Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1996-05-09
1997-07-29
Ramsuer, Robert W.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514252, 544121, 544337, 544357, 544364, 544367, A61K 31495, A61K 31535, C07D41310, C07D41314
Patent
active
056522380
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
The subject invention discloses carboxylic and phosphate esters of substituted-hydroxyacetyl piperazine phenyl oxazolidinones. The compounds and their salts are water soluble which makes them particularly useful for IV and oral administration for the treatment of microbial infections. The compounds are effective against a number of human and veterinary pathogens, including multiply-resistant staphylococci, enterococci and streptococci, as well as anerobic organisms such as bacteroides and clostridia species, and acid-fast organisms such as Mycobacterium tuberculosis. The compounds are particularly useful because they are effective against the latter organism wich is known to be responsible for infections in persons with AIDS. Information Disclosure Statement
U.S. Pat. Nos. 5,164,510 and related 5,225,565 and 5,182,403 discloses 5'indolinyl-5.beta.-amidomethyloxazolidinones, 3-(fused-ring substituted)phenyl-5.beta.-amidomethyloxazolidinones, and 3-(nitrogen substituted)phenyl-5.beta.-amidomethyloxazolidiones wich are useful as antibacterial agents.
PCT/US93/03570 discloses hydroxyacetyl diazene phenyl oxazolidinoes similar to the subject compounds except that the subject compounds are substituted with carboxylic and phosphate esters (i.e., R is --C(O)--R.sub.1, --PO.sub.3.sup..dbd. or --P(O)(OH).sub.2) and are water soluble.
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 oxozolidiones.
European Patent Publication 316,594 discloses 3-substituted styryl oxozolidiones.
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: ##STR1## or pharmaceutailly acceptable salts thereof wherein:
R is --C(O)--R.sup.1, --PO.sub.3.sup..dbd. or --P(O)(OH).sub.2 ;
R.sup.1 is C.sub.1-6 alkyl, --N(R.sup.4).sub.2, C.sub.1-6 alkyl-N(R.sup.4).sub.2, -phenyl-N(R.sup.4).sub.2, -phenyl-NHC(O)CH.sub.2 NH.sub.2, --C.sub.2 H.sub.4 -morpholinyl, pyridinyl, C.sub.1-6 alkyl-OH, C.sub.1-6 alkyl-OCH.sub.3, C.sub.1-6 alkyl C(O)CH.sub.3, --O--C.sub.1-6 alkyl-OCH.sub.3, C.sub.0-3 alkyl-piperazinyl (optionally substituted with C.sub.1-3 alkyl), imidazolyl, C.sub.1-6 alkyl-COOH, --C(CH.sub.2 OH).sub.2 CH.sub.3 ;
R.sup.2 and R.sup.3 are independently selected from hydrogen or F, except at least one of R.sup.2 or R.sup.3 is F;
R.sup.4 are independently selected from hydrogen or C.sub.1-6 alkyl.
Preferred compounds of the subject invention are where R is --C(O)--R.sup.1 and R.sup.1 is --CH.sub.3, --CH.sub.2 N(CH.sub.3).sub.2, --C.sub.2 H.sub.4 -morpholinyl or --CH.sub.2 OH. Even more preferred is where the compound is an optically pure enantiomer having the S- configuration at C5 of the oxazolidinone ring. More preferable is where one of R.sup.2 and R.sup.3 is F and the other is hydrogen.
In another aspect, the subject invention is directed toward a method for treating microbial infections in warm blooded animals by administering to a warm blooded animal in need thereof an effective amount of a compound of Formula I as described above. 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 carboxylic and phosphate esters of substituted-hydroxyacetyl piperazinyl phenyl oxazolidinones of structural Formula I as defined above. The compounds are useful antimicrobial agents, effective against a number of human and veterinary pathogens, including multiply-resistant staphylococci, enterococci and streptococci, as well as anaer
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patent: 5164510 (1992-11-01), Brickner
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WO93/09103, (May 1993).
WO93/23384 (Nov. 1993).
Gregory, WA, et al., J. Med. Chem., 32, 1673-81 (1989).
Gregory, WA, et al., J. Med. Chem., 33, 2569-78 (1990).
Wang, C., et al., Tetrahedron, 45, 1323-26 (1989).
D-H Park, Brittelli, DR, et al., J. Med. Chem, 35, 1156-1165 (1992).
Barbachyn Michael R.
Brickner Steven J.
Hutchinson Douglas K.
Corneglio Donald L.
Gammill Martha A.
Pharmacia & Upjohn Company
Ramsuer Robert W.
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