DE1801390B2 - 6,9,21-TRIHALOGENE STEROIDS, PROCESS FOR THEIR MANUFACTURE, MEDICATIONS CONTAINING THEM AND 6,21-DIHALOGENE INTERMEDIATE PRODUCTS - Google Patents

Description

The invention relates to 6,9,21-trihalogen steroids formula

HO

r CH,

wherein X is a fluorine, chlorine or bromine atom and Y is a chlorine or fluorine atom. \

2. Method of making new 6,9,21-tri-2 ° F

halogen steroids of the formula

wherein X is a fluorine, chlorine or bromine atom and Y is a chlorine or fluorine atom.

The present invention further relates to a process for the preparation of the new 6,9,21-trihalogenosteroids of the general formula I, characterized in that the 9.1! Double bond of a starting steroid of the general formula is bonded in a manner known per se
30th

CH ₂ Y

O =

"CH ₃

CO

wherein X is a fluorine, chlorine or bromine atom and Y is a chlorine or fluorine atom, thereby characterized in that in a known manner to the 9, ll position double bond one Starting steroids of the general formula

CH ₃

(Π)

40

CH, Y

CO

-CH ₃

45

hypohalous acid HOX ', where X' denotes a chlorine or bromine atom, is added and - if in the products ultimately desired, X denotes a fluorine atom, 9a-chlorine or 9'-bromo-I 1 / f-hydroxy compound also known per se Way into the 9,11-epoxy and finally the epoxy ring with hydrogen fluoride opens.

3. 6a-Fluoro-21-chloro-16λ-methyl-1,4,9 (1 L) -pregnatriene-3,20-dione.

4. 6a-fluoro-21-chloro-9,11 / f-epoxy-16 "-methyl-9 / J-pregna-1,4-diene-3,20-dione.

5. 6 <x, 21-difluoro-16a-methyl-1,4,9 (1 L) -pregnatriene-3,20-dione.

6. 6a, 21 - difluoro - 9.1 l / i - epoxy - 16α - methyl-9 /? - pregna-1,4-diene-3,20-dione.

hypohalous acid HOX ', where X' is a chlorine or bromine atom. means, attaches and - if in the Ultimately desired products X denotes a fluorine atom - the 9 <x -chloro or 9a-bromo-11/3-hydroxy compound likewise converted into the 9,11-epoxide in a manner known per se and finally the epoxide ring opens with hydrogen fluoride.

The addition of hypohalous acid to the 9, 11-position double bond of II takes place after the generally known working methods for this, preferably by treating the 9,11 double bond with reagents that are known to make HOX 'free in the course of the reaction, such as. B. Dibromodimethylhydantoin, N-X'-acylamide, in particular N-bromo- (or chloro-) acetamide, or N-X'-acylimide, especially N-bromine (or chlorine) succinimide.

If the ultimately desired 6,9,21-trihalogenosteroids are to be 9a-fluorine compounds, after the addition of HOX 'to the 9.1! /? - OH group, e.g. B. by treatment with basic reagents such as NaOH, KOH, K ₂ CO ₃ , potassium acetate, pyridine and the like at a preferably elevated reaction temperature, closed to the 9.11-Oxidoring, which is then closed by means of hydrofluoric acid

converted into the II /? - OH-9a fluorine group will.

The new 6,9,2 l-trihalosteroids according to the invention of the given general formula I are characterized by a high anti-inflammatory effect from, as in the following table using the example of the 6a-fluoro-9 ", 21-dichloro-1 l /? - hydroxy-16a-methyl-1,4-pregnadiene-3,20-dione (b) Compared to the known 6 * -fluoro-l 1 ^, 21-dihydroxy-16a-methyl-1,4-pregnadiene-3,20-dione (a) identifies. The intensity of action was determined according to the known vasoconstriction test, with low, medium and high-grade vasoconstriction was rated between 0 and 100 in healthy male volunteers Determined between the ages of 18 and 38 years. The active ingredient was in a water-oil-ointment base, the concentration being 0.01, 0.001 and 0.0001%, applied.

