KR20110131227A - Estrogen receptor ligands and methods of use thereof - Google Patents

Abstract

The present invention relates to a method of reducing testosterone levels by reducing luteinizing hormone (LH) in male subjects or irrespective of LH levels, treating, inhibiting, reducing the incidence, reducing or inhibiting advanced prostate cancer, and progressive prostate A palliative treatment of cancer.

Description

ESTROGEN RECEPTOR LIGANDS AND METHODS OF USE THEREOF

The present invention relates to a method of reducing testosterone levels by reducing luteinizing hormone (LH) in male subjects or irrespective of LH levels, treating, inhibiting, reducing the incidence, reducing or inhibiting advanced prostate cancer, and progressive prostate A palliative treatment of cancer.

Estrogen means a group of resistant and synthetic hormones that are important for and used for tissue and bone maintenance. Estrogens are endocrine modulators in the cellular processes involved in the development and maintenance of the reproductive system. Prevention of postmenopausal hot flashes and postmenopausal osteoporosis, the role of estrogen in reproductive biology, is well known. Estradiol is the major endogenous human estrogen and is found in both women and men.

The biological action of estrogens and antiestrogens is manifested through two intracellular receptors, estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ). Endogenous estrogens are typically potential 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 typically function differently in different tissues. For example, SERM may be an ERα antagonist in the breast but may be a partial ERα agonist in the uterus, bone and cardiovascular system. Compounds that act as estrogen receptor ligands are therefore useful for the treatment of various symptoms and disorders.

Prostate cancer is one of the most frequently diagnosed non-skin cancers among men in the United States, with more than 180,000 new cases, the second most common cause of cancer death, with nearly 29,000 deaths expected this year. Patients with advanced prostate cancer typically receive androgen deprivation therapy (ADT) by luteinizing hormone releasing hormone (LHRH) agonists or bilateral testicular resection. Androgen deprivation therapy not only reduces testosterone but also reduces estrogen levels because estrogen is derived from the aromatization of testosterone and the testosterone levels are deficient by ADT. Estrogen deficiency induced by androgen deprivation therapy causes significant side effects, including hot flashes, gynecomastia and breast pain, bone loss, decreased bone quality and strength, osteoporosis and life-threatening fractures, harmful lipid changes, and cardiovascular disease and myocardial muscle Infarction, and depression and other mood changes. It is believed that many of the side effects of estrogen deficiency of ADT are mediated by ERα.

Leuprolide Acetate (Lupron®) is a nonapeptide analog of naturally occurring gonadopropine-releasing hormone (GnRH or LH-RH). Lutrolide acetate is an LH-RH superagonist that eventually inhibits LH secretion by the pituitary gland. Lutropide Acetate acts as a potential inhibitor of gonadotropin secretion, inhibiting ovarian and testicular steroid production. In humans, administration of leuprolide acetate results in an initial increase in circulating levels of luteinizing hormone (LH) and follicle stimulating hormone (FSH), resulting in gonad hormones (testosterone and dihydrotestosterone in men, and estrone in premenopausal women). And estradiol). However, continuous administration of leuprolide acetate results in decreased LH and FSH levels. In men, testosterone is reduced to castration levels (50 ng / dL or less). In premenopausal women, estrogen is reduced to postmenopausal levels. Testosterone is known to be a stimulus to cancer cells of the prostate. Thus, inhibition of testosterone secretion or inhibition of testosterone action is required in the treatment of prostate cancer. Looprolide acetate can be used for LH inhibition, which reduces and lowers serum testosterone to castration levels to treat prostate cancer.

Before the introduction of LHRH agonists, castration testosterone levels were achieved by increasing estrogen activity in the pituitary gland via estrogen, primarily diethylstilbestrol (DES). DES is equally effective at inhibiting testosterone to castration levels, equivalent to LHRH agonists. Patients receiving DES did not show hot flashes or bone loss, but had a higher gynecomastia rate than ADT treated with LHRH agonists. Unfortunately, very potentially 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 prevent testosterone levels from being increased, prevent bone loss, hot flashes, and / or gynecomastia and suppress testosterone levels to castration, which can be used to treat prostate cancer.

Summary of the Invention

In one embodiment, the present invention provides a method of reducing total serum testosterone levels in a male subject comprising administering a therapeutically effective amount of a compound of Formula I-XII, described below.

In one embodiment, the invention is a method of reducing total serum testosterone levels in a male subject comprising administering a therapeutically effective amount of a compound of formula I-XII, described below, wherein the total serum testosterone reduction is serum luteinizing It provides a method characterized by a decrease in hormone levels.

In one embodiment, the invention is a method of reducing total serum testosterone levels in a male subject comprising administering a therapeutically effective amount of a compound of formula I-XII, described below, wherein the total serum testosterone reduction is serum luteinizing Provided is a method characterized by a lack of hormonal levels.

In one embodiment, the present invention provides a method of reducing total serum testosterone levels in a male subject comprising administering a therapeutically effective amount of a compound of formula I-XII, described below, wherein administering the compound is an androgen deprivation therapy (ADT). To prevent or treat an adverse event associated with the subject), and wherein the subject has a prostate cancer.

In one embodiment, the present invention provides a method for androgen deprivation therapy in a subject comprising administering a therapeutically effective amount of a compound of Formula I-XII as described below. In another embodiment, the subject is prostate cancer Has

In one embodiment, the invention provides a method of treating, inhibiting, reducing the incidence, reducing the severity, or inhibiting advanced prostate cancer, comprising administering a therapeutically effective amount of a compound of Formula I-XII as described below. .

In one embodiment, the present invention provides a method of palliative treatment of advanced prostate cancer, comprising administering a therapeutically effective amount of a compound of formula I-XII, described below.

The compounds of the present invention prevent testosterone levels from being increased, prevent bone loss, hot flashes, and / or gynecomastia and suppress testosterone levels to castration, which can be used to treat prostate cancer.

The subject matter of the present invention is particularly described and explicitly claimed in the conclusion section of the present specification. However, the present invention will be best understood with reference to the following detailed description in conjunction with the accompanying drawings, together with the objects, features and advantages thereof, both for the configuration and the method of implementation.
1 shows serum testosterone (solid line) and total androgen (dotted line) levels after oral administration of Compound IV at 30 mg / kg daily (first dose on day 0) in intact male monkeys. (See Example 8)
2 shows testosterone levels in intact rats treated with Compound IV (0.3, 1, 10, 30 mg / kg). ^I is P <0.05 vs. Intact vehicle control is shown. BLOQ values are shown graphically at the limit of quantitation 0.08 ng / mL. (See Example 9).
3 depicts the inhibitory effect of Compound IV on 17β-HSD5 enzyme activity. (See Example 12).
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 with 0.3 units of thrombin. Aggregation was monitored for 5 minutes and expressed as a percentage of vehicle control (see Example 13).
5 is a comprehensive synthetic scheme for the preparation of compounds II-XII (see Example 1).
6 is a synthetic scheme for preparing Compound IV (see Example 2).
7 is a synthetic scheme for preparing Compound VI (see Example 3).
8 is a synthetic scheme for preparing Compounds IX and X (see Example 5).
9 shows testosterone levels after 24 hours, 72 hours and 168 hours at doses of 3 mg / kg, 10 mg / kg and 300 mg / kg in intact rats treated with Compound IV. (See Example 9).
10 shows LH levels of intact testicular extracted (ORX) rats treated with Compound IV at 0.3 mg / kg, 1 mg / kg, 3 mg / kg, 10 mg / kg and 30 mg / kg doses (FIG. 10A). ), FSH level (FIG. 10B), testosterone level (FIG. 10C), prostate weight level (FIG. 10D), seminal vesicle weight level (FIG. 10E), and anus muscle weight (FIG. 10F). ^I is P <0.05 vs. Intact vehicle control is shown. ^O is P <0.05 vs. ORX vehicle control is shown. BLOQ values are graphically represented at the limit of quantitation of 0.08 ng / mL (see Example 9).
FIG. 11 shows intact and prostate size in ORX rats by administering Compound IV (FIG. 11A) and DES (FIG. 11B) at different doses (see Example 15).
12 shows the difference between DES and Compound IV; DES cross-reacts with glucocorticoid receptors (GR), while Compound IV does not (FIG. 12A); DES cross-reacts with androgen receptors (AR). It mildly stimulates and mildly inhibits AR action (ie it is a partial agonist / antagonist), whereas Compound IV does not (FIG. 12B); DES abolishes estrogen related receptor (ERR) transfer activity, whereas Compound IV does not (FIG. 12C). (See Example 15).
FIG. 13 shows the effect on hot flashes attenuation at 5 mg / kg, 10 mg / kg, 15 mg / kg and 30 mg / kg doses of Compound IV in a morphine withdrawal model. N = 7 animals per group. 17β-E2 was used at 5 mg / kg in 100% DMSO (see Example 14).
FIG. 14 shows dose dependent monkey body weight (kg) reduction by administering Compound IV for 91 days (˜20% at 100 mg / kg). No signal of gynecomastia or hyperestrogenity was observed. (See Example 16)
FIG. 15 shows dose dependent serum testosterone level reduction (ng / mL) after daily oral administration of Compound IV as compared to the positive control (LHRH agonist). The dashed line represents the testosterone level of the chemically castrated patient and the thick dashed line represents the testosterone level of the surgically castrated monkey (see Example 16).
FIG. 16 depicts dose dependent prostate-specific antigen (PSA) levels in monkeys at baseline and by administering Compound IV at day 28. FIG. PSA levels were significantly reduced with Compound IV treatment (see Example 16).
FIG. 17 depicts dose dependent prostate volume using intracranial transrectal ultrasonography (TRUS) by administering Compound IV at week 6, as compared to the positive control (LHRH agonist). (See Example 16)
FIG. 18 depicts dose dependent organ weights (prostate, seminal vesicles and testes) as a percentage of control group in day 90 monkeys by administering Compound IV (FIG. 18A). Prostate weight at 13 weeks autopsy in monkeys after oral administration of Compound IV daily (FIG. 18B). (See Example 16).
19 depicts dose dependent average total testosterone levels (nmol / L) in humans over a period of 1-11 days by administering Compound IV (100 mg, 300 mg, 600 mg and 1000 mg). (See Example 17)
20 depicts dose dependent mean LH levels (IU / L) in humans over a period of 1-10 days by administering Compound IV (100 mg, 300 mg, 600 mg and 1000 mg). (See Example 17)
FIG. 21 depicts dose dependent average free testosterone levels (pg / mL) in humans over a period of 1-10 days by administering Compound IV (100 mg, 300 mg, 600 mg and 1000 mg) (Example 17 Reference)
FIG. 22 shows dose dependent average PSA levels (μg / L) in humans over a period of 1-10 days 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) in intact rats after 14 days recovery of Compound IV administration. ^I represents P <0.05 vs intact control (see Example 10)
For simplicity and clarity of illustration, it will be understood that the components shown in the figures are not necessarily drawn to scale. For example, the scale of some components may be exaggerated relative to other components for clarity. Further, where considered appropriate, reference numerals will be repeated among the figures to indicate corresponding or analogous components.

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

In one embodiment, the compounds described herein and / or compositions comprising them will be useful for reducing total serum testosterone levels in male subjects.

In one embodiment, the compounds described herein and / or compositions comprising them will be useful for reducing total serum testosterone levels in male subjects, wherein the decrease in total serum testosterone occurs by decreasing serum luteinizing hormone (LH) levels. .

In one embodiment, in one embodiment, a compound described herein and / or a composition comprising the same will be useful for reducing total serum testosterone levels in a male subject, wherein the decrease in total serum testosterone is associated with a decrease in serum luteinizing hormone levels. Irrelevant

In one embodiment, the invention comprises administering a therapeutically effective amount of a compound represented by the structure of Formula I, or an isomer thereof, a pharmaceutically acceptable salt, a pharmaceutical product, a polymorph, a hydrate, or a combination thereof To reduce total serum testosterone levels in male subjects:

Where

Y is C (O) or CH ₂ ;

R ₁ , 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 an optionally aromatic 3-7 membered substituted or unsubstituted heterocycle ring;

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 a protected hydroxyl group;

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 to 6 carbon atoms, 3-7 membered cycloalkyl, 3-7 membered heterocycle, 5-7 membered aryl; 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 linear alkyl of 1-7 carbons, branched alkyl of 1-7 carbons, or cyclic alkyl of 3-8 carbons.

In additional embodiments of the methods described herein, the compound of Formula I is represented by Formula IA:

Wherein R ₁ , R ₂ , R ₃ , R ₄ , j and k are as defined for Formula I.

In one embodiment, the invention comprises administering a therapeutically effective amount of a compound represented by a compound of Formula II, or an isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate, or combination thereof To provide a method for reducing total serum testosterone levels in male subjects:

In one embodiment, the invention comprises administering a therapeutically effective amount of a compound represented by a compound of Formula III, or an isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or combination thereof To provide a method for reducing total serum testosterone levels in male subjects:

In one embodiment, the invention comprises administering a therapeutically effective amount of a compound represented by a compound of Formula IV, or an isomer thereof, a pharmaceutically acceptable salt, a pharmaceutical product, a polymorph, a hydrate, or a combination thereof To provide a method for reducing total serum testosterone levels in male subjects:

In one embodiment, the invention comprises administering a therapeutically effective amount of a compound represented by a compound of Formula V, or an isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate, or combination thereof To provide a method for reducing total serum testosterone levels in male subjects:

In one embodiment, the invention comprises administering a therapeutically effective amount of a compound represented by a compound of Formula VI, or an isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate, or combination thereof To provide a method for reducing total serum testosterone levels in male subjects:

In one embodiment, the invention comprises administering a therapeutically effective amount of a compound represented by a compound of Formula VII, or an isomer thereof, a pharmaceutically acceptable salt, a pharmaceutical product, a polymorph, a hydrate, or a combination thereof To provide a method for reducing total serum testosterone levels in male subjects:

In one embodiment, the invention comprises administering a therapeutically effective amount of a compound represented by a compound of Formula VIII, or an isomer thereof, a pharmaceutically acceptable salt, a pharmaceutical product, a polymorph, a hydrate, or a combination thereof To provide a method for reducing total serum testosterone levels in male subjects:

In one embodiment, the invention comprises administering a therapeutically effective amount of a compound represented by a compound of Formula IX, or an isomer thereof, a pharmaceutically acceptable salt, a pharmaceutical product, a polymorph, a hydrate, or a combination thereof To reduce total serum testosterone levels by reducing luteinizing hormone (LH) levels in male subjects with prostate cancer:

In one embodiment, the invention comprises administering a therapeutically effective amount of a compound represented by a compound of Formula X, or an isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate, or combination thereof To provide a method for reducing total serum testosterone levels in male subjects:

In one embodiment, the invention comprises administering a therapeutically effective amount of a compound represented by a compound of Formula XI, or an isomer thereof, a pharmaceutically acceptable salt, a pharmaceutical product, a polymorph, a hydrate, or a combination thereof To provide a method for reducing total serum testosterone levels in male subjects:

In one embodiment, the present invention comprises administering a therapeutically effective amount of a compound represented by a compound of formula XII, or an isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate, or combination thereof To provide a method for reducing total serum testosterone levels in male subjects:

In one embodiment, the invention comprises administering a therapeutically effective amount of a compound of formula IA, I-XII or an isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or combination thereof, Provided are methods for reducing total serum testosterone levels in male subjects. In another embodiment, the male subject has prostate cancer. In another embodiment, the total serum testosterone is reduced below about 100 ng / dL. In another embodiment, the total serum testosterone is reduced below about 50 ng / dL. In another embodiment, the total serum testosterone is reduced below about 25 ng / dL.

In one embodiment, the invention comprises administering a therapeutically effective amount of a compound of formulas IA, I-XII or an isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or combination thereof A method of reducing total serum testosterone levels in a subject, wherein said total serum testosterone reduction is caused by a decrease in serum luteinizing hormone (LH) levels. In another embodiment, the male subject has prostate cancer. In another embodiment, the total serum testosterone is reduced below about 100 ng / dL. In another embodiment, the total serum testosterone is reduced below about 50 ng / dL. In another embodiment, the total serum testosterone is reduced below about 25 ng / dL.

In one embodiment, the invention comprises administering a therapeutically effective amount of a compound of formulas IA, I-XII or an isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or combination thereof A method of reducing free serum testosterone levels in a subject, wherein the free serum testosterone reduction is caused by a decrease in serum luteinizing hormone (LH) levels. In another embodiment, the male subject has prostate cancer.

In one embodiment, the invention comprises administering a therapeutically effective amount of a compound of formulas IA, I-XII or an isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or combination thereof A method of reducing total serum testosterone levels in a subject, wherein said reducing total serum testosterone is independent of reducing serum luteinizing hormone (LH) levels. In another embodiment, the male subject has prostate cancer. In another embodiment, the total serum testosterone is reduced below about 100 ng / dL. In another embodiment, the total serum testosterone is reduced below about 50 ng / dL. In another embodiment, the total serum testosterone is reduced below about 25 ng / dL.

In one embodiment, the invention comprises administering a therapeutically effective amount of a compound of formulas IA, I-XII or an isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or combination thereof A method of reducing free serum testosterone levels in a subject, wherein the free serum testosterone reduction is independent of reducing serum luteinizing hormone (LH) levels. In another embodiment, the male subject has prostate cancer.

In one embodiment, the invention provides a method of reducing total serum testosterone or free serum testosterone levels in a male subject, wherein the male subject has prostate cancer. In another embodiment, the subject has advanced prostate cancer.

