EA013818B1 - Multi-substituted selective androgen receptor modulators and methods of use thereof - Google Patents

Abstract

This invention provides androgen receptor targeting agents (ARTA). The agents define a new subclass of compounds, which are selective androgen receptor modulators (SARM). The SARM compounds represented by the structure of formula IV:wherein X is O; G is O or S; T is OH; R is (C-C)-alkyl, halo(C-C)- alkyl, dihalo(C-C)--alkyl, trihalo(C-C)--alkyl, CHF, CHF, CF, CFCF; phenyl, halogen, (C-C)-alkenyl or OH; Ris CH, Ris F, Cl, Br, I, CN, NO, COR, COOH, CONHR, CF, Sn(R); Z is NO, CN, COR, COOH, or CONHR; Q is (C-C)-alkyl, halogen, CF, CN C(R), Sn(R), N(R), NHCOCH, NHCOCF, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH, NHCSCF, NHCSR NHSOCH, NHSOR, OH, OR, COR, OCOR, OSOR, SOR, SR; wherein p' is an integer of 1-4; m is an integer of 1-3, and/or isomer, pharmaceutically acceptable salt, hydrate or N-oxide or any of their combinations. Several of the SARM compounds have been found to have an unexpected androgenic and anabolic activity of a nonsteroidal ligand for the androgen receptor. Other SARM compounds have been found to have an unexpected antiandrogenic activity of a nonsteroidal ligand for the androgen receptor. The SARM compounds, either alone or as a composition, are useful for a) male contraception; b) treatment of a variety of hormone-related conditions, for example conditions associated with Androgen Decline in Aging Male (ADAM), such as fatigue, depression, decreased libido, sexual dysfunction, erectile dysfunction, hypogonadism, osteoporosis, hair loss, anemia, obesity, sarcopenia, osteopenia, osteoporosis, benign prostate hyperplasia, alterations in mood and cognition and prostate cancer; c) treatment of conditions associated with Androgen Decline in Female (ADIF), such as sexual dysfunction, decreased sexual libido, hypogonadism, sarcopenia, osteopenia, osteoporosis, alterations 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 muscular wasting conditions; e) preventing and/or treating dry eye conditions; f) oral androgen replacement therapy; and/or g) decreasing the incidence of, halting or causing a regression of prostate cancer.

Description

The present invention was carried out in whole or in part with the support of the government with a grant under the number K29 CA068096 provided by the National Cancer Institute, the National Institute of Health and a grant under the number K15 ΗΌ35329 provided by the National Institute of Child Health and Human Development, the National Institute of Health. The government may have certain rights to an invention.

FIELD OF THE INVENTION

The present invention relates to agents directed to the androgen receptor (ACT), which demonstrate the androgenic and anabolic activity of the non-steroidal ligand for the androgen receptor. Agents form a new subclass of compounds that are selective androgen receptor modulators (8AKM), useful for a) male contraception; b) treatment of various hormone-dependent conditions, for example, conditions associated with a decrease in androgens in older men (ΑΌΑΜ); c) treatment of conditions associated with a decrease in androgens in women (AE1R); g) treatment and / or prevention of acute and / or chronic conditions associated with muscle atrophy; e) prevention and / or treatment of dry eye conditions; e) oral androgen replacement therapy; and / or g) reducing the incidence, cessation, or inducing regression of prostate cancer.

Background of the Related Art

The androgen receptor (AK) is a ligand-activated transcriptional regulatory protein that mediates the induction of male sexual development and function through interaction with endogenous androgens. Androgens are commonly known as male sex hormones. Androgenic hormones are steroids that are produced in the body by the testes and adrenal cortex or can be synthesized in a laboratory. Androgenic steroids play an important role in many physiological processes, including the development and maintenance of male sexual characteristics, such as muscle and bone mass, prostate growth, spermatogenesis and the nature of the hairline in men (Ma18isho1o, Epbosgsho1. MeE C1sh. N. At. 23: 857 -75 (1994)). Endogenous steroidal androgens include testosterone and dihydrotestosterone (ΌΗΤ). Testosterone is the main steroid secreted by the testes, and is the primary circulating androgen found in plasma in men. Testosterone is converted to ΌΗΤ by enzyme 5 alpha reductase in many peripheral tissues. ΌΗΤ is thought to act as an intracellular neurotransmitter for most androgenic activities (ΖΙιοιι. Et al., Mo1c. Eppospo1. 9: 208-18 (1995)). Other steroidal androgens include testosterone esters such as cypionate, propionate, phenylpropionate, cyclopentylpropionate, isocaproate, enanthate and decanoate, and other synthetic androgens such as 7-methylnortestosterone (ΜΕΝΤ) and its acetate ester (8ipbagash et al., 1-A1-A1 No. g1e51o51egope (ΜΕΝΤ): Thieu OrDta1 Apgodep Rog Ma1e SoShgaserbop, App. Meb., 25: 199-205 (1993) (8ipagat)). Since AK is involved in sexual development and function in men, AK is a likely target for male contraception or other forms of hormone replacement therapy.

Global population growth and a social understanding of family planning have stimulated a large number of contraceptive studies. Contraception is a difficult task under any circumstances. It is fraught with a cultural and social dimension, religious complications and, most importantly, significant health concerns. This situation is only exacerbated when the subject concentrates on male contraception. Despite the availability of suitable contraceptives, historically society has turned to women to be responsible for contraception and its consequences. Although worrying about sexually transmitted diseases has forced men to develop more secure and responsible sexual habits, women still often make the main decision when choosing a contraceptive. Women have a wide selection, ranging from temporary mechanical devices such as tampons and diaphragms to temporary chemical agents such as spermicides. Women also have more permanent remedies available, such as physical devices, including intrauterine devices (ΐυΌ) and birth control caps, as well as more permanent chemical treatments, such as birth control pills and subcutaneous implants. However, to date, the only means available to men are those that include condom use, as well as a vasectomy. The use of a condom, however, is not approved by many men due to loss of sexual sensitivity, interruption of sexual spontaneity and the significant possibility of pregnancy due to rupture or misuse. Vasoectomy is also not approved. If more convenient methods of birth control were available to men, especially long-term methods that do not require any preparatory work before sexual intercourse, such methods could probably significantly increase men's responsibility for contraception.

The introduction of male sex steroids (for example, testosterone and its derivatives) seems particularly promising in this regard due to the combination of the gonadotropin-suppressing and androgen-substituting properties of these compounds (81gbpGe8Ge8e8e8e8e8e8e8e8e8e8e8e8e8e8e8e8e8e8e8e8e8e8e8e8e8e8e8e8e8e8e8e8e8e8e8e8e8e8e8e8e8e8e8e8e8e8e8e8e8e8e8e8e8e8e8e8e8e8e8e8e8e8e8e8e8e8e8e8e8e8e8e8e8e8e8e8e8e8e8e8e8e8e8e8e8e8e8e8e8e8e8e8e8e2e2e , о Р Р о Р ти 8 8 8 б 8 И т оп оп оп,,,,,, И у у у у у у у у у у у а а а а а а а ас ас ас ас ас ерб ерб ерб ерб ерб,, 28 28 28:: 1977 1977 1977 1977 1977 1977 1977 1977 1977 (1977). perm

- 1 013818 (azoospermia) or reduces production to a very low level (oligospermia). The degree of spermatogenic suppression necessary to obtain infertility is not exactly known. However, a recent report by the World Health Organization showed that weekly intramuscular injections of testosterone enanthate result in azoospermia or severe oligospermia (i.e., less than 3 million sperm per ml) and infertility in 98% of men receiving therapy (Uog1b Nea1111-Ogdashha1yup Tak Rogse Op.Mejubk Apb VediShyup οί Ma1e RegShyu, SopyaserIuE Ешсасу οί Te51о51egope-1pyiseb Akhookretia apb O1shokreksha ίη Ugta1 Mep, Regshu apb 81eg1111u 65: 821-29 (1996).

A variety of testosterone esters have been developed that are more slowly absorbed after intramuscular administration and thus lead to a greater androgenic effect. Testosterone enanthate is the most widely used of these esters. Although testosterone enanthate has been found to be preferred as a hormonal agent for male contraception, it has several drawbacks, including the need for weekly injections and the presence of superphysiological peak testosterone levels immediately after intramuscular administration (\ Uy. EyesTeklok1egope Epepreptum Rexepot Mephot: MISSESHG SOSGGASERTSUE ESHsasu 81ib, Eeg (P11u apb 81epShu 65: 626-36 (1996)).

Steroid ligands that bind to AB and act as androgens (for example, testosterone enanthate) or as antiandrogens (for example, cyproterone acetate) have been known for a long time, and they have been used clinically (Woo 1988). Although non-steroidal anti-androgens are clinically used to treat hormone-dependent prostate cancer, the use of non-steroidal androgens has not been reported. For this reason, research in the field of male contraceptives has focused exclusively on steroid compounds.

Prostate cancer is one of the most common cancers in the US population, with hundreds of thousands of new cases every year. Unfortunately, it was found that more than sixty percent of newly diagnosed cases of prostate cancer are pathologically advanced, without treatment and with a poor prognosis. One approach to this problem is the early diagnosis of prostate cancer using screening programs, which thus reduces the number of patients with advanced prostate cancer. Another strategy, however, is to develop drugs for the prevention of prostate cancer. One third of all people over the age of 50 have a latent form of prostate cancer, which can be activated into a life-threatening clinical form of prostate cancer. It was shown that the frequency of latent prostate tumors increases significantly with each decade of life, starting from 50 years (5.3-14%) to 90 years (40-80%). The number of people with latent prostate cancer is the same for all cultures, ethnic groups and races, but still the incidence of clinically aggressive cancer varies markedly. This suggests that environmental factors may play a role in the activation of latent prostate cancer. Thus, the development of strategies for the treatment and prevention of prostate cancer can have a comprehensive impact, both medically and economically.

Osteoporosis is a systemic skeletal disease characterized by low bone mass and deterioration of bone tissue, followed by an increase in bone fragility and susceptibility to fractures. In the United States, more than 25 million people experience this condition, causing more than 1.3 million fractures every year, including 500,000 spinal fractures, 250,000 hip fractures, and 240,000 wrist fractures annually. Hip fractures are the most serious consequences of osteoporosis, 5-20% of patients die within one year, and up to 50% of survivors become disabled. Elderly people have the highest risk of osteoporosis and thus it is predicted that the problem will increase significantly with an aging population. It is predicted that the incidence of fractures will triple in the next 60 years, and as a result of one study, it was even estimated that in 2050 there will be 4.5 million hip fractures.

Women are at a higher risk of osteoporosis than men. Women experience a sharp acceleration in the process of bone loss within five years after menopause. Other risk factors include smoking, alcohol abuse, a sedentary lifestyle, and low calcium intake. However, osteoporosis also often occurs in men. It has been unequivocally established that the mineral density of the bones of men decreases with age. Decreased bone mineral content and density correlate with reduced bone strength and predispose to fractures. The molecular mechanisms underlying the pleiotropic effects of sex hormones in non-reproductive tissues are only beginning to be investigated, but it is clear that physiological concentrations of androgens and estrogens play an important role in maintaining bone homeostasis throughout life. Therefore, when a deficiency of androgen or estrogen occurs, an increase in the rate of bone remodeling occurs, which upsets the balance of resorption and formation in favor of resorption, which leads to a general loss of bone mass. In men, a natural decrease in sex hormones in adulthood (a direct decrease in androgens, as well as a decrease in estrogen levels resulting from the peripheral aromatization of androgens) are associated with bone fragility. This effect is also observed in neutered men.

