Neighboring group participation. Part 17 Stereoselective synthesis of some steroidal 2-oxazolidones, as novel potential inhibitors of 17α-hydroxylase-C17,20-lyase

Article abstract of DOI:10.1016/j.steroids.2008.06.011

During the alkaline methanolysis of 3β-acetoxy-21-chloropregn-5-ene-20β-N-phenylurethane (4a), and its 4-monosubstituted (4b-e) and 3,5-disubstituted (4f) phenyl derivatives, cyclization occurs, in the course of which 17β-[3-(N-phenyl)-2-oxazolidon-5-yl]androst-5-en-3β-ol (5a) and its substituted phenyl derivatives (5b-f) are formed. The cyclization takes place with (N^--5) neighboring group participation. The reaction of 3β-acetoxy-21-azidopregn-5-en-20β-ol (3d) with triphenylphosphine gave 3β-acetoxy-21-phosphiniminopregn-5-en-20β-ol, which reacted in situ with carbon dioxide with the participation of the sterically favored 20β-OH to give the unsubstituted steroidal cyclic carbamate (8). Oppenauer oxidation of the 3β-hydroxy-exo-heterocyclic steroids (5a-f, 9) yielded the corresponding Δ⁴-3-ketosteroids (7a-f, 10). The inhibitory effects (IC₅₀) of these compounds on rat testicular C_17,20-lyase were investigated with an in vitro radioligand incubation technique. The N-unsubstituted 17β-(2-oxazolidon-5-yl)-androst-4-en-3-one derivative (10) was found to be a potent inhibitor (IC₅₀ = 3.0 μM).

Full text of DOI:10.1016/j.steroids.2008.06.011

steroids 7 3 ( 2 0 0 8 ) 1375–1384
available at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/steroids
Neighboring group participation
Part 17 Stereoselective synthesis of some steroidal
2-oxazolidones, as novel potential inhibitors of
17␣-hydroxylase-C17,20-lyaseଝ
Dóra Ondréa, János Wölflinga, Zoltán Iványia, Gyula Schneidera,∗
István Tóthb, Mihály Szécsib, János Juleszb
,
a
Department of Organic Chemistry, University of Szeged, Dóm tér 8, H-6720 Szeged, Hungary
Endocrine Unit and Research Laboratory, University of Szeged, Korányi Fasor 8, H-6720 Szeged, Hungary
b
a r t i c l e i n f o
a b s t r a c t
Article history:
During
the
alkaline
methanolysis
of
3␤-acetoxy-21-chloropregn-5-ene-20␤-N-
Received 28 February 2008
Received in revised form
18 June 2008
phenylurethane (4a), and its 4-monosubstituted (4b–e) and 3,5-disubstituted (4f) phenyl
derivatives, cyclization occurs, in the course of which 17␤-[3-(N-phenyl)-2-oxazolidon-
5-yl]androst-5-en-3␤-ol (5a) and its substituted phenyl derivatives (5b–f) are formed.
The cyclization takes place with (N−-5) neighboring group participation. The reaction
of 3␤-acetoxy-21-azidopregn-5-en-20␤-ol (3d) with triphenylphosphine gave 3␤-acetoxy-
21-phosphiniminopregn-5-en-20␤-ol, which reacted in situ with carbon dioxide with the
participation of the sterically favored 20␤-OH to give the unsubstituted steroidal cyclic
carbamate (8). Oppenauer oxidation of the 3␤-hydroxy-exo-heterocyclic steroids (5a–f, 9)
yielded the corresponding ꢀ4-3-ketosteroids (7a–f, 10). The inhibitory effects (IC50) of these
compounds on rat testicular C17,20-lyase were investigated with an in vitro radioligand
incubation technique. The N-unsubstituted 17␤-(2-oxazolidon-5-yl)-androst-4-en-3-one
derivative (10) was found to be a potent inhibitor (IC50 = 3.0 ␮M).
Accepted 25 June 2008
Published on line 5 July 2008
Keywords:
Heterocyclic steroids
Neighboring group participation
In vitro inhibition
2-Oxazolidones
© 2008 Elsevier Inc. All rights reserved.
1.
Introduction
androgen-dependent in the majority of cases [1,2]. Jarman
and coworkers recently reported the synthesis of abiraterone
Prostatic cancer is the second leading cause of cancer-related
mortality worldwide. 17␣-Hydroxylase-C17,20-lyase (P45017␣
[17-(3-pyridyl)androsta-5,16-dien-3␤-ol] and its 4-en-3-one
analog, which display high inhibitory values toward P45017␣
and have become a clinical candidates for the treatment of
prostatic cancer [3]. A common approach to the synthesis of
potent steroidal inhibitors of P45017␣ has been the design of
substrate-like molecules bearing a heterocycle at C17␤, with
privileged heteroatoms (N, O or S) which can interact as the
sixth ligand with the heme iron of the enzyme [4].
)
is a key enzyme regulating the androgen biosynthetic path-
way, catalyzing both 17␣-hydroxylation and cleavage of the
C17–C20 side-chain of 21-carbon steroids in both the testes
and the adrenals. Inhibition of this enzyme can block andro-
gen synthesis at an early stage, and may therefore be
useful in the treatment of prostatic carcinoma, which is
ଝ
For preceding paper in this series, see reference Szájli et al.
Corresponding author. Tel.: +36 62 544276; fax: +36 62 544200.
∗
E-mail address: schneider@chem.u-szeged.hu (G. Schneider).
0039-128X/$ – see front matter © 2008 Elsevier Inc. All rights reserved.
doi:10.1016/j.steroids.2008.06.011

1376
steroids 7 3 ( 2 0 0 8 ) 1375–1384
We recently set out to synthesize a novel series of steroidal
then poured into 10% NaHCO3 solution (100 ml). The CH2Cl2
fraction was washed thoroughly with water, dried over anhy-
drous Na2SO4 and evaporated to dryness. The residue was
subjected to chromatographic separation with a mixture of
CH2Cl2/hexane (1:1).
oxazolines, tetrahydrooxazin-2-ones and dihydrooxazines, in
which there is a heterocycle containing two heteroatoms at
position 17␤ of androst-5-en-3␤-ol [5–7]. We report here the
syntheses of a variety of steroidal compounds with the com-
mon structural feature of a C-17 2-oxazolidone on the steroid
skeleton, as presumed inhibitors of P45017␣
.
2.3.2. 3ˇ-Acetoxy-21-chloropregn-5-ene-20ˇ-N-
phenylurethane (4a)
2.
Experimental
4a (2.30 g; 89%), mp 212–213 ◦C, Rf = 0.8 (ss A); [˛]2D0 − 40 (c 1 in
CHCl3) (found C, 69.88; H, 8.05. C30H40ClNO4 requires C, 70.09;
H, 7.84%). 1H NMR (ı, ppm, CDCl3): 0.76 (s, 3H, 18-H3), 1.00 (s, 3H,
19-H3), 2.03 (s, 3H, Ac–CH3), 3.58 (dd, 1H, J = 12.3 Hz, J = 3.9 Hz)
and 3.86 (dd, 1H, J = 12.3 Hz, J = 2.7 Hz): 21-H2, 4.61 (m, 1H, 3-H),
5.06 (d, 1H, J = 10.2 Hz, 20-H), 5.37 (d, 1H, J = 5.4 Hz, 6-H), 6.78 (br
s, 1H, N–H), 7.08 (t, 1H, J = 7.6 Hz, 4ꢀ-H), 7.32 (t, 2H, J = 7.6 Hz, 3ꢀ-
and 5ꢀ-H), 7.43 (d, 2H, J = 7.6 Hz, 2ꢀ- and 6ꢀ-H). 13C NMR (ı, ppm,
CDCl3): 12.6 (C-18), 19.2 (C-19), 20.8, 21.4 (Ac–CH3), 24.2, 24.4,
27.7, 31.6 (C-8), 31.7, 36.5, 36.9, 38.0, 38.9, 42.1, 47.3, 50.0, 50.1,
55.7, 73.9 (C-3), 74.4 (C-20), 120.5 (2C, C-2ꢀ and C-6ꢀ), 122.2 (C-6),
124.4 (C-4ꢀ), 128.9 (2C, C-3ꢀ and C-5ꢀ), 137.1 (C-1ꢀ), 139.8 (C-5),
153.4 (N–CO), 170.7 (Ac–CO). MS (CI): 531 (M++NH4+, 100%), 134
(28%).
2.1.
General
Melting points (mp) were determined on a Kofler block
and are uncorrected. Specific rotations were measured in
CHCl3 (c 1) at 20 ◦C with a POLAMAT-A (Zeiss-Jena) polarime-
ter and are given in units of 10−1◦ cm2 g−1
. Elementary
analysis data were determined with a PerkinElmer CHN ana-
lyzer model 2400. The reactions were monitored by TLC on
Kieselgel-G (Merck Si 254 F) layers (0.25-mm thick); solvent
systems (ss) (A) CH2Cl2, (B) ethyl acetate/CH2Cl2 (5:95, v/v), (C)
ethyl acetate/CH2Cl2 (10:90 v/v) and (D) ethyl acetate/CH2Cl2
(50:50, v/v).
The spots were detected by spraying with 5% phospho-
molybdic acid in 50% aqueous phosphoric acid. The Rf values
were determined for the spots observed by illumination at 254
and 365 nm. Flash chromatography: silica gel 60, 40–63 ␮m. All
solvents were distilled prior to use. NMR spectra were recorded
on Bruker AM 400 and Bruker DRX 500 instruments. Chemical
shifts are reported in ppm (ı-scale), and coupling constants
(J) in Hertz. For the determination of multiplicities, the J-MOD
pulse sequence was used.
