FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
NOVEL PRODRUGS OF SUBSTITUTED PIPERIDINO PHENYLOXAZOLIDINONES
2. APPLICANT (S)
(a) NAME : Wockhardt Limited
(b)NATlONALITY : Indian
(c) ADDRESS : Wockhardt Towers
Bandra-Kurla Complex, Bandra (E)
Mumbai -400 051, India
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in
which it is to be performed.

NOVEL PRODRUGS OF SUBSTITUTED PIPERIDINO PHENYLOXAZOLIDINONES
FIELD OF INVENTION
The present invention relates to prodrugs of geminally disubstituted piperidino phenyloxazolidinones having antimicrobial activity with improved pharmacokinetic profile. The invention also relates generally to processes for preparation of the prodrug, its salts , hydrates , polymorphs and their conversion to pharmaceutical compositions containing the prodrugs, its salts , hydrates , polymorphs and to methods for treating or preventing microbial infections using the prodrugs.
BACKGROUND OF INVENTION
Oxazolidinones represent a novel chemical class of synthetic antimicrobial agents. Linezolid represents the first member of this class to be used clinically. Oxazolidinones display activity against important Gram-positive human and veterinary pathogens including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin resistant enterococci (VRE) and p-lactam resistant Streptococcus pneumoniae (PRSP).
There are several patents cited in the literature, which refer to oxazolidinones having antibacterial activity. Piperidinylphenyl moiety bearing oxazolidinones are described in following patents: WO95/25106 discloses substituted piperidino phenyloxazolidinones. WO96/13502 discloses phenyloxazolidinones having a multisubstituted azetidinyl or pyrrolidinyl moiety. PCT application Nos PCT/IN03/00237, PCT/IN03/00238 and PCT/IN04/00276 discloses piperidinyl phenyl oxazolidinones of antimicrobial use. However in all above cited patents, prodrugs of geminally disubstituted piperidino phenyloxazolidinones having antimicrobial activity with improved pharmacokinetic profile are not disclosed. Indian provisional patent application 719/MUM2006 dated May 9, 2006 discloses the oxazolidinone (5S)-N-{3-[3,5-difluoro-4-(4-methoxymethyl-4-hydroxypiperidine-1yl)phenyl]-2-oxo-oxazolidin-5-yl methyl}-acetamide.
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The produgs of (5S)-A/-{3-[3,5-Difluoro-4-(4-methoxymethyl-4-hydroxypiperidine-1-yl)phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide, in the present invention shows improved therapeutically favorable pharmacokinetic profile amenable for the development of once a day dosing oxazolidinone having oral, IV and IM route of administration. The compounds of the invention thus establish their ability to give in vivo protection to human beings and animals and be useful clinically.
SUMMARY OF INVENTION
The present invention relates generally to prodrugs of piperidino substituted phenyloxazolidinone compounds of Formula-I.

wherein,
R1is selected from the group comprising a) CORa,


or
(M)n b)
c) amino acid residue attached via carbonyl of the amino acid, the amino acid residue is selected from alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan tyrosine or valine wherein M is hydrogen or monovalent or divalent cation selected from Na+, K+, Mg2+, Ca2+;
n is 2 for monovalent cation or n is 1 for divalent cation; Ra is selected from C1-C6 alkyl, d-C6 alkyl substituted with hydroxyl, carboxylic acid, amine; R2 is H or -COOCH2OCOCH3; Z if present is an amino acid derivative,
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wherein amino acid may be selected from a group comprising of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan tyrosine or valine or the salts, hydrates, polymorphs thereof.
Additionally the invention provides a process or processes for preparing the compounds of invention of Formula I and their polymorphs.
The invention also relates generally to pharmaceutical compositions containing the compounds of invention and to methods for treating or preventing microbial infections using the compounds.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides compounds of the Formula I

wherein,
R1 is selected from the group comprising
a) CORa,

b)
c) amino acid residue attached via carbonyl of the amino acid, the amino acid residue is selected from alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan tyrosine or valine
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wherein M is hydrogen or monovalent or divalent cation selected from Na+, K+,
Mg2,Ca2+;
n is 2 for monovalent cation or n is 1 for divalent cation;
Ra is selected from C1-C6 alkyl, C1-C6 alkyl substituted with hydroxyl,
carboxylic acid, amine;
R2 is H or -COOCH2OCOCH3;
Z if present is an amino acid derivative,
wherein amino acid may be selected from a group comprising of alanine, arginine,
asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine,
isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine,
tryptophan tyrosine or valine
or the salts, hydrates, polymorphs thereof.
