NO130824B - - Google Patents

Description

Analogy method in the production of

therapeutically active 6a, 9a, 21-trihalogeneti-16a-methyl-11B-hydroxy-1,4-pregnadiene-3,20-3,2-diones.

The present invention relates to an analogous process for the production of therapeutically active 6cc,9a,21-trihalo-16a-methyl-11P-hycr,j/.y-i , 4-pregnadiene-3 , 2D-diones of Jen. general formula:- where X denotes fluorine, chlorine or bromine, and Y denotes chlorine or fluorine.

The new 6a,9a,21-trihalosteroids are prepared by adding to the 9,11-double bond in a steroid of the general formula:

where Y has the meaning given above, in a manner known per se, a subhalo acid adds HOX', where X' is chlorine or bromine, and - if X is to be fluorine in the final product - in a manner known per se transfers 9a-chlorine - or 9a-bromo-11P-hydroxy compound to the 9,11-epoxide and finally opens the epoxy ring with hydrogen fluoride.

The addition of hypohalic acid to the 9,11-double bond in the steroid of the formula II is carried out according to the well-known methods for this reaction, preferably by treating 9,11-double Itbi:>;!-ingsn 'ned reagents which in a known manner releases HOX' during the reaction, such as e.g. dibromdimethylhydanto.in , N-X'-acylamide-, especially N-bromo (or chloro-)-acetamide or N-X'-acylimide, especially N-bromo (or chloro-)-succinimide.

If a 9a-fluoro compound is desired as a 6a,9a,21-trihalogen steroid, after the addition of HOX' to the 9,11-double bond, the 9a-bromo (or chloro-)-11P-hydroxy grouping will be transferred to a 9,11- oxidation, e.g. by treatment with basic reagents such as sodium hydroxide, potassium hydroxide, potassium carbonate, potassium acetate, pyridine, etc., preferably at an elevated reaction temperature, after which the 9,11-oxidation is transferred to the 1-1P-hydroxy-9a-fluoro group by of hydrogen fluoride.

The new 6a, 9a-, 21-trihalogen steroids of the general formula I are distinguished by a high anti-inflammatory effect, which is illustrated in the table below for the new compound 6a-fluoro-9a, 21-dichloro-113-hydroxy- 16α-methyl-L, 4-pregnadiene-3,20-dione (b)

in comparison with the known compound 6a-fluoro-11P,21-dihydr-

oxy-16α-methyl-1,4-pregnadiene-3,2Q-dione (a). Uirkni's intensity was determined using the well-known vasoconstriction test performed on healthy male subjects aged 18 - 33 years, with the vasoconstriction being assessed on a scale from 0 to IDO. The active ingredient was used in concentrations of 0, Dl%, ^, 001%

and 0.0001/6 in a water-oil-salt road base.

The test results show that the new 6a,9a,21-trihalogen steroids have a significantly stronger effect than the known compound b) in all dose ranges. Moreover, they are distinguished by an earlier onset of action and by the fact that they more quickly reach the maximum effect. The compounds do not induce sodium retention. They exhibit a weak diuretic activity. The new compounds are - when they combine, with the usual carriers and diluents in Galenic pharmacy - suitable e.g. for a) local treatment of contact dermatitis, exe<p.>r:' of a different kind, neurodermatitis, erythrodermae, burn rings, pruritus vulvae et ani, rosacea, erythematodes cutaneus, psoriasis, lichen ruberplanus verrucosus; b) oral treatment of acute and chronic polyarthritis, neurodermatitis, bronchial asthma, high fever, etc.

The starting products of the general formula II used in the preparation of the 6a,9a,21-trihalogen steroids have also not been previously described. They can, for example, be prepared from the known 6a-fluoro-21-acetoxy-16a-methyl-1,4,9(11)-pregnatriene-3,20-dione. according to methods known per se. When saponifying the 21-acyloxy group, f. e.g. ' in methanepl/methylene chloride with potassium hydroxide at 0 - 5°C with formation of the 21-alcohol (melting point 190 - 192-°C) cg f o rny et . f ores t r i ng of the f r i c, jo r t e 21 -hy dr oxy 1 group with a sulfochloride, e.g. methanesulfonic acid chloride, in pyridine at 0 - 5°C first obtains 6a-fluoro-21-mesyloxy-16a-methyl-1,4,9(l'i)-pregnatriene-3,20-dione (melting point 149 - 150°C) . Finally, the 21-mesyloxy group is replaced by the halogen atom desired in the final product, e.g. in dimethylformamide, preferably at an elevated temperature. For example, using potassium hydrogen fluoride gives the corresponding 21-fluorine compound and with lithium chloride the corresponding 21-chloro compound. However, the 21-chloro compound can also be prepared from the 21-alcohol (melting point 190 - 192°C) by treatment with thionyl chloride in pyridine.

The examples below illustrate their production

new steroids.

Example 1

Dissolve 5.5 g of 6a-fluoro-21-chloro-16a-methyl-1,4,9(11)-pregnatriene-3,20-dione (melting point 208 - 209°C) in 100 ml of tetrahydrofuran, after which 5.5 g N-chlorosuccinimide and 44 ml 1N perchloric acid and the mixture is stirred for 2.5 hours at 35°C. The reaction solution is poured into ice water, and the precipitated material is filtered off, washed neutrally and dried. The thus obtained 60-fluoro-9,21-dichloro-113-hydroxy-16a-methyl-1,4-pregnadiene-3,20-dione is recrystallized from acetone-hexane. Melting point 233 - 235°C. Yield: 90% of the theoretical. UV:£23B = 15,800.

