E-2-[4-(4-CHLORO-1,2-DIPHENYL-BUT-1 -ENYL)PHENOXY]ETHANOL AND
PHARMACEUTICAL COMPOSITIONS THEREOF

The present invention relates to E-2-[4-(4-chloro-l,2-diphenyl-but-l-
enyl)phenoxy]ethanol (I) having serum cholesterol lowering properties and to
pharmaceutical compositions thereof. Compound (I) is useful in reducing serum
cholesterol levels and in the treatment of atherosclerosis. It is also potentially useful
in the hormone replacement therapy (HRT).
It has been demonstrated that elevated levels of serum cholesterol associated
with low density lipoproteins (LDL) are a major contributing factor in the
development and progression of atherosclerosis. Therefore it is desirable to provide a
method for reducing serum cholesterol levels in patients with hypercholesterolemia
or at risk of developing hypercholesterolemia.
International patent application WO 97/32574 describes the use of
Z-2-[4-(4-chloro-I,2-diphenyI-but-l-enyl)phenoxy]ethanol for lowering serum
cholesterol. The compound has no significant estrogenic side effects in uterine tissue
but is able to block the adverse effects of estrogen on uterus. Therefore this
compound is especially useful in lowering serum cholesterol. The corresponding E-
isomer is not described in this patent application.
Z-2-[4-(4-chloro-l,2-diphenyl-but-l-enyl)phenoxy]ethanol is a metabolite of
known antiestrogen drug toremifene. Toremifene (Z-4-chloro-l,2-diphenyl-I-[4-[2-
(N,N-dimethylamino)ethoxy]-phenyl]-l-butene) is currently used clinically for the
treatment of estrogen receptor positive breast cancer.
Now it has been found that E-2-[4-(4-chloro-l,2-diphenyl-but-l-
enyI)phenoxy]ethanol (I) is significantly more potent in lowering serum total
cholesterol but approximately equal in uterine effects when compared to the
corresponding Z-isomer. This was unexpected since the E-isomer of toremifene is
purely estrogenic in uterine tissue. Furthermore, it has been found that the E-isomer
of the invention is able to inhibit cholesterol biosynthesis directly whereas the
corresponding Z-isomer has not such effect.
Thus, E-2-[4-(4-chloro-l,2-diphenyl-but-l-enyl)phenoxy]ethanol (I) is
especially useful in lowering serum cholesterol and in the prevention or treatment of
atherosclerosis. Compound (I) is also potentially useful in the hormone replacement
therapy (HRT).
Accordingly, the invention provides a novel compound useful in lowering
serum cholesterol levels said compound being E-2-[4-(4-chloro-l,2-diphenyl-but-l-
enyl)phenoxy]ethanol and having the structure (I)

or a pharmaceutically acceptable ester thereof.
Pharmaceutically acceptable esters include esters made with aliphatic
carboxylic acids, preferably C,.f, acids, e.g. acetic acid, and made with aroma-tic
carboxylic acids, e.g. C7.12 acids such as benzoic acid. The aliphatic and aromatic
acids may optionally be substituted by e.g. one or more Cj.4alkyl.
The invention also provides a pharmaceutical composition comprising E-2-
[4-(4-chloro-l,2-diphenyl-but-l-enyl)phenoxy]ethanol or a pharmaceutically
acceptable ester thereof as an active ingredient together with a pharmaceutically
acceptable carrier.
The invention also provides a method of lowering serum cholesterol levels
which method comprises administering to a patient in need of such treatment an
effective amount of E-2-[4-(4-chloro-1,2-diphenyl-but-1 -enyl )phenoxy]ethanol or a
pharmaceutically acceptable ester thereof.
The invention also provides a method for the prevention or treatment of
atherosclerosis which method comprises administering to a patient in need of such
treatment an effective amount of E-2-[4-(4-chloro-l ,2-diphenyl-but-1-
eny!)phenoxy]ethanol or a pharmaceutically acceptable ester thereof.
The invention also provides a method of hormone replacement therapy (HRT)
which method comprises administering to a patient in need of such therapy an
effective amount of E-2-[4-(4-chloro-l,2-diphenyl-but-l-enyl)phenoxy]ethanol or a
pharmaceutically acceptable ester thereof.
The compound of the invention may be administered in a variety of ways
including orally, parenterally or transdermally using conventional forms of
preparations, such as capsules, tablets, granules, powders, suppositories, injections,
patches, suspensions and syrups. The term "effective amount" means an amount of
compound of.the invention which is capable of lowering serum total cholesterol
levels or capable of blocking the adverse effects of estrogen particularly on uterus or
inhibiting menopausal symptoms. The compound of the invention may be
administered according to the method of the invention monthly, weekly or daily or
several times a day depending upon the patient's needs. A typical daily oral dosage is
within the range of from about 0.5 mg to about 1000 mg, preferably from about 10
mg to about 800 mg, of the active compound. However, the dosage may be properly
varied depending on the age, body weight and conditions of the patient as well as on
the administration method. The compound of the invention may be administered
alone or together with other active compounds.
The compositions according to the invention can be prepared by the methods
commonly employed in the art. In addition to the active compound the compositions
may contain pharmaceutically acceptable additives commonly used in the art, such as
carriers, binders, excipients, lubricants, suspending agents and diluents. The amount
of the active compound in the compositions of the invention is sufficient to produce
the desired therapeutical effect, for example about 0.5 to 1000 mg, preferably about
10 mg to 800 mg, in unit dosage for both oral and parenteral administration.
The following examples illustrate the synthesis of the compound of the
invention.
EXAMPLES
Example 1. Preparation of E-2-l4-(4-chloro-l,2-diphenyl-but-1-
enyl)phenoxy]ethanol
a) E-4-[4-(2-benzy]oxyethoxy)phenyl]-3,4-diphenyl-but-3-en-1 -ol
The alkylation of the starting phenol with benzyl-(24oromoethyl)ether was
carried out as described in Example 1 of the International Patent Application WO
96/07402 with the exception that now the starting compound was the other geometric
isomer, E-4-(4-hydroxy-l,2-diphenyl-but-1-enyl)-phenol which was prepared by the
method described in United States Patent 4,996,225. The product was extracted to
toluene. The toluene phases were combined, washed with water, dried and
evaporated to dryness. The residue was recrystallized from a minor quantity of
toluene and the precipitated product was used in the next step without further
purification.