CN102976973A - Selective androgen receptor modulator and method for using thereof - Google Patents

Abstract

The invention relates to a selective androgen receptor modulator and a method for using thereof. Specifically, the invention provides a SARM compound and application of treating various diseases or illnesses in individuals. The diseases or illnesses especially comprise muscle marasmus diseases or illnesses or bone related diseases or illnesses.

Description

Selective androgen receptor modulators and methods of use thereof

This application is a divisional application of the Chinese patent application 200580018468.2 with the title of "selective androgen receptor modulator and method of use thereof" submitted on June 7, 2005.

Background technique

The androgen receptor ("AR") is a ligand-activated transcriptional regulatory protein that mediates the induction of male sexual development and function through its endogenous androgenic activity. Androgens are often called male sex hormones. Androgens are steroids that are produced in the body by the testes and adrenal cortex, or can be synthesized in the laboratory. Androgenic steroids play an important role in many physiological processes, including the development and maintenance of male sexual characteristics such as muscle and bone mass, prostate growth, spermatogenesis, and male hair distribution (Matsumoto, Endocnnol. Met. Clin. N. Am. 23: 857-75(1994)). Endogenous steroid androgens include testosterone and dihydrotestosterone ("DHT"). Testosterone is the major steroid secreted by the testes and is the major circulating androgen found in male serum. In many peripheral tissues, testosterone is converted to DHT by the enzyme 5α-reductase. It is therefore believed that DHT acts as an intracellular mediator for most androgenic effects (Zhou et al., Molec. Endocrinol. 9:208-18 (1995)). Other steroid androgens include esters of testosterone such as cypionate, propionate, phenylpropionate, cyclopentylpropionate, isocarporate, enanthate, and caprate, and other synthetic androgens such as 7-Methylnortestosterone ("MENT") and its acetate (Sundaram et al., "7Alpha-Methyl-Nortestosterone (MENT): The Optimal Androgen For Male Contraception," Ann.Med, 25:199-205 (1993 )("Sundaram")). Since AR is involved in male sexual development and function, AR is a likely target for male contraception or other forms of hormone replacement therapy.

BMD (bone mineral density) decreases with age in both men and women. Decreased bone mineral content (BMC) and BMD correlates with decreased bone strength, predisposing patients to fractures.

Osteoporosis is a systemic skeletal disorder characterized by low bone mass, degeneration of bone tissue, and consequent increased bone fragility and susceptibility to fracture. The condition affects more than 25 million people in the United States and causes more than 1.3 million fractures each year, including 500,000 spine fractures, 250,000 hip fractures, and 240,000 wrist fractures each year. Hip fractures are the most serious consequence of osteoporosis, killing 5-20% of individuals each year and disabling more than 50% of survivors. Older adults are at greatest risk for osteoporosis, so the problem is expected to increase as the population ages. The incidence of fractures worldwide is expected to triple within the next 60 years, with one study estimating 4.5 million hip fractures worldwide in 2050.

Women are at greater risk of osteoporosis than men. Bone loss accelerates markedly in women within 5 years of postmenopause. Other factors that increase this risk include smoking, alcohol abuse, a sedentary lifestyle, and low calcium intake. However, men also frequently develop osteoporosis. It is well established that bone mineral density decreases with age in men. Decreased bone mineral content and density are associated with decreased bone strength and susceptibility to fractures. The molecular mechanisms underlying the pleiotropic effects of sex hormones in nonreproductive tissues are just beginning to be understood, but it is clear that physiological concentrations of androgens and estrogens play an important role in maintaining bone homeostasis throughout the lifespan. Thus, when androgen or estrogen loss occurs, the result is an increased rate of bone remodeling, tipping the balance of resorption and formation in favor of resorption, which results in a loss of overall bone mass. In men, a natural decrease in mature sex hormones (direct decrease in androgens and lower levels of estrogens derived from peripheral aromatization of androgens) is associated with bone fragility. This effect was also observed in castrated males.

Muscular wasting refers to progressive loss of muscle mass and/or progressive weakness and degeneration of muscles, including skeletal or voluntary muscles that control movement, heart muscle that controls the heart (cardiomyopathy), and smooth muscle. Chronic muscle wasting is a chronic condition (ie, lasting over a long period of time) characterized by progressive loss of muscle mass, weakness and degeneration of muscles.

The loss of muscle mass that occurs during sarcopenia can be characterized by the catabolic degradation of myosin. Proteolysis occurs because of an unusually high rate of protein degradation, an unusually low rate of protein synthesis, or a combination of both. Muscle protein degradation, whether caused by high levels of protein degradation or low levels of protein synthesis, results in loss of muscle mass and leads to muscle wasting.

Muscle wasting is associated with a chronic, neuropathic, genetic or infectious pathology, disease, ailment or condition. These include muscular dystrophies, such as Duchenne muscular dystrophy and myotonic dystrophy; muscle atrophy, such as post-polio muscular atrophy (PPMA); cachexia, such as cardiac cachexia, AIDS cachexia and cancer cachexia, nutritional Leprosy, diabetes, kidney disease, chronic obstructive pulmonary disease (COPD), cancer, end-stage renal failure, sarcopenia, emphysema, osteomalacia, HIV infection, AIDS, and cardiomyopathy.

In addition, other environments and conditions are associated with and can lead to muscle wasting. These include chronic low back pain, advanced age, central nervous system (CNS) injury, peripheral nerve injury, spinal cord injury, chemical injury, central nervous system (CNS) injury, peripheral nerve injury, spinal cord injury, chemical injury, burns, or injury leading to immobilization of limbs, disuse deconditioning in prolonged hospitalization, and alcoholism.

An intact androgen receptor (AR) signaling pathway is critical for proper development of skeletal muscle. Furthermore, an intact AR-signaling pathway increases muscle lean mass, muscle strength, and muscle protein synthesis.

Muscle wasting can have dire health consequences, if not diminished. For example, changes that occur during muscle wasting can result in a weakened physical condition that is detrimental to the individual's health, leading to increased susceptibility to infection and poor performance status. Furthermore, muscle wasting is a strong predictor of morbidity and mortality in patients with cachexia and AIDS.

There is an urgent need for a pioneering approach to the prevention and treatment of osteoporosis and other bone-related diseases and muscle wasting, especially chronic muscle wasting, both at the basic science level and at the clinical level. The present invention fulfills this need.

Contents of the invention

In one embodiment, the present invention provides a selective androgen receptor modulator (SARM) compound represented by the structure of formula (I) or a prodrug, analog, isomer, metabolite, derivative, Pharmaceutically acceptable salts, drug products, polymorphs, crystals, impurities, N-oxides, hydrates, or any combination thereof:

where X is O;

Z is NO ₂ , CN, COR or CONHR;

Y is I, CF ₃ , Br, Cl, F or Sn(R) ₃ ;

Q is CN;

T is OH, OR, -NHCOCH ₃ , NHCOR or OC(O)R;

R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, _CH2F , _CHF2 , _{CF3 , CF2CF3} , aryl, phenyl, halogen, alkenyl, or OH; and

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

In another embodiment, the present invention provides a selective androgen receptor modulator (SARM) compound represented by the structure of formula (III), or a prodrug, analog, isomer, metabolite, derivative, pharmaceutical Acceptable salts, drug products, polymorphs, crystals, impurities, N-oxides, hydrates, or any combination thereof:

In another embodiment, the present invention provides a selective androgen receptor modulator (SARM) compound represented by the structure of formula (IV) or a prodrug, analog, isomer, metabolite, derivative, pharmaceutical Acceptable salts, drug products, polymorphs, crystals, impurities, N-oxides, hydrates, or any combination thereof:

where X is O;

T is OH, OR, NHCOCH ₃ , NHCOR or OC(O)R;

Z is H, alkyl, _NO2 , CN, COOH, COR, NHCOR or CONHR;

Y is H, alkyl, _CF3 , halogen, hydroxy-alkyl or alkylaldehyde;

A is a group selected from:

in

R ₂ , R ₃ , R ₄ , R ₅ , R ₆ are independently H, halogen, CN, NO ₂ , NHCOCF ₃ ;

R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, _CH2F , _CHF2 , _{CF3 , CF2CF3} , aryl, phenyl, halogen, alkenyl, or OH; and

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

In one embodiment according to this aspect of the invention X is O, or in another embodiment T is OH, or in another embodiment _R1 is _CH3 , or in another embodiment , Z is NO ₂ , or in another embodiment, Z is CN, or in another embodiment, R ₂ , R ₃ , R ₅ , R ₆ are H, and R ₄ is NHCOCF ₃ , or in another embodiment In one embodiment, R ₂ , R ₃ , R ₅ , R ₆ are H, and R ₄ is F, or in another embodiment, R ₂ , R ₃ , R ₅ , R ₆ are H, or in another embodiment In one embodiment, Z is in the para position, or in another embodiment, Y is in the meta position, or in another embodiment, any combination thereof.

In another embodiment, the present invention provides a pharmaceutical composition comprising a SARM compound of formula (I), (III) or (IV) and a suitable carrier or diluent.

In another embodiment, the present invention provides the use of a compound of formula (I), (III) or (IV), or a composition containing the same, for the treatment of an individual suffering from a bone-related disorder.

In another embodiment, the present invention provides the use of a compound of formula (I), (III) or (IV), or a composition containing it, for increasing bone strength or bone mass or promoting bone formation in a subject.

In another embodiment, the present invention provides the use of a compound of formula (I), (III) or (IV) for treating, preventing, suppressing, inhibiting or reducing the incidence of muscular wasting in an individual.

In another embodiment, the present invention provides the use of a compound of formula (I), (III) or (IV) for increasing muscle performance, muscle size, muscle strength or any combination thereof in an individual.

In another embodiment, the present invention provides the use of a compound of formula (I), (III) or (IV), or a composition containing it, for the treatment of obesity or diabetes associated with metabolic syndrome in an individual.

In another embodiment, the present invention provides the use of a compound of formula (I), (III) or (IV), or a composition containing it, for promoting or accelerating recovery after a surgical procedure.

In another embodiment, the present invention provides the use of a compound of formula (I), (III) or (IV), or a composition containing it, for promoting or suppressing spermatogenesis in a male individual.

Description of drawings

Figure 1 : Effects of SARM, DHT and PTH on the differentiation of rat bone marrow cells into osteoblast lineages.

Figure 2 : Effects of SARM, DHT and PTH on TRAP-positive multinucleated osteoclasts.

Figure 3 : Maximum load on the femur measured by the 3-point bending method of the femur.

Figure 4: Trabecular bone mineral density of the distal femur as measured by pQCT analysis.

Figure 5 : Pharmacology of compound III in intact rats.

Figure 6 : Organ weights of Compound III-treated castrated rats expressed as a percentage of intact controls. *P value <0.05 vs. intact control.

中的S形曲线E_max模型进行非线性回归分析获得。 Figure 7 : Organ weight maintenance dose-response curve of compound III in castrated rats. The _Emax and _ED50 values of the levator ani (closed triangle), prostate (open circle) and seminal vesicle (closed square) were obtained by using

The sigmoid curve E _max model in is obtained by nonlinear regression analysis.

Figure 8 : Organ weights of Compound III-treated castrated rats expressed as a percentage of the intact pair. *P value <0.05 vs. intact control.

中的S形曲线E_max模型进行非线性回归分析获得。 Figure 9 : Organ weight regeneration dose-response curve of Compound III in castrated rats. The _Emax and _ED50 values of the levator ani (closed triangle), prostate (open circle) and seminal vesicle (closed square) were obtained by using

The sigmoid curve E _max model in is obtained by nonlinear regression analysis.

Figure 10 : Serum concentration-time profile of Compound III orally administered in PEG300 in healthy volunteers.

Figure 11 : Serum Concentration-Time Profile of Compound III Solution vs. Solid Oral Dosage Form.

Figure 12 : Serum concentration-time curves of different dosage forms of Compound III administered at 30 mg.

Figure 13 : Dose vs. AUC _0-inf of oral solution (G100401).

Figure 14 : Dose vs. C _max for oral solutions.

Figure 15 : Cholesterol lowering by compound III in rats.

Detailed ways

In the following detailed description, numerous specific details are set forth in order to provide a thorough understanding of the invention. It will be understood, however, by those skilled in the art that the present invention may be practiced without these specific details. In other instances, well-known methods, procedures and components have not been described in detail so as not to limit the invention.

