxyphenyl) butyl) imino))

erythromycin F = 196 - 198'C.

  aD: + 18.8 (C = 1% CHCl3). EXAMPLE 13: 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 ((4- (phenylamino) 4-oxobutyl) imino)) erythromycin

  F = 190-192'C. aD = +8 (C = 1% CHCl3).

  EXAMPLE 14: 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 ((3- (phenylthio) propyl) imino)) erythro-

mycine F = 204 - 206'C.

  aD: + 19 (C = 0.9% CHCl3). EXAMPLE 15: 11,12-dideoxy 3-de ((2,6-dideoxy 3-C-methyl 3-0- methyl alpha-L-ribohexopyranosyl) oxy) 6-0- methyl 3-oxo35 12,11- (oxycarbonyl ((2 - ((phenylcarbonyl) amino) ethyl) imi-

no)) erythromycin

F = 240'C

aD: - 2 (C = 1% CHCl3).

  EXAMPLE 16 11,12-dideoxy 3-de ((2,6-dideoxy 3-C-methyl 3-0-

  methyl alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo 12.11 (oxycarbonyl ((3-phenoxypropyl) imino)) irythromycin

F = 222 - 225'C.

aD: + 20 (C = 0.9% CHCl3).

  EXAMPLE 17 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-

  ((2- (phenylmethoxy) ethyl) imino)) irythromycin

F = 207'C.

  EXAMPLE 18: 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-methoxyphenyl) ethyl) imino))

erythromycin F = 218 - 220'C.

  aD: + 15.5 (C = 1% CHCl3). EXAMPLE 19 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 ((4- (1H-indol-4-yl) butyl) imino)) erythromycin

  F = 208 - 212'C. aD: + 22 '(C = 1% CHCl3).

  EXAMPLE 20: 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 ((4- (3-aminophenyl) butyl) imino))

  erythromycin F = 200 - 202'C and 210'C.

  aD: + 23 (C = 1% CHCl3). EXAMPLE 21: 11,12-dideoxy 3-de ((2,6-dideoxy 3-C-methyl 3-O-mithyl alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo30 12,11- (oxycarbonyl ((4- (2-chlorophenyl) butyl) imino))

erythromycin F = 193 - 195'C.

  aD: +23 (C = 1% CHCl3). EXAMPLE 22: 11,12-dideoxy 3-de ((2,6-dideoxy 3-C-methyl 3-O-35 methyl alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo 12,11- ( oxycarbonyl ((4- (3-chlorophenyl) butyl) imino))

erythromycin F = 191 - 193'C.

aD: + 22 '(C = 1% CHCl3).

  EXAMPLE 23: 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 ((4- (4-hydroxyphenyl) butyl) imino)) erythromycin F = 220 - 222'C. EXAMPLE 24 11,12-dideoxy 3-of ((2,6-dideoxy 3-C-methyl 3-O- methyl alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo 12,11- (oxycarbonyl ((4- (4- (1-oxobutyl) phenyl) butyl) imino))

erythromycin F = 134 - 136'C.

  EXAMPLE 25: 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 ((4- (4- (1-oxoethyl) phenyl) butyl) imino))

irythromycin F = 170 - 172'C.

  EXAMPLE 26 11,12-dideoxy 3-of ((2,6-dideoxy 3-C-methyl 3-O- methyl alpha-L-ribohexopyranosyl) oxy) 6-0-methyl 3-oxo 12,11- (oxycarbonyl ((3- (phenylsulfonyl) propyl) imino))

erythromycin F = 202 - 204'C.

  aD: + 21 (C = 1% CHCl3). EXAMPLE 27 11,12-dideoxy 3-de ((2,6-dideoxy 3-C-methyl 3-O- methyl alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo25 12,11- (oxycarbonyl ((4- (4-butylphenyl) butyl) imino)) erythromycin F = 134 - 135'C. aD: + 19.5 (C = 1% CHCl3). EXAMPLE 28 11,12-dideoxy 3-de ((2,6-dideoxy 3-C-methyl 3-O-30 methyl alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo 12,11- ( oxycarbonyl ((4- (4- quinoline) butyl) imino))

erythromycin F = 170 - 172'C.

