SUBSTITUTED OXAZOLIDINONE DERIVATIVES FIELD OF INVENTION
The present invention provides substituted oxazolidinone derivatives, which can be used as antimicrobial agents
Compounds disclosed can be used for the treatment or prevention of a condition caused by or contributed to by bacterium such as multiply-resistant Staphylococci, Streptococci, Enterococci, Bactenoides spp, Clostridia spp, Mycobacterium spp, Bacillus spp, Corynebacterium spp , Clostridia spp , Peptostreptococcus spp , Listeria spp , Legionella spp , Haemophilus influenza, Moraxella, Escherecia faecahs, Escherecia coll
Processes for the preparation of disclosed compounds, pharmaceutical compositions containing the disclosed compounds, and method of treating microbial infection are provided
BACKGROUND OF THE INVENTION
The international microbiological community continues to express serious concern that the evolution of antibiotic resistance could result in strains against which currently available antibacterial agents will be ineffective Gram positive pathogens, for example, Staphylococci, Enterococci and Streptococci are particularly important because of the development of resistant strains which are both difficult to treat and eradicate from the hospital environment once established Examples of such strains are methecin resistant Staphylococcus aureus (MRSA), methecin resistant Staphylococcus epidermidis (MRSE), methecin resistant coagulase negative Staphylococcus (MRCNS), glycopeptide-intermediate resistant Staphylococcus aureus (GISA), Vancomycin-resistant Enterococci (VRE), penicillin resistant Streptococcus pneumoniae and multiply resistant Enterococcus faecium There is also now increasing resistance appearing towards agents such as (3-Lactams, quinolones and macrobides used for the treatment of upper respiratory tract infection, also caused by certain gram-negative strains including H Influenza and M Catamhalis
Oxazohdinones are a new class of synthetic antimicrobial agents, which kill gram-positive pathogens by inhibiting a very early stage protein synthesis Oxazohdinones inhibit the formation of ribosomal initiation complex involving 30S and 50S 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 Exemplary
members of oxazohdinones are linezolide (US Patent No 5, 688, 792) and eperezolid
(Formula Removed)
WO 02/06278 discloses substituted phenyl oxazohdinones, which are useful antimicrobial agents, effective against a number of human and veterinary pathogens including gram-positive bacteria and acid-fast organisms
WO 03/008389 discloses substituted phenyl oxazohdinones, which are useful antimicrobial agents, effective against a number of human and veterinary pathogens, including gram-positive aerobic bacteria such as multiply-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
WO 03/107870 discloses oxazohdinone derivatives, which are useful antimicrobials agents, effective against number of human and veterinary pathogens
US Patent Nos 5,700,799, 5,547,950 and WO 93/23384 disclose oxazohdinones derivatives containing a substituted diazine moiety which are useful antimicrobial agents, effective against a number of human and veterinary pathogens The compounds are particularly useful because they are effective against the latter organisms, which are known to be responsible for infection in person with AIDS
Pae A N , et al, Bioorganic & Medicinal Chemistry Letters 9, 2679-2684, (1999) and Pae A N , et al, Bioorganic & Medicinal Chemistry Letters 9, 2685-2690, (1999) disclose oxazohdinone derivatives, which are active against gram-positive strains including the resistant strains of Staphylococcus and Enterococcus
Tucker A J , et al, J Med Chem , 41, 3727-3735 (1998) discloses oxazolidinone compounds among each of the pyridine, pyndazine and pynmidine structural classes which have antibacterial activity against gram-positive pathogens
SUMMARY OF THE INVENTION
The present invention provides substituted oxazolidinone derivatives, which can be used as antimicrobial agents, and processes for the synthesis of these compounds
Pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers or polymorphs of these compounds having same type of activity are also provided
Pharmaceutical compositions containing the compounds, and which may also contain pharmaceutically acceptable carriers, excipients or diluents, which can be used for the treatment or prevention of microbial infectious
Other objects will be set forth in accompanying description, which follows and in part will be apparent from the description or may be learnt by the practice of the invention
In accordance with one aspect, there are provided compounds having the structure of Formula 1, as shown in accompanied drawings, their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers, N-oxides, prodrugs, polymorphs or metabolites, wherein Ri and R4 are independently selected from
• hydrogen and optionally substituted
• alkyl
• alkenyl
• alkynyl
• cycloalkyl wherein optional substituent is selected from
o halogen o hydroxy o alkoxy
• optionally substituted aryl or heterocycle wherein optional substituent is selected from the
group comprising of
o halogen o hydroxy
o mercapto
o alkoxy
o alkyl
o acyl
o acyloxy
o haloalkyl
o amino
o cyano
o nitro
o thio
o thioalkyl
R.2 and R3 are independently selected from
• hydrogen
• halogen
• alkyl
• haloalkyl
U and V are independently selected from
• hydrogen
• alkyl
• haloalkyl X is halogen
In accordance with a second aspect, there is provided a method for treating or preventing a mammal suffering from a condition caused by or contributed to by microbial infectious, comprising administering to the said mammal, a therapeutically effective amount of a compound or pharmaceutical composition disclosed herein
The microbial infection may be caused by bacterium such as multiply-resistant Staphylococci, Streptococci, Enterococci, Bactenoides spp , Clostridia spp, Mycobacterium spp , Bacillus spp , Corynebactenum spp , Clostridia spp , Peptostreptococcus spp , Listeria spp, Legionella spp, Haemophilus influenza, Moraxella spp, Enterococcus faecalis, Enterococcus faecium or Escherecia coh
The said conditions may be, for example, community acquired pneomonia, upper and lower respiratory tract infections, skin and soft tissue infections, hospital acquired lung infections or bone and joint infections, and other bacterial infections such as mastitis, catether infection, foreign body or prosthesis infections
In accordance with a third aspect, there is provided processes for the preparation of compounds disclosed herein
The term "alkyl" as used herein refers to branched or unbranched saturated hydrocarbon chain having from 1 to 6 carbon atoms, example, but are not limited to, includes methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, n-hexyl
The term "alkenyl" as used herein refers to branched or unbranched unsaturated hydrocarbon chain having from 2 to 6 carbon atoms, example, but are not limited to, includes ethylene, the propylene and the like
The term "alkynyl" as used herein refers to branched or unbranched unsaturated hydrocarbon chain having from 2 to 6 carbon atoms, example, but are not limited to, includes ethynyl, propynyl and the like
The term "cycloalkyl" as used herein refers to cychcalkyl of from 3 to 7 carbon atoms having a single cyclic ring or multiple condensed rings, example, but are not limited to, includes cyclopropyl, cyclobutyl, cyclopentyl and the like
The term "alkoxy" as used herein refers to the group R-O-wherein R is cycloalkyl or alkenyl and the like
The term "thio" as used herein refers to the group -SH
The term "thioalkyl" as used herein refers to -S-alkyl The term "haloakyl" as used herein refers to alkyl of which one or more hydrogen (s) is/are replaced by halogen
The term "acyl" as used herein refers to -C(O)R in which R is alkyl, cycloalkyl,
heterocyclyl or aryl The term "acyloxy" as used herein refers to -OC(O)R in which R is
hydrogen, alkyl, cycloalkyl, heterocyclyl or aryl
The term "halogen" as used herein refers to fluorine, chlorine, bromine or iodine
The term "aryl" as used herein stands for an aromatic radical having 6 to 14 carbon atoms, example of aryl is, but is not limited to, phenyl, naphthyl, anthryl and biphenyl, and the like
The term "heterocycle" refers to non-aromatic or aromatic ring system having one or more heteroatom(s) wherein the said heteroatom(s) is/are selected from the group consisting of nitrogen, sulphur and oxygen and the ring system refers mono, bi or tricyclic, example of heterocycle, but not limited to, thienyl, furyl, pyrolyl, pyrazolyl, pyndyl, pynmidyl, pyrazinyl, pyridazinyl, quinohnyl, isoquinolinyl, quinazohnyl, quinoxahnyl, phthalazinyl, cinnohnyl, thiazolyl, benzthiazolyl, isothiazolyl, oxazolyl, benoxazolyl, isoxazolyl, lmidazolyl, benzimidazolyl, pyrazolyl, indolyl and isoindolyl and the like