Decreased androgen in men with aging (AOAM) refers to a progressive decrease

- 2 013818 androgen production, usually occurring in men older than middle age. The syndrome is characterized by changes in the physical and intellectual fields that correlate and can be corrected by manipulating the androgenic environment. ΑΌΑΜ is characterized by a biochemical decrease not only in serum androgens, but also in other hormones such as growth hormone, melatonin and dehydroepiandrosterone. Clinical manifestations include fatigue, depression, decreased libido, sexual dysfunction, erectile dysfunction, hypogonadism, osteoporosis, hair loss, obesity, sarcopenia, osteopenia, benign prostatic hyperplasia, anemia, mood and perceptual changes, and prostate cancer.

Female Androgen Deficiency (ΑΌΙΡ) refers to a variety of hormone-dependent conditions, including those common to women over middle-aged conditions. The syndrome is characterized by sexual dysfunction, decreased sexual libido, hypogonadism, sarcopenia, osteopenia, osteoporosis, changes in perception and mood, anemia, depression, hair loss, obesity, endometriosis, breast cancer, uterine cancer and ovarian cancer.

Muscle loss refers to progressive muscle loss and / or progressive muscle weakening and degeneration, including skeletal or voluntarily contracting muscles that control movement, heart muscles that control the heart (cardiomyopathy) and smooth muscles. Chronic muscle loss is a chronic condition (that is, persisting over a long period of time), characterized by progressive loss of muscle mass, muscle weakness and degeneration. The loss of muscle mass that occurs during muscle atrophy can be characterized by the breakdown or degradation of muscle proteins. 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 caused by a high rate of protein degradation or a low rate of protein synthesis leads to a decrease in muscle mass and muscle atrophy. Muscle atrophy is associated with chronic, neurological, genetic or infectious pathologies, diseases, diseases or conditions. These include muscular dystrophies, such as Duchenne muscular dystrophy and myotonic dystrophy; muscle atrophy, such as post-polio muscle atrophy (PPMA); cachexia, such as cardiac cachexia, AIDS cachexia and cancer cachexia, malnutrition, leprosy, diabetes, kidney disease, chronic obstructive pulmonary disease (SORI), cancer, advanced renal failure, emphysema, osteomalacia, HIV infection, AIDS and cardiomyopathy. In addition, other circumstances and conditions are associated with muscle atrophy and can cause atrophy. These include chronic lower back pain, general aging, trauma to the central nervous system (CNS), trauma to the peripheral nerve, trauma to the spinal cord, chemical trauma, damage to the central nervous system (CNS), damage to the peripheral nerve, damage to the spinal cord, chemical damage, burns, maladaptation from non-use that occurs during limb immobilization, long-term hospitalization due to illness or injury, and alcoholism. Muscle atrophy without treatment can have dire health consequences. For example, changes that occur during muscle atrophy can lead to a weakened physical condition that is detrimental to an individual’s health, leading to increased susceptibility to infection, poor working condition, and a tendency to trauma.

New innovative approaches are urgently needed both at the level of basic science and at the clinical level to obtain compounds that are applicable for a) male contraception; b) treatment of various hormone-dependent conditions, for example, conditions associated with a decrease in androgen during aging men (ΑΌΑΜ), such as fatigue, depression, decreased libido, sexual dysfunction, erectile dysfunction, hypogonadism, osteoporosis, hair loss, anemia, obesity, sarcopenia, osteopenia osteoporosis, benign prostatic hyperplasia, changes in mood and perception, and prostate cancer; c) treatment of conditions associated with ΑΌΙΡ, such as sexual dysfunction, decreased sexual libido, hypogonadism, sarcopenia, osteopenia, osteoporosis, changes in perception and mood, depression, anemia, hair loss, obesity, endometriosis, breast cancer, uterine cancer and cancer ovaries; g) treatment and / or prevention of acute and / or chronic conditions of muscle loss; e) prevention and / or treatment of dry eye conditions; e) oral androgen replacement therapy and / or g) reducing the incidence, termination or induction of regression of prostate cancer.

SUMMARY OF THE INVENTION

In one embodiment, the present invention provides androgen receptor targeting agents (ΑΚΤΑ). Agents form a new subclass of compounds that are selective androgen receptor modulators (8ΑΚΜ). It was found that some of the compounds 8ΑΚΜ have unexpected androgenic and anabolic activity of the non-steroidal androgen receptor ligand. It was found that other compounds 8ΑΒΜ have unexpected antiandrogenic activity of the non-steroidal ligand for the androgen receptor. Compounds 8ΑΚΜ, either on their own or in the form of compositions, are useful for a) male contraception; b) treatment of various hormone-dependent conditions, for example, conditions associated with a decrease in androgens in older men (ΑΌΑΜ), such as fatigue, depression, decreased libido, sexual dysfunction, erek

- 3 013818 severe dysfunction, hypogonadism, osteoporosis, hair loss, anemia, obesity, sarcopenia, osteopenia, osteoporosis, benign prostatic hyperplasia, changes in mood and recognition and prostate cancer; c) treatment of conditions associated with a decrease in androgens in women (ΆΌΙΕ), such as sexual dysfunction, decreased sexual libido, hypogonadism, sarcopenia, osteopenia, osteoporosis, changes in recognition ability and mood; depression, anemia, hair loss, obesity, endometriosis, breast cancer, uterine cancer and ovarian cancer; g) treatment and / or prevention of acute and / or chronic conditions of muscle loss; e) prevention and / or treatment of dry eye conditions; e) oral androgen replacement therapy; and / or g) reducing the incidence, termination or induction of regression of prostate cancer.

In one embodiment, the present invention provides a compound - a selective androgen receptor modulator (8ABM) of formula IV

represents O or 8;

T represents OH;

B represents _(C1-C6) alkyl, halo _(C1-C6) alkyl, dihalo _(C1-C6) alkyl, trihalo _(C1-C6) alkyl, CH ₂ F, CHP _2, CP _3, CP ₂ CP ₃ , phenyl, halogen, (C ₂ -C ₆ ) alkenyl or OH;

In ₁ represents CH ₃ ;

Vz represents P, C1, Br, I, CU, ΝΟ2, SOV, COOH, SOKHNI. CP3, 8p (B) s;

Ζ represents ΝΟ ₂ , ΟΝ, COB, COOH or SUN;

O is (C ₁ -C ₆ ) alkyl, halogen, CP ₃ , CH, C (B) ₃ , 8p (B) ₃ , OH (B) ₂ , HNSOSN ₃ , HNSOSR ₃ , YNSOV, INSOKHN, INSOOV, OSOINV , SOX 11 V, HNS8CH ₃ , HNS8SR ₃ , YNS8V, YN8O ₂ CH ₃ , YN8O2V, OH, OB, SOV, OSV, O8O2V, 8O2V, 8V;

p 'is an integer having a value of 1-4; and t is an integer having a value of 1-3.

In another embodiment, the present invention provides an isomer, pharmaceutically acceptable salt, hydrate or Ν-oxide of a compound of formula IV, or any combination thereof.

In one embodiment, the compound of formula IV is a compound having the structure of formula 1

and / or an isomer thereof, a pharmaceutically acceptable salt, hydrate or Ν-oxide, or any combination thereof.

In yet another embodiment, the compound of formula IV is a compound having the structure of formula 2

and / or its isomer, pharmaceutically acceptable salt, hydrate or Ν-oxide, or any combination thereof.

In a further embodiment, the compound of formula IV is a compound having the structure of formula 3

and / or its isomer, pharmaceutically acceptable salt, hydrate or Ν-oxide, or any combination thereof.

In yet another embodiment, the compound of formula IV is a compound having the structure of formula 4:

- 4 013818

and / or an isomer thereof, a pharmaceutically acceptable salt, hydrate or Ν-oxide, or any combination thereof.

In yet another embodiment, the compound of formula IV is a compound having the structure of formula 5

and / or an isomer thereof, a pharmaceutically acceptable salt, hydrate or Ν-oxide, or any combination thereof.

In a further embodiment, the compound of formula IV is a compound having the structure of formula 7

and / or an isomer thereof, a pharmaceutically acceptable salt, hydrate or Ν-oxide, or any combination thereof.

In a further embodiment, the compound of formula IV is a compound having the structure of formula 11

and / or an isomer thereof, a pharmaceutically acceptable salt, hydrate or Ν-oxide, or any combination thereof.

In yet another embodiment, the compound of formula IV is a compound having the structure of formula 12

and / or an isomer thereof, a pharmaceutically acceptable salt, hydrate or Ν-oxide, or any combination thereof.

In one embodiment, the present invention provides a compound, a selective androgen receptor modulator (8AKM) of formula 6

and / or an isomer thereof, a pharmaceutically acceptable salt, hydrate or Ν-oxide, or any combination thereof.

In yet another embodiment, the present invention provides a compound, a selective androgen receptor modulator (8AKM) of formula 8

and / or an isomer thereof, a pharmaceutically acceptable salt, hydrate or Ν-oxide, or any combination thereof.

In yet another embodiment, the present invention provides a selective androgen receptor modulator (8AKM) of formula 9

- 5 013818

and / or its isomer, pharmaceutically acceptable salt, hydrate or Ν-oxide, or any combination thereof.

In one embodiment, compound 8LCM of the present invention is an androgen receptor agonist. In another embodiment, compound 8LVM of any of formulas IV, 6, 8, 9 is an androgen receptor antagonist. In another embodiment, compound 8LAM of any of formulas IV, 6, 8, 9 binds irreversibly to the androgen receptor. In another embodiment, compound 8LAM of any of formulas IV, 6, 8, 9 binds reversibly to the androgen receptor.

In one embodiment, the present invention provides a composition comprising a compound, a selective androgen receptor modulator of the present invention and / or an isomer thereof, a pharmaceutically acceptable salt, hydrate or Ν-oxide, or any combination thereof.

In another embodiment, the present invention provides a method for binding a androgen receptor selective modulator compound to an androgen receptor, comprising the step of contacting an androgen receptor compound and a androgen receptor selective modulator compound of the present invention and / or its isomer, a pharmaceutically acceptable salt, hydrate or Ν-oxide thereof, or any of them a combination, in an amount effective to bind a compound, a selective androgen receptor modulator, to an androgen receptor.

In another embodiment, the present invention provides a method of suppressing spermatogenesis in a subject, comprising contacting a subject’s androgen receptor with a compound - a selective modulator of the androgen receptor of the present invention and / or its isomer, a pharmaceutically acceptable salt, hydrate or Ν-oxide, or any combination thereof, in an amount effective to suppress sperm formation.

In another embodiment, the present invention provides a method of contraception in men, comprising the step of administering to the subject a compound, a selective androgen receptor modulator of the present invention and / or an isomer thereof, a pharmaceutically acceptable salt, hydrate or Ν-oxide, or any combination thereof, in an amount effective to suppress the formation of sperm in the subject, thereby providing effective contraception to the subject.

