CA1207799A - 1,1,2-triphenylbut-1-ene derivatives - Google Patents

Abstract

Abstract of the Disclosure Novel (E)-1-[4'-(2-alkylaminoethoxy)phenyl]-1-(3'-hydroxyphenyl)-2-phenylbut-1-enes of the general formula wherein R1 and R2 may be the same or different, provided that, when R1 and R2 are the same, each of them is a methyl or ethyl radical, and when R1 and R2 are different, one of them is hydrogen and the other is a methyl or ethyl radical and the therapeutically compatible salts thereof, have a marked anti-estrogenic effect and are suitable for treating hormone-dependent mammary tumors.
The compounds can be prepared by dehydrating carbinols of the general formula wherein R1 and R2 may be the same or different, provided that, when R1 and R2 are the same, each of them is a methyl or ethyl radical, and when R1 and R2 are different, one of them is a benzyl radical and the other is a methyl or ethyl radical; and wherein R3 is hydrogen or an easily hydrolyzable protecting group, through the action of mineral acid while removing any protecting group present, isolating through crystallization the E-form from the pair of isomers obtained, and removing by hydrogenolysis any benzyl group present.
Compositions comprising the subject 1,1,2-triphenylbut-l-ene derivatives are described also.
The corresponding novel 1,1,2-triphenylbut-1-ene derivatives having the (Z) configuration are also disclosed.

Description

1,1,2-TRIPHENYLBUT-l-ENE DERIVATIVES

Field of the Invention:
The invention relates to novel 1,1,2-triphenylbut-l-ene derivatives having valuable therapeutic properties, and to compositions containing said derivatives. The compounds have a marked anti-estrogenic effect and are useful in the treatment of hormone-dependent mammary tumors.
Background Art:
10Compounds having this basic structure and a dialkylaminoalkoxy radical in para position to one of the phenyl radicals on the C-atom 1 of the but-l-ene chain are already described in Rritish Patent Specification No. 1,013,907. One of them, the (Z)-l-15[4'-(2-dimethylaminoethoxy)phenyl]-1,2-diphenylbut-1-ene (tamoxifen, INN rec.) is a specific estrogen ~ antagonist. By virture of its marked anti-estrogenic activity, this active ingredient has already prcved successful in the therapy of hormone-dependent mammary tumors.
German Offenlegungsschrift No. 2 807 599 has disclosed that a metabolite of tamoxifen, the (Z)-l-[4'-(2-dimethylaminoethoxy)phenyl]-1-(4'-hydroxyphenyl)-

2-phenylbut-1-ene ("4-hydroxytamoxifen") hac an anti estrogenic effect comparable to tamoxifen. As reflected by European application No. 0 002 097, this also applies to a series of 1-[4'-(2-alkylaminoalkoxy)phenyl]-1-[4'-hydroxyphenyl)-2-phenylbut-1-enes ("4-hydroxytamoxifen derivatives").

.

77~

srief Summary of the Inven tion It has now surprisingly been found that by moving the hydroxy group from position 4 to position 3, compounds are obtained whose E-forms are clearly superior to tamoxifen in respect of binding affinity to the estrogen receptor. sy virtue of this high specific affinity to the estrogen receptor, the compounds of the present invention exhibit not only marked anti-uterotrophic activity but also an inhibitory effect on mammary tumors, which, as is shown by the example of compound 1 hereinbelow, is above the activity of tamoxifen. 1,1,2-Triphenylbut-l-ene derivatives of the general formula (1) below, whose configuration includes the E-form and the Z-form, but preferably corresponds to the E-form, their preparation, their use and compositions containing same, comprise the subject matter of the present invention.

O--C~2CH2N'\ ~2 (1) HC

In formula (1) r Rl and R may be the same or different, provided that, when Rl and R are the same, each of them is a methyl or ethyl radical, and when Rl and R are differen~, one of them is hydrogen and the other is a methyl or ethyl radical. Specific compounds encompassed by formula (1) are as follows:

g _ 1 2 Compound No. RR M.P. Example 1 CH3 CH3 162 to 163C 1 h 2 C2~I5 C2H5 121C 2 a . ' CH3 H 125 to 127C 3 _ C~ g ~ 17~ ~o 175C .
~w__ Detailed Descri~tion of the Invention:
In this specification, the designations E and Z-- forms relate to the position of the 3-hydroxyphenyl group (priority 1) on ~he C-atom 1 with respect to the position of the unsubstituted phenyl group (priority 1) on the C-atom 2 of the double bond [nomenclature rule: R . T . Morrison, R.N. Boyd, Lehrbuch der Organischen Chemie, Verlag Chemie, p. 167 (1974)].
The E and Z-forms are clearly distinguished by the resonance signals of the protons in the alkylamino group and in the -O-CH2- group of the -OCH2CH2NRlR2 side-chain. In the instant compounds, the signals of the E-form occur at higher field than those of the Z~form [D.J. Collins, J.J. Hobbs and C.W. Emmers, J.
Med. Chem., 14, 952 11971)].
.

