MXPA97004253A - Derivatives of 9-0-oxima of erythromycin or dotated with antibioot activity - Google Patents

Abstract

The present invention relates to compounds of formula (I) wherein A, R2, M, n, m and r have the meanings reported in the description, processes for their preparation and pharmaceutical compositions containing them as active ingredients. The compounds of formula (I) are useful in the treatment of infectious diseases

Description

DERIVATIVES OF ERITROMYCIN A 9-O-OXIMA WITH ANTIBIOTIC ACTIVITY DESCRIPTION OF THE INVENTION The present invention relates to erythromycin A derivatives endowed with antibiotic activity, useful in the treatment of infectious diseases, and, more particularly, related to derivatives of 9- [0- (aminoalkyl) oxime] of erythromycin A endowed with antibiotic activity against Gram-positive and Gram-negative microorganisms. Erythromycin A [The Merck Index, XI Ed., No. 3626] is a well-known macrolide that exists naturally, endowed with antibiotic activity, which has the following structure: REF: 24812 '- In addition to being active against some non-bacterial microorganisms such as rikettsias and mycoplasmas, erythromycin A is endowed with antibacterial activity mainly against Gram-positive microorganisms such as streptococci, staphylococci and pneumococci, but it is also effective against some Gram microorganisms. -negatives such as, for example, Haemophilus influenzae, - Neisseriea gonorrhoeae and Bordetella pertussis. In addition to the well-known activity against the prokaryotic organisms mentioned above, it has recently been described in the literature that erythromycin A and other macrolide antibiotics are active against eukaryotic parasites [P. A. Lartey et al., Advances in Pharmacology, 2_8, 307-343 (1994). Also in the case of erythromycin A, in the same way as with other antibacterial drugs, resistance phenomena were observed with some bacterial strains. In particular, the phenomenon was observed in the treatment of infections caused by stafilocos following the prolonged administration of erythromycin A [A. Kucers and N. McK. Bennett, The use of antibiotics, A Comprehensive Revie with Clinical Emphasis, Illiam Heinemann Medical, IV Ed., (1987) 851-882. The interest towards macrolide antibiotics is derived from its use in clinical and veterinary therapy in the treatment of various infectious diseases such as, for example, infections of the respiratory tract, gastrointestinal tract, urogenital tract and external organs such as skin, eyes and ears. Because of its high instability in an acidic environment, erythromycin A is irreversibly converted, for example in the gastrointestinal tract following oral administration, into derivatives lacking antibiotic activity, thus giving it little bioavailability on the active principle [H. A. Kirst, Annual Reports in Medicinal Chemistry, 2J5, 119-128 (1989)]. To overcome the above drawbacks, the research was directed to compounds which, while maintaining the good antibiotic properties of erythromycin A, would be characterized by superior stability to acids and better pharmacokinetic properties such as, for example, oral bioavailability. , blood concentration, tissue penetration and superior half-life. Within this field, we can mention as an example the carbamates and carbonates of erythromycin A or the 9-0-oxime of erythromycin A described in European Patent Applications Nos. 0216169 and No. 0284203 (both in the name of Beecha Group PLC) and the compounds described in European Patent Application No. 0033255 (Roussel-Uclaf). European Patent Application No. 0033255, in particular, describes 9-0-oxime derivatives of erythromycin A of formula: R-A-0-N = Ery wherein Ery represents the residue of erythromycin A wherein the oxime group (-N = Ery) is in place of the carbonyl group at position 9 (0 = Ery); the letter A represents a straight or branched chain alkyl group with from 1 to 6 carbon atoms; R represents, inter alia, an alkoxy group optionally substituted with from 1 to 6 carbon atoms, or a group [-N (R?) R2] wherein Ri and R2, the same or different, represent a hydrogen atom or a alkyl group optionally substituted with from 1 to 6 carbon atoms. The compounds described in European Patent Application No. 0033255 such as, for example, 9- [O- [(2-methoxyethoxy) methyl] oxime] of erythromycin A, known under the name Non-proprietary International of Roxitro icina [The Merck Index, XI Ed., No. 8253], the 9- [O- [(2-dimethylamino) ethyl] oxime] of erythromycin A and the 9- [O- [(2-diethylamino) ethyl] oxime) of erythromycin A have an in vitro activity spectrum comparable to that of erythromycin A , but are endowed with superior stability to acids and with better pharmacokinetic properties. The compounds, therefore, exhibit antibiotic activity against Gram-positive bacteria such as staphylococci, streptococci and pneumococci, and against some Gram-negative bacteria such as, for example, Hae ophilus influenzae and Haemophilus pertussis. Now, we have found compounds derived from the 9-O-oxime of erythromycin A and more particularly, compounds derived from the erythromycin A 9- [0- (aminoalkyl) oxime], partially included but not exemplified in the European Patent Application No. 0033255, which have a broader spectrum of antibacterial activity against Gram-positive microorganisms and, particularly, against Gram-negative microorganisms, and improved pharmacokinetic properties such as, for example, a longer duration of action and a longer half-life of tissue removal, with respect to the compounds described in the aforementioned European Patent Application. An object of the present invention, therefore, are compounds of the formula: (I) wherein A is a phenyl group or a heterocycle with 5 or 6 members, containing one or more heteroatoms selected from nitrogen, oxygen and sulfur, optionally substituted with from 1 to 3 groups, the same or different, selected from alkyl or alkoxy groups straight or branched chain of 1 to 4 carbon atoms, alkylenedioxy groups of 1 to 2 carbon atoms, alkylsulfonyl groups of 1 to 4 carbon atoms, phenyl, phenoxy, hydroxy, carboxy, nitro, halogen and trifluoromethyl groups; R_ and R2, the same or different, represent a hydrogen atom or an alkyl group of 1 to 4 carbon atoms straight or branched chain; n is 1 or 2; m is an integer between 1 and 8; r is an integer between 2 and 6; M represents a group of formula: wherein R3 is a hydrogen atom or a methyl group; and the pharmaceutically acceptable salts thereof. The oximes of Formula (I) may have the configuration Z or E.