In another embodiment, the present invention provides a hormone therapy method comprising the step of contacting a subject’s androgen receptor with a selective androgen receptor modulator compound of any embodiment of the present invention and / or its isomer, pharmaceutically acceptable salt, hydrate or Ν-oxide, or any combination thereof, in an amount effective to effect a change in androgen-dependent state.

In another embodiment, the present invention provides a hormone replacement therapy method comprising the step of contacting a subject’s androgen receptor with a selective androgen receptor modulator of the present invention and / or an isomer thereof, a pharmaceutically acceptable salt, hydrate or Ν-oxide, or any combination thereof, in an amount effective for implementing changes in androgen-dependent state.

In another embodiment, the present invention provides a method of treating a subject having a hormone-dependent state, comprising the step of administering to the subject a compound - a selective modulator of the androgen receptor of the present invention and / or its isomer, a pharmaceutically acceptable salt, hydrate or Ν-oxide or any combination thereof, in an amount effective to implement changes in androgen-dependent state.

In another embodiment, the present invention provides a method of treating a subject suffering from prostate cancer, comprising the step of administering to said subject a compound - a selective androgen receptor modulator of the present invention and / or its isomer, a pharmaceutically acceptable salt, hydrate or или-oxide, or any combination thereof, in an amount effective for treating prostate cancer in a subject.

In another embodiment, the present invention provides a method for preventing prostate cancer in a subject, comprising the step of administering to the subject a compound - a selective androgen receptor modulator of the present invention and / or an isomer thereof, a pharmaceutically acceptable salt, hydrate or окс-oxide, or any combination thereof, in an amount effective for prevention of prostate cancer in a subject.

In another embodiment, the present invention provides a method of arresting the development of prostate cancer in a subject suffering from prostate cancer, comprising the step of administering to said subject a compound and the selective androgen receptor modulator of the present invention and / or its isomer, pharmaceutically acceptable salt, hydrate or Ν-oxide or any of them combinations, in an amount effective to delay the development of prostate cancer in a subject.

In another embodiment, the present invention provides a method for preventing cancer recurrence.

- 6 013818 prostate in a subject suffering from prostate cancer, comprising the step of administering to said subject a compound - a selective modulator of the androgen receptor of the present invention and / or its isomer, a pharmaceutically acceptable salt, hydrate or Ν-oxide or any combination thereof, in an amount effective for prevention of relapse, prostate cancer in a subject.

In another embodiment, the present invention provides a method for treating recurrence of prostate cancer in a subject suffering from prostate cancer, comprising the step of administering to said subject a compound - a selective androgen receptor modulator of the present invention and / or its isomer, a pharmaceutically acceptable salt, hydrate or Ν-oxide or any of them combinations, in an amount effective to treat recurrence of prostate cancer in a subject.

In another embodiment, the present invention provides a method of treating a dry eye condition in a subject suffering from a dry eye condition, comprising the step of administering to said subject a compound and the selective androgen receptor modulator of the present invention and / or its isomer, a pharmaceutically acceptable salt, hydrate or Ν-oxide or any combinations thereof, in an amount effective to treat a dry eye condition in a subject.

In another embodiment, the present invention provides a method for preventing dry eye in a subject, comprising the step of administering to said subject a compound, a selective androgen receptor modulator of the present invention and / or its isomer, a pharmaceutically acceptable salt, hydrate or Ν-oxide, or any combination thereof, in an amount effective in preventing dry eyes in a subject.

The new compounds are selective androgen receptor modulators of the present invention, either alone or in the form of a pharmaceutical composition, are suitable for a) male contraception; b) treating various hormone-dependent conditions, such as conditions associated with ΆΌΆΜ, such as fatigue, depression, decreased libido, sexual dysfunction, erectile dysfunction, hypogonadism, osteoporosis, hair loss, obesity, sarcopenia, osteopenia, benign prostatic hyperplasia and mood changes and recognition; c) treatment of conditions associated with ΆΌΙΡ, such as sexual dysfunction, decreased sexual libido, hypogonadism, sarcopenia, osteopenia, osteoporosis, changes in recognition ability and mood, depression, anemia, hair loss, obesity, endometriosis, breast cancer, uterine cancer and ovarian cancer; g) treatment and / or prevention of acute and / or chronic conditions of muscle loss; e) prevention and / or treatment of dry eye conditions; e) oral androgen replacement therapy; and / or g) reducing the incidence, stopping, or causing regression of prostate cancer.

The selective androgen receptor modulator compounds of the present invention have significant advantages over steroid androgen treatment, since the selective androgen receptor modulator compounds of the present invention, as shown by the ίη-νίνο experiments, have the androgenic and anabolic activity of the non-steroidal ligand for the androgen receptor. Accordingly, the selective androgen receptor modulator compounds have the androgenic and anabolic activity of the non-steroidal ligand for the androgen receptor and do not cause serious side effects, do not have uncomfortable routes of administration or high cost, but have the advantages of oral bioavailability, lack of cross-reactivity with other receptors steroids and a long biological half-life.

List of figures

The present invention will be understood and appreciated more fully, based on the following detailed description, which is considered together with the drawings, which demonstrate the following.

FIG. 1 - androgenic and anabolic activity of compounds 1 and 2 in rats. The rats were left untreated (intact control), castrated (castrated), treated with a dose of 1.0 mg / day of compound 1 or treated with a dose of 1.0 mg / day of compound III, and the weight of androgen-sensitive tissues (prostate, seminal vesicles and anus muscle) was determined.

FIG. 2 - androgenic and anabolic activity of compound 7 in rats. Rats were castrated on day 0 and daily doses were administered subcutaneously (0.05 to 3 mg / day) of compound 7 in a DMSO / PEG vehicle. Rats were euthanized on the last day and the wet weights of androgenic (prostate and seminal vesicles) and anabolic (raising muscle) organs were determined.

Information confirming the possibility of carrying out the invention

In one of the embodiments of the present invention provides agents directed to the androgen receptor (ACT). Agents form a new subclass of compounds that are selective modulators of androgen receptor (8AKM). It has been found that several of the 8AKM compounds have unexpected antiandrogenic and anabolic non-steroidal ligand activity for the androgen receptor. It was found that other compounds 8AKM have unexpected antiandrogenic activity of a non-steroidal ligand for the androgen receptor. Compounds 8AKM, either on their own or in the form of compositions, are suitable for a) male contraception; b) treatment of various hormone-dependent conditions, for example, conditions associated with decreased androgen in older men (AEAM), such as fatigue, depression, decreased libido, sexual dysfunction, erectile dysfunction, hypogonadism, osteoporosis, hair loss, anemia, obesity, sarcopenia, osteopenia , os

- 7 013818 theoporosis, benign prostatic hyperplasia, changes in mood and recognition and prostate cancer; c) treatment of conditions associated with a decrease in androgens in women (ΆΌΙΕ), such as sexual dysfunction, decreased sexual libido, hypogonadism, sarcopenia, osteopenia, osteoporosis, changes in recognition ability and mood, depression, anemia, hair loss, obesity, endometriosis, breast cancer, uterine cancer and ovarian cancer; g) treatment and / or prevention of acute and / or chronic conditions of muscle loss; e) prevention and / or treatment of dry eye conditions; e) oral androgen replacement therapy; and / or g) reducing the incidence, termination or induction of regression of prostate cancer.

In one embodiment, the present invention provides a compound - a selective androgen receptor modulator (8ABM) of formula IV

where X represents O;

represents O or 8;

T represents OH;

B represents (C ₁ -C ₆ ) alkyl, halogen (C ₁ -C ₆ ) alkyl, dihalogen (C ₁ -C ₆ ) alkyl, trihalo (C ₁ -C ₆ ) alkyl, CH ₂ E, CHE ₂ , CE ₃ , CE ₂ CE ₃ , phenyl, halogen, (C ₂ -C ₆ ) alkenyl or OH;

In ₁ represents CH ₃ ;

Vz represents E, C1, Br, I, CU, ΝΟ2, SOV, COOH, SOKHNI. CE3, 8p (B) s;

Ζ represents ΝΟ ₂ , ΟΝ, COB, COOH or SUN;

O is (C ₁ -C ₆ ) alkyl, halogen, CE ₃ , CH, C (B) ₃ , 8p (B) ₃ , OH (B) ₂ , HNSOSN ₃ , HNSOSE ₃ , YNSOV, KhNOSYNV, YNSOOV, OSOINV , SOYNV, KhNS8CH ₃ , KhNS8SE ₃ , YNS8V, YN8O ₂ CH ₃ , YN8O ₂ V, OH, OB, OWL, OOS, O8O ₂ V, 8O ₂ V, 8V; p 'is an integer having a value of 1-4; and t is an integer having a value of 1-3.

In one embodiment, the present invention provides a compound of formula IV, where p 'is 1. In one embodiment, the present invention provides a compound of formula IV where p' is 2. In one embodiment, the present invention provides a compound of formula IV, where p ' has a value of 3. In one of the embodiments the present invention provides a compound of formula IV, where p 'is a value of 4.

In one embodiment, the present invention provides an isomer 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 hydrate of a compound of formula IV. In another embodiment, the present invention provides a β-oxide of a compound of formula IV. In another embodiment, the present invention provides a combination of any of the isomer, pharmaceutically acceptable salt, hydrate or Ν-oxide of a compound of formula IV. In one embodiment, compound 8ABM is a compound of formula IV, wherein B ₃ is E. In another embodiment, compound 8ABM is a compound of formula IV, where B ₃ is C1. In another embodiment, compound 8ABM is a compound of formula IV, wherein B ₃ is Vg. In another embodiment, compound 8ABM is a compound of formula IV, where B ₃ is I. In another embodiment, compound 8ABM is a compound of formula IV, where B ₃ is SC. In another embodiment, compound 8ABM is a compound of formula IV, where B ₃ is itself NΟ ₂ . In another embodiment, compound 8ABM is a compound of formula IV, wherein B ₃ is COB. In another embodiment, compound 8ABM is a compound of formula IV, wherein B ₃ is COOH. In another embodiment, compound 8ABM is a compound of formula IV, wherein B ₃ is COMNB. In another embodiment, compound 8ABM is a compound of formula IV, wherein B ₃ is CE ₃ . In another embodiment, compound 8ABM is a compound of formula IV, wherein B ₃ is 8 pV ₃ . In one embodiment, compound 8ABM is a compound of formula IV, where m is 1. In another embodiment, compound 8ABM is a compound of formula IV, where m is 2. In another embodiment, compound 8ABM is a compound of IV, where m is 3.

Substituent B is defined in the present invention as alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH ₂ E, CHE ₂ , CE ₃ , CE ₂ CE ₃ ; phenyl, halogen, alkenyl or hydroxyl (OH). In one embodiment, the compound of formula IV is a compound having the structure of formula 1

- 8 013818 and / or its isomer, pharmaceutically acceptable salt, hydrate or Ν-oxide or any combination thereof.

In yet another embodiment, the compound of formula IV is a compound having the structure of formula 2

and / or its isomer, pharmaceutically acceptable salt, hydrate or Ν-oxide, or any combination thereof.

