CH624967A5 - Process for the preparation of polyhalogenated steroids - Google Patents

Description

The invention relates to a process for the preparation of new polyhalogenated steroids, namely from 9a, 21-diha-10 logen-llß, 17a-di-hydroxy-6a-fluoro-16a-methyl-pregna-l, 4-di-en- 3,20-dione-17-esters of the general formula

15

: H2X2

/ sf »

OAc

I I

s \ / \

• • v • • •

i 1 Xli 3

✓ V V

(I)

25th

wherein Ac and Xi have the meanings given above and Ra is the acyl radical of an organic sulfonic acid, treated with an alkali metal halide MX2, where M is an alkali metal and X2 is chlorine or bromine, in the presence of an aprotic organic solvent, the dielectric constant of which is at least 29.

2. The method according to claim 1, characterized in that one is treated with a lithium halide LÌX2.

3. The method according to claim 1, characterized in that dimethylformamide is used as the solvent.

4. The method according to any one of claims 1-3, characterized in that a compound of formula I is prepared, wherein Xi is chlorine or fluorine, X2 is chlorine and Ac is the acyl radical of a lower aliphatic monocarboxylic acid having 2 to 7 carbon atoms.

5. The method according to any one of claims 1-3, characterized in that a compound of formula I is prepared in which Ac is propionyl.

6. The method according to any one of claims 1-3, characterized in that 21-chloro-6a, 9a-difluoro-llß, 17a-dihydroxy-16a-methyl-pregna-l, 4-diene-3,20-dione- 17-propio-nat.

7. The method according to any one of claims 1-3, characterized in that 21-chloro-6a, 9a-difluoro-llß, 17a-dihydroxy-16a-methyl-pregna-l, 4-diene-3,20-dione- 17-acetate produces.

8. The method according to any one of claims 1-3, characterized in that 21-chloro-6a, 9a-difluoro-llß, 17a-dihydroxy-16a-methyl-pregna-1,4-diene-3,20-dione- 17-valeria-nat.

In our Swiss Patent No. 621 801 a process for the production of 2-chloro-9a, 21-dihalogen-

wherein Xi represents chlorine or fluorine, X2 bromine or chlorine and Ac represents the acyl radical of a carboxylic acid.

Carbon-containing compounds and radicals hereinafter referred to as “lower” preferably contain up to and with 7 carbon atoms.

An acyl group Ac is preferably derived from the carboxylic acids with 1 to 18 carbon atoms customary in steroid chemistry, in particular from corresponding aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or aliphatic carboxylic acids. The radical Ac is in particular a straight-chain or branched lower alkanoyl, e.g. Acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, 2-ethyl-butyryl, 2,2- or 3,3-dimethyl-40-butyryl, hexanoyl or heptanoyl, but also a hydroxy-lower alkanoyl, e.g. 3-hydroxypropionyl, phenoxy lower alkanoyl, e.g. Phenoxyacetyl, halogeno lower alkanoyl e.g. Chloroacetyl, or carboxy lower alkanoyl, e.g. 3-carboxy-propionyl or 4-carboxy-butyryl, alkenoyl, e.g. Undecylenoyl, 45 cycloalkyl-lower alkanoyl, e.g. Cyclopentyl-propionyl or cyclohexylacetyl, optionally substituted benzoyl, e.g. B. benzoyl, or optionally substituted phenyl-lower alka-noyl or lower alkanoyl, e.g. B. Phenylacetyl.

