WO2004108744A2

WO2004108744A2 - Azalides and azaketolides having antimicrobial activity

Info

Publication number: WO2004108744A2
Application number: PCT/IN2004/000137
Authority: WO
Inventors: Prasad K Deshpande; Milind D Sindkhedkar; Vijaya N Desai; Shrikant V Gupte; Ravindra D Yeole; Mahesh V Patel; Noel J De Souza
Original assignee: Prasad K Deshpande; Milind D Sindkhedkar; Vijaya N Desai; Shrikant V Gupte; Ravindra D Yeole; Mahesh V Patel; Noel J De Souza
Priority date: 2003-05-19
Filing date: 2004-05-18
Publication date: 2004-12-16
Also published as: WO2004108744A3

Abstract

The present invention relates to novel azalides and azaketolides having antimicrobial activity, methods for their preparation, pharmaceutical compositions containing the compounds and methods of treating microbial infections with the compounds.

Description

Azalides and Azaketolides Having Antimicrobial Activity

FIELD OF THE INVENTION

The present invention relates to novel azalides and azaketolides having antimicrobial activity, pharmaceutical compositions containing the compounds and methods of treating microbial infections with the compounds.

BACKGROUND OF THE INVENTION

Macrolides are a well-known family of antibacterial agents, the progenitor of which is erythromycin A discovered in 1952 from a soil sample collected in the Philippines.

Structurally modified second generation macrolide antibiotics developed to overcome some of the limitations of erythromycin A led to newer molecules, the three most clinically useful of which are roxithromycin, clarithromycin and azithromycin. Like erythromycin, clarithromycin is a 14-membered macrolide, but azithromycin is a 15- membered macrolide incorporating, as its name suggests, a nitrogen atom, which is at the position 10 in the 15-membered macrolide template. Azithromycin is thus commonly referred to as a 15-membered azalide antibiotic. Although, in comparison to erythromycin, both clarithromycin and azithromycin are reported to have enhanced antibacterial activity, improved pharmacokinetic properties, an expanded spectrum of activity and attenuated gastrointestinal side effects, they have poor activity against macrolide-resistant bacteria as does erythromycin A.

A third generation of macrolide antibiotics has recently been unveiled, referred to as the class of ketolides. Ketolides are a class of semisynthetic 14-membered ring macrolide derivatives, characterized by a keto function at position 3 of the macrolactone ring replacing the L-cladinose moiety present in the erythromycin, clarithromycin and azithromycin molecules. The most well-known representative of the ketoiide class is telithromycin.

Structural changes in ketolides are reported to render them significantly different from macrolides and azalides in being active against a number of erythromycin A -resistant Gram-positive cocci such as Streptococcus pneumoniae. They are, however, inactive against MLSβ-resistant Staphylococcus aureus.

As with other bacterial agents, bacterial pathogenic strains having resistance or insufficient susceptibility to erythromycin, clarithromycin, roxithromycin, azithromycin, telithromycin and generally to the classes of macrolides, azalides and ketolides have emerged over time and are identified in patients suffering from such ailments as community-acquired pneumonia, upper and lower respiratory tract infections, skin and soft tissue infections, meningitis, hospital-acquired lung infections and bone and joint infections. Particularly problematic pathogens include methicillin-resistant S. aureus (MRSA), vancomycin-resistant enterococci (VRE) and penicillin- and macrolide/azalide/ketolide- resistant S. pneumoniae. Therefore, the vanguard of development calls for therapies identifying newer macrolide, azalide, ketoiide compounds with antibacterial activity, and/or unanticipated selectivity against various target microorganisms, particularly erythromycin-, clarithromycin-, roxithromycin-, azithromycin-, and telithromycin-resistant strains.

The following references relate to various macrolide, azalide and ketoiide derivatives as having antibacterial activity.

United States patent US 4,331 ,803 discloses the 6-O-methyl derivative of erythromycin i.e. clarithromycin.

The patent US 4,349,545 discloses roxithromycin.

The azalide azithromycin is referred to in United States patent US 4,517,359. 13- membered and 14-membered azalides are described in United States patent US 5,215,980 and US 6,329,345.

The synthesis and antimicrobial activity of the ketoiide, telithromycin, is described in United States patent US 5,635,485.

The laid open PCT application WO 03/014136 A1 describes novel 11-a azalide compounds. Without admitting that the above cited patents and patent applications, with the possible exception in part of WO 03/014136, have a bearing on the present application, there remains a need in the art for readily available azalide, diazalide and azaketolide antimicrobial compounds which possess potent activity against a broad range of bacteria.

In particular, there is no previous report, to our knowledge of a prepared and characterised macrolide compound, which is the same as those to be found prepared and characterised in the present invention.

The novel 15 membered aza analogs of macrolides, azalides and ketolides, viz. the azalides and azaketolides of this invention possess superior potent, surprising and unexpected activity against various microbial infections as described herein.

SUMMARY OF THE INVENTION

The present invention relates to a novel class of compounds selected from the group consisting of compounds of Formula I wherein,

X is selected from the group consisting of 1 ) C=0,

2) CH(ORe),

3) CH(NR_bR_c),

4) C=NOR, wherein R is selected from the group consisting of a Hydrogen, b C-i-C-io alkyl, c substituted C^C-io alkyl, d C2-C-10 alkenyl, e substituted C2-C10 alkenyl, f C2-C-10 alkynyl, g substituted C2-C10 alkynyl, h (CH₂)_P-M-U-Q where p is an integer 1-6, M is -0-, -NH-, -C(0)-, U is linear or branched Ci to C₆ alkyl, aryl, heteroaryl or aryloxy; Q is hydrogen, C1 -C6 alkoxy, aryl, heteroaryl, aryloxy, NRbR_c- when U is linear or branched C-i to C₆ alkylene, Q is hydrogen, C1-C6 alkoxy, aryl, heteroaryl , aryloxy or NRbRc and when U is aryl, heteroaryl or aryloxy, Q is absent i CH2CH=CH-A, wherein A is selected from the group consisting of hydrogen ii aryl ii substituted aryl v heteroaryl v substituted heteroaryl vi hydroxy vii C1 -C6 alkoxy viii halogen (F, Cl, Br, I), ix cyano, x COORg, xi NR Rc, xii C(0)R_d

R1 = hydrogen, Cι-C₆ alkyl, substituted Cι_rC₆ alkyl, C₂-C₆ alkenyl, substituted C₂-C₆ alkenyl, C₂-C₆ alkynyl, substituted C₂-C₆ alkynyl, C(O)NRbRc, R2 = hydrogen or hydroxyl protecting group. R3 = hydrogen, d-C₆ alkyl, substituted C-ι-C₆ alkyl, C₂-C₆ alkenyl, substituted C -C₆ alkenyl, C₂-C₆ alkynyl, substituted C₂-C₆ alkynyl. R4 = hydrogen, fluorine, chlorine, bromine, methyl, wherein R_a, Rb, R_c, Rd, Re are independently selected from the group consisting of: 1. Hydrogen,

2. C1-C6 alkyl,

3. C2-C6 alkenyl,

4. C2-C6 alkynyl, 5. C3-C7 cycloalkyl,

6. heterocyclyl,

7. aryl,

8. heteroaryl,

9. aralkyl, 10.aralkenyl,

H .aralkynyl,

12. heteroaralkyl,

13. aralkanoyl,

14. heteroaralkanoyl, 15.aroyl,

16. heteroaroyl,

17. substituted C1-C6 alkyl,

18. substituted C2-C6 alkenyl,

19. substituted C2-C6 alkynyl, 20. substituted C3-C7 cycloalkyl,

21. substituted heterocyclyl,

22. substituted aryl,

23. substituted heteroaryl,

24. substituted aralkyl, 25. substituted aralkenyl,

26. substituted aralkynyl,

27. substituted heteroaralkyl,

28. substituted aralkanoyl,

29, substituted heteroaralkanoyl, 30. substituted aroyl,

31. substituted heteroaroyl; R_f is selected from the group consisting of

1 ) hydrogen,

2) C-1-C1₀ alkyl group, C₂-Cι₀ alkenyl, C₂-C₁₀ alkynyl, optionally substituted C_rCιo alkyl group, optionally substituted C₂-C-io alkenyl, optionally substituted C2-C1₀ alkynyl, the substituents are selected from the group consisting of a. halogen (F, Cl, Br, I), b. cyano, c. COOR_a, d. NR Rc, e. C(0)R , f. OR_e 3) aryl,

4) substituted aryl,

5) heteroaryl,

6) substituted heteroaryl,

7) aralkyl, 8) substituted aralkyl,

9) aralkenyl,

10)substituted aralkenyl,

1 1 )aralkynyl,

12)substituted aralkynyl, 13)heteroaralkyl,

14)substituted heteroaralkyl,

15)aralkanoyl,

16)substituted aralkanoyl,

17)heteroaralkanoyl, 18)substituted heteroaralkanoyl,

19)aroyl,

20)substituted aroyl,

21)heteroaroyl,

22)substituted heteroaroyl, 23)C₃-C₇ cycloalkyl

24)Substituted cycloalkyl,

25) heterocyclyl

26)substituted heterocyclyl

27)cyano, 28)COOR_a

29)NR_bR_c,

30)C(O)R_d

31)C(=NO)R_d

32)C(0)NR Rc

33)OR_e wherein R_a, Rb, R_c, d, R_e are as defined above.

z and z' together with the carbon to which they are attached form C=0 or z' is hydrogen and z is hydroxyl or OR_g wherein R_g is selected from the group consisting of

1 )

(which is designated as cladinose when R₂' is hydrogen) wherein R₂' is defined as . hydrogen, i. hydroxyl protecting group, ii. C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl chain optionally substituted with one more substituents selected from the group consisting of hydroxy, cyano, halogen, COOR_a, NR Rc, C(0)Rd iv. C(0)NR_bR_c, v.

where n is an integer 1-6.

2) -C(0)R_d,

3) -C(0)NR_bR_c, wherein R_b, R_c, R have the same definitions as above, or an optical isomer, enantiomer, diastereomer, racemate or racemic mixture thereof, or pharmaceutically acceptable salts, esters or prodrugs thereof. Compounds of the above formula are useful as antimicrobial agents for the treatment of microbial infections in a subject such as human and animal.

