Synthesis and biological activity of novel pyrimidinone containing thiazolidinedione derivatives

Article abstract of DOI:10.1016/S0968-0896(02)00107-4

A series of pyrimidinone derivatives of thiazolidinediones were synthesized. Their biological activity were evaluated in insulin resistant, hyperglycemic and obese db/db mice. In vitro PPARγ transactivation assay was performed in HEK 293T cells. PMT13 showed the best biological activity in this series. PMT13 (5-[4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy] phenylmethyl]thiazolidine-2,4-dione) showed better plasma glucose, triglyceride and insulin-lowering activity in db/db mice than rosiglitazone and pioglitazone. PMT13 showed better PPARγ transactivation than the standard compounds. Pharmacokinetic study in Wistar rats showed good systemic exposure of PMT13. Twenty-eight day oral toxicity study in Wistar rats did not show any treatment-related adverse effects.

Full text of DOI:10.1016/S0968-0896(02)00107-4

Bioorganic & Medicinal Chemistry 10 (2002) 2671–2680
Synthesis and Biological Activity of Novel Pyrimidinone
Containing Thiazolidinedione Derivatives§
Gurram R. Madhavan,a,* Ranjan Chakrabarti,b,* Reeba K. Vikramadithyan,b
Rao N. V. S. Mamidi,b V. Balraju,a B.M. Rajesh,a Parimal Misra,b Sunil K. B. Kumar,b
Braj B. Lohray,a Vidya B. Lohraya and Ramanujam Rajagopalanb
aDiscovery Chemistry, Dr. Reddy’s Research Foundation, Bollaram Road, Miyapur, Hyderabad 500 050, India
bDiscovery Biology, Dr. Reddy’s Research Foundation, Bollaram Road, Miyapur, Hyderabad 500 050, India
Received 17 December 2001; accepted 8 March 2002
Abstract—A series of pyrimidinone derivatives of thiazolidinediones were synthesized. Their biological activity were evaluated in
insulin resistant, hyperglycemic and obese db/db mice. In vitro PPARg transactivation assay was performed in HEK 293T cells.
PMT13 showed the best biological activity in this series. PMT13 (5-[4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]
phenylmethyl]thiazolidine-2,4-dione) showed better plasma glucose, triglyceride and insulin-lowering activity in db/db mice than
rosiglitazone and pioglitazone. PMT13 showed better PPARg transactivation than the standard compounds. Pharmacokinetic
study in Wistar rats showed good systemic exposure of PMT13. Twenty-eight day oral toxicity study in Wistar rats did not show
any treatment-related adverse effects. # 2002 Elsevier Science Ltd. All rights reserved.
Introduction
of rosiglitazone with different heterocycles. One of the
promising analogues that resulted from this effort; a
TZD with indole as the heterocycle (DRF-2189) has
already been reported9 by us. In our efforts to improve
the biological profile of these analogues, we have
replaced the indole ring with monocyclic heterocycles
like pyrimidinone having amidine moiety in the ring (as
shown in Fig. 1). Some angiotensin antagonists were
reported with this heterocycle.10 We report here the
structure–activity relationship (SAR) studies of several
TZDs featuring pyrimidinone moiety as shown in
Figure 1.
Type 2 diabetes is characterised by high level of blood
glucose, insulin and impaired insulin action.1 In recent
years, the treatment of type 2 diabetes has been revolutio-
nized with the advent of thiazolidinedione (TZD) class of
molecules that ameliorate insulin resistance and thereby
normalize elevated blood glucose levels.2 These TZDs
are synthetic, high-affinity ligands of peroxisome pro-
liferator activated receptor-gamma (PPARg); a member
of the nuclear receptor family that controls the expres-
sion of genes in the target tissues of insulin action.3,4
Within a short time after the launch of the TZDs, several
reports of treatment-related toxicity have been published.
Troglitazone, the first TZD marketed, was withdrawn due
to severe liver toxicity.5 Rosiglitazone, the second TZD
launched is a potent ligand of PPARg6 and shows effi-
cient insulin sensitization in type 2 diabetes patients.7
However, even rosiglitazone has been associated with
liver, cardiovascular and hematological toxicity.8
Chemistry
A general strategy to synthesize thiazolidinediones V is
shown in Scheme 1. The starting material, pyrimidinone
was prepared according to the literature10,11 as shown in
Scheme 2. The pyrimidinones were treated with 4-(2-
bromoethoxy) benzaldehyde12 in the presence of NaH
and LiBr at 80 ꢀC in DMF for 16 h to give a mixture of
O- and N-alkylated compounds in which the latter was
the major product. Separation of mixtures by column
chromatography yielded both the compounds whose
structures were confirmed by NMR and IR and confirmed
with the structurally-related series of pyrimidinones.13
The IR of N-alkylated isomer showed distinct amide
In order to synthesize novel TZDs with better safety
and efficacy, we modified the N-methyl-2-pyridyl moiety
*Corresponding authors. Tel.: +91-40-304-5439; fax: +91-40-304-
5438; e-mail: madhavangr@drreddys.com (G.R. Madhavan); ranjan-
chakrabarti@drreddys.com (R. Chakrabarti)
§DRF Pub. No. 190.
0968-0896/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0968-0896(02)00107-4

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G. R. Madhavan et al. / Bioorg. Med. Chem. 10 (2002) 2671–2680
Figure 1. Modification of rosiglitazone to pyrimidinone derivatives of thiazolidinediones.
Scheme 1. (a) 4-[2-Bromoethoxy]benzaldehyde, NaH, LiBr, 80 ꢀC, DMF, 16 h; (b) 2,4-thiazolidine dione, piperidine–PhCO2H, toluene, reflux, 2–
4 h; (c) rhodanine, NaOAc, 120 ꢀC, 0.5 h; (d) m-CPBA, DMF, 0 ꢀC–rt, 5 h; (e) 10% Pd/C, 1,4-dioxane, 60 psi H2, RT, 24 h.
Scheme 2. (m) (i) EtOH, KOH, 0 ꢀC–rt, 3 h; (ii) P2O5, 24 h.
carbonyl absorption near 1650cmꢁ1 that did not appear
in O-alkylated isomers.The aldehyde II in the N-alkylated
compound was condensed with 2,4-thiazolidine-dione to
give unsaturated condensed product III in high yields.
This unsaturated compound III was hydrogenated over
Pd/C in dioxane as the solvent to give saturated thiazoli-
dinedione V as a fluffy powder. In the case of cytosine
derived thiazolidinedione IX, the cytosine amine was acy-
lated with acetic anhydride in pyridine and the amine
acylated cytosine VII was alkylated at lactam nitrogen
with 4-(2-bromoethoxy) benzaldehyde, with potassium
carbonate as base in DMF at 80 ꢀC. The aldehyde VIII
was condensed with 2,4-thiazolidinedione (Scheme 3).
to give a condensed product (IVb), which in turn con-
verted to oxazolidinedione IV by oxidation with m-
CPBA. Oxadiazolidinedione compound was prepared
from aldehyde (IIb) by converting it to oxime and then
to the N-hydroxy uredo (Scheme 4)14 and cyclizing it to
the oxadiazolidinedione.
