Specification
NOVEL OXAZOLIDINONE COMPOUNDS AS ANTIINFECTIVE AGENTS
CROSS-REFERENCE TO RELATED APPLICATIONS
j The present application is a Patent Cooperation Treaty application and claims the benefit
'of U.S. Provisional Application No. 60/872,640, filed December 4, 2006, which is relied on herein and incorporated herein by reference in its entirety.
FIELD OF THE INVENTION
The present invention relates to novel oxazolidinone compounds with antibacterial .[activity, their stereoisomers, their prodrugs, their pharmaceutically acceptable salts thereof. The ipresent invention also provides, pharmaceutical compositions comprising the compound of formula (I) and their use as therapeutic agents
BACKGROUND OF THE INVENTION
In general, bacterial pathogens may be classified as either Gram-positive or Gram-negative pathogens. Antibiotic compounds with effective activity against both Gram-positive (and Gram-negative pathogens are generally regarded as having a broad spectrum of activity.
Gram-positive pathogens, for example, Staphylococci, Enterococci, Streptococci and
Mycobacteria, are of interest because of the development of resistant strains, which are both
difficult to treat and difficult to eradicate from the hospital environment once established.
Examples of these resistant strains are methicillin resistant staphylococcus (MRS), methicillin
.resistant coagulase negative slaphylococci (MRCNS), penicillin resistant Streptococcus
i
ipneumomae (PRSP), and multi-drug resistant Enterococcus faecium (MREF). Further, resistant
!
Strains of Gram-negative such as H. influenzae and M. catarrhalis have been identified (F.D.
Lowry, "Antimicrobial Resistance: The Example oiStaphylococcus aureus,'' Clin. Invest., 2003
111(9), 1265-1273).
The escalation of resistance to antibiotics once usefij! for treatment of bacterial infections , resulting from such pathogens is problematic in the United States and Europe (Drugs Exp. Clin. IJRes. 1994, XX, 215-224; Am. i. Surg. 1995, .5A (Suppl.). SS-12S; Drug.s, 1994, 48, 678-688; 'and Current Pharmaceutical Design, 1996, Vol.2, No.2, ppl75-l94). At present, the major
clinical effective antibiotic for treatment of such resistant Gram-positive pathogens is
vancomycin, a glycopeptide. However, antibacterial resistance to vancomycin and other gJ,ycopeptides is also emerging and escalating. Thus, the development of new synthetic and semi-synthetic antibacterial compounds effective against resistanct bacteria is the subject of constant current research.
One class of synthetic compounds that have been developed is the oxazolidinone compounds, exemplified by eperezoid and linezolid, which constitute a class of orally-active, synthetic antibacterial agents. OxazoUdinones are a new class of synthetic antimicrobial agents which kill gram positive pathogens by inhibiting a very early stage of protein synthesis. Oxazolidinones inhibit the formation of the ribosomal initiation complex involving 30S and SOS ribosomes leading to the prevention of initiation complex formation. Due to their mechanism of action, these compounds are active against pathogens resistant to other clinically useful antibiotics.
WO 95/07271 (Barbachyn et al.) describes oxazine and thiazine oxazolidinone derivatives such as linezolid and its analog, which are useful antimicrobial agents and are , effective against a number of human and veterinary pathogens, including gram-positive aerobic bacteria such as multiple drug-resistant staphylococci, streptococci and enterococci as well as anaerobic organisms such as Bacteroides spp. and Clostridia spp. species, and acid-fast organisms such as Mycobacterium tuberculosis, Mycobacterium avium and Mycobacterium spp.
Ij U.S. Pat. No. 5,792,765 to Riedl et al. describes a series of substituted oxazolidinones (cyanoguanidine, cyanoamidines, and amidines) useful as antibacterial medicaments. U.S. Pat. No. 5,910,504 to Hutchinson describes a series of heteroaromatic ring substituted phenyl oxazolidinones. WO 98/54161 (Hester et al.) describes amides, thioamides, ureas, and thioureas which are antibacterial agents. U.S. Pat. No. 5,880,118 describes substituted oxazine and thiazine oxazolidinone antimicrobials. U.S. Pat. No. 6,968,962 describes phenyloxazoiidinones having a C--C bond to 4-8 membered heterocyclic rings. U.S. Pat. No, 5,981,528 describes antibiotic oxazolidinone derivatives. U.S. Pat. No. 5,254,577 describes nitrogen heteroaromatic rings attached to phenyloxazolidinone. U.S. Pat Nos. 5,547,950 and 5,700,799 also describe the phenyl piperazinyl oxazolidinones.
j PCT patent application, Ser. No. PCT/USOO/28872 describes mixtures of linezolid and
other antibacterial agents. The PCT Publication W093/23384 describes phenyloxazoiidinones containing a substituted diazine moiety and their uses as antimicrobials. WO93/09103 describes
suustituted aryi and heteroaryl-phenyioxazolidinones useful as antibacterial agents. WO90/02744 describes 5-indoiinyl-5P-amidomethyloxa2olidinones, 3-(fused ring substituted) phenyNSp-amidomethyioxazolidinones, which are usefii! as antibacterial agents. European Patent Publication 352,781 describes phenyl and pyridyl substituted phenyl oxazolidinones. European Patent Application 312,000 describes phenylmethyl and pyridinylmethyl substituted phenyl oxazolidinones.
Other references describing various phenyloxazolidinones include U.S. Pat Nos. 4,801,600and4,921,869;Gregory W. A., etal., J. Med. Chem.. 32, 1673-81 (1989); Gregory W. A., et al., J. Med Chem., 33, 2569-78 (1990); Wang C, et al., Tetrahedron, 45, 1323-26 (1989); Brittelli, et al., J. Med. Chem., 35, 1156 (1992); and Bio-organic and Medicinal Chemistry Letters, 9, pp. 2679-2684, 1999.
SUMMARY OF THE INVENTION
The present inventors have discovered a class of antibiotic compounds containing an oxazolidinone ring which has useful activity against Gram-positive and Gram-negative pathogens, including MRSA and MRCNS.
Accordingly, the present invention describes an oxazolidinone derivative having antibiotic activity, which is a compound and/or a pharmaceutically acceptable salt and/or a stereoisomer of said compound, wherein said compound has the formula (I)
R4 O
R3-A-R2-/ ^>—N
R
(I)
wherein:
R, is selected from hydroxy, amino, azido, Ci-Cg alkyl, Ci-Ca alkoxy, NHC(=Z)R. wherein Z is 0 or S, and R is hydrogen or optionally substituted alkyl, alkoxy, cycloalky) or
cycloalkoxy;
i R2 is a five-membered heterocyclic aromatic moiety containing one to three atoms
If
selected from N, O and S;
; A is-{CHR\, wherein R^ represents hydrogen or hydroxy!, n represents 1-5;
R3 is an optionally substituted five or six membered heteroaryl, having at least one nitrogen atom;
n represents 1-5;
R4 and R5 are independently selected from hydrogen or fluoro;
with the proviso that when R, is NHC(^0)CH3, and R2 is imidazole, R3 is not a substituted triazole; i and including the stereoisomers, prodrugs, and pharmaceulically acceptable salts thereof
In further aspects of the present invention, the optional substituents on R include halogen, cyano, amino or hydroxyl.
In still flither aspects of the present invention, the optional substituents on R3 include hydrogen^ halogen, cyano, hydroxy alkyl, haloalkyl or alkoxy.
The present invention further provides prodrugs of a compound having the formula (I) and methods of preparing prodrugs of a compound having the formula (I).
In accordance with other aspects, the present invention also provides a method of producing antibiotic activity against pathogens in a subject, said method comprising administering to said subject an effective amount of an oxazolidinone derivative of formula (I).
The present invention also provides a method of treating a bacteria! infection in a subject, said method comprising administering to said subject an effective amount of an oxazolidinone derivative of formula (I).
The present invention ftirther provides pharmacentical compositions comprising
oxazolidinone derivatives of formula (I) and one or more pharmaceutically-acceptable
1! . . excipients.
DETAILED DESCRIPTION OF THE INVENTION
To describe the invention, certain terms are defined herein as follows.
The use of singular includes the use of plural. In a non-limiting example, a recitation of "a derivative" includes a single derivative, as well as multiple derivatives.
Unless defined otherwise, all technical and scientific terms used herein have the same mpanino as nnrnmnnlv understood to one of ordinary skill in the art to which this invention
belongs. Although any methods, devices, and materials similar or equivalent to those described herein can be used in the practice or testing of the invention, the preferred methods, devices and materials are now described.
The ferm "compound" is used to denote a molecular moiety of unique, identifiable chemical structure. A molecular moiety ("compound") may exist in a free species form, in which it is not associated with other molecules. A compound may also exist as part of a larger aggregate, in which it is associated with other molecule(s), but nevertheless retains its chemical identity. A solvate, in which the molecular moiety of defined chemical structure ("compound") is associated with a molecule(s) of a solvent, is an example of such an associated form. A hydrate is a solvate in which the associated solvent is water. The recitation of a "compound" refers to the molecular moiety itself (of the recited structure), regardless whether it exists in a free form or and an associated forms.
The term "stereoisomers" is used to refer to both optical isomers and geometrical isomers. A recitation of the chemical structure of the compound encompasses all structural variations possible within the structure as shovm.
Thus, some of the described compounds have optical centers. If the optical configuration at a given optical center is not defined with specificity, the recitation of chemical structure covers all optical isomers produced by possible configurations at the optical center. The term "optical isomer" defines a compound having a defined optical configuration at least one optical center. This principle applies for each structural genus described herein, as well as for each subgenus and for individual structures. For example, the recitation of a molecular portion as
O
•0
' ' " -R-
encompasses optical isomers with R and S configurations at the optical center (which arises when R' and R^ are not identical):
■l-N
For the purpose of additional illustration, the recitation "a compound of the structure", for example:
generically encompasses
both enantiomers individually, such as:
K O
, as well
as the racemic mixture thereof
The individual optica! isomers may be obtained by using reagents in such a way to obtain
single isomeric form in the process wherever applicable or by conducting the reaction in the
presence of reagents or catalysts in their single enantiomeric form. Some of the preferred
rnethods of resolution of racemic compounds include use of microbial resolution, resolving the
diastereomeric salts, amides or esters formed with chiral acids such as mandelic acid,
camphorsulfonic acid, tartaric acid, lactic acid, and the like, wherever applicable or chiral bases
such as brucine, cinchona alkaloids and their derivatives, and the like. Commonly used methods
are compiled by Jaques et al. in "Enantiomers, Racemates and Resolution" (Wiley Interscience, IP 1981). Where appropriate the compounds of formula (I) may be resolved by treating with chiral
amines, aminoacids, aminoalcohols derived from aminoacids; conventional reaction conditions
may be employed to convert acid into an amide; the diastereomers may be separated either by
fractional crystallization or chromatography and the stereoisomers of compound of formula (I)
may be prepared by hydrolyzing the pure diastereomeric amide, ester or salt.
Some of the described compounds may exist as geometrical isomers (e.g., (E), (Z), etc.). if the geometrical configuration is not self-evident from the structure shown, the recitation of the structure genericaliy covers all possible geometrical isomers. This principle applies for each structural genus described herein, as well as for each subgenus and for individual structures.
The compounds of formula (I) described herein may form salts and thus, can be administered lo a subject in the sah form. The term "derivative" is used as a common term for the compound and its salts. Thus, the claim language "a derivative, which is a compound and/or
a pharmaceutically-acceptable salt of said compound" is used to define a genus that includes any form of the compound of the given chemical structure and the salts of the recited compound. The use of the term "and/or" is intended to indicate that, for.a compound of a given chemical structure, a claim to a "derivative" covers the compound individually, all of its salts individually, and the mixtures of compounds and the salt(s). The term "pharmaceutically-acceptable salts" is intended to denote salts that are suitable for use in human or animal pharmaceutical products. The use of the term "pharmaceutically-acceptable" is not intended to limit the claims to substances ("derivatives") found only outside of the body.
A "composition" may contain one compound or a mixture of compounds. A "pharmaceutical composition" is any composition useful or potentially useful in producing physiological response in a subject to which such pharmaceutical composition is administered, fhe term "pharmaceutically acceptable," with respect to an excipient, is used to define non-toxic substances generally suitable for use in human or animal pharmaceutical products.
As used herein, the term "alkyl," is intended to include both branched and straight-chain saturated or unsaturated aliphatic hydrocarbon groups having a specified number of carbon atoms. Preferably the alkyl groups of the invention have from 1 to 10 carbon atoms. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkyl chain. Non-limiting examples of suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyi, and t-butyl. Exemplary 'alkyl' groups include methyl, ethyl, propyl, isopropyl and the like.
As used herein, the term "cycloalkyl," is intended to include non-aromatic mono- or multicyclic ring systems comprising about 3 to about 10 carbon atoms. Exemplary cycloaikyi' groups, include cyclopropyl, cyclobutyl, cyclopentyl, and the like.
I As used herein, the term "alkoxy," is intended to mean a chain of carbon atoms bonded to ail oxygen atom and is defined as 'alkyl-0-', wherein the alkyl group is as defined above. The chains of carbon atoms of the alkoxy groups described and claimed herein are saturated, may be straight chain or branched. Exemplary 'alkoxy' groups include methoxy, ethoxy, propoxy, isopropoxy and the like.
As used herein, the term "cycioaikoxy" is intended to mean "cycioaiky]-0-*', wherein alkyl group is as defined as above. Exemplary 'cycloalkoxy' group includes cyclopropoxy, cyclobutoxy, cyclopentoxy and the like.
I As used herein, a "five or six membered heteroaryl" means an aromatic monocyclic ring system comprising about 3 to about 10 ring atoms, preferably about 3 to about 6 atoms, in which one or more of the ring atoms is an element other than carbon, for example O, S or N alone or in combination. The heteroaryl may be optionally substituted by replacing an available hydrogen on the ring by one or more substituents, which may be Ihe same or different. The prefix aza, oxa or thia before the heteroaryl root name means that at least a nitrogen, oxygen or sulfur atom respectively, is present as a ring atom. Exemplary five membered heteroaryl groups include pyrrole, imidazole, triazole ([l,2,3]tria2ole and [l,2,4]triazo]e, [],3,4]lria2ole), thiazole, oxazole, isboxazole, pyrazole, [l,2,4]oxadia2ole & [1,3,4], [l,3,4]thiadia2ole, and the like. Exemplary six membered heteroaryl groups include pyridine, pyrimidine, and the like.
The term "substituted", as used herein, means that one or more hydrogens on the designated atom are replaced with a selection from the indicated groups, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound.
The terms "individual," "subject," and "patient" refer to any subject for whom diagnosis, treatment, or therapy is desired. In one embodiment, the individual, subject, or patient is a human. Other subjects may include animals including, but not limited to cattle, sheep, horses, dogs, cats, guinea pigs, rabbits, rats, primates, opossums and mice.
ii The terms "treatment," "treating," "treat," and the like are used herein to refer generally
to obtaining a desired pharmacological and/or physiological effect. The effect may be prophylactic in terms of completely or partially preventing a disease or symptom thereof and/or may be therapeutic in terms of a partial or complete stabilization or cure for a disease and/or adverse effect attributable to the disease. "Treatment" as used herein covers any treatment of a disease in a subject, particularly a human, and includes: (a) preventing the disease or symptom from occurring in a subject which may be predisposed to the disease or symptom, but has not yet been diagnosed as having it; (b) inhibiting the disease symptom, i.e., arresting its development; oi" (c) relieving the disease symptom, i.e., causing regression of the disease or symptom.
The term "prodrug" is used to refer to a compound (and/or its salt) capable of converting, either directly or indirectly, into compounds described herein by the action of enzymes, gastric acid and the like under in vivo physiological conditions {e.g., enzymatic oxidation, reduction and/or hydrolysis). Prodrugs of the present application may be prepared from compound having the formula (I) in a known manner. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in DESIGN OF PRODRUGS (1985); Wihnan, 14 BIOCHEM. SOC. TRANS. 375-82 (1986); STELLA ET AL„ Prodrugs: A Chemical Approach to Targeted Drug Delivery in DIRECTED DRUG DELIVERY 247-67 (1985), each of which is incorporated by reference herein in its entirety.
The term "therapeutically effective amount" shall mean that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, .system or patient that is being sought.
One embodiment of the present invention provides an oxazolidinone derivative, which is a compound and/or a pharmaceutical J y acceptable salt and/or a stereoisomer of said compound, wherein said compound has the formula (I)
wherein:
Ri is selected from hydroxy, amino, azido, Ci-Cs alkyl, Ci-Cs aikoxy, NHC(=Z)R. wherein Z is O or S, and R is hydrogen or optionally substituted alkyl, aikoxy, cycloalkyi or cycloalkoxy;
R2 is a five-membered heterocyclic aromatic moiety containing one to three atoms selected from N, O and S;
A is-(CHRV wherein R^represents hydrogen or hydroxyl, n represents 1-5;
R3 is an optionally substituted five or six membered heteroaryl, having at least one nitrogen atom;
n represents 1-5;
R4 and R5 are independently selected from hydrogen or fluoro;
with the proviso that when R, is NHC(=0)CH3, and R2 is imidazole, R3 is not a substituted triazole;
and incJuding (he stereoisomers, prodrugs, and pharmaceuticaily acceptable salts thereof.
One aspect (Aspect-I) of the present invention provides a compound of formula (I), wherein -R3-A-R2- represents:
N
R3 "o' ' , R
N-N N-Q
According to the above aspect, the present invention provides compound of formula (I) (Aspect-U), wherein R3 represents optionally substituted heteroaryl rings selected from
N
According to the above Aspecl-1 and Aspect-ll, the present invention provides compounds of formula (1), wherein Ri represents -NHC(=0)R, and wherein R represents optionally substituted alkyl or cycloalkyl.
According to the above Aspect-I and Aspect-II, the present invention provides compounds of formula (1), where Rj represents -NHC(=0)R, wherein R represents optionally substituted alkoxy or cycloaikoxy.
According to the above Aspect-! and Aspect-Il, the present invention provides compounds of formula (1), where Ri represents -NHC(=S)R, wherein R represents optionally substituted alkyl or cycloalkyl.
According to the above Aspect-I and Aspect-II, the present invention provides compounds of formula (I), where Ri represents -NHC(=S)R, wherein R represents optionally substituted alkoxy or cycloaikoxy.
Another aspect of the present invention provides a compound of formula (II),
ai)
wherein R, and R3 are as defined for formula (I).
Another aspect of the present invention provides a compound of formula (II), wherein R3 represents optionally substituted;
N^ i or V-^r
Another aspect of the present invention provides a compound of formula (III),
ail)
wherein K\ and R3 are as defined for formula (I).
Another aspect of the present invention provides a comound of formula (III), wherein R3 represents optionally substituted:
I Another aspect of the present invention provides a compound of formula (IV),
av)
wherein R| and R3 are as defined for formula (I).
Another aspect of the present invention provides a comound of formula (IV), wherein R3 represents optionally substituted:
,^=r% ■
Another aspect of the present invention provides a compound of formula (V),
a, o
wherein Ri and R3 are as defined for formula (I).
Another aspect of the present invention provides a comound of formula (V), wherein R3 represents optionally substituted:
/=N ^N, f^::::,^
Another aspect of the present invention provides a compound of formula (VI),
R4 0
Ra'^^
^5 '
(VI)
erein R| and R3 are as defined for formula (I).
Another aspect of the present invention provides a comound of formula (VI), wherein R3 represents optionally substituted
]j Another aspect of the present invention provides a compound of formula (VU),
(VII)
wherein Ri and R3 are as defined for formula (I).
Another aspect of the present invention provides a comound of formula (VII), wherein R3 represents optionally substituted:
cv.r>i-.c:H,CK:>^c>-i.t:v
r»t f^ fV
N-V'. K^A " ' "
N..
Another aspect of the present invention provides a compound of formula (VHI),
wherein R| and R3 are as defined for formula (I).
Another aspect of the present invention provides a compound of formula (VIII), wherein. R3 represents optionally substituted;
ti^Ni-^ ^VF, l^^^ " 1 °' Another aspect of the present invention provides a compound of formula (IX),
^^
wherein Ri and R3 are as defined for formula (I).
Another aspect of the present invention provides a comound of formula (IX), wherein R3 represents optionally substituted:
Another aspect of the present invention provides a compound of formula (X),
wherein Ri and R3 are as defined for formula (1).
Another aspect of the present invention provides a compound of formula {X), wherein R3 represents optionally substituted
(\ rY
N*=^ i '^/■.- K^
or
nother aspect of the present invention provides a compound of formula (XI),
R4
wherein Rj and R3 are as defined for formula (I).
Another aspect of the pregent invention provides a compound of formula (XI), wherein R3 represents optionally substituted:
' Another aspect of the present invention provides a compound of formula (t), having a basic salt chosen from the salts of Li, Na, K, Ca, Mg, Fe, Cu, Zn, Mn and Al; salts of organic bases; salts of natural amino acids; salts of guanidine; and salts of ammonium.
In another embodiment of the present invention, the compound of formula (I) can be provided along with a "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient", both of which are used interchangeably herein, to form a pharmaceutical composition.
Another aspect of the present invention provides for prodrugs of the compounds of formula (I), including, for example, the following:
STRUCTURES
N^\ /^N
N=U
a
NV
N O O
U U /v
o o
NH^.HCL
'>=. V, Y
O-X'-^-^YYV--
o ' 6
O 6
o I li
o o
N-^\ y>^N
r-
o o
=\ K
o
o.
0 0.
o ' 6
NH^.HCI
Another aspect of the present invention provides a method of producing antibacterial ctivity against pathogens in a subject, said method comprising administering to said subject an ffective amount of an oxazolodinone derivative of formula (I), in one variant of this aspect, the athogen is a Gram positive pathogen. In another variant of this aspect, the pathogen is a Gram egative pathogen. In another variant of this aspect, the pathogen is an antibiotic-resistant Gram ositive pathogen. In another variant of this aspect, the pathogen is an antibiotic-resistant Gram legative pathogen.
Another aspect of the present invention provides a method of producing antibacterial
.ctivity against pathogens in a subject, said method comprising administering to said subject an I :ffective amount of an oxazoiidinone derivative of formula (TI).
Another aspect of the present invention provides a method of producing antibacterial ictivity against pathogens in a subject, said method comprising administering to said subject an iffective amount of an oxazoiidinone derivative of formula (111).
Another aspect of the present invention provides a method of producing antibacterial ictivity against pathogens in a subject, said method comprising administering to said subject an effective amount of an oxazoiidinone derivative of formula (IV).
Another aspect of the present invention provides a method of producing antibacterial ictivity against pathogens in a subject, said method comprising administering to said subject an effective amount of an oxazoiidinone derivative of formula (V).
Another aspect of the present invention provides a method of producing antibacterial aptivity against pathogens in a subject, said method comprising administering to said subject an effective amount of an oxazolidinone derivative of formuia (VI).
Another aspect of the present invention provides a method of producing antibacterial activity against pathogens in a subject, said method comprising administering to said subject an effective amount of an oxazolidinone derivative of formula (VII).
Another aspect of the present invention provides a method of producing antibacterial activity against pathogens in a subject, said method comprising administering to said subject an effective amount of an oxazolidinone derivative of formula (VIII).
Another aspect of the present invention provides a method of producing antibacterial
activity against pathogens in a subject, said method comprising administering to said subject an
il effective amount of an oxazolidinone derivative of formula (IX).
Another aspect of the present invention provides a method of producing antibacterial activity against pathogens in a subject, said method comprising administering to said subject an effective amount of an oxazolidinone derivative of formula (X).
Another aspect of the present invention provides a method of producing antibacterial activity against pathogens in a subject, said method comprising administering to said subject an effective amount of an oxazolidinone derivative of formula (XI).
, Another aspect of the present invention provides a pharmaceutical composition
comprising an oxazolidinone derivative of formula (I) and one or more pharmaceulically-acceptable excipients.
Another aspect of the present invention provides a pharmaceutical composition comprising an oxazolidinone derivative of formula (II) and one or more pharmaceutically-acceptable excipients.
Another aspect of the present invention provides a pharmaceutical composition
comprising an oxazolidinone derivative of formula (III) and one or more pharmaceutically-
acceptable excipients.
ij Another aspect of the present invention provides a pharmaceutical composition
comprising an oxazolidinone derivative of formula (IV) and one or more pharmaceutically-acceptable excipients.
appropriate materials. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds. All temperatures are in degrees Celsius unless otherwise noted.
In another aspect, the compounds of the present invention have a chiral centre at the C5-pdsition, which have the formula (lA)
(lA)
\===/ >—^^;^^Ki
R5
The present invention includes the pure enantiomer or diastereomer depicted above and mixtures of the 5(R) and 5(S) enantiomers or diastereomers, for example a racemic mixture or equal mixtures of diastereomers.
The individual optical isomers or required isomers may be obtained by using reagents in such a way to obtain single isomeric form in the process wherever applicable or by conducting the reaction in the presence of reagents or catalysts in their single enantiomeric form. Some of the preferred methods of resolution of racemic compounds include use of microbial resolution, resolving the diastereomeric salts formed with chiral acids such as mandelic acid, camphorsulfonic acid, tartaric acid, lactic acid, and the like wherever applicable or chiral bases such as brucine, cinchona alkaloids and their derivatives and the like. Commonly used methods are compiled by Jaques et al in "Enantiomers, Racemates and Resolution" (Wiley Interscience, 1981). Where appropriate the compounds of formula (I) may be resolved by treating with chiral amines, aminoacids, aminoalcohols derived from aminoacids; conventional reaction conditions may be employed to convert acid into an amide; the diastereomers may be separated either by fractional crystallization or chromatography and the stereoisomers of compound of formula (I) may be prepared by hydrolyzing the pure diastereomeric amide.
Pharmaceutically acceptable salts forming part of this invention include salts derived
from inorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu, Zn, Mn; salts of organic bases such as
N,N'-diacetyiethylenediamine, betaine, caffeine, 2-diethylaminoethanol, 2-
dimethylaminoethanol, N-ethyJmorpholine, N-ethylpiperidine, glucamine, glucosamine, hydrabamine, isopropylamine, methylglucamine, morpholine, piperazine, piperidine, procaine,
H I
26
purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine,
diethanolamine, meglumine, ethylenediamine, N.N'-diphenylethylenediamine, N,N'-
cjibenzylelhylenediamine, N-benzyl phenylethylamine, choline, choline hydroxide,
dicyclohexylamine, metformin, benzylamine, phenylethylamine, diaikylamine, trialkylamine,
Ihiamme, aminopyrimidine, aminopyridine, purine, spermidine, and the like; chiral bases like
alkylphenylamine, glycinol, phenyl glycine! and the like, salts of natural amino acids such as
glycine, alanine, valine, leucine, isoleucine, norleucine, tyrosine, cystine, cysteine, methionine,
proline, hydroxy proline, histidine, ornithine, lysine, arginine, serine, threonine, phenylalanine;
unnatural amino acids such as D-isomers or substituted amino acids; guanidine, substituted
guanidine wherein the substituents are selected from nitro, amino, alkyl such as methyl, ethyl,
propyl and the like; alkenyl such as ethenyl, propenyl, butenyl and the like; alkynyl such as
ethynyl, propynyl and the like; ammonium or substituted ammonium salts and aluminum salts.
Salts may include acid addition salts where appropriate which are, sulphates, nitrates, if phosphates, perchlorates, borates, haiides, acetates, tartrates, maleates, citrates, succinates,
palmoates, methanesulphonates, benzoates, salicylates, hydroxynaphlhoates, benzenesulfonates,
ascorbates, glycerophosphates, ketoglutarates and the like. Pharmaceutically acceptable solvates
may be hydrates or comprising other solvents of crystallization such as alcohols.
The compounds of the present invention may be formulated and administered in a
prodrug form. In general, prodrugs comprise functional derivatives of the compounds of the
formula (I) which are capable of being enzymatically activated or converted into the more active
parent form. Thus, in the treatment methods of the present invention, the term "administering"
encompasses the treatment of the various disorders described with the compound specifically
disclosed or with a compound which may not be specifically disclosed, but which converts to the
specified compound in vivo after administration to the patient. Conventional procedures for the
selection and preparation of suitable prodrug derivatives are described, for example, in Design of
Prodrugs (1985). See also, Wihnan, 14 Biochem. Soc. Trans. 375-82 (1986); Stella el al..
Prodrugs: A Chemical Approach to Targeted Drug Delivery in Directed Drug Delivery 247-67
(1985).
The pharmaceutical composition may be in the forms normally employed, such as tablets, capsules, powders, syrups, solutions, suspensions and the like, may contain flavorants. sweeteners etc. in suitable solid or liquid carriers or diluents, or in suitable sterile media to form
injectable solutions or suspensions. Such compositions typically contain from 0.1 to 50%, preferably 1 to 20% by weight of active compound, the remainder of the composition being pharmaceuticaiiy acceptable carriers, diluents or solvents.
Suitable pharmaceuticaiiy acceptable carriers include solid fillers or diluents and sterile aqueous or organic solutions. The active ingredient will be present in such pharmaceutical compositions in the amounts sufficient to provide the desired dosage in the range as described above. Thus, for oral administration, the active ingredient can be combined with a suitable solid or liquid carrier or diluent to form capsules, tablets, powders, syrups, solutions, suspensions and the like. The pharmaceutical compositions, may, if desired, contain additional components such as flavourants, sweeteners, excipients and the like. For parenteral administration, the active ingredient can be combined with sterile aqueous or organic media to form injectable solutions or suspensions. For example, solutions in sesame or peanut oil, aqueous propylene glycol and the like can be used, as well as aqueous solutions of water-soluble phannaceutically-acceptable acid addition salts or salts with base of the compounds. Aqueous solutions with the active ingredient dissolved in polyhydroxylated castor oil may also be used for injectable solutions. The injectable solutions prepared in this manner can then be administered intravenously, intraperitoneally, subcutaneously, or intramuscularly, with intramuscular administration being preferred in
humans.
For nasal administration, the preparation may contain the active ingredient of the present irivention dissolved or suspended in a liquid carrier, in particular an aqueous carrier, for aerosol application. The carrier may contain additives such as solubilizing agents, such as propylene glycol, surfactants, absorption enhancers such as lecithin (phosphatidylcholine) or cyclodextrin or preservatives such as parabenes.
■ Tablets, dragees or capsules having talc and/or a carbohydrate carried binder or the like
are particularly suitable for any oral application. Preferably, carriers for tablets, dragees or capsules include lactose, com starch and / or potato starch. A syrup or elixir can be used in cases where a sweetened vehicle can be employed.
The dosage regimen utilizing the compounds of the present invention is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof
28
employed. An ordinarily skilled physician, veterinarian or clinician can readily determine and
prescribe the effective amount of the drug required to prevent, counter or arrest the progress of
the condition. I,
Oral dosages of the present invention, when used for the indicated effects, will range
between about 0.01 mg per kg of body weight per day (mg/kg/day) to about 500 mg/kg/day.
