Quinolones used as MRS inhibitors and bactericides

Details Quinolones used as MRS inhibitors and bactericides Quinolones used as MRS inhibitors and bactericides

2000-10-26

2001-11-20

Seaman, D. Margaret (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C514S155000

Reexamination Certificate

active

06320051

ABSTRACT:

The present invention relates to novel 2-(NH— or O— subsubstituted) quinolones which are inhibitors of methionyl t-RNA synthetase (MRS), processes for their preparation and their use in therapy as anti-bacterial agents.
t-RNA synthetases are involved in protein biosynthesis so that inhibition thereof may be expected to lead to a cessation of cell growth. Thus, for instance, the compound mupirocin, produced by the organism
Pseudomonas fluorescens
, is an anti-bacterial agent and is used as the active ingredient in the product Bactroban, marketed by SmithKline Beecham. Mupirocin has been shown to be an inhibitor of the isoleucyl t-RNA synthetase. Each t-RNA synthetase represents a separate target for drug discovery. t-RNA synthetase inhibitors which are selective for bacterial cells over mammalian cells are of considerable therapeutic interest as they have the potential to be used as anti-bacterial agents.
The sequence of the t-RNA synthetase genes in organisms such as
S aureus
have recently been determined, see for instance European Patent application no 97300317.1 (SmithKline Beecham,
S aureus
MRS), thereby assisting the process of identifying inhibitors.
Various classes of 2-aminoquinolones have been previously described, for instance WO 96/060884 (as antiarrhytmic agents) and EP 0143630, and U.S. Pat. No. 4,005,205 (as H-2 histamine receptor antagonists).
We have now found a novel class of 2-(NH— or O— substituted) quinolones which are potent inhibitors of methionyl t-RNA synthetase. Accordingly, the present invention provides compounds of the formula (I):
in which:
R
1
is optionally substituted aryl or optionally substituted heteroaryl;
R
2
is hydrogen, C
(1-6)
alkyl, arylC
(1-4)
alkyl, arylC
(2-4)
alkenyl or C
(1-6)
alkylcarbonyl;
R
3
is selected from halo, cyano, hydroxy, (C
1-6
)alkyl (optionally substituted by halo, hydroxy, amino, mono to perfluoro(C
1-3
)alkyl, carboxy or (C
1-6
)alkoxycarbonyl). (C
3-7
)cycloalkyl, C
(1-6)
alkoxy, amino, mono- or di-(C
1-6
)alkylamino, acylamino, carboxy, (C
1-6
)alkoxycarbonyl, carboxy(C
1-6
)alkyloxy, (C
1-6
)alkylthio, (C
1-6
)alkylsulphinyl, (C
1-6
)alkylsulphonyl, sulphamoyl, mono- and di-(C
1-6
)alkylsulphamoyl, carbamoyl, mono- and di-(C
1-6
)alkylcarbamoyl, and heterocyclyl;
m is 0 or an integer from 1 to 3;
X is CHR
4
(wherein R
4
is hydrogen, C
(1-6)
alkyl or aryl), C
(2-4)
alkylene, C
(3-4)
alkenylene or CO;
Y is a linker group having from 2 to 6 methylene groups in a straight chain and in which one or more methylene groups may have one or more C
(1-6)
alkyl, C
(1-6)
alkoxy or C
(1-6)
alkylidenyl substituents and in which chain 1,2- or 1,3-carbon atoms may be linked by a C
(2-3)
alkylene or a C
3
alkenylene bridge;
R
1
and X or R
1
and R
2
may be linked by a polymethylene chain to form a 5 to 7 membered ring, optionally substituted by C
(1-6)
alkyl;
X and R
2
, X and Y or Y and R
2
may be linked by a polymethylene chain to form a 4 to 7 membered ring, optionally substituted by C
(1-6)
alkyl;
Z is NH or O; and
salts thereof, preferably pharmaceutically acceptable salts thereof.
Compounds of formula (1) are inhibitors of
S aureus
methionyl tRNA synthetase.
Representative examples of R
1
when aryl include phenyl and naphthyl, each of which may be optionally substituted with up to four substituents. Representative examples of such substituents include C
(1-6)
alkyl, C
(1-6)
alkoxy, halo, cyano, amino, sulphamoyl, phenylcarbonyl, aryl, and benzyloxy. Preferably, the phenyl or naphthyl is substituted by two or three lipophilic substituents such as chloro, bromo, iodo, methyl, ethoxy, allyloxy, phenethyloxy or trifluoromethyl.
Representative examples of R
1