The present invention is also directed to a method of treating a subject having a condition caused by or contributed to by microbial infection, which comprises administering to the said subject a therapeutically effective amount of a compounds of Formula I.

The present invention is also directed to a method for preventing a microbial infection which comprises administering to a subject at risk for developing a microbial infection a prophylactically effective amount of a compound of Formula I.

The present invention is further directed to a method of preventing a subject from suffering from a condition caused by or contributed to by microbial infection, which comprises administering to the subject a prophylactically effective amount of the compounds of Formula I.

Other objects and advantages will become apparent to those skilled in the art from a review of the ensuing specification.

DETAILED DESCRIPTION OF TERMS

Relative to the above description, certain definitions apply as follows:

Definitions

Examples of Cι-C₁₀ alkyl, are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, and their branched isomers such as isobutyl, tert-butyl. The term "C₂-Cι₀ alkenyl" refers to straight or branched-chain hydrocarbon radicals comprising two to ten carbon atoms, respectively, which contain one or more carbon-carbon double bonds. The term "C₂-Cιo alkynyl" refers to straight or branched chain hydrocarbon radicals comprising two to ten carbon atoms respectively, which contain one or more carbon- carbon triple bonds. The substituted C₁-C1₀ alkyl, substituted C2-C10 alkenyl, C2-C10 substituted alkynyl is defined as the respective alkyl, alkenyl, alkynyl substituted, by independent replacement of one or two or three of the hydrogen atoms thereon with Cl, Br, F, I, N0₂, CN, OH, haloalkyl, C1-C6 alkoxy, C1-C6 thioalkoxy, amino, alkylamino, dialkylamino, mercapto, formyl, carboxy, alkoxycarbonyl and carboxamide (C(O)NR'R").

Examples of alkylene groups of U are methylene (-CH₂-), ethylene (-CH₂CH₂-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-) or their branched isomers.

Examples of C1-C6 alkoxy are methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy, pentyloxy, hexyloxy.

The term "aryl" refers to a mono or bicyclic carbocyclic ring system having one or two aromatic ring including but not limited to phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl and the like.

The term "heteroaryl" refers to five or six membered aromatic ring with at least one carbon atom replaced by an atom selected from the group of N, O, S. The ring may be connected to the remaining part of the molecule via any of the ring atoms. For example pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, thienyl, triazolyl, triazinyl, furanyl, N-oxo- pyridyl, and the like. It includes the fused biaryl systems such as indolyl, quinolinyl, isoquinolinyl, benzothiazolyl, benzoxazolyl, benzothienyl, N-oxo-quinolyl, benzimidazolyl, benzopyranyl, benzoisothiazolyl, benzodiazinyl, benzofurazanyl, indazolyl, indolizinyl, benzofuryl, quinoxalinyl, pyrrolopyridinyl, furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3,2-b]pyridinyl, furo[2,3-b]pyridinyl), naphthyridinyl, phthalazinyl, pyridopyridyl, quinazolinyl, thienofuryl, thienopyridyl, thienotheinyl, purinyl (such as 9H- purin-1-yl, 6-amino-9H-purin-9-yl), pyridinyl-1 H-pyrazol-1-yl and the like. It also includes the fused or branched biaryl systems such as phenyl-imidazolyl, pyridyl-imidazolyl, pyridyl-thiazolyl, pyridinyl-triazolyl, pyridyl-isoxazolyl and the like.

The "aralkyl" is defined as an alkyl group substituted with an aryl group for example benzyl, benzhydryl, trityl, wherein the aryl group may be optionally substituted as defined below. The "heteroaralkyl" is defined as an alkyl group substituted with an heteroaryl group for example pyridyl methyl wherein the heteroaryl group may be optionally substituted as defined below.

The "aroyl" group refers to a carbonyl group attached to an aryl group for example benzoyl, wherein the aryl group may be optionally substituted as defined below.

The "heteroaroyl" is defined as a carbonyl group attached to an heteroaryl group for example pyridyl carbonyl, wherein the heteroaryl group may be optionally substituted as defined below.

The "aralkanoyl" refers a carbonyl group attached to an aralkyl group for example phenylacetyl,

The "heteroaralkanoyl" refers a carbonyl group attached to an heteroaralkyl group for example pyridylylacetyl,

The aryl or the heteroaryl group can be optionally substituted with one, two, or three substituents independently selected from lower alkyl such as Ci-Cβ, substituted lower alkyl such as C-ι-C₆ alkyl, cyano, hydroxy, halogen, amino, formyl, carboxy, carboxamide, C1-C6 alkoxy, C1-C6 thioalkoxy, amino, alkylamino, dialkylamino, mercapto, nitro, carboxy, aikoxycarbonyl and aminocarbonyl.

The cycloalkyl refers to 3-7 membered cyclic structures for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl.

The heterocyclyl refers to 3-7 membered cyclic structures including (one or more heteroatoms such as N, O, S or can be defined as up to 4 heteroatoms selected from N, O, S. Examples of heterocyclyls are oxetanyl (oxetane is a four membered ring with an oxygen in the ring oxetanyl is a substituted oxetane). pyrrolidinyl, pyrazolinyl, imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, isoxazolinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2- oxopiperidinyl, 2-oxopyrrolidinyl, 4-oxopiperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, 1 ,3-dioxolane and the like.)

The "hydroxyl protecting group" as used herein refers to an easily removable group which is known in the art to protect a hydroxyl group against undesirable reaction during synthetic procedures and to be selectively removable. The use of hydroxy-protecting groups against undesirable reactions during a synthesis procedure and any such protecting groups are known cf., for example, T. H. Greene and P.G. M. Wuts, Protective Groups in Organic Synthesis, 2^nd edition, John Wiley & sons, New York (1991). Examples of hydroxyl protecting groups include but are not limited to acetyl, benzoyl, methoxymethyl, methoxyethoxymethyl, benzyl, trimethylsilyl, tertbutyldimethylsilyl and the like.

The terms "halo", "halide" and "halogen" as used herein refer to an atom selected from fluorine, chlorine, bromine and iodine. The term "formyl" as used herein refers to a group of formula -CHO. The term "sulphonyl" refers to a group of formula

O

II

— s —

O

The term "carboxamide" as used herein refers to a group of formula -C(0)NR'R" wherein R' and R" are independently selected from hydrogen or C1-C6 alkyl or R' and R" taken together may optionally be -(CH₂)_t- where "t" is an integer from 2-6.

The term "ester" or "alkoxycarbonyl" refers to an C1-C6 alkoxy group attached to the parent molecular moiety through a carbonyl group such as methoxycarbonyl (COOMe), ethoxycarbonyl (C0₂Et), and the like.

The terms "Me", "Et", "Ph", "allyl" stands for methyl, ethyl, phenyl and CH₂CH=CH₂ respectively. "MEM" stands for methoxyethoxymethyl.

The phrase "pharmaceutically acceptable salts" as used herein refers to one or more salts of the free base of the invention which possess the desired pharmacological activity of the free base and which are neither biologically nor otherwise undesirable.

These salts may be obtained from inorganic or organic acids. Examples of inorganic acids are hydrochloric acid, nitric acid, hydrobromic acid, sulphuric acid or phosphoric acid. Examples of organic acids are acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulphonic acid, p- toluene sulphonic acid, salicyclic acid and the like.

Also included are the salts with various amino acids such as alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, praline, serine, threonine, tryptophan, tyrosine or valine or the optically active isomers thereof or the racemic mixtures thereof or dipeptides, tripeptides and polypeptides derived from the monoaminoacid units thereof.

The phrase "pharmaceutically acceptable salts" as used herein also refers to one or more salts of the free acid of the invention which possess the desired pharmacological activity of the free acid and which are neither biologically nor otherwise undesirable.

These suitable salts are furthermore those of the inorganic or organic bases. Inorganic bases such as KOH, NaOH, Ca(OH)₂, AI(OH)₃. The organic base salts from basic amines such as ethylamine, triethylamine, diethanolamine, ethylenediamine, guanidine or heterocyclic amines such as piperidine, hydroxyethylpyrrolidine, hydroxyethylpiperidine, morpholine, piperazine, N-methyl piperazine and the like or basic amino acids such as optically pure and racemic isomers of arginine, lysine, histidine, tryptophan and the like.

Some of the compounds of the present invention may have trans and cis isomers and geometric E- and Z- isomers. Also some of the compounds according to this invention may exist as diastereomers. In addition, where the process for the preparation of the compounds according to the invention give rise to mixture of stereoisomers, these isomers, may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared as a single stereoisomer or in racemic form as a mixture of some possible stereoisomer.

Furthermore, some of the crystalline forms for the compounds may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds may form solvates with water (i.e. hydrates) which contains various amounts of water, for instance the hydrate, hemihydrate and sesquihydrate forms. Also the compound can form solvates with common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention.

The present invention also includes within its scope prodrugs of the compounds of this invention. In general, such prodrugs will be functional derivatives of the compounds which are readily convertible in vivo into the required compound. Thus, in the methods of the treatment of the present invention, the term "administrating shall incompass the treatment of the various disorders described with the compound specifically disclosed, or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration of the compound to the patient. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example in "Design of Prodrugs", Ed. H. Bundgaard, Elseiver, 1985.

The present invention encompasses certain compounds, dosage forms, and methods of administering the compounds to a human or other animal subject. Specific compounds and compositions to be used in the invention must, accordingly, be pharmaceutically acceptable. As used herein, such a "pharmaceutically acceptable" component is one that is suitable for use with humans and / or animals without undue adverse side effects (such as toxicity, irritation, and allergic response) commensurate with a reasonable benefit/risk ratio.

The pharmaceutical compositions are prepared according to conventional procedures used by persons skilled in the art to make stable and effective compositions. In the solid, liquid, parenteral and topical dosage forms, an effective amount of the active compound or the active ingredient is any amount, which produces the desired results.

For the purpose of this invention the pharmaceutical compositions may contain the active compounds of the invention, their derivatives, salts and hydrates thereof, in a form to be administered alone, but generally in a form to be administered in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice. Suitable carriers which can be used are, for example, diluents or excipients such as fillers, extenders, binders, emollients, wetting agents, disintegrants, surface active agents and lubricants which are usually employed to prepare such drugs depending on the type of dosage form.

