CH531492A - Antiinflammatory pregnene-diones - Google Patents

Abstract

Trihydroxypregnene-3,20-diones (I) and especially 11 beta, 17 alpha, 21-trihydroxy-15, 16 beta-methylene-pregnene (4)-(and pregna-1,4-diene)-3,20-dione, for use as anti-inflammatories. R6 and R9 independently are H, halogen, R17, R21 independently are OH or O-acyl; Z is CO or beta-CH2OH. Preparation of (I) and 1,2-dehydro-deriv. by numerous methods e.g. (a) microbiological 11-hydroxylation of (I) (Z=CH2); (b) 1,2-dehydrogenation of a cmpd. (I); (c) adding HOCl or HOBr to the 9,11-double bond a cmpd. (I) or its, 1,2-dehydro-derivs. (Z = HC). In an example 11 beta, 17 alpha-21-trihydroxy-15,16 beta-methylene-pregnene (4)-3,20-dione, m.p. 219-221 degrees is obtained by microbiological hydroxylation of 17 alpha, 21-dihydroxy-15,16 beta-methylene-pregnene (4)-3,20-dione using Coniothyrium hellebori as organism.

Description

       

  
 



  Process for the production of new steroids of the Pregnan range
The invention relates to a process for the preparation of new steroids of the formula
EMI1.1
 in which R6 and Rg independently of one another are hydrogen, fluorine, chlorine or bromine, R21 is hydroxy or acyloxy and Z is carbonyl or ß-hydroxymethylene or 1,2 dehydro derivatives thereof.



   An acyloxy group preferably contains the residue of a saturated or unsaturated aliphatic or cycloaliphatic, an araliphatic or aromatic carboxylic acid having up to 20, preferably up to 12, carbon atoms. Examples of such acids are formic acid, acetic acid, pivalic acid, propionic acid, butyric acid, caproic acid, enanthic acid, oleic acid, palmitic acid, stearic acid, succinic acid, malonic acid, fumaric acid, tintronic acid, cyclohexylpropionic acid, phenylacetic acid and benzoic acid.



   Preferred compounds obtainable according to the invention are those in which R6 and R9 are hydrogen or fluorine, R21 is hydroxy and Z, B-hydroxymethylene.



   The method according to the invention is characterized in that a steroid of the formula
EMI1.2
 where R6, R9 and Z have the above meaning and Ac is an acyl radical, or the 1,2-dehydro derivative of such a steroid is saponified at least in the 17a position.



   For the preparation of the starting materials, reference can be made to Belgian patent specification No. 760 392.



   The steroids obtainable according to the invention are endocrine, in particular anti-inflammatory, effective. They can be used as remedies in the form of pharmaceutical preparations which they contain as a mixture with a pharmaceutical, organic or inorganic inert carrier material suitable for enteral, percutaneous or parenteral administration. The pharmaceutical preparations can be in solid, semi-solid or liquid form. They may contain auxiliaries, such as preservatives, stabilizers, wetting agents or emulsifiers, salts to change the osmotic pressure or buffers.



  They can also contain other therapeutically valuable substances.



   example 1
300 mg of 17a, 21-diacetoxy-11-hydroxy-15ss, 16P-methylene-pregn-4-en-3,20-dione were dissolved in 30 ml of methanol and stirred with 150 mg of NaHCO3 for 6 hours at room temperature. For work-up, it was poured onto ice-water and extracted with methylene chloride. The organic extract was washed neutral with water, dried with Na2SO4 and evaporated in vacuo. The residue was chromatographed on 30 g of silica gel. With benzene-propanol (95: 5), pure 2 1-acetoxy-11ss, 17a-dihydroxy-lSss, 16ss-methylen-pregn-4-en-3,20-dione was first eluted. The following fractions yielded 11ss, 17a, 21-trihydroxy-15ss, 16ss-methylen-pregn-4-en-3,20-dione, m.p. 218-220 "C.

 

   Example 2
921 mg of 21-acetoxy-17-hydroxy-lSss, 16ss-methylene-pregn-4-en-3,11,20-trione and 46 mg of potassium carbonate were dissolved in 25 ml of methanol and stirred for 2 hours at room temperature. For work-up, it was poured into ice water and extracted with methylene chloride. By washing neutral with water, drying with Na2SO4 and evaporating the solvent in vacuo, 863 mg of crude product were obtained from the organic extract. This was chromatographed on silica gel. With benzene-propanol (9: 1), pure 17,21-dihydroxy-lSss, 16ss-methylene-pregn-4-ene-3,11,20-trione was isolated. Melting point 2170 (dec.). [a] D25 = +180 (c = 0.1 in dioxane).


    

Claims (1)

PATENT CLAIM Process for making new steroids of the formula EMI2.1 in which R6 and Rg are independently hydrogen, fluorine, chlorine or bromine, R21 is hydroxy or acyloxy and Z is carbonyl or β-hydroxymethylene, or 1,2 dehydro derivatives thereof, characterized in that a compound of the formula EMI2.2 wherein Ac is an acyl radical, or a corresponding 1,2-dehydroderivative thereof saponified at least in the 17a position. SUBClaim Process according to claim, characterized in that one starts out from compounds in which R6 and Rg represent hydrogen or fluorine and Z is ss-hydroxymethylene.