In one embodiment, the present invention provides a selective androgen receptor modulator (SARM) compound represented by the structure of formula (I) or a prodrug, analog, isomer, metabolite, derivative, Pharmaceutically acceptable salts, drug products, polymorphs, crystals, impurities, N-oxides, hydrates, or any combination thereof:

where X is O;

Z is NO ₂ , CN, COR or CONHR;

Y is I, CF ₃ , Br, Cl, F or Sn(R) ₃ ;

Q is CN;

T is OH, OR, -NHCOCH ₃ , NHCOR or OC(O)R;

R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, _CH2F , _CHF2 , _{CF3 , CF2CF3} , aryl, phenyl, halogen, alkenyl, or OH; and

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

In another embodiment, the present invention provides a SARM represented by the structure of formula (II):

where X is O;

Z is NO ₂ , CN, COR or CONHR;

Y is I, CF ₃ , Br, Cl, F or Sn(R) ₃ ;

R is alkyl or OH; and

Q is CN.

In one embodiment, the present invention provides a selective androgen receptor modulator (SARM) compound represented by the structure of formula (III), or a prodrug, analog, isomer, metabolite, derivative, pharmaceutically acceptable Accepted salts, drug products, polymorphs, crystals, impurities, N-oxides, hydrates, or any combination thereof:

In another embodiment, the present invention provides a selective androgen receptor modulator (SARM) compound represented by the structure of formula (IV) or a prodrug, analog, isomer, metabolite, derivative, pharmaceutically acceptable Accepted salts, drug products, polymorphs, crystals, impurities, N-oxides, hydrates, or any combination thereof:

where X is O;

T is OH, OR, NHCOCH ₃ , NHCOR or OC(O)R;

Z is H, alkyl, _NO2 , CN, COOH, COR, NHCOR or CONHR;

Y is H, alkyl, _CF3 , halogen, hydroxy-alkyl or alkylaldehyde;

A is a group selected from:

in

R ₂ , R ₃ , R ₄ , R ₅ , R ₆ are independently H, halogen, CN, NO ₂ , NHCOCF ₃ ;

R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, _CH2F , _CHF2 , _{CF3 , CF2CF3} , aryl, phenyl, halogen, alkenyl, or OH; and

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

In one embodiment according to this aspect of the invention X is O, or in another embodiment T is OH, or in another embodiment _R1 is _CH3 , or in another embodiment , Z is NO ₂ , or in another embodiment, Z is CN, or in another embodiment, R ₂ , R ₃ , R ₅ , R ₆ are H, and R ₄ is NHCOCF ₃ , or in another embodiment In one embodiment, R ₂ , R ₃ , R ₅ , R ₆ are H, and R ₄ is F, or in another embodiment, R ₂ , R ₃ , R ₅ , R ₆ are H, or in another embodiment In one embodiment, Z is at the para position, or in another embodiment, Y is at the meta position, or in another embodiment, any combination thereof.

In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I), (II), (III) or (IV) or a prodrug, analog, isomer, metabolite, Derivatives, pharmaceutically acceptable salts, drugs, polymorphs, crystals, impurities, N-oxides, hydrates or any combination thereof and a suitable carrier or diluent.

In one embodiment, "alkyl" refers to a saturated aliphatic hydrocarbon, which includes linear, branched and cyclic alkyl groups. In one embodiment, the alkyl group has 1-12 carbons. In another embodiment, the alkyl group has 1-7 carbons. In another embodiment, the alkyl group has 1-6 carbons. In another embodiment, the alkyl group has 1-4 carbons. The alkyl group may be unsubstituted or substituted with one or more groups selected from the group consisting of halogen, hydroxy, alkoxycarbonyl, amido, alkylamido, dialkylamido, nitro, amino, alkane Amylamino, dialkylamino, carboxyl, thio and thioalkyl.

In one embodiment, "alkenyl" refers to an unsaturated hydrocarbon including straight chain, branched chain and cyclic groups having one or more double bonds. An alkenyl group can have one double bond, two double bonds, three double bonds, etc. Examples of alkenyl groups are ethenyl, propenyl, butenyl, cyclohexenyl and the like. Alkenyl can be unsubstituted or substituted with one or more groups selected from the group consisting of halogen, hydroxy, alkoxycarbonyl, amido, alkylamido, dialkylamido, nitro, amino, alkyl Amino, dialkylamino, carboxy, thio and thioalkyl.

"Haloalkyl" means an alkyl group as defined above which is substituted by one or more halogen atoms, in one embodiment by F, in another embodiment by Cl, in another embodiment by Br is substituted, in another embodiment, with I.

"Aryl" means an aromatic group having at least one carbocyclic aryl or heterocyclic aryl group, which may be unsubstituted or substituted with one or more groups selected from the group consisting of halogen, haloalkyl, hydroxy, Alkoxycarbonyl, amido, alkylamido, dialkylamido, nitro, amino, alkylamino, dialkylamino, carboxyl or thio or thioalkyl. Non-limiting examples of aromatic rings are phenyl, naphthyl, pyranyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyrazolyl, pyridyl, furyl, thienyl, thiazolyl, imidazolyl, isoxazole Base etc.

"Hydroxy" means an OH group. Those skilled in the art understand that when T in the compound of the present invention is OR, R is not OH.

In one embodiment, the term "halo" or "halogen" refers to F in one embodiment, Cl in another embodiment, Br in another embodiment, or Br in another embodiment I.

In one embodiment, "aralkyl" refers to an alkyl group attached to an aryl group, wherein alkyl and aryl are as defined above. An example of aralkyl is benzyl.

In one embodiment, the present invention provides SARM compounds and/or their analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, pharmaceuticals, hydrates, N-oxides, prodrugs, polymorphs substances, impurities or crystals or any combination thereof. In another embodiment, the present invention provides analogs of SARM compounds. In another embodiment, the present invention provides derivatives of SARM compounds. In another embodiment, the present invention provides isomers of SARM compounds. In another embodiment, the present invention provides metabolites of SARM compounds. In another embodiment, the present invention provides a pharmaceutically acceptable salt of a SARM compound. In another embodiment, the present invention provides a medicament of a SARM compound. In another embodiment, the present invention provides a hydrate of a SARM compound. In another embodiment, the present invention provides N-oxides of SARM compounds. In another embodiment, the present invention provides prodrugs of SARM compounds. In another embodiment, the present invention provides polymorphs of SARM compounds. In another embodiment, the present invention provides a crystal of a SARM compound. In another embodiment, the present invention provides an impurity of a SARM compound. In another embodiment, the present invention provides a composition comprising a SARM compound, or in another embodiment, an analog, derivative, isomer, metabolite, pharmaceutically acceptable salt of a SARM compound of the present invention , drug product, hydrate, N-oxide, prodrug, polymorph, impurity or combination of crystals.

In one embodiment, the term "isomer" includes, but is not limited to, optical isomers and analogs, structural isomers and analogs, conformational isomers and analogs, and the like.

In one embodiment, the term "isomer" is meant to include optical isomers of the SARM compound. Those skilled in the art will appreciate that the SARMs of the present invention contain at least one chiral center. Thus, the SARMs used in the methods of the invention may exist in optically active or racemic forms, and may be isolated in optically active or racemic forms. Some compounds may also exhibit polymorphism. It is to be understood that the present invention includes any racemic, optical, polymorphic or stereoisomeric forms, or mixtures thereof, which have properties useful in the treatment of the androgen-related disorders described herein. In one embodiment, the SARM is the pure (R)-isomer. In another embodiment, the SARM is the pure (S)-isomer. In another embodiment, the SARM is a mixture of (R) and (S) isomers. In another embodiment, the SARM is a racemic mixture containing equal amounts of the (R) and (S) isomers. It is well known in the art how to prepare optically active forms (eg, by resolution of racemic forms by recrystallization techniques, by synthesis from optically active starting materials, by chiral synthesis or by chromatographic separation using chiral stationary phases).

The invention includes "pharmaceutically acceptable salts" of the SARMs of the invention, which can be prepared in one embodiment using amino-substituted SARMs with organic and inorganic acids, such as citric and hydrochloric acids. In another embodiment, pharmaceutically acceptable salts can also be prepared by treating the phenolic compound with an inorganic base such as sodium hydroxide. In another embodiment, esters of phenolic compounds can be prepared by using aliphatic and aromatic carboxylic acids such as acetic acid and benzoate.

The present invention also includes N-oxides of the amino substituents of the SARMs described herein.

The present invention provides derivatives of SARM compounds. In one embodiment, "derivatives" include, but are not limited to, ether derivatives, acid derivatives, amide derivatives, ester derivatives, and the like. In another embodiment, the present invention also includes hydrates of SARM compounds. In one embodiment, "hydrate" includes, but is not limited to, hemihydrate, monohydrate, dihydrate, trihydrate, and the like.

In other embodiments, the present invention provides metabolites of SARM compounds. In one embodiment, "metabolite" means any substance produced from another substance by metabolism or a metabolic process.

In other embodiments, the present invention also provides medicaments of SARM compounds. In other embodiments, the term "medicament" refers to a composition suitable for pharmaceutical use (pharmaceutical composition) as described herein.

Selective Androgen Modulators (SARMs)

Selective androgen receptor modulators (SARMs) are a class of androgen receptor targeting agents (ARTAs) that exhibit androgenic and anabolic activity of non-steroidal ligands of the androgen receptor. These new active agents are used in men for the treatment of various hormone-related conditions such as sexual dysfunction, decreased libido, erectile dysfunction, hypogonadism, sarcopenia, osteopenia, osteoporosis, cognitive and mood changes, depression , anemia, hair loss, obesity, benign prostatic hyperplasia and/or prostate cancer. Additionally, SARMs are used in oral androgen replacement therapy as well as in prostate cancer imaging. In addition, SARMs are used in women to treat various hormone-related conditions such as sexual dysfunction, decreased libido, hypogonadism, sarcopenia, osteopenia, osteoporosis, cognitive and mood changes, depression, anemia, hair loss, obesity , endometriosis, breast cancer, uterine cancer and ovarian cancer.

As contemplated herein, the present invention provides a class of selective androgen receptor modulator (SARM) compounds. These compounds useful in the prevention and treatment of muscle wasting and bone-related disorders are classified as androgen receptor agonists (AR agonists), partial agonists or androgen receptor antagonists (AR antagonists).

A receptor agonist is a substance that binds to a receptor and activates it. Receptor partial agonists are substances that bind to a receptor and partially activate it. Receptor antagonists are substances that bind to receptors and inactivate them. As exemplified herein, in some embodiments, SARM compounds of the invention have tissue-selective effects, e.g., wherein the individual active agents are agonists, partial agonists and/or antagonists, depending on the tissue in which the receptor is expressed . For example, SARM compounds stimulate muscle tissue while inhibiting prostate tissue. In one embodiment, the SARMs used in the treatment and prevention of muscle wasting are agonists and thus serve to bind and activate the AR. In another embodiment, the SARM is an AR antagonist and thus serves to bind and inactivate AR. Assays to determine whether a compound of the invention is an agonist or antagonist of AR are known to those skilled in the art. For example, AR agonistic activity can be determined 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 using a gravimetric assay. AR antagonistic activity can be determined by monitoring the ability of SARM compounds to inhibit the growth of AR-containing tissues.

In another embodiment, the SARM compounds of the invention may be classified as partial AR agonists/antagonists. SARMs are AR agonists in some tissues, leading to increased transcription of AR-responsive genes (eg, muscle anabolic effects). In other tissues, these compounds act as competitive inhibitors of AR by testosterone/DHT to prevent the agonistic effects of endogenous androgens. In one embodiment, the term SARM or Selective Androgen Receptor Modulator refers to a compound that modulates the activity of the androgen receptor. In one embodiment, the SARM is an agonist, or in another embodiment, an antagonist.

In one embodiment, the SARM has antagonistic activity in the gonads of the individual and agonistic activity in the periphery, such as muscle. These activities are demonstrated herein in terms of effects on prostate tissue versus levator ani muscle tissue, as exemplified in Figures 3, 4 or 5.

In one embodiment, the SARM compounds of the invention bind reversibly to the androgen receptor, or in another embodiment, irreversibly bind the androgen receptor. In one embodiment, the SARM compound reversibly binds to the androgen receptor. In another embodiment, the SARM compound irreversibly binds to the androgen receptor. Compounds of the invention may contain functional groups (eg, affinity tags) that alkylate (ie, covalently bond) the androgen receptor. Thus, in this case, the compound binds irreversibly to the receptor and thus cannot be replaced by steroids such as the endogenous ligands DHT and testosterone.

In one embodiment, modulation of the androgen receptor refers to the ability of a compound to stimulate or enhance signaling through the receptor and, in another embodiment, through any or all of the downstream effects of receptor signaling.