Any suitable route of administration may be employed for providing the patient with an effective dosage of the compound of the invention their derivatives, salts and hydrates thereof. For example, oral, rectal, parenteral (subcutaneous, intramuscular, intravenous), transdermal, topical and like forms of administration may be employed. Dosage forms include (solutions, suspensions, etc) tablets, pills, powders, troches, dispersions, suspensions, emulsions, solutions, capsules, injectable preparations, patches, ointments, creams, lotions, shampoos and the like.

The prophylactic or therapeutic dose of the compounds of the invention, their derivatives, salts or hydrates thereof, in the acute or chronic management of disease will vary with the severity of condition to be treated, and the route of administration. In addition, the dose, and perhaps the dose frequency, will also vary according to the age, body weight and response of the individual patient. In general, the total daily dose range, for the compounds of the invention, the derivatives, salts or hydrates thereof, for the conditions described herein, is from about 200 mg to about 1500 mg, in single or divided doses. Preferably, a daily dose range should be between about 400 mg to 1200 mg, in single or divided dosage, while most preferably a daily dose range should be between about 500 mg to about 1000 mg in divided dosage. While intramuscular administration may be a single dose or up to 3 divided doses, intravenous administration can include a continuous drip. It may be necessary to use dosages outside these ranges in some cases as will be apparent to those skilled in the art. Further, it is noted that the clinician or treating physician will know how and when to interrupt, adjust, or terminate therapy in conjunction with individual patient's response. The term "an amount sufficient to eradicate such infections but insufficient to cause undue side effects" is encompassed by the above - described dosage amount and dose frequency schedule.

Pharmaceutical compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets, or tablets, or aerosol sprays, each containing a predetermined amount of the active ingredient, as a powder or granules, or as a solution or a suspension in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion. Such compositions may be prepared by any of the methods of pharmacy, but all methods include the step of bringing into association the active ingredient with the carrier, which constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation.

The compositions of the present invention include compositions such as suspensions, solutions, elixirs, aerosols, and solid dosage forms. Carriers as described in general above are commonly used in the case of oral solid preparations (such as powders, capsules and tablets), with the oral solid preparations being preferred over the oral liquid preparations. The most preferred oral solid preparation is tablets.

Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are employed. Examples of suitable carriers include excipients such as lactose, white sugar, sodium chloride, glucose solution, urea, starch, calcium carbonate, kaolin, crystalline cellulose and silicic acid, binders such as water, ethanol, propanol, simple syrup, glucose, starch solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose, potassium phosphate and polyvinyl pyrrolidone, disintegrants such as dried starch, sodium alginate, agar powder, laminaria powder, sodium hydrogen carbonate, calcium carbonate, Tween (fatty acid ester of polyoxyethylenesorbitan), sodium lauryl sulfate, stearic acid monoglyceride, starch, and lactose, disintegration inhibitors such as white sugar, stearic acid glyceryl ester, cacao butter and hydrogenated oils, absorption promoters such as quaternary ammonium bases and sodium lauryl sulfate, humectants such as glycerol and starch, absorbents such as starch, lactose, kaolin, bentonite and colloidal silicic acid, and lubricants such as purified talc, stearic acid salts, boric acid powder, polyethylene glycol and solid polyethylene glycol.

The tablet, if desired, can be coated, and made into sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets, or tablets comprising two or more layers. If desired, tablets may be coated by standard aqueous or non-aqueous techniques. In molding the pharmaceutical composition into pills, a wide variety of conventional carriers known in the art can be used. Examples of suitable carriers are excipients such as glucose, lactose, starch, cacao butter, hardened vegetable oils, kaolin and talc, binders such as gum arabic powder, tragacanth powder, gelatin, and ethanol, and disintegrants such as laminaria and agar.

In molding the pharmaceutical composition into a suppository form, a wide variety of carriers known in the art can be used. Examples of suitable carriers include polyethylene glycol, cacao butter, higher alcohols, gelatin, and semi-synthetic glycerides.

In one embodiment of the present invention are azalides and azaketolides having the Formula I and isomers thereof.

* mixture of isomers

** isomer separated by HPLC

Specific Compounds of the Invention

1. 9-0-Allyloxyimino-11 ,12-dideoxy-11a-aza-1 la-homoerythromycin (mixture of isomers);

2. 9-0-Allyloxyimino-11 ,12-dideoxy-11a-aza-1 la-homoerythromycin (isomer A)

3. 9-0-Allyloxyimino-11 ,12-dideoxy-11a-aza-1 la-homoerythromycin (isomer B)

4. 9-0-Allyloxyimino-11 ,12-dideoxy-11a-aza-1 la-homoerythromycin (isomer C) 5. 9-0-Allyloxyimino-11 ,12-dideoxy-11a-methyl-11a-aza-1 la-homoerythromycin (mixture of isomers);

6. 9-0-Allyloxyimino-11 ,12-dideoxy-6-0-methyl-11a-aza-1 la-homoerythromycin (mixture of isomers); 7. 9-0-Allyloxyimino-11 ,12-dideoxy-6-0-methyl-11 a-N-methyl-11 a-aza-11 a- homoerythromycin (mixture of isomers);

8. 9-0-[3-(Quinolin-3-yl)-prop-2-en-1-yl]-oxyimino-11 ,12-dideoxy-11 a-aza-1 la- homoerythromycin (mixture of isomers);

9. 9-0-Methoxyethoxymethyloxyimino-1 1 ,12-dideoxy-1 1 a-aza-11 a-homoerythromycin (mixture of isomers);

10.9-O-Hydroxyimino-11 ,12-dideoxy-6-0-methyl-1 1 a-aza-1 la-homoerythromycin (mixture of isomers);

11.9-0-Methoxyethoxymethyloxyimino-1 1 ,12-d id eoxy-1 1 a-methyl-11 a-aza-1 l a- homoerythromycin (mixture of isomers); 12.9-0-Allyloxyimino-1 1 ,12-dideoxy-11 a-(3-phenylprop-1 -yl)- 1 1 a-aza-11 a- homoerythromycin (mixture of isomers);

13.9-0-Allyloxyimino-11 ,12-dideoxy-11 a-N-benzoyl-11 a-aza-1 l a-homoerythromycin (mixture of three isomers);

14.9-0-Allyloxyimino-11 ,12-dideoxy-11 a-N-benzoyl-1 1 a-aza-1 1 a-homoerythromycin (mixture of two isomers);

15.9-0-Allyloxyimino-11 ,12-dideoxy-6-0-methyl-11 a-N-benzoyl-11 a-aza-1 la- homoerythromycin (mixture of isomers);

16.9-0-Allyloxyimino-11 , 12-dideoxy-2'-0-benzoyl-6-0-methyl-11 a-N-benzoyl-11 a-aza-

I la-homoerythromycin (mixture of isomers); 17.9-0-[3-(Quinolin-3-yl)-prop-2-en-1-yl]-oxyimino-11 ,12-dideoxy-6-0-methyl-11a-aza-

I I a-homoerythromycin (mixture of isomers);

18.9-0-[3-(3-Methoxyphenyl)-prop-2-en-1-yl]-oxyimino-11 ,12-dideoxy-6-0-methyl-11a- aza-1 la-homoerythromycin (mixture of isomers);

19.9-0-Hydroxyimino-11 ,12-dideoxy-11 a-aza-1 la-homoerythromycin (mixture of isomers);

20.9-0-Hydroxyimino-11 ,12-dideoxy-11 a-(3-phenylprop-1 -yl)-(-1 1 a-aza-11 a- homoerythromycin (mixture of isomers);

21.9-0-Allyloxyimino-1 1 ,12-dideoxy-3-descladinosyl-3-0-(2-methyl-3-nitrobenzoyl)-11a- aza-1 la-homoerythromycin (mixture of isomers); 22.9-0-Allyloxyimino-11 ,12-dideoxy-3-descladinosyl-3-0-benzoyl-6-0-methyl~11a- benzoyl-11 a-aza-1 l a-homoerythromycin (mixture of isomers);

23.9-0-Allyloxyimino-11 ,12-dideoxy-3-descladinosyl-3-oxo-6-0-methyl-11a-N-methyl- 1 1 a-aza-1 la-homoerythromycin (mixture of isomers); 24.9-0-Allyloxyimino-11,12-dideoxy-3-descladinosyl-3-oxo-6-0-methyl-11 a-aza-1 la- homoerythromycin (mixture of isomers);

25.11 ,12-Dideoxy-6-0-methyl-11 a-aza-11 a-homoerythromycin (mixture of isomers);

26.11 ,12-Dideoxy-3-descladinosyl-6-0-methyl-11 a-aza-1 la-homoerythromycin (mixture of isomers);

27.11 ,12-Dideoxy-3-descladinosyl-2'-acetyl-6-0-methyl-11 a-aza-1 la- homoerythromycin (mixture of isomers);

28.11,12-Dideoxy-6-0-methyl-11 a-(3-phenylprop-1 -yl)-11 a-aza-11 a-homoerythromycin (mixture of isomers); 29.11 ,12-Dideoxy-3-descladinosyl-3-oxo-6-0-methyl-11 a-aza-1 la-homoerythromycin (mixture of isomers).

Particularly preferred compounds of the invention are:

9-0-Allyloxyimino-11 ,12-dideoxy-6-0-methyl-11 a-aza-11 a-homoerythromycin (mixture of isomers);

9-0-Hydroxyimino-11 ,12-dideoxy-6-0-methyl-11 a-aza-1 la-homoerythromycin (mixture of isomers);

9-0-Hydroxyimino-11 ,12-dideoxy-11a-(3-phenylprop-1-yl)-(-11 a-aza-1 la- homoerythromycin (mixture of isomers); 11 ,12-Dideoxy-6-0-methyl-11 a-aza-1 la-homoerythromycin (mixture of isomers);

In a further embodiment of the invention is a process for the preparation of azalides and azaketolides having formula I, wherein the variables have the previously defined meanings, the method comprising the process will be better understood in connection with the following synthetic Schemes 1 -6: The synthesis of the compounds of the invention can be broadly summarized as a. Synthesis of the novel azalides b. Further manipulations to generate the desired novel terminal compounds (substituted azalides) c. Synthesis of azaacylides d. Synthesis of the novel azaketolides. a) Synthesis of the novel azalides.