  EXAMPLE 29: 11,12-dideoxy 3-de ((2,6-dideoxy 3-C-methyl 3-O-35 methyl alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo 12,11- ( oxycarbonyl ((4 ((2,2'-bithiophen) 5-yl) butyl) imino)) erythromycin

F = 147 - 149'C.

  EXAMPLE 30 11,12-dideoxy 3-de ((2,6-dideoxy 3-C-mithyl 3-O-

  methyl alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo 12.11 (oxycarbonyl ((3-oxo 3- (2-thiazolyl) amino) propyl) imino)) erythromycin EXAMPLE 31: 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 ((4- (4-ethylphenyl ) butyl) imino))

erythromycin F = 191 - 193'C.

  aD: + 20 (C = 1% CHCl3). EXAMPLE 32 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 ((4- (4- (4-chlorobenzoyl) 3-methylphenyl) butyl) imino)) erythromycin

  F = 143 - 145'C. aD: + 8 (C = 1% CHCl3).

  EXAMPLE 33 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 ((9H-fluoren-2-yl) imino>)) rythromycin

F = 215 - 217'C.

aD: + 20 (C = 1% CHCl3).

  By operating as above, the following compounds of formula (I) were prepared:

Z R

H (C H 2) È F

H H (C tt 2) 5- C1 iO H (C H 2) 6C1

H (C H 2) 5 - O C H 3

H (C H z) 6 0 C H 3 -i l

H (C H 2) 5 5S

H (C (H 2) 6

(cH) H

(C H 2)> 4

c5 (C H 2) Ci Ci

Z R

H (CH 2) 4C F 3

O C H 3

H (CHz) s5 C H 3

0CR3

0CH3

O C H 3

H (CH 2 4

O C H 3

O C H 3

H (C H 2 2 H 5

H (C H 2) H

H (C H 2) 4C F 3

Z R

H (Ci 2) 4--5 C3 H

H (C H 2) 4

NO z

H (C H 2) - - C1

H (C H 2) 5 O C3 H

* H (C H 2) 6

H (CH2) 6 C1

H (C H 2) 5

Cl z R

H (C H 2) 5 -

lq'O2

1H (C H 2) 5S

This

H (CH 2) 6--

NO2

H (C H 2) 5

(C2) 5--

0CH3

O C H 3

H (G (CH2) 6 C H3

Z R

H (C H 2) 4

so H

H (C H 2H) 4 O <

H (CH 2) 4-N _

-NOT

H (C H2) H 4

(C2) 4 5

  PREPARATION i: 4- (2-thienyl) butylamine

  STAGE A: 4- (2-thienyl) butylamide. A mixture of 40 ml of dichloro- is stirred for 3 hours at 60 ° C.

  ethane, 5.1 ml of 4- (2-thienyl) butyric acid, and 10.2 ml of thionyl chloride. The dichloroethane is evaporated, the product obtained is poured onto concentrated ammonia, cooled to 0 C. The product obtained is drained and dried. 4.29 g of product are obtained which is chromatographed on silica eluting with a methylene chloride-methanol mixture (92-8). Homogeneous fractions are collected in TLC, concentrated and filtered. The product obtained is pasted in isopropyl ether, drained and dried. 1.18 g of sought product is obtained (F = 84-86 C). STAGE B: 4- (2-thienyl) butylamine 1.1 g of 4- (2-thienyl) butylamide are added dropwise at 0 C in a mixture containing 30 ml of THF and 1.06 g of hydride. lithium aluminum. The mixture is left to return to ambient temperature, stirred at ambient temperature for 4 h 30 min, then 1 hour at 30 ° C. and 16 hours at ambient temperature. Cool to 0 C, add 3 ml of a water THF mixture (2-1) then 8 ml of water, then 6 ml of a saturated solution of double sodium tartrate and potassium salt. We filter and concentrate. The product obtained is taken up in ethyl ether, washed with sodium carbonate and then with water and the aqueous phases are extracted with ethyl ether. The organic phases are combined, dried over sodium sulfate,

  filters and concentrates. 0.91 g of a product is obtained which is dissolved in 12 ml of an ethyl acetate-ethanol mixture (95-5). Cool to 0 C and add a solution of chloro acid.