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

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

In one embodiment, the invention comprises administering a therapeutically effective amount of a compound of formula IA, I-XII or an isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or combination thereof, Provided are methods for reducing total serum testosterone levels in male subjects. In another embodiment, the total serum testosterone is reduced below about 100 ng / dL. In another embodiment, the total serum testosterone is reduced below about 50 ng / dL. In another embodiment, the total serum testosterone is reduced below about 25 ng / dL. In another embodiment, the total serum testosterone is reduced below about 75 ng / dL. In another embodiment, the total serum testosterone is reduced between about 75 ng / dL-100 ng / dL. In another embodiment, the total serum testosterone is reduced between about 50 ng / dL -75 ng / dL. In another embodiment, the total serum testosterone is reduced between about 40 ng / dL-50 ng / dL. In another embodiment, the total serum testosterone is reduced between about 25 ng / dL-50 ng / dL. In another embodiment, the total serum testosterone is reduced between about 40 ng / dL-60 ng / dL.

Testosterone can be measured as "free" (ie, biologically available and unbound) or "total" (including percentage of unutilized protein bound) serum levels. Men 40 years of age or older without prostate cancer show low levels of total testosterone levels below 250 ng / dL (<8.7 nmol / L) or free testosterone levels below 0.75 ng / dL (<0.03 nmol / L).

In one embodiment, the methods of the present invention provide a method of reducing total serum and / or free testosterone levels in a male subject with prostate cancer irrespective of a decrease in luteinizing hormone (LH) levels or by a decrease in LH levels. In other embodiments, the testosterone level will be a decrease from the level before treatment. In other embodiments, the total serum testosterone level is reduced below 100 ng / dL. In another embodiment, total serum testosterone levels are reduced below 50 ng / dL. In another embodiment, total serum testosterone levels are reduced to 25 ng / dL or less. In another embodiment, free serum testosterone levels are reduced to 2 ng / dL or less. In other embodiments, the free serum testosterone level is reduced below 1 ng / dL. In another embodiment, free serum testosterone levels are reduced to 0.5 ng / dL or less. In another embodiment, free serum testosterone levels are reduced to 0.25 ng / dL or less.

Methods of measuring free serum testosterone levels and total serum testosterone levels include monitoring testosterone levels during treatment by blood tests. Total testosterone is a combination of circulating testosterone and free / non-binding hormone that binds to carrier proteins (albumin, SHBG, transcotin, transferrin). Total testosterone levels may be influenced by several factors, including protein levels in the blood that transports the hormones into the body, age, obesity, and interference associated with commonly used test methods.

Useful methods for measuring free testosterone (FT) can be complex (equilibrium dialysis and free testosterone calculated (CFT)) or simple (commercial FT kit "Coat-A-Count") using analog tracers. In another embodiment, the measurement of total testosterone and free testosterone serum levels can be achieved by simultaneously measuring total testosterone and SHBG (eg, Irma-Count, DPC) followed by free testosterone calculation (CFT). In other embodiments, the determination of total testosterone and free testosterone can be in accordance with knowledge in the art.

In one embodiment, the invention treats a combination of one or more other forms of ADT with a compound of Formulas IA, I-XII, or an isomer thereof, a pharmaceutically acceptable salt, a pharmaceutical product, a polymorph, a hydrate, or a combination thereof A method of reducing total serum testosterone levels or free serum testosterone levels in a male subject is provided, the method comprising administering in an effective effective amount. In other embodiments, the total or free serum testosterone reduction is caused by a decrease in serum luteinizing hormone (LH) levels. In other embodiments, the decrease in total or free serum testosterone levels is independent of the decrease in serum luteinizing hormone levels.

The methods of the present invention comprise administering a combination of other forms of ADT and a compound of the present invention. In one embodiment, other forms of ADT include LHRH agonists. In another embodiment, the LHRH agonist is selected from leuprolide acetate (Lupron®) (US Pat. Nos. 5,480,656; 5,575,987; 5,631,020; 5,643,607; 5,716,640; 5,814,342; 6,036,976, all herein Incorporated by reference) or goserelin acetate (Zoladex®) (US Pat. No. 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, other forms of ADT include anti-androgens. In another embodiment, the anti-androgen comprises bicalutamide, flutamide, panisteride, dutasteride, MDV3100M, nilutamide, chlormadinone, or a combination thereof.

In one embodiment, the methods of the present invention comprise administering a therapeutically effective amount of an anti-androgen and a compound of the present invention. In one embodiment, the methods of the present invention comprise administering a therapeutically effective amount of an LHRH agent and a compound of the present invention. In one embodiment, the methods of the present invention comprise administering a therapeutically effective amount of an anti-androgen, an LHRH agonist, and a compound of the present invention.

In one embodiment, the present invention provides luteinizing hormone (LH) in a male subject with prostate cancer for the purpose of producing androgen deprivation therapy (ADT), comprising administering a therapeutically effective amount of a compound of formulas IA, I-XII. ) A method of reducing total serum testosterone levels and / or free testosterone levels, either by decreasing levels or irrespective of a decrease in luteinizing hormone levels. In another embodiment, the compound is compound IV.

In another embodiment, the invention comprises administering a therapeutically effective amount of a compound of formula IA, I-XII or an isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or combination thereof, Provided are methods for androgen deprivation therapy (ADT) in a subject. In another embodiment, the subject has prostate cancer. In another embodiment, the compound is compound IV.

In other embodiments, ADT is used to treat prostate cancer, delay prostate cancer progression, or prevent and / or treat prostate cancer recurrence.

In one embodiment, the present invention provides a method of treating prostate cancer, delaying prostate cancer progression, or preventing and / or treating recurrence of prostate cancer, comprising administering a compound of the present invention. In another embodiment, the compounds of the invention comprise LHRH analogs, reversible anti-androgens (such as bicalutamide or flutamide), anti-estrogens, anticancer agents, 5-alpha reductase inhibitors, aromatase inhibitors, progestins, selective Administration with androgen receptor modulators (SARMS), or agents acting through other nuclear hormone receptors.

In one embodiment, the invention comprises administering a compound of formulas IA, I-XII, treatment of prostate cancer and reduction of LH levels and total serum testosterone and / or free serum It provides a method of reducing testosterone levels. In another embodiment, compound IV is administered.

Androgen deprivation therapy not only reduces testosterone but also reduces estrogen levels because estrogen is derived from the aromatization of testosterone. Estrogen deficiency induced by androgen deprivation therapy includes hot flashes, gynecomastia and breast pain, bone loss, decreased bone quality and strength, osteoporosis, osteopenia, and life-threatening fractures, harmful lipid changes and higher cardiovascular disease and myocardial infarction, It causes significant side effects including loss of libido, impotence, muscle mass loss (muscle loss), fatigue, cognitive dysfunction, and depression and other mood changes.

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

In one embodiment, the invention comprises administering a therapeutically effective amount of a compound of Formulas IA, I-XII or an isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate or combination thereof A method of reducing total serum testosterone levels in male subjects, wherein administration of a compound of Formulas IA, I-XII, or an isomer thereof, a pharmaceutically acceptable salt, a pharmaceutical product, a polymorph, a hydrate, or a combination thereof Preventing, inhibiting, reducing the incidence, inhibiting or treating side effects associated with therapy (ADT), wherein the subject provides a method characterized by having prostate cancer. In other embodiments, the decrease in total or free serum testosterone levels is by or independent of a decrease in LH levels.

In one embodiment, administration of a compound of the present invention inhibits, reduces, inhibits or treats the occurrence of typical side effects associated with traditional androgen deprivation therapy (ADT). In another embodiment, the subject has prostate cancer. Prevention and / or reduction of such side effects is for placebo or control. In one embodiment, typical side effects associated with the traditional androgen deprivation therapy (ADT) include hot flashes, gynecomastia, decreased bone density and increased fractures. In another embodiment, administration of a compound of the present invention prevents the occurrence of hot flashes found when using traditional forms of androgen deprivation therapy (ADT). In another embodiment, administration of a compound of the present invention prevents the occurrence of gynecomastia found when using traditional androgen deprivation therapy (ADT). In another embodiment, administration of a compound of the present invention prevents a decrease in bone density (BMD) found when using traditional androgen deprivation therapy (ADT). In another embodiment, administration of a compound of the present invention prevents the increase in fractures found when using traditional androgen deprivation therapy (ADT). In other embodiments, the fracture increase is a pathological fracture, non-traumatic fracture, vertebral fracture, non-vertebral fracture, new morphological fracture, clinical fracture, or a combination thereof.

In one embodiment, the term “traditional androgen deprivation therapy” relates to testicular resection (surgical castration) in which the surgeon removes the testicles. In another embodiment, the term “traditional androgen deprivation therapy” relates to the administration of luteinizing hormone-releasing hormone (LHRH) analogues: such drugs reduce the amount of testosterone produced by the testes. Examples of LHRH analogs useful in the United States include Lupron, Viadur, Eligard, Goserelin (Zoladex), Tryptorelin (Trelstar), and Histrelin (Vantas). In another embodiment, the term “traditional androgen deprivation therapy” relates to the administration of anti-androgens: anti-androgens block the body's ability to use androgens. Even after testectomy or LHRH analogue treatment, small amounts of androgen are still produced by the adrenal glands. Examples of anti-androgen drugs include flutamide (Eulexin), bicalutamide (Casodex), and nilutamide (Nilandron). In another embodiment, the term “traditional androgen deprivation therapy” relates to the administration of a luteinizing hormone-releasing hormone (LHRH) antagonist such as Plenaxis; Degarelix (Firmagon) is a novel LHRH antagonist approved by the FDA in 2008 for the treatment of advanced prostate cancer. In another embodiment, the term “traditional androgen deprivation therapy” relates to administering 5α-reductase inhibitors such as Finasteride (Proscar) and Dutasteride (Avodart): The 5α-reductase inhibitor is more active in testosterone. Blocks the body's ability to convert to androgen, 5α-dihydrotestosterone (DHT). In another embodiment, the term “traditional androgen deprivation therapy” relates to the administration of testosterone biosynthesis inhibitors such as ketoconazole (Nizoral). In another embodiment, the term "traditional androgen deprivation therapy" relates to the administration of an estrogen such as diethylstilbestrol or 17β-estradiol.

In one embodiment, the term “facial flushing” refers to a sudden feeling of heat on the top or all of the body, redness of the face and neck, red spots on the chest, back, and arms, sweating, chills, and the like.

In one embodiment, the term “gynecomastia” means positive enlargement of the male breast by proliferation of the mammary gland component, which may or may not be associated with pain. Gynecomastia is clinically defined as the presence of a gummy or firm mass extending concentrically from the nipple. Symptoms known as pseudogynecomastia or fatty mastopathy are characterized by fat accumulation without glandular hyperplasia. Gynecomastia is usually bilateral or unilateral.

In one embodiment, the methods of the present invention are directed to treating testosterone reduction in men with prostate cancer or advanced prostate cancer without causing bone loss or hot flashes. In another embodiment, the methods of the present invention utilize compounds IA, I-XII, which do not cause specific side effects such as bone loss and hot flashes, which are currently common in androgen deprivation therapy (ADT) for prostate cancer. Without the potential to reduce testosterone, the primary stimulus to prostate cancer.

In another embodiment, Table 8 (Example 11) below demonstrates that administration of Compound IV reduces testosterone without causing bone loss.

In one embodiment, the methods of the present invention are directed to a reduction in testosterone levels, further treating advanced prostate cancer by administering a compound of formulas IA, I-XII. In one embodiment, the methods of the present invention are directed to a decrease in testosterone levels that further inhibits, reduces incidence, decreases or inhibits advanced prostate cancer by administering a compound of formulas IA, I-XII. In one embodiment, the methods of the present invention are directed to a decrease in testosterone levels, further providing palliative treatment of advanced prostate cancer by administering a compound of formulas IA, I-XII.

In one embodiment, the methods of the invention relate to the treatment of advanced prostate cancer. In one embodiment, the methods of the present invention relate to inhibition, reduced incidence, reduced severity or inhibition of advanced prostate cancer. In one embodiment, the methods of the present invention are directed to palliative treatment of advanced prostate cancer. In another embodiment, the methods of this invention make use of a compound of formulas IA, I-XII. In another embodiment, the present invention relates to the treatment of advanced prostate cancer. In another embodiment, the present invention relates to the inhibition 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 inhibition of advanced prostate cancer.

The term "advanced prostate cancer" refers to a metastatic cancer that originates in the prostate gland and metastasizes extensively, such as surrounding tissue, to the seminal vesicle, pelvic lymph nodes or bones, or other body parts. The pathology of prostate cancer is graded by the Gleason rating from 1 to 5 in order of malignancy. In other embodiments, patients with significant risk of progressive disease and / or death from prostate cancer will be included in the definition, and patients with cancer outside the prostate envelope with low disease stages, such as IIB, clearly have a "progressive" disease. Have

In one embodiment, the methods provided herein and / or the use of the compounds provided herein are effective in providing feedback on the hypothalamic-pituitary-testicular 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 its activity. In one embodiment, feedback on the hypothalamic-pituitary-testis axis (HPT axis) reduces LH levels. In one embodiment, feedback on the hypothalamic-pituitary-testis axis (HPT axis) reduces total serum testosterone levels. In one embodiment, feedback on the hypothalamic-pituitary-testis axis (HPT axis) reduces free serum testosterone levels. In one embodiment, feedback on the hypothalamic-pituitary-testis axis (HPT axis) reduces the serum, tissue or tumor levels of androgens.

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

The pituitary gland is the line that regulates testosterone levels in the body. At low testosterone levels, the pituitary gland releases luteinizing hormone (LH). This hormone causes the testicles to produce more testosterone. Testosterone levels increase during puberty. Testosterone levels are highest at approximately 20-40 years of age, and then gradually decrease in older men. Women have a much smaller amount of testosterone in the body than men. However, testosterone plays an important role throughout the body in both men and women. It affects brain, bone and muscle mass, fat distribution, vascular system, energy levels, genital tissue, and sexual function. Most 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, the decrease in total serum testosterone or free serum testosterone levels independent of a decrease in serum luteinizing hormone levels is due to an increase in sex hormone-binding globulin (SHBG). In another embodiment, the decrease in total serum testosterone or free serum testosterone levels is due to an increase in sex hormone-binding globulin (SHBG). In another embodiment, the decrease in total serum testosterone or free serum testosterone levels independent of a decrease in serum luteinizing hormone (LH) levels is due to inhibition of testosterone production and secretion by Leidihi cells in the testes. In another embodiment, a decrease in total serum testosterone or free serum testosterone levels independent of a decrease in serum luteinizing hormone (LH) levels is due to decreased adrenal steroid production.

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

Hydroxysteroid dehydrogenase (HSD) classes are involved in the conversion of circulating steroids. 17β-HSD5 converts androstenedione to testosterone and estrone to estradiol. It is also involved in prostaglandin synthesis. In one embodiment, the compounds of the present invention inhibit HSD in particular 17β-hydroxysteroid dehydrogenase 5 (17β-HSD5). This inhibition prevents peripheral / extratesticular testosterone synthesis, which may result in incomplete reduction of total or free serum testosterone beyond the HPT axis regulation or allow for locally increased intracellular testosterone levels (all of which are detrimental to ADT). This will be useful for ADT.

LHRH agonist therapy, namely androgen deprivation therapy (ADT) achieved by administering a luteinizing hormone releasing hormone agonist (LHRH) or an analog thereof, initially stimulates gonadotropin release from the pituitary gland and testosterone production from the testes (flare then reduce gonadotropin release and reduce both testosterone and estrogen levels. The "immediate response" caused by LHRH agonist therapy has a negative effect on the treatment of prostate cancer due to increased androgen / testosterone levels. In addition, LHRH therapy is associated with an increased risk of diabetes and cardiovascular disease (Smith (2008) Current Prostate Reports . 6 : 149-154).

To overcome the immediate effects of LHRH therapy, anti-androgen monotherapy (bicalutamide, flutamide, chlormadinone), LHRH / antiandrogen combination therapy approach, and LHRH antagonist (degarelix) have been proposed. (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 the subject. Bicalutamide antiandrogen monotherapy has been shown to be less effective than ADT in patients with prostate cancer with bone metastasis. In addition, side effects observed with bicalutamide therapy include breast pain, breast enlargement (gynecomastia and breast pain) (Suzuki et al., Ibid). Additional risks of anti-androgen therapy include increased liver transaminase (Sharifi et al. Ibid).

In one embodiment, the present invention does not produce a "flare" effect, but overcomes the side effects associated with estrogen deficiency caused by testosterone reduction using traditional ADT methods, while reducing LH levels and thus total serum testosterone And / or decrease in free serum testosterone levels. The use of the methods / compounds of the invention may be directed to bone tissue maintenance (agonist effects on bone tissue), thrombotic potential and / or hot flashes and / or to less or neutral breast tissue than estradiol or diethylstilbestrol It provides tissue-selective estrogen activity that produces an effect.

In one embodiment, Compound IV shows an agonist effect but no antagonist effect (Examples 6 and 7), so Compound IV will not cause an increase in gonadotropin and testosterone.

In one embodiment, Compound IV shows agonist activity (Examples 8-11), demonstrating potent pharmacological response for serum hormone, testosterone and total androgen reduction.

In one embodiment, the methods provided herein using the compounds and / or compositions provided herein are effective in reducing or eliminating bone resorption caused by LH reduction using traditional ADT. In one embodiment, the use of the methods provided herein and / or the compositions provided herein is effective to reduce or eliminate bone resorption caused by testosterone reduction using traditional ADT. In one embodiment, the methods provided herein using the compositions provided herein are effective to reduce or eliminate bone resorption caused by a decrease in estrogen as a result of a decrease in LH levels. In one embodiment, the methods provided herein using the compounds and / or compositions provided herein prevent bone resorption associated with reduced LH levels using traditional ADT. In one embodiment, the methods provided herein utilizing the compounds and / or compositions provided herein prevent bone loss associated with endogenous LH, testosterone and / or estradiol reduction using traditional ADT. In one embodiment, the methods provided herein using the compounds and / or compositions provided herein increase bone density (BMD) while providing a reduction in LH levels. In one embodiment, the methods provided herein utilizing the compounds and / or compositions provided herein increase the bone volume percentage while providing endogenous LH, testosterone and / or estradiol levels reduction.

In some embodiments, the present invention provides a method for avoiding and / or reducing thromboembolism by administering a compound of the present invention or an isomer, pharmaceutical product, polymorph, hydrate or combination thereof.

