JP2014524479A - Estrogen receptor ligands and methods of use thereof - Google Patents

Abstract

The present invention relates to a method for reducing testosterone levels in male subjects by reducing luteinizing hormone (LH) or independent of LH levels, as well as prostate cancer, advanced prostate cancer, castration resistant prostate. (CRPC), methods of treating, suppressing, reducing incidence, reducing severity, or inhibiting prostate cancer, advanced prostate cancer, metastatic castration resistant prostate cancer (mCRPC) Castration therapy for castration resistant prostate cancer (CRPC) and metastatic castration resistant prostate cancer (mCRPC) and prostate cancer, advanced prostate cancer, castration resistant prostate cancer (CRPC) and metastatic castration Reduces or increases PSA levels and / or SHBG levels in subjects suffering from resistant prostate cancer (mCRPC) It relates to methods for increasing the Le.

Description

  The present invention treats castration resistant prostate cancer (CRPC) and its symptoms, reduces incidence, reduces severity, inhibits progression, or survival of men with CRPC. Methods for increasing and methods for reducing serum prostate specific antigen (PSA) levels and serum testosterone levels in male subjects suffering from castration resistant prostate cancer (CRPC).

  Estrogens refer to a group of endogenous synthetic hormones that are important for tissue and bone maintenance and are used for tissue and bone maintenance. Estrogens are endocrine regulators in cellular processes that are involved in the development and maintenance of the reproductive system. The role of estrogens in reproductive biology, prevention of postmenopausal hot flashes, and prevention of postmenopausal osteoporosis is well established. Estradiol is the major endogenous human estrogen and is found in both women and men.

  The biological effects of estrogens and antiestrogens are manifested through two distinct intracellular receptors, estrogen receptor α (ERα) and estrogen receptor β (ERβ). Endogenous estrogens are typically potent activators of both receptor subtypes. For example, estradiol acts as an ERα agonist in many tissues, including breast, bone, cardiovascular and central nervous system tissues. Selective estrogen receptor modulators generally act differently in different tissues. For example, a SERM can be an ERα antagonist in the breast, but can be a partial ERα agonist in the uterus, bone and cardiovascular system. Thus, compounds that act as estrogen receptor ligands are useful for treating a variety of conditions and disorders.

  Prostate cancer is one of the most frequently diagnosed non-skin cancers in men in the United States, the second most common cause of cancer death, and 241,740 new cases in 2012 in the United States Cases and 28,472 deaths are expected. In up to 30% of patients with prostate cancer who received primary treatment by radiation or surgery, metastatic disease develops within 10 years of primary treatment. A metastatic disease called metastatic CRPC (mCRPC) occurs in approximately 50,000 patients per year.

  Patients with advanced prostate cancer receive androgen deprivation therapy (ADT) with luteinizing hormone-releasing hormone (LHRH) agonists, LHRH antagonists, or bilateral testicular removal.

  Patients with metastatic prostate cancer who are not receiving hormonal medication are first treated using primary ADT that results in castration (serum total testosterone levels <50 ng / dL). Symptoms are improved by ADT, but ADT does not cure these patients. Unfortunately, prostate cancer cells eventually become castration resistant and these men develop advanced disease. Men with mCRPC have a very poor prognosis, symptoms associated with severe cancer, and a life expectancy of less than 16 months.

  In males, EDT reduces not only testosterone levels, but also estrogen levels because estrogen is derived from aromatization of testosterone and its levels are depleted by androgen deprivation therapy. As a result, ADT also reduces estrogen to “castration” levels.

  Estrogen deficiency induced by androgen deprivation therapy is hot flashes, gynecomastia and breast pain, bone loss, loss of bone quality and strength, osteoporosis and life-threatening fractures, harmful lipid changes, cardiovascular Causes serious side effects including increased disease and myocardial infarction, and depression and other mood swings. Many of the side effects of ADT estrogen deficiency are thought to be mediated by ERα.

  Leuprolide acetate (Lupron®) is a synthetic nonapeptide analog of natural gonadotropin releasing hormone (GnRH or LHRH). Leuprolide acetate is an LHRH superagonist that ultimately suppresses LH secretion by the pituitary gland. Leuprolide acetate acts as a potent inhibitor of gonadotropin secretion, resulting in suppression of ovarian and testicular steroidogenesis. In humans, administration of leuprolide acetate results in the first increase in circulating levels of luteinizing hormone (LH) and follicle stimulating hormone (FSH), and gonadal steroids (testosterone and dihydrotestosterone in men and estrone and premenopausal women). Leads to a transient increase in the level of estradiol). However, continuous administration of leuprolide acetate results in decreased levels of LH and FSH. In men, testosterone is reduced to castration levels (less than 50 ng / dL). In premenopausal females, estrogen is reduced to postmenopausal levels. Testosterone is a known irritant for prostate cancer cells. Thus, suppression of testosterone secretion or inhibition of testosterone action is a necessary component of prostate cancer therapy. Leuprolide acetate can be used for LH suppression, which is the reduction and reduction of serum testosterone to castration levels to treat prostate cancer.

  Prior to the introduction of the LHRH agonist, castration levels of testosterone were achieved by increasing estrogen activity in the pituitary gland with estrogen, primarily diethylstilbestrol (DES). DES was equally effective as an LHRH agonist in suppressing testosterone to castration levels. Patients treated with DES had neither hot flashes nor bone loss, but had a higher proportion of gynecomastia than ADT with LHRH agonists. Unfortunately, highly potent pure estrogens, such as DES and estradiol, are often associated with a high risk of severe cardiovascular and thromboembolic complications, which have limited their clinical use.

  The compounds of the present invention are non-steroidal selective ERα agonists. In the treatment of CRPC and metastatic CRPC (mCRPC) patients, these novel small molecules increase the levels of serum sex hormone or steroid hormone binding globulin (SHBG), thereby stimulating prostate growth and prostate cancer By reducing the circulating level of serum free testosterone in the form of, the testosterone levels are further suppressed for patients undergoing ADT (ie, the testosterone levels in these patients are already castrated). Since the compounds of the present invention are ERα agonists, they also include the ability to maintain bone, reduce the incidence of hot flashes, and avoid insulin resistance and deleterious lipid changes commonly associated with LHRH agonists and antagonists. Improve the side effects of estrogen deficiency.

In one embodiment, the present invention provides a therapeutically effective amount of a compound of formula I or an isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate or any of the following described herein. Treating, suppressing, reducing incidence, reducing severity, inhibiting progression, or inhibiting castration, including administering these combinations, including castration resistant prostate cancer (CRPC) and its symptoms Methods for increasing survival in men with sexual prostate cancer are provided.

  In one embodiment, the present invention relates to a male subject suffering from castration resistant prostate cancer (CRPC) comprising administering a therapeutically effective amount of a compound of formula I as described herein below. Methods are provided for reducing serum PSA levels. In another embodiment, the compound is Compound IV, as described herein below.

  In one embodiment, the present invention relates to a male subject suffering from castration resistant prostate cancer (CRPC) comprising administering a therapeutically effective amount of a compound of formula I as described herein below. A method of reducing serum testosterone levels is provided. In another embodiment, the compound is Compound IV, as described herein below.

  In one embodiment, the present invention provides sex hormones in a subject suffering from castration resistant prostate cancer (CRPC) comprising administering a therapeutically effective amount of a compound of formula I as described herein below. Alternatively, a method for increasing the serum concentration of steroid hormone binding globulin (SHBG) is intended. In another embodiment, the compound is Compound IV, as described herein below.

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

  The subject matter considered as the invention is particularly pointed out and distinctly claimed in the concluding portion of the specification. However, the present invention, together with its objects, features and advantages, both in terms of organization and method of operation, is best understood by referring to the following detailed description when read in conjunction with the accompanying drawings. obtain.

FIG. 1 shows serum testosterone (solid line) and total androgen (dotted line) levels in intact male monkeys after daily oral administration of Compound IV at 30 mg / kg (first dose on day 0). (See Example 8) FIG. 2 shows testosterone levels in intact rats treated with Compound IV (0.3 mg / kg, 1 mg / kg, 10 mg / kg, 30 mg / kg). ^I represents P <0.05 relative to the intact vehicle control. BLOQ values are represented graphically at the limit of quantification (0.08 ng / mL). (See Example 9) FIG. 3 shows the inhibitory effect of Compound IV on 17β-HSD5 enzyme activity. (See Example 12) FIG. 4 shows in vitro aggregation of human platelets in the presence of DES, 17β-estradiol (E2), and Compound IV. Platelet rich plasma (PRP) was incubated with vehicle, E2, DES, or Compound IV for 30 seconds before inducing aggregation by 0.3 units of thrombin. Aggregation was monitored for 5 minutes and expressed as a percentage of the vehicle control. (See Example 13) FIG. 5 shows a general synthetic scheme for the preparation of compounds II-XII. (See Example 1) FIG. 6 shows a synthetic scheme for the preparation of compound IV. (See Example 2) FIG. 7 shows a synthetic scheme for the preparation of compound VI. (See Example 3) FIG. 8 shows a synthetic scheme for the preparation of compounds IX and X. (See Example 5) FIG. 9 shows testosterone levels in intact rats treated with Compound IV after 24 hours, 72 hours and 168 hours with doses of 3 mg / kg, 10 mg / kg and 300 mg / kg. (See Example 9) FIG. 10 shows LH levels in treated intact and orchitotomized (ORX) rats with doses of 0.3, 1 mg / kg, 3 mg / kg, 10 mg / kg and 30 mg / kg of compound IV. (FIG. 10A), FSH level (FIG. 10B), testosterone level (FIG. 10C), prostate weight level (FIG. 10D), seminal vesicle weight level (FIG. 10E) and levator ani muscle weight (FIG. 10F). ^I represents P <0.05 relative to the intact vehicle control. ^O represents P <0.05 relative to the ORX vehicle control. BLOQ values are represented graphically at the limit of quantification (0.08 ng / mL). (See Example 9) FIG. 10 shows LH levels in treated intact and orchitotomized (ORX) rats with doses of 0.3, 1 mg / kg, 3 mg / kg, 10 mg / kg and 30 mg / kg of compound IV. (FIG. 10A), FSH level (FIG. 10B), testosterone level (FIG. 10C), prostate weight level (FIG. 10D), seminal vesicle weight level (FIG. 10E) and levator ani muscle weight (FIG. 10F). ^I represents P <0.05 relative to the intact vehicle control. ^O represents P <0.05 relative to the ORX vehicle control. BLOQ values are represented graphically at the limit of quantification (0.08 ng / mL). (See Example 9) FIG. 10 shows LH levels in treated intact and orchitotomized (ORX) rats with doses of 0.3, 1 mg / kg, 3 mg / kg, 10 mg / kg and 30 mg / kg of compound IV. (FIG. 10A), FSH level (FIG. 10B), testosterone level (FIG. 10C), prostate weight level (FIG. 10D), seminal vesicle weight level (FIG. 10E) and levator ani muscle weight (FIG. 10F). ^I represents P <0.05 relative to the intact vehicle control. ^O represents P <0.05 relative to the ORX vehicle control. BLOQ values are represented graphically at the limit of quantification (0.08 ng / mL). (See Example 9) FIG. 10 shows LH levels in treated intact and orchitotomized (ORX) rats with doses of 0.3, 1 mg / kg, 3 mg / kg, 10 mg / kg and 30 mg / kg of compound IV. (FIG. 10A), FSH level (FIG. 10B), testosterone level (FIG. 10C), prostate weight level (FIG. 10D), seminal vesicle weight level (FIG. 10E) and levator ani muscle weight (FIG. 10F). ^I represents P <0.05 relative to the intact vehicle control. ^O represents P <0.05 relative to the ORX vehicle control. BLOQ values are represented graphically at the limit of quantification (0.08 ng / mL). (See Example 9) FIG. 10 shows LH levels in treated intact and orchitotomized (ORX) rats with doses of 0.3, 1 mg / kg, 3 mg / kg, 10 mg / kg and 30 mg / kg of compound IV. (FIG. 10A), FSH level (FIG. 10B), testosterone level (FIG. 10C), prostate weight level (FIG. 10D), seminal vesicle weight level (FIG. 10E) and levator ani muscle weight (FIG. 10F). ^I represents P <0.05 relative to the intact vehicle control. ^O represents P <0.05 relative to the ORX vehicle control. BLOQ values are represented graphically at the limit of quantification (0.08 ng / mL). (See Example 9) FIG. 10 shows LH levels in treated intact and orchitotomized (ORX) rats with doses of 0.3, 1 mg / kg, 3 mg / kg, 10 mg / kg and 30 mg / kg of compound IV. (FIG. 10A), FSH level (FIG. 10B), testosterone level (FIG. 10C), prostate weight level (FIG. 10D), seminal vesicle weight level (FIG. 10E) and levator ani muscle weight (FIG. 10F). ^I represents P <0.05 relative to the intact vehicle control. ^O represents P <0.05 relative to the ORX vehicle control. BLOQ values are represented graphically at the limit of quantification (0.08 ng / mL). (See Example 9) FIG. 11 shows prostate size in intact and ORX rats by administering Compound IV (FIG. 11A) and DES (FIG. 11B) at different doses. (See Example 15) FIG. 12 shows the difference between DES and Compound IV. DES cross-reacts with the glucocorticoid receptor (GR), whereas compound IV does not (FIG. 12A). DES cross-reacts with the androgen receptor (AR). DES moderately stimulates and moderately inhibits AR action (ie, DES is a partial agonist / antagonist), while compound IV does not (FIG. 12B). DES inhibits estrogen-related receptor (ERR) transactivation, whereas compound IV does not (FIG. 12C). (See Example 15) FIG. 12 shows the difference between DES and Compound IV. DES cross-reacts with the glucocorticoid receptor (GR), whereas compound IV does not (FIG. 12A). DES cross-reacts with the androgen receptor (AR). DES moderately stimulates and moderately inhibits AR action (ie, DES is a partial agonist / antagonist), while compound IV does not (FIG. 12B). DES inhibits estrogen-related receptor (ERR) transactivation, whereas compound IV does not (FIG. 12C). (See Example 15) FIG. 12 shows the difference between DES and Compound IV. DES cross-reacts with the glucocorticoid receptor (GR), whereas compound IV does not (FIG. 12A). DES cross-reacts with the androgen receptor (AR). DES moderately stimulates and moderately inhibits AR action (ie, DES is a partial agonist / antagonist), while compound IV does not (FIG. 12B). DES inhibits estrogen-related receptor (ERR) transactivation, whereas compound IV does not (FIG. 12C). (See Example 15) FIG. 13 shows the effect of Compound IV on the reduction of hot flashes in the morphine withdrawal model at doses of 5 mg / kg, 10 mg / kg, 15 mg / kg and 30 mg / kg. N = 7 animals per group. 17β-E2 was used at 5 mg / kg in 100% DMSO. (See Example 14) FIG. 14 shows a dose-dependent reduction in body weight (kg) of monkey by administering Compound IV for 91 days (about 20% at 100 mg / kg). No gynecomastia or hyperestrogenic signs were observed. (See Example 16) FIG. 15 shows dose-dependent reduction of serum testosterone levels (ng / mL) in monkeys after daily oral administration of Compound IV compared to a positive control (LHRH agonist). The dotted line shows the testosterone level in the chemically castrated patient, and the thick dashed line shows the testosterone level in the surgically castrated monkey. (See Example 16) FIG. 16 shows dose-dependent prostate specific antigen (PSA) levels (ng / mL) in monkeys at baseline and on day 28 by administering Compound IV. PSA levels were significantly reduced by treatment with Compound IV. (See Example 16) FIG. 17 shows the dose-dependent prostate volume using transrectal ultrasound (TRUS) in monkeys compared to a positive control (LHRH agonist) by administering Compound IV at week 6. (See Example 16) FIG. 18 shows the dose-dependent organ weight (prostate, seminal vesicle and testis) at day 90 as a percentage of control monkeys by administering Compound IV (FIG. 18A). Prostate weight at week 13 autopsy after daily oral administration of Compound IV in monkeys (FIG. 18B). (See Example 16) FIG. 18 shows the dose-dependent organ weight (prostate, seminal vesicle and testis) at day 90 as a percentage of control monkeys by administering Compound IV (FIG. 18A). Prostate weight at week 13 autopsy after daily oral administration of Compound IV in monkeys (FIG. 18B). (See Example 16) FIG. 19 shows dose-dependent mean total testosterone levels (nmol / L) in humans over a 1-11 day period by administering Compound IV (100 mg, 300 mg, 600 mg and 1000 mg). (See Example 17) FIG. 20 shows dose-dependent mean LH levels (IU / L) in humans over a 1-10 day period by administering Compound IV (100 mg, 300 mg, 600 mg and 1000 mg). (See Example 17) FIG. 21 shows dose-dependent mean free testosterone levels (pg / mL) in humans over a 1-10 day period by administering Compound IV (100 mg, 300 mg, 600 mg and 1000 mg). (See Example 17) FIG. 22 shows dose-dependent mean PSA levels (μg / L) in humans over a 1-10 day period by administering Compound IV (100 mg, 300 mg, 600 mg and 1000 mg). (See Example 17) FIG. 23 shows dose-dependent serum testosterone levels (ng / mL) after 14 days of recovery of Compound IV administration in intact rats. ^I represents P <0.05 relative to the intact control. (See Example 10) FIG. 24 shows the percent reduction in serum PSA in 7 subjects with castration resistant prostate cancer (CRPC) treated with 2000 mg of Compound IV (Study 3). FIG. 25 shows a flowchart describing the procedure of Study 6 (Example 27). FIG. 26 shows the study details for each of the clinical trials with Compound IV in human subjects (healthy, untreated prostate cancer patients and castration resistant prostate cancer patients) (Examples 25 and 26). ). FIG. 27 shows SHBG induction by Compound IV in patients who did not receive treatment from Study 2 and Study 5 (FIG. 27A) and in CRPC patients who received concurrent ADT from Study 3 (FIG. 27B). , And shows the relationship between SHBG and percent free testosterone (free T%). In the Study 2 and Study 5 trials, baseline SHBG is induced at approximately 150-700% after 28 days of treatment with Compound IV (FIG. 27A). SHBG induction correlates strongly with a reduction in free T% [free T (pg / mL) / total T (pg / mL) ^* 100]. The regression of the relationship shows that about 400% induction of SHBG is associated with about 75% reduction in free T%. Patients who have not received multiple treatments are dense in this range across all doses of Compound IV. Significantly, this strong relationship is maintained in CRPC patients undergoing concurrent ADT from Study 3 even when judged from therapy with Compound IV for only 15 days (FIG. 27B). Open symbols represent the baseline (BL) and filled symbols are treated with Compound IV as described herein below (Example 26). FIG. 28 shows treatment from studies 2 and 5 on day 7 (FIG. 28A); day 14 (FIG. 28B); day 21 (FIG. 28C) and day 28 (FIG. 28D) of treatment with Compound IV. FIG. 6 shows the change in percent free testosterone relative to the change in PSA in prostate cancer patients not receiving (Example 26). FIG. 28 shows treatment from studies 2 and 5 on day 7 (FIG. 28A); day 14 (FIG. 28B); day 21 (FIG. 28C) and day 28 (FIG. 28D) of treatment with Compound IV. FIG. 6 shows the change in percent free testosterone relative to the change in PSA in prostate cancer patients not receiving (Example 26). FIG. 29 shows the change in PSA versus the change in SHBG in prostate cancer patients not receiving treatment from studies 2 and 5 on day 28. Extensive SHBG induction allows over 50% reduction in PSA (Example 25). FIG. 30 shows the change in percent free testosterone relative to the change in PSA in castration resistant prostate cancer patients from Study 3 on Day 15 (7 subjects) and Day 30 (3 subjects). (Example 26). FIG. 31 shows the molar ratio of SHBG to total testosterone as a function of time in prostate cancer patients not receiving treatment from studies 2 and 5 (solid line). The dotted line represents the percentage of free testosterone (free T%) as a function of time (Example 25). FIG. 32 shows the percent change in SHBG relative to the mean trough value of Compound IV, calculated based on the results of Study 1 and Study 2 on day 28 and extrapolation to lower doses of 125 mg, 250 mg and 500 mg. This suggests that even at lower doses of Compound IV, SHBG can be elevated enough to significantly suppress free T% and PSA (Example 25). FIG. 33 shows a flowchart describing the procedure of Study 3 (Example 26).

  It should be understood that for simplicity and clarity of illustration, elements shown in the figures are not necessarily drawn to scale. For example, some dimensions of elements may be exaggerated relative to other elements for clarity. Further, where considered appropriate, reference numerals may be repeated in the figures illustrating corresponding or similar elements.

  In the following detailed description, numerous specific details are set forth in order to provide a thorough understanding of the present invention. However, those skilled in the art will appreciate that the invention may be practiced without these specific details. In other instances, well known methods, procedures, and components have not been described in detail so as not to obscure the present invention.

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

  In one embodiment, the compounds described herein and / or compositions comprising them may be used to reduce total serum testosterone levels and reduce prostate specific antigen (PSA) in male subjects. In one embodiment, the reduction in total serum testosterone levels is up to the castration level. In one embodiment, the reduction in total serum testosterone levels does not reach castration levels. In one embodiment, the decrease in total serum testosterone levels is to a level less than achievable with ADT alone.

  In one embodiment, the compounds described herein and / or compositions comprising them may be used to reduce prostate specific antigens regardless of their reduction or lack in testosterone levels.

  In one embodiment, the compounds described herein and / or compositions comprising the same may be used to reduce total serum testosterone levels in a male subject, wherein the reduction of total serum testosterone is serum Caused by a reduction in luteinizing hormone (LH) levels.

  In one embodiment, the compounds described herein and / or compositions comprising the same may be used to reduce total serum testosterone levels in a male subject, wherein the reduction of total serum testosterone is serum It is unrelated to the reduction of luteinizing hormone levels.

  In one embodiment, the compounds described herein and / or compositions comprising the same may be used to reduce percent serum free testosterone (free T%) in male subjects.

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

  In one embodiment, a compound described herein and / or a composition comprising the same is an LHRH agonist or LHRH antagonist for increasing progression-free or overall survival in a subject suffering from prostate cancer Can be used in combination. In another embodiment, the prostate cancer is advanced prostate cancer. In another embodiment, the prostate cancer is castration resistant prostate cancer (CRPC). In another embodiment, the CRPC is metastatic CRPC (mCRPC). In another embodiment, the subject is surgically castrated. In another embodiment, the subject is chemically castrated.

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

In one embodiment, the invention provides a therapeutically effective amount of a compound represented by the structure of Formula I, or an isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate, or any combination thereof. Providing a method of reducing total serum testosterone levels in a male subject, comprising the step of:
Where
Y is C (O) or CH ₂ ;
R ₁ and R ₂ are independently hydrogen, halogen, hydroxyl, alkoxy, cyano, nitro, CF ₃ , N (R) ₂ , sulfonamide, SO ₂ R, alkyl, haloalkyl, aryl, O—Alk—NR _5. R ₆ or O-Alk-heterocycle, wherein the heterocycle is a 3-7 membered substituted or unsubstituted heterocyclic ring, optionally aromatic;
R ₃ , R ₄ are independently hydrogen, halogen, hydroxyalkyl, hydroxyl, alkoxy, cyano, nitro, CF ₃ , NHCOR, N (R) ₂ , sulfonamide, SO ₂ R, alkyl, haloalkyl, aryl or protected The hydroxyl being
R is alkyl, hydrogen, haloalkyl, dihaloalkyl, trihaloalkyl, CH ₂ F, CHF ₂ , CF ₃ , CF ₂ CF ₃ , aryl, phenyl, halogen, alkenyl, CN, NO ₂ , or OH;
R ₅ and R ₆ are independently hydrogen, phenyl, an alkyl group of 1-6 carbon atoms, 3-7 membered cycloalkyl, 3-7 membered heterocycle, 5-7 membered aryl, or R ₅ And R ₆ together with the nitrogen atom form a 3-7 membered ring,
j and k are independently 1 to 4,
Alk is a linear alkyl of 1-7 carbons, a branched alkyl of 1-7 carbons, or a cyclic alkyl of 3-8 carbons.
In a further embodiment of the methods described herein, the compound of formula I is represented by formula IA:
In which R ₁ , R ₂ , R ₃ , R ₄ , j and k are as defined for formula I. In one embodiment, the present invention provides a therapeutically effective amount of a compound represented by a compound of formula II or an isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate or any combination thereof. A method of reducing total serum testosterone levels in a male subject is provided.

In one embodiment, the present invention provides a therapeutically effective amount of a compound represented by a compound of formula III or an isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate or any combination thereof. A method of reducing total serum testosterone levels in a male subject is provided.

In one embodiment, the invention provides a therapeutically effective amount of a compound represented by a compound of formula IV or an isomer thereof, a pharmaceutical, a pharmaceutically acceptable salt, a polymorph, a hydrate, or any combination thereof. A method of reducing total serum testosterone levels in a male subject is provided.

In one embodiment, the present invention provides a therapeutically effective amount of a compound represented by a compound of formula V, or an isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate, or any combination thereof. A method of reducing total serum testosterone levels in a male subject is provided.

In one embodiment, the present invention provides a therapeutically effective amount of a compound represented by a compound of formula VI or an isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate, or any combination thereof. A method of reducing total serum testosterone levels in a male subject is provided.

In one embodiment, the invention provides a therapeutically effective amount of a compound represented by a compound of formula VII, or an isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate, or any combination thereof. A method of reducing total serum testosterone levels in a male subject is provided.

In one embodiment, the present invention provides a therapeutically effective amount of a compound represented by a compound of formula VIII or an isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate or any combination thereof A method of reducing total serum testosterone levels in a male subject is provided.

In one embodiment, the invention provides a therapeutically effective amount of a compound represented by a compound of formula IX, or an isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate, or any combination thereof. A method of reducing total serum testosterone levels by reducing luteinizing hormone (LH) levels in a male subject with prostate cancer, comprising:

In one embodiment, the invention provides a therapeutically effective amount of a compound represented by a compound of formula X or an isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate or any combination thereof A method of reducing total serum testosterone levels in a male subject is provided.

In one embodiment, the present invention provides a therapeutically effective amount of a compound represented by a compound of formula XI or an isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate or any combination thereof A method of reducing total serum testosterone levels in a male subject is provided.

In one embodiment, the invention provides a therapeutically effective amount of a compound represented by a compound of formula XII or an isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate, or any combination thereof. A method of reducing total serum testosterone levels in a male subject is provided.

In one embodiment, the invention provides a therapeutically effective amount of a compound represented by the structure of Formula I, or an isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate, or any combination thereof. Providing a method of reducing free serum testosterone levels in a male subject, comprising the step of:
Where
Y is C (O) or CH ₂ ;
R ₁ and R ₂ are independently hydrogen, halogen, hydroxyl, alkoxy, cyano, nitro, CF ₃ , N (R) ₂ , sulfonamide, SO ₂ R, alkyl, haloalkyl, aryl, O—Alk—NR _5. R ₆ or O-Alk-heterocycle, wherein the heterocycle is a 3-7 membered substituted or unsubstituted heterocyclic ring, optionally aromatic;
R ₃ , R ₄ are independently hydrogen, halogen, hydroxyalkyl, hydroxyl, alkoxy, cyano, nitro, CF ₃ , NHCOR, N (R) ₂ , sulfonamide, SO ₂ R, alkyl, haloalkyl, aryl or protected The hydroxyl being
R is alkyl, hydrogen, haloalkyl, dihaloalkyl, trihaloalkyl, CH ₂ F, CHF ₂ , CF ₃ , CF ₂ CF ₃ , aryl, phenyl, halogen, alkenyl, CN, NO ₂ , or OH;
R ₅ and R ₆ are independently hydrogen, phenyl, an alkyl group of 1-6 carbon atoms, 3-7 membered cycloalkyl, 3-7 membered heterocycle, 5-7 membered aryl, or R ₅ And R ₆ together with the nitrogen atom form a 3-7 membered ring,
j and k are independently 1 to 4,
Alk is a linear alkyl of 1-7 carbons, a branched alkyl of 1-7 carbons, or a cyclic alkyl of 3-8 carbons.

In a further embodiment of the methods described herein, the compound of formula I is represented by formula IA:
In which R ₁ , R ₂ , R ₃ , R ₄ , j and k are as defined for formula I.

In one embodiment, the present invention provides a therapeutically effective amount of a compound represented by a compound of formula II or an isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate or any combination thereof. A method of reducing free serum testosterone levels in a male subject is provided.

In one embodiment, the present invention provides a therapeutically effective amount of a compound represented by a compound of formula III or an isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate or any combination thereof. A method of reducing free serum testosterone levels in a male subject is provided.

In one embodiment, the invention provides a therapeutically effective amount of a compound represented by a compound of formula IV or an isomer thereof, a pharmaceutical, a pharmaceutically acceptable salt, a polymorph, a hydrate, or any combination thereof. A method of reducing free serum testosterone levels in a male subject is provided.

In one embodiment, the present invention provides a therapeutically effective amount of a compound represented by a compound of formula V, or an isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate, or any combination thereof. A method of reducing free serum testosterone levels in a male subject is provided.

In one embodiment, the invention provides a therapeutically effective amount of a compound represented by a compound of formula VI or an isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate, or any combination thereof. A method of reducing free serum testosterone levels in a male subject is provided.

In one embodiment, the invention provides a therapeutically effective amount of a compound represented by a compound of formula VII, or an isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate, or any combination thereof. A method of reducing free serum testosterone levels in a male subject is provided.

In one embodiment, the present invention provides a therapeutically effective amount of a compound represented by a compound of formula VIII or an isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate or any combination thereof A method of reducing free serum testosterone levels in a male subject is provided.

In one embodiment, the invention provides a therapeutically effective amount of a compound represented by a compound of formula IX, or an isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate, or any combination thereof. A method of reducing free serum testosterone levels by reducing luteinizing hormone (LH) levels in a male subject with prostate cancer is provided.

In one embodiment, the invention provides a therapeutically effective amount of a compound represented by a compound of formula X or an isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate or any combination thereof A method of reducing free serum testosterone levels in a male subject is provided.

In one embodiment, the present invention provides a therapeutically effective amount of a compound represented by a compound of formula XI or an isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate or any combination thereof. A method of reducing free serum testosterone levels in a male subject is provided.

In one embodiment, the present invention provides a therapeutically effective amount of a compound represented by a compound of formula XII or an isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate or any combination thereof. A method of reducing free serum testosterone levels in a male subject is provided.

In one embodiment, the invention provides a therapeutically effective amount of a compound represented by the structure of Formula I, or an isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate, or any combination thereof. Providing a method for reducing the percent free serum testosterone (free T%) in a male subject comprising the steps of:
Where
Y is C (O) or CH ₂ ;
R ₁ and R ₂ are independently hydrogen, halogen, hydroxyl, alkoxy, cyano, nitro, CF ₃ , N (R) ₂ , sulfonamide, SO ₂ R, alkyl, haloalkyl, aryl, O—Alk—NR _5. R ₆ or O-Alk-heterocycle, wherein the heterocycle is a 3-7 membered substituted or unsubstituted heterocyclic ring, optionally aromatic;
R ₃ , R ₄ are independently hydrogen, halogen, hydroxyalkyl, hydroxyl, alkoxy, cyano, nitro, CF ₃ , NHCOR, N (R) ₂ , sulfonamide, SO ₂ R, alkyl, haloalkyl, aryl or protected The hydroxyl being
R is alkyl, hydrogen, haloalkyl, dihaloalkyl, trihaloalkyl, CH ₂ F, CHF ₂ , CF ₃ , CF ₂ CF ₃ , aryl, phenyl, halogen, alkenyl, CN, NO ₂ , or OH;
R ₅ and R ₆ are independently hydrogen, phenyl, an alkyl group of 1-6 carbon atoms, 3-7 membered cycloalkyl, 3-7 membered heterocycle, 5-7 membered aryl, or R ₅ And R ₆ together with the nitrogen atom form a 3-7 membered ring,
j and k are independently 1 to 4,
Alk is a linear alkyl of 1-7 carbons, a branched alkyl of 1-7 carbons, or a cyclic alkyl of 3-8 carbons.

In a further embodiment of the methods described herein, the compound of formula I is represented by formula IA:
In which R ₁ , R ₂ , R ₃ , R ₄ , j and k are as defined for formula I.

In one embodiment, the present invention provides a therapeutically effective amount of a compound represented by a compound of formula II or an isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate or any combination thereof. A method of reducing the percentage of free serum testosterone (free T%) in a male subject is provided.

In one embodiment, the present invention provides a therapeutically effective amount of a compound represented by a compound of formula III or an isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate or any combination thereof. A method of reducing the percentage of free serum testosterone (free T%) in a male subject is provided.

In one embodiment, the invention provides a therapeutically effective amount of a compound represented by a compound of formula IV or an isomer thereof, a pharmaceutical, a pharmaceutically acceptable salt, a polymorph, a hydrate, or any combination thereof. A method of reducing the percentage of free serum testosterone (free T%) in a male subject is provided.

In one embodiment, the present invention provides a therapeutically effective amount of a compound represented by a compound of formula V, or an isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate, or any combination thereof. A method of reducing the percentage of free serum testosterone (free T%) in a male subject is provided.

In one embodiment, the invention provides a therapeutically effective amount of a compound represented by a compound of formula VI or an isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate, or any combination thereof. A method of reducing the percentage of free serum testosterone (free T%) in a male subject is provided.

In one embodiment, the invention provides a therapeutically effective amount of a compound represented by a compound of formula VII, or an isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate, or any combination thereof. A method of reducing the percentage of free serum testosterone (free T%) in a male subject is provided.

In one embodiment, the invention provides a therapeutically effective amount of a compound represented by a compound of formula VIII, or an isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate, or any combination thereof. A method of reducing the percentage of free serum testosterone (free T%) in a male subject is provided.

In one embodiment, the invention provides a therapeutically effective amount of a compound represented by a compound of formula IX, or an isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate, or any combination thereof. A method of reducing the percentage of free serum testosterone (free T%) by reducing luteinizing hormone (LH) levels in a male subject with prostate cancer is provided.

In one embodiment, the invention provides a therapeutically effective amount of a compound represented by a compound of formula X or an isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate or any combination thereof A method of reducing the percentage of free serum testosterone (free T%) in a male subject is provided.

In one embodiment, the present invention provides a therapeutically effective amount of a compound represented by a compound of formula XI or an isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate or any combination thereof A method of reducing the percentage of free serum testosterone (free T%) in a male subject is provided.

In one embodiment, the invention provides a therapeutically effective amount of a compound represented by a compound of formula XII or an isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate, or any combination thereof. A method of reducing the percentage of free serum testosterone (free T%) in a male subject is provided.

In one embodiment, the invention provides a therapeutically effective amount of a compound represented by the structure of Formula I, or an isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate, or any combination thereof. Treating, suppressing, reducing incidence, reducing severity, inhibiting progression, or inhibiting castration resistant prostate cancer (CRPC) and symptoms thereof Provide a way to increase the survival of men with cancer,
Where
Y is C (O) or CH ₂ ;
R ₁ and R ₂ are independently hydrogen, halogen, hydroxyl, alkoxy, cyano, nitro, CF ₃ , N (R) ₂ , sulfonamide, SO ₂ R, alkyl, haloalkyl, aryl, O—Alk—NR _5. R ₆ or O-Alk-heterocycle, wherein the heterocycle is a 3-7 membered substituted or unsubstituted heterocyclic ring, optionally aromatic;
R ₃ , R ₄ are independently hydrogen, halogen, hydroxyalkyl, hydroxyl, alkoxy, cyano, nitro, CF ₃ , NHCOR, N (R) ₂ , sulfonamide, SO ₂ R, alkyl, haloalkyl, aryl or protected The hydroxyl being
R is alkyl, hydrogen, haloalkyl, dihaloalkyl, trihaloalkyl, CH ₂ F, CHF ₂ , CF ₃ , CF ₂ CF ₃ , aryl, phenyl, halogen, alkenyl, CN, NO ₂ , or OH;
R ₅ and R ₆ are independently hydrogen, phenyl, an alkyl group of 1-6 carbon atoms, 3-7 membered cycloalkyl, 3-7 membered heterocycle, 5-7 membered aryl, or R ₅ And R ₆ together with the nitrogen atom form a 3-7 membered ring,
j and k are independently 1 to 4,
Alk is a linear alkyl of 1-7 carbons, a branched alkyl of 1-7 carbons, or a cyclic alkyl of 3-8 carbons.

In a further embodiment of the methods described herein, the compound of formula I is represented by formula IA:
In which R ₁ , R ₂ , R ₃ , R ₄ , j and k are as defined for formula I.

In one embodiment, the present invention provides a therapeutically effective amount of a compound represented by a compound of formula II or an isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate or any combination thereof. Treating, suppressing, reducing incidence, reducing severity, inhibiting progression, or inhibiting castration resistant prostate cancer (CRPC) and symptoms thereof A method for increasing the survival of men with cancer.

In one embodiment, the present invention provides a therapeutically effective amount of a compound represented by a compound of formula III or an isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate or any combination thereof. Treating, suppressing, reducing incidence, reducing severity, inhibiting progression, or inhibiting castration resistant prostate cancer (CRPC) and symptoms thereof A method for increasing the survival of men with cancer.

In one embodiment, the invention provides a therapeutically effective amount of a compound represented by a compound of formula IV or an isomer thereof, a pharmaceutical, a pharmaceutically acceptable salt, a polymorph, a hydrate, or any combination thereof. Treating, suppressing, reducing incidence, reducing severity, inhibiting progression, or inhibiting castration resistant prostate cancer (CRPC) and symptoms thereof A method for increasing the survival of men with cancer.

In one embodiment, the present invention provides a therapeutically effective amount of a compound represented by a compound of formula V, or an isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate, or any combination thereof. Treating, suppressing, reducing incidence, reducing severity, inhibiting progression, or inhibiting castration resistant prostate cancer (CRPC) and symptoms thereof A method for increasing the survival of men with cancer.