  gaseous hydrogen in ethyl acetate. The hydrochloride of the expected product precipitates. It is drained, dried and 0.675 g of sought product is obtained in the form of the hydrochloride (F = 168-170 C). The corresponding base is obtained by alkaline treatment, extraction with ethyl acetate, drying over sodium sulfate, filtration and concentration. PREPARATION 2: 4- (1,1'-biphenyl) 4-yl butylamine STAGE A: Cool to -40 ° C, a suspension containing 150 cc of tetrahydrofuran, 5.46 g of 4-phenylbenzaldehyde and, 9 g of bromide N- (3-bromopropyl) phthalimide triphenyl phosphonium. Then introduced 3.37 g of terbutylate

  potassium. The temperature is allowed to rise to -15 ° C. and 5 maintains stirring at -15 ° C. for 1 hour.

  Poured onto ice, extracted with ethyl acetate, washed with water, the organic phases are dried over Na2SO4, filtered and concentrated. 19 g of product are obtained which is dissolved in methylene chloride and chromatography on silica10, eluting with an ethyl acetatehexane mixture (3-7). We concentrate. Impaste in hexane, drain, dry under reduced pressure and isolate 8.5 g of the desired product melting at 112 114 ° C. Microanalysis:% calculated% found C% 81.56 C% 81.4 H% 5.42 H% 5.3 N% 3.96 N% 3.8 STAGE B: 4- (1,1'- biphenyl) 4 -yl but-3-enylamine20 A mixture containing 280 ml of ethanol, 7.9 g of product prepared in stage A, and 1.3 ml of hydrazine hydrate is brought to reflux. The mixture is allowed to return to room temperature, the precipitate obtained is filtered and washed with ethanol. It is concentrated, poured onto a solution of 2N hydrochloric acid and extracted with ethyl acetate. The organic phases are washed with water, dried, filtered and concentrated under pressure

  scaled down. 2.89 g of sought product is obtained. F = 188 194'C. STAGE C: 4- (1,1'-biphenyl) 4-yl butylamine30 Place in a hydrogen apparatus, 17 ml of methanol, 1.74 g of product prepared in stage B and 0.17 g of cat-

  10% Pd lyser on carbon. The hydrogenation is maintained overnight. It is filtered, washed and concentrated. The product obtained is impregnated with ethyl acetate, ice-cold, wrung and dried under reduced pressure at 80 ° C. 1.55 g of sought product is obtained, melting at 260 ° C.

  PREPARATION 3: 4- (2,4,6-trimethylphenyl) butylamine By operating as in preparation 2, the

  sought after product in hydrochloride form.

  F = 218 - 220'C. PREPARATION 4: 4- (4-methylphenyl) butylamine By operating as in preparation 2, the desired product was obtained. F = 202,204'C.

  PREPARATION 5: 4- (2,4-dimethylphenyl) butylamine By operating as in preparation 2, the desired product was obtained.

  F = 126 - 128'C. PREPARATION 6: 4- (2-methoxyphenyl) butylamine

  By operating as in preparation 2, the desired product was obtained.

  F = 122 - 124'C.15 EXAMPLES OF PHARMACEUTICAL COMPOSITIONS

  Compounds were prepared containing: Product of Example 1 ...........

