Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
10S8610
The present invention relates to novel 17~, 21-
diesters of 17~, 21-dihydroxy steroids of the pregnane
series containing a basic 21-ester grouping and having
valuable anti-inflammatory activity.
It is known that certain 17a. 21-diesters of the
pregnane series possess topical anti-inflammatory activity
which. in some cases, can be of a high order. In general,
these steroids tend to be principally employed for the
topical treatment of external inflammatory conditions.
Also. these compounds generally possess substantially
hydrophobic acyloxy ester groupings in the 17- and 21-
positions and in the absence of any water-solubilising group
these compounds cannot therefore be conveniently employed
in aqueous preparations. e.g. for otic or ophthalmic use.
We have now discovered a new class of 17a, 21-
diesters of the pregnane series having high systemic activity
as well as good topical anti-inflammatory activity. The
steroids moreover contain a water-solubilising or potentially
water-solubilising ester grouping in the 21-position.
These new steroids have a basic nitrogen-containing
21-ester grouping and can be represented by the general formula
- 2 -
1058610 2
CH20COR
~ = O
~ ~ CORl (I)
o
wherein X represents a ~-hydroxy or keto group, Y represents a fluorine or
chlorine atom, Rl represents a hydrogen atom or an alkyl group containing
1-3 carbon atoms~ R represents a group of formula -(Q 2)nNR3R4 (wherein
n is 1, 2 or 3 and R3 and R4, which may be the same or different, each
represents an alkyl group containing 1-4 carbon atoms or R3 and R4 together
with the adjacent nitrogen atom form a saturated Cl 3 alkyl-substituted or
w ubstituted monocyclic heterocyclic 4- to 7-membered ring, preferably 6-
membered, which may, if desired, further contain a sulphur or oxygen atom
or another nitrogen atom) or R2 represents a Cl 3 alkyl-substituted or un-
substituted, nitrogen-containing, 6-membered monocyclic heterocyclic ring
attached to the adjacent carbonyl group via a carbon atom of the ring, and
- - - represents a single or double bond, and acid addition salts thereof.
According to the present invention we provide a process for the
preparation of compounds of the general formula
CH20COR2
= O
X ~ OCORl (I)
I CH3
~j/ \~ _ I
Y
~\/
~wherein X represents a ~-hydroxy or keto group, Y represents a fluorine or
chlo~ine atom, Rl represents a hydrogen atom or an alkyl group containing 1-3
carbon atoms, R represents a group of formula -(C~12)nNR R (wherein n is 1,
2 or 3 and R3 and R4, which may be the same or different, each represents an
,~ ;` s .1
3-
1058610
alkyl group containing 1-4 carbon atoms or R3 and R4 together with the
adjacent nitrogen atom form a saturated Cl 3 alkyl-substituted or unsubstituted
~onocyclic heterocyclic 4- to 7-membered ring which may, if desired, further
contain a sulphur or oxygen atom or another nitrogen atom), or R2 represents
a Cl 3 alkyl-substituted or unsubstituted nitrogen-containing 6-membered
monocyclic heterocyclic ring, attached to the adjacent carbonyl group via a
carbon atom of the ring, and _ _ _ represents a single or double bond] and
acid addition salts thereof which comprises reacting a compound of formula
CH2RS
C = O
X ~ OcH3Rl Il
0~
lwherein Rl, X, Y and --- are as hereinbefore defined and R5 represents a
hydroxy group or a group of formula -OCO(CH2)nZ (wherein n is as hereinbefore
dofinod and Z represents a readily displaceable substituent)] with a compound
of formula
H.R III
[wherein R6 represents a group of formula -OCOR2 (wherein R2 is as defined
above) or a reactive derivative thereof, when R5 in formula Il represents a
hydroxy group; or R6 represents a group of formula -N ~ R4 twherein R3
and R are as above defined) when R in formula II represents a group of
formula -OCO(CH2)nZ (wherein n and Z are as above defined)] or a functional
derivative thereof; and, if desired, converting the resulting compound of
formula I into an acid addition salt thereof.
