PHARMACEUTICAL PREPARATIONS

PREPARATIONS PHARMACEUTIQUES

English Abstract

Abstract



Topically applicable pharmaceutical preparation,
containing a D-homosteroid of the formula


Image I

in which R6 signifies hydrogen, methyl,
chlorine or fluorine, R9 signifies
hydrogen, fluorine or chlorine, R11 sig-
nifies oxo or (.alpha.-H,.beta.-OH), R17a signifies
hydroxy or acyloxy, R20 signifies a
group -O-R201 or -CH2 -R21, R201 signifies
lower-alkyl, chloro-lower-alkyl or fluoro-
-lower-alkyl, R21 signifies hydrogen,
chlorine, fluorine, hydroxy or acyloxy
and the dotted 1,2-bond signifies an
optional C-C bond, and, where R20 is a
group -O-R201, a double bond can be
present in the 16,17-position,



and a compound of the formula

Image II

in which R1 signifies hydrogen, halogen,
lower-alkyl or lower-alkoxy and R2, R3 and
R4 signify hydrogen, lower-alkoxy, hydroxy-
-lower-alkoxy or two adjacent symbols R1,
R2, R3 and R4 together signify methylene-
dioxy, and at least one symbol R1, R2, R3
or R4 contains oxygen.

Claims

- 11 -
The embodiments of the invention in which an exclusive property
or privilege is claimed are defined as follows:
1. A process for the preparation of topically applicable
pharmaceutical compositions, which process comprises mixing
a D-homosteroid of the formula

Image I

in which R6 signifies hydrogen, methyl,
chlorine or fluorine, R9 signifies
hydrogen, fluorine or chlorine, R11
signifies oxo or (.alpha.-H,.beta.-OH), R17a sig-
nifies hydroxy or acyloxy, R20 sig-
nifies a group -O-R201 or -CH2-R21
R201 signifies lower-alkyll chloro-
-lower-alkyl or fluoro-lower-alkyl, R21
signifies hydrogen, chlorine, fluorine,
hydroxy or acyloxy and the dotted 1,2-
-bond signifies an optional C-C bond,
and, where R20 is a group -O-R201, a
double bond can be present in the 16,17-
-position,


-12-

and a compound of the formula

Image II

in which R1 signifies hydrogen, halogen,
lower-alkyl or lower-alkoxy and R2, R3 and
R4 signify hydrogen, lower-alkoxy, hydroxy-
lower-alkoxy or two adjacent symbols R1,
R2, R3 and R4 together signify methylene-
dloxy, and at least one symbol R1, R2, R3 or
R4 contains oxygen,
the concentration of the D-homosteroid of formula I amounting
to between about 0.001 and 0.5% and that of the compound of
formula II to between about 0.5 and 10%, by weight, and
bringing the mixture into a suitable topically applicable
galenical form.
2. A process according to claim 1, wherein the D-homosteroid
of formula I is unsaturated in the 1,2-position and R6 is
hydrogen, R9 is hydrogen or fluorine, R11 is hydroxy, R17a is
acyloxy, especially C1-7-alkanoyloxy, R20 is a group -CH2-R21


-13-

and R21 is acyloxy, especially C1-7-alkanoyloxy, or hydrogen
or hydroxy.

