FIELD OF THE INVENTION
The present invention relates to certain substituted phenyl oxazolidinones and to processes for the synthesis of the same. This invention also relates to pharmaceutical compositions containing the compounds of the present invention as antimicrobials. The compounds are useful antimicrobial agents, effective against a number of human and veterinary pathogens, including gram-positive aerobic bacteria such as multiple-resistant staphylococci, streptococci and enterococci as well as anaerobic organisms such as Bacterioides spp. and Clostridia spp. species, and acid fast organisms such as Mvcobacterium tuberculosis, Mycobacterium avium and Mycobacterium spp.
BACKGROUND OF THE INVENTION
increasing antibacterial resistance in Gram-positive bacteria has presented a formidable treatment problem. The enterococci, although traditionally no virulent pathogens, have been shown, when associated with Vancomycin resistance, to have an attributable mortality of approximately 40%. Staphylococcus aureus, the traditional pathogen of postoperative wounds, has been resistant to Penicillin due to production of penicillinases. This resistance was overcome by the development of various penicillinase stable ß lactams. But the pathogen responded by synthesizing modified target penicillin binding protein- 2' leading to less affinity for p lactam antibiotics and a phenotype known as Methicilline Resistant S. aureus (MRSA). These strains, till recently were susceptible to Vancomycin, which inspite of its various drawbacks, has become the drug of choice for MRSA infections. Streptococcus pneumoniae is a major pathogen causing pneumonia, sinusitis and meningitis. Until very recently it was highly susceptible to penicillin. Recently though, different PBP 2' strains with different susceptibility to penicillin have been reported from across the globe.
Oxazolidinones are a new class of synthetic antimicrobial agents, which kill gram-positive pathogens by inhibiting a very early stage of protein synthesis. Oxazolidinones inhibit the formation of ribosomal initiation complex involving SOS and SOS ribosomes leading to
prevention of initiation complex formation. Due to their novel mechanism of action, these compounds are active against pathogens resistant to other clinically useful antibiotics.
J. Medicinal Chemistry 1998, 41, 3727-3735; describes pyridine, diazine, triazene, heteroaromatic rings directly attached to the piperazinyl oxazolidinone core.
J. Organic Chemistry 1999,64, 6019-6022 and J. Organic Chemistry 2000, 65, 1144-1157.
Biorganic and Med. Chem. Letters; 2001, 11, 1829-1832 discloses oxazolidinone derivatives which are active against gram positive strains including the resistant strains of Staphylococcus and Enterococcus;
J. Medicinal Chemistry; 1968, 11, 305-311 describes the synthesis of various benzo-2,1,3-oxadiazoles and their N-oxides.
Organic Process Research Development 2003,7,436-445 describes the synthesis of 5-bromobenzofurazan .
J. Cardiovascular Pharmacology 1982, 4, 344 discloses a new benzoxadiazolyl dihydropyridine derivative.
WO04/056817 discloses substituted biaryl-oxazolidinyl derivatives effective against gram positive and gram negative pathogens.
WO04/056818 discloses substituted biaryl-oxazolidinyl derivatives effective against gram positive and gram negative pathogens.
WO04/014392 discloses piperazinyl oxazolidinyl acetamide derivatives as antimicrobials.
WO03/008389 discloses substituted phenyl oxazolidinones, which are useful antimicrobial agents, effective against a number of human and veterinary pathogens, including gram- positive aerobic bacteria such as multiple-resistant Staphylococci, Streptococci and Enterococci as well as anaerobic organisms such as Bactericides spp. Clostridium spp. and acid fast organisms such as Mycobacterium tuberculosis, Mycobacterium avium and Mycobacterium spp.
WO03/007870 discloses oxazohdinone derivatives, which are useful antimicrobial agents, effective against human and veterinary pathogens.
WO03/072575 discloses 3-cyclyl-5-(nitrogen containing 5-membereed ring) methyl oxazolidinones and their use as antimicrobials .
WO 03/022824 discloses oxazohdinone and/or isoxazoline as antibacterial agent.
WO 03/072553 discloses N-aryl-2-oxazolidinone-5-carboxamides and their derivatives and their use as antibacterial.
WO03/006447 discloses oxazohdinone compounds having thiocarbonyl functionality as antibacterial agents.
WO 03/022824 discloses oxazohdinone and/or isoxazoline as antibacterial agent.
WO02/06278 discloses phenyl oxazohdinone derivatives as antimicrobials.
WO 01/94342 and US6, 689,779 disclose novel oxazohdinone derivatives having pyridine or pyrimidine moiety and a process for the preparation thereof
WO 01/80841 discloses use of thioamide oxazolidinones for the treatment of bone resorption and osteoporosis
WOOO/29396 discloses novel substituted phenyloxazolidione derivatives for producing antibacterial medicament for treating human being and animals.
WOOO/32599 discloses oxazohdinone compounds having thiocarbonyl functionality as antibacterial agents.
WO 99/64416 discloses substituted oxazolidinyl derivatives as antimicrobials.
WO 99/64417 discloses substituted oxazolidinyl derivatives as antimicrobials.
WO 98/01446 discloses 6-membered heteroaryl ring containing 2 or 3 ring nitrogen atoms, attached to the piperazinyl oxazolidinyl derivatives as antimicrobials.
wo 98/01447 discloses pyridyl-piperazinyl oxazolidinyl derivatives as antimicrobials
WO 98/54161 and US 6255304 disclose oxazolidinone antibacterial agents having a thiocarbonyl functionality.
WO 93/23384 discloses novel substituted aryl and heterocyclylphenyl oxazolidinones useful as antibacterial agents.
WO 93/09103 discloses novel substituted aryl and heteroarylphenyl oxazolidinones useful as antibacterial agents.
EP352781 discloses phenyl-methyl and pyridinyl-methyl substituted oxazolidinones.
US5,547,950 and US5,700,799 disclose the novel substituted aryl and heterocyclylphenyl oxazolidinones useful as antibacterial agents.
US Patent No. 5,719,154 describes substituted or unsubstituted 2-pyrimidinyi, 4-pyrimidinyl, or 3-pyridazinyl rings directly attached to the piperazinyl oxazolidinyl core.
US Patent No. 5,736,545 discloses substituted piperazinyl oxazolidinyl derivatives as antimicrobials.
US 5,565,571, US 5,801,246, US 5,756,732, US 5,654,435, US 5,654,428 disclose novel substituted aryl and heteroaryl phenyloxazolidinones which are useful as antibacterial agents.
Other references disclosing various phenyloxazolidinones include U.S. Patent Nos. 4,801,600 and 4,921,869; Gregory W.A., et al, J.Med.Chem., 1989; 22: 1673-81; Gregory W.A., et al, JMedChem., 1990; 22: 2569-78; Wang C, et al, Tetrahedron, 1989; 45: 1323-26; Brittelli, et al, J.Med.Chem. Chem., 1992; 25: 1156; Annual reports in Medicinal Chemistry, Vol 35, pp 135-144; Bio-organic and Medicinal Chemistry Letters, 1999; 9: 2679-84; Antibacterial & Antifungal Drug Discovery & Development Summit, Strategic Research Institute, June 28-29, 2001, Amsterdam, The Netherlands; Posters No. 1822, 1823, 1824, 1825, 1826, 1827, 1828, 1829, 1830, 1831, 1832, 1833 and 1834, 40"" Interscience Conference on Antimicrobial Agents and Chemotherapy, Sept 17-20, (2000), Toronto, Canada; and Posters No 1023, 1040, 1041,
1042, 1043, 1044,1045, 1046, 1047, 1048, 1049, 1050, and 1051, 41'' Interscience Conference on Antimicrobial Agents and Chemotherapy, December 16-19, (2001), Chicago, USA.
SUMMARY OF THE INVENTION
Oxazolidinone derivatives, which have a good activity against multiple resistant gram-positive pathogens, like methicilline resistant Staphylococcus aureus (MRSA), Vancomycin-resistant Enterococci (VRE) and Streptococcus pneumonia. Some of these molecules have activity against multiple drug resistant tuberculosis (MDR-TB) strain, while others have significant activity against important anaerobic bacteria.
Benzoxadiazole phenyloxazolidinones derivatives exhibiting good antibacterial activity against Gram positive pathogens like MRSA, VRE and PRSP against MDR-TB and MAI strains, Gram negative pathogens like moraxella catarrhalis and haemophilus influenza in order to provide safe and effective treatment of bacterial infection are provided.
Processes for the synthesis of benzoxadiazole phenyloxazolidinones derivatives represented by Formula I as shown in the accompanied drawing, and its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, stereoisomers, prodrugs or polymorphs are also provided wherein,
Ri is ORj , SRj [wherein Rj is hydrogen, alkyl, alkenyl, cycloalkyi, aryl, aralkyi, heterocyclyl, heteroaryl, heteroarylalkyi or heterocyclylalkyl], NHY1Rf [wherein Y1 is (C=0), (C=S) or SO2 and Rr is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyi, aryl, aralkyi, heteroaryl, heterocyclyl, heteroarylalkyi or heterocyclylalkyl], NRfRq [wherein Rf is as defined earlier and Rq is hydrogen, alkyl, cycloalkyl, aryl, aralkyi, heteroaryl, heterocyclyl, heteroarylalkyi or heterocyclyl], heterocyclyl or heteroaryl;
U and V are independently selected from hydrogen, lower (C1-6) alkyl and halogens (CI, F or Br);
Y and W can be no atom or selected from group consisting of O, CH2, CO, CH2NH, -NHCH2, -CH2NHCH2, -CH.-N (RiOCH2-, CH2(Re)N-, CH(R11), S, CH2(C0), NH, NRe, (C0)CH2, N(Re)CON(Re), N(Re)C(=S)N(Re), SO2 or SO, wherein Rn is optionally substituted C1-12 alkyl, C3-12 cycloalkyi, C1-6 alkoxy, C 1-6 alkyl, C1-6alkylcarbonyl, C1-6 alkylcarboxy, aryl or heteroaryl
,Re is hydrogen, optionally substituted C1-12 alkyl, C3-12 cycloalkyl, C1-6 alkoxy, C1-6 alkyl, C1-6 alkylcarbonyl, C1-6 alkylcarboxy, aryl or heteroaryl;
A can be no group or selected from group consisting of;
(Formula Removed)

wherein,
XisCH, CH-S, CH-OorN;
Q is O , N or S;
n is an integer 0-1 and m is an integer from 0-2.
Compounds disclosed herein can be useful antimicrobial agents, effective against a number of human and veterinary pathogens, particularly aerobic and Gram-positive bacteria, including multiply-antibiotic resistant staphylococci and streptococci, as well as anaerobic organisms such as Mycobacterium tuberculosis and other mycobacterium species.
Pharmaceutical compositions comprising the compounds of the invention their enantiomers, diastereomers, polymorphs, pharmaceutically acceptable salts, pharmaceutically acceptable solvates, N-oxides or metabolites in combination with pharmaceutically acceptable carriers and optionally included excipients are also provided herein.
For preparing pharmaceutical compositions from the compounds described herein pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, suppositories and ointments. A solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, or tablets disintegrating agents; it can also be as finely divided solid which is in admixture with the finely divided active compound. For the preparation of tablets, the active compound is mixed with carrier having the necessary binding
as finely divided solid which is in admixture with the finely divided active compound. For the preparation of tablets, the active compound is mixed with carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain from about 5 to about 70 percent of the active ingredient. Suitable solid carriers are lactose, pectin, dextrin, starch, gelatin, tragacanth, low melting wax, cocoa butter and the like. The term "preparation" is intended to include the formulation of the active compound with encapsulating material as carrier providing a capsule in which the active component (with or without other carriers) is surrounded by carrier, which is thus in association with it. Similarly, capsules can be used, as solid dosage forms suitable for oral administration.
