Synthesis of regioisomeric 17β-N-phenylpyrazolyl steroid derivatives and their inhibitory effect on 17α-hydroxylase/C17,20-lyase

Article abstract of DOI:10.1016/j.steroids.2010.02.013

The reaction of 3β-hydroxy-21-hydroxymethylidenepregn-5-en-3β-ol-20-one (1) with phenylhydrazine (2a) affords two regioisomers, 17β-(1-phenyl-3-pyrazolyl)androst-3-en-3β-ol (5a) and 17β-(1-phenyl-5-pyrazolyl)androst-5-en-3β-ol (6a). The direction of the r

Full text of DOI:10.1016/j.steroids.2010.02.013

Steroids 75 (2010) 450–456
Contents lists available at ScienceDirect
Steroids
journal homepage: www.elsevier.com/locate/steroids
Synthesis of regioisomeric 17␤-N-phenylpyrazolyl steroid derivatives and their
inhibitory effect on 17␣-hydroxylase/C17,20-lyase
Zoltán Iványia, János Wölflinga, Tamás Görbea, Mihály Szécsib, Tibor Wittmannb, Gyula Schneidera,∗
a Department of Organic Chemistry, University of Szeged, Dóm tér 8, H-6720 Szeged, Hungary
b 1st Department of Medicine, University of Szeged, Korányi fasor 8-10, H-6720 Szeged, Hungary
a r t i c l e i n f o
a b s t r a c t
Article history:
The reaction of 3␤-hydroxy-21-hydroxymethylidenepregn-5-en-3␤-ol-20-one (1) with phenylhy-
drazine (2a) affords two regioisomers, 17␤-(1-phenyl-3-pyrazolyl)androst-3-en-3␤-ol (5a) and
17␤-(1-phenyl-5-pyrazolyl)androst-5-en-3␤-ol (6a). The direction of the ring-closure reactions of 1 with
p-substituted phenylhydrazines (2b–e) depends strongly on the electronic features of the substituents.
Oppenauer oxidation of 3␤-hydroxy-17␤-exo-heterocyclic steroids 5a–e and 6a–e yielded the corre-
sponding ꢀ4-3-ketosteroids 9a–e and 10a–e. The inhibitory effects (IC50) of these compounds on rat
testicular C17,20-lyase were investigated by means of an in vitro radioligand incubation technique.
© 2010 Elsevier Inc. All rights reserved.
Received 30 November 2009
Received in revised form 4 January 2010
Accepted 22 February 2010
Available online 3 March 2010
Keywords:
Regioisomeric 17␤-N-phenylpyrazolyl
steroids
p-Substituted phenylhydrazine
P45017␣ inhibitors
1. Introduction
2. Experimental
Steroids bearing heterocycles fused to the D-ring of the steroid
nucleus have been of pharmaceutical interest [1]. The syntheses of
abirateron [17-(3-pyridyl)androst-5,16-dien-3␤-ol] and its 4-en-
3-one analog were reported recently; these display high inhibitory
activities against 17␣-hydroxylase/C17,20-lyase (P45017␣). It has
been suggested that such activity is related to the presence of the
heterocyclic moiety in ring D, with the nitrogen lone pair coordi-
nating to the heme iron atom at the active site of the enzyme [2].
Brodie and coworkers recently described a number of inhibitors
of P45017␣, of which 17-imidazolyl, pyrazolyl, isoxazolyl, oxazolyl
and thiazolyl steroids are very potent [3–5].
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) polarimeter and are given in
units of 10−1◦ cm2 g−1. Elementary analysis data were determined
with a PerkinElmer CHN analyzer model 2400. The reactions were
monitored by TLC on Kieselgel-G (Merck Si 254 F) layers (0.25 mm
thick); solvent systems (ss) (A) acetone/toluene/hexane (35:30:30,
v/v), (B) diisopropyl ether. The spots were detected by spraying
with 5% phosphomolybdic 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
We recently reported a series of 17␤-tetrahydrooxazinolyl,
dihydrooxazinyl, oxazolidonyl and oxazolinyl steroids. The
inhibitory effects of these compounds on rat testicular C17,20
-
lyase were investigated by means of an in vitro radioincubation
technique [6–9].
on a Bruker DRX 500 instrument at 500 (1H NMR) or 125 MHz (13
C
NMR). 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.
To continue our program, we set out to synthesize a novel
series of phenylpyrazolyl steroid regioisomers in which there is a
heterocycle containing two N atoms at position 17␤ of androst-5-
en-3␤-ol, to obtain answers to the following questions: (1) How is
the cyclization process influenced by the substituents on the phenyl
ring? (2) How do the decreases in enzyme activity of the regioiso-
mers in the 3␤-hydroxy- and ꢀ4-3-ketosteroid series 5a–e, 6a–e
and 9a–e, 10a–e differ?
2.2. General procedure for preparation of 17ˇ-(1-phenyl-, and
p-substituted-1-phenyl-3-pyrazolyl)androst-5-en-3ˇ-ol (5a–e)
and 17ˇ-(1-phenyl-, and
p-substituted-1-phenyl-5-pyrazolyl)androst-5-en-3ˇ-ol (6a–e)
(Method A) Compound 1 [7] (2.07 g, 6 mmol) and potassium
acetate (1.2 g, 12 mmol) were dissolved in glacial acetic acid (75 ml)
and phenylhydrazine hydrochloride (2a) or one of its p-substituted
derivatives (2b–e) (1.1 equivalent) was added. The reaction
∗
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 © 2010 Elsevier Inc. All rights reserved.
doi:10.1016/j.steroids.2010.02.013

Z. Iványi et al. / Steroids 75 (2010) 450–456
451
mixture was stirred at room temperature for 6 h, and was then
poured into ice-cold water (500 ml). The precipitate that formed
was filtered off and washed with water. The residue obtained
was dissolved in CH2Cl2 and chromatographed on silica gel,
starting with CH2Cl2/hexane (1:1, v/v) as eluent, followed by
CH2Cl2/hexane (2:1, v/v) and CH2Cl2 to afford 5a–e and 6a–e.
(Method B) Compound 1 [7] (2.07 g, 6 mmol) was suspended
in CH2Cl2 (50 ml) and phenylhydrazine hydrochloride (2a) or one
of its p-substituted derivatives (2b–e) (1.1 eqivalent) was added,
followed by the dropwise addition of BF3·OEt2 (50%) (2 mmol,
0.25 ml). The reaction mixture was stirred for 6 h. After the
disappearance of the starting material (TLC monitoring), satu-
rated NaHCO3 solution (100 ml) was added and the mixture was
stirred until bubbling ceased. The organic layer was washed with
water, dried over anhydrous Na2SO4 and concentrated in vacuo.
The residue was chromatographed on silica gel starting with
CH2Cl2/hexane (1:1, v/v) as eluent, followed by CH2Cl2/hexane (2:1,
v/v) and CH2Cl2 to afford 5a–e and 6a–e.
128.2, and 129.3 (4C, C-2ꢀꢀ, C-3ꢀꢀ, C-5ꢀꢀ, and C-6ꢀꢀ), 134.6, 137.8, 138.9
(C-5), 140.9, 145.4.
2.2.3. 17ˇ-(1-p-Cyanophenyl-3-pyrazolyl)androst-5-en-3ˇ-ol
(5c) and 17ˇ-(1-p-cyanophenyl-5-pyrazolyl)androst-
5-en-3ˇ-ol (6c)
The resulting crude product was chromatographed on silica gel
with CH2Cl2/hexane (2:1) to yield 5c (with Method A: 250 mg, 9%;
with Method B: 1.9 g, 71%), mp 273–275 ◦C, Rf = 0.50 (ss A); [␣]D
20
−47 (c 1 in CHCl3) (found C, 78.65; H, 8.06. C29H35N3O requires C,
78.87; H, 7.99%).
Continued elution with CH2Cl2 resulted in 6c (with Method A:
2.30 g, 85%; with Method B: 250 mg, 9%), mp 183–186 ◦C, Rf = 0.45
20
(ss A); [␣]D
C
−129 (c 1 in CHCl3) (found C, 78.69; H, 8.25.
29H35N3O requires C, 78.87; H, 7.99%). 1H NMR (ı, ppm, CDCl3):
0.63 (s, 3H, 18-H3), 0.95 (s, 3H, 19-H3), 2.86 (t, 1H, J = 9.8 Hz, 17-H),
3.47 (m, 1H, 3-H), 5.31 (s, 1H, 6-H), 6.35 (d, 1H, J = 2.0 Hz, 4ꢀ-H), 7.53
(d, 2H, J = 8.3 Hz, 2ꢀꢀ- and 6ꢀꢀ-H), 7.67 (d, 1H, J = 2.0 Hz, 3ꢀ-H), 7.77 (d,
2H, J = 8.3 Hz, 3ꢀꢀ- and 5ꢀꢀ-H). 13C NMR (125 MHz, CDCl3, ı (ppm)):
13.3 (C-18), 19.3 (C-19), 20.7, 24.3, 29.2, 31.6, 31.7, 32.3, 36.5, 37.2,
37.4, 42.2, 44.8, 47.0, 49.9, 56.1, 71.6 (C-3), 106.9 (C-4ꢀ), 112.2, 118.0
(CN), 121.1, 127.3, and 133.1: (4C, C-2ꢀꢀ, C-3ꢀꢀ, C-5ꢀꢀ and C-6ꢀꢀ), 139.9
(C-3ꢀ), 140.9 (C-5), 143.2, 145.3.