In the methods of the present invention, the compounds herein described in detail can
form the active ingredient, and are typically administered in admixture with suitable
If
pharmaceutical diluents, excipients or carriers (collectively referred to herein as 'carrier'
materials) suitably selected with respect to the intended form of administration, that is, oral
tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical
practices.
' The following schemes describe procedures for making representative compounds of the
present invention. Moreover, by utilizing the procedures described in detail, one of ordinary skill
in the art can readily prepare additional compounds of the present invention claimed herein.
NHBn
(Cbz)BnN
(Cbz)BnN
--^Xv.
Y
o
R5
^"-r^^^-b^s..-
R5
n
Y'
O
R4
Rs"^*
12
)-
(Cbz)BnN-=\ Kn MsC'^^^N /=\ KQ
H2N
HO
S Q'^h^n,
<5 77
RA O
Rs
76
NC >==^ )=\ Xn
R4 O
R Rs
reacting compounds of general formula 10, wherein Ri, R4 and R5 are same as explained in formula (I), in presence of reagent such as, but not limited with prop-2-yn-lro!,.
cuprous iodide, /V.TV-diisopropylethylamine in presence of solvent such as, but not limited
to dimethylformamide to obtain compounds of general formula 74. (li) reacting compounds of general formula 74 with reagent such as, but not limited to mesy!
chloride, triethylamine to obtain compounds of general formula 75. (iii) reacting compounds of general formula 75 with reagent such as, but not limited to i potassium cyanide or sodium cyanide to obtain compounds of general formula 76. (iv) reacting compounds of genera! formula 76 with reagent such as, but not limited to
hydroxylamine to obtain compounds of general formula 77. (v) reacting compounds of general formula 77 with reagent such as, but not limited to triethyl
orthoformate, acetic anhydride to obtain compounds of general formula 78.
SCHEME X
HoN
61
reacting compounds of general formula 79, wherein X is CH orN and R,, R4 and Rs are as defined in formula (1), with reagent such as, but not limited to hydrogen sulfide in presence of solvent, but not limited to dioxane. dimethylformamide to obtain compounds
of general formula 80.
reacting compounds of general formula 80 with reagem such as, but not limited to RCOCH2CI to obtain compounds of general formula 81 wherein R is optionally substituted alkyl.
SCHEME XI
^ 82
84
(i) reacting compounds of general formula 82, wherein R3 is hetero aryl compounds, with
general compounds of formula 83, wherein Ri, R4 and Rs are as defined in formula (1), in presence of reagent such as, but not limited with cuprous iodide, N.N-diisopropylethylamine in presence of solvent such as, but not limited to acetonitrile to obtain compounds of general formula 84.
SCHEME XH
3 R3 CN ~ ^^ -""'
85
R4 O
t-BuOOC-/ V-N 9
N 86 ^OH
(i) reacting compounds of general formula 63, wherein R3 is selected from heteroaryi such as triazole or pyridine, with reagent such as, but not limited to potassium carbonate, bromoacetonitrile to obtain compounds of general formula 85.
(ii) reacting compounds of general formula 85 with reagent such as, but not limited to hydroxyl amine to obtain compounds of general formula 86.
(iii) reacting compounds of general formula 87, wherein R4 and R5 are as defined in formula (I), with reagent such as, bul not limited to triphenylphosphane, water, tetrahydrofuran and acetic anhydride, pyridine to obtain compounds of general formula 88, wherein Ri is
I!
as defined in formula (I), (iv) reacting compounds of general formula 88 with compounds of general formula 86, with reagent such as, but not limited to N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide (EDCI), hydroxybenzotriazole (HOBT), N,N-or dicyclohexylcarbodiimide (DCC), 2-(l//-7-azabenzotriazol-l-yI)-l,l,3,3-tetramethyl uronium hexafluorophosphate (HATU) in presence of solvent such as, but not limited to dimethylformamide to obtain
47
ij compounds of general formula 89, wherein R3 is selected from heteroaryl such as triazole i or pyridine.
Any of the compounds of the following general formulae (I-i), (I-ii), (I-iii), (I-iv) & (I-v), wherein R2, R3, R4, R5 & A are as defined in the general formula (I) can be prepared by following any one or more of the similar methodologies described in the above schemes I-XIl. Conversion-I:
RT —A—R.
O
K
-OH
R4 O
Rs a-i)
■N3
Convension-D:
R5
.N3
R,—A—R.
R, (!-")
O
X,
-NH'
Conversion-ni:
R4 O
R3-A-R.-^-N^°
R5
Conversion-IV:
R4 O
R4
■ NH;
R4 Q
R5 a-i")
R4 O
-NH;
Rj A Rj
NH. R
R5
R5 a-iv)
Conversion-V:
' P,-.-R,7"VNN
-NH.
-^"--h-h^
NH. R
R5
R5 (I-v)
The novel compounds of the present invention were prepared according to the procedure of the following schemes and examples, using appropriate materials and are Rirther exemplified by the following specific examples. The most preferred compounds of the invention are any or all of those specifically set forth in these examples. These compounds are not, however, to be construed as forming the only genus that is considered as the invention, and any combination of the compounds or their moieties may itself form a genus. The following examples further illustrate details for the preparation of the compounds of the present invention. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds. All temperatures are degrees Celsius unless otherwise noted.
ii
I) Preparation 1: 2-Fluoro-4-nitro-benzoic acid
F
Hooc—<\ /r-N02
A solution of 2^fluoro-4-nitro toluene (50 grams, 322.0 mmol) dissolved in a mixture of acetic acid (625 mL) and concentrated sulfuric acid (157 mL), was treated with an aqueous solution of chromium trioxide (116 grams, 1160.0 mmol, in 100 mL water at 100 °C) for 3 hours. The reaction mixture was poured into ice-cold water (2 Litres) and extracted with diethyl ether (2 x'l Litres). Evaporation of the volatiles left a residue, which-was dissolved in 10% aqueous Dotassiumcarbonate solution (1 Litre) and extracted with diethyl ether (300 mL). The aqueous layer was acidified with diluted hydrogen chloride and the solid obtained was filtered and dried. Yield; 66%, MS(m/z): 186 (IVlVl),
'H NMR (300 MHz, CDCI3): 6 8.24 (dd.J = 1.6 & 7.0 Hz, IH). 8.14-8.04 (m, 2H). Preparation 2: Tert-butyl 2-fluoro-4-nitro-benzoate
NO'
To a solution of 2-fluoro-4-nitrobenzoic acid (12.0 grams, 64.9 mmol) in dichloromethane, triethylamine (26 mL, 194.6 mmol) and 4-(dimethylamino) pyridine (2.37 grams, 19.5 mmol) were added followed by the addition of di-tert-butyl dicarbonate_(22.5 mL, 97.0 mmol) at 10 °C. The resuiting mixture was stirred at room temperature for 2 hours. Solvent was evaporated and the residue obtained was dissolved in ethyl acetate (300 mL), washed with water (2 xl50 mL). 5% citric acid solution (2 x 150 mL) and brine solution (150 mL). Finally the ot-ganic layer was dried over anhydrous sodium sulfate and volatiles were evaporated. Yield: 98%,
'H NMR (300 MH2, CDCh): 5 8.05-8.03 (m, 2H), 8.0)-7.96 (m, IH), ) .63 (s, 9H). Preparation 3: 2-FIuoro-4-nitro-phenyl-hydrazine
R
I-/V,
H2NHN-^^V-N02
To a solution of I,2-dinuoro-4-nitro-benzene (25 grams, 157.2 mmol) in ethanoi was added hydrazine hydrate (15.72 grams, 314.5 mmol) drop wise at 80 "C. It was stirred for 2 hours at the same temperature. Ethanol was removed in rotavapor and the solid obtained was filtered and triturated in diethyl ether. The free flowing solid obtained after decanting the supernatant liquid was dried under high vacuum to obtain 26.7 grams of title compound. Yield: 99.2 %, MS(m/2): 172(M"*"+l),
'H NMR (300 MHz, CDCb): 5 8.05 (dd, J= 2.5 & 9.1 Hz, IH), 7.89 (dd, J= 2.5 & 11.8Hz, IH), 7.24 (I, J-8.7 Hz, IH), 6.01 (bs, IH), 3.75 (s. 2H). Preparation 4: Ethyl l-(2-fluoro-4-nitro-phenyI)-lH-pyrazole-4-carboxyIate
H3CH2COOC,^^..^^ W.
To a solution of 2-fluoro-4-nitro-phenyl)-hydra2lne (17.0 grams, 99.4 mmol) in ethanol (350 mL) were added ethyl 2-formyl-3-oxo-propionate' (18.6 grams, 129.2 mmol) and sodium acetate (8.2 grams, 99.4 mmol) and stirred at room temperature for half an hour and then at 80 °C for 3 hours. Ethanol was removed in rotavapor and the residue obtained was dissolved in ethyl
50
acetate. Ethyl acetate portion was washed successively with water (100 mL x 2), saturated sodium bicarbonate solution (50 mL) and brine (100 mL). Organic layer was then dried over anhydrous sodium sulfate and concentrated to obtain a brown solid. Triturated with diethyl ether and filtered to get 13.6 grams of free flowing solid. Yield; 49%, MS(m/z):280(M'+l),
'H NMR (300 MHz, CDCI3): 6 8.64 (d, J = 2.5 Hz, 1H), 8.18-8.30 (m, 4H), 4.36 (q, 7=7.1 Hz,
2H), 1.39(1,7-7.1 Hz,3H).
Preparations: [l-(2-Fluoro-4-nitro-phcnyl)-lH-imidazoM-yl}-Tnethanol
F
A mixture of 1,2-difluoronitrobenzene (22 grams, 138.4 mmol), diisopropyiethyiamine (150 mL) and 4-hydroxymethyl imidazole (18.62 grams, 138.4 mmol) was heated to 100 °C for 3 hours. The bottom layer was separated from the two layers formed and water was added to obtain yellow solid. It was filtered, dried and washed with 10% acetone in hexane. Yield: 91 %, 'H NMR (CDCb, 300 MHz): 5 8.15-8.25 (m, 2H), 7.94 (m, IH), 7.61 (m, IH), 7.32 (s IH), 4.72
(s, 2H).
Preparation 6: 4-(Tert-butyI-dimethyl-silanyloxyme«iyI)-l-(2-fluoro-4-nitro-phenyl)-lH-
imidazole
F TBDMSO"""
Ten - Butyldimeihylsilyl chloride (4.76 grams, 31 mmol) was added to a mixture of [1-(2-fluoro-4-nitro-phenyl)-lH-imidazol-4-yl]'methanol (5 grams, 20.6 mmol) and imidazole (2.85 grams, 41.2 mmol) in dimethylformamide (50 mL) at 10-15 °C in portions. The resulting mixture was stirred at room temperature for 16 hours. Dimethylformamide was distilled under vacuum and to the residue obtained was added water. The solid obtained was filtered and dried. Yield: 61 %,
51
'1^ NMR (CDCb, 300 MHz): 6 8T6-8.18 (m, 2H), 7.89-7.90 (m, IH), 7.51-7.62 (m, IH), 7.26 (s. IH), 4.77 (s. 2H), 0.94 (s, 9H), 0.11 (s, 6H).
Prepararion 7: Benzy|-(4-nitro-2-flouro-phenyI)-aniine
BnNH
To a suspension of 3,4-difluoronilroben2ene (J 0.0 grams, 63.0 mmol) in ■I dimethylformamide (100 mL) was added N-ethyl diisopropylamine (12.2 grams, 94.5 mmol)
drop wise at room temperature followed by the addition of benzylamine (8.1 grams, 76.6 mmol).
Reaction mixture was stirred overnight at room temperature and then poured into cold water with
continuous stirring. Fine solids obtained were filtered & dried.
Yield: 70%.
lR(KBr, cm''):3354, 1612, 1549, 1493,1288, 1185, 1068,876,810,732,542,
MS(m/z); 247(M'"),246,91,
'H NMR (CDCI3, 200 MHz); 5 7.98-7.86 (m, 2H), 7.42-7.25 (m. 5H), 6.67-6.58 (m. IH) 5.08
(bs,lH), 4.50-4.46 (m,2H).
Preparation 8: N-Hydroxy-2-H,2,41triazol-l-yl-acetainidinc
OH
To a solution of [1,2,4] Triazol-l-yl-acetonitrile (1.5 grams, 13.9 mmol) in ethanol were added sodiun
carbonate (4.4 grams, 41.7 mmol) and hydroxylamine hydrochloride (3.86 grams, 55.5 mmol). Tht
mixture was heated to 80 °C for overnight. The reaction mixture was concentrated and extracted wit!
ethyl acetate and purified by column to get the desired product (1.9 grams).
Yield: 97%
'H NMR (200 MHz, CDCb+DMSO): 6 9.34 (bs, IH), 8.51 (s, IH), 7.95 (s, IH), 5.58 (bs, 2H),
4.74 (s, 2H).
ES-MS(m/z): 142 (M"'+l)
Preparation 9 : 2-(Pyridin-2-yI)acetohydrazide
li To a solution of Ethyi-2-(pyridine-2-yi)acetate (2.3 grams, 11.5 mmol) in ethanoi hydrazine
hydrate (2mL) was added and the reaction mixture was refluxed for 3hours. The solvent was co-evaporated with toluene to obtain the product as white solid 1.2 grams.
Yield: 71%
Preparation 10:Tert-butyl 4-amino-2-f1uoro-benzoate
R
Tert-Butyl-2-Fluoro-4-nitro-ben2oate (15 grams, 62.2 mmol) was added to a solution of aihmonium chloride (34 grams, 622.0 mmol) in a mixture of water (45 mL) and ethanol (90 mL) at 95 °C, followed by the addition of iron powder (10.5 grams, 187 mmoi) in three lots. Stirring was continued at that temperature for J hour. The solids were filtered off in hot condition and the filtrate was evaporated. The residue obtained was dissolved in water (100 mL) and extracted With diethyl ether (2 x 150 mL). The organic layer was dried over sodium sulfate and the volatiles were evaporated. Yield: 98%, MS(m/z);2]0(M^-l),
'I'J NMR (300 MHz, CDCb): 5 7.70 (t.V= 8.4 Hz, IH), 6.45 (d, J - 8.5 Hz, IH), 6.37 (dd, J = \,6& n.OHz, IH), 1.58 (s,9H). Preparation 11: Benzyl-I5-aniinomethyl-2-oxo-oxazoIidin-3-yI)-2-fluoro-phenyll-carbamate
Bn(Cbz)N—(\ />—N 1
'■ To a solution of benzyl-(4-[5-azidomethyl-2-oxo-oxazolidin-3-yl)-2-fluoro-phenyl]-
carbamate (6 grams, 12.6 mmol) in tetrahydrofuran (50 mL) was added triphenylphosphine in small batches (3.64 grams, 14 mmol) and stirred for 4 hours. The reaction mixture was then
heated to 40-50 «C for 16 hours after the addition of water (I mL). Solvent was evaporated and the residue obtained was purified by column chromatography on silica gel using methanol and chloroform (1:9) as eiuent to obtain the title compound, "^ield: 70%,
IR(KBr, cm-'): 3334, 2926, 2606, 2497, 1751, 1655. 1524, 1475, ]44], 1226, 108], 1037,850, 753,591,
MS (m/z): 450(M^+1), 386, 376, 279,
'H NMR (300 MHz, CDCh): 6 7.52-6.58 (m, 14 H), 5.15 (s, 2H), 4.80 (s, 2H), 4.78-4.58 (m,
lH),3.93(t,J = 8.7H2, 1H),3.81 (t,J=7.8 Hz, 1H).3.16-2.90 (m,2H),
Preparation 12: Pyrazol-1-yl-acetonitrile
\ / CN
., To a solution of pyrazole (10 grams, 14.7 mmol) in dry dimethylformamide (150 mL)
was added anhydrous potassium carbonate and stirred at room temperature for 10 minutes. Bromo acetonitrile (40 mL, 58.8 mmol) was then added and stined at ice temperature. The reaction mixture was then allowed to stir at room temperature overnight. Potassium carbonate was filtered off and the filtrate concentrated at reduced pressure. The resulting mass was then diluted with ethyl acetate (500 mL) and the ethyl acetate layer was washed with brine solution and dried over sodium sulphate. Volatiles were evaporated and the residue obtained was purified by column chromatography over silica gel using ethyl acetate and petroleum ether (1:4) as eiuent. Title compound was obtained as light yellow liquid. Yield: 69%,
IR (neat, cm-'): 3250, 3126. 2988, 1663, 1518, 1395, 1288 and 757, MS (m/z); 107 (MVI),
'H NMR (200 MHz, CDCI3): 5 7.61- 7.60 (m, IH). 7.57- 7.55 (m, IH), 5.11 (s, 2H). Preparation 13: N-|3-(4-Acetyl-3-fluoro-phenyl)-2-oxo-oxazolidin-5-y!mcthyIl-acetamide
The compound has been synthesized according to the reported procedure (J. Med. Chem. 1992. 35,1156-1165)
Preparation 14: N-{3-[4-(2-Bromo-acefyl).3-fluoro-phenyll-2-oxo-oxazoIidin-5-ylmethyI}. acetamide
To a solution of N-[3-(4-acetyl-3-fluoro-pheny!)-2-oxo-oxa201idin-S-ylmethyl]-acetamide (450 ^L, 1.53 mmol) in methanol (5 mL) was added bromine (0.12 mL, 2.29 mmol) at 0 "C and stirred for 5 hours. The temperature was slowly increased from 0 °C to room temperature. Water (1 mL) was added and the reaction mixture was allowed to stir at room temperature for additional 1 hour. Evaporation of methanol gave white color solid. Yield: 55%,
IR(ICBr, cm''): 3282, 2919, 1733,1626, 1414, 1197. 1054. 862 and 752, MS(m/z):375(MV2).295.
'H NMR (200 MHz, CDCb): 5 7.96 (t, J= 8.4 Hz, IH), 7.60 (dd, J= 2.0 & 11.7 Hz, IH), 7.27-7.^1 (m, IH), 6.17 (bs, IH), 4.89- 4.77 (m, IH), 4.48 (d, ^ = 2.4 Hz. 2H), 4.13- 4.04 (m, IH), 3.87- 3.79 (m, IH), 3.71- 3.65 (m. 2H), 2.02 (s, 3H). Preparation 15: Benzyl {4-I5(S)-(acetylaininomethyl)-2-oxo-oxazo!idin-3-yl]-2-flouro-
phenyO-bcnzyl-carbamate
Bn(Cbz)N—<\ /)~^^ \ H
r
/ Benzyl-[4-(5-azidomethyl-2-oxo-oxazolidin-3-yI)-2-nuoro-phenyl]-carbamate (650 mg, 13.7 mmol) was treated with thiolacetic acid (1.5 mL) at room temperature for 24 hours. Excess solvent was evaporated and the residue obtained was purified by column chromatography on silica gel using methanol and chloroform (1:9) as eluent to obtain the title compound as white solid.
55
Yield: 67%.
Alternatively, a solution of ben2yI-[5-aminomethyI-2-oxo-oxa2oHdin-3-yl)-2-fluoro-phenyl]-carbamate (3 grams. 6.68 mmol) and pyridine (1.1 mL, 13.36 mmol) in chloroform (75 mL) was treated with acetic anhydride (0.96 mL,10.02 mmol) at 0°C and stirred at room temperature for half an hour. The reaction mixture was extracted with chloroform (3 x 100 mL) after the addition of water (200 mL). The combined organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue obtained was purified by column chromatography on silica
gel using methanol and chloroform (1:9) as eluent to obtain the title compound as white solid,
■f
Yields: 52%,
lR(KBr,cm"'): 3323, 1755, 1707, 1520,1403, 1218, 1125,
MS (m/2): 492(M''+1), 448, 428, 391, 384, 351, 314,
'H NMR (CDCb, 200 MHz): 5 7.50-7.01 (m, 13H), 6.20 (bs, IH), 5.15 (s, 2H), 4.80-4.70 (m,
3H), 3.75-3.57 (m, 3H), 1.99 (s. 3H).
Preparation 16: N-[3-(4-Aniino-3-fluoro-phenyl)-2-oxo-oxazolidin-5(S)-yl-methyll-
acctamide
F q
A solution of benzyl (4-r5-(acetylamino methyl)-2-oxo-oxazolidin-3-yl]-2-flouro-phenyl}-benzyl-carbamate (200 mg, 0.41 mmoi) in methanol (25 mL) was treated with 10% palladium on cliarcoal (84 mg, 0.80 mmol) under hydrogen atmosphere for 16 hours. The catalyst was filtered over a pad of celite and the filtrate was concentrated. The residue obtained was purified by column chromatography on silica gel using methanol and chloroform (1:9) as eluent to obtain the title compound as white solid.
Yield: 61%,
IR (KBr, cm-'): 3436, 3356, 2926, 2855, 1733, 1664, 1522, 1420, 1228,
MS(m/z): 268(M^+1),
HNMR(DMSO-d6,400MHz):S8.20(t,y^5.6Hz, 1H),7.31 (dd. 7= 3.5 & 10.0 Hz, IH).
^p5(dd,.7 = 2.4 & 8.8 HzJHX 6.76(dd,y=8.8& 9.9Hz, U^X 5.0 (s,2H), 4.70-4.62 (m,lH), .01 {t,J= 8.8 Hz. IH), 3.64 (dd. J= 6.4 & 9.1 Hz, IH), 3.38 (I, J- 8.6 Hz, 2H), 1.86 (s, 3H).
'reparation 17: N-I3-(4-Azido-3-fluoro-phenyI)-2-oxo-oxazolidin-5(S)-yl-methyl|-cetamide
O
To a solution of N-[3-(4-amino-3-fIuoro-phenyl)-2-oxo-oxazoIidin-5-yI-methyI]-
icetamide (200 mg, 0.75 mmol) in 50 % aqueous hydrogen chloride (20 mL) was added sodium
litrile (104 mg, 1.5 mmol) in small batches at 5-10 °C . An aqueous solution of sodium azide(98
ng, 1.5 mmol) and sodium acetate (1.28 grams, 15 mmol) was added after 0.5 hours and stirring
vas continued for 15 minutes. Reaction mixture was then diluted with water & extracted with
ithyi acetate (2 x 50 mL). Ethyl acetate layer was washed with brine and dried over sodium
i! mlfate and concentrated. The residue obtained was purified by column chromatography on silica
?el using methanol and chloroform (1:9) as eluent to obtain the title compound as light brown
solid.
YJeld: 59%,
m(KBr, cm-'): 3266, 3075, 2925, 2130, 1745, 1653. 1516, 1415, 1308,
MS (m/z): 294 (M"'+l), 281, 268, 253,
'HNMR(DMSO-d6, 400MHz):5 8.21 (t, J= 5.6 Hz, IH); 7.58 (dd, 7 = 2.4 & 12.3 Hz,lH);
7,''36-7.16 (m, 2H); 4.76-4.70 (m, IH); 4.11 (t, J= 8.8 Hz, IH); 3.73 (dd, J= 6.4 & 9.1 Hz, IH);
3.41 (t,y=5.6H2,2H); L83 (s, 3H).
Preparation 18: 2-Pyrazol-l-yI-thioacetamide
To a solution of pyrazol-lyl-acetonitrile (10 grams, 93.5 mmol) in ethanol was added triethyi amine (19 mL, 140 mmoi). Hydrogen suiphide(H2S) gas was then passed through
57
reacuun ..UAIU.C lu. j nours ai room lemperaiure. the organic solvent was evaporated and the residue was purified by column chromatography over silica gel using ethyl acetate and petroleum ether (1:3) as eiuent. Title compound was obtained as light yellow solid. Yield: 62%,
IR (KBr, cm-'): 3301, 314], 2965, 1732, 1636, 973 and 740, MS(m/z): 142(M"'+1),
'H NMR (200 MHz, CDCh): 6 7.97 (bs, 2H), 7.64 (d, J = 2.0 Hz, IH), 7.50 (d,J= 2.0 Hz, IH),
6.37 (t, J =2.0Hz, IH), 5.21 (s,2H).
Preparation 19: Ethyl ]-(4-amino-2-fluoro-phenyl)-lH-pyra2ole-4-carboxylate
F
il
To a solution of ethyl l-(2-fluoro-4-nitro-phenyl)-lH-pyrazole-4-carboxylate (35.2
grams, 126.2 mmol) and ammonium chloride (67.5 grams, 1261.6 mmol) in a mixture of cthanol
and water (2:1, 400 mL) was added iron powder (21.19 grams, 378.5 mmol) in small batches. U
was stirred for 1.5 hours at the same temperature. Reaction mixture was then filtered in hot
condition and solid was washed with ethyl acetate. Filtrate was concentrated and the residue
obtained was dissolved in diethyl ether (500 mL). The ether layer was washed with brine
solution (200 mL) and concentrated to obtain 31.4 grams of light yellow solid. li Yield: 99%,
MS (m/z): 250 (M^+l),
'HNMR(300MH2, CDCI3): 6 8.27 (d. J = 2.3 Hz, IH), 8.07 (s, IH); 7.51 (i,J = 8.7 Hz, IH),
6148-6.53 (m, 2H), 4.32 (q,y= 7.1 Hz, 2H), 3.94 (s, 2H), 1.36 (uJ= 7.1 Hz. 3H).
Preparation 20: 4-I4-(Tcrt-butyl-dimethyI-silanyloxymethyl)-imidazoI-I-ylI-3-fluoro-phenylamine
Ammonium chloride (53 grams, 53.5 mmol) and 4-(tert-butyNdimethyI-siianyloxymethyl)-l-(2-nuoro-4-nitro-phenyl)-lH-imida2ole (35 grams, 97 mmol) were added to admixture of ethanol and water (2:1, 315 mL) and heated to 60 °C for 5 minutes. Iron powder (16.62 grams, 291 mmol) was added in portions and after the completion of addition the reaction mixture was heated to 95 "C for 5 hours. Inorganic material was filtered over a pad of celite and the filtrate was concentrated. The residue obtained was extracted with diethyl ether, which upon concentration afforded the product. Yield: 97.2%,
'H NMR (CDCI3, 300 MHz): 5 7.59-7.60 (m, IH), 7.03-7.13 (m, 2H), 6.45-6.53 (m, 2H), 4.77 (s, 2H), 4.00 (s, 2H), 0.95 (s, 9H). 0.11 (s. 6H). Preparation 21: N']'-Benzyl-2-nuoro-benzene-l,4-diamine
F
BnNH
To a solution of benzyI-(4-nitro-2-fluoro-phenyI)-amine (5.0 grams, 20.3 mmol) in methanol (70 mL) was added nickel chloride hexahydrate (9.5 grams, 42.86 mmo!) and cooled to 0 °C. Sodium borohydride (2.35 grams, 61 mmol) was added to the reaction mixture in small bkches and stirred at 5-10 °C for 1 hour. The reaction mixture was extracted with ethyl acetate (2 X 250 mL) after the addition of water. Ethyl acetate layer was washed with brine, dried over sodium sulfate and concentrated. Purification of the residue by column chromatography over silica gel using methanol: chloroform (1:9) gave the title compound as a brown liquid. Yield: 68%,
IR (Neat, cm"'): 3361, 3030, 1522, 1219, 956, 802, 732, 668, 597, MS(m/z):217(M''+l),216,
'H NMR (CDCh, 200 MHz): 5 7.34-7.24 (m, 5H), 6.57-6.31 (m, 3H), 4.27 (s. 2H), 3.63-3.50 (m, 2H).
ii
" -• -•'*- 'T'—* ^--^^'i'i-KAn-nfinvv^arhnnvl9niino-2-fluoro-benzoate
NHCbz
To a stirred solution of tert-buiyl 4-amino-2-fluoro-benzoate (13 grams, 61.6 mmol) and sodium bicarbonate (21 grams, 246 mmol) in tetrahydrofiiran (200 mL), benzyloxy barbonyl chloride (CBz-Cl) (43 mL) was added at 0 ""C. The resulting mixture was stirred at room temperature for 16 hours and later it was heated to 50 "C for 3 hours. Solids were filtered off and filtrate was evaporated. The residue obtained was washed with hexane (100 mL) and dried. Yield: 98%,
'H NMR (300 MHz, CDCI3): 5 7.81 (t, J= 8.4 Hz, IH), 7.43-7.35 (m, 5H), 7.03 (dd, J= 2.0 & 8.6 Hz, IH), 6.93 (bs, IH), 5.21 (s, 2H), 1.60 (s, 9H). Preparation 23: 4-Benzyloxycarbonylamino-2-fluoro-benzoic acid
NHCbz
'■ To a solution of tert-butyl 4-benzyioxycarbonylamino-2-fluoro-ben2oate (21.0 grams, 60.9 mmol) in dichloromethane (100 mL), trifluoroaceticacid (100 mL) was added drop wise at 0 °C and stirred at room temperature for Ihour. Solvent was evaporated and the residue obtained was washed with diethyl ether (100 mL) to obtain pale yellow solid. Yield: 92%, MS(m/z):288(M^-l), 'H NMR (400 MHz, CDCb+DMSO-dfi): 5 12.20 (hump, -OH), 7.83 (t, J- 8.6 Hz, IH), 7.22-
7:58 (m,7H), 5.20 (s,2H).
Preparation 24: Methyl 2-(4-benzyloxycarbonylamino-2-fluoro-ben7,oylamino)-3- hydroxy-propionate
HO-/ H
To a solution of 4-benzyloxycarbonylamino-2-fluoro-benzoic acid (15.7 grams, 54.3 mmol) in dry tetrahydrofuran (400 mL), l-(3-Dimethylaminopropyl)-3-ethylcarbodiimide
60
hydrochloride (12.5 mL, 70.6 mmol), hydroxybenzotriazole (8.8 grams. 65.2 mmol). L-Serine
methyl ester hydrochloride (12.6 grams, 81.5 mmol) and diisopropyiethylamine (28 mL, 217.0
mmol) were added at room temperature and stirred for Ihour. Solvent was evaporated and the
residue obtained was dissolved in ice-cold water. Aqueous layer was extracted with ethyl acetate
(250 mL X 2) and the total organic layer was washed with 5% potassium carbonate solution
followed by brine solution. Finally it was dried over sodium sulphate and volatiles were
evaporated to obtain pale yellow solid.
Yield: 85%.
MS(my2):389(M^l),
'H NMR (300 MHz, CDCI3); 5 7.99 (t,J= 8.6 Hz, IH), 7.52-7.68 (m, 2HX 7.40 (bs, 5H), 6.97-
7.08 (m, 2H), 4.85 (bs, IH), 4.05 (s, 2H), 3.58 (s, 3H). 2.58 (bs, IH).