~ -3a-
. . .
10586~0
The compounds of formula I possess, as indicated
above, both topical and systemic anti-inflammatory activity
and are thus useful as general purpose anti-inflammatory
agents. They are well absorbed on oral administration.
In addition, the marked skin thinning effect observed
as an unwanted side-effect of certain widely used topical ~
anti-inflammatory steroids is not observed with the compounds
according to the invention in tests upon rats.
The above compounds also possess systemic immuno-
suppressive activity and are thus useful in the treatment of
allergic disorders and inflammatory disorders having
a significant immunological component. In experiments
in rats it has been observed that the ratio of immuno-
suppressive to anti-inflammatory activity of the compounds
according to this invention is greater than that of
betamethasone.
In formula I above NR R preferably represents a
diethylamino group or an unsubstituted saturated 6-membered
heterocyclic ring, e.g. a piperidino or more preferably
a morpholino group; n is~advantageously l. Alternatively,
R2 in formula I may advantageously represent an unsubstituted
aromatic 6-membered nitrogen-containing heterocyclic ring
attached to the adjacent carbonyl group via a carbon atom,
-- 4 --
10586~0
e.g. a pyridyl group, particularly the 3-pyridyl group.
R in formula I advantageously represents an alkyl
group containing 1 - 3 carbon atoms, namely a methyl,
ethyl, propyl or isopropyl group, an ethyl group,
however, being preferred. In formula I, Y preferably
represents a fluorine atom. X preferably represents
a ~-hydroxy group; --- preferably represents a double bond.
The present invention further includes acid
addition salts of the above compounds of formula I
particularly their hydrochlorides, hydrobromides, nitrates,
phosphates, sulphates, p-toluene sulphonates. methane-
sulphonates, sulphosalicylates, maleates, fumarates,
gluconates, citrates, tartrates, acetates, ascorbates,
lactates and succinates. In order to attain aqueous solutions
of acid addition salts of weakly basic compounds of formula I,
such as those in which R2 is morpholinomethyl, the pH of the
solution is preferably adjusted to an acidic value.
The steroids according to the invention and their
salts can generally be obtained as crystal forms containing
water and other molecules of solvation.
1058610
An especially preferred compound of formula I
according to the invention by virtue of its particularly
favourable anti-inflammatory activity is 9a-fluoro-1~ -
hytroxy-16B-methyl-21-morpholinoacetoxy-17-propionyloxy-
pregna-1,4-diene-3,20-dione. Other preferred compounts
of formula I include 9a-fluoro-11~-hydroxy-16B-methyl-
21-nicotinyloxy-17-propionyloxy pregna-1,4-diene-3,20-
dione;
21-diethylaminoacetoxy-9a-fluoro-1~ -hydroxy-l~ -methyl-
17-propionyloxy-pregna-1,4-diene-3,20-dione;
9-fluoro-llB-hydroxy-l~ -methyl-21-piperidinoacetoxy-
17-propionyloxypregna-1,4-diene-3,20-dione;
9a-chloro-21-diethylaminoacetoxy-1~ -hydroxy-16B-methyl-
17-propionyloxypregna-1,4-diene-3,20-tione; and
9-chlo~o-llB-hydroxy-l~ -methyl-21-nicotinyloxy-17-
propionyloxypregna-1,4-diene-3,20-dione. Further
preferred compounds according to the invention are the
acid addition salts, especially the hydrochlorides, of
the above mentioned specific compounds of formula I.
-6-
10S8610
When R5 in formula II represents a hydToxy
group, it is palticularly preferred to use a reactive
derivative of the compound of fo~mula III in which R6
represents a group OCOR2 (wherein R2 is as defined above),
e.g. the corresponding acid anhydride or more preferably
_7_
1058610
halide e.g. chloride of a functional equivalent thereof
such as a corresponding and additional salt.
