CH531493A - 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 are independently hydrogen, fluorine or chlorine, R17 and R21 are independently hydroxy or acyloxy, or their 1,2-dehydro derivatives.



   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, citric acid, cyclohexylpropionic acid, phenylacetic acid and benzoic acid.



   Preferred compounds according to the invention are those in which R6 and R9 are hydrogen or fluorine and R17 and R21 are hydroxy or Cs-alkanoyloxy.



   The inventive method is characterized in that the 1 1-keto group of a compound of the formula
EMI1.2
 or a corresponding 1,2-dehydroderiyate thereof reduced to the hydroxyl group with protection of the 3- and 20-keto groups.



   The protection of the keto groups in the 3- and 20-positions can be achieved, for example, by ketalization. If R17 and R2t simultaneously represent hydroxy groups, a 20-keto group can also be protected by formation of the 17,20; 20,21-bismethylenedioxy derivative. The 11 keto group of the protected compound can be reduced with complex metal hydrides such as lithium aluminum hydride, sodium borohydride or diisobutylaluminum hydride.



   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 medicaments which they contain mixed 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 for changing the osmotic pressure or buffers. They can also contain other therapeutically valuable substances.



   example
1.0 g of 2 1-acetoxy-17-hydroxy-15ss, 16ss -methylene-pregn-4-en-3,11,20-trione was dissolved in 25 ml of pyridine and with a solution of 5.4 g of semicarbazide in 6 ml of water are added.



  A cold mixture of 25 ml of pyridine and 6.2 ml of concentrated hydrochloric acid was then added with stirring. The mixture was stirred at room temperature for 2 hours, then 6 g of sodium acetate were added and the mixture was largely evaporated in vacuo. The crystalline 3,20-disemicarbazone was precipitated by adding water. It was filtered off, dried in vacuo and dissolved in 10 ml of N, N-dimethylformamide and 20 ml of tetrahydrofuran. This solution was added within 30 minutes to a stirred suspension of 1.0 g of LiBH4 in 50 ml of tetrahydrofuran. The mixture was stirred for a further 2 hours, neutralized with aqueous acetic acid, and the mixture was concentrated to a small volume in vacuo. After adding a lot of water, the product precipitated, was filtered off and dissolved in 30 ml of acetic acid.

  After adding 3 g of pyruvic acid and 15 ml of pyridine sulfate solution, the mixture was kept at room temperature for 15 hours. It was then poured into plenty of water and extracted with ethyl acetate. After chromatography on silica gel and recrystallization from acetone / isopropyl ether, the extract yielded pure 11ss, 17.2 1-trihydroxy-15fl, 16ss-methylenepreg-4-en-3,20-dione with a melting point of 218-220.


    

Claims (1)

PATENT CLAIM Process for making new steroids of the formula EMI2.1 in which R6 and Rg are independently hydrogen, fluorine or chlorine, R17 and R21 are independently hydroxy or acyloxy, or their 1,2-dehydro derivatives, characterized in that the 11-keto group of a compound of the formula EMI2.2 EMI2.3 or a corresponding 1,2-dehydro derivative thereof is reduced to the hydroxyl group with protection of the 3- and 20-keto groups. SUBClaim Process according to patent claim, characterized in that one starts from compounds in which R6 and Rg represent hydrogen or fluorine and R17 and R21 represent hydroxy or C¯6-alkanoyloxy.