Field of Invention
The present invention provides ketolide derivatives which can be used as antibacterial agents Compounds disclosed herein can be used for the treatment or prevention of a condition caused by or contributed to by gram positive, gram negative or anaerobic bacteria, more particularly against bacterium, for example, Staphylococci, Streptococci, Enterococci, Haemophilus, Moraxalla spp, Chlamydia spp, Mycoplasm, Legionella spp, Mycobacterium, Helicobacter, Clostridium, Bacteroides Corynebacterium, Bacillus or Enterobactericeae Processes for the preparation of disclosed compounds, pharmaceutical compositions containing the disclosed compounds, and method of treating bacterial infections are also provided
Background of the Invention
The first generation macrohdes erythromycin A and the early derivatives are characterized by bacteriostatic or bactericidal activity for most gram-positive bacteria, atypical pathogens, and many community acquired respiratory infections and in patients with penicillin allergy However, erythromycin A causes numerous drug-drug interactions, has relatively poor absorption, poor local tolerance, loses its antibacterial activity under acidic conditions by degradation and the degraded products are known to be responsible for undesired side effects (Itoh, Z et al, Am J Physiol, 1984, 247 688, Omura, S et al, J Med Chem, 1987, 30, 1943) Various erythromycin A derivatives have been prepared to overcome the acid instability and other problems associated with it
Roxithromycin, clarithromycin and azithromycin have been developed to address the limitation of erythromycin A Both clarithromycin and azithromycin have proved to be important drugs in the treatment and prophylaxis of atypical mycobacterial infections in patients with HIV
Macrohdes have proved to be effective drugs in the treatment of many respiratory tract infections However, increasing resistance among S pneumoniae has prompted the search for new compounds that retain the favorable safety profile, and a spectrum of activity and are confined to respiratory pathogens Consequently, numerous investigators have prepared chemical derivatives of erythromycin A in an attempt to obtain analogs having modified or improved profiles of antibiotic activity Ketolides exhibit greater efficacy and safety, have broader spectrum of activities, and are particularly effective against resistant pathogens, hence have been developed as next generation macrohdes
U S Patent No 5, 635, 485 and U S Patent No 5,747,467 discloses erythromycin compounds that are useful in the treatment of bacterial infections in warm-blooded animals U S Patent No 5, 866, 549 and U S Patent No 6,472,372 discloses novel semi-synthetic macrohdes having antibacterial activity, more particularly, 6-O-substituted erythromycin ketohde derivatives and method of treating bacterial infections WO 00/62783 and WO 00/44761 discloses ketohde antibactenals that are useful in the treatment of bacterial and protozoal infections and in the treatment of other conditions involving gastric motility U S Patent No 6,433,151 discloses erythromycin derivatives and their use as medicament for the treatment of infection caused by gram positive bacteria, Haemophilus influenzae Morraxalla spp U S Patent Nos 6,458,771 and 6,399,582 disclose ketohde antibactenals useful in the treatment of bacterial and protozoal infections and in the treatment of other conditions involving gastric motility US Patent Application Nos 2002/0115621 and 2003/0013665 disclose macrolide compounds that are useful as antibacterial and antiprotozoal agents in mammals, including man, as well in fish and birds Other references disclosing ketohde compounds include Alexis Denis and Alain Bonnefoy, Drugs of the Future, 26 (10), 975-84 (2001), Champney W S , et al, Current Microbiology, 42, 203-10 (2001)
Summary of the Invention
The present invention provides ketohde derivatives, which can be used in the treatment or prevention of bacterial infection, and processes for the synthesis of these compounds Pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers, polymorphs of these compounds having same type of activity are also provided Pharmaceutical compositions containing the disclosed compounds together with pharmaceutically acceptable carriers, excipients or diluents, which can be used for the treatment of bacterial infection Other object will be set forth in accompanying description which follows and in part will be apparent from the description or may be learnt by the practice of the invention
In one aspect, provided herein are compounds having the structure of Formula I,
(Formula Removed)
pharmaceutically acceptable salts, pharmaceutical^ acceptable solvates, enantiomers,
diastereomers and polymorphs thereof, wherein
R1 can be hydrogen or hydroxy protecting group wherein, hydroxy protecting group can be
benzoyl, tetrahydropyranyl and tnalkylsilylethers, R2 is CH3, R3 can be C2H5, -CH2-CH=CH2
or -CH2CH2F, W is -(CH2)3-J-, wherein J can be CH2 or (CH2)0-1-N(CO)-Ra,
R can be

(Formula Removed)
wherein
X1-X3 can be independently CH or N, X4-X8 can be independently CH, CR4 or N, X9 can be O, S, N, NH or CH, X10 can be NH or S, Ra can be thienyl, furyl, pyrazolyl, oxazolyl, tetrazolyl, pyridinyl, lmidazolyl, chloropyridinyl, fluoropyridinyl, chloropyridinyl, aminopyridinyl, pyrazinyl, pynmidinyl, aminopynmidinyl, quinohnyl, pyrrolo-pyridinyl, pyrrolo-thiazolyl or optionally substituted phenyl, R'a can be hydrogen or furyl, Rb can be hydrogen or amino, Re can be hydrogen, thienyl, furyl, pyrazolyl, pyridinyl, aminopyridinyl, pyrazinyl, pynmidinyl, pyrrolyl, lmidazolyl or optionally substituted phenyl, Rd can be thienyl, pyrazolyl, lmidazolyl, triazolyl, pyrrolyl or tetrahydrofuryl
In another aspect, there is provided a method for treating or preventing a mammal suffering from a condition caused by or contributed to by gram positive, gram negative or anaerobic bacteria, comprising administering to said mammal, a therapeutically effective amount of a compound or a pharmaceutical composition disclosed herein
The bacterial infection may be caused by bacterium, for example, Staphylococci, Streptococci, Enterococci, Haemophilus, Moraxalla spp, Chlamydia spp, Mycoplasm, Legionella spp, Mycobacterium Helicobacter Clostridium, Bacteroides, Corynebacterium, Bacillus or Enterobactericeae The said conditions may be, for example, community acquired pneumonia, upper and lower respiratory tract infections, skin and soft tissue infections, hospital acquired lung infections or bone and joint infections, and other bacterial infections, for example, mastitis, catheter infection, foreign body, prosthesis infections or peptic ulcer disease
In yet another aspect, there are provided processes for the preparation of compounds disclosed herein
The said optionally substituted phenyl may be substituted with one or more substituent(s) independently selected from halogen, amino, nitro, methyl, methoxy, lmidazolyl, dimethylamino, tetrazolyl, pyrrolyl, dicyclopropylamino, CF3, NHCOCH3, NHCH(CH3)2, NHCOPh or NHCH3 As used herein the term "polymorphs" includes all crystalline form and amorphous form for compounds described herein In addition, some of the compounds described herein may form solvates with water (i-e hydrate, hemihydrate or sesquihydrate) or common organic solvents Such solvates are also encompassed within the scope of this invention The term "pharmaceutically acceptable salts" refer to a salt prepared from pharmaceutically acceptable organic or inorganic acids, such salts includes hydrochlorides, sulfates, phosphates, tartarates, fumarates, citrates and the like The free base forms of compounds of the present invention may be prepared from the salt forms, if desired, by contacting the salt with dilute aqueous solution of a base The acid addition salts may differ from the free base forms of the compounds of this invention in such physical characteristics as solubility and melting point The salt forms differ from the compound described herein in certain physical properties such as solubility, but the salts are otherwise equivalent for purposes of this invention The term "pharmaceutically acceptable carriers" is intended to include non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type The compounds of present invention include stereoisomers The term "stereoisomer" refers to compounds, which have identical chemical composition, but differ with regard to arrangement of the atoms and the groups in space These include enantiomers, diastereomers, geometrical isomers, atropisomer and comformational isomers Geometric isomers may occur when a compound contains a double bond or some other feature that gives the molecule a certain amount of structural rigidity An atropisomer is a conformation of a reference compound that converts to the reference compound only slowly on the NMR or laboratory time scale Conformational isomers (or conformers or rotational isomers or rotamers) are stereoisomers produced by rotation about bonds, and are often rapidly interconverting at room temperature Racemic mixtures are also encompassed within the scope of this invention Enantiomers and Diastereomers are as defined by the IUPAC 1974 Recommendations for Section E
Detailed Description of the Invention
The compounds disclosed herein may be prepared by techniques well known in the art and familiar to the average synthetic organic chemist In addition, the compounds of the present invention may be prepared by the following reaction sequences as depicted in Scheme I, II, III and IV
(Formula Removed)
The compound of Formula I can be prepared according to Scheme I Thus, clarithromycin of Formula II is hydrolyzed to give a compound of Formula III, which on protection with a reagent of Formula R12O or R1X (wherein X is halogen) gives a compound of Formula IV (wherein R1is the hydroxy protecting group, for example, benzoyl,
tetrahydropyranyl or trialkylsilylethers), which on desmethylation at 3'-N-dimethyl group gives a compound of Formula V, which on alkylation with a reagent of Formula R3CHO, R 2CO or R X gives a compound of Formula VI (wherein R3 is as defined earlier), which on reaction with a reagent, for example, triphosgene or ethylene dicarbonate gives a compound of Formula VII, which on reaction with a organic base, for example, tetramethyl guanidine or tnmethylamine gives a compound of Formula VIII, which on oxidation gives a compound of Formula IX, which on reaction with N,N'-carbonyldnmidazole gives a compound of Formula X, which on reaction with a compound of Formula R-W-NH2 gives a compound of Formula XI (wherein W and R are the same as defined earlier), which on fluorination gives a compound of Formula XII, which is finally deprotected to give a compound of Formula I
The hydrolysis of clarithromycin of Formula II to give a compound of Formula III can be carried out in the presence of an inorganic or organic acid, for example, hydrochloric acid, sulphuric acid or dichloroacetic acid
The hydroxyl protection of a compound of Formula III with a reagent of Formula R12O or R1x to give a compound of Formula IV can be carried out in a solvent, for example, dichloromethane, dichloroethane, chloroform, carbon tetrachloride or ethyl acetate
The hydroxyl protection of a compound of Formula III with a reagent of Formula R12O or R X can be carried out in the presence of an organic base, for example, triethylamine, dnsopropylethylamine, pyridine, tributylamine or 4-(N-dimethylamino) pyridine
The desmethylation of a compound of Formula IV to give a compound of Formula V can be carried out in the presence of a desmethylating agent, for example, N-iodosuccinimide iodine in acetic acid or dnsopropylazodicarboxylate
The desmethylation of a compound of Formula IV can be carried out in a solvent, for example, acetonitnle, tetrahydrofuran, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, ethyl acetate or mixture thereof
The alkylation of a compound of Formula V with a reagent of Formula R3CHO, R32 CO or R3X to give a compound of Formula VI can be carried out in a solvent, for example, dimethylformamide, acetonitnle, methanol, acetone, tetrahydrofuran or mixture thereof
The alkylation of a compound of Formula V can be carried out in an inorganic or organic base, for example, sodium hydrogen carbonate, potassium carbonate, cesium carbonate, sodium hydride, pyridine, triethylamine, sodium acetate, sodium thiosulphate or dnsopropyl ethylamine

The alkylation of a compound of Formula V with a reagent of Formula R CHO can also be carried out with a reducing agent, for example, sodium cyanoborohydride, sodium borohydride or sodium tnacetoxyborohydride in the presence of an organic acid, for example, acetic acid or dichloroacetic acid in a solvent, for example, methanol, ethanol, propanol or isopropanol
The reaction of a compound of Formula VI to give a compound of Formula VII can be carried out in a solvent, for example, chloroform, dichloromethane, carbon tetrachloride or dichloroethane
The reaction of a compound of Formula VI to give a compound of Formula VII can be carried out in the presence of an organic base, for example, triethylamine, dnsopropyl ethylamine, pyridine, tributylamine or 4-(N-dimethylamino) pyridine
The reaction of a compound of Formula VII to give a compound of Formula VIII can be carried out in a solvent, for example, dimethylformamide, tetrahydrofuran, dimethylsulphoxide or mixture thereof
The oxidation of a compound of Formula VIII to give a compound of Formula IX can be carried out with an oxidizing agent, for example, Dess-Martin periodinane, N-chloro succinimide, pyridinium chlorochromate, Swern Oxidation reagent (oxalyl chloride and dimethylsulfoxide), Pfitzner-Moffatt Oxidation reagent (dicyclohexylcarbodiimide and dimethylsulfoxide), Jones Oxidation reagent (chromic acid, aqueous sulfuric acid and acetone), pyndinium dichromate or l-ethyl-3-(3-dimethylaminopropyl) carbodumide hydrochloride N-Chlorosuccinamide can be used in combination with dimethylsulphide and l-ethyl-3(3-dimethylaminopropyl)carbodnmide hydrochloride can be used in combination with dimethylsulfoxide
The oxidation of a compound of Formula VIII to give a compound of Formula IX can be carried out in a solvent, for example, chloroform, dichloromethane, carbon tetrachloride, dimethylsulfoxide or dichloroethane
The reaction of a compound of Formula IX with N,N'-carbonyldiimidazole to give a compound of Formula X can be carried out in a solvent, for example, dimethylformamide, acetonitrile, tetrahydrofuran or mixture thereof
The reaction of a compound of Formula IX with N,N'-carbonyldnmidazole can be carried out in an inorganic base, for example, sodium hydrogen carbonate, sodium acetate, sodium thiosulphate, potassium carbonate, cesium carbonate or sodium hydride
The reaction of a compound of Formula X with a compound of Formula R-W-NH2to
give a compound of Formula XI can be carried out in a solvent system, for example, acetonitrile/water, dimethylformamide/water or dimethylformamide
The fluorination of a compound of Formula XI to give a compound of Formula XII can be carried out with a fluorinating agent, for example, N-fluorobenzene sulfonimide or selectfluor (also as described by G Sankar Lai and Syvret R G in Chem Rev 1996, 96, 1737-1755) The fluonnation of a compound of Formula XI can be carried out in a solvent, for example, dimethylformamide, tetrahydrofuran, dimethylsulphoxide or mixture thereof
The fluonnation of a compound of Formula XI can be carried out in the presence of an inorganic base, for example, potassium carbonate, sodium hydride, sodium acetate, sodium thiosulphate, potassium-t-butoxide, sodiun-t-butoxide, lithium diisopropylamide, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium isopropoxide, potassium isopropoxide or lithium carbonate
The deprotection of a compound of Formula XII to give a compound of Formula I can be carried out in an alcohol, for example, methanol, ethanol, propanol or isopropanol
(Formula Removed)
The compound of Formula I can also be prepared according to Scheme II Thus, a compound of Formula IV is reacted with a reagent, for example, triphosgene or ethylene dicarbonate to give a compound of Formula XIV, which on reaction with a organic base, for example, tetramethyl guanidine or tnmethyl amine gives a compound of Formula XV, which on oxidation gives a compound of Formula XVI, which on desmethylation at 3'-N-dimethyl group gives a compound of Formula XVII, which on alkylation with a reagent of Formula R3CHO, R32 CO or R3X (wherein X, and R3 are as defined earlier), gives a compound of Formula IX, which on fluonnation gives a compound of Formula XVIII, which on reaction with N,N'-carbonyldnmidazole gives a compound of Formula XIX, which on reaction with a compound of Formula R-W-NH2 gives a compound of Formula XII (wherein W and R are the same as defined earlier), which is finally deprotected to give a compound of Formula XIII
The reaction of a compound of Formula IV to give a compound of Formula XIV can be carried out in a solvent, for example, dichloromethane, chloroform, carbon tetrachloride or dichloroethane
The reaction of a compound of Formula IV to give a compound of Formula XIV can be carried out in the presence of an organic base, for example, triethylamine, pyridine, dnsopropylethylamine or 4-(N-dimethylamino) pyridine
The reaction of a compound of Formula XIV to give a compound of Formula XV can be carried out in a solvent, for example, dimethylformamide, tetrahydrofuran, dimethylsulphoxide or mixture thereof
The oxidation of a compound of Formula XV to give a compound of Formula XVI can be carried out with an oxidizing agent, for example, Dess-Martin penodinane, N-chlorosuccinimide, pyridinium chlorochromate, Swern Oxidation reagent (oxalyl chloride and dimethylsulfoxide), Pfitzner-Moffatt Oxidation reagent (dicyclohexylcarbodnmide and dimethylsulfoxide), Jones Oxidation reagent (chromic acid, aqueous sulfuric acid and acetone), pyndinium dichromate or 1-ethy 1-3-(3-dimethyl aminopropyl) carbodnmide hydrochloride
The oxidation of a compound of Formula XV to give a compound of Formula XVI can be carried out in a solvent, for example, chloroform, dichloromethane, carbon tetrachloride, dimethylsulphoxide or dichloroethane
The desmethylation of a compound of Formula XVI to give a compound of Formula
XVII can be carried out in the presence of a desmethylating agent, for example, N-iodo succinimide, iodine in acetic acid or dnsopropyl azodicarboxylate
The desmethylation of a compound of Formula XVI to give a compound of Formula
XVII can be carried out in a solvent, for example, acetonitrile, tetrahydrofuran,
dichloromethane, dichloroethane, chloroform, carbontetrachlonde, ethyl acetate or mixture
thereof
The quenching of desmethylation reaction can be carried out in the presence of a quenching agent, for example, sodium bisulphite, sodium carbonate, potassium carbonate, cesium carbonate, sodium acetate or mixture thereof
The alkylation of a compound of Formula XVII with a reagent of Formula R3CHO, R32 CO or R3X to give a compound of Formula IX can be carried out in a solvent, for example, dimethylformamide, acetonitnle, methanol, acetone, tetrahydrofuran or mixture thereof
The alkylation of a compound of Formula XVII can be carried out in the presence of an inorganic or organic base, for example, sodium hydrogen carbonate, potassium carbonate, cesium carbonate, sodium hydride, pyridine, triethylamine, sodium acetate, sodium thiosulphate or dnsopropylethylamine
The fluorination of a compound of Formula XVII to give a compound of Formula
XVIII can be carried out with a fluorinating agent, for example, N-fluorobenzene sulfonimide
or selectfluor (also as described by G Sankar Lai and Syvret R G in Chem Rev 1996, 96,
1737-1755)
The fluonnation of a compound of Formula XVII can be carried out in a solvent, for example, dimethylformamide, tetrahydrofuran, dimethylsulphoxide or mixture thereof
The fluonnation of a compound of Formula XVII can be carried out in the presence of an inorganic base, for example, potassium carbonate, cesium carbonate, sodium hydride, sodium acetate, sodium thiosulphate or potassium-z-butoxide
The reaction of a compound of Formula XVIII with N,N'-carbonyldnmidazole to give a compound of Formula XIX can be carried out in a solvent, for example, dimethylformamide, acetonitnle, tetrahydrofuran or mixture thereof
The reaction of a compound of Formula XVIII with N,N'-carbonyldnmidazole can be carried out in the presence of an inorganic base, for example, sodium hydrogen carbonate, potassium carbonate, cesium carbonate, sodium acetate, sodium thiosulphate or sodium hydride
The reaction of a compound of Formula XIX with a compound of Formula R-W-NH2 to give a compound of Formula XII can be earned out in a solvent system, for example, dimethylformamide/water, acetonitrile/water or dimethylformamide
The deprotection of a compound of Formula XII to give a compound of Formula I can be carried out in an alcohol, for example, methanol, ethanol, propanol or isopropanol