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

In one embodiment, Example 13 discloses a specific toxicity study wherein in vitro studies using human platelets show that Compound IV has much lower procoagulant activity than DES. Thus, Compound IV, an ER-selective agonist, will deliver the prostate cancer benefits of DES with less risk of thrombotic complications than DES, and will also deliver the benefits of LHRH agonists or antagonists without causing bone loss, hot flashes or harmful lipid profiles. .

Diethylstilbestrol (DES) therapy alone or in combination with other ADTs has shown that DES prevents bone resorption in patients with prostate cancer. The use of DES has been known as a treatment for prostate cancer, but the effects of DES on angiogenesis and malignant tumors are thought to be mediated by DES metabolites and not through estrogen receptors. In addition, the dose level of DES administered for therapeutic purposes presents a number of adverse side effects, including vascular disease, cardiovascular disease, thrombotic toxicity, gynecomastia, erectile dysfunction and decreased libido (Scherr and Pitts, ibid and Presti, JC Jr. (1996) JAMA. 275 (15): 1153-6).

In one embodiment, the present invention overcomes the side effects of LHRH agonist or antagonist therapies, either alone or in combination with anti-androgens or DESs. In another embodiment, the methods of the present invention provide androgen deprivation therapy, without adverse estrogen deficiency side effects such as harmful bone related symptoms, and without estrogen stimulating side effects such as breast milk. In another embodiment, the methods of the present invention provide LH without producing an “immediate” effect, while overcoming the side effects associated with a general increase in estrogen agonists observed in DES therapy and overcoming the side effects associated with estrogen deficiency caused by a decrease in LH. Reduced levels and thus reduced total and / or free serum testosterone levels. The use of the methods / compounds of the present invention provides tissue-selective estrogen activity, thereby providing bone tissue maintenance (agonist effect on bone tissue), decreased thrombus potential and neutral effects on breast tissue.

Antiestrogenic effects at hypothalamic levels of traditional selective estrogen receptor modulators (SERMs) such as tamoxifen, toremifene and raloxifene increase gonadotropin levels or LH levels in men, potentially increasing testosterone serum levels (Tsouri et. al., 2008, Fertility and Sterility doi: 10.1016). In contrast, the methods of the present invention provide LH reduction in male subjects comprising administration of a compound of formulas IA, I-XII.

Additional of Compounds of Formula I Example :

In one embodiment of the process of the invention, Y of the compound of formula I is C (O). In other embodiments, 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-heterocycle, and Alk of Alk-NR ₅ R ₆ are linear alkyl of 1-7 carbons, 1-7 carbons. Branched alkyl, or cyclic alkyl of 3-8 carbons. In another embodiment, said alkyl is ethylene (-CH ₂ CH _2- ). In another embodiment, Alk is methylene (-CH _2- ). In another embodiment, the Alk is propylene (-CH ₂ CH ₂ CH _2- ). In another embodiment, the Alk is 2-methylpropylene (-CH ₂ CH (CH ₃ ) CH _2- ).

이다. 본 발명의 방법의 다른 구현예에서, 식 I 또는 IA의 화합물의 R₁ 는 히드록실이다. 본 발명의 방법의 다른 구현예에서, 식 I 또는 IA의 화합물의 R₁ 는 알콕시이다. 본 발명의 방법의 다른 구현예에서, 식 I 또는 IA의 화합물의 R₁ 및 R₂ 는 독립적으로 수소, 할로겐, 히드록실, 알콕시, 시아노, 니트로, CF₃, N(R)₂, 술폰아미드, SO₂R, 알킬, 할로알킬, 아릴, O-Alk-NR₅R₆ 또는 O-Alk-헤테로사이클이며, 상기 헤테로사이클은 임의로 방향족인, 3-7 원 치환 또는 비치환 헤테로사이클 고리 이다. 본 발명의 방법의 다른 구현예에서, 식 I 또는 IA의 화합물의 R₁ 및 R₂ 는 독립적으로, 할로겐, 히드록실, 알콕시, 시아노, 니트로, CF₃, N(R)₂, 술폰아미드, SO₂R, 알킬, 할로알킬, 아릴, O-Alk-NR₅R₆ 또는 O-Alk-헤테로사이클이며, 상기 헤테로사이클은 임의로 방향족인, 3-7 원 치환 또는 비치환 헤테로사이클 고리 이다. 다른 구현예에서, 식 I 또는 IA의 화합물의 R₂ 는 할로겐이다. 다른 구현예에서, 식 I 또는 IA의 화합물의 R₂ 는 F이다. 다른 구현예에서, 식 I 또는 IA의 화합물의 R₂ 는 Cl이다. 다른 구현예에서, 식 I 또는 IA의 화합물의 R₂ 는 Br이다. 다른 구현예에서, 식 I 또는 IA의 화합물의 R₂ 는 I이다. 다른 구현예에서, 식 I 또는 IA의 화합물의 R₂ 는 히드록실이다. 다른 구현예에서, R₁ 및/또는 R₂ 는 CF₃이다. 다른 구현예에서, R₁ 및/또는 R₂ 는 CH₃ 이다. 다른 구현예에서, R₁ 및/또는 R₂ 는 할로겐이다. 다른 구현예에서, R₁ 및/또는 R₂ 는 F이다. 다른 구현예에서, R₁ 및/또는 R₂ 는 Cl이다. 다른 구현예에서, R₁ 및/또는 R₂ 는 Br이다. 다른 구현예에서, R₁ 및/또는 R₂ 는 I이다. 다른 구현예에서, 식 I의 R₂는 파라 포지션에 있다.In one embodiment of the process of the invention, R ₁ of the compound of formula I or IA is in a para position. In one embodiment of the process of the invention, R ₁ and R ₂ of the compound of formula I or IA are different. In another embodiment of the process of the invention, R ₁ and R ₂ of the compound of formula I or IA are the same. In another embodiment of the methods of the invention, R ₁ of the compound of formula I or IA is

to be. In another embodiment of the methods of the invention, R ₁ of the compound of formula I or IA is hydroxyl. In another embodiment of the process of the invention, R ₁ of the compound of formula I or IA is alkoxy. In another embodiment of the process of the invention, R ₁ and R ₂ of the compound of formula I or IA 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 heterocycle is an optionally aromatic 3-7 membered substituted or unsubstituted heterocycle ring. In another embodiment of the process of the invention, 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, which heterocycle is an optionally aromatic 3-7 membered substituted or unsubstituted heterocycle ring. In another embodiment, R ₂ in the compound of formula I or IA is halogen. In another embodiment, R ₂ of the compound of formula I or IA is F. In another embodiment, R ₂ of the compound of formula I or IA is Cl. In another embodiment, R ₂ of the compound of formula I or IA is Br. In another embodiment, R ₂ of the compound of formula I or IA is I. In another embodiment, R ₂ of the compound of formula I or IA is hydroxyl. In other embodiments, R ₁ and / or R ₂ are CF ₃ . In other embodiments, R ₁ and / or R ₂ are CH ₃ . In other embodiments, R ₁ and / or R ₂ are halogen. In other embodiments, R ₁ and / or R ₂ are F. In other embodiments, R ₁ and / or R ₂ are Cl. In other embodiments, R ₁ and / or R ₂ are Br. In other embodiments, R ₁ and / or R ₂ are I. In other embodiments, R ₂ in formula I is in a para position.

In one embodiment of the process of the invention, R ₃ and R ₄ of the compound of formula I or IA are the same. In other embodiments, R ₃ and R ₄ of the compound of formula I or IA are different. In other embodiments, j and k of compounds of Formula I or IA are independently 1. In other embodiments, R ₃ and R ₄ of the compound of formula I or IA are independently halogen, haloalkyl, hydroxyl or alkyl. In other embodiments, R ₃ and R ₄ of the compound of formula I or IA are independently F. In other embodiments, R ₃ and R ₄ of the compound of formula I or IA are independently Br. In other embodiments, R ₃ and R ₄ of the compound of formula I or IA are independently Cl. In other embodiments, R ₄ is in a para position. In other embodiments, R ₃ Is in the ortho position. In other embodiments, R ₃ Is in the meta position. In other embodiments, R ₃ And / or R ₄ is CF ₃ . In other embodiments, R ₃ And / or R ₄ is CH ₃ .

In one embodiment of the process 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 other embodiments, the ring is a saturated or unsaturated ring. In other embodiments, the ring is a substituted or unsubstituted ring. In another embodiment, R ₅ and R ₆ of the compound of formula I or IA together with nitrogen form a piperidine ring. In another embodiment, R ₅ and R ₆ of the compound of formula I or IA together with nitrogen form a pyrazine ring. R ₅ and R ₆ of the compounds of formula I or IA together with nitrogen form a piperazine ring. R ₅ and R ₆ of the compounds of formula I or IA together with nitrogen form a morpholine ring. R ₅ and R ₆ of the compounds of formula I or IA together with nitrogen form a pyrrole ring. R ₅ and R ₆ of the compound of formula I or IA form pyrrolidine. R ₅ and R ₆ of the compounds of formula I or IA together with nitrogen form a pyridine ring. In other embodiments, the ring is substituted by halogen, alkyl, alkoxy, alkylene, hydroxyl, cyano, nitro, amino, amide, COOH, or aldehyde.

In another embodiment of the process of the invention, R ₁ of the compound of formula I or IA and R ₂ of the compound of formula I or IA are independently O-Alk-heterocycle or OCH ₂ CH ₂ -heterocycle. In another embodiment, the term “heterocycle” group refers to a ring structure that, in one embodiment, includes, in addition to carbon atoms, sulfur, oxygen, nitrogen, or a combination thereof as part of the ring. In other embodiments, the heterocycle is a 3-12 membered ring. In other embodiments, the heterocycle is a 6 membered ring. In other embodiments, the heterocycle is a 5-7 membered ring. In other embodiments, the heterocycle is a 4-8 membered ring. In other embodiments, the heterocycle is unsubstituted or halogen, haloalkyl, hydroxyl, alkoxy, carbonyl, amido, alkylamido, dialkylamido, cyano, nitro, CO ₂ H, amino, alkylamino , Dialkylamino, carboxyl, thio and / or thioalkyl. In other embodiments, the heterocycle can be fused with other saturated or unsaturated cycloalkyl or heterocyclic 3-8 membered rings. In other embodiments, the heterocycle ring is a saturated ring. In other embodiments, the heterocycle ring is an unsaturated ring. In other embodiments, the heterocycle is piperidine. In other embodiments, the heterocycle is pyridine. In other embodiments, the heterocycle is piperidine, pyridine, furan, thiophene, pyrrole, pyrrolidine, pyrazine, piperazine or pyrimidine.

The term "cycloalkyl" means a non-aromatic, monocyclic or polycyclic ring comprising carbon and hydrogen atoms. Cycloalkyl groups have at least one carbon-carbon double bond in the ring unless the ring is aromatic by the presence of a carbon-carbon double bond. Examples of cycloalkyl groups include, but are not limited to, (C3-C7) cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, and cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl And saturated cyclic and bicyclic terpenes such as cycloheptenyl and (C3-C7) cycloalkenyl groups, and unsaturated cyclic and bicyclic terpenes. Cycloalkyl groups can be substituted or unsubstituted by one or more substituents. Preferably, said cycloalkyl group is a monocyclic ring or a bicyclic ring.

The term "alkyl" means, in one embodiment, a saturated aliphatic hydrocarbon comprising straight chain, branched chain and cyclic alkyl groups. In one embodiment, the alkyl group has 1-12 carbons. In other embodiments, the alkyl group has 1-7 carbons. In other embodiments, the alkyl group has 1-6 carbons. In other embodiments, the alkyl group has 1-4 carbons. In other embodiments, the cyclic alkyl group has 3-8 carbons. In other embodiments, the cyclic alkyl group has 3-12 carbons. In other embodiments, the branched chain alkyl is alkyl substituted by an alkyl side chain of 1-5 carbons. In another embodiment, the branched chain alkyl is alkyl substituted by a haloalkyl side chain of 1-5 carbons. The alkyl group is substituted with halogen, haloalkyl, hydroxyl, alkoxy carbonyl, amido, alkyl amido, dialkyl amido, nitro, amino, alkylamino, dialkylamino, carboxyl, thio and / or thioalkyl It can be unsubstituted.

"Alkenyl" means, in other embodiments, an unsaturated hydrocarbon comprising straight, branched, and cyclic groups having one or more double bonds. Alkenyl groups may have one double bond, two double bonds, three double bonds, and the like. In other embodiments, the alkenyl group has 2-12 carbons. In other embodiments, the alkenyl group has 2-6 carbons. In other embodiments, the 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, alkoxy carbonyl, amido, alkylamido, dialkylamido, nitro, amino, alkylamino, dialkylamino, carboxyl, thio and / or thioalkyl. Can be.

"Aryl" groups are selected from halogen, haloalkyl, hydroxy, alkoxy, carbonyl, amido, alkylamido, dialkylamido, nitro, amino, alkylamino, dialkylamino, carboxy or thio or thioalkyl It means an aromatic group having at least one carbocyclic aromatic group or heterocyclic aromatic group, which may be unsubstituted or 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 other embodiments, the aryl group is a 4-12 membered ring. In other embodiments, the aryl group is a 6 membered ring. In other embodiments, the aryl group is a five membered ring. In other embodiments, the aryl group is a 2-4 fused ring system.

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

A "haloalkyl" group is, in another embodiment, an alkyl group as defined above substituted with one or more halogen atoms, eg, F, Cl, Br or I.

A "hydroxyl" group is, in another embodiment, an OH group. If R ₁ , R ₂ or R ₃ in the compounds of the invention are OR, those skilled in the art will understand that R is not OH.

In one embodiment, the term "halogen" or "halo" means halogen such as F, Cl, Br or I.

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

For protected hydroxyl groups, in some embodiments, incorporation of substituents bonded to the oxygen moieties of the benzene ring, which substituents can be readily removed. In some embodiments, the phenolic protecting group is methyl ether (methoxy), alkyl ether (alkoxy), benzyl ether (Bn), methoxymethyl (MOM) ether, benzoyloxymethyl (BOM) ether, benzyl, carbenzoxy , 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, phena Seal ether, 4-bromophenacyl ether, cyclopropylmethyl ether, allyl ether, propargyl ether, isopropyl ether, cyclohexyl ether, t-butyl ether, 2,5-dimethylbenzyl ether, 4-methoxybenzyl Ether, o-nitrobenzyl ether, 2,6-dichlorobenzyl ether, 3-4-dichlorobenzyl Ter, 4- (dimethylamino) carbonylbenzyl ether, 4-methylsulfinylbenzyl ether, 4-anthrylmethyl ether, 4-picolyl ether, heptafluoro-o-tolyl, tetrafluoro-4-pyridyl Ether, trimethylsilyl (TMS) ether, t-butyldimethylsilyl (TBDMS) ether, t-butyldiphenylsilyl (TBDPS) ether, triisopropylsilyl (TIPS) ether, aryl formate, arylacetate, aryl levulinate , Aryl pivaloate, aryl benzoate, aryl 9-fluorene carboxylate, aryl methyl carbonate, 1-adamantyl carbonate, t-butyl carbonate, t-methylsulfinylbenzyl carbonate, 2,4-dimethylpent- 3-yl carbonate, aryl 2,2,2-trichloroethyl carbonate, aryl benzyl carbonate, aryl carbamate, dimethylphosphinyl ether (Dmp-OAr), dimethylphosphinothionyl ester (Mpt-OAr), diphenylphosph Pinotionyl ester (Dpt-OAr), aryl It may include a carbon-sulfonate, aryl pole toluene sulfonate or aryl 2-formyl-benzenesulfonate.

In one embodiment, the process of the invention comprises N, N-bis (4-hydroxyphenyl) -4-propylbenzamide (II) or an isomer thereof, a pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate Or combinations thereof. In another embodiment, the methods of the invention comprise 4,4 ′-(2,3-dimethyl-benzylazandiyl) diphenol (III) or an isomer thereof, a pharmaceutically acceptable salt, a pharmaceutical product, a polymorph, Hydrates or combinations thereof are used. In another embodiment, the methods of the present invention provide 3-fluoro-N- (4-fluorophenyl) -4-hydroxy-N- (4-hydroxyphenyl) benzamide (IV) or an isomer thereof, pharmaceutical Acceptable salts, pharmaceutical products, polymorphs, hydrates or combinations thereof. In another embodiment, the methods of the invention comprise N, N-bis (4-hydroxyphenyl) -2,3-dimethylbenzamide (V) or isomers thereof, pharmaceutically acceptable salts, pharmaceutical products, polymorphs , Hydrates or combinations thereof. In another embodiment, the methods of the invention comprise N, N-bis (4-hydroxyphenyl) -2-naphthylamide (VI) or an isomer thereof, a pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate Or combinations thereof. In another embodiment, the methods of the present invention provide 3-fluoro-4-hydroxy-N, N-bis (4-hydroxyphenyl) benzamide (VII) or isomers thereof, pharmaceutically acceptable salts, pharmaceuticals Use products, polymorphs, hydrates or combinations thereof. In another embodiment, the methods of the present invention provide 4-((4-fluorophenyl) (4-hydroxybenzyl) amino) phenol (VIII) or isomers thereof, pharmaceutically acceptable salts, pharmaceutical products, polymorphs , Hydrates or combinations thereof. In another embodiment, the process of the invention is 4-fluoro-N- (4-hydroxy-phenyl) -N- [4- (2-piperidin-1-yl-ethoxy) -phenyl] -2 -Trifluoromethyl-benzamide (IX) or isomers thereof, pharmaceutically acceptable salts, pharmaceutical products, polymorphs, hydrates or combinations thereof. In another embodiment, the methods of the present invention provide a hydrochloride of IX (HCl salt of IX) or 4-fluoro-N- (4-hydroxy-phenyl) -N- [4- (2- (piperidine-1). -Yl-ethoxy) -phenyl] -2-trifluoromethyl-benzamide hydrochloride (X) or isomers thereof, pharmaceutically acceptable salts, pharmaceutical products, polymorphs, hydrates or combinations thereof. In an example, the method of the present invention may comprise 3-fluoro-4-hydroxy-N- (4-hydroxyphenyl) -N-phenylbenzamide (XI) or an isomer thereof, a pharmaceutically acceptable salt, a pharmaceutical product. , Polymorphs, hydrates, or combinations thereof In another embodiment, the process of the invention comprises 3-fluoro-N, N-bis- (4-hydroxy-phenyl) -2-methyl-benzamide (XII) Or isomers, pharmaceutically acceptable salts, pharmaceutical products, polymorphs, hydrates or combinations thereof.

