Field of the 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 Chlamidia spp Mycoplasm Legionella spp Mycobacteimm Helicobacter Clostridium Bacteioides Corynehactenum Bacillus or Enter obactei iceae Processes for the preparation ot disclosed compounds, pharmaceutical compositions thereof and method of treating bacterial infections are also provided
Background of the Invention
The first generation macrolides erythromycin A and the early derivatives are characterized by bacteriostatic or bactericidal activity tor 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 denvatives 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 favoiable safety profile, and a spectrum of activity and aie 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 macrolides
U S Patent No 6 455 505 and U S Patent No 6 313 101 disclose new derivatives of erythromycin their preparation process and their use as medicaments U S Patent No 6 420 343 and U S Patent No 6 664,238 disclose novel macrohde compounds that are useful as antibacterial and antiprotozoal agents U S Patent No 6 399,582 discloses novel macrohde compounds that are useful as antibacterial antiprotozoal agents and in the treatment involving gastric motility US Patent Application No 2002/0193320 discloses novel semi-synthetic macrohdes and compositions which are antibactenal agents WO 99/35157 and WO 04/096823 discloses compounds that are useful antibacterial and antiprotozoal agents and for othei applications Other references disclosing ketolide compounds include Alexis Denis and Alain Bonnefoy Drugs of the Future 26 (10) 975-84 (2001) Champney W S et al Cuirent Miciobiology 42, 203-10 (2001) A Denis et al Bioorg Med Chem Lett 10(2000)2019-2022
Summary of the Invention
The present invention relates to ketolide derivatives which can be used in the prevention mitigation and treatment of bacterial infection The invention also relates to the methods of preparation and method of use of the compounds Pharmaceutically acceptable salts pharmaceutically acceptable solvates enantiomers diastereomers polymorphs and metabolites 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 aspects 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 pharmaceutically acceptable solvates polymorphs prodrugs stereoisomers tautomeric forms N-oxides and metabolites thereof wherein R can be
-NR2(COR3)

(Formula Removed)
wherein
R2 and R3 can be independently
(Formula Removed)
wherein X3-X13 can be independently C(R4)0-2 N(R4)0-1 O or S
R5-R10 can be independently hydrogen halogen C1-5, alkyl C1-5 alkoxy amino nitro cyano
aryl or heteroaryl
X2 can be CR4 or N wherein R4 and R'4 independently in each occurrence can be hydrogen or
C1-3 alkyl, — can be an optional bond,
Z1 can be hydiogen or methyl
Z2 can be hydrogen halogen C1-3 alkyl C1-3 alkoxy amino nitro, cyano or amido
Z3 can be hydrogen fluorine chlorine bromine or iodine
X1 can be CR4 CR4R4N NR4 O or S
Y can be hydrogen or methyl Y is hydiogen provided R is -AR:(COR5)
In an embodiment there are piovided compounds of Formula I pharmaceutically acceptable salts pharmaceutically acceptable solvates polymoiphs prodrugs stereoisomers, tautomeric forms N-oxides and metabolites thereof wherein Y is methyl and R is the same as defined earlier
In another aspect provided herein aie compounds selected from
11 12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12 1 l-[oxycarbonyl-4-(4-(3-aminophenvl)-imidazol-l-yl]-butyhmino] erythromycin A
11 12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12 1 l-[oxycarbonyl-(4-(4-(4-methyl-3-aminophenyl)-imidazol-l-yl]-butyhmino] erythiomycin A
11 12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12 1 l-[oxycarbonyl-(4-(N-(2-thiazolyl)-nicotinamido)-butyhmino] erythromycin A
2-Methyl-l 1 12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12 1 l-[oxycarbonyl-4-(4-(3-ammophenyl)-imidazol-l-yl)-butyhmino] eiythromycm A
2-Methyl-l 1 12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,l l-[oxycarbonyl-(4-(4-thiophen-2-yl-imidazol-l-yl)-butyhmino] erythromycin A
2-Methyl-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-(4-( 1H-benzimidazo-l-yl)-butyhmino] erythromycin A
2-Methyl-l 1 12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12 1 l-[oxycarbonyl-4-(4-phenyl-imidazol-l-yl)-butyhmino] erythromycin A
2-Methyl-l 1 12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12 1 l-[oxycarbonyl-4-(4-(3-amino-4-methylphenyl)-imidazol-l-yl)-butyhmino] eiythromycm A
