MX2014002105A - Estrogen receptor ligands and methods of use thereof. - Google Patents

Abstract

The present invention relates to methods for reducing testosterone levels by reduction of luteinizing hormone (LH) or independent of LH levels in a male subject and methods of treating, suppressing, reducing the incidence, reducing the severity, or inhibiting prostate cancer, advanced prostate (5) cancer, castration resistant prostate cancer (CRPC), metastatic castration resistant prostate cancer (mCRPC) and palliative treatment of prostate cancer, advanced prostate cancer, castration resistant prostate cancer (CRPC) and metastatic castration resistant prostate cancer (mCRPC), and methods of reducing high or increasing PSA levels and/or increasing SHBG levels in a subject suffering from prostate cancer, advanced prostate cancer, castration resistant prostate cancer (CRPC) and metastatic (10) castration resistant prostate cancer (mCRPC). The compounds of this invention suppress free or total testosterone levels despite castrate levels secondary to ADT and reduce high or increasing PSA levels.

Description

LIGANDS OF ESTROGEN RECEIVER AND METHODS OF USE OF THE SAME Field of the invention The present invention relates to methods for treating, eliminating, reducing the incidence, reducing the severity or inhibiting the progression of castration-resistant prostate cancer (CRPC) and its symptoms, or increasing the survival of men with CRPC and methods for decreasing serum prostate-specific antigen (PSA) levels and serum testosterone levels in a male subject suffering from castration-resistant prostate cancer (CRPC).

BACKGROUND OF THE INVENTION Estrogen refers to a group of endogenous and synthetic hormones important for the bone and tissue maintenance and used for it. Estrogens are endocrine regulators in cellular processes involved in the development and maintenance of the reproductive system. The role of estrogens in reproductive biology, the prevention of postmenopausal hot flashes and the prevention of postmenopausal osteoporosis has been established. Estradiol is the main endogenous human estrogen and is found in both women and men.

The biological actions of estrogens and antiestrogens are manifested through two different intracellular receptors, the estrogen receptor alpha (ERa) and the estrogen receptor beta (ERP).

Normally, endogenous estrogens are potent activators of both receptor subtypes. For example, estradiol acts as an ERa agonist in many tissues including breast, bone, cardiovascular and central nervous system tissues. Usually, selective modulators of estrogen receptors act differently on different tissues. For example, a SERM can be an ERa antagonist in the breast, but it can be a partial agonist ERa in the uterus, bones and cardiovascular system. The compounds that act as estrogen receptor ligands are, therefore, useful in the treatment of a variety of conditions and disorders.

Prostate cancer is one of the non cutaneous cancers diagnosed most frequently among men in the United States and the second most common cause of cancer death with 241 740 new cases and 28,472 deaths expected in 2012 in the United States. Up to 30% of patients with prostate cancer who undergo primary treatment by radiation or surgery develop metastatic disease within 10 years after primary treatment. Approximately 50000 patients per year develop a metastatic disease called metastatic CRPC (mCRPC).

Patients with advanced prostate cancer undergo androgen deprivation therapy (ADT), either by agonists of luteinizing hormone-releasing hormone (LHRH), LHRH antagonists or bilateral orchiectomy.

Primary ADT, which causes castration (total serum testosterone levels <50 ng / dL), is used to initially treat patients with hormone-resistant prostate cancer. Although the symptoms improve with ADT, this therapy does not cure patients. Unfortunately, over time the prostate cancer cells become resistant to castration and the disease of these men evolves. Men with mCRPC have a very poor prognosis, severe symptoms linked to cancer and a life expectancy of less than 1 6 months.

In men, androgen deprivation therapy not only reduces testosterone levels, but also estrogen levels, since estrogen is derived from the aromatization of testosterone, whose levels are drastically reduced by ADT. As a consequence, ADT also reduces estrogen to castration levels.

Estrogen deficiency induced by androgen deprivation therapy causes important side effects including hot flushes, gynecomastia and mastalgia, loss of bone mass, decreased quality and bone hardness, osteoporosis and life-threatening fractures, changes Adverse lipids and more cardiovascular diseases and myocardial infarcts, depression and other mood changes. It is believed that many of the side effects of estrogen deficiency by ADT are mediated by ERa.

Leuprolide acetate (Lupron®) is a synthetic nonapeptide analogue of the gonadotropin-releasing hormone (GnRH or LHRH). He Leuprolide acetate is a superagonist of LHRH that eventually eliminates LH secretion by the pituitary. Leuprolide acetate acts as a potent inhibitor of gonadotropin secretion, resulting in the elimination of ovarian and testicular steroidogenesis. In humans, administration of leuprolide acetate results in an initial increase in the levels of luteinizing hormone (LH) and circulating follicle-stimulating hormone (FSH), leading to a transient increase in gonadal spheroids (testosterone and dihydrosterone in men). and estrone and estradiol in premenopausal women). However, continuous administration of leuprolide acetate results in decreased levels of LH and FSH. In men, testosterone is reduced to castration levels (below 50 ng / dL). In premenopausal women, estrogen is reduced to postmenopausal levels. Testosterone is a known stimulus for cancer cells in the prostate. Therefore, eliminating testosterone secretion or inhibiting the actions of testosterone represents a necessary component of prostate cancer therapy. Leuprolide acetate can be used for the elimination of LH, which involves reducing and decreasing serum testosterone levels to castration levels in order to treat prostate cancer.

Before LH RH agonists were introduced, castration testosterone levels were achieved by increasing the estrogen activity in the pituitary by estrogen, mainly diethylstilbestrol (DES). DES was equally effective as LHRH agonists to bring testosterone to levels of castration. Patients treated with DES did not present hot flushes or bone loss, but had higher rates of gynecomastia than with ADT with LHRH agonists. Unfortunately, it is usual that pure and very potent estrogens such as DES and estradiol are associated with an elevated risk of serious cardiovascular and thromboembolic complications, limiting their clinical use.

The compounds of this invention are selective non-steroidal agonists of ERa. In the treatment of patients with CRPC or metastatic CRPC (mCRPC), these novel small molecules reduce the testosterone levels of patients undergoing ADT (ie, the testosterone levels of these patients were already at castration levels) at the same time. To reduce the levels of steroid or sexual hormone binding globulin (SH BG) in serum, and thus reduce the circulating levels of testosterone in circulating serum, the form of testosterone that stimulates prostatic growth and prostate cancer. Since they are ERa agonists, the compounds of the present invention also improve the sequential effects of estrogen deficiency which include the ability to maintain the bones, reduce the incidence of hot flashes and prevent adverse changes and resistance to insulin commonly associated with LHR H agonists and antagonists.

Brief description of the invention In one embodiment, this invention provides a method for treating, eliminating, reducing the incidence, reducing the severity or inhi bing the evolution of castration-resistant prostate cancer (CRPC) and its symptoms, or increase the survival of men with castration-resistant prostate cancer by administering a therapeutically effective amount of a compound of formula I or its isomer, salt pharmaceutically acceptable, pharmaceutical product, polymorph, hydrate or any combination of the: (I) as described hereinafter.

In one embodiment, this invention provides a method for decreasing serum PSA levels in a male subject suffering from castration-resistant prostate cancer (CRPC) comprising the administration of a therapeutically effective amount of a compound of Form I, as described below. In another embodiment, the compound is Compound IV, as described hereinbelow.

In one embodiment, this invention provides a method for decreasing serum testosterone levels in a male sex subject suffering from castration-resistant prostate cancer (CRPC) which comprises administering a quantity Therapeutically effective of a compound of formula I, as described hereinafter. In another embodiment, the compound is Compound IV, as described herein below.

In one embodiment, this invention relates to a method for increasing the serum concentration of steroid hormone binding globulin (SH BG) in a subject suffering from castration-resistant prostate cancer (CRPC) comprising the administration of an amount Therapeutically effective of a compound of formula I, as described hereinafter. In another embodiment, the compound is Compound IV, as described herein below.

In another embodiment, castration-resistant prostate cancer (CRPC) is metastatic CRPC (mCRPC). In another embodiment, the subject has high or increasing levels of prostate-specific antigen (PSA). In another embodiment, the subject receives, in addition, androgen deprivation therapy (ADT). In another embodiment, administration of the compound does not cause side effects associated with androgen deprivation therapy (ADT). In another modality, side effects are selected from the group consisting of: hot flushes, gynecomastia, increased body fat, bone loss, decreased bone mineral density and increased risk of fracture. In another embodiment, the compound or its isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or any combination thereof is administered in a dose of 125 mg per day, 250 mg per day or 500 mg per day.

BRIEF DESCRIPTION OF THE DRAWINGS The matter considered as the invention is particularly indicated and claimed in the final part of the description. However, the invention can be better understood by referring to the following detailed description both with regard to the organization and method of operation and its objectives, characteristics and advantages if read together with the accompanying drawings in which: Figure 1 illustrates the levels of serum testosterone (full line) and total androgen (dotted line) in intact male monkeys after daily oral administration of 30 mg / kg of Compound IV (first dose on Day 0). (See Example 8.) Figure 2 illustrates the testosterone levels in intact rats treated with Compound IV (0.3, 1, 10, 30 mg / kg). 'implies P < 0.05 against intact vehicle controls. The BLOC values are represented graphically in the limit of quantification 0.08 ng / mL. (See Example 9.) Figure 3 illustrates the inhibitory effect of Compound IV on the enzymatic activity of 1 7 -HSD5. (See Example 1 2.) Figure 4 illustrates the in vitro aggregation of human platelets in the presence of DES, estradiol 17β (E2) and Compound IV. Platelet rich plasma (PRP) was incubated with a vehicle, E2, DES or Compound IV for 30 seconds before inducing aggregation with 0.3 units of thrombin. Aggregation was monitored for 5 minutes and expressed as a percentage of vehicle control. (See Example 1 3.) Figure 5 illustrates the synthetic synthetic scheme of preparation of Compounds ll-XII. (See Example 1.) Figure 6 illustrates the synthetic scheme of preparation of Compound IV. (See Example 2.) Figure 7 illustrates the synthetic scheme of preparation of the Compound VI. (See Example 3.) Figure 8 illustrates the synthetic scheme of preparation of Compounds IX and X. (See Example 5.) Figure 9 illustrates the testosterone levels in intact rats treated with Compound IV after 24 h, 72 h and 168 h at doses of 3 mg / kg, 10 mg / kg and 300 mg / kg. (See Example 9.) Figures 10A-F illustrate LH levels (Figure 10A), FSH levels (Figure 10B), testosterone levels (Figure 10C), prosthetic weight levels (Figure 10D), seminal vesicle weight levels (Figure 10E) and weight of the levator ani muscle (Figure 10F) of intact and orchiectomized rats (ORX) with doses of 0.3 mg / kg, I mg / kg, 3 mg / kg, 10 mg / kg and 30 mg / kg of Compound IV. 'implies P < 0.05 against intact vehicle controls. ° implies P < 0.05 against controls with ORX vehicle. The BLOC values are represented graphically in the limit of quantification 0.08 ng / mL. (See Example 9.) Figures 11A-B illustrate the prosthetic size in intact rats and ORX by administering different doses of Compound IV (Fig.

I I A) and DES (Fig. 11B). (See Example 15.) Figures 12A-C illustrate the differences between DES and the Compound IV. While DES reacts cross-linked with the glucocorticoid receptor (GR), while Compound IV does not (Figure 12A). DES reacts cross-reactive with the androgen receptor (AR). It slightly stimulates the action of AR and inhibits it slightly (that is, it is a partial agonist / antagonist), while Compound IV does not (Figure 12B). DES cancels the transactivation of the estrogen-related receptor (ERR), while Compound IV does not (Figure 12C). (See Example 1 5.) Figure 13 illustrates the effect of Compound IV on the attenuation of hot flushes in a morphine abstinence model at doses of 5 mg / kg, 10 mg / kg, 15 mg / kg and 30 mg / kg. N = 7 animals per group. 17β-2 to 5 mg / kg in 100% DMSO was used. (See Example 14.) Figure 14 illustrates the dose-dependent reduction in body weight (kg) in monkeys (~ 20% to 100 mg / kg) by administering Compound IV for 91 days. No evidence of gynecomastia or hyperestrogenicity was observed. (See Example 16.) Figure 15 illustrates reductions in dose-dependent serum testosterone level in monkeys (ng / mL) following daily oral administration of Compound IV as compared to the positive control (LHRH agonist). The dotted line indicates the testosterone level of chemically castrated patients and the bold dashed line indicates the testosterone level of surgically castrated monkeys. (See Example 16.) Figure 16 illustrates the levels of prosthetic antigen specific (PSA) dose-dependent (ng / mL) in monkeys when administering Compound IV at the reference and on day 28. PSA levels were significantly reduced with the treatment with Compound IV. (See Example 16.) Figure 17 illustrates the dose-dependent prosthetic volume by transrectal ultrasound (TRUS) in monkeys compared to the positive control (LHRH agonist) upon admixing Compound IV at week 6. (See Example 16.) Figures 18A-B illustrate the weights of the dose-dependent organs (prostate, seminal vesicle and testes) as a percentage of control monkeys on day 91 when administering Compound IV (Figure 18A). Weight of the prostate at the time of necropsy during week 1 3 after oral administration of Compound IV (Fig. 18B). (See Example 16.) Figure 19 illustrates total dose-dependent testosterone levels (nmol / L) in humans for a period of 1 to 11 days upon administration of Compound IV (1000 mg, 300 mg, 600 mg and 1000 mg). (See Example 1 7.) Figure 20 illustrates median levels of dose-dependent LH (IU / L) in humans for a period of 1 to 10 days when administering Compound IV (100 mg, 300 mg, 600 mg and 1000 mg). (See Example 1 7.) Figure 21 illustrates the mean levels of dose-dependent free testosterone (pg / mL) in humans for a period of 1 to 10 days upon administration of Compound IV (100 mg, 300 mg, 600 mg and 1000 mg). (See Example 1 7.) Figure 22 illustrates average dose dependent PSA levels (pg / L) in humans for a period of 1 to 10 days upon administration of Compound IV (1000 mg, 300 mg, 600 mg and 1000 mg) . (See Example 1 7.) Figure 23 illustrates dose-dependent serum testosterone levels (ng / mL) in intact rats after 14 days of recovery from the administration of Compound IV. 'implies P < 0.05 against intact controls. (See Example 1 0.) Figure 24 illustrates the percent reduction of serum PSA in seven subjects with castration-resistant prostate cancer (CRPC) who were treated with 2000 mg of Compound IV (Study 3).

Figure 25 illustrates a flow chart describing the procedure of Study 6 (Example 27).

Figure 26 illustrates the details of the study for each of the clinical studies for Compound IV in human subjects: healthy patients, with prostate cancer without previous treatment and with castration-resistant prostate cancer (Examples 25 and 26).

Figures 27A-B illustrate the induction of SHBG by Compound IV and the ratio of SHBG to the percentage of free testosterone (% Free T) in untreated patients from Study 2 and Study 5 (Figure 27A) and in patients with CRPC in simultaneous ADT of Study 3 (Figure 27B). In the trials of Study 2 and Study 5, the reference of SHBG is induced with ~150-700% after 28 days of therapy with Compound IV (Figure 27A). The induction of SHBG is closely related to the% reduction of Free T [Free T (pg / mL) / Total T (pg / mL) * 100]. The regression of the relationship shows that an induction of -400% in SHBG is associated with reductions of ~ 75% in% of Free T. A large number of patients without prior treatment are grouped in this range for all doses of Compound IV. It is important that this close relationship be maintained in patients with CRPC in simultaneous ADT of Study 3 (Figure 27B) even when only 1 5 days of therapy with Compound IV are contemplated. The unfilled symbols represent the reference (BL) and the symbols with padding represent treatment with Compound IV, as described hereinafter (Example 26).

Figures 28A-D illustrate the percentage change of free testosterone as a function of the change of PSA in patients with prostate cancer without prior treatment of studies 2 and 5 on day 7 (Figure 28A); day 14 (Figure 28B); day 21 (Figure 28C) and day 28 (Figure 28D) of the treatment with Compound IV (Example 26).

Figure 29 illustrates the change of PSA against the change of SHBG in patients with prostate cancer without previous treatment of studies 2 and 5 on day 28. The amplitude of SHBG induction is able to reduce more than 50% of PSA (Example 25).

Figure 30 illustrates the percentage change of free testosterone against the change of PSA in patients with castration-resistant prostate cancer from study 3 on day 15 (7 subjects) and day 30 (3 subjects) (Example 26).

Figure 31 illustrates the molar ratio of SHBG and total testosterone as a function of time in patients with prostate cancer without previous treatment of studies 2 and 5 (solid line). The dotted line represents the percentage of free testosterone (% Free T) as a function of time (Example 25).

Figures 32A-B illustrate the percentage change of SHBG against the average minimum of Compound IV as calculated based on the results of Study 1 and Study 2 on day 28, and extrapolation for doses lower than 125 mg, 250 mg and 500 mg. This suggests that even with lower doses of Compound IV, SH BG may rise enough to significantly reduce the% Free T and PSA (Example 25).

Figure 33 illustrates a flow chart describing the procedure of Study 3 (Example 26).

It will be noted that the elements illustrated in the figures were not necessarily drawn to scale for purposes of clarity and simplicity. For example, the dimensions of some of the elements may have been exaggerated with respect to other elements for clarity. In addition, when considered appropriate, the reference numbers may be repeated between the figures to indicate corresponding or analogous elements.

Detailed description of the present invention In the following detailed description numerous specific details are presented in order to provide a thorough understanding of the invention. However, those skilled in the art will understand that the The present invention can be carried out without these specific details. In other instances, known methods, methods and components are not described in detail so as not to overshadow the present invention.

In one embodiment, the compounds as described herein and / or the compositions comprising them can be used to reduce the total serum testosterone levels in a male subject.

In one embodiment, the compounds as described herein and / or the compositions comprising them can be used to reduce the total levels of serum testosterone and the specific prostatic antigen (PSA) in a male subject. In one embodiment, the reduction of total serum testosterone levels reaches castration levels. In one embodiment, the reduction in total serum testosterone levels does not reach castration levels. In one embodiment, the reduction of total serum testosterone levels reaches levels lower than the levels obtainable only with ADT.

In one embodiment, the compounds as described herein and / or the compositions comprising them can be used to reduce the levels of specific prosthetic antigen independently of the reduction or lack of reduction of testosterone levels.

In one embodiment, the compounds as described herein and / or the compositions comprising them can be used to reduce the total serum testosterone levels in a male subject and the reduction of serum testosterone occurs by a reduction in serum luteinizing hormone (LH) levels.

In one embodiment, the compounds as described herein and / or the compositions comprising them can be used to reduce total serum testosterone levels in a male subject and the reduction of total serum testosterone does not depend on a reduction in luteinizing hormone levels in serum.

In one embodiment, the compounds as described herein and / or the compositions comprising them can be used to reduce the percentage of free testosterone (% Free T) in serum in a male subject.

In one embodiment, the compounds as described herein and / or the compositions comprising them can be used to treat, eliminate, reduce the incidence, reduce the severity or inhibit the progression of castration-resistant prostate cancer (CRPC ) and its symptoms, or increase the survival of men with castration-resistant prostate cancer. In another embodiment, CRPC is metastatic CRPC (mCRPC). In another embodiment, the subject receives, in addition, androgen deprivation therapy.

In one embodiment, the compounds as described herein and / or the compositions comprising them can be used in combination with LHRH agonists or antagonists for increase the survival without evolution or the overall survival of a subject suffering from prostate cancer. In another modality, prostate cancer is advanced prostate cancer. In another embodiment, prostate cancer is castration-resistant prostate cancer (CRPC). In another embodiment, CRPC is metastatic CRPC (mCRPC). In another modality, the subject is surgically castrated. In another modality, the subject is chemically castrated.

In one embodiment, the compounds as described herein and / or the compositions comprising them can be used to increase the survival of men with castration-resistant prostate cancer (CRPC). In another embodiment, CRPC is metastatic CRPC (mCRPC). In another embodiment, the subject receives, in addition, androgen deprivation therapy.

In one embodiment, this invention provides a method for reducing total serum testosterone levels in a male subject comprising the administration of a therapeutically effective amount of a compound, or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph , hydrate or any combination thereof, represented by the structure of formula I: where And it is C (O) or CH2; Ri, R2 are independently hydrogen, halogen, hydroxyl, alkoxy, cyano, nitro, CF3, N (R) 2, sulfonamide, SO2R, alkyl, haloalkyl, aryl, 0-Alk-N RsR6 or O-Alk-heterocycle wherein the heterocycle is a substituted or unsubstituted heterocyclic ring of 3 to 7 members, optionally aromatic; R3, R4 are independently hydrogen, halogen, hydroxyalkyl, hydroxyl, alkoxy, cyano, nitro, CF3, N HCO R, N (R) 2, sulfonamide, S02 R, alkyl, haloalkyl, aryl or protected hydroxyl; R is alkyl, hydrogen, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2, CF 3, C F 2 C F 3, aryl, phenyl, halogen, alkenyl, CN, N 0 2 or OH; R5 and R6 are independently hydrogen, phenyl, an alkyl group of 1 to 6 carbon atoms, a cycloalkyl of 3 to 7 members, a heterocycle of 3 to 7 members, an aryl of 5 to 7 members; or R5 and Re form a ring of 3 to 7 members with the nitrogen atom; j and k are independently 1-4; Y Alk is a linear alkyl of 1 to 7 carbons, branched alkyl of 1 to 7 carbons or cycloalkyl of 3 to 8 carbons; In further embodiments of the methods described herein, the compound of Formula I is represented by formula IA: (??) where Ri, R ?, R3, R, j and k are those defined by Formula I. In one embodiment, this invention provides a method for reducing total serum testosterone levels in a male subject comprising administering a therapeutically effective amount of a compound, or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof, represented by a compound of formula II: (I I) In one embodiment, this invention provides a method for reducing total serum testosterone levels in a male subject comprising administering a therapeutically effective amount of a compound, or its isomer, salt pharmaceutically acceptable, pharmaceutical, polymorph, hydrate or any combination thereof, represented by a compound of formula I I I: (I I I) In one embodiment, this invention provides a method for reducing total serum testosterone levels in a male subject comprising the administration of a therapeutically effective amount of a compound, or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph , hydrate or any combination thereof, represented by a compound of formula IV: (IV) In one embodiment, this invention provides a method for reducing total serum testosterone levels in a male subject comprising the administration of a therapeutically effective amount of a compound, or its isomer, pharmaceutically acceptable salt, pharmaceutical prodrug, polymorph, hydrate or any combination from the, represented by a com ponent of formula V: (V) In one embodiment, this invention provides a method for reducing total serum testosterone levels in a male subject comprising the administration of a therapeutically effective amount of a compound, or its isomer, pharmaceutically acceptable salt, pharmaceutical product. , polymorph, hydrate or any combination thereof, represented by a compound of formula VI: (SAW) In one embodiment, this invention provides a method for reducing total serum testosterone levels in a male subject comprising the administration of a therapeutically effective amount of a compound, or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph , hydrate or any combination thereof, represented by a compound of formula VI I: (VI I) In one embodiment, this invention provides a method for reducing total serum testosterone levels in a male subject comprising the administration of a therapeutically effective amount of a compound, or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph , hydrate or any combination thereof, represented by a compound of formula VI II: In one embodiment, this invention provides a method for reducing total serum testosterone levels by reducing the levels of luteinizing hormone (LH) in a male subject suffering from prostate cancer comprising the administration of a Therapeutically effective amount of a compound, or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof, represented by a compound of formula IX: (IX) In one embodiment, this invention provides a method for reducing total serum testosterone levels in a male subject comprising administering a therapeutically effective amount of a compound, or its isomer, salt pharmaceutically acceptable, pharmaceutical, polymorph, hydrate or any combination thereof, represented by a compound of formula X: (X) In one embodiment, this invention provides a method for reducing total serum testosterone levels in a male subject comprising the administration of a therapeutically effective amount of a compound, or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph , hydrate or any combination thereof, represented by a compound of formula XI: (XI) In one embodiment, this invention provides a method for reducing total serum testosterone levels in a male subject comprising administering a therapeutically effective amount of a compound, or its isomer, pharmaceutically acceptable salt, pharmaceutical product, pol imorph, hydrate or any combination of them, represented by a compound of formula XI I: (XI I) In one embodiment, this invention provides a method for reducing serum free testosterone levels in a male subject comprising administering a therapeutically effective amount of a compound, or its isomer, pharmaceutically acceptable salt, prod uct. pharmaceutical, pol imorph, hydrate or any combination thereof, represented by the structure of formula I: (I) where And it is C (O) or CH2; R i, R 2 are independently hydrogen, halogen, hydroxyl, alkoxy, cyano, nitro, CF 3, N (R) 2, sulfonamide, SO 2 R, alkyl, haloalkyl, aryl, O-Alk-N RsRe or O-Alk-heterocycle in the that the heterocycle is a substituted or unsubstituted heterocyclic ring of 3 to 7 members, optionally aromatic; R3, R4 are independently hydrogen, halogen, hydroxyalkyl, hydroxyl, alkoxy, cyano, nitro, CF3, NHCOR, N (R) 2 > sulfonamide, SO2 R, alkyl, haloalkyl, aryl or protected hydroxyl; R is alkyl, hydrogen, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2, CF 3, C F 2 C F 3, aryl, phenyl, halogen, alkenyl, CN, N 0 2 or OH; R5 and R6 are independently hydrogen, phenyl, an alkyl group of 1 to 6 carbon atoms, a cycloalkyl of 3 to 7 members, a heterocycle of 3 to 7 members, an aryl of 5 to 7 members; or R5 and Re form a ring of 3 to 7 members with the nitrogen atom; j and k are independently 1-4; Y Alk is a linear alkyl of 1 to 7 carbons, branched alkyl of 1 to 7 carbons or cycloalkyl of 3 to 8 carbons; In further embodiments of the methods described herein, the compound of Formula I is represented by formula IA: where Ri, R ?, R3, R4, j and k are those defined by Formula I.

In one embodiment, this invention provides a method for reducing serum free testosterone levels in a male subject comprising the administration of a therapeutically effective amount of a compound, or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph , hydrate or any combination thereof, represented by a compound of formula II: In one embodiment, this invention provides a method for reducing serum free testosterone levels in a male subject comprising the administration of a therapeutically effective amount of a compound, or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph , hydrate or any combination thereof, represented by a compound of Formula I I I: (I I I) In one embodiment, this invention provides a method for reducing serum free testosterone levels in a male subject comprising the administration of a therapeutically effective amount of a compound, or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph , hydrate or any combination thereof, represented by a compound of formula IV: In one embodiment, this invention provides a method for reducing serum free testosterone levels in a male subject comprising administering a therapeutically effective amount of a compound, or its isomer, salt pharmaceutically acceptable, pharmaceutical, polymorph, hydrate or any combination thereof, represented by a compound of formula V: (V) In one embodiment, this invention provides a method for reducing serum free testosterone levels in a male subject comprising the administration of a therapeutically effective amount of a compound, or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph , hydrate or any combination thereof, represented by a compound of formula VI: (SAW) In one embodiment, this invention provides a method for reducing serum free testosterone levels in a male subject comprising administering a therapeutically effective amount of a compound, or its isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate or any combination thereof, depicted by a compound of formula VI I: (VI I) In one embodiment, this invention provides a method for reducing serum free testosterone levels in a male subject comprising the administration of a therapeutically effective amount of a compound, or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph , hydrate or any combination thereof, represented by a compound of formula VI II: In one embodiment, this invention provides a method for reducing serum free testosterone levels by reducing luteinizing hormone (LH) levels in a male sex subject who suffers from prostate cancer comprising the administration of a therapeutically effective amount of a compound, or its isomer, pharmaceutically acceptable salt, pharmaceutical product, pol imorph, hydrate or any combination thereof, represented by a compound of formula IX: In one embodiment, this invention provides a method for reducing serum free testosterone levels in a male subject comprising administering a therapeutically effective amount of a compound, or its isomer, pharmaceutically acceptable salt, prod uct. pharmaceutical, pol imorph, hydrate or any combination thereof, represented by a compound of formula X: In one embodiment, this invention provides a method for reducing serum free testosterone levels in a male subject comprising the administration of a therapeutically effective amount of a compound, or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph , hydrate or any combination thereof, represented by a compound of formula XI: (XI) In one embodiment, this invention provides a method for reducing serum free testosterone levels in a male subject comprising the administration of a therapeutically effective amount of a compound, or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph hydrate or any combination thereof, represented by a compound of formula XI I: (XII) In one embodiment, this invention provides a method for reducing the percentage of free testosterone in serum (% Free T) in a male subject comprising the administration of a therapeutically effective amount of a compound, or its isomer, pharmaceutically salt acceptable, pharmaceutical product, polymorph, hydrate or any combination thereof, represented by the structure of formula I: (i) where And it is C (O) or CH2; Ri, R2 are independently hydrogen, halogen, hydroxyl, alkoxy, cyano, nitro, CF3, N (R) 2, sulfonamide, S02R, alkyl, haloalkyl, aryl, 0-Alk-N RsR6 or O-Alk-heterocycle wherein the heterocycle is a substituted or unsubstituted heterocyclic ring of 3 to 7 members, optionally aromatic; R 3, R 4 are independently hydrogen, halogen, hydroxyalkyl, hydroxyl, alkoxy, cyano, nitro, C F 3, N HCO R, N (R) 2, sulfonamide, SO 2 R, alkyl, haloalkyl, aryl or protected hydroxyl; R is alkyl, hydrogen, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3) CF2CF3, aryl, phenyl, halogen, alkenyl, CN, N02 or OH; R5 and R6 are independently hydrogen, phenyl, an alkyl group of 1 to 6 carbon atoms, a cycloalkyl of 3 to 7 members, a heterocycle of 3 to 7 members, an aryl of 5 to 7 members; or R5 and Re form a ring of 3 to 7 members with the nitrogen atom; j and k are independently 1-4; Y Alk is a linear alkyl of 1 to 7 carbons, branched alkyl of 1 to 7 carbons or cycloalkyl of 3 to 8 carbons; In further embodiments of the methods described herein, the compound of Formula I is represented by formula IA: (IA) where Ri, R2, 3, R4, j and k are those defined by Formula I.

In one embodiment, this invention provides a method for reducing the percentage of free testosterone in serum (% Free T) in a male subject comprising the administration of a therapeutically effective amount of a compound, or its isomer, pharmaceutically salt acceptable, pharmaceutical, polymorph, hydrate or any combination thereof, represented by a compound of formula II: (II) In one embodiment, this invention provides a method for reducing the percentage of free testosterone in serum (% Free T) in a male subject comprising the administration of a therapeutically effective amount of a compound, or its isomer, pharmaceutically salt acceptable, pharmaceutical product, polymorph, hydrate or any combination thereof, represented by a compound of formula III: (I I I) In one embodiment, this invention provides a method for reducing the percentage of free testosterone in serum (% Free T) in a male subject comprising the administration of a therapeutically effective amount of a compound, or its isomer, pharmaceutically salt acceptable, pharmaceutical product, polymorph, hydrate or any combination thereof, represented by a compound of formula IV: In one embodiment, this invention provides a method for reducing the percentage of free testosterone in serum (% Free T) in a male subject comprising administering a therapeutically effective amount of a compound, or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof, represented by a compound of formula V: (V) In one embodiment, this invention provides a method for reducing the percentage of free testosterone in serum (% Free T) in a male subject comprising the administration of a therapeutically effective amount of a compound, or its isomer, pharmaceutically salt acceptable, pharmaceutical product, polymorph, hydrate or any combination thereof, represented by a compound of formula VI: (SAW) In one embodiment, this invention provides a method for reducing the percentage of free testosterone in serum (% Free T) in a male subject comprising the administration of a therapeutically effective amount of a compound, or its isomer, pharmaceutically salt acceptable, pharmaceutical, polymorph, hydrate or any combination thereof, represented by a compound of formula VII: (VII) In one embodiment, this invention provides a method for reducing the percentage of free testosterone in serum (% Free T) in a male subject comprising the administration of a therapeutically effective amount of a compound, or its isomer, pharmaceutically salt acceptable, pharmaceutical product, polymorph, hydrate or any combination thereof, represented by a compound of formula VIII: (VI I I) In one embodiment, this invention provides a method for reducing the percentage of free testosterone in serum (% Free T) by reducing the levels of luteinizing hormone (LH) in a male subject suffering from prostate cancer comprising the administration of a therapeutically effective amount of a compound, or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof, represented by a compound of formula IX: (IX) In one embodiment, this invention provides a method for reduce the percentage of free testosterone in serum (% Free T) in a male subject comprising the administration of a therapeutically effective amount of a compound, or its isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate or any combination of them, represented by a compound of formula X: (X) In one embodiment, this invention provides a method for reducing the percentage of free testosterone in serum (% Free T) in a male subject comprising the administration of a therapeutically effective amount of a compound, or its isomer, pharmaceutically salt acceptable, pharmaceutical product, polymorph, hydrate or any combination thereof, represented by a compound of formula XI: (XI) In one embodiment, this invention provides a method for reducing the percentage of free testosterone in serum (% Free T) in a male subject comprising the administration of a therapeutically effective amount of a compound, or its isomer, pharmaceutically salt acceptable, pharmaceutical product, polymorph, hydrate or any combination thereof, represented by a compound of formula XI I: (XII) In one embodiment, this invention provides a method to treat, eliminate, reduce the incidence, reduce the severity or inhibit the progression of castration-resistant prostate cancer (CRPC) and its symptoms, or increase the survival of men with prostate cancer. castration resistant comprising the administration of a therapeutically effective amount of a compound or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof, represented by the structure of formula I: (l) where And it is C (O) or CH2; Ri, 2 are independently hydrogen, halogen, hydroxyl, alkoxy, cyano, nitro, CF3, N (R) 2, sulfonamide, SO2R, alkyl, haloalkyl, aryl, O-Alk-NRsRe or O-Alk-heterocycle wherein the heterocycle is a substituted or unsubstituted heterocyclic ring of 3 to 7 members, optionally aromatic; R3, R4 are independently hydrogen, halogen, hydroxyalkyl, hydroxyl, alkoxy, cyano, nitro, CF3, NHCOR, N (R) 2, sulfonamide, SO2R, alkyl, haloalkyl, aryl or protected hydroxyl; R is alkyl, hydrogen, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3l aryl, phenyl, halogen, alkenyl, CN, N02 or OH; R5 and 6 are independently hydrogen, phenyl, an alkyl group of 1 to 6 carbon atoms, a cycloalkyl of 3 to 7 members, a heterocycle of 3 to 7 members, an aryl of 5 to 7 members; or R5 and Re form a ring of 3 to 7 members with the nitrogen atom; j and k are independently 1-4; Y Alk is a linear alkyl of 1 to 7 carbons, branched alkyl of 1 at 7 carbons or cycloalkyl of 3 to 8 carbons; In further embodiments of the methods described herein, the compound of Formula I is represented by the formula IA: (IA) where Ri, R ?, R3, R4, j and k are those defined by Formula I.

In one embodiment, this invention provides a method for treating, eliminating, reducing the incidence, reducing the severity or inhibiting the progression of castration-resistant prostate cancer (CRPC) and its symptoms, or increasing the survival of men with castration-resistant prostate cancer comprising administering a therapeutically effective amount of a compound or its isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate or any combination thereof, represented by a compound of formula II: (II) In one embodiment, this invention provides a method to treat, eliminate, reduce the incidence, reduce the severity or inhibit the progression of castration-resistant prostate cancer (CRPC) and its symptoms, or increase the survival of men with prostate cancer. castration resistant comprising the administration of a therapeutically effective amount of a compound or its isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate or any combination thereof, represented by a compound of formula III: (II .; In one embodiment, this invention provides a method to treat, eliminate, reduce the incidence, reduce the severity or inhibit the evolution of castration-resistant prostate cancer (CRPC) and its symptoms, or increase the survival of men with castration-resistant prostate cancer comprising administering a therapeutically effective amount of a compound or its isomer, pharmaceutically acceptable salt , pharmaceutical product, polymorph, hydrate or any combination thereof, represented by a compound of formula IV: In one embodiment, this invention provides a method to treat, eliminate, reduce the incidence, reduce the severity or inhibit the progression of castration-resistant prostate cancer (CRPC) and its symptoms, or increase the survival of men with prostate cancer. castration resistant comprising the administration of a therapeutically effective amount of a compound or its isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate or any combination thereof, represented by a compound of formula V: In one embodiment, this invention provides a method for treating, eliminating, reducing the incidence, reducing the severity or inhibiting the progression of castration-resistant prostate cancer (CRPC) and its symptoms, or increasing the survival of men with castration-resistant prostate cancer comprising administering a therapeutically effective amount of a compound or its isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate or any combination thereof, represented by a compound of formula SAW : (SAW) In one embodiment, this invention provides a method for treating, eliminating, reducing the incidence, reducing the severity or inhi bing the evolution of castration-resistant prostate cancer (CRPC) and its symptoms, or increase the survival of men with castration-resistant prostate cancer comprising administering a therapeutically effective amount of a compound or its isomer, pharmaceutically acceptable salt , pharmaceutical product, polymorph, hydrate or any combination thereof, represented by a compound of formula VII: In one embodiment, this invention provides a method to treat, eliminate, reduce the incidence, reduce the severity or inhibit the progression of castration-resistant prostate cancer (CRPC) and its symptoms, or increase the survival of men with prostate cancer. castration-resistant comprising administering a therapeutically effective amount of a compound or its isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate or any combination thereof, represented by a compound of formula VIII: (VIII) In one embodiment, this invention provides a method to treat, eliminate, reduce the incidence, reduce the severity or inhibit the progression of castration-resistant prostate cancer (CRPC) and its symptoms, or increase the survival of men with prostate cancer. castration-resistant comprising the administration of a therapeutically effective amount of a compound or its isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate or any combination thereof, represented by a compound of formula IX: (IX) In one embodiment, this invention provides a method for treating, eliminating, reducing the incidence, reducing the severity or inhibiting the progression of castration-resistant prostate cancer (CRPC) and its symptoms, or increase the survival of men with castration-resistant prostate cancer comprising administering a therapeutically effective amount of a compound or its isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate or any combination thereof, represented by a compound of formula X: In a fashion, this invention provides a method for treating, eliminating, reducing the incidence, reducing the severity or inhibiting the progression of castration-resistant prostate cancer (CRPC) and its symptoms, or increasing the survival of men. with castration-resistant prostate cancer comprising administering a therapeutically effective amount of a compound or its isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate or any combination thereof, represented by a compound of formula XI: In one embodiment, this invention provides a method to treat, eliminate, reduce the incidence, reduce the severity or inhibit the progression of castration-resistant prostate cancer (CRPC) and its symptoms, or increase the survival of men with prostate cancer. castration-resistant comprising the administration of a therapeutically effective amount of a compound or its isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate or any combination thereof, represented by a compound of formula XII: (XI I) In one embodiment, this invention provides a method for reducing prostate-specific antigen (PSA) levels in serum in a male subject suffering from prostate cancer. castration-resistant (CRPC) comprising the administration of a therapeutically effective amount of a compound, or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof, represented by the structure of formula I : where And it is C (O) or CH2; Ri, R2 are independently hydrogen, halogen, hydroxyl, alkoxy, cyano, nitro, CF3, N (R) 2, sulfonamide, SO2R, alkyl, haloalkyl, aryl, 0-Alk-NR5Re or O-Alk-heterocycle wherein the heterocycle is a substituted or unsubstituted heterocyclic ring of 3 to 7 members, optionally aromatic; R3, RA are independently hydrogen, halogen, hydroxyalkyl, hydroxyl, alkoxy, cyano, nitro, CF3, NHCOR, N (R) 2, sulfonamide, SO2R, alkyl, haloalkyl, aryl or protected hydroxyl; R is alkyl, hydrogen, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, halogen, alkenyl, CN, N02 or OH; R5 and Re are independently hydrogen, phenyl, an alkyl group of 1 to 6 carbon atoms, a cycloalkyl of 3 to 7 members, a heterocycle of 3 to 7 members, an aryl of 5 to 7 members; or Rs and 6 form a ring of 3 to 7 members with the nitrogen atom; j and k are independently 1-4; Y Alk is a linear alkyl of 1 to 7 carbons, branched alkyl of 1 to 7 carbons or cycloalkyl of 3 to 8 carbons; In further embodiments of the methods described herein, the compound of Formula I is represented by formula IA: where R i, R 2, R 3, R 4, j and k are those defined by Formula I.

