NO129570B - - Google Patents

Description

Analogue process for the production of therapeutically effective 17α-acyloxy-11S-methyl-19-norpregn-4-ene—; ...

3,20-diones.

For.eliggen.de invention, relates to a method to forward ten Iling ..of. 1 7;a-acylpxy- 116-methyl 1- 19-nprpregn-^-en- 3^,20-^ 4.. diones with the .general, formula:.. ,., ........ ..

where Y is a hydrogen or chlorine atom and the dotted line indicates a possible 6(7) double bond...." -

Examples of the alkyl radicals which are included in the structural formula stated above are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl and their isomeric groups with a branched chain.

The 17-acyloxy compounds of formula I are prepared by acylation of corresponding 1-7-hydroxy compounds with the

general formula:

where Y here and in the following has the same meaning as stated above. This acylation can be carried out by means of conventional methods using the appropriate acid anhydride or acid halide in the presence of a strong acid, e.g. p-toluenesulfonic acid. Under such conditions, it is possible that some 3-enol acetate will form in the reaction. To improve the yield obtained through these conventional methods, the obtained reaction product can be dissolved in an alcohol such as methanol and treated with a small amount of concentrated mineral acid such as concentrated hydrochloric acid, which causes a conversion of 3-enol acetate to 3-keto-A - the system. Since this side reaction can occur when using these conventional acylation methods, it is preferred to use an acylation method known to the person skilled in the art in order to avoid this enol acetate conversion. One such method is that which involves the use of a complex compound formed by a combination of a metal halide (e.g. phosphorus or antimony pentachloride), an organic acid halide and a halogenated aliphatic solvent (e.g. chloroform, carbon tetrachloride, dichloroethane , trichlorethylene and analogues) under anhydrous conditions. The reaction is preferably carried out by adding the steroid compound to the complex compound in a lower-nitroparaffin solvent having a high dielectric constant

(e.g. nitromethane) and keep the reaction mixture at relatively low temperatures, e.g. from 0°-5°C. A particular example of

the preferred acylation method is the formation of the complex compound by combining 1,1,2-trichlorotrifluoroethane, antimony pentachloride and acetyl chloride to which is added nitromethane followed by 17α-hydroxy-11S-methyl-19-norpregn-i»-ene-3J20-dione . After reaction at 0°-5°C for 15 minutes and by keeping the mixture at room temperature for 45 minutes, 17α-acetoxy-116-methyl-19-norpregn-M-ene-3,20-dione is obtained as the resulting product .

The t>17ot, 20-dihydroxy-11S-methyl-19-norpregn-4-en-3-ones, which are useful as precursors to the 17α-hydroxy and subsequent 17α-acyloxy compounds of formula I, can be prepared using the following synthesis plan based on already described starting materials such as 3-Alkoxy-17a-ethyl-173-hydroxy-113-methylgona-1,3>5(10)-triene. The initial step consists of dehydration of the previously mentioned starting material with a reagent such as thionyl chloride in pyridine to obtain the corresponding 17(20)-dehydro compound. The latter compound is hydroxylated, preferably with osmium tetroxide in pyridine, to give the 17cc, 20-diol, which undergoes a Birch reduction using lithium in liquid ammonia, to give the 2,5(10)-diene 3~enoleter. Hydrolysis of this enolet gives the corresponding 3-keto-A h intermediate, which serves as starting material for the oxidation reaction with Jones' reagent, this oxidation giving the 17o-hydroxy compounds of formula I. Subsequent acylation gives the 17<x-acyloxy compounds of formula I and this completes the synthesis. The reaction sequence is particularly illustrated by dehydration of 17α-ethyl-118-methylestra-1,3,5(10-trien-3>HØ-diol 3 methyl ether with thionyl chloride in pyridine to obtain 116-methyl-19-norpregna-1,3j5( 10),17(20)-tetraen-3-ol 3-methyl ether, which ether is hydroxylated with osmium tetroxide in pyridine to 116-methyl-19-norpregna-1,3,5(10 )-trien-3,17ot,20- triol 3-methyl ether Birch reduction of the last compound using lithium in liquid ammonia gives 11B-methyl-19-norpregna-2,5(10)-diene-3,17a,20-triol 3-methyl ether, which is hydrolysed with dilute hydrochloric acid in methanol to 17a,20-dihydroxy-HB-methyl-19-norpregn-4-en-3-one.