2-Methyl-l 1 12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12 1 l-[oxycarbonyl-(4-(4-Imidazo[4 5-b]pyndin-3-yl)-butyhmino] erythromycin A
2-Methyl-l 1 12-dideoxy-3-0-dedadinosyl-6-0-methyl-3-oxo-12 1 l-[oxycarbonyl-4-(4-(4-fluorophenyl)-imidazol-l-yl)-butyhmino] erythromycin A or
their pharmaceutically acceptable salts pharmaceutically acceptable solvates polymorphs prodrugs steieoisomers tautomeric forms N-oxides or metabolites
In another aspect provided herein is a method for prevention mitigation or treatment in 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 mav be caused by bacterium for example Staphylococci Streptococci Enteiococci Haemophilus Moicnalla spp Chlamydia spp Mycoplasm Legionella spp Mycobacteimm Heiicobactei Clostridrum Bacteroides Corynebacterum Bacillus or Enterobacteiiceae
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 catether infection foreign body prosthesis infections or peptic ulcer disease
In another aspect provided herein are processes for the preparation of the compounds disclosed herein
The following definitions apply to the terms as used herein
The term aryl stands for an aromatic radical having 6 to 14 carbon atoms Examples of aryl include, but are not limited to phenyl napthyl anthryl and biphenyl and the like
The term Tieteroaryl' refers to non-aromatic or aromatic ring system having one or moie heteroatom (s) wherein the said hetero atom (s) is/ are selected from the group comprising of nitrogen sulphur and oxygen and the nng system includes mono bi or tricyclic
The said aryl and heteroaryl may optionally be substituted with one or more substituent(s) independently selected from halogen hydroxy nitro mercapto cyano alkyl haloalkyl, cycloalkyl cycloalkenyl, alkoxy haloalkoxy thioalkyl, cycloalkoxy -NR11R12 -CONR11R12 -COOR12 -CONHR12 -OCOR12 -COR,2 -NHSO2R12 and-SO2NHR12 wherein R11 and R12 are independently selected from hydrogen or alkyl
The term polymorphs includes all ciystallme form as well as amorphous form for compounds described herein and as such aie intended to be included in the present invention
The phrase '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 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 means approved by regulatory agency of the federal or a state government or listed in the U S Pharmacopoeia or other generally recognized pharmacopoeia for use in animals and more particularly in humans
The term pharmaceutically acceptable solvates refers to solvates with water (1 e hydrates hemihydrate or sesquihydrate) or pharmaceutically acceptable solvents for example solvates with common organic solvents as ethanol and the like Such solvates are also encompassed within the scope of the disclosure
The present invention also includes within its scope " prodrugs" of these agents In general such prodrugs will be functional derivatives of these compounds which are readily
convertible in vivo into the required compound They may be carrier-linked or bioprecursors The carrier-linked prodrugs may be bipartite tripartite or mutual prodrugs Prodrugs are intended to improve drug efficacy by improving solubility and consequently absorption and distribution as desired Conventional procedure for the selection and preparation of suitable prodrug derivatives are described, for example in ' design of prodrugs ' ed H Bundgaard and Elsevier 1985 Enantiomers and Diastereomers are as defined by the IUPAC 1974 Recommendations for Section E
Detailed Description of the Invention
The compounds described 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 and II
(Scheme Removed)
The compound of Formula X 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 R'20 or R'X (wherein X is halogen) gives a compound of Formula IV (wherein R1 is hydroxy protecting group for example, COPh tetrahvdropyranyl tnalkylsilylethers and the like) which on reaction with a reagent for example tnphosgene or ethylene dicarbonate gives a compound of Formula V which on reaction with a organic base for example, tetramethyl guanidine or tnmethylamine gives a compound of Formula VI, which on oxidation gives a compound of Formula VII which on reaction with N N'-carbonyldnmidazole gives a compound of Formula VIII which on reaction with a compound of Formula R-(CH2)4-NH? gives a compound of Formula IX (wherein R is the same as defined earlier) which is finally deprotected to give a compound of Formula X
