WO2010015703A2

WO2010015703A2 - Novel 6-o-substituted 15-membered 8a- and 9a-lactams

Info

Publication number: WO2010015703A2
Application number: PCT/EP2009/060273
Authority: WO
Inventors: Stjepan Mutak; Drazen Pavlovic
Original assignee: Glaxosmithkline Istrazivacki Centar Zagreb D.O.O.
Priority date: 2008-08-07
Filing date: 2009-08-07
Publication date: 2010-02-11
Also published as: WO2010015703A3

Abstract

The invention relates to novel anti-bacterial 15-membered 6-O-substituted-8a-aza-8a- homoerythromycin A and 6-O-substituted-9a-aza-9a-homoerythromycin A, their 6-O- substituted-3-O-decladinosyl-3-oxy and 6-O-substituted-3-O-decladinosyl-3-oxo compound of the general formula (I), wherein A represents NH; and B simultaneously represents -C(O)-, or A represents -C(O)- and B simultaneously represents NH; R⁴ represents: a straight or branched chain C₃-C₇ alkyl group containing a moiety selected from piperazin-1,4-yl, 2-methyl-piperazin-1,4-yl, 2-methyl-piperazin-1,4-yl-S(O)₂, NH and N(CH₃), or containing two NH moieties; wherein the second alkyl carbon atom is substituted by a hydroxy substituent, and the terminal carbon atom or heteroatom is substituted by phenyl (itself optionally substituted); or prop-2-enyl (i.e. allyl) optionally substituted by naphthyl or quinolinyl; or CH₂-oxiranyl group; and R⁵ represents (a) dimethylamino [-N(CH₃)₂] or (b) dimethylamino-N-oxide [-N(O)(CH₃)₂] group.

Description

Novel 6-0-substituted 15-membered 8a- and 9a-lactams

Technical Problem

The present invention relates to novel semisynthetic 15-membered 8a- and 9a-lactams derived from the class of 6-O-allylerythromycin A. Especially, it relates to novel 15- membered 6-O-substituted-8a-aza-8a-homoerythromycin A and 6-O-substituted-9a-aza- 9a-homoerythromycin A, to their 6-O-substituted-3-O-decladinosyl-3-oxy and 6-O- substituted-3-O-decladinosyl-3-oxo analogues, to intermediates for their preparation and a process for their preparation, to their pharmaceutically acceptable salts and solvates and to a process for the preparation of pharmaceutical compositions.

Prior Art

Erythromycin is a macrolide antibiotic, whose structure is characterized by a 14- membered lactone ring having C-9 ketone and two sugars, L-cladinose and D- desosamine, which are glycosidically bound at C-3 and C-5 positions to the aglycone part of the molecule (McGuire, J. Antibiot. Chemother. 2 (1952) 281 ). For more than 40 years erythromycin A has been considered to be a safe and active antimicrobial agent for treating respiratory and genital infections caused by gram-positive bacteria of the strains like Legionella, Mycoplasma, Chlamidia and Helicobacter. The observed changes in bioavailability after the application of oral preparations, gastric intolerance in many patients and the loss of activity in an acidic medium are the main disadvantages of the therapeutic use of erythromycin A. The spirocyclization of the aglycone ring is successfully inhibited by the chemical transformation of C-9 ketone or of hydroxyl groups at C-6 and/or C-12 position. Thus oximation of C-9 ketone of erythromycin A with hydroxylamine hydrochloride, Beckmann rearrangement of the obtained 9(E)-oxime and reduction of the thus formed 6,9-imino ether (6-deoxy-9-deoxo-9a-aza-9a- homoerythromycin A 6,9-cyclic imino ether), gave 9-deoxo-9a-aza-9a-homoerythromycin A, the first semisynthetic macrolide having a 15-membered azalactone ring (Kobrehel G. et al., US 4,328,334, May 1982). By reductive methylation of the newly introduced endocyclic 9a-amino group according to Eschweiler-Clark process, 9-deoxo-9a-methyl- 9a-aza-9a-homoerythromycin A (azithromycin), a prototype of a new azalide antibiotic class was synthesized (Kobrehel G. et al., BE 892 357, July 1982). In addition to the broad antimicrobial spectrum including gram-negative bacteria, azithromycin is also characterized by a long biological half-life, a specific transport mechanism to the site of application and a short therapy period. Azithromycin easily penetrates and accumulates inside human fagocyte cells resulting in improved activity on intracellular pathogenic microorganisms from classes Legionella, Chlamidia and Helicobacter. It is known as well that by an O-methylation of C-6 hydroxyl group clarithromycin (6-O- methyl-erythromycin A) is obtained (Morimoto S. et al., J. Antibiotics 37 (1984) 187). In relation to erythromycin A, clarithromycin is much more stable in acidic medium and exhibits improved in vitro activity against gram-positive bacterial strains (Kirst H. A. et al., Antimicrobial Agents and Chemother. 33 (1989) 1419-1422). A novel type of macrolide antibiotics, ketolides, has been discovered during last decade of 20 century research on 14-membered macrolides, whose structure is characterized by a 3-keto group instead of a neutral sugar, L-cladinose (Agouridas C. et al., EP 596802 A1 , May 1994; Le Martret O., FR 2697524 A1 , May 1994). Ketolides exhibit significantly improved in vitro activity against MLS₆ (macrolide, lincosamide and streptogramine B) induced-resistant organisms (Jamjian C, Antimicrob. Agents Chemother., 41 (1997) 454- 459).

It has been described as well that by Beckmann rearrangement of 6-O-methyl- erythromycin A 9(E)- and 9(Z)-oximes, hydrolysis of cladinose of the obtained 8a- and 9a- lactams, protection of 2'-hydroxyl group of desosamine, an acylation reaction, an oxidation of 3-hydroxyl group and deprotection, gave 15-membered 8a- and 9a-ketolides from the class of 6-O-methyl-erythromycin A (Lazarevski G. et al., WO99/51616, October 1999).

The object of this invention is to provide novel 6-O-substituted derivatives of 8a-aza-8a- homoerythromycin A and 9a-aza-9a-homoerythromycin A, their 3-O-decladinosyl-3-oxy as well as 3-O-decladinosyl-3-oxo analogues, their pharmaceutically acceptable salts and solvates, methods and intermediates for their preparation and their use in pharmaceutical preparations.

Detailed Description

In one aspect, the present invention provides novel 15-membered 6-O-substituted-8a- aza-8a-homoerythromycin A and 6-O-substituted-9a-aza-9a-homoerythromycin A, their 6- O-substituted-3-O-decladinosyl-3-oxy and 6-O-substituted-3-O-decladinosyl-3-oxo compound of the general formula (I)

(I)

or a pharmaceutically acceptable salt or solvate thereof, wherein A represents NH; and B simultaneously represents -C(O)- , or A represents -C(O)- and B simultaneously represents NH; R¹ represents OH , L-cladinosyl group of formula (II)

(H) or together with R² represents =0

R² represents hydrogen or together with R¹ represents =0, R³ represents hydrogen or C₁-C₃ alkanoyl group, R⁴ represents:

(a) a straight or branched chain C₃-C₇ alkyl group containing a moiety selected from piperazin-1 ,4-yl, 2-methyl-piperazin-1 ,4-yl, 2-methyl-piperazin-1 ,4-yl-S(O)₂, NH and N(CH₃), or containing two NH moieties; wherein the second alkyl carbon atom is substituted by a hydroxy substituent, and the terminal carbon atom or heteroatom is substituted by phenyl (itself optionally substituted by one substituent selected from methoxy, ethoxy, nitro, fluoro, trifluoromethyl, or C(O)CH₃,), pyridyl, quinolinyl, isoquinolinyl, 3-carboxy-1-cyclopropyl-4-oxo-1 ,4-dihydro-quinolinyl (itself optionally substituted in the 6 or 7 position by fluoro or chloro);

(b) prop-2-enyl (i.e. allyl) optionally substituted with one or more substituents selected from naphthyl or quinolinyl; or

(c) CH₂-oxiranyl group; and

R⁵ represents (a) dimethylamino [-N(CH₃)₂] or (b) dimethylamino-N-oxide [-N(O)(CH₃)₂] group.

In one aspect the present invention provides the compounds of Examples 1 to 68 or a pharmaceutically acceptable salt or solvate thereof.

The compounds of the present invention may be in the form of and/or may be administered as a pharmaceutically acceptable salt. For a review on suitable salts see Berge et al., J. Pharm. Sci. 66 (1977) 1-19.

Typically, a pharmaceutical acceptable salt may be readily prepared by using a desired acid or base as appropriate. The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent. For example, an aqueous solution of an acid such as lactobionic acid may be added to a solution of a compound of formula (I) in a solvent such as acetonitrile, acetone or THF, and the resulting mixture evaporated to dryness, redissolved in water and lyophilised to obtain the acid addition salt as a solid. Alternatively, a compound of formula (I) may be dissolved in a suitable solvent, for example an alcohol such as isopropanol, and the acid may be added in the same solvent or another suitable solvent. The resulting acid addition salt may then be precipitated directly, or by addition of a less polar solvent such as diisopropyl ether or hexane, and isolated by filtration.

The skilled person will appreciate that where the compound of formula (I) contains more than one basic group bis salts (2:1 acid:compound of formula (I)) or tris salts (3:1 acid:compound of formula (I)) may also be formed and are salts according to the present invention.

Suitable addition salts are formed from inorganic or organic acids which form non-toxic salts and examples are lactobionate, mandelate (including (S)-(+)-mandelate, (R)-(-)- mandelate and (R,S)-mandelate), hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, nitrate, phosphate, hydrogen phosphate, acetate, trifluoroacetate, maleate, malate, fumarate, lactate, tartrate, citrate, formate, gluconate, succinate, ethyl succinate (4-ethoxy-4-oxo-butanoate), pyruvate, oxalate, oxaloacetate, saccharate, benzoate, alkyl or aryl sulphonates (eg methanesulphonate, ethanesulphonate, benzenesulphonate or p- toluenesulphonate) and isethionate. In one embodiment, suitable salts include lactobionate, citrate, succinate, (L)-(+)-tartrate, (S)-(+)-mandalete and bis-(S)-(+)- mandalete, for example lactobionate, citrate, succinate and (L)-(+)-tartrate, such as lactobionate and citrate.

Pharmaceutically acceptable base salts include ammonium salts, alkali metal salts such as those of sodium and potassium, alkaline earth metal salts such as those of calcium and magnesium and salts with organic bases, including salts of primary, secondary and tertiary amines, such as isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexyl amine and N-methyl-D-glucamine.

Compounds of the invention may have both a basic and an acidic centre may therefore be in the form of zwitterions.

Those skilled in the art of organic chemistry will appreciate that many organic compounds can form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as "solvates". For example, a complex with water is known as a "hydrate". Solvates of the compounds of the invention are within the scope of the invention. The salts of the compounds of formula (I) may form solvates (e.g. hydrates) and the invention also includes all such solvates.

In one embodiment of the present invention, A represents NH, B represents C=O group, R¹ represents L-cladinosyl group of formula (II) and R² and R³ both represent hydrogen, R⁴ represents a prop-2-enyl, i.e. allyl group optionally substituted with one or more substituents selected from naphthyl or quinolinyl, and R⁵ represents dimethylamino. In one embodiment of the present invention, A represents C=O, B represents NH group, R¹ represents L-cladinosyl group of formula (II) and R² and R³ both represent hydrogen, R⁴ represents a prop-2-enyl, i.e. allyl group optionally substituted with one or more substituents selected from naphthyl or quinolinyl, and R⁵ represents dimethylamino.

In one embodiment of the present invention, A represents NH, B represents C=O group, R¹ represents OH, R² and R³ both represent hydrogen, R⁴ represents a prop-2-enyl, i.e. allyl group optionally substituted with one or more substituents selected from naphthyl or quinolinyl, and R⁵ represents dimethylamino.

In one embodiment of the present invention, A represents C=O, B represents NH group, R¹ represents OH, R² and R³ both represent hydrogen, R⁴ represents a prop-2-enyl, i.e. allyl group optionally substituted with one or more substituents selected from naphthyl or quinolinyl, and R⁵ represents dimethylamino.

In one embodiment of the present invention, A represents NH, B represents C=O group, R¹ represents OH, R² represents hydrogen, R³ represents acetyl group, R⁴ represents a prop-2-enyl, i.e. allyl group optionally substituted with one or more substituents selected from naphthyl or quinolinyl, and R⁵ represents dimethylamino.

