Title of Invention	NOVEL CEPHALOSPORINS
Abstract	The present invention relates to novel compounds of the general formula (I), their derivatives, analogs, tautomeric forms, stereoisomers, polymorphs, hydrates, solvates, pharmaceutically acceptable salts and compositions, metabolites and prodrugs thereof. The present invention more particularly provides novel cephalosporin antibiotics of the general formula (I). Also included is a method for treatment of infectious diseases in a mammal comprising administering an effective amount of a compound of formula (I) as described above.

Title of Invention

NOVEL CEPHALOSPORINS

Abstract

The present invention relates to novel compounds of the general formula (I), their derivatives, analogs, tautomeric forms, stereoisomers, polymorphs, hydrates, solvates, pharmaceutically acceptable salts and compositions, metabolites and prodrugs thereof. The present invention more particularly provides novel cephalosporin antibiotics of the general formula (I). Also included is a method for treatment of infectious diseases in a mammal comprising administering an effective amount of a compound of formula (I) as described above.

Full Text	Field of the invention The present invention relates to cephalosporin antibiotics of the general formula (I), their derivatives, analogs, tautomeric forms, stereoisomers, polymorphs, hydrates, solvates, pharmaceutically acceptable salts and compositions, metabolites and prodrugs thereof, which have strong antibacterial activity against gram-positive bacteria including methicillin resistant Staphylococcus aureus and also against gram-negative bacteria. The present invention more particularly provides novel quaternary ammonium cephems and derivatives thereof, represented by the general formula (I), these compounds are extremely useful for the treatment of infectious diseases. The present invention also provides a process for the preparation of the above said cephalosporin antibiotics of the general formula (I), their derivatives, analogs, stereoisomers, polymorphs, hydrates, solvates, pharmaceutically acceptable salts and compositions, metabolites and prodrugs thereof. This invention also relates to intermediates useful in the preparation of such compounds. Background of the invention Cephalosporins are beta-lactams in which the beta-lactam ring is fused to a 6-membered dihydrothiazine ring, thus forming the cephem nucleus. A side chain modification to the cephem nucleus confers in addition to pharmacokinetic advantages an improved spectrum of antibacterial activity. Bacterial pathogens are classified as either gram-positive or gram- negative and many antibacterial agents, including antibiotics are specific against one or other gram-class of pathogens. Antibacterial agents effective against both gram-positive and gram-negative pathogens are therefore generally regarded as having a broad-spectrum of activity. In general, 1st generation cephalosporins have better activity against gram-positive bacteria and are less active against gram-negative bacteria, while the 3rd generation agents, with a few exceptions, have a better gram-negative activity and less of gram-positive activity. It is only the 4th generation agents that have both gram- positive and gram-negative activity; few quaternary ammonium cephalosporins are also reported in the literature and some of them are summarized below. Few prior art references, which disclose the closest compounds, are given here: I) US 5,571,909 discloses compounds of the formula wherein Q is CH or N; P is a hydroxylated amine or a hydroxylated heterocyclic amine including N-methyl-bis(2-hydroxyethyl) amine, racemic- 3,4-trans-dihydroxy-l-methylpyrrolidine, (3S,4S)-3,4-trans-dihydroxy-l- methyl-pyrrolidine, (3R,4R)-3,4-trans-dihydroxy-1 -methylpyrrolidine, meso- 3,4-dihydroxy-1 -methylpyrrolidine, (2S ,4R)-4-hydroxy-1 -methyl-2-pyrrolidine methanol, 3,4-cis-dihydroxy-1 -methylpiperidine, 3,4-trans-dihydroxy-1 - methylpiperidine, or tropine. II) JP 0363010792 discloses compounds of the formula wherein n is an integer from 1 to 6; R1 is H or a substituted lower alkyl group; R is a lower alkyl or a lower cycloalkyl group; R is an organic residue bonded through O, S or NH, amino or nitrogen containing heterocyclic group; Q is N or CR4 and R4 is H or halogen. III) US 4,754,031 discloses compounds of the formula wherein Ri is an aliphatic or a cyclo aliphatic radical with upto 6 carbon atoms, and A is a pyridinium radical or a radical of the formula IV) JP-62030788 discloses the following general structure: wherein n is an integer from 1 to 5; R1 is a carboxyl substituted lower alkyl group; R2, and R3, R4 are H, OH, OCH3 or acetoxy; it can also be a general formula as follows: wherein R5 is H, or a protecting group of the amino function; R6 is H or a protection of the carboxyl group; R7 is a protected carboxyl substituted lower alkyl group; Y is S or S->0 and X is either a halogen or can be a formula as follows: wherein n is an integer from 1 to 5; R8, R9and R10 are H, OH (protected) and Ru is H, CH3. Objective of the invention The primary objective of the present invention is to provide cephalosporins of the formula (I), which can enhance the biological activity over a wide variety of gram-negative and gram-positive bacteria and also against resistant bacterial strains like MRSA and VRE. Another objective of the present invention is to provide a process for the preparation of compounds of the general formula (I). Summary of the invention The present invention provides cephalosporins of the general formula (I), their derivatives, analogs, tautomeric forms, stereoisomers, polymorphs, their solvates, pharmaceutically acceptable salts and compositions, metabolites and prodrugs thereof, wherein Xi is represented by O, S, or S—>0; X2 is represented by N or CH; R2 represents hydrogen, haloalkyl, substituted lower alkyl (Q-C4) groups, substituted or unsubstituted protected carboxy-(CrC4) groups, an aliphatic or a cycloaliphatic radical with upto 6 carbon atoms, and furthermore -N-OR2 is in the syn position; T represents a quaternary nitrogen atom, which can be a part of an open chain system, or it is an open chain attached to a cyclic system, or the nitrogen is attached directly to cyclic systems which can have chiral, racemic or meso substitutions. This is represented by the general formulae I, II and III and details of the substitution are given below; R] represents OR wherein, R represents hydrogen or alkyl groups of pharmaceutically acceptable salts and esters that are commonly employed in the cephalosporin chemistry. Detailed description of the invention The present invention provides cephalosporins of the general formula their derivatives, analogs, tautomeric forms, stereoisomers, polymorphs, their solvates, pharmaceutically acceptable salts and compositions, metabolites and prodrugs thereof, wherein the suitable group represented by Ri is selected from OR, wherein R represents hydrogen or alkyl groups of pharmaceutically acceptable salts and esters that are commonly employed in the cephalosporin chemistry. Xi is represented by O, S or S—>0. X2 is represented by N or CH. Suitable groups represented by R2 are selected from hydrogen, linear or branched (C1-C4) alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, t-butyl and the like which may be substituted; haloalkyl groups such as chloromethyl, chloroethyl, trifluoromethyl, trifluoroethyl, dichloromethyl, dichloroethyl, trichloromethyl, difluoromethyl and the like; furthermore R2 may be substituted by groups such as a carboxylic acid and its derivatives, or may be a group of the formula: Suitable groups represented by R4 and R5 may be the same or different and independently represent hydrogen, substituted or unsubstituted linear or branched (C1-C4) alkyl groups which may be substituted; haloalkyl groups which may be substituted; halogen atoms such as fluorine, chlorine, bromine, iodine; or it can be a group of the formula wherein R7 and R8 represent hydrogen, linear or branched (CrC4) alkyl groups which may be substituted. Suitable groups represented by R^ are selected from hydrogen, substituted or unsubstituted linear or branched (C1-C4) alkyl groups which may be substituted; substituted alkyl protective groups such as straight, branched, partially cyclic, cyclic alkanoyloxyalkyl groups such as acetoxymethyl, acetoxyethyl, pivaloyloxymethyl, pivaloyloxyethyl, cyclohexaneacetoxyethyl and the like; alkoxyformyloxyalkyl groups such as ethoxycarbonyloxyethyl and the like; alkoxyalkyl groups; 2-oxacycloalkyl groups; 2-oxo-l,3- dioxolylmethyl groups such as 4-methyl-2-oxo-l, 3-dioxol-5-ylmethyl group and the like; 1-oxygenated-1C to 12C-alkyl groups; substituted aralkyl groups such as phenacyl, phthalidyl and the like; aryl groups such as phenyl, tolyl, xylyl, indanyl and the like. T represents a quaternary nitrogen atom, which can be a part of an open chain system, or is an open chain attached to a cyclic system, or the nitrogen is attached directly to cyclic systems, which can have chiral, racemic, or meso substitution. This is represented by the general formulae I, II and III and details of the substitution are given below. Formula I: Suitable group represented by R8, R9 and Rio which may be same or different and independently represent hydrogen, lower alkyl (CrC4) groups, hydroxyl (which may be protected as benzyl ether and the like), amino (which may be protected as benzyl ether, benzyloxycarbonyl (Cbz), t-butoxycarbonyl (t-Boc), trityl, trifluoracetyl and the like), carboxylic acid (which may be protected as alkyl ester and the like); Rn represents lower alkyl (CrC3) groups; R12 and R13 represents hydrogen or are combined together to form a 5 to 6 membered ring which may be saturated or unsaturated such as cyclohexyl, cyclopentyl, phenyl, and the like; any one of X or Y represents a quaternary nitrogen atom and the linkage to the cephalosporin moiety is through the quaternary nitrogen atom; Z is represented by hydrogen, hydroxyl (which may be protected as benzyl ether and the like), hydroxyl-diaryl-methyl groups such as hydroxy-diphenyl-methyl and the like, chiral or racemic, substituted or unsubstituted, linear or branched (C1-C4) alkyl groups which may be substituted; alkoxy groups such as methoxy, ethoxy, n-propoxy, isopropoxy and the like, which may be substituted; monoalkylamino groups such as - NHCH3, -NHC2H5, -NHC3H7> -NHC6H13, and the like, which may be substituted; dialkylamino groups such as -N(CH3)2, -NCH3(C2H5), -N(C2H5)2 and the like, which may be substituted; carboxylic acids and its derivatives such as amides, esters (such as methyl ester, ethyl ester and the like); acylamino groups such as -NHC(=0)CH3, -NHC(=0)C2H5, -NHC(=0)C3H7> - NHC(=0)C6H13, and the like, which may be substituted; alkoxyalkyl groups such as methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl and the like, which may be substituted; the sulfamoyl group, aralkoxy groups such as phenylmethoxy, phenylethoxy, phenylpropoxy, and the like which may be substituted; aryloxy groups such as phenoxy, napthoxy and the like which may be substituted, and n is an integer in the range of 0 - 3. Formula II: Suitable groups represented by Ru are selected from lower alkyl (CrC3) groups; R13 represents substituted lower alkyl groups which may be substituted; R14 and Ri5 may be the same or different and are represented by substituted or unsubstituted alkyl radicals, groups such as phenyl and the like which is optionally substituted by groups such as halogens, haloalkyl, alkyl, alkoxy; bicyclic groups such as napthyl and the like, optionally substituted carbocyclic groups, saturated and unsaturated heterocyclic groups such as furyl, piperdinyl, piperazine and the like. R14 and R15 can together with the N atom form a three to seven membered cyclic ring, an unsaturated monocyclic aromatic rings such as pyridyl and the like which may be substituted;_heterocyclic rings such as pyrrolidinyl and the like which may be substituted. Formula III: Suitable groups represented by R16 may be hydrogen, lower alkyl (Cr C3) groups or haloalkyl groups; R17 represents alkyl, haloalkyl and alkoxy groups selected from linear or branched (C1-C4) alkoxy groups comprising from methoxy, ethoxy, n-propoxy, isopropoxy and the like. X3 represent C, N. X4 represents O or S. The term analog includes a compound, which differs from the parent structure by one or more C, N, O or S atoms. Hence, a compound in which one of the N atoms in the parent structure is replaced by an S atom is an analog of the former. The term stereoisomer includes isomers that differ from one another in the way the atoms are arranged in space, but whose chemical formulas and structures are otherwise identical. Stereoisomers include enantiomers and diastereoisomers. The term tautomers include readily interconvertible isomeric forms of a compound in equilibrium. The enol-keto tautomerism