DE1083815B - Process for the preparation of therapeutically active steroid compounds - Google Patents

Description

Process for the preparation of therapeutically active steroid compounds The invention relates to a method for producing therapeutically more effective Steroid compounds.

It was found that 6,21-difluoro-11ß, 17a-dioxy-4-pregnen-3,20-dione and 6,21-difluoro-17a-oxy-4-pregnen-3,11,20-trione (6 , 21-Difluoro-21-deoxyhydrocortisone and 6,21-Difluoro-21-deoxy-cortisone) in particular their 6a-fluoroepimers and the corresponding 17a, 21-epoxides, which are strongly anti-inflammatory, which are formed at the same time as the fluorine atom is introduced through the elimination of hydrogen fluoride and have glucocorticoid activity and are therefore suitable for the effective treatment of rheumatoid arthritis. The glucocorticoid effect of 6a, 21-difluoro-21-deoxyhydrocortisone is twice as great as that of hydrocortisone; its anti-inflammatory effect is 8 to 20 times that of hydrocortisone. At the same time, its administration increases the sodium excretion to 1.35 times and the water excretion to 2 times the normal value. The compounds of the invention are also useful in the treatment of skin, eye and ear infections (both in humans and valuable domestic animals) and in the treatment of contact dermatitis and other allergic conditions. For this purpose, they are brought into the usual dosage forms using suitable carriers; In the form of pills, tablets, capsules, solutions, syrups or elixirs, and for parenteral administration in the form of liquid preparations such as are common for natural and synthetic adrenal cortical hormones. For topical application, they are expediently processed into ointments, creams, lotions, etc. In the preparation of the above-mentioned dosage forms, antibiotics that supplement or reinforce the effect of the steroid compounds, as well as germicides or other desired compounds can be added.

The compounds which can be prepared according to the invention can be obtained according to the following reaction scheme. In the above formulas, R denotes an organic radical, in particular a hydrocarbon radical having 1 to 10 carbon atoms, e.g. B. the methyl, ethyl, phenyl, tolyl or naphthyl radical, preferably the methyl radical; R 'denotes an H, β-OH group or keto oxygen. The fluorine substituent in the 6-position can be both α and β.

To carry out the erlindungsgemäßen procedure is 6-fluoro-ILSS, 17a, 21-trioxy-4-pregnene-3,20-dione (6-fluoro hydrocortisone) (I) or its 1 1-keto compound - the said compounds can be prepared by the in Patent specification 1037 452 are prepared - with an organic sulfonyl halide, such as methanesulfonyl chloride, toluenesulfonyl chloride, toluenesulfonylbronlide, benzenesulfonyl chloride, naphthylsulfonyl chloride and the like. Treated. Methanesulfonic acid halide and, in particular, methanesulfonic acid chloride are preferred. The reaction takes place preferably in a solvent such as pyridine, benzene, toluene and the like. If a solvent is used, an amine such as pyridine should be present in an amount equimolar to the sulfonyl halide in order to bind the hydrogen halide formed. The reaction temperatures are preferably between - 10 and + 60'C, provided that the solvent does not solidify both given lower temperature limit. When using pyridine, dioxane, toluene or the like, reaction temperatures between 0 and 10 ° C are suitable. When using benzene, the reaction temperature must be above 5'C because the benzene solidifies even at relatively high temperatures. The reaction time is generally between 30 minutes and 8 hours. After the reaction has ended, the 6-fluoro-11ß, 17a, 21-trioxy-4-pregnen-3,20-dione-21-sulfonate (II) or its 11-keto compound obtained is obtained in a conventional manner, e.g. B. by evaporating the solvent or diluting with water and precipitating the product with dilute hydrochloric acid.

The 6-fluoro-11β, 17a, 21-irioxy-4-pregnen-3,20-dione-21-sulfonate or its 11-keto derivative is then treated with a fluorinating agent in an inert solvent. Suitable fluorinating agents are potassium fluoride and silver fluoride. or antimony fluoride, suitable inert solvents dimethyl sulfoxide, acetonitrile, diethylformamide or ethylene glycol. A particularly favorable combination is potassium fluoride in dimethyl sulfoxide. The reaction is preferably carried out with heating. It usually lasts 6 to 24 hours. In most cases, 15 to 20 hours is sufficient. The reaction mixture is then diluted with an organic solvent, such as methylene chloride, chloroform, benzene, etc., and in a conventional manner, e.g. B. purified by chromatography, or by solvent extraction.