The above-identified readily displaceable
substituent Z may be for example a halogen atom, e.g.
a bromine or iodine atom, or, more preferably, a chlorine
atom; or an aromatic or aliphatic sulphonyloxy group, e.g.
a p-toluenesulphonyloxy or methanesulphonyloxy group.
The reaction of the compounds of formulae II
and III is preferably effected in a solvent medium, e.g.
a ketone such as acetone or methylethyl ketone; an
acyclic ether such as diethyl ether or a cyclic ether
such as tetrahydrofuran; an ester such as ethyl acetate;
an amide solvent such as dimethylformamide or
dimethylacetamide; or ~ halogenated hydrocarbon such
as methylene chloride, advantageously at an elevated
temperature. e.g. at the reflux temperature of the
reaction mixture.
lOS8610
When R in formula II above represents a halo-
acyloxy substituent or H.R ~ fDrmulaI~ is in the 3Dm of an
acid halide, the reaction is conveniently effected in
the presence of an acid acceptor e.g. a tertiary organic
base such as pyridine, collidine or triethylamine.
When R in formula III represents -NR R4, the compound
III can be used in excess to provide the above-mentioned
acid acceptor.
The acid addition salts of compounds of formula I
may be prepared for example by treating the parent
compound with an appropriate acid in water or an organic
solvent medium, e.g. an alcohol such as ethanol or a
hydrocarbon such as benzene.
The above-identified compounds of formula II
wherein R5 represents a group of formula -OCO(CH2~n Z
may be readily prepared, fbr example, by reacting the
parent 21-hydroxy steroid with an appropriately sub-
stituted acylating agent, e.g. a halide or anhydride, e.g.
a chloroacyl chloride or anhydride. This reaction is
advantageously effected in a solvent medium, e.g. a
solvent as mentioned above for the reaction of the
compounds of formulae II and IIIo
1058610
The starting materials of formula II above
wherein R5 represents an iodoacyloxy group may, if
desired, be prepared by reacting the corresponding compound of
formula II wherein R5 represents a chloroacyloxy group
with a source of iodide ions, e.g. an iodide salt such
as sodium iodide, the reaction being advantageously
effected in a polar solvent medium such as a ketone
solvent e.g. acetone or methylethylketone; an acyclic
ether, e.g. diethyl ether or a cyclic ether, e.g.
tetrahydrofuran; or an smide solvent such AQ
dimethyla~etamide or dimethylformamide.
The invention further comprises pharmaceutical
compositions for human and veterinary practice comprising
at least one compound of formula I (as herein before
defined) or non-toxic acid addition salt thereof, together
with one or more carriers or excipients with or without
additional therapeutic agentsO
Examples of compositions for topical administration
include ointments, lotions, creams, powders and aerosol
sprays; suppositories and retention enemas for the
surface treatment of rectal areas; vaginal inserts;
sterile drops and ointments for eye and ear treatment;
slowly dissolving buccal pellets e.g. for the treatment of
aphthous ulcers; chewing gum providing a slow release
- 10
1058610
of the medicament for the treatment of the mucous
membranes of the mouth and throat; nose and throat
sprays and applications.
Antibacterial agents, such as antibiotics e.g.
aureomycin, neomycin, or chemical agents, such as,
chiniofon may if desired be added to the steroid
preparations detailed above for therapeutic advantage.
The proportion of active steroid in the topical
compositions according to the invention will depend upon
the precise nature of the formulation, but will generally
be within the range of 0.0001% - 5% by weight,
advantageously 0.001% - 0.5% by weight and preferably
0.01% - 0.25% by weight.
The preparations may be administered once daily or
more frequently dependent upon the nature of the condition
being treated. Particularly beneficial results may be
obtained in some cases by the use of occlusive dressings
when the steroid is applied to the skin.
