KR20070059110A - 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 - Google Patents

Abstract

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.

Description

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

The present invention relates to a method for the treatment or prevention of androgen deficiency in a male individual, the method comprising administering to the individual an effective amount of a selective estrogen receptor modulator (SERM). The present invention further relates to a method for treating or preventing a disease or disorder caused by the androgen deficiency.

Publications and other materials used herein to clarify the background of the present invention, and examples to provide additional detail, particularly in practice, are incorporated by reference.

Testosterone in men

Androgens, male sex hormones, are responsible for the development of male sexual characteristics. Moreover, it is necessary for reproduction. The main component of androgen is testosterone, which is essential for the development of internal and external male sex organs, has a secondary effect on muscle growth, determines the distribution and density of hair growth, in relation to erythropoiesis and erythropoiesis and It has a positive effect on the distribution of cognitive function. Lack of testosterone (hypogonadism) can be classified into two principle forms, referred to as primary and secondary hypogonadism. Diseases based on testosterone deficiency include, for example, osteoporosis, muscular atrophy, senescence outfall symptoms, reduction in libido and potency, depression and anemia.

Primary Hypogonadism

Lack of testosterone production or reduced testosterone production in the body due to testicular dysfunction of the testosterone, a major synthetic site of testosterone, is referred to as primary hypogonadism. Primary hypogonadism is congenital or acquired agonism, XYY syndrome, XX male, Nonan's Syndrome, gonadotropin, Leydig cell tumors, maldescended testes, venous varicose veins Sertoli-Cell-Only Syndrome, latent testicles, bilateral torsion, testicular, testectomy, Klinefelter syndrome, chemotherapy, alcoholic or heavy metal damage, and common diseases (renal failure) Testicular failure caused by cirrhosis of the liver, cirrhosis of the liver, diabetes mellitus, myotonic dystrophy). Patients with primary hypogonadism exhibit an intact feedback mechanism in that low serum testosterone levels are associated with high FSH (follicular stimulating hormone) and LH (luteinizing hormone) concentrations. However, due to testicles or other insufficiency, high LH concentrations are not effective to stimulate testosterone production.

Secondary Hypogonadism

If the main reason for the disease is hypothalamic or pituitary dysfunction, the disease is termed secondary (or hypogonadal gonadotropin) hypogonadism. This includes idiopathic gonadotropin or LH-releasing hormone deficiency. This type of hypogonadism is Kalman syndrome, Prader-Labhart-Willi's Syndrome, Lawrence-Moon-Biedl's Syndrome, Pituitary insufficiency / semaoma, Pasqualin syndrome Pasqualini's Syndrome, hemochromatosis, hyperprolactinemia, or pituitary-hypothalamic injury from tumors, trauma, radiation, or obesity. Since patients with secondary hypogonadism do not exhibit an intact feedback pathway, low testosterone concentrations are not associated with increased LH or FSH levels. Thus, these men have low testosterone serum levels, but gonadotropin usually has a low range.

Age-Related Testosterone Deficiency

Men experience a slow but continual decrease in mean serum testosterone after approximately 20-30 years. Scholars estimate that the decline is about 1-2% per year. Moreover, as men age, the circadian rhythm of testosterone concentrations is often muted, dampened or completely eliminated. Untreated testosterone deficiency in older men may cause various physiological changes, including sexual dysfunction, reduced libido, muscle mass loss, decreased bone density, stagnant mood, and decreased cognitive function. The net result is menopausal age, also known as late onset gonadal hypothyroidism or androgen reduction (ADAM) in older men.