In one embodiment, this invention provides a method for reducing serum prostate-specific antigen (P SA) levels in a male subject suffering from castration-resistant prostate cancer (CR PC) comprising the administration of an amount Therapeutically effective of a compound, or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof, represented by a composed of formula I I: (I I) In one embodiment, this invention provides a method for reducing serum prostate-specific antigen (PSA) levels in a male subject suffering from castration-resistant prostate cancer (CRPC) comprising the administration of a therapeutically effective amount. of a compound, or of its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof, represented by a compound of formula III: (I I I) In one embodiment, this invention provides a method for reducing serum prostate specific antigen (PSA) levels in a male subject suffering from prostate cancer. castration-resistant (CRPC) comprising the administration of a therapeutically effective amount of a compound, or its isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate or any combination thereof, represented by a compound of formula IV: (IV) In one embodiment, this invention provides a method for reducing serum prostate-specific antigen (PSA) levels in a male subject suffering from castration-resistant prostate cancer (CRPC) comprising the administration of a therapeutically effective amount. of a compound, or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof, represented by a compound of formula V: (V) In one embodiment, this invention provides a method for reducing prostate-specific antigen (PSA) levels in serum in a male subject suffering from castration-resistant prostate cancer (CRPC) comprising the administration of a therapeutically effective amount. of a compound, or of its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof, represented by a compound of formula VI: (SAW) In one embodiment, this invention provides a method for reducing prostate-specific antigen (PSA) levels in serum in a male subject suffering from castration-resistant prostate cancer (CRPC) comprising the administration of a therapeutically effective amount. of a compound, or of its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof, represented by a compound of formula VI I: In one embodiment, this invention provides a method for reducing serum prostate-specific antigen (PSA) levels in a male subject suffering from castration-resistant prostate cancer (CRPC) comprising the administration of a therapeutically effective amount. of a compound, or of its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof, represented by a compound of formula VI II: (VI I I) In one embodiment, this invention provides a method for reducing serum prostate specific antigen (PSA) levels in a male subject suffering from prostate cancer. castration-resistant (CRPC) comprising the administration of a therapeutically effective amount of a compound, or its isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate or any combination thereof, represented by a compound of formula IX: In one embodiment, this invention provides a method for reducing serum prostate-specific antigen (PSA) levels in a male subject suffering from castration-resistant prostate cancer (CRPC) comprising the administration of a therapeutically effective amount. of a compound, or of its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof, represented by a compound of formula X: In one embodiment, this invention provides a method for reducing serum prostate-specific antigen (PSA) levels in a male subject suffering from castration-resistant prostate cancer (CRPC) comprising administering a therapeutically amount effective of a compound, or of its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof, represented by a compound of formula XI: (XI) In one embodiment, this invention provides a method for reducing specific prostate antigen (PSA) levels in serum in a male subject suffering from castration-resistant prostate cancer (C RPC) comprising the administration of a quantity Therapeutically effective of a compound, or its isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate or any combination thereof, represented by a compound of formula XI I: In one embodiment, this invention provides a method for reducing the percentage of free testosterone in serum (% Free T) in a patient with castrated CRPC (i.e., with testosterone levels below 50 ng / dL) at levels obtainable with ADT alone comprising the administration of a therapeutically effective amount of a compound, or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof, represented by the structure of formula I: (l) where And it is C (O) or CH2; Ri, R2 are independently hydrogen, halogen, hydroxyl, alkoxy, cyano, nitro, CF3, N (R) 2, sulfonamide, S02R, alkyl, haloalkyl, aryl, O-Alk-N RsRe or O-Alk-heterocycle wherein the heterocycle is a substituted or unsubstituted heterocyclic ring of 3 to 7 members, optionally aromatic; R 3, R 4 are independently hydrogen, halogen, hydroxyalkyl, hydroxyl, alkoxy, cyano, nitro, C F 3, N HCOR, N (R) 2, sulfonamide, SO 2 R, alkyl, haloalkyl, aryl or protected hydroxyl; R is alkyl, hydrogen, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, halogen, alkenyl, CN, N02 or OH; R5 and R6 are independently hydrogen, phenyl, an alkyl group of 1 to 6 carbon atoms, a cycloalkyl of 3 to 7 members, a heterocycle of 3 to 7 members, an aryl of 5 to 7 members; or R5 and e form a 3 to 7 membered ring with the nitrogen atom; j and k are independently 1-4; Y Alk is a linear alkyl of 1 to 7 carbons, branched alkyl of 1 to 7 carbons or cycloalkyl of 3 to 8 carbons; In further embodiments of the methods described herein, the compound of Formula I is represented by formula IA: where Ri, R ?, R3, R4, j and k are those defined by Formula I.

In one embodiment, this invention provides a method for reducing the percentage of free testosterone in serum (% Free T) in a patient with castrated CRPC (i.e., with testosterone levels below 50 ng / dL) at levels obtainable with ADT alone comprising the administration of a therapeutically effective amount of a compound, or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof, represented by a compound of formula II: ("I) In one embodiment, this invention provides a method for reducing the percentage of free testosterone in serum (% Free T) in a a patient with castrated CRPC (ie, with testosterone levels below 50 ng / dL) at levels obtainable with ADT alone comprising the administration of a therapeutically effective amount of a compound, or its isomer, pharmaceutically acceptable salt, pharmaceutical product , polymorph, hydrate or any combination thereof, represented by a compound of formula III: (I I I) In one embodiment, this invention provides a method for reducing the percentage of free testosterone in serum (% Free T) in a patient with castrated CRPC (i.e., with testosterone levels below 50 ng / dL) at levels obtainable with ADT alone comprising the administration of a therapeutically effective amount of a compound, or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof, represented by a compound of formula IV: In one embodiment, this invention provides a method for reducing the percentage of free testosterone in serum (% Free T) in a patient with castrated CRPC (i.e., with testosterone levels below 50 ng / dL) at levels obtainable with ADT alone comprising the administration of a therapeutically effective amount of a compound, or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof, represented by a compound of formula V: (V) In one embodiment, this invention provides a method to reduce the percentage of free testosterone in serum (% Free T) in a patient with castrated CRPC (i.e., with testosterone levels per below 50 ng / dL) at levels obtainable with ADT alone comprising the administration of a therapeutically effective amount of a compound, or its isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate or any combination thereof, represented by a compound of formula VI: (SAW) In one embodiment, this invention provides a method for reducing the percentage of free testosterone in serum (% Free T) in a patient with castrated CRPC (i.e., with testosterone levels below 50 ng / dL) at levels obtainable with ADT alone comprising administering a therapeutically effective amount of a compound, or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof, represented by a compound of formula VI I: (VII) In one embodiment, this invention provides a method for reducing the percentage of free testosterone in serum (% Free T) in a patient with castrated CRPC (i.e., with testosterone levels below 50 ng / dL) at levels obtainable with ADT alone comprising the administration of a therapeutically effective amount of a compound, or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof, represented by a compound of formula VI II: (VII I) In one embodiment, this invention provides a method for reducing the percentage of free testosterone in serum (% Free T) in a patient with castrated CRPC (i.e., with testosterone levels below 50 ng / dL) at levels obtainable with ADT alone comprising the administration of a therapeutically effective amount of a compound, or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof, represented by a compound of formula IX: (IX) In one embodiment, this invention provides a method for reducing the percentage of serum testosterone in serum (% Free T) in a patient with castrate CRPC (ie, with testosterone levels below 50 ng / dL) at levels obtainable with ADT alone comprising the administration of a therapeutically effective amount of a compound, or its isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate or any combination thereof, represented by a compound of formula X: In one embodiment, this invention provides a method for reducing the percentage of free testosterone in serum (% Free T) in a patient with castrated CRPC (i.e. with testosterone levels per below 50 ng / dL) at levels obtainable with ADT alone comprising the administration of a therapeutically effective amount of a compound, or its isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate or any combination thereof, represented by a compound of formula XI: (XI) In one embodiment, this invention provides a method for reducing the percentage of free testosterone in serum (% Free T) in a patient with castrated CRPC (i.e., with testosterone levels below 50 ng / dL) at levels obtainable with ADT alone comprising the administration of a therapeutically effective amount of a compound, or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof, represented by a compound of formula XI I: (XII) In one embodiment, this invention provides a method to treat, eliminate, reduce the incidence, reduce the severity or inhibit the progression of castration-resistant prostate cancer (CRPC) and its symptoms, or increase the survival of men with prostate cancer. castration resistant by administering a therapeutically effective amount of a compound of formula IA, 1-12, or of its isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate or any combination thereof. In another modality, castration is surgical. In another form, castration is chemical. In another embodiment, CRPC is metastatic CRPC (mCRPC). In another modality, the method additionally treats, eliminates, reduces the incidence, reduces the severity or inhibits new bone metastases. In another modality, the method additionally treats, eliminates, reduces the incidence, reduces the severity or inhibits new metastases or that aggravates soft tissue metastasis (lymph or visceral lymph nodes). In another modality, the androgen deprivation therapy (ADT) that the subject received was not successful. In another embodiment, the subject additionally receives androgen deprivation therapy (ADT). In another embodiment, the subject additionally receives LHRH agonists or antagonists. In another embodiment, the LHRH agonist is leuprolide acetate. In another modality, the subject underwent orchidectomy. In another embodiment, the subject has high or increasing levels of prostate-specific antigen (PSA). In another embodiment, administration of the compound does not cause side effects associated with androgen deprivation therapy (ADT).

In another modality, the method additionally treats, eliminates, reduces the incidence, reduces the severity or inhibits the advanced prostate cancer. In another modality, the method additionally provides a palliative treatment for advanced prostate cancer. In another embodiment, the compound is Compound IV. In another embodiment, the compound is administered in a dose of 1 25 mg / per day. In another embodiment, the compound is administered in a dose of 250 mg / per day. In another embodiment, the compound is administered in a dose of 500 mg / per day.

In one embodiment, this invention provides a method to treat, eliminate, reduce the incidence, reduce the severity or inhibit the progression of castration-resistant prostate cancer (CRPC) and its symptoms, or increase the survival of men with prostate cancer. castration resistant by administering a therapeutically effective amount of estradiol, ethinylestradiol, steroidal estrogen agonists, non-steroidal estrogen agonists or combinations thereof.

In one embodiment, this invention provides a method for reducing total serum testosterone levels in a male subject suffering from castration-resistant prostate cancer (CRPC) comprising the administration of a therapeutically effective amount of a compound of Formula IA, 1-12 or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof. In another modality, castration is surgical. In another form, castration is chemical. In another embodiment, CRPC is metastatic CRPC (mCRPC). In other modality, the method additionally treats, eliminates, reduces the incidence, reduces the severity or inhibits new bone metastases. In another modality, the method additionally treats, eliminates, reduces the incidence, reduces the severity or inhibits new metastases or that aggravates soft tissue metastasis (lymph or visceral lymph nodes). In another modality, the androgen deprivation therapy (ADT) that the subject received was not successful. In another embodiment, the subject additionally receives androgen deprivation therapy (ADT). In another embodiment, the subject additionally receives LHRH agonists or antagonists. In another embodiment, the LH RH agonist is leuprolide acetate. In another modality, the subject underwent orchidectomy. In another embodiment, the subject has high or iasing levels of prostate-specific antigen (PSA). In another embodiment, administration of the compound does not cause side effects associated with androgen deprivation therapy (ADT). In another modality, the method additionally treats, eliminates, reduces the incidence, reduces the severity or inhibits the advanced prostate cancer. In another modality, the method additionally provides a palliative treatment for advanced prostate cancer. In another embodiment, the compound is Compound IV. In another embodiment, the compound is administered in a dose of 1 25 mg / per day. In another embodiment, the compound is administered in a dose of 250 mg / per day. In another embodiment, the compound is administered in a dose of 500 mg / per day. In another embodiment, the total serum testosterone is reduced below about 1 00 ng / dL. In another embodiment, the total serum testosterone is reduced below about 50 ng / dL. In another embodiment, the total serum testosterone concentration is reduced below about 25 ng / dL. In another embodiment, the total serum testosterone concentration is reduced below about 10 ng / dL. In another embodiment, the total serum testosterone concentration is reduced below about 5 ng / dL. In another embodiment, the total serum testosterone concentration is reduced below about 1 ng / dL.

In one embodiment, this invention provides a method for decreasing total serum testosterone levels in a male subject suffering from castration-resistant prostate cancer (CRPC) comprising the administration of a therapeutically effective amount of estradiol, ethinylestradiol. , steroid estrogen agonists, non-steroidal estrogen agonists or combinations of them.

In one embodiment, this invention provides a method for decreasing serum free testosterone levels in a male subject suffering from castration-resistant prostate cancer (CRPC) comprising the administration of a therapeutically effective amount of a compound of Formula IA, l-XII or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof. In another modality, castration is surgical. In another form, castration is chemical. In another embodiment, CRPC is metastatic CRPC (mCRPC). In another modality, the method additionally treats, eliminates, reduces the incidence, reduces the severity or inhibits new bone metastases. In other modality, the method additionally treats, eliminates, reduces the incidence, reduces the severity or inhibits new metastases or that aggravates soft tissue metastasis (lymph or visceral lymph nodes). In another modality, the androgen deprivation therapy (ADT) that the subject received was not successful. In another embodiment, the subject additionally receives androgen deprivation therapy (ADT). In another embodiment, the subject additionally receives LHRH agonists or antagonists. In another embodiment, the LH RH agonist is leuprolide acetate. In another modality, the subject underwent orchidectomy. In another embodiment, the subject has high or iasing levels of prostate-specific antigen (PSA). In another modality, administration of the compound does not cause side effects associated with androgen deprivation therapy (ADT). In another modality, the method additionally treats, eliminates, reduces the incidence, reduces the severity or inhibits the advanced prostate cancer. In another modality, the method additionally provides a palliative treatment for advanced prostate cancer. In another embodiment, the compound is Compound IV. In another embodiment, the compound is administered in a dose of 125 mg / per day. In another embodiment, the compound is administered in a dose of 250 mg / per day. In another embodiment, the compound is administered in a dose of 500 mg / per day. In another embodiment, serum free testosterone is reduced to levels below castration levels. In another embodiment, serum free testosterone is reduced to levels below those observed with LHRH agonists or antagonists or with surgical castration.

In one embodiment, this invention provides a method for decreasing serum free testosterone levels in a male subject suffering from castration-resistant prostate cancer (CRPC) comprising administering a therapeutically effective amount of estradiol, ethinylestradiol. , steroid estrogen agonists, non-steroidal estrogen agonists or combinations of them.

In one embodiment, this invention provides a method for decreasing the percentage of free testosterone in serum (% Free T) in a male subject suffering from castration-resistant prostate cancer (CRPC) comprising the administration of an amount Therapeutically effective of a compound of formula IA, I-XII or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof. In another modality, castration is surgical. In another form, castration is chemical. In another embodiment, CRPC is metastatic CRPC (mCRPC). In another modality, the method additionally treats, eliminates, reduces the incidence, reduces the severity or inhibits new bone metastases. In another modality, the method additionally treats, eliminates, reduces the incidence, reduces the severity or inhibits new metastases or that aggravates soft tissue metastasis (lymph or visceral lymph nodes). In another modality, the androgen deprivation therapy (ADT) that the subject received was not successful. In another embodiment, the subject additionally receives androgen deprivation therapy (ADT). In another modality, the subject receives additionally agonists or antagonists of LHRH. In another embodiment, the LHRH agonist is leuprolide acetate. In another modality, the subject underwent orchidectomy. In another embodiment, the subject has high or increasing levels of prostate-specific antigen (PSA). In another embodiment, administration of the compound does not cause side effects associated with androgen deprivation therapy (ADT). In another modality, the method additionally treats, eliminates, reduces the incidence, reduces the severity or inhibits the advanced prostate cancer. In another modality, the method additionally provides a palliative treatment for advanced prostate cancer. In another embodiment, the compound is Compound IV. In another embodiment, the compound is administered in a dose of 1 25 mg / per day. In another embodiment, the compound is administered in a dose of 250 mg / per day. In another embodiment, the compound is administered in a dose of 500 mg / per day. In another embodiment, serum free testosterone is reduced to levels below castration levels. In another embodiment, serum free testosterone is reduced to levels below those observed with LHRH agonists or antagonists or with surgical castration.

In one embodiment, this invention provides a method for decreasing the percentage of free testosterone in serum (% Free T) in a male subject suffering from castration-resistant prostate cancer (CRPC) comprising the administration of an amount Therapeutically effective of estradiol, ethinylestradiol, steroidal estrogen agonists, non-steroidal estrogen agonists or combinations of them.

In one embodiment, this invention provides a method for decreasing serum PSA levels in a male subject suffering from castration-resistant prostate cancer (CRPC) comprising administering a therapeutically effective amount of a compound of formula IA, I-XI I or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof. In another modality, castration is surgical. In another form, castration is chemical. In another embodiment, CRPC is metastatic CRPC (mCRPC). In another modality, the method additionally treats, eliminates, reduces the incidence, reduces the severity or inhibits new bone metastases. In another modality, the method additionally deals with, eliminates, reduces the incidence, reduces the severity or inhibits new metastases or that aggravates soft tissue metastases (lymph or visceral lymph nodes). In another modality, the androgen deprivation therapy (ADT) that the subject received was not successful. In another embodiment, the subject additionally receives androgen deprivation therapy (ADT). In another embodiment, the subject additionally receives LHRH agonists or antagonists. In another embodiment, the LHRH agonist is leuprolide acetate. In another modality, the subject underwent orchidectomy. In another embodiment, the subject has high or increasing levels of prostate-specific antigen (PSA). In another embodiment, administration of the compound does not cause side effects associated with androgen deprivation therapy (ADT). In another modality, the method additionally treats, eliminates, reduces the incidence, reduces the severity or inhibits the advanced prostate cancer.

In another modality, the method additionally provides a palliative treatment for advanced prostate cancer. In another embodiment, the compound is Compound IV. In another embodiment, the compound is administered in a dose of 125 mg / per day. In another embodiment, the compound is administered in a dose of 250 mg / per day. In another embodiment, the compound is administered in a dose of 500 mg / per day. In another embodiment, the serum PSA levels are reduced by at least 10% with respect to the reference. In another embodiment, serum PSA levels are reduced by at least 30% from the reference. In another embodiment, serum PSA levels are reduced by at least 50% from the reference. In another embodiment, serum PSA levels are reduced by at least 70% with respect to the reference. In another embodiment, the serum PSA levels are reduced by at least 90% with respect to the reference.

In one embodiment, this invention provides a method for decreasing serum PSA levels in a male subject suffering from castration-resistant prostate cancer (CRPC) comprising the administration of a therapeutically effective amount of estradiol, ethinylestradiol, steroid estrogen agonists, non-steroidal estrogen agonists or combinations of them.

In one embodiment, this invention provides a method for increasing levels of sex hormone-binding globulin (SHBG) in serum in a male subject suffering from castration-resistant prostate cancer (CRPC) comprising the administration of a quantity therapeutically effective of a compound of formula IA, I-XII or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof. In another modality, castration is surgical. In another form, castration is chemical. In another embodiment, CRPC is metastatic CRPC (mCRPC). In another modality, the method additionally treats, eliminates, reduces the incidence, reduces the severity or inhibits new bone metastases. In another modality, the method additionally treats, eliminates, reduces the incidence, reduces the severity or inhibits new metastases or that aggravates soft tissue metastasis (lymph or visceral lymph nodes). In another modality, the androgen deprivation therapy (ADT) that the subject received was not successful. In another embodiment, the subject additionally receives androgen deprivation therapy (ADT). In another embodiment, the subject additionally receives LHRH agonists or antagonists. In another embodiment, the LHRH agonist is leuprolide acetate. In another modality, the subject underwent orchidectomy. In another embodiment, the subject has high or increasing levels of specific prostate antigen (PSA). In another embodiment, administration of the compound does not cause side effects associated with androgen deprivation therapy (ADT). In another modality, the method additionally treats, eliminates, reduces the incidence, reduces the severity or inhibits the advanced prostate cancer. In another modality, the method additionally provides a palliative treatment for advanced prostate cancer. In another embodiment, the compound is Compound IV. In another embodiment, the compound is administered in a dose of 125 mg / per day. In another modality, the compound is administered in a dose of 250 mg / per day. In another embodiment, the compound is administered in a dose of 500 mg / per day.

In one embodiment, this invention provides a method for increasing levels of sex hormone-binding globulin (SHBG) in serum in a male subject suffering from castration-resistant prostate cancer (CRPC) comprising the administration of a quantity Therapeutically effective of estradiol, ethinylestradiol, steroidal estrogen agonists, non-steroidal estrogen agonists or combinations of them.

In one embodiment, this invention provides a method for decreasing free serum testosterone levels and / or the percentage of free testosterone in serum (% Free T) in a male subject suffering from castration-resistant prostate cancer. which comprises administering a therapeutically effective amount of a compound of formula IA, I-XII or its i isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof, in combination with other forms of ADT. In another modality, the androgen deprivation therapy (ADT) that the subject received was not successful. In another embodiment, other forms of ADT refer to LHRH agonists. In another embodiment, the LHRH agonist is leuprolide acetate. In another embodiment, other forms of ADT refer to LHRH antagonists. In another embodiment, the LHRH antagonist is degarelix. In another modality, the subject underwent orchidectomy. In another modality, the subject presents high or increasing levels of prosthetic antigen specific (PSA). In another embodiment, administration of the compound does not cause side effects associated with androgen deprivation therapy (ADT). In another modality, the method additionally provides a palliative treatment for advanced prostate cancer. In another embodiment, the compound is Compound IV. In another embodiment, the compound is administered in a dose of 125 mg / per day. In another embodiment, the compound is administered in a dose of 250 mg / per day. In another embodiment, the compound is administered in a dose of 500 mg / per day. In another embodiment, serum free testosterone is reduced to levels below castration levels. In another embodiment, serum free testosterone is reduced to levels below those observed with LHRH agonists or antagonists or with surgical castration.

In one embodiment, this invention provides a method for decreasing free serum testosterone levels and / or the percentage of free testosterone in serum (% Free T) in a male subject suffering from castration-resistant prostate cancer. , comprising administering a therapeutically effective amount of a compound of formula IA, 1-12 or its isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate or any combination thereof, in combination with a selective estrogen receptor modulator. (BE M). In another modality, prostate cancer is advanced prostate cancer. In another embodiment, prostate cancer is castration-resistant prostate cancer (CRPC). In another modality, prostate cancer is prostate cancer resistant to metastatic castration (mCRPC). In another embodiment, the SERM is selected from a group consisting of tamoxifen, toremifene, Raloxifene, clomiphene, femarelle, ormeloxifene, and lasofoxifene. In another modality, the SERM is tamoxifen. In another modality, the SERM is raloxifene. In another modality, the SERM is toremifene. In another modality, the SERM is ormeloxifene. In another modality, the subject underwent orchidectomy. In another modality, the androgen deprivation therapy (ADT) that the subject received was not successful. In another embodiment, the subject has high or increasing levels of specific prostate antigen (PSA). In another embodiment, administration of the compound does not cause side effects associated with androgen deprivation therapy (ADT). In another modality, the method additionally provides a palliative treatment for advanced prostate cancer. In another embodiment, the compound is Compound IV. In another embodiment, the compound is administered in a dose of 1 25 mg / per day. In another embodiment, the compound is administered in a dose of 250 mg / per day. In another embodiment, the compound is administered in a dose of 500 mg / per day. In another embodiment, the percentage of free testosterone in serum is reduced below about 1%. In another embodiment, the percentage of free testosterone in serum is reduced below about 0.5%. In another embodiment, the percentage of free testosterone in serum is reduced below about 0.4%. In another embodiment, the percentage of free testosterone in serum is reduced below about 0.25%. In another modality, the percentage of free testosterone is reduced in serum below about 0.1%. In another embodiment, the percentage of free testosterone in serum is reduced below about 0.05%. In another embodiment, the percentage of free testosterone in serum is reduced to levels below castration levels. In another embodiment, the percentage of free testosterone in serum is reduced to levels below those observed with LHRH agonists or antagonists or with surgical castration.

In one embodiment, this invention provides a method for decreasing free testosterone levels and / or the percentage of free testosterone in serum (% Free T) in a male subject suffering from prostate cancer comprising the administration of a Therapeutically effective amount of estradiol, ethinylestradiol, steroidal estrogen agonists, non-steroidal estrogen agonists or combinations thereof.

In one embodiment, this invention provides a method of secondary hormone therapy for serum PSA and free serum testosterone levels in a male subject suffering from castration-resistant prostate cancer (CRPC) comprising the administration of a therapeutically effective amount of a compound of formula IA, 1-12 or its isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate or any combination thereof. In another modality, castration is surgical. In another form, castration is chemical. In another embodiment, CRPC is metastatic CRPC (mCRPC). In another modality, the method additionally treats, eliminates, reduces the incidence, reduces the severity or inhibits new bone metastases. In another modality, the method additionally treats, eliminates, reduces the incidence, reduces the severity or inhibits new metastases or that aggravates soft tissue metastasis (lymph or visceral lymph nodes). In another modality, the androgen deprivation therapy (ADT) that the subject received was not successful. In another embodiment, the subject receives, in addition, androgen deprivation therapy (ADT). In another embodiment, the subject additionally receives LHRH agonists or antagonists. In another embodiment, the LH RH agonist is leuprolide acetate. In another modality, the subject underwent orchidectomy. In another embodiment, the subject has high or increasing levels of prostate-specific antigen (PSA). In another embodiment, administration of the compound does not cause side effects associated with androgen deprivation therapy (ADT). In another modality, the method additionally treats, eliminates, reduces the incidence, reduces the severity or inhibits the advanced prostate cancer. In another modality, the method additionally provides a palliative treatment for advanced prostate cancer. In another embodiment, the compound is Compound IV. In another embodiment, the compound is administered in a dose of 125 mg / per day. In another embodiment, the compound is administered in a dose of 250 mg / per day. In another embodiment, the compound is administered in a dose of 500 mg / per day.

In one embodiment, this invention provides a method for treating, eliminating, reducing the incidence, reducing the severity or inhibiting related bone events (SRE) in a male subject suffering from castration-resistant prostate cancer (CRPC) who comprises administration of a therapeutically effective amount of a compound of formula IA, I-XII or its isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate or any combination thereof. In another modality, castration is surgical. In another form, castration is chemical. In another embodiment, CRPC is metastatic CRPC (mCRPC). In another modality, the method additionally treats, eliminates, reduces the incidence, reduces the severity or inhibits new bone metastases. In another modality, the method additionally treats, eliminates, reduces the incidence, reduces the severity or inhibits new metastases or that aggravates soft tissue metastasis (lymph or visceral lymph nodes). In another modality, the androgen deprivation therapy (ADT) that the subject received was not successful. In another embodiment, the subject receives, in addition, androgen deprivation therapy (ADT). In another embodiment, the subject additionally receives LHRH agonists or antagonists. In another embodiment, the LH RH agonist is leuprolide acetate. In another modality, the subject underwent orchidectomy. In another embodiment, the subject has high or increasing levels of specific prostate antigen (PSA). In another embodiment, administration of the compound does not cause side effects associated with androgen deprivation therapy (ADT). In another modality, the method additionally treats, eliminates, reduces the incidence, reduces the severity or inhibits the advanced prostate cancer. In another modality, the method additionally provides a palliative treatment for advanced prostate cancer. In another embodiment, the compound is Compound IV. In another embodiment, the compound is administered at a dose of 125 mg / per day. In another embodiment, the compound is administered in a dose of 250 mg / per day. In another embodiment, the compound is administered in a dose of 500 mg / per day.

The term "related bone event" (SRE) refers to the objective of a compound and includes fractures, pathological fractures, spinal cord compression, radiation or bone surgery, new bone metastases, loss of bone mass or a combination of them.

In one embodiment, the related bone events treated using the methods provided herein and / or using the compositions provided herein, are fractures, which in one embodiment are pathological fractures, non-traumatic fractures, vertebral fractures, non-vertebral fractures, fractures. morphometric or a combination of these. In some modalities, fractures may be simple, exposed, transverse, green-stem or compound. In one modality, fractures can occur in any bone of the body. In one modality, it is a fracture in either or more than one of the bones of the arm, wrist, hand, finger, leg, ankle, foot, toe, clavicle or a combination thereof.

In another embodiment, the methods and / or compositions provided herein are effective in the treatment, provide, suppression, inhibition or reduction of the risk of bone events, such as pathological fractures, spinal cord compression, hypercalcemia, pain related to bones or their combination.

In another modality, the related bone events that they wish to treat using the methods provided herein and / or using the compositions provided herein, comprise the need for bone surgery and / or bone radiation, which in some embodiments, is performed for the treatment of resulting pain, in one modality, of bone damage or nerve compression. In another embodiment, the osseous events that are desired to be treated using the methods provided herein and / or using the compositions provided herein, comprise spinal cord compression or the need for changes in anti-neoplastic therapy, which includes changes in hormone therapy in a subject. In some modalities, the bone events that are desired to be treated using the methods provided herein and / or using the compositions provided herein, comprise treating, suppressing, preventing, reducing the incidence of or delaying the evolution or severity of the condition. bone metastasis or loss of bone mass. In one modality, the loss of bone mass may include osteoporosis, osteopenia or a combination of these. In one modality, bone events may comprise any combination of the modalities indicated herein.

In one embodiment, this invention provides a method for decreasing levels of bone turnover markers in a male sex subject who does not suffer from castration-resistant prostate cancer (C RPC) comprising the administration of a therapeutically effective amount of a compound of formula IA, I-XII or its isomer, pharmaceutically acceptable salt, pharmaceutical prodrug, polymorph, hydrate or any combination thereof. In another modality, castration is surgical. In another form, castration is chemical. In another embodiment, CRPC is metastatic CRPC (mCRPC). In another modality, the method additionally treats, eliminates, reduces the incidence, reduces the severity or inhibits new bone metastases. In another modality, the method additionally treats, eliminates, reduces the incidence, reduces the severity or inhibits new metastases or that aggravates soft tissue metastasis (lymph or visceral lymph nodes). In another modality, the androgen deprivation therapy (ADT) that the subject received was not successful. In another embodiment, the subject receives, in addition, androgen deprivation therapy (ADT). In another modality, the subject additionally receives LHRH agonists or antagonists. In another embodiment, the LHRH agonist is leuprolide acetate. In another modality, the subject underwent orchidectomy. In another embodiment, the subject has high or increasing levels of prostate-specific antigen (PSA). In another embodiment, administration of the compound does not cause side effects associated with androgen deprivation therapy (ADT). In another modality, the method additionally treats, eliminates, reduces the incidence, reduces the severity or inhibits the advanced prostate cancer. In another modality, the method additionally provides a palliative treatment for advanced prostate cancer. In another embodiment, the compound is Compound IV. In another embodiment, the compound is administered in a dose of 1 25 mg / per day. In another embodiment, the compound is administered in a dose of 250 mg / per day. In another modality, the compound is administered in a dose of 500 mg / per day. In another embodiment, bone turnover markers are C-telopeptide (CTX) and / or bone-specific alkaline phosphatase.

In one embodiment, this invention provides a method for treating, eliminating, reducing the incidence, reducing the severity or inhibiting related bone events (SRE) in a male subject suffering from castration-resistant prostate cancer (CRPC) who comprises the administration of a therapeutically effective amount of a compound of formula IA, 1-12 or its isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate or any combination thereof. In another modality, castration is surgical. In another form, castration is chemical. In another embodiment, CRPC is metastatic CRPC (mCRPC).

In one embodiment, this invention provides a method for reducing side effects linked to estrogen deficiency (hot flushes, bone loss, insulin resistance, change in body composition, increase in fats) in a male subject who suffers from advanced prostate cancer or from castration-resistant prostate cancer comprising the administration of a compound of formula IA, I-XII or its isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate or any combination thereof. In another embodiment, the subject receives, in addition, androgen deprivation therapy (ADT). In another embodiment, the subject additionally receives LHRH agonists or antagonists. In another embodiment, the LHRH agonist is leuprolide acetate.

In another modality, castration is surgical. In another form, castration is chemical. In another embodiment, CRPC is metastatic CRPC (mCRPC). In another modality, the man is a man with advanced prostate cancer or prostate cancer resistant to advanced castration who was castrated surgically.

In another modality, the method additionally treats, eliminates, reduces the incidence, reduces the severity or inhibits new bone metastases. In another modality, the method additionally treats, eliminates, reduces the incidence, reduces the severity or inhibits new metastases or that aggravates soft tissue metastasis (lymph or visceral lymph nodes). In another modality, the androgen deprivation therapy (ADT) that the subject received was not successful. In another embodiment, the subject receives, in addition, androgen deprivation therapy (ADT). In another embodiment, the subject additionally receives LHRH agonists or antagonists. In another embodiment, the LH RH agonist is leuprolide acetate. In another modality, the subject underwent orchidectomy. In another embodiment, the subject has high or increasing levels of specific prostate antigen (PSA). In another embodiment, administration of the compound does not cause side effects associated with androgen deprivation therapy (ADT). In another modality, the method additionally treats, eliminates, reduces the incidence, reduces the severity or inhibits the advanced prostate cancer. In another modality, the method additionally provides a palliative treatment for advanced prostate cancer. In another embodiment, the compound is Compound IV. In another embodiment, the compound is administered in a dose of 1 25 mg / per day. In another embodiment, the compound is administered in a dose of 250 mg / per day. In another embodiment, the compound is administered in a dose of 500 mg / per day.

In one embodiment, this invention provides a method for decreasing the production levels of androgen precursors of the adrenal glands in a male subject suffering from castration-resistant prostate cancer (CRPC) comprising administering a quantity therapeutically. effective of a compound of formula IA, 1-12 or its isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate or any combination thereof. In another modality, castration is surgical. In another form, castration is chemical. In another embodiment, CRPC is metastatic CRPC (mCRPC). In another modality, the method additionally treats, eliminates, reduces the incidence, reduces the severity or inhibits new bone metastases. In another modality, the method additionally treats, eliminates, reduces the incidence, reduces the severity or inhibits new metastases or that aggravates soft tissue metastasis (lymph or visceral lymph nodes). In another modality, the androgen deprivation therapy (ADT) that the subject received was not successful. In another embodiment, the subject receives, in addition, androgen deprivation therapy (ADT). In another embodiment, the subject additionally receives LHRH agonists or antagonists. In another embodiment, the LHRH agonist is leuprolide acetate. In another modality, the subject underwent orchidectomy. In another embodiment, the subject has high or increasing levels of specific prostate antigen (PSA).

In another embodiment, administration of the compound does not cause side effects associated with androgen deprivation therapy (ADT). In another modality, the method additionally treats, eliminates, reduces the incidence, reduces the severity or inhibits the advanced prostate cancer. In another modality, the method additionally provides a palliative treatment for advanced prostate cancer. In another embodiment, the compound is Compound IV. In another embodiment, the compound is administered in a dose of 125 mg / per day. In another embodiment, the compound is administered in a dose of 250 mg / per day. In another embodiment, the compound is administered in a dose of 500 mg / per day. In another embodiment, androgen precursors are used by prostate cancer cells to produce testosterone or dihydrotestosterone (DHT). In another embodiment, the androgen precursors are dehydroepiandrosterone sulfate (DHEAS) and / or dehydroepiandrosterone (DHEA).

In one embodiment, "a subject suffering from castration-resistant prostate cancer" refers to a subject who was previously treated with androgen deprivation therapy (ADT), who responded to the ADT and who at the time has levels of PSA > 2 ng / mL or > 2 ng / mL, which represents an increase of 25% above the minimum point obtained with the ADT. In another embodiment, the expression refers to a subject who, despite being kept on androgen deprivation therapy, is diagnosed with an evolution of serum PSA. In another embodiment, the subject has a total level of castration level testosterone (< 50 ng / dL). In another modality, the Subject presents increases in serum PSA in two consecutive evaluations performed with at least 2 weeks of separation. In another modality, the subject was effectively treated with ADT. In another embodiment, the subject has a history of serum PSA response after initiating ADT. In another embodiment, the subject was treated with ADT and had an initial PSA response in serum, but at the present time a level of PSA > 2 ng / mL and an increase of 25% above the minimum point observed with ADT.

The term "serum PSA response" refers to a modality of at least 90% reduction of serum PSA value prior to the start of ADT at < 1 0 ng / mL or at undetectable levels of serum PSA (<0.2 ng / mL) at any time or, in another modality, at least 50% reduction with respect to the serum PSA reference or, in another modality, of at least 90% reduction with respect to the serum PSA reference or, in another modality, of at least 30% reduction with respect to the serum PSA reference or, in another modality, of at least 10% % reduction compared to the serum PSA reference.

The term "evolution of serum PSA" refers to, in one embodiment, an increase of 25% or more of serum PSA and an absolute increase of 2 ng / ml or more relative to the minimum or, in another embodiment, to PSA in serum > 2 ng / mL or > 2 ng / mL and an increase of 25% with respect to the minimum point after the start of the androgen deprivation therapy (ADT).

In another form, the expression "minimum point" refers to the Lowest PSA level when a patient undergoes ADT.

In one embodiment, this invention provides a method for reducing total serum testosterone levels in a male subject comprising administration of a therapeutically effective amount of a compound of formula IA, 1- XI I or its isomer, pharmaceutically salt acceptable, pharmaceutical product, polymorph, hydrate or any combination thereof. In another embodiment, the subject suffers from prostate cancer. In another embodiment, the total serum testosterone is reduced below about 100 ng / dL. In another embodiment, the total serum testosterone is reduced below about 50 ng / dL. In another embodiment, the total serum testosterone concentration is reduced below about 25 ng / dL. In another modality, the total serum testosterone concentration is reduced below about 10 ng / dL. In another embodiment, the total serum testosterone concentration is reduced below about 5 ng / dL. In another embodiment, the total serum testosterone concentration is reduced below about 1 ng / dL. In another embodiment, the subject suffers from castration-resistant prostate cancer (CRPC). In another embodiment, CRPC is metastatic CRPC (mCRPC). In another modality, the androgen deprivation therapy (ADT) that the subject received was not successful. In another embodiment, the subject receives, in addition, androgen deprivation therapy (ADT). In another embodiment, the compound is Compound IV. In another embodiment, the compound is administered in a dose of 1 25 mg / per day. In another embodiment, the compound is administered in a dose of 250 mg / per day.

In another embodiment, the compound is administered in a dose of 500 mg / per day.

In one embodiment, this invention provides a method for reducing total serum testosterone levels in a male subject comprising administration of a therapeutically effective amount of a compound of formula IA, 1-12 or its isomer, pharmaceutically acceptable salt. , pharmaceutical product, polymorph, hydrate or any combination of them, where the reduction of total serum testosterone levels occurs by lowering luteinizing hormone (LH) levels in serum. In another embodiment, the subject suffers from prostate cancer. In another embodiment, the total serum testosterone is reduced below about 100 ng / dL. In another embodiment, the total serum testosterone is reduced below about 50 ng / dL. In another embodiment, the total serum testosterone concentration is reduced below about 25 ng / dL. In another embodiment, the subject suffers from castration-resistant prostate cancer (CRPC). In another embodiment, CRPC is metastatic CRPC (mCRPC). In another modality, the androgen deprivation therapy (ADT) that the subject received was not successful. In another embodiment, the subject receives, in addition, androgen deprivation therapy (ADT). In another embodiment, the compound is Compound IV. In another embodiment, the compound is administered in a dose of 125 mg / per day. In another embodiment, the compound is administered in a dose of 250 mg / per day. In another embodiment, the compound is administered in a dose of 500 mg / per day.

