MXPA00009424A

MXPA00009424A - 3',3'-n-bis-substituted macrolide lhrh antagonists

Info

Publication number: MXPA00009424A
Application number: MXPA/A/2000/009424A
Authority: MX
Inventors: Daryl R Sauer; Fortuna Haviv; John Randolph; Nicholas A Mort; Christopher R Dalton; Milan Bruncko; Michele A Kaminski; Bradley W Crawford; Lisa Marie Frey; Jonathon Greer
Original assignee: Abbott Laboratories
Priority date: 1998-03-27
Filing date: 2000-09-26
Publication date: 2001-07-31

Abstract

Disclosed are 3',3'-N-bisdesmethyl-3',3'-N- bis-substituted-6-O-methyl-11- deoxy-11,12-cyclic carbamate erythromycin A derivatives of formula (I) which are antagonists of lutenizing hormone-releasing hormone (LHRH). Also disclosed are pharmaceutical compositions comprising the compounds, methods of using the compounds and the process of making the same.

Description

ANTIGONISTS OF LHRH, MACROLIDA 3'.3'-N-BIS- SUBSTITUTE TECHNICAL FIELD The present invention relates to a class of macrolide compounds which are antagonists of lutenizing hormone-releasing hormone (LHRH), to pharmaceutical compositions comprising the compounds; to methods of using the compounds and to the process for their preparation. More particularly, the present invention relates to cyclic 11, 12-carbamate derivatives of 3 ', 3'-N-bis-desmethyl-3', 3'-nb -s-substituted-6-0-methyl-11 -deoxy-erythromycin A, which are LHRH antagonists.

BACKGROUND OF THE INVENTION Gonadotropins, the follicle stimulating hormone (FSH), lutenizing hormone (LH) and chorionic gonadotropin (CG) are necessary for ovulation, spermatogenesis and sex steroid biosynthesis. A single hypothalamic hormone, gonadotropin-releasing hormone (GnRH), also known as LHRH, is responsible for regulating the secretion of both FSH and LH in mammals. LHRH is a decapeptide having the structure: pyro-Glu1-Hi2-Trp3-Ser4-Tyr5-Gly6-Leu7-Arg8-Pro9-Gly10-NH2 where the exponents designate the position of each aminoacyl residue in the decapeptide chain.

LHRH is released from the hypothalamus and binds to a receptor in the pituitary gland, causing the release of LH and FSH that subsequently act on the gonads to stimulate the synthesis of steroidal sex hormones. The pulsatile release of LHRH and, thus, the release of LH and FSH, control the reproduction cycle in both animals and humans. Acute doses of LHRH agonists increase the levels of LH and steroidal sex hormones in both animals and humans. Paradoxically, chronic doses of LHRH agonists suppress the level of LH and steroidal sex hormones. Consequently, the effect of multiple doses of LHRH agonists is to suppress the formation of estrogen in females and the production of testosterone in males. The same effect is observed in both animals and humans, after administering acute or chronic doses of LHRH antagonists. In recent years considerable research effort has been devoted to finding LHRH antagonists. These efforts have produced many peptide antagonists of LHRH that suppress LH and reproductive hormones in mammals when administered in an acute or chronic manner. See, for example, M. J. Karten in Modes of Action of GnRH and GnRH analogs, edited by W. F. Crowley and P. M. Conn, p. 277 (1992). The literature has reported that LHRH antagonists are useful in the treatment of a variety of conditions in which suppression of sex steroids plays a key role, including contraception, delayed puberty, treatment of benign prostatic hyperplasia, the palliative treatment or remission of hormone-dependent prostate tumors, the treatment of cryptorachidism, hirsutism in women, gastric motility disorders, dysmenorrhea and endometriosis. Current LHRH antagonists are decapeptides which, due to their low oral bioavailability, are administered intravenously or subcutaneously. No heterocyclic non-peptide antagonist has been reported in the literature; see, for example, WO 95/280405, WO 95/29900, WO 97/22707, WO 97/21704 and WO 97/2103. LHRH antagonists that are not peptides have the potential advantage of improved oral bioavailability and are smaller molecules. However, it is not known from reports in the literature of macrolide compounds, as LHRH antagonists. The macrolide antibiotics and the prokinetic agents of macrolide are known. For example, antibiotics derived from erythromycin, which contain 11, 12-cyclic carbamate moieties are described in EP 248 279 A2. The 3'-N-substituted erythromycin derivatives, which are effective antibacterial agents, are described in EP 0 559 896 A1. The prokinetic agents of macrocyclic lactone (macrolide) are known. See J. S. Gidda and co-inventors, in European patent application No. 0349100, published on January 3, 1990, which describes 12 member macrolides for use as gastrointestinal motility enhancers. S. Omura and Z. Itoh, in U.S. Patent 4,677,097, issued June 30, 1987; European application No. 215,355, published on March 25, 1987 and European application No. 213,617, published on March 11, 1987, describe erythromycin derivatives A, B, C and D, which are useful as stimulants of the movement of contraction in the digestive tract. Additionally, T. Sunazu and coauthors, Chem. Pharm. Bull., 37 (10): 2701-2709 (1989) describes quaternary derivatives of 6,9-semiacetal of 8,9-anhydroerythromycin A, and 6,9-epoxide of 9,9-dihydro-erythromycin, with motor stimulating activity gastrointestinal. None of these references describes the erythromycin derivatives A, 3 ', 3'-N-bis-desmethyl-3', 3'-N-bis-substituted-6-O-methyl-11-deoxy-11.12-cyclic carbamate the present invention, which are effective as LHRH antagonists. The cyclic 11, 12-carbamate derivatives of 3'-N-demethyl-3'-N-monosubstituted-6-O-methyl-11-deoxy-11,12-erythromycin A are described in the US application of the same successor in title. , presented concurrently with this one. The cyclic 11, 12-carbamate derivatives of 3 ', 3'-N-bis-desmethyl-3', 3'-N-bis-substituted-6-O-methyl-11-deoxy-erythromycin A of the present invention are described herein.

BRIEF DESCRIPTION OF THE INVENTION In one aspect, the present invention relates to a compound having the formula: or its pharmaceutically acceptable salt or ester; wherein: A is selected from the group consisting of: (a) -C, (b) -N; and (c) -O; X and Y, independently in each occurrence, are selected from the group consisting of: (a) hydrogen; (b) haiogenide; (c) trifluoromethyl; (d) alkoxy; (e) alkyl; (f) aryl; and (g) substituted aryl; R and R 'are selected from the group consisting of: (a) alkyl, (b) cycloalkyl; (c) heterocyclic; (d) substituted heterocyclic, (e) alkylcycloalkyl, (f) substituted alkylcycloalkyl, (g) alkylaryl, (h) alkylheterocyclic, (!) alkenyl, (j) alkynyl, (k) -C (S) -NHR4, C ( NR4) -NHR4, where R4 is hydrogen, alkyl or aryl; and (I) - (CH2) n-C (CH2) m-R5, where m is 2, 3, 4 or 5; and R5 is alkyl, alkoxy, aryl or substituted aryl; R2V R3, independently in each occurrence, are: (a) hydrogen; (b) methyl; or R2 and R3 together form a cyclic portion, when A is C; R3 is absent when A is N; and n = 1, 2 or 3. In another aspect, the present invention relates to a process for preparing the compound of formula I. The process comprises the steps of: (a) reacting a compound of the formula: with sodium hexamethiidisilazide and carbonyldiimidazole, to produce a compound of the formula: (b) reacting the compound obtained in step (a) with an amino compound of the formula: followed by deprotection of the 2 ', 4"-protected hydroxyl groups, to give a compound of the formula (c) stepwise demethylating the 3'-amino, treating the compound obtained in step (b), with iodine, in the presence of a base to produce a compound of the formula: and (d) alkylating the 3 ', 3'-N-bis-demethylated compound, obtained in step (c), with an alkylating agent.

In another embodiment of the process, the process comprises the steps of: c) selectively demethylating the compound obtained in step (b), to obtain the compound of the formula: d) alkylating the 3'-N-demethylated compound obtained in step (c), with an alkylating agent, to give a compound of the formula: e) demethylating the 3'-amino by treating the compound obtained in step (d) with iodine, in the presence of a base, to give a compound of the formula: f) alkylating the 3'-N-demethylated compound obtained in step e), with an alkylating agent. The compounds of the invention exhibit little or no antibacterial activity, but bind to the LHRH receptors and are effective LHRH antagonists. In such a way, these compounds are effective in the treatment of prostate cancer, endometriosis, precocious puberty and other types of diseases that are related to sex hormones. Accordingly, in another aspect of the invention, the present invention relates to pharmaceutical compositions that are useful as LHRH antagonists and suppress LH, testosterone, estradiol and estrogen in mammals. In yet another aspect, the present invention relates to a method for suppressing levels of sex hormones in male or female mammals, comprising administering to a host in need of such treatment, a therapeutically effective amount of an LHRH antagonist compound in combination. with a therapeutically effective amount of an antiandrogen agent.

DETAILED DESCRIPTION OF THE INVENTION The terms "lower alkyl" or "alkyl", when used herein, refer to straight or branched chain alkyl radicals containing from 1 to 20 carbon atoms, sometimes represented as Cx-Cy-alkyl , where x and y, respectively, represent the minimum number and the maximum number of carbon atoms in the alkyl radical. Examples of lower alkyl include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl, tertiary butyl, n-pentyl, 1-methyl butyl, 2,2-dimethylbutyl, 2-methylpentyl, 2,2-dimethylpropyl, n-hexyl and the like. The term "alkoxy" or "lower alkoxy", when used herein, refers to lower alkyl groups as defined above, which are attached to an oxygen atom in an ether linkage. Examples of alkoxy include, but are not limited to: methoxy, ethoxy, isopropoxy, n-pentyloxy, terbutoxy, n-octyloxy, and the like. This alkoxy radical may also contain a ring including, but not limited to, a ring of five or six atoms, composed of carbons, which may contain one or two heteroatoms, such as nitrogen, oxygen. The term "alkenyl", as used herein, refers to a branched or straight hydrocarbon chain, comprising two to twenty carbon atoms, preferably four to twelve carbon atoms, especially about eight to ten carbon atoms , which also comprises one or more double bonds of carbon to carbon, preferably around one to three double bonds. The compounds of the present invention can have a known configuration, or they can exist as mixtures of isomers. The term "alkynyl", as used herein, refers to a straight or branched hydrocarbon chain, comprising two to twenty carbon atoms, preferably four to twelve carbon atoms, especially about eight to ten carbon atoms , which also comprises one or more triple carbon to carbon ligatures, preferably around a triple ligature. The compounds of the invention may have a known configuration or may exist as a mixture of isomers. The term "cycloalkyl", as used herein, refers to a monocyclic, saturated hydrocarbon group having from three to seven carbon atoms in the ring, including, but not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. , cycloheptyl and the like. The cyclic group may be optionally substituted, for example, with lower alkyl, hydroxy, halogen or an amino. The term "alkylcycloalkyl", as used herein, refers to a cycloalkyl group as defined above, attached to a lower alkyl radical. The alkylcycloalkyl group is attached to the precursor portion by the alkyl radical, where the alkyl radical is from one to six carbon atoms. Examples include, but are not limited to: cyclopropylmethyl, cyclopropyethyl, cyclobutylmethyl, and the like. The term "aryl", as used herein, refers to a monocyclic, fused bicyclic, or tricyclic fused carbocyclic ring system having one or more aromatic rings including, but not limited to: phenyl, naphthyl, tetrahydronaphthyl, phenanthrenyl, biphenylenyl , indanyl, indenyl and the like. The term "substituted aryl", as used herein, refers to an aryl group as defined herein, substituted by independent replacement of one, two or three of the hydrogen atoms, with Cl, Br, F, I, OH, cyano, mercapto, nitro, alkyl of 1 to 3 carbon atoms, haloalkyl of 1 to 3 carbon atoms, alkoxy of 1 to 6 carbon atoms, thioalkoxy of 1 to 6 carbon atoms, methoxymethoxy, amino, alkyl of 1 to 3 carbon-amino atoms, di (to Iq ui I of 1 to 3 carbon atoms) amino, formyl, carboxy, akoxycarbonyl, alkyl of 1 to 3 carbon atoms-CO-O-, alkyl of 1 to 3 carbon atoms carbon-CO-NH or carboxyamide; except that tetrafluorophenyl and pentafluorophenyl are also included within the definition of "substituted aryl". The term "arylalkyl", as used herein, refers to an aryl group as defined above, connected to an alkyl group as defined above. The arylalkyl group is attached to the precursor portion by means of an alkyl group, where the alkyl group is from one to six carbon atoms. The aryl group in the arylalkyl group may be substituted as defined above. Examples include, but are not limited to, [3- (4-hydroxy) phenyl] propyl, [3- (1-methyl) (4-hydroxy) phenyl] propyl, (4-hydroxybenzyl) methyl and the like. The terms "heterocyclic ring" or "heterocyclic" or "heterocycle", as used herein, refer to any 3 or 4 member ring containing a heteroatom selected from oxygen, nitrogen and sulfur; or a 5, 6 or 7 member ring containing one, two or three nitrogen atoms; a nitrogen atom and a sulfur atom, or a nitrogen atom and an oxygen atom. The 5-membered ring has 0 to 2 double bonds and the 6 and 7-membered ring has 0 to 3 double bonds. The nitrogen heteroatoms may optionally be quaternized. The term "heterocyclic" also includes bicyclic groups, wherein any of the above heterocyclic rings is fused to a benzene ring or a cyclohexane ring or other heterocyclic ring (e.g., indolyl, quinolyl, isoquinolyl, tetrahydroquininoyl, and the like) ). Heterocyclics include: azetidinyl, benzimidazolyl, 1,4-benzodioxanyl, 1,3-benzodioxolyl, benzoxazolyl, benzothiazolyl, benzothienyl, dihydroimidazolyl, dihydropyranyl, dihydrofuranyl, dioxanyl, dioxolanyl, furyl, homopiperidinyl, imidazolyl, imidazolinyl, imidazolidinyl, indo I ini I or, indolyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isoxazolidinyl, isoxazolyl, morpholinyl, naphthyridinyl, oxazolidinyl, oxazolyl, piperazinyl, piperidinyl, pyrazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolyl, pyrrolyl, quinolinyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl. , thiazolyl and thienyl. Heterocyclics can be unsubstituted or monosubstituted or disubstituted with substituents independently selected from hydroxy, halo, oxo (= 0), alkylimino (R * N =, where R * is a lower alkyl group), cycloalkyl, aryl, arylalkyl and lower alkyl . In addition, heterocycles containing nitrogen may be N-protected. The term "(heterocyclic) alkyl", as used herein, refers to a heterocyclic group as defined above, connected to a lower alkyl radical, as defined above. The (heterocyclic) alkyl group is attached to the precursor portion by means of an alkyl group, where the alkyl group is from 1 to 6 carbon atoms. Examples include, but are not limited to: 2-pyridylmethyl, 4-pyridylmethyl, 2-pyridylethyl, 3-pyridylpropyl, 2-pyridylpropyl, 4-pyridylpropyl, 2-furylmethyl, and the like. The term "(heterocyclic) substituted alkyl", as used herein, refers to a heterocycloalkyl group, as defined above, in which the heterocyclic group or the alkyl group is substituted by independent replacement of one, two or three of the hydrogen atoms thereof, with Cl, Br, F, I, OH, cyano, mercapto, nitro, alkyl of 1 to 3 carbon atoms, haloalkyl of 1 to 3 carbon atoms, alkoxy of 1 to 6 carbon atoms , thioalkoxy of 1 to 6 carbon atoms, hydroxyalkyl, methoxymethoxy, amino, alkylamino of 1 to 3 carbon atoms, di (to I qui] of 1 to 3 carbon atoms) amino, carboxyaldehyde, carboxy, alkoxycarbonyl, alkyl of 1 to 3 carbon atoms-CO-O-, alkyl of 1 to 3 carbon atoms-CO-NH- or carboxyamide. Examples include, but are not limited to, 3 - [(5-methyl) -2-pyridyl] propyl, 3 - [(6-methyl) -2-pyridyl] propyl, 4 - [(6-methyl) -2-pyridi I] butyl, (5-nitro) -2-thienylmethyl, and the like. The term "heteroaryl", as used herein, refers to a cyclic aromatic radical having from five to ten ring atoms, of which one ring atom is selected from S, O and N; zero, one or two ring atoms are additional heteroatoms, selected from S, O and N; and the remaining ring atoms are carbon; the radical being attached to the rest of the molecule by any of the ring atoms; for example: pyridinyl, pyrazinyl, pyriridinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, thienyl, furanyl, quinolinyl, isoquinolinyl and the like. The term "substituted heteroaryl", as used herein, refers to a heteroaryl group as defined herein, substituted by independent replacement of one, two or three of the hydrogen atoms, with Cl, Br, F, I, OH, alkyl of 1 to 3 carbon atoms, alkoxy of 1 to 6 carbon atoms, methoxymethoxy, amino, or alkylamino of 1 to 3 carbon atoms; or it may also refer to a mono-oxo-substituted heteroaryl compound, such as, for example, 4-oxo-1 H-quinoline. The term "aprotic solvent", as used herein, refers to a solvent that is relatively inert in terms of proton activity, that is, it does not act as a proton donor. Examples include, but are not limited to: hydrocarbons, such as hexane and toluene; for example, halogenated hydrocarbons, such as, for example: methylene chloride, ethylene chloride, chloroform and the like; heterocyclic compounds, such as, for example, tetrahydrofuran and N-methylpyrrolidinone; ethers, such as diethyl ether and bis-methoxymethyl ether, as well as various other compounds, such as dimethylformamide, acetonitrile, acetone and ethyl acetate. Such compounds are well known to those skilled in the art and it will be obvious to those skilled in the art that individual solvents or mixtures thereof may be preferred for specific compounds and reaction conditions, depending on factors such as the solubility of the reagents, the reactivity of the reagents and preferred temperature scales, for example. Other discussions of aprotic solvents can be found in organic chemistry texts or in specialized monographs, for example: Organic Solvent Physical Properties and Methods of Purification, 4a. edition, edited by John A. Riddick and others, volume II of the Techniques of Chemistry series, John Wiley & Sons, NY, 1986. As used herein, the term "pharmaceutically acceptable salt" refers to those salts which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human and lower animals, without toxicity. irritation, allergic response and the like, undue; and is consistent with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge and coauthors describe pharmaceutically acceptable salts, in detail, in J. Pharmaceutical Sciences, 66: 1-19 (1977), incorporated herein by this reference. The salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately, by reacting the free base function with a suitable organic or inorganic acid. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or with organic acids such as acetic acid, acid oxalic, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid; or by the use of other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include: the adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphor sulfonate, citrate, cyclopentane propionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, iodhydrate, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate , succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate and the like. Representative salts of alkali metal and alkaline earth metal include salts of sodium, lithium, potassium, calcium, magnesium and the like. Other pharmaceutically acceptable salts include, when appropriate, the non-toxic ammonium, quaternary ammonium and amine cation salts formed by the use of counter ions, such as haiogenide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkylsulfonate and Arylsulfonate. As used herein, the term "pharmaceutically acceptable esters" refers to esters that are hydrolyzed in vivo and include those that are readily decomposed in the human body to leave the parent compound or its salt. Suitable ester groups include, for example, pharmaceutically acceptable aliphatic carboxylic acid derivatives, in particular alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, wherein each alkyl or alkenyl portion advantageously has no more than six carbon atoms. Examples of particular esters include formates, acetates, propionates, butyrates, acrylates and ethylsuccinates. There may be numerous asymmetric centers in the compounds of the present invention. Except when noted otherwise, the present invention contemplates the various stereoisomers and mixtures thereof. Consequently, whenever a ligature is represented by a wavy line, it is intended that a mixture of stereo orientations, or an individual isomer of assigned or unassigned orientation, may be present.

