WO2006129257A2

WO2006129257A2 - Ketolide derivatives as antibacterial agents

Info

Publication number: WO2006129257A2
Application number: PCT/IB2006/051686
Authority: WO
Inventors: Biswajit Das; Anjan Chakrabarti; Gobind Singh Kapkoti; Atul Kashinath Hajare; Rita Katoch; Ashok Rattan
Original assignee: Ranbaxy Laboratories Limited
Priority date: 2005-05-30
Filing date: 2006-05-26
Publication date: 2006-12-07
Also published as: WO2006129257A3

Abstract

The present invention provides ketolide derivatives, which can be used as antibacterial agents. In particular, compounds described herein can be used for treating or preventing conditions caused by or contributed to by gram positive, gram negative or anaerobic bacteria, more particularly against, for example, Staphylococci, Streptococci, Enterococci, Haemophilus, Moraxalla spp., Chlamydia spp., Mycoplasm, Legionella spp., Mycobacterium, Helicobacter, Clostridium, Bacteroides, Corynebacterium, Bacillus or Enterobactericeae. Also provided are processes for preparing such ketolide. derivatives, pharmaceutical compositions thereof, and methods of treating bacterial infections. The compounds have the following structure, Formula (I), wherein R can be Formula (II), (wherein Zi can be hydrogen or melhyl, 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, CR4 R’4N, NR4, O or S, X2 can be CR4 or N wherein R4 and R'4 independently in each occurrence can be hydrogen or C1-3 alky, R2 and R3 can be independently Formula (III), wherein, X3-X13 can be independenËy C(R4 ) 0-2, N(R4)0-1, O or S, R5-R10 can be independently hydrogen, halogen, C1-3 alkyl, C1-3 alkoxy, amino, nilro, cyano, aryl or heteroaryl), Y is hydrogen or methyl, and is an optional single bond.

Description

KETOLIDE DERIVATIVES AS ANTIBACTERIAL AGENTS

Field of the Invention

The present invention provides ketolide derivatives, which can be used as antibacterial agents. Compounds described herein can be used for the treating or preventing conditions caused by or contributed to by Gram-positive, Gram-negative or anaerobic bacteria, more particularly against, for example, Staphylococci, Streptococci, Enterococci, Haemophilus, Moraxalla spp., Chlamydia spp., Mycoplasm, Legionella spp., Mycobacterium, Helicobacter, Clostridium, Bacteroides, Corynebacterium, Bacillus, Enterobactericeae or any combination thereof. Also provided are processes for preparing compounds described herein, pharmaceutical compositions thereof, and methods for treating bacterial infections.

Background of the Invention

First generation macrolides 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., /. 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 were developed to address the limitations of erythromycin A. Both clarithromycin and azithromycin were found to be important drugs in the treatment and prophylaxis of atypical mycobacterial infections in patients with HIV.

Macrolides were found to be effective drugs in the treatment of many respiratory tract infections. However, increasing resistance among S. pneumoniae has prompted a search for new compounds that retain favorable safety profiles, retain 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, ketolides have been developed as next generation macrolides. U.S. Patent Nos. 6,455,505 and 6,313,101 disclose new derivatives of erythromycin, their preparation process and their use as medicaments. U.S. Patent Nos. 6,420,343 and 6,664,238 disclose novel macrolide compounds that are described as useful as antibacterial and antiprotozoal agents. U.S. Patent No. 6,399,582 discloses novel macrolide compounds that are described as useful as antibacterial, antiprotozoal agents and in the treatment involving gastric motility. U.S. Patent Application No. 2002/0193320 discloses novel semi-synthetic macrolides and compositions which are described as antibacterial agents. PCT Publication Nos. WO99/35157 and WO 04/096823 disclose compounds that are described as useful antibacterial and antiprotozoal agents and for other applications. Other references disclosing ketolide compounds include Alexis Denis and Alain Bonnefoy, Drugs of the Future, (2001), 26(10): 975-84 ; Champney WS et al.,

Current Microbiology, (2001), 42:203-10; A. Denis et al., Bioorg. Med. Chem. Lett, 2000, 10:2019-2022.

However, there remains a need for ketolide derivatives which can be used as antibacterial agents on a wide variety of Gram-positive, Gram-negative or anaerobic bacteria.