In one embodiment, this invention provides a method for reducing serum free testosterone levels in a male subject comprising the administration of a therapeutically effective amount of a compound of the formulas IA, 1-12 or its isomer, pharmaceutically salt acceptable, pharmaceutical product, polymorph, hydrate or any combination thereof, where the reduction of serum free testosterone occurs by reducing the levels of luteinizing hormone (LH) in serum. In another modality, the male subject suffers from prostate cancer. In another embodiment, the subject suffers from castration-resistant prostate cancer (CRPC). In another embodiment, CRPC is metastatic CRPC (mCRPC). In another modality, the androgen deprivation therapy (ADT) that the subject received was not successful. In another embodiment, the subject receives, in addition, androgen deprivation therapy (ADT). In another embodiment, the compound is Compound IV. In another embodiment, the compound is administered in a dose of 125 mg / per day. In another embodiment, the compound is administered in a dose of 250 mg / per day. In another embodiment, the compound is administered in a dose of 500 mg / per day.

In one embodiment, this invention provides a method for reducing total serum testosterone levels in a male subject comprising administration of a therapeutically effective amount of a compound of formula IA, 1-12 or its isomer, pharmaceutically acceptable salt , pharmaceutical product, polymorph, hydrate or any combination of them, where the reduction of total serum testosterone is independent of the reduction of luteinizing hormone (LH) levels in serum. In another modality, the male subject suffers from prostate cancer. In another embodiment, total serum testosterone is reduced below about 100 ng / dL. In another embodiment, total serum testosterone is reduced below about 50 ng / dL. In another embodiment, the total serum testosterone concentration is reduced below about 25 ng / dL. In another embodiment, the subject suffers from castration-resistant prostate cancer (CRPC). In another embodiment, CRPC is metastatic CRPC (mCRPC). In another modality, the androgen deprivation therapy (ADT) that the subject received was not successful. In another embodiment, the subject receives, in addition, androgen deprivation therapy (ADT). In another embodiment, the compound is Compound IV. In another embodiment, the compound is administered in a dose of 1 25 mg / per day. In another embodiment, the compound is administered in a dose of 250 mg / per day. In another embodiment, the compound is administered in a dose of 500 mg / per day.

In one embodiment, this invention provides a method for reducing serum free testosterone levels in a male subject comprising the administration of a therapeutically effective amount of a compound of formula IA, 1-12 or its isomer, pharmaceutically acceptable salt. , pharmaceutical product, polymorph, hydrate or any combination thereof, where the reduction of serum free testosterone levels is independent of the reduction of luteinizing hormone levels in serum. In other modality, the male subject suffers from prostate cancer. In another embodiment, the subject suffers from castration-resistant prostate cancer (CRPC). In another embodiment, CRPC is metastatic CRPC (mCRPC). In another modality, the androgen deprivation therapy (ADT) that the subject received was not successful. In another embodiment, the subject receives, in addition, androgen deprivation therapy (ADT). In another embodiment, the compound is Compound IV. In another embodiment, the compound is administered in a dose of 125 mg / per day. In another embodiment, the compound is administered in a dose of 250 mg / per day. In another embodiment, the compound is administered in a dose of 500 mg / per day.

In one embodiment, this invention provides methods for reducing total serum testosterone, free serum testosterone levels or the percentage of free testosterone in serum (% Free T) in a male subject, wherein said male subject He suffers from prostate cancer. In another embodiment, said subject suffers from advanced prostate cancer. In another embodiment, the subject suffers from castration-resistant prostate cancer (CRPC). In another embodiment, CRPC is metastatic CRPC (mCRPC). In another modality, the androgen deprivation therapy (ADT) that the subject received was not successful. In another embodiment, the subject receives, in addition, androgen deprivation therapy (ADT). In another embodiment, the compound is Compound IV. In another embodiment, the compound is administered in a dose of 125 mg / per day. In another embodiment, the compound is administered in a dose of 250 mg / per day. In another embodiment, the compound is administered in a dose of 500 mg / per day.

The term "percentage of free testosterone in serum (% Free T)" refers, in one modality, to the level of free testosterone in serum (pg / mL) divided by the total level of serum testosterone (pg / mL), multiplied by one hundred [Free T (pg / mL) / Total T (pg / mL) * 100], In one embodiment, the reduction of testosterone serum concentrations is reversible and returns to the reference levels after treatment with the compounds of this invention.

In another embodiment, serum testosterone concentrations are reversible after treatment with Compound IV according to Figure 23 and Example 10.

In one embodiment, this invention provides methods for reducing total serum testosterone levels in a male subject comprising administration of a therapeutically effective amount of a compound of formula IA, 1-12 or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof. In another embodiment, total serum testosterone is reduced below about 100 ng / dL. In another embodiment, total serum testosterone is reduced below about 50 ng / dL. In another embodiment, total serum testosterone is reduced below about 25 ng / dL. In another embodiment, total serum testosterone is reduced below about 75 ng / dL. In another embodiment, total serum testosterone is reduced to between 75 ng / dL and 100 ng / dL. In another embodiment, the concentration of total testosterone in serum is reduced to about between 50 ng / dL and 75 ng / dL. In another embodiment, total serum testosterone is reduced to around 40 ng / dL to 50 ng / dL. In another embodiment, the total serum testosterone concentration is reduced to between 25 ng / dL and 50 ng / dL. In another modality, total serum testosterone is reduced to around between 40 ng / dL and 60 ng / dL. In another embodiment, total serum testosterone is reduced to between about 10 ng / dL and 50 ng / dL. In another embodiment, total serum testosterone is reduced to between 10 ng / dL and 25 ng / dL. In another embodiment, total serum testosterone is reduced to between about 1 ng / dL and 25 ng / dL. In another embodiment, total serum testosterone is reduced to between about 1 ng / dL and 10 ng / dL. In another embodiment, total serum testosterone is reduced to between about 0.1 ng / dL and 1 ng / dL. In another embodiment, total serum testosterone is reduced to between about 0.1 ng / dL and 10 ng / dL. In another embodiment, the subject suffers from castration-resistant prostate cancer (CRPC). In another embodiment, CRPC is metastatic CRPC (mCRPC). In another modality, the androgen deprivation therapy (ADT) that the subject received was not successful. In another embodiment, the subject receives, in addition, androgen deprivation therapy (ADT). In another embodiment, the compound is Compound IV. In another embodiment, the compound is administered in a dose of 125 mg / per day. In another embodiment, the compound is administered in a dose of 250 mg / per day. In another embodiment, the compound is administered in a dose of 500 mg / per day.

In one embodiment, this invention provides methods to reduce the percentage of free testosterone in serum (% Free T) in a male subject comprising the administration of a therapeutically effective amount of a compound of formula IA, 1- XII or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph , hydrate or any combination of them. In another embodiment, the percentage of free testosterone in serum (% Free T) is reduced below about 1%. In another embodiment, the percentage of free testosterone in serum (% Free T) is reduced below about 0.5%. In another embodiment, the percentage of free testosterone in serum (% Free T) is reduced below about 0.25%. In another embodiment, the percentage of free testosterone in serum (% Free T) is reduced below about 0.05%. In another embodiment, the subject suffers from castration-resistant prostate cancer (CRPC). In another embodiment, CRPC is metastatic CRPC (mCRPC). In another modality, the androgen deprivation therapy (ADT) that the subject received was not successful. In another embodiment, the subject receives, in addition, androgen deprivation therapy (ADT). In another embodiment, the compound is Compound IV. In another embodiment, the compound is administered in a dose of 125 mg / per day. In another embodiment, the compound is administered in a dose of 250 mg / per day. In another embodiment, the compound is administered in a dose of 500 mg / per day.

Testosterone can be measured as levels in "free" (ie, bioavailable and unbound) or "total" serum (which includes the percentage of bound and unavailable protein). In one embodiment, total serum testosterone comprises free testosterone and bound testosterone.

Men without prostate cancer older than 40 years show lower testosterone levels and have a total testosterone level of less than 250 ng / dL (<8.7 nmol / L) or a free testosterone level of less than 0.75 ng / dL (< 0.03 nmol / L). The methods of the present invention provide a method for reducing serum testosterone levels. In one embodiment, the methods provided reduce total serum testosterone. In one embodiment, the methods provided reduce total serum testosterone.

In one embodiment, the methods of this invention provide a method for reducing the levels of total and / or free testosterone in serum independently of the reduction of luteinizing hormone (LH) levels in a male subject suffering from cancer. prostate. In another modality, changes in testosterone levels should be a reduction in the level prior to treatment. In another embodiment, total serum testosterone is reduced below about 100 ng / dL. In another embodiment, total serum testosterone is reduced below about 50 ng / dL. In another embodiment, total serum testosterone is reduced below about 25 ng / dL. In another embodiment, the level of free testosterone is reduced below about 2 ng / dL. In another embodiment, the level of free testosterone is reduced below about 1 ng / dL. In another embodiment, the level of free testosterone is reduced below about 0.5 ng / dL. In another embodiment, the level of free testosterone is reduced below about 0.25 ng / dL. In another modality, the subject suffers from cancer of castrate-resistant prostate (CRPC). In another embodiment, CRPC is metastatic CRPC (mCRPC). In another modality, the androgen deprivation therapy (ADT) that the subject received was not successful. In another embodiment, the subject receives, in addition, androgen deprivation therapy (ADT). In another embodiment, the compound is Compound IV. In another embodiment, the compound is administered in a dose of 125 mg / per day. In another embodiment, the compound is administered in a dose of 250 mg / per day. In another embodiment, the compound is administered in a dose of 500 mg / per day.

Methods for determining serum free testosterone levels and total serum testosterone levels include monitoring testosterone levels over the course of the treatment period by blood tests. Total testosterone is a combination of circulating testosterone bound to carrier proteins (albumin, SHBG, transcortin, transferrin) and the free / unbound hormone. Total testosterone levels can be affected due to several factors that include the level of proteins in the blood that carries the hormone in the body, age, obesity and the interferences associated with commonly used methods of analysis.

The available methods for measuring free testosterone (FT) can be complex (equilibrium dialysis and calculated free testosterone (CFT)) or simple (the commercial FT kit "Coat-A-Count") with an analogous indicator. In another modality, the measurement of total testosterone and free testosterone levels in serum can be obtained simultaneously measuring total testosterone and SHBG (for example, Irma-Count, DPC) and then the calculated free testosterone (CFT). In another embodiment, the measurement of total testosterone and free testosterone is made according to the knowledge of the person skilled in the art.

In one embodiment, this invention provides a method for reducing total serum testosterone levels, serum free testosterone levels or the percentage of free testosterone in serum (% Free T) in a male subject comprising the administration of a therapeutically effective amount of a combination of one or more forms of ADY and of a compound of formula IA, 1-12 or its isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate or any combination thereof. In another embodiment, the reduction of free or total testosterone in serum occurs by reducing the level of luteinizing hormone (LH) in serum. In another embodiment, the reduction of free or total serum testosterone levels is independent of the reduction of luteinizing hormone (LH) levels in serum. In another embodiment, the subject suffers from castration-resistant prostate cancer (CRPC). In another embodiment, CRPC is metastatic CRPC (mCRPC). In another modality, the androgen deprivation therapy (ADT) that the subject received was not successful. In another embodiment, the compound is Compound IV. In another embodiment, the compound is administered in a dose of 125 mg / per day. In another embodiment, the compound is administered in a dose of 250 mg / per day. In another embodiment, the compound is administered in a dose of 500 mg / per day.

In one embodiment, this invention provides a method for reducing total serum testosterone levels, serum free testosterone levels or the percentage of free testosterone in serum (% Free T) in a male subject comprising the administration of a therapeutically effective amount of a combination of one or more selective estrogen receptor modulators (SERM) and a compound of formula IA, I-X 11 or its isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate or any combination of they. In another embodiment, the subject suffers from advanced prostate cancer. In another embodiment, the subject suffers from castration-resistant prostate cancer (CRPC). In another embodiment, CRPC is metastatic CRPC (mCRPC). In another embodiment, the SERM is selected from a group consisting of tamoxifen, toremifene, raloxifene, clomiphene, femarelle, ormeloxifene, and lasofoxifene. In another modality, the SERM is tamoxifen. In another modality, the SERM is raloxifene. In another modality, the SERM is toremifene. In another modality, the SERM is ormeloxifene. In another modality, the androgen deprivation therapy (ADT) that the subject received was not successful. In another embodiment, the compound is Compound IV. In another embodiment, the compound is administered in a dose of 125 mg / per day. In another embodiment, the compound is administered in a dose of 250 mg / per day. In another embodiment, the compound is administered in a dose of 500 mg / per day.

In one embodiment, this invention provides a method to treat, eliminate, reduce the incidence, reduce the severity or inhibit the evolution of castration-resistant prostate cancer (CRPC) and its symptoms, or increase the survival of men with castration-resistant prostate cancer comprising administering a therapeutically effective amount of a combination of one or other forms of ADT and a compound of formula IA, I-XII, or of its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof. In another embodiment, CRPC is metastatic CRPC (mCRPC). In another modality, the androgen deprivation therapy (ADT) that the subject received was not successful. In another embodiment, the compound is Compound IV. In another embodiment, the compound is administered in a dose of 125 mg / per day. In another embodiment, the compound is administered in a dose of 250 mg / per day. In another embodiment, the compound is administered in a dose of 500 mg / per day.

In one embodiment, this invention provides a method for reducing serum PSA levels in a male subject suffering from castration-resistant prostate cancer (CRPC) comprising the administration of a therapeutically effective amount of a combination of a or more forms of ADT and a compound of formula IA, 1-12 or its isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate or any combination thereof. In another embodiment, CRPC is metastatic CRPC (mCRPC). In another modality, the androgen deprivation therapy (ADT) that the subject received was not successful. In another embodiment, the compound is Compound IV. In another embodiment, the compound is administered in a dose of 125 mg / per day. In another embodiment, the compound is administered in a dose of 250 mg / per day. In another embodiment, the compound is administered in a dose of 500 mg / per day.

In one embodiment, this invention provides a method for reducing free testosterone levels, the percentage of free testosterone in serum and / or serum PSA in a male subject suffering from advanced prostate cancer comprising the administration of a therapeutically effective amount. of a combination of one or more forms of ADT and a compound of formula IA, I-XII or its isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate or any combination thereof. In another embodiment, CRPC is metastatic CRPC (mCRPC). In another modality, the androgen deprivation therapy (ADT) that the subject received was not successful. In another embodiment, the compound is Compound IV. In another embodiment, the compound is administered in a dose of 125 mg / per day. In another embodiment, the compound is administered in a dose of 250 mg / per day. In another embodiment, the compound is administered in a dose of 500 mg / per day.

The methods of this invention comprise the administration of a combination of estrogen receptor ligands and a compound of this invention. In one embodiment, the estrogen receptor ligands selectively include selective estrogen receptor modulators (SERM). Examples of SERM include, but are not limited to: tamoxifen, toremifene, reloxifene, clomiphene, femarelle, ormeloxifene and lasafoxifene.

The methods of this invention comprise the administration of a combination of other forms of ADT and a compound of this invention. In one embodiment, other forms of ADT include an LHRH agonist. In another embodiment, the LHRH agonist includes leuprolide acetate (Lupron®) (US 5 480 656, US 5 575 987, 5 631 020, 5 643 607, 5 716 640, 5 814 342, 6 036 976, which are incorporated herein by this reference) or goserelin acetate (Zoladex®) (US 7 1 18 552; 7 220 247; 7 500 964 which are incorporated herein by this reference). In one embodiment, other forms of ADT inckiyen an LHRH antagonist. In another embodiment, LHRH antagonists include degarelix. In one embodiment, other forms of ADT include antiandrogens. In another embodiment the antiandrogens include bicalutamide, flutamide, finasteride, dutasteride, enzalutamide, nilutamide, chlormadinone or any combination thereof. In one modality, other forms of ADT include bilateral orchiectomy.

In one embodiment, the methods of this invention comprise the administration of a therapeutically effective amount of an antiandrogen and a compound of this invention. In one embodiment, the methods of this invention comprise administration to a therapeutically effective amount of an LHRH agonist and a compound of this invention. In one embodiment, the methods of this invention comprise the administration of a therapeutically effective amount of an antiandrogen, an LHRH agonist and a compound of this invention. In another embodiment, the compound is Compound IV. In other modality, the compound is administered in a dose of 125 mg / per day. In another embodiment, the compound is administered in a dose of 250 mg / per day. In another embodiment, the compound is administered in a dose of 500 mg / per day.

In one embodiment, this invention provides a method for reducing total serum testosterone levels, serum free testosterone levels and / or the percentage of free testosterone in serum (% Free T) by reducing luteinizing hormone levels ( LH) or independently of the reduction of luteinizing hormone levels in a male subject having prostate cancer in order to produce an androgen deprivation therapy (ADT) which comprises administering a therapeutically effective amount of a compound of formula IA, l-XII. In another embodiment, the compound is Compound IV. In another embodiment, the compound is administered in a dose of 125 mg / per day. In another embodiment, the compound is administered in a dose of 250 mg / per day. In another embodiment, the compound is administered in a dose of 500 mg / per day. In another embodiment, prostate cancer is castration-resistant prostate cancer (CRPC). In another embodiment, CRPC is metastatic CRPC (mCRPC). In another modality, the androgen deprivation therapy (ADT) that the subject received was not successful. In another embodiment, the subject receives, in addition, androgen deprivation therapy (ADT).

In another embodiment, this invention provides a method for androgen deprivation therapy (ADT) in a subject comprising the administration of a therapeutically effective amount of a compound of formula IA, I-XII or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof. In another embodiment, said subject suffers from prostate cancer. In another embodiment, prostate cancer is castration-resistant prostate cancer (CRPC). In another embodiment, CRPC is metastatic CRPC (mCRPC). In another embodiment, the compound is Compound IV. In another embodiment, the compound is administered in a dose of 1 25 mg / per day. In another embodiment, the compound is administered in a dose of 250 mg / per day. In another embodiment, the compound is administered in a dose of 500 mg / per day. In another modality, the androgen deprivation therapy (ADT) that the subject received was not successful. In another embodiment, the subject receives, in addition, androgen deprivation therapy (ADT).

In another modality, ADT is used to treat prostate cancer, to delay the progression of prostate cancer or to prevent and / or treat the recurrence of prostate cancer. In another embodiment, prostate cancer is castration-resistant prostate cancer (CRPC). In another embodiment, CRPC is metastatic CRPC (mCRPC).

In one embodiment, the invention provides a method for treating prostate cancer or delaying the progression of prostate cancer comprising administering a compound of this invention. In one embodiment, this invention provides a method for preventing and / or treating recurrence of prostate cancer which comprises administering a compound of this invention. In another embodiment, prostate cancer is castration-resistant prostate cancer (CRPC). In other modality, CRPC is metastatic CRPC (mCRPC).

In one embodiment, this invention provides a method for increasing the chances of survival of a subject who has prostate cancer, advanced prostate cancer, castration-resistant prostate cancer or metastatic castration-resistant prostate cancer which comprises administering a compound of this invention. In another embodiment, administering a compound of this invention in combination with LHRH analogs, reversible antiandrogens (such as bicalutamide, flutamide or enzalutamide), antiestrogens, anti-cancer drugs, 5 alpha reductase inhibitors, aromatase inhibitors, progestins, androgen receptor modulators (MRSA) or agents that act through other nuclear hormone receptors. In another modality, the androgen deprivation therapy (ADT) that the subject received was not successful. In another embodiment, the compound is Compound IV. In another embodiment, the compound is administered in a dose of 125 mg / per day. In another embodiment, the compound is administered in a dose of 250 mg / per day. In another embodiment, the compound is administered in a dose of 500 mg / per day.

In one embodiment, the present invention provides a method for treating prostate cancer and reducing total serum testosterone and / or serum free testosterone levels by reducing LH levels or independently of the reduction in LH levels which comprises administering a compound of the formula IA, I-XI I. In another embodiment, the administration of Compound IV. In another modality, the compound is administered in a dose of 125 mg / per day. In another embodiment, the compound is administered in a dose of 250 mg / per day. In another embodiment, the compound is administered in a dose of 500 mg / per day. In another embodiment, prostate cancer is castration-resistant prostate cancer (CRPC). In another embodiment, CRPC is metastatic CRPC (mCRPC).

Androgen deprivation therapy not only reduces testosterone, it also lowers estrogen levels since estrogen comes from the aromatization of testosterone. Estrogen deficiency induced by androgen deprivation therapy causes important side effects including hot flushes, gynecomastia and mastalgia, loss of bone mass, decreased quality and bone hardness, osteoporosis, osteopenia and life-threatening fractures , lipid adverse changes and cardiovascular diseases and major myocardial infarctions, loss of libido, impotence, loss of muscle mass (sarcopenia), fatigue, cognitive dysfunction, depression and other mood changes.

In other embodiments, this invention provides a method for treating any disease, disorder or symptom associated with ADT. In other embodiments, this invention provides a method for treating any disease, disorder or symptom associated with the deprivation of testosterone. Each disease, disorder or symptom represents an individual embodiment of this invention.

In one embodiment, this invention provides a method for reducing total serum testosterone levels, serum free testosterone levels and / or the percentage of free testosterone in serum (% Free T) in a male subject comprising administering a therapeutically effective amount of a compound of formulas IA, 1-12 or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof, wherein said compounds administered of the formulas IA, I-XI 1 or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph , hydrate or any combination of them, treats, prevents, suppresses, reduces the incidence or inhibits the side effects associated with androgen deprivation therapy (ADT), where said subject suffers from prostate cancer. In another modality, the reduction of serum total testosterone levels is achieved by reducing LH levels or is independent of the reduction in LH levels. In another embodiment, the subject suffers from castration-resistant prostate cancer (CRPC). In another embodiment, CRPC is metastatic CRPC (mCRPC). In another modality, the androgen deprivation therapy (ADT) that the subject received was not successful. In another embodiment, the subject receives, in addition, androgen deprivation therapy (ADT). In another embodiment, the compound is Compound IV. In another embodiment, the compound is administered in a dose of 1 25 mg / per day. In another embodiment, the compound is administered in a dose of 250 mg / per day. In another embodiment, the compound is administered in a dose of 500 mg / per day.

In one modality, administer the compounds of this invention suppresses, reduces the incidence, inhibits or treats the typical side effects associated with traditional androgen deprivation therapy (ADT). In another embodiment, the subject suffers from prostate cancer. In another embodiment, prostate cancer is castration-resistant prostate cancer (CRPC). In another embodiment, CRPC is metastatic CRPC (mCRPC). In another modality, the androgen deprivation therapy (ADT) that the subject received was not successful. In another embodiment, the subject receives, in addition, androgen deprivation therapy (ADT). In another embodiment, the compound is Compound IV. In another embodiment, the compound is administered in a dose of 125 mg / per day. In another embodiment, the compound is administered in a dose of 250 mg / per day. In another embodiment, the compound is administered in a dose of 500 mg / per day.

Said prevention and / or reduction of side effects are relative to the placebo or control group. In one embodiment, typical side effects associated with traditional androgen deprivation therapy (ADT) include hot flushes, gynecomastia, decreased bone mineral density, and increased bone fractures. In another embodiment, administering the compounds of this invention prevents the onset of hot flashes as would be seen by using traditional forms of androgen deprivation therapy (ADT). In another embodiment, administering the compounds of this invention prevents gynecomastia as would be seen by employing traditional forms of androgen deprivation therapy (ADT). In another embodiment, administering the compounds of this invention prevents the decrease of bone mineral density (6MD) which could be seen by using traditional forms of androgen deprivation therapy (ADT). In another embodiment, administering the compounds of this invention prevents an increase in bone fractures from occurring as would be seen using traditional forms of androgen deprivation therapy (ADT). In another modality, bone fractures refer to pathological fractures, fractures not caused by trauma, vertebral fractures, non-vertebral fractures, new morphometric fractures, clinical fractures or a combination of them.

In one embodiment, administering the compounds of this invention decreases total serum testosterone without causing typical side effects associated with traditional androgen deprivation therapy (ADT). In another embodiment, the subject suffers from prostate cancer. In yet another modality, the subject suffers from advanced prostate cancer. In another embodiment, the subject suffers from castration-resistant prostate cancer (CRPC). In another embodiment, CRPC is metastatic CRPC (mCRPC). In another modality, the androgen deprivation therapy (ADT) that the subject received was not successful. In another embodiment, the subject receives, in addition, androgen deprivation therapy (ADT). In another embodiment, the compound is Compound IV. In another embodiment, the compound is administered in a dose of 125 mg / per day. In another embodiment, the compound is administered in a dose of 250 mg / per day. In another embodiment, the compound is administered in a dose of 500 mg / per day.

In one embodiment, typical associated side effects with traditional androgen deprivation therapy (ADT) include hot flashes, gynecomastia, decreased bone mineral density and increased bone fractures. In another embodiment, typical side effects associated with traditional ADT include increased body fat. In another embodiment, administering the compounds of this invention does not cause hot flushes as would be seen by using traditional forms of androgen deprivation therapy (ADT). In another embodiment, administering the compounds of this invention does not cause gynecomastia as would be seen by employing traditional forms of androgen deprivation therapy (ADT). In another embodiment, administering the compounds of this invention does not cause a decrease in bone mineral density (BMD) as would be seen when using traditional forms of androgen deprivation therapy (ADT). In another embodiment, administering the compounds of this invention does not cause an increase in bone fractures as would be seen when using traditional forms of androgen deprivation therapy (ADT). In another modality, the increase in bone fractures includes pathological fractures, fractures not caused by trauma, vertebral fractures, non-vertebral fractures, new morphometric fractures, clinical fractures or a combination of them. In yet another embodiment, administering the compounds of this invention does not cause increased body fat as would be seen by using traditional forms of androgen deprivation therapy (ADT). In another embodiment, the compound is Compound IV. In another embodiment, the compound is administered in a dose of 125 mg / per day. In another modality, the compound is administered in a dose of 250 mg / per day. In another embodiment, the compound is administered in a dose of 500 mg / per day.

In one embodiment, administering the compounds of this invention decreases free testosterone levels without causing typical side effects associated with traditional androgen deprivation therapy (ADT). In another embodiment, the subject suffers from prostate cancer. In yet another modality, the subject suffers from advanced prostate cancer. In another embodiment, the subject suffers from castration-resistant prostate cancer (CRPC). In another embodiment, CRPC is metastatic CRPC (mCRPC). In another modality, the androgen deprivation therapy (ADT) that the subject received was not successful. In another embodiment, the subject receives, in addition, androgen deprivation therapy (ADT). In another embodiment, the compound is Compound IV. In another embodiment, the compound is administered in a dose of 125 mg / per day. In another embodiment, the compound is administered in a dose of 250 mg / per day. In another embodiment, the compound is administered in a dose of 500 mg / per day.

In one embodiment, administering the compounds of this invention decreases the percentage of free testosterone (% Free T) without causing typical side effects associated with traditional androgen deprivation therapy (ADT). In another embodiment, the subject suffers from prostate cancer. In yet another modality, the subject suffers from advanced prostate cancer. In another embodiment, the subject suffers from castration-resistant prostate cancer (CRPC). In another embodiment, CRPC is metastatic CRPC (mCRPC). In another modality, The androgen deprivation therapy (ADT) that the subject received was not successful. In another embodiment, the subject receives, in addition, androgen deprivation therapy (ADT). In another embodiment, the compound is Compound IV. In another embodiment, the compound is administered in a dose of 125 mg / per day. In another embodiment, the compound is administered in a dose of 250 mg / per day. In another embodiment, the compound is administered in a dose of 500 mg / per day.

In one modality, the term "hot flushes" refers to a sudden sensation of heat in the upper part or in the whole body, blushing of the face and neck, appearance of red spots on the chest, back and arms, copious sweat, chills, etc.

In one modality, the term "gynecomastia" refers to a benign breast enlargement in males that results from a proliferation of the mammary glandular component, which may or may not have associated pain. Gynecomastia is clinically defined by the presence of a gummy or firm mass that extends concentrically from the nipples. The disorder known as pseudoginecomastia or lipomastia is characterized by fat deposits without glandular proliferation. Although gynecomastia is commonly bilateral, it can be unilateral.

In one embodiment, the methods of this invention aim to treat men with prostate cancer or advanced prostate cancer or castration-resistant prostate cancer (CRPC) or metastatic castration-resistant prostate cancer (mCRPC) by reducing testosterone without causing bone loss either or hot flashes. In one embodiment, the methods of this invention aim to treat men with prostate cancer or advanced prostate cancer or castration-resistant prostate cancer (CRPC) or metastatic castration-resistant prostate cancer (mCRPC) by reducing of testosterone without causing bone loss, gynecomastia or hot flushes.

Compound IV does not increase the proliferation of prostate epithelial cancer cells in vitro. Compound IV offers, mechanically, several key advantages over existing therapies such as gonadotropin-releasing hormone (GnRH) agonists and GnRH antagonists. Compound IV is specific for the estrogen receptor and is bioavailable orally in rats, dogs, monkeys and humans. Unlike GnRH agonists and GnRH antagonists, which cause hot flushes and significant bone loss and increase the risk of fractures, Compound IV attenuates morphine abstinence-induced flushing (Example 14) in rats and maintains total trabecular bone mass and mineral bone density in the distal femur of rats even at doses that suppress LH and serum testosterone to a maximum (Example 11).

In another embodiment, the methods of this invention utilize compounds IA, I-XI I, where compounds have the potential to reduce testosterone, a primary stimulus for prostate cancer without also causing certain side effects such as loss. of bone mass and hot flushes that are common in current androgen deprivation therapies (ADT) for prostate cancer.

In another embodiment, Table 8 (Example 11) below demonstrates the reduction of testosterone without further causing loss of bone mass by the administration of Compound IV.

In one embodiment, the methods of this invention aim to reduce testosterone levels and further treat advanced prostate cancer by administration of a compound of formulas IA, I-XII. In another embodiment, the administration of Compound IV. In another embodiment, the compound is administered in a dose of 125 mg / per day. In another embodiment, the compound is administered in a dose of 250 mg / per day. In another embodiment, the compound is administered in a dose of 500 mg / per day.

In one embodiment, the methods of this invention are aimed at reducing testosterone levels and additionally treating castration-resistant prostate cancer by administering a compound of formulas IA, 1-12. In another embodiment, the administration of Compound IV. In another embodiment, the compound is administered in a dose of 125 mg / per day. In another embodiment, the compound is administered in a dose of 250 mg / per day. In another embodiment, the compound is administered in a dose of 500 mg / per day.

In one embodiment, the methods of this invention aim to reduce testosterone levels that additionally treat castration-resistant prostate cancer (mCRPC) by administering a compound of formulas IA, I-XII. In another embodiment, the administration of Compound IV. In another embodiment, the compound is administered in a dose of 125 mg / per day. In other modality, the compound is administered in a dose of 250 mg / per day. In another embodiment, the compound is administered in a dose of 500 mg / per day.

In one embodiment, the methods of this invention aim to reduce testosterone levels and additionally suppress, reduce the incidence, reduce severity or inhibit advanced prostate cancer by administering a compound of formulas IA, 1-12. In another embodiment, the methods of this invention aim to reduce testosterone levels and further suppress, reduce frequency, reduce severity or inhibit advanced prostate cancer by administration of compound IV. In another embodiment, the compound is administered in a dose of 125 mg / per day. In another embodiment, the compound is administered in a dose of 250 mg / per day. In another embodiment, the compound is administered in a dose of 500 mg / per day.

In one embodiment, the methods of this invention aim to reduce testosterone levels and additionally provide palliative treatment of prostate cancer, CRPC or mCRPC by administration of a compound of formulas IA, 1-12. In another embodiment, the methods of this invention aim to reduce testosterone levels and additionally provide palliative treatment of advanced prostate cancer by the administration of a compound IV. In another embodiment, the compound is administered in a dose of 125 mg / per day. In another embodiment, the compound is administered in a dose of 250 mg / per day.

In another embodiment, the compound is administered in a dose of 500 mg / per day.

In one embodiment, the methods of this invention are aimed at treating advanced prostate cancer. In another embodiment, the methods of this invention are intended to suppress, reduce incidence, reduce severity or inhibit advanced prostate cancer. In a modality, the methods of this invention aim at the palliative treatment of advanced prostate cancer. In another embodiment, this invention aims to suppress advanced prostate cancer. In another embodiment, this invention aims to reduce the incidence of advanced prostate cancer. In another embodiment, this invention aims to reduce the severity of advanced prostate cancer. In another embodiment, this invention aims to inhibit advanced prostate cancer comprising administering a compound of this invention.

In one embodiment, the methods of this invention are aimed at treating castration-resistant prostate cancer. In another embodiment, the methods of this invention are intended to suppress, reduce incidence, reduce severity or inhibit castration-resistant prostate cancer. In one embodiment, the methods of this invention aim at the palliative treatment of castration-resistant prostate cancer. In another embodiment, this invention aims to suppress castration-resistant prostate cancer. In another embodiment, this invention aims to reduce the frequency of castration-resistant prostate cancer.

In another embodiment, this invention aims to reduce the severity of castration-resistant prostate cancer. In another embodiment, this invention aims to inhibit castration-resistant prostate cancer. In another embodiment, this invention aims to increase the chances of survival of a subject with castration-resistant prostate cancer. In another embodiment, the methods of this invention use a compound of the formulas IA, I-XII. In another embodiment, the methods of this invention use a compound IV. In another embodiment, the methods of this invention utilize a compound of the formulas IA, I -XI I together with an LHRH agonist. In another embodiment, the methods of this invention utilize compound IV together with the LHRH agonist. In another embodiment, the methods of this invention use a compound IV together with leuprolide acetate (Lupron®). In another embodiment, the methods of this invention use a compound of the formulas IA, I-XI I together with leuprolide acetate (Lupron®). In another embodiment, the methods of this invention use a compound of formulas IA, I -XI I together with an LHRH antagonist. In another embodiment, the methods of this invention utilize a compound IV together with an LH RH antagonist. In another embodiment, the methods of this invention utilize compound IV together with degarelix. In another embodiment, the methods of this invention utilize a compound of the formulas IA, I -XI I together with degaralix. In another embodiment, the methods of this invention use a compound of the formulas IA, I-XI I together with an antiandrogen. In another embodiment, the methods of this invention use compound IV together with a antiandrogen.

In one embodiment, the methods of this invention aim to treat metastatic prostate cancer resistant to castration. In one embodiment, the methods of this invention are intended to suppress, reduce incidence, reduce severity, or inhibit castration-resistant metastatic prostate cancer. In one embodiment, the methods of this invention aim at the palliative treatment of castration-resistant metastatic prostate cancer. In another embodiment, this invention aims to suppress metastatic prostate cancer resistant to castration. In another embodiment, this invention aims to reduce the incidence of metastatic prostate cancer resistant to castration. In another embodiment, this invention aims to reduce the severity of metastatic prostate cancer resistant to castration. In another embodiment, this invention aims to inhibit metastatic prostate cancer resistant to castration. In another embodiment, this invention aims to increase the survival probabilities of a subject with metastatic prostate cancer resistant to castration. In another embodiment, the methods of this invention utilize a compound of the formulas IA, I-XII. In another modality, the methods of this invention use a compound IV. In another embodiment, the methods of this invention utilize a compound of the formulas IA, I-XII together with an agonist of LH RH. In another embodiment, the methods of this invention utilize a compound IV together with an LH RH agonist. In another embodiment, the methods of this invention they use a compound IV together with leuprolide acetate (Lupron®). In another embodiment, the methods of this invention use a compound of the formulas IA, I-XI I together with leuprolide acetate (Lupron®). In another embodiment, the methods of this invention use a compound of formulas IA, I -XI I together with an LHRH antagonist. In another embodiment, the methods of this invention utilize a compound IV together with an LHRH antagonist. In another embodiment, the methods of this invention utilize compound IV together with degarelix. In another embodiment, the methods of this invention use a compound of formulas IA, I -XI I together with degarelix. In another embodiment, the methods of this invention use a compound of the formulas IA, I-XI I together with an antiandrogen. In another embodiment, the methods of this invention use the compound IV together with an antiandrogen.

In another embodiment, this invention aims to increase the chances of survival of a subject with advanced prostate cancer, CRPC or mCRPC. In another embodiment, the methods of this invention use a compound of the formulas IA, I-XII. In another embodiment, the methods of this invention use a compound of the formulas IA, I -XI I together with an LHRH agonist. In another embodiment, the methods of this invention use a compound of the formulas IA, I-XI I together with leuprolide acetate (Lupron®). In another embodiment, the methods of this invention use a compound of formulas IA, I -XI I together with an LHRH antagonist. In another embodiment, the methods of this invention utilize a compound IV together with an LHRH antagonist. In another embodiment, the methods of this invention use the compound IV together with degarelix. In another embodiment, the methods of this invention use a compound of formulas IA, I -XI I together with degarelix. In another embodiment, the methods of this invention utilize a compound of the formulas IA, I-XII together with an antiandrogen. In another embodiment, the methods of this invention use the compound IV together with an antiandrogen.

In another embodiment, this invention aims to increase the chances of survival of a subject with advanced prostate cancer, CRPC or mCRPC. In another embodiment, the methods of this invention use compound IV. In another embodiment, the methods of this invention utilize a compound IV together with an LHRH agonist. In another embodiment, the methods of this invention use a compound IV together with leuprolide acetate (Lupron®). In another embodiment, the methods of this invention utilize a compound IV together with an LHRH antagonist. In another embodiment, the methods of this invention utilize compound IV together with degarelix.

The term "advanced prostate cancer" refers to metastatic cancer that originated in the prostate and that has metastasized extensively beyond the prostate as in surrounding tissues to include seminal vesicles, pelvic lymph nodes, or bone. other parts of the body. The pathologies of prostate cancer are scored with a Gleason score of 1 to 5 in order of increasing malignancy. In another modality, patients with significant risk of progressive disease and / or death from prostate cancer should be included in the definition and any patient with cancer outside the prosthetic capsule with disease stages as low as IBB clearly has "advanced" disease.

Men with advanced prostate cancer usually receive treatment to block the production of androgens that are male sex hormones that can help the growth of a prosthetic tumor. However, prostate cancer that initially responds to antiandrogen therapy eventually develops the ability to grow without androgens. These cancers are usually referred to as hormone-refractory, androgen-independent, or castration-resistant.

In one modality, advanced prostate cancer is a prostate cancer resistant to castration.

The term "castration-resistant prostate cancer" (CRPC) refers to prostate cancer that is considered refractory to hormones, which has not been treated with hormones, independent of androgens or resistant to surgical or chemical castration.

In another modality, castration-resistant prostate cancer (CRPC) is an advanced prostate cancer that developed despite the irresponsive castration and / or ongoing ADT. In another embodiment, ADT refers to the treatment consisting of leuprolide acetate (Lupron®).

In one embodiment, castration-resistant prostate cancer is defined as prostate cancer that continues to progress or worsen or adversely affect the patient's health despite previous surgical castration, continued treatment with agonists (e.g., leuprolide) or antagonists (degarelix) of gonadotropin-releasing hormones, antiandrogens (e.g., bicalutamide, flutamide, enzalutamide, ketoconazole, aminoglutamide), chemotherapeutic agents (e.g., docetaxel, paclitaxel, cabazitaxel, adriamycin, mitoxantrone, estramustine, cyclophosphamide), kinase inhibitors (imatinib (Gleevec®) or gefitinib (Iressa®)) or other cancer therapies (eg vaccines (sipuleucel-T (Provenge®), GVAX, etc.), Mass inhibitors (abiraterone ) and herbal (PC-SPES) as observed when observing the increase or growth of serum levels of the prostate specific antigen (PSA), metastasis, bone metastasis, pain, involvement of lymph nodes, serum markers or increase in size of the tumor growth, diagnostic markers for worsening the prognosis or the patient's condition In another modality, castration-resistant prostate cancer is defined like a prostate cancer resistant to hormones.

