Synthesis and antithrombotic activity study of some new thienopyridine derivatives

Article abstract of DOI:10.2174/157017811796064476

During the course of our investigation in the field of thienopyridine based antithrombotic agents, we have identified and synthesized 4'-(6,7-dihydro-4H- thieno[3,2-c]pyridin-5-ylmethyl)-biphenyl-2-carboxylic acid derivatives 5a-i, a thienopyridine derivative with good in vivo activity against thrombus formation. These findings prompted us to prepare new 4'-(6,7-dihydro-4H-thieno[3,2-c] pyridin-5-ylmethyl)-bipheny1-2-carboxylic acid derivatives bearing different acid derivatives 5a-i in the hope of increasing activity and better understanding the influence of esters and amides on the thrombus formation.

Full text of DOI:10.2174/157017811796064476

412
Letters in Organic Chemistry, 2011, 8, 412-415
Synthesis and Antithrombotic Activity Study of Some New Thienopyridine
Derivatives
Nageswar R. Challa*,a,b, Mahesh R. Ghantac and Pratap R. Padic
aResearch and Development, Srini Pharmaceuticals Ltd, Plot No. 10 & 11, Type C, Road No. 8, Film Nagar, Jubilee
Hills, Hyderabad-500 033, A.P, India
bDepartment of Chemistry, Osmania University, Tarnaka, Hyderabad-500 007, AP, India
cResearch and Development, Macleod’s Pharmaceuticals Ltd, Andheri (East), Mumbai-400 093, India
Received December 28, 2010: Revised February 16, 2011: Accepted February 21, 2011
Abstract: During the course of our investigation in the field of thienopyridine based antithrombotic agents, we have
identified and synthesized 4'-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-ylmethyl)-biphenyl-2-carboxylic acid derivatives
5a-i, a thienopyridine derivative with good in vivo activity against thrombus formation. These findings prompted us to
prepare new 4'-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-ylmethyl)-biphenyl-2-carboxylic acid derivatives bearing different
acid derivatives 5a-i in the hope of increasing activity and better understanding the influence of esters and amides on the
thrombus formation.
Keywords: Antiplatelet agents, antithrombotic agents, in-vivo, thienopyridine, thrombus formation.
INTRODUCTION
report the synthesis of new compounds 5a-i (Scheme 1) and
studied their in vivo biological activity in male Wister rats
comparing with Clopidogrel.
Biphenyl system is the key structural unit in most of the
sartans, nonpeptide antagonists of angiotensin II receptors
which have been used for the treatment of hypertensive
disorders [1a-d]. In this context, biphenyl-carboxylic acid [2]
and its derivatives [3] have received substantial attention.
Similarly tetrahydrothienopyridine is an important
phamacophore of many drug molecules, reported as
antibacterials [4] non-peptide GPIIb/IIIa antagonists [5],
platelet aggregators and antithorombotic agents [6]. As part
of our studies directed towards the development of
pharmacologically important new molecules, now we have
taken up the study of synthesis and antithrombotic activity of
tetrahydrothienopyridine derivatives having biphenyl-2-
carboxylic acid moiety. We wanted to investigate some new
beneficial properties if biphenyl-2-carboxylic acid and
tetrahydrotheino pyridine like cores were combined in one
molecule. To the best of our knowledge, there is no evidence
in the literature of the development of a molecular scaffold
containing core tetrahydrothienopyridine through nitrogen to
benzylic carbon of the biphenyl core moiety.
RESULTS AND DISCUSSION
Chemistry
Bromomethyl biaryl derivative 1 and 4,5,6,7-tetrahydro
thieno[3,2-c]pyridine hydrochloride 2 are used as precursors
in the synthesis of 4'-(6,7-dihydro-4H-thieno-[3,2-c]pyridin-
5-ylmethyl)-biphenyl-2-carboxylic acid derivatives 5a-i.
Benzylation of thienopyridine derivative 2 in methanol in the
presence of K2CO3, to provide compound 3, alkaline
hydrolysis of nitrile function of compound 3 in ethylene
glycol medium and subsequent functionalization of the
resulted carboxylic acid derivative 4 furnished the desired
compounds 5a-i (Scheme 1). All the compounds are fully
characterized based on their Mass, IR and NMR spectral data
and elemental analysis.