The compounds prepared according to the invention are useful because of their valuable pharmacological properties. They are, for example, "potent progestational and estrogen-inhibiting agents. The pharmacological activity of the compounds of formula I is particularly illustrated by the progestational activity of 17a-acetoxy-118-methyl-19-norpregn-4-ene-3j20-dione when this compound is tested on rabbits according to the Clauberg test at subcutaneously administered doses varying from 0.0002 to 0.05 mg. In relation to the standard compound, i.e. progesterone, the above compound has a potency of 10-20x10^%. The anti-estrogenic activity to the compounds of formula I is particularly illustrated by the above-mentioned compound, which, by determination according to the method of Edgren and Calhoun, Proe. Soc. Exp. Biol. Med., 94, 537 (1957), in mice,

were subcutaneously administered doses varying from 0.001 to 0.1 mg, showed an effect of approximately 10,000% relative to the standard compound, i.e., progesterone.

In order to compare the therapeutic properties of compounds of formula I with previously known compounds, comparative experiments were carried out. Three representative compounds prepared according to the invention, namely 17a-acetoxy-11g-methyl-19-norpregn-4-ene-3,20-dione, 17a-acetoxy, 11b-methyl-19_norpregna-4, 6-dien-3>20- dione and 17a-acetoxy-b-chloro-113-methyl-19-norpregna-4,6-dien-3,20-dione (in the following designated compounds A, B and C, respectively), were thus compared in the following biological experiments with their 11-desmethyl analogues, namely 17a-acetoxy-19-norpregn-4-ene-3j20-dione (Steroids, 1, 185, 1963), 17a-acetoxy-19-norpregna-4,6-diene-3,20 -dione (Helvetica Chemica Acta, 50, 269, 1967) and 17a-acetoxy-6-chloro-19-norpregna-4,b-diene-3,20-dione (US Patent No. 3•250•792)( designated compounds D, E and F, respectively).

Progestsional activity (Clauberg analysis)

Not fully developed female rabbits with a weight of approx

1 kg is given 5 micrograms of estra-1,3»5(10 )-triene-*3j 17B_diol for six days. At the end of this period, the test compound is administered in selected doses ranging from 0.001 to 0.02 mg, subcutaneously or buccally in oil, daily for 5 days. A ..control animal was treated with the vehicle alone. The activity is determined by measuring the degree of abortion in the lumenal epithelium of the uterus at the end of the five-day treatment. The results obtained are compared to those obtained with subcutaneously administered progesterone, which was the reference for this experiment. The progestational response of at least 2 is required to demonstrate activity. The potency of the compound is determined by comparing the minimum effective dose of the compound to the respective dose of the control compound.

From the above data it is clear that the compounds produced according to the invention have much higher potency as progestational agents than their corresponding previously known 11-desmethyl analogues.

Anti-estrogenic activity

Groups of immature white female mice, 21 days old, which were not pretreated, were subjected to subcutaneous injection once a day for a period of 3 days with 0.1 ml of corn oil solution containing 0.3 micrograms of estrone together with selected doses of the test compound varying from 0.001 to 0.1 mg.

24 hours after the last injection, the animals were killed and their uteri removed, cleaned and weighed. These uterine weights were compared with those from a group of control animals treated with corn oil containing the same dose of estrone alone. The activity is measured by the degree of retardation of the weight of the uterus compared to estrone-treated control animals, which provides an illustration of antagonism for estrone-simulated uterine weight. A compound is termed active if it produces a uterine response that is significantly smaller (P- 0.01) than the control value<p>. Activity can be expressed in percent activity of the reference compound progesterone which has an efficiency or strength of 100%. This efficiency is determined by comparing the minimum effective dose of the compound in relation to the respective dose of the control compound.

The compounds prepared according to the present invention have a distinctly higher activity as anti-estrogenic agents than their 11-desmethyl analogues.

The following examples illustrate the invention, in that the quantities are expressed as parts by weight unless otherwise stated, and in that the ratio between parts by weight and parts by volume is the same as that between grams and milliliters.

Example 1 17a-acetoxy-118-methyl-19-norpregn-4-ene-3,20-dione.

To 7 parts of 1,1,2-trichlorotrifluoroethane, 1.76 parts of antimony pentachloride were added with stirring and the mixture was cooled to 0.5°C, after which 0.5 parts of acetyl chloride were added dropwise. Stirring was continued at said temperature i

about 15 minutes after which 8 parts of nitromethane were added.

To the resulting two-phase system was then added 0.6b parts of 17ct-hydroxy-113-methyl-19-norpregna-ii-ene-3,20-dione and the reaction mixture was stirred for 15 minutes at 0-5°C, and then i

45 minutes at room temperature.

