AU2007201969B2 - Halogenated selective androgen receptor modulators and methods of use thereof - Google Patents

Description

AUSTRALIA Patents Act 1990 COMPLETE SPECIFICATION STANDARD PATENT Applicant: UNIVERSITY OF TENNESSEE RESEARCH FOUNDATION Invention Title: HALOGENATED SELECTIVE ANDROGEN RECEPTOR MODULATORS AND METHODS OF USE THEREOF The following statement is a full description of this invention, including the best method of performing it known to me/us: HALOGENATED SELECTIVE ANDROGEN RECEPTOR MODULATORS AND METHODS OF USE THEREOF 5 FMLD OF INVEST ION [0001] The present invention ielates to a novel class of androgen receptor targeting agents (ARTA), which are selective androgen receptor modulators (SARM). The SARM compounds are useful for a) male contraception; b) treatment of a variety of hormone related conditions, for example conditions associated with Androgen Decline in Aging Male (ADAM), such as fatigue, depression, decreased libido, sexual dysfunction, erectile dysfunction, hypogonadism, osteoporosis, hair loss, anemia, obesity, sarcopenia, osteopeia, osteoporosis, benign prostate hyperplasia, alterations in mood and cognition and prostate cancer; c) treatment of conditions associated with Androgen Decline in Female (ADIF), such as sexual'dysfanction, decreased sexual libido, hypogonadisnm, sarcopenia, osteopenia, osteoporosis, alterations in cognition and mood, depression, anemia, hair loss, obesity, endometriosis, breast cancer, uterine cancer and ovarian cancer, d) treatment and/or prevention of acute and/or chronic muscular wasting conditions; e) preventing and/or treating dry eye conditions; f) oral androgen replacement therapy; g) decreasing the incidence of, halting or causing a regression of prostate cancer; and/or h) inducing apoptosis in a cancer cell. BRACKGROUIND OF THE INVENTION 5 (0002] The androgen receptor ("AR") is a ligand-activated transcriptional regulatory protein that mediates induction of male sexual development and function through its activity with endogenous androgens. Androgens are generally kmown as the male sex hormones. The androgenic hormones are steroids which are produced in the body by the testes and the cortex of the adrenal gland or can be synthesized in the laboratory. D Androgenic steroids play an important role in many physiologic processes, including the development and maintenance of male sexual characteristics such as muscle and bone mass, prostate growth, spermatogenesis, and the male hair pattern (Matsumoto, Endocrinol. Met Clin. N. Am. 23:857-75 (1994)). The endogenous steroidal androgens