(Formula Removed)
A compound of Formula I can also be prepared according to Scheme III Thus, a compound of Formula XVI is fluonnated to give a compound of Formula XX, which on reaction with N,N'-carbonyldumidazole gives a compound of Formula XXI, which on reaction with a compound of Formula R-W-NH2 gives a compound of Formula XXII (R & W are the same as defined earlier), which on deprotection gives a compound of Formula XXIII, which on desmethylation at 3'-N-dimethyl group gives a compound of Formula XXIV, which is alkylated with a reagent of Formula R3CHO, R32 CO or R3X (wherein X and R3 are as defined earlier) to give a compound of Formula XIII
The fluonnation of a compound of Formula XVI to give a compound of Formula XX can be carried out with a fluorinating agent, for example, N-fluorobenzene sulfonimide or selectfluor (also as described by G Sankar Lai and Syvret R G in Chem Rev 1996, 96, 1737-1755)
The fluonnation of a compound of Formula XVI to give a compound of Formula XX can be carried out in a solvent, for example, dimethylformamide, tetrahydrofuran, dimethyl sulphoxide or mixture thereof
The fluonnation of a compound of Formula XVI can be carried out in the presence of an inorganic base, for example, potassium carbonate, sodium hydride, sodium acetate, sodium hydrogen carbonate, cesium carbonate, sodium thiosulphate, potassiun-t-butoxide, sodiun-t-butoxide, lithium dnsopropylamide, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium isopropoxide, potassium isopropoxide or lithium carbonate
The reaction of a compound of Formula XX with N,N'-carbonyldnmidazole to give a compound of Formula XXI can be carried out in a solvent, for example, dimethylformamide, tetrahydrofuran, acetonitrile or mixture thereof
The reaction of a compound of Formula XX with N, N'-carbonyldnmidazole can be carried out in the presence of an inorganic base, for example, sodium hydrogen carbonate, potassium carbonate, cesium carbonate, sodium acetate, sodium thiosulphate or sodium hydride
The reaction of a compound of Formula XXI with a compound of Formula R--t-NH2 to give a compound of Formula XXII can be carried out in a solvent system, for example, acetonitrile/water or dimethylformamide/water
The deprotection of a compound of Formula XXII to give a compound of Formula
XXIII can be carried out in an alcohol, for example, methanol, ethanol, propanol or
isopropanol
The desmethylation of a compound of Formula XXIII to give a compound of Formula
XXIV can be carried out in a solvent, for example, acetonitrile, tetrahydrofuran,
dichloromethane, dichloroethane, chloroform, carbontetrachloride, ethyl acetate or mixture
thereof
The desmethylation of a compound of Formula XXIII to give a compound of Formula XXIV can be carried out in the presence of a desmethylating agent, for example, N-iodo succinimide, iodine in acetic acid or dusopropyl azodicarboxylate
The quenching of desmethylation reaction can be carried out in the presence of a quenching agent, for example, sodium bisulphite, sodium carbonate, potassium carbonate, cesium carbonate, sodium acetate or mixture thereof
■5
The alkylation of a compound of Formula XXIV with a reagent of Formula R CHO, R32 CO or R3X to give a compound of Formula I can be carried out in a solvent, for example, dimethylformamide, acetonitrile, methanol, acetone, tetrahydrofuran or mixture thereof
The alkylation of a compound of Formula XXIV can be carried out in the presence of an inorganic or organic base, for example, sodium hydrogen carbonate, potassium carbonate, cesium carbonate, sodium hydride, pyridine, triethylamine, sodium acetate, sodium thiosulphate or dnsopropyl ethylamine
(Formula Removed)
The compound of Formula I can also be prepared according to Scheme IV Thus, a compound of Formula XX (wherein R1 is benzoyl) is deprotected to give a compound of Formula XXV, which on desmethylation at 3'-N-dimethyl group gives a compound of Formula XXVI, which on alkylation with a reagent of Formula R3CHO, R32 CO or R3X (wherein, X and R is as defined earlier) gives a compound of Formula XXVII, which on protection with a reagent of Formula R12O or R1X (wherein X is halogen) gives a compound of Formula XVIII (wherein R1 is the same as defined earlier), which on reaction with N,N'-carbonyldumidazole gives a compound of Formula XIX, which on reaction with a compound
of Formula R--t-NH2 gives a compound of Formula XII (R is the same as defined earlier), which is finally deprotected to give a compound of Formula XIII
The deprotection of a compound of Formula XX to give a compound of Formula
XXV can be carried out in an alcohol, for example, methanol, ethanol, propanol or
isopropanol
The desmethylation of a compound of Formula XXV to give a compound of Formula
XXVI can be carried out in the presence of a desmethylating agent, for example, N-
lodosuccinimide, iodine in acetic acid or dnsopropyl azodicarboxylate
The desmethylation of a compound of Formula XXV can be carried out in a solvent, for example, acetonitrile, tetrahydrofuran, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, ethyl acetate or mixture thereof
The quenching of desmethylation reaction can be carried out in the presence of a quenching agent, for example, sodium bisulphite, sodium carbonate, potassium carbonate, cesium carbonate, sodium acetate or mixture thereof
The alkylation of a compound of Formula XXVI with a reagent of Formula R3CHO, R32CO or R3X to give a compound of Formula XXVII can be carried out in a solvent, for example, dimethylformamide, acetonitrile, tetrahydrofuran, acetone, methanol or mixture thereof
The alkylation of a compound of Formula XXVI can be carried out in the presence of an inorganic or organic base, for example, sodium hydrogen carbonate, potassium carbonate, cesium carbonate, sodium hydride, pyridine, triethylamine, sodium acetate, sodium thiosulphate or dnsopropyl ethylamine
The hydroxyl protection of a compound of Formula XXVII with a reagent of Formula R12O or R1X to give a compound of Formula XVIII can be carried out in a solvent, for example, dichloromethane, dichloroethane, carbontetrachloride, chloroform or acetone
The hydroxyl protection of a compound of Formula XXVII with a reagent of Formula R12O or R1X can be carried out in the presence of an inorganic base, for example, potassium carbonate, cesium carbonate, sodium carbonate, sodium bicarbonate or potassium bicarbonate
The reaction of a compound of Formula XVIII with N, N'-carbonyldnmidazole to give a compound of Formula XIX can be carried out in a solvent, for example, dimethylformamide, tetrahydrofuran, acetonitrile or mixture thereof
The reaction of a compound of Formula XVIII with N, N'-carbonyldnmidazole can be carried out in the presence of an inorganic base, for example, sodium hydrogen carbonate, potassium carbonate, cesium carbonate, sodium acetate, sodium thiosulphate or sodium hydride
The reaction of a compound of Formula XIX with a compound of Formula R--t-NH2 to give a compound of Formula XII can be carried out in a solvent system, for example, acetonitrile/water, dimethylformamide/water or dimethyformamide
The reaction of a compound of Formula XII to give a compound of Formula I can be carried out in an alcohol, for example, methanol, ethanol, propanol or isopropanol
In the above schemes, where the specific bases, oxidizing agents, solvents, etc , are mentioned, it is to be understood that other bases, oxidizing agents, solvents, etc , known to those skilled in the art may be used Similarly, the reaction temperature and duration may be adjusted according to the desired needs
The compounds disclosed herein possess antibacterial activity against gram-positive, gram-negative and anaerobic bacteria They are useful as antibacterial agents for the treatment of bacterial infections in human and animal
Compounds of the present invention useful for such purpose are listed below
2-α-Fluoro-5-0-(3 '-N-desmethyl-3 '-N-allyl)- 11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,1 l-[oxycarbonyl-((4-(4-phenyl-pyrazol-l-yl)-butyl)-imino)] erythromycin A (Compound No 1),
2-α-Fluoro-5-0-(3 '-N-desmethyl-3 '-N-ethyl)-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbony l-((4-(4-pyndin-3-yl-1 H-imidazol-1 -yl)-pentyl)-imino)] erythromycin A (Compound No 2),
2-α-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(4-pyndin-4-yl-1 H-imidazol-1 -yl)-butyl)-imino)] erythromycin A (Compound No 3)
2-α-Fluoro-5-0-(3 '-N-desmethyl-3 '-N-allyl)-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(4-pyndin-4-yl-1 H-imidazol-1 -yl)-butyl)-imino)] erythromycin A (Compound No 4),
2-α-Fluoro-5-0-(3 '-N-desmethyl-3 '-N-ethyl)-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,l 1-[oxycarbonyl-((4-(4-phenyl-pyrazol-l-yl)-butyl)-imino) erythromycin A (Compound No 5),
2-α-Fluoro-5-0-(3 '-N-desmethyl-3 '-N-ethyl)-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,l l-[oxycarbonyl-((4-(indazol-2-yl)-butyl)-imino)] erythromycin A (Compound No 6),
2-α-Fluoro-5-O-(3 '-N-desmethyl-3 '-N-allyl)-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,1 l-[oxycarbonyl-((4-(indazol-2-yl)-butyl)-imino)]erythromycin (Compound No 7),
2-α-Fluoro-5-0-(3 '-N-desmethyl-3 '-N-ethyl)-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,l l-[oxycarbonyl-((4-(3-pyndin-3-yl-pyrazol-l-yl)-butyl)-imino)] erythromycin A (Compound No 8),
2-α-Fluoro-5-0-(3 '-N-desmethyl-3 '-N-ethyl)-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,l l-[oxycarbonyl-((4-(indazol-l-yl)-butyl)-imino)] erythromycin A (Compound No 9),
2-α-Fluoro-5-0-(3 '-N-desmethyl-3 '-N-ethyl)-11,12-dideoxy-3-0-decladinosy 1-6-O-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(4-pyrazin-2-yl-1 H-imidazol-1 -yl)-butyl)-imino)] erythromycin A (Compound No 10),
2-α-Fluoro-5-0-(3 '-N-desmethyl-3 '-N-ethyl)-11,12-dideoxy-3-0-decladinosyl-6-0-methy 1-3-oxo-12,11 -[oxycarbonyl-((4-(4-thiophen-3-yl-1 H-imidazol-1 -yl)-butyl)-imino)] erythromycin A (Compound No 11),
2-α-Fluoro-5-0-(3 '-N-desmethyl-3 '-N-allyl)-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(4-thiophen-3-yl-1 H-imidazol-1 -yl)-butyl)-imino)] erythromycin A (Compound No 12),
2-α-Fluoro-5-0-(3 '-N-desmethyl-3 '-N-ethyl)-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-0X0-12,1 l-[oxycarbonyl-((4-(4-quinohn-3-yl-lH-imidazol-l-yl)-butyl)-imino)] erythromycin A (Compound No 13),
2-α-Fluoro-5-0-(3 '-N-desmethyl-3 '-N-allyl)-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,1 l-[oxycarbonyl-((4-indazol-l-yl)-butyl)-imino)] erythromycin A (Compound No
14),
2-α-FIuoro-5-0-(3 '-N-desmethyl-3 '-N-ethyl)-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(4-pynmidin-5-yl-1 H-imidazol-1 -yl)-butyl)-imino)] erythromycin A (Compound No 15),
2-α-Fluoro-5-0-(3 '-N-desmethyl-3 '-N-allyl)-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(4-pynmidin-5-yl-1 H-imidazol-1 -yl)-butyl)-imino)] erythromycin A (Compound No 16),
2-α-Fluoro-5-0-(3 '-N-desmethyl-3 '-N-ethyl)-11,12-dideoxy-3-0-decladinosy 1-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(4-furan-2-y 1-1 H-imidazol-1 -yl)-butyl)-imino)] erythromycin A (Compound No 17),
2-α-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,l l-[oxycarbonyl-((4-(4-thiophen-2-yl-lH-imidazol-l-yl)-butyl)-imino)] erythromycin A (Compound No 18),
2-α-Fluoro-5-0-(3 '-N-desmethyl-3 '-N-ethyl)-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(4-(4-chloro-phenyl)-1 H-imidazol-1 -yl)-butyl)-imino)] erythromycin A (Compound No 19),
2-α-Fluoro-5-0-(3 '-N-desmethyl-3 '-N-allyl)-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(4-(4-chloro-phenyl)-1 H-imidazol-1 -yl)-butyl)-immo)] erythromycin A (Compound No 20),
2-α-Fluoro-5-0-(3 '-N-desmethyl-3 '-N-ethyl)-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbony l-((4-(4-pyndin-2-yl-1 H-imidazol-1 -yl)-butyl)-imino)] erythromycin A (Compound No 21),
2-α-Fluoro-5-0-(3 '-N-desmethyl-3 '-N-allyl)-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(4-pyndin-2-yl-1 H-imidazol-1 -yl)-butyl)-imino)] erythromycin A (Compound No 22),
2-α-Fluoro-5-0-(3'-N-desmethyl-3'-N-allyl)-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,l l-[oxycarbonyl-((9-(4-amino-butyl)-9H-punn-6-yl)-imino)] erythromycin A (Compound No 23),
2-α-Fluoro-5-0-(3'-N-desmethyl-3'-N-allyl)-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,1 l-[oxycarbonyl-((4-(3-pyndin-3-yl-lH-pyrazol-l-yl)-butyl)-imino)] erythromycin A (Compound No 24),
2-α-Fluoro-5-0-(3 '-N-desmethyl-3 '-N-2-fluoroethyl)-11,12-dideoxy-3 -O-decladinosyl-6-0-methy 1-3-oxo-12,11 -[oxycarbonyl-((4-(4-(4-chloro-pheny 1)-1 H-imidazol-1 -yl)-butyl)-imino)] erythromycin A (Compound No 25),
2-α-Fluoro-5-0-(3 '-N-desmethyl-3 '-N-2-fluoroethyl)-11,12-dideoxy-3 -O-decladinosyl-6-0-methy 1-3-oxo-12,11 -[oxycarbonyl-((4-(4-pyndin-2-y 1)-1 H-imidazol-1 -yl)-butyl)-imino)] erythromycin A (Compound No 26),
2-α-Fluoro-5-0-(3 '-N-desmethyl-3 '-N-ethy l)-desosaminy 1-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-(4-(3H-Imidazo[4,5-b]pyndine-2-yl)-butyl) lminoerythromycin A (Compound No 27),