  ....... 150 mg Excipient qs .......................... 1 g Details of the excipient: starch, talc, 20 magnesium stearate Product of Example 2 .................... 150 mg Excipient qs .............. DTD:. ........... 1 g Detail of the excipient: starch, talc, magnesium stearate 25 Product of Example 3 .................. .. 150 mg Excipient qs .......................... 1 g Details of the excipient: starch, talc, magnesium stearate Product of l 'example 4 .................... 150 mg30 Excipient qs ............... DTD: ...... ..... 1 g Details of the excipient: starch, talc, magnesium stearate Product of Example 5 .................... 150 mg Excipient qs .......................... 1 g Details of the excipient: starch, talc, magnesium stearate PHARMACOLOGICAL STUDY OF THE PRODUCTS OF THE INVENTION Method dilutions in liquid medium A series of tubes is prepared in which the same quantity of sterile nutritive medium is distributed. Increasing quantities of the product to be studied are distributed in each tube, then each tube is seeded with a bacterial strain. After incubation for twenty-four hours in an oven at..DTD: 37 ° C., the inhibition of growth is assessed by trans-illumination, which makes it possible to determine the concentrations.

  minimum inhibitory tions (C.M.I.) expressed in micro-10 grams / cm3.

  The following results were obtained: Bacterial strains with GRAM + Products Ex. 1 Ex. 2 Ex. 3 Ex. 4 Ex. 15 Staphylococcus aureus 0.08 0.08 0.04 0.15 0.04

  011UC4 Staphylococcus aureus 0.08 0.08 0.04 - -

  011HT17 Staphylococcus aureus 0.08 0.15 0.08 011G025I Staphylococcus epidermidis 0.08 0.08 0.08 0.6 0.08 012 GOllI Streptococcus pyogenes <0.02 <0.02 <0.02 0.04 0, 04 group A 02A1UC1 Streptococcus agalactiae 0.15 0.15 0.08 <0.02 S 0.02 group B 02BlHT1 Streptococcus sp <0.02 <0.02 <0.02 group C 02COCB3 Streptococcus faecalis 0.08 <0 , 02 <0.02 0.04 group D 02D2UC1 Streptococcus faecium 0.08 0.04 <0.02 0.04 0.04 group D 02D3HT1 Streptococcus sp 0.04 <0.02 0.02 0.04 <0 , 02 group G 02GOGR5 Streptococcus mitis <0.02 <0.02 <0.02 0.15 02mitCB1 Streptococcus mitis 0.6 02mitGR16I Streptococcus agalactiae 0.3 0.3 0.6 0.3 0.15 group B 02BlSJ1 Streptococcus sp 0.15 0.15 0.3 group C 02COCB1 Streptococcus pneumoniae 0.08 0.08 0.04 <0.02 <0.02 032UC1 Streptococcus pneumoniae 0.08 0.15 0.15 0.15 0.15 SJ5 In addition, the products of Examples 1, 2, 3, 4 and 15 showed an interesting activity on the following gram bacterial strains: Haemophilus Influenzae 351HT3, 35 1CB12,

351CA1 and 351GR6.

Claims (15)

