TW200304806A - Irreversible selective androgen receptor modulators and methods of use thereof - Google Patents

Abstract

In one embodiment, this invention provides a class of androgen receptor targetmg agents (ARTA). The agents define a new subclass of compounds, which are selective androgen receptor modulators (SARM). The SARM compounds have unexpected antiandrogenic activity of a nonsteroidal ligand for the androgen receptor. In one embodiment, the SARM compounds bind irreversibly to the androgen receptor. In another embodiment, the SARM compounds are androgen receptor antagonists, which bind irreversibly to the androgen receptor. In another embodiment, the SARM compounds are alkylating agents. 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; g) decreasing the incidence of, halting or causing a regression of prostate cancer; and/or h) inducing apoptosis in a cancer cell.

Description

(i) (i) 200304806 发明 Description of the invention (The description of the invention should state the technical field, prior art, content, implementation, and drawings of the invention. Brief description of the government's rights and interests. The invention is based on the National Cancer Research , Under the grant certificate number R29 CA068096 granted by the National Institutes of Health, and under the grant certificate number R15 HD35329 granted by the National Institute of Child Health and Human Development, National Institutes of Health, in whole or in part in the government Implementation with support. The government may have certain rights in the invention. TECHNICAL FIELD The present invention relates to an androgen receptor-targeted agent (ARTA), which confirms the antiandrogenic activity of a nonsteroidal ligand to the androgen receptor, and / or that it irreversibly binds to the androgen receptor. These agents are defined as the sub-group of compounds, which are selective androgen receptor modulators (sarms) that can be used; a) male contraception; b) treatment of a variety of hormone-related symptoms, such as males in aging males Symptoms associated with a decrease in hormones (ADAM); c) Treatment of symptoms associated with androgen decrease (ADIF) in female 2; d) treatment and / or prevention of acute and / or chronic muscle wasting symptoms; e) prevention and / or Treatment of dry eye symptoms and phantom oral androgen replacement therapy; g) reduce the incidence of prostate cancer, stop, or cause it to recover; and / or cause cell death in cancer cells. The fine androgen receptor (" AR ") is a ligand-activated transcription-regulating protein. Its" :: and its activity with endogenous androgens "mediates the sexual development and function of male sex hormones-generally called males. Androgenic hormones. Androgens are produced by testosterone and adrenal cortex in the steroid test body, or may be 0%. Androgen steroids play a role in many physiological processes.

(2) important roles, including the development and maintenance of male sexual characteristics, such as muscle and bone mass, prostate growth, spermatogenesis, and male hair style (Matsmnoto,

Endocrinol Met. Clin. N. Am. 23: 857-75 (1994)). Endogenous steroid androgens include testosterone and dihydrotestosterone (" DHT "). Testosterone is the main steroid secreted by testis' and is the main circulating androgen found in male plasma. Testosterone is 5 alpha in many peripheral tissues. -Reductase is converted to DHT. Therefore, DH D is considered to act as an intracellular mediator for most androgenic effects (Zhou et al., Mole. Endocrinol. 9: 208-18 (1995)). Other steroid androgens Includes esters of fluorenone, such as cypionate, propionate, phenylpropionate, cyclopentylpropionate, isohexanoate, heptanoate and caprate, and others Synthetic androgens, such as 7-methyl-normethylone ("MENT) (Sundaram et al.," 7 α-methyl-normethylone (MENT): the most appropriate androgen for male contraception, Ann. Med., 25 · 199-205 (1993) ('' Sundaram ,,)). Because AR is related to male sexual development and function, AR is a possible target for achieving male contraceptive or other hormone replacement therapies. 'Social alertness' has stimulated many studies on contraception. Contraception is a difficult topic in any case. It is full of cultural and social stigma, religion, and most importantly, important health concerns. When this topic focuses on male contraception: this condition only Will worsen. "In the history of the effectiveness of appropriate contraceptive devices, society has always expected women to be responsible for the contraception and its consequences. Although concerns over sexually transmitted diseases have made men more vocal / Wang Si needs the need to develop safe and responsible habits, but women still take the lead in contraceptive options. Women have many choices, from temporary mechanisms to mechanical devices, such as sponges and diaphragms, 200304806 (3) To temporary chemical devices, such as spermicides. Women also have more permanent options, such as physical devices, including IUD and cervical cap, and more permanent chemical treatments, such as birth control pills And subcutaneous implants. However, the only options available to men to date include condom use and vasectomy. However, condoms make Use is not preferred by many men because of reduced sexual sensitivity, spontaneous interruption of sex, and the significant possibility of pregnancy due to rupture or misuse. Vasectomy is also not preferred. If more convenient fertility control is available Methods can be used by men, especially long-term methods, which do not require preparatory activities just before sex. This method can significantly increase the possibility that men are more responsible for contraception. In this regard, male sex steroids (such as fluorenone And its derivatives) have been shown to be particularly promising due to the combined gonadotropin-inhibition and androgen-substituting properties of these compounds (Stdnberger et al., "Chronic administration of fluorenone enanthate" for The role of sperm production and plasma radon, maturation hormone, and luteinizing hormone content: possible. Male radon contraceptives, fertility = preliminary assessment of infertility 28: 1320_28 (1977)). Chronic administration of high-dose ketones will completely abolish sperm production (absence of sperm) or reduce it to a very low content (too few sperm). 0 is the peak production | Incorrectly understood. However, a recent report by the World Health Organization has shown that intramuscular injection of bi-heptanoic acid vinegar every week can result in azoospermia or severe hypospermia (3 million sperm) and infertility in 98% of men treated. ", (The World Health Organization Task Force's Concern for Men's Manner and Regulation, π 睪 ketone trap M ,, > j Contraceptive effect of donor sperm and too little sperm. 65: 821-29 (1996)) 〇 (4) A variety of acetophenones have been developed, which are in the muscle /, so it will cause larger males to go away, and the posterior system will be absorbed more slowly by F / double I. The ketones are the most Widely used by users. Although from the viewpoint of establishing male contraception ... This is a kind of ester neutrality, fluorenone enanthate is already a viable point for hormonal agents. The burden must be injected weekly, and kidney, '隹 It has several deficiencies J 夂 It is connected to the intramuscular physiology tip + content of fluorenone (Wu, " 睪 g with heptanoic acid \ after shooting' has a superb effect: a fine ride from a multicenter contraceptive study Entry in normal males: 626-36 (1996)). ", Public test", Fertility and Infertility 65 # _ Alcohol anti-androgens are non-steroidal androgenic, and have been specifically designed to combine AR and act as androgens (such as steroids such as bisheptin (eg, cyproterone acetate)) or as anti-androgenic For many years, it has been used clinically (Wul988). Although: niche, it has been known to be used clinically for hormone-dependent prostate gland, and has not been reported. Therefore, regarding male contraceptives, injections on steroids. ^ Prostate cancer is the second most common diagnosis of hundreds of thousands of new cases diagnosed in the itching year in men in the United States, with more than sixty percent of newly diagnosed cases now. Fortunately, The previous department has been progressed, "There is a cure for sores, and the prognosis of anxiety. The pathology is a way to deal with this problem. It is a kind of treatment for this problem. Wan Fei, who has gone through the advanced inspection procedures earlier than before." Lang Shiyou, and follow up, to reduce the number of patients with adenocarcinoma. However, the prevention of forefront face breeding is the development of anti-cancer drugs. All males over 50 years old A ^, Ding 1/2 have a potential ascending type of prostate cancer, which, J Xiao / tongue has become a life-threatening preclinical: two cancer form. The frequency of potential prostate tumors has been shown to increase substantially with the maternal life span of ten years, ranging from 50 years (5.3-M%) to 90 years (40-80%). (5) (5) 200304806 The number of people with potential prostate cancer is the same across all cultures, ethnic groups and races, but the frequency of clinically strong cancers is not significantly different. This implies that environmental factors = can activate the potential prostate Cancer 丨 plays a role. Therefore, the development of treatment and prevention strategies against prostate cancer can have the greatest overall impact on both the medicine and the economy against prostate cancer. Osteoporosis is a systemic osteoporotic disease, characterized by low bone mass and bone tissue degradation, which results in increased bone fragility and susceptibility to fractures. In the United States, this symptom affects more than 25 million people and causes fractures in more than L3 million people each year, including vertebrae of 50,000 people, bodies of 250,000 people, and, _ A man's wrist is broken. Hip fractures are the most serious result of osteoporosis. Among them, 5-20% of patients die before death, and more than 50% of survivors become disabled. The elderly are at the greatest risk of osteoporosis, and the problem will increase dramatically as the population ages. Fractures worldwide are forecast to triple in the next 60 years. One study estimated that by 2050 there will be… million human body fractures worldwide. Women are at greater risk of osteoporosis than men. Women will experience the sharp acceleration of bone loss during the five-year period after menopause. Other factors that increase this risk include smoking, alcohol abuse, sedentary lifestyles, and money intake. But 1 osteoporosis also often occurs in men. It is well established that bone mineral density in men decreases with age. The decrease in bone mineral content and density is related to the decrease in bone strength. JL is susceptible to fractures. In non-reproductive tissues, the molecular mechanism of pro-multi-organizational effects of sex hormones is just beginning to be understood, 200304806

But it is clear that the physiological concentrations of androgens and estrogens play an important role in maintaining the stability of bones and the like throughout the life cycle. Therefore, when androgen or estrogen loss occurs, there is an incremental increase in the rate of bone modification, which will skew the balance between wear and formation to be beneficial to wear and tear ', which will promote the overall loss of bone mass. In men, the natural decline of sex hormones during the febrile phase (direct decline in androgens, and lower levels of estrogen, due to the aromatization of the androgen's periphery) is accompanied by bone fragility. This effect is also found in men who have had their testicles circumcised. Decreased androgen in aging men (ADAM) refers to a gradual decrease in androgen production, usually in men after middle age. This symptom cluster is characterized by changes in physical and intellectual range, which are interrelated with the androgen environment and can be corrected by manipulation of the androgen environment. The biochemical characteristics of ADAM are not only a decrease in serum androgens, but also a decrease in other hormones such as growth hormone, melatonin, and dehydroepiandrosterone. Clinical phenomena include fatigue, depression, hyposexuality, sexual dysfunction, erectile dysfunction, hypogonadism, osteoporosis, hair loss, obesity, oligosarcoma, bone deficiency, benign prostatic hyperplasia, anemia, mood and cognition Changes and prostate cancer. Androgen deficiency (ADIF) in women refers to a variety of hormone-related symptoms, including those commonly found in middle-aged women. This desire group is characterized by sexual dysfunction, hyposexuality, hypogonadism, oligosarcoma, bone, lack, osteoporosis, cognitive and mood changes, anemia, depression, hair loss, obesity, uterus Endometrium, tissue ectopic formation, breast cancer, uterine cancer and ovarian cancer. (7) 200304806 Muscle consumption refers to the progressive loss of muscle mass, and / or weakening and degeneration ', including the control of moving skeletal or voluntary muscles (cardiomyopathy), and smooth muscle. Chronic muscle wasting (ie, lasting for a long period of time) is characterized by muscle loss and muscle weakening and degeneration. The loss of meat mass during muscle consumption can be characterized by muscle protein breakdown or white matter degradation ', protein synthesis due to an unusually high rate of protein degradation, or a combination of both. Protein Degradation Due to a high degree of protein degradation or a low degree of protein synthesis, it leads to a decrease in muscle mass' and muscle consumption. Symptoms of chronic, neuropathic, hereditary, or infectious pathology. It includes muscular dystrophy such as Duchenne muscular camp tonic malnutrition; muscle atrophy such as posterior gray matter muscle F; cachexia such as cardiac cachexia, AIDS cachexia and cancer malnutrition, leprosy, diabetes, kidney disease, chronic obstruction? Cancer , End-stage renal failure, emphysema, osteomalacia, HIV-induced cardiomyopathy. In addition, 'other conditions and symptoms are linked to and can be consumed. It includes chronic lower back pain, progressive aging, CNS injury, peripheral nerve contusion, spinal tap injury, chemical Caismen system (CNS) injury, peripheral nerve injury, spinal cord injury, burns when the limbs are fixed The abolitions used to regulate long-term hospitalization due to symptoms or injuries, and alcoholism. Without muscle loss, it can have dire health effects. For example, changes that occur in the intervening period may lead to a weakened physical condition, the gradual increase of muscles, and the control of the heart. A chronic tide of meat quality. Eggs, unusually low resolution, whether caused, are associated with, disease or malnutrition and cachexia of muscular 3 atrophy (PPMA), disease (COPD), infection, AIDS and can cause the central nervous system of the muscles Injuries, central neurochemical injuries, the use of 'because the disease is consumed if the muscle exhaustion period is maintained' are harmful to 200304806 (8) to the health of the individual, resulting in an increase in the susceptibility to infection 'adverse manifestations and susceptibility to injury. On both the basic science and clinical levels, there is an urgent need for new and innovative research approaches to develop compounds that can be used for a) male contraception; b) treatment of multiple hormone-related symptoms, such as androgen decline in aging men (ADAM) Associated symptoms, such as fatigue, depression, hyposexuality, sexual dysfunction, erectile dysfunction, hypogonadism, osteoporosis, hair loss, anemia, obesity, oligosarcoma, osteoporosis, osteoporosis, benign prostate Hyperplasia, changes in mood and cognition, and prostate cancer; c) Treatment of symptoms associated with ADIF, such as sexual dysfunction, hyposexuality, hypogonadism, oligomuscular deficiency, osteoporosis, osteoporosis, cognitive And mood changes, depression, anemia, hair loss, obesity, endometrial tissue formation, breast cancer, uterine cancer, and ovarian cancer; d) treatment and / or prevention of acute and / or chronic muscle wasting symptoms; e) Prevent and / or treat dry eye symptoms; f) oral androgen replacement therapy; g) reduce the incidence of prostate cancer 'to stop it or cause it to recover Cause; and / or h) cause zero cell holes in cancer cells. SUMMARY OF THE INVENTION In a specific embodiment, the present invention provides an androgen receptor-targeted agent (ARTA). This agent defines a novel subgroup of compounds that are selective androgen receptor modulators (SARMs). This SARM compound has a surprising anti-androgenic activity of a non-steroidal ligand to the androgen receptor. In the private case, "SARM compounds are irreversibly bound to androgen fa." In another specific embodiment, the SARM compound is an androgen (9) (9) 200304806 hormone party antagonist, which irreversibly binds one item and is prepared to the androgen receptor. In another example, the SARM compound is a "f" compound and a base-forming agent. SARM mouth, 疋, alone or as a composition, can be used for a) stomach %%, less insertion, private owner, a) male contraception; b) treatment of symptoms / such as androgen decline in aging men (: D: M) related symptoms, such as fatigue, depression, hyposexuality, premature sexual function, erectile dysfunction, hypogonadism, osteoporosis, hair loss, anemia, obesity, oligosclerosis, Osteoporosis, osteoporosis, benign spleen hyperplasia, mood and cognitive changes, and prostate cancer; c) treatment of symptoms associated with androgen decline (ADIF) in women, such as sexual dysfunction, hyposexuality, Hypogonadism, oligosarcoma, osteopenia, osteoporosis, cognitive and mood changes, depression, anemia, hair fall, obesity, endometrial tissue formation, breast cancer, uterine cancer and ovarian cancer; d) treatment and / or prevention of acute and / or chronic muscle wasting symptoms; e) prevention and / or treatment of dry eye symptoms; f) oral androgen replacement therapy; g) reducing the incidence of prostate cancer, stopping it or causing it recovery ; And / or h) cause cell death in cancer cells. In a specific embodiment, the present invention provides a selective androgen receptor modulator (SARM) compound, which is represented by the structure of Formula I:

X is a bond, 0, CH2, NH, s, Se, PR, NO, or NR; G is 0 or S; 200304806

(ίο) T is OH, OR, -NHCOCH3 or NHCOR; R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, halogen, dilute Group or OH; heart is CH3, CH2F, CHF2, CF3, CH2CH3 or CF2CF3; R2 is F, a, Br, I, ch3, CF3, OH, CN, no2, nhcoch3, NHCOCF3, NHCOR, alkyl, aralkyl , OR, NH2, NHR, NR〗, SR; R3 is F, Cl, Br, I, CN, N02, COR, COOH, CONHR, CF3, SnR3, or R3 and the benzene ring to which it is connected form a fused ring The system is represented by the following structure:

h

YYZ is N02, CN, COR, COOH, or CONHR; Y is CF3, F, Br, Cl, I, CN, or SnR3; Q is SCN, NCS, OCN, or NCO; n is an integer from 1-4; and m is 1 An integer of -3. In another specific embodiment, the present invention provides analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, pharmaceutical products, hydrates or N-oxides of compounds of formula I, or Any combination. In a specific embodiment, G in compound I is 0. In another specific embodiment, X in compound I is zero. In another specific embodiment -17- 200304806

(11) τ in Compound I is OH. In another embodiment, R! In the compound is CH3. In another embodiment, z in the compound I is. In another embodiment, z in compound I is CN. In another embodiment, γ in the compound is Cf3. In another embodiment, Q in compound I is NCS. In another embodiment, Q in compound I is in the para position. In another embodiment, Z in compound I is in the para position. In another embodiment, Y in the compound is in the meta position. In another specific embodiment, G in compound j is 0 'T is 0H, Ri is CH3, X is 0, Z is N02, Y is CF3, and Q is NCS. In another specific embodiment, the present invention provides a selective androgen receptor modulator (SARM) compound, which is represented by the structure of formula π:

Where X is a bond, 0, CH2, NH, S, Se, PR, N0 or NR; G is 0 or S; heart is CH3, CH2F, chf2, cf3, 012, 13 or CF2CF3; T is OH, OR, -NHCOCH3 or NHCOR; R is alkyl, i-alkyl, dihaloalkyl, trialkyl, CH2F, CHF2, CF3, CF2CF3 'aryl, phenyl, halogen, fluorenyl, or OH; A is Ring, selected from:

-18- 200304806

(12) B is a ring selected from:

Where A and B cannot be benzene rings at the same time; Z is N02, CN, COOH, COR, NHCOR or CONHR; Y is CF3, F, I, Br *, Cl, CN, CR3 or SnR3;

Qi is NCS, SCN, NCO or OCN;

Q2 is hydrogen, alkyl, halogen, CF3, CN, CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR, NHS02CH3, NHS02R, OR, COR, OCOR, OS02R , S02R, SR,

Q3 and Q4 are independently hydrogen, alkyl, halogen, CF3, CN-, CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR, NHS02CH3, NHS02R, OR , COR, OCOR, 0S02R, S02R or SR;

Wi is 0, NH, NR, N, 0, or S; and W2 is N or NO. 19- 200304806

(13) In another specific embodiment, the present invention provides analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, pharmaceutical products, hydrates or N-oxides of compounds of formula II , Or any combination thereof. In a specific embodiment, G in compound II is 0. In another specific embodiment, X in compound II is zero. In another embodiment, T in compound II is OH. In another embodiment, & in Compound II is ch3. In another embodiment, z in compound II is no2. In another embodiment, Z in compound II is CN. In another embodiment, Y in compound II is CF3. In another embodiment, Qi in compound II is NCS. In another embodiment, Qi in compound II is in the para position. In another embodiment, Z in compound II is in the para position. In another embodiment, Y in compound II is in the meta position. In another embodiment, G in compound II is O, T is OH, R! Is CH3, X is 0, Z is N02, Y is CF3, and Qi is NCS. In another embodiment In the present invention, a selective androgen receptor modulator (SARM) compound is provided, which is represented by the structure of formula III: 7

Where X is a bond, 0, CH2, NH, S, Se, PR, NO or NR; G is 0 or S; T is OH, OR, -NHCOCH3 or NHCOR; 200304806

(14) Z is N02, CN, COOH, COR, NHCOR or CONHR; Y is CF3, F, I, Bi :, Cl, CN, CR3 or SnR3; Q is SCN, NCS, OCN or NCO;

R is alkyl, A alkyl, dialkyl, trialkyl, CH2F, chf2, cf3, cf2cf3, aryl, phenyl, halogen, alkenyl, or oh: and CH3, CH2F, CHF2, CF3 , CH2CH3, or CF2CF3. In another specific embodiment, the present invention provides an analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate or N-oxide of a compound of formula III, or Any combination. In a specific embodiment, G in compound III is 0. In another specific embodiment, X in compound III is zero. In another embodiment, T in compound III is OH. In another embodiment, Ri in Compound III is CH3. In another embodiment, Z in compound III is N02. In another embodiment, Z in compound III is CN. In another embodiment, Y in compound m is CF3. In another embodiment, Q in compound III is NCS. In another embodiment, Q in compound III is in the para position. In another embodiment, Z in compound III is in the para position. In another embodiment, Y in compound III is in the meta position. In another embodiment, G in compound III is 0, T is OH, Ri is CH3, X is 0, Z is N02, Y is CF3, and Q is NCS. In another specific embodiment, the present invention provides a selective androgen receptor modulator (SARM) compound, which is represented by the structure of formula IV: 200304806 (15)

IV where X is a bond, 0, CH2, NH, S, Se, PR, NO or NR; Z is N02, CN, COOH, COR, NHCOR or CONHR; Y is CF3, F, I, Br, Cl, CN, CR3 or SnR3; Q is SCN, NCS, OCN or NCO; and R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, Halogen, feminine or OH. In another specific embodiment, the present invention provides analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, pharmaceutical products, hydrates or N_oxides of compounds of formula IV, or Any combination. In a specific embodiment, X in compound IV is Q. In another specific embodiment, z in compound iv is no2. In another embodiment, Z in compound IV is CN. In another embodiment, Y in compound IV is CF3. In another embodiment, Q in compound IV is NCS. In another specific embodiment, the present invention provides a selective androgen receptor modulator (SARM) compound, represented by the structure of Formula V, and / or its analogs, derivatives, isomers, metabolites, A pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, or any combination. -22- 200304806 (16)

NCS

In a specific embodiment, any SARM compound of formula IΛΓ is an androgen receptor antagonist. In another embodiment, any SARM compound of Formula I-V irreversibly binds to an androgen receptor. In another specific embodiment, any of the SARM compounds of Formula I-V is an androgen receptor antagonist, which is irreversibly bound to the androgen receptor. In another specific embodiment, any SARM compound of formula I-V is a calcining agent. In a specific embodiment, the present invention provides a composition comprising any selective androgen receptor modulator compound of Formula IV, and / or its analogs, derivatives, isomers, metabolites, pharmaceuticals Acceptable (salt, pharmaceutical product, hydrate, N-oxide, or any combination thereof). In another embodiment, the present invention provides a pharmaceutical composition comprising any selective androgen of formula IV Receptor modulator compounds 'and / or their analogs, derivatives, isomers, metabolites, pharmaceutical products, hydrates, N-oxidation #' or any combination thereof; and appropriate carriers or diluents. In a specific embodiment, the present invention further provides a method for binding a selective androgen receptor modulator compound to an androgen receptor, which comprises the following steps: the androgen receptor and any of the selective androgen receptors of formula IV Phytoregulatory compounds and / or their analogs, derivatives, isomers, new: metabolites, pharmaceutically acceptable salts, 1 drug products, hydrates, team oxygen-23- 200304806

(17) A compound or any combination thereof in an amount effective to bind a selective androgen receptor modulator compound to an androgen receptor. In another specific embodiment, the present invention further provides a method for irreversibly binding a selective androgen receptor modulator compound to an androgen receptor, which includes the following steps: Contacting a selective androgen receptor modulator compound and / or its analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, pharmaceutical products, hydrates, N-oxides or any combination thereof, The amount is effective to irreversibly bind a selective androgen receptor modulator compound to the androgen receptor. In another specific embodiment, the present invention further provides a method for alkylating an androgen receptor, which includes the following steps: regulating any androgen receptor and selective androgen receptor of formula ι-ν Agent compounds and / or their analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, pharmaceutical products, hydrates, N-oxides, or any combination thereof, in an amount effective to androgen Body alkylation. In another specific embodiment, the present invention provides a method for inhibiting spermatogenesis in a patient, which comprises the following steps: the patient's androgen receptor and any selective androgen receptor modulator of formula IV Compounds and / or their analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, pharmaceutical products, hydrates, N-oxides, or any combination thereof are contacted in an amount effective to inhibit sperm production. In another specific embodiment, the present invention provides a method of contraception in male patients, comprising the steps of administering to the patient any selective androgen receptor modulator compound of formula IV and / Or its analog, Yan 24-24 (18) 200304806

Biology, isomers, metabolites, pharmacologically active substances, --- salts, medicines, tritium inhibition products, hydrates, N-oxides, or any combination thereof, the amount of which can be " "

Sperm production in patients to achieve patient contraception. W In another specific embodiment, the present invention further provides a method of healing, which includes the following steps, the patient's male species is primed to fight, T Λ ,,, I diploid h formula IV < any choice Sexual androgen receptor modulator compounds and / or compounds, derivatives, isomers, metabolites, pharmacologically η or similar amounts thereof, pharmaceutical products, hydrates, N-oxides or any of them Acetate salt, 0-acid, can effectively combine with selective androgen receptor modulators

The main androgen 敎 I ′ and achieve changes in androgen-dependent symptoms. '. In another specific embodiment, the present invention provides a method for seedling, seedling, and therapy, which includes the following steps, the choice of the patient's male, tonic, and mesophyll blood type IV. Sexual androgen receptor modulator compound & any human, or its analogous derivative, isomer, metabolite, pharmaceutically acceptable substance, ^ ±. Double salt, repeated product, hydrate, N-oxidation Substances or any combination thereof, its oral effect achieves changes in androgen-dependent symptoms. In another specific embodiment, the present invention further provides a method for treating a patient with hormone-related symptoms, which includes the option of administering to the disease M any formula IV Sexual androgen receptor modulator compounds and / or analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, pharmaceutical products, hydrates, N-oxides, or any combination thereof, in amounts that can be Effectively binds selective androgen receptor modulator compounds to the androgen receptor 'and achieves changes in androgen-dependent symptoms. In another specific embodiment, the present invention further provides a method for treating a patient suffering from -25-200304806 (19) a patient with prostate cancer, which comprises the following steps of administering any selective androgen receptor modulator of formula IV Substances, derivatives, isomers, metabolites, salts, pharmaceutical products, hydrates, N_oxides, or any of them are effective in treating prostate cancer in patients. In another specific embodiment, the present invention further provides method steps for delaying the progression of prostate cancer in a patient with prostate cancer, and administering to the patient any selective androgen compound of formula LV and / or its analogue, derivative Compounds, isomers, pharmaceutically acceptable salts, medicinal products, hydrates, and any combination thereof, the amount of which can be effectively delayed in a patient. The forefront is listed in another specific embodiment. The present invention further improves the prostaglandin adenocarcinoma The next step in preventing the recurrence of prostate cancer in a patient is to administer to the patient a selective dosing compound of any formula and / or its analog, derivative, isomer, pharmaceutically acceptable salt, A pharmaceutical product, hydration, or any combination thereof, in an amount effective to prevent health in a patient.

In another specific embodiment, the present invention provides a method for preventing prostate cancer, which includes the following steps: a selective androgen receptor modulator compound and / or a biological, isomer, metabolite, pharmaceutical The product can be connected to a product, a hydrate, an N-oxide, or any combination thereof, which is effective for preventing prostate cancer.丨 'Contribute to the patient and / or its type: a scientifically acceptable combination, the amount of which can be planted in the patient to pre-poor the patient to administer Formula 1-its analogs, derived salts, medicinal amounts One can be present in a patient, including the following hormone receptor modulation, metabolism, N-oxide or adenocarcinoma progression. A method for treating patients, which includes recurrence of androgen receptor modulators, metabolites, and N-oxide retinocarcinoma. 26- (20) (20) 200304806 In another specific embodiment, this The invention is a method for treating recurrence of prostate cancer in patients with adenocarcinoma, and repeating the steps, administering to the patient any of the following compounds and / or analogues Body regulators, painkillers, by-products, alkaloids, pharmacologically acceptable salts, medicine :, any combination of metabolism products, the amount of which can be in the disease = Γ Ν_ oxide or in another item and :: Treatment for the recurrence of prostate cancer. In another specific embodiment, the present invention provides a method for treating dry eye symptoms in a patient, and " " ^ ^ ^ -V TV ^ "/, the following steps are performed to the disease = The formula ... selective androgen receptor modulators: substances, derivatives, isomers, metabolites, pharmaceutical products, human skin, \ T 卞 工 J 接 接 < spouts or N-emulsions or Any combination thereof is effective in treating dry eye in a patient. In another specific implementation, the present invention provides a method for preventing dry eye symptoms, which comprises: ... Hormone receptor modulator compounds and, biology, isomers, progenitor cells, pharmacological 4: class: substances, derivatives, hydrates or N-oxides or any combination thereof :: =, effective medicine prevention Eye. Herein, in another specific embodiment, the present invention is a method of inducing cells in a cell ... The method includes the following steps: Selective androgen receptor in == and any formula! -V Modulators, di analogs, derivatives, chimeras, / or its isomers, metabolites, drugs :, Pharmaceutical products, hydrates, N-oxides, or any combination thereof can effectively cause cell death in cancer cells., 200304806

In another embodiment, the present invention provides a method for preparing a selective androgen receptor modulator (SARM) compound, the compound having the structure of Formula I. Table TF ·

Where X is 0, NH, S, Se, PR or NR; G is 0 or S; T is OH, OR, -NHCOCH3 or NHCOR; R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl , CH2F, CHF2, CF3, CF2 CF3, aryl, phenyl, halogen, fluorenyl, or OH; CH3, CH2F, CHF2, CF3, CH2CH3, or CF2CF3; R2 is F, a, Br, I, CH3, CF3 , QH, CN, N02, NHCOCH3, NHCOCF3, NHCOR, alkyl, aralkyl, OR, NH2, NHR, NR2, SR; R3 is F, Cl, Br, I, CN, N02, COR, COOH, CONHR, CF3, SnR3, or R3 forms a fused ring system with the benzene ring to which it is connected, and is represented by the following structure:

Z is N02, CN, COR, COOH or CONHR; -28- 200304806 (22) Y is CF3, F, Br, Cl, I, CN or SnR3; Q is SCN, NCS, OCN or NCO; n is 1-4 An integer; and m is an integer from 1 to 3. This method includes the following steps to make a compound of formula VIII:

Where Z, Y, G, Ri, T, R3 and m are as defined above, and L is a releasing group, which is coupled with a compound of formula IX:

Wherein Q, X, R2 and η are as defined above. In a specific embodiment, the coupling step is performed in the presence of a base. In another specific embodiment, the leaving group L is Br. In another embodiment, the compound of formula VIII is made in the following manner i) The compound of formula X is prepared by the ring-opening action of the cyclic compound of formula XI

-29- (23) 200304806

And Ti is 0 or NH; and the above definitions, wherein L, &, G, and T are all ii) make the amine of formula XII:

Among them, Z, Y, R3 and m are all set up as above to react with the compound of formula X to produce a characterizing compound of formula VlIi.

: The process is performed in the presence of HBr. This method further comprises converting the selective androgenic agent i in one embodiment to another analogue, isomer, metabolite, derivative, pharmaceutical of a receptor modulator (SARM) compound in another embodiment. Steps of acceptable salts, pharmaceutical products, N-oxides, hydrates, or any combination thereof. In another specific embodiment, the present invention provides a method for preparing a selective androgen incinerator (SARM) compound. The compound is represented by the structure of formula II:

NH

B

-30200304806

(24) where X is 0, NH, S, Se, PR or NR; G is 0 or S; & CH3, CH2F, CHF2, CF3, CH2CH3 or CF2CF3; T is OH, OR, -NHCOCH3 or NHCOR; R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, functional element, alkenyl, or OH; A is a ring selected from:

Where A and B cannot be benzene rings at the same time; Z is N02, CN, COOH, COR, NHCOR or CONHR; Y is CF3, F, I, Br, Cl, CN, CR3 or SnR3;

Qi is NCS, SCN, NCO or OCN; Q2 is hydrogen, alkyl, halogen, CF3, CN, CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, 200304806

(25) OCONHR, CONHR, NHCSCH3, MiCSCF3, NHCSR, NHS02CH3, NHS02R, OR, COR, 〇c〇R, 〇S02R, S02R, SR,

Q3 and Q4 are independently hydrogen, alkyl, self-prime, CF3, CN, CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR, NHS02CH3, NHS02R, OR , COR, OCOR, OS02R, S02R, or SR; W! Is O, NH, NR, N, O, or S; and W2 is N or NO; this method includes the following steps, so that the compound of formula XIII:

L wherein A, G, Xin and D are as defined above, and L is a leaving group, which is coupled with a compound of formula HX-B, wherein B and X are as defined above. In a specific embodiment, the coupling step is performed in the presence of a base. In another specific embodiment, the leaving group L is Br. In another specific embodiment, the compound of formula XIII is prepared in the following manner i) The ring-opening effect of the cyclic compound of formula XI is used to prepare the compound of formula X 200304806 (26)

XI x where L, &, G, and T are as defined above, and but 1 is 0 or NH; and ii) an amine of formula A-NH2, where A is as defined above, in the presence of a coupling reagent, and formula X The compounds are reacted to produce amidamine of formula XIII.

In a specific embodiment, step XI is performed in the presence of HBr. In another embodiment, the method further comprises converting a selective androgen receptor modulator (SARM) compound into its analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, medicine Product, N-oxide, hydrate, or any combination thereof. In another embodiment, the present invention provides a method for preparing a selective androgen receptor modulator (SARM) compound.

I --Q m where X is 〇, NH, S, Se, PR or NR; -33- 200304806

G is 0 or S; T is OH, OR, -NHCOCH3 or NHCOR; Z is N02, CN, COOH, COR, NHCOR or CONHR; Y is CF3, F, I, Br, Cl, CN, CR3 or SnR3; Q Is SCN, NCS, OCN or NCO;

R is alkyl, haloalkyl, dialkyl, trihaloalkyl, ch2f, chf2, cf3, cf2cf3, aryl, phenyl, halogen, feminyl, or OH: and CH3, CH2F, CHF2, CF3, CH2CH3 or CF2CF3; This method includes the following steps to make a compound of formula XIV:

Where Z, Y, G, Xin and D are as defined above, and L is a leaving group, which is coupled with a compound of formula XV:

Where Q and X are as defined above. In a specific embodiment, the coupling step is performed in the presence of a base. In another specific embodiment, the release group L is Bm ·. In another embodiment, the compound of formula XIV is prepared in the following manner: 200304806

(28) i) Preparation of a compound of formula X by ring opening of a cyclic compound of formula XI

XI X where L, Xin and D are as defined above, G is 0, and D 1 is 0 or where ^ 1, and ii) make the amine of formula XVI

NH2 XVI is reacted with a compound of formula X in the presence of a coupling reagent to produce a compound of formula XIV.