In one embodiment of the present invention, A represents C=O, B represents NH group, R¹ represents OH, R² represents hydrogen, R³ represents acetyl group, R⁴ represents a prop-2-enyl, i.e. allyl group optionally substituted with one or more substituents selected from naphthyl or quinolinyl, and R⁵ represents dimethylamino.

In one embodiment of the present invention, A represents NH, B represents C=O group, R₁ and R² together represent =0, R³ represents hydrogen, R⁴ represents a prop-2-enyl, i.e. allyl group optionally substituted with one or more substituents selected from naphthyl or quinolinyl, and R⁵ represents dimethylamino.

In one embodiment of the present invention, A represents C=O, B represents NH group, R¹ and R² together represent =0, R³ represents hydrogen, R⁴ represents a prop-2-enyl, i.e. allyl group optionally substituted with one or more substituents selected from naphthyl or quinolinyl, and R⁵ represents dimethylamino.

In one embodiment of the present invention, A represents C=O, B represents NH group, R¹ and R² together represent =0, R³ represents hydrogen, R⁴ represents CH₂-oxiranyl group, and R⁵ represents dimethylamino-N-oxide group.

In one embodiment of the present invention, A represents C=O, B represents NH group, R¹ and R² together represent =0, R³ represents hydrogen, R⁴ represents CH₂-oxiranyl group, and R⁵ represents dimethylamino group. In one embodiment of the present invention, R⁴ represents 2"-oxy-3"-(2-phenyl- ethylamino)-propyl group, 2"-oxy-3"-(3-phenyl-propylamino)-propyl group, 2"-oxy-3"-(4- phenyl-butylamino)-propyl group, 2"-oxy-3"-[2-(4-methoxy-phenyl)-1 -methyl-ethylamino]- propyl group, 2"-oxy-3"-[methyl-(2-(4-nitro-phenyl)-ethyl)-amino]-propyl group, 2"-oxy-3"- [1-methyl-2-(4-nitro-phenyl)-ethylamino]-propyl group, 2"-oxy-3"-(2-pyridin-3-yl- ethylamino)-propyl group, 2"-oxy-3"-[(pyridin-2-ylmethyl)-amino]-propyl group, 2"-oxy-3"- [2-(1 H-indol-3-yl)-ethylamino]-propyl group, 2"-oxy-3"-(2-pyridin-2-yl-ethylamino)-propyl group, 2"-oxy-3"-[(pyridin-3-ylmethyl)-amino]-propyl group, 3"-[4-(4-fluoro-phenyl)- piperazin-1-yl]-2"-oxy-propyl group, 2"-oxy-3"-[4-(4-nitro-phenyl)-piperazin-1-yl]-propyl group, 2"-oxy-3"-[4-(4-nitro-phenyl)-piperazin-1-yl]-propyl group, 3"-[4-(4-acetyl-phenyl)- piperazin-1 -yl]-2"-oxy-propyl group, 3"-[4-(2-ethoxy-phenyl)-piperazin-1 -yl]-2"-oxy-propyl group, 2"-oxy-3"-(quinolin-6-ylamino)-propyl group, 2"-oxy-3"-(quinolin-3-ylamino)-propyl group, 2"-oxy-3"-[4-(isoquinoline-7-sulfonyl)-2-methyl-piperazin-1-yl]-propyl group, 2"-oxy- 3"-isobutylamino-propyl group, 3"-[4-(3-carboxy-7-chloro-1-cyclopropyl-4-oxo-1 ,4-dihydro- quinolin-6-yl)-piperazin-1-yl]-2"-oxy-propyl group, 3"-[4-(3-carboxy-1-cyclopropyl-6-fluoro- 4-OXO-1 ,4-dihydro-quinolin-7-yl)-piperazin-1-yl]-2"-oxy-propyl group, 3"-[4-(3-carboxy-1- cyclopropyl-4-oxo-1 ,4-dihydro-quinolin-6-yl)-piperazin-1-yl]-2"-oxy-propyl group, 3"-[2-(3- carboxy-7-chloro-1-cyclopropyl-4-oxo-1 ,4-dihydro-quinolin-7-ylamino)-ethylamino]-2"-oxy- propyl group, 3"-[2-(3-carboxy-1-cyclopropyl-6-fluoro-4-oxo-1 ,4-dihydro-quinolin-7- ylamino)-ethylamino]-2"-oxy-propyl group, 3-(3'-quinolyl)-2-propenyl group, 3-(4'-quinolyl)- 2-propenyl group, 3-(1 '-naphtyl)-2-propenyl group, 3-(3'-quinolyl)-2-propenyl group, 3-(4'- quinolyl)-2-propenyl group, 3-(1 '-naphtyl)-2-propenyl group, 2"-oxy-3"-[4-(3- trifluoromethyl-phenyl)-piperazin-1 -yl]-propyl group.

In one embodiment of the present invention, A represents C=O, B represents NH group, R¹ represents L-cladinosyl group of formula (II), R² and R³ both represent hydrogen, R⁴ represents CH₂-oxiranyl group, and R⁵ represents dimethylamino-N-oxide group.

In one embodiment of the present invention, A represents C=O, B represents NH group, Ri represents L-cladinosyl group of formula (II), R₂ and R₃ both represent hydrogen, R₄ represents CH₂-oxiranyl group, and R₅ represents dimethylamino group.

It will be understood that the present invention covers all combinations of aspects, suitable, convenient and preferred groups described herein.

Compounds of the present invention may be prepared according to the following processes:

Step 1 :

In a first step, a 6-O-allylerythromycin A of the formula (III), prepared according to the method of U.S. Patent No. 4,990,602, (III)

may be converted into the corresponding oxime. Oximation is a well-known reaction usually performed with hydroxylamine hydrochloride in the presence of appropriate inorganic or organic bases in a suitable protic or aprotic solvent. Hydroxylamine hydrochloride is used in a 1 to 15-equimolar excess, preferably in a 10-equimolar excess with regard to 6-O-allylerythromycin. As suitable bases alkali hydroxides, carbonates, hydrogen carbonates and acetates are used whereas as solvents C₁-C₃ alcohols are used. The preferred base is sodium carbonate or sodium acetate and the preferred solvent is methanol. In general, the reaction is performed at a temperature from 0 to 80⁰C, preferably at 65°C, within 2 hours to a few days, but mainly it is accomplished within 8 to 20 hours. The work-up procedure is performed in the usual manner, e.g. by evaporation of the solvent under vacuum, addition of a mixture of water and organic solvent followed by extraction in an alkaline medium, preferably at pH 8.0-10.0. As solvents for the extraction of the product methylene chloride, chloroform, ethyl acetate, diethylether and toluene are used, with chloroform being the preferred one. The product is isolated by the separation of the organic layer and evaporation of the solvent, which yields a mixture of 6-O- allylerythromycin A 9(E)- and 9(Z)-oximes of the formula (IV)

in a ratio of about 1 :1. If necessary, the separation of the isomers is performed by chromatography on a silica gel column by using the system methylene chloride-methanol- ammonium hydroxyde 90:9:1.5, which yields a chromatographically homogeneous 6-0- allyl-erythromycin A 9(E)-oxime of the formula (IVa)

and chromatographically homogeneous 6-0-allyl-erythromycin A 9(Z)-oxime of the formula (IVb)

Step 2:

Conversion of 6-O-allyl-erythromycin A 9(E)-oxime of the formula (IVa) into 6-O-allyl-9a- aza-9a-homoerythromycin A of the general formula (I)

wherein A represents NH group, B represents C=O group, R¹ represents L-cladinosyl group of the formula (II)

("I)

R² and R³ are the same and represent hydrogen, R⁴ represents a prop-2-enyl, i.e. allyl group, and R⁵ represents dimethylamino, is performed by Beckmann rearrangement (see "Comprehensive Organic Chemistry", I. O. Sutherland (Ed.), Pergamon Press, NewYork, 1979, Vol. 2, 398-400 and 967-968). Beckmann rearrangement is performed under acidic, neutral and basic conditions. Common acidic reagents catalyzing the rearrangement include cone, sulfuric acid, polyphosphoric acid, thionyl chloride, phosphoric pentachloride, sulfur dioxide and formic acid. Due to the sensibility of macrolide molecule in an acidic medium and especially due to the ease of cleavage of neutral sugar L-cladinose, these reagents are not suitable for the rearrangement of oxime of the formula (IVa) into 6-O-allyl-9a-aza-9a- homoerythromycin A of the general formula (I), wherein A, B, R¹, R², R³, R⁴, and R⁵ have the above-mentioned meanings. Preferably, Beckmann rearrangement of oxime (IVa) is performed by initial O-sulfonation of oxime hydroxyl with alkylsulfonyl halides, arylsulfonyl halides or arylsulfonyl anhydrides. Intermediate oxime sulfonate is isolated or, usually, the rearrangement into the desired product is performed in situ. Generally, sulfonation and rearrangement are performed in the presence of organic or inorganic bases.

Suitable sulfonation reagents catalyzing the rearrangement of oxime (IVa) include methansulfonyl chloride, benzenesulfonyl chloride, 4-acetylamidosulfonyl chloride, p- toluenesulfonyl chloride, anhydrides of benzenesulfonic and p-toluenesulfonic acid. The reaction is performed in the presence of inorganic bases such as sodium hydrogen carbonate or potassium carbonate or in presence of organic bases such as pyridine, 4- dimethylaminopyridine, triethylamine and N,N-diisopropyl-amine. Suitable solvents include aqueous mixtures such as acetone-water mixture and dioxan-water mixture, and organic solvents such as methylene chloride, chloroform, ethyl acetate, diethyl ether, tetrahydrofuran, toluene, acetonitrile and pyridine. Generally, the reaction is performed by the use of 1-3 equimolar excess of the sulfonation reagent and with the same or greater equimolar amount of the base at a temperature from -20 to 50⁰C. Pyridine is often used as the solvent and as the base at the same time. Suitably, Beckmann rearrangement of oxime (IVa) is performed in an acetone-water mixture with a double equimolar excess of p-toluensulfochloride and sodium hydrogen carbonate. If necessary, the product is purified by chromatography on a silica gel column by the use of the solvent system methylene chloride-methanol-ammonium hydroxyde 90:9:1.5, yielding a chromatographically homogenous 6-O-allyl-9a-aza-9a-homoerythromycin A.

Beckmann rearrangement of 6-O-allylerythromycin A 9(Z)-oxime of the formula (IVb) into 6-O-allyl-8a-aza-8a-homoerythromycin A of the general formula (I), wherein A represents C=O group, B represents NH group, R¹ represents L-cladinosyl group of the formula (II), R² and R³ are the same and represent hydrogen, R⁴ represents a prop-2-enyl, i.e. allyl group, and R⁵ represents dimethylamino, is performed in an analogous manner as with 9(E)-oxime (IVa).

Step 3: 6-O-allyl-9a-aza-9a-homoerythromycin A or 6-O-allyl-8a-aza-8a-homoerythromycin A of Step 2 of the general formula (I), wherein A, B, R¹, R², R³, R⁴, and R⁵ have the above- mentioned meanings, are subjected, if appropriate, to the action of strong acids, preferably 0.25-1.5 M hydrochloric acid, in a mixture of water and lower alcohols, preferably methanol, ethanol or isopropanol, at room temperature within 10-30 hours, yielding 3-O-decladinosyl-3-oxy analogues of 6-O-allyl-9a-aza-9a-homoerythromycin A or 6-O-allyl-δa-aza-δa-homoerythromycin A of the general formula (I), wherein A represents NH group and B represents C=O group, or A represents C=O group and B represents NH group, R¹ represents OH group, R² and R³ are the same and represent hydrogen, R⁴ represents a prop-2-enyl, i.e. allyl group, and R⁵ represents dimethylamino.

