OA12891A - Oxazolidinone derivatives as antimicrobials. - Google Patents

Oxazolidinone derivatives as antimicrobials. Download PDF

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OA12891A
OA12891A OA1200500023A OA1200500023A OA12891A OA 12891 A OA12891 A OA 12891A OA 1200500023 A OA1200500023 A OA 1200500023A OA 1200500023 A OA1200500023 A OA 1200500023A OA 12891 A OA12891 A OA 12891A
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alkyl
substituted
formula
cycloalkyl
alkoxy
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OA1200500023A
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Anita Mehta
Rao Ajjarapu Venkata Subrahmanya Raja
Ashok Rattan
Sonali Rudra
Ajay Singh Yadav
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Ranbaxy Lab Ltd
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    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
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Description

012891
0XAZOLIDINONE DERIVATIVES AS ANTIMICROBIALS
FÏELD OF THE INVENTION
The présent invention relates to certain substituted phienyl oxazolidinones and toprocesses for the synthesis of the same. This invention also relates to phannaceuticalcompositions containing the compounds of the présent invention as antimicrobials. Thecompounds are useful antimicrobial agents, effective against a number of human andveterinary pathogens, including gram-positive aérobic bacteria such as multiple-resistantstaphylococci, streptococci and enterococci as well as anaérobie organisme such asBacterioides spp. and Clostridia spp. species, and acid, fast organisme such asMycobacterium tuberculosis, Mycobacterium avium and Mycobacterium spp.
BACKGROUND OF THE INVENTION
Increasing antibacterial résistance in Gram positive bacteria has presented aformidable treatment problem. The enterococci, althougb traditionally non virulent i pathogens, bave been shown, wh.en associated with Vancomycin résistance, to hâve anattributable mortality of approximately 40%. Staphylococcus aureus, the traditionalpathogen of post operative wounds, has been résistant to Penicillin due to production ofpenicillinases. This résistance was overcome by the development of various penicillinasestable β lactams. But the pathogen responded by synthesizing a modified target penicillinbinding protein- 2' leading to less affînity for β lactam antibiotics and a phenotype knownas Methicillin Résistant S. aureus (MRSA). These strains, till recently were susceptible toVancomycin, which inspite of its various drawbacks, has become the drug of choice forMRSA 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 hâvebeep reporte,d from across the globe.
Oxazolidinones :are a new class of synthetic antimicrobial agents which kill grampositive pathogens by iiihibiting a very early stage of protein synthesis. Oxazolidinonesinhibit the formation of ribosomal initiation complex involving 30S and 50S ribosomesleading to prévention of initiation complex formation. Due to their novel mechanism ofaction, these compounds are active against pathogens résistant to other clinically usefulantibiotics. 012891 WΟ 02/06278 application discloses phenyloxazolidinone dérivatives asantimicrobiais. WO 93/23384 application discloses phenyloxazolidinones containing a substituteddiazine moiety and their uses as antimicrobials. WO 93/09103 application discloses substituted aryl and heteroaryl- phenyl-oxazolidinopes useful as antibacterial agents. W090/02744 application discloses 5-indolinyl-5P-amidom.ethyloxazolidinones, 3-(fiisjed ring £fubstituted)phenyl-5p-amidomethyloxazolidinones wh.ich are useful asanti|?acteriall!agents.
European Pateiit Publication 352,781 discloses phenyl and pyridyl substitutedphenyl oxazolidinones.
European Patent Application 312,000 discloses phenylmettiyl and pyridinylmethyl
I substituted phenyl oxazolidinones. U.S. Patent No, 5,254,577 discloses nitrogen heteroaromatic rings attached tophenyloxazolidinone. U.S. Patent Nos. 5,547,950 and 5,700,799 also disclose the phenyl piperazinyloxazolidinones. J. Med. Chem. 1998; 41: 3727-3735; describes pyridine, diazene, triazene,heteroaromatic rings dinectly attached to the piperazinyl oxazolidinone core. WO 98/01446 iescribes 6-menibered heteroaryl ring containing 2 or 3 ringnitrogen atoms, attached to the piperazinyl oxazolidinyl core. WO 98/01447 discloses pyridyl ring (optionally substituted) attached to thepiperazinyl oxazolidinyl core. U.S. Patent No. 5,719,154 describes substituted or unsubstituted 2-pyrimidinyl, 4-pyrimidinyl, or 3-pyridazinyl rings directly attached to the piperazinyl oxazolidinyl core. WO 00/32599 discloses phenyl oxazolidinyl as antimicrobials.
U.S. Patent No. 5,736,545 describes azolyl piperazinyl phenyl oxazolidinoneswhiçh contains azolyl ring as a five membered heterocychc ring wherein in ail the casesthe piperaziiie nitrogen atom is attached to the carbon atom of the carbon nitrogen double bond of the five membered heterocyclic ring. The heterocycle ring contains more than one heteroatbm. The five membered ring heterocycle ( azolyl ring) is of the generalformula: wherein A, B, and C are independently oxygen (O), nitrogen (N), sulfur (S) orcarbon (C).
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; 32: 1673-81;
Gregory W.A., et al., J.Med.Chem., 1990; 33: 2569-78; Wang C., et al., Tetrahedron, 1989; 45: 1323-26; Brittelli, et al., J.Med. Chem., 1992; 35: 1156; Annual reports in Médicinal Cfaemistry, Vol 35, pp 135-144; Bio-organic and Médicinal Chemistry Letters,1999; 9: 2679-84; Antibacterial & Antifungal Drug Discovery & Development Surnmit,
Straitegic Research Instiltute, June 28-29, 2001, Amsterdam, The Netherlands; Posters No.182S2, 1823,'1824,1825;, 1826,1827,182&,1829,1830,1831,1832, 1833, and 1834,40*
Interscience Conférence 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, 41Bt Interscience Conférence on Antimicrobial Agents andChemotherapy, Sept 22-25, (2001), Chicago, USA.
SUMMARY OF THE INVENTION
The objective of fhis invention is to synthesize, identify and profile oxazolidinonemolécules which hâve good activity against multiply résistant gram positive pathogenslike MRSAj VRE and PRSP. Some of these molécules hâve activity against MDR-TBand MAI ^trains, while others hâve significant activity against important anaérobiebacteria.
The compounds of the présent invention are related by their substitutedphenyloxazolidinone ring structure in the compounds disclosed in the publicationsdescribed above except that the subject compounds hâve a diazine moiety attached to the 012891 pheüyloxazoïidinone which is further substituted by heterocyclic, aryl, substituted aryl,heteroaroamàtic ring, th’erefore the compounds are unique and hâve superior antibacterialactivity.
Another object of the présent invention is to provide processes for the novel5 pheriyloxazolidinones dérivatives that exhibit significanüy greater antibacterial activity,than available with the présent compounds against multiply résistant gram positivepathogens like MRSA, VRE and PRSP against MDR-TB and MAI strains, in order to provide safe and effective treatment of bacterial infections.
In order to achieve the above-mentioned objectives and in accordance with the10 püipose of trie invention as enxbodied and broadly described herein, there is provided apïoQess for ithe synthesis of novel phenyJoxazolidinone dérivatives represented by
Forrpula I
15 FORMULAI wherein T is five membered (un)substituted heterocyclic ring with exclusively oneheterôatom selected from oxygen, nitrogen and sulphur; aryl, substituted aryl,bound to the ring C. Preferred forms of T are selected ftom aryl and five 20 membered heteroaryl which are further substituted by a group represented by R, wherein R is selected from the group consisting of H, CHO, Ci„6 alkyl, F, Cl, Br,I,—CN, COR5,COORs, N(R6,R7), NHCOC(R8, R9), NHCOORio, CON (R6, R7),CH2NO2, NO2, CH(OAc)2, CH2Rg, CHR9, -CH=N-ORi0( -C=CH-R5,OR5, SR5, -C(R9)=C(R9)NO2, Cm2 alkyl substituted with one or more of F, Cl, 25 Br, I, OR4, SR4, wherein R4 and R5 are independently selected from H, C™ alkyl, C3_i2 cycloalkyl, Ci .g alkoxy, Ci_6 alkyl substituted with one or more of F, Cl, Br, Ior OH, aryl, heteroaryl; Rg and R7, are independently selected from H,optionally substituted C1-12 alkyl, C3-i2 cycloalkyl, C1-6 alkoxy; Rg and R§ areindependently selected from H, C1-6 alkyl, F, Cl, Br, I, Ci-i2 alkyl substituted with 012891 one or more of F, Cl, Br, I, OR5, SR5, N(Re,R7); Rjo= H, optionally substituted Cj.12 alkyl, C3.12 cycloalkyl, Ci.6 alkoxy, Ci-6 alkyl, aryl, heteroaryl;n is an integer in the range ftom 0 to 3; X is C, CH, CH-S, CH-O, N, CHNRn, CHCH2NRlb CCH2NR11, wherein Ru is 5 hydrogen, optionally substituted C142 alkyl, C312 cycloalkyl, C16 alkoxy, C 16 alkyl' Cmalkylcarbonyl, Cm alkylcarboxy, aryl, heteroaryl; Y and Z are independently selected from hydrogen, C1-6 alkyl, C342 andcycloalkyl Co 3 bridging groups; U and V are independently selected from hydrogen, optionally substituted C, 6 10 alkyl, F, Cl, Br, C112 alkyl substituted with one or more of F, Cl, Br, I, preferably U and V are hydrogen or fluoro;
Ri is selected from the group consisting of - NHC(=O)R2, N(R.3, R4), -NR2C(=S)R3, -NR2C(t-S)SR3) wherein R2 is hydrogen, C,42 alkyl, C312 cycloalkyl, C,^alkoxy, CIh5 alkyl substituted with one or more of F, Cl, Br, I or OH; R3,R| are 15 independently selected from hydrogen, CH2 alkyl, CW2 cycloalkyl, Cl 5 alkoxy,
Cj^ $lkyl substituted with one or more of F, Cl, Br, I or OH.
Prefèrred compounds of Formula I hâve Ri as acetamide, thioacetamide orhalolgen substituted acetamide and the mpst preferred compounds in this sériés would beprepared as the optically pure enantiomers having the (S)-configuration according to the 20 Cahn-Ingold-Prelog notation at C5 of the oxazolidinone ring. The (S)-enantiomer of thissériés of compounds is preferred since it has two times more antibacterial activity than thecorresponding racemic compound. The scope of the individual isomers and mixture ofenantiomers of the structural Formula I are also covered in this invention. 012891
Still jmore preferred compounds of the Formula I containing D ring as fiiranyl,thiophene, aüd pyrrolyl ring Systems and fiirther substituted by substitutions G, J and L isrepresented by Formula H wherein
Ri is selected from the group consisting of (1) -NHC(=0)R2; (2) -NÇRs, R»);(3) -NR2C(=S)R3; (4) -NR2C(=S)SR3 wlierein R2, R3, Ri are independentlyhydrogen, C1-12 alkyl, C3.12 cycloalkyl, C1-6 alkoxy, Cm alkyl substituted one ormore of F, Cl, Br, I, OH; preferably Ri is of the formula -NH(C=O)R2 wherein R2is CH3, CH2F, CHF2j CF3, CH2CI. CHCL2, CC13 or CHC1CH3; U andV are independently selected from hydrogen, optionally substituted Cmalkyl,, F, Cl, Br, Ç1-12 alkyl substituted with one or more of F, Cl, Br, I; preferablyU and V are hydrogen and fluoro; Y and Z are independently selected front (1) hydrogen, (2) Cj-s alkyl, (3) C3.12cycloalkyl (4) C0-3 bridging group; X is selected from C, CH, CH-S, CH-O, N, CHNRn, CHCH2NRn, CCHjNRu;wherein Rj j is hydrogen, optionally substituted Cj 2 alkyl, C312 cycloalkyl, C,_galkoxy, C ,_6 alkyl, Cm alkylcarbonyl, Cj-e alkylcarboxy, aryl, heteroaryl;
Qi is selected from O, S, NRn, wherein ZRn is as defined above; G, J, L are independently selected from H, Cm alkyl, F, Cl, Br,I, -CN, CHO,CORS,COOR5, CH(OAc)2, N(R,R7), NHCOQRe, R9, Rio), CON (R, R7),NHCpORio, CH2NO2, N02, CH2R8, CHR9, -CH = N-OR0, -C=CH-R5, 0R5,SR5, ;-C(R9)~C(R9)NO2, Cm2 alkyl substituted with one or more of F, Cl, Br, I, 1 OR4, SR); wherein R5 is selected from H, C1-12 alkyl, C3.12 cycloalkyl, Cm alkoxy,Cm alkyl substituted with one or more of F, Cl. Br, I or OH, aryl, heteroaryl; Reand R7, are independently selected from 3ï, optionally substituted C1-12 alkyl, C3-12 012891 cycloalkyl, C]-6 alkoxy; Rg and R9 are independently selected from H, C]-6 alkyl, F, Cl, Br, ζ Ci-i2 alkyl substituted with one or more of F, Cl, Br, I, OR5, SR5, N(R6,R7); Rio= H, optionally substituted C1-12 alkyl, C3-12 cycloalkyl, Ci-β alkoxy,
Ci-6 alkyl, aryl, heteroaryl.