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

Suitable pharmaceutically acceptable salts of the amines of the compounds of the process of the invention can be prepared from inorganic or organic acids. In one embodiment, the inorganic salts of the amines are bisulfate, borate, bromide, chloride, hemisulfate, hydrobromate, hydrochlorate, 2-hydroxyethylsulfonate (hydroxyethanesulfonate), iodate, iodide Ids, isothionates, nitrates, persulfates, phosphates, sulfates, sulfamate, sulfanilates, sulfonic acids (alkylsulfonates, arylsulfonates, halogen substituted alkylsulfonates, halogen substituted arylsulfonates), sulfonates and thio Cyanate.

In one embodiment, examples of organic salts of amines may be selected from organic acids of aliphatic, cycloaliphatic, aromatic, aromatic aliphatic, heterocyclic, carboxylic and sulfonic compounds, examples being acetate, arginine, aspartate, aspart Corbate, adipate, anthranilate, alginate, alkalate carboxylate, substituted alkane carboxylate, alginate, benzenesulfonate, benzoate, bisulfate, butyrate, bicarbonate, biartrate, carboxylate, sheet Latex, camphorlate, camphorsulfonate, cyclohexylsulfate, cyclopentanepropionate, calcium edetate, chamlate, carbonate, clavulanate, cinnamate, dicarboxylate, digluconate, dodecylsulfonate, Dihydrochloride, decanoate, enanthuates, ethanesulfonate, e Tate, edysylate, estoleate, ecylate, fumarate, formate, fluoride, galacturonate, gluconate, glutamate, glycolate, gluconate, glucoheptanoate, glycerol phosphate, gluceptate, Glycolyl arsanilate, glutarate, glutamate, heptanoate, hexanoate, hydroxymaleate, hydroxycarboxylic acid, hexyl resornate, hydroxybenzoate, hydroxy naphtholate, hydrofluorate, lactate , Lactobinoate, laurate, maleate, maleate, methylenebis (beta-oxynaphtholate), malonate, mandelate, mesylate, methane sulfonate, methyl bromide, methylnitrate, methylsulfonate, monopotassium Maleate, mucate, monocarboxylate, nitrate, naphthalenesulfo Yate, 2-naphthalenesulfonate, nicotinate, lead sillate, N-methylglucamine, oxalate, octanoate, oleate, pamoate, phenyl acetate, picrate, phenylbenzoate, pivalate, propionate , Phthalate, pecinate, phenylpropionate, palmitate, pantothenate, polygalaturate, pyruvate, quinate, salicylate, succinate, stearate, sulfanilate, subacetate, tartarate , Theophylline acetate, p-toluenesulfonate (tosylate), trifluoroacetate, terephthalate, tannate, theoacrylate, trihaloacetate, triethiodide, tricarboxylate, undecanoate and valerian Rate.

In one embodiment, examples of inorganic salts of carboxylic acids or phenols include alkali metals including ammonium, lithium, sodium, potassium, cesium; Alkaline earth metals including calcium, magnesium, aluminum; Zinc, barium, choline, quaternary ammonium.

In other embodiments, examples of organic salts of carboxylic acids or phenols include organic amines including arginine, aliphatic organic amines, cycloaliphatic organic amines, aromatic organic amines, benzanthine, t-butylamine, benetamine (N-benzylphenethylamine ), Dicyclohexylamine, dimethylamine, diethanolamine, ethanolamine, ethylenediamine, hydramine, imidazole, lysine, methylamine, megamine, N-methyl-D-glucamine, N, N'-dibenzyl Ethylenediamine, nicotinamide, organic amines, omitin, pyridine, picolies, piperazine, procaine, tris (hydroxymethyl) methylamine, triethylamine, triethanolamine, trimethylamine, tromethamine and urea Can be selected from.

In one embodiment, the salt reacts the product in free base or free acid form with one or more suitable acid or base equivalents in a solvent or medium in which the salt is insoluble or in a solvent such as water, and the solvent or medium Can be formed in a vacuum or by conventional means such as by freeze drying or by removing ions of the salt present by exchange with other ions or a suitable ion exchange resin.

In one embodiment, the methods of the present invention utilize pharmaceutically acceptable salts of the compounds of the present invention. In one embodiment, the methods of this invention make use of pharmaceutically acceptable salts of compounds of Formulas IA, I-XII. In one embodiment, the methods of this invention make use of amine salts of compounds of formulas IA, I-XII. In one embodiment, the methods of this invention make use of phenol salts of compounds of formulas IA, I-XII.

In one embodiment, the methods of the invention comprise a free base, free acid, non-charged or non-complexed compound of formula IA, I-XII, and / or isomers, pharmaceutical products, hydrates, polymorphs or their Use a combination.

In some embodiments, compounds of the invention comprise three phenyl groups bonded by amide bonds. In one embodiment, the compounds of the present invention have a non-charged structure. In another embodiment, the compounds of the present invention are free base structures. In another embodiment, the compounds of the present invention are free acid structures. In other embodiments, the compounds of the invention are non-complexed structures. In another embodiment, the compounds of the present invention are non-ionized structures. In another embodiment, the compound of the present invention is a pharmaceutically acceptable salt. In another embodiment, the compounds of the present invention comprise hydrochloric acid (HCl) salts.

In one embodiment, the methods of this invention make use of the isomers of the compounds of formulas IA, I-XII. In one embodiment, the methods of the present invention utilize a pharmaceutical product of a compound of formulas IA, I-XII. In one embodiment, the methods of the present invention utilize hydrates of compounds of formulas IA, I-XII. In one embodiment, the methods of this invention make use of polymorphs of the compounds of formulas IA, I-XII. In one embodiment, the methods of this invention make use of metabolites of the compounds of formulas IA, I-XII. In another embodiment, the methods of the present invention utilize a composition comprising a compound of formulas IA, I-XII, or in another embodiment, an isomer, metabolite, pharmaceutical product of a compound of formulas IA, I-XII. Hydrates and polymorphs.

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

In one embodiment, the term "isomer" is meant to include the optical isomers of the compound. In one embodiment, the term “isomer” is meant to include the stereoisomers of the compound. The compound of the present invention is cis Or trans It has an amide bond that can be isomerized. It is to be understood that the present invention includes optically active, or stereoisomeric forms, or mixtures thereof, and their use for applications contemplated within the scope of the invention.

In another embodiment, the present invention includes hydrates of such compounds. In one embodiment, the term “hydrate” includes hemihydrates, monohydrates, dihydrates, trihydrates, and the like as known in the art.

Synthetic procedure

Compounds of formula I or IA can be readily prepared, for example, by reacting a substituted diphenyl amine with benzoic acid or benzoyl halide in the presence of a base to produce benzamide. In one embodiment, the base is pyridine. In another embodiment, the benzoyl halide is benzoyl chloride. In another embodiment, hydroxyl substituents are protected during the reaction of diphenylamine with benzoic acid or benzoyl chloride. In another embodiment, the protecting group for the hydroxyl is optionally removed in the final step. See US Patent 2009/00624231, which is incorporated herein by reference in its entirety.

For example, the compound of formula IA:

Wherein R ₁ , R ₂ , R ₃ and R ₄ , j and k are as defined above;

을

of

와 반응시켜

React with

을 생산하고;

To produce;

The diphenyl amine (3) in the presence of a base

와 반응시켜

React with

It may be prepared by a process comprising the step of producing.

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 and the protecting group is removed to give free hydroxyl or optionally reacted with Cl-Alk-heterocycle or Cl-Alk-NR ₅ R ₆ to obtain a compound of formula IA:

Wherein R ₁ , R ₂ , R ₃ and R ₄ are independently other than OH, O-Alk-NR ₅ R ₆ or O-Alk-heterocycle, R ₁ ′, R ₂ ′, R ₃ ′ and R ₄ ′ is R ₁ , R ₂ , R ₃ and R _4, respectively.

As another example, the process for preparing the compound of formula IA is:

(Wherein R ₁ , R ₂ , R ₃ and R ₄ are as defined above)

In the presence of a base

을

of

와 반응시켜

React with

Producing a step.

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 and the protecting group is removed to give free hydroxyl or optionally reacted with Cl-Alk-heterocycle or Cl-Alk-NR ₅ R ₆ to obtain a compound of formula IA:

Wherein R ₁ , R ₂ , R ₃ and R ₄ are independently other than OH, O-Alk-NR ₅ R ₆ or O-Alk-heterocycle, R ₁ ′, R ₂ ′, R ₃ ′ and R ₄ ′ is R ₁ , R ₂ , R ₃ and R _4, respectively.

In one embodiment, Formula II is prepared according to Example 1 and FIG. 5.

In another embodiment, Formula III is prepared according to Example 1 and FIG. 5.

In a further embodiment, the compound of formula IV is:

In the presence of a base

을

of

와 반응시켜

React with

을 수득한 후,

After obtaining

Deprotecting the protecting group to give compound IV:

를

To

It can be produced by obtaining.

Wherein P and P 'are the same or different protecting groups. In one embodiment, compound IV is prepared according to example 2 and FIG. 6.

In another example, compound V is prepared according to Example 1 and FIG. 5.

In a further example, compound VI is prepared according to Example 3 and FIG. 7.

In another embodiment, compound VII is prepared according to Example 1 and FIG. 5.

In another embodiment, compound VIII is prepared according to Example 4 and FIG. 5.

In another embodiment, compound IX is prepared according to Example 5 and FIG. 8.

In another example, Compound X Hydrochloride is prepared according to Example 5 and FIG. 8.

In another example, compound XI is prepared according to Example 1 and FIG. 5.

In another example, compound XII is prepared according to Example 1 and FIG. 5.

Suitable hydroxyl protecting groups are, for example, methyl ether (methoxy), benzyl ether (benzyloxy) methoxymethyl (MOM) ether, benzoyloxymethyl (BOM) ether, benzyl, carbenzoxy, 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-bro Mofenacyl ether, cyclopropylmethyl 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-diclobenzyl Ter, 4- (dimethylamino) carbonylbenzyl ether, 4-methylsulfinylbenzyl 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 (TIPS) ether, aryl formate, arylacetate, aryl levulinate , Aryl pivaloate, aryl benzoate, aryl 9-fluorenecarboxylate, aryl methyl carbonate, 1-adamantyl carbonate, t-butyl carbonate, 4-methylsulfinylbenzyl 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), diphenylforce Pinotionyl Ester (Dpt-OAr), Ah And a methanesulfonate, aryl toluenesulfonate or aryl 2-formyl-benzenesulfonate.

The process of the invention involves the use of compounds IA, I-XII, and the preparation of the compounds of the invention comprises the step of reacting diphenyl amine 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 combinations thereof. In one embodiment, the base is pyridine.

The process of the invention involves the use of compounds IA, I-XII, and the process for the preparation of the compounds of the invention involves the deprotection of protected hydroxyls. In other embodiments, the deprotection conditions depend on the protecting group. In some embodiments, said deprotection step comprises hydrogenation in the presence of Pd / C. In other embodiments, the deprotection comprises a reaction with BBr ₃ . In another embodiment, the deprotection step comprises reaction with an acid.

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

Pharmaceutical composition

In some embodiments, the present invention comprises administering a composition comprising said compound. As used herein, the term "pharmaceutical composition" means a "therapeutically effective amount" of the active ingredient, ie the compound of the invention and a pharmaceutically acceptable carrier or diluent. A "therapeutically effective amount" means an amount that provides a therapeutic effect for a given symptom and method of administration.

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

In another embodiment, the invention includes a pharmaceutical product of a compound described herein. "Pharmaceutical product" means, in another embodiment, a composition (pharmaceutical composition) suitable for pharmaceutical use as described herein.

The compounds of the present invention can be administered alone or as active ingredients of the formulation. Accordingly, the present invention also encompasses pharmaceutical compositions of the compounds of formula I which comprise, for example, one or more pharmaceutically acceptable carriers.

Numerous standard references that describe procedures for preparing various formulations suitable for administration of the compounds according to the invention are useful. Examples of possible agents include, for example, Handbook of Pharmaceutical Excipients, American Pharmaceutical Association (current edition); Pharmaceutical Dosage Forms: Tablets (Lieberman, Lachman and Schwartz, editors) current edition, published by Marcel Dekker, Inc., and Remington's Pharmaceutical Sciences (Arthur Osol, editor), 1553-1593 (current edition).

The mode of administration and formulation are closely related to the therapeutic amount of the compound or composition that is desirable and effective for a given therapeutic application.

Suitable formulations include, but are not limited to, oral, rectal, sublingual, mucosal, nasal, eye, subcutaneous, intramuscular, intravenous, transdermal, spinal, spinal cavity, intraarticular, intraarterial, subarachnoid, bronchial, lymph Formulations for intrauterine administration, and systemic delivery of other active ingredients. Formulations suitable for oral administration are preferred.

For the preparation of such pharmaceutical formulations, the active ingredient is mixed with the pharmaceutical carrier according to typical pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration.

In preparing the compositions of the oral dosage form, any of the usual pharmaceutical media can be used. Thus, for example, for liquid oral preparations such as suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavors, preservatives, colorants and the like. For solid oral preparations such as, for example, powders, capsules and tablets, suitable carriers and additives include starch, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Due to its ease of 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 preparations, the carrier will usually comprise sterile water and may include other ingredients, such as ingredients to aid or preserve solubility. Injectable solutions can also be prepared using suitable stabilizers.

In some applications, the active agent is encapsulated in a liposome or other encapsulant medium or the active agent is covalently linked, chelated or coordinated onto a suitable biomolecule such as for example selected from proteins, lipoproteins, glycoproteins and polysaccharides. It would be advantageous to use in a "vectorized" form, such as by fixation.

The methods of treatment of the present invention using preparations suitable for oral administration may be presented as discrete units such as capsules, cachets, tablets or lozenges, each containing a predetermined amount of active ingredient as a powder or granules, for example. have. Optionally, suspensions in aqueous liquids or non-aqueous liquids can be used, such as syrups, elixirs, emulsions or drafts.

Tablets may be made by compression or molding, or by wet granulation, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing the active compound in a suitable machine, for example in a free-flowing form such as a powder or granules which are optionally mixed with a binder, disintegrant, lubricant, inert diluent, surfactant or excipient. Molded tablets consisting of the powdered active compound and a suitable carrier can be prepared by molding in a suitable machine.

Syrups can be prepared by adding the active compound to a concentrated aqueous solution of sugar, for example sucrose, and also adding any auxiliary component (s) thereto. Such auxiliary component (s) may include flavoring agents, suitable preservatives, agents that retard crystallization of sugars, and agents that increase the solubility of other components such as polyhydroxy alcohols such as glycerol or sorbitol.

Formulations suitable for parenteral administration include sterile aqueous formulations of the active compounds, which are preferably isotonic with the blood of the recipient (eg physiological saline). Such formulations may include suspending and thickening agents and liposomes or microparticle systems designed to target the blood component or one or more organs. The formulations may be presented in unit dose or in multiple dosage forms.

Parenteral administration can include any suitable form of systemic delivery. Administration can be, for example, intravenous, intraarterial, intrathecal, intramuscular, subcutaneous, intraperitoneal, and the like, and can be carried out by means of infusion pumps (external or insertable) or other means suitable for the desired mode of administration.

Nasal and other mucosal spray formulations (eg, inhalable forms) may include aqueous solutions of the tablets of the active ingredient and preservatives and isotonic agents. Such formulations are preferably adjusted to a pH and isotonic state compatible with the nose or other mucous membranes. Alternatively, it may be in the form of a finely divided solid powder in the gas carrier. Such formulations may be delivered by any suitable means or method, such as nebulizers, nebulizers, metered dose inhalers and the like.

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

Transdermal formulations incorporate the active agent into a cellulose medium, for example a thixotropic or gelatinous carrier such as methyl cellulose or hydroxyethyl cellulose, and then a transdermal device adapted to hold the resulting formulation in contact with the skin of the wearer. It can be prepared by packing in.

In addition to the above ingredients, the formulations of the present invention may comprise one or more accessory ingredient (s) selected from, for example, diluents, buffers, flavoring agents, binders, disintegrants, surfactants, thickeners, lubricants, preservatives (including antioxidants), and the like. It may further comprise.

The formulations of the present invention may have a rapid release, slow release, delayed release or other release profile known in the art.

In one embodiment, the invention comprises administering an oral composition comprising a compound of formulas IA, I-XII, by reducing LH hormone or by reducing LH hormone in a male subject with prostate cancer. Irrespective of a) reducing total serum testosterone levels; b) providing a method for reducing free serum testosterone levels. In additional embodiments, the method of the present 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. Use

In one embodiment, the invention comprises administering an oral composition comprising a compound of formulas IA, I-XII, by reducing LH hormone or by reducing LH hormone in a male subject with prostate cancer. Provides a way to treat prostate cancer regardless. In additional embodiments, the present 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. Provided is a method for treating prostate cancer in a male subject having prostate cancer, by reducing LH or irrespective of LH hormone reduction.

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

In one embodiment, the methods of the present invention comprise administering a compound of the present invention in various dosages. In one embodiment, the compound of the present invention is administered at a dosage of 1-1500 mg per day. In an additional embodiment, the compounds of the invention are 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 per day -60mg, 50-100mg per day, 50-200mg per day, 150-300mg per day, 25-50mg per day, 5-50mg per day, 200-500mg per day, 150-500mg per day, 200-1000mg per day , 300-1500 mg per day, or 100-1000 mg per day.