Representative prodrugs of the invention are:
Phosphoric acid mono-(1 -{4-[(S)-5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2,6-
difluorophenyl}-4-methoxymethyl-piperidin-4-yl) ester;
Phosphoric acid mono-(1 -{4-[(S)-5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2,6-
difluoro-phenyl}-4-methoxymethyl-piperidin-4-yl) ester di sodium salt;
Phosphoric acid mono-(1 -{4-[(S)-5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2,6-
difluoro-phenyl}-4-methoxymethyl-piperidin-4-yl) ester di Potassium salt;
Phosphoric acid mono-(1 -{4-[(S)-5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2,6-
difluoro-phenyl}-4-methoxymethyl-piperidin-4-yl) ester magnesium salt;
Phosphoric acid mono-(1 -{4-[(S)-5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2,6-
difluoro-phenyl}-4-methoxymethyl-piperidin-4-yl) ester calcium salt;
Phosphoric acid mono-(1 -{4-[(S)-5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2,6-
difluoro-phenyl}-4-methoxymethyl-piperidin-4-yl) ester arginine salt;
Phosphoric acid mono-(1-{4-[(S)-5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2,6-
difluoro-phenyl}-4-methoxymethyl-piperidin-4-yl) ester lysine salt;
1-{4-[(S)-5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2,6-difluoro-phenyl}-4-
methoxymethyl-piperidin-4-yl acetate;
2-Amino-acetic acid 1 -{4-[(S)-5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2,6-
difluoro-phenyl}-4-methoxymethyl-piperidin-4-yl ester;
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2-Amino-propionic acid 1-{4-[(S)-5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2,6-difluoro-phenyl}-4-methoxymethyl-piperidin-4-yl ester hydrochloride salt; 2-Amino-propionic acid 1 -{4-[(S)-5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2,6-difluoro-phenyl}-4-methoxymethyl-piperidin-4-yl ester triflouroacetic acid salt; 2-Amino-3-methyl butyric acid 1-{4-[(S)-5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2,6-difluoro-phenyl}-4-methoxymethyl-piperidin-4-yl ester; 4-{[1-{4-[(5S)-5-(acetylaminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-2,6-difluorophenyl}-4-(methoxymethyl)piperidin-4-yl]oxy}-4-oxobutanoicacid;
(R)-N-Acetyl-N-{3-{4-(4-methoxymethyl-4-acetoxy-piperidin-1-yl)-3,5-difluorophenyl}-2-oxo-oxazolidin-5-yl methylamino-carbonyl-oxy-methyl}-acetate; (R)-N-Acetyl-N-{3-{4-(4-methoxymethyl-4-hydroxy-piperidin-1-yl)-3,5-difluorophenyl}-2-oxo-oxazolidin-5-yl methyl amino-carbonyl-oxy-methyl}-acetate. The compounds of invention have shown significantly better pharmacokinetic advantage suitable for once a day dosing. The prodrugs show good water solubility and therefore IV, IM formulations and oral formulations are possible.
In another embodiment the present invention relates to method of preparation of the prodrugs of the invention. The starting materials are prepared by following procedures described in US Patent 5,668,286, US 2004/0063954 (corresponding PCT application WO 2004/007489), US 2005/0143421 (corresponding PCT application WO 2005/054234) or by procedures that would be well known to one of ordinary skill in art of synthetic organic chemistry.
The following abbreviation are used in the text: DCM for dichloromethane, DMAP for 4-dimethylaminopyridine, DMF for N,N-dimethylformamide, DMSO for dimethyl sulfoxide, EtOAc for ethyl acetate, TEA for triethylamine, THF for tetrahydrofuran, Ac20 for acetic anhydride, PPTS for pyridinium tosylate, PTSA for para-toluene sulfonic acid, LDA for lithium diisopropylamine.
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Similarly on treatment with a suitable amino acid compound of formula (C) afforded amino acid salts of formula (E).

