G.H. Chen et al. / Chinese Chemical Letters 21 (2010) 287–289
289
Table 1
Platelet aggregation inhibitory activities of target compounds.
No
R1
IC50 (mmol/L)
No
R2
n
IC50 (mmol/L)
11a
11b
11c
11d
11e
11f
H
3.6
28.2
2.1
13a
13b
13c
13d
13e
13f
2-Chlorophenyl
1
1
1
1
2
2
35.4
42.3
51.4
13.8
4.3
3-Methyl
2-Chloro
3-Chloro
2,3-Dichloro
2-Methoxyl
3-Chlorophenyl
2,3-Dichlorophenyl
2-Methoxyphenyl
2-Phenoxyethyl
26.4
39.7
1.6
2-(3-Tolyloxy)ethyl
12.3
in acetonitrile, followed by salt formation in HCl/EtOH to provide targets 11a–11f. In Scheme 2, epoxy derivative 12,
which was obtained from 6 in the presence of NaH in THF by the usual manner, was treated with substituted piperazine
in isopropanol, then by salt formation in HCl/EtOH to afford another series of targets 13a–13f. Date of IR, 1H NMR
and MS for representative compounds were given in Ref. [10].
Twelve target compounds were synthesized and evaluated for their platelet aggregation inhibitory activities in vitro
according to Ref. [11], with SARP as reference control. Blood was obtained from ulnar vein and was treated with 3.8%
sodium citrate (1 part citrate to 9 parts of blood). Platelet-rich plasma (PRP) was prepared by centrifugation at 500 rpm
for 5 min. A cuvette containing 250 mL of PRP and 20 mL of test compound solution was placed in the aggregometer
and allowed to incubate for 5 min, PRP was challenged with 20 mL of collagen suspension and platelet aggregation
was recorded continuously. The inhibitory activities of targets compounds were measured with various concentrations,
and the concentration producing 50% inhibition (IC50) was calculated.
The biological results of target compounds were summarized in Table 1. Preliminary biological tests suggested that
four compounds displayed remarkable platelet aggregation inhibitory activities. Especially, two compounds (11c,11f)
had lower IC50 than that of SARP (2.8 mmol/L). Further modification is currently ongoing in our group to investigate
their SAR and explore potential new pharmacological target.
References
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[3] R. Kikumoto, A. Tobe, H. Fukami, et al. J. Med. Chem. 27 (1984) 645.
[4] N.A. Colabufo, F. Berardi, R. Perrone, et al. J. Med. Chem. 49 (2006) 6607.
[5] R. Kikumoto, H. Fukami, H. Hara, et al. EP 0072942.
[6] R. Kikumoto, H. Hara, K. Ninomiya, et al. J. Med. Chem. 33 (1990) 1818.
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[8] N. Tanaka, R. Goto, R. Ito, et al. Chem. Pharm. Bull. 48 (2000) 1729.
[9] G.H. Chen, S. Wang, H.J. Zhang, CN 101279899, 2008.
[10] For compound 5, 1H NMR (500 MHz, CDCl3): d 7.52 (d, 1H, J = 16.4 Hz, –CH ), 7.13 (d, 1H, J = 16.4 Hz, –CH ), 6.80–7.60 (m, 13H, Ar–
H), 5.15 (s, 2H, –CH2–), 3.83 (s, 3H, –OCH3). ESI-MS (m/z): 317 [M+H]+. IR (KBr): 3063, 3032, 2977, 2927, 2866, 1601, 1498, 1452, 1243,
752, 697. For compound 6, 1H NMR (300 MHz, CDCl3): d 6.72–7.23 (m, 8H, Ar–H), 4.75(s, 1H, –OH), 3.75 (s, 3H, –OCH3), 2.90 (m, 4H, –
CH2CH2–). ESI-MS (m/z): 227 [MÀH]À. IR (KBr): 3526, 3031, 2936, 2860, 1592, 1501, 1455, 1256, 865, 753, 695. For compound 11a, 1H
NMR (300 MHz, CDCl3): d 14.08 (brs, 1H, HCl), 13.77 (brs, 1H, HCl), 6.65–7.34 (m, 13H, Ar–H), 4.54 (m, 2H, –OCH2CH2N–), 4.18 (m, 2H,
–OCH2CH2CH2–), 3.76 (m, 2H, –OCH2CH2N–), 3.74 (s, 3H, –OCH3), 3.54–4.01 (m, 8H, piperazine), 3.24 (m, 2H, –OCH2CH2CH2–), 2.81–
2.93 (m, 4H, ArCH2CH2–), 2.34 (m, 2H, –OCH2CH2CH2–). ESI-MS (m/z): 475 [M+H]+. IR (KBr): 3409, 2918, 2406, 2292, 1601, 1494, 1454,
1249, 750, 696. For compound 13a, 1H NMR (500 MHz, CDCl3): d 11.96 (brs, 1H, HCl), 6.71–7.39 (m, 12H, Ar–H), 5.44 (m, 1H, –OCH2–),
4.69 (m, 1H, –OCH2–), 4.14 (m, 1H, –CHOH), 3.90 (brs, 1H, –OH), 3.73 (s, 3H, –OCH3), 3.25–3.76 (m, 8H, piperazine), 3.18 (m, 1H, –
NCH2CHOHCH2–), 3.01 (m, 1H, –NCH2CHOHCH2–), 2.83–2.92 (m, 4H, ArCH2CH2–). ESI-MS (m/z): 481[M+H]+. IR (KBr): 3272, 2939,
2836, 2438, 1601, 1494, 1454, 1246, 758, 690. For compound 13e, 1H NMR (500 MHz, CDCl3): d 13.94 (brs, 1H, HCl), 12.79 (brs, 1H, HCl),
6.64–7.34 (m, 13H, Ar–H), 4.60 (m, 1H, –OCH2CHOHCH2–), 4.50 (m, 2H, –OCH2CH2N–), 4.13 (m, 1H, –OCH2CHOHCH2–), 4.06 (m, 1H, –
CHOH), 3.73 (s, 3H, –OCH3), 3.49–3.99 (m, 8H, piperazine), 3.87 (m, 2H, –OCH2CH2N–), 3.25 (m, 2H, –NCH2CHOHCH2–), 2.81–2.90 (m,
4H, ArCH2CH2–). ESI-MS (m/z): 491 [M+H]+. IR (KBr): 3410, 2956, 2381, 1600, 1489, 1454, 1252, 755, 692.
[11] G.V.R. Bron, Nature 194 (1962) 927.