UTILISATION D'UN MODULATEUR SELECTIF DU RECEPTEURS DES OESTROGENES DANS LA FABRICATION D'UNE PREPARATION PHARMACEUTIQUE UTILISEE DANS UNE METHODE DE TRAITEMENT OU DE PREVENTION DESINSUFFISANCES ENDROGENIQUES

USE OF A SELECTIVE ESTROGEN RECEPTOR MODULATOR FOR THE MANUFACTURE OF A PHARMACEUTICAL PREPARATION FOR USE IN A METHOD FOR THE TREATMENT OR PREVENTION OF ANDROGEN DEFICIENCY

Abrégé français

L'invention concerne l'utilisation d'un modulateur sélectif du récepteur des oestrogènes, ou d'un isomère, d'un mélange d'isomères, d'un métabolite ou d'un sel pharmaceutiquement acceptable de celui-ci, dans la fabrication d'une préparation pharmaceutique utilisée dans une méthode de traitement ou de prévention des insuffisances androgéniques, ou des maladies ou troubles causés par les insuffisances androgéniques chez un individu mâle.

Abrégé anglais

This invention relates to a use of a selective estrogen receptor modulator, or
an isomer, isomer mixture, metabolite or a pharmaceutically acceptable salt
thereof for the manufacture of a pharmaceutical preparation for use in a
method for the treatment or prevention of androgen deficiency or diseases and
disorders caused by androgen deficiency in a male individual.

Revendications

17
CLAIMS
1. The use of a selective estrogen receptor modulator, or an isomer, isomer
mixture,
metabolite or a pharmaceutically acceptable salt thereof for the manufacture
of a
pharmaceutical preparation for use in a method for the treatment or prevention
of
androgen deficiency in a male individual.
2. The use according to claim 1 wherein the selective estrogen receptor
modulator is
a triphenylalkane compound, a triphenyl-alkene compound, where the alkene
chain
is halogen-substituted butene or propene, a benzothiophene compound, EM652,
EM800, EM776, EM651, EM312, ICI 182780, ERA-923, zindoxifene, deacetylated
zindoxifene, ZK119010, TSE-4247, lasoxifene, a lasoxifene analogue,
nafoxidine,
basedoxifene, GW5638, GW7604, ICI 164384, RU 58668, RU 39411 or EM 319,
or an isomer, isomer mixture, metabolite or a pharmaceutically acceptable salt
thereof.
3. The use according to claim 2 wherein the selective estrogen receptor
modulator is
a triphenylbutene compound of the formula (I)
<IMG>
wherein R1 is H, halogen, OCH3, or OH; and
R2 is
a)
<IMG>
where X is O, NH or S; and n is an integer from 1 to 4; and

18
R4 and R5, which are the same or different, are a 1 to 4 carbon alkyl, H,
-CH2C.ident.CH or -CH2CH2OH; or
R4 and R5 form an N-containing five- or six-membered ring or
heteroaromatic ring; or
b) -Y-(CH2)n CH2-O-R6
where Y is O, NH or S and n is an integer from 1 to 4; and
R6 is H, -CH2CH2OH, or -CH2CH2C1; or
c) 2,3-dihydroxypropoxy, 2-methylthioethoxy, 2-chloroethoxy, 1-ethyl-2-
hydroxyethoxy, 2,2-diethyl-2-hydroxyethoxy or carboxymethoxy; and
R3 is H, halogen, OH or -OCH3 or an isomer, isomer mixture, metabolite or a
pharmaceutically acceptable salt thereof.
4. The use according to claim 2 wherein the selective estrogen receptor
modulator is
a triphenylbutene compound of the formula (I)
<IMG>
wherein R1 is H, halogen, OCH3, or OH; and
R2 is
a)
<IMG>
where i) X is NH or S; and n is an integer from 1 to 4; and
R4 and R5, which are the same or different, are a 1 to 4 carbon alkyl, H,
-CH2C.ident.CH or -CH2CH2OH; or
R4 and R5 form an N-containing five- or six-membered ring or
heteroaromatic ring; or

