DE1801390A1 - 6,9,21-trihalosteroids - Google Patents

Description

"I" ^l " ^l l | ^l !!! ⁱ !!" | ^l ! | i | ^l | l !: ^l ! i '] | i | i | !!! ^{| l} | l |! l! ' ^l l ^! l ^{| l} ! ' ^h """

'Berlin, the 3o. September 1968

SCHERING AG. ·. ·

Patent department;

Dr.Pa/Lu/P. llol 1801390

6, 9, 21 - irihalogen steroids

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

■ HO

(D

wherein X is fluorine, chlorine or bromine and Y is chlorine or Mean 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 9.11 double bond of a starting steroid of the general formula is formed in a manner known per se

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009821/1881

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hypohalous acid HOX ¹ , in which X 'denotes a chlorine or bromine atom, and - if X denotes a fluorine atom in the ultimately desired products - the 9 <z-chloro or 9a-bromo-11ß-hydroxy compound is also added is converted into the 9A ^1- EP ⁰ Xi-CL in a known manner and finally opens the epoxy ring with hydrogen fluoride.

The addition of hypohalous acid to the 9 double bond content of II takes place according to this well-known working methods, preferably by loading \ treatment of the 9 ₁ 11 "double bond with reagents that make known to be in the course of the reaction HOX 'free such. B. dibromodimethylhydantoin, N-X'-acylamide, in particular N-bromo (or chloro) acetamide, or N-X'-acylimide, in particular N-bromo (or chloro) succinimide

If the ultimately desired 6,9> 21-trihalogenosteroids are to be 9a-fluorine compounds, after ^{the addition of HOX 1} to the 9iH double bond, the 9a-bromine (or chlorine) llß-OH group is likewise known, z. B. by treatment with basic reagents such as NaOH, KOH, IL) ⁰ Ox »potassium acetate, pyridine and the like at a preferably elevated reaction temperature, closed to form the 9,11-oxidizing ring, which is then converted into the

is converted «,

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- 3 - P. llol / 3o. 9th 196 8

The novel 6,9,21-trihalogenosteroids of the given general formula I are distinguished by a high anti-inflammatory effect, as shown in the following table using the example of 6a-fluoro-9a, 21-dicbaor-11ß-hydroxy-16a-methyl- 1,4-pregnadiene-3,2odione (b) in comparison to the known 6oc-fluoro-llß, 21-dihydro: xy-16a-methyl-1,4-pregnadiene-3,2o-dione (a). The intensity of action was determined according to the known vasoconstriction test, with low, medium and high-grade vasoconstriction between 0 and 100 being assessed on healthy male test subjects aged 18-38 years Concentration o, ol _t ο, οοΐ and O ₁ O00 % , applied

TABEL

Active ingredient I> osis observation time in S-cd. in ^: / o 1 2 · ■ 3 4 5-6

a) 6a-fluoro-lia, 21-dihy- o, ol 0 25 4o. 5o loo drox5 ^r -i6a-nethyl-I, ^ - ο, οοΐ 0 2o 33 75 loo pregnadien-3,2o-dione ο, οοοΐ 0 15 25 5o 9o loo

b) 6a-fluoro-9a, 21-dichlo> -o, ol 12 4-7 89 loo llß-hydroxy-16a-methyl-o, ool 11 ^ 4 72 loo l, 4-pregnadiene-3,2o o _t oool 0 29 48 88 loo dion

- 4 - 009821/1881

- 4 - P. Hol / 3o. 9. 68

The test results show that the 6,9,21-trihalogenosteroids according to the invention have a significantly higher intensity of action than the known substance a) in all dose ranges. In addition, they are characterized by an earlier onset of action and reach their maximum effect quicker, "The connections do not cause sodium retention hervor.Sie have slight diuretic Widcurgjait The new compounds are - in combination with the usual ■■ galenic pharmacy carriers and diluents. - well suited for the treatment of z. B ₀ , ■ _

a) 1 ο k a 1: Contact dermatitis, eczema of the most varied Type, lieurodermatitis, erythroderma "burns" j Pruritus vulvae et ani, rosacea, erythematodes cutaneus,! Psoriasis, Liehen ruber planus verrucosus |

b) oral: - acute and chronic polyarthritis, neurodermatitis, Bronchial asthma, hay fever etc. »,

The ones used to make the 6,9,21-trihalosteroids | Starting products of the general formula II are also not prescribed. For example, from the. known 6a-fluoro-21-acetoxy-16a-methyl-1,4,9 (H) -pregnatriene-3,2o-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 0-5 ° G

.00982 1/1881 -. '■. ^:

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'■■■■ - 5 - · · P. llpl / -36. 9. "68

with formation of the 21-alcohol (P. 19o-192 ° E) and renewed esterification of the released 21-hydroxyl group with sulfochlorides, z. B. methanesulphonic acid chloride, in pyridine at 0-5 ° C., 6a-i'luoro-21-mesyloxy-16a-methyl-1,4, 9 (11) ~ vxegna.tT ± en. ~ 3 , 2o -dione (P _e 149-150 ° C). The 21-mesyloxy group is finally used in e.g. B. Dimethylformamide is preferably replaced by the ultimately desired halogen atom at elevated temperature: with, for example, potassium hydrogen fluoride, the corresponding 21-fluorine compound is obtained _? with lithium chloride the corresponding 21-chlorine compound. The 21-chloro compound can also be prepared from the 21-alcohol (P. 19o-192 ° 0) by treatment with thionyl chloride in pyridine.

The following examples serve to further illustrate the present invention.

For example;

5.5 g of 6a-fluorine-21-chloro-16a-methyi-l / l- ₅ 9 (ll) -pregnatrien-5,2o-dione (P. 2o8-2o9 ° C) are dissolved in 100 ml of tetrahydrofuran, with 5 »5 g of N-chlorosuccinimide and 44 ml of ln-perchloric acid are added and stirred for 2 1/2 hours at 35 ° C. The reaction solution is poured into ice water, the

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Sucked off the fallen substance, washed neutral and dried. The resulting 6a ~ 3? Luor-9i21-dichl> · -llßhydro3cy-16a-methyl-l _$ 4 ~ pregnaaien 3s2o-aion is from acetone-hexane umkristallisierti F. 233-235 ° G ν '"Ausbeu te 9o% the theory, UV: € 15 233'- 8oo "

Example 2 ^:;

\ 7 S 6a-fluoro-21-> chlor-16a ^ methyl ~ l _i 4 »9 (ll) '- pregnatriene - 3,2o-dione are dissolved in 150 ml of tetrahydrofuran, with. lo, 5 S N-Bromsucoinimid and 65 ml ln-perchloric acid and 15 minutes' stirring at 35 ° G Heaktionslösung is poured into ice-water, üfatriumsulfit added and stirred for 3o minutes. The precipitated substance is filtered off with suction, washed neutral and dried. After recrystallization from acetone-hexane, 6.9 g of 6a-fluorine-21-chloro-9-bromo-11ß-hydroxy-16a-methyl-1,4-pregnadiene-3 are obtained _r 2odion received ^ F ₈ 218 ° 0 (dec.) ». OT: Eg ^ ₁ - 14 5oo.

8.6 g of 6ö-i ^l iuor-21-clilor-9-bromo-llß-hydroxy-16a-methyll, 4-pregnadiene-3i2o-diön are dissolved in 160 ml of ethanol and

40 ml of iDetra% drofi »a] tt 'with 16 g of aluminum acetate 45 meowing ',:;. '..- "- 0 0.9'8-ZI- / 1881-

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- 7 - P. Hol / 3o. 9. 68

heated to reflux. The reaction mixture is stirred into ice water, and 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. By eluting with hexane / acetone mixtures, the 6a-3? Luoro-21-chloro-9 »Hß-epo3cy-16a-methyl-9β ^ pregna-1,4-diene ~ 3» 2o ~ dione is obtained * P. 139 -139.5 ° C (isopropyl ether) \ - 15 8oo.

15 ml of dimethylformamide are cooled to -15 ° C. and mixed with 15 ml of hydrogen fluoride while stirring. To this mixture, 3-15 g of 6a-fluoro-21-chloro-9113-epoxy-16amethyl-9ß-pregna-1,4-diene-3,2o-dione, dissolved in 5 ml of dimethylforaamide, are added dropwise. Left to stand for 18 hours at 5 ° C and 9 hours at 20 ° C. The reaction solution is poured into ice water / xalium hydrogen carbonate, the substance which has precipitated out is suctioned off, dried and recrystallized from acetone / ßexane. The 6a, 9-difluoro-21 ~ chloro-llß-hydroxy-16a-methyl-1,4-pregnadiene-3,2odione thus obtained ech ^ ilz't at 215-216 ° C (decomp.) J IJV: Cgxo - 16 2oo; Yield & o% of theory. .

