Note: Descriptions are shown in the official language in which they were submitted.
'lZ~
17M 145-062
"Androstane Carbothioates"
The present invention relakes to anti-inflammatory
steroids of the adrostane series. More particularly
the present invention relates to processes for the
preparation of certain new androstane compounds and to
such compounds when prepared by the said processes.
Anti-inflammatory steroids are most typically
of the corticoid type, i.e. are pregnane derivatives.
Our United Kingdom Patents Nos. 1384372, 1438940
and 1514476 describe esters of certain androstane
17~-carboxylic acids having anti-inflammatory activity.
European Patent Application No. 79300500.0 (Publication
No. 0004741) describes esters of androstane 17~-
carbothioic acids also possessing anti-inflammatory
activity. We have now discovered that certain
androstane compounds containing a haloalkyl carbothioate
grouping in the 17~-position have particularly
advantageous anti inflammatory properties as discussed
in greater detail below.
The new androstane compounds may be represented
by the formula
COSR
~ J , (Ia)
wherein Rl represents a fluoro-7 chloro- or bromo-
methyl group or a 2'-fluoroethyl group; R2 represents
a group COR6 where R6 is a Cl 3 alkyl group or
... ~
~ 3
OR and R together form a 16~,17~-isopropylidenedioxy
group; R represents a hydrogen atomt a methyl
group Iwhich may be in either the ~- or B- configuraton)
or a methylene group; R4 represents a hydrogen,
chlorine or fluorine atom; R5 represents a hydrogen
or fluorine atom and symbol ....-~ represents a
singLe or double bond.
The new compounds of formula (Ia~ have good
an~i-inflammatory activity, particularly on topical
application, as judged by the McKenzie patch test
in man and as measured by the reduction of croton
oil induced oedema when the compounds are applied
topically to the skin of mice and ratsO
Certain of the compounds show good topical
anti-inflammatory ac~ivity in the croton oil ear
test coupled with minimal hypothalamus-pituitary-
adrenal-suppressive activity after topical application
! in the same animal species. These results indicate
that such compounds may be of value in the loca1
treatment of inflammation in man and animals with
minimal liability to cause undesired systemic side
effects.
The present invention relates to processes
for preparing two such compounds of formula Ia
as hereinbefore defined viz S-fluoromethyl 6~,9~-
di~luoro~ -hydroxy~16~-methyl-3-oxo~17~-propionyloxy-
androsta-1,4-diene-17~-carbothioate and the corresponding
S-chloromethyl analogue and to such compounds when
prepared by the said processes. The present application
i divided out of Canadian Patent Application No~
370,853 which latter application describes and
claims processes for preparing the remaining compounds
of formula Ia and such remaining compounds when
prepared by said processes.
Thus according to the present invention there
is provided a process for the preparation of compounds
of the formula:-
~ ~5~
cosp~l
- CH3
(I~
o
F
wherein Rl represents a fluoromethyl or chloromethyl
group; in which process
(a1 a compound corresponding to formula I but
containing either a free l7R-carbothioic acid group
(or functionally equivalent group) or a free 17~-
hydroxy group, any other reactive groups present
optionally being in protected form, is subjec~ed
to esterification;
(b) a compound corresponding to formula I but
containing a 17~-substituent of formula -COSCH2Y
(wherein Y represents a displaceable substituent)
is reacted with a compound serving to replace the
group Y by a fluorine or chlorine atom, whereby
a compound of formula I is formed;
(c) a compound corresponding to formula I but
carrying an ll-oxo group is subjected to reduction
to orm the re~uired llR-hydroxy androstane; ~~
(d) a compound corresponding to formula I but
carrying a protected llR-hydroxy group i~ ~ubjected
to deprotection;
(e) a compound corresponding to formula I but
having a 9,ll~double bond (and no substituent in
the ll-position) is reacted with one or more reagents
serving to introduce the required 9-halo-llR-hydroxy
grouping.
The compounds of the present invention have
good anti-inflammatory activity coupled with minimal
~\
- 4
hypothalamus-pituita_y-adrenal-suppressive activity
when applied topically.
In particular they possess a favourable ratio
of topical anti-inflammatory activity to undesired
systemic activity.