As depicted in the Scheme 1 , erythromycin A oxime or roxithromycin or clarithromycin oxime or clarithromycin or the 9-hydroxy and 9-amino derivatives of erythromycin and clarithromycin are used as the starting materials for the reactions. All the above starting materials are used with optionally protected hydroxyl and amino groups with a suitable protecting group familiar to those skilled in the art. Exemplary protecting groups are, but are not limited to silyl ethers such as trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, triisopropylsilyl. The groups include benzyl, allyl, acetyl, benzoyl, pivalolyl and the like. For the amino protection, benzyloxycarbonyl, acetyl, tert-butoxycarbonyl (henceforth BOC) and the like may be used. The suitable macrolide starting material, depicted by compound (la) in the Scheme 1 , is treated with an oxidative diol cleavage reagent for example, sodium metaperiodate or lead tetraacetate, in a suitable solvent such as chloroform, methylene chloride, benzene or toluene at temperatures ranging from -78 °C to +80 °C for 0.1 h to 24 h. Preferably the reaction is performed with lead tetra acetate in methylene chloride at 0 °C to 25 °C, for preferably 0.5 to 2 hr to afford the diol cleaved dicarbonyl compound (lb, wherein X, R1 , R2, R2', R3 have the same meaning as the respective compound la).

Scheme 1

The compound (lb) obtained from Scheme 1 , is dissolved in a polar protic solvent such as methanol or ethanol, preferably in methanol and treated with a source of ammonia such as ammonium acetate, ammonium formate or ammonia at room temperature for 0.5 to 24 h, preferably with ammonium acetate at 10 to 25 °C, for 4 h. The reaction mixture is further treated with a reducing agent such as sodium borohydride, sodium cyanoborohydride or Pd/C in presence of hydrogen gas or in presence of ammonium formate and the reaction is stirred for 2-72 h. Typically the reaction is performed with 10 equivalents of sodium cyanoborohydride and left at room temperature overnight to give the azalide, compound (lc). Scheme 2

(b) Further manipulations to generate the desired terminal compounds (substituted azalides).

The manner in which the following procedures are to be used to provide the actual compounds listed in the table will be readily apparent to those persons in the art of synthesis. The examples described in the Experimental Section later in this specification are illustrative and representative of how these procedures are to be used for all of the compounds listed in the table.

(i) N-alkylation:

For the N-alkylation of the newly inserted nitrogen atom in the macrolide ring i.e. the formation of compound (Id), in Scheme 3, with the exception of when Rf is CH₃, the reductive amination reaction with a suitable aldehyde is done. The respective aldehyde is added to the azalide or the diazalide in a polar protic solvent such as methanol, ethanol, isopropanol at -78 °C to 150 °C, preferably in methanol at room temperature. The reaction is further treated with a reducing agent such as sodium cyanoborohydride, sodium borohydride, hydrogen gas in presence of 10% palladium on carbon to give compound (Id). Scheme 3

For the N-methylation i.e. compound (Id), Scheme 3, when Rf is CH_3ι the Eschweiler- Clarke method is used. For the methylation, the azalide is treated with 1-3 molar equivalents of formaldehyde and formic acid in a halogenated solvent e.g. chloroform, dichloromethane or carbon tetrachloride at temperatures ranging from 20 °C to the reflux temperature of the respective solvent.

(ii) Extension of the C-9 allyloxyimino moiety via the Heck coupling reaction.

The azalide derived from 9-O-allyl-erythromycin A oxime or 9-O-allyl-clarithromycin oxime, (the 9-O-allyl compounds are prepared according to the procedures described in the patent EP 260 938). Compound (le), where X is ON-O-allyl, is treated with palladium (II) or palladium (0) catalyst such as palladium acetate (Pd(OAc)₂) in presence of a phosphine such as triphenylphosphine, tri(o-totyl) phosphine and a base such as triethylamine, sodium carbonate, sodium bicarbonate, or in presence of sodium acetate, in a suitable solvent such as N,N-dimethylformamide (DMF), acetonitrile, tetrahydrofuran (THF) to give the compound (If), Scheme 4.

Scheme 4

(Ie) (If)

X is C=N-0-allyl

Ar is aryl or heteroaryl

(iii) Synthesis of the C-3 derivatives:

For the synthesis of the C-3 derivatives, the cladinose sugar is removed by hydrolysis according to procedures described in the art. Before derivatizing the generated C-3 hydroxyl, the 2'-OH of the 5-desosamine is protected as shown in Scheme 5. The 3-O-cladinose sugar of the azalide is cleaved with an inorganic acid such as hydrochloric acid, sulphuric acid at temperature ranging from -10 °C to 60 °C for 0.5 to 24 h. In a preferred embodiment the reaction is done with 1 N hydrochloric acid at room temperature for 2h to give compound (Ih) Scheme 5.

Before derivatizing the generated C-3-hydroxyl, the 2'-OH group of the 5-desosamine is protected as shown in Scheme 5 by use of an acetyl group. The acetylation is done using acetyl chloride or acetic anhydride in presence or absence of a base in a suitable solvent such as acetone, acetonitrile or dichoromethane, preferably with acetic anhydride in acetone at room temperature for 6-24 h to give compound (Im, R₂ = COCH₃), Scheme 5. An alternate protecting group may also be used by treatment of the compound (Ih) with reagents such as benzoyl chloride, benzoic anhydride, benzyl chloroformate, hexamethyldisilazane or trialkylsilyl chloride. Scheme 5

c) Synthesis of azaacylides:

The 3-hydroxyl compound (Im) is treated with 1-(3-dimethylaminopropyl)-3-ethyl- carbodiimide hydrochloride, 4-N,N-dimethylaminopyridine, and a suitable carboxylic acid, preferably substituted phenylacetic acids such as 4-nitrophenylacetic acid in a halogenated solvent preferably dichloromethane at -20 °C to 50 °C, preferably at -10 to

10° for 2 h to 200 h, preferably for 24h to give compound (In, Rd = preferably suitable

Phenyl).

d) Synthesis of azaketolides:

The conversion of the 3-hydroxy group to 3-ketone is accomplished by using a Corey- Kim oxidation with N-chlorosuccinimide-dimethyl sulphide (NCS-DMS) or a Moffat oxidation with carbodiimide-dimethylsulphoxide (DMSO) complex in the presence of pyridinium trifluoroacetate or Dess-Martin periodinane. Such name reactions are carried out according to general procedures described in the art. In a preferred embodiment, the compound (Im, R₂=COCH3), from Scheme 6 is added to a preformed complex of NCS-DMS in a chlorinated solvent such as dichloromethane or chloroform at about 10 to 25 °C. After stirring for about 0.5 to 4 h, a tertiary amine such as triethylamine or diisopropylethylamine is added to get the corresponding 3-ketone compound (Ip).

The alkylation at the C-2 position, can be achieved by treating the compound (Ip) with and alkyl halide such as iodomethane in the presence of a base such as sodium hexamethyldisilazane or potassium t-butoxide in a suitable solvent such as N,N- dimethylformamide (DMF), acetonitrile, tetrahydrofuran (THF) to give the compound (Iq, R4=CH₃), Scheme 6.

Fluorination at the C-2 position, can be achieved by using a fluorinating reagent, such as N-fluorobenzenesulfonimide (NFSI), 1-(chloromethyl)-4-fluoro-1 ,4- diazoniabicyclo[2.2.2]octane bisftetrafluoroborate] (SELECTFLUOR™) in the presence of a base to give compound (Iq, R4=F).

Typically the compound (Ip), was treated with either SELECTFLUOR in the presence of sodium hexamethyldisilazane in DMF or N-fluorobenzenesulfonimide with potassium t- butoxide as the base in tetrahydrofuran. The reaction was conducted at temperature ranging from -78 °C to +60 °C, preferably at -78°C to -50°C for time 5 min. to 24 h, preferably 15h.

Scheme 6

These compounds have antimicrobial activity against susceptible and drug resistant Gram positive and Gram-negative bacteria. In particular, they are useful as broad spectrum antibacterial agents for the treatment of bacterial infections in humans and animals. These compounds are particularly active against S. aureus, S. epidermidis, S. pneumoniae, S.pyogenes, Enterococci, Moraxella catarrhalis and H. influenzae. These compounds are particularly useful in the treatment of community-acquired pneumonia, upper and lower respiratory tract infections, skin and soft tissue infections, meningitis, hospital-acquired lung infections, and bone and joint infections.

Minimal inhibitory concentration (MIC) has been an indicator of in vitro antibacterial activity widely used in the art. The in vitro antimicrobial activity of the compounds is determined by the microdilution broth method following the test method from the National Committee for Clinical Laboratory Standards (NCCLS). This method is described in the NCCLS Document M7-A4, Vol.17, No.2, "Methods for Dilution Antimicrobial Susceptibility Test for Bacteria that Grow Aerobically - Fourth Edition", which is incorporated herein by reference.

The compounds inhibited the growth of these bacteria with MIC's in the range of about 0.5 μg/mL to about 32 μg/mL; in a preferred range the compounds inhibited the growth of bacteria with MICs in a range of about 0.5 μg/mL to about 8 μg/mL. in a more preferred range, the compounds inhibited the growth of bacteria with MICs in a range of about 0.5 μg/mL to about 4 μg/mL.

Thus the compounds are useful for treating bacterial infections such as those stated in table-1.

Table 1

Microorganism

Staphylococcus aureus

Staphylococcus epidermidis

Moraxella catarrhalis

Enterococcus faecalis

Haemophilus influenzae This invention further provides a method of treating bacterial infections, or enhancing or potentiating the activity of other antimicrobial agents, in warm-blooded animals, which comprises administering to the animals a compound of the invention alone or in admixture with another antibacterial agent in the form of a medicament according to the invention.

The following examples describe in detail the chemical synthesis of representative compounds of the present invention. The procedures are illustrations, and the invention should not be construed as being limited by chemical reactions and conditions they express. No attempt has been made to optimize the yields obtained in these reactions, and it would be obvious to one skilled in the art that variations in reaction times, temperatures, solvents, and/or reagents could increase the yields.

