NZ200475A

NZ200475A - Topical anti-inflammatory compositions containing d-honosteroids

Info

Publication number: NZ200475A
Application number: NZ200475A
Authority: NZ
Inventors: G Klecak; M Mueller
Original assignee: Hoffmann La Roche
Priority date: 1981-06-11
Filing date: 1982-04-30
Publication date: 1985-08-30
Also published as: IL65976A0; AU8463582A; CA1188616A; DK175782A; PH18457A; EP0067347A1

Description

New Zealand Paient Spedficaiion for Paient Number £00475 2 0 04 Prior ri-y Dats{3): . 11 ~M Complete Specification Filed: o,e> Class: Publication Date: . P.O. Journal, No: ■ ftUGWeiS ','i'ink HO NEW ZEALAND No.: Date: PATENTS ACT, 1953 COMPLETE SPECIFICATION PHARMACEUTICAL PREPARATIONS C? We, F. HOFFMANN-LA ROCHE & CO. AKTIENGESELLSCHAFT, 124-184 Grenzacherstrasse, Basle, Switzerland, a Swiss company, _ jMSh.. -Jt/ hereby declare the invention for which51-/ we pray that a patent may be granted to jaae/us, and the method by which it is to be performed, to be particularly described in and by the following statement: - (followed by la) 2 004 7 la- RAN 4051/a The present invention is concerned with topically applicable pharmaceutical preparations which have, in 5 particular, antiinflammatory activity. The preparations in accordance with the invention contain as the active substances a D-homosteroid of the formula COR 0 I g in which R signified hydrogen, methyl, 9 chlorine or fluorine, R signifies hydrogen, fluorine or chlorine, R^"1 signifies oxo or (a-H,i3-0H), R17a sig- nifies hydroxy or acyloxy, R signifies a group -0-R201 or -CH2-R21, R201 sig- nifies lower-alkyl, chloro-lower-alkyl 21 or fluoro-lower-alky1, R signifies hydrogen, chlorine, fluorine, hydroxy 2 004-75 or acyloxy and the dotted 1,2-bond signifies an optional C-C bond, and, • where R20 is a group -O-R20^", a double bond can be present in the 16,17--position, and a compound of the formula II in which R signifies hydrogen, halogen, 2 3 lower-alkyl or lower-alkoxy and R , R and 4 R signifies hydrogen, lower-alkoxy, hydroxy- -lower-alkoxy or two adjacent symbols 12 3 4 R , R , R and R together signify methyl- 1 2 enedioxy, and at least one symbol R , R , 3 4 R or R 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. 20047 C^__?-alkanoyloxy groups such as acetoxy, propionyloxy and butyryloxy are preferred. Lower-alkyl groups contain 1 to 6, preferably 1 to 4, carbon atoms and can be straight-chain or branched-chain. Examples of such groups are methyl, ethyl, propyl and n-butyl. Lower-alkoxy groups contain 1 to 6, preferably 1 to 4, carbon atoms and the lower alkyl moiety can be straight-chain or branched-chain.

