A. Hachem et al. / Bioorg. Med. Chem. Lett. 12 (2002) 2511–2514
2513
Starting from the cis isomer 24Z (J=11.8 Hz), the
deprotection of the alcohol followed by a second Swern
oxidation gave the required aldehyde 25. The addition
of the pentyl Grignard reagent followed by a saponifi-
cation led to the target molecule 27 (6 steps, 16% over-
all yield from 21).
7. Starting from 7Z, it was possible to replace the acidic
function in position 1 by various functional groups. The
synthesis of such analogues will be described in the full
paper.
8. McDougal, P. G.; Rico, J. C.; Rico, J. G.; Oh, Y. I.; Con-
don, B. D. J. Org. Chem. 1986, 51, 3388.
9. Firouzabadi, H.; Saradarian, A. R.; Naderi, M.; Vessal, B.
Tetrahedron 1984, 40, 5001.
Biological tests. In order to improve the solubility of
these acids in water, we have prepared the correspond-
ing sodium salts11 and used the latter derivatives for the
biological tests. Preliminary data on the in vitro biolo-
gical activity of representative examples are summarized
in Table 1. The anti-platelet activity of the compounds
was measured by studying their antagonist 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 (2 mg/
mL), a physiological agonist that causes endogenous
thromboxane A2 synthesis. The IC50 values are expres-
sed in mM (Scheme 3).
10. These isomers were separated by SiO2 chromatography
using as eluent a 20:80 mixture of ether and low boiling
(<60 ꢁC) petroleum ether. TLC 24Z, Rf=0.26; 24E,
Rf=0.21.
11. 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 key intermediate 6 as well as for the
final products submitted to biological tests, as their sodium
salts: 6; IR (NaCl, film, n cmꢀ1): 1701 (C¼O); 1605 (C¼C
1
arom.); 1107 (Ph-Si). H NMR (90 MHz, CDCl3, d): 9.92 (s,
1H, CHO); 7.81–7.04 (m, 14H, arom.); 4.72 (t, 1H, CHOSi,
J=6.1); 1.8–1.5 (m,2H, CH2CHOSi); 1.14–0.99 (m, 6H,
CH2(CH2)3CH3; 1.05 s, 9H, C(CH3)3); 0.82 (t, 3H, CH2CH3).
13C NMR (22.5 MHz, CDCl3, d): 191.6 (CHO); 145.9; 136.2;
135.7; 133.9; 133.4; 132.1; 129.6; 129.4; 128.5; 128 ; 127.6;
127.5; 127.3 (arom.); 75.3 (CHOSi); 39.8 (CH2CHOSi); 31.5
(CH2CH2CH3); 27 (C(CH3)3); 24.2 (CH2(CH2)2CH3); 22.3
(CH2CH3); 19.2 (C(CH3)3); 13.8 (CH2CH3); anal. calcd for
C29H36O2Si: C78.33, H 8.16 ; found: C77.82, H 8.11. 9 ;
white powder (mp 140 ꢁC); IR (NaCl, nujol, n cmꢀ1): 3310
(OH); 1560 (C¼O). 1H NMR (90 MHz, D2O, d): 7.29–7.08 (m,
4H, arom.); 6.40 (d, 1H, ArCH¼C H ;J=11.6); 5.70 (dt, 1H,
ArCH¼CH; J=11.3, 6.3); 4.57 (t, 1H, CHOH, J=6.6); 2.41–
2.02 (m, 4H, CH¼CHCH2; CH2CO2Na); 1.85–1.45 (m, 4H,
All compounds described in Table 1 are antagonists of
thromboxane (TP) receptors. The selective TP-receptor
antagonist Bay u 3405, inhibits collagen-induced aggre-
gation of human platelets illustrating that TP-receptors
are implicated in this response. The arachidonate meta-
bolite, 12(R) HETE, was studied against U-46619-
induced aggregation of rabbit platelets and shown to be
active. The most active compounds 9, 11 and 13 are
potent TP-receptor antagonists in U-46619-induced
platelet aggregation but the ketone derivative (11) is
more active in collagen-induced platelet aggregation
showing the crucial role of the secondary alcohol func-
tion. The pyridine type analogue (27) is less potent in
both types of aggregation.
CH2CHOH;
CH2CH2CO2Na);
1.28–0.85
(m,
6H,
CH2(CH2)3CH3); 0.69 (t, 3H, CH2CH3, J=6). 13CNMR
(22.5 MHz, D2O, d) 182.3 (CO2Na); 145.2; 138.3; 133.5; 129.8;
129.0; 128.4; 127.3; 125.2 (4 Carom. and C ¼C); 74.8
(CHOH); 39.1 (CH2CHOH); 37.2 (CH2CO2Na); 32.2
(CH2CH2CH3); 29.0 (CH=CHCH2 ); 26.8; 25.8
(CH2CH2CO2Na; CH2(CH2)2CH3); 23.0 (CH2CH3); 14.4
(CH2CH3); anal. calcd for C18H25O3Na: C69.21, H 8.07;
found: C69.40, H 8.03. 11; white powder (mp 174 ꢁC); IR
(NaCl, nujol, n cmꢀ1): 1675 (ketone); 1550 (C¼O carbox-
In conclusion, we have reported short and versatile
sequences towards stabilized analogues of poly-
unsaturated fatty acid metabolites. Some of these
derivatives are good inhibitors of platelet aggregation.
