V. A. Nair et al. / Tetrahedron Letters 46 (2005) 4821–4823
4823
9. Rosen, J.; Day, A.; Jones, T. K.; Nazdan, A. M.; Stein, R.
B. J. Med. Chem. 1995, 38, 4855.
10. Bohl, C. E.; Chang, C.; Mohler, M. L.; Chen, J.; Miller,
D. D.; Swaan, P. W.; Dalton, J. T. J. Med. Chem. 2004,
47, 3765.
tive group on the amino functionalitywas then removed
bydissolving it in absolute ethanol and treating it with
acetyl chloride under ice-cold conditions, followed by
stirring at room temperature for 2 h; which upon concen-
tration followed bywashing in aqueous medium and
extraction into ethyl acetate gave the free amine 12.
Thereafter, to the solution of compound 12 in chloro-
form, thiophosgene, and sodium bicarbonate were added
at 0 °C and stirred overnight at room temperature to
yield the target compound 13.19 The synthetic strategy out-
lined herein provides a facile route to the development of
a new class of androgen receptor ligands with a tracer
that helps to identify, understand and establish the
mechanism of action along with a detailed insight to
the receptor–ligand binding interactions. Simultaneously
computational studies using molecular modeling tech-
niques are also being carried out bydocking the ligand
into the androgen receptor model that we developed,
so as to provide a theoretical rationale to substantiate
the experimental mechanistic observations of the binding
interactions and the resulting structure activityrelation-
ships. Efforts are ongoing to confirm the binding loci by
X-raycrystallographic techniques as well.
11. Morris, J. J.; Hughes, L. R.; Len, A. T.; Taylor, P. J.
J. Med. Chem. 1991, 34, 447.
12. James, K. D.; Ekwuribe, N. N. Synthesis 2002, 7, 850.
13. Yin, D.; Gao, W.; Kearby, J. D.; Xu, H.; Chung, K.; He,
Y.; Marhefka, C. A.; Veverka, K. A.; Miller, D. D.;
Dalton, J. T. J. Pharmacol. Exp. Ther. 2003, 304, 1334.
14. Kirkovsky, L.; Mukherjee, A.; Yin, D.; Dalton, J. T.;
Miller, D. D. J. Med. Chem. 2000, 43, 581.
15. Yin, D.; Xu, H.; Kirkovsky, L. I.; Miller, D. D.; Dalton, J.
T. J. Pharmacol. Exp. Ther. 2003, 304, 1323.
16. Mukherjee, A.; Kirkovsky, L. I.; Kimura, Y.; Marvel, M.
M.; Miller, D. D.; Dalton, J. T. Biochem. Pharmacol.
1999, 58, 1259.
17. Hwang, D. J.; Xu, H.; Mustafa, S. M.; Dalton, J. T.;
Miller, D. D. Synthesis of isothiocyanate derivatives of
irreversible selective androgen receptor modulators
(SARMs) and biological testing in prostate cancer cell
lines. Unpublished Results—Presented at the 229th Amer-
ican Chemical Society Meeting (Division of Medicinal
Chemistry), San Diego, 2005.
18. Hexamethyl ditin is highly toxic when inhaled or in
contact with skin and is also dangerous to the environ-
ment. Therefore it should be handled with adequate
precautions and care. For more information: ꢀToxicityof
tin and its compoundsꢁ: Winship, K. A. Adverse Drug
React. Acute Poison. Rev. 1988, 7, 19.
Acknowledgements
We thank the Department of Defense (DOD) for the
grant ꢀNovel Strategyfor Prostate Cancer Imaging: Syn-
thesis and Pharmacologyof Nonsteroidal Ligands ꢁ
DAMD17-01-1-0103 and the National Institute of
Health (NIH) for the grant ꢀNovel Irreversible Nonste-
roidal Selective Androgen Receptor Modulators
(SARMs) for Prostate Cancerꢁ DK 065227. The Ameri-
can Chemical Society, Division of Medicinal Chemistry
is gratefullyacknowledged for a pre-doctoral fellowship
for M.L.M.