3. A process according to claim 2, wherein in the D-homo-
steroid of formula I a double bond is present in the 1,2-
position and R6 and R9 are hydrogen, R11 is hydroxy, R17a is
propionyloxy or especially butyryloxy, R20 is a group -CH2-R21
and R21 is acetoxy, hydroxy or especially hydrogen.
4. A process according to claim 1, wherein the D-homosteroid
is 17a-butyryloxy-11.beta.-hydroxy-D-homopregna-1,4-diene-3,20-dione.
5. A process according to claim 1, wherein in the compound of
formula II R1 and R4 are hydrogen, R2 is ethoxy, isopropoxy or
especially butoxy and R3 is methoxy.
6. A process according to claim 6, wherein the compound of
formula II is D,L-4-(3-butoxy-4-methoxybenzyl)-2-imidazolidinone.
7. A process according to claim 1, wherein the D-homosteroid
is 17a-butyryloxy-11.beta.-hydroxy-D-homopregna-1,4-diene-3,20-dione,
17a-butyryloxy-9-fluoro-11.beta.-hydroxy-D-homopregna-1,4-diene-3,
20-dione, 21-acetoxy-9-fluoro-11.beta.-hydroxy-17a-propionyloxy-D-
homopregna-1,4-diene-3,20-dione, 17a-butyryloxy-11.beta., 21-dihydro-
D-homopregna-1,4-diene-3,20-dione or 17a-butyryloxy-21-chloro-
9-fluoro-11.beta.-hydroxy-D-homopregna-1,4-diene-3,20-dione and the
compound of formula II is D,L-4-(3-butoxy-4-methoxybenzyl)-2-
imidazolidinone or D,L-4-(3-isopropoxy-4-methoxybenzyl)-2
imidazolidinone.
8. A process in accordance with claim 1 wherein the D-homo-
steroid is 17a-butyryloxy-11.beta.-hydroxy-D-homopregna-1,4-diene-
3,20-dione and the compound of formula II is D,L-4-(3-butoxy-



-14-

4-methoxybenzyl)-2-imidazolidinone.
9. A composition for topical application, comprising a D-
homosteroid of the formula

Image I

in which R6 signifies hydrogen, methyl,
chlorine or fluorine, R9 signifies
hydrogen, fluorine or chlorine, R11
signifies oxo or (.alpha.-H,.beta.-OH), R17a sig-
nifies hydroxy or acyloxy, R20 sig-
nifies a group -O-R201 or -CH2-R21,
R201 signifies lower-alkyl, chloro-
lower-alkyl or fluoro-lower-alkyl, R21
signifies hydrogen, chlorine, fluorine,
hydroxy or acyloxy and the dotted 1,2-
bond signifies an optional C-C bond,
and, where R20 is a group -O-R201, a
double bond can be present in the 16, 17-
position;


-15-



and a compound of the formula

Image II

in which R1 signifies hydrogen, halogen,
lower-alkyl or lower-alkoxy and R2, R3 and
R4 signify hydrogen, lower-alkoxy, hydroxy-
lower-alkoxy or two adjacent symbols R1,
R2, R3 and R4 together signify methylene-
dioxy, and at least one symbol R1, R2, R3
or R4 contains oxygen;

the concentration of the D-homosteroid of formula I amounting
to between about 0.001 and 0.5%, and that of the compound of
formula II to between about 0.5 and 10%, by weight,
the mixture being in a suitable topically applicable
galenical form.

10. A composition according to claim 9, wherein the D-homo-
steroid of formula I is unsaturated in the 1,2-position and
R6 is hydrogen, R9 is hydrogen or fluorine, R11 is hydroxy,
R17a is acyloxy, especially C1-7 -alkanoyloxy, R20 is a