Preferred D-homosteroids of formula I are those which are unsaturated in the 1,2-position and is 9 11 17a hydrogen, R is hydrogen or fluorine, R is (a-H, g-OH), R is acyloxy, especially C-^_^-alkanoyloxy, R^° is a group 21 21 -CH^-R and R is acyloxy, especially C^_^-alkanoyloxy, or hydrogen or hydroxy. Especially preferred are the 1,2- 6 9 -unsaturated D-homosteroids of formula I in which R and R are hydrogen, R"*""^ is (a-H, g-OH), R*^a is propionyloxy or 21 21 especially butyryloxy, R is a group -CH2~R and R is acetoxy, hydroxy or especially hydrogen. Examples of preferred D-homosteroids of formula I are: 17a-Butyryloxy-9-fluoro-110-hydroxy-D-homopregna--1,4-diene-3,20-dione; 21-acetoxy-9-fluoro-ll/3-hydroxy-17a-propionyloxy-D--homopregna-1,4-diene-3,20-dione; 17a-butyryloxy-llfi,21-dihydroxy-D-homopregna-l,4--diene-3 , 20-dione •, and especially 17a-butyryloxy- 11/3-hydroxy-D-homopregria-l, 4-diene- ' -3,20-dione. f " 20 JUNi985 Examples of other D-homosteroids of formula I are: 21-Chloro-ll0,17a-dihydroxy-9-fluoro-D-homopregna-1, 4-diene-3,20-dione; 17a-butyryloxy-21-chloro-9-fluoro-110-hydroxy-D-homo-5 pregna-1,4-diene-3,20-dione; 17a,21-diacetoxy-9-fluoro-110-hydroxy-D-homopregna--l,4-diene-3,20-dione; 17a-butyryloxy-ll0,21-dihydroxy-9-fluoro-D-homopregna--1,4-diene-3,20-dione; 10 9-chloro-17a,21-dihydroxy-ll0-hydroxy-D-homopregna- -1,4-diene-3,20-dione; 21-ace toxy-9-fluoro-110-hydroxy-17 a-propi onyloxy-D--homopregn-4-ene-3,20-dione; * 17a-butyryloxy-ll0-hydroxy-D-homopregn-4-ene-3,20-15 -dione; 110-hydroxy-3-oxo-l7 a-propionyloxy-D-homoandros ta--1,4-diene-17a0-carboxylic acid methyl ester; 110-hydroxy-3-oxo-l7a-propionyloxy-D-homoandrosta--1,4-diene-17a0-carboxylic acid chloromethyl ester; 20 17a-acetoxy-6a,9-difluoro-110-hydroxy-3-oxo-D-homo- androsta-1,4-diene-17a0-carboxylic acid methyl ester.

Preferred compounds of formula II in the scope of 1 4 the present invention are those in which R and R are 2 hydrogen, R is ethoxy, isopropoxy or especially butoxy and is methoxy, especially D,L-4-(3-butoxy-4-methoxy-benzyl ) -2-irnidazolidinone .

Compounds of formula II are described, for example, in New Zealand Patent Specification No. 162836. Further, it is known, for example from New Zealand Patent Specifications Nos. 180233, 185046 and 192642, that D-homosteroids have an intiinflammatory 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 invention.

Examples of topical application forms of the preparations in accordance with the invention are fatty ointments, ointments, creams, hydrophilic creams, gels and lotions. 200475 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 concentration of a compound of formula II amounts to between about 0.5% and 10%, preferably between about 2% and 5%.

The preparations in accordance with the invention can contain one or more D-homosteroids of formula I or one or 10 more compounds of formula II.

The manufacture of the preparations in accordance with the invention can be carried out in a manner which is familiar to any person skilled in the art by mixing the active substance components with suitable, non-toxic, 15 inert, compatible solid or liquid carrier materials, including the usual adjuvants such as stabilizing, preserving, wetting or emulsifying agents. 200475 The following Examples illustrate the present invention: Example 1 An ointment having the following composition is 5 manufactured in a manner known per se: 17a-Butyryloxy-llj3-hydroxy-D- -homopregna-1,4-diene-3,20-dione * 0.05 g or 0.01 g D,L-4-(3-Butoxy-4-methoxybenzyl)- -2-imidazolidlnone * 5 g Vaseline, white 3 5 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: 2004 17a-Butyryloxy-9-fluoro-llj3--hydroxy-D-homopregna-1,4- -diene-3,20-dione 0.01 g or 0.005 D,L-4-(3-Butoxy-4-methoxy- benzyl)-2-imidazolidinone 2.5 g Vaseline, white 35 g Wax, white 5 g Paraffin oil, viscous 19 g DEHYMULS E 7 g Water, deionized ad 100 g Example 3 A fatty ointment having the following composition is manufactured in a manner known per se: 17a-Butyryloxy-ll0,21-dihydroxy-15 -D-homopregna-1,4-diene-3,20-dione 0.01 g or 0.05 g D,L-4-(3-Butoxy-4-methoxy- benzyl)-2-imidazolidinone 2.5 g Paraffin oil 10 g Wax, microcrystalline 15 g Vaseline 72.5 g 2 004 75 " 9 - Example 4 A cream having the following composition is manufactured in a manner known per se: 21-Acetoxy-9-fluoro-110-hydroxy- -17a-propionyloxy-D-homopregna-l,4- -diene-3,20-dione 0 .01 g D,L-4-(3-Butoxy-4-methoxy- benzyl)-2-imidazolidinone 4 .0 g Glycerine monostearate .0 g Tween 60 * 2 .0 g Cetyl alcohol .0 g Paraffin oil, viscous 7 .0 g Methyl paraben ** 0 .15 g Propylene glycol .0 g Water, deionized ad 100 g * Polyethylene oxide sorbitan stearate ** Methyl 4-hydroxybenzoate Example 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-110-hydroxy-D-homo-pregna-1,4-diene-3,20-dione as the active substance

