NZ621476B2 - Use of an aromatase inhibitor for the treatment of hypogonadism and related diseases - Google Patents

Abstract

Disclosed herein is the use of the aromatase inhibitor 4,4'-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile in the manufacture of a medicament for the treatment of hypogonadism in a male patient with serum total testosterone levels below 400 ng/dl, wherein the compound is provided in a form comprising from about 0.001 mg to about 1.0 mg 4,4'-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile per dose. m comprising from about 0.001 mg to about 1.0 mg 4,4'-[fluoro-(1-H-1,2,4-triazol-1-yl)methylene]bisbenzonitrile per dose.

Description

USE OF AN AROMATASE INHIBITOR FOR THE TREATMENT OF HYPOGONADISM AND RELATED DISEASES FIELD OF THE INVENTION This invention relates to a method of sing testosterone levels and treating hypogonadism and related diseases with the aromatase inhibitor 4,4‘—[fluoro—(1-H—1,2,4— triazol-1—yl)methylene]-bisbenzonitrile. The present invention further relates to a method of increasing testosterone levels and treating hypogonadism and related diseases with the aromatase inhibitor 4,4'-[fluoro-(1-H—1,2,4—triazolyl)methylene]-bisbenzonitrile in a particular dosing regimen. The ion also relates to pharmaceutical compositions comprising said aromatase inhibitor 4,4'-[fluoro—(1-H-1,2,4—triazol—1~yl)methylene]- bisbenzonitrile, optionally in combination with other active ingredients. Furthermore, the present invention relates to kits comprising said pharmaceutical itions together with instructions how to administer them.

BACKGROUND OF THE INVENTION The enzyme ase (CYP 19) is highly expressed in adipose tissue, where it converts testosterone to estradiol. in human overweight or obesity, excess adipose tissue is associated with excess ase activity, which in turn results in higher levels of estradiol in both men and women. ln overweight and obese men, the relative excess of estradiol can feed back to the hypothalamic pituitary axis, ssing gonadotropin secretion and thereby ssing testicular testosterone production as well as spermatogenesis. Thus, severe obesity is associated with relative androgen deficiency in men. This condition can be called OHH or obese hypogonadotropic hypogonadism or hypogonadotropic hypogonadism in obese men.

In the 1999—2002 National Health and Nutrition Examination Survey data set, 27.5% of men over the age of 20 in the United States had a Body Mass Index (BMI) above kg/m2. The prevalence of obesity is expected to continue to increase in the United States, and in both developed and developing ies around the world. In one study of 160 men referred for medical or al treatment of obesity, hypogonadotropic nadism was present in 36% overall. In this study, the prevalence of hypogonadotropic nadism rose linearly from 7.4% in those with a BMI of 30— kg/m2 to 59.2% in those with a BMI above 50 kg/m2 [Hofstra, et al 2008]. Based on the PCT/U82012/053844 prevalence of obesity, we estimate that up to 1.5 million men in the US and 1 million men in Europe would have androgen deficiency due to hypogonadotropic hypogonadism.

The consequences of testosterone deficiency are many, including symptoms of decreased libido, decreased spontaneous ons, decreased fertility, loss of body hair and reduced shaving, low bone mineral density, increased risk of fractures, decreased muscle mass and strength and fatigue [Bhasin, et al 2006]. In on, more recent studies have demonstrated that testosterone deficiency in older men and in men with y is also associated with metabolic abnormalities including insulin resistance, glucose intolerance, and lipid abnormalities, contributing to an increased incidence of metabolic syndrome, and likely increased risk of cardiovascular disease. in one study, up to 15% of diabetic men had clear hypogonadism (testosterone < 300 ng/dL or < 8 nmol/L) and up to 50% had testosterone in the lower range of normal (<12 nmoI/L or < 450 ng/dL) [Kapoor, et al 2006 and 2007]. An association has been established between low testosterone levels and various cardiovascular risk factors. Recent epidemiological studies have also linked low testosterone with cardiovascular mortality [Maggio et al. 2009] Guidelines for the treatment of male hypogonadism have been developed by several organizations, including the ine Society of the United States stating that "We recommend testosterone y for symptomatic men with androgen deficiency, who have low testosterone levels, to induce and maintain secondary sex characteristics and to improve their sexual function, sense of well-being, muscle mass and strength, and bone mineral density" [Bhasin, et al 2006]. ement of terone is typically recommended by either intramuscular or transdermal routes as the standard of care for men with documented hypogonadism (testosterone < 300 ng/dL associated with symptoms of low testosterone) and can ize libido, muscle mass and strength [Bhasin, et al 2006]. in addition, testosterone replacement improves insulin resistance in men with hypogonadism ci, et al 2007].

Next to overweight and y and its associated excess aromatase activity, other causes of hypogonadism in men include y testicular failure, which may be due to endogenous defects or acquired due to trauma, infection, or chemo- or radiation y, and secondary failures with suppression of gonadotropins that may be due to , itant diseases, or hypothalamic pituitary disorders.

Current therapies for terone deficiency are limited. Most hypogonadal men are treated with intramuscular injections of testosterone every 2 to 4 weeks, typically requiring a visit to a health care provider. Some men choose testosterone gels or patches PCT/U82012/053844 that are usually d daily. Men with OHH desiring fertility may be treated with intra- muscular or subcutaneous injections of HCG or tropins. There are various complications of testosterone replacement which may include gynecomastia due to the excessive sion of exogenous testosterone to estradiol, infertility due to suppression of gonadotropins, mood swings due to the rise and fall of testosterone after intramuscular ions, and injection site or application site irritation. Excess testosterone can lead to polycythemia rocytosis), prostate enlargement, sleep apnea, and worsening heart failure, in addition to aggressiveness. The Endocrine Society recommends st starting testosterone therapy in patients with breast or prostate cancer, a palpable prostate nodule or induration or prostate-specific antigen r than 3 ng/ml without further urological evaluation, erythrocytosis (hematocrit > 50%), hyperviscosity, untreated obstructive sleep apnea, severe lower urinary tract symptoms with international Prostate Symptom Score (lPSS) , et al 1992] greater than 19, or class ill or IV heart failure", and that "men receiving testosterone therapy should be monitored using a standardized plan" [Bhasin, et al 2006].

Oral en therapies are generally contraindicated because of first pass hepatic effects that dramatically suppress HDL, se thrombogenic factors, and often cause liver function abnormalities. These hepatic effects of androgens have also so far limited the clinical utility of ive androgen or modulators (SARMs). [9] Some cially available aromatase inhibitors have also been tested for efficacy in hypogonadal men in a few, small proof of concept studies. Letrozole, given at doses of 2.5 mg weekly, increased total testosterone into the normal range, suppressed total estradiol, and increased LH and FSH in 12 OHH men [de Boer, et al 2005, Loves, et al 2008]. At this fixed dosing interval, free testosterone rose above the normal range in approximately half of the subjects. Other investigators have assessed the effects of aromatase inhibitors (letrozole [de Boer, et al 2005, Lapauw, et al 2009, Loves, et al 2008] CGS 20267 [Trunet, et al 1993] and anastrozole [Medras, et al 2007]) in uncontrolled studies.

One potential draw-back of all clinical studies ted so far is that the aromatase inhibitors used in studies — anastrozole and letrozole — were developed for the treatment of hormone dependent cancers such as breast cancer in post—menopausal women and might therefore not be lly le to treat hypogonadism in male patients, in particular in view of the optimal dosages and dosing regimen, and the potential side effects. Dosages and dosing regimens assessed so far in the clinical trials comprised the weekly administration of 2.5 mg or 1 mg of the respective aromatase inhibitor for the treatment of hypogonadism — which corresponds to the dosages used for adjuvant treatment of postmenopausal women with hormone receptor positive early breast cancer, but not an optimized treatment regimen for hypogonadism.

Indeed, human PK/PD studies of marketed aromatase inhibitors in men with hypogonadism have shown that e.g. letrozole at a 2.5 mg weekly dose resulted in excessive free testosterone levels in imately half the subjects , et al, 2008].

There have been no studies so far to fully assess the effects of aromatase inhibitors on testosterone levels and how to actually achieve ization of testosterone levels in men with hypogonadism. id="p-12" id="p-12" id="p-12" id="p-12" id="p-12" id="p-12" id="p-12" id="p-12" id="p-12" id="p-12" id="p-12" id="p-12"

[12] Thus, optimized treatment regimens providing the relief of the testosterone deficiency driven symptoms of hypogonadism with minimal side effects are ed. The development of an aromatase inhibitor especially suited for male patients with decreased terone levels would e a novel ent option for this so far insufficiently targeted disease. id="p-13" id="p-13" id="p-13" id="p-13" id="p-13" id="p-13" id="p-13" id="p-13" id="p-13" id="p-13" id="p-13" id="p-13"

[13] in addition to the clinically approved non-steroidal aromatase Inhibitors anastrozole, letrozole and fadrozole, which are approved for the ent of hormone dependent breast cancer by daily administration of dosages in the mg range, several other aromatase inhibitors have been described in the patent and scientific literature. One of these compounds is the aromatase inhibitor 4,4'-[fluoro-(1—H-1,2,4—triazo| yl)methylene]bisbenzonitrile, also known as 4-[cCyanophenyl)~a-fluoro—1-(1,2,4— triazolyl)methyl]-benzonitrile or CGP47645, first bed in 1992 [EP 490 816 and US ,637,605], having the following structural formula CGP47645 is a fluoro-derivative of letrozole with a prolonged duration of action.

Preliminary in-vitro and in-vivo experiments with this compound in rats and monkeys showed a similar up to 10 fold higher y of aromatase inhibition as letrozole, and demonstrated the potential for less than daily treatment regimen. A once weekly administration of 3 mg/kg of CGP47645 was considered as an effective dose achieving l castration in adult female rats [Batzl-Hartmann et al, 1994]. It was concluded that the half—life of CGP47645 is long enough to maintain endocrine cy similar to that of ovariectomy with a once-weekly dosing schedule [Bhatnagar et al, 1996]. However, no r s of this drug compound have been d out and its potential for the treatment of hormone dependent cancers or other diseases such as endometriosis was never investigated.

Currently, there are no oral pharmacological treatment regimens approved to treat hypogonadism and/or testosterone deficiency in obese male patients in the US and most other countries. As set out above, currently, testosterone, HCG or tropin injections are so far the only option for these patients. Therefore, there is an important unmet l need in this population for the development of a pharmacological treatment that reduces the disorders and symptoms associated with testosterone deficiency.

In particular, an oral therapy that normalizes systemic testosterone, but does not significantly increase local hepatic exposure to ens would be highly desirable. In addition, it would be desirable to have a treatment regimen available achieving a more physiologic testosterone replacement.

In consideration of all problems and disadvantages connected with the so far known treatment options for male hypogonadism and testosterone deficiency, in particular hypogonadotropic hypogonadism in obese or overweight men, it would be highly advantageous to provide a new ent option overcoming the aforementioned drawbacks and indeed providing relief or at least improvement for these patients.

Y OF THE INVENTION Accordingly, in a first aspect the present invention relates to the compound 4,4'- 3O [fluoro-(1—H-1,2,4-triazol—1-y|)methylene]bisbenzonitrile for use in the treatment of a male patient in need of increased testosterone levels. [18A] In ular, the present invention provides use of the nd 4,4'-[fluoro—(1-H- 1,2,4—triazoly|)methylene]bisbenzonitrile in the manufacture of a medicament for treatment of hypogonadism in a male patient with serum total testosterone levels below 400 ng/dl, wherein the compound is provided in a form comprising from about 0.001 mg to about 1.0 mg 4,4'—[fluoro—(1—H-1,2,4-triazolyI)methylene]bisbenzonitrile per dose, and wherein the compound is for administration according to a dosing regimen having a dosing periodicity g from about one dose once daily to about one dose once every 60 days.

In one embodiment said male patient is overweight or obese. in a second aspect the t invention relates to the compound 4,4'-[f|uoro-(1—H- triazo|yl)methylene]bisbenzonitrile for use in the treatment of hypogonadism in a male patient. id="p-21" id="p-21" id="p-21" id="p-21" id="p-21" id="p-21" id="p-21" id="p-21" id="p-21" id="p-21" id="p-21" id="p-21"

[21] in a third aspect, the present invention relates to the compound 4,4'-[f|uoro-(1-H- 1,2,4—triazolyl)methylene]bisbenzonitrile for use in the treatment of nadism in an overweight or obese male patient.