In another embodiment, modulation of the androgen receptor refers to the ability of a compound to attenuate or eliminate signal transduction through the receptor and, in another embodiment, any or all of the downstream effects of receptor signaling.

In another embodiment, the SARMs of the invention can interact with homologs of the androgen receptor. The term "homologue of the androgen receptor" refers in one embodiment to a structurally or in another embodiment to a functionally related receptor, the modulation of which is desired. The SARMs of the present invention may interact with estrogen receptors in one embodiment, or in another embodiment, with other cell surface molecules involved in synthetic pathways, or in another embodiment, with other cell surface molecules involved in steroidogenesis. other cell surface molecules of the pathway, or in another embodiment, interact with other cell surface molecules involved in the metabolic pathway.

In one embodiment, the invention also provides compositions comprising a SARM of the invention, or in another embodiment, compositions comprising SARMs of the invention.

In one embodiment, the composition is a pharmaceutical composition, in another embodiment it is a pill, tablet, capsule, micronized or non-micronized capsule, solution, suspension, emulsion, Elixirs, gels, creams, suppositories, or parenteral formulations.

In one embodiment, micronized capsules contain particles comprising a SARM of the invention, wherein the term "micronized" as used herein refers to particles having a particle size of less than 100 microns, in another embodiment, less than 50 microns, or in another embodiment In one embodiment, less than 35 microns, or in another embodiment, less than 15 microns, or in another embodiment, less than 10 microns, or in another embodiment, less than 5 microns.

The pharmaceutical composition may be administered in any effective and convenient manner, such as by intravascular (i.v.), intramuscular (i.m.), intranasal (i.n.), subcutaneous (s.c.), sublingual, oral, rectal, intrathecal delivery Administer or administer by any means that can deliver the recombinant virus/composition to the tissue (eg needle or catheter). Alternatively, topical administration may be desired for mucosal cells, for dermal or ocular administration. Another mode of administration is via inhalation or aerosol formulations.

For administration to mammals, especially humans, it is expected that the physician will determine the actual dosage and duration of treatment which will be most appropriate for the individual and which may vary with the age, weight and response of the particular individual.

In one embodiment, the composition to be administered may be a sterile solution, or in another embodiment, an aqueous or non-aqueous solution, suspension or emulsion. In one embodiment, the composition may contain propylene glycol, polyethylene glycol, injectable organic esters such as ethyl oleate, or cyclodextrin. In another embodiment, the composition may also contain wetting, emulsifying and/or dispersing agents. In another embodiment, the composition may also contain sterile water or any other sterile injectable medium.

In one embodiment, a composition of the invention may comprise a SARM of the invention, or any combination thereof, and one or more pharmaceutically acceptable excipients.

In one embodiment, a "pharmaceutical composition" may refer to a therapeutically effective amount of one or more compounds of the invention together with suitable excipients and/or carriers for use in the methods of the invention. In one embodiment, the composition will contain a therapeutically effective amount of a SARM of the invention. In one embodiment, the term "therapeutically effective amount" may refer to an amount that provides a therapeutic effect for a given condition and administration regimen. In one embodiment, the composition can be administered by any method known in the art.

In one embodiment, the composition of the present invention is formulated as an oral or parenteral dosage form, such as uncoated tablet, coated tablet, pill, capsule, powder, granule, dispersion or suspension. In another embodiment, the compositions of the invention are formulated for intravenous administration. In another embodiment, the compounds of the invention are formulated for transdermal administration in the form of an ointment, cream or gel. In another embodiment, the compounds of the invention are formulated for nasal administration as an aerosol or spray. In another embodiment, the compositions of the invention are formulated as liquid dosage forms. Examples of suitable liquid dosage forms include solutions or suspensions, creams, syrups or elixirs, solutions and/or suspensions in water, pharmaceutically acceptable fats and oils, alcohols or other organic solvents including esters agent.

According to embodiments of the present invention, suitable excipients and carriers may be solid or liquid, and the type is generally selected based on the type of administration being used. Liposomes can also be used to deliver the compositions. Examples of suitable solid carriers include lactose, sucrose, gelatin and agar. Oral dosage forms may contain suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents and melting agents. For example, liquid dosage forms may contain suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweetening agents, thickening agents and melting agents. Parenteral and intravenous forms also contain minerals and other substances to make them compatible with the type of injection or delivery system chosen. Of course, other excipients may also be used.

The SARMs of the invention can be administered in various dosages. In one embodiment, the SARM is administered at a dose of 0.1-200 mg/day. In another embodiment, the SARM is administered at a dose of 0.1-10 mg, or in another embodiment, 0.1-25 mg, or in another embodiment, 0.1-50 mg, or in another embodiment, 0.3 - 15 mg, or in another embodiment 0.3-30 mg, or in another embodiment 0.5-25 mg, or in another embodiment 0.5-50 mg, or in another embodiment 0.75-15 mg , or in another embodiment, 0.75-60 mg, or in another embodiment, 1-5 mg, or in another embodiment, 1-20 mg, or in another embodiment, 3-15 mg, or In another embodiment, 30-50 mg, or in another embodiment, 30-75 mg, or in another embodiment, 100-2000 mg.

The SARMs of the invention can be administered in various dosages. In one embodiment, the SARM is administered at a dose of 1 mg. In another embodiment, the SARM is administered at a dose of 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg or 100 mg give.

In one embodiment, the compounds and compositions of the invention are useful in any of the methods of the invention, as described herein. In one embodiment, the use of a SARM or a composition containing the same is useful in inhibiting, suppressing, increasing or stimulating a desired response in an individual, as will be appreciated by those skilled in the art. In another embodiment, the composition may also contain other active ingredients whose activity is useful for the particular application for which the SARM compound is being administered.

In one embodiment, the present invention provides an ASARM compound of the present invention, or a prodrug, analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, drug product, polymorph, crystal, impurity thereof , N-oxide, hydrate or any combination thereof for the following applications: 1) treat bone-related disorders; 2) prevent bone-related disorders; 3) suppress bone-related disorders; 4) inhibit bone-related disorders; 5) increase individual 5) increase individual bone mass; 6) for inhibiting osteoclastogenesis. In one embodiment, the SARM compound is a compound of formula I, II, III or IV described herein.

In one embodiment, the bone-related disorder is a genetic disease, or in another embodiment, the bone-related disorder is caused as a result of a treatment regimen for a given disease. For example, in one embodiment, the SARMs of the invention are used to treat a bone-related disorder caused as a result of androgen deprivation therapy in response to a given prostate cancer in an individual.

In one embodiment, the present invention provides the use of a SARM compound for preventing a bone-related disorder in an individual. In another embodiment, the present invention provides the use of a SARM compound for suppressing a bone-related disorder in an individual. In another embodiment, the present invention provides the use of a SARM compound for inhibiting a bone-related disorder in an individual. In another embodiment, the SARM compound is a compound of formula (I), (II), (III) or (IV). In another embodiment, the SARM compound is a compound of formula (I), (II), (III) or (IV) or a prodrug, analog, isomer, metabolite, derivative, pharmaceutically acceptable Accepted salts, drug products, polymorphs, crystals, impurities, N-oxides, hydrates, or any combination thereof.

In one embodiment, the bone-related disorder is osteoporosis. In another embodiment, the bone-related disorder is osteopenia. In another embodiment, the bone-related disorder is increased bone resorption. In another embodiment, the bone-related disorder is a bone fracture. In another embodiment, the bone-related disorder is bone fragility. In another embodiment, the bone-related disorder is decreased BMD. In another embodiment, the bone-related disorder is any combination of osteoporosis, osteopenia, increased bone resorption, fractures, bone fragility, and decreased BMD. Each condition represents a separate embodiment of the invention.

In one embodiment, "osteoporosis" refers to thinning and loss of bone mass due to depletion of calcium and bone protein. In another embodiment, osteoporosis is a systemic skeletal disease characterized by low bone mass and degeneration of bone tissue with consequent increased bone fragility and susceptibility to fracture. In one embodiment, patients with osteoporosis have abnormal bone strength resulting in an increased risk of fracture. In another embodiment, osteoporosis depletes the calcium and protein collagen normally present in the bone, leading in one embodiment to abnormal bone mass or decreased bone density. In another embodiment, a bone affected by osteoporosis may be fractured by a minor fall or injury that would not normally result in a fracture. In one embodiment, the fracture may be in the form of a crack (eg, a hip fracture) or a collapse (eg, a compression fracture of the spine). The spine, hip, and wrist are the usual sites for fractures caused by osteoporosis, although fractures can occur in other bone regions as well. In another embodiment, unchecked osteoporosis results in postural changes, body deformities, and reduced mobility.

In one embodiment, osteoporosis results from androgen deprivation. In another embodiment, osteoporosis occurs with androgen deprivation. In another embodiment, the osteoporosis is primary osteoporosis. In another embodiment, the osteoporosis is secondary osteoporosis. In another embodiment, the osteoporosis is postmenopausal osteoporosis. In another embodiment, the osteoporosis is juvenile osteoporosis. In another embodiment, the osteoporosis is idiopathic osteoporosis. In another embodiment, the osteoporosis is senile osteoporosis.

In another embodiment, the primary osteoporosis is type I primary osteoporosis. In another embodiment, the primary osteoporosis is type II primary osteoporosis. Each type of osteoporosis represents a separate embodiment of the invention.

In another embodiment, osteoporosis and osteopenia are systemic skeletal diseases characterized by low bone mass and microarchitectural deterioration of bone tissue. In one embodiment, "microarchitectural degeneration" refers to thinning of trabecular bone (as defined below) and loss of connectivity between trabecular bones. In another embodiment, "osteoporosis" is defined as a BMD of 2.5 standard deviations (SD) or less below the mean for young adults. In another embodiment, "osteoporosis" is defined as a BMC of 2.5SD or less below the mean for young adults. In another embodiment, "osteoporosis" is defined as a BMD of 2.0 SD or less below the mean for young adults. In another embodiment, "osteoporosis" is defined as a BMC of 2.0 SD or less below the mean for young adults. In another embodiment, "osteoporosis" is defined as a BMD of 3.0 SD or less below the mean for young adults. In another embodiment, "osteoporosis" is defined as a BMC of 3.0 SD or less below the mean for young adults. Each definition of osteoporosis or osteopenia represents a separate embodiment of the invention.

In another embodiment, "osteoporosis" is defined as a BMD below 2.5 SD of the mean for young adults. In another embodiment, "osteoporosis" is defined as a BMC below 2.5 SD of the mean for young adults. In another embodiment, "osteoporosis" is defined as a BMD below 2.0 SD of the mean for young adults. In another embodiment, "osteoporosis" is defined as a BMC below 2.0 SD of the mean for young adults. In another embodiment, "osteoporosis" is defined as a BMD below 3.0 SD of the mean for young adults. In another embodiment, "osteoporosis" is defined as a BMC below 3.0 SD of the mean for young adults. Each definition of osteoporosis represents a separate embodiment of the invention.

Methods of assessing osteoporosis and osteopenia are well known in the art. For example, in one embodiment, a patient's BMD, measured by densitometry and expressed in g/ ^cm2, is compared to a "normal value" to obtain a "T score" for a sex-matched young adult Average of peak bone mass. In another embodiment, a Z-score is obtained by comparing the amount of bone loss in a patient with the expected amount of bone loss in a population of the same age and sex. In another embodiment, "osteoporosis" is defined as a T-score of 2.5 SD or less below the mean for young adults. In another embodiment, "osteoporosis" is defined as a Z-score of 2.5 SD or less below the young adult mean. In another embodiment, "osteoporosis" is defined as a T-score of 2.0 SD or less below the young adult mean. In another embodiment, "osteoporosis" is defined as a Z-score of 2.0 SD or less below the young adult mean. In another embodiment, "osteoporosis" is defined as a T-score of 3.0 SD or less below the young adult mean. In another embodiment, "osteoporosis" is defined as a Z-score of 3.0 SD or less below the young adult mean.

In another embodiment, "osteoporosis" is defined as a T-score below 2.5 SD of the mean for young adults. In another embodiment, "osteoporosis" is defined as a Z-score below 2.5 SD of the young adult mean. In another embodiment, "osteoporosis" is defined as a T-score below 2.0 SD of the young adult mean. In another embodiment, "osteoporosis" is defined as a Z-score below 2.0 SD of the young adult mean. In another embodiment, "osteoporosis" is defined as a T-score below 3.0 SD of the young adult mean. In another embodiment, "osteoporosis" is defined as a Z-score below 3.0 SD of the young adult mean. Each definition of osteoporosis represents a separate embodiment of the invention.