Liquid form preparations include solutions suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection. Such solutions are prepared so as to be acceptable to biological systems (isotonicity, pH, etc.). Liquid preparations can also be formulated in solution in aqueous polyethylene glycol solution. Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing, and thickening agents as desired. Aqueous suspension suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, i.e., natural or synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose and other well-known suspending agents.
Ointment preparations contain compounds of Formula I and its salts with a physiologically acceptable carrier. The carrier is desirably a conventional water-dispersible hydrophilic or oil-in-water carrier, particularly a conventional semi-soft or cream-like water-dispersible or water soluble, oil-in-water emulsion infected surface with a minimum of discomfort. Suitable compositions may be prepared by merely incorporating or homogeneously admixing finely divided compounds with the hydrophilic carrier or base or ointment.
The pharmaceutical preparation can be in unit dosage form. In such forms, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete capsules, powders in vials or ampoules and ointments capsule, cachet, tablet, gel, or cream itself or it can be the appropriate number of any of these packaged forms.
The quantity of active compound in a unit dose of preparation may be varied or adjusted from less than 1 mg to several grams according to the particular application and the potency of the active ingredient.
In therapeutic use as agents for treating bacterial infections the compounds utilized in the pharmaceutical method of this invention are administered at the initial dosage of about 3 mg to about 40 mg per kilogram daily. The dosages, however, may be varied depending upon the requirements of the patient and the compound being employed. Determination of the proper dosage for a particular situation is within the smaller dosages, which are less than the optimum dose. Small increments until the optimum effect under the daily dosage may be divided and administered in portions during the day if desired.
In another aspect, process for the synthesis of compounds of Formula I are provided. Pharmaceutically acceptable acid addition salts of the compounds of Formula I may be formed with inorganic or organic acids, by methods well known in the art.
Prodrugs of compounds of Formula I. In general, such prodrugs will be functional derivatives of these compounds, which readily get converted in vivo into defined compounds. The artisan of ordinary skill in the art knows conventional procedures for the selection and preparation of suitable prodrugs.
Other advantages of the invention will be set forth in the description which follows, and in part will be apparent from the description, or may be learned by the practice of the invention.
The following definitions apply to terms as used herein;
The term "alkyl" unless and otherwise specified refers to a monoradical branched or unbranched
saturated hydrocarbon chain having from I to 20 carbon atoms. This term is exemplified by
groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, n-hexyl, n-decyl,
tetradecyl, and the like.
It may further be substituted with one or more substituents selected form the group consisting of
alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy,
alkoxycarbonylamino, azido, cyano, halogen, hydroxy, oxo, thiocarbonyl, carboxy,
carboxyalkyi, aryl, heterocyclyl, heteroaryl, arylthio, thiol, alkylthio, aryloxy, nitro,
aminosulfonyl, aminocarbonylamino, -NHC(=0)Rf, -NRfRq, -C(=0)NRtRq, -NHC(=0)NRtRq,, -
C(=0)heteroaryl, C(=0)heterocyclyl, -0-C(=0)NRtRq [wherein Rf and Rq are independently selected from alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, aralkyl, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl], nitro, -SO2R6 (wherein R(, is alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl, aryl, heterocyclyl, heteroaryl, heteroarylalkyl or heterocyclylalkyl). Unless otherwise constrained by the definition, all substituents may be further substituted by 1-3 substituents chosen from alkyl, carboxy, -NRfRq, -C(=0)NR(Rq, -OC(=0) NRfRq , -NHC(=0)NRtRq (wherein Rf-and Rq are the same as defined earlier), hydroxy, alkoxy, halogen, CF3, cyano, and -SO2R6, (where R6 are the same as defined earlier);
or an alkyl group as defined above may also be interrupted by 1-5 atoms of groups independently chosen from oxygen, sulfur and -NRg- [ wherein Ra is chosen from hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, acyl, aralkyl,-C(=0)ORf [wherein Rf is the same as defined earlier], SO2R6 (where R6 is as defined earlier), -C(=0)NRfRq (wherein Rf and Rq are as defined earlier)]. Unless otherwise constrained by the definition, all substituents may be further substituted by 1-3 substituents chosen from alkyl, carboxy, -NRfRq, -C (=0)NRfRq, -O-C(=0)NRfRq wherein Rf and Rq are the same as defined earlier hydroxy, alkoxy, halogen, CF3, cyano, and -SO2R6 (where R6 is same as defined earlier);
or an alkyl group as defined above that has both substituents as defined above and is also interrupted by 1-5 atoms or groups as defined above.
The term "alkenyl" unless and otherwise specified refers to a monoradical of a branched or unbranched unsaturated hydrocarbon group preferably having from 2 to 20 carbon atoms with cis or trans geometry. In the event that alkenyl is attached to the heteroatom, the double bond cannot be alpha to the heteroatom.
It may further be substituted with one or more substituents selected from the group consisting of alkyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, -NHC (=0)Rf, -NRfRq, -C(=0)NRfRq, -NHC(=0)NRfRq , -0-C(=0)NRfRq (wherein Rf and Rq are the same as defined earlier), alkoxycarbonylamino, azido, cyano, halogen, hydroxy, 0x0, thiocarbonyl, carboxy, arylthio, thiol, alkylthio, aryl, aralkyl, aryloxy, heterocyclyl, heteroaryl, heterocyclyl alkyl, heteroaryl alkyl, aminosulfonyl, aminocarbonylamino, alkoxyamino, nitro, SO2R6 (wherein R6 are is same as defined earlier). Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1-3 substituents chosen from alkyl, carboxy.
hydroxy, alkoxy, halogen, -CF3, cyano, -NRfRq, -C(=0)NRfRq, -0-C(=0)NRfRq (wherein Rf and Rq are the same as defined earlier) and -S02R6( where R6 is same as defined earlier).
The term "alkynyl" unless and otherwise specified refers to a monoradical of an unsaturated hydrocarbon, preferably having from 2 to 20 carbon atoms.
In the event that alkynyl is attached to the heteroatom, the triple bond cannot be alpha to the heteroatom.
It may further be substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, 0x0, thiocarbonyl, carboxy, arylthio, thiol, alkylthio, aryl, aralkyl, aryloxy, aminosulfonyl, aminocarbonylamino, nitro, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl, -NHC(=0)Rf, -NRfRq, -NHC(=0)NRfRq , -C(=0)NRfRq, -O-C(=0)NRtRq (wherein Rf and Rq are the same as defined earlier), -SO2R6 (wherein R6 is same as defined earlier). Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1-3 substituents chosen from alkyl, carboxy, carboxyalkyl, hydroxy, alkoxy, halogen, CF3, -NRfRq, -C(=0)NRfRq, -NHC(=0)NRfRq, -C(=0)NRfRq (wherein Rf and Rq are the same as defined earlier), cyano, and -SO2R6 (where R(, is same as defined earlier).
The term "cycloalkyl" refers to cyclic alkyl groups of from 3 to 20 carbon atoms having a single cyclic ring or multiple condensed rings, which may optionally contain one or more olefinic bonds, unless or otherwise constrained by the definition. Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclooctyl, cyclopentenyl, and the like, or multiple ring structures such as adamantanyl, and bicyclo [2.2.1] heptane, or cyclic alkyl groups to which is fused an aryl group, for example indane, and the like.
It may further be substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, 0x0, thiocarbonyl, carboxy, carboxyalkyl, arylthio, thiol, alkylthio, aryl, aralkyl, aryloxy, aminosulfonyl, aminocarbonylamino, -NRfRq, -NHC (=0) NRfRq, -NHC (=0) Rf, -C (=0) NRfRq, -0-C (=0)NRfRq (wherein Rf and Rq are the same as defined earlier), nitro, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl, SO2-R6 (wherein R6 is same as defined earlier). Unless
otherwise constrained by the definition, all substituents may optionally be further substituted by 1-3 substituents chosen from alkyl, carboxy, hydroxy, alkoxy, halogen, CF3, -NRfRq, -C{=0)NR,Rq, -NHC(=0)NRtRq , -0-C(=0)NRfRq (wherein Rf and Rq are the same as defined earlier),cyano, and -S02R6( where Re is same as defined earlier).
The term "alkoxy" denotes the group 0-alkyl wherein alkyl is the same as defined above.
The term "aryl" herein refers to a carbacyclic aromatic group, for example phenyl, biphenyl or napthyl ring and the like optionally substituted with 1 to 3 substituents selected from the group consisting of halogen (F, C1, Br, I), hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, acyl, aryloxy, CF3, cyano, nitro, COORe(wherein Re is hydrogen, alkyl, alkenyl, cycloalkyl, aralkyl, heterocyclylalkyl, heteroarylalkyl), NHC(=0)Rf, -NR,Rq, -C(=0)NRfRq, -NHC(=0)NRfRq, -O-C(=0)NRfRq( wherein Rf and Rq are the same as defined earlier), -SO2R6 (wherein R6 is same as defined earlier), carboxy, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl or amino carbonyl amino. The said aryl group may optionally be fused with cycloalkyl group, wherein the said cycloalkyl group may optionally contain heteroatoms selected from the group consisting of O, N, and S.
The term "aralkyl" refers to alkyl-aryl linked through alkyl (wherein alkyl is the same as defined above) portion and the said alkyl portion contains carbon atoms from 1-6 and aryl is as defined below.
The term "heteroaryl" unless and otherwise specified refers to an aromatic or bicyclic aromatic group having 5 to 10 atoms in which I to 4 carbon atoms in a ring are replaced by heteroatoms selected from the group comprising of O, S or N, optionally substituted with 1 to 4 substituent(s) selected from the group consisting of halogen (F, C1, Br, I), hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, acyl, carboxy, aryl, alkoxy, aralkyl, cyano, nitro, heterocyclyl, heteroaryl, -NRfRq, CH=NOH, -(CH2)wC(=0)Rg [wherein w is an integer from 0-4 and Rg is hydrogen, hydroxy, OR,, NRfRq, -NHORz or -NHOH], -C(=0)NRfRq and -NHC(=0)NRfRq , -SO2Re, -O-C(=0)NRfRq, -0-C(=0)Rf, -0-C(=0)0Rf (wherein R6, Rj, Rf and Rq are the same as defined earlier). Unless or otherwise constrained by the definition, the substituents are attached to the ring atom, be it carbon or heteroatom.
Examples of heteroaryl groups are oxazolyl, imidazolyl, pyrrolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, thiazolyl, oxadiazolyl, benzoimidazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, thienyl, isoxazolyl, triazinyl, furanyl, benzofuranyl, indolyl, benzothiazolyl, benzoxazolyl, and the like.
The term 'heterocyclyl" unless and otherwise specified refers to a non aromatic monocyclic or bicyclic cycloalkyi group having 5 to 10 atoms in which 1 to 4 carbon atoms in a ring are replaced by heteroatoms selected from the group comprising of O, S or N, and are optionally benzofused or fused heteroaryl of 5-6 ring members and/or are optionally substituted wherein the substituents are selected from the group consisting of halogen (F, C1, Br, I), hydroxy, alkyl, alkenyl, alkynyl, cycloalkyi, acyl, aryl, alkoxy, alkaryl, cyano, nitro, oxo, carboxy, heterocyclyl, heteroaryl, -0-C(=0)Rt-, -0-C(=0)OR,; -C(=0)NRfRq, SO2R6, -0-C(=0)NRf-Rq, -NHC(=0)NRfRq, -NRfRq (wherein R6, Rf and Rq are the same as defined earlier)or guanidines. Unless or otherwise constrained by the definition, the substituents are attached to the ring atom, be it carbon or heteroatom. Also unless or otherwise constrained by the definition the said heterocyclyl ring may optionally contain one or more olefinic bond(s).
Examples of heterocyclyl groups are oxazolidinyl, tetrahydrofuranyl, dihydrofuranyl, dihydropyridinyl, dihydroisoxazolyl, dihydrobenzofuryl, azabicyclohexyl, dihydroindolyl, piperidinyl or piperazinyl.