The term "polymorphs" as used herein includes all crystalline forms for compounds described herein In addition, some of the compounds described herein may form solvates with water (l-e hydrate, hemihydrate or sesquihydrate) or common organic solvents Such solvates are also encompassed within the scope of this invention
The term "drug-resistance" as used herein refers to the characteristics of a microbe to survive in the presence of a currently available antimicrobial agent at its routine, effective concentration
The phrase "pharmaceutically acceptable salts" denotes salts of the free base which
possess the desired pharmacological activity of the free base and which are neither biologically
nor otherwise undesirable Suitable pharmaceutically acceptable salts may be prepared from an
inorganic or organic acid Example of such inorganic acids include, but not limited to,
hydrochloric, hydrobromic, hydroiodic, nitrous (nitrite salt), nitric (nitrate salt), carbonic,
sulfuric, phosphoric acid and like Appropriate organic acids include, but not limited to,
aliphatic, cycloahphatic, aromatic, heterocyclic, carboxylic and sulfonic classes of organic acids,
such as, for example, formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric,
citric, ascorbic, glucuronic, maleic, fumanc, pyruvic, aspartic, glutamic, benzoic, anthranihc,
mesylic, salicylic, p-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic),
methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, toluenesulfonic, 2-
hydroxyethanesulfonic, sulfanilic, stearic, algenic, beta-hydroxybutync,
cyclohexylaminosulfonic, galactanc and galacturonic acid and the like
Where the compounds according to the invention have at least one chiral center, they may accordingly exist as enantiomers Where the compounds according to invention possess two or more chiral centers, they may additionally exist as diastereomers It is to be understood that all such isomers, for example, R or S and mixtures (RS) therefore are encompassed within the scope of the present invention
DETAILED DESCRIPTION OF THE INVENTION
The compounds disclosed herein may be prepared by techniques well known in the art and familiar to the average synthetic organic chemist In addition, the compounds of the present invention may be prepared by the following reaction sequences as depicted in Schemes I and II of the accompanied drawings
SCHEME I
The compound of Formula IV can be prepared according to Scheme I, as shown in the accompanied drawings Thus, reacting a compound of Formula II [prepared as in U S patent No 5,547,950, S E Scaus and E N Jacobson, Tetrahedron Letter, (1996), 37(44), 7937, K C Grega et Al, J Org Chem , (1995), 60(16), 5255] with a compound of Formula III [prepared as in ZChem, (1987), 27(2), 70, Coll Czech Chem Commu (1995), 50, 1019] to give a compound of Formula IV (wherein Ri, R2, R3, R4, U, V and X are the same as defined earlier)
The reaction of a compound of Formula II with a compound of Formula III is carried out in a suitable solvent such as chloroform, dichloromethane, carbon tetrachloride or dicholoroethane
The reaction of a compound of Formula II with a compound of Formula III is carried out in the presence of an organic base such as triethylamine, pyridine, dusopropylamine, propylamine or N-methylamine
SCHEME II
The compound of Formula VI can be prepared according to Scheme II, as shown in the accompanied drawings Thus, reacting a compound of Formula V [prepared as in S J Bncker et al, J Med Chem (1996), 39, 673] with a compound of Formula III [prepared as in ZChem,
(1987), 27(2), 70, Coll Czech Chem Commu (1995), 50, 1019] to give a compound of Formula VI (wherein R1, R2, R3, R4, U, V and X are the same as defined earlier)
The reaction of a compound of Formula V with a compound of Formula III is carried out in a suitable solvent such as chloroform, dichloromethane, carbon tetrachloride or dicholoroethane
The reaction of a compound of Formula V with a compound of Formula III is carried out in the presence of an organic base such as tnethylamine, pyridine, dnsopropylamine, propylamine or N-methylamine
In the above scheme, where the specific bases, solvents, etc, are mentioned, it is to be understood that bases, solvents, etc, known to those skilled in the art may also be used Similarly, the reaction temperature and duration may be adjusted according to the desired needs
The compounds disclosed herein possess antimicrobial activity against gram-positive and certain gram-negative bacteria They are useful as antibacterial agents for the treatment of bacterial infections in human and animal
Compounds of the present invention useful for such purpose are listed below (also shown in Table I)
-N-[3-(4-(3-Fluoro-4-(1-formamido-2',2',2'-tnchloroethyl)-l-piperazinyl)phenyl)-2-oxo-5-oxazohdinyl)methyl]-acetamide (Compound No 1),
-N-[3-(4-(3-Fluoro-4-(1-acetamido-2',2',2'-trichloroethyl)-l-piperazinyl)phenyl)-2-oxo-5-oxazohdinyl)methyl]-acetamide (Compound No 2),
-N-[3-(4-(3-Fluoro-4-(1-tnchloroacetamido-2',2',2'-tnchloroethyl)-l-piperazinyl)phenyl)-2-oxo-5-oxazolidinyl)methyl]-acetamide (Compound No 3),
-N-[3-(4-(3-Fluoro-4-( 1 '-trifluoroacetamido-2',2',2-tnchloroethyl)-1 -piperazinyl)phenyl)-2-oxo-5-oxazolidinyl)methyl]-acetamide (Compound No 4),
-N-[3-(4-(3-Fluoro-4-( 1 '-formamido-2',2',2'-tnbromoethyl)-1 -piperazinyl)phenyl)-2-oxo-5-oxazohdinyl)methyl]-acetamide (Compound No 5),
-N-[3-(4-(3-Fluoro-4-( 1 '-acetamido-2',2',2'-tnbromoethyl)-1 -piperazinyl)phenyl)-2-oxo-5-oxazohdinyl)methyl]-acetamide (Compound No 6),
-N-[3-(4-(3-Fluoro-4-(1-tnfluoroacetamido-2',2',2'-tnbromoethyl)-l-piperazinyl)phenyl)-2-oxo-5-oxazohdinyl)methyl]-acetamide (Compound No 7),
-N-[3-(4-(3-Fluoro-4-(1-benzamido-2',2',2'-tnchloroethyl)-l-piperazinyl)phenyl)-2 -oxo-5-oxazolidinyl)methyl]-acetamide (Compound No 8),
-N-[3-(4-(3-Fluoro-4-(1-(2,4-dichloro-5-fluorobenzamido)-2',2',2,-tnchloroethyl)-l-piperazinyl)phenyl)-2-oxo-5-oxazohdinyl)methyl]-acetamide (Compound No 9),
-N-[3-(4-(3-Fluoro-4-(1-benzamido-2',2',2'-tribromoethyl)-l-piperazinyl)phenyl)-2-oxo-5-oxazolidinyl)methyl]-acetamide (Compound No 10),
-N-[3-(4-(3-Fluoro-4-(1-(2,4-dichloro-5-fluorobenzamido)-2',2',2'-tnbromoethyl)-l-piperazinyl)phenyl)-2-oxo-5-oxazolidinyl)methyl]-acetamide (Compound No 11),
—N-[3-(4-(3-Fluoro-4-(1-formamido-2',2',2'-tnfluoroethyl)-l-piperazinyl)phenyl)-2-oxo-5-oxazohdinyl)methyl]-acetamide (Compound No 12),
-(S)-N-[3-(4-(3-Fluoro-4-(l'-formamido-2',2',2'-tnchloroethyl)-l-piperazinyl)phenyl)-2-oxo-5-oxazohdinyl)methyl]-acetamide (Compound No 13),
- (S)-N-[3-(4-(3-Fluoro-4-( 1 '-acetamido-2',2',2'-tnchloroethyl)-1 -piperazinyl)phenyl)-2-oxo-5-
oxazolidinyl)methyl]-acetamide (Compound No 14),
-(S)-N-[3-(4-(3-Fluoro-4-(1-tnchloroacetamido-2',2',2'-tnchloroethyl)-l-piperazinyl)phenyl)-2-oxo-5-oxazolidinyl)methyl]-acetamide (Compound No 15),
-(S)-N-[3-(4-(3-Fluoro-4-(1-tnfluoroacetamido-2',2',2'-tnchloroethyl)-l-piperazinyl)phenyl)-2-oxo-5-oxazolidinyl)methyl]-acetamide (Compound No 16),
-(S)-N-[3-(4-(3-Fluoro-4-(1-formamido-2',2',2'-tnbromoethyl)-l-piperazinyl)phenyl)-2-oxo-5-oxazolidinyl)methyl]-acetamide (Compound No 17),
-(S)-N-[3-(4-(3-Fluoro-4-(1-acetamido-2',2,,2'-tnbromoethyl)-l-piperazinyl)phenyl)-2-oxo-5-oxazolidinyl)methyl]-acetamide (Compound No 18),
- (S)-N-[3-(4-(3-Fluoro-4-( 1 '-tnchloroacetamido-2',2',2'-tnbromoethyl)-1 -piperazinyl)phenyl)-2-
oxo-5-oxazolidinyl)methyl]-acetamide (Compound No 19),
-(S)-N-[3-(4-(3-Fluoro-4-(1-tnfluoroacetamido-2',2',2'-tribromoethyl)-l-piperazinyl)phenyl)-2-oxo-5-oxazolidmyl)methyl]-acetamide (Compound No 20),
- (S)-N-[3-(4-(3-Fluoro-4-( 1 '-formamido-2',2',2'-tnfluoroethyl)-1 -piperazinyl)phenyl)-2-oxo-5-
oxazolidinyl)methyI]-acetamide (Compound No 21),
-(S)-N-[3-(4-(3-Fluoro-4-(1-acetamido-2',2',2'-tnfluoroethyl)-l-piperazinyl)phenyl)-2-oxo-5-oxazolidinyl)methyl]-acetamide (Compound No 22),
- (S)-N-[3-(4-(3-Fluoro-4-( i '-formamido-2',2',2'-tnchloroethyl)-1 -piperazinyl)phenyl)-2-oxo-5-
oxazohdinyl)methyl]-tnfluoracetamide (Compound No 23),
-(S)-N-[3-(4-(3-Fluoro-4-(1-acetamido-2',2',2'-tnchloroethyl)-l-piperazinyl)phenyl)-2-oxo-5-oxazolidinyl)methyl]-tnfluoracetamide (Compound No 24),
- (S)-N-[3-(4-(3-Fluoro-4-( 1 '-tnchloroacetamido-2',2',2'-tnchloroethyl)-1 -piperazinyl)phenyl)-2-
oxo-5-oxazolidinyl)methyl]-tnfluoroacetamide (Compound No 25),
-(S)-N-[3-(4-(3-Fluoro-4-(l'-tnfluoroacetamido-2',2',2'-tnchloroethyl)-l-piperazinyl)phenyl)-2-oxo-5-oxazolidinyl)methyl]-tnfluoroacetamide (Compound No 26),
-(S)-N-[3-(4-(3-Fluoro-4-(1-formamido-2',2',2'-tnbromoethyl)-l-piperazinyl)phenyl)-2-oxo-5-oxazoIidinyl)methyl]-tnfluoroacetamide (Compound No 27),
