3332
M. Yoshida et al. / Bioorg. Med. Chem. Lett. 15 (2005) 3328–3332
3. Benzothiazole derivatives in common with the structure of
1 were quite recently reported as p56lck inhibitors by Das,
J.; Lin, J.; Moquin, R. V.; Shen, Z.; Spergel, S. H.;
Wityak, J.; Doweyko, A. M.; DeFex, H. F.; Fang, Q.;
Pang, S.; Pitt, S.; Shen, D. R.; Schieven, G. L.; Barrish, J.
C. Bioorg. Med. Chem. Lett. 2003, 13, 2145.
4. Uetrechet, J. In Drug Metabolizing Enzymes; Lee, J. S.,
Obach, R. S., Fisher, M. B., Eds.; FontisMedia and
Marcel Dekker: New York, 2003, pp 87–145.
5. Dolle, R. E. J. Comb. Chem. 2004, 6, 623.
6. (a) Alsina, J.; Jensen, K. J.; Albericio, F.; Barany, G.
Chem. Eur. J. 1999, 5, 2787; (b) Jensen, K. J.; Alsina, J.;
´
Songster, M. F.; Vagner, J.; Albericio, F.; Barany, G. J.
Am. Chem. Soc. 1998, 120, 5441; (c) Boojamra, C. G.;
Burrow, K. M.; Thompson, L. A.; Ellman, J. A. J. Org.
Chem. 1997, 62, 1240.
Figure 2. Plasma concentration of screening hit compound 1, deriv-
atives 5n and 13b after iv administration to BDF1 female mice at a
dose of 10 mg/kg (n = 2, mean). The concentration of remained
compounds was determined by HPLC.
7. Nishida, A.; Fuwa, M.; Naruto, S.; Sugano, Y.; Saito, H.;
Nakagawa, M. Tetrahedron Lett. 2000, 41, 4791.
8. IRORI, a Discovery Partners International Company:
9. (a) Nicolaou, K. C.; Pfefferkorn, J. A.; Mitchell, H. J.;
Roecker, A. J.; Barluenga, S.; Cao, G.-O.; Affleck, R. L.;
Lillig, J. E. J. Am. Chem. Soc. 2000, 122, 9954; (b)
Nicolaou, K. C.; Evans, R. M.; Roecker, A. J.; Hughes,
R.; Downes, M.; Pfefferkorn, J. A. Org. Biomol. Chem.
2003, 1, 908.
was converted to the cyclopropylamide of 13b, deriva-
tive 13b showed an excellent plasma concentration
(t1/2 = 3.29 h). This result suggested that metabolic
hydrolysis of the amide bond of Region 2 was controlled
by placing the cyclopropylamide instead of cyclohexyl-
amide. The excellent concentration of 13b in plasma also
brought about a strong inhibitory effect on tumor
growth with a single dosing of 20 mg/kg (Exp. 4).
Although the urethane derivatives (14b15 for example)
showed strong in vitro activity, they were not applied
in an in vivo test on account of their low solubility.
10. Katz, L. J. Am. Chem. Soc. 1951, 73, 4007.
11. Sedalk, M.; Hanuek, J.; Holcapek, M.; Sterba, V. J. Phys.
Org. Chem. 2001, 14, 187.
12. Tsuruo, T. Jpn. J. Cancer Chemother. 1987, 14, 2809, and
other references cited therein.
1
13. Compound 5n: yellow powder, mp 157–160 °C; H NMR
(270 MHz, DMSO-d6, d): 12.2 (s, 1H), 10.9 (s, 1H), 8.40
(d, 1H, J = 1.6 Hz), 7.71 (d, 1H, J = 8.9 Hz), 7.57–7.62 (m,
3H), 7.51 (dd, 1H, J = 9.5, 6.2 Hz), 2.41–2.60 (m, 1H),
1.60–1.93 (m, 5H), 1.10–1.52 (m, 5H); MS (APCI, m/z)
448, 450 [M+1]+; HRMS (ESI) Calcd for
C21H19Cl2N3O2S: [M+1]+, 448.06533. Found: 448.06831.
14. Compound 13b: off-white solid, mp 290–292 °C; 1H NMR
(270 MHz, DMSO-d6, d): 12.6 (s, 1H), 10.9 (s, 1H), 8.39
(d, 1H, J = 1.6 Hz), 7.72 (d, 1H, J = 8.6 Hz), 7.58–7.62 (m,
3H), 7.51 (dd, 1H, J = 9.5, 6.5 Hz), 1.91–2.09 (m, 1H),
0.82–1.01 (m, 4H); MS (APCI, m/z) 406, 408 [M+1]+;
HRMS (EI) Calcd for C18H13Cl2N3O2S [M+2]+, 407.0079.
Found: 407.0076.
In conclusion, derivative 13b, which had both biological
potency and excellent plasma concentration, was de-
signed as a derivative of a screening hit compound 1.
Synthesized compound 13b exhibited strong in vivo
inhibitory effect on tumor growth.
References and notes
1. Gibbs, J. B. Science 2000, 287, 1969.
2. (a) Hayakawa, I.; Shioya, R.; Agatsuma, T.; Furukawa, H.;
Naruto, S.; Sugano, Y. Bioorg. Med. Chem. Lett. 2004, 14,
455; (b) Hayakawa, I.; Shioya, R.; Agatsuma, T.; Furuk-
awa, H.; Sugano, Y. Bioorg. Med. Chem. Lett. 2004, 14,
3411; (c) Hayakawa, I.; Shioya, R.; Agatsuma, T.; Furuk-
awa, H.; Naruto, S.; Sugano, Y. Bioorg. Med. Chem. Lett.
2004, 14, 4383; (d) Hayakawa, I.; Shioya, R.; Agatsuma, T.;
Sugano, Y. Chem. Pharm. Bull. 2005, 53, 638.
1
15. Compound 14b: off-white solid, mp 335–338 °C (dec.); H
NMR (270 MHz, DMSO-d6, d): 12.0 (br s, 1H), 10.9 (s,
1H), 8.39 (d, 1H, J = 1.9 Hz), 7.66 (d, 1H, J = 8.6 Hz),
7.54–7.61 (m, 3H), 7.50 (dd, 1H, J = 9.5, 6.5 Hz), 4.25 (q,
2H, J = 7.0 Hz), 1.29 (t, 3H, J = 7.0 Hz); MS (APCI, m/z)
410, 412 [M+1]+; HRMS (EI) Calcd for C17H13Cl2N3O3S
[M]+, 409.0055. Found: 409.0056.