NO128765B - - Google Patents

Description

Analogous process for the production of progestatively active 4,6-dichloro-16-methylene-.,A. ' -pregnadiene (and A ' pregnatriene)-3,20-diones.

The present invention relates to an analogous process for the production of progestatively active 4,6-dichloro-16-methylene-A4'6-pregnadiene (and A1'4'6-pregnatriene)-3,20-diones with the general formula where R means hydroxy or alkanoyloxy with up to 8 carbon atoms

and the dotted bond in the 1,2 position is facultative.

An alkanoyloxy group is, for example, the acetoxy, butyroyloxy or caproyloxy group.

Compounds of formula I may find use as progestative agents. When R is hydroxy, the compounds can be administered parenterally, and when R is alkanoyloxy, the compounds can be administered orally or parenterally.

The method according to the invention is characterized by treating a steroid with the formula

where R has the above meaning,

with chlorine and a proton acceptor and optionally dehydrochlorinates the resulting byproduct 2,4-dichlorosteroid with the formula

or that one esterifies a steroid with the formula I, where R is hydroxy.

The chlorination is suitably carried out by introducing chlorine i

a reaction medium containing the starting steroid of formula II. The chlorination can be carried out in the presence of a proton acceptor, for example an N,N-di-lower-alkyl-lower-alkanoyl-amide, such as dimethylformamide or dimethylacetamide; a lower alkylene oxide, such as ethylene oxide or propylene oxide, in a solvent, such as a lower alkane carboxylic acid, e.g. propionic acid or acetic acid. On the other hand, the proton acceptor can be added in conjunction with the treatment of the starting steroid with chlorine. In this case, a compound with the formula is obtained as the primary chlorination product

This intermediate can be dehydrochlorinated without further purification by treatment with a proton acceptor, such as a nitrogen-containing, heterocyclic base, e.g. picoline or pyridine.

If the proton acceptor is present at the beginning of the chlorination, it can also serve as a solvent for the starting steroid of formula II. On the other hand and preferably, the reaction mixture contains other solvents. Suitable solvents are the usual inert organic solvents, e.g. ethers, such as lower alkyl ethers, e.g. ethyl ether or dioxane; chlorinated hydrocarbons such as chloroform or carbon tetrachloride. The chlorine can be introduced in a manner known per se into the reaction mixture, e.g. in the form of a solution in a lower alkane carboxylic acid, such as propionic acid. The chlorination is conveniently carried out at lower temperatures, preferably between -40° and room temperature, especially between -30° and 0°. The chlorination can also be carried out with a solution of chlorine in carbon tetrachloride using chloroform as a solvent for the starting steroid at temperatures between 0° and room temperature, after which the solvent is removed and joins a treatment with a proton acceptor.

During the chlorination of 1(2)-saturated starting steroids, 2,4,6-trichloro-steroids of formula III can be obtained as by-products0

The progestational activity of A, B, C, D and E was investigated: A : 4, 6-dichloro-17oc-hydroxy-16-methylenepregna-4, 6-diene-3, 20- dione acetate.

B: 4,6-dichloro-17oc-hydroxy-16-methylene-pregna-1,4,6-triene-3,20-dioneacetate.

C: 4,6-dichloro-17oc-hydroxypregna-4,6-diene-3,20-dione acetate.

D: 4,6-dichloro-17α-hydroxy-16α-methylpregna-4,6-diene-3,20-dioneacetate.

E : 4, 6-dichloro-17c-hydroxypregna-1, 4, 6-triene-3, 20-dioneacetate.

The progestative activity of the above compounds was determined by administering the compounds for five consecutive days to estrogen-pretreated, immature female rabbits. At autopsy, the uterus is removed and the histological preparation is prepared from the uterine cross-section. The histological section is assessed microscopically for the purpose of progestative activity, which is determined by an endometrial response of a secretory type. This trial was carried out at different dose levels to determine the lowest dose at which significant progestative activity was observed.

Results

The starting materials are predominantly known compounds or belong to known compound classes. They can be produced according to methods known per se, for example in analogy to the methods used in certain cases in the examples below. All temperatures are given in degrees Celsius.

EXAMPLE 1

To a solution of 3.9 g of 6-chloro-17oc-acetoxy-16-methylene-pregna-4,6-diene-3,20-dione in 25 ml of alcohol-free chloroform, at 0°, 11.3 ml of a 0, 87 molar solution of chlorine in carbon tetrachloride. The resulting solution is stirred for one hour at 0°, after which the solvents are removed under reduced pressure. The resulting foam is treated with 10 ml of dry pyridine and stirred for 2 hours at room temperature. After adding 200 ml of ether, the mixture is extracted twice each time with 150 ml of 1-N hydrochloric acid. The ethereal solution is dried, triturated with ether and gives 2.4 g of crude product, which is chromatographed on 100 g of silica gel. Elution with 2% ethyl acetate in benzene gives 2a,4,6-trichloro-17a-acetoxy-16-methylenepregna-4,6-diene-3,20-dione, which after crystallization from methylene chloride-ether melts at 235 - 233 °

(starting decomposition at 225°).

Further elution with 5% ethyl acetate in benzene gives 4,6-di-chloro-17oc-acetoxy-16-methylenepregna-4, 6-diene-3, 20-dione, melting point 218-219° (from methylene chloride ether).

EXAMPLE 2

A solution of 0.250 g of 2a,4,6-trichloro-17oc-acetoxy-16-methylene-pregna-4,6-diene-3,20-dione, 0.1 g of lithium chloride and 3 ml of dry dimethylformamide is heated a 1/2 hour under nitrogen under reflux. The solution is cooled and poured into 100 ml of ice water. The precipitate is filtered and dried in air. The crude product thus obtained is chromatographed on 6 g of neutral aluminum oxide (activity I). Elution with petroleum ether (60 - 90°) and methylene chloride (1:1) and then with methylene chloride alone gives 4,6-dichloro-17oc-acetoxy-16-methylenepregna-1,4,6-triene-3,20-dione as after crystallization from ether-methylene chloride melts at 225 - 228°.

Claims (1)

Analogous process for the production of progestatively active 4,6-dichloro-16-methylene-A4'^-pregnadiene (and A^'<4>'^-pregnatriene)-3,20-diones of the general formula where R means hydroxy or alkanoyloxy with up to 8 carbon atoms, and the dotted bond in the 1,2-position is facultative, characterized by treating a steroid with the formula where R has the above meaning. with chlorine and a proton acceptor and optionally dehydrochlorinates the resulting 2, 4-dichlorosteroid as a byproduct with the formula or that one esterifies a steroid with the formula I, where R is hydroxy.