In one embodiment, the term "BMD" refers to a measured calculation of actual bone mass. The absolute amount of bone measured by BMD generally correlates with bone strength and its weight-bearing capacity. Just as measuring blood pressure can help predict stroke risk, measuring BMD can predict fracture risk.

In one embodiment, BMD can be measured by BMD mapping techniques. In one embodiment, the bone density of the hip, spine, wrist, or calcaneus can be measured by various techniques. A preferred method of measuring BMD is dual energy X-ray absorptiometry (DEXA). BMD of the hip, anterior-posterior (AP) spine, lateral vertebrae, and wrist can be measured using this technique. Measurements at any site can predict the overall risk of fracture, but information obtained from a specific site is the best information for predicting a fracture at that site. Quantitative computed tomography (QCT) is also used to measure BMD of the spine. See, e.g., "Nuclear Medicine: "Quantitative Procedures" by Walmer HW et al., Toronto Little, Brown & Co. Published, 1983, pp. 107-132; "Assessment of Bone Mineral Part 1," J Nucl Medicine, pp 1134-1141 (1984); and "Bone Mineral Density of The Radius" J Nucl Medicine 26:13-39 (1985). Each method of measuring BMD represents a separate embodiment of the invention.

In one embodiment, "osteopenia" refers to a BMD or BMC that is 1-2.5 SD below the mean for young adults. In another embodiment, "osteopenia" refers to bone calcification or decreased bone density. In one embodiment, the term encompasses all skeletal systems with this condition. Each definition or method of diagnosis of a disorder disclosed herein represents a separate embodiment of the invention.

In one embodiment, the term "fracture" refers to a fracture of a bone, including vertebral fractures and non-vertebral fractures. In one embodiment, the term "bone fragility" refers to a state of fragility that predisposes a bone to fracture.

In one embodiment, said bone-related disorder is treated with a SARM compound of the invention or a combination thereof. In another embodiment, additional osteostimulatory compounds may be provided to the subject prior to, concurrently with, or after administration of one or more SARMs of the invention. In one embodiment, the osteostimulatory compound may contain natural or synthetic substances.

In one embodiment, the osteostimulatory compound may include bone morphogenetic protein (BMP), growth factors such as epidermal growth factor (EGF), fibroblast growth factor (FGF), transforming Growth factors (TGF-α or TGF-β), insulin growth factor (IGF), platelet-derived growth factor (PDGF), hedgehog proteins such as sonic hedgehog, indian hedgehog, and desert hedgehog ), hormones such as follicle-stimulating hormone, parathyroid hormone, parathyroid hormone-related peptide, activin, inhibin, frizzled protein, frzb protein or frazzled protein, BMP-binding proteins such as chordin and fetuin, cytokines such as IL- 3. IL-7, GM-CSF, chemokines such as eosinophil chemokine, collagen, osteocalcin, osteonectin, etc.

In another embodiment, a composition for treating a bone disorder of the invention may contain one or more SARMs of the invention, one or more other osteostimulatory compounds, and osteogenic cells. In one embodiment, the osteogenic cells can be stem cells or progenitor cells, which can be induced to differentiate into osteoblasts. In another embodiment, the cells may be osteoblasts.

In another embodiment, a nucleic acid encoding a bone stimulating compound may be administered to said individual and is considered part of the present invention.

In one embodiment, osteoporosis, osteopenia, increased bone resorption, bone fractures, bone fragility, decreased BMD, and other conditions or diseases of the invention are caused by hormonal disturbances, disruptions, or imbalances. In another embodiment, these conditions occur independently of hormonal disturbances, disruptions or imbalances. Each possibility represents a separate embodiment of the invention.

In one embodiment, the hormonal disorder, disorder or imbalance comprises hormonal excess. In another embodiment, the hormonal disorder, disorder or imbalance comprises a hormone deficiency. In one embodiment, the hormone is a steroid hormone. In another embodiment, the hormone is estrogen. In another embodiment, the hormone is an androgen. In another embodiment, the hormone is a glucocorticoid. In another embodiment, the hormone is a corticosteroid. In another embodiment, the hormone is luteinizing hormone (LH). In another embodiment, the hormone is follicle stimulating hormone (FSH). In another embodiment, the hormone is any other hormone known in the art. In another embodiment, the hormonal disorder, disorder or imbalance is associated with menopause. In another embodiment, the hormone deficiency is the result of a specific procedure as a by-product of treating the individual's disease or condition. For example, the hormone deficiency may be the result of loss of androgen in the individual as a result of treatment for prostate cancer in the individual.

Each possibility represents a separate embodiment of the invention.

In one embodiment, the present invention provides the use of a SARM compound for increasing bone strength in a subject. In another embodiment, the SARM compound is a compound of formula (I), (II), (III) or (IV). In another embodiment, the SARM compound is a compound of formula (I), (II), (III) or (IV) or a prodrug, analog, isomer, metabolite, derivative, pharmaceutically acceptable Accepted salts, drug products, polymorphs, crystals, impurities, N-oxides, hydrates, or any combination thereof. Thereby, the individual bone strength is increased.

In another embodiment, the individual has osteoporosis. In another embodiment, the osteoporosis is hormonally induced.

In one embodiment, the present invention provides the use of a SARM compound for increasing bone mass in a subject. In another embodiment, the SARM compound is a compound of formula (I), (II), (III) or (IV). In another embodiment, the SARM compound is a compound of formula (I), (II), (III) or (IV) or a prodrug, analog, isomer, metabolite, derivative, pharmaceutically acceptable Accepted salts, drug products, polymorphs, crystals, impurities, N-oxides, hydrates, or any combination thereof, or compositions containing the same.

In another embodiment, the individual has osteoporosis. In another embodiment, the osteoporosis is hormonally induced. In another embodiment, the individual has sarcopenia or cachexia. In another embodiment, the method of the present invention provides for increasing bone mass in an individual, the bone mass being cortical bone mass. In another embodiment, the bone mass is trabecular bone mass. In another embodiment, the bone mass is cancellous bone mass.

In one embodiment, the present invention provides the use of a SARM compound for promoting bone formation. In another embodiment, the SARM compound is a compound of formula (I), (II), (III) or (IV). In another embodiment, the SARM compound is a compound of formula (I), (II), (III) or (IV) or a prodrug, analog, isomer, metabolite, derivative, pharmaceutically acceptable Accepted salts, drug products, polymorphs, crystals, impurities, N-oxides, hydrates, or any combination thereof, or compositions containing the same.

In another embodiment, the SARM compound stimulates or enhances osteoblastogenesis. In another embodiment, the SARM compound inhibits osteoclast proliferation.

In one embodiment, the present invention provides osteogenesis via stimulation or enhanced proliferation of osteoblasts. In one embodiment, the term "osteoblast" refers to a cell involved in bone formation. In one embodiment, osteoblasts, which are involved in bone formation, form tissue into which minerals are deposited to give bone strength. In another embodiment, the invention provides osteogenesis induced by inhibition of osteoclasts, or in another embodiment, osteogenesis inhibited of osteoclast activity. In one embodiment, the term "osteoclast" refers to cells involved in bone remodeling, particularly bone resorption.

In one embodiment, a bone disease or disorder is treated by the methods of the invention via stimulation of osteogenesis. In another embodiment, the treatments of the invention provide for preservation of bone mass. Bone mass is maintained by a balance between the activity of bone-forming osteoblasts and the activity of bone-destroying osteoclasts. In one embodiment, the compounds and methods of the invention provide a means to maintain this balance.

Figures 1-2 illustrate that the SARM compound III induces the differentiation of bone marrow cells into osteoblasts and inhibits the induction of osteoclasts, indicating the direct effect of SARMs on osteoblasts and osteoclasts, which play a role in increasing bone marrow in patients with osteoporosis. Quantity is useful.

In one embodiment, the present invention provides a SARM compound of the present invention or its prodrug, analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, drug product, polymorph, crystal, impurity , N-oxide, hydrate or any combination thereof for the following applications: 1) treatment of muscle wasting disease; 2) prevention of muscle wasting disease; 3) treatment, prevention, suppression, suppression or reduction of muscle muscle loss caused by muscle wasting disease reducing; 4) treating, preventing, inhibiting, reducing or suppressing muscle wasting resulting from muscle wasting; and/or 5) treating, preventing, inhibiting, reducing or suppressing muscle protein catabolism resulting from muscle wasting. In one embodiment, the SARM compound is a compound of formula (I), (II), (III) or (IV) described herein. In another embodiment, the invention provides compositions comprising a SARM compound of the invention for use in the methods described herein.

In one embodiment, the present invention provides the use of a SARM compound for the treatment of an individual suffering from muscle wasting. In another embodiment, the SARM compound is a compound of formula (I), (II), (III) or (IV). In another embodiment, the SARM compound is a compound of formula (I), (II), (III) or (IV) or a prodrug, analog, isomer, metabolite, derivative, pharmaceutically acceptable Accepted salts, drug products, polymorphs, crystals, impurities, N-oxides, hydrates, or any combination thereof, or compositions containing the same. Thus, an individual suffering from muscle wasting is treated.

In another embodiment, the use of a SARM compound for treating an individual suffering from muscle wasting comprises administering a pharmaceutical composition comprising the SARM compound. In another embodiment, the administering step comprises injecting said pharmaceutical composition in liquid form intravenously, intraarterially or intramuscularly into said subject; subcutaneously implanting a pellet containing said pharmaceutical composition into said subject orally administering said pharmaceutical composition in liquid or solid form to said individual; or topically applying said pharmaceutical composition to said individual's skin surface.

Muscle is the body tissue that functions primarily as a source of strength. There are three types of muscles in the body: a) skeletal muscles - the muscles responsible for moving the extremities and external regions of the body; b) myocardium - the heart muscle; c) smooth muscles - the muscles in the arterial and intestinal walls.

A wasting disease or condition is defined herein as a condition or disease characterized at least in part by abnormal, progressive loss of body, organ or tissue weight. A wasting condition can occur as a result of pathology, such as cancer or infection, or it exists as a result of a physiological or metabolic state, such as degeneration of disuse, which may occur as a result of prolonged bed rest or immobilization of limbs. Wasting disorders may also be age-related. Weight loss that occurs during a wasting disorder can be characterized by loss of total body weight, or loss of organ weight such as loss of bone or muscle mass due to a decrease in tissue protein.

In one embodiment, "muscle wasting" or "muscular wasting," as used herein, are used interchangeably to refer to the progressive loss of muscle mass and/or muscles including the skeletal or voluntary components that control movement. Progressive weakness and degeneration of the heart muscle, the heart muscle that controls the heart, and smooth muscle. In one embodiment, the muscle wasting condition or disease is a chronic muscle wasting condition or disease. "Chronic muscle wasting" is defined herein as the chronic (ie, sustained over an extended period of time) progressive loss of muscle mass and/or the chronic progressive weakness and degeneration of muscle.

The loss of muscle mass that occurs during muscle wasting can be characterized by the breakdown or degradation of muscle protein via myoprotein catabolism. Protein catabolism occurs because of an unusually high rate of protein degradation, an unusually low rate of protein synthesis, or a combination of both. Protein catabolism, whether caused by a high degree of protein degradation or a low rate of protein synthesis, results in reduced muscle mass browning and muscle wasting. The term "catabolism" has its art-recognized meaning, in particular referring to the energy-burning form of metabolism.

Muscle wasting can occur as a result of a pathology, disease, ailment or condition. In one embodiment, the pathology, ailment, disease or condition is chronic. In another embodiment, the pathology, ailment, disease or condition is genetic. In another embodiment, the pathology, ailment, disease or condition is neuropathic. In another embodiment, the pathology, ailment, disease or condition is infectious. As described herein, the pathology, disease, condition or disorder to which the compounds and compositions of the invention are administered is a disorder that directly or indirectly produces wasting (ie, loss) of muscle mass, ie, muscle wasting.

In one embodiment, the muscular wasting disorder in an individual is that the individual suffers from muscular dystrophy; muscular atrophy; X-linked spinobulbar muscular atrophy (SBMA); cachexia; malnutrition; tuberculosis; leprosy; diabetes; kidney disease; chronic obstructive pulmonary disease ( COPD); cancer; end-stage renal failure; sarcopenia; emphysema; osteomalacia; or cardiomyopathy.

In another embodiment, said muscle wasting disease is due to enterovirus, Epstein-Barr virus, herpes zoster, HIV, trypanosome, influenza, coxsackie virus, rickettsia, trichinella, schistosomiasis, Caused by mycobacterial infection.

