CH616437A5 - Process for the preparation of 3,20-diketopregnenes having an 11beta-acetal group and their derivatives - Google Patents

Abstract

A pharmacologically active 11 beta -hydroxysteroid is modified by replacing the 11 beta -hydroxy group with an acetal group of formula I, in which R1 and R2 are each a C1-8 alkyl group. The process consists in reacting the 11 beta -hydroxysteroid with a 1-alkoxybenzocyclobutene of formula II. This modification results in an improvement in the solubility of the 11 beta -hydroxysteroids in slightly polar solvents, which facilitates their conversion to a pharmaceutical form. The modified steroids are useful as anti-inflammatory agents and glucocorticoids. <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.

To achieve this object, the invention provides the method defined in claim 1.

In particular, the process according to the invention makes it possible to prepare the steroids of formula:

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 the formula Y-COOH in which Y is an alkyl, cycloalkyl group having 3 to 6 carbon atoms, arylalkyl or aryl; for example acetic, propionic, valeric, cyclohexane carboxylic, phenylacetic, benzoic and toluic acids. 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 process are physiologically active substances which have glucocorticidal activity.

616437

4

cooid and anti-inflammatory and which can therefore be used in place of the glucocorticoids known for the treatment of chronic progressive polyarthritis, and for this purpose they can be administered like hydrocortisone, by adjusting the dose for example according to the relative power of the particular steroid. Furthermore, the steroids 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 anogenital pruritis. .

When administered orally the present compounds can be used at a daily dose of 0.1-200 mg / 70 kg and preferably 0.3-100 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.

The 3,20-diketopregnenes of formula III are prepared by reacting a 1-hydroxy-3,20-diketopregnene, that is to say the 11β-hydroxy counterpart of the steroid of formula III, with a 1- alkoxybenzocyclobutene of formula:

GOLD.

II

\ R

in which R'2 is a hydrogen atom or an alkyl group having from 1 to 7 carbon atoms. The reaction, which is new, can be carried out under neutral conditions in an aprotic solvent, for example a hydrocarbon such as benzene or toluene. Although the reaction conditions are not critical, the reaction is preferably carried out at the reflux temperature of the solvent or close to it.

This reaction is useful not only for the preparation of the present steroids but also for the preparation of other steroids containing an 11β-hydroxy group which must be protected during multistage syntheses. The blocking group can be easily removed by acid hydrolysis.

Various variants and modifications of the present process will be clear to those in the art. For example, when the 11β-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

21-Chloro-1 1 ß- [ethoxy (2-n ^ thylplwnyl) n ^ thoxy] -9-fluoro-2 ', 2'-dimethylpregn-4-eno [16 a, 17-d] - [1,3 ] dioxolane-3,20-dione

A suspension of 684 mg of 21-chloro-9-fluoro-1 1 ß-hydroxy-2 ', 2 / -dimethylpregn-4-eno- [16a, 17-d] [1,3] dioxolane is heated to reflux. 3.20-dione in 17 ml of anhydrous toluene containing 444 mg of l-ethoxy-1,2-dihydrobenzocy-s clobutene in a nitrogen atmosphere. After a few minutes a homogeneous solution is obtained. After approximately 6 h the solution is cooled and then it is absorbed on a column of 20 mg of silica gel. Elution from the column with a 1: 4 mixture of chloroform-hexane gives unreacted 1-ethoxy-1,2-dihydro-10-benzocyclobutene. Further elution of the column with 1: 4 and 1: 1 mixtures of chloroform-hexane gives the product in the form of 0.90 g of a foam. This is dissolved in the minimum amount of ether, diluted with 10 ml of hexane and maintained at a temperature of approximately 5 ° C to obtain 355 mg of a solid substance which melts at 171-180 ° vs. Recrystallization of this substance from a mixture of ethyl acetate-hexane gives 205 mg of the desired compound which melts at 182-185 ° C.

20 Example 2

21 - (Acetyloxy) -11 ß- [ethoxy (2-methylphenyl) methoxy] -9-fluoro-2 /, 2'-dimethylpregna-1, 4-dieno [16a, 17-d] [l, 3] dioxolane- 3.20-dione 1.0 g of 21-triamcinolone-acetonide acetate is dissolved in 37 ml of anhydrous xylenes in an oil bath maintained at about 125 ° C in a nitrogen atmosphere. 1.11 g of 1-ethoxybenzocyclobutene are added and after 18 h the reaction is incomplete. The following new amounts of 1-ethoxybenzocyclobutene are added at the indicated time intervals:

30

35

0.3 ml 0.3 ml 0.3 ml 0.3 ml 0.3 ml

(9 p.m.) (24 h) (28 h) (46 h) and (48 h)

40

45

50

The solution is evaporated and the residue is dissolved in chloroform and chromatographed on a 25 mg column of silica gel. Eluting the column with 1: 4 to 1: 1 mixtures of chloroform-hexane removes non-steroid impurities. Further elution with a 4: 1 mixture of chloroform-hexane and chloroform gives 0.8 g of the desired substance. The solid is dried to obtain the desired compound which melts at 105-110 ° C.

Examples 3-6

By proceeding as in Example 1 but by substituting the steroid indicated in column I for 21-chloro-9-fluoro-1 ^ -hydroxy-2 ', 2'-dimethylpregn-4-eno [16a, 17-d ] [l, 3] dioxo-lane-3,20-dione, and the compound indicated in column II with 1-ethoxy-1,2-dihydrobenzocyclobutene, the steroid indicated in column III is obtained.