The solution was again cooled to 0-5°C and a solution of 3 parts sodium acetate in 2 parts water was added. Stirring at room temperature was continued for 30 minutes after which the mixture was extracted with chloroform. The chloroform layer was separated, washed successively with dilute aqueous sodium bicarbonate and water and then dried over anhydrous sodium sulfate. Distillation of this solution under reduced pressure gives the impure product, which is purified chromatographically on silica gel followed by elution with 10% ethyl acetate in benzene. Evaporation of the eluate to dryness gives a solid, which is further purified by recrystallization from ether, which gives 17o-acetoxy-118-methyl-19-norpregn-4-ene-3,20-dione, melting point 190-191.5 °C.

Using a molecularly equivalent amount of the appropriate 17-hydroxy compound instead of the starting material used in the preceding acylation method gives the following products of formula I.

Use of 17a-hydroxy-113-methyl-19-norpregna-4,6-dien-3»20-dione gives 17a-acetoxy-11B-methyl-19-norpregna-4,6-dien-3,20-dione, which gives infrared maxima in chloroform solution at about 5.78, 5.83, 6.01, 6.22 and 6.28 microns.

Likewise, 6-chloro-17o-nydroxy-118-methyl-19-norpregna-4,6-dien-3,20-dione reacts in the above-mentioned acylation method and gives 17a-acetoxy-b-chloro-11B-methyl-19- norpregna-4.6-diene-3,20-dione, which gives infrared maxima in chloroform solution at about 5.78, 5.5, b.02, 6.23 and 6.30 microns.

Acylation of 6α-chloro-17α-hydroxy-11B-methyl-19-norpregn-4-ene-3,20-dione gives 17α-acetoxy-60-chloro-11B-methyl-19-norpregn-4-ene-3, 20-dione, which gives infrared maxima in chloroform solution at about 5.76, 5.82, 5.94 and 6.1b microns.

Use of a molecularly equivalent amount of n-butyryl chloride instead of acetyl chloride as used in the previous method gives 17a-n-butyryloxy-11g-methyl-19-norpregn-4-ene-3,20-dione, which gives infrared maxima in chloroform solution at about 5.78, 5.84, 6.01 and 6.21 microns.

Example 2 17ot-acetoxy-llg-methyl-19-norpregn-4-ene-3,20-diop.

One part of 17α-hydroxy-116-methyl-19-norpregn-4-n-3,20-dione was dissolved in 52.5 parts of acetic acid. 10.8 parts of acetic anhydride and 1 part of p-toluenesulfonic acid monohydrate were added to this solution. The resulting reaction mixture was stirred until all the p-toluenesulfonic acid was dissolved, and then it was kept at room temperature for 24 hours. The solution was then dissolved in 500 parts of water and stirred for 2 hours. The resulting solidified product was filtered off, dissolved in 180 parts of ethyl acetate, washed successively with dilute sodium bicarbonate solution and water, dried over sodium sulfate and distilled to dryness to give the crude product, 17a-acetoxy-11g-methyl-19-norpregn -4-ene-3,20-dione, which is characterized by infrared maxima in chloroform at approx. 5.80-, 5.82, 6.02 and 6.20 microns. To improve the yield by saturating the complete conversion of any 3-enol acetate formed in the reaction, the impure reaction product can be distilled in methanol and treated with a small amount of concentrated hydrochloric acid for 2 to 3 minutes at room f. >^pérå't'ur.

Claims (3)

1. Analogous method for the production of pharmacologically active 17α-acyloxy-11B-methyl-L9-norpregr.-1'-ene-3,:;-diones, with the general" formula where<\>Y is a hydrogen or chlorine atom, and where the dotted line means a possible 6(7) dohtu Lt bond, characterized in that the corresponding 17c-h; ' the oxy compound is acylated. 2. Analogous process for the reduction of i.7a-acetoxy-11B-methyl-19-norpregn-4-ene-3,20-uion according to claim 1, characterized in that 17a-hydroxy-11B-methyl-19-norpregn- 4-ene~3>20-dione is acylated with a complex compound formed by the combination of antimony pentachloride, 1,1,2-trichlorotrifluoroethane and acetyl chloride. 3. X-ray diffraction method for the preparation of 17a-acetoxy-11B-methyl-19-norpregn-4-ene-3,20-dione according to claim 1,.-..characterized by 17α-hydroxy-11B-methyl-19-norpregn-4-ene-3,20-dione is acylated with acetic anhydride in the presence of p-toluenesulfonic acid monohydrate and acetic acid. followed by treatment ay the resulting impure material with hydrochloric acid. :