19
where ii) X is O, and n is an integer from 1 to 4; and
one of R4 and R5 is -CH2C.ident.CH or -CH2CH2OH and the other is H or
a C1-C4-alkyl; or R4 and R5 form an imidazole ring, an N-containing
six-membered ring or heteroaromatic ring; or R2 is
b) -Y-(CH2)n CH2-O-R6
where Y is O, NH or S and n is an integer from 1 to 4; and
R6 is H, -CH2CH2OH, or -CH2CH2C1; or R2 is
c) 2,3-dihydroxypropoxy, 2-methylthioethoxy, 2-chloroethoxy, 1-ethyl-2-
hydroxyethoxy, 2,2-diethyl-2-hydroxyethoxy or carboxymethoxy; and
R3 is H, halogen, OH or -OCH3 or an isomer, isomer mixture, metabolite or a
pharmaceutically acceptable salt thereof.
5. The use according to any of the foregoing claims wherein the selective
estrogen
receptor modulator is a compound with tissue specific antiestrogenic or
estrogenic
effects suitable for men.
6. The use according to claim 5 wherein the selective estrogen receptor
modulator is
selected from the group consisting of
(Z)-2- [3 -(4-Chloro-1,2-diphenyl-but-1-enyl)phenoxy]ethanol,
(Z)-2- {2-[4-(4-Chloro-1,2-diphenylbut-1-enyl)phenoxy]ethoxy} ethanol
(fispemifene),
(Z)- {2-[3-(4-Chloro-1,2-diphenylbut-1-enyl)phenoxy]ethyl} dimethylamine,
(E)-3-{4-Chloro-1-[4-(2-hydroxyethoxy)phenyl]-2-phenyl-but-1-enyl}-phenol,
(E)-3-{4-Chloro-1-[4-(2-imidazol-1-yl-ethoxy)phenyl]-2-phenyl-but-1-enyl}-
phenol,
(Z)-3-{4-Chloro-1-[4-(2-imidazol-1-yl-ethoxy)phenyl]-2-phenyl-but-1-enyl}-
phenol, and
(Z)-2-[4-(4-chloro-1,2-diphenyl-but-1-enyl)phenoxy]ethanol (ospemifene),
or an isomer, isomer mixture, metabolite or a pharmaceutically acceptable salt

20
thereof.
7. The use according to claim 6 wherein the selective estrogen receptor
modulator is
fispemifene or metabolite or a pharmaceutically acceptable salt thereof.
8. A use of a selective estrogen receptor modulator as defined in any of the
claims
1-7, or an isomer, isomer mixture, metabolite or a pharmaceutically acceptable
salt
thereof in the manufacture of a pharmaceutical preparation useful for
prevention or
treatment of a disease or disorder in a male individual, said disease or
disorder
being caused by androgen deficiency in said individual.
9. The use according to claim 8, wherein said disease or disorder is selected
from
the group consisting of
- hypogonadism, particularly but not restricted to secondary hypogonadism
resulting
from disease or disorders such as Kallman's Syndrome, Prader-Labhart-Willi's
Syndrome, Laurence-Moon-Biedl's Syndrome, pituitary insufficiency/adenomas,
Pasqualini's Syndrome, hemochromatosis, hyperprolactinemia, pituitary-
hypothalamic injury from tumors, trauma, radiation, obesity, chronic illness,
such as
diabetes mellitus, hypotyroidism or other disease or disorder that may affect
central
production of gonadotropin;
- age-related testosterone deficiency and diseases or disorders resulting
therefrom,
such as impaired muscle strength, sexual dysfunction, decreased libido, loss
of
muscle mass, decreased bone density, depressed mood, and decreased cognitive
function; and
- any muscular atrophy/dystrophies; lipodistrophy; long-term critical illness;
sarcopenia; frailty or age-related functional decline; reduced muscle strength
and
function; muscle wasting from HIV; chronic renal failure, reduced bone density
or
growth; catabolic side effects of glucocorticoids; chronic fatigue syndrome;
reduced
bone fracture repair; acute fatigue syndrome and muscle loss following
elective
surgery; cachesia; chronic catabolic state; eating disorders; side effects of
chemotherapy; wasting; depression; nervousness irritability; stress; growth

21
retardation; senescence outfall symptoms; reduced cognitive function; anaemia;
male contraception; infertility; Syndrome X; diabetic complications or
obesity.
10. The use according to claim 9 wherein
said disease or disorder is selected from the group consisting of
hypogonadism,
particularly but not restricted to secondary hypogonadism and diseases or
disorders
resulting therefrom and age-related testosterone deficiency and diseases or
disorders
resulting therefrom,
and
said selective estrogen receptor modulator is a triphenylbutene compound of
the
formula (I)
<IMG>
wherein R1 is H, halogen, OCH3, or OH; and
R2 is
a) <IMG>
where X is O, NH or S; and n is an integer from 1 to 4; and
R4 and R5, which are the same or different, are a 1 to 4 carbon alkyl, H,
-CH2C.ident.CH or -CH2CH2OH; or
R4 and R5 form an N-containing five- or six-membered ring or
heteroaromatic ring; or
b) -Y-(CH2)n CH2-O-R6
where Y is O, NH or S and n is an integer from 1 to 4; and
R6 is H, -CH2CH2OH, or -CH2CH2Cl; or

22
c) 2,3-dihydroxypropoxy, 2-methylsulfamylethoxy, 2-chloroethoxy, 1-ethyl-2-
hydroxyethoxy, 2,2-diethyl-2-hydroxyethoxy or carboxymethoxy; and
R3 is H, halogen, OH or -OCH3 or an isomer, isomer mixture, metabolite or a
pharmaceutically acceptable salt thereof.
11. The use according to claim 10 wherein said selective estrogen receptor
modulator is a triphenylbutene compound of the formula (I)
<IMG>
wherein R1 is H, halogen, OCH3, or OH; and
R2 is
a) <IMG>
where i) X is NH or S; and n is an integer from 1 to 4; and
R4 and R5, which are the same or different, are a 1 to 4 carbon alkyl, H,
-CH2C.ident.CH or -CH2CH2OH; or
R4 and R5 form an N-containing five- or six-membered ring or
heteroaromatic ring; or
where ii) X is O, and n is an integer from 1 to 4; and
one of R4 and R5 is -CH2C.ident.CH or -CH2CH2OH and the other is H or
a C1-C4-alkyl; or R4 and R5 form an imidazole ring, an N-containing
six-membered ring or heteroaromatic ring; or R2 is
b) -Y-(CH2)n CH2-O-R6
where Y is O, NH or S and n is an integer from 1 to 4; and
R6 is H, -CH2CH2OH, or -CH2CH2Cl; or R2 is