S-chloromethyl 6~,9~-difluoro-llB-hydroxy-
16~-methyl-3-oxo-17-propionyloxyandrosta-1,4-diene-
17~-carbothioate is especially preferred in view
of its particularly favourable ratio of topical
anti-inflammatory activity to undesired systemic
activity and in addition minimal skin atrophy.
As stated above the compounds of formula
(I) may be prepared by a variety of different
processesO
One such process comprises esterifying an
androstane compound corresponding to formula (I)
but con~aining either a free 17~-carbothioic acid
I group (or functionally equivalent group) or a free
17~-hydroxy group, any other reactive groups present
op~ionally being in protected form.
For example, a salt of the parent 17B-carbothioic
acid such as an alkali metal~ e.g. lithium, sodium
or potassium, salt or an alkylammonium, e.g. triethyl-
ammonium or tetrabutylammonium, salt may be reacted
~5 with an appropriate alkylating agent, preferably
in a polar solvent such as a ketone, e.g. acetone
or an amide such as dimethylformamide, dimethylac~tamide
or hexamethyl-phosphoramide, conveniently at a
temperature of 15 to 100C. The alkylating agent
may comprise an appropriate dihalo compound i.e.
one containing a ~urther halogen atom (preferably
a bromine or iodine atom) in addltion to the halogen
atom of the desired Rl group. This process is
particularly applicable to the preparation of compounds
in which Rl i~ a choromethyl group, the alkylating
agent advantageously being bromochloromethane.
Alternatively, the parent 16~-methyl-17~-
.~
hydroxy-17~-carbothioates corresponding to compounds
of formula I may be subjected to esterification
of the 17~-hydroxyl group. This may be effected
by conventional techniques, e.g. by rea~ting the
parent 17~ hydroxy compound with a mixed anhydride
of propionic acid, which may, for example, be generated
in situ by reacting the propionic acid with an
appropriate anhydride such as trifluoroacetic anhydride,
preferably in ~he presence of an acid catalyst,
e.g. p-toluene-sulphonic acid or sulphosalicylic
acid. Alternatively, the mixed anhydride may be
generated 1n situ by reaction of a symmetrical
anhydride of propionic acid with an appropriate
further acid, e.g. trifluoroacetic acid.
The reaction is advantageously effected in
an organic solvent medium such as benzene, methylene
chloride or an excess of the carboxylic acid employed,
i the reaction being conveniently effected at a temperature
of 20-100C.
Alternativelyr the 17~-hydroxy group may
be esterified by reaction of the parent 17~-hydroxy
compound with the appropriate acid anhydride or
acid chloride, if desired, in the presence of non-
hydroxylic solvents, e.g~ chloroform, methylene
chloride or benzene, and preferably in the presence
of a strong acid catalyst, e.g. perchloric acid,
p-toluene sulphonic acid or a strongly acidic cation
exchange resin~ e.g. Amberlite *IR 120, the reaction
being conveniently effected at a ~emperature of
25 to 100C.
The compounds of formula (I) may also be
prepared by reacting a corresponding androstane
compound containing a 17~-substituent of formula
-COSCH2Y (wherein Y represents a displaceable substituent)
with a compound serving to replace the group Y
by a fluorine or chlorine atom.
Thus the compounds of formula (I) may be
*Trade Mark
54~4
subjected to a halogen exchange reaction serving
to replace the group Y where this is halogen by
a different halogen substituent. Thus the fluoromethyl
17~-carbothioate compound of the invention may
be prepared from the corresponding iodomethyl 17~-
carbothioate compound using an appropriate fluoride
e.g. silver monofluoride or silver difluoride.
The starting iodomethyl 17B-carbothioate compound
may be prepared from the corresponding chloromethyl
17~ carbothioate compound using for example, an
alkali metal, alkaline earth metal or quaternary
ammonium iodide e.g. sodium iodide.
The reaction is advantageously effected in
a solvent medium comprising for example acetone,
acetonitrile, methyl ethyl ketone~ dimethylformamide,
dimethylacetamide or ethanol.
The foregoing reactions may also be carried
out on starting materials having a variety of substituents
or groupings which are subsequently converted into
those substituents or groupings which are present
in the compounds of the invention as defined above.
