Note: Descriptions are shown in the official language in which they were submitted.
~L1299~
The present invention relates to an anti-inflamma-
tory steroid of the androstane series.
In our British Patent Specification No. 1,438,940,
we describe and claim anti-inflammatory steroids having the
general formula ol-R4
Rl~~R2
~ I
0~
wherein X`represents a hydrogen, chlorine or fluorine atom;
Rl represents a ~-hydroxy group, an oxo group or (when X
is a chlorine atom) a ~-chlorine atom;
R represents a hydrogen atom, a methylene group or an
~- or ~-methyl group;
R represents a hydrogen atom or a Cl 4 alkyl group;
R4 represents a fluoro-, chloro-, bromo-, or iodo-methyl
group or a fluoroethyl group; and represents
11294~7
-- 2 --
a single or double bond.
We have now discovered a new compovnd fal]ing
within the broad scope of general formula I above and having
particularly advantageous properties compared with close
analogues thereof specifically described in our above-men-
tioned Patent Specification.
The new compound is chloromethyl 17a-acetoxy-9~-
fluoro-ll~-hydroxy-16~-methyl-3-oxoandrosta-1,4-diene-17~-
carboxylate. It has been found that this compound has a
high topical anti-inflammatory activity in man, as measured
by the McKenzie patch test, coupled with a relatively weak
systemic activity, for example as measured by depression of
the thymus weight in mice. Furthermore when the compound
is applied locally to the skin of mice, it shows a good ratio
of anti-inflammatory activity, as measured by the reduction
of croton oil-induced oedema, to undesired systemic activity,
as measured by the depression of the hypothalamo-pituitary-
adrenal axis. These results indicate that the compound of
the invention will be of value in the local treatment of
inflammations in man and animals with minimal liability to
cause undesired systemic side effects.
The new compound according to ~he present invention
can be prepared, for example, according to the methods
described in British Patent Specifications Nos 1,384,372
and 1,438,940.
Thus, according to a further feature of the present
invention, we provide a process for the preparation of the
:' :
1129~C~7
above mentioned compound according to the invention which
comprises esterifying the corresponding 17a-acetoxy-andro-
stane-17~-carboxylic acid (or functional equivalent thereof)
or chloromethyl 17a-hydroxy-androstane-17~-carboxylate to
produce the compound according to the invention.
Thus, for example, the compound of the invention may
be prepared by reacting a salt of the parent 17~-acetoxy
17~-carboxylic acid with a compound of formula ClCH2Y
wherein Y is an appropriate displaceable substituent, e.g.
a halogen atom other than fluorine, preferably bromine or
iodine. The preferred halo cGmpound is iodochloromethane.
The above-described reaction is advantageously effect-
ed using as the salt of the parent 17~-carboxylic acid an
alkali metal, e.g. lithium, sodium, potassium or caesium
salt or an ammonium salt such as the triethylammonium salt
or a quaternary ammonium salt such as the tetrabutylammonium
salt, conveniently in a polar solvent, particularly a
dipolar aprotic solvent such as an amide solvent such as
dimethylformamide, dimethylacetamide or hexamethylphosphor-
amide or a sulphoxide solvent such as dimethylsulphoxideconveniently at a temperature in the range 15-100C.
According to a further feature of the present
invention we provide a further process for the preparation
of the compound according to the invention which comprises
subjecting a corresponding iodomethyl or bromomethyl 17~-
carboxylate to a halogen exchange reaction serving to
replace the halogen substituent in the halomethyl group by
1:~L294~
chlorine. Thus, the chloromethyl 17~-carboxylate compound
may be prepared from the corresponding iodomethyl or bromo-
methyl 17~-carboxylate compound by reaction with for
example an alkali metal, alkaline earth metal or an
ammonium chloride, e.g. lithium chloride. The reaction is
advantageously effected in a solvent medium comprising
for example acetone, methy] ethyl ketone, dimethylformamide,
dimethylacetamide, hexamethylphosphoramide or ethanol.
The 17a-acetoxy-17~-carboxylic acid may be pre-
pared according to the process described in our BritishPatent No. 1384372 as illustrated in the Preparation given
hereinafter.
