Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1996-03-05
1997-11-18
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
5142368, 544137, A61K 31535
Patent
active
056887922
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
The subject invention discloses oxazine and thiazine oxazolidinone derivatives. The compounds are useful antimicrobial agents, effective against a number of human and veterinary pathogens, including gram-positive aerobic bacteria such as multiply-resistant staphylococci, streptococci and enterococci as well as anaerobic organisms such as Bacteroides spp. and Clostridia spp. species, and acid-fast organisms such as Mycobacterium tuberculosis, Mycobacterium avium and Mycobacterium spp.
INFORMATION DISCLOSURE
The present compounds are similar to piperazine containing ring structures such as those disclosed in the publications below except that the distal nitrogen atom is replaced with an oxygen, sulfur, sulfinyl, sulfonyl, sulfimidoyl or sulfonimidoyl. The instant compounds are unique in that typically the unsubstituted piperazinyl oxazolidinone compounds have little useful antibacterial activity whereas the activity observed for the corresponding oxazine and thiazine derived oxazolidinones is high.
PCT/US93/03570 application discloses oxazolidinones containing a substituted diazine moiety and their uses as antimicrobials.
PCT/US92/08267 application discloses substituted aryl and heteroaryl-phenyl-oxazolidinones useful as antibacterial agents.
PCT/US89/03548 application discloses 5'indolinyl-5.beta.-amidomethyloxazolidinones, 3-(fused-ring substituted)phenyl-5.beta.-amidomethyloxazolidinones, and 3-(nitrogen substituted)phenyl-5.beta.-amidomethyloxazolidinones which are useful as antibacterial agents.
Other references disclosing various oxazolidinones include U.S. Pat. Nos. 4,801,600, 4,921,869, Gregory W. A., et al., 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); and Brittelli, et al., J. Med. Chem., 35, 1156 (1992).
European Patent Publication 352,781 discloses phenyl and pyridyl substituted phenyl oxazolidinones.
European Patent Publication 316,594 discloses 3-substituted styryl oxazolidinones.
European Patent Publication 312,000 discloses phenylmethyl and pyridinylmethyl substituted phenyl oxazolidinones.
SUMMARY OF THE INVENTION
In one aspect the subject invention is a compound of structural Formula I: ##STR2## or pharmaceutically acceptable salts thereof wherein: X is O, S, SO, SO.sub.2, SNR.sup.10 or S(O)NR.sup.10 ; following: F, Cl, hydroxy, C.sub.1 -C.sub.8 alkoxy, C.sub.1 -C.sub.8 acyloxy or O--CH.sub.2 --Ph, CO.sub.2 H, CO.sub.2 R or (CH.sub.2).sub.m R.sup.11 (m is 1 or 2); H or CH.sub.3 ; with chloro, fluoro, hydroxy, C.sub.1 -C.sub.8 alkoxy, amino, C.sub.1 -C.sub.8 alkylamino or C.sub.1 -C.sub.8 dialkylamino) or -p-toluenesulfonyl; and n is 0, 1 or 2.
Preferred compounds where n is 0 are: !acetamide; nyl!methyl!acetamide; methyl!acetamide; or !acetamide.
Preferred compounds where n is 1 are: yl!acetamide; dinyl!methyl!acetamide; l!methyl!acetamide; acetamide; amide; yl!-2-oxo-5-oxazolidinyl!methyl!acetamide; oxyacetamide; amide; ylcarbamate; or loroacetamide.
Preferred compounds where n is 2 are: l!methyl!acetamide; azolidinyl!methyl!acetamide; idinyl!methyl!acetamide; or l!methyl!acetamide.
In another aspect, the subject invention is directed toward a method for treating microbial infections in patients by administering to a patient in need thereof an effective mount of a compound of Formula I as described above. The compound can be administered in a pharmaceutical composition either orally, parenterally or topically. Preferably, the compound is administered in an amount of from about 0.1 to about 100 mg/kg of body weight/day, more preferably, from about 3.0 to about 50 mg/kg of body weight/day.
DETAILED DESCRIPTION OF THE INVENTION
The present invention discloses oxazine and thiazine oxazolidinones of structural Formula I as defined above. The compounds are useful antimicrobial agents, effective against a number of human and veterinary pathogens, particularly gram-positive aerobic bacteria such as multiply-resistant staphylococci, streptococci and enterococci as
REFERENCES:
patent: 4348393 (1982-09-01), Bourgery et al.
patent: 4801600 (1989-01-01), Wang et al.
patent: 4921869 (1990-05-01), Wang et al.
Gregory, W.A., et al., J. Med. Chem., 32, 1673-81 (1989).
Barbachyn Michael R.
Brickner Steven J.
Hutchinson Douglas K.
Bucknum Michael
Corneglio Donald L.
Gammill Martha A.
Pharmacia & Upjohn Company
Shah Mukund J.
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