As mentioned above, arise in the fluorination small amounts of 6-fluoro-1-oxy-1 ß respectively. -keto-17a, 21-oxido-4-pregnen-3,20-dione, which also has glucocorticoid and anti-inflammatory properties and, in particular, considerable diuretic properties, which are useful in the treatment of chronic heart congestion, liver cirrhosis, kidney syndromes and pre , -eclampsia valuable.

The 21-fluoride can also be produced via the 21-iodide, which also produces some 17a, 21-epoxide. To prepare the 21-iodine compound, the 21-sulfonate is dissolved in a chemically bonded oxygen-containing solvent, e.g. B. an alkanone such as acetone with an alkali iodide, e.g. B. sodium, potassium or lithium iodide implemented. The iodide is preferably used in excess (3 to 20 moles of iodide per mole of steroid). The reaction mixture is extracted 3 heated to reflux for 30 minutes and then the resulting 6-fluoro-21-iodo-11FL, 17a-dioxy-4-pregnene-3,20-dione or its 11-keto compound by exhaust steam of the solvent . It can be further processed as such or in a form purified by recrystallization from organic solvents such as acetone, ethanol, etc.

The 21-iodide dissolved in a solvent such as acetonitrile, dimethylformamide or ethylene glycol is then reacted with a fluoride such as silver fluoride, antimony fluoride, potassium fluoride, etc. Silver fluoride in acetonitrile is preferred. The fluoride is added gradually in small amounts. Protect the solution from exposure to light during the reaction, which usually takes about 30 minutes to 6 hours. The reaction mixture is then concentrated and the product is extracted. Virtually pure 6,21-difluoro-11ß, 17a-dioxy-4-pregnen-3,20-dione or 6,21-difluoro-17a-oxy-4-pregnen-3,11,20-trione are obtained.

If the starting material contained a left hydroxyl group, this can be oxidized by known methods, e.g. B. in acetic acid with molar amounts or a small excess of 10 to 30 l) /, chromium trioxide. Other suitable oxidizing agents are halogen amides or imides, e.g. B. N-bromoacetamide, N-chlorosuccinimide or N-bromosuccinimide in pyridine, dioxane or other suitable solvents. When the oxidation is complete, the oxidizing agent (if it has been oxidized with chromic acid) is usually destroyed by adding methyl alcohol, ethyl alcohol and the like. When using N-bromoacetamide, N-bromosuccinimide or other N-haloacylan iides and imides, bisulfite is preferably added. The 6,21-difluoro-17a-oxy-4-pregnen-3,11,20-trione thus obtained is then isolated in the usual way, e.g. B. by extraction with solvents that are immiscible with water, such as methylene chloride, ether, benzene, toluene and the like., Or by chromatography.

In the process steps described above, both the 6a-fluorine such as the 6P fluorepi-inere can be used.

The latter changes into the 6a-epimer in an acidic or basic medium. For example, it is obtained when the 6fl isomer is treated in an organic solvent such as chloroform at a temperature of O'C with an anhydrous mineral acid such as hydrochloric acid in the presence of alcohol. This temperature should be maintained during the entire acid addition. The reaction mixture can then be washed several times with dilute alkali and water. After evaporation under reduced pressure, the 6P-epimer is obtained in good yield. The following examples explain the process according to the invention, the individual stages of which represent measures known per se. Example 1 a) 6a-fluoro-Ilfl, 17a, 21-trioxy-4-pregnen-3,20-dione-21-methanesulfonate (II) To a solution of 770 mg of crude 6a-fluoro-11β, 17a, 21- trioxy-4-pregnen-3,20-dione (I) in 10 cem of pyridine cooled to 0 to 5 ° C., 0.7 cc of methanesulfonyl chloride is added. The mixture is placed in ice water and stirred for 4 hours. When diluting with 100 ccm 511 /, iger HCl, the crystalline 21-methanesulfonate (II) precipitates, which is filtered off. Yield 900 mg, mp 189 to 192 ° C. (decomposition). Infrared analysis in mineral oil showed absorptions at 3560, 3420 cm-' (O H); 1725 cm-'(20-ketone); 1655 cm- '(A4-3 ketone) 1640, 1617 cm-' (C = C); 1350, 1200, 1170 cm- '(OS 0, -).