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 R^O or R'X 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 ot Formula R^O or R'X can be carried out in the presence of an organic base for example tnethylamine dnsopropylethylamine pyridine tnbutylamine or 4-(N-dimethylamino) pyridine
The reaction of a compound of Formula IV with tnphosgene to give a compound of Formula V can be carried out in a solvent for example chloroform dichloromethane carbon tetrachloude or dichloroethane
The reaction of a compound of Formula IV to give a compound of Formula V can be carried out in the presence of an organic base for example tnethylamine dnsopropyl ethylamine pyridine tnbutylamine or 4-(N-dimethylamino) pyridine
The reaction of a compound of Formula V with tetramethyl guanidine to give 'a compound of Formula VI can be earned out in a solvent for example dimethylformamide tetrahydroturan dimethylsulfoxide or mixture thereof
The oxidation of a compound of Formula VI to give a compound of Formula VII can be carried out with an oxidizing agent for example Dess-Martin penodinane N-chloro succimmide pyndinium 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) pyridinium dichromate or l-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride N-Chlorosuccinamide can be used in combination with dimethyl sulphide and l-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride can be used in combination with dimethylsulfoxide
The oxidation of a compound of Formula VI to give a compound of Formula VII can be carried out in a solvent for example chloroform dichloromethane caibon tetrachloride dimethylsulfoxide or dichloroethane
The reaction of a compound of Formula VII with N N'-carbonyldnmidazole to give a compound of Formula VIII can be carried out in a solvent for example dimethylformamide acetonitnle tetrahydrofuran or mixture thereof
The reaction of a compound of Formula VII 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 VIII with a compound of Formula R-(CH2)4-NH2 to give a compound of Formula IX can be carried out m a solvent system for example acetonitnle/water dimethylformamide/water or dimethylformamide
The deprotection of a compound of Formula IX to give a compound of Formula X can be carried out in an alcohol for example methanol ethanol propanol or isopropanol
(Scheme Removed)
The compound ot Formula XIV can be prepared according to Scheme II Thus alkylation of a compound of Foimula VII gives a compound of Formula IX, which on reaction with N N'-carbonyldnmidazole gives a compound of Formula XII which on reaction with a compound of Formula R-(CH2)4-NH2 gives a compound of Formula XIII (wherein R is the same as defined earlier) which is finally deprotected to give a compound of Formula XIV
The alkylation of a compound of Formula VII with a reagent of Formula R X to give a compound of Formula XI can be carried out in a solvent for example, dimethylformamide acetomtnle tetrahydrofuran dimethylsulfoxide or mixture thereof
The alkylation of a compound of Formula VII can be carried out in an inorganic or organic base for example sodium hydrogen carbonate potassium carbonate cesium carbonate, sodium hydride or potassiun-t-butoxide
The reaction of a compound of Formula XI with N N'-carbonyldnmidazole to give a compound of Formula XII can be carried out in a solvent for example dimethylformamide acetomtnle tetrahydrofuran or mixture thereof
The reaction of a compound of Formula XI 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 XII with a compound of Formula R-(CH2)4-NFT to give a compound of Formula XIII can be carried out in a solvent system for example acetonitrile/water, dimethylformamide/water or dimethylformamide
The deprotection of a compound of Formula XIII to give a compound of Formula XIV can be carried out in an alcohol for example methanol ethanol, propanol or isopropanol
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 l
useful for such purpose are listed below
11 12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12 1 l-[oxycarbonyl-4-(4-(3-aminophenyl)-imidazol-l-yl]-butyhmino] erythromycin A (Compound No 1)
11 12-dideoxy-3-0-decladinosyl-6-0-mefhyI-3-oxo-12 1 l-[oxycarbonyl-(4-(4-(4-methyl-3-aminophenyl)-imidazol-l-yl]-butyhmino] erythromycin A (Compound No 2)
11 12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12 1 l-[oxycarbonyl-(4-(N-(2-thiazolyl)-nicotinamido)-butyhmino] erythromycin A (Compound No 3)
