NO131119B - - Google Patents

Description

Process for the production of new 16/V-alkyl-11-oxygenated steroids of the pregnane series.

The present invention relates to a method for the production of new 16(3-alkyl-11-oxygenated steroids of the pregnane series.

The 16[3-alkyl steroids obtained by the method according to the invention are advantageous intermediates which can be transferred to 16[3-alkyl cortical steroids. The latter compounds have an extremely strong anti-inflammatory effect which is significantly stronger than the anti-inflammatory effect of the original cortical steroids, and they are particularly effective in the treatment of arthritis and similar diseases. They provide a cortisone-like effect in extremely small doses, whereby unwanted side effects are kept to a minimum. It is new that 16(5-alkyl steroids have this effect, as all previously substituted modifications of cortical steroids with increasing anti-inflammatory effects have included the introduction of α-substituents.

In the method according to the invention, 16(3-alkyl-3-substituted 11-oxygenated-16-preg-nen-20-one or a 16(3-alkyl-3-substituted 11-oxygenated-16-allopregen-20-one) can be used as starting materials 20-on which corresponds to the following general formula:

In this general formula, X denotes

hydrogen or halogen, Y denotes hydrogen in the a- or (3-position, Z denotes oxygen, dioxolane, a- or (3-acyloxy or hydroxy, R denotes alkyl and R' denotes a hydroxyl group or oxygen. I 5 (6) -style-

ling, a double bond may or may not be present.

The above-mentioned A<1>(<i>16-alkyl starting materials for the process according to the invention, namely 16-alkyl-3-substituted-11-oxygenated-16-pregnen-20-ones or 16-alkyl-3 -substituted-11-oxygen-nerte-16-allopregnen-20-ones can be prepared by reacting the corresponding 16-pregnenes or 16-allopregnes with diazoalkanes such as diazomethane, diazoethane, diazopropane or diazobutane, whereby the corresponding 3- substituted-11-oxygenated-16a, 17a-alkylenazopregnan-azo-allopregnan-20-ones corresponding to fur-20-ones or 3-substituted-11-oxygenated general formula:

in which R', X, Y and Z have the meanings given above, while R" denotes hydrogen or alkyl. Here, too, a double bond may or may not be present in the 5(6) position. When these compounds are heated, nitrogen is evolved and there primarily the corresponding 16-alkyl-3-substituted-11-oxygenated-16-pregnen-20-ones or 16-alkyl-3-substituted-11-oxygenated-16-allopregnen-20-ones are formed, which are therefore starting materials for the method according to the invention and as mentioned corresponds to the following general formula: In a preferred embodiment of the invention, 3a-acetoxy-16(3-methyl-16-preg-nen-11,20-dione is used as starting material which corresponds to the following general formula: it has been found that the 3a-acyloxy-16(3-alkyl-16-pregnan-11,20-diones can be hydrogenated in the presence of hydrogenation catalysts such as palladium on calcium carbonate so that 3a-acyloxy-16(3-alkylpregnan-11,20- diones corresponding to the following general formula:

in which R denotes alkyl and R"' denotes acyl.

The compounds obtained by the method according to the invention can easily be transferred to 16(3-methyl-cortical steroids which are effective anti-inflammatory agents. An example of such a method is the following: A 16|3-alkyl-3a, 17a-dihydroxypreg -nan-11,20-dione is brominated to form a 16a-alkyl-21-bromo-3a,17a-dihydroxypregnan-11,20-dione This compound is reacted with an acylating agent to form a 16[3-alkyl -3a, 17a-21-trihydroxypregnan-11,20-dione-21-acylate. When the latter compound is reacted with an oxidizing agent such as N-bromosuccinimide or chromic acid, a 16(3-alkyl-17a, 21- dihydroxypregnan-3,11,20-trione-21-acylate On bromination of the latter compound, a 16(3-alkyl-4-bromo-17a, 21-dihydroxypregnan-3,11,20- trione-21-acylate. This compound is reacted with semicarbazide hydrochloride, whereby the 3-semicarbazone of a 16(3-alkyl-17a, 21-dihydroxy-4-pregnene-3,11,20-trione-21-acylate is formed. The latter compound is reacted with pyruvic acid in aqueous acetic acid, whereby 16|3-alkyl-17a,21-di-hydroxy-4-pregnene-3,11,20-trione-21-acylate is formed.This compound can also be termed

16(3-alkyl cortisone acylate) and is an effective anti-inflammatory agent.