The object of the present invention, therefore, are the compounds of Formula (I) having the Z or E configuration, with a preference for the latter. The compounds of Formula (I) are endowed with antibiotic activity and are characterized by high acid stability and good pharmacokinetic properties, thus being used in human or veterinary therapy for the treatment of various infectious diseases such as, for example, infections of the central nervous system, the upper and lower respiratory tract, the gastrointestinal tract, the urogenital tract, the odontological tissue and external organs such as the skin, eyes and ears. In the present description, unless otherwise specified, with the term alkyl group of 1 to 4 carbon atoms we propose an alkyl group of 1 to 4 straight or branched chain carbon atoms such as a methyl, ethyl group , n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl; with the term alkoxy group of 1 to 4 carbon atoms we propose a straight or branched chain alkoxy group of 1 to 4 carbon atoms such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and ter-butoxy; with the term alkylenedioxy group of 1 to 2 carbon atoms we propose a methylenedioxy or ethylenedioxy group. With the term 5- or 6-membered heterocycle containing 1 or more heteroatoms selected from nitrogen, oxygen and sulfur, we propose a heterocycle preferably selected from pyridine, pyrrole, pyrrolidine, furan, tetrahydrofuran and thiophene. Preferred compounds are compounds of Formula (I) wherein A represents a phenyl group or a heterocycle selected from pyridine and furan, optionally substituted with from 1 to 3 groups selected from hydroxy, methoxy, methylenedioxy, n-butoxy, phenoxy groups , phenyl, methylsulfonyl, nitro, halogen and trifluoromethyl; Ri and R2, being the same, represent a hydrogen atom or a methyl group, R3 represents a hydrogen atom. The still more preferred compounds are the compounds of Formula (I) wherein A represents a phenyl group optionally substituted with a group selected from phenoxy, nitro and trifluoromethyl, Ri and R2, being the same, represent a hydrogen atom or a methyl group; n is equal 1; m is equal to 6; r is equal to 2; R3 represents a hydrogen atom. The pharmaceutically acceptable salts of the compounds of Formula (I) are the salts with acids with organic or inorganic acids such as, for example, hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, acetic, tartaric, citric, benzoic, succinic acids. and glutaric. Specific examples of preferred compounds of Formula (I) are: (E) -9- [0- [2- [6- (phenylethylamino) hexylamino] ethyl] oxime] of erythromycin A; (E) -9- [0- [2-] 2- (phenylmethylamino) ethylamino] ethyl] oxime] of erythromycin A; (E) -9- [0- [2- [6- (phenylmethylamino) hexylamino] hexyl] oxime] of erythromycin A; (E) -9- [0- [6-] 3- (phenylmethylamino) propylamino] hexyl] -oxime] erythromycin A; (E) -9- [0- [6- [5 (phenylmethylamino) pentalimino] hexyl] -oxime] of erythromycin A; (E) -9- [0- [2- [8- (phenylmethylaminio) octylamino] ethyl] -oxime] erythromycin A; (E) -9- [0- [2- [5- (phenylmethylamino) pentylamino] ethyl] -oxime] erythromycin A; (E) -9- [-0- [5- [6- (phenylmethylamino) hexylamino] ethyl] oxime] of erythromycin A; (E) -9- [O- [3- [6- (phenylmethylamino) hexylamino] propyl] -oxime] erythromycin A; (E) -9- [0- [3- [4- (phenylmethylamino) butylamino] propyl] -oxime] erythromycin A; (E) -9- [O- [2- [N-methyl-6- (N '-methyl-N' phenylmethylamino) -hexylamino] ethyl] oxime] of erythromycin A (E) -9- [O- [2 - [6- [(biphenyl-4-yl) methylamino] -exylamino] -ethyl] oxime] of erythromycin A; (E) -9- [0- [2- [6- [(3-phenoxyphenyl) methylamino] hexylamino] -ethyl] oxime] erythromycin A; (E) -9- [0- [2- [6- [(4-phenoxyphenyl) methylamino] hexylamino] -ethyl] oxime] erythromycin A; (E) -9- [0- [2- [6- (2-Furylmethylamino) hexylamino] ethyl] -oxime] erythromycin A; (E) -9- [0- [2- [6- (3-pyridylmethylamino) hexylamino] -ethyl] oxime] of erythromycin A; (E) -9- [0- [2- [6- [(4-methoxyphenyl) methylamino] hexylamino] -ethyl] oxime] erythromycin A; (E) -9- [0- [2- [6- [(4-n-butioxyphenyl) methylamino] -hexylamino] ethyl] oxime] erythromycin A; (E) -9- [0- [2- [ß- [(3, -methylenedioxyphenyl) methylamino] -hexylamino] ethyl] oxime] of erythromycin A; (E) -9-fO- [2- [6- [(-methylsulfoni-phenyl) -methylamino] -hexylamino] -ethyl] oxime] of erythromycin A; (E) -9- [O- [2- [6- [(4-fluorophenyl) methylamino] -hexylamino] ethyl] oxime] of erythromycin A; (E) -9- [0- [2- [6- [(2-trifluoromethylphenyl) methylamino] -hexylamino] ethyl] oxime] erythromycin A; (E) -9- [0- [2- [6- [(3-trifluoromethylphenyl) methylamino] -hexylamino] ethyl] oxime] of erythromycin A; (E) -9- [0- [-2- [6- [[(4-trifluoromethylphenyl) methylamino] -hexylamino] ethyl] oxime] erythromycin A; (E) -9- [0- [2- [6- [(2-hydroxyphenyl) methylamino- [hexylamino] ethyl] oxime] of erythromycin A; (E) -9- [0- [2- [6- [(3-hydroxyphenyl) methylamino] -hexylamino] ethyl] oxime] of erythromycin A; (E) -9- [0- [2- [6- [(4-hydroxyphenyl) methylamino] methylamino] hexylamino] ethyl] oxime] erythromycin A; (E) -9- [0- [2- [6. [(3, 5, dichloro-2-hydroxyphenyl) -methylamino] hexylamino] ethyl] oxime] of erythromycin A; (E) -9- [0- [2- [6- [(2-nitrophenyl) methylamino] -hexylamino] ethyl] oxime] erythromycin A; (E) -9- [0- [2- [6- [(3-nitrophenyl) methylamino] -hexylamino] ethyl] oxime] of erythromycin A; (E) -9- [0- [2- [6- [(4-nitrophenyl) methylamino] -hexylamino] ethyl] oxime] of erythromycin A; (E) -9- [O- [2- [ß- [(4-hydroxy-2-nitrophenyl) methylamino] -hexylamino] ethyl] oxime] of erythromycin A; (E) -9- [0- [2- [ß- [(3-hydroxy-4-nitrophenyl) methylamino] -hexylamino] ethyl] oxime] of erythromycin A; (E) -9- [0- [2- [N-methyl-6- [N'-methyl-N '- (4-trifluoromethyl-phenyl) -ethylamino] -hexylamino] -ethyl] oxime] of erythromycin A; The preparation of the compounds of Formula (I), object of the present invention, can be carried out according to the synthetic method described below. The method comprises, at the beginning, the condensation reaction between a suitable amino acid of the formula: HN-CCHa) w -, - C00H CIT) where Ri and m have the meanings reported above; with an acyl chloride of formula: A- (CH2) r .-? - C0Cl (III) where A and n have the meanings reported above. The condensation reaction is carried out, according to conventional techniques, in an inert solvent and in the presence of a base such as, for example, an alkali metal hydroxide, to obtain the compounds of the formula: A- (CHa;? - i-C0N- (CHa) or .-? - C00H (IV) where A, Ri, n and m have the meanings reported above. The N-acyl amino acids of formula (IV) obtained in this way are further condensed, according to conventional techniques, with an amino ester of formula: Ra HN- (CHa) ».- •. -C00R .-- where R2 and _ have the meanings reported above; R represents a methyl or ethyl group, to obtain the compounds of the formula: R, Ra I I A-.CHaJn-, -CON- (CHa) TO-i -CON- (CHa), .--. -COOR * (VI ' where A, Ri, R2, R4, n, m and r have the meanings reported above. Working according to conventional techniques, the compounds of Formula (VI) are subsequently reduced, for example with sodium borohydride, in the presence of acids, lithium aluminum hydride, dimethyl-borane sulfide, or by catalytic hydrogenation, to the aminoalcohols corresponding to formula: R, Ra I I A- (CHa) n-C0N- (CHa) «.- C0N- (CHa) * .- 0H (VID) where A, Ri, R2, n, m and r have the meanings reported above. The aminoalcohols of Formula (VII) are then converted to the corresponding sulfonyl derivatives of Formula (VIII), for example by means of methanesulfonyl chloride or p-toluenesulfonyl chloride, and subsequently condensed with 9-O-oxim of erythromycin A or 9-0-oxime 6-0-methylerythromycin A, both representative according to Formula (IX), to obtain the compounds of Formula (I): I I (VII) > A- (CHa) «- N- (CHa)« - N- (CHa), .- 0R. (VIII) I I A- (CHa) «- N- (CHa)» - N- (CHa) «.- 0-NsM (I) where A, R, R2, M, n, m and r have the meanings reported above; R5 represents a mesyl or tosyl group. The reaction between the compounds of Formula (VIII) and the oximes of Formula (IX) is carried out in an inert organic solvent such as, for example, tetrahydrofuran, ethyl ether or 1,2-dimethoxyethane, in the presence of potassium ter-butoxide and ether 18- corona-6 as a complexing agent. It is clear to the man skilled in the art that when the sulfonylation reaction is carried out using the compounds of Formula (VII) wherein one or both of the substituents R x, R 2 represent a hydrogen atom, it may be necessary to protect the atom or nitrogen atoms, before carrying out the sulfonylation reaction. In this case, the condensation of the N-protected sulfonyl derivatives obtained in this way with the oximes of Formula (IX), analogously to what was previously reported, and the subsequent deprotection carried out according to conventional methods, allows obtaining the compounds of Formula (I) wherein one or both substituents Ri and R2 represent a hydrogen atom. For a bibliographic reference to the protection of amines see [T. W. Greene and P.G.M. Wuts, Protective groups in organic synthesis, John Wiley & Sons, Inc., 2a. Ed., (1991), 309-.405]. The compounds of Formula (II), (III) and (V) are known or are prepared easily according to known methods. Also the oximes of Formula (IX) are known compounds, and can be prepared according to conventional methods comprising, for example, the reaction of erythromycin A or 6-0-methylerythromycin A with hydroxylamine hydrochloride.

The esters of Formula (VI) can optionally be prepared according to an alternative synthetic method comprising, first, the condensation of a suitable amino acid of Formula (II) with an amino ester of formula (V), to obtain the compounds of formula: H (CHaJ «.- i-C00R * (X) where R -.f R2 R4 m and r have the meanings reported above. It is clear to the person skilled in the art that before carrying out the condensation between the amino acid of Formula (II) and the amino ester of formula (V), it may be necessary to adequately protect, according to what is already reported for the reaction of sulfonylation, the amino group of the amino acid of Formula (II). Subsequent condensation of the compounds of Formula (X) with a compound of Formula (III), carried out according to conventional techniques, and optional deprotection, allows then to obtain the compounds of Formula (VI).

The preparation of the compounds of Formula (I) where at least one of the two substituents Ri and R2 represents a group selected from ethyl, N-butyl and isobutyl, it can be carried out according to an alternative synthetic method which is described below. The method comprises, first, the acylation of the nitrogen atom or atoms of the aminoalcohols of Formula (VII) wherein one or both substitutes Ri and R2 represent a hydrogen atom. For example, by using a compound of Formula (VII) wherein both substituents Ri and R2 represent a hydrogen atom, and working according to conventional techniques in the presence of a suitable acyl chloride (R'COCl), it is possible to obtain the compounds of formula: COR 'COR' A- (CHa> n-N- (CHa; »- N- (CHa ^ -0C0R '(XI) where A, n, m and r have the meanings reported above; R 'represents an alkyl group of 1 to 3 carbon atoms, straight or branched chain.

The reduction of the compounds of Formula (XI), carried out according to conventional methods, makes it possible to obtain the compounds of the formula: A- (CHaJr, - (CHaJ * .- OH (XII) where A, n, m and r have the meanings reported above; Ri and R2 represent ethyl, n-propyl, n-butyl or isobutyl groups, which, converted into the corresponding sulfonyl derivatives and condensed with the oximes of Formula (IX), analogously to the previously reported, allows to obtain the compounds of formula : I I A- (CHa)? - N- (CHa > t «.- N-CCHa)« .- 0-N = M (I) where A, M, n, m and r have the meanings "3" reported above Ri and R2 represent ethyl, n-propyl, n-butyl or isobutyl groups.

An alternative synthetic process with respect to those previously reported for the preparation of the compounds of Formula (I), object of the present invention, is described below. The process comprises, first, the oxidation of a suitable N-protected aminoalcohol such as, for example, an N-benzyloxycarbonyl-amino alcohol of Formula (XIII), in the presence of sodium hypochlorite and free radical 2, 2, 6,6-tetramethylpiperidinoxy (TEMPO), in an inert organic solvent, to obtain the compounds of Formula (XIV): Hi- (CHa) »- 0H > HN- < CH.J -, - CH0 (XIV) (XIII) where m has the meanings reported above; Z represents a protective group Examples of inert organic solvents usable in the oxidation reaction are, for example, methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane, ethyl acetate, benzene and toluene.

The amination of the aldehyde obtained in this way in the presence of an appropriate amino alcohol of Formula (XV) and the reduction of the intermediate formed, for example, in the presence of sodium borohydride, allows to obtain the aminoalcohols of Formula (XVI): Z H I I (XIV) * HaN- (CHa) «.- 0H > HN- (CHa) «.- N- (CHa)« .- 0H (XV) (XVI) where Z, m and r have the meanings reported above. The additional protection of the compounds of Formula (XVI) in the nitrogen of the amino and, in this order, the conversion to the corresponding sulfonyl derivatives, the condensation with the oximes of Formula (IX) and the deprotection of the nitrogen atoms, analogously to what was previously reported , allow to obtain the compounds of formula: H HaN- (CHa r.-N- (CHa) r-0-N * M (XVII) wherein M, m and r have the meanings reported above: Intermediate oximes of Formula (XVII), condensed with a suitable aldehyde of Formula (XVIII) and reduced, for example by catalytic hydrogenation, make it possible to obtain the compounds of Formula (I) : H H I I (XVII) * A- (CHa? -i-CHO> A- (CHa) n-N- (CHa) »- N- (CHa), .- 0-N = M (XVIII) (I) where A, M, n, m and r have the meanings reported above. The compounds of Formula (XIII), (XV) and (XVIII) are known or are easily prepared according to known methods. Compounds of Formula (I) wherein one or both substituents R and R 2 represent a hydrogen atom, prepared according to one of the methods previously described, can optionally be alkylated at the nitrogen atom or atoms of the di-amino moiety according to conventional methods comprising, for example, condensation with a suitable aldehyde and reduction of the intermediate obtained.

