Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1998-06-10
2000-02-08
Higel, Floyd D.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514419, 548200, 548571, A61K 31425, A61K 3140, C07D20716, C07D27706
Patent
active
060228857
DESCRIPTION:
BRIEF SUMMARY
This invention relates to chemical compounds having metallo-.beta.-lactamase inhibitory and antibacterial properties. The invention also relates to methods for the preparation of such compounds, to pharmaceutical compositions containing them, and to uses thereof.
Metallo-.beta.-lactamases confer resistance to the vast majority of .beta.-lactam based therapies, including carbapenems and jeopardise the future use of all such agents. As a result of the increased use of carbapenems and other .beta.-lactam antibiotics the clinical climate is becoming more favourable for the survival of clinical strains which produce metallo-B-lactamases, and metallo-.beta.-lactamases have now been identified in common pathogens such as Bacillus fragilis, Kiebsiella, Pseudomonas aeruginosa and Serratia marcescens. Emerging knowledge emphasises that metallo-.beta.-lactamases have the potential to present a crisis situation for antimicrobial chemotherapy. U.S. Pat. No.4,046,889, U.S. Pat. No.4,105,776, U.S. Pat. No.4,307,110, U.S. Pat. No.4,316,906, BE868532, CH635087, J55057561, J55009060, U.S. Pat. No.4,283,407, EP0001978, Saunders et al., J. Computer-Aided Molecular Design 1987, 1, 133 and Waller et al., J. Med. Chem. 1993, 36, 2390 disclose various substituted proline and thiazolidine compounds having anti-hypertensive activity.
According to the present invention there is provided a method of treatment of bacterial infections in humans or animals which comprises administering, in combination with a .beta.-lactam antibiotic, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or in vivo hydrolysable ester thereof: ##STR2## wherein:
X is S, S(O).sub.n or CH.sub.2 ;
n is 1 or 2
R is hydrogen, a salt forming cation or an in vivo hydrolysable ester-forming group;
R.sub.1 and R.sub.2 are each hydrogen or an organic substituent group;
R.sub.3 is hydrogen, (C.sub.1-6)alkyl optionally substituted by up to three halogen atoms, (C.sub.2-6)alkenyl, (C.sub.2-6)alkynyl, aryl, aryl(C.sub.1-6)alkyl, heterocyclyl or heterocyclyl(C.sub.1-6)alkyl; and
R.sub.4 is hydrogen, or an in vivo hydrolysable acyl group.
The compound of formula (I) may exist in a number of isomeric forms, all of which, including racemic and diastereoisomeric forms, are encompassed within the scope of the present invention.
It is preferred that the stereochemistry at the carbon atom marked * is D-, i.e. is S when X=S and is R when X=CH.sub.2 and R.sub.1, R.sub.2 =H or alkyl.
Although racemic and other mixtures of (*) D- and L- diastereomers of known compounds of formula (I) have been described, there has been little or no attempt to isolate pure D- isomers as herein defined because the anti-hypertensive activity of the compounds has been found to reside predominantly in the L-isomer.
R.sub.3 aryl(C.sub.1-6)alkyl includes optionally substituted benzyl, phenethyl and phenylpropyl.
Certain compounds of formula (I) including compounds where R.sub.3 represents (C.sub.1-6)alkyl substituted by up to three halogen atoms, aryl, aryl(C.sub.1-6)alkyl, heterocyclyl or heterocyclyl(C.sub.1-6)alkyl, hereinafter defined as R.sub.3.sup.1 and X is S are novel and as such form part of the invention. Compounds of formula (I) in which R.sub.3 is R.sub.3.sup.1 and X is S are hereafter referred to as compounds of formula (IA).
Preferably R.sub.3 is optionally substituted benzyl, more preferably benzyl.
The preferred stereochemistry at the carbon atom marked (+) is S.
R.sub.4 is preferably hydrogen, lower alkylcarbonyl, optionally substituted benzoyl or optionally substituted phenyl lower alkyl carbonyl.
Suitable examples of R.sub.4 include hydrogen and acetyl.
In general formula (I), R.sub.1 and R.sub.2 denotes hydrogen or an organic group. This may suitably be linked through a carbon atom. For example, R.sub.1 or R.sub.2 may represent hydrogen or a group of formula --R.sup.5, where R.sup.5 denotes an unsubstituted or substituted (C.sub.1-10)hydrocarbon group.
Preferably, R.sub.1 or R.sub.2 represents hydrogen, (C.sub.1-10)alkyl, aryl, h
REFERENCES:
patent: 4046889 (1977-09-01), Ondetti et al.
patent: 4105776 (1978-08-01), Ondetti et al.
patent: 4283407 (1981-08-01), Maten et al.
patent: 4307110 (1981-12-01), Condon et al.
patent: 4316906 (1982-02-01), Ondetti et al.
J. Med. Chem. 1993 vol. 36 pp. 2390-2403, Waller et al., Three dimensional quantitative structure-activity relationship of angiotesin converting enzyme and thermolysin inhibitors.
J. Computer-Aided Molecular Design 1987, 1, pp. 133-142, A theoretical study of angiotension-converting enzyme inhibitors.
Bateson John Hargreaves
Gilpin Martin Leonard
Payne David John
Higel Floyd D.
Kanagy James M.
Kinzig Charles M.
SmithKline Beecham p.l.c.
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