DE1123321B - Process for the preparation of therapeutically active steroid compounds - Google Patents

Description

Process for the production of therapeutically active steroid compounds The invention relates to a process for the production of therapeutically active steroid compounds of the general formula C Hz F C - = O C H3, R OH CHaI. X O F. in which R, H, OH or keto oxygen, X is a halogen with an atomic weight of 17 to 80 and the fluorine substituent in the 6-position can be in the x or β position.

The compounds which can be prepared according to the invention have a high degree anti-rheumatic, anti-arthritic, anti-inflammatory and glucocorticoid effects. For example, 1-dehydro-6x, 9x, 21-trifluoro-21-deoxyhydrocortisone (6x, 9x, 21-trifluor - 1 lß, 17x - dioxy - 1,4 - pregnadiene - 3,20-dione) about ten to fifteen times anti-inflammatory effectiveness of hydrocortisone. It also exercises a cheap Effect on mineral metabolism. The compounds obtainable according to the invention are used to treat inflammation of the skin, eyes and ears of people and valuable pets as well as for the treatment of contact dermatitis and other allergic ones Apparitions suitable. They can be administered in the usual dosage forms take place, e.g. B. in the form of pills, tablets, capsules, syrups or elixirs for oral use or in the form of liquid preparations, as they are for natural and synthetic corticosteroid hormones are common for injections. For the local They are applied in the form of ointments, creams, lotions and the like. The above-mentioned dosage forms can besides the steroid compounds according to the invention also contain antibiotics, germicides or other substances.

The process according to the invention, in which the sequence of the individual process stages can be varied, is represented by the following equation in which R 'is an organic radical, preferably a hydrocarbon radical having 1 to 10 carbon atoms, e.g. B. represents the methyl, ethyl, phenyl, tolyl, naphthyl radical or the like, preferably the methyl radical and X is a halogen with an atomic weight of 17 to 80 inclusive, ie fluorine, chlorine or bromine.

For the production of 6,21-difluoro-9x-halogen-1 lß, 17x-dioxy-1,4-pregnadiene-3,20-diones and its 11-keto derivative becomes a 6-fluoro-9x-halo-1, 17a, 21-trioxy-1,4-pregnadiene-3,20-dione (1-Dehydro-6-fluoro-9x-halohydrocortisone) (1) with an organic sulfonyl halide converted to the corresponding 21-ester (II) and the 21-alkyl or 21-aryl sulfonate obtained with a fluorinating agent into the corresponding 6,21-difluoro-9a-halogenl3, 17x-dioxy-1,4-pregnadiene-3,20-dione (111) transferred. The 6,21-difluoride can then to the corresponding 6,21-difluoro-9a-halogen-17x-oxy-1,4-pregnadiene-3,11,20-trione (V) are oxidized. The 6-fluoro-9x-halogen-l Iß, 17x, 21-trioxy-1,4-pregnadiene-3,20-dione-21-alkyl- Or -arylsulfonat can also with an iodinating agent such as sodium iodide, to the corresponding 21-iodine steroid (IV) converted and then converted into the 21-fluoro steroid (III) will. The 11-keto analogue can also be used as the starting material in the process described above 1-dehydro-6-fluoro-9x-halocortisone can be used.

In another embodiment, the 6,21 - difluoro - 9x - halogen - 1 Iß, 17x - dioxy-1,4-pregnadiene-3,20-diones of the invention can be obtained by microbiological dehydration of the 1 (2) position of 6.21 -Difluor-9x-halogen-lIß, 17a-dioxy-4-pregnen-3,20-dione are produced with microorganisms of the genus Septomyxa affinis in the presence of a steroid promoter. The fluorination is advantageously carried out in a solvent such as pyridine, benzene, toluene and the like, at temperatures between -10 and -60.degree. When using solvents such as benzene and toluene, an amount of sulfonyl halide that is at least equivalent to the amount of amine base used, e.g. Pyridine, to be present to the arising during the reaction hydrogen halide binding. The reaction time is usually about 4 to 24 hours, after which the product, 6-fluoro-9x-halogen-11ß, 17x, 21-trioxy-1,4-pregnadiene-3,20-dione-21-alkyl or -arylsulfonate ( I1) is obtained in the usual way, e.g. B. by evaporating the solvent or by diluting the reaction mixture with water and precipitating the product with dilute hydrochloric acid.

