Selective androgen receptor modulators, analogs and derivatives thereof and uses thereof

Abstract

This invention provides new compounds and uses thereof in treating a variety of diseases or conditions in a subject, including, inter alia, prostate cancer, muscle wasting diseases and/or disorders or a bone-related diseases and/or disorders.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application claims the benefit of U.S. Provisional Application Ser. No. 60 / 831,880, filed Jul. 19, 2006 and U.S. Provisional Application Ser. No. 60 / 831,988, filed Jul. 19, 2006; both of which are hereby incorporated by reference in their entirety.FIELD OF THE INVENTION[0002]This invention provides nuclear hormone receptor binding compounds, compositions comprising the same and methods of use thereof in treating a variety of diseases or conditions in a subject, including, inter alia, prostate cancer, muscle wasting and diseases or disorders related thereto, and / or or bone-related diseases or disorders.BACKGROUND OF THE INVENTION[0003]The nuclear hormone receptor superfamily is one of the largest classes of transcription factors and is involved in abundant physiological processes. The 48 members of this family are divided into three classes with class 1 comprised of receptors for androgens (AR), estrogens (ER-α and ER-β), glucocortico...

AI Technical Summary

Benefits of technology

[0235]In another embodiment, this invention provides a method of treating reducing the severity of, reducing the incidence of, delaying the onset of, or reducing pathogenesis of rheumatoid arthritis in a subject, comprising the step of administering to said subject a compound of formula (I) and / or its isomer, pharmaceutically acceptable salt, pharmaceutical product, crystal, N-oxide, hydrate or any combination thereof, to the subject.

[0236]In another embodiment, this invention provides a method of treating reducing the severity of, reducing the incidence of, delaying the onset of, or reducing pathogenesis of chronic kidney disease in a subject, comprising the step of administering to said subject a compound of formula (I) and / or its isomer, pharmaceutically acceptable salt, pharmaceutical product, crystal, N-oxide, hydrate or any combination thereof, to the subject.

[0237]In another embodiment, this invention provides a method of treating reducing the severity of, reducing the incidence of, delaying the onset of, or reducing pathogenesis of end stage renal disease in a subject, comprising the step of administering to said subject a compound of formula (I) and / or its isomer, pharmaceutically acceptable salt, pharmaceutical product, crystal, N-oxide, hydrate or any combination thereof, to the subject.

[0238]In another embodiment, this invention provides a method of treating reducing the severity of, reducing the incidence of, delaying the onset of, or reducing pathogenesis of frailty in a subject, comprising the step of administering to said subject a compound of formula (I) and / or its isomer, pharmaceutically acceptable salt, pharmaceutical product, crystal, N-oxide, hydrate or any combination thereof, to the subject.

[0239]In another embodiment, this invention provides a method of treating reducing the severity of, reducing the incidence of, delaying the onset of, or reducing pathogenesis of hypogonadism in a subject, comprising the step of administering to said subject a compound of formula (I) and / or its isomer, pharmaceutically acceptable salt, pharmaceutical product, crystal, N-oxide, hydrate or any combination thereof, to the subject.

[0240]In another embodiment, this invention provides a method of treating reducing the severity of, reducing the incidence of, delaying the onset of, or reducing pathogenesis of age-related functional decline in a subject, comprising the step of administering to said subject a compound of formula (I) and / or its isomer, pharmaceutically acceptable salt, pharmaceutical product, crystal, N-oxide, hydrate or any combination thereof, to the subject.

Problems solved by technology

Contraception is a difficult subject under any circumstance.

However, to date, the only options available for men include the use of condoms and vasectomy.

Condom use, however is not favored by many men because of the reduced sexual sensitivity, the interruption in sexual spontaneity, and the significant possibility of pregnancy caused by breakage or misuse.

The elderly are at greatest risk of osteoporosis, and the problem is therefore predicted to increase significantly with the aging of the population.

However, osteoporosis also occurs frequently in males.

Decreased amounts of bone mineral content and density correlates with decreased bone strength, and predisposes to fracture.

Consequently, when androgen or estrogen deprivation occurs there is a resultant increase in the rate of bone remodeling that tilts the balance of resorption and formation to the favor of resorption that contributes to the overall loss of bone mass.

Muscle protein catabolism, whether caused by a high degree of protein degradation or a low degree of protein synthesis, leads to a decrease in muscle mass and to muscle wasting.

In addition, other circumstances and conditions are linked to and can cause muscle wasting.

Muscle wasting, if left unabated, can have dire health consequences.

For example, the changes that occur during muscle wasting can lead to a weakened physical state that is detrimental to an individual's health, resulting in increased susceptibility to bone fracture and poor physical performance status.

In addition, muscle wasting is a strong predictor of morbidity and mortality in patients suffering from cachexia and AIDS.

In the United States (US), there is a rising incidence and prevalence of kidney failure.

Burns result in a testosterone reduction, nitrogen level reduction and a reduction in bone mineral density (BMD), which may persist even as long one year following the injury and is associated with impaired wound healing, increased infection risks, erosion of lean body mass, hampered rehabilitation, and delayed reintegration of burn survivors into society.

Catabolic effects initiated as a result of the burn lead to significant involuntary weight loss, further compounding the problem.

Spinal cord injuries (SCI) may result in the alteration central neurotransmitter secretion or production, which in turn may cause a hypothalamus-pituitary-adrenal axis dysfunction, leading to decreases in testosterone and other hormone levels.

The effects of the loss of lean body mass include the development of wounds and impaired healing mechanisms.

Because of poor nutrition and protein combined with immobilization, patients with spinal cord injury are at high risk for bed sores.

Compounding the problem, for example in diabetes, is the presence of neuropathy, which increases the risk of foot ulceration.

While there are many treatments and therapies for these conditions, none are ideal.

Images