FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rule l3)
1. TITLE OF THE INVENTION
TRISUBSTITUTED BIARYL OXAZOLIDINONES AS AN ANTIMICROBIAL AGENTS
2. APPLICANT(S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS: Wockhardt Limited, D4-MIDC Area, Chikalthana,
Aurangabad - 431 210 (M.S.) INDIA.
3. PREAMBLE TO THE DESCRIPTION
The invention relates to substituted biaryloxazolidinones having antimicrobial
activity.
The following specification particularly describes the invention and the manner in
which it is to be performed.


Field of the Invention
The present invention relates to the family of substituted biaryl oxazohdinones having antimicrobial activity. The invention also relates to pharmaceutical compositions containing the compounds and to methods for treating or preventing microbial infections using the compounds of present invention.
Background of the Invention
Oxazohdinones represent a novel chemical class of synthetic antimicrobial agents, with a first representative, Linezolid, of this class. Oxazohdinones display activity against Gram-positive human and veterinary pathogens including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin resistant enterococci (VRE) and P-lactam resistant Streptococcus pneumoniae (PRSP). Notwithstanding the foregoing, there is an ongoing need for new antibacterial agent. There are several patents cited in the literature, which refer to oxazohdinones having antibacterial activity. Biaryl moiety bearing oxazohdinones are described in following patents applications; US 2004/147760 Al and WO 2003/072553 Al, WO 2001/94342 Al, WO 2004/048350 A2, WO 2004/056819 Al, WO 2005/058886, WO 2005/ 012271 A2. The invention provides novel biaryl oxazohdinones.
Summary of the Invention
In one aspect, the invention provides novel (dialkyl hydroxyl methane)pyridino phenyl oxazohdinones of Formula (I),

wherein,
R1 and R2 are independently selected from a group of C1-C6 alkyl, substituted alkyl, heteroaryl or substituted heteroaryl.

R3 is -H, C1-C6 alkyl group, substituted alkyl group or PO3H2
R4 is selected from a group of
(i) - C(X)NR6R.7, wherein X = O or S, and R6 and R7 are independently selected from H, C1-6 alkyl group or substituted alkyl group.
(ii) -CH2-Y-R.8, wherein Y = -NH or O; and R8 is alkanoyl, aminoalkanoyl, alkoxycarbonyl or heteroaryl group.
R5 is selected from -H or a halogen.
and pharmaceutically acceptable salts thereof.
In another aspect, there is provided processes for preparation of novel (dialkyl hydroxyl methane) pyridino phenyl oxazohdinones of Formula (I) and various intermediates used in the process thereof.
Other aspects will be set forth in the description which follows, and in part will be apparent from the description or may be learnt by the practice of the invention.
Detailed Description of the Invention
In one of the aspect, invention provides novel (dialkyl hydroxyl methane)pyridino phenyl oxazohdinones of Formula (I),

wherein,
Ri and R2 are independently selected from a group of C1-C6 alkyl, substituted alkyl, heteroaryl or substituted heteroaryl.

R3 is -H, C1-C6 alkyl group, substituted alkyl group or PO3H2
R4 is selected from a group of
(i) - C(X)NR6R7, wherein X = O or S, and R6 and R7 are independently selected from H, C1-6 alkyl group or substituted alkyl group.
(ii) -CH2-Y-R8, wherein Y = -NH or O; and R8 is alkanoyl, aminoalkanoyl, alkoxycarbonyl or heteroaryl group.
R5 is selected from -H or a halogen.
and pharmaceutically acceptable salts thereof.
Description of terms
The terms " C1-C6 alkyl" refer to saturated, straight, or branched chain hydrocarbon radicals derived from a hydrocarbon moiety containing between one and six carbon atoms by removal of a single hydrogen atom. Exemplary C1-C6 alkyl radicals include but are not limited to methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, and n-hexyl.
The term "substituted alkyl" refers to a " C1-C6 alkyl" group as previously defined, substituted by independent replacement of one, two or three of the hydrogen atoms thereon with substituents including, but not limited to, -F, -CI, -Br, -I, -OH, -NO2, -CN, C3-C12-cycloalkyl, aryl, heteroaryl or C1-C6 alkoxy group.
The term "C3-C12-cycloalkyl" denotes a monovalent group derived from a monocyclic or bicyclic saturated carbocyclic ring compound by the removal of a single hydrogen atom. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [2.2.1]heptyl, and bicyclo [2.2.2] octyl.


The term "alkanoyl" unless otherwise indicated, includes -C(O)- C1-C6 alkyl groups wherein " C1-C6 alkyl group" is as defined above.
The term "aminoalkanoyl" group may be an amino acid residue derived from one of the 20 naturally occurring amino acids or the optically active isomers thereof, or the racemic mixtures thereof. The amino acid residue is derived from, but not limited to, alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine.
The term "alkoxycarbonyl" represents an ester group, i.e. an C1-C6 alkoxy group, attached to the parent molecular moiety through a carbonyl group such as methoxycarbonyl, ethoxycarbonyl and the like.
The term " C1-C6 alkoxy" refers to a C1-C6 alkyl group, as previously defined, attached to the parent molecular moiety through an oxygen atom. Examples of C1-C6 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, tert-butoxy, neopentoxy and n-hexoxy.
The term "heteroaryl" refers to a cyclic aromatic radical having from five to ten ring atoms of which one ring atom is selected from S, O and N; one, two, or three ring atoms may be additional heteroatom's independently selected from S, O and N; and the remaining ring atoms are carbon, the radical being joined to the rest of the molecule via any of the ring atoms, such as, for example, pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, and the like.
The term "substituted heteroaryl " refers to a " heteroaryl " group as previously defined, substituted by independent replacement of the hydrogen atoms thereon with substituents including, but not limited to, -F, -CI, -Br, -I, -OH, -NO2, -CN, C1-C6 alkyl or C3-C12-cycloalkyl.


