GB2042519A

GB2042519A - 1,1,2-triphenylethane and -ethylene derivatives

Info

Publication number: GB2042519A
Application number: GB8000362A
Authority: GB
Original assignee: Biorex Laboratories Ltd
Current assignee: Biorex Laboratories Ltd
Priority date: 1979-01-17
Filing date: 1980-01-07
Publication date: 1980-09-24
Also published as: GB2042519B; FR2446810A1; DE3001285A1; IT1140520B; FR2446810B1; IT8019259A0; JPS55100345A

Abstract

The present invention provides new compounds of the general formula:- <IMAGE> wherein R1 is a methyl, ethyl or ???,???,???- trifluoroethyl radical, R2, R3 and R4, which can be the same or different, are hydrogen or halogen atoms, R5 and R6, which can be the same or different, are hydrogen atoms or alkyl radicals containing up to 6 carbon atoms or R5 and R6, together with the nitrogen atom to which they are attached, represent a heterocyclic radical and R7 and R8 are both hydrogen atoms or R7 and R8 together represent a further valency bond, with the proviso that when R1 is a methyl or ethyl radical, R4 is a halogen atom; and the pharmacologically- acceptable acid-addition salts thereof. The present invention also provides processes for the preparation of these compounds, as well as pharmaceutical compositions containing them.

Description

SPECIFICATION 1,1,2-triphenylethane and -ethylene derivatives The present invention is concerned with new 1,1,2-triphenyl-ethane and -ethylene derivatives, with the preparation thereof and with pharmaceutical compositions containing them.

The new substituted ethylene derivatives according to the present invention are compounds of the general formula:

wherein R1 is a methyl, ethyl or ss,ss,ss-trifluoroethyi radical, R2, R3 and R4, which can be the same or different, are hydrogen or halogen atoms, R5 and R6, which can be the same or different, are hydrogen atoms or alkyl radicals containing up to 6 and preferably up to 3 carbon atoms or R5 and R5, together with the nitrogen atom to which they are attached, represent a heterocyclic radical and R7 and R8 are both hydrogen atoms or R7 and F8 together represent a further valency bond, with the proviso that when R1 is a methyl or ethyl radical, R4 is a halogen atom; and the pharmacologically-acceptable acid-addition salts thereof.

The compounds of general formula (I) in which R7 and R8 together represent a further valency bond can have the cis- or trans-configuration or can be mixtures of both configurations.

When R2, R3 and/or R4 is a halogen atom, it is preferably a fluorine atom.

When F5 and R6 are alkyl radicals, they are preferably methyl or ethyl radicals and when F5 and R6, together with the nitrogen atom to which they are attached, represent a heterocyclic radical, this can be, for example, a radical derived from pyrrolidine, imidazoline, pyrazoline, piperidine, piperazine or morpholine.

The new compounds according to the present invention can be prepared, for example, in the following manner: A phenylacetic acid compound of the general formula:

in which R2 has the same meaning as above, is reacted with an anisole derivative of the general formula:

in which R4 has the same meaning as above, to give a deoxybenzoin derivative of the general formula:

in which R2 and R4 have the same meanings as above, this derivative (IV) then being reacted with sodium hydride and an alkyl halide of the general formula:: R1 - Hal (V) in which R1 has the same meaning as above and Hal is a halogen atom, to give an a-substituted deoxygenzoin derivative of the general

in which R1, R2 and R4 have the same meanings as above, which is demethylated to give the corresponding nhenol of the aeneral formula

in which R1, R2 and R4 have the same meanings as above, this compound (VII) then being reacted with a Grignard reagent of the general formula::

in which F3 and Hai have the same meanings as above, to give a carbinol of the general formula

in which F1, R2, R3 and R4 have the same meanings as above, dehydration of which gives the corresponding ethylene derivative of the general formula:

in which F1, R2, R3 and R4 have the same meanings as above, which ethylene derivative is then separated into its cis and trans isomers by fractional crystallisation of the isomeric acetate mixture and the individual deacetylated isomers reacted with a p-(N,N-dialkylamino)-ethyl halide acid-addition salt to give the desired compound (I) (R7 + F8 = a valency bond).

When it is desired to obtain compounds (I), in which R7 and R8 are both hydrogen atoms, the appropriate acetylated isomer of (X) is reduced, for example with hydrogen in the presence of an appropriate catalyst, then deacetylated and thereafter reacted with a p-(N,N-dialkylamino)-ethyl halide.

If desired, the compounds (I) according to the present invention can be reacted with a non-toxic inorganic or organic acid to give the corresponding acid-addition salt.

We have found that the new compounds (I) possess valuable anti-oestrogenic properties and are useful in the management of breast cancer and also for the stimulation of ovulation in infertility. Accordingly, the present invention also provides pharmaceutical compositions containing at least one compound of general formula (I), in admixture with a solid or liquid pharmaceutical diluent or carrier.

The following Examples are given for the purpose of illustrating the present invention: Example 1 a) A mixture of 65 g. phenylacetic acid and 100 g. trifluoroacetic anhydride was stirred to give a homogeneous solution to which were added 52 ml. anisole. After standing for 20 hours at ambient temperature, the reaction mixture was poured into ice and water. The precipitate obtained was filtered off, washed with water and aqueous sodium bicarbonate solution and then with diethyl ether and dried to give 75 g. of thin layer chromatographically pure 4-methoxydeoxybenzoin; m.p. 73.5 - 75"c.

b) 22.6 g. 4-Methoxydeoxybenzoin in 200 ml. dry dimethylformamide were treated portionwise with 4.8 g. sodium hydride (50% dispersion in oil). The reaction mixture was stirred for 2 hours, cooled to 0 C. and 12 ml. ss,ss,ss-trifluoroethyl iodide added thereto. Stirring was continued at ambient temperature for 20 hours and at 50"C. for 1 hour, whereafter the reaction mixture was poured into ice and dilute hydrochloric acid.