In one embodiment, the invention provides a therapeutically effective amount of a compound represented by a compound of formula VI or an isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate, or any combination thereof. Treating, suppressing, reducing incidence, reducing severity, inhibiting progression, or inhibiting castration resistant prostate cancer (CRPC) and symptoms thereof A method for increasing the survival of men with cancer.

In one embodiment, the invention provides a therapeutically effective amount of a compound represented by a compound of formula VII, or an isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate, or any combination thereof. Treating, suppressing, reducing incidence, reducing severity, inhibiting progression, or inhibiting castration resistant prostate cancer (CRPC) and symptoms thereof A method for increasing the survival of men with cancer.

In one embodiment, the present invention provides a therapeutically effective amount of a compound represented by a compound of formula VIII or an isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate or any combination thereof Treating, suppressing, reducing incidence, reducing severity, inhibiting progression, or inhibiting castration resistant prostate cancer (CRPC) and symptoms thereof A method for increasing the survival of men with cancer.

In one embodiment, the invention provides a therapeutically effective amount of a compound represented by a compound of formula IX, or an isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate, or any combination thereof. Treating, suppressing, reducing incidence, reducing severity, inhibiting progression, or inhibiting castration resistant prostate cancer (CRPC) and symptoms thereof A method for increasing the survival of men with cancer.

In one embodiment, the invention provides a therapeutically effective amount of a compound represented by a compound of formula X or an isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate or any combination thereof Treating, suppressing, reducing incidence, reducing severity, inhibiting progression, or inhibiting castration resistant prostate cancer (CRPC) and symptoms thereof A method for increasing the survival of men with cancer.

In one embodiment, the present invention provides a therapeutically effective amount of a compound represented by a compound of formula XI or an isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate or any combination thereof Treating, suppressing, reducing incidence, reducing severity, inhibiting progression, or inhibiting castration resistant prostate cancer (CRPC) and symptoms thereof A method for increasing the survival of men with cancer.

In one embodiment, the invention provides a therapeutically effective amount of a compound represented by a compound of formula XII or an isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate, or any combination thereof. Treating, suppressing, reducing incidence, reducing severity, inhibiting progression, or inhibiting castration resistant prostate cancer (CRPC) and symptoms thereof A method for increasing the survival of men with cancer.

In one embodiment, the invention provides a therapeutically effective amount of a compound represented by the structure of Formula I, or an isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate, or any combination thereof. Providing a method of reducing serum prostate specific antigen (PSA) levels in a male subject suffering from castration resistant prostate cancer (CRPC), comprising:
Where
Y is C (O) or CH ₂ ;
R ₁ and R ₂ are independently hydrogen, halogen, hydroxyl, alkoxy, cyano, nitro, CF ₃ , N (R) ₂ , sulfonamide, SO ₂ R, alkyl, haloalkyl, aryl, O—Alk—NR _5. R ₆ or O-Alk-heterocycle, wherein the heterocycle is a 3-7 membered substituted or unsubstituted heterocyclic ring, optionally aromatic;
R ₃ , R ₄ are independently hydrogen, halogen, hydroxyalkyl, hydroxyl, alkoxy, cyano, nitro, CF ₃ , NHCOR, N (R) ₂ , sulfonamide, SO ₂ R, alkyl, haloalkyl, aryl or protected The hydroxyl being
R is alkyl, hydrogen, haloalkyl, dihaloalkyl, trihaloalkyl, CH ₂ F, CHF ₂ , CF ₃ , CF ₂ CF ₃ , aryl, phenyl, halogen, alkenyl, CN, NO ₂ , or OH;
R ₅ and R ₆ are independently hydrogen, phenyl, an alkyl group of 1-6 carbon atoms, 3-7 membered cycloalkyl, 3-7 membered heterocycle, 5-7 membered aryl, or R ₅ And R ₆ together with the nitrogen atom form a 3-7 membered ring,
j and k are independently 1 to 4,
Alk is a linear alkyl of 1-7 carbons, a branched alkyl of 1-7 carbons, or a cyclic alkyl of 3-8 carbons.

In a further embodiment of the methods described herein, the compound of formula I is represented by formula IA:
In which R ₁ , R ₂ , R ₃ , R ₄ , j and k are as defined for formula I.

In one embodiment, the present invention provides a therapeutically effective amount of a compound represented by a compound of formula II or an isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate or any combination thereof. A method of reducing serum prostate specific antigen (PSA) levels in a male subject suffering from castration resistant prostate cancer (CRPC) is provided.

In one embodiment, the present invention provides a therapeutically effective amount of a compound represented by a compound of formula III or an isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate or any combination thereof. A method of reducing serum prostate specific antigen (PSA) levels in a male subject suffering from castration resistant prostate cancer (CRPC) is provided.

In one embodiment, the invention provides a therapeutically effective amount of a compound represented by a compound of formula IV or an isomer thereof, a pharmaceutical, a pharmaceutically acceptable salt, a polymorph, a hydrate, or any combination thereof. A method of reducing serum prostate specific antigen (PSA) levels in a male subject suffering from castration resistant prostate cancer (CRPC) is provided.

In one embodiment, the present invention provides a therapeutically effective amount of a compound represented by a compound of formula V, or an isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate, or any combination thereof. A method of reducing serum prostate specific antigen (PSA) levels in a male subject suffering from castration resistant prostate cancer (CRPC) is provided.

In one embodiment, the invention provides a therapeutically effective amount of a compound represented by a compound of formula VI or an isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate, or any combination thereof. A method of reducing serum prostate specific antigen (PSA) levels in a male subject suffering from castration resistant prostate cancer (CRPC) is provided.

In one embodiment, the invention provides a therapeutically effective amount of a compound represented by a compound of formula VII, or an isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate, or any combination thereof. A method of reducing serum prostate specific antigen (PSA) levels in a male subject suffering from castration resistant prostate cancer (CRPC) is provided.

In one embodiment, the present invention provides a therapeutically effective amount of a compound represented by a compound of formula VIII or an isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate or any combination thereof A method of reducing serum prostate specific antigen (PSA) levels in a male subject suffering from castration resistant prostate cancer (CRPC) is provided.

In one embodiment, the invention provides a therapeutically effective amount of a compound represented by a compound of formula IX, or an isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate, or any combination thereof. A method of reducing serum prostate specific antigen (PSA) levels in a male subject suffering from castration resistant prostate cancer (CRPC) is provided.

In one embodiment, the invention provides a therapeutically effective amount of a compound represented by a compound of formula X or an isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate or any combination thereof A method of reducing serum prostate specific antigen (PSA) levels in a male subject suffering from castration resistant prostate cancer (CRPC) is provided.

In one embodiment, the present invention provides a therapeutically effective amount of a compound represented by a compound of formula XI or an isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate or any combination thereof A method of reducing serum prostate specific antigen (PSA) levels in a male subject suffering from castration resistant prostate cancer (CRPC) is provided.

In one embodiment, the invention provides a therapeutically effective amount of a compound represented by a compound of formula XII or an isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate, or any combination thereof. A method of reducing serum prostate specific antigen (PSA) levels in a male subject suffering from castration resistant prostate cancer (CRPC) is provided.

In one embodiment, the invention provides a therapeutically effective amount of a compound represented by the structure of Formula I, or an isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate, or any combination thereof. Providing a method of reducing percent free testosterone (free T%) to a level that cannot be achieved by ADT alone in castrated (ie, testosterone levels less than 50 ng / dL) CRPC patients, comprising the steps of:
Where
Y is C (O) or CH ₂ ;
R ₁ and R ₂ are independently hydrogen, halogen, hydroxyl, alkoxy, cyano, nitro, CF ₃ , N (R) ₂ , sulfonamide, SO ₂ R, alkyl, haloalkyl, aryl, O—Alk—NR _5. R ₆ or O-Alk-heterocycle, wherein the heterocycle is a 3-7 membered substituted or unsubstituted heterocyclic ring, optionally aromatic;
R ₃ , R ₄ are independently hydrogen, halogen, hydroxyalkyl, hydroxyl, alkoxy, cyano, nitro, CF ₃ , NHCOR, N (R) ₂ , sulfonamide, SO ₂ R, alkyl, haloalkyl, aryl or protected The hydroxyl being
R is alkyl, hydrogen, haloalkyl, dihaloalkyl, trihaloalkyl, CH ₂ F, CHF ₂ , CF ₃ , CF ₂ CF ₃ , aryl, phenyl, halogen, alkenyl, CN, NO ₂ , or OH;
R ₅ and R ₆ are independently hydrogen, phenyl, an alkyl group of 1-6 carbon atoms, 3-7 membered cycloalkyl, 3-7 membered heterocycle, 5-7 membered aryl, or R ₅ And R ₆ together with the nitrogen atom form a 3-7 membered ring,
j and k are independently 1 to 4,
Alk is a linear alkyl of 1-7 carbons, a branched alkyl of 1-7 carbons, or a cyclic alkyl of 3-8 carbons.

In a further embodiment of the methods described herein, the compound of formula I is represented by formula IA:
In which R ₁ , R ₂ , R ₃ , R ₄ , j and k are as defined for formula I.

In one embodiment, the present invention provides a therapeutically effective amount of a compound represented by a compound of formula II or an isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate or any combination thereof. A method of reducing percent free testosterone (free T%) to a level that cannot be achieved by ADT alone in castrated (ie, testosterone levels less than 50 ng / dL) CRPC patients is provided.

In one embodiment, the present invention provides a therapeutically effective amount of a compound represented by a compound of formula III or an isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate or any combination thereof. A method of reducing percent free testosterone (free T%) to a level that cannot be achieved by ADT alone in castrated (ie, testosterone levels less than 50 ng / dL) CRPC patients.

In one embodiment, the invention provides a therapeutically effective amount of a compound represented by a compound of formula IV or an isomer thereof, a pharmaceutical, a pharmaceutically acceptable salt, a polymorph, a hydrate, or any combination thereof. A method of reducing percent free testosterone (free T%) to a level that cannot be achieved by ADT alone in castrated (ie, testosterone levels less than 50 ng / dL) CRPC patients is provided.

In one embodiment, the present invention provides a therapeutically effective amount of a compound represented by a compound of formula V, or an isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate, or any combination thereof. A method of reducing percent free testosterone (free T%) to a level that cannot be achieved by ADT alone in castrated (ie, testosterone levels less than 50 ng / dL) CRPC patients.

In one embodiment, the invention provides a therapeutically effective amount of a compound represented by a compound of formula VI or an isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate, or any combination thereof. A method of reducing percent free testosterone (free T%) to a level that cannot be achieved by ADT alone in castrated (ie, testosterone levels less than 50 ng / dL) CRPC patients.

In one embodiment, the invention provides a therapeutically effective amount of a compound represented by a compound of formula VII, or an isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate, or any combination thereof. A method of reducing percent free testosterone (free T%) to a level that cannot be achieved by ADT alone in castrated (ie, testosterone levels less than 50 ng / dL) CRPC patients.

In one embodiment, the present invention provides a therapeutically effective amount of a compound represented by a compound of formula VIII or an isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate or any combination thereof A method of reducing percent free testosterone (free T%) to a level that cannot be achieved by ADT alone in castrated (ie, testosterone levels less than 50 ng / dL) CRPC patients.

In one embodiment, the invention provides a therapeutically effective amount of a compound represented by a compound of formula IX, or an isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate, or any combination thereof. A method of reducing percent free testosterone (free T%) to a level that cannot be achieved by ADT alone in castrated (ie, testosterone levels less than 50 ng / dL) CRPC patients.

In one embodiment, the invention provides a therapeutically effective amount of a compound represented by a compound of formula X or an isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate or any combination thereof A method of reducing percent free testosterone (free T%) to a level that cannot be achieved by ADT alone in castrated (ie, testosterone levels less than 50 ng / dL) CRPC patients.

In one embodiment, the present invention provides a therapeutically effective amount of a compound represented by a compound of formula XI or an isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate or any combination thereof A method of reducing percent free testosterone (free T%) to a level that cannot be achieved by ADT alone in castrated (ie, testosterone levels less than 50 ng / dL) CRPC patients.

In one embodiment, the invention provides a therapeutically effective amount of a compound represented by a compound of formula XII or an isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate, or any combination thereof. A method of reducing percent free testosterone (free T%) to a level that cannot be achieved by ADT alone in castrated (ie, testosterone levels less than 50 ng / dL) CRPC patients.

  In one embodiment, the present invention provides a therapeutically effective amount of a compound of formula IA, I-XII or an isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate or any combination thereof. Treating, suppressing, reducing incidence, reducing severity, inhibiting progression, or inhibiting castration-resistant prostate cancer (CRPC) and its symptoms, including the step of administering A method for increasing the survival time of men having In another embodiment, the castration is surgical castration. In another embodiment, the castration is a chemical castration. In another embodiment, the CRPC is metastatic CRPC (mCRPC). In another embodiment, the method further treats, suppresses new bone metastasis, reduces incidence, reduces severity, or inhibits. In another embodiment, the method further treats, suppresses, reduces the incidence of new or worsening soft tissue metastases (visceral and lymph nodes), Reduce or inhibit severity. In another embodiment, the subject has been unsuccessful for androgen deprivation therapy (ADT). In another embodiment, the subject further receives androgen deprivation therapy (ADT). In another embodiment, the subject further receives an LHRH agonist or LHRH antagonist. In another embodiment, the LHRH agonist is leuprolide acetate. In another embodiment, the subject is undergoing orchiectomy. In another embodiment, the subject has elevated or increased prostate specific antigen (PSA) levels. In another embodiment, administering the compound does not cause side effects associated with androgen depletion therapy (ADT). In another embodiment, the method further treats, suppresses, reduces incidence, reduces severity, or inhibits advanced prostate cancer. In another embodiment, the method further provides waiting for advanced prostate cancer. In another embodiment, the compound is Compound IV. In another embodiment, the compound is administered at a dosage of 125 mg per day. In another embodiment, the compound is administered at a dosage of 250 mg per day. In another embodiment, the compound is administered at a dosage of 500 mg per day.

  In one embodiment, the present invention provides a castration resistant prostate cancer (CRPC) and its steps comprising administering a therapeutically effective amount of estradiol, ethinyl estradiol, a steroidal estrogen agonist, a nonsteroidal estrogen agonist, or a combination thereof. Methods of treating, suppressing, reducing the incidence, reducing the severity, inhibiting progression, or increasing the survival of men with castration resistant prostate cancer are provided.

  In one embodiment, the present invention provides a therapeutically effective amount of a compound of formula IA, I-XII or an isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate or any combination thereof. A method of reducing total serum testosterone levels in a male subject suffering from castration resistant prostate cancer (CRPC) comprising administering is provided. In another embodiment, the castration is surgical castration. In another embodiment, the castration is a chemical castration. In another embodiment, the CRPC is metastatic CRPC (mCRPC). In another embodiment, the method further treats, suppresses new bone metastasis, reduces incidence, reduces severity, or inhibits. In another embodiment, the method further treats, suppresses, reduces incidence, reduces severity, or inhibits new or worsening soft tissue metastases (visceral and lymph nodes). In another embodiment, the subject has been unsuccessful for androgen deprivation therapy (ADT). In another embodiment, the subject further receives androgen deprivation therapy (ADT). In another embodiment, the subject further receives an LHRH agonist or LHRH antagonist. In another embodiment, the LHRH agonist is leuprolide acetate. In another embodiment, the subject is undergoing orchiectomy. In another embodiment, the subject has elevated or increased prostate specific antigen (PSA) levels. In another embodiment, administering the compound does not cause side effects associated with androgen depletion therapy (ADT). In another embodiment, the method further treats, suppresses, reduces incidence, reduces severity, or inhibits advanced prostate cancer. In another embodiment, the method further provides waiting for advanced prostate cancer. In another embodiment, the compound is Compound IV. In another embodiment, the compound is administered at a dosage of 125 mg per day. In another embodiment, the compound is administered at a dosage of 250 mg per day. In another embodiment, the compound is administered at a dosage of 500 mg per day. In another embodiment, total serum testosterone is reduced to less than about 100 ng / dL. In another embodiment, total serum testosterone is reduced to less than about 50 ng / dL. In another embodiment, the total serum testosterone concentration is reduced to less than about 25 ng / dL. In another embodiment, the total serum testosterone concentration is reduced to less than about 10 ng / dL. In another embodiment, the total serum testosterone concentration is reduced to less than about 5 ng / dL. In another embodiment, the total serum testosterone concentration is reduced to less than about 1 ng / dL.

  In one embodiment, the invention suffers from castration resistant prostate cancer (CRPC) comprising administering a therapeutically effective amount of estradiol, ethinyl estradiol, a steroidal estrogen agonist, a nonsteroidal estrogen agonist, or a combination thereof. A method of reducing total serum testosterone levels in a male subject who is

  In one embodiment, the present invention provides a therapeutically effective amount of a compound of formula IA, I-XII or an isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate or any combination thereof. A method of reducing serum free testosterone levels in a male subject suffering from castration resistant prostate cancer (CRPC) is provided comprising the step of administering. In another embodiment, the castration is surgical castration. In another embodiment, the castration is a chemical castration. In another embodiment, the CRPC is metastatic CRPC (mCRPC). In another embodiment, the method further treats, suppresses new bone metastasis, reduces incidence, reduces severity, or inhibits. In another embodiment, the method further treats, suppresses, reduces incidence, reduces severity, or inhibits new or worsening soft tissue metastases (visceral and lymph nodes). In another embodiment, the subject has been unsuccessful for androgen deprivation therapy (ADT). In another embodiment, the subject further receives androgen deprivation therapy (ADT). In another embodiment, the subject further receives an LHRH agonist or LHRH antagonist. In another embodiment, the LHRH agonist is leuprolide acetate. In another embodiment, the subject is undergoing orchiectomy. In another embodiment, the subject has elevated or increased prostate specific antigen (PSA) levels. In another embodiment, administering the compound does not cause side effects associated with androgen depletion therapy (ADT). In another embodiment, the method further treats, suppresses, reduces incidence, reduces severity, or inhibits advanced prostate cancer. In another embodiment, the method further provides waiting for advanced prostate cancer. In another embodiment, the compound is Compound IV. In another embodiment, the compound is administered at a dosage of 125 mg per day. In another embodiment, the compound is administered at a dosage of 250 mg per day. In another embodiment, the compound is administered at a dosage of 500 mg per day. In another embodiment, free serum testosterone is reduced to a level below castration. In another embodiment, free serum testosterone is reduced to a level below that which has been observed with LHRH agonists or LHRH antagonists or surgical castration.

  In one embodiment, the invention suffers from castration resistant prostate cancer (CRPC) comprising administering a therapeutically effective amount of estradiol, ethinyl estradiol, a steroidal estrogen agonist, a nonsteroidal estrogen agonist, or a combination thereof. A method of reducing serum free testosterone levels in a male subject who is present.

  In one embodiment, the present invention provides a therapeutically effective amount of a compound of formula IA, I-XII or an isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate or any combination thereof. A method is provided for reducing the percent serum free testosterone (free T%) in a male subject suffering from castration resistant prostate cancer (CRPC) comprising administering. In another embodiment, the castration is surgical castration. In another embodiment, the castration is a chemical castration. In another embodiment, the CRPC is metastatic CRPC (mCRPC). In another embodiment, the method further treats, suppresses new bone metastasis, reduces incidence, reduces severity, or inhibits. In another embodiment, the method further treats, suppresses, reduces incidence, reduces severity, or inhibits new or worsening soft tissue metastases (visceral and lymph nodes). In another embodiment, the subject has been unsuccessful for androgen deprivation therapy (ADT). In another embodiment, the subject further receives androgen deprivation therapy (ADT). In another embodiment, the subject further receives an LHRH agonist or LHRH antagonist. In another embodiment, the LHRH agonist is leuprolide acetate. In another embodiment, the subject is undergoing orchiectomy. In another embodiment, the subject has elevated or increased prostate specific antigen (PSA) levels. In another embodiment, administering the compound does not cause side effects associated with androgen depletion therapy (ADT). In another embodiment, the method further treats, suppresses, reduces incidence, reduces severity, or inhibits advanced prostate cancer. In another embodiment, the method further provides waiting for advanced prostate cancer. In another embodiment, the compound is Compound IV. In another embodiment, the compound is administered at a dosage of 125 mg per day. In another embodiment, the compound is administered at a dosage of 250 mg per day. In another embodiment, the compound is administered at a dosage of 500 mg per day. In another embodiment, free serum testosterone is reduced to a level below castration. In another embodiment, free serum testosterone is reduced to a level below that which has been observed with LHRH agonists or LHRH antagonists or surgical castration.

  In one embodiment, the invention suffers from castration resistant prostate cancer (CRPC) comprising administering a therapeutically effective amount of estradiol, ethinyl estradiol, a steroidal estrogen agonist, a nonsteroidal estrogen agonist, or a combination thereof. A method of reducing the percentage of serum free testosterone (free T%) in a male subject who is living.

  In one embodiment, the present invention provides a therapeutically effective amount of a compound of formula IA, I-XII or an isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate or any combination thereof. A method of reducing serum PSA levels in a male subject suffering from castration resistant prostate cancer (CRPC) is provided comprising the step of administering. In another embodiment, the castration is surgical castration. In another embodiment, the castration is a chemical castration. In another embodiment, the CRPC is metastatic CRPC (mCRPC). In another embodiment, the method further treats, suppresses new bone metastasis, reduces incidence, reduces severity, or inhibits. In another embodiment, the method further treats, suppresses, reduces incidence, reduces severity, or inhibits new or worsening soft tissue metastases (visceral and lymph nodes). In another embodiment, the subject has been unsuccessful for androgen deprivation therapy (ADT). In another embodiment, the subject further receives androgen deprivation therapy (ADT). In another embodiment, the subject further receives an LHRH agonist or LHRH antagonist. In another embodiment, the LHRH agonist is leuprolide acetate. In another embodiment, the subject is undergoing orchiectomy. In another embodiment, the subject has elevated or increased prostate specific antigen (PSA) levels. In another embodiment, administering the compound does not cause side effects associated with androgen depletion therapy (ADT). In another embodiment, the method further treats, suppresses, reduces incidence, reduces severity, or inhibits advanced prostate cancer. In another embodiment, the method further provides waiting for advanced prostate cancer. In another embodiment, the compound is Compound IV. In another embodiment, the compound is administered at a dosage of 125 mg per day. In another embodiment, the compound is administered at a dosage of 250 mg per day. In another embodiment, the compound is administered at a dosage of 500 mg per day. In another embodiment, serum PSA levels are reduced by at least 10% from baseline. In another embodiment, serum PSA levels are reduced by at least 30% from baseline. In another embodiment, serum PSA levels are reduced by at least 50% from baseline. In another embodiment, serum PSA levels are reduced by at least 70% from baseline. In another embodiment, serum PSA levels are reduced by at least 90% from baseline.

  In one embodiment, the invention suffers from castration resistant prostate cancer (CRPC) comprising administering a therapeutically effective amount of estradiol, ethinyl estradiol, a steroidal estrogen agonist, a nonsteroidal estrogen agonist, or a combination thereof. A method of reducing serum PSA levels in a male subject who is

  In one embodiment, the present invention provides a therapeutically effective amount of a compound of formula IA, I-XII or an isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate or any combination thereof. A method is provided for increasing sex hormone binding globulin (SHBG) levels in a male subject suffering from castration resistant prostate cancer (CRPC) comprising administering. In another embodiment, the castration is surgical castration. In another embodiment, the castration is a chemical castration. In another embodiment, the CRPC is metastatic CRPC (mCRPC). In another embodiment, the method further treats, suppresses new bone metastasis, reduces incidence, reduces severity, or inhibits. In another embodiment, the method further treats, suppresses, reduces incidence, reduces severity, or inhibits new or worsening soft tissue metastases (visceral and lymph nodes). In another embodiment, the subject has been unsuccessful for androgen deprivation therapy (ADT). In another embodiment, the subject further receives androgen deprivation therapy (ADT). In another embodiment, the subject further receives an LHRH agonist or LHRH antagonist. In another embodiment, the LHRH agonist is leuprolide acetate. In another embodiment, the subject is undergoing orchiectomy. In another embodiment, the subject has elevated or increased prostate specific antigen (PSA) levels. In another embodiment, administering the compound does not cause side effects associated with androgen depletion therapy (ADT). In another embodiment, the method further treats, suppresses, reduces incidence, reduces severity, or inhibits advanced prostate cancer. In another embodiment, the method further provides waiting for advanced prostate cancer. In another embodiment, the compound is Compound IV. In another embodiment, the compound is administered at a dosage of 125 mg per day. In another embodiment, the compound is administered at a dosage of 250 mg per day. In another embodiment, the compound is administered at a dosage of 500 mg per day.

  In one embodiment, the invention suffers from castration resistant prostate cancer (CRPC) comprising administering a therapeutically effective amount of estradiol, ethinyl estradiol, a steroidal estrogen agonist, a nonsteroidal estrogen agonist, or a combination thereof. Methods of increasing sex hormone binding globulin (SHBG) levels in a male subject.

  In one embodiment, the present invention provides a therapeutically effective amount of a compound of formula IA, I-XII or isomers, pharmaceutically acceptable salts, pharmaceuticals, polymorphs, water, in combination with other forms of ADT. A method of reducing serum free testosterone levels and / or percent serum free testosterone (free T%) in a male subject suffering from advanced prostate cancer comprising administering a Japanese or any combination thereof provide. In another embodiment, the subject has been unsuccessful for androgen deprivation therapy (ADT). In another embodiment, another form of ADT refers to an LHRH agonist. In another embodiment, the LHRH agonist is leuprolide acetate. In another embodiment, another form of ADT refers to an LHRH antagonist. In another embodiment, the LHRH antagonist is degarelix. In another embodiment, the subject is undergoing orchiectomy. In another embodiment, the subject has elevated or increased prostate specific antigen (PSA) levels. In another embodiment, administering the compound does not cause side effects associated with androgen depletion therapy (ADT). In another embodiment, the method further provides waiting for advanced prostate cancer. In another embodiment, the compound is Compound IV. In another embodiment, the compound is administered at a dosage of 125 mg per day. In another embodiment, the compound is administered at a dosage of 250 mg per day. In another embodiment, the compound is administered at a dosage of 500 mg per day. In another embodiment, free serum testosterone is reduced to a level below castration. In another embodiment, free serum testosterone is reduced to a level below that which has been observed with LHRH agonists or LHRH antagonists or surgical castration.

  In one embodiment, the present invention provides a therapeutically effective amount of a compound of formula IA, I-XII or an isomer thereof, a pharmaceutically acceptable salt, a pharmaceutical, in combination with a selective estrogen receptor modulator (SERM). Decrease serum free testosterone levels and / or serum free testosterone percentage (free T%) in a male subject suffering from prostate cancer comprising administering a polymorph, hydrate or any combination thereof Provide a method. In another embodiment, the prostate cancer is advanced prostate cancer. In another embodiment, the prostate cancer is castration resistant prostate cancer (CRPC). In another embodiment, the prostate cancer is metastatic castration resistant prostate cancer (mCRPC). In another embodiment, the SERM is selected from the group consisting of tamoxifen, toremifene, raloxifene, clomiphene, femarelle, olmeroxifene and lasofoxifene. In another embodiment, the SERM is tamoxifen. In another embodiment, the SERM is raloxifene. In another embodiment, the SERM is toremifene. In another embodiment, the SERM is olmeroxifene. In another embodiment, the subject is undergoing orchiectomy. In another embodiment, the subject has been unsuccessful for androgen deprivation therapy (ADT). In another embodiment, the subject has elevated or increased prostate specific antigen (PSA) levels. In another embodiment, administering the compound does not cause side effects associated with androgen depletion therapy (ADT). In another embodiment, the method further provides waiting for advanced prostate cancer. In another embodiment, the compound is Compound IV. In another embodiment, the compound is administered at a dosage of 125 mg per day. In another embodiment, the compound is administered at a dosage of 250 mg per day. In another embodiment, the compound is administered at a dosage of 500 mg per day. In another embodiment, the percent serum free testosterone is reduced to less than about 1%. In another embodiment, the percent serum free testosterone is reduced to less than about 0.5%. In another embodiment, the percent serum free testosterone is reduced to less than about 0.4%. In another embodiment, the percent serum free testosterone is reduced to less than about 0.25%. In another embodiment, the percent serum free testosterone is reduced to less than about 0.1%. In another embodiment, the percent serum free testosterone is reduced to less than about 0.05%. In another embodiment, the percent free serum testosterone is reduced to a level below castration. In another embodiment, the percent free serum testosterone is reduced to a level less than that observed by LHRH agonists or LHRH antagonists or surgical castration.

  In one embodiment, the present invention provides a male subject suffering from prostate cancer comprising administering a therapeutically effective amount of estradiol, ethinyl estradiol, a steroidal estrogen agonist, a nonsteroidal estrogen agonist, or a combination thereof. Provides a method for reducing serum free testosterone levels and / or serum free testosterone percent (free T%).

  In one embodiment, the present invention provides a therapeutically effective amount of a compound of formula IA, I-XII or an isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate or any combination thereof. A method of secondary hormone therapy for serum PSA and serum free testosterone levels in a male subject suffering from castration resistant prostate cancer (CRPC) is provided, comprising the step of administering. In another embodiment, the castration is surgical castration. In another embodiment, the castration is a chemical castration. In another embodiment, the CRPC is metastatic CRPC (mCRPC). In another embodiment, the method further treats, suppresses new bone metastasis, reduces incidence, reduces severity, or inhibits. In another embodiment, the method further treats, suppresses, reduces incidence, reduces severity, or inhibits new or worsening soft tissue metastases (visceral and lymph nodes). In another embodiment, the subject has been unsuccessful for androgen deprivation therapy (ADT). In another embodiment, the subject further receives androgen deprivation therapy (ADT). In another embodiment, the subject further receives an LHRH agonist or LHRH antagonist. In another embodiment, the LHRH agonist is leuprolide acetate. In another embodiment, the subject is undergoing orchiectomy. In another embodiment, the subject has elevated or increased prostate specific antigen (PSA) levels. In another embodiment, administering the compound does not cause side effects associated with androgen depletion therapy (ADT). In another embodiment, the method further treats, suppresses, reduces incidence, reduces severity, or inhibits advanced prostate cancer. In another embodiment, the method further provides waiting for advanced prostate cancer. In another embodiment, the compound is Compound IV. In another embodiment, the compound is administered at a dosage of 125 mg per day. In another embodiment, the compound is administered at a dosage of 250 mg per day. In another embodiment, the compound is administered at a dosage of 500 mg per day.

  In one embodiment, the present invention provides a therapeutically effective amount of a compound of formula IA, I-XII or an isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate or any combination thereof. Treating, suppressing, reducing incidence, and reducing the severity of bone related events (SRE) in male subjects suffering from castration resistant prostate cancer (CRPC), including administering A method of reducing or inhibiting is provided. In another embodiment, the castration is surgical castration. In another embodiment, the castration is a chemical castration. In another embodiment, the CRPC is metastatic CRPC (mCRPC). In another embodiment, the method further treats, suppresses new bone metastasis, reduces incidence, reduces severity, or inhibits. In another embodiment, the method further treats, suppresses, reduces incidence, reduces severity, or inhibits new or worsening soft tissue metastases (visceral and lymph nodes). In another embodiment, the subject has been unsuccessful for androgen deprivation therapy (ADT). In another embodiment, the subject further receives androgen deprivation therapy (ADT). In another embodiment, the subject further receives an LHRH agonist or LHRH antagonist. In another embodiment, the LHRH agonist is leuprolide acetate. In another embodiment, the subject is undergoing orchiectomy. In another embodiment, the subject has elevated or increased prostate specific antigen (PSA) levels. In another embodiment, administering the compound does not cause side effects associated with androgen depletion therapy (ADT). In another embodiment, the method further treats, suppresses, reduces incidence, reduces severity, or inhibits advanced prostate cancer. In another embodiment, the method further provides waiting for advanced prostate cancer. In another embodiment, the compound is Compound IV. In another embodiment, the compound is administered at a dosage of 125 mg per day. In another embodiment, the compound is administered at a dosage of 250 mg per day. In another embodiment, the compound is administered at a dosage of 500 mg per day.

  The term “bone related event (SRE)” refers to a composite endpoint that includes a fracture, pathological fracture, spinal cord compression, bone irradiation or surgery, new bone metastasis, bone loss, or a combination thereof.

  In one embodiment, the bone-related event using the methods provided herein and / or utilizing the compositions provided herein is a fracture, which in one embodiment is a disease. Fracture, non-traumatic fracture, vertebral fracture, non-vertebral fracture, morphological fracture, or a combination thereof. In some embodiments, the fracture can be a simple fracture, an open fracture, a transverse fracture, a sapwood fracture, or a comminuted fracture. In one embodiment, the fracture may be against any bone in the body, which in one embodiment is an arm, wrist, hand, finger, leg, ankle, foot, toe, buttocks, clavicle, or combinations thereof. Any one or more bone fractures.

  In another embodiment, the methods and / or compositions provided herein treat or prevent bone-related events such as pathological fractures, spinal cord compression, hypercalcemia, bone-related pain, or combinations thereof. Effective in suppressing, inhibiting or reducing the risk of the bone-related event.

  In another embodiment, a bone-related event sought to be treated using the methods provided herein and / or utilizing the compositions provided herein is bone surgery and / or bone Including requiring irradiation, which in some embodiments is for the treatment of pain resulting from bone damage or nerve compression in one embodiment. In another embodiment, a bone-related event sought to be treated using the methods provided herein and / or utilizing the compositions provided herein is spinal cord compression, or Including requiring changes in antineoplastic therapy (including changes in hormone therapy). In some embodiments, the bone-related event sought to be treated using the methods provided herein and / or utilizing the compositions provided herein is bone metastasis, or bone loss. Treatment, suppression, prevention, reducing incidence, or delaying progression or severity. In one embodiment, the bone loss can include osteoporosis, osteopenia, or a combination thereof. In one embodiment, a bone-related event may include any combination of the embodiments listed herein.

  In one embodiment, the present invention provides a therapeutically effective amount of a compound of formula IA, I-XII or an isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate or any combination thereof. A method of reducing the level of bone metabolic markers in a male subject suffering from castration resistant prostate cancer (CRPC) comprising the step of administering. In another embodiment, the castration is surgical castration. In another embodiment, the castration is a chemical castration. In another embodiment, the CRPC is metastatic CRPC (mCRPC). In another embodiment, the method further treats, suppresses new bone metastasis, reduces incidence, reduces severity, or inhibits. In another embodiment, the method further treats, suppresses, reduces incidence, reduces severity, or inhibits new or worsening soft tissue metastases (visceral and lymph nodes). In another embodiment, the subject has been unsuccessful for androgen deprivation therapy (ADT). In another embodiment, the subject further receives androgen deprivation therapy (ADT). In another embodiment, the subject further receives an LHRH agonist or LHRH antagonist. In another embodiment, the LHRH agonist is leuprolide acetate. In another embodiment, the subject is undergoing orchiectomy. In another embodiment, the subject has elevated or increased prostate specific antigen (PSA) levels. In another embodiment, administering the compound does not cause side effects associated with androgen depletion therapy (ADT). In another embodiment, the method further treats, suppresses, reduces incidence, reduces severity, or inhibits advanced prostate cancer. In another embodiment, the method further provides waiting for advanced prostate cancer. In another embodiment, the compound is Compound IV. In another embodiment, the compound is administered at a dosage of 125 mg per day. In another embodiment, the compound is administered at a dosage of 250 mg per day. In another embodiment, the compound is administered at a dosage of 500 mg per day. In another embodiment, the bone metabolism marker is C-telopeptide (CTX) and / or bone specific alkaline phosphatase.

  In one embodiment, the present invention provides a therapeutically effective amount of a compound of formula IA, I-XII or an isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate or any combination thereof. Treat, suppress, reduce incidence, reduce severity, reduce frequency, or reduce hot flashes in male subjects suffering from castration resistant prostate cancer (CRPC), including administering, or A method of inhibiting is provided. In another embodiment, the castration is surgical castration. In another embodiment, the castration is a chemical castration. In another embodiment, the CRPC is metastatic CRPC (mCRPC).

  In one embodiment, the invention comprises administering a compound of formula IA, I-XII or an isomer thereof, a pharmaceutically acceptable salt, a pharmaceutical, a polymorph, a hydrate, or any combination thereof. Reduce estrogen deficiency-related side effects (hot flashes, bone loss, insulin resistance, changes in body composition, fat gain) in male subjects with advanced or castration resistant prostate cancer Provide a method. In another embodiment, the subject further receives androgen deprivation therapy (ADT). In another embodiment, the subject further receives an LHRH agonist or LHRH antagonist. In another embodiment, the LHRH agonist is leuprolide acetate. In another embodiment, the castration is surgical castration. In another embodiment, the castration is a chemical castration. In another embodiment, the CRPC is metastatic CRPC (mCRPC). In another embodiment, the male is a surgically castrated male with advanced prostate cancer or castration resistant prostate cancer.

  In another embodiment, the method further treats, suppresses new bone metastasis, reduces incidence, reduces severity, or inhibits. In another embodiment, the method further treats, suppresses, reduces incidence, reduces severity, or inhibits new or worsening soft tissue metastases (visceral and lymph nodes). In another embodiment, the subject has been unsuccessful for androgen deprivation therapy (ADT). In another embodiment, the subject further receives androgen deprivation therapy (ADT). In another embodiment, the subject further receives an LHRH agonist or LHRH antagonist. In another embodiment, the LHRH agonist is leuprolide acetate. In another embodiment, the subject is undergoing orchiectomy. In another embodiment, the subject has elevated or increased prostate specific antigen (PSA) levels. In another embodiment, administering the compound does not cause side effects associated with androgen depletion therapy (ADT). In another embodiment, the method further treats, suppresses, reduces incidence, reduces severity, or inhibits advanced prostate cancer. In another embodiment, the method further provides waiting for advanced prostate cancer. In another embodiment, the compound is Compound IV. In another embodiment, the compound is administered at a dosage of 125 mg per day. In another embodiment, the compound is administered at a dosage of 250 mg per day. In another embodiment, the compound is administered at a dosage of 500 mg per day.