In one embodiment, the methods of the present invention comprise administering a compound of the present invention in various dosages. In one embodiment, the compound of the present invention is administered at a dosage of 3 mg. In additional embodiments, the compounds of the present invention are administered in dosages of 10 mg, 30 mg, 50 mg, 100 mg, 200 mg, 300 mg, 450 mg, 500 mg, 600 mg, 900 mg, 1000 mg or 1500 mg.

In one embodiment, the methods of the present invention comprise administering a compound of the present invention in various dosages. In one embodiment, the compound of the present invention is administered at a dosage of 0.1 mg / kg / day. In additional embodiments, the compounds of the present invention comprise 0.2 to 30 mg / kg / day, or 0.2 mg / kg / day, 0.3 mg / kg / day, 1 mg / kg / day, 3 mg / kg / day, 5 mg / kg / day, 10 mg / kg / day, 20 mg / kg / day or 30 mg / kg / day.

In one embodiment, the methods of the present invention provide the use of a pharmaceutical composition comprising a compound of formulas IA, I-XII. In additional embodiments, the methods of the present invention comprise 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. Provides use of the composition.

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

For administration to mammals, especially humans, the physician will determine the actual dosage and duration of treatment, which will be best suited for the individual and will vary with age, weight, sex and / or the response of the particular individual.

In some embodiments, the compositions of the present invention will comprise the compounds of the present invention in any form or embodiment described herein. In some embodiments, a composition of the present invention will consist of a compound of the present invention in any form or embodiment described herein. In some embodiments, the compositions of the present invention will consist essentially of the compounds of the present invention in any form or embodiment described herein. In some embodiments, the term "comprising" includes directed active ingredients and other active agents, such as the compounds of the present invention, and pharmaceutically acceptable carriers, excipients, emollients, stabilizers, and the like, known in the pharmaceutical industry. it means. In some embodiments, the term “consisting essentially of” may include the active ingredient indicated as the only active ingredient, but for the stabilization, preservation, etc. of the formulation, or other compounds not directly involved in the therapeutic effect of the indicated active ingredient. Means a composition. In some embodiments, the term “consisting essentially of” can mean a component that promotes release of the active ingredient. In some embodiments, the term “consisting of” means a composition containing the active ingredient and a pharmaceutically acceptable carrier or excipient.

Any use of any of the compounds described herein can be used to treat any of the diseases, disorders or symptoms described herein and will be understood to represent embodiments of the invention. In one embodiment, the compound is a free base, free acid, non-charged or non-complexed compound.

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

Example

Example  One

expression II - XII General synthetic procedures and synthetic intermediates for the compounds of

Organic solvents, surfactants, antioxidants, and the like that 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 can be purchased from Dow Chemical Company (Midland, MI), ICI Americas, Inc (Wilmington, DE) or Abitec Corporation (Janesville, WI). .

The estrogen receptor ligands described herein can be prepared in a variety of ways known in the art. For example, the estrogen receptor ligands described herein can be prepared by the synthetic methods described in US 2009/0062341, the disclosure of which is incorporated herein by reference in its entirety.

N, N- Vis  Aryl Benzamide  General Synthesis of Derivatives

General Synthesis of Diarylaniline (FIG. 5) . A mixture of arylamine (1.5 equiv), aryl iodide (1 equiv), K ₂ CO ₃ (2 equiv), CuI (0.1 equiv) and L-proline (0.2 equiv) were mixed together and dissolved in dry DMSO at room temperature It was. The reaction mixture was then stirred and heated at 90 ° C. for 28 hours. The mixture was cooled to room temperature and hydrolyzed with water. EtOAc was added to partition the solution. 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 / hexanes as eluent to afford the corresponding diarylaniline.

Bis- (4 -methoxyphenyl ) amine (1a) : pale yellow solid, 73% yield. Mp 98.6-99.0 ° C. ¹ H NMR (CDCl ₃ , 300 MHz) δ 6.63-6.81 (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. Mp 106.3-106.5 ° C. ¹ H NMR (CDCl ₃ , 300 MHz) δ7.24-7.18 (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 ° 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 Benzamides . A mixture of arylaniline (1 equiv), benzoyl chloride (1.3 equiv), and pyridine (6 equiv) were mixed together and dissolved in dry THF at room temperature. The mixture was stirred and refluxed for 24 hours. The reaction solution was cooled to room temperature and hydrolyzed by addition of 2N HCl solution. The solution was extracted with ethyl acetate. The organic layer was washed with saturated aqueous NaHCO ₃ solution to remove excess acid, dried over anhydrous MgSO ₄ , and concentrated under reduced pressure. The residue was purified by flash column chromatography using EtOAc / hexane (3/7 v / v) to afford the corresponding benzamide compound.

3- Fluoro- N- (4- fluorophenyl ) -4 -methoxy- N- (4 -methoxyphenyl ) benzamide (2a) : yellow solid, Mp 54-56 ° C. ¹ H NMR (CDCl ₃ / TMS) δ 7.24-7.11 (m, 4H), 7.05-6.97 (m, 4H), 6.85-6.78 (m, 3H), 3.86 (s, 3H), 3.79 (s, 3H) . MS (ESI) m / z 370.1 [M + H] ⁺

4- Fluoro- 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, 3 H), 3.71 (s, 3 H). MS m / z 442.1 (M + Na) ⁺ .

4 -methoxy- N- (4 -methoxyphenyl ) -N- (4- fluorophenyl ) -benzamide (2c) : white solid, 97% yield, Mp 133.5-134.5 ° 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- benzoylphenyl ) -2 -naphthylamide (2d) : white solid, 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) ⁺ .

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, 3 H), 3.71 (s, 3 H). MS m / z 442.1 (M + Na) ⁺ .

General procedure for the demethylation of a benzamide derivative 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 allowed to slowly warm up to room temperature and stir overnight at room temperature. The mixture was cooled to 0 ° C. in an ice bath and hydrolyzed by the addition of water. EtOAc was added to partition the solution. Separating the organic layer; 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 afford 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) δ9.55 (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 and characterized as described herein above 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).

Of the benzamide-benzyloxyphenyl General Procedure for Debenzylation . The compound was dissolved in EtOH in a 250 mL hydrogenation vessel. Pd / C powder (5% mol) was added to the solution. The reaction vessel was mounted to a hydrogenation apparatus under 20 psi pressure hydrogen gas. The reaction was monitored until the starting material disappeared. Then the solvent was removed under reduced pressure. The residue was purified by flash column chromatography using hexanes / EtOAc = 3 / 2v / v to afford the desired product.

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

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

The following compounds were synthesized and characterized as described herein 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 . To a hydroxyphenyl solution containing benzamide analogue (1 equiv) in acetone, K ₂ CO ₃ (3 equiv) and N-chloroethyl-piperidine hydrochloride (1.2 equiv) were added. The solution was heated to reflux for 6 hours. The solution was evaporated to dryness. The residue was hydrolyzed by addition of 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 using methylene chloride / methanol = 9/1 v / v to afford the desired compound. Hydrochloride was prepared by adding HCl in Et ₂ O to the methanol solution of the compound and then evaporating the solvent.

The following compounds were synthesized and characterized as described herein 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).

Compound # rescue Physical identification II

¹ H NMR (DMSO-d6, 300 MHz) δ 9.46 (s, 2H, 2 X OH), 7.27-7.26 (m, 2H, ArH), 7.06-7.04 (m, 2H, ArH), 6.99-6.97 (m , 4H, ArH), 6.66-6.65 (m, 4H, ArH), 2.50 (s, 2H, CH2, overlapped with DMSO peak), 1.53-1.52 (m, 2H, CH2), 0.82 (t, J = 7.33 Hz, 3H, CH 3). m / z 346.0 (MH) III

Tan foam, 41% yield. Mp 147-150 ° C. _{^{1 H NMR (DMSO- d 6,}} 300 MHz) δ 8.92 (s, 2H), 7.07 (d, J = 7.33 Hz, 1H), 7.00-6.94 (m, 2H), 6.76-6.72 (m, 4H), 6.63-6.59 (m, 4H), 4.72 (s, 2H), 2.23 (s, 3H), 2.16 (s, 3H). m / z 320.2 (M + H) ⁺ IV

Tan solid, 92% yield. Mp 110-112 ° C. _{^{1 H NMR (DMSO- d 6,}} 300 MHz) δ10.14 (bs, 1H), 9.71 (bs, 1H), 7.26-7.11 (m, 5H), 7.05-6.99 (m, 3H), 6.78 (t, J = 8.61 Hz, 2H), 6.68 (d, J = 8.68 Hz, 2H). m / z 364.1 (M + Na) ⁺ V

¹ H NMR (DMSO-d6, 300 MHz) δ9.47 (bs, 2H, 2 X OH), 7.18 (d, J = 8.30 Hz, 2H, ArH), 7.06 (d, J = 7.08 Hz, 1H, ArH ), 7.00-6.92 (m, 4H, ArH), 6.78 (d, J = 8.30 Hz, 2H, ArH), 6.51 (d, J = 8.06 Hz, 2H, ArH), 2.22 (s, 3H, CH3), 2.15 (s, 3 H, CH 3). m / z 334.3 (M + H) &lt; + &gt; VI

White solid, 70% yield. Mp 264.3-265.2 ° C (decomposed). ¹ H NMR (DMSO- d ₆ , 500 MHz) δ9.46 (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). m / z 356 (M + H) ⁺ VII

¹ H NMR (DMSO- d ₆ , 300 MHz) δ 10.25 (bs, 1H, OH), 9.48 (bs, 2H, 2 X OH), 7.12-6.95 (m, 6H, ArH), 6.80-6.65 (m , 5H, ArH). m / z 338.0 (MH) ^- VIII

Yellow oil, 92% yield. _{^{1 H NMR (DMSO- d 6,}} 500 MHz) δ9.29 (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). m / z 307.8 (MH) ^- IX
And X
(IX HCl Salt)

White solid, 57.7% yield. ¹ H NMR (DMSO- d ₆ , 300 MHz) δ9.57 (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). m / z 501.0 (MH) ^- XI

¹ H NMR (DMSO-d6, 300 MHz) δ9.95 (bs, 1H, OH), 9.47 (bs, 2H, 2 X OH), 7.02-6.95 (m, 6H, ArH), 6.75-6.72 (m, 1H, ArH), 6.68-6.66 (m, 4H, ArH). m / z 324.0 (M + H) &lt; + &gt; XII

Light red solid. 72.0% yield. Mp> 240 ° C. ¹ H NMR (DMSO- d ₆ , 300 MHz) δ9.50 (bs, 2H), 7.19-6.79 (m, 7H), 6.61 (d, J = 8.93 Hz, 2H), 6.53 (d, J = 7.79 Hz , 2H), 2.23 (s, 3H). m / z 336.0 (M ⁻ H) ⁻ .

Example  2

expression IV Synthesis of Compounds (FIG. 6)

Step 1: 4- Fluoro -N- (4- Methoxyphenyl Synthesis of Aniline (1c)

4-fluoroaniline (78.63 g, 0.708 mol), 4-iodoanisole (138.00 g, 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) was mixed together in a dry 1 L three neck round bottom flask equipped with a stir bar, reflux condenser and argon inlet. Anhydrous DMSO (300 mL) was added at room temperature. The reaction mixture was stirred and heated at 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 to partition the solution. The EtOAc layer was separated. The aqueous layer was extracted with 100 mL of EtOAc. The EtOAc layers were combined, washed with brine (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, hexanes / EtOAc = 9/1 v / v) to afford 4-fluoro-N- (4-methoxyphenyl) aniline (1c) as a yellow solid product, Obtained as 99.70 g, 77.6% yield. Mp 46-48 ° C. MS (ESI) m / z 218.1 [M + H] +, 1 H NMR (DMSO- d 6, 300 MHz) δ7.77 (bs, 1H), 7.03-6.98 (m, 4H), 6.93-6.82 (m , 4H), 3.70 (s, 3H).

Step 2: 3- Fluoro -N- (4- Fluorophenyl )-4- Methoxy -N- (4- Methoxyphenyl Synthesis of Benzamide (2a).

4-Fluoro-N- (4-methoxyphenyl) aniline (1c) (90.78 g, 0.418 mol) and 3-fluoro in a dry 1 L three necked round bottom flask equipped with a stir bar, reflux condenser and argon inlet Rho-4-methoxybenzoyl chloride (94.55 g, 0.501 mol) was mixed together and dissolved in anhydrous THF (200 mL). Anhydrous pyridine (132.22 g, 1.672 mol) was added via syringe under argon at room temperature. The reaction mixture was stirred and heated to reflux overnight. The reaction mixture was cooled to room temperature and filtered to remove the pyridine salt. The solution was concentrated to remove THF solvent. The residue oil was washed with 200 mL of 2N HCl solution and extracted with ethyl acetate (2 × 200 mL). The combined organic layer was washed with saturated aqueous Na ₂ CO ₃ solution (150 mL) to remove excess benzoyl chloride and acid, dried over MgSO ₄ (50 g) and concentrated under reduced pressure to give an oil. The residue was purified by flash column chromatography using silica-gel with CH ₂ Cl ₂ / acetone (50/1 v / v) to afford 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 dried under argon at room temperature CH ₂ It was dissolved in Cl ₂ (600 mL). BBr ₃ (374.75 g, 1.496 mol) was added dropwise while stirring through a syringe at 0 ° C. in an ice bath under argon. The reaction solution was allowed to stir overnight at room temperature. The solution was then poured with 1 L ice water with stirring. The slurry mixture was stirred at room temperature for 2 hours. The white precipitate was filtered off, washed with water (2x 100 mL) and dried in vacuo. 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 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) to give a pale tan solid. It was obtained, which was recrystallized twice from a hot EtOAc / hexane solution to give a white crystalline solid in 104.0 g, 81.6% yield. Mp 110-112 ° C. MS (ESI) m / z 364.1 [M + Na] +, 1 H NMR (DMSO- d 6) δ10.14 (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

expression VI Synthesis of Compounds (FIG. 7)

4-( Benzoyloxy ) -N- (4- Methoxyphenyl Synthesis of aniline (1d).

4-benzoyloxyaniline (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) was mixed together and dissolved in dry 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 / hexanes (1/9 v / v) to give the corresponding diarylaniline as a yellow solid in 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) ⁺ .

N- (4- Benzoyloxyphenyl ) -N- (4- Methoxyphenyl )-2- Naphtamide  Synthesis of (2d).

In a dry three-neck round bottom flask equipped with a magnetic stirrer and a reflux condenser, one equivalent of 4- (benzoyloxy) -N- (4-methoxyphenyl) aniline (0.80 g, 2.62 mmol) was added 1.5 equivalents of 2- Mix with 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 / hexane (3/7 v / v) to give the pure corresponding naphtamide compound as a white solid at 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) ⁺ .

N, N- Vis (4- Hydroxyphenyl )-2- Naphthylamide  ( VI ) Synthesis.

Compound N- (4-benzoyloxyphenyl) -N- (4-methoxyphenyl) -2-naphtamide (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 1.0 M CH ₂ Cl ₂ solution, 3.26 mmol) was added dropwise via stirring at room temperature. The reaction solution was allowed to stir overnight at room temperature. The mixture was cooled to 0 ° C. in an ice bath and hydrolyzed by the addition of water. EtOAc was added to partition the solution. Separating the organic layer; 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 reduced pressure. The residue was purified by flash column chromatography using silica-gel with CH ₃ OH / CH ₂ Cl ₂ (1/9 v / v) to afford the desired phenolic compound as a white solid in 0.27 g, 70% yield. Mp 264.3-265.2 ° C. (decomposed). ¹ H NMR (DMSO- d ₆ , 500 MHz) δ9.46 (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

expression VIII Synthesis of Compounds.

4-((4- Fluorophenyl )(4- Hydroxybenzyl ) Amino) phenol ( VIII ) Synthesis.

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 under argon at room temperature. The reaction solution was stirred and heated to reflux for 6 hours. The reaction was then quenched by addition of 10 mL of MeOH at 0 ° C. The solvent was removed under reduced pressure. The residue was flash column chromatography (silica-gel, CH ₂ Cl ₂ / MeOH = 9/1 v / v) to give a yellow oil in 0.26 g, 92% yield. _{^{1 H NMR (DMSO- d 6,}} 500 MHz) δ9.29 (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

expression IX  And synthesis of the compound of X (FIG. 8).

Synthesis of Diarylaniline . Arylamide (1.5 equiv), aryl iodide (1 equiv), K ₂ CO ₃ (2 equiv), CuI (1 equiv) and L-proline (0.2 equiv) were mixed together and dissolved in dry 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. 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 using EtOAc / hexane (3/7 v / v) as solvent to afford the corresponding diarylaniline. Bis- (4 -methoxyphenyl ) amine (1a) : pale yellow solid, 73% yield. ¹ H NMR (CDCl ₃ , 300 MHz) δ 6.63-6.81 (m, 8H), 5.37 (s, br, 1H), 3.78 (s, 6H). MS m / z 228.4 (MH) ⁺ .

4- With flow -N, N- Vis (4- Methoxyphenyl )-2-( Trifluoromethyl ) Benzami Synthesis of de (2e).

In a dry three-neck round bottom flask equipped with a magnetic stirrer and a reflux condenser, 1 equivalent of bis- (4- methoxyphenyl) amine (1a) (0.73 g, 3.18 mmol) was added in 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) were mixed. 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 afford the pure corresponding benzamide compound as colorless oil in 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, 3 H), 3.71 (s, 3 H). MS m / z 442.1 (M + Na) ⁺ .

4- Fluoro -N, N- Vis (4- Hydroxyphenyl )-2-( Trifluoromethyl ) Benzia Synthesis of mead (3a).