Active ingredient

dose in %

Observation time in hours

a) (w-Fluoro-1 1 / J.21-dihydroxy-16a-methyll, 4-pregnadiene-3,20-dione

b) 6 "-Fluoro-9a, 21-dichloro-1 M-hydroxy-loft-methyl-1,4-pregnadiene-3,20-dione

The test results show that the 6,9,21-trihalogenosteroids according to the invention compared to the known Substance a) have a significantly higher intensity of action in all dose ranges. About that In addition, they are characterized by an earlier onset of action and also reach their maximum effect more quickly. The compounds do not cause sodium retention. S> e have mild diuretic Effects. The neaen compounds are - in combination with those in galenic pharmacy usual carriers and diluents well suited for the treatment of z. B.

a) local: contact dermatitic, eczema of the most varied Type, neurodermatitis, erythroderma, burns, pruritus vulvae et ani, rosacea, erythematosus cutaneus, psoriasis, Liehen ruber planus verrueosus;

b) oral: acute and chronic polyarthritis, neurodermatitis, Bronchial asthma, hay fever and others

The starting materials of the general formula used for the production of the 6,9,21-trihalogen steroids II are also not described above. You can, for example, from the known 6a-fluoro-21-acetoxy-16 * -methyl-1,49 (II) -pregnatrien-3,20-dione be prepared by working methods known per se: by saponifying the 21-acyloxy group, e.g. in Methanol / methylene chloride with potassium hydroxide at 0 to 5 ° C with formation of the 21-alcohol (F. 190 up to 192 ° C) and re-esterification of the released 21-hydroxyl group with sulfochlorides, e.g. B. Methanesulfonic acid chloride, in pyridine at 0 to 5'C, initially gives 6a-fluoro-21-mesyloxy-16 * -methyl-1,4,9 (11 ) -pregnatnen-3,20-dione (F. 149 to 150 "C). The 21-mesyloxy group is finally used in e.g. B. dimethylformamide, preferably at an elevated temperature replaced by the ultimately desired halogen atom: with z. B. receives potassium hydrogen fluoride one the corresponding 21-fluorine compound, with lithium chloride the corresponding 21-chloro compound. The 21-chlorine compound is also from the 21 alcohol (m.p. 190 to 192 ° C) by treatment with Thionyl chloride can be prepared in pyridine.

The following examples serve to further illustrate the present invention.

0.01 0 25th 40 50 100 0.001 0 20th 55 75 100 0.0001 0 15th 25th 50 0.01 12th 47 89 100 0.001 11th 44 72 100 0.0001 0 29 48 88 100 By S game 1

90 100

5.5 g of 6a-fluoro-21-chloro-16 "-methyl-l, 4,9 (ll) -pregnatriene-3,20-dione (mp 208-209 ⁰ C) are dissolved in 100 ml of tetrahydrofuran with 5 , 5 g of N-chlorosuccinimide and 44 ml of 1N-perchloric acid are added and the mixture is stirred at 35 ° C. for 2 ¹ l for _{2 hours.} The reaction solution is poured into ice water, the precipitated substance is filtered off with suction, washed neutral and dried. The 6a-fluoro-9,21-dichloro-11 / S-hydroxy-16a-methyl-1,4-pregnadiene-3,20-dione obtained in this way is recrystallized from acetone-hexane; Mp 233-235 ° C; Yield 90% of theory; UV: f ₂₃₈ = 15,800.

Example 2

7 g of 6ix-fluoro-21-chloro-16a-methyl-l, 4,9 (ll) -pregnatrien-3,20-dione are dissolved in 150 ml of tetrahydrofuran, with 10.5 g of N-bromosuccinimide and 65 ml of In- Perchloric acid was added and the mixture was stirred at 35 ° C. for 15 minutes. The reaction solution is poured into ice water, sodium sulfite is added and the mixture is stirred for 30 minutes. The precipitated substance is filtered off with suction, washed neutral and dried. After recrystallization from acetone-hexane, 6.9 g of α-fluoro-21-chloro-9-bromo-II / α-hydroxy-16a-methyl-1,4-pregnadiene-3,20-dione are obtained; Mp 218 ° C (dec.); UV: F ₂₄₁ = 14,500.