The compounds of Formula (I) are thus obtained wherein Ri and R2 / the same or different, represent an alkyl group of 1 to 4 carbon atoms straight or branched chain. The preparation of the compounds of Formula (I) with Z or E configuration is carried out according to one of the synthetic schemes described above, using the oxime of Formula (IX) in the desired configuration [J. C. Gasc et al., The Journal of Antibiotics, 44_ 313-330, (1991)]. The compounds of Formula (I) are endowed with antibacterial activity against various Gram-positive and Gram-negative microorganisms, and are useful in clinical and veterinary therapy, for the treatment of various infectious diseases such as, for example, system infections. central nervous system, lower and upper respiratory tract, gastrointestinal tract, urogenital tract, dental tissue and external organs such as the skin, eyes and ears. The compounds, additionally, turned out to be active with respect to several Gram-positive microorganisms of clinical interest, resistant to erythromycin A or, more generally, to macrolide antibiotics characterized by the presence of a 14- or 15-member macrolactone. The antibacterial activity of the compounds of Formula (I) against Gram-positive microorganisms such as Streptococcus pyogenes, Streptococcus pneumoniae, Enterococcus faecalis and Staphylococcus aureus, and Gram-negative microorganisms such as Escherichia coli and Klebsiella pneumoniae was evaluated by means of in vitro tests suitable for evaluating the minimum concentration of antibiotic that allows the inhibition of bacterial growth (MIC) (Example 23). Roxithromycin and clarithromycin were used as reference compounds [The Merck Index, XI Ed. ', Nos. 8253 and 2340, respectively). The antibacterial activity of the compounds of Formula (I) against Gram-positive microorganisms was found to be practically comparable to that of roxithromycin and clarithromycin, macrolides both characterized by a high antibacterial activity in vitro (Table 1). With respect to Gram-negative microorganisms and, particularly, against Enterobacteriaceae such as Escherichia coli and Klebsiella pneumoniae, the compounds of Formula (I) were found to be markedly more active than both reference compounds (Table 2). At this point, it is interesting to note that the compounds of Formula (I), object of the present invention, turned out to be more active than roxithromycin, described in European Patent Application No. 0033255 mentioned above, and selected as the compound of choice with with respect to several other derivatives such as, for example, 9- [0- [(2-dimethylamino) ethyl] oxime] of erythromycin A [J. C. Gasc et al., The Journal of Antibiotics 44, 313-330, (1991)]. On the other hand, the compounds of Formula (I) were found to be active in vivo (Table 3). The in vivo antibacterial activity of the compounds of Formula (I), expressed as the average protective dose PC5o (mg / kg), was evaluated by experimental lung infection induced in mice by Streptococcus pyogenes (Example 23). Considering the in vivo activity data, it is evident that the compounds of Formula (I) are characterized by a prolonged duration of action and a prolonged half-life of tissue removal.

In fact, after intraperitoneal administration in mice, the compounds of Formula (I) are rapidly and widely distributed in the whole organism, and tissue levels were found to be higher than plasma levels. This is particularly evident considering the PD50 values for compounds of Formula (I) administered 24 hours before or 1 hour after infection. The values, in fact, turn out to be substantially unchanged after administration 24 hours before or 1 hour after infection. In the case of experimental lung infection induced in mice by Streptococcus pyogenes, a pathogen traditionally responsible for respiratory diseases, effective concentrations of compounds of Formula (I) administered intraperitoneally at the pulmonary level 24-48 hours after administration persist. The reference compounds roxithromycin and clarithromycin administered 24 hours before infection, instead of this, were found to be inactive. Therefore, the compounds of Formula (I) are also endowed with pulmonary selectivity, and can be used advantageously in the treatment of respiratory tract infections. In addition to the activity mentioned above against bacterial microorganisms, the compounds of Formula (I) object of the present invention were found to be active against eukaryotic pathogens. In particular, they turned out to be markedly active against protozoa such as Plasmodium falciparum, which is the well-known malaria parasite. The compounds of Formula (I), therefore, can also be advantageously used in the treatment of malarial diseases. In addition to being characterized by a broad spectrum of antibiotic activity against Gram-positive and Gram-negative and protozoan microorganisms, by a good stability to acids and by good pharmacokinetic properties, the compounds of Formula (I) present, in the mouse, a acute toxicity comparable to that of roxithromycin. Therefore, being characterized by a high safety of use, they can be used advantageously in human and veterinary therapy. The compounds of Formula (I) will preferably be used in a suitable dosage form useful for "oral, parenteral, suppository or topical administration." Object of the present invention, therefore, are pharmaceutical compositions containing a therapeutically effective amount of one or more compounds of Formula (I) in admixture with a pharmaceutically acceptable carrier The pharmaceutical forms comprise tablets, capsules, syrups, injectable solutions ready for use, or to be prepared when used by dilution of a lyophilized material, suppositories, solutions , creams, ointments, and ophthalmic lotions For veterinary use, in addition to the above compositions, it is possible to prepare solid or liquid concentrates to be diluted in the food or drinking water, according to the type of composition, in addition to a Therapeutically effective amount of one or more compounds of Formula (I), will contain excipients or dilution solid or liquid entities for pharmaceutical or veterinary use, and optionally other additives of normal use in formulation such as thickening, aggregation, lubrication, disintegrating, flavoring and coloring agents.

To treat particular infections, the compound of Formula (I) could be in association with an effective amount of another active ingredient. The effective amount of the compound of Formula (I) can vary according to different factors such as the seriousness and stage of the infection, the affected organ or system, the characteristics of the host species, the susceptibility of the responsible bacterial species. of the infection, and the selected route of administration. The therapeutic dose will usually be between 0.5 and 100 mg / kg of body weight / day, and could be administered in a single dose or in more daily doses. In order to illustrate the present invention, without limiting it, the following examples are now given. The structures of the compounds of Formula (I) and of the synthetic intermediates for their preparation were confirmed by lK NMR or 13 C NMR spectroscopy. The values of the significant signals of the most advanced intermediates and of the compounds of Formula (I) are reported below.

EXAMPLE 1 Preparation of N-benzoyl-6-aminohexanoic acid A solution of benzoyl chloride (0.18 mol) in ethyl ether (160 ml) and a 1 N sodium hydroxide solution (180 ml) were added contemporaneously to a mixture of acid 6-aminohexanoic acid (0.15 mol) in ethyl ether (150 ml) and water (200 ml) containing sodium hydroxide (0.15 mol) was kept under stirring at a temperature between 0-5 ° C. At the end of the additions, the reaction mixture was brought to room temperature, and kept under stirring for another 4 hours. After separation of the phases, the aqueous phase was washed with ethyl ether (200 ml) and acidified to red congo with concentrated hydrochloric acid. After extraction with ethyl acetate (3 x 200 ml) the collected organic phases were washed with a saturated aqueous solution of sodium chloride (200 ml), dried over sodium sulphate and evaporated under reduced pressure.

N-benzoyl-6-aminohexanoic acid, used as such in the subsequent reactions, was thus obtained. Working analogously, the following compounds were prepared: N-benzoyl-3-aminopropanoic acid; N-benzoyl glycine; N-benzoyl-8-aminooctanoic acid; N-phenylacetyl-6-aminohexanoic acid; N-phenylacetyl glycine; N-benzoyl-N-isopropyl-4-aminobutanoic acid; N-benzoyl-N-isopropyl-6-aminohexanócio acid.

EXAMPLE 2 Preparation of ethyl N- [6- (benzoylamino) -hexanoyl] glycine ester A solution of dicyclohexylcarbodiimide (112 mmol) in anhydrous tetrahydrofuran (44 ml) was gradually added to a suspension of N-benzoyl-6-aminohexanoic acid (93.5 mmol) ) prepared as described in Example 1, glycine ethyl ester hydrochloride (112 mmol), triethylamine (112 mmol) and anhydrous 1-hydroxybenzotriazole (112 mmol) in tetrahydrofuran (330 ml), and kept under stirring at 0 °. C. The reaction mixture was brought to room temperature and kept under stirring for 16 hours. At the end, a precipitate formed, which was removed by filtration, and the filtrate obtained in this way was evaporated under reduced pressure. The residue was collected with ethyl acetate (300 ml) and subsequently washed with a 5% hydrochloric acid solution (2 x 100 ml), with a saturated solution of sodium chloride (100 ml), with a 5% sodium bicarbonate solution (2 x 100 ml) and, finally, with a saturated solution of sodium chloride (100 ml). The organic phase was dried over sodium sulfate, and evaporated to dryness under reduced pressure, thereby obtaining the N- [6- (benzoylamino) hexanoyl) glycine ethyl ester, which was used as such in the subsequent reactions. Working analogously, the following compounds were prepared: N- [(benzoylamino) acetyl] glycine ethyl ester; N- [6- (phenylacetylamino) hexanoyl] -glycine ethyl ester; N- [(phenylacetylamino) acetyl] glycine ethyl ester; 6- [6- (Benzoylamino) hexanoylamino] hexanoate ethyl; Methyl N- [5- (benzoylamino) pentanoyl] glycine ester; 6- [5- (Benzoylamino) pentanoylamino] hexanoate methyl; Methyl N- [7- (benzoylamino) heptanoyl] glycine ester; 5- [6- (Benzoylamino) hexanoylamino] pentanoate methyl; 6- [(Benzoylamino) acetylamino] hexanoate methyl; 3- [6- (Benzoylamino) hexanoylamino] propionate methyl, 6- [N-isopropyl (phenylacetylamino) acetylamino] hexanoate ethyl; 6- [4- (Benzoylamino) butanoylamino] hexanoate methyl; 4- [N-isopropyl-4- (N '-isopropyl-4- (N' -isopropyl-N '-benzoylamino) butanoylamino] butanoate methyl.

EXAMPLE 3 Preparation of the ethyl ester of N- (6-aminohexanoyl) -glycine a) 6-Aminohexanoic acid (100 g, 0.762 mmol) and, gradually, a solution of di-tert-butyl dicarbonate (168 g, 0.762 mol) were added. in methanol (140 ml) to a solution of sodium hydroxide (33.54 g; 0.831 mol) in water (840 ml) and methanol (400 ml).

The reaction mixture was kept under stirring at room temperature for 4 hours. After that, solid di-tert-butyl bicarbonate (17.5 g) was added again., 0.08 moles), keeping stirring for another 16 hours. The reaction mixture was then washed with hexane (2 x 400 ml), acidified to pH 1.5 with a solution of potassium disulfate, and extracted with ethyl acetate (3 x 450 ml). The collected organic phases were dried over sodium sulfate, and evaporated to dryness, thus affording 6- (tert-butoxycarbonyl-amino) hexanoic acid as an oil (163 g). b) working analogously to what was described in Example 2, 6- (tert-butoxycarbonylamino) hexanoic acid (163 g) was directly condensed with the glycine ethyl ester hydrochloride (117 g); 0.845 moles), thus obtaining the ethyl ester of N- [6- (tert-butoxycarbonylamino) hexanoyl] -glycine (285 g) as a crude product, which was used as such in the subsequent reaction. p.f. 76-77 ° C (isopropyl ether). c) A solution of 6 N hydrochloric acid (150 ml) in ethyl acetate (150 ml) was added to a solution of N- [6- (tert-butoxycarbonylamino) hexanoyl] glycine ethyl ester (285 g) in ethyl acetate. ethyl (500 ml), maintained under stirring at room temperature. After 24 hours, a precipitate formed, which was filtered, washed with ethyl acetate and ethyl ether, and dried in an oven (50 ° C) under vacuum. The N- (6-aminohexanoyl) glycine ethyl ester (93 g) was thus obtained as a crude product, which was used as such in the subsequent reactions.

TLC (methylene chloride methanol: ammonia = 10: 2: 1) Rf = 0.2.

EXAMPLE 4 Preparation of the ethyl ester of N- [6-. (4-fluorobenzoyl) amino] hexanoyl] glycine A solution of 4-fluorobenzoyl chloride (47.4 mmol) in methylene chloride (30 ml) was gradually added to a suspension of N- (6-amino-hexanoyl) glycine ethyl ester (39.5 mmol), prepared as described in Example 3, and triethylamine (87 mmol) in methylene chloride (150 ml), kept under stirring at 0 ° C.

