Selective Androgen Receptor Modulators
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 4 997
Hz, J ) 1.8 Hz, 1H, ArH), 7.90 (d, J ) 9.0 Hz, 1H, ArH), 7.92-
7.89 (m, 2H, ArH), 7.04-7.01 (m, 2H, ArH), 6.34 (s, 1H, OH),
4.34 (d, J ) 9.9 Hz, 1H, CHHa), 4.12 (d, J ) 9.9 Hz, 1H, CHHb),
2.96 (q, J ) 7.2 Hz, 2H, CH2), 1.47 (s, 3H, Me), 1.05 (t, J ) 7.2
Hz, Me). Anal. (C20H19F3N2O6) C, H, N.
hydroxy-2-methyl-N-(4-nitro-3-trifluoromethylphenyl)propi-
onamide HCl salt, was obtained as a solid. The salt was
dissolved in CHCl3 (20 mL per 0.5 g) and water (20 mL per
0.5 g). To this solution 5 molar equiv of NaHCO3 was added
and the mixture was stirred at -5 to -10 °C for 10 min. A
small amount of ethyl acetate was added to dissolve the
organic compound. After 10 min, 2 molar equiv of thiophosgene
was added in one portion. This mixture was stirred at room
temperature overnight. The reaction mixture was evaporated
to dryness and the residue was resuspended in a small amount
of water. The aqueous phase was extracted three times with
ethyl acetate. The ethyl acetate extracts were combined, dried
with MgSO4, and evaporated to give the product as a light
yellowish solid: 85%; mp 58-60 °C; 1H NMR (DMSO) 9.16 (s,
1H, NH), 8.12 (s, 1H, ArH), 8.07 (s, 1H, ArH), 8.05 (s, 1H, ArH),
7.20 (d, 2H, ArH), 6.90 (d, 2H, ArH), 4.50 (d, 1H, CHHa), 4.20
(d, 1H, CHHb), 3.35 (s, 1H, OH), 1.63 (s, 3H, CH3). Anal.
(C18H14F3N3O5S) C, H, N.
S-3-(4-F lu or op h en yla m in o)-2-h yd r oxy-2-m eth yl-N-(4-
n itr o-3-tr iflu or om eth ylp h en yl)p r op ion a m id e (S-17). The
title compound was an amber-colored oil: 36%; 1H NMR
(CDCl3) δ 9.22 (s, 1H, NH), 8.05 (m, 3H, ArH), 6.9 (m, 2H,
ArH), 6.7 (m, 2H, ArH), 3.84 (d, J ) 13 Hz, 1H, CH2(1)), 3.8
(s, 1H, OH), 3.6 (bs, 1H, NH), 3.24 (d, J ) 13 Hz, 1H, CH2(2)),
1.58 (s, 3H, Me); Calcd Mass 401.10, [M - H] 400.2. Anal.
Calcd (C17H15F4N3O4‚0.25acetone): C 51.27, H 4.0, N 10.10.
Found: C 51.05, H 3.96, N 9.90.
S-3-(4-Acetyla m in op h en yla m in o)-2-h yd r oxy-2-m eth yl-
N-(4-n it r o-3-t r iflu or om et h ylp h en yl)p r op ion a m id e (S-
18). Preparative TLC was used to purify S-18, with 10%
methanol in chloroform as the mobile phase. The title com-
pound was a tan powder: 27%; mp 143-145 °C; 1H NMR
(DMSO-d6) δ 10.48 (s, 1H, NH), 9.48 (s, 1H, NH), 8.48 (d, J )
2.1 Hz, 1H, ArH), 8.28 (dd, J ) 9.0 Hz, J ) 2.1 Hz, 1H, ArH),
8.16 (d, J ) 9.0 Hz, 1H, ArH), 7.21 (d, J ) 8.0 Hz, 2H, ArH),
6.57 (d, J ) 8.0 Hz, 2H, ArH), 6.06 (s, 1H, OH), 5.10 (bs, 1H,
NH), 3.41 (dd, J ) 12, 3 Hz, 1H, CH2(1)), 3.11 (dd, J ) 12, 3
Hz, 1H, CH2(2)), 1.93 (s, 3H, Me), 1.41 (s, 3H, Me). Anal.
(C19H19F3N4O5) C, H, N.