Example 2

7 g of 6oc-fluoro-21-chloro-16oc-methyl 1-1,4,9(11)-pregnatriene-3,20-dione are dissolved in 150 ml of tetrahydrofuran, after which 10.5 g of N-bromosuccinimide and 65 ml of 1N-perchloric acid, and the mixture is stirred for 15 minutes at 35°C. The reaction solution is poured into ice water, where sodium sulphite is added, and the mixture is stirred for 30 minutes. The precipitated material is filtered off, washed neutrally and dried. After recrystallization from acetone-hexane, 6.9 g of 6a-fluoro-21-chloro-9-bromo-11P-hydroxy-16a-methyl-1,4-pregnadiene-3,20-dione with melting point 218°C ( split). ^^ :^- 2 eels = 14,500.

Example 3

8.6 g of 6a-fluoro-2i-chloro-9-bromo-113-hydroxy-16a-methyl-1,4-pregnadiene-3,20-dione in 160 ml of ethanol and 40 ml of tetrahydrofuran are refluxed for 45 minutes with 16 g potassium acetate.

The reaction mixture is stirred in ice water, and the precipitated material is filtered off, washed with water and dried. The isolated crude product is chromatographed over silica gel. Elution with mixtures of hexane and acetone gives 6oc-fluor-21-kl or-9, - e p o x y - 16a-methyl-9p-pregna-1,4-dien-3,20-dione with melting point 139 - 139, 5 C (isopropyl ether). UV: £248 = 15,800.

15 ml of dimethylformamide is cooled to -15°C and 15 ml of hydrogen fluoride is added while stirring. To this mixture is added drop-

add 3.15 g of 6a-fluoro-21-chloro-9,11P-epoxy-16a-methyl-9P-pregna-1,4-diene-3,20-dione dissolved in 5 ml of umethylformamide, and the mixture obtained is allowed to stand for 18 hours at 5°C and for 9 hours at 20°C. The reaction solution is poured into ice water/potassium hydrogen carbonate,

and the thereby precipitated material is filtered, dried and recrystallized from acetone/hexane. The obtained 6a,9-difluoro-21-chloro-1l3-hydroxy-16a-methyl-1,4-pregnadiene-3,20-dione melts at 215 -

216°C (decomposes). UV:&238<=><1>6 200. Yield: 80% of the theoretical.

Example 4

3 g of 6a-21-difluoro-16a-methyl-1,4,9(11)-pregnatriene-3,20-dione (melting point 229 - 231°C) in 70 ml of tetrahydrofuran are reacted with

3 g of N-chlorosuccinimide and 24 ml of 1N-perchloric acid, and the reaction mixture

none is worked up as described in example 1. The obtained 6a,21-difluoro-9-chloro-11P-hydroxy-16a-methyl-1,4-pregnadiene-3,20-dione melts after recrystallization from acetone-benzene at 235 - 256 °C. UU: ei' 2 3 8 15 900. • Dividend: 65$ of the theoretical.

Example 5

9.8 g 6a, 21-dif 1 uor-16a-methyl 1-1, 4,9 (11 )-pregnatriene-3,20-

dione in 210 ml of tetrahydrofuran is stirred for 10 minutes at 35°C with 14.7 g of M-bromosuccinimide and 91 ml of 1[\l-perchloric acid, and the reaction mixture is worked up as described in example 2. The obtained 6a,.? 1-difluoro-9-bromo-11B-hydroxy-16a-methyl-1,4-pregnadiene-3,20-

dione recrystallizes from acetone. Melting point 210°C (decomposes). Ui-bytto: 98$ of the riet theoretical.

Example 6

10 g of 6α,21-difluoro-9-bromo-1β-hydroxy-16α-methyl-1,4-pregna-diene-3,20-dione in 250 ml of ethanol and 100 ml of tetrahydrofuran are added to 20 g of anhydrous potassium acetate, after which the mixture boil with reflux cooling for 60 minutes and work up as described in example 3. The obtained oa,21-difluoro-9,110-epaxy-15a-methnyl-9β<->pregna-1,4-diene-3,20-dione melts at 177 - 179°C. Yield: 92/6 of the theoretical.

7.6 g of 6α,21-difluoro-9,113-epoxy-16α-methyl-9α-pregna-1,4-diene-3,20-dione are added at -20°C to a mixture of 40 ml of dimethylformamide and 40 ml of hydrogen fluoride, and the mixture is stirred for 24 hours at room temperature. The reaction mixture is worked up as described in example 3. The obtained 6a,9,21-trifluoro-11P*-hydroxy-16a-methyl-1,4-pregnadiene-3,20-dione is recrystallized from acetone/hexane. Melting point 287 - 289°C (sp al tes ). Yield: 80%' of the theoretical.

Claims (1)

Analogous procedure for the production of therapeutically effective 6a,9a,21-trihalo-16a-methyl-11p-hydroxy-1,4-pregnadiene-3,20-diones of general formula: where X denotes fluorine, chlorine or bromine, and Y denotes chlorine or fluorine, characterized in that to the 9,11-double bond in a steroid of the general formula: where Y has the meaning given above, in a manner known per se, a subhalo acid adds HOX', where X<1> is chlorine or bromine, and - if X is to be fluorine in the final product - in a manner known per se transfers 9a -chloro- or 9a-bromo-lip-hydroxy compound to the 9,11-epoxide and finally opens the epoxy ring with hydrogen fluoride.