Muscular dystrophies are genetic disorders characterized by progressive weakness and degeneration of the skeletal or voluntary muscles that control movement. Myocardium and some other involuntary muscles are also affected in some types of muscular dystrophies. The main types of muscular dystrophy (MD) are: Duchenne muscular dystrophy, myotonic dystrophy, Duchenne muscular dystrophy, Becker muscular dystrophy, limb-girdle dystrophy, facioscapulohumeral muscular dystrophy, Congenital muscular dystrophy, oculopharyngeal muscular dystrophy, distal muscular dystrophy, and Emery-Dreifuss muscular dystrophy.

Muscular dystrophy can affect people of all ages. While some types begin to become apparent in infancy or childhood, others are not apparent until middle age or later. Duchenne MD is the most common type, especially affecting children. Myotonic dystrophy is the most common of these disorders in adults.

Muscle atrophy (MA) is characterized by muscle wasting or loss and a decrease in muscle mass. For example, post-polio MA is a muscle wasting disorder that occurs as part of post-polio syndrome (PPS). The atrophy includes weakness, muscle fatigue and pain.

Another type of MA is X-linked spinobulbar muscular atrophy (SBMA - also known as Kennedy's disease). The disorder is caused by a defect in the androgen receptor gene on the X chromosome, affects only males, and develops in adulthood. Since the major etiology is androgen receptor mutations, androgen replacement therapy is not a current treatment strategy. There have been several studies in which exogenous testosterone propionate was administered to elevate androgen levels with the expectation of overcoming androgen insensitivity and possibly providing anabolic effects. The use of supraphysiological levels of testosterone supplementation will have limitations and other potentially serious complications.

Cachexia is weakness and weight loss caused by or as a side effect of a disease. Cardiac cachexia, the wasting of myoproteins in cardiac and skeletal muscles, is a feature of congestive heart failure. Cancer cachexia is a syndrome that occurs in patients with solid tumors and hematological malignancies and is manifested by weight loss and massive depletion of adipose tissue and lean mass.

Cachexia is also seen in acquired immunodeficiency syndrome (AIDS), and human immunodeficiency virus (HIV)-associated myopathy and/or muscle weakness/wasting are relatively common clinical manifestations of AIDS. Individuals with HIV-associated myopathy or muscle weakness or wasting experience significant weight loss, generalized or concentric muscle weakness, tenderness, or muscle atrophy.

Sarcopenia is a wasting disease that afflicts elderly chronically ill patients and is characterized by loss of muscle mass and loss of function. Moreover, increases in lean body mass are associated with reduced morbidity and mortality in certain muscle-wasting disorders. In addition, other environments and conditions are associated with and can lead to muscle wasting. For example, studies have shown paraspinal muscle wasting in severe cases of chronic low back pain.

Muscle wasting is also associated with advanced age. Common weakness in old age is thought to result from muscle wasting. As the body ages, the proportion of skeletal muscle replaced by fibrous tissue increases. The result is a marked decrease in muscle strength, performance and endurance.

Prolonged hospitalization due to illness or injury or degeneration from disuse, such as occurs when limbs are immobilized, can also lead to muscle wasting. Studies have shown persistent unilateral muscle wasting and consequently reduced lean body mass in long-term hospitalized patients with injury, chronic pain, burns, trauma, or cancer.

Injury or damage to the central nervous system (CNS) has also been associated with muscle wasting. Injury or damage to the CNS can be caused, for example, by disease, trauma, or chemicals. Examples are central nervous injury or damage, peripheral nerve injury or damage, and spinal cord injury or damage.

In another embodiment, muscle wasting is the result of alcoholism and can be treated with compounds and compositions of the invention which represent embodiments of the invention.

In one embodiment, the present invention provides the use of a SARM compound for preventing muscle wasting in a subject. In another embodiment, the SARM compound is a compound of formula (I), (II), (III) or (IV). In another embodiment, the SARM compound is a compound of formula (I), (II), (III) or (IV) or a prodrug, analog, isomer, metabolite, derivative, pharmaceutically acceptable Accepted salts, drug products, polymorphs, crystals, impurities, N-oxides, hydrates, or any combination thereof. In another embodiment, the administration comprises administration of the SARM and/or its prodrug, analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, drug, hydrate, N-oxide or any combination thereof and a pharmaceutical composition of a pharmaceutically acceptable carrier. Thereby, muscle wasting is prevented in the individual.

In one embodiment, the present invention provides the use of a SARM compound for the treatment of muscular wasting associated with a chronic disease. In another embodiment, the SARM compound is a compound of formula (I), (II), (III) or (IV). In another embodiment, the SARM compound is a compound of formula (I), (II), (III) or (IV) or a prodrug, analog, isomer, metabolite, derivative, pharmaceutically acceptable Accepted salts, drug products, polymorphs, crystals, impurities, N-oxides, hydrates, or any combination thereof, or compositions containing the same. In another embodiment, said SARM compound is administered orally to said individual.

In one embodiment, the present invention provides the use of a SARM compound for preventing muscle wasting in a subject. In another embodiment, muscle wasting is suppressed in the individual. In another embodiment, muscle wasting is inhibited in the individual. In another embodiment, the incidence of muscle wasting in the individual is reduced. In another embodiment, the SARM compound is a compound of formula (I), (II), (III) or (IV). In another embodiment, the SARM compound is a compound of formula (I), (II), (III) or (IV) or a prodrug, analog, isomer, metabolite, derivative, pharmaceutically acceptable Accepted salts, drug products, polymorphs, crystals, impurities, N-oxides, hydrates, or any combination thereof, or compositions containing the same.

In another embodiment, the present invention provides a SARM compound of the present invention or a prodrug, analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, drug product, polymorph, crystal, impure Substances, N-oxides, hydrates or any combination thereof, or compositions containing them are used for treating, preventing, suppressing, inhibiting or reducing the incidence of muscle wasting in individuals.

In another embodiment, the present invention provides a SARM compound of the present invention or a prodrug, analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, drug product, polymorph, crystal, impure Use of compounds, N-oxides, hydrates, or any combination thereof, or compositions containing them, in increasing individual muscle performance, muscle size, muscle strength, or any combination thereof.

In another embodiment, the SARM compounds and compositions of the present invention are used to promote or accelerate recovery after surgical procedures.

In one embodiment, the present invention provides the use of a SARM compound for reducing fat mass in a subject. In another embodiment, the SARM compound is a compound of formula (I), (II), (III) or (IV). In another embodiment, the SARM compound is a compound of formula (I), (II), (III) or (IV) or a prodrug, analog, isomer, metabolite, derivative, pharmaceutically acceptable Accepted salts, drug products, polymorphs, crystals, impurities, N-oxides, hydrates, or any combination thereof, or compositions containing the same.

In another embodiment, the invention provides a SARM compound of the invention, for example a compound having a structure of formula (I), (II), (III) or (IV) or a prodrug, analog, isomer, Metabolites, derivatives, pharmaceutically acceptable salts, pharmaceuticals, polymorphs, crystals, impurities, N-oxides, hydrates or any combination thereof, or compositions containing them in the treatment of individuals with metabolic syndrome Applications related to obesity or diabetes.

In one embodiment, the individual suffers from a hormonal imbalance, disorder or disease. In another embodiment, the individual is a postmenopausal individual.

In one embodiment, the present invention provides the use of a SARM compound for increasing lean body mass in a subject. In another embodiment, the SARM compound is a compound of formula (I), (II), (III) or (IV). In another embodiment, the SARM compound is a compound of formula (I), (II), (III) or (IV) or a prodrug, analog, isomer, metabolite, derivative, pharmaceutically acceptable Accepted salts, drug products, polymorphs, crystals, impurities, N-oxides, hydrates, or any combination thereof. Thus, increasing individual lean mass.

In another embodiment, the individual suffers from a hormonal imbalance, disorder or disease. In another embodiment, the individual is a postmenopausal individual.

Figures 3-7 show that Compound III is anabolic and has minimal androgenic activity, thus these compounds may be useful in the treatment of patient populations in which androgens were contraindicated in the past. Compound III has been shown to stimulate muscle growth in the presence or absence of testosterone while exerting an antiproliferative effect on the prostate, thus in one embodiment the SARMs of the invention restore lost muscle mass in patients with sarcopenia or cachexia.

In one embodiment, the SARM of the present invention is administered intravenously to a subject by injecting said pharmaceutical composition in liquid form. In another embodiment, the SARM of the present invention is administered intraarterially by injecting said pharmaceutical composition in liquid form into a subject. In another embodiment, the SARM of the present invention is administered intramuscularly by injecting said pharmaceutical composition in liquid form into a subject. In another embodiment, the SARM of the present invention is administered by implanting a pellet containing said pharmaceutical composition subcutaneously in an individual. In another embodiment, the SARM of the present invention is administered orally by administering said pharmaceutical composition in liquid or solid form to a subject. In another embodiment, the SARMs of the present invention are administered topically via application of said pharmaceutical composition to the skin surface of an individual.

In one embodiment, the present invention provides safe and effective methods for treating, preventing, suppressing, inhibiting or reducing muscle loss and/or muscle protein catabolism resulting from muscle wasting. In another embodiment, the invention is used to treat an individual suffering from muscular wasting or, in another embodiment, a bone-related disorder. In another embodiment, the individual is a mammalian individual.

In one embodiment, the present invention relates to a method for preventing, suppressing, suppressing obesity in an individual or reducing the incidence of obesity in an individual, which includes the optional compound of the present invention in an amount effective for preventing, suppressing, suppressing obesity in an individual, or reducing the incidence of obesity in an individual. Androgen receptor modulators (SARM) and/or their analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, pharmaceuticals, hydrates, N-oxides, prodrugs, polymorphs, Crystals or any combination thereof are administered to the individual.

In one embodiment, the SARM compounds of the invention alter leptin levels in an individual. In another embodiment, the SARM compound reduces leptin levels. In another embodiment, the SARM compounds of the invention increase leptin levels in an individual. Leptin is known to have an effect on appetite in obese mice, resulting in weight loss, so it is associated with obesity.

In one embodiment, the SARMs of the invention affect circulating levels of leptin, or, in one embodiment, tissue levels of leptin. In one embodiment, the term "leptin level" refers to the serum level of leptin. As contemplated herein, the SARM compounds of the invention have effects on leptin both in vitro and in vivo. Leptin levels can be measured by methods known to those skilled in the art, for example by commercially available ELISA kits. In addition, leptin levels can be determined by in vitro or in vivo assays by any method known to those skilled in the art.

Since leptin is involved in the control of appetite, weight loss, food intake and energy expenditure, modulating and/or controlling leptin levels is useful in treating, preventing, inhibiting or reducing the incidence of obesity in individuals suffering from obesity are useful treatments. Modulating leptin levels can lead to decreased appetite, reduced food intake and increased energy expenditure in individuals, and thus may be helpful in the management and treatment of obesity.

In one embodiment, the term "obesity" is defined as an increase in body weight beyond the limits of skeletal and bodily needs, with the resultant excessive accumulation of fat in the body.

In one embodiment, the term "obesity-related metabolic disorder" refers to a disorder caused by, as a consequence of, exacerbated by, or secondary to obesity. Non-limiting examples of such conditions are osteoarthritis, type II diabetes, hypertension, stroke and heart disease.

In another embodiment, the term "osteoarthritis" refers to a non-inflammatory degenerative joint disease occurring mainly in the elderly and characterized by degeneration of articular cartilage, bone hypertrophy, and changes in the synovial limbus and synovium. In another embodiment, it is accompanied by pain and stiffness, especially after prolonged activity.

In one embodiment, the term "diabetes" refers to a relative or absolute deficiency of insulin leading to uncontrolled carbohydrate metabolism. Clinically, most patients can be classified as insulin-dependent diabetes mellitus (IDDM or type I diabetes) or non-insulin-dependent diabetes mellitus (NIDDM or type II diabetes mellitus).

In other embodiments, the term "elevated blood pressure" or "hypertension" refers to recurrent hypertension above 140/90 mmHg. Chronic high blood pressure can lead to changes in blood vessels in the fundus, thickening of the heart muscle, kidney failure, and brain damage.

In other embodiments, the term "stroke" refers to damage to nerve cells in the brain caused by insufficient blood supply, usually from ruptured blood vessels or blood clots. In other embodiments, the term "cardiac disease" refers to a dysfunction of the normal function and activity of the heart, including heart failure.

Furthermore, androgens have recently been shown to be involved in the commitment of mesenchymal pluripotent cells to the myogenic lineage and prevent differentiation into the adipocyte lineage (Singh et al., Endocrinology, 2003, Jul 24). Accordingly, selective androgen receptor modulator compounds are useful in methods of blocking adipogenesis and/or altering stem cell differentiation as described herein.