23
c) 2,3-dihydroxypropoxy, 2-methylthioethoxy, 2-chloroethoxy, 1-ethyl-2-
hydroxyethoxy, 2,2-diethyl-2-hydroxyethoxy or carboxymethoxy; and
R3 is H, halogen, OH or -OCH3 or an isomer, isomer mixture, metabolite or a
pharmaceutically acceptable salt thereof.
12. The use according to claim 11 wherein the selective estrogen receptor
modulator
is selected from the group consisting of
(Z)-2-[3 -(4-Chloro-1,2-diphenyl-but-1-enyl)phenoxy]ethanol,
(Z)-2-{2-[4-(4-Chloro-1,2-diphenylbut-1-enyl)phenoxy]ethoxy}ethanol
(fispemifene),
(Z)-{2-[3-(4-Chloro-1,2-diphenylbut-1-enyl)phenoxy]ethyl}dimethylamine,
(E)-3-{4-Chloro-1-[4-(2-hydroxyethoxy)phenyl]-2-phenyl-but-1-enyl}-phenol,
(E)-3-{4-Chloro-1-[4-(2-imidazol-1-yl-ethoxy)phenyl]-2-phenyl-but-1-enyl}-
phenol,
(Z)-3-{4-Chloro-1-[4-(2-imidazol-1-yl-ethoxy)phenyl]-2-phenyl-but-1-enyl}-
phenol, and
(Z)-2-[4-(4-chloro-1,2-diphenyl-but-1-enyl)phenoxy]ethanol (ospemifene),
or an isomer, isomer mixture, metabolite or a pharmaceutically acceptable salt
thereof.
13. The use according to claim 12 wherein the selective estrogen receptor
modulator
is fispemifene or an isomer, isomer mixture, metabolite or a pharmaceutically
acceptable salt thereof.

Description

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USE OF A SELECTIVE ESTROGEN RECEPTOR MODULATOR FOR THE MANUFACTURE
OF A PHARMACEUTICAL PREPARATION FOR USE IN A METHOD FOR THE TREATMENT
OR PREVENTION OF ANDROGEN DEFICIENCY
FIELD OF THE INVENTION
This invention relates to a method for treatment or prevention of androgen
deficiency in a male individual, said method comprising administering to the
individual an effective amount of a selective estrogen receptor modulator
(SERM).
The invention concerns further methods for treatment or prevention of diseases
or
disorders caused by said androgen deficiency.
BACKGROUND OF THE INVENTION
The publications and other materials used herein to illuminate the background
of the
invention, and in particular, cases to provide additional details respecting
the
practice, are incorporated by reference.
Testosterone in men
Masculine sex hormones, the androgens, are responsible for the development of
the
masculine sex characteristics. Furthermore, they are required for
reproduction. The
main element of the androgens is testosterone, which is imperative for the
development and the function of the internal and external masculine sex
organs,
which has a supportive influence regarding muscle growth, which determines the
distribution and the density of hair growth, which has a positive influence
with
respect to the production of erythrocytes and with respect to the distribution
of
erythropoietiin and the cognitive functions. A shortage of testosterone
(hypogonadism) may be classified into two principle forms, which are
designated
primary and secondary hypogonadism. Diseases based on testosterone shortage
include for instance osteoporosis, muscle atrophy, senescence outfall
symptoms,

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the decrease of libido and potency, depression and anaemia.
Primary hypogonadism
The lack of testosterone production or a decreased testosterone production
within
the body, originating from a malfunction of the testicles, which is the main
synthesis location of testosterone, is designated primary hypogonadism.
Primary hypogonadism includes the testicular failure due to congenital or
acquired
anorchia, XYY Syndrome, XX males, Noonan's Syndrome, gonadal dysgenesis,
Leydig cell tumors, maldescended testes, varicocele, Sertoli-Cell-Only
Syndrome,
cryptorchidism, bilateral torsion, vanishing testis syndrome, orchiectomy,
Klinefelter's Syndrome, chemotherapy, toxic damage from alcohol or heavy
metals,
and general disease (renal failure, liver cirrhosis, diabetes, myotonia
dystrophica).
Patients with primary hypogonadism show an intact feedback mechanism in that
the
low serum testosterone concentrations are associated with high FSH (follicle-
stimulating hormone) and LH (luteinizing hormone) concentrations. However,
because of testicular or other failures, the high LH concentrations are not
effective
at stimulating testosterone production.
Secondary hypogonadism
If the main reason for the diseases is a malfunction of the hypothalamus or
the
hypophysis the disease is named secondary (or hypogonadotrophic) hypogonadism.
This involves an idiopathic gonadotropin or LH-releasing hormone deficiency.
This
type of hypogonadism includes Kallman's Syndrome, Prader-Labhart-Willi's
Syndrome, Laurence-Moon-Biedl's Syndrome, pituitary insufficiency/adenomas,
Pasqualini's Syndrome, hemochromatosis, hyperprolactinemia, or pituitary-
hypothalamic injury from tumors, trauma, radiation, or obesity. Because
patients
with secondary hypogonadism do not demonstrate an intact feedback pathway, the
lower testosterone concentrations are not associated with increased LH or FSH
levels. Thus, these men have low testosterone serum levels but have
gonadotropins
in the normal to low range.