As shown in Scheme 2, (S)-N-{3-{4-(4-methoxymethyl-4-hydroxy-piperidin-1-yl)-3,5-difluorophenyl}-2-oxo-oxazolidin-5-yl methyl}- acetamide (A) was hydrolyzed by 6N HCI by refluxing in methanol for overnight to afford (S)-N-{3-{4-(4-methoxymethyl-4-hydroxy-piperidin-1-yl)-3,5-difluorophenyl}-2-oxo-oxazolidin-5-ylmethyl}-amine (F). Compound (F) was treated with carbonochloridic acid chloride (prepared according to procedure given in WO 2005 / 028473) in presence of diisopropylethylamine in dichloromethane at 0 °C for 30 min then at room temperature for 4 hours to provide (S)-N-{3-{4-(4-methoxymethyl-4-hydroxy-piperidin-1-yl)-3,5-difluorophenyl}-2-oxo-oxazo- lidin-5-yl amino methyl -carbonyl-oxy-methyl}-acetate (G). Compound (G) when treated with acetic anhydride in presence of triethylamine and N,N-dimethylaminopyridine afford two different products under identical conditions. Compound (G) with equivalent amount of acetic anhydride affords (R)-N-Acetyl-N-{3-{4-(4-methoxymethyl-4-hydroxy-piperidin-1-yl)-3,5-difluorophenyl}-2-oxo-oxazolidin-5-yl methylamino-carbonyl-oxy-methyl}-acetate (H) and with excess of acetic
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anhydride affords (R)-N-Acetyl-N-{3-{4-(4-methoxymethyl-4-hydroxy-piperidin-1 -yl)-3,5-difluorophenyl}-2-oxo-oxazolidin-5-yl methylamino-carbonyl-oxy-methyl}-acetate
(I).

As shown in Scheme 3, compound of formula (A) is converted to compound of formula (J) by ester coupling reactions using the suitable acid such as amino acid, succinic acid.
The oxazolidinone antibacterial agents of this invention have potential for treatment of specially Gram-positive infections including multi-resistant strains. In contrast to compounds of the prior art, they demonstrate bactericidal activity against different resistant microorganisms and in particular different strains of Enterococcus faecalis. In addition they display activity against linezolid-resistant S. aureus strains, linezolid-resistant £. faecalis strains and in particular linezolid-resistant S. pneumoniae strains. These compounds are useful for the treatment of Gram-positive or Gram-negative microbial infections in humans and other warm-blooded animals by parenteral, intra-muscular, oral or topical administration. The infection in human and other warm-blooded animals can be systemic or topical.
Examples of infections that may be treated with the compounds of the present invention include central nervous system infections, external ear infections, infections of the middle ear, such as acute otitis media, infections of the cranial sinuses, eye infections, infections of the oral cavity, such as infections of the teeth, gums and mucosa, upper respiratory tract infections, lower respiratory tract infections, genitourinary infections, gastrointestinal infections, gynecological infections, septicemia, bone and joint infections, skin and skin structure infections, bacterial endocarditis, burns, antibacterial prophylaxis of surgery, and antibacterial prophylaxis in immunosuppressed patients, such as patients receiving cancer chemotherapy, or organ transplant patients. Specifically, infectious diseases that
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may be treated with the compounds of the present invention are gram-positive infections such as osteomyelitis, endocarditis and diabetic foot.
The compounds described herein are useful for the treatment or prophylaxis of Gram-positive or Gram-negative microbial infections in humans and other warmblooded animals. The oxazolidinone antibacterial compounds of this invention are useful for treatment of Gram-positive infections including those, which result from multi-resistant strains. The compounds of this invention are useful antimicrobial agents effective against various humans and veterinary pathogens specially included Linezolid-resistant strains.
In contrast to Linezolid, the compounds described herein demonstrate bactericidal activity against different resistant microorganisms and in particular different strains of Enterococcus faecalis. In addition they display activity against linezolid-resistant S. aureus strains, linezolid-resistant E. faecalis strains and in particular linezolid-resistant S. pneumoniae strains.
The infection in human and other warm-blooded animals can be systemic or topical. The compounds of this invention may be used to prevent infections caused by Gram-positive and Gram-negative bacteria by administering the compound 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, immune-comprised or the like.