In another embodiment, the present invention is directed to a method of promoting, increasing or assisting weight loss in a subject comprising a selective androgen receptor modulator (SARM) of the present invention in an amount effective to promote, increase or assist weight loss in a subject and/or its analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, drugs, hydrates, N-oxides, prodrugs, polymorphs, crystals or any combination thereof administered to the individual A step of.

In another embodiment, the present invention relates to a method of reducing, suppressing, suppressing or reducing appetite in a subject comprising a selective androgen receptor modulator of the present invention in an amount effective to reduce, suppress, suppress or reduce appetite in a subject ( SARM) and/or its analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, drugs, hydrates, N-oxides, prodrugs, polymorphs, crystals or any combination thereof Describe individual steps.

In another embodiment, the present invention relates to a method of modifying the body composition of an individual comprising a selective androgen receptor modulator (SARM) of the invention and/or an analog thereof in an amount effective to alter the body composition of the individual , derivatives, isomers, metabolites, pharmaceutically acceptable salts, drugs, hydrates, N-oxides, prodrugs, polymorphs, crystals, or any combination thereof, to the individual. In one embodiment, altering body composition comprises altering an individual's lean body mass, lean body mass, or a combination thereof.

In another embodiment, the present invention is directed to a method of altering lean body mass or lean body mass in an individual comprising a selective androgen receptor modulator (SARM) of the invention in an amount effective to alter lean body mass or lean body mass in an individual and/or its analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, drugs, hydrates, N-oxides, prodrugs, polymorphs, crystals or any combination thereof administered to the individual A step of.

In another embodiment, the present invention is directed to a method of converting fat to lean mass in a subject comprising administering a selective androgen receptor modulator (SARM) of the present invention and/or in an amount effective to convert fat to lean mass in a subject or its analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, drugs, hydrates, N-oxides, prodrugs, polymorphs, crystals or any combination thereof to the individual step .

In another embodiment, the present invention is directed to a method of treating an obesity-associated metabolic disorder in an individual comprising a selective androgen receptor modulator (SARM) of the invention and/or an amount effective to treat the obesity-associated metabolic disorder in the individual or its analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, drugs, hydrates, N-oxides, prodrugs, polymorphs, crystals or any combination thereof to the individual step .

In another embodiment, the present invention is directed to a method of preventing, suppressing, inhibiting or reducing an obesity-associated metabolic disorder in an individual comprising a selected amount of the present invention effective in preventing, suppressing, inhibiting or reducing an obesity-associated metabolic disorder in an individual. Sexual androgen receptor modulators (SARM) and/or their analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, pharmaceuticals, hydrates, N-oxides, prodrugs, polymorphs , crystals, or any combination thereof, to said individual.

In one embodiment, the obesity-related metabolic disorder is hypertension. In another embodiment, the condition is osteoarthritis. In another embodiment, the disorder is type II diabetes. In another embodiment, the condition is elevated blood pressure. In another embodiment, the condition is stroke. In another embodiment, the condition is heart disease.

In another embodiment, the present invention is directed to a method of reducing, suppressing, inhibiting or reducing lipogenesis in a subject comprising administering a selective androgen receptor modulator of the present invention in an amount effective to reduce, suppress, suppress or reduce lipogenesis in a subject. SARM and/or its analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, drugs, hydrates, N-oxides, prodrugs, polymorphs, crystals or any combination thereof The step of administering to said individual.

In another embodiment, the present invention relates to a method of altering stem cell differentiation in an individual comprising administering a selective androgen receptor modulator (SARM) of the invention and/or an analog, derivative thereof, in an amount effective to alter stem cell differentiation in the individual A compound, isomer, metabolite, pharmaceutically acceptable salt, drug, hydrate, N-oxide, prodrug, polymorph, crystal or any combination thereof is administered to said individual.

In another embodiment, the present invention is directed to a method of altering leptin levels in an individual comprising a selective androgen receptor modulator (SARM) of the invention and/or an analog thereof in an amount effective to alter leptin levels in the individual , derivatives, isomers, metabolites, pharmaceutically acceptable salts, drugs, hydrates, N-oxides, prodrugs, polymorphs, crystals, or any combination thereof, to the individual.

In another embodiment, the present invention is directed to a method of lowering, suppressing, inhibiting or reducing leptin levels in an individual comprising administering a selective androgen receptor of the invention in an amount effective to lower, suppress, inhibit or reduce leptin levels in an individual. SARM and/or its analogs, derivatives, isomers, metabolites, pharmaceutically acceptable salts, drugs, hydrates, N-oxides, prodrugs, polymorphs, crystals or The steps of administering to said individual are in any combination.

In one embodiment, the SARM used in the following is a compound represented by formula (I), (II), (III) or (IV): a) treats, prevents, suppresses, inhibits or reduces obesity; b) promotes, Increase or aid in weight loss; c) reduce, suppress, suppress, or reduce appetite; d) alter body composition; e) alter lean or fat-free mass; f) convert fat to lean; g) treat, prevent, suppress , inhibit or reduce an obesity-related metabolic disorder in an individual, such as hypertension, osteoarthritis, type II diabetes, elevated blood pressure, stroke or heart disease; h) reduce, suppress, inhibit or reduce lipogenesis in an individual; i) alter stem cell differentiation and/or j) altering leptin levels.

In one embodiment, the SARM compounds of the invention find use in treating or arresting the progression of diabetes, or treating the symptoms of diabetes. In another embodiment, the SARM compounds of the invention are used to treat diabetes-associated co-morbidities. These conditions include: hypertension, cerebrovascular disease, atherosclerotic coronary artery disease, macular degeneration, diabetic retinopathy (eye disease) and blindness, cataract-systemic inflammation (characterized by inflammatory markers such as erythrocyte sedimentation rate or C- Elevated reactive protein), birth defects, pregnancy-related diabetes, preeclampsia and gestational hypertension, renal disease (renal insufficiency, renal failure, etc.), neuropathy (diabetic neuropathy), superficial and systemic fungal infections, congestive heart failure , gout/hyperuricemia, obesity, hypertriglyceridemia, hypercholesterolemia, fatty liver disease (nonalcoholic fatty liver disease or NASH), and diabetes-related skin diseases such as diabetic lipoid necrosis ( NLD), diabetic blisters (diabetic vesicular disease), exanthematous xanthelasma, sclerosis of the digits, diffuse granuloma annulare, and acanthosis nigricans.

In one embodiment, the present invention provides a method for: a) treating, preventing, suppressing, inhibiting atherosclerosis; b) treating, preventing, suppressing, inhibiting liver damage due to fat deposition, which comprises effective A selective androgen receptor modulator (SARM) of the present invention and/or its analogs, derivatives, isomers, metabolites in an amount for treating, preventing or inhibiting atherosclerosis and liver damage due to fat deposition , a pharmaceutically acceptable salt, drug, hydrate, N-oxide, prodrug, polymorph, crystal or any combination thereof, or a step of administering a composition containing the same to an individual.

In one embodiment, the SARM compound of the present invention is used for: a) treating, preventing, suppressing, suppressing or reducing atherosclerosis; b) treating, preventing, suppressing, suppressing liver damage caused by fat deposition.

In one embodiment, atherosclerosis refers to a chronic, complex disease that can begin by damaging the innermost layer of an artery. In another embodiment, causes of damage to the arterial wall may include a) elevated cholesterol levels in the blood; b) high blood pressure; c) tobacco smoke; d) diabetes. In another embodiment, despite the fact that tobacco smoke may exacerbate atherosclerosis and accelerate its growth in coronary, aortic and leg arteries, the condition is treatable in smokers. Similarly, in another embodiment, the methods of the invention may be used to treat individuals with a family history of premature cardiovascular disease that increases the risk of atherosclerosis.

In one embodiment, liver damage due to fat deposition refers to an increase in fat in hepatocytes forming fatty liver, which may be associated with or result in inflammation of the liver. This can lead to scarring and hardening of the liver. When scarring becomes extensive, it is called cirrhosis. In another embodiment, fat accumulates in the liver, resulting in obesity. In another embodiment, fatty liver is also associated with diabetes, hypertriglyceridemia, and excessive alcohol use. In another embodiment, fatty liver can occur with certain diseases such as tuberculosis and malnutrition, intestinal bypass surgery for obesity, excess vitamin A in the body or use of certain drugs such as valproic acid (trade name: Depakene/Depakote) and Corticosteroids (cortisone, prednisone). Sometimes fatty liver occurs as a complication of pregnancy.

In one embodiment, the method for treating a subject is a human, in another embodiment the subject is male, or in another embodiment the subject is female.

In another embodiment, the present invention provides the use of a SARM of the present invention, or a composition containing it, for promoting or suppressing spermatogenesis in a male individual. Some SARMs of the invention additionally exhibit androgenic activity, thus stimulating spermatogenesis. In another embodiment, the SARMs of the invention exhibit antagonistic activity in the gonads of an individual, thereby suppressing spermatogenesis. In one embodiment, the SARM is thus useful as a contraceptive.

It is to be understood that any use of the SARMs of the invention, including in particular in applications relating to diseases or conditions related to muscle, fat, heart, liver, gonads or bone tissue, is also part of the invention, wherein the SARMs of the invention Administration of the compounds or compositions containing them advantageously alters the course of these diseases or conditions.

The following examples are provided to more fully illustrate preferred embodiments of the invention. However, they should in no way be construed as limiting the broad protective scope of the invention.

Example

Embodiment 1 :

Effect of selective androgen receptor modulator (SARM) compound III on the differentiation of progenitor cells into osteoblasts and The role of bone cells

Materials and methods

chemical

Compound III, THT and PTH were prepared at concentrations ranging from 1 nM to 1 μM.

animal

Four-month-old female rats were euthanized, and the femurs of the animals were excised. Any muscle and connective tissue on the femur was removed and stored on ice in minimal essential medium (MEM) containing penicillin, streptomycin, and amphotericin B until cell culture.

Bone Marrow Cell Culture

All cell culture materials were purchased from Invitrogen (Carlsbad, CA). Femurs were first washed in 70% ethanol and washed three times with 5 ml each of penicillin and streptomycin. Both ends of the femur were snapped off and the bone marrow cells were flushed with 15 ml of MEM containing penicillin, streptomycin and amphotericin B into a 50 ml conical tube and stored on ice. Do the same step for all femurs. The bone marrow cells were pooled and centrifuged at 1000 rpm for 5 minutes in a clinical centrifuge. Cells were resuspended in MEM without phenol red and supplemented with 10% charcoal-desorbed serum, penicillin, streptomycin, and amphotericin B. Grind the cells through a 22g needle, count them under a microscope, inoculate 1.5 million cells per well in a 6-well plate without phenol red and supplement with 15% active carbon-desorbed serum, penicillin, streptomycin, 300ng/ml amphotericin B, 0.28mM ascorbic acid and 10mM β-glycerophosphate in MEM to differentiate to fibroblast/osteoblast lineage, and seeded at 2.5 million cells per well in a 24-well plate without phenol red and supplemented with 10% activated carbon Desorbed serum, penicillin, streptomycin and 300ng/ml amphotericin B in MEM to differentiate into osteoclast lineage. The medium was changed on day 2 and treated with the hormones. Osteoclast cultures were performed in the presence of 50ng RANK ligand and 10ng GM-CSF to induce osteoclastogenesis. For osteoclast cultures, completely change the medium every three days. For osteoblast cultures, half of the medium was changed every three days to preserve the growth factors secreted by the cells.

cell staining

At the end of 12 days, cells were fixed in 10% buffered formalin for fibroblast cultures and 4% formaldehyde for osteoclast cultures. Fibroblasts were stained for alkaline phosphatase activity and the O.D. was measured at 405 nm using a spectrophotometer as previously described. Osteoclasts were stained for tartrate-resistant acid phosphatase activity (TRAP), and cells with 2 or more nuclei were counted microscopically and plotted as previously described.

result

SARM is a potent inducer of myeloid cell differentiation into osteoblast and osteoclast lineages

Androgens have anabolic effects on bone, and the benefits of androgens as bone-protective hormones have been clearly demonstrated in conditions such as androgen deprivation therapy for prostate cancer and androgen deficiency in the elderly. However, the use of ectopic androgens is limited due to their side effects and due to the risk of conversion of androgens to estrogens.

