HRP20040830A2 - Multi-substituted selective androgen receptor modulators and methods of use thereof - Google Patents

Description

Statement of government interest

[0001] This invention was made in whole or in part with the support of the government under grant number (Grant number) R29 CA068096 awarded by the National Cancer Institute, National Institute of Health, and awarded under grant number R15 HD35329 by the National Institute of Child Health and Human Development, National Institute of Health. The government may have certain rights in an invention.

Field of invention

[0002] This invention relates to androgen receptor targeting agents (Androgen Receptor Targeting Agents, ARTA), which demonstrate the androgenic and anabolic activity of a non-steroidal ligand for the androgen receptor. The agents define a new subclass of compounds, which are selective androgen receptor modulators (Selective Androgen Receptor Modulators, SARMs), useful for a) male contraception; b) treatment of various hormone-related conditions, for example conditions related to androgenic decline in the aging male (Androgen Decline in Aging Male, ADAM); c) treatment of conditions related to androgenic decline in women (Androgen Decline In Female, ADIF); d) treatment and/or prevention of acute and/or chronic conditions of muscle deterioration; e) prevention and/or treatment of dry eye condition; f) oral androgen replacement therapy; and/or g) reducing the incidence, stopping and inducing regression of prostate cancer.

State of the art

[0003] The androgen receptor ("AR") is a ligand-activated transcriptional regulatory protein that mediates the induction of male sexual development and function through its activity with endogenous androgens. Androgens are generally known as male sex hormones. Androgenic hormones are steroids that are produced in the body by the testicles and adrenal cortex or can be synthesized in the laboratory. Androgenic steroids play an important role in many physiological processes, including the development and maintenance of male sex characteristics, such as muscle and bone mass, prostate growth, spermatogenesis, and male hair pattern (Matsumoto, Endocrinol. Met. Clin. N. Am. 23:857 -75 (1994)). Endogenous steroidal androgens include testosterone and dihydrotestosterone ("DHT"). Testosterone is the main steroid secreted by the testes and is the primary circulating androgen found in the plasma of men. Testosterone is converted to DHT by the enzyme 5-alpha reductase in many peripheral tissues. DHT is thus thought to serve as an intracellular mediator of most androgenic actions (Zhou, et al., Molec. Endrocrinol. 9:208-18 (1995)). Other steroidal androgens include testosterone esters, such as cypionate, propionate, phenylpropionate, cyclopentylpropionate, isocarporate, enanthate, and decanoate esters, and other synthetic androgens, such as 7-methyl-nortestosterone ("MENT") and its acetate ester (Sundaram et al. ., "7 Alpha-Methyl-Nortestosterone ("MENT"): The Optimal Androgen For Male Contraception", Ann. Med., 25:199-205 (1993) ("Sundaram")). Because the AR is involved in male sexual development and function, the AR is a likely target for the implementation of male contraception or other forms of hormone replacement therapy.

[0004] Worldwide population growth and social awareness of family planning have stimulated quite a lot of research on contraception. Contraception is a difficult subject under any circumstances. It is burdened with a cultural and social stigma, religious implications, and most undoubtedly a significant health concern. This situation only worsens when the topic focuses on male contraception. Despite the availability of suitable contraceptives, society has historically held women responsible for contraceptive decisions and their consequences. Although concern about sexually transmitted diseases has made men more aware of the need to develop a safe and responsible sexual lifestyle, women still often bear the brunt of contraceptive choices. Women have a wide choice, from temporary mechanical devices, such as sponges and diaphragms, to temporary chemical agents, such as spermicides. Women also have more permanent options available, such as physical devices, including IUDs, and cervical caps, as well as longer-term options, such as birth control pills and subcutaneous implants. However, today the only options available for men include condom use and vasectomy. However, many men are not inclined to use condoms due to reduced sexual sensitivity, interruption of sexual spontaneity, and significant possibility of pregnancy caused by tearing or incorrect use. Vasectomies are also not popular. If more convenient methods of birth control were available to men, especially long-term methods that do not require any preparatory activity immediately before intercourse, such methods could significantly increase the likelihood that men would take more responsibility for contraception.

[0005] Administration of male sex steroids (eg testosterone and its derivatives) has shown promise in this regard, due to the combined gonadotropin suppression and androgen replacement properties of these compounds (Steinberger et al., "Effect of Chronic Administration of Testosterone Enanthate on Sperm Production and Plasma Testosterone, Follicle Stimulating Hormone, and Luteinizing Hormone levels: A Preliminary Evaluation of a Possible Male Contraceptive, Fertility and Sterility 28:1320-28 (1977)).Chronic administration of large doses of testosterone completely abolishes sperm production (azoospermia) or is decreases to a very low level (oligospermia). The degree of spermatogenic suppression required to produce infertility is not precisely known. However, a recent World Health Organization report has shown that weekly intramuscular injections of testosterone enanthate result in azoospermia or severe oligospermia (ie, less than 3 millions of sperm per ml) and infertility in 98% of men ca receiving therapy (World Health Organization Task Force on Methods And Regulation of Male Fertility, "Contraceptive Efficacy of Testosterone-Induced Azoospermia and Oligospermia in Normal Men", Fertility and Sterility 65:821-29 (1996)).

[0006] Various testosterone esters have been developed, which are more slowly absorbed after intramuscular injection and thus result in a greater androgenic effect. Testosterone enanthate is the most widely used of these esters. While testosterone enanthate has been valuable in establishing the feasibility of hormonal agents for male contraception, it has several drawbacks, including the need for weekly injections and the presence of supraphysiological peak levels of testosterone immediately after intramuscular injection (Wu, "Effects of Testosterone Enanthate in Normal Men: Experience From a Multicenter Contraceptive Efficacy Study," Fertility and Sterility 65:626-36 (1996)).

[0007] Steroid ligands that bind AR and act as androgens (eg testosterone enanthate) or as antiandrogens (eg cyproterone acetate) have been known for many years and are used clinically (Wu 1988). Although NSAIDs are in clinical use for hormone-dependent prostate cancer, NSAIDs have not been reported. For this reason, research into male contraceptives has focused only on steroid compounds.

[0008] Prostate cancer is one of the most common cancers in men in the United States, with hundreds of thousands of new cases diagnosed each year. Unfortunately, over sixty percent of newly diagnosed prostate cancer cases are found to be pathologically advanced, incurable and with a dismal prognosis. One approach to this problem is to find prostate cancer earlier through screening programs to reduce the number of patients with advanced prostate cancer. Another strategy, however, is to develop drugs to prevent prostate cancer. One third of all men over the age of 50 have a latent form of prostate cancer that can be activated into a life-threatening form of clinical prostate cancer. It is shown that the frequency of latent prostate tumors essentially increases with each decade of life from the 50s (5.3-14%) to the 90s (40-80%). The number of people with latent prostate cancer is the same across cultures, ethnicities, and races, yet the incidence of clinically aggressive cancer varies significantly. This suggests that environmental factors may play a role in activating latent prostate cancer. In this way, the development of treatment and prevention strategies against prostate cancer can have the greatest medical and economic overall impact against prostate cancer.

[0009] Osteoporosis is a systemic disease of the skeleton, characterized by low bone mass and degenerative changes in bone tissue, resulting in increased bone fragility and susceptibility to fracture. In the US, the condition affects more than 25 million people and causes more than 1.3 million fractures each year, including 500,000 spine, 250,000 hip and 240,000 wrist fractures annually. Hip fractures are the most serious consequence of osteoporosis, with 5-20% of patients dying within one year and over 50% of survivors being disabled. The elderly are at the greatest risk of osteoporosis, and because of this, the problem is predicted to grow significantly with the aging of the population. It is predicted that the incidence of fractures worldwide will triple over the next 60 years, and one study calculated that there will be 4.5 million hip fractures worldwide in 2050.

[00010] Women are at a higher risk of osteoporosis than men. Women experience a sharp acceleration in bone loss during the five years after menopause. Other factors that increase risk include smoking, alcohol abuse, a sedentary lifestyle, and low calcium intake. However, osteoporosis also often occurs in men. It is well established that bone mineral density in men decreases with age. Decreased amounts of bone mineral content and density correlate with decreased bone strength and make them prone to fracture. The molecular mechanisms underlying the pleiotropic effects of sex hormones in non-reproductive tissues are only beginning to be understood, but it is clear that physiological concentrations of androgens and estrogens play an important role in maintaining bone homeostasis throughout the entire life cycle. As a consequence, when androgen or estrogen deprivation occurs, there is a resulting decrease in the rate of bone remodeling, which upsets the balance of resorption and formation in favor of resorption, contributing to overall bone loss. In men, the natural decline of sex hormones at maturity (direct decline in androgens as well as lower estrogen levels resulting from peripheral aromatization of androgens) is associated with bone weakness. This effect is also observed in castrated males.

[00011] Androgen Decline in the Aging Male (ADAM) refers to a progressive decrease in androgen production, common in men after middle age. The syndrome is characterized by changes in the physical and intellectual domains, which correlate, and can be corrected, with manipulation of the androgenic environment. ADAM is biochemically characterized, not only by reducing serum androgen, but also other hormones, such as growth hormone, melatonin, and dehydroepiandrosterone. Clinical manifestations include malaise, depression, decreased libido, sexual dysfunction, erectile dysfunction, hypogonadism, osteoporosis, hair loss, obesity, sarcopenia, osteopenia, benign prostatic hyperplasia, anemia, changes in mood and cognition, and prostate cancer.

[00012] Androgen Deficiency in Female (ADIF) refers to a variety of hormone-related conditions, including those common in women after middle age. The syndrome is characterized by sexual dysfunction, decreased sexual libido, hypogonadism, sarcopenia, osteopenia, osteoporosis, changes in cognition and mood, anemia, depression, hair loss, obesity, endometriosis, breast cancer, uterine cancer, and ovarian cancer.

[00013] Muscle wasting refers to progressive loss of muscle mass and/or progressive weakening and degeneration of muscles, including skeletal or voluntary muscles that control movement, cardiac muscles that control the heart (cardiomyopathy), and smooth muscle. Chronic muscle wasting is a chronic condition (i.e. lasting for a long period of time), characterized by progressive loss of muscle mass, weakening and degeneration of muscles. The loss of muscle mass that occurs during muscle wasting can be characterized by the breakdown or degradation of muscle protein. Protein degradation occurs due to an unusually high rate of protein degradation, an unusually low rate of protein synthesis, or a combination of both. Protein degradation, whether caused by a high level of protein degradation or a low level of protein synthesis, leads to a decrease in muscle mass and muscle wasting. Muscle wasting is associated with chronic, neurological, genetic or infectious pathologies, diseases, conditions or conditions. These include muscular dystrophies, such as Duchenne muscular dystrophy and myotonic dystrophy; muscle atrophy, such as post-polio muscle atrophy (PPMA); cachexias, such as cardiac cachexia, AIDS cachexia and cancer cachexia; malnutrition, leprosy, diabetes, kidney disease, chronic obstructive pulmonary disease (COPD), cancer, end-stage renal failure, emphysema, osteomalacia, HIV infection, AIDS and cardiomyopathy. In addition, other circumstances and conditions related to this can cause muscle wasting. These include chronic low back pain, advanced age, central nervous system (CNS) injury, peripheral nerve injury, spinal cord injury, chemical injury, central nervous system (CNS) injury, peripheral nerve injury, spinal cord injury, chemical injury, burns , loss of fitness due to disuse that occurs when a limb is immobilized, long-term hospitalization due to illness or injury, and alcoholism. Muscle wasting, if left unabated, can have devastating health consequences. For example, the changes that occur during muscle wasting can lead to a weakened physical state, which is detrimental to an individual's health, resulting in increased susceptibility to infection, weakness, and susceptibility to injury.

[00014] New innovative approaches are urgently needed both on a scientific basis and on a clinical level to develop compounds useful for a) male contraception; b) treatment of various hormone-related conditions, for example conditions related to androgenic decline in the aging male (Androgen Decline in Aging Male, ADAM), such as malaise, depression, decreased libido, sexual dysfunction, erectile dysfunction, hypogonadism, osteoporosis, hair loss , anemia, obesity, sarcopenia, osteopenia, osteoporosis, benign prostatic hyperplasia, changes in mood and cognition, and prostate cancer; c) treatment of conditions associated with androgen deficiency in women (ADIF), such as sexual dysfunction, decreased sexual libido, hypogonadism, sarcopenia, osteopenia, osteoporosis, changes in cognition and mood, depression, anemia, hair loss, obesity, endometriosis, breast cancer , uterine cancer and ovarian cancer; d) treatment and/or prevention of acute and/or chronic conditions of muscle deterioration; e) prevention and/or treatment of dry eye condition; f) oral androgen replacement therapy; and/or g) reducing the incidence, stopping and inducing regression of prostate cancer.

Presentation of the essence of the invention

[00015] In one embodiment, the present invention provides androgen receptor targeting agents (Androgen Receptor Targeting Agents, ARTA). The agents define a new subclass of compounds, which are selective androgen receptor modulators (Selective Androgen Receptor Modulators, SARMs). Several SARM compounds have been found to have the unexpected androgenic and anabolic activity of a nonsteroidal androgen receptor ligand. Other SARM compounds have been found to have the unexpected antiandrogenic activity of nonsteroidal androgen receptor ligands. SARM compounds, alone or as a composition, are useful for a) male contraception; b) treatment of various hormone-related conditions, for example conditions associated with androgenic atrophy in the aged male (ADAM), such as malaise, depression, decreased libido, sexual dysfunction, erectile dysfunction, hypogonadism, osteoporosis, hair loss, anemia, obesity, sarcopenia , osteopenia, osteoporosis, benign prostatic hyperplasia, changes in mood and cognition and prostate cancer; c) treatment of conditions associated with androgen deprivation in women (ADIF), such as sexual dysfunction, decreased sexual libido, hypogonadism, sarcopenia, osteopenia, changes in cognition and mood, depression, anemia, hair loss, obesity, endometriosis, breast cancer, cancer uterine and ovarian cancer; d) treatment and/or prevention of acute and/or chronic conditions of muscle deterioration; e) prevention and/or treatment of dry eye condition; f) oral androgen replacement therapy; and/or g) reducing the incidence, stopping and inducing regression of prostate cancer.