-(S)-N-[3-(4-(3-Fluoro-4-(1-acetamido-2',2',2'-tnbromoethyl)-l-piperazinyl)phenyl)-2-oxo-5-oxazolidinyl)methyl]-tnfluoroacetamide (Compound No 28),
-(S)-N-[3-(4-(3-Fluoro-4-(1-tnchloroacetamido-2',2,,2'-tnbromoethyl)-l-piperazinyl)phenyl)-2-oxo-5-oxazolidinyl)methyl]-tnfluoroacetamide (Compound No 29),
- (S)-N-[3-(4-(3-Fluoro-4-( 1 '-tnfluoroacetamido-2',2',2'-tnbromoethyl)-1 -piperazinyl)phenyl)-2-
oxo-5-oxazolidinyl)methyl]-tnfluoroacetamide (Compound No 30),
-(S)-N-[3-(4-(3-Fluoro-4-(l'-formamido-2',2',2'-tnfluoroethyl)-l-piperazinyl)phenyl)-2-oxo-5-oxazolidinyl)methyl]-tnfluoroacetamide (Compound No 31),
- (S)-N-[3-(4-(3-Fluoro-4-( 1 '-acetamido^'^'^'-trifluoroethyl)-1 -piperazinyl)phenyl)-2-oxo-5-
oxazolidinyl)methyl]-tnfluoroacetamide (Compound No 32),
-(S)-N-[3-(4-(3-Fluoro-4-(l'-tnchloroacetamido-2',2',2'-tnfluoroethyl)-l-piperazinyl)phenyl)-2-oxo-5-oxazolidinyl)methyl]-tnfluoroacetamide (Compound No 33),
- (S)-N-[3-(4-(3-Fluoro-4-( 1 '-formamido-2',2',2'-tnchloroethyl)-3-methyl-1 -piperazinyl)
phenyl)-2-oxo-5-oxazohdinyl) methylj-acetamide (Compound No 34),
-(S)-N-[3-(4-(3-Fluoro-4-(l'-acetamido-2',2',2'-tnchloroethyl)-3-methyl-l-piperazinyl)phenyl)-2-oxo-5-oxazohdinyl) methyl]-acetamide (Compound No 35),
-(S)-N-[3-(4-(3-Fluoro-4-(1-tnchloroacetamido-2',2',2'-tnchloroethyl)-3-methyl-l-piperazinyl) phenyl)-2-oxo-5-oxazohdinyl) methylj-acetamide (Compound No 36),
-(S)-N-[3-(4-(3-Fluoro-4-(1-tnfluoroacetamido-2',2',2'-tnchloroethyl)-3-methyl-l-piperazinyl) phenyl)-2-oxo-5-oxazohdinyl) methylj-acetamide (Compound No 37),
- (S)-N-[3-(4-(3-FIuoro-4-( 1 '-formamido-2',2',2'-tnbromoethyl)-3-methyl-1 -piperazinyl)
phenyl)-2-oxo-5-oxazolidinyl) methyl]-acetamide (Compound No 38),
-(S)-N-[3-(4-(3-Fluoro-4-(1-acetamido-2',2',2'-tnbromoethyl)-3-methyl-l-piperazinyl) phenyl)-2-oxo-5-oxazohdinyl) methyl]-acetamide (Compound No 39),
-(S)-N-[3-(4-(3-Fluoro-4-(l'-trichloroacetamido-2',2,,2'-tnbromoethyl)-3-methyl-l-piperazinyl) phenyl)-2-oxo-5-oxazolidinyl) methyl]-acetamide (Compound No 40),
-(S)-N-[3-(4-(3-Fluoro-4-(1-tnfluoroacetamido-2',2,,2'-tnbromoethyl)-3-methyl-l-piperazinyl) phenyl)-2-oxo-5-oxazohdinyl) methyl]-acetamide (Compound No 41),
- (S)-N-[3-(4-(3-Fluoro-4-( 1 '-formamido-2',2',2'-trifluoroethyl)-3-methyl-1 -piperazinyl) phenyl)-
2-oxo-5-oxazohdinyl) methyl]-acetamide (Compound No 42),
-(S)-N-[3-(4-(3-Fluoro-4-(l'-acetamido-2',2',2'-tnfluorethyl)-3-methyl-l-piperazinyl) phenyl)-2-oxo-5-oxazolidinyl) methyl]-acetamide (Compound No 43),
-(S)-N-[3-(4-(3-Fluoro-4-(l'-trichloroacetamido-2,,2',2'-tnfluoroethyl)-3-methyl-l-piperazinyl) phenyl)-2-oxo-5-oxazohdinyl) methylj-acetamide (Compound No 44),
- (S)-N-[3-(4-(3-Fluoro-4-( 1 '-formamaido-2',2',2'-tncholroethyl)-3-methyl-1 -piperazinyl)
phenyl)-2-oxo-5-oxazolidinyl) methyl]-tnfluoroacetamide (Compound No 45),
-(S)-N-[3-(4-(3-Fluoro-4-(l'-acetamido-2',2',2'-tnchloroethyl)-3-methyl-l-piperazinyl) phenyl)-2-oxo-5-oxazohdinyl) methylj-tnfluoroacetamide (Compound No 46),
- (S)-N-[3-(4-(3-Fluoro-4-( 1 '-tnchloroacetamido-2',2',2'-tnchloroethyl)-3-methyl-1 -piperazinyl) phenyl)-2-oxo-5-oxazolidinyl) methylj-tnfluoroacetamide (Compound No 47),
- (S)-N-[3-(4-(3-Fluoro-4-( 1 '-tnfluoroacetamido-2',2',2'-trichloroethyl)-3-methyl-1 -piperazinyl) phenyl)-2-oxo-5-oxazolidinyl) methyl]-tnfluoroacetamide (Compound No 48),
-(S)-N-[3-(4-(3-Fluoro-4-(l'-formamido-2',2',2'-tribromoethyl)-3-methyl-l-piperazinyl) phenyl)-2-oxo-5-oxazohdinyl) methylj-tnfluoroacetamide (Compound No 49),
- (S)-N-[3-(4-(3-Fluoro-4-(1-acetamido-2',2',2'-tnbromoethyl)-3-methyl-l-piperazinyl) phenyl)-
2-oxo-5-oxazolidinyl) methyl]-trifluoroacetamide (Compound No 50),
-(S)-N-[3-(4-(3-Fluoro-4-(1-tnchloroacetamido-2',2',2'-tribromoethyl)-3-methyl-l-piperazinyl) phenyl)-2-oxo-5-oxazolidinyl) methylj-tnfluoroacetamide (Compound No 51),
-(S)-N-[3-(4-(3-Fluoro-4-(1-tnfluoroacetamido-2',2',2'-tribromoethyl)-3-methyl-l-piperazinyl) phenyl)-2-oxo-5-oxazohdinyl) methylj-tnfluoroacetamide (Compound No 52),
-(S)-N-[3-(4-(3-Fluoro-4-(l'-formamido-2',2',2'-tnfluoroethyl)-3-methyl-l-piperazinyl) phenyl)-2-oxo-5-oxazohdinyl) methyI]-tnfluoroacetamide (Compound No 53),
- (S)-N-[3-(4-(3-Fluoro-4-( 1 '-acetamido-2',2',2'-tnfluoroethyl)-3-methyl-1 -piperazinyl) phenyl)-2-oxo-5-oxazohdinyl) methyl]-trifluoroacetamide (Compound No 54),
pharmaceutical^ acceptable salts, pharmaceutical^ acceptable solvates, enantiomers, diastereomers, N-oxides, prodrugs, polymorphs and metabolites thereof
Table I
(Table Removed)

This invention further provides a method of treating bacterial infections, or enhancing or potentiating the activity of other antibacterial agents, in a mammal having conditions caused by or contributed to by bacterial infection, which comprises administering to the mammal a compound of the invention alone or in admixture in the form of a medicament according to the invention The term "treating" or "treatment" include administering, either simultaneously, separately or sequentially, a pharmaceutically effective amount of a composition containing one
or more of the compounds disclosed herein to a mammal that desires inhibition of bacterial growth The pharmaceutically effective amount of the compound used to practice the present invention for treatment varies depending on the manner of administration, the age, weight, and general health of the mammal treated, and ultimately will be decided by the physicians
The compounds of the present invention may be administered to a mammal such as human by any route appropriate to the condition to be treated, suitable routes including oral, rectal, nasal, topical (including buccal and sublingual), vaginal and parenteral (including subcutaneous, intramascular, intravenous, intradermal, intrathecal and epidural) The preferred route may vary with, for example, the condition of the recipient as well the ease of preparation and administration
The pharmaceutical compositions of the present invention comprise a pharmaceutically effective amount of a compound described herein formulated together with one or more pharmaceutically acceptable carriers "The term pharmaceutically acceptable carriers" is intended to include non-toxic, inert solid, semi-solid or liquid filler, diluents, encapsulating material or formulation auxiliary of any type
Solid form preparation for oral administrations include capsules, tablet, pills, powder, granules, sachets and suppository For solid form preparation, the active compound is mixed with at least one inert, pharmaceutically acceptable excipients or carrier such as sodium citrate, dicalcium phosphate and/or a filler or extenders such as starches, lactose, sucrose, glucose, mannitol and silicic acid, binders such as carboxymethylcellulose, alginates, gelatins, polyvinylpyrrohdinone, sucrose, acacia, disintegrating agents such as agar-agar, calcium carbonate, potato starch, alginic acid, certain silicates and sodium carbonate, absorption acceletors such as quaternary ammonium compounds, wetting agents such as cetyl alcohol, glycerol mono stearate, adsorbants such as Kaolin, lubricants such as talc, calcium stearate, magnesium stearate, solid polyethyleneglycol, sodium luaryl sulphate and mixture thereof In the case of capsules, tablets, pills, the dosage form may also comprise buffering agents
The solid preparation of tablets, capsules, pills and granules can be prepared with coating and shells such as enteric coating and other coatings well known in the pharmaceutical formulating art
Liquid form preparation for oral administration includes pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs For liquid form preparation, the active
compound is mixed with water or other solvent, solubihzing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, dimethylformamide, oils (such as cottonseed, groundnut, corn, germ, olive, castor and sesame oil), glycerol, and fatty acid esters of sorbitan and mixture thereof Besides inert diluents, the oral composition can also include adjutants such as wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents and perfuming agents
Injectable preparations such as sterile injections, aqueous suspensions may be formulated according to the art using suitable dispersing or wetting and suspending agent Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride
Dosage form for topical administration of a compound of the present invention includes ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches The active compound is admixed under sterile condition with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required Ophthalmic formulations, eardrops, eye ointments, powder and solution are also contemplated as being within the scope of this invention