The term "acyl" refers to -C(=0)R" wherein R" is selected from the group hydrogen, alkyl, cycloalkyi, aryl, aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl or heterocyclylalkyl.
"Substituted amino" unless and otherwise specified refers to a group -N (Rk) 2 wherein each Rk is independently selected from the group hydrogen [provided that both Rk groups are not hydrogen (defined as "amino")], alkyl, alkenyl, alkynyl, aralkyl, cycloalkyi, aryl, heteroaryl, heterocyclyl, heterocyclylalkyl, heteroarylalkyl, acyl, SO2R6 (wherein Re is the same as defined above), -C(=T)NRrRq or NHC(=T)NRfRq (wherein T, Rf and Rq are the same as defined earlier)
The term "leaving group" generally refers to groups that exhibit the desirable properties of being labile under the defined synthetic conditions and also, of being easily separated from synthetic products under defined conditions. Examples of such leaving groups includes but not limited to
halogen (F, C1, Br, I), triflates, tosylate, mesylates, alkoxy, thioalkoxy, hydroxy radicals and the like.
The term "protecting groups" is used herein to refer to known moieties which have the desirable property of preventing specific chemical reaction at a site on the molecule undergoing chemical modification intended to be left unaffected by the particular chemical modification. Also the term protecting group, unless or other specified may be used with groups such as hydroxy, amino, carboxy and examples of such groups are found in T.W. Greene and P.G.M. Wuts, "Protective groups in organic synthesis", 2nd ED, John Wiley and Sons, New York, N.Y., which is incorporated herein by reference. The species of the carboxylic protecting groups, amino protecting groups or hydroxy protecting group employed is not so critical so long as the derivatised moieties/moiety is/are stable to conditions of subsequent reactions and can be removed at the appropriate point without disrupting the remainder of the molecule.
The term "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds of Formula 1 are modified by making its acid or base salts. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acids salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
The present invention is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include C-13 and C-14.
The compounds of this invention contain one or more asymmetric carbon atoms and thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. All such isomeric forms of these compounds are expressly included in the present invention. Each stereogenic carbon may be of the R or S configuration. Although the specific compounds exemplified in this application may be depicted in a particular stereochemical configuration, compounds having either the opposite stereochemistry at any given chiral center or mixtures thereof are envisioned as part of the invention. Although amino
acids and amino acid side chains may be depicted in a particular configuration, both natural and unnatural farms are envisioned as part of the invention.
DETAILED DESCRIPTION OF THE INVENTION
The compounds described herein are represented by general Formula I, and may be prepared by techniques well known in the art and familiar to the skilled synthetic organic chemist. In addition, the compounds of the present invention may be prepared by the following reaction sequence as depicted in Scheme I, II, III, IV and V of the accompanied drawing.
SCHEME-I
The compound of Formula IV can be prepared following Scheme I, as shown in the accompanied drawing. Thus, a compound of Formula II [wherein U, V and R1 are same as defined earlier] is reacted with a compound of Formula III (wherein hal is chlorine, bromine or fluorine) to yield a compound of Formula IV.
The reaction of compound of Formula II with a compound of Formula III, to yield a compound of Formula IV, is carried out in an organic solvent for example dimethyl formamide, 1,4-dioxane or tetrahydrofuran and a base for example triethylamine, 4-dimethylamino pyridine or N-methyl morpholine in the presence of a palladium catalyst for example dichlorobistriphenylphosphine palladium (II) or tetrakistriphenylphosphine palladium (0).
Compounds prepared following scheme I are:
N-({(5S)-3-[4-(2,l,3-benzoxadiazol-5-yl)-3-fluorophenyl]-2-oxo-l,3-oxazolidin-5-yl}methyl)acetamide(Compound No.l)
N-({(55)-3-[4-(2,l,3-benzoxadiazol-5-yl)-3,5-dif1uorophenyl]-2-oxo-I,3-oxazolidin-5-yl}methyl)acetamide(Compound No.2)
SCHEME-II
The compound of Formula IX can be prepared following Scheme II, as shown in the accompanied drawings. Thus, a compound of Formula V (wherein U, V, W and A are as defined earlier, P is a protecting group and G is H or a leaving group as mesyl, tosyl or triflyl) is reacted with a compound of Formula VI (wherein Het is a heterocyclyl or heteroaryl) to yield a compound of Formula VII which on deprotection gives compound of Formula VIII. The compound of Formula VIII on reaction with a compound of Formula III gives a compound of Formula IX.
The reaction of compound of Formula V with a compound of Formula VI, to yield a compound of Formula VII is carried out in an organic solvent for example dimethyl formamide, 1,4-dioxane or tetrahydrofuran and a base for example sodium hydride, potassium hydride or lithium hydride.
Further, the compound of Formula VII is deprotected to give the compound of Formula VIII in the presence of agent such as trifluoroacetic acid in dichloromethane or hydrochloric acid in ethanol.
The reaction of the compound of Formula VIII with the compound of Formula III to give the compound of Formula IX, is carried out in an organic solvent for example tetrahydrofuran, benzene, dimethylformamide or carbon tetrachloride using a base for example cesium carbonate, sodium tertiary butoxide or potassium tertiary butoxide in the presence of a catalyst for example Tris (dibenzelideneacetone) dipalladium(O), palladium diacteate or palladium dichloride with a suitable ligand for example l,r-binaphthalene-2,2'-diylbis(diphenylphosphine), tri-tert-butylphosphine, di-l-adamantyl(butyl)phosphine or biphenyl-2-yl(di-tert-butyl)phosphine.
Compounds prepared following scheme II are:
(5R)-3-{4-[4-(2,1,3-benzoxadiazol-5-yl)piperazin-1 -yl]-3-fluorophenyl }-5-( IH-1,2,3-triazol-1 -ylmethyl)-l,3-oxazolidin-2-one(Compound No.3);
(5R)-3-{4-[4-(2,l,3-benzoxadiazol-5-yl)piperazin-l-yl]-3-fluorophenyl}-5-(2//-l,2,3-triazol-2-ylmethyl)-1,3-oxazolidin-2-one(Compound No.4);
(5R)-3-(4-{ [ 1 -(2,1,3-benzoxadiazol-5-yl)piperidin-4-yl]oxy}-3-fluorophenyl)-5-( 1H-1,2,3-triazol-1 -yimethyl)-1,3-oxazolidin-2-one(Compound No.5).
SCHEME- III
The compound of Formulae XIII and XVII can be prepared following Scheme III, as shown in the accompanied drawings.
Path A: A compound of Formula V (wherein U, V, W, A, P and G are as defined earlier) is reacted with a compound of Formula X (Het and P are same as defined earlier) to yield a compound of Formula XI which on further deprotection gives a compound of Formula XII. The compound of Formula XII on reaction with a compound of Formula III gives a compound of Formula XIII.
Path B- A compound of Formula V(wherein U, V, W, A, P and G are as defined earlier) is reacted with a compound of Formula XIV (wherein Het is same as defined earlier) to yield a compound of Formula XV which on deprotection gives a compound of Formula XVI. The compound of Formula XVI on reaction with a compound of Formula III gives a compound of Formula XVII.
The reaction of compound of Formula V with a compound of Formula X (Path A) to yield a compound of Formula XI is carried out in an organic solvent for example dimethyl formamide, 1,4-dioxane or tetrahydrofuran and a base for example sodium hydride, lithium hydride or potassium hydride.
Further the compound of Formula XI is deprotected to give the compound of Formula XII in the presence of a deprotecting agent such as trifluoroacetic acid in dichloromethane or hydrochloric acid in ethanol.
The reaction of the compound of Formula XII with the compound of Formula III to give the compound of Formula XIII, is carried out in an organic solvent for example tetrahydrofuran, benzene, dimethylformamide or carbon tetrachloride and a base for example cesium carbonate, sodium tertiary butoxide or potassium tertiary butoxide in the presences of a catalyst for example Tris (dibenzelideneacetone) dipalladium(O) Pd2(dba)3, palladium diacteate or palladium dichloride with a suitable ligand for example I,r-binaphthalene-2,2'-diylbis(diphenylphosphine),
tri-tert-butylphosphine, di-l-adamantyl(butyl)phosphine or biphenyl-2-yl(di-tert'-buty-phosphine.
The reaction of compound of Formula V with a compound of Formula XIV (Path B) to yield a compound of Formula XV, is carried out in an organic solvent for example tetrahydrofuran, benzene, dimethylformamide or carbon tetrachloride using suitable coupling agent such as diethyl diazocarboxylate or disopropyl diazocarboxylate and in the presence of a catalyst selected from triphenyl phosphine, trioctyl phosphine or tributyl phosphine.
Further the compound of Formula XV is deprotected to give the compound of Formula XVI in the presence of a deprotecting agent such as trifluoroacetic acid in dichloromethane or hydrochloric in ethanol.
The reaction of the compound of Formula XVI with the compound of Formula III to give the compound of Formula XVII, is carried out in an organic solvent for example tetrahydrofuran, benzene, dimethylformamide or carbon tetrachloride and a base for example cesium carbonate, sodium tertiary butoxide or potassium tertiary butoxide in the presences of a catalyst for example Tris (dibenzelideneacetone) dipalladium(O), palladium diacteate or palladium dichloride with a suitable ligand for example l,r-binaphthalene-2,2'-diylbis(diphenylphosphine), di-1-adamantyl(butyl)phosphine or biphenyl-2-yl(di-tert-butyl)phosphine.
Compounds prepared following scheme III are;
(55)-3-{4-[4-(2,l,3-benzoxadiazol-5-yl)piperazin-l-yl]-3-fluorophenyl}-5-[(isoxazol-3-ylamino)methyl]-l,3-oxazolidin-2-one(Compound No.6);
(55)-3-(4-{ [ 1 -(2,1,3-benzoxadiazol-5-yl)piperidin-4-yl]oxy}-3-fluorophenyl)-5-[(isoxazol-3-ylamino)methyl]-I,3-oxazolidin-2-one(Compound No.7);
(5R)-3-{4-[4-(2,l,3-benzoxadiazol-5-yl)piperazin-l-yl]-3-fluorophenyl}-5-(isoxazol-3-ylmethyl)-1,3-oxazolidin-2-one(Compound No.8);
(5R)-3-(4-{[l-(2,l,3-benzoxadiazol-5-yl)piperidin-4-yl]oxy}-3-fluorophenyl)-5-[(isoxazol-3-yloxy)methyl]-1,3-oxazolidin-2-one(Compound No.9).
SCHEME-IV
The compounds of Formulae XIX and XX can be prepared following Scheme IV, as shown in the accompanied drawings. Thus, a compound of Formula XVIll is coupled with 5-formylbenzofuroxan to yield a compound of Formula XIX, which on further deoxygenation gives a compound of Formula XX.
The reaction of a compound of Formula XVIII with 5-formylbenzofuroxan to give a compound of Formula XIX is carried out in an organic solvent for example tetrahydrofuran, dimethyl formamide or 1,4-dioxane in the presence of a reducing agent for example sodium triacetoxy borohydride or sodium borohydride.
The compound of Formula XIX is further deoxygenated to give a compound of Formula XX in an organic solvent for example ethanol or methanol in the presence of a catalyst for example triphenyl phosphine, trioctyl phosphine or tributyl phosphine.
Compounds prepared following scheme IV are:
N-{[(55)-3-(3-fluoro-4-{4-[(oxido-2,l,3-benzoxadiazol-5-yl)methyl]piperazin-l-yl}phenyl)-2-0X0-1,3-oxazolidin-5-yl]methyl}acetamide(Compound No. 10);
N-[((55)-3-{4-[4-(2,l,3-benzoxadiazol-5-ylmethyl)piperazin-l-yl]-3-fluorophenyl}-2-oxo-l,3-oxazolidin-5-yl)methyl]acetamide(Compound No.l 1).