Extraction with diethylether followed by filtration of a toluene solution of the product through ten times its weight of neutral alumina gave 19.5 g. a-(ss,ss,ss-trifluoroethyl)-4-methoxydeoxybenzoin which, after recrystallisation from diethyl ether-petroleum ether (1:9 v/v), had a melting point of 79 - 80 c.

c) 19 g. a-(t3,P,P-Trifluoroethyl)-4-methoxydeoxy-benzoin were demethylated by heating under reflux with 40 g. pyridine hydrochloride for 30 minutes, whereafter thin layer chromatography showed the absence of starting materials. Ice and dilute hydrochloric acid were added to the cooled mixture, extraction of which with diethyl ether gave 18 g. a-(ss,ss,ss-trifluoroethyl)-4-hydroxydeoxybenzoin in the form of an oil which slowly acidifed.

d) 13 g. a-(ss,ss,ss-Trifluoroethyl)-4-hydroxydeoxybenzoin, which had been dried by evaporation with toluene in a vacuum, were dissolved in dry diethyl ether and added to an ethereal solution of phenyl magnesium bromide which had been prepared from 2.6 g. magnesium and 12 ml. bromobenzene. The reaction mixture was heated under reflux for 3 hours, cooled and poured into dilute hydrochloric acid and ice. Extraction with diethyl ether gave 1 ,2-diphenyl-2-(P,P,B-trifluoroethyl)-l -(4-hydroxyphenyl)-ethanol, which was dehydrated by heating under reflux with 5% hydrochloric acid in ethanol for 3 hours to give 19.5 g. of a mixture of cis- and trans-4,4,4-trifluoro-1 ,2-diphenyl-1 -(4-hydroxyphenyl)-but-1 -ene.

The mixture was converted into the acetate by reaction with acetic an hydride in pyridine at ambient temperature for 20 hours. The product was isolated by extraction with diethyl ether and recrystallised from diethyl ether-petroleum ether (1:3 v/v) to give 10 g. of pure trans-4,4,4-trifluoro-1 ,2-diphenyl-1 -(4- acetoxyphenyl)-but-1-ene; m.p. 111 - 112 c.

e) 10 g. of the trans-isomer obtained in d) above were boiled in 100 ml. ethanolic 5% sodium hydroxide solution for 1 hour to give the corresponding phenol, without isomerisation.

f) 9 g. of the phenol obtained in e) above in a solution of 1.5 g. sodium in ethanol were treated with 5.5 g.

N,N-dimethylaminoethyl chloride hydrochloride. The reaction mixture was heated under refluxfor7 hours, cooled and poured into a mixture of ice and dilute hydrochloric acid. Extraction with diethyl ether removed 2.7 g. of unchanged starting phenol. The aqueous layer was rendered alkaline with 2N aqueous sodium hydroxide solution and then extracted with diethyl ether. The ethereal extract was evaporated and the residue recrystallised from diethyl ether-petroleum ether (b.p. 40 - 60"C) (4:1 v/v) to give 5.5 g.

trans-1 -[4-)f3-dimethylaminoethoxy)-phenyl]-1 ,2-diphenyl-4,4,4-trifluorobut-1 -ene; m.p. 105- 1 060C.

The mother liquor from the recrystallisation contained some cis product, indicating that isomerisation had taken place up to an extent of about 5%.

g) 5 g. of the trans compound obtained in f) above in diethyl ether were added to a solution of 2.6 g. citric acid in diethyl ether. The precipitate obtained was filtered off, washed with diethyl ether and recrystallised from acetone to give 7.1 g. trans-1 -[4-(ss-dimethylaminoethoxy)-phenyl]-1,2-diphenyl-4,4,4-trifl uorobut-1 -ene citrate; m.p. 143 - 144'C.

Example 2 a) 72 ml. Titanium tetrachloride were added dropwise over the course of 2 hours to a mixture of 100 g.

phenylacetyl chloride and 82 g. 2-fluoroanisole in 150 ml. petroleum ether (b.p. 40 - 60"C.). The reaction mixture was eft to stand at ambient temperature for 3 hours and then added to a mixture of ice and diethyl ether. The mixture was stirred until decomposition was complete and then filtered. The solid was washed with water and dissolved in chloroform and the solution then dried over anhydrous sodium sulphate, filtered and concentrated to a small volume. Upon adding diethyl ether and cooling, there were obtained 65 g.

3-fluoro-4-methoxydeoxybenzoin; m.p. 107.5-109"C.

The ethereal filtrate was washed with water, dried over anhydrous sodium sulphate and treated with charcoal. Concentration of the solution gave a further 11 g. of product.

b) A solution of 20 g. 3-fluoro-4-methoxydeoxybenzoin in 200 ml. dimethylformamide was treated portionwise with 3.9 g. sodium hydride (50% dispersion in oil). The reaction mixture was stirred for a total of 4 hours and 13 ml. ss,ss,ss-trifluoroethyl iodide then added thereto. Stirring was continued at 20"C. for 20 hours and at 40 - 50 C. for 3 hours. After cooling, the reaction mixture was poured into dilute hydrochloric acid and ice.After extraction with diethyl ether, followed by filtration of a solution of the product in toluene through 10 times its weight of neutral alumina, there were obtained 20 g. a-(ss,ss,ss-trifluoroethyl)-3-fluoro-4- methoxydeoxybenzoin; m.p. 57 - 58"C. (recrystallised from diethyl etherpetroleum ether (1:9 v/v).

c) the methoxydeoxybenzoin obtained in b) above was demethylated by heating under reflux with 50 g.

pyridine hydrochloride. After cooling, dilute hydrochloric acid was added, followed by extraction with diethyl etherto to give 20 g. a-(ss,ss,ss-trifluoroethyl)-3-fluoro-4-hydroxydeoxybenzoin which was recrystal I ised from petroleum ether; m.p. 85.5 - 87.5 C.