The present invention encompasses certain compounds, compositions, dosage forms, and methods of administering the compounds to a human or other animal subject. In an embodiment of the invention, the pharmaceutical compositions contain an effective amount of the active compounds of the invention, its derivatives, prodrugs, salts or hydrates thereof described in this specification in admixture with a pharmaceutically acceptable carrier, diluent or excipients, and optionally other therapeutic ingredients. Specific compounds, compositions and dosage forms to be administered must, be pharmaceutically acceptable. As used herein, such a "pharmaceutically acceptable" component is one that is suitable for use with humans and/or animals without undue adverse side effects (such as toxicity, irritation, and
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allergic response) commensurate with a reasonable benefit/risk ratio. The pharmaceutical compositions are prepared according to conventional procedures used by persons skilled in the art to make stable and effective compositions. In the dosage forms, an effective amount of the active compound or the active ingredient is any amount, which produces the desired results. An effective amount can also be that amount of the active compound or active ingredient that will elicit the biological or medical response that is being sought.
For the purpose of this invention a pharmaceutical composition will contain one or more of the active compounds of the invention salts, and/or 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.
The compounds and compositions can be administered to a human or other animal by any suitable route of administration including, for example, oral, rectal, vaginal, parenteral (subcutaneous, intramuscular, intravenous), transdermal, topical and like. Dosage forms include solutions, suspensions, tablets, pills, powders, troches, dispersions, suspensions, emulsions, solutions, pellets, gels, granules, capsules, injectable preparations, patches, ointments, creams, liniments, salves, cachets, aerosol sprays, lotions, shampoos and the like.
The prophylactic or therapeutic dose of the prodrugs their salts and/or hydrates thereof, in the prevention, acute or chronic management of infection or disease will vary depending on one or more factors which include but are not limited to the severity of condition to be treated, the risk and the route of administration. In addition, the dose, and perhaps the dose frequency, will also vary according to the age, sex, body weight and response of the individual patient. In general, the total daily dose range, for the compounds of the invention, the derivatives, salts, prodrugs or hydrates thereof, for the conditions described herein, is from about 200 mg to about 1500 mg, in single or divided doses. In a non- limiting embodiment, a daily
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dose range should be between about 400 mg to 1200 mg, in single or divided dosage, while most preferably a daily dose range should be between about 500 mg to about 1000 mg in divided dosage. While parenteral administration may be a single dose or up to 3 divided doses, intravenous administration can include a continuous drip.
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 practioner will know how and when to interrupt, adjust, or terminate therapy in conjunction with individual patient's response or condition or whether the infection is active or the treatment is prophylatic. 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.
A specific embodiment of the invention is that the pharmacokinetic profile of a compound of the invention is such that it permits administration of a once-a-day dosing.
Pharmaceutical compositions of the present invention suitable for oral administration may be presented as discrete units, for example, 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 compositions of the present invention include compositions such as suspensions, solutions, elixirs, aerosols, and solid dosage forms. Carriers as described in general below are commonly used in the case of oral solid preparations (such as powders, capsules and tablets), with the oral solid preparations being
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preferred over the oral liquid preparations. The most preferred oral solid preparation
is tablets and capsules.
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 powder, tragacanth powder, gelatin, and ethanol, and disintegrants such as laminaria and agar.
Desirably, each oral dosage form 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.
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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 parenterally for intramuscular, intravenous or subcutaneous administration in which case parenteral dosages are employed. Parenteral dosages employed may be in the form of ready to use dosage forms or solutions for parenteral dosage may be diluted prior to its use.
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.
A third preferred route of administration is topically, 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.
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.
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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.
A non-limiting embodiment of the invention is the preparation of storage 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.
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. An advantage of this invention is that compounds have favourable safety advantages as compared to Linezolid, in particular do not cause or lower the potential to cause myelosuppression. Myelosuppression is known to be a typical class-specific toxicological feature of the oxazolidinone class of antibacterial agents.
Following examples illustrates the methods of preparation of the compounds of the invention and are provided only as examples, but not to limit the scope of the compounds of invention.