2.3.3. 3ˇ-Acetoxy-21-chloropregn-5-ene-20ˇ-N-
(4-fluorophenyl)urethane (4b)
4b (1.8 g; 67%), mp 211–213 ◦C, Rf = 0.6 (ss A); [˛]D20 − 26 (c 1,
in CHCl3) (found C, 67.54; H, 7.45. C30H39ClFNO4 requires C,
67.72; H, 7.39%). 1H NMR (ı, ppm, CDCl3): 0.75 (s, 3H, 18-
H3), 1.00 (s, 3H, 19-H3), 2.03 (s, 3H, Ac–CH3), 3.57 (dd, 1H,
J = 12.3 Hz, J = 3.9 Hz) and 3.85 (dd, 1H, J = 12.3 Hz, J = 2.7 Hz): 21-
H2, 4.61 (m, 1H, 3-H), 5.04 (d, 1H, J = 10.2 Hz, 20ꢀ-H), 5.37 (d,
1H, J = 4.8 Hz, 6-H), 6.78 (br s, 1H, N–H), 7.01 (t, 2H, J = 8.7 Hz,
3ꢀ- and 5ꢀ-H), 7.39 (s, 2H, 2ꢀ- and 6ꢀ-H). 13C NMR (ı, ppm,
CDCl3): 12.6 (C-18), 19.2 (C-19), 20.8, 21.4 (Ac–CH3), 24.2,
24.4, 27.7, 31.6, 31.7 (C-8), 36.5, 36.9, 38.0, 38.8, 42.1, 47.3,
50.0 (2C), 55.7, 74.0 (C-3), 74.4 (C-20), 115.5 (2C, J = 22.4 Hz,
C-3ꢀ and C-5ꢀ), 120.1 (2C, J = 9.1 Hz, C-2ꢀ and C-6ꢀ), 122.2 (C-
6), 134.1 (J = 2.6 Hz, C-1ꢀ), 139.8 (C-5), 152.8 (N–CO), 158.8
(J = 241.8 Hz, C-4ꢀ) 170.9 (Ac–CO). MS (CI): 549 (M++NH4+, 100%),
134 (8%).
2.2.
3ˇ-Acetoxy-21-chloropregn-5-en-20ˇ-ol (3c)
Compound 3b (3.76 g; 10 mmol) was suspended in CCl4
(40 ml) and Ph3P (3.93 g, 15 mmol) was added. After a 6-h
reflux, the solvent was evaporated off. The resulting crude
product was chromatographed on silica gel with a mix-
ture of CH2Cl2/hexane (80:20) to obtain 3c (2.44 g, 62%), mp
220–223 ◦C, Rf = 0.5 (ss A); [˛]D20 − 47 (c 1 in CHCl3) (found C,
70.08; H, 8.75. C23H35ClO3 requires C, 69.94; H, 8.93%). 1H
NMR (ı, ppm, CDCl3): 0.79 (s, 3H, 18-H3), 1.03 (s, 3H, 19-
H3), 2.03 (s, 3H, Ac–CH3), 3.46 (dd, 1H, J = 10.8 Hz, J = 6.6 Hz)
and 3.70 (d, 1H, J = 10.8 Hz): 21-H2, 3.75 (m, 1H, 20-H), 4.60
(m, 1H, 3-H), 5.37 (d, 1H, J = 4.8 Hz, 6-H). 13C NMR (ı, ppm,
CDCl3): 12.3 (C-18), 19.3 (C-19), 20.8, 21.4 (Ac–CH3), 24.6,
24.8, 27.7, 31.7 (C-8), 31.9, 36.6, 37.0, 38.1, 39.3, 42.6, 50.0,
2.3.4. 3ˇ-Acetoxy-21-chloropregn-5-ene-20ˇ-N-
(4-chlorophenyl)urethane (4c)
4c (2.10 g; 76%), mp 207–209 ◦C, Rf = 0.5 (ss A), [˛]D20 − 24 (c 1
in CHCl3) (found C, 65.78; H, 7.08. C30H39Cl2NO4 requires C,
65.69; H, 7.17%). 1H NMR (ı, ppm, CDCl3): 0.75 (s, 3H, 18-
H3), 1.00 (s, 3H, 19-H3), 2.03 (s, 3H, Ac–CH3), 3.57 (dd, 1H,
J = 12.3 Hz, J = 3.9 Hz) and 3.84 (dd, 1H, J = 12.3 Hz, J = 2.7 Hz):
21-H2, 4.60 (m, 1H, 3-H), 5.05 (d, 1H, J = 10.2 Hz, 20-H), 5.37
(d, 1H, J = 4.8 Hz, 6-H), 6.81 (br s, 1H, N–H), 7.27 (d, 2H,
J = 8.4 Hz, 3ꢀ- and 5ꢀ-H), 7.38 (d, 2H, J = 8.4 Hz, 2ꢀ- and 6ꢀ-H).
13C NMR (ı, ppm, CDCl3): 12.6 (C-18), 19.2 (C-19), 20.8, 21.4
(Ac–CH3), 24.2, 24.4, 27.7, 31.6 (C-8), 31.7, 36.4, 36.9, 38.0,
38.8, 42.1, 47.2, 50.0 (2C), 55.7, 74.0 (C-3), 74.5 (C-20), 119.7
(2C, C-2ꢀ and C-6ꢀ), 122.2 (C-6), 128.9 (3C, C-3ꢀ, C-4ꢀ and C-
5ꢀ), 136.7 (C-1ꢀ), 139.8 (C-5), 152.5 (N–CO), 170.9 (Ac–CO). MS
(CI): 565 (M++NH4+, 100%), 419 (20%), 360 (17%), 239 (18%), 134
(45%).
51.3, 53.0, 55.8, 73.6 (C-5ꢀ), 73.9 (C-3), 122.3 (C-6), 139.8
(C-5), 170.5 (Ac–CO). MS (CI): 412 (M++NH4
(48%).
, 100%), 376
+
2.3.
3ˇ-Acetoxy-21-chloropregn-5-ene-20ˇ-N-phenylu
rethane (4a–f)
2.3.1. General procedure
Compound 3c (1.97 g; 5 mmol) was dissolved in CH2Cl2 (30 ml)
and phenyl isocyanate or substituted phenyl isocyanate
(2.5 equiv.) in CH2Cl2 (20 ml) and triethylamine (0.1 ml) were
added. The reaction mixture was refluxed for 6 h, and was

steroids 7 3 ( 2 0 0 8 ) 1375–1384
1377
and diluted with water. The resulting precipitate was filtered
off, dissolved in CH2Cl2 and chromatographed on silica gel
with a mixture of ethyl acetate/CH2Cl2 (5:95).
2.3.5. 3ˇ-Acetoxy-21-chloropregn-5-ene-20ˇ-N-
(4-bromophenyl)urethane (4d)
4d (2.45 g; 82%), mp 209–212 ◦C, Rf = 0.70 (ss A), [˛]D20 − 17 (c 1
in CHCl3) (found C, 60.52; H, 6.78. C30H39BrClNO4 requires C,
60.76; H, 6.63%). 1H NMR (ı, ppm, CDCl3): 0.75 (s, 3H, 18-H3),
1.00 (s, 3H, 19-H3), 2.03 (s, 3H, Ac–CH3), 3.57 (dd, 1H, J = 12.3 Hz,
J = 3.9 Hz) and 3.84 (dd, 1H, J = 12.3 Hz, J = 2.7 Hz): 21-H2, 4,61 (m,
1H, 3-H), 5.04 (d, 1H, J = 10.2 Hz, 20-H), 5.37 (d, 1H, J = 4.8 Hz, 6-
H), 6.88 (br s, 1H, N–H), 7.33 (d, 2H, J = 8.4 Hz, 3ꢀ- and 5ꢀ-H), 7.42
(d, 2H, J = 8.4 Hz, 2ꢀ- and 6ꢀ-H). 13C NMR (ı, ppm, CDCl3): 12.6 (C-
18), 19.2 (C-19), 20.8, 21.5 (Ac–CH3), 24.2, 24.4, 27.7, 31.6, 31.7
(C-8), 36.5, 36.9, 38.0, 38.9, 42.1, 47.2, 50.0 (2C), 55.7, 74.0 (C-3),
74.5 (C-20), 115.7 (C-4ꢀ), 120.1 (2C, C-2ꢀ and C-6ꢀ), 122.2 (C-6),
131.8 (2C, C-3ꢀ and C-5ꢀ), 137.2 (C-1ꢀ), 139.8 (C-5), 152.5 (N–CO),
171.0 (Ac–CO). MS (CI): 611 (M++NH4+, 100%), 324 (12%).
2.4.2. 17ˇ-[3-(N-Phenyl)-2-oxazolidon-5-yl]androst-5-en-
3ˇ-ol (5a)
5a (820 mg; 94%), mp 267–269 ◦C, Rf = 0.4 (ss B); [˛]2D0 − 92 (c 1 in
CHCl3) (found C, 77.42; H, 8.37. C28H37NO3 requires C, 77.20; H,
8.56%). 1H NMR (ı, ppm, CDCl3): 0.83 (s, 3H, 18-H3), 1.04 (s, 3H,
19-H3), 3.53 (m, 1H, 3-H), 3.63 (t, 1H, J = 8.2 Hz) and 4.00 (t, 1H,
J = 8.2 Hz): 4ꢀ-H2, 4.59 (m, 1H, 5ꢀ-H), 5.35 (d, 1H, J = 5.2 Hz, 6-H),
7.12 (t, 1H, J = 8.0 Hz, 4ꢀꢀ-H), 7.36 (t, 2H, J = 8.0 Hz, 3ꢀꢀ- and 5ꢀꢀ-H),
7.52 (d, 2H, J = 8.0 Hz, 2ꢀꢀ- and 6ꢀꢀ-H). 13C NMR (ı, ppm, CDCl3):
12.4 (C-18), 19.4 (C-19), 20.6, 23.2, 24.6, 31.7 (C-8), 31.7, 31.9, 36.5,
37.2, 38.7, 42.2, 42.7, 50.1, 50.3, 54.4, 55.9, 71.7 (C-3), 74.8 (C-5ꢀ),
118.2 (2C, C-2ꢀꢀ and C-6ꢀꢀ), 121.2 (C-6), 123.8 (C-4ꢀꢀ), 129.0 (2C, C-
3ꢀꢀ and C-5ꢀꢀ), 138.4 (C-1ꢀꢀ), 141.0 (C-5), 155.1 (N–CO). MS (EI): 435
(M+, 100%), 417 (17%), 402 (9%), 324 (10%), 106 (53%).
