Oxazolidinone derivatives and their use as antibacterial agents

Details Oxazolidinone derivatives and their use as antibacterial agents Oxazolidinone derivatives and their use as antibacterial agents

2000-02-18

2001-02-27

Stockton, Laura L. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S063000, C514S376000, C546S271400, C548S110000, C548S231000

Reexamination Certificate

active

06194441

ABSTRACT:

This application is a 371 of PCT/GB98/02477 filed Aug. 18, 1998.
The present invention relates to antibiotic compounds and in particular to antibiotic compounds containing an oxazolidinone ring. This invention further relates to processes for their preparation, to intermediates useful in their preparation, to their use as therapeutic agents and to pharmaceutical compositions containing them.
The international microbiological community continues to express serious concern that the evolution of antibiotic resistance could result in strains against which currently available antibacterial agents will be ineffective. 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. The compounds of the present invention are regarded primarily as effective against Gram-positive pathogens because of their particularly good activity against such pathogens.
Gram-positive pathogens, for example Staphylococci, Enterococci, Streptococci and mycobacteria, are particularly important 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 such strains are methicillin resistant staphylococcus (MRSA), methicillin resistant coagulase negative staphylococci (MRCNS), penicillin resistant
Streptococcus pneumoniae
and multiply resistant
Enterococcus faecium.
The major clinically effective antibiotic for treatment of such resistant Gram-positive pathogens is vancomycin. Vancomycin is a glycopeptide and is associated with nephrotoxicity and ototoxicity. Furthermore, and most importantly, antibacterial resistance to vancomycin and other glycopeptides is also appearing. This resistance is increasing at a steady rate rendering these agents less and less effective in the treatment of Gram-positive pathogens.
The present inventors have discovered a class of antibiotic compounds containing an oxazolidinone ring which has useful activity against Gram-positive pathogens including MRSA and MRCNS and, in particular, against various strains exhibiting resistance to vancomycin and against
E. faecium
strains resistant to both aminoglycosides and clinically used &bgr;-lactams.
We have now discovered a range of compounds which have good activity against a broad range of Gram-positive pathogens including organisms known to be resistant to most commonly used antibiotics. In comparison with compounds described in the art (Walter A. Gregory et al in J. Med. Chem. 1990, 33,2569-2578 and Chung-Ho Park et al in J. Med. Chem. 1992, 35, 1156-1165) the compounds also possess a favourable toxicological profile.
Accordingly the present invention provides a compound of the formula (I):
wherein:
R
1
is chloro, fluoro, (1-4C)alkanesulfonyloxy, azido, or of the formula —NHC(═O)R
a
wherein R
a
is hydrogen. (1-4C)alkoxy, chloromethyl, dichloromethyl, cyanomethyl, methoxymethyl, acetylmethyl or (1-4C)alkyl;
R
2
and R
3
are independently hydrogen or fluoro;
R
4
is hydrogen, (1-4C)alkyl, halo or trifluoromethyl;
R
5
and R
6
are independently selected from hydrogen, (1-4C)alkyl, halo, trifluoromethyl, an acetylene of the formula -≡-H or -≡-(1-4C)alkyl, or a group of the formula (IA)
wherein Z is hydrogen or (1-4C)alkyl; X and Y are independently selected from hydrogen, (1-4C)alkyl, halo, cyano, nitro, —S(O)
n
(1-4C)alkyl (wherein n is 0, 1 or 2), aminosulfonyl, (1-4C)alkylaminosulfonyl, di-(1-4C)alkylaminosulfonyl, trifluoromethyl, pentafluoroethyl, (1-4C)alkanoyl, carbarnoyl, N-(1-4C)alkylcarbamoyl, N,N-di-(1-4C)alkylcarbamoyl; or one of X and Y is selected from the above list and the other is selected from phenyl, phenylcarbonyl, —S(O)
n
-phenyl (wherein n is 0, 1 or 2), N-(phenyl)carbamoyl, phenylaminosulfonyl, heteroaryl, heteroarylcarbonyl, —S(O)
n