The llB~hydroxy compounds of formula ~I)
may thus be prepared by reduction of a corresponding
ll-oxo compound, e.g. using an alkali metal or
alkaline earth metal borohydride, e.g. sodium or
calcium borohydride, conveniently in an alcoholic
or aqueous alcoholic solvent such as methanol or
ethanol.
Such an ll-keto compound may be prepared
by oxidation of a corresponding ll~-hydroxysteroid,
for example using a chromic acid reagent such as
Jones' reagent.
An 116-hydroxy compound of formula (I) may
also be obtained by deprotection of a corresponding
compound having a protected hydroxyl group at the
llB-position, for example a tri Cl 6 alkylsilyloxy
group such as the trimethylsilyloxy group or a
.~
;~ 5469L
perfluoro- or chloro-alkanoyloxy group such as
the trifluoroacetoxy group~ Removal of the protecting
groups may be effected by hydrolysis, the trialkylsilyl
group being readily removed by mild acid or basic
hydrolysis or particularly conveniently using fluoride
e.g. hydrogen fluoride or an ammonium fluoride.
The perfluoro- or chloro-alkanoyl protecting group
may also be removed by mild acid or basic hydrolysis
or alcoholysis. Such a protected hydroxyl group
may be introduced, for example, by reacting an
llB-hydroxy steroid with an appropriate reagent
such as a trialkylsilyl halide or a perfluoro-
or chloro-alkanoic anhydride.
Compounds of formula (I~ may also be produced
by reaction of a corresponding compound having
a 9,11-double bond ~and no substituent in the 11-
position) with reagents serving to introduce the
required 9~-halo~ hydroxy group. This may involve
initial formation of a bromohydrin by reaction
with an N-bromo-amide or -imide such as N-bromosuccinimide,
followed by formation of the corresponding gB,llB-
epoxide by treatment with a base and reaction of
the epoxide with hydrogen fluoride to introduce
the required fluorohydrin grouping.
The above mentioned compounds containing
a free -COSH group in the 17~-position may be prepared
for example by aminolysis with rearrangement of --.
a suitable 17~ thiocarbamoyloxycarbonyl androstane.
The 17~-thiocarbamoyloxycarbonyl androstane is a
mixed anhydride of the corresponding 17B-carboxylic acid
and a thiocarbamic acid and is conveniently prepared by
reaction of a salt of the 176-carboxylic acid 17-ester
or 16~, 17~-acetonide with a thiocarbamoyl halide.
The thiocarbamoyloxycarbonyl group is N,N-disubstituted,
and may thus have the formula -COOCSNR R , where
RA and R , which may be the same or different, are
alkyl groups, e.g. Cl_4 alkyl groups or RA and RB
-- 8 --
together with the nitrogen atom to which they are
a~tached form a 5-8 membered ring which may optionally
con~ain an additional hetero atom selected from oxygen,
nitrogen and sulphur and/or which may optionally be
substituted by one or two C1 3 alkyl e.g. methyl groups.
Preferably RA and RB are Cl 4 alkyl substituents, the
N,N-dimethylthiocarbamoyl group being preferred. The
thiocarbamoyl halide is preferably the chloride. The
reaction may be accelerated by the addition of an iodide
salt e.g. sodium iodide.
The initial androstane 17~-carboxylate salt
may be for example, an alkali metal, e.g. sodium
or potassium, alkaline earth metal, e.g. calcium,
salt or a salt of a tertiary amine, e.g. triethylamine.
Aminolysis with rearrangement may be carried
out for example by heating the mixed anhydride to an
elevated temperature e.g. in the presence of ammonia,
a primary amine or more preferably a s~condary amine
such as diethylamine or pyrrolidine. In the starting
17B-carboxylic acids, the 16~- and 17~-positions will
conveniently be substituted by a 16~-methyl group and
a 17~-propionyloxy group respectively, viz the groupings
desired for the final product of formula (I~.
