5684
V. Verones et al. / European Journal of Medicinal Chemistry 45 (2010) 5678e5684
[15] A. Kurimoto, T. Ogino, H. Kawakami. JP Patent 1998/005318.
[16] T. Tanaka, E. Iwashita, A. Tarao, A. Amenomori, Y. Ono. JP Patent 1998/005092.
[17] J.M. Reimund, P. Raboisson, G. Pinna, C. Lugnier, J.J. Bourguignon, C.D. Muller,
Biochem. Biophys. Res. Commun 288 (2001) 427e434.
428.2 [M þ H ꢂ HCl] (100), 429.2 (30); Calcd for C24H26ClN7O: C
62.13%; H 5.65%; N 21.13%, found: C 62.32%; H 5.54%; N 21.29%.
[18] P. Raboisson, C. Lugnier, C. Muller, J.M. Reimund, D. Schultz, G. Pinna, A. Le
Bec, H. Basaran, L. Desaubry, F. Gaudiot, M. Seloum, J.J. Bourguignon, Eur. J.
Med. Chem. 38 (2003) 199e214.
[19] B. Geng, G. Breault, J. Comita-Prevoir, R. Petrichko, J.C. Eyermann, P. Doig,
E. Gorseth, B. Noonan, Bioorg. Med. Chem. Lett. 18 (2008) 4368e4372.
[20] H. Aligayer, D.D. Boyd, M.M. Heiss, E.K. Abdalla, S.A. Curley, G.E. Gallick, Cancer
94 (2002) 344e351.
[21] A.P. Belsches-Jablonski, J.S. Biscardi, D.R. Peavy, D.A. Tice, D.A. Romney,
S.J. Parsons, Oncogene 20 (2001) 1465e1475.
[22] L.A. MacMillan-Crow, J.S. Greendorfer, S.M. Vickers, J.A. Thompson, Arch.
Biochem. Biophys 377 (2000) 350e356.
[23] N. Rucci, M. Susa, A. Teti, Anticancer Agents Med. Chem. 8 (2008) 342e349.
[24] M. Missbach, E. Attman, M. Susa, Curr. Opin. Drug Discov. 3 (2000) 541e548.
[25] M. Azam, V. Nardi, W.C. Shakespeare, C.A. Metcalf III, R.S. Bohacek, Y. Wang,
R. Sundaramoorthi, P. Sliz, D.R. Veach, W.G. Bornmann, B. Clarkson,
D.C. Dalgarno, T.K. Sawyer, G.Q. Daley, Proc. Natl. Acad. Sci. U.S.A. 103 (2006)
9244e9249.
[26] G. Martinelli, S. Soverini, G. Rosti, M. Baccarani, Leukemia 19 (2005)
1872e1879.
[27] M. Azam, V. Nardi, W.C. Shakespeare, C.A. Metcalf, R.S. Bohacek, Y. Wang,
R. Sundaramoorthi, P. Sliz, D.R. Veach, W.G. Bornmann, B. Clarkson,
D.C. Dalgarno, T.K. Sawyer, G.D. Daley, Proc. Natl. Acad. Sci. 103 (2006)
9244e9249.
5.6.4. 4-(2-Chlorophenyl)amino-6-[2-(morpholino)ethyl]-
5a,6,11,11a-tetrahydroquinazolino[3,2-e] purine hydrochloride 11d
Beige solid, yield 45%, mp ¼ 310e312 ꢁC. 1H NMR (300 MHz,
DMSO-d6):
d 3.16 (m, 2H), 3.46 (m, 2H), 3.65e3.95 (m, 6H), 4.60 (t,
2H, J ¼ 6.0 Hz), 5.38 (s, 2H), 7.14 (m, 1H), 7.27 (t, 1H, J ¼ 7.7 Hz),
7.34e7.49 (m, 4H), 7.59 (d, 1H, J ¼ 7.8 Hz), 7.91 (d, 1H, J ¼ 7.8 Hz),
8.30 (s, 1H), 9.13 (br s, 1H), 10.86 (br s, 1H). MS m/z 462.2
[M þ H ꢂ HCl] (100), 463.2 (30), 464.2 (35), 465.2 (10); Calcd for
C24H25Cl2N7O: C 57.84%; H 5.06%; N 14.23%, found: C 57.98%; H
4.90%; N 14.35%.
