Novel oximes having 5-benzyl-2,4-thiazolidinedione as antihyperglycemic agents: Synthesis and structure-activity relationship

Article abstract of DOI:10.1016/S0960-894X(00)00003-2

Oximes having 5-benzyl-2,4-thiazolidinedione were prepared, and their PPAR γ agonistic activities and blood glucose lowering activities were evaluated. Biaromatic and methyl groups, attached to the oxime moiety, and the ethylene bridge between oxime and p

Full text of DOI:10.1016/S0960-894X(00)00003-2

Bioorganic & Medicinal Chemistry Letters 10 (2000) 373±375
Novel Oximes Having 5-Benzyl-2,4-thiazolidinedione as
Antihyperglycemic Agents: Synthesis and Structure±Activity
Relationship
Hiroaki Yanagisawa, a,* Makoto Takamura, a Eriko Yamada, a Sachie Fujita, a
Toshihiko Fujiwara, b Makoto Yachi, b Aya Isobe b and Yuka Hagisawa b
aMedicinal Chemistry Research Laboratories, Sankyo Co., Ltd., Hiromachi, Shinagawa-ku, Tokyo 140, Japan
bPharmacology and Molecular Biology Research Laboratories, Sankyo Co., Ltd., Hiromachi, Shinagawa-ku, Tokyo 140, Japan
Received 1 November 1999; accepted 16 December 1999
AbstractÐOximes having 5-benzyl-2,4-thiazolidinedione were prepared, and their PPAR g agonistic activities and blood glucose
lowering activities were evaluated. Biaromatic and methyl groups, attached to the oxime moiety, and the ethylene bridge between
oxime and phenoxy groups are favorable to biological activities. # 2000 Elsevier Science Ltd. All rights reserved.
Introduction
derivatives of TZD, which have a wide variety of sub-
stituents at the p-position of 5-benzyl-TZD.13 The X-ray
Type II diabetes (non-insulin dependent diabetes melli-
tus; NIDDM) is one of the major causes of several
chronic diseases, such as retinopathy, nephropathy,
neuropathy and cardiovascular diseases.1 Long-term
hyperglycemia, caused by insucient insulin secretion
from pancreas and/or insulin resistance in muscle, liver
and adipose tissues, brings about an aggravation of
diabetes. Therefore, it is important to regulate the blood
glucose level in order to control diabetes.2±4 Treatment
of diabetes has been carried out with a combination of
diet, exercise and hypoglycemic agents, such as sulfo-
nylureas, which stimulate pancreatic b-cells and increa-
ses secretion of insulin to lower the blood glucose
level.5,6 However, sulfonylureas often cause severe
hypoglycemia and weight gain, and become poorly
e€ective as a long-term treatment.7
structure analysis of apo-PPAR g ligand-binding
domain (LBD) and the ternary complex consisting of
PPAR g-LBD, rosiglitazone and SRC-1, have been
reported and the pyridine ring of rosiglitazone occupies
the relatively non-speci®c hydrophobic pocket.14
Here we will describe the synthesis of 5-benzyl-Tz 4
having iminoxyalkoxy groups at the p-position, their
biological activity and spatial requirements for the
activity.
Synthesis
The synthetic procedure of the iminoxyethoxy deriva-
tives 4a±o is shown in Scheme 1. Reaction of N-(2-
hydroxyethoxy)phthalimide 5 with 5-(4-hydroxybenzyl)-
3-tritylthiazolidine-2,4-dione 6 using the Mitsunobu
reagent followed by the removal of the trityl group
gave 7. Treatment of 7 with hydrazine a€orded 8, which
was then condensed with carbonyl compounds to a€ord
4a±o.
Recently new types of agents, troglitazone (1),8 piogli-
tazone (2)9 and rosiglitazone (3),10 which have a thia-
zolidine-2,4-dione (TZD) moiety, are available at the
clinical stage. These drugs are believed to be ligands for
the peroxisome proliferator-activated receptor g (PPAR
g) and improve insulin resistance in the insulin target
organs.11,12 There have been many reports concerning
The iminopropoxy compound 4p was prepared as
shown in Scheme 2. O-Alkylation of the oxime 9 with 10
followed by removal of the THP group gave the propa-
nol 11, which was converted to 4p by the same proce-
dure as the preparation of 7 from 5.
*Corresponding author. Tel.: +81-3-3492-3131; fax: +81-3-5436-
8563; e-mail: hyanag@shina.sankyo.co.jp
0960-894X/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(00)00003-2