Step 4: S-O-Decladinosyl-S-oxy-θ-O-allyl-θa-aza-θa-homoerythromycin A or 3-O-decladinosyl-3- oxy-6-O-allyl-8a-aza-8a-homoerythromycin A of Step 3 of the general formula (I), wherein A, B, R¹, R², R³, R⁴, and R⁵ have the above-mentioned meanings, are subjected, if appropriate, to the reaction of selective acylation of the hydroxyl group at 2'-position of desosamine. Acylation is performed by the use of anhydrides of carboxylic acids having up to 4 carbon atoms, preferably with acetic acid anhydride, in the presence of inorganic or organic bases in an inert organic solvent at a temperature from 0 to 30⁰C yielding 3-0- decladinosyl-S-oxy-θ-O-allyl-θa-aza-θa-homoerythromycin A 2'-O-acetate or 3-0- decladinosyl-3-oxy-6-O-allyl-δa-aza-δa-homoerythromycin A 2'-O-acetate of the general formula (I), wherein A represents NH group and B represents C=O group, or A represents C=O group and B represents NH group, R¹ represents OH group, R² is hydrogen , R³ is acetyl, R⁴ represents a prop-2-enyl, i.e. allyl group, and R⁵ represents dimethylamino. Suitable bases include sodium hydrogen carbonate, sodium carbonate, potassium carbonate, triethylamine, pyridine, tributylamine, more suitably sodium hydrogen carbonate. Suitable inert solvents include methylene chloride, dichloroethane, acetone, pyridine, ethyl acetate, tetrahydrofuran, preferably methylene chloride.

Step 5:

S-O-Decladinosyl-S-oxy-θ-O-allyl-θa-aza-θa-homoerythromycin A 2'-O-acetate or 3-0- decladinosyl-3-oxy-6-O-allyl-3a-aza-δa-homoerythromycin A 2'-0-acetate of Step 4 of the general formula (I), wherein A, B, R¹, R², R³, R⁴, and R⁵ have the above-mentioned meanings, are subjected, if appropriate, to an oxidation of the hydroxyl group at C-3 position of aglycone ring according to a modified Pfitzner-Moffat reaction with N, N- dimethylaminopropyl-3-ethyl-carbodiimide in the presence of dimethylsulfoxide and pyridinium trifluoroacetate as a catalyst, in an inert organic solvent, suitably in methylene chloride, at a temperature from 10⁰C to room temperature, yielding 3-O-decladinosyl-3- oxo-6-O-allyl-9a-aza-9a-homoerythromycin A 2'-O-acetate or 3-O-decladinosyl-3-oxo-6- O-allyl-δa-aza-δa-homoerythromycin A 2'-O-acetate of the general formula (I), wherein A represents NH group and B represents C=O group, or A represents C=O group and B represents NH group, R¹ together with R² represents =0, R³ represents acetyl group, R⁴ represents a prop-2-enyl, i.e. allyl group, and R⁵ represents dimethylamino.

Step 6: S-O-Decladinosyl-S-oxo-θ-O-allyl-θa-aza-θa-homoerythromycin A 2'-O-acetate or 3-0- decladinosyl-S-oxo-θ-O-allyl-δa-aza-δa-homoerythromycin A 2'-0-acetate of Step 5 of the general formula (I), wherein A, B, R¹, R², R³, R⁴, and R⁵ have the above-mentioned meanings, are subjected to deprotection in lower alcohols, suitably in methanol, at a temperature from room temperature to the reflux temperature of the solvent, yielding 3-0- decladinosyl-S-oxo-θ-O-allyl-θa-aza-θa-homoerythromycin A or 3-O-decladinosyl-3-oxo-6- O-allyl-8a-aza-8a-homoerythromycin A of the general formula (I), wherein A represents NH group and B represents C=O group, or A represents C=O group and B represents NH group, R¹ together with R² represents =0, R³ represents hydrogen, R⁴ represents a prop- 2-enyl, i.e. allyl group, and R⁵ represents dimethylamino.

Step 7:

S-O-Decladinosyl-S-oxo-θ-O-allyl-θa-aza-θa-homoerythromycin A or 3-O-decladinosyl-3- oxo-6-O-allyl-8a-aza-8a-homoerythromycin A from the Step 6 are subjected to epoxidation reaction with m-chloroperbenzoic acid in the presence of sodium acetate as a base in an inert organic solvent, suitably in methylene chloride, at a temperature from O⁰C to room temperature, yielding epoxy N-oxide derivatives of the general formula (I), wherein A represents NH group and B represents C=O group, or A represents C=O group and B represents NH group, R¹ together with R² represents =0, R³ represents hydrogen, R⁴ represents CH₂-oxiranyl group, and R⁵ represents dimethylamino N-oxide group.

Step 8:

3-O-Descladinosyl-3-oxo-6-O-(2"-methyloxiranyl)-8a-aza-8a-homoerythromycin A 3'-N- oxide and 3-O-descladinosyl-3-oxo-6-O-(2"-methyloxiranyl)-8a-aza-8a-homoerythromycin A 3'-N-oxide from the Step 7 are subjected to reduction with zinc powder in the presence of ammonium chloride in a mixture of water and lower alcohols, preferably methanol, ethanol or isopropanol, over 3-5 hours at room temperature, yielding 6-0-substituted epoxy derivatives of the general formula (I), wherein A represents NH group and B represents C=O group, or A represents C=O group and B represents NH group, R¹ together with R² represent =0, R³ represents hydrogen, R⁴ represents CH₂-oxiranyl group, and R⁵ represents dimethylamino.

Step 9:

3-O-Descladinosyl-3-oxo-6-O-(2"-methyloxiranyl)-8a-aza-8a-homoerythromycin A and 3- O-descladinosyl-3-oxo-6-O-(2"-methyloxiranyl)-8a-aza-8a-homoerythromycin A from the

Step 8 are subjected to nucleophilic ring opening with selected amines (for the list of selected amines see Chart 1 ) in the presence of lithium perchlorate in an inert organic solvent, suitably in isopropanol at reflux temperature, yielding diastereoisomeric β-amino alcohol derivatives of the general formula (I), wherein A represents NH group and B represents C=O group, or A represents C=O group and B represents NH group, R¹ together with R² represent =0, R³ represents hydrogen, R⁴ represents a straight or branched chain C₃-C₇ alkyl group containing a moiety selected from piperazin-1 ,4-yl, 2- methyl-piperazin-1 ,4-yl, 2-methyl-piperazin-1 ,4-yl-S(O)₂, NH and N(CH₃), or containing two NH moieties; wherein the second alkyl carbon atom is substituted by a hydroxy substituent, and the terminal carbon atom or heteroatom is substituted by phenyl (itself optionally substituted by one substituent selected from methoxy, ethoxy, nitro, fluoro, trifluoromethyl, or C(O)CH₃,), pyridyl, quinolinyl, isoquinolinyl, S-carboxy-i-cyclopropyM- oxo-1 ,4-dihydro-quinolinyl (itself optionally substituted in the 6 or 7 position by fluoro or chloro); and R⁵ represents dimethylamino.

Step 10: 3-O-Decladinosyl-3-oxo-6-O-allyl (ketolide) analogues from the step 6 are subjected to Heck reaction with suitable naphthyl or quinolinyl halides, in the presence of a palladium catalyst, such as palladium(ll) acetate, tetrakis(triphenylphosphine)palladium(0), tris(dibenzylideneacetone)dipalladium(0) or the like, preferably palladium(ll) acetate, and a suitable phosphine ligand, such as triphenylphosphine, bis(diphenylphosphino)methane, 1 ,2-bis(diphenylphosphino)ethane, 1 ,3-bis(diphenylphosphino)propane, 1 ,4- bis(diphenylphosphino)butane, tri-o-tolylphosphine, or the like, preferably tri-o- tolylphosphine, in an aprotic solvent, such as tetrahydrofuran, N,N-dimethylformamide, dimethylsulfoxide, acetonitrile or the like, preferably acetonitrile, at from 4O⁰C to about 15O⁰C for 0.5 hour to about 48 hours, preferably at 9O⁰C for 5 hours, yielding 6-O- substituted alkenyl derivatives of the general formula (I), wherein A represents NH group and B represents C=O group, or A represents C=O group and B represents NH group, R¹ together with R² represents =0, R³ represents hydrogen, R⁴ represents a prop-2-enyl (i.e. allyl) substituted with one or more substituents selected from naphthyl or quinolinyl, and R⁵ represents dimethylamino.

Pharmaceutically acceptable addition salts, which are also an object of the present invention are obtained by the reaction of new compounds from the class of 6-0- substituted-8a-aza-8a-homoerythromycin A and 6-O-substituted-9a-aza-9a- homoerythromycin A of the general formula (I), wherein A, B, R¹, R², R³, R⁴, R⁵ have the above-mentioned meanings, with at least equimolar amount of an appropriate inorganic or organic acid such as hydrochloric, hydroiodic, sulfuric, phosphoric, acetic, citric, stearic, succinic, ethylsuccinic, methanesulfonic, benzenesulfonic, p-toluenesulfonic and laurylsulfonic acids in a solvent inert to the reaction. The addition salts are isolated by filtration if they are insoluble in a solvent inert to the reaction, by precipitation with a non- solvent or by evaporation of the solvent, mostly by method of lyophilization.

Compounds according to the invention may exhibit a broad spectrum of antimicrobial activity, in particular antibacterial activity, against a wide range of clinical pathogenic microorganisms. Using a standard microtiter broth serial dilution test, compounds of the invention have been found to exhibit useful levels of activity against a range of pathogenic microorganisims, for example gram positive bacteria. The compounds of the invention may be active against strains which include Staphylococcus aureus, Streptococcus pneumoniae, Moraxella catarrhalis, Streptococcus pyogenes, Haemophilus influenzae, Enterococcus faecalis, Chlamydia pneumoniae, Mycoplasma pneumoniae and Legionella pneumophila. The compounds of the invention may also be active against resistant strains, for example erythromycin resistant strains. Thus, for example, the compounds of the invention may be active against erythromycin resistant strains of Streptococcus pneumoniae, Streptococcus pyogenes and Staphylococcus aureus.

The compounds of the invention may therefore be useful for treating a variety of diseases caused by pathogenic microorganisms, in particular bacteria, in human beings and animals. It will be appreciated that reference to treatment includes acute treatment or prophylaxis as well as the alleviation of established symptoms.

Thus, according to another aspect of the present invention we provide a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in therapy.

According to a further aspect of the invention we provide a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in the treatment or prophylaxis of systemic or topical microbial infections in a human or animal body.

According to a further aspect of the invention we provide the use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for use in the treatment or prophylaxis of systemic or topical microbial infections in a human or animal body.

According to a yet further aspect of the invention we provide a method of treatment of the human or non-human animal body to combat microbial infections comprising administration to a body in need of such treatment of an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.

While it is possible that, for use in therapy, a compound of the invention may be administered as the raw chemical it is preferable to present the active ingredient as a pharmaceutical formulation e.g. when the agent is in admixture with a suitable pharmaceutical excipient, diluent or carrier selected with regard to the intended route of administration and standard pharmaceutical practice.

Accordingly, in one aspect, the present invention provides a pharmaceutical composition or formulation comprising a compound of the invention or a pharmaceutically acceptable salt or solvate thereof in association with a pharmaceutically acceptable excipient, diluent and/or carrier. The excipient, diluent and/or carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. In another aspect, the invention provides a pharmaceutical composition comprising, as active ingredient, a compound of the invention or a pharmaceutically acceptable salt or solvate thereof in association with a pharmaceutically acceptable excipient, diluent and/or carrier for use in therapy, and in particular, in the treatment of human or animal subjects suffering from a condition susceptible to amelioration by an antimicrobial compound.

In another aspect, the invention provides a pharmaceutical composition comprising a therapeutically effective amount of the compounds of the present invention and a pharmaceutically acceptable excipient, diluent and/or carrier (including combinations thereof).

There is further provided by the present invention a process of preparing a pharmaceutical composition, which process comprises mixing a compound of the invention or a pharmaceutically acceptable salt or solvate thereof, together with a pharmaceutically acceptable excipient, diluent and/or carrier.

The compounds of the invention may be formulated for administration in any convenient way for use in human or veterinary medicine and the invention therefore includes within its scope pharmaceutical compositions comprising a compound of the invention adapted for use in human or veterinary medicine. Such compositions may be presented for use in a conventional manner with the aid of one or more suitable excipients, diluents and/or carriers. Acceptable excipients, diluents and carriers for therapetic use are well known in the pharmaceutical art, and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (A. R. Gennaro edit. 1985). The choice of pharmaceutical excipient, diluent and/or carrier can be selected with regard to the intended route of administration and standard pharmaceutical practice. The pharmaceutical compositions may comprise as - or in addition to - the excipient, diluent and/or carrier any suitable binder(s), lubricant(s), suspending agent(s), coating agent(s), solubilising agent(s).