Summary of the Invention

Ketolide derivatives, which can be used in the treatment or prevention of bacterial infection, and processes for the synthesis of these compounds are provided. Pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers, polymorphs of these compounds having same type of activity are also provided. Pharmaceutical compositions containing the described compounds together with pharmaceutically acceptable carriers, excipients or diluents, which can be used for the treatment of bacterial infections are also provided. Thus in one aspect, provided herein are compounds having the structure of Formula I,

pharmaceutically acceptable salts, pharmaceutically acceptable solvates, polymorphs, prodrugs, stereoisomers, tautomeric forms, N-oxides or metabolites thereof, wherein R can be

(wherein Zi can be hydrogen or methyl, Z₂ can be hydrogen, halogen, Ci_₃ alkyl, Ci_₃ alkoxy, amino, nitro, cyano or amido, Z₃ can be hydrogen, fluorine, chlorine, bromine or iodine, Xi can be CR₄, CR₄R₄N, NR₄, O or S, X₂ can be CR₄ or N wherein R₄ and R₄ independently in each occurrence can be hydrogen or C_1-3 alkyl,

R₂ and R₃ can be independently

wherein, X₃-Xi₃ can be independently C(R₄)O_-2, N(R₄)O-I, O or S, R₅ -Rio can be independently hydrogen, halogen, C_1-3 alkyl, C_1-3 alkoxy, amino, nitro, cyano, aryl or heteroaryl),

Y can be hydrogen or methyl, and - A - — can be an optional single bond.

In an embodiment, provided herein are compounds of Formula I, pharmaceutically acceptable salts, pharmaceutically acceptable solvates, polymorphs, prodrugs, stereoisomers, tautomeric forms, N-oxides or metabolites thereof, wherein Y is methyl and R is the same as defined earlier.

In another aspect, provided herein are illustrative compounds including: l l,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,ll-[oxycarbonyl-4-(4-(3- aminophenyl)-imidazol-l-yl]-butylimino] erythromycin A, l l,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,ll-[oxycarbonyl-(4-(4-(4-methyl- 3-aminophenyl)-imidazol-l-yl]-butylimino] erythromycin A, l l,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,l l-[oxycarbonyl-(4-(N-(2- thiazolyl) -nicotinamide) -butylimino] erythromycin A,

2-Methyl-ll,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,ll-[oxycarbonyl-4-(4- (3-aminophenyl)-imidazol-l-yl)-butylimino] erythromycin A,

2-Methyl-ll,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,ll-[oxycarbonyl-(4-(4- thiophen-2-yl-imidazol-l-yl)-butylimino] erythromycin A,

2-Methyl-ll,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,ll-[oxycarbonyl-(4- (lH-benzimidazo-l-yl)-butylimino] erythromycin A, 2-Methyl-ll,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,ll-[oxycarbonyl-4-(4- phenyl-imidazol-1-yl) -butylimino] erythromycin A,

2-Methyl-ll,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,ll-[oxycarbonyl-4-(4- (3-amino-4-methylphenyl)-imidazol-l-yl)-butylimino] erythromycin A,

2-Methyl-ll,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,ll-[oxycarbonyl-(4-(4- Imidazo[4,5-b]pyridin-3-yl)-butylimino] erythromycin A,

2-Methyl-ll,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,ll-[oxycarbonyl-4-(4- (4-fluorophenyl)-imidazol-l-yl)-butylimino] erythromycin A,

2-Methyl-ll,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,ll-[oxycarbonyl-(4-(5- flouro-lH-benzimidazo-l-yl)-butylimino] erythromycin A, 2-Methyl-ll,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,ll-[oxycarbonyl-4-(4- (4-aminopyridyl)-imidazol-l-yl)-butylimino] erythromycin A, or pharmaceutically acceptable salts, pharmaceutically acceptable solvates, polymorphs, prodrugs, stereoisomers, tautomeric forms, N-oxides or metabolites thereof.

In yet another aspect, provided herein are pharmaceutical compositions comprising therapeutically effective amounts of one or more compounds of compounds described herein together with one or more pharmaceutically acceptable carriers, excipients, or diluents.

In another aspect, provided herein are methods for treating or preventing conditions caused by or contributed to by bacterial infections comprising administering to a mammal in need thereof therapeutically effective amounts of one or more compounds of compounds described herein.

The methods may include one or more of the following embodiments. For example, the condition can be selected from community acquired pneumonia, upper or lower respiratory tract infections, skin or soft tissue infections, hospital acquired lung infections, hospital acquired bone or joint infections, mastitis, catether infection, foreign body, prosthesis infections or peptic ulcer disease. In another embodiment, the bacterial infection can be caused by gram positive, gram negative or anaerobic bacteria.

In yet another embodiment, the Gram-positive, Gram-negative or anaerobic bacteria can be selected from Staphylococci, Streptococci, Enterococci, Haemophilus, Moraxalla spp., Chlamydia spp., Mycoplasm, Legionella spp., Mycobacterium, Helicobacter, Clostridium, Bacteroides, Corynebacterium, Bacillus or Enterobactericeae. In a particular embodiment, the bacterium is cocci. In another particular embodiment, the cocci is drug resistant.

