AU2005279178A1 - 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

Description

WO 2006/024689 PCT/F12005/000333 1 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 5 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). 10 The invention concerns further methods for treatment or prevention of diseases or disorders caused by said androgen deficiency. BACKGROUND OF THE INVENTION 15 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 20 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, 25 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 erythropoictin and the cognitive functions. A shortage of testosterone (hypogonadism) may be classified into two principle forms, which are designated 30 primary and secondary hypogonadism. Diseases based on testosterone shortage include for instance osteoporosis, muscle atrophy, senescence outfall symptoms,

Claims (13)

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 5 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 10 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 15 thereof.

3. The use according to claim 2 wherein the selective estrogen receptor modulator is a triphenylbutene compound of the formula (I) R2 R3 R1 Cl 20 wherein R1 is H, halogen, OCH 3 , or OH; and R2 is a)4 a) -X-(CH 2 )n--CH 2 -N R5 where X is 0, NH or S; and n is an integer from I to 4; and WO 2006/024689 PCT/F12005/000333 18 R4 and R5, which are the same or different, are a 1 to 4 carbon alkyl, H, -CH 2 C= CH or -CH 2 CH 2 OH; or R4 and R5 form an N-containing five- or six-membered ring or heteroaromatic ring; or 5 b) -Y-(CH 2 )nCH 2 -O-R6 where Y is 0, NH or S and n is an integer from 1 to 4; and R6 is H, -CH 2 CH 2 OH, or -CH 2 CH 2 Cl; or c) 2,3-dihydroxypropoxy, 2-methylthioethoxy, 2-chloroethoxy, 1-ethyl-2 hydroxyethoxy, 2,2-diethyl-2-hydroxyethoxy or carboxymethoxy; and 10 R3 is H, halogen, OH or -OCH 3 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) R2 R3 R1 15 CI wherein R1 is H, halogen, OCH 3 , or OH; and R2 is a) R4 R5 where i) X is NH or S; and n is an integer from 1 to 4; and 20 R4 and R5, which are the same or different, are a 1 to 4 carbon alkyl, H, -CH 2 C=CH or -CH 2 CH 2 OH; or R4 and R5 form an N-containing five- or six-membered ring or heteroaromatic ring; or WO 2006/024689 PCT/F12005/000333 19 where ii) X is 0, and n is an integer from 1 to 4; and one of R4 and R5 is -CH 2 C=CH or -CH 2 CH 2 OH 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 5 b) -Y-(CH 2 )nCH 2 -0-R6 where Y is 0, NH or S and n is an integer from 1 to 4; and R6 is H, -CH 2 CH 2 OH, or -CH 2 CH 2 Cl; or R2 is c) 2,3-dihydroxypropoxy, 2-methylthioethoxy, 2-chloroethoxy, 1-ethyl-2 hydroxyethoxy, 2,2-diethyl-2-hydroxyethoxy or carboxymethoxy; and 10 R3 is H, halogen, OH or -OCH 3 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 15 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, 20 (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-l-[4-(2-imidazol-1-yl-ethoxy)phenyl]-2-phenyl-but-1-enyl} 25 phenol, (Z)-3-{4-Chloro-1-[4-(2-imidazol-1-yl-ethoxy)phenyl]-2-phenyl-but-l-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 WO 2006/024689 PCT/F12005/000333 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. 5

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 10 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 15 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 20 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 25 - 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 30 surgery; cachesia; chronic catabolic state; eating disorders; side effects of chemotherapy; wasting; depression; nervousness irritability; stress; growth WO 2006/024689 PCT/F12005/000333 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 5 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 10 said selective estrogen receptor modulator is a triphenylbutene compound of the formula (I) R2 R3 RI(I C1 wherein R1 is H, halogen, OCH 3 , or OH; and R2 is a) R4 -X-(CH 2 )n--CH 2 -N 15 R5 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, -CH 2 C=CH or -CH 2 CH 2 OH; or R4 and R5 form an N-containing five- or six-membered ring or 20 heteroaromatic ring; or b) -Y-(CH 2 )nCH 2 -0-R6 where Y is 0, NH or S and n is an integer from I to 4; and R6 is H, -CH 2 CH 2 OH, or -CH 2 CH 2 Cl; or WO 2006/024689 PCT/F12005/000333 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 -OCH 3 or an isomer, isomer mixture, metabolite or a pharmaceutically acceptable salt thereof. 5