Many of the early stage prostate cancers require androgens for growth. However, advanced prostate cancers are usually independent of androgens, or resistant to hormones. In men with castration-resistant prostate cancer, tumor cells may have the ability to grow in the absence of androgens (hormones that promote the development and maintenance of male sexual characteristics).

In one embodiment, the expression "androgen deprivation therapy" (ADT) or "traditional androgen deprivation therapy" refers to orchiectomy (surgical castration) where the surgeon removes the testicles. In another embodiment, the expression "androgen deprivation therapy" or "traditional androgen deprivation therapy" refers to the administration of luteinizing hormone-releasing hormone analogues (LHRH). These drugs lower the amount of testosterone produced by the testes. Examples of LHRH analogues available in the United States include leuprolide (Lupron®, Viadur®, Eligard®), goserelin (Zoladex®), triptorelin (Trelstar®) and histrelin (Vantas®). In another embodiment, the expression "androgen deprivation therapy" or "traditional androgen deprivation therapy" refers to the administration of antiandrogens. Antiandrogens block the body's ability to use any androgen. Even after orchiectomy or during treatment with LHRH analogues, a small amount of androgens is still produced by the adrenal glands. Examples of antiandrogenic drugs include enzalutamide, flutamide (Eulexin®), bicalutamide (Casodex®) and nilutamide (Nilandron®). In another embodiment, the expression "androgen deprivation therapy" or "traditional androgen deprivation therapy" refers to the administration of hormone releasing hormone (LHRH) antagonists such as abarelix (Plenaxis ®) and degaralix (Firmagon ® ) (approved for use by the FDA in 2008 to treat advanced prostate cancer). In another embodiment, the term "androgen deprivation therapy" or "traditional androgen deprivation therapy" refers to the administration of 5a inhibitors. reductase such as finasteride (Prosear®) and dutasteride (Avodart®). 5a reductase inhibitors block the body's ability to convert testosterone into the most active androgen, 5a-dihydrotestosterone (DHT). In another embodiment, the term "androgen deprivation therapy" or "traditional androgen deprivation therapy" refers to the administration of testosterone biosynthesis such as ketoconazole (Nizoral®). In another embodiment, the term "androgen deprivation therapy" or "traditional androgen deprivation therapy" refers to the administration of estrogens, such as diethylstilbestrol or 17p-estradiol. In another embodiment, the expression "androgen deprivation therapy" or "traditional androgen deprivation therapy" refers to the administration of 17a-hydroxylase / C 17, 20 Mass (CYP1 7A1) inhibitors such as abiraterone (Zytiga®) .

In one embodiment, the methods of this invention are intended to treat, suppress, reduce incidence, reduce severity, inhibit, provide palliative care or increase the chances of survival of prostate cancer of a subject. In one embodiment, the methods of this invention are intended to treat, suppress, reduce incidence, reduce severity, inhibit, provide palliative care or increase the chances of survival of advanced prostate cancer of a subject. In one embodiment, the methods of this invention are intended to treat, suppress, reduce incidence, reduce severity, inhibit, provide palliative care or increase the chances of survival of prostate cancer resistant to the castration. In one embodiment, the methods of this invention are intended to treat, suppress, reduce incidence, reduce severity, inhibit, provide palliative care or increase the chances of survival of castration-resistant metastatic prostate cancer. In another embodiment, the subject has high or increasing levels of specific prostate antigen (PSA).

In one modality, the levels of specific prostate antigen (PSA) that are considered normal depend on age. In one embodiment, the levels of specific prostate antigen (PSA) that are considered normal depend on the size of the prostate of a male subject. In one embodiment, PSA levels in the range between 2.5-1 0 ng / mL are considered "elevated to the limit". In another modality, PSA levels above 1 0 ng / mL are considered "elevated".

In one mode, the rate of change or "speed of PSA "is high In one embodiment, the rate of change or" PSA velocity "greater than 0.75 / year is considered high.

In one embodiment, this invention aims to treat a subject with high or increasing PSA levels comprising administering a compound of this invention. In one embodiment, the invention aims to treat a subject with high or increasing PSA levels despite ongoing ADT or a history of ADT, surgical castration or despite treatment with antiandrogens and / or LHRH agonist. In another embodiment, the treatment uses compounds of this invention. In another embodiment, the treatment uses compound IV.

In one embodiment, the present invention relates to a method for reducing prostate-specific antigen (PSA) levels in a subject comprising administering a compound of the present invention. In one embodiment, the present invention relates to a method for reducing levels of specific prostate antigen (PSA) in a subject comprising administering a compound of formulas IA, I-XII. In another embodiment, by administration of compound IV. In one embodiment, this invention aims at a method for reducing prostate-specific antigen (PSA) levels in a subject comprising administering a compound of formulas IA, 1-12 together with the LHRH agonist. In another modality, the administration of a compound IV together with the LHRH agonist. In one embodiment, this invention aims at a method for reducing prostate-specific antigen (PSA) levels in a subject comprising administering a compound of formulas IA, 1-12 together with the LH RH antagonist. In another embodiment, the administration of a compound IV together with the LHRH antagonist. In one embodiment, this invention aims at a method for reducing prostate-specific antigen (PSA) levels in a subject which comprises administering a compound of formulas IA, 1-12 together with leuprolide acetate (Lupron®). In another embodiment, the administration of a compound IV together with leuprolide acetate (Lupron®). In one embodiment, this invention is directed to a method for reducing prostate-specific antigen (PSA) levels in a subject which comprises administering a compound of formulas IA, I-XII together with degarelix In another embodiment, the administration of a compound IV together with degarelix. In another embodiment, the subject suffers from advanced prostate cancer. In another embodiment, the subject suffers from castration-resistant prostate cancer (CRPC). In another embodiment, CRPC is metastatic CRPC (mCRPC). In another modality, the androgen deprivation therapy (ADT) that the subject received was not successful. In another embodiment, compound IV is administered in a dose of 125 mg / per day. In another embodiment, compound IV is administered in a dose of 250 mg / per day. In another embodiment, compound IV is administered in a dose of 500 mg / per day.

In one embodiment, this invention provides methods for treating castration-resistant prostate cancer by compounds of this invention and, therefore, requires reduced chemotherapy.

In one embodiment, the present invention provides a method for treating, suppressing, reducing the incidence, reducing severity, increasing the chances of survival or inhibiting prostate cancer resistant to chemotherapy. In another modality, chemotherapy comprises a treatment with docetaxel or paclitaxel.

In one embodiment, the present invention provides a method for treating, suppressing, reducing the incidence, reducing the severity, increasing the chances of survival or inhibiting a prostate cancer resistant to the GnRH agonist. In another embodiment, the GnRH agonist is leuprolide.

In one embodiment, the present invention provides a method to treat, suppress, reduce incidence, reduce severity, increase the chances of survival or inhibiting a prostate cancer resistant to the GnRH antagonist (GRHA). In another modality, the GRHA agonist is degarelix.

In one embodiment, the present invention provides a method for treating, suppressing, reducing incidence, reducing severity, increasing the chances of survival or inhibiting prostate cancer resistant to antiandrogens. In another modality, the antiandrogen is bicalutamide, flutamide or enzalutamide.

In one embodiment, the present invention provides a method for treating, suppressing, reducing incidence, reducing severity, increasing the chances of survival or inhibiting a vaccine-resistant prostate cancer.

In one embodiment, this invention provides a method for treating, suppressing, reducing the incidence, reducing the severity, increasing the chances of survival or inhibiting an abiraterone-resistant prostate cancer.

In one embodiment, the methods provided herein and / or using the compounds provided herein provide feedback in an effective manner to the hypothalamic-pituitary-gonadal axis (HPT axis). Feedback refers to the ability of a substance produced in an organ or tissue to regulate the activity of another organ or tissue that affects its own activity. In one modality, feedback to the hypothalamic-pituitary-gonadal axis (HPT axis) results in the reduction of LH levels. In one modality, feedback to the hypothalamic-pituitary-gonadal axis (HPT axis) results in the reduction of total serum testosterone levels. In one modality, feedback to the hypothalamic-pituitary-gonadal axis (HPT axis) results in the reduction of serum free testosterone levels. In one modality, feedback to the hypothalamic-pituitary-gonadal axis (HPT axis) results in the reduction of serum, tissue or tumor levels of androgens.

The hypothalamic-pituitary-gonadal axis (HPT) refers to the endocrine physiological system that regulates the hormonal levels in the hypothalamus, the pituitary gland and the testes. LHRH (luteinizing hormone-releasing hormone) is released by the hypothalamus and stimulates the pituitary to synthesize and secrete LH and FSH (gonadotropins). Then, LH and FSH act on the testes to stimulate the production of testosterone and sperm. Testosterone then has a direct negative feedback effect on the secretion of hypothalamic LHRH and an indirect negative feedback effect on the pituitary production of FSH and LH. Estrogens, androgens, and serum proteins (eg, inhibin) also have a negative effect on the secretion of LHRH and the secretion of LH and FSH.

The pituitary gland is a gland that controls the levels of testosterone in the body. When the level of testosterone is low, the pituitary gland releases luteinizing hormone (LH). This hormone induces the production of more testosterone in the testes. The level of testosterone increases during puberty. The highest level of testosterone is observed around 20-40 years of age and then gradually decreases in older men. Women have a much lower amount of testosterone in their bodies compared to men, but testosterone plays an important role throughout the body in both men and women. It affects the brain, muscle and bone mass, fat distribution, vascular system, energy levels, genital tissues and sexual function. Most of the testosterone in the blood is linked to a protein called sex hormone binding globulin (SHBG) or another protein called albumin. Testosterone that is not bound (or "free") can also be clinically determined.

In another modality, reducing total serum testosterone, free serum testosterone levels or the percentage of free testosterone in serum (% Free T) independent of a reduction in serum luteinizing hormone levels is due to the increase in binding globulin. of sex hormones (SH BG). In another modality, decreasing free testosterone levels independent of a reduction in luteinizing hormone levels in serum is due to the increase in sex hormone binding globulin (SH BG). In another modality, decreasing the percentage of free testosterone in serum (% Free T) independent of a reduction in luteinizing hormone levels in serum is due to the increase in sex hormone binding globulin (SHBG). In another modality, decreasing serum free or total serum testosterone levels independent of the reduction of serum luteinizing hormone (LH) levels is due to the inhibition of the production or secretion of testosterone mediated by Leydig cells. in the testicles In another modality, decreasing serum free or total serum testosterone levels independently of the reduction of luteinizing hormone levels in serum (LH) is due to the decrease in adrenal steroidogenesis.

In one embodiment, the compounds as described herein and / or the compositions comprising them can be used for the reduction of luteinizing hormone (LH) levels. In another embodiment, the compounds and / or compositions of this invention can be used to reduce endogenous sex hormones.

Members of the hydroxysteroid dehydrogenase family (HSD) participate in the conversion of circulating steroids. 1 7 -HSD5 converts androstenedione to testosterone and estrone to estradiol. In addition, it participates in the synthesis of prostaglandin. In one embodiment, the compounds of this invention inhibit HSD, specifically the inhibition of 1 7p-hydroxysteroid dehydrogenase 5 (17-HSD5). Such inhibition may be useful in ADT by preventing extragonadal / peripheral testosterone synthesis that may be left out of HPT axis control and cause incomplete reduction of total or free testosterone in serum or that allows localized increase in testosterone levels intracellular Either of the two cases could be harmful to the ADT.

Androgen deprivation therapy (ADT) achieved by the LH RH agonist therapy, ie the administration of luteinizing hormone-releasing hormone (LHRH) agonists or analogs thereof, results in an initial stimulation of the release of gonadotropin in the pituitary and the production of testosterone in the testes (called "exacerbated reaction") followed by a decrease in gonadotropin release and a decrease in testosterone and estrogen levels alike. The "exacerbated reaction" caused by LHRH agonist therapy has a negative impact on the treatment of prostate cancer due to the increase in testosterone / androgen levels. In addition, LHRH therapy has been associated with an increased risk of diabetes and cardiovascular disease (Smith (2008) Current Prostate Reports 6: 149-154).

In an effort to overcome the exacerbation effects of LHRH therapy, antiandrogen monotherapy (bicalutamide, flutamide, chlormadinone) combined with antiandrogen / LHRH and LHRH (deregalix) antagonist approaches (Suzuki er a / ., (2008) Int. J. Clin. Oncol., 13: 401-410, Sharifi, N. et al., (2005) JAMA, 294 (2): 238-244). Antiandrogen monotherapy does not reduce androgen levels in a subject. Antiandrogenic monotherapy with bicalutamide was found to be less effective than ADT in patients with prostate cancer with bone metastases. In addition, the adverse effects observed with bicalutamide therapy include breast tenderness and breast enlargement (gynecomastia and mastodynia) (Suzuki et al., Ibid.). An additional risk of antiandrogen therapy includes the increase of hepatic transaminases (Sharifi et al., Ibid).

In one embodiment, the present invention provides a reduction in LH levels and thus a reduction in Total serum testosterone and / or serum free testosterone levels without producing the "exacerbated" effect, while overcoming the adverse effects associated with estrogen deficiency caused by the reduction of testosterone using traditional ADT methods. The methods / uses of the compounds in question provide estrogenic activities of tissue selection that provide maintenance of the bone tissue (agonist effect on the bone tissue), decreased thrombogenic potential and / or hot flashes and / or neutral or minor effects on the breast tissue that estradiol or diethylstilbestrol.

In one embodiment, compound IV shows agonists but no antagonistic effect (Examples 6 and 7) so that compound IV would not cause an increase in gonadotropins and testosterone.

In one embodiment, compound IV shows agonist activity (Examples 8-1 1) demonstrating a strong pharmacological response to the reduction of hormones in serum, testosterone and total androgens.

In one embodiment, compound IV is a selective non-steroidal alpha estrogen receptor (ERa) agonist that binds to the estrogen receptor (ER) with nanomolar affinity for both ERa and ER. Although many estrogenic ligands cross-react with other nuclear hormone receptors, the actions of compound IV are specific for ERa and ER. Compound IV has a 16-fold selectivity in relative transactivation potency for ERa and ER3, and approximately 1400 times less potency in its ability to stimulate ER-mediated transcription compared to estradiol.

In another embodiment, the methods provided herein using compounds and / or compositions provided herein are effective in reducing or eliminating bone resorption effects caused by the reduction of LH using traditional forms of ADT. In one embodiment, the methods provided herein using compounds and / or compositions provided herein, are effective in reducing or eliminating bone resorption effects caused by the reduction of testosterone levels using traditional forms of ADT. In one embodiment, the methods provided herein using compositions provided herein are effective in reducing or eliminating bone resorption effects caused by the reduction of estrogen as a result of the reduction of LH levels. In one embodiment, methods provided herein that utilize compounds and / or compositions provided herein avoid the effects of bone resorption associated with the reduction of LH levels using traditional forms of ADT. In one embodiment, methods provided herein that utilize compounds and / or compositions provided herein avoid bone loss associated with testosterone, endogenous LH, and / or estradiol reduction using traditional forms of ADT. In one embodiment, methods provided herein that utilize the compounds and / or compositions provided herein increase bone mass density (BMD) while providing reduction in LH levels. In one embodiment, the methods provided herein that use the compounds and / or compositions provided herein increase the percentage of bone volume while providing reduction in the levels of testosterone, endogenous LH and / or estradiol.

In some embodiments, this invention provides a method for preventing and / or reducing thromboembolism by administering a compound of this invention or its isomer, pharmaceutical, polymorph, hydrate or any combination thereof.

In one embodiment, methods provided herein that utilize the compounds and / or compositions provided herein are effective in breast tissue. In one embodiment, the methods provided herein using compounds and / or compositions provided herein provide for a reduction in LH levels, while preventing gynecomastia associated with the reduction of LH levels obtained by traditional ADT. .

In one embodiment, Example 13 describes special toxicity studies where in vitro studies with human platelets showed that compound IV had much less procoagulatory activity than DES. In this way, compound IV, a selective ER agonist, should provide the benefits of DES prostate cancer with less risk of thrombotic events than DES, as well as provide the benefits of the LHRH agonist or antagonist without causing bone loss, hot flashes or adverse lipid profiles.

Diethylstilbestrol (DES) therapy alone or together with other ADTs showed that DES prevents bone resorption in patients with prostate cancer. Although the use of DES has been promoted as a therapy for prostate cancer, it is believed that the effects of DES on angiogenesis and malignancy are mediated by DES metabolites and are thought to act through the estrogen receptor . In addition, the dosage levels of DES administered for therapeutic uses have numerous adverse side effects including cardiovascular disease, cardiovascular morbidity, thrombotic toxicity, gynecomastia, erectile dysfunction, and decreased libido (Scherr and Pitts, ibid and Presti, JC Jr. (1996) JAMA 275 (15): 1 1 53-6).

In one embodiment, the present invention overcomes the negative side effects of antagonist or LHRH agonist therapy, alone or in combination with antiandrogens or DES. In another embodiment, the methods of the subject invention provide androgen deprivation therapy without adverse side effects of estrogen deprivation such as bone related adverse conditions and without adverse side effects of estrogen stimulation, such as gynecomastia. In another embodiment, the methods of the present invention provide for the reduction of LH levels and, therefore, a reduction of total / free serum testosterone levels, without producing the "exacerbated" effect while overcoming the adverse effects associated with the estrogen deficiency caused by the reduction of LH and overcome the adverse effects associated with a general increase in estrogen agonist observed with DES therapy. The methods / uses of the compounds in question provide estrogenic tissue selection activities that provide bone tissue maintenance (agonist effect on bone tissue), reduced thrombogenic potential and neutral affections on breast tissue.

The antiestrogenic effects of traditional selective modulators of estrogen receptors (SE RM) such as tamoxifen, toremifene and raloxifene at the hypothalamic level results in an increase in gonadotropin levels or an increase in LH levels in men and, in this way, it results in an increase in serum testosterone levels (Tsouri et al., 2008, Fertility and Sterility doi: 1 0. 1 016). In contrast, the methods of this invention provide for a reduction of LH in a male subject which comprises administering a compound of formulas IA, I-XII.

Additional modalities of the Comm of Formula I: In a modality of the methods of this invention, Y of the compound of the formula I is C (O). In another modality, Y is CH2. In another embodiment, R1 and R2 of the compound of the formula I or IA are independently O-Alk-N RsRe or O-Alk-heterocycle In another embodiment the Alq of said O-Alk-heterocycle, O-Alq-NRsRe , -Alk-heterocycle and Alk-N R5R6 as described hereinabove is a linear alkylene of 1 to 7 carbons, branched alkyl of 1 to 7 carbons or cyclic alkyl of 3-8 carbons. In another embodiment, the alkyl is an ethylene (-CH2C H2-). In another embodiment, the Alk is methylene (-CH2). In another modality, Alk is propylene (-CH2CH2CH2-). In another modality, the Alq ethylpropylene (-CH2CH (CH3) CH2 In one embodiment of the methods of this invention, Ri of the compound of formula I or IA are in the para position. In one embodiment of the methods of this invention Ri and R2 of the compound of formula I or IA are different. In another embodiment of the methods of this invention R1 and R2 of the compound of formula I or IA are the same. In another embodiment of the methods of this invention R1 of the compound of formula I or IA is In another embodiment of the methods of this invention R1 of the compound of the formula I or IA is hydroxyl. In another embodiment of the methods, R 1 of the compound of formula I or IA is alkoxy. In another embodiment of the methods, R1 and R2 are independently hydrogen, halogen, hydroxyl, alkoxy, cyano, nitro, CF3, N (R) 2, sulfonamide, SO2R, alkyl, haloalkyl, aryl, 0-Alq-NRsR6 or O- Alkheterocycle wherein the heterocycle is a substituted or unsubstituted heterocyclic ring of 3-7 members, optionally aromatic. In another embodiment of the methods, R1 and R2 of the compound of formula I or IA are independently hydrogen, halogen, hydroxyl, alkoxy, cyano, nitro, CF3, N (R) 2, sulfonamide, S02R, alkyl, haloalkyl, aryl, O-Alk-NRsRe or O-Alk-heterocycle wherein the heterocycle is a substituted or unsubstituted heterocyclic ring of 3-7 members, optionally aromatic. In another embodiment of the methods, R2 of the compound of formula I or IA is halogen. In another embodiment of the methods, R2 of the compound of the formula I or IA is F. In another embodiment of the methods, R2 of the compound of formula I is Cl. In another embodiment of the methods, R2 of the compound of formula I or IA is Br. In another embodiment of the methods, R2 of the compound of the formula I or IA is I. In another embodiment of the methods, R2 of the compound of the formula I or IA is hydroxyl. In another embodiment of the methods, R1 and / or R2 is CF3. In another embodiment, R1 and / or R2 is CH3. In another embodiment, R1 and / or R2 is a halogen. In another embodiment, R1 and / or R2 is F. In another embodiment, R1 and / or R2 is Cl. In another embodiment, R1 and / or R2 is Br. In another embodiment, R1 and / or R2 is I. In another embodiment, R1 and / or R2 is I. embodiment, R2 of the compound of the formula I is in the para position.

In one embodiment of the methods of this invention, R3 and R4 of the compound of formula I or IA are the same. In another embodiment of the methods of this invention, R3 and R4 of the compound of formula I or IA are different. In another embodiment of the methods, j and k of the compound of formula I or IA are independently 1. In another embodiment of the methods, R3 and R of the compound of formula I or IA are independently halogen, haloalkyl, hydroxyl or alkyl. In another embodiment of the methods, R3 and R of the compound of the formula I or IA are independently F. In another embodiment of the methods, R3 and R4 of the compound of the formula I or IA are independently Br. In another embodiment of the methods , R3 and R of the compound of the formula I or IA are independently Cl. In another embodiment, R4 is in the para position. In another mode, R3 is in the ortho position. In another modality, R3 is in the meta position. In another embodiment, R3 and / or R4 is CF3. In another embodiment, R3 and / or R4 is CH3.

In one embodiment of the methods of this invention, R5 and 6 of the compound of formula I or IA form a 3- to 7-membered ring with a nitrogen atom. In another modality, the ring is a saturated or unsaturated ring. In another embodiment, the ring is a substituted or unsubstituted ring. In one embodiment of the methods of this invention, R5 and Re of the compound of formula I or IA form a piperidine ring with nitrogen. In another embodiment of the methods, R5 and Re of the compound of the formula I or IA form a pyrazine ring with the nitrogen. In another embodiment of the methods, R5 and Re of the compound of the formula I or IA form a piperazine ring with the nitrogen. In another embodiment of the methods, R5 and Re of the compound of formula I or IA form a morpholine ring with nitrogen. In another embodiment of the methods, R5 and Re of the compound of formula I or IA form a pyrrolo ring with nitrogen. In another embodiment of the methods, R5 and Re of the compound of formula I or IA form a pyrrolidine ring. In another embodiment of the methods, R5 and R6 of the compound of the formula I or IA form a pyridine ring with the nitrogen. In another embodiment, the ring is substituted with halogen, alkyl, alkoxy, alkylene, hydroxyl, cyano, nitro, amino, amide, COOH or an aldehyde.

In another embodiment of the methods of this invention, R1 of the compound of the formula I or IA and R2 of the compound of the compound of the formula I or IA are independently O-Alk-heterocycle or OCH2CH2-heterocycle. In another embodiment, the term "heterocycle" group refers, in one embodiment, to a ring structure that further comprises carbon, sulfur, oxygen, nitrogen or any other atoms. combination of these as part of the ring. In another embodiment, the heterocycle is a 3 to 1 2-membered ring. In another embodiment, the heterocycle is a 6-membered ring. In another embodiment, the heterocycle is a 5- to 7-membered ring. In another embodiment, the heterocycle is a 4 to 8 member ring. In another embodiment, the heterocycle group may be unsubstituted or substituted by halogen, haloalkyl, hydroxyl, alkoxy, carbonyl, amido, alkylamido, dialkylamido, cyano, nitro, CO2H, amino, alkylamino, dialkylamino, carboxyl, thio and / otioa I qui I o. In another embodiment, the heterocycle ring may be fused to another saturated or unsaturated heterocyclic or 3 to 8 membered cycloalkyl ring. In another embodiment, the heterocyclic ring is a saturated ring. In another embodiment, the heterocyclic ring is an unsaturated ring. In another embodiment, the heterocycle is piperidine. In another embodiment, the heterocycle is pyridine. In another embodiment, the heterocycle is piperidine, pyridine, furan, thiophene, pyrrolo, pyrrolidine, pyrazine, piperazine or pyrimidine.

The term "cycloalkyl" refers to a monocyclic or polycyclic non-aromatic ring comprising carbon and hydrogen atoms. The cycloalkyl group may have one more carbon-carbon double bonds in the ring provided the ring is not aromatic by its presence. Examples of cycloalkyl groups include, but are not limited to, cycloalkyl (C3-C7) groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl and saturated cyclic and bicyclic terpenes and (C3-C7) cycloalkenyl groups such as cyclopropenyl, cyclobutenyl, Cyclopentenyl, cyclohexenyl and cycloheptenyl and bicyclic and cyclic unsaturated terpenes. A cycloalkyl group may not be substituted or substituted with one or two substituents. Preferably, the cycloalkyl group is a monocyclic ring or a bicyclic ring.

The term "alkyl" refers, in one embodiment, to a saturated aliphatic hydrocarbon that includes straight chain, branched and cyclic alkyl groups. In one embodiment, the alkyl group has from 1 to 12 carbons. In another embodiment, the alkyl group has from 1 to 7 carbons. In another embodiment, the alkyl group has from 1 to 6 carbons. In another embodiment, the alkyl group has from 1 to 4 carbons. In another embodiment, the cyclic alkyl group has from 3 to 8 carbons. In another embodiment, the cyclic alkyl group has from 3 to 12 carbons. In another embodiment, the branched alkyl is an alkyl substituted by alkyl side chains of 1 to 5 carbons. In another embodiment, the branched alkyl is an alkyl substituted by haloalkyl side chains of 1 to 5 carbons. The alkyl group may be unsubstituted or substituted by halogen, haloalkyl, hydroxyl, alkoxycarbonyl, amido, alkylamido, dialkylamido, nitro, amino, alkylamino, dialkylamino, carboxyl, thio and / or thioalkyl.

An "alkenyl" group refers, in another embodiment, to an unsaturated hydrocarbon that includes straight chain, branched chain and cyclic groups having one or more double bonds. The alkenyl group can have a double bond, two double bonds, three double bonds, etc. In another embodiment, the alkenyl group has from 2 to 12 carbons. In another embodiment, the alkenyl group has from 2 to 6 carbons. In another embodiment, the alkenyl group has from 2 to 4 carbons.

Examples of alkenyl groups are ethenyl, propenyl, butenyl, cyclohexenyl, etc. The alkenyl group may be unsubstituted or substituted by halogen, alkoxy, alkoxycarbonyl, amido, alkylamido, dialkylamido, nitro, amino, alkylamino, diacylamino, carboxyl, thio and / or thioalkyl.

An "aryl" group refers to an aromatic group having at least one carbocyclic aromatic group or heterocyclic aromatic group which may be unsubstituted or substituted by one or more groups selected from halogen, haloalkyl, hydroxy, alkoxycarbonyl, amido , alkylamido, dialkylamido, nitro, amino, alkylamino, diacylamino, carboxy or thio or thioalkyl. Non-limiting examples of the aryl rings are phenyl, naptyl, pyranyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyrazolyl, pyridinyl, furanyl, thiophenyl, thiazolyl, imidazolyl, isoxazolyl, and the like. In another embodiment, the aryl group is a 4 to 8 member ring. In another embodiment, the aryl group is / are a ring / s of 4 to 12 members. In another embodiment, the aryl group is a 6-membered ring. In another embodiment, the aryl group is a 5-membered ring. In another embodiment, the aryl group is a system of 2 to 4 fused rings.

In the group "aldehyde" refers, in one embodiment, to an alkyl or alkenyl substituted by a formyl group, wherein the alkyl or alkenyl are as defined above. In another embodiment, the aldehyde group is an aryl or phenyl group substituted by a formyl group, where the aryl is as defined above. Examples of aldehydes are: formyl, acetal, propanal, butanal, pentanal, benzaldehyde. In another embodiment, the aldehyde group is a formyl group.

A "haloalkyl" group refers, in another embodiment, to an alkyl group as defined above, which is substituted by one or more halogen atoms, e.g. , by F, Cl, Br or I.

A "hydroxyl" group refers, in another embodiment, to an OH group. One skilled in the art understands that when Ri, R2 or R3 of the compounds of the present invention is OR, then R is not OH.

In one embodiment, the term "halogen" refers to a halogen, such as F, Cl, Br or I.

In another embodiment, the phrase "phenol" refers to an alcohol (OH) derivative of benzene.

In reference to the protected hydroxyl, in some embodiments it includes the incorporation of a substituent attached to an oxygen moiety attached to a benzene ring, where the substituent can be easily removed. In some embodiments, the phenolic protecting groups may include: methyl ether (methoxy), alkyl ether (alkoxy), benzyl ether (Bn), methoxymethyl ether (MOM), benzoyloxymethyl ether (BOM), benzyl, carbobenzoxy, methoxyethoxymethyl ether (MEM ), 2- (trimethylsilyl) ethoxymethyl ether (SEM), methylthiomethyl ether (MTM), phenylthiomethyl ether (PTM), azidomethyl ether, cyanomethyl ether, 2,2-dichloro-1,1-difluoroethyl ether, 2-chloroethyl ether, 2-bromoethyl ether, tetrahydropyranyl ether (THP), 1-ethoxyethyl ether (EA), phenacyl ether, 4-bromophenacyl ether, cyclopropylmethyl ether, allyl ether, propargyl ether, isopropyl ether, cyclohexyl ether, tert-butyl ether, 2,6-dimethylbenzyl ether, 4-methoxybenzyl ether, O-nitrobenzyl ether, 2,6-dichlorobenzyl ether, 3,4-dichlorobenzyl ether, ether of 4- (dimethylamino) carbonylbenzyl, 4-methylsulfinylbenzyl ether, 4-anthrylmethyl ether, 4-picolyl ether, heptafluoro-p-tolyl, tetrafluoro-4-pyridyl ether, trimethylsilyl ether ( TMS), t-butyldimethylsilyl ether (TBDMS), t-butyldiphenylsilyl ether (TBDPS), triisopropylsilyl ether (TIPS), aryl format, arylacetate, aryl levulinate, arylpivaloate, aryl benzoate, aryl 9-fluorencarboxylate, methylaryl carbonate, 1-adamantyl carbonate, tert-butyl carbonate, 4-methylsulfinylbenzyl carbonate, 2,4-dimethylpent-3-yl carbonate, 2,2,2-trichloroethylaryl carbonate, benzylaryl carbonate, carbamate aryl, dimethylphosphyl ether (Dmp-OAr), dimethylphosphinothionyl ether (Mpt-OAr), diphenylphosphinothionyl ether (Dpt-OAr), aryl methanesulfonate, aryl toluenesulfonate or aryl 2-formylbenzenesulfonate.

In one embodiment, the methods of this invention use N, N-bis (4-hydroxyphenyl) -4-propylbenzamide (II) or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof. In another embodiment, the methods of this invention use 4,4 '- (2,3-dimethyl-benzylazanodiyl) diphenol (III) or its isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate or any combination thereof. In another embodiment, the methods of this invention utilize 3-fluoro- / V- (4-fluorophenyl) -4-hydroxy- / V- (4-hydroxyphenyl) benzamide (IV) or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination of these. In one embodiment, the methods of this invention use / V, / V-bis (4-hydroxyphenyl) -2,3-dimethylbenzamide (V) or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination of these. In one embodiment, the methods of this invention utilize A /, A / -bis (4-hydroxyphenyl) -2-naphthylamide (VI) or its isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate or any combination thereof. In another embodiment, the methods of this invention utilize 3-fluoro-4-hydroxy-A /, / S / -bis (4-hydroxyphenyl) -benzamide (VI I) or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination of these. In another embodiment, the methods of this invention utilize 4 - ((4-fluorophenyl) (4-hydroxybenzyl) amino) phenol (VI II) or its isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate or any combination thereof. In another embodiment, the methods of this invention utilize 4-fluoro- / V- (4-hydroxy-phenyl) - / [- (4- (2-piperidin-1-yl-ethoxy) -phenyl] -2-trifluoromethyl- benzamide (IX) or its isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate or any combination thereof. In another embodiment, the methods of this invention utilize a hydrochloride salt of IX (HCl salt of IX) or 4-fluoro- / V- (4-hydroxy-phenyl) - / V- [4- (2- piperidin-1-yl-ethoxy) -phenyl] -2-trifluoromethyl-benzamide (X) or its isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate or any combination thereof. In another embodiment, the methods of this invention utilize 3-fluoro-4-hydroxy- / V- (4-hydroxyphenyl) - / V-phenylbenzamide (XI) or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination of these. In another embodiment, the methods of this invention utilize 3-fluoro- / V, A / -bis- (4-hydroxy-phenyl) -2-methyl- benzamide (XII) or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof.

In one embodiment the methods of this invention utilize "pharmaceutically acceptable salts" of the compounds that can be produced by reaction of a compound of this invention with an acid or a base.

Suitable pharmaceutically acceptable salts of amines of the methods of the present invention can be prepared from an inorganic acid or from an organic acid. In one embodiment, examples of inorganic salts of amines are bisulfates, borates, bromides, chlorides, hemisulfates, hydrobromonates, hydrochlorates, 2-hydroxyethyl sulfonates (hydroxyethanesulfonates), iodates, iodides, isothionates, nitrates, persulfates, phosphates, sulfates, sulfamates, sulphanilates , sulfonic acids (alkylsulfonates, arylsulfonates, halogen-substituted alkylsulfonates, halogen-substituted arylsulfonates), sulfonates and thiocyanates.

In one embodiment, examples of organic salts of amines can be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carbocyclic and sulfonic classes of organic acids, examples of which are acetates, arginines, aspartates, ascorbates, adipates, anthranilates, algenates, alkane carboxylates, substituted alkane carboxylates, alginates, benzenesulfonates, benzoates, bisulfates, butyrates, bicarbonates, bitartrates, carboxylates, citrates, camphorates, camphorsulfonates, cyclohexyl sulfamates, cyclopentanopropionates, calcium edetates, camsylates, carbonates, clavulanates, cinnamates, dicarboxylates, digluconates, dodecylsulfonates, dihydrochlorides, decanoates, enantutates, ethanesulfonates, edetates, edisilates, estolates, esilates, fumarates, formates, fluorides, galacturonates, gluconates, glutamates, glycolates, glucorate, glycoheptanoates, glycerophosphates, gluceptates, glycolylaminosanilates, glutarates, glutamate, heptanoates, hexanoates, hydroxymethols, hydroxycarboxylic acids, hexylresorcinates, hydroxybenzoates, hydroxynaphthates, hydrofluorates, lactates, lactobionates, laurates, maleates, maleates, methylenebis (beta-oxinaphthoate), malonates, mandelatos, mesylates, methanesulfonates, methyl bromides, methylnitrates, methylsulfonates, mono-propionate maleates, mucates, monocarboxylates, naphthalenesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, napsylates, / V-methylglucamines, oxalates, octanoates, oleates, pamoates, phenylacetates, picrates, phenylbenzoates, pivalates, propionates, phthalates , pectinates, phenylpropionates, palmitates, pantotenates, polygalactones, pyruvates, kinatos, salicylates, succinates, stearates, sulfanilate, subacetates, tartrates, theophylline acetates, p-toluenesulfonates (tosylates), trifluoroacetates, terephthalates, tannates, theoclates, trihaloacetates, triethyodide, tricarboxylates, undecanoates and valerate.

In one embodiment, examples of inorganic salts of carboxylic acids or phenols can be selected from ammonium, alkali metals including lithium, sodium, potassium, cesium; alkaline earth metals including calcium, magnesium, aluminum; zinc, barium, hills, quaternary ammoniums.

In another embodiment, examples of organic salts of carboxylic acids or phenols can be selected from arginine, organic amines to include aliphatic organic amines, organic alicyclic amines, aromatic organic amines, benzathines, t-butylamines, benetam inas (A / -benzylphenethylamine), dicyclohexylamines, dimethylamines, diethanolamines, ethanolamines, ethylenediamines, hydramines, im-idazoles, lysines, methylamines, meglamines, / V-methyl-D-glucamines,? /,? / '- dibencylethylenedianes, nicotinamides, organic amines, ornithines, pyridines, picolines, piperazines, procaine, tris (hydroxymethyl) methylamine, triethylamine, triethanolamines, trimethylamines, tromethamines and ureas.

In one embodiment, salts can be formed by conventional means, such as by reacting the free base or free acid form of the product with one or more equivalents of the appropriate acid or base in a solvent or medium in which the salt is insoluble in a solvent such as water, which is removed in vacuo or by lyophilization or by ion exchange of an existing salt with another ion or suitable ion exchange resin.

In one embodiment, the methods of this invention utilize a pharmaceutically acceptable salt of the compounds of this invention. In one embodiment, the methods of this invention utilize a pharmaceutically acceptable salt of the compounds of formulas IA, I-XII. In one embodiment, the methods of this invention use a salt of an amine of the compounds of the formulas IA, I-XII. In a embodiment, the methods of this invention utilize a salt of a phenol of the compounds of formulas IA, I-XII.

In one embodiment, the methods of this invention utilize a free base, free acid, non-complex or non-charged compounds of the formulas IA, I-XI I and / or their isomer, pharmaceutical, hydrate, polymorph or combinations thereof.

In some embodiments of this invention, the compounds of this invention comprise three phenyl groups that are held together by an amide bond. In one embodiment, the compounds of this invention are uncharged structures. In another embodiment, the compounds of this invention are free base structures. In another embodiment, the compounds of this invention are structures of free acids. In another embodiment, the compounds of this invention are non-complex structures. In another embodiment, the compounds of this invention are non-ionized structures. In another embodiment, the compounds of this invention are pharmaceutically acceptable salts. In another embodiment, the compounds of this invention are hydrochloride (HCl) salts.

In one embodiment, the methods of this invention use an isomer of a compound of the formulas IA, I-XII. In one embodiment, the methods of this invention utilize a pharmaceutical product of a compound of the formulas IA, I-X 11. In one embodiment, the methods of this invention utilize a hydrate of a compound of the formulas IA, I-XII. In one embodiment, the methods of this invention use a polymorph of a compound of the formulas IA, I-XII. In another modality, The methods of this invention utilize a metabolite of a compound of the formulas IA, I-XI I. In another embodiment, the methods of this invention use a composition comprising a compound of the formulas IA, I-XII, as described herein, or, in another embodiment, a combination of isomer, metabolite, pharmaceutical product. , hydrate, polymorph of a compound of the formulas IA, I-XII.

In one modality, the term "isomer" includes, but is not limited to, optical and analogous isomers, structural and analogous isomers, conformational isomers and the like, and the like.

In one embodiment, the term "isomer" is intended to encompass the optical isomers of the com pound. In one modality, the term "isomer" is intended to encompass the stereoisomers of the compound. The compounds of this invention possess an amide bond which may be in its cis or trans isomerization. It is understood that the present invention comprises any optically active or stereoisomeric form or mixtures thereof and that the use of these for any of the applications is considered within the scope of the present invention.