2-Methyl-l l,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12 1 l-[oxycarbonyl-4-(4-(3-aminophenyl)-imidazol-l-yl)-butyhmino] erythiomycin A (Compound No 4)
2-Methyl-l 1 12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12 1 l-[oxycarbonyl-(4-(4-thiophen-2-yl-imidazol-l-yl)-butyhmino] erythromycin A (Compound No 5)
2-Methyl-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-(4-( 1H-benzimidazo-l-yl)-butyhmino] erythromycin A (Compound No 6)
2-Methyl-l 1 12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,l l-[oxycarbonyl-4-(4-phenyl-imidazol-l-yl)-butyhmino] erythromycin A (Compound No 7),
2-Methyl-l 1 12-dideoxy-3-0-decladmosyl-6-0-methyl-3-oxo-12,l l-[oxycarbonyl-4-(4-(3-amino-4-methylphenyl)-imidazol-l-yl)-butyhmino] erythromycin A (Compound No 8)
2-Methyl-l 1 12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,l l-[oxycarbonyl-(4-(4-Imidazo[4 5-b]pyndin-3-yl)-butyhmino] erythiomycin A (Compound No 9)
2-Methyl-l 1 12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12 1 l-[oxycarbonyl-4-(4-(4-fluorophenyl)-imidazol-l-yl)-butyhmino] erythiomycin A (Compound No 10) or
their pharmaceutically acceptable salts, pharmaceutically acceptable solvates polymorphs prodrugs, stereoisomers tautomeric forms N-oxides or metabolites
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 antibactenal agents for the treatment of bacterial infections in human and animal
Compositions provided herein include an active ingredient alone oi in combination with pharmaceutically acceptable carner(s) as defined above The active ingredient comprises of a compound of general Formula I or a salt or a metabolite or a prodrug thereof A process tor the preparation of a pharmaceutical composition as defined herein comprises of bringing a compound of general Formula I or a salt or a metabolite oi a prodrug thereof into association with a pharmaceutically acceptable carrier
Solid form preparations for oral administration may include capsules tablets pills powder granules and suppositories For solid form preparations active compound is mixed with at least one inert pharmaceutically acceptable excipient or carrier such as sodium
citrate dicalcium phosphate and/or a filler extenders such as starch lactose sucrose glucose mannitol and silicic acid, binders such as carboxymethyl cellulose alginates gelatins polyvinylpyrroledinone suciose acacia, disintegrating agents such as agar-agar calcium carbonate, potato starch aliginic acid, certain silicates and sodium caibonate, absorption accelerators such as quaternary ammonium compounds, wetting agents such as cetyl alcohol glycerol mono stearate adsorbents such as Kaolin, Lubricants such as talc calcium stearate magnesium stearate solid polyethyleneglycol, sodium lauryl sulphate and mixture thereof
Auxiliary agents such as solubilisers, surfactants viscosity modifiers coloring agents preservatives antioxidants, taste masking agents flavouring agents pH modifiers may also be incorporated into the composition
In case of capsules tablets, pills the dosage form may also comprise butfenng agents
The solid preparation of tablets capsules pills granules can be prepared with coating and shells such as enteric coating and other coatings well known in the pharmaceutical formulating art
Liquid form prepaiations for oral administration include pharmaceutically acceptable emulsions solution suspensions syrups and elixirs For liquid form preparations, active compound is mixed with water or other solvent solubilizing agents and emulsifiers such as ethyl alcohol isopropyl alcohol, ethyl carbonate ethyl acetate benzyl alcohol benzyl benzoate propylene glycol 1 3-butylene glycol dimethyl formamide oils (such as cottonseed ground corn germ live caster and sesamine oil) glycerol and fatty acid ester of sorbitan and mixture thereof
Besides inert diluents, the oral composition can also include adjuvant such as wetting agents emulsifying agents suspending agents sweetening agents flavoring agents and perfuming agents
Formulations described herein may be formulated so as to provide quick sustained or delayed release of the active compound after administration to the patient by employing procedures well known to the art The term patient as used herein refers to a mammal which is the object of treatment observation or experiment
The pharmaceutical preparation is in unit dosage form in such torm the preparation is subdivided into unit doses containing appropriate quantities of the active compound