19. Compound 10: Yield: 60%; NMR (1H, 300 MHz, CDCl3):
1.40 (m, 9H, 3CH3), 1.57 (s, 3H, CH3), 4.5 (d, 1H, CH),
4.7 (d, 1H, CH), 6.8 (m, 2H, ArH, J = 2.5 Hz, 8.8 Hz), 7.5
(m, 2H, ArH, J = 2.5 Hz, 8.8 Hz), 7.2 (m, 1H, ArH,
J = 0.6 Hz, 8.5 Hz), 7.8 (m, 1H, ArH, J = 2.4 Hz, 8.5 Hz),
8.2 (m, 1H, ArH, J = 0.6 Hz, 2.4 Hz), 8.0 (br, 1H, NH),
8.7 (br, 1H, NH); MS: 536.1 (MꢀH); C22H24IN3O5, calcd:
C, 49.17; H, 4.50; N, 7.82. Found: C, 49.10; H, 4.39; N,
25
7.76; ½aꢁD ꢀ25.4 (c 1.0, MeOH) 11: Yield: 53%; NMR (1H,
300 MHz, CDCl3): 0.9 (m, 9H, 3CH3), 1.40 (m, 9H,
3CH3), 1.52 (s, 3H, CH3), 4.6 (d, 1H, CH), 4.8 (d, 1H,
CH), 6.8 (m, 2H, ArH, J = 2.7 Hz, 8.6 Hz), 7.6 (m, 2H,
ArH, J = 2.7 Hz, 8.6 Hz), 7.4 (m, 1H, ArH, J = 0.7 Hz,
8.2 Hz), 7.8 (m, 1H, ArH, J = 2.3 Hz, 8.2 Hz), 7.9 (m, 1H,
ArH, J = 0.7 Hz, 2.3 Hz), 8.1 (br, 1H, NH), 8.7 (br, 1H,
NH); MS: 572.2 (MꢀH); C25H33N3O5Sn, calcd: C, 52.29;
References and notes
1. Evans, R. M. Science 1988, 240, 889.
2. Van Dort, M. E.; Robins, D. M.; Wayburn, B. J. Med.
Chem. 2000, 43, 3344.
3. Tucker, H.; Chesterson, G. J. J. Med. Chem. 1988, 31, 885.
4. Dalton, J. T.; Mukherjee, A.; Zhu, Z.; Kirkovsky, L.;
Miller, D. D. Biochem. Biophys. Res. Commun. 1998, 244,
1.
5. Nair, V. A.; Mustafa, S. M.; Mohler, M. L.; Fisher, S. J.;
Dalton, J. T.; Miller, D. D. Tetrahedron Lett. 2004, 45,
9475.
6. Nair, V. A.; Mustafa, S. M.; Mohler, M. L.; Fisher, S. J.;
Dalton, J. T.; Miller, D. D., Studies on some selective
androgen receptor modulators. Unpublished Results—Pre-
sented at the 228th American Chemical SocietyMeeting
(Division of Medicinal Chemistry), Philadelphia, 2004.
7. Marhefka, C. A.; Gao, W.; Chung, K.; Kim, J.; He, Y.;
Yin, D.; Bohl, C.; Dalton, J. T.; Miller, D. D. J. Med.
Chem. 2004, 47, 993.
25
H, 5.79; N, 7.32. Found: C, 52.15; H, 5.70; N, 7.21; ½aꢁD
ꢀ37.5 (c 1.0, MeOH) 12: Yield: 42%; NMR (1H,
300 MHz, CDCl3): 1.48 (s, 3H, CH3), 4.4 (d, 1H, CH),
4.6 (d, 1H, CH), 6.4 (d, 2H, ArH, J = 2.8 Hz, 8.9 Hz), 6.6
(d, 2H, ArH, J = 2.8 Hz, 8.9 Hz), 7.2 (m, 1H, ArH,
J = 0.5 Hz, 8.5 Hz), 7.8 (m, 1H, ArH, J = 2.4 Hz, 8.5 Hz),
8.2 (m, 1H, ArH, J = 0.5 Hz, 2.4 Hz), 8.1 (br, 2H, NH2),
8.3 (br, 1H, NH); MS: 460.1 (M+Na+); C17H16IN3O3,
calcd: C, 46.70; H, 3.69; N, 29.02. Found: C, 46.65; H,
25
3.57; N, 29.1; ½aꢁD +54.3 (c 1.0, MeOH) 13: Yield: 35%;
NMR (1H, 300 MHz, CDCl3): 1.5 (s, 3H, CH3), 4.5 (d,
1H, CH), 4.7 (d, 1H, CH), 6.8 (m, 2H, ArH, J = 2.7 Hz,
9.0 Hz), 7.2 (m, 2H, ArH, J = 2.7 Hz, 9.0 Hz), 7.3 (m, 1H,
ArH, J = 0.5 Hz, 8.5 Hz), 7.8 (m, 1H, ArH, J = 2.4 Hz,
8.5 Hz), 8.2 (m, 1H, ArH, J = 0.5 Hz, 2.4 Hz), 8.5 (br, 1H,
NH); MS: 502.3 (M+Na+); C18H14IN3O3S, calcd: C,
45.11; H, 2.94; N, 8.77. Found: C, 45.15; H, 2.85; N,
8. Marhefka, C. A.; Moore, B. M., II; Bishop, T. C.;
Kirkovsky, L. I.; Mukherjee, A.; Dalton, J. T.; Miller, D.
D. J. Med. Chem. 2001, 44, 1729.
25
8.69; ½aꢁD +65.8 (c 1.0, MeOH).