Note: Descriptions are shown in the official language in which they were submitted.
-- 1 --
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~
--2--
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
TABLE 1
_ 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~
4--
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~
6 --
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)
1H3
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
`
- 9 -
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).
39
-- 10 --
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.
EXAMPLE 1
.. _
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
12 -
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~
- 13 -
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
- 14 -
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
- 16 -
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
- 17 -
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
- 18 -
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
- 19
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
- 20 -
.
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~
- 22 -
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~
- 23 -
Utilizing the appropriate starting materials and
following the ~enexal pro~edures detailed hereinabove,the
following additional compounds of the invention are
obtained:
EXAMPLE 3
(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~
- 24 -
EXAMPLE 4
(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,
CH2CH3
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~
- 25 -
EXAMPLE 5
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).
EXAMPLE 6
. _
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.
- 26 -
.
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~
- 28 -
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~
- 29 -
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~
- 30 -
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.