Alternatively, the parent 17-hydroxy-17~-carboxylate
corresponding to the compound according to the invention may
be sub3ected to esterification of the 17a-hydroxyl group,
the 17a-hydroxy-17~-carboxylate being prepared for example
by esterifying the corresponding 17a-hydroxy-17B-carboxylic
acid by the methods described above.
The esterification of the 17a-hydroxy group in the
preparation of the new androstane compound may, if desired,
be effected by conventional techniques, e.g. by reacting
! the parent 17-hydroxy compound with a mixed anhydride of
acetic acid, which may, for example, be generated in situ
by reating acetic acid with an appropriate anhydride such
as trifluoroacetic anhydride preferably in the presence
of an acid catalyst, e.g. p-toluene-sulphonic acid or
sulphosalicylic acid. Alternatively, the mixed anhydride
.,~,
llZ9~
may be generated ln situ by reacting acetic anhydride
with an appropriate further acid, e.g. trifluoroacetic acid.
The esterification reaction is advantageously effect-
ed in an organic solvent medium such as benzene, methylene
chloride or an excess of the carboxylic acid employed in
forming the mixed anhydride, the reaction being conveniently
effected at a temperature of 20-100C.
Alternatively, the 17a-hydroxy group may be
esterified by reaction of the parent 17a-hydroxy compound
with acetic anhydride or acetyl 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 temperature of 25 to 100C.
For the preparation of the 17a-ester of the 173-
carboxylic acid which may be employed in the preparation
of the compound of the invention, it is preferred to treat
the parent 17-hydroxy-17~-carboxylic acid with acetic
anhydride, if desired in the presence of a base such as
potassium carbonate. This reaction is conveniently
effected at an elevated temperature. Any mixed anhydride
formed may be solvolysed under ac dic (e.g. aqueous acetic
acid) or basic (e.g. aqueous pyridine or diethylamine/
acetone) conditions. Alternatively, the parent 17a-
hydroxy-17~-carboxylic acid may be treated with acetyl
11~,9~7
-- 6
chloride, preferably in a solvent such as a halogenated
hydrocarbon e.g. methylene chloride, and advantageously
in the presence of a base such as triethylamine, preferably
at a low temperature e.g. 0C.
As is well known to those skilled in the art it
may frequently be convenient to elaborate the desired
substituents in the 17- and 17~-positions at an inter-
mediate stage of the preparation of the compound of the
invention, one or more other substituents (or unsaturation)
being introduced at a later stage.
There are also provided pharmaceutical compositions
(including veterinary compositions) for use in anti-
inflammatory therapy, comprising the said compound accord-
ing to the invention together with one or more pharmaceutical
carriers or excipients. Compositions adapted for topical
administration are particularly preferred in view of the
high topical activity of the compound of the invention.
However since the compound has some systemic activity,
following appropriate routes of administration,
~0 compositions adapted for internal use are also of value.
Thus the active androstane compound may advantageously
be formulated into a preparation 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. Examples
of various types of preparation for topical administration,
include ointments, lotions, creams, powders, drops, (e.g.
';~
~Z9~7
for the nose, throat, lung or skin), suppositories,
retention enemas, chewable or suckable tablets or pellets
(e.g. for the treatment of aphthous ulcers), capsules
or cartridges, for use in an inhaler or insufflator, and
aerosols, (e.g. for the nose, throat or lung).
Ointments and creams may, for example, be formulated
with an aqueous or oily base with the addition of suitable
thickening and/or gelling agents and/or solvents. Such
base may thus, for example, include water and/or an oil
such as liquid paraffin or a vegetable oil such as arachis
oil or castor oil, or a solvent such as a polyethylene
glycol having an average molecular weight in the range
200-fj00 or a mono- or di-ethylene glycol monoethyl ether or
propylene carbonate. Thickening agents which may be used
according to the nature of the base include soft paraffin,
aluminium stearate, cetostearyl alcohol, polyethylene
glycols having an average molecular weight in the range
4,000-6,000, woolfat and beeswax and/or glyceryl mono-
stearate and/or non-ionic emulsifying agents.