Compound 4-fluoro-N, N-bis (4-methoxyphenyl) -2- (trifluoromethyl) benzamide (2e) (1.00 g, 2.38 mmol) was dried at room temperature CH ₂ Cl ₂ (30 mL )). BBr ₃ (10 mL of 1.0 M CH ₂ Cl ₂ solution, 10.0 mmol) was added dropwise via syringe at room temperature. The reaction solution was stirred overnight at room temperature. The mixture was cooled to 0 ° C. in an ice bath and hydrolyzed by the addition of water. EtOAc was added to partition the solution. Separating the organic layer; The aqueous layer was extracted twice with EtOAc. Combine organic layers, wash with brine and dry anhydrous MgSO ₄ Dried over. The solvent was removed under reduced pressure. The residue was purified by flash column chromatography using silica gel with CH ₃ OH / CH ₂ Cl ₂ (1/9 v / v) to afford the pure desired phenolic compound as a white solid in 0.86 g, 92.5% yield. ¹ H NMR (DMSO- d ₆ , 300 MHz) δ9.55 (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) ⁺ .

4- Fluoro -N- (4- Hydroxyphenyl ) -N- [4- (2-piperidin-1-yl)- Ethoxy ) Pe Neil] -2- ( Trifluoromethyl ) Benzamide  ( IX )

To a solution of 4-fluoro-N, N-bis (4-hydroxyphenyl) -2 (trifluoromethyl) benzamide (3a) (0.61 g, 1.56 mmol) in acetone, 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 afford the desired compound as a white solid in 0.45 g, 57.7% yield. ¹ H NMR (DMSO- d ₆ , 300 MHz) δ9.57 (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 the methanol solution of the compound and then evaporating the solvent.

Example  6

Estrogen Receptor Binding Affinity, Agonist and Antagonist Activity

Of [2,4,6,7- ³ H (N)] of natural high-affinity ligand ER-estradiol ^([3 H] E2) and expressed by the bacterial GST fusion ER-α or ER-β ligand binding domain ( In vitro competitive radioligand binding assays using LBD) proteins were used to determine the ER binding affinity of these compounds.

Way

The recombinant ER-α or ER-β in combination with ^[3 H] E ₂ was determined equilibrium dissociation constant (Kd) of ^[3 H] E _2. To measure total and non-specific binding, proteins were incubated with increasing concentrations of [ ³ H] E _{2 in} the presence or absence of high levels of unlabeled E ₂ at 18 ° C. for 18 hours. Aside from non-specific binding, nonlinear regression was used to determine the Kd of E ₂ (ERα: 0.71 nM; ERβ: 1.13 nM). In addition, the [ ³ H] E ₂ required to saturate ER-α and ER-βLBD was determined to be 4-6 nM.

Increasing concentrations of compound (range: 10 ⁻¹¹ to 10 ⁻⁶ M) were incubated with [ ³ H] E ₂ (5.7 nM) and ER LBD using the above conditions. After incubation, plates were harvested using GF / B filters on Unifilter-96 Harvester (PerkinElmer) and washed three times with very cold buffer B (50 mM Tris, pH 7.2). The filter plate was dried 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 in the TopCount® NXT Microplate Scintillation Counter using a setting for 3H in Microscint cocktail (PerkinElmer).

^[3 H] (determined by incubating with 10 ^-6 M unlabeled E ₂₎ determining the specific binding of ^[3 H] E ₂ by subtracting the non-specific binding of E ₂ at each concentration of compound, and this compound under test member It is expressed as a percentage of specific binding. The concentration of the compound (IC ₅₀ ) that reduced the specific binding of [ ³ H] E ₂ by 50% was determined. Next, the equilibrium binding constant (Ki) of the compounds was calculated as _{follows: K i = K d X IC} 50 / (K d + L), where K _d is ^[3 H] and the equilibrium dissociation constant for E ₂ (ER -α = 0.11 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

Binding assays show that the ligand binds to ER-α and ER-β in a range of concentrations ranging from 3.75 nM to 1000 nM or more and isoform selective to non-isoform selective selectivity. The results from representative compounds are listed in Table 2.

Binding Results for Selected Compounds compound ER-α Ki (nM) ER-β Ki (nM)

3.75


81.6

3.81


6.44

21.7


15.2

7.13


35.9

9


72

6.06


76.92

13


19

14.79


646.32

15


57

15.12


25.02

Compound IV binds to ERα and ERβ. Of [2,4,6,7- ³ H (N)] of natural high-affinity ligand ER-estradiol ^([3 H] E ₂₎ and by the bacteria expressing GST-fusion that ERα or ERβ ligand binding domain (LBD) protein The ER binding affinity of Compound IV was measured using an in vitro competitive radioligand binding assay. In this assay, ERα and ERβ binding affinity of Compound IV ( Ki Value) were 21.7 ± 1.7 nM (n = 3) and 15.2 ± 4.1 nM (n = 3), respectively. Upon binding to ER, Compound IV initiates a series of complex molecular reactions that result in expression or inhibition of the target gene involved in pharmacological response in a tissue selective manner. In transient transfection assays, compound IV was an ERα and ERβ agonist and demonstrated greater ability to stimulate ERα-mediated transcriptional activity as compared to ERβ. Estradiol stimulates ERα and ERβ with 5.1 times greater selectivity for ERα, while Compound IV shows 49.0 fold selectivity for ERα. Thus, Compound IV has a relative 9.7-fold selectivity (normalized to estradiol values) in terms of relative transcriptional activity against ER [alpha] relative to ER [beta]. In addition, no antagonistic effect was observed in estradiol (1 nM) -stimulated transcriptional activity by Compound IV at concentrations of 10 μM or less. Many steroidal ligands cross react with other nuclear hormone receptors, but the action of Compound IV is specific for ERα and ERβ. Compound IV was subjected to glucocorticoid receptor (GR), mineralocorticoid receptor (MR), progesterone receptor (PR), androgen receptor (AR), and farnesoid X in both agonist and antagonist modes in transcriptional activity analysis Screening for Cross Reactivity of Human Receptor (FXR), Liver X Receptor (LXT), Peroxysome Proliferator Activated Receptors (PPAR-α and PPAR-γ), and Retinoid X Receptor (RXR-α) to Human Isoforms It was. Compound IV did not show any agonist or antagonist activity in this assay, supporting the conclusion that Compound IV does not functionally cross-react with these nuclear hormone receptor superfamily members.

Example  7

Transcriptional Activation of Selected Compounds

Transcriptional activation assays in agonist and antagonist modes were performed to determine whether the compound was an agonist, antagonist or partial.

Way

Rat estrogen receptors (ER-α and ER-β) were cloned from rat ovary cDNA into the pCR 3.1 plasmid vector backbone. Sequencing was performed to determine the absence of mutation. HEK-293 cells were plated at 100,000 cells per well in 24 well plates in Dulbecco's Minimal Essential Media (DMEM) + 5% charcoal-free fetal bovine serum (csFBS). The cells were transfected with 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-. The cells were treated for 24 hours after transfection with various concentrations of compounds or combinations of compounds and estradiol to determine antagonist activity 48 hours after transfection, luciferase assays were performed.

result

Screening of the compounds of the present invention in transcriptional activation systems indicated that the compounds of the present invention belong to all three classes of agents, antagonists and partial agents. Examples of agonists and antagonists are given in Table 3. Tranactivation results matched well with binding results for isoform selectivity.

Table 3 provides EC ₅₀ and IC ₅₀ transcriptional activation for some selected compounds of the invention.

compound ER -α
EC ₅₀  ( nM ) ER -β
EC ₅₀  ( nM ) ER -α
IC ₅₀  ( nM ) ER -β
IC ₅₀  ( nM )

0.65




40.4



> 1000



> 1000

> 1000


> 1000


2.207


145

Example  8

Cynomolgus  Testosterone Inhibition in Monkeys

Germline-intact male cynomolgus monkeys (n = 2) of 2 years of age were received during the study according to the USDA guidelines (except fasting prior to oral administration) with free access to primate diet and water. Animals received an oral gavage dose of 30 mg / kg of the compound of formula IV once daily in a microemulsion vehicle of Tween 80 / deionized water for 7 consecutive days. At 1 (baseline), 3, 4, 5, 6, and 7 days, serum samples were removed by venipuncture before oral dose administration. Testosterone and total androgen were each quantified using enzymatic immunoassay (EIA) with or without the HPLC method. After 6 days of treatment of the compound of formula IV, a time-dependent decrease in testosterone and total androgen was evident (testosterone / dihydrotestosterone). Compounds of formula IV inhibited testosterone levels by 58% and 64% in Animal # 1 and Animal # 3, respectively, compared to baseline values (solid line in FIG. 1; see Table 4). Similarly, total androgen levels were 56% inhibited in animals # 1 and # 3 compared to baseline values (dashed line in FIG. 1; see Table 4).

Consistent with the estrogen feedback of the pituitary-testicular axis in males, these results indicate that serum hormones (testosterone and total) in intact nonhuman primates (cynomolgus monkeys) after repeated oral administration (30 mg / kg) of the compound of formula IV Strong pharmacological response to inhibition of androgens).

Testosterone and total androgen levels in intact male monkey serum receiving 30 mg / kg oral dose of compound of formula IV daily (first dose on day 0). Testosterone Total androgen Serum level (pg / mL) Serum level (pg / mL) Work Animals 1 Animals 3 Animals 1 Animals 3 0 (baseline) 1120 617 1868 1643 2 937 479 1178 847 3 784 437 1078 786 4 552 415 988 924 5 403 276 966 664 6 474 221 819 726
Percentage reduction from baseline
Percentage reduction from baseline Work Animals 1 Animals 3 Animals 1 Animals 3 0 (baseline) 100 100 100 100 2 16 22 37 48 3 30 29 42 52 4 51 33 47 44 5 64 55 48 60 6 58 64 56 56

Example  9

Rat  of mine LH  And suppression of testosterone hormone levels

In vivo dose-response studies were performed to assess the effect of Compound IV on LH inhibition in intact and testicular excision (ORX) male rats. In intact and ORX animals, Compound IV significantly inhibited LH levels compared to each control at a dose of ≧ 10 mg / kg daily. (Inhibition of the same pattern was observed for FSH levels). LH inhibition greatly reduced testosterone levels (BLOQ) below the quantitative limit of 0.08 ng / mL, and reduced their weight because the prostate, seminal vesicles and anus muscles were very androgen-dependent organs. In intact animals, a dose dependent decrease in these target organ crabs was noted with the seminal vesicle and anus muscle weights of the levels of castrated controls. Prostate weight was significantly reduced in intact animals, but this value did not reach the castrated control level. The results are summarized in Table 6 below.

Material and method :

Male Sprague-Dawley rats weighing approximately 200 g were maintained in a 12-h light / dark cycle with an unlimited supply of food (2016 Teklad Global 16% Protein Rodent Diet, Harlan, Madison, Wis.). The animal protocol was reviewed and approved by the Animal Experimentation Ethics Committee of the University of Tennessee.

Test materials for this study were quantified and dissolved in 10% DMSO (Fisher) diluted with PEG 300 (Acros Organics, NJ) to prepare a suitable dosage formulation. For this study, 60 male Sprague-Dawley rats were randomized to body weight and assigned to one of 12 treatment groups (n = 5 animals / group). The treatment groups are listed in Table 5. Animals were housed in groups of 2-3 animals per group. Vehicles were administered daily to controls (intact and testicular excision (ORX)). Compound IV was administered via subcutaneous injection to both intact and ORX groups at doses of 0.3, 1, 3, 10 and 30 mg / kg / day (200 μL).

After a 14-day dosing regimen, animals were anesthetized (ketamine / xylazine, 87:13 mg / kg) and sacrificed and body weight was recorded. In addition, the ventral prostate, seminal vesicles and anus muscles were removed, external tissues were removed and quantified individually. Organ weights were normalized to body weight and expressed as percentage of intact controls. Blood was collected from the abdominal aorta and allowed to coagulate under isoflurane anesthesia. Serum was separated by centrifugation and stored at −80 ° C. before measurement of serum hormone levels. Serum luteinizing hormone (LH) and follicle stimulating hormone (FSH) concentrations were measured by rat pituitary luminescence analysis (Millipore, Billerica, Mass.) According to manufacturer's instructions. The lower limit of quantitation 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 LLOQ of 0.08 ng / mL. (BLOQ) serum hormone values below the lower limit of quantification were excluded from the group mean analysis. Thus, the values reported for LH and T in the group with sample BLOQ are below the actual values. This analytical method provided an estimate of the most conservative LH and T inhibition. Fisher's Least Signigicant Difference test was used to compare individual dose groups to intact and ORX vehicle controls. Significance was previously defined as P-value <0.05.

Treated group group Gonad state Dose ( mg Of kg Of day ) Test substance One Intact - Vehicle 2 ORX - Vehicle 3 Intact 0.3 Compound IV 4 Intact One Compound IV 5 Intact 3 Compound IV 6 Intact 10 Compound IV 7 Intact 30 Compound IV 8 ORX 0.3 Compound IV 9 ORX One Compound IV 10 ORX 3 Compound IV 11 ORX 10 Compound IV 12 ORX 30 Compound IV

Intact  And ORX Rat  Progesterone Hormone Levels (Table 6)

LH levels (mean ± SD) in intact and ORX vehicle controls were 1.46 ± 0.64 and 11.1 ± 3.9 ng / mL, respectively. Compound IV reduced LH levels dose-dependently in intact animals, resulting in a statistically significant reduction of daily dose ≧ 3 mg / kg. LH levels in intact Compound IV treated animals were 0.863 ± 0.384, 0.704 ± 0.530, 0.395 ± 0.302, 0.226 ± 0.165, and 0.236 ± 0.176 ng after administration of 0.3, 1, 3, 10 and 30 mg / kg / day, respectively. / mL. LH levels in ORX males were also significantly reduced by Compound IV treatment. In ORX animals, LH levels were 15.4 ± 2.9, 13.5 ± 2.2, 6.5 ± 5.6, 0.425 ± 0.135, and 0.368 ± 0.119 ng / mL, respectively, after administration of 0.1, 1, 3, 10 and 30 mg / kg / day, respectively. It was. The results are presented graphically in FIG. 10A.

Intact  And ORX Rat  My follicle stimulating hormone levels (Table 6)

FSH levels in intact and ORX vehicle controls were 20.9 ± 8.5 and 93.5 ± 13.8 ng / mL, respectively. In intact animals, Compound IV reduced FSH levels dose-dependently and a significant decrease was observed at doses> 10 mg / kg / day. FSH levels in intact Compound IV treated animals were 17.3 ± 6.4, 15.7 ± 7.3, 18.4 ± 7.7, 9.2 ± 4.0, and 6.3 ± 1.8 ng, respectively, after administration of 0.3, 1, 3, 10 and 30 mg / kg / day, respectively. / mL. In ORX animals, LH levels were 115 ± 17, 114 ± 22, 65.2 ± 31.9, 27.6 ± 8.2, and 15.1 ± 4.1 ng / mL, respectively, after administration of 0.3, 1, 3, 10 and 30 mg / kg / day, respectively. . The results are presented graphically in Figure 10b.

Intact  And ORX Rat  My testosterone levels

Serum testosterone in the intact vehicle control was 2.4 ± 1.1 ng / mL. The lower limit of quantitation for T was 0.08 ng / mL. Values less than 0.08 ng / mL are indicated below the limit of quantitation (BLOQ). In intact animals, the compound of formula IV reduced T levels dose-dependently and a significant decrease was observed at doses of ≧ 3 mg / kg / day. Testosterone levels in intact animals treated with the compound of formula IV were 2.6 ± 1.7, 1.6 ± 1.0, 0.7 ± 0.4, BLOQ, and BLOQ ng, respectively, after administration of 0.3, 1, 3, 10 and 30 mg / kg / day, respectively. / mL. In ORX animals, T levels were BLOQ for all Compound IV treated groups and vehicle treated groups. Results for intact animals are presented graphically in FIG. 10C (and FIG. 2) (shown as quantitative limits for graphically presenting BLOQ values).

After 24h, 74h and 168h, as shown in FIG. 9, Compound IV was administered at doses of 3 mg / kg, 10 mg / kg and 300 mg / kg to induce rapid and potent inhibition of serum testosterone in intact male rats. Measured.

Organ weight (Table 6)

Prostate, seminal vesicles and anus muscles were measured to confirm the inhibition of T. Organ weights (mean ± SD) are shown in FIGS. 10 d, 10e and 10f, respectively. Dose-dependent decreases in prostate, seminal vesicles and anus muscles were observed in intact animals treated with Compound IV. Intact animals weighed 84.0 ± 19.2, 75.2 ± 20.7, 68.2 ± 8.1, 45.1 ± 20.0, and 43.6 ± 8.8 after administration of 0.3, 1, 3, 10 and 30 mg / kg / day, respectively. Prostate weights in ORX animals were 19.0 ± 4.2, 17.4 ± 3.4, 19.6 ± 6.7, 22.9 ± 5.4, and 20.6 ± 2.1, respectively, after administration of 0.3, 1, 3, 10 and 30 mg / kg / day. Intact seminal vesicle weights were 76.2 ± 7.8, 66.3 ± 27.2, 51.8 ± 28.5, 19.1 ± 7.0, and 17.9 ± 3.3, respectively, after administration of 0.3, 1, 3, 10, and 30 mg / kg / day. The seminal vesicle weights in the ORX animals were 12.2 ± 1.3, 16.6 ± 5.4, 16.5 ± 4.8, 13.3 ± 1.9, and 12.9 ± 2.1, respectively, after administration of 0.3, 1, 3, 10 and 30 mg / kg / day. The intact anus muscle weights were 86.9 ± 10.0, 82.1 ± 12.1, 65.2 ± 4.4, 57.8 ± 11.2, and 58.1 ± 4.7 after administration of 0.3, 1, 3, 10 and 30 mg / kg / day, respectively. Anus muscle weights in ORX animals were 4.5 ± 6.6, 49.6 ± 7.0, 53.6 ± 10.0, 51.1 ± 4.9, and 49.2 ± 4.2, respectively, after administration of 0.3, 1, 3, 10 and 30 mg / kg / day. LH inhibition and organ weight data are summarized in Table 6.