In the more preferred compounds represented by Formula II ring C may be 6-8membered in size and the larger rings may hâve either two or three carbons between eachnitrqgen atom, for example:
The ring C naay be bridged to form a bicyclic System as shown below:
When ring C is optionally substituted at positions Y and Z with alkyl groups,cycloalkyl groups, fluoro group, carboxylic and corresponding esters, amides, substitutedalkyls or bridging alkyl groups are as shown below: —K ^—\ -p N— —X N-\_f
Va
—X N— —X
\—J N— —X N—
When ring C is 6 membered in. size and X is -CH-(NHRi O, or >CCH2NHRi 1-, thefolldwing rings are preferred ones wherein Ru is the same as defimed earlier. Λ_ R11 R11 R11 N— H·
RL11
A
S R11 \ N„ R-i 1 012891
In addition to the above, ring C also inclmdes the following structures:
(CHdn r\
5 Still more preferred compounds of Formula Π when Qi =Formula IH NRn, is represented T>y
FORMULA III wherein > Ri isselected. from the group consisting of (1) -NHC (==0)1^ (2) -N(R3, R4); (3) -NR2C(=S)R3; (4) -NR2C(=S)SR3 wherein R2, R3, R4 are independentlyhydrogen, Ci -12 alkyl, C3.12 cycloalkyl, Cm alkoxy, Cm alkyl substituted one ormore ,of F, Cl, Br, I, OH; preferab ly Ri is of the formula -NH(C=0)R2 wherein R2is CB3, CHzF, CHF2, CF3j CH2CI. CHClz, CC13; 012891 U and V are independently selected. from hydrogen, oplionally substituted Ci-ealkyl,,F, Cl, Br, Çi_12 alkyl substituted with one or more of F, Cl, Br, I; preferablyU and V are hydrogen and fluoro. Y and Z are independently selected. from (1) hydrogen, (2) Cm alkyl, (3) C3-12 5 cycloalkyl (4) C0.3 bridging group; X is selected from C, CH, CH-S, Cïï-O, N, CHNRlb CHCH2NRn, CCHzNTRnîwherein Rn is hydrogen, optionally substituted C]12 alkyl, C312 cycloalkyl, CV5alkoxy, C ,_6 alkyl, Cu alkylcarbonyl, Cm alkylcarboxry, aryl, heteroaryl; G, J, L are independently selected from H, Ci-e alkyl, F, Cl, Br,I, -CN, .0 COR5,COOR5, N(R^,R7), NHCOC(Rs, R9, Rio), CON (Rô, R7), NHCOORio, CH2^O2, NOî, CH2Rs, CHR9î -CH=N-ORio, -c=ch-r5, OR5îSR5, :C(R9)=C(R9)NO2, C1-12 alkyl substituted with one or more of F, C3, Br, I,OR4,1SR4; wherem R5 is selected from H, Cm alkyl, C3.12 cycloalkyl, C1-6 alkoxy,Ci-6 dlkyl substituted with one or more of F, Cl, Br, Γ or OH, aryl, heteroaryl; Ré Î5 and R7, are independently selected from H, optionally substituted Cm alkyl, C3-12 cycloalkyl, C1-6 alkoxy; Rg and Rg are independently selected from H, Ci-6 alkyl,F, Cl, Br, I, C1-12 alkyl substituted with one or more of F, Cl, Br, I, OR5, SR5, ; N(Ré,R7);, Rio= H, optionally substituted C1.12 alkyl, C3.i2 cycloalkyl, Ci.6 alkoxy,Cm alkyl, aryl, heteroaryl; iO n is an integer in the range from O to 3.
More preferred G, J and L substitutions are nitro, aldeZhydes and halides.
Still tpore preferred compounds of Formula H is represented by Formula IV
wherein Qi=oxygen in Formula H, and 012891
Ri is selected from the group consisting of (1) -NZHC(=O)R2; (2) -NÇR3, R4); (3) _NR2C(=S)R3; (4) -NR2C(=S)SR3 wherein R2, R3, R4 are independezntlyhydrogen, Cm2 alkyl, C3_12 cycloalkyl, C1-6 alkoxy, Ci^ alkyl substituted one ormore of F, Cl, Br, I, OH; preferably Ri is of the forrtrula -NH(C=O)R2 wherein R2is CH3, ch2f, chf2, CF3, CH2C1. CHC12, CC13; U and V are independently selected from hydrogen, optionally substituted Ci-ealkyll, F, Cl, Br, .Cm 2 alkyl substituted with one or more of F, Cl, Br, I; preferablyU and V are hydrogen and fluoro; Y and Z are independently selected from (1) hydrogen, (2) Ci_$ alkyl, (3) Ο3-ι2cycloalkyl (4) C0-3 bridgûug group; X is selected from C, CH, CH-S, CH-O, N, CHNRn, CHCH2NRn, CŒfcNRn;wherein Rn is hydrogen, optionally substituted Cj 12 alkyl, C312 cycloalfkyl, C16alkoxy, C alkyl, Ci-6 alkylcarbonyl, Ci-6 alkylcarboxy, aryl, heteroaryl; G, J, L are independently selected from H, C3-6 alkyl, F, Cl, Br,I, -CN,COR5,COOR5, NCR^Rt), NHCOC(R8, R9, Rio), NHCOORio, COH (Rô, R7),CH2NO2, NO2, CH2Rs, CHR9, -CH = N-ORio, -C=CH-R5) OR_s, SRs, - C(Rs)=C(R9) NO2, Ci.i2 alkyl substituted with one or more of F, Cl, Br, I, OR4,SR4; yherein R5 is selected from H, Cj-π alkyl, C3.12 cycloalkyl, Ci-β alkoxy, C1-6alkyl substituted with one or more of F, Cl, Br, I or OH, aryl, heteroaxyl; Rô and R7, are independently selected from H, optionally substituted Cm alkyl, C3-i2 I ! cycloalkyl, Ci-β alkoxy; ZRs and R9 are independently selected from H, C^é alkyl,F, Cl, Br, I, Ci-ii2 alkyl substituted with one or more of F, Cl, Br, I, OR5, SR5,N(Rî,R7);, Rio= H, optionally substituted Cm2 alkyl, C3-12 cycloalkyl, alkoxy,Ci_6 alkyl, aryl, heteroaryl; n is an integer in the range from 0 to 3.
More preferred G, J and X substitutions are nitro, aldéhydes and halides.
The preffered compounds of Formula IV are as folloxvs: (S)-N-[[3-[3-Fhioro-4-[4-(5-nitro-2-furanyl)-l-piperazinyl]phenyl]-2-oxzo-5- oxazolidinyl]methyl]acetamide 10 5 012891
Still more preferred compounds of Formula II is represented by Formula V
with Qi = sulphur in Formula Π, wherein
Ri is selected fiom the group consisting of (1) —NHC(=O)R2; (2) -N(R3, R4);(3) -NR.2C(=S)R3; (4) -NR2C(=S)SR3 wherein R2, R3, R4 are independentlyhydrogen, C142 alkyl, C342 cycloalkyl, Ci-6 alkoxy, Cj-6 alkyl substituted orne or of ) more F, Cl, Br, I, OH; preferably Ri is of the formula -NH(C=O)R2 wherein R2 is CH3JcH2F, CHF2, CF3s ch2ci. chci2, CC13; U and V are independently selected fiom hydrogen, optionally substituted <4-6alkyl^ F, Cl, Br, Ci-12 alkyl substituted with one or more F, Cl, Br, I; preferably Uand V are hydrogen and fluoro. ; 5 Y and Z are independently selected from (1) hydrogen, (2) Ci-6 alkyl, (3) C3-12 cycloalkyl (4) C0.3 bridging group; X is selected from C, CH, CH-S, CH-O, N, CHNRi 1, CHCHiNRn.CCHzNRu;wherein Rn is hydrogen, optionally substituted Cj.l2 alkyl, C3_12 cycloalkyl, C16alkoxy, C μ6 alkyl, Calkylcarbonyl, Ci-e alkylcarboxy, aryl, heteroaryl; 0 G, J, L are independently selected from H, C1-6 alkyl, F, Cl, Br,I, -CN, COR5,COOR5, N(R6,R7), NHCOC(R8, R9, Rio), NHCOORw, CON (R&amp; R7),CH2NO2, NO2, CH2Rs, CHR9, -CH=N-ORio, -C-CH-Rs, ORS,SRs, rC(R9)=C(R9)NC>2, C1.12 alkyl substituted witki one or more F, Cl, Br, I, OR4,SR4; yvherein R5 .is selected from H, C1-12 alkyl, C3-12 cycloalkyl, C1-6 alkoxy, Ci^ 5 alkyl!substituted with one or more of F, Cl, Br, I or OH, aryl, heteroaryl- Rj and R7, are independently selected from H, optionally substituted C1-12 alkyl, C3-12cycloalkyl, Ci-s alkoxy; Rg and R9 are independently selected from H, Ci -6 alkyl, il 012891 F, Cl, Br, I, Ci-i2 alkyl substituted with one or more of F, Cl, Br, I, ORs, SR5, N(R&amp;R7);, Rio= H, optionally substituted C1.12 alkyl, C3-12 cycloalkyl, Cm alkoxy,
Cm alkyl, aryl, heteroaryl; n is an integer in the range from 0 to 3.
More preferred G, J and L substitutions are nitro, aldéhydes and halides.
The preferred compounds of Formula V are as follows: (S)-N-[[3-[3-Fluoro-4-[4-(5-nitro-2-thienyl)-l-piperazinyl]phenyl]-2-oxo-5- oxazolidinyl]methyl]acetamide (S)-H-[[3-[3-Fluoro-4-[4-(5-formyl-2-tlïienyI)-l-piperazinyl]phenyl]-2-oxo-5- oxaz<jtlidinyl]methyl]acetamide
The 'compounds of the présent invention are useful as antimicrobial agents,effective against a number of human and veterinary pathogens, particularly aérobic Gram-positive bacteria, including multiply-antibiotic résistant staphylococci and streptococci, aswell as anaérobie organisms such as Mycobacterium tuberculosis and othermycobacterium species.
For preparing pharmaceutical compositions from the compounds described by thisinvention, inert, phaimaceutically acceptable carriers can be either solid or liquid. Solidform préparations include powders, tablets, dispersible granules, capsules, cachets,suppositories, and ointments. A solid carrier can be one or more substances which mayalso |act as diluents, flavouring agents, solubilizers, lubricants, suspending agents, binders,of tablets disintegrating agents; it can also be as fînely divided solid which is in admixturewithl the finply divided active compound. For the préparation of tablets, the activecompound i$ mixed with carrier having the necessary binding properties in suitableproportions ànd compacted in the shape and size desired. The powders and tabletspreferably contain from about 5 to about 70 percent of the active ingrédient. Suitablesolid carriers are lactose, pectin, dextrin, starch, gelatin, tragacanth, low melting wax,cocoa butter, and the like. The tenu "préparation" is intended to include the formulationof the active compound with encapsulating material as carrier providing a capsule inwhich 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 formssuitable for oral administration. 12 012891
Liquid form préparations include solutions, suspensions, and émulsions. As anexample may "be mentioned water or water-propylene glycol solutions for parentéralinjection. Such solutions are prepared so as to be acceptable to biological Systems(isotonicity, pH, etc.). Liquid préparations can also be formulated in solution in aqueous 5 polyethylene glycol solution. Aqueous solutions suitable for oral use can be prepared bydissolving the active component in water and adding suitable colorants, flavours,stabilizing, ^nd thickening agents as desired. Aqueous suspension suitable for oral usecan be madç by dispersing the fïnely divided active component in water with viscousmatèrial, i.e., natural or synthetic gums, restas, methyl cellulose, sodium carboxymethyl 10 cellulose, and other well-known suspending agents.
Ointaent préparations contain heavy métal salts of a compound of Formula I witha physiologically acceptable carrier. The carrier is desirably a conventional water-dispersible hydrophilic or oil-in-water carrier, particularly a conventional semi-soft orcream-like water-dispersible or water soluble, oil-in-water émulsion infected surface with 15 a minimum of discomfort. Suitable compositions may be prepared by merelyincorporating or homogeneously admixing fïnely divided compounds with thehydrophilic carrier or base or ointaent.
Preferably, the pharmaceutical préparation is in unit dosage form. In such form,the préparation, is subdivided into unit doses containing appropriate quantifies of the 20 active comppnent. Thé unit dosage forfn can be a packaged préparation, the packagecont'ataing discrète capsules, powders in vials or ampoules, and ointments capsule,cachet, tablet, gel, or creatn itself or it can be the appropriate number of any of thesepackaged forms. ' The quantity of active compound in a unit dose of préparation may be varied or 25 adjusted from less than 1 mg to several grams according to the particular application andthe potency of the active ingrédient.
In therapeutic use as agents for treating bacterial infections the compoundsutilized in the pharmaceutical method of this invention are administered at the initialdosage of about 3 mg to about 40 mg per kilogram daily. The dosages, however, may be 30 varied depehding upon the requirements of the patient and the compound beingempjoyed. Détermination of the proper dosage for a particular situation is within the 13 012891 smajler dosages which are less than the optimum dose. Small incréments until theoptirnum effiect under the daily dosage may be divided and administered in portionsduriftg the day if desired. la order to achieve the above mentioned objects in accordance with the propose ofthe invention as embodied and broadly described herein, there are provided process forthe synthesis of compounds of Formulae I, II, III, IV and V. Pharmaceutically acceptablenon-toxic acid addition salts of the compounds of the présent invention of Foimulae I, II,ΠΙ, IV and V may be formed with inorganic or organic acids, by methods well known inthe art.