2.2.1. 17ˇ-(1-Phenyl-3-pyrazolyl)androst-5-en-3ˇ-ol (5a) and
17ˇ-(1-phenyl-5-pyrazolyl)androst-5-en-3ˇ-ol (6a)
The resulting crude product was chromatographed on silica gel
with CH2Cl2/hexane (1:1) to yield pure 5a (with Method A: 620 mg,
24%; with Method B: 1.95 g, 78%), mp 153–155 ◦C, Rf = 0.55 (ss A);
20
[␣]D −60 (c 1 in CHCl3) (found C, 80.55; H, 8.82. C28H36N2O
2.2.4. 17ˇ-(1-p-Tolylphenyl-3-pyrazolyl)androst-5-en-3ˇ-ol
(5d) and 17ˇ-(1-p-toly- 5-pyrazolyl)androst-5-en-3ˇ-ol (6d)
The resulting crude product was chromatographed on silica gel
with CH2Cl2/hexane (1:1) to yield 5d (with Method A: 500 mg, 19%;
requires C, 80.73; H, 8.71%). 1H NMR (ı, ppm, CDCl3): 0.59 (s, 3H,
18-H3), 1.02 (s, 3H, 19-H3), 2.80 (t, 1H, J = 8.3 Hz, 17-H), 3.54 (m, 1H,
3-H), 5.38 (d, 1H, J = 2.3 Hz, 6-H), 6.27 (d, 1H, J = 2.0 Hz, 4ꢀ-H), 7.23
(t, 1H, J = 6.5 Hz, 4ꢀꢀ-H), 7.42 (t, 2H, J = 6.5 Hz, 3ꢀꢀ- and 5ꢀꢀ-H), 7.68 (d,
2H, J = 6.5 Hz, 2ꢀꢀ- and 6ꢀꢀ-H), 7.83 (d, 1H, J = 2.0 Hz, 5ꢀ-H). 13C NMR
(125 MHz, CDCl3, ı (ppm)): 13.1 (C-18), 19.4 (C-19), 20.9, 24.7, 26.3,
31.7, 32.0, 32.3, 37.3, 37.9, 42.3, 43.7, 50.3, 50.4, 56.2, 71.8 (C-3),
106.8 (C-4ꢀ), 118.8 (2C, C-2ꢀꢀ and C-6ꢀꢀ), 121.6, 125.7, 126.6, 129.3
(2C, C-3ꢀꢀ and C-5ꢀꢀ), 134.7, 140.9, 153.2, 155.2. Continued elution
with CH2Cl2/hexane (2:1) resulted in 6a (with Method A: 1.60 g,
64%; with Method B): (400 mg, 16%), mp 223–226 ◦C (Ref. [10]: mp
with Method B: 2.45 g, 94%), mp 167–170 ◦C, Rf = 0.58 (ss A); [␣]D
20
−63 (c 1 in CHCl3) (found C, 80.76; H, 8.75. C29H38N2O requires C
80.89; H, 8.89%). 1H NMR (ı, ppm, CDCl3): 0.59 (s, 3H, 18-H3), 1.01
(s, 3H, 19-H3), 2.36 (s, 3H, 4ꢀꢀ-CH3), 2.84 (t, 1H, J = 9.8 Hz, 17-H), 3.53
(m, 1H, 3-H), 5.37 (d, 1H, J = 2.5 Hz, 6-H), 6.26 (d, 1H, J = 2.3 Hz, 4ꢀ-H),
7.22 and 7.54 (d, 4H, J = 8.0 Hz, 2ꢀꢀ-, 3ꢀꢀ-, 5ꢀꢀ- and 6ꢀꢀ-H), 7.78 (d, 1H,
J = 2.3 Hz, 5ꢀ-H). 13C NMR (125 MHz, CDCl3, ı (ppm)): 13.1 (C-18),
19.4 (C-19), 20.8, 20.9 (4ꢀꢀ-CH3), 24.7, 26.5, 31.6, 31.9, 32.3, 36.6,
37.3, 37.7, 42.3, 43.8, 49.9, 50.3, 56.2, 71.7 (C-3), 106.5 (C-4ꢀ), 119.2
(2C, C-2ꢀꢀ and C-6ꢀꢀ), 121.5, 127.1, 129.8 (2C, C-3ꢀꢀ and C-5ꢀꢀ), 135.9,
137.7, 140.9 (C-5), 154.7. Continued elution with CH2Cl2/hexane
(2:1) resulted in 6d (1.60 g, 46%), mp 166–168 ◦C, Rf = 0.50 (ss A);
222–224 ◦C), Rf = 0.48 (ss A); [␣]D −133 (c in CHCl3) (found C,
20
80.61; H, 8.55. C28H36N2O requires C, 80.73; H, 8.71%). 1H NMR (ı,
ppm, CDCl3): 0.67 (s, 3H, 18-H3), 0.96 (s, 3H, 19-H3), 2.84 (t, 1H,
J = 8.3 Hz, 17-H), 3.47 (m, 1H, 3-H), 5.31 (d, 1H, J = 5.0 Hz, 6-H), 6.27
(d, 1H, J = 1.5 Hz, 4ꢀ-H), 7.36 (d, 2H, J = 6.3 Hz, 2ꢀꢀ- and 6ꢀꢀ-H), 7.40 (t,
1H, J = 6.3 Hz, 4ꢀꢀ-H), 7.45 (t, 2H, J = 6.3 Hz, 3ꢀꢀ- and 5ꢀꢀ-H), 7.60 (d, 1H,
J = 1.5 Hz, 3ꢀ-H). 13C NMR (125 MHz, CDCl3, ı (ppm)): 13.3 (C-18),
19.3 (C-19), 20.7, 24.4, 29.5, 31.6, 31.7, 32.3, 36.5, 37.2 (2C), 42.2,
44.3, 46.9, 49.9, 56.0, 71.6 (C-3), 105.5 (C-4ꢀ), 121.3 (C-6), 126.9 and
128.9 (4C, C-2ꢀꢀ, C-3ꢀꢀ, C-5ꢀꢀ and C-6ꢀꢀ), 128.1, 139.3, 140.4, 140.8,
144.4.
20
[␣]D −128 (c 1 in CHCl3) (found C, 80.68; H, 8.94. C29H38N2O
requires C, 80.89; H, 8.89%). 1H NMR (ı, ppm, CDCl3): 0.68 (s, 3H,
18-H3), 0.95 (s, 3H, 19-H3), 2.41 (s, 3H, 4ꢀꢀ-CH3), 2.78 (t, 1H, J = 9.8 Hz,
17-H), 3.45 (m, 1H, 3-H), 5.29 (s, 1H, 6-H), 6.29 (d, 1H, J = 1.5 Hz, 4ꢀ-
H), 7.24 (overlapping multiplets, 4H, 2ꢀꢀ-, 3ꢀꢀ-, 5ꢀꢀ-, 6ꢀꢀ-H), 7.65 (d, 1H,
J = 1.5 Hz, 3ꢀ-H). 13C NMR (125 MHz, CDCl3, ı (ppm)): 13.4 (C-18),
19.3 (C-19), 20.7, 21.2 (4ꢀꢀ-CH3), 24.4, 29.6, 31.6, 31.7, 32.3, 36.5,
37.2 37.3, 42.2, 44.5, 46.9, 49.9, 56.0, 71.6 (C-3), 105.6 (C-4ꢀ), 121.2
(C-6), 126.8 and 129.7 (4C, C-2ꢀꢀ, C-3ꢀꢀ, C-5ꢀꢀ and C-6ꢀꢀ), 136.2, 137.8
(C-5ꢀ), 139.0, 140.9 (C-5), 145.7.
2.2.2. 17ˇ-(1-p-Chlorophenyl-3-pyrazolyl)androst-
5-en-3ˇ-ol (5b) and
17ˇ-(1-p-chlorophenyl-3-pyrazolyl)androst-5-en-3ˇ-ol (6b)
The resulting crude product was chromatographed on silica gel
with CH2Cl2/hexane (1:1) to yield 5b (with Method A: 300 mg, 11%;
2.2.5. 17ˇ-(1-p-Methoxyphenyl-3-pyrazolyl)androst-5-en-3ˇ-ol
(5e) and
with Method B: 1.90 g, 70%), mp 177–179 ◦C, Rf = 0.57 (ss A); [␣]D
17ˇ-(1-p-methoxyphenyl-5-pyrazolyl)androst-5-en-3ˇ-ol (6e)
The resulting crude product was chromatographed on silica
gel with CH2Cl2/hexane (2:1) to yield 5e (with Method A: 1.65 g,
61%; with Method B: 280 mg, 10%), mp 150–152 ◦C, Rf = 0.50 (ss
20
−54 (c 1 in CHCl3) (found C, 74.34; H, 7.67. C28H35ClN2O requires
C, 74.56; H, 7.82%).
