5,6-Diarylanthranilo-1,3-dinitriles as a new class of antihyperglycemic agents

Article abstract of DOI:10.1016/j.bmcl.2009.02.118

Various functionalized mono- and diarylanthranilo-1,3-dinitriles were synthesized and evaluated for their in vitro antihyperglycemic activity against the PTP-1B, glucose-6-phosphatase, glycogen phosphorylase and α-glucosidase enzymes. Among various screen

Full text of DOI:10.1016/j.bmcl.2009.02.118

Bioorganic & Medicinal Chemistry Letters 19 (2009) 2158–2161
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
5,6-Diarylanthranilo-1,3-dinitriles as a new class of antihyperglycemic agents q
Fateh V. Singh a, Amrita Parihar a, Sumit Chaurasia a, Amar B. Singh b, Salil P. Singh a,
Akhilesh K. Tamrakar b, Arvind K. Srivastava b, Atul Goel a,
*
a Division of Medicinal and Process Chemistry, Central Drug Research Institute, Lucknow 226 001, India
b Division of Biochemistry, Central Drug Research Institute, Lucknow 226 001, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Various functionalized mono- and diarylanthranilo-1,3-dinitriles were synthesized and evaluated for
their in vitro antihyperglycemic activity against the PTP-1B, glucose-6-phosphatase, glycogen phosphor-
Received 21 November 2008
Revised 20 January 2009
Accepted 27 February 2009
Available online 4 March 2009
ylase and
o-1,3-dinitriles 3a, 3b, and 3d showed good inhibitory activity against PTP-1B with IC50 values of 58–
72 M. Three of the test compounds showed significant (25–37%) lowering of plasma glucose level at
24 h in sucrose-challenged streptozotocin-induced diabetic Sprague–Dawley rat model.
Ó 2009 Elsevier Ltd. All rights reserved.
a-glucosidase enzymes. Among various screened compounds, 5,6-diaryl substituted anthranil-
l
Keywords:
Diarylanthranilo-1,3-dinitriles
1,2-Teraryl
PTP 1B inhibitor
STZ-S model
Antihyperglycemic
Type 2 diabetes is multifactorial disease characterized by high
level of blood glucose, insulin and impaired insulin action, having
an increasingly adverse impact on morbidity, mortality and overall
health care costs especially in the developed and fast developing
countries.1,2 The number of diabetic complains are continuously
growing with a currently estimated worldwide incidence of about
194 million people and expected to increase to 330 million by
2025.3 The remedies available in modern system of medicine for
the treatment of type 2 diabetes patients have been focused on die-
tary management of obesity4 to improve insulin sensitivity, sulfo-
nylureas5 to enhance insulin secretion, metformin6 to inhibit
hepatic glucose output, and acarbose7 to inhibit or reduce the rate
of glucose absorption from the gut. Recently, the treatment of type
2 diabetes has been revolutionized with the advent of thiazolidin-
edione (TZD) class of drugs (rosiglitazone, pioglitazone) that com-
bat insulin resistance and thereby normalize elevated blood
glucose levels.8 Although these synthetic drugs showed significant
therapeutic potential but are associated with risk of hepatotoxicity,
weight gain and edema.9 So an unmet need for a safe insulin sen-
sitizer devoid of side effects continues to exist.
form by inhibiting enzymes that catalyze insulin receptor dephos-
phorylation. Based on several compelling evidences that the pro-
tein tyrosine phosphatase 1B (PTP-1B) catalyzes insulin receptor
dephosphorylation10 and is involved physiologically and patholog-
ically in terminating insulin signaling. Therefore PTP-1B enzyme
has emerged as a legitimate molecular target for type 2 diabetes.
Several small-molecule therapeutics with high degree of potency
have been reported in the literature but designing PTP1B inhibitors
with high affinity and selectivity and with desirable physico-
chemical properties poses a real challenge.11 During our drug
development program on diabetes, we found that 6-aryl-2H-pyr-
an-2-one-3-carbonitriles12 and their ring transformed products
such as dibenzofurans,13 naphtho[2,1-b]furans,13 benzofurans13
and 3,4,5-triaryl-1H-pyrroles14 possess interesting antihyperglyce-
mic activity. Recent literature reveals that 1,3-teraryls containing
electron donor or acceptor groups have been reported as insulin
sensitizers.15 In this line, several 1,3-teraryl derivatives have been
explored to uncover their antihyperglycemic activity but little
attention has been paid to similar 1,2-teraryl systems with elec-
tron donor–acceptor moieties possibly due to lack of general syn-
thetic protocols for making them.