374
H. Yanagisawa et al. / Bioorg. Med. Chem. Lett. 10 (2000) 373±375
All compounds were obtained as a single isomer. The
geometrical structure of 4f was determined to be (E)-
isomer by the X-ray analysis. Other oxime compounds
are considered to be (E)-isomers which are thermo-
dynamically more stable than the corresponding (Z)-
isomer.
The blood glucose lowering activity of 4a was weaker
than 3 but more potent than 2. 2-Pyridine 4b had more
potent activity than 3- and 4-pyridines 4c, 4d. In the 4-
biphenylyl series (4e±h), the compounds where R2 are
methyl (4f) and ethyl (4g) had the excellent blood glu-
cose lowering activity, whereas 4h (R2=Pr) showed the
weak activity and 4e (R2=H) was inactive. 3-Biphenyl
4i was less active than 4-biphenyl 4f but still had an
ecacy equivalent to 2. 2-Biphenyl 4j was the least
active among the biphenylyl series (4f, 4i, 4j) having
R2=Me. Phenylpyridines 4k, 4l had an ecacy com-
parable to 4a. 4-(2-pyridyl)phenyl derivative 4m had the
most potent lowering activity in the pyridylphenyl deri-
vatives (4m±o). Trimethylene analogue 4p of 4f showed
the weak blood glucose lowering activity.
Biological Results and Discussion
The oxime compounds prepared above were evaluated
for their PPAR g agonistic activity and for their blood
glucose lowering activity in hyperglycemic kk mice. The
results are summarized in Table 1 compared with the
hydrochloride salt of 2 and the maleate salt of 3.
Phenyl and pyridyl compounds 4a±d activated PPAR g
with EC50 values in the range of 1.7 to 7.9 mM, of which
4d was the weakest. Addition of the phenyl or pyridyl
group to 4a,4b and 4c improved the activity (4a!4f, 4i,
4m±o; 4b!4k; 4c!4l) except for 4j, which could not
activate PPAR g. Biphenyls 4f, 4i and 6-phenyl-3-pyri-
dine 4l were more active than 3, and 4-(2- and 3-pyr-
idyl)phenyl derivatives 4m, 4n were as active as 3. 4-(4-
pyridyl)phenyl derivative 4o was less potent than the
other pyridylphenyl derivatives 4m, 4n. Shortening (4e)
or lengthening (4g, 4h) of R2 in 4f diminished the PPAR
g agonistic activity, of which 4e and 4h were inactive at
100 mM. Also, elongation (4p) of the carbon chain
between the oxime oxygen atom and phenolic oxygen
atom of 4f lost the PPAR g agonistic activity.
A good correlation of PPAR g agonistic activity with
antihyperglycemic activity had been observed in the
thiazolidinedione series.15 Potent PPAR g agonists 4f,
4l, 4m e€ectively lowered blood glucose and the weak
agonists 4e, 4h, 4j, 4p did not show signi®cant blood
glucose lowering activity. However, 4i and 4n had
moderate blood glucose lowering activity in spite of
their potent PPAR g agonistic ability and, on the other
hand, 4b and 4g showed potent blood glucose lowering
activity despite moderate PPAR g agonistic activity.
The moderate deviations observed in these compounds
may be caused by their metabolism and/or bioavailability.
In conclusion, the favorable features of the oxime series
for promoting the PPAR g activity are as follows:
Scheme 1.
Scheme 2.