In another embodiment, this invention additionally includes compound hydrates. In one embodiment, the term "hydrant" refers to heme hydrate, monohydrate, dihydrate, trihydrate or others known in the art.

Synthetic processes The compounds of Formula I or IA can be prepared in simple form, for example, by reacting a substituted benzyl acid diphenyl amine or benzoyl halide in the presence of a base to provide a benzamide. In one embodiment, the base is pyridine. In another embodiment, the benzoyl halide is benzoyl chloride. In another embodiment, a hydroxyl substituent is protected during the reaction between the diphenylamine and the benzoic acid or benzoyl halide. In another embodiment, the protective group for the hydroxyl is optionally removed in the last step. See also US publication No. 2009/00624231 and US patent 8 1 58 828 which are incorporated herein in their entirety by this reference.

For example, a compound of the formula (IA): (IA) where Ri, R2, R3, and R4, j and k are those defined above; can prepare by a process that comprises reacting With Diphenylamine is reacted (3) (4) in the presence of a base to obtain (5) where if Ri, R2, R3 and R are independently OH, 0-Alq-RsR6 or O-Alk-heterocycle, then R1 ', R2', R3 ', R4' are a protected hydroxyl group, where the protecting group is removed to obtaining the free hydroxyl or optionally followed by the reaction with CI-Alk-heterocycle or CI-Alq-NRsRe to provide a compound of the formula IA: (IA) where, if R1, R2, R3 and 4 are independently different from OH, O-Alk-R5Re or O-Alk-heterocycle, then Ri ', R2', R3 ', R' are Ri, R2, R3 and R4, respectively .

As a further example, a process for the preparation of the compound of Formula IA: (IA) where R1, R2, R3, and R are as described above, they comprise reacting in the presence of a base to provide where if Ri, R2, R3 and R4 are independently OH, 0-Alq-RsR6 or O-Alk-heterocycle, then R1 ', R2', R3 ', R4' are a protected hydroxyl group, where the protecting group is removed to obtain the free hydroxyl or optionally followed by the reaction with CI-Alk-heterocycle or CI-Alq-N R5 R6 to provide a compound of the formula IA: where, if Ri, R2, R3 and 4 are inaepenately different from OH, O-Alk-R5Re or O-Alk-heterocycle, then R1 ', R2', R3 ', R4' are R1, R2, R3 and R4, respectively .

In one example, Compound II is prepared according to Example 1 and Figure 5.

In another example, Compound III is prepared according to Example 1 and Figure 5.

In a further example, a compound of formula IV (Compound (IV) can be prepared by reacting (eleven); with (1 2) presence of a base to obtain (13); followed by deprotection of the protecting groups to obtain Compound IV: (IV) wherein P and P 'are the same or different protecting groups.

In one example, Compound IV is prepared according to Example 2 and Figure 6.

In another example, Compound V is prepared according to Example 1 and Figure 5.

In a further example, Compound VI is prepared according to Example 3 and Figure 7.

In another example, Compound VI I is prepared according to Example 1 and Figure 5.

In another example, Compound VI II is prepared according to Example 4 and Figure 5.

In another example, Compound IX is prepared according to Example 5 and Figure 8.

In another example, Compound X hydrochloride is prepared according to Example 5 and Figure 8.

In another example, Compound XI is prepared according to Example 1 and Figure 5.

In another example, Compound XI I is prepared according to Example 1 and Figure 5.

Suitable hydroxyl protecting groups include, for example, a methyl ether (methoxy), benzyl ether (benzyloxy), methoxymethyl ether (MOM), benzoyloxymethyl ether (BOM), benzyl, carbobenzoxy, methoxyethoxymethyl ether (MEM), 2- (trimethylsilyl ether ) ethoxymethyl (SEM), methylthiomethyl ether (MTM), phenylthiomethyl ether (PTM), azidomethyl ether, cyanomethyl ether, 2,2-dichloro-1,1-difluoroethyl ether, 2-chloroethyl ether, 2-bromoethyl, tetrahydropyranyl ether (THP), 1-ethoxyethyl ether (EA), phenacyl ether, 4-bromophenacyl ether, cyclopropylmethyl ether, allyl ether, propargyl ether, isopropyl ether, cyclohexyl ether, ether -butyl, benzyl ether, 2,6-dimethylbenzyl ether, 4-methoxybenzyl ether, o-nitrobenceyl ether, 2,6-dichlorobenzyl ether, 3,4-dichlorobenzyl ether, 4- (dimethylamino) carbonylbenzyl ether, 4-methylsulfinylbenzyl ether, 4-anthrylmethyl ether, 4-picolyl ether, heptafluoro-p-tolyl, ether of tetrafluoro-4-pyridyl, trimethylsilyl ether (TMS), f-butyldimethylsilyl ether (TBDMS), ε-butyldiphenylsilyl ether (TBDPS), trisopropylsilyl ether (TI PS), aryl formate, arylacetate, aryl levulinate, arylpivaloate, aryl benzoate, aryl 9-fluorencarboxylate, methylaryl carbonate, 1-adamantyl carbonate, tert-butyl carbonate, 4-methylsulfinylbenzyl carbonate, 2,4-dimethylpent-3-yl carbonate, carbonate 2, 2,2-trichloroethylaryl, benzylaryl carbonate, aryl carbamate, dimethylphosphinyl ether (Dmp-OAr), dimethylphosphinothionyl ether (Mpt-OAr), diphenylphosphinothionyl ether (Dpt-OAr), aryl methanesulfonate, aryl toluenesulfonate or aryl-formylbenzenesulfonate.

The methods of the present invention comprise the use of compounds of formula IA or I-XII, wherein the process of preparing the compounds of this invention comprises the reaction of a diphenylamine with benzoyl chloride in the presence of a base. Suitable bases include, for example, pyridine, triethylamine, K2CO3, CS2CO3, Na2CO3, methylamine, imidazole, benzimidazole, histidine, tributylamine or any combination thereof. In one embodiment, the base is pyridine.

The methods of the present invention comprise the use of compounds of formula IA or I-XI I in which the process of preparing the compounds of this invention comprises deprotection of a protected hydroxyl. In another modality, the conditions of deprotection depend on the protective group. In a lg modalities, the deprotection stage comprises the hydrogenation in the presence of Pd / C. In another embodiment, the deprotection comprises the reaction with G3. In another embodiment, the deprotection step comprises the reaction with an acid.

In further examples, the Compounds of formula IA or I-XI I are prepared according to Figures 5-8 and Examples 1-5.

Pharmaceutical compositions In some embodiments, the present invention provides methods of use that comprise the adm istration of a composition comprising the disclosed compounds. As used herein, "pharmaceutical composition" means a "therapeutically effective amount" of the active ingredient, ie, the composition of the present invention, together with a pharmaceutically acceptable carrier or diluent. A "therapeutically effective amount" as used herein refers to that amount which provides a therapeutic effect for a given condition and administration regimen.

As used herein, the term "admister" refers to placing a subject in contact with a compound of the present invention. As used herein, adm istration can be achieved in vitro, ie in a test tube, or in vivo, ie in cells or tissues of living organisms, for example, human beings. In one embodiment, the present invention comprises the adm istration of compounds of the present invention to a male subject.

This invention provides, in other embodiments, pharmaceutical products of the compounds described herein. The term "pharmaceutical product" refers, in other embodiments, to a composition suitable for pharmaceutical use (pharmaceutical composition), for example, as described herein.

The compounds of the invention can be administered alone or as active ingredients of a formulation. Therefore, the present invention also includes pharmaceutical com positions of Formula I compounds containing, for example, u or more pharmaceutically acceptable carriers.

Many standard references describing procedures are available to prepare various formulations suitable for administration to the compounds according to the invention. Both Handbook of Pharmaceutical Excipients, American Pharmaceutical Association (current issue); Pharmaceutical Dosage Forms: Tablets (Lieberman, Lachman and Schwartz, editors) current edition, published by Marcel Dekker, I nc. , as Remington's Pharmaceutical Sciences (Arthur Osol, editor), 1 553-1 593 (current edition) contain examples of possible formulations and preparations.

The mode of administration and the dosage forms are related to the therapeutic amounts of the compound or the desirable and effective com positions for the given treatment application.

Suitable dosage forms include, so no taxative, oral, rectal, sublingual, through mucosal, nasal, ophthalmic, subcutaneous, intramuscular, intravenous, transdermal, spinal, intrathecal, intraarticular, intraarterial, subarachnoid, bronchial, lymphatic, and intrauterine administration, and other dosage forms for systemic administration of active ingredients. Formulations suitable for oral administration are preferred.

The active ingredient must be mixed with a pharmaceutical carrier according to conventional pharmaceutical composition techniques to prepare such pharmaceutical dosage forms. The carrier can take a variety of forms depending on the form of preparation desired for administration.

Any of the usual pharmaceutical media can be used in preparing the compositions in oral dosage form. Therefore, for liquid oral preparations such as, for example, suspensions, elixirs and solutions, suitable additives and carriers include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like. For solid oral preparations such as, for example, powders, capsules and tablets, suitable additives and carriers include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Due to their easy administration, tablets and capsules represent the most advantageous oral dosage unit form. If desired, the tablets could be coated with sugar or enteric coating by standard techniques.

In the case of parenteral formulations, the carrier It will usually include sterile water, although it could include other ingredients, for example, ingredients that improve solubility or preservation. Injectable solutions can also be prepared, in which case suitable stabilizing agents can be employed.

In some applications, it may be advantageous to use the active agent in a "vectorized" form, such as by encapsulating the active agent in a liposome or other encapsulating medium, or by fixing the active agent, for example, by covalent bonding, chelation or associative coordination, in a suitable biomolecule, such as those selected from proteins, lipoproteins, glycoproteins and polysaccharides.

The methods of treatment of the present invention employing formulations suitable for oral administration can be presented as discrete units such as capsules, wafers, tablets or dragees, each with a predetermined amount of the active ingredient, for example, as a powder or granules. Optionally, a suspension can be employed in an aqueous liquor or a non-aqueous liquid, such as a syrup, an elixir, an emulsion or a potion.

A tablet can be made by compression or molding, or wet granulation, optionally with one or more secondary ingredients. The tablets can be prepared by compression in a suitable machine with the active compound in freely flowing form, such as a powder or granules, which optionally is mixed, for example, with a binder, disintegrant, lubricant, inert diluent, surfactant or agent. of download. Molded tablets comprising a mixture of the active compound powder with a suitable carrier can be manufactured by molding in a suitable machine.

It is possible to produce a syrup by adding the active compound to a concentrated aqueous solution of a sugar, for example, sucrose, to which any secondary ingredients or ingredients can also be added. Such side ingredients may include flavors, suitable preservatives, agents for delaying the crystallization of sugar and agents for increasing the solubility of any other ingredient, such as a polyhydric alcohol, for example, glycerol or sorbitol.

Formulations suitable for parenteral administration may comprise a sterile aqueous preparation of the active compound, which is preferably isotonic, with the blood of the recipient (eg, physiological saline). Such formulations may include suspending agents and thickening agents, and liposomes or systems of other microparticles designed with the blood components or one or more organs as targets. The formulations can be presented in unit or multiple dosage forms.

Parenteral administration can comprise any suitable form of systemic administration. For example, administration can be intravenous, intraarterial, intrathecal, intramuscular, subcutaneous, intramuscular, intra-abdominal (eg, intraperitoneal), etc. , and can be carried out by infusion pumps (external or implantable) or any other suitable means for the desired administration modality.

Nasal and other mucosal aerosol formulations (eg, inhalable forms) may comprise purified aqueous solutions of the active compounds with preservatives and isotonic agents. Such formulations are preferably adjusted to pH and isotonic state compatible with nasal membranes or other mucous membranes. Alternatively, they may be in the form of fine solid powders suspended in a gaseous carrier. Such formulations can be administered by any suitable method or means, for example, by nebulizer, atomizer, metered dose inhaler or the like.

Formulations for rectal administration may be presented as a suppository with a suitable carrier such as cocoa butter, hydrogenated fats or hydrogenated fatty carboxylic acids.

It is possible to prepare the transdermal formulations by incorporating the active agent into a gelatinous or thixotropic carrier such as a cellulose medium, for example, methylcellulose or hydroxyethylcellulose, and the resulting formulation is packaged in a transdermal device adapted to be fixed in dermal contact with the skin of the user.

In addition to the ingredients mentioned above, the formulations of the present invention may also include one or more secondary ingredients selected from, for example, diluents, buffer solutions, flavoring agents, binders, disintegrants, surfactants, thickeners, lubricants, preservatives (including antioxidants) and the like.

The formulations of the present invention may be immediate release, sustained release, delayed start release or any other release profile known to one skilled in the art.

In one embodiment, the present invention provides methods for a) reducing total serum testosterone levels; b) reducing serum free testosterone levels by reducing luteinizing hormone (LH) or independently of reducing the hormone LH in a male subject suffering from prostate cancer; c) secondary hormone therapy of serum PSA levels and free serum testosterone in a male subject suffering from prostate cancer; d) treat, eliminate, reduce the incidence, reduce the severity or inhibit the evolution of castration-resistant prostate cancer (CRPC) and its symptoms; or increase the chances of survival of men with castration-resistant prostate cancer; e) decreasing serum PSA levels in a male subject suffering from prostate cancer; f) increasing levels of sex hormone-binding globulin (SH BG) in a male subject suffering from prostate cancer; g) inhibit bone related events (SRE) in a male subject suffering from prostate cancer; h) reducing levels of bone turnover markers in a male subject suffering from prostate cancer; i) inhibit hot flashes in a sex subject male who suffers from prostate cancer; and / or j) reducing the production levels of adrenal androgen precursors of a suprarenal gland in a male subject suffering from prostate cancer comprising the administration of an oral composition comprising a compound of formulas IA, I-XII. In another embodiment, the subject suffers from castration-resistant prostate cancer (CRPC). In another embodiment, the subject suffers from prostate cancer resistant to metastatic castration (mCRPC). In additional embodiments, the methods of this invention employ an oral composition comprising a compound of formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII, formula IX, formula X, formula XI or formula XII .

In one embodiment, this invention provides a method for treating prostate cancer by reducing LH levels or not dependent on the reduction of LH levels in a male subject suffering from prostate cancer comprising the administration of a Oral composition comprising a compound of formulas IA, I-XII. In further embodiments, this invention provides methods of treating prostate cancer by reducing LH levels or not dependent on the reduction of LH levels in a male subject suffering from prostate cancer comprising the administration of a composition. oral comprising a compound of formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII, formula IX, formula X, formula XI or formula XII. In another embodiment, the subject suffers from prostate cancer resistant to castration (CRPC). In another embodiment, the subject suffers from prostate cancer resistant to metastatic castration (mCRPC).

It will be understood that the present invention comprises any embodiment of a compound as described herein, which in some embodiments is referred to as "a compound of the present invention".

In one embodiment, the methods of the present invention may comprise administration of a compound of the present invention in various doses. In one embodiment, a compound of this invention is administered in a dose of 1 -3000 mg per day. In additional embodiments, a compound of the present invention is administered in doses of 1-10 mg per day, 3-26 mg per day, 3-60 mg per day, 3-16 mg per day, 3-30 mg per day, 1 0-26 mg per day, 15-60 mg, 50-1 00 mg per day, 50-200 mg per day, 100-250 mg per day, 125-300 mg per day, 20-50 mg per day, 5-50 mg per day, 200-500 mg per day, 125-500 mg per day, 500- 1000 mg per day, 200 -1000 mg per day, 1000-2000 mg per day, 1000-3000 mg per day, 1 25-3000 mg per day, 2000-3000 mg per day, 300-1500 mg per day or 100-1000 mg per day. In one embodiment, a compound of the present invention is administered in a dose of 125 mg per day. In one embodiment, a compound of the present invention is administered in a dose of 250 mg per day. In one embodiment, a compound of the present invention is administered in a dose of 300 mg per day. In one embodiment, a compound of the present invention is administered in a dose of 500 mg per day. In one embodiment, a compound of the present invention is administered in a dose of 600 mg per day. In one embodiment, a compound of the present invention is administered in a dose of 1000 mg per day. In one embodiment, a compound of the present invention is administered in a dose of 2000 mg per day. In one embodiment, a compound of the present invention is administered in a dose of 3000 mg per day. In another embodiment, the compound is Compound IV.

In one embodiment, the methods of the present invention may comprise administration of a compound of the present invention in various doses. In one embodiment, a compound of the present invention is administered in a dose of 3 mg. In additional embodiments, a compound of this invention is administered in a dose of 10 mg, 30 mg, 50 mg, 1 00 mg, 1 25 mg, 200 mg, 250 mg, 300 mg, 450 mg, 500 mg, 600 mg, 900 mg, 1000 mg, 1500 mg, 2000 mg, 2500 mg or 3000 mg. In another embodiment, the compound is Compound IV.

In one embodiment, the methods of the present invention may comprise administration of a compound of the present invention in various doses. In one embodiment, a compound of the present invention is administered in a dose of 0.1 mg / kg / day. In additional embodiments, a compound of the present invention is administered in a dose between 0.2 to 30 mg / kg / day, or 0.2 mg / kg / day, 0.3 mg / kg / day, 1 mg / kg / day, 3 mg / kg / day, 5 mg / kg / day, 10 mg / kg / day, 20 mg / kg / day or 30 mg / kg / day.

In one embodiment, the methods of the present invention are provided for use in pharmaceutical compositions comprising a compound of formulas IA, 1-12. In modalities Further, the methods of the present invention are provided for use in a pharmaceutical composition comprising a compound of formula II, formula III, formula IV, formula V, formula VI, formula VI I, formula VI II, formula IX, formula X , formula XI or formula XII.

In certain embodiments, the pharmaceutical composition is a solid dosage form. In another embodiment, the pharmaceutical composition is a tablet. In another embodiment, the pharmaceutical composition is a capsule. In another embodiment, the pharmaceutical composition is a solution. In another embodiment, the pharmaceutical composition is a transdermal patch.

In one embodiment, the use of a compound of the present invention or a composition comprising it will have utility in inhibiting, suppressing, enhancing or stimulating a desired response in a subject, as will be understood by one skilled in the art. In another embodiment, the compositions may further comprise additional active ingredients, whose activity is useful for the particular application for which the compound of the present invention is administered.

For administration to mammals, and particularly to humans, the physician is expected to determine the actual dose and duration of treatment, which will be most suitable for an individual and which may vary according to age, weight and / or response. of the particular individual.

In some embodiments, any of the compositions of the present invention will comprise a compound of the present invention in any form or embodiment as described in I presented. In some embodiments, any of the compositions of the present invention will consist of a compound of the present invention in any form or embodiment as described herein. In some embodiments, the compositions of the present invention will consist essentially of a compound of the present invention in any form or embodiment as described herein. In some embodiments, the term "comprises" refers to the inclusion of the indicated active agent, such as the compound of the present invention, as well as to the inclusion of other active agents and carriers, excipients, emollients, stabilizers, etc., pharmaceutically acceptable, as they are known in the pharmaceutical industry. In some embodiments, the expression "consists essentially of" refers to a composition whose sole active ingredient is the indicated active ingredient. Nevertheless, other compounds that are used to stabilize, preserve, etc., the formulation may be included, but not directly involved in the therapeutic effect of the indicated active ingredient. In some embodiments, the expression "consists essentially of" may refer to the components that facilitate the release of the active ingredient. In some embodiments, the term "consists of" refers to a composition that contains the active ingredient and a pharmaceutically acceptable carrier or excipient.

It should be understood that any use of any of the compounds as described herein may be used in the treatment of any disease, disorder or condition as described herein, and represents one embodiment of the present invention. In one embodiment, the components are a free base, a free acid, a non-charged or non-complex compound.

The following examples are presented to more fully illustrate the preferred embodiments of the invention. However, they should not be considered in any way as limiting the scope of the invention.

Examples Example 1 General procedures for the synthesis of compounds of formulas I-XI I and synthetic intermediates Solvents, surfactants and organic antioxidants, etc. , which can be used in the compositions described herein are usually available from commercial sources. For example, PEG-300, polysorbate 80, Captex ™ 200, Capmul ™ MCM C8 can be purchased, for example, from the Dow Chemical Company (Midland, MI), ICI Americas, I nc (Wilmington, DE) or Abitec Corporation (Janesville, Wl).

The estrogen receptor ligands described herein may be prepared in a variety of ways known to those skilled in the art. For example, the estrogen receptor ligands described herein can be prepared by synthetic methods described in U.S. Patent Application Publication No. 2009/0062341 and U.S. Pat. 8 158828, whose descriptions are incorporated herein in their entirety by this reference.

General synthesis of derivatives of A /, A / -bis arylbenzamide General synthesis of diarylanilines (Figure 5) Arylamine (1.5 equivalent), aryl iodide (1 equivalent), K2CO3 (2 equivalents), Cul (0.1 equivalent) and ..- proline (0.2 equivalent) were mixed. and the mixture was dissolved in anhydrous DMSO at room temperature. The mixture was then stirred and the reaction mixture was heated at 90 ° C for 28 hours. The mixture was cooled to room temperature and hydrolyzed with water. EtOAc was added to divide the solution. The EtOAc layer was separated, washed with brine and dried with anhydrous MgSO 4. The solvent was removed under reduced pressure. The solid residue was purified by flash column chromatography (silica gel) with 5% EtOAc / hexanes as eluent to obtain the corresponding diarylaniline.

Bis- (4-methoxyphenyl) amine (1a): pale yellow solid, 73% yield. P.f. 98.6-99.0 ° C. 1 H NMR (CDCl 3, 300 MHz) d 6.93-6.81 (m, 8 H), 5.37 (s, br, 1 H), 3.78 (s, 6 H). MS m / z 228.4 (M-H) + / V- (4-Methoxyphenyl) -phenylamine (1b): pale yellow solid, 70% yield. P.f. 106.3 -106.5 ° C. 1 H NMR (CDCl 3, 300 MHz) d 7.24-7.18 (m, 3H), 7.08-7.06 (m, 2H), 6.92-6.84 (m, 4H), 5, 61 (s, br, 1H), 3.79 (s, 3H). MS m / z 200.1 (M + H) +.

N- (4-Fluorophenyl) -A / -4-methoxyphenylamine (1c): pale yellow solid, 54% yield. P.f. 60, 6-61.0 ° C. 1 H NMR (CDCl 3, 300 Hz) d 7.11-6.83 (m, 8H), 3.78 (s, 3H). MS m / z 217 (M) +.

A / - (4-Benzyloxyphenyl) -N-4-methoxyphenylamine (1d): pale yellow solid, 54% yield. P.f. 108, 0-108.4 ° C. 1 H NMR (CDCl 3, 300 MHz) d 7, 34-7.08 (m, 5H), 6.90-6.81 (s, 3H), 3.78 (s, 3H). MS m / z 306 (M + H) +.

General synthesis of benzamides. Arylaniline (1 equivalent), benzoyl chloride (1.3 equivalents) and pyridine (6 equivalents) were mixed, and the mixture was dissolved in anhydrous THF at room temperature. The mixture was stirred and heated to reflux for 24 hours. The reaction solution was cooled to room temperature and hydrolyzed by the addition of 2N HCl solution. The solution was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of NaHCC > 3 to remove the excess acid, dried in MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography with EtOAc / hexanes (3/7 v / v) to provide the corresponding benzamide compounds. 3-Fluoro-A / - (4-fluorof in i l) -4-methoxy-A / - (4-methoxyphenyl) benzamide (2a): yellow solid, P.f. 54-56 ° C, 1H NMR (CDCU / TMS) d 7.24-7.11 (m, 4H), 7.05-6.97 (m, 4H), 6.85-6.78 (m, 3H), 3.86 (s, 3H), 3.79 (s, 3H). MS (ESI) m / z 370.1 [M + H] + 4-Fluoro- / V, A / -bis (4-methoxyphenyl) -2- (trifluoromethyl) benzamide (2b): colorless oil, 84.2% yield. 1 H NMR (CDCl 3, 300 MHz) d 7.34-7.26 (m, 4 H), 7.09-7.01 (m, 3 H), 6.91 (d, 2 H, J = 8.7 Hz) , 6.87 (d, 2H, J = 8.7 Hz), 3.80 (s, 3H), 3.71 (s, 3H). MS m / z 442, 1 (M + Na) \ 4-Methoxy-A / - (4-methoxyphenyl) -A / - (4-fluorophenyl) -benzamide (2c): white solid, 97% yield, M.p. 133, 5.0-134.5 ° C. 1 H NMR (CDCl 3, 300 MHz) d 8.11-6.66 (m, 15H), 3.74 (s, 3H), 3.73 (s, 3H). MS m / z 384 (M + H) +.

A / - (4-Methoxyphenyl) - / V- (4-benzyloxyphenyl) -2-naphthylamide (2d): white solid, 58% yield. P.f. 174, 9-175.5 ° C. 1 H NMR (CDCl 3, 300 MHz) d 8.04 (s, 1 H), 7.77-7.74 (m, 2 H), 7.64-7.61 (m, 1 H), 7.51-7, 43 (m, 4H), 7.40-7.31 (m, 4H), 7.13-7.10 m, 4H), 6.88-6.78 (m, 4H), 4.99 (s) , 2H), 3.74 (s, 3H). MS m / z 460 (M + H) +. 4-Fluoro- / V, A / -bis (4-methoxyphenyl) -2- (trifluoromethyl) benzamide (2e): colorless oil, 84.2% yield. 1 H NMR (CDCl 3, 300 MHz) d 7.34-7.26 (m, 4 H), 7.09-7.01 (m, 3 H), 6.91 (d, 2 H, J = 8.7 Hz) , 6.87 (d, 2H, J = 8.7 Hz), 3.80 (s, 3H), 3.71 (s, 3H). MS m / z 442, 1 (M + Na) +.

General procedure of demethylation of benzamide derivatives with BBr3. A methoxybenzamide compound was dissolved in dry CH 2 Cl 2, added dropwise at 0 ° C BBr 3 (1.0 M CH 2 Cl 2 solution). The reaction solution was heated slowly to room temperature and stirred overnight at room temperature. The reaction was heated slowly to room temperature and stirred overnight at room temperature. The mixture was cooled to 0 ° C in an ice bath and hydrolyzed by the addition of water. EtOAc was added to divide the solution. The organic layer was separated and the aqueous layer was extracted with EtOAc. The organic layer was washed with brine and dried with anhydrous MgSO 4. The solvent was removed under reduced pressure. The residue was purified by flash column chromatography with CH3OH / CH2C I2 (1/9 v / v) to provide the corresponding phenolic compounds. 4-Fluoro-A /, / V-bis (4-hydroxyphenyl) -2- (trifluoromethyl) benzamide (3a): white solid, 92.5% yield. 1 H NMR (DMSO-d 6, 300 MHz) d 9.55 (s, 1 H), 9.53 (s, 1 H), 7.69-7.58 (m, 2H), 7.46-7 , 39 (m, 1 H), 7, 1 8 (d, 2H, J = 8.7 Hz), 6.93 (d, 4H, J = 8.7 Hz), 7.03 (d, 2H, J = 8.4 Hz), 6.78 (d, 2H, J = 8.7 Hz), 6.57 (d, 2H, J = 8, 7 Hz). MS m / z 392, 1 (+ H) +.

The following compounds were synthesized as described herein and are characterized and summarized in Table 1: A /, / V-bis (4-hydroxyphenyl) -4-propylbenzamide (II); 3-fluoro- / V- (4-fluorophenyl) -4-hydroxy- / V- (4-hydroxyphenyl) benzamide (IV); A /, A / -bis (4-hydroxyphenyl) -2,3-dimethylbenzamide (V); 3-fluoro-4-hydroxy-A /, A / -bis (4-hydroxyphenyl) -benzamide (VII); 3-fluoro-4-hydroxy-A / - (4-hydroxyphenyl) -N-phenylbenzamide (XI); and 3-fluoro- / V-bis (4-hydroxyphenyl) -2-methylbenzamide (XII).

General procedures of debenzylation of benzyloxyphenyl-benzamides. A benzyloxyphene lbenzamide compound was dissolved in EtOH in a hydrogenation receptacle of 250 μl. Pd / C powder (5 mol%) was added to the solution. The reaction vessel was placed in a hydrogenation apparatus at a hydrogen gas pressure below 20 psi. The reaction was monitored by TLC until the starting material disappeared. Then, the solvent was removed under reduced pressure. The residue was purified by flash column chromatography with hexanes / EtOAc = 3/2 v / v to provide the desired product.

The following compounds were synthesized as described herein and are characterized and summarized in Table 1: / V, / V-bis (4-hydroxyphenyl) -2-naphthylamide (VI).

General procedures for reducing unprotected benzamides. The benzamide compounds were dissolved in 20 μl of anhydrous THF at room temperature. H3-3 (SMe2) was added with a syringe at room temperature in argon. The reaction solution was stirred and heated to reflux for 6 hours. Then, the reaction was activated by the addition of 10 μL of MeOH at 0 ° C. The solvent was removed under reduced pressure. The residue was subjected to flash column chromatography (silica gel, ChhCh / MeOH = 9/1 v / v) to provide the desired product.

The following com ponents were synthesized as described hereinabove and are characterized and summarized in Table 1: 4,4 '- (2,3-dimethylbenzylazanodiyl) diphenol (III); 4 - ((4-fluorophenyl) (4-hydroxybenzyl) amino) phenol (VIII).

General synthesis of 0- (2-piperidin-1-methoxy) -benzamides and the like. K2C03 (3 equivalents) and / V-chloroethyl-piperidine hydrochloride salt (1.2 equivalents) were added to a hydroxyphenyl solution containing benzamide analogue (1 equivalent) in acetone. The solution was heated to reflux for 6 hours. The solution was evaporated to dryness. The residue was hydrolyzed by the addition of water and then extracted with ethyl acetate. The organic layers were separated and dried with anhydrous MgSO 4. The solvent was removed under reduced pressure. The residue was purified by flash column chromatography with methylene chloride / methanol = 9/1 v / v to provide the desired compound. The hydrochloride salts were prepared by the addition of HCl in Et20 to the methanol solution of the compounds followed by the evaporation of the solvents. The following compounds were synthesized as described hereinabove and are characterized and summarized in Table 1: 4-fluoro-A / - (4-hydroxyphenyl) - / N / - (4- (2- (piperidine- 1-yl) ethoxy) phenyl) -2- (trifluoromethyl) benzamide (IX) and 4-fluoro-A / - (4-hydroxyphenyl) - / N / - (4- (2- (piperidin-1-yl) hydrochloride ethoxy) phenyl) -2- (trifluoromethyl) benzamide (X) which is the HCl salt of IX.

TABLE 1 . Physical characterization of compounds of formulas l-XI I Comp.

Structure PHYSICAL CHARACTERIZATION n.

II X H N R (DMSO-dg, 300 MHz) 69.46 (s, 2H, 2 X OH), 7.27-7.26 (m, 2H, ArH), 7.06-7.04 (m, 2H, ArH), 6, 99-6, 97 (m, 4H, ArH ), 6.66-6.65 (m, 4H, ArH), 2.50 (s, 2H, CH2, overlapped with DMSO peak), 1.53-1.52 (m, 2H, CH2), 0 , 82DDt, J = 7.33 Hz, 3H, CH3). / z 346.0 (M-H) " III Toasted colored foam, 41% yield. P.f. 147-150 ° C. ¾ NMR (DMSO-de, 300 MHz) 58, 92 (s, 2H), 7.07 (d, J = 7.33 Hz, 1H), 7.00-6.94 (m, 2H), 6.76 -6, 72 (m, 4H), 6, 63-6, 59 (m, 4H), 4.72 (s, 2H), 2.23 (s, 3H), 2.16 (s, 3H). m / z 320.2 (M + H) + IV. Solid tan color, 92% yield. P.f. 110-112 ° C. ¾ NMR (DMSO-dg, 300 MHz) 510.14 (bs, 1H), 9.71 (bs, 1H), 7.26-7.11 (m, 5H), 7, 05-6, 99 (m , 3H), 6.78 (t, J = 8.61 Hz, 2H), 6.68 (d, J = 8.68 Hz, 2H). m / z 364.1 (M + Na) + V. ¾ NMR (DMSO-de, 300 MHz) 59.47 (bs, 2H, 2 X OH), 7, 18 (d, J = 8.30 Hz, 2H, ArH), 7.06 (d, J = 7.08 Hz, 1H, ArH), 7.00- 6.92 (m, 4H, ArH), 6.78 (d, J = 8.30 Hz, 2H, ArH), 6.51 (d, J = 8.06 Hz, 2H, ArH), 2.22 (s, 3H, CH3). m / z 334.3 (M + H) + SAW. White solid, 70% performance. P.f. 264.3-265.2 ° C (decomposed). XH NMR (DMSO-de, 500 MHz) d 9.46 2H), 7.98 (s, 1H), 7.85-7.75 (m, 2H), 7.75-7.73 (m, 2H), 7.54-7.48 (m, 2H), 7.45-7.43 (m, 1H), 7.05 (s, 4H), 6.66 (s, 4H). m / z 356 (M + H) + Example 2 Synthesis of the compound of formula IV (Figure 6) Stage 1: Synthesis of 4-fluoro-A / - (4-methoxyphenyl) aniline (1 c) 4-fluoroaniline (78.63 g, 0.708 mol), 4-iodoanisole (138.00 g, 0.590 mol), anhydrous K2C03 (122.23 g, 0.884 mol), Cul (1 1, 23 g, 58, 96 mmol) and L-proline (1 3.58 g, 0.1 mole) in a dry 1 L three-neck round bottom flask in which a stir bar, a reflux condenser and an inlet were placed. argon. D Anhydrous SO (300 ml_) was added at room temperature. The reaction mixture was stirred and heated at 90 ° C for 20 hours with argon. Then, the mixture was cooled to room temperature and hydrolyzed with water (300 ml_). EtOAc (200 ml_) was added to partition the solution. The EtOAc layer was separated. The aqueous layer was extracted with 100 ml of EtOAc. The EtOAc layers were combined, washed with brine (2x1.00 ML) and dried with anhydrous MgSO4 (50 g). The solvent was removed under reduced pressure. The brown oily residue was purified by flash column chromatography (silica gel, hexanes / EtOAc = 9/1 v / v) to give 4-fluoro-A / - (4-methoxyphenyl) aniline (1 c) as a solid product white, 99.70 g, 77.8% yield. P. f. 46-48 ° C. MS (ESI) m / z 218, 1 [M + H] +, 1 H NMR (DMSO-d 6, 300 MHz) d 7.77 (bs, 1 H), 7.03-6.98 (m, 4H ), 6.93-6.82 (m, 4H), 3.70 (s, 3H). 1c 2a Step 2: Synthesis of 3-fluoro-A / - (4-fluorophenyl) -4-methoxy-A / - (4-methoxyphenyl) benzamide (2a) 4-Fluoro- / V- (4-methoxyphenyl) aniline (1c) (90.78 g, 0.418 mol) and 3-fluoro-4-methoxybenzoyl chloride (94.55 g, 0.501 mol) were mixed and dissolved in Anhydrous THF (200 mL) was placed in a dry 1 L three-neck round bottom flask in which a stir bar, a reflux condenser and an argon inlet were placed. Anhydrous pyridine (132.22 g, 1.672 mol) was added at room temperature with a syringe and in argon. The reaction mixture was stirred and heated to reflux overnight. Then, the reaction mixture was cooled to room temperature and filtered to remove the pyridine salt. The solution was concentrated to remove the THF solvent. The residual oil was washed with 200 mL of 2N HCl solution and extracted with ethyl acetate (2 x 200 mL). The combined organic layer was washed with a saturated aqueous solution of Na 2 CO 3 (1 50 mL) to remove the excess acid and benzoyl chloride, dried in MgSO 4 (50 g), filtered and concentrated under reduced pressure to produce an oil. The residue was purified by flash column chromatography with ChhCh / acetone (50/1 v / v) to provide the corresponding pure benzamide compound as a yellow solid. P.f. 54-56 ° C. MS (ESI) m / z 370.1 [+ H] +, 1 H NMR (CDCIs / TMS) d 7.24-7, 1 1 (m, 4H), 7.05-6.97 (m, 4H), 6.85-6.78 (m, 3H), 3.86 (s, 3H), 3.79 (s, 3H).

Stage 3: Synthesis of 3-fluoro- / V- (4-fluorophenyl) -4-hydroxy- / / - (4-hydroxyphenyl) benzamide (IV) The compound 3-fluoro-A / - (4-fluorophenyl) -4-methoxy-W- (4-methoxyphenyl) benzamide (2a) (1 38.0 g, 0.374 mol) in dry CH2Cl2 (600 mL) was dissolved in room temperature in argon. BBr3 (374.75 g, 1, 496 mol) was added dropwise with stirring by syringe at 0 ° C in a bath with ice under argon. The reaction solution was allowed to stir at room temperature overnight. Then, it was poured into the solution in 1 L of ice water with stirring. The suspension mixture was stirred at room temperature for 2 hours. The white precipitate was filtered, washed with water (2 x 100 mL) and dried in vacuo. The CH 2 C I 2 layer was separated, dried with anhydrous MgSO (50 g), filtered and concentrated reduced pressure to dryness. The white precipitate and the residue of the CH2Cl2 solution were combined and purified by flash column chromatography (silica gel, CH2C12 / acetone / MeOH = 90/7/3 v / v / v) to obtain a solid of color pale roast which was recrystallized from a hot EtOAc / hexanes solution twice to obtain a white crystalline solid, 104.0 g, 81.6% yield. P.f. 1 1 0-1 12 ° C. MS (ESI) m / z 364, 1 [M + Na] +, 1 H NMR (DMSO-d6) d 10, 14 (bs, 1 H), 9.71 (bs, 1 H), 7.25- 7, 11 (m, 5H), 7.05-6.99 (m, 3H), 6.78 (t, J = 8.6 Hz, 1 H), 6.68 (d, J = 8, 7 Hz, 2H).

Example 3 Synthesis of the compound of formula VI (Figure 7) Synthesis of 4- (benzyloxy) - / V- (4-methoxyphenyl) aniline (1 d). 4-Benzyloxyaniline (16.6 g, 83.31 mmol), 4-iodoanisole (1 5.0 g, 64.09 mmol), K2CO3 (1.762 g, 1 28, 1 8 mmol) were mixed. (1.22 g, 6.41 mmol) and L-proline (1.48 g, 12.82 mmol) and dissolved in anhydrous DMSO (1 20 ml_) at room temperature. It was then stirred and the reaction mixture was heated at 90 ° C for 48 hours. The mixture was cooled to room temperature and hydrolyzed with water. EtOAc was added to divide the solution. The EtOAc layer was separated, washed with brine and dried with anhydrous MgSO 4. The solvent was removed under reduced pressure. The solid residue was purified by flash column chromatography (silica gel), EtOAc / hexanes (1/9 v / v) to give the corresponding diarylaniline as a solid product yellow, 9.8 g, 50% yield. P.f. 1 08.0-108.4 ° C. 1 H NMR (CDCIs, 300 MHz) d 7, 34-7.25 (m, 5H), 6.90-6.81 (m, 8H), 5.02 (s, 2H), 3.78 (s) , 3H). MS m / z 306 (M + H) +.

Synthesis of / V- (4-benzyloxyphenyl) -A / - (4-methoxyphenyl) -2-naphtamide (2d) An equivalent of 4- (benzyloxy) -A / - (4-methoxyphenyl) aniline (0.80 g, 2.62 mmol) was mixed with 1.5 equivalents of 2-naphthoyl chloride (0.75 g, 3, 93 mmol) and 4 equivalents of pyridine (0.83 g, 10.48 mmol) in a dry three-necked round bottom flask in which a magnetic stir bar and a reflux condenser were placed. The mixture was dissolved in anhydrous THF (30 ml_) and heated to reflux for 20 hours. The reaction mixture was cooled to room temperature and filtered. The solvent was removed under reduced pressure. The residue was purified by flash column chromatography with silica gel with EtOAc / hexanes (3/7 v / v) to give the corresponding pure naphthamide compound as a white solid, 0.70 g, 58% yield. P.f. 174.9-175, 5 ° C. 1 H NMR (CDC, 300 MHz) d 8.04 (s, 1 H), 7, 77-7.74 (m, 2H), 7.64-7.61 (m, 1 H), 7.51 -7.43 (m, 4H), 7.40-7.31 (m, 4H), 7, 1 3-7, 10 (m, 4H), 6.88-6.78 (m, 4H), 4.99 (s, 2H), 3, 74 (s, 3H). MS m / z 460 (M + H) +.

