3558 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 15
Woo et al.
Analysis of survival and update of efficacy from the international
letrozole breast cancer group. J. Clin. Oncol. 2003, 21, 2101-2109.
(e) Milla-Santos, A.; Milla, L.; Portella, J.; Rallo, L.; Pons, M.; Rodes,
E.; Casanovas, J.; Puig-Gali, M. Anastrozole versus tamoxifen as
first-line therapy in postmenopausal patients with hormone-dependent
advanced breast cancer. A prospective, randomized, phase III study.
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NMR δH (270 MHz, CDCl3) 4.55 (s, 2H), 5.20 (s, 2H), 7.01 (d, J
) 7.6 Hz, 1H), 7.08 (1s, 1H), 7.28-7.48 (m, 5H), 7.57 (d, J ) 7.6
Hz, 1H).
4-[(3-Benzyloxy-4-trifluoromethylbenzyl)[1,2,4]triazol-4-ylami-
no]benzonitrile (18e). The title compound was prepared in a
manner similar to that for 2b, using NaH (60% dispersion in oil,
0.392 g, 9.8 mmol), 1a (1.815 g, 9.8 mmol), and 18d (2.945 g, 9.8
mmol) in anhydrous DMF (50 mL) to give 18e as light-yellow
plates (3.011 g, 68%) after recrystallization from i-PrOH: mp 184-
185 °C; 1H NMR (270 MHz, DMSO-d6) 5.11 (s, 2H), 5.25 (s, 2H),
6.71 (AA′BB′, 2H), 7.01 (d, J ) 7.6 Hz, 1H), 7.26-7.42 (m, 6H),
7.56 (d, J ) 7.6 Hz, 1H), 7.75 (AA′BB′, 2H), 8.81 (s, 2H). Anal.
(C24H18F3N5O) C, H, N.
(4) ATAC Trialists’, Group. Results of the ATAC (Arimidex, tamoxifen,
alone or in combination) trial after completion of 5 years’ adjuvant
treatment of breast cancer. Lancet 2005, 365, 60-62.
4-[(3-Hydroxy-4-trifluoromethylbenzyl)[1,2,4]triazol-4-ylami-
no]benzonitrile (18f). The title compound was hydrogenated (over
18 h) in a manner similar to that for 2c, using 18e (2.25 g, 5.0
mmol) and Pd-C (5% by weight, 0.10 g) in THF/MeOH (1:1) (100
mL) to give 18f as a white solid (1.65 g, 92%) after precipitation
(5) The Breast International, Group (BIG) 1-98 Collaborative, Group.
A comparison of letrozole and tamoxifen in postmenopausal women
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1
from acetone witth hexane: mp >190 °C (dec); H NMR (270
MHz, DMSO-d6) 5.08 (s, 2H), 6.73 (AA′BB′, 2H), 6.89-6.95 (m,
2H), 7.46 (d, J ) 7.9 Hz, 1H), 7.77 (A′BB′, 2H), 8.84 (s, 2H),
10.64 (br s, 1H). Anal. (C17H12F3N5O) C, H, N.
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women: lack of diurnal variation, effect of ovariectomy, age and
weight. J. Steroid Biochem. Mol. Biol. 1981, 14, 1101-1105. (b)
Tseng, L.; Mazella, J.; Lee, L. U.; Stone, M. L. Oestrogen sulphatase
and oestrogen sulphotransferase in human primary mammary carci-
noma. J. Steroid Biochem. 1983, 19, 1413-1417. (c) Santner, S. J.;
Feil, P. D.; Santen, R. J. In situ estrogen production via the estrone
sulfatase pathway in breast tumors: relative importance vs. the
aromatase pathway. J. Clin. Endocrinol. Metab. 1984, 59, 29-33.
(d) James, V. H. T.; McNeill, J. M.; Lai, L. C.; Newton, C. J.;
Ghilchik, M. W.; Reed, M. J. (1987). Aromatase activity in normal
breast and breast tumor tissues: in vivo and in vitro studies. Steroids
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Honjo, H.; Tamura, T.; Noguchi, T.; Okada, H.; Sasaki, H.; Tada,
A.; Terashima, Y.; Nakamura, J.; Yoshihama, M. Estrogen productiv-
ity of endometrium and endometrial cancer tissue. Influence of
aromatase on proliferation of endometrial cancer cells. J. Steroid
Biochem. Mol. Biol. 1993, 44, 463-468. (f) Miller, W. R. Aromatase
inhibitors. Where are we now? Br. J. Cancer 1996, 73, 415-417.
(g) Bajetta, E.; Zilembo, N.; Bichisao, E.; Martinetti, Q.; Buzzoni,
R.; Pozzi, P.; Bidoli, P.; Ferrari, L.; Celio, L. Tumor response and
estrogen suppression in breast cancer patients treated with aromatase
inhibitors. Ann. Oncol. 2000, 11, 1017-1022.
(9) (a) Adams, J. B.; Garcia, M.; Rochefort, H. Estrogenic effects of
physiological concentrations of 5-androstene-3R,17â-diol and its
metabolism in MCF-7 human breast cancer cells. Cancer Res. 1981,
41, 4720-4726. (b) Dauvois, S.; Labrie, F. Androstenedione and
androst-5-ene-3R,17â-diol stimulate DMBA-induced mammary tu-
mours. Role of aromatase. Breast Cancer Res. Treat. 1989, 13, 61-
69. (c) Naitoh, K.; Honjo, H.; Yamamoto, T.; Urabe, M.; Ogino, Y.;
Yasumura, T.; Nambara, T. Oestrone sulphate and sulphatase activity
in human breast cancer and endometrial cancer. J. Steroid Biochem.
1989, 33, 1049-1054. (d) Chetrite, G. S.; Cortes-Prieto, J.; Philippe,
J. C.; Wright, F.; Pasqualini, J. R. Comparison of estrogen concentra-
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72, 23-27.
Acknowledgment. This work was supported by Sterix Ltd.,
which is part of the Ipsen group. We thank A. C. Smith for
technical support and C. M. Parker for assistance in preparing
the manuscript.
Supporting Information Available: (A) Combustion/elemental
analysis results for 2b, 2, 3b-d,f, 3, 4b,d,f, 4, 5b-e,h,k, 5, 7c,e-
f, 9b,d-f, 10b-e, 11b,d-f, 11, 12b,d,f, 13b-f, 14b-c,e, 14, 15b-
d, 16h, 16, 17d, and 18b,e; (B) HPLC data for biologically tested
compounds; (C) LRMS/HRMS data for compounds except 1a, 1,
11c, 15b, and 16f; (D) 13C data for 4d,f, 5i, 5, 7b,f, 7, 9c,e-h, 9,
12b-f, 15b, 16h, and 16; (E) X-ray crystallographic data for 5.
This material is available free of charge via the Internet at http://
pubs.acs.org. In addition, the crystallographic data have been
deposited with the Cambridge Crystallographic Data Centre as
CCDC 628906 and are available free of charge on application to
CCDC, 12 Union Road, Cambridge, CB2 1EZ, U.K. (fax, (+44)
1223 336033; e-mail, deposit@ccdc.cam.ac.uk).
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