2.3.6. 3ˇ-Acetoxy-21-chloropregn-5-ene-20ˇ-N-
(4-methoxyphenyl)urethane (4e)
4e (2.15 g; 77%), mp 204–206 ◦C, Rf = 0.5 (ss A); [˛]D20 − 26 (c 1
in CHCl3) (found C, 68.65; H, 7.62. C31H42ClNO5 requires C,
68.43; H, 7.78%). 1H NMR (ı, ppm, CDCl3): 0.75 (s, 3H, 18-H3),
1.00 (s, 3H, 19-H3), 2.03 (s, 3H, Ac–CH3), 3.56 (dd, 1H, J = 12.3 Hz,
J = 3.6 Hz) and 3.85 (dd, 1H, J = 12.3 Hz, J = 2.4 Hz): 21-H2, 3.79 (s,
3H, O–CH3), 4.61 (m, 1H, 3-H), 5.03 (d, 1H, J = 10.2 Hz, 20-H), 5.37
(d, 1H, J = 4.2 Hz, 6-H), 6.74 (br s, 1H, N–H), 6.86 (d, 2H, J = 8.1 Hz,
3ꢀ- and 5ꢀ-H), 7.34 (d, 2H, J = 8.1 Hz, 2ꢀ- and 6ꢀ-H). 13C NMR (ı,
ppm, CDCl3): 12.5 (C-18), 19.2 (C-19), 20.8, 21.4 (Ac–CH3), 24.2,
24.4, 27.7, 31.6 (C-8), 31.7, 36.5, 36.9, 38.0, 38.8, 42.0, 47.4 (C-21),
50.0, 50.1, 55.4, 55.7, 73.9 (C-3), 74.8 (C-20), 114.1 (2C, C-3ꢀ and
2.4.3. 17ˇ-[3-(N-4-Fluorophenyl)-2-oxazolidon-5-
yl]androst-5-en-
3ˇ-ol (5b)
5b (820 mg; 90%), mp 174–177 ◦C, Rf = 0.60 (ss C); [˛]D20 − 89 (c 1 in
CHCl3) (found C, 74.02; H, 8.15. C28H36FNO3 requires C, 74.14;
H, 8.00%). 1H NMR (ı, ppm, CDCl3): 0.83 (s, 3H, 18-H3), 1.03 (s,
3H, 19-H3), 3.53 (m, 1H, 3-H), 3.61 (t, 1H, J = 8.3 Hz) and 3.97 (t,
1H, J = 8.3 Hz): 4ꢀ-H2, 4.59 (m, 1H, 5ꢀ-H), 5.35 (d, 1H, J = 4.8 Hz, 6-
H), 7.06 (m, 2H, 3ꢀꢀ- and 5ꢀꢀ-H), 7.48 (dd, 2H, J = 9.0 Hz, J = 4.6 Hz,
2ꢀꢀ- and 6ꢀꢀ-H). 13C NMR (ı, ppm, CDCl3): 12.4 (C-18), 19.4 (C-19),
20.6, 23.2, 24.7, 31.6, 31.7 (C-8), 31.9, 36.5, 37.2, 38.7, 42.2, 42.7,
50.1, 50.6, 54.4, 55.9, 71.7 (C-3), 74.8 (C-5ꢀ), 115.6 (2C, J = 22.5 Hz,
C-3ꢀꢀ and C-5ꢀꢀ), 119.9 (2C, J = 7.5 Hz, C-2ꢀꢀ and C-6ꢀꢀ), 121.2 (C-6),
134.5 (J = 3.0 Hz, C-1ꢀꢀ), 141.0 (C-5), 155.2 (N–CO), 159.1 (J = 242 Hz,
C-4ꢀꢀ). MS (CI): 471 (M++NH4+, 100 %), 266 (18%).
5ꢀ), 120.3 (C-6), 122.2 (2C, C-2ꢀ and C-6ꢀ), 131.1 (C-1ꢀ), 139.7 (C-5),
152.8 (N–CO), 155.7 (C-4ꢀ), 170.7 (Ac–CO). MS (CI): 561 (M++NH4
100%), 324 (11%).
,
+
2.3.7. 3ˇ-Acetoxy-21-chloropregn-5-ene-20ˇ-N-
(3,5-dimethylphenyl)urethane (4f)
4f (2.45 g; 90%), mp 189–191 ◦C, Rf = 0.7 (ss A); [˛]2D0 − 28 (c 1 in
CHCl3) (found C, 70.54; H, 8.26. C32H44ClNO4 requires C, 70.89;
H, 8.18%). 1H NMR (ı, ppm, CDCl3): 0.75 (s, 3H, 18-H3), 1.00 (s, 3H,
19-H3), 2.03 (s, 3H, Ac–CH3), 2.30 (s, 6H, 3ꢀ- and 5ꢀ-CH3), 3,57 (dd,
1H, J = 12.3 Hz, J = 3.9 Hz) and 3.85 (dd, 1H, J = 12.3 Hz, J = 2.7 Hz):
21-H2, 4.61 (m, 1H, 3-H), 5.04 (d, 1H, J = 10.2 Hz, 20-H), 5.37 (d,
1H, J = 4.8 Hz, 6-H), 6.65 (br s, 1H, N–H), 6.72 (s, 1H, 4ꢀ-H), 7.06 (s,
2H, 2ꢀ- and 6ꢀ-H). 13C NMR (ı, ppm, CDCl3): 12.6 (C-18), 19.2 (C-
19), 20.8, 21.3 (2C, 3ꢀ-CH3 and 5ꢀ-CH3), 21.4 (Ac–CH3), 24.2, 24.4,
27.7, 31.6 (C-8), 31.7, 36.5, 36.9, 38.0, 38.9, 42.1, 47.3 (C-21), 50.0,
50.1, 55.7, 73.9 (C-3), 74.3 (C-20), 116.2 (2C, C-2ꢀ and C-6ꢀ), 122.2
(C-6), 125.0 (C-4ꢀ), 137.7 (C-1ꢀ), 138.7 (2C, C-3ꢀ and C-5ꢀ), 139.8 (C-
5), 152.5 (N–CO), 170.7 (Ac–CO). MS (CI): 559 (M++NH4+, 100%),
122 (10%).
2.4.4. 17ˇ-[3-(N-4-Chlorophenyl)-2-oxazolidon-5-yl]
androst-5-en-3ˇ-ol (5c)
5c (830 mg; 88%), mp 217–219 ◦C, Rf = 0.50 (ss C); [˛]D20 − 95 (c 1 in
CHCl3) (found C, 71.68; H, 7.84. C28H36ClNO3 requires C, 71.55;
H, 7.72%). 1H NMR (ı, ppm CDCl3): 0.83 (s, 3H, 18-H3), 1.03 (s,
3H, 19-H3), 3.52 (m, 1H, 3-H), 3.60 (t, 1H, J = 8.4 Hz) and 3.96 (t,
1H, J = 8.4 Hz): 4ꢀ-H2, 4.59 (m, 1H, 5ꢀ-H), 5.35 (d, 1H, J = 5.2 Hz,
6-H), 7.32 (d, 2H, J = 9.0 Hz, 3ꢀꢀ- and 5ꢀꢀ-H), 7.48 (d, 2H, J = 9.0 Hz,
2ꢀꢀ- and 6ꢀꢀ-H). 13C NMR (ı, ppm, CDCl3): 12.4 (C-18), 19.4 (C-19),
20.6, 23.2, 24.7, 31.6, 31.7 (C-8), 31.9, 36.5, 37.2, 38.6, 42.2, 42.7,
50.1, 50.2, 54.3, 55.9, 71.7 (C-3), 74.9 (C-5ꢀ), 119.3 (2C, C-2ꢀꢀ and
C-6ꢀꢀ), 121.2 (C-6), 129.0 (3C, C-3ꢀꢀ, C-4ꢀꢀ and C-5ꢀꢀ), 137.0 (C-1ꢀꢀ),
141.0 (C-5), 154.9 (N–CO). MS (EI): 469 (M+, 100%), 451 (14%), 140
(44%), 105 (14%).
2.4.
17ˇ-[3-(N-Aryl)-2-oxazolidin-5-yl]androst-5-en-
2.4.5. 17ˇ-[3-(N-4-Bromophenyl)-2-oxazolidon
3ˇ-ols (5a–f)
-5-yl]androst-5-en-3ˇ-ol (5d)
5d (915 mg; 89%) mp 247–250 ◦C, Rf = 0.40 (ss B); [˛]D20 − 95 (c 1 in
CHCl3) (found C, 65.45; H, 6.92. C28H36BrNO3 requires C, 65.37;
H, 7.05%). 1H NMR (ı, ppm, CDCl3): 0.83 (s, 3H, 18-H3), 1.03 (s,
3H, 19-H3), 3.52 (m, 1H, 3-H), 3.59 (t, 1H, J = 8.2 Hz) and 3.96 (t,
1H, J = 8.2 Hz): 4ꢀ-H2, 4.59 (m, 1H, 5ꢀ-H), 5.35 (d, 1H, J = 5.2 Hz,
6-H), 7.42 (t, 2H, J = 9.2 Hz) and 7.47 (t, 2H, J = 9.2 Hz): 2ꢀꢀ-, 3ꢀꢀ-, 5ꢀꢀ-
, 6ꢀꢀ-H. 13C NMR (ı, ppm, CDCl3): 12.4 (C-18), 19.4 (C-19), 20.7,
23.3 24.7, 31.7 (2C), 32.0, 36.6, 37.3, 38.8, 42.3, 42.8, 50.2 (2C),
2.4.1. General procedure
The individual compounds 4a–f (2 mmol) were dissolved in
methanol (40 ml), NaOCH3 (432 mg, 8 mmol) was added, and
the solution was kept at the boiling point. The progress of the
reaction was monitored by TLC. Refluxing was continued until
the starting material had been fully consumed (about 60 min).