5.6.5. 4-(2-Bromophenyl)amino-6-[2-(morpholino)ethyl]-
5a,6,11,11a-tetrahydroquinazolino[3,2-e] purine hydrochloride 11e
Beige solid, yield 38%, mp ¼ 311e313 ꢁC. 1H NMR (300 MHz,
DMSO-d6):
d 3.16 (m, 2H), 3.47 (m, 2H), 3.67e4.04 (m, 6H), 4.61 (t,
2H, J ¼ 6.0 Hz), 5.39 (s, 2H), 7.14 (m, 1H), 7.22 (t, 1H, J ¼ 7.4 Hz),
7.34e7.53 (m, 4H), 7.76 (d, 1H, J ¼ 7.4 Hz), 7.91 (d, 1H, J ¼ 7.8 Hz),
8.32 (s, 1H), 9.27 (br s, 1H), 10.98 (br s, 1H). MS m/z 506.0
[M þ H ꢂ HCl] (80), 507.1 (20), 508.1 (100), 509.1 (25); Calcd for
C24H25BrClN7O: C 53.10%; H 4.64%; N 18.06%, found: C 53.26%; H
4.57%; N 18.12%.
[28] V.G. Brunton, E. Avizienyte, V.J. Fincham, B. Serrels, C.A. Metcalf, T.K. Sawyer,
M.C. Frame, Cancer Res. 65 (2005) 1335e1342.
[29] T. O’Hare, R. Pollock, E.P. Stoffregen, J.A. Keats, O.M. Abdullah, E.M. Moseson,
V.M. Rivera, H. Tang, C.A. Metcalf, R.S. Bohacek, Y. Wang, R. Sundaramoorthi,
W.C. Shakespeare, D. Dalgarno, T. Clackson, T.K. Sawyer, M.W. Deininger,
B.J. Druker, Blood 104 (2004) 2532e2539.
5.6.6. 4-Benzylamino-6-[2-(morpholino)ethyl]-5a,6,11,
11a-tetrahydroquinazolino[3,2-e]purine hydrochloride 11f
Beige solid, yield 53%, mp ¼ 278e280 ꢁC. 1H NMR (300 MHz,
[30] Y. Wang, W.C. Shakespeare, W.S. Huang, R. Sundaramoorthi, S. Lentini, S. Das,
S. Liu, G. Banda, D. Wen, X. Zhu, Q. Xu, J. Keats, F. Wang, S. Wardwell, Y. Ning,
J.T. Snodgrass, M.I. Broudy, K. Russian, D. Dalgarno, T. Clackson, T.K. Sawyer,
Bioorg. Med. Chem. Lett. 18 (2008) 4907e4912.
DMSO-d6):
d 3.12 (m, 2H), 3.43 (m, 2H), 3.63e3.96 (m, 6H), 4.63 (t,
[31] A. Kurimoto, T. Ogino, S. Ichii, Y. Isobe, M. Tobe, H. Ogita, H. Takaku, H. Sajiki,
K. Hirota, H. Kawakami, Bioorg. Med. Chem. 11 (2003) 5501e5508.
[32] H. Guthmann, M. Könemann, T. Bach, Eur. J. Org. Chem. (2007) 632e638.
[33] A. Hasan, P.C. Srivastava, J. Med. Chem. 35 (1992) 1435e1439.
[34] Y. Isobe, M. Tobe, H. Ogita, A. Kurimoto, T. Ogino, H. Kawakami, H. Takaku,
H. Sajiki, K. Hirota, H. Hayashi, Bioorg. Med. Chem. 11 (2003) 3641e3647.
[35] C. Martins, M. Gunaratnam, J. Stuart, V. Makwana, O. Greciano, A.P. Reszka,
L.R. Kelland, S. Neidle, Bioorg. Med. Chem. Lett. 17 (2007) 2293e2298.
[36] S. Leonce, V. Perez, M.R. Casabianca-Pignede, M. Anstett, E. Bisagni, G. Atassi,
Invest. New Drugs 14 (1996) 169e180.
2H, J ¼ 6.0 Hz), 4.94 (m, 2H), 5.38 (s, 2H), 7.12 (t, 1H, J ¼ 7.4 Hz),
7.22e7.50 (m, 8H), 8.35 (s, 1H), 8.97 (br s, 1H), 11.16 (br s, 1H). MS m/
z 442.2 [M þ H ꢂ HCl] (100), 443.3 (30); Calcd for C25H28ClN7O: C
62.82%; H 5.90%; N 20.51%, found: C 62.98%; H 5.79%; N 20.63%.
