Antibacterial agents

Details Antibacterial agents Antibacterial agents

2001-08-22

2003-01-07

Rao, Deepak R. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S211030, C514S211070, C514S212030, C514S218000, C514S327000, C514S431000, C540S460000, C540S463000, C540S488000, C540S491000, C540S492000, C540S527000, C546S221000, C549S010000

Reexamination Certificate

active

06503897

ABSTRACT:

This invention relates to a novel class of N-formyl hydroxylamine derivatives having antibacterial activity, and to pharmaceutical and veterinary compositions comprising such compounds.
BACKGROUND OF THE INVENTION
In general, bacterial pathogens are classified as either Gram-positive or Gram-negative. Many antibacterial agents (including antibiotics) are specific against one or other Gram-class of pathogens. Antibacterial agents effective against both Gram-positive and Gram-negative pathogens are therefore generally regarded as having broad-spectrum activity.
Many classes of antibacterial agents are known, including the penicillins and cephalosporins, tetracyclines, sulfonamides, monobactams, fluoroquinolones and quinolones, aminoglycosides, glycopeptides, macrolides, polymyxins, lincosamides, trimethoprim and chloramphenicol. The fundamental mechanisms of action of these antibacterial classes vary.
Bacterial resistance to many known antibacterials is a growing problem. Accordingly there is a continuing need in the art for alternative antibacterial agents, especially those which have mechanisms of action fundamentally different from the known classes.
Amongst the Gram-positive pathogens, such as Staphylococci, Streptococci, Mycobacteria and Enterococci, resistant strains have evolved/arisen which makes them particularly difficult to eradicate. Examples of such strains are methicillin resistant
Staphylococcus aureus
(MRSA), methicillin resistant coagulase negative Staphylococci (MRCNS), penicillin resistant
Streptococcus pneumoniae
and multiply resistant
Enterococcus faecium.
Pathogenic bacteria are often resistant to the aminoglycoside, &bgr;-lactam (penicillins and cephalosporins), and chloramphenicol types of antibiotic. This resistance involves the enzymatic inactivation of the antibiotic by hydrolysis or by formation of inactive derivatives. The &bgr;-lactam (penicillin and cephalosporin) family of antibiotics are characterised by the presence of a &bgr;-lactam ring structure. Resistance to this family of antibiotics in clinical isolates is most commonly due to the production of a “penicillinase” (&bgr;-lactamase) enzyme by the resistant bacterium which hydrolyses the &bgr;-lactam ring thus eliminating its antibacterial activity.
Recently there has been an emergence of vancomycin-resistant strains of enterococci (Woodford N. 1998 Glycopeptide-resistant enterococci: a decade of experience. Journal of Medical Microbiology. 47(10):849-62). Vancomycin-resistant enterococci are particularly hazardous in that they are frequent causes of hospital based infections and are inherently resistant to most antibiotics. Vancomycin works by binding to the terminal D-Ala-D-Ala residues of the cell wall peptidioglycan precursor. The high-level resistance to vancomycin is known as VanA and is conferred by a genes located on a transposable element which alter the terminal residues to D-Ala-D-lac thus reducing the affinity for vancomycin.
In view of the rapid emergence of multidrug-resistant bacteria, the development of antibacterial agents with novel modes of action that are effective against the growing number of resistant bacteria, particularly the vancomycin resistant enterococci and &bgr;-lactam antibiotic-resistant bacteria, such as methicillin-resistant
Staphylococcus aureus
, is of utmost importance.
BRIEF DESCRIPTION OF THE INVENTION
This invention is based on the finding that certain N-formyl hydroxylamine derivatives have antibacterial activity, and makes available a new class of antibacterial agents.
Although it may be of interest to establish the mechanism of action of the compounds with which the invention is concerned, it is their ability to inhibit bacterial growth, which makes them useful. However, it is presently believed that their antibacterial activity is due, at least in part, to intracellular inhibition of bacterial polypeptide deformylase (PDF) enzyme.
