NO132533B - - Google Patents

Description

The present invention relates to an analytical method for the production of new and valuable derivatives of 1,2-diphenylethane, which have very strong estrogenic properties.

The new derivatives of 1,2-diphenylethane which are produced according to the present process are compounds with the general formula "

where R^ and R^, which may be the same or different, are alkyl radicals containing up to 6 carbon atoms, with the proviso that R^ and R2 are not both methyl or ethyl radicals.

When R^ and R^ are alkyl radicals containing 3-6 carbon atoms, they can be e.g. n-propyl, isopropyl, n-butyl, n-pentyl or•n-hexyl radicals.

The analogy method according to the invention is characterized by the fact that

a) an ether of general formula II

where R" is an alkyl radical containing up to 6 carbon atoms, is reacted with a halogen compound of general formula III where R^ and R2 have the above meanings, Z denotes a hydroxyl group and Y denotes H, or Y and Z together denote a ... oxygen atom, and Hal denotes a halogen atom, whereby a compound of the general formula is obtained:

where Rp R2 and R" have the meanings given above, after which a compound of formula (IVb) is hydrogenated to a compound of formula (IVa) which is dealkylated to form the corresponding dihydroxyfur bond,

or

b) for the preparation of compounds of general formula (I) in which R1 and R? .... are alkyl radicals containing 3 - 6 carbon atoms, that an acid halide of general formula X

where Hal has the meaning given above and R3 is an alkyl radical containing 3-6 carbon atoms, is reacted with an ether of general formula (II) to form a ketone of general formula XI: where R^ and R" have the meanings given above , which ketone is then reduced to the corresponding secondary alcohol of the general formula: where R" and R" have the meanings given above, after which this alcohol is halogenated to the corresponding halide of the general formula. where R", and Hal have the meanings given above, which are reacted with magnesium and jade in a known manner to give the corresponding Grignard-for bond of general formula: where R", R^ and Hal have the meanings given above, which compound is reacted with halide of formula XIII to form a compound of formula:

where R" and R^ have the meanings given above, which are then dealkylated to the corresponding dihydroxy compound of formula I.

The condensation of compound (II) and haloketone (III) is advantageously carried out in the presence of concentrated sulfuric acid or anhydrous aluminum chloride at a reduced temperature, e.g. at a temperature of -25°C to 0°C, while the condensation of compound (II) and the secondary alcohol (III) is advantageously carried out in the presence of anhydrous aluminum chloride at ambient temperature or at slightly elevated temperatures, e.g. up to 40°C.

The hydrogenation of the unsaturated diethers (IVb) is advantageously carried out catalytically in glacial acetic acid in the presence of a palladium or platinum catalyst.

The dealkylation of the obtained compounds of formula (IVa) can be carried out, e.g. by means of hydrobromic acid in acetic acid.

It has been found that some of the 4,4'-dihydroxy compounds according to the present invention are difficult to purify by recrystallisation. This problem can be easily overcome by etherification of the 4,4'-dihydroxy compound with a suitable benzyl halide, for example benzyl chloride, in the presence of an alkali metal hydroxide, preferably sodium hydroxide. This etherification is conveniently carried out in an inert solvent. The dibenzyl ethers thus obtained can be easily recrystallized. Furthermore, the purified dibenzyl ethers can then be easily converted back into the corresponding dihydroxy compounds by hydrogenolysis, e.g. by dissolving the dibenzyl ether in glacial acetic acid and shaking the solution with hydrogen in the presence of a suitable catalyst, such as palladium charcoal or platinum charcoal.

The new compounds produced according to the present method exhibit a strong estrogenic activity.

This activity makes it particularly suitable for the treatment of prostate hypertrophy.

One of the methods commonly used for determining the estrogenic activity of a compound is the so-called "vaginal horn test" described by Emmett in "Hormone Assay" published by The Academic Press, New York 1950. This test has been carried out by a representative compound according to the invention compared to closely related compounds according to DAS 1,902,331. The results of this test are as follows:

Compounds of the following general formula were compared:

As can be seen from the table, the compound according to the invention is significantly more active than the corresponding other compounds which do not contain a fluorine atom. Furthermore, the test shows that the eg non-halogenated compounds are completely inactive in this test.