1
ylate). H NMR (90 MHz, D2O, d): 7.67–7.45 (m, 2H, arom.);
7.41–7.14 (m, 2H, arom.); 6.22 (d, 1H, ArCH=CH, J=11.7);
5.65 (dt, ArCH¼CH, J=11.5, 7.5); 2.72 (t, 2H, ArCOCH2,
J=7.5); 2.39–2.00 (m, CH¼CHCH2; CH2CO2Na); 1.85–1.37
(m, 4H, CH2(CH2)2CH3; CH2CH2CO2Na); 1.30–1.04 (m, 4H,
CH2(CH2)2CH3); 0.79 (t, 3H, CH2CH3). 13CNMR
(22.5 MHz, D2O, d) 202.2 (C¼O); 183.1 (CO2Na); 138.7;
137.3; 134.9; 133.9; 129.2; 128.9; 128.6; 126.8 (Carom. and
C¼C); 39.1 (ArCOCH2; 38.0 (CH2CO2Na); 32.1
(CH2CH2CH3); 29.1 (CH¼CHCH2); 27.0 (CH2CH2CO2Na;
CH2(CH2)2CH3); 23.1 (CH2CH3); 14.4 (CH2CH3); anal. calcd
for C18H23O3Na: C69.66, H 7.47; found: C69.69, H 7.38. 13;
white powder (mp 165 ꢁC); IR (NaCl, nujol, n cmꢀ1): 3350
(OH); 1560 (C¼O). 1H NMR (90 MHz, D2O, d): 7.24–6.94 (m,
4H, arom.); 4.53 (t, 1H, CHOH, J=7.0); 2.72–2.43 (m, 2H,
ArCH2CH2); 2.32–2.06 (m, 2H, CH2CO2Na); 1.95–1.29 (m,
8H, CH2(CH2)3CH2CO2Na; CH2CHOH); 1.29–0.96 (m, 6H,
CH2(CH2)3CH3); 0.80–0.50 (m, 3H, CH2CH3). 13CNMR
(22.5 MHz, D2O, d) 185.8 (CO2Na); 146.5; 145.4; 130.6; 129.8;
128.5; 125.8 (Carom.); 76.6 ( CHOH); 40.7; 40.1; 37.8
(CH2CHOH; CH2(CH2)3CH2CO2Na); 33.8; 33.3; 31.3
(CH2CH2CH3; ArCH2CH2CH2); 28.3; 27.5 (CH2CH2CO2Na;
CH2(CH2)2CH3)); 24.5 (CH2CH3); 15.9 (CH2CH3); anal. calcd
for C18H27O3Na: C68.77, H 8.66; found: C68.71, H 8.53. 27;
References and Notes
1. See for instance: Babubri, F.; Fiandanese, V.; Marchese,
G.; Punzi, A. Tetrahedron 2000, 56, 327. Prakesch, M.; Gree,
D.; Gree, R. J. Org. Chem. 2001, 66, 3146 and references cited
therein.
2. See Han, X.; Corey, E. J. Org. Lett. 2000, 16, 2543 and
references cited therein.
3. Lagarde, M.; Boutillon, M. M.; Guichardant, M.;
Lellouche, J. P.; Beaucourt, J. P.; Vanhove, A.; Gree, R.
Biochem. Pharmacol. 1989, 38, 1863.
4. For a recent example (L-6310333) see: Johnson, T. E.;
Holloway, M. K.; Vogel, R.; Rutledge, S. J.; Perkins, J. P.;
Rodan, G. A.; Schmidt, A. J. Steroid Biochem. Mol. Biol.
1997, 63, 1.
5. Gree, R.; Hachem, A. M.; Gree, D.; Le Floc’h, Y.; Rolland,
Y.; Simonet, S.; Verbeuren, T. Eur. Pat. Appl. EP 650, 953;
Chem. Abst. 1995, 123, 83092.
6. These isomers were separated by SiO2 chromatography
using as eluent a 5:95 mixture of ether and low boiling
(<60 ꢁC) petroleum ether. TLC 7Z, Rf=0.47; 7E, Rf=0.42,
after three elutions.
1
IR (NaCl, nujol, n cmꢀ1): 3450 (OH); 1570 (C¼O). H NMR
(90 MHz, D2O, d): 7.95–7.69 (m, 1H, arom.); 7.45–7.22 (m, 2H,