General Methods

Method-1 Preparation of 9-0-allyloxyimino-11 ,12-dideoxy-11 a-aza-11 a-homoervthromvcin/9-O- allyloxyimino-11 ,12-dideoxy-6-0-methyl-11 a-aza-11a-homoervthrothromvcin/9-Q- methoxyethoxymethyloxyimino-11 ,12-dideoxy-11 a-aza-11 a-homoervthromvcin Step-1 : A mixture of 9-O-allyloxyimino erythromycin/9-0-allyloxyimino-6-0-methyl- erythromycin/9-O-methoxyethoxymethyloxyimino erythromycin (10 mmol) was stirred with lead tetracetate (13 mmol) in 50 ml dichloromethane at a temperature between 0- 10°C for 45-60 minutes under nitrogen atmosphere. Progress of the reaction was monitored by TLC. The reaction mixture was filtered and to a filtrate aqueous bicarbonate solution was added slowly. Organic layer was washed with water and concentrated under vacuum at 25-35 °C to afford formyl-methyl ketone compound. This compound was used immediately for the next reaction. Step-2:

The crude compound obtained as above was stirred with ammonium acetate (200 mmol) in methanol (50 ml) for 3 hours. The addition of sodium cyanoborohydride (50 mmol) was made to the reaction mixture and stirred for 12 -24 hours at 25-35 °C. The reaction progress was monitored by TLC. The mixture was concentrated and was washed with aqueous bicarbonate solution followed by water. Organic layer was concentrated in vacuum to provide corresponding 11 ,12-dideoxy-11 a-aza-11a- homoerythromycin as a crude product. The desired product was purified by silica gel column chromatography.

Method-2 Preparation of 9-0-allyloxyimino-1 1 ,12-dideoxy-1 1a-methyl-1 1 a-aza-1 1 a- homoervthromvcin/9-0-allyloxyimino-11 ,12-dideoxy-6-0-methyl-1 1 a-methyl-11a-aza- 1 1 a-homoervthrothromvcin/9-0-methoxyethoxymethyloxyimino-1 1 ,12-dideoxy-1 1 a- methyl-11 a-aza-11 a-homoerythromycin A mixture of 9-0-allyloxyimino-1 1 ,12-dideoxy_r1 1 a-aza-1 1 a-homoerythromycin/9-O- allyloxyimino-11 ,12-dideoxy-6-0-methyl-11 a-aza-11a-homoerythrothromycin/9-0- methoxyethoxymethyloxyimino-11 ,12-dideoxy-1 1 a-aza-1 1 a-homoerythromycin (8 mmol) was stirred with 37% formaldehyde aqueous solution (80 mmol) and 98% formic acid (10 mmol) in 50 ml chloroform at a temperature between 50-60°C for 12-15 hours under nitrogen atmosphere. Progress of the reaction was monitored by TLC. The reaction mixture was washed with a aqueous bicarbonate solution followed by water and the organic layer was concentrated under vacuum at 45-55 °C to afford crude 11 ,12- dideoxy-1 1a-methyl-1 1 a-aza-homoerythromycin. The desired product was purified by silica gel column chromatography.

Method-3 Preparation of 9-0-allyloxyimino-2'-benzoyl-1 1 ,12-dideoxy-1 1 a-benzoyl-1 1 a-aza-1 1 a- homoervthromvcin/9-0-allyloxyimino-6-0-methyl-2'-benzoyl-1 1 ,12-dideoxy-1 1 a- benzoyl-1 1 a-aza-1 1 a-homoervthrothromvcin/9-0-methoxyethoxymethyloxyimino-2'- benzoyl-11 ,12-dideoxy-11 a-benzoyl-11 a-aza-1 la-homoervthromvcin A mixture of 9-0-allyloxyimino-1 1 ,12-dideoxy-1 1 a-aza-11 a-homoerythromycin/9-0- allyloxyimino-6-0-methyl-11 ,12-dideoxy-11 a-aza-1 1a-homoeryhtrothromycin/9-0- methoxyethoxymethyloxyimino-1 1 , 12-dideoxy-1 1 a-aza-1 1 a-homoerythromycin (1 mmol) was stirred with benzoylchloride (10 mmol) and triethylamine (10 mmol) in 50 ml dichloromethane at a temperature between 25-35°C for 24-36 hours under nitrogen atmosphere. Progress of the reaction was monitored by TLC. The reaction mixture was washed water and the organic layer was concentrated under vacuum at 45-55 °C to afford crude corresponding 2'-0-benzoyi-11 ,12-dideoxy-1 1 a-benzoyl-1 1a-aza- homoerythromycin. The desired product was purified by silica gel column chromatography. Method-4

Preparation of 9-0-allyloxyimino-11 a-benzoyl-11.12-dideoxy-11 a-aza-11a- homoervthromvcin/9-0-allyloxyimino-6-0-methyl-11 ,12-dideoxy-11a-benzoyl-11a-aza-

11 a-homoervthrothromvcin/9-0-methoxyethroxymethyloxyimino-11.12-dideoxy-11 a- benzoyl-11 a-aza-11a-homoerythromvcin

A mixture of 9-0-allyloxyimino-2'-benzoyl-11 ,12-dideoxy-11a-benzoyl-11a-aza-11a- homoerythromycin/9-0-allyloxyimino-6-0-methyl-2'-benzoyl-11 ,12-dideoxy-11a- benzoyl-11 a-aza-11 a-homoeryhtrothromycin/9-0-methoxyethoxymethyloxyimino-2'- benzoyl-11 ,12-dideoxy-11a-benzoyl-11 a-aza-1 la-homoerythromycin (1 mmol) was stirred 50 ml methanol at a temperature between 25-35°C for 12-15 hours. Progress of the reaction was monitored by TLC. Solvent was evaporated under vacuum to afford crude corresponding 11 ,12-dideoxy-11a-benzoyl-11a-aza-homoerythromycin. The desired product was purified by silica gel column chromatography.

Method-5

Preparation of 9-0-allyloxyimino-11a-(3-phenylprop-1-yl) -11 ,12-dideoxy-11 a-aza-11a- homoervthromvcin/9-Q-allyloxyimino-6-0-methyl-11 ,12-dideoxy-11a-(3-phenylprop-1- yl)-11 a-aza-11a-homoervthrothromvcin/9-Q-methoxyethoxymethyloxyimino-11 ,12- dideoxy-11 a-O-phenylprop-l -v0-11 a-aza-11 a-homoervthromvcin A mixture of 9-0-allyloxyimino-11 ,12-dideoxy-11 a-aza-11a-homoerythromycin/9-0- allyloxyimino-6-0-methyl-11 ,12-dideoxy-11a-aza-11a-homoeryhtrothromycin/9-0- methoxyethoxymethyloxyimino-11 ,12-dideoxy-11 a-aza-1 la-homoerythromycin (1 mmol) and cinnamyl aldehyde (10 mmol) in methanol (25 ml) was stirred for 5-6 hours. The addition of sodium cyanoborohydride (15 mmol) was made to the reaction mixture and stirred for 48 -52 hours at 25-35 °C. The reaction progress was monitored by TLC. The mixture was concentrated and was washed with aqueous bicarbonate solution followed by water. Organic layer was concentrated in vacuum to provide corresponding 11a-(3- phenylprop-1-yl) -11 ,12-dideoxy-11 a-aza-1 la-homoerythromycin as a crude product. The desired product was purified by silica gel column chromatography.

Method-6

Preparation of 9-Q-r(quinolin-3-vD-prop-2-en-1-vπoxyimino-11 ,12-dideoxy-11 a-aza-11a- homoervthromvcin /9-0- r(3-methoxyphenyl)-prop-2-en-1-vπoxyimino-11 ,12-dideoxy-

11 a-aza-11a-homoervthromvcin/9-0-r(quinolin-3-yl)-prop-2-en-1-vn oxyimino-6-O- methyl-11 ,12-dideoxy-11 a-aza-11a-homoervthrothromvcin / f(3-methoxyphenyl)-prop-2- en-1-yl1oxyimino-6-0-methyl-11 ,12-dideoxy-11 a-aza-11a-homoervthrothromvcin

A mixture of 9-0-allyloxyimino-11 ,12-dideoxy-11 a-aza-11a-homoerythromycin/9-0- allyloxyimino-6-0-methyl-11 ,12-dideoxy-11 a-aza-11a-homoeryhtrothromycin (1 mmol) tri-o-tolylphosphine (0.8 mmol), 3-bromoanisole/3-bromoquinoline (1.5 mmol), sodium acetate/triethylamine (2 mmol) and 10 mole% palladium acatate in dimethylformamide or acetonitrile (25 ml) was stirred in a sealed tube at 50° for 1 hour then at 120°C for 5-6 hours under inert atmosphere. The reaction progress was monitored by TLC. The mixture was filtered and the filtrate was concentrated. The residue was extracted with ethyl acetate. The organic layer was washed with water. Organic layer was concentrated in vacuum to provide corresponding 9-0-[(substituted)-prop-2-en-1- yl]oxyimino-11 ,12-dideoxy-11 a-aza-1 la-homoerythromycin as a crude product. The desired product was purified by silica gel column chromatography.

Method-7 Preparation of 9-0-hvdroxyimino-11 ,12-dideoxy-11 a-aza-11 a-homoervthromvcin/9-O- hvdroxyimino-11a-(3-phenylprop-1-yl) -11 ,12-dideoxy-11 a-aza-1 la-homoerythromycin /hvdroxyimino-6-0-methyl-11.12-dideoxy-11 a-aza-11 a-homoervthrothromvcin A mixture of 9-0-allyloxyimino-11 ,12-dideoxy-11 a-aza-11a-homoerythromycin/9-0- allyloxyimino-11 , 12-dideoxy-11 a-(3-phenylprop-1 -yl)-11 a-aza-11 a-homoerythromycin / 9-0-hydroxyimino-6-0-methyl-11 ,12-dideoxy-11a-aza-11a-homoerythrothromycin (1.0 mmol), palladium acetate (10 mole%), triphenylphosphine (1.1 mmol) and triethylammonium acetate ((1.0 mmol) in a mixture of dioxane water (10:1 , 25 ml)) was stirred at 80° for 45 minutes to 1 hour under inert atmosphere. The reaction progress was monitored by TLC. The mixture was filtered and the filtrate was concentrated. The residue was extracted with ethyl acetate. The organic layer was washed with water. Organic layer was concentrated in vacuum to provide corresponding 9-O-hydroxyimino- 11a-(substituted/unsubstituted-11 ,12-dideoxy-11 a-aza-1 la-homoerythromycin as a crude product. The desired product was purified by silica gel column chromatography.