9~

Characteristic distinguishing features of the novel E and Z-forms of 1-[4'-(2-dialkylaminoethoxy)phenyl]-1-(3'-hydxoxyphenyl)-2-phenylbut-1-ene compounds are indicated in Table 2 below~

~ABLE 2 ~1 R2 Isomer M.P. Slgnals ._ ~
~ethyl E form 162 to 163 N(CH 3 2.17 (Example 1 h) oCH-3 2 3 88 __. .. . ~
~ethyl 15 (Example I i) Z-~orm l73 o(H-332 4 05 ethyl (Example 2 a) E-form 121 N(CH2CH3~2 3 90 . _ ethyl (Example 2 b) Z-form 156 N(OEIZCE3)2 1.01 The present invention further provides a method of preparing an isomeric mixture of E-form and Z-form of compounds of the general formula (1~, which comprises dehydrating carbinols of the general formula (2) :p ~ ;

7~
~5--R
o-CH2CH2N ~ ~2 ~3 (2) R3-~

1~

wherein R and R may be the same or different, provided that, when R and R are the same, each of them is a methyl or ethyl radical, and when Rl and R~ are different, one of them is a benzyl radical and the other is a methyl or ethyl radical; and wherein P~3 is hydrogen or an easily hydrolyzable protecting group, in a manner known per se, through the action of mineral acid.
Optionally, with removal of the protecting group, the ~form of compound may be isolated from the pair of isomers obtained and removing any benzyl group present by hydrogenolysis. The tetrahydropyranyl group is preferred as an easily hydrolyzable protecting group. The removal of the protecting group and dehydration is achieved with mineral acid in an alcoholic medium, preferably in hydrochloric ethanolic solution. The isolation of the E-form by crystallization can be performed both with the acid-addition salts and with the free bases. Any ben~yl group removal can be performed selectively by hydrogenolysis at room temperature with palladium-on-carbon.
By way of illustration, the compounds of the invention can be prepared as follows:
The starting compound of formula (3) ~.~

'7~

CN30 ~ ~-CN~ ~ ~3~

can be obtained by Friedel-Crafts reaction of methoxy-benzene with phenylacetyl chloride. By reacting 1-(4'-methoxyphenyl)-2-phenylethan-1-one (3) with ethyl bror.1ide in dimethylfor.mamide and in the presence of sodium hydride, 1-(4'-methoxyphenyl)-2-phenyl-n-butan l-one (4) CN30 ~ ~-IN ~ (4 .
is obtained. An ether cleavage of (4) with pyridine hydrochloride leads to 1-~4'-hydroxyphenyl)-2-phenyl-n-butan-l-one ~5) HO~--~H~3 (5) ~H3 .

By reacting (5) with compounds of the general formula R R N-CH2CH2Cl (6) wherein R1 and R may be the same or different, provided that, when R and R are the same, each of them is a methyl or ethyl radical, and when s R and R are different, one of them is a benzyl radical and the other is a methyl ox ethyl radical, compounds of the general formula (7) RlR2N-CH2CH20 ~ ~-~H ~ (7) are obtained, wherein Rl and R2 are as defined in conjunction with formula (6) abovec Compounds of the general formula ~7) are then reacted with 3'-(2-tetrahydropyranyloxy)phenyl magnesium bromide to form the diastereomeric carbinols of tho general formula . 10 (8) ~ o ~ ~8) wherein Rl and R2 are as defined in conjunction with formu~s (6) and (73. In the presence of mineral acid, compounds of the general formula (8) spli. off the tetrahydropyranyl group readily at room temperaturè and dehydrate under the influence of heat to form a pair of isomers, from which the E-isomer can be isolated by crystallization in both its salt and its base form, the benzyl radical of said E-isomer being removed by ~2~'77~3 hydrogenolysis in the event that any benzyl radical is present, to give compounds of the general formula (1) hereinabove.
Equivalent to the compounds of formula (1) for the purposes of the present invention are the therapeutically compatible salts thereof. Such salts are typically the corresponding acid addition salts formed, for example, from non-toxic, pharmaceutically acceptable inorganic or organic acids, e 7 g. by conventional chemical methods. Such acid addition salts include, for e~ample, ~hose derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoxic, nitric and the like; and those prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tart~ric, citric, ascorbic, pamoic, maleic, hydroxymaleic/ phenylacetic, glutamic, benzoic, salicylic, sulfanilic, fumaric, toluenesulfonic, and the like.
In the tests conducted, ~he compounds of thQ present invention have been found to have a high, therapeutically useful, anti-estrogenic effect.
- The determination of the binding affinity to the estradiol receptor was made using rabbit uterus cytosol.
In comparison to tamoxifen, the claimed compounds ~5 exhibited approximately ten times higher binding affinity.
The anti-uterotrophic effect was not measured, as is customary, after prepuberal female rats had been treated with active ingredient fox three days (Dorfman `