2-α-Fluoro-5-0-(3 '-N-desmethyl-3 '-N-ethy l)-desosammyl-11,12-dideoxy-3-0-decladinosy 1-6-0-methy 1-3-oxo-12,11 -[oxycarbonyl-(4-(4-Tetrazol-1 -yl-imidazol-1 -yl)-butyl) lminoerythromycin A (Compound No 28),
2-α-Fluoro-5-0-(3 '-N-desmethyl-3 '-N-ethy l)-desosaminyl-11,12-dideoxy-3-0-decladinosyl-6-O-methy 1-3-oxo-12,11 -[oxycarbony l-(4-( 1 H-Benzoimidazol-2-yl)-butyl)iminoerythromycin A (Compound No 29),
2-α-Fluoro-5-0-(3 '-N-desmethyl-3 '-N-ethyl)-desosaminyl-11,12-dideoxy-3-0-decladinosy 1-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-(4-[4-(6-Fluoro-pyndin-3-yl)-imidazol-l -yl]-butyl) lminoerythromycin A (Compound No 30),
2-α-Fluoro-5-0-(3 '-N-desmethyl-3 '-N-ethy l)-desosaminyl-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-(4-(3H-Imidazo[4,5-c]pyndine-2-yl)-butyl) lminoerythromycin A (Compound No 31),
2-α-Fluoro-5-0-(3 '-N-desmethyl-3 '-N-ethyl)-desosaminy 1-11,12-dideoxy-3-0-decladinosy 1-6-O-methy 1-3 -oxo-12,11- [oxycarbony l-(4-(4-[ 1,2,4] Tnzol-1 -yl-pheny 1)-butyl)iminoerythrornycin A (Compound No 32),
2-α-Fluoro-5-0-(3 '-N-desmethyl-3 '-N-ethy l)-desosaminyl-11,12-dideoxy-3-0-decladinosy 1-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-(4-(4-Imidazol-1 -yl-phenyl)-butyl)iminoerythromycin A (Compound No 33),
2-α-Fluoro-5-0-(3 '-N-desmethyl-3 '-N-ethyl)-desosaminyl-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-(4-[4-(6-Chloro-pyndin-3-yl)-imidazol-l-yl]-butyl) lminoerythromycin A (Compound No 34),
2-α-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-desosaminyl-11,12-dideoxy-3-0-decladinosyl-6-O-methy 1-3-oxo-12,11 -[oxycarbonyl-(3-[ 1 -(4-Amino-buty 1)-1 H-imidazol-4-y 1]-phenyl)iminoerythromycin A (Compound No 35),
2-α-Fluoro-5-0-(3 '-N-desmethyl-3 '-N-ethy l)-desosaminy 1-11,12-dideoxy-3-0-decladinosy 1-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-(4-(4-Pyndin-3-yl-thiazol-2-yl)-butyl)iminoerythromycin A (Compound No 36),
2-α-Fluoro-5-0-(3 '-N-desmethyl-3 '-N-ethy l)-desosaminy 1-11,12-dideoxy-3-0-decladinosy 1-6-0-methyl-3-oxo-12,l l-[oxycarbonyl-(3-[2-(4-Amino-butyl)-thiazol-4-yl]-phenyl) lminoerythromycin A (Compound No 37),
2-α-Fluoro-5-0-(3 '-N-desmethyl-3 '-N-ethy l)-desosaminy 1-11,12-dideoxy-3-0-decladinosyl-6-O-methy 1-3-oxo-12,11 -[oxycarbony l-(4-(4-Pyrazol-1 -y 1-imidazol-1 -y l)-butyl) lminoerythromycin A (Compound No 38),
2-α-Fluoro-5-0-(3 '-N-desmethyl-3 '-N-ethyl)-desosaminyl-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,ll-[oxycarbonyl-(4-([l,4']-Bipyrazolyl-l'-yl)-butyl)iminoerythromycin A (Compound No 39),
2-α-Fluoro-5-0-(3 '-N-desmethyl-3 '-N-ethy l)-desosaminy 1-11,12-dideoxy-3-0-decladinosy 1-6-0-methyl-3-oxo-12,11 -[oxycarbony l-(4-(4-Imidazol-1 -yl-pyrazol-1 -yl)-butyl) lminoerythromycin A (Compound No 40),
2-α-Fluoro-5-0-(3 '-N-desmethyl-3 '-N-ethy l)-desosaminy 1-11,12-dideoxy-3-0-decladmosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-(4-(4-Pyrazol-1 -yl-imidazol-1 -yl)-butyl) lminoerythromycin A (Compound No 41),
2-α-Fluoro-5-0-(3 '-N-desmethyl-3 '-N-ethy l)-desosaminyl-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,l l-[oxycarbonyl-(4-[3,3']Bithiophenyl-5-yl-butyl)iminoerythromycin A (Compound No 42),
2-α-Fluoro-5-0-(3 '-N-desmethyl-3 '-N-ethyl)-desosaminyl-11,12-dideoxy-3-Odecladinosyl-6-0-methyl-3-oxo-12,11-[oxycarbonyl-(4-[2,3']Bithiophenyl-5'-yl-butyl)iminoerythromycin A (Compound No 43),
2-α-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-desosaminyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11-[oxycarbonyl-(4-(4-Furan-2-yl-thiaophen-2-yl)-butyl)iminoerythromycin A (Compound No 44),
2-α-Fluoro-5-0-(3 '-N-desmethyl-3 '-N-ethyl)-desosaminyl-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11-[oxycarbonyl-(4-(4-Oxazol-5-yl-imidazol-l-yl)-butyl)iminoerythromycin A (Compound No 45),
2-α-Fluoro-5-0-(3 '-N-desmethyl-3 '-N-ethy l)-desosaminy 1-11,12-dideoxy-3-0-decladinosy 1-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-(4-(3-Pyrrol-1 -yl-[ 1,2,4]tnazol-1 -yl)-butyl) lminoerythromycin A (Compound No 46),
2-α-Fluoro-5-0-(3 '-N-desmethyl-3 '-N-ethy l)-desosaminy 1-11,12-dideoxy-3-0-decladinosy 1-6-0-methyl-3-oxo-12,l l-[oxycarbonyl-(4-(5-Thiophen-2-yl-tetrazol-2-yl)-butyl) lminoerythromycin A (Compound No 47),
2-α-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-desosaminyl-ll,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-l 2,11 -[oxycarbonyl-(4-(4-Thiophen-3-yl-pyrazol-1 -yl)-butyl) lminoerythromycin A (Compound No 48),
2-α-Fluoro-5-0-(3 '-N-desmethyl-3 '-N-ethy l)-desosaminy 1-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,l l-[oxycarbonyl-(4-(4-Furan-3-yl-pyrazol-l-yl)-butyl)iminoerythromycin A (Compound No 49),
2-α-Fluoro-5-0-(3 '-N-desmethyl-3 '-N-ethy l)-desosaminy 1-11,12-dideoxy-3-0-decladinosy 1-6-0-methyl-3-oxo-12,11-[oxycarbonyl-(4-(4-Furan-2-yl-pyrazol-l-yl)-butyl)iminoerythromycin A (Compound No 50),
2-α-Fluoro-5-0-(3 '-N-desmethyl-3 '-N-ethy l)-desosaminy 1-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11-[oxycarbonyl-(4-(5-Phenyl-tetrazol-2-yl)- butyl)iminoerythromycin A (Compound No 51),
2-α-Fluoro-5-0-(3 '-N-desmethyl-3 '-N-ethy l)-desosaminy 1-11,12-dideoxy-3-0-decladinosy 1-6-0-methyl-3-oxo-12,11-[oxycarbonyl-(4-[5-(4-Methoxy-phenyl)-tetrazol-2-yl]-butyl) lminoerythromycin A (Compound No 52),
2-α-Fluoro-5-0-(3 '-N-desmethyl-3 '-N-ethy l)-desosaminy 1-11,12-dideoxy-3-0-decladinosy 1-6-O-methy 1-3-oxo-12,11 -[oxycarbonyl-(4-(5-Furan-3-yl-imidazol-1 -yl)-butyl)iminoerythromycin A (Compound No 53),
2-α-Fluoro-5-0-(3 '-N-desmethyl-3 '-N-ethy l)-desosaminy 1-11,12-dideoxy-3-0-decladinosy 1-6-0-methyl-3-oxo-12,11-[oxycarbonyl-(4-(6-Pyrazol-l-yl-pyndin-3-yl)-butyl)iminoerythromycin A (Compound No 54),
2-α-Fluoro-5-0-(3 '-N-desmethyl-3 '-N-ethy l)-desosaminyl-11,12-dideoxy-3-Odecladinosyl-6-0-methy 1-3-oxo-12,11 -[oxycarbonyl-(4-(4-Pyndin-3-yl-pyrazol-1 -yl)-butyl)iminoerythromycin A (Compound No 55),
2-0t-Fluoro-5-O-(3 '-N-desmethyl-3 '-N-ethyl)-desosaminyl-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11-[oxycarbonyl-(4-(5-Thiophen-2-yl-pyridin-3-yl)-butyl)imino-erythromycin A (Compound No 56),
2-α-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-desosaminyl-l 1,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11-[oxycarbonyl-(4-(4-Phenyl-thiophen-2-yl)-butyl)iminoerythromycin A (Compound No 57),
2-α-Fluoro-5-0-(3 '-N-desmethyl-3 '-N-ethyl)-desosaminyl-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,l l-[oxycarbonyl-(N-(4-Amino-butyl)-N-thiazol-2-yl-mcotinimido)]erythromycin A (Compound No 58),
2-α-Fluoro-5-0-(3 '-N-desmethyl-3 '-N-ethy l)-desosaminy 1-11,12-dideoxy-3-0-decladinosy 1-6-0-methyl-3-oxo-12,11-[oxycarbonyl-(N-(4-Amino-butyl)-N-thiazol-2-yl-nicotimmido)]erythromycin A (Compound No 59),
2-α-Fluoro-5-0-(3 '-N-desmethyl-3 '-N-ethyl)-desosaminy 1-11,12-dideoxy-3-0-decladinosy 1-6-0-methyl-3-oxo-12,l l-[oxycarbonyl-(4-[4-(6-Pyrrol-l-yl-pyridin-3-yl)-imidazol-l-yl]-butyl)iminoerythromycin A (Compound No 60),
2-α-Fluoro-5-0-(3 '-N-desmethyl-3 '-N-ethyl)-desosaminyl-11,12-dideoxy-3-0-decladinosy 1-6-O-methy 1-3-oxo-12,11 -[oxycarbonyl-(4-(6-Pyrrol-1 -yl-pyridin-3-y 1)-butyl)iminoerythromycin A (Compound No 61),
2-cc-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-desosaminyl-11,12-dideoxy-3-0-decladinosyl-6-O-methy 1-3-oxo-12,11 -[oxycarbony l-(4-(2-Pyrrol-1 -yl-thiazol-5-yl)-butyl)iminoerythromycin A (Compound No 62),
2-α-Fluoro-5-0-(3 '-N-desmethyl-3 '-N-ethyl)-desosaminyl-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-(4-(6-Imidazol-l -yl-pyridin-3-yl)-butyl) lminoerythromycin A (Compound No 63),
2-α-Fluoro-5-0-(3 '-N-desmethyl-3 '-N-ethyl)-desosaminyl-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,l l-[oxycarbonyl-(4-[4-(Tetrahydro-furan-2-yl)-pyridin-3-yl]-butyl) lminoerythromycin A (Compound No 64),
2-α-Fluoro-5-0-(3 '-N-desmethyl-3 '-N-ethy 1)-11,12-dideoxy-3-0-decladmosy 1-6-0-methy 1-3-oxo-12,l l-[oxycarbonyl-((4-(4-p-tolyl-imidazol-l-yl)-butyhmino)] erythromycin A (Compound No 65),
2-α-Fluoro-5-0-(3 '-N-desmethyl-3 '-N-ethyl)-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-(4-(4-(4-aminophenyl)-imidazol-1 -yl)-butylimino)] erythromycin A (Compound No 66),
2-α-Fluoro-5-0-(3'-N-desmethyl-3'-N-ethyl)-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbony l-(4-(4-(4-methy 1-3-aminopheny l)-imidazol-1 -yl)-butyhmino)] erythromycin A (Compound No 67),
2-ct-Fluoro-5-0-(3 '-N-desmethyl-3 '-N-ethyl)-11,12-dideoxy-3-0-decladinosy 1-6-0-methyl-3-oxo-12,l l-[oxycarbonyl-((4-(4-(3-imidazol-lyl)-phenyl)imidazol-l-yl)-butyhmino)] erythromycin A (Compound No 68),
2-α-Fluoro-5-0-(3 '-N-desmethyl-3 '-N-ethyl)-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbony l-(4-(4-(3-(N,N-dicyclopropyl-amino)-phenyl)-imidazol-1 -y 1)-butylimino)] erythromycin A (Compound No 69),
2-α-Fluoro-5-0-(3 '-N-desmethyl-3 '-N-ethyl)-11,12-dideoxy-3-0-decIadinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbony l-(4-(4-(3-(N,N-dimethyl-amino)phenyl)-imidazol-1 -yl)-butyhmino)] erythromycin A (Compound No 70),
2-α-Fluoro-5-0-(3 '-N-desmethyl-3 '-N-ethyl)-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,l l-[oxycarbonyl-((4-(4-(3-(tetrazol-lyl)-phenyl)-imidazol-l-yl)-butyhmino)] erythromycin A (Compound No 71),
2-α-Fluoro-5-0-(3 '-N-desmethyl-3 '-N-ethyl)-11,12-dideoxy-3-0-decladinosy 1-6-0-methyl-3-oxo-12,11 -[oxycarbony l-((4-(4-(2-(pyrrol-1 y l)-thiozol-5-y l)-imidazol-1 -yl)-buty hmino)] erythromycin A (Compound No 72),
2-oc-Fluoro-5-0-(3 '-N-desmethyl-3 '-N-ethyl)-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(4-(3-tnfluoromethyl-phenyl)-imidazol-1 -yl)-butyhmino)] erythromycin A (Compound No 73),
2-α-Fluoro-5-0-(3 '-N-desmethyl-3 '-N-ethyl)-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,l l-[oxycarbonyl-((4-(N-(thiazol-2-yl)-benzimido)-butyhmino)] erythromycin A (Compound No 74),
2-α-Fluoro-5-0-(3 '-N-desmethyl-3 '-N-ethyl)-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,l l-[oxycarbonyl-(4-(4-(2-amino-pynmidin)-5-yl)-imidazol-l-yl)-butyhmino)] erythromycin A (Compound No 75),
2-α-Fluoro-5-0-(3 '-N-desmethyl-3 '-N-ethyl)-11,12-dideoxy-3-0-decladinosy 1-6-0-methy 1-3-oxo-12,11 -[oxycarbony l-((4-(4-(4-(pyrrol-1 y l)-pheny l)-imidazol-1 -y l)-buty hmino)] erythromycin A (Compound No 76),
2-α-Fluoro-5-0-(3 '-N-desmethyl-3 '-N-ethyl)-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbony l-((4-(4-(3-(pyrrol-1 y l)-pheny l)-imidazol-1 -y l)-buty hmino)] erythromycin A (Compound No 77),
2-α-Fluoro-5-0-(3 '-N-desmethyl-3 '-N-ethyl)-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,l l-[oxycarbonyl-(4-(4-(3-(N-acetyl-amino)-phenyl)-imidazol-l-yl)-butyhmino)] erythromycin A (Compound No 78),
2-α-Fluoro-5-0-(3 '-N-desmethyl-3 '-N-ethyl)-11,12-dideoxy-3-Odecladinosy 1-6-O-methyl-3-oxo-12,11 -[oxycarbony l-(4-(4-(3-(N-isopropyl-amino)-phenyl)-imidazol-1 -y 1)-butylimino)] erythromycin A (Compound No 79),
2-α-Fluoro-5-0-(3 '-N-desmethyl-3 '-N-ethyl)-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(4-(3-nitrophenyl)-imidazol-1 -yl)-butyhmino)] erythromycin A (Compound No 80),
2-α-Fluoro-5-0-(3 '-N-desmethyl-3 '-N-ethyl)-11,12-dideoxy-3-0-decladinosy 1-6-O-methyl-3-oxo-12,11 -[oxycarbonyl-(4-(4-(3-(N-benzoy l-amino)-phenyl)-imidazol-1 -yl)-buty limino)] erythromycin A (Compound No 81),
2-α-Fluoro-5-0-(3 '-N-desmethyl-3 '-N-ethyl)-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,l l-[oxycarbonyl-((4-(4-(3,4-dimethyl-phenyl)-imidazol-l-yl)-butyhmino)] erythromycin A (Compound No 82),
5-0-(3 '-N-desmethyl-3 '-N-ethyl)-11,12-dideoxy-3-0-decladinosy l-6-0-methyl-3-oxo-12,11-[oxycarbonyl-(((4-(4-Pyndin-3-yl-thiazol-2-yl)-butyhmino)] erythromycin A (Compound
No 83),
2-α-Fluoro-5-0-(3 '-N-desmethyl-3 '-N-ethyl)-11,12-dideoxy-3-0-decladinosy 1-6-O-methy 1-3-oxo-12,l 1-[oxycarbonyl-((4-(4-(4-fluorophenyl)-imidazol-l-yl)-butylimino)] erythromycin A (Compound No 84),
2-α-Fluoro-5-0-(3 '-N-desmethyl-3 '-N-ethyl)-11,12-dideoxy-3-Odecladinosyl-6-0-methyl-3-oxo-12,l l-[oxycarbonyl-((4-(4-(4-methoxy-phenyl)-imidazol-l-yl)-butyhmino)] erythromycin A (Compound No 85),
2-α-Fluoro-5-0-(3 '-N-desmethyl-3 '-N-ethyl)-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,l l-[oxycarbonyl-((4-(N-(benzthiazol-2-yl)-benzimido)-butyhmino)] erythromycin A (Compound No 86),
2-α-Fluoro-5-0-(3 '-N-desmethyl-3 '-N-ethyl)-11,12-dideoxy-3-0-decladinosy 1-6-O-methyl-3-oxo-12,l l-[oxycarbonyl-((4-(N-(thiazol-2-yl)-nicotinamido)-butylimmo)] erythromycin A (Compound No 87),
2-α-Fluoro-5-0-(3 '-N-desmethyl-3 '-N-ethyl)-11,12-dideoxy-3-0-decladinosy 1-6-O-methyl-3-oxo-12,11 -[oxycarbonyl-(4-(4-(3-(N-methy l-amino)-pheny l)-imidazol-1 -y l)-butyhmino)] erythromycin A (Compound No 88),
2-α-Fluoro-5-0-(3 '-N-desmethyl-3 '-N-ethyl)desosaminyl-11,12-dideoxy-3-0-decladinosyl-6-0-methy 1-3-oxo-12,11 - [oxycarbony l-(4-(4-(4-(2-aminopyridy l)-imidazol-1 -yl)-butyhmino)] erythromycin A (Compound No 89),
2-α-Fluoro-5-0-(3 '-N-desmethyl-3 '-N-ethy l)desosaminy 1-11,12-dideoxy-3-0-decladinosy 1-6-0-methyl-3-oxo-12,l l-[oxycarbonyl-(4-(4-(5-(2-aminopyridyl)- 2H-tetrazol-5-yl)-butylimino)] erythromycin A (Compound No 90),