References
[37] SYBYL 6.9.1, Tripos Inc., 1699 South Hanley Road, St. Louis, MO 63144-2913,
USA
[1] H. Rosemeyer, Chem. Biodivers. 1 (2004) 361e401.
[2] M. Legraverend, D.S. Grierson, Bioorg. Med. Chem. 14 (2006) 3987e4006.
[3] D. O’Hagan, C. Schaffrath, S.L. Cobb, J.T.G. Hamilton, C.D. Murphy, Nature 416
(2002) 279e289.
[4] M. Braendvang, L.L. Gundersen, Bioorg. Med. Chem. 13 (2005) 6360e6373.
[5] J.L. Kelley, M.P. Krochmal, J.A. Linn, Ed.W. McLean, F.E. Soroko, J. Med. Chem.
31 (1988) 606e612.
[38] H.M. Berman, J. Westbrook, Z. Feng, G. Gary, T.N. Bhat, H. Weissig,
I.N. Shindyalov, P.E. Bourne, Nucl. Acids Res. 28 (2000) 235e242.
[39] D. Dalgarno, T. Stehle, S. Narula, P. Schelling, M.R. van Schravendijk, S. Adams,
L. Andrade, J. Keats, M. Ram, L. Jin, T. Grossman, I. MacNeil, C. Metcalf,
W. Shakespeare, Y. Wang, T. Keenan, R. Sundaramoorthi, R. Bohacek,
M. Weigele, T. Sawyer, Chem. Biol. Drug Des 67 (2006) 46e57.
[40] M. Clark, R.D. Cramer III, N. van Opdenbosch, J. Comput. Chem. 10 (1989)
982e1012.
[41] G. Jones, P. Willett, R.C. Glen, A.R. Leach, R. Taylor, J. Mol. Biol. 267 (1997)
727e748.
[42] R. Wang, L. Lai, S.J. Wang, Comput. Aided Mol. Des 16 (2002) 11e26.
[43] I.V. Tetko, V.Y. Tanchuk, J. Chem, Inf. Comput. Sci. 42 (2002) 1136e1145.
[44] I.V. Tetko, V.Y. Tanchuk, T.N. Kasheva, A.E.P. Villa, J. Chem, Inf. Comput. Sci. 41
(2001) 1488e1493.
[45] I.V. Tetko, J. Gasteiger, R. Todeschini, A. Mauri, D. Livingstone, P. Ertl,
V.A. Palyulin, E.V. Radchenko, N.S. Zefirov, A.S. Makarenko, V.Y. Tanchuk,
V.V. Prokopenko, J. Comput, Aid. Mol. Des. 19 (2005) 453e463.
[46] I.V. Tetko, Drug Discov. Today 10 (2005) 1497e1500.
(2005).
[6] B.L. Eriksen, U.S. Sørensen, C. Hougaard, D. Peters, T.H. Johansen, P. Christo-
phersen. EP Patent 2008/053648.
[7] J.L. Kelley, J.A. Linn, J.W.T. Selway, J. Med, Chem. 32 (1989) 218e224.
[8] A. Kurimoto, T. Ogino, S. Ichii, Y. Isobe, M. Tobe, H. Ogita, H. Takaku, H. Sajiki,
K. Hirota, H. Kawakami, Bioorg. Med. Chem. 12 (2004) 1091e1099.
[9] J.L. Kelley, J.A. Linn, J.W.T. Selway, J. Med. Chem. 34 (1991) 157e160.
[10] L.S. Chong, M.C. Desai, B. Gallagher, M. Graupe, R.L. Halcomb, H. Yang, J.R.
Zhang. US Patent 2007/015615.
[11] J.J. Bourguignon, L. Desaubry, P. Raboisson, C.G. Wermuth, C. Lugnier, J. Med.
Chem. 40 (1997) 1768e1770.
[12] E. Boichot, J.L. Wallace, N. Germain, M. Corbel, C. Lugnier, V. Lagente,
J.J. Bourguignon, J. Pharmacol. Exp. Ther. 292 (2000) 647e653.
[13] J.W. Coe, A.F.J. Fliri, T. Kaneko, E.R. Larson. US Patent 1992/009554.
[14] K. Hirota, Y. Isobe, N. Chiba, H. Satoh, H. Takaku, H. Matsui, H. Ogita. JP Patent
1997/002310.