Diagnosis and Treatment of Testosterone Deficiency

The general range of testosterone levels changes as well as the definition of limiting values for diagnosing hypogonadism. The report of the Endocrine Society's Second Annual Andropause Consensus Meeting (Endocrine Society, 2002) described three categories for screening and diagnosing hypogonadism in men over 50: 1) total testosterone <200 ng / dL (ie, 7 nmol / L), approve the diagnosis of androgen deficiency except for severe hypothalamic or pituitary disease in men with hypogonadal gonadotropin;

2) If the total testosterone level is between 200 and 400 ng / dL (ie 7-14 nmol / L), additional measurements and further evaluation of testosterone should be considered before considering testosterone treatment; 3) If the total testosterone level is> 400 ng / dL (ie 14 nmol / L), then it is not testosterone deficiency. Many studies have used a range of 300-350 ng / dL (ie 10-12 nmol / L) of total testosterone as the definitive range for hypogonadal patients (Testosterone and Aging, Clinical Research Directions 2004, ed. Liverman CT and Blaxer DG). In addition to low testosterone serum concentrations, signal (s) and / or syndrome (s) of testosterone deficiency should be for diagnostic purposes. Usually treatment is a substitution therapy that can be measured directly based on testosterone concentrations in the serum effectively. The purpose of testosterone replacement is to increase serum testosterone levels to normal levels. Recently, testosterone / androgen compounds have been used for the treatment of hypogonadism.

Selective Estrogen Receptor Modulators

"SERM" (selective estrogen receptor modulator) has both analogous and estrogen properties (Kauffman & Bryant, Drug News Perspect 8: 531-539, 1995). The effect can be tissue-specific as in the case of tamoxifen and toremifene, which have a pseudo-estrogen effect in bone, a partial-like estrogen effect in the uterus and liver, and a pure anti-estrogen effect in breast cancer. Raloxifene and droloxyphene are similar to tamoxifen and toremifene except that their antiestrogenic properties are predominant. They are known to reduce total and LDL cholesterol, thus reducing the risk of cardiovascular disease, preventing osteoporosis in postmenopausal women and inhibiting the growth of breast cancer.

Investigations and / or reviews of commercialized SERM compounds are published in V Craig Jordan, J Medicinal Chemistry (2003): 46, No. 7.

Summary of the Invention

Surprisingly, the inventors of the present invention have found that compounds belonging to the group of selective estrogen receptor modulators are effective in raising serum testosterone levels in men.

Accordingly, the present invention relates to the treatment or prophylaxis of androgen deficiency in male individuals, the 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. . Moreover, the present invention relates to a method relating to the prevention or treatment of a disease or disorder in a male individual, said disease or disorder being caused by androgen deficiency of said individual, said method being defined in claims 1-6 to the individual. Administering an effective amount of a selective estrogen receptor modulator, or an isomer mixture, a metabolite, or a pharmaceutically acceptable salt thereof.

1 shows the serum concentration of testosterone in men over time during treatment with different doses of pifemifen.

Justice

The term “treatment” or “treating” should be understood to include the cure of the disease or disorder, the amelioration or alleviation of the disease or disorder, and the delay in the progression or onset of the disease or disorder.

The term "prevention" should be understood to include not only lowering the risk of an individual from developing the disease or disorder, but also full protection and prevention.

The term "individual" means a human or animal subject.

The expression "effective amount" is meant to include any amount of other agents in the present invention that is sufficient to produce the desired therapeutic result, especially when administered to an animal or human subject.

The term "androgen deficiency" refers to a condition in male subjects with reduced serum levels of male sex hormones, particularly testosterone and dihydrotestosterone.

The term “testosterone deficiency” refers to a condition in male individuals in which the serum levels of testosterone have decreased and, in particular, have decreased to below, or to a low range of, the normal reference level.

The term “selective estrogen receptor modulator” and any particular compound belonging to this group should be understood to include any geometrical isomer, any stereoisomer, racemate or other mixture of isomers of the compound. Moreover, as well as metabolites, pharmaceutically acceptable salts and other derivatives such as esters are also included.

SERM To treat androgen deficiency using or By preventing , Diseases or disorders that can be prevented or treated

We believe that SERMs are useful in the prevention and treatment of any disease or disorder caused by androgen deficiency in male individuals.