The starting materials employed in the process
described h~rein for the preparation of the compounds
of the present invention are new and include compounds
of the general formula tII) --
Ra
RC~ ~ R-CH3
~ (II)
O ~
F
'~
6~
wherein Ra represents a thiocarbamoyloxycarbonyl
group -COOCSNRARB where RA and R~ are as defined
above, or a group of the formula -COSRlA, where
RlA represents a hydrogen atom or a chloromethyl
or fluoromethyl group or is a group convertible
thereto and ~b represents a propionyloxy group;
or where Ra represents a group COSRlA, Rb is optionally
a hydroxy group;
R represents a hydroxy or protected hydroxy
group (in either the ~- or B-configuration) or
an oxo group;
Rd represents a fluorine atom, or Rc and
Rd together represent a carbon-carbon bond or an
epoxy group in the ~-configuration; and salts of
those compounds which have a free carbothioic acid
group; with the exclusion of compounds of formula
(Ia) as hereinbefore definedO
! Where Rc represents a pro~ected hydroxy group,
this may, for example be a trialkylsilyloxy group
or a perfluoro- or perchloro-alkanoyloxy group
as defined previously.
The 17~-hydroxy 17~-carbothioic acids of
formula (II) and salts thereof may be converted
into the 17~-hydroxy 17B-carbothioates of formula
(II) where Ra represents the group COSRl as defined
in formula (I) or into the 17B-carbothioic acid
17~-propionic acid ester of formula (II) by the --
processes described above for preparing the compounds
of formula (I). The esterification of the 17~-
hydroxy group is preferably effected with propionic
acid chloride in a solvent such as a halogenated
hydrocarbon e.g. dichloromethane, and advantageously
in the presence of a base such as triethylamine,
preferably at a low temperature e.g. 0C.
The 17~-hydroxy 17B-carbothioic acids of
formula (II) and salts thereof are thus particularly
useful intermediates for preparing the androstane
!,`~`, ~
-- 10 --
17B-carbothioates of the present invention; those
in which Rc represents a h~droxy group in the ~-
configuration or an oxo group being preferred.
6~,9~-difluoro-11~,17~-dihydroxy-16~ methyl-
3-oxoandrosta-1,4-diene-17~-carbothioic acid and
the corresponding ll-ketone and salts thereof are
especially preferred compounds of formula (II).
One advantage of the above intermediates is
that they permit direct haloalkylation to give haloalkyl
17~-carbothioates when the corresponding thiols RlSH
are not available. The salts of these 17~-hydroxy
17~-carbothioic acids may, for example be alkali
metal, e.g. lit~ium, sodium or potassium salts; tertiary
amine salts, e.g. pyridinium or triethylammonium
salts; or quaternary ammonium salts, eOg. tetrabutylammonium
salts.
The 17~-hydroxy 17~-carbothioic acids may,
i for example, be prepared by reaction of a reactive
derivative of a corresponding 17~-hydroxy-17~-carboxylic
acid with hydrogen sulphide or a sulphide or hydrosulphide
salt thereof. In general, the ca~ion of the sulphide
or hydrosulphide salt may be for example an alkali
metal salt such as sodium or potassium hydrogen sulphide.
The above-mentioned reactive derivatives corresponding
to compounds of formula (II) where Rb is a hydroxyl
group and the group -CoR7 is present at the 17B position
wherein R7 represents a group of the formula ~~
Y - - X
N ''~
z
in which X, Y and Z, which may be the same or different,
each represent CH or N, one or two of X, Y and Z
being N, the heterocyclic ring optionally being substituted
- 3 r~o5 9~69L
~ 11 --
on at least one carbon atom by a lower alkyl group
(eOg. with 1 to 4 carbon atoms, such as a methyl
group) and/or where the heterocyclic ring contains
two adjacent carbon atoms, the said ring optionally
carrying a benzene ring fused to the said adjacent
carbon atoms.
The above-mentioned reactive derivatives
corresponding to formula (Il) are preferably prepared
by reacting corresponding 17~-hydroxy 17~-carboxylic
acids of formula (II) wi~h a symmetric or asymmetric
compound of the formula:
R - W - R7 (III)
wherein W represents the group CO, CS, SO or S02
and the groups R7, which may be the same or different,
have the above meanings.
The compounds of formula (III) are conveniently
symmetric. In general, compounds of formula (III)
in which W represents CO, CS or SO will be used.
Thus, for example, especially useful compounds
include N,N'-carbonyldi(1,2,4-triazole), N,N'-carbonyl-
dibenzotriazole, N,N'-carbonyldibenzimida201e,
N,N'-carbonyldi(3,5-dimethylpyrazole)~ N,N'-thionyldi-
imidazole and especially N,N'-carbonyldiimidazole
and N,N'-thiocarbonyldiimidazole.