In a further embodiment, the compound of formula IV is a compound having the structure of formula 3

and / or its isomer, pharmaceutically acceptable salt, hydrate or Ν-oxide, or any combination thereof.

In yet another embodiment, the compound of formula IV is a compound having the structure of formula 4

and / or its isomer, pharmaceutically acceptable salt, hydrate or Ν-oxide, or any combination thereof.

In yet another embodiment, the compound of formula IV is a compound having the structure of formula 5

and / or its isomer, pharmaceutically acceptable salt, hydrate or Ν-oxide, or any combination thereof.

In a further embodiment, the compound of formula IV is a compound having the structure of formula 7

and / or an isomer thereof, a pharmaceutically acceptable salt, hydrate or Ν-oxide, or any combination thereof.

In a further embodiment, the compound of formula IV is a compound having the structure of formula 11

and / or an isomer thereof, a pharmaceutically acceptable salt, hydrate or Ν-oxide, or any combination thereof.

In yet another embodiment, the compound of formula IV is a compound having the structure of formula 12

R

and / or an isomer thereof, a pharmaceutically acceptable salt, hydrate or Ν-oxide, or any combination thereof.

In one embodiment, the present invention provides a selective modulator compound.

and / or its isomer, pharmaceutically acceptable salt, hydrate or Ν-oxide, or any combination thereof.

In yet another embodiment, the present invention provides a compound, a selective androgen receptor modulator (LOAN) of formula 8

and / or an isomer thereof, a pharmaceutically acceptable salt, hydrate or Ν-oxide, or any combination thereof.

In yet another embodiment, the present invention provides a selective androgen receptor modulator (LOAN) of formula 9

and / or an isomer thereof, a pharmaceutically acceptable salt, hydrate or Ν-oxide, or any combination thereof.

An alkyl group refers to a saturated aliphatic hydrocarbon, including straight and branched chain groups and cyclic alkyl groups. In one embodiment, the alkyl group has 1-12 carbon atoms. In another embodiment, the alkyl group has 1-7 carbon atoms. In another embodiment, the alkyl group has 1-6 carbon atoms. In another embodiment, the alkyl group has 1-4 carbon atoms. Alkyl groups may be unsubstituted or substituted by one or more groups selected from halogen, hydroxy, alkoxycarbonyl, amido, alkylamido, dialkylamido, nitro, amino, alkylamino, dialkylamino, carboxyl, thio and thioalkyl.

A haloalkyl group refers to an alkyl group as defined above that is substituted with one or more halogen atoms, for example P, C1, Br or I.

The hydroxyl group belongs to the OH group. Alkenyl group refers to a group having at least one carbon-carbon double bond. The halogen group includes P, C1, Br or I.

As provided in the description, the present invention relates to the use of the ZAEM compound and / or its isomer, a pharmaceutically acceptable salt, hydrate, Ν-oxide, or combinations thereof. In one embodiment, the invention relates to the use of an isomer of a LOAN compound. In another embodiment, the invention relates to the use of a pharmaceutically acceptable salt of the compound LOAN. In another embodiment, the invention relates to the use of a hydrate of a ZAE compound. In another embodiment, the invention relates to the use of the Ν-oxide compound LOAN.

As defined in the present invention, the term isomer includes, but is not limited to, optical isomers and analogs, structural isomers and analogs, conformational isomers and analogs and the like.

In one embodiment, the present invention encompasses the use of various optical isomers of the ZAE compound. As will be understood by those of ordinary skill in the art, the LOAN compounds of the present invention contain at least one chiral center. Accordingly, loan compounds used in the methods of the present invention can exist in and be isolated in optically active or racemic form. Some compounds may also exhibit polymorphism. It is understood that the present invention encompasses any racemic, optically active, polymorphic or stereoisomeric form or mixtures thereof, if the form has properties useful in the treatment of androgen-dependent conditions described in the present invention. In one embodiment, the loan compounds are pure (E) -isomers. In another embodiment, the loan compounds are pure (H) -isomers. In another embodiment, the loan compounds are a mixture of (E) and (H) isomers. In another embodiment, the loan compounds are a racemic mixture containing an even amount of (E) and (H) isomers. It is well known in the art how to obtain optically active forms (for example, by resolution of a racemic form by recrystallization, synthesis from optically active starting materials, chiral synthesis or by chromatographic resolution using a chiral stationary phase).

The invention includes pharmaceutically acceptable salts of amino substituted compounds with organic and inorganic acids, for example, such as citric acid and hydrochloric acid. The invention also includes I-oxides of amino substituents of the compounds described in the present invention. 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.

In addition, the present invention also includes hydrates of 8ABM compounds. The term hydrate includes, but is not limited to, hemihydrate, monohydrate, dihydrate, trihydrate and the like.

In another embodiment, the present invention provides a method for producing a selective androgen receptor modulator (8ABM) compound of formula I

where X represents O, YAN, 8, 8e, PB or YaV;

C represents O or 8;

T represents OH, OB, -YANCOCH ₃ or YANSOV;

B represents alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH2P, CHP2, CP3, CP2CP3, aryl, phenyl, halogen, alkenyl or OH;

B1 is CH3, CH2P, CHP2, CP3, CH2CH3, or CP2CP3;

B ₂ represents P, C1, Br, I, CH ₃ , CP ₃ , OH, NW, YAO ₂ , YANOSOS ₃ , YANOSR ₃ , YANSOV, alkyl, arylalkyl, OB, YAN ₂ , YANV, YaV ₂ , 8B;

B ₃ represents P, C1, Br, I, NW, NW ₂ , COB, COOH, SOYANV, SR ₃ , 8pV ₃ or B ₃ together with the benzene ring to which it is attached forms a condensed ring system represented by the structure

Ζ represents ΝΟ ₂ , ΟΝ, COB, COOH _3, or UNION;

Υ represents СР ₃ , Р, Вг, С1, I, СЯ or 8пВ ₃ ;

O is H, alkyl, halogen, CP ₃ , NW, CB ₃ , 8pV ₃ , YB ₂ , YANOSOSH ₃ , NΗСΟСР ₃ , YANSOV, YANSOYANV, YANSOOV, OSOYANV, SOKHNI, YANS8CH ₃ , YANS8SR ₃ , YANS8V, YAN8O ₂ CH ₃ , ΝΗ8Ο ₂ Β, OH, OV, OWL, OSB, O8O ₂ V, 8O ₂ V, 8V; or O together with the benzene ring to which it is attached represents a condensed ring system represented by structures A, B or C

η is an integer having a value of 1-4; and t is an integer having a value of 1-3; which comprises a step of condensing a compound of formula VII

where Ζ, Υ, C, B ₁ , T, B ₃ and t are as defined above, and b represents a leaving group, with a compound of formula VIII

where O. X, B ₂ and η are as defined above.

In one embodiment, the condensation step is carried out in the presence of a base. In another embodiment, the leaving group b is Br. In another embodiment, the compound of formula VII is obtained by

- 11 013818

ί) obtaining a compound of formula IX by opening the ring of a cyclic compound of formula X

where b, K ₁ , C and T are as defined above, and Τι represents O or ΝΗ; and ίί) an amine reaction of formula XI

where Υ, K ₃ and t are, as defined above, with a compound of formula IX, in the presence of a condensing reagent, to obtain a compound of formula VII

νπ

One of ordinary skill in the art will recognize that when Τι is O or ΝΗ, T in compound VIII is O or ΝΗ ₂ . Accordingly, when T in compound I is OK, the process will include an additional step for converting OH to OK by reacting, for example, with an alkyl halide KK. When T in compound I is ΝΗΟΌΚ. ΝΗίΌί.Ή ₃ . the process will include an additional step of converting ΝΗ ₂ to ΝΗΟΌΚ or ΝΗίΌί.Ή ₃ by reaction, for example, with the corresponding acyl chloride C1COK or C1CO2.

In one embodiment, step (a) is performed in the presence of ΗΒτ. In another embodiment, the method further includes the step of converting the selective androgen receptor modulator (8AKM) compound to its isomer, pharmaceutically acceptable salt, Ν-oxide, hydrate, or any combination thereof.

In one embodiment, the condensation step as defined above is carried out in the presence of a base. Any suitable base that will deprotonate hydrogen from an —XN residue (eg, a phenol residue when X is O) and allow condensation to take place can be used. Non-limiting examples of bases are carbonates such as alkali metals, for example sodium carbonate (Na ₂ CO ₃ ), potassium carbonate (K ₂ CO ₃ ), and cesium carbonate (Cg ₂ CO ₃ ); bicarbonates such as alkali metal bicarbonates, for example sodium bicarbonate (NaΗCO ₃ ), potassium bicarbonate (CPSO ₃ ), alkali metal hydrides such as sodium hydride (ΝαΗ), potassium hydride (ΚΗ) and lithium hydride (ΟΗ) and the like.

The leaving group b is defined in the present invention as any leaving group, usually considered for chemical reactions, as will be known to the average specialist. Suitable leaving groups are halogens, for example T, C1, Br and I; alkyl sulfonate esters (-O ₈ O ₂ K), where K represents alkyl groups, for example methanesulfonate (mesylate), trifluoromethanesulfonate, ethanesulfonate, 2,2,2-trifluoroethanesulfonate, perfluorobutanesulfonate; arylsulfonate esters (-O ₈ O ₂ Lt), where Ar is an aryl group, for example p-toluenesulfonate (tosylate), benzenesulfonate, which may be unsubstituted or substituted with methyl, chlorine, bromine, nitro and the like; NO ₃ , NO ₂ or sulfate, sulfite, phosphate, phosphite, carboxylate, imino ester, Ν ₂ or carbamate.

The reaction is usually 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; dimethyl sulfoxide (DMSO), dimethylformamide (DMF) and dimethylacetamide (EMAS). The reaction is conveniently carried out at a temperature in the range of, for example, from −20 to 120 ° C., for example, at or near ambient temperature.

The condensing reagent as defined above is a reagent capable of converting a carboxylic acid / thiocarboxylic acid of the formula X into their reactive derivatives, thereby allowing condensation with the corresponding amine to form an amide / thioamide bond. A suitable reactive derivative of a carboxylic acid / thiocarboxylic acid is, for example, an acyl halide / thioacyl halide, for example an acyl / thioacyl chloride, formed by reacting an acid / thio acid and an inorganic acid chloride, for example thionyl chloride; mixed anhydride, for example an anhydride formed by reacting an acid and chloroformate, such as isobutyl chloroformate; active ester / thioether,

- 12 013818 for example an ester / thioester formed by reacting an acid / thio acid and phenol, an ester / thio ester or alcohol, such as methanol, ethanol, isopropanol, butanol or ид hydroxybenzotriazole; an acyl / thioacylazide, for example, an azide formed by reacting an acid / thioacid and an azide, such as diphenylphosphorylazide; an acyl cyanide / thioacyl cyanide, for example a cyanide formed by reacting an acid and a cyanide, such as diethyl phosphoryl cyanide; or the product of an acid / thio acid and carbodiimide reaction such as dicyclohexylcarbodiimide.

The reaction is usually carried out in a suitable inert solvent or diluent, as described above, respectively, in the presence of a base such as triethylamine, and at a temperature in the range as described above.