PREFERRED MODALITIES Preferred compounds of the invention comprise those in which R and R 'are alkyl, alkenyl, cycloalkyl, heterocyclic, (heterocyclic) alkyl or alkylcycloalkyl; X and Y are independently chloro, fluoro, dioxolane, hydrogen or alkoxy; A is -C; R2 and 3 are hydrogen or cyclopropyl and n is 1. Representative compounds of the invention are selected from the group consisting of: 11, 12- (cyclic carbamate) 3 ', 3'-N-bisdesmethyl-3', 3'- N-bis-cyclopropylmethyl-11-deoxy-11- [carboxy (3,4-dichlorophenethylamino)] - 6-O-methyl-erythromycin A; 11, 12- (cyclic carbamate) of 3 ', 3'-N-bis-desmethyl-3', 3'-N-bis-cyclobutyl-11-deoxy-11- [carboxy (3,4-dichlorophenethylamino)] -6-O-methyl-erythromycin A; 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3', 3'-N-bis-cyclopropylmethyl-11-deoxy-11- [carboxy (4-chlorophenethylamino)] - 6-O -methyl-epromycin A; 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3', 3'-N-bis-cyclobutyl-11-deoxy-11- [carboxy (4-chlorophenethylamino)] - 6-0 -methyl-erythromycin A; 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3'-N-cyclobutyl-3'-Nisopropyl-3'-N-isopropyl-11-deoxy-11- [carboxy (4- chlorphenethylamine)] - 6-O-methyl-erythromycin A; 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3'-N-isopropyl-3'-N-propyl-11-deoxy-11- [carboxy (4-chlorophenethylamino)] - 6 -O-methyl-erythromycin A; 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3'-N-cyclopropylmethyl-3'-N-propyl-11-deoxy-11- [carboxy (4-cyranophenylamino)] - 6 -O-methyl-erythromycin A; 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3'-N-etiII-3'-N-isopropyl-11-deoxy-11- [carboxy (4-chlorophenethylamino)] -6-O-metii-erythromycin A; 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3'-N-cyclobutylmethyl-3'-N-cyclopropylmethyl-11-deoxy-11- [carboxy (4-chlorophenethylamino)] - 6 -O-methyl-erythromycin A; 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3', 3'-N-bis-cyclopropylmethyl-11-deoxy-11- [carboxy (4-chlorophenethylamino)] - 6 -0-methyl-erythromycin A; 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3', 3'-N-bis-cyclopropylmethyl-11-deoxy-11 - [carboxy (4-chlorophenethylamine)] -6-O-methyl-erythromycin A; 11,12- (cyclic carbamate) 3 ', 3'-N-bisdesmethyl-3', 3'-N-bis-cyclobutyl-11-deoxy-11 - [carboxy- (4-chloro-3-f Iorofenet ilamino)] - 6-O-metii-erythromycin A; 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3', 3'-N-bis-cyclopropylmethyl-11-deoxy-11- [carboxy (4-chloro-3-fluorophenethyl amino) ] -6-O-methyl-erythromycin A; 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3', 3'-N-bis-cyclobutyl-11-deoxy-11- [carboxy (4-chloro-3-fluorofenetylamino)] -6-O-methyl-erythromycin A; 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3', 3'-N-bis-cyclopropylmethyl-11-deoxy-11- [carboxy (3-cioro-4-fluoro phenethyl amino )] - 6-O-methyl-erythromycin A; 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3'-N-cyclopentyl-3'-N-cyclopropylmethyl-11-deoxy-11- [carboxy (3-chloro-4-fluorophenethyl amino)] - 6-O-methyl-erythromycin A; 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3', 3'-N-bis-cyclopropylmethyl-11-deoxy-11- [carboxy (3,4-difluorophenethyl amino)] - 6-O-methyl-erythromycin A; 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3', 3'-N-bis-cyclobutyl-11-deoxy-11- [carboxy (3,4-difluoro phenethyl amino)] -6-O-methyl-erythromycin A; 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3'-N-cyclobutyl-3'-N-cyclopropylmethyl-11-deoxy-11- [carboxy (3-chloro-4-fluorophenethyl amino)] - 6-0-methyl-erythromycin A; 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3', 3'-N-bis- [3, - (3-pyridyl) propyl] -11-deoxy-11 - [ca rboxi - (3-chloro-4-f luorof eethylamino)] - 6-O-methyl-erythromycin A; 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3'-N-cyclopropylmethyl-3'-N- (4-hydroxymethyl-2-furyl) -11-deoxy-11- [carboxy] (3-chloro-4-fluorophenethylamino)] - 6-O-methyl-erythromycin A; 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3'-N-cyclopropylmethyl-3'-N- (4-pyridyl) propyl-11-deoxy-11 - [carboxy (3-) chloro-4-fluorophenethylamino)] - 6-O-methyl-erythromycin A; 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3', 3'-N-cycloproylmethyl-3'-N- (4-hydroxymethyl-2-furyl) -11-deoxy-11 - [carboxy (3-cyano-4-fluorophenethylamino)] - 6-O-methyl-erythromycin A 11,12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3'-N-cyclopropylmethyl-3'-N- (2-furyl) methyl-11-deoxy-11- [carboxy (3- chloro-4-fluorophenethylamino)] - 6-0-methyl-erythromycin A; 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3'-N-cyclopropylmethyl-3'-N- [6-methyl (2-pyridyl)] methyl-11-deoxy-11- [ carboxy (3-chloro-4-fluorophenethylamino)] - 6-O-methyl-erithromycin A; 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3'-N-bis- (1-methylcyclopropyl) methyl-11-deoxy-11- [carboxy (3-chloro-4-fluorophenethylamino )] - 6-0-methyl-erythromycin A; 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3'-N-bis (1-methylcyclopropylmethyl) methyl-11-deoxy-11- [carboxy (3,4-dichlorophenethylamino)] - 6-O-methyl-erythromycin A; 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3'-N- (1-methylcyclopropyl) methyl-3'-N-cyclopropylmethyl-11-deoxy-11- [carboxy (3-) chloro-4-fluorophenethylamino)] - 6-O-methyl-erythromycin A; 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3'-N- (1-methylcyclopropyl) methyl-3'-cyclopropiimethyl-11-deoxy-11- [carboxy- (3,4- dichlorophenethylamino)] - 6-O-methyl-erythromycin A; 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3'-N-isopropyl-3'-cyclopropylmethyl-11-deoxy-11- [carboxy (3-chloro-4-fluorophenethylamino)] -6-0-methyl-erythromycin A; 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3'-N-isopropyl-3'-N-cyclopropylmethyl-11-deoxy-11- [carboxy (3,4-dichlorophenethylamino)] -6-0-methyl-erythromycin A; 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3'-N-isopropyl-3'-N- (1-methylcyclopropyl) methyl-11-deoxy-11- [carboxy (3- chloro-4-fluorophenethylamino)] - 6-O-methyl-erythromycin A; 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3'-N-isopropyl-3'-N- (1-methylcyclopropyl) methyl-11-deoxy-11- [carboxy (3, 4-dichlorophenethylamino)] - 6-0-methyl-erythromycin A; 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3'-N-cyclopropylmethyl-3'-N- (bis-cyclopropyl) methyl-11-deoxy-11- [carboxy (3- chloro-4-fluorophenethylamino)] - 6-0-methyl-erythromycin A; 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3'-N-cyclopropylmethyl-3'-N- (bis-cyclopropyl) methyl-11-deoxy-11- [carboxy (3, 4-dichlorophenethylamino)] - 6-O-methyl-erythromycin A; 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3'-N-cyclopropylmethyl-3'-N- (2,2-dimethylpropyl) -11-deoxy-11 - [carboxy - (3 -chloro-4-fluorophenethylamino)] - 6-O-methyl-erythromycin A; 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3'-N-cyclopropylmethyl-3'-N- (2,2-dimethylpropyl) -11-deoxy-11- [carboxy (3 , 4-dichlorophenethylamino)] - 6-0-methyl-erythromycin A; 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3'-N-cyclopropylmethyl-3'-N- [3- (4-hydroxy-3-methoxyphenyl) -1-methyl] propyl-11- deoxy-11- [carboxy (3-chloro-4-fluorophenethylamino)] - 6-O-metii-erythromycin A; 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3'-N-cyclopropylmethyl-3'-N- [3- (4-hydroxy-3-methoxyphenyl) -1-methyl] propyl-11- deoxy-11- [carboxy (3,4-dichlorophenethylamino)] - 6-O-methyl-erythromycin A; 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3'-N-cyclobutyl-3'-N- (1-methylcyclopropyl) methyl-11-deoxy-11- [carboxy (3- chloro-4-fluorophenethylamino)] - 6-0-methyl-erythromycin A; 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3'-N-cyclobutyl-3'-N- (1-methylcyclopropyl) methyl-11-deoxy-11- [carboxy (3, 4-dichlorophenethylamino)] - 6-0-methyl-erythromycin A; 11,12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3'-N-cyclopro-ylmethyl-3'-N- (1-ethylcyclopropyl) methyl-11-deoxy-11- [carboxy (3 -chloro-4-fluorophenethylamino)] - 6-O-methyl-erythromycin A; 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3'-N-cyclopropylmethyl-3'-N- (1-ethylcyclopropyl) methyl-11-deoxy-11- [carboxy- (3 , 4-dic! Orphenethylamino)] - 6-0-methyl-erythromycin A; 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3'-N-cyclopropylmethyl-3'-N- (1-phenylcyclopropyl) methyl-11-deoxy-11- [carboxy (3 -chloro-4-fluorophenethylamino)] - 6-O-methyl-erythromycin A; 11, 12- (cyclic carbamate) 3 ', 3'-N-bisdesmethyl-3'-N-cyclopropyl methyl-3'-N- (1-phenyl or pro-I) m ethyl-11-deoxy -11 - [carboxy (3,4-diciorphene-phenylamino)] - 6-0-methyl-erythromycin A; 11,12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethi-3'-N-ethyl-3'-N- (1-methylcyclopropyl) methyl-11-deoxy-11- [carboxy (3- chloro-4-fluorophenethylamino)] - 6-0-methyl-erythromycin A; 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3'-N-ethyl-3'-N- (1-methylcyclopropyl) methyl-11-deoxy-11- [carboxy- (3 , 4-dichlorophenethylamino)] - 6-O-methyl-erythromycin A; 11, 12- (cyclic carbamate) of 3 \ 3'-N-bisdesmethyl-3'-N-isobutyl-3'-N- (1-methylcyclopropyl) methyl-11-deoxy-11- [carboxy] (3-chloro-4-fluorophenethylamino)] - 6-0-methyl-erythromycin A; 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3'-N-isobutyl-3'-N- (1-methylcyclopropyl) methyl-11-deoxy-11- [carboxy (3, 4-dichlorophenethylamino)] - 6-0-methyl-erythromycin A; 11,12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3'-N-cyclopropylmethyl-3'-N- (1-allylcyclopropy) methyl-11-deoxy-11- [carboxy- ( 3-chloro-4-fluorophenethylamino)] - 6-0-methyl-erythromycin A; 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3'-N-cyclopropylmethyl-3'-N- (1-amino-cyclopropyl) methyl-11-deoxy-11- [carboxy (3, 4-dichlorophenethylamino)] - 6-O-methyl-erythromycin A; 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3'-N-cyclopropylmethyl-3'-N- (1-benzylcyclopropyl) methyl-11-deoxy-11 - [carboxy (3 -chloro-4-fluorophenethylamino)] - 6-O-methyl-erythromycin A; 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3'-N-cyclopropylmethyl-3'-N- (1-benzylcyclopropyl) methyl-11-deoxy-11 - [carboxy (3, 4-dichlorophenethylamino)] - 6-O-methyl-erythromycin A; 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3'-N-bis- (1-methylcyclobutyl) methyl-11-deoxy-11- [carboxy (3-chloro-4-fluorophenethylamino )] - 6-0-methyl-erythromycin A; 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3'-N-bis- (1-methylcyclobutyl) methyl-11-deoxy-11- [carboxy (3,4-dichloro phenethyl amino )] - 6-O-methyl-erythromycin A; 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3'-N-cyclopropylmethyl-3'-N- (1-methylcyclobutyl) methyl-11-deoxy-11- [carboxy (3-) chloro-4-fluorophenethylamino)] - 6-0-methyl-erythromycin A; and 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3'-N-cyclopropylmethyl-3'-N- (1-methylcyanobutyl) methyl-11-deoxy-11- [carboxy- ( 3,4-dichlorophenethylamino)] - 6-O-methyl-erythromycin A. The most preferred compounds of the invention are: 11, 12- (cyclic carbamate) 3 ', 3'-N-bisdesmethyl-3'-N- bis-cyclopropylmethyl-11-deoxy-11- [carboxy (3-chloro-4-fluoro-phenethyl-amino)] - 6-O-methyl-erythromycin A; 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3'-N-b1scyclobutyl-11-deoxy-11- [carboxy (3-chloro-4-fluorophenethylamino)] - 6-O- methyl-erythromycin A; 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3', 3'-N-bis- (1-methylcyclopropyl) methyl-11-deoxy-11- [carboxy (3-chloro- 4-fluorophenethylamino)] - 6-O-methyl-erythromycin A; and 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3'-N-isopropyl-3'-N- (1-methylcyclopropyl) methyl-11-deoxy-11- [carboxy (3 -chloro-4-fluorophenethylamino)] - 6-O-methyl-erythromycin A.

EFFECT AND UTILITIES OF THE LHRH AGONISTS AND ANTAGONISTS The LHRH agonist and antagonist compounds of the present invention are useful for the treatment of precocious puberty, prostate cancer, benign prosthetic hyperplasia (BPH), endometriosis, uterine fibroids, breast cancer, acne, premenstrual syndrome, polycystic ovarian syndrome and diseases that are the result of excesses or deficiencies in the production of gonadal hormones, in any of the sexes of humans and animals. The LHRH antagonists of the present invention are also useful for controlling reproduction in both females and males. The compounds of the invention are useful for suppressing levels of testosterone and dihydroxytestosterone (DHT) in males, and estrogen and estradiol in females. In the practice of the method of this invention, an effective amount of a compound of the invention or a pharmaceutical composition containing it is administered to the human or animal that needs or desires said treatment. Those compounds or compositions can be administered by a variety of routes, depending on the specific end use; and include routes of oral, parenteral (including subcutaneous, intramuscular and intravenous administration), vaginal (in particular for anticoagulation), rectal, buccal (including sublingual), transdermal or intranasal administration. The most appropriate route, in any given case, will depend on the use, the particular active ingredient, the subject involved and the judgment of the medical practitioner. The compound or composition can also be administered by means of slow-release, depot or implant formulations, as described more fully below. In general, to modulate sex hormone levels in male or female mammals, for the uses described hereinabove, it is expedient to administer the active ingredient in amounts between about 1 and 200 mg / kg of body weight per day, preferably between 1 and 30 mg / kg of body weight per day. This administration can be achieved through a single daily administration, by distribution in several applications, or by slow release, in order to obtain the most effective results. The exact dose and the exact regimen for the administration of these compounds and compositions will necessarily depend on the needs of the individual subject being treated, the type of treatment, the degree of distress or need, and the judgment of the medical practitioner. In general, parenteral administration requires less dosage than other methods of administration, which depend more on absorption. Another additional aspect of the present invention relates to pharmaceutical compositions containing as active ingredient a compound of the present invention, compositions comprising said compound in admixture with a non-toxic, pharmaceutically acceptable carrier. As mentioned above those compositions can be prepared for use in parenteral administration (subcutaneous, intramuscular or intravenous), particularly in the form of liquid solutions or suspensions; for use in vaginal or rectal administration, particularly in semi-solid forms, such as creams and suppositories; for oral or buccal administration, particularly in the form of tablets or capsules, or intranasally, in particular in the form of powders, nasal drops or aerosols. The compositions can be conveniently administered in unit dosage form and can be prepared by any of the methods well known in the pharmaceutical art, for example, as described in Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, USA, 1970 The formulations for parenteral administration may contain as common excipients, sterile water or saline; polyalkylene glycols, such as polyethylene glycol, oils of vegetable origin, hydrogenated naphthalenes and the like. Formulations for administration by inhalation can be solid and contain as excipients, for example, lactose, or they can be aqueous or oily solutions for administration in the form of nasal drops. For buccal administration, typical excipients include, sugars, calcium stearate, magnesium stearate, pregelatinized starch and the like. It is particularly convenient to deliver the compounds of the present invention to the subject, for extended periods of time, for example, for periods of one week to one year of an individual administration. Various forms of slow-release, depot or implant doses can be used. For example, a dosage form may contain a non-toxic, pharmaceutically acceptable salt of a compound of the invention that has a slow degree of solubility in body fluids.; for example: (a) an acid addition salt with a polybasic acid, such as phosphoric acid, sulfuric acid, citric acid, tartaric acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalene-monosulfonic or disulfonic acids; polygalacturonic acid, and the like; (b) a salt with a polyvalent metal cation, such as zinc, calcium, bismuth, barium, magnesium, aluminum, copper, cobalt, nickel, cadmium and the like; or with an organic cation formed, for example, from N, N-debenzylethylenediamine or ethylenediamine; or (c) combinations of (a) and (b), for example, a zinc tannate salt. Additionally, the compounds of the present invention, or preferably a relatively insoluble salt, such as those just described, can be formulated in a gel; for example, an aluminum monostearate gel, for example, with sesame oil, suitable for injection. Particularly preferred salts are zinc salts, zinc tannate salts, pamoate salts and the like. Another type of slow release depot formulation for injection would contain the compound or salt dispersed or encapsulated in a non-antigenic, nontoxic, slowly degrading polymer, such as a polylactic acid / polyglycolic acid polymer, for example, as it was described in US Patent No. 3,773,919 The compounds of the invention or, preferably, the relatively insoluble salts, as described above, can be formulated into cholesterol matrix pellets, in particular for use in animals. slow release, depot or implant, for example, liposomes, are well known in the literature, see, for example, Sustained and Controlled Relay Drug Delivery Systems, JR Robinson ed., Marcel Dekker, Inc., New York, 1978. Reference can be found with respect to compounds of the LHRH type, for example, in US Patent 4,010,125.