The pharmaceutical preparation is in unit dosage form In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component The unit dosage form can be packaged preparation, the package containing discrete capsules, powders, in vials or ampoules, and ointments capsule, sachet, tablet, gel, cream itself or it can be the appropriate number of any of these packaged forms
The quantity of active compound in unit dose of preparation may be varied or adjusted from less than 1 mg to several grams according to the particular application and potency of the active ingredient
In therapeutic use as agents for treating bacterial infections the compounds utilizing 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 patients 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 portion during the day if desired
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 do not constrained the scope of the present invention as defined by the claims
Experimental Details
General Procedure
Preparation of compound of Formula IV
A suspension of racemic compound of Formula II (1 equiv) in a solvent (2-5 mL) was cooled in an ice bath To this cooled suspension a base (1 2 equiv) was added and stirring continued To this solution, compound of Formula III was added dropwise and stirring continued The mixture was diluted with chloroform used for the reaction and the solution washed with water and brine The chloroform layer was dried over anhydrous sodium sulphate and concentrated to afford the crude product The crude product was purified by column chromatography using petroleum ether-ethylacetate mixture to afford the desired product
The following compounds were prepared by following the above general procedure
Compound No 1 N-[3-(4-(3-Fluoro-4-(1-formamido-2',2',2'-tnchloroethyl)-l-piperazinyl) phenyl)-2-oxo-5-oxazolidinyl) methyl]-acetamide
1HNMR (200MHZ, CDCl3) δ 8 36 (s, 1H), 7 41 (dd, J=14 1 Hz, J=2 6 Hz, 1H), 6 90-7 20 (m,
3H), 5 39 (s, 1H), 4 78 (bm, 1H), 3 50-3 80 (m, 4H), 2 85-3 30 (m, 4H), 2 01 (s, 3H)
Compound No 2 N-[3-(4-(3-Fluoro-4-(1-acetamido-2',2',2'-tnchloroethyl)-l-piperazinyl) phenyl)-2-oxo-5-oxazolidinyl) methyl]-acetamide
1HNMR (200MHz, CDCl3) δ 7 38 (dd, J=14 1 Hz, J=2 6 Hz, IH), 7 05 (d, J=8Hz, 1H), 6 90 (t,
J=9 1 Hz, IH), 6 30-6 60 (m, 2H), 5 36 (s, 1H), 4 76 (bm, lH), 4 01 (t, J=9Hz, IH), 3 55-3 80
(m, 4H), 2 80-3 20 (m, 8H), 2 17 (s, IH), 2 02 (s, 3H)
Compound No 3 N-[3-(4-(3-Fluoro-4-(l'-tnchloroacetamido-2',2',2'-tnchloroethyl)-l-piperazinyl) phenyl)-2-oxo-5-oxazohdinyl) methyl]-acetamide
1HNMR (200MHZ, CDCl3) δ 7 43 (dd, J=14 1 Hz, J=6 2 Hz, IH), 7 05 (d, J=8Hz, 1H), 6 92 (t,
J=9 I Hz, IH), 6 24 (bt, J=l 1Hz, IH), 5 29 (d, IH), 4 78 (bt, IH), 4 02 (t, J=9Hz, IH), 3 55-3 80
(m, 4H), 2 90-3 30 (m, 8H), 2 02 (s, 3H)
Compound No 4 N-[3-(4-(3-Fluoro-4-(l'-trifluoroacetamido-2',2',2'-tnchloroethyl)-l-piperazinyl) phenyl)-2-oxo-5-oxazohdinyl) methyl]-acetamide
1HNMR (200MHz, CDCl3) δ 8 10 (s, IH), 7 47 (dd, J=14 Hz, J=2 6 Hz, IH), 7 07 (d, J=8 Hz,
IH), 6 92 (t, J=9 1 Hz IH), 6 20 (bt, J=l 1Hz, IH), 4 78 (bt, IH), 4 03 (t, J=9 Hz, 1H),3 50-3 80
(m, 8H), 2 95-3 15 (m, 4H), 2 03 (s, 3H)
Compound No 5 N-[3-(4-(3-Fluoro-4-(1-formamido-2',2',2'-tnbromoethyl)-l-piperazinyl) phenyl)-2-oxo-5-oxazohdinyl) methyl]-acetamide
1HNMR (200MHz, CDCl3) δ 8 10 (s, IH), 7 47 (dd, J=14 Hz, J=2 6 Hz, IH), 7 27 (m, IH), 7 08
(d, J=8 Hz IH), 6 92 (t, J=9 1Hz, IH), 6 10 (bt, J=l 1Hz, IH), 4 78 (bt, IH), 4 03 (t, J=9 Hz, IH),
3 50-3 80 (m, 8H), 2 95-3 15 (m, 4H), 2 03 (s, 3H)
Compound No 6 N-[3-(4-(3-Fluoro-4-(1-acetamido-2',2',2'-tnbromoethyl)-l-piperazinyl) phenyl)-2-oxo-5-oxazolidinyl) methyl]-acetamide
1HNMR (200MHz, CDCl3) δ 7 42 (dd, J=14 1 Hz, J=6 2 Hz, IH), 7 07 (d, J=8Hz, IH), 6 92 (t,
J=9 1 Hz, IH), 6 18 (bt, J=l 1Hz, IH), 5 31 (d, IH), 4 75 (bt, IH), 4 02 (t, J=9Hz, IH), 2 85-3 80
(m, 12H),2 18 (s, 3H), 2 03 (s, 3H)
Compound No 7 N-[3-(4-(3-Fluoro-4-(1-tnfluoroacetamido-2',2',2'-tnbromoethyl)-l-piperazinyl) phenyl)-2-oxo-5-oxazohdinyl) methylj-acetamide
1HNMR (200MHz, CDCl3) δ 8 10 (s, IH), 7 45 (dd, J=14 Hz, J=2 6 Hz, IH), 7 80 (d, J=8 Hz
IH), 6 92 (t, J=9 1 Hz IH), 6 69 (bt, J=l 1Hz, IH), 4 79 (bt, IH), 4 03 (t, J=9 Hz, IH), 3 50-3 80
(m, 8H), 2 95-3 15 (m, 4H), 2 03 (s, 3H)
Compound No 8 N-[3-(4-(3-Fluoro-4-(1-benzamido-2',2',2'-trichloroethyl)-l-piperazinyl) phenyl)-2-oxo-5-oxazolidinyl) methylj-acetamide
1HNMR (200MHZ, CDCl3) δ 7 83 (t, J=9 Hz, 2H), 7 35-7 60 (m, 4H), 7 02 (d, J=8 Hz, 1H), 6 91 (t, J=9 1 Hz, 1H), 6 81 (d, J=9Hz, 1H), 6 54 (bt, J=l 1 Hz, 1H), 5 60 (d, 1H), 4 75 (bt, 1H), 4 0 (t, J=9Hz, 1H), 3 60-3 80 (m, 4H), 2 85-3 80 (m, 8H), 2 01 (s, 3H)
Compound No 9 N-[3-(4-(3-Fluoro-4-(l'-(2,4-dichloro-5-fluorobenzamido)-2',2,,2'-tnchloroethyl)-l-piperazinyl) phenyl)-2-oxo-5-oxazohdinyl) methyl]-acetamide
1HNMR (200MHz, CDCl3) δ 7 35-7 70 (m, 4H), 7 02 (d, J=8 Hz, 1H), 6 90 (t, J=9 1 Hz, 1H),
6 70 (bt, J=l 1Hz, 1H), 5 55 (d, 1H), 4 75 (bt, 1H), 4 00 (t, J=9Hz, 1H), 3 60-3 80 (m, 4H), 2 90-
3 30 (m, 8H), 2 00 (s, 3H)
Compound No 10 N-[3-(4-(3-Fluoro-4-(1-benzamido-2',2',2'-tnbromoethyl)-l-piperazinyl) phenyl)-2-oxo-5-oxazohdinyl) methyl]-acetamide
1HNMR (200MHz, CDC13) δ 7 80 (d, 2H), 7 35-7 70 (m, 6H), 6 85-7 10 (m, 3H), 4 78 (bt, 1H),
4 0 (t, J=9Hz, 1H), 3 0-3 80 (m, 12H), 2 01 (s, 3H)
Compound No 11 N-[3-(4-(3-Fluoro-4-(l'-(2,4-dichloro-5-fluorobenzamido)-2',2',2'-tnbromoethyl)-l-piperazinyl) phenyl)-2-oxo-5-oxazohdinyl) methyl]-acetamide
1HNMR (200MHz, CDCl3) δ 7 71 (d, 2H), 7 51 (d, 1H), 7 27-7 45 (m, 3H), 7 03 (d, J= 8Hz,
1H), 6 92 (t, J=9 1 Hz, 1H), 6 39 (t, 1H), 4 78 (bt, 1H), 4 0 (t, J=9Hz, 1H), 3 55-3 80 (m, 4H),
2 95-3 45 (m, 8H),2 01 (s, 3H)
Compound No 12 N-[3-(4-(3-Fluoro-4-(1-formamido-2',2',2,-tnfluoroethyl)-l-piperazinyl) phenyl)-2-oxo-5-oxazohdinyl) methylj-acetamide
1HNMR (200MHz, CDC13) δ 8 44 (bt, 1H), 8 25-8 35 (m, 1H), 7 45-7 70 (m, 2H), 6 90-7 15
(m, 2H), 5 47 (bm, 1H), 4 84 (bt, 1H), 4 11 (t, 1H), 3 60-3 90 (m, 4H), 2 80-3 20 (m, 8H), 2 02
(s, 3H)
Preparation of S isomer of compound of Formula VI
A suspension of chiral compound of Formula V (1 equiv) in a solvent (2-5 mL) was cooled in an ice bath To this cooled suspension a base (1 2 equiv) was added and stirring
continued To this solution, compound of Formula III was added dropwise and stirring continued The mixture was diluted with the chloroform and the solution washed with water and brine The chloroform layer was dried over anhydrous sodium sulphate and concentrated to afford the crude product The crude product was purified by column chromatography using petroleum ether-ethylacetate mixture to afford the desired product The following compounds were prepared by following the above general procedure
Compound No 13 (S)-N-[3-(4-(3-Fluoro-4-(1-formamido-2',2',2'-tnchloroethyl)-l-piperazinyl) phenyl)-2-oxo-5-oxazohdinyl) methylj-acetamide
1HNMR (200MHZ, CDC13) δ 8 47 (s, 1H), 7 39 (dd, J=14 1 Hz, J=2 6 Hz, 1H), 6 85-7 10 (m,
3H), 5 43 (d, 1H), 4 76 (bm, 1H), 4 01 (t, J=9 Hz, 1H), 3 55-3 80 (m, 4H), 2 80-3 75 (m, 8H),
2 02 (s, 3H)
Compound No 14 (S)-N-[3-(4-(3-Fluoro-4-(1-acetamido-2,2,2-tnchloroethyl)-l-piperazinyl) phenyl)-2-oxo-5-oxazolidinyl) methyl]-acetamide
1HNMR (200MHz, CDCl3) δ 7 36 (dd, J=14 1 Hz, J=2 6 Hz, IH), 7 05 (d, J=8 8Hz, 1H), 6 75-
6 90 (m, IH), 6 58 (bt, J=9Hz, IH), 5 35 (d, IH), 4 77 (bm, IH), 4 01 (t, J=9Hz, IH), 3 55-3 80
(m, 4H), 2 90-3 15 (m, 8H), 2 03 (s, 3H)
Compound No 15 (S)-N-[3-(4-(3-Fluoro-4-(l'-tnchloroacetamido-2',2',2'-tnchloroethyl)-l-piperazinyl) phenyl)-2-oxo-5-oxazohdinyl) methyl]-acetamide
1HNMR (200MHz, CDCl3) δ 8 10 (s, IH), 7 47 (dd, J=14 lHz,J=2 6 Hz, IH), 7 05 (d, J=8 Hz,
IH), 6 92 (t, IH), 6 25 (bt, J=l 1Hz, IH), 4 78 (bt, IH), 4 03 (t, J=9Hz, IH), 3 55-3 80 (m, 4H),
2 90-3 15(m,4H),2 03(s, 3H)
Compound No 16 (S)-N-[3-(4-(3-Fluoro-4-(l'-tnfluoroacetamido-2',2',2'-tnchloroethyl)-l-piperazinyl) phenyl)-2-oxo-5-oxazolidmyl) methyl]-acetamide
1HNMR (200MHz, CDCl3) δ 8 09 (s, IH), 7 47 (dd, J=14 lHz,J=2 6 Hz, IH), 7 07 (d, J=8 Hz,
IH), 6 92 (t, IH), 6 39 (bt, J=l 1Hz, IH), 5 30 (d, J=1H), 4 79 (bm, IH), 4 02 (t, J=9Hz, IH),
3 59-3 80 (m, 8H), 2 95-3 15 (m, 4H), 2 02 (s, 3H)
Compound No 17 (S)-N-[3-(4-(3-Fluoro-4-(1-formamido-2',2',2'-tnbromoethyl)-l-piperazinyl) phenyl)-2-oxo-5-oxazolidmyl) methyl]-acetamide
1HNMR (200MHz, CDCl3) δ 8 48(s, IH), 7 39 (dd, J=14 lHz,J=2 6 Hz, 1H), 7 04 (d, J=8 Hz,
1H), 6 92 (t, IH), 6 40 (bt, J=l 1Hz, IH), 5 35 (d, IH), 4 76 (bM, IH), 4 03 (t, J=9Hz, IH), 3 55-
3 80 (m, 4H), 2 89-3 30 (m, 8H), 2 02 (s, 3H)
Compound No 18 (S)-N-[3-(4-(3-Fluoro-4-(l'-acetamido-2',2',2'-tnbromoethyl)-l-piperazmyl) phenyl)-2-oxo-5-oxazoIidinyl) methyl]-acetamide
1HNMR (200MHz, CDCl3) δ 7 41 (dd, J=14 lHz,J=2 6 Hz, IH), 7 07 (d, J=8 Hz, IH), 6 91 (t,
IH), 6 34 (t, IH), 5 32 (d, IH), 4 79 (bm, IH), 4 02 (t, J=9Hz, IH), 3 60-3 86 (m, 4H), 2 85-3 30
(m, 8H),2 19(s, 3H), 2 03 (s, 3H)