Antithrombotic Activity
Thus we have targeted the synthesis of 4'-(6,7-Dihydro-
4H-thieno [3,2-c]pyridin-5-ylmethyl)-biphenyl-2-carboxylic
acid (4) with an objective to study their antithrombotic
activity. Moreover, we optimized the required pharmaco-
phore which is having more antithrombotic activity over the
existing Clopidogrel by studying different acid derivatives
using different alcohols to get different ester derivatives and
amines to get different amides. From these results and as a
consequence of the computational studies, in this paper, we
All the thienopyridine based biphenyl derivatives were
evaluated in carotid arterial thrombosis model induced by
iron (III) chloride to observe the inhibition of thrombus
formation. The inhibitory activity was improved by studying
with substituted biphenyl compounds. To check the impact
on the thrombus formation different acid derivatives were
chosen 5a-i. Among the all derivatives, esters showed
significant antithrombotic activity over the amides 5a-i.
Among all compounds, the methyl ester 5a showed
statistically significant inhibition of thrombus formation
induced by FeCl3. The other esters (5b, 5c, 5f, 5g, 5h & 5i)
from the series showed moderate activity. The increased
effect of methyl ester 5a is due to the lower alkyl chain. It
*Address correspondence to this author at the Research and Development,
Srini Pharmaceuticals Ltd, Plot No. 10 & 11, Type C, Road No. 8, Film
Nagar, Jubilee Hills, Hyderabad-500 033, A.P, India; Tel: +91-9490
372331; Fax: 08694-271288; E-mail: nagu_osmania@yahoo.co.in
1570-1786/11 $58.00+.00
© 2011 Bentham Science Publishers Ltd.

Synthesis and Antithrombotic Activity Study
Letters in Organic Chemistry, 2011, Vol. 8, No. 6
413
.HCl
HN
CN
N
Br
a
S
S
CN
3
1
2
b
.HCl
N
R
O
HO
O
c
N
S
S
5a-i
4
where R= -OCH3, -OEt, -O-n-Propyl, -O-isopropyl, -NH2, -NH-Ph, -O-n-butyl, -O-isobutyl, -O-t-butyl
Scheme 1. a) Methanol, K2CO3, Reflux; b) KOH, ethylene glycol, 150°C; c) SOCl2, Toluene, R-OH or R-NH2.
was confirmed by checking the inhibitory effect of other
alkyl esters. If the length of the alkyl chain from ester carbon
increases, the effect of thrombus inhibition is suppressed.
The physical properties of the tested samples (5a-i) are
shown in Table 1. And also their in vivo antithrombotic
activity against male Wister rats was studied and the results
are furnished in Graph 1.
Table 1. Physical Properties of Thienopyridine Derivatives
Compound
R
M.R (°C)
Yield
5a
5b
5c
5d
5e
5f
-MeO
-EtO
120
110
130
150
165
125
128
135
142
80
75
85
70
60
65
70
75
65
-t-BuO
-NH2
Graph 1. Graphical comparison of thienopyridine derivatives with
clopidogrel bisulphate on inhibition of thrombus formation in
FeCl3-induced arterial thrombosis in model SD Rats (Pre-treatment-
1hr).
-NH-Ph
-n-PrO
-i-PrO
-n-BuO
-i-BuO
5g
5h
5i
EXPERIMENTAL
General
All solvents used were of commercial grade purchased
from a qualified vendor. Melting point Range reported was
uncorrected. The FT-IR spectra were recorded in the solid
state as KBr dispersion using a Perkin-Elmer 1650 FT-IR
spectrophotometer. Thin layer chromatography was
performed on Merck precoated Silica-gel 60F254 plates using
UV light as visualizing agent. 1H NMR spectra were
recorded on 400 MHz Gemini Varian spectrometer using
DMSO-d6 as solvent and tetramethylsilane as an internal
standard. The mass spectra were recorded on an Agilent
6310 Ion Trap. Microanalyses of compounds 5a-i were
performed by Elementar vario micro analyzer.