Z

In a specific embodiment, step (a) is performed in the presence of HBr. In another embodiment, the method further comprises converting a selective androgen receptor modulator (SARM) compound into its analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, medicine Product, N_oxide, hydrate, or any combination thereof. In another specific embodiment, the present invention provides preparation selective male stimulation 200304806

(29) A method of a receptor receptor modulator (SARM) compound, which is represented by a structure of formula IV:

IV

Where X is 0, NH, S, Se, PR, or NR; Z is N02, CN, COOH, COR, NHCOR, or CONHR; Y is CF3, F, I, Br, Cl, CN, CR3, or SnR3; Q is SCN , NCS, OCN, or NCO; and R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2 CF3, aryl, phenyl, halogen, fluorenyl, or OH; this The method includes the following steps:

Where Z and Y are as defined above, and L is a leaving group, which is coupled to a compound of formula XVIII:

HX

-36- 200304806

(30) where Q, X and R2 are as defined above. In a specific embodiment, the coupling step is performed in the presence of a base. In another specific embodiment, the leaving group L is Br. In another embodiment, the compound of formula XVII is made in the following manner i) The compound of formula X is prepared by the ring-opening action of the cyclic compound of formula XI

Where L, Xin and D are as defined above, G is 0, and D 1 is 0 or NH: and ii) the amine of formula XVIX

Y XVIX

Z is reacted with a compound of formula X in the presence of a coupling reagent to produce a compound of formula XVII.

XVII In a specific embodiment, step VII is performed in the presence of HBr. At 200304806

(31) In another specific embodiment, the method further includes the step of purifying the SARM compound using a mixture of ethanol and water. In another specific embodiment, the method further comprises converting a selective androgen receptor modulator (SARM) compound into its analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, medicine Product, oxide, hydrate, or any combination thereof. The novel selective androgen receptor modulator compound of the present invention, whether alone or as a pharmaceutical composition, can be used for a) male contraception; b) treatment of a variety of hormone-related symptoms, such as symptoms associated with ADAM, such as fatigue, Depression, hyposexuality, sexual dysfunction, erectile dysfunction, hypogonadism, osteoporosis, hair loss, obesity, oligosarcoma, bone deficiency, benign prostatic hyperplasia, and changes in mood and cognition; c) treatment Symptoms associated with ADIF, such as sexual dysfunction, hyposexuality, hypogonadism, sarcopenia, osteoporosis, osteoporosis, cognitive and mood changes, depression, anemia, hair loss, obesity, uterus Visceral tissue ectopic formation, breast cancer, uterine cancer and ovarian cancer; d) treatment and / or prevention of acute and / or chronic muscle wasting symptoms; e) prevention and / or treatment of private eye symptoms; o oral androgen replacement therapy; g ) Reduce the incidence of prostate cancer 'to stop it or cause it to recover; and / or h) cause cell death in cancer cells. The selective androgen receptor modulator compound of the present invention provides an important advance over steroid androgen therapy, because the selective androgen receptor modulator compound of the present invention has been proven to have non-steroids in vivo Androgen and anabolic activity of allosterone on androgen receptor. Therefore, choose 抶 200304806

(32) Androgen receptor androgen and inconvenient administration are lacking in other advantages. In a specific "agent" (ARTA) c selective androgen alcohol ligands androgen specific examples. In another embodiment of the body knot resistance agent, it is a symptom associated with a symptom alone or an element, erectile dysfunction anemia, obesity, glandular hyperplasia, male irritability in women, hyposexuality, and looseness. Yu Yuluo, obesity, and sub-portionant compounds have anabolic activity on androgens by non-steroidal ligands, and will not be accompanied by severe side effects, patterns or high costs, but also have oral bioavailability, steroid receptors Cross Reactivity and Long Biological Half-Life Detailed Description of the Invention In the examples, the present invention provides an androgen receptor as the target > This agent defines a novel subgroup of compounds that are receptor modulators (SARMs) . SARM compounds have surprising anti-androgenic activity with nonsteroidal receptors. In one embodiment, the SARM compound is irreversibly bound to the androgen receptor. In a specific embodiment, the SARM compound is an androgen receptor irreversibly bound to the androgen receptor. In another, SARM compounds are alkylating agents. SARM compounds, without composition, can be used for a) male contraception; b) treatment of a variety of stresses, such as androgen decline (ADAM) in aging men such as fatigue, depression, hyposexuality, sexual dysfunction, hypogonadism, bone Osteoporosis, hair loss, sarcopenia, osteopenia, osteoporosis, benign prostases and cognitive changes, and prostate cancer; c) treatment of symptoms associated with decreased dystrophin (ADIF) such as sexual dysfunction, Hypogonadism, oligosarcoma, lack of bone, changes in bone intelligence and mood, depression, anemia, hair loss, endometrial tissue formation, breast cancer, uterine cancer and ovarian 200304806 (33) cancer; d) treatment and / Or prevent acute and / or chronic muscle wasting symptoms; e) prevent and / or treat dry eye symptoms; f) oral androgen replacement therapy; g) reduce the incidence of prostate cancer, stop it or cause it to recover; and / or h) Cause cell death in cancer cells. In a specific embodiment, the present invention provides a selective androgen receptor modulator (SARM) compound, which is represented by the structure of Formula I:

(R2) n -Q

I X is a bond, 0, CH2, NH, S, Se, PR, NO or NR; G is O or S; T is OH, OR, -NHCOCH3 or NHCOR;

R is an alkyl group, a haloalkyl group, a dihaloalkyl group, a trihaloalkyl group, a CH2F, a CHF2, a CF3, a CF2 CF3, an aryl group, a phenyl group, a fluorenyl group, a fluorenyl group, or an OH group; the heart is CH3, CH2F, CHF2, CF3, CH2CH3 or CF2CF3; R2 is F, a, Br, I, CH3, CF3, OH, CN, N02, NHCOCH3, NHCOCF3, NHCOR, alkyl, aralkyl, OR, NH2, NHR, NR, SR, SR, R3 is F, Cl, Br, I, CN, N02, COR, COOH, CONHR, CF3, SnR3, or R3 forms a fused ring system with the benzene ring to which it is connected, which is represented by the following structure:

200304806

(34) Z is N02, CN, COR, COOH or CONHR; Y is CF3, F, Br, Cl, I, CN or SnR3; Q is SCN, NCS, OCN or NCO; n is an integer from 1-4; and m is an integer from 1-3. In a specific embodiment, the invention provides analogs of a compound of formula I. In another embodiment, the invention provides derivatives of compounds of formula I. In another embodiment, the present invention provides an isomer of a compound of formula I. In another embodiment, the present invention provides a metabolic product of a compound of formula I. In another embodiment, the present invention provides a pharmaceutically acceptable salt of a compound of Formula I. In another embodiment, the invention provides a pharmaceutical product of a compound of formula I. In another embodiment, the present invention provides a hydrate of a compound of formula I. In another embodiment, the present invention provides an N-oxide of a compound of formula j. In another specific embodiment, the present invention provides any analog, derivative, metabolite, isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate or N_oxide of the compound of formula I combination. In a specific embodiment, G in Compound I is 0. In another specific embodiment, X in compound I is 0. In another embodiment, T in compound I is OH. In another embodiment, R1 in compound I is CH3. In another embodiment, z in compound I is n02. In another embodiment, z in compound I is CN. In another embodiment, Y in compound I is CF3. In another specific example, q in compound I is NCS. In another embodiment, 200304806 (35) Q in Compound I is in the para position. In another embodiment, Z in compound I is in the para position. In another embodiment, Y in compound 1 is in the meta position. In another embodiment, G in compound I is 0, T is 0H, Ri is CH3, X is 0, Z is No2, Y is CF3, and Q is NCS. In another specific embodiment, the present invention provides a selective androgen receptor modulator (SARM) compound, which is represented by the structure of formula II:

Where X is a bond, 0, CH2, NH, S, Se, PR, N0 or NR; G is 0 or S; ~ is CH3, CH2F, CHF2, CF3, CH2 CH3 or CF2 CF3; T is OH, OR , -NHCOCH3 or NHCOR; R is an alkyl group, an i-alkyl group, a dihaloalkyl group, a tridrug alkane group, CH2F, chf2, cf3, CF2CF3, aryl group, phenyl group, halogen, alkenyl group, or 0H; A is a ring , Selected from:

B is a ring selected from: 200304806 (36)

Where A and B cannot be benzene rings at the same time; Z is N02, CN, COOH, COR, NHCOR or CONHR; Y is CF3, F, I, Br, Cl, CNCR3 or SnR3;

Qi is NCS, SCN, NCO or OCN; Q2 is hydrogen, alkyl, halogen, CF3, CN, CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR, NHS02CH3 , NHS02R, OR, COR, OCOR, OS02R, S02R, SR,

Q3 and Q4 are independently hydrogen, alkyl, self-prime, CF3, CN, CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR, NHS02CH3, NHS02R, OR , COR, OCOR, 0S02R, S02R or SR;

Wi is 0, NH, NR, N, O, or S; and W2 is N or NO. In a specific embodiment, the present invention provides analogs of compounds of formula II 200304806

(37) things. In another embodiment, the invention provides derivatives of compounds of formula II. In another embodiment, the present invention provides an isomer of a compound of formula II. In another embodiment, the present invention provides a metabolic product of a compound of formula II. In another embodiment, the present invention provides a pharmaceutically acceptable salt of a compound of Formula II. In another embodiment, the invention provides a pharmaceutical product of a compound of formula II. In another embodiment, the present invention provides a hydrate of a compound of formula II. In another embodiment, the present invention provides an N-oxide of a compound of Formula II. In another embodiment, the invention provides any analog, derivative, metabolite, isomer, pharmaceutically acceptable salt, medicinal product, hydrate, or N-oxide combination of a compound of Formula II . In a specific embodiment, G in compound II is 0. In another specific embodiment, X in compound II is 0. In another embodiment, T in compound II is OH. In another embodiment, the heart of compound η is CH3. In another embodiment, Z in compound II is N02. In another embodiment, Z in compound II is CN. In another embodiment, Y in compound II is CF3. In another embodiment, Qi in compound II is NCS. In another embodiment, Qi in compound II is in the para position. In another embodiment, Z in compound II is in the para position. In another embodiment, the amidine in compound η is in the meta position. In another embodiment, G in compound II is 0, T is OH, Ri is CH3, X is 0, Z is NO2, Y is CF3, and NCS is 0. In another embodiment, The present invention provides a selective male stimulation.

(38) a serotonin receptor modulator (SARM) compound, represented by the structure of formula III:

Where X is a bond, 0, CH2, NH, S, Se, PR, NO or NR; G is 0 or S; T is OH, OR, -NHCOCH3 or NHCOR; Z is N02, CN, COOH, COR, NHCOR or CONHR; Y is CF3, F, I, Br, Cl, CN, CR3 or SnR3; Q is SCN, NCS, OCN or NCO;

R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, halogen, alkenyl, or OH: and ~ is CH3, CH2F, CHF2, CF3, CH2 CH3 or CF2 CF3. In a specific embodiment, the invention provides analogs of compounds of formula III. In another embodiment, the invention provides derivatives of compounds of formula III. In another embodiment, the present invention provides an isomer of a compound of formula III. In another embodiment, the present invention provides a metabolic product of a compound of formula III. In another embodiment, the invention provides a pharmaceutically acceptable salt of a compound of formula III. In another embodiment, the invention provides a pharmaceutical product of a compound of formula III. In another embodiment, the present invention provides a hydrate of a compound of formula III. 200304806

(39) In a specific embodiment, the present invention provides an N-oxide of a compound of formula III. In another specific embodiment, the present invention provides any analog, derivative, metabolite, isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate, or N-oxide combination of a compound of Formula III . In a specific embodiment, G in compound III is 0. In another specific embodiment, X in compound III is 0. In another embodiment, T in compound III is OH. In another embodiment, Ri in Compound III is CH3. In another embodiment, Z in compound III is N02. In another embodiment, Z in compound III is CN. In another embodiment, Y in compound III is CF3. In another embodiment, Q in compound III is NCS. In another embodiment, Q in compound III is in the para position. In another embodiment, Z in compound III is in the para position. In another embodiment, Y in compound III is in the meta position. In another embodiment, G in compound III is 0, T is OH, Ri is CH3, X is 0, Z is N02, Y is CF3, and Q is NCS. In another embodiment, the present invention provides a selective androgen receptor modulator (SARM) compound, which is represented by the structure of formula IV:

IV where X is a bond, 0, CH2, NH, S, Se, PR, NO or NR; 200304806

(40) Z is N02, CN, COOH, COR, NHCOR or CONHR; Y is CF3, F, I, Br, Cl, CN, CR3 or SnR3; Q is SCN, NCS, OCN or NCO; and R is alkyl , Haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, halogen, alkenyl, or OH. In a specific embodiment, the invention provides analogs of a compound of formula IV. In another embodiment, the invention provides derivatives of compounds of formula IV. In another embodiment, the present invention provides isomers of compounds of formula IV. In another embodiment, the present invention provides a metabolic product 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 invention provides a pharmaceutical product of a compound of formula IV. In another embodiment, the present invention provides a hydrate of a compound of formula IV. In another embodiment, the present invention provides an N-oxide of a compound of Formula IV. In another embodiment, the present invention provides any analog, derivative, metabolite, isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate, or N-oxide combination of a compound of Formula IV . In a specific embodiment, X in compound IV is zero. In another specific embodiment, Z in compound IV is N02. In another embodiment, Z in compound IV is CN. In another embodiment, Y in compound IV is CF3. In another embodiment, Q in compound IV is NCS. In another embodiment, the present invention provides a selective androgen receptor modulator (SARM) compound, which is represented by the structure of formula V: 200304806 (41)

NCS V

In a specific embodiment, the present invention provides analogs of a compound of formula V. In another embodiment, the invention provides derivatives of compounds of formula V. In another embodiment, the present invention provides an isomer of a compound of formula V. In another embodiment, the present invention provides a metabolic product of a compound of formula v. In another embodiment, the invention provides a pharmaceutically acceptable salt of a compound of formula V. In another embodiment, the invention provides a pharmaceutical product of a compound of formula V. In another embodiment, the present invention provides a hydrate of a compound of formula V. In another embodiment, the present invention provides N-oxides of compounds of formula V. In another specific embodiment, the present invention provides any analog, derivative, metabolite, isomer, pharmaceutically acceptable <salt, medicinal product, hydrate or N_oxide of a compound of formula V Of combination. As intended to be included herein, other particular embodiments of the compounds included within the scope of the present invention are compounds v_. It should be understood that those included in the scope of the present invention are analogs, derivatives &amp; metabolites, isomers, pharmaceutically acceptable salts of these compounds 200304806 (42)

VI

Explanation of Qian 1 νπ where Q is NCS, SCN, NCO, or OCN. The substituent r is defined herein as an alkyl group, a self-alkyl group, a dialkyl group, a trihaloalkyl group, a CH2F, a CHF2, a CF3, a CF2CF3; an aryl group, a phenyl group, a halogen, an alkenyl group or a hydroxyl group (OH) . ffalkylπ refers to saturated aliphatic hydrocarbons, including straight chain, branched chain and cycloalkyl. In a specific embodiment, the alkyl group has M2 carbons. In another embodiment, the alkyl group has 1-7 carbons. In another embodiment, the alkyl group has 1-6 carbons. In another embodiment, the alkyl group has 1-4 carbons. This alkyl group may be unsubstituted, or substituted with one or more groups, and the substituent is selected from the group consisting of S element, mesityl group, oxofluorenyl group, acid amine group, alkynylamino group, difedonylamine Base, nitro, amine, amine, diamine, thio, thio and thio. "Haloalkylπ means an alkyl group, as defined above, which is substituted by one or more halogen atoms, for example by F, Cl, Br or I." Aryl "means an aromatic group having at least one carbocyclic ring Group or heterocyclic aromatic 200304806

(43) An aromatic group of the group, which may be unsubstituted or substituted by one or more groups, and the substituent is selected from the group consisting of sulfonium, i-alkyl, hydroxyl, alkoxycarbonyl, amido, and fe Acid amine, dialkyl, nitro, amine, amine, diamine, carboxyl or thio or thioalkyl. Non-limiting examples of aryl rings are phenyl, naphthyl, phenanyl, eryl, eryl, phenyl, phenyl, phenyl, phenyl, sulfanyl, thiophenyl, Soul Junji, Mi Miji, different name Junji and so on. πhydroxyπ refers to an OH group. "Amidino" refers to a group having at least one carbon-to-carbon double bond. Halo means F, Cl, Br or I. '' Aralkyl? Means an alkyl group bonded to an aryl group, wherein both alkyl and aryl are as defined above. An example of an aralkyl group is benzyl. As intended herein, the invention relates to SARM compounds and / or their analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, pharmaceutical products, hydrates, N-oxides or The purpose of the combination. In one embodiment, the invention relates to the use of analogs of SARM compounds. In another embodiment, the present invention relates to the use of derivatives of SARM compounds. In another embodiment, the present invention relates to the use of isomers of SARM compounds. In another specific embodiment, the present invention relates to the use of metabolic products of SARM compounds. In another embodiment, the present invention relates to the use of a pharmaceutically acceptable salt of a SARM compound. In another embodiment, the present invention relates to the use of pharmaceutical products of SARM compounds. In another embodiment, the present invention relates to the use of a hydrate of a SARM compound. In another specific embodiment, the present invention relates to a SARM compound 200304806