The LHRH ANTAGONIST ACTIVITY Representative compounds of the present invention were evaluated in in vitro tests for rat pituitary LHRH receptor binding (pK1) and for inhibition of LH from rat pituitary cells for antagonistic potency (pA2). The tests employed the methods detailed in F. Haviv and co-authors, J. Med. Chem., 32: 2340-2344 (1989). The receptor binding affinity (pK |) is the negative logarithm of the equilibrium dissociation constants. The results of the pK | for the representative compounds of the present invention are presented in table 1.

TABLE I The pA2 value is the negative logarithm of the antagonist concentration that bypasses the response curve produced by the leuprolide agonist at a concentration twice as high. Leuprolide is the LHRH agonist having the pyro-Glu1-His2-Trp3-Ser4-Tyr5-D-Leu6-Leu7-Arg8-Pro9-NHEt structure and is described and claimed in US Patent 4,005,063. Typically pA2 values of 7.0 or greater are indicative of good LHRH antagonist potency. The pA2 values for representative compounds are indicated in Table 2 below.

TABLE 2 METHODS OF SYNTHESIS The compounds and processes of the present invention will be better understood in connection with the synthesis schemes 1 to 6 that follow, which illustrate the methods by which the compounds of the invention can be prepared. The compounds are prepared using commercially available or synthesized reagents.

ABBREVIATIONS The abbreviations that have been used in the descriptions of the scheme and the examples that come later are: Ac by acetyl; APCI by chemical ionization at atmospheric pressure; CDI by carbonyldiimidazide; CH3CN by acetonitrile; Cl or DCI by chemical ionization by desorption; DMF by dimethylformamide; ESI by ionization by electrospray; EtOAc for ethyl acetate; FAB by bombardment with fast atoms; FTIR by infrared Fourier transformation spectroscopy; HPLC by high performance liquid chromatography; IR by infrared spectroscopy; MeOH by methanol; MHz per megahertz; MIC by microscope; MS by mass spectra; NaHMDS by sodium hexamethyldisilazide; NMR by nuclear magnetic resonance; Rf by retention factor; Rt by retention time; TBAF by tetrabutylammonium fluoride; THF by tetrahydrofuran; TLC by thin layer chromatography; TMS by trimethylsilyl; TMS Cl by trimethylsilyl chloride and DCM by dichloromethane. The starting material 1, 6-O-methyl-erythromycin A (clarithromycin, commercially available as BIAXIN® from Abbott Laboratories) is protected at the 2 'and 4"positions by reaction with a suitable hydroxy protecting reagent, such as those described by TW Greene and PGM Wuts in Protective Groups in Organic Synthesis, 2nd edition, John Wiley &Son, Inc., 1991. Protective hydroxy reactants include, for example: acetic anhydride, benzoic anhydride, benzyl chloroformate, hexamethyldisilazane or trialkylsilyl chloride, in an aprotic solvent.

SCHEME 1 25 SCHEME 1 (continued) As shown in scheme 1, protection of the 2'-hydroxy and 4"-hydroxy groups of 6-O-methylerythromycin A (1) can be achieved, sequentially or simultaneously to give the compound (2), where Rp is a hydroxy protecting group A preferred protecting Rp group is trimethylsilyl or acetyl Examples of aprotic solvents are dichloromethane, chloroform, DMF, tetrahydrofuran (THF), N-methylpyrrolidinone, dimethyl sulfoxide, diethyl sulfoxide, N, N-dimethylformamide, N, N-dimethylacetamide, hexamethylphosphoric triamide, a mixture thereof or a mixture of one of these solvents with ether, tetrahydrofuran, 1,2-dimethoxyethane, acetonitrile, ethyl acetate, acetone and the like. aprotic do not adversely affect the reaction and are preferably: dichloromethane, chloroform, DMF, tetrahydrofuran (THF), N-methylpyrrolidinone or a mixture thereof Compound (2) protected with sodium hexamethyldisilazide or sodium hydride in a solvent aprót at 0-25 ° C, and carbonyldiimidazole, to produce the compound (3). The treatment of the compound (3) with an amino compound of the formula H? without solvent or in acetonitrile at 25-80 ° C, followed by deprotection, results in the formation of N-substituted cyclic carbamate, represented by compound (4). The deprotection of the protecting groups of 2'-hydroxy and 4"-hydroxy to obtain the compound (4) is carried out by the methods described by TW Greene and PGM W? Ts in Protective Groups in Organic Synthesis, 2nd edition, John Wiley &Son, Inc., 1991.

In one embodiment of the process demethylation of the 3'-N-dimethyl group is obtained stepwise, treating the compound (4) with iodine, in the presence of a suitable base, such as sodium acetate, and a light or thermal source; after which it is inactivated with sodium thiosulfate and treated to remove the first methyl group to produce the compound (5). The second methyl group is eliminated by treating with iodine, with a moderate base, such as tribasic potassium phosphate, and with a light source, to form bisdesmethylamine (6). N-demethylation can also be effected by reaction of the compound (4) with chloroformate reagents, such as benzyl chloroformate, allyl chloroformate, vinyl chloroformate and the like. The alkylation of the 3'-N-bis-desmethyl compound (6) is obtained by reaction with an appropriate aldehyde or ketone, in the presence of a metal hydride, such as sodium cyanoborohydride or sodium triacetoxyborohydride, or in. presence of a Pd / C catalyst, in a protic or non-protic solvent, under a hydrogen atmosphere. The aldehydes and ketones that can be used in the preparation of compound (7) include, for example: cyclopropylcarboxaldehyde, acetone, n-propanal, cyclohexanone, cyclopentanone, isovaleraldehyde, cyclobutanone, isopropyl aldehyde, 2'-pyridinecarboxyaldehyde, -thiazole-carboxyaldehyde. The alkylation of the 3 ', 3'-N-bisdesmethyl compound (6) can also be obtained by reaction with an appropriate alkylating agent, in the presence of a base, by methods known in the art, to give the compound (7). Alkylating agents which can be used in the preparation of compound (7) include the lower alkyl halides, co or ethyl bromide, lower alkyl halides substituted with halogen, lower alkyl halides substituted with cyano, lower alkyl halides substituted with hydroxy, other lower alkenyl halides, such as methylallyl chloride, lower alkynyl halides, such as propargyl bromide, lower cycloalkyl halides, lower cycloalkylmethyl halides, such as cyclopropylmethyl halides and cyclopropylbenzyl. In another embodiment of the process, both demethylation and alkylation are carried out sequentially, as illustrated in scheme 2. The first demethylation of compound (4) is carried out as described above, to obtain the compound ( 5), which is then monoalkylated in the manner described above to give (8). The second demethylation is then obtained as described above, to give the compound (9), which is then alkylated to produce the compound 7.

SCHEME 2 Scheme 3 illustrates a specific modality of the general scheme described in scheme 1. As illustrated in scheme 3, the treatment of 2'-acetyl-6-O-methyl-erythromycin A (10) with trimethylsilyl chloride produces the compound (11). Compound (11) is treated with sodium hexamethyldisilazide and carbonyldiimidazole to give the derivative 12-O-acylimidazole, which is subsequently reacted with 3,4-dichlorophenethylamine to form the cyclic 11, 12-carbamate derivative. The cyclic 11,12-carbamate thus obtained is treated with methanol to give the compound (12). deprotection of the 4"-protected hydroxy group is accomplished by methods known in the art, to give the compound (13) .The treatment of the compound (13) with iodine, in the presence of sodium acetate, followed by inactivation of the reaction with sodium bisulfite, produces the compound (14) .The second demethylation is achieved by treating 14 with iodine, tribasic potassium phosphate and a light source, to form the bis-demethylamine (15) .. The bisalkylation of the 3'-nitrogen is obtained by reaction with cyclopropanecarboxyaldehyde, in the presence of sodium cyanoborohydride in methanol and acetic acid, to give the final product, compound (16).

SCHEME 3 Já 45 SCHEME 3 (continued) 1É Scheme 4 illustrates a specific embodiment of the general example described in scheme 2, which involves the treatment of 2'-acetyl-6-O-methyl-erythromycin A (10) with trimethylsilyl chloride, to give the compound (11) . The compound (11) is treated with sodium hexamethyldisilazide and carbonyldiimidazole to give the derivative 12-O-acylimidazole, which is subsequently reacted with 4-chlorophenethylamine to form the cyclic 11, 12-carbamate derivative. The cyclic 11, 12-carbamate thus obtained is treated with methanol to give the compound (17). The deprotection of the hydroxy group 4"-protected by methods known in the art is achieved to give the compound (18) .The treatment of the compound (18) with iodine, in the presence of sodium acetate, followed by inactivation of the mixture of reaction with sodium bisulfite, produces the compound 19. The first alkylation is obtained by reaction with acetone, in the presence of sodium cyanoborohydride in methanol and a few drops of acetic acid, to give the final product, the compound (20). it achieves the second dealkylation by treating (20) with iodine, sodium acetate and a light source to form the demethylamine (21). The alkylation of the 3'-nitrogen is obtained by reaction with cyclobutanone in the presence of sodium cyanoborohydride in methanol and acetic acid. , to give the final product, the compound (22).

SCHEME 4 £ SCHEME 4 (continued) Scheme 5 illustrates a third example for a preparation method, for an example described here. In this example, different alkyl groups are added to the amine (23) in a sequential manner to form (25).

SCHEME 5 M.

The above can be better understood by reference to the following examples, which are presented to illustrate and not to limit the scope of the inventive concept.

EXAMPLES EXAMPLE 1 11,12-CYCLEIC ICARBAMATE) OF 3 ', 3'-N-BISDESMETIL-3'.3'-N- BISCICLOPROPYLMETIL-11-DESOXY-11-rCARBOXY- (4- CHLOROPHENETHYLAMINE) 1-6-Q- METHYL-ERYTHROMYCIN A 6-O-methyl-erythromycin (commercially available from Abbott Laboratories as BIAXIN®, in the 2 'position, with the acetyl protecting group was protected by the methods described in the literature.

Step 1: 2'-O-acetyl-4"-O-trimethylsilyl-6-O-methyl-erythromycin A (Compound 11, scheme 3) 45 g (57 mmol) of 2'-0-acetyl-6 was dissolved 0-methyl-erythromycin A in 450 ml of CH 2 Cl 2 and cooled to 0 ° C in an ice / water bath, 13.8 ml (171 mmol) of pyridine was added in one portion, followed by the dropwise addition of 14.5 ml ( 114 mmol) of TMS-CI for a period of 15 minutes The reaction was stirred for one hour, under the protection of a drying tube, after which the TLC (CH2Cl2: MeOH, 9: 1) indicated the complete conversion to a new material, less polar. Then the reaction was quenched with 500 ml of 0.5 M NaH2PO4, the organic layer was separated and washed with 300 ml of water, 300 ml of saturated sodium bicarbonate, 300 ml of water and 100 ml of water. of brine, before drying over sodium sulfate, filtering and concentrating, the residue was crystallized from acetonitrile to give 48 g of (11) (98%). p.f. 235-237 ° C (CH 3 CN); Rf = 0.5 (CH2Cl2: MeOH, 9: 1); MS ESI (M + H) + at m / z 862. NMR with 13 C (75 MHz, CDCl 3) delta 221.0, 175.6, 169.9, 100.0, 96.0, 80.5, 80.3, 78.3, 77.8, 76.4, 74.1, 73.2, 72.0, 69.0 , 67.1, 65.2, 62.7, 50.3, 49.4, 45.1, 44.9, 40.5, 38.7, 38.6, 37.1, 35.6, 30.9, 22.1, 21.5, 21.4, 20.9, 19.7, 19.2, 19.2, 19.8, 17.8, 15.9, 15.8, 12.1, 10.4, 8.9 , 0.8.

Step 2: 11, 12- (cyclic carbamate) of 4"-Q-trimethylsilyl-11-deoxy-11-rcarboxy- (3,4-dichlorophenethylamino) 1-6-Q-methyl-erythromycin A- (Compound 12 Scheme 3) 6.0 g (6.96 mmol) of compound (11) from the previous step was dissolved in 10 ml of anhydrous THF, then diluted with 50 ml of DMF The resulting solution was cooled in an ice / water bath and treated with 5.64 g (34.8 mmol) of 1, 1'-carbonyldiimidazole in one portion, followed by the portionwise addition of 1.0 g (25 mmol) of NaH (60% suspension in oil). at room temperature and stirred under nitrogen for one hour, after which the TLC [EtOAc: MeOH, 95: 5, visualization with Ce (IV)] indicated complete conversion to a more polar material, active uv .. The reaction was quenched carefully with water and then divided by 300 ml of EtOAc and 300 ml of water. The organic phase was collected and washed with 300 ml of 1N NaOH, 2 x 300 ml of water and 200 ml of brine, before drying over sodium sulfate and concentrating. A sample of the resulting colorless foam was subjected to mass spectral analysis, which showed the desired (M + H) + at m / z 938. The remaining material was dissolved in 25 ml of acetonitrile, treated with 5.0 g (26 mmol) of 3,4-dichlorophenethylamine and stirred under nitrogen at 55 ° C. After 48 hours, TLC [EtOAc: MeOH, 95: 5, visualization with Ce (IV)] indicated complete conversion to a less polar material, which precipitated on cooling to room temperature. The resulting precipitate was recrystallized from acetonitrile to give 5.74 g of the protected cyclic carbamate as colorless needles. MS (ESI) (M + H) + at m / z 1059; NMR with 13 C (75 MHz, CDCl 3) delta 216.4, 176.3, 170.1, 157.2, 139.3, 132.2, 131.1, 130.3, 130.1, 128.4, 100.2, 96.3, 82.8, 80.5, 79.9, 79.0 ,. 77.5, 76.2, 67.4, 65.4, 62.8, 50.5, 49.6, 45.5, 45.3, 44.8, 41.8, 39.2, 38.7, 38.5, 35.7, 32.6, 31.0, 22.2, 21.2, 21.6, 20.2, 19.3, 18.8, 16.1, 14.3. , 14.1, 10.2, 9.2, 1.9, 0.8. 5.74 g (5.42 mmol) of the protected cyclic carbamate was suspended in 250 ml of methanol and the suspension was heated to 55 ° C under the protection of a drying tube. After 24 hours the TLC [Methylene Chloride: MeOH, 9: 1, visualization with Ce (IV)] indicated the complete conversion to a new more polar material, which crystallized upon cooling to room temperature. The resulting solid was crystallized from MeOH / water to give 5.24 g of compound (12) (74% of 11). p.f. 112-114 ° C; Rf = 0.65 (methylene chloride: MeOH, 9: 1); MS (ESI) (M + H) + at m / z 1017. HRMS m / z (M + H) + calculated 999.5116; observed, 999.5110. NMR with 1H (300 MHz, CDCl 3) d 7.46 (d, J = 2 Hz, Ar H), 7.35 (d, J = 8 Hz, Ar H), 7.19 (dd, J = 8, 2 Hz, Ar H) , 4.91 (d, J = 4.4 Hz, 1H), 4.56 (d, J = 7 Hz, 1H, C-1 'CH), 3.75 (d, J = 10 Hz, 1H, C-3 CH), 3.70 ( s, 1H, C-11 CH), 3.67 (d, J = 8 Hz, 1H, C-1 'CH), 3.75 (d, J = 10 Hz, 1H, C-3 CH), 3.70 (s, 1H , C-11 CH), 3.67 (d, J = 8 Hz, 1H, C-5 CH), 3.31 (s, 3H, C-6 OCH3), 3.07 (s, 3H, C-6 OCH3), 2.38 ( d, J = 15 Hz, 1H, C-2"CH), 2.28 (s, 6H, C-2 'N (CH3) 2, 1.43 (s, 3H, C-6 CHa), 1-40 (s, 3H, C-12, CH3), 1.07 (d, J = 23 Hz, 3H * 7 C-10 CH3), 0.82 (t, J = 7 Hz, 3H, C-15 CH3), 0.16 (s, 9H, C-4"OSI (CH3) 3. NMR with 13 C (75 MHz, CDCl 3) d 216.1, 176.5, 157.2, 139.3, 132.1, 131.0, 130.2, 130.0, 128.4, 102.4, 96.6, 82.8, 80.6, 79.9, 79.0, 78.0, 76.1, 73.1, 71.1, 68.0, 65.2, 64.7, 60.3, 50.6, 49.6, 45.5, 45.3, 44.8, 44.8, 40.0 (2C), 39.1, 38.9, 35.6, 32.6, 28.6, 28.6, 22.1, 21.8, 21.7, 20.1, 19.2 , 18.8.16.0, 14.1, 14.0, 10.2, 9.0, 0.8.