Compound No 19 (S)-N-[3-(4-(3-Fluoro-4-(l'-tnchloroacetamido-2',2',2'-tnbromoethyl)-l-piperazinyl) phenyl)-2-oxo-5-oxazohdinyl) methyl]-acetamide
1HNMR (200MHz, CDCI3) 5 8 09 (s, IH), 7 47 (dd, J=14 lHz,J=2 6 Hz, IH), 7 07 (d, J=8 Hz,
IH), 6 91 (t, IH), 6 37 (bt, J=l 1Hz, IH), 4 78 (bm, IH), 4 02 (t, IH), 3 50-3 85 (m, 8H), 2 95-
3 20 (m, 84), 2 02 (s, 3H)
Compound No 20 (S)-N-[3-(4-(3-Fluoro-4-(l'-tnfluoroacetamido-2',2',2'-tnbromoethyl)-l-piperazinyl) phenyl)-2-oxo-5-oxazohdinyl) methylj-acetamide
1HNMR (200MHz, CDCl3) δ 8 10 (s, IH), 7 47 (dd, J-14 lHz,J=2 6 Hz, IH), 6 85-7 15 (m, 2H),
6 31 (t, IH), 4 78 (bm, IH), 4 02 (t, J=9Hz, IH), 3 45-3 85 (m, 8H), 2 90-3 10 (m, 4H), 2 02 (s,
3H)
Compound No 21 (S)-N-[3-(4-(3-Fluoro-4-(l'-formamido-2',2',2'-tnfluoroethyl)-l-piperazinyl)
phenyl)-2-oxo-5-oxazohdinyl) methyl]-acetamide
1HNMR (200MHz, CDC13) 8 8 43 (s, 1H0, 7 39 (dd, J=14 1 Hz, J=2 6 Hz, IH), 7 04 (d,
J=8 8Hz, IH), 7 06 (d, J=8Hz, IH), 6 90 (t, J= 9Hz, IH), 6 47 (d, J=9Hz, IH), 5 46 (bt, IH), 4 77
(bm, IH), 4 02 (t, J=9Hz, IH), 3 60-3 85 (m, 4H), 2 70-3 15 (m, 8H), 2 02 (s, 3H)
Compound No 22 (S)-N-[3-(4-(3-Fluoro-4-(l'-acetamido-2',2',2'-tnfluoroethyl)-l-piperazinyl) phenyl)-2-oxo-5-oxazolidinyl) methyl]-acetamide
1HNMR (200MHZ, CDCl3) δ 7 42 (dd, J=14 lHz,J=2 6 Hz, 1H), 7 05 (d, J=8 Hz, 1H), 6 91 (t,
J= 9 Hz, 1H), 6 14 (bt, J=l 1Hz, 1H), 5 39 (bt, 1H0, 4 74 (bm, 1H), 4 02 (t, J=9Hz, 1H), 3 55-
3 80 (m, 4H), 2 75-3 15 (m, 8H), 2 13 (s, 1H), 2 03 (s, 3H)
Compound No 23 (S)-N-[3-(4-(3-Fluoro-4-(l'-formamido-2',2',2'-tnchloroethyl)-l-piperazinyl) phenyl)-2-oxo-5-oxazolidinyl) methylj-acetamide
1HNMR (200MHz, CDCl3) δ 8 08 (bs, IH), 7 45 (dd, J=14 lHz,J=2 6 Hz, 1H), 7 08 (d, J=8 Hz,
1H), 6 90 (t, IH), 4 86 (bm, IH), 4 11 (t, J=9Hz, IH), 3 59-3 80 (m, 8H), 2 90-3 20 (m, 4H)
Compound No 24 (S)-N-[3-(4-(3-Fluoro-4-(l'-acetamido-2',2',2'-tnchloroethyl)-l-piperazinyl) phenyl)-2-oxo-5-oxazolidinyl) methylj-acetamide
1HNMR (200MHz, CDCl3) δ 7 41 (dd, J=14 lHz,J=2 6 Hz, IH), 7 05 (d, J=8 Hz, IH), 6 93 (t,
IH), 6 11 (dd, J=14Hz, J= 2 6 Hz, IH), 5 35 (d, IH), 4 85 (bM, IH), 4 11 (t, IH), 3 60-3 95 (m,
4H), 2 80-3 20 (m, 8H), 2 20 (s, 3H)
Compound No 25 (S)-N-[3-(4-(3-Fluoro-4-(l'-tnchloroacetamido-2',2',2'-tnchloroethyl)-l-piperazinyl) phenyl)-2-oxo-5-oxazohdinyl) methyl]-acetamide
1HNMR (200MHz, CDCI3) 5 8 10 (s, IH), 7 30-7 50 (m, 2H), 7 07 (d, J=8 Hz, IH), 6 92 (t, IH),
4 83 (bm, IH), 4 11 (t, J=9Hz, IH), 3 50-3 95 (m, 8H), 2 90-3 15 (m, 4H)
Compound No 26 (S)-N-[3-(4-(3-Fluoro-4-(l'-trifluoroacetamido-2',2',2'-tnchloroethyl)-l-piperazinyl) phenyl)-2-oxo-5-oxazohdinyl) methylj-acetamide
1HNMR (200MHz, CDCl3) δ 8 09 (s, IH), 7 72 (dd, J=14 lHz,J=2 6 Hz, IH), 7 08 (d, J=8 Hz,
IH), 6 92 (t, IH), 4 85 (bm, IH), 4 11 (t, IH), 3 55-3 95 (m, 8H), 2 90-3 20 (m, 4H)
Compound No 27 (S)-N-[3-(4-(3-Fluoro-4-(1-formamido-2',2',2'-tnbromoethyl)-l-piperazinyl) phenyl)-2-oxo-5-oxazohdinyl) methyl]-acetamide
1HNMR (200MHZ, CDC13) δ 8 48(s, IH), 7 47 (dd, J=14 lHz,J=2 6 Hz, 1H), 7 05-7 20 (m, 2H),6 38 (bm, IH), 5 41 (d, IH), 4 85 (bm, IH), 4 13 (t, J=9Hz, IH), 3 65-3 95 (m, 4H), 3 00-
3 45 (m, 8H)
Compound No 28 (S)-N-[3-(4-(3-Fluoro-4-(l'-acetamido-2',2',2'-tnbromoethyl)-l-piperazinyl) phenyl)-2-oxo-5-oxazohdinyl) methylj-acetamide
1HNMR (200MHz, CDCl3) δ 6 910-7 45 (m, 4H), 6 10 (d, IH), 5 32 (d, IH), 4 83 (bm, IH),
4 11 (t, J=9Hz, IH), 3 55-3 80 (m, 4H), 2 75-3 15 (m, 8H), 2 13 (s, 3H), 2 03 (s, 3H)
Compound No 29 (S)-N-[3-(4-(3-Fluoro-4-(l'-tnchloroacetamido-2',2',2'-tnbromoethyl)-l-piperazinyl) phenyl)-2-oxo-5-oxazohdinyl) methylj-acetamide
1HNMR (200MHz, CDC13) δ 8 62 (s, IH), 7 47 (dd, J=14 lHz,J=2 6 Hz, IH), 7 05-7 20 (m,
2H), 6 95 (t, IH), 4 85 (bm, IH), 3 60-4 20 (m, 8H), 3 05-3 25 (m, 4H)
Compound No 30 (S)-N-[3-(4-(3-Fluoro-4-(l'-tnfluoroacetamido-2',2',2'-tnbromoethyl)-l-piperazinyl) phenyl)-2-oxo-5-oxazohdinyl) methylj-acetamide
1HNMR (200MHz, CDCl3) δ 8 10 (s, IH), 7 35-7 65 (m, 2H), 7 08 (d, J=8 Hz, IH), 6 92 (t, IH),
4 85 (bm, IH), 4 11 (t, J=9Hz, lH), 3 50-3 90 (m, 8H), 2 90-3 10 (m, 4H)
Compound No 31 (S)-N-[3-(4-(3-Fluoro-4-(l'-formamido-2',2',2'-tnfluoroethyl)-l-piperazinyl) phenyl)-2-oxo-5-oxazolidinyl) methyl]-acetamide
1HNMR (200MHz, CDCl3) δ 8 09 (s, IH), 7 57 (t, IH), 7 43 (dd, J=14 1 Hz, J=2 6Hz, IH), 7 10
(d, J=8Hz, IH), 6 92 (t, IH), 4 87 (bm, IH), 4 11 (t, J=9 Hz, IH), 3 55-3 95 (m, 8H), 2 90-3 25
(m, 4H)
Compound No 32 (S)-N-[3-(4-(3-Fluoro-4-(l'-acetamido-2',2',2'-tnfluoroethyl)-l-piperazinyl) phenyl)-2-oxo-5-oxazohdinyl) methylj-acetamide
1HNMR (200MHz, CDCl3) δ 7 39 (dd, J=14 1HZ, J=2 6Hz, 2H), 7 05 (d, J=8 Hz, IH), 6 92 (t,
IH), 5 39 (d, IH), 4 82 (bm, IH), 4 11 (t, J=9 Hz, IH), 3 55-3 95 (m, 4H), 2 75-3 20 (m, 8H),
2 13 (s, 3H)
Compound No 33 (S)-N-[3-(4-(3-Fluoro-4-(l'-tnchloroacetamido-2',2',2'-tnfluoroethyl)-l-piperazinyl) phenyl)-2-oxo-5-oxazohdinyl) methyl]-acetamide
1HNMR (200MHZ, CDCl3) δ 6 85-7 60 (m, 4H), 5 53 (m, 1H), 4 85 (bm, 1H), 4 11 (t, J=9Hz,
1H), 3 60-3 95 (m, 4H), 2 65-3 20 (m, 6H)
Compound 34, (S)-N-[3-(4-(3-Fluoro-4-( 1 '-formamido-2',2',2'-tnchloroethyl)-3-methyl-1 -
piperazinyl) phenyl)-2-oxo-5-oxazolidinyl) methyl]-acetamide
1HNMR (200MHz, CDCl3) δ 8 46 (s, 1H), 7 43 (dd, J=14 lHz,J=2 6Hz, 1H), 7 35 (dd,
J=14 lHz,J=2 6Hz, 1H), 7 0-7 15 (m, 1H), 6 88 (t, J=9 1Hz, 1H), 6 68 (d, J=4Hz, 1H), 6 45(t,
1H), 5 83 (d, 1H), 4 77 (bm, 1H), 4 01 (t, J=9Hz, 1H), 3 60-3 85 (m, 4H), 3 15-3 55 (m, 4H),
2 60-3 10 (m, 4H), 2 02 (s, 3H), 1 34 (d, 3H)
Compound 35 (S)-N-[3-(4-(3-Fluoro-4-(l'-acetamido-2',2',2'-trichloroethyI)-3-methyl-l-
piperazinyl) phenyl)-2-oxo-5-oxazohdinyl) methyl]-acetamide
1HNMR (200MHz, CDCl3) δ 7 30-7 50 (m, 1H), 7 0-7 10 (m, 1H), 6 87 (t, J=9 1Hz, 1H), 6 45
(t, 1H), 6 20-6 35 (m, 1H), 5 43 (d, 1H), 4 76 (m, 1H), 4 01 (t, J=9Hz, 1H),
3 60-3 85 (m, 4H), 2 85-3 50 (m, 8H), 2 14 (s, 3H), 2 02 (s, 3H), 1 31 (d,), 1 25 (d)
Compound 36 (S)-N-[3-(4-(3-Fluoro-4-(1-tnchloroacetamido-2',2',2'-trichloroethyl)-3-methyl-1-piperazinyl) phenyl)-2-oxo-5-oxazohdinyl) methylj-acetamide
1HNMR (200MHz, CDCI3) 5 8 17 (s), 8 05 (s), 7 46 (dd, J=14Hz,J=2 6Hz, 1H), 7 05 (d, J=8Hz,
1H), 6 90 (t, J=9 1Hz, 1H), 6 49 (t, 1H), 4 78 (m, 1H), 4 02 (t, J=9Hz, 1H), 3 15-3 85 (m, 7H),
2 75-3 0 (m, 2H), 2 03 (s, 3H), 1 40(d)
Compound 37 (S)-N-[3-(4-(3-Fluoro-4-( 1 '-tnfluoroacetamido-2',2',2'-trichloroethyl)-3-methyl-1-piperazinyl) phenyl)-2-oxo-5-oxazolidinyl) methylj-acetamide
1HNMR (200MHZ, CDCl3) δ 8 17 (s), 8 05 (s), 7 46 (dd, J=14Hz, J=2 6Hz, 1H), 7 05 (d, J=8Hz, 1H), 6 90 (t, J=9 1Hz, 1H), 6 49 (t, 1H), 4 78 (m, 1H), 4 02 (t, J=9Hz, 1H), 3 15-3 85 (m, 7H),
2 75-3 0 (m, 2H), 2 03 (s, 3H), 1 50 (d), 1 40(d)
Compound 38 (S)-N-[3-(4-(3-Fluoro-4-( 1 '-foimamido-2\2,,2,-mbromoe%l)-3-methyl-1 -
piperazinyl) phenyl)-2-oxo-5-oxazolidinyl) methyl]-acetamide
1HNMR (200MHz, CDCI3) δ 8 17 (s), 8 05 (s), 7 46 (dd, J=14Hz, J=2 6Hz, 1H), 7 07 (d, J=8Hz,
1H), 6 89 (t, J=9 1Hz, 1H), 6 19 (t, 1H), 4 75 (m, 1H), 4 03 (t, J=9Hz, 1H), 3 60-3 80 (m, 6H),
3 20-3 50 (m, 5H), 2 70-3 0 (m, 3H), 2 03 (s, 3H), 1 50(d), 1 42 (d)
Compound 39 (S)-N-[3-(4-(3-Fluoro-4-(l'-acetamido-2',2',2'-tribromoethyl)-3-methyl-l-
piperazinyl) phenyl)-2-oxo-5-oxazohdinyl) methyl]-acetamide
1HNMR (200MHz, CDCl3) δ 8 39 (s), 7 41 (dd, J=14Hz, J=2 6Hz, 1H), 6 85-7 10 (m, 2H),
6 15-6 45 (m, 2H), 5 46 (d, 1H), 4 77 (m, 1H), 3 95-4 20 (m, 2H), 3 45-3 85 (m, 4H), 2 90-3 35
(m, 6H), 2 03 (s, 3H), 1 36 (d), 1 25 (d)
Compound 40 (S)-N-[3-(4-(3-Fluoro-4-( 1 '-tnchloroacetamido-2',2',2'-tnbromoethyl)-3-methyl-1-piperazinyl) phenyl)-2-oxo-5-oxazolidinyl) methyl]-acetamide
1HNMR (200MHz, CDCl3) δ 7 39 (dd, J=14Hz, J=2 6Hz, 1H), 7 05 (d, J=8Hz, 1H), 6 87 (t,
J=9 1 Hz, 1H), 6 35 (m, 1H), 6 11 (m, 1H), 5 37 (d, 1H), 4 77 (m, 1H), 4 0 (t, J=9Hz, 1H), 3 45-
3 85 (m, 4H), 3 05-3 30 (m, 6H), 2 17 (s, 3H), 2 03 (s, 3H), 1 45 (d), 1 30 (d)
Compound 41 (S)-N-[3-(4-(3-Fluoro-4-( 1 '-tnfluoroacetamido-2',2',2'-tnbromoethyl)-3-methyl-1-piperazinyl) phenyl)-2-oxo-5-oxazolidinyl) methyl]-acetamide
1HNMR (200MHz, CDCl3) δ 8 17 (s), 8 05 (s), 7 44 (dd, J=14Hz, J=2 6Hz, 1H), 7 07 (d, J=8Hz,
1H), 6 89 (t, J=9 1Hz, 1H), 6 31(t, 1H), 4 76 (m, 1H), 4 02 (t, J=9Hz, 1H), 3 55-3 80 (m, 3H),
3 15-3 50 (m, 3H), 2 20-2 80 (m, 2H), 2 02(s, 3H), 1 50(d), 1 41(d)
Compound 42 (S)-N-[3-(4-(3-Fluoro-4-(l'-formamido-2',2',2,-tnfluoroethyl)-3-methyl-l-
piperazinyl) phenyl)-2-oxo-5-oxazohdinyl) methylj-acetamide
1HNMR (200MHZ, CDCl3) δ 7 42 (dd, J=14Hz, J=2 6Hz, 1H), 7 05 (d, J=8Hz, 1H), 6 93 (t,
J=9 1Hz, 1H), 6 24 (t, 1H), 4 76 (m, 1H), 4 02 (t, J=9Hz, 1H), 3 60-3 80 (m, 4H), 3 05-3 35 (m,
6H), 2 70-2 85 (m, 1H), 2 03 (s, 3H), 1 16 (d, 3H)
Compound 43 (S)-N-[3-(4-(3-Fluoro-4-(l'-acetamido-2',2',2'-tnfluorethyl)-3-methyl-l-
piperazinyl) phenyl)-2-oxo-5-oxazohdinyl) methyl]-acetamide