The présent invention also includes within its scope prodrugs of the compounds of
Formulae I, Π, III, IV and V. In general, such prodrugs will be functional dérivatives of these compounds which readily get converted in vivo into defîned compounds. «
Conyentional procedures for tlie sélection and préparation of suitable prodrugs areknoy/n.
Tlie 'invention àlso includes pharmaceutically acceptable salts, enantiomers,solvatés, polymorphs, diastereomers, N-oxides, métabolites in combination withpharmaceutically acceptable carrier and optionally included excipient.
Other objects and advantages of the invention will be set forth in the descriptionwhich follows, and in part will b© apparent from the description, or may be leamed by thepractice of the invention. The objects and the advantages of the invention may bereleased and obtained by means of the mechanism and combination pointed out in theappended. daims.
DETA1LED DESCRIPTION OF THE INVENTION
The bompounds of the présent invention may be prepared by following thereaction sequences as depicted in the schemes defîned below. 14 012891
Mainly eight different amines of Formula VI
identified as ten different cores, namely -(S)-N-[[3-[3-Fluoro-4-(N-piperazinyl)phenyl]-2-oxo-5-oxazolidinyI]methyl]acetapaide (core I); -(S)-N - [ [3-[4-(Nj-piperazinyl)phenyl]-2-oxo-5 -oxazolidLinyl]methyl]acetamide (core II); (S)-N-[[3-[3-Fluoro-4-(N-piperazmyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]-2-chloropropionamide (core Uî); (S)-N-[[3-[3-Fluoro-4-(N-piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]metliyl]-difluoroacetamide (core IV>; (S)-N-[[3-Fluoro-[4-(l-piperazinyl)-phenyl]-2-oxo-5-oxazolidinyl]-dichloroacetamide (Core V) (S)-N-[[3-Fluoro-[4-(3-methyl-l-piperazinyl)-phenyl]-2-oxo-5-oxazolidinyl]-acetamide (Core VI) (S)-N-[[3-[3-Fluoro-4-(N-piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]-methyl]fluoroacetamide (core VU) (S)-N- [[3-[3-Fluoro-[4-[3-( 1 a,5a,6a)-[6-(N-methyl)aininomethyl]-3-azabicyclo- [3.1.0]liexane]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (Core VIH) (S)-N-[[3-[3-Flulcro-4-(l-homopiperazenyl)phenyl]-2-oxo-5-oxazoIidnyl]Methyl]acetamide (Core IX) (S)-N-[[3-[3-Fluoro-4-(l-piperidnyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (Core X)were nsed for analoguingpurposes.
Key intermediate amines of Formula VI for the analogue préparation were prepared from. commercially available reagents wherein amines of Formula VI is defined as: Mi is NH, NHR, CHNHR, -CHCH2NHR, -CCH2NHR wLerein R is H, ethyl, methyl, isopropyl, acetyl, cyclopropyl, alkoxy, or acetyl and U, V, Y., Z, n and Ri are as defined for Formulait. 15 012891
Some amines of Formula VI are already known in the literature and are given byréférencé and if they hâve been made for the first ti_me or by a different procedures orvariation of known procedure they are described in detail in the experimental, section.
Optically pure amines of Formula VI could be obtained either by one of a number5 of assymetric synthèses ,or altematively by resolution zfrom a racemic mixture by sélectivecrystallizatïon of a sal*t prepared, with an appropriate optically active acid such asdibehzoyl tartrate or 10-camphorsulfonic acid, followed by treatment with base to afford the optically pure amine.
The compounds of the présent invention represented by general Formula I may be0 prepared by the method of reaction in Scheme I:
SCHEME-I
In Scheme I, the heteroaromatic group with Che corresponding appezndage can beintrqduced on the nitrogen atom of ring C of compounds of Formula VI by one of themethods described below to give Formula I, wherein RX2 is a suitable leaving group well 012891 knoVn to ône of ordinajy skill in the art such as fluoro, chloro, bromo, iodo, SCH3, -SO2CH3, -SO2CF3, Tos or OC0H5 etc., and R, T, Μι, X, RbU, V, Y and Z are as defined earlier.
The amine of structure of Formula VI is reacted with a heteroaromatic compound5 of Formula R-T-R12 wherein R, T and R12 are the same as defined earlier. Preferably, theréaction of Formula VI with R-T-R12 is carried out in a suitable solvent in the presence ofa base such as potassium carbonate, N-ethyldiisopropyl amine or dipotassium hydrogen phosphate.
The préparation of the compounds of Formula II (where heterocycle is a 510 membered ring of Formula VU wherein R12 is a suitable leaving group and G, J, L, Qi are the same as defined earlier) is accomplished as etxemplified below in Scheme II: 15
SCHEME-II
FORMULA-II 17 20
The amine of Formula VI is reacted with a heteroaromatic compound of
Formula VII to give a compound of Formula H. The reaction is canied out in a suitable solvent such as dimethylformamide, dimethylacetamide, acetonitrile^ dimethylsulfoxide
or ethylene glycol at a suitable température in the range of -7<3°C to 1SO°C to afffordcompounds of Formula H· The presence of a suitable base such as triethylamine,diisopropylethylamine, potassium carbonate, sodium bicarbonate, dipotasslumhydrogenphosphate is useiul in some cases to ixnprove the yield of the reaction. 5 Altemativ'ely, for the préparation of compounds of Formula I, heteroaromatic compound of the Formula VU, such as 2-bromo-thiophene is reacted with the inteijmediate amine of Formula VI in the presence of ligands such as Palladium dibepzylidenis acetone [Pd2(dba)3] or Pd(OA02 with 2,2’-Bis-(diphenylphosphino)-l3l’- binapthyl (BÎNAP) and bases such as césium carbonate or sodium, t-butoxide (Ref: J. Org. 3 Chepi. 1999,,'w, 6019-6022 and J. Org. Chem, 2000, 65, 1144-1157). Other ligands snchi as ethylenediamine or TMEDA along with bases such as césium carbonate or potassiumphosphate may also be used (Synlett, 2002,3, 427-430).
The transformations effected are described in the experimental section. In theaboyé synthetic methods where spécifie acids, “bases, solvents, catalysts, oxidising agents,reducing agents etc. are mentioned, it is to be understood that the other acids, bases,solvents, catalysts, oxidising agents, reducing agents etc. may be used. Similarly, thereaction température and duration of the reaction may be adjusted according to the need.An illustrative list of pardcular compounds according to the iavention and capable: ofbeing produced by the above mentioned schemcs include: 3 (S)-^-[[3-[3-Fluoro-4-[4-(5-nitro-2-thienyl)-l-piperazinyL]phenyl]-2-oxo-5- oxazôlidinyl]methyl]acetamide (Compound No.l) (S)-hp[[ 3 - [3-Fluôro-4-[4-(5-fonn5Îl-2-thienyl)-1 -piperazinyljphenyl] -2-oxo-5 -oxazolidinyl]methyl]acetamide (Compound No.2) (S)-N-[[3-[3-Fluoro-4-[4-(5-formyl-2-furyl)-l-piperazinyL]phenyl]-2-oxo-5-5 oxazolidin.yl]methyl]acetamide (Compound No. 3) (S)-N-[[3-[3-Fluoro-4-[4-(5-nitro-2-furyl)-l-piperazmyl]pZhenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (Compound No. 4) (S)-N-[[3-[3-Fluoro-4-[4-{3-thienyl(2-nitro)-5-acetyloxy}methylacetate]-l-piperazinyl]phenyl]-2-oxo-5-oxazolidin.yl]acetamide (Compound No. 5) 3 (S)- N-[[3-[4-[N-l-(5-nitro-2-thienyl) piperazinyl]-phenyl] -2-oxa-5-oxazolidinyl]- methyl]-acetamide (Compound No. 6) (S)-N-[[3-[3-Fluoro-4-[N-l-{4-(5-nitro-2-thienyl)piperazimyl}]-phenyl]-2-oxo-5-oxazolidin.yl]-methyl]-2-chloro-propion-amide (Compound No. 7) 18 012891 (S)-N-[[3-[3 -Fluoro-4- [4-(5-nitro-2-thienyl)- l-prperazinyl]phenyl]-2 -oxo-5-oxazolidinyl]methyl]diiluoroacetamide (Compound No. 8) (S)-Np[[3-[-3-Fluoro -4-[N-1 -(5-nitro-2-thienyl)-i)iperazinyl]phenyl] -2-oxo-5-oxozolidinyl]methyl]dichloro acetamide (CompoundNo 9) (S)-hÎ-[[3-[-3-Fluoro-4-[(5-nitro-2-thienyl)-3-melhyl-l-piperazinyl]phenyl]-2-oxo5-oxqzolidinylJmethyl] acetamide (Compound No. 10) (S)-N-[[3-[3-Fluoro-4-[4-(5-nitro-2-thienyl)-l-pijieraziiiyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]fluoroacetamide (Compoun<i No. 11) (S)-N-[[3-[3-Fluoro-4-[3-(la,5a,6a)-[6-{N-(5-ntitro-2-thienyl)-N- methyl}aminomethyl]-3-azabicyclo-[3.1.0]hexane]phenyl]-2-oxo-5- oxazolidinyl]methyl]acetamide (CompoundNo 12). (S)-N-[[3-[3-Fluoro-4-[4-(5-nitro-2-thienyl)-l-homopiperazinyl]phenyl]-2-oxo-5-oxazolidnyl]methyl] acetamide (Compound No. L 3) (S)-N-[[3-[3 -Fluoro-4- [4-(5-nitro-2-&amp;ryl)-1 -hom.opiperazinyl]phenyl]-2-oxo-5 -oxazolidinyljmethyl] acetamide (CompoundNo. 14) (S)-N-[[3-[3-Fluoro-4-[4-{3-thienyl(2-nitro)5-foxmyl}-l-piperazinylZ]phenyl]-2-oxo-5-oxazolidÎny]]-meth.yl]acetamÎde (Compouund No. 15) (S)-Nf[[3-[3-Fluoro-4-[N-l-[4-{N-methyl-N-(5-nitro-2-furyl)}amino]-l-piperadinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (Compound No.16) (S)-N!-[[3-[3-Fluoro-4- [3-(1α, 5α, ‘6a)-[6- {N-(5-mitro-2-furyl)-N- methy}aminomethyl]-3-azabicyclo [3T.0]hexane] phenyl]-2-oxo-5- oxazolidinyl]methyl]acetamide (Compound No. 17)
Pharmacologicat Testing 1 The compounds of the invention display antibacterial activity when tested by theagar incorporation method. The following minimum infcïibitory concentrations (pg/ml)were obtained for représentative compounds of the invention which are givem below inthe following tables. GUIDE TO TABLE ABBREVIATIONS: 1) S.aureus ATCC 25923 —Staphylococus aureus A.TCC 25923 2) MRSA15187 -Methicillin Résistant Staphyloco-ccus aureus 3) Ent. fiiecalis ATCC 29212 —Enterococcusfaecaiis ATCC 29212 4) Ent. faecium 6A - Enterococcus faecium 6A Kan®, Cipro® 5) Strep. pne. ATCC 6303 —Streptococcus pneumomiae ATCC 6303 6) Strep.pyog. ATCC 19615 -Streptococcus pyogenes 7) S. epidermidis - Sîaphylococcus epidermidis ATCC 12228 19 012891 T AB LE-17
20 1289 1
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: COMPOUNDNo.l tecmî—< ? vn <M O 0.25 1 0.25 I i <0.1235 I ©t—1 1 <0.12 i 1 0.25 1 te CM ©‘ te CM © | <0.125 1 O 1— c 00 1 <0.12 1 l____0.25 1 te CM O l 0.25_____I te CM T“< g tzi ETH o CM Ό © CM te CM © © © P CO © \D CM CM Ό © CO »—1 t*4 Λ © oo oo CO r—< A ce CM O 1 U LNZ te <© © © © CM © KO © CM © O-3 KO O Ό M3 O o OC »—4 ce ce oo /V T—< T—< t— P— H Φ 0 % te cm o © O © © te © © o »e CM CM we CM o CM CM 04 C4 hJ ? oo —< »—< CM cm’ © P··! CM ? Λ» © i—1 Π) ce ni ce 8 U A O K te 03 te rM o o O © © CM © © © c© o O O c o P·· 'J Ph o ce •^· 00 CM 1-H CM CM CM 1-H Tt” CM CM CM r·* © g <Z) © V H ffi CM CM CM CM © CM © CM © © © C5 CM © CM _© CM te CM 0? S Λ Λ ce Λ TT Λ •’ί ce CM ce ’t Λ 00 ce ό Pt © 0 : «n CM fe JM |.O3 CM ce· © o © © te CM © te CM te te CM CM C<~) we 04 te 04 CM ce CM ce 04 ce S A ’t r-* © ’Sf © © © Λ. © © A Λ Λ © © © te CM C' O\ to- ns W-1 oo <3\ © 00 C* i ATCC 49601 ©>, CM «4Ό CM ë ATCC 1723 CO TCC 700897 O\ ce rH ! ε ü te ce U ε 4 4 Mulare F21 /1 ulare B-78/3 © te ce S >3 1 CJ g ε 4 i ü g M~ te. 5$ B T—1 CM ε 4 sS tô CM Ok SÎ S O\ te te S? ïâ ÇJ g Si oo rH ε 4 1 1 s O\ T-H Si 4 4 ATCC 19210 -< S g < *^î ’S •S S 45 •3 •S S •3 s s à S § g (J s s St § s s s g i fû <3 3 g £ Q ’Pnl Q 3 g intri h ,g e *«sa intri aviu ,3I g .3 3 g .3 £ O *> Q 3 i iss s iss :si <? ce © r—1 <M ce rH T »e Mj, 7 ©t—1 1 rt i ed S ed S ed S Ma- Ό O i§ Mi •a S Mai· â Mai· 3 Mai- Mai '4 g CO o CM O ce o s »e © o» © OC O O\ © © T-M r-4 ex1—c ce r-H rH te © r· ï-· 00 T“l 24 012891
The in vitro antibacterial activity of the conxpounds were demonstrated by the agarincorporation method (NCCLS M 7 andM 100-SS documents). Brieflys the compoundswere dissolved in DMSO and doubling dilution of "the compounds were imcorporated intoMeer Hilton agar before solidification. Inoculunn was prepared by suspending 4 to 5colonies into 5 ml of normal saline solution and adjusting the turbility to 0.5 Macfarlandturbïdity standard tables (1.5 x 10&amp; CFU/ml), aftex appropriate dilutions, 10^ CFU/spotwas transfered into the surface of dried plate and incubated for 18 hoixrs (24 hours forMRSN studies). The concentration showing no .growth of the inoculated culture wasrecorded. as the MIC. Appropriate ATCC standard strains were simultaneously tested andresult recorded only when the MIC's against standard antibiotics were within theacceptable range.