Results and Discussion
All the thiazolidinedione analogues of pyrimidinones
were examined for their plasma glucose (PG) and tri-
glyceride (TG) lowering activities in insulin-resistant
and hyperlipidemic db/db mice after oral treatment for
6 days. Rosiglitazone at 30 mg/kg/day for 6 days
showed 65% PG and 41% TG lowering activity and
used as a standard for comparison. The results after 6
Oxazolidinone IV was prepared by condensation of pyr-
imidinone aldehyde (IIb) in the presence of NaOAc at
120 ꢀC neat with 2-thio-1,3-oxazolidine 4-one (rhodanine)

G. R. Madhavan et al. / Bioorg. Med. Chem. 10 (2002) 2671–2680
2673
Scheme 3. (f) Ac2O, pyridine; (g) K2CO3, DMF, 80 ꢀC, 12 h; (h) 2,4-thiazolidinedione, piperidine–PhCO2H, toluene, reflux, 4 h.
Scheme 4. (i) NH2OH, NaOAc, EtOH, reflux, 3 h; (j) NaCNBH3, 4 N HCl, dioxane; (k) KOCN, H2O, AcOH, 30 ꢀC, 1 h; (l) ClCO2Et, 1 N NaOH,
30 ꢀC, 1 h.
days of treatment (Table 1) revealed that compound
IIIb showed 55% reduction in PG and 63% reduction in
TG. Its saturated version, compound Vb (2-ethyl-4-
methyl pyrimidinone derivative) (PMT13), showed 73%
reduction in PG and 85% reduction in TG. Other deri-
vatives like Va (2,4-dimethyl-pyrimidinone) showed less
PG reduction compared to PMT13 even at a dose of
100 mg/kg/day. The substitution at the 2-position of
pyrimidinone has an effect on the efficacy of the com-
pounds, PG reduction increased from methyl to ethyl
derivatives in db/db mice and decreased towards n-pro-
pyl and n-butyl derivatives (Vc and Vd). Among these,
the ethyl derivative was found to be the best compound
(Vb, PMT13). When the alkyl group at the C-2 position
of pyrimidinone was changed to benzyl group (IIIf)
there was a significant reduction in the activity of the
compound as compared to IIIb. This may be due to the
electron withdrawing nature of the aromatic group.
When the pyrimidinone IIIb was changed to cyclic urea
(IX), it failed to show any activity at 30 mg/kg. The
activity of the oxazolidinedione (IV) derivative of pyr-
imidinones was not better than that of thiazolidinedione
IIIb. To improve the activity, we substituted CH3 at C-4
position of the pyrimidinone ring with CF3 (Ve), but did
not show desirable effect.
activity than other two series. Based on the PG and TG
lowering-activity in db/db mice, PMT13 was selected
for further studies.
PMT13 was compared with rosiglitazone and pioglita-
zone, two marketed thiazolidinedione insulin sensitizers.
A comparative concentration dependent study was
performed in HEK 293T cells to evaluate the PPARg
transactivation potential. PMT13 showed better activa-
tion than pioglitazone. At higher concentration, PMT13
and rosiglitazone showed similar transactivation poten-
tial, but, at lower concentrations PMT13 showed better
activation (Table 2). In the in vivo dose–response study
in db/db mice, PMT13 showed better reduction in
plasma triglyceride, glucose and insulin levels than rosi-
glitazone and pioglitazone (Table 3). These results indi-
cate that PMT13 is more potent and efficacious than the
standard compounds.
Generally, thiazolidinediones have shown hemotoxicity
and hepatotoxicity in both animal and clinical studies.5,8
A 28-day probe toxicity study for PMT13 was per-
formed in Wistar rats. PMT13 at 100 mg/kg dose
showed no mortality, clinical signs of toxicity or changes
in body weight or food consumption. However, mild
changes in hemoglobin (ꢁ7%) and liver weight (+7%)
were observed. The biochemical and histological findings
are not suggestive of any treatment-related adverse effects.
Compound (XIII) was prepared by cyclizing its oxime
intermediate (Scheme 4), but it did not show any inter-
esting activity. Our study showed that among thiazo-
lidinedione, oxazolidinedione and diazolinedione series
of compounds, only thiazolidinediones showed better
To evaluate the pharmacokinetic profile of PMT13, a
single dose (10 mg/kg) oral study was performed in

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G. R. Madhavan et al. / Bioorg. Med. Chem. 10 (2002) 2671–2680
Table 1. SAR studies of pyrimidinones 1–IX
Compd
Heterocycles
(HET)
X
S
Y
C
Double
bond
Dose
(mg/kg/day)
% Redn.
in PG
% Redn.
in TG
IIIb
Yes
Yes
Yes
No
No
No
No
30
100
30
55
27
10
56
73
40
29
63
NE
NE
76
IIIf
S
O
S
S
S
S
C
IV
C
Va
CH
CH
CH
CH
100
30
Vb (PMT13)
85
Vc
Vd
30
48
30
15
Ve
IX
S
S
CH
C
No
30
30
53
43
Yes
NE
NE
XIII
O
S
N
No
No
30
30
14
65
NE
41
Rosiglitazone
CH
Male db/db mice were treated orally with the compounds for 6 days and plasma glucose and triglyceride levels were measured. Percentage reduction
was calculated according to the formula: 1ꢁ[(TT/OT)/(TC/OC)]ꢂ100; TT: test day treated, OT: zero day treated, TC: test day control, OC: Zero
day control; NE: no effect; PG: plasma glucose; TG: plasma triglyceride.

G. R. Madhavan et al. / Bioorg. Med. Chem. 10 (2002) 2671–2680
Table 2. Effect of PMT13, rosiglitazone and pioglitaone in PPAR transactivation assay
2675
Concentration (mM)
PMT13 (Fold activation)
Rosiglitazone (Fold activation)
Pioglitazone (Fold activation)
0.010
0.050
0.200
1.0
0.92
2.58
7.79
16.66
20.04
0.80
1.80
4.46
15.04
19.33
0.1
0.3
1.2
3.8
6.0
5.0
HEK 293T cells were transfected with GAL4-PPARg1 and pgl2-gal4X5-Luc plasmids. Transfected cells were treated with the compounds at the
concentrations mentioned. Each data point represents mean of two experiments.