(44) Use of N-lice compound. In another embodiment, the present invention relates to any analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, I drug product, hydrate, or N-oxide of the SARM compound of the present invention. The use of the combination. Tian Fang, and the term "isomer" when used in this article includes, but is not limited to, optics, structures and analogs, structural isomers and analogs, configuration isomers and analogs, and the like. In one embodiment, the present invention covers the use of various optical isomers of SARM compounds. Those skilled in the art should understand that the SARM of the present invention. There is at least one palm center. Therefore, &lt; SARM, used in the method of the present invention, may exist in optically active or racemic form and be isolated. These compounds can also show polymorphism. It should be understood that the present invention encompasses any racemic, optically active, polymorphic or stereoisomer: formula, a mixture thereof, which form has properties that can be used to treat the androgen phase or symptoms described herein. In a specific embodiment, SARM is related to human v &gt; Xu structure. In another specific embodiment, SARM is a pure pyrene isomer. In a specific embodiment, SARM is a mixture of amidine and amidine. In a specific embodiment, the SARM is a racemic mixture containing equal amounts of rhenium and osmium isomers. In this technique, it is known how to prepare optical activity &lt; outer, ^ (Μ For example, through the analysis of the racemic form, by recrystallization technology, through the synthesis from "active starting materials, , "Chromatographic Separation). % This invention includes amine-substituted compounds and pharmaceutically acceptable salts of organic and inorganic μ (such as stilbene and hydrochloric acid). The invention also includes this article τ 200304806

N-oxide of the amine substituent of the compound. Pharmaceutically acceptable salts can also be prepared from phenolic compounds by treatment with an inorganic base such as sodium hydroxide. The brewing class of the separable compounds can also be made of aliphatic and square compounds such as acetic acid and benzoates. The invention further includes derivatives of SARM compounds. "Derivatives" / words include, but are not limited to, ether derivatives, acid derivatives, siamine derivatives, deliberate derivatives, and the like. In addition, the present invention further includes a hydrate of a SARM compound. The term ", hydrate" includes, but is not limited to, hemihydrate, monohydrate, dihydrate, trihydrate, etc. The present invention further includes the metabolites of SARM compounds. The term "metabolites" means to borrow Any substance produced by metabolism or metabolic process by another substance. The invention further includes pharmaceutical products of SARM compounds. "Pharmaceutical product," means a composition (medical composition) suitable for medical use as defined herein. In another embodiment, the present invention provides the preparation of a selective androgen receptor of the present invention. Modifier (SARM) compound method. The method of the present invention is suitable for large-scale preparation, because all steps lead to highly pure compounds, so to avoid complex purification procedures that will eventually reduce yield. Therefore, the present invention provides for synthesis A method for non-steroidal activator compounds that can be used for industrial large-scale synthesis and to provide highly pure products in high yields. In a specific embodiment, the present invention provides the preparation of selective androgen receptor modulators ( SARM) compound, the compound is represented by the formula 丨 structure table 200304806 (46)

Show:

Where X is 〇, NH, S, Se, PR or NR; G is 〇 or S; T is OH, OR, -NHCOCH3 or NHCOR; R is alkynyl, halide, dihalo, trihalo , CH2 F, CHF2, CF3, CF2CF3, aryl, phenyl, halogen, alkenyl or OH; CH3, CH2F, CHF2, CF3, CH2CH3 or CF2CF3; R2 is F, a, Br, I, CH3, CF3 , OH, CN, N02, NHCOCH3, NHCOCF3, NHCOR, alkyl, aralkyl, OR, NH2, NHR, NR), SR; R3 is F, Cl, Br, I, CN, N02, COR, COOH, CONHR , CF3, SnR3, or R3 together with the benzene ring to which they are attached form a fused ring system, which is represented by the following structure:

Z is N02, CN, COR, COOH, or CONHR; Y is CF3, F, Br, Cl, I, CN, or SnR3; Q is SCN, NCS, OCN, or NCO; n is an integer from 1-4; and 200304806

(47) m is an integer from 1 to 3; this method includes the following steps to make a compound of formula VIII:

Where Z, Y, G, Ri, T, R3 and m are as defined above, and L is a releasing group, which is coupled with a compound of formula IX:

Q, X, 112 and 11 are as defined above. In a specific embodiment, the coupling step is performed in the presence of a base. In another specific embodiment, the leaving group L is Br. In another embodiment, the compound of formula VIII is made in the following manner i) The compound of formula X is prepared by the ring-opening action of the cyclic compound of formula XI

G XI

G HO

X wherein L, Ri, G and T are as defined above, and I is 0 or NH; and ii) the amine of formula XII: 200304806 (48)

Hair: Minna Continued Reacts with a compound of formula X to make a compound of formula VIII

In a specific embodiment, step XI is performed in the presence of HBr. In another embodiment, the method further comprises converting a selective androgen receptor modulator (SARM) compound into its analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, medicine Product, N-oxide, hydrate, or any combination thereof. In another embodiment, the present invention provides a method for preparing a selective androgen receptor modulator (SARM) compound, which compound is represented by the structure of Formula II. A〆

B Π

Where X is 〇, NH, S, Se, PR or NR; 200304806

G is 0 or S; heart is CH3, CH2F, chf2, cf3, ch2ch3 or cf2cf3; T is OH, OR, -NHCOCH3 or NHCOR; R is alkyl, halo, dihalo, trihalo, Ch2 p, CHF2, CF3, CF2 CF3, aryl, phenyl, autogen, alkenyl or OH; A is a ring selected from:

B is a ring selected from

Where A and B cannot be benzene rings at the same time; Z is N02, CN, COOH, COR, NHCOR or CONHR; Y is CF3, F, I, Br, Cl, CNCR3 or SnR3;

Qi is NCS, SCN, NCO or OCN; Q2 is hydrogen, alkyl, autogen, CF3, CN, CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR, NHS02CH3 200304806

(50), NHS02R, OR, COR 'OCOR, OS02R, S02R, SR,

Q3 and Q4 are independent of each other: hydrogen, alkyl, halogen, CF3, CN, CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR, NHS02CH3, NHS02R, OR, COR, OCOR, OS02R, S02R or SR;

Wi is 0, NH, NR, N, O, or S; and W2 is N or NO; this method includes the following steps to make a compound of formula XIII:

Wherein, 0, 111 and D are as defined above, and 1 ^ is a leaving group, which is coupled with a compound of formula 1 ^, wherein B and X are as defined above. In a specific embodiment, the coupling step is performed in the presence of a base. In another specific embodiment, the leaving group L is Br. In another embodiment, the compound of formula XIII is prepared in the following manner i) The compound of formula X is prepared by the ring-opening action of the cyclic compound of formula XI

XI X 200304806

(51) wherein L, Xin, G, and T are as defined above, and D 1 is 0 or NH; and ii) an amine of formula A-NH2, where A is as defined above, in the presence of a coupling reagent, and formula X The compounds are reacted to produce amidamine of formula XIII.

In a specific embodiment, step XI is performed in the presence of HBr. In another embodiment, the method further comprises converting a selective androgen receptor modulator (SARM) compound into its analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, medicine Product, N-oxide, hydrate, or any combination thereof. In another embodiment, the present invention provides a method for preparing a selective androgen receptor modulator (SARM) compound, which compound is represented by the structure of formula III:

Q m where X is 0, NH, S, Se, PR or NR; G is 0 or S; T is OH, OR, -NHCOCH3 or NHCOR; Z is N02, CN, COOH, COR, NHCOR or CONHR; Y is CF3, F, I, Br, Cl, CN, CR3 or SnR3; 200304806

(52) Q is SCN, NCS, OCN or NCO;

R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, halogen, fluorenyl, or OH: and CH3, CH2F, CHF2, CF3 , CH2CH3 or CF2CF3; This method includes the following steps:

Z

Where Z, Y, G, Xin and D are as defined above, and L is a leaving group, which is coupled with a compound of formula XV:

I one-Q

XV where Q and X are as defined above. In a specific embodiment, the coupling step is performed in the presence of a base. In another specific embodiment, the leaving group L is Br. In another embodiment, the compound of formula XIV is prepared in the following manner i) The compound of formula X is prepared by the ring-opening action of a cyclic compound of formula XI

XI X 200304806 (53) 1 ^^ where L, Xin and Ding are as defined above, G is 0, and 1 \ is 0 or NH: and ii) make the formula XVI amine

nh2 XVI is reacted with a compound of formula X in the presence of a coupling reagent to produce a compound of formula XIV.

Z

In a specific embodiment, step (a) is performed in the presence of ΗΒ1 ·. In another embodiment, the method further comprises converting a selective androgen receptor modulator (SARM) compound into its analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, medicine Product, N-oxide, hydrate, or any combination thereof. In another embodiment, the present invention provides a method for preparing a selective androgen receptor modulator (SARM) compound, which compound is represented by the structure of formula IV:

IV 200304806

(54) where X is 0, NH, S, Se, PR or NR; Z is N02, CN, COOH, COR, NHCOR or CONHR; Y is CF3, F, I, Br, Cl, CN, CR3 or SnR3; Q is SCN, NCS, OCN, or NCO; and R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, halogen, alkenyl, or OH;

Where Z and Y are as defined above, and L is a leaving group, which is coupled to a compound of formula XVIII:

Wherein Q and XR2 are as defined above. In a specific embodiment, the coupling step is performed in the presence of a base. In another specific embodiment, the leaving group L is Br. In another embodiment, the compound of formula XVII is made in the following manner i) The compound of formula X is prepared by the ring-opening action of the cyclic compound of formula XI

XI X 200304806 (55) where L, Xin, and D are as defined above, G is 0, and D is 0 or ΝΗ: and ii) the amine of formula XVIX

Y

XVIX is reacted with a compound of formula X in the presence of a coupling reagent to produce a compound of formula XVII.

In a specific embodiment, step XI is performed in the presence of HBr. In another embodiment, the method further comprises converting a selective androgen receptor modulator (SARM) compound into its analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, medicine Product, N-oxide, hydrate, or any combination thereof. As demonstrated herein, the applicant has found that when the purification steps of SARM compounds are performed in the presence of non-toxic organic solvents and water, such as ethanol and water, for example, by recrystallization from a mixture of ethanol and water, they are obtained in high yields. Highly pure product with superior crystalline stability. In addition, the use of non-toxic organic solvents / water for purification is safe and inexpensive, and can avoid

Use a hazardous bag to convert chemical substances into environmentally friendly materials (56) Toxic organic solvents, such as hexane, any biohazards that may occur. In a specific embodiment, the non-toxic organic solvent is ethanol. Therefore, in a specific embodiment, the present invention provides a synthetic method for preparing the SARM compound described in the present invention, which involves purification steps, including crystallization of a SARM product using a non-toxic organic solvent and water mixture. In a specific embodiment, the non-toxic organic solvent is ethanol. In a specific embodiment, the crystallization step includes mixing an ethanol-containing liquid containing the SARM compound with water 'to crystallize the SARM compound. In the specific embodiment t ', the method further includes the step of collecting the SARM compound by filtration. The method of the present invention is suitable for large-scale production because the compound is uniformly pure in all steps, thereby avoiding a repetition that ultimately reduces yield. Therefore, the present invention provides a method for synthesizing a non-steroidal stimulus, which can be used for industrial large-scale synthesis and a pure product in a high yield. In addition, the method of the present invention utilizes safe and inexpensive reagents and purification steps, thereby avoiding undesired toxicological issues that may be toxic, environmentally unfriendly or biologically unstable reagents. Those skilled in the art should understand that in the method invented by any non-toxic organic solvent, for example, alcohols, such as methanol or ethanol, aromatics, such as toluene and xylene, DMS〇, TH [F, cyclohexane, etc. . In a specific embodiment, the non-toxic organic solvent is ethanol. Suitable for ethanol with purity grade. In one embodiment, it is pure ethanol. In another specific embodiment, ethanol is a compound that contains a heterogeneous purifying agent and provides a complete and complete compound. Since it occurs, it is suitable for family compounding. Ethanol denaturant 200304806

(57) Ethanol solutions such as toluene and methanol. Those skilled in the art should understand that when h is 0 or NH, T in compound VIII is 0 or NH2. Therefore, when T in compound I is OR, the reaction will involve another step of converting OH to OR by reacting with, for example, an alkyl autogen R-X. When T in compound I is NHCOR, NHCOCH3, the reaction will involve another step of converting NH2 to NHCOR or NHCOCH3 by reacting with, for example, its corresponding hafnium chloride C1COR or C1C0CH3. In a specific embodiment, the coupling step defined above is performed in the presence of a base. Any suitable base that deprotonates the hydrogen of the -XH moiety (eg, a phenol moiety when X is 0) and allows coupling can be used. Non-limiting examples of bases are carbonates, such as alkali metal carbonates, such as sodium carbonate (Na2 C03), potassium carbonate (K2 C03), and cesium carbonate (Cs2 C03); bicarbonates, such as metal bicarbonates, such as Bicarbonate (NaHC03), potassium bicarbonate (KHC03), alkali metal hydrides, such as sodium hydride (NaH), potassium hydride (KH), and lithium hydride (LiH). Leaving group L is defined herein as any removable group conventionally considered for chemical reactions, as known to those skilled in the art. Suitable leaving groups are halogens, such as F, C1, fluorene, and I; alkylsulfonates (-0S02R), where R is an alkyl group, such as methanesulfonate (methanesulfonate), trifluoromethanesulfonate , Ethane sulfonate, 2,2,2-trifluoroethane sulfonate, perfluorobutane sulfonate; aryl sulfonates (-0SO2 Ar), where Ar is aryl, For example, p-toluidine methyl ester (tosylate), benzene sulfonate, which may be unsubstituted or substituted with methyl, chlorine, bromine, nitro, etc .; No3, No2 or sulfuric acid Salt, sulfite, &gt;#acid, phosphite, metaester, imide, N2 or amine 200304806 (58) carbamate This reaction (tetrahydrofuran, such as aniline CDMF) and up to 120 ° C above, the carboxylic acid is converted into amidoamine / sex derivative acid and si-free / sulfur such as chloroformic acid via acid /. Isopropanol,: fluorenyl /. Substances such as azide / ethyl phosphorus醯 imine such as reaction may be &gt; appropriately

π is conveniently carried out in a suitable inert solvent or diluent, for example, 'aromatic amines such as eridine; aliphatic and aromatic hydrocarbons, toluene and xylene; dimethyl sulfoxide (DMS0), dimethyl Formamidine dimethylacetamide (DMAC). This reaction is suitably carried out at a temperature of, for example, about 20 °, for example, at or near ambient temperature. A coupling reagent is defined as a reagent capable of making a metabolite / thiol of formula X into a reactive derivative thereof, and thus capable of coupling with an individual amine to form thioxamine. A suitable reaction of a carboxylic acid / thiocarboxylic acid is, for example, a self-chemical hydrazone / self-chemical thiosulfate, such as a base gas formed by the reaction of an acid / sulfur organic chloride (such as disulfinated sulfite). ; Mixed anhydrides, such as anhydrides formed by the reaction of acid with isobutyl chloroformate; active esters / thioesters, such as thio acids and solvents, acetic acid / thioesters or alcohols, such as methanol, ethanol, butanol or Ester / thiosulfanyl sulfur-based azide formed by the reaction of N-hydroxybenzotriazole, such as the azide formed by the reaction of an acid / thio acid with diphenylphosphonium azide ; Thiothiocyanocyanide, such as a cyanide formed by the reaction of an acid with a cyanide, such as cyanide II; or the reaction product of an acid / thio acid and carbodicyclohexylcarbodiimide. Conveniently, it is carried out in the presence of a base, such as triethylamine, in a suitable inert solvent or diluent as described above, and within a temperature range such as described above. Biological activity of selective androgen modulator compounds 200304806

(59) The SARM compounds provided herein are selective androgen receptor modulator (SARM) compounds, which have the surprising anti-androgenic activity of non-steroidal ligands to the androgen receptor. In addition, several SARM compounds are irreversibly bound to the androgen receptor. Furthermore, several SARM compounds of the present invention are alkylating agents. As intended herein, a suitably substituted SARM compound of the present invention may be used for a) male contraception; b) treatment of a variety of hormone-related symptoms, such as symptoms associated with decreased androgen decline (ADAM) in aging men, such as fatigue , Depression, hyposexuality, sexual dysfunction, erectile dysfunction, hypogonadism, osteoporosis, hair loss, anemia, obesity, oligosarcoma, osteoporosis, osteoporosis, benign prostatic hyperplasia, mood and cognition The above changes and prostate cancer; c) treatment of symptoms associated with ADIF, such as sexual dysfunction, hyposexuality, hypogonadism, oligosarcoma, osteopenia, osteoporosis, cognitive and mood changes, depression , Anemia, hair loss, obesity, endometrial tissue formation, breast cancer, uterine cancer, and ovarian cancer; d) treatment and / or prevention of acute and / or chronic muscle wasting symptoms; e) prevention and / or treatment of dry eyes Symptoms; f) oral androgen replacement therapy; g) reducing the incidence of prostate cancer, stopping it or causing it to recover; and / or h) causing cancer In the cells die. As used herein, the receptors for extracellular signaling molecules are collectively referred to as &quot; cell signaling receptors &quot;. Many cells send message receptors as transmembrane proteins on the cell surface; when they bind to extracellular signal molecules (meaning ligands), they become activated so that they can generate intracellular messages that alter cell behavior Step response. In contrast, in some cases (60) 200304806