The reaction mixture was then neutralized with dilute HCl,

1378
steroids 7 3 ( 2 0 0 8 ) 1375–1384
54.5, 56.0, 71.7 (C-3), 74.9 (C-5ꢀ), 116.7 (C-4ꢀꢀ), 119.7 (2C, C-2ꢀꢀ and
C-6ꢀꢀ), 121.2 (C-6), 132.0 (2C, C-3ꢀꢀ and C-5ꢀꢀ), 137.7 (C-1ꢀꢀ), 141.1
(C-5), 154.8 (N–CO). MS (CI): 533 (M++NH4+, 100%), 134 (12%).
lized from ethyl acetate/CHCl3 to obtain pure 9 (330 mg; 91%),
mp 330 ◦C, Rf = 0.40 (ss D); (found C, 73.67; H, 9.12. C22H33NO3
requires C, 73.50; H, 9.25%. 1H NMR (ı, ppm, DMSO): 0.71 (s,
3H, 18-H3), 0.96 (s, 3H, 19-H3), 3.05 (t, 1H, J = 8.2 Hz) and 3.46
(t, 1H, J = 8.2 Hz): 4ꢀ-H2, 4.45 (m, 1H, 5ꢀ-H), 4.58 (br s, 1H, OH),
5.26 (d, 1H, J = 4.0 Hz, 6-H), 7.38 (s, 1H, NH). 13C NMR (ı, ppm,
DMSO): 12.0 (C-18), 18.9 (C-19), 20.1, 22.3, 23.9, 25.3, 31.1, 31.2,
36.0, 36.8, 38.3, 41.8, 42.0, 44.6, 49.6, 53.7, 55.2, 69.8 (C-3), 77.0
(C-5ꢀ), 120.0 (C-6), 141.2 (C-5), 158.7 (N–CO). MS (EI): 359 (M+,
100%), 341 (82%), 274 (42%), 105 (33%).
2.4.6. 17ˇ-[3-(N-4-Methoxyphenyl)-2-oxazolidon
-5-yl]androst-5-en-3ˇ-ol (5e)
5e (845 mg; 90%), mp 292–295 ◦C, Rf = 0.30 (ss C); [˛]D20 − 97 (c 1 in
CHCl3) (found C, 74.98; H, 8.34. C29H39NO4 requires C, 74.81; H,
8.44%). 1H NMR (ı, ppm, CDCl3): 0.83 (s, 3H, 18-H3), 1.03 (s, 3H,
19-H3), 3.52 (m, 1H, 3-H), 3.59 (t, 1H, J = 8.2 Hz) and 3.95 (t, 1H,
J = 8.2 Hz): 4ꢀ-H2, 3.80 (s, 3H, O–CH3), 4.57 (m, 1H, 5ꢀ-H), 5.35 (d,
1H, J = 5.2 Hz, 6-H), 6.90 (d, 2H, J = 9.0 Hz, 3ꢀꢀ- and 5ꢀꢀ-H) 7.42 (d,
2H, J = 9.0 Hz, 2ꢀꢀ- and 6ꢀꢀ-H). 13C NMR (ı, ppm, CDCl3): 12.4 (C-
18), 19.4 (C-19), 20.6, 23.2, 24.7, 31.6, 31.7 (C-8), 31.9, 36.6, 37.2,
38.7, 42.2, 42.7, 50.1, 50.8, 54.4, 55.5 (O–CH3), 56.0, 71.7 (C-3),
74.8 (C-5ꢀ), 114.2 (2C, C-3ꢀꢀ and C-5ꢀꢀ), 120.2 (2C, C-2ꢀꢀ and C-6ꢀꢀ),
121.2 (C-6), 131.6 (C-1ꢀꢀ), 141.0 (C-5), 155.5 (N–CO), 156.2 (C-4ꢀꢀ).
MS (CI): 483 (M++NH4+, 100%), 141 (23%), 128 (21%).
2.6.
3ˇ-Acetoxy-17ˇ-[3-(N-aryl)-2-oxazolidon-5-yl]
androst-5-enes (6a–f)
2.6.1. General procedure
The individual compounds 5a–f (1 mmol) were dissolved in
a mixture of pyridine (5 ml) and acetic anhydride (3 ml,
30 mmol), and the solution was left to stand for 24 h and then
poured onto ice (50 g). The resulting precipitate was filtered off,
washed and dried. The crude products 6a–f were crystallized
from methanol.
2.4.7. 17ˇ-[3-(N-3,5-dimethylphenyl)-2-oxazolidon
-5-yl]androst-5-en-3ˇ-ol (5f)
5f (810 mg; 87%), mp 262–264 ◦C, Rf = 0.60 (ss C); [˛]D20 − 97 (c 1
in CHCl3) (found C, 77.54; H, 9.05. C30H41NO3 requires C, 77.71;
H, 8.91%). 1H NMR (ı, ppm, CDCl3): 0.83 (s, 3H, 18-H3), 1.03 (s,
3H, 19-H3), 2.32 (s, 6H, 3ꢀꢀ- and 5ꢀꢀ-CH3), 3.53 (m, 1H, 3-H), 3.60
(t, 1H, J = 8.3 Hz) and 3.97 (t, 1H, J = 8.3 Hz): 4ꢀ-H2, 4.55 (m, 1H,
5ꢀ-H), 5.35 (d, 1H, J = 5.2 Hz, 6-H), 6.77 (s, 1H, 4ꢀꢀ-H), 7.14 (s, 2H,
2ꢀꢀ- and 6ꢀꢀ-H). 13C NMR (ı, ppm, CDCl3): 12.4 (C-18), 19.4 (C-19),
20.6, 21.4 (2C, 3ꢀꢀ-CH3 and 5ꢀꢀ-CH3), 23.3, 24.7, 31.6, 31.7 (C-8),
31.9, 36.5, 37.2, 38.7, 42.2, 42.7, 50.1, 50.5, 54.4, 56.0, 71.6 (C-3),
74.8 (C-5ꢀ), 116.2 (2C, C-2ꢀꢀ and C-6ꢀꢀ), 121.1 (C-6), 125.7 (C-4ꢀꢀ),
138.3 (C-1ꢀꢀ), 138.6 (2C, C-3ꢀꢀ and C-5ꢀꢀ), 141.1 (C-5), 155.1 (N–CO).
MS (CI): 481 (M++NH4+).
2.6.2. 3ˇ-Acetoxy-17ˇ-[3-(N-phenyl)-2-oxazolidon
-5-yl]androst-5-ene (6a)
6a (430 mg; 90%), mp 217–219 ◦C, Rf = 0.50 (ss A); [˛]D20 − 84 (c 1
in CHCl3) (found C, 75.62; H, 8.35. C30H39NO4 requires C, 75.44;
H, 8.23%). 1H NMR (ı, ppm, CDCl3): 0.83 (s, 3H, 18-H3), 1.05 (s,
3H, 19-H3), 2.03 (s, 3H, Ac–CH3), 3.63 (t, 1H, J = 8.2 Hz) and 4.00
(t, 1H, J = 8.2 Hz): 4ꢀ-H2, 4.60 (overlapping multiplets, 2H, 3-H
and 5ꢀ-H), 5.37 (d, 1H, J = 5.2 Hz, 6-H), 7.12 (t, 1H, J = 8.0 Hz, 4ꢀꢀ-
H), 7.32 (t, 2H, J = 8.0 Hz, 3ꢀꢀ- and 5ꢀꢀ-H), 7.53 (d, 2H, J = 8.0 Hz,
2ꢀꢀ- and 6ꢀꢀ-H). 13C NMR (ı, ppm, CDCl3): 12.4 (C-18), 19.3 (C-19),
20.5, 21.4 (Ac–CH3), 23.2, 24.6, 27.7, 31.6 (C-8), 31.9, 36.6, 36.9,
38.1, 38.6, 42.7, 50.0, 50.3, 54.3, 55.8, 73.8 (C-3), 74.8 (C-5ꢀ), 118.2
(2C, C-2ꢀꢀ and C-6ꢀꢀ), 122.1 (C-6), 123.8 (C-4ꢀꢀ), 129.0 (2C, C-3ꢀꢀ and
C-5ꢀꢀ), 138.4 (C-1ꢀꢀ), 139.9 (C-5), 155.1 (N–CO), 170.5 (Ac–CO). MS
(CI): 495 (M++NH4+, 100%), 239 (11%), 111 (3%).
2.5.
(8)
3ˇ-Acetoxy-17ˇ-(2-oxazolidon-5-yl)androst-5-ene
To a solution of 3d [5] (2 g, 5 mmol) in dry acetone (100 ml) satu-
rated with CO2 was added a solution of Ph3P (1.44 g, 5.5 mmol)
in acetone (30 ml) at room temperature during 30 min. CO2 was
bubbled through the solution for 6 h, and the mixture was then
stored overnight. The reaction mixture was concentrated in
vacuo and the residual product was chromatographed on silica
gel with CH2Cl2, yielding pure 8 (1.260 g; 63%), mp 265–267 ◦C,
2.6.3. 3ˇ-Acetoxy-17ˇ-[3-(N-4-fluorophenyl)
-2-oxazolidon-5-yl]androst-5-ene (6b)
6b (410 mg; 82%), mp 234–236 ◦C, Rf = 0.50 (ss A); [˛]D20 − 86 (c 1 in
CHCl3) (found C, 72.58; H, 7.86. C30H38FNO4 requires C, 72.70; H,
7.73%). 1H NMR (ı, ppm, CDCl3): 0.83 (s, 3H, 18-H3), 1.05 (s, 3H,
19-H3), 2.03 (s, 3H, Ac–CH3), 3.61 (t, 1H, J = 8.2 Hz) and 3.97 (t, 1H,
J = 8.2 Hz): 4ꢀ-H2, 4.59 (overlapping multiplets, 2H, 3-H and 5ꢀ-
H), 5.37 (d, 1H, J = 4.8 Hz, 6-H), 7.05 (t, 2H, J = 8.8 Hz, 3ꢀꢀ- and 5ꢀꢀ-H),
7.48 (dd, 2H, J = 8.8 Hz, J = 4.4 Hz, 2ꢀꢀ- and 6ꢀꢀ-H). 13C NMR (ı, ppm,
CDCl3): 12.3 (C-18), 19.3 (C-19), 20.5, 21.3 (Ac–CH3), 23.2, 24.6,
27.6, 31.6 (C-8), 31.8, 36.6, 36.9, 38.0, 38.6, 42.7, 50.0, 50.5, 54.3,
55.8, 73.8 (C-3), 74.8 (C-5ꢀ), 115.6 (2C, J = 22.5 Hz, C-3ꢀꢀ and C-5ꢀꢀ),
119.2 (2C, J = 7.7 Hz, C-2ꢀꢀ and C-6ꢀꢀ), 122.1 (C-6), 134.5 (J = 2.6 Hz,
C-1ꢀꢀ), 140.0 (C-5), 155.1 (N–CO), 159.1 (J = 243 Hz, C-4ꢀꢀ), 170.4
(Ac–CO). MS (CI): 513 (M++NH4+, 100%), 454 (9%).