The preparation of a 17~-hydroxy 17B-carbothioic
acid having the formula (II) as he~ein defined
in conveniently effected by reaction of a 17~-hydroxy
17B-carboxylic acid with a compound of formula
(III) followed by reaction of the intermediate
product having the 17B-COR7 grouping with hydrogen
sulphide or a salt thereof preferably ln situ without
isolation of the intermediate.
The 17~ propionyloxy 17B-carbothioic acid
of formula (II) may be obtained in a similar manner
directly from the corresponding 17~-propionyloxy
`\ !
6~
17R-carboxylic acid by reaction with a compound
of formula (III). The 17~-propionyloxy 17~-carboxylic
acids may be prepared by esterification of the
corresponding 17-hydroxy 17B-carboxylic acids
by the methods described in BP 1,384,372.
The reaction with the compound of formula
(III~ is conveniently effected in the presence
of an inert anhydrous solvent e.g. a substituted
amide solvent such as N,N-dimethylformamide or
N,N-dimethylace~amide, desirably in the absence
of water, advantageously at or below ambient temperature
e.g. at a temperature of from -30C to +30C.
The reaction is conveniently effected under approximately
neutral conditions, advantageously in an inert
atmosphere, e.g. under nitrogen. The same solvents
and conditions are also applicable to the subsequent
reaction with H2S or a salt ~hereof. The heterocyclic
I compound e.g. imidazole or 1,2,~-triazole formed
as a by-product may, for example, be readily removed
by extraction with water.
The foregoing reactions may also be carried
out on compounds having a variety of substituents
or groupings which are subsequently converted as
described previously to compounds of formula (I).
The androstane 17B-carboxylic acid starting
materials employed in the above processes may be
prepared in conventional manner, e~g. by oxidation~--
of an appropriate 21-hydroxy-20-keto pregnane for
example with periodic acid, in a solvent medium
3G and preferably at room temperature. Alternatively,
sodium bismuthate may be employed to Pffect the
desired oxidative removal of the 21-carbon atom
of a 17-acyloxy pregnane compound. As will be
appreciated should the starting pregnane compound
contain any substituent sensitive ~o the above
desired oxidation~ such a group should be suitably
protected.
; , .
~ z~ 6~
The following examples illustrate the inv~ntion.
Melting points were determined in C on a
Kofler block and are uncorrected. Optical rotations
were determined at room temperature on solutions
in dioxan.
T~loc~ (Thin layer chromatography), p,l.c~
(Preparative layer chromatography) and h.p.l.c.
(High performance liquid chromatography) were carried
out over silica.
Solutions were dried over magnesium sulphate
unless stated otherwise.
~L2~6~
- 14 -
Preparation I
6~,9~-Difluoro~ hydroxy-16~-meth~1-3-oxo-17~-
propionyloxy androsta-1,4-diene-17~-carbothioic
acid (I)
a) 6~,9~-Difluoro-ll~-hydroxy-16~-methyl-3 oxo-17~-
E~ropionyloxyandrosta-1,4-diene-17B-carboxylic acid
A solution of 6~,9~-difluoro-11~,17~-dihydroxy-
16~-methyl-3-oxoandrosta-1,4-diene-17~-carboxylic
acid (2.113 g) and triethylamine (2.5 ml) in dichloro-
methane (60 ml) was stirred at treated at ca 0Cwith propionyl chloride (1.85 ml). After 1 H the
mixture was diluted with more solvent (50 ml) and
washed successively with 3% sodium hydrogen carbonate,
water, 2N-hydrochloric acid, water, saturated brine,
lS then dried and evaporated to a buff solid. This
was dissolved in acetone (50 ml) and diethylamine
(2.5 ml? was added~ After 1 h at 22C the solvent
i was removed in vacuo and the residual gum was dissolved
in water (30 ml) Acidification to pH 1 with 2N-
hydrochloric acid precipitated a solid, which was
collected, washed with water, and dried to give
the title carboxylic acid 17~ ~roPionate (2.230 g),
m.p. 220-225, [~]D ~4 (c 0.70).