Preservatives, stabilisers, dyes and even flavouring agents may be provided in the pharmaceutical composition. Examples of preservatives include sodium benzoate, sorbic acid and esters of p-hydroxybenzoic acid. Antioxidants and suspending agents may be also used.

For some embodiments, the agents of the present invention may also be used in combination with a cyclodextrin. Cyclodextrins are known to form inclusion and non- inclusion complexes with drug molecules. Formation of a drug-cyclodextrin complex may modify the solubility, dissolution rate, bioavailability and/or stability property of a drug molecule. Drug-cyclodextrin complexes are generally useful for most dosage forms and administration routes. As an alternative to direct complexation with the drug the cyclodextrin may be used as an auxiliary additive, e. g. as a carrier, diluent or solubiliser. Alpha-, beta- and gamma-cyclodextrins are most commonly used and suitable examples are described in WO 91/1 1172, WO 94/02518 and WO 98/55148.

The compounds of the invention may be milled using known milling procedures such as wet milling to obtain a particle size appropriate for tablet formation and for other formulation types. Finely divided (nanoparticulate) preparations of the compounds of the invention may be prepared by processes known in the art, for example see International Patent Application No. WO 02/00196 (SmithKline Beecham).

The routes for administration (delivery) include, but are not limited to, one or more of: oral (e. g. as a tablet, capsule, or as an ingestable solution), topical, mucosal (e. g. as a nasal spray or aerosol for inhalation), nasal, parenteral (e. g. by an injectable form), gastrointestinal, intraspinal, intraperitoneal, intramuscular, intravenous, intrauterine, intraocular, intradermal, intracranial, intratracheal, intravaginal, intracerebroventricular, intracerebral, subcutaneous, ophthalmic (including intravitreal or intracameral), transdermal, rectal, buccal, epidural and sublingual.

There may be different composition/formulation requirements depending on the different delivery systems. By way of example, the pharmaceutical composition of the present invention may be formulated to be delivered using a mini-pump or by a mucosal route, for example, as a nasal spray or aerosol for inhalation or ingestable solution, or parenterally in which the composition is formulated by an injectable form, for delivery, by, for example, an intravenous, intramuscular or subcutaneous route. Alternatively, the formulation may be designed to be delivered by both routes.

Where the agent is to be delivered mucosally through the gastrointestinal mucosa, it should be able to remain stable during transit though the gastrointestinal tract; for example, it should be resistant to proteolytic degradation, stable at acid pH and resistant to the detergent effects of bile.

Where appropriate, the pharmaceutical compositions can be administered by inhalation, in the form of a suppository or pessary, topically in the form of a lotion, solution, cream, ointment or dusting powder, by use of a skin patch, orally in the form of tablets containing excipients such as starch or lactose, or in capsules or ovules either alone or in admixture with excipients, or in the form of elixirs, solutions or suspensions containing flavouring or colouring agents, or they can be injected parenterally, for example intravenously, intramuscularly or subcutaneously. For parenteral administration, the compositions may be best used in the form of a sterile aqueous solution which may contain other substances, for example enough salts or monosaccharides to make the solution isotonic with blood. For buccal or sublingual administration the compositions may be administered in the form of tablets or lozenges which can be formulated in a conventional manner. It is to be understood that not all of the compounds need be administered by the same route. Likewise, if the composition comprises more than one active component, then those components may be administered by different routes.

The compositions of the invention include those in a form especially formulated for parenteral, oral, buccal, rectal, topical, implant, ophthalmic, nasal or genito-urinary use. For some applications, the agents of the present invention are delivered systemically (such as orally, buccally, sublingually), more preferably orally. Hence, preferably the agent is in a form that is suitable for oral delivery.

If the compound of the present invention is administered parenterally, then examples of such administration include one or more of: intravenously, intraarterial^, intraperitoneal^, intrathecally, intraventricular^, intraurethrally, intrasternally, intracranially, intramuscularly or subcutaneously administering the agent, and/or by using infusion techniques.

For parenteral administration, the compound is best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood. The aqueous solutions should be suitably buffered (preferably to a pH of from 3 to 9), if necessary. The preparation of suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well-known to those skilled in the art.

The compounds according to the invention may be formulated for use in human or veterinary medicine by injection (e.g. by intravenous bolus injection or infusion or via intramuscular, subcutaneous or intrathecal routes) and may be presented in unit dose form, in ampoules, or other unit-dose containers, or in multi-dose containers, if necessary with an added preservative. The compositions for injection may be in the form of suspensions, solutions, or emulsions, in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising, solubilising and/or dispersing agents. Alternatively the active ingredient may be in sterile powder form for reconstitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.

The compounds of the invention can be administered (e. g. orally or topically) in the form of tablets, capsules, ovules, elixirs, solutions or suspensions, which may contain flavouring or colouring agents, for immediate-, delayed-, modified-, sustained-, pulsed- or controlled-release applications.

The compounds of the invention may also be presented for human or veterinary use in a form suitable for oral or buccal administration, for example in the form of solutions, gels, syrups, mouth washes or suspensions, or a dry powder for constitution with water or other suitable vehicle before use, optionally with flavouring and colouring agents. Solid compositions such as tablets, capsules, lozenges, pastilles, pills, boluses, powder, pastes, granules, bullets or premix preparations may also be used. Solid and liquid compositions for oral use may be prepared according to methods well known in the art. Such compositions may also contain one or more pharmaceutically acceptable carriers and excipients which may be in solid or liquid form.

The tablets may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine, disintegrants such as starch (preferably corn, potato or tapioca starch), sodium starch glycollate, croscarmellose sodium and certain complex silicates, and granulation binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin and acacia.

Additionally, lubricating agents such as magnesium stearate, stearic acid, glyceryl behenate and talc may be included.

Solid compositions of a similar type may also be employed as fillers in gelatin capsules.

Preferred excipients in this regard include lactose, starch, a cellulose, milk sugar or high molecular weight polyethylene glycols. For aqueous suspensions and/or elixirs, the agent may be combined with various sweetening or flavouring agents, colouring matter or dyes, with emulsifying and/or suspending agents and with diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof.

The compounds of the invention may also be administered orally in veterinary medicine in the form of a liquid drench such as a solution, suspension or dispersion of the active ingredient together with a pharmaceutically acceptable carrier or excipient.

The compounds of the invention may also, for example, be formulated as suppositories e.g. containing conventional suppository bases for use in human or veterinary medicine or as pessaries e.g. containing conventional pessary bases.

The compounds according to the invention may be formulated for topical administration, for use in human and veterinary medicine, in the form of ointments, creams, gels, hydrogels, lotions, solutions, shampoos, powders (including spray or dusting powders), pessaries, tampons, sprays, dips, aerosols, drops (e.g. eye ear or nose drops) or pour- ons.

For application topically to the skin, the agent of the present invention can be formulated as a suitable ointment containing the active compound suspended or dissolved in, for example, a mixture with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water. Alternatively, it can be formulated as a suitable lotion or cream, suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate, a polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

The compounds may also be dermally or transdermal^ administered, for example, by use of a skin patch.

For ophthalmic use, the compounds can be formulated as micronised suspensions in isotonic, pH adjusted, sterile saline, or, preferably, as solutions in isotonic, pH adjusted, sterile saline, optionally in combination with a preservative such as a benzylalkonium chloride. Alternatively, they may be formulated in an ointment such as petrolatum.

As indicated, the compound of the present invention can be administered intranasally or by inhalation and is conveniently delivered in the form of a dry powder inhaler or an aerosol spray presentation from a pressurised container, pump, spray or nebuliser with the use of a suitable propellant, e. g. a hydrofluoroalkane such as 1 ,1 ,1 ,2- tetrafluoroethane (HFA 134AT"") or 1 ,1 ,1 ,2,3,3,3-heptafluoropropane (HFA 227EA), carbon dioxide or other suitable gas. In the case of a pressurised aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. The pressurised container, pump, spray or nebuliser may contain a solution or suspension of the active compound, e. g. using a mixture of ethanol and the propellant as the solvent, which may additionally contain a lubricant, e. g. sorbitan trioleate.

Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound and a suitable powder base such as lactose or starch.

For topical administration by inhalation the compounds according to the invention may be delivered for use in human or veterinary medicine via a nebuliser.

The compounds of the invention may also be used in combination with other therapeutic agents. The invention thus provides, in a further aspect, a combination comprising a compound of the invention or a pharmaceutically acceptable derivative thereof together with a further therapeutic agent.

When a compound of the invention or a pharmaceutically acceptable salt or solvate thereof is used in combination with a second therapeutic agent active against the same disease state the dose of each compound may differ from that when the compound is used alone. Appropriate doses will be readily appreciated by those skilled in the art. It will be appreciated that the amount of a compound of the invention required for use in treatment will vary with the nature of the condition being treated and the age and the condition of the patient and will be ultimately at the discretion of the attendant physician or veterinarian. The compounds of the present invention may for example be used for topical administration with other active ingredients such as corticosteroids or antifungals as appropriate.

The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation and thus pharmaceutical formulations comprising a combination as defined above together with a pharmaceutically acceptable carrier or excipient comprise a further aspect of the invention. The individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations by any convenient route.

When administration is sequential, either the compound of the invention or the second therapeutic agent may be administered first. When administration is simultaneous, the combination may be administered either in the same or different pharmaceutical composition.

When combined in the same formulation it will be appreciated that the two compounds must be stable and compatible with each other and the other components of the formulation. When formulated separately they may be provided in any convenient formulation, conveniently in such manner as are known for such compounds in the art.

The compositions may contain from 0.01-99% of the active material. For topical administration, for example, the composition will generally contain from 0.01-10%, more preferably 0.01-1% of the active material.

Typically, a physician will determine the actual dosage which will be most suitable for an individual subject. The specific dose level and frequency of dosage for any particular individual may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the individual undergoing therapy.

For oral and parenteral administration to humans, the daily dosage level of the agent may be in single or divided doses.

For systemic administration the daily dose as employed for adult human treatment it will range from 2-100mg/kg body weight, preferably 5-60mg/kg body weight, which may be administered in 1 to 4 daily doses, for example, depending on the route of administration and the condition of the patient. When the composition comprises dosage units, each unit will preferably contain 200mg to 1g of active ingredient. The duration of treatment will be dictated by the rate of response rather than by arbitrary numbers of days.

In the procedures that follow, reference to an Intermediate by number is typically provided. This is provided merely for assistance to the skilled chemist to identify the starting material used. The starting material may not necessarily have been prepared from the batch referred to. In addition, the preparation of an Example compound is typically presented as a series of individual reaction steps, for example (a), (b), (c), etc. This is also provided merely for assistance to the skilled chemist to identify a suitable sequence of reaction steps to prepare the Example. Although each of the reaction steps indicated will have been carried out as described, the steps (a), (b), (c), etc. may not have been performed in one continuous sequence from the same batch of starting materials.

In the procedures that follow, reference is made to certain compounds being made "using a similar procedure". As is appreciated by those skilled in the art, such analogous processes may involve variations in synthetic procedure, for example in the solvent(s) used for extraction, or in the eluting solvent system used for chromatographic purification.

Compounds of the present invention are illustrated by the following Examples, which do not limit the scope of the invention in any way.

EXAMPLE 1 6-O-allyl-9a-aza-9a-homoerythromycin A

6-O-allylerythromycin A 9(E)-oxime IVa (3.95 g, 5 mmoL) was dissolved in acetone (130 ml.) and the resulting solution was cooled to 0-5⁰C. Subsequently, a solution of p- toluenesulfonylchloride (2.6 g, 10.0 mmoL) in acetone (40 ml.) and an aqueous sodium bicarbonate (0.83 g, 10.0 mmoL, 130 ml.) were added dropwise thereto within an hour, and the mixture was stirred for an additional 45 min before warming up to room temperature. The reaction mixture was stirred at room temperature for further 8 hours, acetone was evaporated in a vacuum, and the resulting aqueous solution was extracted with chloroform (40 ml.) at pH 5.0 and pH 9.0. The organic phase at pH 9.0 was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude material was purified by column chromatography, eluted with 10% MeOH in methylene chloride containing 1 % aqueous ammonia, to yield 6-O-allyl-9a-aza-9a-homoerythromycin A (2.8 g, 71%) as a white solid. Rf 0.26, ethylacetate-n-hexane-diethylamine, 100:100:20. MS m/z 789 (MH⁺, 89%).