The amount of a compound of the present invention that will be effective in the treatment of a particular disorder or condition and can be determined by standard clinical
techniques In addition, in vitro or in vivo assays may optionally be employed to help identify optional dosage ranges
Examples set forth below demonstrate general synthetic procedures for the preparation of representative compounds The examples are provided to illustrate particular aspects of the disclosure and do not constrain the scope of the present invention as defined by the claims
Experimental Details General Procedure Preparation of N-Thiazol-2-yl-nicotinamide Step 1 Preparation of Nicotinoyl Chloride
A solution of nicotinic acid (1 equiv ) in thionyl chloride was stirred at 120 C for about three hours The reaction mixture was then concentrated To it was added benzene and the reaction mixture was again concentrated to obtain the solid product
Step II Preparation of Thiazol-2-yl-nicotinamide
A solution of Thiazol-2-yl-amme (1 equiv ) and nicotinoyl chloride (1 equiv ) in pyridine was stirred at 90 °C for about 45 minutes The reaction mixture was then poured in cold water and the solid product obtained was filtered through sintered funnel to get the titled product
Preparation of 5-[l-(4-Ammobutyl)-lH-imidazole-4-yl]-2-methyl-phenylamine
Step I Preparation of l-(4-Methyl-3-nitrophenyl)ethanone
4-Methylacetophenone in cone sulfuric acid was cooled to 0-5 °C To it was added nitrating
mixture (1 equiv ) with vigorous stirring After completion of addition the reaction mixture
was further stirred below 10 C for about 30 minutes Reaction mixture was then poured onto
ice-chilled water extracted with dichloromethane The organic layer was washed with water
and the solvent was removed under reduced pressure to get yellowish solid as crude product
Step II Preparation of 2-Bromo-l-(4-methyl-3-mtrophenyl )-ethanone A solution of l-(4-Methyl-3-nitrophenvl)ethanone in carbon tetrachloride was cooled to 0-5 C To this was added bromine (1 0 eq ) drop wise at 0-5°C with vigorous stirring The reaction mixture was further stirred at 15°C for about one hour After completion of reaction chilled water was added to the reaction mixture The organic layer was separated and the product in the remaining aqueous layer was extiacted with carbon tetrachloride Both the
organic layers were combined and washed with water The organic solvent was then removed under reduced pressure to get desired product
Step III Preparation of 4-(4-Methyl-3-nitrophenyl)-1H-imidazole
A solution of 2-Bromo-l-(4-methyl-3-nitrophenyl)-ethanone in formamide (20 equiv ) was heated at about 180 °C for about one hour The reaction mixture was then poured in ice-cold water with stirring The pH was made acidic followed by extraction with ethyl acetate The aqueous layer was basified followed by extraction with ethyl acetate The layers were combined and washed with water and brine and then dried over anhydious sodium sulfate The organic layer was then concentrated and vacuum dried to get the desired product
Step IV Preparation of 2-{4-[4-(4-Methyl-3-nitrophenyl)-imidazole-l-yl]-butyl}-isoindole-1 3-dione
A solution of 4-(4-Methyl-3-nitrophenyl)-lH-imidazole in dry dimethylformamide was cooled to 0 C To this was added sodium hydride (1 5 equiv ) portion wise for about one hour This was followed by the addition of N-4-bromobutyl phthalimide (1 2 equiv ) The reaction mixture was stirred for about three hours The reaction mixture was then poured in ice-cold watei and extracted with ethyl acetate The organic layer was washed with water and brine and then dried over anhydrous sodium sulfate The organic layer was then concentrated and vacuum dried to get the desired product The crude product was purified on silica gel column using mixture ot methanol and dichloromethane as eluent The desired product was further purified by crystallization
Step V Pieparation of 4-[4-(4-Methyl-3-nitrophenyl)-imidazole-l-yl]-butylamine A solution of 2-(4-[4-(4-Methyl-3-mtrophenyl)-imidazole-l-yl]-butylj-isoindole-l 3-dione in ethanol and hydrazine hydiate (10 equiv ) was heated at 60 °C for about two hours The reaction mixture was then cooled and the solid bypioduct was filtered out The filtrate was concentrated by applying reduced pressure To this was added dichloromethane and the solution was stirred for some time till a solid product appears The solid was then filtered and washed with dichloromethane The solvent was remo\ed to get the desired product
