Substituted phenyloxazolidinones and their use as antibiotics

Details Substituted phenyloxazolidinones and their use as antibiotics Substituted phenyloxazolidinones and their use as antibiotics

2000-05-25

2002-12-17

McKane, Joseph K. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S230500, C514S255050, C514S269000, C514S274000, C514S272000, C514S341000, C514S363000, C514S371000, C544S105000, C544S331000, C544S405000, C544S316000, C544S355000, C546S271400, C548S129000, C548S204000, C548S229000

Reexamination Certificate

active

06495551

ABSTRACT:

This is a U.S. National Stage filing under 35 U.S.C. 371 of International Patent Application No. PCT/GB98/03496, filed Nov. 24, 1998, which is based on British Patent Application No. 9725244.9, filed Nov. 29, 1997.
The present invention relates to antibiotic compounds and in particular to antibiotic compounds containing an oxazolidinone 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 coaguiase 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 an oxazolidinone 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 &bgr;-lactams.
We have now discovered a range of compounds which have 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 (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 the present invention provides a compound of the formula (I):
wherein R
1
is hydroxy, amino, chloro, fluoro, (1-4C)alkanesulfonyloxy, azido, (1-4C)alkoxy, or of the formula —NHC(═O)R
a
wherein R
a
is hydrogen, (1-4C)alkoxy, chloromethyl, dichloromethyl, cyanomethyl, methoxymethyl, acetylmethyl or (1-4C)alkyl;
R
2
and R
3
are independently hydrogen or fluoro;
R
5
and R
6
are independently selected from hydrogen, (1-4C)alkyl, halo and trifluoromethyl;
R
4
is —X—Y—Het.;
wherein X is a direct bond or —CH(OH)— and
Y is —(CH
2
)
m
—, —(CH
2
)
n
—NH—(CH
2
)
m
—, —CO—(CH
2
)
m
—, —CONH—(CH
2
)
m
—, —C(═S)NH—(CH
2
)
m
— or —C(═O)O—(CH
2
)
m
—;
or wherein X is —(CH
2
)
n
— or —CH(Me)—(CH
2
)
m
— and Y is —(CH
2
)
m
—NH—(CH
2
)
m
—, —CO—(CH
2
)
m
—, —CONH—(CH
2
)
m
—, C(═S)NH—(CH
2
)
m
—, —C(═O)O—(CH
2
)
m
— or —S(O)
p
—(CH
2
)
m
—;
or wherein X is —CH
2
O—, —CH
2
NH— or —CH
2
N(R)— [wherein R is (1-4C)alkyl] and Y is —CO—(CH
2
)
m
—, —CONH—(CH
2
)
m
— or —C(═S)NH—(CH
2
)
m
—; and additionally Y is —SO
2
— when X is —CH
2
NH— or —CH
2
N(R)— [wherein R (1-4C)alkyl], and Y is —(CH
2
)
m
— when X is —CH
2
O— or —CH
2
N(R)—;
wherein n is 1, 2 or 3; m is 0, 1, 2 or 3 and p is 0, 1 or 2; and when Y is —(CH
2
)
m
—NH—(CH
2
)
m
— each m is independently selected from 0, 1, 2 or 3;
wherein Het. is a heterocyclic ring [which heterocyclic ring may be unsaturated (linked via either a ring carbon or ring nitrogen atom to —X—Y—) or saturated (linked via a ring nitrogen atom to —X—Y—), with the proviso that when it is unsaturated and linked via nitrogen to —X—Y— the ring is not quaternised] which heterocyclic ring is optionally substituted on an available carbon atom by up to three substituents independently selected from (1-4C)alkyl [optionally substituted by trifluoromethyl, (1-4C)alkyl S(O)
p
— (wherein p is 0, 1 or 2), carbamoyl, N-(1-4C)alkyicarbamoyl, di(N-(1-4C)alkyl)carbamoyl, (1-4C)alkoxy, (1-4C)alkoxycarbonyl, cyano, nitro, amino, N-(1-4C)alkylamino, di(N-(1-4C)alkyl)amino or (1-4C)alkanoylamino], halo, trifluoromethyl, (1-4C)alkyl S(O)
p