Table 3. Comparative effect of PMT13, rosiglitazone and pioglitazone in db/db mice
Compd
Dose (mg/kg/day)
Plasma glucose (Percent Reduction)
Triglyceride (% reduction)
Insulin (% reduction)
PMT13
PMT13
PMT13
Rosigltazone
Rosigltazone
Rosigltazone
Pioglitazone
Pioglitazone
Pioglitazone
0.3
3.0
10.0
0.3
3.0
10.0
0.3
31.1ꢃ2.5
57.5ꢃ1.2
72.2ꢃ0.9
18.5ꢃ5.6
42.3ꢃ3.4
47.1ꢃ2.7
19.4ꢃ3.5
38.5ꢃ2.4
46.2ꢃ2.9
31.5ꢃ3.1
53.8ꢃ2.5
59.4ꢃ1.8
NE
23.6ꢃ2.5
40.5ꢃ1.12
14.7ꢃ1.9
36.1ꢃ1.7
46.9ꢃ1.6
16.7ꢃ1.2
69.2ꢃ3.1
77.3ꢃ2.4
NE
30.5ꢃ3.1
41.7ꢃ4.4
12.2ꢃ2.1
45.6ꢃ2.3
57.8ꢃ1.3
3.0
10.0
Male db/db mice were treated for 15 days orally with the compounds at the doses mentioned. Values are meanꢃSE (n=5). Percentge reduction was
calculated as mentioned in Table 1.
Wistar rats. The compound showed good oral exposure
and pharmacokinetic profile as shown in Table 4.
of the metabolic syndrome. Further development work
on this compound is in progress.
Conclusion
Experimental
Untreated insulin resistance not only leads to hyperglyce-
mia, but also hyperlipidemia. Insulin-sensitizing thiazoli-
dinediones, marketed recently, are known to act through
PPARg. In this communication, we have shown that pyr-
imidinone derivatives of thiazolidinedione have an inter-
esting insulin-sensitizing property. PMT13, the best
compound in this series is a potent PPARg activator and
showed plasma glucose, insulin and triglyceride-lowering
activity. In both in vivo and in vitro studies, the com-
pound showed better efficacy than the reference thiazoli-
dinediones (i.e., pioglitazone and rosiglitazone).
Subchronic oral toxicity study in Wistar rats did not show
any treatment-related adverse effects. The compound has
also shown good systemic exposure in rats after oral
administration. It is important to note that a drug that
ameliorates insulin resistance and also lowers triglycer-
ide is preferable for treatment of both hyperglycemia
and cardiovascular complications of type 2 diabetes
patients. Therefore, by virtue of its potent PPARg acti-
vation, antidiabetic and triglyceride lowering activity
PMT13 is a potential drug candidate for the treatment
Animals and treatment
Male C57 BL/Ks J-db/db mice were from the breeding
stock of DRF animal house generated from an original
stock of Jackson Laboratories, Maine, USA. All ani-
mals were maintained under 12 h light and 12 h dark
cycle at 25ꢃ1 ꢀC. All animals were given standard chow
(National Institute of Nutrition, India) and water ad
libitum. All animal experiments were carried out in
accordance with internationally valid guidelines. All
experimental protocols were approved by DRF animal
ethics committee.
In preliminary studies db/db mice (8–9 weeks) were trea-
ted with drugs orally at 30 or 100 mg/kg/day for 6 days.
Animals in control groups received vehicle alone (0.25%
CMC, 10mL/kg). During dose response study, db/db
mice were treated with PMT13, rosiglitazone and piogli-
tazone at 0.3, 3 and 10mg/kg/day doses for 15 days.
Blood samples were collected from animals, in fed state,
under mild ether anesthesia from retro-orbital sinus 1 h
after drug administration. Plasma samples were separated
for glucose, triglycerides and insulin measurement.
Table 4. Pharmacokinetic profile of PMT13 in Wistar rats
For subacute toxicity study, 6–8-week old Wistar rats
(obtained from National Institute of Nutrition, Hyder-
abad, India) of either sex (110–160 g) were divided ran-
domly into two groups, each consisting of four males
and four females. PMT13 was administered orally daily
at 100 mg/kg dose, while the control group received the
vehicle only. On the day of termination (28th day),
Parameters
PMT13
AUC(0-1) (mg h/mL)
Cmax (mg/mL)
tmax (h)
206.84ꢃ43.78
39.23ꢃ4.55
1.25ꢃ0.88
0.26ꢃ0.09
3.02ꢃ1.12
Kel (hꢁ1
t1/2 (h)
)

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G. R. Madhavan et al. / Bioorg. Med. Chem. 10 (2002) 2671–2680
blood was collected from retro-orbital sinus under light
ether anesthesia for clinical pathological parameters
followed by autopsy and macroscopic examination.
Synthesis
Melting points were determined on Veego melting point
apparatus and are uncorrected. Infra red spectra were
recorded on Perkin-Elmer FT-IR 1600 spectrometer.
Proton nuclear magnetic resonance (1H NMR) spectra
were recorded on a Varian Gemini 200 MHz spectro-
meter with TMS as the internal standard. Mass spectra
were recorded on HP-5989A mass spectrometer. Ele-
mental analysis was performed with Perkin-Elmer, 2400
series II CHN-O analyzer. Column chromatography
was performed by using silicagel (200–400 mesh, SRL)
with the indicated solvent. 4-(2-Bromoethoxy) benzal-
dehyde11 and pyrimidinones were prepared according to
the general method10,11 given in Scheme 2.
PPAR transactivation assay
The response element (UASGAL4 X 5) is present
upstream of pFR-Luc reporter (Promega, WI, USA)
that contains Simian virus early promoter for luciferase
assay. GAL4 fusions were made by fusing human
PPARg1 ligand binding domain (amino acids: 174–475)
to the C-terminal end of yeast GAL4 DNA binding
domain (amino acids: 1–147) of pM1 vector. pAdVan-
tage vector was used to enhance luciferase expression.
HEK 293T cells were transfected with relevant plasmids
by superfect as per the supplier’s instruction manual.
Forty-two h after transfection, cells were treated for
18 h with the test compounds. DMSO (0.1%) was used
as blank. Luciferase activity was determined as fold
activation relative to untreated cells by using Luclite kit
(Packard Instrument Co, Meriden, CT, USA) in a
Packard Top Count (Packard Instrument Co.)
