Synthesis and in vitro activities on anti-platelet aggregation of N,N′-di(2-substituted-phenyl)-4-methoxy isophthalamides and benzene-1,3-disulfonamides

Article abstract of DOI:10.1016/j.cclet.2011.05.032

On the propose of searching for the SAR and obtaining novel antiplatelet aggregating drugs, we have described the synthesis procedure and the activities in vitro on antiplatelet aggregation of two series of derivatives, which contain both 18 N,N′-di(2-substitutedphenyl)-4-methoxyisophthalamides (2a-2r) of the 2 series and nine N,N′-di(2-substitutedphenyl)-4-methoxybenzene-1,3- disulfonamides (3a-3i) of the 3 series. The results showed that three compounds 2e, 2i and 3g emerged as significant activities of antiplatelet aggregation, superior to two reference drugs picotamide and aspirin, and eight compounds 2j, 2k, 2l, 2o, 2p, 2q, 2r and 3i merely superior to picotamide. The preliminary SAR shows that it is favorable for the 2 series to increase the activities via the steric hindrance substituents attached to the two side chain benzene rings at 2-positions. And the arylamides of the 2 series have better the activity values than the arylsulfonamides of the 3 series respective except for 3b and 3g. On the contrary, electrostatic factors would not contribute evidently to the activities of the two series. The structures of 15 compounds newly synthesized have been established by MS and ¹H NMR and been first reported in this paper.

Full text of DOI:10.1016/j.cclet.2011.05.032

Available online at www.sciencedirect.com
Chinese Chemical Letters 22 (2011) 1139–1142
www.elsevier.com/locate/cclet
Synthesis and in vitro activities on anti-platelet aggregation of
N,N0-di(2-substituted-phenyl)-4-methoxy isophthalamides and
benzene-1,3-disulfonamides
a
a
a
b
Xiu Jie Liu a, , Xin He , Cheng Ling Shi , Jie Meng , Ying Lu Shao ,
*
Hong Qiang Si a, Tao Hu a
a The College of Chemistry and Chemical Engineering, Tianjin University of Technology, Tianjin 300384, China
b The College of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China
Received 14 December 2010
Available online 18 July 2011
Abstract
On the propose of searching for the SAR and obtaining novel antiplatelet aggregating drugs, we have described the synthesis
procedure and the activities in vitro on antiplatelet aggregation of two series of derivatives, which contain both 18 N,N0-di(2-
substitutedphenyl)-4-methoxyisophthalamides (2a–2r) of the 2 series and nine N,N0-di(2-substitutedphenyl)-4-methoxybenzene-
1,3-disulfonamides (3a–3i) of the 3 series. The results showed that three compounds 2e, 2i and 3g emerged as significant activities
of antiplatelet aggregation, superior to two reference drugs picotamide and aspirin, and eight compounds 2j, 2k, 2l, 2o, 2p, 2q, 2r
and 3i merely superior to picotamide. The preliminary SAR shows that it is favorable for the 2 series to increase the activities via the
steric hindrance substituents attached to the two side chain benzene rings at 2-positions. And the arylamides of the 2 series have
better the activity values than the arylsulfonamides of the 3 series respective except for 3b and 3g. On the contrary, electrostatic
factors would not contribute evidently to the activities of the two series. The structures of 15 compounds newly synthesized have
1
been established by MS and H NMR and been first reported in this paper.
# 2011 Xiu Jie Liu. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Synthesis; Anti-platelet aggregating; Isophthalamides; Benzene-1; 3-Disulfonamides
Picotamide (1) also known as N,N0-bis(3-pycolyl)-4-methoxylisophthalamide, is an antiplatelet drug with a dual
inhibitory action [1]. Thus, picotamide inhibits both thromboxane A2 (TxA2) receptors and TxA2 synthase and, at
variance with aspirin, does not interfere by endothelial prostacyclin (PGI2) production [2]. Since 2000 we have
reported that a series of structure analogues of picotamide were designed and synthesized via replacing the two 3-
pycolyl groups in picotamide with two substituted phenyl groups. Various arylamide compounds so obtained exhibited
higher antiplatelet aggregation activities than that of picotamide [3,4]. In order to search for the SAR and obtain novel
antiplatelet aggregating drugs, we got two coutour maps of electrostatic QSAR and steric QSAR from CoMFA in
2004. The results indicated that the activities of the referenced analogues were influenced evidently by electrostatic
and steric factors. On this basis, more and more active compounds were designed and synthesized [5].