The terms "halo", "halide", and "halogen" refer to an atom selected from fluorine, chlorine, bromine, and iodine.
The term "pharmaceutically acceptable salts" refers to those carboxylate salts, esters, and prodrugs of the compound of the invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention. Pharmaceutically acceptable salts are well known in the art and refer to the relatively non-toxic, inorganic and organic acid addition salts of the compound of the present invention. For example, S. M. Berge, et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977) which is incorporated herein by reference. The salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base function with a suitable organic acid. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using


counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.
"therapeutically effective amount" is an amount of a compound of the present invention that when administered to a patient ameliorates a symptom of bacterial infection.
Numerous asymmetric centers may exist in the compounds of the present invention. Except where otherwise noted, the present invention contemplates the various stereoisomers and mixtures thereof.
In the chemical structures depicted, a wavy line, indicates that the stereochemistry at the chiral center to which the wavy line is connected is either an R or S configuration where the wavy line is connected to a carbon atom.
Unless indicated otherwise, "compound of the invention" or "compounds of the invention" includes the compound itself as well as pharmaceutically acceptable salts thereof.
An embodiment of the invention is to provide novel compounds of Formula (I),


R1 0R

(I)
wherein,
R1 and R2 are independently selected from a group of C1-C6 alkyl, substituted alkyl, heteroaryl or substituted heteroaryl.
R3 is -H, C1-C6 alkyl group, substituted alkyl group or PO3H2
R4 is selected from a group of


(i) - C(X)NR6R7, wherein X = O or S, and R6 and R7 are independently selected from H, C1-6 alkyl group or substituted alkyl group.
(ii) -CH2-Y-R8, wherein Y = -NH or O; and R8 is alkanoyl, aminoalkanoyl, alkoxycarbonyl or heteroaryl group.
R5 is selected from -H or a halogen.
and pharmaceutically acceptable salts thereof.
Specific compounds of invention are:
N-{[(5S)-3-{3-fluoro-4-[6-(l-hydroxy-l-methylethyl)pyridin-3-yl]phenyl}-2-oxo-l,3-oxazolidin-5-yl]methyl}acetamide;
(5R)-3- {3-fluoro-4-[6-( 1 -hydroxy-1 -methylethyl)pyridin-3-yl]phenyl} -2-oxo-1,3-oxazolidine-5-carboxamide;
Methyl {[(5S)-3-{3-fluoro-4-[6-(l-hydroxy-l-methylethyl)pyridin-3-yl]
phenyl} -2-oxo-1,3 -oxazolidin-5-yl]methyl} carbamate;
(5/?)-3-{3-fluoro-4-[6-(l-hydroxy-l-methylethyl) pyridin-3-yl]phenyl}-5-
[(isoxazol-3-yloxy)methyl]-1,3-oxazolidin-2-one;
A^-{[(55)-3-(3-fluoro-4-{6-[3,3,3-trifluoro-l-hydroxy-l-(2,2,2-trifluoroethyl) propyl] pyridin-3-yl}phenyl)-2-oxo-l,3-oxazolidin-5-yl]methyl}acetamide;
Diastereomeric mixture of N-{[(5S)-3-{3-fluoro-4-[6-(l-hydroxy-l-
methylpropyl) pyridin-3 -yl]phenyl} -2-oxo-1,3 -oxazolidin-5-yl]methyl}
acetamide;
Diastereomer A & B of N-{[(5S)-3-{3-fluoro-4-[6-(l-hydroxy-l-methylpropyl) pyridin-3-yl] phenyl}-2-oxo-1,3-oxazolidin-5-yl]methyl} acetamide;


l-[5-(4-{(5iS)-5-[(acetylamino) methyl]-2-oxo-l,3-oxazolidin-3-yl}-2-fluoro phenyl)pyridin-2-yl]-l-methylethyl L-alaninate.methane sulonic acid salt;
l-(5-{4-[(5S)-5-(acetamide methyl)-2-oxo-l,3-oxazolidin-3-yl]-2-fluoro
phenyl}pyridin-2-yl)-l-methylethyl L-valinate methanesulfonate;
l-[5-(4-{(5S)-5-[(acetylamino) methyl]-2-oxo-l,3-oxazolidin-3-yl}-2-fluoro phenyl) pyridin-2-yl]-l-rnethylethyl glycinate.methanesulfonic acid salt and
l-[5-(4-{(5S)-5-[(acetylamino) methyl]-2-oxo-l,3-oxazolidin-3-yl}-2-fluoro phenyl) pyridin-2-yl]-l-methylethyl dihydrogen phosphate.
In another aspect, the invention further provides processes of preparation of compounds of Formula (I) as depicted in scheme-a and scheme-b which includes the steps of:

n-BuLi
Br-^^Br —
R2 2

R1-/-/ V-Br + Bu3Sn-\J>-NvJ^
R2 N

R4


(Ph3)2PdCI2




1. N-Boc-L-amino acid R1
DCC, DMAP 2.Acid, solvent
m-CPBA 2.) 5%, Pd/C, H2
1.)(BnO)2P-N(i-C3H7)2 R1 OR

la

Scheme-a


lb



Raney Nickel

Scheme-b
A compound of Formula (3) may be prepared by any of the methods known in the art including those described in Tetrahedron Letters, 41 (2000), p 335 or by procedures that would be well known to one of ordinary skill in the art of synthetic organic chemistry. Compound (3) on condensation with compound of Formula (5) (where compound (5) is prepared by refluxing compound of Formula 4 with hexamethylditin as depicted in scheme-c) in presence of a base provide biaryl oxazolidinone compound of Formula (I) of the invention. Alternatively, compound (I) of the invention can be prepared by reduction of a mixture of optically pure or diastereomeric mixture of oxazolidinone compound of Formula (6) as depicted in scheme-b. Compound of Formula (I) when stirred with a solution of N-protected-L-amino acid residue in presence of a coupling reagent and N-protected L-amino acid ester compound so obtained on heating with methanesulfonic acid afford biaryl oxazolidinone amino acid ester compound of Formula la. Compound of Formula (I) when stirred with phosphate primer provide dibenzyl phosphate ester that on reduction afford biaryl oxazolidinone phosphate compound of Formula lb.
In yet another aspect of invention there is provided a method of preparation of the compound of Formula (I) that includes the steps of converting compound of Formula (4) into compound of Formula (5) using a suitable catalyst in presence of an aprotic organic solvent.
A further embodiment of the invention is to provide a method of preparation of the compound of Formula (I) that includes the steps of converting compound of Formula (4) into compound of Formula (5) under reflux using a suitable catalyst like hexamethylditin and dichlorobistriphenylphosphine palladium (II) or both in presence


of an aprotic organic solvent like 1,4-dioxane, dimethyl sulfoxide, dimethylformamide, hexamethylphosphorotriamide and the like.
O O
/=\ K0 [(n-C4H8)3Sn]2 /= ^
F * F 5
In yet another aspect of invention there is provided a method of preparation of the compounds of Formula (I) that includes the steps of condensing compound of Formula (3) and (5) with a base in an aprotic organic solvent in presence of a catalyst to provide compound of Formula (I).
Another embodiment of the invention is to provide a method of preparation of the
compounds of Formula (I) that includes the steps of condensing compound of
Formula (3) and (5) with a base like triethylamine in an aprotic organic solvent such
as N,N-dimethylformamide, 1,4-dioxane, dimethyl sulfoxide,
hexamethylphosphorotriamide and the like, in presence of a catalyst like dichlorobistriphenyphospine palladium (II) (10 mole %) to provide compound of Formula (I).
In yet another aspect of the invention, there is provided a method of preparation of the compound of Formula (I) that includes the steps of converting compound of the Formula (6) into compound of Formula (I) using a reducing agent in presence of an alcoholic solvent.
Another embodiment of the invention is to provide a method of preparation of the compound of Formula (I) that includes the steps of heating a reaction mixture of compound (6) with a reducing agent like Raney Nickel, palladium charcoal and the like, in presence of an alcoholic solvent like ethanol, methanol and the like.
In yet another aspect of the invention there is provided a method of preparation of the compound of Formula la that includes the steps of converting compound of Formula (I) into biaryl oxazolidinone amino acid ester compound of Formula la using a solution of suitable N-protected amino acid residue in a halogenated solvent in


presence of a coupling reagent and a nucleophilic catalyst and hydrolysing the N-Boc protected L-amino acid ester compound so obtained with suitable acid.
Another embodiment of the invention is to provide a method of preparation of the compound of Formula la that includes the steps of converting compound of Formula (I) into biaryl oxazolidinone amino acid ester compound of Formula la using a solution of suitable N-protected amino acid residue such as w-tert.-butoxycarbonyl-L-amino acid in a halogenated solvent like dichloromethane, chloroform, carbontetrachloride and the like, in presence of a coupling reagent like dicyclohexylcarbodiimide, an azole like tetrazole and a nucleophilic catalyst such as N,N-dimethylaminopyridine and hydrolysing the N-Boc protected L-amino acid ester compound so obtained with a suitable acid like methanesulfonic acid.
In yet another aspect of the invention there is provided a method of preparation of the compound of Formula lb that that includes the steps of converting compound of Formula (I) into biaryl oxazolidinone phosphate compound of Formula lb using a phosphate primer in presence of a halogenated solvent and reducing dibenzyl phosphate ester so obtained with a reducing agent.
Another embodiment of the invention is to provide a method of preparation of the compound of Formula lb that that includes the steps of converting compound of Formula (I) into biaryl oxazolidinone phosphate compound of Formula lb using a phosphate primer like dibenzyl-N,N-diisopropyl phosphoramidite and tetrazole in presence of a halogenated solvent like dichloromethane, chloroform, carbontetrachloride and the like, and reducing dibenzyl phosphate ester so obtained with a reducing agent such as 5% palladium on carbon.
The oxazolidinone antibacterial agents of this invention have potential for treatment of Gram-positive infections including multi-resistant strains. These compounds are useful for the treatment of Gram-positive or Gram-negative microbial infections in humans and other warm-blooded animals by either parenteral, oral or topical administration. The infection in human and other warm-blooded animals can be systemic or topical.


The compounds of this invention are useful to prevent infections caused by Gram-positive and Gram-negative bacteria by administering the compounds to a subject that is at risk for developing an infection caused by Gram-positive or Gram-negative bacteria. A subject at risk for developing an infection may be a health care worker, surgical patient and the like.
The compositions of the present invention include such as suspensions, solutions, elixirs, aerosols, and solid dosage forms. Carriers as described in general above are commonly used in the case of oral solid preparations (such as powders, capsules and tablets), with the oral solid preparations being preferred over the oral liquid preparations. The most preferred oral solid preparation is tablets.
Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are employed. Examples of suitable carriers include excipients such as lactose, white sugar, sodium chloride, glucose solution, urea, starch, calcium carbonate, kaolin, crystalline cellulose and silicic acid, binders such as water, ethanol, propanol, simple syrup, glucose, starch solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose, potassium phosphate and polyvinyl pyrrolidone, disintegrants such as dried starch, sodium alginate, agar powder, laminaria powder, sodium hydrogen carbonate, calcium carbonate, Tween (fatty acid ester of polyoxyethylenesorbitan), sodium lauryl sulfate, stearic acid monoglyceride, starch, and lactose, disintegration inhibitors such as white sugar, stearic acid glyceryl ester, cacao butter and hydrogenated oils, absorption promoters such as quaternary ammonium bases and sodium lauryl sulfate, humectants such as glycerol and starch, absorbents such as starch, lactose, kaolin, bentonite and colloidal silicic acid, and lubricants such as purified talc, stearic acid salts, boric acid powder, polyethylene glycol and solid polyethylene glycol.
The tablet, if desired, can be coated, and made into sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets, or tablets comprising two or more layers.