INTERMEDIATE-1
(S)-N-{3-[3,5-Difluoro-4-(4-methoxymethyl-4-di-0-benzylphosphoryloxy-piperidine-
1yl)- phenyl]-2-oxo-oxazolidin-5-yl methyl}-acetamide
To a solution of (S)-N-{3-[3,5-Difluoro-4-(4-methoxymethyl-4-hydroxypiperidine-1yl)-
phenyl]-2-oxo-oxazolidin-5-yl methyl}-acetamide (0.2mmol) and tetrazole (0.6mmol)
in dichloromethane (5ml) was added dibenzyl N,N,diisopropylphosphoramidite
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(0.4mmol) and the resulting mixture was stirred for 4h. The resulting solution was cooled to 0 °C and 0.6 ml of 0.5M m-chloroperbenzoic acid solution in dichloromethane was added. After 4h, the solvent was evaporated under residue pressure and the residue chromatographed on a column of silica gel to obtain the product as a off-white solid in 75% yield. M.F.= C33H38F2N3O8P; M+1= 674.
INTERMEDIATE-2
(S)-N-{3-[3,5-Difluoro-4-(4-(S)-2-terf-Butoxycarbonylamino-propionyl-4-methoxymethyl-piperidine-1-yl)phenyl]-2-oxo-oxazolidin-5-yl methyl}-acetamide To a solution of 4.1 g (21.69mmol) of N-Boc-alanine in dichloromethane (30ml), under argon, was added DCC (4.2 g, 21.7mmol), at 0-5 °C. The resulting mixture was stirred for 0.5 h. To this solution, N-{(S)-3-[3,5-Difluoro-4-(4-hydroxy-4-methoxymethyl-piperidin-1 -yl)phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide, 3 g (7.2mmol) and DMAP 2.52g (21.7mmol) were added successively. The reaction mass stirred at room temperature for 15-20 hrs. The reaction mixture was filtered under suction and the residue further washed with additional dichloromethane (50ml). The filtrate was washed with water (100ml x 2), dried over sodium sulfate, and the solvent evaporated under reduced pressure. The residue was chromatographed on a column of silica gel to obtain the product as a white hygroscopic, solid, 0.5g, in 12% yield. MF= C27H38F2N4O8; Mass: 585 (M+1).
EXAMPLE-1
Phosphoric acid mono-(1-{4-[(S)-5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2,6-difluorophenyl}-4-methoxymethyl-piperidin-4-yl) ester To a suspension of (S)-N-{3-[3,5-difluoro-4-(4-methoxymethyl-4-di-0-benzylphosphoryl- oxypiperidine-1 yl)phenyl]-2-oxo-oxazolidin-5-yl methyl}-acetamide (0.15 mmol) and 20mg of 20 % palladium hydroxide in 20 ml of a mixture of dichloromethane /aqueous methanol was stirred at room temperature for 6h. The catalyst was filtered and the residue evaporated under reduced pressure. The residue obtained was triturated with water to obtain a white solid as product in 70% yield. Mp.= >140 °C; M.F.= C19H26F2N3O8P;M+1=493
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EXAMPLE-2
Phosphoric acid mono-(1 -{4-[(S)-5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2,6-difluoro-phenyl}-4-methoxymethyl-piperidin-4-yl) ester di potassium salt To a solution of phosphoric acid mono-(1-{4-[(S)-5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2,6-difluorophenyl}-4-methoxymethyl-piperidin-4-yl) ester (5.0g, O.OIOmol) anhydrous methanol (50ml) at 0-5 °C, under argon, was added anhydrous potassium carbonate (1.385 gm, 0.010 mol). The reaction mixture was stirred at 5-10 °C for 2 hours. The ice-bath was removed and the stirring continued further at 30-35 °C for 1 hour. The reaction mixture was filtered and the filtrate evaporated under reduced pressure. Acetone (25ml) was added to the residue and triturated. The solvent was decanted. This procedure was repeated twice with acetone (50ml). Acetone after the third trituration was decanted and the residue dried under reduced pressure to obtain the product as white solid, 5.1g, in 89% yield Mp >165 °C; MF: C19H24F2K2N3O8P.
EXAMPLE-3
Phosphoric acid mono-(1-{4-[(S)-5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2,6-difluorophenyl}-4-methoxymethyl-piperidin-4-yl) ester arginine salt To a solution of phosphoric acid mono-(1-{4-[(S)-5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2,6-difluorophenyl}-4-methoxymethyl-piperidin-4-yl) ester (5.0g, O.OI0 mol) anhydrous ethanol (50ml) at 25-30 °C, under argon, was added arginine (1.76 gm, 0.010 mol). The reaction mixture was stirred at 80-85 °C for 0.5 h. Water (5ml) was added to the reaction mixture and stirring continued further for 1h at 80-85 °C. The reaction mixture was filtered and the filtrate evaporated under reduced pressure. Acetone (25ml) was added to the residue and triturated. The solvent was decanted. This procedure was repeated twice with acetone (50ml). Acetone after the third trituration was decanted and the residue dried under reduced pressure to obtain the product as white solid, 6.1g, 91% yield.