Preparation of 4-[2-[2,4-disubstituted-6-oxo-1,6-dihydro-
1-pyrimidinyl]ethoxy] benzaldehyde (IIa–f)
Preparation of 4-[2-[4-methyl-2-propyl-6-oxo-1,6-dihy-
dro-1-pyrimidinyl]ethoxy] benzaldehyde (IIc). To a stir-
red suspension of NaH (570mg, 22.57 mmol) in dry DMF
(35 mL) at 25ꢀC was added a solution of 4-methyl-2-pro-
pyl-1,6-dihydro-6-pyrimidinone (2.64 g, 17.36 mmol) in
dry DMF. After the effervescence had ceased (about
15min), anhydrous LiBr (3.51 g, 40mmol) was added
followed by 4-[2-bromoethoxy]benzaldehyde12 (4.37 g,
19.08 mmol) in dry DMF at the same temperature. The
reaction was continued at 80 ꢀC for 16 h. The reaction
mixture was cooled to room temperature, poured into
water and extracted with ethyl acetate (EtOAc), the
combined EtOAc extracts were washed with water,
brine, dried over Na2SO4 and concentrated. The crude
compound was chromatographed on silicagel using 3:7
EtOAc–petroleum ether, to yield 1.61 g (31%) of the
title compound. IR (KBr) 1700, 1680 cmꢁ1; 1H NMR (d
in CDCl3) 9.80 (s, 1H), 7.82 (d, J=8.72 Hz, 2H), 6.95 (d,
J=8.72 Hz, 2H), 4.45 (t, J=5.30 Hz, 2H), 4.35 (t, 5.30Hz,
2H), 2.92 (t, J=7.50 Hz, 2H), 2.25 (s, 3H), 1.92–1.70 (m,
2H), 1.20 (t, J=7.50 Hz, 3H); CIMS m/z 301 (M+H)+.
Analysis calcd for C17H20N2O3: C, 67.98; H, 6.71; N,
9.32. Found: C, 68.10; H, 6.52; N, 9.44%.
Pharmacokinetic studies
All studies were carried out in male Wistar rats obtained
from National Institute of Nutrition (Hyderabad, India).
The animals (200–225gm) were fasted 12h before starting
the experiment and they had free access to water
throughout the experiment period. Animals were fed 3 h
after drug administration.
Single-dose pharmacokinetics. Animals were adminis-
tered the drug at 10 mg/kg per orally as 0.5% CMC
suspension and about 0.3 mLof blood sample was col-
lected into heparinised microfuge tubes at different time
points from retro-orbital sinus. To 0.1 mLof plasma,
internal standard (another thiazolidinedione) was added
and drugs were extracted with a suitable solvent mixture.
Solvent was evaporated and residue was reconstituted
with mobile phase and injected into HPLC system. The
samples were analyzed by reverse-phase HPLC to gen-
erate plasma concentration time profiles.
In the same manner, the following compounds were
obtained.
Pharmacokinetic parameters such as AUC(0-1), Kel, half-
life, Cmax and tmax were calculated using non-compart-
mental model analysis. AUC(0-1) is the area under the
plasma concentration versus time curve extrapolated to
infinity, Kel is the elimination rate constant, Cmax is the
observed maximum plasma concentration and tmax is the
time at which maximum concentration (Cmax) is reached.
Preparation of 4-[2-[2,4-dimethyl-6-oxo-1,6-dihydro-1-
pyrimidinyl]ethoxy] benzaldehyde (IIa). Yield=30%; IR
1
(KBr) 1742, 1710, 1685 cmꢁ1; H NMR (d in CDCl3)
9.90 (s, 1H), 7.80 (d, J=8.70 Hz, 2H), 7.02 (d, J=
8.70 Hz, 2H), 6.20 (s, 1H), 4.50–4.30 (m, 4H), 2.70 (s,
3H); CIMS m/z 273 (M+H)+. Analysis calcd for
C15H16N2O3: C, 66.16; H, 5.92; N, 10.28. Found: C,
66.36; H, 5.83; N, 10.40%.
HPLC assay. The HPLC system includes a Waters LC
Module-1, Millennium software and a Suplecosil C18
(ODS) column (5mm, 4.6ꢂ250 mm). Analysis of PMT13
was carried out using 0.05M NaH2PO4 buffer (pH: 4.0)/
methanol/acetonitrile (55:7:38; v/v) as mobile phase at a
flow rate of 1 mL/min. Eluate from the column was mon-
itored by UV detector (Waters LC Module) set at 275 nm.
Under these conditions retention times for PMT13 and
IS were, respectively, 8.5 and 12.0 min. Absolute recov-
ery was >95%, the limit of quantification was 0.2 mg/
mLand response was linear up to 50 mg/mL.
Prepration of 4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-
pyrimidinyl]ethoxy] benzaldehyde (IIb). Yield=42%; IR
1
(KBr) 1700, 1681 cmꢁ1; H NMR (d in CDCl3) 9.90 (s,
1H), 7.80 (d, J=8.70 Hz, 2H), 6.98 (d, J=8.70 Hz, 2H),
6.20 (s, 1H), 4.52–4.25 (m, 4H), 3.02 (q, J=7.40 Hz, 2H),
2.30 (s, 3H), 1.40 (t, J=7.40 Hz, 3H); CIMS m/z 287
(M+H)+. Analysis calcd for C16H18N2O3: C, 67.11; H,
6.33; N, 9.78. Found: C, 67.01; H, 6.25; N, 9.49%.

G. R. Madhavan et al. / Bioorg. Med. Chem. 10 (2002) 2671–2680
2677
Preparation of 4-[2-[2-butyl-4-methyl-6-oxo-1,6-dihydro-
1-pyrimidinyl] ethoxy]benzaldehyde (IId). Yield=31%;
crystalline compound was filtered and washed with water
and dried to afford the title compound. Yield=1.23 g,
ꢀ
1
1
IR (KBr) 1701, 1692 cmꢁ1; H NMR (d in CDCl3) 9.90
99%; mp: 240–242 C; IR (KBr) 1739, 1697, 1643; H
NMR (d in CDCl3) 12.40 (bs, 1H, D2O exchangeable),
7.75 (s, 1H), 7.54 (d, J=8.72 Hz, 2H), 7.02 (d, J=
8.72 Hz, 2H), 6.15 (s, 1H), 4.45–4.15 (m, 4H), 2.91 (t,
J=7.65 Hz, 2H), 2.20 (s, 3H), 1.90–1.65 (t, J=7.65 Hz,
3H); CIMS m/z 400(M+H)+. Analysis calcd for C20
H21N3O4S: C, 60.13; H, 5.29; N, 10.52. Found: C,
60.00; H, 5.13; N, 10.46%.
(s, 1H), 7.84 (d, J=8.72 Hz, 2H), 6.98 (d, J=8.72 Hz,
2H), 6.20 (s, 1H), 4.52–4.30 (m, 4H), 2.96 (t, J=7.47 Hz,
2H), 2.26 (s, 3H), 1.90–1.70 (m, 2H), 1.70–1.50 (m, 2H),
1.01 (t, J=7.47 Hz, 3H); EIMS m/z 315 (M+). Analysis
calcd for C18H22N2O3: C, 68.76; H, 7.05; N, 8.91.
Found: C, 68.54; H, 7.28; N, 8.59%.