In the following, an embodiment of the invention is described as an example.

Example:

Preparation of 3a-acetoxy- 16\ 5- methylpregnane-11, 20-dione.

A solution of 200 mg of 3α-acetoxy-16-methyl-16-pregnene-11,20-dione (prepared as described below)

200 mg of catalyst was added to 20 ml of methanol

sator consisting of palladium on calcium-

carbonate with 25 percent palladium. Blendin-

gen was stirred in a hydrogen atmosphere (1

atm. pressure, 25° C) until the uptake of hydrogen had ended. The mixture was then filtered, the filtrate evaporated to dryness and the residue recrystallized from a mixture of ether and hexane, whereby pure 3α-acetoxy-16|3-methylpregnan-11,20-dione was obtained as needles with melting point

CHC1

160-162° C. X max;

5.80, 5.85, 8.0 (a) nCHCl 3 = + 96° (C = 1.00).

Analysis:

Calculated for C^H.^O,: C 74.19 per cent,

H 9.33 percent."

Found: C 74.15 per cent, H 9.15 per cent.

The 3α-acetoxy-16-methyl-16-pregnene-

11,20-dione which was used as starting feed-

rial in this example is produced by walking

starting from the known compound 3α-acetoxy-16-pregnene-11,20-dione and using follow-

following procedure:

In a 500 ml 3-necked flask provided with

cooler, production funnel and supply line

ning for nitrogen was placed 20 g of potassium

hydroxide in 90 ml of water, 100 ml of methanol and 100 ml of ether. A solution of 10 g of N-methyl-N-nitrosotosylamide in 50 ml of ether was placed

in the production funnel.

Diazomethane was formed by heating

flask to 40-50° C and carefully add solution of N-methyl-N-nitrosotosylamide in ether from the production funnel. Nitrogen was used to drive the diazomethane into a solution of 20 g of 3a-acetoxy-16-pregnene-

11,20-dione in 100 ml of tetrahydrofuran and 120

ml of ether. The process was allowed to continue until the solution remained yellow for several hours. Pro-

the product, 3α-acetoxy-16ct,17α-methylene-azo-pregnan-11,20-dione, was then precipitated from the reaction mixture in copious amounts. After 16 hours of standing, the mixture was filtered,

the product washed with ether and dried in air

ten. Its melting point is 186-190° C (decomposition).

37.4 g of 3α-acetoxy-16α, 17α-methylene-azo-pregnane-11,20-dione was placed in a 500 ml round-bottomed flask and heated on oil

bath 1 vacuum (pressure 0.6 mmHg). A pressure gauge and a 12 liter flask were placed in the line between the round flask and the collection container in front of the vacuum pump.

pretty. When the oil bath temperature reached 180°

C, the 3a-acetoxy-16a, 17a-methylene-azo-pregnan-11,20-dione began to melt during develop-

ling of nitrogen. The maximum pressure reached was 83 mm. After a 10-minute rest at 180-182° C, the smelting was

CH OH

cooled. It had a lmg^ s = 249, E%,

191. The melt was taken up in about 150 ml of acetone and the solution filtered through diatomaceous earth. It was then evaporated to a volume of about 100 ml and ether was slowly added to the boiling solution until crystallization occurred. The crystals obtained consisted of 3α-acetoxy-16-methyl-16-pregnene-11,20-dione with m.p.

OTT OTT

166—167° C. I max 249. Em 9300.

In a similar way one obtained by using

diazo-ethane, 3α,-acetoxy-16-ethyl-16-pregnene 11,20-dione and diazopropane, 3α-acetoxy-16-propyl-16-pregnene-11,20-dione.

Claims (2)

1. Process for the production of compounds, which can be used as intermediates in the production of 16|3-alkyl cortical steroids with a strong anti-inflammatory effect and with the general formula: in which X denotes hydrogen or halogen, Y denotes hydrogen in the a- or (3-position, Z denotes oxygen, dioxylan, an acyloxy or hydroxyl group in the a- or (3-position, R denotes alkyl and R' denotes a hydroxyl group or oxygen, characterized in that, in the presence of a palladium-on-calcium carbonate catalyst, a compound with the general formula is hydrogenated: in which X, Y, Z, R and R' have the meanings indicated above. 2. Process according to claim 1 for the production of 3a-acetoxy-16p-methylpregnan-11,20-dione, characterized in that as starting material uses 3α-acetoxy-16-methyl-16-pregnene-11,20-dione.