  In one embodiment, the present invention provides a therapeutically effective amount of a compound of formula IA, I-XII or an isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate or any combination thereof. A method is provided for reducing the level of androgen precursor production in the adrenal gland in a male subject suffering from castration resistant prostate cancer (CRPC) comprising administering. In another embodiment, the castration is surgical castration. In another embodiment, the castration is a chemical castration. In another embodiment, the CRPC is metastatic CRPC (mCRPC). In another embodiment, the method further treats, suppresses new bone metastasis, reduces incidence, reduces severity, or inhibits. In another embodiment, the method further treats, suppresses, reduces incidence, reduces severity, or inhibits new or worsening soft tissue metastases (visceral and lymph nodes). In another embodiment, the subject has been unsuccessful for androgen deprivation therapy (ADT). In another embodiment, the subject further receives androgen deprivation therapy (ADT). In another embodiment, the subject further receives an LHRH agonist or LHRH antagonist. In another embodiment, the LHRH agonist is leuprolide acetate. In another embodiment, the subject is undergoing orchiectomy. In another embodiment, the subject has elevated or increased prostate specific antigen (PSA) levels. In another embodiment, administering the compound does not cause side effects associated with androgen depletion therapy (ADT). In another embodiment, the method further treats, suppresses, reduces incidence, reduces severity, or inhibits advanced prostate cancer. In another embodiment, the method further provides waiting for advanced prostate cancer. In another embodiment, the compound is Compound IV. In another embodiment, the compound is administered at a dosage of 125 mg per day. In another embodiment, the compound is administered at a dosage of 250 mg per day. In another embodiment, the compound is administered at a dosage of 500 mg per day. In another embodiment, the androgen precursor is utilized by prostate cancer cells to produce testosterone or dihydrotestosterone (DHT). In another embodiment, the androgen precursor is dehydroepiandrosterone sulfate (DHEAS) and / or dehydroepiandrosterone (DHEA).

  In one embodiment, a “subject suffering from castration resistant prostate cancer” has been previously treated with androgen deprivation therapy (ADT), is responsive to ADT, and currently has a serum> 2 ng / mL. Refers to a subject with PSA or with> 2 ng / mL serum PSA and representing a 25% increase above the lowest point achieved with ADT. In another embodiment, the term refers to a subject diagnosed with serum PSA progression despite ongoing androgen deprivation therapy. In another embodiment, the subject has a castration level of serum total testosterone (<50 ng / dL). In another embodiment, the subject has a serum PSA that is elevated in two consecutive assessments separated by at least 2 weeks. In another embodiment, the subject has been effectively treated with ADT. In another embodiment, the subject has a history of serum PSA response after initiation of ADT. In another embodiment, the subject has been treated with ADT and had an initial serum PSA response, but now a 25% increase over the lowest point observed in> 2 ng / mL serum PSA and ADT Have

  The term “serum PSA response” refers, in one embodiment, to at least 90% reduction in serum PSA levels prior to the onset of ADT, <10 ng / mL or undetectable levels of serum PSA at any time (<0.2 ng / mL), or in another embodiment, at least 50% decrease from baseline in serum PSA, or in another embodiment, at least 90% decrease from baseline in serum PSA, or in another embodiment, Refers to at least 30% decrease from baseline in serum PSA, or in another embodiment at least 10% decrease from baseline in serum PSA.

  The term “serum PSA progression” refers, in one embodiment, to a 25% or greater increase in serum PSA from the lowest point and an absolute increase of 2 ng / ml or greater, or in another embodiment,> 2 ng / mL. Serum PSA, or> 2 ng / mL serum PSA and 25% increase above the lowest point after initiation of androgen deprivation therapy (ADT).

  In another embodiment, the term “bottom point” refers to the lowest PSA level while the patient is undergoing ADT.

  In one embodiment, the present invention provides a therapeutically effective amount of a compound of formula IA, I-XII or an isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate or any combination thereof. A method is provided for reducing total serum testosterone levels in a male subject comprising the step of administering. In another embodiment, the male subject has prostate cancer. In another embodiment, total serum testosterone is reduced to less than about 100 ng / dL. In another embodiment, total serum testosterone is reduced to less than about 50 ng / dL. In another embodiment, the total serum testosterone concentration is reduced to less than about 25 ng / dL. In another embodiment, the total serum testosterone concentration is reduced to less than about 10 ng / dL. In another embodiment, the total serum testosterone concentration is reduced to less than about 5 ng / dL. In another embodiment, the total serum testosterone concentration is reduced to less than about 1 ng / dL. In another embodiment, the subject suffers from castration resistant prostate cancer (CRPC). In another embodiment, the CRPC is metastatic CRPC (mCRPC). In another embodiment, the subject has been unsuccessful for androgen deprivation therapy (ADT). In another embodiment, the subject further receives androgen deprivation therapy (ADT). In another embodiment, the compound is Compound IV. In another embodiment, the compound is administered at a dosage of 125 mg per day. In another embodiment, the compound is administered at a dosage of 250 mg per day. In another embodiment, the compound is administered at a dosage of 500 mg per day.

  In one embodiment, the present invention provides a therapeutically effective amount of a compound of formula IA, I-XII or an isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate or any combination thereof. A method is provided for reducing total serum testosterone levels in a male subject comprising administering, wherein the reduction of total serum testosterone occurs by a reduction in serum luteinizing hormone (LH) levels. In another embodiment, the male subject has prostate cancer. In another embodiment, total serum testosterone is reduced to less than about 100 ng / dL. In another embodiment, total serum testosterone is reduced to less than about 50 ng / dL. In another embodiment, the total serum testosterone concentration is reduced to less than about 25 ng / dL. In another embodiment, the subject suffers from castration resistant prostate cancer (CRPC). In another embodiment, the CRPC is metastatic CRPC (mCRPC). In another embodiment, the subject has been unsuccessful for androgen deprivation therapy (ADT). In another embodiment, the subject further receives androgen deprivation therapy (ADT). In another embodiment, the compound is Compound IV. In another embodiment, the compound is administered at a dosage of 125 mg per day. In another embodiment, the compound is administered at a dosage of 250 mg per day. In another embodiment, the compound is administered at a dosage of 500 mg per day.

  In one embodiment, the present invention provides a therapeutically effective amount of a compound of formula IA, I-XII or an isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate or any combination thereof. A method is provided for reducing free serum testosterone levels in a male subject comprising administering, wherein the reduction in free serum testosterone occurs by a reduction in serum luteinizing hormone (LH) levels. In another embodiment, the male subject has prostate cancer. In another embodiment, the subject suffers from castration resistant prostate cancer (CRPC). In another embodiment, the CRPC is metastatic CRPC (mCRPC). In another embodiment, the subject has been unsuccessful for androgen deprivation therapy (ADT). In another embodiment, the subject further receives androgen deprivation therapy (ADT). In another embodiment, the compound is Compound IV. In another embodiment, the compound is administered at a dosage of 125 mg per day. In another embodiment, the compound is administered at a dosage of 250 mg per day. In another embodiment, the compound is administered at a dosage of 500 mg per day.

  In one embodiment, the present invention provides a therapeutically effective amount of a compound of formula IA, I-XII or an isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate or any combination thereof. A method is provided for reducing total serum testosterone levels in a male subject comprising administering, wherein the reduction of total serum testosterone is independent of a reduction in serum luteinizing hormone (LH) levels. In another embodiment, the male subject has prostate cancer. In another embodiment, total serum testosterone is reduced to less than about 100 ng / dL. In another embodiment, total serum testosterone is reduced to less than about 50 ng / dL. In another embodiment, the total serum testosterone concentration is reduced to less than about 25 ng / dL. In another embodiment, the subject suffers from castration resistant prostate cancer (CRPC). In another embodiment, the CRPC is metastatic CRPC (mCRPC). In another embodiment, the subject has been unsuccessful for androgen deprivation therapy (ADT). In another embodiment, the subject further receives androgen deprivation therapy (ADT). In another embodiment, the compound is Compound IV. In another embodiment, the compound is administered at a dosage of 125 mg per day. In another embodiment, the compound is administered at a dosage of 250 mg per day. In another embodiment, the compound is administered at a dosage of 500 mg per day.

  In one embodiment, the present invention provides a therapeutically effective amount of a compound of formula IA, I-XII or an isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate or any combination thereof. A method is provided for reducing free serum testosterone levels in a male subject comprising administering, wherein the reduction of free serum testosterone levels is independent of the reduction of serum luteinizing hormone levels. In another embodiment, the male subject has prostate cancer. In another embodiment, the subject suffers from castration resistant prostate cancer (CRPC). In another embodiment, the CRPC is metastatic CRPC (mCRPC). In another embodiment, the subject has been unsuccessful for androgen deprivation therapy (ADT). In another embodiment, the subject further receives androgen deprivation therapy (ADT). In another embodiment, the compound is Compound IV. In another embodiment, the compound is administered at a dosage of 125 mg per day. In another embodiment, the compound is administered at a dosage of 250 mg per day. In another embodiment, the compound is administered at a dosage of 500 mg per day.

  In one embodiment, the invention provides a method of reducing total serum testosterone, free serum testosterone levels or percent free serum testosterone (free T%) in a male subject, said male subject having prostate cancer Have In another embodiment, the subject has advanced prostate cancer. In another embodiment, the subject suffers from castration resistant prostate cancer (CRPC). In another embodiment, the CRPC is metastatic CRPC (mCRPC). In another embodiment, the subject has been unsuccessful for androgen deprivation therapy (ADT). In another embodiment, the subject further receives androgen deprivation therapy (ADT). In another embodiment, the compound is Compound IV. In another embodiment, the compound is administered at a dosage of 125 mg per day. In another embodiment, the compound is administered at a dosage of 250 mg per day. In another embodiment, the compound is administered at a dosage of 500 mg per day.

The term “percentage of free serum testosterone (T% free)” refers, in one embodiment, to free serum testosterone level (pg / mL) divided by total serum testosterone level (pg / mL) multiplied by 100 [free T (pg / mL) / Total T (pg / mL) ^* 100].

  In one embodiment, the reduction in testosterone serum concentration is reversible and returns to baseline levels after treatment with a compound of the invention.

  In another embodiment, according to FIG. 23 and Example 10, the serum concentration of testosterone is reversible after treatment with Compound IV.

  In one embodiment, the present invention provides a therapeutically effective amount of a compound of formula IA, I-XII or an isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate or any combination thereof. A method is provided for reducing total serum testosterone levels in a male subject comprising the step of administering. In another embodiment, total serum testosterone is reduced to less than about 100 ng / dL. In another embodiment, total serum testosterone is reduced to less than about 50 ng / dL. In another embodiment, total serum testosterone is reduced to less than about 25 ng / dL. In another embodiment, total serum testosterone is reduced to less than about 75 ng / dL. In another embodiment, the total serum testosterone is reduced from about 75 ng / dL to 100 ng / dL. In another embodiment, the total serum testosterone is reduced from about 50 ng / dL to 75 ng / dL. In another embodiment, the total serum testosterone is reduced from about 40 ng / dL to 50 ng / dL. In another embodiment, the total serum testosterone concentration is reduced from about 25 ng / dL to 50 ng / dL. In another embodiment, the total serum testosterone is reduced from about 40 ng / dL to 60 ng / dL. In another embodiment, the total serum testosterone is reduced from about 10 ng / dL to 50 ng / dL. In another embodiment, the total serum testosterone is reduced from about 10 ng / dL to 25 ng / dL. In another embodiment, the total serum testosterone is reduced from about 1 ng / dL to 25 ng / dL. In another embodiment, the total serum testosterone is reduced from about 1 ng / dL to 10 ng / dL. In another embodiment, the total serum testosterone is reduced from about 0.1 ng / dL to 1 ng / dL. In another embodiment, the total serum testosterone is reduced from about 0.1 ng / dL to 10 ng / dL. In another embodiment, the subject suffers from castration resistant prostate cancer (CRPC). In another embodiment, the CRPC is metastatic CRPC (mCRPC). In another embodiment, the subject has been unsuccessful for androgen deprivation therapy (ADT). In another embodiment, the subject further receives androgen deprivation therapy (ADT). In another embodiment, the compound is Compound IV. In another embodiment, the compound is administered at a dosage of 125 mg per day. In another embodiment, the compound is administered at a dosage of 250 mg per day. In another embodiment, the compound is administered at a dosage of 500 mg per day.

  In one embodiment, the present invention provides a therapeutically effective amount of a compound of formula IA, I-XII or an isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate or any combination thereof. A method of reducing percent serum free testosterone (free T%) in a male subject comprising administering is provided. In another embodiment, the percent serum free testosterone (free T%) is reduced to less than about 1%. In another embodiment, the percent serum free testosterone (T% free) is reduced to less than about 0.5%. In another embodiment, the percent serum free testosterone (T% free) is reduced to less than about 0.25%. In another embodiment, the percent serum free testosterone (T% free) is reduced to less than about 0.05%. In another embodiment, the subject suffers from castration resistant prostate cancer (CRPC). In another embodiment, the CRPC is metastatic CRPC (mCRPC). In another embodiment, the subject has been unsuccessful for androgen deprivation therapy (ADT). In another embodiment, the subject further receives androgen deprivation therapy (ADT). In another embodiment, the compound is Compound IV. In another embodiment, the compound is administered at a dosage of 125 mg per day. In another embodiment, the compound is administered at a dosage of 250 mg per day. In another embodiment, the compound is administered at a dosage of 500 mg per day.

  Testosterone can be measured as “free” (ie, bioavailable and unbound) or “total” (including the percentage of protein bound and not available) serum levels. In one embodiment, the total serum testosterone comprises free testosterone and bound testosterone.

  Men who do not have prostate cancer over the age of 40 clearly show low testosterone levels (total testosterone levels of less than 250 ng / dL (<8.7 nmol / L), or less than 0.75 ng / dL (<0. Having a free testosterone level of 03 nmol / L). The methods of the present invention provide a method of reducing serum testosterone levels. In one embodiment, the method achieved lower total serum testosterone. In another embodiment, the method achieved lower free serum testosterone.

  In one embodiment, the methods of the present invention may be used to measure total serum testosterone levels and / or in male subjects with prostate cancer independent of or by reducing luteinizing hormone (LH) levels. A method of reducing free testosterone levels is provided. In another embodiment, the change in testosterone level should be a reduction from the pre-treatment level. In another embodiment, the total serum testosterone level is reduced to less than 100 ng / dL. In another embodiment, total serum testosterone is reduced to less than 50 ng / dL. In another embodiment, the total serum testosterone is reduced to less than 25 ng / dL. In another embodiment, the free testosterone level is reduced to less than 2 ng / dL. In another embodiment, free testosterone levels are reduced to less than 1 ng / dL. In another embodiment, the free testosterone level is reduced to less than 0.5 ng / dL. In another embodiment, free testosterone levels are reduced to less than 0.25 ng / dL. In another embodiment, the subject suffers from castration resistant prostate cancer (CRPC). In another embodiment, the CRPC is metastatic CRPC (mCRPC). In another embodiment, the subject has been unsuccessful for androgen deprivation therapy (ADT). In another embodiment, the subject further receives androgen deprivation therapy (ADT). In another embodiment, the compound is Compound IV. In another embodiment, the compound is administered at a dosage of 125 mg per day. In another embodiment, the compound is administered at a dosage of 250 mg per day. In another embodiment, the compound is administered at a dosage of 500 mg per day.

  The method of determining free serum testosterone levels and total serum testosterone levels includes monitoring the testosterone levels throughout the treatment period by a blood test. Total testosterone is a combination of circulating testosterone bound to a carrier protein (albumin, SHBG, transcortin, transferrin) and a free / unbound hormone. Total testosterone levels can be affected by several factors, including the level of protein in the blood that transports hormones into the body, age, obesity, and interference associated with commonly used test methods.

  The available methods for measuring free testosterone (FT) are simple (commercially available FT kits ", even though they are complex (equilibrium dialysis and calculation of free testosterone (CFT)) using analog tracers. Coat-A-Count "). In another embodiment, measurement of total testosterone and free testosterone serum levels can be accomplished by simultaneous measurement of total testosterone and SHBG (eg, Irma-Count, DPC) followed by calculation of free testosterone (CFT). . In another embodiment, the measurement of total testosterone and free testosterone is according to the knowledge of one skilled in the art.

  In one embodiment, the invention relates to one or more other forms of ADT and a compound of formula IA, I-XII or isomers, pharmaceutically acceptable salts, pharmaceuticals, polymorphs, hydrates Or a method of reducing total serum testosterone levels, free serum testosterone levels or free serum testosterone percentage (free T%) in a male subject, comprising administering a therapeutically effective amount combination with any of these combinations provide. In another embodiment, the reduction in total serum testosterone or free serum testosterone is caused by a reduction in serum luteinizing hormone (LH) levels. In another embodiment, the decrease in total serum testosterone levels or free serum testosterone levels is independent of a decrease in serum luteinizing hormone levels. In another embodiment, the subject suffers from castration resistant prostate cancer (CRPC). In another embodiment, the CRPC is metastatic CRPC (mCRPC). In another embodiment, the subject has been unsuccessful for androgen deprivation therapy (ADT). In another embodiment, the compound is Compound IV. In another embodiment, the compound is administered at a dosage of 125 mg per day. In another embodiment, the compound is administered at a dosage of 250 mg per day. In another embodiment, the compound is administered at a dosage of 500 mg per day.

  In one embodiment, the invention relates to one or more selective estrogen receptor modulators (SERMs) and a compound of formula IA, I-XII or isomers, pharmaceutically acceptable salts, pharmaceuticals, polymorphs. In a male subject comprising administering a therapeutically effective amount combination with a hydrate or any combination thereof, in a total serum testosterone level, free serum testosterone level or free serum testosterone percentage (free T%) Provide a way to reduce. 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, the CRPC is metastatic CRPC (mCRPC). In another embodiment, the SERM is selected from the group consisting of tamoxifen, toremifene, raloxifene, clomiphene, femarel, olmeloxifene and lasofoxifene. In another embodiment, the SERM is tamoxifen. In another embodiment, the SERM is raloxifene. In another embodiment, the SERM is toremifene. In another embodiment, the SERM is olmeroxifene. In another embodiment, the subject has been unsuccessful for androgen deprivation therapy (ADT). In another embodiment, the compound is Compound IV. In another embodiment, the compound is administered at a dosage of 125 mg per day. In another embodiment, the compound is administered at a dosage of 250 mg per day. In another embodiment, the compound is administered at a dosage of 500 mg per day.

  In one embodiment, the invention relates to one or more other forms of ADT and a compound of formula IA, I-XII or isomers, pharmaceutically acceptable salts, pharmaceuticals, polymorphs, hydrates Or treating, inhibiting, reducing the incidence, reducing the severity of castration-resistant prostate cancer (CRPC) and its symptoms comprising administering a combination of therapeutically effective amounts with any of these combinations Or methods of inhibiting progression or increasing survival in men with castration resistant prostate cancer. In another embodiment, the CRPC is metastatic CRPC (mCRPC). In another embodiment, the subject has been unsuccessful for androgen deprivation therapy (ADT). In another embodiment, the compound is Compound IV. In another embodiment, the compound is administered at a dosage of 125 mg per day. In another embodiment, the compound is administered at a dosage of 250 mg per day. In another embodiment, the compound is administered at a dosage of 500 mg per day.

  In one embodiment, the invention relates to one or more other forms of ADT and a compound of formula IA, I-XII or isomers, pharmaceutically acceptable salts, pharmaceuticals, polymorphs, hydrates Alternatively, a method of reducing serum PSA levels in a male subject suffering from castration resistant prostate cancer (CRPC) comprising administering a therapeutically effective amount of a combination with any of these combinations. In another embodiment, the CRPC is metastatic CRPC (mCRPC). In another embodiment, the subject has been unsuccessful for androgen deprivation therapy (ADT). In another embodiment, the compound is Compound IV. In another embodiment, the compound is administered at a dosage of 125 mg per day. In another embodiment, the compound is administered at a dosage of 250 mg per day. In another embodiment, the compound is administered at a dosage of 500 mg per day.

  In one embodiment, the invention relates to one or more other forms of ADT and a compound of formula IA, I-XII or isomers, pharmaceutically acceptable salts, pharmaceuticals, polymorphs, hydrates Or administering a therapeutically effective amount of a combination with any of these combinations, free testosterone levels, serum free testosterone percentage and / or serum in a male subject suffering from advanced prostate cancer A method for reducing PSA is provided. In another embodiment, the CRPC is metastatic CRPC (mCRPC). In another embodiment, the subject has been unsuccessful for androgen deprivation therapy (ADT). In another embodiment, the compound is Compound IV. In another embodiment, the compound is administered at a dosage of 125 mg per day. In another embodiment, the compound is administered at a dosage of 250 mg per day. In another embodiment, the compound is administered at a dosage of 500 mg per day.

  The methods of the invention comprise administering a combination of an estrogen receptor ligand and a compound of the invention. In one embodiment, estrogen receptor ligands include, but are not limited to, selective estrogen receptor modulators (SERMs). Examples of SERMs include, but are not limited to, tamoxifen, toremifene, raloxifene, clomiphene, femarel, olmeroxifene and lasofoxifene.

  The methods of the invention comprise administering a combination of another form of ADT and a compound of the invention. In one embodiment, the other form of ADT comprises an LHRH agonist. In another embodiment, the LHRH agonist is 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, all of which are incorporated herein by reference) or goserelin acetate (Zoladex®) (US 7,118,552; 7,220, 247; 7,500,964, all of which are incorporated herein by reference. In one embodiment, the other form of ADT comprises an LHRH antagonist. In another embodiment, the LHRH antagonist comprises degarelix. In one embodiment, the other form of ADT includes an antiandrogenic agent. In another embodiment, the antiandrogenic agent comprises bicalutamide, flutamide, finasteride, dutasteride, enzalutamide, nilutamide, chlormadinone, or any combination thereof. In one embodiment, another form of ADT includes bilateral orchiectomy.

  In one embodiment, the methods of the invention comprise administering a therapeutically effective amount of an antiandrogen and a compound of the invention. In one embodiment, the method of the invention comprises administering a therapeutically effective amount of an LHRH agonist and a compound of the invention. In one embodiment, the methods of the invention comprise administering a therapeutically effective amount of an antiandrogen agent, an LHRH agonist and a compound of the invention. In another embodiment, the compound is Compound IV. In another embodiment, the compound is administered at a dosage of 125 mg per day. In another embodiment, the compound is administered at a dosage of 250 mg per day. In another embodiment, the compound is administered at a dosage of 500 mg per day.

  In one embodiment, the present invention relates to male subjects with prostate cancer for the purpose of performing androgen depletion therapy (ADT) comprising administering a therapeutically effective amount of a compound of formula IA, I-XII. Reduces total serum testosterone levels, free serum testosterone levels and / or free serum testosterone percentage (free T%) in the body by reducing luteinizing hormone (LH) levels or independently of reducing luteinizing hormone levels Provide a method. In another embodiment, the compound is Compound IV. In another embodiment, the compound is administered at a dosage of 125 mg per day. In another embodiment, the compound is administered at a dosage of 250 mg per day. In another embodiment, the compound is administered at a dosage of 500 mg per day. In another embodiment, the prostate cancer is castration resistant prostate cancer (CRPC). In another embodiment, the CRPC is metastatic CRPC (mCRPC). In another embodiment, the subject has been unsuccessful for androgen deprivation therapy (ADT). In another embodiment, the subject further receives androgen deprivation therapy (ADT).

  In another embodiment, the invention provides a therapeutically effective amount of a compound of formula IA, I-XII or an isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate or any combination thereof. A method for androgen depletion therapy (ADT) in a subject is provided. In another embodiment, the subject has prostate cancer. In another embodiment, the prostate cancer is castration resistant prostate cancer (CRPC). In another embodiment, the CRPC is metastatic CRPC (mCRPC). In another embodiment, the compound is Compound IV. In another embodiment, the compound is administered at a dosage of 125 mg per day. In another embodiment, the compound is administered at a dosage of 250 mg per day. In another embodiment, the compound is administered at a dosage of 500 mg per day. In another embodiment, the subject has been unsuccessful for androgen deprivation therapy (ADT). In another embodiment, the subject further receives androgen deprivation therapy (ADT).

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

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

  In one embodiment, the invention relates to a subject having prostate cancer, advanced prostate cancer, castration resistant prostate cancer or metastatic castration resistant prostate cancer comprising administering a compound of the invention. Provide a way to increase survival. In another embodiment, LHRH analogs, reversible antiandrogens (eg, bicalutamide, flutamide, or enzalutamide), antiestrogens, anticancer agents, 5-alpha reductase inhibitors, aromatase inhibitors, progestins, selective Administering a compound of the invention in combination with an agent that acts via an androgen receptor modulator (SARM) or other nuclear hormone receptor. In another embodiment, the subject has been unsuccessful for androgen deprivation therapy (ADT). In another embodiment, the compound is Compound IV. In another embodiment, the compound is administered at a dosage of 125 mg per day. In another embodiment, the compound is administered at a dosage of 250 mg per day. In another embodiment, the compound is administered at a dosage of 500 mg per day.

  In one embodiment, the invention treats prostate cancer by reducing LH levels, or independently of reducing LH levels, comprising administering a compound of formula IA, I-XII, Methods are provided for reducing serum testosterone levels and / or free serum testosterone levels. In another embodiment, administering Compound IV. In another embodiment, the compound is administered at a dosage of 125 mg per day. In another embodiment, the compound is administered at a dosage of 250 mg per day. In another embodiment, the compound is administered at a dosage of 500 mg per day. In another embodiment, the prostate cancer is castration resistant prostate cancer (CRPC). In another embodiment, the CRPC is metastatic CRPC (mCRPC).

  Androgen deprivation therapy not only reduces testosterone levels but also estrogen levels. Since estrogen is derived from aromatization of testosterone, estrogen levels are also lower. Estrogen deficiency induced by androgen deprivation therapy is hot flashes, gynecomastia and breast pain, bone loss, bone quality and strength loss, osteoporosis, osteopenia, life-threatening fractures, harmful lipid changes, cardiovascular Causes serious side effects including increased disease and myocardial infarction, loss of libido, impotence, loss of muscle mass (sarcopenia), fatigue, cognitive dysfunction, and depression and other mood swings.

  In other embodiments, the present invention provides a method of treating any disease, disorder, or symptom associated with ADT. In other embodiments, the present invention provides methods of treating any disease, disorder, or symptom associated with testosterone depletion. Each disease, disorder, or symptom represents a separate embodiment of the present invention.

  In one embodiment, the present invention provides a therapeutically effective amount of a compound of formula IA, I-XII or an isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate or any combination thereof. Providing a method of reducing total serum testosterone levels, free serum testosterone levels and / or free serum testosterone percentage (free T%) in a male subject comprising administering said compound of formula IA, I-XII or Said administering the isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate or any combination thereof treats and prevents side effects associated with androgen depletion therapy (ADT); Suppress, reduce incidence or inhibit what happens, the subject has prostate cancer. In another embodiment, the reduction in total serum testosterone levels or free serum testosterone levels is by reducing LH levels or independent of reducing LH levels. In another embodiment, the subject suffers from castration resistant prostate cancer (CRPC). In another embodiment, the CRPC is metastatic CRPC (mCRPC). In another embodiment, the subject has been unsuccessful for androgen deprivation therapy (ADT). In another embodiment, the subject further receives androgen deprivation therapy (ADT). In another embodiment, the compound is Compound IV. In another embodiment, the compound is administered at a dosage of 125 mg per day. In another embodiment, the compound is administered at a dosage of 250 mg per day. In another embodiment, the compound is administered at a dosage of 500 mg per day.

  In one embodiment, administering the compound of the invention suppresses typical side effects associated with conventional androgen deprivation therapy (ADT), reduces the incidence, inhibits the side effects from occurring, or Take action. In another embodiment, the subject has prostate cancer. In another embodiment, the prostate cancer is castration resistant prostate cancer (CRPC). In another embodiment, the CRPC is metastatic CRPC (mCRPC). In another embodiment, the subject has been unsuccessful for androgen deprivation therapy (ADT). In another embodiment, the subject further receives androgen deprivation therapy (ADT). In another embodiment, the compound is Compound IV. In another embodiment, the compound is administered at a dosage of 125 mg per day. In another embodiment, the compound is administered at a dosage of 250 mg per day. In another embodiment, the compound is administered at a dosage of 500 mg per day.

  Such prevention and / or reduction of side effects is relative to the placebo or control group. In one embodiment, typical side effects associated with conventional androgen deprivation therapy (ADT) include hot flashes, gynecomastia, decreased bone mineral density and increased fracture. In another embodiment, administering the compound of the invention prevents hot flashes from occurring as found using conventional forms of androgen depletion therapy (ADT). In another embodiment, administering the compound of the invention prevents gynecomastia from occurring as found using conventional forms of androgen deprivation therapy (ADT). In another embodiment, administering the compound of the invention prevents bone mineral density (BMD) reduction as found using conventional forms of androgen depletion therapy (ADT). In another embodiment, the step of administering a compound of the invention prevents the occurrence of increased fracture as found using conventional forms of androgen depletion therapy (ADT). In another embodiment, a fracture refers to a pathological fracture, an atraumatic fracture, a vertebral fracture, a non-vertebral fracture, a new morphological fracture, a clinical fracture, or a combination thereof.

  In one embodiment, administering the compound of the invention reduces total serum testosterone without causing typical side effects associated with conventional androgen deprivation therapy (ADT). In another embodiment, the subject has prostate cancer. In yet another embodiment, the subject has advanced prostate cancer. In another embodiment, the subject has castration resistant prostate cancer (CRPC). In another embodiment, the CRPC is metastatic CRPC (mCRPC). In another embodiment, the subject has been unsuccessful for androgen deprivation therapy (ADT). In another embodiment, the subject further receives androgen deprivation therapy (ADT). In another embodiment, the compound is Compound IV. In another embodiment, the compound is administered at a dosage of 125 mg per day. In another embodiment, the compound is administered at a dosage of 250 mg per day. In another embodiment, the compound is administered at a dosage of 500 mg per day.

  In one embodiment, typical side effects associated with conventional androgen deprivation therapy (ADT) include hot flashes, gynecomastia, decreased bone mineral density and increased fracture. In another embodiment, typical side effects associated with conventional ADT include increased body fat. In another embodiment, administering the compound of the invention does not result in hot flashes as found using conventional forms of androgen depletion therapy (ADT). In another embodiment, the step of administering a compound of the invention does not result in gynecomastia as found using conventional forms of androgen deprivation therapy (ADT). In another embodiment, administering the compound of the present invention does not result in bone mineral density (BMD) reduction as found using conventional forms of androgen depletion therapy (ADT). In another embodiment, administering the compound of the invention does not result in an increase in fracture as found using conventional forms of androgen depletion therapy (ADT). In another embodiment, the increased fracture is a pathological fracture, an atraumatic fracture, a vertebral fracture, a non-vertebral fracture, a new morphological fracture, a clinical fracture, or a combination thereof. In yet another embodiment, administering a compound of the invention does not result in an increase in body fat as found using conventional forms of androgen deprivation therapy (ADT). In another embodiment, the compound is Compound IV. In another embodiment, the compound is administered at a dosage of 125 mg per day. In another embodiment, the compound is administered at a dosage of 250 mg per day. In another embodiment, the compound is administered at a dosage of 500 mg per day.

  In one embodiment, administering a compound of the invention reduces free testosterone levels without causing the typical side effects associated with conventional androgen deprivation therapy (ADT). In another embodiment, the subject has prostate cancer. In yet another embodiment, the subject has advanced prostate cancer. In another embodiment, the subject has castration resistant prostate cancer (CRPC). In another embodiment, the CRPC is metastatic CRPC (mCRPC). In another embodiment, the subject has been unsuccessful for androgen deprivation therapy (ADT). In another embodiment, the subject further receives androgen deprivation therapy (ADT). In another embodiment, the compound is Compound IV. In another embodiment, the compound is administered at a dosage of 125 mg per day. In another embodiment, the compound is administered at a dosage of 250 mg per day. In another embodiment, the compound is administered at a dosage of 500 mg per day.

  In one embodiment, administering a compound of the invention reduces the percent free testosterone (free T%) without causing the typical side effects associated with conventional androgen deprivation therapy (ADT). In another embodiment, the subject has prostate cancer. In yet another embodiment, the subject has advanced prostate cancer. In another embodiment, the subject has castration resistant prostate cancer (CRPC). In another embodiment, the CRPC is metastatic CRPC (mCRPC). In another embodiment, the subject has been unsuccessful for androgen deprivation therapy (ADT). In another embodiment, the subject further receives androgen deprivation therapy (ADT). In another embodiment, the compound is Compound IV. In another embodiment, the compound is administered at a dosage of 125 mg per day. In another embodiment, the compound is administered at a dosage of 250 mg per day. In another embodiment, the compound is administered at a dosage of 500 mg per day.

  In one embodiment, the term “hot flash” refers to a sudden hot sensation in the upper or whole body, flushing of the face and neck, red wrinkles appearing on the chest, back and arms, intense sweating, shivering due to cold, and the like.

  In one embodiment, the term “gynecomastia” refers to benign enlargement of the male breast resulting from the proliferation of glandular components of the breast and may or may not be painful. Gynecomastia is clinically defined by the presence of a rubbery or stiff mass that extends concentrically from the nipple. A condition known as pseudogynecomastia, or lipomastia, is characterized by fat deposition without glandular growth. Gynecomastia is usually bilateral but may be unilateral.

  In one embodiment, the method of the present invention can be achieved by reducing testosterone without reducing bone mass and hot flashes, thereby reducing prostate cancer or advanced prostate cancer or castration resistant prostate cancer (CRPC) or metastatic. It is intended to treat men with castration resistant prostate cancer (mCRPC). In one embodiment, the method of the present invention provides prostate cancer or advanced prostate cancer or castration resistant prostate cancer (CRPC) or metastatic castration without also resulting in bone loss, gynecomastia and hot flashes. It is intended to treat men with resistant prostate cancer (mCRPC).

  Compound IV does not increase proliferation of prostate epithelial cancer cells in vitro. Mechanistically, Compound IV provides several important advantages over existing therapies, such as gonadotropin releasing hormone (GnRH) agonists and GnRH antagonists. Compound IV is specific for the estrogen receptor and is orally bioavailable in rats, dogs, monkeys and humans. In contrast to GnRH agonists and GnRH antagonists, which lead to hot flashes and significant bone loss and increase the risk of fracture, Compound IV reduces the hot flashes induced by morphine withdrawal in rats (Example 14); Even at doses that maximally suppress LH and serum testosterone, cancellous bone mass and bone mineral density are fully maintained in the distal femur of rats (Example 11).

  In another embodiment, the methods of the invention utilize compounds IA, I-XII, where the compound is a specific side effect that is common in current androgen depletion therapy (ADT) for prostate cancer, such as bone It has the potential to reduce testosterone, the primary irritant for prostate cancer, without also causing dose reduction and hot flashes.

  In another embodiment, Table 8 below (Example 11) herein clearly demonstrates the reduction of testosterone without also resulting in bone loss by administering Compound IV.

  In one embodiment, the methods of the invention are directed to reducing testosterone levels by administering a compound of formula IA, I-XII, thereby further treating advanced prostate cancer. In another embodiment, by administering Compound IV. In another embodiment, the compound is administered at a dosage of 125 mg per day. In another embodiment, the compound is administered at a dosage of 250 mg per day. In another embodiment, the compound is administered at a dosage of 500 mg per day.

  In one embodiment, the methods of the invention are directed to reducing testosterone levels by administering a compound of formula IA, I-XII, thereby further treating castration resistant prostate cancer. In another embodiment, by administering Compound IV. In another embodiment, the compound is administered at a dosage of 125 mg per day. In another embodiment, the compound is administered at a dosage of 250 mg per day. In another embodiment, the compound is administered at a dosage of 500 mg per day.

  In one embodiment, the methods of the invention are directed to reducing testosterone levels by administering a compound of formula IA, I-XII, thereby further treating metastatic castration resistant prostate cancer (mCRPC). To do. In another embodiment, by administering Compound IV. In another embodiment, the compound is administered at a dosage of 125 mg per day. In another embodiment, the compound is administered at a dosage of 250 mg per day. In another embodiment, the compound is administered at a dosage of 500 mg per day.

  In one embodiment, the method of the invention is directed to reducing testosterone levels by administering a compound of formula IA, I-XII, thereby further inhibiting and reducing the incidence of advanced prostate cancer. Reduce or inhibit severity. In another embodiment, the methods of the invention are directed to reducing testosterone levels by administering Compound IV, thereby further inhibiting advanced prostate cancer, reducing incidence, and reducing severity. Reduce or inhibit. In another embodiment, the compound is administered at a dosage of 125 mg per day. In another embodiment, the compound is administered at a dosage of 250 mg per day. In another embodiment, the compound is administered at a dosage of 500 mg per day.

  In one embodiment, the methods of the present invention are directed to reducing testosterone levels by administering a compound of formula IA, I-XII, thereby further waiting for advanced prostate cancer, CRPC or mCRPC waiting therapy provide. In another embodiment, the methods of the present invention are directed to reducing testosterone levels by administering Compound IV, thereby further providing standby treatment for advanced prostate cancer. In another embodiment, the compound is administered at a dosage of 125 mg per day. In another embodiment, the compound is administered at a dosage of 250 mg per day. In another embodiment, the compound is administered at a dosage of 500 mg per day.