Lotions may be formulated with an aqueous or oily
base and will in general also include one or more of the
following namely, emulsifying agents, dispersing agents,
thickening agents, solvents, colouring agents, suspending
agents and perfumes.
Powders for application to the skin may be formed
with the aid of any suitable powder base e.g. talc, lactose
or starch. Drops may be formulated with an aqueous
1~294~
vehicle also comprising one or more dispersing agents,
suspending agents or solubilising agents etc.
Spray compositions may for example be formulated
as aqueous solutions or suspensions or as aerosols with the
use of a suitable propellant, e.g. dichlorodifluoromethane,
trichlorofluoromethane, dichlorotetrafluoroethane, carbon
dioxide or other suitable gas.
Capsules and cartridges for use in an inhaler or
insufflator, of e.g. gelatin, may be formulated containing
a powder mix of the compound of the invention and a suitable
powder base such as lactose or starch.
The proportion of the active androstane compound in
the topical compositions according to the inven~L.jn depends
on the precise type of formulations to be prepared but
will generally be within the range of from 0.001 to 5.0%
weight. Generally however for most types of preparations
advantageously the proportion used will be within the range
of from 0.005 to 0.5% and preferably 0.01 to 0.25~.
However with powders for inhalation or insufflation the
proportion used will be within the range of from 0.1 - 2%.
The forgoing formulations for topical application to
the skin may be used for the treatment of inflammatory
dermatoses of humans and animals, for example eczema, which
are normally responsive to corticosteroid th~rapy, and
also of less responsive conditions such as psoriasis in
humans.
The formulations for administration by inhalation
94~7
or insufflation are intended for administration on a prcp-
hylactic basis to humans suffering from allergic and/or
inflammatory conditions of the nose, throat or lungs such
as asthma and rhinitis, including hay fever. Aerosol
formulations are preferably arranged so that each metered
dose or 'puff' of aerosol contains 25-200 ,ug, preferably
about 50 ~ug of the compound of the invention.
Administration may be several times daily, for example 2,3
or 4 times, giving for example 1,2 or 3 doses each time.
The overall daily dose with an aerosol will be within the
range 100 ,ug - 2000 jug, preferably, 200-800 ~ug. The
overall daily dose and the metered dose delivered by
capsules and cartridges in an inhaler or insufflator will
generally be double those with aerosol formulations.
Topical preparations may be administered by one or
more applications per day to the affected area; over skin
areas occlusive dressings may often be used with advantage.
For internal admi~istration the new compound accord-
ing to the invention may, for example, be formulated for
oral, parenteral or rectal administration. For oral
administration, syrups, elixirs, powders and granules may
be used which may be formulated in conventional manner.
Dosage unit forms are however preferred as described below.
For parenteral administration the compounds may be
presented in sterile aqueous or oily vehicles, suitable
oily vehicles including arachis oil and olive oil.
Preferred forms of preparation for internal
, llZ9~7
- 10
administration are dosage unit forms i.e. presentations
in unitary form in which each unit contains a desired dose
of the active steroid. Such dosage unit forms con-tain
from lmg to 20mg preferably from 2.5 to 10 mg of the
active steroid. For oral administration suitable dosage
unit forms include tablets, coated tablets and capsules.
For parenteral administration dosage unit forms include
sealed ampoules or vials each containing a desired dose
of the steroid. Suppositories, which may be prepared
for example with conventional commercial suppository bases,
provide a dosage unit form for rectal administration.
The compound according to -the invention may in
general be given by internal administration in cases where
systemic adreno-cortical therapy is indicated.
In general terms preparations for internal adminis-
tration may contain from 0.05 to 10% of the active ingred-
ient dependent upon the type of preparation involved.
The daily dose may vary from 2.5 to 60mg. e.g. 5 - 30 mg,
dependent on the condition being treated, the route
of administration and the duration of treatment desired.
The compositions according to the invention may also
include one or more preservatives or bacteriostatic agents
e.g. methyl hydroxy benzoate, propyl hydroxy benzoate,
thiomersa], chlorocresol or benzalkonium chloride. The
compositions according to the invention may also contain
other active ingredients such as antimicrobial agents,
particularly antibiotics, such as neomycin, nystatin,
'~
~129~7
gentamycin, tetracyclines and clioquinol.