Step 3.- 11, 12- (cyclic carbamate) of 11 -deoxy-11-rcarboxy- (3,4-dichlorophenethylamino) 1-6-Q-methyl-erithromycin A.- (compound 13, scheme 3) . 5.24 g (5.15 mmol) of the compound (12) from the previous step was dissolved in 50 ml of THF, treated with 5.4 ml of TBAF (1M / THF, 2.6 mmol) and stirred at room temperature. After two hours TLC [CHCl3: MeOH: NHOH, 90: 8: 1, visualization with Ce (IV)] indicated complete conversion to a new more polar material. The reaction mixture was partitioned between 300 ml of ethyl acetate and 300 ml of water. The organic phase was washed with 200 ml of saturated sodium bicarbonate, with 200 ml of water and with 200 ml of brine, before drying in sodium sulfate and concentrating. The resulting residue crystallized from acetonitrile to give 4.82 g of compound (13) (99%). Rf = 0.45 (CHCl3): MeOH: NH4OH, 90: 8: 1); p.f. 240-243 ° C; MS (FAB) (M + H) + at m / z 945. 1 H NMR (300 MHz, CDCl 3) delta 7.45 (d, J = 2 Hz, 1H, Ar H), 7.35 (d, J = 8 Hz, 1H , Ar H), 7.19 (dd, J = 8.2 Hz, 1H, Ar H), 4.44 (d, J = 7 Hz, 1H, C-1 'CH), 3.75 (d, J = 10 Hz, 1H, C -3, CH), 3.69 (s, 1H, C-11 CH), 3.33 (s, 3H, C-3"OCH03), 3.07 (s, 3H, C-6 OCH3), 2.29 (s, 6H, C -3 'N (CH3) 2), 2.19 (d, J = 10 Hz, 1.H, C-4"OH), 1.44 (s, 3H, C-7 CH3), 1.40 (s, 3H, C- 12 CH3), 1.31 (d, J = 6H, 3H, C-6"CH3), 1.26 (s, 3H, C-3" CH3), 1.15 (d, J = 7 Hz, 3H, C-8 CH3) , 1.12 (d, J = 8 Hz, 3H, C-4 CH3), 1.02 (d, J = 7 Hz, 3H, C-10 CH3), 0.83 (t, J = 8 Hz, 3H, C-15 CH3 ). NMR with 13 C (75 MHz, CDCl 3), delta 216.2, 176.4, 157.2, 139. 3, 132.1, 131.0, 130.2, 130.1, 128.4, 102.9, 96.2, 82.8, 80.1, 78. 9, 77.9, 77.8, 76.2, 72.6, 70.9, 68.9, 65.8, 65.6, 60.3, 50.6, 49.5, 45.5, 45.3, 44.8, 40.2 (2C), 39.0, 38.9, 34.8, 32.6, 28.5, 21.9, 21.5, (2C), 20.2, 18.9, 18.7, 16.0, 14.2, 14.1, 10.2, 9.0. IR (KBr) a 3430, 2970, 2940, 1760, 1735, 1710, 1460, 1420, 1380, 1235, 1170, 1070, 1055, 1010, 1000 cmA Analysis calculated for C47H74N2N2O13.0.5 H2O: C, 59.11; H, 7.91; N, 2.93; Found: C, 59.13; H, 8.12; N, 2.89.

Step 4.- 11,12- (cyclic carbamate) of 3'-N-demethyl-1 / j-deoxy-11-rcarboxy- (3,4-dichlorophenethylamino) 1-6-Q-methylene-er Thromycin A (compound 14, scheme 3). 2.5 g (2.65 mmol) of the compound (13) was dissolved in 50 ml of methanol and treated with 1.80 g (13.25 mmol) of NaOAc.3H20 and 0.71 g (2.78 mmol) of 12. The solution was irradiated with a 500 W halogen work lamp and stirred at room temperature. After two hours, TLC indicated complete conversion of the starting compound to a new, more polar material. The excess of 12 was quenched by the dropwise addition of 1M Na 2 S 2 O 3. The reaction mixture was concentrated and the resulting residue was partitioned between 200 ml of EtOAc and 200 ml of saturated sodium bicarbonate. The organic phase was washed with 100 ml of brine, dried over sodium sulfate, filtered and concentrated. The resulting residue was purified on a column of silica gel (elution with CHCl3: MeOH: NH4OH, 90: 8: 1) to give 1.75 g (71%) of compound 14, as an amorphous solid. Rf = 0.33 (CHCl3: MeOH: NH4OH, 98: 8: 1); p.f. 136-142 ° C (acetonitrile / water); MS (FAB) (M + H) + at m / z 931. NMR with 1H (300 MHz, CDCl 3) delta 7.45 (d, J = 2 Hz, 1H, Ar H), 7.35 (d, J = 8 Hz, 1H , Ar H), 7.19 (dd, J = 8.2 Hz, 1H, Ar H), 4.42 (d, J = 7 Hz, 1H, C-1 'CH), 3.74 (d, J = 9 Hz, 1H, C -3 CH), 3.69 (s, 1H, C-11 CH), 3.32 (s, 3H, C-3"OCH3), 3.07 (s, 3H, C-6 OCH3), 2.42 (s, 3H, C- 3 'NCH3), 1.44 (s, 3H, C-6 CH3), 1.41 (s, 3H, C-12 CH3), 1.31 (d, J = 6 Hz, 3H, C-6"CH3), 1.26 ( s, 3H, C-3"CH3), 1.41 (s, 3H, C-12 CH3), 1.31 (d, J = 6 Hz, 3H, C-6" CH3), 1.26 (s, 3H, C-3"CH3), 1.16 (d, J = 7 Hz, 3H, C-8 CH3), 1.07 (d, J = 8 Hz, 3H, C-4 CH3), 1-03 (d, J = 7 Hz, 3H , C-10 CH3), 0.82 (t, J = 7 Hz, 3H, C-15 CH3). NMR with 13 C (75 MHz, CDCl 3) delta 216.2, 176.2, 157.1, 139.2, 132.2, 131.0, 130.3, 130.2, 128.4, 102.4, 96.2, 82.7, 80.5, 78.8, 77.8, 77.7, 76.3, 75.0, 72.7, 68.6, 65.7, 60.3, 50.7, 50.6, 49.5, 45.4, 45.3, 44.8, 39.0, 38.9, 38.8, 37.3, 34.8, 33.3, 32.6, 21.9, 21.5, 21.3, 20.1, 18.9, 18.7 16.0, 14.2, 14.1, 10.2, 9.6 IR (KBr) a 3420, 2970, 2940, 1760, 17 35, 1710, 1460, 1420, 1380, 1235, 1170, 1065, 1050, 1010, 1000 crn "1. Analysis calculated for C46H72Cl2N2O13.0.75 H2O: C, 56.39; H, 7.44; N, 2.81. Found: C, 56.63; H, 7.36; N, 2.78.

Step 5: 11.12- (cyclic carbamate) of 3 ', 3'-bisdesmethyl-11-deoxy-11-rcarboxy (3,4-dichlorophenethylamino) 1-6-O-methyl-erythromycin A (compound 15, scheme 4). A solution of 2.0.7 g (2.19 mmol) of compound 14 was dissolved in 50 ml of methanol and treated dropwise with a solution of 2.32 g of K3PO4 (11.0 mmol) in 5 ml of water, followed by 1.11 g (4.38 g). mmol) of 12 in a single portion. The solution was irradiated with a halogen working lamp, 500 W, which maintained the reaction at reflux temperature. After 0.75 hour the iodine color had dissipated and the reverse phase HPLC indicated partial conversion to a new more polar material. The reaction mixture was concentrated to 1/3 of its volume and divided between 400 ml of ethyl acetate and 100 ml of saturated sodium bicarbonate solution. The organic layer was washed with 300 ml of water and 300 ml of brine before drying (Na2SO4), filtering and concentrating. The resulting residue was resubjected to the reaction conditions described above. After one hour the iodine color had dissipated and the reverse phase HPLC indicated the total conversion to a new more polar material. The reaction mixture was concentrated to 1/3 of its volume and divided between 400 ml of ethyl acetate and 100 ml of saturated sodium bicarbonate solution. The organic layer was washed with 300 ml of water and 300 ml of brine before drying in sodium sulfate, filtering and concentrating. The resulting residue was crystallized from acetonitrile to give 1.25 g of compound 15 (62%), m.p. 223-225 ° C (EtOAc). MS (FAB) (M + H) + at m / z 917. NMR with H (300 MHz, CDCl 3) delta 7.46 (d, J = 2 Hz, Ar H), 7.35 (d, J = 8 Hz, Ar H) , 7.19 (dd, J = 8, 2 Hz, Ar, H), 4.39 (d, J = 7 Hz, C-1 'CH), 4.04-3.98 (m, 1H, C-5"CH), 3.32 ( s, 3H, C-3"OCH3), 2.68-2.61 (m, 1H, C-8 CH), 1.44 (s, 3H, C-6, CH3), 1.41 (s, 3H, C-12, CH3) , 1-06 (d, J = 8 Hz, 3H, C-4 CH3), 1.03 (d, J = 7 Hz, 3H, C-10 CH3), 0.83 (t, J = 7 Hz, 3H, C- 15 CH3). NMR with 13 C (75 MHz, CDCl 3) delta 216.0, 176.1, 157.1, 139.1, 132.1, 130.9, 130.2, 130.1, 128.3, 102.3, 96.1, 82.7, 80.5, 78.8, 77.8, 77.7, 77.3, 76.3, 72.6, 68.5, 65.7, 60.3.52.4, 50.6, 49.3, 45.3, 45.2, 44.7, 41.3, 38.9, 38.7, 34.7, 32.5, 21.8, 21.4, 21.0, 20.0, 18.8, 18.6, 15.9, 14.2, 14.1, 10.1, 9.6. IR (KBr) nu 3440, 2970, 2930, 17.60, 1735,1165, 1065, 1010 cm "1.

Step 6: 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3', 3'-N-biscyclopropylmethyl-1-deoxy-11-rcarboxy-4-chlorophenethylamino) 1-6-O- methyl-erythromycin A (compound 16. scheme 3). 290 mg (0.32 mmol) of compound 15 from the previous step was dissolved in 15 ml of methanol and treated with 460 mg (6.6 mmol) of cyclopropanecarboxyaldehyde, 80 mg (1.3 mmol) of sodium cyanoborohydride and 7 drops of acetic acid. , up to pH 5-6; and the mixture was stirred at room temperature. After 24 hours TLC [CHCl3: MeOH, 98: 2, visualization with Ce (IV)] indicated complete conversion to a new less polar material. The reaction was concentrated and the resulting residue was partitioned between 159 ml of ethyl acetate and 150 ml of water. The organic layer was washed with 150 ml of water, 150 ml of brine, before drying in sodium sulfate, filtering and concentrating. The resulting residue was purified on a column of silica gel (elution with chloroform: MeOH: NH 4 OH 90: 8: 1) and crystallized from acetonitrile to give 180 mg of (16) (56%), as fine needles. MS (FAB) (M + H) + at m / z 1025 NMR with 1H (300 MHz, CDCl 3) delta 7.46 (d, J = 2 Hz, 1H), 7.35 (d, J = 8, 1H), 720 / dd , J = 8, 1.8, 1H), 4.93 (d, J = 5, 1H); 4.90 (dd, J = 9, 2.2, 1H), 4.49 (d, J = 7, 1H), 4.05-4.02 (m, 1H), 3.90-3.81 (series of m, 3H), 3.75 (d, J = 10, 1H), 3.70 (s, 1H), 3.67 (d, J = 7, 1H), 3.51-3.48 (m, 1H), 3.34 (s, 3H), 3.17-3.12 (series of m, 2H), 3.07 (s, 3H), 3.05-2.84 (series of multiplets, 5H), 2.64-2.59 (series of m, 3H), 2.38 (d, J = 15, 1H9, 2.22 (d, J = 7, 1H), 2.19 (d, J = 7, 1H), 2.14 (d, J = 10, 1H), 1.94-1.87 (series of multiplets, 2H), 1.78-1.76 (series of m, 2H), 1.66-1.52 (series of m, 4H), 1.43 (s, 3H), 1.40 (s, 3H), 1.31 (d, J = 6, 3H), 1.26-1.20 (series of multiplets, 9H), 1.17-1.15 (series of m, 6H ), 1.03 (d, J = 7.0, 3H), 0.86-0.81 (series of m, 5H), 0.57 (t, J = 10.0, 2H), 0.47 (t, J = 10.0, 2H), 0.13-0.11 ( m, 4H). NMR with 13 C (CDCl 3) delta 216.3, 176.3, 157.2, 139.3, 132.2, 131.0, 130.3, 130.1, 128.4, 103.1, 96.0, 82.8, 80.3, 78.9,77. 8, 76.2, 72.6, 70.4, 59.1, 65.8, 61.7, 60.4, 54.5, 40.6, 49.5, 45.6, 45.3, 44.8, 39.1, 39.0, 39.0, 39.0, 34.5, 32.6, 30.3, 21.9, 21.5, 21.5, 20.2, 18. 9, 18.6, 16.0, 14.2, 14.1, 10.4, 10.2, 9.0, 5.5, 2.7. Analysis calculated for C53H82Cl2N2O? 3: C, 62.04; H, 8.05; N, 2.73; Found: C, 61.66; H, 8.10; N, 2.59.

EXAMPLE 2 11.12- (CYCLIC CARBAMATE) OF S'.S'-N-BISDESMETIL-S'.S'-N BISCICLOBUTIL-11-DESOXY-11-rCARABOXY- (4-CHLOROPHENEYL-AMINO) I-6-Q-METHYL -ERITHROMYCIN A The title compound was prepared according to the procedure described in Example 1, except that the cyclopropanecarboxyaldehyde is replaced with cyclobutanone. The product was purified on a column of silica gel to give an amorphous solid. Rf = 0.58 (CHCl3: MeOH: NH4OH, 94: 5: 1). IR (KBr) nu 3440, 2960, 2925, 1755, 1730, 1460 1380, 1165, 1105.1065, 1050 cmA NMR with 1H (300 MHz, CDCl 3) delta 7.45 (d, J = 2 Hz, 1H), 7.34 ( d, J = 8 Hz, 1H), 7.19 (dd, J = 8, 2 Hz, 1H), 4.92 (d, J = 5 Hz, 1H), 4.89 (dd, J = 11, 2 Hz, 1H), 4.40 (d, J = 7 Hz, 1H), 4.02-3.99 (m, 1H), 3.88-3.78 (m, 2H), 3.72 (d, J = 10 Hz, 1H9, 3.69 (s, 1H), 3.65 (d, J = 7, 1H), 3.47-3.44 (m, 1H), 3.33 (s, 3H), 3.31-3.26 (series of m, 2H), 3.12 (c, J = 7 Hz, 2H), 3.07 (s, 3H), 3.05-2.84 (series of multiplets, 6H), 2.65-2.61 (m, 1H); 2.50 (wide singlet, 1H), 2.38 (d, J = 7 Hz, 1H), 2.14-1.43 (series of multiplets, 21H), 1. 41 (s, 3H), 1.40 (s, 3H), 1.30 (d, J = 6 Hz, 3H), 1.24-1.20 (series of multiplets, 11H), 1.15 (d, J = 7 Hz, 3H), 1.11 (d, J = 7 Hz, 3H), 0.82 (t, J = 7 Hz, 3H). NMR with 13 C (75 MHz, CDCl 3) delta 216.4, 176.3, 157.2, 139. 2, 132.1, 131.0, 130.2, 130.1, 128.4, 103.3, 95.9, 82.8, 80.3, 78. 8, 77.8, 77.7, 76.2, 72.6, 70.7, 69.2, 65.7, 60.3, 58.8, 54.3, 50.6, 49.5, 45.5, 45.2, 44.7, 39.0, 38.9, 38.8, 34.8, 32.6, 21.2, 30.0, 29.7, 21. 9, 21.5, 20.1, 18.9, 18.6, 16.0, 15.6, 14.2, 14.1, 10.2, 9.0. MS (FAB) (M + H) + at m / z 1025 Analysis calculated for C53H82CI2N2013: C, 62.04; H, 8.05; N, 2.73 Found: C, 61.94; H, 8.24, N, 2.61.

EXAMPLE 3 11.12- (3'.3'-BISDESMETIL-3'.3'-N-BISCYCLOPROPYLMETHYL-11-DESOXY-11-rCARBOXY- (4- CHLOROPHENETHYLAMINE) 1-6-Q-METHL-ERYTHROMYCIN CYCLIC CARBAMATE prepared the title compound as described in Example 1, but replacing 3,4-dichlorophenethylamine with 4-chlorophenethylamine The product crystallized from CH 3 CN / water: Rf = 0.38 (8% MeOH / DCM, 0.1%: NH 4 OH IR (KBr) nu 3440, 2970, 2940, 1765, 1735, 1715, 1490, 1460, 1420, 1380, 1330, 1280, 1235, 1170, 1130, 1110, 1095, 1070, 1055, 1015, 1000 cm ' 1. NMR with 1H (300 MHz, CDCI3) delta 7.30-7.22 (series of m, 4H), 4.96-4.92 (series of m, 2H), 4.40 (d, J = 67.1 Hz, 1H), 4.04-3.97 ( m, 1H), 3.87-3.80 (m, 2H), 3.75-3.70 (series of m, 3H), 3.64 (d, J = 7.5 Hz, 1H), 3.50-3.40 (m, 1H), 3.34 (s, 3H), 3.28-3.20 (m, 2H), 3.20-3.09 (m, 2H), 3.07 (s, 3H), 3.06-2.80 (series of m, 5H), 2.68-2.57 (m, 1H), 2.54- 2.43 (m, 1H), 2.38 (d, J = 15.3 Hz, 1H), 2.10 (d, J = 10.2 Hz, 1H), 2.08-1.98 (series of m, 3H), 1.97-1.82 (series of m, 6H), 1.80-1.74 (m, 2H), 1.67-1.50 (series of m, 7H), 1.42 (s, 3H), 1.40 (s, 3H), 1.29 (d, J = 6.1 Hz, 3H), 1.25 (s, 3H), 1.22 (d, J = 6.4 Hz, 3H), 1.02 (d, J = 6.8 Hz, 3H9, 0.83 (t, J = 7.3 Hz, 3H).

NMR with 13 C (75 MHz, CDCl 3) delta 216.2, 176.3, 157.2, 137.5, 131.9, 130.3, 128.5, 103.4, 96.0, 82.8, 80.4, 78.9, 77.9, 77.8, 76.3, 72.7, 70.9, 69.3, 65.8, 60.4, 58.9, 50.7, 49.5, 45.6.45.3, 45.0, 39.1, 39.0, 34.9, 32.9, 32.7, 31.2, 30.1, 22.0, 21.5, 20.2, 18.9, 18.6, 16.0, 15.7, 14.2, 14.1, 10.3, 9.0. MS (FAB) (M + H) + at m / z 991. Analysis calculated for C53H83CIN2013: C, 64.19; H, 8.44; N, 2.82; Found: C, 64.10; H, 8.54; N, 2.79.