The receptor system is inside the cell to activate it; therefore, it is hydrophobic 'to spread beyond the thin and the signaling ligand must enter the cell. These signaling molecules must be small enough and the plasma membrane of the cell. Steroids are an example of a small hydrophobic knife that directly spreads across the plasma membrane of the target cell. # 处 人 s, ^ ,,,, and $ $ intracellular cells send message receptors. These receptors are structurally related and form the intracellular receptor supergroup (or steroid-hormone receptor supergroup). Steroid hormone receptors include progesterone receptors, estrogen receptors, androgen stimulants, steroids, glucocorticoid receptors, and mineral corticosteroid receptors. In one case, "Lu Lu, A y 丨 丄" &quot; Xiao Doushi, the invention is directed to the androgen receptor. 'When the dimer can be blocked to prevent ligands' three-dimensional structure of the substance In the space created by the structure, it is spheroidized into the sleeve, and its affinity is maintained so that the substance binds to this binding site more frequently than before. The stylistic transmission to the cell causes cell activation. During activation, the Transcription of the cause. But this substance and the receptor 'activate cells. In this substance, it can be formed. In some cases, it is enough to start the activation process (except that the ligand binds to the receptor and the body binds. When a The substance binds to the acceptor and is coordinated to the three-dimensional and sleeve shape of the receptor. The better the ball is, the tighter it fits. This phenomenon is called affinity. Hormones, they will compete with hormones, and once bound, You can respond to the message in some way. This is called the chemical acceptor system and then directly adjusts the chemical bond between the specific atom and the acceptor's atom that the specific group may have affinity to. Changes in the patterns referred to post transduction). The present invention in another particular embodiment of the selective androgen by # 200304806

(61) A body modulator compound, which is an antagonist compound. A receptor activator is a substance that binds to and activates a receptor. A receptor antagonist is a substance that binds to and inactivates a receptor. Therefore, in one embodiment, the SARM compounds of the present invention can be used to bind to and inactivate steroid hormone receptors. In a specific embodiment, the antagonist compound of the present invention is an antagonist that binds to an androgen receptor. In another embodiment, the compound has a high affinity for the androgen receptor. The test for determining whether the compound of the present invention is an AR activator or antagonist is known to those skilled in the art. For example, AR stimulating activity can be measured by monitoring the ability of a SARM compound to maintain and / or stimulate the growth of AR-containing tissues such as the prostate and seminal vesicles, which is measured by weight. AR antagonistic activity can be measured by monitoring the ability of SARM compounds to inhibit the growth of AR-containing tissues. Androgen receptor is the androgen receptor of any species, such as mammals. In a specific embodiment, the androgen receptor is an androgen receptor in humans. The compounds of the invention bind reversibly or irreversibly to the androgen receptor. In a specific embodiment, the SARM compound is reversibly bound to the androgen receptor. In another embodiment, a SARM compound reversibly binds to an androgen receptor in a mammal. In another embodiment, the SARM compound reversibly binds to the androgen receptor in humans. The reversible binding of a compound to a receptor means that the compound can detach from the receptor after binding. In another embodiment, the SARM compound is irreversibly bound to the androgen receptor. In a specific embodiment, a SARM compound is irreversibly bound to an androgen receptor in a mammal. In another specific embodiment 200304806

In (62), the SARM compound is irreversibly bound to a human androgen receptor. Therefore, in a specific embodiment, the compounds of the present invention may contain a functional group (such as an affinity marker), which allows the aroylation of the androgen receptor (meaning covalent bond formation). Therefore, in this case, the compound is an alkylating agent, which is irreversibly bound to the receptor, and therefore cannot be replaced by a steroid such as the endogenous ligands DHT and fluorenone. "πalkylating agent" is defined herein as an agent that forms a carbyl compound (forms a covalent bond) with cellular components such as DNA, RNA or enzymes. It is a highly reactive chemical that will be introduced Alkyl groups are incorporated into biologically active molecules to prevent their inherent function. Alkylated moieties are an electrophilic group that interact with nucleophilic moieties in cellular components. For example, in a In a specific embodiment, the alkylation is an isocyanate partial group, which is an electrophilic group that forms a covalent bond with a nucleophilic group circle (N, O, S, etc.) in a cell component. In another specific embodiment, the alkylation is an isothiocyanate moiety, which is another type that forms a covalent bond with a nucleophilic group (N, 0, S, etc.) in the cell component Electrophilic group. In another embodiment, the 'alkylated group is a haloalkyl group (CH2X, where X is a halogen), which is a covalent group that forms a covalent bond with a nucleophilic group in a cell component An electrophilic group of a bond. In another embodiment, the alkylating group is _Alkyl-amido (NHCOCH2 X, where X is halogen) 'It is an electrophilic group that forms a covalent bond with a nucleophilic group in a cell component. In a specific embodiment, The SARM compound of the present invention is an androgen receptor antagonist, which is an androgen incinerator that irreversibly binds to mammals (such as humans). In a specific embodiment, the compound is an alkylating agent. (63) 200304806

A specific step of realizing the androgen receptor, the agent compound and the substance, any combination of pharmacological compounds of the compound and the specific examples of selective androgens include the following steps: a modulator product, a drug or any of its hormone receptors Tuning the method of specific examples for selective androgen, isomers, hydrates, hormone receptor alkanes The substances, derivatives, and medicinal products of the present invention can be effectively combined with 0-into-step extraction compounds to androgens and the analogues, derivative salts, and medicines in amounts that are effective until the androgen receptor is further improved. The agent compound and substance, and any combination thereof in pharmacy, provide a step to make the patient a compound product of medicine, pharmacy. Therefore, in binding selectivity, it includes regulating the metabolism of hormone receptors to produce N-oxides or hormone receptors. In another inverse binding method, the method includes androgen receptors, progenitors, and N-oxidation selective androgen and another &amp; hormone receptor alkane and the present invention %, Derivatives, and medicinal products can effectively cause males to undergo epiphysis in another spermatozoa, and in the analogues and derivative embodiments of the present invention, the modulator compound androgen receptor / or a similarly acceptable salt thereof is contacted with its Among the amount of androgen receptor, the receptor modulator of the present invention contacts the androgen and / or a scientifically acceptable combination thereof. Among the dosing compounds, the present invention includes the regulation of metabolism by the hormone receptor to produce N-oxides. Or base. In the present invention, the invention includes the following steps: hormone receptor modulation, metabolism steps, a method for providing a receptor, selective androgenic, isomers, hydrates, and selective androgenic for a non-hormonal receptor. Structure products, hydrated irreversibly. For providing an androgen receptor and / or a similarly acceptable salt thereof in an amount androgen that is inhibited in a patient and / or an acceptable amount thereof (64) 200304806 The structure compound sperm is effective in the treatment of the invention-derived drug. The biological product that is achieved in the treatment is achieved in the contact with the patient's medical product, hydrate, N • oxide or any combination thereof, which effectively inhibits sperm production. In another specific embodiment, the present invention provides a male patient avoidance, which comprises the steps of administering to the patient a selected hormone receptor modulator compound of the present invention and / or a quasi-derivative or derivative thereof. Substances, isometabolic compounds, pharmaceutically acceptable salts, medicinal products, water, N-lice compounds, or any combination thereof, in an amount effective to inhibit manufacturing in the patient, thereby achieving patient contraception. In another specific embodiment, the present invention further provides a method of hormones, which includes the following steps, and the patient's androgen receptor and the &lt; selective androgen receptor modulator compound and / or its analogue , Compounds, isomers, metabolites, pharmaceutically acceptable salts, medicines, hydrates, N-oxides, or any combination thereof, in an amount that can be a selective androgen receptor modulator compound to androgens Receptors, and changes in androgen-dependent symptoms. In another specific embodiment, the present invention provides a method of hormone replacement treatment, which includes the following steps, the patient's androgen receptor and the present selective androgen receptor modulator compound and / or its analog, derivative , Isomers, metabolites, pharmaceutically acceptable salts, medicines, hydrates, N-oxides, or any combination thereof, in an amount effective for changes in androgen-dependent symptoms. In another specific embodiment, the present invention further provides a method for treating patients with hormone-related symptoms, which comprises the steps of administering the selective androgen receptor modulator compound of the present invention to a compound and / or ( 65) (65) 200304806 Analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, pharmaceutical products, hydrates, N-oxides or any combination thereof, and f can effectively bind selectivity Androgen receptor modulator compounds to androgen receptor moon beans, and achieve changes in androgen-dependent symptoms. Androgen-dependent symptoms that can be treated in accordance with the present invention include those associated with aging, such as hypogonadism, oligosarcoma, erythropoiesis, osteoporosis, and any other later measured low-androgen-dependent (eg, ) Symptoms of content. In another embodiment, the present invention further provides a method for treating a patient with allele cancer, which comprises the steps of administering to the patient a selective androgen receptor modulator of the present invention. Compounds and / or their analogs bamboo organisms, isomers, metabolites, pharmaceutically acceptable salts, medicinal products, hydrates, N_oxides or any combination thereof in an amount effective for treating prostate cancer in patients . In another specific embodiment, the present invention provides a method for preventing prostate cancer in a patient, comprising the steps of administering to the patient the selective androgen receptor hydrazone compound of the present invention and / Or its analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, pharmaceutical products, hydrates, N-oxides, or any combination thereof, in an amount effective to prevent prostate cancer in a patient. In another specific embodiment, the present invention further provides a method for delaying the progression of prostate cancer in a patient with prostate cancer, comprising the steps of 'administering the selective androgen receptor of the present invention to the patient. Body modulator compounds and / or their analogs, derivatives, isomers, metabolism products 200304806

, A pharmaceutically acceptable salt, a medicinal product, a hydrate, an N-oxide, or any combination thereof, in an amount effective to delay the progression of prostate cancer in a patient. In another specific embodiment, the present invention further provides a method for preventing the recurrence of prostate cancer in a patient with prostate cancer, which comprises the following steps, and administers the selectivity of the present invention to the patient. Androgen receptor modulator compounds and / or their analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, pharmaceutical products, hydrates, N-oxides, or any combination thereof, the amount of which can be Effective prevention of recurrence of prostate cancer in patients. In another specific embodiment, the present invention provides a method for treating recurrence of prostate cancer in a patient with prostate cancer, comprising the steps of administering the selective androgen of the present invention to the patient. Receptor modulator compounds and / or their analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, pharmaceutical products, hydrates, N_oxides, or any combination thereof, the amount of which may be in the patient Effective treatment of recurrence of prostate cancer. Furthermore, the stimulating effect of the androgen receptor can stimulate the production of tears, so the SARM compounds of the present invention can be used to treat dry eye symptoms. Therefore, according to another specific embodiment of the present invention, a method for treating dry eye symptoms in a patient with dry eye is provided. The method includes the following steps. Androgen receptor modulator compounds and / or their analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, pharmaceutical products, hydrates or N-oxides or any combination thereof, the amount may be in Effective treatment of dry eyes in patients. According to another specific embodiment of the present invention, there is provided a method for preventing dry eye symptoms in a patient, which includes the following steps: administering the patient to a formula -7 ^. (67) 200304806

Selective androgen by I-V or its analogs, derivatives, isomers, metabolites, acceptable salts, medicinal products, hydrates or N-oxides or any of them ... Effectively prevent dry eyes. A method for zeroing cells in prostate cancer, which includes the following steps to make the cells

Selective androgen receptor modulator compounds and / or their analogs: biology, isomers, metabolites, pharmaceutically acceptable salts, medicinal products, hydrates, N-oxides or any of them in cancer Effectively induce fines in cells. Order combination contact, the amount of which is defined herein, &quot; cell zeroing &quot; or stylized cell death, is: a form of cell death, the stylized sequence of events will cause the cell to shed Hazardous substances are released into the surrounding area. The μ-cell nulling system removes old thin fetuses, fetuses, fetuses, fetuses, a ηII, and necessary cells and unhealthy cells, while developing and maintaining health. Play a decisive role.

= When defined in the text '&quot; contact &quot; means the compound of the present invention: said = sample with enzyme, placed in a test tube, flask, tissue culture anode, array, plate, microplate, Capillary or similar to allow temperature and time for SARM to bind to enzyme

Samples and SARMs are used by I for A and others; other methods of specifically combining component contact are to familiarize yourself with this option by selecting 'depending on the type of inspection plan you want to be operated and two' as standard. 'And it is known to those skilled in this art. Two: 1 specific embodiment towels' "contact, the word means this ... the mouth system was introduced into the patients being treated, and let the compound-7A-200304806

(68) Contact with androgen receptors in vivo. As used herein, the term "treatment" includes both preventive and disease-relief treatments. The terms π-reducing "suppression" and π-inhibition used herein have meanings generally understood as reducing or decreasing. Herein The term "progress" is used in the sense of increasing scope or severity, advancing, growing, or becoming worse. The term "recurrence" as used herein, # means the recovery of the disease after its remission. As used herein, the term '' delayed π 'means stop, obstruct, slow down, defer, maintain, or prevent. The term "administration" as used herein refers to bringing a patient into contact with a SARM compound of the invention. As used herein, administration can be achieved in vitro, meaning in a test tube, or in vivo, meaning in a living organism, such as a cell or tissue of a human. In one embodiment, the invention encompasses administering a compound of the invention to a patient. The term "sexual desire" as used in this article means sexual need. The π-erection π-word used in this article means that it can be upright. An erection tissue is a tissue that can be greatly expanded and become hard by the expansion of many of the blood vessels it contains. 'Hypogonadism' is a symptom characterized by abnormality of the gonads that reduces functional activity and retards growth and sexual development. '' Bone deficiency π means reducing the calcification or density of bone. It is a term covering all skeletal systems in which such symptoms are found. "Osteoporosis" refers to the thinning of bones as bone mass decreases. This is caused by the depletion of calcium and bone proteins. Osteoporosis makes people susceptible to fractures, which is often a slow healing and Bad healing. Unchecked 200304806

(69) Osteoporosis may cause posture changes, physical deformities, and reduced mobility. "BPH (benign prostatic hyperplasia)" is a non-malignant enlargement of the prostate gland, and is the most common abnormal hyperplasia found in any internal organs, and the main cause of incidence in adult men. BPH occurs in more than 75% Among men over the age of 50, 88% infection rate is reached during the age of 90. BPH will constantly cause a slow squeeze of the urethra (prostate urethra) part across the prostate. This is due to the incomplete emptying of the bladder and The urgency of urination 'causes patients to experience continuous urges to urinate. Obstruction of urinary flow may also lead to general lack of control over urination, including difficulty in initiating urination when needed, and difficulty in preventing urination because it is not able to empty from the bladder Urine is a symptom known as overflow urinary incontinence, which may cause urinary obstruction and urinary failure. Cognitive power refers to the process of understanding, and it is clearly stated that it is to perceive, understand, think, learn And the process of judgment. Cognition is in the fields of psychology, linguistics, computer science, neuroscience, mathematics, ethnography, and philosophy. The term refers to the temperament or state of mind. As intended in this context, change means any positive or negative change in cognition and / or mood. "Depression," the term refers to the physical, mood, and The disease of thinking affects the way people eat, sleep, and the way a person feels and thinks about things. Signs and symptoms of depression include loss of interest in activities, loss of food or overeating, loss of emotional expression, feeling empty, hopelessness, pessimism, feelings of guilt or helplessness, social disengagement, fatigue, sleep disorders, 'attention, recall or decision making Difficulty, can't sleep, irritating, headache, digestive disorder or slow 200304806 200304806

(70) Sexual pain. The term "hair loss 11" is medically called baldness, which refers to baldness, as in the very common type of male pattern baldness. Baldness typically begins with small patches of hair on the scalp, and sometimes progresses to complete baldness and even loss of body hair. Hair fall affects both men and women. "Anemia" means having below or below normal red blood cells in the blood

Symptoms of the amount of heme. As a result, the oxygen-carrying capacity of blood is reduced. People with anemia may feel tired and fatigued, appear pale, develop palpitations, and often become short of breath. Anemia is caused by four basic factors: a) bleeding (bleeding); b) lysis of red blood cells (excessive destruction of red blood cells); c) insufficient production of red blood cells; and d) insufficient normal hemoglobin. There are many forms of anemia, including aplastic anemia, benzene poisoning, Fanconi anemia, neonatal hemolytic disease, transitory spherocytosis, iron deficiency anemia, osteopetrosis, malignant anemia, sickle cell disease, thalassemia Symptoms, spinal dysplasia, and a variety of bone marrow diseases. As intended for inclusion herein, the present invention