Synthesis of / V, / V-bis (4-hydroxyphenyl) -2-naphthylamide (VI) The compound / V- (4-benzyloxyphenyl) -A / - (4-methoxy-phenyl) -2-naphthamide (2d) (0.50 g, 1.09 mmol) was dissolved in dry CH2C I2 (30 mL) at room temperature. BBr3 (3.26 mL of a solution of 0.02 M H 2 Cl 2, 3.26 mmol) was dripped with agitation by syringe at room temperature. The reaction solution was allowed to stir overnight at room temperature. The mixture was cooled to 0 ° C in an ice bath and hydrolyzed by the addition of water. EtOAc was added to divide the solution. The organic layer was separated; the aqueous layer was extracted with EtOAC twice. The organic layers were combined, washed with brine and dried with anhydrous MgSO 4. The solvent was removed in vacuo. The residue was purified by flash column chromatography with silica gel with CH 3 OH / C H 2 C I 2 (1/9 v / v) to provide the desired pure phenolic compound as a white solid, 0.27 g, white solid, 70% of performance. P.f. 264.3-265.2 ° C (decomposed). 1 H NMR (DMSO-d 6, 500 MHz) d 9.46 (s, 2H), 7.98 (s, 1 H), 7.85-7.75 (m, 2H), 7.75-7, 73 (m, 2H), 7.54-7.48 (m, 2H), 7.45-7.43 (m, 1 H), 7.05 (s, 4H), 6.66 (s, 4H) ). MS m / z 356 (M + H) +.

Example 4 Synthesis of the compound of formula VI I I Synthesis of 4 - ((4-fluorophenyl) (4-hydroxybenzyl) amino) phenol (VI I I) The compound / V- (4-fluorophenyl) -4-hydroxy-A / - (hydroxyphenyl) benzamide (0.30 g, 0.93 mmol) was dissolved in 20 ml of anhydrous THF at room temperature. H3B (SMe2) (1.86 mL of 2M THF solution, 3.71 mmol) was added with a syringe at room temperature in argon. The reaction solution was stirred and heated to reflux for 6 hours. Then, the reaction was quenched by the addition of 10 mL of MeOH at 0 ° C. The solvent was removed under reduced pressure. The residue was subjected to flash column chromatography (silica gel, S? S /? T ?? = 9/1 v / v) to give a yellow oil, 0.26 g, 92% yield. 1 H NMR (DMSO-de, 500 MHz) d 9.29 (s, 1 H), 9.24 (s, 1 H), 7.09 (d, 2 H, J = 8.3 Hz), 6.98 (d , 2H, J = 9.0 Hz), 6.94-6.91 (m, 2H), 6.73 (d, 2H, J = 9.0 Hz), 6.68-6.64 (m, 4H), 4.70 (s, 2H). MS m / z 307.8 (M-H) \ Example 5 Synthesis of the compound of formulas IX and X (Figure 8) Synthesis of diarylanilines. Arylamine (1.5 equivalent), aryl iodide (1 equivalent), K2C03 (2 equivalents), Cul (0.1 equivalents) and L-proline (0.2 equivalents) were mixed and the mixture was dissolved in anhydrous DMSO. room temperature. The mixture was then stirred and the reaction mixture was heated at 90 ° C for 28 hours. The mixture was cooled to room temperature and hydrolyzed with water. EtOAc was added to divide the solution. The EtOAc layer was separated, washed with brine and dried with anhydrous MgSO 4. The solvent was removed under reduced pressure. The solid residue was purified by column chromatography ultrafast (silica gel) with EtOAc / hexanes (3/7 v / v) as solvent to obtain the corresponding diarylaniline. Bis- (4-methoxyphenyl) amine (1 a): pale yellow solid, 73% yield. 1 H NMR (CDC, 300 MHz) d 6.93-6.81 (m, 8H), 5.37 (s, br, 1 H), 3.78 (s, 6H). MS m / z 228.4 (M-H) +.

Synthesis of 4-fluoro-A /, A -bis (4-methoxyphenyl) -2- (trifluoromethyl) benzamide (2e) 1 equivalent of bis- (4-methoxyphenyl) amine (1 a) (0.73 g, 3.18 mmol) was mixed with 1.2 equivalents of 4-fluoro-2-trifluoromethylbenzoyl chloride (0.87 g, 3%). , 82 mmol) and 6 equivalents of pyridine (1.51 g, 19.08 mmol) in a dry three-necked round bottom flask in which a magnetic stir bar and a reflux condenser were placed. The mixture was dissolved in anhydrous THF (20 mL) and heated at 90 ° C for 20 hours. The reaction mixture was cooled to room temperature and filtered. The solvent was removed under reduced pressure. The residue was purified by flash column chromatography with silica gel with EtOAc / hexanes (3/7 v / v) to provide the corresponding pure benzamide compound as a colorless oil, 1.12 g, 84.2% yield. 1 H NMR (CDCl 3, 300 MHz) d 7.34-7.26 (m, 4H), 7.09-7.01 (m, 3H), 6.91 (d, 2H, J = 8.7 Hz ), 6.87 (d, 2H, J = 8.7 Hz), 3.80 (s, 3H), 3.71 (s, 3H). MS m / z 442, 1 (M + Na) +.

Synthesis of 4-fluoro-A /, A / -bis (4-hydroxyphenyl) -2- (trifluoromethyl) benzamide (3a) The compound 4-fluoro- /, A / -bis (4-methoxyphenyl) -2- (trifluoromethyl) benzamide (2e) (1.00 g, 2.38 mmol) in dry CH2Cl2 (30 mL) was dissolved in room temperature. BBr3 (10 mL of a 1.0 M CH2Cl2 solution, 10.0 mmol) was added dropwise with agitation by syringe at room temperature. The reaction solution was allowed to stir overnight at room temperature. The mixture was cooled to 0 ° C in an ice bath and hydrolyzed by the addition of water. EtOAc was added to divide the solution. The organic layer was separated; the aqueous layer was extracted with EtOAC twice. The organic layers were combined, washed with brine and dried with MgSC > 4 anhydrous. The solvent was removed in vacuo. The residue was purified by flash column chromatography with silica gel with CH3OH / CH2Cl2 (1/9 v / v) to provide the desired pure phenolic compound as a white solid, 0.86 g, 92.5% yield. 1 H NMR (DMSO-c, 300 MHz) d 9.55 (s, 1H), 9.53 (s, 1H), 7.69-7.8 (m, 2H), 7.46-7.39 ( m, 1H), 7.18 (d, 2H, J = 8.7 Hz), 6.93 (d, 4H, J = 8.7 Hz), 7.03 (d, 2H, J = 8.4 Hz ), 6.78 (d, 2H, J = 8.7 Hz), 6.57 (d, 2H, J = 8.7 Hz). MS m / z 392.1 (M + H) +.

Synthesis of 4-fluoro-A / - (4-hydroxyphenyl) - / \ / - [4- (2-piperidin-1 -i I) -ethoxy) f in i I] -2- (trifluoromethyl) benzamide (IX) K2CO3 (1.29 g, 9.36 mmol) and W-chloroethyl-piperidine hydrochloride salt (0.34 g, 1.87 mmol) were added to a solution of 4-fluoro- / V, / V-bis. (4-hydroxyphenyl) -2- (trifluoromethyl) benzamide (3a) (0.6 g, 1. 56 mmol) in acetone. The solution was heated to reflux for 20 hours. The solution was evaporated to dryness. The residue was purified by flash chromatography (silica gel; methylene chloride / methanol = 9/1 v / v) to give the desired compound as a white solid, 0.45 g, 57.7% yield. 1 H NMR (DMSO-de, 300 MHz) d 9.57 (s, 1H), 7.71-7.68 (m, 2H), 7.47-7.44 (m, 1H), 7.28 ( d, 1H, J = 9.0 Hz), 7.18 (d, 1H, J = 8.7 Hz), 7.13 (d, 1H, J = 8.7 Hz), 7.05 (d, 1H, J = 8.4 Hz), 6.97 (d, 1H, J = 9.0 Hz), 6.80-6.76 (m, 2H), 6. 57 (d, 1H, J = 87, Hz), 4.06 (t, 1H, J = 6.0 Hz), 3.93 (t, 1H, J = 6.0 Hz), 2.66 (t , 1H, J = 5.7 Hz), 2.55 (t, 1H, J = 5.4 Hz), 2.44 (s, 2H), 2.36 (s, 2H), 1.49-1.37 (m, 6H). MS m / z 501.0 M-H) -.

The hydrochloride salt (X) was prepared by the addition of HCl in Et 2 O to the methanol solution of the compounds followed by the evaporation of the solvents.

Example 6 Agonist and antagonist activity, binding affinity to estrogen receptors The binding affinity of ER to the compounds was determined by a competitive in vitro binding assay with radioligands with [2,4,6,7-3H (N)] - estradiol Q3H] E2), an ER ligand with affinity naturally elevated, and the GST protein expressed in bacteria from ligand-binding domain (LBD) ER-a or ER-β fusion.

Method Recombinant ER-a or ER-β was combined with [3H] E2 to determine the equilibrium dissociation constant (??) for [3H] E2. The protein was incubated with increasing concentrations of [3H] E2 with and without a high concentration of unlabelled E2 at 4 ° C for 18 h to determine the total and non-specific binding. The non-specific binding was subtracted and the Kd of E2 was determined (ERa: 0.71 nM; ER: 1.13 nM) by non-linear regression. In addition, it was determined that the concentration of [3H] E2 needed to saturate LBD of ER-a and ER-β was 4-6 nM.

Increasing concentrations of the compounds (range: 10 1 to 106 M) were incubated with [3 H] E2 (5.7 nM) and LBD of ER under the conditions described above. After incubation, the plates were cultivated with GF / B filters in the Unifilter-96 harvester (PerkinElmer) and washed three times with ice-cold B buffer (50 mM Tris, pH 7.2). The filter plates were dried at room temperature, then 35 μ Microscint-O cocktail was added. to each cavity and the filtration plates were sealed with TopSeal-A. Radioactivity was measured with a TopCount® NXT microplate scintillation counter using the 3 H configuration in the Microscint cocktail (PerkinElmer).

The specific binding of [3 H] E2 to each concentration of the compounds was determined by subtracting the non-specific binding of [3 H] E2 (determined by incubation with unlabeled 10 ~ 6 M E2) and expressing it as a percentage of specific binding in the absence of the test compound. The concentration of the compounds that reduced the specific binding of [3H] E2 by 50% (IC50) was determined. Then, the equilibrium binding constant (K) of the compounds was calculated by: ¡= dx I Cso / (d + L), where d is the equilibrium dissociation constant of [3H] E2 (ER-a = 0.71 nM, ER-ß = 1, 1 3 nM) and L is the concentration of [3H] E2 (ER-a: 5.7 nM; ER-β: 5.7 nM).

Results Binding assays revealed that the ligands bind to ER-a and ER-β at various concentrations ranging from 3.75 nM to more than 1000 nM, and that it varies selectively between the compound selecting isoforms and not select The results of representative compounds are listed in Table 2.

?? Compound IV binds ERa and ER with nanomolar affinity. The binding affinity of ER of Compound IV was determined by a competitive in vitro binding assay to radioligands with [2,4,6,7-3H (N)] - estradiol ([3H] E2), an ER ligand with naturally high affinity, and GST protein expressed in ligand-binding domain (LBD) bacteria from ER-a or ER-β fusion. In this assay, the binding affinities of ERa and ER (K i values) of Compound IV were 21.7 ± 1.7 nM (n = 3) and 15.2 ± 4.1 nM (n = 3), respectively. By joining ER, Compound IV initiates a complex series of molecular events that lead to the expression or repression of target genes involved in the pharmacological response in a selective form of tissue. In transient transfection assays, Compound IV is an ERa and ER agonist with high potency demonstrated to stimulate ERa-mediated transcriptional activation compared to that mediated by ERp. While estradiol activates ERa and ERβ with a selectivity 5.1 times greater than the selectivity for ERa, Compound IV shows 49.0 times the selectivity for ERa. Therefore, Compound IV has a selectivity 9.7 times greater than the transactivation potency (normalized for estradiol values) for ERa compared to ERp. In addition, no antagonistic effects were observed in transcriptional activation stimulated with estradiol (1 nM) by Compound IV in concentrations up to 10 μ. Although many steroidal ligands cross-react with other nuclear hormone receptors, the actions of Compound IV are specific for ERa and ER. Compound IV was analyzed for cross-reactivity against rat isoforms of the glucocorticoid receptor (GR), mineralocorticoid receptor (MR), progesterone receptor (PR), androgen receptor (AR) and human isoforms of the farnesoid X receptor (FXR ), hepatic X receptor (LXR), receptors activated by the proliferation of peroxisomes (PPAR-ct and PPAR-?) and retinoid X receptor (RXR-a) in both agonist and antagonist mode of transcriptional activation assays. Compound IV did not exhibit agonist or antagonist activity in any of these assays, which supports the conclusion that Compound IV does not functionally cross-react with these members of the nuclear hormone receptor superfamily.

Example 7 Transactivation of selected compounds Transactivation assays were performed in agonist and antagonist mode to identify whether the compound is agonist, antagonist or partial.

Method The estrogen receptors of rats (ER-a and ER-ß) were cloned from rat ovarian cDNA in a plasmid vector backbone pCR3.1. Sequencing was performed to determine the absence of any mutation. The HEK-293 cells were plated at 1,00,000 cells per well in a 24-well plate in Dulbecco's Minimum Essential Medium (DMEM) + fetal bovine serum treated with charcoal (csFBS) at 5%. The cells were transfected with Lipofectamine (Invitrogen, Carlsbad, CA) with 0.25 pg of ERE-LUC, 0.02 pg of CMV-LUC (renilla luciferase) and 1 2.5 ng of rat ER-a or ng of rat ER-ß. The cells were treated 24 h after transfection with ^ various concentrations of compounds or a combination of compounds and estradiol to determine the antagonist activity. Luciferase assays were performed 48 hours after transfection.

Results The analysis of the compounds of this invention in the transactivation system revealed that the compounds belonged to the three classes, that is, they were agonists, antagonists and partial agonists. An example of agonist and antagonist is set forth in Table 3. The transactivation results were very consistent with the isoform selectivity binding results.

Table 3 shows the EC50 and I C50 transactivation values for some selected compounds of the present invention.

Table 3. Transactivation (both agonist and antagonist) selected compounds of the present invention Example 8 Testosterone suppression in Cynomolgus monkeys During the study, two-year-old Cynomolgus monkeys with intact gonads (n = 2) lived according to the USDA guidelines with free access to primate and water diet (except for fasts prior to the administration of oral doses). The animals were given an oral daily forced-feed dose of 30 mg / kg of the compound of formula IV in a Tween 80 microemulsion vehicle / deionized water for 7 consecutive days. They were obtained serum samples by venipuncture before oral dose administration on days 1 (reference), 3, 4, 5, 6 and 7. Total androgens and testosterone were quantified by an enzyme immunoassay (EIA) method combined with HPLC method or no, respectively. After 6 days of treatment with the compound of formula IV, reductions in testosterone and total androgens (testosterone / dihydrotestosterone) were evident depending on the dose. The compound of formula IV reduced testosterone levels by 58% and 64% in animal number 1 and animal number 3, respectively, with respect to reference values (see solid lines in Figure 1, Table 4). Similarly, total androgen levels were reduced by 56% in both animals, numbers 1 and 3 (see dotted lines in Figure 1, Table 4), compared to reference values.

These results, consistent with the estrogen response of the pituitary-gonadal axis in males, demonstrate a strong pharmaceutical response to the elimination of serum hormones (testosterone and total androgens) in intact nonhuman primates (Cynomolgus monkeys) after repeated oral doses ( 30 mg / kg) of the compound of formula IV.

Table 4. Serum levels of testosterone and total androgens in intact male monkeys with daily oral administration of 30 mg / kg compound of formula IV (first dose on day 0) Example 9 Elimination of levels of LH and testosterone hormone in rats An in vivo dose response study was carried out to evaluate the effect of Compound IV on the elimination of LH in intact or orchiectomized male rats (ORX). In both intact animals and ORX, Compound IV significantly reduced LH levels with doses = 10 mg / kg per day compared to controls respective. (The same pattern of elimination was observed in FSH levels.) The elimination of LH resulted in very low testosterone levels below the limit of quantification (BLOQ), of 0.08 ng / mL, and decreased prostate weight. , seminal vesicles and levator ani muscle since these are very androgen dependent organs. In intact animals, the dose-dependent reductions in the weights of these target organs were observed and the weights of the seminal vesicles and the levator ani muscle decreased to the level of castrated controls. Although the prostate weights were significantly reduced in intact animals, these values did not reach the level of castrated controls. The results are summarized in Table 6, below.

Materials and methods: Male Sprague-Dawley rats of approximately 200 g of weight in a cycle of 12 h light / dark with food (diet for rodents 2016 Teklad Global with 16% protein, Harán, Madison, Wl) and water available ad libitum. The animal protocol was evaluated and approved by the Animal Use and Care Committee of the University of Tennessee.

The test article of the present assay was weighed and diluted in 10% DIVISO (Fisher), and diluted with PEG 300 (Acros Organics, NJ) to prepare the appropriate dose formulations. For this study, 60 (sixty) male Sprague-Dawley rats were randomized according to their body weight and assigned to one of twelve treatment groups (n = 5 animals / group). In the Table 5 lists the treatment groups. The animals were placed in groups of 2 or 3 animals per cage. Vehicle was administered daily to control groups (intact and orchiectomized (ORX)) and Compound IV by injection (200 μ? _) At doses of 0.3, 1, 3, 10 and 30 mg / kg / day both at intact groups like ORX.

After a 14-day dosing regimen, the animals were sacrificed with anesthesia (Ketamine / Xylacinam 87:13 mg / kg) and body weights were recorded. In addition, the ventral prostate, the seminal vesicles and the levator ani muscle were excised, external tissue removed and weighed individually. The weight of the organs was normalized with the body weight and expressed as an intact control percentage. Blood was taken from the abdominal aorta under anesthesia with isoflurane and allowed to clot. Serum was prepared by centrifugation and stored at -80 ° C prior to the determination of serum hormone levels. The concentrations of luteinizing hormone (LH) and follicle stimulating hormone (FSH) were determined by Luminex rat pituitary assay (Millipore, Billerica, MA) according to the manufacturer's instructions. The lower limit of quantification for this assay was 3.2 pg / mL for LH and 32 pg / mL for FSH. Testosterone was determined by Testosterone EIA (Alpco Diagnostics, Salem, NH) with a LLOQ of 0.08 ng / mL. Serum hormone values that were found below the limit of quantification (BLOQ) were omitted from the analysis of the group averages. Therefore, the reported value of LH and T in the groups with BLOC samples is higher than the actual value. This method of The trial provided the most conservative estimate of elimination of LH and T. The Fisher's test of least significant difference was used to compare the individual dose groups with the intact vehicle control groups and ORX. The significance was previously defined as value P < 0.05.

Table 5. Treatment groups.

Levels of luteinizing hormone in intact rats and ORX (Table 6) The LH levels (mean ± SD) in intact vehicle control groups and ORX were 1.46 ± 0.64 and 1.1 ± 3.9 ng / mL, respectively. Compound IV reduced LH levels in a dose-dependent manner in intact animals and achieved statistically significant reductions with daily doses = 3 mg / kg. LH levels in intact animals treated with Compound IV were 0, 863 ± 0.384, 0.704 ± 0.530, 0.395 ± 0.302, 0.226 ± 0.165 and 0.236 ± 0.76 ng / mL, after doses of 0.3, 1, 3, 1 0 and 30 mg / kg / day, respectively. LH levels in male ORX rats also decreased significantly with the treatment with Compound IV. The LH levels in ORX animals were 1 5,4 ± 2,9, 13,5 ± 2,2, 6,5 ± 5,6, 0,425 ± 0, 1 35 and 0,368 ± 0, 1 1 9 ng / mL, after doses of 0, 3, 1, 3, 10 and 30 mg / kg / day, respectively. The results are presented in graphic form in Figure 1 0A.

In intact and orchiectomized rats, doses of 10 mg / kg / day of Compound IV significantly reduced luteinizing hormone (LH) levels, resulting in levels in endogenous testosterone castration serum.

Levels of follicle-stimulating hormone in intact rats and ORX (Table 6) Serum FSH levels in intact vehicle control groups and ORX were 20.9 ± 8.5 and 93.5 ± 1.8 ng / mL, respectively. In intact animals, Compound IV reduced in form dose dependent FSH levels and significant reductions were observed with dose = 10 mg / kg / day. The levels of FSH in intact animals treated with Compound IV were 1 7.3 ± 6.4, 1 5.7 ± 7.3, 18.4 ± 7.7, 9.2 ± 4.0 and 6.3 ± 1.8 ng / mL, after doses of 0, 3, 1, 3, 10 and 30 mg / kg / day, respectively. The LH levels in ORX animals were 1 15 ± 17, 1 14 ± 22, 65.2 ± 31, 9, 27.6 ± 8.2 and 1 5, 1 ± 4, 1 ng / mL, after doses of 0.3, 1, 3, 1 0 and 30 mg / kg / day, respectively. The results are presented in graphic form in Figure 1B.

Testosterone levels in intact rats and ORX Serum testosterone levels in intact vehicle control groups were 2.4 ± 1.1 ng / mL. The lower limit of quantification for T was 0.08 ng / mL. The values below 0, 08 ng / mL are called below the limit of quantification (BLOQ). In intact animals, Compound IV reduced T-levels in a dose-dependent manner and significant reductions were observed with doses = 3 mg / kg per day. Testosterone levels in intact animals treated with compound of formula IV were 2.6 ± 1.7, 1.6 ± 1.0, 0.7 ± 0.4, BLOC and BLOC ng / mL, after doses of 0.3, 1, 3, 10 and 30 mg / kg per day, respectively. In ORX animals, T levels were found BLOC for all groups treated with compound IV and for the group treated with vehicle. The results corresponding to the intact animals are presented graphically in Figure 10C (and Figure 2) (the BLOQ values are represented in the limit of quantification for illustrative purposes).

The rapid and potent elimination of serum testosterone in intact male rats was measured with the administration of Compound IV at doses of 3 mg / kg, 10 mg / kg and 300 mg / kg after 24 h, 72 h and 168 h, such as It is presented in Figure 9.

Weight of organs (Table 6) The weights of the prostate, the seminal vesicles and the levator ani muscle were determined to confirm the elimination of T and the data (mean ± SD) are presented in Figures 10D, 10E and 10F, respectively. In intact animals treated with Compound IV, decreases in the weight of the prostate, the seminal vesicles and the levator ani muscle were observed. The weights of the prostate in intact animals were 84.0 ± 19.2, 75.2 ± 20.7, 68.2 ± 8.1, 45.1 ± 20.0 and 43.6 ± 8.8, after doses of 0.3, 1, 3, 10 and 30 mg / kg / day, respectively. The prostate weights in ORX animals were 19.0 ± 4.2, 17.4 ± 3.4, 19.6 ± 6.7, 22.9 ± 5.4 and 20.6 ± 2.1, after doses of 0.3, 1, 3, 10 and 30 mg / kg / day, respectively. The weights of the seminal vesicles in intact animals were 76.2 ± 7.8, 66.3 ± 27.2, 51.8 ± 28.5, 19.1 ± 7.0 and 17.9 ± 3.3 , after doses of 0.3, 1, 3, 10 and 30 mg / kg / day, respectively. The weights of seminal vesicles in ORX animals were 12.2 ± 1.3, 16.6 ± 5.4, 16.5 ± 4.8, 13.3 ± 1.9 and 12.9 ± 2.1, after doses of 0.3, 1, 3, 10 and 30 mg / kg / day, respectively. The weights of the levator ani muscles in intact animals were 86.9 ± 10.0, 82.1 ± 12.1, 65.2 ± 4.4, 57.8 ± 11.2 and 58.1 ± 4 , 7, after doses of 0.3, 1, 3, 10 and 30 mg / kg / day, respectively. The weights of the levator ani muscles in ORX animals were 54.5 ± 6.6, 49.6 ± 7.0, 53.6 ± 10.0, 51.1 ± 4.9 and 49.2 ± 4 , 2, after doses of 0.3, 1, 3, 10 and 30 mg / kg / day, respectively.

The data on elimination of LH and organ weight are summarized in Table 6.

Table 6. In vivo effect of the compound of formula IV on the weight of organs and hormones in serum.

. P < 0.05, vehicle intact. D. P < 0.05, vehicle in ORX.

In intact and orchiectomized rats, doses of 10 mg / kg / day of Compound IV significantly reduced luteinizing hormone (LH) levels, which resulted in levels in endogenous testosterone castration serum.

Compound IV did not increase the proliferation of cancerous epithelial cells of the prostate in vitro. Compound IV offers, mechanically, several key advantages over existing therapies such as gonadotropin-releasing hormone (GnRH) agonists and G nRH antagonists. Compound IV is specific for the estrogen receptor and is bioavailable orally in rats, dogs, monkeys and humans. Unlike GnRH agonists and Gn RH antagonists, which cause hot flushes, significant bone loss and increased risk of fractures, Compound IV attenuates morphine abstinence-induced flushing in rats and maintains trabecular bone mass. in complete form and mineral bone density in the distal femur of rats even in doses that suppress LH and serum testosterone to the maximum.

Example 10 Recovery of testosterone levels after the elimination of Compound IV in rats and monkeys The reversibility of chemical castration with Compound IV was studied.

Materials and methods: 35 (thirty five) male Sprague rats were kept Dawley of approximately 200 g of weight in a cycle of 12 h light / dark with food (diet for rodents 2016 Tekiad Global with 16% protein, Harán, Madison, Wl) and water available ad libitum. The animal protocol was evaluated and approved by the Animal Use and Care Committee of the University of Tennessee.

The test article of the present assay was weighed and diluted in PEG 300 (1 00%) (Acros Organics, NJ) to prepare the appropriate dose formulations. The animals were randomly assigned to one of the ten treatment groups (n = 5 animals / group). Table 7 lists the treatment groups. The animals were placed in groups of 2 or 3 animals per cage. Group 1 was sacrificed at the beginning of the study (Day 1) to determine the reference levels of testosterone in intact animals. Groups 2-7 received daily doses of 1, 3 or 30 mg / kg for oral forced feeding (~ 200 uL) for 3 days. Groups 2, 3 and 4 were sacrificed on day 4 to measure the maximum suppression of testosterone. Groups 5, 6 and 7 were allowed to recover for 14 days with a period of drug-free elimination.

Table 7. Treatment groups.

Results: The serum testosterone levels of intact rats were 6.4 ± 3.1 ng / mL (mean ± S.D) in the reference. Administration for 3 days of Compound IV at doses of 3 and 30 g / kg reduced serum testosterone levels significantly at 1.47 ± 0.26 and 1.62 ± 0.49 ng / mL, respectively. No significant elimination was observed in animals that received 1 mg / kg of Compound IV for 3 days. It is important that the serum testosterone levels were 3.3 ± 1, 92, 3.00 ± 1, 06 and 3.8 ± 1.72 in the animals that received 1, 3 or 30 mg / kg, respectively, of Compound IV for three days when measured after the recovery period of 14 days and there were no statistically significant differences with respect to testosterone concentrations in reference serum in intact rats, as illustrated in Figure 23.

This study confirms previous results that show that Compound IV rapidly eliminates serum testosterone levels in intact male rats. The reduction of serum testosterone levels was observed in dosage groups that received = 3 mg / kg / day for 3 days. No significant reduction in serum testosterone was observed in the dose group of 1 mg / kg. However, after 14 days of recovery, serum testosterone levels returned to the level of intact controls. This study shows that pharmacological castration by Compound IV is reversible in rats.

The effect of Compound IV on the reduction and recovery of testosterone levels in intact male monkeys was assessed in conjunction with an oral pharmacokinetic study. 30 mg / kg of Compound IV per day were administered to 3 male Cynomolgus monkeys without previous treatment (2 to 3 years) by forced feeding for 7 consecutive days. Blood samples were taken and divided into serum and plasma for quantitative measurements of testosterone and Compound IV, respectively. The results show that the daily oral doses of Compound IV significantly decreased the levels of circulating androgens (mainly testosterone and dihydrotestosterone) in the three monkeys by up to 47% compared to the reference levels (levels of 1 591 ± 72, 5, 997 ± 1 04 and 852 ± 1 36 ng / mL, respectively for reference, Day 2 and Day 6 of treatment [mean ± SEM]). After a recovery period of 18 days without drugs, androgen levels returned to normal and did not differ significantly from pre-treatment reference levels (1757.7 ± 369.5 ng / mL after recovery). ).

Example 1 1 Bone preservation despite the reduction of LH and testosterone in rats (Table 8) The effect of the compound of formula IV of the treatment on bones was studied. Oral administration of the compound of formula IV totally prevented the loss of bone mass associated with the elimination of LH in intact male rats. A significant reduction of LH was induced in intact animals with the compound of formula IV in doses = 10 mg / kg per day. Although the compound of formula IV did not significantly reduce LH at a dose of 1 mg / kg per day, significant reductions in the prostate, seminal vesicles and the levator ani muscle were evident at this dose, indicating that the reduction in Testosterone in circulation was physiologically important for these organs that respond to androgens. However, 1 mg / kg per day of the compound of formula IV maintained the trabecular bone volume (measured in the distal femur) at the level of intact controls. When administered in doses of 10 and 30 mg / kg per day, the compound of formula IV increased the bone volume of the femur distal significantly above the volume of intact controls. These data show that compound IV increased trabecular bone mineral density (BMD) and percentage bone volume at a dose level that reduces LH levels in intact rats. The results of this study are presented in Table 8.

Table 8. In vivo effects of Compound IV on serum hormone parameters, organ and bone weight of rats. to P < 0.05 against intact vehicle. D P < 0.05, against vehicle in ORX.

Example 12 Effects on the enzymatic activity of hydroxysteroid dehydrogenase 5 17ß (17-HSD5) Members of the HSD family participate in the conversion of circulating steroids. 17-HSD5 converts androstenedione to testosterone and estrone to estradiol. In addition, it participates in the synthesis of prostaglandin. This demonstrated the ability of some compounds of the present invention to inhibit the activity of 1 7P-HSD5.

Method Human 1 7P-HSD5 was cloned into the pG EX 4t1 vector and purified protein was prepared. The purified protein was incubated with the representative compound of the present invention, androstenedione 1 4C and NADPH in a suitable buffering solution. The testosterone synthesized with ethyl acetate was extracted, air dried, spotted and run on a thin layer chromatography (TLC) plate. TLC was exposed to Phosphorimager and the intensity of the testosterone band was quantified. Indometycin was used as a positive control (LH RH agonist).

Results Compound IV was evaluated and had a partial inhibitory effect on the enzymatic activity of 1 73-HSD5. As expected, the positive control (LH RH agonist) exhibited strong inhibition of this enzyme, as presented in Figure 3.

Example 13 Toxicity studies A study was carried out to compare the thrombotic potential of Com position IV and of diethylethylbestrol (DES, positive control) by the human platelet aggregation assay in vitro. HE used blood from healthy male donors in the study since the target treatment population is male for Compound IV (elimination of LH). Platelet-rich plasma was previously incubated with estradiol (E2), DES, Compound IV or vehicle for 30 seconds and then thrombin (0.3 units) was added to induce platelet aggregation. The results of the study show that prior incubation with DES increased platelet aggregation induced by thrombin approximately 1 0 times. However, Compound IV and estradiol decreased the aggregation in the platelet-rich plasma. These data show that Compound IV has reduced the reactivity of human platelets in vitro in comparison with DES and suggests that Compound IV may have lower tromboembolic potential than DES (Figure 4).

Example 14 Effect of Compound IV on hot flashes A study was conducted to investigate the effect of Compound IV on hot flushes with the morphine-dependent rat model (model M D) developed by Simpkins et al. (1 983) and it was shown that it presents a series of simulations with the hot flashes of menopause. In addition to simulations of the human condition, this experimental animal model has a return time that makes it a high performance analysis tool to identify compounds that can alleviate vasomotor symptoms through the temperature of the tail skin (TST). The TA-40 probes from TST (Data Sciences I nternational, N) were fixed to the base of the tails and reference temperature measurements were obtained for 1 5 minutes. After 15 minutes, the animals were treated with naloxone (1 mg / kg, SQ) to reverse the effects of morphine. The skin temperature of the tail (TST) was measured for one hour after treatment with naloxone with a sampling frequency of 5 seconds during the course of the experiment. Once the data were acquired, the average of the temperature variation recorded every 60 seconds for each animal was calculated and analyzed further. The reference temperature was recorded as the average temperature acquired during the 1 5 minutes prior to the administration of naloxone. The area under the curve (AUC) was calculated by subtracting all values subsequent to naloxone administration to the reference using a linear trapezoidal method.

Compound IV attenuated hot flashes in the morphine abstinence model (see Figure 13) with better results with 10 mg of Compound IV. 1 7ß E2 5 mg / kg in 100% DMSO was used.

Example 15 Compound IV against DES in rats Before LH RH agonists were introduced, castration testosterone levels were achieved by increasing the estrogen activity in the pituitary by estrogen, mainly diethylstilbestrol (DES). DES was equally effective than LHRH agonists to bring testosterone to castration levels. Patients treated with DES did not present hot flushes or bone loss, but had higher rates of gynecomastia than with ADT with LHRH agonists. Unfortunately, it is usual for pure and very potent estrogens such as DES and estradiol to be associated with an elevated risk of serious cardiovascular and thromboembolic complications, which limits their clinical use. It has been hypothesized, although it has not been demonstrated, that the increased risk of venous thromboembolic complications with DES is due to its cross-reactivity with other hormone receptors. In vitro studies with human platelets showed that Compound IV had a much lower procoagulant activity than DES. Therefore, Compound IV, a selective ER-alpha agonist, can present the benefits of DES for prostate cancer, as well as present the benefits of an LHRH agonist without causing osteoporosis or adverse lipid profiles.

Compound IV is as effective as DES in reducing prostate size in ORX rats and rats exhibiting a moderate increase in prostate size (Figures 11A-B).

In Figures 12A-12C the differences between DES and Compound IV, where DES cross-reacted with the glucocorticoid receptor (GR) (Figure 1 2A) and the androgen receptor (AR) (Figure 12B), while Compound IV did not. In addition, DES antagonized estrogen-related receptor transactivation (ERR), whereas Compound IV did not did. Compound IV did not cross-react with any of the three ERR isoforms (ERR-a, ERR-β and ERR-α), as illustrated in Figure 1 2C.

Example 16 Toxicity study in monkeys - 90 days Cynomolgus macaques reared in colonies in Mauritius were obtained. The eventual study was designed as a 39-week evaluation of the pharmacology and toxicology of Compound IV and the positive control (LHRH agonist) in male Cynomolgus monkeys over a period of 13 weeks. A total of 39 sexually mature male monkeys aged 5 to 8 years were randomly assigned to five groups before the start of treatment. The groups included: 1) vehicle control, 2) Compound IV 1 mg / kg, 3) Compound IV 10 mg / kg, 4) Compound IV 100 mg / kg and 5) positive control (LHRH agonist). The drug was administered orally through the side of the cage once a day for 39 weeks with vehicle control (Tween 80 / PRANG ™) for Groups 1 and 5, or Compound IV in vehicle for Groups 2, 3 and 4. The dose levels of Compound IV were 1, 1 0 and 1 00 mg / kg / day for Groups 2, 3 and 4, respectively. The oral doses were administered in a dose volume of 10 mL / kg calculated on the basis of the most recent body weight for each animal (Figure 14). In addition, animals in Group 5 received a daily subcutaneous injection of positive control (LHRH agonist) (constant volume of 0.02 mL) during the 39 weeks corresponding to the period of the study. The general appearance and clinical signs were observed and recorded daily. Routine evaluations and other studies were carried out as indicated in the test protocol. Selected parameters include, but are not limited to, testosterone, prostate-specific antigen (PSA), and prosthetic weight and volume.

Testosterone and total PSA levels were quantified in serum samples (after the standard procedure) through an enzyme immunoassay (EIA) and a chemiluminescence immunoassay (LIA, ALPCO Diagnostics, Salem NH), respectively. Blood samples were obtained from all the animals (fasting) to evaluate the testosterone at the reference point (ie, before starting the treatment) and on days 1, 3, 7, 14, 28, 64 and 90. collected blood samples from all animals (fasting) for PSA determinations at the reference point and during week 6. For the purpose of discussion, the results for samples with concentrations below the limit of quantification (BLQ) for assays of testosterone and PSA are calculated as ½ of the lower limit of quantification (LLOQ) of the assay and are considered "estimated final concentrations". The data in Tables 9 to 16 are presented as "only quantifiable concentrations" (ie, excludes BLQ values) in addition to the "estimated final concentrations" (ie, samples with BLQ results included as ½ LLOQ of the assay). The prosthetic volume in live animals was measured under the anesthesia effect by transrectal ultrasound procedure (TRUS) at the reference point and at week 6. The width and height of the prostate were recorded. The prosthetic volumes were calculated as anchoxanchoxalturax pi / 6 and normalized for body weight. The wet weight of the prostate was recorded at necropsy after removing fat and foreign tissues.

Results and Discussion: Serum testosterone levels are presented in Figure 15 and in Tables 9 to 12. At the benchmark, testosterone levels for all monkeys participating in the study were found in the normal range for sexually mature adult male Cynomolgus monkeys . However, testosterone levels were significantly reduced in monkeys receiving 1 00 mg / kg / day of Compound IV and in monkeys treated with positive control (LH RH agonist). Testosterone levels in the positive control group (LHRH agonist) illustrated a biphasic change with a significant initial increase (ie, exacerbated growth) of 47.4% and 547% (p <0.01) on days 1 and 3, respectively, followed by reductions of 3.6%, 67%, 73%, 83% and 85% on days 7, 14, 28, 64 and 90 (see Figure 15 and Tables 9 to 12). No similar explosive growth was observed in any of the animals treated with Compound IV, even at the highest dose levels (ie, 100 mg / kg / day). The dose and duration of treatment were important for the pharmacological action of Compound IV. Dosage of 100 mg / kg / day reduced serum testosterone by 60%, 51%, 42%, 79% and 92% on days 3, 7, 14, 28 and 64, respectively, relative to the reference value (see Figure 15). and Tables 9 and 1 0). After 90 days of treatment with 100 mg / kg / day of Compound IV, the testosterone level of 6 of 10 monkeys in Group 4 was reduced to concentrations below the assay quantification limit (see Table 11). The average serum testosterone level of monkeys in Group 4 was reduced by 96% compared to the respective reference levels (Estimated final concentrations, ie, testosterone levels for 6/10 monkeys with BOQ values are calculated as 50% of the LLOQ concentration, see Table 10). It is important to note that by day 90 Compound IV at 100 mg / kg / day reduced serum testosterone to levels significantly lower than those of the positive control (LHRH agonist) (p = 0.013).

Table 9. Average serum testosterone levels (ng / mL) in intact male monkeys after daily oral administration of Compound IV; © Estimated final concentrations Testosterone assay: LLOQ = 0.246 ng / mL; @The BLOC values are calculate as 0.123 ng / mL, half of LLOQ.