d) A solution of 20 g. of the hydroxydeoxybenzoin obtained inc) above in 60 ml. dry diethyl ether was added to a solution of phenyl magnesium bromide prepared from 4 9. magnesium and 17 ml.

bromobenzene in diethyl ether and the reaction mixture heated under gentle reflux for 3 hours. The reaction mixture was then poured into dilute hydrochloric acid and ice, followed by extraction with diethyl ether to give 1 ,3-diphenyl-3-(B,B,P-trifl uoroethyl)l -(3-fluoro-4-hydroxyphenyl)-ethanol which was dehydrated by heating under reflux in 100 ml. 10% hydrochloric acid in ethanol for 2 hours. The reaction mixture was cooled and extracted with diethyl ether to give a mixture of cis- and trans-4,4,4-trifluoro-1,2-diphenyl-1-(3-fluoro-4- hydroxyphenyl)-but-1 -ene.

This mixture was converted into the corresponding acetates by the action of 60 ml. acetic anhydride in 100 ml. pyridine at 20"C. for 20 hours. The acetates were treated with charcoal in diethyl ether and then crystallised from ethanol to give 12.5 g. of pure trans-4,4,4-trifluoro-1,2-diphenyl-1-(3-fluoro-4- acetoxyphenyl)-but-1-ene; m.p.115 - 116.5 C.

e) 12 g. of the trans-acetate obtained in d) above in 100 ml. 3% ethanolic sodium hydroxide solution were heated under reflux for 1 hour, then cooled and poured into ice and dilute hydrochloric acid. Extraction with diethyl ether gave an oil which crystallised from petroleum ether (b.p. 40 - 60"C) to give 9 g. trans-4,4,4 trifluoro-1 ,2-diphenyl-1 -(3-fluoro-4-hydroxyphenyl)-but-1 -ene; m.p. 126-128"C.

f) A solution of 6.5 g. of the hydroxy compound obtained in e) above in 50 ml. dimethylformamide was treated portionwise with 1 g. sodium hydride (50% dispersion in oil). The reaction mixture was stirred for 1 hour, 3 ml. ethyl bromoacetate were added thereto and the reaction mixture then heated at about 60"C. for 2 hours. After cooling, the reaction mixture was poured into dilute hydrochloric acid and ice. Extraction with diethyl ether and crystallisation of the product from diethyl ether-petroleum ether (b.p. 40 - 60 C.) (1 :5 v/v gave 7.5 g. trans-4,4,4-trifluoro-1, 2-diphenyl-1 -(3-fluoro-4-carboethoxy-methoxyphenyl)-but-1 -ene; m.p. 96 97.5"C.

g) 7.5 g. of the ester obtained in f) above in 60 ml. 3% ethanolic sodium hydroxide solution was heated under reflux for 1 hour and then poured into dilute hydrochloric acid. After extraction with diethyl ether and crystallisation of the product from diethyl etherpetroleum ether (1 :4 v/v), there were obtained 7 g. trans 4,4,4-trifluoro-1 ,2-diphenyl-1 -(3-fluoro-4-carboxy-methoxyphenyl)-but-1 -ene; m.p. 155 - 157 5"c.

h) A mixture of 5.5 g. of the acid obtained in g) above and 3.5 g. phosphorus pentachloride, which had been added portionwise, was heated on a water-bath for 30 minutes and then evaporated under reduced pressure. The residue was taken up in dry toluene and treated with diethylamine until basic, whereafter the reaction mixture was heated on a water-bath for 3 hours. After cooling, the reaction mixture was poured into dilute hydrochloric acid and ice. Extraction with diethyl ether and treatment of the solution with charcoal gave 7 g. trans-4,4,4-trifluoro-1 ,2-diphenyl-1 -[34luoro-4-(N,N-diethylarnidomethoxy)-phenyl]-but-1 -ene in the form of an oil.

i) The amide obtained in h) above was dried by evaporation with toluene, dissolved in diethyl ether and the ethereal solution added to a suspension of 0.8 g. lithium aluminium hydride in diethyl ether. The reaction mixture was heated under reflux for 1.5 hours, cooled and cautiously added to ice. Extraction with diethyl ether gave 6.3 g. trans-1-[3-fluoro-4-(ss-diethylaminoethoxy)-phenyl]-1,2-diphenyl-4,4,4-trifluorobut-1-ene in the form of an oil.

j) 6 g. of the butene compound obtained in i) above were dissolved in diethyl ether and added dropwise to a solution of 3 g. citric acid in 300 ml. diethyl ether. The precipitate obtained was filtered off, thoroughly washed with diethyl ether and recrystallised several times from acetone-diethyl ether (2:1 v/v) to give 4.3 g.

trans-1 -[3-fI uorn-4-(-diethyIaminoethoxy)-phenyl]-1 ,2-diphenyl-4,4,4-trifluorobut-1 -ene citrate; m.p. 129- 132"C.

Example 3 a) A solution of 16 g. 3-fluoro-4-methoxydeoxy-benzoin (see Example 2 a)) in 200 ml. dimethylformamide was treated portionwise with 3.2 g. sodium hydride (50% suspension in oil). The reaction mixture was stirred for 3 hours and then 12 g. ethyl iodide added thereto. Stirring was continued at 20"C. for 20 hours and at 40 50 C for 2 hours. After cooling, the reaction mixture was poured into dilute hydrochloric acid and ice.

Extraction with diethyl ether and concentration of the dried ethereal extract to a small volume gave 17 g.

