A. Hachem et al. / Tetrahedron Letters 43 (2002) 5221–5223
5223
Table 1. Biological activities of compounds
Inhibition of platelet aggregation (IC50, mM)a
5. Fieser, L. F.; Seligman, A. J. J. Am. Chem. Soc. 1938, 60,
170–176.
6. Vogel, A. Vogel’s Textbook of Practical Organic Chem-
istry, 5th ed.; Longman Group, Harlow, UK, 1989; p.
1189.
Compounds
U 46619
Collagen
7. All new compounds have spectral and analytical data in
agreement with the indicated structures. We thank Drs. J.
P. Volland and M. Amm (IdRS) for the microanalyses.
Spectral and analytical data for the final products submit-
ted to biological tests, as their sodium salts. Compound
12: IR (NaCl, film, w cm−1): 3402 (OH), 1567 (CꢀO); 1H
NMR (90 MHz, CD3OD): l 7.94–7.23 (m, 6 H, arom.),
12
14
20
21
0.2
23
0.3
17
NT
4
25
142
146
57
0.26
NT
Bay u 3405
12 (R) HETE
a n=2–5 in all experiments; NT, not tested.
5.44 (t, 1 H, CH
CH2-CO2Na), 2.70–2.48 (m, 2 H, CH2-CH2
1.71 (m, H, CH2-CHOH), 1.67–1.11 (m,
CH2(CH2)3CH3), 0.88 (t, 3 H, CH2CH3
, J=5.7); 13C
6
OH, J=6.1), 3.12–3.01 (m, 2 H, CH2
-CO2Na), 2.05–
H,
6 -
6
sured by studying their inhibitory effects on human and
rabbit washed platelets (WP) respectively aggregated
with U 46619 (0.2 mM), a stable mimetic analogue of
thromboxane A2 or with collagen (1 mg/ml), a physiolog-
ical agonist that causes endogenous thromboxane A2
synthesis. The IC50 values are expressed in mM.
2
6
6
6
6
NMR (22.5 MHz, D2O): l 181.8 (CO2Na), 140.3, 139.8,
133.1, 131.6 (4 C quat. arom.), 129.7, 128.3, 127.5, 125.3,
124.2, 122.5 (6 CH arom.), 71.3 (CHOH), 39.6
(C
6
H2CHOH), 38.1, 33.4, 32.1 (C
6
H2C
6
H2CO2Na,
H2CH3),
C
6
H2CH2CH3), 25.9 (C
6
H2(CH2)2CH3), 22.9 (C
6
All compounds described in Table 1 are antagonists of
thromboxane (TP) receptors. The arachidonate metabo-
lite, 12 (R) HETE, inhibits U 46619-induced platelet
aggregation; Bay u 3405, a selective TP-receptor antag-
onist, is a potent inhibitor of platelet aggregation induced
by collagen, illustrating that activation of the TP-recep-
tors is implicated. For the naphthalene analogue, the best
antagonist activity is obtained with 12 on U 46619- and
collagen-induced platelet aggregation. However, the
quinoline analogue, 20 shows an equipotent antagonist
activity than 12 on U 46619-induced platelet aggregation,
but is less active against collagen-induced platelet aggre-
gation; the saturated lipophilic side chain influences the
inhibitory activity of 20 in comparison with 21 on U
46619- but not on collagen-induced platelet aggregation.
There is an apparent correlation between the order of
potency with the naphthalene analogues against the two
platelet activators, which does not exist with the quino-
line analogues.
14.2 (CH3). Anal. calcd for C19H23NaO3: C, 70.79; H,
7.19. Found: C, 71.41; H, 7.45%. Compound 14: IR
(NaCl, film, w cm−1): 3388 (OH), 1637 (CꢀC), 1560 (CꢀO);
1H NMR (90 MHz, CD3OD): l 8.19 (s, 1 H, arom.),
7.94–7.29 (m, 5 H arom. and C
H, CHꢀCHCO2Na, J=15.8), 5.45 (t, 1 H, CH
6.0), 2.0–1.7 (m, 2 H, CH2-CHOH), 1.63–1.26 (m, 6 H,
CH2(CH2)3CH3), 0.88 (t, 3 H, CH2CH3
, J=5.9); 13C
NMR (22.5 MHz, CD3OD): l 175.4 (CO2Na), 142.8,
141.4 (C quat. and CHꢀCHCO2Na), 135.6, 134.6, 131.9,
130.4, 128.3, 127.1, 126.7, 125.3, 124.6, 124.1 (9 CH arom.