[00016] In one embodiment, the present invention provides a selective androgen receptor modulator (SARM) compound represented by the structure of formula I:

[image]

wherein X is a bond, O, CH2, NH, Se, PR, NO or NR;

G is O or S;

T is OH, OR, -NHCOCH 3 or NHCOR;

R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, halogen, alkenyl or OH;

R 1 is CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 3 or CF 2 CF 3 ;

R2 is F, Cl, Br, I, CH3, CF3, OH, CN, NO2, NHCOCH3, NHCOCF3, NHCOR, alkyl, arylalkyl, OR, NH2, NHR,

NR2, SR;

R3 is F, Cl, Br, I, CN, NO2, COR, COOH, CONHR, CF3, SnR3,

or R3 together with the benzene ring, to which it is attached, forms a fused ring system represented by the structure:

[image]

Z is NO 2 , CN, COR, COOH, or CONHR;

Y is CF 3 , F, Br, Cl, I, CN or SnR 3 ;

Q is H, alkyl, halogen, CF3, CN CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR,

OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR NHSO2CH3, NHSO2R, OH, OR, COR, OCOR, OSO2R,

SO2R, SR;

or Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C:

[image]

n is an integer from 1-4; and

m is an integer from 1-3.

[00017] In another embodiment, the present invention provides an analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, hydrate, or N-oxide of a compound of formula I, or any combination thereof.

[00018] In one embodiment, X in compound I is O. In another embodiment, G in compound I is O. In another embodiment, Z in compound I is NO 2 . In another embodiment, Z in compound I is CN. In another embodiment, Y in Compound I is CF3. In another embodiment, Q in Compound I is NHCOCH 3 . In another embodiment, Q in compound I is F. In another embodiment, T in compound I is OH. In another embodiment, R 1 in compound I is CH 3 . In another embodiment, Q in Compound I is F and R 2 is CH 3 . In another embodiment, Q in Compound I is F and R 2 is Cl.

[00019] In another embodiment, the present invention provides a selective androgen receptor modulator (SARM) compound represented by the structure of formula II:

[image]

wherein p is an integer from 2-5 and the remainder of the substituents are as defined above for Compound I. In one embodiment, p is 5.

[00020] In another embodiment, the present invention provides an analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, hydrate or N-oxide of a compound of formula II, or any combination thereof.

[00021] In another embodiment, the present invention provides a selective androgen receptor modulator (SARM) compound represented by the structure of formula V:

[image]

wherein

R2 is F, Cl, Br, I, CH3, CF3, OH, CN, NO2, NHCOCH3, NHCOCF3, NHCOR, alkyl, arylalkyl, OR, NH2, NHR,

NR2, SR;

R3 is F, Cl, Br, I, CN, NO2, COR, COOH, CONHR, CF3, SnR3,

or R3 together with the benzene ring to which it is attached forms the fused ring system represented

structure:

[image]

R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3; aryl, phenyl, halogen, alkenyl or OH;

Z is NO 2 , CN, COR, COOH, or CONHR;

Y is CF 3 , F, Br, Cl, I, CN or SnR 3 ;

Q is H, alkyl, halogen, CF3, CN CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR NHSO2CH3, NHSO2R, OH, OR, COR, OCOR, OSO2R. SO2R, SR;

or Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C:

[image]

n is an integer from 1-4; and

m is an integer from 1-3.

[00022] In another embodiment, the present invention provides an analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, hydrate, or N-oxide of a compound of formula V, or any combination thereof.

[00023] In another embodiment, Z in compound V is NO2. In another embodiment, Z in compound V is CN. In another embodiment, Y in Compound V is CF3. In another embodiment, Q in Compound V is NHCOCH 3 . In another embodiment, Q in compound V is F. In another embodiment, Q in compound V is F and R 2 is CH 3 . In another embodiment, Q in compound V is F and R 2 is Cl.

[00024] In another embodiment, the present invention provides a selective androgen receptor modulator (SARM) compound represented by the structure of formula VI:

[image]

wherein p' is an integer from 1-4 and the other substituents are as defined above for Compound V. In one embodiment, p' is 5.

[00025] In another embodiment, the present invention provides an analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, hydrate, or N-oxide of a compound of formula VI, or any combination thereof.

[00026] In another embodiment, a SARM is represented by a structure

[image]

[00027] In another embodiment, a SARM is represented by a structure

[image]

[00028] In another embodiment, a SARM is represented by a structure

[image]

[00029] In one embodiment, the SARM compound of the present invention is an androgen receptor agonist. In another embodiment, the SARM compound of any one of Formulas I-VI is an androgen receptor antagonist. In another embodiment, the SARM compound of any one of Formulas I-VI irreversibly binds to the androgen receptor. In another embodiment, the SARM compound of any one of Formulas I-VI reversibly binds to the androgen receptor.

[00030] In one embodiment, the subject invention provides a composition containing the compound of the selective androgen receptor modulator of the subject invention and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate or N-oxide or any combination thereof.

[00031] In another embodiment, the present invention provides a pharmaceutical composition containing the compound of the selective androgen receptor modulator of the present invention and/or its analog, derivative, isomer, metabolite, pharmaceutical product, hydrate or N-oxide or any combination thereof; and a suitable carrier or diluent.

[00032] In another embodiment, the subject invention provides a method of binding a compound of a selective androgen receptor modulator to an androgen receptor, which consists of the step of bringing the androgen receptor into contact with a compound of a selective androgen receptor modulator of the subject invention and/or its analog, derivative, isomer, metabolite , a pharmaceutically acceptable salt, pharmaceutical product, hydrate, or N-oxide, or any combination thereof, in an amount effective to bind the selective androgen receptor modulator compound to the androgen receptor.

[00033] In another embodiment, the subject invention provides a method of suppressing spermatogenesis in a subject, which consists of bringing the subject's androgen receptor into contact with the compound of the selective androgen receptor modulator of the subject invention and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate or N-oxide or any combination thereof, in an effective amount to suppress sperm production.

[00034] In another embodiment, the subject invention provides a method of contraception in a male subject, which consists of the step of administering to the subject a compound of the selective androgen receptor modulator of the subject invention and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate or N-oxide or any combination thereof, in an amount effective to suppress sperm production in the subject, thereby effecting contraception in the subject.

[00035] In another embodiment, the subject invention provides a method of hormone therapy, which consists of the step of bringing the subject's androgen receptor into contact with the compound of the selective androgen receptor modulator of the subject invention and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate or N-oxide or any combination thereof, in an amount effective to effect an androgen dependent state change.

[00036] In another embodiment, the subject invention provides a method of hormone replacement therapy, which consists of the step of bringing the subject's androgen receptor into contact with the compound of the selective androgen receptor modulator of the subject invention and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, a pharmaceutical product, hydrate or N-oxide or any combination thereof, in an amount effective to alter the androgen dependent state.

[00037] In another embodiment, the subject invention provides a method of treating a subject who has a hormonally related condition, which consists of the step of administering to the subject a compound of the selective androgen receptor modulator of the subject invention and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate or N-oxide or any combination thereof, in an amount effective to effect an androgen dependent state change.

[00038] In another embodiment, the subject invention provides a method of treating a subject suffering from prostate cancer, which consists of the step of administering to said subject a compound of the selective androgen receptor modulator of the subject invention and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate or N-oxide or any combination thereof, in an amount effective to treat prostate cancer in a subject.

[00039] In another embodiment, the subject invention provides a method of preventing prostate cancer in a subject, which consists of the step of administering to the subject a compound of the selective androgen receptor modulator of the subject invention and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate or N-oxide or any combination thereof, in an amount effective to prevent prostate cancer in a subject.

[00040] In another embodiment, the subject invention provides a method of stopping the progression of prostate cancer in a subject suffering from prostate cancer, which consists of the step of administering to said subject a compound of the selective androgen receptor modulator of the subject invention and/or its analog, derivative, isomer, metabolite, a pharmaceutically acceptable salt, pharmaceutical product, hydrate, or N-oxide, or any combination thereof, in an amount effective to arrest the progression of prostate cancer in the subject.

[00041] In another embodiment, the subject invention provides a method of preventing the recurrence of prostate cancer in a subject suffering from prostate cancer, which consists of the step of administering to said subject a selective androgen receptor modulator compound of the subject invention and/or its analog, derivative, isomer, metabolite , a pharmaceutically acceptable salt, pharmaceutical product, hydrate, or N-oxide, or any combination thereof, in an amount effective to prevent recurrence of prostate cancer in the subject.

[00042] In another embodiment, the subject invention provides a method of treating the recurrence of prostate cancer in a subject suffering from prostate cancer, which consists of the step of administering to said subject a compound of the selective androgen receptor modulator of the subject invention and/or its analog, derivative, isomer, metabolite , a pharmaceutically acceptable salt, pharmaceutical product, hydrate, or N-oxide, or any combination thereof, in an amount effective to treat a recurrence of prostate cancer in a subject.

[00043] In another embodiment, the subject invention provides a method of treating a dry eye condition in a subject suffering from dry eyes, which consists of the step of administering to said subject a compound of the selective androgen receptor modulator of the subject invention and/or its analog, derivative, isomer, metabolite, a pharmaceutically acceptable salt, pharmaceutical product, hydrate, or N-oxide, or any combination thereof, in an amount effective to treat dry eyes in a subject.

[00044] In another embodiment, the subject invention provides a method of preventing dry eye condition in a subject, which consists of the step of administering to said subject the compound of the selective androgen receptor modulator of the subject invention and/or its analog, derivative, isomer, metabolite, pharmaceutical private salt, pharmaceutical product, hydrate or N-oxide or any combination thereof, in an amount effective to prevent dry eyes in the subject.

[00045] In another embodiment, the present invention provides a process for preparing a selective androgen receptor modulator (SARM) compound represented by the structure of formula I:

[image]

wherein X is O, NH, S, Se, PR, or NR;

G is O or S;

T is OH, OR, -NHCOCH 3 or NHCOR;

R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, halogen, alkenyl or OH;

R 1 is CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 3 or CF 2 CF 3 ;

R2 is F, Cl, Br, I, CH3, CF3, OH, CN, NO2, NHCOCH3, NHCOCF3, NHCOR, alkyl, arylalkyl, OR, NH2, NHR, NR2, SR;

R3 is F, Cl, Br, I, CN, NO2, COR, COOH, CONHR, CF3, SnR3,

or R3 together with the benzene ring, to which it is attached, forms a fused ring system represented by the structure:

[image]

Z is NO 2 , CN, COR, COOH, or CONHR;

Y is CF 3 , F, Br, Cl, I, CN or SnR 3 ;

Q is H, alkyl, halogen, CF3, CN CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR NHSO2CH3, NHSO2R, OH, OR, COR, OCOR, OSO2R. SO2R, SR;

or Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C:

[image]

n is an integer from 1-4; and

m is an integer from 1-3.

a process comprising the step of coupling a compound of formula VII:

[image]

wherein Z, Y, G, R1, T, R3 and m are as defined above and L is a leaving group, with a compound of formula VIII:

[image]

wherein Q, X, R 2 and n are as defined above.

[00046] In one embodiment, the coupling step is performed in the presence of a base. In another embodiment, the leaving group L is Br. In another embodiment, a compound of formula VII is prepared

i) by preparing the compound of formula IX by opening the ring of the cyclic compound of formula X

[image]

wherein L, R 1 , G and T are as defined above and T 1 is O or NH; and

ii) by reacting amines of formula XI

[image]

wherein Z, Y, R 3 and m are as defined above, with a compound of formula IX, in the presence of a coupling reagent, to produce a compound of formula VII.

[image]

[00047] In one embodiment, step (a) is performed in the presence of HBr. In another embodiment, the process further comprises the step of converting the selective androgen receptor modulator (SARM) compound into its analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, N-oxide, hydrate, or any combination thereof.

[00048] The novel selective androgen receptor modulator compounds of the present invention, either alone or as a pharmaceutical composition, are useful for a) male contraception; b) treatment of various hormone-related conditions, for example ADAM-related conditions, such as malaise, depression, decreased libido, sexual dysfunction, erectile dysfunction, hypogonadism, osteoporosis, hair loss, obesity, sarcopenia, osteopenia, benign prostatic hyperplasia and changes in mood and cognition; c) treatment of conditions associated with ADIF, such as sexual dysfunction, decreased sexual libido, hypogonadism, sarcopenia, osteopenia, osteoporosis, cognitive and mood changes, depression, anemia, hair loss, obesity, endometriosis, breast cancer, uterine cancer and ovarian cancer ; d) treatment and/or prevention of acute and/or chronic muscle wasting conditions; e) prevention and/or treatment of dry eye condition; f) oral androgen replacement therapy; and/or g) reducing the incidence, stopping or inducing regression of prostate cancer.

[00049] The selective androgen receptor modulator compounds of the present invention offer a significant advance in steroid androgen therapy, since the selective androgen receptor modulator compounds of the present invention have been shown in-vivo to have the androgenic and anabolic activity of a nonsteroidal androgen receptor ligand. In this way, compounds of selective androgen receptor modulators have the androgenic and anabolic activity of a non-steroidal ligand for the androgen receptor and will not be accompanied by serious side effects, inconvenient routes of administration, or high costs, while still having the advantages of oral bioavailability, lack of cross-action with other steroid receptors and long biological half-lives.

Brief description of the drawing

[00050] The subject invention will be more fully understood and appreciated from the following detailed description taken in conjunction with the accompanying drawings in which:

Figure 1: Androgenic and anabolic activity of Compounds 1 and 2 in rats. Rats were left untreated (intact control), castrated (castrated control), treated with 1.0 mg/day of Compound 1 or treated with 1.0 mg/day of Compound III, and the weight of androgen reactive tissues (prostate, seminal vesicles and levator ani muscle).

