Bioorganic & Medicinal Chemistry Letters 10 (2000) 1831±1834
Synthesis and Evaluation of Quinoline Carboxyguanidines as
Antidiabetic Agents
Dolores Edmont, Richard Rocher, Christophe Plisson and Jacques Chenault*
Â
Institut de Chimie Organique et Analytique, Universite d'Orleans, BP 6759, 45067 Orleans Cedex 2, France
Â
Â
Received 29 March 2000; revised 19 June 2000; accepted 20 June 2000
AbstractÐThe synthesis and in vivo activities of a series of substituted quinoline carboxyguanidines as a possible novel class of
antidiabetic agents is described. # 2000 Elsevier Science Ltd. All rights reserved.
Introduction
Chemistry
The number of people suering from diabetes around the
world increases day by day. Predictions estimate from
110 million in 1994, numbers will reach 300 million in
2025.1 About 90% of cases are diabetes of type II
(NIDDM), and recent therapies to treat this type of
diabetes require the use of oral hypoglycaemic drugs.
Amongst the dierent hypoglycaemic drugs in force at
present, guanidine derivatives2 are often prescribed, the
most well known being metformin.
The 10 synthons with a 4-oxo-1,4-dihydroquinolinic
structure 3a±d and 4d±e, or a quinolinic structure 5a±c and
6, suitable for all further syntheses, have been obtained
from commercially available substituted arylamines in
three steps as shown in Scheme 1.
The ®rst step involves an enamine bond formation,
which was achieved in high yield by condensation of di-
methyl acetylenedicarboxylate (DMAD) or ethyl ethoxy-
methylenemalonate (DEEM) with arylamine 1a±e. The
intermediates fumarate 2a±c or malonate 2d±e were then
cyclized using diphenylether at re¯ux.6
Quinolones, more known for their antibacterial activity,
sometimes display hypoglycaemic activity. Indeed,
according to Baker and Bramhall3 in 1972, these molecules
act on the glucidic metabolism.
Finally, compounds 4d±e or 5a±c were obtained by
alkylation with potassium carbonate and ethyl bromide,
and compound 6 by chlorination with phosphorus oxy-
chloride.
Recent work4 showed clearly the ecacy of some
quinolones in inhibiting the activity of the ATP-K+
channel of the b cell pancreatic membrane, inducing the
production of insulin. These quinolones act according
to a mechanism similar to sulfonylureas. Moreover,
some molecules of this family, the 7-substituted 4-oxo-
1,4-dihydroquinoline-3-carboxylic acids, inhibit the
aldo reductase enzyme5 in vivo.
The carbonylguanidine moiety was introduced by an
addition±elimination reaction between guanidine and the
ester function7 of synthons 3a, 4d±e, 5a±c and 6 (Scheme
2). All N-[(4-oxo-1,4-dihydroquinolin)carbonyl]guanidine
compounds 7, 8d±e and 9a, or N-[(quinolin)carbo-
nyl]guanidine compounds 10a±c and 11a were isolated
as the hydrochloride salt.
We therefore decided to synthesize some quinolinoyl-
guanidines in which some structural modi®cations have
been performed. We also report on the in vivo activities
of these compounds as hypoglycaemic agents.
In order to assess the importance of each atom in the car-
bonylguanidine moiety, analogues were also synthesized,
including carbonylaminoguanidine, carbonylaminobigua-
nidine, carbonylaminourea and carbonylaminotetrazole.
We envisaged the formation of both the carbonylamino-
guanidine and carbonylaminobiguanidine moiety via a
nucleophilic substitution reaction between the amino
*Corresponding author. Tel.: +33-2-3849-4588; fax: +2-3841-7281;
e-mail: j.chenault@univ-orleans.fr
0960-894X/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(00)00354-1