test). A hormonal counter-regulatory reaction is not to be expected of prepuberal animals within this short txeatment time and therefore nothing definite can be said about the anti-estrogenic properties of the active ingredient administered. ~or this reason, puberal female rats were s~jected to treatment with active ingredient for three weeks. In this tes~ the claimed compounds exhibited a marked antiuterotrophic effect, partly above the activity of tamoxifen.
To measure the inhibitory effect on the ma~nary tumor, compound 1 ("3~hydroxytamoxifen") was selected from the instant substances and compared with tamoxifen under the same test conditionsO The claimed compound proved to be clearly superior to tamoxifen in the inhibitory activity on the tumor.
The compounds according to the invention are thus a valuable contribution to the store of pharmaceutical preparations and can above all be used for treating ma~mals having malignant mammary tumors.
The present invention moreover relates to compositions comprising a compound of the general ; formula (1) or therapeuti~ally compatible salt thereof as active ingredient and a nontoxic ph~ceutically acceptable carrier therefor, e.g. one or more of the conventional ~5 pharmaceutical carriers and adjuvants. The active ingredient is present in an effective amount (an anti-estrogenically effective amount, an anti-uterotrophically effective amount, or a tumor-inhibiting effective amount).

The claimed compounds are preferably administered orally. As a rule, the daily oral dose is 0.01 to 0.2 g., preferably 0.02 to 0.1 g., for a mammal weighing approximately 70 kg. Nevertheless, it may be necessary to depart from said amounts, depending on the individual response to the medicament, the nature of its formulation and the time or interval at which it is administered. Thus, in some cases it may be sufficient to manage with less than th~ above-mentioned lower amount, while in other cases the upper limit ~entioned above has to be exceeded. If larger quantities are administeredj it may be advisable to divide them into several single doses spread over the day.
The active ingredients can be processed for oral administration in conventional form, e.g. as capsules, tablets or dragees. By mixture with solid, powdery carriers, such as potato starch or corn starch, with additives such as sodi~ ci~ra~e or calcium carbonate and bindi~g agents such as polyvinyl pyrrolidone, gelatin or cellulose derivatives, optionally with the addition of lubricating agents such as magnesium stearate, sodium lauryl sulfate or polyethylene glycols, they can be processed into tablets or dragee cores. Naturally, for the forms of oral administration, masking flavoring may be added.
Further suitable orms of administration are telescopically joinable capsules made, for instance, of hard gelatin, as well as closed soft gelatin capsules containing a softening agent, e~g. glycerin.

77~1~

The telescopically joinable capsules contain the active ingredient preferably as granules, e.g. mixed with fillers such as lactose, saccharose, mannitol, starches such as potato starch or amylopectin, cellulose derivatives or highly disperse silicic acids.
In soft gelatin capsules, the active ingredient is preferably dissolved or suspended in suitable liquids, e.g. in plant oils or liquid polyethylene glycols.
, Without further elaboration, it is believed that one of ordinary skill in ~he ar~ can, using the pre ceding description, practice the present invention to its fullest extent. Therefore, the following examples are to be construed as merely illustrative and not limitative of the remainder of the specification and lS claims in any way whatsoever.

.. _ 1-[4'-Dimethylaminoethoxy)phenyl]-1~(3'-hydroxyphenyl)-2-phenylbut l-ene PreParation of the Precursors a) 1 (4'-Methoxyphenyl)-2-phenx~ethan-1-one To 10.8 g. (0.10 mole) methoxybenzene and 1309 g.
(0.09 mole) phenylacetyl chloride in 1.0 1. methylene chloride there are added, by small amounts, 13.3 g.
~0.10 mole) aluminium chloride at room temperature and with strong agitation. The reaction mixture is agitated fox a further 2 hours and then is poured onto ice and 50 ml. hydrochloric acid are added. After separation of the organic phase, the aqueous solution is shaken out twice with 5QO ml. methylene chloride each time, the combined organic phases are washed with water and the solvent is removed ln vacuo. The sm~ary residue is freed of the vola~ile components by steam distillation and the remaining solid is crystallized from ethanol after filtration and washing with water.
Obtained are colorless crystals having a melting point of 75C; Rf 0.7 [CHC13/CH30H (9/1)]; yield. 18.3 g.
10 (90~6).

15 142 ~226.2) H~NMR spectrum*
(CDC13) : 3.77 s ~3) OCH3 4.18 s (2) CH2 6.87 d (2) aromatic H [J=~.O]
7.2 s (5) aromatic H
7.97 d (2) aromatic ~ [J~9~0]
.
*taken at 60 ~z;
chemical shifts quoted in ppm using TMS as standard (~=0.0); relative intensities added in parentheses;
s = singlet; d = doublet: t = triplet; m = multiplet;
J = coupling constant in Hz.
~ .
b~ 1-(4' Methoxyphen~1)-2-phenyl-n butan-l-one 2.4 G. (0.10 mole) sodium hydride are suspended in 300 ml. nitrogen-saturated/ anhydrous dimethylformamide . -~Z~77~

and after the slow addition of 22.6 g. (0.10 mole) 1-(4'-methoxyphenyl)-2-phenylethan-1-one in 50 ml.
anhydrous diMethylformamide, are agitated for a further hour at 40C. Then 13.1 g (0.12 mole) ethyl bromide in 50 ml. anhydrous dimethylformamide are added dropwise at 30~C with agitation for a further 2 hours. To the reaction mixture is added 100 ml. water, and the resultan~ mixture is then shaken out twice . with 250 ml. e~her each time and the collected ether phases are carefully washed with water~ After drying over sodium sulfate, the ether is removed in vacuo and the residue is crys~alliæed from ethanol. Obtained are colorless crystals having a melting point of 44C;
Rf 0.55 (CH2C12); yield: 24.7 g. (97~).