Figure 2: Androgenic and anabolic activity of Compound 7 in rats. Rats were castrated on day 0 and received daily subcutaneous doses (0.05 to 3 mg/day) of Compound 7 in a DMSO/PEG vehicle. Rats were sacrificed on the last day and wet androgenic (prostate and seminal vesicle) and anabolic (levator ani) organ weights were determined.

Detailed description of the invention

[00051] In one embodiment, the present invention provides androgen receptor targeting agents (Androgen Receptor Targeting Agents, ARTA). The agents define a new subclass of compounds, which are selective androgen receptor modulators (Selective Androgen Receptor Modulators, SARMs). Several SARM compounds have been found to have the unexpected androgenic and anabolic activity of a nonsteroidal androgen receptor ligand. Other SARM compounds have been found to have the unexpected antiandrogenic activity of a nonsteroidal androgen receptor ligand. SARM compounds, alone or as a composition, are useful for a) male contraception; b) treatment of various hormone-related conditions, for example conditions related to androgenic decline in the aging male (Androgen Decline in Aging Male, ADAM), such as malaise, depression, decreased libido, sexual dysfunction, erectile dysfunction, hypogonadism, osteoporosis, hair loss , anemia, obesity, sarcopenia, osteopenia, benign prostatic hyperplasia, changes in mood and cognition, and prostate cancer; c) treatment of conditions related to androgenic decline in women (Androgen Decline In Female, ADIF), such as sexual dysfunction, reduced sexual libido, hypogonadism, sarcopenia, osteopenia, osteoporosis, cognitive and mood changes, depression, anemia, hair loss, obesity , endometriosis, breast cancer, uterine cancer and ovarian cancer; d) treatment and/or prevention of acute and/or chronic conditions of muscle deterioration; e) prevention and/or treatment of dry eye conditions; f) oral androgen replacement therapy; and/or g) reducing the incidence, stopping and inducing regression of prostate cancer.

[00052] In one embodiment, the present invention provides a selective androgen receptor modulator (SARM) compound represented by the structure of formula I:

[image]

wherein X is a bond, O, CH2, NH, Se, PR, NO or NR;

G is O or S;

T is OH, OR, -NHCOCH 3 or NHCOR;

R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3; aryl, phenyl, halogen, alkenyl or OH;

R 1 is CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 3 or CF 2 CF 3 ;

R2 is F, Cl, Br, I, CH3, CF3, OH, CN, NO2, NHCOCH3, NHCOCF3, NHCOR, alkyl, arylalkyl, OR, NH2, NHR, NR2, SR;

R3 is F, Cl, Br, I, CN, NO2, COR, COOH, CONHR, CF3, SnR3,

or R3 together with the benzene ring, to which it is attached, forms a fused ring system represented by the structure:

[image]

Z is NO 2 , CN, COR, COOH, or CONHR;

Y is CF 3 , F, Br, Cl, I, CN or SnR 3 ;

Q is H, alkyl, halogen, CF3, CN CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR NHSO2CH3, NHSO2R, OH, OR, COR, OCOR, OSO2R. SO2R, SR;

or Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C:

[image]

n is an integer from 1-4; and

m is an integer from 1-3.

[00053] In one embodiment, this invention provides an analog of a compound of formula I. In another embodiment, this invention provides a derivative of a compound of formula I. In another embodiment, this invention provides an isomer of a compound of formula I. In another embodiment, this invention provides a metabolite of a compound of formula I In another embodiment, this invention provides a pharmaceutically acceptable salt of a compound of formula I. In another embodiment, this invention provides a pharmaceutical product of a compound of formula I. In another embodiment, this invention provides a hydrate of a compound of formula I. In another embodiment, this invention provides an N-oxide of the compound of formula I. In another embodiment, this invention provides a combination of any of the analogs, derivatives, metabolites, isomers, pharmaceutically acceptable salts, pharmaceutical products, hydrates or N-oxides of the compound of formula I.

[00054] In one embodiment, the subject invention provides a compound of formula I, wherein X is O. In another embodiment, the subject invention provides a compound of formula I, wherein G is O. In another embodiment, the subject invention provides a compound of formula I, wherein Z is NO2. In another embodiment, the present invention provides a compound of formula I, wherein Z is CN. In another embodiment, the present invention provides a compound of formula I, wherein Y is CF3. In another embodiment, Q is NHCOCH 3 . In another embodiment, the subject invention provides a compound of formula I, wherein Q is F. In another embodiment, the subject invention provides a compound of formula I, wherein T is OH. In another embodiment, the present invention provides a compound of formula I, wherein R 1 is CH 3 . In another embodiment, the present invention provides a compound of formula I, wherein Q is F and R 2 is CH 3 . In another embodiment, the present invention provides a compound of formula I, wherein Q is F and R 2 is Cl.

[00055] The substituents Z, Y and R3 can be in any position of the bearing ring

and substituents (hereinafter "ring A"). In one embodiment, substituent Z is in the para position of ring A. In another embodiment, substituent Y is in the meta position of ring A. In yet another embodiment, substituent Z is in the para position of ring A and substituent Y is in the meta position of ring A.

[00056] Substituents Q and R 2 can be in any position of the ring bearing these substituents (hereinafter "ring B"). In one embodiment, the substituent Q is in the para position of ring B. In another embodiment, the substituent Q is in the para position of ring B. In another embodiment, the substituent Q is NHCOCH3 and is in the para position of ring B.

[00057] As discussed herein, when the integers m and n are greater than one, the substituents R 2 and R 3 are not limited to one particular substituent, and may be any combination of substituents listed above.

[00058] In another embodiment, the present invention provides a selective androgen receptor modulator (SARM) compound represented by the structure of formula II:

[image]

wherein p is an integer from 2-5 and the other substituents are as defined above for compound I.

[00059] In one embodiment, the subject invention provides a compound of formula II, wherein p is 2. In one embodiment, the subject invention provides a compound of formula II, wherein p is 3. In one embodiment, the subject invention provides a compound of formula II, wherein p is 4. In one embodiment, the present invention provides a compound of formula II, wherein p is 5.

[00060] In one embodiment, the present invention provides an analog of a compound of formula II. In another embodiment, the present invention provides a derivative of a compound of formula II. In another embodiment, the present invention provides an isomer of a compound of formula II. In another embodiment, the present invention provides a metabolite of a compound of formula II. In another embodiment, the present invention provides a pharmaceutically acceptable salt of a compound of formula II. In another embodiment, the present invention provides a pharmaceutical product of a compound of formula II. In another embodiment, the present invention provides a hydrate of a compound of formula II. In another embodiment, the present invention provides the N-oxide of a compound of formula II. In another embodiment, the present invention provides a combination of any of the analogs, derivatives, metabolites, isomers, pharmaceutically acceptable salts, pharmaceutical products, hydrates or N-oxides of the compound of formula II.

[00061] In another embodiment, the present invention provides a selective androgen receptor modulator (SARM) compound represented by the structure of formula III:

[image]

wherein X is a bond, O, CH2, NH, Se, PR, NO or NR;

G is O or S;

T is OH, OR, -NHCOCH 3 or NHCOR;

R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3; aryl, phenyl, halogen, alkenyl or OH;

R 1 is CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 3 or CF 2 CF 3 ;

R2 is F, Cl, Br, I, CH3, CF3, OH, CN, NO2, NHCOCH3, NHCOCF3, NHCOR, alkyl, arylalkyl, OR, NH2, NHR, NR2, SR;

R3 is F, Cl, Br, I, CN, NO2, COR, COOH, CONHR, CF3, SnR3, or

R3 together with the benzene ring, to which it is attached, forms a fused ring system represented by the structure:

[image]

Z is NO 2 , CN, COR, COOH, or CONHR;

Y is CF 3 , F, Br, Cl, I, CN or SnR 3 ;

Q is H, alkyl, halogen, CF3, CN CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR NHSO2CH3, NHSO2R, OH, OR, COR, OCOR, OSO2R. SO2R, SR;

or Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C:

[image]

n is an integer from 1-4; and

m is an integer from 1-3.

[00062] In one embodiment, the present invention provides an analog of a compound of formula III. In another embodiment, the present invention provides a derivative of a compound of formula III. In another embodiment, the present invention provides an isomer of a compound of formula III. In another embodiment, the present invention provides a metabolite of a compound of formula III. In another embodiment, the present invention provides a pharmaceutically acceptable salt of a compound of formula III. In another embodiment, the present invention provides a pharmaceutical product of a compound of formula III. In another embodiment, the present invention provides a hydrate of a compound of formula III. In another embodiment, the present invention provides the N-oxide of a compound of formula III. In another embodiment, the present invention provides a combination of any of the analogs, derivatives, metabolites, isomers, pharmaceutically acceptable salts, pharmaceutical products, hydrates or N-oxides of the compound of formula III.

[00063] In one embodiment, the subject invention provides a compound of formula III, wherein X is O. In another embodiment, the subject invention provides a compound of formula III, wherein G is O. In another embodiment, the subject invention provides a compound of formula III, wherein Z in compound III is NO2. In another embodiment, the present invention provides a compound of formula III, wherein Z is CN. In another embodiment, the present invention provides a compound of formula III, wherein Y is CF3. In another embodiment, the present invention provides a compound of formula III, wherein Q is NHCOCH3. In another embodiment, Q is F. In another embodiment, the present invention provides a compound of formula III, wherein T is OH. In another embodiment, the present invention provides a compound of formula III, wherein R 1 is CH 3 . In another embodiment, the present invention provides a compound of formula III, wherein Q is F and R 2 is CH 3 . In another embodiment, the present invention provides a compound of formula III, wherein Q is F and R 2 is Cl.

[00064] In another embodiment, the present invention provides a selective androgen receptor modulator (SARM) compound represented by the structure of formula IV:

[image]

wherein p' is an integer from 1-4 and the other substituents are as defined above for compound III.

[00065] In one embodiment, the subject invention provides a compound of formula IV, wherein p' is 1. In one embodiment, the subject invention provides a compound of formula IV, wherein p' is 2. In one embodiment, the subject invention provides a compound of formula IV, wherein p' is 3. In one embodiment, the present invention provides a compound of formula IV wherein p' is 4.

[00066] In one embodiment, the present invention provides an analog of a compound of formula IV. In another embodiment, the present invention provides a derivative of a compound of formula IV. In another embodiment, the present invention provides an isomer of a compound of formula IV. In another embodiment, the present invention provides a metabolite of a compound of formula IV. In another embodiment, the present invention provides a pharmaceutically acceptable salt of a compound of formula IV. In another embodiment, the present invention provides a pharmaceutical product of a compound of formula IV. In another embodiment, the present invention provides a hydrate of a compound of formula IV. In another embodiment, the present invention provides the N-oxide of a compound of formula IV. In another embodiment, the present invention provides a combination of any of the analogs, derivatives, metabolites, isomers, pharmaceutically acceptable salts, pharmaceutical products, hydrates or N-oxides of the compound of formula IV.

[00067] In another embodiment, the present invention provides a selective androgen receptor modulator (SARM) compound represented by the structure of formula V:

[image]

wherein

R2 is F, Cl, Br, I, CH3, CF3, OH, CN, NO2, NHCOCH3, NHCOCF3, NHCOR, alkyl, arylalkyl, OR, NH2, NHR, NR2, SR;

R3 is F, Cl, Br, I, CN, NO2, COR, COOH, CONHR, CF3, SnR3, or

R3 together with the benzene ring, to which it is attached, forms a fused ring system represented by the structure:

[image]

R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, halogen, alkenyl or OH;

Z is NO 2 , CN, COR, COOH, or CONHR;

Y is CF 3 , F, Br, Cl, I, CN or SnR 3 ;

Q is H, alkyl, halogen, CF3, CN CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR NHSO2CH3, NHSO2R, OH, OR, COR, OCOR, OSO2R. SO2R, SR; or

Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C:

[image]

n is an integer from 1-4; and

m is an integer from 1-3.

[00068] In one embodiment, this invention provides an analog of a compound of formula V. In another embodiment, this invention provides a derivative of a compound of formula V. In another embodiment, this invention provides an isomer of a compound of formula V. In another embodiment, this invention provides a metabolite of a compound of formula V. In another embodiment, this invention provides a pharmaceutically acceptable salt of a compound of formula V. In another embodiment, this invention provides a pharmaceutical product of a compound of formula V. In another embodiment, this invention provides a hydrate of a compound of formula V. In another embodiment, this invention provides an N-oxide compound of formula IV. In another embodiment, the present invention provides a combination of any of the analogs, derivatives, metabolites, isomers, pharmaceutically acceptable salts, pharmaceutical products, hydrates or N-oxides of the compound of formula V.

[00069] In another embodiment, the present invention provides a compound of formula V, wherein Z is NO2. In another embodiment, the present invention provides a compound of formula V, wherein Z is CN. In another embodiment, the present invention provides a compound of formula V, wherein Y is CF3. In another embodiment, the present invention provides a compound of formula V, wherein Q is NHCOCH3. In another embodiment, the subject invention provides a compound of formula V, wherein Q is F. In another embodiment, the subject invention provides a compound of formula V, wherein Q is F and R 2 is CH 3 . In another embodiment, the present invention provides a compound of formula V, wherein Q is F and R 2 is Cl.

[00070] In another embodiment, the present invention provides a selective androgen receptor modulator (SARM) compound represented by the structure of formula VI:

[image]

wherein p' is an integer from 1-4 and the other substituents are as defined above for compound V. In one embodiment, the present invention provides a compound of formula VI, wherein p' is 1. In one embodiment, the present invention provides a compound of formula VI, wherein p' is 2. In one embodiment, the subject invention provides a compound of formula VI, wherein p' is 3. In one embodiment, the subject invention provides a compound of formula VI, wherein p' is 4.