The following examples are given to illustrate the present invention:

"Example 1

A mixture of 100 g freshly distilled 2-fluoroanisole and 50 g 3-chloropentan-2-one, b.p. 134 137°C, was cooled to -20°C, after which 125 ml of concentrated sulfuric acid was added dropwise with stirring over a period of 2 hours. After further stirring for 6 hours, the reaction mixture was poured into ice water. The mixture was then extracted with diethyl ether, the ether extract dried and the ether distilled off, after which the oily residue was heated for 2 hours at 235-240°C at 15 mm Hg, and the obtained distillate was separated. The residue was then distilled at 160-170°C/0.03 mm Hg and gave a major fraction of 20 g of an oil which could not be crystallized. This oil was then dissolved in 150 ml of glacial acetic acid and shaken in a hydrogen atmosphere in the presence of 1.2 g of palladium charcoal (10%) until hydrogen uptake ceased. The reaction mixture was then filtered and evaporated to give about 20 g of a mixture of threo- and erythro-3,3 *- difluoro-4,4'-dimethoxy-α-eth-yl-α'-methyl-dibenzyl. After crystallization of this mixture from methanol, the erythro compound was isolated, which had a melting point of 106 - 107°C. ;A solution of 7 .5 g erythro-3,3'-difluoro-4,4'-dimethoxy-α-ethyl-α'-methyldibe nzy1 in 70 ml of glacial acetic acid and 40 ml of hydrobromic acid was heated under reflux in a nitrogen atmosphere for 6 1/2 hours. After cooling, the reaction mixture was poured over ice and extracted with ether. The ethereal extracts were washed with water and extracted with 2N sodium hydroxide solution. The alkaline extract was acidified and extracted with ether. Evaporation of the ethereal extract gave 6 g of a yellowish solid which was dissolved in benzene and passed through a column containing 50 g of silica gel. Concentration of the eluate resulted in cleavage of erythro-3,3'-difluoro-4,4'-d-ihydroxy-α-ethyl-α'-methyl-dibenzyl which had a melting point of 152-153°C. Example 2 26 g of aluminum chloride was added over the course of 1 hour to a stirred mixture of 26 g of o-fluoroanisole and 12>5 g of 3-chloropentanol-2 in a nitrogen atmosphere. The reaction mixture was heated to 35°C for 60 hours and then transferred to ice water. The reaction mixture was extracted with ether and then shaken with an aqueous solution of sodium carbonate to remove unwanted acidic phenolic material. The remaining ethereal phase was dried and evaporated to give a neutral material which was fractionally distilled. The fraction boiling at 165 - 175°C/0.2 mm Hg (10 g). was recrystallized from methanol and gave 1.3 g of erythro-3,3'-difluoro-4,4T<->dimethoxy-a-ethyl-a'-methyl-diben-zyl which had a melting point of 106 - 107°C and was identical to the product obtained in example 1. This dimethoxy compound was demethylated by heating in a mixture of 25 ml of glacial acetic acid and 10 ml of hydrobromic acid under a nitrogen atmosphere at 140°C for 5 hours. The solution was then cooled and diluted with water. 1.05 g of erythro-3,3r<->difluoro-4,4'-dihydroxy-α-ethyl-α'-methyl-dibenzyl were thus obtained which, after recrystallization from benzene, had a melting point of 152 - 153°C , and was identical to the product obtained in example 1. The non-crystalline mother liquor was demethylated in a similar manner. A product of 7.5 g was obtained and combined with the phenolic fraction (6 g, b.p. 180-190°C/0.2 mm Hg) and mixed with 13 g of benzyl chloride in a solution of 4 g of sodium hydroxide in 100 ml of alcohol. The reaction mixture was refluxed for 2 hours and then cooled and diluted with water. 1.9 g of a precipitate of erythro-3,3'-difluoro-4,4r<->dibenzyloxy-a-ethyl-a'-methyl-dibenzyl were obtained which, after recrystallization from benzene/petroleum ether, had a melting point of 131 - 132.5°C. This compound can be debenzylated by dissolving in 50 ml of acetic acid, adding 0.5 g of palladium charcoal and shaking with hydrogen for 1 hour. After filtering off the catalyst and working up the filtrate, 1.1 g of erythro-3,3-difluoro-4,4'-dihydroxy-α-ethyl-α'-methyl-dibenzyl were obtained. ;Example 3 ;Approx. 70 g of butyryl chloride was added over a period of 30 minutes with stirring to a mixture of 81 g o-fluoroanisole, lOOg aluminum chloride and lOO ml carbon disulphide: After further stirring for 4 hours, the reaction mixture was transferred into ice water and then extracted into ether. The ethereal extract was concentrated over aqueous, free sodium sulfate and evaporated. and the residue recrystallized from methanol, whereby o-fluoroanisylbutyrophenone was obtained. A solution of 4 g of sodium borohydride in 20 ml of water was added with stirring to a solution of approx. 40 g of b-fluoroanisyl-butyrophenone in 200 ml of methanol cooled to 0°C. The reaction mixture was stirred for 3 hours, diluted with water and extracted with benzene. The benzene extract gave 1-o-fluoroanisyl-n-butanol. A 0.2 M solution of 1-o-fluoroanisyl-n-butanol in dry benzene was added to a cooled suspension of 86 g phosphorus pentabromide in 50 ml dry. ether. After stirring for 1 1/2 hours, the reaction mixture was transferred to ice water. The 1-o-fluoranisyl-n-butyl bromide product thus prepared was extracted with benzene, and the benzene solution, after complete drying, was transferred with stirring to a mixture of 4 g of magnesium, 0.01 g of iodine and 20 ml of dry ether. The reaction mixture was refluxed for 15 hours and then transferred to a mixture of ice and dilute hydrochloric acid. The mixture was extracted with ether, the ethereal extract dried and evaporated and the residue recrystallized from chloroform/ether (b.p. 40 - 60°C). 5.5 g of meso-3,3'rdifluoro-4,4'-dimethoxy-α,α'-dipropyl-dibenzyl" were thus obtained, which had a melting point of 168 - 169°C.