Preparation 25: Methyl 2-(4-benzyloxycarbonylaniino-2-fluoro-pheny!)-4,5-oxa2oIe-4-
carboxyiate
A solution of methyl 2-(4-benzyloxycarbonylamino-2-fluoro-benzoylamino)-3-hydroxy-propionate (6.0 grams, 15.4 mmol) in dry tetrahydrofuran (125 mL) was treated with Burgess reagent (4.0 grams, 16.9 mmol) at 75 °C for 3 hours. Solvent was evaporated and organic compound was extracted with ethyl acetate. It was washed with water, 5% potassium carbonate solution and saturated brine solution successively. Finally it was dried over anhydrous sodium sulphate and volatiles were evaporated. The residue obtained was purified by column chromatography (60 -120 mesh silica gel) by using 25% ethyl acetate; hexane solvent system. Yield: 72 %, MS(m/z):373(M"+l),
'H NMR (300 MHz, CDCI3): 6 7.85 (t, J= 8.2 Hz, IH), 7.46 (d, 7= 13.3 Hz, IH), 7.40 (s, 5H), 7.08 (d, J= 6.1 Hz, 2H), 5.20 (s, 2H), 4.95 (t,7= 9.2 Hz, IH), 4.68-4.52 (m, 2H). PrcDaraeion 26: Benzyl [3-nuoi*-4-(4-hydroxyniethyl-oxazoI-2-yl)-phenyll-carbamate
NHCbz
Methyl-2-(4-benzyloxycarbonylamino-2-fiuoro-phenyl)-oxazoIe-4-carboxylate (4.5
grams, 12.2 mmol) was added to a suspension of lithium aluminium hydride (925 mg, 24.3 mmol) in tetrahydrofuran (HO mL) at 0 °C and stirred for 10 minutes. The reaction was quenched by the addition of water at cold condition and stirred for 30 minutes. Solids were filtered off and the filtrate was concentrated to obtain a pale yellow solid.
Yield; 72%,
II
MS(m/z):341 (M^l),
'H NMR (300 MHz, DMSO-dfi): 5 8.03 (s, IH), 8.92 (t, ./= 8.6 Hz, IH), 7.55 {d, J = 13.6 Hz,
IH), 7.43-7.32 (m, 6H), 5.27 (t, J= 5.6 Hz. IH), 5.20 (s, 2H), 4.43 (d, J= 5.5 Hz, 2H).
Preparation 27; Benzyl {4-[4-(tert-butyI-dimethyl-silanyIoxyme(byI)-o.\azol-2-yl}-3-n»f>ro-
phenylj-carbamate
To a solution of benzyl [3-fluoro-4-(4-hydroxymelhyl-oxazol-2-yl)-phcnyl]-carbamate
(4.5 grams, 13.2 mmol) and imidazole (1.8 grams, 26.3 mmol) in dimethylformamide (45 mL),
tert - Butyldimethylsilyl chloride (3.0 grams, 19.7 mmol) was added at 0 "C and stirred at room
temperature for 30 minutes. Solvent was evaporated and the residue obtained was dissolved in
water. It was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The volaliles
were evaporated to obtain a pale yellow solid.
Yield: 84%,
'H NMR (300 MHz, CDCb): 8 7.93 (t, J =8.4 Hz, IH), 7.61 (s, 1H),7.51 (dd,y- 1.8& U.I
Hz, IH), 7.43-7.34 (m, 5H), 7.09 (dd, 7 = 2.0 & 6.6 Hz, IH), 6.82 (s, IH), 5.21 (s, 2H), 4.65 (s,
2H), 0.93 (s, 9H), 0.06 (s, 6H).
Preparation 28: Ethyl [l-(4-benzyloxycarbonyIamino-2-nuoro-phenyl)-lH-pyrazoIe-4-
carboxylate
H3CH2COOC, _
^ V-NHCbz
To a solution of ethyl l-(4-amino-2-fluoro-phenyI)-m-pyra2oie-4-carboxylafe (32.65 grams, 131.14 mmol) in tetrahydroftiran (800 mL) was added sodium bicarbonate (44.06 grams, 524.56 mmol) followed by the addition of benzylchioroformate (56.13 mL, 393.42 mmol) drop wise at ice temperature. Stirring was continued overnight at room temperature. Reaction mixture was then filtered and the solid obtained was washed with tetrahydrofuran. The filtrate was concentrated to obtain a semisolid, which was stirred in hexane for 15 minutes to obtain 42.0 grams of light yellow solid. Yield: 83%, MS(m/z):384(M^+l),
'HNMR(300MHZ, CDCl3):6 8.41 (d,J = 2AHz, IH), 8.10(s, IH), 7.77 (t, J - 8.7, IH) 7.64 (d,./ = n .3 Hz, IH), 7.35-7.42 (m, 4H), 7.08 (dt, y = 1.1 & 8.8 Hz, 1H), 6.90 (s, 1H), 5.22 (s, 2H), 4.34 (q,y-7.1 Hz, 2H), 1.37 (t, 7= 7.1 Hz, 3H). Preparation 29: Benzyl [3'lluoro-4-(4-hydroxymethyl-pyrazol-l-yl)-phcnyIl-carbamate
HO
"X^N-O"'^^^^^ ■
To a suspension of lithium aluminum hydride (1.9 grams, 52.22 mmol) in dry
tetrahydrofuran (250 mL) was added ethyl l-(4-benzyloxycarbonylamino-2-fluoro-phenyl)-lH-
pyra2ole-4-carboxylate (10.0 grams. 26.11 mmol) in small batches at 0 ''C and stirring was
continued for additional one hour at the same temperature. Reaction mixture was quenched by ft adding 10% potassium carbonate solution (20 mL). The filtrate obtained after filtration was
concentrated. The residue thus obtained was dissolved in ethyl acetate, washed with water (150
mL X 2) and brine solution (100 mL x 1) successively. Organic layer was then dried over
anhydrous sodium sulfate and concentrated to obtain 7.76 grams of yellow color product.
Yield: 87.7%, MS(m/z):342(M"'+l),
■H NMR (300 MHz. CDCI3): 5 7.94 (d, 7^ 2.4 Hz, IH), 7.72-7.78 (m, 2H), 7.61 (d, 7 = 11.0 Hz, !H), 7.37-7.40 (m, 4H), 7.05 (d, J=^ 8,4 Hz, IH). 6.84 (s, IH), 5.21 (s, 2H), 4.67 (bs, 2H).
Preparation 30: Benzyl {4-I4-(tert-butyI-dimethyl-silanoyIoxymethyl)-pyrazoM-y||-3-fluoro-phenyl)-carbaniate
TBDMSO'
NHCbz
The title compound is prepared by following the procedure as described in preparation
27, by taking appropriate starting materials.
Yield: 83.17%,
MS(m/z):.456(M''+l),
'H NMR (300 MHz, CDCI3): 5 7.86 (d, 7 = 2.7 Hz, IH), 7.75 (t. J= 8.7 Hz, IH), 7.65 (s. IH), 7.60 {d,J= 13.5 Hz, IH), 7.35-7.41 (m, 4H), 7.05 (d, 7- 8.8 Hz, IH), 6.78 (s, IH), 5.21 (s, 2H), 4.72 (s, 2H). 0.95 (s, 9H), 0.18 (s, 6H).
Preparation 31: Benzyl {4-|4-(tert-butyl-dimethyl-silanyloxy)-imidazol-l-yl]-3-nuoro-ptienyl} carbamate
F
I N—(\ /V-NHCbz
The title compound is prepared by following the procedure as described in preparation
28, by taking appropriate siarting materials.
Yield: 75.5%,
'H NMR (300 MHz, CDCI3): 5 7.10-7.82 (m, I OH), 5.21 (s, 2H), 4.75 (s, 2H), 0.95 (s, 9H). 0.15
(s, 6H).
li
Preparation 32: Benzyl 4-(benzyI-benzyIoxycarbonyl-amino)-3-fluoro-phenyl)-carbaniate
F . -
Bn(Cbz)N—4 V-NHCbz
The lille compound is prepared by following the procedure as described in preparation 28, by taking appropriate starting materials. Yield: 45%.
MS (m/z): 485 (M^+1), 441, 377, 351, IR (KBr, cm-1): 3315, 3033, 2930, 1693, 1536,
'H NMR (CDCI3, 200 MHz): 8 7.36-7.22 (m, 17 H); 6.05 (bs, 2H); 5.17 (s, 4H). 4.77 (s, 2H). Preparation 33: Prep 3-{4-(4-(Tert-butyl-dimethyl-silanyloxymethyl)-oxazol-2-yI|-3-fluoro-phenyl}-5-(R)-hydroxymethyI-oxazolidin-2-one
TBDMSO
To a solution of benzyl {4-f4-(tert-butyl-dimethyl-si!anyloxymethyl)-oxazol-2-yl}-3-fluoro-phenyl}-carbamate (5,0 grams, 10.9 mmol) in dry tetrahydrofuran (125 mL) n-butyl lithium (8.5 mL, 13.2 mmol) was added slowly at -78 °C and stirred for 1 hour. R-{-)-Glycidyl butyrate (!.7 mL, 12.1 mmol) was added at the same temperature and stirred over night at room temperature. Reaction mixture was quenched by the addition of saturated ammonium chloride solution. The organic layer was separated and dried over anhydrous sodium sulfate and volatiles were evaporated. The residue obtained was stirred in diethyl ether and the solid obtained was filtered to obtain a white solid. Yield: 55%, .MS (m/z): 471 (M^-I).
'H NMR (300 MHz, CDCI3): 8 8.02 (t, J = 8.5 Hz, IH), 7.65-7.56 (m, 2H), 7.35 (dd, J = 6.6 &' 2.2 Hz, IH), 4.86-4.74 (m,3H), 4.13-3.98 -,
Tert-Butyl 4-(5-a2idomethyl-2-oxo-oxazolidin-3-yl)-2-fluoro-benzoate (28 grams, 83.33 mmol) was dissolved in dichloromethane (110 mL). Trifluoroacetic acid (110 mL) was added to it drop wise at 0-5 °C and stirred at room temperature for 2 hours. Trifluoroacetic acid and dichloromethane were completely evaporated. Hexane was added to the residue obtained and stirred for a while. The solid obtained was filtered and dried. Yield: 90.5 %,
'HNMR(300MHz, CD3OD):6 8.01 (t,y=8.6Hz, IH), 7.66 (dd, J = 2.1 & 13.5 Hz, IH),4.95 (m, IH), 4.23 (t,y=9.2 Hz, IH), 3.94 (dd,y = 6.2 & 9.3 Hz, IH). 3.82-3.64 (m. 2H). Preparation 46: 4-(S-Aminoniethyl-2-oxo-oxazolidin-3-yl)-2-fluoro-benzaniide
Ji
To a teirahydrofuran solution of 4-(5-azidomethyl-2-oxo-oxazolidin-3-yi)-2-fluoro-
benzamide (17 grams, 60.9 mmol) was added triphenyl phosphene (20.8 grams, 79.1 mmol) at
room temperature and stirred for 2 hours. Water (12 mL) was added to the reaction mixture and
refluxed at 90 °C for 5 hours. The reaction mixture was then concentrated and the residue
triturated with benzene. Benzene was decanted and the trituration process was repeated for 4-5 times. Solid obtained by this way was dried and used for the next step. Yield: 73 %.
'HNMR(300MHz, CDCI3): S 7.75 (t, J= 8.63 Hz, IH), 7.61-7.53 (m. 3H), 7.41 (dd,y=2.1 & 8.7 Hz, IH), 4.72-4.62 (m, IH), 4.10 (l,J=9.0 Hz, IH), 3.89 (dd, y= 6.4 & 9.0 Hz, IH), 2.94-2.78 (m, 2H).
Preparation 47: 4-(5-Azidomethyl-2-oxo-oxazoIidin-3-yl)~2-f1uoro-benzaniide
R O
H2N V_/ V-^v-N3
!! To a solution of 4-(5-azidomethyI-2-oxo-oxazoiidin-3-yI)-2-fluoro-benzoic acid (12.5 grams, 44.6 mmol) in dichloromethane was added thionyl chloride (62.5 mL) and heated to 60 °C for 3 hours. Thionyl chloride was removed completely and ammonia solution (100 mL) was added to the resulting residue at 0 °C. Temperature was allowed to come to room temperature and stirred for 2 hours. Chloroform was added and washed with brine solution. Chloroform layer was dried over sodium sulfate and concentrated to obtain the title compound. Yield: 96%,
'H NMR (300 MHz, DMSO-dg): 8 7.75 (t, /= 8.4 Hz, IH), 7.62-7.52 (m, 3H), 7.40 (dd, J = 2.1 &^8.7 Hz, IH), 4.98-4.88 (m, IH), 4.17 (t, J= 9.3 Hz, IH), 3.86-3.66 (m. 3H).
Preparaiion 43: (R)-4.(5-(Azidorneth}'l)-2-o.\ooxazolid!n-3-yI)-2-fluoro-N'-(2-(pYridin-2-yl)acetyl)benzohydrazide
O f\ O
^N O ^ V/ VJ^N3
The title compound is prepared by following the procedure as described in preparation 47, by taking appropriate starting materials. Yield: 59%
72
'HNMR (400 MHz, DMSO): 5 10.20 (bs, 2H), 8.50 - 8.47 (m, IH), 7.80 -7.65 (m, 2H), 7.55 (dd, y= 1.9 Hz, 7.8 Hz, IH), 7.46 - 7.38 (m, 2H ), 7.28 - 7.24 ( m, IH ), 4.95 - 4.85 (m, IH), 4.18(t.J=9.4Hz, IH), 3.85-3.78 (m,lH). 3.72 (s,2H), 3.35-3.25 (m,2H), ES-MS(m/z); 412.5 (M^
Preparation 49: 5-(R)-a2idomethyl-3-{4-[4-(tert-butyl-dimethyI-silanyloxymethyl)-pyrazol-I -yi|-3-fluoro-phcny l)'OxazoJidin-2-one
I ^
TBDMSO "
N3
To a solution of 3-(4-[4-(tert-butyI-dimethyI-siIanyIoxymethyl)-pyra2ol-J-yI]-3-fluoro-phenyl}-2-oxo-oxazolidin-5-(R)-ylmethyl methanesulfonate (7.46 grams, 14.95 mmol) in dimethyllbrmamide (100 mL) was added sodium azide (4.86 grams, 74.73 mmol) and stirred at 75 "C for 2.5 hours. Solvent was removed by distillation under reduced pressure. Water (100 mL) was added to the residue and extracted with ethyl acetate (150 mL x 2). Combined ethyl acetate layer was washed with brine (100 mL x 1) and concentrated to obtain 4.83 grams of title compound as solid. Yield: 72.55%, MS(m/2):447(M''+l),
'H NMR (300 MHz, CDCI3): 6 7.85-7.92 (m, 2H), 7.67-7.80 (m, 2H), 7.22 (dd, /- 1.6 & 8.9 Hz, IH), 4.80-4.87 (m, IH), 4.71 (s, 2H), 4.12 (t, J = 9.0 Hz, IH), 3.90 (dd, J= 2.6 & 6.3 Hz, IH), 3.68 (dq, J= 4.4 & 13.3 Hz, 2H), 0.93 (s, 9H), 0.20 (s, 6H).
Preparation 50: 5-(R)-azidomethyI-3-|3-fluoro-4-(4-hydroxymethyl-pyrazol-l-yl)-phenyli-oxazolidin-2-one
HO-
I N-<\ />-N I
N3
To a mixture of tetrahydrofuran (5 mL), water (5 mL) and acetic acid (15 mL) was added
5-(R)-a2idomethyL3-{4-[4-(tert-butyl-dimelhyl-silanyloxymethyl)-pyrazol-l-yl]-3-fluoro-
phenyl}-oxazolidin-2-one (4.83 grams, 14.5 mmol) and stirred overnight at room temperature
./^n^ -_J:.— u:„„,i—„ta o^i,,tir»r, xw^c aHHp.d to thc rcactlon mixture and diluted with ethyl
acetate. Organic layer was separated and washed with 5% ammonia solution and
successively. Finally it was dried over anhydrous sodium sulfate and concentrated to obtaii
grams of title compound as solid.
Yield: 100%,
MS(m/z):333(M^+l),
'H NMR (300 MHz, CDCb): 8 8.00 (d, J= 2.7 Hz, IH), 7.89 (t, J - 8.9 Hz, IH), 7.72-7.7
2H), 7.22(dd,y= 1.5 & 7.5 Hz, IH), 4.81-4.88 (m. IH), 4.71 (s, 2H), 4,18 (t, ./= 8.9 Hz^
3.91 (dd,J=2.6&6.2H2, IH), 3.69 (dq, J = 4.3 & 13.3 Hz, 2H), 1.71 (bs, IH).
Preparation 51: 5-Azidoniethyl-3-[3-chIoromethyl-imidazol-l-yl)-3-flouro-phcnyl]-
oxazolidin-2-one
:l
F O
J. N^\ y-K I
A mixture of 5-azidomethyl-3-[3-fluoro-4-(hydroxymelhyI-imidazoI-!-y])-ph oxazoiidin-2-one (7 grams, 21 mmol) and thionyi chloride (175 mL) was stirred at temperature for 16 hours. Thionyi chloride was evaporated and the residue was treatec aqueous sodiumbicarbonate solution at 5 "C to neutral pH. It was extracted with ethyl a (100 mL x 2) and the combined organic layer was washed with brine (100 mL). Finally dried over anhydrous sodium sulfate and volatiles were evaporated to obtain the title compc Yield: 96 %,
'H NMR (300 MHz, CDCI3): 6 8.0 (s, IH), 7.69-7.80 (m, 2H), 7.32-7.44 (m, 2H). 4.82-4." IH), 4.61 (s, 2H), 4.12 (t, J = 8.9 Hz, HI), 3.88-3.94 (m, IH), 3.72-3.82 (m, IH) 3.65 (d
5.J & 13.5 Hz, IH).
Preparation 52: 5-(R)-azidomethyI-3-|4-(4-chloromethyl-pyrazol-l-yl)-3-nuoro-ph
oxazo(idin-2-one
The title compound is prepared by following the procedure as described in prep 5], by taking appropriate starting materials. Yield: 99%,
MS(m/z):352(M"'+l),
'H NMR (300 MHz, CDCI3) 6 8.03 (d, J= 2.4 Hz, IH), 7.90 (t, J= 8.9 Hz, IH), 7.73-7.82 (m, 2H), 7.24 (dd, y = 1.4 & 10.9 Hz, IH), 4.79-4.89 (m, IH), 4.64 (s, 2H), 4.12 (t, 7= 8.9 Hz, IH), 3.91 (dd, J= 2.6 & 6.2 Hz, IH), 3.69 (dq, J= 4.5 & 13.3 Hz, 2H).
Preparation 53: 5-AzidoinethyI-3-{4-(4-(tert-butyl-dimethyl-siIanyIoxyniethyl)-imidazol-^.
yIl-3-fluoro-phenyl}-oxazoIidin-2-one
TBDMSO
The title compound is prepared by following the procedure as described in preparation 49, by taking appropriate starting materials. Yield: 98%,
'H NMR (300 MHz, CDCI3): 5 7.68-7.75(m, 2H), 7.29-7.44(m, 2H), 7.16 (s, IH), 4.79-4.88(m, IH), 4.80 (s, 2H), 4.10-4.18 (m, 2H), 3.65 (dd, J= 4.2 & 13.0 Hz, IH). 0.97 (s, 9H), 0.12 (s, 6H). Preparation 54: 5-Azidomethyl-3-(3-fluoro-4-(hydroxymethyl-imidazol-l-yO-phcnyll-oxazolidin-2-one
A solution of 5-azidomethyl-3-{4-[4-(tert-butyl-dimethyl-silanyloxymethyl)-imidazol-I-y]]-3-fIuoro-phenyl}-oxa7n)id)n-2-one (35 grams. 447 mmol) in a mixture of acetic acid: trinuoroacetic acid: water (3:1:1, 875 mL) was stirred at room temperature for 16 hours. Solvents were evaporated under rotary evaporation and the residue obtained was scratched in ether 10 obtain white solid. It was filtered and dried under vacuum. Yield: 91%,
'l4 NMR (300 MHz, CD3OD): 5 7.96 (t, 7 = 1.2 Hz, IH), 7.84 (dd, J= 2.4 & 13.5 Hz, IH), 7.61 (m, IH), 7.48-7.52 (m, IH), 4.80-4.90 (m, IH), 7.41 (s. IH). 4.60 (s, 2H), 4.24 (t, J = 9.0 Hz, IH), 3.92-3.97 (m, IH), 3.78-3.84 (m, IH), 3.65 (dd,J= 5.1 & 13.5 Hz, IH). Preparation 55: BenzyI-(4-|S-azidomethyI-2-oxo-oxazoHdin-3-yl)-2-fluoro-phenyll-
carbamate
Bn(Cb2)N
The title compound is prepared by following the procedure as described in preparation 44, by taking appropriate starting materials. Yield: 65%,
lR(KBr, cm-'): 3386, 3032, 2928. 2108, 1707, 1674, 1521, 1403, 1297, 1218, 1133, 1036, 752,
699,
MS (m/z): 476 (M^+I), 420, 419, 384,
'HNMR(CDa3,200MHz):57.51-6.97(m, I3H), 5.16 (s, 2H), 4.81 (s, 2H), 4.75-4.60 (m, IH),
4.01-3.15 {m,4H).
Preparation 56: Tert-butyl [3-(4-carbamoyl-3-nuoro-phenyl)-2-oxo-oxa2olidin-5(S)-
ylmethyl|~carbainate
I!
^,
o
NHBoc
To a solution of 4-(5(S)-aminomethyl-2-oxo-oxazolidin-3-yl)-2-fluoro-benzamide (8 grams, 31.6 mmol) and triethylamine (13.2 mL, 94.8 mmol) in tetrahydrofuran/methanol (1:1) mixture was added Di-tert-Buty! dicarbonate (10.8 mL, 47.4 mmol) drop wise at 0-5 "C. Reaction mixture was then stirred at room temperature overnight. Solvent was evaporated and the residue dissolved in ethyi acetate. Ethyl acetate layer was washed with water 3-4 timcii, dried over sodium sulfate and concentrated to obtain the title compound. Yield: 90%,
'HNMR(300MHz,CDC]3):5 8.01 (i,J=8.8Hz. IH). 7.63 (dd, J= 2.0 & 14.8 Hz, IH), 7.1 (d, 7.i=8.4Hz, IH), 5.52 (bs,2H). 5.01 (bs, IH), 4.65-4.75 (m. !H), 4.01 (t, J =8.9 Hz, IH), 3.82 (dd, y= 6.5 & 8.9 Hz, IH), 3.40-3.32 (m, 2H), 1.32 (s, 9H).
Preparation 57: Preparation of tert-butyl [3-(3-fluoro-4-thiocarbamoyl-phenyI)-2-oxo-0 X azo lid in-5(S)-ylmethyll-carbamate
NHBoc
^ To a solution of tert-butyl [3-(4-carbamoyl-3-fluoro-phenyl)-2-oxo-oxazolidin-5(S)-ylmethyl]-carbamate (11 grams, 31.1 mmol) in dry dioxane was added Lawesson's reagent (7.56 grams, 18.7 mmol) and heated to 60 °C for 1 hour. Dioxane was evaporated completely and the residue dissolved in ethyl acetate. The ethyl acetate layer was washed with water 8-10 times, dried over sodium sulfate and concentrated. Pure product (8.2 grams) was obtained by column chromatographic purification on basic alumina using 1% methanol in chloroform as eluent. Yield: 71.3%,
'H NMR (300 MHz, CDCi3): 5 8.49 (t, 7 = 9.3 Hz. IH), 7.86 (bs, 2H), 7.72 (dd, J= 2.2 & 15.5 Hz, IH), 7.12(dd,y= 1.8 & 8.8 Hz, IH), 4.97 (bs, )H), 4.83-4.78 (m, ]H), 4.08 (t, J= 9.1 Hz, IH), 3.90 (dd,J = 6.7 & 8.9 Hz, IH), 3.56 (dd,J = 4.2 & 6.4 Hz, 2H), 1.42 (s,9H).
Preparation 58: Tert-bu(yl {3-[4-(4-chlorometbyI-thiazoI-2-yl)-3-fluoro-phenyl|-2-oxo-oxazoIidin-S(S)-ylmelhyl}-carbaniate
F. O
A mixture of tert-butyl [3-(3-fluoro-4-thiocarbamoyl-phenyl)-2-oxo-oxazolidin-5(S)-yimethylj-carbamate (5 grams, 13.5 mmol) and dichloroacetone (1.7 grams. 13.5 mmol) in toluene was refluxed at 110 °C for 2 hours. Toluene was evaporated and the residue purified by column chromatography over basic alumina using 1% methanol in chloroform to obtain pure product. Yield: 47%.
'HNMR(300MHZ, CDC13):5 7.90(t,J=8.7Hz, IH), 7.41 (dd,J=2.2& 13.5, IH). 7.21 (bs, IH), 5.0J (bs, IH), 4.79 (bs, IH). 4.71 (s, 2H). 4.10 (bs, IH), 3.90 (bs. IH), 3.50 (bs, 2H), 1.41
(s,9H). Pi*eparation59:3-{4-[4-(Tert-butyi-dimethyl-sUanyloxymethyl)-pyrazol-l-yll-3-fluoro-
phenyl}-2-oxo-oxazoUdin-5-(R)-ylmethyl melhanesulfonate
F O
To a solution of 3-{4-[4-(tert-butyl-dimethyI-silanyIoxymethyl)-pyrazoM-yiJ-3,5-difluoro-phenyl}-5-(R)-hydroxymethy!-oxazolidin-2-one (5.5 grams, ' 13.06 mmol) in dichloromethane (50 mL) was added triethylamine (7.27 mL, 52.26 mmol) and cooled to 0 "C. Methane sulfonylchloride (2.02 mL, 26.13 mmol) was added to it and stirred for 40 minutes at room temperature. Reaction mixture was then diluted with dichloromethane and washed with water (200 mL x 2) and brine solution (200 mL x 1) successively. Organic layer was dried over anhydrous sodium sulfate and concentrated to obtain 6.5 grams of white solid. Yield: 99.8%, MS(m/z):500(MV]X
'H NMR (300 MHz. CDCI3): 6 7.85-8.00 (m, 2H), 7.67-7.74 (m, 2H), 7.21-7.26 (m, IH), 4.91-5.02 (m, ]H), 4.70(d, J= 7.3 Hz, 2H), 4.49 (dq, J=3.5 & ]].7 Hz, 2H), 4.19 (t,7 = 9.1 Hz. IH), 3.99 (t, y= 6.4 Hz, IH), 3.12 (s, 3H), 0.95 (s, 9H), 0.20 (s, 6H). Preparation 60:3-{4-|4-(Tert-butyI-dimethyl-si!anyloxynietbyl)-iniidazol-l-yl]-3-fluoro-
phenyI}-2-oxo-oxazolidin-5-ylmethyI mcthanesulfonate
TBDMSO
O
The title compound is prepared by following the procedure as described in preparation 59, by taking appropriate starting materials.
Y'ield:95.2%,
' H NMR (300 MHz, CDCI3): 5 7.65-7.72 (m, 2H),7.25-7.50 (m, 2H), 7.10 (s, 1H). 4.96-4.97 (m,
IH), 4.75 (d, J= 0.9 Hz. 2H), 4.42-4.51 (m, 2H), 4.07-4.21(m, 2H), 3.10 (s. 3H), 0.93 (s, 9H),
0.12(s,6H).
Preparation 61: (S)-4-(S-(aminomethyI)-2-oxooxazoUdin-3-yI)-2-fluoro-N'-(2-(pyridin-2-
II yi)acetyl)benzohydrazide
\»%-:-'
To a solution of (R)-4-(5-(azrdomethyl)-2-oxooxazo(idin-3-y()-2-fluoro-N'-(2-(pyridin-2-yl)acelyl)benzohydrazide (2grams) in methanol-dioxane mixture, 20% Pd-C was added and the reaction mixture was hydrogenated (50 Psi) for 6 hours. The solution was finally filtered over celitebed; the filterate was concentrated under reduced pressure. The crude residue (i.4grams) was taken for the next step.
ii
Preparation 62: (S)-lcrt-butyl (3-(3-nuoro-4-(2-(2-(pyi-idin-2-yi)acetyI) hydrazinecarbonyl)phenyl)~2-oxooxazolidin-5-yl)me(hy!carbamate
O
The crude (S)-4-(5-(aminomethyl)-2-oxooxazolidin-3-yl)-2-fluoro-N'-(2-(pyridin-2-yl)acetyl) benzohydrazide (1.4 grams, 3.62 mmol) was dissolved in THF-H2O (2:1) mixture and sodium bicarbonate (900 mg, 10.71 mmol) was added to it. Then, (Boc)20 (1.18 grams, 5.41 mmoi) was added dropwise to it at 0 "C and the reaction mixture was stirred at room temperature for overnight. Finally it was diluted with water and extracted with ethyl acetate. The solvent was removed under reduced pressure and the residue was purified by column chromatography Igram.
Yield: 57%.
lR(KBr,cm-'): 3298,2976, 1749, 1678, 1624, 1516, 1410, 1167, 1001,918,872,752 'IINMR(400MHZ, DMSO):5 10.27(s, IH), 10.13 ( s,lH ), 8.49 - 8.48 (m, IH), 7.77 (dd,/ = (.6 Hz, 7.5 Hz, IH)), 7.68 (t, 7 = 8.3 Hz, IH), 7.57 (dd,y= 1.9 Hz, n.2H2, IH), 7.46 - 7.38 (m, 2H), 7.34-7.26 (m,lH), 7.22-7.18 (m,1H), 4.80-4.70 (m.lH),4.14,(t,J= 9.1 Hz, IH ), 3.86 - 3.80 (m, IH), 3.73 ( s, 2H ), 3.32-3.24 ( m, 2H ). 1.35 { s, 9H ).
ES-MS(m/z);488(M^+])
ii
Preparation 63: l-Frop-2-yne-lH-pyrazoI
A solution of pyrazole (2.0 grams, 29.4 mmol) and dry potassium carbonate (6.1 grams, 44.1 mmol) in dimethylformamide (20 mL) was treated with propargyl bromide (5.75 grams, 44.1 mmol) for 16 hours at room temperature. Inorganic material was filtered off and filtrate was diluted with water (100 mL). It was then extracted with ethyl acetate (2 x 100 mL) and the organic layer was washed with brine. Finally it was dried over sodium sulfate and volatiles were evaporated. The residue obtained was purified by column chromatography on silica gel using
ii
ethyl acetate and petroleum ether (1:4) to obtain the title compound as brown liquid.
Yield: 55%,
IR (Neat, cm"'): 3290, 3060, 2926, 2126, 1599, 1396, 1089, 1050,
MS(m/z): 107 (M^-l), 99,
' H NMR (CDCb, 200 MHz): 5 7.59-7.30 (m, 2H), 6.23 (s, 1H), 4.93 (s, 2H), 2.50 (s, ! H).
Preparation 64: EthyJ l-prop-2-yne3-amino-lH-pyra2oI-4-caraboxylate
EtOOC
" The title compound is prepared by following the procedure as described in preparation
63, by taking appropriate starting materials.
Yield: 12%. '
IR (Neat, cm"'): 3442,3294,2981, 1682, 1552, 1384, 1231, 1100, MS(m/z):194(MVl),99,
'M NMR (CDCh, 200 MHz): 5 7.61 (s, IH), 5.23 (bs, 2H), 4.77 (d, J= 2.5 Hz, 2H), 4.30 (q, J = 7.1 Hz, 2H), 2.50 (t, J = 2.5 Hz, IH), 1.34 (t, J =7.1 Hz,3H). Preparation 65: l-Prop-2-ynyl-lH-[l,2,41triazole
The title compound is prepared by following the procedure as described in preparatior '3, by taking appropriate starting materials.
