Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-07-30
2001-08-07
McKane, Joseph K. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C546S215000, C546S217000
Reexamination Certificate
active
06271383
ABSTRACT:
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 coagulase 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 rending theses 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 narrow range of compounds that is not suggested by the art and which has 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 (for example 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 posses a favourable toxicological profile.
Accordingly the present invention provides a compound of the formula (I):
wherein:
R
1
is hydroxy, chloro, fluoro, (1-4C)alkanesulfonyloxy, amino, azido, (1-4C)alkoxy, (1-4C)alkythio, (1-4C)alkylaminocarbonyloxy;
or the formula —NHC(═O)R
b
wherein R
b
is hydrogen, (1-4C)alkoxy, amino, chloromethyl, dichloromethyl, cyanomethyl, methoxymethyl, acetylmethyl, methylamino, dimethylamino or (1-4C)alkyl;
or R
1
is of the formula —NHS(O)
n
(1-4C)alkyl wherein n is 0, 1 or 2;
R
2
and R
3
are independently hydrogen or fluoro;
D is O, S, SO, SO
2
or NR
7
;
when D is O, R
4
and R
5
are independently hydroxy, bromo, oxo (═O), (1-4C)alkyl, (1-4C)alkanoylamino-(1-4C)alkyl, hydroxy-(1-4C)alkyl, carboxy, (1-4C)alkoxycarbonyl, AR-oxymethyl, AR-thiomethyl (wherein AR is as defined hereinbelow) or independently as defined for R
7
hereinbelow;
when D is S, SO, SO
2
or NR
7
, R
4
and R
5
are independently oxo (═O), (1-4C)alkyl, (1-4C)alkanoylamino-(1-4C)alkyl, hydroxy-(1-4C)alkyl, carboxy, (1-4C)alkoxycarbonyl, AR-oxymethyl, AR-thiomethyl (wherein AR is as defined hereinbelow) or independently as defined for R
7
hereinbelow;
R
6
is hydrogen, (1-4C)alkyl, hydroxy, (1-4C)alkoxy or (2-4C)alkanoyloxy;
>A—B— is of the formula >C═(R
a
)—, >CHCHR
a
—, or >C(OH)CHR
a
—(>represents two single bonds) wherein R
a
is hydrogen or (1-4C)alkyl;
R
7
is hydrogen, cyano, 2-((1-4C)alkoxycarbonyl)ethenyl, 2-cyanoethenyl, 2-cyano-2-((1-4C)alkyl)ethenyl, 2-((1-4C)alkylaminocarbonyl)ethenyl, AR (as defined hereinbelow) or a tetrazole ring system (optionally mono-substituted in the 1- or 2-position of the tetrazole ring) wherein the tetrazole ring system is joined to the nitrogen in NR
7
by a ring carbon atom;
or R
7
is of the formula R
10
CO—, R
10
SO
2
—, R
10
CS—
wherein R
10
is AR (as defined hereinbelow), cyclopentyl or cyclohexyl (wherein the last two-mentioned cycloalkyl rings are optionally mono- or disubstituted by substituents independently selected from (1-4C)alkyl (including geminal disubstitution), hydroxy, (1-4C)alkoxy, (1-4C)alkylthio, acetamido, (1-4C)alkanoyl, cyano and trifluoromethyl), (1-4C)alkoxycarbonyl, hydrogen, amino, trifluoromethyl, (1-4C)alkylamino, di((1-4C)alkyl)amino, 2,3-dihydro-5-oxothiazolo-[3,2-A]pyrimidin-6-yl, 2-(2-furyl)ethenyl, 2-(2-thienyl)ethenyl,2-phenylethenyl (wherein the phenyl substituent is optionally substituted by up to three substituents independently selected from (1-4C)alkoxy, halo and cyano), 3,4-dihydropyran-2-yl, coumal-5-yl, 5-methoxy-4-oxopyran-2-yl, N-acetylpyrrolidin-2-yl, 5-oxo-tetrahydrofuran-2-yl, benzopyranone or (1-10C)alkyl [wherein (1-10C)alkyl is optionally substituted by hydroxy, cyano, halo (1-10C)alkoxy, trifluoromethyl, (1-4C)alkoxy-(1-4C)alkoxy, (1-4C)alkoxy-(1-4C)alkoxy-(1-4C)alkoxy, (1-4C)alkanoyl, (1-4C)alkoxycarbonyl, amino, (1-4C)alkylamino, di((1-4C)alkyl)amino, (1-6C)alkanoylamino, (1-4C)alkoxycarbonylamino,