Bacterial polypeptide deformylases (PDF) (EC 3.5.1.31), are a conserved family of metalloenzymes (Reviewed: Meinnel T, Lazennec C, Villoing S, Blanquet S, 1997, Journal of Molecular Biology 267, 749-761) which are essential for bacterial viability, their function being to remove the formyl group from the N-terminal methionine residue of ribosome-synthesised proteins in eubacteria. Mazel et al. (EMBO J. 13(4):914-923, 1994) have recently cloned and characterised an
E. coli
PDF. As PDF is essential to the growth of bacteria and there is no eukaryotic counterpart to PDF, Mazel et al. (ibid), Rajagopalan et al. (J. Am. Chem. Soc. 119:12418-12419, 1997) and Beckeretal., (J. Biol Chem. 273(19):11413-11416, 1998) have each proposed that PDF is an excellent anti-bacterial target.
Certain N-formyl hydroxylamine derivatives have previously been claimed in the patent publications listed below, although very few examples of such compounds have been specifically made and described:
EP-B-0236872 (Roche)
WO 92/09563 (Glycomed)
WO 92/04735 (Syntex)
WO 95/19965 (Glycomed)
WO 95/22966 (Sanofi Winthrop)
WO 95/33709 (Roche)
WO 96/23791 (Syntex)
WO 96/16027 (Syntex/Agouron)
WO 97/03783 (British Biotech)
WO 97/18207 (DuPont Merck)
WO 98/38179 (GlaxoWelicome)
WO 98/47863 (Labs Jaques Logeais)
The pharmaceutical utility ascribed to the N-formyl hydroxylamine derivatives in those publications is the ability to inhibit matrix metalloproteinases (MMPs) and in some cases release of tumour necrosis factor (TNF), and hence the treatment of diseases or conditions mediated by those enzymes, such as cancer and rheumatoid arthritis. That prior art does not disclose or imply that N-formyl hydroxylamine derivatives have antibacterial activity.
In addition to these, U.S. Pat. No. 4,738,803 (Roques et al.) also discloses N-formyl hydroxylamine derivatives, however, these compounds are disclosed as enkephalinase inhibitors and are proposed for use as antidepressants and hypotensive agents. Also, WO 97/38705 (Bristol-Myers Squibb) discloses certain N-formyl hydroxylamine derivatives as enkephalinase and angiotensin converting enzyme inhibitors. This prior art does not disclose or imply that N-formyl hydroxylamine derivatives have antibacterial activity either.
Our copending International patent application no. PCT/GB99/00386 discloses that certain N-formyl hydroxylamine derivatives have antibacterial activity. One class of compounds disclosed as having such activity has general formula (IA):
wherein the various “R” substituents are as specified in the document. The compounds useful in accordance with the present invention differ in structure from those of PCT/GB99/00386 principally in that the acyclic amidoalkyl radical shown as lying to the right of the curved line in formula (IA) is replaced by a cyclic radical.
DETAILED DESCRIPTION IF THE INVENTION
According to the first aspect of the present invention there is provided a compound of formula (I) or a pharmaceutically or veterinarily acceptable salt, hydrate or solvate thereof:
wherein:
R
1
represents hydrogen, methyl, or trifluoromethyl
R
2
represents a group R
10
-(X)
n
-(ALK)- wherein
Rl, represents hydrogen, a C
1
-C
6
alkyl, C
2
-C alkenyl, C
2
-C
6
alkynyl, cycloalkyl, aryl, or heterocyclyl group, any of which may be unsubstituted or substituted by (C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy, hydroxy, mercapto, (C
1
-C
6
)alkylthio, amino, halo (including fluoro, chloro, bromo and iodo), trifluoromethyl, cyano, nitro, -COOH, -CONH
2
, -COOR
A
, -NHCOR
A
, -CONHR
A
, -NHR
A
, -NR
A
R, or -CONR
A
R
B
wherein R
A
and R
B
are independently a (C
1
-C
6
)alkyl group, and
ALK represents a straight or branched divalent C
1
-C
6
alkylene, C
2
-C
6
alkenylene, C
2
-C
6
alkynylene radical, and may be interrupted by one or more non-adjacent —NH—, —O— or —S— linkages,
X represents —NH—, —O— or —S—, and
n is 0 or 1; and
R
3
and R
4
, taken together with the carbon atoms to which they are respectively attached, form an optionally substituted saturated carbocyclic or heterocyclic ring of 5 to 16 atoms, which may be benz-fused or fused to a second optionally substituted saturated carbocyclic or heterocycl

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