If desired, tablets may be coated by standard aqueous or non-aqueous techniques. In molding the pharmaceutical composition into pills, a wide variety of conventional carriers known in the art can be used. Examples of suitable carriers are excipients such as glucose, lactose, starch, cacao butter, hardened vegetable oils, kaolin and talc, binders such as gum arabic, tragacanth, gelatin, and ethanol, and disintegrants such as laminaria and agar.
In molding the pharmaceutical composition into a suppository form, a wide variety of carriers known in the art can be used. Examples of suitable carriers include polyethylene glycol, cacao butter, higher alcohols, gelatin, and semi-synthetic glycerides.
A second preferred method is parenteral i.e. for intramuscular, intravenous or subcutaneous administration.
A third preferred route of administration is topical, for which creams, ointments, shampoos, lotions, dusting powders and the like are well suited. Generally, an effective amount of the compound according to this invention in a topical form is from about 0.1% w/w to about 10% w/w of the total composition. Preferably, the effective amount of the compound of the invention is 1% w/w of the total composition.
In addition to the common dosage forms set out above, the compounds of the present invention may also be administered by controlled release means and/or delivery devices such as those described in U.S. Patent Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123 and 4,008,719; the disclosures of which are hereby incorporated by reference.
Desirably, each tablet contains from about 200 mg to about 1500 mg of the active ingredient. Most preferably, the tablet, cachet or capsule contains either one of three dosages, about 200 mg, about 400 mg, or about 600 mg of the active ingredient.
When the pharmaceutical composition is formulated into an injectable preparation, in formulating the pharmaceutical composition into the form of a solution or suspension,


all diluents customarily used in the art can be used. Examples of suitable diluents are water, ethyl alcohol, polypropylene glycol, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol, and sorbitan esters. Sodium chloride, glucose or glycerol may be incorporated into a therapeutic agent.
The antimicrobial pharmaceutical composition may further contain ordinary dissolving aids, buffers, pain-alleviating agents, and preservatives, and optionally coloring agents, perfumes, flavors, sweeteners, and other drugs.
For topical application, there are employed as non-sprayable forms, viscous to semisolid or solid forms comprising a carrier compatible with topical application and having a dynamic viscosity preferably greater than water. Suitable formulations include but are not limited to solutions, suspensions, emulsions, creams, ointments, powders, liniments, salves, aerosols, etc., which are, if desired, sterilized or mixed with auxiliary agents, e.g. preservatives, antioxidants, stabilizers, wetting agents, buffers or salts for influencing osmotic pressure, etc. For topical application, also suitable are sprayable aerosol preparations wherein the active ingredient preferably in combination with a solid or liquid inert carrier material.
A specific embodiment of the invention is the preparation of stable compositions of the compounds of the invention of Formula I. Such stable compositions can be advantageously made through the use of selective stabilizers. Different stabilizers are known to those skilled in the art of making pharmaceutical compositions. Of special utility for making storage stable compositions of the compound of the invention of Formula I, stabilizers such as disodium ethylenediaminetetraacetic acid (EDTA), tromethamine, cyclodextrins such as gamma-cyclodextrin, hydroxy-propyl-gamma-cyclodextrin have been found to be useful.
In a specific embodiment of the invention, the pharmaceutical compositions contain an effective amount of the active compounds of the invention, its derivatives, polymorphs, salts or hydrates thereof described in this specification as hereinbefore described in admixture with a pharmaceutically acceptable carrier, diluent or excipients, and optionally other therapeutic ingredients.


The compounds of this invention are useful antimicrobial agents effective against various humans and veterinary pathogens specially including Linezolid-resistant strains.
For the purpose of this invention the pharmaceutical compositions may contain the active compounds of the invention, their derivatives, polymorphs, salts and hydrates thereof, in a form to be administered alone, but generally in a form to be administered in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice. Suitable carriers which can be used are, for example, diluents or excipients such as fillers, extenders, binders, emollients, wetting agents, disintegrants, surface active agents and lubricants which are usually employed to prepare such drugs depending on the type of dosage form.
Any suitable route of administration may be employed for providing the patient with an effective dosage of the compound of the invention their derivatives, polymorphs, salts and hydrates thereof. For example, oral, rectal, vaginal, parenteral (subcutaneous, intramuscular, intravenous), nasal, transdermal, topical and like forms of administration may be employed. Dosage forms include (solutions, suspensions, etc) tablets, pills, powders, troches, dispersions, suspensions, emulsions, solutions, capsules, injectable preparations, patches, ointments, creams, lotions, shampoos and the like.
The prophylactic or therapeutic dose of the compounds of the invention, their derivatives, polymorphs, salts or hydrates thereof, in the acute or chronic management of disease will vary with the severity of condition to be treated, and the route of administration. In addition, the dose, and perhaps the dose frequency, will also vary according to the age, body weight and response of the individual patient. In general, the total daily dose range, for the compounds of the invention, the derivatives, polymorphs, salts or hydrates thereof, for the conditions described herein, is from about 10 mg to about 5000 mg. Preferably, a daily dose range should be between about 100 mg to 1500 mg, in single or divided dosage. It may be necessary to use dosages outside these ranges in some cases as will be apparent to those skilled in the art.