34luoroA-methoxy-a-ethyldeoxybenzoin; m.p. 64- 66"C.

b) The deoxybenzoin compound obtained in a) above and 30 g. pyridine hydrochloride were heated under reflux for 40 minutes, cooled and dilute hydrochloric acid added thereto. Extraction with diethyl ether gave 15.3 g.3-fluoro-4-hydroxy-a-ethyldeoxybenzoin in the form of an oil.

c) A solution of 15.5. g. of the hydroxy compound obtained in b) above in 50 ml. dry diethyl ether was added to a solution of phenyl magnesium bromide prepared from 4 g. magnesium and 27 g. bromobenzene in diethyl ether. The reaction mixture was heated under reflux for 2 hours, cooled and poured into dilute hydrochloric acid and ice. Extraction with diethyl ether gave 1,2-diphenyl-2-ethyl-1-(3-fluoro-4- hydroxyphenyl)-ethanol which was dehydrated by heating under reflux with 100 ml. 10% ethanolic hydrochloric acid for 2 hours. Extraction with diethyl ether gave a mixture of cis- and trans-1,2-diphenyl-1-(3fluoro-4-hydroxyphenyl)-but-1 -ene which was converted into a mixture of acetates by reacting with 25 ml.

acetic anhydride in 50 ml. pyridine at 20"C. for 20 hours. Extraction with diethyl ether and crystallisation of the product from ethanol gave 7 g. of pure trans-1,2-diphenyl-1-(3-fluoro-4-acetoxyphenyl)-but-1-ene; m.p.

100-102"C.

d) The trans-acetate obtained in c) above in 60 ml. 3% ethanolic sodium hydroxide solution was heated under reflux for 1 hour, then cooled and acidified with dilute hydrochloric acid. Extraction with diethyl ether and crystallisation of the product from petroleum ether gave 5.5. g. 1,2-diphenyl-1-(3-fluoro-4- hydroxyphenyl)-but-1 -ene; m.p. 127 - 1 280c.

e) 5 g. of the butene compound obtained in d) above, 4 g. N,N-dimethylaminoethyl chloride hydrochloride and 4 g. sodium carbonate in 60 ml. acetone were heated under reflux for 10 hours while stirring. After cooling, the reaction mixture was diluted with water and extracted with diethyl ether to give an oil. This oil was triturated several times with water to remove any residue of N,N-dimethylaminoethyl chloride. It was then redissolved in diethyl ether, the ethereal solution was dried with anhydrous sodium sulphate and added to 300 ml. of a 1% solution of citric acid in diethyl ether. The precipitate obtained was left to settle overnight, then separated and crystallised from acetone-diethyl ether (3:1 v/v) to give 5.8 g.

trans-1 -[3-fluoro-4-(ss-dimethylaminoethoxy)-phenyl]-1,2-diphenylbut-1 -ene citrate. m.p. 119 - 121 C.

Example 4 a) A solution of 16 g.4-hydroxy-a-(ss,ss,ss-trifluoroethyl)-deoxybenzoin (see Example 1 c)) in 80 ml. dry diethyl ether was added to a solution of 4-fluorophenyl magnesium bromide, prepared from 6 g. magnesium and 30 ml. 4-fluorobromobenzene in 100 ml. dry diethyl ether. The reaction mixture was heated under reflux for 2 hours, cooled and poured into dilute hydrochloric acid and ice. Extraction with diethyl ether gave 1 -(4-hydroxyphenyl)-1 -(4-fl uorophenyl )-2-phenyl-2-(ss,ss,ss-trifl uoroethyl)-ethanol, which was dehydrated by heating under reflux with 10% hydrochloric acid in ethanol for 3 hours.Extraction with diethyl ether gave a mixture of cis- and trans -(4-hydroxyphenyl)-1 -(4-fluorophenyl )-2-phenyl-4,4,4-trifluorobut-1 -ene which was converted into a mixture of the corresponding acetates by reacting with 40 ml. acetic anhydride in 80 ml.

pyridine at 20 C. for 20 hours. The trans acetate was isolated by extraction with diethyl ether and recrystallised from ethanol to give 8.4 g. pure trans-1-(4-acetoxyphenyl)-1-(4-fluorophenyl)-2-phenyi-4,4,4- trifluorobut-1-ene; m.p. 141 - 1420C.

b) A solution of 8.2 g. of the trans acetate compound obtained in Example 4 a) in 80 ml. of 5% ethanolic sodium hydroxide solution was refluxed for 1 hour, then cooled and poured into dilute hydrochloric acid and ice. Extraction with diethyl ether and crystallisation from diethyl ether/petroleum ether (b.p. 40 - 60"C.) (1:3 v/v) gave 3.4 g. pure trans-I -(4-hydroxyphenyl )-1 -(44luorophenyl)-2-phenyl-4,4,4-trifluorobut-1 -ene; m.p.

142-143"C.

c) 8 g. of hydroxy compound obtained in Example 4 b), 8 g. N,N-dimethylaminoethyl chloride hydrochloride and 8 g. sodium carbonate in 80 ml. butanonewere heated under reflux,while stirring, for 10 hours. After cooling, the reaction mixture was diluted with water and extracted with diethyl ether to give an oil, crystallisation of which from diethyl ether/petroleum ether (b.p. 40 - 60"c.) (1:2 v/v) gave 4.8 g. pure trans-1 -[4-(P-dimethylaminoethoxy)-phenyl]-1 -(44luorophenyl)-2-phenyl-4,4,4-trifluorobut-1 -ene; m.p. 89 90"C.

d) A solution of 4.8 g. of the amine obtained in Example 4 c) in 30 ml. acetone was added to a solution of 2.5 citric acid in 20 ml. acetone and then evaporated to dryness. Crystallisation of the residue from diethyl ether/acetone (3:1 v/v) gave 6.1 g. pure trans-1 -[-4-(ss-dimethylaminoethoxy)-phenyl]-1-(4-fluorophenyl)-2- phenyl-4,4,4-trifluorobut-1 -ene citrate; m.p. 151 - 152 C.