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Age-related testosterone deficiency,
Men experience a slow but continuous decline in average serum testosterone
after
approximately age 20 to 30 years. Researchers estimate that the decline is
about 1-
2% per year. Moreover, as men age, the circadian rhythm of testosterone
concentration is often muted, dampened, or completely lost. The untreated
testosterone deficiency in older men may lead to a variety of physiological
changes,
including sexual dysfunction, decreased libido, loss of muscle mass, decreased
bone
density, depressed mood, and decreased cognitive function. The net result is
male
andropause, also known as late-onset hypogonadism or androgen decline in the
ageing male (ADAM).
Diagnosis and treatment of testosterone deficiency
The normal ranges for testosterone concentration vary as well as the
definition of
the limit value to diagnose hypogonadism. The report of the Endocrine
Society's
Second Annual Andropause Consensus Meeting (Endocrine Society, 2002)
delineated three categories for consideration in screening and diagnosing
hypogonadism in men over 50 years of age: 1) if total testosterone is _ 200
ng/dL
(i.e., 7 nmol/L), diagnosis of androgen deficiency is confirmed; serious
hypothalamic or pituitary disease in men with hypogonadotropic hypogonadism to
be ruled out; 2) if total testosterone levels are between 200 and 400 ng/dL
(i.e., 7-14
nmol/L), additional measures of testosterone and further evaluation before
considering testosterone therapy are recommended; and 3) if total testosterone
levels are > 400 ng/dL (i.e., 14 nmol/L), there is no testosterone deficiency.
Many
studies have used the 300 to 350 ng/dL (i.e., 10-12 nmol/L) range of total
testosterone as a cutoff for identifying hypogonadal patients (in Testosterone
and
Aging, Clinical Research Directions 2004, ed. Liverman CT and Blaxer DG). In
addition to the low testosterone serum concentration, sign(s) and/or
symptom(s) of
testosterone deficiency should be present for the diagnosis.

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The treatment is usually a substitution therapy which effectively can be
measured
directly based on the testosterone concentration in serum. The aim of the
testosterone substitution is to increase the testosterone concentration in
serum to the
normal value. Currently, testosterone/androgen compounds are used as
treatments
for hypogonadism.
Selective estrogen receptor modulators
"SERM"s (selective estrogen receptor modulators) have both estrogen-like and
antiestrogenic properties (Kauffinan & Bryant, Drug News Perspect 8:531-539,
1995). The effects may be tissue-specific as in the case of tamoxifen and
toremifene
which have estrogen-like effects in the bone, partial estrogen-like effect in
the
uterus and liver, and pure antiestrogenic effect in breast cancer. Raloxifene
and
droloxifen are similar to tamoxifen and toremifene, except that their
antiestrogenic
properties dominate. They are known to decrease total and LDL cholesterol,
thus
deminishing the risk of cardiovascular diseases, and they may prevent
osteoporosis
and inhibit breast cancer growth in postmenopausal women.
A review of investigated and/or marketed SERM compounds is published in V
Craig Jordan, J Medicinal Chemistry (2003):46, No.7.
SUMMARY OF THE INVENTION
The inventors of the present invention have surprisingly found that compounds
belonging to the group of selective estrogen receptor modulators are effective
in
raising the serum testosterone level in men.
Thus, this invention concerns a method for treatment or prevention of of
androgen
deficiency in a male individual, said method comprising administering to the
individual an effective amount of a selective estrogen receptor modulator, or
an
isomer, isomer mixture, metabolite or a pharmaceutically acceptable salt
thereof.

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Furthermore, this invention concerns a method for prevention or treatment of a
disease or disorder in a male individual, said disease or disorder being
caused by
androgen deficiency in said individual, said method comprising administering
to the
individual an effective amount of a selective estrogen receptor modulator as
defined
5 in any of the claims 1-6, or an isomer, isomer mixture, metabolite or a
pharmaceutically acceptable salt thereof.
BRIEF DESCRIPTION OF THE DRAWING
Figure 1 shows serum concentration of testosterone in men versus time during
treatment with different doses of fispemifene.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
The tem "treatment" or "treating" shall be understood to include complete
curing of
a disease or disorder, amelioration or alleviation and of said disease or
disorder and
delaying the progress or onset of said disease or disorder.
The term "prevention" shall be understood to include complete prevention,
prophylaxis, as well as lowering the individual's risk of falling ill with
said disease
or disorder.
The term "individual" refers to a human or animal subject.
The expression "effective amount" is meant to include any amount of an agent
according to the present invention that is sufficient to bring about a desired
therapeutical result, especially upon administration to an animal or human
subject.