Rf = 0.50 (ss D); [˛]20 − 76 (c 1 in CHCl3) (found C, 71.92; H, 8.54.
D
C
24H35NO4 requires C, 71.79; H, 8.79%). 1H NMR (ı, ppm, CDCl3):
0.79 (s, 3H, 18-H3), 1.04 (s, 3H, 19-H3), 2.03 (s, 3H, Ac–CH3), 3.21
(t, 1H, J = 8.1 Hz) and 3.57 (t, 1H, J = 8.1 Hz): 4ꢀ-H2, 4.60 (overlap-
ping multiplets, 2H, 3-H and 5ꢀ-H), 4.98 (br s, 1H, N–H), 5.37 (d,
1H, J = 4.8 Hz, 6-H). 13C NMR (ı, ppm, CDCl3): 12.3 (C-18), 19.2
(C-19), 20.5, 21.3 (Ac–CH3), 23.1, 24.5, 27.6, 31.6 (C-8), 31.8, 36.6,
36.9, 38.0, 38.6, 42.6, 45.7, 50.0, 54.2, 55.8, 73.8 (C-3), 78.8 (C-5ꢀ),
122.1 (C-6), 139.8 (C-5), 160.5 (N–CO), 170.5 (Ac–CO). MS (CI): 419
(M++NH4+).
2.6.4. 3ˇ-Acetoxy-17ˇ-[3-(N-4-chlorophenyl)
2.5.1. 17ˇ-(2-Oxazolidon-5-yl)androst-5-en-3ˇ-ol (9)
-2-oxazolidon-5-yl]androst-5-ene (6c)
Compound 8 (401 mg, 1 mmol) was dissolved in methanol
(20 ml) containing NaOCH3 (10 mg, 0.18 mmol) and the solution
was allowed to stand for 24 h. It was then diluted with water,
and the precipitate that formed was filtered off and recrystal-
6c (490 mg; 95%), mp 277–279 ◦C, Rf = 0.60 (ss A); [˛]D20 − 83 (c
1 in CHCl3) (found C, 70.22; H, 7.63. C30H38ClNO4 requires C,
70.36; H, 7.48%). 1H NMR (ı, ppm, CDCl3): 0.83 (s, 3H, 18-H3),
1.04 (s, 3H, 19-H3), 2.03 (s, 3H, Ac–CH3), 3.60 (t, 1H, J = 8.3 Hz)

steroids 7 3 ( 2 0 0 8 ) 1375–1384
1379
and 3.96 (t, 1H, J = 8.3 Hz): 4ꢀ-H2, 4.60 (m, 2H, 3-H and 5ꢀ-H),
2.7.
17ˇ-[3-(N-Aryl)-2-oxazolidon-5-yl]androst-4-en-
5.37 (d, 1H, J = 4.2 Hz, 6-H), 7.32 (d, 2H, J = 9.0 Hz, 3ꢀꢀ- and 5ꢀꢀ-
H), 7.48 (d, 2H, J = 9.0 Hz, 2ꢀꢀ- and 6ꢀꢀ-H). 13C NMR (ı, ppm,
CDCl3): 12.3 (C-18), 19.2 (C-19), 20.5, 21.3 (Ac–CH3), 23.1, 24.6,
27.6, 31.5 (C-8), 31.8, 36.6, 36.9, 38.0, 38.5, 42.6, 49.9, 50.1, 54.3,
55.8, 73.8 (C-3), 74.8 (C-5ꢀ), 119.2 (2C, C-2ꢀꢀ and C-6ꢀꢀ), 122.1 (C-
6), 128.9 (3C, C-3ꢀꢀ, C-4ꢀꢀ and C-5ꢀꢀ), 137.0 (C-1ꢀꢀ), 139.8 (C-5),
154.8 (N–CO), 170.4 (Ac–CO). MS (CI): 529 (M++NH4+, 100%), 239
(18%).
3-ones (7a–f) and
17ˇ-(2-oxazolidon-5-yl)androst-4-en-3-one (10)
2.7.1. General procedure
The individual compounds 5a–f or 9 (2 mmol) were dissolved
in toluene (60 ml), aluminum isopropoxide (2.04 g, 10 mmol)
and cyclohexanone (20 ml) were added, and the mixture was
stirred at the boiling point. The disappearance of the starting
material was followed by TLC. When the reaction was com-
plete, dilute H2SO4 (1%, 200 ml) was added to the reaction
mixture. Most of the organic solvent was removed in vacuo and
the residual emulsion was extracted with CH2Cl2. The organic
phase was evaporated down and the resulting crude product
was chromatographed on silica gel with ethyl acetate/CH2Cl2
(5:95).
2.6.5. 3ˇ-Acetoxy-17ˇ-[3-(N-4-bromophenyl)
-2-oxazolidon-5-yl]androst-5-ene (6d)
6d (490 mg; 88%), mp 284–286 ◦C, Rf = 0.60 (ss A); [˛]D20 − 91 (c 1 in
CHCl3) (found C, 64.58; H, 7.02. C30H38BrNO4 requires C, 64.74;
H, 6.88%). 1H NMR (ı, ppm, CDCl3): 0.83 (s, 3H, 18-H3), 1.04 (s,
3H, 19-H3), 2.03 (s, 3H, Ac–CH3), 3.59 (t, 1H, J = 8.2 Hz) and 3.96 (t,
1H, J = 8.2 Hz): 4ꢀ-H2, 4.59 (overlapping multiplets, 2H, 3-H and
5ꢀ-H), 5.37 (d, 1H, J = 4.8 Hz, 6-H), 7.42 (d, 2H, J = 9.2 Hz) and 7.47
(d, 2H, J = 9.2 Hz): 2ꢀꢀ-, 3ꢀꢀ-, 5ꢀꢀ-, 6ꢀꢀ-H. 13C NMR (ı, ppm, CDCl3):
12.3 (C-18), 19.2 (C-19), 20.5, 21.3 (Ac–CH3), 23.1, 24.6, 27.6, 31.5
(C-8), 31.8, 36.6, 36.9, 38.0, 38.5, 42.6, 49.9, 50.0, 54.2, 55.8, 73.8
(C-3), 74.8 (C-5ꢀ), 116.5 (C-4ꢀꢀ), 119.5 (2C, C-2ꢀꢀ and C-6ꢀꢀ), 122.1
(C-6), 131.8 (2C, C-3ꢀꢀ and C-5ꢀꢀ), 137.5 (C-1ꢀꢀ), 139.8 (C-5), 154.8
(N–CO), 170.4 (Ac–CO). MS (CI): 575 (M++NH4+, 44%), 334 (26%),
324 (100%), 231 (73%).
2.7.2. 17ˇ-[3-(N-Phenyl)-2-oxazolidon-5-yl]androst-4
-en-3-one (7a)
7a (610 mg; 70%), mp 261–263 ◦C, Rf = 0.40 (ss B); [˛]D20 + 21 (c 1
in CHCl3) (found C, 77.43; H, 8.24. C28H35NO3 requires C, 77.56;
H, 8.14%). 1H NMR (ı, ppm, CDCl3): 0.87 (s, 3H, 18-H3), 1.20 (s,
3H, 19-H3), 3.63 (t, 1H, J = 8.4 Hz) and 4.00 (t, 1H, J = 8.4 Hz): 4ꢀ-
H2, 4.59 (m, 1H, 5ꢀ-H), 5.73 (s, 1H, 4-H), 7.12 (t, 1H, J = 7.6 Hz,
4ꢀꢀ-H), 7.37 (t, 2H, J = 7. 6 Hz, 3ꢀꢀ- and 5ꢀꢀ-H), 7.52 (d, 2H, J = 7.6 Hz,
2ꢀꢀ- and 6ꢀꢀ-H). 13C NMR (ı, ppm, CDCl3): 12.4 (C-18), 17.3 (C-
19), 20.5, 23.2, 24.5, 32.0, 32.7, 33.9, 35.3 (C-8), 35.6, 38.5, 38.6,
42.7, 50.2, 53.7, 54.3, 55.0, 74.7 (C-5ꢀ), 118.1 (2C, C-2ꢀꢀ and C-6ꢀꢀ),
123.8 (2C, C-4 and C-4ꢀꢀ), 129.0 (2C, C-3ꢀꢀ and C-5ꢀꢀ), 138.3 (C-1ꢀꢀ),
155.0 (N–CO), 171.0 (C-5), 199.5 (C-3). MS (EI): 433 (M+, 100%),
284 (10%), 119 (18%), 106 (63%).
2.6.6. 3ˇ-Acetoxy-17ˇ-[3-(N-4-methoxyphenyl)
-2-oxazolidon-5-yl]androst-5-ene (6e)
6e (420 mg; 82%), mp 263–265 ◦C, Rf = 0.50 (ss A); [˛]D20 − 89 (c 1
in CHCl3) (found C, 73.55; H, 8.02. C31H41NO5 requires C, 73.34;
H, 8.14%. 1H NMR (ı, ppm, CDCl3): 0.83 (s, 3H, 18-H3), 1.04
(s, 3H, 19-H3), 2.03 (s, 3H, Ac–CH3), 3.59 (t, 1H, J = 8.3 Hz) and
3.95 (t, 1H, J = 8.3 Hz): 4ꢀ-H2, 3.80 (s, 3H, O–CH3), 4.59 (overlap-
ping multiplets, 2H, 3-H and 5ꢀ-H), 5.37 (d, 1H, J = 4.8 Hz, 6-H),
6.90 (d, 2H, J = 8.8 Hz, 3ꢀꢀ-and 5ꢀꢀ-H), 7.42 (d, 2H, J = 8.8 Hz, 2ꢀꢀ-
and 6ꢀꢀ-H). 13C NMR (ı, ppm, CDCl3): 12.3 (C-18), 19.3 (C-19),
20.5, 21.4 (Ac–CH3), 23.2, 24.6, 27.7, 31.6 (C-8), 31.9, 36.6, 36.9,
38.1, 38.6, 42.6, 50.0, 50.8, 54.3, 55.4 (O–CH3), 55.8, 73.8 (C-3),
74.8 (C-5ꢀ), 114.2 (2C, C-3ꢀꢀ and C-5ꢀꢀ), 120.1 (2C, C-2ꢀꢀ and C-6ꢀꢀ),
122.1 (C-6), 131.7 (C-1ꢀꢀ), 139.9 (C-5), 155.4 (N–CO), 156.2 (C-4ꢀꢀ),
170.5 (Ac–CO). MS (CI): 525 (M++NH4+, 100%), 508 (16%), 141
(14%).