b) A solution of 6~,9~-difluoro-11~ hydroxy-
16~-methyl-3-oxo-17~-propionyloxyandrosta-1,4-diene-
17B-carboxylic acid (2.130 g) solvated with ethyl -
~acetate (1/2 mole) and triethylamine (0.66 ml)
in dichloromethane (50 ml) was stirred under nitrogen
and treated with dimethylthiocarbamoyl chloride
(1.80 g). After 6 days at room temperature, the
intermediate dimethylthiocarbamic anhydride (1.435 g)
is crystallised from ethyl acetate. A portion
(95 mg) being removed for characterisation. The
remaining anhydride was dissolved in diethylamine
(12 ml) then stirred and heated at reflux under
nitrogen for 6 h. The resulting brown solution
'~
~2~)S46~
- 15 -
was added to a mixture of concentrated hydrochloric
acid (50 ml~ ~ater (250 ml) and ethyl acetate (50 ml).
The products were further extracted with ethyl
acetate, then the acid products were back-extracted
into 5% sodium carbonate solution. The aqueous
; phase was acidified with 6N-hydrochloric acid (50 ml)
and extracted with ethyl acetate. The extracts
were washed with N-hydrochloric acid and water,
dried and evaporated to a buff solid. This was
recrystallized from ethyl acetate to give pale buff
crystals (0.418 g) of the title 17B-carbothioic acid.
The analytical sample was obtained after
two recrystallizations from ethyl acetate as white
crystals, m.p. 136-139, [~]D ~30 (c 0.56).
Preparation II
S-Iodomet~yl 6~,9~-difluoro-11~ hydroxy-16~-methyl-3-oxo-
17~-propionyloxyandrosta-1,4-diene-17B-carbothioate (II~
A~solution of the compound of Example 1 (hereinafter
disclosed) (303 mg) and sodium iodide (1~200 9)
in acetone (30 ml) was stirred and heated under
reflux for 5 h~ Ethyl acetate (75 ml) was then
added and the solution was washed successively
with wa~er, 10% sodium thiosulphate solution, 5%
sodium hydrogen carbonate solution and water, dried
and evaporated to give an off white foam (525 mg).
P~loc~ in chloroform-acetone ~6:1) gave an off- -
~white foam which was crystallized twice from acetone
without being heated above room temperature to
give colourless crystals of the title S-iodomethyl
ester (317 mg). The product was used directly
for the preparation of the corresponding fluoromethyl
17B-carbothioate as described in Example 2.
Preparation III
S-Chloromethyl 6~,9~-difluoro 16-methyl-3-oxo-
~, 17~-pro~ionyloxy-11~-trifluoroacetoxyandrosta-1,4-
diene-17~-carbothioate (III)
-- ~2~15~4
- 16 -
A solution of the compound of Example 1 (hereinafter
disclosed) ~1~0 mg) in dry tetrahydrofuran (2 m~ and pyridine
(O.lml) was treated wi~h trifluoroacetic anhydride (0.05 ml)
and the mixture was kept at room temperature for 0.5 h. The
reaction mixture was poured into water and the product was
extracted with ethyl acetate (3x). The organic extracts were
washed with water, dried and evaporated to give the
homogen~ous title trifluoroacetate (116 mg) according to H nmr
spec~roscopy (singlet at 8.59l, l9-protons, in deuterio-
chloroform) and t.l.c. on silica (acetone-petrol, b.p.
40-60C, 1:3) An analytical sample from e~her-pentane had
m.p. 158-162, [~]D +56 (c 0.23).
Preparation IV
6a,9a-Difluoro-11~,17a-dihydroxy-16a-methyl-3-oxoandrosta-
15 1,4-diene-17~-carbothioic acid (IV)
A solution of 6,9a-difluoro~ ,17a-dihydroxy-16a-
methyl-3-oxoandrosta-1,4-diene-17~-carboxylic acid (12.0 g)
in dry dimethylformamide (250 ml) was stirred and treated
with N,~'-carbonyldiimidazole (9.94 g) under nitrogen a~
20 room t~mperature. After 4 h, hydrogen sulphide was passed
through the solution for O.S h and the mixture was kept for
a further 0.5 h. The reaction mixture was poured into 2N-
hydrochloric acid (500 ml) containing ice (ca 250 g). The
resulting precipitate was collected, washed with water and
25 dried ln vacuo to give the title thioacid as a white solid
(11.47 g), m.pO 230 - 232, [a]D +94 (c 0.91).