is an example. The term polymorphs include crystallographically distinct forms of compounds with chemically identical structures. The term pharmaceutically acceptable solvates includes combinations of solvent molecules with molecules or ions of the solute compound. The term derivative refers to a compound obtained from a compound according to formula (I), an analog, tautomeric form, stereoisomer, polymorph, hydrate, pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, by a simple chemical process converting one or more functional groups, such as, by oxidation, hydrogenation, alkylation, esterification, halogenation, and the like. Pharmaceutically acceptable salts of the present invention include alkali metals like Li, Na, and K, alkaline earth metals like Ca and Mg, salts of organic bases such as diethanolamine, a-phenylethylamine, benzylamine, piperidine, morpholine, pyridine, hydroxyethylpyrrolidine, choline hydroxyethylpiperidine, and the like, ammonium or substituted ammonium salts, aluminum salts. Salts also include amino acid salts such as glycine, alanine, cystine, cysteine, lysine, arginine, phenylalanine, guanidine etc. Salts may include acid addition salts where appropriate, which are, sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartrates, maleates, citrates, succinates, palmoates, methanesulphonates, tosylates, benzoates, salicylates, hydroxynaphthoates, benzenesulfonates, ascorbates, glycerophosphates, ketoglutarates and the like. Pharmaceutically acceptable solvates may be hydrates or comprising other solvents of crystallization such as alcohols. A term once described, the same meaning applies for it, throughout the patent Particularly useful compounds according to the invention include the chiral compounds listed below as well as their racemates: 1. (6R,7R) 7/3-{2-{2-Aminothiazol-4-yl}-2-[(Z)-methoxyimino]-acetylamino}- 3-[[N, N-dimethyl- N- [(R)-l-(4-chlorophenyl)]ethyl]ammonio]methyl-8- oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylate; 2. N-[[{2-(4-Methoxybenzylcarbonyl)}-(6R,7R)7/3- {2-(2-aminotrityl-1,3- thiazol-4-yl)-2-[(Z)-methoxyimino]-acetylamino}-8-oxo-5-thia-l- azabicyclo[4.2.0]oct-2-ene-3yl]methyl]-N,N-dimethyl-N-[(R)-l-(l,2,3,4- tetrahydronaphthyl)]ammonio]methyl]ethanaminium iodide; 3. N-[[{2-(4-Methoxybenzylcarbonyl)}-(6R,7R) 70-{2-(2-amino-1,3-thiazol-4- yl)-2-[(Z)-methoxyimino]-acetylamino}-8-oxo-5-thia-l-azabicyclo[4.2.0] oct-2-ene-3yl]methyl]-N,N-dimethyl-N-[(R)-1 -(1,2,3,4-tetrahydronaphthyl)] ammonio]methyl]ethanaminium iodide; 4. (6R,7R) 7/3- {2- {2-Aminothiazol-4-yl}-2-[(Z)-methoxyimino]-acetylamino} - 3 - [N,N-dimethy 1-N- [(R)-1 -(1,2,3,4-tetrahydronaphthyl)]ammonio]methyl-8- oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylate; 5. (6R,7R) 7/3- {2- {2-Aminothiazol-4-yl}-2-[(Z)-methoxyimino]-acetylamino}- 3-[[N,N-dimethyl-N-[(S)-l-(4-chlorophenyl)] ethyl]ammonio]methyl-8-oxo- 5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylate; 6. N-[[ {2-(4-Methoxybenzylcarbonyl)}-(6R,7R)7/3- {2-(2-aminotrityl-1,3- thiazol-4-yl)-2-[(Z)-methoxyimino]-acetylamino}-8-oxo-5-thia-l-azabicyclo [4.2.0]oct-2-ene-3yl]methyl]-N,N-dimethyl-N-[(R)-l-(cyclohexyl) ethyl]ethanaminium iodide. 7. (6R,7R) 7/3- {2- {2-Aminothiazol-4-yl}-2-[(Z)-methoxyimino]-acetylamino}- 3-[N, N-dimethyl- N- [(R)-l-(cyclohexyl) ethyl]ammonio]methyl-8-oxo-5- thia-1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylate; 8. N-[[{2-(4-Methoxybenzylcarbonyl)}-(6R,7R)7/3-{2-(2-aminotrityl-l,3- thiazol-4-yl)-2-[(Z)-methoxyimino]-acetylamino}-8-oxo-5-thia-l-azabicyclo [4.2.0]oct-2-ene-3yl]methyl]-N-[(4-{2-fluoro-4-[3-(5-acetylamino methyl)- 1,3-oxazolidin-2-one]phenyl} -1 -methylpiperazin-1 -ium)iodide; 9. [(6R,7R)7/3- {2- {2-Aminotritylthiazol-4-yl} -2-[(Z)-methoxyimino]-acetyl amino} -3-[(4- {2-fluoro-4-[3-(5-acetylaminomethyl)-1,3-oxazolidin-2-one] phenyl} -1 -methylpiperazin-1 -ium)]methyl-8-oxo-5-thia-1 -azabicyclo [4.2.0]oct-2-en-2-carboxylate; 10. N-[[ {2-(4-Methoxybenzylcarbonyl)}-(6R,7R)7/3- {2-(2-aminotrityl-1,3- thiazol-4-yl)-2-[(Z)-methoxyimino]-acetylamino}-8-oxo-5-thia-l-azabicyclo [4.2.0]oct-2-ene-3yl]methyl]-N-[(4-{2-fluoro-4-[3-(5-dichloroacetyl amino methyl)-1,3-oxazolidin-2-one]phenyl} -1 -methylpiperazin-1 -ium) iodide; 11. [(6R,7R) 7/3-{2-{2-Aminotrityl thiazol-4-yl}-2-[(Z)-methoxyimino]-acetyl amino} -3-[(4- {2-fluoro-4-[3-(5-dichloroacetylaminomethyl)-1,3-oxazolidin- 2-one]phenyl} -1 -methylpiperazin-1 -ium)]methyl-8-oxo-5 -thia-1 -azabicyclo [4.2.0]oct-2-en-2-carboxylate; 12. N-[[ {2-(4-Methoxybenzylcarbonyl)}-(6R,7R) 7/3- {2-(2-aminotrityl-1,3- thiazol-4-yl)-2-[(Z)-methoxyimino]-acetylamino}-8-oxo-5-thia-l-azabicyclo [4.2.0]oct-2-ene-3yl]methyl]-N-[(4-{2-fluoro-4-[3-(5-difluoroacetyl amino methyl)-1,3 -oxazolidin-2-one]phenyl} -1 -methylpiperazin-1 -ium) iodide; 13. [(6R,7R)7/3- {2- {2-Aminotritylthiazol-4yl}-2-[(Z)-methoxyimino]- acetylamino}-3-[(4-{2-fluoro-4-[3-(5-difluoroacetylaminomethyl)-1,3- oxazolidin-2-one]phenyl} -1 -methylpiperazin-1 -ium)]methyl-8-oxo-5-thia-1 - azabicyclo[4.2.0]oct-2-en-2-carboxylate and 14.7-( {(2Z)-2-(2-Amino-1,3-thiazol-4-yl)-2-[(2-methoxy-2-oxoethoxy)imino] acetyl} amino)- 3-[[N, N-dimethyl- N- [(R)-l-(4-chlorophenyl)] ethyl] ammonio] methyl -8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylate. According to another feature of the present invention, there is provided a process as shown in the following scheme, for the preparation of compounds of the formula (I), wherein all the groups are as defined earlier. Scheme I It comprises, condensation of the compound of formula (la) or its active . derivative with the reactive derivative of the formula (lb) as shown below. Scheme I Wherein R, represents -OR, where R represents hydrogen, or alkyl or a trimethylsilyl/alkali metal salt, or a substituted benzyl or carboxylic acid protecting group commonly employed in cephalosporin chemistry; A is hydrogen or silyl or trityl and E is a group which forms a basis that a compound of formula (lb) is in the reactive form; for example halogen or any leaving group or OH or an activated ester, in the presence or absence of a base and solvent to produce novel compounds of the formula (I). The compound of formula (la) can be prepared by utilizing the conventional procedures available in cephalosporin chemistry. Condensation employing acids or acid halides or an activated ester may be effected in aqueous and non-aqueous reaction media, conveniently at temperatures from -50°C to +50°C, preferably -20°C to +30°C, if desired in the presence of an acid binding agent. Suitable reaction media include aqueous ketones such as aqueous acetone, MIBK, esters such as ethyl acetate, halogenated hydrocarbons such as chloroform, dichloromethane, dichloroethane, o-dichlorobenzene, amides such as N, N-dimethylacetamide, N, N-dimethylformamide, nitriles such as acetonitrile, acids such as acetic acid, propionic acid, alcohols such as ethanol, methanol, isopropylalcohol, t- butylalchol, and also includes toluene, xylene, tetrahydrofuran, dioxane, dimethylsulfoxide, pyridine, water, a mixture thereof or the like or mixtures of two or more such solvents. Suitable acid binding agents include tertiary amines such as triethylamine or N, N-dimethylaniline, N-methyl morpholine, inorganic bases such as calcium carbonate or sodium bicarbonate, and oxiranes of the lower 1,2-alkylene oxides type such as ethylene oxide, propylene oxide or molecular sieves, which bind hydrogen halide liberated in the acylation reaction. Condensations employing acids are desirably conducted in the presence of a condensation agent, for example a carbodiimide such as N,N'- dicyclohexylcarbodiimide, 1 -(3-dimethylaminopropyl)-3-ethylcarbodiimide, a carbonyl compound such as carbonyldiimidazole, or an isoxazolinium salt such as N-ethyl-5-phenylisoxazolinium perchlorate. Acylation reactions of this type are desirably effected in an anhydrous reaction medium. Scheme II It comprises, condensation of the compound of formula (Ic) or its active derivative with the reactive derivative of formula (lb) to finally yield the compounds of formula (I) as shown below. Wherein B independently represents acyl group, hydroxyl or halogens such as chlorine or iodine and all the other symbols are as described above. The compound of formula (I) can be prepared from the compound of formula (Id) by utilizing the conventional procedures available for quaternary cephalosporin synthesis in the literature. It is appreciated that in any of the above-mentioned reactions any reactive functional group in the substrate molecule may be protected according to the conventional chemical practice. Suitable protecting groups in any of these reactions are those used conventionally in the art, and the methods of formation and removal of such protecting groups are those conventional methods appropriate to the molecule being protected Pharmaceutically acceptable salts of the present invention include alkali metals like Li, Na, and K, alkaline earth metal like Ca and Mg, salts of organic bases such as diethanolamine, a-phenylethylamine, benzylamine, piperidine, morpholine, pyridine, hydroxyethylpyrrolidine, hydroxyethylpiperidine, choline and the like, ammonium or substituted ammonium salts, aluminum salts. Salts also include amino acid salts such as glycine, alanine, cystine, cysteine, lysine, arginine, phenylalanine, guanidine etc. Salts may include acid addition salts where appropriate like sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartarates, maleates, citrates, succinates, palmoates, methanesulphonates, tosylates, benzoates, salicylates, hydroxynaphthoates, benzenesulfonates, ascorbates, glycerophosphates, ketoglutarates and the like. Compounds of the formula (I) may form solvates of DMF, hydrates and the like. The pharmaceutically acceptable ester groups are substituted alkyl esters; straight, branched, cyclic or partially cyclic alkanoyloxyalkyl esters such as acetoxymethyl ester, acetoxyethyl ester, pivaloyloxymethyl ester, pivaloyloxyethyl ester, cyclohexaneacetoxyethyl ester and the like; alkoxyformyloxyalkyl esters such as ethoxycarbonyloxyethyl ester and the like; alkoxyalkyl esters; 2-oxacycloalkyl esters; 2-oxo-l,3-dioxolylmethyl esters such as 4-methyl-2-oxo-l, 3-dioxol-5-ylmethyl ester and the like; 1- oxygenated-lC to 12C-alkyl esters; substituted aralkyl esters such as phenacyl ester, phthalidyl ester and the like; aryl esters such as phenyl ester, tolyl ester, xylyl ester, indanyl ester and the like. It should be noted that compounds of the invention may contain groups that may exist in tautomeric forms, and though one form is named, described, displayed and/or claimed herein, all the forms are intended to be inherently included in such name, description, display and/or claim. The stereoisomers of the compounds forming part of this invention may be prepared by using reactants in their single enantiomeric form, in the process wherever possible or by conducting the reaction in the presence of reagents or catalysts in their single enantiomeric form or by resolving the mixture of stereoisomers by conventional methods. Some of the preferred methods include use of microbial resolution, resolving the diastereomeric salts formed with chiral acids such as mandelic acid, camphorsulfonic acid, tartaric acid, lactic acid, and the like wherever applicable or by using chiral bases such as brucine, cinchona alkaloids, their derivatives and the like. Prodrugs of the compounds of formula (I) are also contemplated by this invention. A prodrug is an active or inactive compound that is modified chemically through in-vivo physiological action, such as hydrolysis, metabolism and the like, into a compound of the invention following administration of the prodrug to a patient. The suitability and techniques involved in making/using prodrugs are well known to those skilled in the art. Various polymorphs of the compounds of the general formula (I), forming part of this invention may be prepared by crystallization of the compounds of formula (I) under different conditions. For example, using different commonly used solvents, or their mixtures for recrystallization; crystallizations at different temperatures; various modes of cooling, ranging from very fast to very slow cooling during crystallizations. Heating or melting the compounds followed by cooling gradually or immediately, one can also obtain polymorphs. The presence of polymorphs may be determined by solid probe NMR spectroscopy, IR spectroscopy, differential scanning calorimetry and powder X-ray diffraction or other such techniques. Pharmaceutically acceptable solvates of the compounds of the formula (I) forming part of this invention may be prepared by conventional methods such as dissolving the compounds of the formula (I) in solvents such as water, methanol, ethanol, mixture of solvents such as acetone:water, dioxane:water, N,N-dimethylformamide:water and the like, preferably water and recrystallization by