2078
L. Zhi et al. / Bioorg. Med. Chem. Lett. 13 (2003) 2075–2078
7.12 (m, 1H), 7.01 (d, J=8.5 Hz, 1H), 6.97–6.90 (m, 2H), 5.87
References and Notes
(bs, 1H), 5.72 (s, 1H), 4.72 (d, J=13 Hz, 1H), 4.52 (d, J=13
Hz, 1H), 2.37 (d, J=1.2 Hz, 3H), 1.55 (s, 3H), 1.51 (s, 9H) and
1.40 (s, 3H). To 9 (R=30-F) (1.9 g) in dichloromethane (100
mL) at rt was added Et3N (3 mL) and NBS(1.1 equiv) and the
reaction completed in 10 min to give 10 (R=30-F, R0=50-Br)
1. For SAR information of pharmacophore 1 and clinical
opportunities of nonsteroidal progestins, see: (a) Zhi, L.; Teg-
ley, C. M.; Kallel, E. A.; Marschke, K. B.; Mais, D. E.; Got-
tardis, M. M.; Jones, T. K. J. Med. Chem. 1998, 41, 291. (b)
Edwards, J. P.; West, S. J.; Marschke, K. B.; Mais, D. E.;
Gottardis, M. M.; Jones, T. K. J. Med. Chem. 1998, 41, 303.
(c) Tegley, C. M.; Zhi, L.; Marschke, K. B.; Gottardis, M. M.;
Yang, Q.; Jones, T. K. J. Med. Chem. 1998, 41, 4354. (d) Zhi,
L.; Tegley, C. M.; Edwards, J. P.; West, S. J.; Marschke, K. B.;
Gottardis, M. M.; Mais, D. E.; Jones, T. K. Bioorg. Med.
Chem. Lett. 1998, 8, 3365. (e) Zhi, L.; Tegley, C. M.;
Marschke, K. B.; Mais, D. E.; Jones, T. K. J. Med. Chem.
1999, 42, 1466.
2. (a) Edwards, J. P.; Zhi, L.; Pooley, C. L. F.; Tegley, C. M.;
West, S. J.; Wang, M.-W.; Gottardis, M. M.; Pathirana, C.;
Schrader, W. T.; Jones, T. K. J. Med. Chem. 1998, 41, 2779.
(b) Zhi, L.; Tegley, C. M.; Pio, B.; Edwards, J. P.; Motamedi,
M.; Jones, T. K.; Marschke, K. B.; Mais, D. E.; Risek, B.;
Schrader, W. T. J. Med. Chem. 2003, in press.
1
as a yellow oil (90%). H NMR (CDCl3) 7.30–7.23 (m, 2H),
7.10 (t, J=1.8 Hz, 1H), 6.98 (d, J=8.4 Hz, 1H), 5.72 (d,
J=1.1 Hz, 1H), 4.74 (d, J=12 Hz, 1H), 4.46 (d, J=12 Hz,
1H), 2.35 (d, J=1.1 Hz, 3H), 1.53 (s, 3H), 1.51 (s, 9H) and
1.35 (s, 3H). The mixture of 10 (R=30-F, R0=50-Br) (2 g),
K2CO3 (1.2 equiv) and MeI (1.5 equiv) in DMF (50 mL) was
stirred at rt for 2 h to give the methylated product after pur-
ification (78%), which was treated with NaH (1 equiv) in
DMF at 80 ꢀC for 10 min to provide the cyclized product in
72% yield. Removal of N-tBoc protection by standard proce-
dure afforded 11p (R=7-F, R0=9-Br) as colorless oil, 1H
NMR (acetone-d6) 7.58 (t, J=1.7 Hz, 1H), 7.45 (d, J=8.5 Hz,
1H), 7.17 (dd, J=9.8 and 2.3 Hz, 1H), 6.71 (d, J=8.5 Hz, 1H),
5.68 (br s, 1H), 5.51 (s, 1H), 5.40 (s, 2H), 2.12 (s, 3H) and 1.26
(s, 6H).
