CH618186A5 - Process for the preparation of 3,20-diketopregnenes having a 11beta-acetal group. - Google Patents

Abstract

The steroids of formula I, as well as their 1,2- or 6,7-dehydro derivatives, are prepared by condensing a corresponding 11 beta -hydroxy-3,20-diketopregnene with a benzaldehydedialkylacetal of formula II. In these formulae: R1 is an alkyl group, R2 is a hydrogen atom, an alkyl group, an alkoxy group or a halogen atom, R3 is a hydrogen atom, an acyloxy group, a halogen atom or a hydroxyl group; R4 is a hydrogen or halogen atom, R5 is a hydrogen atom, an alkyl or aryl group, R6 is an alkyl or aryl group, R7 is a hydrogen atom, a chlorine atom or a methyl group and R8 is a hydrogen atom, a chlorine atom or a methyl group. The steroids of formula I possess glucocorticoid and anti-inflammatory activity and are soluble in slightly polar solvents. <IMAGE>

Description

The object of the present invention is the preparation of steroids having local and general anti-inflammatory activity and which can be easily composed in slightly polar solvents such as castor oil or propylene carbonate.

This goal will be clear to those skilled in the art and the steroids of the present process meet this goal.

The present steroids are those of formula:

20

CH ..- R

-0.

:This.

■ nc

'R,

and their 1,2- and 6,7-dehydro derivatives; pregn-4-enes and pregna-1,4-dienes are preferred. In the formula I and throughout the description, the symbols have the meaning below:

Ri is an alkyl group;

R2 is a hydrogen atom, an alkyl group, an alkoxy group or a halogen atom;

R3 is a hydrogen atom, an acyloxy group, a halogen atom or a hydroxyl group;

R4 is a hydrogen or halogen atom;

Rs is a hydrogen atom, an alkyl or aryl group;

R6 is an alkyl or aryl group;

R7 is a hydrogen, fluorine or methyl group and

Rs is a hydrogen atom, chlorine or a methyl group.

The term "alkyl" used throughout the description refers to straight or branched chain alkyl groups having from 1 to 8 carbon atoms. Preferred are alkyl groups having 1 to 3 carbon atoms.

The term "halogen" used here refers to fluorine, chlorine, bromine and iodine.

The term "acyloxy" used herein refers to groups where the acyl moiety is a physiologically acceptable acid residue derived from an organic acid. Examples of monocarboxylic acids are those of formula Y-COOH in which Y is an alkyl, cyclo-alkyl group having 3 to 6 carbon atoms, arylalkyl or aryl; for example acetic, propionic, valeric, cyclohexane carboxylic acids,

phenylacetic, benzoic and toluic. Examples of polycarboxylic acids are malonic, succinic, glutaric, adipic, pimelic and phthalic acids.

The term "aryl" used herein refers to a phenyl or phenyl group substituted by 1 or 2 alkyl groups, alkoxy or halogen atoms.

The term "alkoxy" used herein refers to a group of the formula alkyl-O- where the alkyl group has the above meaning.

The steroids of the present method are physiologically active substances which have an anti-inflammatory and glucocorticoid activity and which can therefore be used in place of the known glucocorticoids for the treatment of chronic progressive polyarthritis, and for this purpose it is possible to administer them like hydrocortisone, adjusting the dose for example according to the relative potency of the particular steroid. In addition, the steroid ss of the present method can be used locally in place of glucocorticoids known for the treatment of skin conditions such as dermatitis, psoriasis, sunburn, neurodermatitis, eczema and pruritis. anogenital.

When administered orally, the present compositions can be used at a daily dose of 0.1 to 200 mg / 70 kg and preferably 0.3 to 100 mg / 70 kg. If administered locally, the present compounds can be used in an amount of 0.01 to 5.0% by weight and preferably 0.05 to 2.0% by weight in a conventional cream or lotion. 65 The 3,20-diketopregnenes of formula I are prepared by reacting an 11 ß-hydroxy-3,20-diketopregnene corresponding to the steroid of formula I with a benzaldehyde dialkyl acetal of formula:

618186

4

gold.

^ V ~ X j "

The reaction can be carried out in an aprotic solvent, for example a hydrocarbon such as benzene or toluene. The reaction is carried out under acidic conditions (for example in the presence of an organic acid such as p-toluene sulfonic acid) and it can be carried out at the reflux temperature of the solvent or close to it.

Various variants and modifications of the present process will be clear to those in the art. For example, when the 11 p-hydroxy-3,20-diketopregnene used to prepare the present steroids contains additional hydroxyl groups, they must be protected before continuing the reactions described above.