^ield: 89%,
i!
R(Neat, cm"'): 3124,2970,2129, 1505, 1427, 1275,1138, 1018,
4S(m/z): 105 (M""-!), 97, 91,
H NMR (CDCI3, 200 MHz): 5 8.31 (s, IH), 7.97 (s, IH), 5.00 {6, J =2.1 Hz, 2H), 2.63 (t, J =
:.5Hz, IH).
^reparation 66: 3-(Trifluoromethyl)-I-prop-2-ynyr-lH-pyrazole
CF.
The title compound is prepared by following the procedure as described in preparatior )3, by taking appropriate starting materials. r'ield:40%,
R (Neat, cm"'): 3309, 2927, 1742, 1384,1242, 1135. 968, 771, 675, vis(m/z): 175(M^+I), 149,
' H NMR (CDCI3, 400 MHz): 5 7.70 (d, 7 = 1.3 Hz, 1H), 6.57 (d, J = 2.4 Hz, 1H), 4.99 (d, J = 2.-1-Iz, 2H), 2.57 (t. J= 2.6 Hz, 1H). Preparation 67: 3-(lH-Imidazol-4-yl)-pyridine
This compound was synthesized as per the procedure mentioned in J. Med. Chem., 1998, 41,
I! 2'^04. The crude compound (7g) obtained was directly taken for further step.
Preparation 68: 3-(I-Prop-2-ynyMH-imidazol-4-yl)-pyridine
To a solution of 3'(lH-lmida2ol-4-yl)-pyridine (750 mg, 5.17 mmol) in THF was added Na (310mg, 7.76 mmol) followed by the addition of propargyl bromide (1.35 mL, 15.51 mmol) al
'C and the resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was first quenched with water and then extracted with ethyl acetate, washed with water and brine. The combined organic layers were dried over Na2S04 and the concentrated under vacuum
to yield crude product (450 mg) that was directly taken for ftirther step.
IJ Yield: 47%
ES-MS(m/z): 184.(M^+1)
Preparation 69: 3-MethyM-prop-2-ynyl-4H-ll,2,41triazole
N^ N
! M^r-^
The above compound was synthesized in 11% yield following the procedure mentioned in Org.
Le(l.,2004,6, 17,2969
Preparation 70: I-(Fyridin-2-yI)prop-2-yn-l-oI
To a solution of pyridin-2-carboxaldehyde (2 grams, 18.69 mmol) in THF, ethynylmagnesium bromide (45 mL, 0.5M in THF, 22.43 mmol) was added at 0 ''C, and the reaction mixture was stirred at room temperature for 3bours. The reaction was quenched with saturated aqeous ammonium chloride and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure and the crude residue was used for the next step. Following the similar procedure l-(pyridin-3-yl) prop-2-yn-l-o] and l-(pyridin-4-yl)prop-2-yn-
1 -ol were synthesized .
Preparation 71: Benzyl-{2-nuoro-4-[5-(methoxycarbonylamino-methyl)-2-oxo-oxazolidin-3-
yil-phenyl)-carbamate
Bn(Cb2)N
To a solution of benzyl-[5-aminomethyl-2-oxo-oxazolidin-3-yi)-2-fluoro-phenyIj-carbamate (1 gram, 2.22 mmol) and triethylamine (337 mg, 3.33 mmol) in chloroform (25 mL) was added chloromethylformate (252 mg, 2.66 mmol) at 0 °C. The reaction mixture was allowed (0 come 10 room temperature and stirred for additional half an hour. Water (200 mL) was added to; the reaction mixture and extracted with chloroform (2 x 100 mL). Organic layer was separated and washed with brine. Finally it was dried over sodium sulfate and volatiles were evaporated. The residue obtained was purified by column chromatography on silica gel using methanol and chloroform (1:9) as eluent to obtain title compound as white .solid. Yield: 70%,
IR(KBr, cm''): 3356, 2926, 1756, 1709, 1520, 1043, 1218, MS(myz): 548, 508(M''+1),476, 444, 412. 374, 310, 279,
'H NMR (CDCI3, 200 MHz): 5 7.50-7.04 (m, 13H), 5.16-5.0 (m, 2H), 4.98-4.60 (m, 3H), 4.97 (t, J= 8.4 Hz, IH), 3.98-3.40 (m. 7H). Preparation 72: Methyl (3-(4-Amino-3-fluoro-phenyl)-2-oxo-oxazolidin-5-yI-methyll-
carbamatc
H,N—(v />—N H
'^" "^ // \.^^ :w^ n
A solution of benzyl-(2-fluoro-4-[5-(methoxycarbonylamino-methyl)-2-oxo-oxazolidin-3-yl]-phenyl}-carbamate (2 grams, 4.0 mmol) in methanol (25 mL) was stirred under hydrogen atmosphere for 8 hours in the presence of 10% palladium on charcoal (637 mg, (^i.S mmol). Catalyst was filtered over a pad of celite and the filtrate was concentrated. The residue obtained was purified by column chromatography on silica gel using methanol and chlorofrm (1:19) as eluent to get title compound as white solid.
Yield: 60%,
IRCKBr, cm-'): 3398, 2926, 1722, 1632, 1522, 1428, 1365,
MS (m/z): 284 (M"), 266, 252,
'H NMR (DMSO-d,, 400 MHz): 6 7.64-7.48 (m, 2H), 7.38 (dd, y= 2.4 & J3.4H2, iH), 6.96 (dd,
7= 2.2 & 8.6Hz, IH), 6.76 (dd. y= 8.6 & 9.9Hz. IH), 5.0 (s. 2H), 4.70-4.62 (m, IH), 4.01 (t, y =
9.1Hz, IH), 3.64 (dd,y= 6.1 & 9.1Hz, IH), 3.54 (s,3H), 3.33 (t, J-6.1Hz, 2H).
Preparation 73: Methyr (3-(4-azido-3~fluoro-phenyl)-2-oxo-oxazolidin-5-yl-methyII-
carbamate
'; To a solution of methyl [3-(4-amino-3-fluoro-pheny[)-2-oxo-oxa2oIidin-5-yl-methyi]-carbamate {225 mg, 0.795 mmol) in 50% aqueous hydrochloric acid (25 mL) was added sodium nitirite (109 mg, 0.16 mmol) in small batches at 5-10 °C and stirred for half an hour. A solution of sodium azide (104 mg, 0.16 mmol) and sodium acetate (1.37 grams, 16 mmol) was added to ihe reaction mixture over 15 minutes. The reaction mixture was then diluted with water and extracted with ethyl acetate (2 x 50 mL). The organic layer was washed with brine and dried over sodium sulfate. The volatiles were evaporated and the residue obtained was purified by column chromatography on silica gel using methanol and chioroform (1:9) to get the title compound as brown solid. Yield: 57%,
lR(KBr,cm-'): 3356,2922,2852,2136,2103, 1730, 1600, 1426, 1324, MS (m/z): 310(M'-), 284, 269, 251,
'H NMR (DMS0-d6, 400 MHz): 5 7.64-7.50 (m, 2H), 7.36-7.30 (m, 2H), 4.75-4.70 (m, IH), 4.11 (t,y=8.8Hz, lH),3.76(dd,y=6.4&9.1Hz, IH)', 3.54 (s, 3H), 3.35 (I, J= 5.9Hz, 2H). Preparation 74: 3-[3-FIuoro-4-(4-pyrazol-l-ylmethyl-imidazol-l-yl)-phenyl)-5-isothiocyanatomethyl-oxazolidin-2-one
-NCS
; To a solution of 5-aminomethyl-3-[3-fluoro-4-(4-pyrazoi-l-ylmethyl-imidazol-l-y!)-phenyl]-oxazolidin-2-one (0.6 grams, 1.7 mmol) in dichloromethane (15 mL)'was added triethyl amme (0.7 mL, 4.95 mmol) followed by the drop wise addition of thiophosgene (0.15 mL, 1.98 mmol) at 0-5 °C. The resulting mixture was stirred at the same temperature for 30 minutes. Solvent was evaporated and the residue obtained was purified by column chromatography on silica gel (100-200 mesh) using a mixture of methanol and chlorofonm (1:19) to obtain the title compound. Yield: 27 %,
Preparation 75: 5-Aniinonicthyl-3-{4-|4-(tert-butyI-diniethyI-silanyIoxyinethyI)-imidazol-]-yl]-3-fluoro-phenyl}-oxazolidin-2-one
TBDMSO''^ "^
To a solution of 5-Azidomethyl-3-{4-[4-(tert-butyl-dimethyl-silanyloxymethyl)-imidazol-l-yl]-3-fluoro-phenyl}-oxazolidin-2-one (13.0 grams, 29.15 mmol) in THF wa:s added triphenyl phosphine (8.6 grams, 38.05 mmol) followed by the addition of 1 mL of water after 1 hours. The reaction mixture was heated at 50 °C for overnight. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography (7.20 grams)
Yield: 59%
'l€NMR (400 MHz, DMSO): 8 7.92 (t, V=L3 Hz, IH), 7.74 (dd, 7=2.4, 13.7 Hz, IH), 7.65 (t, J 4.9 Hz, IH), 7.47 (dd, J=l.l, 8.9 Hz, IH), 7.36 (s, IH), 4.67-4.65 (m, IH), 4.61 (s, 2H). 4.12 (t,y=9.1 Hz, IH), 3.91 (dd,y=6.4,9.1 Hz, IH), 3.25 (bs, 2H), 2.85 (dd, J =4.8,12.3 Hz, 2H), 0.89 (s, 9H), 0.08 (s, 6H)
ES-MS(m/z):421 (MVI)
Preparation 76: (S)-N-(3-{4-(4-(tert-Butyl-dimethyI-silanyloxyniethyl)-iniidazoM-yIl-3-
ii
nuoro-phenyl}-oxazoIidin-5-y)niethyJ)-acetaniide
QiZ
TBDMSO
To a solution of 5-Aminomethyl-3-{4-[4-{tert-butyl-dimethyi-silanyloxymethyi)-imidazol-Ky!]-3-huoro-pheny]}-oxa2olidin-2-one (7.0 grams, 16.6 mmol) in DCM was added triethylamine (6.95 mL, 50.0 mmol) followed by the addition of acetic anhydride (4.75 mL, 49.9 mmol) at 0 °C and the resulting mixture was stirred room lemperature for 12 hours. The reaction mixture was extracted with DCM, washed with water and brine. Organic layer was dried over Na2SO-i and concentrated under vacuum. The crude product was purified by column chromatography to Dbtain the desired product as a white solid (6.20 grams,)
Yield; 80%
IR (Neat, cm-'): 3275, 1755, 1662, 1529,1416,1223,839,752
'HNMR: (400MHz,DMSO): 5 8.24 (t, J=5.9 Hz, IH), 7.94(s, IH), 7.72 (dd, J=2.3, 13.4 Hz, IH), 7.66 (I, 7=8.9 Hz, IH), 7.44 (dd, 7 = 1.9, 8.9 Hz, IH), 7.37 (s, IH), 4.81-4.74 (m, IH), 4.61 (s,2H), 4.17(t, J=8.9Hz, IH), 3.78 (dd, J=6.4, 9.1 Hz. IH), 3.44 (t, J=5.5 Hz, 2H), 1.84 (s, 3H), 0.89 (s, 9H), 0.08 (s, 6HI
ES-MS(m/z):463(MVl)
Preparation 77: (S)-N-{3-[3-Fluoro-4-(4-hydroxymethyl-imidazo|-l-yl)-phenyl]-2-oxo-
oKazo!idin-5-y!methy!)-acetamide
To a solution of 2-oxo- N-(3-{4-[4-(ten-Butyl-dimethyI-silanyIoxymethyI)-imida2ol-l-y!3-3-n'uoro-phenyl}-oxazo]Jdin-5-y]methyI)-acetamide (6.20 grams, 13.4 mmol) in THF was added 15 ml of TBAF (IM solution in THF) at 0 ""C. The resulting mixture was stirred at room lemperature for 2 hours. After the completion of the reaction, THF was removed partially and the residue was extracted with ethyl acetate, washed with water and brine The organic layers were
86
dried over Na2S04 and the volatiles were removed under reduced pressure. The crude product was purified by column chromatography (o obtain the desired product (5.0 grams). Yield: 96%
IR(KBr,cm-'): 3242,2962, 1749, 1666, 1529, 1415, 1213,748
H NMR (400 MHz, DMSO): 5 8.26 (I, J=5.8 Hz, IH), 7.92 (s, IH), 7.72 (dd, 7=2.4, 13.7 Hz, IH), 7.65(t,y=8.9H2, IH), 7.45 (dd, 7 = 1.9,8.9 Hz, lH),7.34(s, IH), 4.97 (t, 7=5.6 Hz, IH), 4.79-4.75 (m, IH), 4.41 (d, 7=5.4 Hz, 2H), 4.17 (1,7=8.9 Hz, IH), 3.79 (dd, 7=6.4, 9.4 Hz, IH), 3.43 (t, 7-5.4 Hz, 2H), 1.84 (s, 3H)
BS-MS(m/z): 349(M^+I)
Preparation 78: (S)-N-{3-|4-(4-Cyanomethyl-imidazol-l-yI).3-fluoro-phenyl]-2-oxo-
oxazolidin-5-ylniethyl}-acetamide
F ^
N^ \-/ ^--VN CH3
, O To a solution of N-{3-[3-Fluoro-4-(4-hydroxymethyl-imidazol-l-yl)-phenyl]-2-oxo-oxa2olidin-5-'y!methyI}-acetamide (5 grams, 14.4 mmol) in dry DCM was added trielhyl amine (8.7 grams, 86.1 mmol) and methanesulphonyl chloride (3.0 grams, 26.0 mmol) at 0 °C and stirred at roomtemperature for 2 hours. Reaction mixture was extracted with DCM and concentrated. The crude compound was dissolved in dry DMF and potassium cyanide (1.87 grams, 29.0 mmol) was added and heated to 70 "C for 6 hours. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layers were dried over Na2S04 and evaporated under vacuum. The crude compound was purified by column chromatography to afford the desired compound as a yellow solid (1 gram).
Yield: 29%
IR (Meat, cm''): 2924, 2853, 1753,1664, 1528, 1412,1211
IH NMR (400 MHz, DMSO): 8.22 (t, 7= 5.6 Hz, IH), 8.01 (s, IH), 7.73 (dd, 7= 2.4, 13.7 Hz,
!H), 7.67 (t,7= 8.9 Hz. IH), 7.48 (s, IH), 7.46 (dd, 7= 1.6, 8.9 Hz, IH), 4.77 - 4.75 (m, IH),
4.117 (t. 7= 9.1 Hz, IH), 3.93 (s, 2H). 3.78 (dd, 7 = 6.4, 9.1 Hz, IH), 3.43 (t, 7 = 5.6 Hz, 2H),
1.84 (s,3H).
i:;S-MS(m/2):358(M''+l)
Preparation 79: (S)-N-{3-|3-Fluoro-4-(4-thiocarbamoylmethyl-iniidazo|.l-y0-phenyll-2-oxo-oxazolidin-S-ylmethylJ-acetamide
To a solution of N-{3-[4-(4-Cyanomethyl-imidazol-l-yi>3-fluoro-phenyl]-2-oxo-oxa2olidin-5-
ylmethyl}-acetamide (400 mg, 1.12 mmol)) in dry DMF was passed hydrogen sulphide gas at
100 °C for overnight. The reaction mixture was diluted with ethyl acetate, washed with water
and brine. The combined organic layers were dried over NaiSO^ and purified by column
chromatography to get the desired product as a yellow solid (200 mg)
Yield: 46%
1HNMR(400 MHz, DMSO): 5 9.76 (brs, IH), 9.49(bs, IH), 9.24 (bs, IH), 8.27 (1, J = 5.6 Hz, IH),
7.85 - 7.77 (m, 3H), 7.53 (dd, J = 1.6, 8.9 Hz, 1H), 4.81 - 4.76 (m, 1H), 4.19 (t, J = 8.9 Hz, 1H), 4.02 (s,
2H), 3.82 (dd, J= 6.4,9.1 Hz, 2H), 3.61 - 3.16 (m, IH), 1.84 (s, 3H).
ES-MS(m/z)i392(MVl)
Preparation 80: (S)-N-|3-(3-Fluoro-4-hydrazinothiocarbonyl-phenyI)-2-Oxo-oxazolidin-5-ylmethyll-acetamide
O
CH3
H,N-NH ^—^ Y
O
The above compound was synthesized using the procedure mentioned in Bioorg. Med Chem.
Lett., 2003,73,4193-4196
Preparation 81: (S)-N-{3-I4-(5-Chloromethyl-[l,3i41thiadiazol-2-yI)-3-fluoro-phcnyll-2-
oxo-oxazolidin-5-ylmethyl}-acetamide
H
F, O
88
To a solution of N-[3-(3-Fluoro-4-hydrazinothiocarbonyI-phenyl)-2-oxo-oxazolidin-5-yImethyl]-
acetamide (75 mg, 0.23 mmol) in dry THF was added chloroacetyl chloride (65 mg, 0.58 mmol)
dropwise and refluxed for 1 hour. After the completion of the reaction, solvent was removed and the
residue was purified by column to afford the title product as a white solid (80 mg)
Yield: 91% .
IR (KBr, cm-'): 3305, 1742, 1543, 1419, 1219, 1080, 870, 756
'H NMR (400 MHz, DMSO): 8 8.30 (t, J = 8.9 Hz, IH), 8.23 (t, y-5.9 Hz, IH). 7.76 (dd, J =
2.1, 13.7 Hz, IH), 7.56 (dd, J =2.4, 8.9 Hz, IH), 5.32 (s, 2H), 4.82-4.76 (m, IH), 4.23 (t, 7 =
9.] Hz, IH). 3.82 (dd,./= 6.5, 9.1 Hz, IH), 3.45 (t, J= 5.6 Hz, 2H), 1.84 (s, 3H).
ES~MS(m/2}:385(MVl)
Preparation 82: (S)-N-{3-13-Fluoro-4-(4-hydroxymethyl-[l,2,3Itria2ol-l-yl)-phenyn-2-oxo-oxazolidin-S-ylmethylj-acetamide
F ^
YA .h9 H
N=N ^'=^ Y
O
Following the general procedure the titled compound was synthesized from N-[3-(4-Azido-3-
fluoro-phenyl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide.
Yield: 84%
IR (KBr, cm-'): 2936, 2676, 2493, 2360, 1752, 1528, 1475, 1398, 1036.
IH NMR (400 MHz, DMSO); 6 8.40 (d, J-1.8 Hz, IH), 8.24 (t, J =5.6 Hz, 1H), 7.83 (l, J =8.6Hz, 1H),
6 7.79(s, 2H), 4.19(t,J=9.1 Hz, IH), 3.82 (dd, 6.4 Hz, 9.1 Hz, IH), 3.43 (t, V =5.6 Hz, 2H), 1.84 (s,
3H)
F.S-MS(m/z):350(M +1) Preparation 83: (S)-N-{3-(4-(4-Cyanome(hyI-|l,2,3IfriazoJ-l-yl)-3-nuoro-phenyll-2-oxo-
oxazolidin-5-ylmethyl}-acetamide
,^0 H
N=N
The title compound is prepared by following the procedure as described in preparation 78, by, taking appropriate starting materials. Yield; 76%
!R(KBr. cm-'): 3351, 1756, 1668, 1525, 1416, 1203, 1049, 1009, 751, 686.
IH NMR (400 MHz. DMSO): 6 8.56 (d, J=1.8 Hz, IH), 8.23 (t, 7 =5.9 Hz, IH), 7.86 (t, 7=8.8
Hz, IH), 7.81 (dd, J=2.4 Hz, 13.4 Hz, IH), 7.56-5 7.53 (m, IH), 4.84-4.75 (m, IH), 4.23 (s, 2H),
4.20 (t, J-8.9 Hz, IH), 3.88-3.78 (m, IH), 5 3.44 (t,y=5.6 Hz, 2H), 1.84 (s, 3H).
ES-MS(m/z):359(M''+l)
Preparation 84: (S)-N-(3-{3-FIuoro-4-14-(N-hydroxycarbamimidoylmcthyI)-[l,2,3|triazoM-yI]-phcnyl}-2-oxo-oxazolidin-5-ylmethyI)-acetamide
H,N
To a solution of N-{3-[4-(4-CyanomethyI-[I,2,3]triazoi-I-yI)-3-fluoro-phenyl]-2-oxo-
oxazolidin-5-ylmethyl}-acetamide (300 mg, 0.837 mmol) and hydroxylamine hydrochloride
(230 mg, 3.34mmol) in ethanol, a solution of NajCO] (266 mg, 2.51 mmoi) was added dropwise
and the reaction mixture was stirred at 65 °C for overnight. The solvent was removed under
vacuum and the residue was purified by column chromatography to obtain the required product
as a white solid (300 mg).
Yield: 92%
JR (KBr, cm-'): 2974, 2937, 2739, 2677, 2491. 1732, 1660, 1529, 1475. 1433, 1399, 1243, 1169,
1131. 1036,713.
IH NMR(400 MHz. DMSO): 5 iO.J5(bs, IH), 8.34 (d. J=1.8 Hz, IH), 8.27 (1,7-5.9 Hz, IH),
7;90-7.76(m, 2H), 7.53 (dd,J=1.6Hz, 9.1 Hz, IH), 5.70 (bs,lH), 4.84-4.75 (m, lH),4.19(t,J
=8.8 Hz, IH), 3.83 (dd, J=6.4Hz, 9.2 Hz, IH), 3.5I(s, 2H), 3.44 (t.y=5.3Hz, 2H), 1.84 (s, 3H).
ES-MS(m/z):392(M'^-M)
Example 1: 5-(R)-a2idomethyl-3-13-nuoro-4-(4-pyrazoi-l-y!methyl-oxazol-2-yI)-phenyll-oxazolidin-2-one
o
N
K
N3
., A solution of 5-(R)-azidomethyl-3-[4-(4-chloromethyl-oxazol-2-y!)-3-fluoro-phenyI]-oxazolidin-2-one (0.5 grams, 1.43 mmol) in acetonitrile (15 mL) was treated with pyrazole (0.2 grams, 2.85 mmol) in presence of anhydrous potassium carbonate (0.6 grams, 4.28 mmol) at 85 ^C for 20 hours. Solids were filtered off and filtrate was evaporated. The residue obtained was dissolved in ethyl acetate (100 mL) and it was washed with water (50 mL) and brine solution luccessively. Finally the organic layer was dried over anhydrous sodium sulfate and the volatiles vere evaporated. The residue obtained was purified by column chromatography by using basic ilumina in 0.2% methanol: chloroform system.
Vield: 34%,
, I
H NMR (300 MHz, CDCI3): 5 8.01 (t, J = 8.4 Hz, IH), 7.51-7.65 (m, 4H), 7.35 (dd, J = 2.0 &
S.7 Hz, IH), 6.30 (s, IB), 6.88-6.76 (m, IH), 4.12 (t, J= 8.9 Hz, IH). 3.90 (dd, J- 2.6 & 6.3 Hz,
IH), 3.70 (dq, J = 4.4 & 13.3 Hz, 2H).
Example 2: N-{3-[3-fluoro-4-(4-pyra2oM-yImethyl-oxazol-2-yI)-phenyIJ-2-oxo-oxazondin-
5(S)-ylmethyl)-acetamide
To a solution of 5-(R)-azidomethyl-3-[3-fluoro-4-(4-pyra2ol-l-ylmethyl-oxazol-2-yl)-phenyl]-oxazolidin-2-one (185 mg, 0.53 mmol) in tetrahydrofuran (5 mL) was added triphenyl phosphene (0.28 grams, 1.0 mmoJ) and stirred at room temperature for 2 hours. It was then heated to 75 "C for 1.5. hours after the addition of water (400 ^1). Solvent was evaporated and the residue obtained was dissolved in pyridine (4 mL). Acetic anhydride (150 nl) was added to it at 0 °C and stirred for 30 minutes. Pyridine was removed and the residue obtained was purified by column chromatography by using basic alumina in 1.2% methanol: chloroform. Yiield: 40%, MS (m/z): 400 (M^+1), 332, 279,
Melting Range: 204-206 °C,
'H NMR (300 MHz, DMS0-d6): 5 8.3 (t, J= 5.7 Hz, IH), 8.18 (s, IH), 8.02 (t, 7 = 8.8 Hz, IH),
7,82 (d, J = ].9Hz, IH), 7.68-7.62 (dd,y= 2.3 & 13.8 Hz, IH), 7.50 (dd, J = 2.2 & 13.8 Hz,
1H), 7.45 (dd, J = 0.7 & 1.9 Hz, 1H), 6.31 (dt,./ = 2.1 & 4.1 Hz, 1H), 5.3 (s, 2H), 4.72-4.82 (m,
IH), 4.25 (t, y = 9.2 Hz, IH); 3.80 (dd,y = 2.8 & 6.5 Hz, IH), 3.42 (d, 7= 6.7 Hz, IH), 1.82 (s,
3H).
Example 3: 5-(R)-a2idonnethy|-3-|3-fluoro-4-(4-[l,2,41triazol-l-yImethyl-oxazoI-2-yl)-phenyl)-oxazolidin-2-one
N3
A solution of 5-(R)-azidomethy]-3-[4-(4-ch]oromethyl-oxazol-2-yl)-3-fluoro-phenyl]-oxazoUdin-2-one (0.5 grams, 1.4 mmol) in acetonitrile (15 mL) was treated with triazole (0.2 grams, 2.9 mmol) in presence of anhydrous potassium carbonate (0.6 grams, 4.3 mmol) at 85 "C for 20 hours. Solids were filtered off and filtrate was evaporated. The residue obtained was dissolved in ethyl acetate (100 mL) and it was washed with water (50 mL) and brine solution successively. Finally the organic layer was dried over anhydrous sodium sulfate and the volatiles were evaporated. The residue obtained was purified by column chromatography by using basic alumina in 0.2% methanol: chloroform system. Yiield: 40%,
'IJT NMR (300 MHz, CDCI3): 5 8.30 (s. 1H>, 8.02 (d, J= 8.5 Hz, IH), 7.98 (s, IH), 7.75 (s, IH), 7.62 (dd, y = 2.1 & 10.9 Hz, IH), 7.35 (dd, J = 2.2 & 6.6 Hz, IH), 5.48 (s, 2H), 4.78-4.88 (m, 1H), 4.12(1, .7 = 9.0 Hz, IH). 3.81 (dd, 7-2.7 & 8.2 Hz, IH), 3.68 (dq, J= 4.4 & 13.3 Hz, 2H).
Example 4: N-{3-|3-fluoro-4-(4-[l,2,41triazol-I-ylmethyl-oxazoI-2-yl)-phenyll-2-oxo-
O-iy^y
I To a solution of 5-(R)-a2idomethyI-3-[3-fluoro-4-(4-[l,2,4]triazol-l-ylmethyl-oxazo!-2-yl)-phenyl]-oxazoIidin-2-one (200 mg, 0.5 mmol) in tetrahydrofliran (4 mL) was added tripheny! phosphene (0.28 grams, 1.0 mmol) and stirred at room temperature for 2 hours. It was heated to 75 "C for 1.5 hours after the addition of water (400 (j|). Solvent was evaporated and the residue obtained was dissolved in pyridine (4 mL). Acetic anhydride (150 pi) was added to it at 0 "C and stirred for 30 minutes. Pyridine was removed and the residue obtained was purified by column chromatography by using basic alumina in 1.2% methanol: chloroform. Yield: 63%.
Melting Range: 160-162''C, MS(m/2):401 (M^l), 332,
'H NMR (300 MHz, DMS0-d6): 6 8.64 (s, IH), 8.26 (bs, 2H), 7.95-8.02 (m, 2H), 7.72-7.40 (m, 2H), 5.43 (s, 2H), 4.89-470 (m, IH), 4.17 (t, J = 8.9 Hz, IH), 3.80 (t, J= 6.7 Hz, IH), 3.43 (t, J = \5A H2,2H). 1.84(s, 3H). Example 5: 5-(R)-azidomethyl-3-[3-fluoro-4-(4-imidazol-l-ylincthyI-oxazoI-2-yl)-phenyIl-
Dxazolidin-2-one
R
w T >
The title compound is prepared by following the procedure as described in example 3, by taking appropriate starting materials. MS(m/z):384(MVl),356.
Example 6: Preparation of N-{3-[3-f^uoro-4-(4-imidazoM-ylmcthyI-oxazo^2-yl)-phenyll-2-oxo-oxazoIidill-5 (S)-ylmethyl}-acetamide
s The title compound is prepared by following the procedure as described in example 4, by
taking appropriate starting materials. Yield: 42%,
Melting Range: 198-200 "C, MS (m/2): 400 (M^+l), 332, 279,
'HNMR(DMS0-d6): 5 8.25 (t, J = 5.8 Hz, IH). 8.20(s, IH), 8.00 (t, J= 8.7 Hz, IH). 7.74 (s. IH), 7.45(dd, J=2.1 & 13.8 Hz, IH), 7.50 (dd,./=2.1 & 8.8 Hz, IH), 7.22(bs, IH), 6.91 (s, IH), 5.20 (s, 2H), 4.82-4.72 (m, IH), 4.16 (t, J = 9.0 Hz, JH), 3.79 (dd, J-6.5 & 9.3 Hz, IH). 3.42 (t, J= 5.5 Hz, 2H), 1.82 (s, 3H).
Example 7: Tert-butyl {3-13-fluoro-4-(4-imidazol-I-yImethyl-thia2ol-2-yl)-phenyll-2-oxo-oxazolidin-5(S)-ylinethyl}-carbaniate
R
^ O
A mixture of tert-butyl {3-[4-(4-chloromethyl-thiazol-2-yl)-3-fluoro-phenyI]-2-oxo-
oxazolidin-5(S)-ylmethyl}-carbamate (3 grams, 7.79 mmol), potassium carbonate (4.3 grams ,
31.16 mmol) and imidazole (1.2 erams, 15.58 mmol) in acetonitrile (100 mL) was heated to 75
I °C for 4 hours. Potassium carbonate was separated by filtration and the filtrate concentrated.
The residue obtained was extracted with chloroform. The chloroform layer was dried over
sodium sulfate and concentrated to obtain a brown solid.
Ykld: 89%,
'H NMR (300 MHz, CDCI3): 5 8.24 (i, J = 8.6 Hz, IH), 7.72-7.66 (m, 2H), 7.28-7.24 (m, IH),
7.n-7.06(m, 3H), 5.31 (s, 2H), 4.98 (bs, IH), 4.83-4.78 (m, IH), 4.09 (t, y = 8.0 Hz, IH), 3.92
(dd,J= 6.4 & 9.1 Hz, IH), 3.56 (dd, J= 4.3 & 6.3 Hz, 2H), 1.42 (s, 9H).