The çpmpounds of the présent invention represented by general Formula I may beprepared. by ithe method of reaction in Scheme I. ICey intermediate amines of Formula VIfor the analdgue préparation were prepared by the synthetic procedures described belowor frbm commercially aÿailable reagents.,
Amines already fcnown in the literature are given by reference and if they hâvebeenmade by a different procedures they are described in detail.
Mainly eight different amines of Formula "VI identified as eight different cores namely (S)-N-[[3-[3-Fluoro-4-(N-piperazinyl)pheny'l]-2-oxo-5-oxazolidinyl]methyl] acet-amide (core I), (S)-N-[[3-[4-(N-piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (core'II), (S)-N-[[3-[3-Fluoro-4-(N-piperazmyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]-2-chloropropionamide (core ΙΠ), (S)-N-[[3-[3-Flupro-4-(N-piperazmyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]-difluoroacetamide (core IV), (S)-N-[[3-Fluoro-[4-(l-piperazinyl)-phenyl]-2-oxo-5-oxazolidinyl]- dichloroacetamide (Core V), (S)-N-[[3-Fluoro-[4-(3-methyl-l-piperazinyl)-phenyl]-2-oxo-5-oxazolidinyl]-acetamide (Core Vf), 25 012891 (S)-N-[[3-[3-Fluoro-4-(N-piperazinyl)phenyl]-2-oxo-5-oxazolidmyl]-methyl]fluoroacetamide (core VII) (S)-N-[[3-[3-Fluoro-[4-[3-(la,5a,6a)-[6-(N-methyl)anunomettiyl]-3-azabicyclo-[3.1.0]hexane]phenyl]-2-oxo-5-oxazolidiixyl]metliyl]acetamide (Core VIII) 5 (S)-N-[[3-[3-Fluoro-4-(l-homopiperazenyrl)phenyl]-2-oxo-5- oxazolidnyl]Methyl] acetamide (Core IX) (S)-N-[[3-[3-Fluoro-4-(l-piperidnyl)phenyl]-2-oxo-5-oxazplidmyljmethyl] acetamide (Core X)are siiown in the examples given below. 3 Most of the conipouxids were characterized using NMR, IR and were purified by chrômatography. Crude products were subjected to column chromatographie purificationusing silica gel (100-200 or 60-120 mesh) as stationary phase.
The exemples menti oned below demonstrate the general synthetic procedure aswell as the spécifie préparation for the préparation for the preferred compound. The5 exemples are given to illustrate the details ofthe invention and shouli not be constrained to limit the scope of the présent invention. EXAMPLE 1 2-oxo-5- D The heteroaromatic group with the conesponding appendage can be introduced on the nitrogen 'atom ofring C of compounds of Formula I by the methods described below:
General procedure:
The amine of Formula VI is reacted with a heteroaromatic compound of FormulaVII having Rn as a suitable leaving group such as fluoro, chloro, bromo, iodo, SCH3, - 5 SO2CH3, -SO2CF3, Tos or OCôHs etc. as defîned earlier for Scheme I. <3i, G, J and L areas defîned for Formula H. Tfcie reaction is carried out in a suitable solvent such asdimethylformamide, dimethylacetamide, acetonitrile, dimethylsulfoxide or ethyleneglycol ai a suitable température in the range of-70°C to 180°C to afforâ compounds ofFormula Π. The presence of a suitable base such as triethylamine, diisopropylethylamine, 3 potassium carbonate, sodium bicarbonate, dipotassium hydrogenphospliate is useful insomé cases t<? improve the yield of the reaction.
Analogues of (S)-N-[[3-P-Fluoro-4-(N-piperazi3nyl)phenyl]-oxazolidinyijmêthyl] acetamide(core I) 26
The following conxpounds were made following this method:
Compound No 1: <S)-N-[[3-[3-Fluoro-4-[4-(5-nitro-2-tliienyl-)-l-piperazinyl]plienyI]- 2-oxo-5-oxazolidinyl]methyl]acetamide > To the (S)-N’-[[3-[3-Fluoro-4-(l-piperazùiyl)-phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide trifluoroacetate prepared by the method given in U.S. tâtent No 5,700,799(4.58 mmol) in acetonitrile (40 mL), N-ethyl-diisopropylamine (5.9 g, 0.045 mol) and 5-bromo-2-nitro-thiophene (0.86 g, 5.27 mmol) were added and heatesd at 60 °C for 4 hrs.The reaction mixture was cooled and evaporated in vacuo. The residue was dissolved in. ) dichloromethane (DCM) and washed with water and saturated sodium chloride solution.The organic layer was dried over sodium sulphate and evaporated in vacuo. The residuewas purified by column chromatography using DCM-500 mL, 1%» MeOH/DCM - 200mL, 2% MeOH/DCM -200mL, 3% MeOH/DCM; - 500 mL. The product eluted in 3%MeOH/DCM. Product was sonicated in diethylether for 10 min, filtered and dried in air to
5 get 0.493 g of the title compound. m.p. 171-174 °C lHNMR (CEjCfe): êppm 7.8 (d, 1H), 7.5 (dd, 1H), 7.11 (dd, 1H), 6.9*7 (t, 1H), 6.02 (m,2HL4.77 (urç 1H), 4.01 (t, 1H), 3.85-3.5 (m, 7H), 3.23 (m, 4H), 2.03 (s, 3H) Μ+ί = 464, M+Na = 486, M+K = 502, M-N02 =418 3 Compound No. 2: (S)-N-[[3-[3-Fluoro-4-[4-(5-formyl-2-thienyl-)-l.-pipeiazii]yI]plienyl]-2-oxo-5-oxazolidiiiyl]metliyt] acetamide
To the (S)-N-[[3-[3-Fluoro-4-(l-piperazinyl)-phenyl]-2-oxo-5- oxazolidinyl]melhyl]acetamide trifluoroacetate (2.28 mmol) in acetonitrile (20 mL), N-ettiyl-diisopropylarnine 5 (3 g, 22.8 mmol) and 5-hromo-2-thiophenecarboxaldehyde (0.64 g, 3.4 mmol) were added and heated at 80 °C for 30 hrs. The reaction mixture was cooled and evaporated invacuo. The residue was dissolved in dichloromethane (DCM) and washed with water andsodiijim chloride solution. The organic layer was dried over sodium sulphate andevaporated in vacuo. The residue was purified by column chromatography using DCM- D 200 mL, 1% ÎMeOH/DCM - 200 mL, 2% MeOH/DCM -400mL, 3flÆ> MeOH/DCM - 800 mL. The prciduct eluted in 3% MeOH/DCM. The product was dlgested with hexane,filtered and dried in air tb get 0.06 g of the title compound. m.p. 180 OC (dec), 207 °C. 27 012891 1HNMR (CDCb): Ôppm 9.58 (s, 1H), 7.51 (m, 2H), 7.09 (d, 1H), 6.95 (t, 1H), 6.16 (d,1H), 5.98 (t, 1H), 4.78 (m, 1H), 4.00 (t, 1H), 3.8-3.45 (m, 7H), 3.2 (m, 4H>, 2.03 (s, 3H).M+l = 447, M+Na = 469, M+K = 485
Compound No. 3: (S)-N-[[3-[3-Fluoro-4-[4-(5-formyI-2-furyI)-l-pipera_jzinyI]phenyl]- 2-oxo-5-oxazolidinyl]methyl]acetauiide
To the (S)-N-[[3-[3-Fluoro-4-(l-piperazhyl)-phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (1.14 mmol) in acetonitrile (10 mL), 3ST-ethyl-diisopropylaniin_e (0.29 g, 2.29mmol) and 5-bromo-2-iüraldehyde (0.3 g, 1.72 mmol) were added and hearted ai 80 °C for10 hrs. The reaction mixture was cooled and evaporated in vacuo. The residue was takenin djchlororpethane (DCM) and washed with water and sodium chloride solution. Theorgaüic layer was dried over sodium sulphate and evaporated in vacuo. "The residue waspurifîed by Jçolumn chfomatography DCM-300 xnL, 1% MeOH/DCM — 200 mL, 2%MeOH/DCM -800mL,i 3% MeOH/DCM - 8D0 mL. The product eluted in 3%MeOH/DCM. The product was digested with diethylether, filtered and dried in air to get0.17 g of the title compound. m.p. 176 °C ’HNMR (CDCI3): ôppm 9.11 (m, 1H), 7.5 (dd, 1H), 7.28 (s, 1H), 7.09 (d, OH), 6.96 (t,1H), 6.00 (t, 1H), 5.38 (d, 1H), 4.79 (m, 1H), 4.04 (t, 1H), 3.85-3.55 (m, 7H), 3.1 (m, 4H),2.04 (s, 3H) M+l = 431, M+Na = 453, M+K = 469
Compound No. 4: (S)-N-[[3-[3-Fluoro-4-[4-(5-nitro-2-furyl)-l-piperazi»yI)phenyl]-2-oxo-j5-oxazolidinyl] methyl] acetamide
To the (S)-N-[[3-[3-Fluoro-4-(l -piperazinyl)-phenyl]-2-oxo-5-oxazo lidinyl]methyl]acetamide hydrochloride (1.14 mmol) in N,N-dimethylformamide (10 mL), potassiumcarbonate (1^57 g, 11.4 mmol) was added and stùrred for 15 min. 5-brom_o-2-nitro-furan(0.19g, 1.31 mmol) was added to the réaction, mixture and it was sürred at roomtempérature for 3 hrs, when no reaction took place. Then sodium hydroxicle (0.07 g) wasadded to the reaction mixture and stirred for 17 hrs. The reaction mixture was taken indichloromethane (DCM) and washed with water and sodium chloride solution. Theorganic layer was dried over sodium sulphate and evaporated in vacuo. TZhe residue waspurifîed by column chromatography using DCM-200 mL, 1% MeOH/DCM - 200 mL,2% MeOHZDCM - IL. The product eluted in 2% MeOH/DCM. Th-e product was 28 ο 1289} digested with diethyjether, fîltered and dried in air to get 0.32 g of th.e title compound.
m.p. 191-204°C ’HNMR (CDCfe): Sppm 7.5 (m, 2H), 7.1 (d, 1H), 6.95 (t, 1H), 5.93 (t, 1 H), 5.41 (d, 1H), 4.77 (m, 1H), 4.03 (t, 1H), 3.8-3.5 (m, 7H), 3.17 (m, 4H), 2.02 (s, 3H). 5 M+)l = 448,|M+Na = 470, M+K = 486, M-NO2 = 486.
Compound! No.lj5: (S)-N-[[3-[3-Fluoro-4-[4-{3-tliionyI(2-iiitiO)5-forinyl]-l- piperazinyl] phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide. (S)-N-[[3-[3-Fluoro-4-[N-l[4-[3-thiophene(2-nitro)-(5-acetyloxy)methylacetate]piperazinyl]phenyl]-2-oxo-5-oxazolïdinyl]acetamide (0.16 gm, 0.0269 moles) was D taken in IN HCL (20ml) and stirred at room temparature for 5hrs. The reaction mixturewas extracted with dichloromethane, dried on sodium sulphate and concentrated. Thecrude compound was purified by column chromatography by eluting witli 2% methanol indichloromethane.
Yield: 0.02 g 5 H NMR (DMSO): 10.0(s,lH,CHO )8.18 (m,lH,NH), 7.8(d,lH,Ar-IÎ),7.79(d,lH,Ar-H),|.ll-7.0rn,2H,Ar-H),4.76(m,lH,CH),4.0(t,lH,CH),3.8-3.3(m,llH^2.0(s,3H,CpCH3).