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3 g of 6a-21-difluoro-16a-methyl ~ l, 4,9 (ll) -pregnatriene-3,2odione (P. 229 r 231 ° G) are mixed in 70 ml of tetrahydrofuran with 3 g of N-chlorosuccinimide and 24 ml of ln Perchloric acid reacted and worked up as described in Example 1. The 6a, 21-difluoro-9-chloro-llß-hydroxy-16a-methyll, 4-pregnadiene-3 »2o-dione thus obtained melts after recrystallization from acetone-benzene at 255-256 ° G, \ Wi yield &% of Theory. ·,

B 'e i s ρ i e 1 5:

9.8 g of 6 ", 21-difluoro-16a-met2i3rl-1,4 _f 9 <ll) -pregnatriene-. 3,2odione are stirred in 21o ml of tetrahydrofuran with 14.7 g of N-bromosuccinimide and 91 ml of in-perchloric acid for 10 minutes at 35 ° and worked up as described in Example 2. The 6ce, 21-difluoro thus obtained -9-bromo-llß-hydroxy-16a «methyl-1,4-pregnadiene-3» 2o-dione is recrystallized from acetone; P. 210 ° C. (decomp.) I Yield 98% of theory.

0 0 9 8 217 18 8 1

P. Hol / 5o. 9.

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180t390

Examples:

nadiene-5 »2o-dione are reacted in 250 ml of ethanol and 30 ml of tetrahydrofuran with 20 g of anhydrous potassium acetate, refluxed for 60 minutes and worked up as described in Example 3. The 6a» 21-difluoro-9, Ilß ~ obtained in this way epoxy-16a-methyl-9ß-pa? e6 & a-l, 4-diene-5,2o-dione melts at 177-179 ° O i yield 92 ^ of theory

7.6 g of 6a, 21-difluoro-9, 11ß-epoxy ~ 16a-methyl-9ß-pregna-1,4-diene-3,2o-dione are added to a mixture of 40 ml of dimethylformamide and Mo ml of hydrogen fluoride were added and the mixture was stirred at room temperature for 24 hours. The reaction mixture was worked up as described in Example 3. The δα thus obtained, 9.21-trifluoro-LLSs-hydroxy-16a-methyl- -l, 4-pregnadiene-3 '2o-dione is recrystallised from acetone / hexane melts at 287 ~ ⁱ 289 O ° with decomposition; Yield & o% of theory '

INSPECTED

Claims (1)

P. Hol / 3ο. 9. Claims 1.6,9) 21-trihalosteroids of the formula where X is a fluorine, chlorine or bromine atom and Y is a ¹ chlorine or fluorine atom » (TtJ 6a-fluoro-9 <21-dichloro-11ß-dihydroxy-16a-methyl-1,4-pregnadiene-3,2o-dione. 5. 6α-fluoro-21-chloro-9-brolfi-llß-hydro3ςf-16α-methyl-1 _t 4-pregnadiene-3 _t 2o-dione pregnadiene-3,2o-dione ■ '■. ι ■ 5 * 6a, 21-difluor-9- ^ rom-llß ~ hydro3cy-16a-methyl-l ', 4-preg- . '■ "". :. ¹ V ÖQS821 / INPEQTED ! P. Hol / 3o. 9. ΛΑ ' 18Ö1390 6x6α, 9,21-trifluoro-11β-hydroxy-16a-methyl-1,4-pregna-. diene-3,2o-dione. 7 x 6α, 21-Tue pregnadiene-3,2o-dione. 8. Process for the preparation of new 6,9,21-trihalogenoids of the formula HO. wherein X is a fluorine, chlorine or bromine atom and X is Mean chlorine or fluorine atom, characterized in that that in a manner known per se one can approach the 9 »H permanent Double bond of a parent steroid. common formula CH ₂ -Y öo —CH, 5 Upper Austria 9821/1881 llol / jo. 9. 6β Hypohalogenous acid HOX *, in which X ^c denotes a chlorine or bromine atom, attaches and - if X denotes a fluorine atom in the ultimately desired products, the 9 <x -chlorine or 9 "-bromo-11β-hydroxyl compound also per se converted into the 9,11-epoxide in a known manner and finally opens the epoxide ring with hydrogen fluoride. 9 6a-fluoro-21-chloro-16a-methyl-l _t 4 _v 9 (ll) -pregnatriene-3,2o-dione. lo 6a-fluoro-21-chloro-9, llß-epoxy-iea-methyl-gß-pregna- ^Λ 1,4-diene-3, 2o-dione. 11. 6a _t 21-difluoro-16a-methyl-1,2,4,9 (II) -pregnatrien-3,2odione. Ϊ2 · 6α, 21-difluor-9, llß-epoxy-16a-methyl-9ß-pregna-1,4-diene-3 »2o-dione. 13 · Medicines based on the compounds according to addressed 1-7 0 0 9'JB 2 1/1 8 8 ί