Further, it is noted that the clinician or treating physician will know how and when to interrupt, adjust, or terminate therapy in conjunction with individual patient's response. The term "an amount sufficient to eradicate such infections but insufficient to cause undue side effects" is encompassed by the above - described dosage amount and dose frequency schedule, "therapeutically effective amount" is the amount required to provide a desirable biological effect of restricting the growth of bacteria or killing bacteria.
The term patient as used herein is taken to mean birds, fishes and mammals, for example, humans cats, dogs, horses, sheep, bovine cows, pigs, lambs, rats, mice and guinea pigs.
Pharmaceutical compositions of the invention suitable for oral administration may be presented as discrete units such as capsules, cachets, or tablets, or aerosol sprays, each containing a predetermined amount of the active ingredient, as a powder or granules, or as a solution or a suspension in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion. Such compositions may be prepared by any of the methods of pharmacy, but all methods include the step of bringing into association the active ingredient with the carrier, which constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation.
The invention is further defined by reference to the following examples describing in detail the preparation of the composition of the invention as well as their utility. It will be apparent to those skilled in the art that many modifications, both to materials and methods may be practiced without departing from the purpose and scope of this invention.
The present invention is further illustrated by the following example which are provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.


Experimental
The following abbreviation are used in the text: n-BuLi for n-Butyl Lithium, TLC for Thin Layer Chromatography, MP for Melting Point, MF for Molecular Formula, DCC for dicyclohexylcarbodiimide, DMAP for N,N-dimethylaminopyridine, m-CPBA for meta-chloro per benzoic acid.
Example-1: Diastereomer A of N-([(5S)-3-(3-fluoro-4-["6-(l-hydroxy-l-methylpropyl)payridin-3-yl]phenyl} -2-oxo-1,3 -oxazolidin-5-yl]methyl} acetamide

A mixture of AL({(55)-3-[3-fluoro-4-(tributylstannanyl)phenyl]-2-oxo-l,3-oxazolidin-5-yl}methyl)acetamide (39.33 g, 72.7 mmol), 2-(5-bromopyridin-2-yl)propan-2-ol (23.69 g, 109 mmol) and triethylamine (20.11 ml, 145 mmol) in N,N-dimethyl formamide (160 ml) was flushed with continuous flow of argon under stirring for 15 min. dichloro bistriphenylphosphine palladium (II) (3.8 g) was added to the reaction mixture under argon. Reaction mixture was heated at 100 °C for 16 hr. It was cooled to room temperature, and poured on water, extracted with ethyl acetate was washed with water (250 ml). Layers were separated. Organic layer was dried and concentrated, the residue was purified by flash column chromatography to obtain title compound as a solid in 8.0 g quantity in 28% yield. Mass (M+l) for C20H22FN3O4 = 388.1 MP: 192-193 °C
Example-2: Diastereomer A of N-([(5S)-3-(3-fluoro-4-["6-(l-hydroxy-l-methylpropyl)payridin-3-yl]phenyl} -2-oxo-1,3 -oxazolidin-5-yl]methyl} acetamide
O
/—\\ //—\\ /r~N I
/ XN^ yj ^^NH2
F o
By using the procedure described in Example-1 and by using (5/?)-3-{3-fluoro-4-[6-(tributylstannanyl)pyridin-3-yl]phenyl}-2-oxo-l,3-oxazolidine-5-carboxamide in the


place of N-({(5^)-3-[3-fluoro-4-(tributylstannanyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide, the title compound was obtained in 25% yield. Mass (M+l) for Ci8Hi8FN304 = 360.1 MP: 188-190 °C.
Example-3: Diastereomer A of N-([(5S)-3-(3-fluoro-4-["6-(l-hydroxy-l-methylpropyl)payridin-3-yl]phenyl} -2-oxo-1,3 -oxazolidin-5-yl]methyl} acetamide
o

N I H
O
By using the procedure described in Example-1 and by using methyl ({(55)-3-[3-fluoro-4-(tributylstannanyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)carbamate in the place of A^-({(55)-3-[3-fluoro-4-(tributylstannanyl)phenyl]-2-oxo-l,3-oxazolidin-5-yl}methyl)acetamide, the title compound was obtained in 25% yield. Mass (M+l) for C20H22FN3O5 = 404.1 MP: 220-222 °C.
Example-4: Diastereomer A of N-([(5S)-3-(3-fluoro-4-["6-(l-hydroxy-l-methylpropyl)payridin-3-yl]phenyl} -2-oxo-1,3 -oxazolidin-5-yl]methyl} acetamide
O

By using the procedure described in Example-1 and by using (5J?)-3-[3-fluoro-4-(tributylstannanyl)phenyl]-5-[(isoxazol-3-yloxy)methyl]-1,3-oxazolidin-2-one in the place of N-({(S^-S-fS-fiuoro4-Ctributylstannanyl)pheny]-2-oxo-l,3-oxazolidin-S-yl}methyl)acetamide, the title compound was obtained in 22 % yield. Mass (M+l) for C21H20FN3O5 = 414.1 MP: 182-184 °C.
Example-5: Diastereomer A of N-([(5S)-3-(3-fluoro-4-["6-(l-hydroxy-l-methylpropyl)payridin-3-yl]phenyl} -2-oxo-1,3 -oxazolidin-5-yl]methyl} acetamide

