Fab I inhibitors

Details Fab I inhibitors Fab I inhibitors

2001-10-18

2003-01-07

Kifle, Bruck (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C540S510000

Reexamination Certificate

active

06503903

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to pharmaceutically active compounds which inhibit FabI and are useful for the treatment of bacterial infections.
BACKGROUND OF THE INVENTION
While the overall pathway of saturated fatty acid biosynthesis is similar in all organisms, the fatty acid synthase (FAS) systems vary considerably with respect to their structural organization. Vertebrates and yeast possess a FAS in which all the enzymatic activities are encoded on one or two polypeptide chains, respectively, and the acyl carrier protein (ACP) is an integral part of the complex. In contrast, in bacterial FAS, each of the reactions is catalyzed by a distinct, mono-functional enzyme and the ACP is a discrete protein. Therefore, there is considerable potential for the selective inhibition of the bacterial system by antibacterial agents.
FabI (previously designated EnvM) functions as an enoyl-ACP reductase (Bergler, et al, (1994),
J.Biol.Chem
. 269, 5493-5496) in the final step of the four reactions involved in each cycle of bacterial fatty acid biosynthesis. In this pathway, the first step is catalyzed by &bgr;-ketoacyl-ACP synthase, which condenses malonyl-ACP with acetyl-CoA (FabH, synthase III). In subsequent rounds, malonyl-ACP is condensed with the growing-chain acyl-ACP (FabB and FabF, synthases I and II, respectively). The second step in the elongation cycle is ketoester reduction by NADPH-dependent &bgr;-ketoacyl-ACP reductase (FabG). Subsequent dehydration by &bgr;-hydroxyacyl-ACP dehydrase (either FabA or FabZ) leads to trans-2-enoyl-ACP, which in turn is converted to acyl-ACP by NADH-dependent enoyl-ACP reductase (FabI). Further rounds of this cycle, adding two carbon atoms per cycle, eventually lead to palmitoyl-ACP (16C), where upon the cycle is stopped largely due to feedback inhibition of FabI by palmitoyl-ACP (Heath, et al, (1996),
J.Biol.Chem
. 271, 1833-1836). Thus, FabI is a major biosynthetic enzyme and is a key regulatory point in the overall synthetic pathwayof bacterial fatty acid biosynthesis. Therefore, FabI is an ideal target for antibacterial intervention.
Studies have shown that diazaborine antibiotics inhibit fatty acid, phospholipid and lipopolysaccharide (LPS) biosynthesis and that the antibacterial target of these compounds is FabI. For example, derivative 2b18 from Grassberger, et al (1984)
J. Med Chem
27 947-953 has been reported to be a non-competitive inhibitor of FabI (Bergler, et al, (1994),
J.Biol.Chem
. 269, 5493-5496). Also, plasmids containing the FabI gene from diazaborine resistant
S. typhimurium
conferred diazaborine resistance in
E.coli
(Turnowsky, et al, (1989),
J.Bacteriol
., 171, 6555-6565). Furthermore, inhibition of FabI either by diazaborine or by raising the temperature in a FabI temperature sensitive mutant is lethal. These results demonstrate that FabI is essential to the survival of the organism (Bergler, et al, (1994),
J.Biol.Chem
. 269, 5493-5496).
Recent studies have shown that FabI is also the target for the broad spectrum antibacterial agent triclosan (McMurry, et al, (1998)
Nature
394, 531-532). A crystal structure of the
E. coli
FabI complexed with NAD and triclosan shows that triclosan acts as a site-directed, very potent inhibitor of FabI by mimicking its natural substrate (Levy, et al, (1999)
Nature
398, 383-384). Ward, et al ((1999)
Biochem
. 38, 12514-12525) have shown that there is no evidence for the formation of a covalent complex between FabI and triclosan, which would be analogous to the diazaborines; triclosan differs from these compounds in that it is a reversible inhibitor of FabI. The structural data for the complex of FabI with NAD and triclosan provides important information about FabI as a therapeutic target.