(wherein p is 0, 1 or 2), carboxy, (1-4C)alkoxycarbonyl, carbamoyl, N-(1-4C)alkylcarbamoyl, di(N-(1-4C)alkyl)carbamoyl, (2-4C)alkenyl, cyano, nitro, amino, (2-4C)alkanoylamino, (1-4C)alkoxy, di(N-(1-4C)alkyl)aminomethylimino, hydroxy, oxo or thioxo (═S); and optionally substituted on an available nitrogen atom (if the ring will not thereby be quaternised) by (1-4C)alkyl [optionally substituted by trifluoromethyl, (1-4C)alkyl S(O)
p
— (wherein p is 0, 1 or 2), (1-4C)alkoxy, (1-4C)alkoxycarbonyl, carbamoyl, N-(1-4C)alkylcarbamoyl, di(N-(1-4C)alkyl)carbamoyl, cyano, nitro, amino, N-(1-4C)alkylamino, di(N-(1-4C)alkyl)amino or (1-4C)alkanoylamino] or oxo (to form an N-oxide); and pharmaceutically acceptable salts thereof.
In a further aspect of the invention there is provided a compound of the formula (I) as described hereinabove, wherein when X is a direct bond, Y is additionally —CON(R)— (CH
2
)
m
— [wherein R is (1-4C)alkyl], and the optional substituents on an available carbon atom in the Het. heterocyclic ring additionally include amino.
The term ‘alkyl’ includes straight chained and branched structures. For example, (1-4C)alkyl includes propyl, isopropyl and t-butyl.
Examples of (1-4C)alkyl include methyl, ethyl, propyl, isopropyl and t-butyl; examples of N-(1-4C)alkylcarbamoyl include methylcarbamoyl and ethylcarbamoyl; examples of di(N-(1-4C)alkyl)carbamoyl include di(methyl)carbamoyl and di(ethyl)carbamoyl; examples of (1-4C)alkylS(O)
p
— include methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, methylsulfonyl and ethylsulfonyl; examples of (2-4C)alkenyl include allyl and vinyl; examples of (1-4C)alkoxy include methoxy, ethoxy and propoxy; examples of (2-4C)alkanoylamino include acetamido and propionylamino; examples of N-(1-4C)alkylamino include methylamino and ethylamino; example of di-(N-(1-4C)alkyl)amino include di-N-methylamino, di-(N-ethyl)amino and N-ethyl-N-methylamino; examples of (1-4C)alkoxycarbonyl include methoxycarbonyl and ethoxycarbonyl; examples of halo include fluoro, chloro and bromo; examples of di-(N-(1-4C)alkyl)aminomethylimino include dimethylaminomethylimino and diethylaminomethylimino and examples of (1-4C)alkanesulfonyloxy include methylsulfonyloxy and ethylsulfonyloxy.
A heterocyclic ring means a 5- or 6-membered monocyclic ring or a 5/6 or 6/6 bicyclic ring (linked via either, or any, of the rings) containing up to four heteroatoms selected independently from O, S and N. An unsaturated ring means a fully unsaturated (aromatic) ring and partially unsaturated ring systems (such as, for example, tetrahydropyridine). Preferred examples of unsaturated 5- or 6-membered heterocyclic groups with up to four heteroatoms selected independently from O, S and N are furan, pyrrole, thiophene, those containing one, two or three N atoms (for example, pyrazole, imidazole, pyridine, pyrimidine, pyrazine, pyridazine, 1,2,3- and 1,2,4-triazole), two N atoms and one S atom (for example 1,2,4- and 1,3,4-thiadiazole,

Affiliated with

Also associated with

Rating

Substituted phenyloxazolidinones and their use as antibiotics does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Substituted phenyloxazolidinones and their use as antibiotics, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Substituted phenyloxazolidinones and their use as antibiotics will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2974786