2-α-Fluoro-5-O-(3 '-N-desmethyl-3 '-N-ethyl)desosaminyl-11,12-dideoxy-3-O-decladinosyl-6-O-methy 1-3 -oxo-12,11- [oxycarbony l-(4-(4-(3,4-difluorophenyl)-imidazol-1 -y 1)-butyhmino)] erythromycin A (Compound No 91),
2-α-Fluoro-5-O-(3 '-N-desmethyl-3 '-N-ethyl)desosaminy 1-11,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,11-[oxycarbonyl-(4-(4-(4-(2-chloropyridyl)-imidazol-l-yl)-butyhmino)] erythromycin A (Compound No 92),
2-α-Fluoro-5-O-(3 '-N-desmethyl-3 '-N-ethyl)desosaminyl-11,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,11-[oxycarbonyl-(4-(4-(3-(6-aminopyridyl)-imidazol-l-yl)-burylimino)] erythromycin A (Compound No 93),
2-α-Fluoro-5-O-(3 '-N-desmethyl-3 '-N-ethyl)desosaminyl-11,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,11-[oxycarbonyl-(4-(5-(2-Chloro-pyridin-4-yl)-tetrazol-2-yl])-butylimino)] erythromycin A (Compound No 94),
pharamceutically acceptable salts, pharamceutically acceptable solvates, stereoisomers, prodrugs, metabolites and polymorphs thereof
In the above schemes, where specific bases, acids, solvents etc are mentioned, it is to be understood that other bases, acids, solvents etc , known to those skilled in the art may also be used Similarly, the reaction temperature and duration of the reactions may be adjusted according to the desired needs All the epimers, unless otherwise specified in the above schemes are also encompassed within the scope of the invention
Because of their antibacterial activity, the compounds described herein may be administered to an animal for treatment orally, topically, rectally, internasally, or by parenteral route The pharmaceutical compositions of the present invention comprise a pharmaceutically effective amount of compounds described herein formulated together with one or more pharmaceutically acceptable carriers
Solid form preparation for oral administrations includes capsules, tablet, pills, powder, granules, cachets and suppository For solid form preparation, the active compound is mixed with at least one inert, pharmaceutically acceptable excipients or carrier, for example, sodium citrate, dicalcium phosphate and/or a filler or extenders, for example, starches, lactose, sucrose, glucose, mannitol and silicic acid, binders, for example, carboxymethylcellulose, alginates, gelatins, polyvinylpyrrolidinone, sucrose, acacia, disintegrating agents, for example, agar-agar, calcium carbonate, potato starch, alginic acid, certain silicates and sodium carbonate, absorption acceletors , for example, quaternary ammonium compounds, wetting agents , for example, cetyl alcohol, glycerol mono stearate, adsorbants , for example, Kaolin, lubricants , for example, talc, calcium stearate, magnesium
stearate, solid polyethyleneglycol, sodium luaryl sulphate and mixture thereof In the case of capsules, tablets, pills, the dosage form may also comprise buffering agents
The solid preparation of tablets, capsules, pills and granules can be prepared with coating and shells, for example, enteric coating and other coatings well known in the pharmaceutical formulating art
Liquid form preparation for oral administration includes pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs For liquid form preparation, the active compound is mixed with water or other solvent, solubilizing agents and emulsifiers, for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, dimethylformamide, oils, for example, cottonseed, groundnut, corn, germ, olive, castor and sesame oil), glycerol, and fatty acid esters of sorbitan and mixture thereof Besides inert diluents, the oral composition can also include adjuants, for example, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavouring agents and perfuming agents
Injectable preparations, for example, sterile injections, aqueous suspensions may be formulated according to the art using suitable dispersing or wetting and suspending agent Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride
Dosage form for tropical or transdermal administration of a compound of the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches The active compound is admixed under sterile condition with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required Ophthalmic formulations, eardrops, eye ointments, powder and solution are also contemplated as being within the scope of this invention
The pharmaceutical preparation is in unit dosage form In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component The unit dosage form can be packaged preparation, the package containing discrete capsules, powders, in vials or ampoules, and ointments capsule, sachet, tablet, gel, cream itself or it can be the appropriate number of any of these packaged forms
Examples set forth below demonstrates the general synthetic procedure for the preparation of representative compounds The examples are provided to illustrate particular aspect of the disclosure and do not constrain the scope of the present invention as defined by the claims
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention
EXPERIMENTAL DETAILS General Procedure
Preparation of R-W-NH2
(a) when W= -(CH2)4 -
Preparation of 4-(3H)-imidazol [4,5-b]pyridin-3-yl-butylamine
It was prepared by following the procedure given in US Patent No 5,635,485
(b) When W = -(CH2)3NC(O)G-
Preparation ofN-(4-Aminobutyl)-N-benzothiazole-2-yl-benzamide
Step 1 Preparation of N-Benzothiazol-2-yl-benzamide
To a solution of Benzothiazol-2-ylamine (5 Og, 1 Oeq) in pyridine was added benzoyl
chloride (3 8ml, 1 Oeq) in portions at 25 C After complete addition the reaction mixture was
heated to 70 °C for 45 min Reaction mixture was cooled to 40 °C and poured into ice cold
water The solid was filtered under vacuum and dried to give the desired product
Yield 8 5g
Step II Preparation of N-Benzothiazol-2-vl-N-[4-(l,3-dioxo-l,3-dihydro-isoindol-2-vn-
butyl]-benzamide
To a stirred solution of N-Benzothiazol-2-yl-benzamide (8 5 g, 1 Oeq) in N,N-dimethyl
formamide(90ml) was added sodium hydnde(2g, 1 5eq) in portions at 0 °C, stirred for 30
min To this was added N-(4-bromobutyl)-phthahmide (12 25g, 1 3eq) and stirred for about 2
hours at 0 to 5 °C Reaction mixture was poured into ice-cold water Solid was filtered and
dried under vacuum to give N-Benzothiazol-2-yl-N-[4-(l,3-dioxo-l,3-dihydro-isoindol-2-yl)-
butyl]-benzamide
Yield 12g
Step III Preparation of N-(4-Aminobutyl)-N-benzothiazol-2-yl-benzamide To a solution of N-Benzothiazol-2-yl-N-[4-(l,3-dioxo-l,3-dihydro-isoindol-2-yl)-butyl]-benzamide (6 Og, 1 Oeq) in ethanol (75ml) hydrazine monohydrate (3 72ml, 6 Oeq) was added and reaction mixture was heated to 70 °C for 6h Reaction mixture was cooled to 30 °C and digested with dichloromethane The solid was filtered on celite bed The filtrate was concentrated under reduced pressure The resulting crude was purified by column
chromatography using methanol- dichloromethane-triethylamine as eluant to give N-(4-
Amino-butyl)-N-benzothiazol-2-yl-benzamide
Yield 0 8g
Scheme I
Preparation of compound of Formula HI
To an aqueous solution of hydrochloric acid was added clarithromycin (25 gm, 33 4 mmol) at an ambient temperature in portion The reaction mixture was neutralized with solid sodium bicarbonate and the aqueous layer was extracted with ethyl acetate Organic layer was washed with water, brine, and dried over anhydrous sodium sulphate and the solvent was removed under reduced pressure to afford crude product The crude product was crystallized by using ethyl acetate and hexane
Preparation of compound of Formula IV
To a solution of compound of Formula III (1 equiv) in dichloromethane was added benzoic anhydride (2 5 equiv) followed by triethylamine (6 equiv ) and stirred at an ambient temperature for about 40 hours The reaction was quenched by addition of sodium bicarbonate solution The aqueous layer was extracted with dichloromethane, washed successively with water, brine, and dried over anhydrous sodium sulphate and the solvent was removed under reduced pressure to give crude product The crude product obtained was crystallized by using ethyl acetate and hexane mixture
Preparation of compound of Formula V
To a solution of compound of Formula IV (1 equiv ) in dry acetonitrile dichloromethane (2 1) was added N-iodosuccinimide (2 equiv) at about 0 °C and the reaction mixture was allowed to attain an ambient temperature and stirred The reaction mixture was stirred with a sodium bisulphite solution followed by stirring with sodium carbonate solution Dichloromethane was evaporated under reduced pressure The aqueous layer was extracted with ethyl acetate, washed successively with water, brine, and dried over anhydrous sodium sulphate and then the solvent was removed under reduced pressure to yield a crude product Purification of the crude product was done by silica gel column chromatography (thoroughly neutralized with triethylamine) using 17-25% acetone in hexane to afford the desired product
Preparation of compound of Formula VI
Compound of Formula VI can be prepared by three different methods
Method A
To a solution of compound of Formula V (1 equiv) in acetonitrile was added solid sodium hydrogen carbonate (5 equiv) and ethyl iodide (6 equiv) under argon at an ambient temperature and stirred for about 24 hours, the reaction was quenched by the addition of water Reaction mixture was diluted with ethyl acetate and washed with water followed by brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to yield a crude product Purification of the crude product was done by silica gel column chromatography (thoroughly neutralized with triethylamine) using 10-15% acetone in hexane to afford the desired product
Method B
The compound of Formula V (1 equiv) in acetone and methanol was stirred at an ambient temperature A solution of acetic acid was added and stirred and to it was added sodium cyanoborohydnde (2 equiv) and stirred Solvent was evaporated under reduced pressure and the crude product was extracted with ethyl acetate Ethyl acetate layer was combined and washed with water, brine, and dried over anhydrous sodium sulphate and concentrated under reduced pressure Purification of the crude product was done by silica gel column chromatography (thoroughly neutralized with triethylamine) using 10-20% acetone in hexane to afford the desired product
Method C
To a solution of compound of Formula V (1 equiv) in methanol was added (1-ethoxycyclopropoxy) tnmethylsilane (3 equiv) followed by glacial acetic acid (10 equiv) at an ambient temperature and stirred The reaction mixture was cooled and was added sodium cyanoborohydnde (5 equiv) Then the reaction mixture was stirred and refluxed Methanol was evaporated under reduced pressure, and water was added Organic layer was extracted with ethyl acetate Ethyl acetate layer was combined and washed with water, brine, and dried over anhydrous sodium sulphate and concentrated under reduced pressure Purification of the crude product was done by silica gel column chromatography (thoroughly neutralized with triethylamine) using 10-20% acetone in hexane to afford the desired product
Preparation of compound of Formula VII
To a solution of compound of Formula VI (1 equiv ) in dichloromethane was added triphosgene (1 5 equiv) To it pyridine was added (15 equiv ) slowly After complete addition, reaction mixture was stirred for about 4 hours and the reaction was quenched by addition of ice-cold water Reaction mixture was diluted with dichloromethane and washed with water followed by brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the desired product
Preparation of compound of Formula VIII
To a solution of compound of Formula VII (1 equiv ) in dimethylformamide was added tetramethyl guanidine (2 2 equiv) and heated at 70 °C, stirred for about 10 hours Reaction mixture was cooled to an ambient temperature Organic layer was extracted with ethyl acetate and washed with water followed by brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain the desired product Preparation of compound of Formula IX
To a solution of compound of Formula VIII (1 equiv) in dichloromethane Dess-Martine Penodinane (2 5 equiv) was added and refluxed for about an hour Reaction was cooled to an ambient temperature and quenched by addition of saturated aqueous potassium carbonate solution followed by saturated sodium thiosulphate solution and stirred Aqueous layer was separated and extracted with dichloromethane Dichloromethane layer was washed with water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the desired product
Preparation of compound of Formula X
To a solution of compound of Formula IX (1 equiv) in dimethylformamide tetrahydrofuran (3 2) N, N'-carbonyldnmidazole (3 equiv) at an ambient temperature was added It was cooled, sodium hydride (3 equiv ) was added in portions and was stirred The reaction mixture was quenched by addition of water It was extracted with ethyl acetate The organic layer was washed with water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the desired product
Preparation of compound of Formula XI
Compound of Formula XI can be prepared by two different methods
Method A
The compound of Formula X (1 equiv ) and R--t-NH2 (2 equiv ) were taken in water in acetonitrile and heated at 70 °C, stirred for about 20 hours, reaction mixture was cooled to attain an ambient temperature and acetonitrile was removed under reduced pressure The resulting residue was taken in ethyl acetate and washed with water, brine, dried over anhydrous sodium sulphate, and filtered The filtrate was collected and concentrated under reduced pressure Purification of the crude product was done by silica gel column chromatography (thoroughly neutralized with triethylamine) using 25-30% acetone in hexane to afford the desired product
Method B
The compound of Formula X (1 equiv) and R--t-NH2 (2 equiv) were taken in dimethylformamide and heated at 70 °C, stirred for about 20 hours Reaction mixture was cooled to an ambient temperature, dimethylformamide was evaporated under reduced pressure The resulting crude product was taken in ethyl acetate and washed with water, brine, and dried over anhydrous sodium sulphate and concentrated under reduced pressure Purification of the crude product was done by silica gel column chromatography (thoroughly neutralized with triethylamine) using 25-30% acetone in hexane to afford the desired product
Preparation of compound of Formula XII Method A
To a cold solution of compound of Formula XI (1 equiv) in dimethylformamide was added sodium hydride (1 5 equiv ) in portions Then added N-fluorobenzene sulfonimide (1 2 equiv) Reaction was quenched by addition of water and extracted with ethyl acetate Organic layer was washed with water followed by brine, dried over anhyrdous sodium sulphate and concentrated under reduced pressure
Method-B
To a solution of compound of Formula XI (1 equiv) in tetrahydrofuran was added potassium (tert) butoxide (1 5 equiv) at -15 °C, stirred for 20 min Then added N-fluorobenzene sulfonimide (1 2 equiv) in tetrahydrofuran Reaction mixture was stirred at -15 °C for about 3 hours, quenched by addition of water and extracted with ethyl acetate
Organic layer was washed with water followed by brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure Preparation of compound of Formula XIII
The compound of Formula XII (560 mg, 0 6 mmol) was taken in methanol and refluxed Reaction mixture was cooled to attain an ambient temperature and methanol was evaporated under reduced pressure Purification of the solid mass was done over a silica gel column (thoroughly neutralized with triethylamine) using 20-40% acetone in hexane or 2-6% methanol in dichloromethane to afford the desired product
Scheme II
Preparation of compound of Formula XIV
To a solution of compound of Formula IV (1 equiv) in dichloromethane was added triphosgene (1 5 equiv) To it was added pyridine (15 equiv) slowly After complete addition, reaction mixture was stirred for about 3-4 hours at 0 C The reaction was quenched by addition of ice-cold water Reaction mixture was diluted with dichloromethane and washed with water followed by brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the desired product Preparation of compound of Formula XV
To a solution of compound of Formula XIV (1 equiv) in dimethylformamide was added tetramethyl guanidine (2 2 equiv) and heated at 65-70 °C for about 3-4 hours Reaction mixture was cooled to an ambient temperature Organic layer was extracted with ethyl acetate and washed with water followed by brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain the desired product
Preparation of compound of Formula XVI
To a solution of compound of Formula XV (1 equiv ) in dichloromethane was added Dess-Martine Penodinane (2 5 equiv) and stirred at 30 C for about 1 hour Reaction was quenched by addition of saturated aqueous potassium carbonate solution followed by saturated sodium thiosulphate solution and stirred Aqueous layer was separated and extracted with dichloromethane Dichloromethane layer was washed with water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the desired product
Preparation of compound of Formula XVII