1HNMR (200MHz, CDCl3) δ 8 40 (s), 8 31(s), 7 40 (dd, J=14Hz, J=2 6Hz, 1H), 7 05 (d, J=8Hz,
1H), 6 80-6 95 (m, 1H), 6 60 (d, J=8Hz, 1H), 6 30 (m, 1H), 4 77 (m, 1H), 4 02 (t, J=9Hz, 1H),
3 65-3 85(m, 4H), 2 75-3 35 (m, 7H), 2 02 (s, 3H), 1 29 (d), 1 26(d)
Compound 44 (S)-N-[3-(4-(3-Fluoro-4-( 1 '-trichloroacetamido^'^'^'-tnfluoroethyO-S-methyl-1-piperazinyl) phenyI)-2-oxo-5-oxazohdinyl) methyl]-acetamide
1HNMR (200MHz, CDCl3) δ 7 42 (dd, J=14Hz, J=2 6Hz, 1H), 7 04 (d, J=8Hz, 1H), 6 91(t,
J=9 1Hz, 1H), 6 15-6 35 (m, 2H), 4 77 (m, 1H), 4 02 (t, J=9Hz, 1H), 3 55-3 80 (m, 3H), 2 55-
3 35 (m, 7H), 2 1 l(s), 2 02 (s), 1 27 (d)
Compound 45 (S)-N-[3-(4-(3-Fluoro-4-(l'-formamido-2',2',2'-tnchloroethyl)-3-methyl-l-
piperazinyl) phenyl)-2-oxo-5-oxazohdinyl) methylj-trifluoroacetamide
1HNMR (200MHz, CDCl3) δ 7 43 (dd, J=14Hz, J=2 6Hz, 1H), 7 02-7 23 (m, 2H), 6 91 (t,
J=9 1Hz, 1H), 6 34 (t, 1H), 4 76 (m, 1H), 4 02 (t, J=9Hz, 1H), 3 55-3 80 (m, 4H), 2 80-3 40 (m,
7H), 2 02 (s, 3H), 1 30 (d), 1 26 (d)
Compound 46 (S)-N-[3-(4-(3-Fluoro-4-( 1 '-acetamido-2',2',2'-tnchloroethyl)-3-methyl-1 -
piperazinyl) phenyl)-2-oxo-5-oxazohdinyl) methyl]-tnfluoroacetamide
1HNMR (200MHz, CDCl3) δ 8 47 (s), 8 37 (s), 7 30-7 45 (m, 2H), 7 04 (d, J=8Hz, 1H), 6 90 (t,
J=9 1Hz, 1H), 6 44 (t, 1H), 5 84 (d), 4 84 (m, 1H), 4 11 (t, J=9Hz,lH),2 60-3 90 (m, 11H),1 35
(d,3H)
Compound 47 (S)-N-[3-(4-(3-Fluoro-4-(l'-tnchloroacetamido-2',2',2'-tnchloroethyl)-3-methyl-1 -piperazinyl) phenyl)-2-oxo-5-oxazohdinyl) methyl]-tnfluoroacetamide
1HNMR (200MHZ, CDCl3) δ 7 62 (bm, 1H), 7 30-7 40 (m, 1H), 7 05 (d, J=8Hz, 1H), 6 92 (t,
J=9 1Hz, 1H), 6 19 (d, 1H), 5 44 (d, 1H), 4 85 (bm, 1H), 4 10 (t, J=9Hz, 1H), 2 90-3 90 (m,
10H),2 15 (s, 3H), 1 3(d), 1 27(d)
Compound 48 (S)-N-[3-(4-(3-Fluoro-4-( 1 '-tnfluoroacetamido-2',2',2'-tnchloroethyl)-3-methyl-1 -piperazinyl) phenyl)-2-oxo-5-oxazolidinyl) methyl]-tnfluoroacetamide
1HNMR (200MHz, CDCl3) δ 8 17 (s), 8 05 (s), 7 42 (dd, J=14Hz, J=2 6Hz, 1H), 7 07 (d, J=8Hz,
1H), 6 90 (t, J=9 1Hz, 1H), 4 83 (m), 4 68 (bm), 4 1 l(t, J=9Hz, 1H), 2 70-3 95 (m, 10H), 1 51(d),
1 41(d)
Compound 49 (S)-N-[3-(4-(3-Fluoro-4-(l'-formamido-2',2',2'-tnbromoethyl)-3-methyl-l-piperazinyl)phenyl)-2-oxo-5-oxazolidinyl) methyl]-tnfluoroacetamide
1HNMR (200MHz, CDCl3) δ 8 16 (s), 8 05 (s), 7 35-7 60 (m), 7 06 (d, J=8Hz, 1H), 6 90 (t,
J=9 1Hz, 1H), 4 85 (bm), 4 67 (bm), 4 1 l(t, J=9Hz, 1H), 2 70-3 90 (bm, 10H), 1 51 (d), 1 41(d)
Compound 50 (S)-N-[3-(4-(3-Fluoro-4-(l'-acetamido-2',2',2'-tnbromoethyl)-3-methyl-l-
piperazinyl)phenyl)-2-oxo-5-oxazohdinyl) methyl]-tnfluoroacetamide
1HNMR (200MHz, CDCl3) δ 7 70-7 85 (m, 1H), 7 43 (dd, J=14Hz, J=2 6Hz, 1H), 7 25 (m, 1H),
7 08 (m, 1H), 6 96 (t, J=9 1Hz, 1H), 5 53 (s), 4 85 (bm, 1H), 3 18-3 95 (bm, 11H), 2 19 (s, 3H),
1 51(d), 141(d)
Compound 51 (S)-N-[3-(4-(3-Fluoro-4-(1-tnchloroacetamido-2',2',2'-tnbromoethyl)-3-methyl-1-piperazinyl) phenyl)-2-oxo-5-oxazolidinyl) methylj-trifluoroacetamide
1HNMR (200MHz, CDCl3) δ 8 16 (s), 8 04 (s), 7 70 (bm, 1H), 7 41 (dd, J=14Hz, J=2 6Hz, 1H),
7 05 (d, J=8Hz, 1H), 6 90 (t, J=9 1Hz, 1H), 4 85 (bm), 4 66(bm), 4 1 l(t, J=9Hz, 1H), 3 15-3 90
(bm, 9H), 2 65-3 0 (bm, 3H), 1 51 (d), 1 41 (d)
Compound 52 (S)-N-[3-(4-(3-Fluoro-4-(l'-trifluoroacetamido-2',2',2'-tribromoethyl)-3-methyl-1 -piperazinyl) phenyl)-2-oxo-5-oxazolidinyl) methyl]-tnfluoroacetamide
1HNMR (200MHz, CDCI3-CD3OD) δ 7 30-7 50 (m, 2H), 6 90-7 15 (m, 2H), 4 84 (bm, 1H),
4 1 l(t, J=9Hz, 1H), 2 90-3 85 (m), 1 45 (d)
Compound 53 (S)-N-[3-(4-(3-Fluoro-4-(l'-formamido-2',2',2'-tnfluoroethyl)-3-methyl-l-piperazinyl) phenyl)-2-oxo-5-oxazohdinyl) methylj-trifluoroacetamide
1HNMR (200MHZ, CDCl3) δ 8 33(s), 8 23 (s), 8 17 (s), 7 35-7 45 (m, 1H), 6 85-7 05 (m, 2H),
5 74 (d), 5 53 (d), 4 81 (bm, 1H), 4 09 (t, J=9Hz, 1H), 3 55-3 85 (m, 3H), 2 70-3 35 (m, 8H),
1 27 (d), 1 25 (d)
Compound 54 (S)-N-[3-(4-(3-Fluoro-4-(1-acetamido-2',2',2'-trifluoroethyl)-3-methyl-l-piperazinyl)phenyl)-2-oxo-5-oxazolidmyl) methyl]-tnfIuoroacetamide
1HNMR (200MHz, CDCl3) δ 8 81(bs), 7 35 (dd, J=14Hz, J=2 6Hz, 1H), 7 04 (d, J=8Hz, 1H),
6 89 (t, J=9 1Hz, 1H), 5 10(d), 4 83 (bm, 1H), 4 08 (t, J=9Hz, 1H), 3 55-3 85 (m, 3H), 2 70-3 30
(m, 8H), 2 07 (s, 3H), 1 26 (d, 3H)
Pharmacological testing
Compounds disclosed herein displayed antimicrobial activity against multiply-resistant Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pneumonia, S pyogen, S bovis, S equi,S mutans, M catarrhahs, Enterococcus faecahs, Enterococcus faecmm, Enterococcus durans, Escherecia cob, Salmonella, K oxytosa, P aeruginosa, S marcescens, Acinetobacter, and the like These compounds are useful in the treatment of community acquired pneomoma, upper and lower respiratory tract infections, skin and soft tissue infections, hospital acquired lung infections, bone and joint infections, and other bacterial infections such as mastitis, catether infection, foreign body or prosthesis infections
During last five decades metals or plastics have been increasingly used for different types of devices More than 150 million intravascular catheters are purchased annually by clinics and hospitals in USA, including more than 5 million central venous and pulmonary artery catheters leading to at least 400,000 catheters related blood stream infections These increase the risk of morbidity (such as prolonged hospital stay) and deaths Mortality rates associated with catheter related blood stream infection range from 10-20% Food and Drug Administration (FDA Guidance for Industry, October 1999) Of all the problems associated with such implants, the most severe is infections The commonest microorganisms involved in such infections are
Staphylococcus aureus and S epidermidis Though microorganisms may be implicated Journal of Antimicrobial Chemotherapy (J AC 1993, 31 (SD) 97-102)
At the present time, there are no agents for this indication and the standard regimens includes removal of catheter Vancomycin is usually recommended in the hospital or countries with an increased incidence of MRSA, because of its activity against coagulase negative staphylococcus and S aureus Clinical Infectious Diseases (CID 2001, 32, 1249-1272)
S epidermidis is the causative agent in many incidents of infection of implanted medical device such as catheters, pacemakers, prosthetics joints, cardiac valves and central venous system shunts These infections often recur and tent to be difficult to treat with antibiotics agents Removal of the devices with concurrent administration of antibiotics is usually the only method of eradicating the focus of infections
The biofilm mode of growth is recognized as being of prime importance in the establishment and maintenance of bacterial population within a wide variety of natural habitats including colonization and infections of medical devices This to some extent protects the sessile population from any major fluctuations in the microenvironment from host defences and also from therapeutic effects of antibiotics Resistance of device associated infections has been attributed variously to failure of antibiotics, to penetrate the glycocalyix, show growth rate within nutrient deprived biofilms and/or to innate properties in adherent cells
In device related infections, the correlation between MIC levels and clinical efficacy is poor, leading to the dogma with infected implants have to be removed in order to achieve cure The main characteristics of such infections are the microbial adherence effected by the biofilm and the low growth rate of surface adherent microorganisms The discrepancy between the result of routine antibiotic susceptibility testing and treatment success in device related infections may therefore be due to the fact that bacterial biofilms have different resistant pattern compared with planktonIC bacterial It has been demonstrated that cure rate in experimental device related infections can be predicted by the in vitro bactericidal effect of antibiotics on non-growing and adherent bacteria
Minimum inhibitory concentration (MIC) has been an indicator of in vitro antibacterial activity widely used in the art
Procedure
Medium
a) Cation adjusted Mueller Hinton Agar (MHA-Difco)
b) Trypticase Soya Agar (TSA)
Inoculum preparation
The cultures were streaked on TSA for aerobic cultures and MHA with 5% sheep blood for
fastidious cultures Aerobic cultures were incubated at 37 °C for about 18-24 hours Fastidious
cultures were incubated CO2 incubation (5% CO2) at 37 °C for about 18-24 hours Three to four
well isolated colonies were taken and saline suspensions were prepared in sterile densimat tubes
The turbidity of the culture was adjusted to 0 5-0 7 Mc Farland standard (1 5 x 108 CFU/ml)
The cultures were diluted 10 fold in saline to get inoculum size of approximately 1-2 x 107
organisms/ml
Preparation of drug concentration