Preparation of 4-[2-[2-ethyl-4-trifluoromethyl-6-oxo-1,6-
dihydro-1-pyrimidinyl] ethoxy]benzaldehyde (IIe). Yield=
31%; IR (KBr) 1695, 1692 cmꢁ1; 1H NMR (d in CDCl3)
9.89 (s, 1H), 7.83 (d, J=8.67 Hz, 2H), 6.95 (d, J=
8.67 Hz, 2H), 6.70 (s, 1H), 4.50 (t, J=4.66 Hz, 2H), 4.39
(t, J=4.66 Hz, 2H), 3.1 (q, J=7.4 Hz, 2H), 1.4 (t, J=
7.4 Hz, 3H); CIMS m/z 341 (M+H)+. Analysis calcd
for C16H15F3N2O3: C, 56.47; H, 4.44; N, 8.23. Found:
C, 56.52; H, 4.23; N, 8.17%.
In the same manner, the following compounds were
obtained.
Preparation of 5-[4-[2-[2,4-dimethyl-6-oxo-1,6-dihydro-1-
pyrimidinyl]ethoxy] phenylmethylene]thiazolidine-2,4-dione
(IIIa). Yield=95%; mp 235 ꢀC; IR (KBr) 1743, 1703,
1672; 1H NMR (d in CDCl3) 8.50 (bs, 1H, D2O
exchangeable), 7.80 (s, 1H), 7.48 (d, J=8.40 Hz, 2H),
6.98 (d, J=8.40 Hz, 2H), 6.21 (s, 1H), 4.52–4.30 (m,
4H), 2.70 (s, 3H), 2.25 (s,3H); CIMS m/z 372 (M+H)+.
Analysis calcd for C18H17N3O4S: C, 58.21; H, 4.61; N,
11.31. Found: C, 58.14; H, 4.47; N, 11.52%.
Preparation of 4-[2-[2-benzyl-4-methyl-6-oxo-1,6-dihy-
dro-1-pyrimidinyl]ethoxy] benzaldehyde (IIf). Yield=
31%; IR (KBr) 1695, 1675 cmꢁ1; 1H NMR (d in CDCl3)
9.89 (s, 1H), 7.83 (d, J=8.72 Hz, 2H), 7.45–7.15 (m,
5H), 6.98 (d, J=8.72 Hz, 2H), 6.44 (s, 1H), 4.70 (t, J=
4.71 Hz, 2H), 4.30 (t, J=4.71 Hz, 2H), 4.14 (s, 2H), 2.42
(s, 3H); EIMS m/z 348 (M+). Analysis calcd for C21H20
N2O3: C, 72.39; H, 5.78; N, 8.04. Found: C, 72.48; H,
5.69; N, 7.94%.
Preparation of 5-[4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihy-
dro-1-pyrimidinyl]ethoxy] phenylmethylene]thiazolidine-
2,4-dione (IIIb). Yield=92%; mp 248–250 ꢀC; IR (KBr)
;
1751, 1692 cmꢁ1 1H NMR (d in CDCl3+DMSO-d6)
12.25 (bs, 1H, D2O exchangeable), 7.78 (s, 1H), 7.40 (d,
J=7.40 Hz, 2H), 7.0 (d, J=7.40 Hz, 2H), 6.20 (s, 1H),
4.48–4.24 (m, 4H), 3.0 (q, J=6.4 Hz, 2H), 2.20 (s, 3H),
1.28 (t, J=6.4 Hz, 3H); CIMS m/z 386 (M+H)+. Ana-
lysis calcd for C19H19N3O4S: C, 59.20; H, 4.97; N,
10.90. Found: C, 59.08; H, 4.67; N, 10.55%.
Preparation of 4-[2-[4-N-acetylamino-2-oxo-1,2-dihydro-
1-pyrimidinyl]ethoxy] benzaldehyde (VIII) (Scheme 3).
To the N4-acetyl cytosine [Aldrich sample or can be
prepared from cytosine by acetylation with Ac2O/pyri-
dine (Scheme 3)] (1.8 g, 11.9 mmol) in DMF (30 mL)
was added K2CO3 (3.28 g, 23.8 mmol) and 4-[2-bro-
moethoxy]benzaldehyde (2.72 g, 11.9 mmol), the mix-
ture was heated at 80 ꢀC for 14 h .The reaction mixture
was cooled to RT, filtered and the filterate was worked
up in a usual way to yield 1.8 g (66%) of the product. IR
Preparation of 5-[4-[2-[2-butyl-4-methyl-6-oxo-1,6-dihy-
dro-1-pyrimidinyl]ethoxy] phenylmethylene]thiazolidine-
2,4 - dione (IIId). Yield=31%; IR (KBr) 1734, 1695,
1
1647 cmꢁ1; H NMR (d in CDCl3) 7.80 (s, 1H), 7.40 (d,
J=8.63 Hz, 2H), 6.95 (d, J=8.63 Hz, 2H), 6.21 (s, 1H),
4.55–4.22 (m, 4H), 2.95 (t, J=7.47 Hz, 2H), 2.25 (s, 3H),
1.85–1.60 (m, 2H), 1.60–1.40 (m, 2H), 0.99 (t, J=7.10 Hz,
3H); CIMS m/z 414 (M+H)+. Analysis calcd for C21H23
N3O4S: C, 60.99; H, 5.60; N, 10.16. Found: C, 60.69; H,
5.62, N, 9.79%.
1
(KBr) 1651, 1695 cmꢁ1; H NMR (d in CDCl3) 9.90 (s,
1H), 8.70 (bs, 1H, D2O exchangeable), 7.85 (d, J=8.70 Hz,
2H), 7.75 (d, J=7.80 Hz, 1H), 7.42 (d, J=7.80 Hz, 1H),
6.95 (d, J=8.70 Hz, 2H), 4.40–4.20 (m, 4H), 2.30 (s,
3H); EIMS m/z 301 (M+). Analysis calcd for C15H15
N3O4: C, 59.79; H, 5.02; N, 13.94. Found: C, 59.57; H,
4.85; N, 13.86%.
Preparation of 5-[4-[2-[2-ethyl-4-trifluoromethyl-6-oxo-
1,6-dihydro-1-pyrimidinyl] ethoxy]phenylmethylene]thia-
zoline - 2,4 - dione (IIIe). Yield=31%; mp >250 ꢀC IR
Prepration of 5-[4-[2-[2,4-disubstituted-6-oxo-1,6-dihydro-
1-pyrimidinyl]ethoxy] phenylmethylene]thiazolidine-2,4-
dione [III(a–f)] and 5-[4-[2-[2,4-disubstituted-6-oxo-1,6-
dihydro-1-pyrimidinyl]ethoxy]phenylmethylene]-2-thio-
1,3-oxazolidine-4-one (IV)
1
(KBr) 1748, 1700, 1680 cmꢁ1; H NMR (d in CDCl3+
DMSO-d6) 7.70 (s, 1H), 7.45 (d, J=8.3 Hz, 2H), 6.95 (d,
J=8.3 Hz, 2H), 6.69 (s, 1H), 4.50 (t, J=4.5 Hz, 2H),
4.35 (t, J=4.5 Hz, 2H), 3.11 (q, J=7.2 Hz, 2H), 1.38 (t,
J=7.2 Hz, 3H); CIMS m/z 440 (M+H)+. Analysis
calcd for C19H16F3N3O4S: C, 51.93; H, 3.67; N, 9.56.
