Fatty acid synthase inhibitors

Details Fatty acid synthase inhibitors Fatty acid synthase inhibitors

2002-02-19

2002-12-24

Owens, Amelia (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S465000, C549S447000

Reexamination Certificate

active

06498187

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to the use of compounds as inhibitors of the fatty acid synthase FabH.
BACKGROUND OF THE INVENTION
The pathway for the biosynthesis of saturated fatty acids is very similar in prokaryotes and eukaryotes. However, although the chemical reactions may not vary, the organization of the biosynthetic apparatus is very different. Vertebrates and yeasts possess type I fatty acid synthases (FASs) in which all of the enzymatic activities are encoded on one or two polypeptide chains, respectively. The acyl carrier protein (ACP) is an integral part of the complex. In contrast, in most bacterial and plant FASs (type II) each of the reactions are catalyzed by distinct monofunctional enzymes and the ACP is a discrete protein. Mycobacteria are unique in that they possess both type I and II FASs; the former is involved in basic fatty acid biosynthesis whereas the latter is involved in synthesis of complex cell envelope lipids such as mycolic acids. There therefore appears to be considerable potential for selective inhibition of the bacterial systems by broad-spectrum antibacterial agents (Jackowski, S. 1992. In Emerging Targets in Antibacterial and Antifungal Chemotherapy. Ed. J. Sutcliffe & N. Georgopapadakou. Chapman & Hall, New York; Jackowski, S. et al. (1989). J. Biol. Chem. 264, 7624-7629.)
The first step in the biosynthetic cycle is the condensation of malonyl-ACP with acetyl-CoA by FabH. 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 is in turn 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 whereupon the cycle is stopped largely due to feedback inhibition of FabH and I by palmitoyl-ACP (Heath, et al., (1996), J. Biol. Chem. 271, 1833-1836). Fab H is therefore a major biosynthetic enzyme which is also a key regulatory point in the overall synthetic pathway (Heath, R. J. and Rock, C. O. 1996. J. Biol. Chem. 271, 1833-1836; Heath, R. J. and Rock, C. O. 1996. J. Biol. Chem. 271, 10996-11000).
The antibiotic thiolactomycin has broad-spectrum antibacterial activity both in vivo and in vitro and has been shown to specifically inhibit all three condensing enzymes. It is non-toxic and does not inhibit mammalian FASs (Hayashi, T. et al., 1984. J. Antibiotics 37, 1456-1461; Miyakawa, S. et al., 1982. J. Antibiotics 35, 411-419; Nawata, Y et al., 1989. Acta Cryst. C45, 978-979; Noto, T. et al., 1982. J. Antibiotics 35, 401-410; Oishi, H. et al., 1982. J. Antibiotics 35, 391-396. Similarly, cerulenin is a potent inhibitor of FabB & F and is bactericidal but is toxic to eukaryotes because it competes for the fatty-acyl binding site common to both FAS types (D'Agnolo, G. et al.,1973. Biochim. Biophys. Acta. 326, 155-166). Extensive work with these inhibitors has proved that these enzymes are essential for viability. Little work has been carried out in Gram-positive bacteria.
There is an unmet need for developing new classes of antibiotic compounds that are not subject to existing resistance mechanisms. No marketed antibiotics are targeted against fatty acid biosynthesis, therefore it is unlikely that novel antibiotics of this type would be rendered inactive by known antibiotic resistance mechanisms. Moreover, this is a potentially broad-spectrum target. Therefore, FabH inhibitors would serve to meet this unmet need.
SUMMARY OF THE INVENTION
This invention comprises cinnamate derivatives and pharmaceutical compositions containing these compounds and their use as FabH inhibitors that are useful as antibiotics for the treatment of Gram positive and Gram negative bacterial infections.
This invention further constitutes a method for treatment of a Gram negative or Gram positive bacterial infection in an animal, including humans, which comprises administering to an animal in need thereof, an effective amount of a compound of this invention.