EXAMPLE 2 6-O-allyl-δa-aza-δa-homoerythromycin A

To an ice-cold solution of 6-O-allylerythromycin A 9(Z)-oxime IVb (5.52 g, 7 mmoL) in acetone (50 ml.) were added simultaneously, a solution of p-toluenesulfonylchloride (1.84 g, 14.0 mmoL) in acetone (56 ml_), and an aqueous sodium bicarbonate (1.16g, 14.0 mmoL, 180 ml.) over 1 hour under stirring. The reaction mixture was stirred at room temperature for 4 hours, and acetone was removed under reduced pressure on a rotary evaporator. The remaining aqueous solution was taken up in chloroform (70 ml.) and extracted while adjusting the pH of the solution to 5.0 and 9.0 by the addition of 2M aqueous NaOH. The combined organic extracts at pH 9.0 were evaporated in vacuo to provide a pale yellow solid, which was purified by chromatography on a silica gel column using the system methylene chloride-MeOH-aq. ammonia (90:9:1.5), to afford 4.14 g (75%) of 6-O-allyl-δa-aza-δa-homoerythromycin A as a colorless solid. Rf 0.22, ethylacetate-n-hexane-diethylamine, 100:100:20. MS m/z 789 (MH⁺, 88%).

EXAMPLE 3 S-O-Descladinosyl-S-oxy-θ-O-allyl-θa-aza-θa-homoerythromycin A

The compound of Example 1 (1.58 g, 2.0 mmoL) was dissolved in 0.25 M hydrochloric acid (40 mL) and it was left standing at room temperature for 24 hours. The reaction mixture was extracted with methylene chloride (30 mL) while adjusting the pH of the solution to 9.0 by the addition of aqueous ammonia. The layers were separated and the aqueous layer was extracted with an additional methylene chloride (30 ml_). The combined organic extracts were washed with aqueous 10% sodium bicarbonate, water, dried over sodium sulfate, filtered and concentrated. The crude mixture was purified by flash column chromatography on silica gel (methylene chloride-MeOH-aqueous ammonia; 90:9:1.5), to give 0.65 g (52%) of S-descladinosyl-S-oxy-θ-O-allyl-θa-aza-θa- homoerythromycin A as an off-white solid: Rf 0.20, ethylacetate-n-hexane-diethylamine, 100:100:20. MS m/z 631 (MH⁺, 57%).

EXAMPLE 4 S-O-Descladinosyl-S-oxy-θ-O-allyl-δa-aza-δa-homoerythromycin A

Starting from compound obtained in Example 2, and following the procedure of the Example 3, the title compound was obtained in 60% yield: Rf 0.24, ethylacetate-n- hexane-diethylamine, 100:100:20. MS m/z 631 (MH⁺, 79%).

EXAMPLE 5 2'-O-Acetyl-3-O-descladinosyl-3-oxy-6-O-allyl-9a-aza-9a-homoerythromycin A

To a stirred solution of S-O-descladinosyl-S-oxy-θ-O-allyl-θa-aza-θa-homoerythromycin A (757.0 mg, 1.2 mmoL), obtained according to Example 3, in methylene chloride (25 mL) sodium bicarbonate (440 mg, 5.2 mmoL) and acetic anhydride (0.128 mL, 1.3 mmoL) were added dropwise over 10 minutes. The reaction mixture was stirred at room temperature for 3 hours. The mixture was diluted with an additional methylene chloride (50 mL), washed with saturated aqueous sodium bicarbonate (30 mL) and brine (30 mL), and dried over sodium sulfate, filtered, and concentrated to give the title compound (0.75 g, crude) as a white foam, which was used without further purification. Rf 0.45, ethylacetate-n-hexane-diethylamine, 100:100:20. MS m/z 673 (MH⁺, 52%).

EXAMPLE 6 2'-O-Acetyl-3-O-descladinosyl-3-oxy-6-O-allyl-8a-aza-8a-homoerythromycin A

Starting from compound of Example 4, and following the procedure of the Example 5, the title compound was obtained in 89% yield: Rf 0.40, ethylacetate-n-hexane-diethylamine, 100:100:20. MS m/z 673 (MH⁺, 87%).

EXAMPLE 7 S-O-Descladinosyl-S-oxo-θ-O-allyl-θa-aza-θa-homoerythromycin A

To a solution of 2'-O-acetyl-3-O-descladinosyl-3-oxy-6-O-allyl-9a-aza-9a- homoerythromycin A, compound of Example 5 (807.4 g, 1.2 mmoL) in methylene chloride (15 ml.) dimethyl sulfoxide (1.27 ml.) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.34 g, 7.0 mmoL) were added. The reaction mixture was cooled to 15°C and then, under stirring and maintaining this temperature, a solution of pyridinium trifluoroacetate (1.37 g, 7.0 mmoL) in methylene chloride (5 ml.) was added gradually over 30 minutes. The temperature of the reaction mixture was gradually increased to room temperature, stirring was continued for additional 3 hours, and the reaction was quenched by the addition of brine (20 ml.) and methylene chloride (20 ml_). After adjusting the pH to 9.5 using 2M aqueous NaOH, the reaction mixture was extracted with methylene chloride (2 x 50 ml_). The combined organic extracts were successively washed with brine, saturated aqueous sodium bicarbonate and water, and then dried over anhydrous potassium carbonate. Evaporation of the solvent under reduced pressure afforded 0.80 g of an oily residue, which was subjected to methanolysis at room temperature for 24 hours. Methanol was evaporated under reduced pressure and the obtained residue (0.625 g) was purified by flash column chromatography on silica gel using the solvent system methylene chloride-MeOH-aqueous ammonia (90:9:0.5). Evaporation of the combined fractions with Rf 0.29, yielded the title compound (558.4 g, 74%) as a white solid: Rf 0.29, methylene chloride-MeOH-aqueous ammonia (90:9:0.5). MS m/z 629 (MH⁺, 55%). EXAMPLE 8 S-O-Descladinosyl-S-oxo-θ-O-allyl-δa-aza-δa-homoerythromycin A

To a stirred solution of 2'-O-acetyl-3-O-descladinosyl-3-oxy-6-O-allyl-8a-aza-8a- homoerythromycin A, compound of Example 6 (1.48 g, 2.2 mmoL) in methylene chloride (30 ml.) dimethyl sulfoxide (2.5 ml.) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.7 g, 14.0 mmoL) were added. The reaction mixture was cooled to 15°C, and under stirring and while maintaining this temperature, a solution of pyridinium trifluoroacetate (2.7 g, 14.0 mmoL) in methylene chloride (10 ml.) was added gradually over 30 minutes. Following the procedure of the Example 7, the title compound (1.23 g) was isolated in 89% yield: Rf 0.24, methylene chloride-methanol-conc. ammonium hydroxide 90:9:0.5. MS m/z 629 (MH⁺, 63%).

EXAMPLE 9

3'-N-Oxide-3-O-descladinosyl-3-oxo-6-O-Syn-(2"-methyloxiranyl)-8a-aza-8a- homoerythromycin A (Example 9a); and

3'-N-oxide-3-O-descladinosyl-3-oxo-6-O-Λnf/-(2"-methyloxiranyl)-8a-aza-8a- homoerythromycin A (Example 9b) (a) Method A: Using m-chloroperoxybenzoic Acid

To a solution of compound of Example 8 (629 mg, 1.0 mmoL) in dry dichloromethane (7 mL) cooled to 0⁰C in an ice/water bath, sodium acetate (175 mg, 2.1 mmoL) followed by m-CPBA (1.88 g, 50% w/w, 5.0 mmoL) were added in five portions over 5 min. The reaction mixture was allowed to warm to room temperature and stirred for 24 h under a drying tube. After filtration through a short pad of Celite, the mixture was washed with aqueous Na₂SO₃ (10% w/v), saturated aqueous NaHCO₃, and water and dried over K₂CO₃. Removal of the solvent under reduced pressure gave a pale tan solid that was purified by flash chromatography using CH₂CI₂/Me0H/aq. NH₃ (90:9:0.5) as eluent to afford a mixture of 6-O-syn-, Example 9a and 6-O-anf/-(2"-methyloxiranyl)-3'-N- oxides, Example 9b as a colorless needles (397.7 mg, 60%; syn/anti ratio: 1 :1 according to LC/MS analysis).

3'-N-Oxide-3-O-descladinosyl-3-oxo-6-O-Syn-(2"-methyloxiranyl)-8a-aza-8a- homoerythromycin A: FAB-MS m/z 661 (MH⁺, 78%); ¹³C NMR (CDCI₃) δ 205.4, 174.0, 170.5, 102.8, 80.5, 79.6, 77.2, 76.3, 74.5, 72.5, 71.3, 67.3, 65.8, 59.0, 52.1 , 51.5, 49.7, 46.7, 45.6, 43.1 , 42.5, 41.3, 35.0, 23.9, 23.7, 21.6, 21.5, 16.4, 14.6, 13.8, 11.0, 9.4. 3'-N-Oxide-3-O-descladinosyl-3-oxo-6-O-Λnf/-(2"-methyloxiranyl)-8a-aza-8a- homoerythromycin A: FAB-MS m/z 661 (MH⁺, 85%); ¹³C NMR (CDCI₃) δ 205.0, 174.5, 170.8, 103.0, 81.5, 79.9, 77.2, 76.1 , 74.6, 72.5, 71.1 , 67.4, 66.1 , 59.1 , 52.1 , 51.7, 46.0, 49.5, 46.8, 42.6, 42.4, 41.2, 35.0, 24.7, 23.8, 21.6, 21.5, 16.4, 14.5, 13.7, 11.0, 9.4.

(b) Method B: Using Dimethyldioxirane

To a solution of compound of Example 8 (629 mg, 1.0 mmoL) in acetone (10 ml_), dimethyldioxirane (11.0 ml_, 1.1 mmoL as a 0.1 mmoL/mL solution in acetone) was added and the reaction mixture allowed to stir for 16 h at room temperature. Removal of the solvent under reduced pressure afforded a colorless solid, which was dissolved in dichloromethane and dried over K₂CO₃. Removal of the solvent under reduced pressure and purification by flash chromatography using methylene chloride/methanol/aq. NH₃ (90:9:0.5) as eluent gave a mixture of 6-O-syn-, Example 9a and 6-O-anf/-(2"- methyloxiranyl)-3'-N-oxides, Example 9b (430.8 mg, 65 %) in ratio 4.4:1 according to LC/MS analysis.

EXAMPLE 10

3-O-Descladinosyl-3-oxo-6-O-Syn-(2"-methyloxiranyl)-8a-aza-8a-homoerythromycin A (Example 10a); and

3-O-descladinosyl-3-oxo-6-O-Λnf/-(2"-methyloxiranyl)-8a-aza-8a-homoerythromycin A (Example 10b)

To a solution of 6-O-syn-(2"-methyloxiranyl) and 6-O-anf/-(2"-methyloxiranyl)-3'-N- oxides, of Example 9 (compound 9a and 9b) (994.2 mg, 1.5 mmoL) in ethanol/water (2:1 , 25 mL), Zn powder (980.7 mg, 15 mmol, 10 mol. equiv.) and NH₄CI (803 mg, 15 mmol, 10 mol. equiv.) were added. The reaction mixture was stirred at room temperature for 3 hours, than filtered over short pad of Celite, and the filtrate evaporated to dryness. The residue was redissolved in CH₂CI₂ (25 mL), and washed with saturated aqueous NaHCO₃ solution (2 x 20 mL). The organic layer was dried over K₂CO₃ and evaporated to dryness. The resulting residue was purified by column chromatography, eluting with a gradient of CHCI₃ to 7% MeOH/CHCI₃ to give a 4.5:1 mixture of 6-0-syn-, Example 10a and 6-O- anf/-(2"-methyloxiranyl), Example 10b compounds (657.7 mg, 68%) as a white solid. 3-O-Descladinosyl-3-oxo-6-O-Syn-(2"-methyloxiranyl)-8a-aza-8a-homoerythromycin A (Example 10a): FAB-MS m/z 645 (MH⁺, 78%); ¹³C NMR (CDCI₃) δ 205.2, 174.2, 170.4, 103.4, 80.8, 79.8, 77.2, 74.4, 71.3, 70.7, 69.2, 66.1 , 51.3, 49.7, 46.7, 45.8, 42.8, 42.4, 41.5, 40.4, 28.7, 24.5, 23.6, 21.4, 21.3, 16.3, 14.7, 13.6, 10.9, 9.5. 3-O-Descladinosyl-3-oxo-6-O-Λnf/-(2"-methyloxiranyl)-8a-aza-8a-homoerythromycin A (Example 10b): FAB-MS m/z 645 (MH⁺, 53%); ¹³C NMR (CDCI₃) δ 205.2, 174.8, 170.5, 103.7, 82.0, 80.0, 77.2, 74.3, 71.1 , 70.8, 69.4, 65.9, 51.5, 49.6, 46.6, 46.2, 42.8, 42.4, 41.4, 40.4, 28.6, 25.7, 23.4, 21.4, 21.2, 16.2, 14.7, 13.5, 10.8, 9.6.