Example 8: Tert-butyl {3-l3-nuoro-4-(4-|l,2,41triazol-l-yImethyUthiazol-2-yl)-phenyll-2-
oxo-oxazolidin-5(S)-ylmethyl}-carbamate
NHBoc ■■
I The title compound is prepared by following the procedure as described in example 7, by taking appropriate starting materials. Yield: 63%,
'H NMR (300 MHz, CDCh): 5 8.30 (s. IH), 8.22 (t, y = 8.6 Hz, IH), 7.99 (s, IH), 7.70 (dd, J = 2.2 & 13.5 Hz, IH), 129-122 (m, 2H), 5.54 (s, 2H), 5.04 (s, 2H), 5.04 (bs, IH), 4.83-4.78 (m, IH), 4.08 (t, J= 9.0 Hz, IH), 3.91 (dd, J = 6.6 & 8.8 Hz, IH), 3.56 (dd, J= 4.3 & 6.3 Hz, 2H), 1.41 (s,9H).
Example 9: Tert-butyl {3-[3-fluoro-4-(4-pyrazol-l-ylmethyl-thiazol-2-yl)-phenyll-2-oxo-oxazolidin~5(S)-ylmethyl}-carbamate
NHBoc
The title compound is prepared by following the procedure as described in example 7, by taking appropriate starting materials. Yield: 83.3%.
'HNMR(300MHz, CDCl3):6 8.24(t,J=8.6Hz, IH), 7.65 (dd,J=2.2& 13.5 Hz, IH). 7.60 fd,J=2.3Hz, lH),7.57(d,y= 1.5 Hz. IH), 7.48-7.24 (m, lH),7.09(s, IH), 6.32 (t, J-2.1 Hz, IH), 5.53 (s, 2H), 5.05 (bs, IH), 4.82-4.77 (m, IH), 4.07 (t, J = 9.0 Hz, IH), 3.9 (dd, J = 6.7 & 8.8 Hz, ] H), 3.55 (dd, J = 4.3 & 6.0 Hz, 2H), 1.42 (s, 9H).
Example 10: N-{3-|3-nuoro-4-(4-imidazoM-ylmethyl-thiazol-2-yl)-phenyl)-2-oxo-
oxazo!idin-5(S)-ylincthyI}-acctaniide
F O
Tert~Butyl-{3-[3-fluoro-4-(4-imida2ol-l-ylmethyl-thiazol-2-yl)-phenyi]-2-oxo-DxazoHdin-5(S}-yImethyi}-carbamate (0.5 grams, 1,05 mmol) and trifluoroacetic acid (2.5 mL, 5.27 mmol) were stirred in dichloromethane for Ihour. Dichloromethane and trifluoroacetic acid were completely evaporated and diethyl ether was added to it. The solid thus obtained was dissolved in dichloromethane (10 mL) and pyridine (0.56 mL) was added followed by the addition of acetic anhydride (0.162 mL, 1.6 mmol) at 0 "C. The reaction mixture was stirred at room temperature for 1 hour. Dichloromethane and pyridine was evaporated and the residue obtained after addition of water was collected. Pure product (0.18 grams) was obtained after purification by column chromatography over basic alumina using 2% methanol in chloroform as eluent. Yield: 42%
Melting Range: 192-194 °C. MS(m/z);416(MVl), 348,
'H NMR (300 MHz, CDCI3): 5 8.27 (t, J= 5.7 Hz, IH), 8.20 (t, 7 = 8.8 Hz, IH), 7.79 (s. IH), 7.69 (dd, J-2.1 &14.2H2, IH), 7.59(s, IH), 7.50 (dd,y = 2.1 & 8.8 Hz, IH), 7.26 (s, IH), 6.92 (s, IH). 5.38 (s, 2H), 4.80-4.75 (m, IH), 4.17 (t, J- 9.0 Hz. IH), 3.79 (dd, J= 6.6 & 9.2 Hz, IH), 3.43 (t, y = 5.4 Hz, 2H), L82 (s, 3H).
ii Example 11: N-{3-(3-fluoro-4-(4-|l,2,41friazoM-ylm€thyI-thiazoI-2-yl)-phenyI)-2-oxo-
oxazolidin-5(S)-ylmethyI}-acetamide
K 0
N _>=V >~-o
y -V>^v^ H 0
if N'^N
ij Tert-Butyl-{3-[3-fluoro-4-(4-[l,2,4]triazol-l-ylmethyl-thiazol-2-yl)-phenyl]-2-oxo-oxazolidin-5(S)-ylmethyl}-carbamate (0.5 grams, 1.05 mmol) and trifluoroacetic acid (2.5 mL) were stirred in dichloromethane for 1 hour. Dichloromethane and trifluoroacetic acid were completely evaporated and diethyl ether was added to it. The solid thus obtained was dissolved in'dichloromethane (10 mL) and triethylamine (0.56 mL) was added followed by the addition of acetic anhydride (0.16 mL, 1.6 mmol) at 0 °C. The reaction mixture was stirred at room temperature for I hour. Dichloromethane and triethylamine was evaporated and the residue
obtained after addition of water was collected. Pure product (0.08 grams) was obtained after purification by column chromatography over basic alumina using 2% methanol in chloroform as eluent.
Yield: 22%
Melting Range: 196-198 "C,
MS (m/z): 417 (M^+l), 348, 304,
'HNMR(300MHz,DMSO-d6):5 8.70(s, IH), 8.26 (t, J= 5.8 Hz, IH), 8.16 (t, y-8.8 Hz, IH),
8.01 (s, IH), 7.69 (dd,J= 2.1 & 14.1 Hz, IH), 7.69 (s, IH), 7.50 (dd, J= 2.1 & 8.8 Hz, IH), 5.61
(s, 2H), 4.80-4.75 (m, IH), 4.17 (t, J= 9.1 Hz, IH), 3.79 (dd, J= 6.6 & 9.2 Hz, IH), 3.43 (t, J =
5.4HZ,2H), 1.84(s,3H).
Example 12: N-{3-(3-fluoro-4-(4-pyra2ol-!-ylmethyl-thiazol-2-yl)-phcnyl|-2-oxo-oxazoHdin-
5(S)-ylmethyIJ-acetamide
R \-N T>
Ten-Butyl-{3-[3-fluoro-4-(4-pyrazol-l-ylmethyl-thiazol-2-yl)-phenyl]-2-oxo-oxazolidin-5(S)-
ylmethyl}-carbamate (0.5 grams, 1.05 mmol) and trifluoroacetic acid (2.5 mL) were stirred in
dichloromethane for 1 hour. Dichloromethane and trifluoroacetic acid were completely
evaporated and diethyl ether was added to it. The solid thus obtained was dissolved in ethyl
acetate (25 mL) and pyridine (0.5 mL) was added followed by the addition of acetic anhydride
(0.25 mL) at 0 °C The reaction mixture was stirred at room temperature for 3 hours. Water was
added to the reaction mixture and ethyl acetate layer separated. Water layer was extracted with
ethyi acetate additional 2 times. Combined ethyl acetate portion was dried over sodium sulfate
II and concentrated. Pure product (0.1 grams, 15%) was obtained after purification by column
chromatography over basic alumina using 1% methanol in chloroform as eluent.
Melting Range: 178-180 °C,
U8 Hz, IH), 6.30 a y= 2.1 Hz, IH), 5.51 (s, 2H), 4.81-4.72 (m, IH), 4.17 (l, J = 9.0 Hz, IH), 379 (dd,y= 6.6 & 9.2 Hz, IH), 3.43 (t, J = 5.4 Hz. 2H), 1.82 (s, 3H).
Example 13: N-{3-[3-nuoro-4-(2-pyrazol-l-ylmethyl-thiazol-4-yl)-phenyll-2-oxo-oxazoIidin-5-'yImethyl}-acetamide
To a solution of N-{3-[4-(2-bromo-acetyl)-3-fluoro-phenyl]-2-oxo-oxazolidin-5-yimethyl}-acetamide (300 mg, 0.8 mmoi) in ethanol (2 mL) was added 2-pyrazol-l-yl-thioacetamide (113 mg, 0.8 mmoi) and stirred at room temperature for 16 hours and then
refluxed for additional 3 hours. The reaction mixture was diluted with ethyl acetate {100 mL),
■ ii
washed with saturated sodium bicarbonate solution, water and brine solution. Organic portion
was then dried over sodium sulphate and concentrated. The residue obtained was washed with
petroleum ether to obtain a white solid.
Yield: 90%,
IR(lCBr,cm''): 3335,2926, 1770, 1406. 1194, 1048,751 and 636,
MS(m/z):416(M'*"+l),372,
'HNMR(200MHz,CDCl3,):58.19(t,y-8.6Hz, IH), 7.67-7.57 (m, 4H), 7.26-7.21 (m, IH),
6135 (s. IH). 6.05 (bs. IH), 5.69 (s, 2H), 4.79 (bs, IH), 4.14- 4.05 (m, IH), 3.85- 3.64 (m, 3H),
■!i
2.03 (s. 3H).
Example 14: N-{3-13-nuoro-4-(2[l,2,41lriazol-l-ylmelhyl-thiazoM-yl)-pl!enyll-2-oxo-
98
oxazolidin-5-ylmethyl}-ace(amide
The title compound is prepared by following the procedure as described in example 13, by taking appropriate starting materials. Melting Range: 154-156 °C,
IR(K:Br,cm''):3273. 1740 and 1410,
MS(m/z):4l7(M'^+l), 373,
'H NMR (200 MHz, DMSO-d6+CDCl3): 6 8.25-8.12 (m, 2H), 7.95-7.80 (m, 3H), 7.32- 7.20 (m, 2H), 7.05(s, IH), 5.60 (s,2H), 4.92-4.72 (m, IH), 4.13 (t, 7= 9.0 Hz, IH), 3.95-3.81 (m, IH), 3.24 (bs,2H), 1.94 (s,3H).
/ Example 15: N-{3-[3-Fluoro-4-(2-tetrazol-I-yImethyl-thiazoI-4-yl)-phcnyll-2-oxo-
oxazulidin-5-ylniethyl}-acetamide
R O
N ^CHa
O
:i The title compound is prepared by following the procedure as described in example 13,
by taking appropriate starting materials. Melting Range: 164-166''C,
IR(KBr.cm'): 1742, 1656, 1410 and 1226,
MS (m/2): 374 (MM3), 350, 306, 304 and 261,
'H NMR (200 MHz, CDCb+DMSO-de): 5 9.33 (s, IH), 8.22-8.03 (m, 2H), 7.78 (s, IH), 7.63 (d, J=14.2Hz,lH), 7.27 (d,y= 8.8 Hz, IH), 6.12 (s,2H), 4.82 (bs, IH), 4.12 (t, 7= 8.8 Hz, IH), 3.87 (d, y = 8.8 Hz, IH), 3.59 (bs, 2H), 1.96 (s, 3H).
Example 16: N-{3-(3-FIuoro-4-(2-imidazol-I-yrmethyr-thiazol-4-yl)-phenyIl-2-oxo-oxazoIidin-5-ylmethyI}-acetamidc
QO
R O
o
o
The title compound is prepared by following the procedure as described in example 13, by taking appropriate starting materials. Melting Range: 154-156 *"€,
[R (KBr, cm-'): 1758, 1655 and 1407,
MS (m/z): 416 (M^-t-l), 372, 219 and 108.
'H NMR (200 MHz, CDCb+DMSO-de): 6 8.25-8.05 (m. 2H), 7.81 (d,./- 4.9 Hz, IH), 7.78-7.52 Cm, 2H), 7.29 (d,J= 8.3 Hz, IH), 7.21 (s, IH), 7.05 (s, JH), 5.60 (s, 2H), 4.82 (bs, IH), 4.13 (t,J = 8.8 Hz, IH), 3.87 (t, J= 8.8 Hz, IH), 3.56 (bs, 2H), 1.94 (s, 3H).
Example 17: 5-(R)-azidomethyl-3-(3-fluoro-4-(4-imidazoH-ylmethyl-pyrazol-l-yl)-phenyl)-oxazolidin-2-one
W U,^^ _ ^^.3
To a solution of 5-(R)-a2idomethyl-3-[4-(4-chloromethyl-pyra2ol-l-yl)-3-fluoro-phenyl]-oxazolidin-2-one (1.2 grams, 3.43 mmol) in acetonitrile (25 mL) were added potassium carbonate (1.89 grams, 13.71 mmol), potassium iodide (0.2 grams, catalytic amount) and imidazole (0.47 grams, 6.86 mmol). The reaction mixture was heated to 70 °C for two and half hours. Solvent was removed on a rotavapor and water (100 mL) was added. It was extracted with ethyl acetate and the combined ethyl acetate layer was washed with water (50 mL x 1) and brine (50 mL X 1) successively. Organic layer was concentrated and the residue formed was purified by column chromatography (Basic alumina) with chloroform and methanol. Product came out at 0.5-]% methanol in chloroform Yield: 49.6%. MS (m/z): 384(M''+1),
100
'H NMR (300 MHz, CDCI3): 5 7.83-7.94 (m, 2H), 7.77 (dd, J = 2.4 & 13.9 Hz, IH), 7.65 (s, IH), 7.58(s, IH), 7.22-7.28 (m, IH), 7.10(s, IH), 6.98(s, IH), 5.11 (s, 2H), 4.78-4.88 (m, IH), 4.07-4.16(m. IH), 3.90 (dd,y-2.6 & 6.2 Hz, !H), 3.69 Cdq,y= 4.4 & 13.2 Hz, IH).
Example 18: N-{3-(3-nuoro-4-(4-imidazol-I-ylmc(hyl-pyrazoM-yl)phenyIi-2-oxo-oxa2oIidin-5-(S)-ylme(hyl}-acctamide
F O
^^^ ^-"^N CH3
O
To a solution of 5-(R)-a2idomethyl-3-[3-fluoro-4-(4-pyrazol-l-ylmethyl-pyrazol-l-yl)-ienyl]-oxazoIidin-2'One (0.3 grams, 0.79 mmol) in tetrahydrofiiran (10 mL) was added phenylphosphene (0.27 grams , 1.02 mmol) in small batches at room temperature and stirring as continued for 2 hours. Water (I mL) was added and healed 10 75 °C for 4 hours. Solvent as removed by azeolropic distillation with benzene and the residue obtained was dissolved in rTJdine (5 mL). Acetic anhydride (210 p), 1.56 mmol) was added to it at ice temperature and irrJng was continued for Vs hour. The reaction mixture was diluted with water and then ttracted with ethyl acetate. Ethyl acetate portion was washed with IN hydrochloric acid, water id brine successively. Finally the organic layer was dried over sodium sulfate and concentrated, he title compound was obtained after column chromatographic purification, ield: 27%.
lelting Range: 171-172 "C, IS (m/z): 399 (M*+l),
H NMR (300 MHz, CDCI3): 5 7.94 (d, J= 2.3 Hz. IH). 7.86 (t, J= 8.9 Hz, IH), 7.73 (dd.V = .4& 13.9 Hz, IH), 7.65(s. IH), 7.59(s, IH), 7.22 (dd, y= 1.4 & 8.9 Hz, IH), 7.09(s, IH), 6.97 5, IH), 6.29-6.33 (m, IH), 5.10 (s, 2H), 4.80-4.85 (m, IH), 4.08 (t, J= 9.0 Hz, IH); 3.82 (dd, 7 2.2 & 6.8 Hz, IH), 3.64-3.71 (m, 2H), 2.03 (s, 3H).
Example 19: 5-azidomethyI-3-[3-fluoro-4-(4-pyrazoM-ylmethyl-pyrazol-l -yO-phenyll-ixazolidin-2-one
101
The title compound is prepared by following the procedure as described in example 17, by taking appropriate starting materials. Yield: 57.2%, MS(m/z):384(M*+l),
'HNMR(300MHZ, CDClj): 5 7.98 (d, 7= 2.5 Hz, IH), 7.87 (t, 7= 8.8 Hz, IH), 7.75 (dd, J = 215 & 13.9 Hz, IH). 7.69 (s, IH), 7.55 (d, 7- 1.5 Hz, IH), 7.43 (d, 7=2.1 Hz, IH), 7.21-7,26 (m, IH), 6.28(1,7=2.1 Hz, IH), 5.29 (s, 2H), 4.78-4.88 (m, IH), 4.11 (t, 7= 9.0 Hz, IH), 3.88 (dd,7- 2.6 & 6.2 Hz, IH), 3.68 (dq, 7 = 4.5 & 13.3 Hz, IH).
Example 20: N-{3-(3-fluoro-4-(4-pyrazol-) -ylmethyI-pyrazoI-l-yI)-phenyI]-2-oxo-oxazoIidin-5-(S)-yImethyI)-ace(amide
F O
^N ^^ ^^V-N CH3
T O
The title compound was obtained following the procedure reported for N-{3-[3-fluoro-4-(4-imidazoM-ylmelhy]-pyrazo]-l-yl)pheny]]-2-oxo-oxazoJidin-5-(S)-ylmelhyI}-acetaniide from 5-(R)-azidomethyl-3-[3-fiuoro-4-(4-pyrazol-l-ylmcthyl-pyrazol-l-yl)-phenyl]-oxazolidin-2-one . Yield: 28%,
Melting Range: 186-187 X MS(m/z):399(MVj),
' H NMR (300 MHz, CDCb): 6 7,98 (s, 1H), 7.85 (t, 7 = 8.8 Hz, 1H), 7.68-7.72 (m, 2H), 7.54 (d, J= 1.1 Hz, IH). 7.43(d, 7= 1.5 Hz, IH), 7.18-7.26 (m, 2H), 6.28 (t, 7= 1.9 Hz, IH), 6.11 (bs, IH), 5.29 (s, 2H). 4.80-4.85 (m, IH), 4.08 (t, 7= 9.0 Hz, IH), 3.81 (dd,7= 1.6 & 7.1, IH), 3.64-3.69 (m,2H), 2.02 (s,3H). Example 21: 5-(R)-a2idomethyJ-3-|3-fluoro-4-(4-(],2,4]friazol-l-yJinethyl-pyrazoM-yI)-
phenyt]-oxazolidin-2-one
102
The tille compound is prepared by following the procedure as described in example 17, by taking appropriate starting materials.
Yield: 61%,
I! MS (m/z): 384 (M^+l),
'HNMR(300MHz, CDCI3); 5 8.11 (s, IH), 8.05 (d, J = 2.4 Hz, IH), 7.98 (s, IH), 7.88 (t,J =
8.9 Hz, IH), 7.72-7.81(m, 2H), 7.21-7.28 (m, IH), 5.34 (s, 2H), 4.78-4.88 (m, IH), 4.!2 (t, J =
8.9 Hz, IH), 3.90 (dd, J = 2.6 & 6.2 Hz, IH), 3.68 (dq, J-4.5 & 13.3 Hz, IH).
Example 22: N-{3-13-fluoro-4-(4-(l,2,4]triazol-l-ylmethyl-pyrazol-l-yl)-phenyl]-2-oxo-(>xazolidin-5(S)-ylmethyl}-acetamide
F. O
N I H ^'^'V-N CH3
O
.■ The title compound was obtained following the procedure reported for N-{3-[3-fluoro-4-
(4-imidazol-l-yImethyI-pyrazoI-l-yl)phenyI]-2-oxo-oxazolidin-5-(S)-yImethyl}-acetamide from 5-(R)-azidomethyl-3-[3-fluoro-4-(4-[],2,4]triazol-l-ylmethyl-pyrazol-l-yl)-phenyl]-oxa2ol!din-2-one . Yield: 27%,
Melting Range: 126-127 °C MS(m/z):400(M"'+i),
'H-NMR (300 MHz, CDCI3): 5 8.12(8, IH), 8.04 (d, 7= 2.2 Hz, IH), 7.98 (s, IH), 7.85 (t,J-8.9 Hz, IH), 7.69-7.76 (m, 2H), 7.22 (dd,y= 1.3 & 9.0 Hz, IH), 6.24 (t,y= 6.1 Hz, IH), 5.34 (s, in), 4.76-4.86 (m, IH), 4.08 (t, J= 9.1 Hz, IH), 3.83 (dd. 7-2.2 & 6.9 Hz, IH), 3.62-3.72 (m, 2H), 2.02 (s, 3H). Example 23: 5-azidomcthyI-3-[3-fluoro-4-(4-imidazol-l-ylmethyMmidazol-l-yl)-phenyll-
oxazoIidin-2-one
The title compound is prepared by following the procedure as described in example 17, by taking appropriate starting materials. Yield; 45 %.
'H NMR (300 MHz, CDCI3): 5 7.63-7.74 (m. 3H), 7.33-7.36 (m, 2H), 7.07 (s, 3H), 5.14 (s, 2H), 4.82-4.86 (m, IH), 4.08-4.14 (m, IH), 3.88 (dd, J= 6.3 & 9.0 Hz, IH), 3.78 (dd, 7= 4.4 & 13.2 Hz, IH), 3.68 (dd,J= 4.4 <& 13.2 Hz, IH).
■■* Example 24: N-{3-[3-fluoro-4-(4-imida2ol-l-ylmethyl-imida2ol-l-yl)-phenyl|-2-oxo-
oxazolidin-5-ylinethyl}-acetamide
F O
^"N^x-^ ;=\ /-o
A solution of 5-a2idomethyl-3-[3-fluoro-4-(4-Jmidazol-l-ylmethyl-imidazol-l-yl)-phenyI]-oxazolidin-2-one (6.6 grams, 1.6 mmol) in thioacetic acid (6 mL) was stirred at room temperature for 16 hours. Thiolacetic acid was removed under rotary evaporation and the residue obtained vvas scratched in diethyl ether (10 mL) to obtain the title compound as solid, which was collected on a Buchner funnel. Yield: 69%,
Melting Range: 180-182 °C, MS(m/z):399(M''+l), 331, 'H NMR (300 MHz, CDCI3): 5 8.02 (s, IH), 7.78-7.86 (m, 2H), 7.42-7.64 (m, 4H), 7.22 (t, J =
];.2Hz, IH), 7.01 (t, J = 1.1 Hz, IH), 5.22 (s, 2H), 4.82-4.90 (m, IH), 4.22 (t, 7= 9.0 Hz, IH),
11
i'.86-3.93(m, IH),3.6I (t,y = 4.9 Hz, 2H), 2.00(s, 3H).
Example 25: 5-Azidomethyl-3-[3-fluoro-4-(4-pyra2oI-l-ylinethyl-imidazol-l-yl)-phenyll
oxazolidin>2-onc
F O
\=y
N^~VJ^^VJ^^N3
Tlie title compound is prepared by following the procedure as described in example 17, by taking appropriate starting materials. Yield: 35 %,
'H NMR (300 MHz, CDCI3): 5 7.51-7.82 (m, 4H) 7.26-7.40 (m, 3H), 6.28 (t, J= 2.0 Hz, IH), 5.34 (s, 2H), 4.84-4.90 (m, IH), 4.01 (t, J =8.9 Hz, IH), 3.84-3.92 (m, IH), 3.81 (dd, J = 4.3& 13.4 Hz, IH). 3.62 (dd,J = 4.1 &13.3Hz, IH).
Example 26: N-{3-[3-fluoro-4-(4-pyrazol-l-ylmethyI-imidazol-l-yI)-phenyll-2-oxo-oxazolidm-5-ylmethyl}-acetamidc
F Q
o
The title compound is prepared by following the procedure as described in example 18, by taking appropriate starting materials. Yield: 51%,
Melting Range: 158-160 °C, MS (m/z): 399 (MV)), 355, 331,
'H NMR (300 MHz, CDCI3): 6 7.54-7.74(m, 4H), 7.28-7.40 (m, 3H), 7.15 (s, IH), 6.28 (bs, IH), 5.35 (s,2H), 4.76-4.81 (m, IH), 4.07 (t, 7= 9.0 Hz, IH), 3.66-3.87(m, 3H). 2.05 (s, 3H).
Example 27: S-Azidomethyl-3-(3-fluoro-4-(4-[l,2,4itria2ol-l-yImcfhyl-imidazol-l-yl)-phenyll-oxazolidin-2-one
The iitJe compound is prepared by following the procedure as described in example I7,by lakJng appropriate starting materials. Yield: 58 %,
'H NMR (300 MHz, CDCI3): 6 8.58 (s, IH), 8.02 (s, 2H), 7.84 (dd, J= 2.4 & 13.3 Hz, IH), 7.58-7.66 (m, 2H). 7.46-7.52 (m, IH), 5.4 (s, 2H), 4.85-4.90 (m. IH). 4.10 (t, IH), 3.90 (dd, J- 6.0 & 8''0 Hz, IH), 3.80 (dd, /= 4.4 & 13.3 Hz, IH), 3.68 (dd,/= 4.2 & 13.2 Hz, IH).
Example 26: N-{3-[3-nuoro-4-(4-|l,2,4)triazol-l-ylmethyI-iniidazol-l-yl)-phenyI]-2-oxo-oxazolidin-5-ylmethyl}-acetamide
T
o
i, The title compound is prepared by following the procedure as described in example 18,
by taking appropriate starting materials. Yield: 48.2 %, Melting Range: 171-173 °C, MS(m/z):400(M>l), 331,
'H NMR (300 MHz, CD3OD): 6 8.56 (s. IH), 8.01 (s. 2H), 7.84 (dd, J = 2.4 Sc 13.3 Hz, IH), 7.65-7.68 (m. 2H), 7.48 (d, J= 9.0 Hz. IH), 5.46 (s, 2H), 4.84-4.90 (m, IH), 4.24 (t, J- 9.0 Hz. IH), 3.89 (dd,y = 6.3 & 9.3 Hz, IH), 3.62 (d, y = 4.9 Hz, 2H).
Example 27: {3-l3-Fluoro-4-(4-pyrazol-l-ylmethyl-[l,2,31triazoM-yI)-phenyll-5-hydroxy
rHiit'hirl_nv=\ >-o
I N (K ,) N I
The title compound is prepared by following the procedure as described in example 29,
by taking appropriate starting materials.
Yield: 21%,
I!
Example 32: N-{3-[3-nouro-4-(4-(3-trifluoromethyl-pyrazoI-l-ylmefhyI-(I,23I*f>a2oM-ylI-
phenyi}-2-oxo-oxazolidm-5-ylmethyl}-acetamide
CF3-^ F 0 -N^° H
O
The title compound is prepared by following the procedure as described in example 28, by taking appropriate starting materials. Yield: 38%,
Melting Range: 130-140'*C,
IR(KBr,cm-'):3296, 1735, 1660, 1531,1407, 1246, 1048,776,753,602, MS(m/2): 468(M^+1),
'HNMR(DMS0-d6, 400MH2):5 8.64(d,J'=1.6Hz, IH), 8.24 (t, J = 5.7 Hz, IH), 8.10 (d, J = 1.3 Hz, IH), 7.87(t.J=8.7-Hz. IH), 7.81 (dd, J = 2.4& 13.4 Hz, IH), 7.54 (dd, J= 1.8 & 8.8 Hz), 6.76 (d, J= 2.4 Hz, IH), 5.63 (s, 2H), 4.80-4.77 (m, IH), 4.20 (t, J= 9.0 Hz, IH), 3.82 (dd, y=6.4&9.1 Hz, IH), 3.45(t,y = 5.5Hz,2H), 1.84 (s,3H).
Example 33: Methyl 3-[3-Fluoro-4-(4-imidazol-l-ylmethyMhiazol-2-yl)-phenyll-2-oxo-oxazolidin-S(S)~ylmethyl}-carbamate
F. O ?
o
Tert-Butyl-(3-[3-fluoro-4-(4-imidazol-l-ylmethyl-thiazol-2-yl)-phenyl]-2-oxo-oxazolidin-5(S)-ylmethyl}-carbamate (0.6 grams, 1.26 mmol) and trifluoroacetic acid (3 mC) were stirred in dichloromethane (10 mL) for 1 hour at room temperature. Dichloromethane and trifluoroacetic acid were completely evaporated and diethyl ether was added to it. The solid thus obtained was dissolved in dichloromethane (10 mL) followed by the addition of triethyl amine (0.51 mL, 5.07 mmol) at 0 °C Methyl chloroformate (0.18 mL, 1.9 mmoi) was added dropwise
li
and allowed to stir at room temperature for 1 hour. Volatiles were evaporated and the residue obtained was purified by column chromatography over basic alumina using 2% methanol in chloroform as eluent to obtain the title compound
Yield: 12%,
I' . -
Melting Range: 165-167 **€.
110
MS(m/z):432(M''+l), 364,
'H NMR (300 MHz, DMSO-dft): 5 8.20 (t. J= 8.8 Hz, IH), 7.79 (s, IH), 7.69 (dd, 7= 2.1 & 14.1
Hz, IH), 7.60 (s, IH), 7.56 (bs, IH), 7.50 (dd, J = 2.2 & 8.9 Hz, IH), 7.27 (s, IH), 6.92 (s, H-I),
5.38 (s,2H), 4.82-4.72 (m, IH), 4.18 (t,J = 9.1 Hz, IH), 3.83 (dd, 7= 6.4 & 9.2 Hz, lH),3.54(s,
3H),3.37(t,J=5.7H2,2H).
Example 34: Methyl {3-[3-fluoro-4-(4-pyrazol-J-yltnethyl-oxa2oI-2-y0-phenyli-2-oxo-oxazolidin~5(S)-ylmethyl}~carbamate
N-{3-[3-Fluoro-4-(4-pyrazol-l-ylmethyl-oxazol-2-yl)-phenyl]-2-oxo-oxa2olidin-5(S)-ylmethyl}-acetamide was hydrolyzed with 6N hydrochloric acid to the corresponding amine, which was then converted to the title compound using methyl chioroformate. MS(ni/z):416(M'"-M), Melting Range: 170-172 °C,
'H NMR (400 MHz, CDCI3): 5 8.01 (t, J= 8.5 Hz, IH), 7.55-7.62 (m, 3H), 7.32 (dd, J = 2.2 & 8.6Hz, 2H), 6.29(t,J= 1.9 Hz, IH), 5.34 (d, J = 0.8 Hz, 2H). 5.14 (bs, IH), 4.77-4.83 (m, IH), 4.10 (t, y= 9.0, IH); 3.86 (t, J= 7.9 Hz, IH), 3.68 (s, 3H), 3.54-3.65 (m. 2H).
Example 35: Methyl {3-(3-fluoro-4-(4-[l,2,4Itriazol-l-ylmethyl-thiazol-2-yl)-phenyii-2-oxo-oxazolidin-S(S)-ylmethyI}-carbaniate
F O
V-4 /V-N
\=N \L7^ //-^J. a
^' V^ "^-^N^N 0CH3
0 The title compound is prepared by following the procedure as described in example 33, by taking appropriate starting materials. Yield: 22%, Melting Range: 199-201 °C,
N^S(m/z):433(M^+l), 364,
'H NMR (300 MHz, CDCh): 5 8.30 (s, IH), 8.24 (t, J = 8.7 Hz, IH), 7.99 (s, IH), 7.69 (dd, 7 = 2.1 & 13.4 Hz, IH), 7.29-7.24 (m,2H), 5.55 (s,2H), 5.16 (bs, IH), 4.82-4.81 (m, IH), 4.12 (t, J = 9.0 Hz, IH), 3.88 (t, J= 7.8 Hz, IH), 3.69 (s, 3H), 3.66-3.59 (m, 2H).