Step VI Preparation of 5-[l-(4-Aminobutyl)-1H-imidazole-4-yl]-2-methyl-phenylamme 4-[4-(4-Methyl-3-nitrophenyl)-imidazole-l-yl]-butylamine was taken in Parr apparatus To it was added Palladium/Carbon (50 % wet) The assembly was flushed with nitiogen To it was
added methanol and the assembly was again flushed with nitrogen About 30-40 psi pressure was applied for about four hours The catalyst was then filtered through celite bed washed with mixture of methanol and dichloromethane The solvent was then removed under reduced pressure to get the desired product
The following compounds were prepared similarly as described above
3-[l-(4-Ammobutyl)-lH-imidazole-4-yl]-phenylamine
The title compound was prepared by a procedure analogous to the one described above by
substituting 4-Methylacetophenone with acetophenone
Scheme 1
Preparation of compound of Formula III
To an aqueous solution of hydrochloric acid was added clarithromycin (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 affoid crude product The crude product was crystallized from ethyl acetate and hexane
Preparation of compound of Formula IV
To a solution of compound of Formula III (1 equry ) in dichloromethane was added benzoic anhydride (2 5 equiv ) followed by triethylamine (6 equiv ) and stirred at an ambient temperature for about 30 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 ovei anhydrous sodium sulphate and the solvent was removed under reduced pressure to give crude product The crude product obtained was crystallized from ethyl acetate and hexane mixture
Preparation of compound of Formula V
To a solution of compound of Formula IV (1 equiv ) in dichloromethane was added triphosgene (1 5 equiv ) To it pyridine was added (15 equiv ) slowly After complete addition reaction mixture was stiried for about 4 hours at 0 °C and then quenched by addition of ice-cold water Reaction mixture was diluted with dichloromethane and washed
with water followed by brine dried over anhydious sodium sulphate and concentrated under reduced pressure to afford the desired product
Preparation of compound of Formula VI
To a solution of compound of Formula V (1 equrv ) in dimethylformamide was added tetramethyl guanidine (2 2 equiv ) and heated at about 90 °C stirred for about 8 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 desried product
Preparation of compound of Formula VII
To a solution of compound of Formula VI (1 equiv ) in dichloromethane Dess-Martin Penodinane (2 5 equiv ) was added and lefluxed 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 VIII
To a solution of compound of Formula VII (1 equiv) in dimethylformamide tetrahydrofuran (3 2) was cooled to 0 °C to it was added N N'-carbonyldiimidazole (3 equiv ) and sodium hydride (3 equiv ) and was stirred for about 30 minutes The reaction mixture was quenched by addition of water It was extracted with ethyl acetate The organic layer was washed with water brine dried ovei anhydrous sodium sulphate and concentrated under reduced pressure to afford the desried product
Preparation of compound of Formula IX
The compound of Formula VIII (1 equiv ) and compound of Formula R-(CH2)4-NH2 (3 equiv ) was taken in 10 % water in acetonitrile and heated at about 70 °C for about 14 hours Reaction mixture was cooled to 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 ot Formula X
The compound of Formula IX was taken in methanol and lefluxed 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 to afford the desired product
Scheme II
Preparation of compound of Formula XI
To a solution of compound of Formula VII (1 equiv ) in dimethylformamide was added sodium hydride (1 5 equiv ) in portions at 0 °C stirred for about 20 mm Then methyl iodide (1 1 equiv ) was added 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 sulfate and concentrated under reduced pressure to get the desired product
Preparation of compound of Formula XII
A solution of compound of Formula XI (1 equiv) in dimethylformamide tetrahydrofuran (3 2) was cooled to 0°C to it was added N, N'-carbonyldnmidazole (3 equiv ) and sodium hydride (3 equiv ) and it 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 XIII
The compound of Formula XII (1 equiv ) and compound of Formula R-(CH2)4-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 punfied by silica gel column chromatography (thoroughly neutralized with tnethylamine) using 25-30%) acetone in hexane to afford the desired product