Veterinary preparations are,in general, formulated
in analogous manner to those mentioned above, but with
suitable adaption made for dose and size of the animals
concerned. The steroid compound according to the
invention may also be useful in intramammary preparations.
1058610
Compositions according to the invention also
include compositions for the systemic absorption of the
active compounds, for example, oral, rectal and
parenteral compositions, Since the compounds according
to the invention are highly potent, unit dosage forms
are generally preferred. Convenient unit dosage forms
for internal administration include tablets and
capsules and these may, if desired, be formulated to
give a sustained release of the active material. For
parenteral use, convenient unit dosage forms include
ampoules and vials, the latter being either single or
multiple dose containersO Suppositories for systemic
absorption may be prepared, for example using a convenient
suppository base in conjunction with a suitab-le carrier
to aid absorption from the colon.
Compositions according to the invention for
internal administration, may also include additional
active ingredients such as antibacterial agents, e.g.
neomycin. Compositions for parenteral administration
may also be prepared as sterile dry solid~ for
reconstitution with a sterile diluent, immediately before
useO
_ 12
~586~0
Preparations for systemic use in unit dosage
form may contain from 0,05 to 10~0 mg, preferably 0O50
to 5.0 mg, of the active steroid per unit dosageO
Generally the preparations for internal administration
may contain from OoOl to 50% of active ingredient,
dependent on the type of preparation involved. In
veterinary preparations, dosages vary considerably
depending on the size of the animal and the frequency
of administration of the composition. .
The following Examples illustrate the invention.
Unless otherwise stated ~p~c~l
rotations were measured in dioxan at ca 1% concentration.
Ultraviolet spectra were measured in ethanol. Organic
extracts were dried over magnesium sulphate or sodium
sulphate.
Example 1
9a-Fluoro-ll~-hvdroxy-16~-methyl-21-morpholinoacetoxy-17-
propionyloxypregna-1,4-diene-3,20-dione
(i) A solution of crude betamethasone 17-propionate
21-chloroacetate (8.3 g) and morpholine (6.9 ml) in
anhydrous acetone (275 ml) was refluxed for 1 hour.
- 13
1058610
The mixture was evaporated to give a yellow oil, which
was dissolved in ethyl acetate (350 ml) and extracted
with water (2x 350 ml). The dried organic phase was
evaporated to a yellow oil, which was crystallised from
ethanol to give the title compound as a white powder
(7.5 g), m.pO 124 - 125. An analytical specimen, as
a monohydrate (from ethanol) had m.p. 128 - 130;
~a]D + 62, ~max 237 nm ( 15,630).
(ii) A solution of betamethasone 17-propionate 21-
iodoacetate (1.8 g.) and morpholine (1.27 ml.) in acetone
(AR, 80 ml.) was refluxed for 1~ hours. The mixture
was cooled and evaporated in vacuo to a yellow gum
which was partitioned between ethyl acetate a~d water,
the mixture being adjusted to pH 7 with 2N-hydrochloric
acid. The aqueous phase was extracted further with
ethyl acetate and the combined organic extracts were
washed with water, dried and evaporated under reduced
pressure to an off-white foam (1086 g~)O Crystallisation
and recrystallisation from a~ueous methanol gave colour-
less crystals (1.0 g.) of the title comPound, as a
monohydrate, m.p. 122 - 125, [a]D + 62, AmaX 236.5 nm
( 16,000).
- 14
~058610
Example 2
9a-.Fluoro-ll,~-hydroxy-l~-methyl-21-morpholinoacetG~xy-17-
propionylox~pregna-1,4-diene-3,20-dione hvdrochloride
(i) A solution of betamethasone 17-propionate 21-
morpholinoacetate (2 g3 ln anhydrous ethanol (5 ml) was
treated with 0.6 N HCl in ethanol (6 ml), left for 15
minutes at room temperature in a well stoppered conical
flask and evaporated to give an almost colourless oil.
