Anti-inflammatory 17beta-thioalkyl-16alpha,17alpha-ketal and -acetal androstanes: a new class of airway selective steroids for the treatment of asthma.

Article abstract of DOI:10.1021/jm9604639

The synthesis and anti-inflammatory potencies of a new class of 17beta-thioalkyl-16alpha,17alpha-ketal and -acetal androstanes are described. This new class of steroids was made by fragmentation of 2-thioxo-1,2-dihydropyrid-1-yl esters of the corresponding 17-acids to the 17-radical. The radical generated was trapped using a variety of radicophilic disulfides, giving a steroidal D-ring having acetal or ketal functionality at C-16 and C-17, together with a sulfide link at C-17. Compounds from this series bind to the glucocorticoid receptor with high potency and are functional agonists as measured by their ability to induce tyrosine aminotransferase activity in a rat hepatic cell line in vitro. These 17beta-thioalkyl androstanes potently inhibit Sephadex-induced rat lung inflammation when administered directly into the airways. The high topical potency, together with a low propensity to induce systemic glucocorticoid-like side effects (rat thymus involution), provides the present compounds with a high degree of airway selectivity compared with currently available inhaled glucocorticoids. The presently described 17beta-thioalkyl-16alpha,17alpha-ketal androstanes may be useful for therapies for inflammatory diseases such as asthma.

Full text of DOI:10.1021/jm9604639

4888
J . Med. Chem. 1996, 39, 4888-4896
An ti-in fla m m a tor y 17â-Th ioa lk yl-16r,17r-k eta l a n d -a ceta l An d r osta n es: A New
Cla ss of Air w a y Selective Ster oid s for th e Tr ea tm en t of Asth m a
Michael J . Ashton,* Christopher Lawrence, J an-Anders Karlsson, Keith A. J . Stuttle, Christopher G. Newton,
Bernard Y. J . Vacher, Stephen Webber, and Michael J . Withnall
Dagenham Research Centre, Rhoˆne-Poulenc Rorer Central Research, Rainham Road South, Dagenham, Essex RM10 7XS, U.K.
Received J une 27, 1996X
The synthesis and anti-inflammatory potencies of a new class of 17â-thioalkyl-16R,17R-ketal
and -acetal androstanes are described. This new class of steroids was made by fragmentation
of 2-thioxo-1,2-dihydropyrid-1-yl esters of the corresponding 17-acids to the 17-radical. The
radical generated was trapped using a variety of radicophilic disulfides, giving a steroidal D-ring
having acetal or ketal functionality at C-16 and C-17, together with a sulfide link at C-17.
Compounds from this series bind to the glucocorticoid receptor with high potency and are
functional agonists as measured by their ability to induce tyrosine aminotransferase activity
in a rat hepatic cell line in vitro. These 17â-thioalkyl androstanes potently inhibit Sephadex-
induced rat lung inflammation when administered directly into the airways. The high topical
potency, together with a low propensity to induce systemic glucocorticoid-like side effects (rat
thymus involution), provides the present compounds with a high degree of airway selectivity
compared with currently available inhaled glucocorticoids. The presently described 17â-
thioalkyl-16R,17R-ketal androstanes may be useful for therapies for inflammatory diseases
such as asthma.
In tr od u ction
Asthma is a chronic inflammatory disease of the
airways which is characterized by variable airflow
obstruction and bronchial hyperresponsiveness. Media-
tor and cytokine release from eosinophils, lymphocytes,
and other infiltrating, inflammatory cells produces
epithelial sloughing, plasma protein extravasation from
the tracheobronchial microcirculation, and airway re-
modeling.1,2 Bronchial mucosal inflammation is present
already in patients with mild disease, and inhaled
glucocorticoids are recommended in patients that re-
Although claimed to have a lower oral bioavailability,
quire regular â2-receptor agonist therapy to suppress
the use of this drug is associated with similar systemic
the underlying inflammation.
adverse reactions as those produced by the other two
The most potent and effective anti-inflammatory
new glucocorticoids.6 These side effects have led to the
agents available are the glucocorticoids. Potent gluco-
questioning of the long-term safety of inhaled glucocor-
corticoids like dexamethasone and prednisolone with
ticoids in large parts of the population, and in children
high systemic bioavailability and pronounced anti-
in particular.5 A novel topically airway selective glu-
inflammatory properties have been synthesized.3 How-
cocorticoid is therefore highly desirable for the safe
ever, therapeutic doses of oral glucocorticoids are asso-
treatment of subjects with asthma.
ciated with a range of adverse reactions, the most
obvious being Cushing’s syndrome, altered lipid and
bone metabolism, circulating hormone levels, bone ero-
sion, and vascular effects.3,4 Asthma is a disease of the
airways and glucocorticoids for inhalation have there-
fore been developed in an attempt to reduce systemic
side effects. However, these newer glucocorticoids,
beclomethasone dipropionate (1) and budesonide (2),
retain significant oral bioavailability (g10%) and to-
gether with drug absorbed over the tracheobronchial
mucosa result in significant plasma levels and systemic
side effects at therapeutic doses.3,4 Plasma levels of
cortisone are reduced and the function of the hypo-
thalamine-pituitary-adrenal (HPA) axis is suppressed
Previous work has indicated the importance of the
16R,17R-ketal substitution for increasing glucocorticoid
potency through increased binding to a hydrophobic site
in the glucocorticoid receptor.7 Furthermore, this func-
tionality is labile and is metabolized by microsomal
mono-oxygenases in the liver, the site of attack being
but more importantly are the osteoporosis and the
reduced rate of bone growth in children.3,5
The most recently introduced glucocorticoid for inha-
lation use in asthma is fluticasone propionate (3).
X Abstract published in Advance ACS Abstracts, November 1, 1996.
S0022-2623(96)00463-3 CCC: $12.00 © 1996 American Chemical Society

A New Class of Anti-inflammatory Androstanes
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 25 4889
Sch em e 1
Sch em e 2a
the ketal/acetal carbon atom. Oxygenation is followed
by hydrolytic decomposition, giving 16R-hydroxy-
prednisolone, an essentially inactive fragmentation
product.8
The aim of the present work was to retain the
16R,17R-ketal and/or -acetal functionality, which is
associated with high potency at the glucocorticoid recep-
tor, while introducing novel functionality around the
D-ring which would further enhance systemic metabo-
lism. Synthesis centered around compounds incorpo-
rating the novel 3a-(alkylthio)-1,3-dioxo[3.3]bicyclooctane
skeleton (5) into the D-ring position of the steroid
nuclear backbone. These molecules, together with those
combining further changes in functionalities in the
A-ring of the androstane skeleton (6), have produced a
novel class of compounds, 17â-thioalkyl-16R,17R-ketal/
acetal androstanes, with high potency at the gluco-
corticoid receptor. These compounds possess anti-
inflammatory properties and have indicated remarkably
improved airway selectivity when compared to currently
available glucocorticoids in preclinical models. A de-
tailed pharmacological investigation of the HPA axis is
in press.9
a
Reagents: (i) R1C(dO)R2, perchloric acid, THF; (ii) diethyl
chlorophosphate, THF; (iii) sodium salt of 2-mercaptopyridine
N-oxide, DMF; (iv) R3SSR3, dichloromethane, hν.
acetal 11b (which has been prepared by another route
previously11), and acetalization of 9 with (E)-2-butenal
gave 11c. The ketal 12a has been described previ-
ously.12 Simple hydrolysis of 12a gave the acid 10,
which on acetalization with butanal gave the acetal 12b.
Ch em istr y
With acetal formation, a new chiral center is formed
at the C-20 position, and it was found that, by forming
this acetal with a 17â-carboxylic acid group present, the
R/S ratio could be favorably controlled. In general, both
isomers are formed, but the 20R-isomer was formed
preferentially and the products are depicted as thus,
with the R/S ratio noted. If required, purification to
homogeneity of 11b,c and 12b could be achieved by
chromatography or crystallization.
The acids 11a -c and 12a ,b were successfully acti-
vated by reaction with diethyl chlorophosphate in tetra-
hydrofuran. The resulting mixed anhydrides 13a -c
and 14a ,b were used without isolation by reaction with
the sodium salt of N-hydroxypyridine-2-thione. This
yielded the esters 15a -c and 16a ,b. These esters
(15a -c, 16a ,b) were sufficiently stable to allow isolation
provided they were protected from light, characteriza-
tion was difficult because of the photolytic instability,
and the esters were generally used immediately.
Application of normal ionic chemistry failed to yield
our target molecules. When, for example, acetal or ketal
formation was attempted on the 16R-hydroxy-17-keto
steroids 7 in the presence of mercaptans (Scheme 1),
no products with the desired skeleton 8 were obtained.
Recourse was hence made to radical chemistry. It
was anticipated that the steric integrity of a preformed
16R,17R-acetal or -ketal, bearing a group at C-17 that
could fragment to a 17-radical, would be trapped by
radicophiles such as dialkyl disulfides exclusively on the
â-face, to give the 16R,17R-acetal bearing a 17â-alkylthio
function (Scheme 2). The key synthon required was
thus one in which a 17â-substituent was capable of
collapsing to a radical. The 17â-acid functionality, after
conversion to the 2-thioxo-1,2-dihydropyrid-1-yl ester
(“Barton ester”),10 proved successful.
The ideal starting materials for the preparation of
both 6-H and 6R-F androstanes of this type were the
11â,16R,17R-trihydroxy-17â-carboxylic acids 9 and 10.
