2044
J. Einsiedel et al. / Bioorg. Med. Chem. Lett. 10 (2000) 2041±2044
15. Von der Saal, W.; Engh, R. A.; Eichinger, A.; Gabriel, B.;
References and Notes
Kucznierz, R.; Sauer, J. Arch. Pharm.- Pharm. Med. Chem.
1996, 329, 73. Silberg, A.; Simiti, I.; Mantsch, H. Chem. Ber.
1961, 94, 2887.
16. Kornblum, N.; Powers, J. W.; Anderson, G. J. J. Am.
Chem. Soc. 1959, 81, 4113.
1. For review: Wustrow, D. J.; Wise, L. D. Curr. Pharm.
Design 1997, 3, 391, and references cited therein.
2. For review: Kulagowski, J. J.; Patel, S. Curr. Pharm.
Design 1997, 3, 355, and references cited therein.
3. Sokolo, P.; Giros, P.; Martres, M.-P.; Bouthenet, M.-L.;
Schwartz, J.-C. Nature 1990, 347, 146.
17. Thomas, C.; Orecher, F.; Gmeiner, P. Synthesis 1998,
1491.
4. O'Connor, S. E.; Brown, R. A. Gen. Pharmacol. 1982, 13,
185.
18. Gmeiner, P.; Junge, D.; Kartner, A. J. Org. Chem. 1994,
59, 6766.
5. Schoemaker, H.; Claustre, Y.; Fage, D.; Rouquier, L.;
Chergui, K.; Curet, O.; Oblin, A.; Gonon, F.; Carter, C.;
Benavides, J.; Scatton, B. J. Pharmacol. Exp. Ther. 1997, 280,
83.
6. Glase, S. A.; Akunne, H. C.; Hener, T. G.; Johnson, S. J.;
Kesten, S. R.; MacKenzie, R. G.; Manley, P. J.; Pugsley, T.
A.; Wright, J. L.; Wise, L. D. Bioorg. Med. Chem. Lett. 1996,
6, 1361.
19. For a previous preparation, see: Rosen, T.; Chu, D. T. W.;
Lico, I. M.; Fernandes, P. B.; Shen, L.; Borodkin, S.; Pernet,
A. G. J. Med. Chem. 1988, 31, 1586.
20. rac21: Roussi, G.; Zhang, J. Tetrahedron 1991, 47, 5161.
21 via chiral resolution: Fles, D.; Ghyczy, T. Croat. Chem.
Acta 1964, 36, 27.
21. rac22: Nagai, Y.; Uno, H.; Susumu, U. Chem. Pharm.
Bull. 1977, 25, 1911.
7. Boy®eld, I.; Coldwell, M. C.; Hadley, M. S.; Healy, M. A.
M.; Johnson, C. N.; Nash, D. J.; Riley, G. J.; Scott, E. E.;
Smith, S. A.; Stemp, G. Bioorg. Med. Chem. Lett. 1997, 7,
327.
8. Bolton, D.; Boy®eld, I.; Coldwell, M. C.; Hadley, M. S.;
Johns, A.; Johnson, C. N.; Markwell, R. E.; Nash, D. J.;
Riley, G. J.; Scott, E. E.; Smith, S. A.; Stemp, G.; Wadsworth,
H. J.; Watts, E. A. Bioorg. Med. Chem. Lett. 1997, 7, 485.
9. Thurkauf, A.; Yuan, J.; Chen, X.; He, S. H.; Wasley, J. W.
F.; Hutchison, A.; Woodru, K. H.; Meade, R.; Homan, D.
C.; Donovan, H.; Jones-Hertzog, D. K. J. Med. Chem. 1997,
40, 1.
22. rac23: Sugimoto, H.; Tsuchiya, Y.; Higure, K.; Karibe,
N.; Iimura, Y.; Sasaki, A.; Yamanishi,Y.; Ogura, H.; Araki, S.
JP 2,169,569, 1990; Chem. Abstr. 1991, 114, 6302.
23. Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.;
Maryano, C. A.; Shah, R. D. J. Org. Chem. 1996, 61, 3849.
24. 4o: 1H NMR (CDCl3, 360 MHz): d=1.51 (dddd, J=12.7,
8.0, 6.5, 6.0 Hz, 1H, H-4a), 2.03 (dddd, J=12.7, 9.0, 8.0,
6.5 Hz, 1H, H-4b), 2.28 (dd, J=9.3, 6.5 Hz, 1H, H-2a), 2.39
(ddddt, J=7.5, 6.5, 6.5, 6.0, 7.2 Hz, 1H, H-3), 2.56 (ddd,
J=8.5, 8.0, 6.5 Hz, 1H, H-5a), 2.62±2.71 (m, 3H, H-5b and
NHCH2CH), 2.83 (dd, J=9.3, 7.5 Hz, 1H, H-2b), 3.62 (d,
J=12.7 Hz, 1H, NCH2Ph), 3.66 (d, J=12.7 Hz, 1H, NCH2Ph),
3.77 (s, 2H, oxazole-CH2), 3.91 (s, 3H, OCH3), 6.89 (d, J=8.9 Hz,
1H, Ar), 7.22±7.34 (m, 5H, Ph), 7.49 (dd, J=8.9, 2.4 Hz, Ar),
7.60 (s, 1H, oxazole), 8.06 (d, J=2.4 Hz, 1H, Ar). 13C NMR
(CDCl3, 90 MHz): d=28.9, 37.6, 45.3, 53.6, 54.3, 56.3, 58.5,
60.3, 112.8, 113.7, 118.4, 127.1, 128.3, 129.0, 132.8, 134.1,
135.3, 138.3, 140.4, 156.5, 159.0.
25. Hayes, G.; Biden, T. J.; Selbie, L. A.; Shine, J. Mol.
Endocrinol. 1992, 6, 920.
26. Sokolo, P.; Andrieux, M.; Besancon, R.; Pilon, C.;
Martres, M.-P.; Giros, B.; Schwartz, J.-C. Eur. J. Pharmacol.
1992, 225, 331.
27. Agashari, V.; Sanyal, S.; Buchwaldt, S.; Paterson, A.;
Jovanovic, V.; Van Tol, H. H. M. J. Neurochem. 1995, 65,
1157.
28. Hubner, H.; Haubmann, C.; Utz, W.; Gmeiner, P. J. Med.
Chem. 2000, 43, 756.
29. Based on 4o, further SAR studies are in progress.
10. Thomas, C.; Hubner, H.; Gmeiner, P. Bioorg. Med. Chem.
Lett. 1999, 9, 841.
11. Hogberg, T.; De Paulis, T.; Johansson, L.; Kumar, Y.;
Hall, H.; Ogren, S. O. J. Med. Chem. 1990, 33, 2305. Nilsson,
J.; Wikstrom, H.; Smilde, A.; Glase, S.; Pugsley, T.; Cruciani,
G.; Pastor, M.; Clementi, S. J. Med. Chem. 1997, 40, 833.
12. Simiti, I.; Chindris, E. Arch. Pharm. (Weinheim Ger.)
1971, 304, 425. 1,3-Dichloroacetone (2 eq) was added in 2
portions.
13. Thurkauf, A.; Hutchison, A.; Peterson J., Corn®eld, L.;
Meade, R.; Huston, K.; Harris, K.; Ross, P. C.; Gerber K.;
Ramabhadran, T. V. J. Med. Chem. 1995, 38, 2251. Cacchi, S.;
Misiti, D. Synthesis 1980, 243.
14. Rognan, D.; Mann, A.; Wermuth, C.-G.; Martres, M.-P.;
Giros, B.; Sokolo, P.; Schwartz, J.-C.; Lecomte, J.-M.;
Garrido, F. Eur. Patent 539,281 A1, 1992; Chem. Abstr. 1993,
119, 139085.