DETAILED DESCRIPTION OF THE INVENTION
The compounds of this invention are represented by Formula (I):
wherein,
R
1
is selected from the group consisting of H, C
1-10
alkyl, C
1-3
arylalkyl C
1-3
heteroarylalkyl aryl, heteroaryl, C
1-3
alkyl-C
3-6
cycloalkyl, and C
3-6
cycloalkyl;
R
2
is selected from the group consisting of H, O(CH
2
)
m
aryl, O(CH
2
)
m
heteroaryl, N(R
5
)(CH
2
)
m
heteroaryl, N(R
5
)(CH
2
)
m
heteroaryl, N(R
6
)COaryl, N(R
6
)COheteroaryl, N(R
6
)SO
2
aryl and N(R
6
)SO
2
heteroaryl wherein the aryl and hetroaryl moieties of R
2
and R
3
may be optionally substituted by one or more of CH
3
, CF
3
, OCF
3
, OH, OCH
3
, NH
2
, NHCH
3
, N(CH
3
)
2
, SCH
3
, SOCH
3
, SO
2
CH
3
, halogen, CO
2
H, CO
2
CH
3
) CONH
2
, CON(CH
3
)
2
, NHCOH, NHCOCH
3
, NHSO
2
CH
3
, methylenedioxy; provided that R
2
is H when R
3
is selected from the group consisting of O(CH
2
)
m
aryl, O(CH
2
)
m
heteroaryl, N(R
5
)(CH
2
)
m
aryl, N(R
5
)(CH
2
)
m
heteroaryl, N(R
6
)COaryl, N(R
6
)COheteroaryl, N(R
6
)SO
2
aryl and N(R
6
)SO
2
heteroaryl;
R
3
is selected from the group consisting of H, halogen, OCH
3
, CH
3
, O(CH
2
)
m
aryl, O(CH
2
)
m
heteroaryl, N(R
5
)(CH
2
)m aryl, N(R
5
)(CH
2
)
m
heteroaryl, N(R
6
)COaryl, N(R
6
)COheteroaryl, N(R
6
)SO
2
aryl and N(R
6
)SO
2
heteroaryl; provided that R
3
is selected from the group consisting of O(CH
2
)
m
aryl, O(CH
2
)
m
heteroaryl, N(R
5
)(CH
2
)
m
aryl, N(R
5
)(CH
2
)
m
heteroaryl, N(R
6
)COaryl, N(R
6
)COheteroaryl, N(R
6
)SO
2
aryl and N(R
6
)SO
2
heteroaryl when R
2
and R
4
are H;
R
4
is selected from the group consisting of H, halogen, OCH
3
, and CH
3
;
R
5
is selected from the group consisting of H, C
1-10
alkyl, C
1-3
alkyl-aryl, C
1-3
alkyl-heteroaryl CO(C
1-8
)alkyl, and COaryl and COheteroaryl;
R
6
is selected from the group consisting of H, C
1-10
alkyl,C
1-3
alkyl-aryl and C
1-3
alkyl-heteroaryl; and
m is an integer from 0-3;
or a pharmaceutically acceptable salt thereof.
Also included in the invention are pharmaceutically acceptable salt complexes.
As used herein, “C
1-10
alkyl” or “alkyl” means both straight and branched chain of 1 to 10 carbon atoms, unless the chain length is otherwise limited, including, but not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl and the like. The alkyl may carry substituents such as hydroxy, carboxy, alkoxy, and the like.
The term “cycloalkyl” is used herein to mean cyclic rings, preferably of 3 to 8 carbons, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl, and the like.
The term “arylalkyl” or “heteroarylalkyl” or “heterocyclicalkyl” is used herein to mean C
1-10
alkyl, as defined above, attached to an aryl, heteroaryl or heterocyclic moiety, as also defined herein, unless otherwise indicated.
As used herein,“aryl” means phenyl and naphthyl and substituted aryl such as hydroxy, carboxy, halo, alkoxy, methylenedioxy, etc.
As used herein, “heteroaryl” means a 5-10 membered aromatic ring system in which one or more rings contain one or more heteroatoms selected from the group consisting of N, O or S, such as, but not limited, to pyrrole, pyrazole, furan, thiophene, quinoline, isoquinoline, quinazolinyl, pyridine, pyrimidine, oxazole, thiazole, thiadiazole, triazole, imidazole, benzotriazole, or benzimidazole. As used herein, preferred aryl substituents include halo, including chloro, fluoro, bromo and iodo, in any combination; C
1-10
alkyl, C
1-10
alkoxy, aryloxy, or heteroaryloxy.
The compounds of this invention may contain one or more asymmetric carbon atoms and may exist in racemic and optically active forms. All of these compounds and diastereomers are contemplated to be within the scope of the present invention.
Some of the compounds of this invention may be crystallised or recrystallised from solvents such

Affiliated with

Also associated with

Rating

Fatty acid synthase inhibitors does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Fatty acid synthase inhibitors, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Fatty acid synthase inhibitors will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2986379