  In one embodiment, the methods of the invention are directed to treating advanced prostate cancer. In another embodiment, the methods of the invention are directed to suppressing, reducing the incidence, reducing the severity, or inhibiting advanced prostate cancer. In one embodiment, the methods of the present invention are directed to standby treatment for advanced prostate cancer. In another embodiment, the present invention is directed to the suppression of advanced prostate cancer. In another embodiment, the present invention is directed to reducing the incidence of advanced prostate cancer. In another embodiment, the present invention is directed to reducing the severity of advanced prostate cancer. In another embodiment, the present invention is directed to inhibiting advanced prostate cancer comprising administering a compound of the present invention.

  In one embodiment, the methods of the invention are directed to treating castration resistant prostate cancer. In one embodiment, the methods of the invention are directed to suppressing castration resistant prostate cancer, reducing incidence, reducing severity, or inhibiting. In one embodiment, the methods of the present invention are directed to waiting-out therapy for castration resistant prostate cancer. In another embodiment, the present invention is directed to inhibiting castration resistant prostate cancer. In another embodiment, the present invention is directed to reducing the incidence of castration resistant prostate cancer. In another embodiment, the present invention is directed to reducing the severity of castration resistant prostate cancer. In another embodiment, the present invention is directed to inhibiting castration resistant prostate cancer. In another embodiment, the present invention is directed to increasing the survival time of a subject having castration resistant prostate cancer. In another embodiment, the methods of the present invention utilize a compound of formula IA, I-XII. In another embodiment, the methods of the present invention utilize compound IV. In another embodiment, the methods of the invention utilize a compound of formula IA, I-XII in combination with an LHRH agonist. In another embodiment, the methods of the invention utilize Compound IV in combination with an LHRH agonist. In another embodiment, the methods of the present invention utilize Compound IV in combination with leuprolide acetate (Lupron®). In another embodiment, the methods of the present invention utilize a compound of formula IA, I-XII in combination with leuprolide acetate (Lupron®). In another embodiment, the methods of the invention utilize a compound of formula IA, I-XII in combination with an LHRH antagonist. In another embodiment, the methods of the invention utilize compound IV in combination with an LHRH antagonist. In another embodiment, the methods of the invention utilize compound IV in combination with degarelix. In another embodiment, the methods of the present invention utilize compounds of formula IA, I-XII in combination with degarelix. In another embodiment, the methods of the present invention utilize a compound of formula IA, I-XII in combination with an antiandrogenic agent. In another embodiment, the methods of the present invention utilize Compound IV in combination with an antiandrogenic agent.

  In one embodiment, the methods of the invention are directed to treating metastatic castration resistant prostate cancer. In one embodiment, the methods of the invention are directed to inhibiting, reducing the incidence, reducing the severity, or inhibiting metastatic castration resistant prostate cancer. In one embodiment, the methods of the present invention are directed to waiting for metastatic castration resistant prostate cancer. In another embodiment, the present invention is directed to inhibiting metastatic castration resistant prostate cancer. In another embodiment, the present invention is directed to reducing the incidence of metastatic castration resistant prostate cancer. In another embodiment, the present invention is directed to reducing the severity of metastatic castration resistant prostate cancer. In another embodiment, the present invention is directed to inhibiting metastatic castration resistant prostate cancer. In another embodiment, the present invention is directed to increasing the survival time of a subject having metastatic castration resistant prostate cancer. In another embodiment, the methods of the present invention utilize a compound of formula IA, I-XII. In another embodiment, the methods of the present invention utilize compound IV. In another embodiment, the methods of the invention utilize a compound of formula IA, I-XII in combination with an LHRH agonist. In another embodiment, the methods of the invention utilize Compound IV in combination with an LHRH agonist. In another embodiment, the methods of the present invention utilize Compound IV in combination with leuprolide acetate (Lupron®). In another embodiment, the methods of the present invention utilize a compound of formula IA, I-XII in combination with leuprolide acetate (Lupron®). In another embodiment, the methods of the invention utilize a compound of formula IA, I-XII in combination with an LHRH antagonist. In another embodiment, the methods of the invention utilize compound IV in combination with an LHRH antagonist. In another embodiment, the methods of the invention utilize compound IV in combination with degarelix. In another embodiment, the methods of the present invention utilize compounds of formula IA, I-XII in combination with degarelix. In another embodiment, the methods of the present invention utilize a compound of formula IA, I-XII in combination with an antiandrogenic agent. In another embodiment, the methods of the present invention utilize Compound IV in combination with an antiandrogenic agent.

  In another embodiment, the present invention is directed to increasing the survival time of a subject with advanced prostate cancer, CRPC or mCRPC. In another embodiment, the methods of the present invention utilize a compound of formula IA, I-XII. In another embodiment, the methods of the invention utilize a compound of formula IA, I-XII in combination with an LHRH agonist. In another embodiment, the methods of the present invention utilize a compound of formula IA, I-XII in combination with leuprolide acetate (Lupron®). In another embodiment, the methods of the invention utilize a compound of formula IA, I-XII in combination with an LHRH antagonist. In another embodiment, the methods of the invention utilize compound IV in combination with an LHRH antagonist. In another embodiment, the methods of the invention utilize compound IV in combination with degarelix. In another embodiment, the methods of the present invention utilize compounds of formula IA, I-XII in combination with degarelix. In another embodiment, the methods of the present invention utilize a compound of formula IA, I-XII in combination with an antiandrogenic agent. In another embodiment, the methods of the present invention utilize Compound IV in combination with an antiandrogenic agent.

  In another embodiment, the present invention is directed to increasing the survival time of a subject with advanced prostate cancer, CRPC or mCRPC. In another embodiment, the methods of the present invention utilize compound IV. In another embodiment, the methods of the invention utilize compound IV in combination with an LHRH agonist. In another embodiment, the methods of the present invention utilize Compound IV in combination with leuprolide acetate (Lupron®). In another embodiment, the methods of the invention utilize Compound IV in combination with an LHRH antagonist. In another embodiment, the methods of the present invention utilize Compound IV in combination with degarelix.

  The term "advanced prostate cancer" occurs in the prostate and has spread widely beyond the prostate, for example, to the surrounding tissues, including seminal vesicles, pelvic lymph nodes or bone, or to other parts of the body Refers to metastatic cancer. The condition of prostate cancer is graded from 1 to 5 in order of increasing malignancy by Gleason grading. In another embodiment, patients with a significant risk of advanced disease and / or death from prostate cancer should be included in this definition and have cancer outside the prostate capsule with a disease stage as low as IIB Any patient clearly has a “progressive” disease.

  Men with advanced prostate cancer are often treated to block the production of androgen, a male hormone that can help the growth of prostate tumors. However, prostate cancer that responds first to antiandrogen therapy eventually gives rise to the ability to grow without androgen. Such cancers are often referred to as hormone refractory, androgen-independent, or castration resistant.

  In one embodiment, the advanced prostate cancer is a castration resistant prostate cancer.

  The term “castration resistant prostate cancer” (CRPC) refers to prostate cancer that is considered hormone refractory, hormone naive, androgen independent, or resistant to chemical or surgical castration.

  In another embodiment, castration resistant prostate cancer (CRPC) is a progressive prostate cancer that has developed despite ongoing ADT and / or surgical castration. In another embodiment, ADT refers to a treatment consisting of leuprolide acetate (Lupron®).

  In one embodiment, castration resistant prostate cancer has an increased or higher serum level of prostate specific antigen (PSA), metastasis, bone metastasis, pain, lymph node involvement, size for tumor growth or Increased serum markers, worsening diagnostic markers for prognosis, or previous surgical castration, gonadotropin-releasing hormone agonist (eg, leuprolide) or antagonist (degarelix), antiandrogenic agents (eg, , Bicalutamide, flutamide, enzalutamide, ketoconazole, aminoglutethamide, chemotherapeutic agents (eg, docetaxel, paclitaxel, cabazitaxel, adriamycin, mitoxantrone, estramus , Cyclophosphamide), kinase inhibitors (imatinib (Gleevec®) or gefitinib (Iressa®)) or other prostate cancer therapies (eg vaccines (Cyproecell-T (Provenge®)) )), GVAX, etc.), herbal (PC-SPES) and lyase inhibitors (aviraterone)), despite continued treatment, prostate cancer that continues to progress, or worsens or adversely affects the patient's health Defined. In another embodiment, castration resistant prostate cancer is defined as hormone naive prostate cancer.

  Many early prostate cancers require androgens for growth, while advanced prostate cancer is often androgen-independent or hormone naive. 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 term “androgen depletion therapy” (ADT) or “conventional androgen depletion therapy” is directed to testicular removal (surgical castration) in which the surgeon removes the testicles. In another embodiment, the term “androgen depletion therapy” or “conventional androgen depletion therapy” is directed to administering a luteinizing hormone releasing hormone (LHRH) analog. These drugs reduce the amount of testosterone made by the testis. Examples of LHRH analogs available in the United States include leuprolide (Lupron (R), Viadur (R), Eligard (R)), goserelin (Zoladex (R)), triptorelin (Telstar (R)). ), And histrelin (Vantas®). In another embodiment, the term “androgen depletion therapy” or “conventional androgen depletion therapy” is directed to administering an anti-androgen agent. Antiandrogens block the body's ability to use any androgen. Even after testectomy or during treatment with LHRH analogs, a small amount of androgen is still made by the adrenal glands. Examples of antiandrogenic drugs include enzalutamide, flutamide (Eulexin®), bicalutamide (Casodex®), and nilutamide (Nilandron®). In another embodiment, the term “androgen depletion therapy” or “conventional androgen depletion therapy” refers to a luteinizing hormone-releasing hormone (LHRH) antagonist, such as Abarelix (Plenaxis®) or Degarelix (registered trademark). Trademark)) (subject to approval by the FDA for use in the treatment of advanced prostate cancer in 2008). In another embodiment, the term “androgen depletion therapy” or “conventional androgen depletion therapy” administers a 5α-reductase inhibitor, such as finasteride (Proscar®) and dutasteride (Avodart®). It is intended to do. 5α-reductase inhibitors block the body's ability to convert testosterone to the more active androgen, 5α-dihydrotestosterone (DHT). In another embodiment, the term “androgen depletion therapy” or “conventional androgen depletion therapy” is directed to administering an inhibitor of testosterone biosynthesis, eg, ketoconazole (Nizoral®). In another embodiment, the term “androgen depletion therapy” or “conventional androgen depletion therapy” is directed to administering an estrogen, such as diethylstilbestrol or 17β-estradiol. In another embodiment, the term “androgen depletion therapy” or “conventional androgen depletion therapy” administers a 17α-hydroxylase / C17,20 lyase (CYP17A1) inhibitor, eg, abiraterone (Zytiga®). It is intended to do.

  In one embodiment, the methods of the invention treat, suppress, reduce incidence, reduce severity, inhibit, provide palliative care, or increase survival in a subject. It is intended to make it. In one embodiment, the method of the invention treats, suppresses, reduces incidence, reduces severity, inhibits, provides palliative care, or provides survival for advanced prostate cancer in a subject. Targeting methods to increase In one embodiment, the methods of the invention treat, suppress, reduce incidence, reduce severity, inhibit, provide palliative care, or increase survival time for castration resistant prostate cancer. It is intended to make it. In one embodiment, the method of the invention treats, suppresses, reduces incidence, reduces severity, inhibits, provides palliative care, or provides survival for metastatic castration resistant prostate cancer It is intended to increase. In another embodiment, the subject has elevated or increased prostate specific antigen (PSA) levels.

  In one embodiment, the level of prostate specific antigen (PSA) considered normal is age dependent. In one embodiment, the level of prostate specific antigen (PSA) considered normal depends on the size of the prostate of the male subject. In one embodiment, PSA levels in the range of 2.5-10 ng / mL are considered “high boundary values”. In another embodiment, a PSA level greater than 10 ng / mL is considered “high”.

  In one embodiment, the rate of change or “PSA rate” is high. In one embodiment, a rate of change greater than 0.75 / year or “PSA rate” is considered high.

  In one embodiment, the present invention is directed to the treatment of a subject having elevated or increased PSA levels comprising administering a compound of the present invention. In one embodiment, the present invention has high or increased PSA levels despite ongoing ADT or ADT history, surgical castration, or despite treatment with antiandrogens and / or LHRH agonists Intended for subject treatment. In another embodiment, the treatment utilizes a compound of the invention. In another embodiment, the treatment utilizes Compound IV.

  In one embodiment, the present invention is directed to a method of reducing prostate specific antigen (PSA) levels in a subject comprising administering a compound of the present invention. In one embodiment, the present invention is directed to a method of reducing prostate specific antigen (PSA) levels in a subject comprising administering a compound of formula IA, I-XII. In another embodiment, by administering Compound IV. In one embodiment, the present invention is directed to a method of reducing prostate specific antigen (PSA) levels in a subject comprising administering a compound of formula IA, I-XII in combination with an LHRH agonist. In another embodiment, administering Compound IV in combination with an LHRH agonist. In one embodiment, the present invention is directed to a method of reducing prostate specific antigen (PSA) levels in a subject comprising administering a compound of formula IA, I-XII in combination with an LHRH antagonist. In another embodiment, administering Compound IV in combination with an LHRH agonist. In one embodiment, the present invention provides a method of reducing prostate specific antigen (PSA) levels in a subject comprising administering a compound of formula IA, I-XII in combination with leuprolide acetate (Lupron®). Is targeted. In another embodiment, administering Compound IV in combination with leuprolide acetate (Lupron®). In one embodiment, the present invention is directed to a method of reducing prostate specific antigen (PSA) levels in a subject comprising administering a compound of formula IA, I-XII in combination with degarelix. In another embodiment, administering Compound IV in combination 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, the CRPC is metastatic CRPC (mCRPC). In another embodiment, the subject has been unsuccessful for androgen deprivation therapy (ADT). In another embodiment, Compound IV is administered at a dosage of 125 mg per day. In another embodiment, Compound IV is administered at a dosage of 250 mg per day. In another embodiment, Compound IV is administered at a dosage of 500 mg per day.

  In one embodiment, the present invention provides a method of treating castration resistant prostate cancer using the compounds of the present invention, thereby reducing the need for chemotherapy.

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

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

  In one embodiment, the present invention provides a method of treating, suppressing, reducing incidence, reducing severity, increasing survival, or inhibiting GnRH antagonist (GRHA) resistant prostate cancer To do. In another embodiment, the GRHA agonist is degarelix.

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

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

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

  In one embodiment, utilizing the methods provided herein and / or the compounds provided herein is effective in achieving feedback to the hypothalamus-pituitary-testis axis (HPT axis). Feedback refers to the ability of a substance produced in one organ or tissue to regulate the activity of another organ or tissue that affects the activity of the substance itself. In one embodiment, feedback to the hypothalamus-pituitary-testis axis (HPT axis) results in a reduction in LH levels. In one embodiment, feedback to the hypothalamus-pituitary-testis axis (HPT axis) results in a reduction in total serum testosterone levels. In one embodiment, feedback to the hypothalamus-pituitary-testis axis (HPT axis) results in a reduction in free serum testosterone levels. In one embodiment, feedback to the hypothalamus-pituitary-testis axis (HPT axis) results in a reduction in androgen serum, tissue or tumor levels.

  The hypothalamic-pituitary-testis (HPT) axis refers to the endocrine physiological system that regulates hormone levels in the hypothalmus, pituitary gland and testis. LHRH (Luteinizing Hormone Releasing Hormone) is released by the hypothalamus, stimulates the pituitary gland, synthesizes and secretes LH and FSH (gonadotropin). LH and FSH then act on the testis to stimulate testosterone and sperm production. Testosterone then has a direct negative feedback effect on hypothalamic LHRH secretion and an indirect negative feedback effect on pituitary LH and FSH production. Estrogens, androgens and serum proteins (eg, inhibin) also have a negative effect on LHRH secretion, and LH and FSH secretion.

  The pituitary gland is a gland that controls the level of testosterone in the body. When testosterone levels are low, the pituitary gland releases luteinizing hormone (LH). This hormone induces the testis to make more testosterone. During puberty, testosterone levels increase. Testosterone levels are generally highest at age 20-40 and then gradually decrease in older men. Women have a much lower amount of testosterone in the body compared to men. However, testosterone plays an important role throughout the body in both men and women. Testosterone affects brain, bone and muscle mass, fat distribution, vasculature, energy levels, genital tissue, and sexual function. The majority of testosterone in the blood is bound to a protein called sex hormone binding globulin (SHBG), or another serum protein called albumin. Unbound (or “free”) testosterone can also be determined clinically.

  In another embodiment, reducing total serum testosterone, free serum testosterone levels or percent free serum testosterone (free T%), independently of reducing serum luteinizing hormone levels, is a measure of sex hormone binding globulin (SHBG). Due to the increase. In another embodiment, reducing free testosterone levels independent of decreasing serum luteinizing hormone levels is due to increased sex hormone binding globulin (SHBG). In another embodiment, reducing the percent free testosterone (free T%) independent of reducing serum luteinizing hormone levels is due to an increase in sex hormone binding globulin (SHBG). In another embodiment, reducing total serum testosterone levels or free serum testosterone levels independent of reducing serum luteinizing hormone (LH) levels is due to inhibition of testosterone production or secretion by Leydig cells in the testis. In another embodiment, reducing total serum testosterone levels or free serum testosterone levels independent of reducing serum luteinizing hormone (LH) levels is due to reduced adrenal steroidogenesis.

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

  Hydroxysteroid dehydrogenase (HSD) family members are involved in the conversion of circulating steroids. 17β-HSD5 converts androstenedione to testosterone and estrone to estradiol. In addition, 17β-HSD5 is also involved in prostaglandin synthesis. In one embodiment, the compounds of the invention inhibit HSD, particularly 17β-hydroxysteroid dehydrogenase 5 (17β-HSD5) inhibition. Such inhibition may be useful in ADT by preventing peripheral / extragonadal testosterone synthesis. Peripheral / extragonadal testosterone synthesis may avoid control of the HPT axis and result in incomplete reduction of total or free serum testosterone, or allow locally elevated intracellular testosterone levels, but any of these Can also be detrimental in ADT.

  LHRH agonist therapy, ie androgen depletion therapy (ADT) achieved by administering luteinizing hormone-releasing hormone agonist (LHRH) or analogs thereof, is the first of gonadotropin release from the pituitary gland and testosterone production from the testis. It results in irritation (referred to as “flare reaction”), followed by a decrease in gonadotropin release, and a decrease in both testosterone and estrogen levels. The “flare response” produced by LHRH agonist therapy has a negative impact on prostate cancer treatment by increasing androgen / testosterone levels. Furthermore, 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 flaring effects of LHRH therapy, antiandrogen monotherapy (bicalutamide, flutamide, chlormadinone), combined LHRH / antiandrogen therapy approaches, and LHRH antagonists (Degarelix) have been suggested (Suzuki et al., (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. Bicalutamide antiandrogen monotherapy has been shown to be less effective than ADT in prostate cancer patients with bone metastases. In addition, adverse effects observed with bicalutamide therapy include breast tenderness and breast enlargement (gynecomastia and breast pain). (Suzuki et al., Ibid.) Further risks from antiandrogen therapy include increased liver transaminase. (Sharifi et al., Ibid).

  In one embodiment, the present invention provides a reduction in LH levels and thereby a reduction in total serum testosterone and / or free serum testosterone levels without producing a “flare” effect, while using conventional ADT methods Overcoming the adverse effects associated with estrogen deficiency caused by reduced testosterone. The method / use of the subject compounds is to maintain bone tissue (agonist effect on bone tissue), reduce the potential for thrombus formation and / or reduce hot flash, and / or breast tissue rather than estradiol or diethylstilbestrol. Achieve tissue-selective estrogenic activity that achieves a lesser or neutral effect on.

  In one embodiment, compound IV exhibits an agonistic effect but no antagonistic effect (Examples 6 and 7). Therefore, Compound IV does not result in an increase in gonadotropin and testosterone.

  In one embodiment, Compound IV exhibits agonist activity (Examples 8-11), which clearly shows a robust pharmacological response for the reduction of serum hormones, testosterone and total androgens.

  In one embodiment, compound IV has a non-steroidal selective estrogen receptor α (binding to estrogen receptor (ER) with nanomolar affinity for both estrogen receptor α (ERα) and ERβ. ERα) agonist. Although many estrogenic ligands cross-react with other nuclear hormone receptors, the action of Compound IV is specific for ERα and ERβ. Compound IV has a 16-fold selectivity in relative transactivation potency for ERα and ERβ compared to estradiol, and a potency of about 1400 in its ability to stimulate ERβ-mediated transcription.

  In one embodiment, the methods provided herein utilizing the compounds and / or compositions provided herein reduce or eliminate bone resorption effects brought about by LH reduction using conventional forms of ADT. It is effective to make it. In one embodiment, utilizing the methods provided herein and / or the compositions provided herein reduces the bone resorption effect provided by reducing testosterone levels using conventional forms of ADT or It is effective to make it disappear. In one embodiment, the methods provided herein utilizing the compositions provided herein are effective in reducing or eliminating the bone resorption effect provided by the reduction of estrogens as a result of the reduction in LH levels. It is. In one embodiment, the methods provided herein utilizing the compounds and / or compositions provided herein prevent bone resorption effects associated with reducing LH levels using conventional forms of ADT. . In one embodiment, the methods provided herein utilizing the compounds and / or compositions provided herein are associated with the reduction of endogenous LH, testosterone and / or estradiol using conventional forms of ADT. Prevent bone loss. In one embodiment, the methods provided herein utilizing the compounds and / or compositions provided herein increase bone mass density (BMD) while achieving a reduction in LH levels. In one embodiment, the methods provided herein utilizing the compounds and / or compositions provided herein achieve a reduction in endogenous LH, testosterone and / or estradiol levels, while percent bone volume Increase.

  In some embodiments, the present invention avoids and / or reduces thromboembolism by administering a compound of the present invention or an isomer, pharmaceutical, polymorph, hydrate, or any combination thereof. Provide a method.

  In one embodiment, the methods provided herein utilizing the compounds and / or compositions provided herein are effective in breast tissue. In one embodiment, the methods provided herein utilizing the compounds and / or compositions provided herein prevent gynecomastia associated with reduced LH levels achieved by conventional ADT. Thus, the LH level can be reduced.

  In one embodiment, Example 13 discloses a special toxicity study where in vitro studies using human platelets have shown that compound IV has much lower procoagulant activity than DES. Thus, Compound IV, an ER selective agonist, exerts the benefits of DES in prostate cancer with less risk of thrombogenic events than DES, and also reduces bone mass and increases Or it should exert the benefits of an LHRH agonist or LHRH antagonist without producing a detrimental lipid profile.

  Diethylstilbestrol (DES) therapy alone or in combination with other ADTs showed that DES prevented bone resorption in patients with prostate cancer. Although the use of DES has been promoted as a treatment for prostate cancer, the effects of DES on angiogenesis and malignant tumors are thought to be mediated by DES metabolites and act through estrogen receptors. Is unthinkable. In addition, dose levels of DES administered for therapeutic use can cause a number of harmful effects including vascular disease, cardiovascular morbidity, thrombotoxicity, gynecomastia, erectile dysfunction and loss of libido. Side effects are indicated (Scherr and Pitts, ibid. And Presti, JC Jr. (1996) JAMA. 275 (15): 1153-6).

  In one embodiment, the present invention overcomes the negative side effects of LHRH agonist or LHRH antagonist therapy alone or in combination with antiandrogens or DES. In another embodiment, the methods of the present invention may include androgen without adverse estrogen depletion side effects, such as harmful bone-related conditions, and without adverse estrogen-stimulated side effects, such as gynecomastia. Provide depletion therapy. In another embodiment, the method of the invention overcomes the adverse effects associated with estrogen deficiency caused by LH reduction and overcomes the adverse effects associated with the increase in overall estrogen agonist observed by DES therapy. To achieve a reduction in LH levels and thus a reduction in total and / or free serum testosterone levels without causing a “flare” effect. The method / use of the subject compounds achieves tissue-selective estrogenic activity, thereby realizing bone tissue maintenance (agonist effect on bone tissue), reduced thrombus formation potential and neutral effect on breast tissue.

Antiestrogenic effects of conventional selective estrogen receptor modulators (SERMs) such as tamoxifen, toremifene and raloxifene at the hypothalamic level result in increased gonadotropin levels or increased LH levels in men, thereby increasing testosterone serum levels Potential increase. (Tsouri et al., 2008, Fertility and Sterility doi: 10.016). In contrast, the methods of the invention achieve a reduction in LH in a male subject comprising administering a compound of formula IA, I-XII.
Further embodiments for compounds of formula I:

In one embodiment of the method of the present invention, Y of the compound of formula I is C (O). In another embodiment, Y is CH _2. In another embodiment, R ₁ and R ₂ of the compound of formula I or IA are independently O—Alk—NR ₅ R ₆ or O—Alk-heterocycle. In another embodiment, the O-Alk- _{heterocycle, O-Alk-NR 5 R} 6, -Alk- heterocyclic and _Alk-NR 5 Alk of _{R 6} described herein above, 1-7 Straight chain alkyl of 1 carbon, branched alkyl of 1 to 7 carbon, or cyclic alkyl of 3 to 8 carbon. In another embodiment, the alkyl is ethylene (—CH ₂ CH ₂ —). In another embodiment, Alk is methylene (—CH ₂ —). In another embodiment, Alk is propylene (—CH ₂ CH ₂ CH ₂ —). In another embodiment, Alk is 2-methylpropylene (—CH ₂ CH (CH ₃ ) CH ₂ —).

In one embodiment of the method of the invention, R ₁ of the compound of formula I or IA is in the para position. In one embodiment of the method of the invention, R ₁ and R ₂ of the compounds of formula I or IA are different. In another embodiment of the method of this invention, R ₁ and R ₂ of the compound of formula I or IA are the same. In another embodiment of the method of this invention R _{1 in} the compounds of formula I or IA is
It is. In another embodiment of the method, R ₁ of the compound of formula I or IA is hydroxyl. In another embodiment of the method, R ₁ of the compound of formula I or IA is alkoxy. In another embodiment of the method, R ₁ and R ₂ are independently hydrogen, halogen, hydroxyl, alkoxy, cyano, nitro, CF ₃ , N (R) ₂ , sulfonamide, SO ₂ R, alkyl, haloalkyl, Aryl, O-Alk-NR ₅ R ₆ or O-Alk-heterocycle, wherein the heterocycle is a 3-7 membered substituted or unsubstituted heterocyclic ring, optionally aromatic . In another embodiment of the method, R ₁ and R ₂ of the compound of formula I or IA are independently halogen, hydroxyl, alkoxy, cyano, nitro, CF ₃ , N (R) ₂ , sulfonamide, SO ₂ R , Alkyl, haloalkyl, aryl, O-Alk-NR < ₅ > R < ₆ > or O-Alk-heterocycle, wherein the heterocycle is a 3-7 membered substituted or unsubstituted heterocyclic ring, optionally And aromatic. In another embodiment of the method, R ₂ of the compound of formula I or IA is halogen. In another embodiment of the methods, R ₂ of the compound of formula I or IA is F. In another embodiment of the method, R ₂ of the compound of formula I is Cl. In another embodiment of the method, R ₂ of the compound of formula I or IA is Br. In another embodiment of the methods, R ₂ of the compound of formula I or IA is I. In another embodiment of the method, R ₂ of the compound of formula I or IA is hydroxyl. In another embodiment of the method, R ₁ and / or R ₂ is CF ₃ . In another embodiment, R ₁ and / or R ₂ is CH ₃ . In another embodiment, R ₁ and / or R ₂ is halogen. In another embodiment, R ₁ and / or R ₂ is F. In another embodiment, R ₁ and / or R ₂ is Cl. In another embodiment, R ₁ and / or R ₂ is Br. In another embodiment, R ₁ and / or R ₂ is I. In another embodiment, R ₂ of the compound of formula I is in the para position.

In one embodiment of the method of the invention, R ₃ and R ₄ of the compound of formula I or IA are the same. In another embodiment of the methods of this invention, R ₃ and R ₄ of the compounds 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 method, R ₃ and R ₄ of the compound of formula I or IA are independently halogen, haloalkyl, hydroxyl or alkyl. In another embodiment of the methods, R ₃ and R ₄ of the compound of formula I or IA are independently F. In another embodiment of the method, R ₃ and R ₄ of the compound of formula I or IA are independently Br. In another embodiment of the method, R ₃ and R ₄ of the compound of formula I or IA are independently Cl. In another embodiment, R ₄ is in the para position. In another embodiment, R ₃ is in the ortho position. In another embodiment, R ₃ is in the meta position. In another embodiment, R ₃ and / or R ₄ is CF ₃ . In another embodiment, R ₃ and / or R ₄ is CH ₃ .

In one embodiment of the method of the invention, R ₅ and R ₆ of the compound of formula I or IA together with the nitrogen atom form a 3-7 membered ring. In another embodiment, the ring is a saturated or unsaturated ring. In another embodiment, the ring is a substituted ring or an unsubstituted ring. In another embodiment of the method of this invention, R ₅ and R ₆ of the compound of formula I or IA together with nitrogen form a piperidine ring. In another embodiment of the method, R ₅ and R ₆ of the compound of formula I or IA together with nitrogen form a pyrazine ring. In another embodiment of the method, R ₅ and R ₆ of the compound of formula I or IA together with nitrogen form a piperazine ring. In another embodiment of the method, R ₅ and R ₆ of the compound of formula I or IA together with nitrogen form a morpholine ring. In another embodiment of the method, R ₅ and R ₆ of the compound of formula I or IA together with nitrogen form a pyrrole ring. In another embodiment of the method, R ₅ and R ₆ of the compound of formula I or IA form pyrrolidine. In another embodiment of the method, R ₅ and R ₆ of the compound of formula I or IA together with nitrogen form a pyridine ring. In another embodiment, the ring is substituted with halogen, alkyl, alkoxy, alkylene, hydroxyl, cyano, nitro, amino, amide, COOH or aldehyde.

In another embodiment of the method of the present _{invention, R 2 (R 2 of compound} of the compound of formula I or IA) of a compound of compound of _{R 1} and Formula I or IA compound of formula I or IA are independently , O-Alk-heterocycle or OCH ₂ CH ₂ -heterocycle. In another embodiment, the term “heterocycle” group, in one embodiment, refers to a ring structure that includes sulfur, oxygen, nitrogen or any combination thereof as a ring moiety in addition to a carbon atom. In another embodiment, the heterocycle is a 3-12 membered ring. In another embodiment, the heterocycle is a 6-membered ring. In another embodiment, the heterocycle is a 5-7 membered ring. In another embodiment, the heterocycle is a 4-8 membered ring. In another embodiment, the heterocyclic group is unsubstituted, halogen, haloalkyl, hydroxyl, alkoxy, carbonyl, amide, alkylamide, dialkylamide, cyano, nitro, CO ₂ H, amino, alkylamino, dialkyl It may be substituted with amino, carboxyl, thio and / or thioalkyl. In another embodiment, the heterocyclic ring can be fused to another saturated or unsaturated cycloalkyl or 3-8 membered heterocyclic 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, pyrrole, pyrrolidine, pyrazine, piperazine or pyrimidine.

  The term “cycloalkyl” refers to a non-aromatic monocyclic or polycyclic ring containing carbon and hydrogen atoms. Cycloalkyl groups can have one or more carbon-carbon double bonds in the ring, as long as the ring is not aromatic due to the presence of carbon-carbon double bonds. Examples of cycloalkyl groups include, but are not limited to, (C3-C7) cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, and saturated cyclic terpenes and saturated Bicyclic terpenes and (C3-C7) cycloalkenyl groups such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and cycloheptenyl, as well as unsaturated cyclic terpenes and unsaturated bicyclic terpenes. A cycloalkyl group can be unsubstituted 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 saturated aliphatic hydrocarbons including straight chain, branched chain and cyclic alkyl groups. In one embodiment, the alkyl group has 1-12 carbons. In another embodiment, the alkyl group has 1-7 carbons. In another embodiment, the alkyl group has 1-6 carbons. In another embodiment, the alkyl group has 1-4 carbons. In another embodiment, the cyclic alkyl group has 3-8 carbons. In another embodiment, the cyclic alkyl group has 3-12 carbons. In another embodiment, a branched alkyl is an alkyl substituted with an alkyl side chain of 1-5 carbons. In another embodiment, a branched alkyl is an alkyl substituted with a 1-5 carbon haloalkyl side chain. Alkyl groups may be unsubstituted, substituted with halogen, haloalkyl, hydroxyl, alkoxycarbonyl, amide, alkylamide, dialkylamide, nitro, amino, alkylamino, dialkylamino, carboxyl, thio and / or thioalkyl. Also good.

  An “alkenyl” group refers, in another embodiment, to an unsaturated hydrocarbon, including straight chain, branched chain, and cyclic groups having one or more double bonds. An alkenyl group can have one double bond, two double bonds, three double bonds, and the like. In another embodiment, the alkenyl group has 2-12 carbons. In another embodiment, the alkenyl group has 2-6 carbons. In another embodiment, an alkenyl group has 2-4 carbons. Examples of alkenyl groups are ethenyl, propenyl, butenyl, cyclohexenyl and the like. Alkenyl groups may be unsubstituted or substituted with halogen, hydroxy, alkoxycarbonyl, amide, alkylamide, dialkylamide, nitro, amino, alkylamino, dialkylamino, carboxyl, thio and / or thioalkyl. .

  An “aryl” group is unsubstituted or selected from halogen, haloalkyl, hydroxy, alkoxycarbonyl, amide, alkylamide, dialkylamide, nitro, amino, alkylamino, dialkylamino, carboxy or thio or thioalkyl. An aromatic group having at least one carbocyclic aromatic group or heterocyclic aromatic group, which may be substituted with one or more groups. Non-limiting examples of aryl rings are phenyl, naphthyl, pyranyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyrazolyl, pyridinyl, furanyl, thiophenyl, thiazolyl, imidazolyl, isoxazolyl and the like. In one embodiment, the aryl group is a 4-8 membered ring. In another embodiment, the aryl group is a 4-12 membered ring (s). 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 2-4 fused ring systems.

  An “aldehyde” group, in one embodiment, refers to an alkyl or alkenyl substituted with a formyl group, where alkyl or alkenyl is as defined herein above. In another embodiment, the aldehyde group is an aryl or phenyl group substituted with a formyl group, where aryl is as defined herein 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 that is substituted with one or more halogen atoms, eg, F, Cl, Br, or I.

A “hydroxyl” group refers, in another embodiment, to an OH group. One skilled in the art understands that when R ₁ , R ₂ or R ₃ in the compounds of the present invention is OR, R is not OH.

  In one embodiment, the term “halogen” or “halo” refers to a halogen, eg, F, Cl, Br, or I.

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

  In some embodiments, reference to a protected hydroxyl includes the incorporation of a substituent attached to the oxygen portion of the benzene ring, which can be easily removed. In some embodiments, the phenol protecting group is methyl ether (methoxy), alkyl ether (alkoxy), benzyl ether (Bn), methoxymethyl (MOM) ether, benzoyloxymethyl (BOM) ether, benzyl, carbobenzoxy. , Methoxyethoxymethyl (MEM) ether, 2- (trimethylsilyl) ethoxymethyl (SEM) ether, methylthiomethyl (MTM) ether, phenylthiomethyl (PTM) ether, azidomethyl ether, cyanomethyl ether, 2,2-dichloro- 1,1-difluoroethyl ether, 2-chloroethyl ether, 2-bromoethyl ether, tetrahydropyranyl (THP) ether, 1-ethoxyethyl (EE) ether, phenacyl ether, 4-bromo Enacyl ether, cyclopropyl methyl ether, allyl ether, propargyl ether, isopropyl ether, cyclohexyl ether, t-butyl ether, 2,6-dimethylbenzyl ether, 4-methoxybenzyl ether, o-nitrobenzyl ether, 2,6-dichlorobenzyl Ether, 3,4-dichlorobenzyl ether, 4- (dimethylamino) carbonylbenzyl ether, 4-methylsulfinyl benzyl ether, 4-anthrylmethyl ether, 4-picolyl ether, heptafluoro-p-tolyl, tetrafluoro-4 -Pyridyl ether, trimethylsilyl (TMS) ether, t-butyldimethylsilyl (TBDMS) ether, t-butyldiphenylsilyl (TBDPS) ether, triisopropyl Pyrsilyl (TIPS) ether, arylformate, arylacetate, aryllevulinate, arylpivaloate, arylbenzoate, aryl 9-fluorenecarboxylate, arylmethyl carbonate, 1-adamantyl carbonate, t-butyl carbonate, 4-methylsulfinyl benzyl carbonate, 2,4-dimethylpent-3-yl carbonate, aryl 2,2,2-trichloroethyl carbonate, aryl benzyl carbonate, aryl carbamate, dimethylphosphinyl ester (Dmp-OAr) ), Dimethylphosphinothionyl ester (Mpt-OAr), diphenylphosphinothionyl ester (Dpt-OAr), arylmethanesulfuric acid Phonates, aryl toluene sulfonates or aryl 2-formyl benzene sulfonates can be included.