1) The compounds of formula (I): R   o NO ,, ", g ............." "" ", o ..... (I) ,,,,, O i oz OZ in which, or R represents a radical (CH2) n Ar1, n representing an integer between 1 and 6, Ar1 representing: - either a carbocyclic aryl radical substituted by one or more radicals chosen from the group consisting of free, salified, esterified or amidified carboxyl radicals , hydroxyl radicals, halogen atoms, NO2 radicals, CEN radicals, alkyl, alkenyl or alkynyl, O-alkyl, O-alkenyl or O-alkynyl, S-alkyl, S-alkenyl or S-alkynyl radicals and N-alkyl, N-alkenyl or N-alkynyl, containing up to 12 carbon atoms optionally substituted by one or more halogen atoms, the radical R1 N, R1 and R2 identical or different, representing R2 an atom of hydrogen or an alkyl radical containing up to 12 carbon atoms, the radical   C-R3-, R3 representing an alkyl radical containing up to 12 carbon atoms, or an aryl or hetero radical   aryl optionally substituted, aryl, O-aryl or S-aryl carboxylic or aryl, O-aryl or S-hetero radicals-   5- or 6-membered rocyclics comprising one or more heteroatoms, optionally substituted by one or more of the substituents mentioned above, - either a 5 or 6-membered heterocyclic aryl radical, comprising one or more heteroatoms, optionally substituted by one or more of substituents mentioned above 5,   or R represents an X Ar2 radical in which X represents an alkyl radical containing up to 6 carbon atoms   bone, interrupted by an oxygen atom, a sulfur atom, an SO group, an S02 group, a 10 0 0 0 Il I1 I1 -C- group, an -NH-C- or -C- NH group, and Ar2 represented   an aryl or heteroaryl radical defined above not substi-   killed or substituted by one or more of the possible substituents   Whites of Ar1 and Z represent a hydrogen atom or the remainder of a carboxylic acid containing up to 18 carbon atoms as well as the addition salts with acids of the compounds of formula (I). 2) The compounds of formula (I) as defined in claim 1 in which Z represents an atom hydrogen.   3) The compounds of formula (I) as defined in claim 1 or 2 in which R represents the radical (CH2) 4   Ar1, Ar1 being defined as above. 4) The compounds of formula (I) as defined in any one   The conch of claims 1 to 3 in which Ar1 represents a phenyl radical substituted by one of the radicals listed in   claim 1. 5) The compounds of formula (I) as defined in claim 4 in which Ar1 represents a phenyl radical   substituted by one or more halogen atoms.   6) The compounds of formula (I) as defined in claim 5 in which Ar1 represents a phenyl radical   substituted by one or more chlorine atoms. 7) The compounds of formula (I) as defined in the claim   cation 6 in which Ar1 represents a 4-chlorophenyl radical.   8) The compounds of formula (I) as defined in any one   conch of claims 1 to 3 in which Ar1 represents   a phenyl radical substituted by one or more O- radicals   alkyl containing up to 4 carbon atoms. 9) The compounds of formula (I) as defined in claim 8 in which Ar1 represents a phenyl radical substituted by one or more methoxy radicals. ) The compounds of formula (I) as defined in claim 9 in which Ar1 represents a 4-methoxyphenyl radical.   11) The compounds of formula (I) as defined in resale   dication 1, 2 or 3 in which Ar1 represents an optionally substituted 5-membered heterocyclic aryl radical.   12) The compounds of formula (I) as defined in claim 11 in which Ar1 represents a thienyl radical possibly substituted.   13) The compounds of formula (I) as defined in claim 12 in which Ar1 represents a thienyl radical.   14) The compounds of formula (I) as defined in claim 1, 2 or 3, in which Ar1 represents an optionally substituted biphenyl radical. 15) The compounds of formula (I) as defined in claim 14 , in which Ar1 represents a radical: possibly substituted.   16) The compounds of formula (I) as defined in claim 15, in which Ar1 represents a radical:   17) The compounds of formula (I) as defined in any one of claims 1 to 3, in which R represents   feels a radical X1 Ar2 in which X1 represents an alkyl radical containing up to 6 carbon atoms, interrupted by a radical -NH-C-, 'I   and Ar2 retains the same meaning as before.   