The following examples illustrate the present invent-
ion. All temperatures are in C., and organic extracts
were dried over magnesium sulphate.
Preparation 1
17~-Acetoxy-9a-fluoro-11~-hydroxy-16~-methyl-3-oxoan-
.
drosta-1,4-diene-17~-carboxylic acid
A suspension of 9~-fluoro-11~, 17~-dihydroxy-16~-
methyl-3-oxoandrosta-1,4-diene-17~-carboxylic acid (5.0g)
and potassium carbonate (2.11g.) in acetone (20ml.) was
stirred and treated with acetic anhydride (19.4 ml.),
then heated under reflux for 2 hours. After being cooled,
the mixture was treated with water (63 ml), acidified with
concentrated hydrochloric acid (3 ml.) whilst stirring
at ca 0 for 1 hour. The solid was collected, washed
with water and dried _ vacuo at 50 overnight and then
suspended in acetone (114 ml.) and treated with diethyl-
amine (4.8 ml).
After 30 minutes, volatile material was removed
under reduced pressure and the residue was treated with
water (107 ml); ethyl acetate (600 ml.) was added and the
mixture was acidified to p~A 1 with 2N-hydrochloric acid.
The aqueous phase was separated and further extracted
with ethyl acetate, the combined ethyl acetate phases
were washed well with water, dried and concentrated
to low volume. The solid product was collected, washed
with ethyl acetate and dried ln vacuo at 60 for 2 days
11~294~7
- 12 -
to give the title compound as colourless crystals
(4.916 g )~ ~max (ethanol) 239.5 nm (ElCm 337)
A portion of the title acid (1.01 g.) in methanol
(5 ml.) was converted with 2M methanolic sodium hydroxide
(1.3 ml.) to the sodium salt (976 mg) which was precipitated
with ether.
Preparation 2.
-
Tetra-n-butylammonium and caesium salts of 17~-acetoxy-
9~-fluoro-11~-hydroxy-16~-methyl-3-oxoandrosta-1,4-diene-
-
17~-carboxylic acids.
-
a) Tetra-n-butylammonium salt.
A suspension of the title androstane-17~-carboxylic
acid (2.102 g.) in chloroform (10 ml) was mixed with a
solution of tetra-n-butylammonium hydrogen sulphate
(1.702 g.) and sodium hydroxide (394 g.) in water (10 ml)
and stirred for 30 minutes. The organic layer, containing
the tetra-n-butylammonium androstane-17~-carboxylate,
was separated and used directly.
b) _esium salt
A solution of the androstane-17~-carboxylic acid
(944 mg.) in methanol (20 ml) was stirred and treated with
aqueous 20% caesium carbonate (3.7 ml), giving a
slightly turbid solution of pH7. This was evaporated to
dryness and the residue was re-evaporated twice from
methanol, then dried overnight ln vacuo to give the
caesium salt as a foam (1.592 g)~ ~max 241 nm (Elcm 196)-
Preparation 3
llZ9~7
Chloromethyl 9a-fluoro-11~,17a-dihydroxy-16~-methyl-3-
oxoandrosta-1,4-diene-17~-carboxylate.
A mixture of sodium 9a-fluoro-11~,-7a-dihydroxy-
16~-methyl-3-oxoandrosta-1,4-diene-17$-carboxylate (400 mg.)
and chloroiodomethane (0.36 ml.) in hexamethylphosphor-
amide (1.3 ml.) was stirred at room temperature for
3 1/3 hours. The solution was diluted with ethyl acetate
and washed successively with water (3x), 5% sodium
bicarbonate (lx), water (to pH 5-6), then dried and
evaporated to a yellow solid t443 mg.). This was
triturated with ethyl acetate-ether, then with ether
(twice); the resulting liquors were evaporated to a
foam (230 mg.) which was subjected to preparative layer
chromatography on silica in chloroform-acetone (40:1,
four runs) to give a colourless foam (162 mg). Two
crystallizations from acetone-ether gave the title
chloromethyl ester (37 mg.), mp. 174-178C (decomp.,
Kofler), ~max (ethanol) 237.5 nm (~ 15,400). The mother
liquors were recovered, evaporated and the residue was
crystallized twice from aqueous methanol to give a second
crop (69 mg.), mp. 174-178C (decomp. Kofler).