and CHꢀCHCO2Na), 71.5 (CHOH), 39.8 (CH2CHOH),
32.9 (CH2CH2CH3), 26.9 (CH2(CH2)2CH3), 23.7
(CH2CH3), 14.3 (CH3). Anal. calcd for C19H21NaO3: C,
6
HꢀCHCO2Na), 6.65 (d, 1
6
6
OH, J=
6
6
6
6
6
6
6
6
6
71.23; H, 6.61. Found: C, 71.70; H, 6.96%. Compound 20:
white powder, mp 105–108°C; IR (NaCl, film, w cm−1):
1
3388 (OH), 1581 (CꢀO); H NMR (90 MHz, CD3OD): l
8.14 (d, 1 H, arom., J=8.5), 7.8–7.3 (m, 4 H, arom.), 5.5
(t,
CH2
1.8 (m,
CH2(CH2 3
1
H, CHOH, J=6.6), 3.4–3.18 (m,
CH2CO2Na), 2.9–2.62 (m, 2 H, CH2CH2CO2Na), 2–
H, CH2-CHOH), 1.6–1.11 (m, H,
) CH3), 0.86 (t, 3 H, CH2CH3
, J=6.4); 13C
2
H,
6
6
In conclusion, we have reported short and versatile
sequences towards novel analogues of polyunsaturated
fatty acid metabolites with naphthalene or quinoline
cores. Some of these derivatives are good inhibitors of
platelet aggregation.
2
6
6
6
6
NMR (22.5 MHz, D2O): l 180.5 (CO2Na), 161.2, 145.8,
140.3, 138.0, 127.7, 127.5, 126.0, 122.3 (arom.), 73.8
(CHOH), 39.1 (C
(CH2CH2CO2Na),
(CH2(CH2)2CH3), 22.9 (C
6
H2CHOH), 36.1 (C
32.2 (CH2CH2CH3),
H2CH3), 14.3 (CH3). Anal. calcd
6
H2CO2Na), 35.1
6
6
6
26.1
6
for C18H22NNaO3: C, 66.86; H, 6.86; N, 4.33. Found: C,
67.44; H, 7.10; N, 4.44%. Compound 21: white powder,
165°C (dec.); IR (NaCl, film, w cm−1): 3402 (OH), 1651
References
1. Han, X.; Corey, E. J. Org. Lett. 2000, 2, 2543–2544 and
references cited therein.
2. Gree, R.; Hachem, A. M.; Gree, D.; Le Floc’h, Y.; Rol-
land, Y.; Simonet, S.; Verbeuren, T. Eur. Pat. Appl. EP
650, 953; Chem. Abst. 1995, 123, 83092 and Tetrahedron
Lett. 2002, 43, 5217–5219.
3. See for instance: (a) Babubri, F.; Fiandanese, V.; March-
ese, G.; Punzi, A. Tetrahedron 2000, 56, 327–331; (b)
Prakesch, M.; Gree, D.; Gree, R. J. Org. Chem. 2001, 66,
3146–3151 and references cited therein.
4. Lagarde, M.; Boutillon, M. M.; Guichardant, M.; Lel-
louche, J. P.; Beaucourt, J. P.; Vanhove, A.; Gree, R.
Biochem. Pharmacol. 1989, 38, 1863–1864.
1
(CꢀC), 1567 (CꢀO); H NMR (90 MHz, CD3OD): l 8.23
(d, 1 H, arom., J=8.5), 7.84–7.39 (m, 4 H arom. and
C
6
HꢀCHCO2Na), 7.04 (d, 1 H, CHꢀCH
5.70 (t, 1 H, CHOH, J=6.1), 2.09–1.72 (m, 2 H, CH2
CHOH), 1.61–1.11 (m, 6 H, CH2(CH2)3CH3), 0.86 (t, 3 H,
CH2CH3
, J=6.2); 13C NMR (22.5 MHz, CD3OD): l 174.9
6 CO2Na, J=16.0),
6
6 -
6
6
(CO2Na), 154.9, 146.8, 143.6, 140.2, 138.3, 132.6, 129.2,
127.8, 127.7, 127.5, 120.8, (9 CH arom. and
C
6
HꢀC
6
HCO2Na), 72.6 (CHOH), 40.2 (C
6
H2CHOH), 32.9
H2CH3),
(CH2CH2CH3), 26.8 (C
6
6
H2(CH2)2CH3), 23.6 (C
6
14.4 (CH3). Anal. calcd for C18H20NNaO3: C, 67.28; H,
6.27; N, 4.36. Found: C, 67.13; H, 6.36; N, 4.49%.