Reaction with aldehydes and ketones would yield the
corresponding acetals and ketals 11 and 12. Oxidation
of triamcinolone gave the acid 9; oxidation of triam-
cinolone acetonide gave the corresponding acetonide
11a . Acetalization of the acid 9 with butanal gave the
Photolysis of the esters 15a -c and 16a ,b, using a
tungsten lamp, generated the radical at C-17, which
could be trapped with an appropriate dialkyl disulfide.13
The dialkyl disulfide was used as solvent or in excess
in dichloromethane solution. Radical fragmentation

4890 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 25
Ashton et al.
Sch em e 3a
Sch em e 5a
a
Reagents: (i) potassium superoxide, 18-crown-6, DMF.
Sch em e 4a
a
Reagents: (i) potassium peroxymonosulfate, aqueous acetone;
(ii) m-chloroperoxybenzoic acid, chloroform; (iii) 2,6-di-tert-butyl-
4-methylpyridine, 4A molecular sieve, xenon difluoride, dichloro-
methane.
iron pentacarbonyl/sodium hydroxide in aqueous metha-
nol to give the 1,2-dihydro derivative 24 which was
transformed into the desired product 30 by the corre-
sponding sequence 24 f 26 f 28 f 30 (Scheme 4).
Preparation of further novel analogues of this unusual
androstane could be effected by performing chemistry
on the 17-thio ether products. Thus, oxidation of 17b
with oxone gave the sulfoxide 31 as a mixture of
diastereoisomers. Overoxidation of 17a gave the sulfone
32. Fluorination of the 17-methylthio group of 17b and
18a ,b with xenon difluoride gave the (fluoromethyl)thio
ethers 33-35, respectively (Scheme 5).
a
Reagents: (i) diethyl chlorophosphate, THF; (ii) sodium salt
of 2-mercaptopyridine N-oxide, DMF; (iii) MeSSMe, dichloro-
methane, hν.
and trapping occurred with complete retention of con-
figuration at the C-17 position. Thus, trapping the
radical derived from 15a -c and 16a ,b with dimethyl
disulfide gave the methylthio ethers 17a ,b,e and 18a ,b,
while trapping the radical derived from 15b with diethyl
disulfide or diisopropyl disulfide gave the ethylthio ether
17c and isopropylthio ether 17d , respectively. Irradia-
tion of the esters 15a ,b in the absence of a trapping
agent led to radical fragmentation, and trapping by the
2-mercaptopyridyl functionality itself yielded the 17-
thiopyrid-2-yl ethers 19 and 20.
Biology
In order to investigate the structure-activity rela-
tionships of the compounds, they were initially tested
for binding affinity to the glucocorticoid receptor (iso-
lated from rat thymus tissue). The compounds were
then examined for receptor agonist or antagonist activ-
ity by studying their ability to induce tyrosine amino-
transferase (TAT) activity in rat liver H4IIE cells. All
of the compounds displayed agonist activity (although
compound 20 was only a very weak inducer TAT
activity). The compounds’ in vivo anti-inflammatory
effects were examined by intratracheal administration
directly into rat airways prior to administration of
Sephadex particles. The ratio between inhibition of the
inflammatory response and the effect on the thymus
(organ involution, simultaneous measurement of the two
parameters in the same animal) was obtained. Obvi-
ously, the ideal candidate would have the largest
possible separation between efficacy and side effect. We
hypothesize that the larger this ratio, the wider will be
the clinical therapeutic ratio, and hence safety, in
asthma patients.
Of particular interest to us were compounds bearing
our D-ring substitution pattern with partially reduced
‘A’-ring character. In the case of the 6-H,9-F series, this
was accomplished as follows. 1,2-Dihydrotriamcinolone
(21) was oxidatively cleaved to give the 17-carboxylic
acid 22 (Scheme 3). Subsequent acetalization using the
above described methodology gave the acetal 23 (Scheme
4). The sequence 23 f 25 f 27 f 29 (shown in Scheme
4) was then used as described above to generate the 1,2-
dihydro-17-methylthio ether 29. In the 6,9-difluoro
series, the intermediate 12b was partially reduced by
Str u ctu r e-Activity Rela tion sh ip s
With two exceptions, the steroids described in this
paper exhibited good affinity for the glucocorticoid

A New Class of Anti-inflammatory Androstanes
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 25 4891
Ta ble 1. Comparative Pharmacology of Selected Compounds
receptor binding
IC50 (nM)
TAT ED50
(nm)
lung edema
ED50 (mg/kg, it × 2)
thymus involution
ED50 (mg/kg, it × 2)
topical/
systemic ratio
compound
budesonide (2)
fluticasone propionate (3)
tipredane (4)
17a
17b
17c
17d
17e
18a
18b
19
20
29
30
31
32
33
34
35
2.9
5.0
2.3
1.6
1.7
3.3
5.5
1.8
2.2
2.4
22
0.2
0.1
2.0
0.2
1.7
1.5
7.0
1.1
0.2
0.4
50
0.39
0.05
2.1
0.96
0.47
1.1
0.9
1.8
7.0
>3.0
1.1
0.40
0.11
1.91
0.3
0.33
>1.0
>3.0
>3.0
>3.0
1.3
0.11
>3.0
>3.0
3.6
0.06
>3.0
2.2
>3.0
0.07
0.3
>0.56
>0.43
∼1.0
>2.73
0.40
3.2
0.54
>3.0
>3.0
5.2
1.0
3.0
1.4
4
1.9
4.6
0.20
∼1.0
∼1.0
0.69
0.06
>1.0
1.57
>0.75
0.037
0.065
12
>100
0.7
0.3
23
2.1
2.2
3.2
5.3
3.3
4.3
2.2
13
1.2
1.0
0.3
receptor. The affinity was markedly reduced with
increasing size of the R3 substituent. Thus, replacing
the methylthio group with ethylthio and isopropylthio
decreased affinity by 2- and 4-fold, respectively. The
pyridylthio-substituted compounds were about 10 times
less potent than the methylthio substituent. There was
also a trend of lower affinity for the glucocorticoid
receptor in compounds with groups of increased polarity
at C-17 (methylsulfonyl and methylsulfinyl being less
active than methylthio). It is interesting to note that
tipredane (4) (a 17-methylmercapto compound) under-
goes metabolic sulfoxidation.14 A similar metabolic
transformation would be expected, therefore, to be an
important inactivation pathway in our series. Introduc-
tion of a fluoro group in the 17â-side chain does not
markedly enhance potency of binding to the steroid
receptor. It would appear that the optimal R3 substitu-
ent in the present series of androstane compounds is
methyl with the sulfur atom in its lowest oxidation
state.
The functional assay data (induction of TAT) served
to measure the compounds’ ability to penetrate the
whole cell and to determine whether the compounds
were agonists or antagonists. The TAT data are in
general agreement with the findings of the binding
studies in that activity is sensitive to increases in both
size and polarity in the 17â-position. However, com-
pared with the binding data, the potency differences
were accentuated in the whole cell experiments, indicat-
ing that they are a function of both absorption through
the cell membrane and of affinity for the receptor. Thus,
the trends observed in the binding assay were mirrored
in the functional assay whereby both an increased size
in the R3 region and oxidation of the sulfur atom also
reduced potency.
compounds were considerably more selective than flu-
ticasone propionate. These data may be in accordance
with the expected deactivation of the glucocorticoid
steroid by sulfur oxidation followed by hydrolytic de-
composition to inert 16-hydroxy-17-keto androstanes.
Taken together, these results suggest that fluorina-
tion at the 6R-position or reduction of the 1,2-double
bond in compound 18b to give compound 30 increases
the anti-inflammatory potency and selectivity in vivo
in these substituted androstanes.
Su m m a r y
The chemical syntheses and structure-activity rela-
tionship of a novel series of 17â-thioalkyl-16R,17R-ketal
and -acetal androstanes as selective glucocorticoid topi-
cal anti-inflammatory agents are described. Optimal
selectivity for the airways within the series is achieved
by reduction of the 1,2-double bond in the A-ring or by
fluorination at the 6R-position of the steroid B-ring.
Three compounds have shown greater selectivity than
fluticasone propionate in topical versus systemic activ-
ity. As indicated by the effects on airway inflammation
versus thymus involution, it is anticipated that these
compounds will be potent anti-inflammatory agents by
the inhalation route but have little propensity to
produce glucocorticoid-like systemic side effects.9
Exp er im en ta l Section
Reagents, starting materials, and solvents were purchased
from common commercial suppliers and used as received or
distilled from the appropriate drying agent. Reactions requir-
ing anhydrous conditions were carried out under an atmo-
sphere of nitrogen. All organic solutions were dried over
magnesium sulfate. Concentration refers to evaporation under
aspirator vacuum using a Buchi rotary evaporator. Reaction
products were purified, when necessary, by flash chromatog-
raphy on silica gel (40-63 µm) with the solvent system
indicated. Yields are not optimized. NMR spectroscopic data
were recorded on a Varian VXR 400 MHz instrument and are
consistent with the assigned structures. NMR data are
reported in ppm downfield relative to internal TMS (0 ppm)
as standard. Melting points are uncorrected. Elemental
analyses were performed by the Analytical Department at
Rhoˆne-Poulenc Rorer.
In this limited series of androstanes, 6R-fluoro incor-
poration and/or partial A-ring saturation gave com-
pounds approximately equiactive to parent compounds.
