Bioorganic & Medicinal Chemistry Letters 17 (2007) 1403–1407
Quinazoline and benzimidazole MCH-1R antagonists
Rosa Arienzo, Sue Cramp, Hazel J. Dyke,* Peter M. Lockey, Dennis Norman,
Alan G. Roach, Phil Smith, Melanie Wong and Stephen P. Wren
Argenta Discovery Limited, 8/9 Spire Green Centre, Flex Meadow, Harlow, Essex CM19 5TR, UK
Received 21 September 2006; revised 20 November 2006; accepted 30 November 2006
Available online 2 December 2006
Abstract—We have modified the previously reported 2-aminoquinoline 1 to provide two novel series of MCH-1R antagonists. Rep-
resentative compounds from the quinazoline and benzimidazole series have been shown to be potent and selective, with promising
in vitro eADME profiles.
Ó 2006 Elsevier Ltd. All rights reserved.
Melanin-concentrating hormone (MCH) is a cyclic 19-
amino acid peptide that is produced predominantly by
neurons in the lateral hypothalamus and zona incerta,
which project throughout the brain. The effects of
MCH are mediated through two distinct receptors,
MCH-1R and MCH-2R, both of which are members
of the G protein-coupled receptor (GPCR) super-family.
MCH-1R has been identified in mammals and rodents,
whereas functional MCH-2R has not been found in ro-
dents. The evidence for the role of MCH and the MCH-
1R in body weight and feeding regulation is abundant,1
and supports the hypothesis that MCH-1R antagonists
should provide a novel treatment for obesity. The large
number of patents that disclose novel MCH-1R antago-
nists provides an indication of the interest that this tar-
get has generated.2
ity to our compounds is evident. Related 2-aminoquino-
lines have been the subject of a recent publication by
Jiang et al. at Merck,7 with compound 4 selected for
in vivo efficacy studies. In order to obtain compounds
that did not lie within the generic scope of the Merck
patent, we decided to investigate the replacement of
the quinoline by alternative ring systems. The first
quinoline replacement investigated was the quinoxaline.
Subsequently, we investigated quinazolines and benzim-
idazoles in parallel, and the results obtained are dis-
closed herein.
Quinoxalines were prepared using the route depicted in
Scheme 1. Commercially available 2-hydroxyquinoxa-
line was nitrated using potassium nitrate in concentrated
sulfuric acid to give the 6-nitro derivative 5 selectively in
95% yield. Treatment of 5 with phosphorus oxychloride
and phosphorus pentachloride gave the chloro deriva-
tive 6 in 89% yield. Displacement of the chloro substitu-
ent with the appropriate amine followed by reduction of
the nitro group gave the amine 7, which was coupled
with the appropriate carboxylic acids under standard
conditions to provide an initial set of quinoxaline
amides.
We previously reported the discovery3 and optimisa-
tion4 of a series of quinolines as MCH-1R antagonists.
Compound 1 (Fig. 1) was one of the most potent and
selective analogues prepared during this optimisation.
Recently, others have reported the identification and
structure–activity relationships (SAR) of a related series
of quinolines, exemplified by compound 2.5
During the course of our work on the quinoline series, a
patent application disclosing related compounds was
published by Devita et al. at Merck.6 Example 1 in this
application is depicted as compound 3, and the similar-
The synthetic route used to prepare a series of quinazo-
lines is depicted in Scheme 2. Acylation of 2-aminoace-
tophenone with trichloroacetyl chloride followed by
cyclisation mediated by ammonium acetate in dimethyl-
sulfoxide provided dihydroquinazolinone 8 in overall
Keywords: Obesity; Melanin-concentrating hormone; MCH-1.
*
Corresponding author. Tel.: +44 (0) 1279 645631; fax: +44 (0) 1279
The structure depicted in reference 7 does not match the compound
name, and we believe that compound 4 is the correct structure.
0960-894X/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.11.092