In another aspect, provided herein are processes for the preparation of the compounds of Formula X

Formula X (Formula I wherein, Y = FT)

pharmaceutically acceptable salts, pharmaceutically acceptable solvates, polymorphs, prodrugs, stereoisomers, tautomeric forms, N-oxides or metabolites thereof, wherein R is the same as defined earlier, comprising the steps of:

(a) hydrolyzing clarithromycin of Formula II

Formula II

to form a compound of Formula III;

Formula HI (b) protecting the compound of Formula III by reacting with one or more reagent of Formula R^O or R¹X (wherein X is halogen) to form a compound of Formula IV;

Formula IV

(c) reacting the compound of Formula IV with one or more suitable reagents to form a compound of Formula V;

Formula V

(d) reacting the compound of Formula V with one or more organic bases to form a compound of Formula VI;

Formula VI (e) oxidizing the compound of Formula VI to form a compound of Formula VII;

Formula Vn

(f) reacting the compound of Formula VII with N,N'-carbonyldimidazole to form a compound of Formula VIII;

Formula Vm

(g) reacting the compound of Formula VIII with a compound of Formula R- (CH2)₄-NH2 to form a compound of Formula IX (wherein R is the same as defined in claim 1); and

(h) deprotecting the compound of Formula IX to form a compound of Formula X.

In another aspect, provided herein are processes for the preparation of the compounds of Formula XIV,

(Formula I wherein, Y = CH₃)

pharmaceutically acceptable salts, pharmaceutically acceptable solvates, polymorphs, prodrugs, stereoisomers, tautomeric forms, N-oxides or metabolites thereof, wherein R is the same as defined earlier, comprising the steps of: (a) alkylating a compound of Formula VII with one or more reagents of

Formula CH₃X (wherein X is halogen)

Formula Vn

to form a compound of Formula XI;

Formula XI

(b) reacting the compound of Formula XI with N,N'-carbonyldimidazole to form a compound of Formula XII;

Formula XII

(c) reacting the compound of Formula XII with a compound of Formula R(CH2)₄NH2 to form a compound of Formula XIII; and

(d) deprotecting the compound of Formula XII to form a compound of Formula XIV. Detailed Description of the Invention

In accordance with one aspect, provided herein are compounds having the structure of Formula I,

Formula I pharmaceutically acceptable salts, pharmaceutically acceptable solvates, polymorphs, prodrugs, stereoisomers, tautomeric forms, N-oxides or metabolites thereof, wherein R can be

(wherein Zi can be hydrogen 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, Xi can be CR₄, CR₄R₄N, NR₄, O or S, X₂ can be CR₄ or N wherein R₄ and R₄ independently in each occurrence can be hydrogen or C₁-3 alkyl,

R₂ and R3 can be independently

wherein, X3-X13 can be independently C(R₄)O_-2, N(R₄)O-I, O or S, R₅ -Rio can be independently hydrogen, halogen, C₁-3 alkyl, C₁-3 alkoxy, amino, nitro, cyano, aryl or heteroaryl),

Y can be hydrogen or methyl, and — can be an optional single bond.

In accordance with a further aspect, provided herein are methods for treating a mammal suffering from conditions caused by or contributed to by Gram-positive, Gram- negative or anaerobic bacteria comprising administering to a mammal in need thereof therapeutically effective amounts of one or more compounds or one or more pharmaceutical compositions described herein.

Bacterial infection may be caused by one or more bacteria, for example, Staphylococci, Streptococci, Enterococci, Haemophilus, Moraxalla spp., Chlamydia spp., Mycoplasm, Legionella spp., Mycobacterium, Helicobacter, Clostridium, Bacteroides, Corynebacterium, Bacillus or Enterobactericeae. The conditions treated or prevented 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, or other bacterial infections, for example, mastitis, catether infection, foreign body, prosthesis infections or peptic ulcer disease. In accordance with a third aspect, provided herein are processes for preparing the described compounds.

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 "heteroaryl" refers to non-aromatic or aromatic ring system having one or more heteroatom (s) wherein the hetero atom(s) is/are selected from nitrogen, sulphur and oxygen and the ring system includes mono, bi or tricyclic.

The 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, - NRnRi₂, -CONR_HR_I2, -COOR_I2, -CONHRi₂, -OCORi₂, -CORi₂, -NHSO₂Ri₂ and - SO₂NHRi₂ wherein Rn and Ri₂ are independently selected from hydrogen or alkyl.

The term "polymorphs" includes all crystalline forms as well as amorphous forms for compounds described herein and as such are 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 (i.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.

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, for example, Schemes I and II.

Compounds of Formula X can be prepared, for example, according to Scheme I. Thus, clarithromycin of Formula II can be hydrolyzed to form a compound of Formula III. The compound of Formula III can be protected by reacting with one or more reagents of Formula R^O or R¹X (wherein X is halogen) to form a compound of Formula IV (wherein R¹ is hydroxy protecting group, for example, COPh, tetrahydropyranyl, trialkylsilylethers and the like). The compound of Formula IV can be reacted with one or more reagents, for example, triphosgene or ethylene dicarbonate to form a compound of Formula V. The compound of Formula V can be reacted with one or more organic bases, for example, tetramethyl guanidine or trimethylamine to form a compound of Formula VI. The compound of Formula VI can be oxidized to form a compound of Formula VII. The compound of Formula VII can be reacted with N,N'-carbonyldiimidazole to form a compound of Formula VIII. The compound of Formula VIII can be reacted with a compound of Formula R(CH₂)₄NH₂ to form a compound of Formula IX (wherein R is the same as defined earlier). The compound of Formula IX can be finally deprotected to form a compound of Formula X.