using different crystallization techniques. The present invention also provides a pharmaceutical composition, containing one or more of the compounds of the general formula (I) as defined above, their derivatives, analogs, tautomeric forms, stereoisomers, polymorphs, hydrates, metabolites, prodrugs, pharmaceutically acceptable salts, pharmaceutically acceptable solvates in combination with the usual pharmaceutically employed carriers, diluents and the like, useful for the treatment of bacterial infections. The cephalosporin derivatives provided by the present invention can be employed as pharmaceutical compositions, for example, in the form of pharmaceutical compositions containing the cephalosporin derivatives together with appropriate, pharmaceutically acceptable carriers. The products in accordance with the invention can be administered, for example, perorally, such as in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions, or rectally, such as in the form of suppositories, etc. The compositions may be sterilized and may contain auxiliary agents generally employed in the pharmaceutical art, such as sodium hydrogen carbonate, citric acid, propylene glycol, tween 80, etc. The compounds can be used orally or parenterally. Pharmaceutical compositions containing these compounds can be prepared using conventional procedures familiar to those skilled in the art, such as by combining the ingredients into a dosage form together with suitable, non¬toxic, inert, therapeutically compatible solid or liquid carrier materials and if desired, the usual pharmaceutical adjuvants. The amount of the active ingredient in the composition may be less than 70% by weight. Such compositions typically contain from 1 to 25%, preferably 1 to 15% by weight of active compound, the remainder of the composition being pharmaceutically acceptable carriers, diluents, excipients or solvents. The pharmaceutical composition may be in the forms normally employed, such as tablets, capsules, powders, syrups, solutions, suspensions and the like, may contain flavorants, sweeteners etc. in suitable solid or liquid carriers or diluents, or in suitable sterile media to form injectable solutions or suspensions. Suitable pharmaceutically acceptable carriers include solid fillers or diluents and sterile aqueous or organic solutions. The active compound will be present in such pharmaceutical compositions in the amounts sufficient to provide the desired dosage in the range as described above. Thus, for oral administration, the compounds can be combined with a suitable solid or liquid carrier or diluent to form capsules, tablets, powders, syrups, solutions, suspensions and the like. The pharmaceutical compositions, may, if desired, contain additional components such as flavorants, sweeteners, excipients and the like. For parenteral administration, the compounds can be combined with sterile aqueous or organic media to form injectable solutions or suspensions. For example, solutions in sesame or peanut oil, aqueous propylene glycol and the like can be used, as well as aqueous solutions of water-soluble pharmaceutically-acceptable acid addition salts or alkali or alkaline earth metal salts of the compounds. The injectable solutions prepared in this manner can then be, administered intravenously, intraperitoneally, subcutaneously, or intramuscularly, with intramuscular administration being preferred in humans. The pharmaceutical compositions of the invention show a potent antibacterial activity against a wide range of bacteria including gram-positive and gram-negative bacteria, especially against methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa and are useful as therapeutic agents for infectious diseases Generally, the effective dose for treating a particular condition in a patient may be readily determined and adjusted by the physician during treatment to alleviate the symptoms or indications of the condition or disease. Generally, a daily dose of active compound in the range of about 0.01 to 1000 mg/kg of body weight is appropriate for administration to obtain effective results. The daily dose may be administered in a single dose or divided into several doses. In some cases, depending upon the individual response, it may be necessary to deviate upwards or downwards from the initially prescribed daily dose. Typical pharmaceutical preparations normally contain from about 0.2 to about 500 mg of active compound of formula I and/or its pharmaceutically active salts or solvates per dose. While the compounds of the invention can be administered as the sole active pharmaceutical agent, they can also be used in combination with one or more compounds of the invention or other agents. When administered as a combination, the therapeutic agents can be formulated as separate compositions that are given at the same time or different times, or the therapeutic agents can be given as a single composition. The term "therapeutically effective amount" or "effective amount" refers to that amount of a compound or mixture of compounds of Formula I that is sufficient to effect treatment, when administered alone or in combination with other therapies to a mammal in need of such treatment. The term "animal" as used herein is meant to include all mammals, and in particular humans. Such animals are also referred to herein as subjects or patients in need of treatment. The therapeutically effective amount will vary depending upon the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the particular compound of Formula I chosen, the dosing regimen to be followed, timing of administration, the manner of administration and the like, all of which can readily be determined by one of ordinary skill in the art. The term "treatment" or "treating" means any treatment of a disease in a mammal, including: a) Preventing the disease, that is, causing the clinical symptoms of the disease not to develop; b) Inhibiting the disease, that is, slowing or arresting the development of clinical symptoms; and/or c) Relieving the disease, that is, causing the regression of clinical symptoms. From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, make various changes and modifications of the invention to adapt it to various usages and conditions. The present invention is provided by the examples given below, which are provided by the way of illustration only, and should not be considered to limit the scope of the invention. Variation and changes, which are obvious to one skilled in the art, are intended to be within the scope and nature of the invention, which are defined in the appended claims. Example X Synthesis of (6R,7R)7/S-{2-{2-aminothiazol-4-yl}-2-\|(Z)-methoxyimino\|- acety lamino}-3- [ [N,N-dimethyl-N- [(R)-l-(4-chlorophenyl)] ethyl] ammonio] methyl-8-oxo-5-thia-l-azabicyc!o[4.2.0]oct-2-ene-2-carboxylate. Step 1: Synthesis of 4-methoxybenzyl(6R,7R)7/3-{2-{2-aminotrityl-l,3-thiazol-4- yl}-2-[(Z)-methoxyimino]-acetylamino}-3-(chloromethyl)-8-oxo-5-thia-l- azabicyclo [4.2.0] oct-2-ene-2-carboxylate. To a solution of (2E)- {2-[(triphenylmethyl)amino]-l ,3-thiazol-4- yl}(methoxyimino)acetic acid (7.9g, 0.017mol) in DCM (80ml) under a nitrogen atmosphere, PC15 (4.2g, 0.02mol) was added at once under stirring at 0°C and the stirring was continued under the same conditions for 1.5 hours. To this resultant reaction mass was added a clear solution of 4-methoxybenzyl (7i?)-7-amino-3-(chloromethyl)-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2- carboxylate (ACLE) (6.0g, 0.016mol) in a mixture of acetonitrile (120ml) and N,0-bis(trimethylsilyl)acetamide (7.4 ml) over a period of 0.5 hours and the reaction mixture was maintained under the same condition for 0.5 hours. When the completion of the reaction was confirmed by TLC using ethyl acetate and hexane as the solvent system (1:1) the resultant reaction mass was poured into ice-cold water (150ml), stirred for 10 minutes and later extracted with isopropyl ether (2x75ml). The organic layer was washed with water (3x100ml). To the resultant organic layer ethyl acetate (150ml) was added to get a clear solution that was again washed thoroughly with water (2x100ml). The organic layer was dried over anhydrous sodium sulphate, concentrated under vacuum and then further treated with hexane (150ml) to get the desired solid. The solid obtained was filtered, washed with hexane (50ml) and dried under vacuum to yield the target compound (8.0g, 62%, purity-92.17% by HPLC). 'H NMR (DMSO-d6) 5 (ppm): 3.54 (s, 1H), 3.67 (s, 1H), 3.74 (s, 3H), 3.80 (s, 3H) 4.44 - 4.51 (m, 2H), 5.16 - 5.21 (m, 3H), 5.71 (s, 1H), 6.70 (s, 1H), 6.91- 6.94 (d, 2H), 7.21-7.24 (m, 3H), 7.28-7.37 (m, 16H), 8.86 (s, 1H), 9.58 - 9.6 (d, 1H). Massm/z: 794.1 (M++l). Step 2: Synthesis of N-[[{2-(4-methoxybenzylcarbonyl)}-(6R,7R)7/5-{2-(2- aminotrityl-l,3-thiazol-4-yl)-2-[(Z)-methoxyimino]-acetylamino}-8-oxo-5- thia-l-azabicyclo[4.2.0]oct-2-ene-3yl]methyl]-N,N-dimethyl-N-[(R)-l-(4- chlorophenyl)]ethanaminium iodide. To a solution of the 4-methoxybenzyl (6R,7R) 7jS-{2-{2-aminotrityl-l,3- thiazol-4-yl}-2-[(Z)-methoxyimino]-acetylamino}-3-(chloromethyl)-8-oxo-5- thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (3.0g, 0.0037mol) in methyl ethyl ketone (30ml) was added sodium iodide (2.8 lg, 0.018mol) under stirring at 35°C and the stirring was continued for lhour at the same temperature. The resultant reaction mass was poured into water (50ml) and was extracted with ethyl acetate (3x25ml). The combined organic layer was washed with 10% sodium thiosulphate solution (50ml) followed by water (50ml) and finally with brine solution (50ml). The organic layer was dried over anhydrous sodium sulphate and concentrated under vacuum to yield the desired 4- methoxybenzyl(6R,7R)7jS- {2- {2-aminotrityl-1,3-thiazol-4-yl} -2-[(Z)- methoxyimino]-acetylamino}-3-(iodomethyl)-8-oxo-5-thia-l-aza- bicyclo[4.2.0]oct-2-ene-2-carboxylate compound. To the solution of the 4-methoxybenzyl (6R, 7R) 7/3- {2- {2-aminotrityl- 1,3 -thiazol-4-yl} -2- [(Z)-methoxyimino]-acetylamino} -3 -(iodomethyl)-8-oxo-5 - thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylate compound in DMF (20ml), (lR)-l-(4-chlorophenyl)-N,N-dimethylethanamine (1.38g, 0.0074mol) was added under stirring over a period of 5 minutes at 5°C and was allowed to reach a temperature of 35°C under continuous stirring for a period of 1.5 hours. When the completion of the reaction was confirmed by TLC using methanol and ethyl acetate (2:8) as the solvent system, diethyl ether (50ml) was added to the reaction mass, which was stirred further for 10 minutes. To the residue obtained after removal of the diethyl ether was added DCM (10ml) to get a clear solution, further the compound was precipitated out by adding hexane (25ml) and continuing the stirring for 30 minutes at room temperature. Hexane was removed by decantation to give a solid, which was dried under nitrogen to yield the desired compound (2.0g, 56%). 'H NMR (DMSO-d6) 5 (ppm): 1.07 (s, 3H), 1.71-1.73 (d, 3H), 2.73 (s, 3H), 2.86 (s, 1H), 3.33 - 3.35 (d, 2H), 3.77 (s, 3H), 3.80 (s, 3H), 3.81 (s, 2H), 5.13 (s, 1H), 5.76 (s, 2H), 5.81 (s, 1H), 5.83 (s, 1H) 7.21 - 7.24 (m, 3H), 7.30 - 7.35 (m, 20H), 7.53 - 7.61 (m, 4H), 8.89 (s, 1H), 9.35 - 9.37 (d, 1H), 9.59 - 9.61 (d, 1H). Mass m/z: 942.0 (M++l). Step 3: Synthesis of (6R,7R) 7/S-{2-{2-aminothiazol-4-yl}-2-[(Z)-methoxyimino]- acetylamino}-3- [ [N,N-dimethyl-N- [(R)-l-(4-chlorophenyl)] ethyl] ammonio] methyl -8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylate. To a solution of N-[[{2-(4-methoxybenzylcarbonyl)}-(6R,7R) 7/3-{2-(2- aminotrityl-1,3-thiazol-4-yl)-2-[(Z)-methoxyimino]-acetylamino} -8-oxo-5- thia-l-azabicyclo[4.2.0]oct-2-ene-3yl]methyl]-N,N-dimethyl-N-[(R)-l-(4- chlorophenyl)]ethanaminium iodide (2.0g, 0.0021mol) in DCM (15ml) anisole (10ml) was added under stirring at 5°C followed by trifluoroacetic acid (20ml) dropwise over a period of 10 minutes and the reaction mixture was maintained at same temperature for 3 hours. When the completion of the reaction was confirmed by TLC using methanol and ethyl acetate as the solvent system (8:2), hexane (50ml) was added to the resultant reaction mass and was stirred further for 15 minutes, subsequently the hexane was decanted. This procedure was repeated three times with hexane and then with di-isopropyl ether (30ml) to yield the desired compound. 'H NMR (DMSO-d6) 8 (ppm): 1.73 - 1.75 (d, 3H), 2.80 (s, 3H), 2.91 (s, 3H), 3.73 - 3.76 (d, 1H), 3.84 (s, 3H), 4.44 (s, 1H), 4.62 - 4.65 (d, 1H), 4.85 - 4.87 (d, 1H), 5.3 (s, 1H), 5.36 - 5.39 (m, 1H), 6.82 (s, 2H) 7.23 (s, 2H, D20 exchangeable), 7.56 - 7.64 (m, 4H), 9.38 - 9.4 (d, 1H, D20 exchangeable). Mass m/z: 580.0 (M++l). The following compounds are prepared by the general procedures given in Example 1 with appropriate tertiary amines. 1H), 7.24 (s, 1H, D20 exchangeable), 8.30 (s, 1H, D20 exchangeable). Mass m/z: 934.2 (M+). 