-16-


group -CH2-R21 and R21 is acyloxy, especially C1-7-alkanoyl
oxy, or hydrogen or hydroxy.
11. A composition according to claim 10, wherein in the
D-homosteroid of formula I a double bond is present in the
1,2-position and R6 and R9 are hydrogen, R11 is hydroxy, R17a
is propionyloxy or especially butyryloxy, R20 is a group -CH2-
R21 and R21 is acetoxy, hydroxy or especially hydrogen.
12. A composition according to claim 9, wherein the D-homo-
steroid is 17a-butyryloxy-11.beta.-hydroxy-D-homopregna-1,4-diene-
3,20-dione.
13. A composition according to claim 9, wherein in the com-
pound of formula II R1 and R4 are hydrogen, R2 is ethoxy,
isopropoxy or especially butoxy and R3 is methoxy.
14. A composition according to claim 9, wherein the compound
of formula II is D,L-4-(3-butoxy-4-methoxybenzyl)-2-imidazo-
lidinone.
15. A composition according to claim 9, wherein the D-homo-
steroid is 17a-butyryloxy-11.beta.-hydroxy-D-homopregna-1,4-diene-
3,20-dione, 17a-butyryloxy-9-fluoro-11.beta.-hydroxy-D-homopregna-
1,4-diene-3,20-dione, 21-acetoxy 9-fluoro-11.beta.-hydroxy-17a-
propionyloxy-D-homopregna-1,4-diene-3,20-dione, 17a-butyry-
loxy-11.beta., 21-dihydro-D-homo-pregna-1,4-diene-3,20-dione or
17a-butyryloxy-21-chloro-9-fluoro-11.beta.-hydroxy-D-homopregna-1,
4-diene-3,20-dione and the compound of formula II is D,L-4-
(3-butoxy-4-methoxybenzyl)-2-imidazolidinone or D,L-4-(3-
isopropoxy-4-methoxybenzyl)-2-imidazolidinone.
16. A composition according to claim 9 wherein the


-17-

D-homosteroid is 17a-butyryloxy-11.beta.-hydroxy-D-homopregna-1,4-
diene-3,20-dione and the compound of formula II is D,L-4-(3-
hutoxy-4-methoxybenzyl)-2-imidazolidinone.

Description

til6 RA~? 4_51~



The present invention is concerned with topically
applicable pharmaceutical preparations which have, in
particular, antiinflammatory activity. The preparations in
accordance with the invention contain as the active
substances a D-homosteroid of the formula


coR2c~
R1~Rl?a

I


~6


in which R6 signified hydrogen, methyl,
chlorine or fluorine, R signifies
hydrogen, fluorine or chlorine, Rll
signifies oxo or (~-H,~ OH), R 7a sig-
nifies hydroxy or acyloxy, R20 signifies
a group O-R20l or -CH _R21 R201
nifies lower-alkyl, chloro-lower-alkyl
or fluoro-lower-alkyl, R21 signifies
hydrogen, chlorine, fluorine, hydroxy


Mé/10. 3 . 82


or acyloxy and the dotted 1,2-bond

signifies an optional C-C bond, and,
where R20 is a group -O-R20l~ a double

bond can be present in the 16,17-
-position,
and a compound of the formula

R2 Rl
R ~ r~C II

R4 NH~



in which Rl signifies hydrogen, halogen,
lower-alkyl or lower-alkoxy and R2, R3 and
R4 signifies hydrogen, lower-alkoxy, hydroxy-
-lower-alkoxy or two adjacent symbols
R , R , R and R together signify methyl-
enedioxy, and at least one symbol Rl, R2,
R3 or R4 contains oxygen.



An acyloxy group can be derived from a saturated or
unsaturated aliphatic carboxylic acid containing up to
7 C atoms such as formic acid, acetic acid, propionic acid,
butyric acid, pivalic acid, valeric acid and oenanthic acid.


-- 3 --


Cl 7-alkanoyloxy groups such as acetoxy, propionyloxy and
butyryloxyarepreferred. Lower-alkyl groups can be
straight-chain or branched-chain and can contain 1 to 6,
preferably 1 to 4, carbon atoms. Examples of such groups
are methyl, ethyl, propyl and n-butyl.