Compound No. 5: (S)-N-[[3-[3-Fluoro-4-[4-{3-thionyl-(2-nitro)-5-acetyloxy}methylacetate]-l-piperazinyi]phenyl]-2-oxo-5-oxazoIidïnyl]acetamide. ) (S)-N[[3-[3-Fluoro-4-(N-l-piperazmyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide(0.67 gm,1.53 moles) was dissolved in acetonitrile. To this, N-Bthyl diisopropyl amine(0.397,3.07 moles) and 5-nitro-4-bromo-thiophene-2-acetyloxy methylacetate (0.594gm,2.3 moles) were added and the reaction mixture was heated at 60°C for 6-8 hrs. Thereaction mixture was concentrated. The crude compound was purizfied by columnchromatography eluting with 2% Methanol in dichloromethane. 'HNMR(CDCh): 5ppm 7.76 (s,'lH, Ar-H), 7.53 (d,lH, Ar-H),7.12(d, 1ZH, Ar-H),6.97(m, 1H, ArH), 6.91 (s, 1H, CH), 6.1 (m, 1H, NH), 4.8 (m, 1H, CH), 4.0 (m, 1H, CH), 3.78 (m, 7Hl, CH2), 3.28 (m, 4H, CH2), 2.2 (s, 6H), 2.0 (s, 3H, CH3). 29 012891 EXAMPLE 2
Analogues oJf (S)-N-[[3-:[4-(l-piperazinyl)-phenyl]-2-oxo-5-oxazolidinyl]methyljacetamide (core Π) 5 '
Compound ÏSo. 6: Préparation of (S)- N- [[3-[4-[N-l-(5-nitro-2-thienyl) piperazinyl]-phenyl]-2-oxa-5-oxazolidinyI]-methyl]-acetamide. (S)-N-[[3-[4-(l-piperazinyl)-phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide 10 trifluoroacetate (1.076 mmol) was stirred with acetone and K2C03(200mg) for 5 minutes,then filtered and concentrated under reduced pressure. The residue was dissolved inDMSO and stirred at room température. To this, a stirred solution of K2CO3 (224 mg,1.61 mmol) and 2-bromo-5-nitro-thiophene (246 mg, 1.18 mmol) was added at roomtempérature and stirred for ovemight. The reaction mixture was quenched with water and 15 extracted with DCM. The organic layer was dried over anhydrous Na2SÜ4 andconcentrated under reduced pressure to get the crude product which was purified bycoluinn chroinatography. (Silica gel- 100-200 mesh sige) eluent: 1-2% MeOH in DCM toyield 75 mg ôf the title compound, ‘H NMR (CDC13) δ ppm: 7.84-7.83 (1H, s, -Ar), 7.49-7.46 (2H, d, -Ar), 7.01-6.98 (2H, d, 10 -Ar), 6.06-6.04 (1H, s, -Ar), 5.98-5.96 (1H, m, -NH), 4.810-4.78 (1H, m, -CH), 4.10-4.04 (1H, t, -CH2), 3.83-3.74 (3H, m, -CH2), 3.66-3.55 (4H, s, -CH2), 3.36-3.33 (4H, s, -CH2),2.06 (3H, s, -CH3). M+l= 446, M-N02 = 400 EXAMPLE 3 15 Analogues of (S)-N-[[3-[3-Fluoro-[4-(l-piperazinyl)-phenyI]-2-oxo-5-oxazolÎdinyl]-2-chloro-propionamide. (Core HI)
Compound No. 7: Préparation of (S)-N-[[3-[3-Fluoro-4-[N-l-{4-(5-nitro-2-thieûyl)piperazinyl}]-phenyl]-2-oxo-5-oxazolidinyl]-methyI]-2-cIiloro-propionamide. (S)-N-[[3-Fliioro-[4-(l-piperazinyl)-phenyl]-2-oxo-5-oxazolidinyl]-2-chloro- 10 propionamide (WO 00/32599) (0.22gm,0.454 moles) was taken in acetonitrile. To this,N-ethyldiisopropylaminé (0.117 gm,0.9 moles) and 5-nitro-2-bromo-thiophene (0.13 gm,0.681 moles) were added and the reaction mixture was heated at 60°C for 6-8 hrs. Thereaction mixture was concentrated and the crude compound was purified by columnchromatography eluting with 2% MeOH in dichloromethane. 30 012891 1HNMR (CDCI3): ôppm 8.23 (m, 1H, NH), 7.8 (d, 1H, Ar-H), 7.47 (m, 1H, Ar-H), 6.98(m, 1H, -Ar-H), 6.95 (m, 1H, Ar-H), 6.06 (d, 1H, Ar-H), 4.79 (m, 1H, CH), 4.45 (m, 1H,CH), 4.0 (m, 1H, CH), 3.81 (m, 1H, CH), 3.5 (m, 6H, CH2), 3.22 (m, 4H, NCH2), 1.62 (d,3H, CH3). 5 EXAMPLE 4
Analogues of (S)-N-[[3-[3-Flnoro-4-(N-l-piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]-metliylj-difluoroacetamide (core IV)
CoùipoundlNo. 8: (S)-N-[[3-[3-FIuoro-4-[4-(5-nitro-2-thienyl)-l-piperazinyl]phenyl]- 2-oio-5- oxazolidinyl] methyljdifluoroacetamide 0 To the j(S)-N-[[3-[3-Fluoro-4-(l-piperazinyl)-phenyl]-2-oxo-5-oxazolidinyl]methyl]-diiluoroacetamide (1.06 mmol, prepared as described in WO 00/32599) in acetonitrile (15mL), N-ethyl-diisopropylamine (0.27 g, 2.11 mol) and 5-bromo-2-nitro-thiophene (0.2 g,1.21 mmol) were added and the reaction mixture was heated at 60°C for 5 hrs. Thereaction mixture was cooled and evaporated in vacuo. The residue was dissolved in 5 dichloromethane (DCM) and washed with water and sodium chloride solution. Theorganic layer was dried over sodium sulphate and evaporated in vacuo. The residue waspurified b y column chromatography using DCM-200 mL, 1% MeOH/DCM-100 mL, 2%MeOH/DCM-300mL. The product eluted in 2% MeOH/DCM. The product wastriturated with hexane, filtered and dried in air to get 0.05 g of the title compound. 0 'HW (CDCI3): 5ppm 7.82 (d, 1H), 7.48 (dd, 1H), 7.12 (d, 1H), 6.97 (t, 1H), 6.8 ( t,1H)i 6.2-5.65 (m, 2H), 4.8 (m, 1H), 4.1 (t, 1H), 3.8-3.4 (m,7H), 3.2 (m. 4H). M+H = 499,'M+Na = 522, M+K = 538, M-N02 = 454 EXAMPLE 5
Analogues of (S)-N-[[3-[3-Fluoro-4-(l-piperazinyl)-phenyl]-2-oxo-5-oxazolidinyl]- 5 methyl] dichloroacetamide (Core V)
Compound No 9:(S)-N-[[3-[-3-flnoro -4-[4-(5-nitro-2-thienyl)-l-piperazinyl]plienyl]- 2-oxo-5-oxozoIidinyl]methyl]dicliloro acetamide: (S)-N-[E3-Fluoro-[4-(l-piperazinyl)-phenyl]-2-oxo-5-oxazolidinyl]-dichloroacetamide(0.996 immoles, WO 00/32599) was taken in acetonitrile. To this, were added N- 0 etkyldiisopropylamine (0.35 ml, L .984 m.moles) and 5-nitro-2-bromo-thiophene (309 mg,1.48; immoles). The reaction mixture was heated at 60° C for 6-8 hrs. The reaction 31 012891 mixture was concentrated. The residue obtained was dissolved in ethyl acetate, washedwith water. The organic layer was dried over anhydrous sodium suîphate andconcentrated under reduced pressure to get the crade product. The crude compound waspurifîed by column chromatography eluting with 2¾ MeOH in dichloromethane. The 5 product was triturated with. ether, filtered and dried in air to get 0,15 g of the titleconapound. ‘HWR (CDC13)5 PPfyl: 8.98-8.96 (b, 1H,-NH), 7.833-7.81(d,lH), 7.77-7.49 (dd, 1H),7.11-7.10 (dlH), 7.039^6.970,1H), 6.27(s,lH), 6.18-6.16(d,lH), 4.85-4.84(d,lH), 4.13-4.7(t,lH),3.83-3.78(t,lH), 3.<57-3.58(6H), 3.29-3.24(4- H), 0 EXAMPLE 6
Analogues of (S)-N-[[3-FIuoro-4-(3-methyl-l-piperiizinyI)-phenyl]-2-oxo-5-oxazalidniyl]niethyl]-acetainide (Core VI)
Compound No.10: (S)-N-[[3-[-3-Fluoro-4-[4-(5-nitr*o-2~thienyl)-3-methyl-l-piperazinyl]phenyl]-2-oxo-S-oxozolidinyl]methyl]a«etamide: 5 (S)-N-[[3-Fluoro-[4-(3-methyl-l-piperazinyl)-phenyl] -2-oxo-5-oxazolidinyl]-acetamide(1.5Î5 mmoles) was taken in. acetonïtrile. To this, were added N-ethyldiisopropylamine(1.0J9 ml, 6.22 immoles) and 5-nitro-2-bromo-thioph.ene (485 mg, 2.33 m.moles). Thereacjtion mixture was heated at 60° C for 6-8 hrs. Tlxe reaction mixture was concetrated.The resiuue jjjotained was dissolved in ethyl acetate, washed with water. The organic layer 0 was dried oÿer anhydrous sodium suîphate and concentrated under reduced pressure toget the crude product. The crude compound was purifîed by column chromatographyeluting with 2% MeOH in dichloromethane. The product was triturated with ether,filtered and dried in air to get 0.07 g of the title compound. ’HNIMR (CDC13)5 PPM: 7.817-7.801 (d,lH), 7.507-7.460(d,lH), 7.116-7.087(d,lH), 5 6.958-6.928(t,lH), 5.972-5.956(d,2H),4.787-4.796(t,l H), 4.02-3.99(2H), 3.79-3.29(8H), 3.06-3.01(2H), 2.04(s,3H), 1.05-1.48(d,3H). EXAMPLE 7
Analogues of (S)-N-[[3- Î3-Fluoro-4-(N-piperazimyl)phenyl]-2-oxo-5-oxazolidinyl]-metlivl] fluoroacetamide (core VII) 0 CompoundNo.il: (S)-N-[[3-[3-Fluoro-4-[4-(5-nitro-2-thieuyl)-l-pÎpe;razinyl]!phenyl]-2-oxo-5-oxaz©lidinyI]methyl]fLuoroacetamide 32 012891 Το the (8)-N-[[3-[3-Fluoro-4-(l-piperazinyl)-phenyl]-2-oxo-5-oxazolidinyl]methyl]fluoijoacetamide (0.88 mmol, prepared as described in WO 00/32599) in acetonitrile (15mL), N-ethyl-diisopropylamine (0.23 g, 1.75 mol) and 5-bromo-2-nitro-thiophene (0.16g, 1 mmol) were added and heated at 60 °C for 17 hrs. The reaction mixture was cooledand evaporated in vacuo. The residue was takien in dichloromethane (DCM) and washedwith water and satd. sodium chloride solution. The organic layer was dried over anhyd.sodium sulphate and evaporated in vacuo. The residue was purified by columnchromatography using DCM-400 mL, 1% MeOH/DCM-200 mL, 2c/o MeOH/DCM-6O0mL. The product eluted in 2% MeOH/DCIM. The product was triturated with hexane,filtered and dried in air to get 0.08 g of the title compound. m.p. = 145-150 °C. lHNMR (CDC13): δρρηχ 7.8 (d, 1H), 7.48 (dd, 1H), 7.12 (dd, 1H), 6.96 (t, 1H), 6.79 (m,LH), 6.02 (d, 1H), 4.95-4.7 (m, 3H), 4.04 (t, 1H), 3.85-3.4 (m, 7H), 3.21 (m, 4H) M+È = 482, jM+Na = 504 EXÀMPLE 8
Analogues of (S)-N-[[3-[3-Fluoro-4-[3-Qa,5a,6a)-6-[(j\T-niethyl)arniuoinethyl]-3-azabicyclo-[3.1 .OJliexarie]phenyI]-2-oxo-5-oxazolidiiiyl]methyI] acetamide (Core VIII)
Compound No.12 (S)-N-[[3-[3-Fluoro-4-i3-(la,5a,6a)-[6-{N-(5-nitro-2-thienyl)-N-methyl} aminomethyl]-3-azabicyclo-[3.1.0]tiexane]phenyl]-2-oxo-5-oxazolidinyljmetkvljacetamide (S)-N-[[3-[3-Fluoro-4-[3-(la,5a,6a)-[6-(N-nuethyl)aminornethyl]-3-azabicyclo-[3.1.0]hexane]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (0.84 nuixol, prepared asdescribed in WO 0206278) was taken in acetonitrile (20 mL). To this, were added N-ethyldiisopropylamine (0.43g, 3.36 mmol) and. 5-nitro-2-bromo-thiophene (0.262 g, 1.26mmql) and the reaction mixture was heated at 60° C for 48 hrs. The reaction mixture wasconcjentrated! The résidu fe obtained was dissoLved in ethyl acetate and washed with water.The iorganic j layer was dried over anhydrous sodium sulphate and concentrated underreduced pressure to get the crude product. The crude compound was purified by columnchromatography eluting with 2% MeOH in dichloromethane. The product was trituratedwith ether, filtered and dried in air to get 0.12 g of the title compound. 33 012891 1HNMR (CDC13)5:7.80-7.78 (d,lH), 7.36-7.30 (d,lH), 7.01-6.98 (i,lH), 6.64-6.58(t,lH),6.26 (m,lH), 5.88-5.8(d, 1H), 4.75-4.73 4.01-3.95 (t,lH), 3.Y4-3.56 (5H), 3.36- 3.34 (d,2H), 3.25-3.22 (d,2H), 3.16 (s,3H), 2.Ol(s,3H), 1.63 (s,2H), 1.34 (b, 1H).