Hypogonadism, especially secondary hypogonadism, and age-related testosterone deficiency are examples of disorders that can be treated or prevented by administering SERMs in accordance with the present invention. In addition, certain diseases or disorders caused by hypogonadism or age-related testosterone deficiency may also be treated or prevented. However, other diseases or disorders caused by androgen deficiency but not associated with hypogonadism or age-related testosterone deficiency may also be treated or prevented according to the methods of the present invention.

Thus, examples of specific diseases or disorders that may be treated or prevented in accordance with the present invention may be mentioned below:

Pituitary gland due to eg Kalman syndrome, Prader-Rabat-Willy syndrome, Lawrence-Moon-Bead syndrome, Pituitary insufficiency / semaoma, Pasqualini syndrome, hemochromatosis, hyperprolactinemia, tumors, trauma, radiation, obesity Hypothalamic damage, chronic diseases such as, but not limited to, hypogonadism resulting from other diseases or disorders that may affect the major production of diabetes mellitus, hypothyroidism or gonadotropin Hypogonadism.

Age-related testosterone deficiency and the resulting diseases or disorders, such as impaired muscle strength, sexual dysfunction, reduced libido, muscle volume loss, reduced bone density, depressed mood, and reduced cognitive function; And

Any muscular atrophy / dystrophies; Lipodistrophy; Long-term fatal diseases; Skeletal muscle reduction; Frailty or age-related decline; Reduced muscle strength and function; Muscle weakness caused by HIV; Chronic renal failure, reduced bone density or growth; Catabolic side effects of glucocorticoids; Chronic fatigue syndrome; Reduced fracture repair; Acute fatigue syndrome and muscle loss after scheduled surgery; Cachesia; Chronic catabolism; Eating disorders; Side effects of chemotherapy; decline; depression; Nervousness irritability; stress; Growth retardation; Senile discharge syndrome; Reduced cognitive function; anemia; Male contraception; sterility; Syndrome X; Diabetic complications or obesity.

SERMs that increase testosterone have the potential to provide new treatments for both menopausal and both osteoporosis and sexual dysfunction in both menopause and men and women, also known as late onset gonadal hypothyroidism or androgen reduction (ADAM) in older men. have. Testosterone deficiency in the elderly may include muscle strength (causing tenderness / disorder); Cognitive or sexual function; Or damage to vitality / well-being / quality of life.

In the treatment of androgen deficiency SERM Advantage

SERM, which increases testosterone to fully treat testosterone deficiency, may have several advantages over direct testosterone substitution. The benefits of increased testosterone are achieved by automatically protecting against potential side effects such as prostate irritation, female mastopathy, or adverse effects on lipid metabolism, which are often associated with increased testosterone due to the anti-estrogen or estrogen effects of the SERM compounds. Can be.

It is known that many estrogens / anti-estrogens / phytoestrogens / SERMs have antitumor effects that are modulated through the estrogen receptors, which can potentially prevent and treat prostate cancer (Ho SM: Estrogens and Anti- Estrogens: Key Mediators of Prostate Carcinogenesis and New Therapeutic Candidates. 2004; 91: 491-503) .SERM is antiestrogenic in the breast and therefore can provide prevention for female mastopathy and is often associated with testosterone treatment.

SERMs provide beneficial effects on lipid profiles such as increased HDL, and reduced total cholesterol and LDL. Testosterone is known to reduce HDL, for example, and this adverse effect can interfere with SERM. Both SERM and testosterone have a beneficial effect on bone metabolism by inhibiting bone turnover. Thus, the preventive effect of SERM on bone would be enhanced if it had the ability to increase testosterone.

In conclusion, SERMs, in particular SERMs according to formula (I) shown below, produce a positive response to androgen replacement therapy without the side effects of testosterone, such as adverse effects on the thymus or lipid metabolism or on female mastopathy.