To determine whether SARMs could be therapeutic and avoid the above-mentioned side effects, selective androgen receptor modulators (SARMs) were tested for their ability to be osteoprotective with fewer side effects (as seen with mother hormones). A selective androgen receptor modulator was evaluated. In terms of the ability of dihydrotestosterone (DHT) and parathyroid hormone (PTH) and SARM compound III to differentiate rat primary bone marrow cells into osteoblast and osteoclast lineages, the effects of dihydrotestosterone (DHT) and parathyroid The potency of adenine (PTH) was compared to that of SARM compound III (Figures 1 and 2). Rat bone marrow cells were cultured in culture medium for 12 days in the presence or absence of the hormones described above, and their differentiation into osteoblast and osteoclast lineages was evaluated.

Both DHT and Compound III increased the differentiation of primary myeloid cells into an osteoblastic lineage, as measured by the cells' alkaline phosphatase (ALP) activity (Figure 1). At a concentration of 1 μM, DHT and SARM induced comparable ALP activity, while at lower concentrations of 100 nM and 10 nM, compound III showed a greater induction than DHT, PTH, another bone anabolic hormone, only at higher concentrations ALP staining was not induced at lower concentrations.

Figure 2 shows a marked increase in the number of TRAP-positive multinucleated osteoclasts when the cells were cultured in the presence of RANK ligand and GM-CSF. Cells treated with DHT or SARM significantly inhibited RANK ligand- and GM-CSF-induced proliferation of TRAP-positive multinucleated osteoclasts. PTH inhibited induction at higher concentrations, whereas at lower concentrations, PTH increased the number of TRAP-positive osteoclasts. Estradiol inhibited osteoclastogenesis at all doses evaluated.

Embodiment 2 :

Bone effects of SARMs alone and in combination with the antiresorptive agent alendronate

Materials and methods

Sixty female, nonpregnant, intact 23-week-old Sprague-Dawley rats were obtained from Charles River Laboratories (Wilmington, MA). 2–3 animals were housed per cage and adapted to a 12-h light/dark cycle. Food (7012C LM-485 Mouse/Rat Sterilized Diet, Harlan Teklad, Madison, WI) and water were freely available. The animal protocol for this study was reviewed and approved by the Institutional Animal Care and Use Committee of Tennessee State University.

Sham surgery or ovariectomy was performed on day 0. The study consisted of the following six treatment groups: (1) intact + vehicle, (2) intact + compound III, (3) OVX + vehicle, (4) OVX + compound III, (5) OVX + alendronate, ( 6) OVX + alendronate + compound III. The DMSO:PEG300(10:90) vehicle group was given daily dosage (200L) by gavage from day 1. Animals were sacrificed on day 45 of the study. Femurs were removed, cleared of soft tissue, and stored in saline-soaked gauze at -20°C until analysis. Nine animals died during the study. These deaths were attributed to complications from ovariectomy as well as technical errors in oral administration (ie delivery of dosing solution into the lungs). Dosage groups are listed in Table 1.

Table 1. Treatment groups

The left femur was sent to SkeleTech Inc. (Bothell, WA) for biomechanical strength (three-point bending) and pQCT analysis. Stratec XCT RM and associated software (Stratec Medizintechnik GmbH, Pforzheim, Germany. Software version 5.40C) were used for pQCT analysis. Both the mid-femoral and distal regions were analyzed. Midsection analysis was performed in the region at 50% of the femoral length. Distal analysis was performed in the region at 20% of the femoral length from the distal end. 0.5 mm slices perpendicular to the long axis of the femur were used for analysis. Total bone mineral content, total bone area, total bone mineral density, cortical bone mineral content, cortical bone area, cortical bone mineral density, cortical thickness, periosteal perimeter (annular plane), and endosteal perimeter were measured in the mid-femur . Total bone mineral content, total bone area, total bone mineral density, trabecular bone mineral content, trabecular bone area, and trabecular bone mineral density were measured at the distal femur. After pQCT analysis, femoral strength was determined by three-point bending test. The sagittal diameter (APD) (unit: mm) of the midpoint of the femur was measured with an electronic caliper. The femur was placed on the struts under the three-point bending apparatus in an Instron Mechanical Testing Machine (Instron 4465 refurbished to 5500) (Canton, MA) with the femur facing down anteriorly. The length (L) between the lower pillars was set to 14mm. Center the upper loaded device over the midshaft of the femur. A constant displacement rate of 6 mm/min was applied until the femur fractured. The mechanical tester directly measures the maximum load (F _u ) (unit: N), stiffness (S) (unit: N/mm) and absorbed energy (W) (unit: mJ). The moment of inertia (I) (unit: mm ⁴ ) in the mid-shaft region was calculated by the software in the pQCT analysis of the mid-femur. Stress (σ) (unit: N/mm ² ), elastic modulus (E) (unit: Mpa) and strength (T) (unit: mJ/m ³ ) are calculated by the following formula: Stress: σ=( F _u *L*(a/2))/(4*L); modulus of elasticity: E=S*L ³ /(48*I); and strength: T=3*W*(APD/2) ² /(L*I).

Statistical analysis was performed by Student's T test. Statistically significant differences were considered at P-values less than 0.05.

result:

Femoral maximal loading was determined by 3-point bending of the femur. The results are shown in Figure 3. No difference was observed between the intact vehicle (210N) control group and the OVX vehicle (212N) control group. We observed a trend towards an increase in the maximum load to 224 and 233 Newtons for the compound III treatment group compared to the intact group and the OVX group, respectively. There was no difference between the alendronate (213N) and alendronate + compound III (207N) groups compared with the control group.

Trabecular bone mineral density of the distal femur was analyzed by pQCT. The results are shown in Figure 4. We observed significant trabecular bone loss after OVX. Trabecular bone density decreased from 379 to 215 mg/cm ³ in the intact vehicle control group and the OVX vehicle control group, respectively. In intact animals treated with Compound III, we observed a slight increase in trabecular bone density up to 398 mg/cm ³ . In OVX animals treated with compound III, we observed a significant increase to 406 mg/ ^cm3 relative to the OVX vehicle control group. Alendronate-treated trabecular bone density increased to 480 mg/cm ³ . Combination treatment of alendronate and Compound III showed additive effects, increasing trabecular bone density to 552 mg/cm ³ .

Embodiment 3 :

Androgenic & anabolic activity in intact and ORX rats

Materials and methods

Male Spargue-Dawley rats weighing approximately 200 g were purchased from Harlan Bioproducts for Science (Indianapolis, IN). Animals were maintained on a 12-hour light/dark cycle and had free access to food (7012C LM-485 mouse/rat sterile diet, Harlan Teklad, Madison, WI) and water. Animal protocols were reviewed and approved by the Institutional Animal Care and Use Committee of Tennessee State University. Compound III was evaluated for its anabolic and androgenic activity in intact animals and additionally for dose response in acute orchiectomy (ORX) animals. The regenerative effects of compound III in chronic (9 day) ORX rats were also evaluated.

The compounds were weighed and dissolved in 10% DMSO (Fisher) diluted with PEG 300 (Acros Organics, NJ) for preparation of appropriate dosage concentrations. 2-3 animals were housed in each cage. Intact and ORX animals were randomly assigned into 7 groups consisting of 4-5 animals each. Control groups (intact and ORX) were given vehicle daily. I Compound III was administered to intact and ORX groups via gavage at doses of 0.01, 0.03, 0.1, 0.3, 0.75 and 1 mg/day.

Castrated animals (on the first day of the study) were randomized into 0.01, 0.03, 0.1, 0.3, 0.75 and 1 mg/day dose groups (4-5 animals/group) for dose response evaluation. Dosing was started 9 days after ORX and administered daily for 14 days by gavage. Animals were anesthetized (ketamine/xyalzine, 87:13 mg/kg) after the 14-day dosing regimen and body weights were recorded. In addition, the ventral lobes of the prostate, seminal vesicles, and levator ani were removed and weighed individually, normalized to body weight, and expressed as a percentage of the intact control group. The individual dose groups and the complete control group were compared using the Student's T-test. P-values <0.05 were a priori defined as significant. As a measure of androgenic activity, the ventral lobe of the prostate and seminal vesicle weights were evaluated, while the levator ani muscle weight was used as a measure to evaluate anabolic. Blood was collected from the abdominal aorta, centrifuged, and the serum was frozen at -80°C until serum hormone levels were measured. Serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) concentrations were determined by the University of Virginia Center for Research in Reproduction Ligand Assay and Analysis Core (NICHD (SCCPRR) Grant U54-HD28934).

result :

After administration of doses of 0.01, 0.03, 0.1, 0.3, 0.75 and 1 mg/day, the prostate weights after compound III treatment were 111%±21%, 88%±15%, 77%±17%, 71%± 16%, 71%±10%, and 87%±13% (Fig. 5). Similarly, after doses of 0.01, 0.03, 0.1, 0.3, 0.75 and 1 mg/day, seminal vesicle weight decreased to 94%±9%, 77%±11%, 80%±9%, 73%±12% of the intact control group, respectively. %, 77%±10% and 88%±14%. However, a significant increase in levator ani muscle weight was observed in sham-operated animals when compared to intact controls in all dose groups. Corresponding to 0.01, 0.03, 0.1, 0.3, 0.75 and 1mg/day dose groups, the weight of levator ani muscle was 120%±12%, 116%±7%, 128%±7%, 134%±7% of the intact control, respectively , 125%±9% and 146%±17%. The results are given graphically in FIG. 5 .

中的非线性回归分析进行确定，并在图7中给出。前列腺、精囊和肛提肌的E_max值分别是83%±25%、85%±11%和131%±2%。前列腺、精囊和肛提肌的ED₅₀分别是0.09±0.07、0.17±0.05和0.02±0.01mg/日。Compound III partially maintains prostate weight after orchiectomy. Prostate weights in vehicle-treated ORX controls were reduced to 5% ± 1% of intact controls. At doses of 0.01, 0.03, 0.1, 0.3, 0.75 and 1.0 mg/day, compound III maintained prostate weights of 8%±2%, 20%±5%, 51%±19%, 56%± 9%, 80%±28%, and 74%±12.5%. In castrated controls, seminal vesicle weights decreased to 13% ± 2% of intact controls. Compound III partially maintained seminal vesicle weight in ORX animals. After administration of 0.01, 0.03, 0.1, 0.3, 0.75 and 1.0 mg/day doses, the seminal vesicle weights of the drug-treated animals were 12%±4%, 17%±5%, 35%±10%, 61% of the intact controls, respectively ±15%, 70%±14% and 80%±6%. In ORX controls, levator ani muscle weight decreased to 55% ± 7% of intact controls. In the levator ani muscle of Compound III treated animals we observed anabolic effects. Compound III fully maintained levator ani muscle weight at doses > 0.1 mg/day. Doses >0.1 mg/day resulted in a significant increase in levator ani muscle weight compared to that observed in intact controls. For the 0.01, 0.03, 0.1, 0.3, 0.75 and 1.0 mg/day dose groups, as a percentage of the complete control group, the levator ani muscle weight was 59% ± 6%, 85% ± 9%, 112% ± 10%, 122 %±16%, 127%±12%, and 129.66%±2%. The results are given graphically in FIG. 6 . The _Emax and _ED50 values in each tissue are passed

The non-linear regression analysis in is determined and presented in Fig. 7. The E _max values of prostate, seminal vesicle and levator ani were 83%±25%, 85%±11% and 131%±2%, respectively. The ED ₅₀ of prostate, seminal vesicle and levator ani muscle were 0.09±0.07, 0.17±0.05 and 0.02±0.01 mg/day, respectively.

Serum Hormone Analysis

The serum LH and FSH data of the animals are given in Table 1. LH was decreased in a dose-dependent manner in both intact and castrated animals. After administration of doses >0.1 mg/day, LH levels were below the limit of quantification (0.07 mg/day). A dose of 0.1 mg/day in ORX animals returned LH levels to levels seen in intact controls. Similar effects were also observed for FSH. Significant reductions in FSH levels were observed at doses of 0.75 and 1 mg/day in intact animals. In ORX animals, a dose-dependent decrease in FSH levels was observed. In ORX animals, doses of Compound III >0.1 mg/day returned FSH levels to intact control levels.

Table 1. Serum LH and FSH levels in Arm1 and Arm2 animals. ^a P<0.05 vs. intact control. ^b p<0.05 vs. ORX control.