Continued elution with CH2Cl2/hexane (2:1) resulted in 6b
(with Method A: 2.10 g, 77%; with Method B: 530 mg, 19%), mp
20
A); [␣]D −60 (c 1 in CHCl3) (found C, 78.05; H, 8.50. C29H38N2O2
133–137 ◦C, Rf = 0.50 (ss A); [␣]D −128 (c 1 in CHCl3) (found C,
requires C 77.99; H, 8.58%). 1H NMR (ı, ppm, CDCl3): 0.58 (s, 3H,
18-H3), 1.02 (s, 3H, 19-H3), 2.80 (t, 1H, J = 8.3 Hz, 17-H), 3.54 (m,
1H, 3-H), 3.83 (s, 3H, O-CH3), 5.38 (d, 1H, J = 2.0 Hz, 6-H), 6.24 (d,
1H, J = 2.0 Hz, 4ꢀ-H), 6.94 (d, 2H, J = 7.3 Hz, 3ꢀꢀ- and 5ꢀꢀ-H), 7.56 (d,
2H, J = 7.3 Hz, 2ꢀꢀ- and 6ꢀꢀ-H), 7.72 (d, 1H, J = 2.0 Hz, 5ꢀ-H). 13C NMR
(125 MHz, CDCl3, ı (ppm)): 13.1 (C-18), 19.4 (C-19), 20.8, 24.7, 26.4,
31.7, 32.0, 32.3, 36.6, 37.3, 37.8, 42.3, 43.7, 50.3, 50.4, 55.6 (O-CH3),
56.2, 71.8 (C-3), 106.3 (C-4ꢀ), 114.4 (2C, C-3ꢀꢀ and C-5ꢀꢀ), 120.6 (2C,
20
74.42; H, 7.65. C28H35ClN2O requires C, 74.56; H, 7.82%). 1H NMR
(ı, ppm, CDCl3): 0.66 (s, 3H, 18-H3), 0.96 (s, 3H, 19-H3), 2.78 (t, 1H,
J = 9.3 Hz, 17-H), 3.47 (m, 1H, 3-H), 5.31 (s, 1H, 6-H), 6.30 (s, 1H,
4ꢀ-H), 7.31 (d, 2H, J = 8.3 Hz, 2ꢀꢀ- and 6ꢀꢀ-H), 7.44 (d, 2H, J = 8.3 Hz, 3ꢀꢀ-
and 5ꢀꢀ-H), 7.63 (s, 1H, 3ꢀ-H). 13C NMR (125 MHz, CDCl3, ı (ppm)):
13.3 (C-18), 19.3 (C-19), 20.6, 24.4, 29.4, 31.6, 31.7, 32.3, 36.5, 37.2,
37.4, 42.2, 44.6, 46.9, 49.9, 56.1, 71.6 (C-3), 106.0 (C-4ꢀ), 121.2 (C-6),

452
Z. Iványi et al. / Steroids 75 (2010) 450–456
C-2ꢀꢀ and C-6ꢀꢀ), 121.6 (C-6), 126.7, 134.3, 140.9, 154.7, 157.8. Con-
tinued elution with CH2Cl2 resulted in 6e (with Method A: 590 mg,
22%; with Method B: 2.10 g, 78%), mp 186–188 ◦C, Rf = 0.38 (ss A);
and 5ꢀꢀ-H), 7.78 (d, 1H, J = 3.0 Hz, 5ꢀ-H). 13C NMR (125 MHz, CDCl3,
ı (ppm)): 13.1 (C-18), 19.3 (C-19), 20.8, 21.4 (Ac-CH3), 24.6, 26.2,
27.8, 31.9, 32.3, 36.7, 37.0, 37.8, 38.1, 43.7, 50.3 (2C), 56.1, 73.9 (C-
3), 107.3 (C-4ꢀ), 119.8 (2C, C-2ꢀꢀ and C-6ꢀꢀ), 122.5 (C-6), 126.5 (C-5ꢀ),
129.3 (2C, C-3ꢀꢀ and C-5ꢀꢀ), 131.0 (C-4ꢀꢀ), 139.0 (C-1ꢀꢀ), 139.7 (C-5),
155.5 (C-3ꢀ), 170.4 (Ac-CO).
20
[␣]D −134 (c 1 in CHCl3) (found C, 77.84; H, 8.65. C29H38N2O2
requires C, 77.99; H, 8.58%). 1H NMR (ı, ppm, CDCl3): 0.68 (s, 3H,
18-H3), 0.97 (s, 3H, 19-H3), 2.77 (t, 1H, J = 8.3 Hz, 17-H), 3.49 (m,
1H, 3-H), 3.86 (s, 3H, O-CH3), 5.32 (d, 1H, J = 2.0 Hz, 6-H), 6.24 (d,
1H, J = 1.5 Hz, 4ꢀ-H), 6.95 (d, 2H, J = 7.0 Hz, 3ꢀꢀ- and 5ꢀꢀ-H), 7.26 (d,
2H, J = 7.0 Hz, 2ꢀꢀ- and 6ꢀꢀ-H), 7.57 (d, 1H, J = 1.5 Hz, 3ꢀ-H). 13C NMR
(125 MHz, CDCl3, ı (ppm)): 13.3 (C-18), 19.4 (C-19), 20.7, 24.4, 29.6,
31.6, 31.8, 32.3, 36.5, 37.2, 37.3, 42.2, 44.1, 47.0, 49.9, 55.5 (O-CH3),
56.0, 71.7 (C-3), 105.1 (C-4ꢀ), 114.0 (2C, C-3ꢀꢀ and C-5ꢀꢀ), 121.3 (C-6),
128.2 (2C, C-2ꢀꢀ and C-6ꢀꢀ), 133.4 (C-1ꢀꢀ), 139.0 (C-3ꢀ), 140.8 (C-5),
144.6 (C-5ꢀ), 159.3 (C-4ꢀꢀ).
2.3.4.
3ˇ-Acetoxy-17ˇ-(1-p-chlorophenyl-5-pyrazolyl)androst-5-ene
(8b)
8b (462 mg, 93%), mp 174–177 ◦C, Rf = 0.60 (ss B); [␣]D −151 (c
20
1 in CHCl3) (found C, 73.15, H, 7.68. C30H37N2ClO2 requires C, 73.08;
H, 7.56%). 1H NMR (ı, ppm, CDCl3): 0.66 (s, 3H, 18-H3), 0.97 (s, 3H,
19-H3), 2.02 (s, 3H, Ac-CH3), 2.79 (t, 1H, J = 9.8 Hz, 17-H), 4.57 (m,
1H, 3-H), 5.34 (d, 1H, J = 4.5 Hz, 6-H), 6.29 (s, 1H, 4ꢀ-H), 7.31 (d, 2H,
J = 8.5 Hz, 2ꢀꢀ- and 6ꢀꢀ-H), 7.44 (d, 2H, J = 8.5 Hz, 3ꢀꢀ- and 5ꢀꢀ-H), 7.63
(s, 1H, 3ꢀ-H). 13C NMR (125 MHz, CDCl3, ı (ppm)): 13.3 (C-18), 19.3
(C-19), 20.6, 21.4 (Ac-CH3), 24.5, 27.7, 29.4, 31.7, 32.2, 36.6, 36.9,
37.3, 38.0, 44.5, 46.9, 49.8, 56.0, 73.8 (C-3), 105.9 (C-4ꢀ), 122.2 (C-
6), 128.2 (2C, C-2ꢀꢀ and C-6ꢀꢀ), 129.3 (2C, C3ꢀꢀ and C-5ꢀꢀ), 134.4 (C-4ꢀꢀ),
138.1 (C-1ꢀꢀ), 139.1 (C-3ꢀ), 139.7 (C-5), 145.1 (C-5ꢀ), 170.5 (Ac-CO).
2.3. General procedure for preparation of 3ˇ-acetoxy-17ˇ-(1-
phenyl- and p-substituted-1-phenyl-3-pyrazolyl)androst-5-ene
(7a–e) and 3ˇ-acetoxy-17ˇ-(1-phenyl- and p-substituted-1-
phenyl-5-pyrazolyl)androst-5-ene(8a–e)
The individual compounds 5a–e and 6a–e (1 mmol) were dis-
solved in a mixture of pyridine (5 ml) and acetic anhydride (5 ml)
and the solution was allowed to stand at room temperature for
12 h. The mixture was then diluted with water and the precip-
itate that separated out was filtered off and crystallized from
acetone/hexane.
2.3.5.
3ˇ-Acetoxy-17ˇ-(1-p-cyanophenyl-3-pyrazolyl)androst-5-ene
(7c)
7c (452 mg, 93%), mp 242–244 ◦C, Rf = 0.58 (ss B); [␣]D −36 (c
20
1 in CHCl3) (found C, 76.84; H, 7.65. C31H37N3O2 requires C, 76.99;
H, 7.71%). 1H NMR (ı, ppm, CDCl3): 0.56 (s, 3H, 18-H3), 1.02 (s, 3H,
19-H3), 2.03 (s, 3H, Ac-CH3), 2.77 (t, 1H, J = 9.5 Hz, 17-H), 4.61 (m,
1H, 3-H), 5.40 (s, 1H, 6-H), 6.33 (d, 1H, J = 2.0 Hz, 4ꢀ-H), 7.70 (d, 2H,
J = 8.5 Hz, 2ꢀꢀ- and 6ꢀꢀ-H), 7.80 (d, 2H, J = 8.5 Hz, 3ꢀꢀ- and 5ꢀꢀ-H), 7.89
(d, 1H, J = 2.0 Hz, 5ꢀ-H). 13C NMR (125 MHz, CDCl3, ı (ppm)): 13.1
(C-18), 19.3 (C-19), 20.7, 21.4 (Ac-CH3) 24.6, 26.0, 27.7, 31.9, 32.2,
36.7, 37.0, 37.8, 38.1, 43.8, 50.1, 50.2, 56.1, 73.9 (C-3), 108.6 (C-4ꢀ),
118.3 (2C, C-2ꢀꢀ and C-6ꢀꢀ) 118.6 (CN), 122.4 (C-6), 126.7 (C-5ꢀ), 133.5
(2C, C3ꢀꢀ and C-5ꢀꢀ), 139.7, 143.1 (C-1ꢀꢀ), 156.7 (C-3ꢀ), 170.5 (Ac-CO).