EXAMPLE 4 11,12- (CYCLICAL CARBAMATE) OF S'.S'-BISDESMETIL-S'.S'-N-BISCICLOBUTIL-11-DESOXY-11-rCARBOXY- (4-CHLOROPHENEYL-AMINO) 1-6-O- METI-ERYTHROMYCIN A The title compound was prepared as described in Example 2, but replacing 3,4-dichlorophenethylamine with 4-chlorophenethylamine. The product was crystallized from CH3CN / water. Rf = 0.38 (8% MeOH / DCM0.1% of: NH4OH). IR (KBr) nu 3440, 2970.2940, 1765, 1735, 1715, 1490, 1460, 1420, 1380, 1330, 1280, 1235, 1170, 1130, 1110, 1095, 1070, 1055, 1015, 1000 cmA NMR with 1H (300 MHz, CDCI3) delta 7.30-7.22 (series of m, 4H), 4.96-4.92 (series of m, 2H), 4.40 (d, J = 67.1 Hz, 1H), 4.04-3.97 (m, 1H), 3.87-3.80 (m, 2H), 3.75-3.70 (series of m, 3H), 3.64 (d, J = 7.5 Hz, 1H), 3.50-3.40 (m, 1H), 3.34 (s, 3H), 3.28- 3.20 (m, 2H), 3.20-3.09 (m, 2H), 3.07 (s, 3H), 3.06-2.80 (series of m, 5H), 2.68-2.57 (m, 1H), 2.54-2.43 (m, 1H) ), 2.38 (d, J = 15.3 Hz, 1H), 2.10 (d, J = 10.2 Hz, 1H), 2.08-1.098 (series of m, 3H), 1.97-1.82 (series of m, 6H), 1.80- 1.74 (m, 2H), 1.67-1.50 (series of m, 7H), 1.42 (s, 3H), 1.40 (s, 3H), 1.40 (s, 3H), 1.29 (d, J = 6.1 Hz, 3H) , 1.25 (s, 3H), 1.22 (d, J = 6.4 Hz, 3H), 1.20 (d, J = 5.8 Hz, 3H), 1.15 (d, J = 7.1 Hz, 3H), 1.13 (d, J = 7.8 Hz, 3H), 1.02 (d, J = 6.8 Hz, 3H) ~, 0.83 (t, J = 7.3 Hz, 3H). NMR with 13 C (75 MHz, CDCl 3) delta 3216.2, 176.2, 157.2, 137.5, 131 9, 130.3, 128.5, 103.4, 96.0, 82.8, 80.4, 78.9, 77.9, 77.8, 76.3, 72 7, 70.9, 69.3, 65.8, 60.4, 58.9, 50.7, 49.5, 45.6, 45.3, 45.0, 39.1, 39.0, 34.9, 32.9, 32.7, 31.2, 30.1, 22.0, 21.5, 20.2, 18.9, 18.6, 16.0, 15.7, 14.2, 14.1, 10.3, 9.0. MS (FAB) (M + H) + at m / z 991. Analysis calculated for C53H83CIN2O13: C, 64.19; H, 8.44; N, 2.82; Found: C, 64.10; H, 8.54; N, 2.79.

EXAMPLE 5 11, 12- (CYCLICAL CARBAMATE) OF 3 ', 3'-BISDESMETIL-3'- N-CIC LO BUTIL-3'-N -ISOPROPIL-11-DESOXI-11-rCARBOXI-? (4- CHLOROFE ETHYLAMIN? P -6-O-METHYL-ERYTHROMYCIN A Step 1: 11.12-cyclic carbamate of 4"-0 trimethylsilyl-11-deoxy-1-rcarboxy- (4-clo-deanethylamino) T-6 -Q-methyl-erithromic A (compound 17. scheme 4). 10.2 g (11.8 mmol) of compound 11, obtained in example 1, was dissolved in 10 ml of anhydrous THF, then diluted with 60 ml of DMF. The resulting solution was cooled in an ice / water bath and treated with 9.8 g (60.4 mmol) of 1,1 '-carbonyldiimidazole in a single portion, followed by the portionwise addition of 1.8 g (45 mmol) of NaH ( 60% suspension). The reaction was allowed to warm to room temperature and stirred under nitrogen for one hour, after which the TLC [EtOAc: MeOH, 95: 5, visualization with Ce (IV)] indicated complete conversion to a more polar material, active uv. The reaction was quenched carefully with water, then partitioned between 300 mL of EtOAc and 300 mL of water. The organic phase was collected and washed with 3 x 300 ml of water and 200 ml of brine, before drying over sodium sulfate and concentrating. A sample of the resulting colorless foam was subjected to mass spectrum analysis, which showed the desired (M + H) + at m / z 938. The rest of the material was dissolved in 10 ml of THF, diluted with 40 ml of CH3CN was treated with 18.0 g (115.7 mmol) of 4-chlorophenethylamine and stirred under nitrogen at 50 ° C. After 18 hours TLC [methylene chloride: MeOH, 9: 1, visualization with Ce (IV)] indicated complete conversion to a less polar material. Then the reaction mixture was partitioned between EtOAc (300 ml) and 400 ml of 0.5 N NaH2PO4. The organic phase was collected and washed with another 400 ml of 0.5 N NaH2PQ4, with 5 x 300 ml of water and with 200 ml of brine, before drying in sodium sulfate and concentrating. The resulting residue was recrystallized from CH3CN to give 7.4 g (61% of (11)) of protected cyclic carbamate, as colorless needles. The protected cyclic carbamate was suspended in 75 ml of methanol and the suspension was heated to 50 ° C under the protection of a drying tube. After 18 hours the TLC [CH2Cl2: MeOH, 9: 1, visualization with Ce (IV)] indicated complete conversion to a new more polar material that crystallized by cooling to room temperature. The resulting solid was crystallized from CH3CN to give 6.75 g of compound (17) (58% from (11)): Rf = 0.45 (CH2Cl2: MeOH, 9: 1); MS (DCI) (M + H) + at m / z 983.

Step 2: 11, 12- (cyclic carbamate) of 11-deoxy-11-rcarboxy- (4-chlorophenethylamino) -1,6-O-methyl-erythromycin A (compound 18, scheme 4). 6.75 g (6.87 mmol) of the trimethylsilyl ether (17) obtained in step 1 was dissolved in 50 ml of THF, treated with 7.5 ml of TBAF (1M / THF, 7.5 mmol) and stirred at room temperature. After 1 hour, TLC [CH2Cl2: MeOH, 9: 1, visualization with Ce (iv)] indicated complete conversion to a new, more polar material. The reaction mixture was partitioned between 300 mL of EtOAc and 100 mL of 10% NaHCO3. The organic phase was washed with 2 x 300 ml of water and with 200 ml of brine, before drying in sodium sulfate and concentrating. The resulting residue was crystallized from acetonitrile to give 6.04 mg of compound (18) (97%): Rf = 0.15 (methylene chloride: MeOH, 9: 1); MS (DCI) (M + H) + at m / z 911.

Step 3: 11, 12- (cyclic carbamate) of 3'-N-demethyl-11-deoxy-11-rcarboxy- (4-chlorophenethylamino) 1-6-O-methyl-erythromycin A (compound 19. scheme 4) dissolved 6.04 g (6.63 mmol) of the compound (18) from the previous step, in 60 ml of methanol, and treated with 4.52 g (33.2 mmol) of NaOAc.3H2O and 1.69 g (6.66 mmol) of 12. The solution was irradiated with a halogen working lamp, 500 W, which maintained the reaction at reflux temperature. After three hours, TLC (CHCl3: MeOH: NH4OH, 90: 8: 1) indicated complete conversion to a new, more polar material. The excess of 12 was inactivated by adding 1 M NaHSO 3 dropwise. The reaction mixture was concentrated and the resulting residue was partitioned between 300 ml of methylene chloride and 300 ml of water. The organic phase was washed with 300 ml of saturated sodium bicarbonate, with brine, dried over sodium sulfate, filtered and concentrated to give 5.41 g (91% of compound 19. Rf = 0.15 (CHCl3: MeOH: NH4OH, 90: 8: 1); MS (DCI) (M + H) + at m / z 897.

Step 4: 11, 12- (cyclic carbamate of 3'-N-demethyl-3'-N-isopropyl-11-deoxy-11-rcarboxy- (4-chlorophenethylamino) 1-6-Q-methyl-erythromycin A (compound 20, scheme 4.) 5.40 g (6.03 mmol) of the compound (19) was dissolved in 50 ml of methanol and treated with 7.0 g (120 mmol) of acetone, 454 mg (7.23 mmol) of sodium cyanoborohydride and acetic acid. (dropwise, until pH 5-6) and the mixture was stirred at room temperature.After 24 hours, the TLC [CHCl3: MeOH, 98: 2, visualization with Ce (IV)] indicated complete conversion to a new material. less polar The reaction was concentrated and the residue was partitioned between 300 ml of methylene chloride and 250 ml of water.The organic layer was washed with 200 ml of saturated sodium bicarbonate and 150 ml of brine, before being dried over sodium sulfate. The resulting residue was purified on a column of silica gel (elution with chloroform: MeOH: NHOH, 90: 8: 1) and crystallized from acetonitrile to give 4.23 g (75%) of the compound. (20) .Rf = 0.80 (c! Oroform: MeOH: NH4OH, 90: 8: 1). MS (DCI) (M + H) + at m / z 939.

Step 5: 1, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3'-N-isopropyl-11-deoxy-11-rcarboxy- (4-chlorophenethylamino) 1-6-0- methyl-erythromycin A. 1.6 g (/ 1.7 mmol) of compound 20 was dissolved in 50 ml of methanol and treated with 1.16 g (8.5 mmol) of NaOAc.3H2O and 0.48 g (1.88 mmol) of 12. The solution was irradiated with a halogen working lamp, 500 W, which maintained the reaction at reflux temperature. After three hours, TLC (chloroform: MeOH NH 4 OH, 90: 8: 1) indicated complete conversion to a new, more polar material. The excess iodine is inactivated by the dropwise addition of 1M sodium bisulfate. The reaction mixture was concentrated and the resulting residue was partitioned between 300 ml of methylene chloride and 300 ml of saturated sodium bicarbonate. The organic phase was washed with 300 ml of water, with brine, dried over sodium sulfate, filtered and concentrated to yield 1.13 g (71%) of the compound (21). Rf = 0.50 (chloroform: MeOH: NH 4 OH, 90: 8: 1); MS (DCI) (M + H) + at m / z 925.

Step 6: 11, 12- (cyclic carbamate) of 3 ', 3'-bisdesmethyl-3'-N-cyclobutyl-3'-N-isopropyl-11-deoxy-11-rcarboxy- (4-chlorophenethyl-amino) 1 -6-O-methyl-erythromycin A (compound 22. scheme 4). 110 mg (0.119 mmoi) of compound (21) from the previous step was dissolved in 50 ml of methanol and treated with 1.0 g (14.3 mmol) of cyclobutanone, 15 mg (0.24 mmol) of sodium cyanoborohydride and acetic acid ( dropwise, until pH 5-6) and the mixture was stirred at room temperature. After 72 hours the TLC [chloroform: MeOH, 98: 2, visualization with Ce (IV)] indicated the conversion to a new less polar material. The reaction was concentrated and the resulting residue was partitioned between 100 ml of ethyl acetate and 100 ml of water. The organic layer was washed with 50 ml of brine, before drying over sodium sulfate, filtering and concentrating. The resulting residue was purified on a column of silica gel, eluting with chloroform: MeOH: NH 4 OH (90: 8: 1) to give 65 mg (56% ") of (22). Rf = 0.95 CHCl 3: MeOH: NH 4 OH ( 98: 8: 1); MS (ESI) = (M + H) + at m / z 979; HRMS m / z (M + H) + calculated 979.5662, observed 979.5660. Analysis calculated for C52H83CIN2O? A: C, 63.75; H, 8.53; N, 2.85; Found: C, 63.48; H, 8.71; N, 2.79.

EXAMPLE 6 11.12- (3 'CYCLE CARBAMATE, 3'-N-BISDESMETIL-3'-N-ISOPROPYL-3'-N-PROPYL-11-DESOXY-1-rCARBOXY- (4- CHLOROPHENETHYLAMINE) 1-6- Q-METHYL-ERYTHROMYCIN A The title compound was prepared as described in Example 5, but replacing cyclobutanone with propionaldehyde Rf = 0.35 (chloroform: MeOH: NH4OH, 90: 8: 1); MS (ESÍ) (M) + H) + am / z 967.

EXAMPLE 7 11,12- (CYCLICAL CARBAMATE) OF 3 ', 3'-N-BISDESMETIL-3'-N-CIC OPROPYLMETHYL-3'-N-ISOPROPIL-11-DESOXY-11-rCARBOXY- (4- CHLOROPHENETHYLAMINE) 1 -6-0-METHYL-ERYTHROMYCIN A The title compound was prepared as described in Example 5, but replacing the cyclobutanone with cyclopropanecarboxyaldehyde; p.f. 211-213 ° C (CH3CN); Rf = 0.85 (methylene chloride: methanol, 9: 1). MS (FAB ") (M + H) + at m / z 979. HRMS m / z (M + H) + calculated 979.5662, observed: 979.5659.RTM (KBr) a 3440, 2965, 2930, 1760, 1735, 1715, 1460, 1380, 1235, 1170, 1090, 1065, 1055, 1015 cm'1.

NMR with 13C (CDCI3) delta 216.4, 176.4, 157.2, 137.4, 131.8, 130.3, 128.4, 103.0, 95.9, 82.7, 80.2, 78.8, 77.9, 77.7, 76.2, 72.6, 70.5, 69.1, 65.7, 60.3, 59.6, 50.7 , 49.5, 49.2, 47.5, 45.6, 45.2, 45.0, 39.0, 38.9 (2C), 34.8, 34.3, 32.8 22.9, 21.9, 21.5, 21.4, 20.2, 18.9, 18.6, 16.0, 14.2, 14.1, 11.1, 10.3, 9.0 , 5.7, 2.5. Analysis calculated for C52H8sCIN2013: C, 63.75; H, 8.53; N, 2.85; Found: C, 63.45; H, 8.36; N. 2.72 EXAMPLE 8 11,12- (CYCLICAL CARBAMATE) OF 3'.3'-N-BISDESMETIL-3'-N-ETHYL-3, -N-ISOPROPIL-11-DESOXY-11-rCARBOXY- (4- CHLOROPHENETHYLAMINE) 1- 6-Q-METHYL-ERYTHROMYCIN A The title compound was prepared as described in Example 5, but replacing cyclobutanone with acetaldehyde, mp. 225-229 ° C (CH3CN / water): Rf = 0.70 (CH2Cl2: mEoh 9: 1). MS (ESI) (M + H) + at m / z 953. IR (KBr) a 3440, 2960, 2930, 1760, 1735, 1715, 1460, 1380, 1235, 1170, 1100, 1090, 1065, 1055, 1015 crnA NMR with 13C (CDCI3) delta 216.2, 176.3, 157.2, 137.5, 131.9, 130.3, 128.5, 103.0, 96.0, 82.7, 80.2, 78.9, 77.9, 77.8, 76.3, 72.7, 70.6, 60.1, 65.8, 60.4, 59.9, 50.7 , 49.5, 47.9, 45.6, 45.3, 45.0, 39.1, 39.0 (2C), 38.2, 34.9, 34.5, 32.09, 22.9, 21.9, 21.5, 21.4, 20.1, 19.0, 18.9, 18.7, 15.9, 15.7, 14.2, 14.1, 10.3, 8.9.

EXAMPLE 9-11.12- (CYCLICAL CARBAMATE) OF 3'.3'-BISDESM ETHYL-3'-N-CYCLOBUTILMETIL-3'-N-CICLOPROPLEMETIC-11-DESOXY-11-rCARBOXY- (4-CHLOROPHENETHYLAMINE) 1-6- 0-METHYL-ERYTHROMYCIN A The title compound was prepared as described in Example 5, but replacing cyclobutanone with cyclopropanecarboxyaldehyde Rf = 0.65 (methylene chloride: MeOH, 9: 1; MS (APCI) (M + H) + am / z 1005 IR (KBr) nu: 3440, 2970, 2930, 1760, 1735, 1710, 1460, 1580, 1380, 1235, 1170, 1100, 1090, 1065, 1055, 1015 cm "1. NMR with 13 C (CDCl 3) delta 216.2, 176.3, 157.1, 137.4, 131.8, 130.3, 128.4, 103.0, 95.9, 82.7, 80.2, 78.8, 77.9, 77.7, 76.2, 72.6, 70.4, 69.0, 65.7, 62.7, 60.3, 55.4, 54.4, 54.6, 49.4, 45.4, 45.4, 45.4, 45.4, 45.4, 44.2, 50.9, 50.2, 49.4, 45.2, 45.9, 38.9, 34.3, 32.8, 30.1, 27.0 , 26.6, 21.9, 21.5, 21.4, 20.1, 18.8, 18.6, 18.5, 16.0, 14.2, 14.1, 10.3, 10.2, 8.9, 5.4, 2.6 EXAMPLE 10 11.12- (CYCLICAL CARBAMATE) OF 3'.3'-N- BISDESMETIL-3 ', 3'-N-BISCYCLOPROPYLMETHYL-11-DESOXY-11-rCARBOXY- (4-METHOXY-FENETHYLAMIN-6-O-METHYL-ERYTHROMYCIN A) The title compound was prepared as described in Example 1 , but replacing 3,4-dichlorophenethylamine with 4-mefoxifenethylamine The product crystallized from acetonitrile / water Rf = 0.53 (8% MeOH / DCM, 0.1% NH4OH) IR (KBr) nu: 3440, 2965, 2935, 1755, 1735, 1705, 1610, 1515, 1455, 1380, 1325, 1250, 1235, 1165, 1110, 1070, 1050, 1010, 1000 cm. "1 NMR with 1H (300 MHz, CDCl 3) delta 7.24 (d, J = 8.8 Hz, 2H), 6.83 ( d, J = 8.8 Hz, 2H), 4.98 (dd, J = 10.9, 2.4 Hz, 1H), 4.92 (d, J = 4.4 Hz, 1H), 4.49 (d, J = 67.2 Hz, 1H), 4.08-3.97 (m, 1H), 3. 90-3.78 (m, 2H), 3.78 (s, 3H), 3.73 (s, 2H), 3.66 (d, J = 7.2 Hz, 1H), 3.55-3.44 (m, 1H), 3.33 (s, 3H), 3.18-3.10 (m, 2H), 3.09 (s, 3H), 3. 07-2.78 (series of m, 5H), 2.70-2.56 (series of m, 3H), 2.37 (d, J = 15 * 3 Hz, 1H), 2.21 (d, J = 7.1 Hz, 1H), 2.17 ( d, J = 6.8 Hz, 1H), 2.13 (d, J = 10.2 Hz, 1H9, 2.02-1.86 (m, 2H), 1.77 (d, J = 6.5 Hz, 1H), 1. 68-1.46 (series of m, 4H), 1.42 (s, 3H), 1.40 (s, 3H), 1.30 (d, J = 6. 1 Hz, 3H), 1.25 (s, 3H), 1.22 (d, J = 7.1 Hz, 3H), 1.20 (d, J = 6.1 Hz, 3H), 1.15 (d, J = 7.1 Hz, 3H), 1.14 (d, J = 7.8 Hz, 3H), 1.02 (d, J = 6.7 Hz, 3H), 0.92-0.78 (series of m, 2H ), 0.83 (t, J = 7.5 Hz, 3H), 0. 60-0.53 (m, 2H), 0.50-0.41 (m, 2H), 0.16-0.08 (series of m, 4H). NMR with 13 C (75 MHz. CDCI 3) delta 216.1, 176.2, 158.1, 157.2, 131.0, 129.9, 113.8, 103.1, 95.9, 82.6, 80.3, 78.8, 77.9, 77.8.76.3, 72.6, 70.4, 69.0, 65.7, 61.7, 60.4, 55.2, 54.5, 50.7, 49.5, 45.5, 45.4, 45.3, 39.0, 34.8, 32.6, 30.3, 22.0, 21.5, 21.5, 20.2, 18.9, 18.6, 16.0, 14.3, 14.1, 10.4, 10.3, 9.0, 55. , 2.7. MS (FAB) (M + H) + at m / z 987. Analysis calculated for C54H86N2O14.0.4H2O: C, 65.22; H, 8.80; N.2.82. Found: C, 65.23; H, 8.52; N, 2.74.