The mixture prepared in this manner, to which triethylamine (2 ml) was subsequently added, was brought to room temperature and kept under stirring. After one hour under these conditions, the reaction mixture was washed with a 5% hydrochloric acid solution (2 x 100 ml) and with a saturated solution of sodium chloride (3 x 100 ml). The separated organic phase was dried over sodium sulfate, and evaporated to dryness under vacuum. The N- [6 - [(4-fluorobenzoyl) amino] hexanoyl] glycine ethyl ester was thus obtained as a crude product, used as such in the subsequent reactions. p.f. 121-122 ° C (ethyl acetate). TLC (ethyl acetate) Rf = 0.3 Working analogously, the following compounds were prepared: N- [6- (2-furoylamino) exanoyl] glycine ethyl ester p.f. 104-106 ° C (acetonitrile / isopropyl ether) TLC (methylene chloride: methanol = 95.5) Rf = 0.3.

EXAMPLE 5 Preparation of N- [6- [(4-methoxy-benzoyl) amino] hexanoyl] glycine ethyl ester Working analogously to that described in Example 2, and using 4-methoxybenzoic acid (33 mmoles) and N- (6-aminohexanoyl) glycine ethyl ester (39.5 mmoles), prepared as described in Example 3, the ester was obtained N- [6- [(4-methoxy-benzoyl) amino] hexanoyl] glycine ethyl ester as a crude product, used as such in the subsequent reactions. p.f. 106-107 ° C-TLC (methylene chloride: methanol = 90:10) Rf = 0.46. Working analogously, the following compounds were prepared: N- [6- [(3,4-methylenedioxybenzoyl) amino] -hexanoyl] glycine ethyl ester CCF (methylene chloride: methanol = 90:10) Rf = 0.39; N- [6- [(4-Methylsulfonylbenzoyl) amino] -hexanoyl] glycine ethyl ester m.p. 124-126 ° C TLC (methylene chloride: methanol = 96: 4) Rf = 0.31; N- [6- [(3-trifluoromethylbenzoyl) amino] -hexanoyl] glycine ethyl ester m.p. 102-104 ° C TLC (methylene chloride: methanol = 95: 5) Rf = 0.38.

EXAMPLE 6 Preparation of 2- [7- (phenylmethylamino) hexylamino] ethanol 6N sulfuric acid in ethyl ether (40.9 ml, 700 mmol), prepared by mixing 96% sulfuric acid (33 ml) and ethyl ether (100 ml), was gradually added, to a suspension of N- [6- (benzoylamino) hexanoyl] glycine ethyl ester (46.8 mmol), prepared as described in Example 2, and sodium borohydride (700 μl) in anhydrous tetrahydrofuran (200 ml), and it was kept under agitation at a temperature comprised between 15 ° C and 20 ° C. The reaction mixture was brought to the boiling temperature for 24 hours, and subsequently, it was cooled to 0 ° C. Methanol (150 ml) was then added with stirring. The solvent was evaporated under reduced pressure, and the residue was taken up with a solution of sodium hydroxide -6 N (2 ml), maintaining the resulting mixture at the boiling temperature for 24 hours. The reaction mixture, cooled to room temperature, was then extracted with tetrahydrofuran (2 x 100 ml) and the organic phase was evaporated to dryness, taken up in ethyl acetate, and dried over sodium sulfate. Acidification with an ethereal solution of hydrochloric acid resulted in a precipitate consisting of 2- [6- (phenylmethylamino) hexylamino] ethanol as the hydrochloride salt. The product obtained in this way was used as such in the subsequent reactions. Working analogously, the following compounds were prepared: 2- [2- (phenylmethylamino) ethylamino] ethanol; 2- [6- (2-phenylethylamino) hexylamino] ethanol; 6- [6- (phenylmethylamino) hexylamino] hexanol; 2- [5- (phenylmethylamino) pentylamino) ethanol; 2- [8- (phenylmethylamino) octylamino] ethanol; 5- [6- (phenylmethylamino) hexylamino] pentanol; 6- [3- (phenylmethylamino) propylamino] hexanol; 3- • [6- (phenylmethylamino) hexylamino] propanol; 3- [4- (phenylmethylamino) butylamino] propanol; 6- [2- (phenylmethylamino) ethylamino] hexanol; 6- [N-isopropyl-4- (phenylmethylamino) butylamino] hexanol; 2- [6- [6- [(4-fluorophenyl) methylamino] hexylamino] ethanol; 2- [6- [(4-methoxyphenyl) methylamino] hexylamino] ethanol; 2- [6- [(3,4-methylenedioxyphenyl) methylamino] hexylamino] ethanol; 2- [6- [(3-trifluoromethylphenyl) methylamino] hexylamino] ethanol; 2- [6- [(4-methylsulfonylphenyl) methylamino] hexyl-amino] ethanol; 4- [N-isopropyl-4- (N '-isopropyl-N, -phenylmethylamino) -butylamino] butanol.

EXAMPLE 7 Preparation of 6- [N-acetyl-6- (N -acetyl-N 'phenylmethylamino) hexylamino] hexyl acetate Triethylamine (1.95 ml, 14 mmol) and a solution of acetyl chloride (0.62 ml, 8.69 mmol) in methylene chloride (5 ml) were added gradually to a suspension of 6- [6- (phenylmethylamino) hexylamino] -hexanol ( 1 g, 2.6 mmol), prepared as described in Example 6, in methylene chloride (15 ml), kept under stirring at 0 ° C.

After one hour under stirring at 0 ° C, the reaction mixture was brought to room temperature, and kept under stirring for another 16 hours. The reaction mixture was then washed with a solution of 10% hydrochloric acid (10 ml) and with a saturated solution of sodium chloride. After separation of the phases, the organic phase was dried over sodium sulfate, and evaporated to dryness under vacuum, thus obtaining 6- [N-acetyl-6- (N '-acetyl-N' -phenylmethylamino) acetate. ) hexylamino] -hexyl (1.18 g) as an oil, used as such in subsequent reactions. Working analogously, the following compound was prepared: 2- [N-Acetyl-6- [N '-acetyl-N' (2-phenylethyl) -amino] hexylamino] ethyl acetate EXAMPLE 8 Preparation of 6- [N-ethyl-6- (N '-ethyl-N' -phenylmethylamino) hexylamino] hexanol Working analogously to that described in Example 6, and using 6- [N-acetyl-6- (N '-acetyl-N' -phenylmethylamino) hexylamino) hexyl acetate, prepared as described in Example 7, was prepared 6- [N-ethyl- 6- (N '-ethyl-N' -phenylmethylamino) hexylamino] hexanol. Working analogously, the following compound was prepared: 2- [N-ethyl-6- [N'-ethyl-N '- (2-phenylethyl) amino] hexyl-amino] ethanol EXAMPLE 9 Preparation of 2- [N-benzyloxycarbonyl-6- (N '-benzyloxycarbonyl-N'-phenylmethylamino) hexylamino] ethanol A solution of 1 N sodium hydroxide (44.5 ml) and a 50% toluene solution of chloroformate Benzyl (44.5 mmoles) in ethyl acetate (33 ml) were added gradually and contemporaneously to a solution of 2- [6- (phenylmethylamino) hexylamino] ethanol dihydrochloride (18.5 mmoles), prepared as described in Example 6, in a solution of 1 N sodium hydroxide (37.1 ml) and ethyl acetate (40 ml), kept under stirring at a temperature of 0 ° C. At the end of the additions, the reaction mixture was brought to room temperature, and kept under stirring for 24 hours. After separation of the phases, the aqueous phase was washed with ethyl acetate (2 x 50 ml). The collected organic phases were washed with a saturated solution of sodium chloride (50 ml), dried over sodium sulfate and evaporated to dryness under vacuum. There was thus obtained 2- [N-benzyloxycarbonyl-6- (N '-benzyloxycarbonyl-N' -phenylmethylamino) hexylamino] ethanol, as an oil, used as such in the subsequent reactions. TLC (ethyl acetate: hexane = 50:50) Rf-0.20 Working analogously, the following compounds were prepared: 2- [N-benzyloxycarbonyl-2- (N '-benzyloxycarbonyl-N' -phenylmethylamino) ethylamino] ethanol TLC (ethyl acetate: hexane = 60:40) Rf = 0.25; 6- [N-Benzyloxycarbonyl-6- (N '-benzyloxycarbonyl-N' -phenylmethylamino) hexylamino] hexanol TLC (ethyl acetate.-hexane = 50:50) Rf = 0. twenty-one; 6- [N-B-venyloxycarbonyl-5- (N '-benzyloxycarbonyl-N' -phenylmethylamino) pentylamino] hexanol; 2- [N-Benzyloxycarbonyl-5- (N '-benzyloxycarbonyl-N' -phenylmethylamino) pentylamino] ethanol; 2- [N-Benzyloxycarbonyl-8- (N '-benzyloxycarbonyl-N' -phenylmethylamino) octylamino] ethanol; 5- [N-Benzyloxycarbonyl-6- (N '-benzyloxycarbonyl-N' -phenylmethylamino) hexylamino] pentane1; 6- [N-Benzyloxycarbonyl-3- (N '-benzyloxycarbonyl-N' -phenylmethylamino) propylamino] hexanol; 3- [N-Benzyloxycarbonyl-6- (N '-benzyloxycarbonyl-N' -phenylmethylamino) hexylamino] propanol; 3- [N-Benzyloxycarbonyl-4- (N '-benzyloxycarbonyl-N' -phenylmethylamino) butylamino] propanol; 6- [N-isopropyl-2- [N '-benzyloxycarbonyl-N' - (2-phenylethyl) amino] ethylamino] hexanol. TLC (methylene chloride: methanol: ammonia = 95: 5: 0.5) Rf = 0.33; 6- [N-Benzyloxycarbonyl-4- (N '-isopropyl-N' -phenylmethylamino) butylamino] hexanol TLC (methylene chloride: methanol: ammonia = 95: 5: 0.5) Rf = 0.42; 2- [N-Benzyloxycarboni-1-6- [N '-benzyloxycarbonyl-N' - [(4-fluorophenyl) ethyl] amino] hexylamino] ethanol TLC (ethyl acetate: hexane = 60:40) Rf = 0.35; 2- [N-Benzyloxycarbonyl-6- [N '-benzyloxycarbonyl-N' - [(4-methoxyphenyl) methyl] amino] hexylamino] ethanol TLC (ethyl acetate: hexane = 50:50) Rf = 0.2; 2- [N-benzyloxycarboni-1-6- [N'be-N '- [(3,4-methylene-dioxyphenyl) methyl] amino] hexylamino] ethanol TLC (ethyl acetate: hexane = 60:40) Rf = 0.26; 2- [N-Benzyloxycarbonyl-6- [N '-benzyloxycarbonyl-N' - [(3-trifluoromethylphenyl) methyl] amino] hexylamino] ethanol TLC (ethyl acetate: hexane = 50:50) Rf = 0.25; 2- [N-Benzyloxycarbonyl-6- [N '-benzyloxycarbonyl-N' - [4-methylsulphenylphenyl] methyl] amino) hexyalmino] ethanol TLC (ethyl acetate: hexane = 90:10) Rf = 0.36.