The antithrombotic activity of the compounds was
calculated by using the following formula as,
Thrombus dry weight of the control-dry weight of treatment x 100
Thrombus dry weight of the control
CONCLUSIONS
In conclusion, we have synthesized and characterized 4'-
(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-ylmethyl)-biphenyl-
2-carboxylic acid derivatives. We have also reported the
antithrombotic activity of the synthesized thieno pyridine
derivatives and they have shown good in vivo activity
against thrombus formation.
Synthesis of 4'-(6,7-Dihydro-4H-thieno[3,2-c]pyridin-5-
ylmethyl)-biphenyl-2-carbonitrile (3)
A mixture of compounds 1 (10.0 g, 0.03 mol) and 2 (7.07
g, 0.03 mol) and K2CO3 (7.6 g, 0.05 mol) in methanol (100
mL) was maintained at ambient temperature for over night

414 Letters in Organic Chemistry, 2011, Vol. 8, No. 6
Challa et al.
and progress of the reaction was monitored by TLC. After
the completion of the reaction, filtered the solid and washed
the cake with methanol (10 mL). The wet cake was
suspended in water (100 mL) and filtered the solid material
to afford 3. Yield: (13.6 g; 72%) M.R.: 89-91°C; MS (m/e):
331.2 (M+1). IR (KBr) (cm-1): 1595.41 (-C=C, Aryl),
C, 66.07; H, 5.54; N, 3.50; S, 8.02. Found: C, 66.1; H, 5.55;
N, 3.52; S, 8.12.
4'-(6,7-Dihydro-4H-thieno[3,2-c]pyridin-5-ylmethyl)-
biphenyl-2-carboxylic acid ethyl ester hydrochloride (5b)
IR (KBr) (cm-1): 1704.06 (-C=O), 2925.71 (ArH),
1
1
3445.80 (HCl); MS (m/e): 378.3 (M+1); H NMR (400
2227.70 (-CN), 2913 (-ArH); H NMR: (400 MHz, CDCl3):
MHz; CDCl3): ꢀ 1.1 (t, 3H), 2.8-2.9 (m, 4H), 3.59 (s, 2H),
3.79 (s, 2H), 4.18 (q, 2H), 6.68-7.81 (Aromatic, 10H);
13CNMR (100 MHz, CDCl3): 13.64, 25.45, 50.53, 53.15,
60.84, 61.93, 122.62, 125.17, 127.04, 128.33, 128.68,
129.66, 130.58, 131.04, 131.24, 133.38, 133.85, 137.31,
140.32, 142.09 and 168.84; Elemental analysis: (CHNS)
Anal calcd for C23H24ClNO2S. C, 66.73; H, 5.84; N, 3.38; S,
7.75 Found: C, 66.68; H, 5.83; N, 3.36; S, 7.62.
2.84-2.91,(m, 4H); 3.6, (s, 2H); 3.7, (s, 2H), 6.71, (d, J=5.2
Hz, 1H –ArH, thiophene); 7.07, (d, J=5.2 Hz, 1H –ArH,
thiophene); 7.43, (t, J=7.6 Hz, 1H, ArH biphenyl); 7.50-7.55,
(m, 5H); 7.6, (t, J=7.6 Hz, 1H, ArH biphenyl), 7.7, (d, J=7.6
Hz, 1H, ArH biphenyl).
Synthesis of 4'-(6, 7-dihydro-4H-thieno [3, 2-c] pyridin-5-
ylmethyl)-biphenyl-2-carboxylic acid (4)
A mixture of nitrile derivative 3 (10.0g, 0.03 mol) and
KOH (5.0 g, 0.08 mol) in ethylene glycol (100 mL) was
heated to 150-155°C and maintained till the completion of
the reaction. The progress of the reaction was monitored by
TLC and after the completion of the reaction, solvent was
distilled off under reduced pressure, water (100 mL) was
charged in to the reaction mass and pH of the reaction mass
was adjusted to 4-5 using aqueous HCl. Precipitated
compound 4 was filtered and dried under reduced pressure at
60°C for 4-5 hour. Yield: 10.0 g. (94%) M.R.: 160-165°C,
IR (KBr) (cm-1): 1692.75 (-C=O,-COOH), 2924.13 (-ArH),
3426.06 (-OH). MS (m/e): 348.3 (M-1); 1H NMR (400 MHz,
DMSO): 3.15, (s, 2H); 3.55, (s, 2H); 4.2, (s, 2H); 4.49, (s,
2H); 6.88, (d, J=4.8 Hz, 1H); 7.397-7.745, (m, 9H,
aromatic), 11.55 (s, 1H, -OH).