[00071] In one embodiment, the present invention provides an analog of a compound of formula VI. In another embodiment, the present invention provides a derivative of a compound of formula VI. In another embodiment, the present invention provides an isomer of a compound of formula VI. In another embodiment, the present invention provides a metabolite of a compound of formula VI. In another embodiment, the present invention provides a pharmaceutically acceptable salt of a compound of formula VI. In another embodiment, the present invention provides a pharmaceutical product of a compound of formula VI. In another embodiment, the present invention provides a hydrate of a compound of formula VI. In another embodiment, the present invention provides the N-oxide of a compound of formula VI. In another embodiment, the present invention provides a combination of any of the analogs, derivatives, metabolites, isomers, pharmaceutically acceptable salts, pharmaceutical products, hydrates or N-oxides of the compound of formula VI.

[00072] In one embodiment, the SARM compound is a compound of any one of formulas I-VI, wherein R 2 is F. In another embodiment, the SARM compound is a compound of any one of formulas I-VI, wherein R 2 is Cl. In one embodiment, the SARM compound is a compound of any one of formulas I-VI, wherein R 2 is Br. In one embodiment, the SARM compound is a compound of any of Formulas I-VI, wherein R 2 is I. In another embodiment, the SARM compound is a compound of any of Formulas I-VI, wherein R 2 is CH 3 . In another embodiment, the compound SARM is a compound of any one of formulas I-VI, wherein R 2 is OH. In another embodiment, the SARM compound is a compound of any one of formulas I-VI, wherein R 2 is CF 3 . In another embodiment, the compound SARM is a compound of any one of formulas I-VI, wherein R 2 is OH. In another embodiment, the compound SARM is a compound of any one of formulas I-VI, wherein R 2 is CN. In another embodiment, the SARM compound is a compound of any one of formulas I-VI, wherein R 2 is NO 2 . In another embodiment, the SARM compound is a compound of any one of Formulas I-VI, wherein R 2 is NHCOCH 3 . In another embodiment, the SARM compound is a compound of any one of formulas I-VI, wherein R 2 is NHCOCF 3 . In another embodiment, the SARM compound is a compound of any one of Formulas I-VI, wherein R 2 is NHCOR. In another embodiment, the compound SARM is a compound of any one of formulas I-VI, wherein R 2 is alkyl. In another embodiment, the compound SARM is a compound of any one of formulas I-VI, wherein R 2 is arylalkyl. In another embodiment, the compound SARM is a compound of any one of formulas I-VI, wherein R 2 is OR. In another embodiment, the SARM compound is a compound of any one of formulas I-VI, wherein R 2 is NH 2 . In another embodiment, the SARM compound is a compound of any one of Formulas I-VI, wherein R 2 is NHR. In another embodiment, the SARM compound is a compound of any one of formulas I-VI, wherein R 2 is NR 2 . In another embodiment, the SARM compound is a compound of any one of Formulas I-VI, wherein R 2 is SR.

[00073] In one embodiment, the SARM compound is a compound of any one of formulas I-VI, wherein R3 is F. In another embodiment, the SARM compound is a compound of any one of formulas I-VI, wherein R3 is Cl. In another embodiment, the SARM compound is a compound of any one of formulas I-VI, wherein R3 is Br. In another embodiment, the compound SARM is a compound of any one of formulas I-VI, wherein R 3 is I. In another embodiment, the compound SARM is a compound of any one of formulas I-VI, wherein R 3 is CN. In another embodiment, the SARM compound is a compound of any one of formulas I-VI, wherein R 3 is NO 2 . In another embodiment, the SARM compound is a compound of any one of Formulas I-VI, wherein R 3 is COR. In another embodiment, the SARM compound is a compound of any one of Formulas I-VI, wherein R 3 is COOH. In another embodiment, the SARM compound is a compound of any one of Formulas I-VI, wherein R 3 is CONHR. In another embodiment, the SARM compound is a compound of any one of formulas I-VI, wherein R 3 is CF 3 . In another embodiment, the compound SARM is a compound of any one of formulas I-VI, wherein R 3 is SnR 3 . In another embodiment, the SARM compound is a compound of any one of formulas I-VI, wherein R3 together with the benzene ring to which it is attached forms a compound represented by the structure:

[image]

[00074] In one embodiment, compound SARM is a compound of any one of formulas I-VI, wherein m is 1. In another embodiment, compound SARM is a compound of any one of formulas I-VI, wherein m is 2. In another embodiment , compound SARM is a compound of any of formulas I-VI, wherein m is 3. In one embodiment, compound SARM is a compound of any of formulas I-VI, wherein n is 1. In another embodiment, compound SARM is a compound of either which of formulas I-VI, wherein n is 2. In another embodiment, compound SARM is a compound of any of formulas I-VI, wherein n is 3. In another embodiment, compound SARM is a compound of any of formulas I-VI , where n is 4.

[00075] In another embodiment, a SARM is represented by a structure

[image]

[00076] In another embodiment, a SARM is represented by a structure

[image]

[00077] In another embodiment, a SARM is represented by a structure

[image]

[00078] Substituent R is defined herein as alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3; aryl, phenyl, halogen, alkenyl or hydroxyl (OH).

[00079] An "alkyl" group refers to a saturated aliphatic hydrocarbon, including straight chain, branched and cyclic alkyl groups. In one embodiment, the alkyl group has 1-12 carbons. In another embodiment, the alkyl group has 1-7 carbons. In another embodiment, the alkyl group has 1-6 carbons. In another embodiment, the alkyl group has 1-4 carbons. The alkyl group may be unsubstituted or substituted with one or more groups selected from halogen, hydroxy, alkoxy, carbonyl, amido, alkylamido, dialkylamido, nitro, amino, alkylamino, dialkylamino, carboxyl, thio and thioalkyl.

[00080] A "haloalkyl" group refers to an alkyl group, as defined above, which is substituted with one or more halogen atoms, e.g. F, Cl, Br or I.

[00081] "Aryl" group refers to an aromatic group, which has at least one carbocyclic aromatic group or heterocyclic aromatic group, which may be unsubstituted or substituted with one or more groups selected from halogen, haloalkyl, hydroxy, alkoxy carbonyl, amido, alkylamido , dialkylamido, nitro, amino, alkylamino, dialkylamino, carboxy or thio or thioalkyl. Non-limiting examples of aryl rings are phenyl, naphthyl, pyranyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyrazolyl, pyridinyl, furanyl, thiophenyl, thiazolyl, imidazolyl, isoxazolyl, and the like.

[00082] A "hydroxyl" group refers to an OH group. An "alkenyl" group refers to a group having at least one carbon-to-carbon double bond. A halo group refers to F, Cl, Br or I.

[00083] An "arylalkyl" group refers to an alkyl attached to an aryl, wherein alkyl and aryl are as defined above. An example of an arylalkyl group is a benzyl group.

[00084] As discussed herein, the present invention relates to the use of a SARM compound and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, or combinations thereof. In one embodiment, the invention relates to the use of an analogue of the SARM compound. In another embodiment, the invention relates to the use of SARM compound derivatives. In another embodiment, the invention relates to the use of isomers of the compound SARM. In another embodiment, the invention relates to the use of metabolites of the SARM compound. In another embodiment, the invention relates to the use of a pharmaceutically acceptable salt of the compound SARM. In another embodiment, the invention relates to the use of a pharmaceutical product of the compound SARM. In another embodiment, the invention relates to the use of hydrate of the SARM compound. In another embodiment, the invention relates to the use of the N-oxide of the compound SARM.

[00085] As defined herein, the term "isomer" includes, but is not limited to, optical isomers and analogs, structural isomers and analogs, conformational isomers and analogs, and the like.

[00086] In one embodiment, the present invention encompasses the use of different optical isomers of a SARM compound. Those skilled in the art will appreciate that the SARMs of the present invention contain at least one chiral center. Accordingly, SARMs used in the methods of the present invention may exist and be isolated in optically active or racemic forms. Some compounds may also show polymorphism. It is to be understood that the subject invention encompasses any racemic, optically active, polymorphic or stereoisomeric form, or mixtures thereof, which forms possess properties useful in the treatment of androgen-related conditions described herein. In one embodiment, SARMs are pure (R)-isomers. In another embodiment, SARMs are pure (S)-isomers. In another embodiment, SARMs are a mixture of (R) and (S) isomers. In another embodiment, SARMs are a racemic mixture, containing an equal amount of (R) and (S) isomers. It is well known in the art how to prepare optically active forms (for example, by resolution of the racemic form by recrystallization techniques, by synthesis from optically active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase).

[00087] The invention includes pharmaceutically acceptable salts of amino substituted compounds with organic and inorganic acids, for example, citric acid and hydrochloric acid. The invention also includes the N-oxides of the amino substituents of the compounds described herein. Pharmaceutically acceptable salts can also be prepared from phenolic compounds by treatment with inorganic bases, for example, sodium hydroxide. Also, esters of phenolic compounds can be prepared with aliphatic and aromatic carboxylic acids, for example, esters of acetic acid and benzoic acid.

[00088] This invention further includes derivatives of SARM compounds. The term "derivatives" includes, but is not limited to, ether derivatives, acid derivatives, amide derivatives, ester derivatives and the like. In addition, this invention further includes hydrates of SARM compounds. The term "hydrate" includes, but is not limited to, hemihydrate, monohydrate, dihydrate, trihydrate, and the like.

[00089] This invention further includes metabolites of SARM compounds. The term "metabolite" means any substance produced from another substance by metabolism or a metabolic process.

[00090] This invention further includes pharmaceutical products of SARM compounds. The term "pharmaceutical product" means a composition suitable for pharmaceutical use (pharmaceutical composition), as defined herein.

[00091] In another embodiment, the present invention provides a process for preparing a selective androgen receptor modulator (SARM) compound represented by the structure of formula I:

[image]

wherein X is O, NH, S, Se, PR or NR;

G is O or S;

T is OH, OR, -NHCOCH 3 or NHCOR;

R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, halogen, alkenyl or OH;

R 1 is CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 3 or CF 2 CF 3 ;

R2 is F, Cl, Br, I, CH3, CF3, OH, CN, NO2, NHCOCH3, NHCOCF3, NHCOR, alkyl, arylalkyl, OR, NH2, NHR, NR2, SR;

R3 is F, Cl, Br, I, CN, NO2, COR, COOH, CONHR, CF3, SnR3, or

R3 together with the benzene ring, to which it is attached, forms a fused ring system represented by the structure:

[image]

Z is NO 2 , CN, COR, COOH, or CONHR;

Y is CF 3 , F, Br, Cl, I, CN or SnR 3 ;

Q is H, alkyl, halogen, CF3, CN CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR NHSO2CH3, NHSO2R, OH, OR, COR, OCOR, OSO2R. SO2R, SR; or

Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C:

[image]

n is an integer from 1-4; and

m is an integer from 1-3.

a process comprising the step of coupling a compound of formula VII:

[image]

wherein Z, Y, G, R1, T, R3 and m are as defined above and L is a leaving group, with a compound of formula VIII:

[image]

wherein Q, X, R 2 and n are as defined above.

[00092] In one embodiment, the coupling step is performed in the presence of a base. In another embodiment, the leaving group L is Br. In another embodiment, a compound of formula VII is prepared

i) by preparing the compound of formula IX by opening the ring of the cyclic compound of formula X

[image]

wherein L, R 1 , G and T are as defined above and T 1 is O or NH; and

ii) by reacting amines of formula XI:

[image]

wherein Z, Y, R 3 and m are as defined above, with a compound of formula IX, in the presence of a coupling reagent, to produce a compound of formula VII.

[image]

[00093] It is understood by a person skilled in the relevant field that when T 1 is O or NH, T in compound VIII is O or NH 2 . Thus, when T in compound I is OR, the reaction will involve the further step of converting OH to OR by reaction with, for example, an alkyl halide R-X. When T in compound I is NHCOR, NHCOCH 3 , the reaction will include the further step of converting NH 2 to NHCOR or NHCOCH 3 by reaction with, for example, the corresponding acyl chloride ClCOR or ClCOCH 3 .

[00094] In one embodiment, step (a) is performed in the presence of HBr. In another embodiment, the process further comprises the step of converting the selective androgen receptor modulator (SARM) compound into its analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, N-oxide, hydrate, or any combination thereof.

[00095] In one embodiment, the coupling step defined herein above is performed in the presence of a base. Any suitable base can be used which will deprotonate the hydrogen of the XH moiety (for example, the phenolic moiety when X is O) and allow coupling. Non-limiting examples of bases are carbonates, such as alkali carbonates, for example sodium carbonate (Na 2 CO 3 ), potassium carbonate (K 2 CO 3 ) and cesium carbonate (Cs 2 CO 3 ); bicarbonates, such as alkali metal bicarbonates, for example sodium bicarbonate (NaHCO3), potassium bicarbonate (KHCO3), alkali metal hydrides, such as sodium hydride (NaH), potassium hydride (KH) and lithium hydride (LiH) and the like.

[00096] The leaving group L is defined herein as any leaving group, which is usually considered for chemical reactions, as known to a person skilled in the relevant field. Suitable leaving groups are halogens, for example F, Cl, Br and I; alkyl sulfonate esters (-OSO2R), where R is an alkyl group, for example methanesulfonate (mesylate), trifluoromethanesulfonate, ethanesulfonate, 2,2,2-trifluoroethanesulfonate, perfluorobutanesulfonate; aryl sulfonate esters (-OSOR2Ar), in which Ar is an aryl group, for example p-toluoylsulfonate (tosylate), benzenesulfonate which can be unsubstituted or substituted by methyl, chlorine, bromine, nitro group and the like; NO3, NO2, or sulfate, sulfite, phosphate, phosphite, carboxylate, imino ester, N2, or carbamate.