Found: C, 51.77; H, 3.63; N, 9.84%.
Preparation of 5-[4-[2-[4-methyl-2-propyl-6-oxo-1,6-dihy-
dro-1-pyrimidinyl]ethoxy] phenylmethylene]thiazolidine-
2,4-dione (IIIc). A mixture of 4-[2-[4-methyl-2-propyl-6-
oxo-1,6-dihydro-1-pyrimidinyl]ethoxy] benzaldehyde IIc
(1.0 g, 2.45mmol), thiazolidine-2,4-dione (0.35 g, 3 mmol),
benzoic acid (38.8 mg,0.32 mmol) and piperidine
(30.3 mg, 0.37 mmol) in toluene (10 mL) was refluxed for
2–4 h. with continuous removal of water. The reaction
mixture was cooled to room temperature and the resultant
Preparation of 5-[4-[2-[2-benzyl-4-methyl-6-oxo-1,6-dihy-
dro-1-pyrimidinyl]ethoxy] phenylmethylene]thiazolidine-
2,4 - dione (IIIf). Yield=66%; mp 223 ꢀC; IR (KBr)
;
1733, 1701 cmꢁ1 1H NMR (d in CDCl3+DMSO-d6)
7.74 (s, 1H), 7.44 (d, J=8.71 Hz, 2H), 7.40–7.10 (m,
5H), 6.95 (d, J=8.71 Hz, 2H), 6.26 (s, 1H), 4.38 (s, 2H),

2678
G. R. Madhavan et al. / Bioorg. Med. Chem. 10 (2002) 2671–2680
4.35–4.10 (m, 4H), 2.32 (s, 3H); CIMS m/z 448
(M+H)+. Analysis calcd for C24H21N3O4S: C, 64.41;
H, 4.73; N, 9.39. Found: C, 64.52; H, 4.59; N, 9.03%.
pyrimidinyl]ethoxy]benzaldehyde IIb (5.72 g, 20 mmol)
in ethanol (100 mL). The reaction mixture was refluxed
at 95 ꢀC for 3 h. The reaction mixture was then cooled
to rt concentrated to a volume where crystals of oxime
started separating out and the mixture was kept aside
for 30 min to 1 h at 25 ꢀC. The resultant crystals were
filtered and washed with water and dried to obtain the
title compound, 5.4 g, 90% yield. IR (KBr) 3430,
1680 cmꢁ1; 1H NMR (d in CDCl3+DMSO-d6) 10.56 (s,
1H, OH, D2O exchangeable), 8.08 (s, 1H), 7.55 (d,
J=8.56 Hz, 2H), 6.88 (d, J=8.56 Hz, 2H), 6.20 (s, 1H),
4.51–4.40 (m, 2H), 4.40–4.28 (m, 2H), 3.05 (q,
J=7.06 Hz, 2H), 2.30 (s, 3H), 1.40 (t, J=7.06 Hz, 3H);
CIMS m/z 301 (M+H)+. Analysis calcd for C16H19
N3O3: C, 63.77; H, 6.35; N, 13.94. Found: C, 63.47; H,
6.05; N, 13.66%.
Preparation of 5-[4-[2-[4-acetylamino-2-oxo-1,2-dihydro-
1-pyrimidinyl]ethoxy] phenylmethylene]thiazolidine-2,4-
dione (IX). Yield=1.8 g, 81%; mp 274 ꢀC; IR (KBr)
1720, 1681, 1630 cmꢁ1; 1H NMR (d in CDCl3+DMSO-
d6) 10.85 (s, 1H, D2O exchangeable), 8.11 (d, J=7.2 Hz,
1H),7.74 (s, 1H) 7.55 (d, J=8.30, 2H), 7.17 (d, J=
7.20 Hz, 1H), 7.11 (d, J=8.30 Hz, 2H), 4.40–4.05 (m,
4H), 2.08 (s, 3H); CIMS m/z 401(M+H)+. Analysis
calcd for C18H16N4O5S: C, 53.99; H, 4.03; N, 13.99.
Found: C, 53.69; H, 3.66; N, 13.68%.
Preparation of 5-[4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihy-
dro-1-pyrimidinyl]ethoxy] phenylmethylene]-2-thio-1,3-
oxazolidine-4-one (IVb). An immate mixture of 4-[2-[2-
ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]
benzaldehyde IIb (286 mg, 1.0 mmol), 2-thioxo-4-thia-
zolidinone (rhodanine) (175 mg, 1.5 mmol) and anhy-
drous sodium acetate (246 mg, 3.0 mmol) was heated at
120 ꢀC under reduced pressure (2.0 torr) and stirred for
30 min. After cooling to room temperature the reaction
mixture was poured in to ethyl acetate (80 mL) and
water (20 mL) and stirred for 30 min, the aqueous layer
was separated acidified to pH 4 with 2 N HCl. The solid
separated, which was filtered and dried to yield the title
compound, 207 mg, 54%; IR (KBr) 1710, 1645 cmꢁ1; 1H
NMR (d in CDCl3) 7.76 (d, J=8.62 Hz, 2H), 6.93 (d,
J=8.62 Hz, 2H), 6.59 (s, 1H), 6.17 (s, 1H), 4.50–4.30
(m, 4H), 2.98 (q, J=7.47 Hz, 2H), 2.27 (s, 3H), 1.35 (t,
J=7.47 Hz, 3H); CIMS m/z 386 (M+H)+. Analysis
calcd for C19H19N3O4S: C, 59.20; H, 4.97; N, 10.90.
Found: C, 59.01; H, 4.88, N, 10.61%.
Preparation of 4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydro-
1-pyrimidinyl]ethoxy] benzyl hydroxyl amine (XI). To a
solution of 4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-
pyrimidinyl]ethoxy] benzaldehyde oxime X (301mg,
1.0 mmol) in a mixture of methanol (3 mL) was added 4 N
HCl (2 mL) in dioxane at 30ꢀC was added NaCNBH3
(0.508 mmol) and stirred for 10 min at the same tem-
perature. The reaction mixture was made alkaline to
pH=9.0 with 1 N NaOH and extracted with EtOAc.