4'-(6,7-Dihydro-4H-thieno[3,2-c]pyridin-5-ylmethyl)-
biphenyl-2-carboxylic acid tert-butyl ester hydrochloride
(5c)
IR (KBr) (cm-1): 1722.67 (-C=O), 2979.13 (ArH); MS
1
(m/e): 406.3 (M+1); H NMR (400 MHz; CDCl3): ꢀ 1.25 (s,
9H), 3.15-3.52 (m, 4H), 4.2 (s, 2H), 4.5 (s, 2H), 6.9-1.89
(Aromatic, 10H), 11.2 (s, 1H); 13CNMR (100 MHz, CDCl3):
21.341, 27.474, 48.752, 49.534, 57.822, 81.152, 124.484,
125.260, 126.446, 127.206, 127.382, 129.245, 129.603,
130.263, 130.702, 130.833, 130.969, 132.307, 140.677 and
167.236; Elemental analysis: (CHNS) Anal calcd for
C25H28ClNO2S. C, 67.93; H, 6.38; N, 3.17; S, 7.25. Found:
C, 67.89; H, 6.36; N, 3.14; S, 7.24.
4'-(6,7-Dihydro-4H-thieno[3,2-c]pyridin-5-ylmethyl)-
biphenyl-2-carboxylic acid amide (5d)
Synthesis of 4´-(6,7-dihydro-4H-thieno[3,2-c]pyridine-5-
IR (KBr) (cm-1): 1643.32 (-C=O), 2918.54, (ArH),
3186.10, 3384.78 (-NH2); MS (m/e): 349.3(M+1); H NMR
ylmethyl)-biphenyl-2-carboxylic
hydrochloride (5a)
acid
methyl
ester
1
(400 MHz; CDCl3): 2.81-2.90 (m, 4H), 3.57 (s, 2H), 3.74 (s,
2H), 5.35 (s, NH), 5.79 (s, NH), 6.73, (d, J=5.2, 1H), 7.1 (d,
J=5.2, 1H), 7.38-7.5 (m, Aromatic, 8H); 13CNMR (100 MHz,
CDCl3): 25.46, 50.70, 53.12, 61.73, 122.56, 125.16, 127.45,
128.75, 129.04, 129.17, 130.34, 130.36, 133.43, 133.87,
134.54, 138.49, 139.19, 139.79 and 171.01; Elemental
analysis: (CHNS) Anal calcd for C21H20N2OS. C, 72.38; H,
5.79; N, 8.04; S, 9.20. Found: C, 72.2; H, 5.68; N, 8.01; S,
9.16.
Pyridine (0.2 mmol) was charged into a solution of
compound 4 (2 g, 0.005 mole) in toluene (10 mL) under
nitrogen atmosphere. Reaction mass was cooled to 0-5°C,
thionyl chloride (0.48 mL, 0.066 moles) was slowly added
and reaction mass was maintained for 2-3 hrs at ambient
temperature. Nitrogen was purged into the reaction mass for
5-10 minutes to remove excess SOCl2, methanol (0.27 g;
0.008 moles) was added into the reaction mass slowly over a
period of 20-30 minutes at 0-5°. Reaction mass was
maintained for 2-3 hrs at ambient temperature and poured
into water (10.0 mL) and product was extracted into ethyl
acetate. Organic layer was washed with saturated NaHCO3
solution (10 mL) followed by water (10 mL) and solvent was
distilled off completely under reduced pressure and pH was
adjusted to 2-3 using methanolic HCl (15%) in acetonitrile
(10.0 mL) medium that affords the corresponding acid
derivative (5a). Yield: 1.6 g, (80%).