EXAMPLE 1 1

6-O-[2"-(Syn,anf/)-oxy-3"-(2-phenyl-ethylamino-propyl]-3-O-descladinosyl-3-oxo-8a- aza-8a-homoerythromycin A (Example 11a and Example 11b)

A mixture of 6-O-syn-, Example 10a and 6-O-anf/-(2"-methyloxiranyl), Example 10b compounds (644 mg, 1.0 mmoL), obtained according to the procedure of Example 10, LiCIO₄3H₂O (802.2 mg, 5.0 mmoL, 5.0 mol. equiv.), and amine a (Chart 1 , 5.0 mmoL, 5.0 mol. equiv.) in 2-propanol (2.5 mL) was heated at reflux during 24 h. Upon completion of the reaction, the solution was cooled to room temperature, and CH₂CI₂ (25 mL) was added. The organic layer was washed with water (2 x 25 mL), dried, and concentrated in vacuo. The residual solid was purified by chromatography on silica gel using CH₂CI₂/methanol/aq. NH₃ (90:9:1.5) as eluent to give a mixture of diastereisomeric β- amino alcohols 6-O-[2"-(Syn,anf/)-oxy-3"-(2-phenyl-ethylamino-propyl]-3-O- descladinosyl-3-oxo-8a-aza-8a-homoerythromycin A (Example 11a and Example 11b) (70% isolated yield) in ratio 4.5:1 according to LC/MS analysis. FAB-MS m/z 766 (MH⁺, 65%); ¹³C NMR (CDCI₃) δ 205.4, 175.2, 170.3, 139.7, 128.8, 128.4, 125.9, 103.3, 79.6, 79.2, 77.4, 74.5, 70.9, 70.7, 69.2, 67.7, 67.2, 65.8, 50.6, 50.0, 49.9, 46.7, 43.1 , 42.4, 40.8, 40.3, 35.9, 28.5, 24.5, 24.1 , 21.5, 21.1 , 16.5, 14.9, 13.6, 10.7, 9.4. The following Examples 12 to 35 were prepared starting from mixture of 6-O-syn-, Example 10a and 6-O-anf/-(2"-methyloxiranyl), Example 10b compounds and 5 molar equivalents of amines b-x (Chart 1 ), using the procedure of Example 11.

Chart 1. Amines employed for nucleophilic ring opening of 6-O-syn-, Example 10a and 6- O-antf-(2"-methyloxiranyl), Example 10b compounds

g

Vi/^F \j*- ¹W^" -NO, N N ¹W^"

CF, O m

W

EXAMPLE 12 6-O-[2"-(Syn,anf/>oxy-3"-(3-phenyl-propylamino)-propyl]-3-O-descladinosyl-3-oxo- 8a-aza-8a-homoerythromycin A (Example 12a + Example 12b)

3.3 mg; FAB-MS m/z 780 (MH⁺)

EXAMPLE 13 6-O-[2"-(Syn,anf/>oxy-3"-(4-phenyl-butylamino)-propyl]-3-O-descladinosyl-3-oxo- 8a-aza-8a-homoerythromycin A (Example 13a + Example 13b)

FAB-MS m/z 794 (MH⁺, 91%); ¹³C NMR (CDCI₃) δ 205.0, 175.4, 170.8, 142.2, 128.4, 128.3, 125.7, 103.4, 79.8, 79.7, 77.7, 74.5, 71.3, 70.7, 69.2, 67.0, 66.8, 65.7, 50.2, 49.8, 48.1 , 46.9, 42.9, 42.2, 41.1 , 40.3, 35.6, 28.9, 28.5, 28.1 , 24.9, 23.8, 21.5, 21.2, 16.5, 14.8, 13.7, 10.8, 9.4.

EXAMPLE 14

6-O-{2"-(Syn,anf/>oxy-3"-[2-(4-methoxy-phenyl)-1 -methyl -ethylamino]-propyl}-3-O- descladinosyl-3-oxo-8a-aza-8a-homoerythromycin A (Example 14a + Example 14b)

3.7 mg; FAB-MS m/z 810 (MH⁺)

EXAMPLE 15

6-O-{2"-(Syn,anf/>oxy-3"-[methyl-(2-(4-nitro-phenyl)-ethyl)-amino]-propyl}-3-O- descladinosyl-3-oxo-8a-aza-8a-homoerythromycin A (Example 15a + Example 15b)

2.7 mg; FAB-MS m/z 827 (MH⁺)

EXAMPLE 16 6-O-{2"-(Syn,anf/>oxy-3"-[1-methyl-2-(4-nitro-phenyl)-ethylamino]-propyl}-3-O- descladinosyl-3-oxo-8a-aza-8a-homoerythromycin A (Example 16a + Example 16b)

4.1 mg; FAB-MS m/z 827 (MH⁺)

EXAMPLE 17

6-O-[2"-(Syn,anf/>oxy-3"-(2-pyridin-3-yl-ethylamino)-propyl]-3-O-descladinosyl-3- oxo-8a-aza-8a-homoerythromycin A (Example 17a + Example 17b)

3.8 mg; FAB-MS m/z 767 (MH⁺)

EXAMPLE 18

6-O-{2"-(Syn,anf/>oxy-3"-[(pyridin-2-ylmethyl)-amino]-propyl}-3-O-descladinosyl-3- oxo-8a-aza-8a-homoerythromycin A (Example 18a + Example 18b)

4.9 mg; FAB-MS m/z 753 (MH⁺)

EXAMPLE 19

6-O-{2"-(Syn,anf/>oxy-3"-[2-(1H-indol-3-yl)-ethylamino]-propyl}-3-O-descladinosyl- 3-oxo-8a-aza-8a-homoerythromycin A (Example 19a + Example 19b)

2.9 mg; FAB-MS m/z 805 (MH⁺)

EXAMPLE 20

6-O-[2"-(Syn,anf/>oxy-3"-(2-pyridin-2-yl-ethylamino)-propyl]- 3-O-descladinosyl-3- oxo-δa-aza-δa-homoerythromycin A (Example 20a + Example 20b)

4.9 mg; FAB-MS m/z 767 (MH⁺)

EXAMPLE 21

6-O-{2"-(Syn,anf/>oxy-3"-[(pyridin-3-ylmethyl)-amino]-propyl}-3-O-descladinosyl-3- oxo-8a-aza-8a-homoerythromycin A (Example 21a + Example 21b)

2.1 mg; FAB-MS m/z 753 (MH⁺)

EXAMPLE 22

6-O-{3"-[4-(4-fluoro-phenyl)-piperazin-1-yl]-2"-(syn,anf/)-oxy-propyl}-3-O- descladinosyl-3-oxo-8a-aza-8a-homoerythromycin A (Example 22a + Example 22b)

4.4 mg; FAB-MS m/z 825 (MH⁺)

EXAMPLE 23

6-O-{2"-(Syn,anf/>oxy-3"-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-propyl}-3-O- descladinosyl-3-oxo-8a-aza-8a-homoerythromycin A (Example 23a + Example 23b)

3.5 mg; FAB-MS m/z 875 (MH⁺)

EXAMPLE 24

6-O-{2"-(Syn,anf/>oxy-3"-[4-(4-nitro-phenyl)-piperazin-1-yl]-propyl}-3-O- descladinosyl-3-oxo-8a-aza-8a-homoerythromycin A (Example 24a + Example 24b)

2.9 mg; FAB-MS m/z 854 (MH⁺)

EXAMPLE 25

6-O-{3"-[4-(4-acetyl-phenyl)-piperazin-1-yl]-2"-(syn,anf/>oxy-propyl}-3-O- descladinosyl-3-oxo-8a-aza-8a-homoerythromycin A (Example 25a + Example 25b)

3.1 mg; FAB-MS m/z 849 (MH⁺)

EXAMPLE 26

6-O-{3"-[4-(2-Ethoxy-phenyl)-piperazin-1-yl]-2"-(syn,anf/)-oxy-propyl}-3-O- descladinosyl-3-oxo-8a-aza-8a-homoerythromycin A (Example 26a + Example 26b)

FAB-MS m/z 851 (MH⁺, 94%);¹³C NMR (CDCI₃) δ 205.1 , 175.1 , 170.6, 151.5, 141.0, 122.9, 121.0, 118.4, 1 12.5, 103.4, 80.2, 79.9, 77.8, 74.5, 71.2, 70.8, 69.2, 67.7, 66.9, 65.7, 63.6, 59.9, 53.3, 49.6, 46.8, 42.8, 42.3, 41.8, 41.2, 40.4, 28.8, 24.8, 23.8, 21.5, 21.3, 16.4, 15.0, 14.7, 13.5, 1 1.0, 9.4.

EXAMPLE 27

6-O-[2"-(Syn,anf/>oxy-3"-(quinolin-6-ylamino)-propyl]-3-O-descladinosyl-3-oxo--8a- aza-8a-homoerythromycin A (Example 27a + Example 27b)

1.0 mg; FAB-MS m/z 789 (MH⁺)

EXAMPLE 28

6-O-[2"-(Syn,anf/>oxy-3"-(quinolin-3-ylamino)-propyl]-3-O-descladinosyl-3-oxo-8a- aza-8a-homoerythromycin A (Example 28a + Example 28b)

4.8 mg; FAB-MS m/z 789 (MH⁺)

EXAMPLE 29

6-O-{2"-(Syn,anf/>oxy-3"-[4-(isoquinoline-7-sulfonyl)-2-methyl-piperazin-1-yl]- propyl}-3-O-descladinosyl-3-oxo-8a-aza-8a-homoerythromycin A (Example 29a + Example 29b)

3.9 mg; FAB-MS m/z 936 (MH⁺)

EXAMPLE 30

6-O-[2"-(Syn,anf/>oxy-3"-isobutylamino-propyl]-3-O-descladinosyl-3-oxo-8a-aza-8a- homoerythromycin A (Example 30a + Example 30b)

4.7 mg; FAB-MS m/z 718 (MH⁺)

EXAMPLE 31 6-O-{3"-[4-(3-Carboxy-7-chloro-1-cyclopropyl-4-oxo-1,4-dihydro-quinolin-6-yl)- piperazin-1-yl]-2"-(syn,anf/>oxy-propyl}-3-O-descladinosyl-3-oxo-8a-aza-8a- homoerythromycin A (Example 31a + Example 31b)

2.8 mg; FAB-MS m/z 992 (MH⁺)

EXAMPLE 32

6-O-{3"-[4-(3-Carboxy-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinolin-7-yl)- piperazin-1-yl]-2"-(syn,anf/>oxy-propyl}-3-O-descladinosyl-3-oxo-8a-aza-8a- homoerythromycin A (Example 32a + Example 32b)

4.6 mg; FAB-MS m/z 961 (MH⁺)

EXAMPLE 33

6-O-{3"-[4-(3-Carboxy-1-cyclopropyl-4-oxo-1,4-dihydro-quinolin-6-yl)-piperazin-1-yl]- 2"-(syn,anf/>oxy-propyl}-3-O-descladinosyl-3-oxo-8a-aza-8a-homoerythromycin A (Example 33a + Example 33b)

2.3 mg; FAB-MS m/z 958 (MH⁺) EXAMPLE 34

6-O-{3"-[2-(3-Carboxy-7-chloro-1-cyclopropyl-4-oxo-1,4-dihydro-quinolin-7- ylamino)-ethylamino]-2"-(syn,anf/>oxy-propyl}-3-O-descladinosyl-3-oxo-8a-aza-8a- homoerythromycin A (Example 34a + Example 34b)

3.6 mg; FAB-MS m/z 966 (MH⁺)

EXAMPLE 35

6-O-{3"-[2-(3-Carboxy-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinolin-7-ylamino)- ethylamino]-2"-(syn,anf/>oxy-propyl}-3-O-descladinosyl-3-oxo-8a-aza-8a- homoerythromycin A (Example 35a + Example 35b)

4.1 mg; FAB-MS m/z 950 (MH⁺)

EXAMPLE 36

3-O-Descladinosyl-3-oxo-6-O-[3-(3'-Quinolyl)-2-propenyl]-8a-aza-8a- homoerythromycin A

To a solution of S-O-decladinosyl-S-oxo-θ-O-allyl-δa-aza-δa-homoerythromycin A, compound of Example 8 (1.0 g, 1.59 mmoL), palladium(ll) acetate (67 mg, 0.30 mmoL), and tri(o-tolyl)phosphine (181 mg, 0.60 mmoL) in dry acetonitrile (7 ml_), 3-bromoquinoline (0.61 ml_, 4.47 mmoL) and triethylamine (0.83 ml_, 5.96 mmoL) were added, and the mixture was stirred under argon for 30 minutes. The reaction mixture was warmed up to 60⁰C for 2 h and stirred at 90⁰C for 20 h. The reaction mixture was taken up in ethyl acetate, washed twice with aqueous 5% sodium bicarbonate, once with aqueous 2% tris(hydroxymethyl)aminomethane, and once with brine, dried over sodium sulfate, filtered and concentrated. The crude mixture was purified by flash column chromatography on silica-gel (95:5:0.5 CH2CI2/MeOH/aq. NH3) to give the title compound (736 mg, 61 %) as an off-white solid: FAB-MS m/z 756 (MH⁺, 89%).

