CHEMMEDCHEM
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the target compounds 26a–l;
additional reduction with Pd/C
and hydrogen in methanol gave
target compounds 27a–c.
All target compounds pre-
pared herein were evaluated for
GK activity at 10 mm, with a glu-
cose concentration of 4 mm. The
glucose concentration simulates
moderate blood glucose condi-
tions. The GK activity of com-
pounds is expressed as GK fold
activation; compound GKA22,
a GK activator developed by As-
traZeneca, was used as positive
Scheme 3. Reagents and conditions: a) thiazolidinedione, piperidine, AcOH, toluene, reflux, 4 h; b) ethyl chloroace-
tate, acetone, K2CO3, reflux, 8 h; c) LiOH, THF, reflux, 8 h; d) EDCI, DIPEA, DMF, 8 h.
and 2,4-thiazolidinedione in toluene afforded intermediate 10,
which was then treated with ethyl 2-bromoacetic acid to pro-
vide compound 11, followed by hydrolysis to produce com-
pound 12. Treatment with isopropyl 6-aminonicotinate or
ethyl 6-aminonicotinate in the presence of EDCI and DIPEA af-
forded the desired target compounds 13a,b as depicted in
Scheme 3. (E)-2-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)phe-
noxy)acetamide derivatives 18a,b were prepared from 4-hy-
droxybenzaldehyde 14, as depicted in Scheme 4.
Synthesis of (E)-2-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)-
2-nitrophenoxy)acetamide derivatives 23a,b was carried out as
shown in Scheme 5. The condensation of 4-chloro-3-nitrobenz-
aldehyde (19) and 2,4-thiazolidinedione in toluene afforded
the intermediate 20, which was
control in the activity assays. Potent compounds in GK activa-
tion were selected for further testing in a PPARg transcription
cell-based assay. The effect of tested compounds on the activi-
ty of PPARg transcription was evaluated by luciferase reporter
gene assay, and results are reported relative to the activity of
rosiglitazone.
To evaluate the effect of the relative positions of the GK and
PPARg pharmacophores on the benzene core in GK activation,
a series of meta- and para-oriented compounds (4a,b and 8a–
e) were first assayed (Table 1). Compared with meta-oriented
compounds 4a,b, the corresponding para-oriented com-
pounds 8a–b displayed improved potency for both GK and
PPARg, and 2-aminopyridine derivatives 8a, 8b, and 8d exhib-
then treated with ethyl 2-bromo-
acetic acid to provide compound
21. Compound 21 was hydro-
lyzed by lithium hydroxide to
afford intermediate 22. Then an
intermolecular condensation be-
tween compound 22 and isopro-
pyl 6-aminonicotinate or ethyl
6-aminonicotinate yielded target
compounds 23a,b.
The preparation of (E)-2-(2-
nitro-4-((2,4-dioxothiazolidin-5-
ylidene)methyl)pheny)acetamide
derivatives 27a–l and (E)-2-(2-
amino-4-((2,4-dioxothiazolidin-5-
ylidene)methyl)phenyl)acetamide
derivatives 28a–c was carried
out as depicted in Scheme 6.
The treatment of (E)-5-(4-chloro-
3-nitrobenzylidene)thiazolidine-
2,4-dione (20) with diethyl malo-
nate and sodium hydride in
DMSO afforded intermediate 24,
followed by acidic hydrolysis
and decarboxylation to produce
intermediate 25. This was then
reacted with various 2-amino-
Scheme 4. Reagents and conditions: a) thiazolidinedione, piperidine, AcOH, toluene, reflux, 4 h; b) ethyl chloroace-
tate, acetone, K2CO3, reflux, 8 h; c) LiOH, THF, reflux, 8 h; d) EDCI, DIEPA, DMF, 8 h.
Scheme 5. Reagents and conditions: a) thiazolidinedione, piperidine, AcOH, toluene, reflux, 4 h; b) ethyl hydroxy-
nitrogen heteroaromatics to give acetate, acetone, K2CO3, reflux, 8 h; c) LiOH, THF, reflux, 8 h; d) EDCI, DIEPA, DMF, 8 h.
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