2.3.1. 3ˇ-Acetoxy-17ˇ-(1-phenyl-3-pyrazolyl)androst-5-ene
(7a)
7a (420 mg, 91%), mp 140–143 ◦C, Rf = 0.77 (ss B); [␣]D −49 (c
20
1 in CHCl3) (found C, 78.42; H, 8.44. C30H38N2O2 requires C, 78.56;
H, 8.35%). 1H NMR (ı, ppm, CDCl3): 0.58 (s, 3H, 18-H3), 1.03 (s, 3H,
19-H3), 2.04 (s, 3H, Ac-CH3), 2.80 (t, 1H, J = 8.0 Hz, 17-H), 4.62 (m,
1H, 3-H), 5.41 (t, 1H, J = 2.3 Hz, 6-H), 6.27 (d, 1H, J = 2.0 Hz, 4ꢀ-H), 7.23
(t, 1H, J = 6.3 Hz, 4ꢀꢀ-H), 7.42 (t, 2H, J = 6.3 Hz, 3ꢀꢀ- and 5ꢀꢀ-H), 7.68 (d,
2H, J = 6.3 Hz, 2ꢀꢀ- and 6ꢀꢀ-H), 7.83 (d, 1H, J = 2.0 Hz, 5ꢀ-H). 13C NMR
(125 MHz, CDCl3, ı (ppm)): 13.1 (C-18), 19.4 (C-19), 20.8, 21.4 (Ac-
CH3), 24.7, 26.3, 27.8, 31.9, 32.3, 36.7, 37.0, 37.8, 38.1, 43.7, 50.2,
50.3, 56.1, 74.0 (C-3), 106.8 (C-4ꢀ), 118.8 (2C, C-2ꢀꢀ and C-6ꢀꢀ), 122.5
(C-6), 125.7, 126.6, 129.3 (2C, C-3ꢀꢀ and C-5ꢀꢀ), 139.8, 155.1, 156.1,
170.5 (Ac-CO).
2.3.6.
3ˇ-Acetoxy-17ˇ-(1-p-cyanophenyl-5-pyrazolyl)androst-5-ene
(8c)
8c (432 mg, 89%), mp 233–236 ◦C, Rf = 0.36 (ss B); [␣]D −122 (c
20
1 in CHCl3) (found C, 77.06; H, 7.65. C31H37N3O2 requires C, 76.99;
H, 7.71%). 1H NMR (ı, ppm, CDCl3): 0.63 (s, 3H, 18-H3), 0.97 (s, 3H,
19-H3), 2.01 (s, 3H, Ac-CH3) 2.88 (t, 1H, J = 9.8 Hz, 17-H), 4.57 (m,
1H, 3-H), 5.35 (d, 1H, J = 2.5 Hz, 6-H), 6.34 (s, 1H, 4ꢀ-H), 7.53 (d, 2H,
J = 8.3 Hz, 2ꢀꢀ- and 6ꢀꢀ-H), 7.65 (s, 1H, 3ꢀ-H), 7.77 (d, 2H, J = 8.3 Hz, 3ꢀꢀ-
and 5ꢀꢀ-H). 13C NMR (125 MHz, CDCl3, ı (ppm)): 13.3 (C-18), 19.2
(C-19), 20.6, 21.3 (Ac-CH3), 24.3, 27.7, 29.3, 31.7, 32.3, 36.6, 37.0,
37.4, 38.1, 44.7, 47.0, 49.8, 56.1, 73.7 (C-3), 106.8 (C-4ꢀ), 111.9 (C-
4ꢀꢀ), 118.0 (CN), 122.1 (C-6), 127.2 (2C, C-2ꢀꢀ and C-6ꢀꢀ), 133.0 (2C,
C3ꢀꢀ and C-5ꢀꢀ), 139.7 (C-5), 140.4 (C-3ꢀ), 143.9 and 144.7 (C-1ꢀꢀ and
C-5ꢀ), 170.4 (Ac-CO).
2.3.2. 3ˇ-Acetoxy-17ˇ-(1-phenyl-5-pyrazolyl)androst-5-ene
(8a)
8a (435 mg, 94%), mp 205–208 ◦C (Ref. [10]: mp 205–206 ◦C),
20
25
Rf = 0.45 (ss B); [␣]D −128 (c 1 in CHCl3) (Ref. [10]: [␣]D −110 (c
1 in CHCl3)) (found C, 78.33; H, 8.52. C30H38N2O2 requires C, 78.56;
H, 8.35%). 1H NMR (ı, ppm, CDCl3): 0.67 (s, 3H, 18-H3), 0.97 (s, 3H,
19-H3), 2.02 (s, 3H, Ac-CH3), 2.85 (t, 1H, J = 8.3 Hz), 4.56 (m, 1H,
3-H), 5.34 (d, 1H, J = 4.0 Hz, 6-H), 6.27 (d, 1H, J = 2.0 Hz, 4ꢀ-H), 7.35
(d, 2H, J = 6.3 Hz, 2ꢀꢀ- and 6ꢀꢀ-H), 7.41 (t, 1H, J = 6.3 Hz, 4ꢀꢀ-H), 7.46 (t,
2H, J = 6.3 Hz, 3ꢀꢀ- and 5ꢀꢀ-H), 7.60 (d, 1H, J = 2.0 Hz, 3ꢀ-H). 13C NMR
(125 MHz, CDCl3, ı (ppm)): 13.3 (C-18), 19.3 (C-19), 20.6, 21.4 (Ac-
CH3), 24.4, 27.7, 29.5, 31.7, 32.3, 36.9 (2C), 37.2, 38.1, 44.3, 46.9,
49.8, 55.9, 73.8 (C-3), 105.5 (C-4ꢀ), 122.3, 126.9 and 128.9 (4C, C-2ꢀꢀ,
C-3ꢀꢀ, C-5ꢀꢀ and C-6ꢀꢀ), 128.2, 139.3, 139.7 (C-5), 140.4, 144.4, 170.5
(Ac-CO).
2.3.7. 3ˇ-Acetoxy-17ˇ-(1-p-toly-3-pyrazolyl)androst-5-ene (7d)
7d (442 mg, 93%), mp 163–165 ◦C, Rf = 0.76 (ss B); [␣]D −47 (c 1
20
in CHCl3) (found C, 78.54; H, 8.77. C31H40N2O2 requires C, 78.77; H,
8.53%). 1H NMR (ı, ppm, CDCl3): 0.59 (s, 3H, 18-H3), 1.03 (s, 3H, 19-
H3), 2.03 (s, 3H, Ac-CH3), 2.37 (s, 3H, 4ꢀꢀ-CH3), 2.85 (t, 1H, J = 9.5 Hz,
17-H), 4.62 (m, 1H, 3-H), 5.41 (s, 1H, 6-H), 6.27 (s, 1H, 4ꢀ-H), 7.22 and
2.3.3. 3ˇ-Acetoxy-17ˇ-(1-p-chlorophenyl-3-pyrazolyl)androst-
5-ene (7b)
7.55 (d, 4H, J = 8.0 Hz, 2ꢀꢀ-, 3ꢀꢀ-, 5ꢀꢀ- and 6ꢀꢀ-H), 7.78 (s, 1H, 5ꢀ-H). 13
C
7b (475 mg, 96%), mp 173–175 ◦C, Rf = 0.77 (ss B); [␣]D −42 (c 1
20
NMR (125 MHz, CDCl3, ı (ppm)): 13.1 (C-18), 19.3 (C-19), 20.8, 20.9
(4ꢀꢀ-CH3), 21.4 (Ac-CH3), 24.7, 26.5, 27.8, 31.9, 32.3, 36.7, 37.1, 37.8,
38.1, 43.8, 50.1, 50.2, 56.1, 74.0 (C-3), 106.6 (C-4ꢀ), 119.1 (2C, C-2ꢀꢀ
and C-6ꢀꢀ), 122.5 (C-6), 126.9 (C-5ꢀ), 129.8 (2C, C-3ꢀꢀ and C-5ꢀꢀ), 135.8
and 137.8 (C-1ꢀꢀ and C-4ꢀꢀ) 139.8 (C-5), 154.7 (C-3ꢀ), 170.4 (Ac-CO).
in CHCl3) (found C, 72.95; H, 7.43. C30H37N2ClO2 requires C, 73.08;
H, 7.56%). 1H NMR (ı, ppm, CDCl3): 0.57 (s, 3H, 18-H3), 1.03 (s, 3H,
19-H3), 2.03 (s, 3H, Ac-CH3), 2.78 (t, 1H, J = 12.3 Hz, 17-H), 4.62 (m,
1H, 3-H), 5.40 (d, 1H, J = 5.5 Hz, 6-H), 6.27 (d, 1H, J = 3.0 Hz, 4ꢀ-H),
7.37 (d, 2H, J = 11.0 Hz, 2ꢀꢀ- and 6ꢀꢀ-H), 7.61 (d, 2H, J = 11.0 Hz, 3ꢀꢀ-

Z. Iványi et al. / Steroids 75 (2010) 450–456
453
C28H34N2O requires C, 81.12; H, 8.27%). 1H NMR (ı, ppm, CDCl3):
0.62 (s, 3H, 18-H3), 1.18 (s, 3H, 19-H3), 2.86 (t, 1H, J = 9.8 Hz, 17-H),
5.74 (s, 1H, 4-H), 6.28 (d, 1H, J = 2.0 Hz, 4ꢀ-H), 7.25 (t, 1H, J = 7.5 Hz,
4ꢀꢀ-H), 7.43 (t, 2H, J = 7.5 Hz, 3ꢀꢀ- and 5ꢀꢀ-H), 7.68 (d, 2H, J = 7.5 Hz, 2ꢀꢀ-
and 6ꢀꢀ-H), 7.84 (d, 1H, J = 2.0 Hz, 5ꢀ-H). 13C NMR (125 MHz, CDCl3,
ı (ppm)): 13.2 (C-18), 17.4 (C-19), 20.8, 24.5, 26.3, 32.0, 32.9, 34.0,
35.7, 36.1, 37.6, 38.7, 43.8, 50.0, 54.0, 55.3, 106.9 (C-4ꢀ), 119.0 (2C,
C-2ꢀꢀ and C-6ꢀꢀ), 123.8 (C-4), 126.1, 127.0 (C-5ꢀ), 129.3 (2C, C-3ꢀꢀ and
C-5ꢀꢀ), 139.9 (C-1ꢀꢀ), 154.8 (C-3ꢀ), 171.3 (C-5), 199.4 (C-3).