In vivo effect on serum hormone and organ weight of the compound of formula IV gonad
condition compound Dose
(mg / kg / day) LH
(ng / mL) FSH
(ng / mL) prostate
(% Intact) Seminal vesicle
(% Intact) anus
elevator
(% Intact)
Intact Vehicle - Average 1.46 ^b 20.9 ^b 100.0 ^b 100.0 ^b 100.0 ^b S.D. 0.642 8.49 28.6 13.4 4.97 ORX Vehicle - Average 11.1 ^a 93.5 ^a 13.7 ^a 14.0 ^a 58.8 ^a S.D. 3.87 13.8 2.56 2.93 6.62 Intact Compound IV 0.3 Average 0.863 ^b 17.3 ^b 84.0 ^b 76.2 ^{a, b} 86.9 ^{a, b} S.D. 0.384 6.44 19.2 7.83 10 Intact Compound IV One Average 0.704 ^b 15.7 ^b 75.2 ^b 66.3 ^{a, b} 82.1 ^{a, b} S.D. 0.53 7.26 20.7 27.2 12.1 Intact Compound IV 3 Average 0.395 ^{a, b} 18.4 ^b 68.2 ^{a, b} 51.8 ^{a, b} 65.2 ^a S.D. 0.302 7.72 8.12 28.5 4.35 Intact Compound IV 10 Average 0.226 ^{a, b} 9.25 ^{a, b} 45.1 ^{a, b} 19.1 ^a 57.8 ^a S.D. 0.165 3.97 20 6.98 11.2 Intact Compound IV 30 Average 0.236 ^{a, b} 6.25 ^{a, b} 43.6 ^{a, b} 17.9 ^a 58.1 ^a S.D. 0.176 1.82 8.75 3.33 4.71 ORX Compound IV 0.3 Average 15.4 ^a 116 ^a 19.0 ^{a, b} 12.2 ^a 54.5 ^a S.D. 2.94 17.2 4.19 1.31 6.56 ORX Compound IV One Average 13.5 ^a 114 ^a 17.4 ^a 16.6 ^a 49.6 ^a S.D. 2.18 22.3 3.4 5.36 7.04 ORX Compound IV 3 Average 6.5 65.2 ^a 19.6 ^a 16.5 ^a 53.6 ^a S.D. 5.63 31.9 6.67 4.82 10 ORX Compound IV 10 Average 0.425 ^{a, b} 27.6 ^b 22.9 ^{a, b} 13.3 ^a 51.1 ^a S.D. 0.135 8.16 5.44 1.91 4.88 ORX Compound IV 30 Average 0.368 ^{a, b} 15.1 ^b 20.6 ^{a, b} 12.9 ^a 49.2 ^{a, b} S.D. 0.119 4.11 2.08 2.14 4.21

^a P <0.05 vs. Intact vehicle. ^b P <0.05 vs. ORX vehicle

Example  10

Rat  And compounds in monkeys IV Recovery of testosterone levels after inhibition by

The reversibility of chemical castration using compound IV was studied

Materials and Methods:

35 male Sprague-Dawley rats weighing approximately 200 g were maintained in a 12 hour light / dark cycle with an unlimited supply of food (2016 Teklad Global 16% Protein Rodent Diet, Harlan, Madison, Wis.). The animal protocol was reviewed and approved by the Animal Experimentation Ethics Committee of the University of Tennessee.

The test substance for this study was quantified and dissolved in PEG 300 (100%) (Acros Organics, NJ) to prepare a suitable dosage formulation. Animals were randomly assigned to one of 10 treatment groups (n = 5 animals / group). The 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) for determination of baseline testosterone levels in intact animals. Groups 2-7 were administered 1, 3, or 30 mg / kg via oral gavage daily for 3 days. Groups 2, 3 and 4 were sacrificed on day 4 to determine maximum testosterone inhibition. Groups 5, 6, and 7 were allowed to recover for 14 days with a drug free washout period.

group compound IV  P.O. Dose process County 1 - Baseline County 2 1 mg / kg for 3 days No recovery County 3 3 mg / kg for 3 days No recovery County 4 30 mg / kg for 3 days No recovery County 5 1 mg / kg for 3 days 14 days recovery County 6 3 mg / kg for 3 days 14 days recovery County 7 30 mg / kg for 3 days 14 days recovery

result:

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

This study confirms previous results showing that Compound IV rapidly inhibits serum testosterone levels in intact male rats. Inhibition of serum testosterone levels was observed within dose groups that received ≥ mg / kg / day for 3 days. No significant decrease in serum testosterone was observed in the 1 mg / kg dose group. However, within the 14 day recovery period, serum testosterone levels returned to the level of intact control. This study shows that pharmacological castration by Compound IV in rats is reversible.

The effect of Compound IV on the inhibition and recovery of testosterone levels in intact male monkeys was evaluated along with oral pharmacokinetic studies. Three untreated male cynomolgus monkeys (2-3 weeks old) were administered Compound IV by oral gavage at a dose of 30 mg / kg per day for 7 consecutive days. Blood samples were collected and divided into serum and plasma for quantitative testosterone and Compound IV, respectively. The results show that daily administration of Compound IV reduced circulating androgen (primarily testosterone and dihydrotestosterone) levels below 47% in all three male monkeys compared to basal levels (2 and 6 days treatment [average ± SEM], levels of 159 ± 72.5, 997 ± 104, and 852 ± 136 ng / mL for baseline, respectively). After the 18-day drug-free recovery period, Andorgen levels returned to normal and did not differ significantly from baseline levels before treatment (1757.7 ± 369.5 ng / mL after recovery).

Example  11

Rat  of mine LH  And even testosterone reduction Though  Goal Retention (Table 8)

The effect of the compound of formula IV on bone treatment was studied. Compounds of formula IV administered orally completely prevented bone loss associated with LH inhibition in intact male rats. Significant LH reduction was induced by the compound of formula IV at a dose of ≧ 10 mg / kg per day in intact animals. At 1 mg / kg per day, the compound of formula IV did not significantly reduce LH, but at these doses, a significant decrease in prostate, seminal vesicles and anus muscles was evident, indicating that circulating testosterone reduction was physiologically related to these androgen-reactive organs. It is related. However, 1 mg / kg daily administration of the compound of formula IV maintained the spongy bone volume (measured in the distal femur) at the level of intact control. When administered at 10 and 30 mg / kg doses per day, the compound of formula IV significantly increased bone volume in the distal femur beyond that of the intact control. These data indicate that Compound IV increased spongy bone density (BMD) and bone volume percentage to dose levels that reduced LH levels in intact rats. Data from the study is presented in Table 8.

gonad
condition
compound
Dose
(mg / kg / day)
Bone density
(g / cm ³⁾ Bone Volume Percentage (BV / TV)
(%) prostate
(% Intact) Seminal vesicle
(% Intact) anus
elevator
(% Intact) FSH
(ng / mL) LH
(ng / mL) Intact Vehicle - Average 0.274 ^b 20.2 ^b 100.0 ^b 100.0 ^b 100.0 ^b 9.93 ^b 0.781 ^b S.D. 0.033 3.57 11.1 15.9 11.6 2.94 0.263 ORX Vehicle - Average 0.224 ^a 15.4 ^a 14.8 ^a 10.3 ^a 59.4 ^a 117 ^a 22.0 ^a S.D. 0.025 2.6 4.08 0.767 7.26 40.2 5.81 Intact Compound IV One Average 0.273 ^b 20.0 ^b 69.2 ^{a, b} 44.6 ^{a, b} 80.0 ^{a, b} 14.1 ^{a, b} 0.820 ^b S.D. 0.04 4.08 13.5 15.7 6.69 4.07 0.392 Intact Compound IV 10 Average 0.326 ^{a, b} 25.9 ^{a, b} 30.7 ^{a, b} 12.8 ^{a, b} 58.1 ^a 5.48 ^{a, b} 0.060 ^{a, b} S.D. 0.048 4.76 12.4 0.886 9.68 1.97 0.092 Intact Compound IV 30 Average 0.326 ^{a, b} 25.5 ^{a, b} 30.1 ^{a, b} 14.4 ^{a, b} 56.1 ^a 6.32 ^{a, b} 0.078 ^{a, b} S.D. 0.046 4.49 17.4 1.45 4.67 3.4 0.114

^a P <0.05 vs. Intact vehicle. ^b P <0.05 vs. ORX vehicle

Example  12

17β hydroxysteroid Dehydrogenase  5 (17β- HSD5 Effect on Enzyme Activity

Members of the HSD family are involved in the conversion of circulating steroids. 17β-HSD5 converts androstenedione to testosterone and estrone to estradiol. It is also involved in prostaglandin synthesis. The ability to inhibit 17β-HSD5 activity of some selected compounds of the invention has been demonstrated.

Way

Human 17β-HSD5 was cloned in pGEX 4t1 vector to prepare purified protein. Purified protein was incubated with a representative compound of the invention, ¹⁴ C androstenedione and NADPH in a suitable buffer. The synthesized testosterone was extracted with ethyl acetate, air dried, spotted and run on thin layer chromatography (TLC) plates. TLC was exposed to the phosphorimator and the intensity of the testosterone band was quantified. Indomethacin was used as a positive control (LHRH agonist).

result

Compound IV was tested, which had a partial inhibitory effect on 17β-HSD5 enzyme activity. Indomethacin, a positive control (LHRH agonist), showed strong inhibition on the enzyme as expected, as shown in FIG. 3.

Example  13

Toxicity Study

A study was conducted comparing the thrombotic activity of Compound IV and diethylstilbestrol (DES, positive control) using an in vitro human platelet aggregation assay. Since men are the intended treatment group for Compound IV (LH inhibition), blood from healthy male donors was used in the study. Platelet rich plasma was preincubated for 30 seconds with estradiol (E2), DES, Compound IV or vehicle, and then thrombin (0.3 unit) was added to induce platelet aggregation. The results show that preincubation with DES increased approximately thrombin-induced platelet aggregation. However, compound IV and estradiol reduced platelet rich plasma aggregation. These data demonstrate that Compound IV reduced human platelet reactivity in vitro as compared to DES and suggest that Compound IV has lower thromboembolic activity than DES (FIG. 4).

Example  14

compound IV Effect on hot flashes

A study was conducted to investigate the effect of Compound IV on hot flashes using a morphine dependent rat model (MD model) developed by Simpkins et al (1983) and demonstrated to have some similarities with postmenopausal hot flashes. In addition to the similarity to the human state, this experimental animal model has a short test time, making it a high throughput screening tool for identifying compounds that can relieve vascular motor neurons using tail skin temperature (TST). TST probe TA-40 (Data Sciences International, MN) was taped to the tail base and basal temperature was obtained for 15 minutes. After 15 minutes, animals were treated with naloxone (1 mg / kg, SQ) to reverse the effect of morphine. Tail skin temperature (TST) was measured for 1 hour after naloxone treatment with a sampling cycle of 5 seconds throughout the experimental procedure. After data acquisition, the moving average of temperature was recorded, calculated and further analyzed for every 60 seconds for each animal. Baseline temperature was estimated 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 using the linear trapezoid method.

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

Example  15

Rat  My compound IV vs . DES

Prior to the introduction of LHRH agonists, castration testosterone levels were achieved by increasing estrogen activity in the pituitary gland via estrogen primarily diethylstilbestrol (DES). DES was equally effective as LHRH agonists in achieving testosterone at castration levels. Patients receiving DES did not show hot flashes or bone loss, but had gynecomastia at a higher rate than ADT using LHRH agonists. Unfortunately, pure estrogens with potent potencies such as DES and estradiol are often associated with a high risk of severe cardiovascular and thromboembolic complications, which limit their clinical use. The increased risk of venous thromboembolic complications by DES has been hypothesized to be due to cross-reactivity with other hormone receptors, but this has not been demonstrated. In vitro studies using human platelets showed that Compound IV had much lower procoagulant activity than DES. Thus, Compound IV, ER-alpha selective agonists can deliver the prostate cancer benefits of DES while also causing osteoporosis or deleterious lipid profiles while also delivering the benefits of LHRH agonists.

Compound IV was as effective as DES in reducing prostate size in rats (FIG. 11A) and showed a moderate increase in the prostate size of ORX rats (FIG. 11B).

The difference between DES and Compound IV is shown in FIGS. 12A-12C, where DES cross reacts with glucocorticoid receptor (GR) (FIG. 12A) and androgen receptor (AR) (FIG. 12B), while Compound IV did not. In addition, DES antagonizes estrogen related receptor (ERR) transcriptional activation, while Compound IV did not. Compound IV did not 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

Colony nurture cynomolgus macaques of Mauritius origin. A prospective study was designed as a 39-week oral pharmacology and toxicology assessment of Compound IV and control (LHRH agonist) in male cynomolgus monkeys with a 13-week interim period. A total of 39 sexually mature male monkeys, ages 5-8 years old, were randomly assigned to group 5 prior to initiation of treatment. Groups included 1) vehicle control, 2) 1 mg / kg Compound IV, 3) 10 mg / kg Compound IV, 4) 100 mg / kg Compound IV, and 5) positive control (LHRH agonist). The drug is orally administered by cage-side administration once daily for 39 weeks using vehicle control material (Tween 80 / PRANG ^™ ) for groups 1 and 5, or compound in vehicle for groups 2, 3 and 4. Delivered. Dosage levels of Compound IV were 1, 10 and 100 mg / kg / day for groups 2, 3 and 4, respectively. Oral administration was delivered at the 10 mL / kg dose dose calculated based on the most recent useful body weight for each animal (FIG. 14). Animals in Group 5 were also treated once daily with subcutaneous injections of a positive control (LHRH agonist) for a 39 week study period (0.02 mL constant dose). General appearance and clinical signs were observed and recorded daily. Regular assessments and other study screenings were performed as directed in the study protocol. Selection 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, respectively, using enzyme immunoassay (EIA) and chemiluminescent immunoassay (LIA, ALPCO Diagnostics, Salem NH) (following standard procedures). Blood samples for testosterone evaluation were collected from all animals at the base (fasting state) at baseline (ie, before initiation of treatment) and on days 1, 3, 7, 14, 28, 64 and 90. Blood samples for PSA measurements were collected from all animals (fasted) at baseline and for 6 weeks. For discussion, the results of samples of sub-quantitative limit (BLQ) concentrations for testosterone and PSA analysis were calculated as half of the lower limit of quantification (LLOQ) of the assay and considered as the "final concentration estimate". The data in Tables 9-16 are presented as "quantitative concentrations only" (ie, excluding BLQ values) and "final concentration estimates" (ie, samples with BLQ results are included as half LLOQ of the assay). Prostate volume was measured in living animals at baseline and under anesthesia at week 6 using a transrectal ultrasound (RTUS) procedure. The width and height of the prostate were recorded. Prostate volume was calculated as width x width x height x pi / 6 and normalized to body weight. Wet fat and exogenous tissues were excised and the wet weight of the prostate was recorded at necropsy.

Results and discussion:

Serum testosterone levels are shown in FIG. 15 and Tables 9-12. At baseline, testosterone levels for all monkeys studied were within normal ranges for sexually mature adult male cynomolgus monkeys. However, testosterone levels were significantly decreased in monkeys treated with Compound IV at 100 mg / kg / day and monkeys treated with the positive control (LHRH agonist). Testosterone levels in the positive control (LHRH agonist) were followed by a significant increase (ie, an immediate flare) of 47.4% and 547% (p <0.01) at the initial 47.4% and 1 and 4 days, respectively, 14 2-phase changes of 3.6%, 67%, 73 ^, 83% and 85% reduction were seen at days 28, 64 and 90 (see FIG. 15 and Tables 9-12). Similar immediate effects were not observed at the highest dose levels (ie 100 mg / kg / day) for Compound IV treated animals, with a dose of 100 mg / kg / day compared to baseline 3, On days 7, 14, 28 and 64, they were reduced by 60%, 51%, 42%, 79% and 92%, respectively (see Figure 15 and Tables 9 and 10). After 90 days of treatment with 100 mg / kg / day Compound IV, testosterone levels were reduced to concentrations below the quantitative limit of the assay in 6-10 of Group 4 monkeys (see Table 11). Mean serum testosterone levels in group 4 monkeys were reduced by 96% compared to each baseline ("final concentration estimate", ie, testosterone levels for 6/10 monkeys with BLQ values were calculated as 50% of LLOQ concentration, See Table 10). It is important to note that by day 90, 100 mg / kg / day of Compound IV reduced serum testosterone to significantly lower levels than the positive control (LHRH agonist) (p = 0.013).

Compound IV Mean serum testosterone levels in intact male monkeys after daily oral administration (ng / mL); ^농도 Final concentration estimate. Work
Vehicle
Control Compound IV
1mg / kg Compound IV
10mg / kg Compound IV
100mg / kg Positive control group
(LHRH agonist) Average SEM N Average SEM N Average SEM N Average SEM N Average SEM N 0
Baseline 6.1 1.2 10 7.3 1.0 6 4.9 0.6 6 4.4 0.6 10 4.9 0.9 7 One 8.0 1.7 10 11 1.6 6 7.6 1.1 6 8.0 2.2 10 7.2 0.8 7 3 8.2 2.3 10 7.4 1.2 6 5.1 1.1 6 1.8 ^* 0.5 10 32 ^# 3.8 7 7 5.9 1.2 10 6.7 0.8 6 7.7 1.9 6 2.2 ^* 0.7 9 4.7 2.6 7 14 3.4 0.5 10 3.8 0.4 6 7.1 1.6 6 2.6 0.9 9 1.6 ^# 0.2 7 28 3.8 0.6 10 4.7 0.9 6 9.4 2.1 6 0.9 ^* 0.2 10 1.3 ^# 0.2 7 64 5.1 1.1 10 4.3 0.6 6 5.4 1.5 6 0.3 ^* 0.1 9 0.8 ^{# ＄} 0.2 7 90 3.6 0.6 9 4.2 0.6 4 4.6 1.0 5 0.2 ^* 0.0 10 0.8 ^{# ＄} 0.2 7

Testosterone assay LLOQ = 0.246 ng / mL; BLOQ value is 0.123 ng / mL, calculated as half of LLOQ.