17 182 (254.3) -NMR' spectrum (CDC13) : 0.87 t (3) CH3 [J=7.0]
1.50 to 2.53 m (2) CH2

3.70 s ~3) OCH3

4.38 t (1) CH [J=7.2]
6.80 d (2) aromatic H
~J=9~0]
7.23 s (5) aromatic H
. 7.96 d (2) aromatic H
[J=9.0]

7~9 c) 1-(4'-~x_rox~ nyl)-2-phenyl-n-butan-1-one 25.4 G. (0.10 mole) 1-(4'-methoxyphenyl~-2 phenyl-n-butan-l one and 34.5 g. (0.30 mole) pyridin~
hydrochloride are melted and refluxed at 220C for one hour while being agitated. The melt while still liquid is poured into ic water and the precipitate dissolved in 400 ml. ether. After washing the etheric solution with water, i~ is shaken out with 1 N sodium hydroxide solution. The aqueous alkaline solution is - 10 acidified with 5 N hydrochlc~ric acid and extracted with 500 ml. ether. The organic phase is washed with water and dried over sodium sulfate. The solvent is removed in vacuo and the crude product is cyrstallized from dilute ethanol. Obtained are colorless crystals having a melting point of 131C; Rf 0.45 ~toluene/ethyl acetate (9/1)], yield: 16.3 g. (68%).

C16H162 ~240.3) 1H-NMR spectrum (d6 acetone): 0085 t (3) CH3 [J=7.0]
1.37 to 2.50 m (2) CH2 2~73 to 3.47 wlde(l) OH [exchangeable with D2O3 ` 4.60 t (1~ CH ~J=7.6]
6.87 d (2) aromatic H [J=9.0]
7.33 s (5) aromatic H
8.00 d (2) aromatic H [J=9.0]

~ 7~

; - 15 -d) 1-[4'-~2-Dimethylaminoethoxy)phenyll-2-phenyl-n butan-1-one 2.76 G. (0.12 mole) sodium are dissolved i~ 100 ml.
anhydrous ethanol and 24 g. (0.19 mole) 1-(4'~hydroxy~
phenyl)-2-phenyl-n-butan-1-one are added. To the solution there are slowly added, at reflux temperature, 21.4 g (0.20 mole) dimethylaminoethyl chloride in 150 ml. toluene and the reaction mixture is refluxed for a further 8 hours. After cooling and separation of the insoluble components, the solvent is removed in vacuo and the residue is dissolved in 500 ml. ether.
The etheric solution is shaken out several times with 2 N sodium hydroxide and then washed with wa~er. After drying over sodium sulfate, the ether is removed in vacuo. There is obtained a colorless oil; Rf 0.25 [CHC13/CH30H (9/1)]; yield 19.3 g. (62~).

20 25N2 (311.4) lH-NMR spectrum 20 (CDC13) : 0.88 t (3) CH3 [J=7,0]
1~53 to 2.83 m ~2) CH2 2.28 5 (6) N(CH3)2 2.67 t (2) NCH2 [J=6 D O]
4.03 t (2) OCH2 [J=6.0]
` 25 4.40 t ~1) C~ [J=7.6]
6.87 d (2) aromatic H
[J=8.4]
7.23 s (5) aromatic H
7.97 d (2) aromatic H
[J=8.4]

~77~3 e) 1-~4'-(2=Dimethylaminoethoxy)phenyll-2-~henyl-1-[3'-~2-tetrahvdrop~ranyloxy)phenyll-n-buta~-1-ol [diastereomers]
To 42O2 g. (0.15 mole) 3'-~2-tetrahydropyranyloxy)-phenylmagnesium bromide in 200 ml. anhydrous tetrahydrofuran are carefully added 31.1 g. (0.10 mole) 1-[4'-(2-dimethylaminoethoxy)phenyl~-2-phenyl-n-butan-l-one in 100 ml. anhydrous tetrahydrofuran, and the mixture is then refluxe~ for 2 hours. The cooled reaction solution is added to 150 ml. saturated, aqueous ammonium chloride solution and shaken out with 100 ml.
ether. ~he organic phase is washed with water and, after dr~ing over sodium sulfate, the solvent is removed ln vacuo. The oily residue is freed o~ impurities by chromatography on a column of silica gel with chloroformjmethanol (9/1), and the pure diastereomeric fraction is crystallized from petroleum ether. There are thus obtained colorless crystals having a melting point of 56C; R~ 0.50 ~CHC13/CH30H ~9/1)]; yield 29.9 g.
(61~.