EXAMPLE 10 Preparation of 2- [N-benzyloxycarbonyl-6- (N '-benzyloxycarbonyl-N'-phenylmethylamino) -hexylamino] ethyl methanesulfonate A solution of methanesulfonyl chloride (3.16 mmol) in methylene chloride (5 ml) was added gradually to a solution of 2- [N-benzyloxycarbonyl-6- (N '-benzyloxycarbonyl-N' -phenylmethylamino) hexylamino] -ethanol- "(2.6 mmoles), prepared as described in Example 9, in methylene chloride (15 ml) containing triethylamine (0.44 ml, 3.16 mmol) under stirring and at a temperature of 0 ° C. The reaction mixture was brought to room temperature, maintained under stirring for 5 hours, and it was added to a 5% hydrochloric acid solution (20 ml.) After separation of the phases, the organic phase was washed with 5% hydrochloric acid (10 ml) and with a solution saturated sodium chloride (3 x 10 ml) The organic phase was then dried over sodium sulfite, and evaporated to dryness, thus affording 2- [N-benzyloxycarbonyl-6- (N '-benzyloxycarbonyl-N' methanesulfonate. phenyl-methylamino) hexylamino] ethyl, used as such in the reaction of the following example.

EXAMPLE 11 (E) -9- [O- [2- [N-benzyloxycarbonyl-6- (N '-benzyloxycarbonyl-N' -phenylmethylamino) hexylamino] ethyl] oxime] of erythromycin A respectively (E) -9-O- were added erythromycin oxime A (624 mg, 0.84 mmol), ether 18-crown-6 (220 mg, 0.84 mmol) and a solution of 2- [N-benzyloxycarbonyl-6- (N '-benzyloxycarbonyl-N' -phenyl-methylamino) hexylamino] ethyl-methanesulfonate (0.84 mmol), prepared as described in Example 10, in anhydrous tetrahydrofuran (5 ml) to a suspension of potassium tert-butylate (103 mg, 0.92 mmol) in anhydrous tetrahydrofuran (5 ml), maintained at room temperature under stirring and nitrogen atmosphere. The reaction mixture was kept under stirring at room temperature for 20 hours and, subsequently, was evaporated under reduced pressure. The residue was taken up in ethyl acetate (10 ml) and the mixture obtained in this way was washed with a saturated solution of sodium chloride (10 ml). The aqueous phase was extracted with ethyl acetate (2 x 10 ml) and the collected organic phases were dried over sodium sulfate and evaporated to dryness.

There was thus obtained (E) -9- [0- [2- [N-Benzyloxycarbonyl-6- (N '-benzyloxycarbonyl-N' -phenylmethylamino) hexyl-ammo] ethyl] oxime] of erythromycin A, and was used as such in the subsequent reactions: TLC (methylene chloride: methanol: ammonia = 90: 9: 1) Rf = 0.58 Mass spectrometry (CI) (M + H) + = 1250; NMR IE (200 MHz, CDC13): d (ppm): 7.38-7.10 (m, 15 H, aromatics); 5.18-5.10 (m, 4H, 2 CH2Ph); 3.30 (s 3H, OCH3); 2.26 (s, 6 H, 2 NCH3); 0.81 (t, 3H, CH3CH2). Working analogously, the following compounds were prepared: (E) -9- [O- [2- [N-benzyloxycarbonyl-2- (N '-benzyloxycarbonyl-N' -phenylmethylamino) ethylamino] ethyl] oxime] erythromycin A CCF (methylene chloride: methanol: ammonia = 90: 10: 1) Rf-0.5; X H NMR (200 MHz, CDC13): d (ppm): 7.11-6.97 (m, -15 H, aromatics); 5.18-4.97 (m, 4H, 2 CH2Ph); 3.30 (s, 3H, OCH3); 2.26 (s, 6H, 2 NCH3); 0.81 (t, 3H, CH 3 CH 2); Working analogously, the following compounds were prepared: (E) -9- [O- [6- [N-benzyloxycarbonyl-1- (3- N '-benzyloxycarbonyl-N' -phenylmethylamino) hexylamino] hexyl] oxime] erythromycin A CCF ( methylene chloride: methanol: ammonia: 90: 10: 1) Ff = 0.5; TH NMR (200 MHz, CDC13): d (ppm): 7.11-6.97 (m, 15H, aromatics); 5.18-4.97 (m, 4H, 2 CH 3 CH 2); (E) -9- [O- [6- [N-benzyloxycarbonyl-1- (2- (N '-benzyloxycarbonyl-N' -phenylmethylamino) hexylamino] -3-yl] -erythromycin oxime A CCF (methylene chloride: methanol: ammonia: 90: 10: 1) Rf = 0.6; NMR from H (200 MHz, CDC13): d (ppm): 7.27-6.96 (m, 15H, aromatics); 5.05-4.92 (m, 4H, 2 CHsP'h); 3.17 (s, 3H, OCH3); 2.13 (s, 6H, 2 HCH3); 0.70 (t, 3H, CH 3 CH 2); (E) -9- [O- [6- [N-benzyloxycarboni1-3- (N '-benzyloxycarbonyl-N' -phenylmethylamino) propylamino] hexyl] oxime] erythromycin A CCF (methylene chloride: methanol: ammonia: 90 : 10: 1) Rf = 0.65; Mass spectrometry (C.I.) (M + H) + = 1194; NMR from aH (200 MHz, CDC13): d (ppm): 7.39-7.01 (m, 15H, aromatics); 5.17-5.02 (m, 4H, 2 CH2Ph); 3.30 (s, 3H, OCH3); 2.27 (s, 6H, 2 NCH3); 0.82 (t, 3H, CH 3 CH 2); (E) -9- [0- [6- (N-Benzyloxycarbonyl-5- (N '-benzyloxycarbonyl-N' -phenylmethylamino) pentylamino] hexyl] oxime] erythromycin A; (E) -9- [0- [2- [N-benzyloxycarbonyl-8- (N '-benzyloxycarbonyl-N' -phenylmethylamino) octylamino] ethyl] oxime] erythromycin A; (E) -9- [0- [2- [N-benzyloxycarbonyl- 5- (N '-benzyloxycarbonyl-N' -phenylmethylamino) pentylamino] ethyl] oxime] of erythromycin A; (E) -9- [0- [5- [N-benzyloxycarbonyl-6- (N '-benzyloxycarbonyl-N' phenyl] amino] erythromycin A; (E) -9- [0- [3- [N-benzyloxycarbonyl-6- (N '-benzyloxycarbonyl-N' -phenylmethylamino) hexylamino] propyl] oxime] erythromycin A; (E) -9- [0- [3- [N-benzyloxycarbonyl-4- (N '-benzyloxycarbonyl-N' -phenylmethylamino) butylamino] propyl-oxime] erythromycin A; (E) -9- [0- [6- [N-benzyloxycarbonyl-2- [N '-benzyloxycarbonyl-N' - (2-phenylmethyl) amino] ethylamino] hexyl] oxime] erythromycin A. mp 74-76 ° C Mass spectrometry (CI) (M + H) + = 1172 NMR of -'xH (200 MHz, CDC13): d (ppm): 7.38-7.03 (m, 10 H, aromatics); 5.13-5.03 (m, 2H, CH? Ph); 3.29 (s, 3H, OCH3); 2.25 (s, 6H, 2 NCH3); (E) -9- [O- [6- [N-ethyl-6- (N '-ethyl-N' -phenylmethyl-amino) -hexylamino] hexyl] oxime] of erythromycin A (Compound 1) m.p. 80-82 ° C (acetonitrile) Mass spectrometry (C.I.) (M + H) + = 1094 13 C NMR (50 MHz, CDC13): d (ppm): 175.20; 171.35; 140. 06; 128.86; 128.07 '; 126.62; 102.96; 96.27; 53.54; (E) -9- [0- [2- [N-ethyl-6- [N'-ethyl-N '- (2-phenylethyl) amino] -hexylamino] ethyl] oxime] of erythromycin A (Compound 2) TLC (chloroform: hexane: triethylamine = 45:45:10) Rf = 0.2. Mass spectrometry (C.I.) (M + H) + = 1052 1 H NMR (200 MHz, CDC13): d (ppm): 7.26-7.04 (m, 5H, aromatics); 3.22 (s, 3H, 0CH3); 2.20 (s, 6H, 2 NCH3); 0.79 (t, 3H, CHaCHz); (E) -9- [O- [6- [N-Benzyloxycarboni-1- (N '-isopropyl-N' -phenylmethylamino) butylamino] hexyl] oxime] erythromycin A m.p. 75-77 ° C H-NMR (200 MHz, CDC13): d (ppm): 7.47-7.12 (m, 10H, aromatics); 5.18-4.97 (m, 4H, 2 CHzPh); 3.30 (s, 3H, OCH3); 2.25 (s, 6H, 2 NCH3); 0.82 (t, 3H, CH 3 CH 2); (E) -9- [O- [2- [N-Benzyloxycarbonyl-6- [N '-benzyloxycarbonyl-N' - [(4-fluorophenyl) methyl] amino] hexylamino] ethyl] oxime] erythromycin A CCF (chloride) methylene: methanol: ammonia = 90: 10: 1) Rf = 0.62 NMR of: H (200 MHz, CDC13): d (ppm): 7.38-6.88 (m, 15H, aromatics); 5.17-5.03 (m, 2H, CH? Ph); 3.29 (s, 3H, OCH3); 2.26 (S, 6h, 2 NCH3); 0.81 (t, 3H, CH 3 CH 2); (E) -9- [O- [2- [N-Benzyloxycarbonyl-6- [N '-benzyloxycarbonyl-6- [N' -benzyloxycarbonyl-N '- [(4-methoxyphenyl) -methyl] amino] hexylamino ] ethyl] oxime] erythromycin A CCF (methylene chloride: methanol: = 45:45:10) Rf = 0.3 NMR of XH (200 MHz, CDC13): d (ppm): 7.40-7.23 (m, 10H, 2 PhCH20); 7.20-6.75 (m, 4H, PhOCH3), 5.52-5.17 (m, 4H, 2, CHsPh); 3.77 (s, 3H, PI1OCH3); 3.29 (s, 3H, OCH3); 2.25 (s, 6H, 2 NCH3); 0.82 (t, 3H, CHSCHÍ); (E) -9- [O- [2- [N-Benzyloxycarbonyl-6- [N '-benzyloxycarbonyl-N' - [(3,4-methylenedioxyphenyl) methyl] amino] -hexylamino] ethyl] oxime] of erythromycin A TLC (methylene chloride: methanol: ammonia = 95: 5: 0.5) Rf = 0.31 NMR of XH (200 MHz, CDC13): d (ppm): 7.38-7.22 (m, 10H, 2 PhCH20); 6.78-6.55 (m, 3H, aromatics); 5.90 (s, 2H, OCH20); 5.15-5.02 (m, 4H, 2 CH? Ph); 3.29 (s, 3H, OCH3); 2.26 (s, 6H, 2 NCH3); 0.82 (t, 3H, CH 3 CH 2); (E) -9- [O- [2-N-benzyloxycarboni-1-6- [N '-benzyloxycarbonyl-N' - [(3-trifluoromethylphenyl) methyl] -amino] hexylamino] ethyl] oxime] erythromycin A CCF (chloride methylene: methanol: ammonia = 90: 10: 1) Rf = 0.65 NMR of: H (200 MHz, CDC13): d (ppm): 7.54-7.15 (m, 14H, aromatics); 5.20-5.03 (m, 4H, 2 Cí ^ Ph); 3.30 (s, 3H, OCH3); 2.26 (s, 6H, 2 NCH3); 0.82) t, 3H, CH 3 CH 2); (E) -9- [O- [2- [N-Benzyloxycarbonyl-6- [N '-benzyloxycarbonyl-N' - [(4-methylsulfoniylphenyl) methyl] amino] -ethyl] oxime] erythromycin A CCF ( methylene chloride methanol: ammonia = 95: 5: 0.5) Rf = 0.5 NMR: H (200 MHz, CDC13): d (ppm): 7.90-7.79 (m, 4H, PhS02CH3); 7.48-7.15 (m, 10H, PhCH20); 5.19-5.03 (m, 4H, 2 CHsPh); 3.30 (s, 3H, OCH3); 3.02 (s, 3H, CH3SO2); 2.27 (s, 6H, 2 NCH3); 0.82 (t, 3H, CH 3 CH 2); (E) -9- [O- [4- [N-isopropyl-4- (N '-isopropyl-N' -phenylmethylamino) butylamino] butyl] oxime] of erythromycin A (Compound 3) m.p. 83-85 ° C (hexane) Mass spectrometry (C.I.) (M + H) + = 1066 XH NMR (200 MHz, CDC13): d (ppm): 7.37-7.10 (m, 5H, aromatics); 3 . 50 (s, 2H, CH? Ph)); 3 . 30 (s, 3H, OCH3); 2 . 2 6 (s, 6H, 2 NCH 3); 0 82 (t, 3H, CH 3 CH 2).