[00097] The reaction is conveniently carried out in a suitable inert solvent or diluent such as, for example, tetrahydrofuran, diethyl ether, aromatic amines such as pyridine; aliphatic and aromatic hydrocarbons, such as benzene, toluene, and xylene; dimethylsulfoxide (DMSO), dimethylformamide (DMF) and dimethylacetamide (DMAC) The reaction is conveniently carried out at a temperature in the range of for example -20 to 120C, for example at or near ambient temperature.

[00098] A coupling agent as defined herein above is a reagent capable of converting a carboxylic acid/thiocarboxylic acid of formula X into a reactive derivative thereof, thereby allowing coupling with the corresponding amine to form an amide/thioamide bond. A suitable reactive carboxylic acid / thiocarboxylic acid derivative is for example an acyl halide / thioacyl halide, for example an acyl / thioacyl chloride formed by the reaction of an acid / thioacid and an inorganic acid chloride, for example thionyl chloride; a mixed anhydride, for example an anhydride formed by the reaction of an acid and a chloroformate such as isobutyl chloroformate; an active ester/thioester, for example an ester/thioester formed by the reaction of an acid/thioacid and a phenol, ester/thioester or alcohol such as methanol, ethanol, isopropanol, butanol or N-hydroxybenzotriazole; an acyl/thioacyl azide, for example an azide formed by the reaction of an acid/thioacid and an azide such as diphenylphosphoryl azide; acyl cyanide/thioacyl cyanide, for example a cyanide formed by the reaction of an acid and a cyanide, such as diethylphosphoryl cyanide; or an acid/thioacid reaction product with a carbodiimide such as dicyclohexylcarbodiimide.

[00099] The reaction is conveniently carried out in a suitable inert solvent or diluent as described hereinabove, conveniently in the presence of a base such as triethylamine, and at a range of temperatures as described above.

Biological activity of compounds of selective androgen modulators

[000100] The compounds provided herein are selective androgen receptor modulators (SARM) compounds useful for oral testosterone replacement therapy that have unexpected in-vivo androgen activity and anabolic activity of a nonsteroidal androgen receptor ligand. Further, the appropriately substituted compounds are effective in the treatment of prostate cancer and useful for the imaging of prostate cancer. SARM compounds demonstrate androgenic and anabolic activity in vivo as a nonsteroidal androgen receptor ligand.

[000101] As discussed herein, appropriately substituted SARM compounds of the present invention are useful for a) male contraception; b) treatment of various hormone-related conditions, for example conditions related to androgenic decline in the aging male (Androgen Decline in Aging Male, ADAM), such as malaise, depression, decreased libido, sexual dysfunction, erectile dysfunction, hypogonadism, osteoporosis, hair loss , anemia, obesity, sarcopenia, osteopenia, osteoporosis, benign prostatic hyperplasia, changes in mood and cognition, and prostate cancer; c) treatment of conditions associated with ADIF, such as sexual dysfunction, decreased sexual libido, hypogonadism, sarcopenia, osteopenia, osteoporosis, cognitive and mood changes, depression, anemia, hair loss, obesity, endometriosis, breast cancer, uterine cancer and ovarian cancer ; d); treatment and/or prevention of acute and/or chronic muscle wasting conditions; e) prevention and/or treatment of dry eye condition; f) oral androgen replacement therapy; and/or g) reducing the incidence, stopping and inducing regression of prostate cancer.

[000102] As used herein, receptors for extracellular signaling molecules are collectively referred to as "cell signaling receptors". Many cell signaling receptors are transmembrane proteins on the cell surface; when they bind to an extracellular signaling molecule (i.e., a ligand), they become activated, creating a cascade of intracellular signals that alter cell behavior. In contrast, in some cases, the receptors are inside the cell and the signaling ligand must enter the cell to activate them; these signaling molecules must therefore be small and hydrophobic enough to spread across the plasma membrane of the cell.

[000103] Steroid hormones are one example of small hydrophobic molecules that diffuse directly across the plasma membrane of target cells and bind to intracellular cell signaling receptors. These receptors are structurally related and make up the superfamily of intracellular receptors (or superfamily of steroid hormone receptors). Steroid hormone receptors include progesterone receptors, estrogen receptors, androgen receptors, glucocorticoid receptors, and mineralocorticoid receptors. The present invention is particularly directed to androgen receptors.

[000104] In addition to ligand binding to receptors, receptors can be blocked to prevent ligand binding. When a substance binds to a receptor, the three-dimensional structure of the substance fits into the space created by the three-dimensional structure of the receptor in a spherical and hollow configuration. The better the ball fits in the cavity, the tighter it is held. This phenomenon is called affinity. If the affinity of the substance is higher than the original hormone, it will compete with the hormone and bind to the binding site more often. Once bound, signals can be sent through the receptor into cells, causing the cell to respond in some way. This is called activation. Upon activation, the activated receptor then directly regulates the transcription of specific genes. The substance and receptor may, however, have certain attributes, other than affinity, to activate the cell. Chemical bonds can be formed between the atoms of the substance and the atoms of the receptor. In some cases, this leads to a change in the configuration of the receptor, which is sufficient to initiate the activation of the process (called signal transduction).

[000105] In one embodiment, the present invention is directed to selective androgen receptor modulator compounds that are agonist compounds. A receptor agonist is a substance that binds to receptors and activates them. Thus, in one embodiment, the SARM compounds of the present invention are useful in binding to and activating steroid hormone receptors. In one embodiment, the agonist compound of the present invention is an androgen receptor binding agonist. In another embodiment, the compound has a high affinity for the androgen receptor. In another embodiment, the agonist compound also has an anabolic effect. In another embodiment, the present invention provides selective androgen modulator compounds that have the agonistic and anabolic action of a nonsteroidal compound for the androgen receptor.

[000106] In another embodiment, the present invention is directed to selective androgen receptor modulator compounds that are antagonistic compounds. A receptor antagonist is a substance that binds to receptors and inactivates them. Thus, in one embodiment, the SARM compounds of the present invention are useful in binding to steroid hormone receptors and inactivating them. In one embodiment, the antagonist compound of the present invention is an antagonist that binds to the androgen receptor. In another embodiment, the compound has a high affinity for the androgen receptor.

[000107] In yet another embodiment, the SARM compounds of the present invention may be classified as partial AR agonists/antagonists. SARMs are AR agonists in some tissues, causing increased transcription of AR-reactive genes (eg muscle anabolic effect). In other tissues, these compounds serve as inhibitors of the AR to prevent the agonistic effects of natural androgens.

[000108] Assays to determine whether compounds of the present invention are AR agonists or antagonists are well known to a person skilled in the art. For example, AR agonist activity can be determined by observing the ability of SARM compounds to maintain and/or stimulate the growth of AR-containing tissues, such as the prostate and seminal vesicles, by weight measurement. AR antagonist activity can be determined by observing the ability of SARM compounds to inhibit the growth of AR-containing tissues.

[000109] The compounds of the present invention bind either reversibly or irreversibly to the androgen receptor. In one embodiment, the androgen receptor is a mammalian androgen receptor. In another embodiment, the androgen receptor is a human androgen receptor. In one embodiment, the SARM compounds bind reversibly to the androgen receptor of a mammal, for example a human. Reversible binding of a compound to a receptor means that the compound can be detached from the receptor after binding.

[000110] In another embodiment, the SARM compounds can bind irreversibly to the androgen receptor of a mammal, for example a human. Thus, in one embodiment, the compounds of the present invention may contain a functional group (affinity feature) that allows alkylation of the androgen receptor (i.e., covalent bond formation). Thus, in this case, the compounds are alkylating agents that bind irreversibly to the receptor and, accordingly, cannot be displaced by steroids, such as the endogenous ligands DHT and testosterone. An "alkylating agent" is defined herein as an agent that alkylates (forms a covalent bond) with a cellular component, such as DNA, RNA, or an enzyme. It is a highly reactive chemical that introduces alkyl radicals into biologically active molecules and thus prevents their proper functioning. The alkylating moiety is an electrophilic group that interacts with nucleophilic moieties in cellular components.

[000111] In accordance with one embodiment of the present invention, a method is provided for binding the SARM compounds of the present invention to the androgen receptor by bringing the receptor into contact with the SARM compound and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate or N-oxide or any combination thereof, under conditions effective to cause the selective androgen receptor modulator compound to bind to the androgen receptor. The binding of the selective androgen receptor modulator compounds to the androgen receptor allows the compounds of the present invention to be useful as a male contraceptive and in several hormonal therapies. Agonist compounds bind to the androgen receptor and activate it. Antagonistic compounds bind to the androgen receptor and inactivate it. Binding of agonist or antagonist compounds is either reversible or irreversible.

[000112] In accordance with one embodiment of the subject invention, a method is provided for the suppression of spermatogenesis in a subject by bringing the subject's androgen receptor into contact with the SARM compound of the subject invention and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product or hydrate or N-oxide or any combination thereof, in an amount effective to bind the selective androgen receptor modulator compound to the androgen receptor and suppress spermatogenesis.

[000113] In accordance with another embodiment of the present invention, a method for contraception in a male subject is provided, which consists of the step of administering to the subject a SARM compound of the present invention and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product or of N-oxide hydrate or any combination thereof, in an amount effective to suppress sperm production in the subject, thereby effecting contraception in the subject.

[000114] In accordance with another embodiment of the present invention, there is provided a method for hormone therapy in a patient (i.e. one suffering from an androgen-dependent condition) which includes bringing the patient's androgen receptor into contact with a SARM compound of the present invention and/or its analog, derivative , isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, or N-oxide, or any combination thereof, in an amount effective to bind the selective androgen receptor modulator compound to the androgen receptor and effect an androgen dependent state change.

[000115] In accordance with another embodiment of the present invention, there is provided a method for hormone replacement therapy in a patient (i.e., one suffering from an androgen-dependent condition), which includes contacting the patient's androgen receptor with a SARM compound of the present invention and/or an analog thereof , derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product or hydrate or N-oxide or any combination thereof, in an amount effective to bind the selective androgen receptor modulator compound to the androgen receptor and effect an androgen dependent state change.

[000116] In accordance with another embodiment of the present invention, there is provided a method for treating a subject having a hormone-related condition, which includes administering to the subject a SARM compound of the present invention and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product , hydrate or N-oxide or any combination thereof, in an amount effective to bind the SARM compound to the androgen receptor and effect an androgen dependent state change.

[000117] Androgen-dependent conditions treatable in accordance with the present invention include those conditions associated with aging, such as hypogonadism, sarcopenia, erythropoiesis, osteoporosis, and any other conditions later determined to be dependent on low androgens. androgen levels (eg testosterone).

[000118] In accordance with another embodiment of the present invention, a method is provided for the treatment of a subject suffering from prostate cancer, which contains the step of administering to the subject a SARM compound of the present invention and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product , hydrate or N-oxide or any combination thereof, in an amount effective to treat prostate cancer in a subject.

[000119] In accordance with the second embodiment of the present invention, a method is provided for the prevention of prostate cancer in a subject, which contains the step of administering to the subject the compound SARM of the present invention and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate or N-oxide or any combination thereof, in an amount effective to prevent prostate cancer in the subject.

[000120] In accordance with another embodiment of the present invention, a method is provided for stopping the progression of prostate cancer in a subject suffering from prostate cancer, which contains the step of administering to the subject a SARM compound of the present invention and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, or N-oxide, or any combination thereof, in an amount effective to arrest the progression of prostate cancer in the subject.

[000121] In accordance with another embodiment of the present invention, a method is provided for preventing the recurrence of prostate cancer in a subject suffering from prostate cancer, which contains the step of administering to the subject a SARM compound of the present invention and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, or N-oxide, or any combination thereof, in an amount effective to prevent recurrence of prostate cancer in the subject.

[000122] In accordance with another embodiment of the present invention, a method is provided for the treatment of recurrence of prostate cancer in a subject suffering from prostate cancer, which contains the step of administering to the subject a SARM compound of the present invention and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, or N-oxide, or any combination thereof, in an amount effective to treat recurrence of prostate cancer in a subject.

[000123] Further, stimulation of the androgen receptor stimulates tear production, and thus the SARM compounds of the present invention can be used to treat dry eye conditions. Therefore, in accordance with another embodiment of the present invention, there is provided a method for treating a dry eye condition in a subject suffering from dry eyes, which comprises the step of administering to said subject a selective androgen receptor modulator compound of formula I-IV and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, or N-oxide, or any combination thereof, in an amount effective to treat dry eyes in a subject.

[000124] In accordance with the second embodiment of the present invention, a method is provided for the prevention of dry eye condition in a subject, which contains the step of administering to the said subject a compound of the selective androgen receptor modulator of formulas I-IV and/or its analog, derivative, isomer, metabolite, pharmaceutical an acceptable salt, pharmaceutical product, hydrate, or N-oxide, or any combination thereof, in an amount effective to prevent dry eyes in the subject.

[000125] As defined herein, "contacting" means that a SARM compound of the present invention is introduced into a sample containing an enzyme, in a test tube, flask, tissue culture, chip, grid, plate, microplate, capillary or the like, and is incubated at a certain temperature and for a time sufficient to allow SARM to bind to the enzyme. Methods for contacting samples with SARM or other specific binding components are known to those skilled in the art and may be selected depending on the type of test protocol to be performed. Incubation methods are also standard and known to experts in the relevant field.

[000126] In another embodiment, the term "contacting" means that a SARM compound of the present invention is introduced into a subject receiving treatment, and the SARM compound is allowed to contact the androgen receptor in vivo.

[000127] As used herein, the term "treatment" includes preventive treatment and remititive treatment of a disorder. As used herein, the terms "decreasing", "suppressing" and "inhibiting" have the meanings generally understood to mean decreasing or decreasing. As used herein, the term "progression" means increased extent or severity, progression, growth or deterioration. As used herein, the term "recurrence" means the return of a disease after remission.