These compounds increase testosterone, thus stimulating muscle growth and reducing subcutaneous and visceral abdominal fat in the treatment of obesity; It increases energy and libido, minimizes bone depletion and has a beneficial effect on lipid metabolism.

desirable SERM

Suitable selective estrogen receptor modulators (or SERMs) for use in the present invention are, for example, compounds disclosed in V Craig Jordan (2003).

Thus, suitable SERM compounds for use in the present invention are triphenylalkenes or triphenylalkane compounds, for example WO 01/36360, US 4,996,225, US 5,750,576, WO 99/42427 and, L Kangas, Cancer Chemother Pharmacol (1990) 27 Toremifene metabolites disclosed in: 8-12. Examples of specific drugs disclosed in the above-referenced references may be mentioned toremifene, pifemifen and osfemifen. Drroloxyphene and iodoxifen are also examples of suitable SERMs of triphenylalkane structures.

Other preferred examples of SERM compounds are compounds of benzothiophene structure (for example described in EP 584952, US 4,133,814, US 4,418,068) and arzoxifene.

Further examples of suitable SERMs are EM652, EM800, EM776, EM651, EM312, ICI 182780, ERA-923, gindoxifen and deacetylated gindoxifen, ZK119010, TSE-4247, lasoxifen and analogs thereof, in particular EP 802910 And compounds number 32, ICI 164384, RU 58668, RU 39411 and EM319, disclosed in the disclosed herein, napoxidine, basedoxifene, GW5638, GW7604, Jordan (2003).

Preferably, SERM is a triphenylalkane compound, a triphenyl-alkene compound or an isomer, isomer mixture, metabolite or pharmaceutically acceptable salt thereof, wherein the alkene chain is halogen-substituted butene or propene, benzothiophene Compound, EM652, EM800, EM776, EM651, EM312, ICI182780, ERA-923, gindoxifen, deacetylated gindoxifen, ZK119010, TSE-4247, lasoxifen, lasoxifen analog, napoxidine, base Doxyphene, GW5638, GW7604, ICI 164384, RU 58668, RU 39411 or EM319.

More preferably, SERM is a compound of formula (I) triphenylbutene or an isomer, isomer mixture, metabolite or pharmaceutically acceptable salt thereof:

Where

R 1 is H, halogen, OCH ₃ , or OH;

R2 is

a)

이거나,

Or

b) -Y- (CH ₂ ) _n CH ₂ -O-R6, or

c) 2,3-dihydroxypropoxy, 2-methylsulfamyethoxy, 2-chloroethoxy, 1-ethyl-2-hydroxyethoxy, 2,2-diethyl-2-hydroxyethoxy Or carboxymethoxy,

Wherein X is O, NH or S; n is an integer from 1 to 4;

R 4 and R 5 are the same or different and are 1-4 carbon alkyl, H, —CH ₂ C≡CH or —CH ₂ CH ₂ OH;

R4 and R5 form an N-containing 5- or 6-membered ring or a heteroaromatic ring;

Y is O, NH or S, n is an integer from 1-4;

R 6 is H, —CH ₂ CH ₂ OH, or —CH ₂ CH ₂ Cl;

R 3 is H, halogen, OH or —OCH ₃ .

More preferably, SERM is a triphenylbutene compound of formula (I), or an isomer, isomer mixture, metabolite or pharmaceutically acceptable salt thereof:

Where

R 1 is H, halogen, OCH ₃ , or OH;

R2 is

a)

이거나,

Or

b) -Y- (CH ₂ ) _n CH ₂ -O-R6, or

c) 2,3-dihydroxypropoxy, 2-methylthioethoxy, 2-chloroethoxy, 1-ethyl-2-hydroxyethoxy, 2,2-diethyl-2-hydroxyethoxy or Carboxymethoxy,