Compound No.17 (S)-N-[[3-[3-Flnoro-4-[3-(la, 5a, 6a)-[6-{N-(5-nitro-2-furyI)-N-5 methy} aminomethyl]-3-azabicyclo [3.1.0]h,exane] phenyI]-2-oxo-5- oxazolidinyl] methy 1] ac etamide
The title compound was prepared following the process described in Example 1,Compound No. 4 by using (S)-N-[[3-[3-Fluoro-4-[3-(la, 5a, 6a)-[6- {N-methy} aminomethyl]-3-azabicyclo [3,1 .OJhexane] phenyl]-2-oxo- 10 5-oxazolidinylJmethyl] acetamide.
Yeild: 0.15 g H1 NMR (CDCI3): 7.5 (d,lH, Ar-H), 7.35(d,lH, Ar-H), 7.0 (d,lH Ar-H), 6.6(t, 1H, Ar-H), 5.95(m,lH, -NH), 5.33 (d,lH, Ar-H), 4.7 (m,lH, CH), 3.98 (,ΙΉΖ, CH), 3.72-3.69(m,5H), 3.41-3.38 (d,2H,CH2), 3.23-3.20 (d,2H,CH2), 3.13 (s, 3H, -MCH3), 2.00 (s,3H, 15 COCH3), 1.64 (m, 2H), 1.27 (t, 1H). EXAMPLE 9
Analogues of (S)-N-[[3-[3-Fluoro-4-(l-homopiperazenyl)phenyI]—2-oxo-5-oxazolidnyl] Methyl] acetamide (Cor e IX)
Compound No.13: (S)-N-[[3-[3-Fluoro-4-[4-(5-nitro-2-thienyl)-l-10 homopiperiizenyljplienyl]-2-oxo-5-oxazolidnyl] methyl] acetamide.
The |title Coippound was prepared following the process described in. Example 1 using thecorrèsponding(S)-N-[[^-[3-Fluoro-4-(l-homopiperazinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide instead of (S)-ZN-[[3-[3-Fluoro-4-(l -piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl] acetamide. 15 Yield: 0.22 g ’HNMRiCDCb) : 7.78 (d,lH),7.41(dd,lH),7.02 (dd,lH) 5.96 (m,lEÏ),5.86(d,lH)4.76(m,lH) 4.00 (t,lH), 3.8-3.5 (m,9H), 2.15 (m,2H), 2.02(s,3H). M+H = 478, M+Na«500,M+K =516, M-NO2-432 34 012891
Compound No. 14: (S)-N-[[3-[3-Fluoro-4-[4-(5-nitro-2-furyl)-l-homopiperazinyl]phenyl]-2-oxo-5-oxazolidinyl]inethyl]acetaniide.
The title Compound was prepared following the process described. in Example 1,Compound $o. 4 by using the corresponding (S)-N-[[3-[3-Fluoro—4-(l- i homopiperazinyl)phenyl]-2-oxo-5-oxazolidinyl]methyljacetamide instead of (S)-N-[[3-[3-ljluro-4-(i-piperazmÿl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.
Yield -0.24gm ‘HNMR(CDC13): 7.5(d4H,Ar-H),7.38(d,lH,Ar-H),6.86 (t,lH,Ar-H) 6.0(s,lH,NH),5-33(lH,d,Ar-H), 4.76 (m,lH,CH>, 4.00 (t;lH,CH),3.76-3.69(m,7H5CH2),3-65 ) 3.5(m,2H,CH2), 2.1 l(m,2H,CH2), 2.02 (s,3Ha COCH3). EXAMITLE 10 (S)-N-[[3-[3-Fluorc>-4-(l-piperidnyl)phenyI]-2-oxo-5-oxazolidii*yl]nietIiyl]acetainicie (CoreX)
Compound 3No.l6 (S)-N-[[3-[3-Flnoro-4-[N-l-[4-{lN-methyl-N-(5-nitra-2-i fur)Jl)}aminp)-l-pîperadinyl]phenyI]-2-oxo-5-oxazolidinyl]metliyl]acetamide.
The title compound was prepared following the process described in Example 1,Compound No.4 ,by using(S)-N-[[3-[3-Fluoro-4-[N-l-[4{N-methyl-N-amiiio-l-piperadinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl] acetamide.
Yield: 0.021 g ) ‘H NMR (CDCfe): 7.5 (m,3H,Ar-H), 7.0 (m,2H,Ar-H), 6.0(lH,cn,Mï), 4.7 (m,lH,CH),4.1(t,lH,CH), 3.8-3.5(m,9H,),3-0-2.8 (m,4H,)^.0(s,3H,COCH3).
While the présent invention has been described in ternis of its spécifieembodiments, certain modifications and équivalents will be apparent to those skilled inthe art and are intended to be included within the scope of the présent invention. 35

Claims (23)

  1. 012891 We'Claim:
    1. A compound having the structure of Formula I:
    FORMULAI and its pharmaceutically acceptable salts, solvatés, polymorphs, enantiomerrs,diastereomers, N-oxides, prodrugs or métabolites, wherein ) T isj. fîve membered (un)substituted heterocyclic ring with exclusively orne heteroatom, selected from oxygen, nitrogen and sulphur; aryl, substituted aryl,bound to the ring C including aryl and fîve membered heteroaryl whicli are fertbiersubstituted by a group represented by R, wherein R is selected from the groxrpconsisting of H, CHO, Cj.6 alkyl, F, Cl, Br,I, -CN, COR5,COORs, N(R6,R_7), 5 NHCOC(Rg, Rp, Rio), NHCOOR10, CON (R&amp; R7), CH2NO2, NO2, CH(OAc32, CH2Rg, CHR9, -CH = N-ORio, -C=CH-R5, OR5, SR5, -CÇR9)=C(R9)NO2, Ci .12alkyl substituted with one or more of F, Cl, Br, I, OR4, SRt; wherein R4 and R5 areindependently selected from H, C1-12 alkyl, Cj.n cycloalkyl, C1.6 alkoxy, Cmalkyl substituted with one or more of F, Cl, Br, I or OH, aryl, heteroaryl; R5 and ) R7, are independently selected from H, optionally substituted Cm alkyl, C3—12 cycloalkyl, C1-6 alkoxy; Rg and R9 are independently selected from H, Cj-e alkyl,F, Cl, Br, I, C1-12 alkyl substituted with one or more of F, Cl, Br, I, OR5, SR5,NfRfiiRv); R10= H, optionally substituted Cu2 alkyl, C342 cycloalkyl, Cj.6 alkoxy,Cm alkyl, aryl, heteroaryl; 5 n is an integer in the range from 0 to 3; X is C, CH, CH-S, CH-0, N, CHNRn, CHCH2NRU, CCHiNRn, wherein Rn ishydrogen, optionally substituted C112 alkyl, C312 cycloalkyl, C] g alkoxy, C j 6alkyl, C[-g alkylcarbonyl, Cj.g alkylcarboxy, aryl, heteroaryl; 36 012891 Y and Z are independently selected from hydrogen, C 3 6 alkyl, CJ42 andcycloalkyl Co 3 bridging groups; U and V are independently selected from hydrogen, optionally substituted C, 6alkyl, F, Cl, Br, Cw, alkyl substituted with one or more of F, Cl, Br, I, preferably ) U and V are hydrogen or fluoro; Ri is'selected from the group consisting of - NHC(=O)R2, FT(R3, R4), -NR.2C(=S)R3, -NR.2C(=S)SR3, wherein R2 is hydrogen, C1]2 alkyl, C3 ]2 cycloalkyl, C^ alkoxy,CM alkyl substituted with one or more of F, Cl, Br, I or OH; R3,R<t are D independently selected from hydrogen, Cj 12 alkyl, C312 cycloalkyl, alkoxy, C alkyl substituted with one or more of F, Cl, Br, I or OH.
  2. 2. A compound having the structure of Fonnula H:
    and its pharmaceutically acceptable salts, solvatés, polymorph_s, enantiomers,diastereomers, N-oxides, prodrugs, or métabolites, wherein Ri is selected from the group consisting of (1) -NHC(=O)R2; (2) -NÇR3, R4); (3) -NR2C(=S)R3; (4) -NR2C(=S)SR3 wherein R2, R3, R4 are independently hydrogen, 3 C1-12 alkyl, C3.12 cycloalkyl, Cm alkoxy, Cm alkyl substituted one or more of F, Cl, Br, I, OH; U and V are independently selected from hydrogen, optionally substituted Cmalkyl, F, Cl, Br, C1.12 alkyl substituted with one or more of F, Cl, Br, I; Y and Z are independently selected from (1) hydrogen, (2) Ci_6 alkyl, (3) C3425 cycloalkyl (4) C0.3 bridging group. 37
    X is selected from C, CH, CH-S, CH-O, N, CHNRn, CHCH2NRn, CCH2NRi i;wherein Rn is hydrogen, optionally substituted C112 alkyl, C3_ cycloalkyl, C Malkoxy, C J 5 alkyl, Ci_6 alkvlcarbonyl, Ci-g alkylcarboxy, aryl, heteroaryl; Qi is selected from O, S, NRn, wherein Ru is as defined above; G, J, L are independently selected from H, Ci^ alkyl, F, Cl, Br,I, -CN, CHO,COR5,COOR5, CH(OAc)2, N(R6,R7), NHCOC(R8, Rg, Rio), CON (Rs, R7),NHCOORio, CH2NO2, NO2i CH2R8; CHRg, -CH = N-ORio, -C=CH-R5, CR5,SR5, -C(Rg)=C(Rg)NO2, C1-12 alkyl substituted with one or more of F, Cl, Br, I,OR4, SRi; wherein R5 is selected from H, C1-12 alkyl, C3.12 cycloalkyl, Ch allcoxy,Ci-6 alkyl substituted with one or more of F, Cl, Br, I or OH, aryl, heteroaryl; Rsand R7, are independently selected from H, optionally substituted C1-12 alkyl,; C3-12cycloalkyl, C1-0 alkoxy; R8 and Rg are independently selected from H, Crg alkyl,F, Cl, Br, I, C1-12 alkyl substituted with one or more of F, Cl, Br, I, OR5, SR5,N(R6,R7); Rio= H, optionally substituted C1.12 alkyl, C3.12 cycloalkyl, Ch allcoxy,'C1.6 alkyl, aryl, heteroaryl.
  3. 3. The compound : according to claim 2 wherein in Formula H, ring C is 6-8membered in size or of larger size and the larger rings hâve either two or tdhreecarbons between each nitrogen atom, comprising of: and may be bridged to form a bicyclic System as shown below,
    N— 38 ο 12891 ring C optionally substituted at positions Y and Z with alkyl groups, cycloalkylgroups, fluoro group, carboxylic and corresponding esters, amides, substitutedalkyls or bridging alkyl groups as shown below:
    or ring C is 6 membered in size and X is -CH-(NHRn), or >CCH2NHRn- whichis selected from the group consisting of the following rings wherein Ru is thesametas defined earlier, R11 .N- Ντ~\ N— N—( N— -N \ Ru
    39 or ί ζ,
    in addition to the above, ring C inclndes the following structures:
    40. 012891 when Qi=ZNRii, O or S, the structures are represented by Formulae ΙΠ, IV and V,respeçtively,
    FORMULAIT!
    FORMULA IV
    FORMULA V wheremR-i, Rn, U, V, X, Y, Z, G, J, L and n in Formula ΠΙ, ZFormula IV andFormula V are the same as defïned earlier for Formula II.