  In one embodiment, the method of the invention comprises N, N-bis (4-hydroxyphenyl) -4-propylbenzamide (II) or isomers, pharmaceutically acceptable salts, pharmaceuticals, polymorphs, hydration Or any combination of these. In another embodiment, the method of the invention comprises 4,4 ′-(2,3-dimethyl-benzylazanediyl) diphenol (III) or an isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph. , Hydrates or any combination thereof. In another embodiment, the method of the invention comprises 3-fluoro-N- (4-fluorophenyl) -4-hydroxy-N- (4-hydroxyphenyl) benzamide (IV) or an isomer thereof, pharmaceutically acceptable Salt, pharmaceutical, polymorph, hydrate, or any combination thereof. In another embodiment, the method of the invention comprises N, N-bis (4-hydroxyphenyl) -2,3-dimethylbenzamide (V) or an isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph. , Hydrates or any combination thereof. In another embodiment, the method of the invention comprises N, N-bis (4-hydroxyphenyl) -2-naphthylamide (VI) or an isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, water Use Japanese or any combination of these. In another embodiment, the method of the invention comprises 3-fluoro-4-hydroxy-N, N-bis (4-hydroxyphenyl) -benzamide (VII) or an isomer thereof, a pharmaceutically acceptable salt, a pharmaceutical product. , Polymorphs, hydrates or any combination thereof. In another embodiment, the method of the present invention comprises 4-((4-fluorophenyl) (4-hydroxybenzyl) amino) phenol (VIII) or an isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph. , Hydrates or any combination thereof. In another embodiment, the method of the present invention comprises 4-fluoro-N- (4-hydroxy-phenyl) -N- [4- (2-piperidin-1-yl-ethoxy) -phenyl] -2-trifluoro. Methyl-benzamide (IX) or isomers thereof, pharmaceutically acceptable salts, pharmaceuticals, polymorphs, hydrates or any combination thereof are utilized. In another embodiment, the method of the present invention comprises IX hydrochloride (IX HCl salt) or 4-fluoro-N- (4-hydroxy-phenyl) -N- [4- (2-piperidin-1-yl). -Ethoxy) -phenyl] -2-trifluoromethyl-benzamide hydrochloride (X) or an isomer, pharmaceutically acceptable salt, pharmaceutical, polymorph, hydrate or any combination thereof is utilized. In another embodiment, the method of the invention comprises 3-fluoro-4-hydroxy-N- (4-hydroxyphenyl) -N-phenylbenzamide (XI) or an isomer thereof, a pharmaceutically acceptable salt, a pharmaceutical product. , Polymorphs, hydrates or any combination thereof. In another embodiment, the method of the present invention comprises 3-fluoro-N, N-bis- (4-hydroxy-phenyl) -2-methyl-benzamide (XII) or an isomer, pharmaceutically acceptable salt thereof. , Pharmaceuticals, polymorphs, hydrates or any combination thereof.

  In one embodiment, the methods of the invention utilize a “pharmaceutically acceptable salt” of a compound that can be generated by reaction of a compound of the invention with an acid or base.

  Suitable pharmaceutically acceptable salts of amines of the compounds of the methods of the invention can be prepared from inorganic or organic acids. In one embodiment, examples of inorganic salts of amines include bisulfate, borate, bromide, chloride, hemisulfate, hydrobromide, hydrochlorate, 2-hydroxyethyl sulfonate (hydroxyl). Ethanesulfonate), iodate, iodide, isothionate, nitrate, persulfate, phosphate, sulfate, sulfamate, sulfanilate, sulfonic acid (alkylsulfonate, arylsulfonate, halogen substitution) Alkyl sulfonates, halogen-substituted aryl sulfonates), sulfonates and thiocyanates.

  In one embodiment, examples of organic salts of amines may be selected from the aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic acid classes of organic acids, examples of which Is acetate, arginine, aspartate, ascorbate, adipate, anthranilate, alginates, alkanecarboxylate, substituted alkanecarboxylate, alginate, benzenesulfonate, benzoic acid Salt, hydrogen sulfate, butyrate, bicarbonate, hydrogen tartrate, carboxylate, citrate, camphorate, camphorsulfonate, cyclohexylsulfamate, cyclopentanepropionate, calcium edetate, cansylate , Carbonate, clavulanate, cinnamate, dicarboxylate, digluconate, dodecyl sulfonate, dihydrochloride, Citrate, enanthuates, ethanesulfonate, edetate, edicylate, estolate, esylate, fumarate, formate, fluoride, galacturonate, gluconate, glutamate, glycolate, gluco Glucorates, glucoheptanoate, glycerophosphate, glutepate, glycolylarsanylate, glutarate, glutamate, heptanoate, hexanoate, hydroxymaleate, hydroxycarboxylic acid ), Hexyl resorcinate, hydroxybenzoate, hydroxynaphthoate, hydrofluoride, lactate, lactobionate, laurate, malate, maleate, methylenebis (β-oxynaphtho Ate), malonate, mandelate, mesylate, meta Sulfonate, methyl bromide, methyl nitrate, methyl sulfonate, monopotassium maleate, mucinate, monocarboxylate, nitrate, naphthalene sulfonate, 2-naphthalene sulfonate, nicotinate, napsyl acid Salt, N-methylglucamine, oxalate, octanoate, oleate, pamoate, phenylacetate, picrate, phenylbenzoate, pivalate, propionate, phthalate, pectin Acid salt, phenylpropionate, palmitate, pantothenate, polygalacturates, pyruvate, quinate, salicylate, succinate, stearate, sulfanilate, basic acetic acid Salt, tartrate, theophylline acetate, p-toluenesulfonate (tosylate), trifluoroacetate, Phthalate, tannate, a teoclate, trihalo acetate, triethiodide, tricarboxylic, undecanoate and valerate salts.

  In one embodiment, examples of inorganic salts of carboxylic acids or phenols include ammonium, alkali metals (including lithium, sodium, potassium, cesium); alkaline earth metals (including calcium, magnesium, aluminum); zinc, barium, It may be selected from choline, quaternary ammonium.

  In another embodiment, examples of organic salts of carboxylic acid or phenol include arginine, organic amines (including aliphatic organic amines, alicyclic organic amines, aromatic organic amines), benzathine, t-butylamine, venetamine (N -Benzylphenethylamine), dicyclohexylamine, dimethylamine, diethanolamine, ethanolamine, ethylenediamine, hydrabamine, imidazole, lysine, methylamine, megramin, N-methyl-D-glucamine, N, N'-dibenzylethylenediamine, nicotinamide, organic Amine, ornithine, pyridine, picolies, piperazine, procaine, tris (hydroxymethyl) methylamine, triethylamine, triethanolamine, trimethylamine, tromethami And urea.

  In one embodiment, the salt is obtained by conventional means, for example in a solvent or medium in which the salt is insoluble, or in a solvent, for example in water (which is in vacuo or by lyophilization, or an ion of an existing salt). By reacting the free base or free acid form of the product with one or more equivalents of an appropriate acid or base. Can do.

  In one embodiment, the methods of the invention utilize pharmaceutically acceptable salts of the compounds of the invention. In one embodiment, the methods of the present invention utilize pharmaceutically acceptable salts of compounds of formula IA, I-XII. In one embodiment, the method of the present invention utilizes an amine salt of a compound of formula IA, I-XII of the present invention. In one embodiment, the method of the present invention utilizes a phenol salt of a compound of formula IA, I-XII of the present invention.

  In one embodiment, the method of the invention comprises a free base of Formula IA, I-XII, a free acid, an uncharged or uncomplexed compound, and / or an isomer, pharmaceutical, hydrate, polymorph, or Use a combination of these.

  In some embodiments of the invention, the compounds of the invention contain three phenyl groups held together by amide bonds. In one embodiment, the compounds of the invention are uncharged structures. In another embodiment, the compound of the invention is a free base structure. In another embodiment, the compound of the invention is a free acid structure. In another embodiment, the compound of the invention is an uncomplexed structure. In another embodiment, the compound of the invention is a non-ionized structure. In another embodiment, the compound of the invention is a pharmaceutically acceptable salt. In another embodiment, some compounds of the present invention include hydrochloric acid (HCl) salts.

  In one embodiment, the methods of the present invention utilize isomers of compounds of formula IA, I-XII. In one embodiment, the methods of the invention utilize a pharmaceutical product of a compound of formula IA, I-XII. In one embodiment, the method of the present invention utilizes a hydrate of a compound of formula IA, I-XII. In one embodiment, the methods of the present invention utilize polymorphs of compounds of formula IA, I-XII. In one embodiment, the methods of the invention utilize a metabolite of a compound of formula IA, I-XII. In another embodiment, the method of the invention provides a composition comprising a compound of formula IA, I-XII, as described herein, or in another embodiment, an isomer of a compound of formula IA, I-XII. Utilize compositions comprising combinations of metabolites, pharmaceuticals, hydrates, polymorphs.

  In one embodiment, the term “isomer” includes, but is not limited to, optical isomers and analogs, structural isomers and analogs, conformers and analogs, and the like.

  In one embodiment, the term “isomer” is meant to include optical isomers of the compound. In one embodiment, the term “isomer” is meant to encompass stereoisomers of the compound. The compounds of the present invention have amide bonds that may be their cis or trans isomerization. The present invention encompasses any optical activity, or stereoisomeric form, or mixtures thereof, and their use for any application is considered to be within the scope of the present invention Should be understood.

In another embodiment, the present invention further comprises a hydrate of the compound. In one embodiment, the term “hydrate” refers to hemihydrate, monohydrate, dihydrate, trihydrate or others known in the art.
Synthesis process

  Compounds of formula I or IA can be readily prepared, for example, by reacting a substituted diphenylamine with benzoic acid or benzoyl halide in the presence of a base to give a benzamide. In one embodiment, the base is pyridine. In another embodiment, the benzoyl halide is benzoyl chloride. In another embodiment, the hydroxyl substituent is protected during the reaction between diphenylamine and benzoic acid or benzoyl halide. In another embodiment, the protecting group for hydroxyl is optionally removed in the last step. See also US Patent Application Publication No. 2009/0062423 and US Patent No. 8,158,828, which are incorporated by reference in their entirety.

For example, a compound of formula IA
(Wherein R ₁ , R ₂ , R ₃ and R ₄ , j and k are as described above)
Is
When,
And react together,
To obtain diphenylamine (3),
In the presence of a base,
(Wherein R ₁ , R ₂ , R ₃ and R ₄ are independently OH, O—Alk—R ₅ R ₆ or O—Alk-heterocycle, R ₁ ′, R ₂ ′, R ₃ ′, R ₄ ′ is a protected hydroxyl group), removing the protecting group and obtaining the free hydroxyl, or optionally followed by Cl—Alk-heterocycle or Cl— Compound of formula IA reacted with Alk-NR ₅ R ₆
Wherein R ₁ , R ₂ , R ₃ and R ₄ are independently R ₁ ′, R ₂ ′, R _{4 when they} are independently different from OH, O—Alk—NR ₅ R ₆ or O—Alk-heterocycle. ₃ 'and _{R 4' may} each be prepared by a process comprising the steps of obtaining a R _1, a R 2, _{R 3} and _{R 4).}

As another example, a compound of formula IA
The process for the preparation of (wherein R ₁ , R ₂ , R ₃ and R ₄ are as described above)
When,
In the presence of a base,
(Wherein R ₁ , R ₂ , R ₃ and R ₄ are independently OH, O—Alk—R ₅ R ₆ or O—Alk-heterocycle, R ₁ ′, R ₂ ′, R ₃ ′, R ₄ ′ is a protected hydroxyl group), removing the protecting group and obtaining the free hydroxyl, or optionally followed by Cl—Alk-heterocycle or Cl— Compound of formula IA reacted with Alk-NR ₅ R ₆
Wherein R ₁ , R ₂ , R ₃ and R ₄ are independently R ₁ ′, R ₂ ′, R _{4 when they} are independently different from OH, O—Alk—NR ₅ R ₆ or O—Alk-heterocycle. ₃ ′ and R ₄ ′ are R ₁ , R ₂ , R ₃ and R ₄ , respectively).

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

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

In a further example, a compound of formula IV (compound IV)
Is
When,
In the presence of a base,
And subsequent deprotection of the protecting group gives compound IV
Wherein P and P ′ are the same or different protecting groups. In one example, Compound IV is prepared according to Example 2 and FIG.

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

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

  In another example, compound VII is prepared according to Example 1 and FIG.

  In another example, compound VIII is prepared according to Example 4 and FIG.

  In another example, compound IX is prepared according to Example 5 and FIG.

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

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

  In another example, Compound XII is prepared according to Example 1 and FIG.

  Suitable hydroxyl protecting groups include, for example, methyl ether (methoxy), benzyl ether (benzyloxy), methoxymethyl (MOM) ether, benzoyloxymethyl (BOM) ether, benzyl, carbobenzoxy, methoxyethoxymethyl (MEM). Ether, 2- (trimethylsilyl) ethoxymethyl (SEM) ether, methylthiomethyl (MTM) ether, phenylthiomethyl (PTM) ether, azidomethyl ether, cyanomethyl ether, 2,2-dichloro-1,1-difluoroethyl ether 2-chloroethyl ether, 2-bromoethyl ether, tetrahydropyranyl (THP) ether, 1-ethoxyethyl (EE) ether, phenacyl ether, 4-bromophenacyl ether, cyclopropi Methyl ether, allyl ether, propargyl ether, isopropyl ether, cyclohexyl ether, t-butyl ether, benzyl ether, 2,6-dimethylbenzyl ether, 4-methoxybenzyl ether, o-nitrobenzyl ether, 2,6-dichlorobenzyl ether, 3,4-dichlorobenzyl ether, 4- (dimethylamino) carbonylbenzyl ether, 4-methylsulfinyl benzyl ether, 4-anthrylmethyl ether, 4-picolyl ether, heptafluoro-p-tolyl, tetrafluoro-4-pyridyl Ether, trimethylsilyl (TMS) ether, t-butyldimethylsilyl (TBDMS) ether, t-butyldiphenylsilyl (TBDPS) ether, triisopropylsilyl ( IPS) ether, aryl formate, aryl acetate, aryl levulinate, aryl pivalate, aryl benzoate, aryl 9-fluorene carboxylate, aryl methyl carbonate, 1-adamantyl carbonate, t-butyl carbonate, 4-methyl Sulfinyl benzyl carbonate, 2,4-dimethylpent-3-yl carbonate, aryl 2,2,2-trichloroethyl carbonate, aryl benzyl carbonate, aryl carbamate, dimethyl phosphinyl ester (Dmp-OAr), dimethyl phosphinothionyl ester ( Mpt-OAr), diphenylphosphinothionyl ester (Dpt-OAr), aryl methanesulfonate, aryl tolue Sulfonates or aryl 2-formylbenzene sulfonates.

The process of the invention involves the use of a compound of formula IA or I-XII, and the process for the preparation of the compound of the invention involves the reaction of diphenylamine with benzoyl chloride in the presence of a base. Suitable bases include, for example, pyridine, triethylamine, K ₂ CO ₃ , Cs ₂ CO ₃ , Na ₂ CO ₃ , methylamine, imidazole, benzimidazole, histidine, tributylamine or any combination thereof. In one embodiment, the base is pyridine.

The methods of the invention involve the use of compounds of formula IA or I-XII, and the process for the preparation of the compounds of the invention involves deprotection of the protected hydroxyl. In another embodiment, the deprotection conditions depend on the protecting group. In some embodiments, the deprotection step comprises hydrogenation in the presence of Pd / C. In another embodiment, the deprotection comprises reaction with BBr _3. In another embodiment, the deprotecting step comprises reaction with an acid.

In further examples, compounds of formula IA or I-XII are prepared according to FIGS. 5-8 and Examples 1-5.
Pharmaceutical composition

  In some embodiments, the invention provides a method of use comprising administering a composition comprising the described compound. As used herein, “pharmaceutical composition” means a “therapeutically effective amount” of an active ingredient, ie, a compound of the invention, together with a pharmaceutically acceptable carrier or excipient. “Therapeutically effective amount” as used herein refers to that amount that achieves a therapeutic effect for a given condition and dosing regimen.

  As used herein, the term “administering” refers to contacting a subject with a compound of the invention. As used herein, administration can be accomplished in vitro, ie, in a test tube, or in vivo, ie, in an organism, eg, a human cell or tissue. In one embodiment, the invention encompasses administering a compound of the invention to a male subject.

  The present invention, in another embodiment, provides a pharmaceutical product of the compounds described herein. The term “pharmaceutical”, in other embodiments, refers to a composition (pharmaceutical composition) suitable for pharmaceutical use, eg, as described herein.

  The compounds of the present invention can be administered alone or as an active ingredient of a formulation. Thus, the present invention also includes pharmaceutical compositions of compounds of formula I that contain, for example, one or more pharmaceutically acceptable carriers.

  Numerous standard references are available that describe procedures for preparing various formulations suitable for administering the compounds according to the invention. Examples of potential formulations and preparations are described, for example, in the Handbook of Pharmaceutical Excipients, American Pharmaceutical Association (current edition); Pharmaceutical Dosage Forms: Tablets (Lieberman, Lachman and Schwartz, editors) current edition, publication, Marcel Dekker, Inc. And Remington's Pharmaceutical Sciences (Arthur Osol, Editor), pages 1553 to 1593 (current edition).

  The method of administration and dosage form are closely related to the therapeutic amount of the compound or composition that is desirable and effective for a given treatment application.

  Suitable dosage forms include, but are not limited to, oral, rectal, sublingual, mucosal, nasal, ocular, subcutaneous, intramuscular, intravenous, transdermal, spinal cord, intrathecal, intraarticular, arterial Internal, sub-arachinoid, bronchial, lymphatic, and intra-uterine administration, as well as other dosage forms for systemic delivery of the active ingredient. Formulations suitable for oral administration are preferred.

  To prepare such pharmaceutical dosage forms, the active ingredient can be mixed with the pharmaceutical carrier by conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration.

  In preparing oral dosage form compositions, any of the conventional pharmaceutical media may be employed. Thus, for liquid oral preparations such as suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like. Can be mentioned. For solid oral preparations such as powders, capsules and tablets, suitable carriers and additives include starches, sugars, excipients, granulating agents, lubricants, binders, disintegrants, and the like. It is done. Due to their ease in administration, tablets and capsules represent the most advantageous oral unit dosage forms. If desired, tablets may be sugar coated or enteric coated by standard techniques.

  For parenteral formulations, the carrier usually contains sterile water, but may contain other ingredients, such as ingredients that aid in solubility or for storage. Injectable solutions may also be prepared, in which case appropriate stabilizers may be used.

  In some applications, suitable biomolecules such as proteins, lipoproteins, for example, by encapsulating the active agent in liposomes or other encapsulating media, or by, for example, covalent bonding, chelation, or binding coordination. It may be advantageous to utilize the “vectorized” form of the active agent by immobilizing the active agent to a biomolecule selected from, glycoproteins, and polysaccharides.

  The treatment methods of the invention using formulations suitable for oral administration are individual units such as capsules, cachets, tablets, or lozenges, each containing a predetermined amount of the active ingredient, for example, as a powder or granule. It can be presented as an agent. If desired, suspensions in aqueous or non-aqueous liquids may be used (eg, syrups, elixirs, emulsions, or beverages).

  A tablet may be made by compression or molding or wet granulation, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compression in a suitable machine, and the active compound is needed, for example, with a binder, disintegrant, lubricant, inert excipient, surfactant, or depigmenting agent. In a free-flowing form, for example powders or granules. Molded tablets consisting of a mixture of powdered active compound with a suitable carrier can be made by molding in a suitable machine.

  A syrup may be made by adding the active compound to a concentrated aqueous solution of a sugar, eg, sucrose, and optional auxiliary component (s) may also be added thereto. Such ancillary component (s) include flavoring agents, suitable preservatives, agents that delay sugar crystallization, and agents that increase the solubility of any other ingredients, such as polyhydroxy alcohols such as glycerol. Or it may contain 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, saline). Such formulations can include suspending and thickening agents and liposomes, or other particulate systems designed to target the compound to blood components or one or more organs. The formulation may be presented in unit dose form or multiple dose form.

  Parenteral administration can include any suitable form of systemic delivery. Administration can be, for example, intravenous, intraarterial, intrathecal, intramuscular, subcutaneous, intramuscular, intraabdominal (eg, intraperitoneal), etc., as appropriate for the infusion pump (external or implantable) or the desired administration modality Can be realized by any other suitable means.

  Nasal spray formulations and other mucosal spray formulations (eg, inhalable forms) can include purified aqueous solutions of the active compounds, along with preservatives and isotonic agents. Such formulations are preferably adjusted to a pH and isotonic state compatible with the nasal or other mucosa. Alternatively, they may be in the form of a finely divided solid powder suspended in a gas carrier. Such formulations may be delivered by any suitable means or method, such as by nebulizer, atomizer, metered dose inhaler, and the like.

  Formulations for rectal administration may be presented as a suppository with a suitable carrier such as cocoa butter, hardened fat, or hardened fatty carboxylic acid.

  Transdermal formulations can be prepared by incorporating the active agent into a thixotropic or gelatinous carrier such as a cellulose vehicle, such as methylcellulose or hydroxyethylcellulose, and the formulation thus obtained can then be prepared by the wearer. Filled into a transdermal device adapted to ensure skin contact with the skin.

  In addition to the above components, the preparation of the present invention can be prepared, for example, by using excipients, buffers, flavoring agents, binders, disintegrants, surfactants, thickeners, lubricants, preservatives (antioxidants). One or more auxiliary component (s) selected from such as

  The formulations of the present invention can have immediate release, sustained release, delayed-onset release or any other release profile known to those skilled in the art.

  In one embodiment, the present invention comprises administering an oral composition comprising a compound of formula IA, I-XII, a) reducing total serum testosterone levels; b) a male subject with prostate cancer Decrease free serum testosterone levels in luteinizing hormone (LH) in or independent of LH hormone reduction in c; Secondary hormone therapy; d) treating, suppressing, reducing incidence, reducing severity, inhibiting progression, or inhibiting castration resistant prostate cancer (CRPC) and its symptoms E) Serum PSA levels in male subjects with prostate cancer F) increase sex hormone binding globulin (SHBG) levels in male subjects with prostate cancer; g) inhibit bone related events (SRE) in male subjects with prostate cancer H) reduce the level of bone metabolism markers in male subjects with prostate cancer; i) inhibit hot flashes in male subjects with prostate cancer; and / or j) men with prostate cancer; Of reducing the level of androgen precursor production in the adrenal gland in a subject. In another embodiment, the subject suffers from castration resistant prostate cancer (CRPC). In another embodiment, the subject suffers from metastatic castration resistant prostate cancer (mCRPC). In a further embodiment, the method of the invention comprises 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. Is used.

  In one embodiment, the present invention relates to reducing LH levels in a male subject with prostate cancer, comprising administering an oral composition comprising a compound of formula IA, I-XII, or LH A method of treating prostate cancer is provided independent of the reduction in levels. In a further embodiment, the invention administers 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 Providing a method of treating prostate cancer in a male subject with prostate cancer by reducing LH levels or independently of reducing LH levels. In another embodiment, the subject suffers from castration resistant prostate cancer (CRPC). In another embodiment, the subject suffers from metastatic castration resistant prostate cancer (mCRPC).

  It is to be understood that the invention includes any embodiment of a compound as described herein, which in some embodiments is referred to as a “compound of the invention”.

  In one embodiment, the methods of the invention can include the administration of a compound of the invention at various dosages. In one embodiment, the compounds of the invention are administered at a dosage of 1-3000 mg per day. In a further embodiment, the compound of the invention is 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, 10-26 mg per day, 15-60 mg 50-100 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 to 1000 mg per day, 200 to 1000 mg per day, 1000 to 2000 mg per day, 1000 to 3000 mg per day, 125 to 3000 mg per day, 2000 to 3000 mg per day, 300 to 1500 mg per day, 300 to 1500 mg per day Or administered at a dose of 100~1000mg. In one embodiment, the compounds of the invention are administered at a dosage of 125 mg per day. In one embodiment, the compounds of the invention are administered at a dosage of 250 mg per day. In one embodiment, the compounds of the invention are administered at a dosage of 300 mg per day. In one embodiment, the compounds of the invention are administered at a dosage of 500 mg per day. In one embodiment, the compounds of the invention are administered at a dosage of 600 mg per day. In one embodiment, the compounds of the invention are administered at a dosage of 1000 mg per day. In one embodiment, the compounds of the invention are administered at a dosage of 2000 mg per day. In one embodiment, the compounds of the invention are administered at a dosage of 3000 mg per day. In another embodiment, the compound is Compound IV.

  In one embodiment, the methods of the invention can include the administration of a compound of the invention at various dosages. In one embodiment, the compound of the invention is administered at a dosage of 3 mg. In a further embodiment, the compound of the invention is administered at a dosage of 10 mg, 30 mg, 50 mg, 100 mg, 125 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 invention can include the administration of a compound of the invention at various dosages. In one embodiment, the compounds of the invention are administered at a dosage of 0.1 mg / kg / day. In a further embodiment, the compound of the invention comprises 0.2-30 mg / kg / day, or 0.2 mg / kg / day, 0.3 mg / kg / day, 1 mg / kg / day, 3 mg / kg / day, It is administered at a dose of 5 mg / kg / day, 10 mg / kg / day, 20 mg / kg / day or 30 mg / kg / day.

  In one embodiment, the method of the invention provides for the use of a pharmaceutical composition comprising a compound of formula IA, I-XII. In a further embodiment, the method of the invention comprises a pharmaceutical 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. Provide for the use of things.

  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 invention or a composition comprising the same is useful in inhibiting, suppressing, enhancing, or stimulating a desired response in a subject, as will be appreciated by those skilled in the art. Have In another embodiment, the composition may further comprise additional active ingredients, which activity is useful for the particular application to which the compound of the invention is administered.

  For administration to mammals, particularly humans, it is expected that the physician will determine the actual dosage and duration of treatment, which is most suitable for the individual, and the age, weight, genetic It can vary depending on the nature and / or response.

  In some embodiments, any of the compositions of the present invention comprises a compound of the present invention in any form or embodiment described herein. In some embodiments, any of the compositions of the present invention consists of a compound of the present invention in any form or embodiment described herein. In some embodiments, the compositions of the invention consist essentially of the compounds of the invention in any form or embodiment described herein. In some embodiments, the term “comprising” includes the indicated active agent, eg, a compound of the present invention, as well as other active agents as are known in the pharmaceutical industry, and pharmaceutically acceptable. It includes the inclusion of carriers, additives, emollients, stabilizers and the like. In some embodiments, the term “consisting essentially of” is the active ingredient whose sole active ingredient is indicated, but other compounds (such as for stabilizing the formulation, storing, etc. , Which are not directly involved in the therapeutic effect of the indicated active ingredients). In some embodiments, the term “consisting essentially of” may refer to a component that facilitates release of the active ingredient. In some embodiments, the term “consisting of” refers to a composition containing the active ingredient and a pharmaceutically acceptable carrier or additive.

  It is understood that any use of any of the compounds as described herein may be used in the treatment of any disease, disorder or condition described herein and represents an embodiment of the invention Should. In one embodiment, the compound is a free base, free acid, uncharged or uncomplexed compound.

  The following examples are presented in order to more fully illustrate the preferred embodiments of the invention. However, these should in no way be construed as limiting the broad scope of the invention.

Example 1
General synthetic procedures for compounds of formula II-XII and synthetic intermediates

  Organic solvents, surfactants, antioxidants, and the like, which can be used in the compositions described herein, are typically readily available from commercial sources. For example, PEG-300, Polysorbate 80, Captex ™ 200, Capmul ™ MCM C8 are, for example, Dow Chemical Company (Midland, MI), ICI Americas, Inc (Wilmington, DE) or Abitec Corporation (Janesville, W ) Can be purchased from.

The estrogen receptor ligands described herein can be prepared in a number of ways well known to those skilled in the art. For example, estrogen receptor ligands described herein are disclosed in US Patent Application Publication No. 2009/0062341 and US Pat. No. 8,158,828, the disclosures of each of which are hereby incorporated by reference in their entirety. Can be prepared by the synthetic methods described in (1).
General synthesis of N, N-bisarylbenzamide derivatives

General synthesis of diarylanilines (Figure 5). Arylamine (1.5 eq), aryl iodide (1 _eq), K 2 _CO 3 (2 eq) were mixed and the mixture of CuI (0.1 eq) and L- proline (0.2 eq) together , Dissolved in anhydrous DMSO at room temperature. The reaction mixture was then stirred and heated to 90 ° C. for 28 hours. The mixture was cooled to room temperature and hydrolyzed with water. EtOAc was added to partition the solution. The EtOAc layer was separated, washed with brine and dried over anhydrous MgSO ₄ . The solvent was removed under reduced pressure. The solid residue was purified by flash column chromatography (silica gel) using 5% EtOAc / hexane as eluent to give the corresponding diarylaniline.

Bis- (4-methoxyphenyl) amine (1a): pale yellow solid, 73% yield. Mp 98.6-99.0 ^o C. ¹ H NMR (CDCl ₃ , 300 MHz) δ 6.93-6.81 (m, 8H), 5.37 (s, br, 1H), 3.78 (s, 6H). MS m / z 228.4 (MH) ^<+> .

N- (4-methoxyphenyl) -phenylamine (1b): pale yellow solid, 70% yield. M.M. p. 106.3-106.5 ° C. ¹ H NMR (CDCl ₃ , 300 MHz) δ 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) -N-4-methoxyphenylamine (1c): pale yellow solid, 54% yield. Mp 60.6-61.0 ° C. ¹ H NMR (CDCl ₃ , 300 MHz) δ 7.01-6.83 (m, 8H), 3.78 (s, 3H). MS m / z 217 (M) ^<+> .

N- (4-benzyloxyphenyl) -N-4-methoxyphenylamine (1d): pale yellow solid, 54% yield. Mp 108.0-108.4 ^o C. ¹ H NMR (CDCl ₃ , 300 MHz) δ 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 benzamide. A mixture of arylaniline (1 eq), benzoyl chloride (1.3 eq), and pyridine (6 eq) were mixed together and dissolved in anhydrous THF at room temperature. The mixture was stirred and refluxed for 24 hours. The reaction solution was cooled to room temperature and hydrolyzed by adding 2N HCl solution. The solution was extracted with ethyl acetate. The organic layer was washed with saturated aqueous NaHCO ₃ to remove excess acid, dried over anhydrous MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using EtOAc / hexane (3/7 v / v) to give the corresponding benzamide compound.

3-Fluoro-N- (4-fluorophenyl) -4-methoxy-N- (4-methoxyphenyl) benzamide (2a): yellow solid, Mp 54-56 ^O C, ¹ H NMR (CDCl ₃ / TMS) δ7.24-7.11 (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-N, N-bis (4-methoxyphenyl) -2- (trifluoromethyl) benzamide (2b): colorless oil, 84.2% yield. ¹ H NMR (CDCl ₃ , 300 MHz) δ 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) ^<+> .

4-Methoxy-N- (4-methoxyphenyl) -N- (4-fluorophenyl) -benzamide (2c): white solid, 97% yield, Mp 133.5.0-134.5 ^° C. ¹ H NMR (CDCl ₃ , 300 MHz) δ 8.11-6.66 (m, 15H), 3.74 (s, 3H), 3.73 (s, 3H). MS m / z 384 (M + H) ⁺ .

N- (4-methoxyphenyl) -N- (4-benzyloxyphenyl) -2-naphthylamide (2d): white solid, 58% yield. Mp 174.9-175.5 ^o C. ¹ H NMR (CDCl ₃ , 300 MHz) δ 8.04 (s, 1H), 7.77-7.74 (m, 2H), 7.64-7.61 (m, 1H), 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-N, N-bis (4-methoxyphenyl) -2- (trifluoromethyl) benzamide (2e): colorless oil, 84.2% yield. ¹ H NMR (CDCl ₃ , 300 MHz) δ 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) ⁺ .

General Procedure for the Demethylation of benzamide derivatives using BBr _3. The methoxybenzamide compound was dissolved in dry CH ₂ Cl ₂ . BBr ₃ (1.0 M CH ₂ Cl ₂ solution) was added dropwise at 0 ° C. The reaction solution was slowly warmed to room temperature and stirred overnight at room temperature. The mixture was cooled to 0 ° C. in an ice bath and hydrolyzed by adding water. EtOAc was added to partition the solution. The organic layer was separated. The aqueous layer was extracted with EtOAc. The organic layer was washed with brine and dried over anhydrous MgSO ₄ . The solvent was removed under reduced pressure. The residue was purified by flash column chromatography using CH ₃ OH / CH ₂ Cl ₂ (1/9 v / v) to give the corresponding phenolic compound.

4-Fluoro-N, N-bis (4-hydroxyphenyl) -2- (trifluoromethyl) benzamide (3a): white solid, 92.5% yield. ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 9.55 (s, 1H), 9.53 (s, 1H), 7.69-7.58 (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) ^<+> .

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

  General procedure for debenzylation of benzyloxyphenyl-benzamide. The benzyloxyphenyl-benzamide compound was dissolved in EtOH in a 250 mL hydrogenation bottle. Pd / C powder (5% mol) was added to the solution. The reaction vessel was attached to the hydrogenator under hydrogen gas at a pressure of 20 psi. The reaction was monitored by TLC until the starting material disappeared. The solvent was then removed under reduced pressure. The residue was purified by flash column chromatography with hexane / EtOAc = 3/2 v / v to give the desired product.

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

General procedure for the reduction of deprotected benzamide. The benzamide compound was dissolved in 20 mL anhydrous THF at room temperature. H ₃ B (SMe ₂ ) was added via syringe at room temperature under argon. The reaction solution was stirred and heated to reflux for 6 hours. The reaction was then quenched by adding 10 mL of MeOH at 0 ° C. The solvent was removed under reduced pressure. The residue was subjected to flash column chromatography (silica gel, CH ₂ Cl ₂ / MeOH = 9/1 v / v) to give the desired product.

  The following compounds were synthesized as described herein above and characterized and summarized in Table 1. 4,4 '-(2,3-dimethylbenzylazanediyl) diphenol (III); 4-((4-fluorophenyl) (4-hydroxybenzyl) amino) phenol (VIII).

General synthesis of O- (2-piperidin-1-ylethoxy) -benzamide and analogs. Benzamide analogues (1 eq) acetone solution of hydroxyphenyl _containing, K 2 _CO 3 (3 eq) and N- chloroethyl - was added piperidine hydrochloride (1.2 eq). The solution was heated to reflux for 6 hours. The solution was evaporated to dryness. The residue was hydrolyzed by adding water and then extracted with ethyl acetate. The organic layer was separated and dried over anhydrous MgSO ₄ . The solvent was removed under reduced pressure. The residue was purified by flash chromatography with methylene chloride / methanol = 9/1 v / v to give the desired compound. The hydrochloride salt was prepared by adding HCl in Et ₂ O to a methanolic solution of the compound followed by evaporation of the solvent.

The following compounds were synthesized as described herein above and characterized and summarized in Table 1. 4-fluoro-N- (4-hydroxyphenyl) -N- (4- (2- (piperidin-1-yl) ethoxy) phenyl) -2- (trifluoromethyl) benzamide (IX); and 4-fluoro- N- (4-hydroxyphenyl) -N- (4- (2- (piperidin-1-yl) ethoxy) phenyl) -2- (trifluoromethyl) benzamide hydrochloride (X) (which is the HCl salt of IX) .

(Example 2)
Synthesis of compounds of formula IV (Figure 6).

Step 1: Synthesis of 4-fluoro-N- (4-methoxyphenyl) aniline (1c).

In a dry 1 L 3-neck round bottom flask equipped with a stir bar, reflux condenser and argon inlet, 4-fluoroaniline (78.63 g, 0.708 mol), 4-iodoanisole (138.00 g, 0.0. 590 mol), anhydrous K ₂ CO ₃ (122.23 g, 0.884 mol), CuI (11.23 g, 58.96 mmol) and L-proline (13.58 g, 0.118 mol) were mixed together. Anhydrous DMSO (300 mL) was added at room temperature. The reaction mixture was stirred and heated to 90 ° C. for 20 hours under argon. The mixture was then cooled to room temperature and hydrolyzed with water (300 mL). EtOAc (200 mL) was added and the solution was partitioned. The EtOAc layer was separated. The aqueous layer was extracted with 100 mL EtOAc. The EtOAc layers were combined, washed with brine (2 × 100 mL) and dried over anhydrous MgSO ₄ (50 g). The solvent was removed under reduced pressure. The brown oil residue was purified by flash column chromatography (silica gel, hexane / EtOAc = 9/1 v / v) to give 4-fluoro-N- (4-methoxyphenyl) aniline (1c) as a yellow solid product (99.70 g, 77.8% yield). Mp 46-48 ° C. MS (ESI) m / z 218.1 [M + H] ⁺ , ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 7.77 (bs, 1H), 7.03-6.98 (m, 4H), 6.93-6.82 (m, 4H), 3.70 (s, 3H).

Step 2: Synthesis of 3-fluoro-N- (4-fluorophenyl) -4-methoxy-N- (4-methoxyphenyl) benzamide (2a).

4-Fluoro-N- (4-methoxyphenyl) aniline (1c) (90.78 g, 0.418 mol) in a dry 1 L 3-neck round bottom flask equipped with a stir bar, reflux condenser and argon inlet And 3-fluoro-4-methoxybenzoyl chloride (94.55 g, 0.501 mol) were mixed together and dissolved in anhydrous THF (200 mL). Anhydrous pyridine (132.22 g, 1.672 mol) was added via syringe at room temperature under argon. The reaction mixture was stirred and heated to reflux overnight. The reaction mixture was then cooled to room temperature and filtered to remove the pyridine salt. The solution was concentrated and the THF solvent was removed. The residual oil was washed with 200 mL HCl solution (2N) and extracted with ethyl acetate (2 × 200 mL). The combined organic layers were washed with saturated aqueous Na ₂ CO ₃ (150 mL) to remove excess benzoyl chloride and acid, dried over MgSO ₄ (50 g), filtered and concentrated under reduced pressure to give an oil. Obtained. The residue was purified by flash column chromatography using silica gel with CH ₂ Cl ₂ / acetone (50/1 v / v) to give the pure corresponding benzamide compound as a yellow solid. Mp 54-56 ° C. MS (ESI) m / z 370.1 [M + H] ⁺ , ¹ H NMR (CDCl ₃ / TMS) δ7.24-7.11 (m, 4H), 7.05-6.97 (m, 4H), 6.85-6.78 (m, 3H), 3.86 (s, 3H), 3.79 (s, 3H).

Step 3: Synthesis of 3-fluoro-N- (4-fluorophenyl) -4-hydroxy-N- (4-hydroxyphenyl) benzamide (IV).