I Example 36: Methyl {3-[3-nuoro-4-(4-pyrazoM-ylniethyl-fhiazoN2-yl)-plienyl]-2-oxo-
Dxazolidin-5(S)-ylinetby]}-carban[iate
R
Y
O
OCH3
The title compound is prepared by following the procedure as described in example 33, by taking appropriate starting materials. Yield: 12%, Melting Range: 142-144''C,
MS (m/z): 432 (M^+l), 364,
'!H NMR (300 MHz, DMSO-ds): 6 8.19 (t, 7- 8.8 Hz, IH), 7.87 (d,y= 2.1 Hz, IH), 7.69 (dd, J
= 2.0& 14.2 Hz, IH), 7.56(bs, IH), 7.53-7.46 (m, 3H), 6.30 (t. J = 2.0 Hz, IH), 5.51 (s, 2H),
4.81-4.72 (m, IH), 4.18 (t. 7= 9.1 Hz, IH), 3.83 (dd, y= 6.5 & 9.5 Hz, IH), 3.54 (s, 3H), 3.37 (t.
J=5.2H2,2H).
Example 37: S-Aminomethyl-3-(3-fluoro-4-(2-pyrazol-l-ylmethyI-thiazoM-yl)-phenyll-
oxazolidin-2-one
o
NH
2
A solution of N-{3-[3-fluoro~4-(2-pyrazol-l-ylmethyl-thiazol-4-yl)-phenyl]-2-oxo-
6xazoHdin-5-yimethyI}-acetamide (280 mg, 0.73 mmoi) in 2N hydrochloric acid (10 mL) was
ii
refluxed for 2 hours. Ice-water was added and reaction mixture was neutralized with solid
sodium bicarbonate at 0 °C. The reaction mixture was extracted with chloroform (2 x 100 mL)
and the chloroform layer was then washed with water and brine solution. Organic portion was then dried over sodium sulphate and concentrated to obtain a cream colour solid Yield: 77%,
!R(KBr,cm^'):3416, 1727,1627,1410, 1232, 1193, 1028 and 751,
[v1S(m/z):374(M"+l),
'H NMR (200 MHz, CDCb): 6 8.16 (t, J= 8.6 Hz, IH), 7.64-7.59 (m, 3H), 7.31- 7.24 (m, 2H),
6.32 (s, IH), 5.66 (s, 2H), 4.70 (bs, IH), 4.07- 3.90 (m, 2H), 3.11- 3.00 (m, 2H), 2.20 (bs, 2H).
Example 38: Methyl {3-|3-fluoro-4-(2-pyrazoI-l-ylmethyl-thiazol-4-yI}-phenyll-2-oxo-
oxazolidin-S-ylmcthyl}-carbamate
T o
To a solution of 5-aminomethyl-3-[3-fluoro-4-(2-pyrazoi-1 -ylmethy!-thiazol-4-yI)-phenyi]-oxazolidin-2-one (40 mg, 0.11 mmol) in dry dichloromethane (2 mL) was added triethyl amine (0.03 mL, 0.23 mmol) followed by the addition of methyl chloroformate (0.1 mL, 0.14 mmol) at 0 °C. The reaction mixture was stirred for 0.5 hours at 0 °C and then diluted with dichloromethane (60 mL). Dichloromethane layer was washed with brine solution, dried over sodium sulphate and concentrated. The residue obtained was purified by column chromatography over silica gel (100-200 mesh) using chloroform: methanol (24:1) as eluent. Title compound was obtained as white solid Yield: 61%,
IR (KBr, cm"'): 3361, 2959, 1772, 1542, 1405, 1195, 1145, 865, 752 and 636, MS (m/z): 432 (M'"+l), 400, 374,
'H NMR (400 MHz, CDCb): S 8.20 (t, J = 8.6 Hz, IH), 7.67- 7.59 (m, 4H), 7.27- 7.23 (m, 2H), 6.35(t,y=2.2Hz. IH). 5.69 (s,2H), 5.12 (bs,m), 4.81-4.78 (m,lH). 4.12-4.08 (m, IH), 3.87-3.83 (m, IH), 3.69 (s, 3H), 3.65- 3.55 (m, 2H).
Example 39: Methyl {3-(3-fluoro-4-(3-imidazoM-ylmethyl-pyrazol-l-y0phenyIl-2-oxo-
H ^N OCH3
0
To a solution of 5-(R)-azidomethyl-3-[3-fluoro-4-(4-imida2ol-l-ylmethyl-pyrazol-l-y phenyl]-oxazolidin-2-one (0.17 grams, 0.44 mmol) in tetrahydrofuran(15 mL) was add' rriphenylphosphene (0.23 grams, 0.89 mmol) in small batches at room temperature and stirr for 2 hours. Water (0.7 mL) was added and healed to 75 °C. While stirring for 4 hours. Solve was removed by azeotropic distillation with benzene and the residue obtained was dissolved dichloromethane (10 mL). Triethyl amine (0.19 mL) was added followed by the addition methylchloroformate (0.04 mL, 0.58 mmol) at ice temperature. Stirring was continued for 0 hour at the same temperature. Solvent was removed and few pieces of ice were added. The so obtained was dissolved in chloroform and it was washed with brine. Finally it was dried o^ anhydrous sodium sulfate and the volatiles were evaporated. The residue was purified by colui chromatography (basic alumina) with chloroform and methanol mixture. Product was colleci at 0.3% methanol in chloroform. Yield: 36%, Melting Range: 196-198 °C,
MS(m/z):415(M^+l),
'H NMR (300 MHz, CDCI3): 5 7.93 (d, J= 2.3 Hz, IH), 7.87 (t, J= 8.9 Hz, IH), 7.75 (dd,, 2.4 & 13.9 Hz. IH), 7.61-7.67 (m, 2H), 7.21-7.41 (m, IH), 7.10 (s, IH), 6.98 (s, IH), 5.11 2H), 4.80-4.82 (m, IH), 4.10 (t,y= 9.0 Hz, IH), 3.86 (I, J= 7.2 Hz, HI), 3.69 (s, 3H), 3.55-3 (m, 2H).
Example 40: Methyl {3-[3-fluoro-4-(3-pyrazol-l*yIinethyl-pyrazol-l-yl)phenyIl-2-oxo-
114
oxazoHdin-5-(S)-ylmethy1}-carbamate
Title compound was obtained from 5-(R)-a2idomethyl-3-[3-fluoro-4-(4-pyra2ol-l-ylmethyl-pyrazol-1 -yl)-phenyl]-oxa2olidin-2-one (0.42 grams, 1.09 mmol) following the procedure reported for {3-[3-fluoro-4-(3-imidazol-l-ylmethyl-pyra2ol-l-yl)phenyl]-2-oxo-oxazDJidin-5-(S)-y!methy]}-carbamic acid methyl ester. Yield: 72%,
Melting Range: 156-158 °C, MS(m/z):415(M^+l),
'H NMR (300 MHz, CDCI3): 5 7.98 (d, J= 2.3 Hz, IH), 7.86 (t, J = 8.8 Hz, IH), 7.68-7.78 (m, 2'H), 7.55(s, IH), 7.43(d,J = 2.1 Hz, IH), 7.18-7.25 (m, IH), 6.28 (t, J= 1.9 Hz, IH), 5.31 (s, 2H), 5.15 (bs, IH), 4.75-4.85 (m, IH), 4.09 (t, J= 9.0 Hz, IH), 3.85 (t, J = 7.3 Hz, IH), 3.68 (s, 3H), 3.52-3.66 (m,2H).
Example 41: MethyJ {3-I3-fluoro-4-(3-H,2,41triazoI-l-ylmelhyl-pyra2ol-l-yl)phenyll-2-oxo-(>xazolidin-5-(S)-ylmetbyJ}-carbaniate
N^ L ^N~<1 />-N^ I H
O
,i Title compound was obtained from 5-(R)-azidomethyl-3-[3-fluoro-4-(4-[l,2,4]triazoM-
yimethyl-pyra2ol-l-yl)-phenyl]-oxazolidin-2-one (0.5 grams, 1.31 mmol) following the procedure reported for methyl {3-[3-fluoro-4-(3-[l,2,4]triazol-l-ylmethyl-pyrazol-l-yl)phenyl]-2-oxo-oxazohdin-5-(S)-ylmethyl}-carbamate, Yield: 59%, Melting Range: 128-130 °C,
MS(m/z):415(M''+l),
'HNMR(300MHz, CDCh):6 8.11 (s, IH), 8.05 (d, J = 2.5 Hz, IH). 7.99 (s, IH), 7.87 (t, J =
S.9Hz, ]H), 7.72-7.78 (m,2H), 7.40 (s, IH), 7.24-7.27 (m, IH), 7.20-7.23 (m, IH), 5.14 (s, 2H),
5.16 (t, J-5.8 Hz, IH), 4.76-4.86 (m, IH), 4.10 (t, 7= 9.0 Hz, IH), 3.86 (dd, J= 1.8&7.0Hz,
IH), 3.69 (s, 3H), 3.52-3.65 (m, 2H).
I. J. Org. Chem. 1982, 47, 2216-2217.
Example 42: 5-Aminomethyl-3-[3-fluoro-4-(4-imida2oI-l-ylmethyl-imidazol-l-yl)-phenyll-
oiv:azolidin-2-one
■I-
F
To a solution of 5-azidomethyl-3-[3-fluoro-4-(4-imida2oI-l-ylmethyl-imidazol-l-yi)-phenyi]-oxazoHdin-2-one (1 grams, 2.6 mmoi) in tetrahydrofuran (10 mL) was added tripheny! phosphine (0.9 grams , 3.33 mmoi) in batches at room temperature and stirred for 5 hours . Water (1 mL) was added and the resulting mixture was heated to 60 °C for 3 hours. Tetrahydrofuran was evaporated under reduced pressure and water was evaporated by azeolropic distillation with benzene (4 x 10 mL). The residue obtained was purified by column chromatography on sihca gel (100-200 mesh) using a mixture of methanol and chloroform (1:9) to obtain the title compound. Yield: 100%.
IR(KBr,cm''):3416, 1746, 1533, 1410. 1218, 1137,871,813,746,682, MS (m/z): 359 (M'^+I), 330, 261, 189, 175,
'H NMR (DMSO-dfi, 400 MHz): 6 8.67 (s, IH). 8.60 (s, IH), 7.99 (s, IH), 7.87-7.80 (m, 2H), 7.54 (dd, J = 1.3 & 8.8 Hz, 1H), 5.62 (s, 2H), 4.73-4.66 (m, 1H), 4.15 (t, J = 8.8 Hz, 1H), 3.94 (dd,J=6.2&8.9Hz. IH), 2.93-2.82 (m, 2H).
Example 43: Methyl {3-13-fluoro-4-(4-imidazo!-l-ylmethyl-imidazol-I-yI)-phenyIl-2-oxo-oxazolidln-5-ylmethyt}-carbamate
To a solution of 5-aminomethyl-3-[3-fluoro-4-(4-imida2ol-l-yimethy!-imida2oi-l-yl)-phenyl]-oxazolidin-2-one (0.57 grams, 1.57 mmoi) in dichloromethane (10 mL) was added triethyl amine (0.9 mL, 6.3 mmoi) followed by the drop wise addition of methyl chloroformate (0.25 mL, 3.2 mmoi) at 5-10 °C. Stirring was continued at room temperature for Ihour and then
!)
water (25 mL) was added to the reaction mixture. The aqueous layer was extracted with
lift
dichioro methane (3 x 25 mL). Combined extract was dried over sodium sulfate and concentrated i6 obtain the title compound. Yield: 15%,
Melting Range: 78-80 "C,
MS(m/z):415(M'"+l), 347,
'H NMR (300 MHz, CDCI3): 6 7.62-7.74 (m, 3H) 7.28-7.38 (m, 3H), 7.06 (s, 2H), 5.60 (t, IH), 5.14 (s, 2H), 4.76-4.84 (m, IH), 4.06 (t, 7= 8.9 Hz, IH), 3.86 (t, 7- 7.8 Hz, IH), 3.68 (s, 3H), 3.56-3.64 (m,2H).
Example 44: Methyl {3-[3-fluoro-4-(4-pyrazol-l-ylincthy!-im!dazo!-l-yl)-phenyll-2-oxo-oxazolidin-5-y!methyl}-carbamate
o
The title compound is prepared by following the procedure as described in example 43,
i
by taking appropriate starting materials. Yield: 15%, Melting Point: 130 °C,
MS(m/z):415(MV]), 347,
'H NMR (300 MHz, CDCI3,): 57.54-7.76 (m, 3H) 7.28-7.39 (m, 2H), 7.16 (s, IH), 6.30 (I, J = 2.0 Hz, IH), 5.35 (s, 2H), 5.26 (t, IH), 4.78-4.86 (m, IH). 4.10 (t, 7= 8.9 Hz, IH), 3.86 (t, J = 7.8 Hz, IH), 3.70 (s, 3H), 3.66-3.58 (m, 2H).
Example 45: Methyl {3-(3-fluoro-4-(4-[l,2,4]triazoI-l-ylmethyl-in[iidazoi-l-yl)-phenyll-2-
oxo-oxazolidin-S-yIniethyl}-carbamate
o
The title compound is prepared by following the procedure as described in example 43, ly taking appropriate starting materials, field: 46.6%,
belting Range: 184-186 °C,
AS (m/z): 416 (M"'+l), 347, 303,
H NMR (300 MHz, CDCI3): 5 8.26 (s, IH), 7.96 (s. IH), 7.68-7.76 (m, 2H), 7.26-7,37 (m. 3H),
i'.37 (s, 2H), 5.19 (bs. IH), 4.80-4.95 (m, IH), 4.09 (t. J= 8.9 Hz, IH), 3.87 (t, J- 8.0 Hz, IH),
5.60-3.75 (m,5H).
Example 46: Methyl N-{3-|3-flouro-4-(4-pyrazol-l-yl-methyl-(l,2,3)tnazol-l-yl)-phenyll-2-
:)xo~oxazoHdin-S-ylmethyl}carbaniate
The title compound is prepared by following the procedure as described in example 43, by taking appropriate starting materials. Yield: 75%,
JR(KBr, cm-'): 3432, 3318, 3369, 2921, 1743, 1697, 1531, 1458,
MS (m/z): 416 (M^+1), 384, 160,
'H NMR (DMS0-d6, 400 MHz): 5 8.52 (s, IH), 7.87-7.74 (m, 3H), 7.54-7.46 (m, 3H), 6.27 (t. J
= 2.0 Hz, IH). 5.10 (s,2H), 4.79-4.76 (m, IH), 4.20 (t, J = 2.0 Hz, IH), 3.85 (dd,J=6.4 & 9.4
Hz, IH), 3.54 (s, 3H), 3.38 (t, J= 5.0 Hz, 2H).
Example 47: Ethyl 3-aiiiino-l-(l-{2-nuoro-4-|5-(niethoxycarbonylamino-methyl) -2-oxo-t)xazolidin-3-yll-phenyI}-lH-Il,2,3]triazol-4-ylmethy!)-lH-pyrazoIe-^-carboxyIa(c
I F O
0-CH3
^ Etooc n
O
The title compound is prepared by following the procedure as described in example 28, by taking appropriate starting materials. Yield: 21%,
N^ehing Range: 98-100 "C,
IR(K:Br, cm"'): 3443,2927, 1756, 1609, 1527, 1408, MS (m/z): 504 (M^+2), 503 (M^+1), 475, 410,
'H NMR (DMSO-d6, 400 MHz): 6 8.55 (s, IH), 8.10 (bs, IH), 7.87 (t, J= 8.7 Hz, IH), 7.80 (dd, J =2.2 8c 13.4 Hz, IH), 7.54 (dd,y= 1.1 & 8.1 Hz, 2H), 5.35 (bs, 2H), 5.28 (s, 2H), 4.80-^.75 (m. IH), 4.18-4.15(m, 3H), 3.85{dd, J=6.2&9.1 Hz, IH), 3.55 (s, 3H), 3.39 (d, 7 = 7.0 Hz, 2H), 1.25(t,y=6.9.Hz,3H).
Example 48: Methyl N-p-(3-ilouro-4-(4-Il,2,41triazoI-l-ylmethyl)-[l,2,31triazol-l-yl )-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-carbaraate
F P
■o
o
The title compound is prepared by following the procedure as described in example 28, by taking appropriate starting materials.
Yield: 54%,
1!
Melting Point: I70T,
IRCKBr,cm"'):3420,2938, 1734, 1632, 1530, 1413, 1289, 1241, 1135,1052, 1016,
MS (m/z); 417 (M^+1), 391, 360, 298,
'H NMR (DMSO-de, 400 MHz): 5 8.67 (s, IH), 8.60 (d, J= 1.6 Hz, IH), 8.00 (s, IH), 7.85 (t, = 8.9 Hz, IH), 7.80(dd,J=2.4& 13.4 Hz, IH), 7.53 (dd, 7= 1.3 & 8.0 Hz, 2H), 5.62 (s, 2H 4.81-4.75 (m, IH), 4.20 (l, 7= 9.0 Hz, IH), 3.85 (dd, 7 = 8.8 & 9.1 Hz, IH), 3.55 (s, 3H), 3.: (I, J=5A Hz,2H).
Example 49: Methyl N-{3-[3-Flouro-4-[4-(3-trifluoromethyl-pyrazoi-l-yl-methyl-
|l,2,31'"azoM-yl)-phenyl|-2-oxo-oxazoIidin-S-ylme(hylJ-carbamate
F O
N^\ /^N t H
O The title compound is prepared by following the procedure as described in example 2 by taking appropriate starting materials. Yield: 36%,
Melting Range: 129-130''C.
lR(KBr,cm-'): 3348, 1734, 1531, 1286, 1244, 1128, 1057,987, MS(m/z): 484 (M^+1),
'HNMR(DMSO-d6, 400MHz):6 8.64 (d,7 = 1.9 Hz. IH), 8.11-8.10 (m, IH), 7.87 ( x, J= i Hz, IH), 7.8(dd,y=2.4& 13.4 Hz, IH), 7.53 (dd, J= 1.6 & 6.4 Hz, IH), 6.76 (d, y-2.4 I-IH), 5.63 (s, 2H), 4.80-4.77 (m, IH), 4.20 (t, y= 9.1 Hz, IH), 3.S5 (dd, J= 6.1 &9.1 Hz, U 3.55 (s, 3H). 3.39 (t, J = 5.6 Hz, 2H).
Example 50: O -methyl {3-i3-fluoro-4-(4-pyrazoM-ylmethyl-oxazol-2-yl)-phenyl]-2-o] oxazolidin-5(S)-ylmethyl}-thiocarbamate
T S
The amine obtained from N-{3-[3-fluoro-4-(4-pyrazoJ-l-y]methyl-oxazol-2-yl)-phen; 2-oxo-oxazolidin-5(S)-yimethyl}-acetamide was converted to isothiocyanate derivative in usual way, which on refluxing with methanol gave the title compound.
120
MS (m/z): 432 (M'^+l), 279, 177, 149, Melting Range: 145-147 °C
'H NMR (400 MHz, DMSO-de): 5 9.51 & 9.40 (2t, 7= 5.6 Hz, IH, rotamers in 4:1 ratio), 8.16 [s, IH), 7.99 (t, J= 8.6 Hz, IH), 7.81 (t,./= 2.4 Hz, IH), 7.65 (dd, J= \.9 & 13.7 Hz, IH), 7.45-7.51 (m, 2H), 6.27 (t, J- 2.0 Hz, IH), 5.32 (s, 2H), 4.88-4.98 & 4.75-4.85 (2m, IH. rotamers in a ratio of 4:1), 4.16-4.25 (m, IH), 3.78-3.98 (m, 5H).
Example 51: O-methyl {3-[3-fluoro-4-(4-imidazol-I-ylmethyI-thiazol-2-yI)-phenyl|-2-oxo-o\azolidin-5(S)-ylmethyl}- thiocarbamate
S ^-^ ^■""N^ N 0CH3
s
Ten-Butyl-{3-[3-fluoro-4-(4-imidazol-l-ylmethyl-thiazol-2-yl)-phenyl]-2-oxo-oxazolidin-5(S)-ylmethyl}-carbamate (1.0 gram, 2.1 mmol) and trifluoroacetic acid (3 mL) were stirred in dichloromethane (20 mL) for Ihour at room temperature. Dichloromethane and trifluoroacetic acid were completely evaporated and diethyl ether was added to it. The solid thus obtained was dissolved in dichloromethane (10 mL) followed by the addition of triethylamine (0.51 mL, 5.07 mmol) at 0 °C, Thiophosgene (0.36 mL, 3.16 mmol) was added dropwise and allowed to stir at room temperature for 0.5 hour. Volatiles were evaporated and the residue obtained was dissolved in methanol (25 mL). Reaction mixture was heated to 80 °C for 5 hours and then solvent evaporated. The residue was purified by column chromatograpii)' over basic alumina using !% methanol in chloroform as eluent to obtain the title compound. Yield: 12%,
Melting Range: 169-171 "C, MS (m/z); 448 (MVJ), 432, 380,
'H NMR (300 MHz, DMSO-de): 8 9.54 & 9.46 (2t, J= 5.5 Hz, IH, rotamers in 4:1 ratio). 8.18 (t, 7 =8.7 Hz, IH), 7.78(s, IH), 7.67 (dd, J= 2.] & 14.2 Hz, lH),7.58(s, IH), 7.49 (dd, J= 2.1 & 8.8 Hz, IH), 7.25 (s, IH), 6.91 (s, IH), 5.36 (s, 2H), 4.98-4.89 (2m, IH, rotamers in 4:1 ratio), 4.20 (t,y= 9.0 Hz, IH), 3.91 & 3.86 (2s, 3H, rotamers in 1:4 ratio), 3.88 (l, J= 7.8 Hz, IH). 3.78 (t,y=5.6Hz,2H).
Example 52: O-mcthyl {3-|3-nuoro-4-(4-[l,2,41triazol-l-ylmethyl-thiazol-2-yl)-ph€nyIl-2-oxo-oxazolidin-5(S)-ylmcthyl}-(hiocarbamate
F. O
s
The title compound is prepared by following the procedure as described in example 51, by taking appropriate starting materials. Yield: 32%,
Melting Range: I89-I9rC, MS (m/z): 449 (M^+1), 380, 322,
'H NMR (300 MHz, DMSO-d6): 5 9.57 & 9.48 (2t, .7= 5.6 Hz, IH, rotamers in 4:1 ratio), 8.70 (s, IH), 8.16 (t, y= 8.8 Hz, IH), 8.01 (s, IH), 7.69 (dd, 7= 2.2 & 14.2 Hz, IH), 7.69 (s, IH), 7,.51 (dd, y- 2.2 & 8.8 Hz, IH), 5.61 (s, 2H), 4.97-4.92 & 4.88-4.79 (2m, IH, rotamers in 4:1 ratio), 4.21 (t, y=8.9 Hz, IH), 3.93 & 3.88 (2s, 3H rotamers in 1:4 ratio), 3.88 (t, y = 7.8 Hz, IH), 3.79(t,y=5.6Hz,2H).
li Example 53: O-methyl {3-|3-nuoro-4-(4-pyrazol-l-ylmethyI-thiazol-2-yl)-phenyIl-2-oxo-
oxazolidin-5(S)-ylmethyl}-thiocarbamate
R
The title compound is prepared by following the procedure as described in example 51, by taking appropriate starting materials. Yield: 14%,
Melting Range: 157-158''C, MS (m/z): 448 (M"'+i), 380, 336,
'.H NMR (300 MHz, DMSO-dg): 5 9.56 & 9.48 (2t, y = 5.7 Hz, 1H, rotamers in 4:1 ratio), 8.18 (t, y'=8.8Hz, lH),7.87(dd,y=0.6&2.2Hz, IH), 7.68 (dd,y=2.1 & 14.2 Hz. IH). 7.53-7.46 (m,
122
3,H), 6.30 (t,y= 2.1 Hz, 1H),5.51 (s, 2H), 4.98-4.90 & 4 4.21 {l,J=9.0 Hz, IH), 3.93 & 3.88 (2s, 3H rotamers in (t,y=5.6Hz,2H).
Example 54: O-Methyl {3-|3-nuoro-4-(2-pyrazol-l-ylmethyI-thia2oM-yI)-phenyl]-2-oxo-oxazolidin-5-yImethyl}-fhiocarbamate
To a solution of 5-aminomethyl-3-[3-fluoro-4-(2-pyrazoi-I-yImethyI-thiazoI-4-yi)-phenyi]-oxa2oIidin-2-one (40 mg, 0.11 mmol) in a mixture of water and chloroform (1:1, 2 mL) was added sodium bicarbonate (106 mg, 1.26 mmo!) followed by the addition of thiophosgene (0.2 mL, 0.29 mmol) at 0 °C and stirred for 2 hours at 0 °C. The reaction mixture was diluted with ethyl acetate (50 mL) and the ethyl acetate layer was then washed with brine solution and dried over sodium sulphate. The organic layer was evaporated and the residue was refluxed in rnethanol for 12 hours. Evaporation of methanol left a residue, which was purified by column chromatography over silica gel (100-200 mesh) using chloroform and methanol (24:1) as eluent to obtain a white solid. Yield: 28%,
]R(KBr, cm-'); 3250, 294], 2360, 1764 and 1409, MS (m/'z): 404 (M"-44), 372,
'H NMR (200 MHz, CDCI3): 5 8.18 (t, 7 = 8.6 Hz, IH), 7.66-7.55 (m, 4H), 7.24-7.19 (m. IH), 6.36-6.34 (m, IH), 5.69 (s. 2H), 4.97-4.94 (m, IH), 4.16-4.08 (m, 4H), 4.01 (s, 3H).
Ii:xample 55: Methyl {3-|3-fluoro-4-(4-pyrazoM-ylmethyI-imidazol-l-yl)-phenyll-2-oxo-
-, '>i:'i:-*~<-vim<>fhvtUfhincarbamate
^ A solution of 3-[3-fluoro-4-(4-pyrazol-]-ylmethyl-imidazol-l-yl)-phenyl]-5-
isothiocyanatomethyl-oxazolidin-2-one (0.185 grams, 0.05 mmol) in methanol (10 mL) was heated to 55 °C for 18 hours. Solvent was evaporated and the residue was purified by column chromatography on silica gel (100-200 mesh) using a mixture of methanol and chloroform (1:9) to obtain the title compound. Yield: 78.3%,
Melting Range: 116-188 •'C, MS (m/z): 431(M^+1), 363, 319,
'H NMR (300 MHz, CDCI3.): 5 7.54-7.76 (m, 4H), 7.28-7.40 (m, 3H), 7.16 (s, IH), 6.74 (bs, )H), 6.28(s, IH), 5.35 (s,2H), 5.02-4.92 (bs, JH), 3.90-4.16 (m, 4H),
Example 56: Methyl {3-I3-Fluoro-4-(4-pyrazoI-l-yl-methyr-(l,2,3|tria2oM-yl)-phenyl|-2-
oxo-oxazolidin-5-yl-methyl}-lhiocarbamatc
H
s
The title compound is prepared by following the procedure as described in example 54, by taking appropriate starting materials. Yield: 37%,
.Melting Range: 180-182 "C,
IR (KBr, cm-'): 3445, 2925, 1754, 1530, 1400, 1229, 1047. 755, MS (m/z): 400 (MM 1), 388,
124
'H NMR (DMSO-d6, 400 MHz): 5 9.52 (t,J=5.6 Hz, IH); 8.52 (s,IH); 7.87-7.77 (m,3H); 7.54 (dd, J = 1.9 & 10.0 Hz, 2H); 7.46 (dd, J = 0.5 & 1.0 Hz, 1H); 6.20 (t, y = 2.1 Hz, 1H); 4.97-4.94 (m, IH); 4.23 (t,y- 9.1 Hz, IH); 3.94-3.72 (m, 5H).
Example 57: Methyl N-{3-I3-nouro-4-(4-[l,2,41triazol-l-yImethyl)-[l,2,31tria2ol-l-yI)-phenyll-2-oxo-oxazolidin-S-ylmethy|)-thiocarbaniate
F O
'CH.
Y
The title compound is prepared by following the procedure as described in example 54, by taking appropriate starting materials. Yield: 15%,
Melting Range: 172-173 "C.
IR (KBr, cm"'): 3265, 2925, 1755, 1528, 1406, 1210, 1140, 864, 748, 678, MS (m/2): 400 (M^-32), 388,
'H NMR (DMS0-d6,400 MHz): 5 9.53 & 9.44 (2l, J= 5.8 Hz, IH, rotamers in 4:1 ratio), 8.67 (s, IH); 8.60(d,J= 1.9 Hz, lH)7.99(s, IH), 7.86 (t, J= 8.9Hz, IH), 7.80 (dd,y= 2.4 & 13.4 Hz, IH), 7.54 (dd, 7= 1.6 & 8.9 Hz, IH), 5.62 (s, 2H), 4.98-4.94 (m, IH, rotamers in 4:Tratio), 4:23(t,y=9.1 Hz, IH), 3.94 & 3.89 (2s, 3H, rotamers in 1:4 ratio), 3.93-3.90 (m, IH),3.81 (t, 7
= 5.6Hz,2H).
Example 58: 5-Aminomethyl-3-{3-fluoro-4-14-(3-trinuoromethyl-pyrazol-l-yImethyl-
ll,2,3]triazoM-yl)-phenyll-oxazolidin-2-one
CF.
'^ k
,NH„
A solution of N-{3-[3-flouro-4-[4-(3-trifluoromethyl-pyrazol-l-ylmethyl-[l,2,3]triazol-i-yl]-phenyl}-2-oxo-oxazolidin-5-ylmelhyn-acetamide (300 mg, 0.63 mmol) and 4N hydrochloric acid (2.5 mL) in methanol (2.5 mL) was refluxed for 10 hours. The pH of the reaction mixture was adjusted to 12 by the addition of saturated solution of sodium carbonate. It was then
extracted with chloroform (40 mL x 2) and the combined extract was washed with brine. Finally, it was dried over sodium sulfate and volatiles were evaporated. The residue obtained was purified by column chromatography on silica gel using methanol and chloroform (1:9) as eluent to obtain the title compound as white solid. Yield: 70%,
lR(KBr,cm''):3427, 1741J530, 1412, 1243, 1129,1050,968,772, MS(m/2):426(MVl),
'HNMR(DMS0-d6, 400MHz): 5 8.64(d,y= 1.9 Hz, IH), 8.1i (d,J= i.3 Hz, IH), 7.87 (t, J = 8.6 Hz, IH), 7.82(dd,J=2.4& 13.4 Hz, IH), 7.56 (dd, J= 1.6 & 8.0 Hz, IH), 6.75 (d, J = 2.1 Hz, IH), 5.63 (s, 2H), 4.78- 4.74 (m, IH), 4.20 (t, 7= 9.0 Hz, IH), 4.40 (bs, 2H), 3.94 (dd, J = 6.4 & 9.1 Hz, 2H), 3.03-2.93 (m, 2H).