An alternative approach to improve insulin sensitivity is to
maintain insulin receptor in the active tyrosine-phosphorylated
Thus, we envisaged that synthesis and biological evaluation
of 1,2-teraryl systems with donor–acceptor functionalities such
as 5,6-diarylanthranilo-1,3-dinitriles would be an interesting
scaffold to examine their antihyperglycemic activity. Herein
we report synthesis, in vitro and in vivo antihyperglycemic
activity of functionalized 5,6-diarylanthranilo-1,3-dinitrile deriv-
atives in sucrose-challenged streptozotocin-induced (STZ-S) dia-
betic model.
q
CDRI Communication No. 7335.
* Corresponding author at present address: Institut für Organische Chemie,
Universität Würzburg, Am Hubland, 97074 Würzburg, Germany. Fax: +49 931
8884755.
E-mail addresses: goela@chemie.uni-wuerzburg.de, agoel13@yahoo.com
(A. Goel).
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.02.118

F. V. Singh et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2158–2161
2159
R3
R2
R3
R2
Limited synthetic methodologies are available for the prepara-
SCH3
CN
SCH3
tion of functionalized 1,2-teraryl scaffolds. The most common ap-
proaches for the synthesis of teraryls have been either by the
coupling of biaryltriflate compounds with Grignard reagents in
presence of a palladium catalyst in moderate to good yields,16 or
by the iterative coupling of aryl boronic acid with aromatic ha-
lides17 separately.
CN
KOH
DMF
+
CH2(CN)2
R1
R1
O
O
NH2
2
R4
R4 CN
4
5
During our recent studies on 2H-pyran-2-ones,18 we developed
new protocols for the synthesis of congested arylated benzene
derivatives through nucleophile-induced ring transformation reac-
tions. Similarly in order to prepare functionalized 5,6-diarylanthra-
Entry
5a
5b
5c
5d
R1
F
H
H
OMe
H
R2
H
H
H
H
OMe
H
R3
H
F
CF3
OMe
OMe
H
R4
H
H
H
H
Yield (%)
94
87
90
89
91
92
nilo-1,3-dinitriles scaffolds 3a–f, we attempted the reaction of
a-
5e
5f
H
C6H5
H
cyano-ketene-S,S-acetal with various functionalized deoxybenzo-
ins under alkaline conditions, which afforded 5,6-diaryl-2H-pyr-
an-2-ones 1a–f in excellent yields. Various functionalized
deoxybenzoins were prepared by heating a mixture of functional-
ized phenyl acetic acid and substituted benzenes in polyphospho-
ric acid as described previously.19 The topology of lactones, is the
presence of three electrophilic centers; C-2, C-4 and C-6 in which
latter is highly prone to nucleophiles due to extended conjugation
and the presence of electron-withdrawing functionality at position
3 of the pyran ring. The synthesis of 5,6-diarylanthranilo-1,3-
dinitriles derivatives 3a–f was achieved by stirring an equimolar
mixture of 5,6-diaryl-2H-pyran-2-ones 1a–f, malononitrile 2 and
powdered KOH in DMF 6–8 h at room temperature in 89–94% yield
(Scheme 1). The reaction was monitored by TLC and there after
poured into ice water and neutralized with dilute HCl. The crude
product thus obtained was purified on neutral alumina column
chromatography using 20% chloroform in hexane as eluent and
characterized by spectroscopic analyses.20
Scheme 2.
controlled substitution at different positions onto the central ben-
zene ring. To examine the effect of aryl ring at position C-5 of a
benzene-1,3-dinitrile ring towards their antihyperglycemic activ-
ity, we synthesized a series of functionalized biaryl compounds
5a–f through ring transformation of 5-aryl-6-methyl-2H-pyran-
2-ones 4a–f by using malononitrile 2 as a carbanion source. The
2H-pyran-2-ones 4a–f used as a parent precursors were conve-
niently prepared by the reaction of 2-cyano-3,3-dimethylsulfanyl-
acrylate with substituted phenyl acetones under alkaline
conditions in high yields.18e The synthesis of 5-aryl-6-methyl-4-
methylsulfanyl-anthranilo-1,3-dinitriles 5a–f was achieved by stir-
ring an equimolar mixture of 2H-pyran-2-ones 4a–f, malononitrile
2 and powdered KOH in DMF for 12–15 h at room temperature
(Scheme 2).21
The transformation of 5,6-diaryl-2H-pyran-2-ones 1a–f into
functionalized 5,6-diarylanthranilo-1,3-dinitriles is possibly initi-
ated by Michael addition of the malononitrile carbanion at position
C-6 of lactone 1, followed by intra-molecular cyclization involving
one of the nitrile functionalities of malononitrile and C-3 of the
pyranone ring and further elimination of carbon dioxide to yield
3a–f.