31H39N4 (48g.7) calculated C 7Ç.04 H B.03 N 2.86 found C 76.28 H 7.92 N 2.79 Mol. wt. 489 (determined by mass spectrometry~
IR spectrum (KBr): v(O-H) 3600 to 3100 cm 1 lH-NMR spectrum (d6 DMSO) : 0.6 wide t (3) CH3 1.23 to 1.97 m (8) CH2 2.20 s (6) N(CH3)2 2.37 to 2.77 t (2) NCH2 3.27 to 4.03 m (6) CH, 2xOCH2, OH

5.45 wide s (1) OCH

6.40 to 7.43 m (13) aromatic H

~'7~9 f) 1-~4'-(2-Dimethylaminoe~hox )pheny1]-1-(3'-hydxoxy-phenylj-2-phenyi-n-butan-1-ol [diastereomers]
To 49.0 g. (0.1 mole~ of the pure diastereomeric fraction of 1-[4'-(2 -dimethylaminoethoxy)phenyl]-2-5 phenyl-1-[3'-(2-tetrahydropyranyloxy)phenyl]-n-butan-1-ol in 500 ml. ethyl acetate ~here are added,at room temperature, 200 ml. 1% aqueous hydrochloric acid and the mixture is strongly shaken. The emulsion is neutralized with 5% agueous ammonia solution and, after settliny, the aqueous phase is separated. The organic phase is washed with water and, after drying over sodium sulfate, the solvent is removed in vacuo. The residue is crystallized from ether/petroleum ether (l/l)o Obtained are colorless crystals of the diastereomeric lS mixture having a melting point of 59 to 60C; Rf 0.35 [CHC13/CH30H (7/3~]; yield 36.5 g. (90%).

26 31NO3 (405.5) calculated C 77.01 H 7.70 N 3.45 found C 76.81 H 7~86 N 3.38 Mol. wt. 405 (determined by mass spectrometry) IR spectrum (KBr) : v(O-H~ 3600 to 2400 cm 1 H-NMR spectrum (d6 acetone) : 0.7 t CH3 [J=7.8]
0.87 t CH3 [J=7.6]
1.43 m CH2 2.23 s N(CH3~2 2.30 s N(CH3)2 2~37 to 2.87 m NCH2 3.47 to 4.40 m OCH2, CH
6.20 to 7.73 m aromatic H

g) Preparation according to the invention (E) -1-[4'-(2-Dimethylaminoethoxy)pheny1~
(3~ xy~henyl)-2-phenylbut-1-ene Hydrochloride 40.5 G, (0.1 mole) of the diastereomeric mixture of 1-[4'-(2-dimethylaminoethoxy)phenyl]-1-(3'-- hydroxyphenyl)-2-phenyl~n-butan-1-ol in 500 ml. ethanol are added to 25 ml. concentrated hydrochloric acid and refluxed for 2 hours. Then the solvent is removed ( in vacuo and the residue is crystallized from methanol/
ether (1/1). Obtained are colorless crystals having a melting point of 221C (dec.); R~ 0.25 ~CHC13/CH3OH
(7/3~]; yield 20.3 g. (48~).

C26H30ClN2 (423.9) IR spectrum (KBr) : v~O-H, NH) 3650 to 2600 cm 1 H-N~R spectrum (d4-methanol) : 0.9 t (3) CH3 [J=6.0]
2~5 q (2) CH2 [J=6.0]
2.97 s (6) N(CH3)2 3 5 t (2) NCH2 [J=5.0]
4.27 t (2) OCH2 [J=5.0]
6.53 to 7.30 m (13) aromatic H

~. .

7~9 h) Pr~aration according to the invention (E)-1-[4'-(2-Dimethylaminoethoxy)phenyl]-1~(3'-hydroxyphenyl?-2-phei~ylbut-1-ene 42.~ G. (0.1 mole) (E)-1-[4'-(2-dimethylaminoethoxy)-phenyl]-1-(3'-hydr~xyphenyl)-2-phenylbut-1-ene hydxochloride are suspended in 200 ml. dilute ammonîa solution and shaken ou~ twice with 250 ml. ethyl acetate each time. The organic phase is washed neutral with water andl after drying over sodium sulfate, the solvent is removed ln vacuo. The residue is crystallized from ether. Colorles~ crystals having a melting point of 162 to 163C are obtained;
R~ 0.40 [CHC13/CH30H (7/3)]; yield- 37.2 g. ~96%).

C26H29N2 (387.5) calculated C 80.59 H 7.54 N 3.61 found C 80.50 H 7.60 N 3.55 Mol. wto 387 (detenmined by mass spectrometry) XR spectrwm (KBr~ : v(O-H) 3650 to 3100 cm 1 1H-NMR spectrum :(d6-DMSO) O. 83 t (3) CH3 [J=6 . O]
2.17 s (6~ NlCH3)2 2.27 to 2.73 m (4) CH2N, CH2CH3 3.88 t ~2) OCH2 [J=5.8]
6.40 to 7.37 m ~13) aromatic H
9.37 s (1) OH
[exchangeable with D2O]

, 77g9 .

i) (Z)-l-[4'-(2-Dimethylaminoethoxy)phenyl~
3 -hydroxyphenyl]-2-phenylbut-l-ene The residue of the mother liquor of the crystals ~rom Example l g is suspended in 200 ml. dilute ammonia solution and shaken out twice with 250 ml. ethyl acetate each time. The organic phase is washed with water and, after drying over sodium sulfate, the solvent is removed in vacuo. The residue is crystallized __ __ several times from methanol/water (1/l). Colorless crystals having a melting point of 173 C are obtained;
Rf 0.40 [CHC13/CH30H (7/3)]; yield: 7.7 g (20%).