The compound of Formula XXII can be prepared, according to Scheme V, as shown in the accompanied drawing. Thus, a compound of Formula XXI is coupled with a compound of Formula 111 to yield a compound of Formula XXII.
The reaction of compound of Formula XXI with a compound of Formula III to give the compound of Formula XXII, is carried out in an solvent for example acetonitrile, chloroform or
carbontetrachloride in presence of a base for example disopropyl ethylamine triethylamine or N-methyl morpholine.
Alternatively the reaction of the compound of Formula XXI with the compound of Formula III to give the compound of Formula XXII can also be carried out in an organic solvent for example acetonitrile, tetrahydrofuran, benzene, dimethylformamide or carbon tetrachloride, and a base for example cesium carbonate, sodium tertiary butoxide or potassium tertiary butoxide in the presence of a catalyst for example Tris (dibenzelideneacetone) dipalladium(O), palladium diacteate or palladium dichloride with a suitable ligand for example l,r-binaphthalene-2,2'-diylbis(diphenylphosphine), tri-tert-butylphosphine, di-l-adamantyl(butyl)phosphine or biphenyl-2-yl(di-tert-butyl)phosphine.
Compounds prepared following scheme V are:
iV-{[(55)-3-(4-{[l-(2,I,3-benzoxadiazol-5-yl)piperidin-4-yl]oxy}-3-fluorophenyl)-2-oxo-l,3-oxazolidin-5-yI]methyl}acetamide(Compound No.l2);
N-[((55)-3-{4-[4-(2,l,3-benzoxadiazol-5-yi)piperazin-I-yl]-3-fluorophenyl}-2-oxo-l,3-oxazolidin-5-yl)methyl]acetamide (Compound No. 13);
yV-[((55)-3-{4-[4-(2,l,3-benzoxadiazol-5-yl)piperazin-l-yl]-3,5-difluorophenyl}-2-oxo-l,3-oxazolidin-5-yl)methyl]acetamide(Compound No. 14).
(Formula Removed)

wherein U is F,
(Table Removed)
(Table Removed)
Examples set forth below demonstrate the general synthetic procedure for the preparation of representative compounds. The examples are provided to illustrate particular aspect of the disclosure and should not be constrained to limit the scope of the present invention.
EXPERIMENTAL
Example 1
Synthesis N-({(5S)-3-l4-(2,l,3-benzoxadiazol-5-vl)-3-fluorophenvll-2-oxo-l,3-oxazolidin-5-ylfmeth yl) ace t amide
To N-({(55)-3-[3-fluoro-4-(trimethylstannyl)phenyl]-2-oxo-l,3-oxazolidin-5-yl}methyl)acetamide (0.18 gm) (prepared according to the procedures given in WO 01/94342)in dry dimethyl formamide (15 ml) was added 5-bromo-2,l,3-benzoxadiazole (0.17 gm) (prepared according to the procedure given in Organic Process Research Development 2003,7,436-445), triethylamine (0.11 gm) and dichlorobistriphenylphosphine palladium (II) (0.12gm) and heated for about 3 hrs at 100°C, cooled and diluted with ethyl acetate. The organic layer was washed
with water, dried over sodium sulphate and concentrated. The crude product was purified by
column chromatography using 2% methanol in dichloromethane as eluant to yield the title
compound (0.14 gm).
Melting point: 156-165 °C;
EIMS (m/z): 388 (M+H);
1HNMR(CDC13): 5 7.91 (m, 2H), 7.62 (m, 2H), 7.52 (t, IH), 7.35 (dd, IH), 6.10 (t, IH), 4.84
(m, IH), 4.12 (t, IH), 3.87 (t, IH), 3.71 (m,2H), 2.02 (s, 3H).
Example 2 Synthesis N-({(SS)-3-l4-(2,l,3-benzoxadiazol-5-vl)-3,5-difluorophenvll-2-oxo-l,3-oxazolidin-5-vl}methvl)acetamide
To N-({(55)-3-[3,5-difluoro-4-(trimethylstannyl)phenyl]-2-oxo-l,3-oxazolidin-5-yl}methyl)acetamide(0.21gm) (prepared according to the procedure given in WO 01/94342) in dry dimethyl formamide( 15 ml), was added triethyl amine (0.12gm), 5-bromo-2,l,3-benzoxadiazole(0.19gm) and dichlorobistriphenylphosphine palladium(II) (0.13gm) and heated for about 3 hrs at 100°C. The reaction mixture was filtered and diluted with ethyl acetate, the organic layer was washed with water, dried over sodium sulphate and concentrated. The crude product was purified by column chromatography using 2% methanol in dichloromethane as eluant to yield the title compound (0.035gm). Melting point: 165-168°C;
EIMS (m/z): 388;
'HNMR(CDC13): 5 7.92 (m, 2H), 7.48 (dd, IH), 7.32 (dd, 2H), 5.98 (t, IH), 4.85 (m, IH), 4.09
'HNMR(CDC13): (
(t, IH), 3.84 (m, IH), 3.72 (m, 2H), 2.03 (s, 3H).
Example 3
Synthesis of (5R)-3-{4-f4-(2,l,3-benzoxadiazol-5-vl)piperazin-l-vl]-3-fluoroDhenvl)-5-(lH-l,2,3-triazol-l-vlmethvl)-l,3-oxazolidin-2-one
Step a.- Synthesis of tert-butyl 4-{2-fluoro-4-[(5R)-2-oxo-5-(lH-l,2,3-triazol-l-ylmethyl)-l,3-oxazolidm-3-yl]phenyl}piperazine-l-carboxylate.
To a compound tert-buty\ 4-[2-fluoro-4-((5R)-5-{[(methylsulfonyl)oxy]methyl}-2-oxo-l,3-
oxazolidin-3-yl)phenyl]piperazine-l-carboxylate (4gm) (prepared according to the procedures
W093/23384) taken in dry dimethylformamide (15ml), was added sodium hydride (0.61 gm) and
lH-l,2,3-triazole (0.7ml) and the reaction mixture was stirred for about 17 hrs at 80°C and
extracted with ethyl acetate. The organic layer was washed with water, dried over sodium
sulphate and concentrated. The crude product was purified by column chromatography using (
4%) methanol in dichloromethane as eluant to yield the title compound (1.45gm).
Step b; Synthesis of (5R)-3-(3-fluoro-4-piperazin-1 -ylphenyl)-5-(1H-l,2,3-triazol-1 -ylmethyl)-
l ,5-oxazolidin-2-one.
To the compound (0.7gm), obtained from step a above in dichloromethane (15ml) was added
trifluoroacteic acid(5ml) and stirred for about 2 hrs, the solvent was concentrated. To the residue
was added ethyl acetate(20ml) followed by 10% sodium hydroxide(lOml) till pH 12-14, the
organic layer was separated and washed with water, dried over sodium sulphate and
concentrated to get the title compound (0.98gm).
Step c: Synthesis of(5R)-3-{4-[4-(2,l,3-benzoxadiazol-5-yl) piperazin-l-yl]-3-fluorophenyl}-5-
(1H-1,2,3-triazol-l-ylmethyl)-l,3-oxazolidin-2-one.
To the compound (5R)-3-(3-fluoro-4-piperazin-l-ylphenyl)-5-(lH-1,2,3-triazol-1-ylmethyl)-1,3-
oxazolidin-2-one(0.98gm) (obtained from the Step b above) taken in dry
dimethylformamide(15ml) was added 5-bromo-2,l,3-benzoxadiazol (0.56gm), cesium carbonate
(l.lgm), 2,2'-bis(diphenylphosphino)-l,r-binapthyl(0.14gm) and Tris (dibenzelideneacetone)
dipalladium(O) (0.1 gm) added and heated for about 17 hrs at 100 °C. The reaction mixture was
filtered and the solvent was evaporated and the crude product was purified by column
chromatography using 2% methanol in dichloromethane to get the title product (0.17g).
Melting point: 153-173°C;
EIMS(m/z): 465.17;
'HNMR(DMSO): 5 8.17 (s, 1H), 7.90-7.87 (d, 1H), 7.74 (t, 2H), 7.44 (dd, 1H), 7.13 (m, 2H),
6.89 (s, 1H), 5.15-5.10 (m, 1H), 4.83 (d, 2H), 4.21 (t, 1H), 3.89-3.84 (t, 1H), 3.48 (m, 4H), 3.14
(m, 4H).
Example 4
triazol-2-vlmethvl)-l,3-oxazolidin-2-one
Step a; Synthesis of tert-butyl 4-{2-fluoro-4-[(5R)-2-oxo-5-(2H-l,2,3-triazol-l-ylmethyl)-l,3-
oxazolidin-3-ylJphenyljpiperazine-1 -carboxylate
To tert-butyl 4-[2-fluoro-4-((5R)-5-{[(methylsulfonyl)oxy]methyl}-2-oxo-l,3-oxazolidin-3-
yl)phenyl]piperazine-l-carboxylate (4gm) (prepared according to the procedures
W093/23384)in dry dimethylformamide (15ml), was added sodium hydride (0.6 Igm) and 2H-
1,2,3-triazole (0.7ml) and the reaction mixture was stirred for about 17 hrs at 800C. The reaction
mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over
sodium sulphate and concentrated. The crude product was purified by column chromatography
using ( 3 %) methanol in dichloromethane as eluant to yield the title compound (0.9gm).
Step b; Synthesis of(5R)-3-(3-fluoro-4-piperazin-l-ylphenyl)-5-(2H-l,2,3-triazol-l-ylmethyl)-
1,3-oxazolidin-2-one.
To the compound (0.7gm), obtained from step a above in dichloromethane(15ml) was added
trifiuoroacteic acid(5ml) and stirred for about 2 hrs, the solvent was concentrated and to the
residue was added ethyl acetate(20ml) followed by 10% sodium hydroxide(l0ml) till pH 12-14.
The organic layer which separated out was washed with water, dried over sodium sulphate and
concentrated to get the title compound (0.7gm).
Step c: Synthesis of(5R)-3-{4-[4-(2, l,3-benzoxadiazol-5-yl)piperazin-l-yl]-3-fluorophenyl}-5-
(2H-1,2,3-triazol-1 -ylmethyl)-!, 3-oxazolidin-2-one.
To the compound (0.7gm) obtained from the Step b above in dry dimethylformamide(15ml) was
added 5-bromo-2,l,3-benzoxadiazole (0.4gm), cesium carbonate (0.79gm), 2,2'-
bis(diphenylphosphino)-l,r-binapthyl (0.1gm) and Tris (dibenzelideneacetone) dipalladium(O)
(0.74gm) and heated for about 17 hrs at 1000C. The reaction mixture was filtered and the solvent
was evaporated and the crude product was purified by column chromatography using 2%
methanol in dichloromethane to get the title product (0.2g).
Melting point: 215-220 °C;
'HNMR(DMSO): 5 7.91-7.83 (m,3H), 7.73 (d, 1H), 7.43 (dd, 1H), 7.13 (d, 2H), 6.89 (s, 1H),
EIMS(m/z): 465.21; 'HNMR(DMSO): 5 7 5.18 (m, 1H), 4.86 (d, 2H), 4.22 (t, 1H), 3.91-3.86 (m, 1H), 3.48 (m, 4H), 3.14 (m, 4H).
Example 5
Synthesis of (5R)-3-(4-{fl-(2,l,3-benzoxadiazol-5-vl)pipendin-4-vl/oxv}-3-fluorophenvl)-5-(lH-l,2,3-triazol-l-vlmethvl)-l,3-oxazolidin-2-one
Step a: tert-butyl 4-{4-[(5R)-2-oxo-5-(lH-l,2,3-triazol-l-ylmethyl)-l,3-oxazolidin-3-
yl]phenoxy}piperidine-l-carboxylate.