4'-(6,7-Dihydro-4H-thieno[3,2-c]pyridin-5-ylmethyl)-
biphenyl-2-carboxylic acid phenyl amide (5e)
IR (KBr) (cm-1): 1674.83 (-C=O), 2921.81 (ArH),
1
3386.42 (amide -NH); MS (m/e): 425.3 (M+1); H NMR
(400 MHz; CDCl3): 2.92 (s, 2H), 3.52 (s, 2H), 4.03 (s, 2H),
4.34 (s, 2H), 6.57 (d, J=5.2, 1H), 6.87 (d, J=5.2, 1H), 7.05-
7.75 (Aromatic, 13H), 9.79 (s, 1H, NH); 13CNMR (100
MHz, CDCl3): 20.87, 48.04, 48.97, 57.31, 119.17, 122.79,
123.90, 123.97, 124.12, 124.22, 126.44, 126.68, 127.18,
127.42, 127.56, 128.36, 128.88, 130.44, 130.62, 136.52,
138.11, 138.21, 141.12 and 166.94; Elemental analysis:
(CHNS) Anal calcd for C27H24N2OS. C, 76.38; H, 5.70; N,
6.60; S, 7.55. Found: C, 76.35; H, 5.61; N, 6.48; S, 7.49.
4'-(6,7-dihydro-4H-thieno[3,2-c]pyridine-5-ylmethyl)-
biphenyl-2-carboxylic acid methyl ester hydrochloride (5a)
IR (KBr) (cm-1): 1729.80 (-C=O); 2923.96 (-ArH); MS
1
(m/e): 364.2 (M+1); H NMR (400 MHz; CDCl3): ꢀ 3.2 (s,
2H), 3.4 (s, 1H), 3.6 (s, 3H), 3.7 (s, 1H), 4.2 (s, 2H), 4.5 (s,
2H), 6.88 (d, J=5.2), 7.3-7.8 (aromatic, 9H); 13C NMR (100
MHz, CDCl3): 21.32, 48.81, 49.37, 57.78, 124.31, 124.91,
126.39, 127.21, 127.24, 128.75, 129.63, 129.89, 130.25,
130.78, 130.88, 131.14, 141.10, 142.68, and 167.90;
Elemental analysis: (CHNS) Anal calcd for C22H22ClNO2S.
4'-(6,7-Dihydro-4H-thieno[3,2-c]pyridin-5-ylmethyl)-
biphenyl-2-carboxylic acid propyl ester hydrochloride (5f)
IR (KBr) (cm-1): 1720.2 (-C=O), 2930.81 (ArH). MS
1
(m/e): 392.2 (M+1); H NMR (400 MHz; CDCl3): 0.65 (t,

Synthesis and Antithrombotic Activity Study
Letters in Organic Chemistry, 2011, Vol. 8, No. 6
415
3H), 0.35 (m), 2H), 3.2 (s, 2H), 3.4 (s, 2H), 4.0 (t, 2H), 4.2
(s, 2H), 4.5 (s, 2H), 6.9 (d, 1H0, 7.4-7.8 (m, 9H, aromatic).
13CNMR (100 MHz, CDCl3): 10.2, 22.7, 25.9, 50.2, 58.8,
59.0, 123.9, 127.1, 127.3, 129.2, 129.4, 129.5, 130.2, 133.3,
135.1, 135.2, 135.8, 137.8, 168.0. Elemental analysis:
(CHNS) Anal calcd for C24H26ClNO2S. C, 67.35; H, 6.12; N,
3.27; S, 7.49. Found: C, 67.4; H, 6.20; N, 3.28; S, 7.68.
with ketamine and xylazine. The left carotid artery was
isolated carefully, and a Para film was placed under the
vessel to separate it from the surround tissue. The surface of
the artery was covered with the whatmann paper 3 mm
soaked in FeCl3 (30%) solution for 15 minutes after 1 hr of
test compound administration. The injured carotid artery
segment (0.6 cm) was cut off from which the thrombi were
taken out and weighed (0 hr). After drying for 24 hr at room
temperature, the dried weight of thrombus was measured.