3 1 N II H H H Nv^A/Noi^S. H2N-f T n tt 1 1 w / S 0 'H NMR (DMS0-d6) 5 (ppm): 1.17 - 1.22 (m, 2H), 1.44 - 1.47 (t, 2H), 1.49 - 1.53 (q, 2H), 1.65 - 1.68 (t, 1H), 2.19 (s, 3H), 2.35 (s, 3H), 3.45 (s, 3H) 3.51 (s, 3H), 3.58 (s, 1H), 3.80 (s, 1H), 4.11 (s, 2H), 4.41 - 4.43 (d, 1H), 4.88 (s, 2H), 4.96 - 5.18 (dd, 1H), 6.11-6.16 (m, 8H), 6.93 (s, 1H), 7.84 (s, 2H, D20 exchangeable), 8.60 (s, 1H, D20 exchangeable). Mass m/z: 692.0 (M++l). 4 1 -0 N N N" - S H,N— 2 XSJ o 'H NMR (DMS0-d6) 5 (ppm): 1.67 - 1.70 (m, 2H), 1.74 - 1.77 (t, 2H), 1.79 - 1.83 (q, 2H), 1.85 - 1.88 (t, 1H), 1.99 (s, 3H), 2.75 (s, 3H), 3.49 (s, 3H), 3.54 (s, 1H), 3.80 (s, 1H), 4.11 (s, 2H), 5.11-5.13 (d, 1H), 5.25 - 5.29 (dd, 1H), 6.11 - 6.13 (d, 2H), 6.15 - 6.17 (d, 2H), 7.05 (s, 1H), 7.64 (s, 2H, D20 exchangeable), 9.12 (s, 1H, D20 exchangeable). Mass Antimicrobial Activity Determination of antimicrobial activity The compounds of invention showed in vitro antibacterial activities when tested by the Agar Dilution Method as specified in documents published by the National Committee for Clinical Laboratory Standards (NCCLS), USA. (now CLSI). Briefly, the compounds of invention were weighed, dissolved in Dimethyl Sulfoxide, serially two fold diluted in the same solvent and then incorporated into molten Mueller Hinton Agar in a petridish before solidification, with each petridish containing a different concentration of a compound The bacterial inoculum was prepared by picking 3 to 5 well isolated bacterial colonies with the same morphological appearance from an 18-24 hours old culture with an inoculating loop, transferring the growth to a tube containing 3ml of normal saline and adjusting the turbidity of the saline suspension to 0.5 Mc Farland Turbidity Standard equivalent to a bacterial population of 1.5 x 108 colony forming units (CFU) per millilitre of suspension. The suspension was diluted 1:10 in saline (i.e. 0.5ml suspension + 4.5 ml saline) to get a bacterial population of 1.5 x 107 cfu/ml as inoculum. The bacterial inoculum prepared in the above manner was inoculated onto petri dishes containing Mueller Hinton Agar which had earlier been incorporated with different dilutions of the compounds of invention by a Multipoint Inoculator with each inoculum spot containing approximately 1 x 104 colony forming units (CFU) of bacteria. The inoculated petridishes were incubated at 35° C in an ambient atmosphere for 16-20 hours. The petridishes after incubation were placed on a dark non-reflecting surface and the Minimum Inhibitory Concentration (MIC) was recorded as the concentration, which showed no growth of the inoculated culture. The following minimum inhibitory concentrations (ng/ml) were obtained for representative compounds of the invention, which are given in the Table 1 and Table 2, wherein N= no of strains tested. We Claim: 1. Novel cephalosporins of formula (I) their derivatives, analogs, tautomeric forms, stereoisomers, polymorphs, solvates, pharmaceutically acceptable salts, metabolites and prodrugs thereof wherein, R1 is selected from OR, where R represents hydrogen or alkyl groups of pharmaceutically acceptable salts and esters that are commonly employed in the cephalosporin chemistry. X1 is represented by O, S or S→O; X2 is represented by N or CH; suitable groups represented by R2 are selected from hydrogen, linear or branched (C1-C4) alkyl groups consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t-butyl which are optionally substituted; haloalkyl groups consisting of chloromethyl, chloroethyl, trifluoromethyl, trifluoroethyl, dichloromethyl, dichloroethyl, trichloromethyl and difluoromethyl; furthermore R2 is optionally substituted by groups consisting of carboxylic acid and its derivatives, or may be a group of the formula: suitable groups represented by R4 and R5 may be the same or different and independently represent hydrogen, substituted or unsubstituted linear or branched (C1-C4) alkyl groups consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t-butyl; haloalkyl groups consisting of chloromethyl, chloroethyl, trifluoromethyl, trifluoroethyl, dichloromethyl, dichloroethyl, trichloromethyl and difluoromethyl, which are optionally substituted; halogen atoms consisting of fluorine, chlorine, bromine, iodine; or it can be a group of the formula; wherein R7 and R8 represent hydrogen, linear or branched (C1-C4) alkyl groups consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t-butyl which are optionally substituted; suitable groups represented by R6 are selected from hydrogen, substituted or unsubstituted linear or branched (C1-C4) alkyl groups consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t-butyl; substituted alkyl protective groups consisting of straight, branched, partially cyclic, cyclic alkanoyloxyalkyl groups consisting of acetoxymethyl, acetoxyethyl, pivaloyloxymethyl, pivaloyloxyethyl and cyclohexaneacetoxyethyl; alkoxyformyloxyalkyl groups consisting of ethoxycarbonyloxy ethyl; alkoxyalkyl groups; 2-oxacycloalkyl groups; 2-oxo-l,3-dioxolylmethyl groups consisting of 4-methyl-2-oxo-l and 3-dioxol-5-ylmethyl group; 1-oxygenated- Ci to Ci2-alkyl groups; substituted aralkyl groups consisting of phenacyl and phthalidyl; aryl groups consisting of phenyl, tolyl, xylyl and indanyl; T represents a quaternary nitrogen atom, which can be a part of an open chain system, or is an open chain attached to a cyclic system, or the nitrogen is attached directly to cyclic systems, which can have chiral, racemic, or meso substitution. This is represented by the general formulae I, II and III and details of the substitution are given below Formula I: suitable groups represented by R8, R9 and Ri0 which may be same or different and independently represent hydrogen, lower alkyl (C1-C4) groups, hydroxyl (which are protected as benzyl ether), amino (which is protected as benzyl ether, benzyloxycarbonyl (Cbz), t-butoxycarbonyl (t-Boc), trityl, and trifluoracetyl), carboxylic acid (which is protected as alkyl ester); Rn represents lower alkyl (Cj-C3) groups; R12 and R]3 represent hydrogen or are combined together to form a 5 to 6 membered ring which may be saturated or unsaturated consisting of cyclohexyl, cyclopentyl and phenyl; any one of X or Y represents a quaternary nitrogen atom and the linkage to the cephalosporin moiety is through the quaternary nitrogen atom; Z is represented by hydrogen, hydroxyl (which is protected as benzyl ether), hydroxyl-diaryl-methyl groups consisting of hydroxy-diphenyl-methyl, chiral or racemic, substituted or unsubstituted, linear or branched (C1-C4) alkyl groups consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and t-butyl; alkoxy groups consisting of methoxy, ethoxy, n-propoxy and isopropoxy, which are optionally substituted; monoalkylamino groups consisting of -NHCH3, -NHC2H5, - NHC3H7 and -NHC6H13 which are optionally substituted; dialkylamino groups consisting of -N(CH3)2, -NCH3(C2H5) and -N(C2H5)2 which are optionally substituted; carboxylic acids and its derivatives consisting of amides, esters (consisting of methyl ester and ethyl ester); acylamino groups consisting of - NHC(=0)CH3, -NHC(=0)C2H5, -NHC(=0)C3H7 and -NHC(=0)C6H13, which are optionally substituted; alkoxyalkyl groups consisting of methoxymethyl, ethoxymethyl, methoxyethyl and ethoxyethyl, which are optionally substituted; the sulfamoyl group, aralkoxy groups consisting of phenylmethoxy, phenylethoxy and phenylpropoxy, which are optionally substituted; aryloxy groups consisting of phenoxy and napthoxy which are optionally substituted, and n is an integer in the range of 0 - 3; Formula II: suitable groups represented by Rn are selected from lower alkyl (C1-C3) groups; R13 represents substituted lower alkyl groups selected from methyl, ethyl, propyl and isopropyl; R14 and R15 may be the same or different and are represented by substituted or unsubstituted alkyl radicals, groups consisting of phenyl, which is optionally substituted by groups consisting of halogens, haloalkyl, alkyl, alkoxy; bicyclic groups consisting of napthyl which is optionally substituted, optionally substituted carbocyclic groups, saturated and unsaturated heterocyclic groups consisting of furyl, piperdinyl and piperazinyl. R14 and R15 can together with the N atom form a three to seven membered cyclic ring, an unsaturated monocyclic aromatic rings consisting of pyridyl, which is optionally substituted; heterocyclic rings consisting of pyrrolidinyl, which is optionally substituted. Formula III: suitable groups represented by R16 are hydrogen, lower alkyl (CrC3) groups or haloalkyl groups; R17 represents alkyl, haloalkyl and alkoxy groups selected from linear or branched (CrC4) alkoxy groups consisting of methoxy, ethoxy, n-propoxy and isopropoxy; X3 represents C, N; X4 represents O or S. 2. The compound of claim 1, selected from a group consisting of: (6R,7R) 7/3- {2- {2-Aminothiazol-4-yl}-2-[(Z)-methoxyimino]-acetylamino}- 3-[[N, N-dimethyl- N- [(R)-l-(4-chlorophenyl)]ethyl]ammonio]methyl-8- oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylate; N-[[ {2-(4-Methoxybenzylcarbonyl)}-(6R,7R)7/3- {2-(2-aminotrityl-1,3- thiazol-4-yl)-2-[(Z)-methoxyimino]-acetylamino} -8-oxo-5-thia-1 -azabicyclo [4.2.0]oct-2-ene-3yl]methyl]-N,N-dimethyl-N-[(R)-l-(l,2,3,4- tetrahydronaphthyl)]ammonio]methyl]ethanaminium iodide; N-[[ {2-(4-Methoxybenzylcarbonyl)} -(6R,7R)7/3- {2-(2-amino-1,3-thiazol-4- yl)-2-[(Z)-methoxyimino]-acetylamino}-8-oxo-5-thia-1-azabicyclo[4.2.0] oct-2-ene-3 yljmethyl] -N,N-dimethy 1-N- [(R)-1 -(1,2,3,4-tetrahydronaphthyl)] ammonio]methyl]ethanaminium iodide; (6R,7R)7/3- {2- {2-Aminothiazol-4-yl} -2-[(Z)-methoxyimino]-acetylamino} - 3-[N,N-dimethyl-N-[(R)-l-(l,2,3,4-tetrahydronaphthyl)]ammonio]methyl-8- oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylate; (6R,7R)7/5- {2- {2-Aminothiazol-4-yl} -2-[(Z)-methoxyimino]-acetylamino} - 3-[[N,N-dimethyl-N-[(S)-1 -(4-chlorophenyl)] ethyl]ammonio]methyl-8-oxo- 5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylate; N-[[ {2-(4-Methoxybenzylcarbonyl)} -(6R,7R)7j3- {2-(2-aminotrityl-l ,3- thiazol-4-yl)-2-[(Z)-methoxyimino]-acetylamino}-8-oxo-5-thia-l-azabicyclo [4.2.0]oct-2-ene-3yl]methyl]-N,N-dimethyl-N-[(R)-l-(cyclohexyl)ethyl] ethanaminium iodide; (6R,7R)7/3- {2- {2-Aminothiazol-4-yl} -2-[(Z)-methoxyimino]-acetylamino} - 3-[N, N-dimethyl- N- [(R)-l-(cyclohexyl)ethyl]ammonio]methyl-8-oxo-5- thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylate; N-[[ {2-(4-Methoxybenzylcarbonyl)} -(6R,7R)7/3- {2-(2-aminotrityl-1,3- thiazol-4-yl)-2-[(Z)-methoxyimino]-acetylamino} -8-oxo-5-thia-1 -azabicyclo [4.2.0]oct-2-ene-3yl]methyl]-N-[(4-{2-fluoro-4-[3-(5-acetylamino methyl)- l,3-oxazolidin-2-one]phenyl}-l-methylpiperazin-l-ium)iodide; [(6R,7R)7/?- {2- {2-Aminotritylthiazol-4-yl} -2-[(Z)-methoxyimino]-acetyl amino}-3-[(4-{2-fluoro-4-[3-(5-acetylaminomethyl)-l,3-oxazolidin-2-one] phenyl} -1 -methylpiperazin-1 -ium)]methyl-8-oxo-5-thia-1 -azabicyclo [4.2.0]oct-2-en-2-carboxylate; N-[[ {2-(4-Methoxybenzylcarbonyl)}-(6R,7R)7/3- {2-(2-aminotrityl-1,3- thiazol-4-yl)-2-[(Z)-methoxyimino]-acetylamino} -8-oxo-5-thia-1 -azabicyclo [4.2.0]oct-2-ene-3yl]methyl]-N-[(4-{2-fluoro-4-[3-(5-dichloroacetyl amino methyl)-1,3-oxazolidin-2-one]phenyl} -1 -methylpiperazin-1 -ium)iodide; [(6R,7R) 7/3- {2- {2-Aminotrityl thiazol-4-yl} -2-[(Z)-methoxyimino]-acetyl amino} -3-[(4- {2-fluoro-4-[3-(5-dichloroacetylaminomethyl)-1,3-oxazolidin- 2-one]phenyl} -1 -methylpiperazin-1 -ium)]methyl-8-oxo-5-thia-1 -azabicyclo [4.2.0]oct-2-en-2-carboxylate; N-[[{2-(4-Methoxybenzylcarbonyl)}-(6R,7R) 7/3- {2-(2-aminotrityl-1,3- thiazol-4-yl)-2-[(Z)-methoxyimino]-acetylamino} -8-oxo-5-thia-1 -azabicyclo [4.2.0]oct-2-ene-3yl]methyl]-N-[(4-{2-fluoro-4-[3-(5-difluoroacetyl amino methyl)-1,3-oxazolidin-2-one]phenyl}-1 -methylpiperazin-1 -ium) iodide; [(6R,7R)7/3-{2-{2-Aminotritylthiazol-4yl}-2-[(Z)-methoxyimino]- acetylamino} -3-[(4- {2-fluoro-4-[3-(5-difluoroacetylaminomethyl)-1,3- oxazolidin-2-one]phenyl} -1 -methylpiperazin-1 -ium)]methyl-8-oxo-5-thia-1 - azabicyclo[4.2.0]oct-2-en-2-carboxylate and 7-( {(2Z)-2-(2-Amino-1,3-thiazol-4-yl)-2-[(2-methoxy-2-oxoethoxy)imino] acetyl} amino)-3 - [[N,N-dimethyl-N- [(R)-1 -(4-chlorophenyl)] ethyl] ammonio] methyl-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylate. 3. A pharmaceutical composition comprising a compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof as an active ingredient along with a pharmaceutically acceptable carrier, diluent, excipient or solvate. 4. A pharmaceutical composition as claimed in claim 3, wherein the pharmaceutical composition is in the form of a tablet, capsule, powder, syrup, solution, aerosol or suspension. 5. A pharmaceutical composition as claimed in claim 3, wherein the amount of the compound of claim 1 in the composition is less than 70 % by weight. 6. A method for the treatment of infectious diseases which comprises administering a compound of claim 1 or a pharmaceutically acceptable salt thereof to human or animals.

