Indole compounds

Details Indole compounds Indole compounds

2002-04-02

2002-11-26

Rotman, Alan L. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peroxide doai

C548S491000

Reexamination Certificate

active

06486211

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to indole derivatives, pharmaceutical compositions containing these compounds and their use as inhibitors of the fatty acid synthase FabH and antibacterial agents.
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 at., 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 indole derivatives and pharmaceutical compositions containing these compounds, and their use as FabH inhibitors which 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 is —N(R
1
)—C(R
2
)H—CO
2
H or
Q is O or CH
2
;
R
1
is hydrogen or C
1-5
alkyl;
R
2
is hydrogen, C
1-5
alkyl, (CH
2
)
n
R
3
, CH(OH)CH
3
;
R
3
is OH, CO
2
R
1
, CONH
2
, NH
2
, CH(OH)(CH
2
)
n
NH
3
, NH—C(NH)NH
2
,—SH, —SCH
3
or phenyl which may be substituted or unsubstituted by OH:
R
4
is hydrogen or OH;
n is an integer from 1to 5;
or a pharmaceutically acceptable salt thereof.
Also included in the invention are pharmaceutically acceptable salt complexes.
When used herein the terms ‘alkyl’ includes straight and branched chain groups containing from 1 to 5 carbon atoms, such as methyl, ethyl, propyl and t-butyl.
The compounds of this invention may contain one or more asymmetric carbon atoms and may exist in racemic and optically active forms. The compounds may be in the D or L form. 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 as organic solvents. In such cases solvates may be formned. This invention includes within its scope stoichiometric solvates including hydrates as well as compounds containing variable amounts of water that may be produced by processes such as lyophilisation. All polymorhphs are also included.
Since the antibiotic compounds of the invention are intended for use in pharmaceutical compositions it will readily be understood that they are each provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure and preferably at least 85%, especially at least 95% pure, particularly at least 98% pure (% are on a weight for weight basis). Impure preparations of the compounds may be used for preparing the more pure forms used in the pharmaceutical compositions; these less pure preparations of the compounds should contain at least 1%, more suitably at least 5% and preferably from 10 to 49% of a compound of the formula (I) or salt thereof.
Preferred compounds have Q as O and R is alanyl, prolyl, valyl, isoleucyl or leucyl. The L isomers are preferred. Especially preferred is prolyl. n-methyl alanyl, and leucyl.
Preferred compounds are:
N-methyl-1-(6-chloro-3,4-methylenedioxybenzyl)-5-(2,6-dichlorobenzyloxy)indole-2-carboxy-L-alanine amide:
1-(6-chloro-3,4-methylenedioxybenzyl)-5-(2,6-dichlorobenzyloxy)indole-2-carboxy-L-proline amide;
1-(6-chloro-3,4-methylenedioxybenzyl)-5-(2,6-dichlorobenzyloxy)indole-2-carboxy-L-alanine amide;
(6-chloro-3,4-methylenedioxybenzyl)-5-(2,6-dichlorobenzyloxy)indole-2-carboxy-L-leucine amide;
1-(6-chloro-3,4-methylenedioxybenzyl)-5-(2,6-dichlorobenzyloxy)indole-2-carboxy-L-valine amide: and
1-(6-chloro-3,4-methylenedioxybenzyl)-5-(2,6-dichlorobenzyloxy)indole-2-carboxy-L-isoleucine amide.
Compounds of the formula I wherein Q is O are prepared by the method described in Schemes 1 and 2.
a) 6-chloropiperonyl chloride, NaH, DMF; b) 10% Pd/C, H
2
, EtOAc; c) 2,6 dichlorobenzyl bromide, NaH, DMF; d) KOH, EtOH/THF, reflux Indole ester 1-Scheme-1(Aldrich) and a base (such as sodium hydride) are treated with a solvent (such as DMF) and then 6-chloropiperonyl chloride is added and stirred (6 hours to 30 hours, preferably 20 hours) to yield 2-Scheme-1. 2-Scheme-1 is dissolved in a solvent (such as ethyl acetate) and treated with 10% Palladium on charcoal and the resulting mixture shaken (6 hours to 30 hours, preferably 20 hours) to yield 3-Scheme-1. Alkylation of 3-Scheme-1 with 2,6-dichlorobenzyl bromide using a base (such as sodium hydride) in a solvent (such as DMF) provides 4-Scheme-1. Saponification of 4-Scheme-1 with a base (such as potassium hydroxide) in a solvent

Affiliated with

Also associated with

Rating

Indole compounds does not yet have a rating. At this time, there are no reviews or comments for this patent.

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

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2959736