Synthesis and antidiabetic activity of 2,5-disubstituted-3-imidazol-2-yl-pyrrolo[2,3-b]pyridines and thieno[2,3-b]pyridines

Article abstract of DOI:10.1016/j.bmc.2007.08.005

In the present investigation, two series of 2,5-disubstituted-3-imidazol-2-yl-pyrrolo[2,3-b]pyridines (2a-l) and thieno[2,3-b]pyridines (3a-l) were designed as analogs of BL 11282 (1). The in vitro glucose dependent insulinotropic activity of all the test compounds was evaluated using RIN5F cell based assay and all the test compounds showed glucose and concentration dependent insulin secretion. The in vivo antidiabetic activities of most potent compounds from each series (2c and 3c) were assessed in C57BL/6J mice. Compounds 2c and 3c showed dose dependent insulin secretion and significant glucose reduction in vivo. In general, compounds 2c and 3c were found to be equipotent at all the three different doses selected and with respect to BL 11282, both the test compounds were found to be more potent, at all the time points.

Full text of DOI:10.1016/j.bmc.2007.08.005

Bioorganic & Medicinal Chemistry 15 (2007) 6782–6795
Synthesis and antidiabetic activity of 2,5-disubstituted-
3-imidazol-2-yl-pyrrolo[2,3-b]pyridines and thieno[2,3-b]pyridinesq
Rajesh H. Bahekar,* Mukul R. Jain, Pradip A. Jadav, Vijay M. Prajapati, Dipam N. Patel,
Arun A. Gupta, Ajay Sharma, Robby Tom, Debdutta Bandyopadhya,
Honey Modi and Pankaj R. Patel
Zydus Research Centre, Cadila Healthcare Ltd, Sarkhej-Bavala N.H. 8A, Moraiya, Ahmedabad 382210, India
Received 5 June 2007; revised 31 July 2007; accepted 1 August 2007
Available online 10 August 2007
Abstract—In the present investigation, two series of 2,5-disubstituted-3-imidazol-2-yl-pyrrolo[2,3-b]pyridines (2a–l) and thieno[2,3-
b]pyridines (3a–l) were designed as analogs of BL 11282 (1). The in vitro glucose dependent insulinotropic activity of all the test
compounds was evaluated using RIN5F cell based assay and all the test compounds showed glucose and concentration dependent
insulin secretion. The in vivo antidiabetic activities of most potent compounds from each series (2c and 3c) were assessed in C57BL/
6J mice. Compounds 2c and 3c showed dose dependent insulin secretion and significant glucose reduction in vivo. In general, com-
pounds 2c and 3c were found to be equipotent at all the three different doses selected and with respect to BL 11282, both the test
compounds were found to be more potent, at all the time points.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
Therefore, such compounds are often associated with
hypoglycemic episodes.9
The sulfonylurea class of antidiabetic drugs are known
to block KATP channels in the b-cells and stimulate
insulin secretion both at low and high glucose concen-
trations.1 The strong insulinotropic effect of these com-
pounds at low glucose concentrations is often
associated with the hypoglycemic episodes in diabetic
patients.2 Therefore, agents that augment glucose-in-
duced insulin secretion, without modulating the basal
insulin secretion may be better therapeutic alternatives
to sulfonylureas. In the last two decades, several ary-
limidazolines have been reported as potent stimulators
of insulin secretion in the pancreatic b-cells.3–5 How-
ever, most of the arylimidazolines possess both the
KATP channel activity and a direct effect on exocytosis
of insulin.6–8 Arylimidazolines, which act via KATP
channel are not therapeutically useful since they stimu-
late basal as well as glucose-induced insulin release.
The recent discovery of imidazoline compounds that do
not stimulate basal insulin secretion, lack effect on KATP
channel activity but markedly potentiate glucose-in-
duced insulin secretion has attracted much attention as
possible therapeutic agents for the treatment of type 2
diabetes.10–12 One such novel imidazoline compound is
BL 11282 (1; Fig. 1).13,14 In pancreatic islets of diabetic
db/db mice, BL 11282 was reported to restore the bipha-
sic insulin secretion, by amplifying glucose-induced insu-
lin secretion at a site distal to Ca2+-influx.15,16 Earlier,
we reported synthesis and antidiabetic activity of het-
ero-aryl guanidine derivatives, which were designed as
analog of BL 11282.17 Knowing the in vitro glucose-
dependent insulin secretion potential of BL 11282, in
the present investigation, two series of arylimidazolines
(2,5-disubstituted-3-imidazol-2-yl-pyrrolo[2,3-b]pyridine
(2a–l) and 2,5-disubstituted-3-imidazol-2-yl-thieno[2,3-
b]pyridine (3a–l)) were designed as analogs of BL
11282 (1). Compounds 2a–l and 3a–l were evaluated
in vitro for their glucose-dependent insulinotropic activ-
ity using RIN5F (Rat Insulinoma) cell-based assay.18,19
The in vivo antidiabetic activity of some of the selected
arylimidazolines (compounds 2c and 3c) was assessed,
using hyperglycemic C57BL/6J mice.20,21
Keywords: Arylimidazoline; Type 2 diabetes; Pyrrolo[2,3-b]pyridine;
Thieno[2,3-b]pyridine; Insulinotropic; Antidiabetic.
q
ZRC communication No. 227.
*
Corresponding author. Tel.: +91 2717 250801; fax: +91 2717
250606; e-mail: rajeshbahekar@zyduscadila.com
0968-0896/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2007.08.005

R. H. Bahekar et al. / Bioorg. Med. Chem. 15 (2007) 6782–6795
6783
HN
HN
HN
N
N
N
Cl
R1
R1
R2
R2
N
N
S
N
N
H
H
2a-l
BL11282 (1)
3a-l
2a & 3a: R1=H & R2=H;
2c & 3c: R1=Cl & R2=CH3;
2e & 3e: R1=H & R2=C6H5;
2b & 3b: R1=Cl & R2=H;
2d & 3d: R1=H & R2=CH3;
2f & 3f: R1=Cl & R2=C6H5;
2g & 3g: R1=H & R2=Cyclohex;
2i & 3i: R1=H & R2=C2H5;
2h & 3h: R1=Cl & R2=Cyclohex;
2j & 3j: R1=Cl & R2=C2H5;
2k & 3k: R1=H & R2=CH2-C6H5;
2l & 3l: R1=Cl & R2=CH2-C6H5.
Figure 1. Structures of 2,5-disubstituted arylimidazoline derivatives.
2. Chemistry
tion of compound 7, yields 66–70%.27 Furthermore,
compound 5 was prepared by Duff reaction, which in-
volved formylation of 2,5-disubstituted-1H-pyrrolo[2,3-
b]pyridine (4), at position-3, with hexamethylenetetra-
mine (HMTA) in refluxing aqueous acetic acid.28 The
yields in this reaction were consistently good (69–78%)
and the product was pure enough for the next step.
When the formylation of 2,5-disubstituted-1H-pyrrol-
o[2,3-b]pyridine (4) was attempted under normal Vils-
Several 2,5-disubstituted-3-(4,5-dihydro-1H-imidazol-2-
yl)-1H-pyrrolo[2,3-b]pyridines (2a–l) were synthesized
using the synthetic route outlined in Scheme 1. 2,5-
Disubstituted-1H-pyrrolo[2,3-b]pyridine-3-carbonitriles
(7) were condensed with ethylenediamine (EDA), using
phosphorus pentasulfide (P2S5)22 When the nucleophilic
addition of EDA to compound 7, in the presence of cat-
alytic amounts of other sulfur reagents such as CS223 or
sulfur powder24 was conducted, the formation of the
imidazoline moiety did not take place. Attempts were
also made to prepare the compounds 2a–l, by either con-
densing the compound 7 with EDA using sodium meth-
oxide25 or condensing the corresponding esters of
compound 7 with EDA, in the presence of the trimeth-
ylaluminum.26 Both these reaction conditions lead to
the formation of multiple by-products and poor yields
(ꢀ5%). Compound 7, in turn, was prepared from 2,5-
disubstituted-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde
(5). In general, Compound 5 was first converted to 2,5-
disubstituted-1H-Pyrrolo[2,3-b]pyridine-3-carbaldehyde
oxime (6), mainly as a trans isomer, yields 66–71%.
Dehydration of the corresponding oxime (6) with acetic
anhydride followed by its hydrolysis leads to the forma-
meier
reaction
condition,
using
phosphorus
oxychloride (POCl3) and dimethylformamide (DMF),
formation of 2,5-disubstituted-1H-pyrrolo[2,3-b]pyri-
dine-3-carbaldehyde (5) did not take place. This experi-
ment confirms earlier observations about Vilsmeier
reaction that the formylation of 7-azaindoles did not
take place, when the ‘NH’ of 7-azaindole is unsubstituted.28
Furthermore, 2,5-disubstituted 7-azaindoles (4) were pre-
pared starting from 5-substituted-3-methyl-pyridin-2-yla-
mine by either the directed ortho-lithiation reaction29 or
by the modified Madelung reaction, using sodium ethoxide
as a catalyst.30
The synthesis of 2,5-disubstituted-3-(4,5-dihydro-1H-
imidazol-2-yl)-thieno[2,3-b]pyridine (3a–l) was con-
ducted, by the condensation of 2,5-disubstituted-thie-
CH=NOH
R2
R1
CHO
R2
R1
R1
R2
a
b
N
N
H
N
N
N
5a-l
N
H
H
6a-l
c
4a-l
R1 = H, Cl
R2 = H, CH3, C2H5,
C6H5, Cyclohex,
-CH2-C6H5
CN
HN
N
R1
R1
d
R2
R2
N
N
H
N
N
H
7a-l
2a-l
Scheme 1. Reagents and conditions: (a) HMTA/acetic acid, 6 h, reflux; (b) NH2OH/HCl, 60 ꢁC; (c) Acetic anhydride, 4 h, reflux; (d) EDA/P2S5,
120 ꢁC, 5 h.

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R. H. Bahekar et al. / Bioorg. Med. Chem. 15 (2007) 6782–6795
N
NH
R2
CN
NH2
R1
R1
R1
a
b
R2
R2
S
S
S
N
N
N
8a-l
R1 = H, Cl
9a-l
3a-l
R2 = H, CH3, C2H5, C6H5, Cyclohex, -CH2-C6H5
Scheme 2. Reagents and conditions: (a) HCl/NaNO2/CuCN/NaCN, reflux, 3 h; (b) EDA/P2S5, 120 ꢁC, 5 h.
no[2,3-b]pyridine-3-carbonitrile (9), with EDA, using
P2S5, Scheme 2.22 Compound 9 (yields 66–72%) was pre-
pared from 2,5-disubstituted-thieno[2,3-b]pyridin-3-yla-
mine (8) by Sandmeyer reaction, in which the
diazonium salt was generated in situ, using a mixture
of sodium nitrite (NaNO2) and HCl, followed by the
addition of a mixture of copper(I) cyanide, in an excess
of sodium cyanide solution.31 Compound 8 was pre-
pared in turn starting from 2-mercapto-5-substituted-
nicotinonitrile, via Thorpe–Ziegler isomerization.32
and 10 lM), both in presence or absence of glucose load.
Tolbutamide showed significant insulin secretion both in
presence or absence of glucose load (Table 1).
In pyrrolo[2,3-b]pyridine (2a–l) series, compounds 2c,
2f, and 2j showed highest insulin secretion, compounds
2a–b and 2g–i showed minimal insulin secretion, while
compounds 2d–e and 2k–l showed moderate insulin
secretion, in presence of glucose load. In thieno[2,3-
b]pyridine (3a–l), series, compounds 3c, 3f, and 3j
showed highest insulin secretion, compounds 3a–b and
3g–i showed minimal insulin secretion, while com-
pounds 3d–e and 3k–l showed moderate insulin secre-
tion, in presence of glucose load. In general, insulin
secretion profile of compounds 2c, 2f, 2j, 3c, 3f, and 3j
was found to be better than BL 11282. Furthermore,
among these six compounds from two different series,
compounds 2c and 3c were found to be most potent
compounds.
The overall percentage yield of compounds 2a–l and 3a–
l was found to be in the range of 65–72%. The IR spectra
(KBr; cmÀ1) of compounds 5a–l showed characteristic
peaks for aldehyde group, in the region of 1690 (C@O
stretching), compounds 6a–l showed absorption peaks
for oxime group, in the region of 1160 (–CH@N–
stretching), compounds 7a–l and 9a–l showed peaks
for nitrile group, in the range of 2260 (–CN–stretching).
Final compounds 2a–l and 3a–l showed characteristic
peaks in the region of ꢀ3400 (N–H stretching), ꢀ2885
(C–H stretching), 1610 (N–H bending), 1283 (C–N
stretching), 1172 (C–N stretching) and 771 (C–H bend-
ing). 1H NMR spectra of compounds 5a–l showed charac-
teristic chemical shift (d ppm) at 9.89–9.98, due to 1H of
aldehyde group, compounds 6a–l showed chemical shift
at 11.13-11.19, due to OH of oxime and compounds 2a–
l and 3a–l showed chemical shift at 2.46–2.48 (s, 4H),
due to 4 protons of imidazoline ring. The corresponding
IR, 1H NMR, ESI-MS, and CHN data are presented in
Section 5.2. Synthesis of BL 11282 was conducted by lit-
erature procedure.33
Overall, in both the series, compounds with R1 = H
showed less activity. Thus, compounds 2a, 2g, and 2i,
in pyrrolo[2,3-b]pyridine series and 3a, 3g, and 3i, in thi-
eno[2,3-b]pyridine series were found to be least active
with respect to 2c, 2f, 2j, 3c, 3f, and 3j. Substitution of
R2 with hydrogen (compounds 2b and 3b) or cyclohex
(compounds 2g, 2h, 3g, and 3h) significantly reduces
activity. Compounds with chloro substitution at R1 po-
sition and methyl, ethyl or phenyl substitution at R2
were found to be most active compounds among both
the series, indicating that the electron-withdrawing
group (halogen) at R1 position and hydrophobic substi-
tutions (small alkyl and aryl groups) at R2 position are
favorable. Substitution of R1 with hydrogen and R2
with benzyl group (compounds 2k, 2l, 3k, and 3l)
showed moderate insulin secretion. Overall, the glu-
cose-dependent insulin secretion profile (in vitro results)
of arylimidazolines (2a–l and 3a–l) reported in this com-
munication was found to be better than aryl-guanidines,
reported earlier.17
3. Results and discussion
3.1. In vitro insulin secretion assay results
In vitro glucose-dependent or -independent insulin
secretion properties of BL 11282 and test compounds
(2a–l and 3a–l; at 0.1, 1, and 10 lM concentrations)
were determined using RIN5F cell assay. At 0-mM glu-
cose load, incubation of test and standard compounds
with RIN5F cells showed only basal insulin secretion.
However, in presence of 16.7-mM glucose load, signifi-
cant concentration dependent insulin secretions were
observed, both for standard and test compounds. Fur-
ther to validate the in vitro assay, RIN5F cells were
incubated with Tolbutamide (sulfonylurea; at 0.1, 1,
3.2. The in vivo pharmacodynamic effects
In order to determine the in vivo antidiabetic activity
(insulin secretion and glucose reduction) of the test and
standard compounds, acute single dose 120-min time-
course experiment was conducted, in male C57BL/6J
mice (overnight fasted).20,21 Compounds 2c and 3c were
selected as representative compound from each series