EXAMPLE 12 Preparation of (E) -9- [0- [2- [- (phenylmethylamino) -hexylamino] ethyl] oxime] of erythromycin A (Compound 4) % palladium on charcoal (750 mg) was added to a solution of (E) -9- [0- [2- [N-benzyloxycarbonyl-6- (N '-benzyloxycarbonyl-N' -phenylmethylamino) hexylamino] -ethyl ] oxime] of erythromycin A (5.9 mmol), prepared as described in Example 11, in ethanol (150 ml). The mixture prepared in this way was placed in a Parr hydrogenator charged with hydrogen (1019 kg / cm 2, 1 bar) and kept under stirring at room temperature. After 7 hours, the catalyst was removed by filtration, and the alcohol solution was evaporated to dryness. The (E) -9- [0- [2- [6- (phenylmethylamino) hexylamino] ethyl] oxime] erythromycin A was obtained, purified by chromatography on silica gel (eluent: methylene chloride: methanol: ammonia = 90: 10: 1). Mass spectrometry (C.I.) (M + H) + = 982 13 C NMR (50 MHz, CDC13): d (ppm): 140.48; 128.39; 128.11; 126.88.

Working analogously, the following compounds were prepared: (E) -9- [0- [2- [2- (phenylmethylamino) ethylamino] ethyl] oxime] erythromycin A (Compound 5) 13 C NMR (50 MHz, CDC13): d (ppm): 176.51; 172.36, 140.96; 129.08; 128.95; 127.67; 103.84; 96.86; 53.35; (E) -9- [0- [6- [6- (phenylmethylamino) hexylamino] hexyl] oxime] of erythromycin A (Compound 6) Mass spectrometry (CI) (M + H) + = 1038 13 C NMR (50 MHz, CDC13): d (ppm): 175.24; 171.31; 140. 33; 128.37; 128.13; 126.89; 102.92; 96.27, 54.01; (E) -9- [0- [6- [3- (phenylmethylamino) propylamino] hexyl] -oxime] erythromycin A (Compound 7). Mass spectrometry (C.I.) (M + H) + = 995 C NMR (50 MHz, CDC13): d (ppm): 175.15; 171.37; 140. 41, 128.38, 128.09, 126.89, 102.92; 96.27, 54.04; (E) -9- [0- [6- [5- (phenylmethylamino) pentylamino] hexyl] -oxime] erythromycin A (Compound 8) XH NMR (200 MHz, CDC13): d (ppm): 7.35-7.15 (m, 5H, aromatics); 3 . 75 (s, 2H, CH? Ph), 2. 25 (s, 6H, 2 NCH3): 0. 81 (t, 3H, CH 3 CH 2); (E) -9- [0- [2- [8- (phenylmethylamino) octylamino] ethyl] oxime] erythromycin A (Compound 9) XH NMR (200 MHz, CDC13): d (ppm): 7.40-.7.15 (m, 5H, aromatics); 3.75 (s, 2H CHjPh); 3.29 (s, 3H, OCH3); 2.25 (s, 6H, 2 NCH3); 0.82 (t, 3H, CH 3 CH 2); (E) -9- [O- [2- [5- (phenylmethylamino) pentylamino] ethyl] oxime] erythromycin A (Compound 10) 13 C NMR (50 MHz, CDC13): d (ppm): 174.96; 172.00, 140.31; 128.39, 128.14; 126.93, 103.16; 96.20, 53.98, (E) -9- [0- [5- [6- (phenylmethylamino) hexylamino] pentyl] -oxime] erythromycin A (Compound 11); 13 C NMR (50 MHz, CDC13): d (ppm): 175.24; 171.24; 140.41; 128.38; 128.13; 126.88; 102.97; 96.28, 54.06; (E) -9- [0- [3- [6- (phenylethylamino) exylamino] propyl] oxime] of erythromycin A (Compound 12); 13 C NMR (50 MHz, CDC13): d (ppm): 175.23; 171.46; 140.45; 128.39; 128.13; 126.88, 102.99; 96.29, 50.06; (E) -9- [0- [3- [4- (phenylmethylamino) butylamino] propyl] -oxime] erythromycin A (Compound 13); 13 C NMR (50 MHz, CDC13): d (ppm): 175.22, 171.45; 140.35; 128.39, 128.13; 126.90; 102.98; 96.26; 53.94; (E) -9- [O- [6- [N-isopropyl-2- (2-phenylethylamino) ethyl] -amino] hexyl] oxime] erythromycin A (Compound 14) m.p. 93-95 ° C Mass spectrometry (C.I.) (M + H) + = 1038 13 C NMR (50 MHz, CDC13): d (ppm): 174.92, 170.96; 139. 71; 128.42; 128.10; 125.79; 102.62; 95.94; 50.93; (E) -9- [O- [6- [N-isopropyl-phenylmethylamino) butylamino] -hexyl] oxime] of erythromycin A (Compound 15) m.p. 78-80 ° C Mass spectrometry (C.I.) (M + H) + = 1052 13 C NMR (50 MHz, CDC13): d (ppm): 175.47; 171.30; 140.95; 128.61; 128.02; 126.70; 116.87; 102.94; 53.94; (E) -9- [Q- [6- [(4-fluorophenyl) methylamino] hexylamino] -ethyl] oxime] of erythromycin A (Compound 16) Mass spectrometry (CI) (M + H) + = 99.5 13C NMR (50 MHz, CDC13): d (ppm): 161.88; 136.06; 129.65, 115.14; (E) -9- [0- [2- [6- [(4-methoxyphenyl) methylamino] -hexylamino] ethyl] oxime] of erythromycin A (Compound 17) Mass spectrometry (CI) (M + H) + = 1011 13 C NMR (50 MHz, CDC13): d (ppm): 158.57; 132.58, 129. 31; 113.76; (E) -9- [O- [2- [6- [(3,4-methylenedioxyphenyl) methylamino] -hexylamino) ethyl] oxime] of erythromycin A (Compound 18) Mass spectrometry (CI) (M + H) + = 1025 13 C NMR (50 MHz, CDC13): d (ppm): 147.65; 146.44; 134.39; 121.18; 108.66; 108.06; (E) -9- [Q- [2- [6- [(3-trifluoromethylphenyl) methylamino] -hexylamino] ethyl] oxime of erythromycin A (Compound 19) Mass spectrometry (CI) (M + H) + = 1050 13 C NMR (50 MHz, CDC13): d (ppm): 141.57; 131.40; 130.63, 128.76; 124.22; 124.72; 123.56; (E) -9- [O- [2- [6- [(4-methylsulfonylphenyl) methylamino] -hexylamino] ethyl] oxime of erythromycin A (Compound 20) Mass spectrometry (CI) (M + H) + = 1059 13 C NMR (50 MHz, CDC13): d (ppm): 147.23; 138.97; 128.79; 127.49.

EXAMPLE 13 Preparation of N-benzyloxycarbonyl-6-aminohexanol Benzyl chloroformate (50% in toluene, 84.8 ml, 0.256 mol) in ethyl acetate (171 ml) and sodium hydroxide solution were added gradually and in a contemporaneous manner. N (256 ml) to a mixture of 6-aminohexanol (25 g, 0.21 mol) in ethyl acetate (250 ml) and water (200 ml) kept under stirring at 0 ° C. The reaction mixture (pH 9) was brought to room temperature, and kept under stirring for 5 hours. After separation of the phases, the aqueous phase was washed with ethyl acetate (200 ml). The collected organic phases were then washed with a saturated solution of sodium chloride (150 ml), dried over sodium sulfate and evaporated to dryness. The residue was taken up in ethyl ether (300 ml) and the formed precipitate was filtered and dried under vacuum at 50 ° C, thereby providing N-benzyloxycarbonyl-6-aminohexanol (44.5 g). p.f. 80-82 ° C.

EXAMPLE 14 Preparation of N-benzyloxycarbonyl-6-amino-hexanal A solution of potassium bromide (1.89 g, 16 mmol) in water (31 ml) was added to a solution of N-benzyloxycarbonyl-6-aminohexanol (40 g, 0.159 mol) , prepared as described in Example 13, in methylene chloride (600 ml) containing the free radical 2, 2, 6, 6-tetramethylpiperidinooxi (TEMPO) (0.248 g, 1.6 mmol). A solution of sodium hypochlocite (215 ml), prepared by mixing a solution of 7% sodium hypochlorite (240 ml) with sodium bicarbonate (4.22 g) and 5% hydrochloric acid (5 ml), was added gradually to reach a pH of 8.7, to the reaction mixture, maintained under stirring at a temperature of 10 ° C. At the end of the addition, after separation of the phases, the organic phase was washed with methylene chloride (2 x 200 ml), dried over sodium sulphate and evaporated to dryness. Thus, N-benzyloxycarbonyl-6-amino-hexanal (39.45 g) was obtained as an oil. TLC (ethyl acetate: hexane = 1: 1) Rf = 0.41.

EXAMPLE 15 Preparation of 2- [6-benzyloxycarbonylamino) hexylamino] ethanol A mixture consisting of N-benzyloxycarbonyl-6-amino-hexanal (35 g; 0.14 moles) and 2-aminoethanol (51.3 g, 0.84 moles) in ethanol (250 ml), in the presence of molecular sieves (3 i), was kept under stirring at room temperature for 2 hours. The reaction mixture was then filtered over celite, and sodium borohydride (6.33 g, 0.168 mol) was added to the resulting solution. After 4 hours under stirring at room temperature, the reaction solvent was evaporated under vacuum, and the residue was taken up with water (500 ml) and ethyl acetate (500 ml). After separation of the phases, the aqueous phase was further extracted with ethyl acetate (200 ml). The collected organic phases were washed with a saturated solution of sodium chloride (250 ml), dried over sodium sulfate and evaporated to dryness, thus obtaining 2- [6- (benzyloxycarbonylamino) exylamino] ethanol (38.36 g) .