To a solution of compound of Formula XVI (1 equiv) in dry acetonitrile dichloromethane (2 1) was added N-iodosuccinimide (2 equiv ) and the reaction mixture was allowed to attain an ambient temperature and stirred for about 3-4 hours Then the reaction mixture was stirred with a sodium bisulphite solution followed by stirring with sodium carbonate solution Dichloromethane was evaporated under reduced pressure The aqueous layer was extracted with ethyl acetate, washed successively with water, brine, and dried over anhydrous sodium sulphate and then the solvent was removed under reduced pressure to yield a crude product
Preparation of compound of Formula IX
To a solution of compound of Formula XVII (1 equiv ) in acetonitrile was added solid sodium hydrogen carbonate (5 equiv ) and ethyl iodide (6 equiv ) under argon at an ambient temperature and stirred for about 18-20 hours Reaction was quenched by the addition of water Reaction mixture was diluted with ethyl acetate and washed with water followed by brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to yield a crude product Purification of the crude product was done by silica gel column chromatography (thoroughly neutralized with triethylamine) using 10-15% acetone in hexane to afford the desired product Preparation of compound of Formula XVIII Method-A
To a solution of compound of Formula IX (1 equiv) in dimethylformamide was added sodium hydride (1 5 equiv) in portions at 0 °C, stirred for about 15 mm Then N-fluorobenzene sulfonimide (1 2 equiv) was added Reaction mixture was stirred at 0 °C for about 3 hour Reaction was quenched by addition of water and extracted with ethyl acetate Organic layer was washed with water followed by brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure
Method- B
To a solution of compound of Formula IX (1 equiv) in tetrahydrofuran was added potassiunw-butoxide at -15 °C, stirred for about 20 min Then N-fluorobenzene sulfonimide (1 2 equiv ) in tetrahydrofuran was added Reaction mixture was stirred at -15 °C for about 2 hours, quenched by addition of water and extracted with ethyl acetate Organic layer was
washed with water followed by brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure
Preparation of compound of Formula XIX
To a solution of compound of Formula XVIII (1 equiv) in dimethylformamide tetrahydrofuran (3 2) was added N, N'-carbonyldnmidazole (3 equiv) at an ambient temperature It was cooled to 0 °C and sodium hydride (3 equiv ) in portions was added and was stirred for about 30 mm Reaction was quenched by addition of water This was extracted with ethyl acetate Ethyl acetate layer was washed with water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the desired product
Preparation of compound of Formula XII
The compound of Formula XIX (1 equiv) and R--t-NH2 (3 equiv) were taken in 10% water in acetonitrile and heated to 65-70 C for about 14 hours Reaction mixture was cooled to attain an ambient temperature, acetonitrile-water was removed under reduced pressure The resulting residue was purified by silica gel column chromatography (thoroughly neutralized with triethylamine) using 25-30% acetone m hexane to afford the desired product Preparation of compound of Formula XIII
The compound of Formula XII was taken in methanol and refluxed for about 12 hours Reaction mixture was cooled to attain an ambient temperature and methanol was evaporated under reduced pressure Purification of the solid mass was done over a silica gel column using 2-6% methanol in dichloromethane
Scheme HI
Preparation of compound of Formula XX Method-A
To a solution of compound of Formula XVI (1 equiv) in dimethylformamide was added sodium hydride (1 5 equiv) in portions at 0°C, stirred for about 15 min To this was added N-fluorobenzene sulfonimide (1 2 equiv) Reaction mixture was stirred at 0 °C for about 4 hours Reaction was quenched by addition of water and extracted with ethyl acetate Organic layer was washed with water followed by brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure
Method-B
To a solution of compound of Formula XVI (1 equiv ) in tetrahydrofuran was added potassium t- butoxide (1 5 equiv) at -15 °C, stirred for about 20 mm Then added N-fluorobenzene sulfonimide (1 2 equiv ) in tetrahydrofuran Reaction mixture was stirred at -15 °C for about 3 hours, quenched by addition of water and extracted with ethyl acetate Organic layer was washed with water followed by brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure
Preparation of compound of Formula XXI
To a solution of compound of Formula XX (1 equiv) in dimethylformamide tetrahydrofuran (3 2) was added N, N'-carbonyldnmidazole (3 equiv) at an ambient temperature It was cooled to 0 °C and sodium hydride (3 equiv ) in portions was added and was stirred for about 30 min Reaction was quenched by addition of water This was extracted with ethyl acetate Ethyl acetate layer was washed with water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the desired product
Preparation of compound of Formula XXII
The compound of Formula XXI (1 equiv) and R--T-NHT (2 equiv) were taken in 10%water in acetonitrile and heated to 65-70 °C for about 14 hours Reaction mixture was cooled to attain an ambient temperature, acetonitrile-water was removed under reduced pressure The resulting residue was purified by silica gel column chromatography (thoroughly neutralized with triethylamine) using 25-30% acetone in hexane to afford the desired product Preparation of compound of Formula XXIII
The compound of Formula XXII (560 mg, 0 6 mmol) was taken in methanol and refluxed Reaction mixture was cooled to attain an ambient temperature and methanol was evaporated under reduced pressure
Preparation of compound of Formula XXIV
To a solution of compound of Formula XXIII (1 equiv ) in dry acetonitrile was added N-iodosuccinimide (2 equiv) and the reaction mixture was allowed to attain an ambient temperature and stirred for 4h Then the reaction mixture was stirred with a sodium bisulphite solution followed by stirring with sodium carbonate solution The aqueous layer was extracted with ethyl acetate, washed successively with water, brine, and dried over anhydrous sodium sulphate and then the solvent was removed under reduced pressure to yield a crude product
Preparation of compound of Formula XIII
To a solution of compound of Formula XXIV (1 equiv) in acetomtrile was added solid sodium hydrogen carbonate (5 equiv) and ethyl iodide (6 equiv) under argon at an ambient temperature and stirred for about 20 hours Reaction was quenched by the addition of water Reaction mixture was diluted with ethyl acetate and washed with water followed by brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to yield a crude product Purification of the crude product was done by silica gel column chromatography (thoroughly neutralized with triethylamine) using 30-35% acetone in hexane to afford the desired product
Scheme IV
Preparation of compound of Formula XXV
The compound of Formula XX was taken in methanol and refluxed Reaction mixture was cooled to attain an ambient temperature and methanol was evaporated under reduced pressure The crude product was purified by column chromatography
Preparation of compound of formula XXVI
To a solution of compound of Formula XXV (1 equiv ) in dry acetomtrile was added N-iodosuccinimide (2 equiv ) and the reaction mixture was allowed to attain an ambient temperature and stirred for about 4 hours Then the reaction mixture was stirred with a sodium bisulphite solution followed by stirring with sodium carbonate solution The aqueous layer was extracted with ethyl acetate, washed successively with water, brine, and dried over anhydrous sodium sulphate and then the solvent was removed under reduced pressure to yield a crude product
Preparation of compound of formula XXVII
To a solution of compound of Formula XXVI (1 equiv ) in acetonitrile was added solid sodium hydrogen carbonate (5 equiv ) and ethyl iodide (6 equiv ) under argon at an ambient temperature and stirred for about 20 hours Reaction was quenched by the addition of water Reaction mixture was diluted with ethyl acetate and washed with water followed by brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to yield a crude product Purification of the crude product was done by silica gel column chromatography (thoroughly neutralized with triethylamine) using 20-25% acetone in hexane to afford the desired product
The following compounds were prepared following the above general procedure
Compound No 1 2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-allyl)-l l,12-dideoxy-3-O-decladinosyl-6-O-methy 1-3-oxo-12,11 -[oxycarbonyl-((4-(4-phenyl-pyrazol-1 -yl)-buty 1)-imino)] erythromycin A, Mass m/z 855 35 [M++l]
Compound No 2 2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)-l l,12-dideoxy-3-O-decladinosy 1-6-O-methy 1-3-oxo-12,11 -[oxycarbonyl-((4-(4-pyridin-3-yl-1 H-imidazol-1 -yl)-pentyl)-imino)] erythromycin A, Mass m/z 858 38 [M++l]
Compound No 3 2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)-l l,12-dideoxy-3-O-decladinosyl-6-O-methy 1-3-oxo-12,11 -[oxycarbonyl-((4-(4-pyridin-4-yl-1 H-imidazol-1 -yl)-butyl)-imino)] erythromycin A, Mass m/z 844 41 [M++l]
Compound No 4 2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-allyl)-l l,12-dideoxy-3-O-decladinosy 1-6-O-methy 1-3-oxo-12,11 -[oxycarbonyl-((4-(4-pyridin-4-y 1-1 H-imidazol-1 -yl)-butyl)-imino)] erythromycin A, Mass m/z 856 39 [M++l]
Compound No 5 2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)-l l,12-dideoxy-3-O-decladinosy 1-6-O-methy 1-3-oxo-12,11 -[oxycarbony l-((4-(4-phenyl-pyrazol-1 -yl)-buty 1)-lmino) erythromycin A, Mass m/z 843 55 [M++l]
Compound No 6 2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)-l l,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,11-[oxycarbonyl-((4-(indazol-2-yl)-butyl)-imino)]erythromycin A, Mass m/z 817 54 [M++l]
Compound No 7 2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-allyl)-l l,12-dideoxy-3-O-decladinosy 1-6-O-methy 1-3-oxo-12,11 -[oxycarbonyl-((4-(indazol-2-yl)-butyl)-imino)] erythromycin, Mass m/z 829 60 [M++l]
Compound No 8 2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)-l l,12-dideoxy-3-O-decladinosyl-6-O-methy 1-3-oxo-12,11 -[oxycarbonyl-((4-(3-pyridin-3-yl-pyrazol-1 -yl)-buty 1)-imino)] erythromycin A, Mass m/z 844 54 [M++l]
Compound No 9 2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)-l l,12-dideoxy-3-O-decladinosyl-6-O-methy 1-3-oxo-12,11 -[oxycarbonyl-((4-(indazol-1 -yl)-butyl)-imino)]erythromycin A, Mass m/z 817 52 [M++l]
Compound No 10 2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)-l l,12-dideoxy-3-O-decladinosyl-6-O-methy 1-3-oxo-12,11 -[oxycarbonyl-((4-(4-pyrazin-2-yl-1 H-imidazol-1 -yl)-butyl)-imino)] erythromycin A, Mass m/z 845 56 [M++l]
Compound No 11 2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)-l l,12-dideoxy-3-O-decladinosy 1-6-O-methy 1-3-oxo-12,11 -[oxycarbonyl-((4-(4-thiophen-3-yl-1 H-imidazol-1 -yl)-butyl)-imino)] erythromycin A, Mass m/z 849 45 [M++l]
Compound No 12 2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-allyl)-l l,12-dideoxy-3-O-decladinosyl-6-O-methy 1-3-oxo-12,11 -[oxycarbonyl-((4-(4-thiophen-3-yl-1 H-imidazol-1 -yl)-butyl)-imino)] erythromycin A, Mass m/z 861 45 [M++l]
Compound No 13 2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)-l l,12-dideoxy-3-O-decladinosyl-6-O-methy 1-3-oxo-12,11 -[oxycarbonyl-((4-(4-quinohn-3-yl-1 H-imidazol-1 -y 1)-butyl)-imino)] erythromycin A, Mass m/z 894 60 [M++l]
Compound No 14 2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-allyl)-l l,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,11-[oxycarbonyl-((4-indazol-l-yl)-butyl)-imino)]erythromycin A, Mass m/z 829 49 [M++l]
Compound No 15 2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)-l l,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,11-[oxycarbonyl-((4-(4-pynmidin-5-yl-lH-imidazol-l-yl)-butyl)-imino)] erythromycin A, Mass m/z 845 46 [M++l]
Compound No 16 2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-allyl)-l l,12-dideoxy-3-O-decladinosy 1-6-O-methy 1-3-oxo-12,11 -[oxycarbony l-((4-(4-pynmidin-5-yl-1 H-imidazol-1 -yl)-butyl)-imino)] erythromycin A, Mass m/z 857 48 [M++l]
Compound No 17 2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)-l l,12-dideoxy-3-O-decladinosyl-6-O-methy 1-3-oxo-12,11 -[oxycarbonyl-((4-(4-furan-2-y 1-1 H-imidazol-1 -yl)-butyl)-imino)] erythromycin A, Mass m/z 833 56 [M++l]
Compound No 18 2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)-l l,12-dideoxy-3-O-decladinosy 1-6-O-methy 1-3-oxo-12,11 -[oxycarbonyl-((4-(4-thiophen-2-yl-lH-imidazol-l-yl)-butyl)-imino)] erythromycin A, Mass m/z 849 57 [M++l]
Compound No 19 2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)-l l,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,11-[oxycarbonyl-((4-(4-(4-chloro-phenyl)-lH-imidazol-l-yl)-butyl)-imino)] erythromycin A, Mass m/z 877 40 [M++l]
Compound No 20 2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-allyl)-l l,12-dideoxy-3-O-decladinosyl-6-O-methy 1-3-oxo-12,11 -[oxycarbonyl-((4-(4-(4-chloro-pheny 1)-1 H-imidazol-l-yl)-butyl)-imino)] erythromycin A, Mass m/z 889 40 [M++l]
Compound No 21 2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)-l l,12-dideoxy-3-O-decladinosyl-6-O-methy 1-3-oxo-12,11 -[oxycarbonyl-((4-(4-pyridin-2-y 1-1 H-imidazol-1 -y 1)-butyl)-imino)] erythromycin A, Mass m/z 844 46 [M++l]
Compound No 22 2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-allyl)-l l,12-dideoxy-3-O-decladinosyl-6-O-methy 1-3-oxo-12,11 -[oxycarbonyl-((4-(4-pyridin-2-y 1-1 H-imidazol-1 -y 1)-butyl)-immo)] erythromycin A, Mass m/z 856 44 [M++l]
Compound No 23 2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-allyl)-l l,12-dideoxy-3-O-decladinosyl-6-O-methyl-3 -oxo-12,11 -[oxycarbonyl-((9-(4-amino-butyl)-9H-punn-6-yl)-lmino)] erythromycin A, Mass m/z 846 45 [M++l]
Compound No 24 2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-allyl)-l l,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(3-pyridin-3-yl-l H-pyrazol-1 -yl)-butyl)-imino)] erythromycin A, Mass m/z 856 61[M++1]
Compound No 25 2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-2-fluoroethyl)-l l,12-dideoxy-3-0-decladinosyl-6-O-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(4-(4-chloro-phenyl)-1H-imidazol-l-yl)-butyl)-imino)]erythromycin A, Mass m/z 895 49 [M++l]
Compound No 26 2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-2-fluoroethyl)-l l,12-dideoxy-3-0-decladinosyl-6-O-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(4-pyridin-2-yl)-1 H-imidazol-1 -yl)-butyl)-imino)]erythromycin A, Mass m/z 862 49 [M++l]
Compound No 27 2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)-desosaminyl-l 1,12-dideoxy-3-O-decladinosyl-6-O-methy 1-3-oxo-12,11 -[oxycarbony l-(4-(3H-Imidazo[4,5-b]pyridine-2-yl)-butyl)iminoerythromycin A, Mass m/z 818 95 [M++l]
Compound No 28 2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)-desosaminyl-l 1,12-dideoxy-3-O-decladinosy 1-6-O-methy 1-3-oxo-12,11 -[oxycarbony l-(4-(4-Tetrazol-1 -y 1-imidazol-l-yl)-butyl)iminoerythromycin A, Mass m/z 835 44 [M++l]
Compound No 29 2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)-desosaminyl-l 1,12-dideoxy-3-O-decladinosyl-6-O-methy 1-3-oxo-12,11 -[oxycarbonyl-(4-( 1 H-Benzoimidazol-2-yl)-butyl)iminoerythromycm A, Mass m/z 817 45 [M++l]
Compound No 30 2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)-desosaminyl-l 1,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,11-[oxycarbonyl-(4-[4-(6-Fluoro-pyridin-3-yl)-imidazol-l-yl]-butyl)iminoerythromycin A, Mass m/z 862 39 [M++l]
Compound No 31 2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)-desosaminyl-l 1,12-dideoxy-3-O-decladmosyl-6-O-methyl-3-oxo-12,11-[oxycarbonyl-(4-(3H-Imidazo[4,5-c]pyridine-2-yl)-butyl) lminoerythromycin A, Mass m/z 818 4 [M++l]
Compound No 32 2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)-desosaminyl-l 1,12-dideoxy-3-O-decladinosy 1-6-O-methy 1-3-oxo-12,11 -[oxycarbony l-(4-(4-[ 1,2,4]Tnzol-1 -yl-phenyl)-butyl)iminoerythromycin A, Mass m/z 844 4 [M++l]
Compound No 33 2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)-desosaminyl-l 1,12-dideoxy-3-O-decladinosy 1-6-O-methy 1-3-oxo-12,11 -[oxycarbony l-(4-(4-Imidazol-1 -y 1-phenyl)-butyl)iminoerythromycin A, Mass m/z 843 5 [M++l]
Compound No 34 2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)-desosaminyl-l 1,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,11-[oxycarbonyl-(4-[4-(6-Chloro-pyridin-3-yl)-imidazol-l-yl]-butyl)iminoerythromycin A, Mass m/z 878 4 [M++l]
Compound No 35 2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)-desosaminyl-l 1,12-dideoxy-3-O-decladinosy 1-6-O-methy 1-3-oxo-12,11 -[oxycarbony l-(3-[ 1 -(4-Amino-buty 1)-lH-imidazol-4-yl]-phenyl)iminoerythromycin A, Mass m/z 858 5 [M++l]
Compound No 36 2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)-desosaminyl-l 1,12-dideoxy-3-O-decladinosy 1-6-O-methy 1-3-oxo-12,11 -[oxycarbonyl-(4-(4-Pyndin-3-yl-thiazol-2-yl)-butyl)iminoerythromycin A, Mass m/z 861 3 [M++l]
Compound No 37 2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)-desosaminyl-l 1,12-dideoxy-3-O-decladinosyl-6-O-methy 1-3-oxo-12,11 -[oxycarbonyl-(3-[2-(4-Amino-butyl)-thiazol-4-yl]-phenyl)iminoerythromycin A, Mass m/z 875 4 [M++l]
Compound No 38 2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)-desosaminyl-l 1,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,l l-[oxycarbonyl-(4-(4-Pyrazol-l-yl-imidazol-l-yl)-butyl)iminoerythromycin A, Mass m/z 833 4 [M++l]
Compound No 39 2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)-desosaminyl-l 1,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,11-[oxycarbonyl-(4-([l,4']-Bipyrazolyl-r-yl)-butyl) lminoerythromycin A, Mass m/z 833 4 [M++l]