Example 5 a) 19 ml. Anisole were added to a solution of 24 g. 4-fluorophenylacetic acid in 25 ml. trifluoroacetic anhydride. The reaction mixture was stirred at ambient temperature for 20 hours and then poured into ice and water. The precipitate obtained was filtered off, washed with water, with an aqueous solution of sodium bicarbonate and then with diethyl ether. After drying and crystallising from toluene, there were obtained 25 g. 4'-fluoro-4-methoxy-deoxybenzoin : m.p. 108.5 - 11 0.S'c.

b) The product of Example 5 a) was dissolved in 200 ml. dry dimethylformamide and then mixed portionwise with 5.0 g. sodium hydride (50% dispersion in oil). The reaction mixture was thereafter stirred for 2 hours, cooled to 0 C. and 12 ml. P,P,P-trifluoroethyl iodide added thereto, followed by stirring at ambient temperature for 20 hours and then at 50"C. for 2 hours. The reaction mixture was subsequently poured into ice and dilute hydrochloric acid and extracted with diethyl ether. The ethereal extract was evaporated, the residue was taken up in toluene and the solution thus obtained was filtered through 10 times its weight of neutral alumina and evaporated to give 29.6 g. a-(ss,ss,ss-trifluoroethyl)-4'-fluoro-4- methoxydeoxybenzoin.

c) 29.4 g. of the deoxybenzoin derivative obtained in Example 5 b) were demethylated by heating under reflux with 65 g. pyridine hydrochloride for 45 minutes, whereafter thin layer chromatography demonstrated the absence of starting material. The mixture was cooled and ice and dilute hydrochloric acid were added thereto, followed by extraction with diethyl ether to give 29 g. a(ss,ss,ss-trifluoroethyl)-4'-fluoro-4- hydroxydeoxybenzoin in the form of an oil.

d) A solution of 14.5 g. of the oily product of Example 5 c) in 70 ml. dry diethyl ether was added to a solution ofphenyl magnesium bromide prepared from 2.6 9. magnesium and 18 9. bromobenzenein 100 ml.

dry diethyl ether. The reaction mixture was heated under reflux for 2 hours, cooled and poured into dilute hydrochloric acid and ice. Extraction with diethyl ether gave 1-phenyl-2-(4-fluorophenyl)-1-(4- hydroxyphenyl)-2-(ss,ss,ss-trifluoroethyl)-ethanol, which was dehydrated by heating under refluxwith 10% hydrochloric acid in ethanol for 3 hours. The reaction mixture was extracted with diethyl ether to give a mixture of cis- and trans-1 -phenyl-2-(4-fluorophenyl-)-1 -(4-hydroxyphenyl)-4,4,4-trifluorobut-1 -ene which was reacted with 40 ml. acetic anhydride in 80 ml. pyridine at 20"C. for 20 hours to give a mixture of the corresponding acetates.The trans acetate was isolated by extraction with diethyl ether and then crystallised from ethanol to give 10.2 g. trans-1 -(4-acetoxyphenyl)-1 -phenyl-2-(44luorophenyl)-4,4,4-trifluorobut-1 -ene; m.p.107.5 - 109.5 C.

e) A solution of 10 g. of the trans acetate compound obtained in Example 5 e) in 80 ml. 5% ethanolic sodium hydroxide solution was refluxed for 1 hour. After cooling, the reaction mixture was poured into dilute hydrochloric acid and ice. Extraction with diethyl ether, evaporation of the extract and crystallisation of the residue from diethyl ether/petroleum ether (b.p. 40 - 60"C.) (1 :3 v/v) gave 8.6 g. trans-1-(4 hydroxyphenyl)-1 -phenyl-2-(44luorophenyl)-4,4,4-trifluorobut-1 -ene; m.p. 154-155.5"C.

f) 8.4 g. of the hydroxy compound obtained in Example 5 e) were mixed with 10 g. sodium carbonate and 10 g. N,N-dimethylaminoethyl chloride hydrochloride, whereafter 80 ml. butan-2-one were added thereto.

The reaction mixture was stirred and heated under reflux for 10 hours. After cooling, the reaction mixture was diluted with water and extracted with diethyl ether to give 7.2 g. of an oil. Crystallisation of this oil from diethyl ether/petroleum ether (b.p. 40 - 60"C. (1:2 v/v) gave 5.9 g. trans-1-[4-(ss-dimethylaminoethoxy)- phenyl]-1 -phenyl-2-(4-fluorophenyl)-4,4,4-trifluorobut-1 -ene; 116.5 - 11 8'C.

g) A solution of 5.8 g. of the amine obtained in Example 5 f) in 40 ml. acetone was added to a solution of 3.1 g. citric acid in 30 ml. acetone and the solution then evaporated to dryness. Crystallisation of the residue from diethyl ether/acetone (3:1 v/v) gave 7.1 g. frans-1-[4-(ss-dimethylaminoethoxy)-phenyl]-1-phenyl-2-(4- fluorophenyl)-4,4,4-trifluorobut-1-ene citrate; m.p. 138.5 -140"C.

Example 6 a) A solution of 14.5 g. a-(ss,ss,ss-trifluoroethyl)-4'-fluoro-4-hydroxydeoxybenzoin (see Example 5 c)) in 70 ml. dry diethyl ether was added to a solution of 4-fluorophenyl magnesium bromide prepared from 2.7 g.

magnesium and 12.5 ml. 4-fluorobromobenzene in 100 ml. dry diethyl ether. The reaction mixture was heated under reflux for 2 hours, cooled and poured into dilute hydrochloric acid and ice. Extraction with diethyl ether gave 1-(4-hydroxyphenyl)-1 ,2-di-(4-fluorophenyl)-2-(ss,ss,ss-trifluoroethyl}-ethanoi, which was dehydrated by heating under reflux for 3 hours with 10% hydrochloric acid in ethanol. Extraction of the reaction mixture with diethyl ether gave a mixture of cis- and trans-i -(4-hydroxyphenyl)-1 ,2-di-(4- fluorophenyl)-4,4,4-trifluoro-but-1-ene which was reacted with 40 ml. acetic anhydride and 80 ml. pyridine at 20"C. for 20 hours to give a mixture of the corresponding acetates.The trans acetate was isolated by extraction with diethyl ether and crystallised from ethanol to give 8.6 g. trans-1-1-(4-acetoxyphenyl)-1,2-di (44luorophenyl)-4,4,44rifluoro-but-1-ene; m.p.151 - 152 C.

b) A solution of 8.5 g. of the trans acetate obtained in Example 6 a) in 80 ml. 5% ethanolic sodium hydroxide solution was refluxed for 1 hour, cooled and poured into dilute hydrochloric acid and ice.