Biological activity of compounds - selective androgen receptor modulators

The compounds provided by the present invention are compounds that are selective modulators of the androgen receptor (8AKM) and which are suitable for oral testosterone replacement therapy, which have unexpected ίη νίνο activity in the form of the androgenic and anabolic activity of the non-steroidal ligand for the androgen receptor. In addition, appropriately substituted compounds are effective in the treatment of prostate cancer and are useful for imaging prostate cancer. Compounds 8AKM demonstrate the ίη νίνο androgenic and anabolic activity of the non-steroidal ligand for the androgen receptor.

As provided by the present invention, suitably substituted 8AKM compounds of the present invention are suitable for a) male contraception; b) treatment of various hormone-dependent conditions, for example, conditions associated with androgen reduction in older men (AEAM), such as fatigue, depression, decreased libido, sexual dysfunction, erectile dysfunction, hypogonadism, osteoporosis, hair loss, anemia, obesity, sarcopenia, osteopenia, osteoporosis, benign prostatic hyperplasia, changes in mood and recognition and prostate cancer; c) treating conditions associated with AEGR, such as sexual dysfunction, decreased sexual libido, hypogonadism, sarcopenia, osteopenia, osteoporosis, changes in recognition ability and mood, depression, anemia, hair loss, obesity, endometriosis, breast cancer, uterine cancer and ovarian cancer; g) treatment and / or prevention of acute and / or chronic conditions of muscle loss; e) prevention and / or treatment of dry eye conditions; e) oral androgen replacement therapy; and / or g) reducing the incidence, termination or induction of regression of prostate cancer.

As used herein, receptors for extracellular signaling molecules are generically referred to as cell signaling receptors. Many cell signaling receptors are transmembrane proteins on the cell surface; when they bind to extracellular signaling molecules (i.e. a ligand), they become activated in such a way that a cascade of intracellular signals is generated that change the behavior of the cell. In contrast, in some cases, the receptors are located inside the cell, and the signal ligand must enter the cell to activate them; these signaling molecules must therefore be small enough and hydrophobic to penetrate the plasma membrane of the cell.

Steroid hormones are one example of small hydrophobic molecules that penetrate directly through the plasma membrane of target cells and bind to intracellular cell signaling receptors. These receptors are structurally linked and constitute the superfamily of intracellular receptors (or the superfamily of steroid hormone receptors). Steroid hormone receptors include progesterone receptors, estrogen receptors, androgen receptors, glucocorticoin receptors, and mineralcorticoid receptors. The present invention is particularly directed to androgen receptors.

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 formed by the three-dimensional structure of the receptor in the basket and ball configuration. The better the ball fits into the basket, the more firmly it is held. This phenomenon is called affinity. If the affinity of a substance is greater than the affinity of a natural hormone, it competes with the hormone and more often binds to the binding site. If binding has occurred, signals can be sent through the receptor to the cells, causing the cell to react in some way. This is called activation. When activated, the activated receptor then directly regulates the transcription of certain genes. But the substance and receptor may have some signs other than the affinity necessary for cell activation. Chemical bonds may form between atoms of a substance and atoms of receptors. In some cases, this leads to a change in the configuration of the receptor, which is enough to start the activation process (what is called signal transduction).

In one embodiment, the present invention is directed to selective androgen receptor modulator compounds, which are agonist compounds. A receptor agonist is a substance that binds to and activates receptors. Accordingly, in one embodiment, compounds 8ABM of the present invention are useful in binding and activating steroid hormone receptors. In one embodiment, the agonist compound of the present

- 13 013818 of the invention is an agonist that binds to the androgen receptor. In another embodiment, the compound has a high affinity for the androgen receptor. In another embodiment, the agonist compound also has anabolic activity. In another embodiment, the present invention provides selective androgen receptor modulator compounds that have the agonistic and anabolic activity of a non-steroidal compound for the androgen receptor.

In another embodiment, the present invention is directed to compounds - selective androgen receptor modulators, which are antagonist compounds. A receptor antagonist is a substance that binds to and inactivates receptors. Accordingly, in one embodiment, compounds 8ABM of the present invention are useful in binding and inactivating steroid hormone receptors. In one embodiment, the antagonist compound of the present invention is an antagonist that binds to androgen receptor. In another embodiment, the compound has a high affinity for the androgen receptor.

In yet another embodiment, compounds 8ABM of the present invention can be classified as partial AB agonists / antagonists of the compound. 8ABMs are AB agonists in some tissues, causing an increase in transcription of AB-responsive genes (e.g., muscle anabolic effect). In other tissues, these compounds serve as AB inhibitors, preventing the agonistic effects of natural androgens.

Assay methods for determining whether the compounds of the present invention are AB agonists or antagonists are known to one skilled in the art. For example, AVagonist activity can be determined by recording the ability of 8ABM compounds to support and / or stimulate the growth of AV-containing tissue, such as the prostate and seminal vesicles, as measured by weight. AV antagonistic activity can be determined by recording the ability of compounds 8ABM to inhibit the growth of containing AV tissue.

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, compounds 8ABM bind reversibly to a androgen receptor in a mammal, such as a human. Reversible binding of compounds to a receptor means that the compound can be separated from the receptor after binding.

In another embodiment, compounds 8ABM bind irreversibly to the androgen receptor of a mammal, such as a human, thus, in one embodiment, the compounds of the present invention may contain a functional group (e.g., an affinity tag) that allows the androgen receptor to be alkylated (i.e., covalent bond formation). Thus, in this case, the compounds are alkylating agents that bind irreversibly to the receptor and, accordingly, cannot be replaced by a steroid, such as endogenous ONT ligands and testosterone. An alkylating agent is defined herein as an agent that alkylates (forms a covalent bond) a cellular component, such as DNA, RNA, or an enzyme. It is a highly reactive chemical substance that introduces alkyl radicals into biologically active molecules and, thus, prevents their proper functioning. An alkylating group is an electrophilic group that interacts with nucleophilic groups in cellular components.

In accordance with one embodiment of the present invention, there is provided a method of binding the compound 8ABM of the present invention to an androgen receptor by contacting the receptor with compound 8ABM and / or its isomer, pharmaceutically acceptable salt, hydrate or Ν-oxide, or any combination thereof, under conditions effective to cause the binding of a selective androgen receptor modulator to an androgen receptor. The binding of a selective androgen receptor modulator to an androgen receptor makes the compounds of the present invention suitable as male contraceptives and in a number of hormonal therapies. Agonistic compounds bind and activate the androgen receptor. Antagonistic compounds bind to and inactivate the androgen receptor. The binding of agonistic or antagonistic compounds is either reversible or irreversible.

According to one embodiment of the present invention, there is provided a method of suppressing spermatogenesis in a subject by contacting the subject's androgen receptor with compound 8ABM of the present invention and / or its isomer, pharmaceutically acceptable salt, hydrate or Ν-oxide or any combination thereof in an amount effective to bind the compound - selective androgen receptor modulator with androgen receptor and suppression of spermatogenesis.

In accordance with another embodiment of the present invention, there is provided a method of contraception in men, comprising the step of administering to the subject compound 8ABM of the present invention and / or its isomer, a pharmaceutically acceptable salt, hydrate or окс-oxide or any combination thereof in an amount effective to suppress sperm production in a subject thus providing effective contraception to the subject.

In accordance with another embodiment of the present invention, a hormonal method is provided.

- 14 013818 therapy in a patient (i.e., suffering from an androgen-dependent condition), which comprises contacting the patient’s androgen receptor with compound 8ΑΚΜ of the present invention and / or its isomer, pharmaceutically acceptable salt, hydrate or Ν-oxide, or any combination thereof, effective for binding the compound - a selective modulator of the androgen receptor to the androgen receptor and effecting a change in the androgen-dependent state.

According to another embodiment of the present invention, there is provided a method of hormone replacement therapy in a patient (i.e., suffering from an androgen-dependent condition), which comprises contacting the patient's androgen receptor with compound 8ΑΚΜ of the present invention and / or its isomer, pharmaceutically acceptable salt, hydrate or Ν-oxide or any their combination, in an amount effective to bind a compound - a selective modulator of androgen receptor to an androgen receptor and to effectively measure eniya in androgen-dependent condition.

According to another embodiment of the present invention, there is provided a method of treating a subject having a hormone-dependent condition, comprising administering to the subject compound 8 соединения of the present invention and / or its isomer, a pharmaceutically acceptable salt, hydrate or Ν-oxide or any combination thereof in an amount effective to bind compound 8ΑΚΜ with the androgen receptor and effecting changes in the androgen-dependent state.

An androgen-dependent condition that can be treated in accordance with the present invention includes those conditions that are associated with aging, namely hypogonadism, sarcopenia, erythropoiesis, osteoporosis, and any other conditions later identified as being dependent on low levels of androgen (e.g. testosterone).

According to another embodiment of the present invention, there is provided a method of treating a subject suffering from prostate cancer, comprising the step of administering to the subject compounds 8 соединения of the present invention and / or its isomer, a pharmaceutically acceptable salt, hydrate or Ν-oxide or any combination thereof in an amount effective for treatment prostate cancer in a subject.

According to another embodiment of the present invention, there is provided a method for preventing prostate cancer in a subject, comprising the step of administering to the subject compounds 8 соединения of the present invention and / or its isomer, a pharmaceutically acceptable salt, hydrate or Ν-oxide or any combination thereof in an amount effective to prevent prostate cancer in the subject.

According to another embodiment of the present invention, there is provided a method for delaying the development of prostate cancer in a subject suffering from prostate cancer, comprising the step of administering to the subject compounds 8 соединения of the present invention and / or its isomer, a pharmaceutically acceptable salt, hydrate or Ν-oxide or any combination thereof in an amount effective to delay the development of prostate cancer in a subject.

According to another embodiment of the present invention, there is provided a method for preventing recurrence of prostate cancer in a subject suffering from prostate cancer, comprising the step of administering to the subject compounds 8 соединения of the present invention and / or its isomer, a pharmaceutically acceptable salt, hydrate or Ν-oxide thereof, or any combination thereof in an amount effective to prevent recurrence of prostate cancer in a subject.

According to another embodiment of the present invention, there is provided a method of treating recurrence of prostate cancer in a subject suffering from prostate cancer, comprising the step of administering to the subject compounds 8 соединения of the present invention and / or its isomer, a pharmaceutically acceptable salt, hydrate or Ν-oxide thereof, or any combination thereof in an amount effective for treating recurrence of prostate cancer in a subject.

In addition, stimulation of the androgen receptor stimulates the production of tears, and accordingly, compounds 8ΑΚΜ 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 of treating a dry eye condition in a subject suffering from a dry eye condition, comprising the step of administering to said subject a compound, a selective androgen receptor modulator of the Ι-ΐν formulas and / or its isomer, a pharmaceutically acceptable salt, hydrate or Ν-oxide or any combination thereof in an amount effective to treat dry eyes in a subject.

In accordance with another embodiment of the present invention, there is provided a method for preventing dry eye in a subject, comprising the step of administering to said subject a compound of androgen receptor selective modulator of Ι-Ιν formulas and / or its isomer, pharmaceutically acceptable salt, hydrate or или-oxide, or any combination thereof an amount effective to prevent dry eyes in a subject.