2.3.8. 3ˇ-Acetoxy-17ˇ-(1-p-tolyl-5-pyrazolyl)androst-5-ene
(8d)
8d (426 mg, 90%), mp 202–204 ◦C, Rf = 0.62 (ss B); [␣]D −120
(c 1 in CHCl3) (found 78.88; H, 8.35. C31H40N2O3 requires C, 78.77;
H, 8.53%).
20
1H NMR (ı, ppm, CDCl3): 0.68 (s, 3H, 18-H3), 0.98 (s, 3H, 19-
H3), 2.02 (s, 3H, Ac-CH3) 2.42 (s, 3H, 4ꢀꢀ-CH3), 2.82 (t, 1H, J = 9.8 Hz),
4.57 (t, 1H, J = 4.8 Hz, 3-H), 5.35 (s, 1H, 6-H), 6.25 (s, 1H, 4ꢀ-H), 7.24
(overlapping multiplets, 4H, 2ꢀꢀ-, 3ꢀꢀ-, 5ꢀꢀ-, 6ꢀꢀ-H), 7.58 (s, 1H, 3ꢀ-H).
13C NMR (125 MHz, CDCl3, ı (ppm)): 13.3 (C-18), 19.3 (C-19), 20.6,
21.2 (4ꢀꢀ-CH3), 21.4 (Ac-CH3) 24.4, 27.7, 29.6, 31.7, 32.3, 36.6, 37.0
37.2, 38.0, 44.2, 46.9, 49.8, 55.9, 73.8 (C-3), 105.2 (C-4ꢀ), 122.3 (C-6),
126.7 and 129.5 (4C, C-2ꢀꢀ, C-3ꢀꢀ, C-5ꢀꢀ and C-6ꢀꢀ), 137.8, 138.1, 139.1
(C-3ꢀ), 139.7 (C-5), 144.3, 170.5 (Ac-CO).
2.4.2. 17ˇ-(1-Phenyl-5-pyrazolyl)androst-4-en-3-one (10a)
10a (365 mg, 44%), mp 197–200 ◦C (Ref. [11]: mp 196–197 ◦C),
20
25
Rf = 0.55 (ss A); [␣]D +17 (c 1 in CHCl3) (Ref. [10]: [␣]D +10 (c
1 in CHCl3)) (found C, 80.97; H, 8.35. C28 34N2O requires C, 81.12;
H
H, 8.27%). 1H NMR (ı, ppm, CDCl3): 0.70 (s, 3H, 18-H3), 1.13 (s,
3H, 19-H3), 2.85 (t, 1H, J = 10.0 Hz, 17-H), 5.69 (s, 1H, 4-H), 6.31
(d, 1H, J = 1.8 Hz, 4ꢀ-H), 7.35 (d, 2H, J = 7.5 Hz, 2ꢀꢀ- and 6ꢀꢀ-H), 7.54
(overlapping multiplets, 3H, 3ꢀꢀ-, 4ꢀꢀ-, 5ꢀꢀ-H), 7.66 (d, 1H, J = 1.8 Hz,
3ꢀ-H). 13C NMR (125 MHz, CDCl3, ı (ppm)): 13.4 (C-18), 17.3 (C-19),
20.6, 24.3, 29.3, 31.8, 32.7, 33.9, 35.6, 36.0, 37.0, 38.5, 44.4, 46.8,
53.5, 55.1, 105.7 (C-4ꢀ), 123.8, 126.9 and 129.1 (4C, C-2ꢀꢀ, C-3ꢀꢀ, C-5ꢀꢀ
and C-6ꢀꢀ), 128.8, 138.5 (C-3ꢀ), 139.2 (C-1ꢀꢀ), 144.9 (C-5ꢀ), 170.8 (C-5),
199.3 (C-3).
2.3.9.
3ˇ-Acetoxy-17ˇ-(1-p-methoxyphenyl-3-pyrazolyl)androst-5-ene
(7e)
7e (420 mg, 86%), mp 175–179 ◦C, Rf = 0.65 (ss B); [␣]D −45 (c
20
1 in CHCl3) (found C, 75.98; H, 8.37; C31H40N2O3 requires C, 76.19;
H, 8.25%). 1H NMR (ı, ppm, CDCl3): 0.59 (s, 3H, 18-H3), 1.02 (s, 3H,
19-H3), 2.03 (s, 3H, Ac-CH3), 2.86 (t, 1H, J = 9.5 Hz, 17-H), 3.83 (s, 3H,
O-CH3), 4.62 (t, 1H, J = 5.3 Hz, 3-H), 5.40 (d, 1H, J = 4.5 Hz, 6-H), 6.26
(d, 1H, J = 2.0 Hz, 4ꢀ-H), 6.95 (d, 2H, J = 9.0 Hz, 3ꢀꢀ- and 5ꢀꢀ-H), 7.58 (d,
2H, J = 9.0 Hz, 2ꢀꢀ- and 6ꢀꢀ-H), 7.73 (d, 1H, J = 2.0 Hz, 5ꢀ-H). 13C NMR
(125 MHz, CDCl3, ı (ppm)): 13.1 (C-18), 19.3 (C-19), 20.8, 21.4 (Ac-
CH3), 24.6, 26.5, 27.8, 31.9, 32.3, 36.7, 37.0, 37.7, 38.1, 43.8, 49.9,
50.2, 55.6 (O-CH3), 56.1, 73.9 (C-3), 106.4 (C-4ꢀ), 114.5 (2C, C-3ꢀꢀ
and C-5ꢀꢀ), 120.9 (2C, C-2ꢀꢀ and C-6ꢀꢀ), 122.5 (C-6), 127.2 (C-5ꢀ), 133.6
(C-1ꢀꢀ), 139.8 (C-5), 154.5 (C-3ꢀ), 158.1 (C-4ꢀꢀ), 170.5 (Ac-CO).
2.4.3. 17ˇ-(1-p-Chlorophenyl-3-pyrazolyl)androst-4-en-3-
one (9b)
9b (352 mg, 39%), mp 164–167 ◦C, Rf = 0.60 (ss A); [␣]D20 +132 (c
1 in CHCl3) (found C, 75.02; H, 7.41. C28H33ClN2O requires C, 74.90;
H, 7.41%). 1H NMR (ı, ppm, CDCl3): 0.61 (s, 3H, 18-H3), 1.19 (s, 3H,
19-H3), 2.83 (d, 1H, J = 9.5 Hz), 5.74 (s, 1H, 4-H), 6.30 (d, 1H, J = 2.0 Hz,
4ꢀ-H), 7.39 (d, 2H, J = 8.3 Hz, 2ꢀꢀ- and 6ꢀꢀ-H), 7.63 (d, 2H, J = 8.3 Hz, 3ꢀꢀ-
and 5ꢀꢀ-H), 7.81 (d, 1H, J = 2.0 Hz, 5ꢀ-H). 13C NMR (125 MHz, CDCl3,
ı (ppm)): 13.2 (C-18), 17.4 (C-19), 20.8, 24.5, 26.3, 32.0, 32.9, 34.0,
35.7, 36.0, 37.6, 38.7, 43.9, 49.9, 54.0, 55.3, 107.3 (C-4ꢀ), 120.1 (2C,
C-2ꢀꢀ and C-6ꢀꢀ), 123.8 (C-4), 127.0 (C-5ꢀ), 129.3 (2C, C-3ꢀꢀ and C-5ꢀꢀ),
131.5 (C-4ꢀꢀ), 138.5 (C-1ꢀꢀ), 155.2 (C-3ꢀ), 171.3 (C-5), 199.5 (C-3).
2.3.10.