1 mg/ml concentration of stock solution of drugs was prepared in dimethylsulfoxide/distilled
water/solvent given in National Committee for Clinical Laboratory Standards (NCCLS) manual
Serial two fold dilutions of the compounds and standard drugs were prepared as per NCCLS
manual
Stock solution was changed according to the need of the experiment
Preparation of Agar Plates
Two ml of respective drug concentration was added to 18 ml of Molten Mueller Hinton agar to
get the required range, for example 0 015 ng/ml - 16 u.g/ml For fastidious cultures 1 ml of sheep
blood was added in Molten Mueller Hinton agar
For control MHA and MHA with 5% sheep blood plates without antibiotic for each set were
prepared One MHA and MHA with 5% sheep blood plate without antibiotic for determining
quality check for media was prepared
Preparation of Teflon template
1 µl of each culture on each plate was replicated with the help of replicator (Denley's multipoint
replicator) The spots were allowed to dry and the plates were incubated for about 18-24 hours at
37°C Fastidious cultures were incubated at 37 °C in CO2 incubator The results were noted
comparing with the control plates
Endpoint definition
The concentration of drug at which there was complete disappearance of growth spot or
formation of less than 10 colonies per spot was considered as Minimum Inhibitory Concentration
(MIC)
The MICs of Quality Control (QC) strains were plotted on the QC chart for agar dilution method
If the MICs were within the range, the results interpreted by comparing MICs of standards
against all organisms with those of test compounds
Precautions & Quality Control Measures Quality Control Strains Staphylococcus aureus ATCC 29213 Enterococcus faecahs ATCC 29212 Eschericia coh ATCC 25922 Pseudomonas aeruginosa ATCC 27853
All 60 cultures were visually checked for purity
Media Control NCCLS disc diffusion assay using 10u.g discs of Gentamicin (Difco) against
Pseudomonas aeruginosa ATCC 27853 A zone diameter of 16-21 mm was considered for
optimum cation (Magnesium and Calcium) content of the media The diameter was plotted in
the media QC chart
Results The compounds disclosed herein were found to be highly active against staphylococci, enterococci and S pneumoniae strains MIC of the disclosed compounds was 0 5-2 u.g/ml for staphylococci including methecin resistant Staphylococcus aureus (MRSAs), 1-2 jig/ml for enterococci including vancomycin resistant enterococci (VREs), 0 25-2 u.g/ml for S pneumoniae strains including DRSP (Drug resistant streptococcus pneumoniae) and 0 5-2 |ig/ml for S pyogenes
References
o National Committee for Clinical Laboratory Standards (NCCLS), Methods for Dilution
Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically - Fifth Edition,
Approved Standard M7-A5, Vol 20 No 2 (January 2000) o National Committee for Clinical Laboratory Standards, Performance Standards for
Antimicrobial Susceptibility Testing - Twelfth informational supplement, M 100-S12,
Vol 22 No 1 (January 2002).

WE CLAIMS :-
1 A compound having the structure of Formula I, as shown in the accompanied
drawings, and its pharmaceutical ly acceptable salts, pharmaceutically acceptable solvates, enantiomers, diasteromers, prodrugs, polymorphs, metabolites or N-oxide wherein R1 and R4 are independently selected from
• hydrogen and optionally substituted
• alkyl
• alkenyl
• alkynyl
• cycloalkyl wherein optional substituent is selected from
o halogen
o hydroxy o alkoxy
• optionally substituted aryl or heterocycle wherein optional substituent is
selected from the group comprising of
o halogen
o hydroxy
o mercapto
o alkoxy
o alkyl
o acyl
o acyloxy
o haloalkyl
o amino
o cyano
o nitro
o thio
o thioalkyl
R2 and R3 are independently selected from
• hydrogen
• halogen
• alkyl
• haloalkyl
U and V are independently selected from
• hydrogen
• alkyl
• haloalkyl X is halogen

2 A compound according to claim 1 wherein R1 is alkyl optionally substituted with halogen
3 A compound according to claim 1 wherein R1 is methyl
4 A compound according to claim 1 wherein R1 is trifluoromethyl
5 A compound according to claim 1 wherein R3 is halogen
6 A compound according to claim 1 wherein R3 is fluorine
7 A compound according to claim 1 wherein U is alkyl
8 A compound according to claim 1 wherein U is methyl
9 A compound according to claim 1 wherein X is halogen
10 A compound according to claim 1 wherein X is fluorine
11 A compound according to claim 1 wherein X is chlorine
12 A compound according to claim 1 wherein X is bromine
13 A compound according to claim 1 wherein R4 is alkyl optionally substituted with halogen
14 A compound according to claim 1 wherein R4 is methyl
15 A compound according to claim 1 wherein R4 is trifluoromethyl
16 A compound according to claim 1 wherein R4 is tnchloromethyl
17 A compound according to claim 1 wherein R4 is aryl optionally substituted with halogen
18 A compound according to claim 1 wherein R4 is phenyl
19 A compound according to claim 1 wherein R4 is 2,4-dichloro-5-fluoro phenyl
20 A compound which is
-N-((3-(4-(3-Fluoro-4(1-formamido-2',2',2'-tnchloroethyl)-l-piperazinyl)phenyl)-2-oxo-5-oxazolidinyl)methyl)-acetamide,
-N-((3-(4-(3-FIuoro-4(1-acetamido-2',2',2'-tnchloroethyl)-l-piperazinyl)phenyl)-2-oxo-5-oxazohdinyl)methyl)-acetamide,
- N-((3-(4-(3-Fluoro-4( 1 '-tnchloroacetamido-2',2',2'-tnchloroethyl)-1 -iperazmyl)phenyl)-
2-oxo-5-oxazolidinyl)methyl)-acetamide,
-N-((3-(4-(3-Fluoro-4(l'-tnfluoroacetamido-2',2',2-tnchloroethyl)-l-piperazinyl)phenyl)-2-oxo-5-oxazohdinyl)methyl)-acetamide,
-N-((3-(4-(3-Fluoro-4(l'-formamido-2',2,,2'-tnbromoethyl)-l-piperazinyl)phenyl)-2-oxo-5-oxazolidinyl)methyl)-acetamide,
-N-((3-(4-(3-Fluoro-4(1-acetamido-2',2',2'-tnbromoethyl)-l-piperazinyl)phenyl)-2-oxo-5-oxazohdinyl)methyl)-acetamide,
-N-((3-(4-(3-Fluoro-4(1-tnfluoroacetamido-2,,2',2'-tnbromoethyl)-l-iperazinyl)phenyl)-2-oxo-5-oxazolidinyl)methyl)-acetamide,
- N-((3-(4-(3-Fluoro-4( 1 '-benzamido-2',2',2'-tnchloroethyl)-1 -piperazinyl)phenyl)-2-oxo-
5-oxazolidinyl)methyl)-acetamide,
-N-((3-(4-(3-Fluoro-4(l'-2,4-dichloro-5-fluorobenzamido-2',2',2'-tnchloroethyl)-l-piperazinyl)phenyl)-2-oxo-5-oxazohdinyl)methyl)-acetamide,
-N-((3-(4-(3-Fluoro-4(1-benzamido-2',2',2'-tnbromoethyl)-l-piperazinyl)phenyl)-2-oxo-5-oxazolidinyl)methyl)-acetamide,
-N-((3-(4-(3-Fluoro-4(1-2,4-dichloro-5-fluorobenzamido-2',2',2'-tribromoethyl)-l-piperazinyl)phenyl)-2-oxo-5-oxazohdinyl)methyl)-acetamide,
-N-((3-(4-(3-Fluoro-4(l'-formamido-2',2,,2'-tnfluoroethyl)-l-piperazinyl)phenyl)-2-oxo-5-oxazohdinyl)methyl)-acetamide,
- (S)-N-((3-(4-(3-Fluoro-4( 1 '-formamido-2',2',2'-tnchloroethyl)-1 -piperazinyl)phenyl)-2-
oxo-5-oxazolidinyl)methyl)-acetamide,
-(S)-N-((3-(4-(3-Fluoro-4(1-acetamido-2',2',2'-tnchloroethyl)-l-piperazinyl)phenyl)-2-oxo-5-oxazolidinyl)methyl)-acetamide,
- (S)-N-((3-(4-(3-Fluoro-4( \ '-tnchloroacetamido-2',2',2'-tnchloroethyl)-1 -
piperazinyl)phenyl)-2-oxo-5-oxazohdinyl)methyl)-acetamide,
- (S)-N-((3-(4-(3-Fluoro-4( 1 '-tnfluoroacetamido-2',2',2'-tnchloroethyl)-1 -
piperazinyl)phenyl)-2-oxo-5-oxazohdinyl)methyl)-acetamide,
_(S)-N-((3-(4-(3-Fluoro-4(1-formamido-2',2',2'-tnbromoethyl)-l-piperazinyl)phenyl)-2-oxo-5-oxazolidinyl)methyl)-acetamide,
_(S)-N-((3-(4-(3-Fluoro-4(l,-facetamido-2',2',2,-tnbromoethyl)-l-piperazinyl)phenyl)-2-oxo-5-oxazolidinyl)methyl)-acetamide,
-(S)-N-((3-(4-(3-Fluoro-4(l'-tnchloroacetamido-2',2',2,-tribromoethyI)-l-piperazinyl)phenyl)-2-oxo-5-oxazohdinyl)methyI)-acetamide,
- (S)-N-((3-(4-(3-Fluoro-4( 1 '-tnfluoroacetamido-2',2',2'-tnbromoethyl)-1 -
piperazinyl)phenyl)-2-oxo-5-oxazolidinyl)methyl)-acetamide,
_(S)-N-((3-(4-(3-Fluoro-4(l'-formamido-2',2',2'-tnfluoroethyl)-l-piperazinyl)phenyl)-2-oxo-5-oxazolidinyl)methyl)-acetamide,
-(S)-N-((3-(4-(3-Fluoro-4(l'-acetamido-2',2',2,-tnfluoroethyl)-l-piperazinyl)phenyl)-2-oxo-5-oxazolidinyl)methyl)-acetamide,
- (S)-N-((3-(4-(3-Fluoro-4( 1 '-formamido-2',2',2'-tnchloroethyl)-1 -piperazinyl)phenyl)-2-oxo-5-oxazolidinyl)methyI)-tnfluoracetamide,
- (S)-N-((3-(4-(3-Fluoro-4( 1 '-acetamido-2',2',2'-tnchloroethyl)-1 -piperazmyl)phenyl)-2-oxo-5-oxazolidinyl)methyl)-tnfluoracetamide,
- (S)-N-((3-(4-(3-Fluoro-4( 1 '-tnchloroacetamido-2',2',2'-tnchloroethyl)-1 -piperazinyl)phenyl)-2-oxo-5-oxazolidinyl)methyl)-tnfluoroacetamide,
- (S)-N-((3-(4-(3-Fluoro-4( 1 '-tnfluoroacetamido-2',2',2'-trichloroethyl)-1 -piperazinyl)phenyl)-2-oxo-5-oxazolidinyl)methyl)-tnfluoroacetamide,
- (S)-N-((3-(4-(3-Fluoro-4( 1 '-formamido-2',2',2'-tnbromoethyl)-1 -piperazmyl)phenyl)-2-oxo-5-oxazolidinyl)methyl)-tnfluoroacetamide,
- (S)-N-((3-(4-(3-Fluoro-4( 1 '-acetamido-2',2',2'-tnbromoethyl)-1 -piperazinyl)phenyl)-2-oxo-5-oxazolidinyl)methyl)-tnfluoroacetamide,
-(S)-N-((3-(4-(3-Fluoro-4(l'-trichloroacetamido-2',2',2'-tnbromoethyl)-l-piperazinyl)phenyl)-2-oxo-5-oxazolidinyl)methyl)-tnfluoroacetamide,