*: Statistically significant (p <0.05) Compound IV 100 mg / kg vs. Vehicle control

#: Statistically significant (p <0.05) positive control (LHRH agonist) vs. Vehicle control

＄: statistically significant (p <0.05) positive control (LHRH agonist) vs. Compound IV 100 mg / kg

Percentage change in mean serum testosterone levels compared to baseline (%); ^농도 Final concentration estimate. Work Vehicle
Control Compound IV 1 mg / kg Compound IV 10 mg / kg Compound IV 100 mg / kg Positive control One 31 44 54 82 47 3 35 1.8 3.5 -60 547 7 -3.2 -8.1 57 -51 -3.6 14 -44 -48 45 -42 -67 28 -38 -35 92 -79 -73 64 -16 -41 11 -92 -83 90 -42 -42 -5.5 -96 -85

Testosterone assay LLOQ = 0.246 ng / mL; BLOQ value is 0.123 ng / mL, calculated as half of LLOQ.

Mean serum testosterone levels (ng / mL) in intact male monkeys after daily compound IV oral administration; ^λ only quantifiable concentration Work Vehicle control Compound IV 1 mg / kg Compound IV 10 mg / kg Compound IV 100 mg / kg Positive control
(LHRH agonist) Average SEM N Average SEM N Average SEM N Average SEM N Average SEM N 0
Baseline 6.1 1.2 10 7.3 1.0 6 4.9 0.6 6 4.4 0.6 10 4.9 0.9 7 One 8.0 1.7 10 11 1.6 6 7.6 1.1 6 8.0 2.2 10 7.2 0.8 7 3 8.2 2.3 10 7.4 1.2 6 5.1 1.1 6 1.8 0.5 10 32 3.8 7 7 5.9 1.2 10 6.7 0.8 6 7.7 1.9 6 2.2 0.7 9 4.7 2.6 7 14 3.4 0.5 10 3.8 0.4 6 7.1 1.6 6 2.6 0.9 9 1.6 0.2 7 28 3.8 0.6 10 4.7 0.9 6 9.4 2.1 6 0.9 0.2 10 1.3 0.2 7 64 5.1 1.1 10 4.3 0.6 6 5.4 1.5 6 0.3 0.1 9 0.8 0.2 7 90 3.6 0.6 9 4.2 0.6 4 4.6 1.0 5 0.2 0.1 4 0.8 0.2 7

Testosterone assay LLOQ = 0.246 ng / mL; ^λ BLQ value excluded.

Percent change in mean testosterone levels compared to baseline; ^λ only quantifiable concentration Work Vehicle
Control Compound IV
1mg / kg Compound IV
10mg / kg Compound IV
100mg / kg positivity
Control One 31 44 54 82 47 3 35 1.8 3.5 -60 547 7 -3.2 -8.1 57 -51 -3.6 14 -44 -48 45 -42 -67 28 -38 -35 92 -79 -73 64 -16 -41 11 -92 -83 90 -42 -42 -5.5 -95 -85

Testosterone assay LLOQ = 0.246 ng / mL; ^λ BLQ value excluded.

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

Mean serum PSA levels (ng / mL) in intact male monkeys after daily oral administration of Compound IV; ^농도 Final concentration estimate. Vehicle control Compound IV 1 mg / kg Compound IV 10 mg / kg Compound IV 100 mg / kg Positive control (LHRH agonist) Average SEM N Average SEM N Average SEM N Average SEM N Average SEM N Before administration 1.1 0.2 10 1.0 0.2 6 0.8 0.1 6 1.0 0.1 10 1.0 0.1 7 4 Weeks 1.0 0.2 10 0.9 0.2 6 0.3 * 0.1 6 0.1 ^& 0.1 10 0.4 ^{# $} 0.1 7

PSA assay LLOQ = 0.0575 ng / mL; ^＠ BLQ value is calculated as 0.02875 ng / mL, half of LLOQ.

*: Statistically significant (p <0.05) Compound IV 10 mg / kg vs. Vehicle control

&: Statistically significant (p <0.05) Compound IV 100 mg / kg vs. Vehicle control

#: Statistically significant (p <0.05) positive control (LHRH agonist) vs. Vehicle control

＄: statistically significant (p <0.05) positive control (LHRH agonist) vs. Compound IV 100 mg / kg

Percent change in mean PSA level compared to baseline; ^농도 Final concentration estimate. Control group Compound IV 1 mg / kg Compound IV 10 mg / kg Compound IV 100 mg / kg Positive control (LHRH agonist) 4-week -7.1 -11 -69 -87 -60

PSA assay LLOQ = 0.0575 ng / mL; ^＠ BLQ value is calculated as 0.02875 ng / mL, half of LLOQ.

Mean serum PSA levels (ng / mL) in intact male monkeys after daily oral administration of Compound IV; ^λ only quantifiable concentration. Vehicle control Compound IV 1 mg / kg Compound IV 10 mg / kg Compound IV 100 mg / kg Positive control (LHRH agonist) Average SEM N Average SEM N Average SEM N Average SEM N Average SEM N Before treatment 1.2 0.2 9 1.0 0.2 6 0.8 0.1 6 1.0 0.1 10 1.0 0.1 7 4-week 1.1 0.1 9 0.9 0.2 6 0.3 0.1 5 0.3 0.1 4 0.4 0.1 7

PSA assay LLOQ = 0.0575 ng / mL; ^λ BLQ values are excluded from the table above.

Percent change in mean PSA level compared to baseline; ^λ only quantifiable concentration. Control group Compound IV
1 mg / kg Compound IV
10mg / kg Compound IV
100mg / kg Positive control 4 Weeks -7.1 -11 -64 -72 -60

PSA assay LLOQ = 0.0575 ng / mL; ^λ BLQ values are excluded from the table above.

Prostate volume was measured by TRUS periodically throughout the study. The results obtained after 6 weeks of treatment demonstrated a potent effect of Compound IV and positive control (LHRH agonist) on monkey prostate. Compound IV inhibited prostate volume by 25% and 45% at 10 mg / kg and 100 mg / kg dose levels, respectively, while decreasing prostate volume by 28% in the positive control (LHRH agonist) (FIG. 17 and table 17 and 18).

Average prostate volume (ratio) in male monkeys after daily oral administration of Compound IV Vehicle control Compound IV 1 mg / kg Compound IV 10 mg / kg Compound IV 100 mg / kg Positive control (LHRH agonist) Average SEM N Average SEM N Average SEM N Average SEM N Average SEM N 6 weeks 438 78 10 468 78 6 327 33 6 242 28 10 315 47 7

Percentage change in mean prostate volume compared to baseline (%) Control group Compound IV 1 mg / kg Compound IV 10 mg / kg Compound IV 100 mg / kg positivity
Control 6 weeks 0 6.8 -25 -45 -28

Prostate weight assessment at necropsy confirmed compound IV-related decreases in prostate volume. After 13 weeks of treatment, Compound IV significantly reduced 24% and 21% mean prostate weights in animals receiving 10 and 100 mg / kg / day, respectively (FIG. 18B and Tables 19 and 20).

Average prostate weight at necropsy in male monkeys after daily oral administration of compound IV (g) Vehicle control Compound IV 1 mg / kg Compound IV 10 mg / kg Compound IV 100 mg / kg Average SEM N Average SEM N Average SEM N Average SEM N 13 Weeks 1.8 0.2 3 1.8 0.4 3 1.3 0.1 3 1.4 0.1 3

Percentage change in mean prostate weight compared to baseline (%) Control group Compound IV 1 mg / kg Compound IV 10 mg / kg Compound IV 100 mg / kg 13 Weeks 0 1.7 -24 -21

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

Example  17

Compound in human IV  Research

A study was conducted to determine the effect of Compound IV on human males. Twelve subjects per population were examined at doses of 100, 300, 600 and 1000 mg of Compound IV. Table 21 shows the average change in LH, serum PSA, free testosterone and total testosterone levels in men following administration of Compound IV at doses of 100, 300, 600 and 1000 mg. Dose dependent average total testosterone levels (nmol / L) were measured in men over a period of 1-11 (FIG. 19). Total testosterone levels decreased 51.9% and 47.9% at doses of 600 mg and 1000 mg, respectively.

Dose dependent average LH levels (IU / L) in humans were measured over a period of 1-10 days (FIG. 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 decreased 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 average PSA levels (μg / L) were measured in humans over a period of 1-10 days (FIG. 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 at the 10 and 30 mg doses.

Average change from baseline 100 mg 300 mg 600 mg 1000 mg serum PSA -9.2% -24.4% -27.5% -29.9% LH 20.7% 46.9% 27.6% 29.2% freedom
Testosterone -17.0% -18.5% -72.7% -53.2% Total testosterone 3.9% 7.3% -51.9% -47.9%

Example  18

compound IV Bioavailability of

Compound IV was rapidly absorbed after oral administration to rats, dogs and monkeys. Oral bioavailability in rats of Compound IV was 6% -25% depending on the formulation administered. Formulations using polyethylene glycol 300 (PEG300) generally produced higher exposures than microemulsions prepared in Tween 80 diluted in deionized water. In dogs, a visual inspection of the plasma concentration-time profile suggests that compound IV undergoes enterohepatic recycling as evidenced by the second peak at the end. Important in dogs, exposure in the male 30 mg / kg PEG300 oral dose group exceeds the exposure required to produce the maximum effect on prostate reduction in the LH inhibiting rat model. In monkeys, preliminary pharmacokinetic studies suggest that oral bioavailability in these species is comparable to or above that in dogs, as evidenced by plasma concentrations of Compound IV and serum testosterone inhibition over a 7 day period. Overall, these data suggest that sufficient oral exposure can be achieved to produce the desired pharmacological effect (based on AUC data) in both non-rodent animal species. Furthermore, endocrine data in rats and monkeys suggest that the pharmacological effect of Compound IV is reversible (ie, serum concentrations of testosterone return to baseline or normal levels when Compound IV treatment is discontinued).

Example  19

compound IV of Pharmacokinetics

Preliminary data from in vitro (mouse, rat, dog, monkey and human) and in vivo (rat) metabolism studies suggest that the conjugation of Compound IV, its hydroxylated metabolite (s) and its N-dealkylated metabolite is an animal. And the overall layout of Compound IV in humans. Species comparisons show that, although only qualitative, 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 suitable rodent and non-rodent species for pharmacological and toxicological evaluation. In vitro studies show that Compound IV does not induce associated CYP450 isoforms (CYP1A2, CYP2B6, or CYP3A4) and does not inhibit CYP1A2, CYP2C19, CYP2D6, or CYP3A4 / 5 at concentrations of <30 μM. CYP2C9 is inhibited by Compound IV but only at high concentrations (Ki = 8 μM), and the possibility of pharmacokinetic drug-drug interactions is considered to be sparse.

Example  20

compound IV Biological activity of

Compound IV exhibits little or no in vitro inhibitory effect (IC ₅₀ ≧ 30 μM) on hERG channels. The compounds reduced dose-dependently APD50 and APD90 at concentrations of 10 and 100 μM in isolated dog Perkinje fibers in vitro. However, Compound IV did not affect hemodynamic or cardiac function (blood pressure, heart rate, electrocardiogram or QT interval) in the telemetered dog at any dose (up to 300 mg / kg). No neuropharmacological or lung effects were observed. A single oral dose of Compound IV of 30 mg / kg or less showed no significant effect on renal function. Only an increase in urine volume and urinary excretion of potassium and chloride was observed at the highest dose tested (100 mg / kg). Oral administration of Compound IV at a dose of 30 to 300 mg / kg in rats produced a significant increase in peristalsis, and 30 mg / kg oral administration of Compound IV in rats significantly affected gastrointestinal motility and gastric acidity. Produced an increase (possibly not due to effects on smooth muscle).

Compound IV was not mutagenic and did not induce structural or numerical chromosomal abnormalities at concentrations of 200 μM or less in human peripheral blood lymphocytes in vitro. Rats and dogs tolerated well after single and repeated oral administration of Compound IV (up to 28 days). No pathological changes were observed in the kidneys, liver, heart and other non-target related organs. Male or female dogs of Compound IV had no significant physical signs, weight effects, clinical pathological changes, ophthalmic, electrocardiographic or histopathological changes for up to 28 days.

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

Claims (52)

Reducing total serum testosterone levels in male subjects, consisting essentially of administering a therapeutically effective amount of a compound of Formula I, or an isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate, or combination thereof How to make:

Where
Y is C (O) or CH ₂ ;
R ₁ , 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 an optionally aromatic 3-7 membered substituted or unsubstituted heterocycle ring;
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 a protected hydroxyl group;
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 to 6 carbon atoms, 3-7 membered cycloalkyl, 3-7 membered heterocycle, 5-7 membered aryl; 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 linear alkyl of 1-7 carbons, branched alkyl of 1-7 carbons, or cyclic alkyl of 3-8 carbons. The method of claim 1,
Wherein said compound of formula I is selected from:

And

The method of claim 1,
Said decrease in total serum testosterone is caused by a decrease in serum luteinizing hormone levels. The method of claim 2,
Said decrease in total serum testosterone is caused by a decrease in serum luteinizing hormone levels. The method of claim 1,
Said decrease in total serum testosterone is independent of a decrease in serum luteinizing neutrophil levels. The method of claim 5,
Wherein said decrease in total serum testosterone is due to an increase in SHBG, inhibition of testosterone production or secretion by Leidihi cells in the testes, or reduction in adrenal steroid production. The method of claim 6,
Wherein said total serum testosterone comprises free testosterone and bound testosterone, wherein a decrease in free testosterone levels independent of a decrease in serum luteinizing hormone levels is due to an increase in SHBG. The method of claim 2,
Said total serum testosterone reduction is independent of a decrease in serum luteinizing hormone levels. The method of claim 8,
Wherein said decrease in total serum testosterone is due to an increase in SHBG, inhibition of testosterone production or secretion by Leidihi cells in the testes, or reduction in adrenal steroid production. 10. The method of claim 9,
Wherein said total serum testosterone comprises free testosterone and bound testosterone, wherein a decrease in free testosterone levels independent of a decrease in serum luteinizing hormone levels is due to an increase in SHBG. The method of claim 1,
And said male subject has prostate cancer. The method of claim 2,
And said male subject has prostate cancer. The method of claim 3,
And said male subject has prostate cancer. The method of claim 4, wherein
And said male subject has prostate cancer. The method of claim 5,
And said male subject has prostate cancer. The method of claim 6,
And said male subject has prostate cancer. The method of claim 1,
Said total serum testosterone is reduced to about 100 ng / dL or less. The method of claim 17,
Said total serum testosterone is reduced to about 50 ng / dL or less. The method of claim 17,
Said total serum testosterone is reduced to about 25 ng / dL or less. The method of claim 2,
Said total serum testosterone is reduced to about 100 ng / dL or less. The method of claim 20,
Said total serum testosterone is reduced to about 50 ng / dL or less. The method of claim 20,
Said total serum testosterone is reduced to about 25 ng / dL or less. The method of claim 3,
Said total serum testosterone is reduced to about 100 ng / dL or less. The method of claim 23, wherein
Said total serum testosterone is reduced to about 50 ng / dL or less. The method of claim 23, wherein
Said total serum testosterone is reduced to about 25 ng / dL or less. The method of claim 4, wherein
Said total serum testosterone is reduced to about 100 ng / dL or less. The method of claim 26,
Said total serum testosterone is reduced to about 50 ng / dL or less. The method of claim 26,
Said total serum testosterone is reduced to about 25 ng / dL or less. The method of claim 5,
Said total serum testosterone is reduced to about 100 ng / dL or less. The method of claim 29,
Said total serum testosterone is reduced to about 50 ng / dL or less. The method of claim 29,
Said total serum testosterone is reduced to about 25 ng / dL or less. The method of claim 6,
Said total serum testosterone is reduced to about 100 ng / dL or less. 33. The method of claim 32,
Said total serum testosterone is reduced to about 50 ng / dL or less. 33. The method of claim 32,
Said total serum testosterone is reduced to about 25 ng / dL or less. The method of claim 1,
The administration of the compound inhibits the occurrence of side effects associated with androgen deprivation therapy (ADT), reduces its incidence, reduces its severity and inhibits or treats the subject, wherein the subject has prostate cancer. . 36. The method of claim 35,
Said total serum testosterone reduction is caused by a decrease in serum luteinizing hormone levels. 36. The method of claim 35,
Said total serum testosterone reduction is independent of a decrease in serum luteinizing hormone levels. 36. The method of claim 35,
And the side effects associated with said ADT are selected from the group consisting of hot flashes, gynecomastia, decreased bone density, and increased fractures. The method of claim 38,
Said typical side effect is hot flashes. The method of claim 38,
Said typical side effect is gynecomastia. The method of claim 38,
The side effect is a decrease in bone density. The method of claim 38,
The fracture increase is pathological fracture, non-traumatic fracture, vertebral fracture, non-vertebral fracture, new morphological fracture, clinical fracture or combination thereof. The method of claim 2,
Administration of the compound prevents or treats side effects associated with androgen deprivation therapy (ADT), and wherein the subject has prostate cancer. The method of claim 43,
Said total serum testosterone reduction is caused by a decrease in serum luteinizing hormone. The method of claim 43,
Said total serum testosterone reduction is independent of serum luteinizing hormone reduction. The method of claim 43,
And the side effects associated with said ADT are selected from the group consisting of hot flashes, gynecomastia, decreased bone density, and increased fractures. 47. The method of claim 46 wherein
Said typical side effect is hot flashes. 47. The method of claim 46 wherein
Said typical side effect is gynecomastia. 47. The method of claim 46 wherein
Said typical side effect is a decrease in bone density. The method of claim 1,
The method is further characterized by treating advanced prostate cancer. The method of claim 1,
And the method further inhibits, reduces the occurrence of, reduces the severity of, or inhibits advanced prostate cancer. The method of claim 1,
The method further provides palliative treatment of advanced prostate cancer.

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