Androgenic & anabolic activity after delayed administration

Compound III partially restored prostate and seminal vesicle weights in ORX animals. For the 0.01, 0.03, 0.1, 0.3, 0.75 and 1.0mg/day dose groups, the prostate recovered to 9%±3%, 11%±3%, 23%±5%, 50%±13%, 62% of the intact control, respectively. %±12% and 71%±5%, while seminal vesicle recovery was 7%±1%, 9%±1%, 23%±8%, 49%±5%, 67%±12% and 67%± 11%. Compound III can completely restore the weight of the levator ani muscle at a dose of >0.1 mg/day. Corresponding to doses of 0.01, 0.03, 0.1, 0.3, 0.75 and 1.0mg/day, the weight of levator ani muscle recovered to 56%±7%, 82%±9%, 103%±11%, 113%±11%, 121% %±7% and 120%±7%. The results are given graphically in FIG. 8 . _Emax and _ED50 values for each tissue were obtained by The non-linear regression analysis in is determined and presented in Fig. 9. The E _max values of prostate, seminal vesicle and levator ani were 75%±8%, 73%±3% and 126%±4%, respectively. The ED ₅₀ of prostate, seminal vesicle and levator ani were 0.22±0.05, 0.21±0.02 and 0.013±0.01 mg/day, respectively.

Embodiment 4 :

Pharmacokinetic profile of a novel oral anabolic SARM compound III:

First analysis in healthy male volunteers

Materials and methods

Each dose level (9 active, 3 placebo) was administered to a group of up to 12 healthy male volunteers in a randomized double-blind study design. Eight groups (aged 18-45 years) were recruited and each group received a single oral dose corresponding to 1, 3, 10, 30 and 100 mg of Compound III in solution (or an equal volume of PEG 300 placebo) or 3 or 30 mg of Compound III in test capsules. The effect of micronization (ie particle size reduction) on the pharmacokinetics of Compound III was studied in a 30 mg solid oral dosage form. Samples for parent drug pharmacokinetic evaluation were collected up to 72 hours post-dose.

result

Compound III in PEG300 based solution at doses of 1, 3, 10, 30 and 100 mg was rapidly absorbed from the gastrointestinal tract. All dose levels resulted in quantifiable plasma concentrations of Compound III up to the last collection time point (72 hours) (Figures 10-12). Compound III exposures ( _Cmax and AUC) increased with increasing dose and were linear over the dose range of 1-100 mg for solution. For Compound III in solution, _Tmax was obtained at 0.8 and 2.3 hours (median = 1.0 hours), whereas _Tmax was obtained at 3.2 and 3.9 hours after administration of the solid oral formulation (Figures 13 and 14). Terminal elimination half-lives ranged from 19 to 22 hours (median = 20 hours) for 1-100 mg solutions and 3 mg capsules, increasing to 27 and 30 hours for 30 mg micronized and non-micronized capsules, but not significantly (p> 0.1). Oral clearance is inversely related to half-life, with 30 mg non-micronized capsules exhibiting the longest half-life and the smallest clearance compared with other dosage forms and doses. The 3 mg non-micronized capsules and solution had equal bioavailability, but micronization improved oral bioavailability (p<0.5) at the higher dose (30 mg) (Figure 12). It is possible that enterohepatic circulation via the hepatobiliary system plays an important role in the redistribution of the parent drug, as indicated by the consecutive second peak in the drug elimination phase.

Example 5

Anabolic and androgenic activity of SARMs

Materials: SARMs were synthesized according to the method described in US Patent Application Publication 2004/0014975A1. Alzet osmotic pumps (model 2002) were purchased from Alza Corp. (Palo Alto, CA).

The tested SARM will include the following:

and

Their activity was compared with that of the following compounds:

Study Design: Immature Sprague-Dawley rats weighing 90-100 mg were randomized into groups of at least 5 animals. One day prior to initiation of drug treatment, animals were individually removed from cages, weighed and anesthetized by intraperitoneal administration of ketamine/dimethoperazine (87/13 mg/kg; approximately 1 mL/kg). When properly anesthetized (ie, unresponsive to toe pinch), the animal's ears were marked for confirmation purposes. The animal was then placed on a sterile pad and its abdomen and scrotum were washed with povidone-iodine and 70% ethanol. The testicles were removed via a midline scrotal incision, sterile sutures were used to ligate the upper testicular tissue, and each testicle was surgically removed. The surgical wound site was closed with sterile stainless steel wound clips, and the site was cleaned with povidone-iodine. Animals were allowed to wake up on sterile pads (until able to stand), and then they were returned to their cages.

Twenty hours later, the animals were re-anesthetized with ketamine/dimethoperazine and an Alzet osmotic pump (model 2002) containing the SARM compound was placed subcutaneously in the scapular region. Osmotic pumps contain the appropriate drug dissolved in polyethylene glycol 300 (PEG 300) (as described in Example 3). Fill the osmotic pump with the appropriate solution the day before implantation. Animals were monitored daily for signs of acute toxicity (eg, lethargy, rough coat) to drug treatments.

After 14 days of drug treatment, the animals were anesthetized with ketamine/dimethoperazine. Animals were sacrificed by exsanguination under anesthesia. Blood samples were collected by abdominal aortic venipuncture and whole blood cell analysis was performed. A part of the blood sample was placed in a separation tube and centrifuged at 12000g for 1 minute. The plasma layer was removed and stored frozen at -20°C. The ventral lobe of the prostate, seminal vesicles, levator ani, liver, kidneys, spleen, lungs and heart were removed, other tissues cleared, weighed and placed in vials containing 10% neutral buffered formalin. The preserved tissue was used for histopathological analysis.

For data analysis, the weights of all organs were normalized to body weight and statistically significant differences were analyzed by one-way ANOVA. Prostate and seminal vesicle weights were used as indices to evaluate androgenic activity, while levator ani muscle weight was used to evaluate anabolic activity.

Testosterone propionate (TP) at increasing doses was used as a positive control for anabolic and androgenic effects. The effect of a particular compound can thus be compared to TP.

Prostate, seminal vesicle, and levator ani weights are expected to be significantly reduced in castrated, vehicle-treated rats due to the severing of endogenous androgen production. Exogenous administration of testosterone propionate, androgenic and anabolic steroids is expected to increase prostate, seminal vesicle and levator ani weights in castrated rats in a dose-dependent manner. The effect of SARM on the weight of prostate, seminal vesicles and levator ani muscle in castrated animals will be evaluated comparatively. Compounds showing lower potency and intrinsic activity in increasing the weight of the prostate and seminal vesicles, and higher potency and intrinsic activity in increasing the weight of the levator ani muscle, would be considered less androgenic, but anabolic, representing Compounds would be useful in the treatment of eg prostate cancer or in the treatment of side effects associated with current treatments for prostate cancer such as androgen deprivation therapy.

Example 6

Lowering of cholesterol levels by SARMs

Materials and methods

[75/25(v/v)])组以及化合物III的四个剂量组。将动物根据它们最近的体重以0、3、10、30或100mg/kg的剂量通过管饲每日一次给予化合物III。在研究期间，大鼠随意饮水和Harlan Taklad Rodent Chow标准实验室饮食。连续给药28日后，将动物禁食过夜，收集血液样品，并处理以得到血清。使用自动实验室测定方法测定血清总胆固醇水平。100 Spargue Dawley rats (50 males and 50 females) were divided into 5 groups (n=10 per sex per group) representing only vehicle (PEG 300:40%

[75/25 (v/v)]) group and four dose groups of compound III. Animals were dosed with Compound III once daily by gavage at doses of 0, 3, 10, 30 or 100 mg/kg according to their most recent body weight. During the study period, rats had ad libitum access to water and a Harlan Taklad Rodent Chow standard laboratory diet. After 28 consecutive days of dosing, the animals were fasted overnight, and blood samples were collected and processed for serum. Serum total cholesterol levels were determined using an automated laboratory assay.

result

Serum cholesterol values in male and female rats in the vehicle only group (0 mg/kg) were 92±13.5 and 102±13 mg/L, respectively. These values are considered to be within the normal historical range of the testing laboratory. Daily oral doses of Compound III of 3 mg/kg or higher caused a significant reduction in total cholesterol levels in both male and female rats. At 3 mg/kg, an approximately 30% reduction in total cholesterol was noted compared to vehicle control animals, with 63 ± 17.4 and 74 ± 14.2 mg/L in males and females, respectively. Overall, no dose-response relationship was observed for reductions in total cholesterol levels in Spargue Dawley rats, although a slightly greater effect was noted in the highest dose group (100 mg/kg/day). The results are presented graphically in FIG. 15 .

The role of SARMs in causing acute toxicity, measured by diagnostic hematology tests and visual inspection of treated animals, will be assessed by suppressing luteinizing hormone (LH) or follicle-stimulating hormone (FSH) as described in Example 4 above. ).

While certain features of the invention have been illustrated and described herein, numerous modifications, substitutions, changes and equivalents will occur to those skilled in the art. It is therefore to be understood that the appended claims are intended to cover all such modifications and changes as fall within the true spirit of the invention.

Claims (30)

1. SARM (SARM) compound or its isomer, pharmacologically acceptable salts or its arbitrary combination by the representative of the structure of formula (III):

2. composition, it contains the SARM compound of claim 1 and suitable carrier or thinner.

3. the composition of claim 2, it also contains Alendronate.

4. the SARM compound of claim 1 or the composition that contains it suffer from application in the bone photo related disorders individuality in treatment.

5. the application of claim 4, wherein said bone photo related disorders are osteoporosis, osteopenia, bone resorption increase, fracture, bone fragility, bone mineral density (BMD) reduction or its arbitrary combination.

6. the application of claim 4, wherein said composition also contains Alendronate.

7. the SARM compound of claim 1 or the composition that contains it are increasing individual bone strength or bone amount or are promoting application in the individual bone forming.

8. the application of claim 7, wherein said composition also contains Alendronate.

9. the application of claim 7, wherein said bone is cortex bone.

10. the application of claim 7, wherein said bone are trabecular bone or spongy bone.

11. stimulating or be enhanced to osteocyte, the application of claim 7, wherein said SARM compound generate.

12. the application of claim 7, wherein said SARM compound suppress osteoclast propagation.

13. suffering from muscle, the application of claim 7, wherein said individuality reduce disease or emaciation.

14. the SARM compound of claim 1 or contain its application of composition in intervention or preventing osteoporosis or osteopenia.

15. the application of claim 9, wherein said individuality suffers from osteoporosis.

16. the application of claim 9, wherein said osteoporosis are that hormone causes.

17. the SARM compound of claim 1 or the composition that contains it in treatment, prevention, compacting, suppress individual wasting disease or reduce application in the incidence of individual wasting disease.

18. the application of claim 17, wherein said wasting disease is caused by pathology, slight illness, disease or illness.

19. the application of claim 18, wherein said pathology, slight illness, disease or illness are nervosa, infectivity, chronic or genetic.

20. the application of claim 19, wherein said pathology, slight illness, disease or illness are muscular dystrophy, myatrophy, the chain ridge bulbar muscular atrophy of X (SBMA), emaciation, malnutrition, leprosy, diabetes, ephrosis, chronic obstructive pulmonary disease (COPD), cancer, renal failure in latter stage, muscle minimizing disease, pulmonary emphysema, osteomalacia, HIV infection, AIDS, congestive heart failure (CHF) or myocardosis.

21. the application of claim 17, wherein said wasting disease are relevant wasting diseases of age; The useless wasting disease of degenerating and being correlated with sexual function; Or described wasting disease is by chronic back pain; Burn; Central nervous system (CNS) damage or infringement; Peripheral nerve injury or infringement; Spinal injury or infringement; Chemical damage or infringement; Perhaps alcoholism causes.

22. the application of claim 17, wherein said composition gives through intravenously, intra-arterial or intramuscular with liquid form; Be implanted subcutaneously in the described individuality with the piller form; Give so that the liquid or solid form is oral; Give with liquid or solid form hypogloeeis; Perhaps described pharmaceutical composition is locally applied to the mucomembranous surface of described individuality.

23. the application of claim 19, wherein said composition are pill, tablet, capsule, solution, suspensoid, emulsion, elixir, gelifying agent, emulsifiable paste, suppository or parenteral administration.

24. the SARM compound of claim 1 or the application of composition in increasing individual muscle behavior performance, muscle size, muscular strength or its arbitrary combination that contains it.

25. the SARM compound of claim 1 or the composition that contains it are in the relevant obesity of the individual metabolism syndrome for the treatment of or the application in the diabetes.

26. the application of claim 25, wherein said individuality suffers from hormone imbalances, disorder or disease.

27. the application of claim 26, wherein said individuality is in climacteric.

28. the application of claim 26, wherein said SARM increases the thin heavy of individuality.

The application during 29. the SARM compound of claim 1 or the composition that contains it recover after promoting or accelerating operation technique.

30. the SARM compound of claim 1 or the composition that contains it promote or the spermatogeny of compacting male individual in application.

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