After drying the oil in vacuo at 50 for 3 hoursj the
residual glassy material was dissolved in the minimum
amount of acetone and stored at 5 for 3 hours. The
product was collected and dried in vacuo at 50 for 3 hours
to glve white crystals of the ~itle compound (1. 85 g).
An analytical specimen (from acetone) in the form of an acetone
solvate had m.p. near 170; [a]D + 95 (dilute hydrochloric
acid); ~ma 238 nm (e 15,300).
(ii) A sample (2.00 g.) of betamethasone 17-propionate
21-mDrpholinoacetate hydrochloride prepared as in (i)
above shown, by p.m.r. spectroscopq, to be solvated with
acetone [ca. 0.5 mole] was dissolved in warm methanol
and the solution was filtered, then evaporated to a
smaller volume by boiling. Ethyl acetate was added
gradually and crystallisation was induced to give colourless
crystals (1.75 g.). Further recrystallisation carried out
- 15 -
1058610
in a similar manner gave, after drying overnight at 50/
0.1 mm, colourless crystals (1.48 g.) of the title
compound, as a hemihydrate, mOp. 175 - 180, [a]D + 93
(ca. 0.1 N-hydrochloric acid), [~]D + 81.5 (dioxan),
AmaX 239 nm ( 15,500). The infrared spectrum (in
nujol) differed from that of the starting sample in the
same medium, and the p.m.r. spectrum (in deuteriochloro-
form) did not reveal solvation by methanol, ethyl acetate
or acetone.
Example 3
9a-Fluoro~ -hydroxy- 16,~-methyl-21-nicotinyloxy- 17- -
proPionyloxypregna-1,4-diene-3,20-dione
Betamethasone 17-propionate (1 gO) in dry
pyridine (17 ml.) was treated with nicotinyl chloride
hydrochloride (1 g.) at room temperature for 80 minutes
and then at 0 for 16 hours. Dilution with water gave
a crude product which was dissolved in benzene, cooled
in ice and treated with hydrogen chloride to give an oil.
The solvent and excess hydrogen chloride were removed
in vacuo. More benzene was added and again removed
in vacuo. The process was repeated once more and then
water was added and the mixture stirred and filtered.
1058610
The insoluble solid was again dissolved in benzene (20 ml.)
and a solution of hydrogen chloride (250 mg.) in
benzene (15 ml.) added~ The solid was filtered off and
partitioned between chloroformand dilute ammonia. The
organic layer was washed, dried and evaporated to give
a froth (810 mg.). A portion (300 mg.) was purified
by preparative thin layer chromatography [silica;
developing 6 times with chloroform: acetone (6:1)] to
give material which crystallised from methanol.
Recrystallisation from methanol afforded the title comPound,
hydrated with half a molecule of water, as fine needles,
m-p. 138 - 139~ ~]D + 113.4,
Example 4
21-Diethvlaminoacetoxy-9a-fluoro-11~-hYdroxy-16~-methyl-
17-propionyloxypregna-1,4-diene-3.20-dione hydrochloride
Betamethasone 17-propionate 21-chloroacetate
(1.9 g.) in acetone (100 ml.) was treated with dry
sodium iodide (2 g.) and the mixture refluxed for 2 hours.
Dilution with water afforded crude 21-iodoacetate which
was dried, dissolved in acetone ~80 ml.) and refluxed with
diethylamine (1.2 ml.).for 1.5 hours-Evaporation ofthesolvent
gave a dark red-brown solid which was filtered through
Florisil (70 g~) in ethyl acetateO The material eluted
1058610
with ethyl acetate was dissolved in benzene and treated
at 0 with hydrogen chloride. The solvent and excess
hydrogen chloride were removed in vacuo and the residue
partitioned between water and etherO The aqueous layer
was freeze dried to yield the title comPound hydrated
with two molecules of water, (1.13 gO) as an amorphous
solid, [a] + 84~4 (H20), AmaX 237 - 239 nm (e 14~800)o
Example 5
9a-Fluoro-ll,B-hydroxy-16~-methyl-21-piperidinoacetoxy-17-
~ropionyloxypregna-1,4-diene-3,20-dione hydrochloride
A mixture of betamethasone 17-propionate 21-iodo-
acetate (1~8 g~) and redistilled piperidine (1~44 ml.)