R. H. Bahekar et al. / Bioorg. Med. Chem. 15 (2007) 6782–6795
6785
Table 1. In vitro glucose-dependent insulin secretion activity of compounds 2a–l and 3a–l
Compound
R1
R2
Concd (lM)
Insulin secretiona (pg/lg/h)
Control 1 (0 mM glucose)
5.8 0.66
10.6 0.62
Control 2 (16.7 mM glucose)
Tolbutamide (0 mM glucose)
Tolbutamide (16.7 mM glucose)
BL 11282 (1)
0.1/1/10
0.1/1/10
0.1/1/10
0.1/1/10
0.1/1/10
0.1/1/10
0.1/1/10
0.1/1/10
0.1/1/10
0.1/1/10
0.1/1/10
0.1/1/10
0.1/1/10
0.1/1/10
0.1/1/10
0.1/1/10
0.1/1/10
0.1/1/10
0.1/1/10
0.1/1/10
0.1/1/10
0.1/1/10
0.1/1/10
0.1/1/10
0.1/1/10
0.1/1/10
0.1/1/10
19.7 0.61/20.7 0.52/34.4 0.16
20.0 0.56/21.4 0.59/35.2 0.36
16.3 0.61/22.4 0.52/36.5 0.36
12.1 0.52/14.1 0.16/28.0 0.36
12.4 0.26/15.2 0.33/29.6 0.51
19.3 0.16/27.7 0.26/41.7 0.22
14.9 0.23/18.0 0.34/32.4 0.27
14.1 0.15/18.1 0.55/32.5 0.44
18.2 0.19/25.5 0.46/39.2 0.56
12.4 0.31/14.3 0.54/28.0 0.26
12.6 0.26/15.0 0.46/28.9 0.28
13.3 0.25/16.4 0.22/29.1 0.28
18.9 0.52/26.1 0.51/39.9 0.59
14.8 0.46/18.2 0.26/32.6 0.16
14.4 0.26/18.3 0.46/31.9 0.18
12.2 0.12/14.2 0.19/28.2 0.16
12.6 0.32/15.0 0.23/29.0 0.49
19.2 0.19/27.5 0.13/41.5 0.29
14.5 0.22/18.9 0.27/31.8 0.18
14.7 0.14/18.0 0.56/31.9 0.12
18.0 0.11/25.4 0.19/39.0 0.34
12.6 0.16/14.7 0.24/28.1 0.36
12.9 0.36/15.1 0.25/28.7 0.22
13.0 0.19/15.5 0.23/29.1 0.11
18.5 0.15/26.5 0.14/39.8 0.49
14.4 0.26/18.8 0.17/31.6 0.19
13.9 0.22/18.2 0.31/31.9 0.20
2a
2b
2c
2d
2e
2f
H
H
Cl
Cl
H
H
CH3
CH3
C6H5
C6H5
H
Cl
H
2g
2h
2i
Cyclohex
Cyclohex
C2H5
Cl
H
2j
Cl
H
C2H5
2k
2l
CH2–C6H5
CH2–C6H5
H
Cl
H
3a
3b
3c
3d
3e
3f
Cl
Cl
H
H
CH3
CH3
C6H5
C6H5
H
Cl
H
3g
3h
3i
Cyclohex
Cyclohex
C2H5
Cl
H
3j
Cl
H
C2H5
CH2–C6H5
CH2–C6H5
3k
3l
Cl
The total insulin content (pg) was divided with total protein (lg) to normalize difference in cell density between wells. n = 3, values represent
mean SD.
a In vitro glucose-dependent (16.7-mM glucose load) insulin secretion with various concentrations of test and standard compounds was measured
using Rat Insulinoma (RIN5F) cells.
along with the standard compound BL 11282. At 0 min
time point (prior to the compounds’ administration),
animals were anesthetized using light ether anesthesia
and blood (15–20 lL) was collected via retro-orbital
route. Immediately after the 0 min blood collection, vehi-
cle (normal saline solution)/test/standard compounds
(suspended in saline solution) were injected to each
group (n = 6), via intraperitoneal (ip) route of adminis-
tration and the subsequent blood sampling was per-
formed at 30, 60, and 120 min. Compounds 2c, 3c, and
BL11282 were administered at 1, 10, and 100 lM/kg/
10 mL doses. The blood samples, which were collected
at different time points, were immediately subjected to
glucose and insulin (only 30 min) estimations.
In the acute single dose 120-min time-course experiment,
both the test compounds (2c and 3c) and the standard
compound showed dose dependent insulin secretion at
2.5
*
*
C57 Control
*
(1µM/kg i.p)
2.0
(10µM/kg i.p)
*
*
1.5
(100µM/kg i.p)
*
1.0
*
*
*
0.5
0.0
BL
2c
3c
Figure 2. The serum insulin levels after single dose ip injection of vehicles/test compounds in C57BL/6J mice (in vivo). C57 mice were fasted
overnight prior to vehicle/compounds administration (intraperitoneally; ip). For insulin estimation, blood samples were collected at 30 min and the
insulin estimation were conducted using rat/mouse insulin ELISA kit. All values are mean SEM, n = 6, *p < 0.01 versus control animals.
BL = BL11282, 2c, compound 2c; 3c, compound 3c.

6786
R. H. Bahekar et al. / Bioorg. Med. Chem. 15 (2007) 6782–6795
30 min, with respect to control (Fig. 2). Among com-
pounds 2c, 3c and BL 11282, at lower dose (1 and
10 lM/kg/ip), both the test compounds showed slightly
higher insulin secretion, with respect to same doses of
BL 11282, while at higher concentration (100 lM/kg/
ip), in vivo insulin secretion profile of BL 11282 and
compounds 2c and 3c was found to be identical. Overall,
these results correspond with our in vitro insulin secre-
tion results (Table 1). In C57BL/6J mice, changes in
blood glucose levels at various time points (30, 60, and
120 min), with compounds 2c, 3c, and BL 11282 are
shown in Figure 3. In general, with respect to control,
all the three compounds tested showed time and dose
dependent glucose reduction. Compounds 2c and 3c
were found to be equipotent in vivo at all the three dif-
ferent doses selected and with respect to BL 11282, both
the test compounds were found to be more potent, at all
the time points. BL 11282 showed glucose reduction
only at 30 and 60-min. time points, while compounds
2c and 3c showed sustained glucose reduction upto
120 min, indicating that compounds 2c and 3c exhibit
longer duration of action.
200
*
*
C57 Control
*
*
*
150
BL (1 µM/kg i.p)
BL (10 µM/kg i.p)
BL (100 µM/kg i.p)
*
100
200
0
0
0
30
60
120
Time (min.)
*
*
C57 Control
2c (1 µM/kgi.p)
2c (10 µM/kgi.p)
150
*
*
*
*
2c (100 µM/kgi.p)
*
100
200
30
60
120
Time (min.)
*
*
C57 Control
3c ( 1 µM/kgi.p)
3c (10 µM/kgi.p)
*
*
150
100
*
*
3c (100 µM/kgi.p)
*
*
30
60
120
Time (min.)
Figure 3. The serum glucose levels after single dose ip injection of vehicles/compounds in C57BL/6J mice (in vivo). C57BL/6J mice were fasted
overnight prior to vehicle/compounds administration (intraperitoneally). For glucose estimation, blood samples were collected at 0, 30, 60, and
120 min and the glucose estimation was conducted with DPEC-GOD/POD method, using Spectramax-190, in 96-microwell plate reader. All values
are mean SEM, n = 6, *p < 0.01 versus control animals.