EXAMPLE 37

3-O-Descladinosyl-3-oxo-6-O-[3-(4'-Quinolyl)-2-propenyl]-8a-aza-8a- homoerythromycin A

Starting from S-O-decladinosyl-S-oxo-θ-O-allyl-δa-aza-δa-homoerythromycin A, compound of Example 8 and 4-chloroquinoline using the procedure of Example 36 the title compound (105 mg, 75%) was obtained as a white solid: FAB-MS m/z 756 (MH⁺, 89%).

EXAMPLE 38

3-O-Descladinosyl-3-oxo-6-O-[3-(1'-naphtyl)-2-propenyl]-8a-aza-8a- homoerythromycin A

Starting from S-O-decladinosyl-S-oxo-θ-O-allyl-δa-aza-δa-homoerythromycin A, compound of Example 8 and 1-iodonaphthalene using the procedure of Example 36 the title compound (85.6 mg, 60%) was obtained as a white solid: FAB-MS m/z 755 (MH⁺, 89%).

EXAMPLE 39

3-O-Descladinosyl-3-oxo-6-O-[3-(3'-quinolyl)-2-propenyl]-9a-aza-9a- homoerythromycin A

Starting from S-O-decladinosyl-S-oxo-θ-O-allyl-θa-aza-θa-homoerythromycin A, compound of Example 7 and 3-bromoquinoline using the procedure of Example 36 the title compound (78 mg, 58%) was obtained as a white solid: FAB-MS m/z 756 (MH⁺, 92%).

EXAMPLE 40

3-O-Descladinosyl-3-oxo-6-O-[3-(4'-quinolyl)-2-propenyl]-9a-aza-9a- homoerythromycin A

Starting from S-O-decladinosyl-S-oxo-θ-O-allyl-θa-aza-θa-homoerythromycin A, compound of Example 7 and 4-chloroquinoline using the procedure of Example 36 the title compound (54 mg, 63%) was obtained as a white solid: FAB-MS m/z 756 (MH⁺, 56%).

EXAMPLE 41

S-O-Descladinosyl-S-oxo-θ-O-tS-O'-naphtylJ^-propenylJ-θa-aza-θa- homoerythromycin A

Starting from S-O-decladinosyl-S-oxo-θ-O-allyl-θa-aza-θa-homoerythromycin A, compound of Example 7 and 1-iodonaphthalene using the procedure of Example 36 the title compound (105 mg, 89%) was obtained as a white solid: FAB-MS m/z 755 (MH⁺, 48%).

EXAMPLE 42

3'-N-Oxide-6-O-Syn-(2"-methyloxiranyl)-8a-aza-8a-homoerythromycin A (Example 42a); and

3'-N-oxide-6-O-Λnf/-(2"-methyloxiranyl)-8a-aza-8a-homoerythromycin A (Example 42b)

Starting from θ-O-allyl-δa-aza-δa-homoerythromycin A, compound of Example 2 using the procedures of Example 9 the title compounds (65%) were obtained as a white solids in ratio 1 :1 according to LC/MS analysis: FAB-MS m/z 821 (MH⁺, 43%).

EXAMPLE 43

6-O-Syn-(2"-methyloxiranyl)-8a-aza-8a-homoerythromycin A (Example 43a); and 6-O-Λnf/-(2"-methyloxiranyl)-8a-aza-8a-homoerythromycin A (Example 43b)

Starting from mixture of 3'-N-oxide-6-O-syn-(2"-methyloxiranyl)-8a-aza-8a- homoerythromycin A (Example 42a) and 3'-N-oxide-6-O-anf/-(2"-methyloxiranyl)-8a- aza-8a-homoerythromycin A (Example 42b) using the procedure of Example 10 the title compounds (73%) were obtained as a white solids in ratio 1 :1 according to LC/MS analysis: FAB-MS m/z 805 (MH⁺, 67%).

EXAMPLE 44

6-O-[2"-(Syn,anf/)-oxy-3"-(2-phenyl-ethylamino)-propyl]-8a-aza-8a- homoerythromycin A (Example 44a + Example 44b)

A mixture of 6-O-syn-, Example 43a and 6-O-anf/-(2"-methyloxiranyl), Example 43b compounds (804 mg, 1.0 mmoL), obtained according to the procedure of Example 43, LiCIO₄3H₂O (802.2 mg, 5.0 mmoL, 5.0 mol. equiv.), and amine a (Chart 1 , 5.0 mmoL, 5.0 mol. equiv.) in 2-propanol (2.5 mL) was heated at reflux for 24 hours. Upon completion of the reaction, the solution was cooled to room temperature, and CH₂CI₂ (25 mL) was added. The organic layer was washed with water (2 x 25 mL), dried, and concentrated in vacuo. The residual solid was purified by chromatography on silica gel using CH₂CI₂/methanol/aq. NH₃ (90:9:1.5) as eluent to give a mixture of diastereisomeric β- amino alcohols 6-O-[2"-(Syn,anf/)-oxy-3"-(2-phenyl-ethylamino)-propyl]-8a-aza-8a- homoerythromycin A (Example 44a + Example 44b) (63% isolated yield) in ratio 1 :1 according to LC/MS analysis. FAB-MS m/z 926 (MH⁺, 65%).

The following Examples 45 to 68 were prepared starting from mixture of 6-O-syn-, Example 43a and 6-O-anf/-(2"-methyloxiranyl), Example 43b compounds and 5 molar equivalents of amines b-x (Chart 1 ), according to the procedure of Example 44.

EXAMPLE 45

6-O-[2"-(Syn,anf/>oxy-3"-(3-phenyl-propylamino)-propyl]-8a-aza-8a- homoerythromycin A (Example 45a + Example 45b)

5.8 mg; FAB-MS m/z 940 (MH⁺, 58%)

EXAMPLE 46

6-O-[2"-(Syn,anf/>oxy-3"-(4-phenyl-butylamino)-propyl]-8a-aza-8a- homoerythromycin A (Example 46a + Example 46b)

8.1 mg; FAB-MS m/z 954 (MH⁺, 91%)

EXAMPLE 47 6-O-{2"-(Syn,anf/>oxy-3"-[2-(4-methoxy-phenyl)-1 -methyl-ethylamino]-propyl}-8a- aza-8a-homoerythromycin A (Example 47a + Example 47b)

3.8 mg; FAB-MS m/z 970 (MH⁺)

EXAMPLE 48

6-O-{2"-(Syn,anf/>oxy-3"-[methyl-(2-(4-nitro-phenyl)-ethyl)-amino]-propyl}-8a-aza- 8a-homoerythromycin A (Example 48a + Example 48b)

5.1 mg; FAB-MS m/z 987 (MH⁺)

EXAMPLE 49

6-O-{2"-(Syn,anf/>oxy-3"-[1-methyl-2-(4-nitro-phenyl)-ethylamino]-propyl}-8a-aza- 8a-homoerythromycin A (Example 49a + Example 49b)

9.5 mg; FAB-MS m/z 987 (MH⁺)

EXAMPLE 50

6-O-[2"-(Syn,anf/>oxy-3"-(2-pyridin-3-yl-ethylamino)-propyl]-8a-aza-8a- homoerythromycin A (Example 50a + Example 50b)

6.9 mg; FAB-MS m/z 927 (MH⁺)

EXAMPLE 51

6-O-{2"-(Syn,anf/>oxy-3"-[(pyridin-2-ylmethyl)-amino]-propyl}-8a-aza-8a- homoerythromycin A (Example 51a + Example 51 b)

3.8 mg; FAB-MS m/z 913 (MH⁺)

EXAMPLE 52

6-O-{2"-(Syn,anf/>oxy-3"-[2-(1 H-indol-3-yl)-ethylamino]-propyl}-8a-aza-8a- homoerythromycin A (Exam

7.7 mg; FAB-MS m/z 965 (MH⁺)

EXAMPLE 53

6-O-[2"-(Syn,anf/>oxy-3"-(2-pyridin-2-yl-ethylamino)-propyl]-8a-aza-8a- homoerythromycin A (Example 53a + Example 53b)

5.8 mg; FAB-MS m/z 927 (MH⁺)

EXAMPLE 54

6-O-{2"-(Syn,anf/>oxy-3"-[(pyridin-3-ylmethyl)-amino]-propyl}-8a-aza-8a- homoerythromycin A (Example 54a + Example 54b)

2.9 mg; FAB-MS m/z 913 (MH⁺)

EXAMPLE 55

6-O-{3"-[4-(4-fluoro-phenyl)-piperazin-1-yl]-2"-(syn,anf/>oxy-propyl}-8a-aza-8a- homoerythromycin A (Example 55a + Example 55b)

7.8 mg; FAB-MS m/z 985 (MH⁺)

EXAMPLE 56

6-O-{2"-(Syn,anf/>oxy-3"-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-propyl}-8a- aza-8a-homoerythromycin A (Example 56a + Example 56b)

5.9 mg; FAB-MS m/z 1035 (MH⁺)

EXAMPLE 57

6-O-{2"-(Syn,anf/>oxy-3"-[4-(4-nitro-phenyl)-piperazin-1-yl]-propyl}-8a-aza-8a- homoerythromycin A (Example 57a + Example 57b)

3.8 mg; FAB-MS m/z 1014 (MH⁺)

EXAMPLE 58

6-O-{3"-[4-(4-acetyl-phenyl)-piperazin-1-yl]-2"-(syn,anf/>oxy-propyl}-8a-aza-8a- homoerythromycin A (Example 58a + Example 58b)

9.0 mg; FAB-MS m/z 1009 (MH⁺, 86%)

EXAMPLE 59

6-O-{3"-[4-(2-Ethoxy-phenyl)-piperazin-1-yl]-2"-(syn,anf/)-oxy-propyl}-8a-aza-8a- homoerythromycin A (Example 59a + Example 59b)

7.1 mg; FAB-MS m/z 101 1 (MH⁺, 94%)

EXAMPLE 60

6-O-[2"-(Syn,anf/>oxy-3"-(quinolin-6-ylamino)-propyl]-8a-aza-8a-homoerythromycin A (Example 60a + Example 60b)

11.5 mg; FAB-MS m/z 949 (MH⁺)

EXAMPLE 61

6-O-[2"-(Syn,anf/>oxy-3"-(quinolin-3-ylamino)-propyl]-8a-aza-8a-homoerythromycin A (Example 61 a + Example 61 b)

8.7 mg; FAB-MS m/z 949 (MH⁺) EXAMPLE 62

6-O-{2"-(Syn,anf/>oxy-3"-[4-(isoquinoline-7-sulfonyl)-2-methyl-piperazin-1-yl]- propyl}-8a-aza-8a-homoerythromycin A (Example 62a + Example 62b)

12.1 mg; FAB-MS m/z 1096 (MH⁺)

EXAMPLE 63

6-O-[2"-(Syn,anf/>oxy-3"-isobutylamino-propyl]-8a-aza-8a-homoerythromycin A (Example 63a + Example 63b)

CH,

6.2 mg; FAB-MS m/z 878 (MH⁺)

