Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-04-05
2004-05-11
Gerstl, Robert (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S229000
Reexamination Certificate
active
06734200
ABSTRACT:
The present invention relates to antibiotic compounds and in particular to antibiotic compounds containing a substituted 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 Grain-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 rendering these agents less and less effective in the treatment of Gram-positive pathogens.
Certain antibacterial compounds containing an oxazolidinone ring have been 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). Such antibacterial oxazolidinone compounds with a 5-methylacetamide sidechain may be subject to mammalian peptidase metabolism. Furthermore, bacterial resistance to known antibacterial agents may develop, for example, by (i) the evolution of active binding sites in the bacteria rendering a previously active pharmacophore less effective or redundant, and/or (ii) the evolution of means to chemically deactivate a given pharmacophore. Therefore, there remains an ongoing need to find new antibacterial agents with a favourable pharmacological profile, in particular for compounds containing new pharmacophores.
We have discovered a class of antibiotic compounds containing a new class of substituted 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.
Accordingly the present invention provides a compound of the formula (I), or a pharmaceutically-acceptable salt, or an in-vivo-hydrolysable ester thereof,
wherein
HET is a C-linked 5-membered heteroaryl ring containing 2 to 4 heteroatoms independently selected from N, O and S, which ring is optionally substituted on an available carbon atom by 1 or 2 substituents independently selected from (1-4C)alkyl, amino, (1-4C)alkylamino, (1-4C)alkoxy, (1-4C)alkoxycarbonyl and halogen, and/or on an available nitrogen atom (provided that the ring is not thereby quaternised) by (1-4C)alkyl; or
HET is a C-linked 6-membered heteroaryl ring containing 2 or 3 nitrogen heteroatoms, which ring is optionally substituted on any available C atom by 1, 2 or 3 substituents independently selected from (1-4C)alkyl, amino, (1-4C)alkylamino, (1-4C)alkoxy, (1-4C)alkoxycarbonyl and halogen;
Q is selected from Q1 to Q9:
wherein
R
2
and R
3
are independently hydrogen or fluoro;
wherein A
1
is carbon or nitrogen; B
1
is O or S (or, in Q9 only, NH); X
q
is O, S or N—R
1
(wherein R
1
is hydrogen, (1-4C)alkyl or hydroxy-(1-4C)alkyl); and wherein in Q7 each A
1
is independently selected from carbon or nitrogen, with a maximum of 2 nitrogen heteroatoms in the 6-membered ring, and Q7 is linked to T via any of the A
1
atoms (when A
1
is carbon), and linked in the 5-membered ring via the specified carbon atom, or via A
1
when A
1
is carbon; Q8 is linked to T via either of the specified carbon atoms in the 5-membered ring, and linked in the benzo-ring via either of the two specified carbon atoms on either side of the linking bond shown; and Q9 is linked via either of the two specified carbon atoms on either side of the linking bond shown;
wherein T is selected from the groups in (TA) to (TD) below (wherein AR1, AR2, AR2a, AR2b, AR3, AR3a, AR3b, AR4, AR4a, CY1 and CY2 are defined hereinbelow);
(TA) T is selected from the following groups:
(TAa) AR1, AR1-(1-4C)alkyl-, AR2 (carbon linked), AR3;
(TAb) AR1—CH(OH), AR2—CH(OH)—, AR3—CH(OH)—;
(TAc) AR1—CO—, AR2—CO—, AR3—CO—, AR4—CO—;
(TAd) AR1—O—, AR2—O—, AR3—O—;
(TAe) AR1—S(O)
q
—, AR
2
—S(O)
q
—, AR3—S(O)
q
— (q is 0, 1 or 2);
(TAf) an optionally substituted N-linked (fully unsaturated) 5-membered heteroaryl ring system containing 1, 2 or 3 nitrogen atoms; p
3
(TAg) a carbon linked tropol-3-one or tropol-4-one, optionally substituted in a position not adjacent to the linking position; or
(TB) T is selected from the following groups:
(TBa) halo or (1-4C)alkyl {optionally substituted by one or more groups each independently selected from hydroxy, (1-4C)alkoxy, (1-4C)alkanoyl, cyano, halo, trifluoromethyl, (1-4C)alkoxycarbonyl, —NRvRw, (1-6C)alkanoylamino, (1-4C)alkoxycarbonylamino,
N
-(1-4C)alkyl-
N
-(1-6C)alkanoylamino, (1-4C)alkylS(O)
q
— (q is 0, 1 or 2), CY1, CY2 or AR1};
(TBb) —NRv
1
Rw
1
;
(TBc) ethenyl, 2-(1-4C)alkylethenyl, 2-cyanoethenyl, 2-cyano-2-((1-4C)alkyl)ethenyl, 2-nitroethenyl, 2-nitro-2-((1-4C)alkyl)ethenyl, 2-((1-4C)alkylaminocarbonyl)ethenyl, 2-((1-4C)alkoxycarbonyl)ethenyl, 2-(AR1)ethenyl, 2-(AR2)ethenyl;
(TBd) R
10
CO—, R
10
S(O)
q
— (q is 0, 1 or 2) or R
10
CS—
wherein R
10
is selected from the following groups:
(TBda) CY1 or CY2;
(TBdb) hydrogen, (1-4C)alkoxycarbonyl, trifluoromethyl, —NRvRw, ethenyl, 2-(1-4C)alkylethenyl, 2-cyanoethenyl, 2-cyano-2-((1-4C)alkyl)ethenyl, 2-nitroethenyl, 2-nitro-2-((1-4C)alkyl)ethenyl, 2-((1-4C)alkylaminocarbonyl)ethenyl, 2-((1-4C)alkoxycarbonyl)ethenyl, 2-(AR1)ethenyl or 2-(AR2)ethenyl; or
(TBdc) (1-4C)alkyl {optionally substituted as defined in (TBa) above, or by (1-4C)alkylS(O)
p
NH— or (1-4C)alkylS(O)
p
-((1-4C)alkyl)N— (p is 1 or 2)};
wherein Rv is hydrogen or (1-4C)alkyl; Rw is hydrogen or (1-4C)alkyl; Rv
1
is hydrogen, (1-4C)alkyl or (3-8C)cycloalkyl; Rw
1
is hydrogen, (1-4C)alkyl, (3-8C)cycloalkyl, (1-4C)alkyl-CO— or (1-4C)alkylS(O)
q
— (q is 1 or 2); or
(TC) T is selected from the following groups:
(TCa) an optionally substituted, fully saturated 4-membered monocyclic ring containing 1 heteroatom selected from O, N and S (optionally oxidised), and linked via a ring nitrogen or sp
3
carbon atom;
(TCb) an optionally substituted 5-membered monocyclic ring containing 1 heteroatom selected from O, N and S (optionally oxidised), and linked via a ring nitrogen atom or a ring sp
3
or sp
2
carbon atom, which monocyclic ring is fully saturated other than (where appropriate) at a linking sp
2
carbon atom;
(TCc) an optionally substituted 6- or 7-membered monocyclic ring containing 1 or 2 heteroatoms independently selected from O, N and S (optionally oxidised), and linked via a ring nitrogen atom or a ring sp
1
or sp
2
carbon atom, which monocyclic ring is fully saturated other than (where appropriate) at a linking sp
2
carbon atom; or
(TD) T is selected from the following groups:
(TDa) a bicyclic spiro-ring system containing 0, 1 or 2 ring nitroge
AstraZeneca AB
Gerstl Robert
Ropes & Gray LLP
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