In a fourth , the present invention relates to the compound 4,4'-[fluoro-(1-H- 1,2,4—triazoIy|)methylene]bisbenzonitrile for use in the treatment of hypogonadotropic hypogonadism in a male patient.

In a further aspect, the present invention relates to the compound 4,4'-[fluoro-(1-H- 1,2,4—triazoly|)methylene]bisbenzonitrile for use in the treatment of hypogonadotropic hypogonadism in an ovenNeight or obese male t.

In a further aspect, the present invention relates to the compound 4,4‘-[f|uoro—(1—H— triazol—1—yl)methylene]bisbenzonitrile for increasing, preferably normalizing testosterone levels in a male patient with hypogonadism or hypogonadotropic nadism, preferably in an oven/veight or obese male patient with hypogonadism or hypogonadotropic hypogonadism.

In a further aspect, the present invention relates to the compound 4,4'-[fluoro-(1-H- 1,2,4—triazol-1—yl)methylene]bisbenzonitrile for use in the treatment of a male patient in need of increased testosterone , wherein the nd is provided in a form comprising from about 0.0005 mg to about 5.0 mg, preferably from about 0.0005 mg to about 2.0 mg 4,4’-[fluoro-(1-H-1,2,4-triazoIyI)methylene]bisbenzonitrile per dose and is for administration according to a dosing regimen having a dosing icity ranging from about once daily to about once every 60 days.

In a further aspect the present invention relates to the use of 4,4'-[fluoro-(1-H-1,2,4- triazoI—1-y|)methylene]bisbenzonitrile for the manufacture of a medicament for the [FOLLOWED BY PAGE 6a] treatment of a male patient in need of increased testosterone levels.

In a further aspect the present invention relates to the use of 4,4'-[fluoro—(1-H-1,2,4— triazolyl)methylene]bisbenzonitrile for the cture of a ment for the increasing, preferably normalizing testosterone levels in an overweight or obese male patient with hypogonadotropic hypogonadism.

A further aspect of the t invention relates to the use of 4,4'—[f|uoro-(1-H-1,2,4- triazol—1-yl)methyiene]bisbenzonitrile for the manufacture of a medicament for the [FOLLOWED BY PAGE 7] PCT/U82012/053844 treatment of a male patient in need of increased testosterone levels, wherein the compound is provided in a form comprising from about 0.0005 mg to about 5.0 mg, ably from about 0.0005 mg to about 2.0 mg 4,4'-[fluoro-(1-H-1,2,4—triazo| hylene]bisbenzonitrile per dose and is for stration according to a dosing regimen having a dosing periodicity ranging from about once daily to about once every 60 days.

In a further aspect the present invention relates to an oral pharmaceutical composition comprising from about 0.0005 mg to about 5.0 mg, preferably from about 0.0005 mg to about 2.0 mg 4,4'—[tluoro-(1-H-1,2,4-triazol~1-y|)methylene]bisbenzonitrile per dose, optionally in combination with one or more ceutically acceptable excipients.

According to a r aspect of the invention there is provided a kit of parts comprising (i) such a pharmaceutical composition comprising fluoro-(1-H-1,2,4— triazol—1~yl)methylene]bisbenzonitriie, optionally in combination with one or more pharmaceutically acceptable excipients; together with (ii) instructions how to administer said pharmaceutical composition for the treatment of a male patient in need of increased testosterone levels, in particular for the treatment of hypogonadism in a male patient, preferably an overweight or obese male patient.

In a further aspect the present invention relates to a method for the treatment of a male patient in need of increased testosterone levels comprising administering to said patient an effective amount of 4,4'~[tluoro-(’l-H-1,2,4—triazo|yl)methylene]bisbenzonitrile. ing to a further aspect of the invention there is provided a method for the treatment of hypogonadism comprising the administration to a male patient in need thereof an effective amount of 4,4'-[fluoro—(‘l-H-1 ,2,4—triazolyl)methylene]bisbenzonitrile. id="p-33" id="p-33" id="p-33" id="p-33" id="p-33" id="p-33" id="p-33" id="p-33" id="p-33" id="p-33" id="p-33" id="p-33"

[33] The dose can be from about 00005 mg to about 5.0 mg, preferably from about 0.0005 mg to about 2.0 mg and administered in a dosing regimen having a dosing icity g from about once daily to about once every 60 days.

ABBREVIATIONS Throughout this specification, the following abbreviations will be used: AE adverse event ANCOVA analysis of covariance model AUC area under the concentration time curve BA bioavailability BE bioequivalence BMD Bone Mineral Density BMI Body Mass lndex EOS end of study FDA Food and Drug Administration GCP good clinical practice GnRH gonadotrophic hormone releasing hormone HOMA—IR homeostatic model assessment of insulin resistance HRQoL Health-related Quality of Life i.v. intravenous(ly) LH luteinizing hormone LLN Lower Limit of the Norm LLOQ lower limit of fication mL millilitre(s) mm Hg millimeters of mercury NCS not clinically significant NOAEL no-observable adverse effect level NTEL no-toxic-effect level o.d. or q.d. once a day p.o. per os / by mouth / orally PD pharmacodynamics pH negative log hydrogen ion concentration PK pharmacokinetics SAE s adverse event SOP rd Operating Procedure TBD to be determined ULN Upper Limit of the Norm DEFINITIONS Throughout this specification and in the claims that follow, the following terms are defined with the following gs, unless explicitly stated otherwise.

As used , the terms "comprising" and "including" are used herein in their open, non-limiting sense.

Where the plural form is used for compounds, salts, and the like, this is taken to mean also a single compound, salt, or the like.

As used herein, "a," "an," "the," "at least one," and "one or more" are used interchangeably.

As used herein, the term "or" is generally employed in the sense as including "and/or" unless the context of the usage clearly indicates otherwise.

Also , the recitations of numerical ranges by endpoints include all numbers subsumed within that range (e.g., 1 to 5 includes 1 , 1.5, 2, 2.75, 3, 3.80, 4, 5, etc.).

The term "aromatase inhibitor" is defined as a compound that prevents the formation of estrogens from their metabolic precursors by inhibiting the enzyme aromatase.

As used herein, the term und" refers to 4,4'-[fluoro-(1—H-1,2,4~triazo|~1— yl)methylenelbisbenzonitrile, also known as 4—[oCyanophenyl)-or-fluoro(1,2,4— triazolyl)-methyl]-benzonitrile or CGP47645, first described in 1992 within EP 490 816 and US 5,637,605, the disclosure of which is hereby orated by reference herein. id="p-42" id="p-42" id="p-42" id="p-42" id="p-42" id="p-42" id="p-42" id="p-42" id="p-42" id="p-42" id="p-42" id="p-42"

[42] The compound 4,4'-[fluoro-(1-H-1,2,4-triazoly|)methylene]bisbenzonitrile is a crystalline compound with a sharp g endotherm at 169.5°C. The crystalline powder is not copic and is poorly soluble in water. 4,4'-[fluoro—(1-H-1,2,4—triazo|—1-yl)methylene]bisbenzonitrile (CGP47645) is a highly specific and potent ase inhibitor which was shown here within to have a longer half life in humans than does letrozole (Femara®), a ed ase inhibitor to which CGP47645 is structurally related. In vitro experiments with human placental microsomal aromatase demonstrated an leo = 6 nM. Oral administration of CGP47645 to rats demonstrated a Tl/z of 75 hours. The exposure expressed as AUC was tional to the administered dose. In two different aromatase dependent experimental models, inhibition of androstenedione-induced uterine hypertrophy in rats and inhibition of DMBA-induced mammary tumors in rats, the EDSO was 0.003 mg/kg and 0.01 mg/kg, respectively. These results suggested CGP47645 is imately 10-fold more potent than letrozole as an aromatase inhibitor.

The term "compound" shall here be understood to cover any and all isomers (e. g., omers, stereoisomers, diastereomers, rotomers, tautomers) or any mixture of isomers, prodrugs, and any pharmaceutically acceptable addition salts of said compound, unless stated otherwise.

PCT/U82012/053844 The term "testosterone level" in the context of the present invention refers to either total testosterone or free testosterone levels measured in blood serum. In one embodiment, the term sterone level" refers to blood serum total testosterone. "Total testosterone" includes testosterone that is bound to sex hormone-binding globulin (SHBG) and is therefore not bioavailable and testosterone which either is free or loosely bound to other proteins (non-SHBG-bound). Free or bioavailable testosterone levels will be calculated from the total testosterone and SHBG . Preferably testosterone levels are determined in the morning, between 6 am and 12 pm, as "morning testosterone ".

Testosterone and SHBG levels can be ined using a simple blood tests med by a laboratory.

The term "a male patient in need of increased testosterone levels" is defined as a male individual having serum total testosterone levels below 450 ng/dL or below 12 nmol/L. In one embodiment the term "a male patient in need of increased testosterone levels" is defined as a male individual having serum total testosterone levels below 400 ng/dL, or below 350 ng/dL, or below 10 nmol/L. In one embodiment the term "a male patient in need of increased testosterone levels" is defined as a male dual having serum total testosterone levels below 300 ng/dL or below 8 nmol/L.

In another embodiment, the term "a male patient in need of increased testosterone " is defined as a male individual having - irrespective of testosterone levels - elevated serum total estradiol levels (and/or elevated total serum estrone andfor e sulfate and/or estriol levels). Elevated estradiol levels within the context of the present invention are defined as estradiol levels being above the ULN of the respective ed assay.

The term "overweight patient" as defined herein refers to a t with a Body Mass Index (BMI) of equal or greater than 25 kg/m2 and less than 30 kg/mz’ calculated from their body weight and body height.

The term "obese patient" as defined herein refers to a t with a Body Mass Index (BMI) of equal or greater than 30 kg/m2, calculated from their body weight and body height. id="p-50" id="p-50" id="p-50" id="p-50" id="p-50" id="p-50" id="p-50" id="p-50" id="p-50" id="p-50" id="p-50" id="p-50"

[50] The Body mass index (BMI), a measurement which compares weight and height, defines people as oven/veight (pre-obese) when their BMI is between 25 kg/m2 and kg/mz, and obese when it is greater than 30 kg/mz.

As used , the term "hypogonadism" is used to refer to subjects having a total testosterone level of less than 400 ng/dL, in certain embodiments of less than 350 ng/dL, 2012/053844 and in further ments of less than 300 ng/dL. Alternatively, the term "hypogonadism" is used to refer to subjects having a total testosterone level of less than 12 nmolIL, in n embodiments of less than 10 nmol/L, and in further embodiments of less than 8 nmol/L. In one embodiment, the term "hypogonadism" is used to refer to a male individual having morning serum total testosterone levels below 300 ng/dL or below 8 nmol/L.

The term "hypogonadotropic patient" as defined herein refers to a patient with opriately low gonadotropins. In particular, a patient with "inappropriately low gonadotropins" is defined as a patient with (i) luteinizing hormone (LH) levels S ULN of the respective approved assay, (ii) follicle stimulating hormone (FSH) levels S ULN, and (iii) estradiol within or above the normal range (defined as 2 LLN of the approved assay).

In another embodiment, the "hypogonadotropic patient" shall have "inappropriately low gonadotropins" as defined above, and normal hypothalamic/pituitary function including (i) prolactin levels within the normal range, (ii) d stimulating hormone (TSH) levels within the normal range, and (iii) ferritin levels within the normal range.

The term onadotropic hypogonadism" or "a patient with hypogonadotropic hypogonadism" as d herein refers to a male subject suffering from nadism as defined herein, and being hypogonadotropic as defined herein.

The term "obese, hypogonadotropic hypogonadism" or "an obese, hypogonadotropic male patient with hypogonadism" or "hypogonadotropic hypogonadism in obese men" as defined herein refers to a male subject being obese as defined herein, suffering from hypogonadism as d herein, and being hypogonadotropic as defined . In one embodiment, such patient is defined as a subject meeting the following criteria: (a) having a Body Mass Index (BMI) 2 30 kg/mz, (b) having a morning serum total testosterone level below 400 ng/dL, preferably below 350 ng/dL, and more ably of below 300 ng/dL, and (0) having inappropriately low gonadotropins as defined herein above, and (d) having normal alamic/pituitary function, as defined herein above.

The term "oventveight hypogonadotropic hypogonadism" or "an overweight, hypogonadotropic male t with hypogonadism" or "hypogonadotropic hypogonadism in oveniveight men" as defined herein refers to a male subject being overweight as defined herein, suffering from hypogonadism as defined herein, and being hypogonadotropic as defined herein. In one embodiment, such patient is defined as a subject meeting the following criteria: (a) having a Body Mass Index (BMI) of equal or greater than 25 kg/m2 and less than 30 kg/mz, (b) having a g serum total testosterone level below 400 ng/dL, preferably below 350 ng/dL, and more preferably of below 300 ngidL, and (0) having inappropriately low gonadotropins, as defined herein above, and (d) having normal hypothalamic/pituitary on, as defined herein above.