Example 3

8.6 g of oa-fluoro ^ l-chloro ^ -bromo-llß-hydroxy-16 * -methyl-1,4-pregnadiene-3,20-dione are dissolved in 160 ml of ethanol and 40 ml of tetrahydrofuran with 16 g of potassium acetate for 45 minutes heated to reflux. The reaction mixture is stirred into ice water, the precipitate which has separated out is filtered off with suction, washed with water and dried. The isolated crude product is chromatographed on silica gel. Eluting with hexane / acetone mixtures gives the 6a-fluoro-21-chloro-9.1 l / i - epoxy - 16λ - methyl - 9β - pregna - 1,4 - diene-3,20-dione; Mp 139-139.5 ° C (isopropyl ether); UV: f ₂₄₈ = 15 800.

15 ml of dimethylformamide are cooled to -15 ° C. and 15 ml of hydrogen fluoride are added while stirring

18 Ol 390

offset. 3.15 g of 6a-fluoro-21-chloro-9.1 Iß- epoxy-16α-methyl- 9 <t -pregnal, 4-diene-3,20-dione dissolved in 5 ml dimethylformamide are added dropwise to this mixture, and 18 Leave to stand for hours at 5 ° C. and 9 hours at 20 ° C. The reaction solution is poured into ice water / potassium hydrogen carbonate, the substance which has precipitated is suctioned off, dried and recrystallized from acetone / hexane. The 6%, 9-difluoro-21-chlorine obtained in this way -11 β - hydroxy -16a - methyll, 4-pregnadiene-3,20-dione melts at 215 to 216 C (decomp.); UV: f _23g = 16,200; yield 80% of theory.

Example 4

3 g of 6α-21 · difluoro-16ct-methyl-1,4,9 (1 l) -pregnatriene-3,20-dione (mp 229-231 ⁰ C) g in 70 ml tetrahydrofuran with 3 N-chlorosuccinimide and 24 m ¹ 1 n-perchloric acid reacted and worked up as described in Example 1. The 6ä, 21-difluoro-9-chloro-1I / J-hydroxy-16a-methyl-1,4-pregnadiene-3,20-dione thus obtained melts after recrystallization from acetone-benzene at 255 to 256 ^° C .; UV _{:, 238} = 15,900; Yield 65% of theory.

Example 5

14.7 g of N-bromosuccinimil and 91 ml of ln-perchloric acid Stirred for 10 minutes at 35.degree. C. and worked up as described in Example 2. The thus obtained 6 *, 21-difluoro-9-bromo-11 // -hydroxy-J6i-methyll, 4-pregnadiene-3,20-dione is recrystallized from acetone; M.p. 210 C (dec.); Yield 98% of theory.

Example 6

10 g oa ^ l-difluoro ^ -bromo-ll / f-hydroxy-loa-methyl-1,4-pregnadiene-3,20-dione are in 250 ml of ethanol and 100 ml of tetrahydrofuran with 20 g of anhydrous Potassium acetate reacted, heated under reflux for 60 minutes and worked up as described in Example 3. The 6a, 21-difluoro-9, ll / 7-epoxy-16 * obtained in this way - methyl -9 / i-pregna- l, 4-diene-3,20-dione melts at 177 to 179 C; Bulging 92% of theory.

7.6 g of 6a, 21-difluoro-9, ll / i-epoxy-16a-methyl-9 / i-pregna-l, 4-diene-3,20-dione are poured into a mixture of 40 ml of dimethylformamide and 40 m) of hydrogen fluoride are added and the mixture is stirred at room temperature for 24 hours. The reaction mixture was worked up as described in Example 3. The 6 *, 9,21-trifluoro-1 l / i-hydroxy-16xmethyl-1,4-pregnadiene-3.20-dione obtained in this way is converted from acetone / 9.8 g 6a, 21-difluoro-16a-methyl-1, 4.9 (1 l) -pregna- 25 hexane recrystallizes and melts at 287 to 289 C triene-3,20-dione are dissolved in 210 ml of tetrahydrofuran with decomposition; Yield 80% of theory.

Claims (1)

Patent claims: 1. 6,9,2 1-trihalogen steroids of the formula
CH ₂ Y CH, 7. Medicaments based on the compounds according to claim 1.