Effect of structurally constrained oxime-ether linker on PPAR subtype selectivity: Discovery of a novel and potent series of PPAR-pan agonists

Article abstract of DOI:10.1016/j.bmc.2010.12.023

A novel series of thaizole and oxazole containing phenoxy acetic acid derivatives is reported as PPAR-pan agonists. Incorporation of structurally constrained oxime-ether based linker in the chemotype of a potent PPARδ selective agonist GW-501516 was adapted as designing strategy. In vitro, selected test compounds 12a, 12c, 17a and 18a showed PPAR-pan agonists activities and among these four compounds tested, 12a emerged as highly potent and efficacious compound, while 17a exhibited moderate and balanced PPAR-pan agonistic activity. In vivo, selected test compounds 12a and 17a exhibited significant anti-hyperglycemic and anti-hyperlipidemic activities in relevant animal models. These results support our hypothesis that the introduction of structurally constrained oxime-ether linker between lipophilic tail and acidic head plays an important role in modulating subtype selectivity and subsequently led to the discovery of potent PPAR-pan agonists.

Full text of DOI:10.1016/j.bmc.2010.12.023

Bioorganic & Medicinal Chemistry 19 (2011) 771–782
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Effect of structurally constrained oxime–ether linker on PPAR subtype
selectivity: Discovery of a novel and potent series of PPAR-pan agonists q
Pankaj Makadia a,b, Shailesh R. Shah b, , Harikishore Pingali a, Pandurang Zaware a, Darshit Patel a,
⇑
Suresh Pola a, Baban Thube a, Priyanka Priyadarshini a, Dinesh Suthar a, Maanan Shah a, Suresh Giri a,
Chitrang Trivedi a, Mukul Jain a, Pankaj Patel a, Rajesh Bahekar a,
⇑
a Zydus Research Centre, Sarkhej-Bavla N.H 8A, Moraiya, Ahmedabad 382 210, India
b Department of Chemistry, Faculty of Science, M. S. University of Baroda, Vadodara 390 002, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel series of thaizole and oxazole containing phenoxy acetic acid derivatives is reported as PPAR-pan
agonists. Incorporation of structurally constrained oxime–ether based linker in the chemotype of a potent
PPARd selective agonist GW-501516 was adapted as designing strategy. In vitro, selected test compounds
12a, 12c, 17a and 18a showed PPAR-pan agonists activities and among these four compounds tested, 12a
emerged as highly potent and efficacious compound, while 17a exhibited moderate and balanced PPAR-
pan agonistic activity. In vivo, selected test compounds 12a and 17a exhibited significant anti-hypergly-
cemic and anti-hyperlipidemic activities in relevant animal models. These results support our hypothesis
that the introduction of structurally constrained oxime–ether linker between lipophilic tail and acidic
head plays an important role in modulating subtype selectivity and subsequently led to the discovery
of potent PPAR-pan agonists.
Received 29 October 2010
Revised 3 December 2010
Accepted 6 December 2010
Available online 13 December 2010
Keywords:
Oxime
Oxazole
Thiazole
PPAR agonist
PPAR-pan agonist
Metabolic syndrome
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
physiological roles in glucose homeostasis, fatty acid metabolism
and cellular differentiation have been reviewed extensively.6–10
Metabolic syndrome is a cluster of closely related disorders
which include mainly obesity, dislipidemia, hyperglycemia and
hypertension that increases the risk of type 2 diabetes mellitus
(T2DM) and cardiovascular diseases. The prevalence of T2DM is
rapidly rising all over the globe at an alarming rate.1 Clinically
T2DM is characterized by increased blood glucose levels, either be-
cause of defect in insulin secretion, insulin resistance or both and is
usually associated with dyslipidemia, hypertension and obesity.
Detailed pathophysiology of this disease is not yet completely
understood. Metabolic defects in the liver, pancreatic b-cells, adi-
pose tissues and skeletal muscles could be the probable reasons
for the development of this disease.
The peroxisome proliferation activated receptors (PPARs) are li-
gand-activated transcription factors belonging to nuclear hormone
receptor super family.2–4 In recent years, development of drugs tar-
geting PPARs has attracted the attention of several research groups
for the reasons that PPARs modulate the genes which are involved
in multiple aspects of lipid and carbohydrate metabolism.5 Three
PPAR
such as liver, kidney, skeletal and cardiac muscles and adrenal
glands. PPAR is known to play an important role in fatty acids oxi-
dation and lipoprotein metabolism.11 PPAR
is expressed in adi-
a is expressed mostly in tissues involved in lipid oxidation,
a
c
pose tissue, macrophages and vascular smooth muscles and is
well known for its role in adipogenesis at a cellular level and in
insulin sensitization.12,13 Recent studies suggest that PPAR
c is also
involved in the expression of many genes that affect energy
metabolism, such as the leptin and adiponectin.14 In contrast to
the specific distributions of PPARa and c, PPARd is ubiquitously
expressed.6 Though PPARd was discovered more than 15 years
ago, it is the least studied and understood subtype among the
PPARs. Recent biological studies have revealed that PPARd activa-
tion significantly increases HDL cholesterol levels and it influences
glycemic control in a primate model of metabolic syndrome.15–17
In addition, various studies have implicated the involvement of
PPARd in adipogenesis, colon cancer, bone metabolism, embryonic
implantation, inflammation and skin development.18,19
distinct PPAR subtypes (
a,
c
and d) have been identified and their
Considering the beneficial effects of selective activation of
PPARa, c and d in animal models and humans, the concept of
simultaneously activating all of the PPAR subtypes with a single
compound, termed as PPAR-pan agonist appeared to be an inter-
esting approach for the treatment of different elements of meta-
bolic syndrome. Further simultaneous activation of all the PPARs
q
ZRC communication # 320.
⇑
Corresponding authors. Tel.: +91 2717 665555; fax: +91 2717 665355 (R.B.).
E-mail addresses: shailesh-chem@msubaroda.ac.in (S.R. Shah), rajeshbahekar@
zyduscadila.com (R. Bahekar).
0968-0896/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2010.12.023

772
P. Makadia et al. / Bioorg. Med. Chem. 19 (2011) 771–782
is believed to reduce the occurrence of adverse side effects, such as
weight gain, fluid accumulation and pulmonary and macular ede-
and characterization data are described in the experimental sec-
tion. Physical, analytical and spectral data of all the final as well
as intermediate compounds are in conformity with the structures
assigned. In general, compounds 12a–f, 17a–f and 18a–f were pre-
pared in good yield under mild reaction conditions.
mas which are often associated with PPAR selective or
agonists by their complimentary roles.20 Bezafibrate (1), a member
of fibrate class of drugs and practically considered as a weak PPAR
a/c dual
a
agonist is in fact a PPAR-pan agonist21 and is the only PPAR-pan
agonist available in the market but needs high dose to exert ther-
apeutic effect that to only in the lipid homeostasis. Currently
development of potent PPAR-pan agonists has become an area of
high thrust among several research groups as there is no potent
PPAR-pan agonist in the market (Fig. 1).15,22–24 Sodelglitazar (2)
and Indeglitazar (3)22 are currently in advanced clinical trials for
the treatment of T2DM and the current status of compound 4 is
undisclosed.23
The gross protein structures of PPARs are similar and possess
identical ligand binding pockets with 60–70% identity in amino
acid sequence in the ligand binding domain.24 As PPARd has a
smaller ligand binding pocket, we believed that it would be more
The synthetic route to intermediates 9a–f is outlined in Scheme
1. Starting materials 6a–f, prepared by reacting phenol or o-cresol
with respective acid chloride or anhydride in the presence of tri-
ethylamine in dichloromethane, were subjected to AlCl3 mediated
Fries rearrangement at 160 °C to obtain the keto compounds 7a–f
in 27–58% yield. Since the ortho-position of phenyl ring in 6b
and 6d is free of any substitution, the Fries migration gave a mix-
ture of two products (ortho and para substituted products) because
of the migration of the acyl group to both ortho and para positions,
which were separated by column chromatography. While 7a, 7c,
7e and 7f were obtained as exclusively para substituted products
for an obvious reason that in the precursors of these compounds
(6a, 6c, 6e and 6f) the ortho-position is occupied by methyl group.
Nucleophilic substitution reaction of the above obtained interme-
diates 7a–f with ethyl chloroacetate in the presence of K2CO3 in
DMF at 60 °C gave the compounds 8a–f. Treatment of the keto
compounds 8a–f with hydroxylamine hydrochloride in the pres-
ence of sodium acetate for 2 h in refluxing ethanol, gave the corre-
sponding oxime derivatives and the E-isomers were formed as
major product as they are thermodynamically more stable than
Z-isomers.33 Synthesis of compounds 12a–f was illustrated in
Scheme 2. Coupling of 10 with 9a–f in the presence of cesium car-
bonate in DMF at 60 °C gave the esters 11a–f, which were hydro-
lyzed under aqueous alkaline conditions to yield the carboxylic
acids 12a–f. Further compounds 17a–f and 18a–f were synthesized
by the reaction of 9a–f with the intermediates 13 and 14, respec-
tively, as outlined in Scheme 3, following the same steps as de-
scribed in Scheme 2. Starting material 10, 13 and 14 were
prepared as described in the literature.15,34
feasible approach to enhance PPAR
incorporating chemical modifications in a PPARd selective ligand
rather than modifying PPAR or dual agonist. To verify our
hypothesis, we selected GW-501516,15 a potent PPARd agonist
a and c binding potential by
a, c
with moderate affinity towards PPARa and PPARc (Fig. 2) as initial
chemotype.
In course of our research directed towards the development of
novel PPAR agonists, recent efforts have been incurred to modulate
the subtype selectivity of ligands, results of which demonstrated
that the subtype selectivity of PPAR agonists is sensitive to chem-
ical modifications in the central spacer (tether) region of the mol-
ecules.25–29 Recently it has also been reported that highly potent
PPARa/c dual agonists can be obtained by replacing alkyl ether
ring spacer with a rigid spacers such as alkenyl, alkynyl, indol ring,
oxime–ether etc.30–32 Based on the above results and serendipity
we hypothesized that incorporation of a structurally constrained
oxime–ether linker in place of a flexible thio ether linker of GW-
501516 could provide us with new class of pan agonist (Fig. 2).
In the present communication we report two different series of
oxime–ether based novel compounds (12a–f, 17a–f and 18a–f) as
a new class of PPAR-pan agonists to establish our hypothesis.
2.2. In vitro PPAR transactivation
Thiazole derivatives 12a–f and oxazole derivatives 17a–f and
18a–f were screened for human PPAR (hPPAR) a, c and d agonistic
activities on full length PPAR receptor transfected in HepG2 cells as
described in the experimental section. WY-14643, Rosiglitazone
and GW-501516 were used as positive controls for PPARa, c and
d respectively. The in vitro PPAR subtype agonistic activities are re-
ported as percent maximal activity of each compound compared to
reference compound and normalized to 100% as summarized in
Table 1. Our aim in the present endeavor was to discover a
2. Results and discussion
2.1. Chemistry
Compounds described in this communication were synthesized
according to Schemes 1–3 and the detailed synthetic procedures
O
O
O
O
OH
O
OH
S
F3C
S
N
H
N
Cl
F
Sodelglitazar (2)
Bezafibrate (1)
O
Br
OH
O
N
O
S
O
OH
OEt
O
Br
O
Indeglitazar (3)
4
Figure 1. PPAR-pan agonists.