Clarithromycin of Formula II can be hydrolyzed in the presence of an inorganic or organic acid, for example, hydrochloric acid, sulphuric acid or dichloroacetic acid. The compound of Formula III can be hydroxyl protected with one or more reagents of Formula R ₂O or R X in one or more solvents, for example, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, ethyl acetate or mixture thereof. The protection can also be carried out in the presence of one or more organic bases, for example, triethylamine, diisopropylethylamine, pyridine, tributylamine, 4-(N- dimethylamino) pyridine or mixture thereof.

Compounds of Formula IV can be reacted in one or more solvents, for example, chloroform, dichloromethane, carbon tetrachloride, dichloroethane or mixture thereof. The reaction can also be carried out in the presence of one or more organic bases, for example, triethylamine, diisopropyl ethylamine, pyridine, tributylamine, 4-(N- dimethylamino) pyridine or mixture thereof.

Compounds of Formula V can be reacted in one or more solvents, for example, dimethylformamide, tetrahydrofuran, dimethylsulfoxide or mixture thereof.

Compounds of Formula VIII can be oxidized by reacting with one or more oxidizing agents, for example, Dess-Martin periodinane, N-chlorosuccinimide, 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), pyridinium dichromate, l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride or mixtures thereof. N-Chlorosuccinamide can be used in combination with dimethyl sulfide and 1- ethyl-3(3-dimethylaminopropyl)carbodiimide hydrochloride can be used in combination with dimethylsulfoxide. Compounds of Formula VIII can also be oxidized in one or more solvents, for example, chloroform, dichloromethane, carbon tetrachloride, dimethylsulfoxide, dichloroethane or mixtures thereof.

Compounds of Formula VII can be reacted with N,N'-carbonyldiimidazole in one or more solvents, for example, dimethylformamide, acetonitrile, tetrahydrofuran or mixture thereof. This reaction can also be carried out in one or more inorganic bases, for example, sodium hydrogen carbonate, sodium acetate, sodium thiosulphate, potassium carbonate, cesium carbonate, sodium hydride or mixture thereof.

Compounds of Formula VIII can be reacted with R(CH₂)₄NH₂ in one or more solvents, for example, water, acetonitrile, dimethylformamide or mixture thereof.

Compounds of Formula IX can be deprotected in one or more alcohols, for example, methanol, ethanol, propanol, isopropanol or mixture thereof.

Compounds of Formula XIV can be prepared, for example, according to Scheme II. Thus, a compound of Formula VII can be alkylated with a compound of Formula R³X (R³ is methyl) to form a compound of Formula IX. The compound of Formula IX can be reacted with N,N'-carbonyldiimidazole to form a compound of Formula XII. The compound of Formula XII can be reacted with a compound of Formula R(CH₂)₄NH₂ to form a compound of Formula XIII (wherein R is the same as defined earlier). The compound of Formula XIII can be finally deprotected to form a compound of Formula XIV.

Compounds of Formula VII can be alkylated in one or more solvents, for example, dimethylformamide, acetonitrile, tetrahydrofuran, dimethylsulfoxide or mixture thereof. This reaction can also be carried out in the presence of one or more inorganic or organic bases, for example, sodium hydrogen carbonate, potassium carbonate, cesium carbonate, sodium hydride, potassium-?-butoxide or mixture thereof.

Compounds of Formula XI can be reacted in one or more solvents, for example, dimethylformamide, acetonitrile, tetrahydrofuran or mixture thereof. The reaction can also be carried out in the presence of one or more inorganic bases, for example, sodium hydrogen carbonate, sodium acetate, sodium thiosulphate, potassium carbonate, cesium carbonate, sodium hydride or mixture thereof.

Compounds of Formula XII can be reacted with R(CH₂)₄NH₂ in one or more solvents, for example, water, acetonitrile, dimethylformamide or mixture thereof. Compounds of Formula XIII can be deprotected in one or more alcohols, for example, methanol, ethanol, propanol, isopropanol or mixture thereof.