MeO
7—v\ /;—<,\ /?— N i
-v
o
By using the procedure described in Example-1 and by using 2-(5-bromopyridin-2-yl)-l-methoxypropan-2-ol in the place of 2-(5-bromopyridin-2-yl)propan-2-ol, the title compound was obtained in 24 % yield. Mass (M+l) for C20H20C12FN3O4 = 418.1 MP: 112-114 °C.
Example-6: Diastereomer A of N-([(5S)-3-(3-fluoro-4-["6-(l-hydroxy-l-methylpropyl)payridin-3-yl]phenyl} -2-oxo-1,3 -oxazolidin-5-yl]methyl} acetamide

MeO
o
By using the procedure described in Example-1 and by using 2-(5-bromopyridin-2-yl)-1 -methoxypropan-2-ol and (5i?)-3- {3-fluoro-4-[6-(tributylstannanyl)pyridin-3-yl]phenyl}-2-oxo-l,3-oxazolidine-5-carboxamide the title compound may be obtained.
Example-7: Diastereomer A of N-([(5S)-3-(3-fluoro-4-["6-(l-hydroxy-l-methylpropyl)payridin-3-yl]phenyl} -2-oxo-1,3 -oxazolidin-5-yl]methyl} acetamide

By using the procedure described in Example-1 by using 2-(5-bromopyridin-2-yl)-l,3-dimethoxypropan-2-ol in the place of 2-(5-bromopyridin-2-yl)propan-2-ol, the title compound was obtained in 24 % yield. Mass (M+l) for C^aFNsOe = 448.1 MP: 126-128 °C.
Example-8: Diastereomer A of N-([(5S)-3-(3-fluoro-4-["6-(l-hydroxy-l-methylpropyl)payridin-3-yl]phenyl} -2-oxo-1,3 -oxazolidin-5-yl]methyl} acetamide

MeO' MeO-
O
By using the procedure described in Example-1 by using 2-(5-bromopyridin-2-yl)-
1,3-dimethoxypropan-2-ol and (5R)-3- {3-fluoro-4-[6-(tributylstannanyl)pyridin-3-
yl]phenyl}-2-oxo-l,3-oxazolidine-5-carboxamide, the title compound may be
obtained.
Example-9: Diastereomer A of N-([(5S)-3-(3-fluoro-4-["6-(l-hydroxy-l-methylpropyl)payridin-3-yl]phenyl} -2-oxo-1,3 -oxazolidin-5-yl]methyl} acetamide
By using the procedure described in Example-1 by using 3-(5-bromopyridin-2-yl)-l,l,l,5,5,5-hexafluoropentan-3-ol in the place of 2-(5-bromopyridin-2-yl)propan-2-ol, the title compound may be obtained.
Example-10: Diastereomer A of N-([(5S)-3-(3-fluoro-4-["6-(l-hydroxy-l-methylpropyl)payridin-3-yl]phenyl} -2-oxo-1,3 -oxazolidin-5-yl]methyl} acetamide

By using the procedure described in Example-1 by using 2-(5-bromopyridin-2-yl)-l,3-dichloropropan-2-ol in the place of 2-(5-bromopyridin-2-yl)propan-2-ol, the title compound may be obtained.
Example-11: Diastereomer A of N-([(5S)-3-(3-fluoro-4-["6-(l-hydroxy-l-methylpropyl)payridin-3-yl]phenyl} -2-oxo-1,3 -oxazolidin-5-yl]methyl} acetamide

By using the procedure described in Example-1 by using 2-(5-bromopyridin-2-yl)-l,3-dicyclopropylpropan-2-ol in the place of 2-(5-bromopyridin-2-yl)propan-2-ol, the title compound may be obtained.
Example-12: Diastereomer A of N-([(5S)-3-(3-fluoro-4-["6-(l-hydroxy-l-methylpropyl)payridin-3-yl]phenyl} -2-oxo-1,3 -oxazolidin-5-yl]methyl} acetamide

F o
A diastereomeric mixture of N-{[(5.S)-3-{3-fluoro-4-[6-(3-hydroxy-l,l-
dioxidotetrahydro thiophen-3-yl)pyridin-3-yl]phenyl}-2-oxo-l,3-oxazolidin-5-
yljmethyl} acetamide (2.16 mmol), in ethanol (12 volumes) was added activated Raney Nickel (10 gm) Reaction mixture was heated at 70-75 °C for 18 hours. Reaction mixture was cooled to room temperature, filtered through a celite bed. The bed was washed with ethanol. Filtrate was concentrated under vacuum and the residue was purified by using silica gel column chromatography to provide title compound in 48% yield.
Mass (M+l) for C21H24FN3O4 = 402.1 MP: 154-156 °C.
Example-13: Diastereomer A of N-([(5S)-3-(3-fluoro-4-["6-(l-hydroxy-l-methylpropyl)payridin-3-yl]phenyl} -2-oxo-1,3 -oxazolidin-5-yl]methyl} acetamide

By using the procedure described in Example-12 and by using optically pure
diastereomer A of A^-{[(55)-3-{3-fluoro-4-[6-(3-hydroxy-l,l-
dioxidotetrahydrothiophen-3 -yl)pyridin-3 -yliphenyl} -2-oxo-1,3 -oxazolidin-5-yl]methyl} acetamide, the title compound may be obtained.