11. The use according to claim 10 wherein said selective estrogen receptor modulator is a triphenylbutene compound of the formula (I) R2 R3 R1 C1 wherein RI is H, halogen, OCH 3 , or OH; and 10 R2 is a) R4 --- X-(CH 2 )ri--CH 2 -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, -CH 2 C=CH or -CH 2 CH 2 OH; or 15 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 I to 4; and one of R4 and R5 is -CH 2 C=CH or -CH 2 CH 2 OH and the other is H or a C1-C4-alkyl; or R4 and R5 form an imidazole ring, an N-containing 20 six-membered ring or heteroaromatic ring; or R2 is b) -Y-(CH 2 )CH2-0-R6 where Y is 0, NH or S and n is an integer from 1 to 4; and R6 is H, -CH 2 CH 2 OH, or -CH 2 CH 2 C1; or R2 is WO 2006/024689 PCT/F12005/000333 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 -OCH 3 or an isomer, isomer mixture, metabolite or a pharmaceutically acceptable salt thereof 5

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 10 (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-enyll phenol, 15 (Z)-3-{4-Cbloro-l-[4-(2-imidazol-1-yl-ethoxy)phenyl]-2-phenyl-but-l-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. 20

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. WO 2006/024689 PCT/F12005/000333 2 the decrease of libido and potency, depression and anaemia. Primary hypogonadism 5 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, 10 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 15 low serum testosterone concentrations are associated with high FSH (follicle stimulating hormone) and LH luteinizingg hormone) concentrations. However, because of testicular or other failures, the high LH concentrations are not effective at stimulating testosterone production. 20 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 25 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 30 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. WO 2006/024689 PCT/F12005/000333 3 Age-related testosterone deficiency Men experience a slow but continuous decline in average serum testosterone after 5 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 10 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 15 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 20 hypogonadism in men over 50 years of age: 1) if total testosterone is 5 200 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 25 considering testosterone therapy arc 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 30 addition to the low testosterone serum concentration, sign(s) and/or symptom(s) of testosterone deficiency should be present for the diagnosis. WO 2006/024689 PCT/F12005/000333 4 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 5 for hypogonadism. Selective estrogen receptor modulators "SERM"s (selective estrogen receptor modulators) have both estrogen-like and 10 antiestrogenic properties (Kauffman & 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 15 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 20 Craig Jordan, J Medicinal Chemistry (2003):46, No.7. SUMMARY OF THE INVENTION The inventors of the present invention have surprisingly found that compounds 25 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 30 individual an effective amount of a selective estrogen receptor modulator, or an isomer, isomer mixture, metabolite or a pharmaceutically acceptable salt thereof. WO 2006/024689 PCT/F12005/000333 5 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 10 Figure 1 shows serum concentration of testosterone in men versus time during treatment with different doses of fispemifene. DETAILED DESCRIPTION OF THE INVENTION 15 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. 20 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. 25 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. 30 WO 2006/024689 PCT/F12005/000333 6 The term "androgen deficiency" shall mean a condition in the male individual where the serum level of masculine sex hormones, particularly testosterone and dihydrotestosterone, is decreased. 5 The term "testosterone deficiency" refers to a condition in the male individual where the serum 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. 10 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. 15 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 20 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 25 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 30 of this invention. WO 2006/024689 PCT/F12005/000333 7 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 5 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; 10 - 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-tern critical illness; 15 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 20 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 25 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. 30 Advantages of SERMs in the treatment of androgen deficiency WO 2006/024689 PCT/F12005/000333 8 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 5 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 10 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. 15 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 20 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 25 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 30 energy and libido and minimize the bone depletion; and have beneficial effects on lipid metabolism.