Oxazolidinone derivatives as antimicrobials

Details Oxazolidinone derivatives as antimicrobials Oxazolidinone derivatives as antimicrobials

2001-07-16

2004-05-11

Ford, John M. (Department: 1624)

Organic compounds -- part of the class 532-570 series

Organic compounds

Nitrogen attached directly or indirectly to the purine ring...

Reexamination Certificate

active

06734307

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to certain substituted phenyl oxazolidinones and to processes for the synthesis of the same. This invention also relates to pharmaceutical compositions containing the compounds of the present invention as antimicrobials. 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 Bacterioides spp. and Clostridia spp. species, and acid fast organisms such as
Mycobacterium tuberculosis, Mycobacterium avium
and Mycobacterium spp.
BACKGROUND OF THE INVENTION
Increasing antibacterial resistance in Gram positive bacteria has presented a formidable treatment problem. The enterococci, although traditionally non virulent pathogens, have been shown, when associated with Vancomycin resistance, to have an attributable mortality of approximately 40%.
Staphylococcus aureus
, the traditional pathogen of post operative wounds, has been resistant to Penicillin due to production of penicillinases. This resistance was overcome by the development of various penicillinase stable &bgr; lactams. But the pathogen responded by synthesizing a modified target penicillin binding protein-2′ leading to less affinity for &bgr; lactam antibiotics and a phenotype known as Methicillin Resistant
S. aureus
(MRSA). These strains, till recently were susceptible to Vancomycin, which inspite of its various drawbacks, has become the drug of choice for MRSA infections.
Streptococcus pneumoniae
is a major pathogen causing pneumonia, sinusitis and meningitis. Until very recently it was highly susceptible to penicillin. Recently though, different PBP 2′ strains with different susceptibility to penicillin have been reported from across the globe.
Oxazolidinones are a new class of synthetic antimicrobial agents which kill gram positive pathogens by inhibiting a very early stage of protein synthesis. Oxazolidinones inhibit the formation of ribosomal initiation complex involving 30S and 50S ribosomes leading to prevention of initiation complex formation. Due to their novel mechanism of action, these compounds are active against pathogens resistant to other clinically useful antibiotics.
WO93/23384 application discloses phenyloxazolidinones containing a substituted diazine moiety and their uses as antimicrobials.
WO93/09103 application discloses substituted aryl and heteroaryl-phenyl-oxazolidinones useful as antibacterial agents
WO90/02744 application discloses 5-indolinyl-5&bgr;-amidomethyloxazolidinones, 3-(fused ring substituted) phenyl-5&bgr;-amidomethyloxazolidinones which are useful as antibacterial agents.
European Patent Publication 352,781 discloses phenyl and pyridyl substituted phenyl oxazolidinones.
European Patent Application 312,000 discloses phenylmethyl and pyridinylmethyl substituted phenyl oxazolidinones.
U.S. Pat. No. 5,254,577 discloses nitrogen heteroaromatic rings attached to phenyloxazolidinone.
U.S. Pat. Nos. 5,547,950 and 5,700,799 also disclose the phenyl piperazinyl oxazolidinones.
Other references disclosing various phenyloxazolidinones include U.S. Pat. Nos. 4,801,600 and 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); Brittelli, et al.,
J.Med. Chem.,
35, 1156 (1992); and
Bio-organic and Medicinal Chemistry Letters,
9, pp. 2679-2684, 1999.
SUMMARY OF THE INVENTION
The objective of this invention is to synthesize, identify and profile oxazolidinone molecules which have good activity against multiply resistant gram positive pathogens like MRSA, VRE and PRSP. Some of these molecules have activity against MDR-TB and MAI strains, while others have significant activity against important anaerobic bacteria.