3ˇ-Acetoxy-17ˇ-(1-p-methoxyphenyl-5-pyrazolyl)androst-5-ene
(8e)
8e (438 mg, 89%), mp 153–156 ◦C, Rf = 0.30 (ss B); [␣]D −124 (c
20
1 in CHCl3) (found C, 76.05; H, 8.42. C31H40N2O3 requires C, 76.19;
H, 8.25%). 1H NMR (ı, ppm, CDCl3): 0.67 (s, 3H, 18-H3), 0.98 (s, 3H,
19-H3), 2.02 (s, 3H, Ac-CH3), 2.77 (t, 1H, J = 9.5 Hz, 17-H), 3.86 (s,
3H, O-CH3), 4.57 (m, 1H, 3-H), 5.35 (s, 1H, 6-H), 6.24 (s, 1H, 4ꢀ-H),
6.95 (d, 2H, J = 8.8 Hz, 3ꢀꢀ- and 5ꢀꢀ-H), 7.25 (d, 2H, J = 8.8 Hz, 2ꢀꢀ- and
6ꢀꢀ-H), 7.57 (s, 1H, 3ꢀ-H). 13C NMR (125 MHz, CDCl3, ı (ppm)): 13.3
(C-18), 19.2 (C-19), 20.6, 21.4 (Ac-CH3) 24.4, 27.7, 29.6, 31.7, 32.2,
36.6, 36.9, 37.2, 38.0, 44.1, 46.9, 49.8, 55.5 (O-CH3), 55.9, 73.8 (C-3),
105.1 (C-4ꢀ), 114.0 (2C, C-3ꢀꢀ and C-5ꢀꢀ), 122.3 (C-6), 128.2 (2C, C-2ꢀꢀ
and C-6ꢀꢀ), 133.3 (C-1ꢀꢀ), 139.0 (C-3ꢀ), 139.7 (C-5), 144.5 (C-5ꢀ), 159.3
(C-4ꢀꢀ), 170.5 (Ac-CO).
2.4.4. 17ˇ-(1-p-Chlorophenyl-5-pyrazolyl)androst-4-en-3-
one (10b)
10b (280 mg, 44%), mp 186–189 ◦C, Rf = 0.56 (ss A); [␣]D −6
20
(c 1 in CHCl3) (found C, 74.81; H, 7.63. C28H33ClN2O requires C,
74.90; H, 7.41%). 1H NMR (ı, ppm, CDCl3): 0.68 (s, 3H, 18-H3), 1.13
(s, 3H, 19-H3), 2.80 (t, 1H, J = 9.8 Hz, 17-H), 5.69 (s, 1H, 4-H), 6.29
(d, 1H, J = 1.3 Hz, 4ꢀ-H), 7.29 (d, 2H, J = 8.5 Hz, 2ꢀꢀ- and 6ꢀꢀ-H), 7.43 (d,
2H, J = 8.5 Hz, 3ꢀꢀ- and 5ꢀꢀ-H), 7.62 (d, 1H, J = 1.3 Hz, 3ꢀ-H). 13C NMR
(125 MHz, CDCl3, ı (ppm)): 13.4 (C-18), 17.3 (C-19), 20.6, 24.2, 29.3,
31.8, 32.7, 33.9, 35.6, 36.0, 37.2, 38.5, 44.5, 46.8, 53.5, 55.2, 106.0
(C-4ꢀ), 123.9 (C-4), 128.1 (2C, C-2ꢀꢀ and C-6ꢀꢀ), 129.3 (2C, C-3ꢀꢀ and
C-5ꢀꢀ), 134.5 (C-4ꢀꢀ), 138.3 (C-1ꢀꢀ), 139.2 (C-3ꢀ), 145.0 (C-5ꢀ), 170.7
(C-5), 199.2 (C-3).
2.4. General procedure for the preparation of 17ˇ-(1-phenyl-,
and p-substituted-1-phenyl-3-pyrazolyl)androst-4-en-3-one
(9a–e) and 17ˇ-(1-phenyl-, and
p-substituted-1-phenyl-5-pyrazolyl)androst-4-en-3-one (10a–e)
The individual compounds 5a–e and 6a–e (2 mmol) were
dissolved in toluene (50 ml), Al(OiPr)3 (1.2 g, 6 mmol) and cyclohex-
anone (25 ml) were added, and the mixture was stirred at 100 ◦C.
The decrease in the starting material was followed by means of
TLC. When the reaction was complete, the mixture was poured into
water (200 ml) in which K/Na-tartrate (5 g) was dissolved. Most of
the organic solvent was removed in vacuo and the residual emul-
sion was extracted with CH2Cl2. The organic phase was evaporated
to dryness and the residual product was chromatographed on silica
gel with ethyl acetate/CH2Cl2 (5:95).
2.4.5. 17ˇ-(1-p-Cyanophenyl-3-pyrazolyl)androst-4-en-3-
one (9c)
9c (186 mg, 21%), mp 240–242 ◦C, Rf = 0.55 (ss A); [␣]D20 +149 (c
1 in CHCl3) (found C, 79.04; H, 7.72. C29H33N3O requires C, 79.24;
H, 7.57%). 1H NMR (ı, ppm, CDCl3): 0.59 (s, 3H, 18-H3), 1.18 (s, 3H,
19-H3), 2.78 (t, 1H, J = 9.5 Hz, 17-H), 5.74 (s, 1H, 4-H), 6.33 (s, 1H,
4ꢀ-H), 7.70 (d, 2H, J = 8.5 Hz, 2ꢀꢀ- and 6ꢀꢀ-H), 7.80 (d, 2H, J = 8.5 Hz, 3ꢀꢀ-
and 5ꢀꢀ-H), 7.90 (s, 1H, 5ꢀ-H). 13C NMR (125 MHz, CDCl3, ı (ppm)):
13.1 (C-18), 17.3 (C-19), 20.7, 24.4, 25.9, 31.9, 32.8, 33.9, 35.7, 35.9,
37.6, 38.6, 43.8, 50.1 53.9, 55.3, 108.5 (C-4ꢀ), 118.3 (2C, C-2ꢀꢀ and
C-6ꢀꢀ) 118.6 (CN), 123.8 (C-4), 126.7 (C-5ꢀ), 133.8 (2C, C3ꢀꢀ and C-5ꢀꢀ),
143.0 (C-1ꢀꢀ), 156.4 (C-3ꢀ), 171.4 (C-5), 199.5 (C-3).
2.4.1. 17ˇ-(1-Phenyl-3-pyrazolyl)androst-4-en-3-one (9a)
9a (310 mg, 37%), mp 196–198 ◦C (Ref. [11]: mp 97–99 ◦C),
20
Rf = 0.67 (ss A); [␣]D +147 (c 1 in CHCl3) (found C, 81.29; H, 8.02.

454
Z. Iványi et al. / Steroids 75 (2010) 450–456
2.4.6. 17ˇ-(1-p-Cyanophenyl-5-pyrazolyl)androst-4-en-3-
one (10c)
2.5. Determination of C17,20-lyase activity and its inhibition in
the rat testis
10c (230 mg, 26%), mp 217–219 ◦C, Rf = 0.47 (ss A); [␣]D +8 (c
1 in CHCl3) (found C, 79.38;, 7.63. C29H33N3O requires C, 79.24;
H, 7.57%). 1H NMR (ı, ppm, CDCl3): 0.65 (s, 3H, 18-H3), 1.12 (s,
3H, 19-H3), 2.88 (t, 1H, J = 9.8 Hz, 17-H), 5.69 (s, 1H, 4-H), 6.34 (d,
1H, J = 1.8 Hz, 4ꢀ-H), 7.51 (d, 2H, J = 8.5 Hz, 2ꢀꢀ- and 6ꢀꢀ-H), 7.65 (d,
1H, J = 1.8 Hz, 3ꢀ-H), 7.60 (d, 2H, J = 8.5 Hz, 3ꢀꢀ- and 5ꢀꢀ-H). 13C NMR
(125 MHz, CDCl3, ı (ppm)): 13.4 (C-18), 17.3 (C-19), 20.6, 24.2, 29.1,
31.8, 32.7, 33.8, 35.6, 36.0, 37.2, 38.5, 44.7, 46.9, 53.5, 55.3, 106.9
(C-4ꢀ), 112.0 (C-4ꢀꢀ), 118.0 (CN), 123.9 (C-4), 127.2 (2C, C-2ꢀꢀ and C-
6ꢀꢀ), 133.1 (2C, C3ꢀꢀ and C-5ꢀꢀ), 140.3 (C-3ꢀ), 143.8 and 144.5 (C-1ꢀꢀ
and C-5ꢀ), 170.5 (C-5), 199.1 (C-3).
20
Inhibitory effects exerted on the
C17,20-lyase activity by
the newly synthesized 17␤-(1-phenyl- and p-substituted-1-
phenylpyrazolyl) steroids (5a–e, 6a–e and 9a–e, 10a–e) were
determined by an in vitro radiosubstrate incubation method
described in earlier publications [7–9].
3. Results and discussion
3.1. Synthetic studies
The reaction between a monosubstituted hydrazine and a
nonsymmetrical ␤-ketoaldehyde leads to the formation of a mix-
ture of pyrazole isomers, even when one of them is present
in a very small amount and the process can be considered
regioselective [12]. In this manner, the reaction of 3␤-hydroxy-21-
hydroxymethylidenepregn-5-en-20-one (1) with methylhydrazine
affords two regioisomers, 17␤-(1-methyl-3-pyrazolyl)androst-5-
en-3␤-ol and 17␤-(1-methyl-5-pyrazoly)androst-5-en-3␤-ol, in
a ratio of 2:1. Despite this observation with methylhydrazine,
Doorenbos and Milewich found that the reaction of 1 with phenyl-
hydrazine in acetic acid or ethanol afforded N-phenylpyrazolyl
derivative 6a in good yield, as the sole product [10]. It is
known that the ␤-nitrogen atom of phenylhydrazine is the
2.4.7. 17ˇ-(1-p-Tolyl-3-pyrazolyl)androst-4-en-3-one (9d)
9d (295 mg, 34%), mp 214–216 ◦C, Rf = 0.65 (ss A); [␣]D20 +131 (c
1 in CHCl3) (found C, 81.06; H, 8.55. C29H36N2O2 requires C, 81.27;
H, 8.47%). 1H NMR (ı, ppm, CDCl3): 0.61 (s, 3H, 18-H3), 1.18 (s, 3H,
19-H3), 2.36 (s, 3H, 4ꢀꢀ-CH3), 2.82 (t, 1H, J = 9.8 Hz, 17-H), 5.74 (s, 1H,
4-H,), 6.24 (d, 1H, J = 2.5 Hz, 4ꢀ-H), 7.21 and 7.54: (d, 4H, J = 8.0 Hz,
2ꢀꢀ-, 3ꢀꢀ-, 5ꢀꢀ-, 6ꢀꢀ-H), 7.78 (d, 1H, J = 2.5 Hz, 5ꢀ-H). 13C NMR (125 MHz,
CDCl3, ı (ppm)): 13.2 (C-18), 17.4 (C-19), 20.8, 20.9 (4ꢀꢀ-CH3), 24.5,
26.3, 32.1, 32.9, 34.0, 35.7, 36.1, 37.7, 38.7, 43.7, 50.1, 54.0, 55.3,
106.5 (C-4ꢀ), 118.9 (2C, C-2ꢀꢀ and C-6ꢀꢀ), 123.8 (C-4), 126.7 (C-5ꢀ),
129.8 (2C, C-3ꢀꢀ and C-5ꢀꢀ), 135.7 and 138.0: (C-1ꢀꢀ and C-4ꢀꢀ), 154.5
(C-3ꢀ), 171.3 (C-5), 199.4 (C-3).