Method-8

Preparation of 11 ,12-dideoxy-11 a-aza-11a-homoervthromvcin/11 ,12-dideoxy-6-0- methyl-11 a-aza-11a-homoervthromvcin/11 ,12-dideoxy-6-0-methyl-11a-(3-phenylprop-

1 -vD-11 a-aza-11 a-homoervthromycin To a mixture of 9-0-hydroxyimino-11 ,12-dideoxy-11 a-aza-11a-homoerythromycin/9-0- hydroxyimino-6-0-methyl-11 ,12-dideoxy-11 a-aza-11 a-homoeryhtrothromycin/9-O- hydroxyimino-6-0-methyl-11a-(3-phenylprop-1-yl)-11 ,12-dideoxy-11 a-aza-1 la- homoerythromycin (1.0 mmol), sodium nitrite (23 mmol) in a mixture of methanol and water (3:1 , 20 ml) was added 2N hydrochloric acid (23 mmol) dorpwisely at 0°C. The reaction mixture stirred at 0° for 1- 4 hours. Chloroform was added and the addition of 2N sodium hydroxide was made to adjust the pH at 8-9. The organic layer separated and was washed with water. Organic layer was concentrated in vacuum to provide corresponding 11 ,12-dideoxy-11 a-(substituted/unsubstituted)-11 a-aza-11 a- homoerythromycin as a crude product. The desired product was purified by silica gel column chromatography.

Method-9

Preparation of 9-0-allyloxyimino-3-descladinosyl-6-0-methyl-11 ,12-dideoxy-11a-aza-

11 a-homoervthromvcin/9-0-allyloxyimino-3-descladinosyl-11 , 12-dideoxy-11 a-methyl- 11 a-aza-11 a-homoerythromycin /3-descladinosyl-6-Q-methyl-11 ,12-dideoxy-11 a-aza-

11 a-homoervthrothromvcin/3-descladinosyl-2'-acetyl-6-0-methyl-11 ,12-dideoxy-11a- aza-11 a-homoervthrothromycin A mixture of 9-0-allyloxyimino-6-0-methyl-11 ,12-dideoxy-11 a-aza-11a- homoerythromycin/9-0-allyloxyimino-11 ,12-dideoxy-11 a-methyl-11 a-aza-11 a- homoerythromycin /6-0-methyl-11 ,12-dideoxy-11 a-aza-11 a-homoerythrothromycin/2'- acetyl-6-0-methyl-11 ,12-dideoxy-11 a-aza-11a-homoerythrothromycin (1.0 mmol), was stirred with 1 N hydrochloric acid (5 ml) at 25-35° for 4- 6 hours. Chloroform was added to the reaction mixture organic layer was discarded. pH of aqueous layer was adjusted to 8-9 by addition of 2 N sodium hydroxide. The mass was extracted with chloroform. The organic layer separated and was washed with water. Organic layer was concentrated in vacuum to provide corresponding 11,12-dideoxy-3-descladinosyl-11a- aza-1 la-homoerythromycin as a crude product. The desired product was purified by silica gel column chromatography.

Method-10 Preparation of 9-0-allyloxyimino-3-descladinosyl-3-araoyl-11 ,12-dideoxy-11 a-aza-11a- homoervthromvcin/9-0-allyloxyimino-3-descladinosyl-3-araoyl-6-0-methyl-11 ,12- dideoxy-11 a-benzoyl-11 a-aza-11 a-homoerythromycin Step-1 :

A mixture of 9-0-allyloxyimino-3-descladinosyl-11 ,12-dideoxy-11 a-aza-11 a- homoerythromycin/9-0-allyloxyimino-3-descladinosyl-6-0-methyl-11 ,12-dideoxy-11a- benzoyl-11 a-aza-1 la-homoerythromycin (2.0 mmol) and acetic anhydride (4.0 mmol) in acetone (35 ml) was stirred at 25-35°C for 12- 14 hours. Solvent was evaporated and the residue was stirred for aqueous sodium bicarbonate solution to provide a solid. The solid was filtered at suction to provide 2'-acetyl derivative of 11 a-aza-11a- homoerythromycin.This was used as such for the next reaction. Step-2: The crude solid obtained a above was treated with 1-(dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (12.0 mmol), 2-methyl-3-nitrobenzoic acid/ benzoic acid and N,N-dimethylaminopyridine (2.2 mmol) in dichloromethane (35 ml) was stirred at 0- 5°C for 12- 24 hours. Solvent was evaporated and the residue was stirred for aqueous sodium bicarbonate solution to provide a solid. The solid was filtered at suction to provide 2'-acetyl-3-araoyl derivative of 11 a-aza-11 a-homoerythromycin.This was used as such for the next reaction. Step-3:

The crude solid obtained as above was stirred in methanol (30 ml) at 12-14°C for 12- 24 hours. The residue was purified on a silica gel column chromatography to provide title compound.

Method-11 Preparation of 11 ,12-dideoxy-3-descladinosyl-3-oxo-11 a-aza-11a- homoervthromvcin/11 ,12-dideoxy-3-descladinosyl-3-oxo-6-0-methyl-11 a-aza-1 la- homoerythromycin A mixture of N-chlorosuccimnmide (3 mmol), dimethylsulfide (4 mmol) in dichloromethane 25 ml was stirred at 0°C for 45 minutes. To this mixture 11 ,12-dideoxy- 3-desclasinosyl-11 a-aza-11 a-homoerythromycin/11 ,12-dideoxy-3-descladinosyl-6-0- methyl-11 a-aza-1 la-homoerythromycin (1.0 mmol) was added. The reaction micture was stirred at 0-5° for 1-2 hours. Triethylamine (1.75 mmol) was added to the reaction mixture and it was further stirred for 1 -2 hours at 0°C. Organic layer was separated. Organic layer was concentrated in vacuum to provide corresponding 11 ,12-dideoxy-3- descladinosyl-3-oxo-11 a-aza-1 la-homoerythromycin as a crude product. The desired product was purified by silica gel column chromatography. Example-1

9-Q-Allyloxyimino-11 ,12-dideoxy-11 a-aza-11 a-homoervthromvcin (mixture of isomers)

Title compound was prepared by using method-1 in 37% yield as a mixture of isomers. TCL system: chloroform: methanol : ammonia (8:2:0.5), Rf: 0.44

M.P.152-158°C

MS (M+1) = 772 (MH⁺, 100%) for M.F. = C₄₀H₇₃N₃θn.

Example-2 9-0-Allyloxyimino-11 ,12-dideoxy-11 a-aza-1 la-homoerythromycin (isomer A)

The isomeric mixture from Example-1 was separated on preparative HPLC. TLC system: chloroform: methanol : ammonia (8:2:0.5), Rf: 0.38 M.P.122-128°C MS (M+1 ) = 772 (MH⁺, 100%) for M.F. = C^H^NsOn.

Example-3 9-0-AHyloxyimino-11 ,12-dideoxy-11 a-aza-1 la-homoerythromycin (isomer B) The isomeric mixture from Example-1 was separated on preparative HPLC. TLC system: chloroform: methanol : ammonia (8:2:0.5), Rf: 0.48 MS (M+1) = 772 (MH⁺, 100%) for M.F. = C^H^NsOn.

Example-4 9-0-Allyloxyimino-11 , 12-dideoxy-11 a-aza-11 a-homoerythromycin (isomer C) The isomeric mixture from Example-1 was separated on preparative HPLC. TCL system: chloroform: methanol : ammonia (8:2:0.5), Rf: 0.48 MS (M+1 ) = 772 (MH⁺, 100%) for M.F. = C₄oH₇₃N₃On.

Example-5

9-0-Allyloxyimino-11 ,12-dideoxy-11a-methyl-11 a-aza-11 a-homoervthromvcin Title compound was prepared by using method-2 in 72% yield as a mixture of isomers. MS (M+1 ) = 786 (MH⁺, 100%) for M.F. = C41H75N3O11.

Example-6 9-0-Allyloxyimino-1 1 ,12-dideoxy-6-Q-methyl-1 1 a-aza-1 1 a-homoervthromvcin Title compound was prepared by using method-1 in 47% yield as a mixture of isomers. MS (M+1 ) = 786 (MH⁺, 100%) for M.F. = C41H75N3O11.

Example-7

9-0-Allyloxyimino-1 1 2-dideoxy-6-Q-methyl-1 1 a-N-methyl-1 1 a-aza-1 l a- homoerythromycin

Title compound was prepared by using method-2 in 78% yield as a mixture of isomers.

MS (M+1 ) = 800 (MH⁺, 100%) for M.F. = C₄₂H₇₇N₃0n.

Example-8

9-0-[3-(Quinolin-3-vD-prop-2-en-1 -vH-oxyimino-1 1 ,12-dideoxy-1 1 a-aza-1 l a- homoerythromycin

Title compound was prepared by using method-6 in 52% yield as a mixture of isomers. MS (M+1 ) = 899 (MH⁺, 100%) for M.F. = C₄gH₇8N₄0n.

Example-9 9-0-Methoxyethoxymethyloxyimino-1 1 ,12-dideoxy-1 1 a-aza-1 1 a-homoervthromvcin Title compound was prepared by using method-1 in 40% yield as a mixture of isomers.

MS (M+1 ) = 820 (MH⁺, 100%) for M.F. = C₄₁H₇₇N₃0₁₃.

Example-10 9-0-Hvdroxyimino-1 1 ,12-dideoxy-6-Q-methyl-1 1 a-aza-1 1 a-homoervthromvcin Title compound was prepared by using method-7 in 55% yield as a mixture of isomers.

MS (M+1 ) = 746 (MH⁺, 100%) for M.F. = C₃₈H₇₁N₃0n. Example-1 1

9-0-Methoxyethoxymethyloxyimino-1 1 ,12-dideoxy-1 1 a-methyl-1 1 a-aza-1 1 a- homoerythromycin

Title compound was prepared by using method-2 in 68% yield as a mixture of isomers. MS (M+1 ) = 834 (MH⁺, 100%) for M.F. = C₄₂H₇₉N₃0₁₃. Example-12

9-0-Allyloxyimino-11 ,12-dideoxy-11a-(3-phenylprop-1-yl)- 11 a-aza-1 la- homoerythromycin

Title compound was prepared by using method-5 in 45% yield as a mixture of isomers. MS (M+1 ) = 890 (MH⁺, 100%) for M.F. = C₄₉H_B3N₃O₁₁.