EXAMPLE-4
2-Amino-propionic acid 1 -{4-[(S)-5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2,6-difluorophenyl}-4-methoxymethyl-piperidin-4-yl ester hydrochloride salt To (S)-N-{3-[3,5-Difluoro-4-(4-(S)-2-te/t-butoxycarbonylamino-propionyl-4-methoxy-methyl-piperidine-1-yl)phenyl]-2-oxo-oxazolidin-5-yl methyl}-acetamide (150 mg),
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under argon was added a solution of HCI gas in I PA (2 ml) at room temperature. The resulting mixture was stirred for 16-18 hrs. The solvent was evaporated under reduced pressure and the residue triturated with diethyl ether. The ether layer was decanted. This procedure was repeated twice and the residual solid dried under vaccum to obtain the product as a highly hygroscopic solid, 103mg, 77% yield.
EXAMPLE-5
2-Amino-propionic acid 1-{4-[(S)-5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2,6-difluorophenyl}-4-methoxymethyl-piperidin-4-yl ester triflouroacetic acid salt To (S)-N-{3-[3,5-Difluoro-4-(4-(S)-2-tert-butoxycarbonylamino-propionyl-4-methoxy-methyl-piperidine-1-yl)phenyl]-2-oxo-oxazolidin-5-yl methyl}-acetamide (150 mg), under argon was added 1 ml TFA in 2 ml dichloromethane at room temperature. The resulting mixture was stirred for 16-18 hrs. The solvent was evaporated under reduced pressure and the residue triturated with diethyl ether. The ether layer was decanted. This procedure was repeated twice and the residual solid dried under vaccum to obtain the product as a highly hygroscopic solid, 98mg, 64% yield.
EXAMPLE-6
(R)-N-Acetyl-N-{3-{4-(4-methoxymethyl-4-hydroxy-piperidin-1-yl)-3,5-difluorophenyl}-2-oxo-oxazolidin-5-yl methyl amino-carbonyl-oxy-methyl}-acetate Step-1: Preparation of (S)-N-{3-{4-(4-methoxymethyl-4-hydroxy-piperidin-1-yl)-3,5-difluorophenyl}-2-oxo-oxazolidin-5-yl methyl}-amine: To a solution of (S)-N-{3-{4-(4-methoxymethyl-4-hydroxy-piperidin-1-yl)-3,5-difluorophenyl}-2-oxo-oxazolidin-5-yl methyl}- acetamide (2.0 gm, 4.84 mmol) in methanol (100 ml) was added 6N HCI (55 ml). The mixture was refluxed for overnight. The reaction mixture was cooled to room temperature and concentrated in vacuum. Ethyl acetate and water were added to the residue and layers were separated. The aqueous layer was made basic (pH 12-13) by the addition of aqueous potassium carbonate. Aqueous layer was extracted three times with methanol chloroform mixture (5:95). The combined organic layer were dried over sodium sulfate and concentrated in vacuum to provide title compound as thick oil in 81% yield. For MF: CITH^NSO^ MS (ES+) m/z 372.
Step-2: Preparation of (S)-N-{3-{4-(4-methoxymethyl-4-hydroxy-piperidin-1-yl)-3,5-difluorophenyl}-2-oxo-oxazolidin-5-yl amino methyl -carbonyl-oxy-methyl}-acetate.
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To a stirred solution of the (S)-N-{3-{4-(4-methoxymethyl-4-hydroxy-piperidin-1-yl)-3,5-difluorophenyl}-2-oxo-oxazolidin-5-yl methyl}-amine (1.65 gm, 4.4 mmol) in dichloromethane (25 ml) was added diisopropylethylamine (1.55 ml, 8.8 mmol) and a solution of 0.78gm (5.1 mmol) carbonochloridic acid chloride (prepared according to procedure given in WO 2005 / 028473) dissolved in 15 ml dichloromethane at 0°C. The reaction mixture was stirred at 0 °C for 30 min then at room temperature for 4 hours. The reaction mixture is partitioned between dichloromethane and water. Organic layer was separated washed with 1N HCI, followed by water. The layers were separated and dried over sodium sulfate. The organic layer was concentrated in vacuum the crude product was and purified by silica gel column chromatography to provide title compound in 850 mg (42%) quantity. For MF: C21H27F2N3O8, MS (ES+) m/z 488.