Example 59: Methyl (3-|3-fIuoro-4-[4-(3-tnfluoromethyl-pyrazol-l-yI-methyI-[I,23hna2ol-]-yl)-pbenyl)-2-oxo-oxazolidin-5-yl~methyl}-tbiocarbamare
Q
"N^A
\=J 1 N
H
CH.
O-^xX
Y
s
The title compound is prepared by following the procedure as described in example 54, by taking appropriate starting materials. Yield: 42%.
Melting Range: 179-180 °C,
IR(KBr, cm''): 3424, 2926. I75I, 1528, 1410. 1242. 1051,816,769, K4S (m/2): 500 (M^l), 275, 200, 131,
'H NMR (DMS0-d6. 400 MHz): 6 9.53 & 9.45 {2X,J= 5.6 Hz, IH, rotamers in 4:1 ratio), 8.64 (d,J-1.6Hz, IH), 8.11 (d,J= 1.3 Hz, IH), 7.87 (t,y= 8.9 Hz, 1H),7.81 (dd, 7 = 2.2 & 13.4 Hz, IH), 7.54 (dd.y = 1.6 & 8.8 Hz, IH), 6.76 (d, J=2.\ Hz, IH), 5.64 (s, 2H), 5.00-4.83 (2m, IH, rotamers in 4:1 ratio), 4.24 (t, 7= 9.1 Hz, IH), 3.95 & 3.90 (2s, 3H, rotamers in 1:4 ratio), 3.93-3.91 (m, IH), 3.81 (t, J=5.6 Hz, 2H).
126
Example 60: N-{3-|3-nuoro-4-(4-imidazol-l-ylmcthyl-thia2ol-2-yl)-phenyIl-2-oxo-oxazolidin-5(S)-ylinethyl}-thioacetamide
F O
T S
A mixture of N-{3-[3-nuoro-4-(4-imida2ol-l-ylmethyi-thiazol-2-yl)-phenyl]-2-oxo-
oxazolidin-5(S)-ylmethyl)-acetamide (0.36 grams, 0.87 mmol) and Lawesson's reagent (0.21
grams, 0.52 mmol) in dry dioxane was heated to 60 °C for 20 minutes. Dioxane was evaporated
completely and the residue purified by column chromatography over basic alumina using 2%
methanol in chloroform as eluent to obtain the title compound
Yield: 53.5%,
Melting Range; 169-171 °C,
MS (m/z): 432 (MVI), 416, 388, 320,
'HNMR(300MHZ, CDCl3):8 10.39 (t, 7= 5.0 Hz, IH), 8.20 (t, y= 8.8 Hz, iH), 7.78(s, IH),
7.70 (dd.y= 2.1 &14.2H2, IH), 7.60 (s, IB), 7.52 (dd,J = 2.1 & 8.8 Hz, IH). 7.26 (s, IH), 6.92
(s, IH), 5.38 (s, 2H). 5.02-4.98 (m, IH), 4.22 (t. = 9.1 Hz, IH), 3.95-3.85 (m, 3H), 2.42 (s, 3H).
II Example 61: N-{3-|3-fluoro-4-(4-(l,2,4]triazol-l-ylmethyl-thiazol-2-yl)-phenyll-2-oxo-
oxazolidin-5(S)-ylinethyl)-thioacetamide
R O
s
.i
The title compound is prepared by following the procedure as described in example 60, by taking appropriate starting materials. Yield; 34.4 %. Melting Range; 180-182 °C,
\AQ it^M- d-i-k rMVlV 389. 320.
'H NMR (300 MHz, DMSO-ds): 5 10.39 (t, J= 5.2 Hz, IH), 8.69 (s, IH), 8.16 (t, 7= 8.8 Hz, liH), 8.00 (s, IH), 7.70 (dd,y= 2.1 & 14.1 Hz, lH),7.69(s, 1H),7.5I (dd,y=2.I & 8.8 Hz, IH) 5.61 (s, 2H). 5.02-4.97 (m, IH), 4.22 (t, J= 9.1 Hz, IH), 3.94-3.85 (m, 3H), 2,44 (s, 3H).
Example 62: N-{3-(3-fluoro-4-(4-pyrazole-I-ylmethyl-thiazoI-2-yl)-phenyll-2-oxo-
oxazolidin-S(S)-ylmethyl}-thioacctamide
The title compound is prepared by following the procedure as described in example 60, by taking appropriate starting materials. Y|ield:24% Melting Range: 166-168 «C.
MS (m/z): 432 (M^+i), 388, 320,
'HNMR(300MHZ, DMSO-d6):5 10.38 (bs, IH), 8.19 (t, J= 8.8 Hz, IH), 7.87 (d, J^ 1.8 Hz, IH), 7.70(dd,J = 2.2& 14.2 Hz, IH), 7.54-7.41 (m. 3H). 6.30 (t, J-2.1 Hz, 1H),5.51 (s, 2H), 5.05-4.95 (m, IH), 4.23 (t, y = 9.0 Hz, 1H), 3.94-3.85 (m, 3H), 2.44 (s, 3H).
Example 63: N-{3-13-Fluoro-4-(2!l,2,41triazoM-ylmethyl-thiazol-4-yl)-phenyll-2-oxo-
Gr.aToVtdiTt-S-ylmethylj'th'wacetamide
The title compound is prepared by following the procedure as described in example 60, by taking appropriate starting materials. Melting Range: 82-84 "C ]R(KBr, cm''): 1752. 1406 and 1196,
MS(m/2):43] (M^-1), 389,
'H NMR (200 MHz, DMSO-dg): 5 10.40 (bs, IH). 8.79 (s. IH), 8.20-8.01 (m, 2H), 7.93 (d, J = 2.4 Hz, IH), 7.60 {d,J= 13.7 Hz, IH), 7.45 (d, J= 8.8 Hz, IH), 5.90 (s, 2H), 5.02 (bs, IH), 4.22 (i,J= 8.8 Hz, IH), 3.98-3.80 (m, 3H). 2.45 (s, 3H).
Example 64: N-{3-[3-FIuoro-4-(2-tetrazol-I-ylmethyl-thiazol-4-yl)-phenyll-2-oxo-oxazolidiii-S-ylnicthyl}-thioacetamide
F 0
T s
The title compound is prepared by following the procedure as described in example 60, by taking appropriate starting materials. pJleiting Range: 96-98 °C, jR(KBr, cm''); 1752, 1408 and 1226, MS (m/z): 389 (M''-44), 356, 220, 219, 179, 148, 101,
'H NMR (200 MHz, DMSO-ds): 8 10.39 (bs, IH), 9.66 (s, IH), 8.08-8.01 (m, 2H), 7.65 {d,J = 14.7 Hz, IH), 7.43 (d. 7= 8.3 Hz, IH), 6.23 (s, 2H), 4.99 (bs, IH), 4.21 (t, J= 8.8 Hz, IH), 3.96-3.81 (m, 3H),2.45(s, 3H).
Example 65: N-{3-(3-fluoro-4-(4-imidazol-l-ylmethyI-imidazol-l-yl)-phenyI]-2-oxo-
oxazolidin-5-ylmcthyI}-thioacetamide
ii F O
The title compound is prepared by following the procedure as described in example 60, by taking appropriate starting materials. Yield: 48%,
Melting Range: 160-162 "^C,
129
S (m/z): 414 (M' + l), 371, 347, 303,
NMR (300 MHz, CDCh): 6 7.60-7.73 (m, 3H), 7.23-7.37 (m, 2H), 7.00-7.10 (m, 3H), 5.10 (s. I), 4.90-5.05 (m, IH), 4.19-4.20 (m, 3H}, 3.89 (U J- 7.1 Hz, IH), 2.54 (s, 3H).
ample 66: N-{3-|3-nuoro-4-(4-pyrazoM-yImethyl-imidazol-l-yl)-phenyl]-2-oxo-azolidin-5-ylmethyl}-thioacetainide
s .
The title compound is prepared by following the procedure as described in example 60,
taking appropriate starting materials, eld: 17.6%,
siting Range: 137-139 X,_ S(m/z):415(M''+l). 347,
NMR (300 MHz, CDCI3): S 8.20 (bs, IH), 7.52-7.76 (m, 4H). 7.21-7.38 (m, 3H), 7.16 (s, I), 6.28(t,y=2.1 Hz, IH), 5.34 (s,2H), 5.00-5.06 (m, IH), 4.22-4.32 (m, 1H)^4.16-4.06 (m, 1)^3.84-3.92 (m, IH), 2.60 (s, 3H).
tample 67: N-{3-[3-nuoro-4-(4-ll,2,41triazol-l-ylmethyl-imidazol-l-yl)-phenyll-2-oxo-.azolidin-5-ylmeihyS}-thioacetamidc
F q
Y
S
The title compound is prepared by following the procedure as described in example 60,
/ taking appropriate starting materials.
ield: 40 %. .
Idling Range: 171-173 ^C,
130
MS(m/z):4I6(MVl), 347,
'H NMR (300 MHz, CDCI3): 6 8.28 (s. IH), 7.89 fs, IH), 7.63-7,73 (m. 2H), 7.22-7.38 (m, 3H), 5.31 (s, 2H), 4.91-5.00 (m, IH), 3.96-4.16 (m, 3H), 3.87 (t, J= 5.3 Hz, IH), 2.51 (s, 2H). {3-[3-Fluoro-4-(4-pyra2o!-l-ylmethyl-[l,2,3]triazol-l-yl)-phenyl]-5-hydroxy methyl-oxazolidin-2-one could be converted into N-{3-[3-flouro-4-(4-pyrazol-l-yl-methyl-(l,2,3)triazoM-yl)-phenyl]-2-oxo-oxa2olidin-5-ylmethy]}acetamide or {3-[3-fluoro-4-(4- pyrazol-1-yl-methyl-|.l,2,3]tria2ol-l-yI)-phenyl]-2-oxo-oxa2oIidin-5-yl-methyI}-thiocarbamic acid methyl ester or N-{3-[3-flouro-4-(4-pyrazoM-yl-methyl-(l,2,3)triazol-l-yl)-phenyl]-2-oxo-oxa2olidin-5-y[melhy]}carbamic acid methyl ester according to the procedures depicted above.
Example 68: (S)-2,2-Dinuoro-N-{3-[3-nuoro-4-(4-ll,2,41triazol-l-ylmethyl-imidazol-l-yl)-phenyl]-2-oxo-oxazolidin-5-yliiicthyl}-acetamide
To a solution of 5-Aminomethyl-3-[3-nuoro-4-(4-[l,2,4]triazol-l-y!methyl-imida2oM-yi)-phcnyl]-oxazolidin-2-one (355 mg, 0.99 mmol) in DCM was added N-methyl morpholin (151 mg, 1.49 mmol) and difluoroacetic acid (0.06 mL, 0.99 mmol) at 0°C dropwise followed by the addition of EDC.HCI (247 mg, 1.29 mmol). The resulting mixture was stirred for 3 hours at room temperature. After the completion of the reaction, reaction mixture was extracted with 6CM, washed with water and brine. The organic layer was dried over Na2S04 and concentrated .The crude product was purified by column chromatography to obtain the desired product as
white solid (100 mg,)
li
Yield: 23%
lk(KBr,cm-'):3403, 1739, 1708, 1531. 1426, 1271, 1129, 1017
'HNMR (400 MHz, DMSO): 5 9.16 (t, 7=5.6 Hz, IH), 8.56 (s, IH), 7.99 (s, IH), 7.94 (s, IH),
7.72 (dd, >2.4,13.4 Hz, IH), 7.67 (t, J=8.9 Hz, IH), 7.56 (s, IH), 7.46-7.45 (m, IH), 6.25 (t.
131
7//f-53.4 Hz, IH), 5.34 (s, 2H), 4.87-4.82 (m. IH), 4.21 (t, 7=9.IHz, IH), 3.83 (dd, 7=6.2, 9.1
Hz, IH), 3.56(1,7=5.6 Hz. 2H)
ES-MS(m/2):436(MVl)
Example 69: (S)-2.2-DichIoro-N-{3-[3-fluoro-4-(4-H,2,4|tmzol-l-yImethyl-imida2oI-l-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide
F O
The title compound was obtained from 5-Aminomelhyl-3-[3-fluoro-4-(4-[l,2,4]lriazol-l-ylmethy]-imida2oI-]-yl)-phenyl]-oxazolidin-2-one and dichloroacetic acid following the procedure described for (S)-2,2-Difluoro-N-{3-[3-fluoro-4-(4-[l,2,4]triazol-l-yImethyl-imidazol-1 -yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl acetamide. Yield: 25%
'H NMR (400 MHz, DMSO): 5 8.97 (t. 7=5.6 Hz, IH), 8.56 (s, IH), 7.98 (s, IH), 7.94 (s, IH), 7.72 (dd, 7 =2.4,13.4 Hz, IH), 7.67 (t,7=8.9 Hz, IH), 7.56 (s, IH), 7.45-7.44 (m, IH), 6.48 (s, IH), 5.34 (s,2H), 4.87-4.84 (m, 1H),4.2I (t, 7=9.1 Hz, IH), 3.83-3.78 (m, IH), 3.56 (t, 7=5.4 llz, 2H) ES-MS (m/z): 468 (M"")
Example 70: (S)-2,2-Dichloro-N- {3-[3-nuoro -4-(4-pyrazol-l-ylniethyl-imidazoI-l-yl)-phenyl]-2-oxo-oxazolidin-5-yImethyl}-propionamide
hi
O
F ^
The title compound was obtained from the corresponding amine using the same procedure described for the preparation of (S)-2,2-Dichloro-N-{3-[3-fluoro-4-(4-[1,2,4]triazo]-l-
ylmethyl-imidazol-l-yl)-phenyl]-2-oxo-oxazolidin-5ylmethyl}acetamide.
IR (KBr, cm''): 3248,3114,3063,1757, 1709, 1530, 1419, 1214,1087, 814, 752 'HNMR (400 MHz, DMSO): 5 8.96 (t, J=5.6 Hz, IB), 7.97 (s, IH), 7.80-7.70 (m, 2H), 7.66 (t, J =8.8 Hz. IH), 7.47 (s, IH), 7.43 (dd,y=1.6. 9.1 Hz, 2H), 6.49 (s, IH), 6.24 (t, J=1.9 Hz, IH), 5.25 (s, IH), 4.90-4.80 (m, IH), 4.20 (t, J=9.1 Hz. IH), 3.80 (dd, 7=6.2, 9.4 Hz, IH), 3.39-3.37 (m, 2H)
.ES-MS(m/z):467(M^+l)
I
Example 71: N- (3-{3-FIuoro-4-I4-(4-pyridin-3-yl-iniidazoM-ylmethyl)-|l,2,31 triazol-l-ylj-phcnyl}-2-oxo-oxazolidin-5-ylmethyl)-acetainide
H==^
F O
I N"f V-N I H
o
1]
The title compound is prepared by following the procedure as described in example 28,
by taking appropriate starting materials.
Yield: 51% li lR(KBr, cm-'):3282, 1754, 1737, 1670, 1531, 1408, 1236, 1050,751
'H NMR (400 MHz, DMSO), 6 8.96 (d, 7 =2.1 Hz, IH), 8.65 (d, 7-1.9 Hz, IH), 8.39 (d, 7=4.8 Hz. IH), 8.24 (t, 7 =5.6 Hz, IH). 8.09 (dt, 7, =7.8 Hz, 72 =1.9 Hz, IH), 7.91 (d, 7=1.1 Hz, IH), 7W7.78 (m, 3H), 7.55-7.52 (m, IH), 7.38-7.34 (m, IH), 5.45 (s, 2H), 4.80-4.77 (m, IH), 4.19 (t,7=9.1 Hz, lH),3.81(dd,7|=6.4Hz,J2-8.4Hz, lH),3.44(t,7=5.6Hz,2H), 1.90 (s,3H)
ES-MS(m/z):477(M'*"+l)
Example 72: (S)-N- (3-{4-(4-(3-Cyano-pyrroI-l-yImethyl)-|l,2,3I triazol-l-yll-3-fluoro-
phenyl)-2-oxo-oxazoiidin-5-ylmethyI)-acctamide
o
The title compound is prepared by following the procedure as described in example 28, tjy taking appropriate starting materials.
133
Yield: 50%
lk(KBr,cm-'): 3332,2229, 1759, 1667, 1528, 1410, 1205,721
1H NMR (400 MHz, DMSO): 8.59 (d, J-1.9 Hz, IH), 8.23 (t, J =5.9 Hz, 1H), 7.88-7.83 (m, 2H)
(t,y=1.8Hz, IH), 7.55-7.52 (m, IH), 7.05 (d, J =2.9 Hz. IH), 6.48 (d, J =2.9 Hz, IH), 5.37 (s,
4.82-4.78 (m, lH),4.19(t.y=9.! Hz, IH), 3.82-3.79 (m, IH), 3.44 (t, 7=5.4 Hz, 2H), 1.83 (s,3H)
ES-MS(m/2):424(M'"+l)
Example 73: (S)-N-^(3-{3-Fluoro-4-[4-(4-melhyMhia2ol-2-ylmethyl)-imidazol-l-ylJ-phenyl}-2-oxo-oxazolidin-5-ylmethyI)-acetamide
F.
H3C
To a solution of N-{3-[3-FIuoro-4-(4~thiocarbamoylmethyl-imidazol-l-yl)-phenyl]-2-oxo-oxazo!idin-5-ylmethyl}-acetamide (200 mg, 0.51 mmol) in ethanol was added chloro acetone (0.02 mL, 0.77 mmol) at room temperature. The reaction mixture was refluxed for overnight. The solvent was evaporated under reduced pressure and the residue was purified by column to afford the title product (30 mg)
Yield; J 4%
IR (Neat, cm"'): 1753,1528,1414,1255,1217, 1063,759
I'H NMR (400 MHz, DMSO): 5 8.23 (t, J =5.9 Hz, IH), 7.96 (s, IH), 7.75 (dd, y = 2.7, 13.7 Hz,
1H). 7.66 (t, J = 8.9 Hz, 1H), 7.46 - 4.44 (m, 2H), 7.08 (d, J = 1.0 Hz, 1H), 4.78 - 4.75 (m, IH),
4.21 (s,2H), 4.17(1,7=9.1 Hz, IH), 3.78 (dd, J = 6.4, 9.1 Hz, IH), 3.43 (t, 7 = 5.4 Hz, 2H).
3.29(s, 3H), 1.84(s,3H).
ES-MS(m/z):430(M^+l)
Example 74: (S)-N-{3-|3-Fluoro-4-(5-ll,2,41triazol-l-ylmethyl-|l,3,41thiadiazol-2-yl)-
I*
phenyll-2-oxo-oxazoIidin-S-ylmethyl)-acetamide
F.
134
To a solution of ]H-[],2,4.1-triazo)e (32 mg, 0.47 mmol) and potassium carbonate (320 mg, 2.3: mmol) in dry DMF at OT N-{3-[4-(5-ChloromethyI-[l,3,4]thiadia2ol-2-yl)-3-fluoro-phenyl]-2-oxo oxazolidin-5-ylmethyl}-acetamide (60 mg, 0.16 mmol) in DMF was added dropwise slowly and stirrei at room temperature for overnight. After the completion of the reaction, reaction mixture was extracted with ethyl acetate for 3 times. The usual work up and purification afforded the desired compound as i white soHd (45 mg). Yield: 69%
IR (KBr, cm-'): 3327, 3117, 1734, 1655, 1533, 1423, 1229, 862, 752, 673
'H NMR (400 MHz, DMSO): 6 8.78(s, IH), 8.27 (t, 7 = 8.6 Hz, IH). 8.231 (t, J = 6.2 Hz, IH), 8.09 (s, IH), 7.74 (dd, J = 2.1, 13.7 Hz, IH), 7.54 (dd, J= 2.4, 8.9 Hz, IH), 6.06 (s, 2H), 4.80-4;"75(m, lH),4.19(t,y=9.1 Hz, 1H),3.81 (dd, J = 6.4 Hz. 9.1 Hz, IH), 3.45 (t.y= 5.6 Hz, 2H), 1.83 (s,3H). I^S-MS(m/2):4I8(M^+l)
.i
Example 75: (S)-N-{3-(3-Fluoro-4-(5-imidazol-l-ylinethyl-[l,3,41thiadiazol-2-yl)-phenyll-2-oxo-oxazoIidm-5-y!methyl}-acetamide
VA -.^-0 H
.CH3
The'title compound was prepared employing the procedure described for (S)-N-{3-[3-Fluoro-' (5-[l,2,4]triazol-l-ylmethyl-[l,3.4]thiadiazol-2-yl)-phenyl]-2-oxooxazolidin-5-ylmethyl}-acetamide.
Yield: 74%
'ft NMR (400 MHz, DMSO): 6 8.26 (t, J =8.6 Hz, IH), 8.22 (t, 7= 5.9 Hz, IH), 7.86 (s. IH), 7.71 (dd, J= 2.1, 14.0 Hz, IH), 7.56 (dd, J= 2.1, 8.9 Hz, IH), 7.33 (s, IH), 6.97 (s, IH), 5.82 (s, 2H).4.80-4.75(m, lH).4.19(t,J=9.1Hz. lH),3.81(dd,y=6.4Hz,9.1Hz, lH),3.44(t,7 =
5i3Hz.2H), 1.83(s.3H).
BS-MS(m/z):"417(MVl)
Example 76: (S)-tert-butyl(3-(3-fluoro-4-(5-(pyridin-2-ylmethyl)-l,3,4-thiadiazol-2-yl)phenyl)-
2ioxooxazolidin-5-yl)methyIcarbamate
N V-i>N^O
To a solution of (S)-tert-butyl (3-(3-fluoro-4-(2-(2-(pyridin-2-
yl)acetyI)hydra2inecarbonyl)phenyl)-2-oxooxa20lidin-5-yl)methylcarbamate (280 mg, 0.57 mmol) in dioxane, Lawesson's reagent (279 mg, 0.69 mmol) was added and refluxed for 3 hours. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography to obtain the titled product 100 mg.
Yield: 36%.
i!
!i
lR(KBr, cm''): 3325,2928. ]759, 1707, 1595, 1506, 1410, 1290, 1252, 1151, 1028,914,806,
753, 682
'HNMR (400 MHz, DMSO): 6 8.55 (d,y= 4.8 Hz, IH), 8.24 (t, J= S.9 Hz, IH), 7.82 (dd, J =
1.9 Hz, 7.8 Hz, IH), 7.74 (dd, 7= 6.7 Hz, 9.1 Hz, IH), 7.58 - 7.50 (m, 2H ), 7.38 - 7.30 (m,
IH), 7.20(bs, IH), 4.82-4.72 (m, IH ), 4.70 (s, 2H), 4.18 (t, J= 8.9 Hz, IH ), 3.92 - 3.86 ( m,
1H ), 3.80 - 3.72 ( m, 3H ), 1.34 ( s, 9H ).
ES-MS(m/z):486(M''+l)
Example 77: (S)-5-(aniinomethyI)-3-(3-nuoro-4-(5-(pyridiii-2-yIinethyl)-l,3»4-thiadiazoI-2-
yI)phenyI)oxazoIidin-2-one
" li
F O
(S)-tert-butyl(3-(3-fluoro-4.(5-(pyridin-2-ylmethyl)-l,3,4-thiadia2ol-2-yt)phenyl)-2-oxooxa2olidin-5-yl)methylcarbamate (300mg) was treated with 60% TFA in dichloromethane for 1 hours. The solvent was evaporated with toluene under reduced pressure and the residue was tAken for next step (170 mg).
Example 78: (S)-N-((3-(3-nuoro-4-(5-(pyridin-2.ylmethyl)-l3,4-thiadia2oI-2-yOphenyl)-2-6'xooxazoIidin-5-yI)methyl)acetainide
^N^M^^^
(S)-5-(aminomethyl)-3-(3-fluoro-4-(5-(pyridin-2-ylmethy!)-l,3,4-thiadiazol-2-yl)phenyl)oxa2olidin-2-one (170nig, 0.44 mmol) was acylated following the standard procedure to yieid 70 mg of the required product.
}R (KBr, cm-'): 3368, 1755, 1682, 1624, 1520, 1420, 1288, 1219, 862. 822, 752 'i4NMR(400 MHz, DMSO): 5 8.59-8.57 (m, IH), 8.27-8.21 (m, 2H), 7.83 (dd, J= 1.9 Hz, 7.5 Hz, IH), 7.72 (dd. J-2.1 Hz, 14.0Hz, JH), 7.53 (dd,J = 2A Hz, 8.8 Hz, 2H), 7.34 - 7.31 (m, IH), 4.80-4.76 (m,lH), 4.70 (s,2H), 4.19 (t,y= 9.1 Hz, IH), 3.81 (dd, J = 6.7 Hz, 9.4 Hz, IH), 3.44 (t,y= 5.4 Hz, 2H), 1.83 (s, 3H) ES-MS(m/2):428(MV])
X
Example 79: (S)-N-{3-(3-Fluoro-4-(4-imidazol-l-ylmethyl-|l,2,3]triazol-l-yl)-phenyl]-2-»xo-oxazolidin-S-ylmethyl}-acetamide
The title compound is prepared by following the procedure as described in example 28,
by taking appropriate starting materials.
Yield: 55%
IR (KBr, cm"'): 3252, 1754, 1673, 1532, 1417, 1218, 1048, 756
'H NMR (400 MHz, DMSO): 6 8.59 (s. IH), 8.24 (bs, IH), 7.82 - 7.78 (m, 3H), 7.54 (dd, 7 =
1.6, 8.9 Hz, m, 7.26 (s. !H), 6.93 (s, IH), 5.39 (s, 2H), 4.82-4.75 (m, )H), 4.19 (t. J = 8.9 Hz,
IH), 3.82 (dd, J= 6.4, 9.1 Hz, IH), 3.44 (t, J= 5.6 Hz, 2H), 1.84 (s, 3H).
ES-MS(m/z):400(M^+l)
Example 80: (S)-N-«3-(3-nuoro-4-(4-(hydroxy(pyridin-2-yI)mcthyl)-lH-l,2,3-triazol-l-
yl)phenyl)-2-oxooxazoHdin-5-yl)methyl)acetamide
O ^ The title compound is prepared by following the procedure as described in example 28, by taking appropriate starting materials. Yield: 46%
II? (Neat, cm"^): 3308,3291, 1755, 1661, 1526, 1408, 1227, 1211, 1039,752 'HNMR (400 MHz, DMSO): 5 8.48 (d, J= 4.3 Hz, IH), S.36 (d, ./= 1.4 Hz, IH), 8.23 (t, 7= 5.9 Hz, IH), 7.86-7.80 (m, 2H), 7.76 (d, J= 2,1 Hz, IH). 7.61 (d, J= 8.0 Hz, IH), 7.51 (d, J= 8.8 Hz, lH),7.34-7.18(m, lH).6.24(d.J-5.1 Hz, IH), 5.93 (d, 7= 5.1 Hz, IH), 4.84-4.75 (m, IH). 4.18(1,7=8.8 Hz, IH), 3.81 (1,7= 5.4 Hz, IH), 3.44 (t,y= 5.3 Hz, 2H). 1.83 (s,3H) ES-MS(m/z):427(M'+l)
Example 81: (S)-N-((3-(3-fluoro-4-(4-(hydroxy(pyridin-3-yl)methyl)-lH-l,2,3-(riazoM-yl)phenyl)-2-oxooxazolidin-5~yI)methyl)acet3mide
•N I
The title compound is prepared by following the procedure as described in example 28, by taking appropriate starting materials. Yield: 65% IR (KBr. cm-'): 3273, 1755, 1658. 1525, 1481, 1406, 1220, 1213, 1145, 1124,752,711,663,
628, 567
'HNMR (400 MHz, DMSO): 5 8.68 (bs, IH), 8.50 (bs, IH), 8.43 (d, J=1.8 Hz, IH), 8.24(t,
j'r5.9Hz, IH), 7.88 - 7.76 (m. 3H), 7.52(dd. J= 1.8hz. 8.8 Hz, IH), 7.39 (dd. >= 4.5Hz, 8.0 Hz.
iH),6.30(d,y = 4.8Hz, 1H)6.01 (d.y = 4.8Hz, IH), 4.82-4.74(m, IH). 4.19(t. J=8.8HZ, IH),
3.8J (dd,y=6.4,9.1 Hz, IH), 3.44(t.>5.6Hz, 2H), 1.84(s,3H).
ES-MS(m/z):427(M*+l)
Example 82: (S)-N-((3-(3-fluoro-4-(4.(pyridin-2.y;merhyI)-lH-I,2,3-friazoNl.yl)phen^ dxooxazolidiii-5-yl)methyI)acetamide
F. O
o
:. A mixture of (S)-N-((3-(3-fluoro-4-(4-(hydroxy(pyridin-2-yl)methyl)-1H-1,2,3-lria2ol-1 -
yl)phenyl)-2-oxooxa2olidin-5-yl)methyl)acetamide{200 mg, 0.42 mmol), glacial acetic acid (10 mL) , 10 % Pd-Cand cone. HCl (ImL) was stirred at roomtemperature for 40 hours under hydrogen atmosphere. The reaction mixture was filtered over celite, the filterate was basified with aq. NH3 solution and extracted with ethyl acetate. The organic layer was dried over anhyd. Na2S04 and concentrated under reduced pressure. The residue was purified by column chromatography to obtain the titled product. Yield: 24% IR (KBr, cm-'): 3265, 3165, 3094, 2932, 1749, 1593, 1433, 1406, 1047, 1005, 906, 816, 750,
ii
679, 602.
'HNMR (400 MHz, DMSO): 5 8.54-8.50 (m, IH), 8.37 (d, J-1.9Hz, IH), 8.23(t, J=5.6Hz, IH),
7'.84(t,J=8.6Hz, lH),7.80-7.77(m, IH), 7.75(dd,/=6.2H2, 8.0Hz, IH), 7.52(dd,y=1.8Hz,
L9Hz, lH),7.36(d,J=7.7H2, IH), 7.26-7.23(m, IH). 4.84-4.75(m, IH), 4.25(s,2H), 4.l9(t,
.^9.1Hz. IH), 3.84-3.79(m, IH), 3.44(t,./=5.6H7., 2H). 1.83fs, 3H).
