DE1063164B - Process for the preparation of an anti-inflammatory steroid compound - Google Patents

Description

The invention relates to a process for the production of an anti-inflammatory steroid compound, namely 6-methyl- Ιίβ, Πα- dioxyl, 4-pregnadiene-3,20-dione from 6-methyl-l 17 a-dioxy-21-iodine-l , 4-pregnadiene-3,20-dione.

To carry out the process according to the invention, 6-methyl-11 / ?, 17a-dioxy -21-iodine-1,4-pregnadiene-3,20-dione is added with a reducing agent such as sodium thiosulfate, potassium thiosulfate, sodium bisulfite, potassium bisulfite or the like. , implemented in an aqueous organic solvent to 6-methyl-l 1 ß, 17 a-dioxy-1,4-pregnadiene-3,20-dione.

The procedure is that the 6-methyl-l Iß, 17a-dioxy-21-iodine-1,4-pregnadiene-3,20-dione z. B. slurried in acetic acid, an aqueous solution of sodium thiosulfate or the like. Adds and the mixture obtained is stirred for 10 minutes to 2 hours at room temperature. The reaction product is extracted from the aqueous mixture by conventional methods, e.g. B. by filtration, or by extracting with an organic, water-immiscible solvent such as ether, benzene, methylene chloride, ethylene chloride, carbon tetrachloride, chloroform, hexane, heptane or the like. And then evaporating the extracts. The obtained 6-methyl-II / ?, 17a-dioxy-l, 4-pregnadiene-3,20-dione is then in a known manner, for. B. purified by recrystallization from ether, acetone, methanol, ethanol, hexane hydrocarbons or from mixtures of these solvents or by chromatography. It can then be used in a known manner, for. B. in acetic acid with chromic anhydride or in pyridine, dioxane or another solvent to 6-methyl-l 7 a-oxyl, 4-pregnadiene-3, ll, 20-trione are oxidized.

The 6-methyl-11ß, 17a-dioxy-21-iodo-1,4-pregnadiene-3,20-dione used as starting material for the process according to the invention can be obtained in such a way that 11 ^, 17a, 21-trioxy -4-pregnen-3,20-dione-3,20-bisketal e.g. B. with perbenzoic acid in the corresponding 5 <x, 6a-epoxy, this with a Grignard reagent in 6-methyl-5 α, ίίβ, Πα, 2ί -tetraoxy -pregnane-3,20-dione-3,20- bis-ketal is converted, the compound obtained is de-ketahsed by acid hydrolysis, the 6-methyl-5a, 11 / ?, 17a, 21-tetraoxy-pregnane-3,20-dione formed is dehydrated in the 4 (5) position with the exclusion of oxygen , the 6-methyl-l iß, 17 a, 21-trioxy-4-pregnen-3,20-dione obtained is microbiologically dehydrated in 1 (2) division, the 1,4-pregnadiene derivative thus produced with an organic sulfonic acid halide treated and the 21-sulfonate formed is reacted with sodium iodide in acetone solution.

The new 6-methyl-II / ?, 17a-dioxy-1,4-pregnadiene-3,20-dione has high physiological effectiveness, as does its 11-keto analogue. Their activity spectra differ in particular with regard to the method of production
an anti-inflammatory
Steroid compound

Applicant:
The Upjohn Company,
Kalamazoo, Mich .. (V. St. A.)

Representative:

Dr. W. Beil and A. Hoeppener, lawyers,
Frankfurt / M.-Höchst, Antoniterstr. 36

Claimed priority:
V. St. v. America September 10th and November 23rd, 1956

Frank Harris Lincoln Jr., William Paul Schneider
and George Basil Spero, Kalamazoo, Mich. (V. St. A.) have been named as inventors

on the mineral and water metabolism of those of naturally occurring adrenal cortex hormones. she cause increased salt and water excretion and are therefore used in the treatment of chronic congestive heart disease, cirrhosis of the liver, nephrotic syndrome, eclampsia and preeclampsia of special meaning. They also have anti-inflammatory, glucocorticoid, anesthetic, uterine, ovarian and adrenal growth-inhibiting as well as adrenocorticoid effectiveness. It is particularly noteworthy their anti-inflammatory effect, with low salt retention at the same time, as can be seen in the following, The tabular results of comparative experiments in which hydrocortisone and deoxycorticosterone, the effectiveness of which was assumed to be 100%, served as comparison substances.