_reparatio 4.
Iodomethyl 17a-Acetoxy-9a-fluoro-ll~-hyd_oxy-16~-methy
3-oxoandrosta-1,4-diene-17~-carboxylate.
A solution of chloromethyl 17a-acetoxy-9~-fluoro-
ll~-hydroxy-16~-methyl-3-oxoandrosta-1,4-diene-17~-
carboxylate (1.056 g) and sodium iodide (3.774 g) in
1 " ;':~
. .
99~(~7
- 14 -
acetone (30 ml) was stirred and heated at reflux for 1.5
hours. The mixture was evaporated, then dissolved in
ethyl acetate and washed with water, aqueous lO~o sodium
thiosulphate, water, aqueous 5% sodium bicarbonate, water
and brine, dried and evaporated to a yellow foam (1.277 g).
The product was isolated after preparative layer
chromatography (chloroform-acetone, 20:1, three runs)
as a foam (951 m~) and this was crystallised twice from
acetone to give the title iodomethyl ester as pale yellow
crystals (677 mg), m.p. 174-176C, [~D + 18.6 (c 1.10,
dioxan).
_eparation 5
Bromomethyl 17-Acetoxy-9-fluoro-11~-hydroxy-1 m _ hyl-3-
oxoandrosta-1,4-diene-17~-carboxylate.
A suspension of sodium 17-acetoxy-9-fluoro-11~-
hydroxy-16~-methyl-3-oxoandrosta-1,4-diene-17~-carboxylate
(250 mg.) in hexamethylphosphoramide (7.5 ml) was stirred
with dibromomethane (4.0 ml.). Solid has dissolved after
ca 15 minutes and reaction was almost complete after 5 hours
as shown by t.l.c. (silica, chloroform-acetone 4:1)
After 5.5 hours the mixture was diluted with 5~ sodium
dicarbonate and extracted with ethyl acetate; the combined
extracts were washed with water, dried and evaporated ln
vacuo to a foam (291 mg.). Preparative layer chromato-
graphy (silica, chloroform-acetone 4:1 three runs) gave the
less polar minor product as crystals (70 mg.); two
recrystallizations from acetone gave the title bromomethyl
1129~ 7
- 15 -
17a-acetoxyandrostane-17~-carboxylate as colourless
crystals (42 mg.), mp. 199-200 (decomp., Kofler),
[a]D + 25 (c 0.51, dioxan), shown by t.l.c. on silica
(chlorofor~, eight runs), and by lH nmr. to be ca 90%
pure.
The following Examples 1-5 illustrate the
preparation of the compound according to the present
invention.
Example 1
10 (a) Sodium 17a-acetoxy-9a-fluoro-11~-hydroxy-16~-
methyl-3-oxoandrosta-1,4-diene 17~-carboxylate (976 mg.)
was treated in hexamethyl phosphoramide (5 ml.) with
chloroiodomethane (0.8 ml.) for 19 hours when the more
reagent (0.8 ml.) for a further 4.5 hours. The mixture
was diluted with ethyl acetate and ether was washed with
water, 5% sodium bicarbonate solution, sodium thiosulphate
and wa~er, dried and evaporated to give the non-acidic
fraction (664 my.). Recrystallization from acetone gave
colourless crystals of the desired chloromethyl ester
20 (472 mg). A portion (170 mg) recrystallized from acetone
gave the analytical sample (144 mg), []D + 32.7 (dioxan
c 0.308), ~ max (ethanol) 239 (~15,100).
(b) The sodium, caesium, and tetra-n-butylammonium
salts of 17a-acetoxy--9a-fluoro-11~-hydroxy-16~-methyl 3-
oxoandrosta-1,4-diene-17~-carboxylic acid were treated,
following a similar procedure to that described in (a)
above, with chloroiodomethane, the solvent and the period
.~
- 16 -
of reaction being specified in the following Table. In the
experiments employing the sodium salt, lithium chloride
was added after the reaction. The amount of the desired
chloromethyl ester present in the reaction mixture was
estimated by HPLC or TLC as indicated.