ES-MS(m/z):4n (M'^-h})
Example 83: (S)-N-((3-(3-nuoro-4-(4-(pyridin-3-ylmethyl)-lH-l,2,3-*riazol-I-yl)phenyl)-2-oxooxazolidin-5-yl)methyl)acetamide
o
The title compound is prepared by following the procedure as mentioned for (S)-N-((3-
(3-nuoro.4-(4-(pyridin-2-ylmethyl)-lH-l,2,3-triazoM-yl)phenyl)-2-oxooxazoIidin-5-yl)methyl) acetamide
Yield: 32%
lk(KBr, cm-'): 3248,3174,3041.2829,1757,1681,1591,1529,1332,1215,1049,821,632 'HNMR (400 MHz, DMSO): 6 8.56(d, J=2.]Hz,n-I), 8.44(dd,./=1.5Hz,4.8H2,lH), 8.39 (d, J =
I8Hz, IH), 8.23 (t,y= 5.7 Hz, IH), 7.84 (t.J= 8.8 Hz, IH), 7.78 (dd,J = 2.4 Hz, 13.4Hz, IH), 7.75 - 7.69 (m, IH), 7.51 (dd, J= 1.8 Hz, 8.5 Hz, IH), 7.34 (dd. J = 4.5 Hz, 7.6 Hz, 1H), 4.82 -4.74 (m, IH), 4.18 (1,7= 8.8 Hz, IH), 4.14 (s. 2H), 3.84-3.76 (m, IH). 3.44 (t, J- 5.4 Hz, 2H). 1.83 (s,3H) ES-MS(myz):411 (MVI)
Example 84: (S)-N-((3-(3-nuoro-4-(4-(pyridBn-4-ylmethyf)-lH-I,2,3-triazoM-yl)phcnyl)-2-oxooxazolidin-5-yl)mcthyl)acctamidc
The title compound is prepared by following the procedure as mentioned for (S)-N-((3-(3-fluoro-4-(4-(pyridin-2-ylmethyl)-lH-l,2,3-tria2ol-l-yl)phenyI)-2-oxooxazolidin-5-yl)methyI)
acetamide.
IR (ICBr, cm-'): 3277. 3154, 2320, 1748, 1651, 1599, 1531, 1414, 1215, SOS, 588
'HNMR (400 MHz, DMSO): 5 8.49 (dd, J= 1.5 Hz, 4.6 Hz, 2H), 8.43 (d,7 = 1.8Hz. IH), 8.23 (t.
Jf= 5.8 Hz, IH), 7.89- 7.79 (m, 2H), 7.52 (dd. J= 1.8 Hz. 8.9 Hz, IH), 7.32 (d. J= 5.8 Hz, 2H),
4.81-4.75 (m, IH), 4.20 (t, 7= 9.2 Hz, IH), 4.10 (s, IH). 3.81 (dd, 7=6.4 Hz, 9.2 Hz, IH),
3.44(t,./=5.2Hz, 2H), 1.82(s, 3H).
ES-MS(m/z):411(M"'+l)
Example 85: (S)-N-{3-|3-Fluoro-4-(3-|l,2,41triazoI-l-ylmethyI-[l,2,4)oxadiazol-5-yl)-phenyll-2-oxo-oxazoUdin-5-ylmethyl)-acetamidc
To a solution of 4-[5-{Acetylamino-melhyl)-2-oxo-oxa2olidin-3-yI]-2-nuoro-ben2oic acid (200 mg, 0.67 mmol) in dry THF were added Hunig's base (87 mg, 0.67mmo]), EDC.HC) (130 mg, 0.67 mmol) and HOBT (91 mg, 0.67 mmol). The mixture was stirred for 5 minutes at room temperature and a solution of N-Hydroxy-2-[l,2,4]triazol-l-yl-acetamidine in THF was added at 0 °C . The mixture was brought to roomtemperature and stirred for overnight. Reaction mixture was concentrated and extracted with ethylacetate and dried over Na2S0/i and concentrated. The crude compound was dissolved with dry DMF and heated to HO - 120 °C for overnight. The usual work up and purification yielded the title compound (60 mg). Yiield: 22%
'HNMR(400MHZ, DMSO):6 8.74(s, IH), 8.22 (l, J = 5.6 Hz. IH), 8.11 (1,^=8.6 Hz, IH), 8.04(s, IH), 7.73 (dd, 7=2.1,13.7 Hz, IH). 7.58 (dd,J= 2.1 Hz, 8.9 Hz, IH), 5.75 (s, 2H), 4.81 - 4.77 (m, IH), 4.19 (t, J= 9.1 Hz, IH), 3.82 (dd, J= 6.2, 9.2 Hz, IH), 3.44 (t. ./= 5.6 Hz, 2H), 1.83 (s,3H). i:-:S-MS(m/z):402(M'+l)
Example 86: (S)-N-(3-{3-Fluoro-4-(l-(l-trityI-lH-imida2ol-4-ylmethyI)-lH-[l,2,31triazoM-yl]-phenyl}-2-oxo-oxazoUdin-5-yImethyl)-acetamide
Tr-N
F.
w The title compound is prepared by following the procedure as mentioned for 4-"Azidomethyl-1-trityl-lH-imidazole and N-[3-(4-Ethynyl-3-nuoro-phenyl)-2-oxo-oxazoHdin-5-ylmethylj-acetamide.
Yield: 47%
'H NMR (400 MHz, DMSO): 5 8.26-8.19 (m,2H). 8.11 (t.7= 8.6 Hz, IH), 7.64 (dd, 7 = 2.1,
13.4 Hz, IH), 7.44 - 7.35 (m, 1 IH), 7.16 (s, IH), 7.11 - 7.07 (m, 6H). 5.51 (s, 2H), 4.76 - 4.73
m, IH), 4.16 (t,J= 8.8 Hz, IH), 3.82 (dd,y= 6.4, 9.1 Hz, IH), 3.43(1,7 = 5.6 Hz. 2H), 1.84 (s, iH).
•S-MS(m/2):642(MVi)
!:xample 87: (S)-N-(3-{3-Fluoro-4-Il-(m-iniida20l-4-yImethyI)-lH-n,2,3]triazoI-4-yIl->henyl}-2-oxo-oxazolidin-5-ylmethyl)-acetamide
The compound N-(3-{3-Fluoro-4-[l-(I-trityl-lH-imidazoi-4-yimethyl)~IH-[I,2,3]triazoi-
l-yl]-phenyl}-2-oxo-oxazolidin-5-ylmethyJ)-acetamide (200 mg,0.31mmol)was stirred with
Tifluoroacetic acid in dichloromethane for 1 hour. The azeotropic removal of TFA with toluene
and the purification over silica gel afforded the title compound (90 mg).
Yield: 72%
I! ,
!R(KBr,cm"'):3285, !740, 1654, 1560, 1415, 1227, 1070,751
'HNIVIR(400MHZ, DMSO):6]2.] (bs, IH), 8.27 (d, 7-3.5 HZ. IH), 8.22 (t, 7= 5.9 Hz, IH),
8.10(t,J=8.6(s,lH), 7.64 (d,7=0.8 Hz, IH), 7.61 (d,7= 2.1 Hz, IH), 7.41 (dd.7= 2.1, 8.6
Hz, IH), 7.23 (s, IH), 5.54 (s, 2H), 4.80-4.75 (m, 1H),4.16 (t, J- 9.1 Hz, IH), 3.78 (dd, J =
6.5, 9.1 Hz, IH), 3.43 (t, 7= 5.4 Hz, 2H), 1.84 (s, 3H)
ES-MS(m/z):400(M'"+I)
Example 88: (S)-N-(3-{4-(l-(l-CyanoinethyHH-imidazol-4-ylmethyl)-IH-[!,2,31triazol-4-yil-3-fluoro-phenyI}-2-oxo-oxazolidiii-S-ylmethyl)-acetaniide
To a solution of N-(3-{3-FIuoro-4-[I-(IH-imidazol-4-yImethyl)-lH-[l,2,3]triazol-4-yl]-phenyl}-2-oxo-oxazolidin-5-ylmethyl)-acetamide (50mg, 0.13 mmol) and potassium carbonate (86 mg, 0.63 mmol) in dry DMF at 0 "C bromoacetonitrile (60 mg, 0.50 m mol) was added drop
IP
wise slowly and stirred at roomtemperature for overnight. The usual work up and purification
produced the title copound (35 mg).
Yield: 64%
IR(KBr, cm-');34I7, 1636, 1384, 1070,754
'H NMR (400 MHz, DMSO): 5 8.40, 8.32 (2d. 7= 3.7 Hz, IH), 8.22 (t, J= 5.6 Hz, IH). 8.13 -
8.07 (m, IH), 7.86, 7.77 (2s, IH rotamers inthe ratio 1:1), 7.63 (d, 7= 13.7 Hz, IH), 7.43 - 7.41
(m, IH), 7.16(s, IH), 5.82(s, IH), 5.54 (s, iH), 5.44 (s, iH), 5.33(s, IH), 4.82 - 4.73 (m, IH),
4.16 (t, 7=9.1 Hz, IH), 3.80-3.76(m, IH), 3.43(t,7=5.4Hz,2H), 1.83 (s.3H)
ES-MS(m/z):439(M''+l)
Example 89: (S)-N-(3-{3-FIuoro-4-I4-(3-niethyHl,2,4]triazol-4-ylniethyI)-Il,2,3]triazoM-yl|-phenyl}-2-oxo-oxazolidin-5-ylinethyl)-acctainide
F.
The title compound is prepared by following the procedure as described in example 28, by taking appropriate starting materials. Yield: 57%
lR(K:Br, cm-'): 2936, 2676, 2493, 2360, 1752, 1528, 1475, 1398, 1036
IH NMR (400 MHz, DMSO); 6 8.62 (s, IH), 8.48 (s, IH), 8.31-8.21 (m, IH), 7.85 (t, J=8.8Hz,
IH), 7.80 (dd,./=2.1 Hz, 13.4 Hz, IH), 7.53 (dd,7-2.5 Hz, 9.1 Hz; IH), 5.39 (s, 2H), 4.85-4.75
(ifi, IH), 4.19 (t,7==8.8 Hz, IH), 3.89-3.78 (m, IH), 3.44 (1,7=5.3 Hz, 2H), 1.83 (s, 3H)
ES-MS(m/z):415(M'"+l)
Example90: (S)-N-(3-{3-Fluoro-4-|4-(4-methyl-thiazol-2-ylmethyl)-|l,2,31tnazoM-yll-
phenyl}-2-oxo-oxazoIidin-5-ylmethyl)-acetamide
F H
H3C-
W .
■S N=N
To a solution of N-{3-[4-(4-Cyanomethyl-[l,2,3]triazol-l-yl)-3-fluoro-phenyI]-2-oxo-oxazolJdJn-5-ylmethyl)-acetamide (200 mg, 0.56 mmol)) in pyridine, triethylamine (0.12 mL,
0.84 mmol) was added and passed H2S gas at room temperature for two days. The reaction
mixture was diluted with ethyl acetate and washed with water, brine and the organic layer was
dried over Na2S04. The solvent was evaporated under reduced pressure to obtain the crude
Ihioamide (200 mg) which was dissolved in ethanol and treated with chloroacetone (59 mg, 0.76
mmol). The resulting mixture was refluxed for overnight. The solvent was evaporated under
reduced pressure and the residue was purified by column chromatography to afford the title
compound (SO mg).
Yield: 33%
IR (Neat, cm"'): 3316, 2924, 1745, 1527, 1408, 1228, 702
IH NMR (400 MHz, DMSO): 8.49 (d, J=1.9Hz, IH), 8.24 (t, J=5.7 Hz, IH), 7.86 (t, y= 8.7
Hz. IH), 7.78(dd,J=2.1, 13.4 Hz, IH), 7.52 (dd, J=1.6, 8.9 Hz, 1 H), 7.14 (d,7=1.1 Hz, IH),
4.82-4.75 (m, IH), 4.46 (s, 2H), 4.19 (t,J=9.0 Hz, IH), 3.81 (dd,7= 6.4, 9.1 Hz, IH), 3.45(t,
J =5.5 Hz, 2H), 2.33 (d, 7=0.8 Hz, 3 H), 1.84 (s, 3H),
ES-MS(m/z):431 (M^+1)
Example 91: (S)-N-{3-[3-Fluoro-4-(4-[l,2,41oxadiazol-3-yImethyl-|l»2,3]triazol-I-yl)-
■> phcnyI]"2-oxo-oxazoIidin-5-ylmethyl}-acetamide
.^ //
A solution of N-(3--{3-Fluoro-4-[4-(N-hydroxycarbamimidoylmethyl)-[l,2,3]triazol-l-yl]-phenyl}-2-oxo-oxazolidin-5-ylmethyl)-acetamide (Igram, 2.56 mmol), BFa.EtiO (0.2 mL) in tr-imethyl orthoformate (20 mL) was refluxed at 120 °C. The solvent was evaporated and Ihe residue was purified by column chromatography to obtain the product as a white solid (600 mg). Yield: 58 %
lR(KBr,cm-'):3422,2925. 1708, 1531, 1407, 1243, 1135,1051, 1017,678.
IH NMR (400 MHz, DMSO): 89.56 (s, IH), 8.48 (d, J =2.1 Hz, IH), 8.23 (t, J=5.6 Hz, IH), 7.84 (t, J =8.8 Hz, IH). 7.80(dd, J=2.4Hz, 13.4 Hz, IH), 7.53 (dd, J =1.6 Hz, 8.0 Hz, IH), 4.84-4.7 (m, IH), 4.34 (s,2H). 4.19 (t,y =9.1 Hz, IH), 3.87-3.78 (m, IH), 3.44 (t, 7=5.3 Hz. 2H), 1.84 {s,3H). ES-MS(m/2):402(M'"+l)'
144
Example 92: (S)-N-(3-{3-FIuoro-4-I4-(5-niethyl-[l,2,4]oxadiazoI-3-y!methyI)-H,2,3Itriazol-l-yIl-pheny|)-2-oxo-oxazolidin-5-ylmethyl)-acetamide
o
F
O
To a solution of N-(3-{3-Fluoro-4-[4-(N-hydroxycarbamimidoylmethyl)-[l,2,3]triazol-l-
y!]-phenyI}-2-oxo-oxa2olidin-5-yImethyl)-acetamide (250 mg, 0.639 mmol) in pyridine acetic
anhydride (0.071 mL, 0.767 mmol) was added and the reaction mixture was refluxed at 120 °C
/"or overnight. Upon completion, the pyridine was removed under reduced pressure and the
residue was purified by column chromatography to obtain the product as a light brown solid (190
mg).
Yield: 72 %
lR(KBr, cm"'):3299, 1750, 1643, 1535,1416, 1227, 1079, 1046,874,756,602.
[i 1$ NMR (400 MHz, DMSO): 6 8.46 (s, IH), 8.29-8.21 (m, IH), 7.89-7.77(m, 2H), 7.53 (dd, J
=1.8 Hz, 9.1 Hz, IH), 4.85-4.75 (m, IH), 4.24 (s, 2H), 4.19 (t, J=9.1 Hz, IH), 3.81 {t,J^ 6.7
Hz, IH), 3.44 (t, J =5.6 Hz, 2H), 3.29 (s, 2H), 1.84 (s, 3H).
ES-MS(m/z):416(M'"+l)
Example 93: (S)-N-{3-l3-Fluoro-4-(4-(l,2,3]triazol-l-yimcthyl-(l,2,31triazol-l-yl)-phenyll-
2-methylcnc-oxazolidin-S-ylmethyI}-acetamide
O
^H^^H^(^\X^W
The title compound is prepared by following the procedure as described in example 28, by taking appropriate starting materials. \^eld:42%
IR(KBr, cm''): 3301, 2924, 1748, 1646, 1528, 1458, 1212, 1053, 872, 745. 590.
1H NMR (400 MHz, DMSO): 5 8.66 (d, J =1.6 Hz, IH), 8.30-8.19 (m, 2H), 7.85 (t, J =8.8 Hz,
IH), 7.80 (dd,J=2.4 Hz, 13.4 Hz, IH), 7.76 (d,J=0.8 Hz, IH), 7.58-7.52 (m, IH), 5.82 (s, 2H),
4.84-4.75 (m, IH), 4.19 (t,y-9.1 Hz, IH), 3.87-3.78 (m, IH), 3.44 (t, J-5.3 Hz, 2H), l.84(s,
3H).
ES-MS(m/2):401 (M'+l)
Example 94: (S)'2,2-Dichloro-N-{3-[3-fluoro-4-(4-[l,2,41tnazol-l-ylmethyI-[l,2,31 tria zol-1 -yl)- phenyl]-2-oxo-oxazoIidin-5-yIniethy/}-ace(amide
O The title compound is prepared by following the procedure as described in example 6S, by taking appropriate starting materials. Yield: 43%
lR(KBr, cm"'): 3422, 2925, 1708, 1531, 1407, 1243, 1135, I05I. 1017,678, IH NMR (400 MHz, DMSO): 6 8.97 (t, y=5.6Hz, IH), 8.66 (s, IH), 8.60(d, 7 =1.8 Hz, IH), 7.98 (s, IH), 7.85 (t. 7-8.5 Hz, IH), 7.79 (dd, 7=2.4 Hz, 13.4 Hz, IH), 7.52 (dd, 7-=1.6 Hz, 8.9 Hz, IH), 6.48 (s, IH), 5.61 (s, 2H), 4.93 - 4.84 (m, !H), 4.23 (t, 7=9.1 Hz, IH), 3.82-3.80 (m, IH), 3.57 (t, 7=5.3 Hz, 2H). ES-MS(m/z):469(M*+l)
t Example 95: (S)-Cyclopropanecarboxylic acid {3-[3-nuoro-4-(4-|l,2,41triazol-l-yImethyl-
ll,2,3|tria2oI-l-yl)-phcnyll-2-oxo-oxazolidin-S-ylmethyl}-amide
The title compound is prepared by following the procedure as described in example 68, by taking appropriate starting materials. Yield: 51%
IHNMR(400MHz, DMSO): 5S.67(s, IH), 8:60 (d, 7 =1.9 Hz, IH), 8.46 (t. 7 =5'.6Hz. IH), 8.00 (s, IH). 7.90-7.84 (m, IH), 7.80 (dd, 7 =2.4 Hz, 13.4 Hz, IH), 7.53 (dd, 7 = 1.6 Hz, 9.1 Hz, IH), 5.62 (s, 2H), 4.84- 4.78 (m, IH), 4.2 (t, 7=9.1 Hz, IH), 3.83 (dd, 7 =6.2 Hz, 9.4 Hz, IH), 150-3.42 (m, 2H), 1.68-I.58(m, IH), 0.82-0.60(m, 4 H) MS(m/z):427(M*+l)
Example %: (S)-2-Cyano-N-{3-|3-nuoro-4-(4-|l,2,41triazol-I-ylmethyl-|l,2,3]triazoM-yl)-phenyIJ-2-oxo-oxazolidin-5-ylmethyl}-acetamide
F.
The title compound is prepared by following the procedure as described in example 68, by taking appropriate starting materials. Yield: 10%
]HNMR(400MH2, DMSO);5 8.70(s, IH), 8.63 (t, J =5.6 Hz, IH), 8.60 (d, y =1.9 Hz, IH), 8.00 (s, IH), 7.86 (t, 7-8.9 Hz, IH), 7.80 (dd, J=2.4 Hz, 13.4 Hz, IH), 7.53 (dd, J=1.6 Hz, 9.1 Hz, IH), 5.62 (s, 21-1), 4.84 - 4.79 (m, IH), 4.21 (t, J=9.1 Hz, IH), 3.81 (dd, J=6.7 Hz, 9.4 Hz, IH), 3.68 (s, 2H), 3.56-3.50 (m, 2H). MS(m/z):426(M^+l)
il Example 97: (R)-5-(azidomcthyl)-3-(3-nuoro-4-(5-{pyridin-2-ylmethyl)-l,3i4-oxadlazol-2-
yl)phcnyl)oxazolidin-2-one
ly^'ti^
To a solution of (R)-4-(5-(azidomethyl)-2-oxooxazoiidin-3-yi)-2-nuoro-N'-(2-(pyridin-2-yi)acetyl)benzohydra2ide (300mg, 0.72 mmol) in acetonitrile POCI3 (57mg, 0.36 mmol) and catalytic amount of DMAP were added and the reaction mixture was refluxed at 80 ^C for overnight. Solvent was removed under reduced pressure and the residue was basified with saturated sodium carbonate and extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulphate. Solvent was evaporated and the residue was purified by
column chromatography to yield the title product 188 mg .
it Yield: 65%
IR (KBr. cm"'): 3070, 2924, 2094, 1629. 1492, 1409, 1209, 962, 748, 565
MMR (400 MHz, DMSO): 5 8.52 - 8.48 (m, 1H), 8.00 (t, J = 8.5 Hz, 1H), 7.82 (dt, J = 1.8Hz, Hz, IH), 7.72(dd.J=2.1 Hz, 13.4 Hz, IH), 7.57 (dd, J = 2.1 Hz, 8,8 Hz, IH), 7,48 (d, ./ = Hz, 1H), 7.34 - 7,30 (m, 1H), 4.98 - 4.90 (m, 1H), 4.54 (s, 2H). 4.20 (t, J - 9.1 Hz, 1H), 3.85
1.7= 6.1 Hz, 9.4 Hz, IH), 3.78 - 3.70 (m, 2H)
-MS(m/z):396(M''+l)
ample 98: (S)-5-(aminomethyl)-3-{3-fluoro-4-(5-(pyridin-2-yImetbyJ)-l,3,4-oxadiazol-2-phenyl)oxazohdin-2-one
F O
U N.,/>-\>^>,
.NH2
To a solution of (R)-5-(azidomethyl)-3-(3-fluoro-4-(5-(pyridin-2-ylmethyl)-l,3,4-adiazol-2-y!)phenyl)oxazolidin-2-one (200 mg) in methanol, 20% Pd-C was added and the iclion mixture was hydrogenated under balloon pressure for 3 hours. The solution was finally tered over celite bed, the filterate was concentrated under reduced pressure. The crude residue as taken for the next step (150 mg).
sample 99: (S)-N-((3-(3-fluoro-4-(S-(pyridin-2-yimethyl)-l,3,4-oxadiazoI-2-yl)phenyl)-2-tooxazolidin-5-yl)incthyl)acetamide
(S)-5-(aminomethyl)-3-(3-fluoro-4-(5-(pyridin-2-ylmethyl)-l,3,4-oxadiazol-2-l)phenyl)oxazolidin-2-one (150 mg, 0.4 mmol) was acylated following the standard procedure ) yield the required product 105 mg. 'ield:63%.
^ (KBr, cm''): 3311, 3086, 2924, 1759, 1583, 1436, 1207,1074, 995, 875, 817, 725. 673, 594 KNMR (400 MHz, DMSO): 6 8.52 - 8.49 (m. IH), 8.22(t, y=5.6Hz, IH), 7.99 (t, J = 8.5 Hz, H), 7.82(dt, J= 1.8Hz, 7.7Hz, IH), 7.70 (dd, J= 2.1Hz, 13.4 Hz, IH), 7.53 (dd,7= 2.1 Hz, 8.8 iz, IH), 7.48 (d, J= 7.7 Hz, IH), 7.34 - 7.30 (m, IH), 4.82-4.74(m, IH), 4.54 (s, 2H), 4.19(t, '=8.8HZ, IH), 3.80 (dd, J= 6.7 Hz, 9.4 Hz, IH), 3.43(t, /=S.6Hz, 2H). I.83(s, 3H).
148
ES-MS(m/z):412(M"'+l)
Example 100: (S)-N-((3-(4-(5-((lH-l,2,4-triazol-l-yl)methyl).l,3,4-oxadiazol-2-yJ)-3-
fluorophenyI)-2-oxooxazoIidin-5-yl)inethy!)acetamide
R O
The title compound is prepared The title compound is prepared by following the cedure as described for (S)-N-((3-(3-f!uoro-4-(5-(pyridin-2-ylmethy])-l,3,4-Dxadiazol-2-5heny!)-2-oxooxazolidin-5-yl)methyl)acetamide.
MMR (400 MHz, DMSO): 5 8.77 (s, IH), 8.23 (t, J= 5.6 Hz, IH), 8.07 (s, IH), 8.00 (t, J= 8.6 , IH), 7.70(dd, J=2.1 Hz, 13.7 Hz, IH), 7.56 (dd,y= 2.2 Hz, 8.9 Hz, IH), 5.93 (s, 2H), 4.82 .75 (m, IH), 4.19 (t, J = 8.8 Hz, IH), 3.81 (dd, 7 = 6.4 Hz, 9.1Hz, IH), 3.44(t, J=5.4Hz, 2H), 3(s, 3H). -MS(m/z):402(M^+l)
OLOGY DATA
The pharmaceutically acceptable compounds of the present invention are useful tibacterial agents having a good spectrum of activity against standard Gram-positive nanisms. vitro:
Minimum Inhibiton Concentrations (MICs) were determined by broth microdilution ;hnique as per the guidelines prescribed in the fifth edition of Approved Standards, NCCLS urrently CLSl) document M7-A5 Vol 20 - No 2. 2000 Villinova, PA. Initial stock solution of e test compound was prepared in DMSO. Subsequent two fold dilutions were carried out in =rile Mueller Hinton Broth (Difco) (MHB). Frozen cultures stocks were inoculated in 25 ml srile MHB in 50 ml Eriyn Meyer flasks.
omposition of MHB is as follows: Beef Extract Powder - 2.0 g/litre. Acid Digest of Casein -f.5 g/ litre, Soluble Starch - 1.5 g/Htre, Final pH 7.3 ±0.1
Flasks were incubated for 4 to 5 hours at 36±1 °C on a rotary shaker at 110 rpm. loculum was prepared by diluting the culture in sterile MHB to obtain a turbidity of 0,5
149
McFarlaiid standard; This corresponds to 1-2 K 10^ CFU/mi. The stock was ftirther diluted in sterile broth to obtain 5^0' to Ixjo" CFU/ml. 50 ^! of the above diluted inoculum was added from 1 -10 wells. The plates were incubated 18 to 20 hours at 37 -^C.
MIC is read as the lowest concentration of the compound that completely inhibits growth of the organism in the microdilution wells as detected by the unaided eye.
Organism Culture No. DRCC No.
Staphylococcus aureus ATCC 3359! 019
Staphylococcus aureus ATCC 49951 213
Staphylococcus aureus ATCC 29213 035
Enterococcus faecaiis ATCC 29212 034
Enterococcus faecalis , NCTC 12201 153
Enterococcus faecium NCTC 12202 154
Escherichia coli ATCC 25922 018
Haemophilus influenzae ATCC 49247 432
Haemophilus influenzae ATCC 49766 433
Haemophilus influenzae ATCC 9006 529
Moraxella catarrholis ATCC 25238 300
Streptococcus pneumoniae ATCC 6303 236
Streptococcus pneumoniae ATCC 49619 237
Streptococcus pneumoniae ATCC 700673 238
Streptococcus mutans 5611
S.aureus -UK^A - 446
S.aureus - MRSA - 448
Saureus - MRS A - 449
Viridans Streptococci
ATCC: American Type Culture Collection, USA NCTC: National Collections of Type Cultures, Colindale, UK DRCC: Dr. Reddy's Culture Collection, Hyderabad, India. The in vitro antibacterial activity data is shown in TABLE 1.
TABLE!:
Example Number
n
34
44
45
54
50
63
67
Minimum Inhibitory Concentration (MIC) (tag/ml) 1-2
0.5-1
1-2
1-2
2-4
0.1-0.2
0.5
0.5-1
In Vivo
Efficacies of the molecules were determined by systemic infection model. In this model, 6-7 weeks old Swiss albino mice (3 Males and 3 Females/group) weighing 21-25 grams were used. S. aureus ATCC 29213 and other strains were cultured on Columbia Blood agar (DIFCO), overnight, at 37^ C for 18 to 24 hours. Inoculum was prepared in 0.9% saline and optical density (OD) was adjusted at 560 nm to get 100 x LD50 dose. Inoculum was diluted 1:1 with 10% Hog Gastric Mucin and 0.5 ml of inoculum was injected intraperitonially to each animal. Test compounds were solubilised in suitable formulation and administered by per-oral, subcutaneous or intra venous route by q.d., b.i.d. or t.i.d. protocol. Animals were observed for 5 to 7 days and survivals were noted. ED50 Value (mg/kg) was calculated by Probit analysis. The in Vivo antibacterial activity data is shown in TABLE 2.
TABLE 2:
Example Number ED50 value (mg/kg)
2 7.10
4 5.38
26 8.5
30 8.5
44 5.02
46 2.53
We Claim:
]. A compound having the structure according to formula (I):
R2 is a five-membered heterocyclic aromatic moiety containing one to three atoms selected from N, O and S; .; A is-(CHR'')n, wherein R1represents hydrogen or hydroxy!, n represents 1-5;
R3 is an optionally substituted five or six membered heteroaryl, having at least one nitrogen atom;
n represents 1 -5;
R4 and R5 are independently selected from hydrogen or fluoro; I with the proviso that when R1 is NHC(=0)CH3, and R2 is imidazole, R3 is not a substituted triazole;
and including the stereoisomers, prodrugs, and pharmaceutically acceptable salts thereof.
3. The compound as claimed in claim 2, wherein R3 represents optionally substitute
heteroaryl rings selected from
I ' ■
4. The compound as claimed in claim 3, wherein R| represents -NHC(=0)R, wherein
represents optionally substituted aikyl or cycloalkyl.
5. The compound as claimed in claim 3, wherein R\ represents -NHC(=0)R, wherein
represents optionally substituted alkoxy or cycloalkoxy.
6. The compound as claimed in claim 3, wherein Ri represents -NHC(=S)R, wherein
represents optionally substituted alky! or cycloalkyl.
7. The compound as claimed in claim 3, wherein R| represents -NHC(=S)R, wherein
represents optionally substituted alkoxy or cycloalkoxy.
wherein R| and R3 are as defined for formula (I)
9. The compound as claimed in claim 8, wherein R3 represents optionally substituted
I
V^r^ N^"^ \ or V^r.
] 0. The compound as claimed in claim 1, is
ii
R4 o
R5
wherein R| and R3 are as defined for formula (I)
11. The compound as claimed in claim 10, wherein R3 represents optionally substituted
C
"J r^N^ N=12. The compound as claimed in claim 1, is
wherein Ri and R3 are as defined for formula (I).
13. The compound as claimed in claim 12, wherein R3 represents optionally substituted
14. The compound as claimed in claim 1, is
RA O
Rs ,
wherein R| and R3 are as defined for formula (I).
15. The compound as claimed in claim 14, is
y^N r^N, js(=^
'^NI- N^'^i" or ^Nf .
16. The compound as claimed in claim J, is
I Rs ■ ■
wherein Ri and R3 are as defined for formula (I).
17. The compound as claimed in claim 16, wherein R3 represents optionally substituted
] 8. The compound as claimed in claim 1, is
R3 ^
wherein Ri and R3 are as defined for formula (I).
I, 19. The compound as claimed in claim 18, wherein R3 represents optionally substituted
Of.«C"+.CVi-.C"K''>-,Oi,tV.
c-f a, ^"T^"
■ N
20. The compound as claimed in claim 1, is
wherein R| and R3 are as defined for formula (1).
21. The compound as claimed in claim 20, wherein R3 represents optionally substituted
29. The compound as claimed in claim 1, wherein the compound is a salt chosen from Li, Na,
K, Ca, Mg, Fe, Cu, Zn, Mn or Al, salts of organic bases, salts of natural amino acids, salts of
guanidine, or salts of ammonixim.
30. A pharmaceutical composition comprising a compound as claimed in claim I, and one or
more pharmaceutically acceptable excipients.
31. A method of producing antibacterial activity against pathogens in a subject, said method
comprising administering to said subject an effective amount of a compound as claimed in claim
1.