Further, a series of functionalized biaryls 7a–c, were prepared
by the reaction of 2H-pyran-2-ones 6a–c with malononitrile 2.
The synthesis of 6-aryl-5-methyl-4-methylsulfanyl-anthranilo-
1,3-dinitriles 7a–c was achieved by stirring an equimolar mixture
of 2H-pyran-2-ones 6a–c, malononitrile 2 and powdered KOH in
DMF for 12–15 h at room temperature (Scheme 3).22
To check the effect of methylsulfanyl group at C-4 position of
compound 7a–c towards the biological activity, we synthesized a
series of biaryl compounds 9a–c by using 6-aryl-5-methyl-2-oxo-
4-piperidin-1-yl-2H-pyran-3-carbonitriles 8a–c as a starting mate-
rial and malononitrile as carbanion source. The synthesis of 9a–c
was achieved by stirring an equimolar mixture of 2H-pyran-2-ones
In order to establish structure–activity relationships, it was
imperative to prepare repertoire of anthranilo-1,3-dinitriles by
O
R2
SMe
O
MeS
CN
R2
R1
CN
O
R1
SMe
KOH
DMF
SMe
CH2(CN)2
+
C
CN
N
CN
O
Me
CN
Me
O
2
R3
DMF
KOH
CH2(CN)2
+
R4
R3
1
O
NH2
2
R4
CN
6
R
R
7
MeOH
R2
R1
O
N
H
SMe
CN
CN
CN
NH2
N
MeS
O
N
NH
R2
R1
-CO2
Me
CN
Me
CN
O
CH2(CN)2
DMF/KOH
H
NH2
CN
R4
R3
O
8
R3
CN
R
9
3
R4
R
Entry
R
Yield (%)
R1
R2
R3
R4
Yield (%)
N
Entry
3a
3b
3c
3d
3e
3f
H
H
H
H
H
H
F
H
H
H
OMe
90
91
94
89
92
90
7a
7b
7c
9a
9b
9c
H
Cl
OMe
H
H
-
-
-
94
91
89
92
89
90
OMe OMe
OMe
H
H
H
OMe
OMe
OMe
piperidine
4-methylpiperidine
piperidine
OMe OMe
H
F
OMe
Scheme 1.
Scheme 3.

2160
F. V. Singh et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2158–2161
8a–c, malononitrile 2 and powdered KOH in DMF for 8–10 h at
room temperature as shown in Scheme 3.22
adding 3.0 mg/mL pNPG to the reaction mixture. The reaction
was followed for 3 min at 405 nm at the interval of 30 s.
All the synthesized compounds were evaluated for in vitro anti-
hyperglycemic activity against glucose-6-phosphatase, glycogen
Compounds 3a, 3b, and 3d showed 81.6% (IC50 58
lM), 61.5%
(IC50 86 M), and 76.9% (IC50 72 M) inhibition respectively
l
l
phosphorylase,
1B enzymes at 100
a control (Table 1).
Protein Tyrosine Phosphatase 1B activity was determined by
the modified method23 using pNPP as substrate. Assay was per-
formed in a final volume of 1.0 mL at 37 °C for 30 min in reaction
buffer containing 10 mM pNPP in 50 mM HEPES buffer pH 7.0 with
1 mM DTT and 2 mM EDTA. The reaction was stopped by the addi-
a
-glucosidase and protein tyrosine phosphatase
M concentration taking sodium vanadate as
against PTP-1B enzyme. Compounds 3c, 5c and 5d showed 74.3%,
55.0% and 50.0% inhibition against glycogen phosphorylase en-
zyme, respectively. The activity profile of the scaffolds (biaryl
and 1,2-teraryls from Scheme 1–3) revealed that teraryl scaffolds
(3a–f) in which a central benzene ring is substituted by adjacent
diaryl rings such as phenyl or 4-methoxyphenyl rings (Scheme 1)
showed good percentage inhibition compare to biaryl ring systems
(5a–f, 7a–c and 9a–c in Scheme 2 and Scheme 3) in in vitro en-
zyme assays. In vitro data of 5,6-diarylanthranilo-1,3-dinitrile
compounds 3a–f prompted us to examine in vivo antihyperglyce-
mic activity of selected compounds in sucrose-challenged strepto-
zotocin model (STZ-S) in Sprague–Dawley rats.