in acetone (80 ml.) was refluxed for ca. 1~ hours then
evaporated in vacuo at room temperature. The residue
was partitioned between a mixture of benzene (100 ml.),
ether (50 ml.), ethyl acetate (50 ml.) and ca 0.5 N
hydrochloric acid (600 ml.), the aqueous phase was
washed with benzene ~2 x S0 ml) then stirred with
chloroform (50 ml.) and basified to pH 8~0 with ammonia.
The aqueous phase was further extracted with chloroform
(3 x 100 ml.) and the combined extracts were washed with
water (20 ml.), decolourised (charcoal), dried and
evaporated in vacuo; the residual foam was triturated
1058610
with petrol to give the 21-piperidinoacetate (1.68 g) as
a pale brown solid, AmaX 237 nm ( 15,200~-
A solution of the crude free base (1.43 g) in
benzene (50 mlO) was cooled to 0 and treated with dry
hydrogen chloride for ca 30 seconds. Volatile material
was removed in vacuo at room temperature, replaced with
fresh benzene and the evaporation was repeated; the
residual material was partitioned between water and
ether and the aqueous phase freeze dried to give the
hydrochloride as a solid (940 mg.) which crystallized
from acetone as colourless needles (799 mgO), mOpO 165-
167.5; concentration of mother liquors gave a second
crop (23 mg.) m.p. 166.5 - 167.5. Recrystallization
of the two crops from acetone gave the analytical sample
of the title compound, hydrated with half a molecule of
water, as colourless hygroscopic needles (688 mg.), m.p.
167.5 - 169.5,[a]D + 80 (very dilute hydrochloric acid),
238 nm (~ 15,700).
max.
- 19
1058610
Example 6
9-Chloro-21-dieth~laminoacetoxy-11~-hydroxy-16~-methyl-
17-propionyloxypregna-1,4-diene-3,20-dione hydrochloride
A solution of 9~-chloro-21-chloroacetoxy-11~-hydroxy-
16~-methyl-17-propionyloxypregna-1,4-diene-3,20-dione
(1.7 g.) in acetone (80 ml.) was treated with sodium
iodide (1.7 g.) and the solution refluxed for 4 hours.
The mixture was poured into water (2 1.) and the precipi-
tated material washed and dried to give the 21-iodoacetate
(1.9 g).
The above iodo-acetate (1.75 g.) in acetone (70 ml.)
was treated with diethylamine ~0.88 ml.) and the mixture
refluxed for 1~ hours. The acetone was removed in vacuo
and water (35 ml.) added. The aqueous mixture was
extracted with chloroform to give the 21-diethylamino-
acetate as a froth (1.6 g.). This material, in benzene
solution, was treated at room temperature with a solution
of hydrogen chloride (106 mg.) in benzene (14.5 ml.).
The benzene was evaporated in vacuo and the residue
partitioned between water and ether. The aqueous solution
was freeze dried to give the title compound (1.41 g.) as
an off white amorphous solid. A portion was purified
further by taking it up in water, extracting with ether,
- 20
10S8610
heating the aqueous solution of the steam bath with charcoal,
filtering and freeze drying the resulting solution, to
give the ~itle compound as a white amorphous solid
solvated with 2.5 molecules of water, [a]D + 92.1 (H2O).
