The synthesis and characterization of a novel insulin sensitizing agent

Article abstract of DOI:10.1055/s-2004-825622

A novel and succinct route to 2-hydroxy-4,6-diarylbenzophenones has been developed through condensation of aryl 1,3-diketones with chalcones. The resultant compounds stimulate insulin-dependent glucose uptake into adipocytes, and improve insulin sensitivity in a rodent model of diabetes.

Full text of DOI:10.1055/s-2004-825622

1446
LETTER
The Synthesis and Characterization of a Novel Insulin Sensitizing Agent
The Synthesis
a
h
nd
C
haracte
r
o
ization of
a
N
m
ovel Insulin Sensi
a
tizing Agen
s
t
W. von Geldern,* Regina P. Brun, Masha Kalmanovich, Denise Wilcox, Peer B. Jacobson
Metabolic Disease Research, Abbott Laboratories, Abbott Park, IL 60064-6098, USA
Fax +1(847)9381674.; E-mail: Thomas.vongeldern@abbott.com
Received 2 March 2004
This manuscript is dedicated to Professor and Dean Clayton H. Heathcock on the occasion of his retirement.
Abstract: A novel and succinct route to 2-hydroxy-4,6-diarylben-
EtOOC
COOEt
zophenones has been developed through condensation of aryl 1,3-
diketones with chalcones. The resultant compounds stimulate insu-
lin-dependent glucose uptake into adipocytes, and improve insulin
sensitivity in a rodent model of diabetes.
OH
(ref 1)
R = COOEt
R = Ar
R
O
-or-
Ar
COOH
O
+
(ref 2)
Key words: cyclizations, diabetes, 2-hydroxybenzophenones,
3
2
Michael additions, phenols
O
OH
R = H, CN
R
X
O
As part of a program to develop novel therapies for the
treatment of Type 2 diabetes, we have discovered that 2-
hydroxy-4,6-diarylbenzophenones like 1 (Figure 1) can
stimulate the uptake of glucose into adipocyte cell lines.
This increase in glucose uptake is intimately dependent on
the presence of insulin, suggesting that compounds like 1
might be useful agents to treat the insulin resistance that is
a hallmark of this disease.
(ref 3)
COOEt
4
2
Scheme 1
Our own retrosynthesis (Scheme 2) involves a unique dis-
section of the central aromatic ring of 2. Like Ivanova and
Tcholakova, we use chalcones as part of the framework
for this ring; however, in the present example they provide
the C4-C6 fragment, rather than supplying C1 and C6 as
in the previous work. The remainder of the ring is built up
from the a-g carbons of a 1,3-dicarbonyl compound,
through sequential Michael and aldol additions. The start-
ing chalcones and b-dicarbonyl compounds are commer-
cially available, or readily prepared through a variety of
routes. The geometry of the condensation is defined by the
mechanism, and permits the flexible assembly of a variety
of substituted analogs.
R1
OH
OH
1
6
3 R
COOH
O
O
R3
R2
4
1
2
Figure 1
Our interest in 1 led us to examine the state of the art for
synthesizing molecules with the general structure 2. Sev-
eral groups have described synthetic approaches to the 2-
hydroxy-4,6-diarylbenzophenone substructure. Dimroth
and Neubauer1 employ the malonate anion as a nucleo-
phile to unravel the triphenylpyrylium cation (Scheme 1);
O
O
O
OH
R
+
R
O
the resultant intermediate recyclizes to give
2
2
(R = COOEt). Oganesyan and coworkers2 substitute aryl-
acetic acids as nucleophile in this sequence, generating a
mixture of products, which includes 2 (R = aryl). In the
method of Ivanova and Tcholakova,3 3-phenyl-2-
butenoates are condensed with chalcones under basic con-
ditions. The resultant cyclohexenones are aromatized to
provide 2 (X = H, CN). While each of these routes is con-
cise, none provided the flexibility we required for study-
ing structure-activity relationships within the series.
Scheme 2
The synthesis of 1 (Scheme 3) exemplifies this approach.
Key intermediate 6 is prepared using the method of Mur-
ray and Wachter.4 The lithium enolate of acetophenone,
formed by treatment with LDA at low temperature, is
quenched with glutaric anhydride. An excess of enolate is
required in order to further deprotonate the b-diketone
formed through this reaction. Under appropriate condi-
tions the desired product 6 is isolated directly from the
workup, as the only acidic product, in 66% yield based on
the limiting reagent.
SYNLETT 2004, No. 8, pp 1446–1448
0
1.
0
7.
2
0
0
4
Advanced online publication: 08.06.2004
DOI: 10.1055/s-2004-825622; Art ID: Y01504ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
The Synthesis and Characterization of a Novel Insulin Sensitizing Agent
1447
pound is minimal in the absence of added insulin, suggest-
ing that agents of this type may have reduced potential to
cause hypoglycemia in vivo.
O
O
O
O
COOH
a,b
c
COOH
O
66%
5
6
7
d,e
main component
of mixture
O
OH
COOH
COOH
O
8
1, 34%
Scheme 3 Reagents and conditions: a) LDA, THF, –78 °C; b) suc-
cinic anhydride (0.5 equiv), –78 °C to r.t.; c) chalcone (1.1 equiv),
piperidine (5 equiv), EtOH, reflux, 2 h; d) Br2 (1 equiv), CH2Cl2, 1 h;
e) DBU, CH2Cl2, 0 °C to r.t.
Condensation of 6 with chalcone is catalyzed by an amine
base; in our brief survey piperidine appears to be optimal,
and ethanol the solvent of choice.5 The reaction provides
a rather complicated mixture of products in which the de-
sired enone 7 predominates after several hours at reflux.
Continued heating leads to the deacylation of 7, giving 8
as a major side product. Compound 7 exists as a single di-
astereomer with the substituents trans- on the newly
formed six-membered ring.
Figure 3
In the ob/ob mouse model of diabetes, A-140017 reduces
blood glucose levels after 5 days of dosing, twice a day
orally, at 30 mg drug/kg animal weight (Figure 3). The ob-
served decrease of >100 mg/dL in plasma glucose levels
is nearly half of the difference between ob/ob and normal
levels. Consistent with our proposed mechanism of ac-
tion, the drug-treated animals have lower insulin levels
than their untreated counterparts.
In practice, this mixture of cyclization products is carried
forward without additional purification. Bromination of 7
followed by base-catalyzed dehydrobromination accom-
plishes the requisite oxidation of cyclohexenone to phe-
nol, and provides the desired 1 in 34% yield as an off-
white solid after precipitation from EtOAc–Et2O.6
In conclusion, we have identified and implemented a nov-
el retrosynthesis of the 2-hydroxy-4,6-diarylbenzophe-
none skeleton. This two-pot sequence, which assembles
the central ring in a single step via the condensation of a
1,3 diketone with an a,b-unsaturated ketone, is amenable
to the preparation of a variety of substituted analogs,
which appear to represent a new class of insulin sensitiz-
ers.
Acknowledgment
The Abbott Analytical Department is thanked for their studies to
identify the structures of key intermediates in the synthesis of 1.
References
(1) Dimroth, K.; Neubauer, G. Chem. Ber. 1959, 92, 2046.
(2) Oganesyan, E. T.; Pyshchev, A. V.; Butenko, L. I. Pharm.
Chem. J. 1999, 33 (9), 480.
(3) Ivanov, Kh.; Tcholakova, Ts. Synthesis 1981, 392.
(4) Murray, W. V.; Wachter, M. P. J. Org. Chem. 1990, 55,
3424.
Figure 2
(5) Experimental Procedure for the Conversion of 6 to 1:
Diketoacid 6 (7.8 g, 33 mmol) is combined with trans-
chalcone (6.25 g, 30 mmol) in 125 mL of EtOH. Piperidine
(20 mL) is added, and the resultant solution is heated at 100
°C for 16 h. The volatiles are removed in vacuo; the residue
is taken up in 600 mL of 0.1 N aq NaOH and extracted once
with 100 mL of Et2O. The aqueous phase is acidified to pH
3 with 1 N H3PO4 and extracted with two 150 mL portions
of EtOAc. These organic extracts are washed with brine,
The insulin sensitizing effects of A-140017 can be dem-
onstrated in in vitro and in vivo models relevant to the
treatment of diabetes. Figure 2 shows the effect of the
drug on the uptake of 3H-2-deoxyglucose (2-DOG, a non-
metabolizable analog of glucose) by 3T3-L1 adipocytes.
A-140017 stimulates 2-DOG uptake in an insulin-depen-
dent manner; at a maximal insulin concentration of 10
nM, a 35% increase is observed. The effect of the com-
Synlett 2004, No. 8, 1446–1448 © Thieme Stuttgart · New York