As used herein, the term "normalization of testosterone levels" is defined as an elevation of the serum total testosterone levels, preferably the morning serum total testosterone levels, to above 300 ng/dL or above 8 nmol/L. In one embodiment, it is defined as an elevation of the serum total testosterone levels, preferably the morning serum total testosterone levels, to above 350 ng/dL, to above 400 ng/dL, to above 450 ng/dL or to above 8 . id="p-58" id="p-58" id="p-58" id="p-58" id="p-58" id="p-58" id="p-58" id="p-58" id="p-58" id="p-58" id="p-58" id="p-58"

[58] As used herein, the term "increasing testosterone levels" is defined as increasing the total morning serum testosterone level after administration of the compound according to the invention by at least 10% in comparison to the testosterone level prior to administration of the compound. In certain embodiments, the term "increasing testosterone levels" is defined as increasing the total morning serum testosterone level after the administration of a therapeutically effective amount of the compound to a male patient according to the invention by at least 15%, at least 20%, at least 25%, at least %, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, or even , in comparison to the testosterone level prior to administration of the compound. id="p-59" id="p-59" id="p-59" id="p-59" id="p-59" id="p-59" id="p-59" id="p-59" id="p-59" id="p-59" id="p-59" id="p-59"

[59] The term "treatment of hypogonadism" as defined herein refers to the treatment of the disease hypogonadism, wherein the disease is defined as set out in the introductory part here . In one aspect, the term "treatment of hypogonadism" ses the treatment of patients with reduced serum testosterone levels.

As used herein, the term "a closing regimen having a dosing periodicity g from about once daily to about once every 60 days" refers to a dosing regimen wherein the active compound could be stered once every 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, ..21, 26, 27, 28, 29, 30 35, 42, 49, 56, 57, 58, 59, 60 days. This term comprises e.g. dosing regimens having (i) a dosing icity ranging from about once daily to about once every 60 days, (ii) a dosing periodicity ranging from about once every 2 days to about once every 40 days or 6 weeks, (iii) a dosing periodicity ranging from about once every 5 days to about once monthly or about once every 4 weeks or about once every 30 days, (iv) a closing periodicity ranging from about once weekly or about once every 7 days to about once every 3 weeks or about once every 20 days, or (v) a dosing icity ranging from about once weekly or about once every 7 days to about once biweekly or once every 10 days.

PCT/U82012/053844 in this context the term "about" shall have the meaning from minus 1 day" for a dosing regimen of once every 3 days to "plus/minus 10 days" for a dosing regimen of once every 60 days. A dosing regimen of "about once every 3 days" refers to a dosing regimen of one dose administered every 3 days plus/minus 1 day; a dosing regimen of "about once weekly" refers to a dosing regimen of one dose stered every 7 day plus/minus 2 days; a dosing regimen of "about once biweekly" refers to a dosing regimen of one dose administered every 14 day plus/minus 3 days; a dosing regimen of "about once every 4 weeks" refers to a dosing regimen of one dose administered every 28 days plus/minus 4 days; a dosing regimen of "about once monthly" refers to a dosing regimen of one dose administered every 30 days plus/minus 4 days; a dosing regimen of "about once every 5 weeks" refers to a dosing n of one dose administered every 35 days plus/minus 5 days; and a dosing n of "about once every 6 weeks" refers to a dosing regimen of one dose administered every 42 days plus/minus 6 days.

As used herein the term "about" in connection with a particular drug dose shall have the meaning of a drug dose in the range of plus/minus 10% w/w, preferably plus/minus % w/w or less, of the nominal drug dose. By way of example, a nominal dose of about 0.01 mg active ingredient may contain from 0.009 to 0.011 mg, preferably from 0.0095 to 0.0105 active ingredient per dose, whereas a nominal dose of about 0.5 mg active ingredient may contain from 4.5 to 5.5 mg, preferably from 4.75 to 5.25 active ingredient per dose.

As used herein, the term "elimination half—life" of a drug refers to the time required for the concentration of the drug in serum or plasma, to decrease by half, in vivo, for example due to degradation and/or clearance or sequestration by l isms.

When determined experimentally by measuring drug tration in plasma samples drawn at s and sive times after drug intake, this ter is named "apparent elimination half-life", designated T112. Methods for pharmacokinetic analysis and determination of drug half—life will be familiar to those skilled in the art. Pharmacokinetic parameters such as "apparent elimination half—life" TA and area under the curve (AUC) can be determined from a curve of plasma or serum concentration of the drug against time. in particular, the following pharmacokinetic definitions shall apply: AUCm the AUC from time zero to time ‘t’, where t is the last sampling time point [mass x time x volume"}.

AUCo..,o the AUC from time zero to infinity [mass x time x volume'l].

PCT/U52012/053844 Cmax the maximum (peak) observed plasma, blood, serum, or other body fluid drug concentration after single dose administration [mass x volume"].

CW The last measurable plasma, blood, serum, or other body fluid drug concentration CL the total body clearance of drug from the plasma [volume x time"].

Clearance values from other body fluids may be noted by use of proper subscripts, for example CLb refers to clearance from the blood and CLu clearance of d drug from the . If the clearance is following extravascular dose and bioavailability parameter is not known, then the notation should be CL/F. t time after drug administration [time] T135] time of last measurable concentration (when CW occurs) Tmax the time to reach maximum (peak) plasma, blood, serum, or other body fluid drug concentration after single dose administration [time].

Ty, the elimination half-life associated with the terminal slope (AZ) of a semilogarithmic concentration-time curve [time].

The drug concentration in plasma and/or serum samples can be determined by a number of different ways, eg. HPLC or LC-MS/MS analyses. In one embodiment, the concentration of 4,4’-[fluoro—(1-H-1,2,4-triazoI—1—yl)methylene]bisbenzonitrile in plasma is analyzed using a validated LC-MS/MS method with a lower limit of quantification (LLOQ) at 0.1 ng/mL or better. in r embodiment, the concentration of fluoro—(1-H-1 ,2,4- triazol-1~yl)methylene]bisbenzonitrile in human plasma is analyzed using a ted LC- MS/MS method with a lower limit of quantification (LLOQ) at 0.025 ng/mL.

As used herein the term "about" in connection with a particular nt elimination ife shall have the meaning of an apparent elimination half-life in the range of plus/minus 20% w/w, preferably plus/minus 15% w/w or less, of the particularly mentioned nt elimination half-life. in one embodiment, the term "about" in connection with a particular apparent elimination half-life shall have the meaning from "plus/minus 2 day" for an apparent elimination ife of about 14 days to "plus/minus 5 days" for an apparent elimination ife of about 30 days. An apparent elimination half-life of about 20 days shall refer to an apparent elimination half-life of 20 days "plus/minus 3 days", an apparent elimination ife of about 25 days shall refer to an apparent elimination half-life of 25 PCT/U52012/053844 days "plus/minus 4 days", and an apparent elimination half-life of about 30 days shall refer to an apparent elimination half-life of 30 days "plus/minus 5 days".

As used herein, the term ment period" refers to the length of the time period wherein the compound is administered to a patient. The phrase "a treatment period of at least about two months" shall have the meaning the compound shall be stered continuously (according to the dosing regimen) for at least 2 months, but potentially also longer, e.g. continuously for at least 3, 4, 5, 6, 7, 8, 9, 10, 11, etc months. In general, treatment could also exceed a time period of 12 months, i.e. the nd might be ered for continuous long term treatment. However, there might be circumstances under which shorter treatment s or intermittent treatment periods are advisable.

As used herein the term "about" in connection with a particular length of treatment period shall have the meaning of minus 5 days" for every month of treatment, is. a treatment period of "about two months" shall refer to a treatment period of two months plus/minus 10 days, a treatment period of "about three months" shall refer to a treatment period of three months plus/minus 15 days, etc.

DETAILED DESCRIPTION OF THE INVENTION The aromatase inhibitor 4,4'-[fluoro-(1-H-1,2,4—triazolyl)methylenelbisbenzonitrile is now shown to have the potential to address specifically the needs of male patients being in need of increased testosterone levels, in particular male patients being overweight or obese and/or suffering from hypogonadism, especially hypogonadotropic hypogonadism.

The aromatase enzyme catalyzes the conversion of nous terone into estradiol and is furthermore in particular present in excess adipose tissue. Elevated serum iol levels may inhibit pituitary LH secretion and thereby reduce serum testosterone level. Administration of 4,4'-[fluoro-(1-H-1,2,4~triazol~1~y|)methylene]bisbenzonitrile, a highly selective aromatase inhibitor, shows dose dependent ion of the conversion of testosterone to estrone, estrone sulfate and estradiol, and thereby an increase of endogenous terone levels. id="p-70" id="p-70" id="p-70" id="p-70" id="p-70" id="p-70" id="p-70" id="p-70" id="p-70" id="p-70" id="p-70" id="p-70"

[70] Whereas conventional medical therapies for hypogonadism work by supplementing testosterone or administration of HCG or gonadotropins, administration of fluoro—(1- H-1,2,4-triazolyl)methylene]bisbenzonitrile inhibits testosterone sion by aromatase, especially local testosterone conversion by aromatase in fat tissue, especially targeting ight or obese patients. Since testosterone deficiency in men, in particular in men with overweight or obesity is often associated with metabolic abnormalities including insulin resistance, glucose intolerance, and lipid abnormalities, contributing to an increased nce of metabolic syndrome, type ll diabetes and cardiovascular diseases, administration of fluoro-(1-H-1,2,4-triazolyl)methylene]-bisbenzonitrile is considered to be especially suited for this patient population.

Accordingly, administration of 4,4'-[fluoro-(1-H-i,2,4—triazol-1~yl)methylene]- zonitrile leads to improved treatment efficacy in overweight or obese male patients with confirmed hypogonadotropic hypogonadism via inhibition of testosterone to estrogen conversion at all sites, especially r in the adipose tissue. Administration is considered especially useful if the ts suffer from one or more disorders selected from insulin resistance, glucose intolerance and dyslipidaemia. Increasing terone levels by administration of 4,4'-[fluoro-(1-H-1,2,4-triazol-i-yl)methylene]bisbenzonitrile is considered especially useful for improving insulin sensitivity, ing glucose metabolism and/or improving the lipid profile in this patient population. id="p-72" id="p-72" id="p-72" id="p-72" id="p-72" id="p-72" id="p-72" id="p-72" id="p-72" id="p-72" id="p-72" id="p-72"

[72] In ular, administration of 4,4'—[fluoro-(1—H-1,2,4-triazolyl)methylene]— bisbenzonitrile is considered to effectively improve insulin sensitivity in the overweight or obese male patient with hypogonadotropic hypogonadism by normalizing testosterone levels. In addition, the treatment according to the invention is thought to improve n sensitivity with improved glycaemic control (as measurable by lower postprandial glucose, lower HbAic levels), to t progression of pre-diabetes to diabetes, to support the reduction of body fat mass and to improve body lean mass.