R. H. Bahekar et al. / Bioorg. Med. Chem. 15 (2007) 6782–6795
6787
4. Conclusion
hexane to get the pure product.28 Using above proce-
dure, total 12 derivatives of 2,5-disubstituted-1H-pyrrolo-
[2,3-b]pyridine-3-carbaldehyde (5a–l) were prepared and
their physicochemical properties and spectral data are
listed below.
The glucose-dependent insulin secretion effect is one of
the most desirable properties of novel insulin secreta-
gogues. The new arylimidazolines (compounds 2a–l and
3a–l), which were designed as analogs of BL 11282
showed significant glucose-dependent insulin secretion
(in vitro and in vivo) and reduction in the blood glucose
level (in vivo). Among all the 24 new compounds tested in
both the series, 5-Chloro-3-(4,5-dihydro-1H-imidazol-2-
yl)-2-methyl-1H-pyrrolo[2,3-b]pyridine (2c) and 5-Chloro-
3-(4,5-dihydro-1H-imidazol-2-yl)-2-methyl-thieno[2,3-
b]pyridine (3c) were found to be more potent than
BL11282, indicating that the pyridine ring of pyrrolo-
[2,3-b]pyridine (2a–l) and thiophene ring of thieno[2,3-
b]pyridine (3a–l) act as bioisosteres of the benzene and
indole ring systems of BL 11282 (1). Combined evalua-
tion of our in vitro and in vivo results indicates that
both the series of aryl imidazoline derivatives could be
useful for the prevention and mitigation of type 2
diabetes.
Yield: 77%; white solid; mp 194–196 ꢁC (reported mp
216–217 ꢁC, recrystallized from water28); IR (KBr):
3389, 2887, 1692, 1612 cmÀ1 1H NMR (300 MHz,
.
DMSO-d6) d 12.67 (br s, 1H, pyrrole ring –NH), 9.91
(s, 1H, –CHO), 8.46 (s, 1H, pyrrole ring –CH), 8.40–
8.35 (m, 2H, pyridine ring), 7.29–7.27 (m, 1H, pyridine
ring); MS (ESI) m/z 147 [M+1]+; Anal. Calcd for
C8H6N2O: C, 65.68; H, 5.47; N 19.15. Found: C,
65.66; H, 5.43; N 19.11.
5.2.1.2. 5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbal-
dehyde (5b). Yield: 78%; white solid; mp 199–202 ꢁC;
1
IR (KBr): 3391, 2885, 1691, 1610, 740 cmÀ1. H NMR
(300 MHz, DMSO-d6) d 12.64 (br s, 1H, pyrrole ring
–NH), 9.94 (s, 1H,–CHO), 8.79 (s, 1H, pyridine ring),
8.46 (s, 1H, pyrrole ring –CH), 7.99 (s, 1H, pyridine ring);
MS (ESI) m/z 183 [M+1]+, 184 [M+2]+; Anal. Calcd for
C8H5ClN2O: C, 53.15; H, 2.76; N 15.50. Found: C,
53.11; H,2.73;N 15.48.
5. Experimental
5.1. Chemistry
5.2.1.3. 5-Chloro-2-methyl-1H-pyrrolo[2,3-b]pyridine-
3-carbaldehyde (5c). Yield: 75%; white solid; mp 210–
212 ꢁC; IR (KBr): 3392, 2889, 1695, 1612, 1376,
Melting points were determined in open glass capillaries,
using a Scientific melting point apparatus and are uncor-
rected. IR spectra were recorded on a Shimadzu FT IR
8300 spectrophotometer (Vmax in cmÀ1, using KBr pel-
1
738 cmÀ1. H NMR (300 MHz, DMSO-d6) d 12.61 (br
s, 1H, pyrrole ring –NH), 9.89 (s, 1H, –CHO), 8.76 (s,
1H, pyridine ring), 7.95 (s, 1H, pyridine ring), 2.67 (s,
3H, –CH3); MS (ESI) m/z 196 [M+1]+, 197 [M+2]+;
Anal. Calcd for C9H7ClN2O: C, 55.49; H, 3.59; N
14.38. Found: C, 55.46; H, 3.55; N 14.35.
1
lets). The H NMR spectra were recorded on a Brucker
Avance-300 spectrometer (300 MHz). 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), br s
(broad singlet), and m (multiplet). Mass spectra (ESI-
MS) were obtained on a Shimadzu LC–MS 2010-A
spectrometer. Elemental analyses were conducted, using
a Perkin-Elmer 2400 CHN analyzer and values within
limit of 0.4% of the theoretical values were taken into
consideration. Purity of synthesized compounds was
checked by precoated TLC plates (E. Merck, Kieselgel
60 F254) and the spots were visualized by iodine vapors.
The chromatographic purification was conducted on sil-
ica gel (100–200-mesh size). All the chemicals used for
the synthesis were purchased from Aldrich Company
Limited, Dorset (UK).
5.2.1.4. 2-Methyl-1H-pyrrolo[2,3-b]pyridine-3-carbal-
dehyde (5d). Yield: 76%; white solid; mp 226–228 ꢁC;
IR (KBr): 3390, 2891, 1695, 1611, 1372 cmÀ1 1H
.
NMR (300 MHz, DMSO-d6) d 12.68 (br s, 1H, pyrrole
ring –NH), 9.93 (s, 1H, –CHO), 8.39–8.33 (m, 2H, pyr-
idine ring), 7.28–7.26 (m, 1H, pyridine ring), 2.68 (s, 3H,
–CH3); MS (ESI) m/z 161 [M+1]+; Anal. Calcd for
C9H8N2O: C, 67.42; H, 4.99; N 17.48. Found: C,
67.40; H, 4.96; N 17.44.
5.2.1.5. 2-Phenyl-1H-pyrrolo[2,3-b]pyridine-3-carbal-
dehyde (5e). Yield: 70%; white solid; mp 232–235 ꢁC;
1
IR (KBr): 3401, 2884, 1691, 1611, 778 cmÀ1. H NMR
(300 MHz, DMSO-d6) d 12.67 (br s, 1H, pyrrole ring
–NH), 9.91 (s, 1H, –CHO), 8.39–8.34 (m, 2H, pyridine
ring), 7.35–7.29 (m, 5H, benzene ring), 7.28–7.26 (m,
1H, pyridine ring); MS (ESI) m/z 223 [M+1]+; Anal.
Calcd for C14H10N2O: C, 75.59; H, 4.49; N 12.59.
Found: C, 75.55; H, 4.46; N 12.59.
5.2. Experimental details
5.2.1. General method for the synthesis of 2,5-disubsti-
tuted-3-(4,5-dihydro-1H-imidazol-2-yl)-1H-pyrrolo[2,3-
b]pyridine (2a–l; Scheme 1)
5.2.1.1. Synthesis of 1H-pyrrolo[2,3-b]pyridine-3-carb-
aldehyde (5a). A mixture of 1H-pyrrolo[2,3-b]pyridine 4
(15.25 mmol) and HMTA (22.85 mmol) in acetic acid
(19 mL) was heated under reflux for 6 h. The reaction
mixture was cooled to room temperature, diluted with
water, and kept overnight. The solid obtained was fil-
tered, washed with excess of ice cold water and dried.
The crude compound obtained was recrystallized from
5.2.1.6. 5-Chloro-2-phenyl-1H-pyrrolo[2,3-b]pyridine-
3-carbaldehyde (5f). Yield: 69%; white solid; mp 190–
192 ꢁC; IR (KBr): 3398, 2887, 1702, 1612, 775,
1
734 cmÀ1. H NMR (300 MHz, DMSO-d6) d 12.69 (br
s, 1H, pyrrole ring –NH), 9.93 (s, 1H, –CHO), 8.75 (s,
1H, pyridine ring), 7.96 (s, 1H, pyridine ring), 7.35–
7.29 (m, 5H, benzene ring); MS (ESI) m/z 268 [M+1]+,

6788
R. H. Bahekar et al. / Bioorg. Med. Chem. 15 (2007) 6782–6795
269 [M+2]+; Anal. Calcd for C14H9ClN2O: C, 65.44; H,
3.50; N 10.90. Found: C, 65.41; H, 3.47; N 10.88.
7.26 (m, 5H, benzene ring), 3.87 (s, 2H, benzyl –CH2);
MS (ESI) m/z 272 [M+1]+, 273 [M+2]+; Anal. Calcd
for C15H11ClN2O: C, 66.49; H, 4.06; N 10.34. Found:
C, 66.46; H, 4.02; N 10.31.
5.2.1.7. 2-Cyclohexyl-1H-pyrrolo[2,3-b]pyridine-3-carb-
aldehyde (5g). Yield: 75%; white solid; mp 198–200 ꢁC;
IR (KBr): 3395, 2894, 1694, 1610, 1448 cmÀ1
.
1H
5.2.1.13. Synthesis of 1H-Pyrrolo[2,3-b]pyridine-3-
carbaldehyde oxime (6a). A mixture of 1H-pyrrolo[2,3-
b]pyridine-3-carbaldehyde 5a (8.22 mmol) and hydrox-
ylamine hydrochloride (15.82 mmol) in water was
heated at 60 ꢁC for 30 min. To it, NaHCO3 (19.64
mmol) was added and the reaction mixture was heated
under reflux for 4 h at 100 ꢁC. The reaction mixture
was cooled to room temperature, the solid obtained
was filtered, washed with the excess of ice-cold water,
and dried. The crude product obtained was recrystal-
lized from hexane to get the pure product.27 Using
above procedure, total 12 derivatives of 2,5-disubsti-
tuted-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde oxime
(6a–l) were prepared and their physicochemical proper-
ties and spectral data are listed below.
NMR (300 MHz, DMSO-d6) d 12.67 (br s, 1H, pyrrole
ring –NH), 9.97 (s, 1H, –CHO), 8.37–8.33 (m, 2H, pyr-
idine ring), 7.29–7.26 (m, 1H, pyridine ring), 2.13–2.11
(m, 1H, cyclohexyl ring), 1.27–1.24 (m, 10H, cyclohexyl
ring); MS (ESI) m/z 229 [M+1]+; Anal. Calcd for
C14H16N2O: C, 73.59; H, 7.00; N 12.26. Found: C,
73.56; H, 6.97; N 12.22.
5.2.1.8. 5-Chloro-2-cyclohexyl-1H-pyrrolo[2,3-b]pyri-
dine-3-carbaldehyde (5h). Yield: 78%; white solid; mp
211–213 ꢁC; IR (KBr): 3408, 2887, 1694, 1610, 1448,
1
742 cmÀ1. H NMR (300 MHz, DMSO-d6) d 12.69 (br
s, 1H, pyrrole ring –NH), 9.93 (s, 1H, –CHO), 8.68 (s,
1H, pyridine ring), 7.94 (s, 1H, pyridine ring), 2.14–
2.11 (m, 1H, cyclohexyl ring), 1.27–1.24 (m, 10H, cyclo-
hexyl ring); MS (ESI) m/z 264 [M+1]+, 265 [M+2]+;
Anal. Calcd for C14H15ClN2O: C, 63.94; H, 5.70; N
10.65. Found: C, 63.91; H, 5.66; N 10.63.
Yield: 71%; white solid; mp 188–190 ꢁC (reported mp
218–219 ꢁC, recrystallized from ethanol–water (1:2)27);
IR (KBr): 3392, 2895, 1611, 1168 cmÀ1 1H NMR
.
(300 MHz, DMSO-d6) d 12.09 (br s, 1H, pyrrole ring
–NH), 11.17 (br s, 1H, –CH@N–OH), 8.21 (s, 1H, pyr-
role ring –CH), 7.85 (d, 1H, J = 7.7 Hz, pyridine ring),
7.77 (s, 1H, –CH@N–OH), 7.41 (d, 1H, J = 7.7 Hz,
pyridine ring), 7.13–7.06 (m, 1H, pyridine ring); MS
(ESI) m/z 162 [M+1]+; Anal. Calcd for C8H7N3O :
C, 59.57; H, 4.34; N 26.06. Found: C, 59.54; H, 4.31;
N 26.02.
5.2.1.9. 2-Ethyl-1H-pyrrolo[2,3-b]pyridine-3-carbalde-
hyde (5i). Yield: 72%; white solid; mp 231–233 ꢁC; IR
(KBr): 3398, 2893, 1690, 1614, 1445, 1368 cmÀ1 1H
.
NMR (300 MHz, DMSO-d6) d 12.69 (br s, 1H, pyrrole
ring –NH), 9.97 (s, 1H, –CHO), 8.39–8.32 (m, 2H, pyr-
idine ring), 7.29–7.25 (m, 1H, pyridine ring), 2.18 (q, 2H,
J = 7.1 Hz, –CH2CH3), 1.27 (t, 3H, J = 7.1 Hz,
–CH2CH3); MS (ESI) m/z 175 [M+1]+; Anal. Calcd
for C10H10N2O: C, 68.88; H, 5.74; N 16.07. Found: C,
68.84; H, 5.73; N 16.04.
5.2.1.14. 5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbal-
dehyde oxime (6b). Yield: 69%; white solid; mp 196–
198 ꢁC; IR (KBr): 3407, 2889, 1614, 1162, 741 cmÀ1
.
5.2.1.10. 5-Chloro-2-ethyl-1H-pyrrolo[2,3-b]pyridine-
3-carbaldehyde (5j). Yield: 68%; white solid; mp 240–
242 ꢁC; IR (KBr): 3397, 2888, 1689, 1617, 1443, 1371,
1H NMR (300 MHz, DMSO-d6) d 11.92 (br s, 1H, pyr-
role ring –NH), 11.13 (br s, 1H, –CH@N–OH), 8.79 (s,
1H, pyridine ring), 8.21 (s, 1H, pyrrole ring –CH), 7.89
(s, 1H, pyridine ring), 7.74 (s, 1H, –CH@N–OH); MS
(ESI) m/z 197 [M+1]+, 198 [M+2]+; Anal. Calcd for
C8H6ClN3O: C, 49.07; H, 3.06; N 21.47. Found: C,
49.04; H, 3.02; N 21.44.
1
736 cmÀ1. H NMR (300 MHz, DMSO-d6) d 12.67 (br
s, 1H, pyrrole ring –NH), 9.98 (s, 1H, –CHO), 8.71 (s,
1H, pyridine ring), 7.94 (s, 1H, pyridine ring), 2.16 (q,
2H, J = 7.1Hz, –CH2CH3), 1.23 (t, 3H, J = 7.1Hz,
–CH2CH3); MS (ESI) m/z 210 [M+1]+, 211 [M+2]+;
Anal. Calcd for C10H9ClN2O: C, 57.51; H, 4.31; N
13.42. Found: C, 57.47; H, 4.28; N 13.39.
5.2.1.15. 5-Chloro-2-methyl-1H-pyrrolo[2,3-b]pyridine-
3-carbaldehyde oxime (6c). Yield: 68%; white solid; mp
173–175 ꢁC; (68% yield); IR (KBr): 3396, 2893, 1610,
1
5.2.1.11. 2-Benzyl-1H-pyrrolo[2,3-b]pyridine-3-carbal-
dehyde (5k). Yield: 72%; white solid; mp 222–225 ꢁC; IR
1369, 1169, 738 cmÀ1. H NMR (300 MHz, DMSO-d6)
d 11.94 (br s, 1H, pyrrole ring –NH), 11.17 (br s, 1H,
–CH@N–OH), 8.76 (s, 1H, pyridine ring), 7.94 (s, 1H,
pyridine ring), 7.71 (s, 1H, –CH@N–OH), 2.69 (s, 3H,
–CH3); MS (ESI) m/z 211 [M+1]+, 212 [M+2]+; Anal.
Calcd for C9H8ClN3O: C, 51.52; H, 3.82; N 20.03.
Found: C, 51.49; H, 3.79; N 20.00.
(KBr): 3406, 2892, 1691, 1609, 1476, 778 cmÀ1 1H
.
NMR (300 MHz, DMSO-d6) d 12.72 (br s, 1H, pyrrole
ring –NH), 9.93 (s, 1H, –CHO), 8.37–8.34 (m, 2H, pyr-
idine ring), 7.37–7.26 (m, 6H, benzene ring and pyridine
ring), 3.85 (s, 2H, benzyl –CH2); MS (ESI) m/z 237
[M+1]+; Anal. Calcd for C15H12N2O: C, 76.18; H,
5.07; N 11.85. Found: C, 76.14; H, 5.04; N 11.83.
5.2.1.16. 2-Methyl-1H-pyrrolo[2,3-b]pyridine-3-carb-
aldehyde oxime (6d). Yield: 69%; white solid; mp 179–
5.2.1.12. 5-Chloro-2-benzyl-1H-pyrrolo[2,3-b]pyridine-
3-carbaldehyde (5l). Yield: 77%; white solid; mp 236–
238 ꢁC; IR (KBr): 3401, 2887, 1689, 1613, 1468,
181 ꢁC; IR (KBr): 3412, 2904, 1613, 1371, 1159 cmÀ1
.
1H NMR (300 MHz, DMSO-d6) d 12.02 (br s, 1H, pyr-
role ring –NH), 11.19 (br s, 1H, –CH@N–OH), 7.87 (d,
1H, J = 7.7 Hz, pyridine ring), 7.75 (s, 1H, –CH@N–
OH), 7.48 (d, 1H, J = 7.8 Hz, pyridine ring), 7.14–7.08
(m, 1H, pyridine ring), 2.63 (s, 3H, –CH3); MS (ESI)
1
768 cmÀ1. H NMR (300 MHz, DMSO-d6) d 12.69 (br
s, 1H, pyrrole ring –NH), 9.91 (s, 1H, –CHO), 8.74 (s,
1H, pyridine ring), 7.95 (s, 1H, pyridine ring), 7.31–