However, the major aim of the present program of work
was the synthesis of compounds with high topical but
low systemic potency. This was achieved in the present
series. The order of selectivity for the reference steroids
examined was fluticasone propionate > budesonide >
tipredane. Four compounds in the current series showed
selectivity greater than that of budesonide using the
ratio between topical to systemic potency, and three
9r-F lu or o-11â,16r,17r-t r ih yd r oxy-3-oxoa n d r ost a -1,4-
d ien e-17â-ca r boxylic Acid (9). A stirred solution of triam-
cinolone (15.0 g, 38 mmol) in DMF (150 mL) was treated with
K2CO3 (15.0 g, 0.11 mol) and then with H2O2 (27% aqueous

4892 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 25
Ashton et al.
solution, 15 mL, 61 mmol), with a slight exotherm (tempera-
ture rose to 38 °C), and the mixture was stirred for 1 h. MeOH
(50 mL) was added and stirring continued for 6 h. A further
volume of H2O2 (10 mL, 41 mmol) was added and stirring
continued for a further 16 h. The reaction mixture was poured
into H2O (2.5 L), and the solution was extracted twice with
EtOAc (1.5 and 1 L). The aqueous phase was acidified with
concentrated HCl (20 mL) and left to stand to give two crops
of 9 (6.5 g, 45%): mp 320 °C dec; 1H NMR (DMSO-d6) 0.95 (s,
3H), 1.28-1.4 (m, 2H), 1.49 (s, 3H), 1.58 (bd, 1H, J ) 14 Hz),
1.72-1.85 (m, 2H), 2.0-2.18 (m, 2H), 2.24-2.42 (m, 2H), 2.55-
2.7 (m, 1H), 4.13 (m, 1H), 4.73 (bd, 1H, J ) 9 Hz), 5.2 (bs,
1H), 5.25 (m, 1H), 6.0 (s, 1H), 6.22 (dd, 1H, J ) 2, 10 Hz), 7.28
(d, 1H, J ) 10 Hz). Anal. (C20H25FO6) C, H.
(11c). As described above for compound 11b, the acid 9 (8.9
g, 23.4 mmol) and crotonaldehyde (7.4 g, 105.3 mmol) afforded
the acid 11c (20R/S 4/1) (9.1 g, 90%): 1H NMR (DMSO-d6)
0.96 (s, 3H), 1.30-1.43 (m, 1H), 1.50 (s, 3H), 1.47-1.60 (m,
2H), 1.64 (dd, 0.6H, J ) 2, 6 Hz), 1.68 (dd, 2.4H, J ) 2, 6 Hz),
1.68-2.0 (m, 5H), 2.34 (dd, 1H, J ) 3.5, 14 Hz), 2.35-2.52
(m, 1H), 2.63 (dt, 1H, J ) 5.5, 14 Hz), 4.15 (c, 1H), 4.87 (d,
0.8H, J ) 5 Hz), 4.95 (d, 0.8H, J ) 7 Hz), 5.07 (d, 0.2H, J ) 6
Hz), 5.28 (m, 0.2H), 5.33-5.40 (m, 1.8H), 5.46 (d, 0.2H, J ) 6
Hz), 5.85 (m, 0.2H), 5.92 (m, 0.8H), 6.03 (s, 1H), 6.23 (dd, 1H,
J ) 2, 10 Hz), 7.29 (d, 1H, J ) 10 Hz). Anal. C24H29FO6‚
1.25H2O C, H.
(20R,S)-16r,17r-(Bu tylid en ed ioxy)-6r,9r-d iflu or o-11â-
h yd r oxy-3-oxoa n d r ost a -1,4-d ien e-17â-ca r b oxylic Acid
(12b). To a stirred suspension of 6R,9R-difluoro-11â,16R,17R-
trihydroxy-3-oxoandrosta-1,4-diene-17â-carboxylic acid (50 g,
126 mmol) in THF (2 L) at 25 °C, under N2, were added
butyraldehyde (59.2 g, 820 mmol) and perchloric acid (1.2 g,
11.8 mmol). The reaction mixture was stirred for 16 h and
then treated dropwise with Et3N (1.2 g, 11.8 mmol). Evapora-
tion of the solvent in vacuo gave a yellow oil which was
partitioned between EtOAc (1 L) and aqueous Na2CO3 (2 M).
The aqueous phase was decanted, washed with more EtOAc
(400 mL), and acidified to pH 2 with HCl (10 M) before being
extracted with Et2O (1 L). The combined Et2O extracts were
washed with H2O and brine, then dried, and concentrated to
give a white solid which was triturated with cyclohexane before
being dried under vacuum at 80 °C overnight to give 12b
(20R/S 4/1) (54.8 g, 96%) as a white solid: mp 182-183 °C;
1H NMR (DMSO-d6) 0.85 (m, 3H), 0.96 (s, 3H), 1.22-1.46 (c,
4H), 1.50 (s, 3H), 1.49-1.62 (m, 3H), 1.79 (c, 1H), 1.90-2.06
(m, 3H), 2.26 (c, 1H), 2.45-2.67 (m, 1H), 4.17 (c, 1H), 4.68 (t,
0.8H, J ) 4 Hz), 4.88 (d, 0.8H, J ) 5 Hz), 5.08 (d, 0.2H, J ) 7
Hz), 5.19 (t, 0.2H, J ) 4.5 Hz), 5.45 (dd, 1H, J ) 1.6, 4 Hz),
5.63 (c, 1H), 6.10 (s, 1H), 6.29 (dd, 1H, J ) 2, 10 Hz), 7.35 (dd,
1H, J ) 1.5, 10 Hz). Anal. (C24H30F2O6) C, H.
Gen er a l P r oced u r e for th e Syn th esis of 17-Alk ylth io
Eth er s: Syn th esis of 9r-F lu or o-11â-h yd r oxy-16r,17r-(iso-
p r op ylid en ed ioxy)-17â-(m eth ylth io)a n d r osta -1,4-d ien -3-
on e (17a ) (11a f 13a f 15a f 17a ). To a stirred solution of
the acid 11a (1.05 g, 2.5 mmol) in THF (35 mL) containing
activated molecular sieves (type 4A, 1g) under an atmosphere
of N2 at 25 °C was added Et3N (0.7 mL, 5 mmol). The mixture
was stirred (0.5 h), treated dropwise (45 min) with diethyl
chlorophosphate (0.54 mL, 3.75 mmol), and then stirred (90
min). The resulting mixture was filtered through a pad of
Celite and the THF evaporated. The crude oil obtained was
taken up in EtOAc (50 mL) and washed with HCl (1 M, 25
mL), H2O (2 × 25 mL) and saturated brine (2 × 25 mL). The
EtOAc phase was dried (Na2SO4), filtered, and concentrated,
affording 9R-fluoro-11â-hydroxy-16R,17R-(isopropylidenedioxy)-
3-oxoandrosta-1,4-diene-17â-carboxylic diethyl phosphoric an-
hydride (13a ) as a crude yellow oil (1.5 g) which was used
without further purification in the next step.
In a reaction vessel protected from light, a stirred solution
of the anhydride 13a (3.4 g) in DMF (30 mL) containing
activated molecular sieves (type 4A, 5g) under N2 was treated
at 20 °C with the sodium salt of 2-mercaptopyridine N-oxide
(1.13 g, 7.6 mmol). After the reaction was completed (TLC),
the reaction mixture was filtered and the filtrate poured into
ice cold H2O (150 mL). The yellow precipitate formed was
collected by filtration, washed with cold water, dissolved in
CH2Cl2 (100 mL), washed with cold H2O and saturated brine,
dried, and concentrated (20 °C, 13 mmHg) to give 2-thioxo-
1,2-dihydropyrid-1-yl 9R-fluoro-11â-hydroxy-16R,17R-(isopro-
pylidenedioxy)-3-oxoandrosta-1,4-diene-17â-carboxylate ester
(15a ) (2.5 g) as a bright yellow solid, which was used directly
in the next step. All the above procedures were carried out
with exclusion of light as far as possible.
P r ep a r a tion of 6r,9r-Diflu or o-11â,16r,17r-tr ih yd r oxy-
3-oxoan dr osta-1,4-dien e-17â-car boxylic Acid (10). A stirred
solution of the acetonide 12a 11 (75.0 g, 0.17 mol) in HCOOH
(1.5 L), under N2, was heated at 80 °C for 2.5 h. The reaction
mixture was concentrated to give a tan solid which was taken
up in more HCOOH (400 mL) and stirred at 80 °C for a further
1 h. The mixture was concentrated, taken up in toluene, and
concentrated again. The residue was taken up in dioxane (1.0
L) and treated with aqueous NaOH (2 M) until the pH was
10-11 and the mixture stirred for 1 h. The mixture was
concentrated to remove the dioxane, but not to dryness, and
taken up in more water and the pH adjusted to 7. The aqueous
phase was washed with EtOAc and acidified to pH 2 to give a
white precipitate which was washed with H2O and dried to
1
give 10 (59.1 g, 87%): mp 308-309 °C dec; H NMR (DMSO-
d6) 0.95 (s, 3H), 1.3-1.55 (m, 5H), 1.6 (dd, 1H, J ) 2, 14 Hz),
1.83 (m, 1H), 2.05 (dd, 1H, J ) 3, 14 Hz), 2.2 (m, 2H), 2.42 (m,
1H), 4.14 (m, 1H), 4.75 (dd, 1H, J ) 2, 9 Hz), 5.2 (bs, 1H), 5.35
(dd, 1H, J ) 1.6, 4 Hz), 5.62 (dddd, 1H, J ) 1.7, 6.7, 8.3, 48.5
Hz), 6.1 (s, 1H), 6.28 (dd, 1H, J ) 2, 10 Hz), 7.26 (dd, 1H, J )
1.5, 10 Hz). Anal. (C20H24F2O6) C, H.