Furthermore, administration of 4,4‘-[fluoro-(1-H-1,2,4-triazol-1—yl)methylene]- bisbenzonitrile is considered to t, improve or treat other conditions ated with hypogonadism including, but is not limited to, decreased libido, decreased neous erections, le dysfunction, decreased fertility, loss of body hair, reduced g, lack of energy, fatigue, impaired cognition, depression, s in mood, low bone mineral density, increased risk of fractures, decreased muscle mass, decreased muscle strength, increased abdominal fat mass, limited body performance capacity and cardiovascular risks. id="p-74" id="p-74" id="p-74" id="p-74" id="p-74" id="p-74" id="p-74" id="p-74" id="p-74" id="p-74" id="p-74" id="p-74"

[74] Administration of 4,4'-[fluoro-(1-H-1,2,4-triazo|—1-yl)methylene]-bisbenzonitrile according to the invention is also considered useful when the male patient is in need of increased muscle mass and strength, when the patient is in need of a normalized body composition, when the patient is in need of a decrease in nal fat mass (as assessed by waist circumference and/or waist/hip circumference ratio), when the patient PCT/U52012/053844 is in need of an improved sexual function and desire, when the patient is in need of increased fertility, and/or when the patient is in need of increased bone mineral density. 4,4'—[fluoro-(1-H-1,2,4—triazolyl)methylene]bisbenzonitrile is a potent and selective tor of aromatase. The leo and K values for aromatase inhibition were determined in the microsomal fraction of human placenta and showed that the compound is a competitive tor with an leo of approximately 6.2 nM [Batzl—Hartmann et al, 1994]. logic studies of 4,4'-[fluoro~(1—H~1,2,4—triazolyl)methylene]bisbenzonitrile in female and male dogs showed that there was no consistent difference in re (AUC and Cmax) between male and female dogs. Tmax values were ranging from 1 h to 24 hrs post dose. Generally, the inter-animal variability in Cmax levels was small. In general, following weekly oral dosing of 4,4'—[fluoro-(1-H—1,2,4—triazolyl)methylene]bisbenzonitrile for 4 or 22 weeks, the mean plasma exposure to the compound was similar to that observed after a single dose at all dose levels tested, ting there is no drug accumulation. An increase in re (AUC and Cmax) was generally proportional to the dose increase for male and female dogs after single and multiple doses of 4,4'-[fluoro-(1- 4—triazolyl)methylene]bisbenzonitrile at all dose levels tested. Furthermore, measurement of testosterone levels in the serum of male dogs after 1, 4 and 12 weeks of dosing showed dramatically elevated testosterone levels at all dose levels demonstrating the potential of 4,4'-[fluoro-(1-H-1 ,2,4-triazolyl)methyleneibisbenzonitrile. id="p-77" id="p-77" id="p-77" id="p-77" id="p-77" id="p-77" id="p-77" id="p-77" id="p-77" id="p-77" id="p-77" id="p-77"

[77] In humans, the compound was lly studied in a single, ascending dose protocol in human female volunteers to assess safety and bility (see Example 3), as well as an 1"C-4,4‘-[fluoro-(1—H-1,2,4-triazol—1-yl)methylene]bisbenzonitrile ADME study (Example 4) to determine tissue half life of the drug. The first study showed that the median Tmax occurred within 1 hour of ingestion, and that the half life was extremely long, approximately 25 days at doses above 0.01 mg. In the human ADME study in postmenopausal women, the compound accumulated in fat tissue at a 1-3 fold rate in comparison to the exposure as plasma, with the same clearance pattern. Given that the excess aromatase activity in overweight or obese hypogonadotropic men with hypogonadism occurs primarily in the adipose tissue, 4,4'-[fluoro-(1-H-1,2,4—triazol yl)methylene]bisbenzonitrile is considered to have the ideal pharmacokinetic distribution profile for optimal ssion of aromatase activity. ssion of adipose aromatase activity is assumed to result in reduction of serum estradiol, increase of LH and FSH, and se in serum testosterone.

PCT/U82012/053844 The ongoing study of f|uoro-(1-H-1,2,4—triazolyl)methylene]bisbenzonitrile for the treatment of obese hypogonadotropic male patients with hypogonadism shows the effectiveness of this new treatment regimen in the target patient population (Example 5).

An effective amount of 4,4'—[fluoro-(1-H-1,2,4-triazoly|)methylene]bisbenzonitrile for the treatment of overweight or obese hypogonadotropic male patients with hypogonadism is considered to be in the range from about 0.0005 mg to about 5.0 mg, ably from about 0.0005 mg to about 2.0 mg, ably from about 0.001 mg to about 1.0 mg, more preferably from about 0.005 mg to about 0.5 mg, most ably from about 0.01 mg to about 0.1 mg, from about 0.005 mg to less than 0.05 mg 4,4'-[fluoro-(1~ H-1,2,4—triazolyl)methylene]bisbenzonitrile per dose. In one embodiment, the effective dose is considered to be higher than 0.0005 mg, 0.001 mg, 0.005 mg, or 0.01 mg, but lower than 2.0 mg, 1.0 mg, 0.5 mg, 0.1 mg, or 0.05 mg 4,4'-[fluoro-(1-H-1,2,4-triazol~1~ yl)methylene]bisbenzonitrile per dose. in an alternative embodiment, the effective dose is considered to be in the range from about 0.005 mg to less than 0.01 mg. id="p-80" id="p-80" id="p-80" id="p-80" id="p-80" id="p-80" id="p-80" id="p-80" id="p-80" id="p-80" id="p-80" id="p-80"

[80] In another embodiment it might be considered to start treatment with a defined loading dose of 4,4'-[fluoro-(1-H-1,2,4-triazol—1-yl)methylene]bisbenzonitrile, and then to assess the testosterone response after a single dose (eg after 1, 2, 3, 4, 5 or 6 days or even more than 6 days after a single dose), and adjust the next dose according to the treatment regimen (e.g. daily dose, weekly dose, or monthly dose) up or down based on the acute testosterone response. In one embodiment of the invention the g dose of 4,4'-[fluoro-(1-H—1,2,4-triazolyl)methylene]bisbenzonitrile dose is 0.3 mg followed by a weekly dose of 0.1 mg.

The t invention discloses an optimized treatment regimen providing relief of the testosterone deficit driven symptoms of hypogonadism with additional beneficiary treatment effects. The pment of an aromatase inhibitor especially suited for nadal male patients provides a novel treatment option for this disease. The present invention especially addresses overweight or obese hypogonadotropic hypogonadal male ts with associated symptoms and disorders.

Accordingly, the present invention concerns the use of the compound 4,4'-[fluoro—(1— H-1,2,4—triazolyl)methylene]bisbenzonitrile in the treatment of a male patient in need of increased testosterone levels. In one ment the present invention concerns the use of the compound 4,4'-[fluoro-(1-H-1,2,4-triazolyl)methylene]bisbenzonitrile in the treatment of an obese or overweight male patient.

PCT/U82012/053844 In one embodiment the t invention concerns the use of the compound 4,4'- o-(1-H-1,2,4-triazol—1-y|)methylene]bisbenzonitrile in the treatment of hypogonadism in a male patient, preferably hypogonadotropic hypogonadism in a male patient, most ably hypogonadotropic hypogonadism in an overweight or obese male patient.

Furthermore, the present invention ns the use of the nd 4,4'-[fluoro- (1-H—1,2,4—triazoIyl)methylene]bisbenzonitrile in the treatment of a male patient in need of increased testosterone levels, wherein the compound is provided in a form comprising from about 0.0005 mg to about 5.0 mg, preferably from about 0.0005 mg to about 2.0 mg 4,4'—[fluoro—(1-H—1,2,4-triazol—1-y|)methylene]—bisbenzonitrile per dose and is for administration according to a dosing regimen having a closing periodicity ranging from about once daily to about once every 60 days.

In the context of the present invention the wording "the use of the compound 4,4'- [fluoro—(i-H-1,2,4—triazolyl)methylene]bisbenzonitrile in the treatment of (...)" shall be construed either as "the compound 4,4'-[fluoro-(1-H-1,2,4-triazoI yl)methylene]bisbenzonitrile for use in the treatment of (...)" or as "use of the compound 4,4'-[fluoro-(1-H-1,2,4-triazolyl)methylene]bisbenzonitrile for the cture of a medicament for the treatment of (...)". Both meanings are equally contemplated within the scope of the invention.

In one embodiment, the patient is a male human patient, preferably an overweight or obese male human patient. Treatment of overweight or obese male human patients is most preferred for hypogonadism and associated conditions; however treatment of other male ts being in need of increased testosterone might also be plated if appropriate. ln one embodiment, the male patient in need of increased testosterone levels s from hypogonadism, preferably hypogonadotropic hypogonadism. In particular, the present invention relates to the treatment of hypogonadotropic hypogonadism in obese or overweight male human patients.

In one embodiment, the present invention s to the use of the compound in the above mentioned patient population for increasing, preferably normalizing terone . In particular, increasing, preferably normalizing testosterone levels in an overweight or obese male patient with hypogonadotropic hypogonadism is considered.

A low serum testosterone concentration predicts or is associated with the lic syndrome and type ll diabetes, in particular in men with overweight or obesity.

WO 36562 Accordingly, in one embodiment, the present invention relates to the use of the compound for the prevention or treatment of one or more disorders selected from metabolic syndrome, type ll diabetes, obesity and cardiovascular e in the above mentioned patients, preferably in patients suffering from hypogonadism or hypogonadotropic hypogonadism, preferably in overweight or obese ts ing from hypogonadism or hypogonadotropic hypogonadism.

In another embodiment, the present invention relates to the use of the compound for the tion or treatment of one or more disorders selected from insulin resistance, e intolerance and dyslipidaemia in the above mentioned patients, preferably in patients suffering from hypogonadism or hypogonadotropic hypogonadism, preferably in overweight or obese patients suffering from hypogonadism or hypogonadotropic hypogonadism.

In a further embodiment, the present invention relates to the use of the compound for the improvement of insulin sensitivity and/or glucose metabolism and/or the lipid profile in the above mentioned patients, preferably in patients suffering from nadism or hypogonadotropic hypogonadism, preferably in ight or obese ts suffering from hypogonadism or hypogonadotropic hypogonadism.

In addition, the present invention relates to the use of the compound for the prevention or treatment of one or more disorders selected from the group consisting of decreased libido, decreased spontaneous erections, erectile dysfunction, decreased fertility, loss of body hair, reduced g, lack of energy, fatigue, impaired cognition, depression, changes in mood, low bone mineral density, increased risk of fractures, decreased muscle mass, decreased muscle strength, increased abdominal fat mass and limited body performance ty, wherein the patient is in need of increased testosterone levels. in particular, the patient has hypogonadism or hypogonadotropic hypogonadism, preferably overweight or obese hypogonadotropic hypogonadism.

In further embodiments of the ion relating to the use of the compound, as herein defined, the compound is ed in a form comprising from about 0.0005 mg to about 5.0 mg, preferably from about 0.0005 mg to about 2.0 mg 4,4'-[fluoro-(1-H-1,2,4- triazol—1-y|)methylene]bisbenzonitrile per dose. E.g. the nd can be provided in a form comprising about 0.0005 mg, about 0.001 mg, about 0.005 mg, about 0.006 mg, about 0.007 mg, about 0.008 mg, about 0.009 mg, about 0.01 mg, about 0.015 mg, about 0.02 mg, about 0.025 mg, about 0.03 mg, about 0.035 mg, about 0.04 mg, about 0.45 mg, about 0.05 mg, about 0.06 mg, about 0.07 mg, about 0.08 mg, about 0.09 mg, about 0.1 mg, about 0.15 mg, about 0.2 mg, about 0.25 mg, about 0.3 mg, about 0.35 mg, about 0.4 WO 36562 PCT/U82012/053844 mg, about 0.45 mg, about 0.5 mg, about 0.75 mg, about 1 mg or at maximum about 2 mg or 5 mg 4,4'-[fluoro-(1-H-1,2,4-triazo|yl)methylene]bisbenzonitrile per dose. E.g. the compound can be provided in a form comprising about 0.1 mg 4,4'-[fluoro-(1-H-1,2,4- triazol—1—yl)methylene]bisbenzonitrile per dose. In one embodiment, the nd is provided in a form comprising about 0.01 mg 4,4'—[fluoro—(1~H—1,2,4-triazo|—1- y|)methylene]bisbenzonitrile per dose.

In particular, the compound is ed in a form comprising from about 00005 mg to about 0.5 mg 4,4'-[fluoro-(1-H-1,2,4-triazo|—1-yl)methylene]bisbenzonitrile per dose, preferably in a form comprising from about 0.001 mg to about 1.0 mg, more preferably from about 0.005 mg to about 0.5 mg, most preferably from about 0.01 mg to about 0.1 mg, or from about 0.005 mg to less than 0.05 mg 4,4'-[fluoro-(1-H—1,2,4-triazol yl)methylene]bisbenzonitrile per dose.

In one embodiment, the compound is to be administered according to a dosing regimen having a dosing periodicity ranging from one dose administered about once daily, preferably once weekly or once biweekly, to one dose administered about once every 60 days. in one embodiment, the present ion relates to the use of the compound according to a dosing regimen with a dosing periodicity of one dose administered about once daily, about once every 2 days, about once every 5 days, about once weekly, about once biweekly, about once every 3 weeks, about once every 4 weeks, about once monthly and about once every 6 weeks, preferably about once weekly or once biweekly.