H. Yanagisawa et al. / Bioorg. Med. Chem. Lett. 10 (2000) 373±375
Table 1. PPAR g agonistic activity and antihyperglycemic activity of oxime derivatives
375
Compound
R1
R2
mp
PPAR ga EC50 (mM)
ÁBGb (%)
4a
4b
4c
4d
4e
4f
4g
4h
4i
Ph
2±Pyridyl
3±Pyridyl
4±Pyridyl
4±Ph±Ph
4±Ph±Ph
4±Ph±Ph
4±Ph±Ph
Me
Me
Me
Me
H
Me
Et
Pr
Me
Me
Me
Me
Me
Me
Me
134±136
119±121
180±182
171±172
125±127
164±166
157±159
82±83
Na salt
Na salt
136±138
186±187
177±179
182
1.7
2.8
2.8
7.9
57
67
43
48
7
>100
0.40
1.6
>100
0.33
>100
1.1
67
67
29
42
23
61
58
58
42
44
20
42
66
3±Ph±Ph
2±Ph±Ph
4j
4k
4l
5±Ph±2±pyridyl
6±Ph±3±pyridyl
4±(2±Pyridyl)±Ph
4±(3±Pyridyl)±Ph
4±(4±Pyridyl)±Ph
0.19
0.64
0.80
1.6
4m
4n
4o
4p
2c
234±235
86±87
>100
7.6
3d
0.73
aActivity was determined using transient transfection assays. See ref 16.
bThe test compounds were mixed with powdered feed F-2 (Funabashi Farms) in a ratio of 0.01% (about 10 mg/kg/day). The mixture was admi-
nistered orally to hyperglycemic male kk mice (4±6 months of age) for 3 days. Values (mean‹SE) are the % change in plasma glucose concentration
of the drug-treated mice relative to vehicle controls. All values are the mean of n=4 or 5.
cThe hydrochloride salt of 2 was used.
dThe maleate salt of 3 was used.
1. introduction of an aromatic group to the m- or p-
position of acetophenone oxime or acetylpyridine
oxime
2. methyl group as R2
3. ethylene bridge (n=2) between the oxygen atoms
of the oxime moiety and phenoxy group.
11. Lehmann, J. M.; Moore, L. B.; Smith-Oliver, T. A.; Wil-
kison, W. O.; Willson, T. M.; Kliewer, S. A. J. Biol. Chem.
1995, 270, 12953.
12. Berger, J.; Bailey, P.; Biswas, C.; Cullinan, C. A.; Doebber,
T. W.; Hayes, N. S.; Saperstein, R.; Smith, R. G.; Leibowitz,
M. D. Endocrinology 1996, 137, 4189.
13. Hulin, B.; McCarthy, P. A.; Gibbs, E. M. Curr. Pharm.
Des. 1996, 2, 85.
The potential candidates are 4f and 4l which have
more potent PPAR g agonistic activity than rosiglitazone
and show strong blood glucose lowering activity.
14. Nolte, R. T.; Wisely, G. B.; Westin, S.; Cobb, J. E.; Lam-
bert, M. H.; Kurokawa, R.; Rosenfeld, M. G.; Willson, T. M.;
Glass, C. K.; Milburn, M. V. Nature 1998, 395, 137.
15. Willson, T. M.; Cobb, J. E.; Cowan, D. J.; Wiethe, R. W.;
Correa, I. D.; Prakash, S. R.; Beck, K. D.; Moore, L. B.;
Kliewer, S. A.; Lermann, J. M. J. Med. Chem. 1996, 39, 665.
16. A cDNA encoding the ligand binding domain (amino
acids 175-475) of human PPARg was obtained with reverse
transcript-polymerase chain reaction. A GAL4-PPARg chi-
meric expression construct, pM-PPARg, was generated by
insertion of the cDNA into the GAL4 expression plasmid pM
(Clontech Laboratories, Inc.) at the BamHI-HindIII site.
HepG2 cells were transfected with pM-PPARg and a GAL4-
responsive reporter plasmid pFR-Luc (Stratagene Cloning
Systems) using FuGENETM6 Transfection Reagent (Boehrin-
ger Mannheim GmbH) according to the manufacturer's
instructions. After 2 h, the cells were seeded in 96-well plates
followed by an additional 24 h of cultivation. Then, the med-
ium was exchanged to DME medium supplemented with 10%
delipided fetal calf serum and the test compound in the
appropriate concentration. After 48 h, luciferare activity in
the cells was measured using LucLiteTM Luciferase Reporter
Gene Assay Kit (Packard BioScience B.V.). EC50 equals
the concentration of compound required to induce 50% of
the maximum luciferase activity. All values are the mean of
n=4.
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