2.7.3. 17ˇ-[3-(N-4-Fluorophenyl)-2-oxazolidon
-5-yl]androst-4-en-3-one (7b)
7b (760 mg; 84%), mp 247–249 ◦C, Rf = 0.30 (ss B); [˛]D20 + 24 (c 1 in
CHCl3) (found C, 74.57; H, 7.36. C28H34FNO3 requires C, 74.47;
H, 7.59%). 1H NMR (ı, ppm, CDCl3): 0.87 (s, 3H, 18-H3), 1.21 (s,
3H, 19-H3), 3.61 (t, 1H, J = 8.2 Hz) and 3.98 (t, 1H, J = 8.2 Hz): 4ꢀ-
H2, 4.59 (m, 1H, 5ꢀ-H), 5.74 (s, 1H, 4-H), 7.07 (t, 2H, J = 8.8 Hz,
3ꢀꢀ- and 5ꢀꢀ-H), 7.49 (dd, 2H, J = 8.8 Hz and J = 4,6 Hz, 2ꢀꢀ- and 6ꢀꢀ-
H). 13C NMR (ı, ppm, CDCl3): 12.4 (C-18), 17.3 (C-19), 20.6, 23.2,
24.5, 32.0, 32.7, 33.9, 35.3 (C-8), 35.6, 38.5, 38.6, 42.8, 50.5, 53.7,
54.3, 55.1, 74.7 (C-5ꢀ), 115.6 (2C, J = 22.4 Hz, C-3ꢀꢀ and C-5ꢀꢀ), 119.9
(2C, J = 7.9 Hz, C-2ꢀꢀ and C-6ꢀꢀ), 123.8 (C-4), 134.5 (J = 2.6 Hz, C-1ꢀꢀ),
155.1 (N–CO), 159.1 (J = 242 Hz, C-4ꢀꢀ), 171.0 (C-5), 199.5 (C-3). MS
(EI): 451 (M+, 100%), 284 (17%), 137 (15%), 124 (53%), 111 (10%).
2.6.7. 3ˇ-Acetoxy-17ˇ[3-(N-3,5-dimethylphenyl)
-2-oxazolidon-5-yl]androst-5-ene (6f)
6f (455 mg; 89%), mp 212–214 ◦C, Rf = 0.60 (ss A); [˛]D20 − 91 (c
1 in CHCl3) (found C, 69.85; H, 8.84. C32H43NO4 requires C,
76.00; H, 8.57%). 1H NMR (ı, ppm, CDCl3): 0.83 (s, 3H, 18-H3),
1.04 (s, 3H, 19-H3), 2.03 (s, 3H, Ac–CH3), 2.32 (s, 6H, 3ꢀꢀ- and
5ꢀꢀ-CH3), 3.60 (t, 1H, J = 8.3 Hz) and 3.96 (t, 1H, J = 8.3 Hz): 4ꢀ-
H2, 4.58 (overlapping multiplets, 2H, 3-H and 5ꢀ-H), 5.37 (d,
1H, J = 4.4 Hz, 6-H), 6.77 (s, 1H, 4ꢀ-H), 7.14 (s, 2H, 2ꢀꢀ- and 6ꢀꢀ-
H). 13C NMR (ı, ppm, CDCl3): 12.3 (C-18), 19.3 (C-19), 20.5, 21.3
(Ac–CH3), 21.4 (2C, 3ꢀꢀ- and 5ꢀꢀ-CH3), 23.2, 24.6, 27.6, 31.6 (C-8),
31.8, 36.6, 36.9, 38.0, 38.6, 42.6, 50.0, 50.5, 54.3, 55.8, 73.8 (C-3),
74.7 (C-5ꢀ), 116.1 (2C, C-2ꢀꢀ and C-6ꢀꢀ), 122.1 (C-6), 125.6 (C-4ꢀꢀ),
138.3 (C-1ꢀꢀ), 138.6 (2C, C-3ꢀꢀ and C-5ꢀꢀ), 139.8 (C-5), 155.0 (N–CO),
170.4 (Ac–CO). MS (CI): 523 (M++NH4+, 100%), 324 (24%), 231
(20%).
2.7.4. 17ˇ-[3-(N-4-Chlorophenyl)-2-oxazolidon
-5-yl]androst-4-en-3-one (7c)
7c (836 mg; 89%), mp 271–274 ◦C, Rf = 0.40 (ss B); [˛]D20 + 7 (c 1 in
CHCl3) (found C, 72.03; H, 7.15. C28H34ClNO3 requires C, 71.85;
H, 7.32%). 1H NMR (ı, ppm, CDCl3): 0.86 (s, 3H, 18-H3), 1.20 (s,
3H, 19-H3), 3.60 (t, 1H, J = 7.9 Hz) and 3.97 (t, 1H, J = 7.9 Hz): 4ꢀ-
H2, 4.59 (m, 1H, 5ꢀ-H), 5.73 (s, 1H, 4-H), 7.32 (d, 2H, J = 9.0 Hz, 3ꢀꢀ-
and 5ꢀꢀ-H), 7.47 (d, 2H, J = 9.0 Hz, 2ꢀꢀ- and 6ꢀꢀ-H). 13C NMR (ı, ppm,
CDCl3): 12.4 (C-18), 17.3 (C-19), 20.5, 23.1, 24.5, 32.0, 32.7, 33.9,
35.3 (C-8), 35.6, 38.5, 38.6, 42.8, 50.1, 54.3, 55.8, 74.7 (C-5ꢀ), 119.2
(2C, C-2ꢀꢀ and C-6ꢀꢀ), 123.8 (C-4), 128.9 (3C, C-3ꢀꢀ, C-4ꢀꢀ and C-5ꢀꢀ),
137.0 (C-1ꢀꢀ), 154.8 (N–CO), 171.0 (C-5), 199.5 (C-3). MS (EI): 467
(M+, 100%), 284 (18%), 153 (14%), 140 (40%).

1380
steroids 7 3 ( 2 0 0 8 ) 1375–1384
determined by an in vitro radiosubstrate incubation method
2.7.5. 17ˇ-[3-(N-4-Bromophenyl)-2-oxazolidon
described in detail in an earlier publication [7].
-5-yl]androst-4-en-3-one (7d)
7d (875 mg; 85%), mp 261–263 ◦C, Rf = 0.40 (ss B); [˛]D20 − 2 (c 1 in
CHCl3) (found C, 65.38; H, 6.82. C28H34BrNO3 requires C, 65.62;
H, 6.69%). 1H NMR (ı, ppm, CDCl3): 0.85 (s, 3H, 18-H3), 1.20 (s,
3H, 19-H3), 3.59 (t, 1H, J = 8.4 Hz) and 3.97 (t, 1H, J = 8.4 Hz): 4ꢀ-H2,
4.59 (m, 1H, 5ꢀ-H), 5.73 (s, 1H, 4-H), 7.42 (d, 2H, J = 9.0 Hz) and
7.47 (d, 2H, J = 9.0 Hz): 2ꢀꢀ-, 3ꢀꢀ-, 5ꢀꢀ- and 6ꢀꢀ-H. 13C NMR (ı, ppm,
CDCl3): 12.5 (C-18), 17.3 (C-19), 20.5, 23.1, 24.5, 32.0 (C-8), 33.9,
35.3, 35.6, 38.5 (2C), 42.8, 50.1, 53.7, 54.3, 55.0, 74.7 (C-5ꢀ), 116.6
(C-4ꢀꢀ), 119.6 (2C, C-2ꢀꢀ and C-6ꢀꢀ), 123.8 (C-4), 131.9 (2C, C-3ꢀꢀ and
C-5ꢀꢀ), 137.5 (C-1ꢀꢀ), 154.7 (N–CO), 170.9 (C-5), 199.4 (C-3). MS (EI):
513 (M+, 100%), 284 (21%), 184 (37%), 105 (19%).
In brief, testicular tissue from adult Wistar rats was homog-
enized with an Ultra-Turrax in Krebs-Ringer phosphate buffer
containing glucose. Aliquots of this homogenate were incu-
bated with 1 ␮M [3H]17␣-hydroxyprogesterone in the presence
of 1 mM NADPH at 37 ◦C for 20 min. The enzymatic reaction
was stopped by the addition of ethyl acetate and freezing. After
extraction, the radioactive 17␣-hydroxyprogesterone and the
product androst-4-ene-3,17-dione were separated by TLC and
a Packard Radiochromatogram Scanner was used to trace the
separated steroids. Spots were scraped and extracted, and
the radioactivity of the androst-4-ene-3,17-dione formed and
the 17␣-hydroxyprogesterone remaining was measured with
liquid scintillation counting. C17,20-lyase activity was calcu-
lated in picomoles of androst-4-ene-3,17-dione formed. Test
compounds were applied at 50 ␮M. Control incubates without
test substances and incubates with the reference compound
ketoconazole were also prepared in every series. At least two
experiments were performed with each test compound; the
standard deviations of the mean enzyme activity results were
within 10%. IC50 values were determined for the more poten-
tial inhibitors. In this case, conversion was measured at five
to six different concentrations of the test compound. IC50
results were calculated by linear regression analysis following
a logit–log transformation of the data.