EXAMPLE 11 11.12- (CYCLICAL CARBAMATE) OF 3'.3'-BISDESMETIL-3 ', 3'-N-BISCICLOPROPYLMETIL-11-DESOXY-11-rCARBOXI- (4- F LUORO FE NETI LAMÍ NO) 1-6-Q -METIL-ERITROMIC INA A The title compound was prepared as described in Example 1, but replacing 3,4-dichlorophenethylamine with 4-fluorophenethylamine. The product was isolated on a column of silica gel (3% MeOH / DCM / 0.2% NH4OH), as an amorphous solid.; p.f. 207-210 ° C (with decomposition) IR (KBr) nu: 3440, 2960, 2930, 2870, 2820, 1755, 1730, 1710, 1505, 1455, 1420, 1375, 1325, 1280, 1230, 1220, 1165, 1125 , 1105, 1075, 1065, 1050, 1010, 995 cm "1 NMR with 1H (300 MHz, CDCI3) delta 7.32-7.25 (series of m, 2H), 6.99-6.93 (series of m, 2H), 4.98-4.92 (series of m, 2H), 4.49 (d, J = 7.1 Hz, 1H), 4.06-4.00 (m, 1H), 3.87-3.80 (m, 2H), 3.75 (d, J = 9.5 Hz, 1H), 3.72 (s, 1H), 3.66 (d, J = 7.1 Hz, 1H), 3.53-3.44 (M, 1H), 3.34 (s, 3H), 3.19-3.11 (m, 2H9, 3.08 (s, 3H), 3.07-2.81 (series m, 5H), 2.68-2.56 (series of m, 3H), 2.38 (d, j = 15.3 Hz, 1H9, 2.23-2.12 (series of m, 3H), 1.98-1.83 (m, 2H ), 1.79-1.75 (m, 2H), 1.68-1.48 (series of m, 5H), 1.42 (s, 3H), 1.40 (s, 3H), 1.30 (d, J = 6.4 Hz, 3H), 1.25 ( s, 3H), 1.23 (d, J = 5.4 Hz, 3H), 1.20 (d, J = 5.8 Hz, 3H), 1116 (d, J = 5.8 Hz, 3H), 1.14 (d, J = 7.4 Hz, 3H), 1.03 (d, J = 6.8 Hz, 3H), 0.92-0.81 (series of m, 2H), 0.83 (t, J = 7.5 Hz, 3H), 0.62-0.52 (m, 2H), 0.51-0.42 (m, 2H); 0.16-0.08 (series of m, 4H) NMR with 13C (300 MHz, .CDCI3) delta 216.2, 176.3, 157.2, 134.7, 130.4, 130.3, 115.2, 114.9, 103.2, 96.0, 82.7, 80.3, 78.9, 78.0, 77.8, 76.3, 72.7, 70.5, 69.1, 65.8, 60.5, 54.6, 50.7, 49.5, 45.6, 45.3, 45.2, 39.1, 39.1, 39.1, 39.2, 39.0, 34.9, 32.7, 30.4, 22.0, 21.5, 20.2, 18.2, 18.6, 16.6, 14.3, 14.1, 10.4, 10.3, 9.0, 5.5, 2.7. MS (FAB) (M + H) + at m / z 975.

EXAMPLE 12 11,12- (CYCLICAL CARBAMATE) OF 3'.3'-N-BISDESMETIL-3 ', 3'-N-BISCICLOBUTIL-11-DESOXY-11-rCARBOXY- (4-CHLORO-3-FLUOROFENETILAMINO) -0 -METIL-ERYTHROMYCIN A The title compound was prepared as described in Example 2, but replacing 3,4-dichlorophenethylamine with 4-chloro-3-fluorophenethylamine. The product was isolated by chromatography on silica gel (3% MeOH / DCM / 0.2% NH4OH) as an amorphous solid. Rf = 0.43 (8% MeOH, 0: 1; NH4OH) IR (KBr) nu: 3440, 2970, 2940, 2880, 1760, 1735, 1710, 1580, 1495, 1460, 1425, 1380, 1330, 1285, 1240, 1170, 1105, 1070, 1055, 1015, 1000 cm "1. NMR with 1H (300 MHz, CDCl 3) delta 7.32-7.26 (m, 1H), 7. 16 (dd, J = 10.2, 2.1 Hz, 1H), 7.07 (dd, J = 8.1, 1.3 Hz, 1H), 4.93-4.8§ (m, 2H), 4.40 (d, J = 7.1 Hz, 1H), 4.06-3.096 (m, 1H), 3.91-3.70 (serle of m, 3H), 3.69 (s, 1H), 3.64 (d, J = 7.1 Hz, 1H), 3.51-3.41 (m, 1H), 3.34 ( s, 2H); 3.30-3.08 (series of m, 4H), 3.06 (s, 3H), 3.06-2.82 (series of m, 5H), 2.68-2.56 (m, 1H9, 2.55-2.44 (m, 1H), 2.37 (d, J = 14.9 Hz, 1H), 2.10, (d, J = 10.5 Hz, 1H), 2.08-1.81 (series of m, 9H), 1.79-1.72 (m, 2H), 1.68-1.46 (series of m, 9H ), 1.42 (s, 3H), 1.40 (s, 3H), 1.29 (d, J = 6.1 Hz, 3H), 1.25 (s, 3H), 1.22 (d, J = 6.4 Hz, 3H), 1.20 (d) , J = 5.8 Hz, 3H), 1.15 (d, J = 7.8 Hz, 3H), 1.12 (d, J = 7.8 Hz, 3H), 1.02 (d, J = 6.8 Hz, 3H), 0.82 (t, J = 7.5 Hz, 3H). NMR with 13C (300 MHz, CDCI3) delta 216.4, 176.4, 157.2, 140.0, 139.9, 130.3, 125.4, 117.3, 117.0, 103.4, 96.0, 82.8, 80.3, 78.9, 77.9, 77.7, 76.2 , 72.6, 70.8, 69.2, 65.7, 60.3, 58.8, 54.4, 50.7, 49.5 ', 45.6, 45.2, 44.8, 39.0 (2C), 38.9, 34.8, 32.8, 32.5, 31.2, 30.1, 21.9, 21.5, 20.1, 18.9 , 18.6, 16.0, 15.7, 14.2, 14.1, 10.2, 9.0 MS (FAB) (M + H) + at m / z 1009. Analysis calculated for C53H82CIFN2O13: C, 63.04; H, 8.19; N, 2.77; Found: C 63.06; H, 8.50; N, 2.68.

EXAMPLE 13 11,12- (CYCLICAL CARBAMATE) OF S'.S'-BISDESMETIL-S'.S'-N-BJSCICLOPROPYLMETIL-11-DESOXY-11-rCARBOXY- (4-CHLORO-3-FLUOROFENETILAMINO) 1-ß- Q-METHYL-ERYTHRONICIN A The title compound was prepared as described in Example 1, but replacing 3,4-dichlorophenethylamine with 4-chloro-3-fluorophenethylamine. The product was isolated in silica gel chromatography (3% MeOH / DCM / 0.2% NH4OH) as an amorphous solid. "Rf = 0.44 (8% MeOH / DCM + 0.1% NH4OH) IR (KBr) nu: 3440, 2970, 2940, 2880, 1760, 1735, 1715, 1585, 1495, 1460, 1425, 1380, 1330, 1285 , 1240, 1170, 1125, 110, 1090, 1070, 1055, 1015, 1000 cm "1. NMR with 1H (300 MHz, CDCl 3) delta 7.32-7.26 (m, 1H), 7.16 (dd, J = 10.2, 2.1 Hz, 1H), 7.07 (dd, J = 8.1, 1.3 Hz, 1H), 4.94-4.88 (m, 2H), 4.49 (d, J = 6.8 Hz, 1H), 4.08-3.98 (m, 1H), 3.92-3.78 (m, 2H), 3.74 (d, J = 9.8 Hz, 1H), 3.70 (s, 1H), 3.66 (d, J = 7.5 Hz, 1H), 3.54-3.43 (m, 1H), 3.33 (s, 3H), 3.20-3.07 (m, 2H), 3.06 (s, 3H9, 3. 05-2.82 (series of m, 5H), 2.70-2.56 (m, 3H), 2.34 (d, J = 15.6 Hz, 1H), 2.24-2.10 (series of m, 3H), 1.98-1.84 (m, 2H) ), 1.80-1.72 (m, 2H9, 1.71-1.46 (series of m, 5H), 1.42 (s, 3H), 1.40 (s, 3H), 1.30 (d, J = 6.1 Hz, 3H); 1.25 (s, 3H); 1.22 (d, J = 57.1 Hz, 3H), 1.21 (d, J = . 8 Hz, 3H), 1.16 (d, J = 7.1 Hz, 3H), 1.13 (d, J = 6.8 Hz, 3H), 1.02 (d, J = 6.8 Hz, 3H), 0.91-0.78 (series of m, 2H), 0.82 (t, J = 7.3 Hz, 3H), 0.63-0.52 (m, 2H), 0.52-0.41 (m, 2H) ), 0.18-0.08 (series of m, 4H). NMR with 13 C (CDCl 3) ~ delta 216.4, 176.4, 159.7, 157.2, 156. 3, 140.0, 139.9, 130.3, 125.4, 117.3, 117.0, 103.1, 96.0, 82.8, 80. 2, 78.9, 77.9, 77.7, 76.2, 72.6, 70.4, 69.1, 65.8, 61.7, 60.3, 54.5, 50.7, 49.5, 45.6, 45.3, 44.8, 39.0 (2C), 34.8.32.8, 30.2, 21.9, 21.5, . 2, 18.9, 18.6, 16.0, 14.2, 14.1, 10.4, 10.2, 9.0, 5.5 (2C), 2.7 (2C). MS (FAB) (M + H) + at m / z 1009 Analysis calculated for C53H82Cl1N2O13.0.2 C6H14.0.2H2O: C, 63.17; H, 8.33; N, 2.72; Found: C, 63.02; H, 8.63; N, 2.63.

EXAMPLE 14 11.12- (3'.3'-N-BISDESM CYTIC CARBAMATE ETI L-3'.3'-N- BISCICLOBUTIL-11-DESOXI- 1-rCARBOXI- (3-CHLORO-4- FLUOROFENETILAMINOnO-METTIL-ERYTHROMYCIN A The title compound was prepared as described in Example 2, but replacing 3,4-dichlorophenethylamine with 3-chloro-4-fluorophenethylamine. NMR with 1H (300 MHz, CDCl 3) delta 7.39 (dd, J =, 7 Hz, .1H, Ar H), 7.22-7.19 (m, 1H, Ar H), 7.04 (dd, J = 9 Hz, 1H, Ar H), 4.41 (d, J = 7 Hz, 1H, C-1 'CH), 4.03-4.00 (m, 1H, C-5"CH), 3.74 (d, J = 10 Hz, 1H, C- 3 CH), 3.70 (s, 1H, C-11 CH), 3.65 (d, J = 7 Hz, 1H, C-5 CH), 3.47-3.44 (m, 1H, C-5 'CH), 3.34 ( s, 3H, C-3"CH), 2.10 (d, J = 10 Hz, 1H, C-4" OH), 1.43 (s, 3H, C-6 CH3), 1.40 (s, 3H, C-12 CH3), 1.30 (d, J = 6, 3H, C-6"CH3), 1.15 (d, J = 7 Hz, 3H, C-2 CH3), 1.13 (d, J = 7 Hz, 3H, C- 4 CH3), 1.03 (d, J = 7 Hz, 3H, C-10 CH3), 0.83 (t, J = 7 Hz, 3H, C-15 CH3). NMR with 13 C (CDCl 3) delta 216.3, 176.3, 157.7, 157.2, 155.8, 136.0, 136.0, 131.0, 128.6, 128.5, 116.4, 116.2, 103.0, 96.0, 82.8, 80.3, 78.9, 77.9, 77.8, 76.2, 72.6, 70.8 , 69.2, 65.7, 60.3, 58.8, 54.3, 50.7, 49.5, 45.7, 45.7, 45.2, 45.2, 45.2, 39.3, 45.2, 39.5, 45.2, 39.5, 39.5, 45.2, 39.5, 39.5, 39.5, 39.5, 39.5, 39.5, 45.5 , 14.2, 14.1, 10.2, 8.9. MS (ESI) (M + H) + at m / z 1009. Analysis calculated for C53H82CIFN2O13: C, 63.05; H, 8.19; N, 2.77 Found: C, 62.89; H, 8.14, N, 281 EXAMPLE 15 11.12- (CYCLICAL CARBAMATE) OF 3'.3'-N-BISDESM ETI L-3'.3'-N- BISCYCLOPROPYLMETHYL-11-DESOXY-11-rCARBOXY- (3-CHLORO-4- FLUOROFENETILAMINO) 1- 6-0-METHYL-ERYTHROMYCIN A The title compound was prepared as described in Example 1, but replacing 3,4-dichlorophenethylamine with 3-chloro-4-fluorophenethylamine. NMR with 1H (300 MHz, CDCl 3) delta 7.40 (dd, J = 2, 7 Hz, 1H), 7.23-7.20 (m, 1H), 7.05 (dd, J = 9 Hz), 1H), 4.95-4.91 (series of m, 2H), 4.50 (d, J = 7 Hz, 1H) , 4.06-4.02 (m, 1H), 3.90-3.78 (series of m, 2H), 3.76 (d, J = 10 Hz, 1H), 3.71 (s, 1H), 3.67 (d, J = 7 Hz, 1H ), 3.51-3.41 (m, 1H), 3.34 (s, 3H), 3.17-3.12 (series of m, 2H), 3.08 (s, 3H), 3.05-2.84 (series of m, 5H), 2.67-260 (señe de m, 3H), 2.39 (d, J = 15 Hz, 1H), 2.23-2.19 (series of m, 2H), 2.13 (d, J = 10 Hz, 1H), 1.95-187 (series of m , 2H), 1.80-1.77 (series of m, 2H), 1.66-1.52 (series of m, 4H), 1.44 (s, 3H), 1.40 (s, 3H), 1.31 (d, J = 6 Hz, 3H ), 1.26 (s, 3H), 1.24-1.21 (series of m, 6H), 1.17-1.14 (series of m, 6H), 1.03 (d, J = 7 Hz, 3H), 0.84 (t, J = 7 Hz, 3H), 0.60-0.56 (m, 2H); 0.49-0.45 (m, 2H), 0.14-0.12 (series of m, 4H). NMR with 13C (75 MHz, .CDCI3) delta 216.3, 176.3, 157.8, 157.2, 155.8, 136.0, 131.0, 128.6, 128.5, 116.4, 116.2, 103.1, 96.0, 82.8, 80.3, 78.9, 77.9, 77.8, 76.3, 72.7 , 70.6, 69.1, 65.8, 60.4, 54.5, 50.7, 49.5, 45.6, 45.6, 45.0, 39.1, 39.2, 39.2, 39.2, 39.2, 39.2, 39.2, 39.2, 39.5, 32.5, 30.3, 21.9, 21.2, 20.2, 18.9, 18.6, 16.0, 14.2, 14.1, 10.4, 10.2 , 9.0, 5.5, 2.7. MS (ESI) (M + H) + at m / z 1009. Analysis calculated for C53H82CIFN2Oi3.0.25 (CH2Cl2): C, 62.04; H, 8.06; N, 2.71; Found: C, 62.44; H, 8.34, N, 2.66.