4'-(6,7-Dihydro-4H-thieno[3,2-c]pyridin-5-ylmethyl)-
biphenyl-2-carboxylic acid isopropyl ester hydrochloride
(5g)
All values are expressed as ±S.E.M. The mean and
standard error for each group was calculated and compared
applying One-way ANOVA followed by Dennett’s multiple
comparison tests using Graph Pad Prism software.
IR (KBr) (cm-1): 1730.3 (-C=O), 2928.32 (ArH); MS
1
(m/e): 392.2 (M+1); H NMR (400 MHz; CDCl3): 1.0 (d,
6H), 3.1 (s, 2H), 3.4 (s, 2H), 4.3 (s, 2H), 4.5 (s, 2H), 4.9 (q,
1H), 6.9 (d, 1H), 7.3-7.8 (m, 9H, aromatic); 13CNMR (100
MHz, CDCl3): 21.20, 48.75, 49.44, 57.76, 68.27, 76.57,
77.00, 77.43, 124.41, 125.14, 126.36, 127.16, 127.33,
129.07, 129.56, 130.29, 130.83, 130.93, 140.90, 143.11 and
167.37; Elemental analysis: (CHNS) Anal calcd for
C24H26ClNO2S. C, 67.35; H, 6.12; N, 3.27; S, 7.49. Found:
C, 67.21; H, 6.15; N, 3.31; S, 7.62.
ACKNOWLEDGEMENTS
The author Nageswar Rao Challa wishes to thank the
management of Srini Pharmaceuticals Limited for their
support during the development of these molecules.
Cooperation from colleagues of analytical research
development is greatly appreciated.
4'-(6,7-Dihydro-4H-thieno[3,2-c]pyridin-5-ylmethyl)-
biphenyl-2-carboxylic acid butyl ester hydrochloride (5h)
SUPPLEMENTARY MATERIAL
IR (KBr) (cm-1): 1735.4 (-C=O), 2970.3 (ArH). MS
(m/e): 406.3 (M+1); H NMR (400 MHz; CDCl3): 0.7 (t,
1
Supplementary material is available on the publishers
Web site along with the published article.
3H), 1.1 (sextet, 2H), 1.4 (q, 2H), 3.2 (s, 2H), 3.4 (s, 2H), 4.0
(t, 2H), 4.2 (s, 2H), 4.5 (s, 2H), 6.9 (d, 1H), 7.4-7.8 (m, 9H,
aromatic); 13CNMR (100 MHz, CDCl3): 13.44, 18.72, 21.29,
30.07, 48.71, 49.46, 57.79, 64.62, 76.58, 77.01, 77.43,
124.47, 125.20, 126.37, 127.15, 127.41, 129.05, 129.77,
130.44, 130.52, 131.15, 14.15, 143.15 and 167.84. Elemental
analysis: (CHNS) Anal calcd for C25H28ClNO2S. C, 67.93;
H, 6.38; N, 3.17; S, 7.25. Found: C, 67.78; H, 6.33; N, 3.07;
S, 7.14.
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IR (KBr) (cm-1): 1740.1 (-C=O), 2985.4 (ArH). MS
1
(m/e): 406.3 (M+1); H NMR (400 MHz; CDCl3): 0.7 (dd,
6H), 1.6 (m, 1H), 3.2 (s, 2H), 3.4 (s, 2H), 3.8 (d, 2H), 4.2 (s,
2H), 4.5 (s, 2H), 6.9 (d, 1H), 7.4-7.8 (m, 9H); 13CNMR (100
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70.99, 76.57, 76.99, 77.42, 124.46, 125.23, 126.36, 127.17,
127.44, 129.06, 129.82, 130.51, 130.93, 131.17, 141.09,
143.17 and 167.92. Elemental analysis: (CHNS) Anal calcd
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Found: C, 67.73; H, 6.31; N, 3.12; S, 7.10.
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[4]
[5]
[6]
Biological Activity
Antithrombotic Activity
All compounds 5a-i and drug reference were suspended
in 0.5% carboxymethyl cellulose (CMC) immediately prior
to dose administration. Antithrombotic activities of all the
compounds were studied at GVK Biosciences Pvt.Ltd.,
Hyderabad, India. Male SD rats were administered orally
control (0.5% CMC) and thienopyridine derivatives at 50
mg/kg individually, after overnight fasting and anesthetized
&