* Corresponding author.
E-mail address: liuxiujie@hotmail.com (X.J. Liu).
1001-8417/$ – see front matter # 2011 Xiu Jie Liu. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2011.05.032

1140
X.J. Liu et al. / Chinese Chemical Letters 22 (2011) 1139–1142
OCH
OCH
OCH
3
3
3
R
R
2
2
CONHCH
SO NH
2
CONH
2
N
R
1
R
1
R
R
R
1
1
2
CONHCH
SO NH
2
CONH
2
R
2
N
1
2
3
Fig. 1. Structures of picotamide 1, arylamides 2 and arylsufonamides 3.
In continuation of our research for more potent derivatives of isophthalamides [6], we report in this paper synthesis
and pharmacological investigation of novel N,N0-di(2-substitutedphenyl)-4-methoxyisophthalamides and benzene-1,
3-disulfonamides of resemble the structure 2 and structure 3, respectively (Fig. 1). First of all, 4-methoxy group was
still maintained at 4-position of the parent benzene ring. Second, with two mono-2-substitutedphenyl rings replacing
the two 3-pyridinemethyl groups, the ten mono-2-substituted arylamides (2a–2j) of the 2 series were prepared to
research the effects of electronic factor and steric factor of different substituents (H, F, Cl, Br, I, CH3, OCH3, NO2,
CH2Ph, CH2CN) on the activity. Third, three pairs of di-2-substituted-arylamides (2k–2n, 2p, 2q) of the 2 series via
the same two substituents (Cl, CH3, OCH3) were also prepared to research the effect of different substituents at the
same 2, 4- and 2, 5-positions. Fourth, besides 2p and 2q, other two di-chlorosubstituted arylamides (2o, 2r) of the 2
series were also prepared to research the effect of the same substituents at four different positions (2, 3-, 2, 4-, 2, 5- and
2, 6-). Fifth, seven mono-2-substituted (3a–3g) and two di-substituted (3h and 3i) arylsulfonamides of the 3 series in
accordance with structure 3 by the isostere were prepared to compare the activities between the two series.
1. Experimental
A total of 27 compounds were enrolled in this study. The synthesis of target compounds were achieved following a
1
described procedure in Scheme 1 [6] and their structures were confirmed by MS and H NMR. Fifteen compounds
were first reported in this paper (Table 1).
2. Antiplatelet aggregation activity in vitro
The activity in vitro on antiplatelet aggregation was evaluated by Venous blood from the mice eye socket vein,
which is based on Born’s test method on mice [7]. Table 2 exhibits the results of 27 target compounds.
OCH
R2
OCH
3
R1
OCH
3
OCH
3
3
CONH
R1
COCl
CH Cl
KMnO /KOH
2
HCHO/HCl
PhH, 95%
H N
2
4
R
2
R1
R2
SOCl
2
4
CONH
COCl
Pyridine /THF
CH Cl
2
HOSO Cl
2
2a-2r
5
6
R1
OCH
3
OCH
3
R2
SO Cl
2
H N
2
SO NH
2
R
2
R1
R1
R2
Pyridine /THF
SO Cl
2
SO2NH
3a-3i
7
Compd.
2a [4]
2b [5]
2c [4]
2d
R1
R2
Compd.
2j [5]
2k
R1
R2
H
Compd.
3a
R1
R2
H
H
H
H
H
H
H
H
H
H
CH2CN
OCH3
OCH3
CH3
CH3
Cl
H
H
F
4-OCH3
5-OCH3
4-CH3
5-CH3
3-Cl
3b
F
H
Cl
2l
3c
Cl
H
Br
2m [6]
2n [6]
2o
3d [6]
3e
CH3
H
I
OCH3
CH2Ph
CH2CN
OCH3
OCH3
H
2e
2f [6]
2g [5]
2h [5]
2i [5]
CH3
OCH3
NO2
CH2 Ph
H
3f
Cl
4-Cl
H
2p
3g
Cl
5-Cl
4-OCH3
5-OCH3
2q
3h
2r[4]
Cl
6-Cl
3i
Scheme 1. Synthesis routes of the arylamides (2a–2r) and arylsulfonamides (3a–3i).