IA

include testosterone and dihydrotestosterone ("DHT"). Testosterone is the pdncipal steroid secreted by the testes and is the primary cinsting androgen found in the plamna of males. Testosterone is converted to DHT by the enzyme 5 alpha-reductase in many peripheral tissues. DHT is thus thought to serve as the intracellular mediator for most 5 androgen actions (Zhou, et al., Molec. EndorinoL 9:208-18 (1995)). Other steroidal androgens include esters of testostermne, such as the cypionate, propionate, phenylpropionate, cyclopentylpropionate, isocarporate, enanthte., and decanoate esters, and other synthetic androgens such as 7-Methyl-Nortestosterone ("MEN') and its acetate ester (Sundaram et al., "7 Alpha-Methyl-Nortestosterone(MENT): The Optimal to Androgen For Male Contraception," Ann. Med., 25:199-205 (1993) ("Sundaram")). Because the AR is involved in male sexual development and function, the AR is a likely target for effecting male contraception or other fArms of hormone replacemnt therapy. [00031 Worldwide population growth and social awareness of family planning have 5 stimulated a great deal of research in contraception. Contraceptidn is a difficult subject under any circumstance. It is fraught with cultural and social stigma, religious implications, and, most certainly, significant health concerns. This situation is only exacerbated when the subject focuses on male contraception. Despite the availability of suitable contraceptive devices, historically, society has looked to women to be 0 responsible for contraceptive decisions and their consequences..Although concern over sexually transmitted diseases has made men more aware of the need to develop safe and responsible sexual habits, women still often bear the brunt of contraceptive choice. Women have a number of choices, from temporary mechanical devices such as sponges and diaphragms to temporary chemical devices such as spermicides. Women also have .5 at their disposal more permanent options, such as physical devices including lUDs and cervical caps as well as more permanent chemical treatments such as birth control pills and subcutaneous implants. However, to date, the only options available for men include the use of condoms and vasectomy. Condom use, however is not favored by many men because of the reduced sexual sensitivity, the interruption in sexual spontaneity, and the o significant possibility of pregnancy caused by breakage or misuse. Vasectomies are also not favored. If more convenient methods of birth control were available to men, particularly long-term methods which require no preparative activity immediately prior 2 to a sexual act, such methods could significantly increase the likelihood that men would take more responsibility for contraception. [0004] A dministration ofthe male sex steroids (e.g., testosterone and its derivatives) has 5 shown particular promise in this regard due to the combined gonadotropin-supressing and androgen-substituting properties of these compounds (Steinberger et al., "Effect of Chronic Administration of Testosterone Rnmnihate on Sperm Production and Plasma Testosterone, Follicle Stimulating Hormone, and Luteinizing Hormone Levels: A Preliminary Evaluation of a Possible Male Contraceptive, Fertility and Sterility 28:1320 10 28 (1977)). Chronic administration of high doses of testosterone completely abolishes spenn production (azoosperinia) or reduces it to a very low level (oligospennia). The degree of spermatogenic suppression necessary to produce infertility is not precisely known. However, a recent report by the World Health Organization showed that weekly ramuscular injections of testosterone enanthate result in azoospemn or severe L5 oligospermi (i.e., less than 3 million sperm per ml) and inf rtility in 98% of men receiving therapy (World Health Organization Task Force on Methods And Regulation ofMale Fertility, "Contraceptive Efficacy of Testosterone-Induced Azoospermia and Oligospernia in Normal Men," Fertility and Stedlity 65:821-29 (1996)). 0 [0105] A variety of testosterone esters have been developed which are more slowly absorbed after intramuscular injection and thus result in greater androgenic effect. Testosterone enanthate is the most widely used of these esters. While testosterone enanthate has been valuable in terms of establishing the feasibility of honmonal agent for male contraception, it has several drawbacks, including the need for weekly 25 injections and the presence of supraphysiologic peak levels of testosterone immediately following intramuscular injection (Wu, "Effects of Testosterone Eanthate in Normal Men: Experience From a Multicenter Contraceptive Efficacy Study," Fertility and Sterility 65:626-3 6 (1996)). 0 [0006] Steroidal ligands which bind the AR and act as androgens (e.g. testosterone enanthate) or as antiandrogens (e.g. cyproterone acetate) have been known for many years and are used clinically (Wu 1988). Although nonsteroidal antiandrogens are in 3 clinical use for hornone-dependent prostate cancer, nonsteroidal androgens have not been reported. For this reason, research on male contraceptives has focused solely on steroidal compounds. 5 [0007] Prostate cancer is one of the most frequently occmring cancers among men in the United States, with hundreds of thousands of new cases diagnosed each year. Unfortunately, over sixty percent of newly diagnosed cases of prostate cancer are found *to be pathologically advanced, with no cure and a dismal prognosis. One approach to this problem is to find prostate cancer earlier through screening programs and thereby io reduce the number of advanced prostate cancer patients. Another strategy, however, is to develop drugs to prevent prostate cancer. One third of all men over 50 years of age have a latent form of prostate cancer that may be activated into the life-thretening clinical prostate cancer form. The frequency of latent prostatic tumors has been shown to increase substantially with each decade of life from the 50s (5.3-14%) to the 90s (40 5 80%). The number of people with latent prostate cancer is the same across all cultures, ethnic groups, and races, yet the frequency of clinically aggressive cancer is markedly different This suggests that environmental factors may play a role in activating latent prostate cancer. Thus, the development of treatment and preventative strategies against prostate cancer may have the greatest. overall impact both medically and economically 0 against prostate cancer. [0008] Osteoporosis is a systemic skeletal diseaseor CHaracterized by low bone mass and deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture. In the U.S., the condition affects more than 25 million people .5 and causes more than 1.3 million fractures each year, including 500,000 spine, 250,000 hip and 240,000 wrist fractures annually. Hip fractures are the most serious consequence of osteoporosis, with 5-20% of patients dying within one year, and over 50% of survivors being incapacitated. The elderly are at greatest risk of osteoporosis, and the problem is therefore predicted to increase significantly with the aging of the population. 0 Worldwide fracture incidence is forecasted to increase three-fold over the next 60 years, and one study estimated that there will be 4.5 million hip fractures worldwide in 2050. 