R. H. Bahekar et al. / Bioorg. Med. Chem. 15 (2007) 6782–6795
6789
m/z 176 [M+1]+; Anal. Calcd for C9H9N3O: C, 61.64; H,
5.13; N 23.97. Found: C, 61.61; H, 5.10; N 23.94.
5.2.1.22. 5-Chloro-2-ethyl-1H-pyrrolo[2,3-b]pyridine-
3-carbaldehyde oxime (6j). Yield: 68%; white solid; mp
171–173 ꢁC; IR (KBr): 3399, 2893, 1612, 1446, 1375,
5.2.1.17. 2-Phenyl-1H-pyrrolo[2,3-b]pyridine-3-carbal-
dehyde oxime (6e). Yield: 66%; white solid; mp 193–195
1169, 736 cmÀ1 1H NMR (300 MHz, DMSO-d6) d
.
11.79 (br s, 1H, pyrrole ring –NH), 11.13 (br s, 1H,
–CH@N–OH), 8.74 (s, 1H, pyridine ring), 7.97 (s, 1H,
pyridine ring), 7.73 (s, 1H, –CH@N–OH), 2.18 (q, 2H,
J = 7.1 Hz, –CH2CH3), 1.26 (t, 3H, J = 7.1Hz,
–CH2CH3); MS (ESI) m/z 225 [M+1]+, 226 [M+2]+;
Anal. Calcd for C10H10ClN3O: C, 53.65; H, 4.47; N
18.78. Found: C, 53.61; H, 4.43; N 18.74.
ꢁC; IR (KBr): 3398, 2897, 1609, 1162, 778 cmÀ1
.
1H
NMR (300 MHz, DMSO-d6) d 12.07 (br s, 1H, pyrrole
ring –NH), 11.17 (br s, 1H, –CH@N–OH), 7.89 (d,
1H, J = 7.7 Hz, pyridine ring), 7.77 (s, 1H, –CH@N–
OH), 7.41 (d, 1H, J = 7.7 Hz, pyridine ring), 7.32–7.26
(m, 5H, benzene ring), 7.15–7.11 (m, 1H, pyridine ring);
MS (ESI) m/z 238 [M+1]+; Anal. Calcd for C14H11N3O:
C, 70.81; H, 4.64; N 17.70. Found: C, 70.78; H, 4.63; N
17.67.
5.2.1.23. 2-Benzyl-1H-pyrrolo[2,3-b]pyridine-3-carbal-
dehyde oxime (6k). Yield: 70%; white solid; mp 182–
184 ꢁC; IR (KBr): 3404, 2889, 1611, 1469, 1161,
1
5.2.1.18. 5-Chloro-2-phenyl-1H-pyrrolo[2,3-b]pyridine-
3-carbaldehyde oxime (6f). yield: 69%; white solid; mp
172–174 ꢁC; IR (KBr): 3401, 2889, 1610, 1164, 775,
773 cmÀ1. H NMR (300 MHz, DMSO-d6) d 12.03 (br
s, 1H, pyrrole ring –NH), 11.14 (br s, 1H, –CH@N–
OH), 7.86 (d, 1H, J = 7.7 Hz, pyridine ring), 7.74 (s,
1H, –CH@N–OH), 7.44 (d, 1H, J = 7.8 Hz, pyridine
ring), 7.27–7.18 (m, 5H, benzene ring), 7.15–7.11 (m,
1H, pyridine ring), 3.87 (s, 2H, benzyl –CH2); MS
(ESI) m/z 252 [M+1]+; Anal. Calcd for C15H13N3O: C,
71.63; H, 5.17; N 16.71. Found: C, 71.61; H, 5.13; N
16.69.
1
734 cmÀ1. H NMR (300 MHz, DMSO-d6) d 11.87 (br
s, 1H, pyrrole ring –NH), 11.18 (br s, 1H, –CH@N–
OH), 8.72 (s, 1H, pyridine ring), 7.98 (s, 1H, pyridine
ring), 7.74 (s, 1H, –CH@N–OH), 7.34–7.27 (m, 5H, ben-
zene ring); MS (ESI) m/z 273 [M+1]+, 274 [M+2]+; Anal.
Calcd for C14H10ClN3O: C, 61.83; H, 3.68; N 15.46.
Found: C, 61.80; H, 3.63; N 15.42.
5.2.1.24. 5-Chloro-2-benzyl-1H-pyrrolo[2,3-b]pyridine-
3-carbaldehyde oxime (6l). Yield: 68%; white solid; mp
188–190 ꢁC; IR (KBr): 3406, 2897, 1608, 1471, 1169,
5.2.1.19. 2-Cyclohexyl-1H-pyrrolo[2,3-b]pyridine-3-carb-
aldehyde oxime (6g). Yield: 71%; white solid; mp 184–
1
186 ꢁC; IR (KBr): 3398, 2892, 1613, 1451, 1167 cmÀ1
.
769 cmÀ1. H NMR (300 MHz, DMSO-d6) d 11.97 (br
1H NMR (300 MHz, DMSO-d6) d 11.89 (br s, 1H, pyr-
role ring –NH), 11.13 (br s, 1H, –CH@N–OH), 7.88 (d,
1H, J = 7.7 Hz, pyridine ring), 7.71 (s, 1H, –CH@N–
OH), 7.44 (d, 1H, J = 7.7 Hz, pyridine ring), 7.14–7.09
(m, 1H, pyridine ring), 2.16–2.13 (m, 1H, cyclohexyl
ring), 1.27–1.21 (m, 10H, cyclohexyl ring); MS (ESI)
m/z 244 [M+1]+; Anal. Calcd for C14H17N3O: C,
69.05; H, 6.98; N 17.26. Found: C, 69.02; H, 6.95; N
17.22.
s, 1H, pyrrole ring –NH), 11.13 (br s, 1H, –CH@N–
OH), 8.78 (s, 1H, pyridine ring), 7.97 (s, 1H, pyridine
ring), 7.74 (s, 1H, –CH@N–OH), 7.29–7.18 (m, 5H, ben-
zene ring), 3.85 (s, 2H, benzyl –CH2); MS (ESI) m/z 287
[M+1]+, 288 [M+2]+; Anal. Calcd for C15H12ClN3O: C,
62.99; H, 4.20; N 14.69. Found: C, 62.96; H, 4.17; N
14.66.
5.2.1.25. Synthesis of 1H-pyrrolo[2,3-b]pyridine-3-car-
bonitrile (7a). A mixture of 1H-pyrrolo[2,3-b]pyridine-3-
carbaldehyde oxime 6a (6.21 mmol) and acetic anhy-
dride (53 mmol) was heated under reflux for 4 h. The
reaction mixture was cooled to room temperature and
poured into ice-cold water. The solid obtained was fil-
tered and washed with excess of ice-cold water. The
white solid was suspended in water (20 mL) and the
aqueous suspension was heated under reflux for 3 h.
The reaction mixture was cooled to room temperature
and poured into ice-cold water. The solid obtained
was filtered, washed with excess of ice-cold water and
the crude product obtained was recrystallized from a
mixture of ethyl acetate hexane (1:9), to get the pure
product.27 Using above procedure, total 12 derivatives
of 2,5-disubstituted-1H-pyrrolo[2,3-b]pyridine-3-carbo-
nitrile (7a–l) were prepared and their physicochemical
properties and spectral data are listed below.
5.2.1.20. 5-Chloro-2-cyclohexyl-1H-pyrrolo[2,3-b]pyr-
idine-3-carbaldehyde oxime (6h). Yield: 70%, white solid;
mp 188–190 ꢁC; IR (KBr): 3404, 2892, 1613, 1439, 1161,
742 cmÀ1. 1H NMR (300 MHz, DMSO-d6) d 11.92 (br s,
1H, pyrrole ring –NH), 11.13 (br s, 1H, –CH@N–OH),
8.78 (s, 1H, pyridine ring), 7.94 (s, 1H, pyridine ring),
7.72 (s, 1H, –CH@N–OH), 2.14–2.11 (m, 1H, cyclohexyl
ring), 1.27–1.22 (m, 10H, cyclohexyl ring); MS (ESI) m/z
279 [M+1]+, 280 [M+2]+; Anal. Calcd for C14H16ClN3O:
C, 60.48; H, 5.76; N 15.12. Found: C, 60.45; H, 5.72; N
15.10.
5.2.1.21. 2-Ethyl-1H-pyrrolo[2,3-b]pyridine-3-carbal-
dehyde oxime (6i). Yield: 66%; white solid; mp 168–
170 ꢁC; IR (KBr): 3403, 2892, 1609, 1443, 1372,
1164 cmÀ1 1H NMR (300 MHz, DMSO-d6) d 11.93
.
(br s, 1H, pyrrole ring –NH), 11.15 (br s, 1H,
–CH@N–OH), 7.84 (d, 1H, J = 7.6 Hz, pyridine ring),
7.75 (s, 1H, –CH@N–OH), 7.46 (d, 1H, J = 7.6 Hz, pyr-
idine ring), 7.14–7.09 (m, 1H, pyridine ring), 2.19 (q, 2H,
J = 7.1Hz, –CH2CH3), 1.26 (t, 3H, J = 7.1Hz,
–CH2CH3); MS (ESI) m/z 190 [M+1]+; Anal. Calcd
for C10H11N3O: C, 63.42; H, 5.81; N 22.19. Found: C,
63.39; H, 5.79; N 22.16.
Yield: 68%; white solid; mp 226–228 ꢁC (reported mp
262–265ꢁC, recrystallized from aqueous ethanol27); IR
(KBr): 3396, 2893, 2237, 1610 cmÀ1
.
1H NMR
(300 MHz, DMSO-d6) d 12.09 (br s, 1H, pyrrole ring
–NH), 8.41 (s, 1H, pyrrole ring –CH), 8.38–8.35 (m,
2H, pyridine ring), 7.29–7.27 (m, 1H, pyridine ring);
MS (ESI) m/z 144 [M+1]+; Anal. Calcd for C8H5N3:

6790
R. H. Bahekar et al. / Bioorg. Med. Chem. 15 (2007) 6782–6795
C, 67.06; H, 3.49; N 29.33. Found: C, 67.02; H, 3.46; N
29.30.
s, 1H, pyrrole ring –NH), 8.69 (s, 1H, pyridine ring),
7.97 (s, 1H, pyridine ring), 2.15–2.11 (m, 1H, cyclohexyl
ring), 1.27–1.24 (m, 10H, cyclohexyl ring); MS (ESI) m/z
261 [M+1]+, 262 [M+2]+; Anal. Calcd for C14H14ClN3:
C, 64.68; H, 5.39; N 16.17. Found: C, 64.64; H, 5.36;
N 16.14.
5.2.1.26. 5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbo-
nitrile (7b). Yield: 67%; white solid; mp 232–234 ꢁC; IR
(KBr): 3401, 2887, 2232, 1612, 743 cmÀ1 1H NMR
.
(300 MHz, DMSO-d6) d 12.04 (br s, 1H, pyrrole ring
–NH), 8.77 (s, 1H, pyridine ring), 8.45 (s, 1H, pyrrole ring
–CH), 7.97 (s, 1H, pyridine ring); MS (ESI) m/z 179
[M+1]+, 180 [M+2]+; Anal. Calcd for C8H4ClN3: C,
54.05; H, 2.25; N 23.65. Found: C, 54.01; H, 2.22; N 23.61.
5.2.1.33. 2-Ethyl-1H-pyrrolo[2,3-b]pyridine-3-carbo-
nitrile (7i). Yield: 68%; white solid; mp 233–235 ꢁC; IR
(KBr): 3394, 2889, 2232, 1611, 1446, 1371 cmÀ1 1H
.
NMR (300 MHz, DMSO-d6) d 11.93 (br s, 1H, pyrrole
ring –NH), 8.35–8.32 (m, 2H, pyridine ring), 7.29–7.24
(m, 1H, pyridine ring), 2.37 (q, 2H, J = 7.1Hz,
–CH2CH3), 1.24 (t, 3H, J = 7.1Hz, –CH2CH3); MS
(ESI) m/z 172 [M+1]+; Anal. Calcd for C10H9N3: C,
70.09; H, 5.25; N 24.53. Found: C, 70.06; H, 5.21; N
24.50.
5.2.1.27. 5-Chloro-2-methyl-1H-pyrrolo[2,3-b]pyridine-3-
carbonitrile (7c). Yield: 69%; white solid; mp 218–220 ꢁC;
1
IR (KBr): 3398, 2896, 2239, 1609, 1367, 739 cmÀ1. H
NMR (300 MHz, DMSO-d6) d 11.98 (br s, 1H, pyrrole
ring –NH), 8.78 (s, 1H, pyridine ring), 7.98 (s, 1H, pyridine
ring), 2.58 (s, 3H, –CH3); MS (ESI) m/z 193 [M+1]+, 194
[M+2]+; Anal. Calcd for C9H6ClN3: C, 56.36; H, 3.13; N
21.92. Found: C, 56.32; H, 3.10; N 21.89.
5.2.1.34. 5-Chloro-2-ethyl-1H-pyrrolo[2,3-b]pyridine-
3-carbonitrile (7j). Yield: 67%; white solid; mp 230–
232 ꢁC; IR (KBr): 3409, 2893, 2236, 1613, 1447, 1370,
1
5.2.1.28. 2-Methyl-1H-pyrrolo[2,3-b]pyridine-3-carbo-
nitrile (7d). Yield: 66%; white solid; mp 225–227 ꢁC; IR
734 cmÀ1. H NMR (300 MHz, DMSO-d6) d 11.97 (br
s, 1H, pyrrole ring –NH), 8.70 (s, 1H, pyridine ring),
7.97 (s, 1H, pyridine ring), 2.36 (q, 2H, J = 7.2 Hz,
–CH2CH3), 1.24 (t, 3H, J = 7.2 Hz, –CH2CH3); MS
(ESI) m/z 209 [M+1]+, 210 [M+2]+; Anal. Calcd for
C10H8ClN3: C, 58.11; H, 3.87; N 20.34. Found: C,
58.08; H, 3.84; N 20.31.
(KBr): 3392, 2896, 2235, 1617, 1364 cmÀ1 1H NMR
.
(300 MHz, DMSO-d6) d 12.02 (br s, 1H, pyrrole ring
–NH), 8.37–8.33 (m, 2H, pyridine ring), 7.29–7.26 (m,
1H, pyridine ring), 2.56 (s, 3H, –CH3); MS (ESI) m/z
158 [M+1]+; Anal. Calcd for C9H7N3: C, 68.71; H,
4.45; N 26.72. Found: C, 68.69; H, 4.42; N 26.69.
5.2.1.35. 2-Benzyl-1H-pyrrolo[2,3-b]pyridine-3-carbo-
nitrile (7k). Yield: 66%; white solid; mp 234–236 ꢁC; IR
5.2.1.29. 2-Phenyl-1H-pyrrolo[2,3-b]pyridine-3-carbo-
nitrile (7e). Yield: 68%; white solid; mp 238–240 ꢁC; IR
(KBr): 3402, 2889, 2229, 1611, 1472, 773 cmÀ1 1H
.
(KBr): 3397, 2895, 2228, 1613, 769 cmÀ1
.
1H NMR
NMR (300 MHz, DMSO-d6) d 11.93 (br s, 1H, pyrrole
ring –NH), 8.41–8.39 (m, 2H, pyridine ring), 7.31–7.26
(m, 6H, benzene ring and pyridine ring), 3.82 (s, 2H,
benzyl –CH2); MS (ESI) m/z 234 [M+1]+; Anal. Calcd
for C15H11N3: C, 77.16; H, 4.72; N 18.00. Found: C,
77.13; H, 4.69; N 17.98.
(300 MHz, DMSO-d6) d 12.04 (br s, 1H, pyrrole ring
–NH), 8.39–8.35 (m, 2H, pyridine ring), 7.35–7.29 (m,
5H, benzene ring), 7.28–7.25 (m, 1H, pyridine ring);
MS (ESI) m/z 220 [M+1]+; Anal. Calcd for C14H9N3:
C, 76.62; H, 4.10; N 19.15. Found: C, 76.59; H, 4.07;
N 19.11.
5.2.1.36. 5-Chloro-2-benzyl-1H-pyrrolo[2,3-b]pyridine-
3-carbonitrile (7l). Yield: 69%; white solid; mp 231–
233 ꢁC; IR (KBr): 3405, 2896, 2234, 1612, 1464,
5.2.1.30. 5-Chloro-2-phenyl-1H-pyrrolo[2,3-b]pyridine-3-
carbonitrile (7f). Yield: 70%; white solid; mp 217–219 ꢁC;
1
IR (KBr): 3403, 2897, 2234, 1610, 773, 736 cmÀ1
.
1H
767 cmÀ1. H NMR (300 MHz, DMSO-d6) d 12.01 (br
NMR (300 MHz, DMSO-d6) d 11.99 (br s, 1H, pyrrole
ring –NH), 8.79 (s, 1H, pyridine ring), 7.99 (s, 1H, pyridine
ring), 7.35–7.29 (m, 5H, benzene ring); MS (ESI) m/z 256
[M+1]+, 257 [M+2]+; Anal. Calcd for C14H8ClN3: C,
66.22; H, 3.15; N 16.55. Found: C, 66.20; H, 3.12; N 16.51.
s, 1H, pyrrole ring –NH), 8.76 (s, 1H, pyridine ring),
7.98 (s, 1H, pyridine ring ), 7.31–7.26 (m, 5H, benzene
ring), 3.84 (s, 2H, benzyl –CH2); MS (ESI) m/z 269
[M+1]+, 270 [M+2]+; Anal. Calcd for C15H10ClN3: C,
6.72; H, 3.73; N 15.69. Found: C, 6.69; H, 3.70; N 15.66.
5.2.1.31. 2-Cyclohexyl-1H-pyrrolo[2,3-b]pyridine-3-car-
bonitrile (7g). Yield: 69%; white solid; mp 216–218 ꢁC;
5.2.1.37. Synthesis of 3-(4,5-dihydro-1H-imidazol-2-
yl)-1H-pyrrolo[2,3-b]pyridine (2a). A mixture of 1H-pyr-
rolo[2,3-b]pyridine-3-carbonitrile 7a ( 2.10 mmol), P2S5
(53 mmol), and EDA (6 mL) was heated under reflux
for 5 h. The reaction mixture was cooled to room tem-
perature and poured into ice-cold water. The solid ob-
tained was filtered, washed with excess of ice cold
water and dried under vacuum. The crude compound
obtained was recrystallized from methanol to get the
pure product.22 Using above procedure, total 12 deriva-
tives of 2,5-disubstituted-3-(4,5-dihydro-1H-imidazol-2-
yl)-1H-pyrrolo[2,3-b]pyridine (2a–l) were prepared and
their physicochemical properties and spectral data are
listed below.
1
IR (KBr): 3399, 2889, 2237, 1609, 1446 cmÀ1. H NMR
(300 MHz, DMSO-d6) d 11.67 (br s, 1H, pyrrole ring
–NH), 8.37–8.33 (m, 2H, pyridine ring), 7.29–7.25 (m,
1H, pyridine ring), 2.13–2.10 (m, 1H, cyclohexyl ring),
1.27–1.24 (m, 10H, cyclohexyl ring); MS (ESI) m/z 226
[M+1]+; Anal. Calcd for C14H15N3: C, 74.57; H, 6.65; N
18.64. Found: C, 74.54; H, 6.62; N 18.61.
5.2.1.32. 5-Chloro-2-cyclohexyl-1H-pyrrolo[2,3-b]pyr-
idine-3-carbonitrile (7h). Yield: 66%; white solid; mp
222–224 ꢁC; IR (KBr): 3402, 2893, 2239, 1615, 1443,
1
740 cmÀ1. H NMR (300 MHz, DMSO-d6) d 11.69 (br

R. H. Bahekar et al. / Bioorg. Med. Chem. 15 (2007) 6782–6795
6791
Yield: 69%; white solid; mp 267–269 ꢁC; IR (KBr): 3393,
7.17 (m, 5H, benzene ring), 6.65 (br s, 1H, imidazoline
ring –NH), 3.55–3.53 (m, 4H, imidazoline ring); MS
(ESI) m/z 298 [M+1]+, 299 [M+2]+; Anal. Calcd for
C16H13ClN4: C, 64.70; H, 4.38; N 18.87. Found: C,
64.67; H, 4.34; N 18.85.
1
2888, 1612 1284, 1175, 769 cmÀ1. H NMR (300 MHz,
DMSO-d6) d 12.03 (br s, 1H, pyrrole ring –NH), 8.46–
8.43 (m, 1H, pyridine ring), 8.24–8.21 (m, 1H, pyridine
ring), 7.89 (s, 1H, pyrrole ring –CH), 7.13–7.09 (m,
1H, pyridine ring), 6.67 (br s, 1H, imidazoline ring
–NH), 3.55–3.52 (m, 4H, imidazoline ring); MS (ESI)
m/z 187 [M+1]+; Anal. Calcd for C10H10N4: C, 64.44;
H, 5.37; N 30.07. Found: C, 64.41; H, 5.34; N 30.04.
5.2.1.43. 2-Cyclohexyl-3-(4,5-dihydro-1H-imidazol-2-
yl)-1H-pyrrolo[2,3-b]pyridine (2g). Yield: 69%; white so-
lid; mp 271–273 ꢁC; IR (KBr): 3398, 2892, 1610, 1446,
1
1283, 1171, 775 cmÀ1. H NMR (300 MHz, DMSO-d6)
5.2.1.38. 5-Chloro-3-(4,5-dihydro-1H-imidazol-2-yl)-
1H-pyrrolo[2,3-b]pyridine (2b). Yield: 68%; white solid;
mp 262–265 ꢁC; IR (KBr): 3398, 2889, 1610, 1285,
d 11.97 (br s, 1H, pyrrole ring –NH), 8.47–8.44 (m,
1H, pyridine ring), 8.25–8.22 (m, 1H, pyridine ring),
7.13–7.08 (m, 1H, pyridine ring), 6.67 (br s, 1H, imidazo-
line ring –NH), 3.57–3.54 (m, 4H, imidazoline ring),
2.17–2.13 (m, 1H, cyclohexyl ring), 1.27–1.22 (m, 10H,
cyclohexyl ring); MS (ESI) m/z 269 [M+1]+; Anal. Calcd
for C16H20N4: C, 71.54; H, 7.45; N 20.86. Found: C,
71.52; H, 7.41; N 20.84.
1174, 774 cmÀ1 1H NMR (300 MHz, DMSO-d6) d
.
12.09 (br s, 1H, pyrrole ring –NH), 8.78 (s, 1H, pyridine
ring), 7.98 (s, 1H, pyridine ring), 7.89 (s, 1H, pyrrole
ring –CH), 6.67 (br s, 1H, imidazoline ring –NH),
3.55–3.51 (m, 4H, imidazoline ring); MS (ESI) m/z 222
[M+1]+, 223 [M+2]+; Anal. Calcd for C10H9ClN4: C,
54.38; H, 4.08; N 25.38. Found: C, 54.35; H, 4.05; N
25.35.
5.2.1.44. 5-Chloro-3-(4,5-dihydro-1H-imidazol-2-yl)-2-
cyclohexyl-1H-pyrrolo[2,3-b]pyridine (2h). Yield: 66%;
white solid; mp 279–281 ꢁC; IR (KBr): 3402, 2896,
5.2.1.39. 5-Chloro-3-(4,5-dihydro-1H-imidazol-2-yl)-2-
methyl-1H-pyrrolo[2,3-b]pyridine (2c). Yield: 67%; white
solid; mp 256–257 ꢁC; IR (KBr): 3395, 2887, 1611, 1376,
1610, 1442, 1286, 1173, 742 cmÀ1
.
1H NMR
(300 MHz, DMSO-d6) d 11.98 (br s, 1H, pyrrole ring
–NH), 8.79 (s, 1H, pyridine ring), 7.99 (s, 1H, pyridine
ring), 6.65 (br s, 1H, imidazoline ring –NH), 3.57–3.55
(m, 4H, imidazoline ring), 2.17–2.14 (m, 1H, cyclohexyl
ring), 1.24–1.20 (m, 10H, cyclohexyl ring); MS (ESI) m/z
304 [M+1]+, 305 [M+2]+; Anal. Calcd for C16H19ClN4:
C, 63.40; H, 6.27; N 18.49. Found: C, 63.37; H, 6.23;
N 18.46.
1
1283, 1168, 736 cmÀ1. H NMR (300 MHz, DMSO-d6)
d 11.98 (br s, 1H, pyrrole ring –NH), 8.79 (s, 1H, pyri-
dine ring), 7.94 (s, 1H, pyridine ring), 6.67 (br s, 1H, imi-
dazoline ring –NH), 3.56–3.54 (m, 4H, imidazoline ring),
2.53 (s, 3H, –CH3); MS (ESI) m/z 236 [M+1]+, 237
[M+2]+; Anal. Calcd for C11H11ClN4: C, 56.24; H,
4.68; N 23.86. Found: C, 56.21; H, 4.65; N 23.84.
5.2.1.45. 3-(4,5-Dihydro-1H-imidazol-2-yl)-2-Ethyl-1H-
pyrrolo[2,3-b]pyridine (2i). Yield: 68%; white solid; mp
236–238 ꢁC; IR (KBr): 3396, 2896, 1612, 1447, 1371,
5.2.1.40. 3-(4,5-Dihydro-1H-imidazol-2-yl)-2-Methyl-
1H-pyrrolo[2,3-b]pyridine (2d). Yield: 71%; white solid;
mp 260–262 ꢁC; IR (KBr): 3396, 2893, 1611, 1372,
1287, 1174 cmÀ1 1H NMR (300 MHz, DMSO-d6) d
.
1
1279, 1173, 774 cmÀ1. H NMR (300 MHz, DMSO-d6)
12.09 (br s, 1H, pyrrole ring –NH), 8.46–8.42 (m, 1H, pyr-
idine ring), 8.24–8.21 (m, 1H, pyridine ring), 7.13–7.09 (m,
1H, pyridine ring), 6.67 (br s, 1H, imidazoline ring –NH),
3.57–3.54 (m, 4H, imidazoline ring), 2.19 (q, 2H, J = 7.2
Hz, –CH2CH3), 1.27 (t, 3H, J = 7.2 Hz, –CH2CH3); MS
(ESI) m/z 215 [M+1]+; Anal. Calcd for C12H14N4:
C, 67.20; H, 6.53; N 26.13. Found: C, 67.16; H, 6.50; N
26.10.
d 12.07 (br s, 1H, pyrrole ring –NH), 8.45–8.42 (m,
1H, pyridine ring), 8.22–8.20 (m, 1H, pyridine ring),
7.13-7.09 (m, 1H, pyridine ring), 6.65 (br s, 1H, imidazo-
line ring –NH), 3.57–3.54 (m, 4H, imidazoline ring), 2.54
(s, 3H, –CH3); MS (ESI) m/z 201 [M+1]+; Anal. Calcd
for C11H12N4: C, 65.92; H, 5.99; N 2.79. Found: C,
65.89; H, 5.96; N 2.77.
5.2.1.41. 3-(4,5-Dihydro-1H-imidazol-2-yl)-2-Phenyl-
1H-pyrrolo[2,3-b]pyridine (2e). Yield: 66%; white solid;
mp 252–253 ꢁC; IR (KBr): 3404, 2889, 1609, 1289,
5.2.1.46. 5-Chloro-3-(4,5-dihydro-1H-imidazol-2-yl)-2-
ethyl-1H-pyrrolo[2,3-b]pyridine (2j). Yield: 69%; white
solid; mp 230–232 ꢁC; IR (KBr): 3397, 2898, 1612,
1176, 776 cmÀ1
.
1H NMR (300 MHz, DMSO-d6) d
1442, 1371, 1284, 1176, 736 cmÀ1
.
1H NMR
12.11 (br s, 1H, pyrrole ring –NH), 8.47–8.45 (m, 1H,
pyridine ring), 8.28–8.25 (m, 1H, pyridine ring), 7.29–
7.17 (m, 5H, benzene ring), 7.14–7.10 (m, 1H, pyridine
ring), 6.63 (br s, 1H, imidazoline ring –NH), 3.56–3.53
(m, 4H, imidazoline ring); MS (ESI) m/z 263 [M+1]+;
Anal. Calcd for C16H14N4: C, 73.19; H, 5.34; N 21.35.
Found: C, 73.16; H, 5.31; N 21.31.
(300 MHz, DMSO-d6) d 11.96 (br s, 1H, pyrrole ring
–NH), 8.77 (s, 1H, pyridine ring), 7.96 (s, 1H, pyridine
ring), 6.66 (br s, 1H, imidazoline ring –NH), 3.56–3.54
(m, 4H, imidazoline ring), 2.18 (q, 2H, J = 7.2 Hz,
–CH2CH3), 1.27 (t, 3H, J = 7.2 Hz, –CH2CH3); MS
(ESI) m/z 250 [M+1]+, 251 [M+2]+; Anal. Calcd for
C12H13ClN4: C, 57.89; H, 5.23; N 22.52. Found: C,
57.86; H, 5.20; N 22.49.
5.2.1.42. 5-Chloro-3-(4,5-dihydro-1H-imidazol-2-yl)-2-
phenyl-1H-pyrrolo[2,3-b]pyridine (2f). Yield: 72%; white
solid; mp 242–245 ꢁC; IR (KBr): 3402, 2889, 1612,
5.2.1.47. 2-Benzyl-3-(4,5-dihydro-1H-imidazol-2-yl)-
1H-pyrrolo[2,3-b]pyridine (2k). Yield: 71%; white solid;
mp 263–265 ꢁC; IR (KBr): 3404, 2897, 1612, 1469,
1286, 1176, 773, 734 cmÀ1
.
1H NMR (300 MHz,
1
DMSO-d6) d 12.09 (br s, 1H, pyrrole ring –NH), 8.81
(s, 1H, pyridine ring), 7.99 (s, 1H, pyridine ring), 7.26–
1282, 1175, 776 cmÀ1. H NMR (300 MHz, DMSO-d6)
d 12.08 (br s, 1H, pyrrole ring –NH), 8.46–8.44 (m,

