NO131131B - - Google Patents

Description

Analogous method for the preparation of therapeutically active 1;2a-methylene-6,7a-dihalogenmethylene-20-

spirox-4-en-3-one compounds.

The present invention relates to an analog remgangsm. it e in the preparation of new, therapeutically active 1,2a.-methylene-6, 7a-dihalo-methylene-20-spirox-4-en-3-one compounds with the general formula: where X is chlorine or fluorine, and may be the same or different, and R<*> is methyl or hydrogen.

The novel process compounds are specific androgen antagonists useful as therapeutic agents in the treatment of hyperandrogenic disorders. They are particularly useful in the treatment of acne caused by hyperandrogenicity. They have approximately the same anti-androgenic activity as the known compound 6-chloro-17-hydroxy-1,2d-methylenepregna-/+, 6-dien-3,20-dione, also called cyproterone, but excel over this compound by to have a surprisingly low progestational activity. The compounds can therefore be used without risk of unwanted side effects.

The method compounds can be administered orally, subcutaneously or topically in suitable preparations. The compounds of formula I are prepared according to the invention by

a) a 6,7i-dihalogenmethylene-20-spiroxa-1,4-dien-3-one compound of the general formula:

where R' and X are as indicated above, is reacted with dimethylsulfoxonium methylide, or

b) a compound with the general formula:

where R' is as indicated above, is reacted with an alkyl or aryl sulfonyl chloride in pyridine.

In alternative a) of the present method, the starting material with formula II is added to a dimethylsulfoxy solution of freshly prepared Corey reagent, dimethylsulfoxonium methy1 id, or: CI-^^SO (CH^) 2 _ • The Corey reagent is used in approx. 5 times molar excess, although the molar ratio of compound II to Corey's reagent may be 1:1-5. The mixture is reacted at the ambient temperature i

3-24 hours, and then a larger amount of water is added. The product, 1,2a-methylen-6, 7a-dihalogenmethylen-20-spirox-/+-en-3~one, (compound I) is common and can be purified by conventional methods.

The starting material, the 6,7a-dihalogenmethylene-20-spiroxa-1,4~dien-3-one compounds of formula II, can be prepared as shown in the following scheme:

Compound (A), 20-spiroxa-4,6-dien-3-one, can be prepared by

to follow the procedure in US patent 3-254'074.

The starting material, 6,7a-dihalogenmethylene-20-spiroxa-1,4-diene - 3-one-urbinde Is en, can be prepared from the corresponding 3~oxo-20-spiroxa-4 j 6-diene by reaction with a halogen-substituted alkali metal acetate, preferably at approx. 200°C in a solvent, such as a high-boiling glycol ether, after which the formed 6,7a-dihalo-methylene-20-spirox-4-en-3-one is treated with dichlorodicyanobenzoquinone, f. e.g. at room temperature, to introduce a double bond in the 1 st illing.

In alternative b) the starting material can be prepared by the method indicated in process diagram 2, starting from 17c-(3-hydroxypropyl)-173-hydroxy-androsta-4~en-3-one (compound K). This compound is reacted with an alkyl orthoformate and an alcohol such as methanol or ethanol, in the presence of a mineral acid to form the 3-Alkoxy-3,5-diene group. Methyl orthoformate and ethyl orthoformate are the preferred reagents, although any of the 1-6 lower alkyl groups may be used. This procedure leads to the formation of compound (L). The latter compound is then treated with chloronil under reflux in an inert solvent which serves to dehydrogenate the compound and remove the alkyl group, thereby forming compound (M). The latter compound is then 6,7;-dihalo-methylated using the desired dihalosodium acetate as described in process scheme 1. The compound formed is compound (N).

Compound N can then be treated with dichlorodicyanobenzoquinone to form a double bond in the 1-2 position (compound P), and this compound is reacted with Corey's reagent to form the 1,2-methylene steroid (compound III).