The combined extracts were washed with brine and
dried over Na2SO4 and concentrated to yeild the title
compound. 272 mg; 90%; IR (KBr) 3400, 3240 cmꢁ1; 1H
NMR (d in CDCl3) 7.23 (d, J=8.72 Hz, 2H), 6.80 (d,
J=8.72 Hz, 2H), 6.18 (s, 1H), 4.45–4.35 (m, 2H), 4.35–
4.20 (m, 2H), 3.98 (s, 2H), 3.01 (q, J=7.56 Hz, 2H), 2.22 (s,
3H), 1.32 (t, J=7.56 Hz, 3H); CIMS m/z 304 (M+H)+.
Analysis calcd for C16H21N3O3: C, 63.35; H, 6.97; N,
13.85. Found: C, 63.27; H, 7.02; N, 13.68%.
Preparation of 5-[4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihy-
dro-1-pyrimidinyl]ethoxy] phenylmethylene]oxazolidine-
2,4 - dione (IV). To a stirred solution of 5-[4-[2-[2ethyl-
4methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy] phenyl-
methylene]-2-thio-1,3-oxazolidine-4-one (I V b) (100 mg,
0.259 mmol) in dry DMF (2 mL) was added 3-chloro-
perbenzoic acid (65%, 179 mg, 0.68 mmol) at 0 ꢀC and
stirred for 30 min at 0–10 ꢀC and then at 30 ꢀC for 5 h.
The reaction mixture was diluted with ethyl acetate
(10 mL), washed with water (5 mL) and then with brine,
dried over Na2SO4 and concentrated. The crude pro-
duct was purified by flash chromatography to yield the
title compound, 72 mg, 75%; IR (KBr) 1745, 1701,
Preparation of 4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydro-
1-pyrimidinyl]ethoxy] benzyl]N-hydroxy urea (XII). To a
stirred solution of 4-[2-[2-ethyl-4-methyl-6-oxo-1,6-di-
hydro-1-pyrimidinyl] ethoxy] benzyl hydroxyl amine XI
(303 mg, 1.0 mmol) in a mixture of water (2 mL) and
acetic acid (0.5 mL) was added a solution of KOCN
(343 mg, 3.0 mmol) in water (1 mL) and stirred for 1 h at
30 ꢀC. The reaction mixture was diluted with water and
extracted with ethyl acetate and the combined organic
layers were washed with brine and dried over Na2SO4
and concentrated to yield, 295 mg, 85%; IR (KBr) 3400,
1
3200cmꢁ1; H NMR (d in CDCl3) 7.18 (d, J=8.65 Hz,
2H), 6.90 (d, J=8.65 Hz, 2H), 6.60 (bs, 1H, D2O
exchangeable), 6.15 (s, 1H), 5.85 (bs, 1H, D2O exchange-
able), 4.70 (s, 2H), 4.50 (bs, 1H, D2O exchangeable), 4.40–
4.30 (m, 2H), 4.22–4.10 (m, 2H), 2.92 (q, J=7.56 Hz, 2H),
2.20 (s, 3H), 1.20 (t, J=7.56 Hz, 3H); EIMS m/z 334
(M+). Analysis calcd for C16H22N2O4: C, 62.73; H,
7.24; N, 9.14. Found: C, 62.65; H, 7.33; N, 9.04%.
1
1670 cmꢁ1; H NMR (d in CDCl3+DMSO-d6) 7.68 (d,
J=8.72 Hz, 2H), 6.91 (d, J=8.72 Hz, 2H), 6.61 (s, 1H),
6.16 (s, 1H), 4.50–4.38 (m, 2H), 4.38–4.00 (m, 2H), 3.12
(q, J=7.47 Hz, 2H), 2.24 (s, 3H), 1.35 (t, J=7.47 Hz,
3H); CIMS m/z 369 (M+). Analysis calcd for C19H19
N3O5: C, 61.78; H, 5.18; N, 11.37. Found: C, 61.57; H,
5.08; N, 11.44%.
Prepration of 5-[4-[2-[2,4-disubstituted-6-oxo-1,6-dihydro-
1-pyrimidinyl]ethoxy] phenylmethyl]thiazolidine-2,4-dione
(Va–e)
Preparation of 4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydro-
1-pyrimidinyl]ethoxy] benzaldehyde oxime (X) (Scheme
4). To a stirred solution of hydroxylamine hydrochlo-
ride (10 g, 143 mmol) and Sodium acetate (20 g,
146.9 mmol) in water (100 mL) at 30 ꢀC was added a hot
solution of 4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-
Preparation of 5-[4-[2-[4-methyl-2-propyl-6-oxo-1,6-dihy-
dro-1-pyrimidinyl]ethoxy] phenylmethyl]thiazolidine-2,4-
dione (Vc). A solution of 5-[4-[2-[4-methyl-2-propyl-6-

G. R. Madhavan et al. / Bioorg. Med. Chem. 10 (2002) 2671–2680
2679
oxo-1,6-dihydro-1-pyrimidinyl]ethoxy] phenylmethyle-
ne]thiazolidine-2,4-dione IIIc (5.0 g, 12.46 mmol) in
dioxane (75 mL) was hydrogenated in the presence of
10%Pd/C (12.0 g) at 60 psi for 24 h. The mixture was
filtered through a bed of Celite. The filtrate was evapo-
rated under reduced pressure and purified by column
chromatography using 2:1 EtOAc/petroleumether to
afford the title compound as white fluffy solid.
Yield=4.6 g, 92%; mp 144–146 ꢀC; IR (KBr) 1750, 1704,
dine-2,4-dione (Ve). Yield=66%; mp 135 ꢀC; IR (KBr)
1
1752, 1715, 1680 cmꢁ1; H NMR (d in DMSO-d6) 7.11
(d, J=8.53 Hz, 2H), 6.77 (d, J=8.53 Hz, 2H), 6.70 (s,
1H), 4.52–4.38 (m, 1H), 4.46 (t, J=4.68 Hz, 2H), 4.28 (t,
J=4.68 Hz, 2H), 3.4 (dd, J=14.21, 3.83 Hz, 1H), 3.20–
2.98 (m, 3H), 1.38 (t, J=7.33 Hz, 3H); CIMS m/z 441
(M+). Analysis calcd for C19H18F3N3O4S: C, 51.70; H,
4.11; N, 9.52. Found: C, 51.85; H, 3.88; N, 9.41%.
