1238
Chem. Biodiversity 2016, 13, 1230 – 1239
[3] H. Noma, H. Funatsu, H. Yamashita, S. Kitano, H. K. Mishima,
1-(4-Chlorophenyl)-3-{4-[(5-methyl-2-{4-[(4-methylpip-
erazin-1-yl)methoxy]phenyl}[1,3]oxazolo[5,4-d]pyrimidin-
7-yl)amino]phenyl}urea (21). The title compound was
S. Hori, Arch. Ophthalmol. 2002, 120, 1075.
[4] N. Thairu, S. Kiriakidis, P. Dawson, E. Paleolog, Angiogenesis
2011, 14, 223.
obtained as
a
yellow solid. Yield: 21.3%. M.p.
[5] J. Folkman, Nat. Rev. Drug Discov. 2007, 6, 273.
[6] A. E. El-Kenawi, A. B. El-Remessy, Brit. J. Pharmacol. 2013,
170, 712.
231 – 233 °C. IR (KBr): 3413, 3132, 1637, 1401, 1068, 833,
515. 1H-NMR (300 MHz, (D6)DMSO): 1.35 (m, 2 H);
1.91 (s, 3 H); 2.32 (s, 5 H); 2.50 – 2.53 (m, 5 H); 2.54 (s, 3
H); 3.88 (s, 2 H); 6.98 (d, J = 8.8, 2 H); 7.32 (d, J = 8.9, 2
H); 7.41 (d, J = 8.9, 2 H); 7.48 (d, J = 8.9, 2 H); 7.79 (d,
J = 8.8, 2 H); 7.99 (d, J = 8.7, 2 H); 8.65 (s, 1 H); 8.81 (s,
1 H); 10.36 (s, 1 H). ESI-MS: 627.2 ([M + H]+). HR-ESI-
TOF-MS: 626.2520 (C33H35ClN8Oþ3 , M+; calc. 626.2521).
1-(3-Chloro-4-fluorophenyl)-3-{4-[(5-methyl-2-{4-[(4-
methylpiperazin-1-yl)methoxy]phenyl}[1,3]oxazolo[5,4-d]-
pyrimidin-7-yl)amino]phenyl}urea (22). The title com-
pound was obtained as a white solid. Yield 20.7%. M.p.
213 – 215 °C. IR (KBr): 3416, 3133, 1637, 1499, 1401,
1068, 835, 517. 1H-NMR (300 MHz, (D6)DMSO):
1.22 – 1.23 (m, 2 H); 1.92 (s, 3 H); 2.31 – 2.51 (m, 10 H);
2.52 (s, 3 H); 4.13 (m, 2 H); 7.18 – 7.19 (m, 1 H);
7.32 – 7.33 (m, 1 H); 7.44 – 7.45 (m, 1 H); 7.81 – 7.82 (m,
4 H); 8.09 – 8.10 (m, 4 H); 8.77 (s, 1 H); 8.95 (s, 1 H);
10.03 (s, 1 H). 13C-NMR (75 MHz, (D6)DMSO): 165.07;
163.05; 161.85; 158.54; 153.03; 152.03; 137.69; 135.23;
134.27; 129.16; 122.11; 119.70; 118.86; 118.75; 118.67;
117.46; 117.17; 115.68; 115.13; 66.62; 54.73; 54.52; 52.55;
45.53; 26.30. ESI-MS: 645.2 ([M + H]+). HR-ESI-TOF-
MS: 644.2433 (C33H34ClFN8Oþ3 , M+; calc. 644.2426).
[7] A. Arcaro, Crit. Rev. Oncol. Hematol. 2015, 95, 154.
[8] J. M. Llovet, S. Ricci, V. Mazzaferro, P. Hilgard, E. Gane, J.-F.
Blanc, A. C. de Oliveira, A. Santoro, J.-L. Raoul, A. Forner,
M. Schwartz, C. Porta, S. Zeuzem, L. Bolondi, T. F. Greten, P.
€
R. Galle, J.-F. Seitz, I. Borbath, D. Haussinger, T. Giannaris,
M. Shan, M. Moscovici, D. Voliotis, J. Bruix, New Engl. J. Med.
2008, 359, 378.
