Aminometyl oxooxazolidinyl benzene derivatives

Details Aminometyl oxooxazolidinyl benzene derivatives Aminometyl oxooxazolidinyl benzene derivatives

2000-02-18

2002-03-26

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S299000, C514S300000, C514S368000, C514S375000, C514S376000, C544S281000, C546S112000, C546S121000, C548S126000, C548S229000

Reexamination Certificate

active

06362191

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 rendering these agents less and less effective in the treatment of Gram-positive pathogens.
The present inventor has 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 that 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,
J. Med. Chem.,
1990, 33, 2569-2578 and Chung-Ho Park et al,
J. Med. Chem.,
1992, 35, 1156-1165) the compounds also possess a favourable toxicological profile.
Accordingly the present invention provides a compound of formula (I),
wherein:
A is linked via a ring carbon atom and is a 5 membered heteroaryl ring containing one nitrogen atom and optionally 1-3 further heteroatoms chosen from oxygen, sulfur and nitrogen, or a bicyclic benzo system containing such a 5 membered heteroaryl ring and is linked via a ring carbon atom in the 5 membered heteroaryl ring, or A is a bicyclic or tricyclic heteroaryl ring system with at least one bridgehead nitrogen and optionally a further 1-3 heteroatoms chosen from oxygen, sulfur and nitrogen and is linked via a ring carbon atom in a ring containing a bridgehead nitrogen;
R
1
is attached to a ring carbon atom and is hydroxy, halo, amino, nitro, cyano, carboxy, thiol, C
1-4
alkanoyloxy, C
1-4
alkoxycarbonyl, dimethylaminomethyleneaminocarbonyl, C
1-4
alkyl, C
2-4
alkenyl, C
2-4
alkynyl, C
1-4
alkoxy, R
5
—, R
5
—O—, R
5
—C
1-4
alkyl-, R
5
—C(O)NH—, [where R
5
is optionally substituted phenyl, an optionally substituted 5- or 6-membered heteroaryl ring, an optionally substituted 5- or 6-membered heterocycle or an optionally substituted bicyclic heteroaryl ring], hydroxyC
1-4
alkyl, carbamoyl, N—(C
1-4
alkyl)carbamoyl, N,N—(C
1-4
alkyl)
2
carbamoyl, thiocarbamoyl, N—(C
1-4
alkyl)thiocarbamoyl, N,N—(C
1-4
alkyl)
2
thiocarbamoyl, trifluoromethyl, C
1-4
alkanoylamino [where the C
1-4
alkanoyl group is optionally substituted by hydroxy], R
6
-thio, R
6
-sulfinyl, R
6
-sulfonyl [where R
6
is C
1-4
alkyl optionally substituted by one or more groups independently selected from cyano, hydroxy and C
1-4
alkoxy], C
1-4
alkanoyl, sulfonamido, C
1-4
alkylamino, di(C
1-4
alkyl)amino, C
1-4
alkoxyC
1-4
alkyl, carbamoylC
1-4
alkyl or cyanoamino, or R
1
is attached to a ring nitrogen atom where such substitution does not result in quaternization and is selected from R
7
—, R
7
—C(O)— [where R
7
is C
1-4
alkyl optionally substituted by cyano, hydroxy or C
1-4
alkoxyl] or C
1-4
alkoxyC(O)—;
n is 0-6;
R
2
and R
3
are independently hydrogen or fluoro;
R
4
is hydrogen, C
1-4
alkyl, C
1-4
alkoxy, amino, chloromethyl, dichloromethyl, cyanomethyl, methoxymethyl, acetylmethyl, methylamino and dimethylamino; or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof.
In this specification the term ‘alkyl’ includes straight chained, branched structures and ring systems. For example, C
1-4
alkyl includes methyl ethyl, propyl, isopropyl, t-butyl, cyclopropane and cyclobutane; C
1-6
alkyl includes methyl, ethyl, propyl, isopropyl. t-butyl, cyclopropane and cyclohexane. However, references to individual alkyl groups such as ‘propyl’ are specific for the straight chained version only, references to individual branched chain alkyl groups such as ‘isopropyl’ are specific for the branched chain version only and references to the cyclo groups such as cyclohexane are specific to the cyclic groups only.
A similar convention applies to other radicals, for example “hydroxyC
1-4
alkyl” includes 1-hydroxyethyl and 2-hydroxyethyl.
The term “halo” refers to fluoro, chloro, bromo and iodo.
“Aryl” means phenyl or naphthyl.
“Heteroaryl” means, unless otherwise further specified, a monocyclic-, bicyclic- or tricyclic-5-14 membered ring that contains some degree of unsaturation, with up to five ring heteroatoms selected from nitrogen, oxygen and sulfur. Examples of “heteroaryl” include thienyl, furanyl, imidazolyl, thiazolyl, pyrimidinyl, pyridinyl, indolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolinyl, xanthene, phenoxathiin and chromene. Examples of a 5 membered heteroaryl ring containing one nitrogen atom and optionally 1-3 further heteroatoms chosen from oxygen, sulfur and nitrogen include pyrrole, imidazole, triazole, thiazole and isoxazole. Examples of a bicyclic benzo system containing a 5 membered heteroaryl ring containing one nitrogen atom and optionally 1-3 further heteroatoms chosen from oxygen, sulfur and nitrogen include indole, benzothiazole and benzimidazole. Examples of bicyclic or tricyclic heteroaryl ring system with at least one bridgehead nitrogen and optionally a further 1-3 heteroatoms chosen from oxygen, sulfur and nitrogen include 3H-pyrrolo[1,2-a]-pyrrole, pyrrolo[2,1-b]thiazole, 1H-imidazo[1,2-a]pyrrole, 1H-imidazo[1,2-a]imidazole, 1H-pyrrolo[1,2-a]benzimidazole, 9H-imidazo[1,2-a]indole, 5H-imidazo[2,1-a]isoindole, 1H,3H-pyrrolo[1,2-c]oxazole, 1H-imidazo[1,5-a]pyrrole, 1H-imidazo[3,4-a]indole, pyrrolo[1,2-b]isoxazole, imidazo[5,1-b]thiazole, imidazo[2,1-b]thiazole, indolizine, pyrrolo[a]quinoline, 2,3-pyrroloisoquinoline, pyrrolo[a]isoquinoline, imidazo[1,2-a]pyridine, imidazo[1,2-a]quinoline, imidazo[2,1-a]isoquinoline, imidazo[1,5-a]pyridine, imidazo[1,5-a]quinoline, imidazo[5,1-a]isoquinoline, pyrazolo[1,5-a]pyridine, pyrrolo[1,2-b]pyridazine, pyrrolo [1,2-c]pyrimidine, pyrrolo[1,2-a]pyrazine, pyrrolo[1,2-a]pyrimidine, pyrido[2,1-c]-s-triazole, s-triazole[1,5-a]pyridine, imidazo[2,1-c]pyrimidine, imidazo[1,2-a]pyrazine, imidazo[1,2-a]pyrimi

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