To tert-buty\ 4-[2-fluoro-4-((5R)-5-{[(methylsulfonyl)oxy]methyl}-2-oxo-l,3-oxazoHdin-3-
yl)phenoxy]piperidine-l-carboxylate (2 gm) (prepared according to the procedures similar to that
given in Biorganic and Medicinal Chemistry Letters 11(2001), 1829-1832) in dry
dimethylformamide (15ml), was added sodium hydride (0.3 gm) and lH-l,2,3-triazole (0.3ml)
and stirred for about 17 hrs at 80°C. The reaction mixture was extracted with ethyl acetate
washed with water, dried over sodium sulphate and concentrated and the crude was purified by
column chromatography using ( 2%) methanol in dichloromethane as eluant to yield the title
compound (0.68gm).
Step b: Synthesis of(5R)-3-[3-fluoro-4-(piperidin-4-yloxy)phenyl]-5-(lH-l,2,3-thazol-l-
ylmethyl)-l,3-oxazolidin-2-one.
To the compound (0.68gm) obtained from step a above taken in dichloromethane(10ml) was
added trifluoroacteic acid(4 ml) and stirred for about 2 hrs, the solvent was concentrated and to
the residue was added ethyl acetate(20ml) followed by 10% sodium hydroxide(10ml) till pH 12-
14. The organic layer which separated out was washed with water, dried over sodium sulphate
and concentrated to get the title compound (1 gm).
Step c: Synthesis of(5R)-3-(4-{[l-(2,l,3-benzoxadiazol-5-yl)pipendin-4-yl]oxy}-3-
fluorophenyl)-5-(lH-l,2,3-triazol-l-ylmethyl)-l,3-oxazolidin-2-one.
To the compound (1 gm) obtained from the Step b above in dry dimethylformamide (10ml) was
added 5-bromo-2,l,3-benzoxadiazole (0.61gm), cesium carbonate (1.2gm), 2,2'-
bis(diphenylphosphino)-l,r-binapthyl (0.51gm) and Tris (dibenzelideneacetone) dipalladium(O)
(0.1 1 gm) and heated for about 17 hrs at 100 °C. The reaction mixture was filtered and the
solvent was evaporated .The crude product was purified by column chromatography using 1%
methanol in dichloromethane to get the title product(0.15g)
Melting point: 148-150°C;
EIMS (m/z): 480.02;
'HNMR(DMSO): 5 7.85 (d, 3H), 7.68 (d, 1H), 7.46 (dd, 1H), 7.28 (t, 1H), 7.15 (d, 1H), 6.85 (s, 1H), 5.2 (m, 1H), 4.86-4.85 (d, 2H0, 4.6 (m, 1HO, 4.22 (t, 1H), 3.9 (m, 1H), 3.72-3.68 (m, 2H), 3.47-3.46 (d, 1H), 2.04 (m, 2H), 1.76 (m, 2H).
Example 6
Synthesis of (5S)-3-{4-f4-(2,l,3-benzoxadiazol-5-vl)piperazin-l-vl]-3-fluorophen\>l}-5-f(isoxazol-3-vlamino)methvl/-l,3-oxazolidin-2-one (Path A)
Step a: Synthesis of tert-butyl 4-(2-fluoro-4-{(5S)-5-[(isoxazol-3-ylammo)methyl]-2-oxo-l,3-
oxazolidin-3-yl}phenyl)piperazine-l -carboxylate.
To tert-butyl- 4-[2-fluoro-4-((5./?)-5-{[(methylsulfonyl)oxy]methyl}-2-oxo-l,3-oxazolidin-3-
yl)phenyl]piperazine-l-carboxylate(lgm) (prepared as per the procedure given in W093/23384)
in dry dimethylformamide (10ml) was added sodium hydride (0.23 gm) and tert-butyl isoxazol-
3-ylcarbamate(0.88gm) and stirred for about 17 hrs at 80°C. The reaction mixture was extracted
with ethyl acetate and the organic layer was washed with water, dried over sodium sulphate and
concentrated. The crude was purified by column chromatography using ( 2%) methanol in
dichloromethane as eluant to yield the title compound(lgm).
Step b: Synthesis of(5S)-3-(3-fluoro-4-piperazin-l-ylphenyl)-5-[(isoxazol-3-ylamino)methyl]-
1,3-oxazolidin-2-one.
To the compound (1 gm) obtained from step a above in dichloromethane(10ml) was added
trifluoroacteic acid(4ml) and stirred for about 2 hrs, the solvent was concentrated and to the
residue was added ethyl acetate(15ml) followed by 10% sodium hydroxide(10ml) till pH 12-14.
The organic layer which separated out was washed with water, dried over sodium sulphate and
concentrated to get the title compound (1.36gm crude weight)
Step c: "Synthesis of(5S)-3-{4-[4-(2, l,3-benzoxadiazol-5-yl)piperazin-l-yl]-3-fluorophenyl}-5-
[(isoxazol-3-ylamino)methyl]-l,3-oxazolidin-2-one.
To the compound (1.36gm) obtained from the Step b above in dry dimethylformamide(10ml)
was added 5-bromo-2,l,3-benzoxadiazol (0.75gm), cesium carbonate (1.47gm), 2,2'-
bis(diphenylphosphino)-l,r-binapthyl (0.18gm) and Tris (dibenzelideneacetone) dipalladium(O)
(0.13gm) added and heated for about 17 hrs at 100 °C. The reaction mixture was filtered and the
solvent was evaporated and the crude product was purified by column chromatography using 1%
methanol in dichloromethane to get the title product (O.lg)
Melting point: 213-215 °C;
EIMS (m/z): 480.26, M+Na 502.22;
'HNMR(DMSO): 5 8.38 (s, 1H), 7.88 (d, 1H), 7.72 (d, 1H), 7.53 (dd, 1H), 7.15 (m, 2H), 6.89 (s,
1H), 6.54(t, 1H), 6.0(s, lH),4.86(m, lH),4.13(t, 1H), 3.79(t, 1H), 3.53 (m, 4H), 3.15 (m,
4H).
Example 7
Synthesis of (5S)-3-(4-{fl-(2,l,3-benzoxadiazol-5-vl)piperidin-4-vl]oxv}-3-fluorophenvl)-5-f(isoxazol-3-vlamino)methy)-l,3-oxazoUdin-2-one (Path A)
Step a; Synthesis of tert-butyl 4-[4-((5R)-5-{[(tert-butoxycarbonyl)(isoxazol-3-
yl)amino]methyl}-2-oxo-l,3'Oxazolidin-3-yl)-2-fluorophenoxy]piperidine-l-carboxylate..
TO tert-butyl 4-[2-fluoro-4-((5R)-5-{[(methylsulfonyl)oxy]methyl}-2-oxo-l ,3-oxazolidin-3-
yl)phenoxy]piperidine-l-carboxylate (1.5 gm) (prepared according to the procedures given in
Biorganic and Medicinal Chemistry Letters 11(2001), 1829-1832) in dry dimethylformamide
(10ml), was added sodium hydride (0.15 gm) and tert-butyl isoxazol-3-ylcarbamate (0.87gm)
and stirred for about 17 hrs at 80°C. The reaction mixture was extracted with ethyl acetate. The
organic layer was washed with water, dried over sodium sulphate and concentrated. The crude
product was purified by column chromatography using ( 2%) methanol in dichloromethane as
eluant to yield the title compound (2gm).
Step b.' Synthesis of(5S)-3-[3-fluoro-4-(piperidin-4-yloxy)phenyl]-5-[(isoxazol-3-
ylamino) methyl]-!, 3-oxazolidin-2-one.
To the compound (2gm) obtained from step a above in dichloromethane(15ml) was added
trifluoroacteic acid(10ml) and stirred for about 2 hrs, the solvent was concentrated and to the
residue was added ethyl acetate(20ml) followed by 10% sodium hydroxide(10ml) till pH 12-14.
The organic layer which separated out was washed with water, dried over sodium sulphate and
concentrated to get the title compound (5gm).
Step c; Synthesis of(5S)-3-[3-fluoro-4-(piperidin-4-yloxy)phenyl]-5-[(isoxazol-3-
ylamino)methyl]-l,3-oxazolidin-2-one.
To the compound (5gm) obtained from the Step b above in dry dimethylformamide (15ml) was
added 5-bromo-2,l,3-benzoxadiazol (2.74gm) (prepared according to the procedure given in
Organic Process Research Development 2003,7,436-445), cesium carbonate (5.38gm), 2,2'-bis(diphenylphosphino)-1,1 '-binapthyl (0.68gm) and Tris (dibenzelideneacetone) dipalladium(O) (0.5gm) and heated for about 17 hrs at 1000C. The reaction mixture was filtered and the solvent was evaporated. The crude product thus obtained was purified by column chromatography using 1% methanol in dichloromethane to get the title product (0.4g) Melting point: 134-140°C; EIMS (m/z): 495.25;
'HNMR(DMSO): 6 8.41 (s, 1H), 7.88 (d, 1H), (d, 1H), 7.6 (dd, 1H), 7.32 (t, 1H), 7.25 (d, 1H), 6.88 (s, 1H), 6.56(t, 1H), 6.03 (s, 1H), 4.8(m, 1H), 4.63-4.62 (m, lH),4.17(t, 1H), 3.81 (m, 4H), 3.49-3.43 (m, 3H), 2.07 (m, 2H), 1.8 (m, 2H).
Example 8
Synthesis of (5R)-3-(4-{fl-(2,l,3-benzoxadiazol-5-vl)piperidin-4-vlfoxv}-3-fIuorophenvl)-5-[(isoxazol-3-vloxv)inethvll-lJ-oxazolidin-2-one (Path B)
Step a.- Synthesis of tert-butyl 4-(2-fluoro-4-{(5R)-5-[(isoxazol-3-yloxy)methyl]-2-oxo-l,3-oxazolidm-3-yl}phenoxy)piperidine-l-carboxylate
To /erz-butyl 4-{2-fluoro-4-[(5R)-5-(hydroxymethyl)-2-oxo-l ,3-oxazolidin-3-yl]phenoxy}piperidine-l-carboxylate (1 gm) (prepared according to the procedures given in Biorganic and Medicinal Chemistry Letters 11(2001), 1829-1832) in dry tetrahydrofuran (10ml) was added triphenyl phosphine(0.99 gm) and 3-hydroxy-isoxazole (0.25gm) and diethylazodicarboxylate(0.75ml) under nitrogen atmosphere and the reaction mixture was stirred for about 17 hrs at room temperature and extracted with ethyl acetate washed with water, dried over sodium sulphate and concentrated. The crude product was purified by column chromatography using 0.5% methanol in dichloromethane as eluant to yield the title compound (0.8 1 gm).
Step b.- Synthesis of(5S)-3-[3-fluoro-4-(piperidin-4-yloxy)phenyl]-5-[(isoxazol-3-ylamino)methyl]-l,3-oxazolidin-2-one.
To the compound (0.81 gm), obtained from step a above in dichloromethane(20ml) was added trifluoroacteic acid(4ml) and stirred for about 2 hrs, the solvent was concentrated and to the residue was added ethyl acetate(20ml) followed by 10% sodium hydroxide(10ml) till pH 12-14.
The organic layer which separated out was and washed with water , dried over sodium sulphate
and concentrated to get the title compound (l.3gm)
Step c: Synthesis of(5S)-2-[3-fluoro-4-(piperidin-4-yloxy)phenyl]-5-[(isoxazol-3-
ylammo)methyl]-l,3-oxazolidin-2-one.
To the compound (1.3gm) obtained from the Step b above in dry dimethylformamide(15ml) was
added 5-bromo-2,l,3-benzoxadiazole (0.71 gm) cesium carbonate (].4gm), 2,2'-
bis(diphenylphosphino)-l,r-binapthyl (0.17gm) and Tris (dibenzelideneacetone) dipalladium(O)
(0.13g) and heated for about 17 hrs at 100 0C. The reaction mixture was filtered and the solvent
was evaporated. The crude product was purified by column chromatography using 1% methanol
in dichloromethane to get the title product (0.07g).