N
-(1-4C)alkyl-
N
-(2-6C)alkanoylamino, (1-4C)alkylS(O)
p
NH—, (1-4C)alkylS(O)
p
((1-4C)alkyl)N—, fluoro(1-4C)alkylS(O)
9
NH—, fluoro(1-4C)alkylS(O)
p
((1-4C)alkyl)N—, phosphono, 1-4C)alkoxy(hydroxy)phosphoryl, di-(1-4C)alkoxyphosphoryl, (1-4C)alkylS(O)
q
—, phenylS(O)
q
— (wherein the phenyl group is optionally substituted by up to three substituents independently selected from (1-4C)alkoxy, halo and cyano), or CY (as defined hereinbelow), wherein p is 1 or 2 and q is 0.1 or 2];
or R
10
is of the formula R
11
C(O)O(1-6C)alkyl wherein R
11
is an optionally substituted 5- or 6-membered heteroaryl, optionally substituted phenyl, (1-4C)alkylamino, benzyloxy-(1-4C)alkyl or optionally substituted (1-10C)alkyl;
or R
10
is of the formula R
12
O— wherein R
12
is optionally substituted (1-6C)alkyl;
or R
7
is of the formula R
d
OC(R
e
)═CH(C═O), R
f
C(═O)—, R
g
N═C(R
h
)C(═O)— or R
i
NHC(R
j
)═CHC(═O)— wherein R
d
is (1-6C)alkyl, R
e
is hydrogen or (1-6C)alkyl, or R
d
and R
e
together form a (3-4C)alkylene chain, R
f
is hydrogen, (1-6C)alkyl, hydroxy(1-6C)alkyl, (1-6C)alkoxy(1-6C)alkyl, amino, (1-4C)alkylamino, di-(1-4C)alkylamino, (1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkoxy, hydroxy(2-6C)alkoxy, (1-4C)alkylamino(2-6C)alkoxy, di-(1-4C)alkylamino(2-6)alkoxy, R
g
is (1-6C)alkyl, hydroxy or (1-6C)alkoxy, R
h
is hydrogen or (1-6C)alkyl, R
i
is hydrogen (1-6C)alkyl, optionally substituted phenyl or an optionally substituted 5- or 6-membered heteroaryl and R
j
is hydrogen or (1-6C)alkyl;
or R
7
is of the formula R
14
(CH(R
13
)(CH
2
)
m
— wherein m is 0 or 1, R
13
is fluoro, cyano, (1-4C)alkoxy, (1-4C)alkylsulfonyl, (1-4C)alkoxycarbonyl or hydroxy, (provided that when m is 0, R
13
is not fluoro or hydroxy) and R
14
is hydrogen or (1-4C)alkyl
wherein AR is optionally substituted phenyl, optionally substituted phenyl(1-4C)alkyl, optionally substituted 5- or 6-membered heteroaryl, optionally substituted naphthyl or an optionally substituted 5/6 or 6/6 bicyclic heteroaryl ring system, in which the bicyclic heteroaryl ring systems may be linked via an atom in either of the rings comprising the bicyclic system, and wherein the mono- and bicyclic heteroaryl ring systems are linked via a ring carbon atom;
wherein CY is a 4-, 5- or 6-membered cycloalkyl ring, a 5- or 6-membered cycloa
McKane Joseph K.
Person Richard V.
Solola Taofiq A.
Zeneca Limited
LandOfFree
Antibiotic oxazolidinone derivatives does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Antibiotic oxazolidinone derivatives, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Antibiotic oxazolidinone derivatives will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2469860