*: Statistically significant (p <0.05), Compound IV 100 mg / kg against vehicle control #: Statistically significant (p <0.05), positive control (LHRH agonist) against vehicle control $: Statistically significant (p <0.05), positive control (LHRH agonist) against Compound IV 100 mg / kg Table 10. Percentage change (%) of average serum testosterone levels compared to baseline; @ Estimated final concentrations.

Testosterone assay: LLOQ = 0.246 ng / mL; @ BLQ values are calculated as 0.123 ng / mL, half of LLOQ.

Table 11. Average serum testosterone levels (ng / mL) in intact male monkeys after the administration of Compound IV; only quantifiable concentrations.

Testosterone assay: LLOQ = 0.246 ng / mL; BLQ values are excluded.

Table 12. Percent change (%) of average serum testosterone levels compared to baseline; Only quantifiable concentrations.

Testosterone assay: LLOQ = 0.246 ng / mL; BLQ values are excluded.

PSA levels were also significantly reduced by Compound IV in four weeks from the start of treatment. PSA reductions of 69% and 87% (average) were observed for monkeys receiving Compound IV at 10 mg / kg and 100 mg / kg for 4 weeks, while PSA levels were reduced by 60% in the group of positive control (LHRH agonist) (Figure 16 and Tables 13-16).

Table 13. Average serum PSA levels (ng / mL) in intact male monkeys after daily oral administration of Compound IV; © Estimated final concentrations PSA assay: LLOQ = 0.0575 ng / mL; @ BLQ values are calculated as 0.02875 ng / mL, half of LLOQ.

*: Statistically significant (p <0.05), Compound IV 10 mg / kg against vehicle control & amp; Statistically significant (p <0.05), Compound IV 100 mg / kg against vehicle control #: Statistically significant (p <0.05), positive control (LHRH agonist) against vehicle control $: Statistically significant (p <0.05), positive control (LHRH agonist) against Compound IV 100 mg / kg Table 14. Percentage change (%) of the average PSA levels compared to the reference; © Estimated final concentrations.

PSA assay: LLOQ = 0.0575 ng / mL; @ BLQ values are calculated as 0.02875 ng / mL, half of LLOQ.

Table 15. Mean serum PSA levels (ng / mL) in intact male monkeys after administration of Compound IV; ? Only quantifiable concentrations.

PSA assay: LLUU = 0.0575 ng / mL; The bLU values are not included in this table.

Table 16. Percentage of change (%) of average PSA levels compared to the reference; Only quantifiable concentrations.

PSA assay: LLOQ = 0.0575 ng / mL; ??? this table does not include the BLQ values.

Prostate volumes were measured by TRUS on a regular basis throughout the study. The results obtained after six weeks of treatment demonstrate a potent effect of Compound IV and the positive control (agonist of LH RH) in the prostate of the monkeys. Compound IV significantly reduced prostate volumes by 25% and 45% at doses of 10 mg / kg and 1 00 mg / kg, respectively, while prostate volumes were reduced by 28% in the group of positive control (LHRH agonist) (Figure 1 7 and Tables 1 7 and 1 8).

Table 1 7. Average prosthetic volumes (ratio) in male monkeys after daily oral administration of Compound IV.

Table 1 8. Percent change (%) of the average prosthetic volumes compared to the reference.

The reductions in prostatic volume linked to Compound IV were confirmed by the evaluation of the weight of the prostate at the time of necropsy. After 1 3 weeks of treatment, Compound IV significantly reduced the average prostate weights by 24% and 21% in animals that received 1 0 and 100 mg / kg / day, respectively (Figure 1 8B and Tables 1 and 9 and 20).

Table 1 9. Average prosthetic weights (grams) in necropsy of male monkeys with daily oral administration of Compound IV.

Table 20. Percentage change (%) of average prosthetic weights compared to the reference.

No obvious effects on platelet aggregation, prothrombin time (PT) or thromboplastin time were observed partial activated (APTT).

Example 17 Studies of Compound IV in humans A study was carried out to determine the effect of Compound IV in men. 12 subjects were examined per cohort with doses of 1 00, 300, 600 and 1000 mg of Compound IV. Table 21 shows the average change in levels of LH, serum PSA, free testosterone and total testosterone in men when administered Compound IV in doses of 1 00, 300, 600 and 1000 mg. The average dose-dependent total testosterone levels (nmol / L) in humans were measured between days 1 -1 1 (Figure 1 9). The total testosterone level decreased 51, 9% and 47.9% with doses of 600 mg and 1000 mg, respectively.

Average dose-dependent LH levels (IU / L) were measured in humans between days 1 -10 (Figure 20). LH levels increased 20.7%, 46.9%, 27.6% and 29.2% with doses of 100 mg, 300 mg, 600 mg and 1000 mg, respectively.

The average dose-dependent free testosterone levels (pg / mL) were measured in humans between days 1-10 (Figure 21). Free testosterone levels decreased by 1.7%, 18.5%, 72.7% and 53.2% at doses of 100 mg, 300 mg, 600 mg and 1000 mg, respectively.

The average dose dependent PSA levels (pg / L) in humans were measured between days 1 -1 0 (Figure 22). The PSA levels decreased 9.2%, 24.4%, 27.5% and 29.9% with doses of 1000 mg, 300 mg, 600 mg and 1000 mg, respectively. No changes were observed for the 10 and 30 mg doses.

Table 21 Average change with respect to the reference These data show the decrease in testosterone and PSA in the context of increased LH during early times in this trial in humans. This supports the elimination of testosterone and the corresponding antiandrogenic effects (elimination of PSA) by mechanisms other than the elimination of the hypothalamo-pituitary-gonadal axis. The mechanism for this independent elimination of LH could be, among others, the direct action of Compound IV on the gonadal or adrenal synthesis of androgens or the sequestration of T in serum due to increases in SHBG.

Example 18 Bioavailability of Compound IV Compound IV was rapidly absorbed after oral doses to rats, dogs and monkeys. The oral bioavailability of Compound IV in rats varies from 6% to 25% depending on the formulation in which the dose was administered. Formulations using polyethylene glycol 300 (PEG300) generally produced higher exposures than microemulsions prepared in Tween 80 diluted in deionized water. In dogs, visual inspection of the plasma concentration / time profiles indicated that Compound IV undergoes an enterohepatic recirculation, as demonstrated by a second peak in the terminal phase. More importantly, in dogs, exposure of the group of males with oral dose of PEG300 of 30 mg / kg exceeded the exposure necessary to produce the maximum effect in prostate reduction in the rat model of LH suppression. In monkeys, preliminary pharmacokinetic studies indicated that the oral bioavailability in this species approaches or exceeds that in dogs, as tested by the plasma concentrations of Compound IV and the suppression of serum testosterone during a seven day period. In their entirety, these data indicate that sufficient oral exposure can be achieved in two species of animals other than rodents to produce the desired pharmacological effect (according to the AUC data). Additionally, the endocrine data of rats and monkeys indicate that the pharmacological effects of Compound IV are reversible (i.e., that the serum concentrations of testosterone return to baseline or normal levels when treatment with Compound IV is interrupted).

Therefore, Compound IV was rapidly absorbed after oral doses to rats, dogs and monkeys. The oral bioavailability of Compound IV varies from 6 to 25% in rats and from 3 to 12% in dogs according to the formulation and route of administration. In monkeys, preliminary pharmacokinetic studies indicated that oral bioavailability in this species approaches or exceeds that in dogs, as evidenced by the plasma concentrations of Compound IV and the suppression of serum testosterone. Additionally, the endocrine data of rats and monkeys (Example 10) indicated that the pharmacological effects of Compound IV are reversible, since serum concentrations of testosterone return to baseline or normal levels when treatment with the Compound is interrupted. IV.

Example 19 Pharmacokinetics of Compound IV Preliminary data from studies of in vitro metabolism (mice, rats, dogs, monkeys and humans) and in vivo (rats) indicated that the conjugation of Compound IV, its hydroxylated metabolites and its N-dealkylated metabolites contribute to the general disposition of the Compound IV in animals and humans. The results of the comparison between species, although it was only qualitative, show that the general profiles of metabolites of non-clinical species adequately reflect the profile generated in human liver microsomes. Based on these results, rats and dogs they are suitable species of rodents and not rodents, respectively, for pharmacological and toxicological evaluations. In vitro studies show that Compound IV does not induce a relevant amount of CYP450 isoforms (CYP 1 A2, CYP2B6 or CYP3A4) and does not inhibit CYP1 A2, CYP2C19, CYP2D6 or CYP3A4 / 5 in concentrations < 30 μ ?. CYP2C9 is inhibited by Compound IV, but only in high concentrations (K, = d μ?) And the appearance of potential pharmacokinetic drug-drug interactions is considered unlikely.

Example 20 Activity outside the objective of Compound IV Compound IV exerts very little inhibitory effects in vitro or none at all (I C 50 = 300 μ?) In the hERG channel. The compound decreased drug-dependent APD50 and APD90 at concentrations of 1 0 and 100 μ in isolated Purkinje canine fibers in vitro. However, Compound IV did not affect cardiac or hemodynamic functions (blood pressure, heart rate, electrocardiogram morphology or QT intervals) in telemetered dogs at any dose (up to 300 mg / kg). No neuropharmacological or pulmonary effects were observed. No relevant effects were observed in renal functions with a single oral dose of up to 30 mg / kg of Compound IV. Only an increase in urine output and urinary chloride and potassium excretion was observed at the highest dose tested (100 mg / kg). Oral administration of Compound IV at doses of 30 to 300 mg / kg in rats produced an increase relevant in peristalsis, and the administration of Compound IV of 30 mg / kg in rats produced an increase in gastrointestinal motility and in gastric acidity (which is probably not due to smooth muscle effects).

Compound IV was not mutagenic and did not induce abnormalities in the number of chromosomes or structure in concentrations up to 200 μ in human peripheral blood lymphocytes in vitro. Compound IV was well tolerated by rats and dogs after repeated individual oral administration (up to 28 days). No pathological changes were observed in kidneys, liver, heart or other organs not related to the targets. There were no serious physical signs, effects on body weight, changes in clinical pathology, ophthalmological, electrocardiographic or histopathological changes associated with oral administration of Compound IV in female dogs or males for up to 28 days.

Example 21 Compound IV decreases testosterone at castration levels A 56 day trial of Compound IV was conducted on young and healthy male volunteers. In the subjects who complied sufficiently with the intake of Compound IV, as determined by the levels of Compound IV in blood, the study showed that 90% of the subjects reached castration levels of total testosterone on day 28 in the group of a dose of 1 500 mg. Free testosterone levels were reduced below the expected levels of surgical castration or those expected from chemical castration with LH H. antagonists or agonists. This is due to a dose-dependent increase in sex hormone-binding globulin (SHBG) observed with Compound IV . SHBG binds strongly to testosterone, rendering it unavailable for activity within the cell, and increasing SHBG levels decreases the testosterone available to act in the cell, potentially providing a pharmacological benefit to the patient. Compound IV that does not occur with surgical castration or castration with LHRH antagonists or agonists. % change from the reference point to the final observation in subjects who had enough with the treatment according to the serum levels of Compound IV † The subjects included in these analyzes are subjects who did not have EDC (except for castration) and to whom a non-compliance could not be confirmed. * 2 subjects reached castration levels and then discontinued treatment probably due to a decrease in compliance with the test drug, as determined by the levels of Compound IV. ** 1 subject reached castration levels and then discontinued the treatment.

Castrated subjects † † The subjects included in these analyzes are subjects who did not have EDC (except for castration) and who could not confirm a noncompliance. * 2 subjects reached castration levels and then discontinued treatment probably due to a decrease in compliance with the test drug, as determined by the levels of Compound IV. ** 1 subject reached castration levels and then discontinued the treatment.

Example 22 Studies of Compound IV in castrated monkeys - 90 days Cynomolgus monkeys reared in colonies were obtained Mauricio. The prospective study was designed as an oral toxicology and pharmacology evaluation of 39 weeks of Compound IV in male Cynomolgus monkeys with a period of 1 3 weeks and comparison of castrated animals with non-castrated animals (Example 16). A total of 49 sexually mature male monkeys aged 5 to 8 years were randomly assigned to 7 groups before the start of treatment. The animals selected for groups 3-7 were castrated according to the NI H guide. The groups included: 1) control with intact vehicle, 2) intact positive control (LHRH agonist), 3) control with castrated vehicle, 4) Compound IV 1 mg / kg castrated, 5) Compound IV 1 0 mg / kg castrated, 6) Compound IV 100 mg / kg castrated and 7) castrated control (LHRH agonist).

The drug was administered orally through the side of the cage once a day for 39 weeks with vehicle control article (Tween 80 / PRANG ™) for Groups 1, 2, 3 and 7, or Compound IV in vehicle for Groups 4, 5 and 6. The dosage levels of Compound IV are 1, 10 and 100 mg / kg / day for Groups 4, 5 and 6, respectively. Oral doses were administered in a dose volume of 10 mL / kg calculated on the basis of the most recent body weight for each animal. In addition, animals in Group 2 and 7 received a daily subcutaneous injection of LHRH agonist (constant volume of 0.02 mL) during the 39 weeks corresponding to the study period. The general appearance and clinical signs were observed and recorded daily. Routine evaluations and other studies were carried out as indicated in the test protocol. Selected parameters include, but are not limited to, testosterone, prostate-specific antigen (PSA), and prosthetic weight and volume.

Testosterone and total PSA levels were quantified in serum samples (after the standard procedure) through an enzyme immunoassay (EIA) and a chemiluminescence immunoassay (LIA, ALPCO Diagnostics, Salem NH), respectively. Blood samples were obtained from all the animals (fasting) to evaluate the testosterone at the reference point (ie, before starting the treatment) and on days 1, 3, 7, 14, 28, 64 and 90. collected blood samples from all animals (fasting) for PSA determinations at the reference point and during week 6. For the purpose of discussion, the results for samples with concentrations below the limit of quantification (BLQ) for testosterone and PSA tests are calculated as ½ of the lower limit of quantification (LLOQ) of the test and are considered "estimated final concentrations". The prostate volume in live animals under the effect of anesthesia was measured by transrectal ultrasound (TRUS) at the reference point and at week 6. The width and height of the prostate were recorded. The prosthetic volumes were calculated as anchoxanchoxalturax p / 6 and normalized for body weight. The wet weight of the prostate was recorded at necropsy after removing fat and foreign tissues.

Results and Discussion: At the benchmark, testosterone levels for all monkeys in groups 1 and 2 of the study are in the normal range for sexually mature adult male Cynomolgus monkeys. However, at the benchmark, testosterone levels for all monkeys in groups 3-7 of the study were reduced to the castration interval for sexually mature adult male Cynomolgus monkeys. The results show that testosterone levels were significantly reduced in the monkeys of the positive control group 2 receiving the LHRH agonist. The levels of testosterone in this intact positive control group (LHRH agonist) illustrate a two-phase change. No similar exacerbation was observed for any of the castrated animals treated with Compound IV. The dose and duration of treatment are important for the pharmacological action of Compound IV.

Unanticipated, Compound IV significantly suppresses serum PSA levels in castrated animals (groups 4, 5 and 6) within four weeks of the initiation of treatment.

The volumes of the prostate are measured by TRUS on a regular basis throughout the study. The intact vehicle control shows a minimum change between the previous dose and 4 weeks. The results demonstrate a potent effect of Compound IV on monkey prostates.

The intact vehicle control shows results similar to those observed in Example 16. The reductions in prostatic volume linked to Compound IV were confirmed by the evaluation of the weight of the prostate at the time of necropsy. After thirteen weeks of treatment, Compound IV significantly reduced the average weight of the prostate in those animals receiving doses of Compound IV.

No obvious effects were observed on platelet aggregation, prothrombin time (PT) or activated partial thromboplastin time (APTT).

Example 23 Studies of Compound IV in humans with prostate cancer subjected to ADT A study was conducted to determine the effect of Compound IV on testosterone and PSA levels in human male sex undergoing ADT for prostate cancer, where ADT treatment results in subjects having castration levels in testosterone. All subjects are required to present histologic evidence of prostate cancer. It is required that patients who have not undergone orchiectomy before and who at the moment receive hormonal liberation analogues - luteinizing hormone for chemical castration do not abandon said treatment during the course of the study.

Twelve subjects were examined per cohort with doses of 100, 300, 600 and 1000 mg of Compound IV. The average dose-dependent free testosterone levels (nmol / L) in humans were measured between days 1-11.

The average dose-dependent free testosterone levels were measured (pg / mL) in humans between days 1-10. The average dose dependent PSA levels (pg / L) in humans between days 1-10 were measured.

Example 24 Studies of Compound IV in healthy human subjects Studies of the toxicity of Compound IV in healthy human subjects Individual and multiple dose studies in healthy human subjects demonstrated that Compound IV was tolerated well in individual doses of up to 1247 mg and multiple doses of up to 997 mg (10, 30, 100, 300, 609 and 997 mg ) for up to 10 days.

Elevated ALT levels were observed above the upper limit of normal in four subjects in the multiple dose study (3 subjects in the 1000 mg group and 1 subject in the 600 mg group). The highest individual ALT value observed was 129 I U / L or 2.6 times the upper limit of normal. Aspartate aminotransferase levels also rose in this material up to 1.9 times the upper limit of normal. No increases in total bilirubin were observed in any subject of the trial.

Effects of Compound IV on serum testosterone levels Total serum testosterone levels were evaluated during the course of the multiple dose study. Total testosterone levels decreased by 1 00% (10/1 0) of the subjects in the 600 mg dose group and by 90% (9/10) of the subjects in the 997 mg dose group. Total testosterone levels decreased by below the lower limit of normality by 40% (4/10) of the subjects in the 600 mg dose group and by 50% (5/1 0) of the subjects in the dose group of 1000 mg. However, no subject had total testosterone levels below 1.73 nmol / L (castration interval) and the total testosterone levels of all subjects returned to normal 6 days after the interruption of Compound IV.

A proof-of-concept study (Study 1) to evaluate the effects of Compound IV on free and total serum testosterone in young, healthy male volunteers who used 600 mg, 1000 mg or 1500 mg of Compound IV in the form of a solution for 56 days showed that in the dose groups of 1000 and 1500 mg some subjects had total serum testosterone levels within the castration range (< 1, 73 nmol / L) and that in the 600 mg dose group no subject had total serum testosterone levels within the castration range (< 1, 73 nmol / L).

A second concept test study (Study 4) was also conducted to evaluate the effects of Compound IV on free and total serum testosterone levels in healthy older male volunteers. In this study, 1000 mg, 1500 mg or 2000 mg of Compound IV in tablet form were administered continuously for 28 days to volunteers.

In both studies, Compound IV showed a dose-dependent increase in sex hormone binding globulin (SHBG). SHBG binds to testosterone, which results in a conjugate that is not available for binding to the androgen receptor and reduces the levels of testosterone that are available to bind to the androgen receptor (as indicated by the levels of free testosterone). In each of the dose groups that were administered, SHBG increased by 300-600% above the reference point and serum free testosterone decreased. In men who were chemically castrated with total testosterone levels < 50 ng / dL, it is expected that free testosterone levels are lower than the levels expected with surgical castration and the administration of hormone-releasing hormone agonists luteinizing (LHRH).

A summary of the details of the different studies in humans is presented in Fig. 26.

Example 25 Studies of Compound IV in subjects of the male sex with prostate cancer Effects of Compound IV on serum testosterone levels -Patients with prostate cancer A study was carried out to establish the doses (Study 2) by comparing doses of 1000 mg and 2000 mg of Compound IV administered once a day with a three month deposit formulation of leuprolide acetate. The main objectives of the study were the evaluation of the proportion of subjects who achieved castration levels of total serum testosterone for Day 60 and who maintained the castration levels from Day 60 to Day 360. 55 (fifty-five) subjects were randomly assigned to the 1000 mg dose group of Compound IV. In the 1,000 mg dose group of Compound IV in subjects who reached Day 60, 65% (24/37) of the subjects achieved castration on Day 60. However, this proportion of subjects who achieved castration was too low to be considered clinically viable as a single androgen deprivation treatment.

Fifty five (55) subjects were randomly assigned to the 2000 mg dose group of Compound IV. In the dose group of 2000 mg of Com Item IV between subjects who reached Day 60, 84% (38/45) of the subjects achieved castration on Day 60.

Fifty-four (fifty-four) subjects were randomly assigned to the leuprolide acetate dose group. In the group treated with leuprolide, among subjects who reached Day 60, 1 00% (46/46) of these subjects achieved castration on Day 60. During the study, 9 (nine) subjects in the dose group of 1,000 mg and 2 (two) subjects in the 2000 mg dose group experienced VTE.

A second objective of study 2 was to compare the incidence and frequency of hot flushes in subjects who were administered Compound IV as opposed to the subjects to whom Lupron was administered. It was shown that men given Compound IV experienced less hot flashes in comparison with men who were given Lupron.

The following table presents the incidence of hot flashes in men who undergo androgen deprivation treatment with an injectable LH-RH agonist (Lupron) as opposed to an oral selective estrogen-receptor-alpha agonist (Component IV). : Another study was carried out (Study 5) to evaluate the impregnation dose of 1000 mg twice daily and 1500 mg twice a day of Compound IV for 28 days. Those subjects who were castrated at Day 28 received either 1000 mg or 2000 mg of Compound IV daily to maintain castration.

Impregnation doses of 1500 mg BI D and 1000 mg BID were assigned randomly to 30 (thirty) and 28 subjects, respectively. Among the subjects who reached Day 28, 90% (18/20) of the subjects in the dose group of 1500 mg BID and 94% (1 7/18) of the subjects in the dose group of 1000 mg IDB reached castration levels of total serum testosterone. During this study, 2 (two) subjects in the dose group of 1500 mg BI D experienced VTE, including fatal pulmonary embolus (PE) and 3 (three) subjects in the 1000 mg dose group BI D they experienced VTE.

A summary of the details of the study is presented in Figure 26.

Table 22. Castration rate for patients with prostate cancer without previous treatment who receive > 14 days of Compound IV. .training 1000 mg 2000 mg 000 mg 1500 ng In patients without prior treatment, when changes were sought in% of free T with respect to the reference point, 81% had at least 50% reduction in% free T after only 7 days of treatment (Figure 28A) . This change in% of free T is associated with PSA reductions when treatment is extended to 14, 21 and 28 days. After one month (Figure 28D) of the treatment with Compound IV, 80% of the patients have both at least 50% reduction in% free T and 50% reduction in PSA with respect to the reference point ( that is, the data grouped in the lower left quadrant in Figure 28C). These patients meet the PCWG2 criteria for PSA response.

The 50% reduction of free T and 50% is redrawn % of PSA in D28 as the change in SHBG as opposed to the change in PSA in Figure 29. Much of the induction of SH BG is able to reduce more than 50% of PSA.

In patients without previous treatment, both treatment with Compound IV and treatment with Lupron increased markedly the molar ratio of SHBG: total T after 28 days of treatment (Figure 31). Since Compound IV induces SHBG and reduces total T, the molar ratio of SHBG to total T is 3 to 7 times higher than in patients treated with Lupron. This increased molar ratio corresponds to a 70% decrease in% free T on day 28 in patients treated with Compound IV, as opposed to a decrease of only 20% in men treated with Lupron (Figure 31). Also all doses of Compound IV show similar and rapid reductions in% free T, indicating that 1000 mg QD is an Emax dose and that lower doses of Compound IV are likely to reduce the% free T.

According to clinical experience, the SHBG data from Study 1 and 2 were extrapolated to decrease the doses (Figures 32A-B), which indicates that even at doses of 125 mg, 250 mg and 500 mg, SHBG can be increased sufficiently to significantly suppress the% of free T and PSA.

Example 26 Studies of Compound IV in male subjects with castration-resistant prostate cancer (CRPC) who undergo ADT: Effects of Compound IV on the evolution of serum PSA When measuring total testosterone, the measurement includes testosterone bound to SHBG, free testosterone and albumin bound testosterone. SHBG binds strongly to testosterone, while free testosterone and testosterone bound to albumin find in balance. Compound IV has been shown to increase SH BG and reduce free testosterone to levels below levels achieved with LH RH agonists or antagonists or surgical castration.

A study was conducted (Study 3) to evaluate the effects of Compound IV in the evolution of serum PSA in men with castration-resistant prostate cancer who have been treated effectively with ADT and who at the time of selection for this study showed evolution of serum PSA. This study consisted of a dose group with 9 subjects.

A summary of the details of the study is presented in Figure 26.

The objectives of this study were: (a) to evaluate the effect of Compound IV on serum PSA levels in men with castration-resistant prostate cancer in androgen deprivation treatment (serum PSA response and PSA evolution in serum); (b) evaluate the effect of Compound IV on serum free testosterone levels; (c) evaluating the effect of Compound IV on SHBG; (d) evaluating the effect of Compound IV on total serum testosterone; (e) evaluate the effect of Compound IV on the development of new bone metastases; (f) evaluate the effect of Compound IV on soft tissue metastasis (lymph and visceral lymph nodes); and (g) assess the safety and tolerability of Compound IV in men with prostate cancer who undergo androgen deprivation treatment.

The subjects were 12 male subjects older than 1 8 years with castration-resistant prostate cancer who were being treated with androgen deprivation treatment (chemical or surgical castration) for at least 6 months, who have serum PSA > 2 ng / mL or > 2 ng / mL and a 25% increase above the minimum point after the start of the androgen deprivation treatment (ADT) at the time of selection for the study. The subjects were kept on androgen deprivation treatment during the study.

To meet the definition of castration-resistant subjects must: (1) have serum PSA in a range detectable on two consecutive occasions followed by an increase in serum PSA to > 2 ng / ml while receiving appropriate treatment of androgen deprivation; (2) have a castrate level of total serum testosterone (<50 ng / dL); (3) have a history of response to serum PSA after the start of ADT (the response to serum PSA is at least 90% reduction in serum PSA at <1 0 ng / mL or a PSA level in non-detectable serum (< 0.2 ng / mL)); (4) have an increase in serum PSA in two consecutive evaluations at least 2 weeks apart and PSA levels in serum > 2 ng / mL or > 2 ng / mL and a 25% increase above the minimum point after the start of the androgen deprivation treatment (ADT); and (5) continue in androgen deprivation treatment throughout this study.

Table 23. Reference hormonal parameters for young and healthy subjects, elderly patients with prostate cancer without prior treatment and patients with prostate cancer resistant to castration of studies 1; 2 and 5; and 3, respectively.

** Study 1 used an RIA method of Free T that showed reduced levels of free T when compared with the preferred dialysis method used in Study 2, 5 and 3.

The dose selected for the study was 2000 mg of Compound IV. Four tablets of Compound IV of 500 mg (dose of 2000 mg) were orally administered daily. It has been shown that this dose increases S HBG and results in a Significant reduction of free testosterone more rapidly than the dose of 1000 mg. They were administered 2000 mg of Compound IV to the subjects daily orally until the completion of the study. Dosing should continue until the serum PSA increases by at least 25% and 2 ng / mL of the minimum point in two successive samples (approximately 30 days apart) after starting treatment with Compound IV. The definition of the PSA evolution of the prostate cancer working group was used (serum PSA increased by at least 25% and 2 ng / mL above the minimum point after starting treatment with Compound IV in two doses of successive samples).

The evaluations of serum PSA concentrations were made at the reference point and on days 15, 30 and 60 (only one patient reached this stage before the study ended).

The study culminated before the evolution of the PSA in any of the subjects. However, if the study had continued, the following protocol would have been followed: After the subject shows an evolution of PSA in serum, the subject follows the treatment with the drug for 30 days and undergoes a follow-up evaluation of the PSA in serum. If the PSA evolution in serum is NOT confirmed in this visit, the subject remains in the study and continues the dosage with Compound IV. If the PSA evolution in serum is confirmed during the visit, the subject withdraws from the study and end-of-study evaluations are carried out. A scheduled follow-up visit for the subjects takes place 30 days after the Last dose of Compound IV.

Main evaluation criterion: The proportion of subjects with a reduction of 50% with respect to the serum PSA reference (confirmed by a second evaluation of the PSA at least one week later).

Secondary evaluation criteria: (1) time for the evolution of serum PSA; (2) proportion of subjects with a reduction > 90% with respect to the serum PSA reference; (3) change in serum free testosterone levels; (4) change in SHBG levels; (5) change in total serum testosterone levels; (6) change in RECIST criteria with respect to the reference; (7) proportion of subjects with new bone metastases; (8) proportion of subjects with new or aggravated metastases in soft tissues (lymph and visceral lymph nodes); (9) evaluate the safety and tolerability of Compound IV in men with prostate cancer in androgen deprivation therapy.

Formulation and supply of drugs: Tablets of Compound IV, 500 mg tablet of concentration formulated with substance of the micronized drug and SDS at 1% w / w.

In figure 33 you can find a flow diagram that describes the study procedures.

Results The trial was completed before, but of the twelve subjects enrolled in the study, seven subjects remained in the study long enough to have data available for evaluation to determine efficacy. The seven subjects showed a reduction in serum PSA with respect to the reference at day 1. In the three subjects who had at least 30 days of exposure to Compound IV, a reduction was observed > 50% of the PSA in serum (Figure 24).

If the study had continued, the following protocol would have been followed: The PSA response rate in serum in men with prostate cancer Castration resistant that continue to receive androgen deprivation therapy and to which Compound IV is administered is the main result of the study and is evaluated in relation to all subjects. The PSA response is defined as a 50% decrease from the reference confirmed by a second PSA value 4 ± one week later. The proportion of subjects with PSA response is estimated and the exact 95% of the Blyth-Still-Casella confidence interval is calculated. This estimate was constructed among subjects in the ITT population. This was done in a similar way for the proportion of subjects presenting a reduction >90% of the PSA with respect to the reference. Figure 24 shows the graphic representation of the percentage of change in the PSA through cascade graphs.

Effect of Compound I V on SHBG levels and relationship between SHBG levels and the percentage of free testosterone In the patients without previous treatment of the trials of Study 2 and Study 5, the reference of SHBG is induced with ~ 1 50-700% after 28 days of therapy with Compound IV (Figure 27A). The induction of SHBG is closely related to the reduction of% of free T [free T (pg / mL) / total T (pg / mL) * 1 00]. The regression of the relationship shows that an induction of ~ 400% in SH BG is associated with ~ 75% reductions in% free T. A large number of patients without prior treatment are grouped in this range for all doses of Compound IV. It is important that this close relationship be maintained in patients with CRPC in ADT of Study 3 (Figure 27B) even when only 1 5 days of therapy with Compound IV are contemplated. The unfilled symbols represent the reference (BL) and the symbols with padding represent treatment with Compound IV, as described above.

Effect of Compound IV on the percentage of free testosterone (% free T) and relationship between PSA levels and the percentage of free testosterone (% free T) Like patients without treatment, patients with CRPC treated with Compound IV show a rapid reduction, greater than 50% in% of free T (Day 15) (Figure 30). This corresponded to a reduction greater than 50% in PSA in 3 of 7 patients (data points filled) after only two weeks of therapy with Compound IV, and 2 of 3 patients after 30 days (data points without filling ).

Rules for the arrest of the subject: When serum PSA in a subject it increases at least 2 ng / mL and 25% of the minimum point after the start of the treatment with Compound IV, the subject remains in the study. PSA is taken in follow-up serum 30 days later. If the follow-up evaluation does NOT confirm the evolution of serum PSA, the subject remains in the study and continues the dosage with Compound IV. If the evolution of the PSA in follow-up serum confirms the evolution of serum PSA, the subject withdraws from the study and the visit of Final study and follow-up visits are carried out.

Evolution of serum PSA: The evolution of serum PSA will be defined according to the PCWG2 criteria. The PCWG2 criteria require a confirmation of the evolution of the PSA that is suspected in an evaluation of 3 to 4 weeks after the PSA level that indicated the possible evolution. The time for the evolution of the PSA for the confirmed cases will be the time from the start of the study drug to the date of the first PSA level that indicated a possible evolution. Patients who die in the trial will be considered failures in terms of survival without progression of PSA. The time for patients who never evolve (censored patients) will be the time from the start of the study drug to its last follow-up date. The Kaplan-Meier method will be used to estimate the survival without evolution of the PSA and associated confidence intervals of 95% at various times. The estimated median survival without progression of the PSA will be estimated if the median is reached.

Evolution of serum PSA (defined by PCWG2): If there was an initial reduction of serum PSA with respect to the reference, then it is used as the date on which the evolution occurred when serum PSA shows an increase of 25% in serum. % or greater than this and an absolute increase of 2 ng / ml or more with respect to the minimum point, but should be confirmed with a second serum PSA value obtained 3 or more weeks later. If there is no reduction of the serum PSA with respect to the reference, then it is used as the date on which the evolution occurred, in which serum PSA shows an increase of 25% or more and an absolute increase of 2 ng. / ml or more after 1 2 weeks, but should be confirmed with a second serum PSA value obtained 3 or more weeks later.

Additional analysis of PSA in serum. 1 . Percentage of change of each moment measured with respect to the reference. 2. Maximum reduction at any time during the study (percentage change from the reference to the minimum point). 3. Duration of the response (measured in days with a reduction of at least 50% with respect to the reference).

Free testosterone: The change was evaluated from the reference to Day 1 5, Day 30, Day 90 and the End of the study in terms of free testosterone levels.

Total Testosterone: The change was evaluated from the reference to Day 15, Day 30, Day 90 and the End of the study in terms of total testosterone levels.

SHBG: The change was evaluated from the reference to Day 1 5, Day 30, Day 90 and the End of the study in terms of SHBG levels.

Example 27 Compound IV as secondary hormone therapy for metastatic castration-resistant prostate cancer (mCRPC) Compound IV (study 6) is studied for the proposed indication of secondary hormone therapy for metastatic castration-resistant prostate cancer (mCRPC).

Compound IV has been shown to increase SHBG in serum and reduce serum free testosterone to levels below that which has been observed with LHRH agonists or antagonists or surgical castration. Compared with the group treated with leuprolide acetate, it has been shown that the group of Compound IV decreases markers of bone turnover compared to the reference and that it has a lower incidence of adverse hot flashes in men with advanced prostate cancer.

The effect of Compound IV as a secondary hormone therapy on serum PSA and free serum testosterone levels in men with castration-resistant metastatic prostate cancer who are followed by androgen deprivation therapy is studied. He This study evaluates the effects of Compound IV on the serum PSA response and the evolution of serum PSA in men with mCRPC in ADT with LHRH agonists, LH RH antagonists or orchidectomy. This study also assesses the risk of VTE of the lowest doses of Compound IV. Secondary assessment criteria include serum free testosterone levels, production of androgen precursors of the adrenal glands (DHEA and DHEAS levels), evolution-free survival and related bone events (SRE).

A summary of the details of the study is presented in Figure 25.

Objectives of the study: (1) to evaluate the effect of Compound IV on serum PSA levels in men with castration-resistant metastatic prostate cancer (mCRPC) who follow androgen deprivation therapy (PSA response in serum and evolution of serum PSA); (2) evaluate the effect of Compound IV on serum free testosterone levels; (3) evaluate the effect of Compound IV on SHBG in serum; (4) evaluate the effect of Compound IV on total serum testosterone; (5) evaluate the effect of Compound IV on the adrenal hormones androgen precursors of the adrenal glands (DHEA and DHEAS); (6) evaluate the effect of Compound IV on the formation of new bone metastases; (7) evaluate the effect of Compound IV on soft tissue metastasis (lymph and visceral lymph nodes); (8) evaluate the effects of Compound IV on related bone events; (9) evaluate the effect of Compound IV on markers of bone turnover; (10) evaluate the incidence and frequency of hot flashes in men treated with Compound IV; (11) evaluate the safety and tolerability of Compound IV in men with prostate cancer undergoing androgen deprivation therapy who did not have a successful ADT.

The study enrolled 75 subjects who are patients with castration-resistant prostate cancer who have radiographic evidence of metastatic disease (any T - any N -M 1). These subjects have a median life expectancy of less than 20 months, that is, a more serious illness than the other subjects with advanced prostate cancer recorded in the previous studies. All the subjects have been previously treated with androgen deprivation therapy (ADT), have responded to the ADT and at the moment have levels of PSA > 2 ng / mL or > 2 ng / mL and represent an increase of 25% above the minimum point obtained with the ADT. Subjects continue ADT during the study.

Each subject receives daily doses of 125 mg of Compound IV, 250 mg of Compound IV or 500 mg of Compound IV, administered orally, until the serum PSA increases by at least 25% and 2 ng / mL from the minimum point in two successive evaluations of serum PSA after the start of treatment with Compound IV.

The tablets of Compound IV of 1 25 mg and 500 mg are formulated with the substance of the micronized drug of Compound IV and sodium dodecyl sulfate (SDS) at 1%, and are supplied in a high density polyethylene (HDPE) bottle of 50 units.

The record in this study is gradual for 1 cycle (30 days) so that the first 25 subjects are registered in the 125 mg dose group of Compound IV. These subjects are evaluated to determine the incidence of venous thromboembolic events (VTE). When the last subject in the 125 mg dose group of Compound IV has completed 1 therapy cycle (30 days) in this dose group and there is an acceptable incidence rate of VTE in this dose group at that time (less than 3), registration is started in the 250 mg dose group of Compound IV. These subjects are evaluated to determine the incidence of VTE. When the 25 subjects in the 250 mg dose group of Compound IV have completed 1 cycle of therapy (30 days) in this dose group and there is an acceptable incidence rate of VTE in this dose group at that time (lower to 3), registration is started in the 500 mg dose group of Compound IV (25 subjects).

The 500 mg dose is expected to increase SHBG in serum and result in a significant reduction of serum free testosterone. The lowest doses, 1 25 mg and 250 mg, are expected to increase serum SHBG, but to a lesser extent, and are added to the protocol to determine the minimum effective dose of Compound IV to produce a serum PSA response. These doses may also have direct effects in reducing the production of androgen precursors of the adrenal glands such as DHEAS and DHEA, which can be used by prostate cancer cells to produce testosterone or dihydrotestosterone (DHT).

One 25 mg of Compound IV, 250 mg per day will be administered daily mg of Compound IV or 500 mg of Compound IV to all subjects in the study until they have developed the evolution of serum PSA (serum PSA has increased by at least 25% and 2 ng / mL above the minimum point by two moments of taking successive samples after beginning treatment with Compound IV). On Day 90, if the subject does not have at least a 50% reduction of serum PSA with respect to the reference and this is confirmed in a second evaluation, the subject will be removed from the study. The total duration of the dosage may be greater than 360 days in subjects who do not show an evolution of serum PSA in the study.

Subjects who show an evolution of serum PSA in two successive evaluations after the start of treatment with Compound IV are removed from the study. On Day 90, any subject who does not show a reduction is removed from the study > 50% in serum PSA with respect to the reference in two successive samples.

After the subject has shown an evolution of PSA in serum, the subject follows the treatment with the drug for 30 days and undergoes a follow-up evaluation of serum PSA. If the PSA evolution in serum is NOT confirmed in this visit, the subject remains in the study and the dosage is continued with Compound IV. If the PSA evolution in serum is confirmed during the visit, the subject withdraws from the study and end-of-study evaluations are carried out.

The evaluations of serum total testosterone, serum free testosterone, serum SHGB concentrations and serum PSA are performed on Days 1, 5, 30 and every 30 days until your serum PSA have increased at least 25% and 2 ng / mL of the minimum point at two successive sample times after the start of treatment with Compound IV. The bone turnover markers are evaluated at the reference point (Day 1), Day 90 and at the end of the study.

The incidence and frequency of hot flashes are evaluated at the reference point (Day 1), Day 30, Day 60, Day 90 and at the end of the study.

Computed tomography of the abdomen / pelvis is performed on Day 0 and every 90 days until the end of the study to evaluate the evolution of the tumor and visceral or soft tissue metastases.