26 29N2 1387.5) calculated C 80.59 H 7.54 N 3.61 found C 30.41 H 7.53 N 3.56 Mol. wt. 387 (determined by mass spectrometry) IR spectrum (KBr) : V(O-H) 3650 to 3100 cm 1 1H-NMR spectrum ~d6-DMSO) : 0.85 t (3) CH3 [J-6.4]
2.23 s (6~ N(CH)3 2.30 to 2.80 m (4) CH2N, CH2CH3 4.05 t ~2) OC~ [J=5.8]
6.10 to 7.33 m (13) aromatic H
9.03 s (l) OH
[exchangeable with D2O]

EXAMPLE 2 a ~ = _ Pre~aration accord ng to the invention (E)-1-[4'-(2-Diethylaminoethoxy)phenyl]-1-(3'-hydroxy~hen ~ but-~-e _ 51.8 G. (0.1 mole) of the pure aiastereomeric fraction, prepared analogously to Example le, of 1-[4'-(2-diethylaminoethoxy)phenyl~-2-phenyl-1 [3'-(2-tetrahydropyranyloxy)phenyl]-n-butan-1-ol [light yellow oil; Rf 0.65 CHC13/CH30H (9/1)] in 500 ml.
ethanol are added to 25 ml. concentrated hydrochloric acid. The mixture is ~hen refluxed for 2 hours and treated as described in Examples 1 g to 1 h. There are thus obtained colorless crystals having a melting point of 121C [CH3OH/H2O (1/1)], Rf 0.30 15 : rcHcl3/cH3oH (7/3)]; yield 10.4 g. (25%).

28 33NO2 (415.6) calculated C80.91 H 8000 N 3.37 found C81.06 H 8.07 N 3.28 Mol. wt. 415 (determined by mass spectrometry) IR spectrum (KBr) : v(O-H) 3600 to 3100 cm 1 H-NMR spectrum (d6-DMSO) : 0.87 wide t (3) CH3 0.37 t (6) N(CH2CH3)2 [J=7.0]
2.20 to 2.87 m (8) CH2N(CH2)2, C~12CH3 3,90 t (2) OCH2 [J=7.0]
6.27 to 7.37 m (13)aromatic H
25 . 9.20 wide s (1) O~
[exchangeable with D2O]

~Z~7~

EXAMPLE 2 b Z-1-[4'-(2-Diethylaminoetho~y)phenyl]-l-t3' phenyl)-2-phenYlbut-l-ene Obtained in analogous fashion to the product of Example 1 i are colorless cyrstals having a melting point of 156C ~methanol/water (1/1)]; Rf 0.30 ; [CHC13/CH30H (7/3)]

C28H33N2 (415.6) calculated C 80.91 H 8.00 N 3.37 found C 80.78 H 8.00 N 3.26 Mol. wt. 415 (determined by mass spectrometry) IR spectrum ~KBr) : v~}H~3600 to 3100 cm 1 ~-NMR spectrum (d6~DMSO) : 0.90 wide t (3) CH3 1.01 t (6) N( ~ CH3~2 [J=7.0]
2.17 to 3.00 m (8) CH2N(C ~), _2C 3 4.03 t (2) OCH2 ~J=7.0]
6.17 to 7.33 (13) aromatic H

8.87 wide s (1) OH
[exchangeable with D2O]

~.2~

Utilizing the appropriate starting materials and following the ~enexal pro~edures detailed hereinabove,the following additional compounds of the invention are obtained:

(E)-1-(3'-Hy roxyphenyl)-1-[4'-(2-methylamino-ethoxv)PhenYl[-2-Dhenvlbut-l-ene ~ ~ , . .
The pxoduct is obt~ined as colorless crystals having a melting point of 125 to lZ7C ~ethanol);
Rf 0.15 [CH~3~H3O~ (7/3)]

C25H27N2 (373.5) calculated C 80.40 H 7.29 N 3.45 found C 80.55 H 7.32 N 3.61 Mol. wt. 373 (determined by mass spectrometry) R spectrum (KBr) : v(o H; N-H) 3600 to 2300 cm 1;
H-NMR spectrum ~d6-DMSO) : 0.83 t (3) CH3 [J=7.0]
2.13 to 2.70 m (2) CH2 2.30 s (3) NCH3 2.73 t 12) NCH3 [J=5.6~
! 3.83 t ~2) OCH2 [3-5.6]
6.40 to 7.43 m (13) aromatic H

~2r~7~

(E)-1-[4'-Eth~laminoethoxy)phenyl]-l-(3~-hydroxyphenyl) 2-phenylbut-1-ene -The product is obtained as colorless cyrstals having a melting point of 174 to 175C ~acetone);
Rf 0.15 CcHcl3/cH3o~ (7/3)]