From here,

i) X is NH or S; n is an integer from 1 to 4;

R 4 and R 5 are the same or different and are 1-4 carbon alkyl, H, —CH ₂ C≡CH or —CH ₂ CH ₂ OH;

R4 and R5 form an N-containing 5- or 6-membered ring or a heteroaromatic ring;

ii) X is O and n is an integer of 1-4;

One of R4 and R5 is -CH ₂ C≡CH or -CH ₂ CH ₂ OH, and the other is H or C1-C4-alkyl; Or R4 and R5 form an imidazole ring, an N-containing 6-membered ring or a heteroaromatic ring; or

Y is O, NH or S and n is an integer of 1-4;

R 6 is H, —CH ₂ CH ₂ OH, or —CH ₂ CH ₂ Cl;

R 3 is H, halogen, OH or —OCH ₃ .

The particular SERM or SERM system mentioned above is merely an example, and other SERMs can likewise be used as appropriate in the present invention.

Preferred SERMs are compounds with tissue specific antiestrogens or estrogen effects suitable for men. Preferred SERMs are estrogens in bone and antiestrogens or hypoallergenic estrogens in other tissues. The classical method of determining the estrogen profile of a compound is to assess the estrogen effect in immature rat or rat uterus (Terenius L, Acta Endocrinol 66; 431-447, 1971). Animals 18 days of age were exposed to the compounds to be investigated for 3 days. On day 4 animals were sacrificed and body weight and uterine mass were recorded. Estrogens increase the size and weight of the uterus (hypertrophic effect), but antiestrogens inhibit this action. Results were given as percentage of estrogen stimulation (100% with estradiol). In this experiment, we used high dose levels, namely 10-50 mg / kg. Compounds that cause uterine hypertrophy ≤ 40% are classified as weak estrogen compounds for this purpose, and compounds that cause uterine hypertrophy ≥70% are classified as strong estrogen compounds and medium to 41-69% uterine hypertrophy The compounds of are classified as intermediate estrogen preparations.

Particular examples of particularly useful SERMs are the specific compounds disclosed in WO 01/36360, ie

(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 (also known as common name pisfemiphene)

(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 (osfemiphene).

The seven compounds mentioned above are all classified as weak estrogen SERMs.

For the purposes of the present invention, SERMs or isomers, isomer mixtures or pharmaceutically acceptable salts thereof can be administered by various routes. Suitable dosage forms include, for example, oral formulations; Parenteral infusions including intravenous, intramuscular, intradermal and subcutaneous infusion; And transdermal or rectal preparations. Suitable oral formulations include, for example, conventional or slow release tablets and gelatin capsules.

The required dosage of SERM compound depends on the particular condition to be treated, the severity of the condition, the duration of treatment, the route of administration and the particular compound to be used. For example, pifemifen can be administered orally, preferably once daily. The daily dose may be 5-1500 mg, preferably 20-1500 mg. Pisfemiphene may be provided alone or in combination with other agents, such as tablets or gelatin capsules, or in any clinically acceptable inactive ingredients used in the pharmaceutical industry.

The invention can be clarified by the following non-limiting experimental part.

Method and substance

Pifemifen has been investigated in humans in two phase I studies, a single dose and a repeated dose study. The effect of pifemiphene on hormone levels is one major center in repeat dose studies. A Phase I repeat study (numbers 101-50202) was performed in 32 healthy 50-68 year olds in a randomized, double-blind, placebo-controlled, 28-day dose-scale expansion study. The main purpose of this study was to investigate tolerability, safety and pharmacokinetics after repeated use of pifemiphene, but the study also focused on the effects of pifemifen on serum testosterone, estradiol and other related hormones. Fit. 10, 30, 100 and 300 mg pisfemiphene doses and placebo per day were administered once daily each morning as capsules containing 10 mg or 100 mg pisfemifen, or placebo. If the previous dose was evaluated to be safe and well tolerated by laboratory safety decisions and mammary gland ultrasound, the dose was escalated to the next higher dose level.