The compounds described 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. Illustrative compounds include these listed below:

11,12-dideoxy-3-O-decladinosyl-6-O-methyl-3 -oxo- 12, 11 - [oxycarbonyl-4-(4-(3 - aminophenyl)-imidazol-l-yl]-butylimino] erythromycin A (Compound No. 1),

11,12-dideoxy-3-O-decladinosyl-6-O-methyl-3 -oxo- 12, 11 - [oxycarbonyl-(4-(4-(4-methyl- 3-aminophenyl)-imidazol-l-yl]-butylimino] erythromycin A (Compound No. 2), l l,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,l l-[oxycarbonyl-(4-(N-(2- thiazolyl) -nicotinamide) -butylimino] erythromycin A (Compound No. 3), 2-Methyl-ll,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,ll-[oxycarbonyl-4-(4- (3-aminophenyl)-imidazol-l-yl)-butylimino] erythromycin A (Compound No. 4),

2-Methyl-ll,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,ll-[oxycarbonyl-(4-(4- thiophen-2-yl-imidazol-l-yl)-butylimino] erythromycin A (Compound No. 5), 2-Methyl-ll,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,ll-[oxycarbonyl-(4- (lH-benzimidazo-l-yl)-butylimino] erythromycin A (Compound No. 6),

2-Methyl-ll,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,ll-[oxycarbonyl-4-(4- phenyl-imidazol-l-yl)-butylimino] erythromycin A (Compound No. 7),

2-Methyl-ll,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,ll-[oxycarbonyl-4-(4- (3-amino-4-methylphenyl)-imidazol-l-yl)-butylimino] erythromycin A (Compound No. 8),

2-Methyl-ll,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,ll-[oxycarbonyl-(4-(4- Imidazo[4,5-b]pyridin-3-yl)-butylimino] erythromycin A (Compound No. 9),

2-Methyl-ll,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,ll-[oxycarbonyl-4-(4- (4-fluorophenyl)-imidazol-l-yl)-butylimino] erythromycin A (Compound No. 10),

2-Methyl-ll,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,ll-[oxycarbonyl-(4-(5- flouro-lH-benzimidazo-l-yl)-butylimino] erythromycin A (Compound No. 11), 2-Methyl-ll,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,ll-[oxycarbonyl-4-(4- (4-aminopyridyl)-imidazol-l-yl)-butylimino] erythromycin A (Compound No. 12), or

pharmaceutically acceptable salts, pharmaceutically acceptable solvates, polymorphs, prodrugs, stereoisomers, tautomeric forms, N-oxides or metabolites thereof. 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 described 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.

Compositions provided herein include an active ingredient alone or in combination with pharmaceutically acceptable carrier(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 for the preparation of a pharmaceutical composition as defined herein comprises of bringing a compound of general Formula I or a salt or a metabolite or 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, sucrose, acacia; disintegrating agents such as agar-agar, calcium carbonate, potato starch, aliginic acid, certain silicates and sodium carbonate; 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 buffering 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 preparations 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 form, 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.

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 included within the scope of the present invention. The examples are provided to illustrate particular aspects of the disclosure and do not limit the scope of the present invention as defined by the claims.

Experimental Details

Example 1: 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 about 120 ⁰C 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 2: Preparation of Thiazol-2-yl-nicotinamide

A solution of Thiazol-2-yl -amine (1 equiv.) and nicotinoyl chloride (1 equiv.) in pyridine was stirred at about 90⁰C 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 title product. Example 2: Preparation of 5-ri-(4-Aminobutyl)-lH-imidazole-4-yl1-2-methyl- phenylamine

Step 1: Preparation of l-(4-Methyl-3-nitrophenyl)ethanone

4-Methylacetophenone in cone, sulfuric acid was cooled to about 0-5 ⁰C. To it was added nitrating mixture (1 equiv.) with vigorous stirring. After completion of addition the reaction mixture was further stirred below 10 ⁰C 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 2: Preparation of 2-Bromo-l-(4-methyl-3-nitrophenyl )-ethanone

A solution of l-(4-Methyl-3-nitrophenyl)ethanone in carbon tetrachloride was cooled to 0-5 C. To this was added bromine (1.0 eq.) drop wise at 0-5 ⁰C with vigorous stirring. The reaction mixture was further stirred at about 15 ⁰C 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 extracted 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 3: Preparation of 4-(4-Methyl-3-nitrophenyl)-lH-imidazole

A solution of 2-Bromo-l-(4-methyl-3-nitrophenyl)-ethanone in formamide (20 equiv.) was heated at about 180⁰C 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 anhydrous sodium sulfate. The organic layer was then concentrated and vacuum dried to get the desired product.

Step 4: 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 0⁰C. 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 water 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 of methanol and dichloromethane as eluent. The desired product was further purified by crystallization.

Step 5: Preparation of 4-[4-(4-Methyl-3-nitrophenyl)-imidazole-l-yl]-butylamine

A solution of 2-{4-[4-(4-Methyl-3-nitrophenyl)-imidazole-l-yl]-butyl}-isoindole-l,3- dione in ethanol and hydrazine hydrate (10 equiv.) was heated at about 60⁰C for about two hours. The reaction mixture was then cooled and the solid byproduct 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 removed to get the desired product. Step 6: Preparation of 5-[l-(4-Aminobutyl)-lH-imidazole-4-yl]-2-methyl- phenylamine

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 nitrogen. 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 compound was prepared analogously to that described above: 3 - [ 1 -(4-Aminobutyl) - 1 H-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 I Example 3: 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 afford crude product. The crude product was crystallized from ethyl acetate and hexane.