Importantly, it has now been discovered that certain compounds are FabI inhibitors and have antibacterial activity, and, therefore, may be useful for the treatment of bacterial infections in mammals, particularly in man.
SUMMARY OF THE INVENTION
This invention comprises compounds of the formula (I), as described hereinafter, which inhibit FabI and are useful in the treatment of bacterial infections.
This invention is also a pharmaceutical composition comprising a compound according to formula (I) and a pharmaceutically acceptable carrier.
This invention is also a method of treating bacterial infections by inhibiting FabI. In a particular aspect, the compounds of this invention are useful as antibacterial agents.
DETAILED DESCRIPTION
This invention comprises compounds of formula (I):
wherein:
R
1
is H, C
1-6
alkyl or Ar—CO
0-6
alkyl;
R
2
is H, C
1-6
alkyl, Ar—C
0-6
alkyl, HO-(CH
2
)
n
— or R′OC(O)—(CH
2
)
n
—;
R
3
is A—C
0-4
alkyl, A—C
2-4
alkenyl, A—C
2-4
alkynyl, A—C
3-4
oxoalkenyl, A—C
3-4
oxoalkynyl, A—C
1-4
aminoalkyl, A—C
3-4
aminoalkenyl, A—C
3-4
aminoalkynyl, optionally substituted by any accessible combination of one or more of R
10
or R
7
;
R
5
is H, C
1-6
alkyl, Ar—C
0-6
alkyl or C
3-6
cycloalkyl-C
0-6
alkyl;
A is H, C
3-6
cycloalkyl, Het or Ar;
R
7
is —COR
8
, —COCR′
2
R
9
, —C(S)R
8
, —S(O)
k
OR′, —S(O)
k
NR′R″, —PO(OR′), —PO(OR′)
2
, —B(OR′)
2
, —NO
2
, or tetrazolyl;
R
8
is —OR′, —NR′R″, —NR′SO
2
R′, —NR′OR′, or —OCR′
2
CO(O)R′;
R
9
is —OR′, —CN, —S(O)
r
R′, —S(O)
k
NR′
2
, —C(O)R′, C(O)NR′
2
, or —CO
2
R′;
R
10
is H, halo, —OR
11
, —CN, —NR′R
11
, —NO
2
, —CF
3
, —CF
3
S(O)
r
—, —CO
2
R′, —CONR′
2
, A—C
0-6
alkyl-, A—C
1-6
oxoalkyl-, A—C
2-6
alkenyl-, A—C
2-6
alkynyl-, A—C
0-6
alkyloxy-, A—C
0-6
alkylamino- or A—C
0-6
alkyl-S(O)
r
—;
R
11
is R′, —C(O)R′, —C(O)NR′
2
, —C(O)OR′, —S(O)
k
R′, or —S(O)
k
NR′
2
;
R′ is H, C
1-6
alkyl, Ar—C
0-6
alkyl or C
3-6
cycloalkyl-C
0-6
alkyl;
R″ is R′, —C(O)R′ or —C(O)OR′;
R′″ is H, C
1-6
alkyl, Ar—C
0-6
alkyl, HO-(CH
2
)
2
—, R′C(O)—, (R′)
2
NC(O)CH
2
— or R′S(O)
2
—;
X is H, C
1-4
alkyl, OR′, SR′, C
1-4
alkylsulfonyl, C
1-4
alkylsulfoxyl, —CN, N(R′)
2
, CH
2
N(R′)
2
, —NO
2
, —CF
3
, —CO
2
R′, —CON(R′)
2
, —COR′, —NR′C(O)R′, F, Cl, Br, I, or CF
3
S(O)
r
—;
k is 1 or 2;
m is 1, 2 or 3;
n is 1 to 6; and
r is 0, 1 or 2;
or a pharmaceutically acceptable salt thereof.
Also included in this invention are pharmaceutically acceptable addition salts and complexes of the compounds of this invention. In cases wherein the compounds of this invention may have one or more chiral centers, unless specified, this invention includes each unique racemic compound, as well as each unique nonracemic compound. These compounds may be synthesized and resolved by conventional techniques. In the formula (I) compounds of the present invention, the (R)-configuration at the 2-position of the 1,4-benzodiazepine ring system is preferred.
In cases in which compounds have unsaturated carbon-carbon double bonds, both the cis (Z) and trans (E) isomers are within the scope of this invention. In cases wherein compounds may exist in tautomeric forms, such as keto-enol tautomers, such as
and
each tautomeric form is contemplated as being included within this invention, whether existing in equilibrium or locked in one form by appropriate substitution with R′. The meaning of any substituent at any one occurrence is independent of its meaning, or any other substituent's meaning, at any other occurrence.
Also included in this invention are prodrugs of the compounds of this invention. Prodrugs are considered to be any covalently bonded carriers which release the active parent drug according to formula (I) in vivo.
The compounds of formula (I) inhibit FabI. Inhibition of this enzyme is useful in the treatment of bacterial infections. Also, the compounds of this invention may be useful as antifungal agents. Additionally, the compounds may be useful in combination with known antibiotics.
With respect to formula (I):
Suitably, R
4
is
in which R&pri

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