4 [00091 Women are at gresfer risk of osteoporosis than men. Women experience a sharp acceleration of bone loss during the five years following menopause. Other factors that increase the risk include smoking, alcohol abuse, a sedentary lifestyle and low calcium intake. However, osteoporosis also occurs frequently in males. It is well established that 5 the bone mineral density of males decrease with age. Decreased amounts of bone mineral content and density correlates with decreased bone strength, and predisposes to fracture. The molecular mechanisms underlying the pleiotropic effects of sex-hormones in non-reproductive tissues are only beginning to be understood, but it is clear that physiologic concentrations of androgens and estrogens play an important role in 1o maintaining bone homeostasis throughout the life-cycle. Consequently, when androgen or estrogen deprivation occurs there is a resultant increase in the rate of bone remodeling that tilts the balance of resorption and formation to the favor of resorption that contributes to the overall loss of bone mass. In males, the natural decline in sex hormones at maturity (direct decline in androgens as well as lower levels of estrogens 5 derived from peripheral aromatization of androgens) is associated with the frailty of bones. This effect is also observed in males who have been castrated. [000101 Androgen decline in the aging male (ADAM) refers to a progressive decrease in androgen production, common in males after middle age. The syndrome is characterized 0 by ;alterations in the physical and intellectual domains that correlate with and can be corrected' by manipulation of the androgen milieu. ADAM is characterized biochemically by a decrease not only in serum androgen, but also in other hormones, such as growth hormone, inelatonin and dehydroepiandrosterone. Clinical manifestations include fatigue, depression , decreased libido, sexual dysfunction, erectile dysfunction, 15 hypogonadism, osteoporosis, hair loss, obesity, sarcopenia, osteopenia, benign prostate hyperplasia, and alterations in mood and cognition. [0001 1]Androgen Deficiency in Female (ADIF) refers to a variety of hormone-related conditions including, common in females after middle agest The syndrome is o characterized by sexual dysfunction, decreased sexual libido, hypogonadism, sarcopenia, osteopenia, osteoporosis, alterations in cognition and mood, anemia, depression, anemia, hair loss, obesity, endometriosis, breast cancer, uterine cancer and ovarian cancer. 5 [00012]Muscle wasting refers to the progressive loss of muscle mass and/or to the progressive weakening and degeneration of muscles, including the skeletal or vohmtary muscles, which control movement, cardiac muscles, which control the heart 5 (cardiomyopathics), and smooth muscles. Chronic muscle wasting is a chronic condition (i.e. persisting over a long period of time) characterized by progressive loss of muscle mass, weakening and degeneration of muscle. The loss of muscle mass that occurs during muscle wasting can be characterized by a muscle protein breakdown or degradation. Protein degradation occurs because of an unusually high rate of protein t0 degradation, an unusually low rate of protein synthesis, or a combination of both. Protein degradation, whether caused by a high degree of protein degradation or a low degree of protein synthesis, leads to a decrease in muscle mass and to muscle wasting. Muscle wasting is associated with chronic, neurological, genetic or infectious pathologies, diseases, illnesses or conditions. These include Muscular Dystrophies such 5 as Duchenne Muscular Dystrophy and Myotonic Dystrophy; Muscle Atrophies such as Post-Polio Muscle Atrophy (PPMA); Cachexias such as Cardiac Cacheaxi, AIDS Cachexia and Cancer Cachexia, malnutrition, Leprosy, Diabetes, Renal Diseaseor CHronic Obstructive Pulmonary Disease (COPD), Cancer, end stage Renal failure, Emphysema, Osteomalacia, HI Infection, AIDS, and Cardiomyopathy, In addition, 0 other circumstances and conditions are linked to and can cause muscle wasting. These include. chronic lower back pain, advanced age, central nervous system (CNS) injury, peripheral nerve injiuy, spinal cord injuryor Chemical injury, central nervous system (CNS) damage, peripheral nerve damage, spinal cord damageor CHemical damage, bums, disuse deconditioning that occurs when a limb is immobilized, long term 5 hospitalization due to illness or injury, and alcoholism. Muscle wasting, if left unabated, can have dire health consequences. For example, the changes that occur during muscle wasting can lead to a weakened physical state that is detrimental to an individual's health, resulting in increased susceptibility to infection, poor performance status and -susceptibility to injury. [00013]New innovative approaches are urgently needed at both the basic science and clinical levels to develop compounds which are useful for a) male contraception; b) 6 treatment of a variety of hormone-related conditions, for example conditions associated with Androgen Decline in Aging Male (ADAM), such as fatigue, depression, decreased libido, sexual dysfunction, erectile dysfunction, hypogonadism, osteoporosis, hair loss, anemia, obesity, sarcopenia, osteopenia, osteoporosis, benign prostate hyperplasia, 5 alterations in mood and cognition and prostate cancer; c) treatment of conditions associated with ADIF, such as sexual dysfunction, decreased sexual libido, hypogonadism, sarcopenia, osteopenia, osteoporosis, alterations in cognition and mood, depression, anemia, hair loss, obesity, endometriosis, breast cancer, uterine cancer and ovarian cancer; d) treatment and/or prevention of acute and/or chronic muscular wasting 10 conditions; e) preventing and/or treating dry eye conditions; f) oral androgen replacement therapy; and/or g) decreasing the incidence of, halting or causing a regression of prostate cancer. 15 SUMMARY OF THE INVENTION [00014]This invention provides a class of androgen receptor targeting agents (ARTA). The agents define a new subclass of compounds, which are selective androgen receptor modulators (SARM). Several of the SARM compounds have been found to have an unexpected androgenic and anabolic activity of a nonsteroidal ligand for the androgen zo receptor. Other SARM compounds have been found to have an unexpected antiandrogenic activity of a nonsteroidal ligand for the androgen receptor. The SARM compounds, either alone or as a composition, are useful for a) male contraception; b) treatment of a variety of hormone-related conditions, for example conditions associated with Androgen Decline in Aging Male (ADAM), such as fatigue, depression, decreased 25 libido, sexual dysfunction, erectile dysfunction, hypogonadism, osteoporosis, hair loss, anemia, obesity, sarcopenia, osteopenia, osteoporosis, benign prostate hyperplasia, alterations in mood and cognition and prostate cancer; c) treatment of conditions associated with Androgen Decline in Female (ADIF), such as sexual dysfunction, decreased sexual libido, hypogonadiam, sarcopenia, osteopenia, osteoporosis, alterations 30 in cognition and mood, depression, anemia, hair loss, obesity, endometriosis, breast cancer, uterine cancer and ovarian cancer; d) treatment and/or prevention of acute and/or chronic muscular wasting conditions; e) preventing and/or treating dry eye conditions; f) 7 oral androgen replacement therapy; g) decreasing the incidence of, halting or causing a regression of prostate cancer; and/or h) inducing apoptosis in a cancer cell. [00015] In one embodiment the present invention provides a method of treatment of conditions associated with Androgen Decline in Female (ADIF) in a subject, the method comprising administering to said subject a selective androgen receptor modulator (SARM) compound represented by the structure of formula (Ila): Z Q Y a N' O X* H t) HO Ila wherein X is 0; Z is CN; Q is F, Cl, Br or I; and R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl,