[000128] As used herein, the term "administration" refers to contacting a subject with a SARM compound of the subject invention. As used herein, administration may be accomplished in vitro, i.e. in a test tube, or in vivo, i.e. in the cells or tissues of living organisms, for example, humans. In one embodiment, the subject invention comprises administering the compounds of the subject invention to a subject.

[000129] The term "libido", as used herein, means sexual desire.

[000130] The term "erectile," as used herein, means the ability to have an erection. Erectile tissue is tissue, which is capable of greatly expanding and becoming rigid, by distension of the numerous blood vessels it contains.

[000131] "Hypogonadism" is a condition that results in or is characterized by abnormally reduced functional activity of the gonads, with retardation of growth and sexual development. "Osteopenia" refers to decreased bone calcification or density. It is a term that encompasses all skeletal systems in which such a condition is observed.

[000132] "Osteoporosis" refers to bone thinning by reduction of bone mass due to depletion of calcium and bone protein. Osteoporosis predisposes a person to fractures, which are often treated slowly and poorly. Uncontrolled osteoporosis can lead to changes in body posture, physical abnormalities and reduced mobility.

[000133] "BPH (Benign Prostate Hyperplasia) Benign prostate hyperplasia" is a non-malignant enlargement of the prostate gland and is the most common non-malignant proliferative abnormality found in any internal organ and is the leading cause of death in adult men. BPH appears in over 75% of men over the age of 50, reaching 88% prevalence in the ninth decade. BPH often results in gradual compression of the part of the urethra that prevents the prostate (prostatic urethra). This causes the patient to experience a frequent urge to urinate due to incomplete emptying of the bladder and urgency to urinate. Urinary flow obstruction can also lead to a general lack of control over urination, including difficulty starting to urinate when desired, as well as difficulty stopping urinary flow due to an inability to empty urine from the bladder, a condition known as overflow urinary incontinence, which can lead to urinary obstruction and until urinary appointment.

[000134] "Cognition" refers to the process of knowing, especially the process of awareness, knowledge, thinking, learning, and judgment. Cognition is related to the fields of psychology, linguistics, computer science, neuroscience, mathematics, ethology and philosophy. The term "mood" refers to a mood or state of mind. As discussed here, changes mean any change, positive or negative, in cognition and/or mood.

[000135] The term "depression" refers to a disease of the body, mood, and thoughts that affect the way a person eats, sleeps, and the way one feels about oneself and thinks about things. Signs and symptoms of depression include loss of interest in activities, loss of appetite or excessive eating, loss of emotional expression, empty mood, feelings of hopelessness, pessimism, guilt, or helplessness, social withdrawal, lethargy, sleep disturbances, difficulty concentrating, remembering, or making decisions. restlessness, irritability, headaches, digestive disorders or chronic pain.

[000136] The term "hair loss", medically known as alopecia, refers to baldness as a very common type of male pattern baldness. Baldness typically begins with a limited area of hair loss on the scalp and sometimes progresses to complete baldness and even loss of body hair. Hair loss affects both men and women.

[000137] "Anemia" refers to the condition of having a lower than normal number of red blood cells or a lower than normal amount of hemoglobin in the blood. The capacity of the blood to transport oxygen is therefore reduced. People with anemia may feel tired and faint easily, look pale, develop tremors, and usually become short of breath. Anemia is caused by four basic factors: a) hemorrhage (bleeding); b) hemolysis (excessive destruction of red blood cells); c) reduced production of red blood cells; d) insufficiently normal hemoglobin. There are many forms of anemia, including aplastic anemia, benzene poisoning, Fanconi anemia, hemolytic disease of the newborn, hereditary spherocytosis, iron deficiency anemia, osteoporosis, pernicious anemia, sickle cell disease, thalassemia, myelodiplastic syndrome, and various bone marrow diseases. As discussed herein, the SARM compounds of the present invention are useful in the prevention and/or treatment of one or more forms of anemia listed above.

[000138] "Obesity" refers to the condition of being substantially above one's normal weight. Traditionally, a person is considered obese if they are more than 20 percent above their ideal weight. Obesity is more precisely defined by the National Institute of Health (NIH) as a Body to Mass Index (BMI) of 30 or above. Obesity is often multifactorial, based on both genetic and behavioral factors. Being overweight due to obesity contributes significantly to health problems. It increases the risk of developing several diseases, including: Type 2 diabetes (occurs in adults); high blood pressure (hypertension); stroke (Cerebrovascular accident or CVA); heart attack (myocardial infarction, MI); cardiac arrest (congestive heart failure); cancer (certain forms such as prostate cancer and colon and rectal cancer); gallstones and gallstones (cholecystitis); colic pain and colic arthritis; osteoarthritis (degenerative arthritis of the knees, hips and lower back); sleep apnea (stoppage of normal breathing during sleep, reduction of oxygen in the blood); and Pickwick's syndrome (obesity, red face, hypoventilation and drowsiness). As discussed herein, the term "obesity" includes any of the obesity-related conditions and diseases listed above. Thus, the SARM compounds of the present invention are useful in the prevention and/or treatment of obesity and any one or more obesity-related conditions and diseases listed above.

[000139] "Prostate cancer" is one of the most common cancers among men in the United States, with hundreds of thousands of new cases diagnosed each year. Over sixty percent of newly diagnosed cases of prostate cancer are found to be pathologically advanced, with no cure and a dismal prognosis. One third of all men over the age of 50 have a latent form of prostate cancer that can be activated into life-threatening clinical prostate cancer. It is shown that the frequency of latent prostate tumors essentially increases with each decade of life from the 50s (5.3-14%) to the 90s (40-80%). The number of people with latent prostate cancer is the same across cultures, ethnicities, and races, yet the incidence of clinically aggressive cancer varies significantly. This suggests that environmental factors may play a role in activating latent prostate cancer.

[000140] In one embodiment, the methods of the present invention comprise administering a SARM compound as the sole active ingredient. However, also included within the scope of the present invention are methods for hormone therapy, for the treatment of prostate cancer, for arresting the progression of prostate cancer, and for preventing and/or treating the recurrence of prostate cancer, comprising the administration of SARM compounds in combination with one or more therapeutic agents . These agents include, but are not limited to: LHRH analogs, reversible antiandrogens, antiestrogens, anticancer drugs, 5-alpha reductase inhibitors, aromatase inhibitors, progestins, agents acting through other nuclear hormone receptors, selective estrogen receptor modulators (SERMs), progesterone , estrogen, PDE5 inhibitors, apomorphine, bisphosphonate and one or more additional SARMs.

[000141] Thus, in one embodiment, the methods of the present invention comprise administering a selective androgen receptor modulator compound in combination with an LHRH analog. In another embodiment, the methods of the present invention comprise administering a selective androgen receptor modulator compound in combination with a reversible antiandrogen. In another embodiment, the methods of the present invention comprise administering a selective androgen receptor modulator compound in combination with an antiestrogen. In another embodiment, the methods of the present invention comprise administering a selective androgen receptor modulator compound in combination with an anticancer drug. In another embodiment, the methods of the present invention comprise administering a selective androgen receptor modulator compound in combination with a 5-alpha reductase inhibitor. In another embodiment, the methods of the present invention comprise administering a selective androgen receptor modulator compound in combination with an aromatase inhibitor. In another embodiment, the methods of the present invention comprise administering a selective androgen receptor modulator compound in combination with a progestin. In another embodiment, the methods of the present invention comprise administering a selective androgen receptor modulator compound in combination with an agent that acts through other nuclear hormone receptors. In another embodiment, the methods of the present invention comprise administering a selective androgen receptor modulator compound in combination with a selective estrogen receptor modulator (SERM). In another embodiment, the methods of the present invention comprise administering a selective androgen receptor modulator compound in combination with progesterone. In another embodiment, the methods of the present invention comprise administering a selective androgen receptor modulator compound in combination with estrogen. In another embodiment, the methods of the present invention comprise administering a selective androgen receptor modulator compound in combination with a PDE5 inhibitor. In another embodiment, the methods of the present invention comprise administering a selective androgen receptor modulator compound in combination with apomorphine. In another embodiment, the methods of the present invention comprise administering a selective androgen receptor modulator compound in combination with a bisphosphonate. In another embodiment, the methods of the present invention comprise administering a selective androgen receptor modulator compound in combination with one or more additional SARMs.

[000142] In one embodiment. the present invention provides a composition and a pharmaceutical composition consisting of a compound of a selective androgen receptor modulator of any of the formulas I-VI and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate or N-oxide or any their combinations; and a suitable carrier or diluent.

[000143] As used herein "pharmaceutical composition" means therapeutically effective amounts of a SARM compound together with pharmaceutically acceptable diluents, preservatives, solvents, emulsifiers, adjuvants and/or carriers. "Therapeutically effective amount", as used herein, refers to that amount which produces a therapeutic effect for a given

state and regime of giving. Such compositions are liquids or lyophilized or otherwise dried formulations and include diluents of varying buffer content (eg tris-HCl, acetate, phosphate), pH and ionic strength, additives such as albumin or gelatin to prevent absorption onto surfaces, detergents (e.g. Tween 20, Tween 80, Pluronic F68, bile acid salts), solubilizing agents (e.g. glycerol, polyethylene glycerol), antioxidants (e.g. ascorbic acid, sodium metabisulfite), preservatives (e.g. thimerosal, benzyl alcohol, parabens), fillers or tone modifiers (e.g. lactose, mannitol), covalent attachment of polymers such as polyethylene glycol to protein, complexation with metal ions, or incorporation of materials into or onto certain preparations of polymer compounds, such as is polylactic acid, polyglycolic acid, hydrogels, etc., or to liposomes, microemulsions, micelles, unilamellar or multilamellar vesicles, erythrocyte ghosts, or spheroplasts. Such compositions will affect the physical state, solubility, stability, rate of release in vivo and rate of clearance in vivo. Controlled or sustained release compositions include formulation in lipophilic depots (eg, fatty acids, waxes, oils).

[000144] The invention also covers certain compositions coated with polymers (eg poloxamers or poloxamines). Other embodiments of the compositions of the invention incorporate particular forms of protective coatings, protease inhibitors, or permeability enhancers for various routes of administration, including parenteral, pulmonary, nasal, and oral. In one embodiment, the pharmaceutical composition is administered parenterally, paracancerously, transmucosally, transdermally, intramuscularly, intravenously, intradermally, subcutaneously, intravaginally, intraperitoneally, intraventricularly, intracranially, or intratumorally.

[000145] Furthermore, as used herein, "pharmaceutically acceptable carriers" are well known to those skilled in the art and include but are not limited to 0.01-0.1M and preferably 0.05M phosphate buffer or 0.8% saline . In addition, such pharmaceutically acceptable carriers can be aqueous and anhydrous solutions, suspensions, and emulsions. Examples of anhydrous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media.

[000146] Parenteral carriers include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's, and solid oil. Intravenous carriers include fluid and nutritional regenerators, electrolyte regenerators, such as those based on Ringer's dextrose and the like. Preservatives and other additives may also be present, such as, for example, antimicrobial substances, antioxidants, integrating agents, inert gases, and the like.

[000147] Controlled or sustained release compositions include formulation in lipophilic depots (eg, fatty acids, waxes, oils). The invention also includes special compositions coated with polymers (eg poloxamers or poloxamines) and a compound coupled to antibodies, directed to tissue-specific receptors, ligands or antigens or coupled to ligands of tissue-specific receptors.

[000148] Other embodiments of the compositions of the invention incorporate particular forms, protective coatings, protease inhibitors or permeability enhancers for various routes of administration, including parenteral, pulmonary, nasal and oral.

[000149] Compounds modified by covalent attachment of water-soluble polymers, such as polyethylene glycol, copolymers of polyethylene glycol and polypropylene glycol, carboxymethyl cellulose, dextran, polyvinyl alcohol, polyvinylpyrrolidone or polyproline, are known to exhibit significantly longer blood half-lives after intravenous administration. injections, but their corresponding unmodified compounds (Abuchowski et al., 1981; Newmark et al.; 1982 ̧ and Katre et al., 1987). Such modifications can also increase the solubility of the compound in aqueous solution, eliminate aggregation, enhance the physical and chemical stability of the compound, and greatly reduce the immunogenicity and reactivity of the compound. As a consequence, the desired biological activity in vivo can be achieved by administering such abducts of the polymeric compound less frequently or in lower doses than with the unmodified compound.

[000150] In yet another embodiment, the pharmaceutical composition can be delivered in a controlled release system. For example, the agent can be administered using an intravenous infusion, an implantable osmotic pump, a transdermal patch, liposomes, or other routes of administration. In one embodiment, a pump may be used (see, supra; Sefton, CRC Crit. Ref. Biomed. Eng. 14:201 (1987); Buchwald et al., Surgery 88:507 (1980); Saudek et al., N . Engl. J. Med. 321:574 (1989). In another embodiment, polymeric materials can be used. In yet another embodiment, the controlled release system can be placed near the therapeutic target, i.e., the brain, thus requiring only a fraction of the systemic dose (see, e.g., Goodson in Medical Applications of Controlled Release, supra, vol.2, pp. 115-138 (1984). Other controlled release systems are discussed in a review by Langer (Science 249:1527-1533 (1990 )).

[000151] The pharmaceutical preparation may contain the SARM itself or further include a pharmaceutically acceptable carrier and may be in solid or liquid form, such as tablets, powders, capsules, pellets, solutions, suspensions, elixirs, emulsions, gels, creams or suppositories, including rectal and urethral suppositories. Pharmaceutically acceptable carriers include gums, starches, sugars, cellulosic materials and mixtures thereof. A pharmaceutical composition containing a SARM agent can be administered to a subject, for example, by subcutaneous implantation of a pellet; in one embodiment, the pellet provides a controlled release of the SARM agent over a period of time. The preparation can also be administered by intravenous, intra-arterial or intramuscular injection of a liquid preparation, oral administration of a liquid or solid preparation, or local application. Administration can also be done using a rectal suppository or urethral suppository.