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The term "androgen deficiency" shall mean a condition in the male individual
where the serum level of masculine sex honnones, particularly testosterone and
dihydrotestosterone, is decreased.
The term "testosterone deficiency" refers to a condition in the male
individual
where the seruni level of testosterone is decreased, particularly decreased to
a serum
level below or at the lower range of the normal reference level. The reference
level
depends on the laboratory methods used.
The wording "selective estrogen receptor modulator" and any specific compound
belonging to this group shall be understood to cover any geometric isomer, any
stereoisomer, racemate or other mixture of isomers of the compound.
Furthermore,
pharmaceutically acceptable salts and other derivatives such as esters as well
as
metabolites are also included.
Diseases or disorders which can be prevented or treated by treating or
preventing androgen deficiency using SERMs
The inventors believe that SERMs are useful for prevention or treatment of any
disease or disorder in male individual, said disease or disorder being caused
by
androgen deficiency.
Hypogonadism, particularly secondary hypogonadism, and age-related
testosterone
deficiency are examples of disorders which can treated or prevented by
administrating SERMs according to this invention. Also specific diseases or
disorders resulting from said hypogonadism or age-related testosterone
deficiency
can be treated or prevented. However, also other diseases or disorders which
are
caused by androgen deficiency but which are unrelated to hypogonadism or age-
related testosterone deficiency may be treated or prevented according to the
method
of this invention.

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Thus, as examples of specific diseases or disorder which can be treated or
prevented according to the present invention can be mentioned:
- hypogonadism, particularly but not restricted to secondary hypogonadism
resulting from diseases or disorders such as Kallman's Syndrome, Prader-
Labhart-
Willi's Syndrome, Laurence-Moon-Biedl's Syndrome, pituitary
insufficiency/adenomas, Pasqualini's Syndrome, hemochromatosis,
hyperprolactinemia, pituitary-hypothalamic injury from tumors, trauma,
radiation,,
obesity, chronic illness, such as diabetes mellitus, hypotyroidism or other
disease or
disorder that may affect central production of gonadotropin;
- age-related testosteroize deficiency and diseases or disorders resulting
therefrom,
such as impaired muscle strength, sexual dysfunction, decreased libido, loss
of
muscle mass, decreased bone density, depressed mood, and decreased cognitive
function; and
- any muscular atrophy/dystrophies; lipodistrophy; long-term critical illness;
sarcopenia; frailty or age-related functional decline; reduced muscle strength
and
function; muscle wasting from HIV; chronic renal failure, reduced bone density
or
growth; catabolic side effects of glucocorticoids; chronic fatigue syndrome;
reduced
bone fracture repair; acute fatigue syndrome and muscle loss followiing
elective
surgery; cachesia; chronic catabolic state; eating disorders; side effects of
chemotherapy; wasting; depression; nervousness irritability; stress; growth
retardation; senescence outfall symptoms; reduced cognitive function; anaemia;
male contraception; infertility; Syndrome X; diabetic complications or
obesity.
SERMs increasing testosterone have the potential to provide novel treatments
for
male andropause, also known as late-onset hypogonadism or androgen decline in
the aging male (ADAM), and both osteoporosis and sexual dysfunction in both
men
and women. Testosterone deficiency in older men may impair muscle strength
(causing frailty/disability); cognitive or sexual function; or vitality/well-
being/quality of life.
Advantages of SERMs in the treatment of androgen deficiency

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~
A SERM increasing testosterone sufficiently to treat testosterone deficiency
may
have several advantages over direct testosterone substitution. The benefits of
the
increased testosterone can be achieved while a SERM compound, due to its anti-
estrogenic or estrogenic effects, simultaneously protects against the
potential side-
effects commonly associated with increased testosterone such as prostate
stimulation, gynecomastia, or adverse effects on lipid metabolism.
It is known that many estrogens/anti-estrogens/phytoestrogens/SERMs have
antitumor effects mediated via estrogen receptor, and they can potentially
prevent
and treat prostate cancer (Ho S-M: Estrogens and Anti-Estrogens: Key Mediators
of
Prostate Carcinogenesis and New Therapeutic Candidates. 2004;91:491-503).
The SERMs are antiestrogenic in breast and could therefore provide protection
against gynecomastia, often associated with testosterone treatments.
The SERMs provide beneficial effects on the lipid profile such as increased
HDL,
and decreased total cholesterol and LDL. Testosterone is known for instance to
decrease HDL, and this adverse effect could thus be counteracted with the
SERM.
Both SERMs and testosterone have beneficial effects on bone metabolism by
inhibiting bone turnover. Thus, the protective effect of a SERM on bone is
likely to
be enhanced if it has the ability to increase testosterone.
To sum up, SERMs, particularly the SERMs according to formula (I) presented
below, produce the positive response of androgen replacement therapy without
the
undesired side effects of testosterone, such as adverse effects on prostate or
on lipid
metabolism, or gynecomastia.
These compounds increase testosterone and thus stimulate muscle growth and
reduce subcutaneous and visceral abdominal fat in the treatment of obesity;
increase
energy and libido and minimize the bone depletion; and have beneficial effects
on
lipid metabolism.