X.J. Liu et al. / Chinese Chemical Letters 22 (2011) 1139–1142
1141
Table 1
Melting points, yields and MS and 1H NMR data of the novel compounds.
Compd.
Mp (8C)
Yield (%)
36
MS (m/z)
1H NMR, d, J (Hz)
2d
199–200
505
(400 MHz, CDCl3): 4.20 (s, 3H), 7.02 (s, 2H), 7.22 (t, 1H, J = 8.8),
7.36 (d, 1H, J = 8.0), 7.40 (s, 1H), 7.59 (d, 2H, J = 8.0), 8.24 (d, 1H, J = 8.8),
8.50 (d, 1H, J = 4.4), 8.54 (s, 1H), 8.66 (d, 1H, J = 8.4), 8.87 (s, 1H), 10.43 (s, 1H)
(400 MHz, CDCl3): 4.22 (s, 3H), 5.90 (t, 2H, J = 14.4), 7.25 (t, 1H, J = 8.0),
7.40(t, 2H, J = 15.6), 7.83 (d, 1H, J = 8.4), 7.87 (s, 1H), 8.26(d, 2H, J = 7.2),
8.40 (d, 1H, J = 8.8), 8.48(d, 1H, J = 8.0), 8.94 (s, 1H), 10.12 (s, 1H)
(400 MHz, CDCl3): 3.85 (d, 3H, J = 2.8), 3.93 (s, 3H), 3.97 (s, 3H), 4.16 (s, 3H),
5.32 (s, 3H), 6.54 (d, 4H, J = 6.4), 6.56 (s, 3H), 7.18 (d, 3H, J = 8.8),
8.25 (q, 2H, J = 10.0), 8.44 (d, 1H, J = 9.6), 8.53 (s, 1H), 8.55 (s, 1H),
8.76 (d, 1H, J = 2.0), 10.39 (s, 1H)
2e
228–229
188–189
30
35
600
467
2k
2l
219–222
40
467
(400 MHz, CDCl3): 3.84 (d, 3H, J = 2.8), 3.87 (s, 3H), 3.93 (s, 3H),
3.97 (s, 3H),4.18 (s, 3H), 6.65 (d, 2H, J = 8.4), 6.87 (t, 2H, J = 16), 20 (d, 1H, J = 9.2),
8.26 (t, 2H, J = 10.8), 8.41 (d, 1H, J = 2.4), 8.68 (s, 1H), 8.79 (d, 1H, J = 2.0),
10.62 (s, 1H)
2o
2p
2q
3a
282–283
254–255
>300
36
50
52
75
501
501
501
419
(400 MHz, DMSO-d6): 4.15 (s, 3H), 7.64 (m, 2H, J = 104), 8.05 (m, 2H, J = 15.2),
8.15 (d, 1H, J = 2.8), 8.17 (d, 1H, J = 2.8), 8.22 (d, 1H, J = 2.8), 8.38 (d, 1H, J = 7.2),
8.61(m, 1H, J = 26), 8,92 (s, 1H), 8.94 (s, 1H)
(400 MHz, DMSO-d6): 4.14 (s, 3H), 7.51 (m, 3H, J = 11.6), 7.61 (m, 1H, J = 11.2),
7.76 (m, 2H, J = 16.0), 8.22 (dd, 1H, J = 10.4), 8.44 (d, 1H, J = 12.0),
8.69 (d, 1H, J = 12.0), 10.31 (s, 1H), 10.55 (s, 1H)
(400 MHz, DMSO-d6): 4.12 (s, 3H), 7.29 (t, 2H, J = 14.4), 7.42 (d, 1H, J = 10.8),
7.64 (m, 2H, J = 11.6), 8.18 (dd, 1H, J = 15.2), 8.54 (d, 2H, J = 6.0), 8.62 (d, 1H, J = 2.0),
10.40 (s, 1H), 10.63 (s, 1H)
210–212
(300 MHz, DMSO-d6): 3.90 (s,3H), 7.18 (d, 2H, J = 6.6), 7.30 (t, 2H, J = 6.6),