Compound 3-fluoro-N- (4-fluorophenyl) -4-methoxy-N- (4-methoxyphenyl) benzamide (2a) (138.0 g, 0.374 mol) was added to dry CH ₂ Cl ₂ (600 mL). Dissolved under argon at room temperature. BBr ₃ (374.75 g, 1.496 mol) was added dropwise with stirring at 0 ° C. under argon in an ice bath with stirring. The reaction solution was stirred overnight at room temperature. The solution was then poured into 1 L ice cold water with stirring. The slurry mixture was stirred at room temperature for 2 hours. The white precipitate was filtered, washed with water (2 × 100 mL) and dried under vacuum. The CH ₂ Cl ₂ layer was separated, dried over anhydrous MgSO ₄ (50 g), filtered and concentrated to dryness under reduced pressure. The white precipitate and the residue from the CH ₂ Cl ₂ solution were combined and purified by flash column chromatography (silica gel, CH ₂ Cl ₂ / acetone / MeOH = 90/7/3 v / v / v). A solid was obtained, which was recrystallized twice from hot EtOAc / hexane solution to give a white crystalline solid (104.0 g, 81.6% yield). Mp 110-112 ° C. MS (ESI) m / z 364.1 [M + Na] ⁺ , ¹ H NMR (DMSO-d ₆ ) δ 10.14 (bs, 1H), 9.71 (bs, 1H), 7.25-7.11 (m, 5H), 7.05 -6.99 (m, 3H), 6.78 (t, J = 8.6 Hz, 1H), 6.68 (d, J = 8.7 Hz, 2H).

(Example 3)
Synthesis of compounds of formula VI (FIG. 7)
Synthesis of 4- (benzyloxy) -N- (4-methoxyphenyl) aniline (1d).

4-Benzyloxyaniline (16.6 g, 83.31 mmol), 4-iodoanisole (15.0 g, 64.09 mmol), K ₂ CO ₃ (17.72 g, 128.18 mmol), CuI (1.22 g, 6 .41 mmol) and L-proline (1.48 g, 12.82 mmol) were mixed together and dissolved in anhydrous DMSO (120 mL) at room temperature. The reaction mixture was then stirred and heated to 90 ° C. for 48 hours. The mixture was cooled to room temperature and hydrolyzed with water. EtOAc was added to partition the solution. The EtOAc layer was separated, washed with brine and dried over anhydrous MgSO ₄ . The solvent was removed under reduced pressure. The solid residue was purified by flash column chromatography (silica gel) using EtOAc / hexane (1/9 v / v) to give the corresponding diarylaniline as a yellow solid (9.8 g, 50% yield). Mp 108.0-108.4 ° C. ¹ H NMR (CDCl ₃ , 300 MHz) δ 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 N- (4-benzyloxyphenyl) -N- (4-methoxyphenyl) -2-naphthamide (2d).

In a dry three-necked round bottom flask equipped with a magnetic stir bar and reflux condenser, 1 equivalent of 4- (benzyloxy) -N- (4-methoxyphenyl) aniline (0.80 g, 2.62 mmol) was added. 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). The mixture was dissolved in anhydrous THF (30 mL) and heated to reflux for 20 hours. The reaction solution was cooled to room temperature and filtered. The solvent was removed under reduced pressure. The residue was purified by flash column chromatography using silica gel with EtOAc / hexanes (3/7 v / v) to give the pure corresponding naphthamide compound as a white solid (0.70 g, 58% yield). ). Mp 174.9-175.5 ° C. ¹ H NMR (CDCl ₃ , 300 MHz) δ 8.04 (s, 1H), 7.77-7.74 (m, 2H), 7.64-7.61 (m, 1H), 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) ⁺ .

Synthesis of N, N-bis (4-hydroxyphenyl) -2-naphthylamide (VI).

The compound N- (4-benzyloxyphenyl) -N- (4-methoxyphenyl) -2-naphthamide (2d) (0.50 g, 1.09 mmol) was dissolved in dry CH ₂ Cl ₂ (30 mL) at room temperature. . BBr ₃ (3.26 mL of a 1.0 M CH ₂ Cl ₂ solution, 3.26 mmol) was added dropwise at room temperature with a syringe with stirring. The reaction solution was stirred overnight at room temperature. The mixture was cooled to 0 ° C. in an ice bath and hydrolyzed by adding water. EtOAc was added to partition the solution. The organic layer was separated. The aqueous layer was extracted twice with EtOAc. The organic layers were combined, washed with brine and dried over anhydrous MgSO ₄ . The solvent was removed under vacuum. The residue was purified by flash column chromatography using silica gel with CH ₃ OH / CH ₂ Cl ₂ (1/9 v / v) to give the pure desired phenol compound as a white solid (0.27 g, White solid, 70% yield). Mp 264.3-265.2 ° C (decomposed). ¹ H NMR (DMSO-d ₆ , 500 MHz) δ 9.46 (s, 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). MS m / z 356 (M + H) ⁺ .

Example 4
Synthesis of compounds of formula VIII.

Synthesis of 4-((4-fluorophenyl) (4-hydroxybenzyl) amino) phenol (VIII).

Compound N- (4-fluorophenyl) -4-hydroxy-N- (hydroxyphenyl) benzamide (0.30 g, 0.93 mmol) was dissolved in 20 mL anhydrous THF at room temperature. H ₃ B (SMe ₂ ) (1.86 mL of 2M THF solution, 3.71 mmol) was added via syringe at room temperature under argon. The reaction solution was stirred and heated to reflux for 6 hours. The reaction was then quenched by adding 10 mL of MeOH at 0 ° C. The solvent was removed under reduced pressure. The residue was subjected to flash column chromatography (silica gel, CH ₂ Cl ₂ / MeOH = 9/1 v / v) to give a yellow oil (0.26 g, 92% yield). ¹ H NMR (DMSO-d ₆ , 500 MHz) δ 9.29 (s, 1H), 9.24 (s, 1H), 7.09 (d, 2H, 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 (MH) -.

(Example 5)
Synthesis of compounds of formula IX and X (FIG. 8).

Synthesis of diarylanilines. Arylamine (1.5 eq), aryl iodide (1 _eq), K 2 _CO 3 (2 eq) were mixed and the mixture of CuI (0.1 eq) and L- proline (0.2 eq) together , Dissolved in anhydrous DMSO at room temperature. The reaction mixture was then stirred and heated to 90 ° C. for 28 hours. The mixture was cooled to room temperature and hydrolyzed with water. EtOAc was added to partition the solution. The EtOAc layer was separated, washed with brine and dried over anhydrous MgSO ₄ . The solvent was removed under reduced pressure. The solid residue was purified by flash column chromatography (silica gel) using EtOAc / hexane (3/7 v / v) as solvent to give the corresponding diarylaniline. Bis- (4-methoxyphenyl) amine (1a): pale yellow solid, 73% yield. ¹ H NMR (CDCl ₃ , 300 MHz) δ 6.93-6.81 (m, 8H), 5.37 (s, br, 1H), 3.78 (s, 6H). MS m / z 228.4 (MH) ^<+> .

Synthesis of 4-fluoro-N, N-bis (4-methoxyphenyl) -2- (trifluoromethyl) benzamide (2e).

In a dry three-necked round bottom flask equipped with a magnetic stir bar and reflux condenser, 1 equivalent of bis- (4-methoxyphenyl) amine (1a) (0.73 g, 3.18 mmol) was added to 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). The mixture was dissolved in anhydrous THF (20 mL) and heated to 90 ° C. for 20 hours. The reaction solution was cooled to room temperature and filtered. The solvent was removed under reduced pressure. The residue was purified by flash column chromatography using silica gel with EtOAc / hexane (3/7 v / v) to give the pure corresponding benzamide compound as a colorless oil (1.12 g, 84.2% yield). ¹ H NMR (CDCl ₃ , 300 MHz) δ 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-N, N-bis (4-hydroxyphenyl) -2- (trifluoromethyl) benzamide (3a).

Compound 4-fluoro-N, N-bis (4-methoxyphenyl) -2- (trifluoromethyl) benzamide (2e) (1.00 g, 2.38 mmol) was added to dry CH ₂ Cl ₂ (30 mL) at room temperature. Dissolved. BBr ₃ (10 mL of a 1.0 M CH ₂ Cl ₂ solution, 10.0 mmol) was added dropwise with stirring at room temperature via syringe. The reaction solution was stirred overnight at room temperature. The mixture was cooled to 0 ° C. in an ice bath and hydrolyzed by adding water. EtOAc was added to partition the solution. The organic layer was separated. The aqueous layer was extracted twice with EtOAc. The organic layers were combined, washed with brine and dried over anhydrous MgSO ₄ . The solvent was removed under vacuum. The residue was purified by flash column chromatography using silica gel with CH ₃ OH / CH ₂ Cl ₂ (1/9 v / v) to give the pure desired phenol compound as a white solid (0.86 g 92.5% yield). ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 9.55 (s, 1H), 9.53 (s, 1H), 7.69-7.58 (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-N- (4-hydroxyphenyl) -N- [4- (2-piperidin-1-yl) -ethoxy) phenyl] -2- (trifluoromethyl) benzamide (IX)

To an acetone solution of 4-fluoro-N, N-bis (4-hydroxyphenyl) -2- (trifluoromethyl) benzamide (3a) (0.61 g, 1.56 mmol) was added K ₂ CO ₃ (1.29 g, 9.36 mmol) and N-chloroethyl-piperidine hydrochloride (0.34 g, 1.87 mmol) were added. 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-d ₆ , 300 MHz) δ 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 (MH) ^- .

Hydrochloride (X) was prepared by adding HCl in Et ₂ O to a methanolic solution of the compound followed by evaporation of the solvent.

(Example 6)
Estrogen receptor binding affinity, agonist and antagonist activity

The ER binding affinity of the ^{compounds, [2,4,6,7- 3 H (N)} ] - estradiol ^([3 H] E2), natural high affinity ER ligands, and GST fusion bacterially expressed ER -Determined using in vitro competitive radioligand binding assay with α or ER-β ligand binding domain (LBD) protein.

Method

Recombinant ER-alpha or ER-beta combined with ^[3 H] _{E ^2,} to determine [3 H] equilibrium dissociation constant of _{E 2 (K d).} To determine total and non-specific binding, proteins are incubated for 18 hours at 4 ° C. with increasing concentrations of [ ³ H] E ₂ with and without high concentrations of unlabeled E ₂ did. Non-specific binding was subtracted and the K _{d of} E ₂ (ERα: 0.71 nM; ERβ: 1.13 nM) was determined using non-linear regression. Furthermore, the concentration of [ ³ H] E ₂ required to saturate ER-α LBD and ER-β LBD was determined to be 4-6 nM.

Increasing concentrations of compounds (range: 10 ⁻¹¹ to 10 ⁻⁶ M) were incubated with [ ³ H] E ₂ (5.7 nM) and ER LBD using the conditions described above. Following incubation, the plates were collected with GF / B filters on a Unifilter-96 Harvester (PerkinElmer) and washed 3 times with ice-cold buffer B (50 mM Tris, pH 7.2). The filter plate was allowed to dry at room temperature, then 35 μl Microscint-O cocktail was added to each well and the filter plate was sealed with TopSeal-A. Radioactivity was counted on a TopCount® NXT microplate scintillation counter using the setting for ³ H in a Microscint cocktail (PerkinElmer).

Specific binding of [ ³ H] E ₂ at each concentration of compound subtracted non-specific binding of [ ³ H] E ₂ (determined by incubation with 10 ⁻⁶ M unlabeled E ₂ ). This was determined by expressing this as the percentage of specific binding in the absence of the test compound. The concentration of compound that reduced the specific binding of [ ³ H] E ₂ by 50% (IC ₅₀ ) was determined. Then, the equilibrium binding constant (K _i ) of the compound is expressed as K _i = K _d × IC ₅₀ / (K _d + L) [where K _d is the equilibrium dissociation constant of [ ³ H] E ₂ (ER− α = 0.71 nM; ER-β = 1.13 nM), L is the concentration of [ ³ H] E ₂ (ER-α: 5.7 nM; ER-β: 5.7 nM)].

result

  By binding assays, ligand bound to ER-α and ER-β at various concentrations ranging from 3.75 nM to over 1000 nM and compound selectivity ranges from isoform selectivity to non-isoform selectivity. It became clear. Results from representative compounds are listed in Table 2.

Compound IV binds to ERα and ERβ with nanomolar affinity. The ER binding affinities of compounds ^{IV, [2,4,6,7- 3 H (N} )] - estradiol _{^{([3 H] E 2)}} , a natural high affinity ER ligands, and GST expressed in bacteria Determined using in vitro competitive radioligand binding assay with fusion ERα or ERβ ligand binding domain (LBD) protein. In this assay, compounds ERα binding affinity of IV (Ki values) and ERβ binding affinities _{(K i} values), respectively, 21.7 ± 1.7nM (n = 3 ) and 15.2 ± 4.1 nM ( n = 3). By binding to the ER, Compound IV initiates a complex series of molecular events that result in the expression or suppression of target genes associated with pharmacological responses in a tissue selective manner. In transient transfection assays, Compound IV is an ERα agonist and an ERβ agonist, clearly showing greater potency of stimulating ERα-mediated transcriptional activation as compared to ERβ-mediated transcriptional activation. Estradiol activates ERα and ERβ, but the selectivity for ERα is 5.1-fold higher, while Compound IV exhibits a 49.0-fold selectivity for ERα. Thus, Compound IV has a 9.7-fold selectivity for ERα over ERβ in relative transactivation potency (normalized to estradiol values). Furthermore, no antagonism was observed in estradiol (1 nM) stimulated transcriptional activation by concentrations of Compound IV up to 10 μM. Many steroid ligands cross-react with other nuclear hormone receptors, but the action of Compound IV is specific for ERα and ERβ. Compound IV is administered in rat isoforms of glucocorticoid receptor (GR), mineralocorticoid receptor (MR), progesterone receptor (PR), androgen receptor (AR) in both agonist and antagonist modes in transcriptional activation assays. Forms, and human isoforms of farnesoid X receptor (FXR), liver X receptor (LXR), peroxisome proliferator activated receptors (PPAR-α and PPAR-γ), and retinoid X receptor (RXR-α) Were screened for cross reactivity. Compound IV did not show any agonist or antagonist activity in any of these assays, which supports the conclusion that Compound IV does not functionally cross-react with these nuclear hormone receptor superfamily members. did.

(Example 7)
Transactivation of selected compounds

  Agonist and antagonist mode transactivation assays were performed to identify whether compounds were agonists, antagonists or partial.

Method

  Rat estrogen receptors (ER-α and ER-β) were cloned from rat ovary cDNA into the pCR3.1 plasmid vector backbone. Sequencing was performed and it was determined that there were no mutations. HEK-293 cells were plated at 100,000 cells per well in a 24-well plate in Dulbecco's Minimum Essential Medium (DMEM) + 5% charcoal-stripped fetal calf serum (csFBS). Using Lipofectamine (Invitrogen, Carlsbad, CA) with 0.25 μg ERE-LUC, 0.02 μg CMV-LUC (Renilla luciferase) and 12.5 ng rat ER-α or 25 ng rat ER-β Cells were transfected. Cells were treated 24 hours after transfection with various concentrations of compound or a combination of compound and estradiol to determine antagonist activity. Luciferase assay was performed 48 hours after transfection.

Results Screening of the compounds of the present invention in a transactivation system revealed that the compounds belonged to all three classes: agonists, antagonists and partial agonists. An example of agonists and antagonists is shown in Table 3. The transactivation results agreed very well with the binding results for isoform selectivity.

Table 3 provides EC ₅₀ transactivation values and IC ₅₀ transactivation values for some selected compounds of the invention.

(Example 8)
Testosterone suppression in cynomolgus monkeys

  Two-year-old intact gonadal cynomolgus monkeys (n = 2) were housed during the study according to USDA guidelines and had free access to primate diet and water (except fasting prior to oral dose administration) ). Animals were given a daily oral gavage dose of 30 mg / kg of the compound of formula IV in a microemulsion vehicle of Tween 80 / deionized water for 7 consecutive days. On day 1 (baseline), day 3, day 4, day 5, day 6, and day 7, serum samples were collected by venipuncture prior to oral dose administration. Testosterone and total androgen were quantified using an enzyme immunoassay (EIA) method, with or without HPLC method, respectively. After 6 days of treatment with the compound of formula IV, a time-dependent decrease in testosterone and total androgens (testosterone / dihydrotestosterone) was evident. The compound of formula IV suppressed testosterone levels by 58% and 64% relative to baseline values in animal # 1 and animal # 3, respectively (see solid line in FIG. 1; see Table 4). Similarly, total androgen levels were suppressed by 56% in both animals # 1 and # 3 compared to baseline values (dashed line in FIG. 1; see Table 4).

  Consistent with pituitary-testicular axis estrogen feedback in males, these results indicate that serum hormones in intact non-human primates (cynomolgus monkeys) following repeated oral doses (30 mg / kg) of compound of formula IV ( It clearly shows a robust pharmacological response to the inhibition of testosterone and total androgens).

Example 9
Inhibition of LH and testosterone hormone levels in rats

In vivo dose response studies were performed in intact and orchidectomized (ORX) male rats to assess the effect of Compound IV on LH suppression. In intact and ORX animals, doses of ≧ 10 mg / kg of compound IV per day significantly suppressed LH levels when compared to their respective controls. (The same pattern of suppression was observed at FSH levels.) LH suppression is a robust decrease in testosterone levels below the limit of quantification (BLOQ) (which is 0.08 ng / mL), and prostate, seminal vesicles, and It resulted in a decrease in the weight of the levator ani muscle (because these are highly androgen-dependent organs). In intact animals, a dose-dependent decrease in the weight of these target organs was noted at the level of castrated controls in seminal vesicle and levator ani muscle weights. Although prostate weight was significantly reduced in intact animals, these values did not reach the level of castrated controls. The results are summarized in Table 6 herein below.
Materials and methods:

  Male Sprague-Dawley rats weighing approximately 200 g are maintained on a 12-hour light / dark cycle with free access to food (2016 Teklad Global (16% protein rodent diet), Harlan, Madison, WI) and water It was possible. The animal protocol was reviewed and approved by the Institutional Animal Care and Use Committee at the University of Tennessee.

  Test articles for this study were weighed and dissolved in 10% DMSO (Fisher) diluted with PEG300 (Acros Organics, NJ) to prepare the appropriate dose formulation. For this study, 60 male Sprague-Dawley rats were randomized by body weight and assigned to one of 12 treatment groups (n = 5 animals / group). Treatment groups are listed in Table 5. Animals were housed in groups of 2-3 animals per cage. A control group (intact and orchiectomy (ORX)) received daily vehicle. Compound IV was injected subcutaneously (200 μL) into both intact and ORX groups at doses of 0.3 mg / kg / day, 1 mg / kg / day, 3 mg / kg / day, 10 mg / kg / day, and 30 mg / kg / day. ).

  Following the 14-day dosing regimen, animals were sacrificed under anesthesia (ketamine / xylazine, 87:13 mg / kg) and body weights were recorded. In addition, the ventral prostate, seminal vesicles, and levator ani muscle were removed and the external tissue was removed and weighed individually. Organ weights were normalized to body weight and expressed as a percentage of intact controls. Blood was collected from the abdominal aorta under isoflurane anesthesia and allowed to clot. Serum was separated by centrifugation and stored at −80 ° C., after which serum hormone levels were determined. Serum luteinizing hormone (LH) and follicle stimulating hormone (FSH) concentrations were determined by the rat pituitary Luminex assay (Millipore, Billerica, Mass.) 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 measured by testosterone EIA (Alpco Diagnostics, Salem, NH) with an LLOQ of 0.08 ng / mL. Serum hormone values below the lower limit of quantification (BLOQ) were excluded from the group mean analysis. Therefore, the reported values for LH and T in the group with sample BLOQ are higher than the measured values. This method of analysis provided the most conservative estimate of LH and T suppression. Fisher's least significant difference test was used to compare individual dose groups with intact and ORX vehicle control groups. Significance was defined a priori as a P value <0.05.

Luteinizing hormone levels in intact and ORX rats (Table 6)

  LH levels (mean ± SD) in the intact and ORX vehicle control groups were 1.46 ± 0.64 ng / mL and 11.1 ± 3.9 ng / mL, respectively. In intact animals, Compound IV reduced LH levels in a dose-dependent manner, reaching a statistically significant reduction with a daily dose of ≧ 3 mg / kg. LH levels in animals treated with intact Compound IV were 0.3 mg / kg / day, 1 mg / kg / day, 3 mg / kg / day, 10 mg / kg / day, and 30 mg / kg / day, respectively. Later, 0.863 ± 0.384 ng / mL, 0.704 ± 0.530 ng / mL, 0.395 ± 0.302 ng / mL, 0.226 ± 0.165 ng / mL, and 0.236 ± 0.176 ng / ML. LH levels in ORX males were also significantly reduced by treatment with Compound IV. In ORX animals, LH levels were 15.4 ± after doses of 0.3 mg / kg / d, 1 mg / kg / d, 3 mg / kg / d, 10 mg / kg / d, and 30 mg / kg / d, respectively. 2.9 ng / mL, 13.5 ± 2.2 ng / mL, 6.5 ± 5.6 ng / mL, 0.425 ± 0.135 ng / mL, and 0.368 ± 0.119 ng / mL. Results are presented graphically in FIG. 10A.

  In intact and orchidectomized rats, Compound IV at a dose of 10 mg / kg / day significantly suppressed luteinizing hormone (LH) levels, resulting in castrated serum levels of endogenous testosterone.

Follicle stimulating hormone levels in intact and ORX rats (Table 6)

  Serum FSH levels in the intact and ORX vehicle control groups were 20.9 ± 8.5 ng / mL and 93.5 ± 13.8 ng / mL, respectively. In intact animals, Compound IV reduced FSH levels in a dose-dependent manner, with a significant reduction observed at doses ≧ 10 mg / kg / day. FSH levels in animals treated with intact Compound IV were 0.3 mg / kg / day, 1 mg / kg / day, 3 mg / kg / day, 10 mg / kg / day, and 30 mg / kg / day, respectively. Later, it was 17.3 ± 6.4, 15.7 ± 7.3, 18.4 ± 7.7, 9.2 ± 4.0, and 6.3 ± 1.8 ng / mL. In ORX animals, LH levels were 115 ± 17 after doses of 0.3 mg / kg / day, 1 mg / kg / day, 3 mg / kg / day, 10 mg / kg / day, and 30 mg / kg / day, respectively. 114 ± 22, 65.2 ± 31.9, 27.6 ± 8.2, and 15.1 ± 4.1 ng / mL. Results are presented graphically in FIG. 10B.

Testosterone levels in intact and ORX rats

  Serum testosterone levels in the intact vehicle control group were 2.4 ± 1.1 ng / mL. The lower limit of quantification for T was 0.08 ng / mL. Values less than 0.08 ng / mL are referred to as below the limit of quantification (BLOQ). In intact animals, the compound of formula IV reduced T levels in a dose-dependent manner, with a significant reduction observed at doses ≧ 3 mg / kg per day. Testosterone levels in intact animals treated with compounds of formula IV were 2.6 ± 1. After doses of 0.3 mg / kg, 1, 3 mg / kg, 10 mg / kg and 30 mg / kg, respectively. 7, 1.6 ± 1.0, 0.7 ± 0.4, BLOQ, and BLOQ ng / mL. In ORX animals, T levels were BLOQ for all groups treated with Compound IV and the vehicle treated group. Results for intact animals are presented graphically in FIG. 10C (and FIG. 2) (for graphical purposes, BLOQ values are expressed as quantitation limits).

  As shown in FIG. 9, rapid and potent suppression of serum testosterone in intact male rats was achieved after 24 hours, 72 hours and 168 hours with compound IV at doses of 3 mg / kg, 10 mg / kg and 300 mg / kg. Measured by dosing.

Organ weight (Table 6)

  Prostate, seminal vesicle, and levator ani muscle weights were measured to confirm T inhibition. Organ weights (mean ± SD) are presented in FIGS. 10D, 10E, and 10F, respectively. A dose-dependent decrease in prostate, seminal vesicle, and levator ani muscle weights was observed in intact animals treated with Compound IV. Prostate weight in intact animals was 84.0 ± after doses of 0.3 mg / kg / day, 1 mg / kg / day, 3 mg / kg / day, 10 mg / kg / day, and 30 mg / kg / day, respectively. 19.2, 75.2 ± 20.7, 68.2 ± 8.1, 45.1 ± 20.0, and 43.6 ± 8.8. Prostate weight in ORX animals was 19.0 ± 4 after doses of 0.3 mg / kg / day, 1 mg / kg / day, 3 mg / kg / day, 10 mg / kg / day, and 30 mg / kg / day, respectively. 0.2, 17.4 ± 3.4, 19.6 ± 6.7, 22.9 ± 5.4, and 20.6 ± 2.1. Seminal vesicle weight in intact animals was 76.2 after doses of 0.3 mg / kg / day, 1 mg / kg / day, 3 mg / kg / day, 10 mg / kg / day, and 30 mg / kg / day, respectively. ± 7.8, 66.3 ± 27.2, 51.8 ± 28.5, 19.1 ± 7.0, and 17.9 ± 3.3. The seminal vesicle weight in ORX animals was 12.2 ± after doses of 0.3 mg / kg / day, 1 mg / kg / day, 3 mg / kg / day, 10 mg / kg / day, and 30 mg / kg / day, respectively. 1.3, 16.6 ± 5.4, 16.5 ± 4.8, 13.3 ± 1.9, and 12.9 ± 2.1. The levator ani muscle weight in intact animals was 86. 6 mg after doses of 0.3 mg / kg / day, 1 mg / kg / day, 3 mg / kg / day, 10 mg / kg / day, and 30 mg / kg / day, respectively. 9 ± 10.0, 82.1 ± 12.1, 65.2 ± 4.4, 57.8 ± 11.2, and 58.1 ± 4.7. The levator ani muscle weight in ORX animals was 54.5 after doses of 0.3 mg / kg / day, 1 mg / kg / day, 3 mg / kg / day, 10 mg / kg / day, and 30 mg / kg / day, respectively. ± 6.6, 49.6 ± 7.0, 53.6 ± 10.0, 51.1 ± 4.9, and 49.2 ± 4.2.

LH suppression and organ weight data are summarized in Table 6.

  In intact and orchidectomized rats, a dose of 10 mg / kg / day of compound IV significantly suppressed luteinizing hormone (LH) levels, resulting in castrated serum levels of endogenous testosterone.

  Compound IV did not increase proliferation of prostate epithelial cancer cells in vitro. Mechanistically, Compound IV offers several important advantages over existing therapies, such as gonadotropin releasing hormone (GnRH) agonists and GnRH antagonists. Compound IV is specific for the estrogen receptor and is orally bioavailable in rats, dogs, monkeys and humans. In contrast to GnRH agonists and GnRH antagonists resulting in hot flashes and significant bone loss and increased risk of fracture, Compound IV reduces hot flashes induced by morphine withdrawal and maximally suppresses LH and serum testosterone in rats Maintains the bone mass and bone mineral density of cancellous bone in the distal femur of the rat even at the dose to be achieved.

(Example 10)
Recovery of testosterone levels following inhibition by Compound IV in rats and monkeys

  The reversibility of chemical castration by Compound IV was studied.

Materials and methods:

  Thirty-five male Sprague-Dawley rats weighing approximately 200 g are maintained on a 12 hour light / dark cycle with food (2016 Teklad Global (16% protein rodent diet), Harlan, Madison, WI) and water. It was made available freely. The animal protocol was reviewed and approved by the Institutional Animal Care and Use Committee at the University of Tennessee.

  Test articles for this study were weighed and dissolved in PEG300 (100%) (Acros Organics, NJ) to prepare the appropriate dose formulation. Animals were randomly assigned to one of 10 treatment groups (n = 5 animals / group). Treatment groups are listed in Table 7. Animals were housed in groups of 2-3 animals per cage. Group 1 was sacrificed at the start of the study (Day 1) to determine baseline testosterone levels in intact animals. Groups 2-7 were given daily doses of 1 mg / kg, 3 mg / kg, or 30 mg / kg by oral gavage (approximately 200 uL) for 3 days. Groups 2, 3, and 4 were sacrificed on day 4 and maximum testosterone suppression was measured. Groups 5, 6, and 7 were allowed to recover for 14 days with a washout period without drug.

result:

  Serum testosterone levels in intact rats were 6.4 ± 3.1 ng / mL (mean ± SD) at baseline. Compound IV administered at doses of 3 mg / kg and 30 mg / kg for 3 days significantly suppressed serum testosterone levels to 1.47 ± 0.26 ng / mL and 1.62 ± 0.49 ng / mL, respectively. . No significant inhibition was observed in animals given 1 mg / kg of Compound IV for 3 days. Most importantly, serum testosterone levels were 3.3 when measured after a 14 day recovery period in animals given 3 mg / kg, 3 mg / kg, or 30 mg / kg of Compound IV, respectively, for 3 days. ± 1.92, 3.00 ± 1.06, and 3.8 ± 1.72, and as shown in FIG. 23, there was no statistically significant difference from baseline serum testosterone concentrations in intact rats.

  This study shows that compound IV rapidly suppresses serum testosterone levels in intact male rats, confirming previous results. We observed suppression of serum testosterone levels in the dose group given ≧ 3 mg / kg / day for 3 days. No significant decrease in serum testosterone was observed in the 1 mg / kg dose group. However, within 14 days of recovery, serum testosterone levels returned to intact control levels. This study shows that pharmacological castration with Compound IV is reversible in rats.

  The effect of Compound IV on the inhibition and recovery of testosterone levels in intact male monkeys was evaluated in conjunction with an oral pharmacokinetic study. Three untreated male cynomolgus monkeys (2-3 years old) were administered Compound IV at 30 mg / kg by daily oral gavage for 7 consecutive days. Blood samples were collected and divided into serum and plasma for quantitative measurement of testosterone and compound IV, respectively. The results show that daily oral doses of Compound IV significantly reduced circulating androgen (mainly testosterone and dihydrotestosterone) levels to 47% compared to baseline levels in all three male monkeys. Shown (baseline, levels 1591 ± 72.5 ng / mL, 997 ± 104 ng / mL, and 852 ± 136 ng / mL [mean ± SEM] for days 2 and 6 of treatment, respectively). Following the 18-day recovery period without drug, androgen levels returned to normal and were not significantly different from baseline levels before treatment (1757.7 ± 369.5 ng / mL after recovery).

(Example 11)
Bone preservation regardless of LH and testosterone reduction in rats (Table 8)

  The effect of the compound of formula IV on bone treatment was studied. The compound of formula IV administered orally completely prevented bone loss associated with LH suppression in intact male rats. In intact animals, the compound of formula IV induced a significant reduction in LH at dose levels of ≧ 10 mg / kg per day. At 1 mg / kg per day, the compound of formula IV did not significantly reduce LH, but at this dose a significant reduction in prostate, seminal vesicles, and levator ani muscle was evident, indicating that circulating testosterone Reduction has been shown to be physiologically related to these androgen responsive organs. However, 1 mg / kg of compound of formula IV per day maintained cancellous bone volume (measured in the distal femur) at the level of intact controls. The compound of formula IV increased bone volume in the distal femur significantly above that of the intact control when administered at doses of 10 mg / kg and 30 mg / kg per day. These data indicate that Compound IV increased cancellous bone mineral density (BMD) and bone volume percent at dose levels that reduced LH levels in intact rats. Data from this study is presented in Table 8.

(Example 12)
Effect on 17β-hydroxysteroid dehydrogenase 5 (17β-HSD5) enzyme activity

  HSD family members are involved in the conversion of circulating steroids. 17β-HSD5 converts androstenedione to testosterone and estrone to estradiol. In addition, it is also involved in prostaglandin synthesis. Here, the ability of some selected compounds of the present invention to inhibit 17β-HSD5 activity was clearly demonstrated.

Method

Human 17β-HSD5 was cloned into pGEX4t1 vector to prepare purified protein. The purified protein was incubated with a representative compound of the invention, ¹⁴ C androstenedione and NADPH in an appropriate buffer. Synthetic testosterone was extracted using ethyl acetate, air dried, spotted and run on a thin layer chromatography (TLC) plate. TLC was exposed to a phosphorimager and the intensity of the testosterone band was quantified. Indomethcin was used as a positive control (LHRH agonist).

result

  Compound IV was tested and had a partial inhibitory effect on 17β-HSD5 enzyme activity. As shown in FIG. 3, the positive control (LHRH agonist) indomethacin showed potent inhibition of this enzyme as expected.

(Example 13)
Toxicity studies

  Studies were performed to compare the thrombus formation potential of Compound IV and diethylstilbestrol (DES, positive control) using an in vitro human platelet aggregation assay. Because males are the intended treatment population for Compound IV (LH suppression), blood from healthy male donors was used in the study. Platelet rich plasma was preincubated with either 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 preincubation with DES increased thrombin-induced platelet aggregation by approximately 10-fold. However, Compound IV and estradiol decreased platelet rich plasma aggregation. These data clearly show that Compound IV reduced human platelet reactivity in vitro compared to DES, suggesting that Compound IV may have a lower thromboembolic potential than DES ( FIG. 4).

(Example 14)
Effect of Compound IV on hot flashes

  Investigating the effect of Compound IV on hot flashes using a morphine-dependent rat model (MD model) developed by Simpkins et al. (1983) and shown to have some similarities with menopausal hot flashes I did some research. In addition to similarities to the human condition, this experimental animal model has a short turnaround time, which makes it possible to reduce vasomotor symptoms using tail skin temperature (TST) It becomes a useful high-throughput screening tool for identifying. TST probe TA-40 (Data Sciences International, MN) was taped to the base of the tail and a baseline temperature was obtained for 15 minutes. After 15 minutes, the animals were treated with naloxone (1 mg / kg, SQ) to counteract the effects of morphine. Tail skin temperature (TST) was measured for 1 hour at a sampling frequency of 5 seconds throughout the experiment after naloxone treatment. Following data collection, a moving average of the temperature recorded every 60 seconds for each animal was calculated and further analyzed. Baseline temperature was calculated as the average temperature obtained over 15 minutes prior to naloxone administration. The area under the curve (AUC) was calculated by subtracting all values after naloxone administration from the baseline using the linear trapezoidal method.

  Compound IV alleviated hot flashes in the morphine withdrawal model (see FIG. 13), with the best results being at 10 mg of Compound IV. 17βE2 was used at 5 mg / kg in 100% DMSO.

(Example 15)
Compound IV against DES in rats

  Prior to the introduction of the LHRH agonist, castration testosterone levels were achieved by increasing estrogen activity in the pituitary gland with estrogen, primarily diethylstilbestrol (DES). DES was as effective as LHRH agonists in suppressing testosterone to castration levels. Patients treated with DES had neither hot flashes nor bone loss, but had a higher proportion of gynecomastia than ADT with LHRH agonists. Unfortunately, highly potent and pure estrogens, such as DES and estradiol, are often associated with a high risk of severe cardiovascular and thromboembolic complications, thereby limiting their clinical use . The increased risk of venous thromboembolic complications due to DES has been postulated to be due to its cross-reactivity with other hormone receptors, but has not been proven. In vitro studies with human platelets have shown that compound IV has much lower procoagulant activity than DES. Therefore, Compound IV, which is an ER-α selective agonist, can exert the benefits of DES in prostate cancer and the benefits of LHRH agonists without causing osteoporosis or harmful lipid profiles.

  Compound IV is as effective as DES in reducing prostate size in rats and showing a moderate increase in prostate size in ORX rats (FIG. 11).

  The difference between DES and Compound IV is shown in FIGS. 12A-12C, where DES cross-reacts with the glucocorticoid receptor (GR) (FIG. 12A) and the androgen receptor (AR) (FIG. 12B), while Compound IV was not. Furthermore, DES antagonizes estrogen-related receptor (ERR) transactivation, whereas compound IV did not. Compound IV was unable to cross-react with any of the three ERR isoforms (ERR-α, ERR-β and ERR-γ) as shown in FIG. 12C.

(Example 16)
Monkey toxicity study-90 days

  Macaque cynomolgus monkeys were obtained from which Mauritius origin colonies were propagated. The prospective study was designed as a 39-week oral pharmacological and toxicological assessment of Compound IV and positive control (LHRH agonist) in male cynomolgus monkeys with a 13-week provisional period. A total of 39 sexually mature male monkeys (5-8 years old) were randomly assigned to 5 groups prior to the start of treatment. Groups included 1) vehicle control, 2) 1 mg / kg of compound IV, 3) 10 mg / kg of compound IV, 4) 100 mg / kg of compound IV, and 5) positive control (LHRH agonist). Drug was delivered orally once daily by cageside administration for 39 weeks (vehicle control article (Tween 80 / PRAN ™) for groups 1 and 5 or compound IV in vehicle for groups 2, 3, and 4) . Compound IV dose levels were 1 mg / kg / day, 10 mg / kg / day, and 100 mg / kg / day for Groups 2, 3, and 4, respectively. Oral doses were delivered at a dose volume of 10 mL / kg calculated based on the most recently available body weight for each animal (Figure 14). Group 5 animals were also given a daily subcutaneous injection (constant volume of 0.02 mL) of the positive control (LHRH agonist) for a 39-week study period. Overall status and clinical signs were observed and recorded daily. Routine assessments and other selected study studies were conducted as indicated in the study protocol. Selected parameters include, but are not limited to, testosterone, prostate specific antigen (PSA), and prostate volume and weight.

  Testosterone and total PSA levels were quantified in serum samples (following standard procedures) using enzyme immunoassay (EIA) and chemiluminescence immunoassays (LIA, ALPCO Diagnostics, Salem NH), respectively. Blood samples for testosterone assessment are at baseline (ie, before the start of treatment) and on days 1, 3, 7, 14, 28, 64, and 90. Collected from all animals (fasted) by eye. Blood samples for PSA determination were collected from all animals (fasted) at baseline and during the sixth week. For discussion purposes, the results for samples with concentrations below the limit of quantification (BLQ) for the testosterone and PSA assays were calculated as one-half of the lower limit of quantification (LLOQ) of the assay, and the “estimated final concentration” Think of it as The data in Tables 9-16 show that in addition to “estimated final concentration” (ie, samples with BLQ results are included as one-half LLOQ of the assay), “only quantifiable concentrations” (ie, BLQ values To be excluded). Prostate volume was measured in live animals under anesthesia using transrectal ultrasound (TRUS) procedures at baseline and week 6. The prostate width and height were recorded. Prostate volume was calculated as width × width × height × π / 6 and normalized to body weight. After removing fat and external tissue from the tissue, the wet weight of the prostate was recorded at necropsy.