909 607/429

Claims (2)

Hydro cortisone6 a-methyl- ll / S, 17a-dioxy- 1,4-pregnadiene- 3,20-dione Glucocorticoid effect (liver glycogen deposition) ... 100% 330% anti-inflammatory effect..100%> 400% deoxy- cortico- steron6a-methyl-ll / 3, 17 a-dioxy-1,4-pregnadiene-3,20-dionNaCl retention ... 100% <2% The 6 /? epimer of the 6-methyl- ll / ^ 7a-aUoxy-l, 4-pregna & en-3,20-dione has the same effect as the 6 <x-epimer. The compound according to the invention can be administered orally in the form of "polyethylene glycol 4000 or 6000" (trade name), tablets containing lactose or sucrose as a diluent, topically in the form of ointments, lotions, jellies, creams, suppositories and aqueous suspensions, and parenterally. The addition of antibiotics and sulfonamides has a beneficial effect on the overall effect of the preparations. The compound which can be prepared according to the process can also be converted into further, physiologically active compounds, e.g. B. the corresponding 9 cc halogen derivative can be converted, which also has glucocorticoids and anti-inflammatory effects. It is obtained from 6-methyl-11JS, 17a-dioxy-1,4-pregnadiene-3,20-dione, which can be prepared according to the process, by splitting water in the 9 (11) position and adding a hypohalous acid to the 9 (II) position Double bond, elimination of hydrogen halide with formation of 6-methyl-9 (II) -oxido-17a-oxy-1,4-pregnadiene-3,20-dione and opening of the epoxy ring with z. B. Hydrogen fluoride to yield the desired 6-methyl-9a-halogen derivative. The following example explains the method according to the invention. EXAMPLE To prepare the 6a-methyl-II / 3,17adioxy-21-iodine-1,4-pregnadiene-3,20-dione used as starting material for the process according to the invention, 164 mg (0.437 millimoles) of l-dehydro-6a are prepared -methylhydrocortisone and 1 ecm pyridine a solution. This is cooled to 0 ° C. and treated with a cooled solution of 75 mg methanesulfonyl chloride in 0.5 ecm pyridine. The mixture is then left to stand at 0 to 5 ° C. for 2 hours. Then ice and sufficient hydrochloric acid to neutralize the pyridine are added and the mixture is extracted three times with 25 ecm of methylene chloride each time. The extracts are combined, washed with cold sodium bicarbonate solution and then with water, dried over anhydrous sodium sulfate and dried under reduced pressure to give crystalline 6a-methyl-II / S, 17a, 21 -trioxy-1,4-pregnadiene-3.20- evaporated dione-21 methanesulfonate. This is dissolved in 15 ecm acetone, treated with a solution of 200 mg sodium iodide in 5 ecm acetone and then heated for 15 minutes under reflux while stirring. It is then concentrated under reduced pressure, whereupon the desired 6a-methyl-II / S, 17a-dioxy-21-iodine-1,4-pregnadiene-3,20-dione is obtained. The crude 6a-methyl-1, 17a-dioxy-21-iodo-1,4-pregnadiene-3,20-dione is slurried with 5 ecm acetic acid and stirred for 45 minutes. An aqueous solution of 250 mg of sodium thiosulfate pentahydrate is then added, whereupon the iodine color disappears. Then 50 ecm of water are added and the mixture is extracted three times with 25 ecm of methylene chloride each time. The methylene chloride extracts are combined and washed with water and cold sodium bicarbonate solution until all of the acetic acid has been neutralized. After drying over anhydrous sodium sulfate, the solution is concentrated to about 15 ecm and chromatographed over 10 g of synthetic magnesium silicate, the following fractions of 50 ecm each being collected: nine fractions of 10% acetone and hexane hydrocarbons, four fractions of 15% acetone and hexane - ao hydrocarbons and a fraction that consists only of acetone. Fractions 6 to 11 are combined and evaporated to give 136 mg of crystals which, after recrystallization from acetone-hexane hydrocarbons, 115 mg (a total yield of 72%) 6a-methyl-lljö, 17a-dioxy-1,4-pregnadiene- 3,20-dione with a melting point of 222-231 ° C. Analysis for C22H30O4. o0 Calculated C 73.71, H 8.44; found C 73.30, H 8.44. As mentioned above, it can be oxidized to the II-keto derivative in a known manner. If the 6 /? - epimers are assumed in the above reaction sequence and the reaction conditions are kept as neutral as possible, the 6 /? - epimer can be obtained from the reaction mixture. B. ethanol, can be converted into the 6a-epimer at room temperature. Patent claims: 1. A process for the preparation of an anti-inflammatory steroid compound of the general Formula: CH ₅ CH _a characterized in that 6-methyl-II / 3,17adioxy-21-iodine-1,4-pregnadiene-3,20-dione reacted in a manner known per se with a reducing agent. 2. The method according to claim 1, characterized in that the reducing agent used is sodium thiosulfate used.