Novel oxazole containing phenylpropane derivatives as peroxisome proliferator activated receptor agonists with hypolipidemic activity

Article abstract of DOI:10.1691/ph.2008.8534

α-Alkoxy arylpropanoic acids containing 2-phenyloxazole-4yl-alkyl moiety are found to be potent hypolipidemic agents. These compounds were potent activators of the peroxisome proliferator activated receptor γ (PPARγ), with moderate PPARα activity and known to cause adverse effects such as weight gain and edema, which are essentially attributed to PPARγ activation. Although extensive work has been done on the phenylpropanoic acid class of compounds, other phenyl propane derivatives such as alcohols, amines, ethers etc. have not received much attention. In order to develop predominant PPARα agonists as hypolipidemic agents with minor chemical modifications on compound III, we have synthesised few (2S)-ethoxyphenylpropane derivatives containing a 2-phenyl-5-methyloxazole- 4ylalkoxy moiety of the general formula IV and evaluated by PPARα and γ transactivation assay in conjugation with in vivo studies in male Swiss albino mice model. Compounds 3c and 3d showed the desired predominant PPARα activity and excellent tryiglyceride reduction in vivo and were selected as lead compounds for further development as hypolipidemic agents.

Full text of DOI:10.1691/ph.2008.8534

ORIGINAL ARTICLES
Zydus Research Centre, Sarkhej-Bavla N.H 8A Moraiya, Ahmedabad, India
Novel oxazole containing phenylpropane derivatives as peroxisome
proliferator activated receptor agonists with hypolipidemic activity
H. Pingali, S. Raval, P. Raval, P. Makadia, P. Zaware, A. Goel, D. Suthar, M. Jain, P. Patel
Received February 8, 2008, accepted March 7, 2008
Harikishore Pingali, Zydus Research Centre, Sarkhej-Bavla N.H 8A Moraiya, Ahmedabad-382210, India
pingalihk@rediffmail.com
Pharmazie 63: 497–502 (2008)
doi: 10.1691/ph.2008.8534
a-Alkoxy arylpropanoic acids containing 2-phenyloxazole-4yl-alkyl moiety are found to be potent hypo-
lipidemic agents. These compounds were potent activators of the peroxisome proliferator activated
receptor g (PPARg), with moderate PPARa activity and known to cause adverse effects such as
weight gain and edema, which are essentially attributed to PPARg activation. Although extensive work
has been done on the phenylpropanoic acid class of compounds, other phenyl propane derivatives
such as alcohols, amines, ethers etc. have not received much attention. In order to develop predomi-
nant PPARa agonists as hypolipidemic agents with minor chemical modifications on compound III, we
have synthesised few (2S)-ethoxyphenylpropane derivatives containing a 2-phenyl-5-methyloxazole-
4ylalkoxy moiety of the general formula IV and evaluated by PPARa and g transactivation assay in
conjugation with in vivo studies in male Swiss albino mice model. Compounds 3c and 3d showed the
desired predominant PPARa activity and excellent tryiglyceride reduction in vivo and were selected as
lead compounds for further development as hypolipidemic agents.
1. Introduction
therapy for the above indications includes the use of sta-
tins which are effective in lowering LDL-cholesterol and
increasing HDL-cholesterol and also found to be safe (La
Rosa et al. 1999). However these drugs are not effective in
lowering triglycerides. The scope of improving the po-
tency of these drugs may be limited in view of recent
reports of undesirable side effects of some super statins
(Evans and Rees 2002). Fibrate compounds such as feno-
Increasing evidence suggests that lipid accumulation in
non adipose tissue, such as pancreatic islet cells and skele-
tal muscle is related to the development of type 2 diabetes
in obese individuals (Kelly and Goodpaster 2001). High
LDL-cholesterol, elevated levels of triglycerides (TG) and
low HDL-cholesterol were identified as factors contribut-
ing to coronary artery disease. The presently available
Scheme 1
O
O
O
Cl
O
O
OH
O
N
O
Cl
II
I
Bezafibrate
Fenofibrate
O
CH3
O
O
O
N
OH
OEt
N
Y
(CH2)n
X
R
III
IV
Pharmazie 63 (2008) 7
497

ORIGINAL ARTICLES
fibrate I and bezafibrate II used to treat hyperlipidemea
and to develop predominant PPARa agonists as hypolipi-
demic agents by the chemical modifications on compound
III, we have synthesised few (2S)-ethoxyphenylpropane de-
rivatives containing a 2-phenyl-5-methyloxazole-4ylalkoxy
moiety of general formula IV and evaluated by PPARa and
g transactivation assay in conjugation with in vivo studies
in male Swiss albino mice model.
are effective in reducing triglycerides, increasing HDL-
cholesterol and lowering LDL-cholesterol are of poor effi-
cacy and need high doses to show significant efficay
(Stales et al. 1998). A combination of statins and fibrates
is found to show adverse effects (Evans and Rees 2002).
These findings led to the discovery of several compounds
in search for potent hypolipidemic agents such as a-alk-
oxy arylpropanoic acids containing 2-phenyloxazole-4yl-
alkyl moiety as in compound III (Hulin et al. 1996) (e.g.
1c and 1d) and few other series of compounds containing
2S-ethoxyphenyl propanoic acid derivatives (Buckle et al.
1996; Cronet et al. 2001; Lohray et al. 2001; Sauerberg
et al. 2002), which display potent hypolipidemic activity.
These compounds were potent activators of the peroxi-
some proliferator activated receptor g (PPARg) with mod-
erate PPARa activity and are known to cause adverse ef-
fects such as weight gain and edema, which are
essentially attributed to PPARg activation. Although exten-
sive work has been done on the phenylpropanoic acid
class of compounds, other phenyl propane derivatives such
as alcohols, amines, ethers etc. have not received much
attention except few compounds containing a phenylpro-
panol group which were reported as hypolipidemic and
anti diabetic compounds (Fagerhag et al. 2001). In conti-
nuation of our anti-diabetic and hypolipidemic research
(Lohray et al. 1999; Reddy et al. 1998; Tudor et al. 2007)
2. Investigations and results
Compounds 1–6 were synthesized as dipicted in the
Scheme. Ethyl-(2S)-ethoxy-3-{4-[2-(5-methyl-2-phenyl-ox-
azol-4-yl) alkoxy]-phenyl}-propanoates 1a–b were synthe-
sized by reacting 5-methyl-2-phenyl-oxazol-4ylalkyl
methane sulfonate (Goto et al. 1971) with ethyl-(2S)-
ethoxy-3-(4-hydroxy-phenyl)-propanoate (Andersson and
Lindstedt 1999) in the presence of potassium carbonate in
dry DMF. These esters were hydrolysed under aqueous
basic conditions to yield the carboxylic acids 1c and 1d.
These esters 1a and 1b were treated with lithium alumi-
num hydride in dry THF to yield corresponding alcohols
2a and 2b which were converted to their corresponding
ethylethers 3c and 3d and methanesulfonyl derivatives 3a
and 3b by reacting with ethyl iodide in the presence of
sodium hydride in DMF and with triethyl amine and
methane sulfonyl chloride in dichloromethane respectively.
The azide derivatives 4a and 4b obtained from 3a and 3b
Scheme 2
O
O
a
b
3c n=1 & R1=Et
3d n=2 & R1=Et
O
O
N
N
n
n
2
1
2a n=1
2b=n=2
1a n=1, R=Et
EtO
COOR
EtO
CH2OH
1b n=2, R=Et
1c n=1 R=H
1d n=2 R=H
c
O
O
O
N
n
O
d
4
N
n
3
4a n=1
4b n=2
EtO
CH2N3
EtO
CH2OR1
3a n=1 & R1=SO2CH3
3b n=2& R1=SO2CH3
e
O
N
O
O
n
O
N
f
CH2NH2
n
5
6
5a n=1
5b n=2
EtO
EtO
CH2NHR2
6a n=1 & R2=COCH3
6c n=2 & R2=COCH3
g
6
6b n=1 & R2=CH(CH3)2
6d n=2 & R2=CH(CH3)2
Reagents and condotions: (a) LiAlH4, dry THF, 0–20 ꢀC, 4 h; (b) NaH, EtI, DMF, 27–28 ꢀC, 4 h; (c) Et3N, CH3SO2Cl, CH2CH2Cl2, 10 ꢀC, 2 h; (d) NaN3,
DMF, 100 ꢀC, 6 h; (e) Ph3P, THF, 27–28 ꢀC, 10 h, H2O, 10 h; (f) Et3N, CH3COCl, CH2Cl2, 27–28 ꢀC, 3 h; (g) NaH, ICH(CH3)2, DMF, 272–8 ꢀC, 8 h
498
Pharmazie 63 (2008) 7

ORIGINAL ARTICLES
respectively by treating them with sodium azide in DMF
resulting respective compounds 3a and 3b lost both in
vitro and in vivo activities. Interestingly the conversion of
hydroxy compound 2a and 2b to their respective ethyl
ether derivatives 3c and 3d made them potent PPARa
compounds with poor PPARg activity. Both these com-
pounds were found twofold more potent towards PPARa
than g and both compounds showed excellent triglyceride
lowering (78% and 71% respectively) activity comparable
to the lead compounds 1c and 1d. The azides 4a and 4b
were found PPARg selective compounds with moderate
reduction in TG. The amines 5a and 5b found moderate
and equipotent towards PPARa and g with 61% and 54%
TG reduction respectively. The amides 6a and 6c and the
isopropyl amines 6b and 6d were found inactive towards
PPARa and exhibited only PPARg activity of the similar
order. But surprisingly 6a showed only 27% reduction in
TG whereas its homologue 6c reduced TG to an extent of
60%. The isopropyl amines 6b and 6d exhibited moderate
reduction in TG. The standard fenofibrate showed 28%
TG reduction at 30 mg/kg/day whereas bezafibrate showed
40% TG reduction at a dose of 300 mg/kg/day when ad-
ministered for 6 days in male swiss albino mice. Rsosigli-
tazone did not show any significant TG reduction in this
model.
These results showed that derivatives of (2S)-ethoxy-3-
{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-alkoxy]-phenyl}-pro-
pionic acid such as alcohols, ethers, amines, azides,
amides etc were useful to modulate the activity towards
PPARa and g subtype and were found to be excellent
hypolipidemic agents, which lowered plasma triglycerides
to a very significant extent. A most interesting finding is
that hydroxy compounds (2a and 2b) were found active
towards PPARg with no activity towards PPARa, whereas
the ethyl ether derivatives 3c and 3d were twofold as po-
at 100 ꢀC were reduced to amines 5a and 5b by the treat-
ment with triphenyl phosphine in THF followed by aque-
ous hydrolysis. Acetylation of amines 5a and 5b with
aceticanhydride gave the respective amides 6a and 6c
whereas the treatment of 5a and 5b with isopropyliodide
gave the compounds 6b and 6d respectively.
3. Discussion
The newly synthesized compounds were screened for ac-
tivity at human PPARa and g subtypes by using an estab-
lished cell-based transactivation assay. Rosiglitazone
(which showed 6.2 fold activity at 0.2 mM concentration)
and fenofibrate (which showed 4.4 fold activity at 10 mM
concentration) were used as the reference standards for
PPARg and PPARa respectively in our studies. The mod-
erate hypertriglyceridimic Swiss albino mice model was
used for the assessment of plasma triglyceride (TG) lower-
ing activity. Compounds 1–6 were evaluated for in vitro
PPAR transactivation potential and subsequently adminis-
tered orally to male Swiss albino mice at a dose of 3 mg/kg/
day for six days and the reduction in plasma triglycerides
(TG) was measured at the end. The results were summar-
ized in the Table. The carboxylic acid derivatives 1c and
1d showed PPARa and g activity and were twofold more
potent towards g than a and showed excellent TG reduc-
tion (78% and 74% respectively). The hydroxy derivative
2a and its homologue 2b showed equipotent induction
(5.6 and 5.0 respectively) in the PPARg transactivation
assay, whereas they were found inactive towards PPARa
and exhibited 71% and 57% TG reduction respectively.
When the hydroxy group in compounds 2a and 2b were
sulfonylated with the bulky methane sulfonyl group the
Table: PPAR Transactivation and plasma triglyceride lowering activity of compounds 1–6
CH3
O
O
OEt
N
(CH2)n
R
(I)
Compd.
n
R
PPAR Transactivationa
In vivo efficacy
a (10 mM)
g (0.2 mM)
% Reduction in TGb
2a
3a
3c
4a
5a
6a
6b
2b
3b
3d
4b
5b
6c
6d
1c
1d
1
1
1
1
1
1
1
2
2
2
2
2
2
2
1
2
CH2OH
CH2OSO2CH3
CH2OEt
CH2N3
CH2NH2
CH2NHCOCH3
CH2NHCH(CH3)2
CH2OH
CH2OSO2CH3
CH2OEt
CH2N3
CH2NH2
CH2NHCOCH3
CH2NHCH(CH3)2
COOH
IA
IA
5.6
1.9
3.8
IA
IA
IA
IA
5.5
1.5
2.1
IA
5.6
1.8
2.8
6.2
3.1
4.2
3.5
5.0
1.0
2.7
6.0
3.8
4.8
3.9
11.0
10.6
6.2
IA
71
24
78
51
61
27
44
57
10
71
67
54
60
24
78
74
IA
28
40
IA
4.8
5.2
IA
COOH
Rosiglitazone
Fenofibrate
Bezafibrate (300 mg/kg/day)
4.4
a Activities are presented by fold induction of PPAR a and g activation. IA indicates inactive.
b Values (mean ꢁ SE) are the % reduction in plasma triglyceride (TG) concentration of the drug-treated mice relative to vehicle controls. All values are the mean of n ¼ 6. IA
indicates inactive.
Pharmazie 63 (2008) 7
499

ORIGINAL ARTICLES
mixture was poured into ice cold water (20 mL) and extracted with ethyla-
tent towards PPARa than g. On contrary to these results
the parent acids (1c and 1d) had twofold activity potent
towards g than a. These results clearly demonstrate that
minor chemical modifications in the functional region of
the compounds lead to significant changes in the in vitro
activity even though they exhibit a similar in vivo profile.
Compounds 3c and 3d which showed the desired predo-
minant PPARa activity were selected as initial lead com-
pounds for further development as hypolipidemic agents.
cetate (3 ꢂ 20 mL). The organic layer was washed with water and brine,
dried over sodium sulfate and evaporated in vacuo. The crude product was
purified by flash column chromatography using 8% ethyl acetate in hexane
as eluent to give 1.79 g of title compound 1a as thick liquid; yield: 91%,
purity: 98% by HPLC; 1H NMR (300 MHz, CDCl3):
d 1.1 (3 H, t,
J ¼ 7.1 Hz), 1.2 (3 H, t, J ¼ 7.0 Hz), 2.4 (3 H, s), 3.0 (2 H, m), 3.5 (2 H,
m), 4.0 (1 H, dd, J ¼ 7.4 & 4.3 Hz), 4.2 (2 H, q, J ¼ 7.1 Hz), 4.9 (2 H, s),
6.8 (2 H, dd, J ¼ 6.7 & 2.0 Hz), 7.1 (2 H, d, J ¼ 1.9 Hz), 7.4 (3 H, m), 8.0
(2 H, dd, J ¼ 5.1 & 1.8 Hz); IR (Nujol) 2881, 1741, 1720, 1587, 1515,
1341, 1251, 1160, 1071, 820 cmꢃ1; ESI/MS m/z: 410 (M þ H)þ.
4.3.2. Ethyl (2S)-ethoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-
phenyl}-propanoate (1b)
4. Experimental
Title compound was prepared from ethyl (2S)-ethoxy-3-(4-hydroxy-phe-
nyl)-propanoate and 2-(5-methyl-2-phenyl-oxazol-4-yl)-ethyl methanesulfo-
nate following the procedure described for compound 1a. Thick liquid;
yield: 93%; purity: 99% by HPLC; 1H NMR (300 MHz, CDCl3): d 1.1
(3 H, t, J ¼ 7.1 Hz), 1.2 (3 H, t, J ¼ 7.0 Hz), 2.4 (3 H, s), 3.0 (4 H, m), 3.5
(2 H, m), 4.0 (1 H, dd, J ¼ 7.4 & 4.3 & Hz), 4.1 (2 H, q, J ¼ 7.1 Hz), 4.2
4.1. In vitro PPAR transactivation assay
4.1.1. Cell culture
HepG2 cells (ATCC, USA) were maintained in growth medium composed
of minimal essential medium (MEM, Sigma) supplemented with 10% fetal
bovine serum (FBS, Hyclone), 1 ꢂ MEM non-essential amino acid (Sigma)
and 1 mM sodium pyruvate and 1% penicillin and streptomycin (Sig-
ma).
(2 H, t, J ¼ 6.7 Hz), 6.8 (2 H, dd, J ¼ 6.7
& 2.0 Hz), 7.1 (2 H, d,
J ¼ 1.9 Hz), 7.4 (3 H, m), 8.0 (2 H, dd, J ¼ 5.1 & 1.8 Hz); IR (Nujol)
2877, 1744, 1583, 1513, 1344, 1245, 1176, 1064, 821 cmꢃ1; ESI/MS m/z:
424 (M þ H)þ.
4.1.2. Transient transfection
HepG2 cells were seeded in 24 well plates at a density of 400000 cells/
well in 1 mL of medium per well. Cells were transfected using the trans-
fection reagent Superfect (Qiagen). Cells were transfected with 0.08 mg of
the pSG5 expression vector containing the cDNA of PPARa or 0.08 mg of
the pSG5 expression vector containing the cDNA of PPARg was cotrans-
fected with PPRE3-TK-luc. Cells were incubated at 37 ꢀC, 5% CO2 for 3 h
after which 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 as-
sayed for luciferase and b-galactosidase activity. The luciferase activity
was determined using a commercial fire-fly luciferase assay according to
the suppliers’s instructions [Promega] in white 96-well plate [Nunc].
b-Galactosidase activity was determined in an ELISA reader at 415 nm.
4.3.3. (2S)-Ethoxy-3-{4-[5-methyl-2-phenyl-oxazol-4-yl-methoxy]-phenyl}-
propanoic acid (1c)
To a solution of ethyl (2S)-ethoxy-3-{4-[5-methyl-2-phenyl-oxazol-4-yl-
methoxy]-phenyl}-propanoate (1a) (1.5 g, 3.66 mmol) in EtOH (10 mL), a
solution of NaOH (0.29 g, 7.3 mmol) in H2O (5 mL) was added and stirred
at 25 ꢀC for 18 h. The reaction mixture was concentrated in vacuo, diluted
with 20 mL water, acidified by HCl and extracted with ethyl acetate
(3 ꢂ 20 mL). The organic layer was washed with water and brine solution,
dried over Na2SO4 and evaporated in vacuo to give 1.27 g of title com-
pound 1c as white solid. m.p. 103–104 ꢀC; yield: 91%, purity: 99% by
HPLC; 1H NMR (300 MHz, CDCl3) : d 1.2 (3 H, t, J ¼ 7.0 Hz), 2.4 (3 H,
s), 3.0 (2 H, m), 3.5 (2 H, m), 4.0 (1 H, dd, J ¼ 7.4 & 4.3 & Hz), 4.9 (2 H,
s), 6.8 (2 H, dd, J ¼ 6.7 & 2.0 Hz), 7.1 (2 H, d, J ¼ 1.9 Hz), 7.4 (3 H, m),
8.0 (2 H, dd, J ¼ 5.1 & 1.8 Hz); IR (KBr) 3411, 2880, 1717, 1622, 1589,
1515, 1340, 1251, 1160, 1071, 820 cmꢃ1; ESI/MS m/z: 382 (M þ H)þ.
4.2. In vivo screenig
An inbred colony of Swiss albino mice (SAM) of 20–30 g body weight
with serum triglyceride levels in the range of 80–120 mg/dl have been
used for screening the compounds. The study protocol was approved by
the institutional animal ethics committee. The test compounds were admi-
nistered orally at a dose of 3 mg/kg/day (fenofibrate at 30 mg/kg/day) to
male Swiss albino mice for 6 days. The blood samples were collected in
fed state one hour after drug administration on the 6th day of treatment
and triglyceride levels were measured. Reduction of serum triglycerides
was calculated according to the formula,
4.3.4. (2S)-Ethoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-
propanoic acid (1d)
Title compound was prepared from 1b following the procedure described
for compound 1c. White solid; m.p. 97–98 ꢀC; yield: 93%; purity: 99% by
HPLC; 1H NMR (300 MHz, CDCl3): d 1.2 (3 H, t, J ¼ 7.0 Hz), 2.4 (3 H,
s), 3.0 (4 H, m), 3.5 (2 H, m), 4.0 (1H , dd, J ¼ 7.4 & 4.3 & Hz), 4.2 (2 H,
t, J ¼ 6.7 Hz), 6.8 (2 H, dd, J ¼ 6.7 & 2.0 Hz), 7.1 (2 H, d, J ¼ 1.9 Hz),
7.4 (3 H, m), 8.0 (2 H, dd, J ¼ 5.1 & 1.8 Hz); IR (KBr), 3409, 2877, 1706,
1612, 1583, 1512, 1342, 1245, 1176, 1064, 821 cmꢃ1; ESI/MS m/z: 396
(M þ H)þ.
% Reduction ¼ 1-{(TT/OT)/(TC/OC)} TT ꢂ 100
where,
TT ¼ serum TG level on test day of treated group, OT ¼ serum TG level
on day 0 of treatment of treated group, TC ¼ serum TG level on test day
of control group, OC ¼ serum TG level on day 0 of treatment of control
group.
4.3.5. (2S)-Ethoxy-3-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-
propan-1-ol (2a)
To a solution of ethyl (2S)-ethoxy-3-{4-[5-methyl-2-phenyl-oxazol-4-yl-
methoxy]-phenyl}-propanoate (1a) (2.0 g, 4.89 mmol) in THF (10 mL),
LiAlH4 (0.185 g, 4.89 mmol) was added in small portions at 0 ꢀC over a
period of 30 min under nitrogen atmosphere and stirred at 20 ꢀC for 4 h.
Excess LiAlH4 was quenched by drop-wise addition of saturated aqueous
Na2SO4 solution at 0–10 ꢀC. Solid residue was filtered and washed with
ethyl acetate. Filtrate was evaporated in vacuo to give 1.74 g of title com-
pound 2a as thick liquid. yield: 97%; purity: 98% by HPLC; 1H NMR
(300 MHz, CDCl3): d 1.17 (3 H, t, J ¼ 6.99 Hz), 2.4 (3 H, s), 2.6–2.8
(2 H, m), 3.4–3.6 (5 H, m), 4.9 (2 H, s), 6.94 (2 H, d, J ¼ 8.64 Hz), 7.12
(2 H, d, J ¼ 8.58 Hz), 7.42–7.46 (3 H, m), 8.0–8.03 (2 H, m); IR (Nujol),
3622, 2927, 1515, 1461, 1341, 1250, 1159, 1070, 835 cmꢃ1; ESI/MS m/z:
368 (M þ H)þ.
4.3. Synthesis
Reagents and solvents were obtained from commercial suppliers and used
without further purification. Flash chromatography was performed using
commercial silica gel (230–400 mesh). Melting points were determined on
a capillary melting point apparatus and are uncorrected. IR spectra were
recorded on a Shimadzu FT IR 8300 spectrophotometer (Vmax in cmꢃ1
,
using KBr pellets or Nujol). The 1H NMR spectra were recorded on a
Brucker Avanc-300 spectrometer (300 MHz). The chemical shifts (d) are
reported in parts per million (ppm) relative to TMS, either in CDCl3 or
DMSO-d6 solution. Signal multiplicities are represented by s (singlet), d
(doublet), dd (doublet of doublet), t (triplet), q (quartet), bs (broad singlet),
and m (multiplet). Mass spectra (ESI-MS) were obtained on Shimadzu
LCMS 2010-A spectrometer. HPLC analysis were carried out at lmax
220 nm using column ODS C-18, 150 nm ꢂ 4.6 nm ꢂ 4 m on AGILENT
1100 series.
4.3.6. (2S)-Ethoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-
propan-1-ol (2b)
Title compound was prepared from 1b following the procedure described
for compound 2a. Off white solid; m.p. 45–47 ꢀC; yield: 84%; Purity:
97% by HPLC; 1H NMR (300 MHz, CDCl3): d 1.1 (3 H, t, J ¼ 6.9 Hz),
2.3 (3 H, s), 2.5 (1 H, dd, J ¼ 13.5 & 6.7 Hz), 2.7 (1 H, dd, J ¼ 12.9 &
6.9 Hz), 2.9 (2 H, t, J ¼ 6.69 Hz), 3.5 (5 H, m), 4.2 (2 H, t, J ¼ 6.69 Hz),
6.8 (2 H, d, J ¼ 8.55 Hz), 7.1 (2 H, d, J ¼ 8.5 Hz), 7.2–7.4 (3 H, m), 7.9
4.3.1. Ethyl (2S)-ethoxy-3-{4-[5-methyl-2-phenyl-oxazol-4-yl-methoxy]-
phenyl}-propanoate (1a)
To
a solution of ethyl (2S)-ethoxy-3-(4-hydroxy-phenyl)-propanoate
(1.15 g, 4.83 mmol) and 4-chloromethyl-5-methyl-2-phenyl-oxazole (1.0 g,
4.83 mmol) in dry DMF (10 mL), K2CO3 (1.33 g, 9.66 mmol) was added
and the reaction mixture was stirred at 60–70 ꢀC for 20 h. The reaction
(2 H, m); IR (KBr) 3290, 2862, 1581, 1448, 1286, 1178, 1056, 835 cmꢃ1
;
ESI/MS m/z: 382 (M þ H)þ.
500
Pharmazie 63 (2008) 7

ORIGINAL ARTICLES
4.3.7. (2S)-Ethoxy-3-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-
propyl methanesulfonate (3a)
J ¼ 6.7 Hz), 6.8 (2 H, d, J ¼ 9.5 Hz), 7.1 (2 H, d, J ¼ 8.5 Hz), 7.4 (3 H,
m), 7.9 (2 H, m); IR (KBr) 2979, 2854, 1610, 1510, 1463, 1384, 1278,
1170, 1091, 947, 690 cmꢃ1; ESI/MS m/z: 407 (M þ H)þ.
To a solution of (2S)-ethoxy-3-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-
phenyl]-propan-1-ol (2a) (1.0 g, 2.72 mmol) in CH2Cl2 (10 mL), Et3N
(0.42 g, 4.08 mmol) was added followed by drop-wise addition of
CH3SO2Cl (0.37 mg, 3.26 mmol) at 0–10 ꢀC under nitrogen atmosphere
and stirred at the same temperature for 2 h. The reaction mixture was di-
luted with CH2Cl2 (50 mL), washed with water, NaHCO3 solution, dil HCl
and brine, dried over Na2SO4 and evaporated in vacuo to give 1.18 g of
title compound 3a as thick liquid; yield: 98%; purity: 98% by HPLC;
1H NMR (300 MHz, CDCl3): d 1.15 (3 H, t, J ¼ 6.99 Hz), 2.4 (3 H, s),
2.7–2.8 (2 H, m), 3.0 (3 H, s), 3.4–3.6 (2 H, m), 3.6–3.7 (1 H, m), 4.0–
4.2 (2 H, m), 4.9 (2 H, s), 6.95 (2 H, d, J ¼ 8.61 Hz), 7.14 (2 H, d,
J ¼ 8.61 Hz), 7.41–7.46 (3 H, m), 8.0–8.03 (2 H, m); IR (Nujol): 3122,
2929, 1530, 1345, 1250, 1215, 1159, 1095, 1069, 828 cmꢃ1; ESI/MS m/z:
446 (M þ H)þ.
4.3.13. (2S)-Ethoxy-3-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-
propylamine (5a)
To
a solution of (4-[4-(3-azido-2S-ethoxy-propyl)-phenoxymethyl]-5-
methyl-2-phenyl-oxazole (4a) (1.2 g, 3.06 mmol) in dry THF (5 mL), Ph3P
(0.96 g, 3.67 mmol) was added and reaction mixture was stirred at 27 ꢀC
for 10 h. H2O (5 ml) was added and the reaction mixture was stirred at
27 ꢀC for 10 h. The reaction mixture was poured into ice cold water
(20 mL) and extracted with ethyl acetate (3 ꢂ 20 mL). The organic extract
was washed with water and brine solution, dried over sodium sulfate and
evaporated in vacuo. The crude product was purified by flash column chro-
matography using 1% MeOH in CHCl3 as eluent to give 828 mg of title
compound 4a as thick liquid. Yield: 72%; purity: 94% by HPLC; 1H NMR
(300 MHz, CDCl3): d 1.2 (3 H, t, J ¼ 6.9 Hz), 2.45 (3 H, s), 2.68 (2 H, d,
J ¼ 5.3 Hz), 2.70–2.84 (2 H, m), 3.53–3.62 (2 H, m), 3.74–4.05 (1 H, m),
5.0 (2 H, s), 6.9 (2 H, d, J ¼ 8.0 Hz), 7.1 (2 H, d, J ¼ 8.58 Hz), 7.42–7.45
(3 H, m), 7.99–8.03 (2 H, m); IR (Nujol) 3411, 2979, 2360, 1510, 1466,
1388, 1179, 1089, 1089, 669 cmꢃ1; ESI/MS m/z: 367 (M þ H)þ.
4.3.8. (2S)-Ethoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-
propyl methanesulfonate (3b)
Title compound was prepared from 2b following the procedure described
for compound 3a. White solid; m.p. 62–64 ꢀC; yield: 84%, purity: 96%
by HPLC; 1H NMR (300 MHz, CDCl3): d 1.1 (3 H, t, J ¼ 7.0 Hz), 2.3
(3 H, s), 2.8 (2 H, m), 2.9 (2 H, t, J ¼ 6.7 Hz), 3.0 (3 H, s), 3.5 (2 H, m),
3.6 (1 H, m), 4.0 (1 H, dd, J ¼ 10.9 & 5.6 Hz), 4.2 (3 H, m), 6.8 (2 H, d,
J ¼ 8.6 Hz), 7.1 (2 H, d, J ¼ 8.5 Hz), 7.4 (3 H, m), 7.9 (2 H, dd, J ¼ 7.9 &
2.2 Hz); IR (KBr) 3110, 2924, 1529, 1350, 1250, 1216, 1150, 1071,
835 cmꢃ1; ESI/MS m/z: 460 (M þ H)þ.
4.3.14. (2S)-Ethoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phe-
nyl}-propylamine (5b)
Title compound was prepared from 4b following the procedure described
for compound 5a. Thick liquid; yield: 76%; purity: 98% by HPLC;
1H NMR (300 MHz, CDCl3): d 1.1(3 H, t, J ¼ 6.91 Hz), 2.3 (3 H, s), 2.6–
2.8 (4 H, m), 2.9 (2 H, t, J ¼ 6.69 Hz), 3.4–3.5 (3 H, m), 4.2 (2 H, t,
J ¼ 6.69 Hz), 6.8 (2 H, d, J ¼ 8.5 Hz), 7.0 (2 H, d, J ¼ 8.4 Hz), 7.4 (3 H,
m), 7.9 (2 H, m); IR (Nujol) 3409, 2979, 2359, 1511, 1465, 1388, 1180,
1091, 927, 669 cmꢃ1; ESI/MS m/z: 381 (M þ H)þ.
4.3.9. 4-[4-(2S,3-Diethoxy-propyl)-phenoxymethyl]-5-methyl-2-phenyl-oxa-
zole (3c)
To an ice cold suspension of NaH (60%) (81.7 mg, 2.04 mmol) in DMF
(1 ml),
a solution of (2S)-ethoxy-3-[4-(5-methyl-2-phenyl-oxazol-4-yl-
methoxy)-phenyl]-propan-1-ol (2a) (500 mg, 1.36 mmol) in DMF (1 ml)
was added drop wise at 10 ꢀC under nitrogen atmosphere and stirred at
25 ꢀC for 0.5 h. Ethyl iodide (254 mg, 1.63 mmol) was added at 27 ꢀC and
the reaction mixture was stirred at 27 ꢀC for 4 h. The reaction mixture was
poured into ice cold water (20 ml) and extracted with ethyl acetate
(20 ml ꢂ 3). The organic extract was washed with water and brine solution,
dried over Na2SO4 and evaporated in vacuo to give 408 mg of title com-
pound 3c as thick liquid. Yield: 76%; purity: 95% by HPLC; 1H NMR
(300 MHz, CDCl3): d 1.13 (3 H, t, J ¼ 6.9 Hz), 1.19 (3 H, t, J ¼ 6.9 Hz),
2.43 (3 H, s), 2.77 (2 H, m), 3.37–3.63 (7 H, m), 4.97 (2 H, s), 6.9 (2 H, d,
J ¼ 8.6 Hz), 7.17 (2 H, d, J ¼ 8.6 Hz), 7.42–7.47 (3 H, m), 8.0–8.03 (2 H,
m); IR (Nujol) 3119, 2901, 1610, 1488, 1380, 1295, 1250, 1210, 1119,
757 cmꢃ1; ESI/MS m/z: 396 (M þ H)þ.
4.3.15. N-{(2S)-Ethoxy-3-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phe-
nyl]-propyl}-acetamide (6a)
To
a solution (2S)-ethoxy-3-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-
phenyl]-propylamine (5a) (500 mg, 1.37 mmol) in CH2Cl2 (5 mL), Et3N
(207 mg, 2.05 mmol) was added followed by drop-wise addition of
CH3COCl (125 mg, 1.64 mmol) at 0–10 ꢀC under nitrogen atmosphere
and stirred at the same temperature for 3 h. The reaction mixture was di-
luted with CH2Cl2 (50 mL), washed with water, NaHCO3 solution, dil HCl
and brine solution, dried over Na2SO4 and evaporated in vacuo. The crude
product was triturated with diethyl ether to give 247 mg of title compound
6a as white solid. m.p. 111–112 ꢀC; yield: 37%, purity: 97% by HPLC;
1H NMR (300 MHz, CDCl3): d 1.2 (3 H, t, J ¼ 6.9 Hz), 2.1 (3 H, s), 2.43
(3 H, s), 2.69–2.77 (2 H, m), 2.78–3.44 (1 H, m), 3.45–3.53 (4 H, m),
4.97 (2 H, s), 5.73 (1 H, s), 6.93 (2H, d, J ¼ 8.61 Hz), 7.12 (2 H, d,
J ¼ 8.58 Hz), 7.42–7.46 (3 H, m), 8.00–8.03 (2 H, m); IR (KBr) 3314,
4.3.10. 4-{2-[4-(2S,3-Diethoxy-propyl)-phenoxy]-ethyl}-5-methyl-2-phenyl-
oxazole (3d)
2970, 2850, 1639, 1609, 1551, 1466, 1377, 1280, 1180, 1090, 829 cmꢃ1
;
ESI/MS m/z: 409 (M þ H)þ.
Title compound was prepared from 2b following the procedure described
for compound 3c. Thick liquid; yield: 57%, purity: 99% by HPLC, 1H NMR
(300 MHz, CDCl3): d 1.1 (3 H, t, J ¼ 6.99 Hz), 1.2 (3 H, t, J ¼ 6.99 Hz), 2.4
(3 H, s), 2.7 (2 H, t, J ¼ 6.6 Hz), 3.0 (2 H, t, J ¼ 6.69 Hz) 3.5 (7 H, complex),
4.2 (2 H, t, J ¼ 6.69 Hz), 6.8 (2 H, dd, J ¼ 1.87 & 6.65 Hz), 7.1 (2 H, d,
J ¼ 8.55 Hz), 7.4 (3 H, m) 7.9 (2 H, m); IR (Nujol) 3119, 2901, 1610,
1512, 1382, 1244, 1215, 1110, 756 cmꢃ1; ESI/MS m/z: 410 (M þ H)þ.
4.3.16. {(2S)-Ethoxy-3-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-
propyl}-isopropyl-amine (6b)
To an ice cold suspension of NaH (60%) (82 mg, 2.06 mmol) in DMF
(1 ml), solution of (2S)-ethoxy-3-[4-(5-methyl-2-phenyl-oxazol-4-yl-
a
methoxy)-phenyl]-propylamine (5a) (500 mg, 1.37 mmol) in DMF (1 ml)
was added drop wise at 10 ꢀC under nitrogen atmosphere and stirred at
25 ꢀC for 30 min. Isopropyl iodide (279 mg, 1.64 mmol) was added at
25 ꢀC and the reaction mixture was stirred below 27 ꢀC for 8 h. The reac-
tion mixture was poured into ice cold water (20 ml) and extracted with
ethyl acetate (20 ml ꢂ 3). The organic extract was washed with water and
brine solution, dried over Na2SO4 and evaporated in vacuo to give 475 mg
of title compound 6b as thick liquid. Yield: 85%; purity: 96% by HPLC;
1H NMR (300 MHz, CDCl3): d 1.09 (3 H, t, J ¼ 6.8 Hz), 1.17 (6 H, d,
J ¼ 5.52 Hz), 2.77–2.92 (4 H, m), 2.43 (3 H, s), 3.25 (1 H, t, J ¼ 6.16 Hz),
3.43–3.92 (2 H, m), 4.96 (2 H, s), 6.97 (2 H, d, J ¼ 8.25 Hz), 7.17 (2 H, d,
J ¼ 8.19 Hz), 7.50–7.92 (5 H, m); IR (Nujol) 3421, 2979, 2880, 2359,
4.3.11. 4-[4-(3-Azido-2S-ethoxy-propyl)-phenoxymethyl]-5-methyl-2-phe-
nyl-oxazole (4a)
To a solution of (2S)-ethoxy-3-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-
phenyl]-propyl methanesulfonate (3a) (1.0 g, 2.25 mmol) in dry DMF
(2 mL), NaN3 (0.73 g, 11.2 mmol) was added and the reaction mixture was
stirred at 100 ꢀC for 6 h. The reaction mixture was poured into ice cold
water (20 mL) and extracted with ethyl acetate (3 ꢂ 20 mL). The organic
extract was washed with water and brine solution, dried over sodium sul-
fate and evaporated in vacuo to give 855 mg of title compound 4a as thick
liquid. Yield: 97%, purity: 98% by HPLC; 1H NMR (300 MHz, CDCl3): d
1.18 (3 H, t, J ¼ 6.99 Hz), 2.4 (3 H, s), 2.7–2.85 (2 H, m), 3.2 (2 H, m),
3.45–3.65 (3 H, m), 4.9 (2 H, s), 6.95 (2 H, d, J ¼ 8.6 Hz), 7.14 (2 H, d,
J ¼ 8.61 Hz), 7.41–7.46 (3 H, m), 8.0–8.03 (2 H, m); IR (Nujol) 2975,
2850, 1610, 1151, 1460, 1380, 1275, 1169, 1090, 973, 690 cmꢃ1; ESI/MS
m/z: 392 (M þ H)þ.
1551, 1466, 1388, 1188, 1099, 1010, 671 cmꢃ1
; ESI/MS m/z: 409
(M þ H)þ.
4.3.17. N-(2S-Ethoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phe-
nyl}-propyl)-acetamide (6c)
Title compound was prepared from 5b following the procedure described
for compound 6a. White solid; m.p. 101–102 ꢀC; yield: 64%; purity: 98%
by HPLC; 1H NMR (300 MHz, CDCl3): d 1.1 (3 H, t, J ¼ 7.0 Hz), 1.9
(3 H, s), 2.3 (3 H, s), 2.6 (2 H, m), 2.9 (2 H, t, J ¼ 6.7 Hz), 3.1 (1 H, m),
3.5 (4 H, m), 4.2 (2 H, t, J ¼ 6.7 Hz), 6.8 (2 H, d, J ¼ 8.6 Hz), 7.0 (2 H, d,
J ¼ 8.5 Hz), 7.4 (3 H, m), 8.0 (2 H, dd, J ¼ 7.9 & 2.3 Hz); IR (KBr) 3311,
4.3.12. 4-{2-[4-(3-Azido-2S-ethoxy-propyl)-phenoxy]-ethyl}-5-methyl-2-phe-
nyl-oxazole (4b)
Title compound was prepared from 3b following the procedure described
for compound 4a. White solid; m.p. 60–63 ꢀC; yield: 71%, purity: 99%
by HPLC; 1H NMR (300 MHz, CDCl3): d 1.2 (3 H, t, J ¼ 7.0 Hz), 2.3
(3 H, s), 2.7 (1 H, dd, J ¼ 13.5 & 6.6 Hz), 2.8 (1 H, dd, J ¼ 13.5 &
6.2 Hz), 2.9 (2 H, t, J ¼ 6.7 Hz), 3.1 (2 H, m), 3.5 (3 H, m), 4.2 (2 H, t,
2974, 2856, 1641, 1610, 1550, 1463, 1373, 1284, 1176, 1099, 829 cmꢃ1
;
ESI/MS m/z: 423 (M þ H)þ.