[000152] The pharmaceutical preparations of the invention can be prepared by known processes of dissolving, mixing, granulating, or forming tablets. For oral administration, SARM agents or their physiologically tolerated derivatives, such as salts, esters, N-oxides and the like, are mixed with additives customary for this purpose, such as carriers, stabilizers, or inert diluents, and converted into customary methods into forms suitable for administration, such as tablets, coated tablets, hard or soft gelatin capsules, aqueous, alcoholic or oily solutions. Examples of suitable inert carriers are common tablet bases such as lactose, sucrose or corn starch in combination with binders such as acacia, corn starch, gelatin, with disintegrating agents such as corn starch, potato starch, alginic acid or with lubricants, such as stearic acid or magnesium stearate.

[000153] Examples of suitable oil carriers or solvents are vegetable or animal oils such as sunflower oil or cod liver oil. Preparations can be made both as dry and wet granules. For parenteral administration (subcutaneous, intravenous, intra-arterial or intramuscular injection), SARM agents or their physiologically tolerated derivatives such as salts, esters, N-oxides, and the like, are converted into a solution, suspension, or emulsion, if desired. , with substances that are customary and suitable for this purpose, for example, solubilizing agents or other auxiliaries. Examples are sterile liquids such as water and oils, with or without the addition of surfactants and other pharmaceutically acceptable adjuvants. Illustrative oils are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, or mineral oil. In general, water, saline, aqueous dextrose and related sugar solutions, and glycols such as propylene glycol and polyethylene glycol are preferred liquid carriers, particularly for injectable solutions.

[000154] The preparation of pharmaceutical compositions containing an active ingredient is very clear in the art. Typically, such compositions are prepared as polypeptide aerosols to be delivered into the nasopharynx or as injectables, or as liquid solutions or suspensions; however, solid forms suitable for solution or suspension, liquid prior to injection, may also be prepared. The preparation can also be emulsified. The active therapeutic ingredient is often mixed with excipients that are pharmaceutically acceptable and compatible with the active ingredient. Suitable excipients are, for example, water, saline, dextrose, glycerol, ethanol or the like, or any combination thereof.

[000155] In addition, the composition may contain smaller amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents, which enhance the effectiveness of the active ingredient.

[000156] The active component can be formulated into the composition as a form of neutralized pharmaceutically acceptable salts. Pharmaceutically acceptable salts include acid addition salts (formed with free amino groups of polypeptides or antibody molecules), formed with inorganic acids such as, for example, hydrochloric or phosphoric acid, or such organic acids as acetic, oxalic, tartaric, mandelic, and the like. Salts formed from free carboxyl groups can also be derived from inorganic bases, such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxide, and such organic bases as isopropylamine, trimethylamine, 2-ethylamino ethanol, histidine , procaine, and the like.

[000157] For local administration to body surfaces, using for example creams, gels, drops and the like, SARM agents or their physiologically tolerant derivatives such as salts, esters, N-oxides and the like can be prepared and applied as solutions, suspensions or emulsions in a physiologically acceptable diluent with or without a pharmaceutical carrier.

[000158] In another embodiment, the active compound can be delivered in a single vesicle, particularly a liposome (see Langer, Science 249: 1527-1533 (1990); Treat et al., in Liposomes in the Therapy of Infectious Disease and Cancer, Lopez- Berestein and Fidler (eds.), Liss. New York, pp. 353-365 (1989); Lopez-Berestein, ibid., pp. 317-327; see generally the same).

[000159] For use in medicine, SARM salts may be pharmaceutically acceptable salts. Other salts may also be useful in the preparation of the compounds of the invention or their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which can, for example, be formed by mixing a solution of a compound according to the invention with a solution of a pharmaceutically acceptable acid, such as hydrochloric acid, sulfuric acid, methanesulfonic acid, fumaric acid, maleic acid, succinic acid acid, acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.

[000160] The following examples are presented to more fully illustrate suitable embodiments of the invention. They should in no way, however, be construed as limiting the broad scope of this invention.

PART OF EXPERIMENTAL DETAILS

EXAMPLE 1 - BINDING AFFINITIES

[000161] Binding affinities were determined as described in He et al., Eur. J. Med. Chem. (2002), 619-634; and as described in Mukherjee et al., Xenobiotica (1996), 26, 117-122.

[image] [image]

EXPERIMENTAL METHODS

[000162] Animals. Immature male Sprague-Dawley rats, weighing 90 to 100 g, were purchased from Harlan Biosciences (Indianapolis, IN). The animals were maintained on a 12-hour light-dark cycle with food and water available ad libitum. The animal protocol was reviewed and approved by the Institutional Laboratory Animal Care and Use Committee.

[000163] Study design. Rats were randomly assigned to treatment groups. One day before starting drug treatment, animals were individually removed from their cages, weighed and anesthetized with an intraperitoneal dose of ketamine/xylazine (87/13 mg/kg; approximately 1 ml per kg). When adequately anesthetized (ie, unresponsive to toe pinch), the animals' ears were tagged for identification purposes. The animals were then placed on a sterile plate and their abdomen and scrotum were washed with betadine and 70% alcohol. Testes were removed through a midline scrotal incision using sterile surgical suture to ligate the supratesticular tissue prior to surgical removal of each testis. The surgical wound site was closed with sterile stainless steel wound clips, and the site was cleaned with betadine. Animals were allowed to recover on a sterile pad (until they could stand) and then returned to their home cage.

[000164] Twenty-four hours later, animals were again anesthetized with ketamine/xylazine and Alzet osmotic pumps (model 2002) were placed subcutaneously in the scapular region. At this stage of the procedure, the scapular region is shaved and cleaned (betadine and alcohol) and a small incision (1 cm) is made using a sterile scalpel. An osmotic pump was inserted and the wound closed with a sterile stainless steel wound clip. The animals were allowed to recover and were returned to their home cage. Osmotic pumps contained the appropriate treatment dissolved in polyethylene glycol 300 (PEG300). The osmotic pumps were filled with the appropriate solution one day before implantation. Animals were observed daily for signs of acute toxicity to drug treatment (eg lethargy, rough coat).

[000165] After 14 days of drug treatment, rats were anesthetized with ketamine/xylazine. The animals were then sacrificed by exsanguination under anesthesia. A blood sample was collected by venipuncture of the abdominal aorta and subjected to complete cellular blood analysis. Part of the blood was placed in a special test tube, centrifuged at 12,000 g for 1 minute, and the plasma layer was removed and frozen at -200 C. The ventral prostate, seminal vesicles, levator ani muscle, liver, kidneys, spleen, lungs and heart were removed and cleaned. of foreign tissue, weighed and placed in sterilized vials containing 10% neutral buffered formalin. Preserved tissues were sent to GTx, Inc. for histopathological analysis.

[000166] For data analysis, all organ weights were normalized to body weight and analyzed for any statistically significant difference using single-factor ANOVA.

Prostate and seminal vesicle weights were used as indexes to evaluate androgenic activity, and levator ani muscle weight was used to evaluate anabolic activity.

THE RESULTS

Compounds 1 and 2

[000167] Androgenic and anabolic activity of compounds 1 and 2 were tested in a castrated rat model after 14 days of administration. Intact controls (non-castrated, untreated) and castrated controls (castrated, untreated) were used as control groups.

[000168] As shown in Table 1 and Figure 1, the weights of prostate, seminal vesicle and levator ani muscle in castrated rats were significantly reduced, due to ablation of endogenous androgen production. Treatment with 1 mg/day of compounds 1 and 2 resulted in an increase in prostate, seminal vesicle and levator ani muscle weights. Compounds 1 and 2 showed weaker activity and intrinsic activity in increasing the weight of the prostate and seminal vesicles, but stronger activity and intrinsic activity in increasing the weight of the levator ani muscle. In particular, compound 1 was able to maintain the levator ani muscle weight of castrated animals at the same level as that of intact animals. Thus, compound 1 is a potent nonsteroidal anabolic agent. This is a significant improvement over previous compounds in that this compound selectively stimulates muscle growth and other anabolic effects, while having a smaller effect on the prostate and seminal vesicles. This may be particularly relevant in older men with concerns related to the development or progression of prostate cancer.

Table 1

[image] * Reference group treated with Compound 1 1 mg/day via osmotic pump

Compound 7

[000169] The androgenic and anabolic activity of compound 7 was investigated in a castrated rat model after 14 days of administration. Intact controls (non-castrated, untreated) and castrated controls (castrated, untreated) were used as control groups. Rats were castrated on day 0 and received a daily subcutaneous dose (0.05 to 3 mg/day) of compound 7 in DMSO/PEG vehicle. Rats were sacrificed on the last day and wet androgenic (prostate and seminal vesicle) and anabolic (levator ani) organ weights were determined.

[000170] As shown in Figure 2, treatment with increasing doses of compound 7 resulted in increases in prostate, seminal vesicle, and levator ani muscle weights in a dose-dependent manner. Compound 7 showed a weaker action and internal activity in increasing the weight of the prostate and seminal vesicle, but a stronger action and internal activity in increasing the weight of the levator ani muscle.

[000171] An expert in the relevant field will appreciate that the subject invention is not limited to what is specifically shown and described here above. Moreover, the scope of the invention is defined by the following patent claims:

Claims (84)