6792
R. H. Bahekar et al. / Bioorg. Med. Chem. 15 (2007) 6782–6795
1H, pyridine ring), 8.28–8.26 (m, 1H, pyridine ring),
7.29–7.17 (m, 5H, benzene ring), 7.16–7.10 (m, 1H, pyr-
idine ring), 6.65 (br s, 1H, imidazoline ring –NH), 3.56–
3.54 (m, 4H, imidazoline ring), 3.87 (s, 2H, benzyl
–CH2); MS (ESI) m/z 277 [M+1]+; Anal. Calcd for
C17H16N4: C, 73.82; H, 5.79; N 20.26. Found: C,
73.80; H, 5.76; N 20.23.
Anal. Calcd for C9H5ClN2S: C, 51.80; H, 2.42; N
13.42. Found: C, 51.77; H, 2.40; N 13.40.
5.2.2.4. 2-Methyl-thieno[2,3-b]pyridin-3-carbonitrile (9d).
Yield: 70%; white solid; mp 111–113 ꢁC; IR (KBr): 3132,
.
2891, 2232, 1364, 873 cmÀ1 1H NMR (300 MHz,
DMSO-d6) d 8.26–8.24 (m, 1H, pyridine ring), 7.97–7.93
(m, 1H, pyridine ring), 7.29–7.26 (m, 1H, pyridine ring),
2.51 (s, 3H, –CH3); MS (ESI) m/z 175 [M+1]+; Anal. Calcd
for C9H6N2S: C, 62.04; H, 3.47; N 16.08. Found: C, 62.02;
H, 3.43; N 16.04.
5.2.1.48. 5-Chloro-3-(4,5-dihydro-1H-imidazol-2-yl)-2-
benzyl-1H-pyrrolo[2,3-b]pyridine (2l). Yield: 70%; white
solid; mp 281–283 ꢁC; IR (KBr): 3404, 2892, 1612,
1468, 1284, 1172, 764 cmÀ1
.
1H NMR (300 MHz,
DMSO-d6) d 12.03 (br s, 1H, pyrrole ring –NH),
8.79 (s, 1H, pyridine ring), 7.97 (s, 1H, pyridine ring),
7.26–7.17 (m, 5H, benzene ring), 6.65 (br s, 1H, imi-
dazoline ring –NH), 3.55–3.53 (m, 4H, imidazoline
ring), 3.86 (s, 2H, benzyl –CH2); MS (ESI) m/z 312
[M+1]+, 313 [M+2]+; Anal. Calcd for C17H15ClN4:
C, 65.64; H, 4.83; N 18.02. Found: C, 65.61; H,
4.80; N 18.00.
5.2.2.5. 2-Phenyl-thieno[2,3-b]pyridin-3-carbonitrile (9e).
Yield: 71%; white solid; mp 106–108 ꢁC; IR (KBr): 3129,
2886, 2228, 874, 769 cmÀ1
.
1H NMR (300 MHz,
DMSO-d6) d 8.29–8.27 (m, 1H, pyridine ring), 7.98–7.95
(m, 1H, pyridine ring), 7.34–7.29 (m, 5H, benzene ring),
7.28–7.26 (m, 1H, pyridine ring); MS (ESI) m/z 237
[M+1]+; Anal. Calcd for C14H8N2S: C, 71.16; H, 3.14; N
11.86. Found: C, 71.13; H, 3.11; N 11.83.
5.2.2. General method for the synthesis of 2,5-disubsti-
tuted-3-(4,5-dihydro-1H-imidazol-2-yl)-thieno[2,3-b]pyri-
dine (3a–l)
5.2.2.6. 5-Chloro-2-phenyl-thieno[2,3-b]pyridin-3-car-
bonitrile (9f). Yield: 69%; white solid; mp 93-95 ꢁC; IR
1
(KBr): 3130, 2889, 2231, 869, 771, 736 cmÀ1. H NMR
5.2.2.1. Synthesis of Thieno[2,3-b]pyridin-3-carbonitri-
le (9a). A mixture of thieno[2,3-b]pyridin-3-ylamine 8
(2.21 mmol), NaNO2 (2.43 mmol), and concentrated
(300 MHz, DMSO-d6) d 8.79–8.76 (m, 1H, pyridine
ring), 7.98–7.97 (m, 1H, pyridine ring), 7.33-7.29 (m,
5H, benzene ring); MS (ESI) m/z 271 [M+1]+, 272
[M+2]+; Anal. Calcd for C14H7ClN2S: C, 62.11; H,
2.61; N 10.35. Found: C, 62.08; H, 2.58; N 10.31.
o
HCl (1 mL) was stirred at 5 C for 2 h. The pH of the
reaction mixture was adjusted with NaHCO3 to 7 and
to it, a mixture of CuCN (2.65 mmol) and NaCN
(2.65 mmol), dissolved in water (5 mL), was added.
The reaction mixture was heated under reflux for 3 h,
cooled to room temperature, diluted with the ice-cold
water, and the solid obtained was filtered, washed with
water, and dried to get the pure compound.31 Using
above procedure, total 12 derivatives of 2,5-disubsti-
tuted-thieno[2,3-b]pyridin-3-carbonitrile (9a–l) were pre-
pared and their physicochemical properties and spectral
data are listed below.
5.2.2.7. 2-Cyclohexyl-thieno[2,3-b]pyridin-3-carbonit-
rile (9g). Yield: 66%; white solid; mp 90–92 ꢁC; IR
(KBr): 3127, 2889, 2234, 1446, 881 cmÀ1 1H NMR
.
(300 MHz, DMSO-d6) d 8.27–8.24 (m, 1H, pyridine
ring), 7.97–7.95 (m, 1H, pyridine ring), 7.29–7.27 (m,
1H, pyridine ring), 2.19–2.17 (m, 1H, cyclohexyl ring),
1.27–1.21 (m, 10H, cyclohexyl ring); MS (ESI) m/z 243
[M+1]+; Anal. Calcd for C14H14N2S: C, 69.39; H,
5.82; N 11.56. Found: C, 69.35; H, 5.80; N 11.53.
Yield: 68%; white solid; mp 96–98 ꢁC; IR (KBr): 3125,
5.2.2.8. 5-Chloro-2-cyclohexyl-thieno[2,3-b]pyridin-3-
carbonitrile (9h). Yield: 68%; white solid; mp 109–
111 ꢁC; IR (KBr): 3127, 2891, 2232, 1443, 874,
1
2886, 2237, 838 cmÀ1. H NMR (300 MHz, DMSO-d6)
d 8.41 (s, 1H, thiophene ring –CH), 8.25–8.24(m, 1H,
pyridine ring), 7.97–7.94 (m, 1H, pyridine ring), 7.27–
7.19 (m, 1H, pyridine ring); MS (ESI) m/z 161 [M+1]+;
Anal. Calcd for C8H4N2S: C, 59.98; H, 2.52; N 17.49.
Found: C, 59.95; H, 2.50; N 17.46.
1
743 cmÀ1. H NMR (300 MHz, DMSO-d6) d 8.80–8.78
(m, 1H, pyridine ring), 7.96–7.93 (m, 1H, pyridine ring),
2.18–2.17 (m, 1H, cyclohexyl ring), 1.27–1.23 (m, 10H,
cyclohexyl ring); MS (ESI) m/z 277 [M+1]+, 278
[M+2]+; Anal. Calcd for C14H13ClN2S: C, 60.75; H,
4.73; N 10.12. Found: C, 60.71; H, 4.70; N 10.10.
5.2.2.2. 5-Chloro-thieno[2,3-b]pyridin-3-carbonitrile (9b).
Yield: 70%; white solid; mp 92–94 ꢁC; IR (KBr): 3129,
2887, 2232, 872, 743 cmÀ1
.
1H NMR (300 MHz,
5.2.2.9. 2-Ethyl-thieno[2,3-b]pyridin-3-carbonitrile (9i).
Yield: 69%; white solid; mp 106–108 ꢁC; IR (KBr): 3132,
DMSO-d6) d 8.41 (s, 1H, thiophene ring –CH), 8.79–8.76
(m, 1H, pyridine ring), 7.96–7.94 (m, 1H, pyridine ring);
MS (ESI) m/z 195 [M+1]+, 196 [M+2]+; Anal. Calcd for
C8H3ClN2S: C, 49.37; H, 1.55; N 14.39. Found: C,
49.34; H, 1.51; N 14.36.
1
2889, 2232, 1446, 1371, 870 cmÀ1. H NMR (300 MHz,
DMSO-d6) d 8.29–8.27 (m, 1H, pyridine ring), 7.97–7.93
(m, 1H, pyridine ring), 7.29–7.27 (m, 1H, pyridine ring),
2.19 (q, 2H, J = 7.1Hz, –CH2CH3), 1.26 (t, 3H,
J = 7.1Hz, –CH2CH3); MS (ESI) m/z 189 [M+1]+; Anal.
Calcd for C10H8N2S: C, 63.80; H, 4.28; N 14.88. Found:
C, 63.77; H, 4.24; N 14.84.
5.2.2.3. 5-Chloro-2-methyl-thieno[2,3-b]pyridin-3-car-
bonitrile (9c). Yield: white solid; mp 99–101 ꢁC; IR
(KBr): 3128, 2896, 2234, 1367, 869, 739 cmÀ1 1H
.
NMR (300 MHz, DMSO-d6) d 8.81–8.77 (m, 1H, pyri-
dine ring), 7.97–7.95 (m, 1H, pyridine ring), 2.48 (s,
3H, –CH3); MS (ESI) m/z 209 [M+1]+, 210 [M+2]+;
5.2.2.10. 5-Chloro-2-ethyl-thieno[2,3-b]pyridin-3-car-
bonitrile (9j). Yield: 66%; white solid; mp 99–101 ꢁC;
IR (KBr): 3129, 2890, 2232, 1447, 1370, 873,