most nucleophilic and that the aldehyde
C atom in a ␤-
2.4.8. 17ˇ-(1-p-Tolyl-5-pyrazolyl)androst-4-en-3-one (10d)
ketoaldehyde is the most susceptible to nucleophilic attack.
The isolated compound was therefore expected to be 17␤-
(1-phenyl-5-pyrazolyl)androst-5-en-3␤-ol (6a). The assignment
of this structure was confirmed when ␤-ketoaldehyde 1 was
treated with 2-phenylsemicarbazide in an acetate buffered
medium to give the 3␤-hydroxy-21-formylpregn-5-en-20-one 22-
(2-phenyl-semicarbazone) derivative, pyrolysis of which yielded
an N-phenylpyrazole as the sole product, which proved to be iden-
tical with 6a.
10d (342 mg, 39%), mp 208–210 ◦C, Rf = 0.52 (ss A); [␣]D −9 (c 1
20
in CHCl3) (found C, 81.36; H, 8.22. C29H36N2O2 requires C, 81.27; H,
8.47%). 1H NMR (ı, ppm, CDCl3): 0.70 (s, 3H, 18-H3), 1.13 (s, 3H, 19-
H3), 2.41 (s, 3H, 4ꢀꢀ-CH3), 2.82 (t, 1H, J = 10.0 Hz, 17-H), 5.69 (s, 1H,
4-H,), 6.27 (d, 1H, J = 1.8 Hz, 4ꢀ-H), 7.23 (overlapping multiplets, 4H,
2ꢀꢀ-, 3ꢀꢀ-, 5ꢀꢀ-, 6ꢀꢀ-H), 7.60 (d, 1H, J = 1.8 Hz, 3ꢀ-H). 13C NMR (125 MHz,
CDCl3, ı (ppm)): 13.4 (C-18), 17.3 (C-19), 20.6, 21.2 (4ꢀꢀ-CH3), 24.3,
29.4, 31.9, 32.7, 33.9, 35.7, 36.0, 37.1, 38.6, 44.4, 46.8, 53.5, 55.1,
105.5 (C-4ꢀ), 123.8 (C-4), 126.7 (2C, C-2ꢀꢀ and C-6ꢀꢀ), 129.6 (2C, C-3ꢀꢀ
and C-5ꢀꢀ), 138.3, 138.7, 138.8, 144.8, 170.8 (C-5), 199.3 (C-3).
We found that, in contrast with the earlier literature obser-
vation, the reaction of 1 with phenylhydrazine hydrochloride in
the presence of potassium acetate in acetic acid solution at room
temperature for 6 h afforded two compounds in a ratio of 2:3.
After chromatographic separation, the minor compound proved
to be 17␤-(1-phenyl-3-pyrazolyl)androst-5-en-3␤-ol (5a), while
the major compound was 17␤-(1-phenyl-5-pyrazolyl)androst-5-
en-3␤-ol (6a). The direction of the ring-closure reactions of 1 with
p-substituted phenylhydrazines (2b–e) depended strongly on the
electronic features of the substituents on the aromatic moiety.
Substituents with an electron-withdrawing character (Cl and CN)
afforded predominantly 5-pyrazolyl derivatives 6b–c. Electron-
donating substituents (CH3 and OCH3) gave mainly 3-pyrazolyl
compounds 5d–e. On theoretical grounds, 1 could exist in either of
the tautomeric forms 1a or 1b, or as some equilibrium mixture of
them. In acetic acid medium, 1b is in dynamic equilibrium with 1a
as indicated by the NMR spectrum in acetic acid-d4. The spectrum
in deuteriochloroform demonstrated that 1a was the main form
present in this solvent [10]. An electron-withdrawing substituent
in the p position in phenylhydrazine decreases the electron density
and the nucleophilicity of the N atom. The favored step in this case
is the reaction of the phenylhydrazine with the more reactive free
C-21 aldehyde group of 1b in the equilibrium mixture. The second
step is the ring-closure process, resulting in 5-pyrazolyl deriva-
tives. Substituents with an electron-donating character increase
the electron density and nucleophilicity of the substituted phenyl-
hydrazines, which react with both the C-20 keto and C-21 formyl
groups in 1a and 1b, resulting predominantly in 3-pyrazolyl deriva-
tives. We found moreover that in CH2Cl2 solution, in the presence
of BF3·OEt2, the formation of 3-pyrazolyl derivatives was increased.
2.4.9. 17ˇ-(1-p-Methoxyphenyl-3-pyrazolyl)androst-4-en-3-
one (9e)
9e (258 mg, 29%), mp 192–194 ◦C, Rf = 0.58 (ss A); [␣]D20 +126 (c
1 in CHCl3) (found C, 77.92; H, 8.45. C28H36N2O2 requires C, 77.74;
H, 8.39%). 1H NMR (ı, ppm, CDCl3): 0.61 (s, 3H, 18-H3), 1.19 (s, 3H,
19-H3), 2.80 (t, 1H, J = 9.3 Hz, 17-H), 3.83 (s, 3H, O-CH3), 5.74 (s, 1H,
4-H), 6.23 (s, 1H, 4ꢀ-H), 6.94 (d, 2H, J = 7.8 Hz, 3ꢀꢀ- and 5ꢀꢀ-H), 7.56 (d,
2H, J = 7.8 Hz, 2ꢀꢀ- and 6ꢀꢀ-H), 7.73 (s, 1H, 5ꢀ-H). 13C NMR (125 MHz,
CDCl3, ı (ppm)): 13.1 (C-18), 17.4 (C-19), 20.7, 24.5, 26.3, 32.0, 32.9,
33.9, 35.7, 36.0, 37.6, 38.7, 43.7, 50.1, 54.0, 55.3, 55.5 (O-CH3), 106.3
(C-4ꢀ), 114.4 (2C, C-3ꢀꢀ and C-5ꢀꢀ), 120.5 (2C, C-2ꢀꢀ and C-6ꢀꢀ), 123.8
(C-4), 126.7 (C-5ꢀ), 134.2 (C-1ꢀꢀ), 154.3 (C-3ꢀ), 157.8 (C-4ꢀꢀ), 171.5
(C-5), 199.6 (C-3).
2.4.10. 17ˇ-(1-p-Methoxyphenyl-5-pyrazolyl)androst-4-en-3-
one (10e)
10e (315 mg, 36%), mp 211–214 ◦C, Rf = 0.44 (ss A); [␣]D −13 (c
20
1 in CHCl3) (found C, 77.54; H, 8.36. C28H36N2O2 requires C, 77.74;
H, 8.39%). 1H NMR (ı, ppm, CDCl3): 0.69 (s, 3H, 18-H3), 1.13 (s, 3H,
19-H3), 2.78 (t, 1H, J = 9.8 Hz, 17-H), 3.85 (s, 3H, O-CH3), 5.69 (s, 1H,
4-H), 6.24 (s, 1H, 4ꢀ-H), 6.94 (d, 2H, J = 8.5 Hz, 3ꢀꢀ- and 5ꢀꢀ-H), 7.23 (d,
2H, J = 8.5 Hz, 2ꢀꢀ- and 6ꢀꢀ-H), 7.57 (s, 1H, 3ꢀ-H). 13C NMR (125 MHz,
CDCl3, ı (ppm)): 13.4 (C-18), 17.3 (C-19), 20.6, 24.2, 29.4, 31.8, 32.7,
33.9, 35.6, 35.9, 37.1, 38.5, 44.1, 46.8, 53.5, 55.1, 55.5 (O-CH3), 105.2
(C-4ꢀ), 114.0 (2C, C-3ꢀꢀ and C-5ꢀꢀ), 123.8 (C-4), 128.1 (2C, C-2ꢀꢀ and
C-6ꢀꢀ), 133.0 (C-1ꢀꢀ), 138.9 (C-3ꢀ), 144.3 (C-5ꢀ), 159.3 (C-4ꢀꢀ), 171.0
(C-5), 199.4 (C-3).

Z. Iványi et al. / Steroids 75 (2010) 450–456
455
Scheme 1. Reagents and conditions: (i) acetic acid, phenylhydrazine or substituted phenylhydrazine, KOAc, rt, 6 h; (ii) pyridine, acetic anhydride, rt, 12 h and (iii) Al(OiPr)3,
cyclohexanone, toluene, reflux.