As defined herein, contacting means that compound 8ΑΚΜ of the present invention is introduced into a sample containing an enzyme in a test tube, flask, tissue culture, chip, matrix, die, microplate, capillary or the like, and incubated at a temperature and time sufficient for binding 8ΑΚΜ to the enzyme. Methods for contacting samples with 8ΑΚΜ or other specific binding components are known to those skilled in the art and may be selected depending on the type of test protocol being conducted. Ways to

- 15 013818 cubations are also standard and are known to the person skilled in the art.

In another embodiment, the term contacting means that the 8ACM compound of the present invention is administered to a subject undergoing treatment and the 8ACM compound is allowed to come into contact with the androgen receptor ίη νίνο.

As used in the description, the term treatment includes prophylactic as well as suppressive disease treatment. As used herein, the terms suppression, reduction, and inhibition have their generally accepted meaning of decreasing or decreasing. As used in the description, the term development means an increase in volume or severity, spread, increase or worsening of the condition. As used herein, the term relapse means the return of the disease after remission.

As used in the description, the term introduction refers to bringing the subject into contact with compound 8AKM of the present invention. As used in the description, the introduction can be carried out ίη νίΐτο, i.e. in vitro, or ίη νίνο, i.e. in the cells or tissues of living organisms, such as humans. In one embodiment, the present invention encompasses the administration of the compounds of the present invention to a subject.

The term libido, as used in the description, means sex drive.

The term erectile, as used in the description, means the ability to erection. Erectile tissue is a tissue that is capable of severe expansion and hardening with the expansion of the numerous blood vessels that it contains.

Hypogonadism is a condition that appears as a result of abnormally reduced functional activity of the gonads, with growth retardation and sexual development.

Osteopenia refers to decreased calcification or bone density. This is a term that covers all skeletal systems in which such a condition is noted.

Osteoporosis refers to thinning of bones with a reduction in bone mass due to depletion of protein and bone calcium. Osteoporosis predisposes a person to fractures, which are often slowly healed and poorly healed. Uncontrolled osteoporosis can lead to changes in gait, physical impairment, and decreased mobility.

BPH (benign prostatic hyperplasia) is a non-cancerous enlargement of the prostate, and is the most common non-cancerous proliferative disorder found in any internal organ, which is the main cause of morbidity in adult men. BPH occurs in more than 75% of people over 50 years old, reaching a frequency of 88% by ninety years. BPH often leads to a gradual compression of the part of the urethra that passes through the prostate (prostatic urethra). This causes patients to experience frequent urination due to incomplete emptying of the bladder and urge to urinate. Delayed urine flow can also lead to a general loss of control of urination, including difficulty in starting urination if desired, as well as difficulties in preventing urine flow due to inability to empty urine from the bladder, a condition known as excessive urinary incontinence, which can lead to difficulty urinating and impaired urination.

Perception refers to the process of cognition, specifically to the method of cognition, knowledge, reflection, study and evaluation. Cognition is associated with the fields of psychology, linguistics, computer science, neuroscience, mathematics, ethology and philosophy.

The term mood refers to a character or state of mind. As discussed here, changes mean any change in the positive or negative side in perception and / or mood.

The term depression refers to a disease that involves the body, mood, and thoughts, and which affects how a person eats, sleeps, and how a person thinks about himself and thinks about things. Signs and symptoms of depression include loss of interest in activities, loss of appetite or gluttony, loss of emotional expression, poor mood, feelings of hopelessness, pessimism, feelings of guilt or helplessness, social unperception, fatigue, sleep disturbance, problems in concentration, remembering or making decisions, anxiety irritability, headaches, digestive upsets or chronic pain.

The term hair loss, in medicine known as alopecia, refers to baldness as in the most common appearance of bald patches in men. Baldness usually begins with loss of hair in separate areas on the back of the head and sometimes progresses to complete baldness and even loss of body hair. Hair loss affects both men and women.

Anemia refers to a condition that determines the presence in the blood of red blood cells in an amount less than normal or hemoglobin in an amount less than normal. Thus, the ability of the blood to carry oxygen is reduced. People with anemia can easily get tired and tired, appear pale, have a fast heartbeat and usually have shortness of breath. Anemia is caused by four main factors: a) hemorrhage (bleeding); b) hemolysis (excessive destruction of red blood cells); c) insufficient production of red blood cells; and d) insufficient amount of normal hemoglobin. Many forms of anemia are known, including aplastic ane.

- 16 013818 miyu, benzene poisoning, Fanconi anemia, hemolytic disease of newborns, hereditary spherocytosis, iron deficiency anemia, osteopetrosis, pernicious anemia, sickle cell anemia, thalassemia, myelodysplastic syndrome and various bone marrow diseases. As provided in the description, compounds 8AKM of the present invention are useful for the prevention and / or treatment of any or most of the above forms of anemia.

Obesity refers to being overweight. Traditionally, people are considered fat if their weight is 20% higher than their ideal weight. Obesity was more accurately defined by the National Institute of Health (Νοίίοηαΐ ъЦЦЦ о о £ £ £а))) ()) as a body mass index (BM1) of 30 or higher. Obesity is often multifactorial based on genetic and behavioral factors. Overweight due to obesity contributes significantly to health problems. It increases the risk of many diseases, including: type 2 diabetes (onset in adulthood); high blood pressure (hypertension); stroke (stroke or SUL); heart attack (myocardial infarction or M1); cardiac arrest (acute cardiac arrest); cancer (some forms, such as prostate cancer and cancer of the colon and rectum); gallstones and gallbladder disease (cholecystitis); gout and gouty arthritis; osteoarthritis (degenerative arthritis) of the knees, thighs and lower back; attacks of sleep apnea (respiratory failure during sleep, decreased oxygen in the blood); and Pickwick syndrome (obesity, facial flushing, hypoventilation, and drowsiness). As provided in the description, the term obesity includes any of the above conditions and diseases associated with obesity. Thus, the 8LCM compounds of the present invention are useful for the prevention and / or treatment of obesity and any one or more of the above conditions and diseases associated with obesity.

Prostate cancer is one of the most common cancers in the US population, with hundreds of thousands of new cases every year. It was found that more than sixty percent of the newly diagnosed cases of prostate cancer are pathologically advanced with the impossibility of treatment and poor prognosis. A third of all people over the age of 50 have a latent form of prostate cancer, which can be activated into a life-threatening clinical form of prostate cancer. It was shown that the frequency of latent prostate tumors increases significantly with every decade of life, starting from 50 years (5.3-14%) to 90 years (40-80%). The number of people with latent prostate cancer is the same for all cultures, ethnic groups and races, but still the incidence of clinically aggressive cancer is markedly different. This suggests that environmental factors may play a role in the formation of latent prostate cancer.

In one embodiment, the methods of the present invention comprise administering 8AKM as a single active component. However, hormone therapy methods are also included in the scope of the present invention for treating prostate cancer, for delaying the development of prostate cancer, and for preventing and / or treating recurrence of prostate cancer, which include administering 8ACM compounds in combination with one or more therapeutic agents. These agents include, but are not limited to: bNHC analogues, reversible antiandrogens, antiestrogens, anti-cancer drugs, 5-alpha reductase inhibitors, aromatase inhibitors, progestins, agents acting through other nuclear hormone receptors, selective estrogen receptor modulators (8EKM) , progesterone, estrogen, ΡΌΕ5 inhibitors, apomorphine, bisphosphonate and one or more additional 8AKM.

Thus, in one embodiment, the methods of the present invention comprise administering a selective androgen receptor modulator compound in combination with an LNH 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 a cancer 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 include administering a selective androgen receptor modulator compound in combination with an agent acting 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 selective estrogen receptor modulators (8EKM). 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 compound

- 17 013818 androgen receptor modulator in combination with a ΡΌΕ5 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 LOANs.

In one embodiment, the present invention provides a composition and a pharmaceutical composition comprising a compound, a selective androgen receptor modulator of any of formulas IV, 6, 8, 9 and / or an isomer thereof, a pharmaceutically acceptable salt, hydrate or Ν-oxide, or any combination thereof; and a suitable carrier or diluent.

As used herein, a pharmaceutical composition means therapeutically effective amounts of a LOAN together with suitable diluents, preservatives, solubilizers, emulsifiers, adjuvant and / or carriers. A therapeutically effective amount, as used herein, refers to an amount that provides a therapeutic effect in relation to a given condition and administration regimen. Such compositions are liquid or lyophilized or otherwise dried formulations and include diluents containing various buffers (e.g., Tris-HC1, acetate, phosphate) of various pH and ionic strength, additives such as albumin or gelatin to prevent surface absorption, detergents (e.g. Tetei 20, Tetei 80, 68υΙοηίο P68, bile salts), solubilizing agents (e.g. glycerin, polyethylene glycerin), antioxidants (e.g. ascorbic acid, sodium metabisulfite), preservatives (e.g. imerosal, benzyl alcohol, parabens), bulk substances or tonicity modifiers (e.g. lactose, mannitol), covalent addition of polymers such as polyethylene glycol with protein, complexation with metal ions, or incorporation of material in or on dispersed preparations of polymer compounds such as polylactic acid , polyglycolic acid, hydrogels, etc., or in liposomes, microemulsions, micelles, monolayer or multilayer vesicles, erythrocyte shadows, or spheroplasts. Such compositions will affect the physical state, solubility, stability, release rate of ίη νίνο, and excretion rate of ίη νίνο. Controlled or sustained release compositions include the composition in lipophilic depots (e.g., fatty acids, waxes, oils).

Also provided in accordance with the invention are dispersion compositions coated with polymers (e.g., poloxamers or poloxamines). Other embodiments of the compositions of the invention include dispersion forms, protective coatings, protease inhibitors or permeation enhancers for various modes of administration, including parenteral, pulmonary, nasal and oral. In one embodiment, the pharmaceutical composition is administered parenterally, paracancerously, transmucosally, transdermally, intramuscularly, intravenously, intradermally, subcutaneously, intrauterine, intraperitoneally, intraventricular, intracranial and intratumoral.

Further, as used herein, pharmaceutically acceptable carriers are known to those skilled in the art and include, but are not limited to, 0.01-0.1 M and preferably 0.05 M phosphate buffer or 0.8% saline. Additionally, such pharmaceutically acceptable carriers may be aqueous or non-aqueous solutions, suspensions and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous carriers include aqueous, aqueous-alcoholic solutions, emulsions or suspensions, including saline and buffered media.

Parenteral carriers include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, Ringer's solutions with lactose, and non-volatile oils. Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers, such as Ringer's dextrose-based replenishers, and the like. Preservatives and other additives may also be present, such as, for example, antimicrobials, antioxidants, combining agents, inert gases, etc.

Controlled and sustained release compositions include the composition in lipophilic depots (e.g., fatty acids, waxes, oils). Also provided in accordance with the invention are dispersion compositions coated with polymers (for example, poloxamers or poloxamines) and compounds associated with antibodies directed against tissue-specific receptors, ligands or antigens, or associated with ligands of tissue-specific receptors.

Other embodiments of the compositions of the invention include dispersion forms, protective coatings, protease inhibitors or penetration enhancers for various modes of administration, including parenteral, pulmonary, nasal and oral.