Results and Discussion:

  Serum testosterone levels are shown in Figure 15 and Tables 9-12. At baseline, testosterone levels for all monkeys under study were within normal limits for sexually mature adult male cynomolgus monkeys. However, testosterone levels were significantly reduced in monkeys receiving Compound IV at 100 mg / kg / day and monkeys treated with a positive control (LHRH agonist). Testosterone levels in the positive control (LHRH agonist) group showed a biphasic change, with an initial significant increase of 47.4% and 547% (p <0.01) on day 1 and 3, respectively (ie, p <0.01). Flare) followed by a decrease of 3.6%, 67%, 73%, 83%, and 85% on days 7, 14, 28, 64 and 90 (See FIG. 15 and Tables 9-12). Similar flare was not observed for any of the animals treated with Compound IV even at the highest dose level (ie, 100 mg / kg / day). The dose and duration of treatment is important for the pharmacological action of Compound IV, and a dose of 100 mg / kg / day is the serum testosterone on days 3, 7, 14, 28 and 64, respectively. Was suppressed by 60%, 51%, 42%, 79% and 92% relative to baseline values (see FIG. 15 and Table 9 and Table 10). After 90 days of treatment with 100 mg / kg / day of compound IV, testosterone levels in 6 out of 10 monkeys in group 4 were reduced to concentrations below the limit of quantification of the assay (see Table 11). Wanna) Mean serum testosterone levels in group 4 monkeys were reduced by 96% compared to their respective baseline values (“estimated final concentration”, ie testosterone levels for 6 of 10 monkeys with BLQ values were , Calculated as 50% of LLOQ concentration, see Table 10). By day 90, it is important to point out that Compound IV at 100 mg / kg / day reduced serum testosterone to a significantly lower level than the positive control (LHRH agonist) (p = 0.013). is there.

  Serum PSA levels were also significantly suppressed by Compound IV within 4 weeks of treatment initiation. PSA reductions of 69% and 87% (on average) are noted for monkeys given Compound IV at 10 mg / kg and 100 mg / kg for 4 weeks, while PSA levels are in the positive control (LHRH agonist) group It was reduced by 60% (Figure 16 and Tables 13-16).

  Prostate volume was measured regularly throughout the study by TRUS. The results obtained after 6 weeks of treatment clearly show the strong effect of compound IV and positive control (LHRH agonist) on monkey prostate. Compound IV significantly suppressed prostate volume by 25% and 45% at dose levels of 10 mg / kg and 100 mg / kg, respectively, while prostate volume was reduced by 28% in the positive control (LHRH agonist) group (FIG. 17). And Tables 17 and 18).

  The reduction in prostate volume associated with Compound IV was confirmed by assessment of prostate weight at necropsy. After 13 weeks of treatment, Compound IV significantly reduced mean prostate weight by 24% and 21% in animals receiving 10 mg / kg / day and 100 mg / kg / day, respectively (FIG. 18B). And Tables 19 and 20).

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

(Example 17)
Compound IV studies on humans.

  A study was conducted to determine the effect of Compound IV on human men. Twelve subjects per cohort were examined with doses of 100 mg, 300 mg, 600 mg and 1000 mg of Compound IV. Table 21 shows the average changes in LH levels, serum PSA levels, free testosterone levels and total testosterone levels in men by administering Compound IV at doses of 100 mg, 300 mg, 600 mg and 1000 mg. Dose-dependent mean total testosterone levels (nmol / L) in humans were measured over a period of 1-11 days (Figure 19). Total testosterone levels were reduced by 51.9% and 47.9% at doses of 600 mg and 1000 mg, respectively.

  Dose-dependent mean LH levels (IU / L) in humans were measured over a period of 1-10 days (Figure 20). LH levels increased by 20.7%, 46.9%, 27.6% and 29.2% at doses of 100 mg, 300 mg, 600 mg and 1000 mg, respectively.

  Dose-dependent mean free testosterone levels (pg / mL) in humans were measured over a period of 1-10 days (FIG. 21). Free testosterone levels were reduced by 17.0%, 18.5%, 72.7% and 53.2% at doses of 100 mg, 300 mg, 600 mg and 1000 mg, respectively.

  Dose-dependent mean PSA levels (μg / L) in humans were measured over a period of 1-10 days (Figure 22). PSA levels were reduced by 9.2%, 24.4%, 27.5% and 29.9% at doses of 100 mg, 300 mg, 600 mg and 1000 mg, respectively. No changes were noted for the 10 mg and 30 mg doses.

  These data show a drop in testosterone and PSA in the context of elevated LH during the early time points in this human study. This supports testosterone suppression and the corresponding antiandrogenic effects (PSA suppression) via mechanisms other than hypothalamic-pituitary-testicular axis suppression. This mechanism for LH-independent suppression may be, among other things, the direct effect of Compound IV on removal of serum T by elevated adrenal or gonadal androgen synthesis or SHBG.

(Example 18)
Bioavailability of Compound IV

  Compound IV was rapidly absorbed after oral administration to rats, dogs and monkeys. The oral bioavailability of Compound IV in rats ranged from 6% to 25% depending on the formulation to which the dose was administered. Formulations using polyethylene glycol 300 (PEG 300) generally resulted in higher exposure than microemulsions prepared with Tween 80 diluted in deionized water. In dogs, visual inspection of the plasma concentration-time profile suggested that Compound IV undergoes enterohepatic recirculation as evidenced by the second peak in the final phase. Importantly, exposure in the male 30 mg / kg PEG300 oral dose group in dogs exceeded the exposure required to produce the maximum effect on prostate reduction in a rat model of LH suppression. In monkeys, preliminary pharmacokinetic studies indicate that oral bioavailability in this species is close to oral bioavailability in dogs, as evidenced by suppression of plasma concentrations of Compound IV and serum testosterone over a period of 7 days Suggested that it was or exceeded. Overall, these data suggest that sufficient oral exposure can be achieved in two non-rodent animal species to produce the desired pharmacological effect (based on AUC data). Furthermore, endocrine data in rats and monkeys suggest that the pharmacological effects of Compound IV are reversible (ie, serum levels of testosterone return to baseline or normal levels when Compound IV treatment is stopped). To do.

  Thus, compound IV was rapidly absorbed after oral administration to rats, dogs and monkeys. The oral bioavailability of Compound IV ranged from 6-25% in rats and 3-12% in dogs depending on the formulation and route of administration. In monkeys, preliminary pharmacokinetic studies suggest that oral bioavailability in this species is close to or better than oral bioavailability in dogs, as evidenced by suppression of plasma concentrations of Compound IV and serum testosterone did. Furthermore, endocrine data in rats and monkeys (Example 10) showed that the pharmacological effects of Compound IV were reversible and that serum testosterone concentrations returned to baseline or normal levels when Compound IV treatment was stopped.

(Example 19)
Pharmacokinetics of Compound IV

Preliminary data from in vitro (mouse, rat, dog, monkey and human) and in vivo (rat) metabolic studies are conjugation of compound IV, its hydroxylated metabolite (s) and its N-dealkylated metabolite. Suggest that it contributes to the overall disposition of Compound IV in animals and humans. Although only qualitative, the results of the interspecies comparison show that the overall metabolite profile of the non-clinical species adequately reflects the profile generated in human liver microsomes. Based on these results, rats and dogs are appropriate rodent and non-rodent species for pharmacological and toxicological evaluation, respectively. In vitro studies indicate that Compound IV does not induce the relevant CYP450 isoform (CYP1A2, CYP2B6, or CYP3A4) and does not inhibit CYP1A2, CYP2C19, CYP2D6, or CYP3A4 / 5 at concentrations <30 μM. CYP2C9 is inhibited by Compound IV only at high concentrations (K _i = 8 μM) and the potential pharmacokinetic drug-drug interactions are thought to be poor.

(Example 20)
Off-target activity of compound IV

Compound IV exerts little or no in vitro inhibitory effect (IC ₅₀ ≧ 300 μM) on hERG channels. The compound dose-dependently reduced APD50 and APD90 at concentrations of 10 and 100 μM in vitro in isolated canine Purkinje fibers. However, Compound IV did not affect hemodynamic function or cardiac function (blood pressure, heart rate, electrocardiographic morphology or QT interval) in telemetered dogs at any dose (up to 300 mg / kg). No neuropharmacological or pulmonary effects were observed. A single oral dose of Compound IV up to 30 mg / kg did not indicate a significant effect on renal function. Only increased urinary excretion and increased urinary excretion of potassium and chloride were observed at the highest dose tested (100 mg / kg). Oral administration of Compound IV at a dose of 30-300 mg / kg in rats resulted in a significant increase in peristalsis, and oral administration of Compound IV at 30 mg / kg in rats resulted in significant gastrointestinal motility and gastric acidity. Increased (not likely due to effects on smooth muscle).

  Compound IV is not mutagenic and did not induce structural or numerical chromosomal abnormalities in human peripheral blood lymphocytes in vitro at concentrations up to 200 μM. Compound IV was well tolerated for rats and dogs after single and repeated oral administration (up to 28 days). No pathological changes were observed in the kidney, liver, heart and other non-target related organs. By day 28, there are no serious physical signs, effects on body weight, clinicopathological changes, ophthalmological, electrocardiographic, or histopathological changes associated with oral administration of Compound IV to male or female dogs It was.

(Example 21)
Compound IV reduces testosterone to castration levels

A 56-day proof-of-concept study of Compound IV was conducted in healthy young male volunteers. In subjects who are well in compliance with Compound IV intake as determined by blood levels of Compound IV, 90% of subjects in the 1500 mg dose group had castration levels of total testosterone by Day 28. Research has shown that it has been reached. Free testosterone levels were reduced to levels below those expected from surgical castration or below levels expected from chemical castration with LHRH agonists or LHRH antagonists. This is due to a dose-dependent increase in sex hormone binding globulin (SHBG) observed with Compound IV. SHBG binds strongly to testosterone, making testosterone unavailable for intracellular activity, and increasing the level of SHBG reduces testosterone that can act intracellularly, surgical castration or Potentially realizes the pharmacological benefits of Compound IV that are not present upon castration with LHRH agonists or LHRH antagonists.

(Example 22)
Compound IV study on castrated monkeys-90 days

  Obtain Macaque cynomolgus monkeys that have been bred in Mauritius colonies. The prospective study is designed as a 39-week oral pharmacological and toxicological assessment of Compound IV in male cynomolgus monkeys with a 13-week provisional period comparing castrated versus non-castrated animals (Example 16). A total of 49 sexually mature male monkeys (5-8 years old) are randomly assigned to 7 groups prior to the start of treatment. Animals selected for groups 3-7 are castrated according to NIH guidelines. Groups are: 1) intact vehicle control, 2) intact positive control (LHRH agonist), 3) castrated vehicle control, 4) castrated 1 mg / kg compound IV, 5) castrated 10 mg / kg compound. IV, 6) Castrated 100 mg / kg Compound IV, and 7) Castrated control (LHRH agonist).

  Drug is delivered orally once daily by cage side administration for 39 weeks (vehicle control article (Tween 80 / PRAN ™) for groups 1, 2, 3 and 7) or in vehicle for groups 4, 5 and 6 Compound IV). Compound IV dose levels are 1 mg / kg / day, 10 mg / kg / day, and 100 mg / kg / day for Groups 4, 5 and 6, respectively. The oral dose is calculated based on the most recently available body weight for each animal and delivered in a dose volume of 10 mL / kg. Groups 2 and 7 animals are also given a daily subcutaneous injection (constant volume of 0.02 mL) of LHRH agonist for a 39-week study period. The overall situation and clinical signs are observed and recorded daily. Routine assessments and other selected research studies will be performed as indicated in the study protocol. Selected parameters include, but are not limited to, testosterone, prostate specific antigen (PSA), and prostate volume and weight.

Testosterone and total PSA levels are quantified in serum samples (following standard procedures) using enzyme immunoassay (EIA) and chemiluminescent immunoassays (LIA, ALPCO Diagnostics, Salem NH), respectively. Blood samples for testosterone assessment are at baseline (ie, before the start of treatment) and on days 1, 3, 7, 14, 28, 64, and 90. Collect from all animals (fasted) to the eye. Blood samples for PSA determination are collected from all animals (fasted) at baseline and during the sixth week. For discussion purposes, the results for samples with concentrations below the limit of quantification (BLQ) for the testosterone and PSA assays were calculated as one-half of the lower limit of quantification (LLOQ) of the assay, and the “estimated final concentration” It is considered. Prostate volume is measured in anesthetized live animals using a transrectal ultrasound (TRUS) procedure at baseline and week 6. The prostate width and height were recorded. The prostate volume is calculated as width × width × height × π / 6 and normalized to body weight. After removing fat and external tissue from the tissue, the wet weight of the prostate is recorded at necropsy.
Results and Discussion:

  At baseline, testosterone levels for all monkeys in study groups 1 and 2 are within normal limits for sexually mature adult male cynomolgus monkeys. However, at baseline, all monkey testosterone levels in study groups 3-7 are reduced to the castration range for sexually mature adult male cynomolgus monkeys. The results show that testosterone levels are significantly reduced in Group 2 monkeys, which are positive controls receiving LHRH agonists. Testosterone levels in this intact positive control (LHRH agonist) group show a biphasic change. Similar flare is not observed in any of the castrated animals treated with Compound IV. The dose and duration of treatment are important for the pharmacological action of Compound IV.

  Unexpectedly, serum PSA levels are significantly suppressed by Compound IV in castrated animals (Groups 4, 5 and 6) within 4 weeks of treatment initiation.

  Prostate volume is measured periodically throughout the study by TRUS. Intact vehicle controls show minimal change before dosing and during 4 weeks. The results clearly show the strong effect of Compound IV on monkey prostate.

  The intact vehicle control shows results similar to those observed in Example 16. The compound IV related reduction in prostate volume is confirmed by assessment of prostate weight at necropsy. After 13 weeks of treatment, Compound IV significantly reduces mean prostate weight in animals receiving Compound IV doses.

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

(Example 23)
Compound IV study for humans with prostate cancer undergoing ADT

  A study was conducted to determine the effect of Compound IV on testosterone and PSA levels in human men undergoing ADT for prostate cancer, where ADT treatment results in subjects with castration levels of testosterone. All subjects are required to show histological evidence of prostate cancer. Patients who have not previously undergone testicular removal and are currently receiving luteinizing hormone-releasing hormone analogs for chemical castration need to remain on this therapy for a series of studies.

  Twelve subjects per cohort will be tested at 100 mg, 300 mg, 600 mg and 1000 mg doses of Compound IV. Dose-dependent mean total testosterone levels (nmol / L) in humans are measured over a period of 1-11 days.

  Dose-dependent mean free testosterone levels (pg / mL) in humans are measured over a period of 1-10 days.

  Dose-dependent mean PSA levels (μg / L) in humans are measured over a period of 1-10 days.

(Example 24)
Study of compound IV on healthy human subjects Toxicity study of compound IV on healthy human subjects

  Single and multiple dose studies in healthy human subjects have shown that compound IV is up to 1247 mg in a single dose and up to 997 mg in multiple doses (10 mg, 30 mg, 100 mg, 300 mg, 609 mg and 997 mg) for up to 10 days. It was well tolerated. An increase in ALT levels above the upper limit of normal was observed in 4 subjects in a multiple dose study (3 subjects in the 1000 mg group and 1 subject in the 600 mg group). The highest single observed value of ALT was 129 IU / L or 2.6 times the upper limit of normal. Aspartate aminotransferase levels were also increased to 1.9 times the upper limit of normal in this subject. No increase in total bilirubin was observed in any subject in this study.

Effect of compound IV on serum testosterone levels

  Serum total testosterone levels were assessed across multiple dose studies. Total testosterone levels were reduced in 100% (10/10) of subjects in the 600 mg dose group and 90% (9/10) of subjects in the 997 mg dose group. Total testosterone levels decreased below the lower limit of normal in 40% (4/10) of subjects in the 600 mg dose group and 50% (5/10) of subjects in the 1000 mg dose group. However, subjects did not have a total testosterone level of less than 1.73 nmol / L (castration range) and the total testosterone levels of all subjects returned to normal within 6 days after Compound IV discontinuation.

  Concept for assessing the effect of Compound IV on serum total testosterone and serum free testosterone in healthy young male volunteers (healthy male volunteers ingested 600, 1000 or 1500 mg of Compound IV in liquid form for 56 days) According to a proof study (Study 1), in the 1000 mg and 1500 mg dose groups, some subjects had serum total testosterone levels within the castration range (<1.73 nmol / L) and in the 600 mg dose arm The subject was also shown not to have serum total testosterone levels (<1.73 nmol / L) within the castration range.

  A second proof-of-concept study (Study 4) was also conducted to assess the effect of Compound IV on serum total testosterone levels and serum free testosterone levels in healthy older male volunteers. In this study, volunteers took 1000 mg, 1500 mg, or 2000 mg of Compound IV in tablet form for 28 consecutive days.

  In both of these 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 level of testosterone available for binding to the androgen receptor (as indicated by the level of free testosterone). ). In each of the dose arms administered in the two studies, SHBG increased 300-600% above baseline and serum free testosterone decreased. In chemically castrated men with total testosterone levels <50 ng / dL, levels of serum free testosterone are predicted by levels expected by surgical castration and administration of luteinizing hormone releasing hormone (LHRH) agonists Expected to be below the level.

  A summary of the details of the various human studies is presented in FIG.

(Example 25)
Study of Compound IV in male subjects with prostate cancer:
Effect of Compound IV on Serum Testosterone Levels-Prostate Cancer Patients

  A dose-setting study (Study 2) was conducted comparing the doses of 1000 mg and 2000 mg of Compound IV administered once daily with a 3-month leuprolide acetate depot formulation. The primary objective of the study was to assess the proportion of subjects who achieved castration levels of serum total testosterone by day 60 and maintained castration levels from day 60 to day 360.

  55 subjects were randomized to a dose arm of 1000 mg of Compound IV. In the 1000 mg Compound IV dose arm in subjects reaching day 60, 65% (24/37) of subjects achieved castration by day 60. However, this proportion of subjects who reached castration was too low to be considered clinically viable as androgen depletion monotherapy.

  55 subjects were randomized into a 2000 mg Compound IV dose arm. In the 2000 mg dose arm of subjects that reached day 60, 84% (38/45) of subjects achieved castration by day 60.

  Fifty-four subjects were randomized to the dose arm of leuprolide acetate. In the leuprolide-treated arm of subjects that reached day 60, 100% (46/46) of these subjects achieved castration by day 60. During the study, 9 subjects in the 1000 mg dose arm and 2 subjects in the 2000 mg dose arm experienced VTE.

  The secondary purpose of Study 2 was to compare the incidence and frequency of hot flashes in subjects who received Compound IV versus subjects who received Lupron. Men who received Compound IV were shown to experience less hot flashes compared to men who received Lupron.

The table below shows the results of the incidence of hot flashes in men receiving androgen depletion therapy with an injectable LHRH agonist (Lupron) versus an oral selective estrogen receptor alpha agonist (Compound IV).

  Another study (Study 5) was conducted to evaluate loading doses of Compound IV of 1000 mg (twice daily) and 1500 mg (twice daily) for 28 days. Subjects who had been castrated on day 28 were given 1000 mg or 2000 mg of Compound IV daily to maintain castration.

  Thirty and 28 subjects were randomized to loading doses of 1500 mg (BID) and 1000 mg (BID), respectively. Of the subjects who reached day 28, 90% (18/20) of subjects in the 1500 mg (BID) dose group and 94% (17/18) of subjects in the 1000 mg (BID) dose group were castrated. A level of serum total testosterone was reached. During this study, two subjects in the 1500 mg (BID) dose group experienced VTE including one fatal pulmonary embolism (PE), and three subjects in the 1000 mg (BID) dose group Experienced VTE.

A summary of the study details is presented in FIG.

  In patients not receiving treatment, 81% reduces free T% by at least 50% after only 7 days of therapy when focusing on the change in free T% from baseline (FIG. 28A). This change in free T% is associated with a reduction in PSA as therapy is extended to 14, 21, and 28 days. After 1 month of therapy with Compound IV (80D), 80% of all patients have both at least a 50% reduction in free T% and a 50% reduction in PSA from baseline (ie, FIG. At 28C, the data is concentrated in the lower left quadrant). These patients meet the PCWG2 criteria for PSA response.

  The reduction in 50% free T and 50% PSA on day 28 is replotted as the change in SHBG versus the change in PSA in FIG. Extensive SHBG induction allows a> 50% reduction in PSA.

  In patients not receiving treatment, both Compound IV and Lupron therapy significantly increase the SHBG: total T molar ratio after 28 days of treatment (FIG. 31). Since compound IV induces SHBG and reduces total T, the molar ratio of SHBG to total T is 3-7 times higher than in Lupron treated patients. This increase in molar ratio corresponds to a 70% decrease in free T% at day 28 in patients treated with Compound IV, as opposed to only a 20% decrease in males treated with Lupron (FIG. 31). All doses of Compound IV also showed a similar rapid decrease in free T%, which is 1000 mg (QD) is the Emax dose, and lower doses of Compound IV may reduce free T%. Suggest that there is.

  Based on clinical experience, the SHBG data from Studies 1 and 2 was extrapolated to lower doses (FIG. 32), which indicates that SHBG is free T% and even at 125 mg, 250 mg and 500 mg doses. It suggests that it can be elevated enough to significantly suppress PSA.

(Example 26)
Study of Compound IV against male subjects with castration resistant prostate cancer (CRPC) undergoing ADT:
Effect of compound IV on serum PSA progression

  When measuring total testosterone, the measurement includes SHBG-bound testosterone, free testosterone and albumin-bound testosterone. SHBG binds strongly to testosterone, while free testosterone and albumin-bound testosterone are in equilibrium. Compound IV has been shown to increase SHBG and reduce free testosterone to levels below those achieved by LHRH agonists or LHRH antagonists or achieved by surgical castration.

  In men with castration resistant prostate cancer who have been effectively treated with ADT and who show serum PSA progression at enrollment in this study, a study (Study 3) was conducted and compounds against serum PSA progression The effect of IV was evaluated. The study consisted of one dose arm containing 9 subjects.

  A summary of the study details is shown in FIG.

  The purpose of this study was to (a) evaluate the effect of Compound IV (serum PSA response and serum PSA progression) on serum PSA levels in men with castration-resistant prostate cancer who continue on androgen deprivation therapy; b) assessing the effect of compound IV on serum free testosterone levels; (c) assessing the effect of compound IV on SHBG; (d) assessing the effect of compound IV on serum total testosterone; (e) Assessing the effect of Compound IV on the development of new bone metastases; (f) assessing the effect of Compound IV on soft tissue metastases (visceral and lymph nodes); and (g) receiving androgen deprivation therapy To evaluate the safety and tolerability of Compound IV in men with prostate cancer It was.

  Subjects are 12 male subjects over 18 years of age with castration resistant prostate cancer who have been treated with androgen deprivation therapy (chemical or surgical castration) for at least 6 months, and androgen depletion At enrollment in the study after initiation of therapy (ADT), have> 2 ng / mL serum PSA or> 2 ng / mL serum PSA and a 25% increase above the lowest point. Subjects continued androgen depletion therapy throughout the study.

To meet the definition of castration resistance, the subject must: (1) have an undetectable range of serum PSA in two consecutive periods, followed by a rise in serum PSA to> 2 ng / ml while undergoing appropriate androgen deprivation therapy; (2) with castration level of serum total testosterone (<50 ng / dL); (3) with history of serum PSA response after initiation of ADT (serum PSA response is <10 ng / mL or undetectable level of serum PSA ( (4) elevation of serum PSA and> 2 ng / mL serum in two consecutive assessments separated by at least 2 weeks. Have PSA levels or have serum PSA levels> 2 ng / mL and 25% increase above the lowest point after initiation of androgen deprivation therapy (ADT); To beauty (5) are continuing to androgen deprivation therapy throughout the study.

  The dose selected for the study was 2000 mg of Compound IV. Four Compound IV tablets (500 mg) (2000 mg dose) were administered orally daily. This dose was shown to increase SHBG and lead to a significant reduction in free testosterone more rapidly than the 1000 mg dose. Subjects were given 2000 mg of Compound IV orally daily until the end of the study. Subject's serum PSA increased by at least 25% and 2 ng / mL from the lowest point in two consecutive sample times (approximately 30 days apart) after initiation of treatment with Compound IV Administration was continued until The definition of prostate cancer working group for PSA progression was used (serum PSA increased by at least 25% and 2 ng / mL from the lowest point in two consecutive sampling times after initiation of treatment with Compound IV. ).

  Assessment of serum PSA concentration was performed at baseline and on days 15, 30, and 60 (only one patient had progressed so far before the study was completed).

  The study was terminated before PSA progression was observed for any of the subjects. However, to continue the study, the following protocol is followed: After the subject exhibits serum PSA progression, the subject continues to receive the drug for 30 days and undergoes a follow-up serum PSA assessment. If serum PSA progression is not confirmed at this visit, the subject remains in the study and continues to receive Compound IV. If serum PSA progression is confirmed at this visit, the subject is withdrawn from the study and a visit assessment at the end of the study is performed. A scheduled follow-up visit for the subject will occur 30 days after the last dose of Compound IV.

  Primary endpoint: The proportion of subjects with a 50% drop from baseline in serum PSA (confirmed by a second PSA assessment at least one week later).

  Secondary endpoints: (1) Time to serum PSA progression; (2) Proportion of subjects with ≥90% decline from serum PSA baseline; (3) Change in serum free testosterone levels; (4) SHBG (5) Change in serum total testosterone levels; (6) Change in RECIST criteria from baseline; (7) Proportion of subjects with new bone metastases; (8) New or worsening soft tissue Percentage of subjects with tissue metastasis (visceral and lymph nodes); (9) To assess the safety and tolerability of Compound IV in men with prostate cancer undergoing androgen deprivation therapy.

  Drug delivery and formulation: 500 mg strength tablets formulated with Compound IV tablets, micronized drug substance and 1% w / w SDS.

  A flow chart describing the study procedure can be found in FIG.

result

  Although the study was completed early, of the 12 subjects enrolled in this study, 7 subjects were long enough to have evaluable data on efficacy. All seven subjects showed a reduction in serum PSA from baseline by day 15. In all three subjects exposed to Compound IV for at least 30 days, a> 50% reduction in serum PSA was observed (FIG. 24).

  If the study continues, follow the following protocol: Serum PSA kinetics in men with castration-resistant prostate cancer receiving compound IV and continuing androgen deprivation therapy is the primary outcome of the study, and all subjects To evaluate. A PSA response is defined as a 50% decline from baseline as confirmed by a second PSA value after 4 ± 1 weeks. Estimate the proportion of subjects with a PSA response and calculate an accurate 95% Blyth-Still-Casella confidence interval. This estimate was constructed in subjects in the ITT population. This was done similarly for the proportion of subjects with a> 90% reduction in PSA from baseline. A graphical depiction of the percent change in PSA by the waterfall diagram is presented in FIG.

Effect of Compound IV on SHBG levels and the relationship between SHBG levels and percent free testosterone

In patients not receiving treatment from studies 2 and 5 trials, baseline SHBG is induced approximately 150-700% after 28 days of compound IV therapy (FIG. 27A). SHBG induction correlates strongly with a reduction in free T% [free T (pg / mL) / total T (pg / mL) ^* 100]. Correlation regression shows that about 400% induction of SHBG is associated with about 75% reduction in free T%. Patients who have not received multiple treatments are dense in this range across all doses of Compound IV. Importantly, this strong correlation is maintained in CRPC patients from Study 3 who are concurrently undergoing ADT even when considered from therapy with Compound IV for only 15 days (FIG. 27B). Open symbols represent the baseline (BL) and filled symbols are treated with Compound IV above.

Effect of Compound IV on the percentage of free testosterone (free T%) and the relationship between PSA levels and percentage of free testosterone (free T%)

  Similar to patients not receiving treatment, CRPC patients receiving Compound IV showed a rapid> 50% reduction in free T% (day 15) (FIG. 30). This is in 3 out of 7 patients after treatment with Compound IV for only 2 weeks (filled data points) and in 2 out of 3 patients after 30 days (open data) Point) Consistent with reduction of PSA by more than 50%.

  Subject stop rule: After initiation of treatment with Compound IV, the subject remains in the study when serum PSA in the subject increases by at least 2 ng / mL from the lowest point and 25% from the lowest point. Follow-up serum PSA is taken after 30 days. If the follow-up assessment does not confirm serum PSA progression, the subject remains in the study and continues to receive Compound IV. If follow-up serum PSA progression confirms serum PSA progression, the subject will withdraw from the study and will have a study visit and follow-up visit.

  Serum PSA progression: Serum PSA progression is defined by PCWG2 criteria. The PCWG2 criteria require confirmation of suspected serum PSA progression by assessment after 3-4 weeks of serum PSA levels that have shown potential for progression. The time to PSA progression for the confirmed examples is the time from the start of the study drug to the date of the first PSA level that indicated the possibility of progression. Patients who die during the study are considered failed for PSA progression free survival. The time for a patient who has not progressed (censored patient) is the time from the start of the study drug to the date of the patient's last follow-up. Kaplan-Meier method is used to estimate PSA progression free survival and associated 95% confidence intervals at various time points. If the median is realized, the estimated median of PSA progression free survival is estimated.

  Serum PSA progression (as defined by PCWG2): When there is an initial decline in serum PSA from baseline, serum PSA has an increase of 25% or more from the lowest point and an absolute increase of 2 ng / ml or more. Used as the date that progression occurred, but should be confirmed by the second serum PSA value obtained after more than 3 weeks. If there is no decline in serum PSA from baseline, use when serum PSA has an increase of 25% or more and an absolute increase of 2 ng / ml or more after 12 weeks, but after 3 weeks or more The second serum PSA value obtained should be confirmed.

Further serum PSA analysis Percent change from baseline to all measured time points.
2. Maximum descent at any point in the study (percent change from baseline to bottom point).
3. Duration of response (measured on days with a reduction of at least 50% from baseline).

  Free testosterone: Assess the change in free testosterone levels from baseline to day 15, day 30, day 90 and the end of the study.

Total testosterone: Assess changes in baseline total testosterone levels from day 15 to day 30, day 30, day 90, and the end of the study.
SHBG: Evaluate changes in baseline from baseline to day 15, day 30, day 90, and end of study.

(Example 27)
Compound IV as a secondary hormone therapy for metastatic castration-resistant prostate cancer (mCRPC)

  Compound IV is studied for the proposed indication of secondary hormone therapy for metastatic castration resistant prostate cancer (mCRPC) (Study 6).

  Compound IV has been shown to increase serum SHBG and reduce serum free testosterone to levels below those that have been observed by LHRH agonists or LHRH antagonists or surgical castration. Compared to the leuprolide acetate treatment group, Compound IV group has been shown to have a lower incidence of hot flash adverse events in men with advanced prostate cancer, with decreased bone metabolic markers from baseline I came.

  To study the effect of Compound IV as a secondary hormone therapy on serum PSA levels and serum free testosterone levels in men with metastatic castration resistant prostate cancer who continue on androgen deprivation therapy. The study evaluates the effect of Compound IV on serum PSA response and serum PSA progression in men with mCRPC undergoing ADT by LHRH agonists, LHRH antagonists, or orchiectomy. This study also assesses the risk of VTE for lower doses of Compound IV. Secondary endpoints include serum free testosterone levels, production of androgen precursors in the adrenal gland (DHEA and DHEAS levels), progression-free survival, and bone-related events (SRE).

  A summary of the study details is presented in FIG.

  Study Objectives: (1) To assess the effects of Compound IV (serum PSA response and serum PSA progression) on serum PSA levels in men with metastatic castration-resistant prostate cancer (mCRPC) who are continuing androgen deprivation therapy (2) assessing the effect of compound IV on serum free testosterone levels; (3) assessing the effect of compound IV on serum SHBG; (4) assessing the effect of compound IV on serum total testosterone. (5) assessing the effect of Compound IV on adrenal androgen precursor hormones (DHEA and DHEAS); (6) assessing the effect of Compound IV on the development of new bone metastases; (7) soft tissue metastases ( Assessing the effect of Compound IV on visceral and lymph nodes); (8 Assessing the effect of Compound IV on bone-related events; (9) assessing the effect of Compound IV on bone metabolism markers; and (10) assessing the incidence and frequency of hot flashes in men receiving Compound IV. (11) To assess the safety and tolerability of Compound IV in men with prostate cancer undergoing androgen deprivation therapy (which has been unsuccessful for ADT).

  Seventy-five subjects, including castration resistant prostate cancer patients with evidence of radiographic metastatic disease (Tany-Nany-M1), are enrolled in the study. These subjects have a median life expectancy of less than 20 months, ie, more serious disease than other subjects with advanced prostate cancer enrolled in previous studies. All subjects were previously treated with androgen deprivation therapy (ADT) and responding to ADT and currently have> 2 ng / mL serum PSA or> 2 ng / from the lowest point achieved with ADT Serum PSA that is mL and represents a 25% increase above the lowest point achieved with ADT. Subjects continue ADT throughout the study.

  125 mg of orally administered to each subject until the subject's serum PSA increased by at least 25% and 2 ng / mL from the lowest point in two consecutive serum PSA assessments after initiation of treatment with Compound IV Daily doses of Compound IV, 250 mg of Compound IV, or 500 mg of Compound IV are given.

  Tablets of Compound IV (125 mg and 500 mg) are formulated with micronized Compound IV drug substance and 1% sodium dodecyl sulfate (SDS) and supplied in 50 count high density polyethylene (HDPE) bottles.

  Enrollment in this study will be a 1-cycle (30-day) time lag to enroll the first 25 subjects into the 125 mg Compound IV dose arm. These subjects are evaluated for the incidence of venous thromboembolization events (VTE). The last subject in the 125 mg Compound IV dose arm completed one cycle of therapy (30 days) in this dose arm, at which time there was an acceptable incidence of VTE (less than 3) in this dose arm. When present, enrollment begins in the 250 mg Compound IV dose arm. These subjects are evaluated for the incidence of VTE. All 25 subjects in the 250 mg Compound IV dose arm completed one cycle of therapy (30 days) in this dose arm, at which time the acceptable incidence of VTE in this dose arm (3 Enrollment into the 500 mg Compound IV dose arm (25 subjects) begins.

  A 500 mg dose is expected to increase serum SHBG and result in a significant reduction in serum free testosterone. Lower doses (125 mg and 250 mg) are expected to increase (but to a lesser extent) serum SHBG, and the protocol adds to determining the minimum effective dose of Compound IV that produces a serum PSA response. These doses also have a direct effect in reducing adrenal production of androgen precursors, such as DHEAS and DHEA, which can be utilized by prostate cancer cells to produce testosterone or dihydrotestosterone (DHT). Can have.

  125 mg of compound IV, 250 mg of compound IV, or 500 mg of compound IV, all subjects in the study develop serum PSA progression (serum PSA was sampled two consecutive times after initiation of treatment with compound IV The subject is administered daily until at least 25% and 2 ng / mL increase over the lowest point in time). On day 90, if the subject does not have at least a 50% reduction in serum PSA from baseline and this is confirmed in the second assessment, the subject is withdrawn from the study. The total duration of administration may be greater than 360 days in subjects who do not show serum PSA progression in the study.

  Subjects with serum PSA progression in two consecutive assessments after initiation of treatment with Compound IV will be withdrawn from this study. On day 90, subjects who do not show> 50% reduction in baseline in serum PSA in 2 consecutive samples are withdrawn from the study.

  After the subject shows serum PSA progression, the subject continues to receive the drug for 30 days and undergoes a follow-up serum PSA assessment. If serum PSA progression is not confirmed at this visit, the subject remains in the study and continues to receive Compound IV. If serum PSA progression is confirmed at this visit, the subject is withdrawn from the study and a visit assessment at the end of the study is performed.

  Evaluation of serum total testosterone concentration, serum free testosterone concentration, serum SHGB concentration and serum PSA concentration was performed on days 15, 30 and at two consecutive sampling times after initiation of treatment with Compound IV. Every 30 days until the body serum PSA increases by at least 25% and 2 ng / mL from the lowest point. Bone metabolic markers are assessed at baseline (Day 1), Day 90, and at the end of the study.

  The incidence and frequency of hot flashes are assessed at baseline (Day 1), Days 30, 60, 90 and at the end of the study.

  Abdominal / pelvic CT scans are performed on day 0 and every 90 days until the end of the study to assess tumor progression and soft tissue or visceral metastases.

  Bone scans are performed on day 0 and every 90 days until the end of the study to assess the occurrence of new bone metastases.

  Primary endpoint: proportion of subjects with a 50% drop in serum PSA by day 90 from baseline (confirmed by second serum PSA assessment after 30 days) (with follow-up confirmation by day 120) .

  Secondary endpoints: (1) Time to serum PSA progression; (2) Percentage of subjects with ≥90% decline from serum PSA baseline; (3) ≥30% decline from serum PSA baseline (4) Change in serum free testosterone level; (5) Change in serum SHBG level; (6) Change in serum total testosterone level; (7) Change in DHEA and DHEAS levels; (8) Time to progression (TTP) assessed by RECIST 1.1 (soft tissue) or by PCWG2 (bone metastasis); (9) Progression-free survival assessed by RECIST 1.1 (soft tissue) or by PCWG2 (bone metastasis) Period (PFS); (10) Change in bone metabolism marker level; (11) Incidence and frequency of hot flashes from baseline Change; (12) new or worsening time to SRE; (13) to evaluate the safety and tolerability of Compound IV in men (are unsuccessful for ADT) with prostate cancer.