TLC (ethyl acetate: methanol: ammonia = 10: 2: 1) Rf = 0.4.

EXAMPLE 16 Preparation of 2- [N-benzyloxycarbonyl-6- (benzyloxycarbonylamino) hexylamino] ethanol Working analogously to that described in Example 9, and using 2- [6- (benzyloxycarbonylamino) -hexylamino] ethanol (38.3 g, 0.13 moles) , prepared as described in Example 15, 2- [N-benzyloxycarbonyl-6- (benzyloxycarbonylamino) hexylamino] ethanol was obtained as an oil. TLC (ethyl acetate: hexane = 65:35) Rf = 0.45.

EXAMPLE 17 Preparation of 2- [N-benzyloxycarbonyl-6- (benzyloxycarbonylamino) hexylamino] ethyl methanesulfonate Working in a similar way to that described in Example 10, and using 2- [N-benzyloxycarbonyl-6- (benzyloxycarbonylamino) hexylamino] ethanol (20 g; 47.8 mmol), prepared as described in Example 16, 2- [N-benzyloxycarbonyl-6- methanesulfonate was obtained. (benzyloxycarbonyl-amino) hexylamino] ethyl (24.35 g) as an oil, used as such in the subsequent reactions.

EXAMPLE 18 Preparation of (E) -9- [O- [2- [N-benzyloxycarbonyl-6- (benzyloxycarbonylamino) hexylamino] ethyl] oxime] of erythromycin A By working analogously to that described in Example 11, and using methanesulfonate of 2- [ N-benzyloxycarbonyl-6- (benzyloxycarbonylamino) hexylamino] ethyl (24.25 g; 47.8 mmol), prepared as described in Example 17, after chromatography on silica gel (eluent: methylene chloride: methanol: ammonia = 95: 5: 0.5), the (E) -9- [0- [2- [N-benzyloxycarbonyl-6- (benzyloxycarbonylamino) hexylamino] ethyl] oxime] of erythromycin A (36.1 g) was obtained. • TLC (methylene chloride: methanol: ammonia = 85: 15: 1.5) Rf = 0.5 NMR of XH (200 MHz, CDC13): d (ppm): 7.39-7.22 (m, 10H, aromatics); 5.14-5.05 (m, 4H, 2 CH¿Ph); 3.29 (s, 3H, OCH3); 2.25 (s, 6H, 2 NCH3), 0.80 (t, 3H, CH3CH2).

EXAMPLE 19 Preparation of (E) -9- [O- [2- (6-amino-hexylamino) ethyl] oxime] of erythromycin A By working analogously to that described in Example 12, and using (E) -9- [0- [2- [N-benzyloxycarbonyl-6- (benzyloxycarbonylamino) hexylamino] ethyl] oxime of erythromycin A, prepared as described in Example 18, after gel chromatography of silica (eluent methylene chloride methanol: ammonia = 85: 15: 1.5), (E) -9- [0- [2- (6-amino-hexyl-amino) ethyl] oxime] was obtained from erythromycin A. TLC (methylene chloride: methanol: ammonia = 85: 15: 1.5) Rf = 0.2. 13 C NMR (50 MHz, CDC13): d (ppm): 175.18; 171.26; 102. 96; 96.28.

EXAMPLE 20 Preparation of (E) -9- [O- [2- [6- [(2-trifluoromethyl-phenyl) methylamino] hexylamino] ethyl] oxime] of erythromycin A (Compound 21) 2-trifluoromethylbenzaldehyde (0.4 g) was added and molecular sieves (4.5 g; 3 i) to a solution of (E) -9- [O- [2- (6-aminohexylamino) ethyl] oxime] of erythromycin A (2 g, 2.24 mmol), prepared as described in Example 19, in ethanol (50 ml), kept under stirring at room temperature. After 2 hours, the molecular sieves were separated by filtration, and 10% palladium on charcoal (0.2 g) was added to the resulting solution. The reaction mixture was placed in a Parr hydrogenator, which was charged with hydrogen (1.019 kg / cm2, 1 bar). After one hour, after the hydrogenation reaction was complete, the catalyst was removed by filtration, and the solvent was evaporated. The residue was purified by chromatography on silica gel (eluent: methylene chloride: methanol: ammonia = 95: 5: 05), thus obtaining (E) -9- [0- [2- [6- [(2- trifluoromethylphenyl) methylamino] -hexylamino] ethyl] oxime] of erythromycin A (2 g).

Mass spectrometry (C.I.) (M + H) + = 1050 13 C NMR (50 MHz, CDC13): d (ppm): 139.14; 131.88, 130. 38; 127.58; 126.81; 125.82. Working analogously, the following compounds were prepared: (E) -9- [0- [2- [6- (3-pyridylmethylamino) hexylamino] -ethyl] oxime] of erythromycin A (Compound 22) Mass spectrometry (CI) (M + H) + = 982 NMR of 13 C (50 MHz, CDC13): d (ppm): 149.66, 148.39, 135.81; 123.40; (E) -9- [O- [2- [6- [(4-trifluoromethylphenyl) methylamino] -hexylamino] ethyl] oxime] erythromycin A (Compound 23) Mass spectrometry (CI) (M + H) + = 1050 13 C NMR (50 MHz, CDC13): d (ppm): 144.73, 128.23; 125.25; 124.26; (E) -9- [O- [2- [6- [(2-hydroxyphenyl) methylamino] hexyl-amino] ethyl] oxime of erythromycin A (Compound 24) Mass spectrometry (CI) (M + H) + = 997 13 C NMR (50 MHz, CDCl 3): d (ppm): 158.37; 128.60; 128.91; 122.54; 118.88; 116.32; (E) -9- [O- [2- [6- [(3-hydroxyphenyl) methylamino] hexylamino] ethyl] oxime of erythromycin A (Compound 25) Mass spectrometry (CI) (M + H) + = 997 NMR of 13C (50 MHz, CDC13): d (ppm): 157.28; 140.46; 129.56; 119.70; 115.55; 114.89; (E) -9- [O- [2- [6- [(4-n-butoxyphenyl) methylamino] hexyl-amino] ethyl] oxime] of erythromycin A (Compound 26) Mass spectrometry (CI) (M + H ) + = 1053 <13> C NMR (50 MHz, CDC13): d (ppm): 158.27; 131.65; 129.40; 114.40; (E) -9- [O- [2- [6- [(3-phenoxyphenyl) methylamino] hexyl-amino] ethyl] oxime] of erythromycin A (Compound 27) Mass spectrometry (CI) (M + H) + = 1073 13 C NMR (50 MHz, CDC13): d (ppm): 157.32; 157.28; 142.69; 129.72; 129.64; 123.16; 122.91; 118.84; 118.52; 117.29; (E) -9- [O- [2- [6- [(4-hydroxyphenyl) methylamino] hexylamino] ethyl] oxime] (Compound 28) Mass spectrometry (CI) (M + H) + = 997 13 C NMR (50 MHz, CDC13): d (ppm): 156.49, 130.00; 128.87; 115.88; (E) -9- [O- [2- [6- [(4-phenoxyphenyl) methylamino] hexylamino] ethyl] oxime erythromycin A (Compound 29) Mass spectrometry (CI) (M + H) + = 1073 NMR of 13 C (50 MHz, CDC13): d (ppm): 157.43; 156.05; 135.43; 129.69; 129.49; 123.07; 118.92; 118.72; 118.67; (E) -9- [O- [2- [6- [(biphenyl-4-yl) methylamino] hexylamino] -ethyl] oxime] of erythromycin A (Compound 30) Mass spectrometry (CI) (M + H) + = 1057 13 C NMR (50 MHz, CDC13): d (ppm): 140.94; 139.86; 139.40; 128.74, 128.58; 127.13; 127.03; (E) -9- [0- [2- [6- [(2-furylmethylamino) hexylamino-ethyl] oxime] of erythromycin A (Compound 31) Mass spectrometry (CI) (M + H) + = 971 NMR 13 C (50 MHz, CDCl 3): d (ppm): 153.92; 141.73; 110.08; 106.81.

EXAMPLE 21 Preparation of (E) -9- [O- [2- [6- [(2, 5-dichloro-2-hydroxy-enyl) methylamino] hexylamino] ethyl] oxime] of erythromycin A (Compound 32) Molecular meshes were added (6 g; 3 i) and 3, 5-dichloro-2-hydroxybenzaldehyde (0.535 g; 2.8 mmoles) to a solution of (E) -9- [O- [2- [6-aminohexyl-amino) ethyl ] oxime] of erythromycin A (2.5 g, 2.8 mmol), prepared as described in Example 19, in anhydrous ethanol (100 ml). The reaction mixture was kept under stirring at room temperature and, after 2 hours, the molecular sieves were separated by filtration and sodium burohydride (0.106 g, 2.89 mmol) was added in portions to the resulting solution. After 3 hours under stirring, the solvent was evaporated under reduced pressure, and the residue was purified by chromatography on silica gel (eluent: methylene chloride: methanol: ammonia = 85: 15: 1.5), thereby obtaining (E) -9- [O- [2- [6- [(3,5-dichloro-2-hydroxyphenyl) methylamino] hexylamino] ethyl] oxime] of erythromycin A ( 2.2 g). Mass spectrometry (C.I.) (M + H) + = 1066 13 C NMR (50 MHz, CDC13): d (ppm): 153.43; 128.43; 126.42; 124.41; 122.91; 121.61. Working analogously, the following compounds were prepared: (E) -9- [O- [2- [6- [(2-nitrophenyl) methylamino] hexylamino] ethyl] oxime erythromycin A (Compound 33) Mass spectrometry (CI) (M + H) + = 1027 NMR de 13C (50 MHz, CDC13): d (ppm): 149.14; 135.79; 133.13; 131.26; 127.87; 124.70; (E) -9- [O- [2- [6- [(3-nitrophenyl) methylamino] hexyl-amino] ethyl] oxime] of erythromycin A (Compound 34) Mass spectrometry (CI) (M + H) + = 1027 13 C NMR (50 MHz, CDC13): d (ppm): 148.37; 142.87; 134.17, 129.22; 122.81; 121.96; (E) -9- [0- [2- [6- [(4-nitrophenyl) methylamino] hexylamino] ethyl] oxime] of erythromycin A (Compound 35) Mass spectrometry (CI) (M + H) + = 1027 13 C NMR (50 MHz, CDC13): d (ppm): 148.41; 147.00; 128.59; 123.60; (E) -9- [O- [2- [6- [(4-hydroxy-3-nitrophenyl) methylamino] -hexylamino] ethyl] oxime] of erythromycin A (Compound 36) Mass spectrometry (CI) (M + H) + = 1043 13 C NMR (50 MHz, CDC13): d (ppm): 157.29; 137.40; 134.05; 128.01; 125.23; 121.70; (E) -9- [O- [2- [6- [(3-hydroxy-4-nitrophenyl) methylamino] -hexylamino] ethyl] oxime] erythromycin A (Compound 37) Mass spectrometry (CI) (M + H) + = 1043 NMR of "13 C (50 MHz, CDC13): d (ppm): 155.50; 151.98, 132.51; 125.13; 119.67; 118.59; EXAMPLE 22 Preparation of (E) -9- [O- [2- [N-methyl-6- (N '-methyl-N' -phenylmethylamino) hexylamino] ethyl] oxime] of erythromycin A (Compound 38) An aqueous solution of formaldehyde at 37% (2 ml, 26. mmoles) and 10% palladium on charcoal (0.82 g) were added, in this order, to a solution of (E) -9- [0- [2- [6- (phenylmethylamino Hexylamino] ethyl] oxime] of erythromycin A (2 g, 2 mmol) prepared as described in Example 12, in a mixture of ethanol: water = 1: 1 (20 ml) kept under stirring at room temperature. The reaction mixture was placed in a Parr hydrogenator charged with hydrogen (1019 kg / cm 2, 1 bar). After 2 hours, the reaction mixture was filtered to remove the catalyst, and the resulting solution was evaporated to dryness. The obtained residue was purified by chromatography on silica gel (eluent: methylene chloride: methanol: ammonia = 90: 10: 1) to provide (E) -9- [O- [2- [N-methyl-6- (N ' -methyl-N '-phenylmethylamino) -hexylamino] ethyl] oxime] of erythromycin A (1.8 g). Mass spectrometry (C.I.) (M + H) + = 1009 13 C NMR (50 MHz, CDC13): d (ppm): 139.20; 129.04; 128.17; 126.86. Working analogously, the following compounds were prepared: (E) -9- [O- [2- [N-Methyl-6- [N '-methyl-N' - (4-trifluoromethyl-phenyldiamlamino] hexylamino] ethyl] oxime] of erythromycin A (Compound 39) Mass spectrometry (C.I.) (M + H) + = 1078 13 C NMR (50 MHz, CDC13): d (ppm): 143.65; 129.12; 129. 03; 125.10; 124.29.