The compounds produced according to the invention thus have valuable pharmacological properties. They are characterized by excellent anti-inflammatory effectiveness, e.g. with local application, which e.g. can be demonstrated in the raw wattegranuloma test on the rat in a dose range of about 0.001 to about 0.3 mg / pellet. The first signs of a systemic effect, e.g. the decrease in body and especially adrenal and thymus weight, only noticeable above the dose of 0.3 mg / pellet. Because of the favorable distribution of the biological properties, the 60 new compounds are in all indications for which glucocorticoids with anti-inflammatory properties are suitable, but in particular as locally applicable anti-inflammatory glucocorticoids, e.g. for the treatment of inflammatory dermatoses, such as eczema, dermatids, or partially corticoid-65-resistant dermatoses, e.g. B. psoriasis, can be used. They can also be used as valuable intermediates for the production of other useful substances, in particular other pharmacologically active steroids.

3rd

624 967

It primarily relates to compounds of formula I in which Xi is fluorine or chlorine, Xz chlorine, and Ac lower alkanoyl, e.g. Propionyl.

The process according to the invention is characterized in that a compound of the general formula

CH0OR

"OwVf3f ° V

! i "H"

S \ l ^; \ / \ / „„

• • • • • »CH

I I X, I 3

• • I. •

e / v y

F

wherein Xi and Ac have the meanings given above and Ra stands for the acyl radical of an organic sulfonic acid, with an alkali metal halide of the formula M-X2 (V), where M stands for an alkali metal, in the presence of an aprotic organic solvent, the dielectric constant of which is at least 29 is treated.

The acyl radical Ra of an organic sulfonic acid is in particular that of an aliphatic or carbocyclic, optionally unsaturated or aromatic sulfonic acid. Such acids include optionally substituted, e.g. halogenated, lower alkanesulfonic acids, cycloalkanesulfonic acids, in which the cycloalkyl radical can be mono- or polycyclic, or optionally by lower alkyl, e.g. B. methyl, lower alkoxy, e.g. B. methoxy, halogen, e.g. B. chlorine or bromine, and / or nitro, substituted benzenesulfonic acids. Typical examples of such acids are trifluoromethanesulfonic acid, (+) - camphor-10-sulfonic acid, 4-bromobenzenesulfonic acid and 3-nitrobenzenesulfonic acid, in particular p-toluenesulfonic acid and especially methanesulfonic acid.

The exchange reaction is carried out in the usual manner known per se. Lithium is preferably used as the alkali metal M. As aprotic organic solvents, in particular, lower alkyl sulfoxides, e.g. Dimethyl sulfoxide, N, N-di-lower alkylamides from lower ali-. phatic carboxylic acids, e.g. N, N-dimethylformamide or N, N-dimethylacetamide, lower alkanitriles, e.g. Acetonitrile, hexane-lower alkylphosphoramides, e.g. B. hexamethylphosphoramide, or ketones, especially aliphatic or cyclo-aliphatic ketones with at most 10 carbon atoms, such as corresponding alkanones, e.g. Acetone, 2-butanone, 2- or 3-pentanone, 2-hexanone or 4-decanone, or cycloalkanones with at most 8 ring carbon atoms, e.g. Cyclopentanone or cyclohexanone, or mixtures of such solvents can be used.

The reaction is expediently carried out between room temperature and the boiling temperature of the reaction mixture, reaction being carried out with at least one equivalent of the alkali metal halide of the formula V.

The starting materials of formula II are known or can be prepared in a manner known per se, e.g. by treating the 21-hydroxy group in a 6a-fluoro-11β-17a, 21-trihydroxy-16a-methyl-9a-Xi-pregna-l, 4-diene-3,20-dione-17-ester by treatment with a reactive Derivative of an organic sulfonic acid of the formula Ra-OH (VI), in particular with a corresponding sulfonic acid chloride of the formula Ra-Cl (Via), in the presence of a base, for example Pyridine, converted into the desired organic sulfonyloxy group -ORa.

The new compounds of the formula I prepared according to the present invention are used as medicinal active substances, preferably for the treatment of inflammation, primarily as locally applicable anti-inflammatory glucocorticoids, usually in the form of pharmaceutical preparations, in particular those for topical use.