S-3-(4-Ch lor op h en oxy)-2-h yd r oxy-2-m eth yl-N-(4-n itr o-
3-tr iflu or om eth ylp h en yl)p r op ion a m id e (S-9). The title
compound was an amber-colored oil: 46%; 1H NMR (CDCl3) δ
9.15 (s, 1H, NH), 8 (m, 3H, ArH), 7.25 (d, J ) 9 Hz, 2H, ArH),
6.86 (d, J ) 9 Hz, 2H, ArH), 4.45 (d, J ) 9 Hz, 1H, CH2(1)),
3.97 (d, J ) 9 Hz, 1H, CH2(2)), 3.33 (s, 1H, OH), 1.60 (s, 3H,
Me); Calcd Mass 418.05, [M-H] 417 (100% base peak), 419
(30% base peak). Anal. Calcd (C17H14ClF3N2O5‚0.25acetone):
C 49.21, H 3.61, N 6.47. Found: C 49.44, H 3.58, N 6.69.
S-3-(4-Br om op h en oxy)-2-h yd r oxy-2-m eth yl-N-(4-n itr o-
3-tr iflu or om eth ylp h en yl)p r op ion a m id e (S-10). The title
1
compound was a light tan-colored oil: 40%; H NMR (CDCl3)
δ 9.2 (s, 1H, NH), 8 (m, 3H, ArH), 7.3 (m, 2H, ArH), 6.7 (m,
2H, ArH), 4.43 (d, J ) 9 Hz, 1H, CH2(1)), 3.98 (d, J ) 9 Hz,
1H, CH2(2)), 3.58 (s, 1H, OH), 1.60 (s, 3H, Me); Calcd Mass
462.00, [M - H] 461 (90% base peak), 463 (100% base peak).
Anal. Calcd (C17H14BrF3N2O5‚0.5propan-2-ol): C 45.05, H 3.68,
N 5.68. Found: C 44.63, H 3.26, N 5.24.
S-2-Hyd r oxy-3-(4-iod op h en oxy)-2-m eth yl-N-(4-n itr o-3-
tr iflu or om eth ylp h en yl)p r op ion a m id e (S-11). The title
1
compound was a light tan-colored oil: 36%; H NMR (CDCl3)
δ 9.14 (s, 1H, NH), 8 (m, 3H, ArH), 7.5 (m, 2H, ArH), 6.7 (m,
2H, ArH), 4.44 (d, J ) 9 Hz, 1H, CH2(1)), 3.97 (d, J ) 9 Hz,
1H, CH2(2)), 3.33 (s, 1H, OH), 1.59 (s, 3H, Me); Calcd Mass
509.99, [M - H] 509. Anal. Calcd (C17H14IF3N2O5‚0.3toluene):
C 42.65, H 3.07, N 5.21. Found: C 42.37, H 3.06, N 5.13.
S-2-Hydr oxy-2-m eth yl-N-(4-n itr o-3-tr iflu or om eth ylph e-
n yl)-3-p-tolyloxyp r op ion a m id e (S-12). The title compound
was an amber-colored oil: 23%; 1H NMR (CDCl3) δ 9.18 (s,
1H, NH), 8 (m, 3H, ArH), 7 (m, 2H, ArH), 6.8 (m, 2H, ArH),
4.44 (d, J ) 9 Hz, 1H, CH2(1)), 3.96 (d, J ) 9 Hz, 1H, CH2(2)),
3.49 (s, 1H, OH), 2.28 (s, 3H, ArMe), 1.59 (s, 3H, Me). Anal.
(C18H17F3N2O5) C, H, N.
S-2-Hyd r oxy-3-(4-m eth oxyp h en oxy)-2-m eth yl-N-(4-n i-
tr o-3-tr iflu or om eth ylp h en yl)p r op ion a m id e (S-13). The
title compound was an amber-colored oil: 30%; 1H NMR
(CDCl3) δ 9.24 (s, 1H, NH), 8 (m, 3H, ArH), 6.8 (m, 4H, ArH),
4.42 (d, J ) 9 Hz, 1H, CH2(1)), 3.94 (d, J ) 9 Hz, 1H, CH2(2)),
3.76 (s, 3H, OMe), 3.65 (bs, 1H, OH), 1.58 (s, 3H, Me); Calcd
Mass 414.10, [M - H] 413. Anal. Calcd (C19H17F3N2O6‚
0.5H2O): C 52.42, H 4.17, N 6.43. Found: C 52.63, H 4.32, N
6.50.