In further ments of the invention relating to the use of the compound, the compound is provided in any form as set out above comprising from about 0.0005 mg to about 1.0 mg per dose, being stered according to a dosing regimen having a dosing periodicity ed from about once daily, about once every two days, about once weekly, about once every 10 days, about once biweekly, about once every 4 weeks, about once monthly and about once every 6 weeks. In particular, the compound is provided in a form comprising from about 0.01 mg to about 0.1 mg 4,4'-[f|uoro-(1—H-1,2,4-triazo| y|)methylene]bisbenzonitrile per dose, e.g. comprising about 0.01 mg, about 0.02 mg, about 0.03 mg, about 0.04 mg, about 0.05 mg, about 0.06 mg, about 0.07 mg, about 0.08 mg or about 0.09 mg per dose, preferably 0.1 mg per dose, being administered according to a dosing n having a dosing periodicity of about once weekly or once biweekly or about every 4 weeks or about once monthly.

In some embodiments, the compound is to be administered on an intermittent basis.

In these embodiments the compound, e.g. a dose that comprises from about 0.0005 mg to about 5.0 mg, preferably from about 0.0005 mg to about 2.0 mg 4,4'-[fluoro-(1—H-1,2,4- triazol—1-yl)methy|ene]bisbenzonitrile, is administered to a patient for at least one day, optionally followed by further doses according to a dosing regimen as described herein above, for e in a dosing regimen having a dosing periodicity ranging from about once daily to about once every 60 days, followed by a period of no dosing for a period of about one day to about 6 month or longer, for example for a period of about one day, of about two days, of about one week, of about 10 days, of about two weeks, of about 4 weeks, of about one month, of about 6 weeks, of about 2 month, of about 3 months, of about 4 month, of about 5 month or of about 6 month. in one aspect of the invention, the compound 4,4'—[fluoro-(1-H-1,2,4-triazol—1- yl)methylene]bisbenzonitrile is provided for oral administration. in another aspect of the invention, the compound 4,4'-[fluoro-(1-H-1,2,4-triazol—1- yl)methylene]bisbenzonitrile when administered to the patient, shows an apparent elimination half-life of at least about 14 days, at least about 20 days, and at least about 25 days. In one embodiment, the compound may even show an apparent ation half-life of at least about 30 days or even at least 35 days. ln another embodiment, the nd may show an apparent elimination half-life of approximately 22 to 29 days. ln another embodiment, the compound may show an apparent elimination half-life of approximately 23 to 27 days. This extraordinary long half-life in humans was demonstrated by way of es 3 and 4. The s observed were completely unexpected in view of the previous rat ments showing a half-life of about a week [Batzl-Hartmann et al, 1994 and Bhatnagar et al, 1996]. This surprising extremely long half-life of the compound in humans gives rise to the particular dosing led of the ion. ln one embodiment of the invention, the nd 4,4'-[fluoro-(1-H-1,2,4—triazol yl)methylene]bisbenzonitrile is to be administered to the patient as defined herein for a treatment period of at least about two months, preferably at least about three months. ln another embodiment, the administration of the compound as defined herein can extend even longer and be provided for continuous treatment.

In addition, the present ion refers to a method for the treatment of a male patient in need of increased testosterone levels comprising administering to said patient an effective amount of f|uoro—(1—H-1,2,4—triazoly|)methylene]bisbenzonitrile.

Furthermore, the invention relates to a method for the treatment of a male patient in need of increased testosterone levels comprising administering to said patient an effective amount of 4,4'-[f|uoro-(1-H-1,2,4-triazolyl)methylene]bisbenzonitrile in a dose from about 0.0005 mg to about 5.0 mg, preferably in a dose from about 0.0005 mg to about 2.0 [Q[Q mg in a dosing regimen having a closing periodicity g from about once once daily to about once every 60 days.

In one embodiment, said male t is obese. In another embodiment said male patient is overweight. In another embodiment, the method is for the treatment of hypogonadism or hypogonadotropic hypogonadism. in particular, the method of treatment is for the treatment of hypogonadism in an overweight or obese male t, preferaby for the ent of hypogonadotropic hypogonadism in an ight or obese male patient.

Said male patient being in need of sed testosterone levels may also be in need of the prevention or treatment of one or more disorders selected from metabolic me, type II diabetes, obesity and cardiovascular disease. In a further ment said patient is in need of the prevention or treatment of one more disorders selected from insulin resistance, glucose intolerance and dyslipidaemia. in particular, the patient is in need of improved n sensitivity, or in need of improved glucose metabolism, or in need of an improved lipid profile. id="p-106" id="p-106" id="p-106" id="p-106" id="p-106" id="p-106" id="p-106" id="p-106" id="p-106" id="p-106" id="p-106" id="p-106"

[106] Said male patient being in need of increased testosterone levels may also be in need of the prevention or treatment of one or more disorders selected from the group consisting of decreased , decreased spontaneous erections, erectile dysfunction, decreased fertility, loss of body hair, reduced shaving, lack of energy, fatigue, impaired cognition, depression, changes in mood, low bone mineral density, increased risk of fractures, decreased muscle mass, decreased muscle strength, increased abdominal fat mass and limited body performance capacity. in a further embodiment, said male patient being in need of increased testosterone levels and/or suffering from hypogonadism is in need of increased muscle mass and th, in need of a normalized body composition, in need of a se in abdominal fat mass, in need of an improved sexual function and desire, in need of increased ity, or in need of increased bone mineral density.

Furthermore, the invention relates to a method for the treatment of a male patient in need of increased testosterone levels comprising administering to said patient an effective amount of 4,4'-[f|uoro-(1-H—1,2,4—triazo|—1-yl)methy|ene]bisbenzonitrile, wherein the administration of the compound ses the testosterone level by at least 10% over the testosterone level prior to administration of the compound. In a further embodiment, administration of the compound normalizes testosterone levels.

All embodiments set out above for the use of the compound 4,4'-[fluoro-(1—H-1,2,4— triazol-1—yl)methylene]bisbenzonitrile for the treatment of one of the aforementioned 2012/053844 diseases shall apply mutatis mutandis for the above mentioned method of treatments of the respective es with this compound.

Accordingly, an effective amount of 4,4'-[fluoro-(1-H-1,2,4-triazol yl)methylene]bisbenzonitrile can be from about 0.0005 mg to about 5.0 mg per dose, from about 0.0005 mg to about 2.0 mg per dose, from about 0.001 mg to about 1.0 mg per dose, or from about 0.005 mg to about 0.5 mg per dose, e.g. 0.001 mg, about 0.005 mg, about 0.006 mg, about 0.007 mg, about 0.008 mg, about 0.009 mg, about 0.01 mg, about 0.015 mg, about 0.02 mg, about 0.025 mg, about 0.03 mg, about 0.035 mg, about 0.04 mg, about 0.45 mg, about 0.05 mg, about 0.06 mg, about 0.07 mg, about 0.08 mg, about 0.09 mg, about 0.1 mg, about 0.15 mg, about 0.2 mg, about 0.25 mg, about 0.3 mg, about 0.35 mg, about 0.4 mg, about 0.45 mg, about 0.5 mg per dose. In particular, an effective amount of 4,4'-[fluoro-(1-H-1,2,4-triazol-1~y|)methylene]-bisbenzonitrile is about 0.01 mg per dose.

An effective amount of 4,4'-[fluoro-(1-H-1,2,4-triazoly|)methylene]bisbenzonitrile selected from about 0.0005 mg to about 5.0 mg per dose, preferably from about 0.0005 mg to about 2.0 mg per dose can be administered according to a dosing regimen having a dosing periodicity ranging from about once daily to about once every 60 days or ranging from about once weekly to about once monthly.

More ically, an effective amount of 4,4'-[fluoro-(1-H-1,2,4-triazol~1~ yl)methylenelbisbenzonitrile from about 0.0005 mg to about 5.0 mg per dose, preferably from about 0.0005 mg to about 2.0 mg per dose, more ably from about 0.01 mg to about 0.1 mg per dose can be administered ing to a dosing regimen having a dosing periodicity selected from about once daily, once every two days, once weekly, about once every 10 days, about once biweekly, about once every 4 weeks, about once monthly and about once every 6 weeks. An effective amount of 4,4'-[fluoro-(1-H-1,2,4— triazol-1—y|)methylene]bisbenzonitrile from about 0.01 mg to about 0.1 mg per dose (eg. about 0.01 mg, about 0.02 mg, about 0.03 mg, about 0.04 mg, about 0.05 mg, about 0.06 mg, about 0.07 mg, about 0.08 mg or about 0.09 mg per dose) can be stered according to a dosing regimen having a dosing periodicity of about once weekly or once biweekly or once every 4 weeks or once monthly. ln another embodiment, the compound shows when administered according to the treatment method of the invention an apparent elimination half-life of at least about 14 days, preferably of at least about 20 days, more preferably of at least about 25 days, and most preferably of at least about 30 days. 2012/053844 In a further embodiment, the invention relates to a method for the treatment of a male patient in need of increased testosterone levels as defined herewithin comprising administering to said patient a single dose of 4,4'-[fluoro-(1-H-1,2,4—triazol yl)methylene]bisbenzonitrile, wherein said dose results in an increased effective blood concentration of testosterone over a period of time from 3 to 30 days. In particular, the serum concentration of testosterone is increased by at least 10% over the serum testosterone concentration prior to administration of the compound.

The compound 4,4’-[fluoro-(1~H—1,2,4~triazol-1~yl)methylene]bisbenzonitrile may be provided in various formulations such as parentally (e.g. aqueous or oily suspensions) or orally (e.g., tablets, powders, capsules, granules, s or oily suspensions).

Preferably, the compound is provided in an orally ble formulation to be administered ing to the described dosing regimen. However, slow release ation or depot or transdermal formulations could also be used to ster the compound.

Thus, according to a further embodiment of the invention, there is provided an oral pharmaceutical formulation comprising from about 0.0005 mg to about 5.0 mg, preferably from about 0.0005 mg to about 2.0 mg 4,4'—[fluoro-(1-H-1,2,4-triazol yl)methylene]bisbenzonitrile per dose, optionally in combination with one or more ceutically able excipients.

In one embodiment, the pharmaceutical composition comprises from about 0.001 mg to about 1.0 mg, preferably from about 0.005 mg to about 0.5 mg, more preferably from about 0.01 mg to about 0.1 mg, eg. about 0.02 mg, about 0.03 mg, about 0.04 mg, about 0.05 mg, about 0.06 mg, about 0.07 mg, about 0.08 mg, or about 0.09 mg, most preferably about 0.01 mg 4,4‘—[fluoro-(1-H-1,2,4—triazol—1-yl)methylene]bisbenzonitrile per dose. id="p-118" id="p-118" id="p-118" id="p-118" id="p-118" id="p-118" id="p-118" id="p-118" id="p-118" id="p-118" id="p-118" id="p-118"

[118] For ing pharmaceutical formulations of the invention, inert, pharmaceutically acceptable excipients can be added to the components of the composition which can either be solid or liquid. Solid form preparations comprise powders, tablets, dispersible granules, capsules and cachets.

A solid pharmaceutically acceptable excipient can be one or more nces which may act as carriers, diluents, ing agents, solubilizers, lubricants, suspending agents, binders, and/or tablet disintegrating agents; it can also be an ulating material.

In powders, a finely divided solid excipient is provided in a mixture with the finely divided active component. In s, the active component is mixed with an excipient PCT/U82012/053844 having the necessary binding properties in suitable proportions and compacted in the shape and size desired.

Suitable excipients include magnesium carbonate, magnesium stearate, talc, lactose, lactose drate, sugar, pectin, dextrin, starch, tragacanth, microcrystalline cellulose, methyl cellulose, sodium carboxymethyl cellulose, corn starch, colloidal anhydrous , titanium dioxide, a low—melting wax, cocoa butter, and the like.

The term formulation is intended to include the mixture of the active component(s) with encapsulating material as a carrier providing a capsule in which the active compound (with or without other carriers) is surrounded by a carrier which is thus in association with it. Similarly, cachets are ed. s, powders, s, and capsules can be used as solid dosage forms suitable for oral administration.

Liquid form compositions include solutions, suspensions, and emulsions. Sterile water or water-propylene glycol solutions of the active compounds may be mentioned as an example of liquid preparations suitable for eral administration. Liquid compositions can also be formulated in solution in aqueous polyethylene glycol solution.

Aqueous solutions for orai administration can be prepared by dissolving the active ent in water and adding suitable nts, flavoring agents, stabilizers, and ning agents as desired. Aqueous suspensions for oral use can be made by dispersing the finely divided active ent in water together with a viscous material such as natural synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, and other suspending agents known to the pharmaceutical formulation art.

The pharmaceutical formulation can be in unit dosage form. In such form, the composition is divided into unit doses ning appropriate quantities of the active ent(s). The unit dosage form can be a packaged preparation, the package containing discrete quantities of the preparations, for example, packeted tablets, es, and s in vials or ampoules. The unit dosage form can also be a capsule, cachet, or tablet itself, or it can be the appropriate number of any of these packaged forms.