P. Makadia et al. / Bioorg. Med. Chem. 19 (2011) 771–782
773
N
R1
R2
O
Het
O
S
F3C
N
S
OH
OH
O
O
O
PPARδ agonist GW501516 (5)
Figure 2. Designing aspect of PPAR-pan agonists.
R1
R1
R2
O
i
ii
R2
O
O
R2
O
O
OEt
R1
OH
O
6a-f
7a-f
8a-f
R1
R2
Me
H
Me
H
R1
a
b
c
d
e
f
Me
Me
Et
Et
n-Pr
iii
HO
R2
N
OEt
O
O
Me
9a-f
Cyclohexyl Me
Scheme 1. Reagents and conditions: (i) anhydrous AlCl3, 160 °C, 2 h; (ii) ethyl chloroacetate, K2CO3, DMF, 60 °C, 18 h; (iii) NH2OHꢀHCl, CH3COONa, ethanol, reflux, 1 h.
N
R1
S
Cl
i
O
R2
O
F3C
S
F3C
9a-f
+
N
N
OEt
10
11a-f
O
R1
R2
a
b
c
d
e
f
Me
Me
Et
Et
n-Pr
Me
H
Me
H
Me
Me
N
R1
ii
O
R2
F3C
S
N
OH
O
12a-f
O
Cyclohexyl
Scheme 2. Reagents and conditions: (i) Cs2CO3, DMF, 60 °C, 18 h; (ii) LiOHꢀH2O, THF, methanol, H2O, 25 °C, 18 h.
O
R1
O
i
+
O
R2
O
9a-f
Cl
R3
N
N
N
R3
OEt
13;
14;
R3 = H
15a f;
-
R3 = H
O
R3 = CH3
16a f;
-
R3 = CH3
R1
R2
Me
H
Me
H
Me
O
R1
ii
a
b
c
d
e
f
Me
Me
Et
Et
n-Pr
O
R2
O
R3
N
N
OH
17a f;
-
R3 = H
O
18a f;
-
R3 = CH3
Cyclohexyl Me
Scheme 3. Reagents and conditions: (i) Cs2CO3, DMF, 60 °C, 18 h; (ii) LiOHꢀH2O, THF, methanol, H2O, 25 °C, 18 h.
PPAR-pan agonist with potent anti-hyperglycemic and anti-hyper-
lipidemic activities. We started designing compounds taking
GW-501516 as initial lead. As GW-501516 is a potent PPARd
the activation towards PPARa and PPARc would be an appropriate
strategy. Our initial efforts towards the above said endeavor
started with the introduction of structurally constrained oxime–
ether as a linker in place of thio ether of GW-501516 as repre-
sented in Figure 2. We choose 4-methyl-2-(4-trifluoromethyl)-thi-
agonist and moderately activates PPARa and PPARc, we felt that
chemical modifications in this chemotype in order to improve

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P. Makadia et al. / Bioorg. Med. Chem. 19 (2011) 771–782
Table 1
In vitro PPAR agonistic activity of test compounds (12a–f, 17a–f and 18a–f)
N
O
O
R1
R1
R1
F3C
O
R2
O
O
R2
O
O
R2
O
S
N
N
N
N
N
OH
OH
OH
O
O
O
18a-f
17a-f
12a-f
a,b
Compound
R1
R2
hPPAR transactivation Emax (%)
a
c
d
12a
12b
12c
12d
12e
12f
17a
17b
17c
17d
17e
17f
18a
18b
18c
18d
18e
18f
Methyl
Methyl
Ethyl
Methyl
H
Methyl
H
Methyl
Methyl
Methyl
H
Methyl
H
Methyl
Methyl
Methyl
H
Methyl
H
99.8 5.2
86.2 4.1
96.4 3.6
97.5 5.4
58.7 2.8
57.9 1.9
84.5 5.5
58.8 3.8
56.4 4.5
42.5 1.2
14.1 0.9
9.7 1.5
45.3 1.8
51.1 2.9
72.6 7.3
68.5 6.1
33.3 1.6
14.1 0.8
76.9 7.1
85.3 2.1
58.4 3.7
64.7 3.2
58.5 3.2
43.4 2.4
52.1 2.2
89.5 4.8
67.2 4.6
72.8 6.6
44.7 4.1
31.4 1.7
18.1 0.9
61.2 4.3
45.9 5.5
61.8 6.4
53.3 2.3
32.1 3.1
29.4 1.7
61.1 2.4
90.1 3.5
60.6 3.0
61.9 6.2
41.4 1.4
48.3 3.5
98.7 7.1
74.5 4.4
52.1 1.8
72.3 2.5
46.4 3.8
51.7 5.5
58.8 1.9
67.6 4.3
48.1 1.1
56.3 3.7
49.2 4.5
46.8 2.7
56.6 5.1
Ethyl
n-Propyl
Cyclohexyl
Methyl
Methyl
Ethyl
Ethyl
n-Propyl
Cyclohexyl
Methyl
Methyl
Ethyl
Ethyl
n-Propyl
Cyclohexyl
Methyl
Methyl
GW-501516
100.4 4.3
a
HepG2 cells transfected with pSG5 expression vector containing the cDNA of hPPAR
a or hPPARc or hPPARd and cotransfected with PPRE3-TK-luc. The luciferase activity
determined using fire-fly luciferase assay and b-galactosidase activity determined in ELISA reader (n = 3).
b
Emax of test compounds compared to reference compounds (WY-14643 for
a
, Rosiglitazone for
c
and GW-501516 for d) normalized to 100%. Fold increase of WY-14643,
M concentration.
Rosiglitazone and GW-501516 Vs DMSO is 8.40 0.21 (PPAR ), 13.49 0.38 (PPAR
a
c
) and 28.54 0.77 (PPARd) respectively at 10 l
azole and 4-methyl-2-phenyloxazole moieties as a lipophilic tail
and synthesized compounds 12a–f and 17a–f containing oxime–
ether with different substitutions at R1 (Fig. 2). As anticipated,
compound 12a possessing methyl group as R1 showed significant
hexyl group at R1, showed equipotent affinity to PPARd but
failed to show good affinity towards PPARa and c as compared
to 17a.
To further support the above findings, we then synthesized
compounds 18a–f, wherein 2-phenyl on the oxazole group was
substituted with methyl group at para position. We observed the
similar trend as shown by compounds 12a–f and 17a–f. As ex-
pected, compound 18a which possess methyl group at R1 is supe-
rior to the other compounds of the series. Compound 18c with
ethyl group at R1 exhibited inferior potency than compound 18a.
Removal of methyl group at R2 position in 18a and 18c is found
to be detrimental in terms of PPARd activity as exhibited by 18b
and 18d. Linear elongation of the chain length in 18a to propyl
group resulted in decreased activity as evident from 18e, while
the compound 18f bearing bulkier cyclohexyl group at R1 showed
good PPARd activity.
Based on the above results compounds 12a, 12c, 12f, 17a and
18a were subjected for EC50 (half maximal effective concentration)
determination and the corresponding EC50 values are presented in
Table 2. Among the five compounds subjected for EC50 determina-
tion, compound 12a emerged as highly potent and efficacious
PPAR-pan agonist with balanced EC50 of 0.008 0.002,
improvement in affinity towards PPARa and PPARc as compared
to GW-501516. This compound exhibited high and balanced effi-
cacy towards all the three PPAR subtypes with Emax of 99.8%,
85.3% and 90.1% towards PPARa, c and d respectively. Replacement
of methyl group at R1 in 12a with ethyl found to be detrimental to
PPAR affinity as seen in the compound 12c. Compounds 12b and
12d bearing no substitution at R2 exhibited poor affinity towards
PPARd compared to their methyl substituted counterpart suggest-
ing the role of methyl group at R2 for PPARd activity. We then in-
tended to optimize the substitution at R1. When the chain length
at R1 was further increased to propyl group, compound 12e
showed unfavorable PPAR affinities. To assess the effect of bulkier
group, we synthesized compound 12f with cyclohexyl group as R1.
Compared to compound 12a, compound 12f showed inferior affin-
ity towards PPAR
a and c but interestingly found equipotent to-
wards PPARd. In another series, the compounds 17a–f which
contains oxazole as a lipophilic tail showed similar tendency as thi-
azole compounds 12a–f. Compound 17a possessing methyl group
at R1 found to be equipotent towards all the three PPAR sub type
0.006 0.002 and 0.01 0.003 lM towards PPARa, c and d, respec-
with Emax of 84.5%, 89.5% and 74.5% towards PPAR
a
,
c
and d,
tively. The compound 12f exhibited low in vitro activity, while
compounds 12c, 17a and 18a showed moderate and balanced
activity (EC50) towards all three PPAR subtype. Although EC50 val-
ues of 12c and 18a was found to be comparable to 17a, however,
compounds 12c and 18a showed moderate Emax (Table 1) and
therefore compounds 12a and 17a were selected for subsequent
in vivo evaluation. Thus the above results reveal the crucial role
of various substitutions at R1 and R2, wherein it is evident from
the data that the methyl group at R2 is essential for PPARd activa-
tion. Further the linear elongation of the chain at R1 found detri-
respectively, and emerged as a most potent compound in the oxa-
zole series. Whereas compound 17c having ethyl group at R1
showed good agonistic activity in all the three PPAR subtypes but
was found to be inferior as compared to 17a. Compounds 17b
and 17d where methyl group was removed at R2 showed decrease
in PPARd activity as compared to their respective parent com-
pounds (17a and 17c). Incorporation of n-propyl chain at R1 (com-
pound 17e) resulted in complete loss of activity towards all three
PPAR subtype. Whereas the compound 17f which possesses cyclo-

P. Makadia et al. / Bioorg. Med. Chem. 19 (2011) 771–782
775
Table 2
EC50 values of selected test compounds
a,b
Compound
R1
R2
hPPAR Transactivation EC50
(l
M)
a
c
d
12a
12c
12f
17a
18a
Bezafibrate
GW-501516
Methyl
Ethyl
Cyclohexyl
Methyl
Methyl
Methyl
Methyl
Methyl
Methyl
Methyl
0.008 0.002
0.12 0.01
1.6 0.21
0.5 0.03
0.15 0.01
42.5 2.5
1.1 0.32
0.006 0.002
0.8 0.02
1.0 0.12
0.3 0.05
0.4 0.01
57.2 5.4
0.8 0.008
0.01 0.003
0.8 0.05
0.7 0.09
0.8 0.07
0.3 0.009
18.9 0.9
0.0012 0.0006
a
HepG2 cells transfected with pSG5 expression vector containing the cDNA of hPPAR
a
or hPPAR
c
or hPPARd and cotransfected with
PPRE3-TK-luc. The luciferase activity determined using fire-fly luciferase assay and b-galactosidase activity determined in ELISA reader.
b
EC50 is the concentration of the test compound that affords half-maximum transactivation activity.
Table 3
serum LDL-C level. All together above in vivo results indicate that
compound 12a exhibits good anti-hyperlipidemic activity in ham-
ster and compound 17a showed very good anti-hyperglycemic
activity in db/db mice.
Anti-hyperglycemic activity of the selected compounds (12a and 17a) in db/db micea
Compound
Dose (mpk/day/po)
%Changeb
Serum glucose
Serum TG
12a
17a
Rosiglitazone
Tesaglitazar
10
10
30
3
ꢁ23.2 3.1
ꢁ59.9 5.4
ꢁ41.1 2.5
ꢁ60.2 6.1
ꢁ36.5 2.5
ꢁ52.4 4.7
ꢁ53.8 4.2
ꢁ54.4 5.0
3. Conclusion
A novel series of thaizole and oxazole containing phenoxy acetic
acid derivatives were discovered as PPAR-pan agonists by incorpo-
rating oxime–ether linker in a potent PPARd agonist GW-501516 as
exemplified by compounds 12a and 17a. These compounds
showed potent and balanced PPAR-pan agonistic activity in vitro.
Further compounds 12a and 17a exhibited potent anti-hyperglyce-
mic and anti-hyperlipidemic effects in rodents. Compound 17a re-
duced plasma glucose and triglycerides significantly in db/db mice,
whereas compound 12a significantly improved serum HDL-C level
along with the reduction in serum LDL-C level in hamster. Together,
these finding suggest that compounds possessing oxime–ether lin-
ker between pharmacophore and lipophilic tail exhibit predomi-
nantly PPAR-pan agonism. The above results clearly established
that incorporation of structurally constrain oxime–ether linker be-
tween the pharmacophore and the lipophilic heterocycle improves
a
Male db/db mice dosed orally (po) with test compounds daily for 14 days and
serum glucose, triglycerides (TG) were measured.
b
Values expressed as % change of compound-treated mice vs vehicle control,
indicated as M SD (n = 6), significant at p <0.05.
mental to PPAR activation while the bulkier substitution at this po-
sition is favorable for the PPARd activation.
2.3. In vivo evaluation
Having encouraged with the in vitro PPAR agonistic activity,
compounds 12a and 17a, being the most potent compounds in
their respective series were selected for in vivo studies in db/db
mice and HF–HC–fructose fed hamster for their anti-hyperglycemic
and anti-hyperlipidemic activities. In male db/db mice, compounds
12a and 17a were dosed orally (po) at 10 mpk/day dose for
14 days. As described in Table 3, both the test compounds 12a
and 17a showed significant reduction in serum glucose and triglyc-
eride (TG), however serum glucose and TG reduction with com-
pound 17a were found to be comparable with Rosiglitazone and
Tesaglitazar. Furthermore, anti-hyperlipidemic activities of com-
pounds 12a and 17a were evaluated in Female hamsters at
10 mpk/day/po dose, for 14 days. As demonstrated in Figure 3,
compound 12a showed statistically significant increase in serum
HDL-C level whereas compound 17a showed improvement in ser-
um HDL-C level but found inferior to compound 12a. Additionally
both the compounds 12a and 17a showed significant reduction in
affinity towards PPARa and PPARc in a selective PPARd agonist.
Further research to optimize this series to develop compounds
with potent anti-hyperglycemic and anti-hyperlipidemic activity
with desired ADME and toxicity profiles is in progress and will
be communicated subsequently.
4. Experimental section
4.1. In vitro PPAR agonistic activity (transactivation assay)
4.1.1. Cell culture
HepG2 cells (ATCC, USA) were maintained in growth medium
composed of MEM (Sigma) supplemented with 10% FBS (Hyclone),
90
Vehicle
140
120
12a
17a
80
70
60
50
Vehicle
100
12a
17a
80
Day 0
Day 7
Day 14
Day 0
Day 7
Day 14
Figure 3. Anti-hyperlipidemic activity of the selected compounds (12a and 17a) in hamster.

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P. Makadia et al. / Bioorg. Med. Chem. 19 (2011) 771–782
1 ꢂ MEM non essential amino acid (Sigma) and 1 mM sodium
14 days. Fasted blood samples were collected from each animal
on day 7 and 14, after 1 h of dose administration and separated ser-
um samples were subjected for the estimation of high density lipo-
protein (HDL) and low density lipoprotein (LDL).
pyruvate and 1% penicillin/streptomycin (Sigma).
4.1.2. Transient transfection
HepG2 cells were seeded in 24 well plates at a density of
400,000 cells/well in 1 mL of medium per well. Cells were transfec-
ted using the transfection reagent superfect (Qiagen). Cells were
4.3. Synthesis
transfected with 0.08
lg of the pSG5 expression vector containing
4.3.1. Synthetic materials and methods
the cDNA of PPAR or PPAR
a
c
or PPARd and co-transfected with
Reagents and solvents were obtained from commercial suppli-
ers and used without further purification. Flash chromatography
was performed using commercial silica gel (230–400 mesh). Melt-
ing points were determined on a capillary melting point apparatus
and are uncorrected. IR spectra were recorded on a Shimadzu FT IR
8300 spectrophotometer (mmax in cmꢁ1, using KBr pellets for solid
compounds or neat for liquid compounds). The 1H NMR spectra
were recorded on a Bruker Avance-300 spectrometer (300 MHz)
and Bruker Avance-400 spectrometer (400 MHz). The chemical
shifts (d) are reported in parts per million (ppm) relative to TMS,
either in CDCl3 or DMSO-d6 solvent. Signal multiplicities are repre-
sented by s (singlet), d (doublet), dd (doublet of doublet), t (triplet),
q (quartet), br s (broad singlet), and m (multiplet). 13CNMR spectra
were recorded on Bruker Avance-400 at 100 MHz either in CDCl3 or
DMSO-d6 solution. Mass spectra (ESI-MS) were obtained on Shima-
dzu LC-MS 2010-A spectrometer. HPLC analysis were carried out at
PPRE3-TK-luc. Cells were incubated at 37 °C, 5% CO2 for 3 h. After
this, 1.0 mL of the medium containing the respective ligands to
the respective wells were added. The cells were then incubated
at 37 °C, 5% CO2 for 20–22 h. After the incubation period, cells were
first washed with PBS, lysed and the supernatant was collected.
Supernatant was then assayed for luciferase and b-galactosidase
activity. The luciferase activity was determined using commercial
fire-fly luciferase assay according to the suppliers’s [Promega]
instructions in white 96-well plate [Nunc]. b-Galactosidase activity
was determined in ELISA reader at 415 nm. The ratio of luciferase
versus b-galactosidase was calculated and fold induction was cal-
culated with respect to DMSO. Percent of maximal efficacy (Emax
of all compounds was calculated comparing to reference com-
pounds (WY-14643 for , Rosiglitazone for and GW-501516 for
)
a
c
d) normalized to 100%. Fold inductions of the standard compounds
were also calculated with respect to DMSO. EC50 values for the test
compounds were calculated by nonlinear regression analysis using
graph pad prism software. Each concentration point represents
values in triplicates.
kmax 220 nm using column ODS C-18, 150 nm ꢂ 4.6 nm ꢂ 4
l on
AGILENT 1100 series.
4.3.2. 40-Hydroxy-30-methylacetophenone (7a)
Anhydrous AlCl3 (22.2 g, 0.166 mol) was added in small por-
tions to O-acetyl-2-methylphenol 6a (25 gm, 0.166 mol) at 25 °C
and reaction temperature was slowly raised to 160 °C and stirred
at the same temperature for 2 h. The reaction mixture was poured
in ice cold 6 N HCl (500 ml) and extracted with ethyl acetate
(200 ml ꢂ 3). The organic extract was washed with water and
brine, dried over Na2SO4 and evaporated under reduced pressure
to yield 20 g crude product as thick oil. The crude product was
purified by column chromatography (10% ethyl acetate in hexane)
to give title compound 7a as yellow solid (7.0 g); yield: 28%; mp:
99–100 °C; purity by HPLC: 99.5%; IR (KBr): 3130, 2925, 1651,
4.2. In vivo anti-hyperglycemic and anti-hyperlipidemic studies
(mice and hamster)
All animals were used from inbred colony which is maintained
on standard laboratory rodent chow ad libitum and the study pro-
tocols were approved by institutional animal ethics committee.
4.2.1. db/db mice experiments
Male db/db mice of 12–14 weeks age and 30–40 g body weight
were selected for the study. The animals were weighed, tail-bled
prior to the start of study and serum/plasma was analyzed for glu-
cose (PG) and triglyceride (TG) levels. The animals were arranged
into an appropriate number of groups with each group having six
animals of the same mean PG, TG and TC levels prior to dosing.
All the animals were orally dosed once daily either with vehicle
(0.5% methylcellulose in water) or test compounds for 14 days
and were fed ad libitum throughout the study. Approximately
1 h after the last dose, animals were tail-bled and serum/plasma
was analyzed for glucose (PG) and triglyceride (TG) levels to calcu-
late percent change due to drug treatment (this takes into account
any changes that may have occurred in the vehicle-treated animals
during the study).
1589, 1514, 1182 cmꢁ1 1H NMR (CDCl3, 300 MHz): d 2.29 (s,
;
3H), 2.56 (s, 3H), 5.92 (s, OH), 6.80 (d, J = 8.3 Hz, 1H), 7.74 (dd,
J = 8.3 and 1.9 Hz, 1H), 7.79 (s, 1H); ESI/MS m/z: 150.7 (M+H)+.
4.3.3. 40-Hydroxyacetophenone (7b)
This compound was prepared from 6b by means of a procedure
similar to that reported for 7a. Off white solid; yield: 40%; mp:
109–110 °C; purity by HPLC: 97.8%; IR (KBr): 3309, 2968, 2424,
1662, 1602, 1577, 1357, 1278, 1219, 1165, 1107, 962, 848, 633,
567 cmꢁ1 1H NMR (CDCl3, 400 MHz): d 2.57 (s, 3H), 6.89 (d,
;
J = 8.8 Hz, 2H), 7.90 (d, J = 8.8 Hz, 2H); ESI/MS m/z: 137.2 (M+H)+.
4.3.4. 1-(4-Hydroxy-3-methylphenyl)propan-1-one (7c)
4.2.2. Hamster experiments
This compound was prepared from 6c by means of a procedure
similar to that reported for 7a. Off white solid; yield: 58%; mp:
130–131 °C; purity by HPLC: 95.3%; IR (KBr): 3365, 2980, 1664,
1593, 1514, 1465, 1352, 1257, 1170, 1132, 1082, 976, 910, 800,
Female hamster of 8–12 weeks age (80–150 g body weight)
were taken for study. Six animals whose average body weight
was not significantly different from the rest of the animals were se-
lected for normal NIN diet. Other animals were put on HF–HC–su-
crose (High fat, high cholesterol and sucrose) diet for 14 days. On
day 14 all the HF–HC–sucrose diet fed animals were selected
which had gained their body weight significantly more than the
normal diet group animals. The selected animals were divided into
different groups in such a way that the average bodyweight of the
animals in each group was not significantly different from the
other groups. All the animals were orally dosed once daily either
with vehicle (0.5% polyethylene glycol in water) or test compounds
(10 mpk, dissolved in 0.5% polyethylene glycol in water) for
675 cmꢁ1 1H NMR (CDCl3, 400 MHz): d 1.20 (t, J = 7.4 Hz, 3H),
;
2.29 (s, 3H), 2.95 (q, J = 7.2 Hz, 2H), 6.86 (d, J = 8.4 Hz, 1H), 7.73
(dd, J = 8.4 and 2.4 Hz, 1H), 7.80 (d, J = 1.2 Hz, 1H); ESI/MS m/z:
165.3 (M+H)+.
4.3.5. 1-(4-Hydroxyphenyl)propan-1-one (7d)
This compound was prepared from 6d by means of a procedure
similar to that reported for 7a. Off white solid; yield: 52%; mp:
147–148 °C; purity by HPLC: 97.4%; IR (KBr): 3217, 2974, 2939,
2808, 1662, 1606, 1572, 1514, 1450, 1357, 1288, 1172, 1112,

P. Makadia et al. / Bioorg. Med. Chem. 19 (2011) 771–782
777
1016, 952, 858, 802 cmꢁ1
;
1H NMR (CDCl3, 400 MHz): d 1.22 (t,
4.3.12. Ethyl 2-(4-butyryl-2-methylphenoxy)acetate (8e)
J = 7.2 Hz, 3H), 2.95 (q, J = 7.2 Hz, 2H), 6.86–6.90 (m, 2H), 7.90–
This compound was prepared from 7e by means of a procedure
similar to that reported for 8a. Off white solid; yield: 98%; mp 70–
71 °C; purity by HPLC: 99.1%; IR (KBr): 3411, 3035, 2873, 1755,
1600, 1500, 1328, 1109 cmꢁ1; 1H NMR (300 MHz, CDCl3): d 0.99 (t,
J = 7.4 Hz, 3H), 1.30 (t, J = 7.1 Hz, 3H), 1.66–1.78 (m, 2H), 2.32 (s,
3H), 2.88 (t, J = 7.3 Hz, 2H), 4.27 (q, J = 7.1 Hz, 2H), 4.70 (s, 2H),
6.70 (d, J = 8.3 Hz, 1H), 7.72–7.79 (m, 2H); ESI/MS m/z: 264.9(M+H)+.
7.93 (m, 2H); ESI/MS m/z: 151.8 (M+H)+.
4.3.6. 1-(4-Hydroxy-3-methylphenyl)butan-1-one (7e)
This compound was prepared from 6e by means of a procedure
similar to that reported for 7a. Yellow solid; yield: 27%; mp: 129–
130 °C; purity by HPLC: 99.6%; IR (KBr): 3269, 3190, 2727, 2414,
1656, 1512, 1407, 1130 cmꢁ1 1H NMR (CDCl3, 300 MHz): d 0.99
;
4.3.13. Ethyl 2-(4-(cyclohexanecarbonyl)-2-methylphenoxy)-
acetate (8f)
(t, J = 7.4 Hz, 3H), 1.66–1.81 (m, 2H), 2.29 (s, 3H), 2.89 (t,
J = 7.3 Hz, 2H), 5.78 (s, OH), 6.81 (d, J = 8.3 Hz, 1H), 7.72–7.79 (m,
2H); ESI/MS m/z: 178.7 (M+H)+.
This compound was prepared from 7f by means of a procedure
similar to that reported for 8a. Thick liquid; yield: 97%; purity by
HPLC: 98.9%; IR: 3425, 2935, 1911, 1757, 1658, 1496, 1247,
4.3.7. Cyclohexyl(4-hydroxy-3-methylphenyl)methanone (7f)
This compound was prepared from 6f by means of a procedure
similar to that reported for 7a. Off white solid; yield: 26%; mp:
144–146 °C; purity by HPLC: 98.7%; IR: 3348, 2858, 1899, 1652,
1589, 1512, 1456, 1269, 914, 827 cmꢁ1; 1H NMR (300 MHz, CDCl3):
d 1.21–1.63 (m, 5H), 1.72–1.74 (m, 1H), 1.80–1.91 (m, 4H), 2.30 (s,
3H), 3.11–3.31 (m, 1H), 6.82 (d, J = 8.3 Hz, 1H), 7.71–7.80 (m, 2H);
ESI/MS m/z: 240.9 (M+Na)+.
1004, 916, 756 cmꢁ1 1H NMR (300 MHz, CDCl3): d 1.21–1.49 (m,
;
8H), 1.71–1.72 (m, 1H), 1.82–1.84 (m, 4H), 2.33 (s, 3H), 3.11–
3.26 (m, 1H), 4.25 (q, J = 7.1 Hz, 2H), 4.71 (s, 2H), 6.69 (d,
J = 9.1 Hz, 1H), 7.74–7.80 (m, 2H); ESI/MS m/z: 304.9 (M+H)+.
4.3.14. (E)-Ethyl 2-(4-(1-(hydroxyimino)ethyl)-2-methylphen-
oxy)acetate (9a)
To a solution of 8a (15 g, 0.064 mol) in ethanol (100 mL), a solu-
tion of hydroxylammonium chloride (8.82 g, 0.127 mol) and sodium
acetate (10.42 g, 0.127 mol) in water (30 ml) was added and the
reaction mixture was heated to reflux for a period of about 1 h.
Reaction mixture was cooled and diluted with water. Solid sepa-
rated was filtered and dried under vacuum to yield 22.7 g of product
as white solid. Yield: 71%; mp 105–107 °C; purity by HPLC: 98.3%;
IR: 3217, 3082, 2981, 2910, 1762, 1604, 1508, 1434, 1415, 1384,
1305, 1278, 1259, 1213, 1168, 1153, 1097, 1074, 945, 889, 813,
4.3.8. Ethyl 2-(4-acetyl-2-methylphenoxy)acetate (8a)
To an ice cold solution of 7a (20 g, 0.133 mol) in DMF (100 ml),
K2CO3 (36.8 g, 0.266 mol) and ethyl chloroacetate (15.9 g,
0.150 mol) was added and reaction mixture was stirred at 60 °C
for 18 h. The reaction mixture was poured in ice cold water
(700 ml) and extracted with ethyl acetate (200 ml ꢂ 3). The organ-
ic extract was washed with water and brine, dried over Na2SO4 and
evaporated under reduced pressure to yield 23.8 g product as thick
oil. Yield: 98%; purity by HPLC: 95.2%; IR: 3435, 3338, 2983, 2929,
1757, 1676, 1600, 1585, 1502, 1440, 1415, 1382, 1359, 1269, 1205,
748 cmꢁ1
2.25 (s, 3H), 2.31 (s, 3H), 4.22 (q, J = 7.1 Hz, 2H), 4.65 (s, 2H), 6.73
(d, J = 8.5 Hz, 1H), 7.37 (dd, J = 8.5 and 2.0 Hz, 1H), 7.45 (s, 1H); 13
;
1H NMR (300 MHz, CDCl3): d 1.32 (t, J = 7.1 Hz, 3H),
C
1182, 1136, 1091, 1068, 1026, 970, 813 cmꢁ1 1H NMR (300 MHz,
;
CDCl3): d 1.32 (t, J = 7.1 Hz, 3H), 2.32 (s, 3H), 2.54 (s, 3H), 4.21 (q,
J = 7.1 Hz, 2H), 4.73 (s, 2H), 6.70 (d, J = 8.2 Hz, 1H), 7.70–7.71 (m,
2H); ESI/MS m/z: 236.8 (M+H)+.
NMR (100 MHz, DMSO-d6): d 11.46, 14.04, 16.14, 60.65, 64.90,
111.13, 124.33, 125.86, 127.85, 129.84, 152.42, 156.23, 168.75;
ESI/MS m/z: 251.9 (M+H)+.
4.3.15. (E)-Ethyl 2-(4-(1-(hydroxyimino)ethyl)phenoxy)acetate
(9b)
4.3.9. Ethyl 2-(4-acetylphenoxy)acetate (8b)
This compound was prepared from 7b by means of a procedure
similar to that reported for 8a. Thick oil; yield: 95%; purity by
HPLC: 92.5%; IR: 3020, 2985, 1755, 1676, 1600, 1508, 1359, 1273,
This compound was prepared from 8b by means of a procedure
similar to that reported for 9a. Off white solid; yield: 81%; mp 91–
92 °C; purity by HPLC: 98.1%; IR: 3300, 2908, 1761, 1600, 1514,
1172, 1085, 1022, 958, 592 cmꢁ1 1H NMR (400 MHz, CDCl3): d
;
1483, 1373, 1259, 1209, 1176, 1076, 1006, 927, 829, 765, 601 cm
ꢁ1
;
1H NMR (400 MHz, CDCl3): d 1.28 (t, J = 7.2 Hz, 3H), 2.26 (s,
1.29 (t, J = 7.2 Hz, 3H), 2.56 (s, 3H), 4.26 (q, J = 7.2 Hz, 2H), 4.69
(s, 2H), 6.92–6.96 (m, 2H), 7.78–7.80 (m, 2H); ESI/MS m/z: 223.3
(M+H)+.
3H), 4.25 (q, J = 7.2 Hz, 2H), 4.64 (s, 2H), 6.90 (d, J = 8.8 Hz, 2H),
7.57 (d, J = 8.8 Hz, 2H); 13C NMR (100 MHz, DMSO-d6): d 11.47,
14.05, 60.70, 64.65, 114.35, 126.86, 130.18, 152.34, 158.00,
168.65; ESI/MS m/z: 238.3 (M+H)+.
4.3.10. Ethyl 2-(2-methyl-4-propionylphenoxy)acetate (8c)
This compound was prepared from 7c by means of a procedure
similar to that reported for 8a. Off white solid; yield: 90%; mp 55–
57 °C; purity by HPLC: 98.0%; IR: 2976, 1755, 1670, 1600, 1498,
4.3.16. (E)-Ethyl 2-(4-(1-(hydroxyimino)propyl)-2-methylphen-
oxy)acetate (9c)
This compound was prepared from 8c by means of a procedure
similar to that reported for 9a. Off white solid; yield: 88%; mp 84–
86 °C; purity by HPLC: 98.7%; IR (KBr): 3277, 2987, 2928, 1753,
1604, 1508, 1437, 1346, 1284, 1205, 1184, 1139, 1072, 1022,
1450, 1381, 1280, 1209, 1145, 1072, 798, 626 cmꢁ1 1H NMR
;
(400 MHz, CDCl3): d 1.19 (t, J = 7.4 Hz, 3H), 1.28 (t, J = 7.2 Hz, 3H),
2.32 (s, 3H), 2.92 (q, J = 7.2 Hz, 2H), 4.24 (q, J = 7.2 Hz, 2H), 4.71
(s, 2H), 6.70 (d, J = 8.0 Hz, 1H), 7.78–7.80 (m, 2H); ESI/MS m/z:
251.3 (M+H)+.
; d 1.14 (t,
956, 856, 754 cmꢁ1 1H NMR (400 MHz, CDCl3):
J = 7.6 Hz, 3H), 1.28 (t, J = 7.2 Hz, 3H), 2.31 (s, 3H), 2.75 (q,
J = 7.6 Hz, 2H), 4.24 (q, J = 7.2 Hz, 2H), 4.66 (s, 2H), 6.68 (d,
J = 8.4 Hz, 1H), 7.37 (dd, J = 8.4 and 2.0 Hz, 1H), 7.44 (s, 1H); 13C
NMR (100 MHz, DMSO-d6): d 8.33, 14.03, 16.02, 30.84, 60.79,
64.90, 110.97, 126.17, 127.80, 129.77, 130.43, 159.51, 168.41,
199.04; ESI/MS m/z: 266.3 (M+H)+.
4.3.11. Ethyl 2-(4-propionylphenoxy)acetate (8d)
This compound was prepared from 7d by means of a procedure
similar to that reported for 8a. Thick liquid; yield: 95%; purity by
HPLC: 93.3%; IR: 3350, 3020, 2983, 2939, 1757, 1679, 1602, 1508,
1417, 1380, 1353, 1301, 1215, 1172, 1080, 1018, 842, 758,
669 cmꢁ1 1H NMR (300 MHz, CDCl3): d 1.21 (t, J = 7.2 Hz, 3H),
;
4.3.17. (E)-Ethyl 2-(4-(1-(hydroxyimino)propyl)phenoxy)acetate
(9d)
This compound was prepared from 8d by means of a procedure
similar to that reported for 9a. White solid; yield: 86%; mp 70–
1.30 (t, J = 7.1 Hz, 3H), 2.91 (q, J = 7.2 Hz, 2H), 4.32 (q, J = 7.1 Hz,
2H), 4.68 (s, 2H), 6.89 (dd, J = 1.9 and 6.9 Hz, 2H), 7.92 (dd, J = 1.9
and 6.9 Hz, 2H).; ESI/MS m/z: 236.9 (M+H)+.

778
P. Makadia et al. / Bioorg. Med. Chem. 19 (2011) 771–782
72 °C; purity by HPLC: 84.6%; IR (KBr): 3355, 2981, 2941, 2877,
4.3.22. (E)-Ethyl 2-(2-methyl-4-(1-(((4-methyl-2-(4-(trifluoro-
methyl)phenyl)thiazol-5-yl)methoxy)imino)propyl)phenoxy)-
acetate (11c)
1705, 1624, 1600, 1514, 1467, 1514, 1448, 1406, 1367, 1313,
1240, 1178, 1116, 1066, 1029, 970, 916, 825 cmꢁ1 1H NMR
;
(300 MHz, CDCl3): d 1.16 (t, J = 7.5 Hz, 3H), 1.32 (t, J = 7.1 Hz, 3H),
2.82 (q, J = 7.6 Hz, 2H), 4.33 (q, J = 7.1 Hz, 2H), 4.64 (s, 2H), 6.92
(dd, J = 6.9 and 1.9 Hz, 2H), 7.54 (dd, J = 6.9 and 1.9 Hz, 2H); 13C
NMR (100 MHz, DMSO-d6): d 10.95, 14.05, 18.28, 60.71, 64.66,
114.47, 127.03, 128.99, 157.18, 157.99, 168.17; ESI/MS m/z:
252.0 (M+H)+.
This compound was prepared from 10 and 9c by means of a pro-
cedure similar to that reported for 10a. Off white solid; yield: 67%;
mp 105–107 °C; purity by HPLC: 98.3%; IR (KBr): 2982, 2935, 1741,
1618, 1508, 1452, 1381, 1321, 1213, 1124, 1066, 1001, 962, 916,
839 cmꢁ1 1H NMR (400 MHz, CDCl3): d 1.08 (t, J = 7.6 Hz, 3H),
;
1.25 (t, J = 7.2 Hz, 3H), 2.31 (s, 3H), 2.55 (s, 3H), 2.68 (q,
J = 7.6 Hz, 2H), 4.24 (q, J = 7.2 Hz, 2H), 4.66 (s, 2H), 5.32 (s, 2H),
6.68 (d, J = 8.4 Hz, 1H), 7.40 (dd, J = 8.4 and 2.0 Hz, 1H), 7.49 (d,
J = 1.6 Hz, 1H), 7.66 (d, J = 8.4 Hz, 2H), 8.01 (d, J = 8.0 Hz, 2H); ESI/
MS m/z: 521.1 (M+H)+.
4.3.18. (E)-Ethyl 2-(4-(1-(hydroxyimino)butyl)-2-methylphen-
oxy)acetate (9e)
This compound was prepared from 8e by means of a procedure
similar to that reported for 9a. Off white solid; yield: 92%; mp 71–
72 °C; purity by HPLC: 97.7%; IR (KBr): 3369, 3033, 2873, 1701,
4.3.23. (E)-Ethyl 2-(4-(1-(((4-methyl-2-(4-(trifluoromethyl)-
phenyl)thiazol-5-yl)methoxy)imino)propyl)phenoxy)acetate
(11d)
1606, 1508, 1026 cmꢁ1 1H NMR (300 MHz, CDCl3): d 0.97 (t,
;
J = 7.4 Hz, 3H), 1.30 (t, J = 7.1 Hz, 3H), 1.51–1.64 (m, 2H), 2.30 (s,
3H), 2.74 (t, J = 7.62 Hz, 2H), 4.27 (q, J = 15.5 & 7.14 Hz, 2H), 4.65
(s, 2H), 6.70 (d, J = 8.52 Hz, 1H), 7.37 (dd, J = 8.5 & 2.5 Hz, 1H),
7.43 (s, 1H); 13C NMR (100 MHz, DMSO-d6): d 14.02, 16.14,
19.51, 26.69, 60.64, 64.88, 111.15, 124.54, 125.93, 128.06, 128.98,
156.16, 168.75; ESI/MS m/z: 279.9 (M+H)+.
This compound was prepared from 10 and 9d by means of a
procedure similar to that reported for 10a. Pale yellow solid; yield:
66%; mp 75–77 °C; purity by HPLC: 98.7%; IR (KBr): 2985, 2966,
2937, 1741, 1612, 1569, 1542, 1512, 1467, 1454, 1406, 1380,
1350, 1321, 1271, 1240, 1211, 1174, 1120, 1066, 1033, 997, 964,
950, 891, 858, 840, 675 cmꢁ1 1H NMR (300 MHz, CDCl3): d 1.12
;
4.3.19. (E)-Ethyl 2-(4-(cyclohexyl(hydroxyimino)methyl)-2-
methylphenoxy)acetate (9f)
(t, J = 7.5 Hz, 3H), 1.31 (t, J = 7.1 Hz, 3H), 2.54 (s, 3H), 2.71 (q,
J = 7.6 Hz, 2H), 4.32 (q, J = 7.1 Hz, 2H), 4.64 (s, 2H), 5.31 (s, 2H),
6.92 (d, J = 8.9 Hz, 2H), 7.59–7.67 (m, 4H), 7.50 (d, J = 8.2 Hz, 2H);
ESI/MS m/z: 507.0 (M+H)+.
This compound was prepared from 8f by means of a procedure
similar to that reported for 9a. Off white solid; yield: 66%; mp 100–
103 °C; purity by HPLC: 85.2%; IR: 3247, 3074, 2929, 1768, 1608,
1506, 1215, 1174, 956, 806 cmꢁ1
;
1H NMR (300 MHz, CDCl3): d
4.3.24. (E)-Ethyl 2-(2-methyl-4-(1-(((4-methyl-2-(4-(trifluoro-
methyl)phenyl)thiazol-5-yl)methoxy)imino)butyl)phenoxy)-
acetate (11e)
1.12–1.32 (m, 9H), 1.62–1.64 (m, 1H), 1.70–1.83 (m, 4H), 2.31 (s,
3H), 4.2 (q, J = 7.1 Hz, 2H), 4.62 (s, 2H), 6.71 (d, J = 8.1 Hz, 1H),
7.01–7.06 (m, 2H); 13C NMR (100 MHz, DMSO-d6): d 14.03, 16.02,
25.75, 25.84, 30.67, 43.26, 60.63, 64.82, 110.69, 125.26, 126.41,
127.27, 130.15, 155.23, 159.15, 168.82; ESI/MS m/z: 320.0 (M+H)+.
This compound was prepared from 10 and 9e by means of a
procedure similar to that reported for 10a. Off white solid; yield:
55%; mp 90–92 °C; purity by HPLC: 95.0%; IR (KBr): 2968, 2872,
1774, 1726, 1616, 1508, 1438, 1327, 1199, 1166, 1122, 1068,
4.3.20. (E)-(2-Methyl-4-{1-[4-methyl-2-(4-trifluoromethyl-
phenyl)-thiazol-5-ylmethoxyimino]-ethyl}-phenoxy)-acetic
acid ethyl ester (11a)
1014, 964, 842 cmꢁ1 1H NMR (400 MHz, CDCl3): d 0.91 (t,
;
J = 7.4 Hz, 3H), 1.26 (t, J = 7.2 Hz, 3H), 1.50–1.52 (m, 2H), 2.31 (s,
3H), 2.54 (s, 3H), 2.66 (t, J = 7.6 Hz, 2H), 4.24 (q, J = 7.2 Hz, 2H),
4.65 (s, 2H), 5.31 (s, 2H), 6.67 (d, J = 8.8 Hz, 1H), 7.34 (dd, J = 8.6
and 2.2 Hz, 1H), 7.48 (d, J = 1.2 Hz, 1H), 7.65 (d, J = 8.4 Hz, 2H),
8.02 (d, J = 8.4 Hz, 2H); ESI/MS m/z: 535.7 (M+H)+.
To
a solution of 10 (1.5 g, 5.14 mmol) and 9a (1.29 g,
5.14 mmol) in dry DMF (10 mL), Cs2CO3 (2.51 g, 7.71 mmol) was
added and reaction mixture was stirred at 60 °C for 18 h. Reaction
mixture was poured into ice cold water (100 mL) and extracted
with ethyl acetate (3 ꢂ 40 mL). The organic extract was washed
with water and brine, dried over Na2SO4 and evaporated under re-
duced pressure. The crude product was purified by column chro-
matography (8% ethyl acetate in hexane) to give title compound
11a as white solid. (1.72 g) yield: 66%; mp 112–114 °C; purity by
HPLC: 98.9%; IR: 3433, 2989, 2935, 1764, 1726, 1616, 1500,
1508, 1452, 1325, 1271, 1240, 1172, 1149, 1114, 1068, 1031,
4.3.25. (E)-ethyl 2-(4-(cyclohexyl(((4-methyl-2-(4-(trifluoro-
methyl)phenyl)thiazol-5-yl)methoxy)imino)methyl)phenoxy)-
acetate (11f)
This compound was prepared from 10 and 9f by means of a pro-
cedure similar to that reported for 10a. Thick liquid; yield: 31%;
purity by HPLC: 95.5%; IR: 3435, 2929, 2854, 1739, 1502, 1450,
1325, 1128, 1066, 904, 675, 605 cmꢁ1 1H NMR (300 MHz, CDCl3):
;
1001, 964, 918, 848, 810 cmꢁ1
;
1H NMR (300 MHz, CDCl3): d 1.30
d 1.26–1.31 (m, 9H), 1.67–1.79 (m, 4H), 2.28 (s, 3H), 2.46 (s, 4H),
4.26 (q, J = 7.1 Hz, 2H), 4.63 (s, 2H), 5.13 (s, 2H), 6.66 (d,
J = 8.1 Hz, 1H), 6.99–7.02 (m, 2H), 7.67 (d, J = 8.2 Hz, 2H), 8.02 (d,
J = 8.1 Hz, 2H); ESI/MS m/z: 575.1 (M+H)+.
(t, J = 7.1 Hz, 3H), 2.24 (s, 3H), 2.31 (s, 3H), 2.54 (s, 3H), 4.27 (q,
J = 7.1 Hz, 2H), 4.65 (s, 2H), 5.32 (s, 2H), 6.70 (d, J = 8.5 Hz, 1H),
7.41–7.44 (m, 1H), 7.44 (s, 1H), 7.65 (d, J = 8.2 Hz, 2H), 8.01 (d,
J = 8.1 Hz, 2H); ESI/MS m/z: 507.1 (M+H)+.
4.3.26. (E)-(2-Methyl-4-{1-[4-methyl-2-(4-trifluoromethyl-
phenyl)-thiazol-5-ylmethoxyimino]-ethyl}-phenoxy)-acetic
acid (12a)
4.3.21. (E)-Ethyl 2-(4-(1-(((4-methyl-2-(4-(trifluoromethyl)-
phenyl)thiazol-5-yl)methoxy)imino)ethyl)phenoxy)acetate (11b)
This compound was prepared from 10 and 9b by means of a
procedure similar to that reported for 10a. Off white solid; yield:
72%; mp 100–102 °C; purity by HPLC: 99.1%; IR (KBr): 3387,
2937, 2854, 1728, 1612, 1514, 1406, 1323, 1236, 1172, 1111,
To a solution of 11a (500 mg, 0.99 mmol) in a mixture of tetra-
hydrofuran (9 mL) and methanol (3 mL) was added another solu-
tion of LiOHꢀH2O (83 mg, 1.97 mmol) in water (3 mL) and the
reaction mixture was stirred at ambient temperature for about
18 h. Solvent was evaporated under reduced pressure, water
(50 ml) was added to the residue, acidified with 1 N HCl to pH 6
and extracted with ethyl acetate (20 ml ꢂ 3). The combined organ-
ic extract was washed with water and brine solution, dried over so-
dium sulfate and evaporated under reduced pressure to yield title
1068, 1001, 898, 829 cmꢁ1 1H NMR (400 MHz, CDCl3): d 1.28 (t,
;
J = 7.2 Hz, 3H), 2.21 (s, 3H), 2.55 (s, 3H), 4.25 (q, J = 7.0 Hz, 2H),
4.64 (s, 2H), 5.33 (s, 2H), 6.89 (d, J = 8.8 Hz, 2H), 7.60–7.64 (m,
2H), 7.65 (d, J = 8.0 Hz, 2H), 8.01 (d, J = 8.0 Hz, 2H); ESI/MS m/z:
493.1 (M+H)+.

P. Makadia et al. / Bioorg. Med. Chem. 19 (2011) 771–782
779
product as off white solid (435 mg). Yield: 92%; mp 158–160 °C;
purity by HPLC: 99.8%; IR (KBr): 3435, 2925, 1718, 1618, 1508,
1450, 1406, 1355, 1325, 1274, 1226, 1174, 1114, 1068, 1010,
DMSO-d6): d 13.89, 15.12,19.66, 27.48, 65.11, 66.47, 111.10,
125.08, 125.98, 126.13, 126.53, 126.99, 128.26, 129.94, 136.52,
151.78, 157.14, 158.68, 163.28, 170.26; ESI/MS m/z: 507.6 (M+H)+.
968, 920, 844, 819, 800 cmꢁ1 1H NMR (300 MHz, DMSO-d6): d
;
1.89 (s, 3H), 1.96 (s, 3H), 2.46 (s, 3H), 4.66 (s, 2H), 5.33 (s, 2H),
6.80 (d, J = 8.6 Hz, 1H), 7.41 (d, J = 8.5 Hz, 1H), 7.47 (s, 1H), 7.8 (d,
J = 8.3 Hz, 2H), 8.0 (d, J = 8.1 Hz, 2H); 13C NMR (100 MHz, DMSO-
d6): d 12.40, 15.14, 16.18, 64.85, 66.49, 111.06, 124.88, 125.92,
126.13, 126.17, 126.55, 127.98, 128.12, 129.87, 136.52, 151.86,
154.94, 157.06, 163.34, 170.20; ESI/MS m/z: 479.0 (M+H)+.
4.3.31. (E)-2-(4-(Cyclohexyl(((4-methyl-2-(4-(trifluoromethyl)-
phenyl)thiazol-5-yl)methoxy)imino)methyl)phenoxy)acetic
acid (12f)
This compound was prepared from 11f by means of a procedure
similar to that reported for 12a. Off white solid; yield: 63%; mp 52–
55 °C; purity by HPLC: 97.2%; IR (KBr): 3435, 2929, 2854, 1739,
1502, 1450, 1325, 1128, 1066, 904, 675, 605 cmꢁ1 1H NMR
;
4.3.27. (E)-2-(4-(1-(((4-methyl-2-(4-(trifluoromethyl)phenyl)-
thiazol-5-yl)methoxy)imino)ethyl)phenoxy)acetic acid (12b)
This compound was prepared from 11b by means of a proce-
dure similar to that reported for 12a. Off white solid; yield: 89%;
mp 150–152 °C; purity by HPLC: 99.3%; IR (KBr): 2926, 2856,
1701, 1612, 1510, 1437, 1327, 1230, 1111, 1068, 999, 900,
(300 MHz, CDCl3): d 1.25–1.29 (m, 6H), 1.71–1.73 (m, 4H), 2.22
(s, 3H), 2.47–2.48 (m, 4H), 4.57 (s, 2H), 5.10 (s, 2H), 6.67 (d,
J = 8.3 Hz, 1H), 6.97 (s, 2H), 7.65 (d, J = 8.3 Hz, 2H), 7.98 (d,
J = 8.0 Hz, 2H); 13C NMR (100 MHz, CDCl3): d 15.34, 16.40, 26.18,
29.64, 44.48, 65.84, 110.98, 125.98, 126.02, 126.38, 126.68,
126.98, 127.40, 129.94, 130.44, 136.81, 151.95, 155.93, 163.19,
164.76; ESI/MS m/z: 547.1 (M+H)+.
825 cmꢁ1 1H NMR (400 MHz, DMSO-d6): d 2.16 (s, 3H), 2.49 (s,
;
3H), 4.65 (s, 2H), 5.36 (s, 2H), 6.92 (d, J = 8.4 Hz, 2H), 7.60 (d,
J = 8.8 Hz, 2H), 7.81 (d, J = 8.4 Hz, 2H), 8.09 (d, J = 8.0 Hz, 2H); 13C
NMR (100 MHz, DMSO-d6): d 12.38, 15.15, 64.71, 66.49, 114.43,
125.57, 126.17, 127.31, 128.36, 129.85, 136.53, 151.93, 154.82,
158.90, 163.39, 170.09; ESI/MS m/z: 465.5 (M+H)+.
4.3.32. (E)-Ethyl 2-(2-methyl-4-(1-(((5-methyl-2-phenyloxazol-
4-yl)methoxy)imino)ethyl)phenoxy)acetate (15a)
This compound was prepared from 13 and 9a by means of a
procedure similar to that reported for 11a. Off white solid; yield:
52%; mp 86–88 °C; purity by HPLC: 94.0%; IR (KBr): 3382, 2981,
2927, 2875, 1759, 1737, 1637, 1606, 1556, 1504, 1448, 1369,
4.3.28. (E)-2-(2-methyl-4-(1-(((4-methyl-2-(4-(trifluoromethyl)-
phenyl)thiazol-5-yl)methoxy)imino)propyl)phenoxy)acetic acid
(12c)
1317, 1278, 1203, 1145, 1068, 1024, 939, 891, 808, 756 cmꢁ1 1H
;
NMR (300 MHz, CDCl3): d 1.32 (t, J = 7.1 Hz, 3H), 2.11 (s, 3H),
2.34 (s, 3H), 2.48 (s, 3H), 4.26 (q, J = 7.1 Hz, 2H), 4.64 (s, 2H), 5.12
(s, 2H), 6.68 (d, J = 8.5 Hz, 1H), 7.35–7.49 (m, 5H), 8.01–8.02 (m,
2H); ESI/MS m/z: 423.0 (M+H)+.
This compound was prepared from 11c by means of a procedure
similar to that reported for 12a. Off white solid; yield: 80%; mp 174–
176 °C; purity by HPLC: 99.3%; IR (KBr): 2982, 2926, 1701, 1616,
1502, 1325, 1228, 1170, 1116, 1068, 1003, 964, 914, 839 cmꢁ1 1H
;
NMR (400 MHz, DMSO-d6): d 0.98 (t, J = 7.6 Hz, 3H), 2.20 (s, 3H),
2.49 (s, 3H), 2.63 (q, J = 7.4 Hz, 2H), 4.67 (s, 2H), 5.35 (s, 2H), 6.81
(d, J = 8.8 Hz, 1H), 7.41 (dd, J = 8.4 and 2.0 Hz, 1H), 4.48 (s, 1H),
7.81 (d, J = 8.4 Hz, 2H), 8.08 (d, J = 8.0 Hz, 2H); 13C NMR (100 MHz,
DMSO-d6): d 11.16, 15.14, 16.22, 19.23, 65.01, 66.51, 111.16,
125.03, 126.07, 126.14, 126.55, 126.66, 128.25, 129.97, 136.52,
151.83, 157.15, 159.83, 163.32, 170.25; ESI/MS m/z: 493.1 (M+H)+.
4.3.33. (E)-Ethyl 2-(4-(1-(((5-methyl-2-phenyloxazol-4-yl)-
methoxy)imino)ethyl)phenoxy)acetate (15b)
This compound was prepared from 13 and 9b by means of a
procedure similar to that reported for 11a. Thick liquid; yield:
59%; purity by HPLC: 98.4%; IR (KBr): 3018, 2983, 2929, 1753,
1604, 1512, 1384, 1319, 1180, 1018, 923, 833, 669 cmꢁ1 1H
;
NMR (400 MHz, CDCl3): d 1.28 (t, J = 7.0 Hz, 3H), 2.21 (s, 3H),
2.48 (s, 3H), 4.25 (q, J = 7.2 Hz, 2H), 4.63 (s, 2H), 5.12 (s, 2H), 6.88
(dd, J = 9.6 and 2.4 Hz, 2H), 7.39–7.45 (m, 3H), 7.58 (dd, J = 9.4
and 2.6 Hz, 2H), 8.00–8.03 (m, 2H); ESI/MS m/z: 409.2 (M+H)+.
4.3.29. (E)-2-(4-(1-(((4-methyl-2-(4-(trifluoromethyl)phenyl)-
thiazol-5-yl)methoxy)imino)propyl)phenoxy)acetic acid (12d)
This compound was prepared from 11d by means of a proce-
dure similar to that reported for 12a. Off white solid; yield: 88%;
mp 167–169 °C; purity by HPLC: 99.5%; IR (KBr): 3411, 2983,
2935, 2883, 1701, 1610, 1510, 1452, 1352, 1325, 1230, 1184,
4.3.34. (E)-Ethyl 2-(2-methyl-4-(1-(((5-methyl-2-phenyloxazol-
4-yl)methoxy)imino)propyl)phenoxy)acetate (15c)
This compound was prepared from 13 and 9c by means of a pro-
cedure similar to that reported for 11a. Off white solid; yield: 55%;
mp 95–97 °C; purity by HPLC: 99.2%; IR (KBr): 2974, 2885, 1757,
1639, 1498, 1377, 1203, 1186, 1149, 1105, 1030, 937, 860,
1170, 1112, 1068, 999, 966, 893, 846, 829, 675 cmꢁ1 1H NMR
;
(300 MHz, DMSO-d6): d 1.00 (t, J = 7.4 Hz, 3H), 2.41 (s, 3H), 2.66
(q, J = 7.4 Hz, 2H), 4.70 (s, 2H), 5.35 (s, 2H), 6.95 (d, J = 8.7 Hz,
2H), 7.62 (d, J = 8.7 Hz, 2H), 7.83 (d, J = 8.3 Hz, 2H), 8.11 (d,
J = 8.2 Hz, 2H); 13C NMR (100 MHz, DMSO-d6): d 11.10, 15.15,
19.22, 64.47, 66.15, 114.56, 126.14, 126.18, 126.57, 127.21,
127.48, 129.94, 136.51, 151.89, 158.78, 159.65, 163.35, 170.02;
ESI/MS m/z: 479.0 (M+H)+.
700 cmꢁ1 1H NMR (400 MHz, CDCl3): d 1.07 (t, J = 7.6 Hz, 3H),
;
1.27 (t, J = 7.0 Hz, 3H), 2.30 (s, 3H), 2.48 (s, 3H), 2.69 (q,
J = 7.6 Hz, 2H), 4.23 (q, J = 7.2 Hz, 2H), 4.64 (s, 2H), 5.11 (s, 2H),
6.66 (d, J = 8.4 Hz, 1H), 7.37–7.47 (m, 5H), 8.00–8.03 (m, 2H); ESI/
MS m/z: 437.2 (M+H)+.
4.3.30. (E)-2-(2-methyl-4-(1-(((4-methyl-2-(4-(trifluoromethyl)-
phenyl)thiazol-5-yl)methoxy)imino)butyl)phenoxy)acetic acid
(12e)
4.3.35. (E)-Ethyl 2-(4-(1-(((5-methyl-2-phenyloxazol-4-
yl)methoxy)imino)propyl)phenoxy)acetate (15d)
This compound was prepared from 13 and 9d by means of a
procedure similar to that reported for 11a. Off white solid; yield:
59%; mp 84–86 °C; purity by HPLC: 92.9%; IR (KBr): 2976, 2923,
1759, 1604, 1558, 1512, 1485, 1454, 1379, 1338, 1315, 1303,
1234, 1195, 1186, 1105, 1082, 1068, 1035, 1024, 954, 910, 833,
This compound was prepared from 11e by means of a procedure
similar to that reported for 12a. Off white solid; yield: 61%; mp
155–157 °C; purity by HPLC: 95.8%; IR (KBr): 3433, 2966, 2872,
1747, 1616, 1506, 1431, 1327, 1242, 1166, 1122, 1068, 1014,
966, 806 cmꢁ1
;
1H NMR (400 MHz, CDCl3): d 0.90 (t, J = 7.4 Hz,
794, 781, 715, 700, 599 cmꢁ1 1H NMR (300 MHz, CDCl3): d 1.07
;
3H), 1.45–1.53 (m, 2H), 2.26 (s, 3H), 2.53 (s, 3H), 2.64 (t,
J = 7.6 Hz, 2H), 4.60 (s, 2H), 5.29 (s, 2H), 6.67 (d, J = 8.4 Hz, 1H),
7.37 (dd, J = 8.4 and 2.0 Hz, 1H), 7.46 (d, J = 1.6 Hz, 1H), 7.64 (d,
J = 8.4 Hz, 2H), 7.98 (d, J = 8.4 Hz, 2H); 13C NMR (100 MHz,
(t, J = 7.6 Hz, 3H), 1.27 (t, J = 7.1 Hz, 3H), 2.47 (s, 3H), 2.79 (q,
J = 7.6 Hz, 2H), 4.28 (q, J = 7.1 Hz, 2H), 4.68 (s, 2H), 5.29 (s, 2H),
6.90 (d, J = 8.7 Hz, 2H), 7.41–7.44 (m, 3H), 7.60 (d, J = 8.7 Hz, 2H),
8.01–8.03 (m, 2H); ESI/MS m/z: 423.1 (M+H)+.