Example-14: Diastereomer A of N-([(5S)-3-(3-fluoro-4-["6-(l-hydroxy-l-methylpropyl)payridin-3-yl]phenyl} -2-oxo-1,3 -oxazolidin-5-yl]methyl} acetamide

By using the procedure described in Example-12 and by using optically pure
diastereomer B of N-{[(55)-3-{3-fluoro-4-[6-(3-hydroxy-l,l-
dioxidotetrahydrothiophen-3-yl)pyridin-3-yl]phenyl}-2-oxo-l,3-oxazolidin-5-yl]methyl}acetamide, the title compound may be obtained.
Example-15: Diastereomer A of N-([(5S)-3-(3-fluoro-4-["6-(l-hydroxy-l-methylpropyl)payridin-3-yl]phenyl} -2-oxo-1,3 -oxazolidin-5-yl]methyl} acetamide

O
By using the procedure described in Example-12 and by using diastereomeric mixture of (5R)-3-{3-fluoro-4-[6-(3-hydroxy-l,l-dioxidotetrahydrothiophen-3-yl)pyridin-3-yl]phenyl}-2-oxo-l,3-oxazolidine-5-carboxamide, the title compound may be obtained.
Example-16: Diastereomer A of N-([(5S)-3-(3-fluoro-4-["6-(l-hydroxy-l-methylpropyl)payridin-3-yl]phenyl} -2-oxo-1,3 -oxazolidin-5-yl]methyl} acetamide

0
By using the procedure described in Example-12 and by using optically pure diastereomer A of (5/?)-3-{3-fluoro-4-[6-(3-hydroxy-l,l-dioxidotetrahydrothiophen-3-yl)pyridin-3-yl]phenyl}-2-oxo-l,3-oxazolidine-5-carboxamide, the title compound may be obtained.
Example-17: Diastereomer A of N-([(5S)-3-(3-fluoro-4-["6-(l-hydroxy-l-methylpropyl)payridin-3-yl]phenyl} -2-oxo-1,3 -oxazolidin-5-yl]methyl} acetamide

O
By using the procedure described in Example-12 and by using optically pure diastereomer B of (5/?)-3-{3-fluoro-4-[6-(3-hydroxy-l,l-dioxidotetrahydrothiophen-3-yl)pyridin-3-yl]phenyl}-2-oxo-1,3-oxazolidine-5-carboxamide, the title compound may be obtained.
Example-18: Diastereomer A of N-([(5S)-3-(3-fluoro-4-["6-(l-hydroxy-l-methylpropyl)payridin-3-yl]phenyl} -2-oxo-1,3 -oxazolidin-5-yl]methyl} acetamide

By using the procedure described in Example-12 and by using N-flXS^-S-IS-fluoro-
4-[6-(4-hydroxy-l,l-dioxidotetrahydro-2H-thiopyran-4-yl)pyridin-3-yl]phenyl}-2-
oxo-l,3-oxazolidin-5-yl]methyl}acetamide, the title compound was obtained in 32 %
yield.
Mass (M+l) for C22H26FN3O4 = 416.
MP: 198-200 °C.
Example-19: Diastereomer A of N-([(5S)-3-(3-fluoro-4-["6-(l-hydroxy-l-methylpropyl)payridin-3-yl]phenyl} -2-oxo-1,3 -oxazolidin-5-yl]methyl} acetamide

O
By using the procedure described in Example-12 by and using (5i?)-3-{3-fluoro-4-[6-(4-hydroxy-1,1 -dioxidotetrahydro-2/7-thiopyran-4-yl)pyridin-3 -yl]phenyl} -2-oxo-1,3-oxazolidine-5-carboxamide, the title compound may be obtained.
Example-20: Diastereomer A of N-([(5S)-3-(3-fluoro-4-["6-(l-hydroxy-l-methylpropyl)payridin-3-yl]phenyl} -2-oxo-1,3 -oxazolidin-5-yl]methyl} acetamide

CH,SO,H. H2Ni O
3 3 -./(

To a cooled solution of n-tert.-butoxycarbonyl-L-alanine (4.8 gm, 25.8 mmol) in mixture of dimethylformamide: dichloromethane (2: 40 ml) at - 5 °C was added dicyclohexylcarbodiimide (2.6 gm, 12.9 mmol), N-{[(5S)-3-{3-fiuoro-4-[6-(l-hydroxy-1 -methylethyl)pyridin-3-yl]phenyl} -2-oxo-1,3-oxazolidin-5-yl]methyl}acetamide (1.0 gm, 2.58 mmol) and N,N-dimethylaminopyridine (1.5 gm, 12.9 mmol) and tetrazole (825 nig, 12.9 mmol). The reaction mixture was stirred for 2 hrs. Solid was filtered, washed with dichloromethane (30 ml). Filtrate was concentrated under vacuum to dryness. The residue was stirred with ethyl acetate (200 ml) for 10 minutes and solid was filtered. Filtrate was concentrated under vacuum and the residue was purified by silica gel column chromatography to provide N-Boc protected L-alanine ester compound in 1.15 gm quantity.
The compound (1.1 gm, 1.97 mmol) was dissolved in tetrahydrofuran (30 ml) and methanesulfonic acid (378 ul, 3.94 mmol) was added. The reaction mixture was heated to 80 °C for 12 hours. It was cooled to 35 °C and filtered at suction to afford title compound in 950 mg quantity in 87 % yield. Mass (M+l for base) for C23H27FN4O5 CH3SO3H - 459.1.
Example-21: Diastereomer A of N-([(5S)-3-(3-fluoro-4-["6-(l-hydroxy-l-methylpropyl)payridin-3-yl]phenyl} -2-oxo-1,3 -oxazolidin-5-yl]methyl} acetamide

CH3S03H. H2N, .0

By using the procedure described in Example-20, and by using N-tert-butoxy-L-valine in the place of N-tert-butoxy-L-alanine the title compound was obtained in 54% yield. Mass (M+l for base) for C25H31FN4O5 CH3SO3H = 487.1.