9r-Flu or o-11â-h yd r oxy-16r,17r-(isop r op yliden edioxy)-
3-oxoa n d r osta -1,4-d ien e-17â-ca r boxylic Acid (11a ).
A
stirred solution of triamcinolone acetonide (2.9 g, 6.7 mmol)
in MeOH (100 mL) was treated with K2CO3 (2.1 g, 15.2 mmol)
and air bubbled through the mixture using a glass scinter.
After 4 h the mixture was concentrated, taken up in H2O (250
mL), and acidified to pH 9 using dilute HCl. The aqueous
phase was washed with EtOAc (100 mL) and acidified to pH
2 using concentrated HCl to give a solid precipitate which was
washed with H2O and sucked dry to give 11a as a white solid
(1.9 g, 68%): mp 311-312 °C; 1H NMR (DMSO-d6) 0.94 (s,
3H), 1.16 (s, 3H), 1.3 (s, 3H), 1.3-1.43 (m, 1H), 1.47-1.62 (c,
2H), 1.49 (s, 3H), 1.68 (bd, 1H, J ) 12.7 Hz), 1.78-1.95 (c,
3H), 2.33 (bdd, 1H, J ) 3.4, 14 Hz), 2.44 (m, 1H), 2.63 (m,
1H), 4.15 (b, 1H), 4.95 (d, 1H, J ) 5.3 Hz), 5.34 (dd, 1H, J )
2, 4 Hz), 6.0 (s, 1H), 6.22 (dd, 1H, J ) 2, 10 Hz), 7.27 (d, 1H,
J ) 10 Hz). Anal. (C23H29FO6) C, H.
P r oced u r e for th e Aceta liza tion of 16r,17r-Dih yd r oxy
F u n ction a lity: P r ep a r a tion of 11b,c a n d 12b. (20R,S)-
16r,17r-(Bu t ylid e n e d ioxy)-9r-flu or o-11â-h yd r oxy-3-
oxoa n d r osta -1,4-d ien e-17â-ca r boxylic Acid (11b). To a
stirred suspension of the trihydroxy acid 9 (7.9 g, 20 mmol) in
THF (65 mL) at 25 °C were added butyraldehyde (9.2 mL, 0.1
mol) and perchloric acid (0.2 g, 1.97 mmol). When the reaction
mixture was homogeneous (1-5 h), the perchloric acid was
neutralized by addition of Et3N (0.2 g, 1.97 mmol). Concentra-
tion gave a solid which was dissolved in aqueous NaOH (2 M),
and the resulting aqueous solution was washed several times
with Et2O. Acidification of the aqueous solution with HCl (10
M) gave a white precipitate which was filtered, washed with
H2O, and dried under vacuum (80 °C, 18 h) to give 11b (20R/S
1
9/1) (8.5 g, 91.5%): mp 205 °C dec; H NMR (DMSO-d6) 0.85
(m, 3H), 0.96 (s, 3H), 1.22-1.46 (c, 4H), 1.50 (s, 3H), 1.49-
1.61 (m, 3H), 1.70-1.97 (m, 4H), 2.33 (dd, 1H, J ) 5, 9 Hz),
2.34-2.50 (m, 1H), 2.62 (dt, 1H, J ) 5.6, 13.5 Hz), 4.15 (c,
1H), 4.67 (t, 0.9H, J ) 5 Hz), 4.85 (d, 0.9H, J ) 5 Hz), 5.08 (d,
0.1H, J ) 6.7 Hz), 5.16 (t, 0.1H, J ) 4.6 Hz), 5.89 (m, 1H),
6.01 (s, 1H), 6.23 (dd, 1H, J ) 1.8, 10 Hz), 7.29 (d, 1H, J ) 10
Hz). Anal. C24H31FO6‚H2O C, H.
A solution of the ester 15a (2.1 g, 3.96 mmol) in MeSSMe
(80 mL) was irradiated with a tungsten lamp (300 W) at -8
°C under N2 until the reaction was complete (1-3 h). MeSSMe
was removed under reduced pressure and the residue purified
by chromatography (CHCl3). The solid obtained after evapora-
tion of the solvent was recrystallized (EtOAc) to give 17a (0.45
g in 7% yield for last three steps), as a white solid: mp 225
(20R,S)-16r,17r-[(E)-2-Bu t en ylid en ed ioxy]-9r-flu or o-
11â-h ydr oxy-3-oxoan dr osta-1,4-dien e-17â-car boxylic Acid

A New Class of Anti-inflammatory Androstanes
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 25 4893
°C; 1H NMR (DMSO-d6) 1.13 (s, 3H), 1.27-1.39 (m, 1H), 1.33
(s, 3H), 1.44 (dd, 1H, J ) 6, 13 Hz), 1.50 (s, 3H), 1.54 (s, 3H),
1.59 (m, 1H), 1.68 (d, 1H, J ) 13 Hz), 1.81 (c, 1H), 1.93-2.03
(m, 2H), 2.11 (s, 3H), 2.35 (dt, 1H, J ) 4, 13 Hz), 2.4 (m, 1H),
2.63 (m, 1H), 4.13 (c, 1H), 4.39 (d, 1H, J ) 6 Hz), 5.34 (c, 1H),
6.01 (s, 1H), 6.23 (dd, 1H, J ) 2, 10 Hz), 7.28 (d, 1H, J ) 10
Hz). Anal. (C23H31FO4S) C, H.
11â-hydroxy-3-oxoandrosta-1,4-diene-17â-carboxylate (15c) (1.90
g) which was used as such.
As described above for compound 17a , the ester 15c (1.85
g) gave, after recrystallization (Et2O), 17e as a white solid (0.25
g, 14% for last three steps) in a stereoisomeric purity greater
than 96%: mp 204-206 °C; 1H NMR (DMSO-d6) 1.17 (s, 3H),
1.33 (m, 1H), 1.44 (dd, 1H, J ) 6, 13 Hz), 1.50 (s, 3H), 1.57
(m, 1H), 1.69 (m, 3H), 1.71 (m, 1H), 1.80 (m, 1H), 1.92-2.04
(m, 2H), 2.10 (s, 3H), 2.33 (m, 1H), 2.30-2.50 (m, 1H), 2.63
(m, 1H), 4.11 (c, 1H), 4.18 (d, 1H, J ) 5.5 Hz), 5.35 (c, 1H),
5.37-5.45 (m, 2H), 5.96 (m, 1H), 6.02 (s, 1H), 6.24 (dd, 1H, J
) 2, 10 Hz), 7.28 (d, 1H, J ) 10 Hz). Anal. (C24H31FO4S) C,
H.
6r,9r-Diflu or o-11â-h yd r oxy-16r,17r-(isop r op ylid en e-
dioxy)-17â-(m eth ylth io)an dr osta-1,4-dien -3-on e (18a) (12a
f 14a f 16a f 18a ). As described above for compound 13a ,
the acid 12a 11 (7.04 g, 16 mmol) gave 6R,9R-difluoro-11â-
hydroxy-16R,17R-(isopropylidenedioxy)-3-oxoandrosta-1,4-di-
ene-17â-carboxylic diethyl phosphoric anhydride (14a ) as a
white foam (9.8 g) which was used as such.
As described above for compound 15a , the mixed anhydride
14a (9.7 g) gave 2-thioxo-1,2-dihydropyrid-1-yl 6R,9R-difluoro-
11â-hydroxy-16R,17R-(isopropylidenedioxy)-3-oxoandrosta-1,4-
diene-17â-carboxylate (16a ) (8.41 g) which was used as such.
As described above for compound 17a , the ester 16a (2.5 g)
gave after purification by chromatography (CH2Cl2/MeOH 19/
1) and crystallization (CH3CN) 18a (0.46 g, 21% for last three
steps) as a white solid: mp 255-256 °C; 1H NMR (DMSO-d6)
1.13 (s, 3H), 1.33 (s, 3H), 1.45 (m, 2H), 1.50 (s, 3H), 1.55 (s,
3H), 1.63 (m, 1H), 1.70 (d, 1H, J ) 13 Hz), 1.96-2.09 (m, 2H),
2.12 (s, 3H), 2.26 (m, 1H), 2.45-2.62 (m, 1H), 4.13 (c, 1H), 4.42
(d, 1H, J ) 6 Hz), 5.41 (dd, 1H, J ) 2, 4 Hz), 5.63 (dddd, 1H,
J ) 1.7, 6.5, 8.4, 48.5 Hz), 6.10 (s, 1H), 6.29 (dd, 1H, J ) 2, 10
Hz), 7.25 (dd, 1H, J ) 1.5, 10 Hz). Anal. (C23H30F2O4S) C, H.
(20R)-16r,17r-(Bu t ylid en ed ioxy)-6r,9r-d iflu or o-11â-
h yd r oxy-17â-(m eth ylth io)a n d r osta -1,4-d ien -3-on e (18b)
(12b f 14b f 16b f 18b). As described above for compound
13a , the acid 12b (14.5 g, 32 mmol) gave (20R,S)-16R,17R-
(butylidenedioxy)-6R,9R-difluoro-11â-hydroxy-3-oxoandrosta-
1,4-diene-17â-carboxylic diethyl phosphoric anhydride (14b)
(19.5 g crude) which was used as such.