780
P. Makadia et al. / Bioorg. Med. Chem. 19 (2011) 771–782
4.3.36. (E)-Ethyl 2-(2-methyl-4-(1-(((5-methyl-2-phenyloxazol-
4-yl)methoxy)imino)butyl)phenoxy)acetate (15e)
669 cmꢁ1 1H NMR (300 MHz, CDCl3): d 1.11 (t, J = 7.5 Hz, 3H),
;
1.30 (t, J = 7.1 Hz, 3H), 2.38 (s, 3H), 2.46 (s, 3H), 2.74 (q,
J = 7.5 Hz, 2H), 4.32 (q, J = 7.1 Hz, 2H), 4.62 (s, 2H), 5.29 (s, 2H),
6.90 (d, J = 8.7 Hz, 2H), 7.24 (d, J = 8.1 Hz, 2H), 7.59 (d, J = 8.7 Hz,
2H), 7.91 (d, J = 8.1 Hz, 2H); ESI/MS m/z: 437.1 (M+H)+.
This compound was prepared from 13 and 9e by means of a
procedure similar to that reported for 11a. Thick liquid; yield:
51%; purity by HPLC: 97.4%; IR: 3018, 2968, 1753, 1508, 1384,
1145, 1026, 929 cmꢁ1
;
1H NMR (400 MHz, CDCl3): d 0.90 (t,
J = 7.2 Hz, 3H), 1.28 (t, J = 7.0 Hz, 3H), 1.47–1.57 (m, 2H), 2.30 (s,
3H), 2.48 (s, 3H), 2.67 (t, J = 7.4 Hz, 2H), 4.24 (q, J = 7.2 Hz, 2H),
4.64 (s, 2H), 5.11 (s, 2H), 6.65 (d, J = 8.4 Hz, 1H), 7.35–7.47 (m,
5H), 8.00–8.03 (m, 2H); ESI/MS m/z: 451.2 (M+H)+.
4.3.42. (E)-Ethyl 2-(2-methyl-4-(1-(((5-methyl-2-(p-tolyl)oxazol-
4-yl)methoxy)imino)butyl)phenoxy)acetate (16e)
This compound was prepared from 14 and 9e by means of a
procedure similar to that reported for 11a. White solid; yield:
45%; mp 110–111 °C; purity by HPLC: 99.1%; IR: 3060, 2958,
4.3.37. (E)-Ethyl 2-(4-(cyclohexyl(((5-methyl-2-phenyloxazol-4-
yl)methoxy)imino)methyl)-2-methylphenoxy)acetate (15f)
This compound was prepared from 13 and 9f by means of a pro-
cedure similar to that reported for 11a. Thick liquid; yield: 55%;
purity by HPLC: 94.1%; IR: 3018, 2931, 2854, 1757, 1500, 1448,
2871, 1743, 1614, 1502, 1190 cmꢁ1 1H NMR (300 MHz, CDCl3): d
;
0.91 (t, J = 7.3 Hz, 3H), 1.29 (t, J = 7.1 Hz, 3H), 1.48–1.62 (m, 2H),
2.71 (s, 3H), 2.30 (s, 3H), 2.46 (s, 3H), 2.67 (t, J = 6.6 Hz, 2H), 4.26
(q, J = 7.2 Hz, 2H), 4.64 (s, 2H), 5.30 (s, 2H), 6.65 (d, J = 8.5 Hz,
1H), 7.21–7.23 (m, 2H), 7.37 (d, J = 8.4 Hz, 1H), 7.46 (s, 1H), 7.90
(d, J = 8.1 Hz, 2H); ESI/MS m/z: 465.0 (M+H)+.
1384, 1149, 1035, 934 cmꢁ1 1H NMR (300 MHz, CDCl3): d 1.19–
;
1.33 (m, 9H), 1.74–1.81 (m, 4H), 2.26 (s, 3H), 2.29 (s, 3H), 2.40–
2.45 (m, 1H), 4.23 (q, J = 7.0 Hz, 2H), 4.62 (s, 2H), 4.95 (s, 2H),
6.64 (d, J = 8.4 Hz, 1H), 7.01–7.04 (m, 2H), 7.39–7.45 (m, 3H),
7.98–8.02 (m, 2H); ESI/MS m/z: 513.2 (M+Na)+.
4.3.43. (E)-Ethyl 2-(4-(cyclohexyl(((5-methyl-2-(p-tolyl)oxazol-
4-yl)methoxy)imino)methyl)-2-methylphenoxy)acetate (16f)
This compound was prepared from 14 and 9f by means of a pro-
cedure similar to that reported for 11a. Thick liquid; yield: 22%;
purity by HPLC: 94.2%; IR: 3130, 3020, 2029, 1732, 1633, 1502,
4.3.38. (E)-Ethyl 2-(2-methyl-4-(1-(((5-methyl-2-(p-tolyl)oxa-
zol-4-yl)methoxy)imino)ethyl)phenoxy)acetate (16a)
1215, 1145, 758 cmꢁ1 1H NMR (300 MHz, CDCl3): d 1.21–1.35
;
This compound was prepared from 14 and 9a by means of a
procedure similar to that reported for 11a. Off white solid; yield:
61%; mp 114–116 °C; purity by HPLC: 98.2%; IR (KBr): 3429,
2981, 2918, 2850, 1724, 1618, 1500, 1433, 1375, 1365, 1313,
(m, 9H), 1.69–1.72 (m, 5H), 2.24 (s, 3H), 2.30 (s, 3H), 2.32 (s, 3H),
4.20 (q, J = 7.1 Hz, 2H), 4.61 (s, 2H), 4.90 (s, 2H), 6.64 (d,
J = 8.1 Hz, 1H), 7.01–7.02 (m, 2H), 7.21 (s, 2H), 7.85 (d, J = 8.0 Hz,
2H); ESI/MS m/z: 527.1 (M+Na)+.
1294, 1269, 1240, 1145, 1002, 981, 918, 858, 817, 794, 727 cmꢁ1
;
1H NMR (300 MHz, CDCl3): d 1.31 (t, J = 7.1 Hz, 3H), 2.23 (s, 3H),
2.30 (s, 3H), 2.41 (s, 3H), 2.47 (s, 3H) 4.27 (q, J = 7.1 Hz, 2H), 4.64
(s, 2H), 5.11 (s, 2H), 6.68 (d, J = 8.5 Hz, 1H), 7.22 (d, J = 8.1 Hz,
2H), 7.41 (dd, J = 8.5 and 2.0 Hz, 1H), 7.49 (d, J = 1.4 Hz, 1H), 7.92
(d, J = 8.1 Hz, 2H); ESI/MS m/z: 437.2 (M+H)+.
4.3.44. (E)-2-(2-Methyl-4-(1-(((5-methyl-2-phenyloxazol-4-yl)-
methoxy)imino)ethyl)phenoxy)acetic acid (17a)
This compound was prepared from 15a by means of a procedure
similar to that reported for 12a. Off white solid; yield: 94%; mp
184–186 °C; purity by HPLC: 99.7%; IR (KBr): 3429, 3049, 3049,
2949, 2916, 2852, 1724, 1632, 1618, 1556, 1508, 1488, 1448,
1436, 1315, 1265, 1242, 1195, 1159, 1145, 1062, 1020, 970, 870,
4.3.39. (E)-Ethyl 2-(4-(1-(((5-methyl-2-(p-tolyl)oxazol-4-yl)-
methoxy)imino)ethyl)phenoxy)acetate (16b)
871, 800., 702 cmꢁ1 1H NMR (300 MHz, DMSO-d6): d 2.14 (s,
;
This compound was prepared from 14 and 9b by means of a
procedure similar to that reported for 11a. Off white solid; yield:
68%; mp 112–113 °C; purity by HPLC: 97.8%; IR (KBr): 2987,
2918, 1757, 1599, 1512, 1500, 1435, 1373, 1273, 1201, 1074,
3H), 2.21 (s, 3H), 2.47 (s, 3H), 4.73 (s, 2H), 5.05 (s, 2H), 6.85 (d,
J = 8.6 Hz, 1H), 7.41 (d, J = 8.6 Hz, 1H), 7.50–7.52 (m, 4H), 7.95
(m, 2H); 13C NMR (100 MHz, DMSO-d6): d 10.17, 12.35, 16.16,
64.74, 66.90, 111.01, 124.78, 125.57, 125.91, 126.96, 128.04,
128.30, 129.10, 130.28, 132.83, 147.77, 154.04, 156.87, 158.60,
170.16; ESI/MS m/z: 395.0 (M+H)+.
1026, 927, 727, 599 cmꢁ1 1H NMR (400 MHz, CDCl3): d 1.28 (t,
;
J = 7.2 Hz, 3H), 2.21 (s, 3H), 2.39 (s, 3H), 2.47 (s, 3H), 4.24 (q,
J = 7.0 Hz, 2H), 4.63 (s, 2H), 5.11 (s, 2H), 6.87 (dd, J = 11.6 and
2.8 Hz, 2H), 7.22 (d, J = 8.4 Hz, 2H), 7.58–7.61 (m, 2H), 7.89 (d,
J = 8.0 Hz, 2H); ESI/MS m/z: 423.2 (M+H)+.
4.3.45. (E)-2-(4-(1-(((5-Methyl-2-phenyloxazol-4-yl)methoxy)-
imino)ethyl)phenoxy)acetic acid (17b)
This compound was prepared from 15b by means of a proce-
dure similar to that reported for 12a. Off white solid; yield: 92%;
mp 186–188 °C; purity by HPLC: 98.9%; IR (KBr): 3072, 2920,
4.3.40. (E)-Ethyl 2-(2-methyl-4-(1-(((5-methyl-2-(p-tolyl)oxazol-
4-yl)methoxy)imino)propyl)phenoxy)acetate (16c)
This compound was prepared from 14 and 9c by means of a
procedure similar to that reported for 11a. Off white solid; yield:
68%; mp 116–118 °C; purity by HPLC: 99.8%; IR (KBr): 2966,
2872, 1743, 1612, 1500, 1448, 1377, 1213, 1149, 1103, 1074, 993,
1718, 1612, 1149, 1103, 1072, 1004, 970, 912 cmꢁ1 1H NMR
;
(400 MHz, CDCl3): d 2.14 (s, 3H), 2.46 (s, 3H), 4.68 (s, 2H), 5.05
(s, 2H), 6.91 (d, J = 8.8 Hz, 2H), 7.46–7.53 (m, 3H), 7.58 (d,
J = 8.8 Hz, 2H), 7.91–7.94 (m, 2H); 13C NMR (100 MHz, DMSO-d6):
d 10.17, 12.34, 64.57, 66.98, 114.37, 125.57, 126.95, 127.20,
128.67, 129.09, 130.27, 132.82, 147.80, 153.93, 158.59, 158.67,
170.07; ESI/MS m/z: 381.1 (M+H)+.
846, 729 cmꢁ1 1H NMR (400 MHz, CDCl3): d 1.07 (t, J = 7.6 Hz,
;
3H), 1.28 (t, J = 7.0 Hz, 3H), 2.30 (s, 3H), 2.38 (s, 3H), 2.47 (s, 3H),
2.69 (q, J = 7.6 Hz, 2H), 4.23 (q, J = 7.0 Hz, 2H), 4.64 (s, 2H), 5.10
(s, 2H), 6.65 (d, J = 8.4 Hz, 1H), 7.22 (d, J = 8.0 Hz, 2H), 7.37 (dd,
J = 8.6 & 2.2 Hz, 1H), 7.47 (d, J = 1.6 Hz, 1H), 7.89 (d, J = 8.0 Hz,
2H); ESI/MS m/z: 451.2 (M+H)+.
4.3.46. (E)-2-(2-Methyl-4-(1-(((5-methyl-2-phenyloxazol-4-yl)-
methoxy)imino)propyl)phenoxy)acetic acid (17c)
This compound was prepared from 15c by means of a procedure
similar to that reported for 12a. Off white solid; yield: 85%; mp
144–145 °C; purity by HPLC: 99.3%; IR (KBr): 3387, 2968, 2875,
1726, 1647, 1597, 1550, 1504, 1446, 1344, 1215, 1149, 1103,
4.3.41. (E)-Ethyl 2-(4-(1-(((5-methyl-2-(p-tolyl)oxazol-4-yl)-
methoxy)imino)propyl)phenoxy)acetate (16d)
This compound was prepared from 14 and 9d by means of a
procedure similar to that reported for 11a. Thick liquid; yield:
45%; purity by HPLC: 96.9%; IR: 3018, 2981, 2937, 1757, 1610,
1512, 1500, 1442, 1299, 1215, 1180, 1078, 1018, 968, 827, 759,
1072, 1004, 970, 912 cmꢁ1 1H NMR (300 MHz, CDCl3): d 0.96 (t,
;
J = 7.6 Hz, 3H), 2.19 (s, 3H), 2.45 (s, 3H), 2.62 (q, J = 7.2 Hz, 2H),
4.71 (s, 2H), 5.04 (s, 2H), 6.81 (d, J = 8.4 Hz, 1H), 7.39 (d,