Compound III is then transferred, according to the invention, to compound I by reaction with an alkyl or a rysulfonyl chloride in pyridine solution. Suitable reagents are toluenesulfonyl chloride or methanesulfonyl chloride. The alkyl or arylsulfonyl chloride is added to the solution of compound III in pyridine solution, and the solution is, after flushing the container with nitrogen, stirred for several hours while the temperature is maintained at approx. 0°C. When the reaction is complete, water and ice are added, and the precipitate that forms is removed by extraction with a suitable solvent such as ethyl acetate. The extract is immediately washed with cold, aqueous dilute mineral acid such as sulfuric acid, washed with water, washed with dilute aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate and filtered. Information on the jsioid is removed by distillation under reduced pressure.

The residue is 1,2α-methylene-6,7α-difluoromethylene-20-spirox-4-en-3-one, compound I.

The following examples will further illustrate the invention.

Example 1

Production of starting material

6, 7a- difluoromethylene- 20- spirox- 4- en- 3- one

1 g of 20-spiroxa-/+, 6-dien-3-one is dissolved in 5 ml of triethylene glycol dimethyl ether (distilled from lithium aluminum hydride). 6 g of chlorodifluorosodium acetate (dried) in 50 ml of dry triethylene glycol dimethyl ether are added dropwise over the course of 2 hours, the reaction mixture being kept at 195-200°C with constant stirring. The reaction mixture is poured over ice and extracted with ether. The ether extract is washed with water and dried. The crude reaction product is eluted through a 100:1 silica gel column, first with benzene, then with an increasing percentage of ether in benzene. The product, 6.7 ol-difluoromethylene-20-spirox-4-en-3~one is recrystallized from heptane and has a melting point of 130-132°C.

6, 7a-difluoromethylene-20-spiroxa-l, 4~ diene-3-one

A solution of 628 mg of 6,7a-difluoromethylene-20-spirox-4-en-3-one in 7 ml of benzene is treated with 497 mg of 2,3-dichloro-5,6-dicyanobenzoquinone while stirring at room temperature. The reaction mixture is brought to reflux and refluxed for 4 hours under nitrogen. The solution is filtered to remove most of the 2,3-dichloro-5,6-dicyanohydroquinone byproduct.

The product is purified by passing it through a column packed with 100:1 silica gel. It is first eluted with benzene, then with an increasing percentage of ether in benzene. The eluate fractions with 5% ether - 100% ether are combined. These fractions are purified again by passing through a column packed with 100:1 neutral aluminum oxide. The final elution is with 10% ether in benzene. The purified product, 6,7α-difluoro-methylene-20-spiroxa-1,4-dien-3-one, is recrystallized from heptane and has a melting point of 149-153°C.

Production of final product

1, 2a- methylene- 6, 7a- difluoromethylene- 20- spirox- 4- en- 3- one

A solution of Corey's reagent is prepared by adding 2.20 mg of trimethylsulfoxonium iodide to a suspension of 40 mg of a 55% dispersion of sodium hydride in mineral oil, in 2 ml of dimethylsulfoxide. The addition is carried out at room temperature under a stream of nitrogen. After 1 hour, the mixture will be ready. 100 mg of 6,7α-difluoromethylene-20-spiroxa-1,4-dien-3-one, prepared as in example 2, is dissolved in 2 ml of dimethylsulfoxide. It is added to the Corey reagent and allowed to react overnight.

The reaction mixture is added approx. 20 ml of water. The product falls out immediately. It is filtered off and washed well with water. The product is purified by passing it through a column packed with 100:1 silica gel. The first elution is with benzene, then with 5% ether in benzene.

77.8 mg of 1,2a-methylene-6,7c-difluoromethylene-20-spirox-4-en-3-one are retained. It is recrystallized first with hexane, then with ether and

o

petroleum ether. The melting point is 155-158 C.