-heteroaryl (wherein n is 0, 1 or 2), N-(heteroaryl)carbamoyl and heteroarylaminosulfonyl; wherein any phenyl group above may be optionally substituted by up to three substituents independently selected from (1-4C)alkyl, cyano, trifluoromethyl, nitro, halo and (1-4C)alkylsulfonyl; wherein any heteroaryl group in X and Y may be optionally substituted on an available carbon atom by (1-4C)alkyl, and optionally substituted on a suitable nitrogen atom by oxo (to form an N-oxide); provided that X, Y and Z do not define a (2-4C)alkenyl group and provided that at least one of R
5
and R
6
is a group of the formula (IA) or an acetylene of the formula -≡-H or -≡-(1-4C)alkyl;
or a pharmaceutically acceptable salt thereof.
The tenn ‘alkyl’ includes straight chained and branched structures. For example, (1-4C)alkyl includes propyl, isopropyl and t-butyl.
Examples of (1-4C)alkoxy include methoxy, ethoxy, propoxy and tert-butoxy; examples of (1-4C)alkyl include methyl, ethyl, propyl, isopropyl and t-butyl; examples of halo include fluoro, chloro and bromo; examples of (1-4C)alkylS(O)
n
— include methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, methylsulfonyl and ethylsulfonyl; examples of (1-4C)alkylaminosulfonyl include methylaminosulfonyl and ethylaminosulfonyl; examples of di-(1-4C)alkylaminosulfonyl include dimethylaminosulfonyl and diethylaminosulfonyl; examples of (1-4C)alkanoyl include formyl, acetyl and propionyl; examples of N-(1-4C)alkylcarbamoyl include methylcarbamoyl and ethylcarbamoyl; examples of N,N-di-(1-4C)alkylcarbarnoyl include dimethylcarbamoyl and diethylcarbamoyl; examples of (1-4C)alkylsulfonyl include methylsulfonyl and ethylsulfonyl; examples of —S(O)
n
-phenyl include phenylthio and phenylsulfonyl; examples of —S(O)
n
-heteroaryl include pyridylthio, pyridylsulfonyl, pyrazinylthio and pyrazinylsulfonyl; examples of N-(heteroaryl)carbamoyl include pyridylcarbamoyl and pyrazinylcarbamoyl; examples of (2-4C)alkenyl group include vinyl and allyl; examples of an acetylene of the formula -≡-(1-4C)alkyl include 2-methylethynyl and 2-ethylethynyl.
The term heteroaryl refers to pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl linked via any ring carbon atom; and also to 5-membered heteroaryl rings containing no more than two heteroatoms, at least one of which is nitrogen (for example thiazole or imidazole), linked via any ring carbon atom.
Suitable pharmaceutically-acceptable salts include acid addition salts such as methanesulfonate, fumarate, hydrochloride, hydrobromide, citrate, maleate and salts formed with phosphoric and sulfuric acid. There may be more than one anion depending on the number of charged functions and the valency of the anions. The salts of certain compounds, for example those in which the group X or Y contains a heteroaryl group (see, for example, Example 11), may be advantageous because of their improved solubility compared with the parent compound.
However, to facilitate isolation of the salt during preparation, salts which are less soluble in the chosen solvent may be preferred whether pharmaceutically-acceptable or not.
The compounds of the present invention have a chiral centre at the C-5 position of the oxazolidinone ring. The pharmaceutically active enantiomer is of the formula (IB):
The present invention includes the pure enantiomer depicted above or mixtures of the 5(R) and 5(S) enantiomers, for example a racemic mixture. If a mixture of 5(R) and 5(S) is used, a larger amount (depending up on the ratio of the enantiomers) will be required to achieve the same effect as the same weight of the pharmaceutically active enantiomer. For the avoidance of doubt the enantiomer depicted above could be either 5R or 5S depending upon the value of R
1
. For example, when R
1
is acetamido, the enantiomer depicted above is the 5S enantiomer.
It is also to be understood that certain compounds of the formula (I) can exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms which possess antibacterial activit

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