In a further embodiment, the invention pertains to an oral pharmaceutical composition as set out above which shows, when administered to the patient, an apparent elimination half-life of 4,4'-[fluoro—(1-H-1,2,4-triazol—1—yi)methylene]bisbenzonitrile of at least about 14 days, preferably of at least about 20 days, more preferably of at least about days and most preferably of at least about 30 days. In one embodiment, the compound may even show an apparent elimination ife of at least about 30 days. In another embodiment, the nd may show an apparent elimination half-life of approximately 22 to 29 days.

In another embodiment, the invention refers to a kit of parts comprising: (i) a pharmaceutical composition comprising the compound 4,4'-[f|uoro-(1-H-1,2,4-triazo|—1- yl)methylene]bisbenzonitrile as defined herewithin; together with (ii) ctions how to administer said pharmaceutical composition for the treatment of a male patient in need of increased testosterone levels, in ular for the treatment of hypogonadism or nadotropic hypogonadism in a male patient, preferably an overweight or obese male patient. These instructions will explain in detail the dosing regimen how the compound is to be administered, as set out in more detail below.

In a further embodiment, the invention refers to a kit of parts comprising: (i) a pharmaceutical composition comprising from about 0.0005 mg to about 5.0 mg, preferably from about 00005 mg to about 2.0 mg, preferably from about 0.001 mg to about 1.0 mg, more preferably from about 0.005 mg to about 0.5 mg, most preferably from about 0.01 mg to about 0.1 mg, or from about 0.005 mg to less than 0.01 mg 4,4'—[fluoro-(1-H-1,2,4— triazoIyl)methylene]bisbenzonitrile per dose; er with (ii) instructions how to administer said pharmaceutical composition. These instructions will explain in detail the dosing regimen how the compound is to be administered, as set out in more detail below.

In a further ment, the kits of parts as d here within comprise instructions stating that ceutical composition is for the treatment of a male patient in need of increased testosterone levels, in particular for the treatment of hypogonadism or hypogonadotropic hypogonadism in a male patient, preferably an overweight or obese male patient. In particular, the instructions state that the pharmaceutical composition is to be administered according to a dosing regimen having a dosing periodicity ranging from about once daily to about once every 60 days, preferably ed from a dosing n having a dosing periodicity of about once every 2 days, about once every 5 days, about once weekly, about once biweekly, about once every 3 weeks, about once every 4 weeks, about once monthly and about once every 6 weeks, preferably about once weekly or once biweekly. id="p-129" id="p-129" id="p-129" id="p-129" id="p-129" id="p-129" id="p-129" id="p-129" id="p-129" id="p-129" id="p-129" id="p-129"

[129] In another embodiment, the instructions of the kits of parts are provided either as a leaflet or in the form of a printed matter on the packaging of the pharmaceutical composition.

This ion is further illustrated by the ing examples which should not be construed as limiting.

EXAMPLES Example 1 - Preparation of 4,4'—[f|uoro-(1-H-1 ,2,4-triazoIyl)methylene]bisbenzonitrile The following example describes a method for the synthesis of 4,4'—[fluoro-(1-H- 1,2,4-triazolyl)methylene]bisbenzonitrile (also known as 4-[d-4—Cyanophenyl)-d—tluoro- 1-1,2,4-triazolyl)-methy|]-benzonitriie or CGP47645) as sed within Lang et al., US.

Patent No. 5,637,605: A solution of 0.8 mmol of potassium hexamethyldisilazane in 1.6 ml of toluene is diluted with 5 ml of THF and, after cooling to —78°C, a solution of 190 mg of 4- cyanophenyl)-1—(1,2,4—triazolyl)methyI]-benzonitrile (see EP—A—236 940, Ex. 20a) in 3 ml of THF is added thereto. After stirring for 1 hour at the same temperature, there are added dropwise to the dark-red solution 301 mg of N-fluoro-dimethylsaccharinsultam in 3 ml of THF. After a r 1.5 hours at -78°C, the reaction mixture is heated to room temperature within 1 hour and poured onto a saturated solution of ammonium chloride in water and then extracted with methylene chloride. Drying over magnesium chloride and concentration of the solvent by evaporation yields the crude product which is purified by means of flash-chromatography (SiOg, hexane/ethyl acetate 9:1, 4:1 to 1:1). TLC (SiOz, CHCI3 [methanol 9:1, Rf =0.85); lR (KBr): 2220 cm"; 1H-NMR (CDCI3): 5 (ppm) = 7.46 and 7.76 (8H,m), 8.07 (1H,s), 8.16 (1H,s). id="p-133" id="p-133" id="p-133" id="p-133" id="p-133" id="p-133" id="p-133" id="p-133" id="p-133" id="p-133" id="p-133" id="p-133"

[133] All disclosure relevant to the ation of 4—[dCyanophenyl)—u—fluoro1,2,4- triazolyl)—methyl]-benzonitriIe described in Lang et al., US. Patent No. 669 is hereby incorporated by reference herein.

The above paragraph refers to 36 940, Ex. 20a. The US. equivalent to EP- 236 940 is , US. Patent No. 4,749,713. Example 20 (a) of ERA-236 940 (US. equivalent Patent No. 713) states that 4-[1-(1,2,4~Triazolyl)-methyl]-benzonitrile is reacted with potassium tert—butoxide and 4-fluorobenzonitrile according to the procedure in Example 2 of US. Patent No. 4,749,713 to yield 4—[d-(4-cyanophenyI)(1,2,4— triazolyl)-methyl]benzonitrile, m.p. 181°C-183°C.

The procedure of Example 2 of US. Patent No. 4,749,713 provides that: A suspension of potassium tert-butoxide (61.6 g) in dimethylformamide (500 mL) is stirred and cooled to -10°C (ice-salt bath), and a on of 4—(1-imidazolylmethyl)—benzonitrile (45.6 g) in dimethylformamide (250 mL) is added so that the reaction ature remains below 0°C. The resulting solution is stirred at 0°C for 0.5 hour and then a solution of 4- fluorobenzonitrile (38.3 g) in ylformamide (100 mL) is added while keeping reaction PCT/U82012/053844 temperature below 5°C. After 0.75 hour, the reaction mixture is neutralized to pH 7 by addition of sufficient 3N hydrochloric acid and the bulk of the solvents are then removed under reduced pressure. The residue is d with water (500 mL) and the crude product is extracted into ethyl acetate (3 x 200 mL). The combined extracts are then ted with 3N hydrochloric acid (3 x 150 mL) and, after washing the latter acid extracts with ethyl acetate (100 mL), the solution is made basic (pH 8) with 6N ammonium hydroxide and the t is again extracted into ethyl acetate (3 x 150 mL). The combined extracts are dried (MgSO4), decolorlzed by treatment with al, and then evaporated to give crude 4-[d-(4-cyanophenyl)imidazolylmethyl]-benzonitrile as an oil. This material is dissolved in isopropanol (250 mL) and the warm solution is d with succinic acid (14.4 9). Upon dilution with diethyl ether (100 mL) and stirring at ambient rature, the hemi- succinate salt separates. The salt is filtered off, washed with a little cold isopropanol and then air dried to afford 4—[d-(4~cyanopheny|)—1-imidazolylmethyl]—benzonitrile hemisuccinate, m.p. 149°C-150°C. The marate salt has m.p. 157°C-158°C. id="p-136" id="p-136" id="p-136" id="p-136" id="p-136" id="p-136" id="p-136" id="p-136" id="p-136" id="p-136" id="p-136" id="p-136"

[136] All sure relevant to the ation of 4—[d-(4-cyanophenyl)(1,2,4-triazo|yl)- methyl]benzonitrile described in Bowman, U. 8. Patent No. 4,749,713 is hereby incorporated by reference herein.

Example 2: Formulations of 4,4'—[fluoro—(1-H-1,2,4—triazol—1-y|)methylene]bisbenzonitrile (CGP47645) 4,4'-[F|uoro-(1-H-1,2,4-triazolyl)methylene]bisbenzonitrile (CGP47645) is provided in the form of hard gelatine capsules representing an immediate release dosage form for oral administration. The dosage form is a hard gelatine capsule containing a white to ish powder in a pink opaque capsule, size 1 or 3. Three strengths are provided, containing 0.1 mg, 0.5 mg or 1.0 mg CGP47645 per hard gelatine capsule. The excipients used to prepare the hard gelatine capsules are lactose, microcrystalline cellulose, corn (maize) starch, sodium starch glycolate, magnesium stearate, colloidal silicon dioxide. All the excipients comply with the requirements of the applicable compendial monographs (Ph.Eur., NF). The hard gelatine capsules are ed in HDPE bottles with aluminum induction seal equipped with child-resistant cap closures.

CGP47645 containing hard gelatine capsules are prepared by the following process: The required excipients, in the respective amounts to yield the final ition as ted in Table 2 below, and the appropriate amount of CGP47645 drug substance are weighed. Then, approximately 50% of corn starch is filled into suitable container, the drug substance is added, ed by the remaining 50% of corn starch to get a sandwich of drug substance between two layers of maize . Blending and g this mixture yields the drug substance (DS) premix. The remaining ents (microcrystalline cellulose, spray-dried lactose, sodium starch glycolate, and colloidal silicon dioxide [Aerosil® 200]) are mixed and sieved and transfer into a suitable container. Then the DS premix is added into container containing the sieved excipients and the e is blended together. Finally, pre—sieved Magnesium stearate is added to the blend containing the DS and this mixture is blended again to yield the final blend. The final blend is filled into hard gelatin capsules. id="p-139" id="p-139" id="p-139" id="p-139" id="p-139" id="p-139" id="p-139" id="p-139" id="p-139" id="p-139" id="p-139" id="p-139"

[139] The following Table 2 indicates the composition of the CGP47645 hard gelatin capsule of 0.1 mg, 0.5, 1 mg and 10 mg strength.

Table 2: Amount per capsule (mg) ingredient Ca sule content —__ CGP47645 0.1 10-0 Lactose monoh drate 96.0 192.0 m 192.0 175.5 Cellulose, Corn Starch 14.15 40-0 Sodium starch ManeSium Stearate 1‘5 3‘0 Silica, colloidal 0.75 1.5 0.75 1.5 1.5 anh drous Casulefillwei-ht 150.0 300.0 -m 295.0 Emot casule shell _-- Caosule shell 48.0 76.0 Total ca tsule wei o ht 198.0 376.0 198.0 376.0 371.0 1 Filled in size 3 capsules; 2 Filled in size 1 capsules Example 3: Single ascending dose study of 4,4'—[Fluoro-(1-H-1,2,4-triazol yI)methylene1bisbenzonitrile (CGP47645) This was a randomized, double-blind, placebo- and active-controlled single ascending dose study in pre- and enopausal women to assess the safety and bility, PK and PD effects of single doses of 4,4'-[F|uoro—(1—H-1,2,4-triazol yl)methylene]bisbenzonitrile (CGP47645). There were 8 s of 8 post-menopausal subjects randomized 6:2, CGP476452placebo, who received single doses of CGP47645 beginning at the dose of 0.01 mg and carried through 20 mg, which reached the limit of the toxicology exposure coverage. Patients received either 0.1 mg, 1 mg, and 10 mg drug substance containing hard gelatin capsules or appropriate matching placebo capsules.

For the lowest two dosing cohorts, 0.1 mg drug containing capsules were used for tituting the CGP47645 oral solutions for dosing the 0.01 and 0.03 dosing th (Cohort 1 and 2).

A minimal toxic dose (MTD) was not reached. A single cohort of 8 pre-menopausal subjects without childbearing potential (Cohort No. 9) received CGP47645 0.1 mg or placebo, randomized 6:2, and one last cohort received letrozole 2.5 mg as an internal ve l cohort for the PD measurements. Table 3 presents the PK parameters based on preliminary analysis of the concentration—time profile obtained from this study.

Table 3: CGP47645 Pharmacokinetics in Post— & Pre—menopausal women -_l-—-6051 49. 0 n—5 128_— 32019 372 --_(n—6 384-- 100530167 NQNA400 7 2 417455 17.3 8 D: "II" N—ACDN (COO booo 2 76731.6 11.4 26.9 ‘-:3 II 17 151 1 0303030) V 33.5 27.0 1 1667.7116——2 [1421CGP47645 ted dose proportional pharmacokinetics and a dose—dependent tion of estrone, estrone sulfate and estradiol. No differences in CGP47645 pharmacokinetics were observed between post- and pre-menopausal women. CGP47645 is rapidly ed with a Tmax of 0.5 — 2 hrs; the median Tmax occurred within 1 hour of ingestion. Both Cmax & AUC increased in a dose—proportional manner. 45 exhibited low inter—subject variability of 10-30% and tely unexpected long half-life in the range of 23 to 27 days.