Full Text

Field of the invention
The present invention relates to cephalosporin antibiotics of the general formula (I), their derivatives, analogs, tautomeric forms, stereoisomers, polymorphs, hydrates, solvates, pharmaceutically acceptable salts and compositions, metabolites and prodrugs thereof, which have strong antibacterial activity against gram-positive bacteria including methicillin resistant Staphylococcus aureus and also against gram-negative bacteria. The present invention more particularly provides novel quaternary ammonium cephems and derivatives thereof, represented by the general formula (I), these compounds are extremely useful for the treatment of infectious diseases.

The present invention also provides a process for the preparation of the above said cephalosporin antibiotics of the general formula (I), their derivatives, analogs, stereoisomers, polymorphs, hydrates, solvates, pharmaceutically acceptable salts and compositions, metabolites and prodrugs thereof. This invention also relates to intermediates useful in the preparation of such compounds.
Background of the invention
Cephalosporins are beta-lactams in which the beta-lactam ring is fused to a 6-membered dihydrothiazine ring, thus forming the cephem nucleus. A side chain modification to the cephem nucleus confers in addition to pharmacokinetic advantages an improved spectrum of antibacterial activity.
Bacterial pathogens are classified as either gram-positive or gram- negative and many antibacterial agents, including antibiotics are specific against one or other gram-class of pathogens. Antibacterial agents effective against both gram-positive and gram-negative pathogens are therefore generally regarded as having a broad-spectrum of activity. In general, 1st generation cephalosporins have better activity against gram-positive bacteria and are less active against gram-negative bacteria, while the 3rd generation agents, with a few exceptions, have a better gram-negative activity and less of gram-positive activity. It is only the 4th generation agents that have both gram- positive and gram-negative activity; few quaternary ammonium cephalosporins are also reported in the literature and some of them are summarized below.
Few prior art references, which disclose the closest compounds, are given here:
I) US 5,571,909 discloses compounds of the formula

wherein Q is CH or N; P is a hydroxylated amine or a hydroxylated heterocyclic amine including N-methyl-bis(2-hydroxyethyl) amine, racemic- 3,4-trans-dihydroxy-l-methylpyrrolidine, (3S,4S)-3,4-trans-dihydroxy-l- methyl-pyrrolidine, (3R,4R)-3,4-trans-dihydroxy-1 -methylpyrrolidine, meso- 3,4-dihydroxy-1 -methylpyrrolidine, (2S ,4R)-4-hydroxy-1 -methyl-2-pyrrolidine methanol, 3,4-cis-dihydroxy-1 -methylpiperidine, 3,4-trans-dihydroxy-1 - methylpiperidine, or tropine.
II) JP 0363010792 discloses compounds of the formula

wherein n is an integer from 1 to 6; R1 is H or a substituted lower alkyl group; R is a lower alkyl or a lower cycloalkyl group; R is an organic residue bonded through O, S or NH, amino or nitrogen containing heterocyclic group; Q is N or
CR4 and R4
is H or halogen.
III) US 4,754,031 discloses compounds of the formula

wherein Ri is an aliphatic or a cyclo aliphatic radical with upto 6 carbon atoms, and A is a pyridinium radical or a radical of the formula

IV) JP-62030788 discloses the following general structure: wherein n is an integer from 1 to 5; R1 is a carboxyl substituted lower alkyl group; R2, and R3, R4 are H, OH, OCH3 or acetoxy; it can also be a general formula as follows:
wherein R5 is H, or a protecting group of the amino function; R6 is H or a protection of the carboxyl group; R7 is a protected carboxyl substituted lower alkyl group; Y is S or S->0 and X is either a halogen or can be a formula as follows:

wherein n is an integer from 1 to 5; R8, R9and R10 are H, OH (protected) and Ru is H, CH3.
Objective of the invention
The primary objective of the present invention is to provide cephalosporins of the formula (I), which can enhance the biological activity over a wide variety of gram-negative and gram-positive bacteria and also against resistant bacterial strains like MRSA and VRE.
Another objective of the present invention is to provide a process for the preparation of compounds of the general formula (I).
Summary of the invention
The present invention provides cephalosporins of the general formula
(I),

their derivatives, analogs, tautomeric forms, stereoisomers, polymorphs, their solvates, pharmaceutically acceptable salts and compositions, metabolites and prodrugs thereof, wherein Xi is represented by O, S, or S—>0; X2 is represented by N or CH; R2 represents hydrogen, haloalkyl, substituted lower alkyl (Q-C4) groups, substituted or unsubstituted protected carboxy-(CrC4) groups, an aliphatic or a cycloaliphatic radical with upto 6 carbon atoms, and furthermore -N-OR2 is in the syn position; T represents a quaternary nitrogen atom, which can be a part of an open chain system, or it is an open chain attached to a cyclic system, or the nitrogen is attached directly to cyclic systems which can have chiral, racemic or meso substitutions. This is represented by the general formulae I, II and III and details of the substitution are given below; R] represents OR wherein, R represents hydrogen or alkyl groups of pharmaceutically acceptable salts and esters that are commonly employed in the cephalosporin chemistry.
Detailed description of the invention
The present invention provides cephalosporins of the general formula
their derivatives, analogs, tautomeric forms, stereoisomers, polymorphs, their solvates, pharmaceutically acceptable salts and compositions, metabolites and prodrugs thereof, wherein the suitable group represented by Ri is selected from OR, wherein R represents hydrogen or alkyl groups of pharmaceutically acceptable salts and esters that are commonly employed in the cephalosporin chemistry. Xi is represented by O, S or S—>0. X2 is represented by N or CH.
Suitable groups represented by R2 are selected from hydrogen, linear or branched (C1-C4) alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, t-butyl and the like which may be substituted; haloalkyl groups such as chloromethyl, chloroethyl, trifluoromethyl, trifluoroethyl, dichloromethyl, dichloroethyl, trichloromethyl, difluoromethyl and the like; furthermore R2 may be substituted by groups such as a carboxylic acid and its derivatives, or may be a group of the formula:

Suitable groups represented by R4 and R5 may be the same or different and independently represent hydrogen, substituted or unsubstituted linear or branched (C1-C4) alkyl groups which may be substituted; haloalkyl groups which may be substituted; halogen atoms such as fluorine, chlorine, bromine, iodine; or it can be a group of the formula
wherein R7 and R8 represent hydrogen, linear or branched (CrC4) alkyl groups which may be substituted.
Suitable groups represented by R^ are selected from hydrogen, substituted or unsubstituted linear or branched (C1-C4) alkyl groups which may be substituted; substituted alkyl protective groups such as straight, branched, partially cyclic, cyclic alkanoyloxyalkyl groups such as acetoxymethyl, acetoxyethyl, pivaloyloxymethyl, pivaloyloxyethyl, cyclohexaneacetoxyethyl and the like; alkoxyformyloxyalkyl groups such as ethoxycarbonyloxyethyl and the like; alkoxyalkyl groups; 2-oxacycloalkyl groups; 2-oxo-l,3- dioxolylmethyl groups such as 4-methyl-2-oxo-l, 3-dioxol-5-ylmethyl group and the like; 1-oxygenated-1C to 12C-alkyl groups; substituted aralkyl groups such as phenacyl, phthalidyl and the like; aryl groups such as phenyl, tolyl, xylyl, indanyl and the like.
T represents a quaternary nitrogen atom, which can be a part of an open chain system, or is an open chain attached to a cyclic system, or the nitrogen is attached directly to cyclic systems, which can have chiral, racemic, or meso substitution. This is represented by the general formulae I, II and III and details of the substitution are given below. Formula I:

Suitable group represented by R8, R9 and Rio which may be same or different and independently represent hydrogen, lower alkyl (CrC4) groups, hydroxyl (which may be protected as benzyl ether and the like), amino (which may be protected as benzyl ether, benzyloxycarbonyl (Cbz), t-butoxycarbonyl (t-Boc), trityl, trifluoracetyl and the like), carboxylic acid (which may be protected as alkyl ester and the like); Rn represents lower alkyl (CrC3) groups; R12 and R13 represents hydrogen or are combined together to form a 5 to 6 membered ring which may be saturated or unsaturated such as cyclohexyl, cyclopentyl, phenyl, and the like; any one of X or Y represents a quaternary nitrogen atom and the linkage to the cephalosporin moiety is through the quaternary nitrogen atom; Z is represented by hydrogen, hydroxyl (which may be protected as benzyl ether and the like), hydroxyl-diaryl-methyl groups such as hydroxy-diphenyl-methyl and the like, chiral or racemic, substituted or unsubstituted, linear or branched (C1-C4) alkyl groups which may be substituted; alkoxy groups such as methoxy, ethoxy, n-propoxy, isopropoxy and the like, which may be substituted; monoalkylamino groups such as - NHCH3, -NHC2H5, -NHC3H7> -NHC6H13, and the like, which may be substituted; dialkylamino groups such as -N(CH3)2, -NCH3(C2H5), -N(C2H5)2 and the like, which may be substituted; carboxylic acids and its derivatives such as amides, esters (such as methyl ester, ethyl ester and the like); acylamino groups such as -NHC(=0)CH3, -NHC(=0)C2H5, -NHC(=0)C3H7> - NHC(=0)C6H13, and the like, which may be substituted; alkoxyalkyl groups such as methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl and the like, which may be substituted; the sulfamoyl group, aralkoxy groups such as phenylmethoxy, phenylethoxy, phenylpropoxy, and the like which may be substituted; aryloxy groups such as phenoxy, napthoxy and the like which may be substituted, and n is an integer in the range of 0 - 3. Formula II:

Suitable groups represented by Ru are selected from lower alkyl (CrC3) groups; R13 represents substituted lower alkyl groups which may be substituted; R14 and Ri5 may be the same or different and are represented by substituted or unsubstituted alkyl radicals, groups such as phenyl and the like which is optionally substituted by groups such as halogens, haloalkyl, alkyl, alkoxy; bicyclic groups such as napthyl and the like, optionally substituted carbocyclic groups, saturated and unsaturated heterocyclic groups such as furyl, piperdinyl, piperazine and the like. R14 and R15 can together with the N atom form a three to seven membered cyclic ring, an unsaturated monocyclic aromatic rings such as pyridyl and the like which may be substituted;_heterocyclic rings such as pyrrolidinyl and the like which may be substituted. Formula III:

Suitable groups represented by R16 may be hydrogen, lower alkyl (Cr C3) groups or haloalkyl groups; R17 represents alkyl, haloalkyl and alkoxy groups selected from linear or branched (C1-C4) alkoxy groups comprising from methoxy, ethoxy, n-propoxy, isopropoxy and the like. X3 represent C, N. X4 represents O or S.
The term analog includes a compound, which differs from the parent structure by one or more C, N, O or S atoms. Hence, a compound in which one of the N atoms in the parent structure is replaced by an S atom is an analog of the former.
The term stereoisomer includes isomers that differ from one another in the way the atoms are arranged in space, but whose chemical formulas and structures are otherwise identical. Stereoisomers include enantiomers and diastereoisomers.
The term tautomers include readily interconvertible isomeric forms of a compound in equilibrium. The enol-keto tautomerism is an example.
The term polymorphs include crystallographically distinct forms of compounds with chemically identical structures.
The term pharmaceutically acceptable solvates includes combinations of solvent molecules with molecules or ions of the solute compound.
The term derivative refers to a compound obtained from a compound according to formula (I), an analog, tautomeric form, stereoisomer, polymorph,
hydrate, pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, by a simple chemical process converting one or more functional groups, such as, by oxidation, hydrogenation, alkylation, esterification, halogenation, and the like.
Pharmaceutically acceptable salts of the present invention include alkali metals like Li, Na, and K, alkaline earth metals like Ca and Mg, salts of organic bases such as diethanolamine, a-phenylethylamine, benzylamine, piperidine, morpholine, pyridine, hydroxyethylpyrrolidine, choline
hydroxyethylpiperidine, and the like, ammonium or substituted ammonium salts, aluminum salts. Salts also include amino acid salts such as glycine, alanine, cystine, cysteine, lysine, arginine, phenylalanine, guanidine etc. Salts may include acid addition salts where appropriate, which are, sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartrates, maleates, citrates, succinates, palmoates, methanesulphonates, tosylates, benzoates, salicylates, hydroxynaphthoates, benzenesulfonates, ascorbates, glycerophosphates, ketoglutarates and the like. Pharmaceutically acceptable solvates may be hydrates or comprising other solvents of crystallization such as alcohols.
A term once described, the same meaning applies for it, throughout the patent
Particularly useful compounds according to the invention include the chiral compounds listed below as well as their racemates:
1. (6R,7R) 7/3-{2-{2-Aminothiazol-4-yl}-2-[(Z)-methoxyimino]-acetylamino}- 3-[[N, N-dimethyl- N- [(R)-l-(4-chlorophenyl)]ethyl]ammonio]methyl-8- oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylate;
2. N-[[{2-(4-Methoxybenzylcarbonyl)}-(6R,7R)7/3- {2-(2-aminotrityl-1,3- thiazol-4-yl)-2-[(Z)-methoxyimino]-acetylamino}-8-oxo-5-thia-l- azabicyclo[4.2.0]oct-2-ene-3yl]methyl]-N,N-dimethyl-N-[(R)-l-(l,2,3,4- tetrahydronaphthyl)]ammonio]methyl]ethanaminium iodide;
3. N-[[{2-(4-Methoxybenzylcarbonyl)}-(6R,7R) 70-{2-(2-amino-1,3-thiazol-4- yl)-2-[(Z)-methoxyimino]-acetylamino}-8-oxo-5-thia-l-azabicyclo[4.2.0] oct-2-ene-3yl]methyl]-N,N-dimethyl-N-[(R)-1 -(1,2,3,4-tetrahydronaphthyl)] ammonio]methyl]ethanaminium iodide;
4. (6R,7R) 7/3- {2- {2-Aminothiazol-4-yl}-2-[(Z)-methoxyimino]-acetylamino} - 3 - [N,N-dimethy 1-N- [(R)-1 -(1,2,3,4-tetrahydronaphthyl)]ammonio]methyl-8- oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylate;
5. (6R,7R) 7/3- {2- {2-Aminothiazol-4-yl}-2-[(Z)-methoxyimino]-acetylamino}- 3-[[N,N-dimethyl-N-[(S)-l-(4-chlorophenyl)] ethyl]ammonio]methyl-8-oxo- 5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylate;
6. N-[[ {2-(4-Methoxybenzylcarbonyl)}-(6R,7R)7/3- {2-(2-aminotrityl-1,3- thiazol-4-yl)-2-[(Z)-methoxyimino]-acetylamino}-8-oxo-5-thia-l-azabicyclo [4.2.0]oct-2-ene-3yl]methyl]-N,N-dimethyl-N-[(R)-l-(cyclohexyl)
ethyl]ethanaminium iodide.
7. (6R,7R) 7/3- {2- {2-Aminothiazol-4-yl}-2-[(Z)-methoxyimino]-acetylamino}- 3-[N, N-dimethyl- N- [(R)-l-(cyclohexyl) ethyl]ammonio]methyl-8-oxo-5- thia-1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylate;
8. N-[[{2-(4-Methoxybenzylcarbonyl)}-(6R,7R)7/3-{2-(2-aminotrityl-l,3- thiazol-4-yl)-2-[(Z)-methoxyimino]-acetylamino}-8-oxo-5-thia-l-azabicyclo [4.2.0]oct-2-ene-3yl]methyl]-N-[(4-{2-fluoro-4-[3-(5-acetylamino methyl)- 1,3-oxazolidin-2-one]phenyl} -1 -methylpiperazin-1 -ium)iodide;
9. [(6R,7R)7/3- {2- {2-Aminotritylthiazol-4-yl} -2-[(Z)-methoxyimino]-acetyl amino} -3-[(4- {2-fluoro-4-[3-(5-acetylaminomethyl)-1,3-oxazolidin-2-one] phenyl} -1 -methylpiperazin-1 -ium)]methyl-8-oxo-5-thia-1 -azabicyclo [4.2.0]oct-2-en-2-carboxylate;
10. N-[[ {2-(4-Methoxybenzylcarbonyl)}-(6R,7R)7/3- {2-(2-aminotrityl-1,3- thiazol-4-yl)-2-[(Z)-methoxyimino]-acetylamino}-8-oxo-5-thia-l-azabicyclo [4.2.0]oct-2-ene-3yl]methyl]-N-[(4-{2-fluoro-4-[3-(5-dichloroacetyl amino methyl)-1,3-oxazolidin-2-one]phenyl} -1 -methylpiperazin-1 -ium) iodide;
11. [(6R,7R) 7/3-{2-{2-Aminotrityl thiazol-4-yl}-2-[(Z)-methoxyimino]-acetyl amino} -3-[(4- {2-fluoro-4-[3-(5-dichloroacetylaminomethyl)-1,3-oxazolidin- 2-one]phenyl} -1 -methylpiperazin-1 -ium)]methyl-8-oxo-5 -thia-1 -azabicyclo [4.2.0]oct-2-en-2-carboxylate;
12. N-[[ {2-(4-Methoxybenzylcarbonyl)}-(6R,7R) 7/3- {2-(2-aminotrityl-1,3- thiazol-4-yl)-2-[(Z)-methoxyimino]-acetylamino}-8-oxo-5-thia-l-azabicyclo [4.2.0]oct-2-ene-3yl]methyl]-N-[(4-{2-fluoro-4-[3-(5-difluoroacetyl amino methyl)-1,3 -oxazolidin-2-one]phenyl} -1 -methylpiperazin-1 -ium) iodide;
13. [(6R,7R)7/3- {2- {2-Aminotritylthiazol-4yl}-2-[(Z)-methoxyimino]- acetylamino}-3-[(4-{2-fluoro-4-[3-(5-difluoroacetylaminomethyl)-1,3- oxazolidin-2-one]phenyl} -1 -methylpiperazin-1 -ium)]methyl-8-oxo-5-thia-1 - azabicyclo[4.2.0]oct-2-en-2-carboxylate and
14.7-( {(2Z)-2-(2-Amino-1,3-thiazol-4-yl)-2-[(2-methoxy-2-oxoethoxy)imino] acetyl} amino)- 3-[[N, N-dimethyl- N- [(R)-l-(4-chlorophenyl)] ethyl] ammonio] methyl -8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylate.
According to another feature of the present invention, there is provided a process as shown in the following scheme, for the preparation of compounds of the formula (I), wherein all the groups are as defined earlier.
Scheme I
It comprises, condensation of the compound of formula (la) or its active
. derivative with the reactive derivative of the formula (lb) as shown below.
Scheme I
Wherein R, represents -OR, where R represents hydrogen, or alkyl or a trimethylsilyl/alkali metal salt, or a substituted benzyl or carboxylic acid
protecting group commonly employed in cephalosporin chemistry; A is hydrogen or silyl or trityl and E is a group which forms a basis that a compound of formula (lb) is in the reactive form; for example halogen or any leaving group or OH or an activated ester, in the presence or absence of a base and solvent to produce novel compounds of the formula (I). The compound of formula (la) can be prepared by utilizing the conventional procedures available in cephalosporin chemistry.
Condensation employing acids or acid halides or an activated ester may be effected in aqueous and non-aqueous reaction media, conveniently at temperatures from -50°C to +50°C, preferably -20°C to +30°C, if desired in the presence of an acid binding agent. Suitable reaction media include aqueous ketones such as aqueous acetone, MIBK, esters such as ethyl acetate, halogenated hydrocarbons such as chloroform, dichloromethane, dichloroethane, o-dichlorobenzene, amides such as N, N-dimethylacetamide, N, N-dimethylformamide, nitriles such as acetonitrile, acids such as acetic acid, propionic acid, alcohols such as ethanol, methanol, isopropylalcohol, t- butylalchol, and also includes toluene, xylene, tetrahydrofuran, dioxane, dimethylsulfoxide, pyridine, water, a mixture thereof or the like or mixtures of two or more such solvents. Suitable acid binding agents include tertiary amines such as triethylamine or N, N-dimethylaniline, N-methyl morpholine, inorganic bases such as calcium carbonate or sodium bicarbonate, and oxiranes of the lower 1,2-alkylene oxides type such as ethylene oxide, propylene oxide or molecular sieves, which bind hydrogen halide liberated in the acylation reaction.
Condensations employing acids are desirably conducted in the presence of a condensation agent, for example a carbodiimide such as N,N'- dicyclohexylcarbodiimide, 1 -(3-dimethylaminopropyl)-3-ethylcarbodiimide, a carbonyl compound such as carbonyldiimidazole, or an isoxazolinium salt such as N-ethyl-5-phenylisoxazolinium perchlorate. Acylation reactions of this type are desirably effected in an anhydrous reaction medium.
Scheme II
It comprises, condensation of the compound of formula (Ic) or its active derivative with the reactive derivative of formula (lb) to finally yield the compounds of formula (I) as shown below.

Wherein B independently represents acyl group, hydroxyl or halogens such as chlorine or iodine and all the other symbols are as described above. The compound of formula (I) can be prepared from the compound of formula (Id) by utilizing the conventional procedures available for quaternary cephalosporin synthesis in the literature.
It is appreciated that in any of the above-mentioned reactions any reactive functional group in the substrate molecule may be protected according to the conventional chemical practice. Suitable protecting groups in any of these reactions are those used conventionally in the art, and the methods of formation and removal of such protecting groups are those conventional methods appropriate to the molecule being protected
Pharmaceutically acceptable salts of the present invention include alkali metals like Li, Na, and K, alkaline earth metal like Ca and Mg, salts of organic bases such as diethanolamine, a-phenylethylamine, benzylamine, piperidine, morpholine, pyridine, hydroxyethylpyrrolidine, hydroxyethylpiperidine, choline and the like, ammonium or substituted ammonium salts, aluminum salts. Salts also include amino acid salts such as glycine, alanine, cystine, cysteine, lysine, arginine, phenylalanine, guanidine etc. Salts may include acid addition salts where appropriate like sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartarates, maleates, citrates, succinates, palmoates, methanesulphonates, tosylates, benzoates, salicylates, hydroxynaphthoates, benzenesulfonates, ascorbates, glycerophosphates, ketoglutarates and the like. Compounds of the formula (I) may form solvates of DMF, hydrates and the like.
The pharmaceutically acceptable ester groups are substituted alkyl esters; straight, branched, cyclic or partially cyclic alkanoyloxyalkyl esters such as acetoxymethyl ester, acetoxyethyl ester, pivaloyloxymethyl ester, pivaloyloxyethyl ester, cyclohexaneacetoxyethyl ester and the like; alkoxyformyloxyalkyl esters such as ethoxycarbonyloxyethyl ester and the like; alkoxyalkyl esters; 2-oxacycloalkyl esters; 2-oxo-l,3-dioxolylmethyl esters such as 4-methyl-2-oxo-l, 3-dioxol-5-ylmethyl ester and the like; 1- oxygenated-lC to 12C-alkyl esters; substituted aralkyl esters such as phenacyl ester, phthalidyl ester and the like; aryl esters such as phenyl ester, tolyl ester, xylyl ester, indanyl ester and the like.
It should be noted that compounds of the invention may contain groups that may exist in tautomeric forms, and though one form is named, described, displayed and/or claimed herein, all the forms are intended to be inherently included in such name, description, display and/or claim.
The stereoisomers of the compounds forming part of this invention may be prepared by using reactants in their single enantiomeric form, in the process wherever possible or by conducting the reaction in the presence of reagents or catalysts in their single enantiomeric form or by resolving the mixture of stereoisomers by conventional methods. Some of the preferred methods include use of microbial resolution, resolving the diastereomeric salts formed with chiral acids such as mandelic acid, camphorsulfonic acid, tartaric acid, lactic
acid, and the like wherever applicable or by using chiral bases such as brucine, cinchona alkaloids, their derivatives and the like.
Prodrugs of the compounds of formula (I) are also contemplated by this invention. A prodrug is an active or inactive compound that is modified chemically through in-vivo physiological action, such as hydrolysis, metabolism and the like, into a compound of the invention following administration of the prodrug to a patient. The suitability and techniques involved in making/using prodrugs are well known to those skilled in the art.
Various polymorphs of the compounds of the general formula (I), forming part of this invention may be prepared by crystallization of the compounds of formula (I) under different conditions. For example, using different commonly used solvents, or their mixtures for recrystallization; crystallizations at different temperatures; various modes of cooling, ranging from very fast to very slow cooling during crystallizations. Heating or melting the compounds followed by cooling gradually or immediately, one can also obtain polymorphs. The presence of polymorphs may be determined by solid probe NMR spectroscopy, IR spectroscopy, differential scanning calorimetry and powder X-ray diffraction or other such techniques.
Pharmaceutically acceptable solvates of the compounds of the formula (I) forming part of this invention may be prepared by conventional methods such as dissolving the compounds of the formula (I) in solvents such as water, methanol, ethanol, mixture of solvents such as acetone:water, dioxane:water, N,N-dimethylformamide:water and the like, preferably water and recrystallization by using different crystallization techniques.
The present invention also provides a pharmaceutical composition, containing one or more of the compounds of the general formula (I) as defined above, their derivatives, analogs, tautomeric forms, stereoisomers, polymorphs, hydrates, metabolites, prodrugs, pharmaceutically acceptable salts, pharmaceutically acceptable solvates in combination with the usual pharmaceutically employed carriers, diluents and the like, useful for the treatment of bacterial infections.
The cephalosporin derivatives provided by the present invention can be employed as pharmaceutical compositions, for example, in the form of pharmaceutical compositions containing the cephalosporin derivatives together with appropriate, pharmaceutically acceptable carriers. The products in accordance with the invention can be administered, for example, perorally, such as in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions, or rectally, such as in the form of suppositories, etc. The compositions may be sterilized and may contain auxiliary agents generally employed in the pharmaceutical art, such as sodium hydrogen carbonate, citric acid, propylene glycol, tween 80, etc. The compounds can be used orally or parenterally.
Pharmaceutical compositions containing these compounds can be prepared using conventional procedures familiar to those skilled in the art, such as by combining the ingredients into a dosage form together with suitable, non¬toxic, inert, therapeutically compatible solid or liquid carrier materials and if desired, the usual pharmaceutical adjuvants. The amount of the active ingredient in the composition may be less than 70% by weight. Such compositions typically contain from 1 to 25%, preferably 1 to 15% by weight of active compound, the remainder of the composition being pharmaceutically acceptable carriers, diluents, excipients or solvents.
The pharmaceutical composition may be in the forms normally employed, such as tablets, capsules, powders, syrups, solutions, suspensions and the like, may contain flavorants, sweeteners etc. in suitable solid or liquid carriers or diluents, or in suitable sterile media to form injectable solutions or suspensions. Suitable pharmaceutically acceptable carriers include solid fillers or diluents and sterile aqueous or organic solutions. The active compound will be present in such pharmaceutical compositions in the amounts sufficient to provide the desired dosage in the range as described above. Thus, for oral administration, the compounds can be combined with a suitable solid or liquid carrier or diluent to form capsules, tablets, powders, syrups, solutions, suspensions and the like. The pharmaceutical compositions, may, if desired, contain additional components such as flavorants, sweeteners, excipients and the like. For parenteral administration, the compounds can be combined with sterile aqueous or organic media to form injectable solutions or suspensions. For example, solutions in sesame or peanut oil, aqueous propylene glycol and the like can be used, as well as aqueous solutions of water-soluble pharmaceutically-acceptable acid addition salts or alkali or alkaline earth metal salts of the compounds. The injectable solutions prepared in this manner can then be, administered intravenously, intraperitoneally, subcutaneously, or intramuscularly, with intramuscular administration being preferred in humans.
The pharmaceutical compositions of the invention show a potent antibacterial activity against a wide range of bacteria including gram-positive and gram-negative bacteria, especially against methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa and are useful as therapeutic agents for infectious diseases
Generally, the effective dose for treating a particular condition in a patient may be readily determined and adjusted by the physician during treatment to alleviate the symptoms or indications of the condition or disease. Generally, a daily dose of active compound in the range of about 0.01 to 1000 mg/kg of body weight is appropriate for administration to obtain effective results. The daily dose may be administered in a single dose or divided into several doses. In some cases, depending upon the individual response, it may be necessary to deviate upwards or downwards from the initially prescribed daily dose. Typical pharmaceutical preparations normally contain from about 0.2 to about 500 mg of active compound of formula I and/or its pharmaceutically active salts or solvates per dose.
While the compounds of the invention can be administered as the sole active pharmaceutical agent, they can also be used in combination with one or more compounds of the invention or other agents. When administered as a combination, the therapeutic agents can be formulated as separate compositions that are given at the same time or different times, or the therapeutic agents can be given as a single composition.
The term "therapeutically effective amount" or "effective amount" refers to that amount of a compound or mixture of compounds of Formula I that is sufficient to effect treatment, when administered alone or in combination with other therapies to a mammal in need of such treatment.
The term "animal" as used herein is meant to include all mammals, and in particular humans. Such animals are also referred to herein as subjects or patients in need of treatment. The therapeutically effective amount will vary depending upon the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the particular compound of Formula I chosen, the dosing regimen to be followed, timing of administration, the manner of administration and the like, all of which can readily be determined by one of ordinary skill in the art.
The term "treatment" or "treating" means any treatment of a disease in a mammal, including:
a) Preventing the disease, that is, causing the clinical symptoms of the disease not to develop;
b) Inhibiting the disease, that is, slowing or arresting the development of clinical symptoms; and/or
c) Relieving the disease, that is, causing the regression of clinical symptoms.
From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, make various changes and modifications of the invention to adapt it to various usages and conditions.
The present invention is provided by the examples given below, which are provided by the way of illustration only, and should not be considered to limit the scope of the invention. Variation and changes, which are obvious to one skilled in the art, are intended to be within the scope and nature of the invention, which are defined in the appended claims.
Example X
Synthesis of (6R,7R)7/S-{2-{2-aminothiazol-4-yl}-2-|(Z)-methoxyimino|- acety lamino}-3- [ [N,N-dimethyl-N- [(R)-l-(4-chlorophenyl)] ethyl] ammonio] methyl-8-oxo-5-thia-l-azabicyc!o[4.2.0]oct-2-ene-2-carboxylate.
Step 1:
Synthesis of 4-methoxybenzyl(6R,7R)7/3-{2-{2-aminotrityl-l,3-thiazol-4- yl}-2-[(Z)-methoxyimino]-acetylamino}-3-(chloromethyl)-8-oxo-5-thia-l- azabicyclo [4.2.0] oct-2-ene-2-carboxylate.