Step3: Preparation of (R)-N-Acetyl-N-{3-{4-(4-methoxymethyl-4-hydroxy-piperidin-1-yl)-3,5-difluorophenyl}-2-oxo-oxazolidin-5-yl methylamino-carbonyl-oxy-methyl}-acetate
To a stirred solution of (S)-N-{3-{4-(4-methoxymethyl-4-hydroxy-piperidin-1-yl)-3,5-difluorophenyl}-2-oxo-oxazolidin-5-yl amino methyl -carbonyl-oxy-methyl}-acetate (0.8 gm,1.6 mmol) in dichloromethane (20 ml) was added triethylamine (0.46 ml, 3.2 mmol) followed by N,N-dimethylaminopyridine (0.05 mg, 0.4 mmol) followed by acetic anhydride (1.9 ml, 19.6 mmol). The reaction mixture stirred at room temperature for 18 hours. Additional acetic anhydride (1.15 ml, 11.8 mmol) was added to the reaction mixture and it was stirred for an additional 24 hr. The reaction mixture was partitioned between dichloromethane (50 ml) and water (20 ml). Organic layer was separated and washed with saturated solution of sodium bicarbonate, followed by water. The organic layer was dried over sodium sulfate and was concentrated under vacuum to provide a residue. The residue was purified by flash chromatography to afford 1.67 gm (93%) title compound. For MF: C23H29F2N3O9, MS (ES+) m/z 530.
EXAMPLE-7
(R)-N-Acetyl-N-{3-{4-(4-methoxymethyl-4-acetoxy-piperidin-1-yl)-3,5-difluorophenyl}-2-oxo-oxazolidin-5-yl methylamino-carbonyl-oxy-methyl}-acetate To a stirred solution of (S)-N-{3-{4-(4-methoxymethyl-4-hydroxy-piperidin-1-yl)-3,5-difluorophenyl}-2-oxo-oxazolidin-5-yl amino methyl-carbonyl-oxy-methyl}-acetate (1.6
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gm,3.2 mmol) in dichloromethane (35 ml) was added triethylamine (1.61 ml, 11.2 mmol) followed by N,N-dimethylaminopyridine (0.10 mg, 0.8 mmol) followed by acetic anhydride (3.8 ml,39.2 mmol). The reaction mixture stirred at room temperature for 24 hr. The reaction mixture was partitioned between dichloromethane (100 ml) and water (50 ml). Organic layer was separated and washed with saturated solution of sodium bicarbonate, followed by water. The organic layer was dried over sodium sulfate and was concentrated under vacuum to provide a residue. The residue was purified by flash chromatography to afford 3.2 gm (92%) title compound. For MF: C25H31F2N3O10, MS (ES+) m/z 572.
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Claims:
1. A prodrug of a compound of formula I,

wherein,
R1is selected from the group comprising d) CORa,

e)
f) amino acid residue attached via carbonyl of the amino acid, the amino acid residue is selected from alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan tyrosine or valine
wherein M is hydrogen or monovalent or divalent cation selected from Na+, K+,
Mg2+, Ca2+;
n is 2 for monovalent cation or n is 1 for divalent cation;
Ra is selected from C1-C6 alkyl, C1-C6 alkyl substituted with hydroxyl, carboxylic acid, amine; R2 is H or -COOCH2OCOCH3; Z if present is an amino acid derivative,
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wherein amino acid may be selected from a group comprising of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan tyrosine or valine or the salts, hydrates, polymorphs thereof.


Dated this 22nd day of September 2006

Abstract
The present invention relates to prodrugs of geminally disubstituted piperidino phenyloxazolidinones having antimicrobial activity with improved pharmacokinetic profile. The invention also relates generally to processes for preparation of the prodrug, to pharmaceutical compositions containing the prodrugs and to methods for treating or preventing microbial infections using the prodrugs.
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