~ABLE
17~ Carboxyl- Solvent ClC~l2I time ¦-iJiCl ~Cr~lc'e Product
ate Salt used 1 ~e (hrs) ( ~ol Pro- ~ analysis
as startiny mo . q. ccl) duct t ~-
matcrial cclded yield
¦after (w/w)~ Product
rcac- ~lCC. to
~ n i .-in~n~ic)n
Sodium ! ~ 2 ) 3 2 . 0 1. 5I 3 1 10 5 ~0
" I~;e2sO 2.1 23.5I 3 I 91.5 68
.. ~e2~ .COCI13 2 .1 23 . 5 ! 3 ~ 61
.. Me2N.CIIO 2.1 23 . 5 I 3 I 88 60
Caesium (Mc2N) 3PO 2.0 5 ¦ _ ~G(th) ~~0
.. Me 2NC~IO 2 . 0 3 3 . 5 1 - 115 ~ 7 5
B U finN C I IC 13 2 . 7 6 9 ¦ _ 10 G -v 3 0
t w/w unless stated otherwise
$ estimatc~l b~ h.p.l.c. or, where indica~ecl (~), by t.l.c.
(appro~imate),with respect to observable in~purities witl
detcction bv ultraviolct absorption arcl ~luorcscencc -
l~ quenchiny (2r,~nm) respectively.
9~7
- 17 -
Example 2
~ mixture of iodomethyl 17ci-acetoxy-9c~-fluoro-11~-
hydroxy-lG~-mcthyl-3-oxoandrosta-1,4-diene-'7~-carboxylate
(50mg.) and lithium chloride (38mg.) in hexa~ethylphosphor-
amide (0.5ml.) was stirred at room temperature ror 1 hour.
The resulting pale-yellow solution was shown to contain the
desired chloromethyl ester by comparison ~lith an authentic
specimen on -thin-layer chromatography on silica in chloro-
form-acetone (10:1, two runs): no`startin~ iodom^thyl ester
remained.
Exam~le 3
., _ .
Chloromethyl 9c~-fluoro-11~, 17c~-dihydro~y-16~-methyl-
3-oxoandrosta-1,4-diene-17~-carboxylate (lmcJ.) was treated
with a portion (O.lml.) of a mixture prepared from ~lacial
acetic acld (lml.), trifluoroacetic anhyclride (0.2ml.) and
a solution (0.025ml) of anhydrous toluene-p-sulphonic acid
in chloroform (concentration ca 80mg/n~]); thc storoid
~ i
il~9~7
1~
,,~
reaction mixture was then heated at 78-80C for 23 minutes.
The resulting solution was cooled and treated with 2N-sodium
carbonate solution (0.5ml.), then extracted with ethyl
acetate (3 x 0.3ml.); the combined extracts were evaporated
under a stream of nitrogen and the residue was dissolved in
chloroform for examination by thin-layer chromatography on
silica. No starting steroid remained and the major product
was shown to be identical to an authentic specimen of the
desired chloromethyl 17~-acetoxyandrostane-17~-carboxylate
by t.l.c. on silica in two solvent systems [chloroform-
acetone (4:1) and ethyl acetate-petrol (bp 40-60C) (1:1)].
Example 4
A suspension of sodium 17~-acetoxy-9a-fluoro-11~-
hydroxy-16~-methyl-3-oxoandrosta-1,4-diene-17~-carboxylate
(250mg.) in hexamethylphosphoramide (7.5ml) was stirred with
chlorobromomethane (3.64ml.). Solid had dissolved after 15
minutes, an~ t.l.c. examination (silica, chloroform-acetone
4:1) after 1,5 hours showed almost complete reaction had
occurred to give a sole major product, equipolar with an
authentic sample of the desired chloromethyl ester. After
3.25 hours the reaction mixture was diluted with ethyl
acetate (20ml) and 5% sodium bicarbonate solution (lOOml):
the aqueous phase was extracted further with ethyl acetate
(2 x 20ml); and the combined extracts were washed with
water (3 x 20ml), dried and evaporated in vacuo to a
colourless crystalline solid (255mg.) which was shown by
its proton magnetic resonance spectrum in deuteriochloro-
form to be the desired chloromethyl ester solvated with
hexamethylphosphoramide (ca. 1/3 mol).