Melting point: 75-100 °C;
EIMS(m/z): 534.21;
'HNMR(DMSO): 5 8.16 (s, 1H), 7.66 (d, 1H), 7.48 (dd, 1H), 7.3 (m, 2H), 7.17 (d, 1H), 7.08-
7.05 (t, 1H), 6.75(s, 1H), 4.99(m, 1H), 4.53 (m, 3H), 4.14-4.11 (t, 1H), 3.95(t, 1H), 3.61 (m,
2H), 3.3 (m, 2H), 2.04 (m, 4H).
Example 9
Synthesis (5R}-3-{4-f4-(2,l,3-benzoxadiazol-5-vl)piperazin-l-vll-3-fluorophenvl}-5-(isoxazol-3-vlmeth\>l}-l,3-oxazolidm-2-one(Path B)
Step a.- Synthesis of tert-butyl 4-(2-fluoro-4-{(5R)-5-[(isoxazol-3-yloxy)methyl]-2-oxo-l,3-oxazolidin-3-yl}phenyl)piperazine-1 -carboxylate
To tert-butyl 4-{2-fluoro-4-[(5R)-5-(hydroxymethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}piperazine-l-carboxylate (1.5 gm) (prepared according to the procedures given in W093/23384) taken in dry tetrahydrofuran (10ml), was added triphenyl phosphine(l .49 gm) and 3-hydroxy-isoxazole (0.38gm) and diethylazodicarboxylate (1.12ml) under nitrogen atmosphere and the reaction mixture was stirred for about 17 hrs at room temperature. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulphate and concentrated. The crude product was purified by column chromatography using 1% methanol in dichloromethane as eluant to yield the title compound (1.4gm). Step b: Synthesis of(5R)-3-(3-fluoro-4-piperazin-l-ylphenyl)-5-[(isoxazol-3-yloxy)methyl]-l,3-oxazolidin-2-one.
To the compound (1.4gm) obtained from step a above in dichloromethane(15ml) was added
trifluoroacteic acid(4ml. The organic layer which separated out was washed with water, dried
over sodium sulphate and concentrated to get the title compound (0.91 gm).
Step c: Synthesis of(5R)-3-{4-[4-(2,l,3-benzoxadiazol-5-yl)piperazm-l-yl]-2-fluorophenyl}-5-
[(isoxazol-3-yloxy)methyl]-l,3-oxazolidm-2-one.
To the compound (0.91gm) obtained from the Step b above in dry dimethylformamide (15ml)
was added 5-bromo-2,l,3-benzoxadiazole (0.52gm), cesium carbonate (1.01 gm), 2,2'-
bis(diphenylphosphino)-l,1-binapthyl (0.13gm) and Tris (dibenzelideneacetone) dipailadium(O)
(0.09gm) and heated for about 17 hrs at 100 °C. The reaction mixture was filtered and the
solvent was evaporated. The crude product was purified by column chromatography using 80%
ethyl acetate in hexane to get the title product (0.03g)
Melting point: 125-143 °C;
EIMS(m/z): 481.25;
'HNMR(DMSO): 5 8.69 (s, 1H), 7.88 (d, 1H) 7.73 (d, 1H), 7.53 (dd, 1H), 7.24 (d, 1H), 7.15 (t,
1H), 6.89(s, 1H), 6.39(s, lH),4.99(m, 1H), 4.47 (m, 2H), 4.18 (t, 1H), 3.91 (t, 1H), 3.53(m,
4H), 3.15(m,4H).
Example 10
Synthesis of N-{l(5S)-3-(3-fluoro-4-{4-f(oxido-2,1,3-benzoxadiazol-5-vl)methvl]piperazin-l-vl}phenvl)-2-oxo-l,3-oxazolidin-5-vllmethvUacetamide
To N-{[(55)-3-(3-fiuoro-4-piperazin-l-ylphenyl)-2-oxo-l,3-oxazolidin-5-yl]methyl}acetamide
trifiuoroacetate (1.72mmoles) (prepared according to the procedures given in W093/23384)
taken in tetrahydrofuran (20ml) was added 5-formyl benzofuroxan (0.34gm), molecular sieves
and stirred for 5 min. followed by the addition of sodium triacetoxy borohydride( 1.45 g) and
stirred for 3 hrs. The reaction mixture was filtered. The crude product was purified by column
chromatography using 4% methanol in dichloromethane as eluant to yield the title compound
(0.4 1 gm)
Melting point: 66-70°C
EIMS (m/z): 388
1HNMR(CDCl3): 5 8.24 (t, 1H), 7.83 (br m, 2H), 7.5 (d, 2H), 7.15 (m, 2H), 4.69 (m, 1H), 4.33
(m, 2H), 4.08 (t, 1H), 3.69 (t, 1H), 3.23 (m, 8H), 1.83 (s, 3H)
Example 11
Synthesis of N-f((5S)-3-{4-f4-(2,l,3-benzoxadiazol-5-vlmethvl}piperazin-l-vll-3-fluorophenvl}-2-0X0-1,3-oxazolidin-5-yl)methyllacetamide
To the Compound No. 10 in absolute ethanol (10ml) was added triphenyl phosphine (0.15 g) and
refluxed for about 3 hrs at (85°C ). The reaction mixture was concentrated and purified by
column chromatography using 3% methanol in dichloromethane to get the title compound (0.08
gm)
Melting point: 165-168 °C;
EIMS (m/z: 469;
'HNMR(DMSO): 5 8.22 (t, 1H), 8.01 (dd, 1H), 7.91 (s, 1H), 7.61 (d, 1H), 7.46 (dd, 1H), 7.15
(d, 1H), 7.07 (t, 1H), 4.69 (m, 1H), 4.06 (t, 1H), 3.69 (m, 4H), 3.39 (m, 2H), 3.01 (m, 4H), 2.61
(m, 4H), 1.83 (s,3H).
Example 12
Synthesis of N-{f(5S)-3-(4-{fl-(2,l,3-benzoxadiazol-5-vl)piperidin-4-yloxvl-3-fluorophenyl)-2-0X0-1,3-oxazolidin-5-Yllmethvliacetamide (Path A)
To tert-butyl 4-(4-{(5S)-5-[(acetyl amino)methyl]-2-oxo-l,3-oxazolidin-3-yl}-2-fluorophenoxy)piperidine-l-carboxylate(0.3gm) (prepared as per the procedure given in Biorganic and Medicinal Chemistry Letters 11(2001), 1829-1832) taken in acetonitrile was added 5-bromo-2,l,3-benzoxadiazole (0.14gm), disopropyl ethylamine (1.16ml)and heated for about 48 hrs at 80 °C. The reaction mixture was filtered and the solvent was evaporated .The crude product was purified by preparative thin layer chromatography using 5% methanol in dichloromethane to get the title product (0.03gm). Melting point: 96-100 °C; EIMS (m/z: 470.13;
'HNMR(CDCl3): 6 7.6 (dd, 1H), 7.47 (dd, 1H), 7.30 (d, 1H), 7.06 (m, 2H), 6.73 (dd, 1H), 5.94 (6s, 1H), 4.76 (m, 1H), 4.49 (m, 1H), 4.03 (t, 1H), 3.76-3.44 (m, 6H, 3.28 (m, 1H), 2.03 (m, 7H).
Example 13
Synthesis of N-f((5S)-3-{4-f4-(2,l,3-benzoxadiazol-5-vl)piperazin-l-Yl]-3-fluorophenvl}-2-oxo-l,3-oxazolidin-5-vl)methvllacetamide (Path B)
To N^-{[(55)-3-(3-fluoro-4-piperazin-l-ylphenyl)-2-oxo-l,3-oxazolidin-5-yl]methyl}acetamide
(0.4gm) (prepared according to the procedures given in WO 93/23384) taken in dry dimethyl
formamide(15 ml), were added cesium carbonate (0.46gm), 5-bromo-2,l,3-benzoxadiazole
(0.23gm), 2,2'-bis(diphenylphosphino)-l,r-binapthyl (0.074gm) and Tris
(dibenzelideneacetone) dipalladium(O) (0.054gm) and the reaction mixture was heated for 17 hrs
at 100"C. The reaction mixture was filtered and the solvent was evaporated. The crude product
was purified by column chromatography using 2% methanol in dichloromethane and sonicated in
ether to get the title compound.
(0.12gm).
Melting point: 201-222 0C;
EIMS (m/z: 455;
1HNMR(CDCl3): 6 7.71 (d, 1H), 7.48 (dd, 1H), 7.33 (dd, 1H), 7.12 (dd, 1H), 6.98 (t, 1H), 6.79
(s, 1H), 5.99 (t, 1H), 4.76 (m, 1H), 4.02 (t, 1H), 3.85-3.55 (m, 3H), 3.47 (m, 4H), 3.24 (m, 4H),
2.03 (s, 3H).
Example 14
Synthesis of N-[((5S)-3-{4-[4-(2,l,3-benzoxadiazol-5-yl)piperazin-l-yl]-3,5-difluorophenvl}-2-0X0-1,3-oxazolidin-5-yl)methyl]acetamide(Path B)
ToN-{[(55)-3-(3,5-difluoro-4-piperazin-l-ylphenyl)-2-oxo-l,3-oxazolidin-5-yl]methyl}acetamide(0.21gm) prepared according to the procedures in US5,547,950) taken in dry dimethyl formamide (10 ml), was added cesium carbonate (0.23 g), 2,2'-bis(diphenylphosphino)-l,r-binapthyl( 0.06gm), 5-bromo-2,l,3-benzoxadiazol (0.12gm) and Tris (dibenzelideneacetone) dipalladium(O) (0.1 gm) added and heated for 17 hrs at 100 °C. The reaction mixture was filtered and the solvent was evaporated. The crude product was purified by column chromatography using 2% methanol in dichloromethane as eluant to yield the title compound (0.025gm) Melting point: 207-213 °C EIMS (m/z): 388
'HNMR(CDCl3): 5 7.91 (m, 2H), 7.62 (m, 2H), 7.52 (t, 1H), 7.35 (dd, 1H), 6.10 (t, 1H), 4.84 (m, 1H), 4.12 (t, 1H), 3.87 (t, 1H), 3.71 (m,2H), 2.02 (s, 3H).
Assay for in vitro Antibacterial Activity
Compounds disclosed herein display antibacterial activity when tested by the agar incorporation method. The following minimum inhibitory concentrations (|a.g/ml) were obtained for representative compounds of the invention, which are given below.
In vitro ( us/ml) activity data:
S.aureus ATCC 25923 —Staphylococcus aureus ATCC 25923;MIC was 0.5-16|a.g/ml with
Linezolid 2 µg/ml.
S.aureus ATCC 15187 -Staphylococcus aureus ATCC 15187; MIC was 0.25-16|ig/ml with
Linezolid 2 µg/ml.
S.aureus MRSA ATCC562 —Methicilline Resistant Staphylococcus aureus ATCC562; MIC was
0.25-16µg/ml with Linezolid 2 µg/ml.
S.aureus MRSA ATCC33 —Methicilline Resistant Staphylococcus aureus ATCC33; MIC was
0.25-16µg/ml with Linezolid 2µg/ml.
Ent. faecalis ATCC 29212 —Enterococcus faecalis ATCC 29212; MIC was 0.25-16|ig/ml with
Linezolid 2µg/ml.
VRE — Vancomycin-resistant enterococci ATCC 6A; MIC was 0.25-16µg/ml with Linezolid 2
µg/ml.
Strep.pyog. ATCC 19615 —Streptococcus pyogenes ATCC 19615 ; MIC was 0.125-8 µ.g/ml with Linezolid 2µg/ml.