ExamPle 7
9-Chloro-ll,B-hydroxy-16,~-meth~1-21-nicotinylox,v-17-
propionyloxypre~na-1.4-diene-3,20-dione
9a-Chloro-11~,21-dihydroxy-16~-methyl-17-
propionyloxypregna-1,4-diene-3,20-dione (l g.) and
nicotinyl chloride hydrochloride (1 g.) were dissolved
in dry pyridine (17 ml.) and stood at room temperature
for 3 hours. The mixture was then poured into water and
the precipitated solid was filtered off and dried.
Recrystallisation from methanol gave the title compound
as a monohydrate, (924 mg.), m.p. 150 (capillary),
[a]D + 129.6, A inflexion 237 - 239 nm (F ca. 19,600).
~xample 8
_ . . . .. .
9a-Fluoro~ -hydroxy-16~-methvl-21-morpholinoacetoxy-17-
propion~loxx~regna-l,4-diene-3,20-dione.
A mixture of 4-morpholinoacetic acid (1.439g,
prepared bythe method of A.L. Remizov and N.V. Khromov-
Borisov, Zhur. Obshchei Khim., 1953, 23, 794; Chem.
Abs. 1954, 48, 3908e.) and thionyl chloride (5.3ml)
- 21 -
1058610
w~s stirred at ro~ temperature for 18~ hours with
exclusion of atm~spheric moisture. Volatile material
was removed by evaporation at room termperature for
one hour and the residual solid was suspended in dry
tetrahydrofuran (lOml). This was then added to a well
stirred suspension of betamethasone 17-propionate (l.Olg)
in dry tetrahydrofuran (10 ml) containing pyridine
(0.31 ml) and stirring was continued at room temperature
for 3~ hours. Solvent was removed under reduced pressure
and the residue was partitioned between water (200ml.)
and ethyl acetate (200ml.) then adjusted to pH 7 with
saturated sodium bicarbonate solution. The aqueous phase
was extracted with ethyl acetate (lOOml.): the combined
organic phases were washed with water, dried (magnesium
sulphate) and solvent was evaporated to give a pale
yellow foam (1.158g.). The foam was partitioned between
ethyl acetate (50ml.) and 2N-hydrochloric acid (50ml.) and
the organic phase was extracted with more acid (20m1.):
the combined acidic aqueous extracts were washed with
ethyl acetate (30ml.) then adjusted to pH 7 with 2N-
sodium carbonate solution whilst being stirred under ethyl
acetate (50ml.). The aqueous phase was separated and
extracted further with ethyl acetate; the combin~d ethyl
1058610
acetate extracts were washed with water, dried ~agnesium
sulphate) and evaporated to an off-white foam (441 mg).
This was crystallized and recrystallized from acqueous
methanol to give the title 21-morpholinoacetate as colourless
crystals (360 mg.), mP 122-125C (Kofler), [a]D+59.3 (c 1.03,
dioxan), ~max(ethanol) 237.5 nm (ElCm 269), which were
almost homogeneous, the major component being identical
with an authentic specimen on thin-layer chromotography
(silica, chloroform-acetate 2:1, and benzene-acetate
1:1).
Preparation 1
9a-Chloro-21-chloroacetoxy-11~-hvdroxy-16~-methyl-17-
propionyl oxYPregna-l~4-diene-3~2o-dione
9a-Chloro-11~, 21-dihydroxy-16~-methyl-17-
propionyloxy-pregna-1,4-diene-3,20-dione (2 g) in dry
tetrahydrofuran (60 ml.) was treated with pyridine
(1.5 ml.) and chloroacetic anhydride (1.5 g.). The
mixture was stood zt room temperature for 2 hours and
then poured into dilute hydrochloric acid (2 1.). The
precipitated solid (2.34 g) was filtered off, washed and
- 23
10586~0
dried, and a portion (640 mgO) was recrystallised from
acetone-petroleum ether to give the title compound (484 mg.),
m.p. 168-170 (capillary), []D + 86.8, (c 1.37%),~ a
238 nm (~ 13,780).