CH

2 F, CHF 2 , CF 3 , CF 2

CF

3 , aryl, phenyl, F, Cl, Br, I, alkenyl or OH; wherein said conditions associated with Androgen Decline in Female (ADIF) comprises sexual dysfunction, decreased sexual libido, hypogonadism, sarcopenia, osteopenia, osteoporosis, alterations in cognition and mood, depression, anemia, endometriosis, breast cancer, uterine cancer or ovarian cancer. [00016) In another embodiment, the present invention provides an analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, impurity, prodrug, polymorph or crystal of the compound of formula (Ila), or any 2284R71 aGHMsue.) 8 polymorph or crystal of the compound of formula (Ila), or any combination thereof. [00017] In one embodiment of formula (Ila), Q is F. In another embodiment of formula (Ila), 0 is Cl. In another embodiment of formula (Ila), Q is I. [00018] PARAGRAPH INTENTIONALLY LEFT BLANK (00019] PARAGRAPH INTENTIONALLY LEFT BLANK [00020] PARAGRAPH INTENTIONALLY LEFT BLANK [00021] PARAGRAPH INTENTIONALLY LEFT BLANK 2284U7_1 PGiMaftmr)9 [00022jn another embodiment the compound of formula (Ha) is represented by the stmature: NC

CF

3 ' OH 5 [00023]1n another embodiment the compound of formula (Ha) is represented by the stucture: NCoCI 10 [00024]In another embodiment, the compound of fonnula (IHa) is represented by the stmuture: NC Br CFOB [00025]In another embodiment, the compound of fonnula (Ha) is represented by the 5 strmture: NC NH O I 10 [00026] In another embodiment, the present invention provides a method of treatment of conditions associated with Androgen Decline in Female (ADIF) in a subject, the method comprising administering to said subject a selective androgen receptor modulator (SARM) compound represented by the structure of formula (Ib): z Y N X ; and 1lb wherein X is 0;