Example-13 9-0-Allyloxyimino-11 ,12-dideoxy-11a-N-benzoyl-11 a-aza-11 a-homoervthromvcin Title compound was prepared by using method-4 in 65% yield as a mixture of isomers.

MS (M+1) = 876 (MH⁺, 100%) for M.F. = C₄₇H₇₇N₃Oι₂.

Example-14 9-0-Allyloxyimino-1 1 ,12-dideoxy-11 a-N-benzoyl-11 a-aza-1 la-homoerythromycin Title compound was prepared by using method-4 in 62% yield as a mixture of isomers.

MS (M+1 ) = 876 (MH⁺, 100%) for M.F. = C₄7H₇₇N₃0₁₂. Example-15

9-Q-Allyloxyimino-1 1 ,12-dideoxy-6-0-methyl-1 1 a-N-benzoyl-1 1 a-aza-1 la- homoerythromycin

Title compound was prepared by using method-4 in 70% yield as a mixture of isomers.

MS (M+1) = 890 (MH⁺, 100%) for M.F. = C₄₈H₇₀N₃O₁₂. Example-16

9-0-Allyloxyimino-11 ,12-dideoxy-2'-0-benzoyl-6-0-methyl-11 a-N-benzoyl-11 a-aza-1 1 a- homoerythromycin

Title compound was prepared by using method-3 in 66% yield as a mixture of isomers.

MS (M+1 ) = 994 (MH⁺, 100%) for M.F. = C₅₅H8₃N₃0₁₃. Example-17

9-Q-r3-(Quinolin-3-vD-prop-2-en-1-yll-oxyimino-1 1 ,12-d id eoxy-6-O-methyl- 1 1 a-aza-1 l a- homoerythromycin

Title compound was prepared by using method-6 in 50% yield as a mixture of isomers. MS (M+1 ) = 913 (MH⁺, 100%) for M.F. = CsoHso^On. Example-18

9-0-r3-(3-MethoxyphenvD-prop-2-en-1-vπ-oxyimino-11.12-dideoxy-6-Q-methyl-11a-aza-

11 a-homoervthromvcin

Title compound was prepared by using method-6 in 57% yield as a mixture of isomers. MS (M+1 ) = 892 (MH⁺, 100%) for M.F. = C₄₈H₈ιN₃θ₁₂.

Example-19 9-0-Hvdroxyimino-11 ,12-dideoxy-11 a-aza-11 a-homoervthromvcin Title compound was prepared by using method-7 in 52% yield as a mixture of isomers.

MS (M+1) = 732 (MH⁺, 100%) for M.F. =

Example-20

9-0-Hvdroxyimino-11 ,12-dideoxy-11a-(3-phenylprop-1-yl)-(-11 a-aza-1 la- homoerythromycin

Title compound was prepared by using method-7 in 55% yield as a mixture of isomers.

MS (M+1 ) = 850 (MH⁺, 100%) for M.F. = C^H^On. Example-21

9-0-Allyloxyimino-11 ,12-dideoxy-3-descladinosyl-3-0-(2-methyl-3-nitrobenzoylV11a- aza-11 a-homoerythromycin

Title compound was prepared by using method-10 in 32% yield as a mixture of isomers.

MS (M+1 ) = 788 (MH⁺, 100%) for M.F. = C₄₀H₆₄N₄On. Example-22

9-0-Allyloxyimino-1 1 ,12-dideoxy-3-descladinosyl-3-0-benzoyl-6-0-methyl-1 1 a-benzoyl-

1 1 a-aza-1 la-homoerythromycin

MS (M+1 ) = 836 (MH⁺, 100%) for M.F. = C47H69N3O10. Example-23

9-0-Allyloxyimino-11 ,12-dideoxy-3-descladinosyl-3-oxo-6-0-methyl-1 1 a-N-methyl-1 1 a- aza-1 la-homoerythromycin

Title compound was prepared by using method-1 1 in 30% yield as a mixture of isomers. MS (M+1 ) = 640 (MH⁺, 100%) for M.F. = C₃ H₆₁N₃0₈. Example-24

9-0-Allyloxyimino-11 ,12-dideoxy-3-descladinosyl-3-oxo-6-Q-methyl-11a-N-methyl-11a- aza- 1 a-homoerythromycin

Title compound was prepared by using method-11 in 28% yield as a mixture of isomers. MS (M+1 ) = 626 (MH⁺, 100%) for M.F. = C₃₃H₅₉N₃0₈.

Example-25 11 ,12-Dideoxy-6-0-methyl-11 a-aza-1 la-homoerythromycin Title compound was prepared by using method-8 in 38% yield as a mixture of isomers.

MS (M+1 ) = 731 (MH⁺, 100%) for M.F. = CsβHroN_∑On. Example-26

11 ,12-Dideoxy-3-descladinosyl-6-0-methyl-11 a-aza-1 la-homoerythromycin Title compound was prepared by using method-9 in 70% yield as a mixture of isomers.

MS (M+1 ) = 573 (MH⁺, 100%) for M.F. = C₃oH₅₆N₂0₈.

Example-27 11 ,12-Dideoxy-3-descladinosyl-2'-acetyl-6-0-methyl-11 a-aza-11 a-homoerythromycin Title compound was prepared by using method-9 in 38% yield as a mixture of isomers.

MS (M+1) = 890 (MH⁺, 100%) for M.F. = C₄₉H₈₃N₃O_{1 L}

Example-28 11 ,12-Dideoxy-6-0-methyl-11a-(3-phenylprop-1-yl)-11 a-aza-1 la-homoerythromycin Title compound was prepared by using method-8 in 32% yield as a mixture of isomers.

MS (M+1 ) = 849 (MH⁺, 100%) for M.F. = C^HsoNzOn.

Example-29

11 ,12-Dideoxy-3-descladinosyl-3-oxo-6-0-methyl-11 a-aza-1 la-homoerythromycin

Title compound was prepared by using method-11 in 34% yield as a mixture of isomers. MS (M+1 ) = 571 (MH⁺, 100%) for M.F. = C₃₀H₆₆N₂O₈.

Claims

We claim

A compound of Formula

Formula I wherein

X is selected from the group consisting of 1) 00,

2) CH(ORe),

3) CH(NR_bR_c), 4) ONOR, wherein R is selected from the group consisting of a Hydrogen, b C₁-C1₀ alkyl, c substituted C1-C1₀ alkyl, d C-2-C₁₀ alkenyl, e substituted C2-C1₀ alkenyl, f C₂-Cιo alkynyl, g substituted C₂-C₁0 alkynyl, h (CH₂)_P-M-U-Q where p is an integer 1-6, M is -0-, -NH-, -C(0)-, U is linear or branched C-i to C₆ alkyl, aryl, heteroaryl or aryloxy; Q is hydrogen, C1 -C6 alkoxy, aryl, heteroaryl, aryloxy, NRbR_c. when U is linear or branched Ci to C_& alkylene, Q is hydrogen, C1 -C6 alkoxy, aryl, heteroaryl , aryloxy or NRbRc and when U is aryl, heteroaryl or aryloxy, Q is absent i CH₂CH=CH-A, wherein A is selected from the group consisting of i hydrogen ii aryl iii substituted aryl iv heteroaryl v substituted heteroaryl vi hydroxy

VU C1-C6 alkoxy viii halogen (F, Cl, Br, I), ix cyano, x COOR_a, xi NRbRc, xii C(0)R

R1 = hydrogen, C C₆ alkyl, substituted Cι-C₆ alkyl, C₂-C₆ alkenyl, substituted C₂-C₆ alkenyl, C -C₆ alkynyl, substituted C₂-C₆ alkynyl, C(0)NRbRc, R2 = hydrogen or hydroxyl protecting group.

R3 = hydrogen, Ci-Cβ alkyl, substituted C-i-C_δ alkyl, C₂-C₆ alkenyl, substituted C₂-C₆ alkenyl, C₂-C₆ alkynyl, substituted C₂-C₆ alkynyl. R4 = hydrogen, fluorine, chlorine, bromine, methyl, wherein R_a, R_b, Rc, R_d, e are independently selected from the group consisting of:

I . Hydrogen, 2. C1-C6 alkyl,

3. C2-C6 alkenyl,

4. C2-C6 alkynyl,

5. C3-C7 cycloalkyl,

6. heterocyclyl, 7. aryl,

8. heteroaryl,

9. aralkyl,

10. aralkenyl,

I I. aralkynyl, 12. heteroaralkyl,

13. aralkanoyl,

14. heteroaralkanoyl,

15. aroyl,

16. heteroaroyl,

17. substituted C1-C6 alkyl, 18. substituted C2-C6 alkenyl, 19. substituted C2-C6 alkynyl, 20. substituted C3-C7 cycloalkyl, 21. substituted heterocyclyl,

22. substituted aryl,

23. substituted heteroaryl,

24. substituted aralkyl,

25. substituted aralkenyl, 26. substituted aralkynyl,

27. substituted heteroaralkyl, 28. substituted aralkanoyl,

29. substituted heteroaralkanoyl,

30. substituted aroyl, 31. substituted heteroaroyl;

R_f is selected from the group consisting of

1 ) hydrogen,

2) C₁-C₁₀ alkyl group, C₂-C₁0 alkenyl, C2-C10 alkynyl, optionally substituted C-1-C₁₀ alkyl group, optionally substituted C2-C10 alkenyl, optionally substituted C₂-C1₀ alkynyl, the substituents are selected from the group consisting of a. halogen (F, Cl, Br, I), b. cyano, c. COOR_a, d. NRbRc, e. C(0)R_d, f. OR_e

3) aryl,

4) substituted aryl, 5) heteroaryl,

6) substituted heteroaryl,

7) aralkyl,

8) substituted aralkyl,

9) aralkenyl, 10)substituted aralkenyl,

1 1 )aralkynyl,

12)substituted aralkynyl,

13)heteroaralkyl, 14)substituted heteroaralkyl,

15)aralkanoyl,

16)substituted aralkanoyl,

17)heteroaralkanoyl,

18)substituted heteroaralkanoyl, 19)aroyl,

20)substituted aroyl,

21 )heteroaroyl,

22)substituted heteroaroyl,

23)C₃-C₇ cycloalkyl 24)Substituted cycloalkyl,

25)heterocyclyl

26)substituted heterocyclyl

27)cyano,

28)COOR_a 29) NRbRc,

30)C(O)R_d

31 )C(=NO)R_d

32)C(0)NR_bR_c

33)0R_e wherein R_a, Rb, R_c, Rd, Re are as defined above.

z and z' together with the carbon to which they are attached form OO or z' is hydrogen and z is hydroxyl or OR_g wherein R_g is selected from the group consisting of

1 )

(which is designated as cladinose when R_2' is hydrogen) wherein R₂' is defined as hydrogen, hydroxyl protecting group, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl chain optionally substituted with one more substituents selected from the group consisting of hydroxy, cyano, halogen, COOR_a, NRbR_c, C(0)R_d iv. C(0)NR_bR_c, v)

where n is an integer 1-6.