Variables for safety and endurance include adverse events, vital signs, 12-induced electrocardiogram, clinical laboratory evaluation, physical examination, ultrasonography (wired), and inhibin b. For pharmacokinetics, the concentration of pifemiphene and its metabolite (s) were evaluated. For pharmacodynamics, serum concentrations of FSH, LH, estradiol, testosterone, SHBG, prolactin, aldosterone, cortisol and TSH before and after treatment were measured and compared to the concentrations in the placebo group.

Against hormones Pisfemiphen  Results for the impact

Surprisingly, pifemifen increased serum concentrations of testosterone, FSH, LH and SHBG for 28 days of treatment (Table 1). Testosterone was statistically significantly increased compared to placebo with 100 mg and 300 mg pifemifen. At the 300 mg dose, the increase in mean total testosterone was about 75% relative to baseline concentration. Two of the six men treated with the highest pifemifen dose had serum testosterone levels above the upper limit of the normal range of treatment (ie, 33 nmol / L). The other two had a significant increase within the reference range. At the 100 mg dose, the average increase in total testosterone was about 32%, and all six men in the group had their testosterone levels increased within the reference range. An increase in total testosterone levels in serum is illustrated by the group in FIG. 1. The lack of safety concerns at any dose suggests that even higher doses may be used if deemed appropriate.

Table 1. Serum total testosterone concentrations (mean and SD) and other hormones during treatment at baseline, and in studies 101-50202 by dose.

Discussion and results

Pifemifen showed a clinically and statistically significant, dose dependent increase in serum testosterone concentrations within 28 days from the start of treatment. In addition, an increase in testosterone serum concentration within 28 days of treatment was observed in all subjects treated with 100 mg or 300 mg pisfemiphene. An increase of 75% from baseline is clinically very significant, and therefore clinical benefit can be expected in low testosterone men. Increases in LH and FSH also suggest that pisfemifen has an antiestrogenic effect on the hypothalamus / pituitary, and the increase in testosterone occurs due to an increase in pituitary hormones. The increase in testosterone is moderate and therefore is expected to be free of the deleterious effects often associated with external testosterone administration. Moreover, SERM will provide protection against possible safety problems with testosterone, such as the development of anterior forest cancer. Thus, SERMs that increase testosterone provide an optimal treatment of hypogonadism, an increase in the efficiency and safety of increased testosterone.

The methods of the present invention may be included in the form of various embodiments, only some of which are disclosed herein. It will be apparent to those skilled in the art that other embodiments exist and do not depart from the spirit of the present invention. Accordingly, the described embodiments are illustrative and should not be construed as limiting.

Claims (13)

Use of an optional estrogen receptor modulator, or an isomer, isomer mixture, metabolite or pharmaceutically acceptable salt thereof, for the preparation of a formulation for use in a method for the treatment or prevention of androgen deficiency in a male individual. The method of claim 1, wherein the selective estrogen receptor modulator is a triphenylalkane compound, a triphenyl-alkene compound, or an isomer, isomer mixture, metabolite or pharmaceutically acceptable salt thereof, wherein the alkene chain is halogen-substituted butene or Propene, benzothiophene compound, EM652, EM800, EM776, EM651, EM312, ICI 182780, ERA-923, gindoxifen, deacetylated gindoxifen, ZKl 19010, TSE-4247, lasoxifen, lasoxi Use of a pen analog, napoxidine, basdoxifene, GW5638, GW7604, ICI 164384, RU 58668, RU 39411 or EM 319. Use according to claim 2, wherein the selective estrogen receptor modulator is a triphenylbutene compound of formula (I), or an isomer, isomer mixture, metabolite or pharmaceutically acceptable salt thereof.