l
tion of 500 lL of 0.1 N NaOH and the absorbance was determined
at 410 nm. A molar extinction coefficient of 1.78 Â 104 MÀ1 cmÀ1
was utilized to calculate the concentration of the p-nitrophenolate
ion produced in the reaction mixture.
The effect of compounds on glucose-6-phosphatase was studied
by pre-incubating the compound in 1.0 mL reaction system for
10 min and then determining the residual glucose-6-phosphatase
activity according to the method of Hubscher and West.24 The
1.0 mL assay system contained 0.3 M citrate buffer (pH 6.0),
28 mM EDTA, 14 mM NaF, 200 mM glucose-6-phosphate, and en-
zyme protein. The mixture was incubated at 37 °C for 30 min after
which 1.0 mL of 10% TCA was added. Estimation of inorganic phos-
phates (Pi) in protein free supernatant was done according to the
method of Taussky and Shorr.25 Glucose-6-phosphatase activity
was defined as micromole Pi released per minute per milligram
protein.
Compounds 3a, 3b, 3d, and 3f were evaluated for in vivo antihy-
perglycemic activity in sucrose-challenged streptozotocin-induced
(STZ-S) male Sprague–Dawley diabetic rats. Metformin was taken
as a positive control. Male albino rats of Sprague–Dawley strain
of body weight 140 20 g were selected for this study. Overnight
fasted rats were made diabetic by intraperitoneal injection of
streptozotocin at 60 mg/kg body weight dose prepared in
100 mM citrate buffer (pH 4.5). Fasting blood glucose level was
measured after 48 h and animals showing blood glucose level
above 10 mM were considered as diabetic. The diabetic rats with
fasting blood glucose values (baseline at 0 min) from 140 to
270 mg/dL were included in this study. Animals were divided into
groups consisting of five animals in each. Rats of experimental
group were given suspension of the test sample at 100 mg/kg dose
by oral administration, where as animals of control group were gi-
ven an equal amount of vehicle (1% gum acacia). An oral sucrose
load of 2.5 g/kg was given to all groups 30 min post administration
of the test sample/vehicle. Blood glucose levels of the animals of all
groups were again measured at 30, 60, 90, 120, 180, 240, 300 and
1440 min (24 h) after sucrose load. Food (not water) was removed
from the cages during the experimental period. Comparing the
AUC of experimental and control groups determined the percent
antihyperglycemic activity.
The glycogen phosphorylase activity is measured by the modi-
fied method of Rall et al.26 Mixture A contained 57 mg glycogen
(substrate), 188 mg glucose-1-phosphate, 42 mg sodium fluoride,
138.8 mg 5’-AMP (4 mM) dissolved in 10 mL water. The reaction
mixture containing 0.2 mL Mixture-A, 0.1 mL enzyme is incubated
for 30 min at 37 °C and reaction terminated by adding 0.1 mL TCA
(10%) and 0.4 mL of 0.1 M sodium acetate. The mixture is kept
overnight at 4 °C and the Pi released is estimated according to
the method of Taussky and Shorr.25
Effect of compounds on
a
-glucosidase27 activity was deter-
mined in 1 mL reaction system in 67 mM sodium phosphate buffer
(pH 6.8) containing 1.0 mg/mL glutathione in the presence of
Among the four-screened compounds, three compounds (3a, 3b
and 3f) demonstrated good antihyperglycemic activity by showing
28.1%, 36.9% and 25.2% blood sugar lowering at 100 mg/kg dose
after 24 h drug treatment (Table 2). The most active compound