Extraction with diethyl ether and crystallisation from diethyl ether/petroleum ether (b.p. 40 - 60"C.) (1:3 v/v) gave 7.8 g. trans-1-(4-hydroxyphenyl)-1,2-di-(4-fluorophenyl)-4,4,4-trifluorobut-1-ene; m.p. 165 - 167 C.

c) 7.7 g. of the hydroxy compound obtained in Example 6 b) were mixed with 8 g. sodium carbonate and 8 g. N,N-dimethylaminoethyl chloride hydrochloride and 80 ml. butan-2-one added thereto. The reaction mixture was then stirred and heated under reflux for 10 hours, cooled, diluted with water and extracted with diethyl ether to give 9.4 g. of an oil, crystallisation of which from diethyl ether/petroleum ether (b.p. 40 60"C.) (1:2 v/v) gave 5.4 g. trans-i -[4-(t3-dimethylaminoethoxy)-phenyl]-1 ,2-di-(44luorophenyl)-4,4,4- trifluorobut-1-ene; m.p. 104- 1060C.

d) A solution of 5.3 g. of the amine obtained in Example 6 c) in 30 ml. acetone was added to a solution of 2.7 g. citric acid in 30 ml. acetone and the solution evaporated to dryness. Crystallisation of the residue from diethyl ether/acetone (3:1 v/v) gave 7.1 g. trans-1 -[4-(Q-dimethylaminoethoxy)-phenyl]-1 ,2-di(4- fluorophenyl)-4,4,4-trifluorobut-l -ene citrate; m.p. 144 - 146"C.

Example 7 a) A solution of 7.8 g. trans-1 -(4-hydroxyphenyl)-1 -(44luorophenyl)-2-phenyl-4,4,4-trifluorobut-1 -ene (see Example 4 b)) in 80 ml. butanone was refluxed with 10 g. N-(2-chloroethyl)-piperidine hydrochloride and 8 g. sodium carbonate for 10 hours, while stirring. The reaction mixture was cooled, diluted with water and extracted with diethyl ether to give an oil, which was stirred with dilute hydrochloric acid for 2 hours. The precipitated hydrochloride was centrifuged and collected, treated with 1 M aqueous sodium hydroxide solution and extracted with diethyl ether. The ethereal extract was washed with water, dried and evaporated.

Crystallisation of the residue from petroleum ether (b.p. 40 - 60"C.) gave 6.2 g. trans-1-[4-(ss- piperidinoethoxy)-phenyl]-1 -(4-fluorophenyl)-2-phenyl-4,4,4-trifluorobut-1 -ene; m.p. 99 - 1 00.50C.

b) A solution of 6.0 g. of the amine obtained in Example 7 9) in 30 ml. acetone was mixed with 3.0 g. citric acid in 30 ml. acetone and the solution evaporated to dryness. Crystallisation of the residue from ethanol/diethyl ether (1:5 v/v) twice gave 7.2 g. trans-1-[4-(ss-piperidinoethoxy)-phenyl]-1-(4-fluorophenyl)-2- phenyl-4,4,4-trifluorobut-1-ene citrate; m.p. 101 - 103 C.

Example 8 a) A solution of 7 g. trans -(4-fluorophenyl)-1 -(4-acetoxyphenyl)-2-phenyl-4,4,4-trifluorobut-1 -ene (see Example 4 a)) in 100 ml. ethyl acetate and 2 g. of palladium on charcoal (10%) was stirred in the presence of hydrogen until the uptake of hydrogen ceased. The catalyst was filtered off and the filtrate evaporated to dryness. Crystallisation of the residue from ethanol gave 7 g. (1 R, 2R) (15, S,2S)-1 -(4-fluorophenyl)-1 -(4 acetoxyphenyl)-2-phenyl-4,4,4-trifluorobutane; m.p. 172 - 174'C.

b) The acetate obtained in Example 8 a) was refluxed in 80 ml. 3% ethanolic sodium hydroxide solution for 1 hour, then cooled and poured into dilute hydrochloric acid and ice. Extraction with diethyl ether gave 6.8 g. of an oil which was dried by evaporation with toluene.

This oil was taken up in 80 ml. butanone and mixed with 8 g. N,N-dimethylaminoethyl chloride hydrochloride and 7 g. sodium carbonate. The reaction mixture was heated under refluxfor 18 hours, while stirring, then cooled and poured into water. Extraction with diethyl ether gave an oil, which was triturated with water and the supernatant liquid decanted off. The insoluble residue was taken up in diethyl ether and the ethereal solution was dried with anhydrous sodium sulphate and charcoaled. After evaporation of the solvent,therewereobtained6.4g.(1R,2R)(1S,2S)-1-(4-fluorophenyl)-1-[4-(ss-dimethylaminoethoxy)- phenyl]-2-phenyl-4,4,4-trifluorobutane.

c) 6.4 g. of the amine obtained in Example 8 b) in 30 ml. acetone were added to a solution of 3.0 g. citric acid in 30 ml. acetone and the solvent evaporated to dryness. Crystallisation of the residue from ethanol/diethyl ether (1 :15 v/v) gave 5.9 g. (iF, 2R) (iS, 2S)-1-(4-fl uorophenyl)-l -[4-(P- dimethylaminoethoxy)-phenylj-2-phenylA,4A-trifiuornbutane citrate; m.p. 146 - 147.5 C.