Example 4: 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 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 over 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.

Example 5: 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 stirred for about 4 hours at 0 ⁰C and then 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.

Example 6: Preparation of compound of Formula VI To a solution of compound of Formula V (I equiv.) in dimethylformamide was added tetramethyl guanidine (2.2 equiv.) and heated at about 90 ⁰C, 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 desired product. Example 7: Preparation of compound of Formula VII

To a solution of compound of Formula VI (1 equiv.) in dichloromethane Dess- Martin Periodinane (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.

Example 8: 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 ⁰C, 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 over anhydrous sodium sulphate and concentrated under reduced pressure to afford the desired product.

Example 9: Preparation of compound of Formula IX

The compound of Formula VIII (1 equiv.) and compound of Formula R(CH₂)₄NH₂ (3 equiv.) was taken in 10 % water in acetonitrile and heated at about 70 ⁰C 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.

Example 10: Preparation of compound of Formula X

The compound of Formula IX 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 to afford the desired product. Scheme II Example 11 : 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 0⁰C, stirred for about 20 min. Then methyl iodide (1.1 equiv.) was added. Reaction mixture was stirred at 0⁰C 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.

Example 12: Preparation of compound of Formula XII A solution of compound of Formula XI (1 equiv.) in dimethylformamide: tetrahydrofuran (3:2) was cooled to 0⁰C, to it was added N, N'-carbonyldiimidazole (3 equiv.) and sodium hydride (3 equiv.) and it 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.

Example 13: 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 65-70⁰C 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.

Example 14: 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 illustrative compounds were prepared following the above general procedure:

Compound No. 1: ll,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,l l- [oxycarbonyl-4-(4-(3-aminophenyl)-imidazol-l-yl]-butylimino] erythromycin A MS (+ ion mode): m/z 826.05 [M+ 1]

Compound No. 2: l l,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,l l- [oxycarbonyl-(4-(4-(4-methyl-3-aminophenyl)-imidazol-l-yl]-butylimino] erythromycin A MS (+ ion mode): m/z 840.08 [M+l]

Compound No. 3: l l,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,l l- [oxycarbonyl-(4-(N-(2-thiazolyl)-nicotinamido)-butylimino] erythromycin A MS (+ ion mode): m/z 872.10 [M+l]

Compound No. 4: 2-Methyl-l l,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,l l- [oxycarbonyl-4-(4-(3-aminophenyl)-imidazol-l-yl)-butylimino] erythromycin A MS (+ ion mode): m/z 840.08 [M+l]

Compound No. 5: 2-Methyl-l l,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,l l- [oxycarbonyl-(4-(4-thiophen-2-yl-imidazol- 1 -yl)-butylimino] erythromycin A MS (+ ion mode): m/z 815.03 [M+l] Compound No. 6: 2-Methyl-l l,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,l 1- [oxycarbonyl-(4-(lH-benzimidazo-l-yl)-butylimino] erythromycin A MS (+ ion mode): m/z 799.03 [M+l]

Compound No. 7: 2-Methyl-l 1, 12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12, 11- [oxycarbonyl-4-(4-phenyl-imidazol-l-yl)-butylimino] erythromycin A MS (+ ion mode): m/z 825.06 [M+l]

Compound No. 8: 2-Methyl-l 1, 12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12, 11- [oxycarbonyl-4-(4-(3-amino-4-methylphenyl)-imidazol-l-yl)-butylimino] erythromycin A MS (+ ion mode): m/z 854.11 [M+l]

Compound No. 9: 2-Methyl-l 1, 12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12, 11- [oxycarbonyl-(4-(4-Imidazo[4,5-b]pyridin-3-yl)-butylimino] erythromycin A MS (+ ion mode): m/z 800.01 [M+l]

Compound No. 10: 2-Methyl-ll,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,l l- [oxycarbonyl-4-(4-(4-fluorophenyl)-imidazol- 1 -yl)-butylimino] erythromycin A MS (+ ion mode): m/z 843.05 [M+l] Compound No. 11: 2-Methyl-ll,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,l l- [oxycarbonyl-(4-(5-flouro-lH-benzimidazo-l-yl)-butylimino] erythromycin A, MS (+ ion mode): m/z 816.99 [M+l] Compound No. 12: 2-Methyl-ll,12-dideoxy-3-O-decladinosyl-6-O-methyl-3-oxo-12,l l- [oxycarbonyl-4-(4-(4-aminopyridyl)-imidazol-l-yl)-butylimino] erythromycin A MS (+ ion mode): m/z 827.01 [M+ 1] Example 15: Microbiological activity

Compounds described herein displayed antibacterial activity in vitro especially against strains which are resistant to macrolides either due to efflux (mef strains) or ribosomal 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 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 ⁰C for about 18-24 hours. Fastidious cultures were incubated CO₂ incubation (5% CO₂) at 37 ⁰C 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 ⁰C 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 faecalis 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 lOμg 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.