3b showed 36.9% sugar lowering activity better than standard drug
metformin, which showed 21.9% sugar lowering activity. The ac-
tive compounds 3a, 3b and 3d showed significant inhibitory effect
against enzyme PTP-1B in a noncompetitive manner and are found
to be safe up to the dose of 250 mg/kg body weight by oral route of
administration. The active compounds have low aqueous solubil-
0.1 mg/mL purified
a-glucosidase. The reaction was started by
Table 1
In vitro antihyperglycemic activity of compounds 3a–f, 5a–f, 7a–c and 9a–c
Entry
% Inhibitiona
G-6-Pase
GP
a-Glucosidase
PTP-1B
3a
3b
3c
3d
3e
3f
5a
5b
5c
5d
5e
5f
7a
7b
7c
9a
9b
9c
7.40
6.80
1.90
5.50
0.30
5.50
8.20
41.8
14.4
0.08
6.10
24.5
0.96
19.3
12.3
38.2
10.9
33.3
NI
10.5
5.70
11.5
14.4
25.9
13.4
NI
17.3
22.1
10.5
6.70
ND
6.70
6.70
17.3
ND
ND
ND
81.6(58
61.5(86
28.2
76.9(72
30.7
48.8
40.2
3.60
58.5
25.6
0.00
ND
l
l
M)
M)
37.9
74.3(79
6.90
13.8
NI
lM)
lM)
Table 2
In vivo antihyperglycemic activity of compounds 3a, 3b, 3d, 3f at 100 mg/kg dose in
STZ-S model
20.0
5.0
55.0
50.0
10.0
11.6
45.0
12.5
37.5
4.70
2.30
15.7
—
Compound
Dose (mg/kg)
Sugar lowering
24 h
5 h
Control
3a
3b
3d
—
504.2 115.2
413.1 108.7
NI
100
100
100
100
100
382.7 96.3(24.1**
)
)
297.2 91.3(28.1**
)
7.30
0.00
31.1
NI
NI
56.4
370.6 89.3(26.5**
260.5 84.4(36.9***
340.0 99.7(17.6)
)
415.6 105.1(17.5)
3f
392.4 88.9(22.1**
398.5 91.8(20.9**
)
)
308.9 84.0(25.2**
322.7 87.5(21.9**
)
)
Metformin
**
***
Values are expressed as mean SD, N = 5, p <0.01 ( ) and p <0.001 ( ) versus
Na-o-Vanadate
—
vehicle treated control. Statistical analysis was made by Dunnett test (Prism Soft-
a
Compounds were evaluated at 100
l
M concentration; ND means: not deter-
ware 3). Blood glucose values are given in mg/dL and
parentheses.
% sugar lowering in
mined; NI means no inhibition. IC50 (lM) values are given in parentheses.

F. V. Singh et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2158–2161
2161
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In summary, we have demonstrated synthesis, in vitro and
in vivo antihyperglycemic activity of a new class of 5,6-diarylan-
thranilo-1,3-dinitriles functionalized with donor–acceptor groups,
which demonstrated good sugar lowering activity. Among various
screened compounds, 4’-amino-4’’-methoxy-6’-methylsulfanyl-
[1,1’;2’,1’’]terphenyl-3’,5’-dicarbonitrile 3b showed 36.9% blood
sugar lowering at 100 mg/kg dose in STZ-S induced male Spra-
gue–Dawley diabetic rats. The compound was found to inhibit
the activity of PTP-1B to a significant level. This may be the under-
lying mechanism of antihyperglycemic activity of this compound.
Further investigations on 5,6-diarylanthranilo-1,3-dinitrile tem-
plate are currently in progress.
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Acknowledgment
Authors are thankful to CSIR (Grant NWP0032), and ICMR, New
Delhi, for financial support. F.V.S., S.C. and S.P.S. are grateful to
CSIR, New Delhi, for research fellowships. A.G. is thankful to Profes-
sor G. Bringmann for his support and to the Alexander von Hum-
boldt Foundation for research fellowship. We thank SAIF, CDRI,
for spectral analyses of the synthesized compounds.
19. Allen, C. F. H.; Barker, W. E.. In Deoxybenzoins: Organic Syntheses; Blatt, A. H.,
Ed.; John Wiley and Sons: New York, 1943; Vol. 2, p 156.