Before the reaction with the fluorinating agent, the 6-fluoro-9x-halogen-11ß, 17x, 21-trioxy-1,4-pregnadiene-3,20-dione-21-alkyl- or -arylsulfonate, e.g. B. with sodium, potassium or lithium iodide, dissolved in one chemically bound oxygen-containing solvents, such as acetone, in the appropriate 21 iodine compound (IV) are transferred. An excess is preferably used for this of iodide (3 to 20 moles of iodide per mole of steroid) and the reaction mixture refluxed for about 3 to 30 minutes. The obtained 6-fluoro-9oc-halogen-21 - iodine - l Iß, 17x - dioxy - 1,4 - pregnadiene - 3,20-dione is produced by evaporation of the Solvent or precipitation with water and filtering off isolated. The 21 iodine steroid can then directly or after previous purification by recrystallization from organic Solvents, such as acetone, ethanol and the like, can be processed further. For this is the 21-iodine steroid (IV) in a solvent such as acetonitrile, dimethylformamide or ethylene glycol, dissolved and treated with a metal fluoride, e.g. B. silver fluoride, antimony fluoride, Potassium fluoride or the like. Treated. Acetonitrile is used as the solvent and metal fluoride Silver fluoride preferred. The metal fluoride is expediently added in small proportions and the reaction mixture during the reaction, which is usually 1/2 to 6 hours takes, protected from light. The reaction mixture is then concentrated and the product 6,21 - difluoro - 9x - halogen - 11β, 17 «- dioxy-1,4-pregnadiene-3,20-dione obtained by extraction in a practically pure form.

As mentioned above, the 6-fluoro-9x-halogenl1ß, 17x, 21 - trioxy - 1,4 - pregnadiene - 3,20 - dione-21-alkyl or aryl sulfonate also directly with a Fluorinating agents such as potassium fluoride, silver fluoride or antimony fluoride in one inert solvents such as dimethyl sulfoxide, acetonitrile, dimethylformamide or Ethylene glycol, are implemented using potassium fluoride as the fluorinating agent and the preferred solvent is dimethyl sulfoxide. Implementation, in general requires about 6 to 24 hours is advantageous with continuous heating carried out. Usually 15 to 20 hours are sufficient for the reaction. The reaction mixture is then diluted with water and treated with an organic solvent such as methylene chloride, Chloroform, benzene and the like, extracted and purified in the usual manner, for example chromatographically or by recrystallization.

The above process steps can also be carried out with the corresponding 11-keto analog be performed. The 6,21-difluoro-9, t-halogen-11ß, 17x-dioxy-1,4-pregnadiene-3,20-dione is used to oxidize the 11ß-hydroxyl group for example in acetic acid solution with chromium trioxide or with a halogenamide or -imide, such as N-bromoacetamide, N-chlorosuccinimide or N-bromosuccinimide, dissolved in pyridine, Dioxane or other suitable solvents. After completion of the oxidation the excess chromium trioxide is usually obtained by adding methyl alcohol or ethyl alcohol and the like and the excess N-bromoacetamide, N-bromosuccinimide or other N-haloacylamides or imides destroyed by the addition of a bisulfite. The 11-ketosteroid then becomes in the usual way, e.g. B. by extraction, with a water immiscible Solvents such as methylene chloride, ether, benzene, toluene or the like, or chromatographically won.

In each of the above process steps, known per se, can be used as starting material the corresponding 6ß-fluoroepimer can be used, which by treatment at 0 ° C or a slightly lower temperature in an organic solvent, such as chloroform, in the presence of an alcohol with an anhydrous mineral acid, like hydrochloric acid, passes into the 6x epimer. The reaction mixture should be during the entire addition of acid are kept at the specified temperature. It can be one after the other washed with several parts of alkali and water and evaporated under reduced pressure whereupon the 6x epimer is obtained in high yield. The individual procedural measures are known for themselves.

The following examples illustrate the invention: Example 1 a) 61,9t-difluoro-Liss, 17x, 21-trioxy-1,4-pregnadien-3,20-dione-21-methanesulfonate To a solution of 0.925 g of 6 Y, 9x -Difluoro-11β, 17x, 21-trioxy-1,4-pregnadiene-3,20-dione in 10 cc of pyridine, which had previously been cooled to 0 to 5 ° C., 0.9 cc of methanesulfonyl chloride were added. The reaction mixture was stirred at 0 to 5 ° C. for 17 hours and then poured into 100 cc of cold 5% hydrochloric acid in order to precipitate the 21-sulfonate. The filtered product weighed 0.832 g after drying and had a melting point of 157 ° C. (decomposition). It was used for the next step without further purification.

b) 6x, 9x, 21-trifluoro-llß, 17x-dioxy-1,4-pregnadiene-3,20-dione (1-dehydro-6x, 9x, 21-trifluoro-21-deoxyhydrocortisone) A mixture of 0.5 g of 6x, 9x-difluoro-11ß, 17x, 21-trioxy - 1,4 - pregnadiene - 3.20 - dione - 21-methanesulphonate and 37 g of potassium fluoride in 10 cc of dimethylsulphoxide Heated for 17 hours on a steam bath while stirring. The reaction mixture was then cooled, poured into 150 cc of water and extracted four times with 100 cc of ethyl acetate each time. After drying over sodium sulfate, the ethyl acetate solution was evaporated to dryness and the residue (452 mg) by chromatography on a column of synthetic Magnesium silicate and recrystallization from acetone-hexane hydrocarbons are known under the trade name B, purified. 63 mg of 6x, 9x, 21-trifluoro-11β, 17x-dioxy-1,4-pregnadiene-3,20-dione were obtained from melting point 267 to 272 ° C (decomposition). The analysis sample melted after Recrystallize from ethyl acetate at 273 to 277 ° C.