2.7.6. 17ˇ-[3-(N-4-Methoxyphenyl)-2-oxazolidon
-5-yl]androst-4-en-3-one (7e)
7e (836 mg; 90%), mp 217–219 ◦C, Rf = 0.40 (ss B); [˛]D20 + 14 (c 1
in CHCl3) (found C, 75.00; H, 8.17. C29H37NO4 requires C, 75.13;
H, 8.04%). 1H NMR (ı, ppm, CDCl3): 0.87 (s, 3H, 18-H3), 1.21 (s,
3H, 19-H3), 3.60 (t, 1H, J = 8.3 Hz) and 3.97 (t, 1H, J = 8.3 Hz): 4ꢀ-
H2, 3.81 (s, 3H, O–CH3), 4.58 (m, 1H, 5ꢀ-H), 5.74 (s, 1H, 4-H), 6.91
(d, 2H, J = 9.0 Hz, 3ꢀꢀ- and 5ꢀꢀ-H), 7.42 (d, 2H, J = 9.0 Hz, 2ꢀꢀ- and 6ꢀꢀ-
H). 13C NMR (ı, ppm, CDCl3): 12.4 (C-18), 17.3 (C-19), 20.6, 23.2,
24.5, 32.0, 32.7, 33.9, 35.3 (C-8), 35.6, 38.5, 38.6, 42.7, 50.8, 53.7,
54.3, 55.1 (O–CH3), 55.4, 74.6 (C-5ꢀ), 114.2 (2C, C-3ꢀꢀ and C-5ꢀꢀ),
120.1 (2C, C-2ꢀꢀ and C-6ꢀꢀ), 123.8 (C-4), 131.6 (C-1ꢀꢀ), 155.3 (N–CO),
156.2 (C-4ꢀꢀ), 171.0 (C-5), 199.4 (C-3). MS (EI): 463 (M+, 100%), 149
(16%), 136 (63%).
3.
Results and discussion
2.7.7. 17ˇ-[3-(N-3,5-dimethylphenyl)-2-oxazolidon
-5-yl]androst-4-en-3-one (7f)
3.1.
Synthetic studies
7f (732 mg; 79%), mp 211–212 ◦C, Rf = 0.50 (ss B); [˛]D20 + 15 (c 1 in
CHCl3) (found C, 77.93; H, 8.52. C30H39NO3 requires C, 78.05; H,
8.52%). 1H NMR (ı, ppm, CDCl3): 0.87 (s, 3H, 18-H3), 1.21 (s, 3H,
19-H3), 2.33 (s, 6H, 3ꢀꢀ- and 5ꢀꢀ-CH3), 3.60 (t, 1H, J = 8.2 Hz) and
3.98 (t, 1H, J = 8.2 Hz): 4ꢀ-H2, 4.56 (m, 1H, 5ꢀ-H), 5.74 (s, 1H, 4-H),
6.78 (s, 1H, 4ꢀꢀ-H), 7.14 (s, 2H, 2ꢀꢀ- and 6ꢀꢀ-H). 13C NMR (ı, ppm,
CDCl3): 12.4 (C-18), 17.3 (C-19), 20.5, 21.5 (2C, 3ꢀꢀ- and 5ꢀꢀ-CH3),
23.2, 24.5, 31.9, 32.7, 33.9, 35.3 (C-8), 35.6, 38.5, 38.6, 42.7, 50.5,
53.7, 54.3, 55.0, 74.6 (C-5ꢀ), 116.1 (2C, C-2ꢀꢀ and C-6ꢀꢀ), 123.8 (C-4),
125.7 (C-4ꢀꢀ), 138.2 (C-1ꢀꢀ), 138.6 (2C, C-3ꢀꢀ and C-5ꢀꢀ), 155.0 (N–CO),
171.1 (C-5), 199.5 (C-3). MS (EI): 461 (M+, 100%), 147 (14%), 134
(84%), 121 (11%).
For the synthesis of the 2-oxazolidone ring at position 17␤ of
the sterane ring, we chose cyclization of the ␣,␤-haloalkyl-
N-arylurethanes in alkaline media. Winstein and coworkers
examined the ring-closure reactions of ␣,␤- and ␣,␥-haloalkyl-
N-arylurethanes under basic conditions [8]. They found that
the N-arylurethane group and its substituted derivatives
reacted at different rates, depending on the inductive and
conjugative effects of the substituents. The cyclization typi-
cally occurred with neighboring group participation, to yield
N-phenyl-2-oxazolidone or N-phenyltetrahydrooxazin-2-one
derivatives, depending on the starting compounds [9]. In the
solvolysis of vicinal halourethanes, 2-oxazolidone derivatives
condensed to the estrane skeleton are formed, which are like-
wise potential pharmacons [10].
To prepare the ␣,␤-diol system on the side-chain of
the sterane skeleton, we chose 3␤-acetoxypregn-5-en-20-
one (1) as starting compound. Oxidation with Pb(OAc)4 in
the presence of BF3·OEt2 furnished 3␤,21-diacetoxypregn-5-
en-20-one (2). Reduction with KBH4 gave two compounds,
3␤,2l-diacetoxypregn-5-en-20␤-ol (3a) and its 20␣ epimer, in
a ratio of 9:1. The required pure epimer 3a was obtained by
flash chromatography. Their selective deacetylation on alka-
line alumina was carried out by an earlier developed method to
obtain 3b [5]. For the formation of substituted phenylurethane
derivatives 4a–f, the starting compound was 3␤-acetoxy-21-
chloromethylpregn-5-en-20␤-ol (3c), which was prepared by
the Appel reaction of 3b [11]. 3c reacted with phenyl iso-
cyanate or substituted phenyl isocyanates in the presence of
2.7.8. 17ˇ-(2-Oxazolidon-5-yl)androst-4-en-3-one (10)
10 (570 mg; 79%), mp 243–246 ◦C, Rf = 0.40 (ss D); [˛]D20 + 85 (c 1
in CHCl3) (found C, 74.06; H, 8.55. C22H31NO3 requires C, 73.91;
H, 8.74%). 1H NMR (ı, ppm, CDCl3): 0.82 (s, 3H, 18-H3), 1.19 (s,
3H, 19-H3), 3.21 (t, 1H, J = 8.1 Hz) and 3.58 (t, 1H, J = 8.1 Hz): 4ꢀ-H2,
4.58 (m, 1H, 5ꢀ-H), 5.07 (s, 1H, 4-H), 5.73 (s, 1H, N–H). 13C NMR (ı,
ppm, CDCl3): 12.4 (C-18), 17.3 (C-19), 20.5, 23.0, 24.4, 32.0, 32.7,
33.9, 35.3 (C-8), 35.6, 38.5 (2C), 42.6, 45.7, 53.7, 54.2, 55.0, 78.6
(C-5ꢀ), 123.8 (C-4), 160.4 (N–CO), 171.2 (C-5), 199.6 (C-3). MS (EI):
357 (M+, 100%), 315 (50%), 234 (21%), 173 (18%), 124 (40%).
2.8.
Determination of C17,20-lyase activity and its
inhibition in the rat testis
The inhibitory effects exerted on the C17,20-lyase activity
by the newly synthesized 17␤-5ꢀ-oxazolidonyl steroids were

steroids 7 3 ( 2 0 0 8 ) 1375–1384
1381
triethylamine to afford the desired 21-chloromethylpregn-5-
en-20␤-arylurethanes 4a–f.
All of the NMR spectra of the N-aryl-substituted hetero-
cycles (5–7) demonstrate the presence of the corresponding
phenyl or substituted phenyl ring. In the 1H NMR spectra of
the N-aryl-2-oxazolidones (6a–f), the signals of the 4ꢀ-H2 pro-
tons appear at around 3.6 and 4.0 ppm, as triplets with J ≈ 8 Hz.
The 5ꢀ-H resonates at 4.6 ppm. The chemical shift of the car-
bamate CO in these compounds in the 13C NMR spectra is at
around 155 ppm. In the Oppenauer products (7), the 4-(sp2-
)H is to be found at 5.7 ppm (singlet) in the 1H NMR spectra,
whereas the C-3s resonate at around 200 ppm (13C).
Compounds 4a–f were subjected to methanolysis in
the presence of four equivalents of NaOCH3. Under these
experimental conditions, N-phenyl-2-oxazolidone (5a), (4ꢀ-
substituted-N-phenyl)-2-oxazolidone rings (5b–e) and (3ꢀ,5ꢀ-
disubstituted-N-phenyl)-2-oxazolidone (5f) were formed in
rapid reactions. The cyclization can be explained by the
nucleophilic attack of the nitrogen atom of the deprotonated
acid amide. This cyclization process is a typical neighboring
group participation. In the notation proposed by Winstein and
Boschan [9], the process can be characterized by the symbol
(N−-5) (Scheme 1).
3.2.
Effects of steroidal 2-oxazolidones on C17,20-lyase
activity
For the formation of the unsubstituted 3␤-acetoxy-17␤-
(2-oxazolidon-5-yl)androst-5-ene (8), we used
a one-pot
The inhibitory effects of compounds 5a–5f, 7a–7f, 9 and
10 on rat testicular C17,20-lyase were investigated with an
in vitro radiosubstrate incubation technique. The phenyl,
4-fluorophenyl and 4-bromophenyl-substituted 17␤-(2-
oxazolidon-5-yl)androst-5-en-3␤-ol derivatives (5a, 5b and
5d) exhibited moderate inhibitory action. When applied at
50 ␮M in the incubates, these compounds decreased the
enzyme activity by 56, 69 and 63%, respectively (Table 1).
The 4-chlorophenyl and 3,5-dimethylphenyl-substituted
cyclization process developed earlier for the formation of
cyclic carbamates of amino sugars [12]. Starting from 3␤-
acetoxy-21-azidopregn-5-en-20␤-ol (3d) [5] and Ph3P, the
3␤-acetoxy-21-phosphiniminopregn-5-en-20␤-ol was formed,
which reacted with CO2 in situ to give an isocyanate intermedi-
ate. This isocyanate reacts with participation of the sterically
favored 20␤-OH group, yielding the required steroidal cyclic
carbamate 8.