The SARM compounds can be used to prevent and / or treat any one or more of the forms of anemia listed above. You mean that this is higher than a person's normal weight. Traditionally, people exceed their 2G percentage of their ideal weight, which is considered to be = 2 explicitly determined by the National Institutes of Health _) as having a body-to-mass number (MI) of 30 or more. Obesity is often based on multiple factors. Overweight due to obesity is good for health = transmission and

To fuel factors. It increases the risk of developing a variety of diseases, type K (adult spread) diabetes; hypertension, hypertension, including · wind of the wind (cerebrovascular -77- 200304806

(71) f CVA); heart attack (myocardial infarction or MI); heart failure (congestive heart failure) &cancer; (some forms of 'such as prostate cancer and colon and rectal cancer)' gallstones and Gallbladder Disease (Cholecystitis); Gout and Gouty Arthritis; Osteoarthritis of the Knee, Hip, and Lower Back (Degenerative Arthritis); Sleep Apnea ... (Failure to breathe normally during sleep, reduce blood oxygen); and Pickwickian's constipation (obesity, red face, hypoventilation, and lethargy). As intended to be included herein, the term "obesity" includes any of the obesity-related symptoms and diseases listed above. Therefore, the sarm compounds of the present invention can be used to prevent and / or 'orally treat obesity and any one or Many of the obesity-related symptoms and diseases listed above. "Splenic adenocarcinoma" is one of the most common cancers in men in the United States, with hundreds of thousands of new cases diagnosed each year. Discovered More than sixty percent of newly diagnosed prostate cancer cases have been pathologically progressed without cure and prognosis for depression. One third of all men over 50 years of age have a potential form of prostate cancer, It can be activated into a life-threatening form of clinical prostate cancer. The frequency of potential prostate tumors has been shown to increase substantially with every ten years of life, from 50 years (5.3- 丨 4%) to 90 years (40 -80%). The number of people with potential prostate cancer is the same across all cultures, ethnic groups, and races, but the frequency of clinically strong cancers is significantly different. This suggests that environmental factors can activate the potential Plays a role in prostate cancer. In a specific embodiment, the method of the present invention comprises administering a SARM compound as a separate active ingredient. However, it is also encompassed within the scope of the present invention for hormone therapy and for the treatment of prostate cancer About delaying the progression of prostate cancer (72) 200304806

Development and pre-administration of SARMs including but not limited to cancer drugs, 5-α 3 through other nuclear stimulants (SERM) ^ bisphosphonates and, therefore, a specific receptor modulator for selective androgen In the examples, the compound and the method of the invention are combined with the use of an anticancer drug, including administration of a selective enzyme inhibitor. Yu selective male. In another androgen receptor embodiment, an agent compound, an agent. The most recurring method is to treat the other side of the androgen receptor P and / or treat the forefront of the abdominal wave, which includes a compound, and use a combination of one or mysterious treatment agent. These kits: LHRH analogues, anti-androgens, anti-estrogens, anti-progenase inhibitors, aromatase inhibitors, lutein preparations, melanin receptors, etc. ^, Selective estrogen receptor-modulating progesterone, estrogen, v PDE5 inhibitor, apomorphine, one or more other SARMs. -A specific embodiment, the method of the present invention comprises administering a selected receptor modulator compound and using an LHRH analog in combination. In another embodiment, the method of the invention comprises administering a selective androgen compound and using a reversible antiandrogen in combination. In another specific aspect, the method of the invention comprises administering selective androgen receptor modulation and using an anti-estrogen in combination. In another specific embodiment, this includes administering a compound that is a selective androgen receptor modulator. In another specific embodiment, the method of the present invention comprises an androgen receptor modulator compound, and it is reduced by 5_α in another specific embodiment. The method of the present invention includes administering a hormone receptor modulator compound, and In the specific embodiment of the combined use of aromatase inhibitors, the method of the present invention includes administering a selection 1 modulator compound and using progesterone in combination. In another aspect, the specific method of the present invention includes the administration of a selective androgen receptor word ^ and the use of a specific embodiment of item G through the action of other nuclear hormone receptors, the method of the present invention includes the administration of a selection Body modulator compounds, and combined use of selective estrogen receptors,

_ 7Q _ 200304806

(73) Suppositories (SERM). In another embodiment, the method of the present invention comprises administering a selective androgen receptor modulator compound and using progesterone. In another embodiment, the method of the present invention comprises administering a selective androgen receptor modulator compound and using estrogen in combination. In another embodiment, the method of the present invention comprises administering a selective androgen receptor modulator compound and using a PDE5 inhibitor in combination. In another embodiment, the method of the present invention comprises administering a selective androgen receptor modulator compound and using apomorphine. In another embodiment, the method of the present invention comprises administering a selective androgen receptor modulator compound and using a bisphosphonate in combination. In another specific embodiment, the method of the invention comprises administering a selective androgen receptor modulator compound and using one or more other SARMs. In a specific embodiment, the present invention provides a composition comprising the selective androgen receptor modulator compound of the present invention, and / or its analogs, derivatives, isomers, metabolites, pharmaceuticals Acceptable salts, pharmaceutical products, hydrates, N-oxides, or any combination thereof. In another specific embodiment, the present invention provides a pharmaceutical composition comprising the selective androgen receptor modulator compound of the present invention, and / or its analogs #, derivatives, isomers, and metabolites , A pharmaceutical product, a hydrate, a team oxide, or any combination thereof; and a suitable carrier or. As used herein, "pharmaceutical composition" means therapeutically effective, accompanied by a suitable diluent, preservative, solubilizer, emulsifier, adjuvant and / or carrier. In this article, a, "a / quote effective amount", to provide specific symptoms and administration of medications to provide treatment "with a liquid or lyophilized or privately in other ways ☆ kinds of compositions Dry formula and contains all kinds of slow 200304806

(74) Diluent (such as Tris-HCl, acetate, phosphate), pH and ionic strength additives, such as albumin or gelatin, to prevent absorption to the surface, cleaning agents (such as Tween 20, Tween 80, Plur 〇nic F68, bile salts), solubilizers (such as glycerol, polyvinyl glycerol), antioxidants (such as ascorbic acid, sodium metabisulfite), preservatives (such as thimerosal, benzyl alcohol, parabens), Bulking substances or osmotic modifiers (such as lactose, mannitol), covalent attachment of polymers such as polyethylene glycol to proteins, mismatches with metal ions, or incorporation of this substance into polymer compounds such as polymer Lactic acid, polyglycolic acid, hydrogel, and other microparticulate preparations, or on microlipids, microemulsions, microcells, monolayer or multilayer vesicles, pseudo red blood cells or spheroids. Such a composition will affect the physical state, solubility, stability, release rate in vivo and clearance rate in vivo. Controlled or sustained release compositions include formulations in lipophilic reservoirs (eg fatty acids, waxes, oils). Also encompassed by the present invention are microparticle compositions that have been coated with a polymer (e.g., poloxamer or polyoxamine). Other specific embodiments of the composition of the present invention incorporate protective coatings in the form of microparticles, protease inhibitors or penetration enhancers for various routes of administration, including parenteral, pulmonary, nasal and oral. In a specific embodiment, the pharmaceutical composition is parenteral, anticancer, transmucosal, transdermal, intramuscular, intravenous, intradermal, subcutaneous, intraperitoneal, indoor, intravaginal, intracranial and Intratumoral administration.

In addition, the "pharmaceutically acceptable carrier" used herein is known to those skilled in the art, and includes but is not limited to 〇 〇1_〇1M, and preferably ⑼5M 200304806

(75) phosphate buffer, or 0.8% saline. In addition, such pharmaceutically acceptable carriers can 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 water, alcoholic / aqueous solutions, emulsions or suspensions, including saline and buffered media. Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's solution, and non-volatile oil. Intravenous vehicles include fluid and nutritional supplements, electrolyte supplements, such as those based on Ringer's dextrose, and the like. Preservatives and other additives may also be present, such as antimicrobials, antioxidants, collectors, inert gases, and the like. Controlled or sustained release compositions are formulated in lipophilic reservoirs (e.g. fatty acids, waxes, oils). Also encompassed by the present invention are microparticle compositions that have been coated with a polymer (such as polyoxygen or polyoxyamine), and antibodies coupled to a tissue-specific receptor, ligand, or antigen, or coupled to tissue A compound that is a ligand for a specific receptor. Other embodiments of the composition of the present invention are incorporated in the form of microparticles, protective coatings, protease inhibitors or penetration enhancers for a variety of administration routes, including parenteral, pulmonary, nasal and oral. It is known to use water-falling polymers such as polyethylene glycol, copolymers of polyethylene glycol and polypropylene glycol, chitomethyl cellulose, dextran, polyethylene glycol, polytetrahydroketone or The modified compound covalently linked to polyproline after intravenous injection, compared with its corresponding unmodified compound, will show in the blood the long life of the carpenter ’s parent (Abuchowski et al. Newmark et al., 1982; and Katre et al., 1987). This modification can also increase compounds in 200304806

(76) Solubility in water and grain fluids, excludes aggregation, improves physical and chemical safety of compounds, and greatly reduces the immunogenicity and reactivity of compounds. Therefore, 'the desired biological activity in vivo can be achieved with less frequent or lower doses by administering such a polymer-compound adduct in comparison with the use of unmodified compounds'. In yet another embodiment, the pharmaceutical composition can be delivered in a controlled release system. For example, the agent can be administered using intravenous infusion, implantable osmotic pumps, transdermal patches, microlipids, or other modes of administration. In a specific embodiment, a pump can be used (see Langer, same as above; 36 lines 〇11, € 1 ^ (: 1 ^ ·

Ref. Biomed. Eng. 14: 201 (1987); Buchwald et al., Surgery 88: 507 (1980); Saudek et al., V. Engl. J. Med. 321: 574 (1989)). In another embodiment, a polymeric substance may be used. In yet another embodiment, the controlled release system can be placed near the target of treatment (meaning the brain), so only one systemic dose is required (see, for example, Goodson, Medical Applications for Controlled Release). , Ibid., Vol. 2, pp. 115-138 (1984)) _. Other controlled release systems are discussed in Langer's review (Science, 249: 1527-1533 (1990)). Pharmaceutical preparations may contain a SARM agent alone, or may further contain a pharmaceutically acceptable carrier, and may be in solid or liquid form, such as tablets, powders, capsules, pellets, solutions, suspensions, elixirs, emulsions, Gels, creams or suppositories, including rectal and urethral suppositories. Pharmaceutically acceptable carriers include gums, starches, sugars, cellulosic materials, and mixtures thereof. A pharmaceutical preparation containing a SARM agent can be administered to a patient by, for example, subcutaneously implanting spherules. In a further specific embodiment, this spherules provide controlled release of the SARM agent over a period of time. This formulation can also be administered intravenously, as a liquid formulation, or by intramuscular injection, 200304806 (77), as a liquid or solid formulation, or by local application. Administration can also be achieved with rectal suppositories or urethral suppositories. The pharmaceutical preparation of the present invention can be prepared by a known method of dissolution, mixing, granulation, or tablet formation. For oral administration, sarM or its physiologically acceptable derivatives, such as salts, esters, and N_oxides, are mixed with additives customarily used in this project, such as vehicles, stabilizers, or inert dilutions. And suitable methods for conversion, such as tablets, coated tablets, hard or soft gelatin capsules, aqueous, alcoholic or oily solutions. Examples of suitable inert vehicles are conventional tablet bases, such as lactose, sucrose, or corn starch, and binders, such as acacia, corn starch, and gelatin, together with disintegrating agents, such as corn starch, potato starch, Alginic acid, or with a lubricant, such as stearic acid or magnesium stearate. Examples of suitable oily vehicles or solvents are vegetable or animal oils, such as sunflower oil or cod liver oil. The formulation can be achieved with dry and moist granules. For parenteral administration (subcutaneous, intravenous, intra-arterial or intramuscular injection), SARM agents or their physiologically acceptable derivatives, such as salts, esters, N-oxides, etc., can be converted into solutions, Suspensions or emulsions, if necessary, use conventional substances suitable for this project, such as solubilizers or other adjuvants. Examples are sterile liquids, such as water and oils, with or without added surfactants, and other pharmaceutically acceptable adjuvants. Illustrative oils are oils of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil or mineral oil. In general, water, saline, aqueous dextrose and related sugar solutions, and glycols, such as propylene glycol or polyethylene glycol, are the preferred liquid carriers, especially for injectable solutions. (78) 200304806

The preparation of pharmaceutical compositions containing active ingredients is straightforward. Typically, this type of combination is used to transfer the nasopharynx to the nasopharynx, or to make an injectable aerosol or suspension into a sense peptide. Solid form in solution or liquid. This formulation can also be combined with or suspended in ingredients and mixed with excipients. The excipients are: two. Active therapeutic ingredients are often compatible. Suitable excipients are, for example, academically accessible * and may be combined with oil, ethanol or the like, or any combination thereof. Wind 纟 * 疋 疋, sugar In addition, combined with a pH buffering agent, the substance may contain a small amount of auxiliary substances such as wetting or emulsifying agents which will enhance the effectiveness of the active ingredients. Acceptable salt forms, formulated to include acid addition salts (with polypeptides or active ingredients that can be neutralized in pharmaceutical compositions. Pharmaceutically acceptable salts, free-form amine formation of antibody molecules), It is formed with inorganic acids, such as hydrochloric acid or phosphoric acid, such as acetic acid, oxalic acid, tartaric acid, phenylglycolic acid, etc. Salts formed from carboxyl groups can also be derived from inorganic tests such as sodium, potassium, ammonium, Calcium or iron hydroxide, and organic bases such as isopropylamine, dimethylamine, 2-ethylaminoethanol, histidine, procaine, etc. Regarding the use of, for example, creams, gels, drops, etc. for topical application When administered to the surface of the body, T 'refers to the use of SARM or its physiologically acceptable derivatives, such as salts, vinegars, N-oxides, in physiologically acceptable diluents, with or without medicine Carriers are prepared and administered as solutions, suspensions or emulsions. In another embodiment, the active compound can be delivered via vesicles, especially microlipids (see Langer, Science 249 ·· 1527-1533 ( 1990); Treat 200304806 (79 ) Et al. Lipoz-Berestein and Fidler (eds.) For the treatment of infectious diseases and cancer, Liss, New York, pp. 353-365 (1989); Lopez-Berestein, ibid., Pp. 317-327 (See generally the same source above). For medical use, the salts of SARM are pharmaceutically acceptable salts. However, other salts can be used to prepare the compounds according to the invention or their pharmaceutically acceptable Suitable pharmaceutically acceptable π 颏 compounds of the present invention include acid addition salts, which can be formed, for example, by mixing a solution of a compound according to the present invention with a mixture of human pharmaceutically acceptable diacids, the acid For example, salt m, methanesulfonic acid, fumaric acid, maleic acid, succinic acid, jujudic acid, oxalic acid, citric acid, tartaric acid, carbonic acid, or phosphoric acid. Only the next example is given by the application method. A more detailed description of the preferred embodiments of the present invention is provided. However, it should never be interpreted as limiting the broad scope of the present invention. Details ^ Details: Experimental methods Cell lines Cell lines used in the studies described herein , Whose source is shown in Table i is:

Source of manifestation Patient Androgen; Estrogen Left supraclavicular lymph node needle Aspiration biopsy Weaving method 50-year-old male Caucasian with stage D1 prostate cancer -_ 200304806

(80) DU145 Epithelial metastatic CNS lesions 69-year-old male Caucasian PC-3 epithelial prostate metastatic bone marrow with grade IV prostate cancer South Africa Human PPC-1 (Primary Prostate Cancer-1) Epithelial Prostate Transurethral Resection with Stage D2 Bad Difference Prostate Cancer 67-year-old black male TSU Epithelial metastatic tumor in cervical lymph nodes with moderately differentiated prostate 73-year-old Japanese male TCCSUP epithelium Analpastic transitional cell carcinoma in the bladder neck 67-year-old female with grade IV bladder cancer HT-29 epithelial urokinase receptor; vitamin D colorectal adenocarcinoma 44-year-old female facial Human CV-1 fibroblasts Normal kidney male adult (day 141) African green monkey MCF-7 breast cancer PPC-1, LNCaP, TSU, PC-3 and DU145 are contained in 2mML-glutamine and supplemented with 10% cattle Fetal serum (FBS) was grown in PPMI_1640 medium. The cells were kept in a humid atmosphere of 5% C02 / 95% air at 37 ° C. Cell growth conditions The chloramine b (SRm 柃, SRB test is used to determine the number of cells during cytotoxicity experiments. The following proposal is used: 200304806

(81) 1. The cells were detached with 0.25% trypsin. 2. The experimental cultures were cultured in 96-well microtiter plates (200 microliters of growing soil per well; 1,000-200,000 cells per well). 3. Fix the culture with 50 μl of 50% TCA (4 ° C). (For details ‘winter cell fixation proposal). # p Fixation 4. Stain D cells for 10 minutes with 50 microliters of 0.4% (w / v) SRB in 1% acetic acid. 5. · Remove SRB and quickly * wash the culture 5 times with 1% acetic acid 'Remove unbound dye **. 6. Air-dry the culture overnight until no visible moisture is in the soil. 7. Dissolve cellular protein-bound SRB for 30 minutes on a shaking platform shaker with 200 μl of unbalanced TriS (10 mM, pH 10.5). 8. The absorbance is read at MO nanometers. * Fast washing procedures are performed to prevent protein-bound SRB desorption. ** On the drain, remove the remaining washing solution completely by tapping the plate vigorously. * The solids of the layer of cells t The following proposals were used to fix the cells: a. 50 microliters of 50% TCA (4t) was gently layered over the growth medium in each well 'to give a final TCA concentration of 10%. b. Incubate the culture at 4 ° C for 1 hour. C • Wash the culture 5 times with tap water to remove TCA, growth medium, low molecular weight metabolites and serum proteins. d • Air dry the board until no visible moisture is present. -88- 200304806