Column I

Column II

Column III

2,21 -dichloro-11 ß-hydroxy-2 ', 2' -

dimethylpregna-1,4-dieno [16a, 17-d] -

[l, 3] dioxolane-3,20-dione

11 ß-hydroxy-2 ', 2'-dimethylpregna-

l, 4,6-trieno [16a, 17-d] [l, 3] dioxolane-

3.20-dione

21 -chloro-1 lß-hydroxy-2,2 ', 2' -tri-

methylpregna-1,4-dieno [16a, 17-d] -

[l, 3] dioxolane-3,20-dione

21 - (benzoyloxy) -11 ß-hydroxy-2 ', 2' -

diphenylpregna-1,4-dieno [16a, 17-d] -

[1,3] dioxolane-3,20-dione l-ethoxy-2-methyl-

1,2-dihydrobenzocyclo-

butene

1 -propoxy-2-ethyl-1,2-

dihydrobenzocyclo-

butene l-ethoxy-l, 2-dihydro-benzocyclobutene

1-ethoxy-1,2- dihydro-benzocyclobutene

2,21 -dichloro-1 lß- [ethoxy (2-ethylphenyl) -

methoxy] -2 ', 2'-dimethylpregna-l, 4-dieno-

[16a, 17-d] [l, 3] dioxolane-3,20-dione lip- [propoxy (2-propylphenyl) methoxy] -2 ', 2'-

dimethylpregna-1,4,6-trieno [16a, 17-d] [1,3] -

dioxolane-3,20-dione

21 -chloro-11 ß- [ethoxy (2-methylphenyl) methoxy] -

2,2 ', 2'-trimethylpregna-1,4-dieno [16a, 17-d] -

[l, 3] dioxolane-3,20-dione

21 - (benzoyloxy) -11 ß- [ethoxy (2-methylphenyl) -

methoxy] -2 ', 2' -diphenylpregna-1,4-dieno-

[16a, 17-d] [l, 3] dioxolane-3,20-dione

B

Claims (12)

616437 2 CLAIMS 1. Process for the preparation of a steroid having in position 11 ß- a group of formula: R, Q-A. / \ _ U- in which R 1 and R 2 are identical or different and are each an alkyl group having from 1 to 8 carbon atoms, characterized in that an l-alkoxybenzocyclobu- formula formula: 15 , 0R. V II wherein R1 is an alkyl group having 1 to 8 carbon atoms and R'2 is a hydrogen atom or an alkyl group having 1 to 7 carbon atoms with an 11β-hydro-xysteroid under substantially neutral conditions. 2. Method according to claim 1 for the preparation of a steroid in which R2 is a methyl group, characterized in that R'2 is a hydrogen atom. 3. Method according to claim 1 for the preparation of a steroid of formula: ch2-r5 -0, Rr III -0 R, or one of its 1,2- or 6,7-dehydro derivatives, in which formula Ri and R2 are as defined above, 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 R8 is a hydrogen or chlorine atom or a methyl group characterized in that a steroid of formula is reacted: çh2-b3 c = o 0. ■ 0 TL 'r, IV or one of its 1,2- or 6,7-dehydro derivatives with a 1-alkoxy-benzocyclobutene of formula II. 4. Method according to claim 3, characterized in that R4 is a fluorine atom, R7 is a hydrogen atom and Rs is a hydrogen atom. 5. Method according to claim 4, characterized in that Rs and R6 are each a methyl group. 6. Method according to claim 5, characterized in that R3 is a hydrogen atom. 6S 7. Method according to claim 5, characterized in that R3 is an acyloxy group. 8. Method according to claim 5, characterized in that R3 is a halogen atom. 3 616437 9. Method according to claim 5, characterized in that R.3 is a hydroxyl group. 10. Method according to claim 4 or 5, characterized in that R2 is a hydrogen atom or a methyl group. 11. Method according to claim 3, characterized in that the product obtained is 21-chloro-11 ß- [ethoxy (2-methyl-phenyl) methoxy] -9-fluoro-2 ', 2' -dimethylpregna-4- eno [16a, 17-d] - [l, 3] dioxolane-3,20-dione. 12. Method according to claim 3, characterized in that the product obtained is 21 - (acetyloxy) -11 ß - [ethoxy (2-methylphenyl) methoxy] -9-fluoro-2 /, 2 / -dimethyl-pregna- 1,4-dieno [16a, 17-d] - [1,3] dioxolane-3,20-dione. lie about the solubility of steroids in general this results in steroids with less activity. Previously, it is also shown that certain steroids having 11-acetal groups have been prepared. For example, s Fukushima et al., J. Org. Chem. 26, 520 (1961) disclose the formation of 11 | 3- (methoxymethyl) -17.20; 20,21-bismethy-lene-dioxypregn-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: 10 11 P-hydroxy-3,20-diketopregnenes having an is acetal or cyclic ketal group at 16,17- well known and widely used as anti-inflammatory agents. Examples of these steroids are halcinonide (21-chloro-9-fluoro-11 ß-hydroxy-2 ', 2' -dimethyl-pregn-4-eno [16a, 17-d] [l, 3] di- oxolane-3,20-dione) and triamcinolone acetonide 20 ^ -fhioro-llß ^ l-dihydroxy ^ '^' - dintethyl-pregna-l ^ -diéno [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 facilitate the difficulties in composing ml ^ -hydroxy-3,20-diketopregnenes having an acetal or ketal group 16,17-cyclic (and in order to prepare new useful anti-inflammatory agents), previously preparations 11-keto- and 11-acyloxy- steroids. Although these variants increase 30 AT Rg -. and their 1,2- and 6,7-dehydro derivatives; pregn-4-enes and pregna-1,4-dienes are preferred. In formula III and throughout the description, the symbols have the meanings below. Ri is an alkyl group; R2 is a hydrogen atom, an alkyl group, an alkoxy group or a halogen atom; ss 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; "0 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. O-alkyl R-CH-O wherein R is an alkyl or aryl group.