Com p etitive Bin d in g Assa y, Cotr a n sfection Assa y,
a n d In Vivo P h a r m a cology. AR binding affinities were
determined using a competitive binding assay, as described
previously.16
AR in vitro functional activity was examined using a
cotransfection assay as previously described.5 All compounds
were assayed at 10 nM and activity was expressed as a percent
activity observed for 1 nM DHT.
AR in vivo activity was examined by administering to
castrated rats a single high dose (1 mg/day) of compound
subcutaneously using osmotic pumps for a period of 14 days.
At the end of the dosing regimen, the animals were sacrificed
and the ventral prostate, seminal vesicle, and levator ani
muscle were dissected and weighed. Organ weights were
normalized to total body weight. The weights of the ventral
prostate and seminal vesicle were used as indicators of
androgenic activity, while the weight of the levator ani muscle
was used as an indicator of anabolic activity. Details of the
experimental protocols and data analysis are described in Yin
et al.13
S-{4-[2-H yd r oxy-2-(4-n it r o-3-t r iflu or om et h ylp h en yl-
ca r ba m oyl)p r op oxy]p h en yl}ca r ba m ic Acid ter t-Bu tyl
Ester (S-14). The title compound was a fluffy white solid:
35%; mp 153-155 °C; 1H NMR (DMSO-d6) δ 10.62 (s, 1H, NH),
9.12 (s, 1H, NH), 8.57 (d, J ) 2 Hz, 1H, ArH), 8.35 (dd, J ) 9
Hz, J ) 2 Hz, 1H, ArH), 8.19 (d, J ) 9.0 Hz, 1H, ArH), 7.2 (m,
2H, ArH), 6.8 (d, 2H, ArH), 6.24 (s, 1H, OH), 4.15 (d, J ) 10
Hz, 1H, CH2(1)), 3.91 (d, J ) 10 Hz, 1H, CH2(2)), 1.44 (s, 9H,
Me), 1.42 (s, 3H, Me). Anal. (C22H24F3N3O7) C, H, N.
S-2-Hyd r oxy-3-(1H-in d ol-5-yloxy)-2-m eth yl-N-(4-n itr o-
3-tr iflu or om eth ylp h en yl)p r op ion a m id e (S-15). The title
compound was a yellowish solid: 48%; 1H NMR (CDCl3) δ 9.26
(s, 1H, NH), 8.11 (s, 1 H, indole NH), 8.10 (s, 1H, ArH), 7.99
(m, 2H, ArH), 7.3 (s 1H, indole H), 7.22 (m, 1H, indole H),
7.17 (d, J ) 2 Hz, 1H, indole H), 6.86 (dd, J ) 9 Hz, J ) 2 Hz,
1H, indole H), 6.48 (m, 1H, indole H), 4.54 (d, J ) 9 Hz, 1H,
CH2(1)), 4.05 (d, J ) 9 Hz, 1H, CH2(2)), 3.73 (s, 1H, OH), 1.62
(s, 3H, Me). Anal. (C19H16F3N3O5) C, H, N.
S-2-Hyd r oxy-3-(4-isoth iocya n a top h en oxy)-2-m eth yl-N-
(4-n it r o-3-t r iflu or om et h ylp h en yl)p r op ion a m id e (S-16).
S-14 (0.5 g) was dissolved in anhydrous ether (20 mL) and
MeOH (30 mL), and 2 molar equiv of 2 M HCl solution was
added. This reaction mixture was allowed to stir at room
temperature under argon overnight. Completeness of the
reaction was determined by the disappearance of S-14 as
monitored by TLC. The reaction mixture was evaporated to
dryness and the resulting material, S-3-(4-aminophenoxy)-2-
Ack n ow led gm en t. We would like to thank Ms.
Melissa Yao, an undergraduate student, for her help in
the synthesis and evaluation of several of the com-
pounds presented in this work. Financial support for
this work was provided by a grant to J .T.D. and D.D.M.
from the National Institute of Diabetes and Digestive
and Kidney Diseases (#1 R01 DK 59800). We would also
like to thank the Van Vleet Professor funds (D.D.M.)
for supporting this project.
Refer en ces
(1) Evans, R. M. The Steroid and Thyroid Hormone Receptor
Superfamily. Science 1988, 240, 889-894.