[9] G. D. Demetri, A. T. van Oosterom, C. R. Garrett, M. E.
Blackstein, M. H. Shah, J. Verweij, G. McArthur, I. R. Judson,
M. C. Heinrich, J. A. Morgan, J. Desai, C. D. Fletcher, S.
George, C. L. Bello, X. Huang, C. M. Baum, P. G. Casali, Lan-
cet 2006, 368, 1329.
[10] S. Sleijfer, I. Ray-Coquard, Z. Papai, A. Le Cesne, M. Scurr, P.
€
Schoffski, F. Collin, L. Pandite, S. Marreaud, A. De Brauwer, M.
van Glabbeke, J. Verweij, J.-Y. Blay, J. Clin. Oncol. 2009, 27, 3126.
[11] N. S. Vasudev, A. R. Reynolds, Angiogenesis 2014, 17, 471.
[12] A. Morabito, M. C. Piccirillo, F. Falasconi, G. De Feo, A. Del
Giudice, J. Bryce, M. Di Maio, E. De Maio, N. Normanno, F.
Perrone, Oncologist 2009, 14, 378.
[13] S. R. Wedge, J. Kendrew, L. F. Hennequin, P. J. Valentine, S.
T. Barry, S. R. Brave, N. R. Smith, N. H. James, M. Dukes, J.
O. Curwen, R. Chester, J. A. Jackson, S. J. Boffey, L. L. Kil-
burn, S. Barnett, G. H. P. Richmond, P. F. Wadsworth, M.
Walker, A. L. Bigley, S. T. Taylor, L. Cooper, S. Beck, J. M.
€
Jurgensmeier, D. J. Ogilvie, Cancer Res. 2005, 65, 4389.
[14] J. M. Wood, G. Bold, E. Buchdunger, R. Cozens, S. Ferrari, J.
Frei, F. Hofmann, J. Mestan, H. Mett, T. O’Reilly, E. Persohn,
1-{4-[(5-Methyl-2-{4-[(4-methylpiperazin-1-yl)methoxy]-
phenyl}[1,3]oxazolo[5,4-d]pyrimidin-7-yl)amino]phenyl}-3-
[3-(trifluoromethyl)phenyl]urea (23). The title compound
€
J. Rosel, C. Schnell, D. Stover, A. Theuer, H. Towbin, F. Wen-
ger, K. Woods-Cook, A. Menrad, G. Siemeister, M. Schirner,
K.-H. Thierauch, M. R. Schneider, J. Drevs, G. Martiny-Baron,
was obtained as
a white solid. Yield: 15%. M.p.
ꢀ
F. Totzke, D. Marme, Cancer Res. 2000, 60, 2178.
206 – 207 °C. IR (KBr): 3415, 3133, 1637, 1401, 1069, 835,
518. 1H-NMR (300 MHz, (D6)DMSO): 1.35 (s, 2 H); 1.98 (s,
3 H); 2.28 – 2.38 (m, 5 H); 2.38 – 2.53 (m, 5 H); 2.53 (s, 3 H);
4.10 – 4.11 (m, 2 H); 7.16 – 7.16 (m, 2 H); 7.28 – 7.30 (m, 2
H); 7.43 – 7.45 (m, 2 H); 7.50 – 7.60 (m, 2 H); 7.79 – 7.81
(m, 2 H); 8.03 – 8.08 (d, J = 1.6, 2 H); 8.97 (s, 1 H); 9.31 (s, 1
H); 10.01 (s, 1 H). ESI-MS: 661.2 ([M + H]+). HR-ESI-
TOF-MS: 660.2788 (C34H35F3N8Oþ3 , M+; calc. 660.2784).