The compounds of the present invention are related by their substituted phenyloxazolidinone ring structure in the compounds disclosed to the publications described above except that the subject compounds have a diazine moiety attached to the phenyloxazolidinone which is further substituted by heterocyclic, aryl, substituted aryl, heteroaroamatic ring therefore the compounds are unique and have superior antibacterial activity.
Another object of the present invention is to provide processes for the novel phenyloxazolidinones derivatives that exhibit significantly greater antibacterial activity, than available with the present compounds against multiply resistant gram positive pathogens like MRSA, VRE and PRSP against MDR-TB and MAI strains, in order to provide safe and effective treatment of bacterial infections.
In order to achieve the above-mentioned objectives and in accordance with the purpose of the invention as embodied and broadly described herein, there is provided a process for the synthesis of novel phenyloxazolidinone derivatives represented by Formula I
wherein
T is five to seven membered heterocyclic ring, aryl, substituted aryl, bound to the ring C with a linker w, preferred forms of T are selected from aryl and five membered heteroaryl which are further substituted by a group represented by R, wherein R is selected from the group consisting of —CN, COR
5
, COOR
5
, N(R
6
, R
7
), CON(R
6
, R
7
), CH
2
NO
2
, NO
2
, CH
2
R
8
, CHR
9
, —CH═N—OR
10
, —C═CH—R
5
, wherein R
5
is selected from H, optionally substituted C
1
-C
12
, alkyl, C
3-12
, cycloalkyl, aryl, heteroaryl, R
6
and R
7
, are independently selected from H, optionally substituted C
1-12
alkyl, C
3-12
cycloalkyl, C
1-6
alkoxy; R
8
and R
9
are independently selected from H, C
5-6
alkyl, F, Cl, Br, C
1-12
alkyl substituted with one or more of F, Cl, Br, I, OR
5
, SR
4
, N(R
6
,R
7
) wherein R
5
is selected from H, C
1-12
alkyl, C
3-12
cycloalkyl, C
1-6
alkoxy, C
1-6
alkyl substituted with one or more F, Cl, Br, I or OH and R
6
and R
7
are the same as defined earlier, R
5
is selected from H, optionally substituted C
5-12
alkyl, C
1-12
alkyl, C
3-12
cycloalkyl, C
1-6
alkoxy, C
1-6
alkyl, aryl, heteroaryl, n is an integer in the range from 0 to 3;
X is CH, CH—S, CH—O and N;
Y and Z are independently selected from hydrogen, C
1-6
alkyl, C
3-12
and cycloalkyl C
0-3
bridging groups;
U and V are independently selected from optionally substituted C
1-6
alkyl, F, Cl, Br, C
1-12
alkyl substituted with one or more of F, Cl, Br, I, preferably U and V are hydrogen or fluoro;
W is selected from the group CH
2
, CO, CH
2
NH, —NHCH
2
, —CH
2
NHCH
2
, —CH
2
—N (R
11
)CH
2
—, CH
2
(R
11
)N—, CH(R
11
), S, CH
2
( CO), NH wherein R
11
is optionally substituted C
1-12
alkyl, C
3-12
cycloalkyl, C
1-6
alkoxy, C
1-6
alkyl, aryl, heteroaryl; and,
R
1
is selected from the group consisting of —NHC(═O)R
2
wherein R
2
is hydrogen, C
1-12
alkyl, C
3-12
cycloalkyl, C
1-6
alkoxy, C
1-6
alkyl substituted with one or more of F, Cl, Br, I or OH, N(R
3
, R
4
), —NR
2
C(═S)R
3
, —NR
2
C(═S)SR
3
wherein R
2
is the same as defined above, R
3
, R
4
are independently selected from hydrogen, C
1-12
alkyl, C
3-12
cycloalkyl, C
1-6
alkoxy, C
1-6
alkyl substituted with one or more of F, Cl, Br, I or OH.
Preferred compounds of Formula I have R
1
as acetamide and the most preferred compounds in this series would be prepared as the optically pure enantiomers having the (S)-configuration according to the Cahn-Ingold-Prelog notation at C
5
of the oxazolidinone ring. The (S)-enantiomer of this series of compounds is preferred since it has two times more antibacterial activity than the corresponding racemic compound. The scope of the individual isomers and mixture of enantiomers of the structural Formula I are also covered in this invention.
Still more preferred compounds of the Formula I containing D ring as furanyl, thienyl and pyrrolyl ring systems and further substituted by substitutions Q and P is represented by Formula II
wherein
U and V are independently selected from optionally substituted C
1-6
alk

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