Preferred D-homosteroids of formula I are those
which are unsaturated in the 1,2-position and R6 is
hydrogen, R9 is hydrogen or fluorlne, Rl1 is hydroxy, R17a
is acyloxy, especially Cl 7-alkanoyloxy, R20 is a group
-CH2-R 1 and R21 is acyloxy, especially Cl 7-alkanoyloxy,
or hydrogen or hydroxy. Especially preferred are the 1,2-
unsaturated D-homosteroids of formula I in which R6 and R9
are hydrogen, Rll is hydroxy, R17a is propionyloxy or
especiallybutyryloxy, R20 is a group -C~2-R21 and R21 is
acetoxy, hydroxy or especially hydrogen. Examples of
preferred D-homosteroids of formula I are:



17a-Butyryloxy-9-fluoro~ -hydroxy-D-homopregna-
-1,4-diene-3,20-dione;
21-acetoxy-9-fluoro-11~-hydroxy-17a-propionyloxy-D-
-homopregna-1,4-diene-3,20-dione;
17a-butyryloxy-11~,21-dihydroxy-D-homopregna-1,4-
-diene-3,20-dione; and especially
17a-butyryloxy-11~-hydroxy-D-homopregna-1,4-diene-

-3,20-dione.

-- 4 --

Examples of other D-homosteroids of formula I are:

21-Chloro-11~,17a-dihydroxy-9-fluoro-D-homopregna-l,
4-diene-3,20-dione;
17a-butyryloxy-21-chloro 9-fluoxo~ -hydroxy-D-homo-
pregna 1,4-diene-3,20-dione;
17a,21-diacetoxy-9-fluoro~ -hydroxy-D-homopregna-
-1,4-diene-3,20-dione;
17a-butyryloxy~ ,21-dihydroxy-9-fluoro-D-homopregna-
-1,4-diene-3,20-dione;
9-chloro-17a,21-dihydroxy-11~-hydroxy-D-homopregna-
-1,4-diene-3,2C-dione;
21-acetoxy-9-fluoro-11~-hydroxy-17a-propionyloxy-D-
-homopregn-4-ene-3,20-dione;
17a-butyryloxy-11~-hydroxy-D-homopregn-4-ene-3,20-
-dione;
ll~-hydroxy-3-oxo-17a-propionyloxy-D-homoandrosta- -
-1,4-diene-17a~-carboxylic a~id methyl ester;
llB-hydroxy-3-oxo-17a-propionyloxy-D-homoandrosta-
-1,4-diene-17a~-carboxylic acid chloromethyl ester;
17a-acetoxy-6a,9-difluoro-11~-hydroxy-3-oxo-~-homo-
androsta-1,4-diene-17a~-carboxylic acid methyl ester.

Preferred compounds of formula II in the scope of
the present invention are those in which Rl and R4 are
hydrogen, R2 is ethoxy, isopropoxy or especially butoxy

-- 5



and R3 is metho~y, especially D,L-4-(3-butoxy 4-methoxy~
benzyl)-2-imidazolidinone.



Compounds of formula II are described, for example,
in German published Patent Specification 2 108 438.
Further, it is known, for example from German yublished
Patent Specifications 2 614 079 and 2 ~38 363 and European
published Patent Specification 13 959, that D-homosteroids

haue an intiinfla~natory activity. It has now been found
that this activity is increased in a surprising manner by
compounds of formula II.



The preparations in accordance with the invention can
be used for the therapy of inflammatory and allergic
dermatological conditions such as psoriasis, eczema (e.g.
chronic eczema), dermatitis (e.g. contact dermatitis and
neurodermatitis) and related diseases. The invention is
concerned with the use of said preparations in the
treatment of inflammatory and allergic dermatological
conditions, as well as a method for the treatment of such
conditions by administration of the preparations in
accordance with the inventionO




Examples of topical application forms of the prep-
arations in accordance with the invention are fatty ointments,
ointments, creams, hydrophilic creams, gels and lotions.


~ 6 --


Conveniently, in the preparations in accordance
with the invention the concentration of a D-homosteroid of
formula I amounts to between about 0.001% and 0.5%,
preferably between about 0.005~ and 0.05~, and the
S concentration of a compound of formula II amounts to
between about 0.5% and 10%, preferably between about 2% and
5%.