Compound No 40 2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)-desosaminyl-l 1,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,11-[oxycarbonyl-(4-(4-Imidazol-l-yl-pyrazol-l-yl)-butyl)immoerythromycin A, Mass m/z 833 4 [M++l]
Compound No 41 2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)-desosaminyl-l 1,12-dideoxy-3-O-decladmosyl-6-O-methy 1-3-oxo-l 2,11-[oxycarbonyl-(4-(4-Pyrazol-l-yl-imidazol-l-yl)-butyl)iminoerythromycin A, Mass m/z 833 4 [M++l]
Compound No 42 2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)-desosaminyl-l 1,12-
dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,11-[oxycarbonyl-(4-[3,3']Bithiophenyl-5-yl-
butyl)iminoerythromycin A, Mass m/z 865 3 [M++l]
Compound No 43 2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)-desosaminyl-l 1,12-
dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,11-[oxycarbonyl-(4-[2,3']Bithiophenyl-5'-
yl-butyl)immoerythromycin A, Mass m/z 865 3 [M++l]
Compound No 44 2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)-desosaminyl-l 1,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,11-[oxycarbonyl-(4-(4-Furan-2-yl-thiophen-2-yl)-butyl)immoerythromycin A, Mass m/z 849 4 [M++l]
Compound No 45 2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)-desosaminyl-l 1,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,11-[oxycarbonyl-(4-(4-Oxazol-5-yl-imidazol-l-yl)-butyl)iminoerythromycin A, Mass m/z 834 4 [M++l]
Compound No 46 2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)-desosaminyl-l 1,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,l l-[oxycarbonyl-(4-(3-Pyrrol-l-yl-[l,2,4]tnazol-l-yl)-butyl) lminoerythromycin A, Mass m/z 833 4 [M++l]
Compound No 47 2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)-desosaminyl-l 1,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,l l-[oxycarbonyl-(4-(5-Thiophen-2-yl-tetrazol-2-yl)-butyl)iminoerythromycin A, Mass m/z 851 4 [M++l]
Compound No 48 2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)-desosaminyl-l 1,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,11-[oxycarbonyl-(4-(4-Thiophen-3-yl-pyrazol-l-yl)-butyl)iminoerythromycin A, Mass m/z 849 4 [M++l]
Compound No 49 2-ot-Fluoro-5-O-(3 '-N-desmethyl-3 '-N-ethyl)-desosaminyl-11,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,11-[oxycarbonyl-(4-(4-Furan-3-yl-pyrazol-l-yl)-butyl)iminoerythromycin A, Mass m/z 833 4 [M++l]
Compound No 50 2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)-desosaminyl-l 1,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,11-[oxycarbonyl-(4-(4-Furan-2-yl-pyrazol-l-yl)-butyl)iminoerythromycin A, Mass m/z 833 4 [M++l]
Compound No 51 2-ot-Fluoro-5-O-(3 '-N-desmethyl-3 '-N-ethyl)-desosaminyl-11,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,11-[oxycarbonyl-(4-(5-Phenyl-tetrazol-2-yl)- butyl)iminoerythromycm A, Mass m/z 845 4 [M++l]
Compound No 52 2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)-desosaminyl-l 1,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,11-[oxycarbonyl-(4-[5-(4-Methoxy-phenyl)-tetrazol-2-yl]-butyl)iminoerythromycin A, Mass m/z 875 3 [M++l]
Compound No 53 2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)-desosaminyl-l 1,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,11-[oxycarbonyl-(4-(5-Furan-3-yl-imidazol-l-yl)-butyl)iminoerythromycin A, Mass m/z 833 5 [M++l]
Compound No 54 2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)-desosaminyl-l 1,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,11-[oxycarbonyl-(4-(6-Pyrazol-l-yl-pyridin-3-yl)-butyl)iminoerythromycin A, Mass m/z 844 4 [M++l]
Compound No 55 2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)-desosaminy 1-11,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,l l-[oxycarbonyl-(4-(4-Pyndin-3-yl-pyrazol-l-yl)-butyl)iminoerythromycin A, Mass m/z 844 5 [M++l]
Compound No 56 2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)-desosaminyl-l 1,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,11-[oxycarbonyl-(4-(5-Thiophen-2-yl-pyridin-3-yl)-butyl)iminoerythromycin A, Mass m/z 860 3 [M++l]
Compound No 57 2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)-desosaminyl-l 1,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,11-[oxycarbonyl-(4-(4-Phenyl-thiophen-2-yl)-butyl)iminoerythromycin A, Mass m/z 859 4 [M++l]
Compound No 58 2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)-desosaminyl-l 1,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,11-[oxycarbonyl-(N-(4-Amino-butyl)-N-thiazol-2-yl-nicotinimido)]erythromycin A, Mass m/z 890 09 [M++l]
Compound No 59 2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)-desosaminyl-l 1,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,11-[oxycarbonyl-(N-(4-Amino-butyl)-N-thiazol-2-yl-nicotinimido)]erythromycin A, Mass m/z 904 4 [M++l]
Compound No 60 2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)-desosaminyl-l 1,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,l l-[oxycarbonyl-(4-[4-(6-Pyrrol-l-yl-pyridin-3-yl)-imidazol-l-yl]-butyl)iminoerythromycin A, Mass m/z 909 5 [M++l]
Compound No 61 2-α-Fluoro-5-O-(3 '-N-desmethy 1-3 '-N-ethyl)-desosaminyl-11,12-dideoxy-3-O-decladmosyl-6-O-methyl-3-oxo-12,11 -[oxycarbony l-(4-(6-Pyrrol-1 -yl-pyridin-3-yl)-butyl)iminoerythromycin A, Mass m/z 834 4 [M++l]
Compound No 62 2-oc-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)-desosaminyl-l 1,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,l l-[oxycarbonyl-(4-(2-Pyrrol-l-yl-thiazol-5-yl)-butyl)iminoerythromycin A, Mass m/z 849 3 [M++l]
Compound No 63 2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)-desosaminyl-l 1,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,11-[oxycarbonyl-(4-(6-Imidazol-l-yl-pyridin-3-yl)-butyl)iminoerythromycin A, Mass m/z 844 4 [M++l]
Compound No 64 2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)-desosaminyl-l 1,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,11-[oxycarbonyl-(4-[4-(Tetrahydro-furan-2-yl)-pyridin-3-yl]-butyl)iminoerythromycin A, Mass m/z 848 4 [M++l]
Compound No 65 2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)-l l,12-dideoxy-3-O-decladinosyl-6-O-methy 1-3-oxo-l 2, 11-[oxycarbonyl-((4-(4-p-tolyl-imidazol-l-yl)-butyhmino)] erythromycin A, Mass m/z 857 08[M++1]
Compound No 66 2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)-l l,12-dideoxy-3-O-decladinosyl-6-O-methy 1-3-oxo-12,11 -[oxycarbonyl-(4-(4-(4-aminopheny l)-imidazol-1 -yl)-butylimino)] erythromycin A, Mass m/z 858 07[M++1]
Compound No 67 2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)-l l,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,11-[oxycarbonyl-(4-(4-(4-methyl-3-aminophenyl)-imidazol-l-yl)-butyhmino)] erythromycin A, Mass m/z 872 1[M++1]
Compound No 68 2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)-l l,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(4-(3-imidazol-1 yl)-phenyl)imidazol-l-yl)-butyhmino)] erythromycin A, Mass m/z 909 12[M++1]
Compound No 69 2-α-Fluoro-5-O-(3 '-N-desmethyl-3 '-N-ethyl)-11,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,11-[oxycarbonyl-(4-(4-(3-(N,N-dicyclopropyl-amino)-phenyl)-imidazol-l-yl)-butyhmino)] erythromycin A, Mass m/z 938 20[M++1]
Compound No 70 2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)-11,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,11-[oxycarbonyl-(4-(4-(3-(N,N-dimethyl-amino)phenyl)-imidazol-l-yl)-butyhmmo)] erythromycin A, Mass m/z 886 12[M++1]
Compound No 71 2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)-11,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,l l-[oxycarbonyl-((4-(4-(3-(tetrazol-lyl)-phenyl)-imidazol-l-yl)-butyhmino)] erythromycin A, Mass m/z 911 09[M++1]
Compound No 72 2-α-Fluoro-5-O-(3 '-N-desmethyl-3'-N-ethyl)-l 1,12-dideoxy-3-O-decladinosy 1-6-O-methy 1-3-oxo-12,11 -[oxycarbonyl-((4-(4-(2-(pyrrol-1 yl)-thiozol-5-yl)-imidazol-l-yl)-butyhmino)] erythromycin A, Mass m/z 915 04[M++1]
Compound No 73 2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)-l l,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,11-[oxycarbonyl-((4-(4-(3-tnfluoromethyl-phenyl)-imidazol-l-yl)-butyhmino)] erythromycin A, Mass m/z 857 08[M++1]
Compound No 74 2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)-l l,12-dideoxy-3-O-decladinosyl-6-O-methy 1-3-oxo-12, 11-[oxycarbonyl-((4-(N-(thiazol-2-yl)-benzimido)-butyhmmo)] erythromycin A, Mass m/z 903 4[M++1]
Compound No 75 2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)-l l,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,11-[oxycarbonyl-(4-(4-(2-amino-pynmidin)-5-yI)-imidazol-l-yl)-butyhmino)] erythromycin A, Mass m/z 680 04 [M++l]
Compound No 76 2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)-l l,12-dideoxy-3-O-decladinosy 1-6-O-methy 1-3-oxo-12,11 -[oxycarbonyl-((4-(4-(4-(pyrrol-1 yl)-phenyl)-imidazol-l-yl)-butyhmino)] erythromycin A, Mass m/z 908 13 [M++l]
Compound No 77 2-ot-Fluoro-5-O-(3 '-N-desmethy 1-3 '-N-ethyl)-11,12-dideoxy-3-O-decladinosyl-6-O-methy 1-3-oxo-12,11 -[oxycarbonyl-((4-(4-(3-(pyrrol-1 yl)-phenyl)-imidazol-l-yl)-butyhmino)] erythromycin A, Mass m/z 908 13 [M++l]
Compound No 78 2-ot-Fluoro-5-O-(3'-N-desmethy 1-3'-N-ethyl)-11,12-dideoxy-3-O-dec ladinosy 1-6-O-methy 1-3 -oxo-12,11- [oxycarbony l-(4-(4-(3 -(N-acety l-amino)-pheny 1)-imidazol-l-yl)-butyhmino)] erythromycin A, Mass m/z 900 11[M++1]
Compound No 79 2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)-11,12-dideoxy-3-O-
decladinosyl-6-O-methyl-3-oxo-12,11-[oxycarbonyl-(4-(4-(3-(N-isopropyl-amino)-phenyl)-
imidazol-l-yl)-butylimino)] erythromycin A, Mass m/z 900 15[M++1]
Compound No 80 2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)-11,12-dideoxy-3-O-
decladinosyl-6-O-methyl-3-oxo-12,11-[oxycarbonyl-((4-(4-(3-nitrophenyl)-imidazol-l-yl)-
butyhmino)] erythromycin A, Mass m/z 888 05[M++1]
Compound No 81 2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)-11,12-dideoxy-3-O-decladinosyl-6-O-methy 1-3-oxo-12,11 -[oxycarbonyl-(4-(4-(3-(N-benzoy l-amino)-phenyl)-imidazol-l-yl)-butylimino)] erythromycin A, Mass m/z 962 18[M++1]
Compound No 82 2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)-l l,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,l l-[oxycarbonyl-((4-(4-(3,4-dimethyl-phenyl)-imidazol-l-yl)-butylimino)] erythromycin A, Mass m/z 871 11[M++1]
Compound No 83 5-O-(3'-N-desmethyl-3'-N-ethyl)-11,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,11-[oxycarbonyl-(((4-(4-Pyridin-3-yl-thiazol-2-yl)-butyhmino)] erythromycin A, Mass m/z 862 4 [M++l]
Compound No 84 2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)-11,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(4-(4-fluorophenyl)-imidazol-1 -yl)-butyhmino)] erythromycin A, Mass m/z 861 05 [M++l]
Compound No 85 2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)-l l,12-dideoxy-3-O-decladinosy l-6-O-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(4-(4-methoxy-phenyl)-imidazol-1 -yl)-butyhmino)] erythromycin A, Mass m/z 873 08 [M++l]
Compound No 86 2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)-l l,12-dideoxy-3-O-decladinosyl-6-O-methy 1-3-oxo-12,11 -[oxycarbonyl-((4-(N-(benzthiazol-2-yl)-benzimido)-butylimino)] erythromycin A, Mass m/z 953 19 [M++l]
Compound No 87 2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)-l l,12-dideoxy-3-O-decladinosyl-6-O-methy 1-3-oxo-12,11 -[oxycarbonyl-((4-(N-(thiazol-2-y i)-nicotinamido)-butyhmino)] erythromycin A, Mass m/z 904 12 [M++l]
Compound No 88 2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)-l l,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,11-[oxycarbonyl-(4-(4-(3-(N-methyl-amino)-phenyl)-imidazol-l-yl)-butyhmino)] erythromycin A, Mass m/z 872 10 [M++l]
Compound No 89 2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-l 1,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,l l-[oxycarbonyl-(4-(4-(4-(2-aminopyridyl)-imidazol-l-yl)-butyhmino)] erythromycin A, Mass m/z 8590 6 [M++l]
Compound No 90 2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-l 1,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,11-[oxycarbonyl-(4-(4-(5-(2-aminopyridyl)-2H-tetrazol-5-yl)-butyhmino)] erythromycin A, Mass m/z 861 03 [M++l]
Compound No 91 2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-l 1,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,l l-[oxycarbonyl-(4-(4-(3,4-difluorophenyl)-imidazol-l-yl)-butyhmino)] erythromycin A, Mass m/z 878 04 [M++l]
Compound No 92 2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-l 1,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,11-[oxycarbonyl-(4-(4-(4-(2-chloropyridyl)-imidazol-l-yl)-butyhmino)] erythromycin A, Mass m/z 878 49 [M++l]
Compound No 93 2-α-Fluoro-5-O-(3 '-N-desmethyl-3 '-N-ethyl)desosaminyl-11,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,l l-[oxycarbonyl-(4-(4-(3-(6-ammopyridyl)-imidazol-l-yl)-butyhmino)] erythromycin A, Mass m/z 859 06 [M++l]
Compound No 94 2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-l 1,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,11-[oxycarbonyl-(4-(5-(2-Chloro-pyridin-4-yl)-tetrazol-2-yl])-butylimino)] erythromycin A, Mass m/z 880 46[M++1]
Microbiological activity
Compounds disclosed herein displayed antibacterial activity in vitro especially against strains which are resistant to macrohdes either due to efflux (mef strains) or nbosomal modification (erm) strains These compounds are useful in the treatment of community acquired pneumonia, upper and lower respiratory tract infections, skin and soft tissue infections, hospital acquired lung infections, bone and joint infections, and other bacterial
infections, for example, mastitis, catether infection, foreign body, prosthesis infections or peptic ulcer disease Minimum inhibitory concentration (MIC) has been an indicator of in vitro antibacterial activity widely used in the art
Procedure Medium
a) Cation adjusted Mueller Hinton Agar (MHA-Difco)
b) Trypticase Soya Agar (TSA)
Inoculum preparation
The cultures were streaked on TSA for aerobic cultures and MHA with 5% sheep blood for fastidious cultures Aerobic cultures were incubated at 37 °C for about 18-24 hours Fastidious cultures were incubated C02 incubation (5% C02) at 37 °C for about 18-24 hours Three to four well isolated colonies were taken and saline suspensions were prepared in sterile densimat tubes The turbidity of the culture was adjusted to 0 5-0 7 Mc Farland standard (1 5 x 108 CFU/ml) The cultures were diluted 10 fold in saline to get inoculum size of approximately 1-2 x 107 organisms/ml Preparation of drug concentration
1 mg/ml concentration of stock solution of drugs was prepared in dimethylsulfoxide/distilled water/solvent given in National Committee for Clinical Laboratory Standards (NCCLS) manual Serial two fold dilutions of the compounds and standard drugs were prepared as per NCCLS manual Stock solution was changed according to the need of the experiment Preparation of Agar Plates
Two ml of respective drug concentration was added to 18 ml of Molten Mueller Hinton agar to get the required range, for example 0 015 µg/ml - 16 µg/ml For fastidious cultures 1 ml of sheep blood was added in Molten Mueller Hinton agar For control MHA and MHA with 5% sheep blood plates without antibiotic for each set were prepared One MHA and MHA with 5% sheep blood plate without antibiotic for determining quality check for media was prepared Preparation of Teflon template
1 µl of each culture on each plate was replicated with the help of replicator (Denley's multipoint replicator) The spots were allowed to dry and the plates were incubated for about 18-24 hours at 37°C Fastidious cultures were incubated at 37 °C in CO2 incubator The results were noted comparing with the control plates Endpoint definition
The concentration of drug at which there was complete disappearance of growth spot or formation of less than 10 colonies per spot was considered as Minimum Inhibitory Concentration (MIC)
The MICs of Quality Control (QC) strains were plotted on the QC chart for agar dilution method If the MICs were within the range, the results interpreted by comparing MICs of standards against all organisms with those of test compounds Precautions & Quality Control Measures Quality Control Strains
Staphylococcus aureus ATCC 29213, Enterococcus faecahs ATCC 29212, Eschericia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853 All 60 cultures were visually checked for purity
Media Control NCCLS disc diffusion assay using 10(ig discs of Gentamicin (Difco) against Pseudomonas aeruginosa ATCC 27853 A zone diameter of 16-21 mm was considered for optimum cation (Magnesium and Calcium) content of the media The diameter was plotted in the media QC chart
Results The MICs of compounds of Formula I against some bacterium are shown in Tables I and II
References
o National Committee for Clinical Laboratory Standards (NCCLS), Methods for Dilution
Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically - Fifth Edition,
Approved Standard M7-A5, Vol 20 No 2 (January 2000)
o National Committee for Clinical Laboratory Standards, Performance Standards for
Antimicrobial Susceptibility Testing - Twelfth informational supplement, M 100-S12,
Vol 22 No 1 (January 2002)
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention
Table I
(Table Removed)
S pneum Streptococcus pneumoniae, H influ Haemophilius influenzae, MRSA MethiciUin resistant Staphylococcus aureus, S pyo Streptococcus pyogenes, E faecalis Enterococcus faecalis S aureus Staphylococcus aureus, All MIC in (J-g/ml