1-{4-[(5-Methyl-2-{4-[(4-methylpiperazin-1-yl)methoxy]-
phenyl}[1,3]oxazolo[5,4-d]pyrimidin-7-yl)amino]phenyl}-3-
(4-methylphenyl)urea (24). The title compound was obtai-
ned as a white solid. Yield: 16.5%. M.p. 225 – 226 °C. IR
(KBr): 3416, 3126, 1636, 1509, 1401, 1256, 1068, 953, 835,
518. 1H-NMR (300 MHz, (D6)DMSO): 1.32 – 1.34 (m,
2 H); 2.16 – 2.18 (m, 3 H); 2.23 – 2.25 (m, 3 H); 2.38 – 2.48
(m, 10 H); 2.54 (s, 3 H); 4.10 (m, 2 H); 7.06 (d, J = 8.3, 2 H);
7.14 (d, J = 9.2, 2 H); 7.31 (d, J = 8.5, 2 H); 7.39 (d, J = 8.5,
2 H); 7.76 (d, J = 8.5, 2 H); 8.05 (d, J = 9.0, 2 H); 8.52 (s, 1
H); 8.56 (s, 1 H); 9.98 (s, 1 H). HR-ESI-TOF-MS: 606.3074
(C34H38N8Oþ3 , M+; calc. 606.3067).
€
[15] P. W. Manley, P. Furet, G. Bold, J. Bruggen, J. Mestan, T.
Meyer, C. R. Schnell, J. Wood, M. Haberey, A. Huth, M.
€
Kruger, A. Menrad, E. Ottow, D. Seidelmann, G. Siemeister,
K.-H. Thierauch, J. Med. Chem. 2002, 45, 5687.
[16] A. Polyzos, J. Steroid Biochem. Mol. Biol. 2008, 108, 261.
[17] M. J. Munchhof, J. S. Beebe, J. M. Casavant, B. A. Cooper, J.
L. Doty, R. C. Higdon, S. M. Hillerman, C. I. Soderstrom, E.
A. Knauth, M. A. Marx, A. M. K. Rossi, S. B. Sobolov, J. Sun,
Bioorg. Med. Chem. Lett. 2004, 14, 21.
[18] G.-H. Kuo, C. Prouty, A. Wang, S. Emanuel, A. DeAngelis, Y.
Zhang, F. Song, L. Beall, P. J. Connolly, P. Karnachi, X. Chen,
R. H. Gruninger, J. Sechler, A. Fuentes-Pesquera, S. A. Mid-
dleton, L. Jolliffe, W. V. Murray, J. Med. Chem. 2005, 48, 4892.
[19] M. Bauser, G. Delapierre, M. Hauswald, T. Flessner, D.
D’Urso, A. Hermann, B. Beyreuther, J. De Vry, P. Spreyer, E.
€
Reissmuller, H. Meier, Bioorg. Med. Chem. Lett. 2004, 14, 1997.
[20] H. Kakuta, X. Zheng, H. Oda, S. Harada, Y. Sugimoto, K.
Sasaki, A. Tai, J. Med. Chem. 2008, 51, 2400.
[21] T. Suzuki, M. N. A. Khan, H. Sawada, E. Imai, Y. Itoh, K.
Yamatsuta, N. Tokuda, J. Takeuchi, T. Seko, H. Nakagawa, N.
Miyata, J. Med. Chem. 2012, 55, 5760.
€
[22] S. Lu, W. Zheng, L. Ji, Q. Luo, X. Hao, X. Li, F. Wang, Eur. J.
Med. Chem. 2013, 61, 84.
[23] J. Herman, L. Thierry, to Katholieke Universiteit Leuven, K.U.
Leuven R&D, WO/2012/035423, 2012.
REFERENCES
[24] T. Seitz, J. Baudoux, H. Bekolo, D. Cahard, J.-C. Plaquevent,
M.-C. Lasne, J. Rouden, Tetrahedron 2006, 62, 6155.
[25] N. Baindur, N. Chadha, M. R. Player, J. Comb. Chem. 2003, 5, 653.
[1] E. M. Paleolog, J. M. Miotla, Angiogenesis 1998, 2, 295.
[2] J. Folkman, Nat. Med. 1995, 1, 27.
€
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