Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1999-01-19
2000-08-29
Rotman, Alan L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514317, 514318, 514359, 546187, 546194, 546242, 546244, 546246, 5462691, A61K 31445, A61K 3141, C07D40100, C07D21168, C07D21126
Patent
active
061109363
DESCRIPTION:
BRIEF SUMMARY
This is a national stage application filed under 35 U.S.C. .sctn.371 of PCT/GB97/01061, filed Apr. 17, 1997.
The present invention relates to antibiotic compounds and in particular to antibiotic compounds containing a furanone 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 a furanone 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 .beta.-lactams.
We have now discovered a range of compounds that is not suggested by the art and which has 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 (for example 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, there is provided a compound of the formula (I): ##STR2## wherein:
R.sup.1 is hydroxy or of the formula --NHC(.dbd.O)(1-4C)alkyl or --NHS(O).sub.n (1-4C)alkyl wherein n is 0, 1 or2;
R.sup.2 and R.sup.3 are independently hydrogen or fluoro;
R.sup.4 and R.sup.5 are independently hydrogen or methyl
>A--B-- is of the formula >C.dbd.CH--, >CHCH.sub.2 --, or >C(OH)CH.sub.2 -- (> represents two single bonds);
D is O, S, SO, SO.sub.2 or NR.sup.7 ;
R.sup.7 is hydrogen, cyano, 2-((1-4C)alkoxycarbonyl)ethenyl, 2-cyanoethenyl, 2-cyano-2-((1-4C)alkyl)ethenyl, 2-((1-4C)alkylaminocarbonyl)ethenyl, AR (as defined hereinbelow) or a tetrazole ring system (optionally mono-substituted in the 1- or 2-position of the tetrazole ring) wherein the tetrazole ring system is joined to the nitrogen in NR.sup.7 by a ring carbon atom;
or R.sup.7 is of the formula R.sup.10 CO--, R.sup.10 SO.sub.2 -- or R.sup.10 CS--
wherein R.sup.10 is AR (as defined hereinbelow), cyclopentyl or cyclohexyl (wherein the last two-mentioned cycloalkyl rings are optionally mono-- or disubstituted by substituents independently selected from (1-4C)alkyl (including geminal disubstitution), hyd
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Desai Rita
Rotman Alan L.
Zeneca Limited
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