Example 2

Production of starting material

17a-(3- hydroxypropyl)- 173- hydroxyandrosta- 4, 6- diene- 3- one

To 1 g of 17α-(3-hydroxypropyl)-176-hydroxyandrost-4-en-3-one, (A) in 100 ml of dry ethanol, 1.5 ml of ethyl orthoformate and 1 g of toluenesulfonic acid are added. The mixture is stirred briefly at room temperature and then diluted with water to obtain crude 3-ethoxy-3,5-diene. This gives, on treatment with N-bromosuccinimide in 30 ml of 5% aqueous dioxane containing 3 ml of glacial acetic acid, the 6-bromo compound which on heating at 90°C for several hours with 0.5 g of lithium bromide and 0.4 g of lithium carbonate in 10 ml of dimethylformamide under nitrogen gives the diene, 17α-(3-hydroxypropy 1)-17S3-hydroxyandrost α-4,6-dien-3-one. 6 , 7 J- - difluormethy 1 en -17a - ( 3-hydroxypropy 1) -17E -hydroxyandrost -4-en - 3-one 1 g of 4,6-diene product et above dissolved in 5 ml of triethylene glycol dimethyl ether heated to 200°C and treated drop by drop over the course of 1 hour at approx. 200°C with a solution of 5 g of sodium chloride-chlorodifluoroacetate in 50 ml of the same solvent. The mixture is cooled and quenched in ice and extracted with ethyl acetate. Drying and concentration gives the crude 6,7a-difluoromethylene derivative. Recrystallization from acetone:hexane gives the purified compound, 6,7o-difluoromethylene-17a-(3-hydroxypropyl)-17p-hydroxyandrost-4-en-3-one. 6,7a-difluoromethylene-17a-(3-hydroxypropyl)-173-hydroxyandrost-1,4-diene-3-one 1 g of the difluoromethylene derivative prepared above is heated in 15 ml of benzene with 0.95 g of 2,3-dichloro- 5,6-dicyanobenzoquinone under reflux under nitrogen for 2 hours. The hydroquinone by-product is filtered off and the diene product is further purified by elution chromatography on silica gel with methanol-chloroform mixtures, and identified as 6,7α-difluoromethylene-17α-(3-hydroxypropyl)-17α-hydroxyandrost-1,4-diene -3-on.

1,2a-methylene-6,7a-difluoromethylene-17a-(3-hydroxypropyl)-170-hydroxyandrost-4-en-3~one

2 g of the dienone prepared above is treated with the Corey reagent

as in example 1, step 3- Recrystallization of the crude product from methanoi gives 1,2a-methylene-6,7c-difluoromethylene-17a-(3-hydroxypropyl)-17S-hydroxyandrost-4-en-3-one.

Production of final product

1, 2g- methylene- 6, 7a- difluoromethylene- 20- spirox- 4-en-3-one

A solution of 750 mg of the dimethylene steroid prepared above

in 1.5 ml of pyridine is treated with 1.05 equivalents of p-toluenesulfony 1-

chloride overnight at room temperature. Dilution of the mixture with benzene, washing with bicarbonate and then with water gives the crude spiro compound. Recross allisation from hexane and then ether-

petroleum ether gives pure compound, 1,2a-methylene-6,7a-difluoromethylene - 20-spirox-4, -en-3-one, m.p. 15^-158 oC.

Claims (1)

Analogous procedure for the production of therapeutically active 1,2a-methylene-6,7a-dihalogenmethylene-20-spirox —4-en-3-one-f orbinde1 se r with the general formula: where R* is hydrogen or methyl, and X is chlorine or fluorine, characterized in that a) a 6,7a-dichloromethylene-20-spiroxa-1,4-dien-3-one compound with the general formula: where R" and X are as indicated above, is reacted with dimethylsulfoxonium methylide, or b) a compound of the general formula: where R' is as indicated above, is reacted with an alkyl or aryl sulfonyl chloride in pyridine.