18) The compounds of formula (I) as defined in claim 17, in which R represents a radical -C H -CH 2-NH-C   the phenyl radical being optionally substituted by one or   more than one of the substituents defined in claim 1.   19) The compounds of formula (I) whose names follow:   - 11,12-dideoxy 3-de ((2,6-dideoxy 3-C-methyl 3-O-methyl alpha-Lribohexopyranosyl) oxy) 6-0-methyl 3-oxo 12,11-   (oxycarbonyl ((4- (4-chlorophenyl) butyl) imino)) erythromycin,   - 11,12-dideoxy 3-de ((2,6-dideoxy 3-C-methyl 3-O-methyl alpha-Lribohexopyranosyl) oxy) 6-O-methyl 3-oxo 12,11-   (oxycarbonyl (4- (4- (4-methoxyphenyl) butyl) imino))) erythromycin,   - 11,12-dideoxy 3-de ((2,6-dideoxy 3-C-methyl 3-O-methyl alpha-Lribohexopyranosyl) oxy) 6-O-methyl 3-oxo 12,11-   (oxycarbonyl ((4- (2-thienyl) butyl) imino)) erythromycin,   - 11,12-dideoxy 3-de ((2,6-dideoxy 3-C-methyl 3-O-methyl alpha-Lribohexopyranosyl) oxy) 6-O-methyl 3-oxo 12,11-   (oxycarbonyl ((4- (1,1'-biphenyl) 4-yl) butyl) imino)) erythromycin,   - 11,12-dideoxy 2-de ((2,6-dideoxy 3-C-methyl 3-O-methyl alpha-Lribohexopyranosyl) oxy) 6-O-methyl 3-oxo 12,11-   (oxycarbonyl ((4 - ((1H) -imidazol-1-yl) butyl) imino)) erythromycin,   - 11,12-dideoxy 3-de ((2,6-dideoxy 3-C-methyl 3-O-methyl alpha-Lribohexopyranosyl) oxy) 6-0-methyl 3-oxo 12,11- (oxy-   carbonyl ((2 - ((phenylcarbonyl) amino) ethyl) imino)) erythromycin. 20) As medicaments, the compounds of formula (I) such   as defined in any one of claims 1 to 18,   as well as their addition salts with pharmaceutical acids only acceptable.   21) As medicaments, the compounds of formula (I) as defined in claim 19, as well as their salts   addition with pharmaceutically acceptable acids. 22) Pharmaceutical compositions containing as a principal   active ingredient at least one medicament defined in any one of claims 18 or 19.   23) Process for preparing the compounds of formula (I) as defined in claim 1, characterized in that a compound of formula (II) is subjected: 10 0% HO O 1. ',, .... ,, .......   OOZ O z in which Z represents the remainder of a carboxylic acid containing up to 18 carbon atoms, to the action of an agent capable of selectively activating the hydroxyl at 11 to obtain the compound of formula (III) : HO 0 IO (III) L h .......... O O   0z ll lHl [I Oz in which R1 represents the remainder of a leaving group, which is subjected to the action of a base, to obtain the compound of formula (IV): 11E00 H T ] (IV)   0 z then submits the compound of formula (IV): - either to the action of a compound of formula (V): R-N = C = O (V)   in which R is defined as in claim 1, to obtain the compound of formula (VI): R -11H 0 N O 0     "". '' ah g W '' '' '' '' '' '' o (VI) OZ which cyclizes either spontaneously by heating, or which is subjected to the action of a cyclization agent to obtain the compound of formula (IA) corresponding: 0A, 0 NO ....... (IA)   i O Z in which Z does not represent a hydrogen atom, - either to the action of carbonyldiimidazole to obtain the compound of formula (VII): N O t XX (VII) \ /   0 ZO then to the action of a compound of formula (VIII): RNH2 (VIII)   in which R is defined as above, to obtain the compound of formula (VI) defined above which spontaneously cyclizes by heating or which is subjected to the action of a   cyclization agent to obtain the corresponding compound of formula (IA), then subject, if necessary, the compound of formula (IA) to the action of a release agent for the hydroxyl function at 2 'and / or if necessary, the action of an acid to form the salt.   24) As new chemicals, the compounds of formulas (III), (IV), (VI) and (VII).   ) As new chemicals, as defined   in claim 23, 11'-deoxy-10,11-dide-hydro 3de 2'-acetate ((2,6-dideoxy 3-C-methyl 3-O-methyl alpha-L-ribo-   hexopyranosyl) oxy) 6-O-methyl 3-oxo erythromycin and the corresponding hydroxy compound 2. 26) As new chemicals, the compounds of formula (VIII) as defined in claim 23, as follows: 4- (2-thienyl) butylamine, 4- (1,1'biphenyl) butylamine, 4 - (4-methylphenyl) butylamine, 4- (2,4-dimethylphenyl) butylamine, 4- (2,4,6-trimethylphenyl) butylamine,   4- (2-methoxyphenyl) butylamine.