To a solution of (2E)- {2-[(triphenylmethyl)amino]-l ,3-thiazol-4- yl}(methoxyimino)acetic acid (7.9g, 0.017mol) in DCM (80ml) under a nitrogen atmosphere, PC15 (4.2g, 0.02mol) was added at once under stirring at 0°C and the stirring was continued under the same conditions for 1.5 hours. To this resultant reaction mass was added a clear solution of 4-methoxybenzyl (7i?)-7-amino-3-(chloromethyl)-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2- carboxylate (ACLE) (6.0g, 0.016mol) in a mixture of acetonitrile (120ml) and N,0-bis(trimethylsilyl)acetamide (7.4 ml) over a period of 0.5 hours and the reaction mixture was maintained under the same condition for 0.5 hours. When the completion of the reaction was confirmed by TLC using ethyl acetate and hexane as the solvent system (1:1) the resultant reaction mass was poured into ice-cold water (150ml), stirred for 10 minutes and later extracted with isopropyl ether (2x75ml). The organic layer was washed with water (3x100ml). To the resultant organic layer ethyl acetate (150ml) was added to get a clear solution that was again washed thoroughly with water (2x100ml). The organic layer was dried over anhydrous sodium sulphate, concentrated under vacuum and then further treated with hexane (150ml) to get the desired solid. The solid obtained was filtered, washed with hexane (50ml) and dried under vacuum to yield the target compound (8.0g, 62%, purity-92.17% by HPLC). 'H NMR (DMSO-d6) 5 (ppm): 3.54 (s, 1H), 3.67 (s, 1H), 3.74 (s, 3H), 3.80 (s, 3H) 4.44 - 4.51 (m, 2H), 5.16 - 5.21 (m, 3H), 5.71 (s, 1H), 6.70 (s, 1H), 6.91- 6.94 (d, 2H), 7.21-7.24 (m, 3H), 7.28-7.37 (m, 16H), 8.86 (s, 1H), 9.58 - 9.6 (d, 1H). Massm/z: 794.1 (M++l). Step 2:
Synthesis of N-[[{2-(4-methoxybenzylcarbonyl)}-(6R,7R)7/5-{2-(2- aminotrityl-l,3-thiazol-4-yl)-2-[(Z)-methoxyimino]-acetylamino}-8-oxo-5- thia-l-azabicyclo[4.2.0]oct-2-ene-3yl]methyl]-N,N-dimethyl-N-[(R)-l-(4- chlorophenyl)]ethanaminium iodide.

To a solution of the 4-methoxybenzyl (6R,7R) 7jS-{2-{2-aminotrityl-l,3- thiazol-4-yl}-2-[(Z)-methoxyimino]-acetylamino}-3-(chloromethyl)-8-oxo-5- thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (3.0g, 0.0037mol) in methyl ethyl ketone (30ml) was added sodium iodide (2.8 lg, 0.018mol) under stirring at 35°C and the stirring was continued for lhour at the same temperature. The resultant reaction mass was poured into water (50ml) and was extracted with ethyl acetate (3x25ml). The combined organic layer was washed with 10% sodium thiosulphate solution (50ml) followed by water (50ml) and finally with brine solution (50ml). The organic layer was dried over anhydrous sodium sulphate and concentrated under vacuum to yield the desired 4- methoxybenzyl(6R,7R)7jS- {2- {2-aminotrityl-1,3-thiazol-4-yl} -2-[(Z)-
methoxyimino]-acetylamino}-3-(iodomethyl)-8-oxo-5-thia-l-aza- bicyclo[4.2.0]oct-2-ene-2-carboxylate compound.
To the solution of the 4-methoxybenzyl (6R, 7R) 7/3- {2- {2-aminotrityl- 1,3 -thiazol-4-yl} -2- [(Z)-methoxyimino]-acetylamino} -3 -(iodomethyl)-8-oxo-5 - thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylate compound in DMF (20ml), (lR)-l-(4-chlorophenyl)-N,N-dimethylethanamine (1.38g, 0.0074mol) was added under stirring over a period of 5 minutes at 5°C and was allowed to reach a temperature of 35°C under continuous stirring for a period of 1.5 hours. When the completion of the reaction was confirmed by TLC using methanol and ethyl acetate (2:8) as the solvent system, diethyl ether (50ml) was added to the reaction mass, which was stirred further for 10 minutes. To the residue obtained after removal of the diethyl ether was added DCM (10ml) to get a clear solution, further the compound was precipitated out by adding hexane (25ml) and continuing the stirring for 30 minutes at room temperature. Hexane was removed by decantation to give a solid, which was dried under nitrogen to yield the desired compound (2.0g, 56%). 'H NMR (DMSO-d6) 5 (ppm): 1.07 (s, 3H), 1.71-1.73 (d, 3H), 2.73 (s, 3H), 2.86 (s, 1H), 3.33 - 3.35 (d, 2H), 3.77 (s, 3H), 3.80 (s, 3H), 3.81 (s, 2H), 5.13 (s, 1H), 5.76 (s, 2H), 5.81 (s, 1H), 5.83 (s, 1H) 7.21 - 7.24 (m, 3H), 7.30 - 7.35 (m, 20H), 7.53 - 7.61 (m, 4H), 8.89 (s, 1H), 9.35 - 9.37 (d, 1H), 9.59 - 9.61 (d, 1H). Mass m/z: 942.0 (M++l). Step 3:
Synthesis of (6R,7R) 7/S-{2-{2-aminothiazol-4-yl}-2-[(Z)-methoxyimino]- acetylamino}-3- [ [N,N-dimethyl-N- [(R)-l-(4-chlorophenyl)] ethyl] ammonio] methyl -8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylate.
To a solution of N-[[{2-(4-methoxybenzylcarbonyl)}-(6R,7R) 7/3-{2-(2- aminotrityl-1,3-thiazol-4-yl)-2-[(Z)-methoxyimino]-acetylamino} -8-oxo-5- thia-l-azabicyclo[4.2.0]oct-2-ene-3yl]methyl]-N,N-dimethyl-N-[(R)-l-(4- chlorophenyl)]ethanaminium iodide (2.0g, 0.0021mol) in DCM (15ml) anisole (10ml) was added under stirring at 5°C followed by trifluoroacetic acid (20ml) dropwise over a period of 10 minutes and the reaction mixture was maintained at same temperature for 3 hours. When the completion of the reaction was confirmed by TLC using methanol and ethyl acetate as the solvent system (8:2), hexane (50ml) was added to the resultant reaction mass and was stirred further for 15 minutes, subsequently the hexane was decanted. This procedure was repeated three times with hexane and then with di-isopropyl ether (30ml) to yield the desired compound. 'H NMR (DMSO-d6) 8 (ppm): 1.73 - 1.75 (d, 3H), 2.80 (s, 3H), 2.91 (s, 3H), 3.73 - 3.76 (d, 1H), 3.84 (s, 3H), 4.44 (s, 1H), 4.62 - 4.65 (d, 1H), 4.85 - 4.87 (d, 1H), 5.3 (s, 1H), 5.36 - 5.39 (m, 1H), 6.82 (s, 2H) 7.23 (s, 2H, D20 exchangeable), 7.56 - 7.64 (m, 4H), 9.38 - 9.4 (d, 1H, D20 exchangeable). Mass m/z: 580.0 (M++l).
The following compounds are prepared by the general procedures given in Example 1 with appropriate tertiary amines.
1H), 7.24 (s, 1H, D20 exchangeable), 8.30 (s, 1H, D20 exchangeable). Mass m/z: 934.2 (M+).
3 1
N
II H H H Nv^A/Noi^S.
H2N-f T n tt 1 1 w /
S 0 'H NMR (DMS0-d6) 5 (ppm): 1.17 - 1.22 (m, 2H), 1.44 - 1.47 (t, 2H), 1.49 - 1.53 (q, 2H), 1.65 - 1.68 (t, 1H), 2.19 (s, 3H), 2.35 (s, 3H), 3.45 (s, 3H) 3.51 (s, 3H), 3.58 (s, 1H), 3.80 (s, 1H), 4.11 (s, 2H), 4.41 - 4.43 (d, 1H), 4.88 (s, 2H), 4.96 - 5.18 (dd, 1H), 6.11-6.16 (m, 8H), 6.93 (s, 1H), 7.84 (s, 2H, D20 exchangeable), 8.60 (s, 1H, D20 exchangeable). Mass m/z: 692.0 (M++l).
4 1
-0
N
N N" - S H,N— 2 XSJ o 'H NMR (DMS0-d6) 5 (ppm): 1.67 - 1.70 (m, 2H), 1.74 - 1.77 (t, 2H), 1.79 - 1.83 (q, 2H), 1.85 - 1.88 (t, 1H), 1.99 (s, 3H), 2.75 (s, 3H), 3.49 (s, 3H), 3.54 (s, 1H), 3.80 (s, 1H), 4.11 (s, 2H), 5.11-5.13 (d, 1H), 5.25 - 5.29 (dd, 1H), 6.11 - 6.13 (d, 2H), 6.15 - 6.17 (d, 2H), 7.05 (s, 1H), 7.64 (s, 2H, D20 exchangeable), 9.12 (s, 1H, D20 exchangeable). Mass

Antimicrobial Activity
Determination of antimicrobial activity
The compounds of invention showed in vitro antibacterial activities when tested by the Agar Dilution Method as specified in documents published by the National Committee for Clinical Laboratory Standards (NCCLS), USA. (now CLSI). Briefly, the compounds of invention were weighed, dissolved in Dimethyl Sulfoxide, serially two fold diluted in the same solvent and then
incorporated into molten Mueller Hinton Agar in a petridish before solidification, with each petridish containing a different concentration of a compound
The bacterial inoculum was prepared by picking 3 to 5 well isolated bacterial colonies with the same morphological appearance from an 18-24 hours old culture with an inoculating loop, transferring the growth to a tube containing 3ml of normal saline and adjusting the turbidity of the saline suspension to 0.5 Mc Farland Turbidity Standard equivalent to a bacterial population of 1.5 x 108 colony forming units (CFU) per millilitre of suspension. The suspension was diluted 1:10 in saline (i.e. 0.5ml suspension + 4.5 ml saline) to get a bacterial population of 1.5 x 107 cfu/ml as inoculum.
The bacterial inoculum prepared in the above manner was inoculated onto petri dishes containing Mueller Hinton Agar which had earlier been incorporated with different dilutions of the compounds of invention by a Multipoint Inoculator with each inoculum spot containing approximately 1 x 104 colony forming units (CFU) of bacteria.
The inoculated petridishes were incubated at 35° C in an ambient atmosphere for 16-20 hours. The petridishes after incubation were placed on a dark non-reflecting surface and the Minimum Inhibitory Concentration (MIC) was recorded as the concentration, which showed no growth of the inoculated culture.
The following minimum inhibitory concentrations (ng/ml) were obtained for representative compounds of the invention, which are given in the Table 1 and Table 2, wherein N= no of strains tested.