26H29N2 (387.5) calculated C 80.59 H 7.54 N 3.61 found C 80.55 H 7.58 N 3.67 Mol. wt. 387 (determined by mass spectrometry~
IR spectrum (KBr) : v (O-H) 3600 to 3100 cm~l;
~ (N-H) 3300 cm~l, 1H-NMR spectrum : 0.85 ~ (3)CH3 [J~7.0]
(d6-DMSO) 0~98 t (3)CH3 [J=7.2]
2.13 ko 2. 73 m (4) NCH2CX3, 2.80 t (2) NCH2 [J=S.6]
3.90 t (2~ OCH2 [J=5.6]
6043 to 7.43 m (13~ aromatic H
. . .
.

7~

A pharmaceutical Preparation containing (E)-l-[4'-(2-dimethylaminoethoxy)phènyl]-l (3'-hydroxYPhenY1)-2-phenylbut-l-ene hydrochloride 21.88 G. powdered (E)-l-[4'-(2-dimethylamino-ethoxy)phenyl] l-(3'-hydroxyphenyl)-2-phenylbut-1-ene hydrochloride are mixed with 40 g. lactose and 140 g.
starch. There are then added 33 g. talcum and 13 g.
calcium stearate. After having been carefully mixed, the resultant mixture is filled into two thousand hard gelatin capsules of a suitable size, each containing lO mg. active ingredient (calculated as free base).

. _ A pharmaceutical preparation containing (E)-1-[4'-~2-ethylaminoethoxy)phenyl]-1-(3'-h droxyphen~yl)-2-phenylbut-l-ene Af~er having been mixed with lll g. mannitol, 15 g.
corn starch and 6 g. alginic acid, 20.0 g. finely : powdered (E)-l-[4'~(2-ethylaminoethoxy)phenyl~
(3'-hydroxyphenyl)-2-phenylbut-l-ene are granulated and the dried granules, after having been carefully mixed with 0.75 g. methyl cellulose and 1.5 g.
magnesium stearate, are compressed into one thousand tablets, each containing 20 mg. active ingredient.

.

Pharmacological Tests a) Binding Affinity to the _ diol Receptor The binding affinity to the estradiol receptor was measured according to the method of N.
Devleeschouwers G. Leclercq, A. Danguy and J.C. Heuson [Europ. J. Cancer, 14, 721-723 (1978~]. The uterus cytosol of female, prepuberal white rabbits of 2 kg.
.~ weight ~New Zealand rabbits) was incubated for 18 hours at 4C with 2.5xlO 9M~3H]-estradiol as well as with the addition of unlab~lled estradiol (control) or test substance of different concentration. The binding affinity to the estradiol receptor is expressed by the concentration of unlabelled estradiol ~control) or test substance which is added to the uterus cytosol and brings about a 50~ replacement of the [3~]-estradiol bound to the estradiol receptor.

~ ~, ... .
.

- 27 ~
T.~BLE 3 Bindin~ Affinl~y of the Test Substances ~ 2 2 --R2 r~ 11 C~ ould ---Rl- R2 R .
. ~ __ .. . . .__ Estradiol _ _ _ 1.3 x 10-9 (control) .

Tamoxi~fen CH3 CH3 -H 3.8 x 10-7 1 C~3 CH3 OH 2.4 x 10-8 2 C2H~ C2H5 OH 6.5 x 10-8 L ~ CH3¦ ~ ~ ON ¦ 3.7 x x) Concentration of the substance which replaces 50% [3H]-estradiol from the estradiol receptor.

~7~

b) Anti-uterotro~hic Effect The anti-uterotrophic effect was determined according to a modlfied "Dorfman Test" ~R. I.
Dorfman, Methods in Hormone Re~search II, p. 707, Academic Press, New York - London, 1962] on puberal, female Sprague-Dawley rats.
The test compounds were put in 0.25~ aqueous agar suspension and administered by stomach tube six times weekly over a period of 21 days. At the end of tes~ing, the uterine weigh~ of th~ animals tr~ated wi h active ingredient was related to the uterine weight of the control animals which only received a blank agar suspension~

~~ABLE 4 .
Anti-uterotrophic ActivitY of the Test Substances Compound No. of Test Dose Utexine Weight No. Animalsmg./kg./compared to ¢ day aontrol _ _ ~ _ Animals Tamoxifen 10 3 -40%
1 10 3 -42%
2 10 3 -39%
3 1~ 3 -53%
, .. _ . _ _.

~2~77~

c) Inhlbitory Effect on the Mammary Tumor The inhibitory effect on the tumor was determined on the model of the 7,12-dimethylhenz(a)anthracene-: induced mammary tumor of the female Sprague-Dawley rat (Hanover breed) according to the method of M.J.
Golder [Europ. J. Cancer 11, 571 (1975)] and D.P.
Griswold et al ~Canc~r Research 26, 2169 (1966~.
The test compounds were put in 0.25% agar suspension and administered by stomach tube six times weekly over a period of 28 days. Twice weekly and on the 28th day of testing the number of animals was determined and the tumor surface (mm2/animal) of the therapy animals and control animals was measured. At the end of testing, the percentage increase of the average tumor surface of the treated animals was determined in comparison to. the control animals, the surface of the latt~r being taken as 100%.