Preparation of compound of Formula XIV
The compound of Formula XIII 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
The following compounds were prepared following the above general procedure
Compound No 1 11 12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12 1 l-[oxycarbonyl-4-(4-(3-aminophenyl)-imidazol-l-yl]-butyhmino] erythromycin A MS (+ ion mode) m/z 826 05 [M+l]
Compound No 2 11 12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12 1 l-[oxycarbonyl-(4-(4-(4-methyl-3-aminophenyl)-imidazol-l-yl]-butyhmino] erythromycin A MS (+ ion mode) m/z 840 08 [M+l]
Compound No 3 11 12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12 1 l-[oxycarbonyl-(4-(N-(2-thiazolyl)-nicotinamido)-butylimino] erythromycin A MS (+ ion mode) m/z 872 10 [M+l]
Compound No 4 2-Methyl-ll 12-dideoxy-3-0-decladinosyl-6-0-methyl-3-o\o-12 11-[oxycaibonyl-4-(4-(3-aminophenyl)-imidazol-l-yl)-butyhmino] erythromycin A MS (+ ion mode) m/z 840 08 [M+l]
Compound No 5 2-Methyl-ll 12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12 11-[oxycarbonyl-(4-(4-thiophen-2-yl-imidazol-l-yl)-but\hmino] erythromycin A MS (+ ion mode) m/z 815 03 [M+l]
Compound No 6 2-Methyl-ll 12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12 11-[oxycarbonyl-(4-(lH-benzimidazo-l-yl)-butyhmino] erythromycin A MS (+ ion mode) m/z 799 03 [M+l]
Compound No 7 2-Methyl-ll 12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12 11-[oxycarbonyl-4-(4-phenyl-imidazol-1 -yl)-butylimino] erythromycin A MS (+ ion mode) m/z 825 06 [M+l]
Compound No 8 2-Methyl-ll 12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12 11-[oxycarbonyl-4-(4-(3-amino-4-methylphenyl)-imidazol-l-yl)-butyhmino] erythromycin A MS (+ ion mode) m/z 854 11 [M+l]
Compound No 9 2-Methyl-ll 12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12 11-[oxycarbonyl-(4-(4-Imidazo[4 5-b]pyndin-3-yl)-butyhmino] erythromycin A MS (+ ion mode) m/z 800 01 [M+l]
Compound No 10 2-Methyl-ll 12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12 11-[oxycarbonyl-4-(4-(4-fluorophenvl)-imidazol-l-yl)-butyhmino] erythromycin A MS (+ ion mode) m/z 843 05 [M+l]
Microbiological activity
Compounds disclosed herein displayed antibacterial activity in vitto 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 catheter infection foreign body prosthesis infections or peptic ulcer disease
Minimum mhibitoiy 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 CO2 incubation (5% CO2) 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 cultuie 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 foi 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 ug/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 01 formation of less than 10 colonies per spot was considered as Minimum Inhibitory Concentiation (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 Piecautions & Quality Control Measures Quality Control Strains
Staphylococcus aureus ATCC 29213 Enterococcus faetahs ATCC 29212, Esther lew toll ATCC 25922, Pseudomonas aeruginosa ATCC 27853 All 60 cultures were visually checked for punty
Media Control NCCLS disc diffusion assay using 10µg 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 ot the media The diameter was plotted in the media QC chart
Results The MICs of some of the compounds of Formula I against some bacterium are shown in Table I
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
MRSA Methicillin resistant, S aureus Staphylococcus auieus, S pyo Streptococcus pyogenes E faecalis Enterococcus faecalis, S pneum Stieptococcus pneumoniae H influ Haemophilus influenzae All MIC in µg/ml
(Table Removed)

WE CLAIM:

1. Compounds having the structure of Formula I,
(Formula Removed)
pharmaceutically acceptable salts, pharmaceutically acceptable solvates, polymorphs, prodrugs, stereoisomers, tautomeric forms, N-oxides and metabolites thereof, wherein,
(Formula Removed)
wherein,
R2 and R3 are independently
(Formula Removed)
wherein, X5-X13 are independently C(R4)0-2, N(R4)0-1, O or S,
R5-R10 are independetly hydrogen, halogen, C1-3 alkyl, alkoxy, amino, nitro, cyano, aryl
or heteroaryl,
X2 is CR4 or N wherein R4 and R'4 independently in each occurrence are hydrogen or
C1-3 alkyl, — is an optional bond,
Z1 is hydrogen or methyl,
Z2 is hydrogen, halogen, C1-3 alkyl, C1-3 alkoxy, amino, nitro, cyano or amido,
Z3 is hydrogen, fluorine, chlorine, bromine or iodine,
X, is CR4, CR4R'4, N, NR4. O or S;
Y is hydrogen or methyl; Y is hydrogen provided R is -NR2(COR3).