R. H. Bahekar et al. / Bioorg. Med. Chem. 15 (2007) 6782–6795
6793
1
734 cmÀ1. H NMR (300 MHz, DMSO-d6) d 8.79–8.76
5.2.2.15. 5-Chloro-3-(4,5-dihydro-1H-imidazol-2-yl)-2-
methyl-thieno[2,3-b]pyridine (3c). Yield: 66%; white so-
lid; mp 161–163 ꢁC; IR (KBr): 3136, 2896, 2232, 1367,
(m, 1H, pyridine ring), 7.98–7.95 (m, 1H, pyridine ring),
2.17 (q, 2H, J = 7.1 Hz, –CH2CH3), 1.24 (t, 3H,
J = 7.1Hz, –CH2CH3); MS (ESI) m/z 223 [M+1]+, 224
[M+2]+; Anal. Calcd for C10H7ClN2S: C, 53.93; H,
3.17; N 12.58. Found: C, 53.90; H, 3.13; N 12.54.
1285, 1175, 873, 741 cmÀ1
.
1H NMR (300 MHz,
DMSO-d6) d 8.83-8.79 (m, 1H, pyridine ring), 7.99–
7.97 (m, 1H, pyridine ring), 6.19 (br s, 1H, imidazoline
ring –NH), 3.54–3.52 (m, 4H, imidazoline ring), 2.46
(s, 3H, –CH3); MS (ESI) m/z 253 [M+1]+, 254 [M+2]+;
Anal. Calcd for C11H10ClN3S: C, 52.48; H, 4.00; N
16.69. Found: C, 52.44; H, 3.98; N 16.66.
5.2.2.11. 2-Benzyl-thieno[2,3-b]pyridin-3-carbonitrile
(9k). Yield: 70%; white solid; mp 88–90 ꢁC; IR (KBr):
3128, 2889, 2237, 1471, 869, 773 cmÀ1
.
1H NMR
(300 MHz, DMSO-d6) d 8.27–8.23 (m, 1H, pyridine
ring), 7.94–7.92 (m, 1H, pyridine ring), 7.33–7.28 (m,
5H, benzene ring), 7.27–7.26 (m, 1H, pyridine ring),
3.81 (s, 2H, benzyl –CH2); MS (ESI) m/z 251 [M+1]+;
Anal. Calcd for C15H10N2S: C, 71.97; H, 4.03; N
11.19. Found: C, 71.94; H, 4.00; N 11.16.
5.2.2.16. 3-(4,5-Dihydro-1H-imidazol-2-yl)-2-methyl-
thieno[2,3-b]pyridine (3d). Yield: 70%; white solid; mp
166–168 ꢁC; IR (KBr): 3129, 2893, 2234, 1364, 1279,
1
1179, 873, 768 cmÀ1. H NMR (300 MHz, DMSO-d6)
d 8.27–8.25 (m, 1H, pyridine ring), 7.97–7.95 (m, 1H,
pyridine ring), 7.27–7.21 (m, 1H, pyridine ring), 6.17
(br s, 1H, imidazoline ring –NH), 3.55–3.52 (m, 4H, imi-
dazoline ring), 2.48 (s, 3H, -CH3); MS (ESI) m/z 218
[M+1]+; Anal. Calcd for C11H11N3S: C, 60.80; H,
5.10; N 19.34. Found: C, 60.77; H, 5.07; N 19.30.
5.2.2.12. 5-Chloro-2-benzyl-thieno[2,3-b]pyridin-3-car-
bonitrile (9l). Yield: 72%; white solid; mp 112–114 ꢁC;
1
IR (KBr): 3129, 2896, 2234, 1462, 874, 767 cmÀ1. H
NMR (300 MHz, DMSO-d6) d 8.79–8.77 (m, 1H, pyri-
dine ring), 7.98–7.95 (m, 1H, pyridine ring), 7.34–7.28
(m, 5H, benzene ring), 3.79 (s, 2H, benzyl –CH2); MS
(ESI) m/z 285 [M+1]+, 286 [M+2]+; Anal. Calcd for
C15H9ClN2S: C, 63.27; H, 3.19; N 9.84. Found: C,
63.24; H, 3.15; N 9.81.
5.2.2.17. 3-(4,5-Dihydro-1H-imidazol-2-yl)-2-phenyl-
thieno[2,3-b]pyridine (3e). Yield: 66%; white solid; mp
181–183 ꢁC; IR (KBr): 3126, 2891, 2234, 1281, 1176,
874, 773 cmÀ1
.
1H NMR (300 MHz, DMSO-d6) d
8.27–8.25 (m, 1H, pyridine ring), 7.97–7.95 (m, 1H, pyr-
idine ring), 7.34–7.29 (m, 5H, benzene ring), 7.24–7.21
(m, 1H, pyridine ring), 6.13 (br s, 1H, imidazoline ring
–NH), 3.55–3.52 (m, 4H, imidazoline ring); MS (ESI)
m/z 291 [M+1]+; Anal. Calcd for C16H13N3S: C, 68.79;
H, 4.69; N 15.04. Found: C, 68.76; H, 4.67; N 15.00.
5.2.2.13. Synthesis of 3-(4,5-dihydro-1H-imidazol-2-
yl)-thieno[2,3-b]pyridine (3a). A mixture of Thieno[2,3-
b]pyridine-3-carbonitrile 9a (0.63 mmol), EDA
(2 mL), and P2S5 (0.23 mmol) was refluxed at 120 ꢁC
for 5 h. The reaction mixture was poured into ice
and extracted with DCM. The DCM layer was washed
with water and brine. Finally, the organic layer was
dried over anhydrous Na2SO4 and evaporated to get
greenish solid. The pure product was obtained by
recrystallization from a mixture of ethyl acetate hex-
ane (1:9).22 Using above procedure, total 12 deriva-
tives of 2,5-disubstituted-3-(4,5-dihydro-1H-imidazol-2-
yl)-thieno[2,3-b]pyridine (3a–l) were prepared and their
physicochemical properties and spectral data are listed
below.
5.2.2.18. 5-Chloro-3-(4,5-dihydro-1H-imidazol-2-yl)-2-
phenyl-thieno[2,3-b]pyridine (3f). Yield: 70%; white solid;
mp 188–190 ꢁC; IR (KBr): 3133, 2892, 2231, 1283, 1172,
869, 772, 739 cmÀ1.1H NMR (300 MHz, DMSO-d6) d
8.81–8.79 (m, 1H, pyridine ring), 7.98–7.97 (m, 1H, pyr-
idine ring), 7.32–7.26 (m, 5H, benzene ring), 6.17 (br s,
1H, imidazoline ring –NH), 3.56–3.52 (m, 4H, imidazo-
line ring); MS (ESI) m/z 315 [M+1]+, 316 [M+2]+; Anal.
Calcd for C16H12ClN3S: C, 61.24; H, 3.85; N 13.39.
Found: C, 61.21; H, 3.83; N 13.36.
Yield: 65%; white solid; mp 142–144 ꢁC; IR (KBr): 3132,
2893, 2234, 1289, 1178, 838, 776 cmÀ1
.
1H NMR
5.2.2.19. 2-Cyclohexyl-3-(4,5-dihydro-1H-imidazol-2-
yl)-thieno[2,3-b]pyridine (3g). Yield: 68%; white solid;
mp 176–178 ꢁC; IR (KBr): 3127, 2891, 2234, 1443,
(300 MHz, DMSO-d6) d 8.41 (s, 1H, thiophene ring
–CH), 8.25–8.24 (m, 1H, pyridine ring), 7.97–7.94 (m,
1H, pyridine ring), 7.27–7.19 (m, 1H, pyridine ring),
6.15 (br s, 1H, imidazoline ring –NH), 3.54–3.52 (m,
4H, imidazoline ring); MS (ESI) m/z 204 [M+1]+; Anal.
Calcd for C10H9N3S: C, 59.09; H, 4.46; N 20.67. Found:
C, 59.06; H, 4.42; N 20.64.
1283, 1173, 881, 773 cmÀ1
.
1H NMR (300 MHz,
DMSO-d6) d 8.29–8.27 (m, 1H, pyridine ring), 7.99–
7.97 (m, 1H, pyridine ring), 7.25–7.21 (m, 1H, pyridine
ring), 6.19 (br s, 1H, imidazoline ring –NH), 3.55–3.53
(m, 4H, imidazoline ring), 2.18–2.15 (m, 1H, cyclohexyl
ring), 1.27–1.23 (m, 10H, cyclohexyl ring); MS (ESI) m/z
286 [M+1]+; Anal. Calcd for C16H19N3S: C, 67.33; H,
6.71; N 14.72. Found: C, 67.30; H, 6.69; N 14.70.
5.2.2.14. 5-Chloro-3-(4,5-dihydro-1H-imidazol-2-yl)-
thieno[2,3-b]pyridine (3b). Yield: 67%; white solid; mp
149–151 ꢁC; IR (KBr): 3134, 2897, 2235, 1289, 1173,
1
872, 747 cmÀ1. H NMR (300 MHz, DMSO-d6) d 8.43
5.2.2.20. 5-Chloro-3-(4,5-dihydro-1H-imidazol-2-yl)-2-
cyclohexyl-thieno[2,3-b]pyridine (3h). Yield: 69%; white
solid; mp 171–173 ꢁC; IR (KBr): 3129, 2895, 2232,
(s, 1H, thiophene ring –CH), 8.79–8.77 (m, 1H, pyridine
ring), 7.99–7.96 (m, 1H, pyridine ring), 6.21 (br s, 1H,
imidazoline ring –NH), 3.55-3.52 (m, 4H, imidazoline
ring); MS (ESI) m/z 238 [M+1]+, 239 [M+2]+; Anal.
Calcd for C10H8ClN3S: C, 50.53; H, 3.39; N 17.68.
Found: C, 50.50; H, 3.36; N 17.64.
1447, 1289, 1171, 874, 776, 743 cmÀ1
.
1H NMR
(300 MHz, DMSO-d6) d 8.81–8.79 (m, 1H, pyridine
ring), 7.98–7.97 (m, 1H, pyridine ring), 6.19 (br s, 1H,
imidazoline ring –NH), 3.54–3.52 (m, 4H, imidazoline