EXAMPLE 23 Pharmacological Activity a) In vitro antibacterial activity The determination of minimum inhibitory concentrations (MIC), with respect to Gram-positive and Gram-negative bacteria was carried out through the micromethod of gradual dilution in broth in double series [National Committee for Clinical Laboratory Standards, 1990; Methods for dilution antimicrobial susceptibility tests for bacteria that gro aerobically; Approved standards M7-A2-NCCLS, Villanova, Pa. 1, using Mueller Hinton broth (MHB) as a culture medium. In the case of demanding bacteria, 5% horse serum (Streptococcus pneumoniae and Streptococcus pyogenes) was added to the medium. Roxithromycin and clarithromycin [The Merck Index, XI Ed., Nos. 8253 and 2340, respectively] were used. The MICs, expressed as (μg / ml), were determined after incubation of the microplates at 37 ° C for 18 hours, evaluating the lower concentration of antibiotic that allows the inhibition of bacterial development, b) Antibacterial activity in vivo The effectiveness Therapy, expressed as the average protective dose (PD50), of the compounds considered of Formula (I) was evaluated by experimental pulmonary infection induced in mouse by Streptococus pyogenes C 203. Albino mice of Charles River (strain CD 1) were used. body weight between 23-35 g, tabulated in groups of 6 per cage and fed normally with standard diet and water ad libitum.

A suspension of S. pyogenes C 203 (corresponding to approximately 108 CFU) in tryptose broth (0.05 ml) was administered intranasally to each mouse anesthetized with a mixture of ethyl ether and chloroform. The compounds that were under examination were administered intraperitoneally as a single dose, in 0.2% Tween suspension, 24 hours before or 1 hour after the infection. The observation of the mortality of the mice lasted up to 10 days from the infection. The calculation of PD50, expressed as (mg / kg), was carried out through the probit analysis. For some representative compounds of Formula (I) the in vitro antibacterial activity against Gram-positive microorganisms (Table 1) and Gram-negative microorganisms (Table 2), and the values of antibacterial activity in vivo (Table 3), are reported as follows .

Table 1 In vitro antibacterial activity, expressed as the MIC minimum inhibitory concentration (μg / ml), of compounds 2, 4-12, 16-19, 21, 23-38 and the reference compounds roxithromycin and clarithromycin, against Gram microorganisms -positives such as Streptococcus pneumoniae BS 3, Streptococcus pneumoniae BS 4, Streptococcus pyogenes A 26, Streptococcus pyogenes C 203, Enterococcus faecalis ATCC 29212 and Staphylococcus aureus PV 14.

MIC (μg / ml)! S. S. S. S. E. S.! Compound! pneumoniae pneumoniae pyogenes pyogenes iaecalis aureus BS 3 BS 4 A 26 C 203 ATCC 29212 PV 14! ! 0.0156 0.0156 0.0156 0.0078 1 0.5! 31! 0.0078 0.0078 0.0078 0.0039 4 0.5 32! 0.0625 0.0312 0.0625 0.0156 2 0.5! 33 I 0.0039 0.0039 0.0039 0.00097 2 0.5! 3. 4 ! 0.0019 0.0039 0.0078 0.0039 1 0.25 i 0.0039 0.0039 0.0078 0.0019! 0.5! 0.25! 36 0.0625 0.0625 0.0625 0.0078! 16 0.5! 37 0.0312 0.0312 0.0312 0.0039! 8 0.5! 38 0.0078 0.0039 0.0156! 0.0078! 8! 0.5! Roxithromycin 0.0312 0.0625 0.0625! 0.0625! 4 ! 1 ! Claritomycin 0.0078 0.0156 0.0078! 0.0078 1! 0.25 The data reported above clearly indicate that the compounds of Formula (I), object of the present invention, are endowed with an antibacterial activity substantially comparable to that of clarithromycin and roxithromycin, with respect to Gram-positive microorganisms.

Table 2 In vitro antibacterial activity, expressed as the MIC minimal inhibitory concentration (μg / ml), of "compounds 2, 4-12, 16-19, 21, 23-38 and of the reference compounds roxithromycin and clarithromycin, against Gram-negative microorganisms such as Escherichia coli ATCC 25922 and Klebsiella pneumoniae ZC 2.

! MIC (μg / ml)! Compound! E. coli. pneumomae! IATCC 25922! ZC 2! 2 ! 16! 64! 4 ! 4) 16! 5 ! 8! 32! 6! 4 ! 16! 7! 4 ! 16! 8! 4 ! 16! 9! 4 ! 16! 10! 4 ! 16! 11! 8 i 16! 12! 8! 32! 16! 2 ! 8! 17! 4 ! 16! 18 2! 16! 19! 2: 8! twenty-one ! 4 ! 16! 23 1! 4 ! 24! 4 ! 8! 25! 8! 16! 26! 1 ! 2 ! 27: 1 2 and 28! 16: 32 29! 1 ! 2 30! 1 ! 2 ! 31! 4 ! 16 25 MIC (μg / ml) i Compound E. coli K. pneumoniae ATCC 25922 ZC 2 32 4 16! 33 4 16! 34 1 8! 35 1 4! 36: 8 32! 37! 4 16! 38! 8 32! Roxithromycin! 28 256 Claritomycin! 64 128 The antibacterial activity of the compounds of Formula (I) against Gram-negative microorganisms such as Escherichia coli and Klebsiella pneumoniae turned out to be markedly higher than that of both reference compounds.

Table 3 In vivo antibacterial activity, expressed as the average protective dose PD5o (mg / kg), 24 hours before and 1 hour after experimental lung infection induced in mice by Streptococcus pyogenes C 203, of compounds 4, 10, 16- 19, 21, 23, 26-27, -29-30, 33-35 and 38 of the reference compounds roxithromycin and clarithromycin.

Compound 'Pulmonary infection C 203) 1 1 hr after infection; 24 hr before infection 4 ! 0.9! 4.78! ! 2.36! 5.8! 16! 3.6! 10.21! 17! 1.17! 8.16! 18! 1.32! 2.23! 19! 1.95! 4.84 1 twenty-one ! 0.82! 5.95! 2. 3 ! 1.46! 3.49! 26! 6.11 i 6.11! 27! 15.6! 15.6! 29! 7.65! 6.1 I 30! 19.3! 19.3! 33! 1.61! 6.11! 3. 4 ! 1.88! 6.8! 35! 3.00! 6.0! 38! 11.8 ¡11.8! Roxithromycin! 0.9! > 25! Claritomycin1 3.25! > fifty ! The compounds of Formula (I) were found to be active in vivo and their activity profile indicates that the compounds exhibit a significantly longer duration of action and a tissue elimination half-life than that of both reference compounds.

It is noted that in relation to this date, the best conodical method for the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Having described the invention as above, property is claimed as contained in the following:

Claims (7)

1. CLAIMS 1. A compound of the formula:
2. R, Ra I i A- (CHa) r »-N- (CHβ)« B-N- < CHa) r-0-N = M (I) wherein A is a phenyl group or a heterocycle with 5 6 6 members, containing one or more heteroatoms selected from nitrogen, oxygen and sulfur, optionally substituted with 1 to 3 groups, the same or different, selected from alkyl or alkoxy groups straight or branched chain of 1 to 4 carbon atoms, alkylenedioxy groups of 1 to 2 carbon atoms, alkylsulfonyl groups of 1 to 4 carbon atoms, phenyl, phenoxy, hydroxy, carboxy, nitro, halogen and trifluoromethyl groups; Ri and R2, the same or different, represent a hydrogen atom or an alkyl group of 1 to 4 carbon atoms straight or branched chain; n is 1 or 2; m is an integer between 1 and 8; r is an integer between 2 and 6; M represents a group of formula: wherein R3 is a hydrogen atom or a methyl group; and the pharmaceutically acceptable salts thereof. 2. A compound according to claim 1, wherein the configuration is E.
3. 3. A compound according to claim 1, wherein A represents a phenyl group or a heterocycle selected between pyridine and furan, optionally substituted with 1 3 selecconados groups from hydroxyl, methoxy, methylenedioxy, n-butoxy, phenoxy, phenyl, methylsulphonyl, nitro, halogen and trifluoromethyl; Ri and R2, equal to each other, represent a hydrogen atom or a methyl group; R3 represents a hydrogen atom.
4. 4. A compound according to claim 1, characterized in that A represents a phenyl group optionally substituted with a group selected from phenoxy, nitro and trifluoromethyl; Rx and R2, equal to each other, represent a hydrogen atom or a methyl group; n is equal to 1, m is equal to 6, r is equal to 2; R3 represents a hydrogen atom.
5. 5. A pharmaceutical composition characterized in that it contains a therapeutically effective amount of one or more compounds of Formula (I) in admixture with a pharmaceutically acceptable carrier.
6. 6. A method for treating infectious diseases in human or veterinary therapy, the method is characterized in that comprises administering a therapeutically effective amount of a compound according to claim 1.
7. 7. A method according to claim 6, characterized in that is for the treatment of malarial diseases.