  4. 4. A compound selected from the grotxp consisting of (S)-N-[ [3- [3 -Fluôro-4-[4-(5-nitro-2-thienyl)-1 -pip erazinyljptrenyl] -2-oxo-5-oxazolidin.yl]methyl]acetamide (Compound No.l) (S)-N-[[3-[3-Fluoro-4-[4-(5-formyl-2-thienyl)-l-piperazinyl]phenyl]-2-oxo-5-oxazolidin.yl]methyl]acetaniide (Compound No.2) (S)-N-[[3-[3-Fluoro-4-[4-(5-formyl-2-furyl)-l-piperazinyl]pZhenyl]-2-oxo-5-oxazolidin.yl]methyl]acetamide (Compound No. 3) 41
    (S)-N-[[3-[3-Fluoro-4-[4-(5-nitro-2-iuryl)-l-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl] acetamide (Compound No. 4) i (S)-N-[[3-[3-Fluoro-4-[4-{3-thienyl(2-ni'tro)-5-acetyloxy}metihylacetate]-l- piperazinyl]phenyl]-2-oxo-5-oxazolidinyl] acetamide (Compound No. 5) (S)- N-[[3-[4-[N-l -(5-nitro-2-thienyl) piperazinyl]-phenyl]-2-oxa-5-oxazolidmyl]-methyl]-acetamide (Compound No. 6) ) (S)-N-[[3-[3-Fluoro-4-[N-1- {4-(5-nitro-2-thienyl)piperaziayl J ]-phenyl]-2-oxo-5 - oxazolidmyl]-methyl]-2-chloro-propionaanide (Compound No. 7) (S)-N-[ [3 -[3 -Fluoro -4-[4-(5-nitro-2-thienLyl)-l -piperazinyljphenyl] -2-oxo-5-oxazôlidinyl]methyl]difluoroacetamide (Compound No. 8) » < (S)-N-[[3-[-3-Fluoro -4-[N-l-(5-nitro-2-Chieuyl)-piperazinyl]phenyl]-2-oxo-5-oxozolidinyl]methyl]dichloro acetamide ^Compound No 9) (S)-N-[[3-[-3-Fluoro-4-[(5-nitro-2-thieny'l)-3-methyl-l-piperazinyl]phenyl]-2-oxo- ) 5-oxozolidinyl]meüiyl] acetamide (Comp-oundNo. 10) (S)-N-[[3-[3-Fluoro-4-[4-(5-nitro-2-thien_yl)-l-piperazmyl]phenyl]-2-oxo-5-oxazolidinyljmethyljfluoroacetamide (Compound No. 11) (S)-N-[[3-[3-Fluoro-4-[3-(la,5a,6a)-[6- -(N-(5-nitro-2-thienyl)-N-methyl}aminomethyl]-3-azabicyclo-[3.1. Ô]hexane]phenyl]-2-oxo-5-oxazolidinyljmethyl] acetamide (Compoiuid No 12). (S)-N-[[3-[3-Fluoro-4-[4-(5-nitro-2-thien.yl)-l-homopiperazinyl]phenyl]-2-oxo-5-i oxazolidnyljmethyl] acetamide (Compoumd No. 13) (S)-N-[[3-[3-Fluoro-4-[4-(5-nitro-2-furyO-l-homopiperazinyl]phenyl]-2-oxo-5-oxazôlidinyl]methyl] acetamide (Compound No. 14) ! i (S)-N-[[3-[3-Fluoro-4-[4-{3-tliienyl(2-nitro)5-formyl}-l-piperazinyl]phenyl]-2-oxo-5-oxazolidiüyl] -methyl]acetamide (Compound No.l 5) (S)4N4p^3-Fluoro-4-[N4-[4-{N-methyJdy-(5mitro42-&amp;iyl)}-aïnino]-l-piperadinyl]phenyl]-2-oxo-5-oxazolidmyil]methyl]acetamide (Compound No.l6) (S)-N-[[3-[3-Fluoro-4-[3-(la, 5a, 6a)-[6-{N-(5-nitro-2-furyl)-N-methy}aminomethyl]-3-azabicyclo [3.1.O]hexane] phenyl]-2-oxo-5-oxazolidinyl]methyl] acetamide (Compoimd No. 17)
  5. 5. A pharmaceutical composition comprising the compound of claims 1, 2, 3 or 4and a pharmaceutical acceptable carrier. 42 012891
  6. 6. A pharmaceutical composition comprising a pharmaceutically effective amount ofcompound according to daims 1, 2, 3 or 4, or aphysiologtcally acceptable acidaddition sait thereof with a pharmaceutical acceptable carrier for treatingmicrdbial infections.
  7. 7. Use of a pharmaceutical composition according to daim 6, in the manufacture of a médicament for treating or preventing microbial infectionsin a mammal.
  8. 8. The use according to claim 7 wherein the microbial infections are caused bygram-positive and gram-negative bacteria.
  9. 9. The use according to claim 8 wherein the gram-positive bacteria are selected from the group consisting of staphylococcus spp., streptococcus spp., bacillusspp., corynebacterum spp., clostridia spp., peptostreptococus spp., listeriaspp. and legionella spp.
  10. 10. Use of a compound having the structure of Formula I 15 V U O
    Z V formulai 20 and its pharmaceutically acceptable s-alts, solvatés, polymorphe, enantiomers,diastereomers, N-oxides, prodrugs or métabolites, wherein T is five membered (un)substituted heterocyclic ring with exclusively oneheteroatom, selected from oxygen, nitrogen and sulphur; aryl, substituted aryl,bound to the ring C including aryl and ftve membered hetero aryl which are furihersubstituted by a group represented by IR, wherein R is selected from the groupconsisting of H, CHO, Cu alkyl, F, Cl, Br,I, -CN, COR5,COORs, N(R«,R7),NHCOC(R8, R9) Rio), NHCOOR10, CON (Re, R7), CH2NO2, NO2, CH(OAc)2, 25 43
    CH2R>, CHR9) :-CH = N-ORio, -C==CH-Rj, OR5) SR5l -C(R9)-C(R9)NO2, C».12alkyl substituted with one or more of F, Cl, Br, I, OR4, SR4; wherein R4 and R5 areindependently selected from H, C1-12 alkyl, C3.12 cycloalkyl, Cm alkoxy, Cmalkyl substituted with one or more of F, CI, Br, I or OH, axyl, heteroaryl; Ra a_ndR7, are independently selected from H, optionally substituted Ci-12 alkyl, C3.-12cycloalkyl, Ci-6 alkoxy; R8 and R9 aie independently selected from H, C1-6 alkyl,F, Cl, Br, I, C1-12 alkyl substituted -with one or more of F, Cl, Br, I, OR5, SEk5,NÎRôjRî); Rio= H, optionally substituted C1-12 alkyl, C3.12 cycloalkyl, C].6 alkoxy,Ci-6 alkyl, aryl, heteroaryl; n is an integer in the range from 0 to 3 ; X is <C, CH, CH-S, CH-O, N, CHNRn, CHCHzNRn, CCHC2NR11, wherein R_n ishydrogen, optio'nally substituted Cj_12 alkyl, C312 cycloalkyl, CJ 6 alkoxy, C μ6alkyl, Cm alkylcarbonyl, Cm alkylcarboxy, aryl, heteroaryl; Y and Z are independently selected from hydrogen, C1S alkyl, C312 a_ndcycloalkyl C03 bridging groups; U and V aie independently selected from hydrogen, optionally substituted C]6alkyl, F, Cl, Br, Cu alkyl substituted with one or more of I7, Cl, Br, I, preferakolyU and V are hydrogen or fluoro; Rj is selected from the group consisting of -NHC(=O)R2, NÇR.3, R4),NR2C(=S) R3, -NR2C(=S)SR3, wherein R2 is hydrogen, CJ12 alkyl, C312cycloalkyl, C] 6 alkoxy, Cj 6 alkyl substituted with one or more of F, Cl, Br, I orOH; R3,R4 are independently selected from hydrogen, C112 alkyl, C3_,2cycloalkyl, C] 6 alkoxy, Clg alkyl substituted with one or more of F, Cl, Br, I orOH in the manufacture of a médicament for treating or preventing aérobic andanaérobie bacterial infections in a mammal. 44 012891
  11. 11. Use of a compound having the structure of Formula II
    and its pharmaceutically acceptbale salts, solvatés, polymorphs, enantiomers,diastereomers, N-oxides, prodrugs or métabolites, wherein 3 Ri is selected from the group consisting of (1)-NHC(=O)R2; (2) -N(K.3, Kt); (3) -NR2C(=S)R3; (4) -NR2C(=S)SR3 wherein R2, R3, K4 are independentlyhydrogen, Ci_j2 alkyl, C3.12 cycloalkyl, Cm alkoxy, CMsalkyl substituted one ormore of F, Cl, Br, I, OH; U and V are independently selected from hydrogen, optLonally substituted Cm 5 alkyl'F, Cl, Br, C]_i2 alkyl substituted with one or more ofF, Cl, Br, I; Y and Z are independently selected from (1) hydrogen, Ç2) Cm alkyl, (3) C3-12cycloalkyl (4) C0-3 bridging group; X is selected from C, CH, CH-S, CH-O, N, CHNRn, CHCH2NR11, CCH2NRn;wherein Rn is hydrogen, optionally substituted Cb]2 alkyl, C>12 cycloalkyl, C16 0 alkoxy, C16 alkyl, Cm alkylcarbonyl, Ci_6 alkylcarboxy, aryl, heteroaryl; Qi is selected from O, S, NR11, wherein Rn is as defineci above; G, J, L are independently selected from H, Cm alkyl, F, Cl, Br,I, -CTST,COR5,COOR5, N(R6,R7), NHCOC(R8j R9, Rio), COIN (Rg, R7), NHCOORao,CH2NO2, NO2, CH2R«, CHR9, -CH=N-OR.10, -C=CH-R5, ORj, 5 SR5, -C(R9)=C(R9)NO2, C1-12 alkyl substituted with 0x1e or more of F, Cl, Br, I, OR4, SR4: wherein R5 is selected from H, C1-12 allcyl, Cj_i2 cycloalkyl, Cm alkoxry,Cm alkyl substituted with one or more of F, Cl, Br, I car OH, aryl, heteroaryl; Rg 45
    and R7, are independently selected iromH, optionally substituted Ci-]2 alkyl, C3-12cycloalkyl, C1-6 alkoxy; Rg and R9 are independently selected ffom H, Ci-5 alkyl,F, Cl, Br, I, Ci-12 alkyl substituted with one or more of F, Cl, Br, I, OR5, SR5,N(Ré,R7); Rio= H, optionally substituted C1-12 alkyl, C3-12 cycloalkyl, Ci-s alkoxy,Ci-6 alkyl, aryl, heteroaryl.
  12. 12. The use of claim 11 wherein ring C is 6-8 membered in size or of largersize and the larger rings hâve either two or three carbons between eachnitrogen atom, comprising of:
    and may be bridged to form a bicyclic System as shown below,
    ring C optionally substituted at positions Y and Z with alkyl groupe, cycloalkylgroups, fluoro group, carboxylic and corresponding esters, amides, substitutedalkyls or bridging alkyl groups as shown below:
    46
    or ring C is 6 membered in size and X is -CH-(NHRn), or >CCH2NHRn- whichis selected from the group consisting of the following rings wherein Ri i is thesame as defîned earlier,
    R11 A R11 λΟ- > '-ό- N— -N R-n R11 R11 \ I I >Q> XQ- R 1 «11 or in addition to the above, ring C includes the following structures:
    47 012891 when Qi=NRii, O or S, the structures are represented by Formulae EU, IV and V, respectively,
    wherein Ri, Ru, U, V, X, Y, Z, G, J, L and n in Formula ΠΙ, Formula IV and Formula V are the same as defined earlier for Formula H in the manufacture of a médicamentfor treating or preventing aérobic and anaérobie bacterial infections.
  13. 13. The use of a compound having the structure of Formula I
    48 012831 and its phannaceutically acceptable salis, solvatés, polymorphe, enantiomers,diastereomers, N-oxides, prodrugs or métabolites, wherein T is fîve membered (un)substituted heterocyclic ring with exclusively oneheteroatom, selected from oxygen, nitrogen and sulphur; aryl, substituted aryl,bound to the ring C including aiyl and five membered heteroaryl which are furthersubstituted by a group represented by wherein R is selected from the groupconsisting of H, CHO, Ci.6 alkyl, F, Cl, Br,I, -CN1 COR5,COOR3, N(R6,R7),NHCOC(Rs, R9, Rio), NHCOORo, COM (R, R7), CH2NO2, NO2, CH(OAc)2,CH2R, CHR9, -CH = N-ORio, -C=CH-R5, OR5, SR5, -C(R9>C(R9)NO2, C,.,2alkyl substituted with one or more of F, Cl, Br, I, OR, SRt; wherein Ri and R5 areindependently selected from H, Ci-12 alkyl, C3_i2 cycloalkyl, Ci.e alkoxy, Ci-ealkyl substituted with one or more of F, Cl, Br, I or OH, aryl, heter<?aryl; Rg and R7, are independently selected from H, optionally substituted Cru alkyl, C3-12 : 1 cycloalkyl, Ci% jalkoxy; R and R9 are independently selected from H, Ci-β alkyl, 1 F, Cl, Br, I, Ci-12 alkyl substituted with one or more of F, Cl, Br, I, OR5, SR5,N(R,R7); Rio= H, optionally substituted Cm2 alkyl, C3.12 cycloalkyl, C:.6 alkoxy,C].6 alkyl, aryl, heteroaryl; n is an integer in the range from 0 to 3; X is C, CH, CH-S, CH-O, N, CHNRn, C3ÏCH2NRU) CCH2NRn; wherein Rn ishydrogen, optionally substituted C142 alkyl, C3l2 cycloalkyl, alkoxy, C Malkyl, Ci-û alkylcarbonyl, Cj-e alkylcarboxy, aryl, heteroaryl; Y and Z are independently selected from hydrogen, C] 6 alkyl, C3 [2 andcycloalkyl Co3 bridging groups; i U and V are independently selected from hydrogen, optionally substituted C] 6alkyl, F, Cl, Br, C1I2 alkyl substituted with. one or more of F, Cl, Br, I, preferablyU and V are hydrogen or fluoro; Ri is selected from the group consisting of -NHC(=O)R2, N(R3, R),NR2C(=S) R3, -NR2C(=S)SR3, wherein R2 is hydrogen, C>12 alkyl, C312 cycloalkyl, C, alkoxy, alkyl substituted with one or more of F, Cl, Br, I or .49 012891 ΟΗ; Κ.3,Κ_4 are independently selected from hydrogen. Ct 2 alkyl, C3.12 cycloalkyl, Ομ6 alkoxy, C16 alkyl substituted. with one or more of F, Cl, Br, I or OH in the manufacture of a médicament for treating or preventing cathéter infections and foreign body or prostheses infections in a mammal.