7.46 (d, 1H, J = 0.3), 7.60 (d, 2H, J = 10.2), 7.95 (d, 2H, J = 1.2), 7.97 (t, 1H, J = 1.2),
8.32 (t, 1H, J = 3.0), 10.92 (s, 1H), 10.93 (s, 1H)
3b
3c
3e
206–207
204–206
198–200
87
38
67
456
489
480
(300 MHz, CDCl3): 4.04 (s, 3H), 6.59 (s, 1 H), 7.01 (q, 3H), 7.10 (m, 5H, J = 21.0),
7.51 (s, 1H), 7.84 (d, 1H, J = 8.7), 8.22 (d, 1H, J = 2.4), 7.51 (s, 1H)
(300 MHz, DMSO-d6): 3.89 (s, 3H), 7.14 (t, 3H, J = 6.6), 7.30 (q, 5H, J = 20.1),
7.41 (d, 1H, J = 8.7), 7.80 (d, 1H, J = 8.6), 7.95 (d, 1H, J = 8.8), 9.94 (s, 1H), 10.06 (s, 1H)
(300 MHz, CDCl3): 3.62 (s, 3H), 3.72 (s, 3H), 3.96 (s, 3H), 6.69 (s, 1H),
6.71 (t, 1H, J = 9.9), 6.75 (s, 2H), 6.85 (d, 1H, J = 6.0), 6.87 (s, 1H), 6.90 (s, 1H),
6.98 (t, 2H, J = 6.0), 7.26 (s, 1H), 7.43 (t, 1H, J = 3.9), 7.50 (s, 1H), 8.30 (d, 1H, J = 2.1)
(300 MHz, DMSO-d6): 3.90 (s, 3H), 3.90 (s, 2H), 3.99 (s, 2H), 6.57 (d, 1H, J = 1.0),
6.83–7.29 (m, 18H), 7.77 (d, 1H, J = 7.2), 7.95 (s, 1H), 9.68 (s, 1H), 9.70 (s, 1H)
(300 MHz, DMSO-d6): 4.17 (s, 3H), 4.01 (s, 2H), 4.14 (s, 2H), 5.58 (d, 1H, J = 7.8),
7.00 (d, 1H, J = 7.8), 7.13 (d, 1H, J = 7.2), 7.26 (s, 1H), 7.35 (d, 2H, J = 7.8), 7.45
(d, 1H, J = 7.5), 7.80 (d, 1H, J = 9.0), 7.97 (s, 1H), 8.68 (s, 1H), 8.75 (s, 1H)
(400 MHz, CDCl3): 3.50 (s, 3H), 3.61 (s, 3H), 3.78 (d, 6H, J = 2.4), 4.01 (s, 3H),
6.52 (t, 1H, J = 23.6), 6.44 (q, 2H, J = 18.4), 6.64 (s, 1H), 6.90 (d, 1H, J = 8.8),
7.22 (s, 1H), 7.38 (d, 2H, J = 8.8), 7.76 (d, 1H, J = 8.8), 8.22 (s, 1H)
(400 MHz, CDCl3): 3.60 (s, 3H), 3.70 (s, 3H), 3.73 (s, 3H), 3.76 (s, 3H), 3.99 (s, 3H),
6.52 (q, 1H, J = 10.8), 6.59 (s, 1H), 6.62 (s, 1H), 6.65 (d, 2H, J = 9.6), 6.69 (s, 1H),
6,91 (d, 1H, J = 10.8), 7.02 (s, 1H), 7.54 (s, 1H), 786 (d, 1H, J = 8.8), 8.35 (s, 1H)
3f
247–248
191–192
73
61
599
497
3g
3h
3i
162–163
177–178
42
50
537
538
The melting points were determined but the thermometer was uncorrected; 1H NMR were recorded in DMSO-d6 or CDCl3 on a Bruker ARX-300 or
400 MHz spectrometer; chemical shifts are recorded in d relative to TMS as internal standard; mass spectral datd were obtained on Agilent 6310.