In postmenopausal women the study showed evidence of efficacy in PD parameters with estrone suppression at least equal to letrozole already at doses of 0.1 mg and 0.3 mg. ln postmenopausal women, the lowest single dose at which transient estrogen ssion was seen was 0.01 mg; and the lowest single dose at which maximal PCT/U82012/053844 estrogen suppression was observed in post—menopausal women, using chemiluminescence or radioimmunoassay, was 0.1 mg. No inhibition of other enzymes involved in steroid hormone synthesis or metabolism was observed; in particular there were no changes in androgen , progesterone, aldosterone, cortisol, ACTH, or 17- keto or 17-OH ds in 24 hour urine collections. A final review of the individual listing for bone density and T-scores determined by DEXA indicated there were no notable changes in bone density over time for subjects in the CGP47645 cohorts that ed a dose of 3 mg or less, or within the letrozole 2.5 mg cohort. For subjects in the 10 mg and mg dose cohorts, there was a small but ally significant decrease in bone density at the lumbar spine, but not at the hip, at 6 months compared to baseline.

Example 4: Pharmacokinetics of a single oral dose of 1 mg 14C-4,4'-[Fluoro~(1-H-1,2,4- triazol-1—yl)methylene]bisbenzonitrile in healthy postmenopausal women — ADME study The study was a single dose, single group, open label ADME study of 8 healthy postmenopausal women. Subjects enrolled in the study received 1 mg CGP47645 labeled with 10 uCi of 14C-CGP47645. The drug dose of 1 mg CGP47645 was seleceted as being presumably eutically relevant based on the animal ADME information and dosage information available for other aromatase tors. The study design consisted of a 28-day screening period, one baseline visit (Day -1), a domiciled period beginning from admission on Day -1 through discharge on Day 7, 2 outpatient visits for PK blood collection on Days 14 (i1) and 21 (i1), 2 subject specific adipose tissue collection visits, and an end-of-study 6 month safety follow-up visit.

The primary goal of this study was to assess the partitioning of CGP47645 into abdominal adipose tissue as a measure of peripheral tissue targeting and to assess whether there may be a longer T1/2 metabolite, as well as to ate the metabolic profile, obtain information on routes of excretion and mass balance. Adipose tissue s were collected in a sparse sampling protocol, where each subject underwent two tions of adipose tissue, with each subject biopsied at different times.

The single oral administration of 1 mg 14C-CGP47‘645 was found to be safe and well tolerated. Following single oral administration of 1 mg 14C-CGP47645 to healthy postmenopausal women, pharmacokinetics of 45 can be characterized by fast and almost complete absorption followed by rapid e in plasma concentrations suggesting extensive distribution into the s. This was followed by a prolonged terminal phase with low but tent plasma concentrations lasting longer than 4000 hrs 2012/053844 post-dose. The terminal elimination half-life was estimated to be imately 28 days.

Concentration time profiles suggest fast equilibration of CGP47645 between tissue and blood followed by slow elimination of 45 from blood which is the rate limiting step for the CGP47645 clearance. This is reflected by parallel terminal slopes in plasma and adipose tissue, i.e. the elimination rates in plasma and tissue are similar.

Approximately 84% of the total radioactivity excreted after 6 days was renally eliminated of which only 16% was red as unchanged drug. No lites were detected in plasma and 14C-CGP47645 was the only radioactive compound detected in all analyzed plasma samples. Concentration—time profiles in plasma of 14C-CGP47645 measured by liquid scintillation ng [LSC] and parent CGP47645 measured by liquid chromatography-mass spectroscopy [LC-MS] were almost super imposable further suggesting absence of metabolite(s) in plasma. However, major mechanism of 14C- CGP47645 elimination appears to be metabolism followed by renal excretion. Three main metabolites identified in urine were a carbinol derivative and two glucuronides of CGP47645. lite patterns were comparable for urine samples from ent time points suggesting that ion of metabolites was the rate limiting step.

Overall, pharmacokinetics of 14C—CGP47645 can be characterized by fast absorption followed by rapid decline in plasma concentrations suggesting extensive distribution into the tissues. The terminal elimination half-life of the parent drug was estimated to be approximately 28 days.

Example 5: Study to analyse whether oral 4,4'-[F|uoro-(1—H-1,2,4—triazol yl)methylene1bisbenzonitrile increases or izes testosterone levels in obese hypogonadotropic hypogonadal men. [149} This is an open—label dose finding study followed by a parallel group, randomized, double-blind study to evaluate the safety, bility and pharmacodynamics of 12 week treatment with F|uoro—(1—H-1,2,4-triazolyl)methylenelbisbenzonitrile (CGP47645) in obese, hypogonadotropic hypogonadal men. The study is designed as a 2—part study, with Part 1 being open-label to best ine the appropriate dose levels to use in Part 2, which has a randomized, double-blind, placebo controlled design. The study assesses the safety and tolerability of CGP47645, and determines whether a low dose of 45 given at a weekly dosing interval normalizes testosterone levels and improves insulin sensitivity in obese, hypogonadotropic hypogonadal (OHH) men when compared with placebo.

PCT/U82012/053844 Study design: As set out above, this is a two-part study in obese, nadotropic hypogonadal (OHH) men, n Part 1 is a single group, open label, non-randomized study ishing appropriate dosing. After all subjects have successfully completed 4 weeks of treatment, they continue for up to a total of 12 weeks of treatment. Then Part 2 follows as a parallel group, randomized, double-blind, placebo-controlled design, for 12 weeks of treatment, with an interim analysis after 4 weeks of treatment. Both Parts of the study have up to a 28 day ing period, a single baseline day, a 12 week treatment period (11 weekly doses), followed by a 3 month follow-up period.

The Screening Period is used to assess eligibility and to taper patients off owed medications. Subjects who meet the inclusion/exclusion criteria at Screening are admitted to Baseline evaluations. Subjects are admitted to the study site the night prior to Oral Glucose Tolerance Test (OGTT) evaluations to ensure fasting conditions are ined. The same ght domiciling applies for all scheduled OGTT evaluation days. Following the first dose, cokinetic (PK), pharmacodynamic (PD), and safety assessments are collected for up to 24 hours. Subjects return to the site 1-2 days prior to each of the next 10 dosing visits for pharmacodynamic blood evaluations in Part 1, and up to 72 hours prior to each dosing visit in Part 2. At the conclusion of the 12 week treatment period, patients are asked to return to the site approximately once every 6 weeks for 3 months for safety follow-up evaluations. Safety ments include physical examinations, ECGs, vital signs, standard clinical laboratory evaluations (hematology, blood try and urinalysis), adverse event and serious adverse event monitoring. PK and PD (sex steroid) assessments take place on multiple occasions throughout the duration of the study, and are collected at the same time whenever both are scheduled on the same visit. id="p-152" id="p-152" id="p-152" id="p-152" id="p-152" id="p-152" id="p-152" id="p-152" id="p-152" id="p-152" id="p-152" id="p-152"

[152] The 0.01 mg dose of CGP47645 administered once weekly was chosen as ng dose on the basis of the extremely long half-life of CGP47645 of approximately 22 -— 29 days in serum and potentially even longer in adipose tissue, its linear PK profile, minimal inter patient variability. Pharmacokinetic modeling was used to define the impact of dose frequency and dose on steady state exposure. Once weekly dosing was selected as the optimal approach for initial evaluation. The model was used to estimate the dose of CGP47645 required to normalize terone in OHH men, and the potential impact of a loading dose. Pharmacodynamic predictions are also based on the minimal dose (0.01 mg) in women trated to have pharmacodynamic effects in the single ascending dose study (Example 3).

PCT/U82012/053844 Thus, for Part 1 of the study, it was decided to start with 0.01 mg as the loading dose, assess the testosterone response at 5 or 6 days after a single dose, and adjust the next weekly dose up or down based on the acute testosterone response. The weekly maintenance dose is not expected to exceed 0.5 mg. For at least the first 4 weeks of treatment, subject’s sex steroid levels are measured prior to their uent dosing. The subsequent dose is the adjusted based on the prior response.

For Part 2, the blinded study, dose ment based on al discussions and/or an algorithm for both CGP47645 and placebo (based on gs in Part 1). A fixed dose regimen consisting of a starting dose of 0.3 mg followed by a 0.1 mg weekly dosing was selected for Part 2 of the study.

For Part 1, the dose range finding part of the trial, if testosterone levels are in the normal range, 1/5 of the loading dose of CGP47645 (0.002 mg) or placebo will be administered in Week 2. if free terone is above normal, the Week 2 dose will be 1/10 (0.001 mg) of the loading dose. lf free testosterone is below normal, the Week 2 dose will be 1,42 of the loading dose (0.005 mg). Subsequent weekly doses are adjusted on a 1/2 log order to achieve normalization of free testosterone levels.

Study Drug: 1 mg (size 1) and 0.1 mg (size 3) capsules of CGP47645 for oral intake as depicted in Example 2; lower doses for this study will be diluted in solution.

Population: A total of approximately 44 subjects will be randomized to participate in the study. The subjects are adult male patients meeting the criteria of obese, hypogonadotropic hypogonadism (OHH) who have passed screening assessments, comply with inclusion / exclusion criteria and have provided written consent. For Part 1, about 14 patients are required, whereas Part 2 ed up to 30 patients, randomized to active and placebo treatment in a 1:1 ratio. id="p-158" id="p-158" id="p-158" id="p-158" id="p-158" id="p-158" id="p-158" id="p-158" id="p-158" id="p-158" id="p-158" id="p-158"

[158] Inclusion criteria se: 1. Males who meet the criteria of obese, hypogonadotropic hypogonadism defined as: Patients with a Body Mass index (BMI) 2 30 kg/m2 ts with a morning serum total testosterone level < 300 ng/dL on at least two separate occasions during the Screening and/or Baseline periods 0. Patients with opriately low gonadotropins at screening given the low terone: i. Luteinizing hormone (LH) s ULN ii. Follicle ating hormone (FSH) s ULN iii. Estradiol within or above the normal range (defined as 2 LLN of the approved assay) PCT/U82012/053844 d. Normal hypothalamic/pituitary function, including: i. Prolactin: within the normal range ii. Thyroid stimulating hormone (TSH): within the normal range iii. Ferritin: within the normal range 2. Patients agree to use a barrier method of contraception (e.g., condom), for the duration of the study and for at least 3 months following their Study Completion visit to prevent compound exposure to their partners.

Exclusion criteria comprise patients with hypogonadism, not d to obesity or as a result of other underlying issues; and patients with significant major organ class illness (eg. kidney or liver disease).

The primary objective of this study is to demonstrate that weekly administration of low doses of CGP47645 normalize testosterone levels in obese, hypogonadotropic hypogonadal (OHH) men. Furthermore, the codynamic effect of CGP47645 on insulin sensitivity (based on R) in OHH men is to be demonstrated. id="p-161" id="p-161" id="p-161" id="p-161" id="p-161" id="p-161" id="p-161" id="p-161" id="p-161" id="p-161" id="p-161" id="p-161"

[161] Secondam obiectives of this study include the assessment of the safety and tolerability of CGP47645 in OHH men, assessment of the codynamic effect of CGP47645 on glucose, insulin and lipid metabolism, and body ition in OHH men, and the determination of the pharmacokinetics of CGP47645 in OHH men.

Assessments and evaluations: The following assessments will be performed during the study: 1. Background, demographic and administrative assessments o Inclusion/exclusion ia; nt medical history/Current medical conditions 0 Demography . Physical examination, including digital prostate examination . International Prostate Symptom Score (lPSS) . Hepatitis screen, HlV screen . Alcohol test, Drug screen . Prolactin, ferritin and thyroid stimulating hormone (TSH) . Drug stration: each time study drug is administered . Study Completion ation . ts 2. Safety and tolerability assessments . Vital signs and body measurements 0 Body height (BMI will be calculated) 0 Body weight* 0 Body temperature 0 Blood pressure, pulse rate . ECG evaluations . logy; Blood chemistry; Urinalysis . Prostate specific antigen (PSA) . Adverse events: from time of first administration of study drug until Study tion. Adverse events occurring before starting study treatment but after signing the ed consent form are recorded on the Medical History/Current Medical Conditions Case Report Form.