6794
R. H. Bahekar et al. / Bioorg. Med. Chem. 15 (2007) 6782–6795
ring), 2.19–2.15 (m, 1H, cyclohexyl ring), 1.28–1.25 (m,
10H, cyclohexyl ring); MS (ESI) m/z 321 [M+1]+, 322
[M+2]+; Anal. Calcd for C16H18ClN3S: C, 60.08; H,
5.67; N 13.14. Found: C, 60.04; H, 5.63; N 13.11.
iments were performed as follows.18,19 Cells were washed
once with PBS solution followed by 40 min. incubation
in fresh Krebs-Ringer Balanced Buffer containing NaCl
(115 mmol/L), KCl (4.7 mmol/L), CaCl2 (1.28 mmol/L),
MgSO4.7H2O (1.2 mmol/L), KH2PO4 (1.2 mmol/L),
NaHCO3 (10 mmol/L), and Hepes (25 mmol/L), con-
taining glucose (1.1 mM) and B.S.A (0.5%), pH 7.4.
The buffer was replaced after 40 min and the cells were
incubated (37 ꢁC) with the test and the standard com-
pounds, at different concentrations, for 30 min both in
the presence (16.7 mM) and absence (0 mM) of glucose
load. The supernatant was collected and the insulin
amount was measured by ultrasensitive Rat insulin ELI-
SA kit (Crystal Chem, IL). The protein was estimated in
the supernatant using Bicinchoninic Acid kit, according
to the manufacturer’s protocol (Sigma–Aldrich, MO).
The total insulin content obtained in picogram (pg)
was divided with the total protein (lg) in order to nor-
malize for differences in cell density between wells.
5.2.2.21. 3-(4,5-Dihydro-1H-imidazol-2-yl)-2-ethyl-thie-
no[2,3-b]pyridine (3i). Yield: 67%; white solid; mp 147–
149 ꢁC; IR (KBr): 3134, 2893, 2232, 1446, 1371, 1282,
1
1170, 873, 774 cmÀ1. H NMR (300 MHz, DMSO-d6) d
8.27–8.25 (m, 1H, pyridine ring), 7.98–7.95 (m, 1H, pyri-
dine ring), 7.27–7.24 (m, 1H, pyridine ring), 6.17 (br s,
1H, imidazoline ring –NH), 3.55–3.52 (m, 4H, imidazoline
ring), 2.19 (q, 2H, J = 7.1Hz, –CH2CH3), 1.24 (t, 3H,
J = 7.1Hz, –CH2CH3); MS (ESI) m/z 232 [M+1]+; Anal.
Calcd for C12H13N3S: C, 62.31; H, 5.66; N 18.17. Found:
C, 62.29; H, 5.63; N 18.14.
5.2.2.22. 5-Chloro-3-(4,5-dihydro-1H-imidazol-2-yl)-2-
ethyl-thieno[2,3-b]pyridine (3j). Yield: 66%; white solid;
mp 152–154 ꢁC; IR (KBr): 3123, 2889, 2229, 1443,
1372, 1286, 1172, 873, 778, 739 cmÀ1
.
1H NMR
5.4. Demonstration of in vivo efficacy of test compounds in
C57BL/6J mice
(300 MHz, DMSO-d6) d 8.79–8.76 (m, 1H, pyridine
ring), 7.99–7.97 (m, 1H, pyridine ring), 6.19 (br s, 1H,
imidazoline ring –NH), 3.54–3.52 (m, 4H, imidazoline
ring), 2.17 (q, 2H, J = 7.1Hz, –CH2CH3), 1.22 (t, 3H,
J = 7.1Hz, –CH2CH3); MS (ESI) m/z 267 [M+1]+, 268
[M+2]+; Anal. Calcd for C12H12ClN3S: C, 54.23; H,
4.55; N 15.81. Found: C, 54.20; H, 4.51; N 15.79.
5.4.1. Animals. Acute single dose 120-min time-course
experiments were conducted in male C57BL/6J mice,
age 8–12 weeks, mean body weight 25–30 g, bred in-
house. Animals were housed in groups of 6 animals
per cage, for a week, in order to habituate them to vivar-
ium conditions (25 4 ꢁC, 60–65% relative humidity,
12:12 h light:dark cycle, with lights on at 6.00 a.m.).
All the animal experiments were conducted according
to the internationally valid guidelines following ap-
proval by the ‘Zydus Research Center Animal Ethical
Committee’.
5.2.2.23. 2-Benzyl-3-(4,5-dihydro-1H-imidazol-2-yl)-
thieno[2,3-b]pyridine (3k). Yield: 70%; white solid; mp
162-164 ꢁC; IR (KBr): 3125, 2887, 2234, 1467, 1279,
1
1172, 869, 773 cmÀ1. H NMR (300 MHz, DMSO-d6)
d 8.25–8.23 (m, 1H, pyridine ring), 7.97–7.95 (m, 1H,
pyridine ring), 7.32–7.29 (m, 5H, benzene ring), 7.24–
7.22 (m, 1H, pyridine ring), 6.13 (br s, 1H, imidazoline
ring –NH), 3.55–3.52 (m, 4H, imidazoline ring), 3.81
(s, 2H, benzyl –CH2); MS (ESI) m/z 294 [M+1]+; Anal.
Calcd for C17H15N3S: C, 69.59; H, 5.15; N 14.32.
Found: C, 69.56; H, 5.11; N 14.29.
5.4.2. Procedure. The in vivo glucose lowering proper-
ties of some of the representative test compounds 2c
and 3c and standard compound BL 11282 were evalu-
ated in C57BL/6J animal models as described below.
Two days prior to the study, the animals were random-
ized and divided into 5 groups (n = 6), based upon
their fed glucose levels. On the day of experiment, food
was withdrawn from all the cages, water was given
ad libitum and animals were kept for overnight fasting.
Vehicle (normal saline)/test/standard compounds were
administered intraperitoneally on a body weight basis
soon after the 0 min. blood collection from each animal
and the subsequent blood collections were done at 30,
60 and 120 min, via retro-orbital route, under light
ether anesthesia.20,21
5.2.2.24. 5-Chloro-3-(4,5-dihydro-1H-imidazol-2-yl)-2-
benzyl-thieno[2,3-b]pyridine (3l). Yield: 68%; white solid;
mp 167–169 ꢁC; IR (KBr): 3122, 2893, 2237, 1451, 1283,
1
1172, 874, 767 cmÀ1. H NMR (300 MHz, DMSO-d6) d
8.81–8.78 (m, 1H, pyridine ring), 7.98–7.96 (m, 1H, pyr-
idine ring), 7.32–7.26 (m, 5H, benzene ring), 6.17 (br s,
1H, imidazoline ring –NH), 3.56–3.52 (m, 4H, imidazo-
line ring), 3.83 (s, 2H, benzyl –CH2); MS (ESI) m/z 328
[M+1]+, 329 [M+2]+; Anal. Calcd for C17H14ClN3S: C,
62.28; H, 4.30; N 12.82. Found: C, 62.24; H, 4.26; N
12.80.
Blood samples were centrifuged and the separated serum
was immediately subjected to glucose estimation. Serum
for insulin estimation was stored at À70 ꢁC until used
for the insulin estimation. The glucose estimation was
conducted with DPEC-GOD/POD method (Ranbaxy
Fine Chemicals Limited, Diagnostic Division, India),
using Spectramax-190, in 96-microwell plate reader
(Molecular Devices Corporation, Sunnyvale, Califor-
nia). Mean values of duplicate samples were calculated
using Microsoft excel and the GraphPad Prism software
(Ver 4.0) was used to plot a 0 min base line corrected
line graph, area under the curve (0–120 min AUC),
5.3. In vitro glucose-dependent insulin secretion (RIN5F
cell assay screening protocol)
Rat Insulinoma (RIN5F) cells were cultured in RPMI
1640 medium supplemented with sodium pyruvate
(1 mM) Hepes and Glucose (4.5 g/L) in a humidified
incubator (5% CO2), at 37 ꢁC. After trypsinization,
RIN5F cells were seeded at a concentration of 0.2 · 106
cells per well, in 12-well plates. The cells were grown
overnight to 80% confluence and insulin secretion exper-

R. H. Bahekar et al. / Bioorg. Med. Chem. 15 (2007) 6782–6795
6795
14. Efendic, S.; Efanov, A. M.; Berggen, P.; Zaitsev, S. V.
Diabetes 2002, 51, S448.
and baseline corrected area under the curve (0 min
BCAUC). The AUC and BCAUC obtained from graphs
were analyzed for one-way ANOVA, followed by Dun-
nett’s post test, using GraphPad prism software. Fur-
thermore, the insulin estimation was conducted using
rat/mouse insulin ELISA kit (Linco Research, Missouri,
USA). Changes in the blood insulin and glucose levels
with compounds 2c, 3c, and BL11282 are shown in Fig-
ures 2 and 3, respectively.
15. Brenner, M. B.; Gromada, J.; Efanov, A. M.; Bokvist, K.;
Mest, H. J. Ann. N. Y. Acad. Sci. 2003, 1009, 332.
16. Efanov, A. M.; Zaitse, S. V.; Mest, H. J.; Raap, A.;
Appelskog, I. B.; Larsson, O.; Berggren, P. O.; Efendic, S.
Diabetes 2001, 50, 797.
17. Bahekar, R. H.; Jain, M. R.; Goel, A.; Patel, D. N.;
Prajapati, V. M.; Gupta, A. A.; Jadav, P. A.; Patel, P. R.
Bioorg. Med. Chem. 2007, 15, 3248.
18. Montrose-Rafizadeh, C.; Wang, Y.; Janczewski, T. E.;
Henderson, T. E.; Egan, J. M. Mol. Cell. Endocrinol. 1997,
130, 109.
19. Wang, X.; Zhou, J.; Doyle, M. E.; Egan, J. M. Endocri-
nology 2001, 5, 1820.
20. Chen, D.; Wang, M. Diabetes Obesity Metabolism 2005, 7,
307.
21. Kim, J. G.; Baggio, L. L.; Bridon, D. P.; Castaigne, J. P.;
Robitaille, M. F.; Jette, L.; Benquet, C.; Drucker, D. J.
Diabetes 2003, 52, 751.
Acknowledgments
We are grateful to the management of Zydus Group for
encouragement. We thank the analytical department for
giving analytical support.
References and notes
22. Anastassiadou, M.; Danoun, S.; Crane, L.; Mouysset, G.
B.; Payard, M.; Caignard, D. H.; Rettori, M. C.; Renard,
P. Bioorg. Med. Chem. 2001, 9, 585.
23. Corbel, J. C.; Uriac, P.; Huet, J.; Martin, C. A. E.;
Advenier, C. Eur. J. Med. Chem. 1995, 30, 3.
24. Doyle, T. J.; Haseltine, J. J. Heterocycl. Chem. 1994, 31,
1417.
1. Ashcroft, F. M. Horm. Metab. Res. 1996, 28, 456.
2. Pfeiffer, E. F.; Thum, C.; Raptis, S.; Beischer, W.; Ziegler,
R. Horm. Metab. Res. 1976, 112.
3. Schulz, A.; Hasselblatt, A. Naunyn Schmiedeberg’s Arch.
Pharmacol 1989, 340, 321.
4. Le Brigand, L.; Virsolvy, A.; Manechez, D.; Godfroid, J.
J.; Guardiola-Lemaitre, B.; Gribble, F. M.; Ashcroft, F.
M.; Bataille, D. Br. J. Pharmacol. 1999, 128, 1021.
5. Eglen, R. M.; Hudson, A. L.; Kendall, D. A.; Nutt, D. J.;
Morgan, N. G.; Wilson, V. G.; Dilon, M. P. Trends
Pharmacol. Sci. 1998, 19, 381.
25. Chapleo, C. B.; Myers, P. L.; Butler, R. C. M.; Davis, J.
A.; Doxey, J. C.; Higgins, S. D.; Mayers, M.; Roach, A.
G.; Smith, C. F. C.; Stillings, M. R.; Welbourn, A. P.
J. Med. Chem. 1984, 27, 570.
26. Neef, G.; Eder, U.; Sauer, G. J. Org. Chem. 1981, 46,
2824.
27. Robison, M. M.; Robison, B. L. J. Am. Chem. Soc. 1956,
78, 1247.
6. Plant, T. D.; Henquin, J. C. Br. J. Pharmacol. 1990, 101, 115.
7. Proks, P.; Ashcroft, F. M. Proc. Natl. Acad. Sci. U.S.A.
1997, 94, 11716.
8. Zaitsev, S. V.; Efanov, A. M.; Efanova, J. B.; Larsson, O.;
Ostenson, C. G.; Gold, G.; Berggren, P. O.; Efendic, S.
Diabetes 1996, 45, 1610.
9. Cerasi, E.; Efendic, S.; Luft, R. Lancet 1969, 2, 301.
10. Morgan, N. G. Exp. Opin. Invest. Drugs 1999, 8, 575.
11. Jakobsen, P.; Madsen, P.; Andersen, H. Eur. J. Med.
Chem. 2003, 38, 357.
28. Verbiscar, A. J. J. Med. Chem. 1972, 15, 149.
29. Hands, D.; Bishop, B.; Cameron, M.; Edwards, J. S.;
Cottrll, I. F.; Wright, S. H. B. A. Synthesis 1996, 877.
30. Herbert, R.; Wibberley, D. G. J. Chem. Soc. 1969, 1505.
31. Furniss, B. S.; Hannaford, A. J.; Smith, P. W. G.;
Tatchell, A. R. Vogel’s Textbook of Practical
Organic Chemistry, 5th ed.; ELBS: England, 1989,
pp 938.
32. Kaigorodova, Y. A.; Vasilin, V. K.; Konyushkin, L.
D.; Usova, Y. B.; Krapivin, G. D. Molecules 2000, 5,
1085.
33. Hary, U.; Roettig, U.; Paal, M. Tetrahedron Lett. 2001,
42, 5187.
12. Morgan, N. G.; Chan, S. L. F.; Mourtada, M.; Monks, L.
K.; Ramsden, C. Ann. N. Y. Acad. Sci. 1999, 381, 217.
13. Mest, H. J.; Raap, A.; Schloss, J.; Treinies, I.; Paal, M.;
Giese, U.; Koivisto, V. Naunyn Schmiedeberg’s Arch.
Pharmacol. 2001, 364, 47.