when heteroaryl include pyrrolyl, thienyl, furanyl, pyridyl, quinolinyl, benzofuranyl, and indolyl, each of which may be optionally substituted with up to three substituents. Preferably, the heteroaryl ring is substituted by two or three lipophilic substituents such as chloro, bromo, iodo, methyl, ethoxy or trifluoromethyl. Representative examples of such substituents include halo.
Preferred examples of aryl and heteroaryl groups for R
1
include phenyl, pyrrolyl and indolyl.
Representative examples of R
2
include hydrogen, iso-propyl, acetyl and optionally substituted benzyl. In further representative examples, R
2
and X may be linked to form an azetidine ring or R
2
and Y may linked to form a piperidine ring. Preferably, R
2
is hydrogen.
Representative examples of R
3
include Cl, Br, Me, MeO.
Representative examples of X include CH
2
optionally substituted by methyl or phenyl, C
2
H
4
, CH
2
CHCH and CO. In further representative examples, X is joined to the ortho position of an aryl R
1
group, for instance optionally susbtituted phenyl, by an optionally substituted polymethylene chain, to form a 5 to 7 membered ring, such that R
1
X forms a cyclopentyl, cyclohexyl or cycloheptyl ring fused to phenyl. X may also be joined to the ortho position of a heteroaryl R
1
group, for instance optionally susbtituted thienyl or indolyl. Preferably, X is CH
2
or R
1
X is a C
(5-7)
cycloalkyl ring fused to an aryl or heteroaryl ring.
Preferably, in Y, when 1,2- or 1,3-carbon atoms in the alkylene chain are linked by a C
(2-3)
-bridge, they form, in combination with the carbons of the chain, a 1,2-cyclobutyl, a 1,2-cyclopentyl or a 1,3-cyclohexyl group. Representative examples of Y include (CH
2
)
n
where n is 2, 3, 4 and 5, CH
2
C(Me)
2
CH
2
, 1,2-cyclobutylmethyl, 1,2-cyclopentylmethyl, 1,2-cyclopentenylmethyl and cis-1,3-cyclohexyl. Preferably, Y is (CH
2
)
3
or 1,2-cyclopentylmethyl.
Preferably, Z is NH.
A sub-group of compounds of formula (I) are those in which R
1
is phenyl, that is compounds of formula (IA):
in which R
2
, R
3
, m, Y, and Z are hereinbefore defined,
R
5
is hydrogen or R
5
and R
6
form a C
(2-3)
alkylene bridge which may be optionally substituted by (C
1-6
)alkyl;
R
7
is selected from halo, cyano, hydroxy, (C
1-6
)alkyl (optionally substituted by halo, hydroxy, amino, carboxy or (C
1-6
)alkoxycarbonyl), mono to perfluoro(C
1-3
)alkyl, (C
3-7
)cycloalkyl, C
(1-6)
alkoxy, arylC
(1-6)
alkoxy, amino, mono- or di-(C
1-6
)alkylamino, acylamino, carboxy, (C
1-6
)alkoxycarbonyl, carboxy(C
1-6
)alkyloxy, (C
1-6
)alkylthio, (C
1-6
)alkylsulphinyl, (C
1-6
)alkylsulphonyl, sulphamoyl, mono- and di-(C
1-6
)alkylsulphamoyl, carbamoyl, mono- and di-(C
1-6
)alkylcarbamoyl, and heterocyclyl; and
n is 0, 1, 2 or 3.
Representative examples of the R
5
/R
6
bridge include —(CH
2
)
2
—, —(CH
2
)
3
— and —CH(CH
3
)CH
2
—.
Representative values of R
7
include halo, for instance chloro, bromo, iodo and (C
1-6
)alkyl, for instance methyl.
A further sub-group of compounds of formula (I) are those in which R
1
is indole or pyrrole, that is compounds of formula (IB) and (IC):
in which R
2
, R
3
, m, Y and Z are hereinbefore defined and R
8
, R
9
, R
10
and p are as hereinbefore defined for R
5
, R
6
, R
7
and n, respectively.
Preferably, in compounds of formula (IB) and (IC), R
2
is hydrogen, Y is (CH
2
)
3
and Z is NH. Preferably, R
8
and R
9
together form a (CH
2
)
3
bridge or, more preferably, are each hydrogen.
Salts may be formed from inorganic and organic acids. Representative examples of suitable inorganic and organic acids from which pharmaceutically acceptable salts of compounds of formaula (I) may be formed include maleic, fumaric, benzoic, ascorbic, pamoic, succinic, bismethylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, hydrochloric, hydrobromic, sulfuric, cyclohexylsulfamic, phosphoric and nitric acids.
When used herein, the term “alkyl” and similar terms such as “alkoxy” includes all straight chain and branched isomers. Representative examples thereof include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, t-butyl, n-pentyl and n-hexyl.
Preferred substituents for an alkyl group include, for example, and unless otherwise defined, halogen, cyano, azido, nitro,

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