Analysis for C "H" 04F3: Calculated. . . . . . . . . . . . . F 14.31; found ............. F 13.06. Example 2 6x, 9x, 21-trifluoro-1ß, 17x-dioxy-1,4-pregnadiene-3,20-dione (1-dehydro-6x, 9x, 21-trifluoro-21-deoxyhydrocortisone) A solution of 0.5 g of 6x, 9x-difluoro-11β, 17x, 21-trioxy-1,4-pregnad ie n-3,20-dione-21-methanesulphonate, obtained according to Example 1, a), in 65 cc of acetone a solution of 0.65 g of sodium iodide in 7 cc of acetone was added. The mixture was refluxed for about 10 minutes on the steam bath and then under evaporated to dryness under reduced pressure. The resulting 21-iodide was at 50 up to 60 ° C in the dark in 55 ccm of acetonitrile and with 0.4 ccm of a 50% treated aqueous solution of silver fluoride. The silver fluoride was with each half an hour apart in three equal parts. After the temperature Had been held at 50 to 60 ° C for 11/2 hours, it was on for 21/2 hours 40 to 50 ° C reduced. The solvent was then reduced under reduced pressure 50 ° C evaporated and the black residue digested three times with 50 ccm of acetone. The acetone solution was chromatographed on a pillar from synthetic magnesium silicate and recrystallization from acetone »Skellysolve B «cleaned. It gave 1-dehydro-6a, 9a, 21-trifluoro-21-deoxyhydrocortisone, the was identical to that obtained in Example 1.

Example 3 100 cc of a medium consisting of 10 % glucose, 2% corn steep water (60% solids) and tap water were placed in each of three 250 cc Erlenmeyer flasks and adjusted to a pH of 4.9. This was followed by sterilization for 45 minutes at a pressure of about 1 kg / cm 2 and then inoculated with a 1 to 2 day old culture of Septomyxa affinis ATCC 6737. The Erlenmeyer flasks were shaken for 3 days at room temperature (about 26 to 28 ° C). The 300 cc was then used as a vaccine for 5 liters of the same glucose-corn steep liquor medium to which 5 cc of an antifoam agent (a mixture of lard oil and octadecanol) had been added. The fermentation tank was placed in a water bath, brought to 28 ° C and its contents stirred (300 revolutions per minute) and aerated (0.3 l of air per 51 fermentation liquid). After 20 hours of incubation after good growth had developed, 1 g of 6a, 9oc, 21-trifluoro-21-deoxyhydrocortisone and 0.5 g of 3-ketobisnor-4-cholen-22-al in 16 cc of dimethylformamide were added and the incubation continued at the same temperature (28 ° C) with aeration for 72 hours (final pH 8.3). The mycelium was filtered off and extracted three times with 200 cc of acetone each time. The fermentation medium was extracted three times with 1 l of methylene chloride each time and the extracts of the fermentation liquid and the mycelium were combined, dried over anhydrous sodium sulfate and evaporated. The residue was purified by chromatography over synthetic magnesium silicate, which is known under the trade name “Florisil”, and recrystallization from acetone “Skellysolve B”. 1-Dehydro-6oc, 9a, 21-trifluoro-21-deoxyhydrocortisone with a melting point of 267 to 272 ° C. (decomposition) was obtained.

Claims (1)

PATENT CLAIM: Process for the preparation of therapeutically effective steroid compounds of the general in which R, H, OH or keto oxygen, X is a halogen of atomic weight 17 to 80 and the fluorine substituent located at the 6-position can be either a- such as .beta.-position, characterized denotes Ge, that a compound of the general formula in which R and X have the above meaning, is reacted in a manner known per se with an organic sulfonyl halide to give the corresponding 21-sulfonate and this is converted into 21-fluoride directly or after previous conversion into 21-iodide with a fluorinating agent, or that one a 6,21-difluoro-9a-halogen-4-pregnen-3,20-dione in 1 (2) position microbiologically dehydrated with Septomyxa affinis. Publications considered Journ. Amer. Chem. Soc., 78, p.2658ff: (1956).