After demethylation of this compound with hydrobromic acid in glacial acetic acid in a similar manner as described in example 2, the corresponding meso-3,3r-difluoro-4,4'-dihydro.xy-a,a'-dipropy1- dibenzyl compound obtained, which had a melting point of 139 - 140°C.

The present invention also includes within its framework pharmaceutical materials containing one or more of the new compounds. These pharmaceutical materials can be administered orally or parenterally in admixture with a solid or liquid pharmaceutical carrier.

Solid materials for oral administration include compressed tablets, pills, dispersible powders and granules. In such solid materials, at least one active compound according to the present invention is mixed with at least one inert diluent, such as tribasic calcium phosphate (Ca3(P04)2), starch, lactose, gelatin, acacia, sucrose, stearic acid, talc, alginic acid or sodium alginate.

night The materials can also contain, as in normal practice, additional

ger compounds other than the inert diluents, e.g. smdremid-'

clay, such as magnesium stearate, as well as sweetening or flavoring substances.

The percentage amount of the active ingredient in the materia-

easily according to the present invention can be varied, as it is necessary

you to have such a relationship that a suitable dose should produce the desired therapeutic effect. Generally, the preparations according to the present invention are to be administered with an effective dose from approx. 0.0001 mg to 1 mg of active substance per kg body weight per day.

Claims (1)

Analogous procedure for the production of new therapeutically active, racemic 1, 2-diphenylethane derivatives of general formula I: where R^ and R^, which may be the same or different, are alkyl radicals containing up to 6 carbon atoms, with the proviso that R^ and R2 do not simultaneously denote methyl or ethyl 1 radicals, characterized by: a ) an ether of general formula II where R" is an alkyl radical containing up to 6 carbon atoms, is reacted with a halogen compound of general formula III where R^ and R^ have the meanings given above, Z denotes a hydroxyl group and Y denotes H, ©iler Y and Z together denote an oxygen atom, and Hal denotes a halogen atom, whereby a compound of the general formula is obtained: where R^, R^ and R" have the meanings given above, after which a compound of formula (IVb) is hydrogenated to a compound of formula (IVa) which is dealkylated with the formation of the corresponding dihydroxyfur bond, or b) for the preparation of compounds of general formula (I) in which R^ and R^ are alkyl radicals. cals containing 3-6 carbon atoms, that an acid halide of general formula X where Hal has the meaning given above and R^ is an alkyl radical containing 3-6 carbon atoms, is reacted with an ether of general formula (II) to form a ketone of general formula XI: where R^ and R" have the meanings given above, which ketone is then reduced to the corresponding secondary alcohol of general formula: where R" and R" have the meanings given above, after which this alcohol is halogenated to the corresponding halide of general for flour : where R", R^ and Hal have the meanings indicated above, which are reacted with magnesium and iodine in a known manner to give the corresponding Grignard compound of general formula: where R", R^ and Hal have the meanings given above, which compound is reacted with halide of formula XIII to form a compound of the formula: where R" and R^ have the meanings given above, which are then dealkylated to the corresponding dihydroxy compound of formula I.