-(S)-N-((3-(4-(3-Fluoro-4(1-tnfluoroacetamido-2',2',2'-tribromoethyl)-l-piperazinyl)phenyl)-2-oxo-5-oxazohdinyl)methyl)-tnfluoroacetamide,
-(S)-N-((3-(4-(3-Fluoro-4(1-formamido-2',2',2'-tnfluoroethyl)-l-piperazinyl)phenyl)-2-oxo-5-oxazolidinyl)methyl)-tnfluoroacetamide,
- (S)-N-((3-(4-(3-Fluoro-4( 1 '-acetamido-2',2',2'-tnfluoroethyl)-1 -piperazinyl)phenyl)-2-
oxo-5-oxazolidinyl)methyl)-tnfluoroacetamide,
-(S)-N-((3-(4-(3-Fluoro-4(l'-tnchloroacetamido-2,,2',2,-tnfluoroethyl)-l-piperazinyl)phenyl)-2-oxo-5-oxazohdinyl)methyl)-tnfluoroacetamide,
-(S)-N-{[3-(3-Fluoro-4-(l'-formamido-2',2',2'-trichloroethyl)-3-methyl-l-piperazinyl) phenyl)-2-oxo-5-oxazohdinyl)methyl]-acetamide},
-(S)-N-{[3-(4-(3-Fluoro-4-(l'-acetamido-2',2',2'-trichloroethyl)-3-methyl-l-piperazinyl) phenyl)-2-oxo-5-oxazolidinyI) methyl]-acetamide,
-(S)-N-{[3-(4-(3-Fluoro-4-(l'-trichloroacetamido-2',2',2'-tnchloroethyl)-3-methyl-l-piperazinyl) phenyl)-2-oxo-5-oxazolidinyl) methyl]-acetamide,
-(S)-N-{[3-(4-(3-Fluoro-4-(l'-tnfluoroacetamido-2',2',2'-tnchloroethyl)-3-methyl-l-piperazinyl) phenyl)-2-oxo-5-oxazolidinyl) methyl]-acetamide,
- (S)-N-{[3-(4-(3-Fluoro-4-( 1 '-formamido-2',2',2'-tribromoethyl)-3-methyl-1 -piperazinyl) phenyl)-2-oxo-5-oxazolidinyl) methyl]-acetamide,
- (S)-N-{ [3-(4-(3-Fluoro-4-( 1 '-acetamido-2',2',2'-tnbromoethyl)-3-methyl-1 -piperazinyl) phenyl)-2-oxo-5-oxazolidinyl) methyl]-acetamide,
- (S)-N-{ [3-(4-(3-Fluoro-4-( 1 '-tnchloroacetamido-2',2',2'-tribrornoethyl)-3-methyl-1 -piperazinyl) phenyl)-2-oxo-5-oxazohdinyl) methyl]-acetamide,
- (S)-N-{ [3-(4-(3-Fluoro-4-( 1 ,-trifluoroacetamido-2',2',2'-tnbromoethyl)-3-methyl-1 -piperazinyl) phenyl)-2-oxo-5-oxazolidinyl) methyl]-acetamide,
-(S)-N-{[3-(4-(3-Fluoro-4-(1-formamido-2',2',2'-trifluoroethyl)-3-methyl-l-piperazinyl; phenyl)-2-oxo-5-oxazolidinyl) methyl]-acetamide,
-(S)-N-{[3-(4-(3-Fluoro-4-(1-acetamido-2',2,,2'-tnfluorethyl)-3-methyl-l-piperazinyl) phenyl)-2-oxo-5-oxazolidinyl) methylj-acetamide,
- (S)-N-{ [3-(4-(3-Fluoro-4-( 1 '-tnchloroacetamido-2',2',2'-trifluoroethyl)-3-methyl-1 -
piperazinyl) phenyl)-2-oxo-5-oxazohdinyl) methyl]-acetamide,
-(S)-N-{[3-(4-(3-Fluoro-4-(l'-formamaido-2',2',2'-tricholroethyl)-3-methyl-l-piperazinyl) phenyl)-2-oxo-5-oxazolidinyl) methyl]-tnfluoroacetamide,
-(S)-N-{[3-(4-(3-Fluoro-4-(1-acetamido-2',2,,2'-tnchloroethyl)-3-methyl-l-piperazinyl) phenyl)-2-oxo-5-oxazolidinyl) methyl]-trifluoroacetamide,
- (S)-N-{ [3-(4-(3-Fluoro-4-( 1 '-trichloroacetamido-2',2',2'-tnchloroethyl)-3-methyl-1 -
piperazinyl) phenyl)-2-oxo-5-oxazolidinyl) methyl]-tnfluoroacetamide,
-(S)-N-{[3-(4-(3-Fluoro-4-(1-tnfluoroacetamido-2',2',2'-tnchloroethyl)-3-methyl-l-piperazinyl) phenyl)-2-oxo-5-oxazolidinyl) methyI]-tnfluoroacetamide,
-(S)-N-{[3-(4-(3-Fluoro-4-(1-formamido-2',2',2'-tnbromoethyl)-3-methyl-l-piperazinyl) phenyl)-2-oxo-5-oxazohdinyl) methyl]-tnfluoroacetamide,
-(S)-N-{[3-(4-(3-Fluoro-4-(l'-acetamido-2',2',2'-tnbromoethyl)-3-methyl-l-piperazinyl) phenyl)-2-oxo-5-oxazolidinyl) methylj-tnfluoroacetamide,
_(S)-N-{[3-(4-(3-Fluoro-4-(l'-tnchloroacetamido-2',2',2'-tnbromoethyl)-3-methyl-l-piperazinyl) phenyl)-2-oxo-5-oxazohdinyl) methyl]-tnfluoroacetamide,
-(S)-N-{[3-(4-(3-Fluoro-4-(1-trifluoroacetamido-2',2',2'-tnbromoethyl)-3-methyl-l-piperazinyl) phenyl)-2-oxo-5-oxazohdinyl) methyl]-trifluoroacetamide,
-(S)-N-{[3-(4-(3-Fluoro-4-(1-formamido-2',2',2'-trifluoroethyl)-3-methyl-l -piperazinyl) phenyl)-2-oxo-5-oxazohdinyl) methyl]-tnfluoroacetamide or
- (S)-N-{ [3-(4-(3-Fluoro-4-( 1 '-acetamido-2',2',2'-tnfluoroethyl)-3-methyl-1 -piperazinyl)
phenyl)-2-oxo-5-oxazolidinyl) methyl]-tnfluoroacetamide,
pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers, N-oxides, prodrugs, polymorphs and metabolites thereof
21 A pharmaceutical composition comprising a therapeutically effective amount of a compound of any of the preceding claims together with pharmaceutically acceptable carrier, excipients or diluents
22 A method for treating or preventing a mammal suffering from a condition caused by or contributed to by bacterial infection, comprising administering to the said subject, a therapeutically effective amount of a compound of any one of the claims 1 to 20
23 A method for treating or preventing a mammal suffering from a condition caused by or contributed to by bacterial infection, comprising administering to the said subject, a therapeutically effective amount of a pharmaceutical composition of claim 21.
24 The method according to claim 22 or 23 wherein said condition is selected from the group consisting of community acquired pneumonia, upper and lower respiratory tract infections, skin and soft tissue infections, bone and joint infections, hospital acquired lung infections, mastitis, catheter infection and foreign body or prosthesis infections
25 The method according to claim 24 wherein said condition is catheter infection
26 The method according to claim 22 or 23 wherein said bacterium is gram-positive or gram-negative
27 The method according to claim 26 wherein gram-positive or gram-negative bacterium is selected from the group comprising of Staphylococci, Streptococci, Enterococci, Bactenoides spp, Clostridia spp, Mycobacterium spp , Bacillus spp, Corynebacterium spp, Clostridia spp , Peptostreptococcus spp , Listeria spp , Legionella spp , Haemophilus influenza, Moraxella, Escherecia faecahs andEscherecia coll
28 The method according to claim 27 wherein said bacterium is a gram-positive coccus
29 The method according to claim 28 wherein gram-positive coccus is drug-resistant
30 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, diasteromers, prodrugs, polymorphs, metabolites or N-oxide, wherein R1 and R4 are independently selected from
• hydrogen and optionally substituted
• alky!
• alkenyl
• alkynyl
• cycloalkyi wherein optional substituent is selected from
o halogen o hydroxy o alkoxy
• optionally substituted aryl or heterocycle wherein optional substituent is
selected from the group comprising of
o halogen o hydroxy o mercapto o alkoxy o alkyl o acyl o acyloxy o haloalkyl o amino o cyano o nitro o thio o thioalkyl R2 and R3 are independently selected from
• hydrogen
• halogen
• alkyl
• haloalkyl
U and V are independently selected from
• hydrogen
• alkyl
• haloalkyl X is halogen,
which method comprises reacting a compound of Formula II with a compound of Formula III, to give a compound of Formula IV (wherein R1, R2, R3, R4, U, V and X are the same as defined earlier) as shown in Scheme I of the accompanied drawings
31. A process according to claim 30 wherein the reaction of a compound of Formula
II with a compound of Formula III to give a compound of Formula IV is carried
out in a suitable solvent selected from the group comprising of dichloromethane,
chloroform and dichloroethane
32 A process according to claim 30 wherein the reaction of a compound of Formula II with a compound of Formula III is carried out in the presence of an organic base selected from the group comprising of tnethylamine, pyridine and dnsopropylamine
33 A process for the preparation of compound of Formula VI, as shown in Scheme II of the accompanied drawings and its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diasteromers, prodrugs, polymorphs, metabolite or N-oxide wherein
Ri and R4 are independently selected from
• hydrogen and optionally substituted
• alkyl
• alkenyl
• alkynyl
• cycloalkyl wherein optional substituent is selected from
o halogen
o hydroxy
o alkoxy optionally substituted aryl or heterocycle wherein optional substituent is selected from the group comprising of
o halogen
o hydroxy
o mercapto
o alkoxy
o alkyl
o acyl
o acyloxy
o haloalkyl
o amino
o cyano
o nitro
o thio
o thioalkyl R2 and R3 are independently selected from
• hydrogen
• halogen
• alkyl
• haloalkyl
U and V are independently selected from
• hydrogen
• alkyl
• haloalkyl X is halogen,
which method comprises reacting a compound of Formula V with a compound of Formula III, to give a compound of Formula VI (wherein R1, R2, R3, R4, U, V and
X are the same as defined earlier) as shown in Scheme II of the accompanied drawings
34 A process according to claim 33 wherein the reaction of a compound of Formula
V with a compound of Formula III to give a compound of Formula VI is carried
out in a suitable solvent selected from the group comprising of dichloromethane,
chloroform and dichloroethane
35 A process according to claim 33 wherein the reaction of a compound of Formula
V with a compound of Formula III is carried out in the presence of an organic
base selected from the group comprising of triethylamine, pyridine and
dusopropylamine
36 The processes for the preparation of compounds of Formulae IV and VI,
substantially as herein described and illustrated by example herein.