Bone scintigraphy is performed on Day 0 and every 90 days until the end of the study to evaluate the development of new bone metastases.

Main evaluation criterion: The proportion of subjects with a reduction of 50% with respect to the reference in serum PSA (confirmed by a second evaluation of serum PSA 30 days later) to Day 90 (with follow-up confirmation at Day 1 20 ).

Secondary evaluation criteria: (1) time until the evolution of serum PSA; (2) proportion of subjects with a reduction = 90% with respect to the reference in serum PSA; (3) proportion of subjects with a reduction = 30% with respect to the reference in serum PSA; (4) change in serum free testosterone levels; (5) change in serum SHBG levels; (6) change in testosterone levels total in serum; (7) change in DHEA and DHEAS levels; (8) time to evaluation (TTP) evaluated by RECIST 1, 1 (soft tissue) or by PCWG2 (bone metastasis); (9) survival without evolution (PFS) evaluated by RECIST 1, 1 (soft tissue) or by PCWG2 (bone metastasis); (10) change in levels of bone turnover marker; (11) change in the incidence and frequency of hot flashes compared to the reference; (1 2) time until new or worsening SREs; (1 3) evaluation of the safety and tolerability of Compound IV in men with prostate cancer who did not have a successful ADT.

To minimize the risk of VTE in the present study: (1) Patients with a personal or family history of abnormal blood clotting or thrombotic disease (arterial or venous thrombotic events such as a history of stroke, deep vein thrombosis (DVT) and / or pulmonary embolus (PE)) will be excluded from the study. (2) Any subject with a modified activated protein C reaction ratio < will be excluded from the study. 2.5 and a mutation of Leiden Factor V, a level of antithrombin < 80% of normal, a homocysteine level > 7 micromoles / liter, the presence of the antiphospholipid antibody or a mutation of the prothrombin gene. (3) All subjects enrolled in this study, if they are not on aspirin therapy or another anticoagulant, will be required to take 81 mg of aspirin per day. Although reports on the efficacy of aspirin for the prevention of VTE have been contradictory, the recent literature supports the hypothesis that low-dose aspirin is as effective as low-molecular-weight heparin for VTE prophylaxis. (4) It will evaluate the VTE risk of all subjects enrolled in the study by using the Caprini venous thromboembolism risk assessment tool. The VTE risk of the subject will be assessed at each visit and, if a change in risk is identified during the study, adequate prevention will be made. More specifically, subjects who experience an event that puts them at high risk of VTE, such as the need for immobilization, long bone fracture, severe trauma, hospitalization, surgery, radiation, etc. They will be closely monitored and instructed on appropriate preventive measures to minimize VTE risks and, when indicated, subjects will be treated with prophylactic anticoagulation therapy. (5) All SAE thromboembolic or cardiovascular events will be considered at least possibly related to Compound IV therapy and will be included in the trial detention rules notwithstanding the investigator's attribution.

The subjects accepted for this study must: Be patients with castration-resistant prostate cancer who have radiographic evidence of metastatic disease (any T - any N - M 1).

· Have been treated with ADT (chemical or surgical) for at least 6 months.

• Have a total castration level testosterone level (< 50 ng / dL).

Have a history of PSA response in serum in the ADT. A PSA response in serum is at least a 90% reduction in the Serum PSA of the serum PSA value before starting the treatment at < 10 ng / mL or an undetectable level of serum PSA (< 0.2 ng / mL).

Have an increasing serum PSA in two successive evaluations with at least 2 weeks apart from each other and serum PSA levels > 2 ng / mL or > 2 ng / mL and an increase of 25% above the minimum point of the ADT. If a subject has been treated with an antiandrogen and has shown an evolution of PSA in serum, the subject will be required to abandon the antiandrogen. Once the antiandrogen (antiandrogen suppression) has been abandoned, the subject should have at least two levels of serum PSA on the rise with at least two weeks of separation from each other.

Continue in the ADT during the present study.

Subjects should agree, if they do not follow anticoagulation therapy or aspirin, to take 81 mg of aspirin per day for the duration of their participation in the present study and for 30 days after completing the dosage with Compound IV.

Figure 25 shows a flow diagram that describes the study procedures.

Clinical visits: Potential study participants will visit the clinical research facilities as necessary to analyze the evaluations. Subjects will have visits regarding the study in the Registry (Day 1) and Days 1 5 and 30. Subjects will return to the clinic every 30 days from Day 30 to Day 90. Those subjects that present a reduction of at least 50% in the serum PSA with respect to the reference will remain in the study and will return to the clinic every 30 days from Day 90 to Day 360 and then every 90 days after Day 360 until its Serum PSA has increased at least 25% and 2 ng / mL of the minimum point after starting treatment with Compound IV, and that this discovery is confirmed with a second evaluation of PSA in serum or that its disease has evolved ( computed tomography or bone scintigraphy).

A follow-up visit will be conducted 30 days after the last dose.

When the serum PSA in a subject has increased at least 2 ng / mL and 25% of the minimum point after the start of the treatment with Compound IV, the subject will have met the criteria for the evolution of the disease. However, the subject must remain in the study until 30 days later, a serum PSA confirmatory follow-up is taken. If the follow-up evaluation does NOT confirm the evolution of serum PSA, the subject should remain in the study and continue the dosage with Compound IV. If the PSA in follow-up serum confirms the evolution of the PSA in serum, the subject must withdraw from the study and the visit of the study end and follow-up visits must be carried out.

On Day 90, any subject that does not show a reduction of PSA in serum > 50% of the referral will be submitted to a confirmation evaluation of serum PSA 30 days after Day 90. The subject should continue with the study drug after the Day 90 and up to the confirmation evaluation. In the confirmation evaluation, if serum PSA is reduced > 50% with respect to the reference, the subject will remain in the study and continue the dosage with Compound IV. If in the confirmation evaluation serum PSA is not reduced > 50% with respect to the reference, the subject will withdraw from the study due to lack of efficacy. The visit of the Study Final and the Follow-up visit must be carried out.

Subjects who show evidence of the evolution of the disease, as documented in the computed tomography (RECIST 1, 1) or two new lesions observed in the bone scintigraphy, will be removed from the study.

Efficacy analysis, serum PSA and serum PSA response.

The PSA response in serum on Day 90 will be the main result and will be evaluated in all subjects. The PSA response in serum will be defined as a reduction > 50% compared to the reference confirmed by a second serum PSA value within 14 days. The main objective is to evaluate the response rate of serum PSA in men with mCRPC who follow ADT and who received Compound IV.

The proportion of subjects presenting a serum PSA response will be estimated and the exact 95% confidence interval Blyth-Still-Casella will be calculated. [twenty] This estimate will be carried out between: (1) subjects among the population with intention to treat (I IT) with subjects who gave up before the evaluation of Day 90 and who are considered not to respond, and (2) subjects among the efficacy population that can be evaluated (EE).

The graphic representation of the percentage of change in the serum PSA from the reference to each PSA evaluation (with emphasis on the evaluation of Day 90) will be through cascade graphics, as described below: The percent change in the serum PSA from the reference to each evaluation will be calculated, and the Y axis will represent the percentage of change, the X axis will have a bar for each particular subject and the order of these bars will be of a smaller percentage decrease of the Serum PSA (this could potentially be an increase for some subject or subjects) up to greater percent fall.

Evolution of serum PSA The evolution of serum PSA will be defined by the PCWG2 criteria shown below. [21] The PCWG2 criteria require a confirmation of the evolution of PSA in serum that is suspected in an evaluation 3-4 weeks after the serum PSA level was obtained, which indicated a possible evolution.

The survival without progression of the PSA will be estimated using the Kaplan-Meier method and associated confidence intervals of 95% will be established. The survival without evolution of a subject will be the time between the first dose of the study until the first date associated with an evolution or confirmed death. Subjects who leave the study or who are lost to follow-up will not be considered after their last contact date. The estimated median survival without progression of the PSA will be estimated if the median is reached.

The time for the evolution of the PSA will be estimated using the Kaplan-Meier method and associated confidence intervals of 95% will be established. The time of evolution of a subject will be the time from the first dose of the study drug to the first date associated with a confirmed evolution. Subjects who die before evolution will not be considered from the date of death. Subjects who leave the study or who are lost to follow-up will not be considered after their last contact date. The estimated median time for evolution will be estimated if the median is reached.

The estimated median survival without evolution of serum PSA will be estimated if the median is reached.

Evolution of serum PSA (defined by PCWG2): If there is an initial reduction of serum PSA relative to the reference, then it is used as the date on which the evolution occurred when serum PSA shows an increase of 25% or more and an absolute increase of 2 ng. / ml or more of the minimum point, but should be confirmed by a second serum PSA value obtained 3 or more weeks later.

If there is no reduction of the serum PSA with respect to the reference, then it is used as the date on which the evolution occurred when the serum PSA shows an increase of 25% or more and an absolute increase of 2 ng. / ml or more after 12 weeks, but should be confirmed by a second serum PSA value obtained 3 or more weeks later.

Free testosterone in serum The change in serum free testosterone levels will be evaluated from the reference to each scheduled evaluation. The change and the percentage change from the reference to each scheduled evaluation will be evaluated by using a paired t-test, if it is determined that the data is normally distributed. Otherwise, an exact Wilcoxon signed rank test will be used to compare the change and percentage change from the reference to each scheduled assessment. This will be done until the number of subjects decreases below 5. Repeated measures models of the mixed model can be used to explore the change in time within each group. The subject will be considered a random effect.

SHBG in serum The change from the reference to each scheduled evaluation will be evaluated in serum SHBG levels. The change and the percentage change will be evaluated from the reference to each evaluation programmed by using a paired t-test, if it is determined that the data is normally distributed. Otherwise, an exact Wilcoxon signed rank test will be used to compare the change and percentage change from the reference to each scheduled assessment. This will be done until the number of subjects decreases below 5. Repeated measures models of the mixed model can be used to explore the change in time within each group. The subject will be considered a random effect.

Total serum testosterone The change will be evaluated from the reference to each scheduled evaluation of serum testosterone levels. The change and the percentage change from the reference to each scheduled evaluation will be evaluated by using a paired t-test, if it is determined that the data is normally distributed. Otherwise, an exact Wilcoxon signed rank test will be used to compare the change and percentage change from the reference to each scheduled assessment. This will be done until the number of subjects decreases below 5. Repeated measures models of the mixed model can be used to explore the change in time within each group. The subject will be considered a random effect.

DHEA and DHEAS The change will be evaluated from the reference to each scheduled evaluation in both DHEA and DHEAS levels. The change and the percentage change from the reference to each scheduled evaluation will be evaluated by using a paired t-test, if it is determined that the data is normally distributed. Otherwise, an exact Wilcoxon signed rank test will be used to compare the change and percentage change from the reference to each scheduled assessment. This will be done until the number of subjects decreases below 5. Repeated measures models of the mixed model can be used to explore the change in time within each group. The subject will be considered a random effect.

Evolution of the disease. Evolution in soft tissue (RECIST 1, 1) The criteria of RECI ST 1, 1 will be used to evaluate the evolution and the response. Both the TTP and the PFS, as defined above, will be estimated between the subjects.

The time to survival without evolution (PFS) will be estimated using the Kaplan-Meier method and associated confidence intervals of 95% will be established. The survival without evolution of a subject will be the time between the first dose of study medication until there is evidence of evolution or death. Subjects who leave the study or who are lost to follow-up will not be considered after their last date contact.

The estimated median of the PFS will be estimated if the median is reached.

The time for evolution (TTP) will be estimated using the Kaplan-Meier method and associated confidence intervals of 95% will be established. The time for the evolution of a subject will be the time between the first dose of study medication until evidence of evolution is recorded. Subjects who die before evolution will not be considered from the date of death. Subjects who leave the study or who are lost to follow-up will not be considered after their last contact date.

The estimated median time for evolution will be estimated if the median is reached.

The best responses of the subject will be determined and the proportion in CR, PR (PR + CR), SD and PD will be estimated, and the exact 95% of the Blyth-Still-Casella confidence interval will be calculated.

Bone evolution Both the TTP and the PFS, as defined below, will be estimated among the subjects that present measurable metastases in the bone scintigraphy.

The time to survival without evolution (PFS) will be estimated using the Kaplan-Meier method and associated confidence intervals of 95% will be established. Survival without The evolution of a subject will be the time between the first dose of the study drug until evidence of evolution or death is recorded. Subjects who leave the study or who are lost to follow-up will not be considered after their last contact date.

The estimated median of the PFS will be estimated if the median is reached.

The time for evolution (TTP) will be estimated using the Kaplan-Meier method and associated confidence intervals of 95% will be established. The time for the evolution of a subject will be the time between the first dose of study medication until evidence of evolution is recorded. Subjects who die before evolution will not be considered from the date of death. Subjects who leave the study or who are lost to follow-up will not be considered after their last contact date.

The estimated median time for evolution will be estimated if the median is reached.

The best responses of the subject will be determined and the proportion in CR, PR (PR + CR), SD and PD will be estimated, and the Blyth-Still-Casella confidence interval of 95% will be calculated.

Bone replacement markers The change will be evaluated from the reference to each scheduled evaluation for each bone turnover marker in each group of treatment. In each of these moments the mean, the standard deviation, the median, the minimum and the maximum of the bone turnover levels will be summarized. The change from the reference to each moment will also be summarized. A paired t test will evaluate within a group whether the change from the reference to each moment is significantly different from zero. This will be done in the ITT population. This will be done in the observed cases and a LOCF analysis will also be carried out. Repeated measures models of the mixed model can be used to explore the change in time within each group. The subject will be considered a random effect.

Hot flushes The subjects will be consulted regarding hot flashes (incidence and frequency). The specific questions that are asked and the definitions of severity are included in Appendix D.

The proportion of subjects who experience hot flushes is presented according to treatment group. The proportion of subjects who experience hot flushes weekly or more frequently is presented according to the treatment group. The proportion of subjects who experience hot flushes daily or more frequently is presented according to the treatment group. The proportion of subjects who experience hot flushes several times a day is presented according to the treatment group.

The proportion of subjects experiencing moderate to severe hot flashes is presented according to treatment group The proportion of subjects experiencing hot flashes from severe to very severe it is presented according to the treatment group.

The change tables express the change in severity between the benchmark and each evaluation.

Related bone events (SRE) SREs are a composite goal that includes pathological fractures, spinal cord compression and radiation or bone surgery.

Time without related bone events will be estimated using the Kaplan-Meier method and associated 95% confidence intervals will be established. The time without related bone events will be the time between the first dose of study medication until evidence of a new SRE or death is recorded. Subjects who leave the study or who are lost to follow-up will not be considered after their last contact date. This analysis will be repeated defining an event as any new or worsening SRE or death. Free time from related bone events (new or worsened SREs) means that is estimated will be calculated if the median is performed.

The time for the appearance of a new related bone event will be estimated using the Kaplan-Meier method and associated confidence intervals of 95% will be established. The time of a subject for the appearance of a new related bone event will be the time from the first dose of study medication to one Documented evidence of a new related bone event. Subjects who die before the appearance of a new related bone event will not be considered from the date of death. Subjects who leave the study or who are lost to follow-up will not be considered after their last contact date. This analysis will be repeated defining an event as a new or worsened SRE.

The estimated median time until the appearance of a new SRE (new or worsened SREs) that is estimated will be calculated if the median is reached.

Example 28 Secondary hormone therapy for metastatic castration-resistant prostate cancer (mCRPC) Estradiol, ethinylestradiol, spheroidal estrogen agonists, and non-steroidal estrogen agonists (Study 6) are studied for the proposed indication of secondary hormone therapy for metastatic castration-resistant prostate cancer (mCRPC).

Estradiol, ethinylestradiol, spheroidal estrogen agonists and non-steroidal estrogen agonists have been shown to increase SHBG in serum and reduce serum free testosterone to levels below what has been observed with LHRH agonists or antagonists or surgical castration. . Compared with the group treated with leuprolide acetate, it has been shown that estradiol, ethinylestradiol, estrogen-spheroidal agonists and estrogen agonists are not steroid decrease markers of bone turnover compared to the reference and have lower incidence of adverse hot flashes in men with advanced prostate cancer.

The effect of estradiol, ethinylestradiol, estrogen steroid agonists, and non-steroidal estrogen agonists as secondary hormone therapy on serum PSA and serum free testosterone levels in men with castration-resistant metastatic prostate cancer who follow a therapy is studied of androgen deprivation. The study evaluates the effects of estradiol, ethinylestradiol, steroid estrogen agonists and non-steroidal estrogen agonists on the serum PSA response and the evolution of serum PSA in men with mCRPC in ADT with LHRH agonists, LHRH antagonists or orchidectomy . The present study also evaluates the risk of VTE of lower doses of estradiol, ethinylestradiol, steroid estrogen agonists and non-steroidal estrogen agonists. Secondary assessment criteria include free testosterone levels, production of androgen precursors of the adrenal glands (DHEA and DHEAS levels), evolution-free survival and related bone events (SRE).

Objectives of the study: (1) to evaluate the effect of estradiol, ethinylestradiol, steroid estrogen agonists and non-steroidal estrogen agonists on serum PSA levels in men with metastatic castration-resistant prostate cancer (mCRPC) who continue to receive a androgen deprivation therapy (PSA response in serum and evolution of serum PSA); (2) to evaluate the effect of estradiol, ethinylestradiol, steroid estrogen agonists and non-steroidal estrogen agonists on serum free testosterone levels; (3) to evaluate the effect of estradiol, ethinylestradiol, steroid estrogen agonists and non-steroidal estrogen agonists on SHBG in serum; (4) evaluate the effect of estradiol, ethinylestradiol, steroid estrogen agonists and non-steroidal estrogen agonists on serum total testosterone; (5) evaluate the effect of estradiol, ethinylestradiol, steroid estrogen agonists and non-steroidal estrogen agonists on androgen precursor hormones of the adrenal glands (DH EA and DHEAS); (6) to evaluate the effect of estradiol, ethinylestradiol, steroid estrogen agonists and non-steroidal estrogen agonists in the development of new bone metastases; (7) evaluate the effect of estradiol, ethinylestradiol, steroid estrogen agonists and non-steroidal estrogen agonists on soft tissue metastases (lymph and visceral lymph nodes); (8) evaluate the effects of estradiol, ethinylestradiol, steroid estrogen agonists and non-steroidal estrogen agonists in related bone events; (9) evaluate the effect of estradiol, ethinylestradiol, steroid estrogen agonists and non-steroidal estrogen agonists on markers of bone turnover; (10) evaluate the incidence and frequency of hot flushes in men treated with estradiol, ethinylestradiol, steroid estrogen agonists and non-steroidal estrogen agonists; (11) evaluate the safety and tolerability of estradiol, ethinylestradiol, estrogen steroid agonists and estrogen agonists not steroid in men with prostate cancer undergoing androgen deprivation therapy who did not have a successful ADT.

The study enrolls 75 subjects who are patients with castration-resistant prostate cancer who have radiographic evidence of metastatic disease (any T - any N -M 1). These subjects have a median life expectancy of less than 20 months, that is, a more serious illness than the other subjects with advanced prostate cancer recorded in the previous studies. All the subjects have been previously treated with androgen deprivation therapy (ADT), have responded to the ADT and at the moment have levels of PSA > 2 ng / mL or > 2 ng / mL, and represent an increase of 25% above the minimum point obtained with the ADT. Subjects continue to receive ADT during the study.

Each subject receives daily doses of 1 25 mg, 250 mg or 500 mg of estradiol, ethinylestradiol, steroid estrogen agonists and nonsteroidal estrogen agonists administered orally until the serum PSA increases by at least 25% and 2 ng / mL from the minimum point in two successive evaluations of serum PSA after treatment with estradiol, ethinylestradiol, steroid estrogen agonists and non-steroidal estrogen agonists.

The 500 mg dose is expected to increase SHBG in serum and result in a significant reduction of serum free testosterone. It is expected that the lowest doses, 125 mg and 250 mg, increase the SHBG in serum, but to a lesser extent, and add to the protocol to determine the minimum effective dose of estradiol, ethinylestradiol, steroid estrogen agonists and non-steroidal estrogen agonists to produce a serum PSA response. These doses may also have direct effects in reducing the production of androgen precursors of the adrenal glands such as DHEAS and DHEA, which can be used by prostate cancer cells to produce testosterone or dihydrotestosterone (DHT). 1 25 mg, 250 mg, 500 mg estradiol, ethinylestradiol, steroid estrogen agonists, and nonsteroidal estrogen agonists will be administered daily to all subjects in the study until they have developed the evolution of serum PSA (serum PSA has increased at least 25% and 2 ng / mL above the minimum point at two successive sampling times after initiation of treatment with estradiol, ethinylestradiol, steroid estrogen agonists and non-steroidal estrogen agonists). On Day 90, if the subject does not have at least a 50% reduction in serum PSA relative to the reference and this is confirmed in a second evaluation, the subject will be removed from the study. The total duration of the dosage may be greater than 360 days in subjects who do not show an evolution of serum PSA in the study.

The evaluations of serum total testosterone, serum free testosterone, serum SHGB concentrations and serum PSA are made on Days 15, 30 and every 30 days until your serum PSA has increased at least 25% and 2 ng / mL of the minimum point in two successive sample moments after the start of treatment with Compound IV. The bone turnover markers are evaluated at the reference point (Day 1), Day 90 and at the end of the study.

The incidence and frequency of hot flashes are evaluated at the reference point (Day 1), Day 30, Day 60, Day 90 and at the end of the study.

Computed tomography of the abdomen / pelvis is performed on Day 0 and every 90 days until the end of the study to evaluate the evolution of the tumor and visceral or soft tissue metastases.

Bone scintigraphy is performed on Day 0 and every 90 days until the end of the study to evaluate the development of new bone metastases.

Main evaluation criterion: The proportion of subjects with a 50% reduction with respect to the serum PSA reference (confirmed by a second serum PSA evaluation 30 days later) at Day 90 (with confirmation of follow-up at Day 120).

Secondary evaluation criteria: (1) Time until the evolution of serum PSA; (2) proportion of subjects with a reduction = 90% with respect to the reference in serum PSA; (3) proportion of subjects with a reduction = 30% with respect to the reference in serum PSA; (4) change in serum free testosterone levels; (5) change in serum SHBG levels; (6) change in serum total testosterone levels; (7) change in DHEA and DHEAS levels; (8) time to evaluation (TTP) evaluated by RECIST 1, 1 (soft tissue) or by PCWG2 (bone metastasis); (9) survival without evolution (PFS) evaluated by RECIST 1, 1 (soft tissue) or by PCWG2 (bone metastasis); (10) change in levels of bone turnover marker; (11) change in the incidence and frequency of hot flashes compared to the reference; (12) time until new or worsening SREs; (1 3) evaluation of the safety and tolerability of Compound IV in men with prostate cancer who did not have a successful ADT.

Free testosterone in serum The change in serum free testosterone levels will be evaluated from the reference to each scheduled evaluation. The change and the percentage change from the reference to each scheduled evaluation will be evaluated by using a paired t-test, if it is determined that the data are normally distributed. Otherwise, an exact Wilcoxon signed rank test will be used to compare the change and percentage change from the reference to each scheduled assessment. This will be done until the number of subjects decreases below 5. Repeated measures models of the mixed model can be used to explore the change in time within each group. The subject will be considered a random effect.

SHBG in serum The change from the reference to each scheduled evaluation will be evaluated in serum SHBG levels. The change will be evaluated and the percentage change from the reference to each scheduled evaluation through the use of a paired t-test, if it is determined that the data are normally distributed. Otherwise, an exact Wilcoxon signed rank test will be used to compare the change and percentage change from the reference to each scheduled assessment. This will be done until the number of subjects decreases below 5. Repeated measures models of the mixed model can be used to explore the change in time within each group. The subject will be considered a random effect.

Total serum testosterone The change will be evaluated from the reference to each scheduled evaluation of serum testosterone levels. The change and the percentage change from the reference to each scheduled evaluation will be evaluated by using a paired t-test, if it is determined that the data are normally distributed. Otherwise, an exact Wilcoxon signed rank test will be used to compare the change and percentage change from the reference to each scheduled assessment. This will be done until the number of subjects decreases below 5. Repeated measures models of the mixed model can be used to explore the change in time within each group. The subject will be considered a random effect.

DH EA and DH EAS The change will be evaluated from the reference to each scheduled evaluation in both the DH EA and the DH EAS levels. The change and the percentage change from the reference to each scheduled evaluation will be evaluated by using a paired t-test, if it is determined that the data are normally distributed. Otherwise, an exact Wilcoxon-sign test will be used to compare the change and the percentage change from the reference to each scheduled evaluation. This will be done until the number of subjects decreases below 5. Repeated measurement models of the mixed model can be used to explore the change in time within each group. The subject will be considered a random effect.

Evolution of the disease. Evolution in soft tissue (RECIST 1, 1) The R ECI ST 1, 1 criteria will be used to evaluate the evolution and the response. Both the TTP and the PFS, as defined above, will be estimated between the subjects.

The time to survival without evolution (PFS) will be estimated using the Kaplan-Meier method and associated confidence intervals of 95% will be established. The survival without evolution of a subject will be the time between the first dose of the study drug until evidence of evolution or death is recorded. Subjects who leave the study or who are lost During the follow-up they will not be considered after their last contact date.

The estimated median of the PFS will be estimated if the median is reached.

The time for evolution (TTP) will be estimated using the Kaplan-Meier method and associated confidence intervals of 95% will be established. The time for the evolution of a subject will be the time between the first dose of study medication until evidence of evolution is recorded. Subjects who die before evolution will not be considered from the date of death. Subjects who leave the study or who are lost to follow-up will not be considered after their last contact date.

The estimated median time for evolution will be estimated if the median is reached.

The best responses of the subject will be determined and the proportion in CR, PR (PR + CR), SD and PD will be estimated, and the Blyth-Still-Casella confidence interval of 95% will be calculated.

Bone evolution Both the TTP and the PFS, as defined below, will be estimated among the subjects that present measurable metastases in the bone scintigraphy.

The time for survival without evolution (PFS) will be estimated using the Kaplan-Meier method and will be established 95% associated confidence intervals. The survival without evolution of a subject will be the time between the first dose of study medication until there is evidence of evolution or death. Subjects who leave the study or who are lost to follow-up will not be considered after their last contact date.

The estimated median of the PFS will be estimated if the median is reached.

The time for evolution (TTP) will be estimated using the Kaplan-Meier method and associated confidence intervals of 95% will be established. The time for the evolution of a subject will be the time between the first dose of study medication until evidence of evolution is recorded. Subjects who die before evolution will not be considered from the date of death. Subjects who leave the study or who are lost to follow-up will not be considered after their last contact date.

The estimated median time for evolution will be estimated if the median is reached.

The best responses of the subject will be determined and the proportion in CR, PR (PR + CR), SD and PD will be estimated, and the Blyth-Still-Casella confidence interval of 95% will be calculated.

Bone replacement markers The change will be evaluated from the reference to each evaluation programmed for each bone turnover marker in each treatment group. In each of these moments the mean, the standard deviation, the median, the minimum and the maximum of the bone turnover levels will be summarized. The change from the reference to each moment will also be summarized. A paired t test will evaluate within a group whether the change from the reference to each moment is significantly different from zero. This will be done in the ITT population. This will be done in the observed cases and a LOCF analysis will also be carried out. Repeated measures models of the mixed model can be used to explore the change in time within each group. The subject will be considered a random effect.

Hot flushes The subjects will be consulted regarding hot flashes (incidence and frequency). The specific questions that are asked and the definitions of severity are included in Appendix D.

The proportion of subjects who experience hot flushes is presented according to treatment group. The proportion of subjects who experience hot flushes weekly or more frequently is presented according to the treatment group. The proportion of subjects who experience hot flushes daily or more frequently is presented according to the treatment group. The proportion of subjects who experience hot flushes several times a day is presented according to the treatment group.

The proportion of subjects experiencing moderate to severe hot flashes is presented according to the treatment group. The proportion of subjects experiencing hot flashes from severe to very severe is presented according to treatment group.

The change tables express the change in severity between the benchmark and each evaluation.

Related bone events (SRE) SREs are a composite goal that includes pathological fractures, spinal cord compression and radiation or bone surgery.

Time without related bone events will be estimated using the Kaplan-Meier method and associated 95% confidence intervals will be established. The time without related bone events will be the time between the first dose of study medication until evidence of a new SRE or death is recorded. Subjects who leave the study or who are lost to follow-up will not be considered after their last contact date. This analysis will be repeated defining an event as any new or worsening SRE or death.

The median time free of related skeletal events (new or worsened SREs) that is estimated will be calculated if the median is performed.

The time for the appearance of a new related bone event will be estimated using the Kaplan-Meier method and associated confidence intervals of 95% will be established. The time of a subject for the appearance of a new related bone event will be the time from the first dose of study medication to documented evidence of a new related bone event. Subjects who die before the appearance of a new related bone event will not be considered from the date of death. Subjects who leave the study or who are lost to follow-up will not be considered after their last contact date. This analysis will be repeated defining an event as a new or worsened SRE.

The median time until the appearance of a new SRE (new or worsened SREs) that is estimated will be calculated if the median is performed.

Although certain features of the invention were illustrated and described herein, those skilled in the art will think of many modifications, substitutions, changes and equivalents. It should be understood, therefore, that the appended claims are intended to cover all such modifications and changes, which are within the true spirit of the invention.

Claims (1)

1. CLAIMS 1. A method to treat, eliminate, reduce the incidence, reduce the severity or inhibit the progression of castration-resistant prostate cancer (CRPC) and its symptoms, or increase the survival of men with castration-resistant prostate cancer by administration of a therapeutically effective amount of a compound of formula I or its isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate or any combination thereof: (l) where And it is C (O) or CH2; Ri, R2 are independently hydrogen, halogen, hydroxyl, alkoxy, cyano, nitro, CF3, N (R) 2, sulfonamide, SO2R, alkyl, haloalkyl, aryl, O-Alk-NRsRe or O-Alk-heterocycle in which the heterocycle is a 3-7 membered substituted or unsubstituted heterocycle ring, optionally aromatic; R3, R4 are independently hydrogen, halogen, hydroxyalkyl, hydroxyl, alkoxy, cyano, nitro, CF3, NHCOR, N (R) 2, sulfonamide, SO2 R, alkyl, haloalkyl, aryl or protected hydroxyl; R is alkyl, hydrogen, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, halogen, alkenyl, CN, N02 or OH; R5 and R6 are independently hydrogen, phenyl, an alkyl group of 1 to 6 carbon atoms, a cycloalkyl of 3 to 7 members, a heterocycle of 3 to 7 members, an aryl of 5 to 7 members; or R5 and Re form a ring of 3 to 7 members with the nitrogen atom; j and k are independently 1-4; Y Alk is a linear alkyl of 1 to 7 carbons, branched alkyl of 1 to 7 carbons or cycloalkyl of 3 to 8 carbons. 2. The method of claim 1, wherein said compound of formula I is selected from: 98 3. The method of claim 1, wherein said compound of formula I is Compound IV: 4. The method of claim 1, wherein said castration-resistant prostate cancer (CRPC) is metastatic CRPC (mCRPC). 5. The method of claim 1, wherein said castration is chemical or surgical (orchiectomy). 6. The method of claim 1, wherein said subject has high or increasing levels of specific prosthetic antigen (PSA). 7. The method of claim 1, wherein said subject also receives androgen deprivation therapy (ADT). 8. The method of claim 1, wherein said administration of the compound does not cause side effects associated with androgen deprivation therapy (ADT). 9. The method of claim 8, wherein said side effects is selected from the group consisting of: hot flushes, gynecomastia, increased body fat, bone loss, decreased bone mineral density and increased risk of fracture. The method of claim 1, wherein said compound or its isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or any combination thereof is administered in a dose of 1 25 mg per day, 250 mg per day or 500 mg per day. day. eleven . A method for decreasing serum PSA levels in a male subject suffering from castration-resistant prostate cancer (CRPC) comprising the administration of a therapeutically effective amount of a compound of formula I or its isomer, pharmaceutically salt acceptable, pharmaceutical product, hydrate or any combination of them: (i) where And it is C (O) or CH2; Ri, R2 are independently hydrogen, halogen, hydroxyl, alkoxy, cyano, nitro, CF3, N (R) 2, sulfonamide, S02R, alkyl, haloalkyl, aryl, O-Alk-NRsRe or O-Alk-heterocycle wherein the heterocycle is a 3-7 membered substituted or unsubstituted heterocycle ring, optionally aromatic; R3, R are independently hydrogen, halogen, hydroxyalkyl, hydroxyl, alkoxy, cyano, nitro, C F3, NHCOR, N (R) 2, sulfonamide, S02R, alkyl, haloalkyl, aryl or protected hydroxyl; R is alkyl, hydrogen, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, halogen, alkenyl, CN, N02 or OH; R5 and Re are independently hydrogen, phenyl, an alkyl group of 1 to 6 carbon atoms, a cycloalkyl of 3 to 7 members, a heterocycle of 3 to 7 members, an aryl of 5 to 7 members; or R5 and Re form a ring of 3 to 7 members with the nitrogen atom; j and k are independently 1-4; Y Alk is a linear alkyl of 1 to 7 carbons, branched alkyl of 1 to 7 carbons or cycloalkyl of 3 to 8 carbons. The method of claim 1, wherein said compound of the formula I is selected from: 303 14. The method of claim 1, wherein said castration-resistant prostate cancer (CRPC) is metastatic CRPC (mCRPC). The method of claim 1, wherein said subject also receives androgen deprivation therapy (ADT). 16. The method of claim 1, wherein said administration of the compound does not cause side effects associated with androgen deprivation therapy (ADT). 17. The method of claim 16, wherein said side effects are selected from the group consisting of: hot flushes, gynecomastia, increased body fat, bone loss, decreased bone mineral density and increased risk of fracture. The method of claim 1, wherein said compound or its isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or any combination thereof is administered in a dose of 1 25 mg per day, 250 mg per day or 500 mg per day. 1 9. A method for decreasing serum osterone levels in a male subject suffering from castration-resistant prostate cancer (CRPC) comprising administering a therapeutically effective amount of a compound of formula I or its isomer , pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof: where And it is C (O) or CH2; Ri, R2 are independently hydrogen, halogen, hydroxyl, alkoxy, cyano, nitro, CF3, N (R) 2, sulfonamide, S02R, alkyl, haloalkyl, aryl, O-Alk-NRsRe or O-Alk-heterocycle in which the heterocycle is a substituted or unsubstituted heterocycle ring of 3 to 7 members, optionally aromatic; R3, 4 are independently hydrogen, halogen, hydroxyalkyl, hydroxyl, alkoxy, cyano, nitro, CF3, NHCOR, N (R) 2, sulfonamide, SO2R, alkyl, haloalkyl, aryl or protected hydroxyl; R is alkyl, hydrogen, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, halogen, alkenyl, CN, N02 or OH; R5 and R6 are independently hydrogen, phenyl, an alkyl group of 1 to 6 carbon atoms, a cycloalkyl of 3 to 7 members, a heterocycle of 3 to 7 members, an aryl of 5 to 7 members; or R5 and 6 form a ring of 3 to 7 members with the nitrogen atom; j and k are independently 1-4; Y Alk is a linear alkyl of 1 to 7 carbons, branched alkyl of 1 to 7 carbons or cycloalkyl of 3 to 8 carbons. 20. The method of the compound claim of formula I is selected from: 21. The method of the compound claim of formula I is Compound IV: 22. The method of claim 1, wherein said castration-resistant prostate cancer (CRPC) is metastatic CRPC (mCRPC). 23. The method of claim 1, wherein said serum osterone levels are total serum osterone levels, free serum osterone levels, the percentage of free osterone in serum (% free T) or a combination of these. 24. The method of claim 1, wherein said subject has high or increasing levels of prostate-specific antigen (PSA). 25. The method of claim 1, wherein said subject also receives androgen deprivation therapy (ADT). 26. The method of claim 19, wherein said subject further receives a ligand of selective estrogen receptor modulators (SERM). 27. The method of claim 1, wherein the serum testosterone is decreased to a value less than about 25 ng / dL, 10 ng / dL, 5 ng / dL or 1 ng / dL. 28. The method of claim 19, wherein the percentage of free serum testosterone (% free T) is decreased to less than about 1%, 0.5%, 0.25% and 0.05%. 29. The method of claim 19, wherein said administration of the compound does not cause side effects associated with androgen deprivation therapy (ADT). 30. The method of claim 29, wherein said side effects is selected from the group consisting of: hot flushes, gynecomastia, increased body fat, bone loss, decreased bone mineral density and increased risk of fracture. 31 The method of claim 19, wherein said compound or its isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or any combination thereof is administered in a dose of 1 25 mg per day, 250 mg per day or 500 mg per day. 32. A method for increasing serum concentrations of steroid hormone-binding globulin (SHBG) in a male subject suffering from castration-resistant prostate cancer (CRPC) comprising the administration of a therapeutically effective amount of a compound of Formula I or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or any combination thereof: where And it is C (O) or CH2; Ri, R 2 are independently hydrogen, halogen, hydroxyl, alkoxy, cyano, nitro, C F 3, N (R) 2, sulfonamide, SO 2 R, alkyl, haloalkyl, aryl, 0-Alk-N Rs R 6 or O-Alk-heterocycle in that the heterocycle is a substituted or unsubstituted heterocycle of 3 to 7 membered, optionally aromatic; R3, R4 are independently hydrogen, halogen, hydroxyalkyl, hydroxyl, alkoxy, cyano, nitro, CF3, N HCOR, N (R) 2, sulfonamide, SO2R, alkyl, haloalkyl, aryl or protected hydroxyl; R is alkyl, hydrogen, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, halogen, alkenyl, CN, N02 or OH; R5 and Re are independently hydrogen, phenyl, an alkyl group of 1 to 6 carbon atoms, a cycloalkyl of 3 to 7 members, a heterocycle of 3 to 7 members, an aryl of 5 to 7 members; or R5 and Re form a ring of 3 to 7 members with the nitrogen atom; j and k are independently 1-4; Y Alk is a linear alkyl of 1 to 7 carbons, branched alkyl of 1 to 7 carbons or cycloalkyl of 3 to 8 carbons. 33. The method of claim 32, wherein said compound of formula I is selected from: 311 34. The method of claim 32, wherein said compound of formula I is Compound IV: 35. The method of claim 32, wherein said castration-resistant prostate cancer (CRPC) is metastatic CRPC (mCRPC). 36. The method of claim 32, wherein said subject also receives androgen deprivation therapy (ADT). 37. The method of claim 32, wherein said administration of the compound does not cause side effects associated with androgen deprivation therapy (ADT). 38. The method of claim 37, wherein said side effects is selected from the group consisting of: hot flushes, gynecomastia, increased body fat, bone loss, decreased bone mineral density and increased risk of fracture. 39. The method of claim 32, wherein said compound or its isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or any combination thereof is administered in a dose of 125 mg per day, 250 mg per day or 500 mg per day. SUMMARY The present invention relates to methods for reducing testosterone levels through the reduction of luteinizing hormone (LH) or independent of LH levels in a male subject, and methods to treat, suppress, reduce incidence, reduce severity, or inhibit prostate cancer, advanced prostate cancer (5), castration-resistant prostate cancer (CRPC), metastatic castration-resistant prostate cancer (mCRPC) and palliative treatment of prostate cancer, advanced prostate cancer, castration-resistant prostate cancer (CRPC), metastatic castration-resistant prostate cancer (mCRPC), and methods to reduce elevated or increasing levels of PSA and / or increased levels of SHBG in a subject suffering from prostate cancer, advanced prostate cancer, castration-resistant prostate cancer (CRPC) and metastatic castration-resistant prostate cancer (10) (mCRPC). The compounds of this invention suppress free or total testosterone levels despite castration levels secondary to ADT and reduce high or increasing levels of PSA.