A compound namely:
11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-4-(4-(3-aminophenyl)-imidazol-l-yl]-butylimino] erythromycin A, 11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-(4-(4-(4-methyl-3-aminophenyl)-imidazol-l-yl]-butylimino] erythromycin A,
11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-(4-(N-(2-thiazolyl)-nicotinamido)-butylimino] erythromycin A,
2-Methyl-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-4-(4-(3-aminophenyl)-imidazol-l-yl)-butylimino] erythromycin A,
2-Methyl-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-(4-(4-thiophen-2-yl-imidazol-l-yl)-butylimino] erythromycin A,
2-Methyl-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-(4-(1H-benzimidazo-l-yl)-butylimino] erythromycin A.
2-Methyl-1 l,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,l l-[oxycarbonyl-4-(4-phenyl-imidazol-l-yl)-butylimino] erythromycin A,
2-Methyl-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-4-(4-(3-amino-4-methylphenyl)-imidazol-1 -yl)-butylimino] erythromycin A,
2-Methyl-11,12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-(4-(4-Imidazo[4,5-b]pyridin-3-yl)-butylimino] erythromycin A,
2-Methyl-11.12-dideoxy-3-0-decladinosyl-6-0-methyl-3-oxo-12,11 -[oxycarbonyl-4-(4-(4-fluorophenyl)-imidazol-l-yl)-butylimino] erythromycin A or
their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, polymorphs, prodrugs, stereoisomers, tautomeric forms, N-oxides or metabolites.
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 selected from: 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 and 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.
The method according to claim 6 wherein the bacterium is drug resistant cocci.
A method for the preparation of compounds of Formula X,

to give a compound of Formula III,
(Formula Removed)
pharmaceutically acceptable salts, pharmaceutically acceptable solvates, polymorphs, prodrugs, stereoisomers, tautomeric forms. N-oxides and metabolites thereof, which method comprises: (a) hydrolyzing clarithromycin of Formula II

(Formula Removed)
(b) protecting the compound of Formula III with a reagent of Formula R12O or R X (wherein X is halogen) to give a compound of Formula IV (wherein R is the hydroxy protecting group, for example, C0Ph, tetrahydropyranyl or trialkylsilylethers),

(Formula Removed)
(c) reacting the compound of Formula IV with a suitable reagent to give a compound of Formula V.

(Formula Removed)
(d) reacting the compound of Formula V with an organic base to give a compound of
Formula VI,
(Formula Removed)
(e) oxidizing the compound of Formula VI to give a compound of Formula VII,
(Formula Removed)
(f) reacting the compound of Formula VII with N,N'-carbonyldimidazole to give a compound of Formula VIII,
(Formula Removed)
(g) reacting the compound of Formula VIII with a compound of Formula R-(CH2)4-NH2 to give a compound of Formula IX (wherein R is the same as defined in claim 1),
(Formula Removed)
(h) deprotecting the compound of Formula IX to give a compound of Formula X. A method for the preparation of compounds of Formula XIV,

(Formula Removed)
pharmaceutically acceptable salts, pharmaceutically acceptable solvates, polymorphs, prodrugs, stereoisomers, tautomeric forms, N-oxides and metabolites thereof, which method comprises:
(a) alkylation of compound of Formula VII with a reagent of Formula CH3X (wherein X is halogen)
to give compound of Formula XI,
(Formula Removed)
(b) reacting the compound of Formula XI with N.N'-carbonyldimidazole to give a compound of Formula XII,
(Formula Removed)
(c) reacting the compound of Formula XII with a compound of Formula R-(CH2)4-NH2 to give a compound of Formula XIII (wherein R is the same as defined in claim 1),
(Formula Removed)
(d) deprotecting the compound of Formula XII to give compound of Formula XIV.