EXAMPLE 16 11,12- (CYCLICAL CARBAMATE) OF 3 ', 3'-N-BISDESM ETHYL-3'-N-CYCLE PE NTIL-3'-N -CICLO PRO PILMETIL-11-D ESOXI -1 -rC ARBOXI- (3-CHLORO-4-FLUOROFE ETHYLAMIN-6-0-METHYL-ERYTHROMYCIN A The title compound was prepared as described in Example 5, but replacing the acetone with cyclopentanone and the cyclobutanone with cyclopropylcarboxyaldehyde, and the 4- chlorphenethylamine with 4-fluoro-3-chlorophenethylamine MS (ESI) (M + H) + at m / z 1095 EXAMPLE 17 11.12- (CYCLICAL CARBAMATE) OF S'.S'-N-BISDESMETIL-S'.S'-N-BISCICLOPROPYLMETIL-11-DESOXY-11-rCARBOXI- (3,4- DIFLUOROFENETILAMIN? N-6-O-METTIL- ERYTHROMYCIN A The title compound was prepared as described in Example 1, but replacing 3,4-dichlorophenethylamine with 3,4-difluorophenethylamine The product was crystallized from CH 3 CN / H 2 O, mp 109-211 ° C (CH 3 CN / water ) IR (KBr) nu: 3442, 2972, 2938, 2883, 2831, 1761, 1735, 1711, 1609, 1519, 1458, 1424, 1379, 1325, 1282, 1235, 1211, 1167, 1126, 1106, 1089, 1067 , 1052, 1012, 1000 cm "1 NMR with 1H (300 MHz, CDCI3) delta 7.22-7.03 (series of m, 3H), 4.95-4.90 (series of m, 2H), 4.49 (d, J = 7.1 Hz, 1H), 4.09-3.97 (m, 1H), 3.92-3.79 (m, 2H), 3.74 (d, J = 9.5 Hz, 1H), 3.70 (s, 1H), 3.66 (d, J = 7.5 Hz, 1H ), 3.54-3.44 (m, 1H), 3.34 (s, 3H), 3.18-3.11 (m, 2H), 3.10-2.80 (series of m, 5H), 3.07 (s, 3H), 2.68-2.57 (m , 3H), 2.38 (d, J = 15.2 Hz, 1H9, 2.23-2.15 (m, 2H), 2.14 (d, J = 10.2 Hz, 1H), 1.98-1.74 (series of m, 4H), 1.71-1.47 (be ie from m, 4H), 1.43 (s, 3H), 1.40 (s, 3H), 1.30 (d, J = 6.4 Hz, 3H), 1.25 (s, 3H), 1.23 (d, J = 6.1 Hz, 3H ), 1.21 (d, J = 5.1 Hz, 3H), 1.16 (d, J = 6.1 Hz, 3H), 1.14 (d, J = 7.1 Hz, 3H), 1.02 (d, J = 7.2 Hz, .3H) , 0.91-0.80 (series of m, 2H), 0.83 (t, J = 7.3 Hz, 3H), 0.62-0.52 (m, 2H); 0.51-0.41 (m, 2H); 0.17-0.07 (series of m, 4H). NMR with 13 C (75 MHz, CDCl 3) delta 216.29, 176.37, 157.19, 152.5, 146.5 (m, 2C), 136.5-135.5 (m, 1C), 125.0-124.7 (m, 1C), 117.9-116.8 (m, 2C) ), 103.16, 96.02, 82.78, 80.29, 78.94, 77.96, 77.83, 76.27, 72.68, 70.49, 69.08, 65.81, 61.81, 60.44, 54.55 (2C), 50.64, 49.48, 45.59, 45.33, 45.03, 39.12, 39.05, 39.02 , 34.89, 32.71, 30.37, 21.97, 21.52, 21.49, 20.18, 18.88, 18.65, 16.01, 14.22, 14.12, 10.40, 10.23, 9.00, 5.48 (2C), 2.69 (2C). MS (FAB) (M + H) + at m / z 993.

Analysis calculated for C53H82F2N2O13.0.2H2O: C, 63.86; H, 8.33; N, 2.81. Found: C, 63.87; H, 8.29; N, 2.80.

EXAMPLE 18 11.13- (CYCLICAL CARBAMATE) OF S'.S'-N-BISDESMETIL-S'.S'-N-BISCICLOBUTIL-11-DESOXY-11-rCARBOXI- (3, 4- DIFLUOROFENETILAMINO) 1-6-Q-METHYL-ERYTHROMYCIN A The title compound was prepared as described in Example 2, but replacing 3,4-dichlorophenethylamine with 3,4-difluorophenethylamine. The product was crystallized from acetonitrile / water, m.p. 220-222 ° C (acetonitrile / water). IR (KBr) nu: 3446, 2977, 2938, 2883, 1745, 1734, 1713, 1607, 1518, 1459, 1425, 1378, 1327, 1284, 1236, 1168, 1103, 1094, 1070, 1055, 1013, 1001 cm "1. NMR with 1H (300 MHz, CDCI3) delta 4.07-3.97 (m, 1H), 3.92-3.78 (series of m, 2H), 3.75 (d, J = 9.1 Hz, 1H), 3.70 (s, 1H ), 3.67 (d, J = 7.8 Hz, 1H), 3.54-3.44 (m, 1H), 3.33 (s, 3H), 3.24-3.11 (m, 2H), 3.10-2.80 (series of m, 5H), 3.07 (s, 3H), 2.68-2.55 (m, 2H), 2.47-2.40 (m, 1H9, 2.37 (d, J = 15.2 Hz, 1H), 2.31 (s, 3H), 2.31-2.19 (m, 1H) ), 2.15 (d, J = 10.1 Hz, 1H9, 1.98-1.72 (series of m, 4H), 1.68-1.46 (series of m, 4H), 1.43 (s, 3H), 1.40 (s, 3H), 1.30 (d, J = 6.1 Hz, 3H), 1.25 (s, 3H), 1.22 (d, J = 6.1 Hz, 3H), 1.22 (d, J = 6.1 Hz, 3H), 1.15 (d, J = 7.4 Hz , 3H), 1.13 (d, J = 7.5 Hz, 3H), 1.02 (d, J = 6.8 Hz, 3H), 0.89-0.78 (m, 1H); 0.83 (t, J = 7.3 Hz, 3H), 0.58-0.46 (m, 2H), 0.15-0.07 (m, 2H). NMR with 13 C (75 MHz, CDCl 3) delta 216.35, 176.43, 157.20, 152.5-146.5 (m, 2C), 136.5-135.5 (m, 1C), 125.0-124.7 (m, 1C), 117.9-116.8 (m, 2C) ), 103.02, 96.13, 82.77, 80.19, 78.94, 77.92, 77.89, 76.26, 72.63, 70.55, 68.96, 65.78, 64.61, 60.34, 58.59, 50.67, 49.49, 45.56, 45.30, 44.99, 39.09 (2C), 39.01, 36.91 , 34.85, 32.69, 29.42, 21.93, 21.49, 20.18, 18.89, 18.68, 16.03, 14.23, 14.13, 10.25, 10.04, 9.01, 4.41, 3.36. MS (FAB) (M + H) + at m / z 953. Analysis calculated for C5oH78F2N2013: C, 63.01; H, 8.25; N, 2.94; Found: C, 63.08; H, 8.28; N, 2.89.

EXAMPLE 19 11,12-CYCLIC ICARBAMATE) OF 3'.3'-N-BISDESM ETl L-3'-N-CICLOBUTIL-3'-N-CICLOPROPYLMETHYL-11-DESOXY-11-rCARBOXY- (3-CHLORINE-4 -FLUOROFE ETILAMINO) 1-6-0-METHYL-ERYTHROMYCIN A (COMPOUND 25. FIGURE 5) A solution of 140 mg was dissolved in 5 ml of methanol. (0.16 mmol) of compound 23, prepared as described in example 5, but replacing 3,4-dichlorophenethylamine with 3-chloro-4-fluorophenethylamine; and treated with 20 mg (0.29 mmol) of cyclobutanone, 40 mg (0.65 mmol) of sodium cyanoborohydride and acetic acid (up to pH 5-6) and the mixture was stirred at room temperature, after 48 hours the TLC [chloroform: methanol, 98: 2, visualization with Ce (IV)] indicated complete conversion to a new, less polar material. The reaction was concentrated and the resulting residue was partitioned between 150 ml of ethyl acetate and 150 ml of saturated sodium bicarbonate. The organic layer was washed with 2 x 150 ml of saturated sodium bicarbonate and 150 ml of brine, before drying in sodium sulfate, filtering and concentrating. The resulting residue was purified on a silica gel column (elution with chloroform: methanol, 9: 1) to give 135 mg of (24) (88%). MS (FAB) (M + H) + at m / z 955. A solution of 135 mg (0.14 mmol) of (24) was dissolved in 4 ml of methanol and treated with 20 mg (0.29 mmol) of cyclopropane-carboxyaldehyde, 140 mg (2.3 mmol) of sodium cyanoborohydride and acetic acid (pH 5-6), and the mixture was stirred at room temperature. After 48 hours, TLC [chloroform: methanol, 98: 2, visualization with Ce (IV)] indicated complete conversion to a new less polar material. The reaction was concentrated and the resulting residue was partitioned between 100 ml of ethyl acetate and 100 ml of saturated sodium bicarbonate. The organic layer was washed with 2 x 150 ml of saturated sodium bicarbonate and with 100 ml of brine, before drying in sodium sulfate, filtering and concentrating. The resulting residue was purified on a silica gel column (elution with chloroform: methanol, 9: 1) to give compound (25). MS (FAB) (M + H) + at m / z 997. Analysis calculated for C52H82CIFN2013: C, 63.05; H, 8.19; N, 2.77; Found: C, 62.92; H, 8.13; N, 3.07.

EXAMPLE 20 11,12- (CHLORIC CARBAMATE) OF 3'.3'-N-BISDESMETIL-3 ', 3'-N-BIS-G3- (2-PYRIDIL) PROPIL1-11-DESOXI-11-GCARBOXY- (3 , 4- DICHLOROPHENETHYLAMINE) 1-6-Q-METHYL-ERYTHROMYCIN A The title compound was prepared as described in Example 1, but replacing the cyclopropanecarboxyaldehyde with 3- (2-pyridyl) propanal. The crude product was purified on a column of silica gel (chloroform to methane-chloroform, 2:98), which produced an amorphous solid. IR (MIC) nu: 2970, 2938, 1758, 1734, 1458, 1423, 1168, 1128, 1104, 1067 1053, 1012, 997 cmA NMR with 13 C (CDCl 3) delta 216.34, 176.43, 157.23, 149.68, 147.47, 139.35, 135.86, 132.20, 131.06, 130.30, 128. 45, 102.92, 96.23, 8286, 80.40, 78.92, 78.17, 77.85, 76.26, 72.89, 70.77, 68.89, 65.91, 62.59, 60.36, 50.72, 49.58, 49.27, 45.59, 45.30, 44.84, 39.02, 35.01, 32.66, 30.67, 30.56, 30.40, 21.46, 21.41, 20.21, 18.94, 18.74, 16.07, 14.22, 14.17, 10.28, 9.14. MS (APCI) at m / z 1157 (M + H) + EXAMPLE 21 11.12- (CYCLICAL CARBAMATE) OF 3 ', 3'-N-BISDESMETIL-3'-N-CICLOPROPYLMETHYL-3'-N-4-HYDROXYMETHYL- ( 2-FURIL) METHYL-11-D ESOXY-11-rC ARBOXI-3.4-DICLOROFENTI LAMINO)] -6-0-METlL-ERYTHROMYCIN A The title compound was prepared as described in example 19, but replacing the compound ( 23) with the compound (15) and the cyclobutanone with 4-hydroxymethyl-2-furaldehyde. MS (FAB) (M + H) + at m / z 1153.

EXAMPLE 22 11.12- (CYCLICAL CARBAMATE) OF 3 ', 3'-N-BISDESMETIL-3'-N-CICLOPROPYLMETHYL-3'-N-r3- (4-PIRIPIL) PROPIL1-11-DESOXI-11- TC ARBOXI - ( 3.4-DI CHLOROF IN ETI LAMINO)! -6-O-METHYL-ERYTHROMYCIN A The title compound was prepared as described in Example 21, but replacing 4-hydroxymethyl-2-furaldehyde with 3- (4-pyridyl) propanal. S purified the crude product on a column of silica gel (chloroform to methanol: chloroform, 2:98), which produced a crystalline solid, p. F. 115-116 ° C. IR (film) nu: 3442, 2970, 2937, 1755, 1458, 1168, 1067, 1053, 1011 cm. "1. NMR with 13 C (CDCl 3) delta 216.28, 176.33, 157.17, 151.13,149.49, 139.27, 132.16, 131.02, 130.25, 130.12, 128.38, 123/82, 102.94, 96.04, 82.80, 80.33, 78.87, 77.87, 77.81, 76.25, 72.69, 70.60, 68.94, 65.78, 62.50, 60.34, 55.14, 50.65.49.47, 48.91, 45.54, 45.27, 44.79, 39.08, 38.99, 34.83, 32.91, 32.61, 30.46, 29.67, 21.90, 21.46, 21.44, 20.17, 18.89, 18.65, 16.03, 14.18, 14.12, 10.23, 9.04, 8.51, 5.38, 2.88, MS (APCI) (M) + H) + am / z 1090- EXAMPLE 23 t1,12- (CYCLICAL CARBAMATE) OF 3 ', 3'-N-BISDESM ETI L-3'-N-CICLOPROPYLMETHYL-3'-N- (4-HYDROXYMETHYL-2-FURYL) METHYL-11- DESOXY- 11-rCARBOXY- (3-CHLORO-4-FLUOROFE ETHYLAMINO) 1-6-Q-METHYLERITROMYCIN A The title compound was prepared as described in Example 19, but replacing the cyclobutanone with 4-hydroxymethyl-2-furaldehyde. MS (FAB (M + H) + at m / z 1137.

EXAMPLE 24 11.12- (CYCLICAL CARBAMATE) OF 3 ', 3'-N-BISDESMETIL-3'-N-CICLOPROPYLMETHYL-3'-N- (2-FURYL) METHYL-11-DESOXY-11- "rCARBOXY- (3- CHLORINE-4-FLUOROPHENETILAMINE) 1-6-Q-METHYLERITROMYCIN A The title compound was prepared as described in Example 19, but replacing cyclobutanone with furaldehyde MS (FAB (M + H) + at m / z 1107.

EXAMPLE 25 11.12- (CYCLICAL CARBAMATE) OF 3'.3'-N-BISDESMETIL-3'-N-CICLOPROPYLMETHYL-3'-N- (6-METHYL-2-PIRIDYL) METI-1-DESOXY-11-rCARBOXY- (3-CHLORO-4-FLUOROFENETILAMINO) T-6-0- METHYLERITROMYCIN A The title compound was prepared as described in Example 19, but replacing the cyclobutanone with 6-methyl-2-pyridylcarboxyaldehyde. MS (FAB (M + H) + at m / z 1132.

EXAMPLE 26 11.12- (CYCLICAL CARBAMATE) OF 3'.3'-N-BIS DESM ETHYL-3'-N-BIS (1-M ETILC I CLO PROPYL) METH L-11-D IS OXY-11-rCARBOXI - ( 3-C LO RO-4- FLUOROFENETILAMIN? N-6-O-METHYLERITROMYCIN A The title compound was prepared as described in Example 15, but replacing the cyclopropanecarboxyaldehyde with 1-methylcyclopropancarboxyaldehyde MS (FAB (M + H) + am / z 1036.

EXAMPLE 27 11 ^ 12- (CYCLICAL CARBAMATE) OF 3 ', 3'-N-BISDESMETIL-3', 3'-N-B IS (1 -METÍ LCICLOPROPIDM ETI L-11 -DESOXI-11 -TC ARBOXI- (3.4 DICHLOROPHENETILAMIN? N-6-O-METHYLERITROMYCIN A The title compound was prepared as described in Example 1, but replacing the cyclopropanecarboxyaldehyde with 1-methylcyclopropancarboxyaldehyde MS (FAB (M + H) + at m / z 1052.

EXAMPLE 28 11,12- (CYCLICAL CARBAMATE) OF 3 ', 3'-N-BISDESMETIL-3'-N- (1-METHYLCYCLOPROPYL) METHYL-3'-N-CICLOPROPYLMETHYL-11-DESOXY-11-GCARBOXY- (3 -CLORO-4-FLUOROFENETILAMINO) 1-6-Q-METHYLERITROMYCIN A The title compound was prepared as described in Example 19, but replacing the cyclobutanone with 1-methylcyclopropancarboxyaldehyde. MS (FAB (M + H) + at m / z 1022.

EXAMPLE 29 11.12- (CYCLICAL CARBAMATE) OF 3 ', 3'-N-BISDESMETIL-3'-N- (1-METHYLCYCLOPROPYL) METHYL-3'-N-CICLOPROPYLMETHYL-11-DESOXY-11-GCARBOXY- (3,4 -DICLOROFENETILAMINO) 1-6-Q-METHYLERITROMYCIN A The title compound was prepared as described in example 28, but replacing 3-chloro-4-fluorophenethylamine with 3,4-dichlorophenethylamine. MS (FAB (M + H) + at m / z 1038 ..

EXAMPLE 30 11,12- (CYCLICAL CARBAMATE) OF S'.S'-N-BISDESMETIL-S'-N-ISOPRO PIL-3'-N -CICLO PRO PILMETI L-11-D ESOXI-11-rC ARBOXI- ( 3- CHLORINE-4-FLUOROFENETILAMINO) 1-6-Q-METHYLERITROMYCIN A The title compound was prepared as described in Example 28, but replacing 1-methylcyclopropanecarboxydehyde with acetone. MS (FAB (M + H) + at m / z .996 EXAMPLE 31 11.12- (CYCLICAL CARBAMATE) OF 3'.3'-N-BISDESMETIL-3'-N-ISOPROPIL-3'-N-CICLOPROPYLMETHYL-11-DESOXY -11-rCARBOXI- (3,4-DICHLOROPHENETILAMINO) 1-6-Q-METHYLERITROMYCIN A The title compound was prepared as described in Example 29, but replacing 1-methylcyclopropancarboxyaldehyde with acetone MS (FAB (M + H) + a / z 1012. EXAMPLE 32 11,12- (CYCLICAL CARBAMATE) OF 3'.3'-N-BISDESMETIL-3'-N-ISO PRO PIL-3'-N- (1 -METÍ LC I CLO PROPIL) MET L-11-D ESOXI -11-rCARBOXY- (3-CHLORO-4-FLUORO FEN ETI LAMIN 0) 1-6-0- METHYLERITROMYCIN A The title compound was prepared as described in example 28, but replacing the cyclopropanecarboxyaldehyde with acetone MS (FAB (M + H) + at m / z 1010.

EXAMPLE 33 11.12- (CYCLICAL CARBAMATE) OF 3 ', 3'-N-BISDESMETIL-3'-N-ISOPROPIL-3'-N- (1-METHYLCYCLOPROPIL) METHYL-11-DESOXY-11-rCARBOXI- (3,4-DICHLOROPHENYLAMINE) 1-6-Q- METHYLERITROMYCIN A The title compound was prepared as described in Example 29, but replacing the cyclopropanecarboxyaldehyde with acetone. MS (FAB (M + H) + at m / z 1026.

EXAMPLE 34 11 .12-CYCLIC ICARBAMATE) OF 3 \ 3'-N-BISDESMETIL-3-N-CICLOPROPYL-3'-N-ISOPROPIL-11-DESOXY-11-rCARBOXY- (4- CHLOROFENETI LAMINO)! -6-O-METHYLERITROMYCIN A The title compound was prepared as described in Example 5, but replacing the cyclobutanone with [(1-ethoxycyclopropyl) oxy] trimethylsilane. MS (FAB (M + H) + at m / z 965.

EXAMPLES 35-60 The compounds of Examples 35-60 described in Table 3 were prepared according to the methods described in the previous examples.