1
1640cmꢁ1; H NMR (d in CDCl3) 8.25 (bs, 1H, D2O
Preparation of 5-[4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihy-
dro-1-pyrimidinyl] ethoxy]phenylmethyl]-1,2,4-oxadiazo-
lidine-3,5-dione (XIII). To a stirred solution of N-[4-[2-
[2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]
ethoxy]benzyl]-N-hydroxyurea XII (346 mg, 1.0 mmol)
in water (2 mL) was added 1 N NaOH (3 mL) followed
by ethyl chloroformate (191 mL, 217 mg, 2.0 mmol) and
stirred for 1 h at 30 ꢀC. The reaction mixture was diluted
with water, acidified to pH 3.0 and extracted with
EtOAc (3ꢂ10 mL). The combined organic layers were
washed with brine, dried over anhydrous Na2SO4 and
concentrated to yield the title compound (283 mg, 76%);
exchangeable), 7.12 (d, J=8.4Hz, 2H), 6.79 (d, J=
7.48Hz, 2H), 6.21 (s, 1H), 4.47 (dd, J=9.36, 4.06 Hz,
1H), 4.41 (t, J=4.47 Hz, 2H), 4.26 (t, J=4.47Hz, 2H),
3.41 (dd, J=14.11, 4.06Hz, 1H), 3.10 (dd, J=14.11,
9.36Hz, 1H), 2.92 (t, J=7.63 Hz, 2H), 2.24 (s, 3H), 1.90–
1.60 (m, 2H), 1.05 (t, J=7.65 Hz, 3H); CIMS m/z 402
(M+H)+. Analysis calcd for C20H23N3O4S: C, 59.83; H,
5.77; N, 10.46. Found: C, 59.68; H, 5.84; N, 10.18%.
In the same manner, the following compounds were
obtained.
IR (KBr) 1745, 1650 cmꢁ1 1H NMR (d in CDCl3+
;
Preparation of 5-[4-[2-[2,4-dimethyl-6-oxo-1,6-dihydro-1-
pyrimidinyl]ethoxy] phenylmethyl]thiazolidine-2,4-dione
(Va). Yield 85%; mp=170 ꢀC; IR (KBr) 1750,
DMSO-d6) 12.40 (bs, 1H, D2O exchangeable), 7.25 (d,
J=8.72 Hz, 2H), 6.90 (d, J=8.72 Hz, 2H), 6.15 (s, 1H),
4.70 (s, 2H), 4.40–4.25 (m, 2H), 4.25–4.12 (m, 2H), 2.91
(q, J=7.56 Hz, 2H), 2.12 (s, 3H), 1.20 (t, J=7.56 Hz,
3H); CIMS m/z 359 (M+H)+. Analysis calcd for
C18H20N4O5: C, 58.06; H, 5.41; N, 15.04. Found: C,
57.99; H, 5.48; N, 14.94%.
1
1697 cmꢁ1; H NMR (d in CDCl3) 8.15 (bs, 1H, D2O
exchangeable), 7.14 (d, J=8.30 Hz, 2H), 6.80 (d, J=
8.30Hz, 2H), 6.21 (s, 1H), 4.50 (dd, J=9.13, 3.73 Hz,
1H), 4.48–4.20 (m, 4H), 3.41 (dd, J=14.12, 3.73 Hz,
1H), 3.13 (dd, J=14.12, 9.13 Hz, 1H), 2.70 (s, 3H), 2.25
(s, 3H); CIMS m/z 374 (M+H)+. Analysis calcd for
C18H19N3O4S: C, 57.89; H, 5.13; N, 11.25. Found: C,
57.68; H, 5.02; N, 11.32%.
Acknowledgements
The authors are thankful to the management of Dr.
Reddy’s group for encouragment. We thank J. Suresh
and H. Jagadheshan for their technical help. We are
thankful to Novo Nordisk, Bagsvaerd, Denmark for
providing PPAR constructs.
Preparation of 5-[4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihy-
dro-1-pyrimidinyl]ethoxy] phenylmethyl]thiazolidine-2,4-
dione (Vb). Yield=82%; mp 155 ꢀC; IR (KBr) 1749,
1
1708, 1670 cmꢁ1; H NMR (d in CDCl3) 8.65 (bs, 1H,
D2O exchangeable), 7.12 (d, J=8.51 Hz, 2H), 6.79 (d,
J=8.51 Hz, 2H), 6.21 (s, 1H), 4.43 (dd, J=9.27, 3.83Hz,
1H), 4.42 (t, J=4.57 Hz, 2H), 4.26 (t, J=4.57 Hz, 2H),
3.41 (dd, J=14.11, 3.83 Hz, 1H), 3.11 (dd, J=14.11,
9.27 Hz, 1H), 2.99 (q, J=7.47 Hz, 2H), 2.25 (s, 3H), 1.34
(t, J=7.47 Hz, 3H); CIMS m/z 388 (M+H)+. Analysis
calcd for C19H21N3O4S: C, 58.90; H, 5.46; N, 10.84.
Found: C, 58.69; H, 5.18; N, 10.67%.
References and Notes
1. DeFronzo, R. A. Diabetologia 1992, 35, 389.
2. Saltiel, A. R.; Olefsky, J. M. Diabetes 1996, 45, 1661.
3. Lehman, J. M.; Moore, L. B.; Smith Oliver, T. A. J. Biol.
Chem. 1995, 270, 12953.
4. Kliewer, S. A.; Lenhard, J. M.; Wilson, T. M. Cell 1995, 83,
813.
5. Liver damage warning for troglitazone. Scrip 1997, 2282, 21.
6. Wilson, 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.; Lehman, J. M. J. Med. Chem. 1996, 39, 665.
7. Patel, J.; Miller, E.; Hu, J.; Granett, J. Diabetes 1997,
46(Suppl. 1); Abstr 0578.
Preparation of 5-[4-[2-[2-butyl-4-methyl-6-oxo-1,6-dihy-
dro-1-pyrimidinyl]ethoxy] phenylmethyl]thiazolidine-2,4-
dione (Vd). Yield=78%; mp 150–152 ꢀC; IR (KBr) 1747,
1
1702, 1640cmꢁ1; H NMR (d in CDCl3) 9.53 (bs, 1H,
D2O exchangeable), 7.13 (d, J=8.40 Hz, 2H), 6.79 (d,
J=8.40 Hz, 2H), 6.22 (s, 1H), 4.45 (dd, J=9.22, 3.83Hz,
1H), 4.42 (t, J=4.57 Hz, 2H), 4.26 (t, J=4.57 Hz, 2H),
3.42 (dd, J=14.12, 3.83Hz, 1H), 3.09 (dd, J=14.12,
9.22 Hz, 1H), 2.95 (t, J=7.47 Hz, 2H), 2.24 (s, 3H), 1.85–
1.65 (m, 2H), 1.58–1.32 (m, 2H), 0.98 (t, J=7.38 Hz, 3H);
CIMS m/z 416 (M+H)+. Analysis calcd for C21H25
N3O4S: C, 60.70; H, 6.06; N, 10.11. Found: C, 60.44; H,
6.08; N, 10.12%.
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