  14. 14. The use of a compound having the structure of Formula II
    FORMULA-Π and its pharmaceutically acceptbale salts, solvatés, polymorphs, enantiomers,diastereomers, N-oxides, prodrugs or métabolites, wherein Ri is selected ifom the group consisting of (1) -NHC(=O)R2; (2) -N(Rj,R4); (3) —ZNR2C(=S)R3; (4) -NR2C(=S)SR3 wherein R2, R3, R4 are independentlyhydrogen, Cm alkyl, C3-12 cycloalkyl, Ci-s alkoxy, Ci-ealkryl substituted one ormore ofF, Cl, Br, I, OH; U and V are independently selected from hydrogen, optionally substituted Ci-6alkyl, F, Cl, Br, C1-12 alkyl substituted with one or more of F, Cl, Br, I; Y and Z are independently selected from (1) hydrogen, (2) Cb6 alkyl, (3) C3-12cycloalkyl (4) C0-3 bridging group; X is selected from C, CH, CH-S, CH-O, N, CHNRn, CHC3î2NRIb CCH2NRn;wherein Ru is hydrogen, optionally substituted C,_]2 alkyl, CJ12 cycloalkyl, Cjalkoxy, C alkyl, C]^ alkylcarbonyl, Cj-ô alkylcarboxy, axyl, heteroaryl; Qi is selected from O, S, NRn, wherein Ru is as defined atoove; G, J, L are independently selected from H, Ci-6 alkyl, F, Cl, Br,I, -CN, COR5,COOR5, N(R6,R7), NHCOC(R8, R9iRi0), CON (R6, r7), nhcoor19. 50 012891 CH2NO2, NO2, CH2R8j CHRç>, -CH = N-ORib, -c=ch-r5, or5, srSj -CÇR-9)=C(R9)NO2, Cm2 alkyl substituted with one or more of F, Cl, Br, L, OR4,SR4; wherein R5 is selected fromH, Ci-l2 alkyl, C3-12 cycloalkyl, Ci-6 alkoxy, C1-6alkyl substituted. with one or more of F, Cl, Br, I or OH, aryl, heteroaryl; Rg and 5 R7, are independently selected from H, optionally substituted C1-12 alkyl, C3-12 cycloalkyl, Ct-g alkoxy; Kg and R9 are indepeniently selected from H, -6 alkyl, F, Cl, Br, I, C1-12 alkyl substituted with one or more of F, Cl, Br, I, OR5, SR5,N(R6,R7);, Rio= H, optionally substituted C1.12 alkyl, C3-12 cycloalkyl, Cl _6 alkoxy,Cj.6 alkyl, aryl or hetero aryl in the manufacture of a médicament fortreating or preventing cathéter infections and foreign body or prosthesisinfections in a mammal.
  15. 15. The use of a compound having the structure of Formula H as defined in claim 14 wherein ring C is 6-8 membered in size or of larger size and thelarger rings hâve either two or three carbons between each nitrogen atom,comprising of:
    and may be bridged to form a bicyclic System as shown below,
    25 ring C optionally substituted at positions Y and Z with alkyl groups, cycloalkyl groups, fluoro group, carboxylic and corresponding esters, amides, substitutedalkyls or bridging alkyl groups as shown below: 30
    51 012891 or ring C is 6 membered in size andX is -CH-(NHRn), or >CCH2NHRii- which is selected from th.e group consisting of the following rings wh-erein Ru is the same as defined earlier,
    N— /N\_zN R11 \ V“\ N—( N—/ \_y
    10 R11 \ Z R1 1 N— <11 15 or in addition to the above, ring C includes the following stnictnrss:
    52 012891 when Qi=NRn, O or S, the structures are represented by Formulae DI, TV and V, respectively,
    FORMULA III
    FORMULA IV
    wherein Ri, Rn, U, V, X, Y, Z, G, J, L and n in Formula HI, Formula IV and Formula V are the same as defined earlier for Formula Π m the manufacture of a médicamentfor treating or preventing cathéter infections and foreign body orprosthesis infections in a mammal. 53
  16. 16. A process for preparing a compound of Formula I
    and iis pharmaceutically acceptable salts, solvatés, polymorphs, enantiomers,diastereomers, N-oxides, prodrugs or métabolites wherein T is fîve membered (un)substituted heterocyclic ring with exclusively onebeteroatom, selected from oxygen, nitrogen and sulphur; aryl, substituted aryl,bound to the ring C including aryl and fîve membered heteroaryl whiLch are furthersubstituted by a group represented by R, wherein R is selected fiom the group I consisting of H, CHO, alkyl, F, Cl, Br,I, -CN, COR5,COOK5, N(R6,R7),NHCOC(R8, Rÿ, Rio), NHCOORio, CON (Ho, JR7), CH2NO2, NO2, CH(OAc)2,CH2R8j CHR9, -CH = N-OR10, -C=CH-R5, OïL5, SR5, -C(R9)=C(R9)NO2j Cm2alkyl substituted with one or more of F, Cl, Br, I, OR4, SR4; wherein R4 and R5 areindependently selected from H, Ci-i2 alkyl, Cs_i2 cycloalkyl, Ci-s alkoxy, Ci-6alkyl substituted with one or more of F, Cl, Br, J or OH, aryl, heteroaryl; Rê andR7, are independently selected from H, optionælly substituted C1-12 alkyl, C3-i2cycloalkyl, C1-6 alkoxy, Rg and R9 are independently selected from H, C1-6 alkyl,F, Cl, Br, I, C1-12 alkyl substituted with one or more of F, Cl, Br, I, OR5, SR5,NÇRîJO); Rio= H, optionally substituted Cu2 alkyl, C3.i2 cycloalkyL, Ci_6 alkoxy,Ci-s alkyl, aryl, heteroaryl; n is an integer in the range from 0 to 3; X is C, CH, CH-S, CH-O, N, CHNRn, CHCH2bJRu, CCH2NRi,; wherein R[t ishydrogen, optionally substituted Ομΐ2 alkyl, C3_12 cycloalkyl, C,_6 alkoxy, Calkyl, Ci-6 alkylcarbonyl, Ci-β alkylcarboxy, aryl, Zheteroaryl; Y and Z are independently selected from hydrogen, Ci e alkyl, C3.12 andcycloalkyl CM bridging groupe; 54 012891 U and V are independently selected from hydrogen, optionally substituted C3 5 alkyl, F, Cl, Br, Cl l2 alkyl substituted with one or more of IF, Cl, Br, I, preferâbly U and V are hydrogen or fluoro; Ri is selected from the group consisting of -NHC(-O)R.2, N(R3, R4), - 5 NR2C(=S). R3, -NR2C(=S)SR3, vzherein R2 is hydrogem, C142 alkyl, C3_12 cycloalkyl, C,^ alkoxy, Ci e alkyl substituted with one or more of F, Cl, Br, I or OH; R3,R4 are independently selected from hydrogen, C1]2 alkyl, C3_12cyclo'alkyl, C) 6 alkoxy, C16 alkyl substituted with one or more of F, Cl, Br, I orOH; ' I 3 which comprises reacting an amine of Formula VI
    5 with a heteroaromatic compound of Formula R-T-R12 wherein T, Ri, Y, Z, U, V and n are the same as defîned earlier and Mi is selected from the group consistingof NH, NHR, CHNHR, -CHCH2NHR, -CCH2NHR wherein. R is H, ethyl, methyl,isopropyl, acetyl, cyclopropyl, alkoxy or acetyl and R32 is a suitable leaving groupselected from the group consisting of fluoro, chloro, foromo, iodo, SCH3, - 3 SO2CH3, -SO2CF3, Tos and OC6H5.
  17. 17. The process of claim 16, wherein the amine of Formula VI reacts with aheteroaromatic compound of Formula R-T-Rn in the presemce of a base selectedfrom the group consisting of potassium carbonate, N-ethyldiisopropylamine anddipotassium hydrogenphosphate. 55 012891
  18. 18. A process for preparing a compound of F* ornula II
    FORMULA.-Il and its pharmaceutically acceptbale salis, solvatés, polymorphs, enantiomers,diastereomers, N-oxides, prodrugs or métabolites, wherein Ri is selected from the group consisting of (1) -NHC(=O)R2; (2) -N(R3,R4); (3) -NR2C(=S)R3; (4) -NR2C(=S)SR.3 wherein R2, R3, R4 are independentlyhydrogen, Cm2 alkyl, C3-12 cycloalkyl, Ci -5 alkoxy, C1-6 alkyl substituted one ormore of F, Cl, Br, I, OH; U and V are independently selected 60m hydrogen, optionally substituted C1-6alkyl, F, Cl, Br, Cm2 alkyl substituted wrth one or more of F, Cl, Br, I; Y and Z are independently selected from (1) hydrogen, (2) Ci-g alkyl, (3) C3.12cycloalkyl (4) C0-3 bridging group; Xis selected from C, CH, CH-S, CH-O, N, CHNRn, CHCH2NRn, CC%NRn;wherein RIt is hydrogen, optionally substituted C112 alkyl, C31, cycloa.lkyl, Cl galkoxy, C w alkyl, C1-5 alkylcarbonyl, Ci_s alkylcarboxy, aryl, heteroaryl; Qj is selected from O, S, NRu, wherein Ru is as defined above; G, J, L are independently selected from H, Ci„6 alkyl, F, Cl, Br,I, -CNf,COR5,COOR5; N(R6,R7), NHCOC(R8, R©, Rio), CON (R6j R7), NHCOOR10,CH2NO2, NO2, CH2R8, CHR9j -CH = N-OR10, -C=CH-R5, OR5, SR5, -C(R9)=C(R9)NO2, Ci .12 alkyl substituted xvith one or more F, Cl, Br, I, OR4, SR4;wherein Rs is selected from H, Cm alkyl, C3_i2 cycloalkyl, Ci-6 alkoxy, Ci-g alkylsubstituted with one or more of F, Cl, Br, I or OH, aryl, heteroaryl; Ré and R7, areindependently selected from H, optionally substituted C1-12 alkyl, C3-i2 cycloalkyl,C1-6 alkoxy; Rs and R9 are independently selected from H, C1-6 alkyl, F, Cl, Br, I, 56
    Ci-12 alkyl substituted with one or more of F, Cl, Br, I, OR5, SRs, N(R6,R7); Rio=H, optionally substituted Cm2 alkyl, C3-12 cycloalkyl, Ci-s alkoxy, C1-6 alkyl, aryl,heteroaryl; comprising reacting a compound of Formula VI
    with a beteroaromatic compound of Formula VU
    G Q1 R12 Formula VU wherein Rb Y, Z, U, V, G, J, L, Qi, and n are the same as defined earlier and Mi_isselected from the group consisting of NH, NHR, CHNHR,CHCH2NHR, -CCH2NHR wherein R is H, ethyl, methyl, isopropyl, acetyl, > cyclopropyl, alkoxy or acetyl and Ri2 is a suitable leaving group selected from tkie group consisting of fluoro, chloro, bromo, iodo, SCH3, -SO2CH3, -SO2CF3, Tosand OC6H5.
  19. 19. The process for preparing a compound of Formula H as described in claim 18wherein ring C in Formula H is 6-8 membered in size or of larger size and thne ) larger rings hâve either two or three carbons betw&amp;en each nitrogen atom, comprising of:
    57 012891 and may be bridged to form a bicyclic System as shown below,
    ring C optionally substituted at positions Y and Z with alkyl groups, cycloalkyl groups, fluoro group, carboxylic and corresponding esters, amid.es, substituted ! 0 alkyls or bridging alkyl groups as shown below:
    or ring C is 6 membered in size and X is -CH-(NHRn), or >CCH2Î<ÎHRn- whichis selected from the group consisting of the following rings wherein Rn is the 5 saine as deâned earlier, 10 15
    y -N Ru
    N— 58 or in addition to the above, ring C includes the following structures;
    when Qi=NRn, O or S, the structures are represented by Formulae DI, IV and V,respectively,
    59 012891
    FORMULA IV
    FORMULA V wherein Ri, Rn, U, V, X, Y, Z, G; J, L and n in Formula ΠΙ, Formula IV andFormula V are the saine as defined earlier for Formula Π.
  20. 20. The process of claim 18 wherein the heteroaromatic compound of Formula VU isreacted with the amine of Formula VI in the presence of ligands selected from ) the group consisting of Pd2(dba)3 and Pd (OAc)2.
  21. 21. The process of claim 18 wherein the heteroaromatic compound of Formula VU is2-bromothiophene.
  22. 22. The process of claim 18 wherein the reaction of compound of Formula VI with acompound of Formula VII is carried out in the presence of a solvent wherein the > solvent is selected from the group consisting of dimethylformamide, dimethylacetamide, acetanitrile, dimethylsulfoxide and ethylene glycol.
  23. 23. The process of claim 18 wherein the reaction of compound of Formula VI with acompound of Formula VII is carried out in the presence of a suitahle basewherein the base is selected from the group consisting of triethylamine ) diisopropylethylamine, potassium carbonate, sodium carbonate and dipotassium hydxogen phosphate. 60
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