  To minimize the risk of VTE in this study: (1) Abnormal blood clotting or thrombotic disease (venous or arterial thrombotic events such as stroke history, deep vein thrombosis (DVT), and / or Subjects with a personal or family history of pulmonary embolism (PE) are excluded from the study. (2) <2.5 modified modified protein C response ratio and factor V Leiden mutation, normal <80% antithrombin level,> 7 micromole / liter serum homocysteine level, antiphospholipid Any subject with the presence of either an antibody or a prothrombin gene mutation is excluded from the study. (3) All subjects enrolled in this study are required to take 81 mg of aspirin daily, even if they are not receiving aspirin or other anticoagulant therapy. Although reports on the effectiveness of aspirin in preventing VTE are contradictory, recent literature supports the hypothesis that low dose aspirin is as effective as low molecular weight heparin for VTE prevention. (4) All subjects enrolled in the study are assessed for their risk of VTE using the Caprini venous thromboembolism risk assessment tool. The subject's risk of VTE is assessed at each visit and appropriate prophylaxis is initiated if a change in risk should be identified during the study. More specifically, subjects who experience a high risk for VTE, such as the need for immobilization, fractures of long bones, acute trauma, hospitalization, surgery, irradiation, etc., are closely monitored. The subject is treated with prophylactic anticoagulant therapy if instructed and, if indicated, appropriate precautions to minimize the subject's risk for VTE. (5) All thromboembolic events or cardiovascular SAEs are considered to be at least associated with Compound IV therapy and are included in the study suspension rule regardless of investigator authority.

Subjects accepted for this study must have the following:
-Including castration resistant prostate cancer patients with evidence of radiographic metastatic disease (Tany-Nany-M1).
-Treated with ADT (chemical or surgical) for at least 6 months.
-Has castration level of serum total testosterone (<50 ng / dL).
-Has a history of serum PSA response to ADT. Serum PSA response is at least 90% reduction in serum PSA from serum PSA value before initiating treatment towards <10 ng / mL or undetectable level of serum PSA (<0.2 ng / mL) is there.
-An elevated serum PSA and serum PSA level> 2 ng / mL or at the lowest point> 2 ng / mL serum PSA level from ADT in two consecutive assessments at least 2 weeks apart And has a 25% increase above the lowest point from ADT. If the subject has been treated with an antiandrogen and shows serum PSA progression, the subject is required to stop the antiandrogen. When the antiandrogen is stopped (antiandrogen stop), the subject should have at least 2 elevated serum PSA levels at least 2 weeks apart.
-Continued ADT throughout this study.
-Consent to take 81 mg of aspirin daily throughout the period of subject participation in this study and for 30 days after completion of Compound IV administration if the subject has not already received anticoagulation therapy or aspirin I have to do it.
A flow chart describing the study procedure is presented in FIG.

  Clinic visits: Potential study participants visit clinical research facilities as needed for screening evaluation. Subjects will conduct study-related visits at enrollment (Day 1) and on Days 15 and 30. Subjects revisit the clinic every 30 days from day 30 to day 90. Those subjects with at least a 50% reduction in serum PSA from baseline remained in the study, and after initiation of treatment with Compound IV, the subject's serum PSA increased by at least 25% and 2 ng / mL from the lowest point. Every 30 days from day 90 to day 360, and then every 90 days after day 360 until findings are confirmed by a second serum PSA assessment, or the subject's disease progresses (CT or bone scan) Revisit the clinic.

  Follow-up visits will occur 30 days after the last dose.

  A subject meets the criteria for disease progression when serum PSA in the subject increases by at least 2 ng / mL and 25% from the lowest point after initiation of treatment with Compound IV. However, subjects should remain in the study until a follow-up serum PSA for confirmation is taken after 30 days. If follow-up assessment does not confirm serum PSA progression, the subject should remain in the study and continue to receive Compound IV. If follow-up serum PSA confirms serum PSA progression, the subject should withdraw from the study and should have a study visit and follow-up visit.

  On day 90, any subject who does not show a reduction in serum PSA of> 50% from baseline will be evaluated for confirmation of serum PSA 30 days after day 90. Subjects should continue study medication after day 90 and until evaluation for confirmation. If the serum PSA is reduced by> 50% from baseline in the validation assessment, the subject remains in the study and continues to receive Compound IV. If the serum PSA does not decrease> 50% from baseline in the validation assessment, the subject is withdrawn from the study due to lack of efficacy. Visits at the end of the study and follow-up visits should be conducted.

  Subjects exhibiting evidence of disease progression must be withdrawn from the study, as evidenced by two new lesions observed with CT imaging (RECIST 1.1 criteria) or bone scan.

Efficacy analysis, serum PSA, and serum PSA response Serum PSA response at day 90 is the primary outcome and will be assessed for all subjects. Serum PSA response is defined as> 50% decline from baseline as confirmed by a second serum PSA value within 14 days. The primary objective is to assess serum PSA kinetics in men with mCRPC continuing ADT given Compound IV.

  Estimate the proportion of subjects with serum PSA response and calculate an accurate 95% Blyth-Still-Casella confidence interval. [20]

This estimation is made at:
(1) subjects in the intended treatment (ITT) population, and subjects who were considered non-responders and dropped out prior to the 90 day assessment, and (2) subjects in the efficacy evaluable (EE) population body.

  A graphical depiction of the percent change in serum PSA from baseline to each PSA assessment (with emphasis on day 90 assessment) is from the waterfall diagram below.

  The percentage change from baseline to each evaluation in serum PSA is calculated, the y-axis represents the percentage change, the x-axis has a bar for each individual subject, and the order of these bars is the smallest percentage in serum PSA Is the largest percentage decline from a decrease in, which can potentially be an increase for some subject (s).

Serum PSA progression Serum PSA progression is defined by the PCWG2 criteria shown below. [21] PCWG2 criteria require confirmation of suspected progression of serum PSA by assessment after 3-4 weeks of serum PSA levels that have shown the likelihood of progression.

  PSA progression free survival is estimated by the Kaplan-Meier method and an associated 95% confidence interval is constructed. A subject's progression-free survival is the time from the first dose of the study to the first date associated with confirmed progression or death. Subjects who have dropped out or become unable to follow up are discontinued on the date of the subject's last contact. If the median is realized, the estimated median of PSA progression free survival is estimated.

  The time to PSA progression is estimated by Kaplan-Meier method and an associated 95% confidence interval is constructed. The time to subject progression is the time from the first dose of study drug to the first date associated with the confirmed progression. Subjects who die before progression are discontinued on the day of death. Subjects who have dropped out or become unable to follow up are discontinued on the date of the subject's last contact. If the median is realized, an estimated median time to progression is estimated.

If the median is realized, an estimated median serum PSA progression free survival is estimated.
Serum PSA progression (as defined by PCWG2):

  If there is an initial decline in serum PSA from baseline, use when serum PSA has an increase of 25% or more from the lowest point and an absolute increase of 2 ng / ml or more as the date that progression has occurred, It should be confirmed by the second serum PSA value obtained after more than 3 weeks.

  If there is no decline in serum PSA from baseline, use when serum PSA has an increase of 25% or more and an absolute increase of 2 ng / ml or more after 12 weeks, but after 3 weeks or more The second serum PSA value obtained should be confirmed.

Evaluate changes in serum free testosterone levels from serum free testosterone baseline to each scheduled assessment. If the data is determined to be normally distributed, changes from baseline to each scheduled evaluation and percentage changes are tested using a paired t-test. Separately, an exact Wilcoxon signed rank test is used to compare changes from baseline to each scheduled evaluation and percentage changes. Do this until the number of subjects is reduced to less than 5. A mixed model repeated measures model may be used to investigate changes over time in each arm. The subject is considered to have a random effect.

Serum SHBG
Assess the change in serum SHBG levels from baseline to each scheduled assessment. If the data is determined to be normally distributed, changes from baseline to each scheduled evaluation and percentage changes are tested using a paired t-test. Separately, an exact Wilcoxon signed rank test is used to compare changes from baseline to each scheduled evaluation and percentage changes. Do this until the number of subjects is reduced to less than 5. A mixed model repeated measures model may be used to investigate changes over time in each arm. The subject is considered to have a random effect.

Serum total testosterone Evaluate changes in serum testosterone levels from baseline to each scheduled assessment. If the data is determined to be normally distributed, changes from baseline to each scheduled evaluation and percentage changes are tested using a paired t-test. Separately, an exact Wilcoxon signed rank test is used to compare changes from baseline to each scheduled evaluation and percentage changes. Do this until the number of subjects is reduced to less than 5. A mixed model repeated measures model may be used to investigate changes over time in each arm. The subject is considered to have a random effect.

DHEA and DHEAS
Evaluate the change from baseline to each scheduled assessment at both DHEA and DHEAS levels. If the data is determined to be normally distributed, changes from baseline to each scheduled evaluation and percentage changes are tested using a paired t-test. Separately, an exact Wilcoxon signed rank test is used to compare changes from baseline to each scheduled evaluation and percentage changes. Do this until the number of subjects is reduced to less than 5. A mixed model repeated measures model may be used to investigate changes over time in each arm. The subject is considered to have a random effect.

Disease progression, soft tissue progression (RECIST 1.1)
Progress and response are assessed using the RECIST 1.1 criteria. Estimate both TTP and PFS as defined below in the subject.
Progression free survival (PFS) is estimated by the Kaplan-Meier method and an associated 95% confidence interval is constructed. A subject's progression-free survival is the time from the first dose of study drug until the evidence of progression or death is recorded. Subjects who have dropped out or become unable to follow up are discontinued on the date of the subject's last contact.
If the median is realized, the estimated median of PFS is estimated.
Time to progression (TTP) is estimated by Kaplan-Meier method and an associated 95% confidence interval is constructed. The time to progression of a subject is the time from the first dose of study drug until evidence of progression is recorded. Subjects who die before progression are discontinued on the day of death. Subjects who have dropped out or become unable to follow up are discontinued on the date of the subject's last contact.
If the median is realized, an estimated median time to progression is estimated.
Determine the subject's best response, estimate ratios in CR, PR (PR + CR), SD, and PD, and calculate an accurate 95% Blyth-Still-Casella confidence interval.

Bone Progression In subjects that exhibit measurable metastases from bone scans, both TTP and PFS are estimated as defined below.
Progression free survival (PFS) is estimated by the Kaplan-Meier method and an associated 95% confidence interval is constructed. A subject's progression-free survival is the time from the first dose of study drug until the evidence of progression or death is recorded. Subjects who have dropped out or become unable to follow up are discontinued on the date of the subject's last contact.
If the median is realized, the estimated median of PFS is estimated.
Time to progression (TTP) is estimated by Kaplan-Meier method and an associated 95% confidence interval is constructed. The time to progression of a subject is the time from the first dose of study drug until evidence of progression is recorded. Subjects who die before progression are discontinued on the day of death. Subjects who have dropped out or become unable to follow up are discontinued on the date of the subject's last contact.
If the median is realized, an estimated median time to progression is estimated.
Determine the subject's best response, estimate ratios in CR, PR (PR + CR), SD, and PD, and calculate an accurate 95% Blyth-Still-Casella confidence interval.

Bone Metabolic Markers The change from baseline to each scheduled evaluation for each bone metabolic marker in each treatment group is evaluated. Mean, standard deviation, median, minimum, and maximum bone metabolism marker levels are summarized at each of these time points. The changes from baseline to each time point are also summarized. A paired t test tests whether the change from baseline to each time point is significantly different from 0 in the arm. This is done for the ITT population. This is done for the observed case and LOCF analysis is also performed. A mixed model repeated measures model may be used to investigate changes over time in each arm. The subject is considered to have a random effect.

Hot flashes Subjects are asked about hot flash events (incidence and frequency). The specific questions asked and definitions of severity are included in Appendix D.
The proportion of subjects experiencing any hot flashes is tabulated for the treatment group. The proportion of subjects experiencing weekly or more hot flashes is tabulated for the treatment group. The proportion of subjects experiencing daily or more hot flashes is aggregated for the treatment group. The proportion of subjects experiencing multiple hot flashes per day is counted for the treatment group.
The proportion of subjects who experience moderate to very severe hot flashes is tabulated for the treatment group. The proportion of subjects who experience severe to very severe hot flashes is tabulated for the treatment group.
The shift table represents the change in severity from baseline to each assessment.

Bone-related events (SRE)
SRE is a composite endpoint that includes pathological fractures, spinal cord compression, and bone irradiation or surgery.
Time without bone-related events is estimated by the Kaplan-Meier method and an associated 95% confidence interval is constructed. The time without the subject's bone-related event is the time from the first dose of the research drug until the evidence of a new SRE or death is recorded. Subjects who have dropped out or become unable to follow up are discontinued on the date of the subject's last contact. This analysis is repeated under the definition of an event as either new or worsening SRE or death.
If the median is realized, an estimated median of time (new or worsening SRE) without bone related events is estimated.
The time to new bone-related event is estimated by Kaplan-Meier method and an associated 95% confidence interval is constructed. The time to the subject's new bone-related event is the time from the first dose of the research drug until evidence of the new bone-related event is recorded. Subjects who die before a new bone-related event are discontinued on the day of death. Subjects who have dropped out or become unable to follow up are discontinued on the date of the subject's last contact. This analysis is repeated under the definition of an event as either a new or worsening SRE.
If the median is realized, an estimated median of time to new SRE (new or worsening SRE) is estimated.

(Example 28)
Secondary hormone therapy for metastatic castration resistant prostate cancer (mCRPC)

  Estradiol, ethinyl estradiol, steroidal estrogen agonists and nonsteroidal estrogen agonists are studied for the proposed indication of secondary hormone therapy for metastatic castration resistant prostate cancer (mCRPC) (Study 6).

  Estradiol, ethinyl estradiol, steroidal estrogen agonists and non-steroidal estrogen agonists have increased serum SHBG and serum free testosterone has been observed below levels that have been observed with LHRH agonists or LHRH antagonists, or by surgical castration Reduce to a level below the specified level. Compared to the leuprolide acetate treatment group, estradiol, ethinyl estradiol, steroidal estrogen agonists and nonsteroidal estrogen agonists show decreased bone metabolic markers from baseline and are hot flash adverse in men with advanced prostate cancer Has a lower incidence of events.

  Estradiol, ethinyl estradiol, steroidal estrogen agonists and nonsteroidal estrogen agonists as secondary hormone therapy for serum PSA levels and serum free testosterone levels in men with metastatic castration resistant prostate cancer who continue on androgen deprivation therapy Study the effects of The study investigated the effects of estradiol, ethinyl estradiol, steroidal estrogen agonists and nonsteroidal estrogen agonists on serum PSA response and serum PSA progression in men with mCRPC undergoing LHRH agonists, LHRH antagonists, or ADT by orchiectomy To evaluate. This study also evaluates the VTE risk of lower doses of estradiol, ethinyl estradiol, steroidal estrogen agonists and nonsteroidal estrogen agonists. Secondary endpoints include serum free testosterone levels, production of androgen precursors in the adrenal gland (DHEA and DHEAS levels), progression-free survival, and bone-related events (SRE).

  Objectives of the study: (1) Estradiol, ethinyl estradiol, steroidal estrogen agonists and nonsteroidal estrogen agonists for serum PSA levels in men with metastatic castration resistant prostate cancer (mCRPC) who continue on androgen deprivation therapy (2) Evaluating the effects of estradiol, ethinyl estradiol, steroidal and non-steroidal estrogen agonists on serum free testosterone levels; (3) Serum To evaluate the effects of estradiol, ethinyl estradiol, steroidal and nonsteroidal estrogen agonists on SHBG (4) assessing the effects of estradiol, ethinyl estradiol, steroidal estrogen agonists and nonsteroidal estrogen agonists on serum total testosterone; (5) estradiol, ethinyl estradiol, steroids on adrenal androgen precursor hormones (DHEA and DHEAS); Evaluating the effects of sex estrogen agonists and nonsteroidal estrogen agonists; (6) evaluating the effects of estradiol, ethinyl estradiol, steroidal estrogen agonists and nonsteroidal estrogen agonists on the development of new bone metastases; (7 ) Estradiol, ethinyl estradiol for soft tissue metastases (visceral and lymph nodes) Evaluating the effects of steroidal and nonsteroidal estrogen agonists; (8) evaluating the effects of estradiol, ethinyl estradiol, steroidal estrogen agonists and nonsteroidal estrogen agonists on bone-related events; (9) bone Assessing the effects of estradiol, ethinyl estradiol, steroidal and nonsteroidal estrogen agonists on metabolic markers; (10) hot flashes in men receiving estradiol, ethinyl estradiol, steroidal estrogen agonists and nonsteroidal estrogen agonists Assessing the incidence and frequency of (11) undergoing androgen deprivation therapy To assess the safety and tolerability of estradiol, ethinyl estradiol, steroidal and non-steroidal estrogen agonists in men with prostate cancer (which has been unsuccessful for ADT).

  Seventy-five subjects, including castration resistant prostate cancer patients with evidence of radiographic metastatic disease (Tany-Nany-M1), are enrolled in the study. These subjects have a median life expectancy of less than 20 months, ie, more serious disease than other subjects with advanced prostate cancer enrolled in previous studies. All subjects were previously treated with androgen deprivation therapy (ADT) and responding to ADT and currently have> 2 ng / mL serum PSA or> 2 ng / from the lowest point achieved with ADT Serum PSA that is mL and represents a 25% increase above the lowest point achieved with ADT. Subjects continue ADT throughout the study.

  Subject's serum PSA increased by at least 25% and 2 ng / mL from the lowest point in two consecutive serum PSA assessments after initiation of treatment with estradiol, ethinyl estradiol, steroidal estrogen agonist or nonsteroidal estrogen agonist Until then, each subject receives a daily dose of 125 mg, 250 mg or 500 mg of estradiol, ethinyl estradiol, steroidal estrogen agonist or nonsteroidal estrogen agonist administered orally.

  A 500 mg dose is expected to increase serum SHBG and result in a significant reduction in serum free testosterone. Lower doses (125 mg and 250 mg) are expected to increase (but to a lesser extent) serum SHBG, and the protocol includes estradiol, ethinyl estradiol, steroidal estrogen agonists or nonsteroidal estrogens that produce a serum PSA response Add to determine the minimum effective dose of the agonist. These doses also have a direct effect in reducing adrenal production of androgen precursors, such as DHEAS and DHEA, that can be utilized by prostate cancer cells to produce testosterone or dihydrotestosterone (DHT). Can do.

  125 mg, 250 mg, 500 mg estradiol, ethinyl estradiol, steroidal estrogen agonist or non-steroidal estrogen agonist, all subjects in the study develop serum PSA progression (serum PSA is estradiol, ethinyl estradiol, steroidal estrogen agonist Or, after the start of treatment with a nonsteroidal estrogen agonist, the subject is dosed daily until 2 consecutive sampling times have increased by at least 25% and 2 ng / mL above the lowest point. On day 90, if the subject does not have at least a 50% reduction in serum PSA from baseline and this is confirmed in the second assessment, the subject is withdrawn from the study. The total duration of administration may be greater than 360 days in subjects who do not show serum PSA progression in the study.

  Evaluation of serum total testosterone concentration, serum free testosterone concentration, serum SHGB concentration, and serum PSA concentration was performed at 15 days, 30 days, and at two consecutive sampling times after initiation of treatment with Compound IV. Every 30 days until the serum PSA increases by at least 25% and 2 ng / mL from the lowest point. Bone metabolic markers are assessed at baseline (Day 1), Day 90, and at the end of the study.

  The incidence and frequency of hot flashes are assessed at baseline (Day 1), Days 30, 60, 90 and at the end of the study.

  Abdominal / pelvic CT scans are performed on day 0 and every 90 days until the end of the study to assess tumor progression and soft tissue or visceral metastases.

  Bone scans are performed on day 0 and every 90 days until the end of the study to assess the occurrence of new bone metastases.

  Primary endpoint: proportion of subjects with a 50% drop in serum PSA by day 90 from baseline (confirmed by second serum PSA assessment after 30 days) (with follow-up confirmation by day 120) .

  Secondary endpoints: (1) Time to serum PSA progression; (2) Percentage of subjects with ≥90% decline from serum PSA baseline; (3) ≥30% decline from serum PSA baseline (4) Change in serum free testosterone level; (5) Change in serum SHBG level; (6) Change in serum total testosterone level; (7) Change in DHEA and DHEAS levels; (8) Time to progression (TTP) assessed by RECIST 1.1 (soft tissue) or PCWG2 (bone metastasis); (9) Progression free survival (PFS) assessed by RECIST 1.1 (soft tissue) or PCWG2 (bone metastasis) (10) changes in bone metabolic marker levels; (11) changes in the incidence and frequency of hot flashes from baseline; (12) Time to shelf or worsening SRE; (13) to evaluate the safety and tolerability of Compound IV in men (are unsuccessful for ADT) with prostate cancer.

Evaluate changes in serum free testosterone levels from serum free testosterone baseline to each scheduled assessment. If the data is determined to be normally distributed, changes from baseline to each scheduled evaluation and percentage changes are tested using a paired t-test. Separately, an exact Wilcoxon signed rank test is used to compare changes from baseline to each scheduled evaluation and percentage changes. Do this until the number of subjects is reduced to less than 5. A mixed model repeated measures model may be used to investigate changes over time in each arm. The subject is considered to have a random effect.

Serum SHBG
Assess the change in serum SHBG levels from baseline to each scheduled assessment. If the data is determined to be normally distributed, changes from baseline to each scheduled evaluation and percentage changes are tested using a paired t-test. Separately, an exact Wilcoxon signed rank test is used to compare changes from baseline to each scheduled evaluation and percentage changes. Do this until the number of subjects is reduced to less than 5. A mixed model repeated measures model may be used to investigate changes over time in each arm. The subject is considered to have a random effect.

Serum total testosterone Evaluate changes in serum testosterone levels from baseline to each scheduled assessment. If the data is determined to be normally distributed, changes from baseline to each scheduled evaluation and percentage changes are tested using a paired t-test. Separately, an exact Wilcoxon signed rank test is used to compare changes from baseline to each scheduled evaluation and percentage changes. Do this until the number of subjects is reduced to less than 5. A mixed model repeated measures model may be used to investigate changes over time in each arm. The subject is considered to have a random effect.

DHEA and DHEAS
Assess the change from baseline to each scheduled assessment at both DHEA and DHEAS levels. If the data is determined to be normally distributed, changes from baseline to each scheduled evaluation and percentage changes are tested using a paired t-test. Separately, an exact Wilcoxon signed rank test is used to compare changes from baseline to each scheduled evaluation and percentage changes. Do this until the number of subjects is reduced to less than 5. A mixed model repeated measures model may be used to investigate changes over time in each arm. The subject is considered to have a random effect.

Disease progression, soft tissue progression (RECIST 1.1)
Progress and response are assessed using the RECIST 1.1 criteria. Estimate both TTP and PFS as defined below in the subject.
Progression free survival (PFS) is estimated by the Kaplan-Meier method and an associated 95% confidence interval is constructed. A subject's progression-free survival is the time from the first dose of study drug until the evidence of progression or death is recorded. Subjects who have dropped out or become unable to follow up are discontinued on the date of the subject's last contact.
If the median is realized, the estimated median of PFS is estimated.
Time to progression (TTP) is estimated by Kaplan-Meier method and an associated 95% confidence interval is constructed. The time to progression of a subject is the time from the first dose of study drug until evidence of progression is recorded. Subjects who die before progression are discontinued on the day of death. Subjects who have dropped out or become unable to follow up are discontinued on the date of the subject's last contact.
If the median is realized, an estimated median time to progression is estimated.
Determine the subject's best response, estimate ratios in CR, PR (PR + CR), SD, and PD, and calculate an accurate 95% Blyth-Still-Casella confidence interval.

Bone Progression In subjects that exhibit measurable metastases from bone scans, both TTP and PFS are estimated as defined below.
Progression free survival (PFS) is estimated by the Kaplan-Meier method and an associated 95% confidence interval is constructed. A subject's progression-free survival is the time from the first dose of study drug until the evidence of progression or death is recorded. Subjects who have dropped out or become unable to follow up are discontinued on the date of the subject's last contact.
If the median is realized, the estimated median of PFS is estimated.
Time to progression (TTP) is estimated by Kaplan-Meier method and an associated 95% confidence interval is constructed. The time to progression of a subject is the time from the first dose of study drug until evidence of progression is recorded. Subjects who die before progression are discontinued on the day of death. Subjects who have dropped out or become unable to follow up are discontinued on the date of the subject's last contact.
If the median is realized, an estimated median time to progression is estimated.
Determine the subject's best response, estimate ratios in CR, PR (PR + CR), SD, and PD, and calculate an accurate 95% Blyth-Still-Casella confidence interval.

Bone Metabolic Markers The change from baseline to each scheduled evaluation for each bone metabolic marker in each treatment group is evaluated. Mean, standard deviation, median, minimum, and maximum bone metabolism marker levels are summarized at each of these time points. The changes from baseline to each time point are also summarized. A paired t test tests whether the change from baseline to each time point is significantly different from 0 in the arm. This is done for the ITT population. This is done for the observed case and LOCF analysis is also performed. A mixed model repeated measures model may be used to investigate changes over time in each arm. The subject is considered to have a random effect.

Hot flashes Subjects are asked about hot flash events (incidence and frequency). The specific questions asked and definitions of severity are included in Appendix D.
The proportion of subjects experiencing any hot flashes is tabulated for the treatment group. The proportion of subjects experiencing weekly or more hot flashes is tabulated for the treatment group. The proportion of subjects experiencing daily or more hot flashes is aggregated for the treatment group. The proportion of subjects experiencing multiple hot flashes per day is counted for the treatment group.
The proportion of subjects who experience moderate to very severe hot flashes is tabulated for the treatment group. The proportion of subjects who experience severe to very severe hot flashes is tabulated for the treatment group.
The shift table represents the change in severity from baseline to each assessment.
Bone-related events (SRE)
SRE is a composite endpoint that includes pathological fractures, spinal cord compression, and bone irradiation or surgery.
Time without bone-related events is estimated by the Kaplan-Meier method and an associated 95% confidence interval is constructed. The time without the subject's bone-related event is the time from the first dose of the research drug until the evidence of a new SRE or death is recorded. Subjects who have dropped out or become unable to follow up are discontinued on the date of the subject's last contact. This analysis is repeated under the definition of an event as either new or worsening SRE or death.
If the median is realized, an estimated median of time (new or worsening SRE) without bone related events is estimated.
The time to new bone-related event is estimated by Kaplan-Meier method and an associated 95% confidence interval is constructed. The time to the subject's new bone-related event is the time from the first dose of the research drug until evidence of the new bone-related event is recorded. Subjects who die before a new bone-related event are discontinued on the day of death. Subjects who have dropped out or become unable to follow up are discontinued on the date of the subject's last contact. This analysis is repeated under the definition of an event as either a new or worsening SRE.

  If the median is realized, an estimated median of time to new SRE (new or worsening SRE) is estimated.

  While particular features of the invention have been illustrated and described herein, many modifications, substitutions, changes, and equivalents will now occur to those skilled in the art. Accordingly, it is understood that the appended claims are intended to cover all such modifications and changes as fall within the true spirit of the invention.

Claims (39)

Castration resistant prostate cancer comprising administering a therapeutically effective amount of a compound of formula I or an isomer thereof, a pharmaceutically acceptable salt, a pharmaceutical, a polymorph, a hydrate, or any combination thereof. CRPC) and methods for treating, suppressing, reducing the incidence, reducing the severity, inhibiting progression, or increasing the survival of men with castration-resistant prostate cancer
[Where:
Y is C (O) or CH ₂ ;
R ₁ and R ₂ are independently hydrogen, halogen, hydroxyl, alkoxy, cyano, nitro, CF ₃ , N (R) ₂ , sulfonamide, SO ₂ R, alkyl, haloalkyl, aryl, O—Alk—NR _5. R ₆ or O-Alk-heterocycle, which is a 3-7 membered substituted or unsubstituted heterocyclic ring, optionally aromatic,
R ₃ , R ₄ are independently hydrogen, halogen, hydroxyalkyl, hydroxyl, alkoxy, cyano, nitro, CF ₃ , NHCOR, N (R) ₂ , sulfonamide, SO ₂ R, alkyl, haloalkyl, aryl or protected The hydroxyl being
R is alkyl, hydrogen, haloalkyl, dihaloalkyl, trihaloalkyl, CH ₂ F, CHF ₂ , CF ₃ , CF ₂ CF ₃ , aryl, phenyl, halogen, alkenyl, CN, NO ₂ , or OH;
R ₅ and R ₆ are independently hydrogen, phenyl, an alkyl group of 1-6 carbon atoms, 3-7 membered cycloalkyl, 3-7 membered heterocycle, 5-7 membered aryl, or R ₅ And R ₆ together with the nitrogen atom form a 3-7 membered ring,
j and k are independently 1 to 4,
Alk is a linear alkyl of 1-7 carbons, a branched alkyl of 1-7 carbons, or a cyclic alkyl of 3-8 carbons]. Said compound of formula I is
The method of claim 1, wherein the method is selected from: 2. The method of claim 1, wherein the compound of formula I is compound IV.
  The method of claim 1, wherein the castration resistant prostate cancer (CRPC) is metastatic CRPC (mCRPC).   The method of claim 1, wherein the castration is chemical or surgical (orchiectomy).   2. The method of claim 1, wherein the subject has high or increased prostate specific antigen (PSA) levels.   The method of claim 1, wherein the subject further receives androgen deprivation therapy (ADT).   2. The method of claim 1, wherein the administering step of the compound does not cause side effects associated with androgen deprivation therapy (ADT).   9. The method of claim 8, wherein the side effect is selected from the group consisting of hot flashes, gynecomastia, increased body fat, decreased bone mass, decreased bone mineral density, and increased risk of fracture.   2. The compound or isomer, pharmaceutically acceptable salt, pharmaceutical, hydrate or any combination thereof is administered at a dose of 125 mg per day, 250 mg per day or 500 mg per day. the method of. Castration resistant prostate cancer (CRPC) comprising administering a therapeutically effective amount of a compound of formula I or an isomer thereof, a pharmaceutically acceptable salt, a pharmaceutical, a hydrate, or any combination thereof. Method for lowering serum PSA levels in an affected male subject
[Where:
Y is C (O) or CH ₂ ;
R ₁ and R ₂ are independently hydrogen, halogen, hydroxyl, alkoxy, cyano, nitro, CF ₃ , N (R) ₂ , sulfonamide, SO ₂ R, alkyl, haloalkyl, aryl, O—Alk—NR _5. R ₆ or O-Alk-heterocycle, which is a 3-7 membered substituted or unsubstituted heterocyclic ring, optionally aromatic,
R ₃ , R ₄ are independently hydrogen, halogen, hydroxyalkyl, hydroxyl, alkoxy, cyano, nitro, CF ₃ , NHCOR, N (R) ₂ , sulfonamide, SO ₂ R, alkyl, haloalkyl, aryl or protected The hydroxyl being
R is alkyl, hydrogen, haloalkyl, dihaloalkyl, trihaloalkyl, CH ₂ F, CHF ₂ , CF ₃ , CF ₂ CF ₃ , aryl, phenyl, halogen, alkenyl, CN, NO ₂ , or OH;
R ₅ and R ₆ are independently hydrogen, phenyl, an alkyl group of 1-6 carbon atoms, 3-7 membered cycloalkyl, 3-7 membered heterocycle, 5-7 membered aryl, or R ₅ And R ₆ together with the nitrogen atom form a 3-7 membered ring,
j and k are independently 1 to 4,
Alk is a linear alkyl of 1-7 carbons, a branched alkyl of 1-7 carbons, or a cyclic alkyl of 3-8 carbons]. Said compound of formula I is
The method of claim 11, selected from: 12. The method of claim 11, wherein the compound of formula I is compound IV.
  The method of claim 11, wherein the castration resistant prostate cancer (CRPC) is metastatic CRPC (mCRPC).   12. The method of claim 11, wherein the subject further receives androgen deprivation therapy (ADT).   12. The method of claim 11, wherein the administering step of the compound does not cause side effects associated with androgen deprivation therapy (ADT).   17. The method of claim 16, wherein the side effect is selected from the group consisting of hot flashes, gynecomastia, increased body fat, decreased bone mass, decreased bone mineral density, and increased risk of fracture.   12. The compound or isomer, pharmaceutically acceptable salt, pharmaceutical, hydrate or any combination thereof is administered at a dose of 125 mg per day, 250 mg per day or 500 mg per day. the method of. Castration resistant prostate cancer comprising administering a therapeutically effective amount of a compound of formula I or an isomer thereof, a pharmaceutically acceptable salt, a pharmaceutical, a polymorph, a hydrate, or any combination thereof. Of reducing serum testosterone levels in a male subject suffering from CRPC)
[Where:
Y is C (O) or CH ₂ ;
R ₁ and R ₂ are independently hydrogen, halogen, hydroxyl, alkoxy, cyano, nitro, CF ₃ , N (R) ₂ , sulfonamide, SO ₂ R, alkyl, haloalkyl, aryl, O—Alk—NR _5. R ₆ or O-Alk-heterocycle, which is a 3-7 membered substituted or unsubstituted heterocyclic ring, optionally aromatic,
R ₃ , R ₄ are independently hydrogen, halogen, hydroxyalkyl, hydroxyl, alkoxy, cyano, nitro, CF ₃ , NHCOR, N (R) ₂ , sulfonamide, SO ₂ R, alkyl, haloalkyl, aryl or protected The hydroxyl being
R is alkyl, hydrogen, haloalkyl, dihaloalkyl, trihaloalkyl, CH ₂ F, CHF ₂ , CF ₃ , CF ₂ CF ₃ , aryl, phenyl, halogen, alkenyl, CN, NO ₂ , or OH;
R ₅ and R ₆ are independently hydrogen, phenyl, an alkyl group of 1-6 carbon atoms, 3-7 membered cycloalkyl, 3-7 membered heterocycle, 5-7 membered aryl, or R ₅ And R ₆ together with the nitrogen atom form a 3-7 membered ring,
j and k are independently 1 to 4,
Alk is a linear alkyl of 1-7 carbons, a branched alkyl of 1-7 carbons, or a cyclic alkyl of 3-8 carbons]. Said compound of formula I is
20. The method of claim 19, wherein the method is selected from: 20. A method according to claim 19, wherein the compound of formula I is compound IV.
  20. The method of claim 19, wherein the castration resistant prostate cancer (CRPC) is metastatic CRPC (mCRPC).   20. The method of claim 19, wherein the serum testosterone level is total serum testosterone level, free serum testosterone level, percent serum free testosterone (free T%), or a combination thereof.   21. The method of claim 19, wherein the subject has elevated or increased prostate specific antigen (PSA) levels.   20. The method of claim 19, wherein the subject further receives androgen deprivation therapy (ADT).   21. The method of claim 19, wherein the subject further receives a selective estrogen receptor modulator (SERM) ligand.   20. The method of claim 19, wherein the serum testosterone is reduced to less than about 25 ng / dL, less than 10 ng / dL, less than 5 ng / dL, or less than 1 ng / dL.   20. The method of claim 19, wherein the serum free testosterone percent (T% free) is reduced to less than about 1%, less than 0.5%, less than 0.25%, and less than 0.05%.   20. The method of claim 19, wherein the administering step of the compound does not cause side effects associated with androgen deprivation therapy (ADT).   30. The method of claim 29, wherein the side effect is selected from the group consisting of hot flashes, gynecomastia, increased body fat, decreased bone mass, decreased bone mineral density, and increased risk of fracture.   20. The compound or isomer, pharmaceutically acceptable salt, pharmaceutical, hydrate or any combination thereof is administered at a dose of 125 mg per day, 250 mg per day or 500 mg per day. the method of. Castration resistant prostate cancer comprising administering a therapeutically effective amount of a compound of formula I or an isomer thereof, a pharmaceutically acceptable salt, a pharmaceutical, a polymorph, a hydrate, or any combination thereof. Method for increasing serum levels of sex hormone or steroid hormone binding globulin (SHBG) in a subject suffering from CRPC)
[Where:
Y is C (O) or CH ₂ ;
R ₁ and R ₂ are independently hydrogen, halogen, hydroxyl, alkoxy, cyano, nitro, CF ₃ , N (R) ₂ , sulfonamide, SO ₂ R, alkyl, haloalkyl, aryl, O—Alk—NR _5. R ₆ or O-Alk-heterocycle, which is a 3-7 membered substituted or unsubstituted heterocyclic ring, optionally aromatic,
R ₃ , R ₄ are independently hydrogen, halogen, hydroxyalkyl, hydroxyl, alkoxy, cyano, nitro, CF ₃ , NHCOR, N (R) ₂ , sulfonamide, SO ₂ R, alkyl, haloalkyl, aryl or protected The hydroxyl being
R is alkyl, hydrogen, haloalkyl, dihaloalkyl, trihaloalkyl, CH ₂ F, CHF ₂ , CF ₃ , CF ₂ CF ₃ , aryl, phenyl, halogen, alkenyl, CN, NO ₂ , or OH;
R ₅ and R ₆ are independently hydrogen, phenyl, an alkyl group of 1-6 carbon atoms, 3-7 membered cycloalkyl, 3-7 membered heterocycle, 5-7 membered aryl, or R ₅ And R ₆ together with the nitrogen atom form a 3-7 membered ring,
j and k are independently 1 to 4,
Alk is a linear alkyl of 1-7 carbons, a branched alkyl of 1-7 carbons, or a cyclic alkyl of 3-8 carbons]. Said compound of formula I is
35. The method of claim 32, wherein: 35. The method of claim 32, wherein the compound of formula I is compound IV.
  33. The method of claim 32, wherein the castration resistant prostate cancer (CRPC) is metastatic CRPC (mCRPC).   35. The method of claim 32, wherein the subject further receives androgen deprivation therapy (ADT).   35. The method of claim 32, wherein the administering step of the compound does not cause side effects associated with androgen deprivation therapy (ADT).   38. The method of claim 37, wherein the side effect is selected from the group consisting of hot flashes, gynecomastia, increased body fat, decreased bone mass, decreased bone mineral density, and increased risk of fracture.   33. The compound or isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or any combination thereof is administered at a dose of 125 mg per day, 250 mg per day or 500 mg per day. the method of.