We Claim:
1. Novel cephalosporins of formula (I)

their derivatives, analogs, tautomeric forms, stereoisomers, polymorphs, solvates, pharmaceutically acceptable salts, metabolites and prodrugs thereof wherein, R1 is selected from OR, where R represents hydrogen or alkyl groups of pharmaceutically acceptable salts and esters that are commonly employed in the cephalosporin chemistry. X1 is represented by O, S or S→O; X2 is represented by N or CH;
suitable groups represented by R2 are selected from hydrogen, linear or branched (C1-C4) alkyl groups consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t-butyl which are optionally substituted; haloalkyl groups consisting of chloromethyl, chloroethyl, trifluoromethyl, trifluoroethyl, dichloromethyl, dichloroethyl, trichloromethyl and difluoromethyl; furthermore R2 is optionally substituted by groups consisting of carboxylic acid and its derivatives, or may be a group of the formula:

suitable groups represented by R4 and R5 may be the same or different and independently represent hydrogen, substituted or unsubstituted linear or branched (C1-C4) alkyl groups consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t-butyl; haloalkyl groups consisting of chloromethyl, chloroethyl, trifluoromethyl, trifluoroethyl, dichloromethyl, dichloroethyl, trichloromethyl and difluoromethyl, which are optionally substituted; halogen atoms consisting of fluorine, chlorine, bromine, iodine; or it can be a group of the formula;
wherein R7 and R8 represent hydrogen, linear or branched (C1-C4) alkyl groups consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t-butyl which are optionally substituted;
suitable groups represented by R6 are selected from hydrogen, substituted or unsubstituted linear or branched (C1-C4) alkyl groups consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t-butyl; substituted alkyl protective groups consisting of straight, branched, partially cyclic, cyclic alkanoyloxyalkyl groups consisting of acetoxymethyl, acetoxyethyl, pivaloyloxymethyl, pivaloyloxyethyl and cyclohexaneacetoxyethyl; alkoxyformyloxyalkyl groups consisting of ethoxycarbonyloxy ethyl; alkoxyalkyl groups; 2-oxacycloalkyl groups; 2-oxo-l,3-dioxolylmethyl groups consisting of 4-methyl-2-oxo-l and 3-dioxol-5-ylmethyl group; 1-oxygenated- Ci to Ci2-alkyl groups; substituted aralkyl groups consisting of phenacyl and phthalidyl; aryl groups consisting of phenyl, tolyl, xylyl and indanyl;
T represents a quaternary nitrogen atom, which can be a part of an open chain system, or is an open chain attached to a cyclic system, or the nitrogen is attached directly to cyclic systems, which can have chiral, racemic, or meso substitution. This is represented by the general formulae I, II and III and details of the substitution are given below Formula I:
suitable groups represented by R8, R9 and Ri0 which may be same or different and independently represent hydrogen, lower alkyl (C1-C4) groups, hydroxyl (which are protected as benzyl ether), amino (which is protected as benzyl ether, benzyloxycarbonyl (Cbz), t-butoxycarbonyl (t-Boc), trityl, and trifluoracetyl), carboxylic acid (which is protected as alkyl ester); Rn represents lower alkyl (Cj-C3) groups; R12 and R]3 represent hydrogen or are combined together to form a 5 to 6 membered ring which may be saturated or unsaturated consisting of cyclohexyl, cyclopentyl and phenyl; any one of X or Y represents a quaternary nitrogen atom and the linkage to the cephalosporin moiety is through the quaternary nitrogen atom; Z is represented by hydrogen, hydroxyl (which is protected as benzyl ether), hydroxyl-diaryl-methyl groups consisting of hydroxy-diphenyl-methyl, chiral or racemic, substituted or unsubstituted, linear or branched (C1-C4) alkyl groups consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and t-butyl; alkoxy groups consisting of methoxy, ethoxy, n-propoxy and isopropoxy, which are optionally substituted; monoalkylamino groups consisting of -NHCH3, -NHC2H5, - NHC3H7 and -NHC6H13 which are optionally substituted; dialkylamino groups consisting of -N(CH3)2, -NCH3(C2H5) and -N(C2H5)2 which are optionally substituted; carboxylic acids and its derivatives consisting of amides, esters (consisting of methyl ester and ethyl ester); acylamino groups consisting of - NHC(=0)CH3, -NHC(=0)C2H5, -NHC(=0)C3H7 and -NHC(=0)C6H13, which are optionally substituted; alkoxyalkyl groups consisting of methoxymethyl, ethoxymethyl, methoxyethyl and ethoxyethyl, which are optionally substituted; the sulfamoyl group, aralkoxy groups consisting of phenylmethoxy, phenylethoxy and phenylpropoxy, which are optionally substituted; aryloxy groups consisting of phenoxy and napthoxy which are optionally substituted, and n is an integer in the range of 0 - 3; Formula II:
suitable groups represented by Rn are selected from lower alkyl (C1-C3) groups; R13 represents substituted lower alkyl groups selected from methyl, ethyl, propyl and isopropyl; R14 and R15 may be the same or different and are represented by substituted or unsubstituted alkyl radicals, groups consisting of phenyl, which is optionally substituted by groups consisting of halogens, haloalkyl, alkyl, alkoxy; bicyclic groups consisting of napthyl which is optionally substituted, optionally substituted carbocyclic groups, saturated and unsaturated heterocyclic groups consisting of furyl, piperdinyl and piperazinyl. R14 and R15 can together with the N atom form a three to seven membered cyclic ring, an unsaturated monocyclic aromatic rings consisting of pyridyl, which is optionally substituted; heterocyclic rings consisting of pyrrolidinyl, which is optionally substituted. Formula III:

suitable groups represented by R16 are hydrogen, lower alkyl (CrC3) groups or haloalkyl groups; R17 represents alkyl, haloalkyl and alkoxy groups selected from linear or branched (CrC4) alkoxy groups consisting of methoxy, ethoxy, n-propoxy and isopropoxy; X3 represents C, N; X4 represents O or S.
2. The compound of claim 1, selected from a group consisting of: (6R,7R) 7/3- {2- {2-Aminothiazol-4-yl}-2-[(Z)-methoxyimino]-acetylamino}- 3-[[N, N-dimethyl- N- [(R)-l-(4-chlorophenyl)]ethyl]ammonio]methyl-8- oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylate;
N-[[ {2-(4-Methoxybenzylcarbonyl)}-(6R,7R)7/3- {2-(2-aminotrityl-1,3- thiazol-4-yl)-2-[(Z)-methoxyimino]-acetylamino} -8-oxo-5-thia-1 -azabicyclo [4.2.0]oct-2-ene-3yl]methyl]-N,N-dimethyl-N-[(R)-l-(l,2,3,4- tetrahydronaphthyl)]ammonio]methyl]ethanaminium iodide; N-[[ {2-(4-Methoxybenzylcarbonyl)} -(6R,7R)7/3- {2-(2-amino-1,3-thiazol-4- yl)-2-[(Z)-methoxyimino]-acetylamino}-8-oxo-5-thia-1-azabicyclo[4.2.0] oct-2-ene-3 yljmethyl] -N,N-dimethy 1-N- [(R)-1 -(1,2,3,4-tetrahydronaphthyl)] ammonio]methyl]ethanaminium iodide;
(6R,7R)7/3- {2- {2-Aminothiazol-4-yl} -2-[(Z)-methoxyimino]-acetylamino} -
3-[N,N-dimethyl-N-[(R)-l-(l,2,3,4-tetrahydronaphthyl)]ammonio]methyl-8-
oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylate;
(6R,7R)7/5- {2- {2-Aminothiazol-4-yl} -2-[(Z)-methoxyimino]-acetylamino} -
3-[[N,N-dimethyl-N-[(S)-1 -(4-chlorophenyl)] ethyl]ammonio]methyl-8-oxo-
5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylate;
N-[[ {2-(4-Methoxybenzylcarbonyl)} -(6R,7R)7j3- {2-(2-aminotrityl-l ,3-
thiazol-4-yl)-2-[(Z)-methoxyimino]-acetylamino}-8-oxo-5-thia-l-azabicyclo
[4.2.0]oct-2-ene-3yl]methyl]-N,N-dimethyl-N-[(R)-l-(cyclohexyl)ethyl]
ethanaminium iodide;
(6R,7R)7/3- {2- {2-Aminothiazol-4-yl} -2-[(Z)-methoxyimino]-acetylamino} -
3-[N, N-dimethyl- N- [(R)-l-(cyclohexyl)ethyl]ammonio]methyl-8-oxo-5-
thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylate;
N-[[ {2-(4-Methoxybenzylcarbonyl)} -(6R,7R)7/3- {2-(2-aminotrityl-1,3-
thiazol-4-yl)-2-[(Z)-methoxyimino]-acetylamino} -8-oxo-5-thia-1 -azabicyclo
[4.2.0]oct-2-ene-3yl]methyl]-N-[(4-{2-fluoro-4-[3-(5-acetylamino methyl)-
l,3-oxazolidin-2-one]phenyl}-l-methylpiperazin-l-ium)iodide;
[(6R,7R)7/?- {2- {2-Aminotritylthiazol-4-yl} -2-[(Z)-methoxyimino]-acetyl
amino}-3-[(4-{2-fluoro-4-[3-(5-acetylaminomethyl)-l,3-oxazolidin-2-one]
phenyl} -1 -methylpiperazin-1 -ium)]methyl-8-oxo-5-thia-1 -azabicyclo
[4.2.0]oct-2-en-2-carboxylate;
N-[[ {2-(4-Methoxybenzylcarbonyl)}-(6R,7R)7/3- {2-(2-aminotrityl-1,3- thiazol-4-yl)-2-[(Z)-methoxyimino]-acetylamino} -8-oxo-5-thia-1 -azabicyclo
[4.2.0]oct-2-ene-3yl]methyl]-N-[(4-{2-fluoro-4-[3-(5-dichloroacetyl amino methyl)-1,3-oxazolidin-2-one]phenyl} -1 -methylpiperazin-1 -ium)iodide; [(6R,7R) 7/3- {2- {2-Aminotrityl thiazol-4-yl} -2-[(Z)-methoxyimino]-acetyl amino} -3-[(4- {2-fluoro-4-[3-(5-dichloroacetylaminomethyl)-1,3-oxazolidin- 2-one]phenyl} -1 -methylpiperazin-1 -ium)]methyl-8-oxo-5-thia-1 -azabicyclo [4.2.0]oct-2-en-2-carboxylate;
N-[[{2-(4-Methoxybenzylcarbonyl)}-(6R,7R) 7/3- {2-(2-aminotrityl-1,3- thiazol-4-yl)-2-[(Z)-methoxyimino]-acetylamino} -8-oxo-5-thia-1 -azabicyclo [4.2.0]oct-2-ene-3yl]methyl]-N-[(4-{2-fluoro-4-[3-(5-difluoroacetyl amino methyl)-1,3-oxazolidin-2-one]phenyl}-1 -methylpiperazin-1 -ium) iodide; [(6R,7R)7/3-{2-{2-Aminotritylthiazol-4yl}-2-[(Z)-methoxyimino]- acetylamino} -3-[(4- {2-fluoro-4-[3-(5-difluoroacetylaminomethyl)-1,3- oxazolidin-2-one]phenyl} -1 -methylpiperazin-1 -ium)]methyl-8-oxo-5-thia-1 - azabicyclo[4.2.0]oct-2-en-2-carboxylate and
7-( {(2Z)-2-(2-Amino-1,3-thiazol-4-yl)-2-[(2-methoxy-2-oxoethoxy)imino] acetyl} amino)-3 - [[N,N-dimethyl-N- [(R)-1 -(4-chlorophenyl)] ethyl] ammonio] methyl-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylate.
3. A pharmaceutical composition comprising a compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof as an active ingredient along with a pharmaceutically acceptable carrier, diluent, excipient or solvate.
4. A pharmaceutical composition as claimed in claim 3, wherein the pharmaceutical composition is in the form of a tablet, capsule, powder, syrup, solution, aerosol or suspension.
5. A pharmaceutical composition as claimed in claim 3, wherein the amount of the compound of claim 1 in the composition is less than 70 % by weight.
6. A method for the treatment of infectious diseases which comprises administering a compound of claim 1 or a pharmaceutically acceptable salt thereof to human or animals.

Documents:

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266-CHE-2006 AMENDED CLAIMS 28-01-2013.pdf

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266-che-2006 claims 20-02-2007.pdf

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Patent Number

257957

Indian Patent Application Number

266/CHE/2006

PG Journal Number

48/2013

Publication Date

29-Nov-2013

Grant Date

22-Nov-2013

Date of Filing

20-Feb-2006

Name of Patentee

ORCHID RESEARCH LABORATORIES LTD

Applicant Address

ORCHID TOWERS, 313, VALLUVAR KOTTAM HIGH ROAD, NUNGAMBAKKAM, CHENNAI-600 034,

Inventors:

#	Inventor's Name	Inventor's Address
1	UMA RAMACHANDRAN	ORCHID CHEMICALS & PHARMACEUTICALS LTD, 476/14, OLD MAHABALIPURAM ROAD, SHOLINGANLLUR, CHENNAI-600119

PCT International Classification Number

A61K31/00

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA