Synthesis and evaluation of some novel dibenzo[b,d]furan carboxylic acids as potential anti-diabetic agents

Article abstract of DOI:10.1016/j.ejmech.2010.05.020

A series of novel dibenzo[b,d]furan mono-carboxylic acid derivatives were synthesized, characterized and evaluated for their ability to inhibit Protein Tyrosine Phosphatase 1B (PTP1B) in vitro in order to use them as potential anti-diabetic agents. Structure-activity relationship study led to the identification of potent compound 5E which inhibited PTP1B with IC₅₀ value of 82 ± 0.43 nM. Compound 5E was screened in vivo as drug candidate for anti-diabetic activity using rosiglitazone maleate as the standard. Compound 5E showed significant reduction in body weight, fed-state whole blood glucose (WBG), fasting WBG, plasma glucose and plasma cholesterol levels and non-significant reduction in fasting plasma triglyceride levels in ob/ob mice. A series of dibenzo[b,d]furan carboxylic acids were synthesized and evaluated for anti-diabetic activity. Compound 5E inhibited PTP1B with IC₅₀ of 82 nM and reduced WBG and plasma glucose in ob/ob mice.

Full text of DOI:10.1016/j.ejmech.2010.05.020

European Journal of Medicinal Chemistry 45 (2010) 3709e3718
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis and evaluation of some novel dibenzo[b,d]furan carboxylic acids as
potential anti-diabetic agents
,
a
a
N. Lakshminarayana a, Y. Rajendra Prasad b , Laxmikant Gharat , Abraham Thomas ,
*
Shridhar Narayanan a 1, A. Raghuram a, C.V. Srinivasan a 1, Balasubramanian Gopalan a
,
,
,1
a Drug Discovery Division, Glenmark Research Center, Mahape, Navimumbai 400709, India
b Pharmaceutical Chemistry Division, AU College of Pharmaceutical Sciences, Andhra University, Visakhapatnam 530 003, Andhra Pradesh, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of novel dibenzo[b,d]furan mono-carboxylic acid derivatives were synthesized, characterized
and evaluated for their ability to inhibit Protein Tyrosine Phosphatase 1B (PTP1B) in vitro in order to use
them as potential anti-diabetic agents. Structureeactivity relationship study led to the identification of
potent compound 5E which inhibited PTP1B with IC50 value of 82 ꢀ 0.43 nM. Compound 5E was
screened in vivo as drug candidate for anti-diabetic activity using rosiglitazone maleate as the standard.
Compound 5E showed significant reduction in body weight, fed-state whole blood glucose (WBG),
fasting WBG, plasma glucose and plasma cholesterol levels and non-significant reduction in fasting
plasma triglyceride levels in ob/ob mice.
Received 13 December 2009
Received in revised form
8 May 2010
Accepted 10 May 2010
Available online 15 May 2010
Keywords:
Dibenzo[b,d]furan carboxylic acid
PTP1B inhibition
Ó 2010 Elsevier Masson SAS. All rights reserved.
Anti-diabetic activity
1. Introduction
formylchromone III [7], and 2-aryl-2-hydroxypropionic acid IV [8].
Some of them also showed reasonable selectivity towards PTP1B.
Protein tyrosine phosphatase 1B (PTP1B), an intracellular non-
receptor PTPase, plays an essential role in the regulation of insulin
signaling pathway by dephosphorylating the activated insulin
receptor [1]. Whole-body knockout studies of mice showed that
PTP1B is a major regulator of insulin sensitivity and body weight
[2,3] and suggested that PTP1B might be a useful target for the
therapy of diabetes and obesity. T-cell PTPase (TCPTP), a phospha-
tase implicated in regulating T-cell activation, has the highest
homology to PTP1B with 74% sequence identity in the catalytic
domain and 100% sequence identity in the catalytic site [4]. Selec-
tive inhibition of PTP1B over TCPTP is therefore highly desirable
and represents one of the most challenging aspects of anti-diabetic
drug discovery [5]. Targeting a second phosphotyrosine binding
pocket (site 2) near the catalytic site has been proposed as one
possible strategy for gaining additional potency and selectivity.
Numerous small molecules have been described over the last
few years with activity against PTP1B. These include oxalylamino-
In the preceding paper, we have reported the discovery of a series
of potent and selective PTP1B inhibitors based on isochroman
mono-carboxylic acid V (Fig.1) [9], adapting the strategyof targeting
site 2. We now report the discovery of another series of potent and
selective PTP1B inhibitors based on dibenzo[b,d]furan mono-
carboxylic acid. The scaffold was designed in such a way that the
mono-carboxylic acid containing moiety was attached to a hetero-
aryl-aryl system so that the side chain would bridge the secondary
phosphotyrosine binding site and the catalytic site of PTP1B, with
a hope to attain superior selectivity and anti-diabetic activity.
2. Chemistry
The designed compounds were synthesized as outlined in
Schemes 1 and 2. Target compounds (5) based on dibenzo[b,d]
furan-carboxylic acid were prepared following the synthetic route
outlined in Scheme 1.
Dibenzo[b,d]furan (1) was chosen as our chemistry starting
point. The starting material was formylated using the method of
Palmer et al. [10] after few minor modifications to improve the
yields. The formylation was carried out at ꢁ40 ꢂC to 28 ꢂC, using n-
butyl lithium and DMF (dimethylformamide), in THF (tetrahydro-
furan). The obtained dibenzo[b,d]furan-4-carboxaldehyde (2) was
then subjected to oxidation to obtain the carboxylic acid. The
benzoic acid
I (Fig. 1) [4], isoxazolecarboxylic acid II [6],
* Corresponding author. Tel.: þ91 891 2504224, þ91 9440132537 (mobile), þ91
891 2844942 (office); fax: þ91 891 2755075.
E-mail addresses: dryejella@yahoo.co.in, dryrp_au@rediffmail.com (Y.R. Prasad).
Currently associated with Orchid Research Laboratories Ltd., Chennai 600119,
1
India.
0223-5234/$ e see front matter Ó 2010 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2010.05.020

3710
N. Lakshminarayana et al. / European Journal of Medicinal Chemistry 45 (2010) 3709e3718
HO2C
N
O
CO2Me
O
O
HO
N
H
O
NH
OH
CO2Me
O
N
HO
O
HO2C
O
II
I
Ki = 5.7 uM (PTP1B)
Ki = 202 uM (TCPTP)
Ki = 18 nM (PTP1B)
Ki = 65 nM (TCPTP)
HO
CF3
O
O
S
Cl
CO2H
N
CHO
O
O
III
IV
Ki = 4.3 uM (PTP1B)
Ki = 51 uM (TCPTP)
IC50 = 3.2 uM (PTP1B)
COOH
O
O
N
H
S
S
V
IC50 = 51.63 nM (PTP1B)
IC50 = 1821 nM (TCPTP)
Fig. 1. Some of the known PTP1B inhibitors.
traditional method of oxidation using potassium permanganate did
not provide reasonable yield. The probable reason for the low yields
might be because of low solubility of the carboxaldehyde in polar
solvents which are usually employed for permanganate mediated
oxidations. The method of Lindgren et al. [11] using sodium chlorite
as an oxidant and sulphamic acid as acid scavenger, employing
acetoneewater mixture as the solvent was found to be reasonable
yielding. The thus obtained dibenzo[b,d]furan-4-carboxylic acid was
then esterified under standard esterification conditions by refluxing
in methanol with catalytic conc. sulphuric acid. The methyl dibenzo
[b,d]furan-4-carboxylate (3) was then subjected to FriedeleCraft’s
acylation with chloroacetyl chloride at low temperatures to obtain
methyl 8-(2-chloroacetyl)-dibenzo[b,d]furan-4-carboxylate (4) as
per the procedure of Gilman et al. [12]. Having obtained the crucial
substituted carboxamide was employed using phosphorous penta-
sulfide as the sulphur source, which was found to be simple and
could be obtained in one-step, without having to make the thio-
amide. The thiazole substituted dibenzo[b,d]furan ester was then
hydrolyzed using aqueous sodium hydroxide to obtain the desired
target compounds (5).
In order to synthesize few specific compounds with phenyl-
acrylic acid substitution on the thiazole ring, iodophenyl
substituted thiazole ring was constructed following the method
depicted in Scheme 1. The obtained iodophenyl compound (6) was
then reacted with an olefin (methyl or tert-butyl acrylate) under
standard Heck reaction conditions [14] using a tertiary amine, tri-
phenyl phosphine and palladium catalyst. This acrylate compound
(7) was then subjected to hydrolysis to obtain appropriate acrylic
acid derivatives of phenylthiazoles, as depicted in Scheme 2.
The appropriate carboxamides required for thiazole formationwere
either purchased from commercial sources or were prepared as per the
depiction in Schemes 3 and 4. The commercially available fluo-
robenzonitrile (9) was used as the starting material for the preparation
of substituted carboxamides. The displacement of fluoro group with
various secondary amines was achieved by reacting in the presence of
a base in a polar solvent like DMF. The obtained cyano compound (10)
was then hydrolyzed to carboxamide (11) using hydrogen peroxide in
alkaline medium following the method of Noller [15].
a
-haloacetyl intermediate for construction of the thiazole ring, the
focus was then turned tovarious methods for the thiazole formation.
The method of Vernin [13] was employed wherein an appropriately
b
a
O
COOMe
3
O
O
CHO
2
1
At this point it was thought worthwhile to incorporate methyl-
2-(2,6-dibromo-phenoxy)-3-phenylpropanoate moiety and see the
impact on the activity. Methyl-2-(2,6-dibromo-4-carbamoylphe-
noxy)-3-phenylpropanoate was prepared in a four-step synthetic
sequence as depicted in Scheme 4. 4-Hydroxybenzaldeheyde (12)
was dibrominated using N-Bromosuccinimde to get 2,6-dibromo-
4-hydroxy benzaldehyde (13). The obtained hydroxyaldehyde (13)
was then etherified under Mitsunobu conditions to obtain the ether
(14). The aldehyde group of (14) was then converted to nitrile (15)
in one-pot using iodine and aqueous ammonia as per the method of
S
O
R
Cl
N
c
d, e
O
O
COOH
COOMe
5
4
Scheme 1. (a) n-BuLi, THF, DMF, ꢁ40 to 28 ꢂC, 6 h; (b) (1) Acetone, aqueous NaClO2,
NH2SO3H, 0e28 ꢂC, 4 h; (2) Methanol, conc. H2SO4, reflux, 5 h; (c) AlCl3, chloroacetyl
chloride, 0e28 ꢂC, dry CHCl3, 6 h; (d) Carboxamide, P4S10, dioxan, reflux, 5 h; (e)
methanol, aqueous NaOH, reflux, 3 h.

N. Lakshminarayana et al. / European Journal of Medicinal Chemistry 45 (2010) 3709e3718
3711
O
S
N
Cl
I
a
b
O
O
COOMe
COOMe
6
4
S
N
S
N
c
Oalkyl
OH
O
O
O
O
COOMe
7
COOH
8
Scheme 2. (a) Iodobenzamide, P4S10, dioxan, reflux, 5 h; (b) alkyl acrylate, Pd(OAc)2, Ph3P, Et3N, 100 ꢂC, 6 h; (c) methanol, aqueous NaOH, reflux, 3 h; or (1) TFA, CH2Cl2, 28 ꢂC, 3 h;
(2) methanol, aqueous NaOH, reflux, 3 h.
Talukdar et al. [16]. The hydration of the cyano group to carbox-
amide as described in Scheme 3, gave the desired methyl-2-(2,6-
dibromo-4-carbamoylphenoxy)-3-phenylpropanoate (16) which
could be utilized for making the thiazole compound. The physical
constants of all the compounds prepared are given in Table 1.
HbA1c (Randox UK); fully automated biochemical analyzer (Day-
tonaÒ, Randox laboratories, UK); pH meter (Orion, USA); refrigerated
table top centrifuge (Heraeus, USA); Sartorius balance (Sartorius,
Germany); animal balance (sensitivity 10 mg, AND corporation,
India); Vortexer (Spinix, India) and Sonicator (Elma, Germany).
3. In vitro pharmacology
4.2. Animal housing and maintenance
The inhibitory activities of the compounds were determined
with minor modifications of the procedure described in the litera-
ture [7]. Inhibitory activity was determined by the release of p-
nitrophenol by hydrolysis of the synthetic substrate, p-nitrophenyl
phosphate (pNPP) at 37 ꢂC. Both continuous as well as end-point
readings were taken for the reaction. Calculations are done on the
basis of continuous reading. The assay was conducted in a total of
Healthy male ob/ob mice (B6.V-Lepob/J) were procured from The
Jackson laboratories, USA. In all the protocols animals were group-
housed in polypropylene cages as per the respective experimental
protocols. Standard laboratory conditions with 10e15 air changes per
hour, continuously monitored environment, room temperature of
22 ꢀ 3 ꢂC with a relative humidity of 30e70% and 12/12 h of fluo-
rescent light/dark cycle were maintained. ob/ob mice were provided
with 11% fat diet (Lab diets, UK). Unless otherwise specified, all the
animals were provided with drinking water ad libitum. Only drinking
water ad libitum was provided when fasting condition was observed.
Standard mice cages with stainless-steel fasting grills as false bottom
(instead of rice bran bedding) were employed to maintain proper
fasting conditions. Standard hygiene procedures (wearing of dispos-
ablehand gloves, facemasks, headcap)and animalwelfareguidelines
as prescribed by the Institutional Animal Ethics Committee were
followed. Animals were randomized based on their AUCg0e120 of
acute plain OGTT. Eight animals were used in each group.
100
(10
(40 ng/
m
m
L reaction volume. For inhibition assay, inhibitor compound
M in DMSO) was added to a mixture containing 1 L enzyme
L of in-house generated human recombinant PTP1B, TCPTP
m
m
or LAR (Leukocyte common Antigen Related)) and reaction buffer
(Hepes 25 mM, pH 7.0, 3 mM DTT, 0.15 M NaCl, 1 mM EDTA and
Nonidet-P40 (NP-40) 0.01%) and was incubated at 37 ꢂC for 10 min.
The reaction was initiated by the addition of p-nitrophenyl phos-
phate (pNPP, 2.5 mM) and after monitoring continuously for 30 min
at 37 ꢂC, the reaction was quenched by addition of NaOH solution
(2.5 mM). The release of p-nitrophenol was determined by
measuring the absorbance at 405 nm. Test compounds and solvents
were added as 1% of total volume. A standard linear curve of p-
4.3. Whole blood glucose (WBG) measurement
nitrophenol (0e20 mM) was generated which was used to calculate
the catalytic activity. IC50 values were derived from three indepen-
dent experiments using the inhibitors at concentrations of 30 nM,
100 nM, 300 nM, 1.0 mM, 3.0 mM and 10.0 mM and calculations are
done using prism software. The same protocol was followed for
inhibition assay with TCPTP and LAR as well, for selectivity studies.
The IC50 values of the compounds are given in Table 2.
The animal’s tail was cleaned with a cotton swab and the tip was
cut using a fine scissor. Tail was gently massaged if required and
a drop of blood was placed in the area specified on the blood
glucose measuring strip to record the WBG value. Reduction in
Br
CHO
4. In vivo pharmacology
Br
CHO
CHO
a
b
O
HO
HO
Br
4.1. Instruments
COOMe
Br
Hand-held glucometer (Ascensia EntrustÒ, Bayer, Germany);
biochemical kit for plasma glucose, cholesterol, triglycerides and
12
14
13
Br
Br
CN
CONH2
O
c
d
O
O
CN
Br
Br
NH2
CN
COOMe
COOMe
a
b
R1
R1
N
R2
N
R2
F
15
16
9
10
11
Scheme 4. (a) NBS, THF, 28 ꢂC, 5 h; (b) PhCH2CH(OH)COOMe, diethylazodicarboxylate,
Ph3P, THF, 60 ꢂC, 16 h; (c) I2, aqueous NH3 solution, THF, 28 ꢂC, 3 h; (d) aqueous 30%
H2O2, aqueous 6 N NaOH solution, ethanol, 50 ꢂC, 4 h.
Scheme 3. (a) K2CO3, DMF, 60 ꢂC, 3 h; (b) (3.5 equiv) aqueous 30% H2O2, aqueous 6 N
NaOH solution, ethanol, 50 ꢂC, 4 h.

3712
N. Lakshminarayana et al. / European Journal of Medicinal Chemistry 45 (2010) 3709e3718
Table 1
Physical constants of compounds prepared.
S
R
N
O
COOH
Comp. No.
R
Yield (%)
84
Mp (ꢂC)
M.Wt/M.F/C, H, N (% Calc.)
C, H, N (% Found)
5A
184e186
309.34/C17H11NO3S; C, 66.01; H, 3.58; N, 4.53; S, 10.37
C, 66.11; H, 3.72; N, 4.71; S, 10.43
NO2
NH2
5B
5C
83
70
202e203
174e176
416.41/C22H12N2O5S; C, 63.46; H, 2.90; N, 6.73; S, 7.70
386.07/C22H14N2O3S; C, 68.38; H, 3.65; N, 7.25; S, 8.30
C, 63.61; H, 3.13; N, 6.82; S, 7.91
C, 68.51; H, 3.80; N, 7.36; S, 8.44
N
5D
91
190e194
414.48/C24H18N2O3S; C, 69.55; H, 4.38; N, 6.76; S, 7.74
C, 69.69; H, 4.52; N, 6.80; S, 7.83
N
N
5E
5F
5G
74
86
79
196e199
205e208
201e203
440.51/C26H20N2O3S; C, 70.89; H, 4.58; N, 6.36; S, 7.28
454.54/C27H22N2O3S; C, 71.34; H, 4.88; N, 6.16; S, 7.05
456.51/C26H20N2O4S; C, 68.40; H, 4.42; N, 6.14; S, 7.02
C, 70.95; H, 4.67; N, 6.53; S, 7.43
C, 71.52; H, 4.99; N, 6.32; S, 7.22
C, 68.52; H, 4.29; N, 6.28; S, 7.19
O
N
N
O
5H
5I
70
83
209e211
241e243
484.57/C28H24N2O4S; C, 69.40; H, 4.99, N, 5.78; S, 6.62
415.42/C23H13NO5S; C, 66.50; H, 3.15; N, 3.37; S, 7.72
C, 69.55; H, 5.11; N, 5.88; S, 6.84
C, 66.68; H, 3.32; N, 3.52; S, 7.88
O
OH
Br
O
O
5J
65
85
91
249e251
242e245
203e205
693.36/C31H19Br2NO6S; C, 53.70; H, 2.76; N,2.02; S, 4.62
496.96/C22H12INO3S; C, 53.13; H, 2.43; N, 2.82; S, 6.45
496.96/C22H12INO3S; C, 53.13; H, 2.43; N, 2.82; S, 6.45
C, 53.91; H, 2.89; N, 2.15; S, 4.88
C, 53.25; H, 2.62; N, 2.99; S, 6.62
C, 53.28; H, 2.62; N, 2.99; S, 6.60
Br
OH
Ph
I
5K
5L
I
O
8A
8B
85
90
96e97
97e99
441.56/C25H15NO5S; C, 68.02; H, 3.42; N, 3.17; S, 7.26
441.56/C25H15NO5S; C, 68.02; H, 3.42; N, 3.17; S, 7.26
C, 68.20; H, 3.66; N, 3.26; S, 7.44
C, 68.19; H, 3.56; N, 3.30; S, 7.41
OH
OH
O

N. Lakshminarayana et al. / European Journal of Medicinal Chemistry 45 (2010) 3709e3718
3713
Table 2
One-way ANOVA, Dunnett's
multiple comparison test: ,***
p<0.0001vs Vehicle
Vehicle
400
300
200
100
0
IC50 ꢀ SEM (nM)a of compounds against various phosphatases.
Cpd.5E,10mg,ip
Rosi,10mg,po
Compound
PTP1B
TCPTP
LAR
5A
5B
5C
5D
5E
5F
5G
5H
5I
5J
5K
5L
8A
8B
515 (6.12)
201 (2.36)
185 (2.92)
257 (2.90)
82 (0.43)
121 (0.88)
280 (3.21)
187 (2.01)
388 (4.54)
177 (1.63)
395 (4.92)
425 (3.66)
620 (3.66)
551 (4.02)
38 (1.78)
730 (4.85)
348 (1.67)
693 (2.01)
961 (3.94)
1655 (4.21)
2065 (3.24)
1630 (2.32)
1431 (3.26)
2096 (5.61)
3144 (3.87)
1875 (3.26)
1615 (3.56)
983 (6.87)
794 (4.89)
136 (2.65)
1323 (6.89)
2872 (3.09)
2686 (4.98)
3752 (5.86)
2989 (7.93)
2067 (6.09)
2942 (8.91)
2144 (4.65)
3248 (8.02)
3574 (6.50)
2647 (4.06)
2102 (5.83)
1981 (2.03)
2065 (4.94)
410 (7.54)
***
***
Treatments
Fig. 3. Effect of PTP1B inhibitor on fed WBG in ob/ob mice on day 7.
(AUCg0e120) was calculated for each animal of respective group with
respect to baseline (pre-dose) values. Statistical analyses were done
by one-way analysis of variance (ANOVA) followed by Dunnett’s or
Bonferroni’s multiple comparison test with respect to corre-
sponding vehicle controls. GraphPad PrismÒ software was used to
evaluate the statistical significance (p < 0.05 is considered signifi-
cant) wherever applicable. The results of in vivo studies are given in
Figs. 2e7.
I (Reference standard)
a
Values are the mean of three independent experiments with SEM in parenthesis.
blood glucose produced by the compound was calculated. Fed-state
WBG was done on day 7.
4.4. Plain OGTT
Animals were fasted for 16e18 h with free access to water and
basal WBG was measured. An oral glucose load of 1.5 g/kg/10 mL
was administered to all the animals. WBG levels were measured at
30, 60, 90 and 120 min post-glucose load by tail cut method using
blood glucose strips. The percent reduction in AUCg0e120 was
calculated. Chronic plain OGTT was done on day 10.
5. Results and discussion
Compound 5A showed an IC50 of 515 ꢀ 6.12 nM. While intro-
duction of a nitrophenyl ring in place of the methyl group as in
compound 5B showed 201 ꢀ 2.36 nM indicating the requirement of
a lipophilic group in C2 position of the thiazole ring and its nitro
reduced analog 5C showed an IC50 of 185 ꢀ 2.92 nM. Alkylating the
amino functionality as in compound 5D showed an IC50 of
257 ꢀ 2.90 nM. Incorporation of a cyclic secondary amine (pyrroli-
dine) in place of a dialkyl amine on the phenyl ring as in compound
5E showed significant improvement in the potency, with an IC50 of
82 ꢀ 0.43 nM, further endorsing the fact that a bulky lipophilic
group is very essential to get optimal potency. Shifting from five
membered (pyrrolidine) to six membered ring (piperidine) as in
compound 5F resulted in slight reduction in activity. While
changing from pyrrolidine to morpholine (compound 5G) also
resulted in reduced activity suggesting that groups with reduced
lipophilicity may not be well tolerated. The secondary phospho-
tyrosine binding site which is lipophilic in nature reacts better with
lipophilic compounds and hence introduction of alkyl substitution
on morpholino group (compound 5H) has improved the activity.
Replacing the pyrrolidine ring with a carboxylic acid group as in
compound 5I resulted in loss of activity. This further confirmed that
increase in polarity at that position results in either reduction or
loss of activity. A bulky substitution like phenyl-arylalkanoyl ether
as in compound 5J resulted in moderate activity suggesting that
4.5. Blood collection and plasma biochemistry determination
Wherever applicable, blood samples were obtained by retro-
orbital bleeding into eppendorf tubes containing anticoagulant (a
10% EDTA solution in 1:100 ratio to blood). The samples were
immediately kept on ice, followed by centrifugation in a refriger-
ated centrifuge at 4 ꢂC and 3000 rpm for about 10 min. Moreover,
5 mL of whole blood was utilized for HbA1c estimation. Plasma
biochemical parameters (glucose, cholesterol and triglycerides)
were determined immediately after separation using commercially
available biochemical kits on a fully automated clinical chemistry
analyzer. Fasting (18 h) biochemical parameter estimation was
done on day 14.
4.6. Data analysis
All the data are expressed as Mean ꢀ S.E. In OGTT experiments
area under the curve of blood glucose levels from 0 to 120 min
Two-way ANOVA, Bonferroni's multiple
comparison test:
*p<0.05,** p<0.001,*** p<0.0001 Vs
Vehicle
Vehicle
One-way ANOVA, Dunnett's multiple
Vehicle
80
70
60
50
Cpd.5E,10mg,ip
comparison test: ,*** p<0.0001vs
Rosi,10mg,po
Cpd.5E,10mg,ip
Rosi,10mg,po
Lean animal
Vehicle
150
100
50
***
**
**
**
*
***
***
***
0
3
6
9
12
15
0
Days of Treatment
Treatment
Fig. 2. Effect of PTP1B inhibitor on body weight in ob/ob mice.
Fig. 4. Effect of PTP1B inhibitor on fasting WBG in ob/ob mice on day 10.

3714
N. Lakshminarayana et al. / European Journal of Medicinal Chemistry 45 (2010) 3709e3718
300
200
100
0
One-way ANOVA, Dunnett's multiple
comparison test: ,*** p<0.0001vs
Vehicle
Vehicle
One-way ANOVA, Dunnett's multiple
comparison test: *** p<0.0001 vs
Vehicle
150
100
50
Vehicle
Cpd.5E,10mg,ip
Rosi,10mg,po
Cpd.5E,10mg,ip
Rosi,10mg,po
***
***
***
0
Tre atme nt
Treatments
Fig. 5. Effect of PTP1B inhibitor on plasma glucose in ob/ob mice day 14.
Fig. 7. Effect of PTP1B inhibitor on plasma triglycerides in ob/ob mice on day 14.
findings of the in vivo studies with compound 5E on body weight
and plasma cholesterol are also concomitant with the published
literature [17,18] which showed that PTP1B knockout mice have
lower adiposity and are resistant to weight gain because of their
increased sensitivity to leptin. Studies by other researchers with
antisense oligonucleotide (ASO) and hyperglycemic ob/ob mice also
showed that reduction in PTP1B resulted in decreased fat deposits
and triglyceride levels in fat by down-regulating genes involved in
lipogenesis in both fat and liver and genes involved in adipocyte
differentiation in fat [19,20].
a bulky ether is indeed a suitable substitution. Introduction of an
iodo group in place of pyrrolidine, as in compound 5K resulted in
drastic loss of activity. Changing the position of the iodo group from
para to meta position as in compound 5L further decreased the
activity. Introduction of an acrylic acid group on the phenyl ring as
in compounds 8A and 8B also showed drastic reduction in activity.
The specificity of the prepared compounds against LAR is in the
range of 2.5e36 times, with 5E showing the maximum specificity. It
can be concluded from compounds 5B, 5I, 5K and 5L that an
electron-withdrawing group on the phenyl ring is not desired.
Selectivity of the compounds against TCPTP is in the range of
1.5e20 times with compound 5E showing maximum selectivity. It
is hypothesized that the side chain of compound 5E offers the
ability to fully occupy the secondary binding site of the enzyme,
with pyrrolidino group being the optimum for eliciting maximum
selectivity and hence it was selected for in vivo study, using rosi-
glitazone maleate as the standard. Compound 5E decreased body
weight from day 3 onwards and it was highly significant at the end
of 2 weeks treatment whereas rosiglitazone maleate increased
body weight from day 3 onwards (Fig. 2). Treatment with
compound 5E and rosiglitazone normalized the hyperglycemic
condition in ob/ob mice. Both the treatments showed significant
reduction (p < 0.001) in fed-state whole blood glucose (WBG) on
day 7 of the study (Fig. 3). Similar trend was observed in fasting
WBG on day 10 of the study with test compound 5E and rosigli-
tazone showing a reduction compared with vehicle (93 ꢀ 15,
91 ꢀ10 and 90 ꢀ 5, 139 ꢀ 8 mg/dL respectively; Fig. 4). Plasma
glucose before the initiation of the study for test group, rosiglita-
zone group and vehicle group was 199 ꢀ 11, 169 ꢀ 9 and
138 ꢀ 8 mg/dL respectively. Two-week treatment with test
compound 5E showed significant reduction in fasting plasma
glucose as compared with rosiglitazone and vehicle (93 ꢀ 9,
124 ꢀ10 and 194 ꢀ17 mg/dL respectively; Fig. 5). Significant
reduction in plasma cholesterol was seen with test compound 5E
treatment as compared with vehicle (138 ꢀ 17 and 193 ꢀ 4
respectively; Fig. 6). Non-significant reduction in fasting plasma
triglycerides was also observed with test compound 5E (Fig. 7). The
6. Conclusion
In summary we have designed a series of potent, novel, non-
phosphonic acid containing PTP1B inhibitors with good specificity
for PTP1B over TCPTP, the most homologous phosphatase to PTP1B.
A strategy of occupying both the catalytic site and the nearby, less
homologous, non-catalytic phosphotyrosyl binding site is
employed in the present study. An examination of the PTP1B
inhibitors synthesized revealed the residues important for
achieving PTP1B specificity and thus provided an opportunity for
designing more potent and selective PTP1B inhibitors. Although
there is much work reported on aryl difluorophosphonate-con-
taining PTP1B inhibitors, the present study was of considerable
interest to define a small molecule, nonphosphonate-containing,
non-peptide, carboxy-based phenylphosphonate mimetic for use as
PTP1B inhibitors. The hitherto unreported mono-carboxy motif
reported herein provides a new approach, which should be of use in
the design of carboxy-based PTP1B inhibitors and could serve as
advanced lead for further optimization.
7. Experimental
All reactions were performed using oven-dried glassware under
an atmosphere of dry nitrogen. Non-aqueous reagents were
transferred under nitrogen by syringe. Organic solutions were
concentrated under reduced pressure using Buchi rotary evapo-
rator. Tetrahydrofuran was distilled from sodium-benzophenone
ketyl immediately prior to use. Dimethyl sulfoxide (DMSO) was
distilled from CaH2. All other reagents and solvents used were of
laboratory grade and were used without further purification.
Reactions and chromatographic fractions were monitored by thin
layer chromatography. TLC silica gel 60F254, Merck was used for TLC
and silica gel (100e200 mesh, SRL, India) was used for column
chromatography.
300
200
100
0
One-way ANOVA, Dunnett's multiple
comparison test: *** p<0.0001 vs
Vehicle
Vehicle
Cpd.5E,10mg,ip
Rosi,10mg,po
***
All the intermediates and the target compounds were purified
from the reaction mixtures by flash column chromatography unless
otherwise specified. Melting points were measured using POLMON
MP-96T-X melting point apparatus and are uncorrected. 1H and 13
C
Treatment
NMR spectra were recorded on Varian Mercury VX 300 spectrom-
Fig. 6. Effect of PTP1B inhibitor on plasma cholesterol in ob/ob mice on day 14.
eter, using tetramethylsilane as an internal standard and DMSO-d6

N. Lakshminarayana et al. / European Journal of Medicinal Chemistry 45 (2010) 3709e3718
3715
as solvent, unless otherwise specified. IR spectra were acquired on
1413, 1302, 1276, 1192, 1058, 792 and 751 cmꢁ1
d6):
1H), 8.23e8.20 (dd, J ¼ 1.8 Hz and 8.7 Hz, 1H), 8.14e8.10 (dd,
J ¼ 1.5 Hz and 7.8 Hz, 1H), 7.97 (d, J ¼ 8.7 Hz, 1H), 7.62 (t, J ¼ 7.8 Hz,
2H), 5.35 (s, 2H), 3.99 (s, 3H); MS (m/z): 303.72 (M þ H)þ.
;
1H NMR (DMSO-
PerkineElmer spectrum-one FT-IR spectrometer, using KBr discs
for solids and as film for liquids and sticky solids. Mass spectra were
run on Thermo LCQ DECA XP MAX mass spectrometer at 20 eV or
50 eV. Elemental analyses were carried out with a PerkineElmer
model 2400 series II apparatus. The results of elemental analyses
were within ꢀ0.4% of the calculated values.
d
8.96 (d, J ¼ 1.2 Hz, 1H), 8.59e8.56 (dd, J ¼ 1.5 Hz and 7.8 Hz,
7.1.2. Synthesis of phenylacrylic acid substituted thiazolo-
dibenzofurans (8)
7.1. Synthesis of intermediates
7.1.2.1. General procedure for the synthesis of substituted thiazolo-
dibenzofurans(6) (Scheme 2). To a solution of iodobenzamide
(4 mmol) in dioxan was added P4S10 (1 mmol) and stirred the
reaction mixture at 28 ꢂC for 30 min. To the above was then added
methyl 8-(2-chloroacetyl)dibenzo[b,d]furan-4-carboxylate (4,
4 mmol) and refluxed the reaction mixture for 5 h. The cooled
reaction mixture was filtered, residue washed with ethyl acetate,
combined the filtrate and washings, dried over Na2SO4, concen-
trated and purified by column chromatography to get the desired
iodophenyl substituted thiazole.
7.1.1. Procedure for the synthesis of methyl 8-(2-chloroacetyl)
dibenzo[b,d]furan-4-carboxylate (Scheme 1)
7.1.1.1. Synthesis of dibenzo[b,d]furan-4-carboxaldehyde (2). To
a solution of dibenzo[b,d]furan (1, 60 mmol) in dry THF (100 mL)
under N2 atmosphere while stirring at ꢁ40 ꢂC was added n-BuLi
(90 mmol) dropwise and was stirred for 30 min at the same
temperature. To the above was then added dry DMF (120 mmol) at
ꢁ40 ꢂC and the reaction mixture was allowed to warm to room
temperature over a period of 2 h and the stirring was continued at
room temperature for 6 h. The reaction mixture was then acidified
with 1 N HCl and extracted with CH2Cl2. The organic layer was then
dried over Na2SO4 and concentrated. The crude material was then
triturated with pentane and decanted off the pentane layer to get
dibenzo[b,d]furan-4-carboxaldehyde. Yield: 91%; Mp: 165e167 ꢂC;
IR (KBr): 3374, 2836, 2741, 1695, 1625, 1596, 1471, 1429, 1393, 1219,
7.1.2.1.1. Methy
8-[2-(4-iodophenyl)thiazol-4-yl]dibenzo[b,d]
furan-4-carboxylate (6A). Yield: 81%; Mp: 224e225 ꢂC; IR (KBr);
2554, 1728, 1611, 1492, 1468, 1432, 1304, 1189, 1179, 1061, 985, 813
and 748 cmꢁ1
;
1H NMR:
d
8.89 (d, J ¼ 1.5 Hz, 1H), 8.54e8.51 (dd,
J ¼ 1.2 Hz and 7.8 Hz, 1H), 8.29 (s, 1H), 8.28e8.25 (dd, J ¼ 1.5 Hz and
8.4 Hz, 1H), 8.09e8.06 (dd, J ¼ 1.8 Hz and 7.8 Hz, 1H), 7.96e7.87 (m,
5H), 7.56 (t, J ¼ 7.8 Hz, 1H), 4.09 (s, 3H); MS (m/z): 512.33 (M þ H)þ.
1188, 1118, 828 and 753 cmꢁ1; 1H NMR (DMSO-d6):
d
10.45 (s, 1H),
7.1.2.1.2. Methy
8-[2-(3-iodophenyl)thiazol-4-yl]dibenzo[b,d]
8.53e8.50 (dd, J ¼ 0.9 Hz and 7.2 Hz, 1H), 8.26 (d, J ¼ 7.2 Hz, 1H),
8.05e8.02 (dd, J ¼ 1.5 Hz and 7.8 Hz, 1H), 7.84 (d, J ¼ 9.1 Hz, 1H),
7.62 (t, J ¼ 7.2 Hz, 2H), 7.52e7.47 (dt, J ¼ 0.9 Hz and 7.2 Hz, 1H); MS
(m/z): 197.21 (M þ H)þ.
furan-4-carboxylate (6B). Yield: 84%; Mp: 210e213 ꢂC; IR (KBr);
2557, 1731, 1614, 1490, 1467, 1434, 1300, 1191, 1182, 1064, 987, 814
and 745 cmꢁ1 1H NMR:
; d 8.65 (s, 1H), 8.48 (s, 1H), 8.28 (d,
J ¼ 7.8 Hz, 1H), 8.16e8.09 (m, 2H), 8.01 (d, J ¼ 7.8 Hz, 1H), 7.81e7.76
(m, 2H), 7.57 (s, 1H), 7.46 (t, J ¼ 7.8 Hz, 1H), 7.21 (d, J ¼ 7.8 Hz, 1H),
4.08 (s, 3H); MS (m/z): 512.33 (M þ H)þ.
7.1.1.2. Synthesis of methyl dibenzo[b,d]furan-4-carboxylate (3). To
a solution of dibenzo[b,d]furan-4-carboxaldehyde (2, 50 mmol) in
acetone (100 mL) was added sulphamic acid (70 mmol) and was
cooled to 0 ꢂC. To the above was then added an aqueous solution of
sodium chlorite (55 mmol) in water (20 mL) dropwise. The reaction
mixture was then gradually warmed to room temperature and
stirred for 4 h. Acetone was then evaporated from the reaction
mixture on rotavapor, diluted the residue with ethyl acetate and
was washed with water. The organic layer was then dried over
Na2SO4 and concentrated. The crude material was then dissolved in
methanol (100 mL) and was refluxed in the presence of catalytic
amount of conc. H2SO4 for 5 h. Methanol was then evaporated from
the reaction mixture on rotavapor, diluted the residue with ethyl
acetate and was washed with aqueous sodium bicarbonate solu-
tion. The organic layer was then dried over Na2SO4 and concen-
trated. Yield: 89%; Mp: 142e144 ꢂC; IR (KBr): 3423, 2948, 1703,
7.1.3. General procedure for the synthesis of phenylacrylate
substituted thiazolo-dibenzofurans (7)
To a solution of iodophenyl substituted thiazole (6, 3 mmol) in
triethylamine (12 mmol) was added tert-butyl or methyl acrylate
(3 mmol) followed by Pd(OAc)2 (0.06 mmol) and triphenyl phosphine
(0.12 mmol) and stirred the reaction mixture at 100 ꢂC for 6 h. The
cooled reaction mixture was then diluted with dichloromethane,
washed with diluted HCl followed by water, dried over Na2SO4,
concentrated and purified by column chromatography to get the
desired phenylacrylate substituted thiazolo-dibenzofurans (7).
7.1.4. General procedure for the synthesis of phenylacrylic acid
substituted thiazolo-dibenzofurans (8)
To a solution of methyl phenylacrylate substituted thiazole
compound (7, 2 mmol) in methanol (10 mL) was added aqueous
sodium hydroxide solution (8 mmol in 5 mL water) and the reac-
tion mixture was refluxed for 3 h. The cooled reaction mixture was
then acidified with 2 N HCl and the precipitated product was
filtered and dried under vacuum to get the title compound.
1632, 1457, 1432, 1398, 1284, 1205, 1150, 1047 and 744 cmꢁ1
NMR (DMSO-d6):
;
1H
d
8.40e8.37 (dd, J ¼ 1.2 Hz and 7.5 Hz,1H), 8.16 (d,
J ¼ 7.2 Hz, 1H), 8.02e7.99 (dd, J ¼ 1.2 Hz and 7.5 Hz, 1H), 7.75 (d,
J ¼ 8.4 Hz, 1H), 7.58e7.52 (dt, J ¼ 0.9 Hz and 8.1 Hz, 2H), 7.48 (t,
J ¼ 7.5 Hz, 1H), 7.45e7.39 (dt, J ¼ 1.2 Hz and 7.8 Hz, 1H), 3.95 (s, 3H);
MS (m/z): 227.23 (M þ H)þ.
7.1.5. General procedure for the synthesis of substituted benzamides
(Scheme 3)
7.1.1.3. Synthesis of methyl 8-(2-chloroacetyl)dibenzo[b,d]furan-4-
carboxylate (4). To a solution of methyl dibenzo[b,d]furan-4-
carboxylate (3, 45 mmol) in dry CHCl3 (150 mL) while stirring at
0 ꢂC, was added aluminium chloride (135 mmol) and stirred at 0 ꢂC
for 30 min. To the above was then added while stirring at 0 ꢂC,
chloroacetyl chloride (45 mmol) and the reaction mixture was
warmed to room temperature and stirred for 6 h. The reaction
mixture was quenched with 2 N HCl and extracted with chloro-
form. The organic layer was then washed with water, dried over
Na2SO4, concentrated and purified by column chromatography.
Yield: 72%; Mp: 173e176 ꢂC; IR (KBr): 3433, 2939, 1742, 1720, 1688,
7.1.5.1. General procedure for the synthesis of 4-substituted benzo-
nitriles (10). To a solution of 4-fluorobenzonitrile (10 mmol) in dry
DMF (20 mL) was added K2CO3 (20 mmol) followed by the
secondary amine (12 mmol) and stirred the reaction mixture at
60 ꢂC for 3 h. The reaction mixture was then diluted with ethyl
acetate, washed with water followed by 1 N HCl, dried over Na2SO4
and concentrated to get the desired secondary amino benzonitrile.
7.1.5.1.1. 4-(Pyrrolidin-1-yl)benzonitrile. Yield:
142e144 ꢂC; IR (KBr): 2979, 2855, 2211, 1608, 1522, 1392, 1175, 956,
814 and 542 cmꢁ1; 1H NMR (CDCl3):
7.42 (d, J ¼ 8.7 Hz, 2H), 6.48
85%;
Mp:
d

3716
N. Lakshminarayana et al. / European Journal of Medicinal Chemistry 45 (2010) 3709e3718
(d, J ¼ 9.3 Hz, 2H), 3.34e3.29 (m, 4H), 2.06e2.01 (m, 4H). MS (m/z):
173.29 (M þ H)þ.
7.1.6.7. Methyl-4-carbamoylbenzoate[4-(carboxymethyl)
benzamide]. Yield: 66%; Mp: 156e159 ꢂC; IR (KBr): 3406, 3191,
7.1.5.1.2. 4-(Piperidin-1-yl)benzonitrile. Yield:
80%;
Mp:
1725, 1658, 1621, 1417, 1397, 1280, 1115, 869, 713 and 538 cmꢁ1; 1H
153e155 ꢂC; IR (KBr): 2939, 2217, 1605, 1514, 1250, 1180, 1123, 913,
NMR:
d
8.16 (br s, 1H), 8.04e7.97 (AB q, J ¼ 8.4 Hz, 4H), 7.59 (br s,
815 cmꢁ1; 1H NMR:
d
7.53 (d, J ¼ 6.9 Hz, 2H), 6.98 (d, J ¼ 7.2 Hz, 2H),
1H), 3.88 (s, 3H); MS (m/z): 178.15 (M ꢁ H)ꢁ.
3.25 (s, 4H), 1.58 (s, 6H); MS (m/z): 187.29 (M þ H)þ.
7.1.5.1.3. 4-(Morpholino)benzonitrile. Yield:
87%;
Mp:
7.1.7. Synthesis of methyl-2-(2,6-dibromo-4-carbamoylphenoxy)-
3-phenylpropanoate (Scheme 4)
132e135 ꢂC; IR (KBr): 2835, 2217, 1605, 1517, 1453, 1384, 1366, 1267,
1221, 1245, 1181, 1048, 928 cmꢁ1; 1H NMR:
d
7.61 (d, J ¼ 7.2 Hz, 2H),
7.1.7.1. Procedure for the synthesis of 3,5-dibromo-4-hydroxy benz-
aldehyde (13). To a solution of 4-hydroxy benzaldehyde (12,
5 mmol) in dry THF (25 mL) was added N-bromosuccinimide
(10 mmol) and the reaction mixture was stirred at 28 ꢂC for 5 h. The
reaction mixture was then diluted with ethyl acetate, washed with
water, dried over Na2SO4 and concentrated. Yield: 84%; Mp:
7.03 (d, J ¼ 6.9 Hz, 2H), 3.74e3.70 (m, 4H), 3.30e3.25 (m, 4H); MS
(m/z): 189.27 (M þ H)þ.
7.1.5.1.4. 4-(2,6-Dimethylmorpholino)benzonitrile. Yield:
87%;
Mp: 161e163 ꢂC; IR (KBr): 2977, 2212, 1605, 1517, 1377, 1255, 1173,
1087, 820, 541 cmꢁ1 1H NMR:
;
d
7.59 (d, J ¼ 7.8 Hz, 2H), 7.03 (d,
J ¼ 9.0 Hz, 2H), 3.80 (d, J ¼ 11.7 Hz, 2H), 3.67e3.61 (m, 2H),
2.51e2.34 (m, 2H), 1.16 (s, 3H), 1.14 (s, 3H); MS (m/z): 217.26
(M þ H)þ.
192e194 ꢂC; 1H NMR:
z): 278.89 (M ꢁ H)ꢁ.
d 9.87 (s,1H), 7.86 (s, 2H), 5.36 (s,1H); MS (m/
7.1.7.2. Procedure for etherification of 3,5-dibromo-4-hydroxy benz-
aldehyde (14). To a solution of 3,5-dibromo-4-hydroxy benzalde-
hyde (13, 8 mmol) in dry THF (30 mL) was added phenyllactic acid
methyl ester (8 mmol) followed by triphenyl phosphine (12 mmol)
and diethylazodicarboxylate (10 mmol) and stirred the reaction
mixture at 60 ꢂC for 16 h. The reaction mixture was then diluted
with ethyl acetate, washed with water, dried over Na2SO4 and
7.1.6. General procedure for the conversion of substituted
benzonitriles to substituted benzamides (11)
To a solution of substituted benzonitrile (6 mmol) in ethanol
(25 mL) was added aqueous 6 N sodium hydroxide solution (15 mL)
and was cooled to 0 ꢂC. To the above was then added aqueous 30%
H2O2 solution (20 mmol) and stirred the reaction mixture at 50 ꢂC
for 4 h. The reaction mixture was then again cooled to 0 ꢂC, acidi-
fied with 3 N H2SO4 solution, evaporated the ethanol from the
reaction mixture, extracted the residue with CH2Cl2, washed with
water, dried the organic layer over Na2SO4 and concentrated to get
the desired substituted benzamide.
concentrated. Yield: 62%; Mp: 189e191 ꢂC; 1H NMR:
d 9.88 (s, 1H),
7.92 (s, 2H), 7.40e7.28 (br s, 5H), 4.93 (m, 1H), 3.72 (s, 3H),
3.42e3.32 (m, 2H); MS (m/z): 443.11 (M þ H)þ.
7.1.7.3. Procedure for the conversion of substituted benzaldehyde to
substituted benzonitrile (15). To a solution of substituted benzal-
dehyde (5 mmol) in THF (20 mL) was added molecular iodine
(5.5 mmol) followed by aqueous 30% ammonia solution (6 mL) and
stirred the reaction mixture at 28 ꢂC for 3 h. The reaction mixture
was then diluted with ethyl acetate, washed with aqueous
sodiumthiosulpahte solution, followed by water, dried over Na2SO4
and concentrated to get the desired substituted benzonitrile. Yield:
80%; Mp: 177e175 ꢂC; IR (KBr): 3080, 2230, 1761, 1446, 1260, 1216,
7.1.6.1. 4-Nitrobenzamide. Yield: 74%; Mp: 201e203 ꢂC; IR (KBr):
3418, 1661, 1592, 1513, 1339, 1117, 636 and 613 cmꢁ1 1H NMR:
;
d
8.31 (d, J ¼ 9.0 Hz, 2H), 8.29 (br s, 1H), 8.10 (d, J ¼ 9.0 Hz, 2H), 7.75
(br s, 1H); MS (m/z): 167.16 (M þ H)þ.
7.1.6.2. 4-(Dimethylamino)benzamide. Yield: 76%; Mp: 165e168 ꢂC;
IR (KBr): 3393, 3203, 2824, 1645, 1606, 1553, 1518, 1422, 1395, 1364,
1228, 1139, 1097, 1034, 895 and 779 cmꢁ1
;
1H NMR:
d
7.71 (d,
1166, 994, 970 and 738 cmꢁ1; 1H NMR:
d 7.72 (s, 2H), 7.40e7.29 (br
J ¼ 8.7 Hz, 2H), 6.67 (d, J ¼ 9.3 Hz, 2H), 5.75 (br s, 2H), 3.03 (s, 6H);
s, 5H), 4.93 (m, 1H), 3.69 (s, 3H), 3.44e3.22 (m, 2H); MS (m/z):
MS (m/z): 165.22 (M þ H)þ.
440.11 (M þ H)þ.
7.1.6.3. 4-(Pyrrolidin-1-yl)benzamide. Yield: 78%; Mp: 173e176 ꢂC;
7.1.7.4. Methyl-2-(2,6-dibromo-4-carbamoylphenoxy)-3-phenyl-
IR (KBr): 3411, 3166, 2969, 2854, 1651, 1601, 1525, 1378, 1190, 830
propanoate (16). Yield: 69%; Mp: 176e179 ꢂC; IR (KBr): 3438, 2952,
and 777 cmꢁ1
;
1H NMR:
d
7.70 (d, J ¼ 8.7 Hz, 2H), 7.58 (br s, 1H),
2925,1747,1719,1435,1318,1195,1183,1018, 772, 746 and 699 cmꢁ1
;
6.87 (br s, 1H), 6.48 (d, J ¼ 8.7 Hz, 2H), 3.26 (t, J ¼ 6.6 Hz, 4H),
1H NMR:
d 8.38 (s, 2H), 7.51 (br s, 2H), 7.40e7.29 (br s, 5H), 4.92 (m,
1.97e1.92 (m, 4H). MS (m/z): 191.28 (M þ H)þ.
1H), 3.70 (s, 3H), 3.42e3.22 (m, 2H); MS (m/z): 458.12 (M þ H)þ.
7.1.6.4. 4-(Piperidin-1-yl)benzamide. Yield: 69%; Mp: 170e172 ꢂC;
7.2. General procedure for the preparation of substituted thiazoles
IR (KBr): 3402, 2937, 1644, 1607, 1393, 1245, 1124, 1099, 914,
(title compounds 5Ae5L, 6A, 8A, 8B)
832 cmꢁ1; 1H NMR:
d
7.72 (d, J ¼ 9.3 Hz, 2H), 7.67 (br s, 1H), 6.98 (br
s, 1H), 6.90 (d, J ¼ 8.7 Hz, 2H), 3.26e3.20 (br s, 4H), 1.57 (br s, 6H);
To a solution of substituted carboxamide (11, 5 mmol) in dioxan
(25 mL) was added P4S10 (1 mmol) followed by methyl 8-(2-
chloroacetyl)dibenzo[b,d]furan-4-carboxylate (4, 4.5 mmol) and
the reaction mixture was refluxed for 5 h. The cooled reaction
mixture was filtered, residue washed with ethyl acetate, combined
the filtrate and washings, dried over Na2SO4, concentrated and
purified by column chromatography to get the desired substituted
thiazolo dibenzo[b,d]furan. The obtained compound was then dis-
solved in methanol (15 mL), was added aqueous sodium hydroxide
solution (10 mmol) to it and refluxed for 3 h. The reaction mixture
was then cooled, evaporated the methanol from the reaction
mixture and acidified the residue with 2 N HCl. The precipitated
target compound was filtered and dried under vacuum as off white
to pale yellow solid. The obtained crude compound was then
purified by flash column chromatography.
MS (m/z): 205.29 (M þ H)þ.
7.1.6.5. 4-(Morpholino)benzamide. Yield: 71%; Mp: 162e165 ꢂC; IR
(KBr): 3385, 2866, 1681, 1605, 1424, 1381, 1240, 1118, 1051,
921 cmꢁ1; 1H NMR:
d
7.76 (d, J ¼ 8.7 Hz, 2H), 7.74 (br s, 1H), 7.05 (br
s,1H), 6.94 (d, J ¼ 8.7 Hz, 2H), 3.74e3.71 (m, 4H), 3.22e3.18 (m, 4H);
MS (m/z): 207.27 (M þ H)þ.
7.1.6.6. 4-(2,6-Dimethylmorpholino)benzamide. Yield: 81%; Mp:
181e183 ꢂC; IR (KBr): 3386, 3218, 2976,1633,1605,1518,1387,1244,
1087, 776 and 631 cmꢁ1; 1H NMR:
d
7.75 (d, J ¼ 9.3 Hz, 2H), 7.73 (br
s, 1H), 7.05 (br s, 1H), 6.94 (d, J ¼ 8.7 Hz, 2H), 3.73e3.36 (m, 4H),
2.33e2.26 (m, 2H), 1.16 (s, 3H), 1.14 (s, 3H); MS (m/z): 235.28
(M þ H)þ.

N. Lakshminarayana et al. / European Journal of Medicinal Chemistry 45 (2010) 3709e3718
3717
7.2.1. 8-(2-Methylthiazol-4-yl)dibenzo[b,d]furan-4-carboxylic acid
(5A)
(m, 4H), 1.99 (br t, J ¼ 6.3 Hz, 4H); 13C NMR (75 MHz): 172.37,
170.55, 160.59, 159.53, 157.85, 148.77, 130.93, 130.69, 129.35, 129.35,
128.73, 128.17, 127.81, 127.50, 127.50, 127.31, 126.99, 123.28, 117.42,
114.94, 114.94, 114.51, 53.58, 53.58, 25.08, 25.08; MS (m/z): 439.40
(M ꢁ H)ꢁ; M.F: C26H20N2O3S.
The reaction was carried out using methyl 8-(2-chloroacetyl)
dibenzo[b,d]furan-4-carboxylate (4, 2 mmol) and acetamide
(1.8 mmol). Yield: 84%; Mp: 184e186 ꢂC; IR (KBr): 2919, 1709, 1493,
1416, 1273, 1260, 1195, 1182, 1065, 808, 747, 712. 1H NMR:
d 13.4 (br
s, 1H), 8.77 (d, J ¼ 1.5 Hz, 1H), 8.52e8.49 (dd, J ¼ 1.5 Hz and 7.8 Hz,
1H), 8.17e8.13 (dd, J ¼ 2.1 Hz and 8.7 Hz, 1H), 8.07e8.04 (dd,
J ¼ 1.5 Hz and 7.8 Hz, 1H), 8.01 (s, 1H), 7.86 (d, J ¼ 8.7 Hz,1H), 7.54 (t,
J ¼ 7.8 Hz, 1H), 2.77 (s, 3H); MS (m/z): 310.29 (M þ H)þ; M.F:
C17H11NO3S; The structure of the compound was confirmed on the
basis of the spectral data. The mass spectrum showed peak at
311.31 corresponding to the molecular ion peak (M þ H)þ. The FT-IR
spectrum showed broad peak at wave number 2919 cmꢁ1 indi-
cating the presence of a eOH (eCOOH) group and an intense peak
at 1709 cmꢁ1 indicating the presence of carboxylic acid (eCOOH).
7.2.6. 8-{2-[4-(Piperidin-1-yl)phenyl]thiazol-4-yl}dibenzo[b,d]
furan-4-carboxylic acid (5F)
The reaction was carried out using methyl 8-(2-chloroacetyl)
dibenzo[b,d]furan-4-carboxylate (4, 2 mmol) and 4-(piperidin-1-
yl)-benzamide (1.8 mmol). Yield: 86%; Mp: 205e208 ꢂC; IR (KBr):
3397, 2930, 1693, 1605, 1476, 1234, 1191, 1126, 1068, 856, 821,
746 cmꢁ1
;
1H NMR:
d
8.86 (d, J ¼ 1.5 Hz, 1H), 8.54e8.51 (dd,
J ¼ 1.5 Hz and 7.8 Hz, 1H), 8.26e8.23 (dd, J ¼ 1.8 Hz and 8.7 Hz, 1H),
8.10e8.04 (m, 2H), 7.93e7.87 (m, 3H), 7.55 (t, J ¼ 7.8 Hz, 1H),
7.15e7.07 (m, 2H), 3.40 (br s, 4H),1.58 (br s, 6H); 13C NMR (75 MHz):
172.37, 170.55, 160.59, 159.53, 157.85, 150.34, 130.93, 130.69, 129.35,
129.35, 128.73, 128.17, 127.81, 127.42, 127.42, 127.31, 126.99, 123.28,
117.42, 114.60, 114.60, 114.51, 48.40, 48.40, 25.40, 25.40, 24.20, MS
(m/z): 455.52 (M þ H)þ; M.F: C27H22N2O3S.
The 1H NMR spectrum in DMSO-d6 showed a broad singlet at
indicating the presence of a eCOOH group and a meta-coupling
doublet at 8.77 for the aromatic proton of dibenzo[b,d]furan.
d 13.4
d
7.2.2. 8-[2-(4-Nitrophenyl)thiazol-4-yl]dibenzo[b,d]furan-4-
carboxylic acid (5B)
7.2.7. 8-[2-(4-Morpholinophenyl)thiazol-4-yl]dibenzo[b,d]furan-4-
carboxylic acid (5G)
The reaction was carried out using methyl 8-(2-chloroacetyl)
dibenzo[b,d]furan-4-carboxylate (4, 2 mmol) and 4-nitro-
benzamide (1.8 mmol). Yield: 83%; Mp: 202e203 ꢂC; IR (KBr): 3412,
The reaction was carried out using methyl 8-(2-chloroacetyl)
dibenzo[b,d]furan-4-carboxylate (4, 2 mmol) and 4-morpholino
benzamide (1.8 mmol). Yield: 79%; Mp: 201e203 ꢂC; IR (KBr): 3419,
2922, 1699, 1614, 1492, 1409, 1194, 1178, 1077, 809, 748, 717 cmꢁ1
;
1H NMR:
d
8.90 (s, 1H), 8.60e8.30 (dd, J ¼ 0.9 Hz and 8.7 Hz, 1H),
2919, 1682, 1606, 1474, 1305, 1231, 1191, 1120, 925, 819, 708 cmꢁ1
;
8.43 (s, 1H), 8.40e8.27 (m, 5H), 8.09 (d, J ¼ 8.4 Hz, 1H), 7.91 (d,
J ¼ 8.7 Hz,1H), 7.58 (t, J ¼ 7.8 Hz,1H). MS (m/z): 415.43 (M ꢁ H)ꢁ; M.
F: C22H12N2O5S.
1H NMR:
d
8.88 (d, J ¼ 2.1 Hz, 1H), 8.55e8.52 (dd, J ¼ 1.2 Hz and
7.5 Hz, 1H), 8.27e8.23 (dd, J ¼ 1.8 Hz and 8.7 Hz, 1H), 8.10 (s, 1H),
8.09e8.06 (dd, J ¼ 1.5 Hz and 7.8 Hz, 1H), 7.94 (d, J ¼ 8.7 Hz, 2H),
7.90 (d, J ¼ 9.0 Hz,1H), 7.56 (t, J ¼ 7.8 Hz, 1H), 7.09 (d, J ¼ 9.0 Hz, 2H),
3.82e3.75 (m, 4H), 3.27e3.24 (m, 4H); MS (m/z): 457.50 (M þ H)þ;
M.F: C26H20N2O4S.
7.2.3. 8-[2-(4-Aminophenyl)thiazol-4-yl]dibenzo[b,d]furan-4-
carboxylic acid (5C)
The reaction was carried out using methyl 8-(2-chloroacetyl)
dibenzo[b,d]furan-4-carboxylate (4, 2 mmol) and 4-amino benza-
mide (1.8 mmol). Yield: 70%; Mp: 174e176 ꢂC; IR (KBr): 3416, 3315,
2920, 1695, 1611, 1489, 1407, 1191, 1176, 1074, 807, 744, 714 cmꢁ1; 1H
7.2.8. 8-{2-[4-(2,6-Dimethylmorpholino)phenyl]thiazol-4-yl}
dibenzo[b,d]furan-4-carboxylic acid (5H)
The reaction was carried out using methyl 8-(2-chloroacetyl)
dibenzo[b,d]furan-4-carboxylate (4, 2 mmol) and 4-(2,6-dimethyl
morpholino)-benzamide (1.8 mmol). Yield: 70%; Mp: 209e211 ꢂC;
IR (KBr): 2973, 2824, 1688, 1607, 1471, 1445, 1286, 1230, 1192, 1158,
NMR:
d
8.86 (d, J ¼ 1.5 Hz, 1H), 8.58e8.54 (dd, J ¼ 1.5 Hz and 7.8 Hz,
1H), 8.26e8.22 (dd, J ¼ 1.8 Hz and 8.7 Hz, 1H), 8.10e8.07 (dd,
J ¼ 1.8 Hz and 7.5 Hz,1H), 7.99 (s,1H), 7.88 (d, J ¼ 8.4 Hz,1H), 7.76 (d,
J ¼ 8.4 Hz, 2H), 7.58 (t, J ¼ 7.8 Hz, 1H), 6.67 (d, J ¼ 8.4 Hz, 2H), 5.74
(br s, 2H). MS (m/z): 387.43 (M þ H)þ; M.F: C22H14N2O3S.
1088, 818 and 710 cmꢁ1 1H NMR:
; d 13.4 (br s, 1H), 8.87 (d,
J ¼ 1.2 Hz, 1H), 8.55e8.51 (dd, J ¼ 1.5 Hz and 7.8 Hz, 1H), 8.27e8.23
(dd, J ¼ 1.5 Hz and 8.1 Hz, 1H), 8.09e8.05 (m, 2H), 7.93 (d, J ¼ 9.0 Hz,
2H), 7.88 (s, 1H), 7.56 (t, J ¼ 7.8 Hz, 1H), 7.09 (d, J ¼ 9.0 Hz, 2H),
3.80e3.65 (m, 4H), 2.37 (t, J ¼ 11.2 Hz, 2H), 1.20 (s, 3H), 1.18 (s, 3H);
MS (m/z): 485.59 (M þ H)þ; M.F: C28H24N2O4S.
7.2.4. 8-{2-[4-(Dimethylamino)phenyl]thiazol-4-yl}dibenzo[b,d]
furan-4-carboxylic acid (5D)
The reaction was carried out using methyl 8-(2-chloroacetyl)
dibenzo[b,d]furan-4-carboxylate (4, 2 mmol) and 4-dimethylamino
benzamide (1.8 mmol). Yield: 91%; Mp: 190e194 ꢂC; IR (KBr): 3418,
7.2.9. 8-[2-(4-Carboxyphenyl)thiazol-4-yl]dibenzo[b,d]furan-4-
carboxylic acid (5I)
2918, 1693, 1609, 1487, 1404, 1189, 1174, 1071, 806, 746, 712 cmꢁ1
;
1H NMR:
d
8.81 (s, 1H), 8.35 (d, J ¼ 7.5 Hz, 1H), 8.23e8.19 (dd,
The reaction was carried out using methyl 8-(2-chloroacetyl)
dibenzo[b,d]furan-4-carboxylate (4, 2 mmol) and 4-(carbox-
ymethyl) benzamide (1.8 mmol). Yield: 83%; Mp: 241e243 ꢂC; IR
(KBr): 3427, 2923, 2549, 1688, 1607, 1475, 1427, 1300, 1191, 1177,
J ¼ 1.5 Hz and 9.0 Hz, 1H), 8.02 (s, 1H), 7.96 (d, J ¼ 7.8 Hz, 1H), 7.90
(d, J ¼ 8.7 Hz, 2H), 7.84 (d, J ¼ 9.0 Hz,1H), 7.46 (t, J ¼ 7.5 Hz,1H), 6.83
(d, J ¼ 8.7 Hz, 2H), 3.00 (s, 6H); MS (m/z): 415.28 (M þ H)þ; M.F:
C24H18N2O3S.