WE CLAIM
1 A compound having the structure of Formula I,
(Formula Removed)
its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers,
diastereomers or polymorphs wherein,
R1 is hydrogen or hydroxy protecting group wherein hydroxy protecting represents benzoyl,
tetrahydropyranyl or tnalkylsilylethers, R2 is CH3, R3 is C2H5, -CH2-CH=CH2 or -
CH2CH2F, W is -(CH2)4-J- wherein J is CH2 or
(CH2)0-1-N(CO)-Ra,
Ris
(Formula Removed)
wherein
X1-X3 are independently CH or N, X4-X8 are independently CH, CR4 or N, X9 is O, S, N, NH or CH, X10 is NH or S, Ra is thienyl, furyl, pyrazolyl, oxazolyl, tetrazolyl, imidazolyl, pyridinyl, fluoropyridinyl, chloropyndinyl, aminopyridinyl, pyrazinyl, pynmidinyl, aminopyrimidinyl, quinolinyl, pyrrolo-pyndyl, pyrrolo-thiazolyl or optionally substituted phenyl, R'a is hydrogen or furyl, Rb is hydrogen or amino, Re is hydrogen, thienyl, furyl, pyrazolyl, pyrazinyl, pyridinyl, aminopyridinyl, pynmidinyl, pyrrolyl, imidazolyl or optionally substituted phenyl, Rd is thienyl, pyrazolyl, imidazolyl, triazolyl, pyrrolyl or tetrahydrofuryl
A compound which is
2-α-Fluoro-5-O-(3 '-N-desmethyl-3 '-N-allyl)-11,12-dideoxy-3-O-decladinosy 1-6-O-methyl-3-oxo-12,l l-[oxycarbonyl-((4-(4-phenyl-pyrazol-l-yl)-butyl)-imino)] erythromycin A,
2-α-Fluoro-5-O-(3 '-N-desmethyl-3 '-N-ethy 1)-11,12-dideoxy-3-O-decladinosy 1-6-O-methyl-3-oxo-12,11-[oxycarbonyl-((4-(4-pyndin-3-yl-lH-imidazol-l-yl)-pentyl)-imino)] erythromycin A,
2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)-ll,12-dideoxy-3-O-decladinosyl-6-O-methy 1-3-oxo-12,11 -[oxycarbonyl-((4-(4-pyndin-4-yl-1 H-imidazol-1 -yl)-butyl)-imino)] erythromycin A,
2-α-Fluoro-5-O-(3 '-N-desmethyl-3 '-N-allyl)-11,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(4-pyndin-4-y 1-1 H-imidazol-1 -y l)-buty l)-imino)] erythromycin A,
2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)-11,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,11-[oxycarbonyl-((4-(4-phenyl-pyrazol-l-yl)-butyl)-imino) erythromycin
A,
2-α-Fluoro-5-O-(3 '-N-desmethyl-3 '-N-ethyl)-11,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,l l-[oxycarbonyl-((4-(indazol-2-yl)-butyl)-imino)] erythromycin A,
2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-allyl)-11,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,11 -[oxycarbony l-((4-(indazol-2-y l)-buty l)-imino)]erythromycin,
2-α-Fluoro-5-O-(3 '-N-desmethyl-3 '-N-ethyl)-11,12-dideoxy-3-O-decladinosy 1-6-O-methyl-3-oxo-12,11-[oxycarbonyl-((4-(3-pyndin-3-yl-pyrazol-l-yl)-butyl)-imino)] erythromycin A,
2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)-ll,12-dideoxy-3-O-decladinosyl-6-O-methy 1-3-oxo-12,1 l-[oxycarbonyl-((4-(indazol-l-yl)-butyl)-imino)] erythromycin A,
2-α-Fluoro-5-O-(3 '-N-desmethyl-3 '-N-ethyl)-11,12-dideoxy-3-O-decladinosy 1-6-O-methyl-3-oxo-12,11 -[oxycarbony l-((4-(4-pyrazin-2-y 1-1 H-imidazol-1 -yl)-butyl)-imino)] erythromycin A (Compound No 10),
2-α-Fluoro-5-O-(3 '-N-desmethyl-3 '-N-ethyl)-l 1,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,11-[oxycarbonyl-((4-(4-thiophen-3-yl-lH-imidazol-l-yl)-butyl)-imino)] erythromycin A,
2-α-Fluoro-5-O-(3 '-N-desmethyl-3 '-N-allyl)-11,12-dideoxy-3-O-decladinosy 1-6-O-methy 1-3-oxo-12,l l-[oxycarbonyl-((4-(4-thiophen-3-yl-lH-imidazol-l-yl)-butyl)-imino)] erythromycin A,
2-α-Fluoro-5-O-(3 '-N-desmethyl-3 '-N-ethyl)-11,12-dideoxy-3-O-decladinosy 1-6-O-methyl-3-oxo-12,11-[oxycarbonyl-((4-(4-quinolin-3-yl-lH-imidazol-l-yl)-butyl)-imino)] erythromycin A,
2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-allyl)-11,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,l l-[oxycarbonyl-((4-indazol-l-yI)-butyl)-imino)] erythromycin A,
2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)-11,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,11 -[oxycarbony l-((4-(4-pyrimidin-5-y 1-1 H-imidazol-1 -yl)-butyl)-imino)] erythromycin A,
2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-allyl)-11,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(4-pyrimidin-5-yl-1 H-imidazol-1 -y l)-buty l)-imino)] erythromycin A,
2-α-Fluoro-5-O-(3 '-N-desmethyl-3 '-N-ethyl)-11,12-dideoxy-3-Odecladinosy l-6-O-methyl-3-oxo-12,11 -[oxycarbony l-((4-(4-furan-2-y 1-1 H-imidazol-1 -yl)-buty l)-imino)] erythromycin A,
2-α-Fluoro-5-O-(3 '-N-desmethy 1-3 '-N-ethyl)-11,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,11-[oxycarbonyl-((4-(4-thiophen-2-yl-lH-imidazol-l-yl)-butyl)-imino)] erythromycin A,
2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)-11,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,11 -[oxycarbony l-((4-(4-(4-chloro-phenyl)-1 H-imidazol-1 -yl)-butyl)-imino)] erythromycin A,
2-α-Fluoro-5-O-(3 '-N-desmethyl-3 '-N-allyl)-l 1,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(4-(4-chloro-phenyl)-l H-imidazol-1 -yl)-butyl)-imino)] erythromycin A,
2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)-11,12-dideoxy-3-O-decladinosyl-6-O-methy 1-3-oxo-12,11 -[oxycarbony l-((4-(4-pyndin-2-yl-1 H-imidazol-1 -yl)-butyl)-imino)] erythromycin A,
2-α-Fluoro-5-O-(3 '-N-desmethy 1-3 '-N-ally 1)-11,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,11 -[oxycarbony l-((4-(4-pyndin-2-yl-1 H-imidazol-1 -y l)-butyl)-imino)] erythromycin A,
2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-allyl)-11,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,l l-[oxycarbonyl-((9-(4-amino-butyl)-9H-punn-6-yl)-imino)] erythromycin A,
2-cc-Fluoro-5-O-(3 '-N-desmethyl-3 '-N-allyl)-l 1,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,11 -[oxycarbony l-((4-(3 -pyndin-3-y 1-1 H-pyrazol-1 -y l)-butyl)-imino)] erythromycin A,
2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-2-fluoroethyl)-11,12-dideoxy-3-O-decladinosyl-6-O-methy 1-3-oxo-12,11 -[oxycarbony l-((4-(4-(4-chloro-phenyl)-1 H-imidazol-1 -y l)-butyl)-lmino)] erythromycin A,
2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-2-fluoroethyl)-l 1,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,11 -[oxycarbonyl-((4-(4-pyndin-2-y 1)-1 H-imidazol-1 -y l)-buty l)-imino)] erythromycin A,
2-α-Fluoro-5-O-(3 '-N-desmethyl-3 '-N-ethyl)-desosaminyl-11,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,11-[oxycarbonyl-(4-(3H-Imidazo[4,5-b]pyndine-2-yl)-butyl)imino] erythromycin A,
2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)-desosaminyl-11,12-dideoxy-3-O-decladinosy l-6-O-methyl-3-oxo-12,11 -[oxycarbony l-(4-(4-Tetrazol-1 -yl-imidazol-1 -y 1)-butyl)imino] erythromycin A,
2-α-Fluoro-5-O-(3 '-N-desmethyl-3 '-N-ethyl)-desosaminyl-11,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,11-[oxycarbonyl-(4-(lH-Benzoimidazol-2-yl)-butyl)imino] erythromycin A,
2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)-desosaminyl-11,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,11-[oxycarbonyl-(4-[4-(6-Fluoro-pyndin-3-yl)-imidazol-l-yl]-butyl)imino] erythromycin A,
2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)-desosaminyl-11,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,11-[oxycarbonyl-(4-(3H-Imidazo[4,5-c]pyndine-2-yl)-butyl)imino] erythromycin A,
2-α-Fluoro-5-O-(3 '-N-desmethyl-3 '-N-ethyl)-desosaminyl-11,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,11-[oxycarbonyl-(4-(4-[l,2,4]Tnzol-l-yl-phenyl)-butyl)imino] erythromycin A,
2-α-Fluoro-5-O-(3 '-N-desmethyl-3 '-N-ethyl)-desosaminyl-11,12-dideoxy-3-O-decladinosy 1-6-O-methy 1-3-oxo-12,11 -[oxycarbonyl-(4-(4-Imidazol-1 -yl-phenyl)-butyl)imino] erythromycin A,
2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)-desosaminyl-11,12-dideoxy-3-O-decladinosy l-6-O-methyl-3-oxo-l 2,11 -[oxycarbony l-(4-[4-(6-Chloro-pyndin-3-yl)-imidazol-l-yl]-butyl)imino] erythromycin A,
2-α-Fluoro-5-O-(3 '-N-desmethyl-3 '-N-ethyl)-desosaminyl-11,12-dideoxy-3 -O-decladinosyl-6-O-methy 1-3-oxo-12,11 -[oxycarbony l-(3-[ 1 -(4-Amino-buty 1)-1 H-imidazol-4-yl]-phenyl)imino] erythromycin A,
2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)-desosaminyl-l 1,12-dideoxy-3-O-decladmosyl-6-O-methyl-3-oxo-12,11 -[oxycarbonyl-(4-(4-Pyndin-3-yl-thiazol-2-yl)-butyl)imino] erythromycin A,
2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)-desosaminyl-11,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,11 -[oxycarbonyl-(3-[2-(4-Amino-butyl)-thiazol-4-yl]-phenyl)imino] erythromycin A,
2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)-desosaminyl-11,12-dideoxy-3-O-decladinosy 1-6-O-methy 1-3-oxo-12,11 -[oxycarbony l-(4-(4-Pyrazol-1 -y 1-imidazol-1 -y 1)-butyl)imino] erythromycin A,
2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)-desosaminyl-11,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,11-[oxycarbonyl-(4-([l,4']-Bipyrazoryl-l'-yl)-butyl)imino] erythromycin A,
2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)-desosaminyl-l 1,12-dideoxy-3-O-decladinosy l-6-O-methyl-3-oxo-12,11 -[oxycarbony l-(4-(4-Imidazol-1 -yl-pyrazol-1 -yl)-butyl)imino] erythromycin A,
2-α-Fluoro-5-O-(3 '-N-desmethy 1-3 '-N-ethyl)-desosaminyl-11,12-dideoxy-3-O-decladinosy l-6-O-methyl-3-oxo-12,11 -[oxycarbony l-(4-(4-Pyrazol-1 -yl-imidazol-1 -yl)-butyl)imino] erythromycin A,
2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)-desosaminyl-11,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,11-[oxycarbonyl-(4-[3,3']Bithiophenyl-5-yl-butyl)imino] erythromycin A,
2-α-Fluoro-5-O-(3 '-N-desmethyl-3 '-N-ethyl)-desosaminyl-11,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,11-[oxycarbonyl-(4-[2,3']Bithiophenyl-5'-yl-butyl)imino] erythromycin A,
2-0t-Fluoro-5-O-(3 '-N-desmethyl-3 '-N-ethyl)-desosaminyl-11,12-dideoxy-3-O-decladinosy 1-6-O-methy 1-3-oxo-12,11 -[oxycarbony l-(4-(4-Furan-2-y l-thiaophen-2-yl)-butyl)imino] erythromycin A,
2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)-desosaminyl-l 1,12-dideoxy-3-O-decladinosyl-6-O-methy 1-3-oxo-12,11 -[oxycarbony l-(4-(4-Oxazol-5-y 1-imidazol-1 -y 1)-butyl)imino] erythromycin A,
2-α-Fluoro-5-O-(3 '-N-desmethyl-3 '-N-ethyl)-desosaminyl-11,12-dideoxy-3-O-decladinosy 1-6-O-methy 1-3-oxo-12,11 -[oxycarbonyl-(4-(3-Pyrrol-1 -yl-[ 1,2,4]tnazol-1 -yl)-butyl) imino] erythromycin A,
2-α-Fluoro-5-O-(3 '-N-desmethyl-3 '-N-ethyl)-desosaminy 1-11,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,11-[oxycarbonyl-(4-(5-Thiophen-2-yl-tetrazol-2-yl)-butyl)imino] erythromycin A,
2-α-Fluoro-5-O-(3 '-N-desmethyl-3 '-N-ethy l)-desosaminyl-11,12-dideoxy-3-O-decladinosy l-6-O-methyl-3-oxo-12,11 -[oxycarbony l-(4-(4-Thiophen-3-yl-pyrazol-1 -yl)-butyl)imino] erythromycin A,
2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)-desosaminyl-11,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,11-[oxycarbonyl-(4-(4-Furan-3-yl-pyrazol-l-yl)-butyl)imino] erythromycin A,
2-α-Fluoro-5-O-(3 '-N-desmethyl-3 '-N-ethyl)-desosaminy 1-11,12-dideoxy-3-O-decladinosy 1-6-O-methy 1-3-oxo-12,11 -[oxycarbonyl-(4-(4-Furan-2-y 1-pyrazol-1 -y 1)-butyl)imino] erythromycin A,
2-α-Fluoro-5-O-(3 '-N-desmethyl-3 '-N-ethyl)-desosaminyl-11,12-dideoxy-3-O-decladinosy 1-6-O-methy 1-3-oxo-12,11 -[oxycarbonyl-(4-(5-Pheny l-tetrazol-2-yl)-butyl)imino] erythromycin A,
2-α-Fluoro-5-O-(3 '-N-desmethyl-3 '-N-ethyl)-desosaminyl-11,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,11-[oxycarbonyl-(4-[5-(4-Methoxy-phenyl)-tetrazol-2-yl]-butyl)imino] erythromycin A,
2-α-Fluoro-5-O-(3 '-N-desmethyl-3 '-N-ethyl)-desosaminy 1-11,12-dideoxy-3-O-decladinosy 1-6-O-methy 1-3-oxo-12,11 -[oxycarbony l-(4-(5-Furan-3-yl-imidazol-1 -yl)-butyl)imino] erythromycin A,
2-α-Fluoro-5-O-(3 '-N-desmethyl-3 '-N-ethyl)-desosaminyl-11,12-dideoxy-3 -O-decladinosy 1-6-O-methy 1-3-oxo-12,11 -[oxycarbonyl-(4-(6-Pyrazol-l-yl-pyndin-3-yl)-butyl)imino] erythromycin A,
2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)-desosaminyl-l 1,12-dideoxy-3-O-decladinosyl-6-O-methy 1-3-oxo-12,11 -[oxycarbony l-(4-(4-Pyndin-3-yl-pyrazol-1 -yl)-butyl)immo] erythromycin A,
2-α-Fluoro-5-O-(3 '-N-desmethyl-3 '-N-ethyl)-desosaminyl-11,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,11-[oxycarbonyl-(4-(5-Thiophen-2-yl-pyndin-3-yl)-butyl)imino] erythromycin A,
2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)-desosaminyl-11,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,11-[oxycarbonyl-(4-(4-Phenyl-thiophen-2-yl)-butyl)imino] erythromycin A,
2-α-Fluoro-5-O-(3 '-N-desmethyl-3 '-N-ethyl)-desosaminyl-11,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,11-[oxycarbonyl-(N-(4-Amino-butyl)-N-thiazol-2-yl-nicotinimido)]erythromycin A,
2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)-desosaminyl-11,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,11-[oxycarbonyl-(N-(4-Amino-butyl)-N-thiazol-2-yl-mcotinimido)]erythromycin A,
2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)-desosaminyl-11,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,11-[oxycarbonyl-(4-[4-(6-Pyrrol-1-yl-pyndin-3-yl)-imidazol-l-yl]-butyl)imino] erythromycin A,
2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)-desosaminyl-11,12-dideoxy-3-O-decladinosy 1-6-O-methy 1-3-oxo-12,11 -[oxycarbonyl-(4-(6-Pyrrol-1 -y l-pyndm-3-yl)-butyl)imino] erythromycin A,
2-oc-Fluoro-5-O-(3 '-N-desmethyl-3 '-N-ethyl)-desosaminyl-l 1,12-dideoxy-3-O-decladinosy 1-6-O-methy 1-3-oxo-12,11 -[oxycarbony l-(4-(2-Pyrrol-1 -y l-thiazol-5-y 1)-butyl)imino] erythromycin A,
2-α-Fluoro-5-O-(3 '-N-desmethyl-3 '-N-ethy l)-desosaminy 1-11,12-dideoxy-3-O-
decladinosy 1-6-O-methy 1-3-oxo-12,11 -[oxycarbony l-(4-(6-Imidazol-1 -yl-pyndin-3-yl)-butyl)imino] erythromycin A,
2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)-desosaminyl-l 1,12-dideoxy-3-O-decladinosy 1-6-O-methy 1-3-oxo-12,11 -[oxycarbony l-(4-[4-(Tetrahydro-furan-2-yl)-pyndin-3-yl]-butyl) imino] erythromycin A,
2-α-Fluoro-5-O-(3 '-N-desmethyl-3 '-N-ethyl)-11,12-dideoxy-3-O-decladinosyl-6-O-methy 1-3-oxo-12,11 -[oxycarbonyl-((4-(4-p-toly 1-imidazol-1 -yl)-butylimino)] erythromycin
A,
2-α-Fluoro-5-O-(3 '-N-desmethyl-3 '-N-ethyl)-11,12-dideoxy-3-O-decladinosyl-6-O-methy 1-3-oxo-12,11 -[oxycarbony l-(4-(4-(4-aminophenyl)-imidazol-1 -y l)-butyhmino)] erythromycin A,
2-α-Fluoro-5-O-(3 '-N-desmethyl-3 '-N-ethyl)-11,12-dideoxy-3-O-decladinosyl-6-O-methy 1-3-oxo-12,11 -[oxycarbonyl-(4-(4-(4-methyl-3-aminophenyl)-imidazol-1 -yl)-butyhmino)] erythromycin A,
2-α-Fluoro-5-O-(3 '-N-desmethyl-3 '-N-ethyl)-11,12-dideoxy-3-O-decladinosy l-6-O-methyl-3-oxo-12,11-[oxycarbonyl-((4-(4-(3-imidazol-lyl)-phenyl)imidazol-l-yl)-butyhmino)] erythromycin A,
2-α-Fluoro-5-O-(3 '-N-desmethyl-3 '-N-ethyl)-l 1,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,11-[oxycarbonyl-(4-(4-(3-(N,N-dicyclopropyl-amino)-phenyl)-imidazol-l-yl)-butyhmino)] erythromycin A,
2-α-Fluoro-5-O-(3 '-N-desmethyl-3 '-N-ethyl)-11,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,11-[oxycarbonyl-(4-(4-(3-(N,N-dimethyl-ammo)phenyl)-imidazol-l-yl)-butylimino)] erythromycin A,
2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)-11,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,11-[oxycarbonyl-((4-(4-(3-(tetrazol-lyl)-phenyl)-imidazol-l-yl)-butyhmino)] erythromycin A,
2-α-Fluoro-5-O-(3 '-N-desmethyl-3 '-N-ethyl)-11,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,11-[oxycarbony l-((4-(4-(2-(pyrrol-lyl)-thiozol-5-yl)-imidazol-l-yl)-butyhmino)] erythromycin A,
2-α-Fluoro-5-O-(3 '-N-desmethyl-3 '-N-ethyl)-11,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,11 -[oxycarbony l-((4-(4-(3-tnfluoromethyl-phenyl)-imidazol-1 -y 1)-butyhmino)] erythromycin A,
2-α-FIuoro-5-O-(3 '-N-desmethyl-3 '-N-ethyl)-11,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,11-[oxycarbonyl-((4-(N-(thiazol-2-yl)-benzimido)-butyhmino)] erythromycin A,
2-α-Fluoro-5-O-(3 '-N-desmethyl-3 '-N-ethyl)-11,12-dideoxy-3-O-decladinosy 1-6-O-methyl-3-oxo-12,11 -[oxycarbony l-(4-(4-(2-amino-pyrimidin)-5-y l)-imidazol-1 -yl)-
butyhmino)] erythromycin A,
2-α-Fluoro-5-O-(3 '-N-desmethy 1-3 '-N-ethyl)-11,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,11 -[oxycarbony l-((4-(4-(4-(pyrrol- lyl)-phenyl)-imidazol-1 -yl)-butyhmino)] erythromycin A,
2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)-11,12-dideoxy-3-O-decladinosyl-6-O-methy 1-3-oxo-12,11 -[oxycarbony l-((4-(4-(3-(pyrrol- lyl)-pheny l)-imidazol-1 -y 1)-butyhmino)] erythromycin A,
2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)-11,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,11-[oxycarbonyl-(4-(4-(3-(N-acetyl-ammo)-phenyl)-imidazol-l-yl)-butyhmino)] erythromycin A,
2-α-Fluoro-5-O-(3 '-N-desmethy 1-3 '-N-ethyl)-11,12-dideoxy-3-O-decladinosy 1-6-O-methyl-3-oxo-12,11-[oxycarbonyl-(4-(4-(3-(N-isopropyl-amino)-phenyl)-imidazol-l-yl)-butyhmino)] erythromycin A,
2-α-Fluoro-5-O-(3 '-N-desmethyl-3 '-N-ethyl)-11,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,11-[oxycarbonyl-((4-(4-(3-nitrophenyl)-imidazol-l-yl)-butyhmino)] erythromycin A,
2-α-Fluoro-5-O-(3 '-N-desmethyl-3 '-N-ethyl)-11,12-dideoxy-3-O-decladinosy 1-6-O-methyl-3-oxo-12,11 -[oxycarbonyl-(4-(4-(3-(N-benzoyl-amino)-phenyl)-imidazol-1 -yl)-butylimmo)] erythromycin A,
2-α-Fluoro-5-O-(3 '-N-desmethyl-3 '-N-ethyl)-11,12-dideoxy-3-O-decladinosy 1-6-O-methyl-3-oxo-12,11-[oxycarbonyl-((4-(4-(3,4-dimethyl-phenyl)-imidazol-l-yl)-butyhmino)] erythromycin A,
5-O-(3'-N-desmethyl-3'-N-ethyl)-11,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,1 l-[oxycarbonyl-(((4-(4-Pyridin-3-yl-thiazol-2-yl)-butyhmino)] erythromycin A,
2-α-Fluoro-5-O-(3 '-N-desmethyl-3 '-N-ethyl)-11,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,11-[oxycarbonyl-((4-(4-(4-fluorophenyl)-imidazol-l-yl)-butyhmino)] erythromycin A,
2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)-11,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,11-[oxycarbonyl-((4-(4-(4-methoxy-phenyl)-imidazol-l-yl)-butyhmino)] erythromycin A,
2-α-Fluoro-5-O-(3 '-N-desmethyl-3 '-N-ethyl)-11,12-dideoxy-3-O-decladinosy l-6-O-methyl-3-oxo-12,11 -[oxycarbony l-((4-(N-(benzthiazol-2-y l)-benzimido)-buty hmino)] erythromycin A,
2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)-11,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,11-[oxycarbonyl-((4-(N-(thiazol-2-yl)-nicotinamido)-butyhmino)] erythromycin A,
2-α-Fluoro-5-O-(3'-N-desmethy 1-3'-N-ethy 1)-11,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,11-[oxycarbonyl-(4-(4-(3-(N-methyl-amino)-phenyl)-imidazol-l-yl)-butylimino)] erythromycin A,
2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-11,12-dideoxy-3-O-decladinosy 1-6-O-methy 1-3-oxo-12,11 -[oxycarbony l-(4-(4-(4-(2-aminopyndy l)-imidazol-1 -yl)-butyhmino)] erythromycin A,
2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-11,12-dideoxy-3-O-decladinosy 1-6-O-methy 1-3-oxo-12,11 -[oxycarbonyl-(4-(4-(5-(2-aminopyndy 1)- 2H-tetrazol-5-yl)-butyhmino)] erythromycin A,
2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-l l,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,11-[oxycarbonyl-(4-(4-(3,4-difluorophenyl)-imidazol-l-yl)-butyhmino)] erythromycin A,
2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-11,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,11-[oxycarbonyl-(4-(4-(4-(2-chloropyndyl)-imidazol-l-yl)-butyhmino)] erythromycin A,
2-α-Fluoro-5-O-(3 '-N-desmethy 1-3 '-N-ethy l)desosaminyl-11,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,11-[oxycarbonyl-(4-(4-(3-(6-aminopyndyl)-imidazol-l-yl)-butyhmino)] erythromycin A,
2-α-Fluoro-5-O-(3'-N-desmethyl-3'-N-ethyl)desosaminyl-11,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,11-[oxycarbonyl-(4-(5-(2-Chloro-pyndin-4-yl)-tetrazol-2-yl])-butylimino)] erythromycin A,
their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers,
diastereomers or polymorphs
A pharmaceutical composition comprising a therapeutically effective amount of a
compound of claim 1 or 2 together with pharmaceutically acceptable carriers, excipients, or
diluents
A method for treating or preventing a mammal suffering from a condition caused by or
contributed to by bacterial infection, comprising administering to the said mammal a
therapeutically effective amount of a compound of claims 1 or 2 or a pharmaceutical
composition of claim 3
The method according to claim 4 wherein the said bacterium is gram positive, gram
negative or anaerobic bacteria and the said condition is community acquired pneumonia,
upper and lower respiratory tract infections, skin and soft tissue infections, hospital
acquired lung infections or bone and joint infections, mastitis, catheter infection, foreign
body, prosthesis infections or peptic ulcer disease
The method according to claim 5 wherein bacterium is selected from Staphylococci, Streptococci, Enterococci, Haemophilus, Moraxalla spp, Chlamydia spp, Mycoplasm, Legionella spp, Mycobacterium, Helicobacter, Clostridium, Bacteroides, Corynebacterium, Bacillus and Enterobactericeae A method for preparing compound of Formula XIII,
(Formula Removed)
pharmaceutically acceptable salts, pharmaceutically acceptable solvates,
enantiomers, diastereomers and polymorphs thereof, wherein, R3, W and R are the same as
defined in claim 1, which method comprises
(a) hydrolyzing clarithromycin of Formula II,
(Formula Removed)
to give a compound of Formula III,
(Formula Removed)
(b) protecting the compound of Formula III with a reagent of Formula R12O or R1x (wherein X is halogen and R1 is the hydroxy protecting group, for example, Benzoyl, tetrahydropyranyl or trialkylsilylethers) to give a compound of Formula IV,
(Formula Removed)
(c) desmethylating the compound of Formula IV at 3 '-N-dimethyl group to give a compound of Formula V,