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). Results: a) The compounds described herein exhibited MIC values against Staphylococcus aureus in the range of between about 0.06 μg/mL to about 2 μg/mL, and even between about 0.06 μg/mL to about 1 μg/mL. b) The compounds described herein exhibited MIC values against sensitive Streptococcus pneumoniae in the range of between about 0.03 μg/mL to about 16 μg/mL. c) The compounds described herein exhibited MIC values against erythromycin resistant Streptococcus pneumoniae in the range of between about 2 μg/mL to about 16 μg/mL. d) The compounds described herein exhibited MIC values against

Haemophilus influenzae in the range of between about 0.06 μg/mL to about 4 μg/mL and even between about 0.06 μg/mL to about 1 μg/mL. e) The compounds described herein exhibited MIC values against Moraxella species in the range of between about 0.06 μg/mL to about 0.5 μg/mL and even between about 0.06 μg/mL to about 0.25 μg/mL. f) The compounds described herein exhibited MIC values against sensitive Streptococcus pyogenes in the range of between about 0.03 μg/mL to about 16 μg/mL. g) The compounds described herein exhibited MIC values against erythromycin resistant Streptococcus pyogenes in the range of between about 0.125 μg/mL to about 16 μg/mL. - SO - li) The compounds described herein exhibited MIC values against methicillin resistant Staphylococcus aureus to about 16 μg/mL. i) The compounds described herein exhibited MIC values against sensitive

Enterococci species in the range of between about 0.06 μg/mL to about 0.5 μg/mL and even between about 0.06 μg/mL to about 0.25 μg/mL. j) The compounds described herein exhibited MIC values against resistant Enterococci species in the range of between about 4 μg/mL to about 16 μg/mL.

Claims

We claim: 1. Compounds having the structure of Formula I,

pharmaceutically acceptable salts, pharmaceutically acceptable solvates, polymorphs, prodrugs, stereoisomers, tautomeric forms, N-oxides or metabolites thereof, wherein R is

(wherein Zi 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, Xi is CR₄, CR₄R^N, NR₄, O or S, X₂ is CR₄ or N wherein R₄ and R'₄ independently in each occurrence are hydrogen or C ₁-3 alkyl,

R₂ and R3 are independently

wherein, X3-X13 are independently C(R₄)O_-2, N(R₄)O-I, O or S, R5-R10 are independently hydrogen, halogen, C₁-3 alkyl, C₁-3 alkoxy, amino, nitro, cyano, aryl or heteroaryl), Y is hydrogen or methyl, and — is an optional single bond, A compound, which is: 11,12-dideoxy-3 -O-decladinosyl-6-O-methyl-3 -oxo- 12, 11 - [oxycarbonyl-4-(4-(3- aminophenyl)-imidazol-l-yl]-butylimino] erythromycin A, 11,12-dideoxy-3 -O-decladinosyl-ό-O-methyl-S -oxo- 12, 11 - [oxycarbonyl-(4-(4-(4- methyl-3-aminophenyl)-imidazol-l-yl]-butylimino] erythromycin A, 11,12-dideoxy-3 -O-decladinosyl-ό-O-methyl-S -oxo- 12, 11 - [oxycarbonyl-(4-(N-(2- thiazolyl) -nicotinamide) -butylimino] erythromycin A, 2-Methyl-l l,12-dideoxy-3-O-decladinosyl-6-O-methyl-3 -oxo- 12,1 l-[oxycarbonyl- 4-(4-(3-aminophenyl)-imidazol-l-yl)-butylimino] erythromycin A, 2-Methyl-l l,12-dideoxy-3-O-decladinosyl-6-O-methyl-3 -oxo- 12,1 l-[oxycarbonyl- (4-(4-thiophen-2-yl-imidazol-l-yl)-butylimino] erythromycin A, 2-Methyl-l l,12-dideoxy-3-O-decladinosyl-6-O-methyl-3 -oxo- 12,1 l-[oxycarbonyl- (4-(lH-benzimidazo-l-yl)-butylimino] erythromycin A, 2-Methyl-l l,12-dideoxy-3-O-decladinosyl-6-O-methyl-3 -oxo- 12,1 l-[oxycarbonyl- 4-(4-phenyl-imidazol-l-yl)-butylimino] erythromycin A, 2-Methyl-l l,12-dideoxy-3-O-decladinosyl-6-O-methyl-3 -oxo- 12,1 l-[oxycarbonyl- 4-(4-(3-amino-4-methylphenyl)-imidazol-l-yl)-butylimino] erythromycin A, 2-Methyl-l l,12-dideoxy-3-O-decladinosyl-6-O-methyl-3 -oxo- 12,1 l-[oxycarbonyl- (4-(4-Imidazo[4,5-b]pyridin-3-yl)-butylimino] erythromycin A, 2-Methyl-l l,12-dideoxy-3-O-decladinosyl-6-O-methyl-3 -oxo- 12,1 l-[oxycarbonyl- 4-(4-(4-fluorophenyl)-imidazol-l-yl)-butylimino] erythromycin A, 2-Methyl-l l,12-dideoxy-3-O-decladinosyl-6-O-methyl-3 -oxo- 12,1 l-[oxycarbonyl- (4-(5-flouro-lH-benzimidazo-l-yl)-butylimino] erythromycin A, 2-Methyl-l l,12-dideoxy-3-O-decladinosyl-6-O-methyl-3 -oxo- 12,1 l-[oxycarbonyl- 4-(4-(4-aminopyridyl)-imidazol-l-yl)-butylimino] erythromycin A, or pharmaceutically acceptable salts, pharmaceutically acceptable solvates, polymorphs, prodrugs, stereoisomers, tautomeric forms, N-oxides or metabolites thereof. A pharmaceutical composition comprising a therapeutically effective amount of one or more compounds of claim 1 together with one or more pharmaceutically acceptable carriers, excipients or diluents.