(20R)-16r,17r-(Bu tyliden edioxy)-9r-flu or o-11â-h ydr oxy-
17â-(m eth ylth io)a n d r osta -1,4-d ien -3-on e (17b) (11b
f
13b f 15b f 17b). As described above for compound 13a ,
the acid 11b (6.4 g, 15.2 mmol) gave (20R,S)-16R,17R-(butyl-
idenedioxy)-9R-fluoro-11â-hydroxy-3-oxoandrosta-1,4-diene-
17â-carboxylic diethyl phosphoric anhydride (13b) as a yellow
oil (7.5 g) which was used as such.
As described above for compound 15a , the mixed anhydride
13b (4.2 g) gave 2-thioxo-1,2-dihydropyrid-1-yl (20R,S)-16R,17R-
(butylidenedioxy)-9R-fluoro-11â-hydroxy-3-oxoandrosta-1,4-di-
ene-17â-carboxylate (15b) (3 g) which was used as such.
As described above for compound 17a , a solution of the ester
15b (2g) in DMF (5 mL) and MeSSMe (75 mL) was irradiated.
After workup, the powder obtained was recrystallized from
EtOAc to give 17b (0.63 g, in 25% yield for last three steps)
as a white solid in a stereoisomeric purity greater than 98%:
mp 187 °C; 1H NMR (DMSO-d6) 0.87 (t, 3H, J ) 7.5 Hz), 1.17
(s, 3H), 1.23-1.61 (m, 7H), 1.50 (s, 3H), 1.61 (m, 1H), 1.80 (m,
1H), 1.93-2.05 (m, 2H), 2.09 (s, 3H), 2.33 (dd, 1H, J ) 3.5, 14
Hz), 2.4 (m, 1H), 2.64 (m, 1H), 4.12 (c, 1H), 4.14 (d, 1H, J )
5.5 Hz), 5.12 (t, 1H, J ) 4.3 Hz), 5.34 (dd, 1H, J ) 2, 4 Hz),
6.01 (t, 1H, J ) 1.5 Hz), 6.23 (dd, 1H, J ) 2, 10 Hz), 7.28 (d,
1H, J ) 10 Hz). Anal. (C24H33FO4S) C, H.
(20R,S)-16r,17r-(Bu tylid en ed ioxy)-17â-(eth ylth io)-9r-
flu or o-11â-h yd r oxya n d r osta -1,4-d ien -3-on e (17c) (15b f
17c). The ester 15b (1 g, 1.9 mmol) was dissolved in dimeth-
ylformamide (5 mL) and diethyl disulfide (35 mL) and irradi-
ated at -40 °C for 3 h under a N2 atmosphere. The solvents
were removed in vacuo (70 °C, 0.4 mmHg), and the residue
was purified by chromatography (CHCl3). The solid obtained
after evaporation of the solvent was recrystallized (EtOAc and
n-hexane) to give 17c (20 R/S 6/1) as a white solid (0.30 g,
1
35%): mp 228-229 °C; H NMR (DMSO-d6) 0.87 (t, 2.55H, J
) 7.4 Hz), 0.89 (t, 0.45H, J ) 7.4 Hz), 1.07 (s, 0.45H), 1.17 (m,
5.55H), 1.27-1.46 (m, 4H), 1.49 (s, 0.45H), 1.50 (s, 2.55H),
1.50-1.60 (m, 3H), 1.71 (d, 1H, J ) 14 Hz), 1.80 (m, 1H), 1.95
(m, 1H), 2.02 (dt, 1H, J ) 3.5, 10.7 Hz), 2.33 (m, 1H), 2.33-
2.47 (m, 1H), 2.64 (m, 1H), 2.68 (m, 2H), 4.12 (d, 0.85H, J )
5.5 Hz), 4.13 (c, 1H), 4.75 (d, 0.15H, J ) 7 Hz), 5.07 (t, 0.15H,
J ) 5.5 Hz), 5.15 (t, 0.85H, J ) 5 Hz), 5.33 (c, 0.85H), 5.38 (c,
0.15H), 6.0 (s, 1H), 6.22 (dd, 1H, J ) 2, 10 Hz), 7.28 (d, 1H, J
) 10 Hz). Anal. (C25H35FO4S) C, H.
As described above for compound 15a , the mixed anhydride
14b (19.5 g) gave after workup 2-thioxo-1,2-dihydropyrid-1-yl
(20R,S)-16R,17R-(butylidenedioxy)-6R,9R-difluoro-11â-hydroxy-
3-oxoandrosta-1,4-diene-17â-carboxylate (16b) (19.5 g) which
was used as such.
As described above for compound 17a , the ester 16b (19.5
g) was dissolved in CH2Cl2 (40 mL) and MeSSMe (430 mL)
and irradiated. The reaction mixture was concentrated; the
residue was taken up in EtOAc (400 mL) and washed succes-
sively with HCl (1 M, 2 × 200 mL), H2O (200 mL), and brine
(2 × 200 mL). The EtOAc solution was dried and concentrated
to give a pale yellow foam (20R/S 4/1) (13.1 g) which was
resolved by preparative HPLC using a Dynamax RP-18 column
and MeOH/H2O as mobile phase. The compound 18b, in a
stereoisomeric purity of greater than 99%, was obtained as a
(20R,S)-16r,17r-(Bu t ylid en ed ioxy)-9r-flu or o-11â-h y-
d r oxy-17â-(isop r op ylth io)a n d r osta -1,4-d ien -3-on e (17d )
(15b f 17d ). The ester 15b (2.40 g, 4.5 mmol) dissolved in
DMF (10 mL) and diisopropyl disulfide (40 mL) was treated
as described above for compound 17a . Recrystallization
(EtOAc and petroleum spirit) gave 17d (20R/S 6/1) as a white
solid (0.6 g, 28%): mp 235 °C; 1H NMR (DMSO-d6) 0.88 (t,
2.55 H, J ) 7.5 Hz), 0.92 (t, 0.45H, J ) 7.5 Hz), 1.05 (s, 0.45H),
1.17 (s, 2.55 H), 1.23 (d, 3H, J ) 7 Hz), 1.28 (d, 3H, J ) 7 Hz),
1.30-1.45 (m, 4H), 1.49 (s, 0.45H), 1.50 (s, 2.55H), 1.50-1.63
(m, 3H), 1.67-1.84 (m, 2H), 1.95 (m, 1H), 2.07 (dt, 1H, J )
3.5, 10 Hz), 2.32 (dd, 1H, J ) 3.5, 14 Hz), 2.35-2.50 (m, 1H),
2.63 (m, 1H), 3.42 (m, 1H), 4.08 (d, 0.85H, J ) 4.5 Hz), 4.15
(c, 1H), 4.73 (d, 0.15H, J ) 6 Hz), 5.08 (t, 0.15H, J ) 4.5 Hz),
5.16 (t, 0.85H, J ) 4.5 Hz), 5.37 (c, 1H), 6.02 (s, 1H), 6.23 (dd,
1H, J ) 2, 10 Hz), 7.28 (d, 1H, J ) 10 Hz). Anal. (C26H37F2O4S)
C, H.
(20R)-16r,17â-[(E)-2-Bu ten ylid en ed ioxy]-9r-flu or o-11â-
h yd r oxy-17â-(m eth ylth io)a n d r osta -1,4-d ien -3-on e (17e)
(11c f 13c f 15c f 17e). As described above for compound
13a , the acid 11c (6.4 g, 15.2 mmol) afforded the crude (20R,S)-
16R,17R-(butylidenedioxy)-9R-fluoro-11â-hydroxy-3-oxoandrosta-
1,4-diene-17â-carboxylic diethyl phosphoric anhydride (13c) as
a yellow oil (7.5 g) which was used as such.
white solid (6.55 g, 45% for last three steps): mp 204-206
1
°C; [R]26 ) +108° (c ) 0.067, CH3CN); H NMR (DMSO-d6)
D
0.87 (t, 3H, J ) 7.5 Hz), 1.16 (s, 3H), 1.33-1.43 (m, 3H), 1.43-
1.54 (m, 1H), 1.50 (s, 3H), 1.54-1.63 (m, 3H), 1.73 (d, 1H, J )
12 Hz), 1.97-2.08 (m, 2H), 2.10 (s, 3H), 2.26 (c, 1H), 2.48-
2.63 (m, 1H), 4.14 (c, 1H), 4.15 (d, 1H, J ) 5.3 Hz), 5.12 (t,
1H, J ) 4.4 Hz), 5.43 (c, 1H), 5.63 (dm, 1H, J ) 48.5 Hz), 6.1
(s, 1H), 6.29 (dd, 1H, J ) 2, 10 Hz), 7.26 (d, 1H, J ) 10 Hz).
Anal. (C24H32F2O4S) C, H.
9r-Flu or o-11â-h ydr oxy-16r,17r-(isopr op yliden ed ioxy)-
17â-(2-p yr id ylth io)a n d r osta -1,4-d ien -3-on e Hyd r a te (19).
The ester 15a (9 g) was dissolved in dichloromethane (300 mL)
and irradiated with a tungsten lamp (300 W) under an
atmosphere of nitrogen. The temperature was maintained at
20 °C by external cooling, and irradiation was continued until
the reaction mixture became colorless to give after workup a
white solid (2.9 g). Recrystallization (Et2O) gave 19 as a yellow
solid (0.63 g, 7%): mp 183-186 °C; 1H NMR (DMSO-d6) 1.14-
1.22 (m, 4H), 1.25-1.42 (m, 1H), 1.38 (s, 3H), 1.47 (s, 3H),
1.47-1.55 (m, 1H), 1.59 (s, 3H), 1.62-1.75 (m, 1H), 1.78-1.92
As described above for compound 15a , the mixed anhydride
13c (2 g) gave after workup the ester 2-thioxo-1,2-dihydro-
pyrid-1-yl (20R,S)-16R,17R-[(E)-2-butenylidenedioxy]-9R-fluoro-

4894 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 25
Ashton et al.