20. General procedure for the synthesis of 3a–f: A mixture of 4-methylsulfanyl-2-
oxo-5,6-diphenyl-2H-pyran-3-carbonitrile 1a–f (1 mmol), malononitrile
(1 mmol) and powdered KOH (1.2 mmol) in dry DMF (5 mL) was stirred at
room temperature for 6–8 h. At the end reaction mixture was poured into ice
water with vigorous stirring and finally neutralized with dilute HCl. The solid
thus obtained was filtered and purified on a neutral alumina column using
chloroform–hexane (1:4) as eluent. Compound 3a: White solid; mp 198–
200 °C; 1H NMR (200 MHz, CDCl3) d 2.27 (s, 3H, SCH3), 5.31 (br s, 2H, NH2),
6.93–6.96 (m, 2H, ArH), 7.00–7.04 (m, 2H, ArH), 7.15–7.22 (m, 6H, ArH); 13C
NMR (50 MHz, CDCl3) d 19.67 (SCH3), 97.92, 100.83, 115.77 (CN), 115.9 (CN),
127.85, 128.21, 128.41, 128.87, 129.57, 131.31, 135.19, 137.18, 147.73, 150.03,
152.03; IR (KBr) 2219 (CN), 3353, 3468 cmÀ1 (NH2); MS (FAB) 342 (M++1).
21. General procedure for the synthesis of compounds 5a–f: A mixture of 5-aryl-3-
cyano-6-methyl-4-methylsulfanyl-2H-pyran-2-ones 4 (1 mmol), malononitrile
(1.2 mmol) and powdered KOH (1.2 mmol) in dry DMF (5 mL) was stirred at
room temperature for 12–15 h. At the end the reaction mixture was poured
into ice water with vigorous stirring and finally neutralized with dilute HCl.
The solid thus obtained was filtered and purified on a neutral alumina column
using chloroform–hexane (1:3) as eluent. Compound 5a: White solid; mp 192–
194 °C; 1H NMR (200 MHz, CDCl3) d 2.20 (s, 3H, CH3), 2.30 (s, 3H, SCH3), 5.22
(br s, 2H, NH2), 7.04–7.19 (m, 4H, ArH); IR (KBr) 2220 (CN), 3352, 3413 (NH2)
cmÀ1; MS (FAB) 298 (M++1); Anal. Calcd for C16H12FN3S: C, 64.63; H, 4.07;
N,14.13. Found: C, 64.69; H, 4.10, N, 14.19.
References and notes
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(b) Aguilar-Bryan, L.; Clement, J. P., II; Gonzalez, G.; Kunjilwar, K.; Babenko, A.;
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22. General procedure for the synthesis of compounds 7a–c and 9a–c: A mixture of 5-
methyl-4-methylsulfanyl-2-oxo-6-aryl-2H-pyran-3-carbonitrile
6
or 5-
7. Coniff, R.; Krol, A. Clin. Ther. 1997, 19, 16.
methyl-4-secondaryamino-2-oxo-6-aryl-2H-pyran-3-carbonitrile 8 (1 mmol),
malononitrile (1 mmol) and powdered KOH (1.2 mmol) in dry DMF (5 mL) was
stirred at room temperature for 12–15 h. At the end the reaction mixture was
poured into ice water with vigorous stirring and finally neutralized with dilute
HCl. The solid thus obtained was filtered and purified on a neutral alumina
column using chloroform–hexane (1:5) as eluent. Compound 7a: white solid;
mp 220–222 °C; 1H NMR (200 MHz, CDCl3) d 2.16 (s, 3H, CH3), 2.59 (s, 3H,
SCH3), 5.12 (br s, 2H, NH2), 7.20–7.25 (m, 2H, ArH), 7.47–7.50 (m, 3H, ArH); IR
(KBr) 2221 (CN), 3348, 3407 (NH2) cmÀ1; MS (FAB) 280 (M++1); Anal. Calcd for
C16H13N3S: C, 68.79; H, 4.69; N,15.04. Found: C, 68.88; H, 4.78, N, 15.16.
Compound 9a: white solid; mp 210–212 °C; 1H NMR (200 MHz, CDCl3) d 1.62–
1.72 (m, 6H, 3CH2), 1.88 (s, 3H, CH3), 3.25–3.34 (m, 4H, 2CH2), 5.02 (br s, 2H,
NH2), 7.20–7.24 (m, 2H, ArH), 7.44–7.50 (m, 3H, ArH); IR (KBr) 2218 (CN),
8. Nolte, R. T.; Wisely, G. B.; Westin, S.; Cobb, J. E.; Lambert, M. H.; Kurokawa, R.;
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Hajduk, P. J.; Janowick, D. A.; Szczepankiewicz, B. G.; Pei, Z.; Hutchins, C. W.;
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3346, 3409 (NH2) cmÀ1
;
MS (FAB) 316 (M+). HRMS calcd for C20H20N4
316.1680, found: 316.1689.
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