3. (a) Kloosterboer, H. J.; Deckers, G. H.; Schoonen,
W. G. E. J.; Hanssen, R. G. J. M.; Rose, U. M.; Verbost, P. M.;
Hsiu, J. G.; William, R. F.; Hodgen, G. D. Steroids 2000, 65,
733. (b) Palmer, S.; Campen, C. A.; Allan, G. F.; Rybczynski,
P.; Haynes-Johnson, D.; Hutchins, A.; Kraft, P.; Kiddoe, M.;
Lai, M.-T.; Lombardi, E.; Pedersen, P.; Hodgen, G. D.;
Combs, D. W. J. Steroids Biochem. Mol. Biol. 2000, 75, 33.
4. Teutsch, G.; Ojasoo, T.; Raynaud, J. P. J. Steroid Biochem.
1988, 35, 549.
5. Gray, G. W.; Hird, M.; Lacey, D.; Toyne, K. J. J. Chem.
Soc., Perkin Trans. 2 1989, 2041.
6. (a) Eisch, J. J.; Dluzniewski, T. J. Org. Chem. 1989, 54,
1269. (b) Walter, H.; Sauter, H.; Winkler, T. Helv. Chim. Acta
1992, 75, 1274.
7. To a solution of 8 (R=7-F) (4 g) in THF (100 mL) at
ꢁ78 ꢀC was slowly added phenyllithium (1.2 equiv) in THF.
The resulting dark red solution was stirred at ꢁ78 ꢀC for 10
min and a solution of tBoc2O (1.6 equiv) in THF was added
via cannula. The reaction mixture was warmed up to 0 ꢀC and
quenched with water. Standard work up followed by chroma-
tography afforded 5.1 g (96%) of product, which was reduced
in THF at rt by LiAlH4 powder and gave 9 (R=30-F) as a
white solid (92%). 1H NMR (CDCl3) 7.26 (d, J=8.5 Hz, 1H),
8. For leading references to cotransfection assays and the
family of closely related intracellular receptors to which the
progesterone receptor belongs, see: (a) McDonnell, D. P.;
Vegeto, E.; Gleeson, M. A. G. Bio/Technology 1993, 11, 1256.
(b) Rosen, J.; Day, A.; Jones, T. K.; Jones, E. T. T.; Nadzan,
A. M.; Stein, R. B. J. Med. Chem. 1995, 38, 4855.
9. For the related nonsteroidal hPR antagonist series, see: (a)
Pooley, C. L. F.; Edwards, J. P.; Goldman, M. E.; Wang,
M. W.; Marschke, K. B.; Crombie, D. L.; Jones, T. K. J. Med.
Chem. 1998, 41, 3461. (b) Hamann, L. G.; Winn, D. T.; Poo-
ley, C. L. F.; Tegley, C. M.; West, S. J.; Farmer, L. J.; Zhi, L.;
Edwards, J. P.; Marschke, K. B.; Mais, D. E.; Goldman,
M. E.; Jones, T. K. Bioorg. Med. Chem. Lett. 1998, 8, 2731. (c)
Zhi, L.; Tegley, C. M.; Pio, B.; West, S. J.; Marschke, K. B.;
Mais, D. E.; Jones, T. K. Bioorg. Med. Chem. Lett. 2000, 10,
415. (d) Zhang, P.; Terefenko, E. A.; Wrobel, J.; Zhang, Z.;
Zhu, Y.; Cohen, J.; Marschke, K. B.; Mais, D. E. Bioorg.
Med. Chem. Lett. 2001, 11, 2747. (e) Zhang, P.; Terefenko,
E. A.; Fensome, A.; Zhang, Z.; Zhu, Y.; Cohen, J.; Winneker,
R.; Wrobel, J.; Yardley, J. Bioorg. Med. Chem. Lett. 2002, 12,
787. (f) Zhang, P.; Terefenko, E. A.; Fensome, A.; Wrobel, J.;
Winneker, R.; Lundeen, S.; Marschke, K. B.; Zhang, Z.
J. Med. Chem. 2002, 45, 4379.