The pr~parations in accordance with the invention can
contain one or more D-homosteroids of formula I or one or
more compounds of formula II.



In accordance wi.th another aspect of the invention,
the present invention provides a process for the preparation
of topically applicable pharmaceutical compositions, which process
comprises mixing a D-homosteroid of the formula I above and a
compound of the formula II above, concentration of the D-homosteroi
of formula I amounting to between about 0.001 and 0.5% and that
of the compound of formula II to between about 0.5 and 10%, by
weight, and bringing the mixture into a suitable topically
applicable galenical form. The techniques for effecting this
are familiar to any person skilled in the art. They involve
mixing the active substance components with suitable non-toxic,
inert, compatible solid or liquid carriQr materials, including
the usual adjuvants such as stabilizing, preserving, wetting or
emulsifying agents.




1~

~ 7 --


The following Examples illustrate the present
invention:



Example 1



An ointment hav~ng the following composition is
manufactured in a manner known per ~e:



17a-Butyryloxy~ hydroxy-D-
-homopregna-1,4~diene-3,20-dione * 0.05 g or 0.01 g
D,~-4-(3-Butoxy-4~methoxybenzyl)-
-2-im1dazolidinone * 5 g
10 Vaseline, white 35 g
Wax, white 4 g
Paraffin oil, viscous 18.995 g or 18.990 g
DEHYMULS E ** 7 . g
Water, deionized ad 100 g



* finely ground
** high molecular weight aliphatic mixed ester; supplier:
Deutsche Hydrierwerke




Example 2



An ointment having the following composition is
manufactured in a manner known per se:

*Trademark


~,. ,
L.' ~ ~ .

~ 8 --

17a-Buty.ryloxy-9-fluoro~
-hydroxy-D-homopregna-1,4-
-diene-3,20-dione 0.01 g or 0.005 g
D,L-4-(3-Butoxy-4-methoxy-
5 benzyl~-2-imidazolidinone 2.5 g
Vaseline, white 35 g
Wax, white 5 Y
Paraffin oil, viscous19 g
DEHYMULS E 7 g
10 Water, deioniæed ad 100 g

Example 3

A fatty ointment having the following composition
is manufactured in a manner known per se:

17a-Butyryloxy-11~,21-dihydroxy-
-D-homopregna-1,4-diene-3,20-dione 0.01 g or 0.05 g
D,L-4-(3-Butoxy-4-methoxy-
benzyl)-2-imida~olidinone 2.5 g
Paraffin oil 10 g
Wax, microcrystalline 15 g
20 Vaseline 72.5 g

- 9 .-


Exam~e_4

A cream having the following composition is manu-
factured in a manner known per se:

21-Acetoxy~9-fluoro~ -hydroxy-
5 -17a-propionyloxy-D homopregna-1,4-
-diene-3,20 dione . 0~01 g or 0.02 g
DJ1-4- (3-Butoxy-4-methoxy-
benzyl)-2-imidazolidinon~ 4.0
Glycerine monostearateio.o g
10 Tween ~0 * 2.0 g
Cetyl alcohol S.0 g
Paraffin oil, viscous7.0 g
Methyl paraben **0.15 g
Propylene glycol 20.0 g
15 Water, deionized ad 100 g

* Polyethylene oxide sorbitan stearate
** Methyl 4~hydroxybenzoate

ExamE~ 5

Preparations corresponding to Examples 1-4 are
20 manufactured in a manner known per se using 0.01 g or 0.03 g
of 17a-butyryloxy-21-chloro-9-fluoro-11~-hydroxy-D~homo-
pregna-1,4-diene-3,20-dione as the active substance

*Trademark

-- 10 --

component of formula I, 3.0 g of D,L-4-(3 isopropoxy-4-
-methoxybenzyl)-2-imidazolidinone (microni2ed) as the
active substance component of formula II and the same
carriers and excipients as in Examples 1-4.