(m, 2H), 1.93-2.05 (m, 1H), 2.29-2.48 (m, 2H), 2.55-2.67 (m,
1H), 3.98 (c, 1H), 4.69 (d, 1H, J ) 6.2 Hz), 5.29 (dd, 1H, J )
1.6, 5 Hz), 6.0 (s, 1H), 6.19 (dd, 1H, J ) 1.8, 10 Hz), 7.2 (d,
1H, J ) 10 Hz), 7.24 (m, 1H), 7.67-7.75 (m, 2H), 8.45 (m, 1H).
Anal. (C27H32FNO4S‚H2O) C, H, N.
(250 mL) and H2O (15 mL) was added NaOH (5.52 g, 138
mmol). To the resulting solution was added the acid 12b
(12.48 g, 27.6 mmol) in one portion, and the suspension was
stirred until a yellow solution was obtained. The reaction
mixture was treated dropwise at room temperature with iron
pentacarbonyl (36.31 mL, 276 mmol) and then heated at 50
°C (20 h) under N2. The cooled reaction mixture was poured
into an ice-cold aqueous solution of H2SO4 (4 M, 1 L), and the
aqueous phase was extracted with CH2Cl2 (750 mL). The
organic phase was washed with brine (500 mL), dried over
sodium sulfate, filtered, and concentrated to approximately
one-half of the original volume. The resulting residue was
filtered through a pad of silica gel, eluting first with CH2Cl2,
then with EtOAc, and finally with a mixture of EtOAc and
MeOH (1:1). Concentration gave a white foam which was
triturated with diisopropyl ether to give (20R,S)-16R,17R-
(butylidenedioxy)-6R,9R-difluoro-11â-hydroxy-3-oxoandrost-4-
ene-17â-carboxylic acid (24) (12.7 g, 88%) as an off-white
solid: mp 210 °C (dec); 1H NMR (DMSO-d6) 0.87 (t, 3H, J ) 8
Hz), 0.93 (s, 2.7H), 0.96 (s, 0.3H), 1.25-1.60 (m, 6H), 1.49 (s,
3H), 1.75 (d, 2H, J ) 13 Hz), 1.91-2.0 (m, 2H), 2.0-2.1 (m,
1H), 2.16 (c, 1H), 2.22-2.37 (m, 2H), 2.37-2.55 (m, 2H), 4.15
(c, 1H), 4.68 (t, 0.9H, J ) 4 Hz), 4.89 (c, 0.9H), 5.10 (d, 0.1H,
J ) 6 Hz), 5.15 (c, 1H), 5.21 (t, 0.1H, J ) 4 Hz), 5.50 (c, 1H),
5.70 (s, 0.1H), 5.81 (s, 0.9H). Anal. (C24H32F2O6) C, H.
By proceeding as described above for compound 13a , the
acid 24 (12.6 g, 27.7 mmol) gave (20R,S)-16R,17R-(butylidene-
dioxy)-6R,9R-difluoro-11â-hydroxy-3-oxoandrosta-1,4-diene-
17â-carboxylic diethyl phosphoric anhydride (26) (17.2 g crude)
which was used as such.
(20R,S)-16r,17r-(Bu t ylid en ed ioxy)-9r-flu or o-11â-h y-
dr oxy-17â-(2-pyr idylth io)an dr osta-1,4-dien -3-on e (20). The
ester 15b (0.60 g, 1.1 mmol) was dissolved in CH2Cl2 (50 mL)
and irradiated with a tungsten lamp (300 W) under N2. The
temperature was maintained at 20 °C by external cooling, and
irradiation was continued until the reaction mixture became
colorless (45 min). The reaction mixture was concentrated and
the product isolated by chromatography (CHCl3). Recrystal-
lization (EtOAc and petroleum spirit) gave 20 (20R/S 6/1) (0.15
g, 27%) as a white solid: mp 215 °C; 1H NMR (DMSO-d6) 0.75
(t, 0.45H, J ) 7 Hz), 0.88 (t, 2.55H, J ) 7 Hz), 1.17 (m, 1H),
1.20 (s, 3H), 1.22-1.45 (m, 3H), 1.46 (s, 3H), 1.45-1.55 (m,
2H), 1.56-1.69 (m, 2H), 1.82 (m, 2H), 1.94 (dt, 1H, J ) 6, 13
Hz), 2.33 (dd, 1H, J ) 4, 13 Hz), 2.40 (m, 1H), 2.62 (dt, 1H, J
) 6, 13 Hz), 3.98 (c, 1H), 4.45 (d, 0.85H, J ) 6 Hz), 5.03 (d,
0.15H, J ) 7 Hz), 5.10 (t, 0.15H, J ) 4 Hz), 5.22 (t, 0.85H, J
) 4 Hz), 5.31 (c, 0.85H), 5.38 (c, 0.15H), 6.0 (s, 1H), 6.19 (dd,
0.85H, J ) 2, 12 Hz), 6.21 (dd, 0.15H, J ) 2, 12 Hz), 7.20 (d,
0.85H, J ) 10 Hz), 7.25 (d, 0.15H, J ) 10 Hz), 7.29 (m, 1H),
7.66 (m, 1H), 7.72 (m, 1H), 8.48 (m, 1H). Anal. (C28H34FNO4S)
C, H, N.
(20R,S)-16r,17r-(Bu t ylid en ed ioxy)-9r-flu or o-11â-h y-
d r oxy-17â-(m eth ylth io)a n d r ost-4-en -3-on e (29) (21 f 22
f 23 f 25 f 27 f 29). To a stirred mixture of 9R-fluoro-
11â,16R,17R-21-tetrahydroxypregn-4-ene-3,20-dione (21) (2 g,
5 mmol) in dry DMF (30 mL) was added potassium superoxide
(1.4 g, 20 mmol) followed by 18-crown-6 (1.3 g, 5 mmol), and
cooling was used to maintain the temperature below 38 °C.
The reaction mixture was stirred (30 min), treated with H2O
(300 mL), adjusted (pH 9), washed with EtOAc, and acidified
(concentrated HCl) to pH 2. The aqueous acidic mixture was
extracted with EtOAc (×3), and the combined organic extracts
were washed with brine, dried, and concentrated to give 9R-
fluoro-11â,16R,17R-trihydroxy-3-oxoandrost-4-ene-17â-carbox-
ylic acid (22) (0.9 g, 46%) as a white solid: mp 267-269 °C
By proceeding as described above for compound 15a , the
mixed anhydride 26 (17.2 g) gave after workup the ester
2-thioxo-1,2-dihydropyrid-1-yl (20R,S)-16R,17R-(butylidene-
dioxy)-6R,9R-difluoro-11â-hydroxy-3-oxoandrosta-1,4-diene-
17â-carboxylate (28) (16.6 g) which was used as such.
By proceeding as described above for compound 17a , the
ester 28 (16.6 g) afforded, after workup, an off-white powder
(12 g) which was purified by chromatography (Et2O and
petroleum spirit, 3:1). The white solid obtained (6 g) was
recrystallized (CH3CN) to give 30 (20R/S 9/1) (4 g) which was
resolved by preparative HPLC using a Dynamax RP-18 column
and MeOH/H2O as mobile phase. The 20R-epimer 30 was
obtained as a white solid (3.4 g, 27% for last three steps): mp
1
dec; H NMR (DMSO-d6) 0.92 (s, 3H), 1.35 (m, 2H), 1.47 (s,
3H), 1.55 (d, 1H, J ) 14 Hz), 1.65 (m, 1H), 1.97 (m, 1H), 2.03
(m, 1H), 2.22 (c, 6H), 2.4 (m, 1H), 2.53 (m, 1H), 4.1 (c, 1H), 4.5
(b, 1H), 4.75 (m, 1H), 4.95 (m, 1H), 5.2 (d, 1H, J ) 6 Hz), 5.66
(s, 1H). Anal. (C20H29FO6) C, H.
As described above for compound 11b, the acid 22 (2.4 g)
gave (5/2) (20R,S)-16R,17R-(butylidenedioxy)-9R-fluoro-11â-
hydroxy-3-oxoandrost-4-ene-17â-carboxylic acid (23) (2.15 g
78%): mp 146-148 °C dec; 1H NMR (DMSO-d6) 0.87 (m, 3H),
0.94 (s, 3H), 1.22-1.46 (c, 4H), 1.50 (s, 3H), 1.49-1.61 (m, 3H),
1.65-1.82 (m, 2H), 1.9-2.02 (m, 3H), 2.19-2.6 (m, 6H), 4.12
(b, 1H), 4.67 (t, 0.7H, J ) 4 Hz), 4.85 (m, 0.7H), 5.05 (m, 1.3H),
5.19 (t, 0.3H, J ) 4 Hz), 5.68 (s, 1H). Anal. (C24H33FO6) C,
H.
As described above for compound 13a , the acid 23 (2.1 g)
gave (20R,S)-16R,17R-(butylidenedioxy)-9R-fluoro-11â-hydroxy-
3-oxoandrost-4-ene-17â-carboxylic diethyl phosphoric anhy-
dride (25) (2.8 g).