1. Selective androgen receptor modulator (Selective Androgen Modulator Receptor, SARM), represented by the structure of formula I: [image] indicated by that X is a bond, O, CH2, NH, Se, PR, NO or NR; G is O or S; T is OH, OR, -NHCOCH 3 or NHCOR; R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, halogen, alkenyl or OH; R 1 is CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 3 or CF 2 CF 3 ; R2 is F, Cl, Br, I, CH3, CF3, OH, CN, NO2, NHCOCH3, NHCOCF3, NHCOR, alkyl, arylalkyl, OR, NH2, NHR, NR2, SR; R3 is F, Cl, Br, I, CN, NO2, COR, COOH, CONHR, CF3, SnR3, or R3 together with the benzene ring, to which it is attached, forms a fused ring system represented by the structure: [image] Z is NO 2 , CN, COR, COOH, or CONHR; Y is CF 3 , F, Br, Cl, I, CN or SnR 3 ; Q is H, alkyl, halogen, CF3, CN CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR NHSO2CH3, NHSO2R, OH, OR, COR, OCOR, OSO2R. SO2R, SR; or Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C: [image] n is an integer from 1-4; and m is an integer from 1-3. 2. Selective androgen receptor modulator (SARM) compound, represented by the structure of formula I: [image] indicated by that X is a bond, O, CH2, NH, Se, PR, NO or NR; G is O or S; T is OH, OR, -NHCOCH 3 or NHCOR; R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, halogen, alkenyl or OH; R 1 is CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 3 or CF 2 CF 3 ; R2 is F, Cl, Br, I, CH3, CF3, OH, CN, NO2, NHCOCH3, NHCOCF3, NHCOR, alkyl, arylalkyl, OR, NH2, NHR, NR2, SR; R3 is F, Cl, Br, I, CN, NO2, COR, COOH, CONHR, CF3, SnR3, or R3 together with the benzene ring, to which it is attached, forms a fused ring system represented by the structure: [image] Z is NO 2 , CN, COR, COOH, or CONHR; Y is CF 3 , F, Br, Cl, I, CN or SnR 3 ; Q is H, alkyl, halogen, CF3, CN CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR NHSO2CH3, NHSO2R, OH, OR, COR, OCOR, OSO2R. SO2R, SR; or Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C: [image] n is an integer from 1-4; and m is an integer from 1-3. or its analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, N-oxide, hydrate, or any combination thereof. 3. Compound of selective androgen receptor modulator according to patent claim 1, characterized in that G is O. 4. Compound of selective androgen receptor modulator according to patent claim 1, characterized in that T is OH. 5. Compound of selective androgen receptor modulator according to patent claim 1, characterized in that R1 is CH3. 6. A compound of selective androgen receptor modulator according to claim 1, characterized in that X is O. 7. A compound of a selective androgen receptor modulator according to claim 1, characterized in that Z is NO2. 8. A compound of a selective androgen receptor modulator according to claim 1, characterized in that Z is CN. 9. A compound of a selective androgen receptor modulator according to claim 1, characterized in that Y is CF3. 10. A selective androgen receptor modulator compound according to claim 1, characterized in that Q is NHCOCH3. 11. Compound of selective androgen receptor modulator according to patent claim 1, characterized in that Q is F. 12. A compound of a selective androgen receptor modulator according to claim 1, characterized in that Q is F and R2 is Cl. 13. Compound of selective androgen receptor modulator according to claim 1, characterized in that it is represented by the structure: [image] 14. Compound of selective androgen receptor modulator according to claim 1, represented by the structure of formula II: [image] indicated by the fact that p is an integer from 2-5. 15. A compound of a selective androgen receptor modulator according to claim 14, characterized in that p is 5. 16. A compound of selective androgen receptor modulator according to patent claim 14, characterized in that it is represented by the structure: [image] 17. A selective androgen receptor modulator compound according to claim 1, characterized in that said compound is an androgen receptor antagonist. 18. A selective androgen receptor modulator compound according to patent claim 1, characterized in that said compound is an androgen receptor agonist. 19. A selective androgen receptor modulator compound according to patent claim 1, characterized in that said compound binds irreversibly to the androgen receptor. 20. A selective androgen receptor modulator compound according to claim 1, characterized in that said compound binds reversibly to the androgen receptor. 21. Composition, characterized in that it contains a compound of selective androgen receptor modulator according to patent claim 1, and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate or N-oxide, or any combination thereof; and a pharmaceutically acceptable carrier or diluent. 22. Pharmaceutical composition, characterized in that it contains an effective amount of the compound of selective androgen receptor modulator according to patent claim 1, and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate or N-oxide, or any their combinations; and a pharmaceutically acceptable carrier, diluent or salt. 23. The method of binding the compound of the selective androgen receptor modulator to the androgen receptor, characterized in that it contains the step of bringing the androgen receptor into contact with the compound of the selective androgen receptor modulator according to patent claim 1, and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt , pharmaceutical product, hydrate or N-oxide, or any combination thereof in an amount effective to bind the selective androgen receptor modulator compound to the androgen receptor. 24. A method of suppressing spermatogenesis in a subject, indicated by the fact that it comprises bringing the subject's androgen receptor into contact with the compound of the selective androgen receptor modulator according to patent claim 1, and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate or N-oxide, or any combination thereof in an amount effective to suppress sperm production. 25. Method of contraception for a male subject, characterized in that it contains the step of administering to said subject the compound of selective androgen receptor modulator according to patent claim 1, and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate or N-oxide , or any combination thereof in an amount effective to suppress sperm production in said subject, thereby effecting contraception in said subject. 26. The method of hormone therapy, characterized in that it contains the step of bringing the subject's androgen receptor into contact with the compound of the selective androgen receptor modulator according to patent claim 1, and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate or N-oxide, or any combination thereof, in an amount effective to alter the androgen dependent state. 27. The method of hormone replacement therapy, characterized in that it contains the step of bringing the subject's androgen receptor into contact with the compound of the selective androgen receptor modulator according to patent claim 1, and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate or N-oxide, or any combination thereof, in an amount effective to alter the androgen dependent state. 28. A method of treating a subject who has a hormone-related condition, characterized in that it contains the step of administering to said subject a selective androgen receptor modulator compound according to patent claim 1, and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate or N-oxide, or any combination thereof, in an amount effective to alter the androgen dependent state. 29. A method of treating a subject suffering from prostate cancer, indicated by the fact that it contains the step of administering to said subject a compound of a selective androgen receptor modulator according to patent claim 1, and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate or N-oxide, or any combination thereof, in an amount effective to treat prostate cancer in said subject. 30. A method of preventing prostate cancer in a subject, indicated by the fact that it contains the step of administering to said subject a compound of a selective androgen receptor modulator according to patent claim 1, and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate or N -oxide, or any combination thereof, in an amount effective to prevent prostate cancer in said subject. 31. A method of stopping the progression of prostate cancer in a subject suffering from prostate cancer, characterized in that it contains the step of administering to said subject a selective androgen receptor modulator compound according to patent claim 1, and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate or N-oxide, or any combination thereof, in an amount effective to arrest the progression of prostate cancer in said subject. 32. A method of preventing the recurrence of prostate cancer in a subject suffering from prostate cancer, indicated by the fact that it contains the step of administering to said subject a selective androgen receptor modulator compound according to patent claim 1, and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate or N-oxide, or any combination thereof, in an amount effective to prevent recurrence of prostate cancer in said subject. 33. A method of treating the recurrence of prostate cancer in a subject suffering from prostate cancer, characterized in that it contains the step of administering to said subject a selective androgen receptor modulator compound according to patent claim 1, and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate or N-oxide, or any combination thereof, in an amount effective to treat recurrence of prostate cancer in said subject. 34. A method of treating a dry eye condition in a subject suffering from dry eyes, indicated by the fact that it contains the step of administering to said subject a selective androgen receptor modulator compound according to patent claim 1, and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate or N-oxide, or any combination thereof, in an amount effective to treat dry eyes in said subject. 35. A method of preventing dry eye in a subject, indicated by the fact that it contains the step of giving the subject a selective androgen receptor modulator compound according to patent claim 1, and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate or of N-oxide, or any combination thereof, in an amount effective to prevent dry eyes in said subject. 36. A selective androgen receptor modulator (SARM) compound represented by the structure of formula V: [image] indicated by that R2 is F, Cl, Br, I, CH3, CF3, OH, CN, NO2, NHCOCH3, NHCOCF3, NHCOR, alkyl, arylalkyl, OR, NH2, NHR, NR2, SR; R3 is F, Cl, Br, I, CN, NO2, COR, COOH, CONHR, CF3, SnR3, or R3 together with the benzene ring, to which it is attached, forms a fused ring system represented by the structure: [image] R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, halogen, alkenyl or OH; Z is NO 2 , CN, COR, COOH, or CONHR; Y is CF 3 , F, Br, Cl, I, CN or SnR 3 ; Q is H, alkyl, halogen, CF3, CN CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR NHSO2CH3, NHSO2R, OH, OR, COR, OCOR, OSO2R. SO2R, SR; or Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C: [image] n is an integer from 1-4; and m is an integer from 1-3. 37. A selective androgen receptor modulator (SARM) compound represented by the structure of formula V: [image] indicated by that R2 is F, Cl, Br, I, CH3, CF3, OH, CN, NO2, NHCOCH3, NHCOCF3, NHCOR, alkyl, arylalkyl, OR, NH2, NHR, NR2, SR; R3 is F, Cl, Br, I, CN, NO2, COR, COOH, CONHR, CF3, SnR3, or R3 together with the benzene ring, to which it is attached, forms a fused ring system represented by the structure: [image] R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, halogen, alkenyl or OH; Z is NO 2 , CN, COR, COOH, or CONHR; Y is CF 3 , F, Br, Cl, I, CN or SnR 3 ; Q is H, alkyl, halogen, CF3, CN CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR NHSO2CH3, NHSO2R, OH, OR, COR, OCOR, OSO2R. SO2R, SR; or Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C: [image] n is an integer from 1-4; and m is an integer from 1-3; or its analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, N-oxide, hydrate, or any combination thereof. 38. A selective androgen receptor modulator compound according to claim 36, characterized in that Z is NO2. 39. A compound of a selective androgen receptor modulator according to claim 36, characterized in that Z is CN. 40. A selective androgen receptor modulator compound according to claim 36, characterized in that Y is CF3. 41. A selective androgen receptor modulator compound according to claim 36, characterized in that Q is NHCOCH3. 42. A selective androgen receptor modulator compound according to claim 36, characterized in that Q is F. 43. A compound of a selective androgen receptor modulator according to claim 36, characterized in that Q is F and R2 is Cl. 44. Compound of selective androgen receptor modulator according to claim 36, represented by the structure of formula VI: [image] indicated by the fact that p' is an integer from 1-4. 45. A selective androgen receptor modulator compound according to claim 36, characterized in that Q is F and p' is 4. 46. A selective androgen receptor modulator compound according to patent claim 36, characterized in that said compound is an androgen receptor antagonist. 47. A selective androgen receptor modulator compound according to claim 36, characterized in that said compound is an androgen receptor agonist. 48. A selective androgen receptor modulator compound according to patent claim 36, characterized in that said compound binds irreversibly to the androgen receptor. 49. A selective androgen receptor modulator compound according to patent claim 36, characterized in that said compound binds reversibly to the androgen receptor. 50. Composition, characterized in that it contains a compound of selective androgen receptor modulator according to patent claim 36, and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate or N-oxide, or any combination thereof; and a pharmaceutically acceptable carrier or diluent. 51. Pharmaceutical composition, characterized in that it contains an effective amount of the compound of selective androgen receptor modulator according to patent claim 36, and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate or N-oxide, or any their combinations; and a pharmaceutically acceptable carrier, diluent or salt. 52. The method of binding the compound of the selective androgen receptor modulator to the androgen receptor, characterized in that it contains the step of bringing the androgen receptor into contact with the compound of the selective androgen receptor modulator according to patent claim 36, and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt , pharmaceutical product, hydrate or N-oxide, or any combination thereof, in an amount effective to bind the selective androgen receptor modulator compound to the androgen receptor. 53. A method of suppressing spermatogenesis in a subject, characterized in that it comprises bringing the subject's androgen receptor into contact with the compound of the selective androgen receptor modulator according to patent claim 36, and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate or N-oxide, or any combination thereof, in an amount effective to suppress sperm production. 54. Method of contraception in a male subject, characterized in that it contains the step of administering to said subject a selective androgen receptor modulator compound according to patent claim 36, and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate or N- oxide, or any combination thereof, in an amount effective to suppress sperm production in said subject, thereby effecting contraception in said subject. 55. The method of hormone therapy, characterized in that it contains the step of bringing the subject's androgen receptor into contact with the compound of the selective androgen receptor modulator according to patent claim 36, and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate or N-oxide, or any combination thereof, in an amount effective to alter the androgen dependent state. 56. The method of hormone replacement therapy, characterized in that it contains the step of bringing the subject's androgen receptor into contact with the compound of the selective androgen receptor modulator according to patent claim 36, and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate or N-oxide, or any combination thereof, in an amount effective to alter the androgen dependent state. 57. A method of treating a subject who has a hormone-related condition, indicated by the fact that it contains the step of administering to said subject a selective androgen receptor modulator compound according to patent claim 36, and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate or N-oxide, or any combination thereof, in an amount effective to alter the androgen dependent state. 58. A method of treating a subject suffering from prostate cancer, characterized in that it contains the step of administering to said subject a selective androgen receptor modulator compound according to patent claim 36, and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate or N-oxide, or any combination thereof, in an amount effective to treat prostate cancer in said subject. 59. A method of preventing prostate cancer in a subject, indicated by the fact that it contains the step of administering to said subject a selective androgen receptor modulator compound according to patent claim 36, and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate or N -oxide, or any combination thereof, in an amount effective to prevent prostate cancer in said subject. 60. A method of stopping the progression of prostate cancer in a subject suffering from prostate cancer, characterized in that it contains the step of administering to the said subject a selective androgen receptor modulator compound according to patent claim 36, and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate or N-oxide, or any combination thereof, in an amount effective to arrest the progression of prostate cancer in said subject. 61. A method of preventing the recurrence of prostate cancer in a subject suffering from prostate cancer, indicated by the fact that it contains the step of administering to said subject a compound of a selective androgen receptor modulator according to patent claim 36, and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate or N-oxide, or any combination thereof, in an amount effective to prevent recurrence of prostate cancer in said subject. 62. A method of treating the recurrence of prostate cancer in a subject suffering from prostate cancer, characterized in that it contains the step of administering to said subject a selective androgen receptor modulator compound according to patent claim 36, and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate or N-oxide, or any combination thereof, in an amount effective to treat recurrence of prostate cancer in said subject. 63. A method of treating a dry eye condition in a subject suffering from dry eyes, characterized in that it contains the step of administering to said subject a selective androgen receptor modulator compound according to patent claim 36, and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate or N-oxide, or any combination thereof, in an amount effective to treat dry eyes in said subject. 64. A method of preventing dry eye in a subject, indicated by the fact that it contains the step of giving the subject a selective androgen receptor modulator compound according to patent claim 36, and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate or of N-oxide, or any combination thereof, in an amount effective to prevent dry eyes in said subject. 65. A process for the preparation of a selective androgen receptor modulator (SARM) compound represented by the structure of formula I: [image] indicated by that, yes X is O, NH, S, Se, PR, or NR; G is O or S; T is OH, OR, -NHCOCH 3 or NHCOR; R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, halogen, alkenyl or OH; R 1 is CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 3 or CF 2 CF 3 ; R2 is F, Cl, Br, I, CH3, CF3, OH, CN, NO2, NHCOCH3, NHCOCF3, NHCOR, alkyl, arylalkyl, OR, NH2, NHR, NR2, SR; R3 is F, Cl, Br, I, CN, NO2, COR, COOH, CONHR, CF3, SnR3, or R3 together with the benzene ring, to which it is attached, forms a fused ring system represented by the structure: [image] Z is NO 2 , CN, COR, COOH, or CONHR; Y is CF 3 , F, Br, Cl, I, CN or SnR 3 ; Q is H, alkyl, halogen, CF3, CN CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR NHSO2CH3, NHSO2R, OH, OR, COR, OCOR, OSO2R. SO2R, SR; or Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C: [image] n is an integer from 1-4; and m is an integer from 1-3. said process comprises the step of coupling a compound of formula VII: [image] wherein Z, Y, G, R1, T, R3 and m are as defined above and L is a leaving group, with a compound of formula VIII: [image] wherein Q, X, R 2 and n are as defined above. 66. The process of claim 65, wherein G is O. 67. The process of claim 65, wherein T is OH. 68. The process of claim 65, wherein R1 is CH3. 69. The process of claim 65, wherein X is O. 70. The process of claim 65, wherein Z is NO2. 71. The process of claim 65, wherein Z is CN. 72. The process of claim 65, wherein Y is CF3. 73. The process of claim 65, wherein Q is NHCOCH 3 . 74. The process of claim 65, wherein Q is F. 75. The process of claim 65, wherein Q is F and R 2 is Cl 3 . 76. The process according to claim 65, characterized in that said selective androgen receptor modulator compound is represented by the structure of formula II: [image] where p is an integer from 2 - 5. 77. The process according to claim 65, characterized in that said selective androgen receptor modulator compound is represented by the structure of formula III: [image] 78. The process according to claim 65, characterized in that said selective androgen receptor modulator compound is represented by the structure of formula IV: [image] where p' is an integer from 1-4. 79. The process according to claim 65, characterized in that said selective androgen receptor modulator compound is represented by the structure of formula V: [image] 80. The process according to claim 65, characterized in that said selective androgen receptor modulator compound is represented by the structure of formula VI: [image] where p' is an integer from 1-4. 81. The process of claim 65, wherein said coupling step is performed in the presence of a base. 82. The process according to claim 65, characterized in that the leaving group L is Br. 83. The process according to claim 65, characterized in that the compound of formula VII is prepared i) by preparing the compound of formula IX by opening the ring of the cyclic compound of formula X [image] wherein L, R 1 , G and T are as defined above and T 1 is O or NH; and ii) by reacting amines of formula XI: [image] wherein Z, Y, R 3 and m are as defined above, with a compound of formula IX, in the presence of a coupling reagent, to produce a compound of formula VII. [image] 84. The process according to patent claim 65, further comprising the step of converting said selective androgen receptor modulator (SARM) compound into its analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, N-oxide, hydrate or any combination of them.