2) -C(0)R_d, 3) -C(0)NR_bR_c

wherein R_b, R_c, R_d have the same definitions as above or an optical isomer, enantiomer, diastereomer, racemate or racemic mixture thereof, or pharmaceutically acceptable salts, esters or prodrugs thereof.

2. A compound selected from the group consisting of

9-0-Allyloxyimino-11 , 12-dideoxy-11 a-aza-11 a-homoerythromycin (mixture of isomers);

9-0-Allyloxyimino-11 , 12-dideoxy-11 a-aza-11 a-homoerythromycin (isomer A);

9-0-Allyloxyimino-11 ,12-dideoxy-11 a-aza-1 la-homoerythromycin (isomer B); 9-0-A!!y!oxyimino-11 , 12-dideoxy-11 a-aza-11 a-homoerythromycin (isomer C);

9-0-Allyloxyimino-11 ,12-dideoxy-11a-methyl-11 a-aza-1 la-homoerythromycin (mixture of isomers);

9-0-Allyloxyimino-11 ,12-dideoxy-6-0-methyi-11 a-aza-1 la-homoerythromycin (mixture of isomers); 9-0-Allyloxyimino-11 ,12-dideoxy-6-0-methyl-11a-N-methyl-11 a-aza-1 la- homoerythromycin (mixture of isomers); 9-0-[3-(Quinolin-3-yl)-prop-2-en-1-yl]-oxyimino-11 ,12-dideoxy-11 a-aza-1 la- homoerythromycin (mixture of isomers);

9-0-Methoxyethoxymethyloxyimino-11 ,12-dideoxy-11 a-aza-11 a-homoerythromycin (mixture of isomers); 9-0-Hydroxyimino-11 ,12-dideoxy-6-0-methyl-11a-aza-1 la-homoerythromycin (mixture of isomers);

9-0-Methoxyethoxymethyloxyimino-11 , 12-dideoxy-11 a-methyl-11 a-aza-11 a- homoerythromycin (mixture of isomers);

9-0-Allyloxyimino-11 ,12-dideoxy-11a-(3-phenylprop-1-yl)- 11 a-aza-11a- homoerythromycin (mixture of isomers);

9-0-Allyloxyimino-11 , 12-dideoxy-11 a-N-benzoyl-11 a-aza-11 a-homoerythromycin (mixture of three isomers);

9-0-Allyloxyimino-11 ,12-dideoxy-11a-N-benzoyl-11 a-aza-1 la-homoerythromycin (mixture of two isomers); 9-0-Allyloxyimino-11 ,12-dideoxy-6-0-methyl-11 a-N-benzoyl-11 a-aza-11 a- homoerythromycin (mixture of isomers);

9-0-Allyloxyimino-11 ,12-dideoxy-2'-0-benzoyl-6-0-methyl-11 a-N-benzoyl-11 a-aza-11 a- homoerythromycin (mixture of isomers);

9-0-[3-(Quinolin-3-yl)-prop-2-en-1-yl]-oxyimino-11 ,12-dideoxy-6-0-methyl-11 a-aza-11a- homoerythromycin (mixture of isomers);

9-0-[3-(3-Methoxyphenyl)-prop-2-en-1-yl]-oxyimino-11 ,12-dideoxy-6-0-methyl-11 a-aza-

I la-homoerythromycin (mixture of isomers);

9-0-Hydroxyimino-11,12-dideoxy-11 a-aza-1 la-homoerythromycin (mixture of isomers);

9-0-Hydroxyimino-11 ,12-dideoxy-11a-(3-phenylprop-1-yl)-(-11 a-aza-11a- homoerythromycin (mixture of isomers);

9-0-Allyloxyimino-11 ,12-dideoxy-3-descladinosyl-3-0-(2-methyl-3-nitrobenzoyl)-11a- aza-11 a-homoerythromycin (mixture of isomers);

9-0-Allyloxyimino-11 ,12-dideoxy-3-descladinosyl-3-0-benzoyl-6-0-methyl-11a-benzoyl-

I I a-aza-1 la-homoerythromycin (mixture of isomers); 9-0-Allyloxyimino-11 ,12-dideoxy-3-descladinosyl-3-oxo-6-0-methyl-11a-N-methyl-11a- aza-1 la-homoerythromycin (mixture of isomers);

9-0-Allyloxyimino-11 ,12-dideoxy-3-descladinosyl-3-oxo-6-0-methyl-11 a-aza-11 a- homoerythromycin (mixture of isomers);

11 ,12-Dideoxy-6-0-methyl-11 a-aza-1 la-homoerythromycin (mixture of isomers); 11 ,12-Dideoxy-3-descladinosyl-6-0-methyl-11 a-aza-11 a-homoerythromycin (mixture of isomers);

11 ,12-Dideoxy-3-descladinosyl-2'-acetyl-6-0-methyl-11 a-aza-1 la-homoerythromycin (mixture of isomers); 11 ,12-Dideoxy-6-0-methyl-11 a-(3-phenylprop-1 -yl)-11 a-aza-11 a-homoerythromycin (mixture of isomers);

11 ,12-Dideoxy-3-descladinosyl-3-oxo-6-0-methyl-11 a-aza-1 la-homoerythromycin (mixture of isomers).

3. A compound selected from the group consisting of

9-0-Allyloxyimino-11 ,12-dideoxy-6-0-methyl-11 a-aza-1 la-homoerythromycin (mixture of isomers); 9-0-Hydroxyimino-11 ,12-dideoxy-6-0-methyl-11 a-aza-1 la-homoerythromycin (mixture of isomers);

9-0-Hydroxyimino-11 ,12-dideoxy-11a-(3-phenylprop-1-yl)-(-11 a-aza-1 la- homoerythromycin (mixture of isomers);

11 ,12-Dideoxy-6-0-methyl-11 a-aza-1 la-homoerythromycin (mixture of isomers).

4. A method for preparing azalides of Claim 1 comprising

(a) treating 9-0-(alkanyl/substituted alkanyl) oxyimino-erythromycin derivative with oxidative diol cleavage reagent in a solvent over a temperature range, to obtain a reaction mixture, (b) filtering the reaction mixture and adding aqueous alkaline solution,

(c) evaporating solvent at low temperature,

(d) treating a residue with ammonium salt of organic acid in a solvent,

(e) treating the reaction mixture with reducing agent,

(f) evaporating solvent and purifying azalide of the invention.

5. A process according to claim 4, wherein the oxidative diol cleavage reagent is lead tetra acetate or sodium metaperiodate.

6. A process according to claim 4, wherein the oxidative diol cleavage reagent is lead tetra acetate.

7. A process according to claim 4, wherein the ammonium salt of organic acid is ammonium formate, ammonium acetate.

8. A process according to claim 4, wherein the ammonium salt of organic acid is ammonium acetate.

9. A process according to claim 4, wherein the reducing agent is sodium cyanoborohydride, sodium triacetoxyborohydride and sodium borohydride.

10. A process according to claim 4, wherein the reducing agent is sodium cyanoborohydride.

11. A process according to claim 4, wherein the solvent is dichloromethane, chloroform, carbon tetrachloride.

12. A process according to claim 4, wherein the solvent is dichloromethane.

13. A process according to claim 4, wherein the temperature range is 0 - 10 °C.

14. A method for preparing azaketolides of Claim 1 comprising

(a) treating 11a-(H/substituted/unsubstituted alkanyl)-11 a-aza-1 la- homoerythromycin derivative with aqueous inorganic acid over a temperature range, to obtain a reaction mixture,

(b) isolating the compound by treating with aqueous alkali to provide a semisolid,

(c) treating the semisolid compound with oxidizing agent and organic base over a temperature range,

(d) evaporating solvent and purifying azaketolide of the invention.

15. A process according to claim 14, wherein the inorganic acid is hydrochloric acid, sulfuric acid.

16. A process according to claim 14, wherein the inorganic acid is hydrochloric acid.

17. A process according to claim 14, wherein the alkali is sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, sodium hydroxide, potassium hydroxide.

18. A process according to claim 14, wherein the alkali is sodium bicarbonate.

19. A process according to claim 14, wherein the oxidizing agent is Dess-Martin periodinane, a combination of oxalyl chloride, dimethyl sulfoxide, trimethyl amine, a combination of chlorine gas and dimethyl sulfide, a combination of N-chlorosuccinimide and dimethylsulfide.

20. A process according to claim 14, wherein the oxidizing agent is a combination of N- chlorosuccinimide and dimethylsulfide.

21. A process according to claim 14, wherein the solvent is dichloromethane, chloroform, carbon tetrachloride.

22. A process according to claim 14, wherein the solvent is dichloromethane.

23. A process according to claim 14, wherein the temperature range is 0 - 10 °C.

24. The use of a compound as claimed in any one of claims 1 - 3 in the preparation of a medicament for use in the therapy of systemic or topical bacterial infections in a human or animal body.

25.The use of a compound as claimed in any one of claims 1 - 3 in the preparation of a medicament for use in the treatment or prophylaxis of systemic or topical bacterial infections in a human or animal body.

26. A composition comprising a compound according to claims 1 - 3 and an excipient, diluent, solvent or carrier.

27. A method for treating a systemic or topical infection comprising administering an effective amount of a compound according to claims 1 - 2 to a patient in need thereof.

28. A method for treating a systemic or topical infection comprising administering an effective amount of a compound according to claim 3 to a patient in need thereof.

1 29. A method for preventing a systemic or topical infection comprising administering an effective amount of a compound according to claims 1 to 2 to a patient at risk for developing the infection.

30. A method for preventing a systemic or topical infection comprising administering an effective amount of a compound according to claim 3 to a patient at risk for developing the infection.