Preparation V
,.", _
6a,9-Difluoro-ll~-hydroxy-16a-methyl-3-oxo-17a-propionyloxy-
androsta l,4-diene-17~-carbothioic acid (V)
A solution of IY (5.0 g~ and triethylamine (6.15 ml)
in dichloromethane (140 ml) was cooled with ice--salt and
treated dropwise with propionyl chloride (4.74 ml). The
reaction mixture was stirred further at ca 0C for 0.75 h
2~6~
then washed successively with 2N~sodium carbonate, water
2N-hydrochloric acid, water and brine. After being dried~
solvent was removed to give a white solld (6.35 g~. This
was redissolved in acetone (120 ml~ and diethylamine (12O5
5 ml): a~ter being stirred at room temperature for 1 h the
volume was reduced to _ 75 ml. The solution was poured
into 2N-hydrochloric acid (200 ml) containing ice (ca 300g)
and the resulting precipitate was collected, washed with
water and dried in ~acuo to a white solid (5.17 g) m.p. 152-
10 155. Recrystallisation of a portion (400 mg) from ethylacetate gave the analytically pure title thioacid 17a-
proplonate ascolourless crystals (290 mg), m.p. 161 - 164,
[~D -27 (c 0.95), whose solid-sta~e infrared spectrum
(in Nujol~ showed a different crystalline form from the
15 sample obtained in Preparation II.
Example
S-Chloromethyl ~a,9a-difluoro-11~-hydro.Yy-16a-methyl-
3-oxo-17-proplonylo~vandrosta-l~4-diene-l7~-carb
thioate
A sol~ltion of I (0.546 g) in dimethylacetamide
(3 ml) was treated with sodi~n hydrogen carbonate (202 mg)
and bromochloromethane (0.16 ml) at 22 for 3 h. The
mixture was treated with 2N hydrochloric acid (50 ml)
and the product was extracted with ethyl acetate. The
~5 extracts were combined and washed successively with 2N
hydrochloric acid, water, saturated brine, dried and
the solvent was removed. Two crystallisations from
ethyl acetate gave the title chloromethyl thiolester
(0.404 g)~ m.p. 272 - 275, [a]D +49 (_ 0.35).
2~
- 18 -
Exam~le 2
S-Fluoromethyl 6~,9~-Difluoro~ -hydroxy-16~-methyl-
17~-propionyloxy-3-oxoandrosta-1,4-diene-17B-carbothioate
A solution of II (310 mg) in acetonitrile ~10 ml)
was stirred with silver fluoride (947 mg) for 3 days
; at room temperature in the dark. Ethyl acetate (100 ml)
was added and the mixture was filtered through kieselguhr.
The filtrate was washed successively with 2N-hydrochloric
acid, water, saturated brine, then dried. The solvent
wsa remove and the residue was subjected to p.l.c.
in chloroform then chloroform-acetone (19 1)~ The
product was eluted with ethyl acetate and crystallised
on concentration of the solution to give the title
fluoromethyl thiolester (0.075 9) m p. 272-273 (dec),
15 [~]D ~30 (c 0.35).
Example 3
I S-chloromethyl 6~,9~-difluoro-11~-hydroxY-16~0-methyl
3-oxo-17~-propionyloxYandrosta-1,4-diene-17B-carbothioate
A solution of III (29 mg) in methanol (2 ml)
was kept at room temperature for 3 h. The mixture
was evaporated to dryness to give the title ll~-alcohol
(25 mg) identified by comparison of its lH nmr spectrum
(in deuteriodimethylsulphoxide) and t.l.c. properties
25 (silica, acetone-petrol b.p. 40-60C, 1~3) with those
of an authentic specimen.
s~
-- 19 --
The active androstane compounds may advantageously
be formulated in conventional manner into preparations
suitable for topical administration with the aid
of a topical vehicle therefor. By topical administration
as used herein, we include administration by insufflation
and inhalation.
The foregoing formulations for topical application
to the skin may be used for the treatment of inflammatory
dermatoses of humans and animals, for example ecæema,
which are normally responsive to corticosteroid therapy,
and also of less responsive conditions such as psoriasis
in humans~
For internal administration the new compounds
according to the invention may, for example, be formulated
in conventional manner for oral, parenteral or rectal
administration.