P. Makadia et al. / Bioorg. Med. Chem. 19 (2011) 771–782
781
J = 8.8 Hz, 1H), 7.46–7.52 (m, 4H), 7.91–7.93 (m, 2H); 13C NMR
(100 MHz, DMSO-d6): d 10.13, 11.10, 16.15, 19.10, 64.75, 66.84,
111.07, 124.90, 125.54, 126.03, 126.97, 127.01, 128.20, 129.07,
130.23, 132.89, 147.67, 156.87, 158.57, 159.03, 170.18; ESI/MS
m/z: 409.2 (M+H)+.
4.3.51. (E)-2-(4-(1-(((5-Methyl-2-(p-tolyl)oxazol-4-yl)methoxy)-
imino)ethyl)phenoxy)acetic acid (18b)
This compound was prepared from 16b by means of a proce-
dure similar to that reported for 12a. Off white solid; yield: 90%;
mp 185–186 °C; purity by HPLC: 99.5%; IR (KBr): 2920, 1720,
1612, 1514, 1500, 1371, 1240, 1182, 1066, 1010, 885, 825,
4.3.47. (E)-2-(4-(1-(((5-Methyl-2-phenyloxazol-4-yl)methoxy)-
imino)propyl)phenoxy)acetic acid (17d)
731 cmꢁ1 1H NMR (300 MHz, DMSO-d6): d 2.13 (s, 3H), 2.35 (s,
;
3H), 2.44 (s, 3H), 4.63 (s, 2H), 5.03 (s, 2H), 6.89 (d, J = 8.8 Hz, 2H),
7.30 (d, J = 8.0 Hz, 2H), 7.57 (d, J = 8.8 Hz, 2H), 7.80 (d, J = 8.0 Hz,
2H); 13C NMR (100 MHz, DMSO-d6): d 10.15, 12.34, 20.99, 64.86,
66.93, 114.39, 124.34, 125.55, 127.16, 128.56, 129.65, 132.63,
140.08, 147.40, 153.90, 158.75, 158.80, 170.25; ESI/MS m/z:
395.2 (M+H)+.
This compound was prepared from 15d by means of a proce-
dure similar to that reported for 12a. Off white solid; yield: 80%;
mp 131–133 °C; purity by HPLC: 98.0%; IR (KBr): 3070, 2956,
2875, 1741, 1651, 1606, 1587, 1558, 1512, 1487, 1467, 1415,
1350, 1321, 1296, 1249, 1215, 1182, 1120, 1105, 1080, 1026,
975, 956, 904, 835, 717, 700 cmꢁ1 1H NMR (300 MHz, DMSO-
;
d6): d 1.05 (t, J = 7.4 Hz, 3H), 2.45 (s, 3H), 2.67 (q, J = 7.4 Hz, 2H),
4.69 (s, 2H), 5.04 (s, 2H), 6.90 (d, J = 8.8 Hz, 2H), 7.50–7.52 (m,
3H), 7.59 (d, J = 8.8 Hz, 2H), 7.91–7.93 (m, 2H); 13C NMR
(100 MHz, DMSO-d6): d 10.15, 11.05, 19.11, 64.48, 66.86, 114.49,
125.55, 126.97, 127.37, 127.45, 129.09, 130.26, 132.89, 147.72,
158.58, 158.63, 158.90, 170.04; ESI/MS m/z: 395.0 (M+H)+.
4.3.52. (E)-2-(2-Methyl-4-(1-(((5-methyl-2-(p-tolyl)oxazol-4-yl)-
methoxy)imino)propyl)phenoxy)acetic acid (18c)
This compound was prepared from 16c by means of a procedure
similar to that reported for 12a. Off white solid; yield: 92%; mp
190–191 °C; purity by HPLC: 99.3%; IR (KBr): 3387, 2972, 2875,
1726, 1504, 1446, 1332, 1215, 1151, 1103, 1004, 970, 821,
732 cmꢁ1 1H NMR (400 MHz, DMSO-d6): d 0.96 (t, J = 7.6 Hz,
;
3H), 2.20 (s, 3H), 2.34 (s, 3H), 2.44 (s, 3H), 2.60 (q, J = 7.4 Hz, 2H),
4.72 (s, 2H), 5.02 (s, 2H), 7.39 (d, J = 8.8 Hz, 1H), 7.46 (s, 1H), 7.80
(d, J = 8.0 Hz, 2H); 13C NMR (100 MHz, DMSO-d6): d 10.12, 11.11,
16.15, 19.10, 20.99, 20.99, 64.68, 66.89, 111.09, 124.36, 124.92,
125.54, 126.05, 127.07, 128.22, 129.64, 132.71, 140.07, 147.29,
156.84, 158.75, 158.99, 170.13; ESI/MS m/z: 423.2 (M+H)+
4.3.48. (E)-2-(2-Methyl-4-(1-(((5-methyl-2-phenyloxazol-4-
yl)methoxy)imino)butyl)phenoxy)acetic acid (17e)
This compound was prepared from 15e by means of a procedure
similar to that reported for 12a. Off white solid; yield: 91%; mp
141–142 °C; purity by HPLC: 99.9%; IR (KBr): 3389, 2935, 2812,
1728, 1728, 1647, 1597, 1504, 1448, 1419, 1342, 1269, 1207,
;
1149, 1070, 1001, 968, 864, 702 cmꢁ1 1H NMR (400 MHz,
4.3.53. (E)-2-(4-(1-(((5-Methyl-2-(p-tolyl)oxazol-4-yl)methoxy)-
imino)propyl)phenoxy)acetic acid (18d)
DMSO-d6): d 0.82 (t, J = 7.2 Hz, 3H), 1.38–1.44 (m, 2H), 2.18 (s,
3H), 2.45 (s, 3H), 2.62 (t, J = 7.6 Hz, 2H), 4.62 (s, 2H), 5.03 (s, 2H),
6.77 (d, J = 8.8 Hz, 1H), 7.37 (d, J = 8.8 Hz, 1H), 7.45 (s, 1H), 7.49–
7.51 (m, 3H), 7.91–7.93 (m, 2H); 13C NMR (100 MHz, DMSO-d6):
d 10.16, 13.89, 16.20, 19.59, 27.38, 65.20, 66.81, 111.03, 124.95,
125.54, 125.90, 126.98, 127.19, 128.17, 129.09, 130.25, 132.54,
147.65, 157.03, 157.91, 158.53, 170.33; ESI/MS m/z: 423.2 (M+H)+.
This compound was prepared from 16d by means of a proce-
dure similar to that reported for 12a. Off white solid; yield: 91%;
mp 155–157 °C; purity by HPLC: 97.5%; IR (KBr): 3433, 2916,
2941, 2875, 2503, 1726, 1643, 1610, 1556, 1512, 1498, 1446,
1434, 1336, 1269, 1244, 1211, 1190, 1074, 987, 970, 871, 827,
; d 1.00 (t,
731, 688 cmꢁ1 1H NMR (300 MHz, DMSO-d6):
J = 7.4 Hz, 3H), 2.34 (s, 3H), 2.43 (s, 3H), 2.67 (q, J = 7.4 Hz, 2H),
4.69 (s, 2H), 5.35 (s, 2H), 6.90 (d, J = 8.8 Hz, 2H), 7.30 (d,
J = 8.1 Hz, 2H), 7.59 (d, J = 8.8 Hz, 2H), 7.82 (d, J = 8.1 Hz, 2H); 13C
NMR (100 MHz, DMSO-d6): d 10.12, 11.06, 19.11, 20.99, 64.48,
66.91, 114.49, 124.36, 125.55, 127.37, 127.47, 129.64, 132.70,
140.72, 147.32, 158.63, 158.75, 158.85, 170.04; ESI/MS m/z:
409.0 (M+H)+
4.3.49. (E)-2-(4-(Cyclohexyl(((5-methyl-2-phenyloxazol-4-yl)-
methoxy)imino)methyl)-2-methylphenoxy)acetic acid (17f)
This compound was prepared from 15f by means of a procedure
similar to that reported for 12a. White solid; yield: 88%; mp 84–
86 °C; purity by HPLC: 95.7%; IR (KBr): 3412, 2926, 2852, 1608,
1500, 1429, 1338, 1300, 1230, 1143, 989, 895, 798, 690 cmꢁ1 1H
;
NMR (400 MHz, CDCl3): d 0.92–0.94 (m, 6H), 1.56–1.59 (m, 1H),
1.65–1.67 (m, 4H), 2.11 (s, 3H), 2.35 (s, 3H), 4.22 (s, 2H), 4.84 (s,
2H), 6.64 (d, J = 8.4 Hz, 1H), 6.95 (d, J = 8.8 Hz, 1H), 6.99 (s, 1H),
7.47–7.49 (m, 3H), 7.88–7.90 (m, 2H); 13C NMR (100 MHz,
DMSO-d6): d 10.17, 16.24, 25.55, 25.73, 30.38, 43.21, 66.47,
99.54, 110.78, 124.92, 125.13, 125.47, 126.03, 126.97, 129.06,
129.57, 130.19, 132.93, 147.45, 158.38, 161.34; ESI/MS m/z:
463.2 (M+H)+.
4.3.54. (E)-2-(2-Methyl-4-(1-(((5-methyl-2-(p-tolyl)oxazol-4-yl)-
methoxy)imino)butyl)phenoxy)acetic acid (18e)
This compound was prepared from 16e by means of a procedure
similar to that reported for 12a. White solid; yield: 68%; mp 151–
152 °C; purity by HPLC: 99.4%; IR (KBr): 2964, 2873, 1728, 1645,
1558, 1338, 1001 cmꢁ1 1H NMR (300 MHz, CDCl3): d 0.91 (t,
;
J = 7.3 Hz, 3H), 1.49–1.51 (m, 2H), 2.30 (s, 3H), 2.39 (s, 3H), 2.46
(s, 3H), 2.68 (t, J = 7.5 Hz, 2H), 4.66 (s, 2H), 5.11 (s, 2H), 6.67 (d,
J = 8.5 Hz, 1H), 7.22 (s, 2H), 7.37 (d, J = 8.5 Hz, 1H), 7.46 (s, 1H),
7.89 (d, J = 8.0 Hz, 2H); 13C NMR (100 MHz, CDCl3): d 10.64,
14.35, 16.50, 20.15, 21.63, 28.61, 65.38, 67.19, 110.96, 124.58,
125.22, 126.34, 127.28, 129.07, 129.15, 129.60, 132.60, 140.66,
147.28, 156.87, 160.19, 172.22; ESI/MS m/z: 437.0 (M+H)+.
4.3.50. (E)-2-(2-Methyl-4-(1-(((5-methyl-2-(p-tolyl)oxazol-4-yl)-
methoxy)imino)ethyl)phenoxy)acetic acid (18a)
This compound was prepared from 16a by means of a procedure
similar to that reported for 12a. Off white solid; yield: 92%; mp
194–196 °C; purity by HPLC: 99.5%; IR (KBr): 3030, 2947, 2914,
2848, 1722, 1618, 1556, 1500, 1436, 1371, 1321, 1265, 1240,
1195, 1145, 1083, 1066, 1014, 970, 916, 873, 800, 729, 661 cmꢁ1
;
4.3.55. (E)-2-(4-(Cyclohexyl(((5-methyl-2-(p-tolyl)oxazol-4-yl)-
methoxy)imino)methyl)-2-methylphenoxy)acetic acid (18f)
This compound was prepared from 16f by means of a procedure
similar to that reported for 12a. White solid; yield: 80%; mp 58–
60 °C; purity by HPLC: 97.2%; IR (KBr): 3431, 2927, 2852, 1618,
1H NMR (300 MHz, DMSO-d6): d 2.13 (s, 3H), 2.20 (s, 3H), 2.35 (s,
3H), 2.46 (s, 3H), 4.73 (s, 2H), 5.0 (s, 2H), 6.85 (d, J = 8.6 Hz, 1H),
7.33 (d, J = 8.0 Hz, 2H), 7.44 (d, J = 8.6 Hz, 1H), 7.49 (s, 1H), 7.84
(d, J = 8.0 Hz, 2H); 13C NMR (100 MHz, DMSO-d6): d 10.13, 12.33,
16.14, 20.99, 64.71, 66.93, 110.99, 124.34, 124.76, 125.55, 125.89,
128.02, 128.30, 129.64, 132.63, 140.09, 147.36, 153.98, 156.84,
158.75, 170.13; ESI/MS m/z: 409.0 (M+H)+.
1560, 1500, 1431, 1332, 1226, 1072, 985, 823, 731 cmꢁ1 1H
;
NMR (300 MHz, CDCl3): d 1.20–1.23 (m, 8H), 2.16–2.17 (m, 3H),
2.32 (s, 3H), 2.34 (s, 3H), 2.36 (s, 3H), 4.88 (s, 2H), 5.01 (s, 2H),

782
P. Makadia et al. / Bioorg. Med. Chem. 19 (2011) 771–782
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