Strep, pnem. AB34 DRSP —Streptococcus pneumoniae AB34 DRSP; MIC was 0.25-8 µg/ml with Linezolid 2 µg/ml.
Strep, pnem. ATCC6303 —Streptococcus pneumoniae ATCC 6303; MIC was 0.125-8µ.g/ml with Linezolid 1 |ig/ml.
M.catt.—Moraxella catarrhalis ATCC 8176; MIC was 2-8(µ.g/ml with Linezolid 2 µg/ml.
H. influ.—Haemophilus influenzae ATCC 49247; MIC was 8-32 )µ.g/ml with Linezolid 8 µg/ml.
B. fragillus— Bacillus fragillus ATCC 25285; MIC was 0.5-16)µ.g/ml with Linezolid 4 µg/ml.
For Linezolid resistant strain.
S.aureus MRSA 32—Methicilline Resistant Staphylococcus aureus 32; MIC was 4-16 |J.g/ml with Linezolid 32 ng/ml.
Ent. faecalis 303 —Enterococcusfaecalis 303; MIC was O.I25-4(ig/ml with Linezolid 16 |ig/ml.
Strep, pnem. ATCC6303 —Streptococcuspneumoniae ATCC 6303; with Linezolid >I6 (ig/ml.
The invitro antibacterial activity of the compounds was demonstrated by the agar dilution method (NCCLS M 7-A5 and M 100-S8 documents). Briefly, the compounds were dissolved in dimethylsulphoxide and doubling dilution of the compounds was incorporated into Muller Hilton agar before solidification. Inoculum was prepared by direct colony suspension in normal saline solution and adjusting the turbidity to 0.5 Macfarland turbidity and subsequently
diluting as per NCCLS guidelines in order to obtain 104 CFU/spot. CFU/ml of few randomly selected cultures was performed. The cultures were replicated on agar plate using Denley's multipoint replicator. The agar plates were incubated for 18 hours-24 hours (24 hours for MRSA studies) at 35+ 2°C. Q.C. strains were also included in each run of the study.
The invitro activity for Haemophilus MICs were performed by using Micro broth dilution method as follows:
Media used : Mueller Hinton Broth ( MHB-Difco ) - Cation adjusted + 5 grams per liter Yeast extract + supplements
Preparation of drug concentrations in 96 well microtitre plates was done as per the NCCLS method. Inoculum was prepared by direct colony suspensions in normal saline and adjusted to I McFarland turbidity and subsequently diluted in broth 100 times as per NCCLS guidelines in order to obtain 105 CFU/spot.
The concentration showing no growth of the inoculated culture was recorded as the MIC. Appropriate ATCC standard strains were simultaneously tested and result recorded only when the MIC's against standard antibiotics were within the acceptable range. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

WE CLAIM:
1. Compounds having the structure of Formula I, as shown in the accompanied drawing and its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers or polymorphs wherein
R1 is ORj , SRj [wherein Rj is hydrogen, alkyl, alkenyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, heteroarylalkyl or heterocyclylalkyl], NHY1Rf [wherein Y1 is (C=0), (C=S) or SO2 and Rf is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl or heterocyclylalkyl], NRfRq [wherein Rf is as defined earlier and Rq is hydrogen, alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl or heterocyclyl], heterocyclyl or heteroaryl;
U and V are independently selected from hydrogen, lower (C1-6) alkyl
and halogens (CI, F or Br);
Y and W can be no atom or selected from group consisting of O, CH2, CO, CHNH, -. NHCH2, -CH2NHCH2, -CH^-N (R11OCH2-, CH2(Re)N-, CH(R11), S, CH2CCO), NH, NRe,
(C0)CH2, N(Re)CON(Re), N(Re)C(=S)N(Re), SO2 or SO, wherein R11, is optionally substituted C1-12 alkyl, C3-12 cycloalkyl, C1-6 alkoxy, C1-6 alkyl, C1-6 alkylcarbonyl, C1-6 alkylcarboxy, aryl or heteroaryl ,Re is hydrogen, optionally substituted C1-12alkyl, C3-12 cycloalkyl, C1-6 alkoxy, C1-6 alkyl, C1-6 alkylcarbonyl, C1-6 alkylcarboxy, aryl or heteroaryl;
A can be no group or selected from group consisting of;
wherein
X is CH, CH-S, CH-O or N;
Q is O , N or S;
n is an integer 0-1 and m is an integer from 0-2. 2. A compound selected from a group consisting of:
N-({(55)-3-[4-(2,l,3-benzoxadiazol-5-yl)-3-fluorophenyl]-2-oxo-l,3-oxazolidin-5-yl}methyl)acetamide(Compound No.l);
N-({(55)-3-[4-(2,l,3-benzoxadiazol-5-yl)-3,5-difluorophenyl]-2-oxo-l,3-oxazolidin-5-yl} methyl)acetamide(Compound No. 2);
(5i?)-3- {4-[4-(2,1,3-benzoxadiazol-5-yl)piperazin-1 -yl]-3-fluorophenyl} -5-( 1N-1,2,3-triazol-l-ylmethyl)-l,3-oxazolidin-2-one(Compound No.3);
(5R)-3- {4-[4-(2,1,3-benzoxadiazol-5-yl)piperazin-1 -yl]-3-fluorophenyl} -5-(2N-1,2,3-triazol-2-ylmethyl)-l,3-oxazolidin-2-one(Compound No.4);
(5R)-3-(4-{[l-(2,l,3-benzoxadiazol-5-yl)piperidin-4-yl]oxy}-3-fluorophenyl)-5-(lN-l,2,3-triazol-l-ylmethyl)-l,3-oxazolidin-2-one(Compound No.5);
(55)-3-{4-[4-(2,l,3-benzoxadiazol-5-yl)piperazin-l-yl]-3-fluorophenyl}-5-[(isoxazol-3-ylamino)methyl]-l,3-oxazolidin-2-one(Compound No.6);
(55)-3-(4- {[1 -(2,1,3-benzoxadiazol-5-yl)piperidin-4-yl]oxy} -3-fluorophenyl)-5-[(isoxazol-3-ylamino)methyl]-l,3-oxazolidin-2-one(Compound No.7);
(55)-3- {4-[4-(2,1,3-benzoxadiazol-5-yl)piperazin-1 -yl]-3-fluorophenyl} -5-(isoxazol-3-ylmethyl)-1,3 -oxazolidin-2-one(Compound No. 8);
(5^)-3-(4- {[ 1 -(2,1,3-benzoxadiazol-5-yl)piperidin-4-yl]oxy} -3-fluorophenyl)-5-[(isoxazol-3-yloxy)methyl]-1,3-oxazolidin-2-one(Compound No.9);
N-{[(55)-3-(3-fluoro-4-{4-[(oxido-2,l,3-benzoxadiazol-5- yl) methyl] piperazin-1-yl}phenyl)-2-oxo-l,3-oxazolidin-5-yl]methyl}acetamide (Compound No. 10);
A'-[((55)-3-{4-[4-(2,l,3-benzoxadiazol-5-ylmethyl)piperazin-l-yl]-3-fluorophenyl}-2-oxo-l,3-oxazolidin-5-yl)methyl]acetamide(Compound No.l 1);
N- {[(55)-3-(4- {[ 1 -(2,1,3-benzoxadiazol-5-yl)piperidin-4-yl]oxy} -3-fluorophenyl)-2-oxo-l,3-oxazolidin-5-yl]methyl}acetamide(Compound No.l2);
N-[((55)-3- {4-[4-(2,1,3-benzoxadiazol-5-yl)piperazin- l-yl]-3-fluorophenyl} -2-oxo-1,3-oxazohdin-5-yl)methyl]acetamide (Compound No. 13);
N-[((55)-3-{4-[4-(2,l,3-benzoxadiazol-5-yl)piperazin-l-yl]-3,5-difluorophenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide(Compound No. 14).
3. A pharmaceutical composition comprising a pharmaceutically effective amount of compound according to any of the preceding claims or pharmaceutically acceptable salt(s) thereof with a pharmaceutical acceptable carrier.
4. A method of treating or preventing microbial infections in a mammal comprising administering to the said mammal, the pharmaceutical composition according to claim 3.
5. The method according to claim 4, wherein the microbial infections are caused by gram-positive and gram-negative bacteria.
6. The method according to claim 4, wherein the gram-positive bacteria are selected from the group consisting of staphylococcus spp., streptococcus spp., bacillus spp., corynebacterum spp., Clostridia spp., peptostreptococus spp., listeria spp. and legionella spp.
7. A method of treating or preventing aerobic and anaerobic bacterial infections in a mammal comprising administering to said mammal, a pharmaceutical composition according to claim 3.
8. A process for preparing a compound of Formula IV, as shown in Scheme I of
the accompanied drawings and its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers or polymorphs wherein,
U and V are independently selected from hydrogen, lower (C1-6) alkyl and
halogens (CI, F or Br);
R1 is ORj , SRj [wherein R, is hydrogen, alkyl, alkenyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, heteroarylalkyl or heterocyclylalkyl], NHy1Rf [wherein y1 is (C=0), (C=S) or SO2 and Rf is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl or heterocyclylalkyl], NRfRq [wherein Rf is as defined earlier and Rq is hydrogen, alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl or heterocyclyl], heterocyclyl or heteroaryl; comprising reacting a compound of Formula II with a compound of Formula 111 to give a compound of Formula IV.
9. The process according to claim 8, wherein the reaction of compound of Formula 11, to give the compound of Formula IV is carried out in an organic solvent for example dimethyl formamide, 1,4-dioxane and tetrahydrofuran.
10. The process according to claim 8, wherein the reaction of compound of Formula II to give the compound of Formula IV is carried out in the presence of a base selected from selected from triethylamine, 4-dimethylamino pyridine and N-methyl morpholine.
11. The process according to claim 8, wherein the reaction of compound of Formula 11 to give the compound of Formula IV carried out in with a catalyst selected from dichlorobistriphenylphosphine palladium (II) and tetrakistriphenylphosphine palladium (0).
12. A process for preparing a compound of Formula IX, as shown in Scheme II of the accompanied drawings and its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers or polymorphs wherein,
U and V are independently selected from hydrogen, lower (C1-6) alkyl and halogens
(CI, F or Br);
W can be no atom or selected from group consisting of O, CH2, CO, CH,NH, -NHCH2, -CH2NHCH2, -CH^-N (R11OCH2-, CH2(Re)N-, CH(R11), S, CH2CCO), NH, NRe, (C0)CH2, N(Re)CON(Re), N(Re)C(=S)N(Re), S02or SO, wherein R11 is optionally substituted C1-12 alkyl, C3-12 cycloalkyl, C1-6alkoxy, C1-6 alkyl, C1-6 alkylcarbonyl, C1-6alkylcarboxy, aryl or heteroaryl ,R is hydrogen, optionally substituted C1-12alkyl, C1-12 cycloalkyl, C1-6
alkoxy, C1-6 alkyl. C1-6alkylcarbonyl, C1-6 alkylcarboxy, aryl or heteroaryl
A can be no group or selected from group consisting of;

wherein
XisCH, CH-S,CH-OorN;
QisO,NorS;
and m is an integer from 0-2;
comprising reacting a compound of Formula V with a compound of Formula VI to give a compound of Formula VII which is deprotected to give a compound of Formula VIII which on further reaction with a compound of Formula III gives a compound of Formula IX.
13. The process according to claim 12, wherein the reaction of compound of Formula V to give the compound of Formula VII is carried out in an organic solvent for example dimethyl formamide, 1,4-dioxane and tetrahydrofuran.
14. The process according to claim 12, wherein the reaction of compound of Formula V to give the compound of Formula VII is carried out in the presence of a base selected from sodium hydride, potassium hydride and lithium hydride.
15. The process according to claim 12, wherein the reaction of compound of Formula Vll, to give the compound of Formula VIll is carried out in the presence of an acid selected from hydrochloric acid in ethanol and trifluoroacetic acid in dichloromethane.
