J. Sakaki et al. / Bioorg. Med. Chem. Lett. 17 (2007) 4804–4807
4807
5. Gernert, D. L.; Neel, D. A.; Boehm, M. F.; Leibowitz, M.
D.; Mais, D. A.; Michellys, P. Y.; Rungta, D.; Reifel-
Miller, A.; Grese, T. A. Bioorg. Med. Chem. Lett. 2004, 14,
2759.
6. Sakaki, J.; Konishi, K.; Kishida, M.; Gunji, H.; Kanaz-
awa, T.; Uchiyama, H.; Fukaya, H.; Mitani, H.; Kimura,
M. Bioorg. Med. Chem. Lett., in press.
7. Ebisawa, M.; Umemiya, H.; Ohta, K.; Fukasawa, H.;
Kawachi, E.; Christoffel, G.; Gronemeyer, H.; Tsuji, M.;
Hashimoto, Y.; Shudo, K.; Kagechika, H. Chem. Pharm.
Bull. 1999, 47, 1778.
preparation. A functional group on the diazepinyl ring
of the antagonists synthesized (6–9, 13, and 15–16)
was found to effect on the RXR antagonistic activity.
The cyano derivative (16f) was evaluated as food admix-
ture in the KK-Ay mice model. The compound was
found to decrease a body weight gain without changing
food intake and also decrease both glucose and insulin
levels, demonstrating its potential for anti-diabetic and
anti-obesity agent.
8. Umemiya, H.; Fukasawa, H.; Ebisawa, M.; Eyrolles, L.;
Kawachi, E.; Eisenmann, G.; Gronemeyer, H.; Hashim-
oto, Y.; Shudo, K.; Kagechika, H. J. Med. Chem. 1997,
40, 4222.
Acknowledgments
We thank Messrs. Junichi Yamanaka and Toshiyuki
Kurihara and Ms. Toshie Kurasawa for synthetic sup-
port. We thank Mses. Serina Nakano and Akiko Kato
for technical support of the reporter gene assay.
9. See Ref. 6 and references cited therein.
10. Synthesis of compound 16f: To a solution of 4-(2-cyano-5-
ethyl-7,7,10,10-tetramethyl-7,8,9,10-tetrahydro-5H-5,13-
diazabenzo[4,5]-cyclohepta[1,2-b]naphthalene-12-yl)-2-flu-
orobenzoic acid methyl ester (5.36 g, 10.5 mmol) in DMF
(100 ml) and THF (100 ml) was added 2 N NaOH (50 ml,
0.10 mol) at room temperature. The reaction mixture was
stirred at the same temperature for 2 h. The mixture was
acidified with 1 N HCl, diluted with H2O, and extracted
with ether. The organic layer was washed with H2O twice,
dried over MgSO4, and evaporated in vacuo. The resulting
solid was washed with hexane/ether (1:1) and dried to give
References and notes
1. Sporn, M. B.; Roberts, M. B.; Goodman, A. B. In The
Retinoids; Academic: Orlando, 1984.
2. Mangelsdorf, D. J.; Umesono, K.; Evans, R. M. In The
Retinoids: Biology, Chemistry, and Medicine, 2nd ed.;
Raven: New York, 1994; p 319.
3. Schulman, I. G.; Crombie, D.; Bissonnette, R. P.; Cesario,
R.; Roegner, K.; Shao, G.; Heyman, R. A. In Handbook of
Experimental Phamacology; Springer: Berlin, 1999; vol.
139, p 215.
1
16f (4.02 g, 88%) as a yellow solid. H NMR (400 MHz,
DMSO-d6) d: 0.99 (3H, s), 1.07 (3H, t), 1.09 (3H, s), 1.19
(3H, t), 1.22 (3H, s), 1.51–1.58 (4H, m), 3.56–3.66 (1H, m),
3.74–3.82 (1H, m), 6.92 (1H, s), 7.02 (1H, s), 7.17 (1H, d),
7.45 (1H, dd), 7.59–7.65 (3H, m), 7.92 (1H, dd), 13.46 (1H,
br).
11. For experimental details, see: Sakaki, J; Konishi, K;
Kishida, M; Kimura, M; Uchiyiama, H; Mitani, H;
WO2004/089916.
4. Gardinier, K. M.; Gernert, D. L.; Grese, T. A.; Neel, D.
A.; Mapes, C. M.; Michellys, P.-Y.; Boehm, M. F.; WO02/
071827 A2, 2002.