As described above for compound 15a , the mixed anhydride
25 (2.8 g) gave 2-thioxo-1,2-dihydropyrid-1-yl (20R,S)-16R,17R-
(butylidenedioxy)-9R-fluoro-11â-hydroxy-3-oxoandrost-4-ene-
17â-carboxylate (27) (2.4 g).
As described above for compound 17a , the ester 27 (2.4 g),
after purification by chromatography (Et2O and petroleum
spirit, 9:1) and recrystallization (cyclohexane), gave 29 (20R/S
9/1) as a white solid (0.58 g, 27% for last three steps): mp
161-163 °C; 1H NMR (DMSO-d6) 0.89 (t, 3H, J ) 7.5 Hz), 1.05
(s, 0.3H), 1.14 (s, 2.7H), 1.25-1.75 (m, 9H), 1.48 (s, 0.3H),
1.49 (s, 2.7H), 1.92-2.10 (m, 3H), 2.03 (s, 0.3H), 2.09 (s,
2.7H), 2.18-2.60 (m, 6H), 4.10 (c, 1H), 4.13 (d, 0.9H, J ) 5.5
Hz), 4.75 (d, 0.1H, J ) 5.5 Hz), 5.03 (c, 0.9H), 5.06 (c, 0.1H),
5.10 (t, 0.1H, J ) 4.3 Hz), 5.14 (t, 0.9H, J ) 4.3 Hz), 5.68 (d,
1H, J ) 1.3 Hz). Anal. (C24H35FO4S) C, H.
1
180 °C; H NMR (DMSO-d6) 0.89 (t, 3H, J ) 7.5 Hz), 1.15 (s,
3H), 1.36-1.54 (m, 7H), 1.49 (s, 3H), 1.72 (d, 1H, J ) 12.5
Hz), 1.93-2.10 (m, 3H), 2.09 (s, 3H), 2.16 (c, 1H), 2.23-2.38
(m, 2H), 2.28-2.54 (m, 2H), 4.13 (c, 1H), 4.17 (d, 1H, J ) 5.4
Hz), 5.13 (c, 2H), 5.50 (dddd, 1H, J ) 1.8, 6.6, 11.5, 47.5 Hz),
5.81 (s, 1H). Anal. (C24H34F2O4S) C, H.
(20R,S)-16r,17r-(Bu t ylid en ed ioxy)-9r-flu or o-11â-h y-
d r oxy-17â-(m eth ylsu lfin yl)a n d r osta -1,4-d ien -3-on e (31).
The 17-methylthio ether 17b (1.0 g, 2.3 mmol) in solution in
acetone (30 mL) was treated dropwise with a solution of
potassium peroxymonosulfate (0.7 g, 1.13 mmol) in H2O (6
mL). The reaction mixture was stirred (7 h) and filtered and
the filtrate concentrated to give a pale yellow gum. This gum
was dissolved in CHCl3 (200 mL), washed with H2O (2 × 200
mL) and brine (200 mL), dried, and concentrated to give a pale
yellow foam. This foam was purified by chromatography to
give 31 (20R/S 3/1) (0.25 g, 24%) as a white solid: mp 175 °C;
1H NMR (DMSO-d6) 0.87 (t, 3H, J ) 7.5 Hz), 1.04 (s, 3H),
1.28-1.43 (m, 3H), 1.43-1.99 (m, 8H), 1.49 (s, 3H), 2.35 (m,
1H), 2.35-2.70 (m, 2H), 2.65 (s, 3H), 4.15 (c, 1H), 5.10 (d, 1H,
J ) 4.4 Hz), 5.32 (c, 1H), 5.48 (t, 1H, J ) 4.4 Hz), 6.03 (s, 1H),
6.23 (dd, 1H, J ) 1.8, 10 Hz), 7.27 (d, 1H, J ) 10 Hz) (only
major isomer is quoted). Anal. (C24H32FO5S) C, H.
9r-Flu or o-11â-h ydr oxy-16r,17r-(isopr opylid en ed ioxy)-
17â-(m eth ylsu lfon yl)a n d r osta -1,4-d ien -3-on e (32). The
17-methylthio ether (17a ) (1.4 g, 3.3 mmol) in solution in
CHCl3 (150 mL) was treated with 3-chloroperoxybenzoic acid
(2.2 g, 6.8 mmol) at 25 °C. When the reaction was completed
(TLC), the reaction mixture was treated with an aqueous
solution of sodium sulfite, then washed successively with H2O,
an aqueous solution of Na2CO3, H2O, and brine, dried, and
concentrated. The residue obtained was purified by chroma-
tography (CHCl3/MeOH, 95:5). Recrystallization (acetone/
(20R,S)-16r,17r-(Bu tylid en ed ioxy)-6r,9r-d iflu or o-11â-
h yd r oxy-17â-(m eth ylth io)a n d r ost-4-en -3-on e (30) (12b f
24 f 26 f 28 f 30). To a degassed (N2) solution of MeOH

A New Class of Anti-inflammatory Androstanes
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 25 4895
hexane) gave 32 (0.24 g, 16%) as a white powder: mp 180 °C;
1H NMR (DMSO-d6) 1.29 (s, 3H), 1.29-1.42 (m, 1H), 1.44 (s,
3H), 1.50 (s, 3H), 1.52 (s, 3H), 1.59 (dd, 1H, J ) 6, 13 Hz),
1.73-1.88 (m, 3H), 1.99 (dt, 1H, J ) 4, 13 Hz), 2.10 (dt, 1H, J
) 6, 13 Hz), 2.35 (dd, 1H, J ) 4, 13 Hz), 2.49-2.70 (m, 2H),
2.96 (s, 3H), 4.18 (c, 1H), 5.15 (d, 1H), J ) 6 Hz), 5.40 (c, 1H),
6.03 (s, 1H), 6.24 (dd, 1H, J ) 2, 10 Hz), 7.28 (d, 1H, J ) 10
Hz). Anal. (C23H31FO6S) C, H.
h at 4 °C. Bound [3H] dexamethasone was separated from free
dexamethasone by a dextran-coated charcoal technique and
quantified by liquid scintillation counting. The IC50 (concen-
tration reducing [3H]dexamethasone binding by 50%) was
calculated from the plot of the fraction bound against added
steroid concentration.
In d u ction of Tyr osin e Am in otr a n sfer a se Activity. Rat
liver H4IIE cells were cultured for 4 days until the cells were
confluent. The medium was replaced by fresh medium,
containing the steroid under test (0-100 nM) which was added
to triplicate wells. After overnight incubation as above, the
medium was removed, the cells were lysed, and the extract
was equilibrated at 37 °C with R-ketoglutarate and pyridoxal
phosphate in phosphate buffer, pH 7.3, in a final volume of 1
mL. Tyrosine aminotransferase activity was initiated by
adding tyrosine and incubating at 37 °C for 10 min. The
reaction was stopped by adding aqueous sodium hydroxide
solution (10 M). The ultraviolet absorbance of the p-hydroxy-
benzaldehyde was measured by a plate reader at 340 nm. The
maximal absorbance change achieved with the standard
(dexamethasone) was used as a reference. The absorbance
change for each concentration of steroid under test was
calculated as a fraction of the maximal absorption achievable
and plotted against steroid concentration. The ED50 was
determined as the concentration causing an increase in
tyrosine aminotransferase activity of 50% of the maximum
achievable.
Syn t h eses of t h e (F lu or om et h yl)t h io E t h er s 33-35.
(2 0 R )-1 6 r,1 7 r-(B u t y l i d e n e d i o x y )-9 r-fl u o r o -1 7 â-
[(flu or om et h yl)t h io]-11â-h yd r oxya n d r ost a -1,4-d ien -3-
on e (33). The compound 17b (2.0 g, 4.58 mmol) was treated
with 2,6-di-tert-butyl-4-methylpyridine (2.05 g, 10 mmol) and
XeF2 (0.85 g, 5.0 mmol) in CH2Cl2 (100 mL) as described for
compound 34 to give after chromatography (CHCl3) a white
solid (0.6 g) which was recrystallized (EtOAc and petroleum
spirit) to give 33 (20R/S 99/1) (0.25 g, 12%) as a white solid:
1
mp 160 °C dec; H NMR (DMSO-d6) 0.87 (t, 3H, J ) 7.5 Hz),
1.09 (s, 3H, J ) 14 Hz), 1.26-1.41 (m, 3H), 1.44-1.50 (m, 1H),
1.50 (s, 3H), 1.54-1.64 (m, 3H), 1.73 (d, 1H, J ) 14 Hz), 1.78-
2.0 (m, 3H), 2.33 (dd, 1H, J ) 3.5, 14 Hz), 2.35-2.50 (m, 1H),
2.62 (m, 1H), 4.17 (c, 1H), 4.38 (d, 1H, J ) 5.5 Hz), 5.09 (t,
1H, J ) 4.4 Hz), 5.45 (dd, 1H, J ) 1.5, 5 Hz), 5.62 (dd, 1H, J
) 10, 52 Hz), 5.68 (dd, 1H, J ) 10, 54 Hz), 6.01 (t, 1H, J ) 1.6
Hz), 6.22 (dd, 1H, J ) 2, 10 Hz), 7.28 (d, 1H, J ) 10 Hz). Anal.
(C24H32F2O4S) C, H.