TABLE 3 58 Cl * Cf 59 ^ onó F, Ct -r ^ * " Hear CE, Cl

Claims

1. - A compound, characterized because it has the formula: or its pharmaceutically acceptable salt or ester; wherein: A is selected from the group consisting of: (a) -C, (b) -N; and (c) -O; X and Y, independently in each occurrence, are selected from the group consisting of: (a) hydrogen; (b) haiogenide; (c) trifluoromethyl; (d) alkoxy; (e) alkyl; (f) aryl; and (g) substituted aryl; R and R 'are selected from the group consisting of: (a) alkyl, (b) cycloalkyl; (c) heterocyclic; (d) substituted heterocyclic, (e) alkylcycloalkyl, (f) substituted alkylcycloalkyl, (g) alkylaryl, (h) alkylheterocyclic, (i) alkenyl, (j) alkynyl, (k) -C (S) -NHR4, C ( NR4) -NHR4, where R4 is hydrogen, alkyl or aryl; and (I) - (CH2) n-C (CH2) m-R5, where m is 2, 3, 4 or 5; and R5 is alkyl, alkoxy, aryl or substituted aryl; R2 and R3, independently in each occurrence, are: (a) hydrogen; (b) methyl; or R2 and R3 together form a cyclic portion, when A is C; R3 is absent when A is N; and n = 1, 2 or 3. The compound according to claim 1, further characterized in that R and R 'are alkyl, alkenyl, cycloalkyl, heterocyclic, (heterocyclic) alkyl or alkylcycloalkyl; X and Y are independently chloro, fluoro, dioxolane, hydrogen or alkoxy; A is -C; R2 and R3 are hydrogen or cyclopropyl and n is 1. 3. A compound, characterized in that it is selected from the group consisting of: 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3', 3 '-N-bis-cyclopropylmethyl-11-deoxy-11- [carboxy (3,4-dichlorophenethylamino)] - 6-O-methyl-erythromycin A; 11, 12- (cyclic carbamate) of 3 ', 3'-N-bis-desmethyl-3', 3'-N-bis-cyclobutyl-11-deoxy-11- [carboxy (3,4-dichlorophenethylamino)] -6-O-methyl-erythromycin A; 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3', 3'-N-bis-cyclopropylmethyl-11-deoxy-11- [carboxy (4-chlorophenethylamino)] - 6-O -methyl-erythromycin A; 11, 12- (cyclic carbamate) of 3 ', 3'-N-bis-demethyl-3', 3'-N-bis-cyclobutyl-11-deoxy-11- [carboxy (4-chlorophenethylamino)] - 6-O -methyl-erythromycin A; 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3'-N-cyclobutyl-3'-Nisopropyl-3'-N-isopropyl-11-deoxy-11- [carboxy (4- chlorphenethylamino)] - 6-O-methyl-erythromycin A; 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3'-N-isopropyl-3'-N-propyl-11-deoxy-11- [carboxy (4-chlorophenethylamine)] -6-O-methyl-erythromycin A; 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3'-N-cyclopropylmethyl-3'-N-propyl-11-deoxy-11- [carboxy- (4-chlorophenethylamino)] - 6-O-methyl-erythromycin A; 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3'-N-etyl-3'-N-isopropyl-11-deoxy-11- [carboxy (4-chlorophenethylamino)] - 6 -0-methyl-erythromycin A; 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3'-N-cyclobutylmethyl-3'-N-cyclopropylmethyl-11-deoxy-11- [carboxy (4-chlorophenethylamino)] - 6 -O-methyl-erythromycin A; 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3', 3'-N-bis-cyclopropylmethyl-11-deoxy-11- [carboxy (4-chlorophenethylamino)] - 6-O -methyl-erythromycin A; 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3', 3'-N-bis-cyclopropylmethyl-11-deoxy-11- [carboxy (4-chlorophenethylamino)] - 6-O -methi -erythromycin A; 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3', 3'-N-bis-cyclobutyl-11-deoxy-11- [carboxy (4-chloro-3-fluorofenetylamino)] -6-O-methyl-erythromycin A; 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmet? I-3', 3'-N-bis-cyclopropylmethyl-11-deoxy-11- [carboxy (4-chloro-3-fluorophenethyl) amino)] - 6-O-methyl-erythromycin A; 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3', 3'-N-bis-cyclobutyl-11-deoxy-11- [carboxy (4-chloro-3-fluorofenetylamino)] -6-O-methyl-erythromycin A; 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3', 3'-N-bis-cyclopropylmethyl-11-deoxy-11- [carboxy (3-chloro-4-fluoro-phenethyl amino )] - 6-O-methyl-erythromycin A; 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3'-N-cyclopentyl-3'-N-cyclopropylmethyl-11-deoxy-11- [carboxy (3-chloro-4- fluorophenethyl amino)] - 6-O-methyl-erythromycin A; 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3', 3'-N-bis-cyclopropylmethyl-11-deoxy-11- [carboxy (3,4-difluoro phenethyl amino)] -6-O-methyl-erythromycin A; 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3', 3'-N-bis-cyclobutyl-11-deoxy-11- [carboxy (3,4-difluoro phenethyl amino)] -6-0-methyl-erythromycin A; 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3'-N-cyclobutyl-3'-N-cyclopropiimethyl-11-deoxy-11- [carboxy (3-chloro-4-fluorophenethyl amino)] - 6-O-methyl-erythromycin A; 11,12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3', 3'-N-bis- [3, - (3-pyridyl) propyl] -11-deoxy-11- [carboxy] (3-chloro-4-fluoro phenethyl amino)] - 6-O-metii-erythromycin A; 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3'-N-cyclopropylmethyl-3'-N- (4-hydroxymethyl-2-furyl) -11-deoxy-11- [carboxy] (3-chloro-4-fluorophenethylamino)] - 6-0-methyl-erythromycin A; 11,12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3'-N-cyclopropylmethyl-3'-N- (4-pyridyl) propyl-11-deoxy-11- [carboxy (3-) chloro-4-fluorophenethylamino)] - 6-0-methyl-erythromycin A; 11,12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3', 3'-N-cyclopropylmethyl-3'-N- (4-hydroxymethyl-2-furyl) -11-deoxy-11- [carboxy (3-chloro-4-fluorophenethylamino)] - 6-0-methyl-erythromycin A; 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3'-N-cyclopropylmethyl-3'-N- (2-furyl) methyl-11-deoxy-11- [carboxy (3- chloro-4-fluorophenethylamino)] - 6-O-methyl-erythromycin A; 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3'-N-cyclopropylmethyl-3'-N- [6-methyl (2-pyridyl)] metii-11-deoxy-11 - [carboxy (3-chloro-4-fluorophenethylamino)] - 6-O-methyl-erythromycin A; 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3'-N-bis- (1-methylcyclopropyl) methyl-11-deoxy-11- [carboxy- (3-chloro-4- fluorofenetylamino)] - 6-O-methyl-erythromycin A; 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3'-N-bis (1-methylcyclopropylmethyl) methyl-11-deoxy-11- [carboxy (3,4-dichlorophenethyl) amino) ] -6-O-methyl-erythromycin A; 11,12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3'-N- (1-methylcyclopropyl) methyl-3'-N-cyclopropylmethyl-11-deoxy-11- [carboxy (3- chloro-4-fluorophenethylamino)] - 6-O-methyl-erythromycin A; 11,12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3'-N- (1-methylcyclopropyl) methyl-3'-cyclopropylmethyl-11-deoxy-11- [carboxy (3, 4-dichlorophenethylamino)] - 6-O-methyl-erythromycin A; 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3'-N-isopropyl-3'-cyclopropylmethyl-11-deoxy-11- [carboxy (3-chloro-4-fluorophenethylamino)] -6-O-methyl-erythromycin A; 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3'-N-isopropyl-3'-N-cyclopropylmethyl-11-deoxy-11- [carboxy (3,4-dichlorophenethylamino)] -6-O-methyl-erythromycin A; 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3'-N-isopropyl-3'-N- (1-methylcyclopropyl) methyl-11-deoxy-11- [carboxy- (3 -chloro-4-fluorophenethylamino)] - 6-O-methyl-erythromycin A; 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3'-N-isopropyl-3'-N- (1-methylcyclopropyl) methyl-11-deoxy-11- [carboxy (3, 4-dichlorophenethylamino)] - 6-O-methyl-erythromycin A; 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3'-N-cyclopropylmethyl-3'-N- (bis-cyclopropyl) methyl-11-deoxy-11- [carboxy (3- chloro-4-fluorophenethylamino)] - 6-O-methyl-erythromycin A; 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3'-N-cyclopropylmethyl-3'-N- (bis-cyclopropyl) methyl-11-deoxy-11- [carboxy (3, 4-dichlorophenethylamino)] - 6-O-methyl-erythromycin A; 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3'-N-cyclopropylmethyl-3'-N- (2,2-dimethylpropyl) -11-deoxy-11- [carboxy (3 -chloro-4-fluorophenethylamino)] - 6-O-methyl-erythromycin A; 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3'-N-cyclopropylmethyl-3'-N- (2,2-dimethylpropyl) -11-deoxy-11- [carboxy (3 , 4-dichlorophenethylamino)] - 6-O-methyl-erythromycin A; 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3'-N-cyclopropylmethi-3'-N- [3- (4-hydroxy-3-methoxyphenyl) -1-methyl] propi l-11-deoxy-11- [carboxy (3-chloro-4-fluorophenethylamino)] - 6-O-methyl-erythromycin A; 11, 12- (cyclic carbamate) of 3 \ 3'-N-bisdesmethyl-3'-N-cyclopropylmethyl-3'-N- [3- (4-hydroxy-3-methoxyphenyl) -1-methyl] propyl-11-deoxy -11- [carboxy (3,4-dichlorophenethylamino)] - 6-0-methyl-erythromycin A; 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3'-N-cyclobutyl-3'-N- (1-methylcyclopropyl) methyl-11-deoxy-11- [carboxy (3- chloro-4-fluorophenethylamino)] - 6-O-methyl-erythromycin A; 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3'-N-cyclobutyl-3'-N- (1-methylcyclopropyl) methyl-11-deoxy-11- [carboxy (3, 4-dichlorophenethylamino)] - 6-O-methyl-erythromycin A; 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3'-N-cyclopropylmethyl-3'-N- (1-ethylcyclopropyl) methyl-11-deoxy-11 - [carboxy- (3- chloro-4-fluorophenethylamino)] - 6-O-methyl-erythromycin A; 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3'-N-cyclopropylmethyl-3'-N- (1-ethylcyclopropyl) methyl-11-deoxy-11- [carboxy (3, 4-dichlorophenethylamino)] - 6-O-methyl-erythromycin A; 11, 12- (cyclic carbamate) 3 ', 3'-N--Bisdesmethyl-3'-N-cyclopropylmethyl-3'-N- (1-feniIciclopropil) met¡l-11-deoxy-11- [carboxy- ( 3-chloro-4-fluorophenethylamino)] - 6-0-methyl-erythromycin A; 11, 12- (cyclic carbamate) 3 ', 3'-N-bisdesmetii-3'-N-cyclopropylmethyl-3'-N- (1-fenilciclopropii) methyl -11-deoxy-11- [carboxy- (3, 4-dichlorophenethylamino)] - 6-O-methyl-erythromycin A; 11, 12- (cyclic carbamate) 3 ', 3'-N--Bisdesmethyl-3'-N-ethyl-3'-N- (1-methylcyclopropyl) methyl-11-deoxy-11- [carboxy- (3- chloro-4-fluorophenethylamino)] - 6-O-methyl-erythromycin A; 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3'-N-ethyl-3'-N- (1-methylcyclopropyl) methyl-11-deoxy-11- [carboxy (3, 4-dichlorophenethylamino)] - 6-O-methyl-erythromycin A; 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3'-N-isobutyl-3'-N- (1-methylcyclopropyl) methyl-11-deoxy-11- [carboxy (3- chloro-4-fluorophenethylamino)] - 6-O-methyl-erythromycin A; 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3'-N-isobutyl-3'-N- (1-methylcyclopropyl) methyl-11-deoxy-11- [carboxy (3, 4-dichlorophenethylamino)] - 6-O-methyl-erythromycin A; 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3'-N-cyclopropylmethyl-3'-N- (1-allylcyclopropyl) methyl-11-deoxy-11- [carboxy (3- chloro-4-fluorophenethylamino)] - 6-O-methyl-erythromycin A; 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3'-N-cyclopropylmethyl-3'-N- (1-allylcyclopropyl) methyl-11-deoxy-11- [carboxy (3, 4-dichlorophenethylamino)] - 6-O-methyl-erythromycin A; 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3'-N-cyclopropylmethyl-3'-N- (1-benzylcyclopropyl) methyl-11-deoxy-11- [carboxy (3- chloro-4-fluorophenethylamino)] - 6-O-methyl-erythromycin A; 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3'-N-cyclopropylmethyl-3'-N- (1-benzylcyclopropyl) methyl-11-deoxy-11- [carboxy (3, 4-dicyorophenethylamino)] - 6-O-methyl-erythromycin A; 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3'-N-bis- (1-methylcyclobutyl) methyl-11-deoxy-11- [carboxy (3-chloro-4-fluorophenethylamino )] - 6-0-methyl-erythromycin A; 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3'-N-bis- (1-methylcyclobutyl) methyl-11-deoxy-11- [carboxy (3,4-dichloro phenethyl amino )] - 6-O-methyl-erythromycin A; 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3'-N-cyclopropoxymethyl-3'-N- (1-methylcyclobutyl) methyl-11-deoxy-11- [carboxy (3- chloro-4-fl.uorophenethylamino)] - 6-O-methyl-erythromycin A; and 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3'-N-cyclopropylmethyl-3'-N- (1-methylcyclobutyl) methyl-11-deoxy-11- [carboxy (3 , 4-dichlorophenethylamino)] - 6-O-methyl-erythromycin A. 4. The compound according to claim 3, further characterized in that it is selected from the group consisting of: 11,12- (cyclic carbamate) 3 ' , 3'-N-bisdesmethyl-3'-N-biscyclopropylmethyl-11-deoxy-11- [carboxy (3-cioro-4-fluoro-phenethyl-amino)] - 6-O-methyl-erythromycin A; 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3'-N-biscyclobutyl-11-deoxy-11- [carboxy (3-chloro-4-fluorophenethylamino)] - 6-O- methyl-erythromycin A; 11,12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3', 3'-N-bis- (1-methylcyclopropyl) methyl-11-deoxy-11- [carboxy (3-chloro- 4-fluorophenethylamino)] - 6-0-methyl-erythromycin A; and - 11, 12- (cyclic carbamate) of 3 ', 3'-N-bisdesmethyl-3'-N-isopropyl-3'-N- (1-methylcyclopropyl) methyl-11-deoxy-11- [carboxy- ( 3-cioro-4-fluorofenetylamino)] - 6-O-methyl-erythromycin A. ^ 5.- A pharmaceutical composition for inhibiting the release of LH, characterized in that it comprises a therapeutically effective amount of a compound according to claim 1, in combination with a pharmaceutically acceptable carrier. 6. A method for inhibiting the release of LH in a mammal in need of such treatment, characterized in that it comprises administering to the mammal a therapeutically effective amount of a compound according to claim 1. 7. A process for preparing a compound represented by the formula: ?, or its pharmaceutically acceptable salt or ester, wherein: A is selected from the group consisting of: (a) -C, (b) -N; and (c) -O; X and Y, independently in each occurrence, are selected from the group consisting of: (a) hydrogen; (b) haiogenide; (c) trifluoromethyl; (d) alkoxy; (e) alkyl; (f) aryl; and (g) substituted aryl; R and R 'are selected from the group consisting of: (a) alkyl, (b) cycloalkyl; (c) heterocyclic; (d) substituted heterocyclic, (e) alkylcycloalkyl, (f) substituted alkylcycloalkyl, (g) alkylaryl, (h) alkylheterocyclic, (i) alkenyl, (j) alkynyl, (k) -C (S) -NHR4, C ( NR4) -NHR4, where R4 is hydrogen, alkyl or aryl; and (l) - (CH2) n-C (CH2) m-R5, where m is 2, 3, 4 or 5; and R5 is alkyl, alkoxy, aryl or substituted aryl; R2 and R3l independently in each occurrence, are: (a) hydrogen; (b) methyl; or R2 and R3 together form a cyclic portion, when A is C; R3 is absent when A is N; and n = 1, 2 or 3 characterized said process because it comprises the steps of: (a) reacting a compound of the formula: with sodium hexamethyldisilazide and carbonyldiimidazole, to produce a compound of the formula: (b) reacting the compound obtained in step (a) with an amino compound of the formula: followed by deprotection of the 2 ', 4"-protected hydroxyl groups, to give a compound of the formula (c) stepwise demethylating the 3'-amino, treating the compound obtained in step (b), with iodine, in the presence of a base to produce a compound of the formula: and (d) alkylating the 3 ', 3'-N-bis-demethylated compound, obtained in step (c), with an alkylating agent. 8. The process according to claim 7, further characterized in that the reaction of step (a) is carried out in an aprotic solvent at 0-25 ° C. 9. The process according to claim 7, further characterized in that the reaction of step (b) is carried out without a solvent or in acetonitrile at 25-80 ° C. 10. The process according to claim 7, further characterized in that demethylation is carried out by reaction of the compound obtained in step (b) with iodine, in the presence of a base and a light or thermal source. 11. The process according to claim 7, further characterized in that demethylation is carried out by reaction of the compound obtained in step (b) with a chloroformate, selected from the group consisting of benzyl chloroformate, allyl chloroformate and vinyl chloroformate. 1

2. The process according to claim 7, further characterized in that the alkylation of step 8d) is carried out by reaction of the compound obtained in step (c) with an aldehyde or a ketone, in the presence of a metal hydride , or in the presence of Pd / C catalyst, in protic or non-protic solvent, under hydrogen. 1

3. The process according to claim 7, further characterized in that the alkylation of step (d) is carried out by reaction of the compound obtained in step (c) with an alkyl haiogenide, in the presence of a base. 1

4. The process according to claim 7, further characterized in that R is alkyl, alkenyl, cycloalkyl, heterocyclic, (heterocyclic) alkyl or alkylcloalkyl; X and Y are independently, in each occurrence: chlorine, fluorine, dioxolane, hydrogen or alkoxy; A is -C; R2 and R3 are independently, in each occurrence, hydrogen; or together they form a cyclopropyl moiety; and n is 1. 1

5. The process according to claim 7, further characterized in that the alkylating agent is cyclopentanone and alkylation is carried out in the presence of sodium cyanoborohydride in methanol. 1

6. The process according to claim 7, further characterized in that the process comprises the steps of: (c) selectively demethylating the compound obtained in step (b), to obtain the compound of the formula: (d) alkylating the 3'-N-demethylated compound obtained in step (c), with an alkylating agent to give a compound of the formula: (e) demethylating the 3'-amino by treating the compound obtained in step (d) with iodine, in the presence of a base, to give a compound of the formula: and (f) alkylating the 3'-N-demethylated compound, obtained in step (e), with an alkylating agent.