Example 9 a) A solution of 12 g. trans-1,2-di-(4-fluorophenyl)-1-(4-acetoxyphenyl)-4,4,4-trifluorobut-1-ene (see Example 6 a)) in 200 ml. ethyl acetate and 6 g. of palladium on charcoal (10%) were stirred in the presence of hydrogen until the uptake of hydrogen ceased. The catalyst was filtered off and the filtrate evaporated to dryness. Crystallisation of the residue from ethanol gave 5.7 g. (1 R,2R) (1 S,2S)-1 ,2-di-(4-fluorophenyl)-1 -(4acetoxyphenyl)-4,4,4-trifluorobutane; m.p. 155-157"C.

b) 5.6 g. of the acetate obtained in Example 9a) were heated under reflux in 60 ml. 3% ethanolic sodium hydroxide for 1 hour, cooled and poured into dilute hydrochloric acid and ice. Extraction with diethyl ether gave an oil which was dried by evaporation with toluene. Upon standing, the oil crystallised to give 5.4 g.

(1 R,2F) (1 S,2S))-i -(4-hydroxyphenyl)-4,4,4-trifluorobutane; m.p. 154 - 1 56'C.

c) 5.4 g. of the hydroxy compound obtained in Example 9 b) in 80 ml. butanone was mixed with 6 g.

N,N-dimethylaminoethyl chloride hydrochloride and 6 g. sodium carbonate. The reaction mixture was heated under reflux, with stirring, for 18 hours, cooled and poured into water. Extraction with diethyl ether gave an oil which was triturated with water, whereafter the supernatant liquid was decanted off. The insoluble residue was taken up in diethyl ether and the ethereal solution dried over anhydrous sodium sulphate and charcoaled. After removing the solvent, there were obtained 5.2 g. (1R,2R) (1 R,2R) (15,25)-i ,2-di-(4- fluorophenyl)-1 -[4-(ss-dimethylaminoethoxy)-phenyl]-4,4,4-trifluorobutane.

d) A solution of 5.2 g. of the amine obtained in Example 9 c) in 30 ml. acetone was added to a solution of 2.4 g. citric acid in 30 ml. acetone and the solution then evaporated to dryness. Crystallisation of the residue from ethanol/diethyl ether(l :15 v/v) gave 5.1 g. (1R,2R) (1 S,2S)-1,2-di-(4-fluorophenyl)-l-[4-(P- dimethylaminoethoxy)-phenylj-4,4,44rifluorobutane citrate; m.p. 139 - 141 'C.

Example 10 A solution of 12g. trans- 1,2-diphenyl-1 -(4-hydroxyphenyl)-4,4,4-trifluorobut-1 -ene (see Example le)) in 120 ml. butanone,15g. N-(2-chloroethyl)-piperidine hydrochloride and 15g. sodium carbonate were heated under gentle reflux for 4 hours, while stirring. After cooling, the reaction mixture was filtered and the filtrate evaporated to dryness. The residue was triturated with dilute hydrochloric acid and centrifuged. The supernatant solution was decanted off and centrifuging repeated twice with distilled water. The residue was treated with a 1% aqueous solution of sodium hydroxide and then extracted with diethyl ether.The ethereal extract was evaporated and the residue crystallised from diethyl ether- petroleum ether (b.p. 40-60"C.) (1 :1 v/v) to give 139. pure trans- 1 ,2-diphenyl-1 -[4-(-piperidino-ethoxy)-phenyl]-4AA4nfiuornbut-1 -ene; m.p.

107-108"c.

10g. of the base thus obtained in 200 ml. dry diethyl ether were treated with excess ethereal hydrochloric acid. The precipitated hydrochloride was filtered off, washed with diethyl ether and crystallised from hot acetone to give 10.5 g. trans-1 ,2-diphenyl-1-[-4-(ss-piperidinoethoxy)-phenyl]-4,4,4-trifluorobut- 1 -ene hydrochloride; m.p. 206-208"c.

As mentioned above, the present invention also includes within its scope pharmaceutical compositions containing at least one of the new compounds according to the present invention, in admixture with a solid or liquid pharmaceutical carrier.

Solid compositions for oral administration include compressed tablets, pills, dispersible powders and granules. In such solid compositions, one of the new compounds is admixed with at least one inert diluent, such as calcium carbonate, starch, alginic acid or lactose. The compositions may also comprise, as is normal practice, additional substances other than inert diluents, for example, lubricating agents, such as magnesium stearate.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the art, such as water and liquid paraffin. Besides inert diluents, such compositions may also comprise adjuvants, such as wetting and suspension agents, and sweetening and flavouring agents.

The compositions according to the present invention, for oral administration, include capsules of absorbable material, such as gelatine, containing one of the new derivatives, with or without the addition of diluents or excipients.

Preparations according to the present invention for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions or emulsions. Examples of non-aqueous solvents or suspending media include propylene glycol, polyethylene glycol, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. These compositions may also contain adjuvants, such as wetting, emulsifying and dispersing agents. They may be sterilised, for example, by filtration through bacteria-retaining filters, by incorporation into the compositions of sterilising agents, by irradiation or by heating. They may also be produced in the form of sterile solid compositions, which can be dissolved in sterile water or some other sterile injectable medium immediately before use.

The percentage of active material in the compositions of the present invention may be varied, it being necessary that it should constitute a proportion such that a suitable dosage for the desired therapeutic effect shall be obtained. In general, the preparations of the present invention should be administered orally or parenterally to humans to give 1 to 100 mg. and preferably 10 - 50 mg. of active substance per day.

The following Examples illustrate pharmaceutical compositions according to the present invention: Example 11 200 mg. tablets are prepared containing: trans -[4-(X-piperidinoethoxy)- phenyl]-1 -(4-fluorophenyl)-2-phenyl 4,4,4-trifluorobut-1 -ene citrate 15 mg.

starch 90 mg.

lactose 95 mg.

magnesium stearate 5 mg.