. TABLE 5 Inhibitor~ Ac~ivity of the Test Subs~ances on the Tumor Compound No. of Test Dose Relativë Increase No. Animalsmg./kg./of the Average _ . .Da~ _ Tumor Surface Blank .
Control lO _ 100%
Tamoxifen 12 3 35 l 12 3 23 .__. ...... ___ _~

, - :~26~7~

From the foregoing description, one of ordinary skill in the art can readily ascertain the essential characteristices of the present invention and, without departing from the spirit and scope thereof, can make various changes in and/or modifications of the invention to adapt it to various usages and conditions. As such, these changes and/or modifications are properl~, equitably and intended to be within the full range of equivalence of the following claims.

Claims (12)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for the preparation of an isomer mixture of E-form and Z-form compounds represented by the formula:

(1) wherein R1 and R2 may be the same or different, provided that, when R1 and R2 are the same, each of them is a methyl or ethyl radical, and when R1 and R2 are different, one of them is hydrogen and the other is a methyl or ethyl radical; or a non-toxic pharmaceutically acceptable salt thereof;
comprising dehydrating a carbinol of the formula:

wherein R1 and R2 may be the same or different, provided that, when R1 and R2 are the same, each of them is a methyl or ethyl radical, and when R1 and R2 are different, one of them is benzyl radical and the other is a methyl or ethyl radical; and wherein R3 is hydrogen or an easily hydrolyzable protecting group, through the action of mineral acid, removing any easily hydrolyzable protecting group if present and optionally forming pharmaceutically acceptable salts of said compounds.

2. A process of claim 1 for preparing said E-form of compound of formula (1) further comprising isolating by crystallization, said E-form of compound from said isomer mixture of E-form and Z-form compounds, removing any benzyl radical if present by hydrogenolysis and optionally forming pharmaceutically acceptable salts of said compounds.

3. A process of claim 1 for preparing (E)-1-[4'-(2-dimethylaminoethoxy)phenyl]-1-(3'-hydroxyphenyl)-2-phenylbut-l-ene or a non-toxic, pharmaceutically acceptable salt thereof wherein R1 and R2 are both methyl.

4. A process of claim 1 for preparing (E)-1-[4'-(2-diethylaminoethoxy)phenyl]-1-(3'-hydroxyphenyl)-2-phenylbut-l-ene or a non-toxic, pharmaceutically acceptable salt thereof wherein R1 and R2 are both ethyl.

5. A process of claim 1 for preparing (E)-1-(3'-hydroxyphenyl)-1-[4'-(2-methylaminoe-thoxy)phenyl]-2-phenylbut-l-ene or a non-toxic, pharmaceutically acceptable salt thereof wherein one of R1 and R2 is hydrogen and the other is methyl.

6. A process of claim 1 for preparing (E)-1-[4'-ethylaminoethoxy)phenyl]-1-(3' hydroxyphenyl)-2-phenylbut-1-ene or a non-toxic, pharmaceutically acceptable salt thereof wherein one of R1 and R2 is hydrogen and the other is ethyl.

7. An isomer mixture of E-form and Z-form compounds of the formula:

wherein R1 and R2 may be the same or different, provided that, when R1 and R2 are the same, each of them is a methyl or ethyl radical, and when R1 and R2 are different, one of them is hydrogen and the other is a methyl or ethyl radical; or a non-toxic pharmaceutically acceptable salt thereof, when prepared by the process of claim 1 or its obvious chemical equivalents.

8. A compound of claim 7 having the E-form or a non-toxic pharmaceutically acceptable sale thereof, when prepared by the process of claim 2 or its obvious chemical equivalents.

9. The compound of claim 7 (E)-1-[4'-(2-dimethyl-aminoethoxy)phenyl]-1-(3'-hydroxyphenyl)-2-phenylbut-l-ene or a non-toxic, pharmaceutically acceptable salt thereof, when prepared by the process of claim 3 or its obvious chemical equivalents.

10. The compound of claim 7 (E)-1-[4'-(2-diethyl-aminoethoxy)phenyl]-1-(3'-hydroxyphenyl)-2-phenylbut-l-ene or a non-toxic, pharmaceutically acceptable salt thereof, when prepared by the process of claim 4 or its obvious chemical equivalents.

11. The compound of claim 7 (E)-1-(3'-hydroxyphenyl)-1-[4'-(2-methylaminoethoxy)phenyl]-2-phenylbut-1-ene or a non-toxic, pharmaceutically acceptable salt thereof, when prepared by the process of claim 5 or its obvious chemical equivalents.

12. The compound of claim 7 (E)-1-[4'-ethylamino-ethoxy)phenyl]-1-(3'-hydroxyphenyl)-2-phenylbut-l-ene or a non-toxic, pharmaceutically acceptable salt thereof, when prepared by the process of claim 6 or its obvious chemical equivalents.