. Serious adverse events: from time of consent until 30 days after Study Completion . Concomitant medications/Significant non-drug therapies: Refer to entry criteria and Concomitant medication for details of recording requirements for allowed and restricted medications during the study. 3. Pharmacokinetic (PK) blood assessments: PK samples will be ted on multiple occasions during the treatment phase of the study. PK assessments will also be collected every 6weeks during the safety follow-up . it is anticipated that the final PK draw will take place at Week , with the possibility of additional samples being collected if there is still clinically relevant detectable blood 45 levels after that time. 4. Pharmacodynamic assessments (to be collected at the same time of day on each tion day) . Sex hormones: o Testosterone (total) 0 Estradiol (total) 0 Sex hormone binding globulin (SHBG) o Bioavailable testosterone o Dihydrotestosterone(DHT) Note: Free testosterone and free estradiol will be calculated from the total testosterone / estradiol and SHBG levels . Luteinizing hormone (LH), follicle stimulating hormone (FSH) and inhibins A and B . Semen analysis for sperm count and motility, only if study is open to non- vasectomized males 0 Body composition (by DEXA) . Body measurements 0 Body weight (derived BMI) o Waist ference, hip circumference (derived waist-hip ratio) . OGTT: Blood sampling at —10 minutes pre—glucose, 0 (pre-glucose), 15, 30, 60, 90, 120 and 180 minutes post—glucose load. 0 Glucose o lnsulin o HOMA~lR and QUICKl (derived from fasting insulin and glucose values) o HbA1c (will be part of safety lab collection) . Fasting lipid parameters (LDL, HDL, triglycerides) . Bone biomarkers: inal telopeptide (CTx1), osteocalcin, bone alkaline atase and lagen type 1 eptide (PINP) . Muscle function assessment by power stair climb . Quality of life questionnaire: Aging Males’ Symptom (AMS) Scale Analysis methods - Efficacy and pharmacodynamic analyses: Part 1 is designed as an open label dose finding phase. The primary efficacy nt at the end of Week 4 in Part 1 is the demonstration that total and free testosterone and estradiol can be normalized in the subjects who have received an appropriate dose.

The primary objective of Part 2 of the study is to assess the impact of normalizing testosterone with CGP47645 on insulin ivity. The data of the primary efficacyfpharmacodynamic le, HOMA—lR, is transformed into log scale, for both baseline and on—treatment values, and analyzed using analysis of covariance at each time point with treatment as a classification variable and baseline as a covariate. Point estimates and 95% confidence intervals of the treatment differences are derived from the analysis of covariance. The related insulin sensitivity index, QUlCKl, is analyzed rly.

The correlation n changes in testosterone level and changes in HOMA-IR values or in QUICKl values is assessed. id="p-166" id="p-166" id="p-166" id="p-166" id="p-166" id="p-166" id="p-166" id="p-166" id="p-166" id="p-166" id="p-166" id="p-166"

[166] The secondary efficacy/pharmacodynamic variables, including sex hormone levels, g and andial glucose (AUC and peak), postprandial insulin, HbA1c, fasting lipids, body weight, waist-to-hip ratio, Luteinizing hormone (LH), follicle stimulating hormone (FSH), inhibin A and B, and muscle function assessment by stair climb power, is similarly analyzed. Log-transformation of the data may be performed as appropriate. For data distributions requiring a nonparametric approach for is, Wilcoxon rank sum test is used.

PCT/U82012/053844 Data on bone biomarkers -— C-terminal teiopeptide (CTx1), osteocalcin, bone alkaline phosphatase and lagen type 1 N-propeptide (PINP) as well as data on semen analysis and quality of life questionnaires are summarized by descriptive statistics. inary results of the l 12 week treatment, open label dose-finding portion of the study: 14 obese, nadai men received weekly oral doses of CGP47645 from 0.003 mg to 5 mg. For example, patients received weekly oral doses of 0.1 mg per dose; of 0.3 mg per dose; of between 0.01 mg and 0.03 mg per dose; of between 0.003 mg and 0.3 mg per dose; of between 0.003 mg and 1 mg per dose; of n 0.1 mg and 0.3 mg per dose; of between 0.01 mg and 1 mg per dose; of between 0.2 mg and 1 mg per dose; of between 0.3 mg and 1 mg per dose; of n 0.1 mg and 3 mg per dose; or of between 1 mg and 5 mg per dose. Doses were adjusted to normalize testosterone, and if cumulative exposures ched the highest single dose exposures tested (20mg) in nopausal women then dosing was stopped during the 12 weeks. All subjects tolerated 45 well without frequent AEs, no SAEs and no withdrawals. Preliminary analysis reveals that testosterone (measured by RIA) rose in all men individually into the normal range and on average into the normal range during treatment. Preliminary results indicate that the average change of testosterone from baseline to week 12 was approximately 2-fold (250 i 22.3 ng/dL to 550 J; 191.8 ng/dL). Based on additional preliminary analysis serum estradiol (measured by LC-MS) was reduced by approximately 30-50% (average change from baseline to week 12 is 24 i 4.9 pg/mL to 18 :t 9.4 pg/mL) but was not suppressed (lower limit of detection is 2 pg/mL) as assessed by highly sensitive LC—MS assays.

CITED AND FURTHER RELATED TURE . Barry M], Fowler FJ, O‘Ieary MP et al (1992). The American Urological Association Symptom Index for benign prostatic hyperplasia. Journal of Urology, 148:1549-1557 . Bathnagar, et al (1996), Pharmacology of Nonsteroidal Aromatase Inhibitors, in "Hormone-dependent cancer" By Jorge R. Pasqualini, Benita S. Katzenellenbogen, Published by Informa Health Care, 1996, ISBN 0824796977, pp 155-168. 0 Hartmann et al (1994) Pharmacological e of CGP47645, a new non— steroidal aromatase inhibitor with a long duration of . In: Rao et al, eds.

Proceedings of the XVI International Cancer Congress, Bologna: Monduzzi Editore, 1994: 3041-3047.

. Bhasin S, Cunningham GR, Hayes FJ, Matsumoto AM, Snyder PJ, Swerdloff RS and Montori VM (2006). Testosterone Therapy in Adult Men with Androgen Deficiency PCT/U82012/053844 Syndromes: An Endocrine Society Clinical Practice Guideline. The Journal of Clinical Endocrinology & Metabolism, 91:1995—2010 . de Boer H, Verschoor L, Ruinemans-Koerts J and Jansen M (2005). Letrozole normalizes serum testosterone in severely obese men with nadotropic hypogonadism. Diabetes, Obesity and Metabolism, 7: 211—215 0 EP 490 816 and US 5,637,605 . Hofstra J, Loves S, van Wageningen B, Ruinemans-Koerts J, Janssen H and de Boer H (2008). High prevalence of hypogonadotropic hypogonadism in men referred for obesity treatment. Netherlands journal of ne, 66: 103-109 . Kapoor D, Aldred H, Clark S, Channer KS and Jones TH (2007). Clinical and Biochemical Assessment of Hypogonadism in Men With Type 2 es. Diabetes Care, 30: 911-917 . Kapoor D, Goodwin E, Channer KS, Jones TH (2006). Testosterone replacement therapy improves insulin resistance, mic control, visceral adiposity and hypercholesterolaemia in hypogonadal men with type 2 diabetes. Eur J Endocrinol. 2006 Jun;154(6):899-906 . Lapauw B, T’Sjoen G, Mahmoud A, Kaufman JM and Ruige JB (2009). Short-term aromatase inhibition: effects on e metabolism and serum leptin levels in young and elderly men. European Journal of Endocrinology, 160: 397—402 o Loves S, ans—Koerts J and de Boer H (2008). Letrozole once a week normalizes serum testosterone in obesity—related male hypogonadism. European Journal of Endocrinology, 158: 741-747 . Maggio M, Basaria S (2009). Welcoming low testosterone as a cardiovascular risk factor. International Journal of impotence Research 21: 4 . Medras M, Jozkov Pawel and Slowinska-Lisowska M (2007). Serum, Seminal Plasma, and Sperm Count ring During Treatment of Idiopathic Gynecomastia With an ase Inhibitor. The Endocrinologist, 17: 302-305 . Naharci Ml, Pinar M, Bolu E and Olgun A (2007). Effect of testosterone on n sensitivity in men with idiopathic hypogonadotropic hypogonadism. Endocrine Practice, 13: 629-635 . Trunet PF, Mueller PH, Bhatnagar AS, Dickes I, Monnet G and White G . Open Dose-Finding Study of a New Potent and Selective Nonsteroidal ase Inhibitor, CGS 20 267, in y Male Subjects. The Journal of Clinical Endocrinology & lism, 77: 319-232 PCT/U82012/053844 The various features and embodiments of the present invention, referred to in individual sections above apply, as appropriate, to other sections, mutatis mutandis.

Consequently features specified in one n may be combined with es specified in other sections, as appropriate.

Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the ing claims.

Claims (20)

WHAT IS CLAIMED IS

1. Use of the nd 4,4'-[fluoro-(1-H-1,2,4—triazoly|)methy|ene]bisbenzonitrile in the manufacture of a medicament for treatment of hypogonadism in a male patient with serum total testosterone levels below 400 ng/dl, wherein the compound is ed in a form comprising from about 0.001 mg to about 1.0 mg 4,4'—[fluoro—(1— H-1,2,4—triazol—1-yl)methylenelbisbenzonitrile per dose, and wherein the compound is for administration ing to a dosing regimen having a dosing periodicity ranging from about one dose once daily to about one dose once every 60 days.

2. The use ing to claim 1, wherein the treatment is for an overweight or obese male patient.

3. The use according to claim 2, n the male patient is a male human patient.

4. The use according to any one of claims 1 to 3, wherein the treatment is for hypogonadotropic hypogonadism.

5. The use according to any one of claims 1 to 4, wherein the male patient has a serum total testosterone level below 300 ng/dl.

6. The use according to any one of claims 1 to 5, wherein the administration of the compound increases the serum total testosterone level by at least 10% in comparison to the serum total testosterone level prior to administration of the 20 compound.

7. The use according to claim 6, wherein the serum total testosterone level is normalised.

8. The use according to any one of claims 1 to 7, wherein the nd is for (i) the prevention or treatment of one or more ers selected from metabolic me, 25 type ll diabetes, obesity and cardiovascular disease, (ii) the prevention or treatment of one or more disorders selected from n resistance, glucose intolerance and dyslipidaemia, (iii) the improvement of insulin sensitivity and/or glucose metabolism and/or the lipid profile, or (iv) the prevention or treatment of one or more disorders ed from the group consisting of decreased libido, decreased spontaneous 30 erections, erectile dysfunction, decreased fertility, loss of body hair, reduced shaving, lack of energy, fatigue, impaired cognition, depression, changes in mood, low bone mineral density, increased risk of fractures, decreased muscle mass, decreased muscle strength, increased abdominal fat mass and limited body performance capacity.

9. The use ing to any one of claims 1 to 8, wherein the compound is provided in a form comprising from about 0.005 mg to about 0.5 mg fluoro-(1-H-1,2,4— 5 triazolyl)methylene]bisbenzonitrile per dose.

10. The use according to claim 9, wherein the compound is provided in a form comprising from about 0.01 mg to about 0.1 mg 4,4'-[fluoro-(1-H-1 riazol yl)methylene]bisbenzonitrile per dose.

11. The use according to claim 9, wherein the nd is provided in a form 10 comprising from about 0.005 mg to less than 0.05 mg 4,4'-[fluoro-(1—H—1,2,4-triazol- 1-yl)methylene]bisbenzonitrile per dose.

12. The use according to any one of claims 1 to 11, wherein the compound is for administration according to a dosing n having a dosing periodicity of about one dose once weekly or about one dose once monthly. 15

13. The use according to any one of claims 1 to 12, wherein the compound when administered to the patient shows an apparent elimination half-life of at least about 14 days.

14. The use according to claim 13, wherein the apparent elimination half-life is at least about 20 days. 20

15. The use according to claim 13, wherein the apparent elimination half—life is at least about 25 days.

16. The use according to claim 13, wherein the apparent elimination half—life is at least about 30 days.

17. The use according to any one of claims 1 to 16, n the medicament is 25 formulated for oral administration.

18. The use according to any one of claims 1 to 17, wherein the medicament further comprises one or more pharmaceutically acceptable excipients.

19. The use according to claim 1, substantially as herein described with reference to any one of the Examples thereof. 30

20. The use according to any one of claims 1 to 18, ntially as herein described.