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Preferable SERMs
Suitable selective estrogen receptor modulators (or SERMs) for use in this
invention
are, for example, the compounds disclosed in V Craig Jordan (2003).
Thus, examples of suitable SERM compounds for use in the present invention are
triphenylalkene or triphenylalkane compounds such as compounds disclosed in WO
01/36360, US 4,996,225, US 4,696,949, US 5,750,576, WO 99/42427 and the
toremifene metabolites disclosed in L Kangas, Cancer Chemother Pharmacol
(1990)27:8-12. As examples of specific drugs disclosed in the aforementioned
references can be mentioned toreinifene, fispeinifene and ospemifene.
Droloxifene
and iodoxifene also examples of suitable SERMs of triphenylalkene structure.
Other preferable examples of SERM compounds are compounds of benzothiophene
structure (described for example in EP 584952, US 4,133,814, US 4,418,068) and
arzoxifene.
As further examples of suitable SERMs can be mentioned EM652, EM800, EM776,
EM651, EM312, ICI 182780, ERA-923, zindoxifene and deacetylated zindoxifene,
ZK119010, TSE-4247, lasoxifene and its analogues, particularly those disclosed
in
EP 802910, nafoxidine, basedoxifene, GW5638, GW7604, compound no. 32
disclosed in Jordan (2003), ICI 164384, RU 58668, RU 39411 and EM 319.
Preferably, the SERM is a triphenylalkane compound, a triphenyl-alkene
compound, where the alkene chain is halogen-substituted butene or propene, a
benzothiophene compound, EM652, EM800, EM776, EM651, EM312, ICI 182780,
ERA-923, zindoxifene, deacetylated zindoxifene, ZK1 19010, TSE-4247,
lasoxifene,
a lasoxifene analogue, nafoxidine, basedoxifene, GW5638, GW7604, ICI 164384,
RU 58668, RU 39411 or EM 319, or an isomer, isomer mixture, metabolite or a
pharmaceutically acceptable salt thereof.
Still more preferably, the SERM is a triphenylbutene compound of the formula
(I)

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R2
I / R3
R1 \ \ \ ~l)
CI
wherein R1 is H, halogen, OCH3, or OH; and
R2 is
a) ~ R4
-X-(CH2)-- CH2 N
R5
5 where X is 0, NH or S; and n is an integer from 1 to 4; and
R4 and R5, which are the same or different, are a 1 to 4 carbon alkyl, H,
-CH2C=CH or -CH2CH2OH; or
R4 and R5 form an N-containing five- or six-membered ring or
heteroaromatic ring; or
10 b) -Y-(CH2)r,CH2-O-R6
where Y is 0, NH or S and n is an integer from 1 to 4; and
R6 is H, -CH2CH2OH, or -CHaCH2C1; or
c) 2,3-dihydroxypropoxy, 2-methylsulfamylethoxy, 2-chloroethoxy, 1-ethyl-2-
hydroxyethoxy, 2,2-diethyl-2-hydroxyethoxy or carboxymethoxy; and
R3 is H, halogen, OH or -OCH3 or an isomer, isomer mixture, metabolite or a
pharmaceutically acceptable salt thereof.
Still more preferably, the SERM is a triphenylbutene compound of the formula
(I)

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11
R2
R3
Ri \ \ \ I (I)
ci
wherein R1 is H, halogen, OCH3, or OH; and
R2 is
a) ~ R4
-X-(CH2)F-CH2-N
R5
where i) X is NH or S; and n is an integer from 1 to 4; and
R4 and R5, which are the same or different, are a 1 to 4 carbon alkyl, H,
-CH2C=CH or -CH2CH2OH; or
R4 and R5 form an N-containing five- or six-membered ring or
heteroaromatic ring; or
where ii) X is 0, and n is an integer from 1 to 4; and
one of R4 and R5 is -CH2C=CH or -CHZCH2OH and the other is H or
a C 1-C4-alkyl; or R4 and R5 form an imidazole ring, an N-containing
six-membered ring or heteroaromatic ring; or R2 is
b) -Y-(CH2)õCH2-O-R6
where Y is 0, NH or S and n is an integer from 1 to 4; and
R6 is H, -CH2CHZOH, or -CH2CH2C1; or R2 is
c) 2,3-dihydroxypropoxy, 2-methylthioethoxy, 2-chloroethoxy, 1-ethyl-2-
hydroxyethoxy, 2,2-diethyl-2-hydroxyethoxy or carboxymethoxy; and
R3 is H, halogen, OH or -OCH3 or an isomer, isomer mixture, metabolite or a
pharmaceutically acceptable salt thereof.
The aforementioned specific SERMs or classes of SERMs are examples only, and
other SERMs may be suitable for use in this invention as well.