Where R 1 is H, halogen, OCH ₃ , or OH; R2 is a)

Or b) -Y- (CH ₂ ) _n CH ₂ -O-R6, or c) 2,3-dihydroxypropoxy, 2-methylthioethoxy, 2-chloroethoxy, 1-ethyl-2-hydroxyethoxy, 2,2-diethyl-2-hydroxyethoxy or Carboxymethoxy, Wherein X is O, NH or S; n is an integer from 1 to 4; R 4 and R 5 are the same or different and are 1-4 carbon alkyl, H, —CH ₂ C≡CH or —CH ₂ CH ₂ OH; R4 and R5 form an N-containing 5- or 6-membered ring or a heteroaromatic ring; Y is O, NH or S and n is an integer of 1-4; R 6 is H, —CH ₂ CH ₂ OH, or —CH ₂ CH ₂ Cl; R 3 is H, halogen, OH or —OCH ₃ . Use according to claim 2, wherein the selective estrogen receptor modulator is a triphenylbutene compound of formula (I), or an isomer, isomer mixture, metabolite or pharmaceutically acceptable salt thereof.

Where R 1 is H, halogen, OCH ₃ , or OH; R2 is a)

Or b) -Y- (CH ₂ ) _n CH ₂ -O-R6, or c) 2,3-dihydroxypropoxy, 2-methylthioethoxy, 2-chloroethoxy, 1-ethyl-2-hydroxyethoxy, 2,2-diethyl-2-hydroxyethoxy or Carboxymethoxy, From here, i) X is NH or S; n is an integer from 1 to 4; R 4 and R 5 are the same or different and are 1-4 carbon alkyl, H, —CH ₂ C≡CH or —CH ₂ CH ₂ OH; R4 and R5 form an N-containing 5- or 6-membered ring or a heteroaromatic ring; ii) X is O and n is an integer of 1-4; One of R4 and R5 is -CH ₂ C≡CH or -CH ₂ CH ₂ OH, and the other is H or C1-C4-alkyl; Or R4 and R5 form an imidazole ring, an N-containing 6-membered ring or a heteroaromatic ring; or Y is O, NH or S and n is an integer of 1-4; R 6 is H, —CH ₂ CH ₂ OH, or —CH ₂ CH ₂ Cl; R 3 is H, halogen, OH or —OCH ₃ . The use according to any one of claims 1 to 4, wherein the selective estrogen receptor modulator is a compound having tissue specific antiestrogens or estrogen effects suitable for men. Use according to claim 5, wherein the selective estrogen receptor modulator is selected from the group consisting of the following compounds or isomers, isomer mixtures, metabolites or pharmaceutically acceptable salts thereof: (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 (pisfemiphene), (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 (osfemiphene). Use according to claim 6, wherein the selective estrogen receptor modulator is pisfemiphene or a metabolite or pharmaceutically acceptable salt thereof. 8. The selective estrogen receptor modulator, or isomer, isomer thereof, according to any one of claims 1 to 7, in the preparation of a formulation useful for the prevention or treatment of said disease or disorder in said individual, caused by androgen deficiency in a male individual. Use of mixtures, metabolites or pharmaceutically acceptable salts. Use according to claim 8, wherein said disease or disorder is selected from the group consisting of: Pituitary gland due to eg Kalman syndrome, Prader-Rabat-Willy syndrome, Lawrence-Moon-Bead syndrome, Pituitary insufficiency / semaoma, Pasqualini syndrome, hemochromatosis, hyperprolactinemia, tumors, trauma, radiation, obesity Hypothalamic damage, chronic diseases such as, but not limited to, hypogonadism resulting from other diseases or disorders that may affect the major production of diabetes mellitus, hypothyroidism or gonadotropin Hypogonadism; Age-related testosterone deficiency and the resulting diseases or disorders, such as impaired muscle strength, sexual dysfunction, reduced libido, muscle volume loss, reduced bone density, depressed mood, and reduced cognitive function; And Any muscular atrophy / dystrophies; Lipodistrophy; Long-term fatal diseases; Skeletal muscle reduction; Frailty or age-related decline; Reduced muscle strength and function; Muscle weakness caused by HIV; Chronic renal failure, reduced bone density or growth; Catabolic side effects of glucocorticoids; Chronic fatigue syndrome; Reduced fracture repair; Acute fatigue syndrome and muscle loss after scheduled surgery; Cachesia; Chronic catabolism; Eating disorders; Side effects of chemotherapy; decline; depression; Nervousness irritability; stress; Growth retardation; Senile discharge syndrome; Reduced cognitive function; anemia; Male contraception; sterility; Syndrome X; Diabetic complications or obesity. 10. The method according to claim 9, wherein the disease or disorder is selected from hypogonadism, in particular, but not limited to, secondary hypogonadism and the disease or disorder caused thereby, and age-related testosterone deficiency and the disease or disorder caused thereby. Wherein said selective estrogen receptor modulator is a triphenylbutene compound of formula (I), an isomer, an isomer mixture, a metabolite or a pharmaceutically acceptable salt thereof:

Where R 1 is H, halogen, OCH ₃ , or OH; R2 is a)

Or b) -Y- (CH ₂ ) _n CH ₂ -O-R6, or c) 2,3-dihydroxypropoxy, 2-methylsulfamyethoxy, 2-chloroethoxy, 1-ethyl-2-hydroxyethoxy, 2,2-diethyl-2-hydroxyethoxy Or carboxymethoxy, Wherein X is O, NH or S; n is an integer from 1 to 4; R 4 and R 5 are the same or different and are 1-4 carbon alkyl, H, —CH ₂ C≡CH or —CH ₂ CH ₂ OH; R4 and R5 form an N-containing 5- or 6-membered ring or a heteroaromatic ring; Y is O, NH or S and n is an integer of 1-4; R 6 is H, —CH ₂ CH ₂ OH, or —CH ₂ CH ₂ Cl; R 3 is H, halogen, OH or —OCH ₃ . Use according to claim 10, wherein said selective estrogen receptor modulator is a triphenylbutene compound of formula (I), or an isomer, isomer mixture, metabolite or pharmaceutically acceptable salt thereof.

Where R 1 is H, halogen, OCH ₃ , or OH; R2 is a)

Or b) -Y- (CH ₂ ) _n CH ₂ -O-R6, or c) 2,3-dihydroxypropoxy, 2-methylthioethoxy, 2-chloroethoxy, 1-ethyl-2-hydroxyethoxy, 2,2-diethyl-2-hydroxyethoxy or Carboxymethoxy, From here, i) X is NH or S; n is an integer from 1 to 4; R 4 and R 5 are the same or different and are 1-4 carbon alkyl, H, —CH ₂ C≡CH or —CH ₂ CH ₂ OH; R4 and R5 form an N-containing 5- or 6-membered ring or a heteroaromatic ring; ii) X is O and n is an integer of 1-4; One of R4 and R5 is -CH ₂ C≡CH or -CH ₂ CH ₂ OH, and the other is H or C1-C4-alkyl; Or R4 and R5 form an imidazole ring, an N-containing 6-membered ring or a heteroaromatic ring; or Y is O, NH or S and n is an integer of 1-4; R 6 is H, —CH ₂ CH ₂ OH, or —CH ₂ CH ₂ Cl; R 3 is H, halogen, OH or —OCH ₃ . Use according to claim 11, wherein the selective estrogen receptor modulator is selected from the group consisting of the following compounds or isomers, isomer mixtures, metabolites or pharmaceutically acceptable salts thereof: (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 (pisfemiphene), (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 (osfemiphene). 13. Use according to claim 12, wherein the selective estrogen receptor modulator is pisfemiphene, or an isomer, isomer mixture, metabolite or pharmaceutically acceptable salt thereof.

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