b) 6a, 21-difluoro-IIP, 17a-dioxy-4-pregnen-3,20-dione (6a, 21-difluoro-21-deoxyhydrocortisone) (IV) A mixture of 20Omg 6a-fluoro-ILß, 17a-dioxy -4-pregnen-3,20-dione-21-methanesulphonate (II) and 10Omg potassium fluoride in 2ccm dimethylsulphoxide are heated on the steam bath for 17 hours. The reaction mixture is then diluted with 50 cc of methylene chloride and washed three times with 10 cc of water. After drying over sodium sulfate, the methylene chloride solution is chromatographed on a column of 10 g of synthetic magnesium sulfate. Elution with Hexankohlenwasserstoffen plus 9% acetone (four fractions from e j 20 cc) gave 28 mg of impure crystals, which on-3-6a-fluoro-llp-oxy-17,21-oxido-4-pregnene by infrared analysis as (V ) were identified. The adsorption maxima in mineral oil were 3410 cm- '(OH); 1807 cm- ' (C = 0 in the 4-ring); 1660 cm- '(, d4-3-keto group); 1625 cm- ' (C = C). The pharmacological properties of this compound are similar to those of the compound (IV).

Further elution with hexane hydrocarbons plus 12 and 1501,) acetone gave 45 mg of 6a, 21-difluorine, 17a-dioxy-4-pregnen-3,20-dione (IV). After recrystallization from ethyl acetate-Hexankohlenwasserstoffen 29 mg of product was obtained, mp 226-230 "C.

The infrared adsorption maxima were at 3600, 3540, 3360 cm- '(OH); 1722 cm- '(20-ketone); 1653 cm- '(A4-3 ketone); 1625 cm- ' (C = C).

c) 6a, 21-difluoro-17a-oxy-4-pregnen-3,11,20-trione (6a, 21-difluoro-21-deso.xycortisone) A solution is prepared from 0.5 g of 6a, 21-difluoro -11 fl, 17a-dioxy-4-pregnen-3,20-dione, 0.15 g chromium trioxide, 10 ccm glacial acetic acid and 0.5 ccm water. The mixture is then stirred for 8 hours at room temperature. The whole is then poured into 50 cc of ice water, neutralized with dilute sodium hydroxide solution, the resulting precipitate is collected on a filter and recrystallized three times from ethyl acetate and hexane hydrocarbons, whereupon 6a, 21-difluoro-17a-oxy-4-pregnen-3,11 , 20-trion receives.

Example 2 6a, 21-difluoro-11ß, 17a-dioxy-4-pregnen-3,20-clione (6a, 21-difluoro-21-deoxyhydrocortisone) and 6a, 21-difluoro-17a-oxy-4-pregnen-3 , 11,20-trione (6a, 21-difluoro-21-deoxycortisone) 6a-fluoro-Ilfl, 17a, 21-trioxy-4-pregnen-3,20-dione is added to the procedure shown in example, a) Methanesulfonyl chloride in pyridine. The 6a - fluorine - 11ß, 17a, 21 - trioxy - 4 - pregnen - 3,20 - dione-21-methanesulfonate obtained is refluxed with potassium iodide in acetone. 6a-fluoro-Ilfl, 17adioxy-21-iodo-4-pregnen-3,20-dione is obtained, which in acetonitrile with aqueous superfluoride solution 6a, 21-difluoro-17a-dioxy-4-pregnen-3,20-dione results and is identical to that obtained according to Example 1, b) .

In the above examples, the corresponding starting materials can also be used 6β-epimers are used, their 6β-conflquration if adhered to about. neutral Reaction conditions is maintained. The 6β-Epunera thus accumulating go into the 6a-epimers over when you get them at O'C or something below in an organic Solvent, such as Chlorofo =, with an anhydrous mineral acid (e.g. HCI) in Presence of alcohol treated. The 6a-epimers are obtained several times Washing with dilute alkali and evaporation under reduced pressure.

Claims (1)

PATENT CLAIM: Process for the production of therapeutically effective steroid compounds of the general formulas in which R 'is an H, β-O H group or keto oxygen, and the fluorine substituent in the 6-position can be both a- and fl-position, characterized in that a compound of the general formula in which R # has the above meaning, treated in a manner known per se with an organic sulfonyl halide, the 21-sulphonate obtained is reacted with a fluoride directly or after prior conversion into the 21-iodide and, if appropriate, the 11-position hydroxyl group of the product obtained is oxidized .