A method for treating or preventing a condition caused by or contributed to by bacterial infection, comprising administering to a mammal in need thereof therapeutically effective amounts of one or more compounds of claim 1.

The method of claim 4, wherein the condition is selected from community acquired pneumonia, upper or lower respiratory tract infections, skin or soft tissue infections, hospital acquired lung infections, hospital acquired bone or joint infections, mastitis, catether infection, foreign body, prosthesis infections or peptic ulcer disease.

The method of claim 4, wherein the bacterial infection is caused by Gram-positive, Gram-negative or anaerobic bacteria.

The method of claim 6, wherein the Gram-positive, Gram-negative or anaerobic bacteria is selected from Staphylococci, Streptococci, Enterococci, Haemophilus, Moraxalla spp., Chlamydia spp., Mycoplasm, Legionella spp., Mycobacterium, Helicobacter, Clostridium, Bacteroides, Corynebacterium, Bacillus or Enterobactericeae.

The method of claim 7, wherein the bacterium is drug resistant cocci. A process for preparing a compound of Formula X,

Formula X (Formula I wherein, Y = Ft) pharmaceutically acceptable salts, pharmaceutically acceptable solvates, polymorphs, prodrugs, stereoisomers, tautomeric forms, N-oxides or metabolites thereof, wherein R is

R₂ and R3 are independently

wherein, X3-X13 are independently C(R₄)O_-2, N(R₄)O-I, O or S, R5-R10 are independently hydrogen, halogen, C₁-3 alkyl, C₁-3 alkoxy, amino, nitro, cyano, aryl or heteroaryl), which comprises the steps of: (a) hydrolyzing clarithromycin of Formula II

Formula II to form a compound of Formula III;

Formula HI

(b) protecting the compound of Formula III by reacting with one or more reagents of Formula RΛO or R¹X (wherein X is halogen) to form a compound of Formula IV;

Formula IV

(c) converting the compound of Formula IV with one or more suitable reagents to form a compound of Formula V;

Formula V

Formula VI

(e) oxidizing the compound of Formula VI to form a compound of Formula VII;

Formula VII

Formula Vm (g) reacting the compound of Formula VIII with a compound of

Formula R(CH₂)₄NH₂ to form a compound of Formula IX; and

(h) deprotecting the compound of Formula IX to form a compound of Formula X.

10. A process for preparing a compound of Formula XIV,

(Formula I wherein, Y= CH₃)

(wherein Zi 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, Xi is CR₄, CR₄R¹ZtN, NR₄, O or S, X₂ is CR₄ or N wherein R₄ and R'₄ independently in each occurrence are hydrogen or C ₁-3 alkyl,

R₂ and R3 are independently

wherein, X3-X13 are independently C(R₄)O_-2, N(R₄)O-I, O or S, R5-R10 are independently hydrogen, halogen, C₁-3 alkyl, C₁-3 alkoxy, amino, nitro, cyano, aryl or heteroaryl), which comprises the steps of:

(a) alkylating the compound of Formula VII with CH₃X (wherein X is halogen)

Formula Vn

to form a compound of Formula XI;

Formula XI (b) reacting the compound of Formula XI with N,N'-carbonyldimidazole to form a compound of Formula XII;

Formula XII

(c) reacting the compound of Formula XII with a compound of

Formula R(CH₂)₄NH₂ to form a compound of Formula XIII; and

(d) deprotecting the compound of Formula XII to form a compound of Formula XIV.