1070, 857, 814, 747, 713 cmꢁ1
;
1H NMR:
d
8.92 (d, J ¼ 1.5 Hz, 1H),
8.55e8.50 (m, 1H), 8.36 (s, 1H), 8.30e8.21 (m, 3H), 8.13e8.06 (m,
3H), 7.92 (d, J ¼ 8.7 Hz, 1H), 7.56 (t, J ¼ 7.8 Hz, 1H); MS (m/z): 414.45
(M ꢁ H)ꢁ; M.F: C23H13NO5S.
7.2.5. 8-{2-[4-(Pyrrolidin-1-yl)phenyl]thiazol-4-yl}dibenzo[b,d]
furan-4-carboxylic acid (5E)
The reaction was carried out using methyl 8-(2-chloroacetyl)
dibenzo[b,d]furan-4-carboxylate (4, 2 mmol) and 4-(pyrrolidin-1-
yl)-benzamide (1.8 mmol). Yield: 74%; Mp: 196e199 ꢂC; IR (KBr):
3433, 2962, 1667, 1615, 1571, 1487, 1469, 1381, 1186, 1173, 819, 741
7.2.10. 8-[2-(3,5-Dibromo-4-(1-carboxy-2-phenylethoxy)phenyl)
thiazol-4-yl]dibenzo[b,d] furan-4-carboxylic acid (5J)
The reaction was carried out using methyl 8-(2-chloroacetyl)
dibenzo[b,d]furan-4-carboxylate (4, 2 mmol) and methyl-2-(2,6-
dibromo-4-carbamoylphenoxy)-3-phenylpropanoate (16,1.8 mmol).
and 715 cmꢁ1
;
1H NMR:
d
8.74 (d, J ¼ 1.5 Hz, 1H), 8.18e8.14 (dd,
J ¼ 1.8 Hz and 8.4 Hz,1H), 8.12 (d, J ¼ 7.5 Hz,1H), 7.97 (s,1H), 7.89 (d,
J ¼ 9.0 Hz, 2H), 7.82e7.79 (dd, J ¼ 1.2 Hz and 7.5 Hz, 1H), 7.76 (d,
J ¼ 8.4 Hz, 1H), 7.32 (t, J ¼ 7.5 Hz, 1H), 6.66 (d, J ¼ 8.7 Hz, 2H), 3.33
Yield: 65%; Mp: 249e251 ꢂC; IR (KBr): 3434, 2923, 1630, 1606, 1490,
1
1449, 1411, 1259, 1191, 1068, 827 and 742 cmꢁ1; H NMR:
d 8.86 (d,

3718
N. Lakshminarayana et al. / European Journal of Medicinal Chemistry 45 (2010) 3709e3718
J ¼ 1.5 Hz, 1H), 8.52e8.49 (dd, J ¼ 1.5 Hz and 7.8 Hz, 1H), 8.28 (s, 1H),
8.25e8.21 (m, 3H), 8.04e8.01 (dd, J ¼ 1.2 Hz and 7.5 Hz, 1H), 7.86 (d,
J ¼ 8.7 Hz, 1H), 7.51 (t, J ¼ 7.5 Hz, 1H), 7.35e7.20 (m, 5H), 5.19 (t,
J ¼ 6.6 Hz, 1H), 3.36e3.25 (m, 2H); MS (m/z): 694.41 (M þ H)þ; M.F:
C31H19Br2NO6S.
eCOOH protons and a doublet at d 8.92 for the aromatic meta-
coupling proton of dibenzo[b,d]furan ring.
7.2.14. (E)-8-{2-[3-(2-Carboxyvinyl)phenyl]thiazol-4-yl}dibenzo[b,
d]furan-4-carboxylic acid (8B)
The reaction was carried out as per the method described for the
preparation of 8A, using methy 8-[2-(3-iodophenyl)thiazol-4-yl]
dibenzo[b,d]furan-4-carboxylate (6B, 3 mmol) to get the ester 7B,
which was then subjected to hydrolysis and the crude product was
purified by flash column chromatography to get the title compound
8B. Yield: 82%; Mp: 217e219 ꢂC; IR (KBr): 3435, 2928, 1699, 1637,
7.2.11. 8-[2-(4-Iodophenyl)thiazol-4-yl]dibenzo[b,d]furan-4-
carboxylic acid (5K)
The reaction was carried out using methyl 8-(2-chloroacetyl)
dibenzo[b,d]furan-4-carboxylate (4, 2 mmol) and 4-iodo benza-
mide (1.8 mmol). Yield: 84%; Mp: 214e216 ꢂC; IR (KBr); 2838, 2551,
1693, 1608, 1490, 1470, 1430, 1301, 1190, 1177, 1059, 982, 815 and
1483, 1431, 1275, 1199, 1074, 752 cmꢁ1 1H NMR:
; d 13.40 (br s, 1H),
746 cmꢁ1
;
1H NMR:
d
13.42 (br s, 1H), 8.89 (d, J ¼ 1.5 Hz, 1H),
12.50 (br s,1H), 8.94 (d, J ¼ 1.5 Hz,1H), 8.55 (d, J ¼ 6.9 Hz,1H), 8.37 (s,
1H), 8.35e8.26 (m, 2H), 8.14 (d, J ¼ 7.2 Hz, 2H), 8.07 (d, J ¼ 7.8 Hz,1H),
7.93e7.85 (m, 2H), 7.75 (d, J ¼ 15.9 Hz,1H), 7.65e7.54 (m, 2H), 6.73 (d,
J ¼ 16.2 Hz, 1H); MS (m/z): 442.22 (M þ H)þ; M.F: C25H15NO5S.
8.54e8.51 (dd, J ¼ 1.2 Hz and 7.8 Hz, 1H), 8.29 (s, 1H), 8.28e8.25
(dd, J ¼ 1.5 Hz and 8.4 Hz, 1H), 8.09e8.06 (dd, J ¼ 1.8 Hz and 7.8 Hz,
1H), 7.96e7.87 (m, 5H), 7.56 (t, J ¼ 7.8 Hz, 1H); MS (m/z): 498.29
(M þ H)þ; M.F: C22H12INO3S.
Acknowledgement
7.2.12. 8-[2-(3-Iodophenyl)thiazol-4-yl]dibenzo[b,d]furan-4-
carboxylic acid (5L)
The reaction was carried out using methyl 8-(2-chloroacetyl)
dibenzo[b,d]furan-4-carboxylate (4, 2 mmol) and 3-iodo benza-
mide (1.8 mmol). Yield: 79%; Mp: 201e204 ꢂC; IR (KBr); 2943,
2555, 1690, 1601, 1494, 1471, 1434, 1305, 1194, 1173, 1064, 986, 810
One of the authors (NLN) thanks Glenmark pharmaceuticals
limited for granting permission to carry out this research work.
References
and 742 cmꢁ1
;
1H NMR:
d
13.40 (br s, 1H), 8.92 (d, J ¼ 1.5 Hz, 1H),
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1486, 1428, 1279, 1196, 1072, 750 cmꢁ1; 1H NMR:
d 13.00 (br s, 2H),
8.92 (d, J ¼ 1.5 Hz, 1H), 8.54 (d, J ¼ 6.3 Hz, 1H), 8.31 (s, 1H),
8.31e8.27 (dd, J ¼ 1.5 Hz and 8.7 Hz, 1H), 8.14 (d, J ¼ 8.4 Hz, 2H),
8.07 (d, J ¼ 6.3 Hz, 1H), 7.93e7.88 (m, 3H), 7.68 (d, J ¼ 16.2 Hz, 1H),
7.56 (t, J ¼ 7.8 Hz, 1H), 6.67 (d, J ¼ 15.9 Hz, 1H); 13C NMR (75 MHz):
172.37, 170.55, 168.10, 160.59, 159.53, 157.85, 143.90, 137.59, 134.65,
130.93, 130.69, 129.35, 128.73, 128.17, 127.88, 127.88, 127.81, 127.31,
126.99, 126.14, 126.14, 123.28, 117.42, 116.80, 114.51; MS (m/z):
442.10 (M þ H)þ; M.F: C25H15NO5S; The structure of the compound
was confirmed on the basis of the spectral data. The mass spectrum
showed peak at 442.10 corresponding to the molecular ion peak
(M þ H)þ. The FT-IR spectrum showed broad peak at wave number
3435 cmꢁ1 indicating the presence of eCOOH group. The 1H NMR
spectrum in DMSO-d6 showed a broad singlet at
d 13.00 for the