1448
T. W. von Geldern et al.
LETTER
dried over Na2SO4, filtered through Celite and concentrated
to give 7 as a semisolid. Crude 7 is dissolved in 250 mL of
CHCl3; a solution of 1.6 mL of bromine (1 equiv) in 10 mL
of CHCl3 is added dropwise over 5 min, and the resultant
solution is allowed to stir at ambient temperature for 1 h. The
volatiles are removed in vacuo; residual bromine is chased
with CHCl3. The residue is dissolved in 250 mL of CHCl3
and cooled to –20 °C; 8 mL of DBU is added dropwise, and
the resultant solution is warmed to ambient temperature and
stirred for 15 h. The volatiles are removed in vacuo; the
residue is taken up in 600 mL of 0.1 N aq NaOH and stirred
for 3 h with 100 mL of Et2O. The ether extract is removed;
the aqueous phase is acidified to pH 3 with 1 N H3PO4 and
extracted with two 150 mL portions of EtOAc. These
organic extracts are washed with brine, dried over Na2SO4,
and filtered through Celite. Reduction in volume to ca. 75
mL provides a solid, which is collected by filtration to give
3.4 g (27% yield) of 1. Further concentration of the mother
liquors provides a second crop of solid 1 (0.9g, 7%).
(6) Analytical data for compound 1: 1H NMR (DMSO, 400
MHz): d = 7.67 (d, 2 H, J = 7.4 Hz), 7.54 (t, 1 H, J = 7.4 Hz),
7.40–7.50 (m, 10 H), 7.15–7.20 (m, 4 H), 6.77 (s, 1 H), 2.83
(m, 2 H), 2.38 (m, 2 H). 13C NMR (DMSO, 100 MHz):
d = 197.0, 174.0, 152.6, 143.9, 140.7, 139.5, 138.1, 137.7,
133.1, 128.9, 128.8, 128.5, 128.2, 128.1, 127.4, 127.3,
127.1, 126.9, 126.0, 123.0, 33.5, 22.1. MS (ESI+): m/z =
405, 423, 445. MS (ESI–): m/z = 421.
Synlett 2004, No. 8, 1446–1448 © Thieme Stuttgart · New York