The following examples illustrate the invention described above; however, they are not intended to limit their scope in any way. Temperatures are given in degrees Celsius.

example

A solution of 6.0 g of 6a, 9a-difluoro-11ß, 17a, 21-tri-hydroxy-16a-methylpregna-l, 4-diene-3,20-dione-17-propionate-21-methanesulfonate in 150 ml of dimethylformamide 18 g of dry lithium chloride are added and the mixture is stirred at 100 ° for 16 hours under a nitrogen atmosphere. The cooled mixture is poured onto ice water; the precipitate formed is filtered off, washed well with water and dissolved in chloroform. After drying, the organic solution is evaporated under a water jet vacuum and the residue is separated by means of preparative thin layer chromatography on silica gel with a 50:50 mixture of toluene and ethyl acetate as the liquid phase. Washing the main zone with ethyl acetate gives 21-chloro-6a, 9a-difluoro-11ß, 17a-dihydroxy-16a-methyl-pregna-l, 4-diene-3,20-dione-17-propionate, which after recrystallization melts from a mixture of chloroform, methanol and diethyl ether at 268 ° (dec.).

Analogously, but starting from the corresponding 17-acetate-21-methanesulfonate or 17-valerianate-21-methanesulfonate, the 21-chloro-6a, 9a-difluoro-11ß, 17a-dihydroxy-16a-methyl-pregna- 1,4-diene-3,20-dione-17-acetate, mp. 269-271 °, and 21-chloro-6a, 9a-difluoro-11ß, 17a-dihydroxy-16a-methylpregna-l, 4-diene- 3.20-dione-17-valerianate, mp 244-245 °.

The 21-methanesulfonate of 6a, 9a-difluoro-11ß, 17a, 21-trihydroxy-16a-methyl-pregna-l, 4-diene-3,20-dione-17-acetate, -17-propionate or -17-valeria-nats is obtained by esterifying the 21-hydroxy group in the corresponding 6 a, 9 a-difluoro-11β, 17 a, 21 -trihydroxy-16 a-methyl-l, 4-pregna-diene-3.20- Dion-17-ester obtained by treatment with methanesulfonic acid chloride in the presence of pyridine at room temperature, for example in the following way:

A solution of 2.75 g of 6a, 9a-difluoro-11ß, 17a, 21-trihydroxy-16a-methyl-pregna-l, 4-diene-3,20-dione-17-propionate in 60 ml of pyridine is added 2.23 ml of methanesulfonic acid chloride are added dropwise with stirring at about −10 ° and then left to stand at room temperature for a further 21 hours. The reaction mixture is then poured onto 1.5 l of ice water and stirred for 20 minutes. The precipitate is filtered off, washed with water, taken up in methylene chloride, the solution dried and evaporated in a water jet vacuum. The 21-mesylate thus obtained is practically pure by thin layer chromatography. It is processed directly without further cleaning.

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Claims (2)

624 967 2nd PATENT CLAIMS 1. Process for the preparation of new polyhalogenated 11β, 17 a-dihydroxy-16a-methyl-pregna-1,4-diene-3,20-dione-17-esters of the general formula ; h2x2 1I0x / J "3 - * •••• OAc f \ l /: \ / \ / \ CPi I 1 J /: N (I) I. # V * I ^ 1 CH, ^ W \ / (f wherein Xi is chlorine or fluorine, X2 is bromine or chlorine, and Ac is an acyl group derived from a carboxylic acid, characterized in that a compound of the general formula HO. \ / \ : h0or 2 a . cf 3i 1 i; * ■ 0Ac / YiV V --CIL (II) I I X, I • • 1' ^ v cf v « F 11 ß-17 a-dihydroxy-6a-fluoro-16a-methylpregna-l, 4-diene-3,20-dione-17-esters are described, which are characterized by a particularly favorable anti-inflammatory activity. It has now surprisingly been found that the same favorable pharmacological properties also occur in the simpler analogues which are unsubstituted in the 2-position.