6r,9r-Diflu or o-17â-[(flu or om eth yl)th io]-11â-h yd r oxy-
16r,17r-(isop r op ylid en ed ioxy)a n d r ost a -1,4-d ien -3-on e
(34). A mixture of 18a (5.06 g, 11.5 mmol), 2,6-di-tert-butyl-
4-methylpyridine (5.19 g, 25.3 mmol), and activated molecular
sieves (type 4A, 7.5 g) in dry CH2Cl2 (250 mL) was stirred for
1.5 h, under argon at 20 °C. XeF2 (2.15 g, 12.7 mmol) was
added in one portion and the mixture stirred at 20 °C (3 h).
The mixture was filtered, and the filtrate was poured into H2O
(500 mL). The organic phase was separated, and the aqueous
phase was extracted with CH2Cl2 (200 mL). The combined
organic phases were washed with saturated brine (100 mL)
and concentrated. The residue was taken up in EtOAc (500
mL) and washed with HCl (1 M, 3 × 250 mL), H2O (250 mL),
and brine (250 mL). The organic phase was dried and
concentrated to give a white solid (3.6 g) which was purified
by preparative HPLC using a Dynamax RP-18 column and
MeOH/H2O as mobile phase. Concentration followed by
crystallization (CH3CN) gave 34 (2.4 g, 46%) as a white solid:
In h ibition of Ra t Lu n g Ed em a a n d Su p p r ession of
Th ym u s Weigh t in Vivo. Test compounds were suspended
in 1% carboxymethyl cellulose/0.2% Tween 80 at double the
required strength and sonicated to form a suspension. This
was administered intratracheally (it) to male rats (Sprague-
Dawley strain, six in each group, each weighing about 350 g)
at 0 and 24 h, with the first dose being coadministered with
saline and the second with Sephadex G200 (cross-linked
dextran) (10 mg/mL) giving a final Sephadex concentration of
5 mg/mL; it dosing was carried out under halothane anesthesia
(4% in oxygen, at 4 L/min for 3 min). At 48 h, the rats were
killed, final body weight was recorded, and the lungs and
thymus were removed and weighed. The doses reducing the
Sephadex-induced edema and the thymus weight by 30%
(ED50) were calculated. Airway selectivity was defined as the
ratio of thymus involution (ED50) and inhibition of lung edema
(ED50).
mp 261-263 °C, [R]26 ) +162° (c ) 0.057, CH3CN); 1H NMR
D
(DMSO-d6) 1.06 (s, 3H), 1.36 (s, 3H), 1.45 (s, 3H), 1.46-1.57
(m, 2H), 1.50 (s, 3H), 1.69 (dt, 1H, J ) 6, 13 Hz), 1.73 (d, 1H,
J ) 13 Hz), 1.82 (dt, 1H, J ) 3, 13 Hz), 2.05 (dt, 1H, J ) 6, 13
Hz), 2.29 (c, 1H), 2.47-2.63 (m, 1H), 4.15 (c, 1H), 4.63 (d, 1H,
J ) 6 Hz), 5.52 (c, 1H), 5.62 (m, 1H), 5.70 (dd, 1H, J ) 10, 54
Hz), 5.74 (dd, 1H, J ) 10, 56 Hz), 6.10 (s, 1H), 6.29 (dd, 1H, J
) 2, 10 Hz), 7.25 (dd, 1H, J ) 2, 10 Hz). Anal. (C23H29F3O4S)
C, H.
Ack n ow led gm en t. We thank Trevor Parker, J anine
Pinel, and Philip Pye for expert technical assistance,
Bob MacKenzie for HPLC purifications, Michael Pod-
more and Mark Vine for spectroscopy, and Anne Stevens
for microanalysis.
(20R)-16r,17r-(Bu t ylid en ed ioxy)-6r,9r-d iflu or o-17â-
[(flu or om et h yl)t h io]-11â-h yd r oxya n d r ost a -1,4-d ien -3-
on e (35). The compound 18b (1.7 g, 3.5 mmol) was treated
with 2,6-di-tert-butyl-4-methylpyridine (1.57 g, 7.66 mmol) and
XeF2 (0.65 g, 3.8 mmol) in CH2Cl2 (100 mL), as described above
for compound 34. After workup, the white powder obtained
(1.3 g) was purified by chromatography (CHCl3) to give 35
(20R/S 99/1) as a white solid (0.32 g, 19%): mp 145-146 °C;
1H NMR (DMSO-d6) 0.87 (t, 3H, J ) 7.5 Hz), 1.08 (s, 3H),
1.31-1.50 (m, 3H), 1.50 (s, 3H), 1.50-1.55 (m, 1H), 1.53-1.68
(m, 3H), 1.75 (d, 1H, J ) 13 Hz), 1.88 (dt, 1H, J ) 3.5, 14 Hz),
2.03 (m, 1H), 2.27 (c, 1H), 2.50-2.66 (m, 1H), 4.17 (c, 1H), 4.40
(d, 1H), 5.11 (t, 1H), 5.53-5.60 (m, 1.5H), 5.62 (dd, 1H, J )
10.6, 52 Hz), 5.65-5.74 (m, 0.5H), 5.69 (dd, 1H, J ) 10.6, 54
Hz), 6.11 (s, 1H), 6.30 (dd, 1H, J ) 2, 10 Hz), 7.24 (dd, 1H, J
) 1.6, 10 Hz). Anal. (C24H31F3O4S) C, H.
Biologica l Meth od s. Ster oid Bin d in g to th e Ra t Th y-
m u s Glu cocor t icoid R ecep t or . Thymi of male adrenal-
ectomized rats were removed, homogenized in 3-(N-morpho-
lino)propanesulfonic acid dithiothreitol buffer, and centrifuged
at 100000g. The supernatant cytosol was used as the source
of receptor. Steroid (1-16 nM in doubling dilutions) and [3H]-
dexamethasone (4 nM) were equilibrated with receptor for 24
Refer en ces
(1) Holgate, S. Mediator and cytokine mechanisms in asthma.
Thorax 1993, 48, 103-109.
(2) Bousquet, J .; Chanez, P.; Lacoste, J . Y.; White, R.; Vic, P.;
Godard, P.; Michel, F. B. Asthma: A disease remodelling the
airways. Allergy 1992, 47, 3-11.
(3) Brattsand, R.; Selroos, O. Current drugs for respiratory diseases.
Glucocorticoids. In Drugs and the Lung; Page, C. P., Metzger,
W. J . Eds.; Raven Press: New York, 1994; pp 101-220.
(4) Check, W. A.; Kaliner, M. A. Pharmacology and Pharmaco-
kinetics of Topical Corticosteroid Derivatives used for Asthma
Therapy. Am. Rev. Respir. Dis. 1990, 144, S44-S51.
(5) Geddes, D. M. Inhaled corticosteroids: benefits and risks.
Thorax 1992, 47, 404-407.
(6) Grahnen, A.; Eckerna¨s, S.-A.; Brundin, R. M.; Ling-Andersson,
A. An assessment of the systemic activity of single doses of
inhaled fluticasone propionate in healthy volunteers. Br. J . Clin.
Pharmacol. 1994, 38, 521-525.
(7) Dahlberg, E.; Thale´n, A.; Brattstand, R.; Gustafsson, J .; J ohans-
son, U.; Roempke, K.; Saartok, T. Correlation between Chemical
Structure, Receptor Binding, and Biological Activity of Some
Novel, Highly Active, 16R,17R-Acetal-Substituted Glucocorti-
coids. Mol. Pharmacol. 1984, 25, 70-78.

4896 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 25
Ashton et al.
(8) Edsba¨cker, S.; Andersson, P.; Lindberg, C.; Ryrfeldt, A° .; Thale´n,
A. Metabolic Acetal Splitting of Budesonide. Drug. Metab.
Dispos. 1987, 15, 412-417.
(12) Kertesz, D. J .; Marx, M. Thiol Esters from Steroid 17â-Carboxylic
Acids: Carboxylate Activation and Internal Participation by 17R-
Acylates. J . Org. Chem. 1986, 51, 2315-2328.
(13) Barton, D. H. R.; Bridon, D.; Zard, S. Z. The Invention of New
Radical Chain Reactions. Part XIII. High Yielding Decarbox-
ylative Chalcogenation of Aliphatic and Alicyclic Acids. Hetero-
cycles 1987, 25, 449-462.
(14) Lan, S. J .; Scanlan, L. M.; Weinstein, S. H.; Varma, R. K.;
Warrack, B. M.; Unger, S. E.; Porubcan, M. A.; Migdalof, B. H.
Biotransformation of Tipredane, A Novel Topical Steroid, in
Mouse, Rat, and Human Liver Homogenates. Drug. Metab.
Dispos. 1989, 17, 532-541.
(9) Foster, M.; Bottoms, S.; J ordan, R.; Wicks, S.; Webber, S.; Stuttle,
K. A. J .; Newton, C. G.; Ashton, M. J .; Karlsson, J .-A. Effects of
a Novel Airway Selective 17-Thiosteroid, RPR106541, on Bio-
markers of Systemic Glucocorticoid Exposure Following 7 Day
Oral Administration. Am. Rev. Respir. Resources, in press.
(10) Barton, D. H. R.; Crich, D.; Motherwell, W. B. New and Improved
Methods for the Radical Decarboxylation of Acids. J . Chem. Soc.,
Chem. Commun. 1983, 939-941.
(11) Brattsand, R. L.; Thalen, B. A. Novel androstane-17â-carboxylic
acid esters, a process and intermediates for their preparation,
compositions and method for the treatment of inflammatory
conditions. Eur. Pat. Application 84850348.8, 1984 (to Aktie-
bolaget Draco).
J M9604639