(82) Results Example 1 Cytotoxicity of the compound in different cell lines R-CTF-T-CA-1, R-CTF-T-BA-1, S-NTBA, compounds V, 5-FU, and taxol, IC5 in prostate cancer cell lines (DU 145, PC-3, TSU, PPC-1, and LNCaP), in other cancer cell lines (TCCSUP, HT-29), and in control cell lines (CV-1) ○ is shown in Tables 2A and 2B and FIG. 1. The results confirmed that Compound V is highly selective for AR-expressing LNCaP prostate cancer cell lines compared to other prostate adenocarcinoma cell lines that do not exhibit AR and to non-prostate cancer cell lines. These results confirm the potential of Compound V as a useful agent in prostate cancer monotherapy. Table 2A- Prostate cancer cell line name structure MW Prostate cancer cell line DU145 PC-3 TSU PPC-1 LNCaP R-CTF-T- CA-1 (μM) Human, 1 471.88 2,6 ± 0, 1 6.1 ± 0.5 1.5 ± 02 2.5 ± 0.1 1.1 ± 0 ^ R-CTF-T- ΒΑ-1 (μΜ) 516.33 3.1 ± 0.1 2.6 ± 0.1 0.6 ± 0.1 1.3 ± 0.1 3-way 4 S-NTBA (μΜ) 371.11 4.7 Soil 0.3 3.1 ± 0.6 3.5 ± 0 ^ 22 ± 02 \ A ± 02 Compound V (μΜ) 0 421.39 74.8 ± 1.2 59.0 ± 6 56.9 ± 2.9 58.1 ± 5.9 26.0 ± S. 3 5-FU (μΜ) 130.1 4.5 ± 03 10.5 soil 0.6 2.7 soil 0.6 5.1 ± 0.5 4.1 soil 0.6 Taxo 丨 (nM) 853.9 2.7 ± 0.3 6.3 ± 0.6 2.4 ± 0.8 2.7 soil 0.3 1.910.3 200304806

(83) Table 2B_ Name structure of other cancer cell lines and control group MW Other cancer cell lines and control group TCCSUP HT-29 CV-1 (control group) R-CTF-τ- CA-1 (μM) f3c 471.88 1.8 ± 0 ^ 6.4 ± 0.5 2.7 ± 1.0 R-CTF-T- ΒΑ-1 (μΜ) 51633 3.8 Soil 0.5 1.6 Soil 0.03 10.8 Soil 0.5 S-NTBA (μΜ) Η Λ 371.11 2.4 ± 0.3 6.3 Soil 0.3 12.7 ± 0.3 Compound ( μM) 421.39 &gt; 100 55.0 ± 1.7 NA 5-FU (μM) 130.1 3.6 ± 0.7 5.4 ± 1.1 5.4 ± 0J Taxol (ηΜ) 853.9 4.3 ± 0.6 6.6 ± 0.6 Example 2 Cytotoxicity of the compound in the LNCaP cell line R- CTF-T-CA-1, R-CTF_T-BA-1, S-NTBA and Compound V IC50 in AR-represented LNCaP prostate cancer cell line and control cell line (CV-1) The results are shown in Table 3 and Fig. 2 (LNCaP) and Fig. 3 (CV-1). After 24 hours of treatment, the IC50s of R-CTF-BA-1, R-CTF-T-CA1, S-NTBA and Compound V in LNCaP cell lines are individually 11.2 // M, 3.5, 4.4 // M And 39.6 // M.

After 6 days of treatment, the IC50 of R-CTF-BA-1, R-CTF-T-CA1, S-NTBA and Compound V in LNCaP cell lines were individually 8.1 / zM, 1.7, 2.1 // M- QO- 200304806

(84) and 33.6 // M. Compare this with the results in the cV-i cell line of the control group, where R-CTF-BA1, R-CTF_T-CA1, and IC50 of TBTA, after treatment for 4 days, were individually 13.9 // M, 4.2 / / M and 4 · 9 // M (compound V-NA). These results confirm that compound V is AR-expressing LNCaP prostate cancer cell line, which is 'dimension-selective' compared to the control cell line. These results confirm the potential of Compound V as a useful agent in monotherapy for prostate cancer. Table 3- Different processing names of R-CTF for LNCaP and CV_1 Structure LNCaP (nM) CV-1 (μM) 24 hours processing 6 days processing 24 hours processing 4 days processing R-CTF-T- BA-1 11.2 ^ 4.6 ( 9-10- 01) 8.1 ± 0 · 8 (9-8-01) 23. 1.6 (9-11-01) 13.9 ± 0.8 (9-1 ΙΙΙ) R-CTF-T · CA-1 3.5 Soil 1.9 (MO-01) 1/7 ± 0 · 1 (9-8-01), 6 · 2 ± 0 · 2 (9-11-01) 4 · 2 ± 0 · 1 (9-11- 01) S-NTBA 「: 〇 ^ 4.4 ± 2.0 (9-10- 01) 2.U0.2 (9-8-01) 48.2 ^ 10.9 (9-11-01) 4.9 ± 0.5 (9-1 ιο) Compound V 〇—- f3c 39.6 ± 2.7 (9-10- 01) 33.6 6.9 (9-8-01) ΝΑ (9-11-01) ΝΑ (9-1 ΙΙΙ) Example 3 Compounds in PC-3 cell line The cytotoxicity IC50 of R-CTF-T-CA-1, R-CTF-T-BA-1, S-NTBA and 5-FU in PC-3 prostate metastatic bone marrow cell line is shown in the table 4 and Figure 4. After 24 hours of processing, the IC50s of R-CTF-BA-1, R-CTF-T-CA1, S-NTBA and 5-FU are individually 22.1 // M, 5 · 8 / / M, &gt; 50 / zM and 22-50. After 4 days of treatment, the IC50 of R-CTF-BA-1, R-CTF-T-CA1, S-NTBA and 5-FU are individually 16.8 200304806

(85) // M, 4.3 // M, 18.0 and 10.9. Table 4-R-CTF-T Excerpts for IC-3 from different treatments of IC50 Name structure IC50 (μM) 24 hours processing 4 days processing R-CTF-T-BA- 1 0 0 f3c 22.1 16.8 R-CIT- T-CA- 1 / 5.8 4.3 S-NTBA 〇2ΝΥ ^ ι 0 JX &gt; 50 18.0 5-FU 20-50 10.9 Example 4 Long-term cytotoxicity of compounds in different cell lines DJ 1-31, DJ 1-29 , S-NTBA and compound V in different prostate cancer cell lines (DU 145, PC-3, TSU, PPC-1 and LNCaP), in other cancer cell lines (TCCSUP, HT-29 and MCF-7), and The IC50 in the control cell line (CV-1) after 1 and 4 days of incubation with the drug is shown in Tables 5 A and B. These results confirm that compound V is highly selective for AR-expressing LNCaP prostate cancer cell lines compared to other prostate cancer cell lines that do not exhibit AR, as well as non-prostate cancer cell lines. These results confirm that compound V is at the forefront 200304806

(86) Possibility as a useful agent in adenocarcinoma monotherapy. Table 5A- Prostate cancer cell line compound structure Drug culture time (days) IC5〇_) ID LNCaP DU 145 PC-3 PPC-1 TSU W 1-31 1 (2.9? 1.2 1_0? 0 · 2 5.4? 0.8 1.9? 0 · 1 1 · 3? 0 · 1 \ __ ¥ η / ^ &gt; Μ ^ ~~ V V '4 3 · 3? 0 · 4 0 · 7? 0.1 5 · 3? 0 · 8 1 · 9? 0 · 1 1 · 1? 0.1 I • DJ 1-29 1 1 · 1? 04 0 · 4? 0 · 1 2 · 3? 0 · 1 0.9? 0 · 1 1.3? 0 · 1 Η \ η \ _ / «^ 4 1 · 8? 0 · 2 0 · 4? 0 · 1 2.4? 0 · 4 1 · 3? 0 · 1 1 · 0? 0 · 1 S-NTBA 〇liSr ^ 9 X 1 1 1 1 · 6? 0 5 5.5? 0.6 7 · 9? 0 · 7 1 · 7? 0 · 2 4 · 9? 0 · 4 4 1 · 8? 0 · 9 4 · 670 · 8 3 · 771 · 1 2 · 7? 0 · 8 2 · 9? 0 · 2 V 1 19 · 8? 10 · 5 62 · 170 · 6 47 · 8 · 4 · 2 63.7 · 4 · 6 54 · 1? 5 · 5 4 12.8? 4 · 1 69 · 7 ? 6 · 5 48 · 5? 10 · 1 62.6? 4.9 55.0? 0 · 8 Table 5B · Compound IDs of other cancer cell lines and control groups Structured drug culture time (days) IC50 (UM) HT-29 TCCSU MCF-7 CV -1 D``1-31 1 54 ^ * 1 2.1 ± 0.3 15-8 ^ 2-7 5-8 ^ 0-3 4 3- ^ 0-7 2 · 1 ± 0.3 14.0 = 4.1 5 · 3 soil 0 · 2 DJ 1-29 1 3-6 ^ 04 2 · 6 people 04 11.9 ^ 0.3 6 · 8 people 0 · 5 4 4.4 people 0 · 2 2 · 5 people 0.4 12 Royal 7 7.3 soil 0.2 S-NTBA 1 19.8 Soil 1 · 0 9.5 Soil 3.6 3-3 ^ 0-6 &gt; 50 4 10 · 8 persons 0.4 4.6 ± 0 · 3 3 · 3 ± 2 · 0 38-6 + 3-6 V 1 85-5 ^ 4-5 90.4 ± 2 · 2 32-7 = ^ 1-9 &gt; 100 4 71-0 ± 1.2 78.1 + 11.2 39 · 4 ± 5.4 &gt; 100 Example 5 Determination of the effects of compounds on cell decay in different cell lines DJ 1-31, DJ 1-29, S-NTBA and compound V in different prostate cancer cell lines (DU 145 , PC-3, TSU, PPC-1, and LNCaP), in other cancer cell lines (TCCSUP, HT-29, and MCF-7), and in control cell lines (CV-1) 200304 ^ 06

(87) The ability to cause cells to wither, and the results are shown in Table 6. Table 6.Compound ID structure enrichment factor LNCaP DU 145 PC «3 PPC-1 TSU HT-29 TCCSUP MCF-7 CV-1 DJ 1-31 1.374 2.500 0.594 1.312 0.848 1.205 0.471 0.938 0.702 DJ 1-29 16.571 18.643 0.531 1.146 1.008 1.667 0.000 1,617 0.786 S-NTBA 0.660 1.929 0.750 0.697 0.705 1.538 0.118 2.012 0.393 CK1-85 2.000 5.071 2.500 1.749 1.167 1.410 1.176 1.926 6.548

It should be clear to those skilled in the art that the present invention is not limited to those specifically described and described above. Instead, the scope of the present invention is defined by the scope of the following patent applications: Brief Description of the Drawings The present invention is more fully understood and understood from the above in conjunction with the accompanying drawings, of which:

Figure 1: Cytotoxicity of SARM compounds in different cell lines. A) Compound V; B) S-NTBA; C) R-CTF-T-CA-1; and D) R-CTF-T-BA-1. Figure 2: Cytotoxicity of SARM compounds in LNCaP prostate cancer cell lines (24-hour and 6-day treatment). A) R-CTF-T-BA-1; B) R-CTF-T-CA-1; C) S-NTBA: and D) Compound V. Figure 3: Cytotoxicity of SARM compounds in CV-1 control cell lines (24-hour and 4-day treatment). A) R-CTF-T-BA-1; B) R-CTF-T-CA-1; QS-NTBA: and D) Compound V. Figure 4: SARM compound in PC-3 bone metastatic prostate cancer cell line -Q4. 200304806

(88) cytotoxicity (24-hour and 4-day treatment). A) R-CTF-T-BA-1; B) R-CTF-T-CA-1; C) S-NTBA; and D) 5-FU.

Claims (1)