Exam~le 5.
A suspension of sodium 17~-acetoxy-9~-fluoro-11~-
hydroxy-16~-methyl-3-oxoandrosta-1,4-diene-17~-carboxylate
(250mg.) in hexamethylphosphoramide (7.5 ml) and dichloro-
methane (3.59ml.) was stirred at room temperature. After
5 minutes a clear solution resulted: after 16 hours t.l.c.
on silica in chloroform-acetone (4:1) showed ca 50% con-
11294~7-
/7
version to a mixture of two products in approximately equal
amounts, one of which was identical to the desired chloro-
methyl ester.
Example 6
Bromomethyl l~a-acetoxy-9a-fluoro~ -hydroxy-16~-
methyl-3-oxoandrosta-1,4-diene-17~-carboxylate (5 mg )
and lithium chloride (4 mg ) in hexamethylphosphoramide
(0,05 ml) were stirred together for 64 hours at room
temperature. Thin-layer chromatography on silica in
chloroform (five runs) showed that no starting bromomethyl
ester remained and that it had all been converted to the
desiredchloromethyl ester as indicated by comparison with
an authentic specimen.
~9~(~7
~D
_ ~q
'~
The following Examples (A) - (D) illustrate topical
formulations in accordance with the invention. In each
Example the active ingredient is chloromethy 17~-acetoxy-
9~-fluoro-11~-hydroxy-16~-methyl-3-oxoandrosta-1,4-diene-
5 17~-carboxylate.
Example (A)
Ointment
Active Ingredient 0.1% w/w
Liquid Paraffin B.P. 10% w/w
10 White soft paraffin to
produce 100 parts by
weight
Ball-mill the active ingredient with a little of the
liquid paraffin until the particle size is reduced to 95%
by number below 5~. Dilute the paste and rinse out the mill
with the remaining liquid paraffin, mix and add the
suspension to the melted white soft paraffin at 50C. Stir
until cold to give a homogenous ointment.
Example (B)
20 Cream ~ w/w
Active ingredient 0.1
Cetostearyl alcohol 10.0
Cetomacrogol 1,000 2.5
White soft paraffin 10.0
25 Liquid paraffin 10.0
Chlorocresol 0.1
Sodium acid phosphate 0.5
Purified water to 100.0
Method of Preparation
The chlorocresol and sodium acid phosphate are
dissolved in the water at about 70-75C. The waxes are
melted together at about 65-70C and added with stirring
to the aqueous phase when this has cooled to 65-70C.
The steroid is micronised (particle size as defined in
BPC 1973 pg.911 for Ultra-Fine powder) and dispersed in a
1~294(~7
portion of liquid paraffin. The steroid suspension and
the remainder of the liquid paraffin are added to the
base with stirring at 60 to 65C. The preparation is
cooled with stirring to ambient temperature.
5 Example (C)
Metered dose_aerosol formulation
per dose % w/w
Active ingredient 0.05 mg 0.059
Fluorotrichloromethane 25.5 mg 30.0
Dichlorodifluoromethane to 85.0 mg to lO0.0
The active ingredient is micronized (particle size
as defined in BPC 1973 pg. 911 for Ultra-Fine powder) and
dispersed in the fluorotrichloromethane. This suspension
is filled into aluminium aerosol containers, the headspace
purged with gaseous dichlorodifluoromethane to exclude
air, and a metered aerosol valve crimped into position on
the container. Liquid dichlorodifluoromethane is pumped
through the metering valve, under pressure, to weight.
_ample (D)_
20 Inhalation capsul ~100 ~g/dose)
per capsule ~_w/w
Active ingredient 0.1 mg 0.4
Lactose to 25.0 mg to 100.0
The active ingredient is micronized (particle size
as defined in BPC 1973 pg. 911 for Ultra-Fine powder) and
blended with lactose in the proportions given in the above
formula. The steroid lactose blend is filled into hard
gelatin capsules to be administered with an inhalation device.