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Preferable SERMs are compounds with tissue specific antiestrogenic or
estrogenic
effects suitable for men. A preferred SERM is estrogenic in bone and
antiestrogenic
or mildly estrogenic in other tissues. A classical method to determine the
estrogenic
profile of a compound is to evaluate estrogenic effect in immature mouse or
rat
uterus (Terenius L, Acta Endocrinol 66:431-447, 1971). The animals are exposed
for 3 days to the compounds to be investigated at the age of 18 days. On the
fourth
day the animals are sacrificed and body weight and uterine weight is recorded.
Estrogens increase the size and weight of the uterus (uterotropic effect)
while
antiestrogens inhibit this action. The results are given as per cent of
estrogen
stimulation (100 % with estradiol). In our tests, we used a high dose level,
i.e. 10-
50 mg/kg. Compounds causing an uterotropic effect < 40 % are for this purpose
classified as weak estrogenic compounds, compounds causing an uterotropic
effect
> 70 % are classified as strong estrogenic compounds and compounds in-between,
an uterotropic effect of 41-69 % are classified as moderate estrogenic agents.
As specific examples of particularly useful SERMs can be mentioned certain
compounds of those disclosed in WO 01/36360, namely
(Z)-2-[3-(4-Chloro-1,2-diphenyl-but-l-enyl)phenoxy]ethanol
(Z)-2-{2-[4-(4-Chloro-1,2-diphenylbut-l-enyl)phenoxy]ethoxy}ethanol (also
known
under the generic name fispemifene)
(Z)- {2-[3-(4-Chloro-1,2-diphenylbut-l-enyl)phenoxy]ethyl} dimethylamine
(E)-3 - {4-Chloro-1-[4-(2-hydroxyethoxy)phenyl]-2-phenyl-but-1-enyl}-phenol
(E)-3- {4-Chloro-l-[4-(2-imidazol-l-yl-ethoxy)phenyl]-2-phenyl-but-l-enyl}-
phenol,
(Z)-3 - {4-Chloro-l- [4-(2-iinidazol-1-yl-ethoxy)phenyl] -2-phenyl-but-l-enyl
} -phenol,
and (Z)- 2-[4-(4-Chloro-1,2-diphenyl-but-l-enyl)phenoxy]ethanol (ospemifene)
The aforementioned seven compounds are all classified as weak estrogenic
SERMs.

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For the purpose of this invention, the SERM or its isomer, isomer mixture or
their
pharmaceutically acceptable salts can be administered by various routes. The
suitable administration forms include, for example, oral formulations;
parenteral
injections including intravenous, intramuscular, intradermal and subcutanous
injections; and transdermal or rectal formulations. Suitable oral formulations
include e.g. conventional or slow-release tablets and gelatine capsules.
The required dosage of the SERM compounds will vary with the particular
condition being treated, the severity of the condition, the duration of the
treatment,
the administration route and the specific compound being employed. For
example,
fispemifene can be administered perorally preferentially once daily. The daily
dose
may be 5 -1500 mg, preferably 20-1500 mg. Fispemifene can be given as tablets
or
other formulations like gelatine capsules alone or mixed in any clinically
acceptable
non-active ingredients which are used in the pharmaceutical industry.
The invention will be illuminated by the following non-restrictive
Experimental
Section.
EXPERIMENTAL SECTION
Methods and materials
Fispemifene has been studied in two phase I studies in humans - in a single
dose
and a repeated dose study. Effect of fispemifene on hormone levels was one
main
focus of the repeated dose study. The phase I repeated dose study (number 101-
50202) was a randomized, double-blind, placebo-controlled 28-day dose-
escalation
study performed in 32 healthy, elderly men, aged 50-68 years. The main
objective
of the study was to investigate the tolerability, safety and phaimacokinetics
of
fispemifene after repeated oral doses, but the study focused also on the
effects of
fispemifene on serum testosterone, estradiol, and other relevant hormones. The
fispemifene doses 10, 30, 100 and 300 mg per day and placebo were administered
once every morning as capsules containing 10 mg or 100 mg of fispemifene, or

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14
placebo. The dose was escalated to the next higher dose level, if the previous
dose
had been safe and well tolerated evaluated by the laboratory safety
determinations
and ultrasound of mammagy glands.
The variables for safety and tolerability were adverse events, vital signs, 12-
lead
ECG, clinical laboratory evaluations, physical examination, ultrasound
examinations (mammary glands) and inhibin b. For pharmacokinetics, the
concentrations of fispemifene and its metabolite(s) were to be evaluated. For
pharmacodynamics, serum concentrations of FSH, LH, estradiol, testosterone,
SHBG, prolactin, aldosterone, cortisol and TSH before and during treatment
were
measured and compared with the concentrations in the placebo-group.
Results on the effects of fispemifene on hormones
Surprisingly, fispemifene increased the serum concentrations of testosterone,
FSH,
LH, and SHBG (Table 1) during the 28 days of treatment. Testosterone was
increased statistically significantly with 100 mg and 300 mg fispemifene
compared
with placebo. With the 300 mg dose, the increase in the mean total
testosterone was
about 75% compared to the baseline concentration. Two out of six men treated
with
the highest fispemifene dose had their serum testosterone level above the
upper
limit of normal range (i.e., 33 nmol/L) during treatment. The rest two had a
significant increase within the reference range. All the six men had normal
testosterone value at baseline. With the 100 mg dose, the increase of the mean
total
testosterone was about 32%, and all the six men in the group had their
testosterone
level increased within the reference range. The increase in total testosterone
levels
in serum is illustrated by group in Figure 1. There were no safety concerns
raised
with any dose suggesting that even a higher dose could be utilized if deemed
appropriate.