Scheme 1 – Reagents and conditions: (a) Pb(OAc)4, BF3·OEt2, MeOH; (b) KBH4, MeOH, rt; (c) Ph3P, CCl4, reflux; (d) NaN3, DMF,
80 ◦C; (e) Ph3P, CO2, acetone, rt; (f) PhNCO, CH2Cl2, rt; (g) NaOMe, MeOH, reflux; (h) Ac2O, pyridine, rt; (i) Al(OiPr)3,
cyclohexanone, toluene, reflux.

1382
steroids 7 3 ( 2 0 0 8 ) 1375–1384
Table 1 – Inhibition of C17,20-lyase activity
Compound Formula
Relative
conversion (%)
Compound
Formula
Relative
conversion (%)
IC50 (␮M)
5a
56
7a
95
5b
69
95
63
NI
7b
7c
7d
7e
91
5c
5d
5e
83
88
NI

steroids 7 3 ( 2 0 0 8 ) 1375–1384
1383
Table 1 (Continued )
Compound
Formula
Relative
Compound
Formula
Relative
IC50 (␮M)
conversion (%)
conversion (%)
5f
82
7f
94
9
NI
10
3.0
Ketoconazole (reference)
0.75
Relative conversions (control incubation with no inhibition is taken as 100%) measured in the presence of 50 ␮M of the compounds tested, and
IC50 results for more potent inhibitors. NI: no inhibition.
containing oxygen, sulfur or four-membered nitrogen hete-
rocycles were less effective inhibitors [20].
17␤-(2-oxazolidon-5-yl)androst-5-en-3␤-ol derivatives (5c and
5f) were weaker inhibitors, decreasing the enzyme activity by
95 and 82%, respectively.
We investigated the presumed C17,20-lyase inhibition of
androstene derivatives with N-aryl or an unsubstituted
2-oxazolidone ring at position 17␤. Compounds were synthe-
sized and tested in both the ꢀ5-3␤-hydroxy and ꢀ4-3-keto
series. Derivatives containing various aryl-substituted oxa-
zolidones were moderate or weak inhibitors, and the
ꢀ5-3␤-hydroxy compounds in most cases exerted somewhat
higher inhibition than their ꢀ4-3-keto counterparts. The
phenyloxazolidonylandrost-5-en-3␤-ol derivative (5a) was
found to be the best inhibitor among the aryl-substituted
oxazolidones. Whereas both 4-methoxyphenyl-oxazolidonyl
derivatives (5e and 7e) were ineffective, even at rather high
(50 ␮M) concentration, in our in vitro C17,20-lyase inhibition
test.
The two compounds bearing a non-substituted oxazoli-
done ring differed markedly from each other in inhibitory
action. The ꢀ5-3␤-hydroxy compound (9) exerted no inhibi-
tion. Transformation to the ꢀ4-3-keto compound increased
the inhibition dramatically: the in vitro inhibitory potential of
the unsubstituted oxazolidonylandrost-4-en-3-one derivative
(10) toward rat testicular C17,20-lyase was found to be similar
to those of ketoconazole and abiraterone.
Most of the substituted 17␤-(2-oxazolidon-5-yl)androst-
4-en-3-one derivatives also exhibited some inhibition. The
enzyme activity was reduced by 83–95% by 7a–7d and 7f
at 50 ␮M. Incubation with the 4-methoxyphenyl-oxazolidonyl
derivatives, either the androst-5-en-3␤-ol or the androst-4-en-
3-one (5e and 7e), resulted in conversions identical to those
in the control experiments; hence, these compounds did not
inhibit rat C17,20-lyase under the test conditions.
The unsubstituted 17␤-(2-oxazolidon-5-yl)androst-5-en-3-
ol derivative (9) was found not to inhibit the enzyme activity,
whereas its androst-4-en-3-one counterpart (10) proved to be
a potent C17,20-lyase inhibitor. The IC50 of 10 is 3.0 ␮M, which is
close to that of ketoconazole (0.75 ␮M), the reference inhibitor
already used in medical practice.
Numerous steroidal compounds bearing heterocyclic sub-
stituents at C-17 have been investigated as concerns
their P45017␣ inhibitory effects [13,14]. Abiraterone and its
derivatives (17-pyridyl-16,17-unsaturated compounds) have
IC50 values in the interval 2–5 ␮M [3,15]. Other C-17 het-
eroaryl (imidazolyl, benzimidazolyl, pyrazolyl and isoxazolyl)
or unsaturated heterocyclic (aminothiazolyl and furanoyl)
derivatives containing a 16,17-double bond are among the
most effective inhibitors, with IC50 values < 0.01 ␮M [4,16–18].
Some compounds with a saturated heterocyclic C-17 sub-
stituent have also been investigated. Derivatives bearing an
aziridine ring were synthesized and tested and the (S) enan-
tiomers of the series were found to be more potent P45017␣
inhibitors, with IC50 values of 0.2–1 ␮M [19]. Compounds
Acknowledgements
This work was supported by the Hungarian Scientific Research
Fund (OTKA T049366 and K72309). Mihály Szécsi’s work was
supported by the award of a Bolyai János Research Fellowship.

1384
steroids 7 3 ( 2 0 0 8 ) 1375–1384
r e f e r e n c e s
[11] Appel R, Halstenberg M. In: Cadogan JIG, editor.
Organophosphorus reagents in organic synthesis. New York:
Academic Press; 1979. p. 378–424.
[12] Kovács J, Pintér I, Messmer A. Unprotected sugar
phosphinimines: a facile route to cyclic carbamates of
amino sugars. Carbohydr Res 1985;141:57–65.
[13] Jarman M, Smith HJ, Nicholls PJ, Simons C. Inhibitors of
enzymes of androgen biosynthesis: cytochrome P45017␣ and
5␣-steroid reductase. Nat Prod Rep 1998;15:495–512.
[14] Baston E, Leroux FR. Inhibitors of steroidal cytochrome P450
enzymes as targets for drug development. Recent Pat
Anti-Cancer Drug Dis 2007;2:31–58.
[15] Barrie SE, Potter GA, Goddard PM, Haynes BP, Dowsett M,
Jarman M. Pharmacology of novel steroidal inhibitors of
cytochrome P45017␣ (17␣-hydroxylase/C17-20 lyase). J Steroid
Biochem Mol Biol 1994;50:267–73.
[16] Burkhart JP, Gates CA, Laughlin ME, Resvick RJ, Peet NP.
Inhibition of steroid C17(20) lyase with C-17-heteroaryl
steroids. Bioorg Med Chem 1996;4:1411–20.
[1] Szájli Á, Wölfling J, Mernyák E, Minorics R, Márki Á, Falkay G,
et al. Neighboring group participation. Part 16.
Stereoselective synthesis and receptor-binding examination
of the four stereoisomers of
16-bromomethyl-3,17-estradiols. Steroids 2006;71:141–53.
[2] Njar VCO, Brodie AMH. Inhibitors of
17␣-hydroxylase/17,20-lyase (CYP17): potential agents for
the treatment of prostate cancer. Curr Pharm Des
1999;5:163–80.
[3] Potter GA, Barrie SE, Jarman M, Rowlands MG. Novel
steroidal inhibitors of human cytochrome P45017␣
(17␣-hydroxylase-C17,20-lyase): potential agents for the
treatment of prostatic cancer. J Med Chem 1995;38:2463–71.
[4] Moreira VMA, Vasaitis TS, Njar VCO, Salvador JAR. Synthesis
and evaluation of novel 17-indazole androstene derivatives
designed as CYP17 inhibitors. Steroids 2007;72:939–48.
[5] Wölfling J, Mernyák E, Sebo˝k M, Schneider G. Synthesis of
some steroidal oxazolines. Collect Czech Chem Commun
2001;66:1831–40.
[17] Handratta VD, Vasaitis TS, Njar VCO, Gediya LK, Kataria R,
Chopra P, Newman Jr D, Farquhar R, Guo Z, Qiu Y, Brodie AM.
Novel C-17-heteroaryl steroidal CYP17
inhibitors/antiandrogens: synthesis, in vitro biological
activity, pharmacokinetics, and antitumor activity in the
LAPC4 human prostate cancer xenograft model. J Med Chem
2005;48:2972–84.
[6] Wölfling J, Hackler L, Mernyák E, Schneider G, Tóth I, Szécsi
M, et al. Neighboring group participation. Part 15.
Stereoselective synthesis of some steroidal
tetrahydro-oxazin-2-ones, as novel presumed inhibitors of
human 5␣-reductase. Steroids 2004;69:451–60.
[18] Ling YZ, Li JS, Liu Y, Kato K, Klus GT, Brodie A. 17-Imidazolyl,
pyrazolyl, and isoxazolyl androstene derivatives: novel
steroidal inhibitors of human cytochrome C17,20-lyase
(P45017␣). J Med Chem 1997;40:3297–304.
[19] Njar VCO, Hector M, Hartmann RW. 20-Amino and
20,21-aziridinyl pregnene steroids: development of potent
inhibitors of 17␣-hydroxylase/C17,20-lyase (P45017␣). Bioorg
Med Chem 1996;4:1447–53.
[7] Wölfling J, Oravecz EA, Ondré D, Mernyák E, Schneider G,
Tóth I, et al. Stereo- selective synthesis of some
17␤-dihydrooxazinyl steroids, as novel presumed inhibitors
of 17␣-hydroxylase-C17,20-lyase. Steroids 2006;71:809–16.
[8] Scott FL, Glick RE, Winstein S. Amido, ureido and urethano
neighbouring group participation. Experientia 1957;13:183–5.
[9] Winstein S, Boschan R. The role of the neighboring groups in
replacement reactions. XVII. Complex neighboring group.
The benzamido group. J Am Chem Soc 1950;72:4669–77.
[10] Ponsold K, Grosse P. Ringschlußreaktionen vicinaler
Halogenurethane der Steroidreihe. J Prakt Chem
1981;323:801–18.
[20] Hartmann RW, Hector M, Wachall BG, Palusczak A, Palzer M,
Huch V, Veith M. Synthesis and evaluation of 17-aliphatic
heterocycle-substituted steroidal inhibitors of
17␣-hydroxylase/C17-20-lyase (P450 17). J Med Chem
2000;43:4437–45.