16. The process according to claim 12, wherein the reaction of compound of Formula VIII, to give the compound of Formula IX is carried out in an organic solvent selected from tetrahydrofuran, benzene, dimethylformamide and carbon tetrachloride.
17. The process according to claim 12, wherein the reaction of compound of Formula VIII, to give the compound of Formula IX is carried out in the presence of a base selected from cesium carbonate, sodium tertiary butoxide and potassium tertiary butoxide.
18. The process according to claim 12, wherein the reaction of compound of Formula VIII, to give the compound of Formula IX carried out in with a catalyst selected from Tris (dibenzelideneacetone) dipalladium(O), palladium diacteate and palladium dichloride.
19. The process according to claim 12, wherein the reaction of compound of Formula VIII, to give the compound of Formula IX carried out in presence of a iigand for example 1,1'-binaphthalene-2,2'-diylbis(diphenylphosphine), tri-tert-butylphosphine, di-1-adamantyl(butyl)phosphine and biphenyl-2-yl(di-tert/-butyl)phosphine.
20. A process for preparing the compounds of Formulae XIII and XVII as shown in Scheme III of the accompanied drawings and its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers or polymorphs wherein,
U and V are independently selected from hydrogen, lower (C1-6) alkyl and halogens
(CI, F or Br);
W can be no atom or selected from group consisting of O, CH2, CO, CH,NH, -NHCH,, -CH2NHCH,, -CH2-N (R11)CH2-, CH2(Re)N-, CH(R11), S, CH2CCO), NH, NRe, (C0)CH2, N(Re)CON(Re), N(Re)C(=S)N(Re), S02or SO, wherein R,, is optionally substituted C1-12 alkyl, C3-12 cycloalkyl, C1-6alkoxy, C1-6alkyl, C1-6ealkylcarbonyl, C1-6 alkylcarboxy, aryl or heteroaryl ,Re is hydrogen, optionally substituted C1-12 alkyl, C3-12 cycloalkyl, C1-6 alkoxy, C 1-6alkyl, C1-6alkylcarbonyl, C1-6 alkylcarboxy, aryl or heteroaryl;
A can be no group or selected from group consisting of;
wherein
XisCH, CH-S, CH-OorN;
QisO,NorS;
m is an integer from 0-2 and Het is a heterocyclyl or heteroaryl;
comprising reacting a compound of Formula V with a compound of Formula X(Path A) to
give a compound of Formula XI, which is further deprotected to give a compound of
Formula XII which on further reaction with a compound of Formula III gives a compound
of Formula XIII.
alternatively reacting a compound of Formula V with a compound of XIV(Path B) to give a
compound of Formula XV which is further deprotected to give a compound of Formula
XVI, which on further reaction with a compound of Formula III gives a compound of
Formula XVII.
21. The process according to claim 20, wherein the reaction of compound of Formula V to give the compound of Formula XI (Path A) is carried out in an organic solvent selected from dimethyl formamide, 1,4-dioxane and tetrahydrofuran.
22. The process according to claim 20, wherein the reaction of compound of Formula V to give the compound of Formula XI, is carried out in the presence of a base selected from sodium hydride, potassium hydride and lithium hydride.
23. The process according to claim 20, wherein the reaction of compound of Formula XI to give the compound of Formula XII carried out in the presence of an acid selected from hydrochloric acid in ethanol and trifluoroacetic acid in dichloromethane.
24. The process according to claim 20, wherein the reaction of compound of Formula XII to give the compound of Formula XIII carried out in an organic solvent selected from tetrahydrofuran, benzene, dimethylformamide or carbon tetrachloride.
25. The process according to claim 20, wherein the reaction of compound of Formula XII to give the compound of Formula XIII, is carried out in the presence of a base selected from cesium carbonate, sodium tertiary butoxide and potassium tertiary butoxide.
26. The process according to claim 20, wherein the reaction of compound of Formula XII to give the compound of Formula XIII, carried out with a catalyst selected from Tris (dibenzelideneacetone) dipalladium(O), palladium diacteate and palladium dichloride.
27. The process according to claim 20, wherein the reaction of compound of Formula XII to give the compound of Formula XIII carried out in the presence of a ligand for example 1,1'-binaphthalene-2,2'-diylbis(diphenylphosphine), tri-tert-butylphosphine, di-I-adamantyl(butyl)phosphine and biphenyl-2-yl(di-/er/-butyl)phosphine.
28. The process according to claim 20, wherein the reaction of compound of Formula V to give the compound of Formula XlV(Path B) is carried out in an organic solvent selected from dimethyl formamide, 1,4-dioxane and tetrahydrofuran .
29. The process according to claim 20, wherein the reaction of compound of Formula V to give the compound of Formula XIV, is carried out in the presence of a base selected from sodium hydride, potassium hydride and lithium hydride.
30. The process according to claim 20, wherein the reaction of compound of Formula XIV to give the compound of Formula XV is carried out in the presence of an acid selected from hydrochloric acid in ethanol and trifluoroacetic acid in dichloromethane.
31. The process according to claim 20, wherein the reaction of compound of Formula XV to give the compound of Formula XVII carried out in an organic solvent selected from tetrahydrofuran, benzene, dimethylformamide and carbon tetrachloride.
32. The process according to claim 20, wherein the reaction of compound of Formula XV to give the compound of Formula XVII, is carried out in the presence of a base selected from cesium carbonate, sodium tertiary butoxide and potassium tertiary butoxide.
33. The process according to claim 20, wherein the reaction of compound of Formula XV to give the compound of Formula XVII, carried out with a catalyst selected from Tris (dibenzelideneacetone) dipalladium(O), palladium diacteate and palladium dichloride.
34. The process according to claim 20, wherein the reaction of compound of Formula XV to give the compound of Formula XVII is carried out in presence of a ligand for example 1,1'-binaphthalene-2,2'-diylbis(diphenylphosphine), tri-/er/-butylphosphine, di-1 -adamantyl(butyl)phosphine and biphenyl-2-yl(di-/er/-butyl)phosphine.
35. A process for preparing the compound of Formula XX as shown in Scheme IV of the
accompanied drawings and its pharmaceutically acceptable salts,
pharmaceutically acceptable solvates, enantiomers, diastereomers or polymorphs wherein,
R1 is ORj , SRj [wherein Rj is hydrogen, alkyl, alkenyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, heteroarylalkyl or heterocyclylalkyl], NHY1Rf [wherein Y1 is (C=0), (C=S) or SO2 and Rf is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl or heterocyclylalkyl], NRfRq [wherein Rf is as defined earlier and Rq, is hydrogen, alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl or heterocyclyl], heterocyclyl or heteroaryl;
U and V are independently selected from hydrogen, lower (C1-6) alkyl
and halogens (CI, F or Br);
Y and W can be no atom or selected from group consisting of O, CH2, CO, CH2NH, -
NHCH,, -CH2NHCH2, -CH2-N (R11)CH2-, CH2(Re)N-, CH(R11), S, CH2CCO), NH, NRe,
(C0)CH2, N(Re)CON(Re), N(Re)C(=S)N(Re), SO2 or SO, wherein R,, is optionally substituted C1-12 alkyl, C3-12 cycloalkyl, C1-6 alkoxy, C1-6 alkyl, C1-6 alkylcarbonyl, C1-6
alkylcarboxy, aryl or heteroaryl ,Re is hydrogen, optionally substituted C1-12 alkyl, C3-12
cycloalkyl, C1-6alkoxy, C 1-6 alkyl, C1-6 alkylcarbonyl. Cue alkylcarboxy, aryl or heteroaryl;
A can be no group or selected from group consisting of;

(Formula Removed)
H, CH-S, CH-OorN;
QisO,NorS;
and m is an integer from 0-2;
comprising reacting a compound of Formula XVIII with 5-formylbenzofuroxan to give a compound of Formula XIX, which is further deoxygenated to give a compound of Formula XX. 36. The process according to claim 35, wherein the reaction of compound of Formula XVIII to give the compound of Formula XIX is carried out in an organic solvent selected from tetrahydrofuran, dimethyl formamide and 1,4-dioxane. 57. The process according to claim 35, wherein the reaction of compound of Formula XVIII to give the compound of Formula XIX is carried out in the presence of a reducing agent selected from sodium triacetoxy borohydride or sodium borohydride. 38. The process according to claim 35, wherein the deoxygenation of compound of Formula XIX to give the compound of Formula XX, is carried out in an organic solvent selected from ethanol or methanol.
39. The process according to claim 35, wherein the deoxygenation of compound of Formula XIX to give the compound of Formula XX, is carried out in presence of triphenyl phosphine, trioctyl phosphine, and tributyl phosphine.
40. A process for making the compound of Formula XXII as shown in Scheme V of
the accompanied drawings and its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers or polymorphs wherein, R1 is ORj , SRj [wherein Rj is hydrogen, alkyl, alkenyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, heteroarylalkyl or heterocyclylalkyl], NHY1Rf [wherein Y1 is (C=0), (C=S) or SO2 and Rf is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl or heterocyclylalkyl], NRfRq [wherein Rf is as defined earlier and Rq is hydrogen, alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl or heterocyclyl], heterocyclyl or heteroaryl;
U and V are independently selected from hydrogen, lower (C1-6) alkyl
and halogens (CI, F or Br);
Y and W can be no atom or selected from group consisting of O, CH2, CO, CH2NH, -NHCH,, -CH.NHCH2, -CH.-N (R11)CH2-, CH2(Re)N-, CH(R11), S, CH2(C0), NH, NR„ (C0)CH2, N(Re)CON(Re), N(Re)C(=S)N(Re), SO2 or SO, wherein R,, is optionally substituted C1-12 a'kyl, C3-12 cycloalkyl, C1-6alkoxy, C 1-6 alkyl, C1-6 alkylcarbonyl, C1-6
alkylcarboxy, aryl or heteroaryl ,Re is hydrogen, optionally substituted C1-12 alkyl, C3-12 cycloalkyl, C1-6 alkoxy, C 1-6 alkyl, C1-6.ealkylcarbonyl, C1-6 alkylcarboxy, aryl or heteroaryl;
A can be no group or selected from group consisting of;
wherein
XisCH, CH-S, CH-OorN;
QisO,NorS;
m is an integer from 0-2;
comprising reacting a compound of Formula XXI with a compound of Formula III to give
a compound of Formula XXII.
41. The process according to claim 40, wherein the reaction of compound of Formula
XVIII, to give the compound of Formula XIX is carried out in an organic selected form acetonitrile, chloroform and carbon tetrachloride.
42. The process according to claim 41, wherein the reaction of compound of Formula
XXI to give the compound of Formula XXII is carried out in the
presence of a base selected from diisopropyl ethylamine, triethylamine and N-methyl morpholine.
43. The process according to claim 40, wherein the reaction of compound of Formula
XVIII, to give the compound of Formula XIX is carried out in an organic selected form tetrahydrofuran, benzene, dimethylformamide and carbon tetrachloride.
44. The process according to claim 40, wherein the reaction of compound of Formula
XXI to give the compound of Formula XXII is carried out in the presence of a base selected from selected from cesium carbonate, sodium tertiary butoxide and potassium tertiary butoxide.
45. The process according to claim 40, wherein the reaction of compound of Formula XXI, to give the compound of Formula XXII, carried out with a catalyst selected from Tris (dibenzelideneacetone) dipalladium (0), palladium diacetate and palladium dichloride.
46. The process according to claim 40, wherein the reaction of compound of Formula XXI, to give the compound of Formula XXII, carried out in presence of a ligand selected from 1,1'-binaphthalene-2,2'-diylbis(diphenyl)phosphine, tri-tert-butylphosphine, di-l-adamantyl(butyl)phosphine and biphenyl-2-yl(di-tert-butyl)phosphine.