Example 12 200 mg. tablets are prepared containing: trans-1 -[4-ss-dimethylaminoethoxy)- phenyl]-1 ,2-diphenyl-4,4,4- trifluorobut-l-ene citrate 15 mg.

starch 90 mg.

lactose 95 mg.

magnesium stearate 5 mg.

Example 13 200 mg. tablets are prepared containing: trans-i -[4-(-dimethylam inoethoxy)- phenyl]-1 -phenyl-2-(4-fluorophenyl)4,4,4-trifluorobut-1 -ene citrate 15 mg.

starch 90 mg.

lactose 95 mg.

magnesium stearate 5 mg.

The compositions according to Examples 10 to 12 are intended for oral administration to humans for the management of breast cancer and also to stimulate ovulation in infertility.

Claims

1. 1,1,2-Triphenylethane and -ethylene derivatives of the general formula:

wherein R1 is a methyl, ethyl or ss,ss,ss-trifluoroethyl radical, R2, R3 and F4, which can be the same or different, are hydrogen or halogen atoms, Rg and R6, which can be the same or different, are hydrogen atoms or alkyl radicals containing up to 6 carbon atoms or F5 and R6, together with the nitrogen atom to which they are attached, represent a heterocyclic radical and R7 and F8 are both hydrogen atoms or R7 and F8 together represent a further valency bond, with the proviso that when R1 is a methyl or ethyl radical, R4 is a halogen atom; and the pharmacologically-acceptable acid-addition salts thereof.

2. trans-i -[4-(-Dimethylaminoethoxy)-phenyIj-1 ,2-diphenyl-4,4,4-trifluorobut-1 -ene and the citrate thereof.

3. trans -[3-Fluoro-4-(ss-dimethylaminoethoxy)-phenyl]-1 ,2-diphenyl-4,4,4-trifluorobut-1 -ene and the citrate thereof.

4. trans-1-[3-Fluoro-4-(ss-dimethylaminoethoxy)-phenyll-1,2-diphenylbut-1-ene and the citrate thereof.

5. trans-i -[4-((3-Dimethylaminoethoxy)-phenyl-1 -(44luorophenyl)-2-phenyl-4,4,4-trifluorobut-1 -ene and the citrate thereof.

6. trans-i -[4-(p-Dimethylaminoethoxy)-phenyl]-1 -phenyl-2-(4-fluorophenyl)-4,4,4-trifluorobut-1 -ene and the citrate thereof.

7. trans-i -[4-(Dimethylaminoethoxy)-phenyI]-1 ,2-di-(44luorophenyl)-4,4,4-trifluorobut-1 -ene and the citrate thereof.

8. trans-1-[4-(-Piperidinoethoxy)-phenyl]-1 -(44luorophenyl)-2-phenyl-4,4,4-trifluorobut-1 -ene and the citrate thereof.

9. (IR,2R), (1S,2S)-1-(4-Fluorophenyl)-1-[4-(ss-dimethylaminoethoxy)-phenyl]-2-phenyl-4,4,4- trifluorobutane ands the citrate thereof.

10. (1 R,2R),(1 S,2S)-1,2-Di-(4-fluorophenyl)-1 [4-(ss-dimethylaminoethoxy)-phenyl]-4,4,4-trifluorobutane and the citrate thereof.

11. trans-i ,2-Diphenyl-1 -[4-(-piperidinoethoxy)-phenyl]-4,4,4-trifiuorobut-1 -ene and the hydrochloride thereof.

12. Process for the preparation of compounds of the general formula given in claim 1, in which R7 and R8 together represent a further valency bond, wherein the cis or trans isomer of a butene derivative of the general formula:

in which R1, R2, R3 and R4 have the same meanings as in claim 1, is reacted with a (3-(N,N-dialkylamino)-ethyl halide acid-addition salt.

13. Process for the preparation of compounds of the general formula given in claim 1, in which R7 and F8 are both hydrogen atoms, wherein a cis or trans isomer of a butene derivative of the general formula given in claim 12 is reduced to give the corresponding butane derivative, followed by reaction with a dialkylamino)-ethyl halide acid-addition salt.

14. Process according to claim 12 or 13, wherein the butene derivative used as starting material is prepared by reacting a phenylacetic acid compound of the general formula:

in which R2 has the same meaning as in claim 1, with an anisole derivative of the general fomrula:-

in which R4 has the same meaning as in claim 1, to give a deoxybenzoin derivative of the general formula::

in which R2 and R4 have the same meanings as in claim 1, which is reacted with sodium hydride and an alkyl halide of the general formula R1-Hal, in which R1 has the same meaning as in claim 1 and Hal is a halogen atom, to give an a-substituted desoxybenzoin derivative of the general formula:-

in which R1, R2 and R4 have the same meanings as in claim 1, which is demethylated to give the correspondinq phenol of the aeneral formula:

in which F1, R2 and R4 have the same meanings as above, which is then reacted with a Grignard reagent of the general formula::

in which F3 has the same meaning as in claim 1 and Hal is a halogen atom to give a carbinol of the general formula:

in which F1, R2, F3 and R4 have the same meanings as in claim 1, which is dehydrated to give the corresponding ethylene derivative of the general formula:

in which R1, R2, R3 and R4 have the same meanings as in claim 1, which is separated into its cis and trans isomers by fractional crystallisation of the isomeric acetate mixture, followed by deacetylation of the individual isomers.

15. Process according to any of claims 12 to 14, wherein the product obtained is reacted with a non-toxic inorganic or organic acid to give the corresponding acid-addition salt.

16. Process for the preparation of compounds according to claim 1, substantially as hereinbefore described and exemplified.

17. Compounds according to claim 1,whenever prepared by the process according to any of claims 12 to 16.

18. Pharmaceutical compositions comprising at least one compound according to claim 1, in admixture with a solid or liquid pharmaceutical diluent or carrier.