Claims

- 10 - 2 004 component of formula I, 3.0 g of D,L-4-(3-isopropoxy-4--methoxybenzyl)-2-imidazolidinone (micronized) as the active substance component of formula II and the same carriers and excipients as in Examples 1-4. n ir-i /{ - 11 - gg ^5r/9- WHAT fWE CLAIM IS SLAXMS-:

1. Topically applicable pharmaceutical preparation, containing a D-homosteroid of the formula COR 20 - - R 17a 10 15 in which R signifies hydrogen, methyl, g chlorine or fluorine, R signifies hydrogen, fluorine or chlorine, R"^ signifies oxo or (a-H,/3-0H) , R^a sig- 20 nifies hydroxy or acyloxy, R sig- 201 21 nifies a group -0-R or -CI^-R , R 201 signifies lower-alkyl, chloro- 21 -lower-alkyl or fluoro-lower-alkyl, R 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 -0-R20"*", a double bond can be present in the 16,17--position, - 12 - 200475 and a compound of the formula in which signifies hydrogen, halogen, 2 3 lower-alkyl or lower-alkoxy and R , R and 4 5 R signify hydrogen, lower-alkoxy, hydroxy- -lower-alkoxy or two adjacent symbols R^",

2 3 4 R , R and R together signify methylene- 12 3 dioxy, and at least one symbol R , R , R 4 or R contains oxygen. 10 2. A preparation according to claim 1, wherein the D- -homosteroid of formula I is unsaturated in the 1,2- -position and R® is hydrogen, R^ is hydrogen or fluorine, R^ is (a-H, B-OH) , R^ a is C^_^-alkanoyloxy, is a 21 21 group -CI^-R and R is C^_^-alkanoyloxy, or hydrogen or hydroxy. 20047 - 13 -

3. A preparation according to claim 1 or 2, wherein in the D-homosteroid of formula I a double bond is present 6 9 11 in the 1,2-position and R and R are hydrogen, R is (a-H, g-OH) , R"^a is propionyloxy or butyryloxy, R^ is 21 21 a group -CH^R and R is acetoxy, hydroxy or hydrogen.

4. A preparation according to any one of claims 1-3, wherein the D-homosteroid is 17a-butyryloxy-ll0-hydroxy- - D-homopregna-1, 4-diene-3, 20-dione.

5. A preparation according to any one of claims 1-4, 1 4 wherein in the compound of formula II R and R are 2 3 hydrogen, R is ethoxy, isopropoxy or butoxy and R is methoxy.

6 . A preparation according to any one of claims 1-5 , wherein the compound of formula II is D,L-4-(3-butoxy-4--methoxybenzyl)-2-imidazolidinone.

7. A preparation according to any one of claims 1-6, wherein the D-homosteroid is 17a-butyryloxy-11(3-hydroxy-D--homopregna-1, 4-diene-3 , 20-dione, 17a-butyryloxy-9-fluoro--110-hydroxy-D-homopregna-l, 4-diene-3, 20-dione , 21-acetoxy- - 9- f luoro-110-hy droxy-17a-propiony loxy-D-homopregna-1,4- A -diene-3,20-dione, 17a-butyryloxy-ll0, 21-dihydro-D-homo-<vpregna-l, 4-aiene-3 , 20-dione or 17a-butyryloxv-21-chloro-9- 2 0 14 RS 4 051/9 -fluoro-110-hydroxy-D-homopregna-l,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 preparation in accordance with any one of claims 1--7, wherein the D-homosteroid is 17a-butyryloxy-ll3-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 . -..cD THiS SOt-L day OF A. J £ SON Pbl. i // • £ rfe. AGHNT^S F OF'l THE APPLICANTS