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Table 1. Serum total testosterone concentrations (mean and SD) and the other
hormones at baseline and during treatment in the fispemifene study 101-50202
by
dose.
Placebo Fispemifene Fispemifene Fispemifene Fispemifene
10 mg 30 mg 100 mg 300 mg
Testosterone Mean SD Mean SD Mean SD Mean SD Mean SD
(nmolli)
Baseline 17.25 4.2 19.33 4.7 15.00 3.5 14.27 4.0 15.67 3.6
Day 8 18.50 4.1 19.83 3.3 14.40 2.1 18.67 5.3 23.17 5.2
Day 15 18.43 4.4 20.50 4.9 15.00 2.7 19.00 6.0 27.00 6.5
Day 22 17.50 8.5 22.00 4.4 15.80 3.9 17.83 4.5 27.83 4.7
Day 28 15.43 3.2 17.40 7.2 14.80 5.3 18.83 4.8 27.50 10.3
FSH (U/I)
Baseline 5.60 3.4 5.42 3.6 9.14 13.4 6.30 5.6 6.80 5.4
Day 8 5.65 2.9 5.87 4.2 9.78 14.2 7.68 7.8 8.80 7.6
Day 15 4.67 1.6 5.20 2.9 10.14 14.6 8.10 9.0 8.73 7.2
Day 22 4.47 1.6 6.60 4.1 10.18 15.1 8.20 9.0 8.85 8.1
Day 28 4.29 1.7 5.66 3.7 8.42 11.6 7.73 7.9 7.57 7.0
LH (Ull)
Baseline 3.11 1.6 3.47 1.0 3.58 2.0 4.12 1.9 4.58 2.7
Day 8 3.29 0.8 3.12 1.5 4.26 2.2 5.52 4.2 . 6.80 3.5
Day 15 3.31 0.9 2.87 1.1 5.02 2.4 6.82 7.5 6.75 4.6
Day 22 2.80 0.8 3.56 1.2 4.32 2.3 7.18 8.3 7.77 6.6
Day 28 2.71 0.9 3.02 0.9 4.42 2.0 7.60 9.6 6.70 4.8
Estradiol
(pmolll)
Baseline 100.6 31.2 106.2 20.9 97.8 17.9 84.3 22.6 102.5 30.0
Day 8 93.8 17.1 94.7 31.2 105.6 29.8 108.3 28.9 104.0 20.0
Day 15 85.0 31.6 81.7 25.4 102.4 22.2 111.5 48.2 97.8 26.9
Day 22 75.0 32.4 116.6 15.1 99.6 20.4 106.3 37.4 95.5 32.9
Day 28 73.6 32.6 75.0 20.1 87.0 22.2 94.5 48.4 89.7 30.9
SHBG
(nmolll)
Baseline 49.1 18.6 47.7 19.9 34.2 12.8 41.7 29.4 50.7 15.1
Day 8 44.5 16.1 46.3 21.1 34.2 12.2 47.7 35.2 64.2 21.3
Day 15 46.0 19.1 48.2 22.8 37.4 20.8 52.0 39.5 66.2 21.1
Day 22 44.9 18.4 50.2 27.1 37.2 19.2 55.7 45.3 65.2 14.8
Day 28 45.0 18.5 45.2 24.3 36.6 19.1 50.8 42.8 58.3 12.3
5
Discussion and conclusions
Fispemifene induced a clinically and statistically significant and dose
dependent
increase in the serum testosterone concentration within 28 days from the start
of the
10 treatment. Also, within the 28-day treatment, the increase in testosterone
serum
concentration was seen in all the subjects treated with 100 mg or 300 mg
fispemifene. An increase of 75% from baseline can be considered clinically
highly
significant, and thus clinical benefits in men with low testosterone can be
expected.
The increases also in LH and FSH suggest that fispemifene has an
antiestrogenic
15 effect on hypothalamus/hypophysis, and that the increase in testosterone
occurs due
to the increase in the hypophyseal hormones. The increase in testosterone is

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moderate and, therefore, no harmful effects often associated with external
testosterone administration are expected. Furthermore, a SERM is likely to
provide
protection against the possible safety problems of testosterone like
development of
prostate cancer. Thus, a SERM increasing testosterone provides an optimal
treatment for hypogonadism, balancing the efficacy and safety of the increased
testosterone.
It will be appreciated that the methods of the present invention can be
incorporated
in the form of a variety of embodiments, only a few of which are disclosed
herein. It
will be apparent for the expert skilled in the field that other embodiments
exist and
do not depart from the spirit of the invention. Thus, the described
embodiments are
illustrative and should not be construed as restrictive.