(Formula Removed)
(d) alkylating the compound of Formula V with a reagent of Formula R CHO, R2 CO or
R3X (wherein X is halogen) to give a compound of Formula VI,
(e) reacting the compound of Formula VI with a suitable reagent to give a compound of Formula VII,
(Formula Removed)
(f) reacting the compound of Formula VII with an organic base to give a compound of Formula VIII,

(Formula Removed)
(g) oxidizing the compound of Formula VIII to give a compound of Formula IX,
(Formula Removed)
(h) reacting the compound of Formula IX with N, N'-carbonyldimidazole to give a compound of Formula X,

(Formula Removed)
(1) reacting the compound of Formula X with a compound of Formula R-W-NH2 to give a compound of Formula XI,
(Formula Removed)
(j) fluorinating the compound of Formula XI to give a compound of Formula XII,
(Formula Removed)
(k) deprotectmg the compound of Formula XII to give a compound of Formula XIII A method for preparing compound of Formula XIII,
(Formula Removed)
pharmaceutically acceptable salts, pharmaceutically acceptable solvates, prodrugs, stereoisomers and polymorphs thereof, wherein R3, W and R are the same as defined in claim 1, which method comprises (a) reacting the compound of Formula IV with a suitable reagent,

(Formula Removed)
to give a compound of Formula XIV,
(Formula Removed)
(b) reacting the compound of Formula XIV with a suitable organic base to give a compound
of Formula XV,

(Formula Removed)
(c) oxidizing the compound of Formula XV to give a compound of Formula XVI,
(Formula Removed)
(d) desmethylating the compound of Formula XVI at 3'-N-dimethyl group to give a
compound of Formula XVII,

(Formula Removed)
(e) alkylating the compound of Formula XVII with a reagent of Formula R CHO, R32 CO or R3X to give a compound of Formula IX,
(Formula Removed)
(f) fluorinating the compound of Formula IX to give a compound of Formula XVIII,

(Formula Removed)
(g) reacting the compound of Formula XVII with N,N'-carbonyldumidazol to give a compound of Formula XIX,

(Formula Removed)
(h) reacting the compound of Formula XIX with a compound of Formula R-W-NH2 to give a compound of Formula XII,
(Formula Removed)
(1) deprotecting the compound of Formula XII to give a compound of Formula XIII 9 A method for preparing compound of Formula XIII,
(Formula Removed)
pharmaceutically acceptable salts, pharmaceutically acceptable solvates, stereoisomers, prodrugs and polymorphs thereof, wherein R3, W and J are the same as defined in claim 1, which method comprises
(a) fluorinating the compound of Formula XVI,
(Formula Removed)
to give a compound of Formula XX,
(Formula Removed)
(b) reacting the compound of Formula XIX with N,N'-carbanoyldnmidazole to give a compound of Formula XXI,
(Formula Removed)
(c) reacting the compound of Formula XXII with a compound of Formula R-W-NH2 to give a compound of Formula XXII,
(Formula Removed)
(d) deprotecting the compound of Formula XXIII to give a compound of Formula XXIII,

(Formula Removed)
(e) desmethylating the compound of Formula XXIII at 3'-N-dimethyl group to give a compound of Formula XXIV,
(Formula Removed)
(f) alkylating the compound of Formula XXIV with a reagent of Formula R CHO, R 2CO or R3Xto give a compound of Formula XIII
10 A method for preparing of compound of Formula XIII,
(Formula Removed)
pharmaceutically acceptable salts, pharmaceutically acceptable solvates, stereoisomers, prodrugs and polymorphs thereof, wherein R , W and R are the same as defined in claim 1, which method comprises
(a) deprotecting the compound of Formula XX (wherein R1 is Benzoyl),
(Formula Removed)
to give a compound of Formula XXV,

(Formula Removed)
(b) desmethylating the compound of Formula XXV at 3-N'-dimethyl group to give a compound of Formula XXVI,

(Formula Removed)
(c) alkylating the compound of Formula XXVI with a reagent of Formula R3CHO, R32CHO
or R3X to give a compound of Formula XXVII,
(Formula Removed)
(d) protecting the compound of Formula XXVII with a reagent of Formula R'20 or R'X (wherein X is halogen) to give a compound of Formula XVIII,

(Formula Removed)
(e) reacting the compound of Formula XVIII with N,N'-carbonyldnmidazole to give a
compound of Formula XIX,
(Formula Removed)
(f) reacting the compound of Formula XIX with a compound of Formula R-W-NH2 to give
a compound of Formula XII,

(Formula Removed)
(g) deprotecting the compound of Formula XII to give a compound of Formula XIII