We presumed that 1a is the main form in this solvent system, and is
favorable for the first step of the reaction of phenylhydrazine with
the C-20 ketone, resulting mainly in 3-pyrazolyl compounds. Oppe-
nauer oxidation of the 3␤-hydroxy compounds 5a–e and 6a–e lead
to the corresponding ꢀ4-3-ketosteroids without any degradation
of the exo-heterocyclic system (Scheme 1).
The optical rotation of the compounds, measured in CHCl3,
20
shows a characteristic picture. The [␣]D
values of 5a–e are
between −47 and −63, while those of 6a–e are between −128
and −133. For the ꢀ4-3-ketosteroids, the corresponding values are
less negative: for 9a–e between −13 and +17, or positive for 10a–e
between +125 and +149.

456
Z. Iványi et al. / Steroids 75 (2010) 450–456
Table 1
an in vitro radiosubstrate incubation technique. Enzyme incuba-
Inhibition of C17,20-lyase activity.
tions with 5c, 5d, 6c and 6e resulted in conversions identical to
those in the control experiments, and hence these compounds did
not inhibit rat C17,20-lyase in vitro even in the rather high concen-
tration of 50 ␮M (Table 1). Most of the other derivatives exhibited
weak inhibition: 5a, 5d, 5e, 6a, 6b, 6d, 9a, 9b, 9d and 10a–e reduced
the enzyme activity by 65–95% when applied at 50 ␮M in the incu-
bates. The p-cyano and p-methoxy derivatives in the ꢀ4-3-oxo
series of the 3-pyrazolyl compounds (9c and 9e) displayed higher
inhibitory effects. The relative conversions at 50 ␮M were 34% and
54%, and IC50 values for these compounds were 22 ␮M and 59 ␮M,
respectively.
The tested compounds did not display efficient inhibition
of rat testicular C17,20-lyase activity in vitro. Only 17␤-(1-p-
cyanophenyl-3-pyrazolyl)androst-4-en-3-one (9c) and 17␤-(1-
p-methoxyphenyl-3-pyrazolyl)androst-4-en-3-one (9e) exerted
somewhat higher, but still weak inhibition. The inhibitory poten-
tials of these two compounds were found to be 100–150 times
weaker than that of the reference ketoconazole. With the only
exception of the 1-phenyl-3-pyrazolyl derivatives (5a and 9a),
the ꢀ4-3-keto compounds were found to be stronger or at least
equally effective C17,20-lyase inhibitors than their 3␤-hydroxy
counterparts. Nevertheless, no systematic difference was observed
between the 3- and 5-pyrazolyl regioisomers, and different sub-
stituents on the phenyl ring did not influence the inhibition
significantly. Investigations are planned to explore other presumed
antiandrogenic properties of the new compounds.
Compounds
Relative conversion,
mean S.D. (%)
IC50 S.D. (␮M)
5a
5b
5c
5d
5e
6a
6b
6c
6d
6e
9a
9b
9c
9d
9e
10a
65
NI
NI
93
95
92
74
NI
89
NI
86
91
34
92
54
87
78
69
86
91
6
4
4
5
3
5
2
5
1
2
2
6
1
1
4
6
22
59
1
2
10b
10c
10d
10e
Ketoconazole (reference)
0.35 0.05
NI: no inhibition.
S.D.: standard deviation.
Relative conversions (the 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.
The structures of the newly synthesized steroidal pyrazoles
5a–e, 6a–e, 7a–e, 8a–e, 9a–e and 10a–e were determined by NMR
spectroscopy. In the 1H NMR spectra, the signals of the phenyl (or
p-substituted phenyl) group appear in the aromatic region. In the
case of the 3-pyrazolyl steroids (5a–e, 7a–e and 9a–e), 4ꢀ-H on the
heteroaromatic ring resonates at ı = 6.23–6.34 ppm, while the sig-
nal of 5ꢀ-H can be found at lower fields: ı = 7.72–7.90 ppm. 4ꢀ-H of
the 5-pyrazolyl derivatives (6a–e, 8a–e and 10a–e) can be observed
at 6.24–6.35 ppm, and 3ꢀ-H at 7.57–7.67 ppm. The 13C NMR spectra
of the synthesized steroids also contain the signals of the heteroaro-
matic ring, one for C-4ꢀ at ∼106 ppm, the C-5ꢀ signal at ∼127 ppm
(5a–e, 7a–e and 9a–e), and the C-3ꢀ signal at ∼139 ppm (6a–e, 8a–e
and 10a–e). In 5a–e and 6a–e, the multiplet at ∼3.50 ppm can be
assigned to 3-H. Acetylation resulted in a shift of the 3-H signal
toward lower fields (ı ∼ 4.60 ppm), while the Ac-CH3 group res-
onates at ı ∼ 2.02 ppm in the 1H NMR spectra, and at ı = 21.4 in the
13C NMR spectra (7a–e and 8a–e). In the Oppenauer products (9a–e
and 10a–e), 4-(sp2-)H is to be found at ı = 5.69–5.74 ppm (singlet)
in the 1H NMR spectra, and the 3-H signal disappears, while the
C-3s resonate at ∼199.5 ppm (13C).
Acknowledgments
This work was supported by the Hungarian Scientific Research
Fund (OTKA K7309) and New Hungary Development Plan (TÁMOP
4.2.2-08/01-2008-0002). Mihály Szécsiꢀ s work was supported by
the award of a Bolyai János Research Fellowship.
References
[1] Schneider G, Wölfling J. Synthetic cardenolides and related compounds. Curr
Org Chem 2004;8:1381–403.
[2] Jarman M, Barrie SE, Llera JM. The 16,17-double bond is needed for
irreversible inhibition of human cytochrome P45017␣ by abiraterone [17-(3-
pyridyl)androst-5,16-di-en-3␤-ol] and related steroid inhibitors. J Med Chem
1998:415375–81.
[3] Ling YZ, Li JS, Liu Y, Kato K, Klus GT, Brodie AMH. 17-Imidazolyl, pyra-
zolyl and isoxazolyl androstene derivatives. Novel steroid inhibitors of human
cytochrome C17,20-lyase (P45017␣). J Med Chem 1997;40:3297–304.
[4] Njar VCO, Kato K, Nnane IP, Grigoryev DM, Long BJ, Brodie AMH. Novel 17-azolyl
steroids, potent inhibitors of human cytochrome 17␣-hydroxylase-C17,20-lyase
(P45017␣): potent agent for the treatment of prostate cancer. J Med Chem
1998;41:902–12.
[5] Zhu N, Ling Y, Lei X, Handratta V, Brodie AMH. Novel P45017␣ inhibitors:
17-(2ꢀ-oxazolyl)- and 17-(2ꢀ-thiazolyl)-androstene derivatives. Steroids
2003;68:603–11.
Apart from 17␤-(1-phenyl-5-pyrazolyl)androst-5-en-3␤-ol
(6a) and 17␤-(1-phenyl-5-pyrazolyl)androst-4-en-3-one (10a) in
the ꢀ4-3-keto series, 17␤-(1-phenyl-3-pyrazolyl)androst-5-en-
3␤-ol (5a) and the substituted derivatives 5b–e and 6b–e appear to
be unknown in the literature. The ꢀ4-3-keto compounds 9b–e and
10b–e have not been synthesized earlier either. Mohareb and Hana
recently reacted 21-N,N-dimethylaminomethylidene-pregn-4-en-
3-one with phenylhydrazine and obtained a compound presumed
to be 17␤-(1-phenyl-3-pyrazolyl)androst-4-en-3-one (9a) [11].
The melting point differs by 100 ◦C from that of ours, the NMR data
did not fully support postulated structure of 9a, and the optical
rotation was not reported.
[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.
[7] Wölfling J, Oravecz EA, Ondré D, Mernyák E, Schneider G, Tóth I, et al. Stereos-
elective synthesis of some 17␤-dihydrooxazinyl steroids, as novel presumed
inhibitors of 17␣-hydroxylase-C17,20-lyase. Steroids 2006;71:809–16.
[8] Ondré D, Wölfling J, Iványi Z, Schneider G, Tóth I, Szécsi M, et al. Neighbor-
ing group participation. Part 17. Stereoselective synthesis of some steroidal
2-oxazolidones, as novel potential inhibitors of 17␣-hydroxylase-C17,20-lyase.
Steroids 2008;73:1375–84.
[9] Ondré D, Wölfling J, Tóth I, Szécsi M, Julesz J, Schneider G. Stereoselective
synthesis of some steroidal oxazolines, as novel potential inhibitors of 17␣-
hydroxylase-C17,20-lyase. Steroids 2009;74:1025–32.
[10] Doorenbos NJ, Milewich L. 17␤-Isoxazoyl and 17␤-pyrazolyl steroids from
3␤-hydroxy-21-formylpregn-5-en-20-one. Structural assignments. J Org Chem
1966;31:3193–9.
3.2. Effects of 17ˇ-N-phenylpyrazolyl steroids on C17,20-lyase
activity
[11] Mohareb RM, Hana HY. Synthesis of progesterone heterocyclic derivatives of
potential antimicrobal activity. Acta Pharm 2008;58:29–42.
[12] Singh SP, Kumar D, Batra H, Naithani R, Rozas I, Elguero J. The reaction between
hydrazines and ␤-dicarbonyl compounds: proposal for a mechanism. Can J
Chem 2000;78:1109–20.
The inhibitory effects of 5a–e, 6a–e, 9a–e and 10a–e on the
C
17,20-lyase activity of rat testicular P45017␣ were investigated with