3. Results
A total of 27 target compounds were synthesized. The results in vitro on platelet using Born’s test method on mice in
Table 2 showed that three compounds 2e, 2i and 3g exhibited significant activities on antiplatelet aggregation, more
than picotamide and aspirin, and eight compounds 2d, 2j, 2k, 2l, 2q, 2r, 3f and 3i only superior to picotamide, while
compounds 2a, 2d and 3b are comparable with picotamide. The rest of the compounds were less active than the two
drugs. The inhibitory rates of 10 compounds (2c, 2f, 2g, 2h, 2m, 2n, 3a, 3c, 3d, 3e) are lower than 5.0%. The
preliminary SAR shows that it is favorite for the 2 series to increase the activities via steric hindrance groups, such as I

1142
X.J. Liu et al. / Chinese Chemical Letters 22 (2011) 1139–1142
Table 2
In vitro data of antiaggregation inhibitory rates of target compounds.
Groups
Conc. (mmol/L)
Congregate rate (%)
Inhibitory rate (%)
IC50 (mmol/L)
Control group of solvent
–
50.5 ꢀ 12.6
30.0 ꢀ 9.8
6.0 ꢀ 0.1
–
–
2a
2b
1.30
1.30
1.30
1.30
1.30
1.30
1.30
1.30
1.30
1.30
1.30
1.30
1.30
1.30
1.30
1.30
1.30
1.30
1.30
1.30
1.30
1.30
1.30
1.30
1.30
1.30
1.30
1.30
1.30
56.5
88.2
1.0
0.77
0.86
–
2c
2d
50.7 ꢀ 12.4
14.1 ꢀ 8.1
6.3 ꢀ 0.9
59.1
81.7
0.0
0.47
0.32
–
2e
2f
2g
52.3 ꢀ 9.0
50.7 ꢀ 11.2
51.6 ꢀ 8.3
5.4 ꢀ 1.4
40.4
0.0
–
2h
2i
–
89.3
95.0
69.4
66.3
0.0
0.02
0.59
0.47
0.36
–
2j
2k
0.0 ꢀ 0.0
10.6 ꢀ 0.5
11.7 ꢀ 2.9
51.9 ꢀ 8.6
52.0 ꢀ 4.9
26.2 ꢀ 5.4
20.1 ꢀ 11.6
21.5 ꢀ 1.5
1.2 ꢀ 11.0
56.7 ꢀ 24.5
7.6 ꢀ 0.5
2l
2m
2n
0.0
–
2o
2p
49.2
61.0
58.1
97.6
0.0
1.40
0.88
0.74
0.36
–
2q
2r
3a
3b
85.0
0.0
0.77
–
3c
3d
51.2 ꢀ 17.2
47.6 ꢀ 9.6
50.7 ꢀ 11.2
0.0 ꢀ 0.0
11.5
0.0
–
3e
–
3f
3g
95.0
95.5
53.9
35.6
56.5
69.6
0.59
0.20
0.95
0.52
0.76
0.33
0.0 ꢀ 6.8
3h
3i
15.9 ꢀ 12.6
22.2 ꢀ 3.7
15.0 ꢀ 4.3
10.5 ꢀ 4.0
Picotamide
Aspirin
and CH2Ph. And the active disubstituted arylamides of the 2 series, especially chloride and methoxy groups, were
developed greatly in proportion than the monosubstitutes but the positions of the two groups would be not related to
the ADP ratio values. And the arylamides and of the 2 series have better activity than that of the arylsulfonamides of
the 3 series except for 3b and 3g. However, no conclusion could be drawn on the effect of electron donating or electron
withdrawing groups on antiplatelet aggregation activities of the two series. Further work is needed to define the role of
these groups.
Acknowledgments
The authors would like to thank the Committee of Science and Technology of Tianjin of China for the financial
support from the Prop Up Research Project (No. 10ZCKFSH00500).
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