Compounds modified by the covalent addition of water-soluble polymers, such as polyethylene glycol, copolymers of polyethylene glycol and polypropylene glycol, carboxymethyl cellulose, dextran, polyvinyl alcohol, polyvinyl pyrrolidone or polyproline, are known to show a significantly longer half-life in blood compared to non-intravenous compounds after intravenous administration (Alibo ^ kk! Et al., 1981; No. \\

- 18 013818 Tagk et al., 1982; and Ka1ge et al., 1987). Such modifications can also increase the solubility of the compound in aqueous solution, eliminate aggregation, increase the physical and chemical stability of the compound, and significantly reduce the immunogenicity and reactivity of the compound. As a result, the desired biological activity of ίη νίνο can be achieved by the introduction of such polymer compound adducts less frequently or at lower doses compared to the unmodified compound.

In yet another embodiment, the pharmaceutical composition may be administered in a controlled release system. For example, the agent may be administered by intravenous infusion, an implantable osmotic pump, a transdermal patch, liposomes, or other modes of administration. In one embodiment, a pump can be used (see Lapdet, Kirga; 8eiop, SHS Sgb. Vek. Wyutbe. Eps. 14: 201 (1987); Wisketa 1b et al., 8itetu 88: 507 (1980); 8aibek et al., N .Up1. 1. Furniture 321: 574 (1989)). In another embodiment, polymeric materials may be used. In another embodiment, a controlled release system may be placed in close proximity to a therapeutic target, i.e. to the brain, which in this way requires only a part of the systemic dose (see, for example, Soobkop, in Mebca1 Arriysayopk οί Сop1to11eb Beeеake, Kirga, νο1. 2, pp. 115-138 (1984)). Other controlled release systems are discussed in the review of Lapdet (8c1epse 249: 1527-1533 (1990)).

The pharmaceutical composition may include the agent 8LKM separately or may, in addition, include a pharmaceutically acceptable carrier, and may be in solid or liquid form, in the form of tablets, powders, capsules, granules, solutions, suspensions, elixirs, emulsions, gels, creams or suppositories including rectal and urethral suppositories. Pharmaceutically acceptable carriers include resins, starches, sugar, cellulosic materials, and mixtures thereof. A pharmaceutical composition containing 8LCM agent may be administered to a subject, for example, by subcutaneous implantation of a granule; in one embodiment, the granule provides a controlled release of 8LCM agent over time. The composition may also be administered intravenously, intraarterially or intramuscularly by injection of a liquid composition, oral administration of a liquid or solid composition, or topical application. The introduction can also be carried out using rectal suppositories or urethral suppositories.

The pharmaceutical compositions of the invention can be obtained by known methods of dissolution, mixing, crushing or tabletting. For oral administration, 8LKM agents or their physiologically acceptable derivatives, such as salts, esters, Ν-oxides, and the like. mixed with additives conventional for this purpose, such as carriers, stabilizers or inert diluents, and are converted by conventional methods into suitable administration forms, such as tablets, coated tablets, hard or soft gelatin capsules, aqueous, alcoholic or oily solutions. Examples of suitable inert carriers are conventional tablet bases such as lactose, sucrose or corn starch in combination with binders such as acacia gum, corn starch, gelatin, with disintegrating agents such as corn starch, potato starch, alginic acid, or with glidants such as stearic acid or magnesium stearate.

Examples of suitable oily vehicles or solvents are vegetable or animal oils, such as fish oil or sunflower oil. The compositions can be obtained in the form of dry and wet granules. For parenteral administration (subcutaneous, intravenous, intraarterial or intramuscular administration), 8LKM agents or their physiologically tolerable derivatives, such as salts, esters,,-oxides, etc. they are converted into a solution, suspension or emulsion, if necessary, with substances generally accepted and suitable for this purpose, for example, solubilizers or other additives. Examples are sterile fluids, such as water and oil, with or without the addition of a surfactant and other pharmaceutically acceptable adjuvants. Examples of oils are oils of petroleum, animal, vegetable or synthetic origin, for example, peanut oil, soybean oil or mineral oil. In general, water, saline, aqueous dextrose and similar sugar solutions, and glycols such as propylene glycols or polyethylene glycols are preferred liquid carriers, especially for injectable solutions.

The preparation of pharmaceutical compositions that contain an active ingredient is well known in the art. Typically, such compositions are prepared as aerosols of a polypeptide delivered to the nasopharynx, or as injections, as either liquid solutions or suspensions; however, solid forms suitable for dissolution or suspension in liquid prior to administration can also be obtained. The composition may also be emulsified. The active therapeutic component is often mixed with excipients that are pharmaceutically acceptable and compatible with the active component. Suitable excipients are, for example, water, saline, dextrose, glycerol / ethanol or the like, or any combination thereof.

In addition, the composition may contain minor amounts of auxiliary substances, such as moisturizing or emulsifying agents, pH buffering agents, which increase the effectiveness of the active component.

The active component may be formulated as neutral pharmaceutically acceptable salt forms. Pharmaceutically acceptable salts include acid addition salts (prepared with free amino groups of a polypeptide or antibody molecule) that are prepared with

- 19 013818 inorganic acids such as, for example, hydrochloric or phosphoric acid, or organic acids such as acetic, oxalic, tartaric, mandelic, etc. Salts derived from free carboxyl groups can also be obtained from inorganic bases, such as, for example, hydroxides of sodium, potassium, ammonium, calcium or ferrous iron, and organic bases such as isopropylamine, trimethylamine, 2-ethylaminoethanol, histidine, procaine and the like.

For topical application to the surface of the body, for example, creams, gels, drops, etc., 8AKM agents or their physiologically acceptable derivatives, such as salts, esters, Ν-oxides, etc., are used. they are prepared and applied in the form of solutions, suspensions or emulsions in a physiologically acceptable diluent with or without a pharmaceutical carrier.

In another embodiment, the active compound can be delivered in a vesicle, in particular in a liposome (see Lapdeg, 8c1epse 249: 1527-1533 (1990); Tgea1 et al., W рокrokotek t Ne Tnegaru есί Shesyöik | Keake apb Sapseg, Lorex Veget apb P1b1eg (ebk), Ykk, No. \ ν Wagk, pp. 353-365 (1989); Lorech-Wegeyet, ibid., pp. 317-327; see ibid.).

For use in medicine, salts of 8AKM are used, which are pharmaceutically acceptable salts. However, other salts may be useful in preparing the compounds of the invention or their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of the invention include acid addition salts, which, for example, can be prepared by mixing a solution of the compound of the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, methanesulfonic acid, fumaric acid, maleic acid, succinic acid , acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.

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

Detailed description of the experimental part

Example 1. The affinity of binding.

The binding affinity was determined as described by He e1 a1. Eig. 1. Meb. Oh. (2002), 619-634; and as described by MikNetsey e1 a1. Hepoyoysa (1996), 26, 117-122.

GO Molecular weight Structure K1 (nM) KVA (%) one Οι ₇ Η _Ι3 Ρ ₅ Ν ₂ Ο ₅ 420.29 3,410,56 17.6 2 C1 ₇ H ₁₀ 1HO ₅ 474.26 ° ^Ρ γ ^ Υ ' ^Ρ 1.37 ± 0.34 13.3. 3 C | ₇ N | 2RbMO5 438.28 Χυ, Χ 11.3 ± 1.1 3,1 4 Spnryudsh 418.3 6,010,7 5.8 5 С17Н ₁₃ Р ₅ К ₂ О5 420.29 Waiting 3,210,3 10.9 6 C1 ₇ H ₁₂ P ₆ S ₂ O ₅ 438.28 9,110.6 3.4 7 SpNvSShdMzOz 436.74 wodge ” 4,910.3 9.1 8 C1 ₇ H ₁₃ C1P ₄ MO ₅ 436.74 10,312,0 4.3 nine C _{| 7} H ₁₃ C12P ₃ MO5 453.2 1,010,09 20,2 10 SRNiRdMoz 402.3 ΧυχΛ ³ 3,410.34 5.9 eleven C ₁₇ H ₁₂ P ₃ M ₂ O ₅ 438.28 10,312,0 5,0 12 C1 ₇ H ₁₀ C1P ₇ £ W 490.71 ΝΑ

- 20 013818

Experimental techniques

Animals. Immature males of 8gadie-OaMeu rats weighing from 90 to 100 g were purchased from Nag1ap Βίο5С1Спес5 ДпФапароШ, ΓΝ). The animals were maintained on a 12-hour day-night cycle with food and water, available in the mode for pleasure. The protocol using the animal was reviewed and approved by the Committee of the Institute for the Care and Use of Laboratory Animals.

Study plan. Rats were randomly assigned to treatment groups. One day before the start of pharmacotherapy, the animals were separately removed from the cage, weighed and anesthetized with an intraperitoneal dose of ketamine / xylazine (87/13 mg / kg; approximately 1 ml per kg of body weight). After anesthetization (i.e., no reaction to a toe injection), the animal's ears were labeled for identification purposes. The animals were then placed on a sterile pillow and their abdominal cavity and scrotum were washed with betadine and 70% ethyl alcohol. The testicles were removed through the midline scrotum incision, and a sterile suture was used to connect the supratesticular tissue before each testicle was surgically removed. The surgical wound site was closed with sterile stainless steel wound clamps and the wound site was washed with betadine. The animals were allowed to come to life on a sterile pillow (until they could stand), and then returned to their cage.

Twenty-four hours later, the animals were re-anesthetized with ketamine / xylazine and the A1xe1 osmotic pump (s) (model 2002) was placed subcutaneously in the scapular region. In this case, the scapular region was shaved and cleaned (betadine and ethanol) and a small incision was made (1 cm) using a sterile scalpel. An osmotic pump was then inserted and the wound was clamped with a sterile stainless steel wound clamp. Animals were given the opportunity to come to their senses and returned to their cages. The osmotic pumps contained an appropriate therapeutic agent dissolved in polyethylene glycol 300 (PEC300). The osmotic pumps were filled with the appropriate solution the day before implantation. Animals were tested daily for symptoms of acute toxicity to pharmacotherapy (e.g. lethargy, tousled hair).

After 14 days of pharmacotherapy, the rats were anesthetized with ketamine / xylazine. The animals were then killed by bleeding under anesthesia. Blood samples were collected by venipuncture of the abdominal aorta and subjected to a complete blood count. Part of the blood was placed in a separate tube, centrifuged at 12000 d for 1 min and the plasma layer was removed and frozen at a temperature of -20 ° C. The ventral prostate, seminal vesicles, anus muscle, liver, kidney, spleen, lungs and heart were removed, cleaned from peripheral tissue, weighed and placed in vessels containing 10% neutral buffered formalin. The stored tissues were sent to OTx, Oche for histopathological analysis.

For data analysis, the weight of all organs was normalized with respect to body weight and analyzed for statistically significant differences using one-factor ANVA.

The weights of the prostate and seminal vesicles were used as indices for assessing androgenic activity, and the weight of the anus lifting muscle was used to assess anabolic activity.

results

Compounds 1 and 2.

The androgenic and anabolic activity of compounds 1 and 2 were studied in a model of castrated rats after 14 days after administration. Intact controls (uncastrated, untreated) and castrated controls (castrated, untreated) were used as control groups.