Preparation 2
Betamethasone 21-chloroacetate 17-propionate
Betamethasone 17-propionate (8.97 g) in dried and
distilled tetrahydrofuran (270 ml) was stirred and treated
with chloroacetic anhydride (4.lg), followed by dry
pyridine (1.57 ml); stirring was continued for 2 hours at
room temperature. Water (50 ml) was added and the
mixture was evaporated at 40. The residue (oil) was
dissolved in ethyl acetate (500 ml.) and extracted first
with a mixture of 2 N hydrochloric acid (30 ml) and water
(270 ml); then with 10% aqueous sodium hydrogen carbonate
(100 ml) and finally with water (500 ml) until the pH of
the washings was neutral. The organic phase was dried
and evaporated at 40. The residue (oil) was dissolved
in ethanol (100 ml) at 60 and evaporated to about 1/3
volume. ~n cooling a white product began to separate, which
was collected and dried in vacuo to give the title comPound
(9.0 g) m.p. 180 - 185.
1058610
Preparation3
Betamethasone 21-iodoacetate 17-proPionate
Crude betamethasone 17-propionate 21-chloroacetate
(4.5 g.) and dry sodium iodide (4.8 g.) in acetone (230 ml.)
were refluxed for 3 hours. After being cooled the
reaction mixture was poured into water (600 ml.) to give,
after prolonged stirring, a colourless solid (4.26 g.).
A portion (194 mg.) was recrystallised twice from methanol
to give the title compound as colourless crystals (122 mg.),
m.p. 180-182, [a]D + 46, ~max 238 nm ( 16,100).
- 25
10586~0
The following Examples illustrate pharmaceutical
compositions according to the invention
Example A:Water - miscible cream
Active ingredient (free base) 0.1% w/w
Beeswax 15.0%
Glycerol 15.0%
Polyoxyethylene 25 lanolin
derivative 2.0%
Methyl paraben 0.08%
Propyl paraben 0.2%
Sodium citrate B.P. 0.15%
Citric acid qs. to pH 6.5-7.5
Water to 100.00%
Melt together the beeswax and polyoxyethylene 25 lanolin
derivative and heat to 75C. Mix some or all of the
glycerol with some or all of the water and heat to 75C.
Dissolve the parabens and sodium citrate in the aqueous
solution and mix the two phases. Stir with cooling
to 50-60C and then either dissolve the active ingredient
in the remaining water and add this to the base with
stirring or ball-mill the active ingredient in the
remaining glycerol and add the resultant suspension to
the base with stirring. Add sufficient citric acid
to adjust the pH to 6.5-7.5, and continue stirring until
coo 1 .
~xample B:Oral tablet
Active ingredient (free base) 0.5 mg.
Lactose 175.5 mg.
Maize starch (dried) 20.0 mg.
Gelatin 2.0 mg.
Magnesium stearate 2.0 mg.
Tween 80 Trace
Total weight 200.0 mg
- 26 -
10S8610
A suspension of 300 mg. of the active ingredient in 2 ml. of water containing
0.1% of Tween* 80 is milled for 16 hours in a 10 ml. nylon pot about three
quarters filled with steatite balls, until 90% by number of the particles
have a diameter of less than 5 microns with none greater than 50 microns.
The maize starch and lactose are blended and passed through a 60 mesh B.S.
sieve and granulated with a solution of gelatin, containing the suspension
of the active ingredient and washings from the nylon pot, by passing through
a 16 mesh B.S. sieve. The granules are dried at 40C overnight, passed
through a 20 mesh B.S. sieve and blended with magnesium stearate and tabletted
using a tabletting machine having a 5/16 inch flat-bevelled punch.
The active ingredient may alternatively be used in the form of a
salt, in which case the quantity used will be that containing 0.5 mg. free
base, the quantity of lactose being correspondingly reduced.
Where the active ingredient dissolves in the water component, the
ball milling stage may be omitted.
~ Trade Mark
. . ~
~ -27-