200304806 Patent application and application 1. A selective androgen receptor modulator (SARM) compound, which is represented by the structure of formula I: IX is a bond, 0 ′ CH2, NH, S, Se, PR, NO or NR; G is 0 or S; T is OH, OR, -NHCOCH3 or NHCOR; R is alkyl, haloalkyl, dihalide Alkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, halogen, alkenyl or OH; ~ is CH3, CH2F, CHF2, CF3, CH2 CH3 or CF2 CF3; R2 is F, C Br, I, CH3, CF3, OH, CN, N02, NHCOCH3, NHCOCF3, NHCOR, alkyl, aralkyl, OR, NH2, NHR, NR2, SR; R3 is F, Cl, Br, I, CN, N02, COR, COOH, CONHR, CF3, SnR3, or R3 together with the benzene ring to which they are connected form a fused ring system, which is represented by the following structure: Z is N02, CN, COR, COOH or CONHR; Y is CF3, F, Br, Cl, I, CN or SnR3; 200304806 Q is SCN, NCS, OCN, or NCO; n is an integer from 1-4; and m is an integer from 1-3. 2. A selective androgen receptor modulator (SARM) compound, which is represented by the structure of Formula I: X is a bond, 0, CH2, NH, S, Se, PR, NO or NR; G is 0 or S; T is OH, OR, -NHCOCH3 or NHCOR; R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, halide, alkenyl, or OH; heart is CH3, CH2F, CHF2, CF3 , CH2CH3 or CF2CF3; R2 is F, a, Br, I, CH3, CF3, OH, CN, N02, NHCOCH3, NHCOCF3, NHCOR, alkyl, aralkyl, OR, NH2, NHR, NR2, SR; R3 is F, Cl, Br, I, CN, N02, COR, COOH, CONHR, CF3, SnR3, or R3 together with the benzene ring to which they are connected form a fused ring system, which is represented by the following structure: 200304806 Z is N02, CN, COR, COOH, or CONHR; Y is CF3, F, Br, Cl, I, CN, or SnR3; Q is SCN, NCS, OCN, or NCO; n is an integer from 1 to 4; and m is 1 An integer of -3; or an analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, N-oxide, hydrate, or any combination thereof. 3. The compound according to item 1 of the scope of patent application, wherein G is 0. 4. The compound according to item 1 of the patent application, wherein T is OH. 5. The compound according to item 1 of the patent application scope has its center at CH3. 6. The compound according to item 1 of the scope of patent application, wherein X is 0. 7. The compound according to item 1 of the scope of patent application, wherein Z is N02. 8. The compound according to item 1 of the scope of patent application, wherein Z is CN. 9. The compound according to item 1 of the scope of patent application, wherein Y is CF3. 10. The compound according to item 1 of the scope of patent application, wherein Q is NCS. 11. The compound according to item 1 of the scope of patent application, wherein G is 0, T is OH, Ri is CH3, X is 0, Z is N02, Y is CF3, and Q is NCS. 12. A compound according to item 1 of the scope of patent application, wherein the compound is an androgen receptor antagonist. 13. A compound according to item 1 of the scope of patent application, wherein the compound is irreversibly bound to the androgen receptor. 14. A compound according to item 1 of the scope of patent application, wherein the compound is an androgen receptor antagonist, which irreversibly binds to the androgen receptor. 200304806 15. A selective androgen receptor modulator (SARM) compound, which is represented by the structure of the formula II TF · B G Π X, Where X is a bond, 0, CH2, NH, S, Se, PR, NO, or NR; G is 0 or S; &amp; is CH3, CH2F, CHF2, CF3, CH2CH3, or CF2CF3; T is OH, OR, -NHCOCH3 or NHCOR; R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, halogen, fluorenyl, or OH; A is ring, select from: B is a ring selected from: 200304806 Where A and B cannot be benzene rings at the same time; Z is N02, CN, COOH, COR, NHCOR or CONHR; Y is CF3, F, I, Br, Cl, CN, CR3 or SnR3; Qi is NCS, SCN, NCO Or OCN; Q2 is hydrogen, alkyl, halogen, CF3, CN CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR, NHS02CH3, NHS02R, OR, COR, OCOR , 0S02R, S02R, SR, Q3 and Q4 are independent of each other: hydrogen, alkyl, halogen, CF3, CN, CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR, NHS02CH3, NHS02R, OR, COR, OCOR, QS02R, S02R, or SR; W! Is 0, NH, NR, N, O, or S; and W2 is N or NO. 16. A selective androgen receptor modulator (SARM) compound, which is represented by the structure of the formula II TF · Π 200304806 Where X is a bond, 0, CH2, NH, S, Se, PR, NO or NR; G is O or S; heart is CH3, CH2F, CHF2, CF3, CH2CH3 or CF2CF3; T is OH, OR,- NHCOCH3 or NHCOR; R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, halogen, fluorenyl, or OH; A is a ring selected from : γ B is a ring selected from: Where A and B cannot be benzene rings at the same time; Z is N02, CN, COOH, COR, NHCOR or CONHR; Y is CF3, F, I, Br, Cl, CN, CR3 or SnR3; Qi is NCS, SCN, NCO Or OCN; Q2 is hydrogen, alkyl, halogen, CF3, CN, CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, 200304806 OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR, NHS02 CH3, NHS02R, OR, COR, OCOR, OS02R, S02R, SR, Q3 and Q4 are independent of each other: hydrogen, alkyl, halogen, CF3, CN, CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR, NHS02CH3, NHS02R, OR, COR, OCOR, OS02R, S02R, or SR; Wi is 0, NH, NR, N, O, or S; and W2 is N or NO. Or an analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, N-oxide, hydrate, or any combination thereof. 17. The compound according to item 15 of the application, wherein G is 0. 18. The compound according to item 15 of the application, wherein T is OH. 19. The compound according to item 15 of the application, wherein &amp; is CH3. 20. The compound according to item 15 of the application, wherein X is 0. 21. The compound according to item 15 of the application, wherein Z is N02. 22. The compound according to item 15 of the application, wherein Z is CN. 23. The compound according to item 15 of the scope of patent application, wherein Y is CF3. 24. The compound according to item 15 of the scope of patent application, wherein it is NCS. 25. Compound according to item 15 of the scope of patent application, where G is 0 and T is OH 200304806 , Ri is CH3, X is 0, Z is N02, Y is CF3, and Qi is NCS. 26. A compound according to item 15 of the application, wherein the compound is an androgen receptor antagonist. 27. A compound according to item 15 of the scope of patent application, wherein the compound is irreversibly bound to the androgen receptor. 28. The compound according to item 15 of the application, wherein the compound is an androgen receptor antagonist, which is irreversibly bound to the androgen receptor. 29. A selective androgen receptor modulator (SARM) compound, which is represented by the structure of formula III: Q ΠΙ where X is a bond, 0, CH2, NH'S, Se, PR, NO or NR; G is 0 or S; T is OH, OR, -NHCOCH3 or NHCOR; Z is N02, CN, COOH, COR, NHCOR or CONHR; Y is CF3, F, I, Br, Cl, CN, CR3 or SnR3; Q is SCN, NCS, OCN or NCO; R is alkyl, haloalkyl, dihaloalkyl, trihalo Alkyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, halogen, alkenyl or OH: and &amp; is CH3, CH2F, CHF2, CF3, CH2CH3 or CF2CF3. 30. A selective androgen receptor modulator (SARM) compound, which is represented by the formula: 111 structure represents: 7 I 4q m where X is a bond, O, CH2, NH, S, Se, PR, NO or NR; G is 0 or S; T is 0H, OR, -NHCOCH3 or NHCOR; Z is N02, CN, COOH, COR, NHCOR or CONHR; Y is CF3, F, I, Br, Cl, CN, CR3 or SnR3; Q is SCN, NCS, OCN or NCO; R is alkyl, ialkyl, dihaloalkyl, Trihaloalkyl, ch2f, chf2, cf3, cf2cf3, aryl, phenyl, halogen, fluorenyl, or OH; and &amp; is CH3, CH2F, CHF2, CF3, CH2CH3, or cf2cf3; or an analogue or isomer thereof , Metabolites, derivatives, pharmaceutically acceptable salts, pharmaceutical products, N-oxides, hydrates, or any combination thereof. 31. The compound according to item 29 of the application, wherein G is 0. 32. The compound according to item 29 of the application, wherein τ is 0H. 33. The compound according to item 29 of the application, wherein &amp; is ch3. 34. The compound according to item 29 of the application, wherein X is 0. 35. The compound according to item 29 of the application, wherein z is No. 02. 36. The compound according to item 29 of the application, wherein z is CN. 200304806 37. The compound according to item 29 of the application, wherein γ is CF3. 38. The compound according to item 29 of the application, wherein q is NCS. 39. The compound according to item 29 of the application, wherein g is 0, T is 0H, Ri is CH3, X is 0, Z is NO, Y is CF3, and Q is ncs. 40. A compound according to item 29 of the scope of application, wherein the compound is an androgen receptor antagonist. 41. A compound according to item 29 of the application, wherein the compound irreversibly binds to the androgen receptor. 42. A compound according to item 29 of the scope of application, wherein the compound is an androgen receptor antagonist, which irreversibly binds to the androgen receptor. 43. The compound according to item 29 of the scope of patent application, which is represented by the structure of formula ν: 44. A composition comprising a selective androgen receptor modulator compound according to claim 1, 15, 29, or 43 and / or its analogs, derivatives, isomers, metabolites, pharmaceuticals Acceptable positions, pharmaceutical products, hydrates or N-oxides or any combination thereof; and appropriate carriers or diluents. 45 · A pharmaceutical composition comprising an effective amount of a selective androgen receptor modulator compound according to item i, 15, 29, or 43 of the scope of patent application, and / or its analogs' derivatives, isomers , Metabolites, Drugs-10- 200304806 Academically acceptable salts, medicinal products, hydrates or N-oxides or any, and orally, and pharmaceutically acceptable carriers, diluents or salts. 46. A method for binding a selective androgen receptor modulator compound to an androgen receptor, which includes the steps of 'bringing an androgen receptor to an application-specific &quot; Selective androgen receptor modulators, 'and' or their analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, pharmaceutical products, hydrates or n-oxides or any of them In combination, the amount is effective to bind the selective androgen receptor withering compound to the androgen receptor. 47. A method of irreversibly binding a selective androgen receptor modulator compound to an androgen receptor, which includes the steps of combining the androgen receptor with a dimorphic modulator compound according to the scope of the patent application, and / or Analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, medicinal products, hydrates or N-oxides or any combination thereof are contacted in amounts effective to irreversibly bind to selective androgen receptor modulation Agent compounds to the androgen receptor. 48.-A method for the alkylation of androgen receptors, including ^ in androgen receptors and selective androgen receptor modulator compounds according to Item Η of the patent application, and / or the like A substance, derivative, isomer, metabolite, pharmaceutically acceptable salt, medicinal product, hydrate or N-oxide or any combination thereof is contacted in an amount effective to alkylate the androgen receptor. It includes the choice of 15, 15, or 43 in the patient's male. 49. A method for inhibiting spermatogenesis in a patient. Contact with a selective androgen receptor modulator compound, and / or its analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, pharmaceutical products, hydrates or N-oxides, or any combination thereof, 2 Liangcho effectively suppresses sperm production. a 50.-A method of contraception in a male patient ', which includes the following steps: Selective androgen receptor modulator compounds', v, 15, 29 or milk or their analogs: derivatives, isomers, metabolites, pharmaceutically acceptable salts, pharmaceutical products, hydrates or N- An oxide or any combination thereof, in an amount effective to inhibit sperm production in the patient, thereby achieving contraception in the patient. 51. A method of hormonal treatment, comprising the steps of bringing a patient's androgen receptor to a selective androgen receptor modulator compound according to the scope of the patent application No. 15, 15, 29, or 43 'and / or its similarity Substance: Derivatives, isomers, metabolites, pharmaceutically acceptable salts, pharmaceutical products, hydrates or N-oxides or any combination thereof are contacted in amounts effective to achieve changes in androgen-dependent symptoms. 5. A method of hormone replacement therapy, which includes the steps of bringing the disease and patient's androgen receptor and a selective androgen receptor modulator compound according to the scope of the patent application No. 丨 15, 15, or ，, and / or Its analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, medicinal products, hydrates or N-oxides or any combination thereof may be contacted in an amount that can achieve androgen-dependent symptoms The change. 53 · T A method for preventing prostate cancer in a patient, comprising the steps of administering a child vortex patient in accordance with No. 丨, 15, 29 or 43 of the scope of application patent -12- 200304806 Selective androgen receptor modulator compounds, and / or their analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, pharmaceutical products, hydrates or N-oxides, or any combination thereof, The amount can effectively prevent prostate cancer in the patient. 54 · A method for treating a patient with hormone-related symptoms, comprising the step of administering to the patient a selective androgen receptor modulator compound according to item 1, 15, 29, or 43 of the scope of patent application And / or its analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, pharmaceutical products, hydrates or N-oxides, or any combination thereof, in an amount effective to achieve androgen-dependent symptoms In the change. 55. A method for treating a patient with prostate cancer, comprising the step of administering to the patient a selective androgen receptor modulator compound according to the scope of application for patent No. 丨, 15, 29, or 43; And / or its analogs, derivatives, isomers, metabolites, pharmaceutically acceptable records, pharmaceutical products, hydrates or N-oxides, or any combination thereof, in an amount effective to treat the prostate in the patient cancer. 56 · —A method for delaying the progression of prostate cancer in a patient with prostate cancer, comprising the steps of administering to the patient a selective androgen according to the scope of patent application No. 1, 15, 29 or 43 Receptor modulator compounds, and / or their analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, pharmaceutical products 'hydrates or N. oxides or any combination thereof' Patients effectively delay the progression of forefront ridges,% ... adenomas. 57 · —A method for preventing the recurrence of prostatic sclerosis J and sores in patients with prostate cancer, which includes the following steps: administering the disease to the patient. The scope of patent application -13- 200304806 The selective androgen receptor modulator compound 'and / or its analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, pharmaceutical products, hydrates or The amount of N_oxide or any combination thereof can effectively prevent the recurrence of prostate cancer in the patient. 58. A method for treating recurrence of prostate cancer in a patient with prostate cancer, comprising the steps of administering to the patient a selective male patient according to item 1, 15, 29, or 43 of the scope of the patent application Hormone receptor modulator compounds, and / or their analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, pharmaceutical products, hydrates or N-oxides, or any combination thereof, the amount of which may be This patient is effective in treating the recurrence of prostate cancer. 59. A method for treating dry eye symptoms in a patient with dry eye, comprising the steps of administering to the patient a selective androgen receptor in accordance with the scope of patent application No. 1, 15, 29 or 43 Body modulator compounds, and / or their analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, pharmaceutical products, hydrates or N-oxides or any combination thereof, the amount of which may be in the patient Effective in treating dry eyes. 60 · A method for preventing dry eye symptoms in a patient, comprising the step of administering to the patient a selective androgen receptor modulator compound according to item 1, 15, 29 or 43 of the scope of patent application, And / or its analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, pharmaceutical products, hydrates or N-oxides, or any combination thereof, in an amount effective to prevent dry eyes in patients . -14- 200304806 61 · A method for causing cell death in prostate cancer cells, comprising the steps of bringing the cell and a selective androgen receptor modulator compound according to item 1, 15, 29, or 43 of the scope of patent application, and / Or its analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, pharmaceutical products, hydrates or N-oxides, or any combination thereof, in an amount effective to cause cells in the cancer cell Wither. 62 · —A method for preparing a selective androgen receptor modulator (SARM) compound, which is represented by the structure of Formula I: Where X is 0, N, S, Se, PR or NR; G is 0 or S; T is OH, OR, -NHCOCH3 or NHCOR; R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl , CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, halogen, fluorenyl, or OH; 仏 is CH3, CH2F, CHF2, CF3, CH2CH3, or CF2CF3; R2 is F, a, Br, I, ch3, CF3, OH, CN, no2, nhcoch3, NHCOCF3, NHCOR, alkyl, aralkyl, OR, NH2, NHR, NR2, SR; R3 is F, Cl, Br, I, CN, N02, COR, COOH, CONHR, CF3 , SnR3, or R3 forms a fused ring system with the benzene ring to which it is attached, and is represented by the following structure: 200304806 Z is N02, CN, COR, COOH, or CONHR; Y is CF3, F, Br, Cl, I, CN, or SnR3; Q is SCN, NCS, OCN, or NCO; n is an integer from 1 to 4; and m is 1 An integer of -3; the method comprises the following steps: Where Z, Y, G, Ri, T, R3 and m are as defined above, and L is a leaving group, which is coupled with a compound of formula IX: Wherein Q, X, 1 ^ 2 and 11 are as defined above. 63. The method according to item 62 of the application, wherein G is 0, T is OH, &amp; is CH3, X is 0, Z is N02, Y is CF3, and Q is NCS. 64. The method according to item 62 of the application, wherein the compound of formula VIII is 200304806. Prepared in the following manner i) By the ring-opening action of the cyclic compound of formula XI, the compound of formula X is prepared Where L, Ri, G, and T are as defined above, and D is 0 or NH; and ii) makes the amine of formula XII: Where Z, Y, R3 and m are as defined above, and react with a compound of formula X in the presence of a coupling reagent to produce a compound of formula VIII. 65. The method according to item 62 of the application, further comprising the step of purifying the compound of formula I using a mixture of ethanol and water. 66. The method according to item 62 of the scope of patent application, further comprising converting the selective androgen receptor modulator (SARM) compound into its analog, isomer, metabolite, derivative, pharmaceutically acceptable Steps of salts, pharmaceutical products, N-oxides, hydrates, or any combination thereof. 200304806 67. A method for preparing a selective androgen receptor modulator (SARM) compound, the compound is represented by the structure of formula II: G Π Where X is 0, NH, S, Se, PR or NR; G is 0 or S; heart is CH3, CH2F, CHF2, CF3, CH2CH3 or CF2CF3; T is OH, OR, -NHCOCH3 or NHCOR; R is alkyl , Haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, halogen, alkyl, or OH; A is a ring selected from: 200304806 Where A and B cannot be benzene rings at the same time; Z is N02, CN, COOH, COR, NHCOR or CONHR; Y is CF3, F, I, Br, Cl, CN, CR3 or SnR3; Qi is NCS, SCN, NCO Or OCN; Q2 is hydrogen, alkyl, halogen, CF3, CN, CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSRNHS02CH3, NHS02R, OR, COR, OCOR, 0S02R, S02R, SR, Q3 and Q4 are independent of each other: hydrogen, alkyl, halogen, CF3, CN, CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR, NHS02CH3, NHS02R, OR, COR, OCOR, OS02R, S02R, or SR; Wi is 0, NH, NR, N, O, or S; and W2 is N or NO; the method includes the following steps to make a compound of formula XIII: Ri T ^ NH L where A, G, R, and T are as defined above, and L is a leaving group, and the formula YX-Β 200304806 Compounds are coupled, where B and X are as defined above. 68. The method according to item 67 of the application, wherein G is 0, T is OH, Ri is CH3, X is 0, z is N02, Y is CF3, and NCS. 69. The method according to item 67 of the scope of patent application, wherein the ammonium compound of formula XIII is prepared in the following manner i) The compound of formula X is prepared by the ring-opening action of the cyclic compound of formula XI Wherein L, Xin, G, and T are as defined above, and 1 ^ is 0 or NH; and ii) an amine of formula A-NH2, wherein A is as defined above and reacted with a compound of formula X in the presence of a coupling reagent, To make formula XIII amidine. RK T 70. The method according to item 67 of the scope of patent application, further comprising the step of purifying the compound of formula II using a mixture of ethanol and water. 71. The method according to item 67 of the scope of patent application, further comprising converting the selective androgen receptor modulator (SARM) compound into its analog, isomer, metabolite, derivative, pharmaceutically acceptable Steps of salts, pharmaceutical products, N-oxygenates, hydrates, or any combination thereof. 72 · A method for preparing a selective androgen receptor modulator (SARM) 200304806 The compound is represented by the structure of formula III: Where X is 0, NH, S, Se, PR or NR; G is 0 or S; T is OH, OR, -NHCOCH3 or NHCOR; Z is No. 02, CN, COOH, COR, NHCOR or CONHR; Y is CF3, F, I, Br, Cl, CN, CR3, or SnR3; Q is SCN, NCS, OCN, or NCO; R is alkyl, lialkyl, dihaloalkyl, trifunctional alkyl, ch2f, CHF2, CF3 , CF2CF3, aryl, phenyl, halide, alkenyl, or OH: and hydrazone is CH3, CH2F, CHF2, CF3, CH2CH3, or CF2CF3; the method includes the following steps to make a compound of formula XIV: Z Where Z, Y, G, Xin and D are as defined above, and L is a leaving group, which is coupled with a compound of formula XV: HX. XV 200304806 Where Q and X are as defined above. 73. The method according to item 72 of the scope of patent application, where G is 0, T is OH, Ri is CH3, X is 0, Z is N02, Y is CF3, and Q is NCS. 74. The method according to item 72 of the scope of patent application, wherein the compound of formula XIV is prepared in the following manner i) The compound of formula X is prepared by the ring-opening action of the cyclic compound of formula XI Where L, Xin, and D are as defined above, G is 0, and 1 \ is 0 or NH; and ii) the amine of formula XVI Reacting with a compound of formula X in the presence of a coupling reagent to produce a compound of formula XIV. 75. The method according to item 72 of the scope of patent application, further comprising the use of ethanol 200304806 A step of purifying the compound of formula III with a mixture with water. 76. The method according to item 72 of the scope of patent application, further comprising converting the selective androgen receptor modulator (SARM) compound into its analog, isomer, metabolism product, derivative, pharmaceutically acceptable salt , Pharmaceutical products, N-oxides, hydrates, or any combination thereof. 77. The method according to item 72 of the scope of application for a patent, wherein the SARM is in the formula V structure table 7JT · · Ύ \ ·