As shown in the table. 1 and FIG. 1, the weight of the prostate, seminal vesicles, and anus lifting muscle in castrated rats decreased significantly due to cessation of endogenous androgen production. Treatment with doses of 1 mg / day of compounds 1 and 2 led to an increase in the weights of the prostate, seminal vesicles and anus muscle. Compounds 1 and 2 showed a lower potency and inherent activity in increasing the weights of the prostate and seminal vesicles, but greater potency and inherent activity in increasing the weight of the anus lifting muscle. In particular, compound 1 was able to maintain the weight of the lifting muscle of the anus in castrated animals at the same level as in intact animals. Thus, compound 1 is a potent non-steroidal anabolic agent. This was a significant step compared to the previous compounds, in that this compound selectively stimulates muscle growth and other anabolic effects with less effect on the prostate and seminal vesicles. This can be especially important for aging men with problems associated with the development or progression of prostate cancer.

Table 1

Intact Neutered ny Connection 1 (pump) Compound 1 (daily injection) Compound 2 (daily injection) Prostate 100 ± 14.3 6.2 ± 2.5 40.3 + 10.0 33.1 ± 8.5 7.2 ± 1.4 Seminal vesicles 101 ± 26.8 8.1 ± 1.8 30.9 ± 5.7 23.6 ± 8.8 7.2 ± 0.9 Anus lifting muscle 102 ± 8.1 40.9 ± 9.4 122.5 ± 10.4 112.8 ± 9.4 55.83 ± 2.84

- 21 013818 * The comparison group, which is treated with compound 1 1 mg / day through an osmotic pump.

Compound 7.

The androgenic and anabolic activity of compound 7 was investigated in a model of castrated rats after 14 days of administration. Intact controls (uncastrated, untreated) and castrated controls (castrated, untreated) were used as control groups. Rats were castrated at day 0, after which they received daily subcutaneous doses (0.05 to 3 mg / day) of compound 7 in a DMSO / PEG vehicle. Rats were euthanized on the final day, and then the wet weights of androgenic (prostate and seminal vesicles) and anabolic (anus lifting muscle) organs were determined.

As shown in FIG. 2, treatment with increasing doses of compound 7 led to an increase in the prostate, seminal vesicles, and anus anus muscle in a dose-dependent manner. Compound 7 showed a lower potency and inherent activity in increasing the weight of the prostate and seminal vesicle, but a greater potency and inherent activity in increasing the weight of the anus lifting muscle.

One skilled in the art can appreciate that the present invention is not limited to what is specifically shown and described above. On the contrary, the scope of the invention is defined by the following claims.

Claims (29)

CLAIM 1. The compound is a selective androgen receptor modulator (8ABM), represented by the structure of formula IV wherein X is O; C represents O or 8; T represents OH; B represents (C1C ₆₎ alkyl, halo (C1C ₆₎ alkyl, dihalo (C1C ₆₎ alkyl, trihalo (C1C ₆₎ alkyl, CH ₂ F, CHP _2, CP _3, CP ₂ CP ₃ phenyl, halogen, (C ₂ -C ₆ ) alkenyl or OH; B1 is CH3; Bz represents P, C1, Br, I, NW, NWO2, SOW, COOH, SOYANV, SRz, 8p (B) s; Ζ represents NW2, NW, SOW, COOH or UNION; O is (C1- _C6 ) alkyl, halogen, CP ₃ , CJ, C (B) ₃ , 8p (B) ₃ , I (B) ₂ , YANOSOSN ₃ , YANOSOSR ₃ , YANSOV, YANSOYANV, YANSOOV, OSOYANV, SOYANV, YANS8CH3, YANS8SR3, YANS8V, YAN8O2CH3, YAN8O2V, OH, OV, SOV, OSOV, O8O2V, 8O2V, 8V; p 'is an integer having a value of 1-4; and t is an integer having a value of 1-3, and / or its isomer, a pharmaceutically acceptable salt, hydrate or I-oxide, or any combination thereof. 2. The compound according to claim 1, represented by the structure of formula 1 and / or its isomer, a pharmaceutically acceptable salt, hydrate or I-oxide, or any combination thereof. 3. The compound according to claim 1, represented by the structure of formula 2 and / or its isomer, a pharmaceutically acceptable salt, hydrate or I-oxide or any combination thereof. 4. The compound according to claim 1, represented by the structure of formula 3 - 22 013818 and / or its isomer, pharmaceutically acceptable salt, hydrate or Ν-oxide, or any combination thereof. 5. The compound represented by the structure of formula 4 and / or its isomer, a pharmaceutically acceptable salt, hydrate or Ν-oxide or any combination thereof. 6. The compound according to claim 1, represented by the structure of formula 5 and / or its isomer, a pharmaceutically acceptable salt, hydrate or Ν-oxide or any combination thereof. 7. The compound according to claim 1, represented by the structure of formula 7 and / or its isomer, a pharmaceutically acceptable salt, hydrate or Ν-oxide or any combination thereof. 8. The compound according to claim 1, represented by the structure of formula 11 and / or its isomer, a pharmaceutically acceptable salt, hydrate or Ν-oxide or any combination thereof. 9. The compound according to claim 1, represented by the structure of formula 12 and / or its isomer, a pharmaceutically acceptable salt, hydrate or Ν-oxide or any combination thereof. 10. The compound is a selective androgen receptor modulator (8AKM), represented by the structure of formula 6 and / or its isomer, a pharmaceutically acceptable salt, hydrate or Ν-oxide, or any combination thereof. 11. The compound is a selective androgen receptor modulator (8AKM), represented by the structure of formula 8 and / or its isomer, a pharmaceutically acceptable salt, hydrate or Ν-oxide, or any combination thereof. 12. The compound is a selective androgen receptor modulator (8AKM) represented by the structure of formula 9 and / or its isomer, a pharmaceutically acceptable salt, hydrate or Ν-oxide or any combination thereof - 23 013818 tion. 13. The compound is a selective androgen receptor modulator according to claims 1-12, wherein said compound is an androgen receptor antagonist. 14. The compound is a selective androgen receptor modulator according to claims 1-12, wherein said compound is an androgen receptor agonist. 15. The compound is a selective androgen receptor modulator according to claims 1-12, wherein said compound binds irreversibly to the androgen receptor. 16. The compound is a selective androgen receptor modulator according to claims 1-12, wherein said compound binds reversibly to the androgen receptor. 17. The composition containing the compound is a selective modulator of the androgen receptor according to claims 112 and / or its isomer, a pharmaceutically acceptable salt, hydrate or Ν-oxide or any combination thereof; and a suitable carrier or diluent. 18. A method for binding a compound - a selective modulator of androgen receptor to an androgen receptor, comprising the step of contacting the androgen receptor with a compound - a selective modulator of androgen receptor according to claims 1-12 and / or its isomer, a pharmaceutically acceptable salt, hydrate or Ν-oxide or any of them a combination, in an amount effective to bind a compound, a selective androgen receptor modulator, to an androgen receptor. 19. The use of a compound - a selective modulator of the androgen receptor according to claims 1-12 and / or its isomer, a pharmaceutically acceptable salt, hydrate or Ν-oxide or any combination thereof for the manufacture of a medicament for the suppression of spermatogenesis in a subject, where the subject's androgen receptor is brought into contact with said compound, a selective androgen receptor modulator, in an amount effective to suppress sperm formation in said subject. 20. The use of the compound - a selective modulator of the androgen receptor according to claims 1-12 and / or its isomer, a pharmaceutically acceptable salt, hydrate or Ν-oxide or any combination thereof for the manufacture of a contraceptive drug in a male subject, wherein said subject is administered the compound is a selective androgen receptor modulator in an amount effective for contraception in said male subject. 21. The use of the compound - a selective modulator of the androgen receptor according to claims 1-12 and / or its isomer, a pharmaceutically acceptable salt, hydrate or Ν-oxide or any combination thereof for the manufacture of a medicament for hormone therapy, wherein the subject’s androgen receptor is contacted with the specified compound is a selective modulator of the androgen receptor in an amount effective to effect a change in the androgen-dependent state of the specified subject. 22. The use of the compound - a selective modulator of the androgen receptor according to claims 1-12 and / or its isomer, a pharmaceutically acceptable salt, hydrate or Ν-oxide, or any combination thereof for the manufacture of a medicament for hormone replacement therapy, wherein the subject’s androgen receptor is contacted with the compound is a selective androgen receptor modulator in an amount effective to effect a change in the androgen-dependent state of the specified subject. 23. The use of compounds - selective modulator of the androgen receptor according to claims 1-12 and / or its isomer, pharmaceutically acceptable salt, hydrate or Ν-oxide or any combination thereof for the manufacture of a medicinal product for the treatment of a subject having a hormone-dependent state, where the specified subject is administered said compound is a selective androgen receptor modulator in an amount effective to effect a change in the androgen-dependent state of said subject. 24. The use of compounds - selective modulator of the androgen receptor according to claims 1-12 and / or its isomer, pharmaceutically acceptable salt, hydrate or Ν-oxide or any combination thereof for the manufacture of a medicament for the treatment of a subject suffering from prostate cancer, where the specified subject administering said compound, a selective androgen receptor modulator, in an amount effective to treat prostate cancer in said subject. 25. The use of the compound - a selective modulator of the androgen receptor according to claims 1-12 and / or its isomer, a pharmaceutically acceptable salt, hydrate or Ν-oxide, or any combination thereof for the manufacture of a medicament for the prevention of prostate cancer in a subject where the specified subject is administered the compound is a selective androgen receptor modulator in an amount effective to prevent prostate cancer in said subject. 26. Use of a selective androgen receptor modulator compound according to claims 1-12 and / or its isomer, pharmaceutically acceptable salt, hydrate or Ν-oxide or any combination thereof for the manufacture of a medicament for delaying the development of prostate cancer in a subject suffering from prostate cancer , where the specified subject is administered the specified compound is a selective androgen receptor modulator in an amount effective to delay the development of prostate cancer in the specified subject. 27. The use of a compound - selective androgen receptor modulator according to claims 1-12 and / or its isomer, a pharmaceutically acceptable salt, hydrate or Ν-oxide or any combination thereof for the manufacture of a medicament for the prevention of recurrence of prostate cancer in a subject suffering from prostate cancer where the specified subject is administered the specified compound is a selective modulator re - 24 013818 androgen receptor in an amount effective to prevent recurrence of prostate cancer in the specified subject. 28. The use of a compound - selective androgen receptor modulator according to claims 1-12 and / or its isomer, pharmaceutically acceptable salt, hydrate or Ν-oxide or any combination thereof for the manufacture of a medicament for the treatment of recurrence of prostate cancer in a subject suffering from prostate cancer , where the specified subject is administered the specified compound is a selective androgen receptor modulator in an amount effective to treat recurrence of prostate cancer in the specified subject. 29. The use of a compound - selective androgen receptor modulator according to claims 1-12 and / or its isomer, a pharmaceutically acceptable salt, hydrate or Ν-oxide or any combination thereof for the manufacture of a medicament for the treatment of dry eyes in a subject suffering from dry conditions eye, where the specified subject is administered the specified compound is a selective androgen receptor modulator in an amount effective to treat dry eye in the specified subject.