The following examples illustrate the invention.

Example 1

9-fluoro-ll ^ - (methoxyphenylmethoxy) -2 ', 2'-dimethvl pregna-l, 4-dieno [16a, 17-d] - [l, 3] dioxolane-3,20-dione

A suspension of 1.0 g of 9-fluoro-11 ß-hydroxy-2 ', 2' -dimethylpregna-1,4-dieno [16a, 17-d] - [1,3] dioxolane-3 is azeotropically distilled. , 20-dione and 2.0 g of benzaldehyde-dimé-thylacétal in 130 ml of benzene containing 15 mg of p-toluene sulfonic acid. After about 25 min, the solution is cooled, washed with a dilute sodium bicarbonate solution and water, dried and evaporated in vacuo to

Column I

6a, 9-difluoro-11ß-hydroxy-2 ', 2'-

dimethylpregn-4-eno- [16ct, 17-d] - [l, 3] -

dioxolane-3,20-dione

9-fluoro-llß-hydroxy-2 ', 2', 6a-tri-

methylpregn-4-eno [16a, 17-d] - [l, 3] -

dioxolane-3,20-dione

9-fluoro-11ß-hydroxy-2 ', 2'-dim0thyl-

pregn-4-eno [16a, 17-d] - [l, 3] dioxo-

lane-3,20-dione obtain 1.3 g of a solid substance. Recrystallization of this substance from a mixture of ethyl acetate-hexane gives 0.9 g of the desired compound which melts at 198-214 ° C.

Example 2

21- (acetyloxy) -9-fluoro-llp- (methoxyphenyl methoxy) -2 ', 2'-dimethylpregna-1,4-dieno [16a, 17-d] - [1,3] dioxolane-3,20-dione A suspension of 1.0 g of 21-triamci-nolone-acetonide acetate is distilled in 150 ml of benzene containing 2.0 g of benzaldehyde-dimethylacetal and 25 mg of p-toluene sulfonic acid, removing the benzene. After about 30 min, the solution is cooled, washed with a dilute sodium bicarbonate solution and water, dried using magnesium sulfate and evaporated to obtain a solid substance which is absorbed on a column of 40 g of siligacel. Eluting the column with a 1: 4 mixture of chloroform: hexane removes non-steroid impurities. A further elution with 3: 7 and 1: 1 mixtures of chloroform-hexane gives 0.96 mg of substance which is recrystallized from a mixture of ethyl acetate hexane to obtain 0.5 g of the desired compound which melts at 196-198 ° C.

Example 3-5

Proceeding as in Example 1, but substituting the steroid indicated in column I for 9-fhioro-11ß-hydroxy-2 ', 2'-dimethylpregna-1, 4-dieno [16a, 17-d] - [1,3] dio-xolane-3,20-dione and the compound indicated in column II with benzaldehyde-dimethylacetal, the steroid indicated in column III is obtained.

i "

15

20

25

30

Column II Column III

4-chlorobenzaldehyde dimethyl acetal 6a, 9-difluoro-11ß- [methoxy- (4-chloro-

phenyl) methoxy] -2 ', 2'-dimethylpregn-4-eno [16a, 17-d] - [l, 3] dioxolane-3,20-dione 3-methoxybenzaldehyde diethyl acetal 9-fluoro-1 ^ - [ethoxy (3-methoxyphenyl) -

methoxy] -2 ', 2', 6'a-trimethylpregn-4-eno [16ct, 17-d] - [l, 3] dioxolane-3,2Ó-dione 2-methylbenzaldéhydedimethyl-acetal 9-fluoro-l ^ - [methoxy (2-methylphenyl) -

methoxy] -2 ', 2'-dimethylpregn-4-eno- [16a, 17-d] - [1,3] dioxolane-3,20-dione

Example 6 9-fluoro-21-hydroxy-l 1 ß- (ntethoxyphonyl methoxy) -2 ', 2'-dimethylpregna-1, 4-dieno [16a, 17-d] - [1,3] dioxolane-3,20 -dione A suspension of 0.7 g of 21- (acetyloxy) -9-fluoro-11 P- (methoxyphenylmethoxy) -2 ', 2 / -dimethylpregna-l, -4-di0no [16ß, 17-d] is cooled. - [1,3] dioxolane-3,20-dione (prepared as

45 it is described in example 2) in 75 ml of methanol up to 0 ° C. then 7 ml of a 10% potassium carbonate solution are added. After 15 min, 20 ml of 20% aqueous acetic acid are added, then water and the solid obtained is filtered and dried under vacuum to obtain the desired compound.