Example-22: Diastereomer A of N-([(5S)-3-(3-fluoro-4-["6-(l-hydroxy-l-methylpropyl)payridin-3-yl]phenyl} -2-oxo-1,3 -oxazolidin-5-yl]methyl} acetamide

CH3S03H. H2N

By using the procedure described in Example-20, and by using N-tert-butoxy-glycine in the place of N-tert-butoxy-L-alanine the title compound was obtained in 64% yield. Mass (M+l for base) for C22H25FN5O4.CH3SO3H - 445.
Example-23: Diastereomer A of N-([(5S)-3-(3-fluoro-4-["6-(l-hydroxy-l-methylpropyl)payridin-3-yl]phenyl} -2-oxo-1,3 -oxazolidin-5-yl]methyl} acetamide

HO. P
HO' P \° Vo
N- J~ ~\_ J- -N 1 H
r 0
A mixture of N-{[(5S)-3-{3-fluoro-4-[6-(l-hydroxy-l-methylethyl)pyridin-3-yl]phenyl}-2-oxo-l,3-oxazolidin-5-yl]methyl}acetamide (10.0 mmol), tetrazole (30.0 mmol), dibenzyl-N,N-diisopropyl phosphoramidite (12.0 mmol) in dichloromethane was stirred at temperature between 0 °C to 35 °C for 3 hrs under argon. Reaction mass was cooled to 0 °C and meta-chloroperbenzoic acid (10.0 mmol) was added to it. The reaction mixture was stirred at 35 °C temperature for 2 hrs. Reaction was quenched with 10 % sodium metabisulfite solution, organic layer separated washed with sodium bicarbonate and water, dried, evaporated up to dryness and purified on column chromatography to obtain dibenzyl phosphate ester, which was stirred under hydrogen pressure (100 PSI) in presence of 5% palladium on carbon in methanol at 30 °C to 35 °C for 4 hours. As the reaction completed, the reaction mixture was filtered over celite bed and filtrate was concentrated under vacuum to provide title compound.

We Claim:
1. Compounds having the structure of Formula (I).


R1 OR
R2 N

wherein,
R1 and R2 are independently selected from a group of C1-C6 alkyl, substituted alkyl, heteroaryl or substituted heteroaryl.
R3 is -H, C1-C6 alkyl group, substituted alkyl group or PO3H2
R4 is selected from a group of
(i) - C(X)NR6R7, wherein X = O or S, and R6 and R7 are independently selected from H, Q.6 alkyl group or substituted alkyl group.
(ii) -CH2-Y-R8, wherein Y = -NH or O; and R8 is alkanoyl, aminoalkanoyl, alkoxycarbonyl or heteroaryl group.
R5 is selected from -H or a halogen.
and pharmaceutical^ acceptable salts thereof.
2. A compound as claimed in claim 1, comprising of;
N- {[(5S)-3- {3-fluoro-4-[6-(l -hydroxy-1 -methylethyl)pyridin-3-yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl]methyl}acetamide;
(5R)-3 - {3 -fluoro-4-[6-( 1 -hydroxy-1 -methylethyl)pyridin-3 -yl]phenyl} -2-oxo-1,3-oxazolidine-5-carboxamide;


Methyl {[(5 S)-3 - {3 -fluoro-4-[6-( 1 -hydroxy-1 -methylethyl)pyridin-3 -yl]
phenyl} -2-oxo-1,3-oxazolidin-5-yl]methyl} carbamate;
(5R)-3 - {3 -fluoro-4- [6-( 1 -hydroxy-1 -methyl ethyl) pyridin-3 -yl] phenyl} -5 -
[(isoxazol-3-yloxy)methyl]-1,3-oxazolidin-2-one;
N-{[(55)-3-(3-fluoro-4-{6-[3,3,3-trifluoro-l-hydroxy-l-(2,2,2-triluoroethyl) propyl] pyridin-3-yl}phenyl)-2-oxo-l,3-oxazolidin-5-yl]methyl}acetamide;
Diastereomeric mixture of N-{[(5S)-3-{3-fiuoro-4-[6-(l-hydroxy-l-
methylpropyl) pyridin-3-yl]phenyl}-2-oxo-l,3-oxazolidin-5-yl]methyl}
acetamide;
Diastereomer A & B of N-{[(5S)-3-{3-fluoro-4-[6-(l-hydroxy-l-methylpropyl) pyridin-3-yl] phenyl} -2-oxo-1,3-oxazolidin-5-yl]methyl} acetamide;
1 -[5-(4- {(55)-5-[(acetylamino) methyl]-2-oxo-1,3-oxazolidin-3-yl}-2-fluoro phenyl)pyridin-2-yl]-l-methylethyl L-alaninate.methane sulonic acid salt;
l-(5-{4-[(5S)-5-(acetamide methyl)-2-oxo-l,3-oxazolidin-3-yl]-2-fluoro
phenyl}pyridin-2-yl)-l-methylethyl L-valinate methanesulfonate;
l-[5-(4-{(55)-5-[(acetylamino) methyl]-2-oxo-l,3-oxazolidin-3-yl}-2-fluoro phenyl) pyridin-2-yl]-l-methylethyl glycinate methanesulfonic acid salt and
l-[5-(4-{(5S)-5-[(acetylamino) methyl]-2-oxo-l,3-oxazolidin-3-yl}-2-fiuoro phenyl) pyridin-2-yl]-l-methylethyl dihydrogen phosphate.
3. A pharmaceutical composition comprising a therapeutically effective amount of compound of the Formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1, in association with a pharmaceutically acceptable carrier, excipient or diluent.


4. A method of treating or preventing microbial infections which comprises administering to a patient in need thereof, an therapeutically effective amount of compound of the Formula (I) as claimed in claim 1.

Abstract
The present invention relates to the family of substituted biaryl oxazolidinones having antimicrobial activity. The invention also relates to pharmaceutical compositions containing the compounds and to methods for treating or preventing microbial infections using the compounds of present invention.