Pharmazie 63 (2008) 7
501

ORIGINAL ARTICLES
4.3.18. (2S-Ethoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phe-
nyl}-propyl)-isopropyl-amine (6d)
Goto Y, Yamazaki M, Hamana M (1971) Studies on azole compounds. III.
Reactions of oxazole N-oxides with phosphoryl chloride and acetic an-
hydride. Chem Pharm Bull 19: 2050–2057.
Title compound was prepared from 5b following the procedure described
for compound 6b. White solid; m.p. 122–125 ꢀC; yield: 82%; purity: 95%
by HPLC; 1H NMR (300 MHz, DMSO-d6): d 1.0–1.1 (9 H, m), 2.3 (3 H,
s), 2.7 (3 H, m), 2.9 (3 H, m), 3.23 (1 H, m), 3.4–3.6 (3 H, complex), 4.1
(2 H, t, J ¼ 6.0 Hz), 6.8 (2 H, d, J ¼ 8.1 Hz), 7.1 (2 H, d, J ¼ 8.1 Hz), 7.5
(3 H, m), 7.8 (2 H, m); IR (KBr) 3433, 2977, 2345, 1702, 1612, 1512,
1484, 1245, 1220, 1099, 1022, 692 cmꢃ1; ESI/MS m/z: 423 (M þ H)þ.
Kelly DE, Goodpaster BH (2001) Skeletal muscle triglyceride an aspect of
regional adiposity and insulin resistance. Diabetes Care 24: 933–941.
La Rosa JC, Hi J, Vupputuri S (1999) Effect of statins on risk of coronary
disease: a meta-analysis of randomized controlled trials. JAMA 282:
2340–2346.
Lohray BB, Bhushan V, Reddy AS, Rao PB, Reddy NJ, Harikishore P,
Vikramadityan RK, Chakrabarti R, Rajagopalan R, Katneni K (1999)
Novel euglycemic and hypolipidemic agents-4. Pyridyl- and quinolinyl-
containing thiazolidinediones. J Med Chem 42: 2569–2581.
Acknowledgements: Authors are grateful to the management of Zydus
Group for encouragement, Dr. B.B. Lohray and Dr. V.B. Lohray for their
guidance and support. We are also thankful to the Analytical Department
for their support.
Lohray BB, Lohray VB, Bajji AC, Kalchar S, Poondra RR, Padakanti S,
Chakrabarti R, Vikramadithyan RK, Misra P, Juluri S, Mamidi NVSR,
Rajagopalan R (2001) (ꢃ)3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-
ethoxypropanoic acid [(ꢃ)DRF 2725]: a dual PPAR agonist with potent
antihyperglycemic and lipid modulating activity.
2675–2678.
J Med Chem 44:
ZRC communication #188.
Reddy KA, Lohray BB, Bhushan V, Reddy AS, Harikishore P, Rao VV,
Saibaba V, Bajji AC, Rajesh BM, Reddy KV, Chakrabarti R, Rajago-
palan R Novel euglycemic and hypolipidemic agents: Part –– 2 antioxi-
dant moiety as structural motif. (1998) Bioorg Med Chem Lett 8: 999–
1002.
Sauerberg P, Pettersson I, Jeppesen L, Bury PS, Mogensen JP, Wasser-
mann K, Brand CL, Sturis J, Woeldike HF, Fleckner J, Andersen AT,
Mortensen SB, Svensson LA, Rasmussen HB, Lehmann SV, Polivka Z,
Sindelar K, Panajotova V, Ynddal L, Wulff EM (2002) Novel tricyclic-
a-alkyloxyphenylpropionic acids: dual PPARa/g Agonista with hypolipi-
demic and antidiabetic activity. J Med Chem 45: 789–804.
Stales B, Dallongeville J, Auwelx J, Schoonjans K, Leitersdorf E, Fruchart
J (1998) Mechanism of action of fibrates on lipid and lipoprotein meta-
bolism. Circulation 98: 2088–2093.
References
Andersson K, Lindstedt AE (1999) New 3-Aryl-2-hydroxypropanoic acid
derivatives. WO 9962870.
Buckle DR, Cantello BC, Cawthorne MA, Coyle PJ, Dean DK, Failer A,
Haigh D, Hindley RM, Jefcott LJ, Lister CA, Pinto IL, Rami HK, Smith
DG, Smith SA (1996) Non thiazolidinedione antihyperglycaemic agents.
1: a-heteroatom substituted b-phenylpropanoic acids. Bioorg Med Chem
Lett 6: 2121–2126.
Cronet P, Petersen JFW, Folmer R, Blomberg N, Sjoblom K, Karlsson U,
Lindstedt E, Bamberg K (2001) Structure of the PPARa and -g ligand
binding Domain in complex with AZ 242; ligand selectivity and agonist
activation in the PPAR family. Structure 9: 699–706.
Evans M, Rees A (2002) The myotoxicity of statins. Curr Opin Lipidol
13: 415–419.
Tudor C, Feige JN, Harikishore P, Lohray VB, Wahli W, Desvergne B,
Engelborghs Y, Gelman L (2007) Association with coregulators is the
major determinant governing PPAR mobility in living cells. J Biol
Chem 282: 4417.
Hulin B, Newton LS, Lewis DM, Genereux PE, Gibbs EM, Clark DA
(1996) Hypoglycemic activity of a series of a-alkylthio and a-alkoxy
carboxylic acids related to ciglitazone J Med Chem 39: 3897–3907.
Fagerhag J, Li L, Lindstedt A, Eva L (2001) New phenalkyloxy phenyl
derivatives. WO patent 01/40170, Chem Abstr 135: 33372.
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