B

Claims (3)

618186 CLAIMS 1. Process for the preparation of a steroid of formula: ch2-r3 R or one of its 1,2- or 6,7-dehydro derivatives in which formula Ri is an alkyl group, R2 is a hydrogen atom, an alkyl group, alkoxy or a halogen atom, R3 is an atom hydrogen, an acyloxy group, a halogen atom or a hydroxyl group; R4 is a hydrogen or halogen atom, Rs is a hydrogen atom, an alkyl or aryl group, Re is an alkyl or aryl group, R7 is a hydrogen, fluorine or methyl group and Rs is a 2s atom of hydrogen, chlorine or a methyl group, characterized in that a steroid of formula is reacted: <VH3 or one of its 1,2- or 6,7-dehydro derivatives with a benzaldé-hyde-dialkoylacetal of formula: vryl ' W L, in which Ri is an alkyl group. 2. Method according to claim 1, characterized in that R4 is a fluorine atom, R7 is a hydrogen atom and Rs is a hydrogen atom. 3. Method according to claim 2, characterized in that R5 and R6 are each a methyl group. 4. Method according to claim 3, characterized in that R3 is a hydrogen atom. 5. Method according to claim 3, characterized in that R3 is an acyloxy group. 6. Method according to claim 3, characterized in that R3 is a halogen atom. 7. Method according to claim 3, characterized in that R3 is a hydroxyl group. 8. Method according to claim 2 or 3, characterized in that R2 is a hydrogen atom or a methyl group. n / a 9. Method according to claim 1, characterized in that the product obtained is 21 -chloro-11 ß- [ethoxy (2-methylphé-nyl) methoxy] -9-fluoro-2 /, 2 / -diméthylpregn-4 -éno [16a, 17-d] - [- l, 3] dioxolane-3,20-dione. 10. Method according to claim 1, characterized in that 55 the product obtained is 9-fluoro-11 P- (methoxy-phenylmeth- oxy) -2 /, 2 / -dimethylpregna-1,4-dieno [16a, 17-d] - [1,3] dioxo-lane-3,20-dione. 11. Method according to claim 1, characterized in that the product obtained is 21- (acetyloxy) -9-fluoro-l 1 ß- (m6th- “O oxyphenylmethoxy) - ', 2'-dimethylpregna-1,4-dieno [16a, 17d -] - [1,3] dioxolane-3,20-dione. 12. Method according to claim 1, characterized in that the product obtained is 21- (acetyloxy) -1 1 p- [ethoxy (2-methyl-phenyl) methoxy] -9-fluoro-2,, 2'-dimethylpregna -l, 4-dieno- [16- 6S cc, 17-d] - [1.3] dioxolane-3,20-dione. 3 618186 11 P-hydroxy-3,20-diketopregnenes having an acetal or cyclic ketal group at 16,17- well known and widely used as anti-inflammatory agents. Examples of these steroids are the halcinonide (21-chloro-9-fluoro-11ß-hydroxy-2 /, 2 / -dimethylpregn-4-eno [16 <x, 17-d] - [1,3] dioxolane- 3,20-dio-ne) and triamcinolane-acetonide (9-fluoro-11ß, 21-dihydroxy-2 ', 2'-dimethylpregna-i, 4-dieno [16a, 17-d] - [l, 3] dioxolane-3,20-dione). The limited solubility of these pregnenes in slightly polar solvents such as ether leads to difficulties for the composition. In order to ease the difficulties in composing lip-hydroxy-3,20-diketopregnenes having an acetal or ketal 16,17-cyclic group (and in order to prepare new useful anti-inflammatory agents), steroids have previously been prepared 11-keto and 11-acyloxy-. Although these variants increase the solubility of steroids in general it results in steroids with less active. Previously, it is also shown that certain steroids having 11-acetal groups have been prepared. For example, Fukushima et al., J. Org. Chem. 26, 520 (1961) disclose the formation of II- (methoxymethyl) -17.20; 20,21-bismethylene-dioxopregn-4-ene-3-one as a by-product during the reaction of hydrocortisone with formaldehyde. Gardi et al., J. Org. Chem., 27, 668 (1962) and Tetrahedron, 21.179 (1965) disclose steroids having 17,21-cyclic acetal groups as substituents and in position 11 - a group of formula: O-alkyl xo R-CH-i in which R is an alkyl or aryl group.