EXAMPLE 64

6-O-{3"-[4-(3-Carboxy-7-chloro-1-cyclopropyl-4-oxo-1,4-dihydro-quinolin-6-yl)- piperazin-1 -yl]-2"-(syn,anf/>oxy-propyl}-8a-aza-8a-homoerythromycin A (Example 64a + Example 64b)

4.3 mg; FAB-MS m/z 1152 (MH⁺) EXAMPLE 65

6-O-{3"-[4-(3-Carboxy-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinolin-7-yl)- piperazin-1 -yl]-2"-(syn,anf/>oxy-propyl}-8a-aza-8a-homoerythromycin A (Example 65a + Example 65b)

3.9 mg; FAB-MS m/z 1121 (MH⁺)

EXAMPLE 66

6-O-{3"-[4-(3-Carboxy-1-cyclopropyl-4-oxo-1,4-dihydro-quinolin-6-yl)-piperazin-1-yl]- 2"-(syn,anf/>oxy-propyl}-8a-aza-8a-homoerythromycin A (Example 66a + Example

6.5 mg; FAB-MS m/z 1118 (MH⁺)

EXAMPLE 67

6-O-{3"-[2-(3-Carboxy-7-chloro-1-cyclopropyl-4-oxo-1,4-dihydro-quinolin-7- ylamino)-ethylamino]-2"-(syn,anf/>oxy-propyl}-8a-aza-8a-homoerythromycin A (Example 67a + Example 6

9.1 mg; FAB-MS m/z 1126 (MH⁺)

EXAMPLE 68

6-O-{3"-[2-(3-Carboxy-1 -cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinolin-7-ylamino)- ethylamino]-2"-(syn,anf/>oxy-propyl}-8a-aza-8a-homoerythromycin A (Example 68a + Example 68b)

12.5 mg; FAB-MS m/z 11 10 (MH⁺)

Biological Data

Using a standard broth dilution method in microtitre, compounds were tested for antibacterial activity (i.e. MICs were determined by the Clinical and Laboratory Standards Institute standards). The compounds in the above examples gave minimum inhibitory concentrations (MICs) less than 1 microgram per millilitre against erythromycin-sensitive and erythromycin-resistant strains of Streptococcus pneumoniae and/or Streptococcus pyogenes.

However, it will appreciated by person skilled in the art that compounds of the invention may have different levels of activity against different strains of the same bacteria.

Throughout the specification and the claims which follow, unless the context requires otherwise, the word 'comprise', and variations such as 'comprises' and 'comprising', will be understood to imply the inclusion of a stated integer or step or group of integers but not to the exclusion of any other integer or step or group of integers or steps.

The application of which this description and claims forms part may be used as a basis for priority in respect of any subsequent application. The claims of such subsequent application may be directed to any feature or combination of features described herein. They may take the form of product, composition, process, or use claims and may include, by way of example and without limitation, the following claims:

Claims

1. Compound of formula (I)

(I)

wherein

A represents NH; and B simultaneously represents -C(O)- , or A represents -C(O)- and B simultaneously represents NH; R¹ represents OH , L-cladinosyl group of formula (II)

("I) or together with R² represents =0 R² represents hydrogen or together with R¹ represents =0, R³ represents hydrogen or C₁-C₃ alkanoyl group, R⁴ represents:

(d) a straight or branched chain C₃-C₇ alkyl group containing a moiety selected from piperazin-1 ,4-yl, 2-methyl-piperazin-1 ,4-yl, 2-methyl-piperazin-1 ,4-yl-S(O)₂, NH and N(CH₃), or containing two NH moieties; wherein the second alkyl carbon atom is substituted by a hydroxy substituent, and the terminal carbon atom or heteroatom is substituted by phenyl (itself optionally substituted by one substituent selected from methoxy, ethoxy, nitro, fluoro, trifluoromethyl, or C(O)CH₃,), pyridyl, quinolinyl, isoquinolinyl, 3-carboxy-1-cyclopropyl-4-oxo-1 ,4-dihydro-quinolinyl (itself optionally substituted in the 6 or 7 position by fluoro or chloro);

(e) prop-2-enyl (i.e. allyl) optionally substituted with one or more substituents selected from naphthyl or quinolinyl; or

(f) CH₂-oxiranyl group;

R⁵ represents (a) dimethylamino [-N(CH₃)₂] or (b) dimethylamino-N-oxide [-N(O)(CH₃)₂] group or a pharmaceutically acceptable salt or solvate thereof.

2. A process for the preparation compound of formula (I) as claimed in claim 1 , characterized in that 6-O-allylerythromycin A of the formula (III)

(III)

is subjected to

(a) reaction with hydroxylamine hydrochloride in the presence of appropriate inorganic or organic base yielding a mixture of 6-O-allylerythromycin A 9(E)- and 9(Z)-oximes of the formula (IV)

which, if appropriate, is subjected to separation on a silica gel column using the system methylene chloride/methanol/aq. NH₃ 90:9:1.5, yielding chromatographically homogeneous 6-O-allyl erythromycin A 9(E)-oxime of the formula (IVa)

and chromatographically homogeneous 6-O-allyl-erythromycin A 9(Z)-oxime of the formula (IVb)

and then to

(b) Beckmann rearrangement with p-toluenesulfonyl chloride, in the presence of sodium hydrogen carbonate in acetone-water solvent mixture yielding in the case of 6-0- allyl erythromycin A 9(E)-oxime of the formula (IVa) a compound of the formula (I), wherein A represents NH group, B represents C=O group, R¹ represents L-cladinosyl group of the formula (II), and R² and R³ both represent hydrogen, R⁴ represents a prop-2- enyl, and R⁵ represents dimethylamino, or in the case of 6-O-allyl erythromycin A 9(Z)- oxime of the formula (IVb) a compound of the formula (I), wherein A represents C=O group, B represents NH group, R¹ represents L-cladinosyl group of the formula (II), R² and R³ both represent hydrogen, R⁴ represents a prop-2-enyl, and R⁵ represents dimethylamino which are subsequently subjected to (c) hydrolysis with strong acids, preferably with 0.25-1.5 N hydrochloric acid, in a mixture of water and lower alcohols, preferably methanol, ethanol or isopropanol, over 10- 30 hours at room temperature, yielding 3-O-decladinosyl-3-oxy compounds of the general formula (I), wherein A represents NH group and B represents C=O group, or A represents C=O group and B represents NH group, R¹ represents OH group, R² and R³ both represent hydrogen, R⁴ represents a 2-prop-enyl group, and R⁵ represents dimethylamino, which are subsequently subjected to

(d) selective acylation of a hydroxyl group at C-2'-position with chlorides or anhydrides of carboxylic acids with up to 4 carbon atoms, in the presence of inorganic or organic bases selected from sodium hydrogen carbonate, sodium carbonate, potassium carbonate, triethyl amine, pyridine, and tributylamine, in a reaction-inert solvent, at a temperature from 0-30°C, yielding 2'-O-C_1-4acyl derivatives of the general formula (I), wherein A represents NH group and B represents C=O group, or A represents C=O group and B represents NH group, R¹ represents OH group, R² is hydrogen , R³ is Ci_-4acyl, R⁴ represents a 2-prop-enyl group, and R⁵ represents dimethylamino group, which are subsequently subjected to

(e) oxidation of a hydroxyl group at C-3 position of the aglycone ring according to a modified Pfitzner-Moffat oxidation with N,N-dimethyl aminopropyl-3-ethyl-carbodiimide in the presence of dimethyl sulfoxide and pyridinium trifluoroacetate as catalyst, in an inert organic solvent, at a temperature from 1 O⁰C to room temperature, yielding 3-oxo compounds of the general formula (I), wherein A represents NH group and B represents C=O group, or A represents C=O group and B represents NH group, R¹ together with R² represetns =0, R³ represents

group, R⁴ represents a 2-prop-enyl group, and R⁵ represents dimethylamino, which are subsequently subjected to (f) deprotection with lower alcohols, at a temperature from room temperature to the reflux temperature of the solvent, yielding a compound of the general formula (I), wherein A represents NH group and B represents C=O group, or A represents C=O group and B represents NH group, R¹ together with R² represent =0, R³ represents hydrogen, R⁴ represents a 2-prop-enyl group, and R⁵ represents dimethylamino, which are subsequently subjected to

(g1 ) epoxidation reaction with m-chloroperbenzoic acid in the presence of sodium acetate as a base in an inert organic solvent, at a temperature from O⁰C to room temperature, yielding 6-O-(2"methyloxiranyl)-3'-N-oxide compounds of the general formula (I), wherein A represents NH group and B represents C=O group, or A represents C=O group and B represents NH group, R¹ together with R² represent =0, R³ represents hydrogen, R⁴ represents CH₂-oxiranyl group, and R⁵ represents dimethylamino N-oxide group, which are subsequently subjected to reduction with zinc powder in the presence of ammonium chloride in a mixture of water and lower alcohols, over 3-5 hours at room temperature, yielding 6-O-(2"methyloxiranyl) compounds of the general formula (I), wherein A represents NH group and B represents C=O group, or A represents C=O group and B represents NH group, R¹ together with R² represent =0, R³ represents hydrogen, R⁴ represents CH₂-oxiranyl group, and R⁵ represents dimethylamino, which are subsequently subjected to nucleophilic ring opening with selected amines in the presence of lithium perchlorate in an inert organic solvent, at reflux temperature, yielding diastereoisomeric β-amino alcohol compounds of the general formula (I), wherein A represents NH group and B represents C=O group, or A represents C=O group and B represents NH group, R¹ together with R² represents =0, R³ represents hydrogen, R⁴ represents a straight or branched chain C₃-C₇ alkyl group containing a moiety selected from piperazin-1 ,4-yl, 2-methyl-piperazin-1 ,4-yl, 2-methyl-piperazin-1 ,4-yl-S(O)₂, NH and N(CH₃), or containing two NH moieties; wherein the second alkyl carbon atom is substituted by a hydroxy substituent, and the terminal carbon atom or heteroatom is substituted by phenyl (itself optionally substituted by one substituent selected from methoxy, ethoxy, nitro, fluoro, trifluoromethyl, or C(O)CH₃,), pyridyl, quinolinyl, isoquinolinyl, 3-carboxy-1-cyclopropyl-4-oxo-1 ,4-dihydro-quinolinyl (itself optionally substituted in the 6 or 7 position by fluoro or chloro), and R⁵ represents dimethylamino, or to (g2) Heck reaction with suitable naphthyl or quinolinyl halides, in the presence of a palladium catalyst, such as palladium(ll) acetate, tetrakis(triphenylphosphine)palladium(0), tris(dibenzylideneacetone)dipalladium(0) or the like, preferably palladium(ll) acetate, and a suitable phosphine ligand, such as triphenylphosphine, bis(diphenylphosphino)methane, 1 ,2-bis(diphenylphosphino)ethane, 1 ,3-bis(diphenylphosphino)propane, 1 ,4-bis(diphenylphosphino)butane, tri-o- tolylphosphine, or the like, preferably tri-o-tolylphosphine, in an aprotic solvent, such as tetrahydrofuran, N,N-dimethylformamide, dimethylsulfoxide, acetonitrile or the like, preferably acetonitrile, at from 4O⁰C to about 15O⁰C for 0.5 hour to about 48 hours, preferably at 9O⁰C for 5 hours, yielding 6-0-substituted alkenyl derivatives of the general formula (I), wherein A represents NH group and B represents C=O group, or A represents C=O group and B represents NH group, R¹ together with R² represents =0, R³ represents hydrogen, R⁴ represents a prop-2-enyl (i.e. allyl) optionally substituted with one or more substituents selected from naphthyl or quinolinyl, and R⁵ represents dimethylamino; (h) reaction with an at least equimolar amount of a suitable inorganic or organic acid, in a reaction-inert solvent, yielding a pharmaceutically acceptable addition salts of the general formula (I), wherein A, B, R¹, R², R³, R⁴, and R⁵ have the above-mentioned meanings, which are isolated by filtration if they are insoluble in the reaction-inert solvent, by precipitation by means of a non-solvent or by evaporation of the solvent, most frequently by lyophilization.

3. A pharmaceutical formulation comprising a compound of Formula (I) as claimed in claim 1 together with a pharmaceutically acceptable diluent or carrier.

4. A compound of Formula (I) as claimed in claim 1 for use as a medicament.

5. A compound of Formula (I) as claimed in claim 4 wherein the medicament is an antimicrobial agent.