-

Z is H, F, Cl,-Br or I; Y is CF3, I, Br, Cl, CN, C(R) 3 or Sn(R) 3 ; o is alkyl, F, I, Br, Cl, CF3, CN, C(R),, Sn(R)3,

N(R)

2 , NHCOCH3, NHCOCFa, NHCOR,

NHCONH

2 , NHCONHR,

NHCONR

2 , NHCOOR, OCONH-R, CONER, NHCSCH3, NHCSCF3, -NHCSR,

NHCSNH

2 , NHCSNHR, NHCSN (R),

NHSO

2

CH

3 , NHSO 2 R, OR, COR, OCOR, OS02R, S02R, SR; or Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C: - NH 0 NH 0 A B C R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF 2 CF3, aryl, phenyl, F, Cl, Br, 1, alkenyl or OH. [00027] In another embodiment, the present invention provides an analog, isomer, metabolite, derivative, pharmaceutically acceptable flB454L1 r.Htmr) '11 salt, pharmaceutical product, hydrate, N-oxide, impurity, prodrug, polymorph or crystal of the compound of formula (Ib), or any combination thereof. 228&'471 CGHMtfrr) 11A 000281 th m embobm ""of fnia (n aor odim& mof Zm i Z hi &uffim In anrigent oisom oftan (R, £ ImonW cl&= a nb iFB. In nadun-tf6 ,a 1 5 PA ARAPonn INTENIONALLY LEFT BLANK 10 s5 ruotr - 'he pog Of tm u (H b) is e m sen ed by the 20 201 ozbpim~the ccmd, Of fcaxle~ (fib) is estdbte 12 [O anmot- aubodhnn the campound of nmminl (J1b) is represented by the Er~ [00034]li anoth embodimnt the compound of timula (JHb) is rp mtdby the Er

CF

3 ooo5U anodmb nt me compound of tnma (11b) is resented by the 10 [000arm anomter embodinj he acmpon of mini (Jlb) 25 raped by te sfructure: Brp CFa::o' 15 13 [000371 In another embodiment the present invention provides a method of treatment of conditions associated with Androgen Decline in Female (ADIF) in a subject, the method comprising administering to said subject a a selective androgen receptor modulator (SARM) compound represented by the structure: NC I0 NH O

H

3 C OH [00038] In another embodiment the present invention provides a method of treatment of conditions associated with Androgen Decline in Female (ADIF) in a subject, the method comprising administering to said subject a a selective androgen receptor modulator (SARM) compound represented by the structure: NC [00039] In an embodiment said conditions associated with androgen decline in female (ADIF) comprises sexual dysfunction, decreased sexual libido, hypogonadism, sarcopenia, osteopenia, osteoporosis, alterations in cognition and mood, depression, anemia, hair loss, obesity, endometriosis, breast cancer, uterine cancer or ovarian cancer. [00040] PARAGRAPH INTENTIONALLY LEFT BLANK [00042] PARAGRAPH INTENTIONALLY LEFT BLANK fl845471 (Ct0Aef.r) 1 THIS PAGE IS LEFT INTENTIONALLY BLANK 2284571 GP-l s 15 THIS PAGE IS LEFT INTENTIONALLY BLANK 228454716 THIS PAGE IS LEFT INTENTIONALLY BLANK 2244.l(GHtbttor) 17 THIS PAGE IS LEFT INTENTIONALLY BLANK 22845471 (GIk-*r) 1 5 BRIE Q!JRFON OF THE1F. 00058] he pnesetin vawion will be ndstnod and - more amhly fwn. to fflalo g denied dcsmcptian ken in qunjunctiou withThe apendd figures which t00050fge jeI Andrg and &Jib i aciy of Carnpounds 1-4. Rats lft uneted Citact ocuirol), mastatd (0 mg/day con r treuie4 with0.1,0.3, 0.5, 0.75 and 1.0 mg/day of compound 1 (Fig 2 (1 3 (Fig IC) or compound 4 (ig 1D), and 1 weight a is (prostal, semimal vehicles and levajr w 1ooeM) I2gn 2: Androgenic and Anabolia atvity of Camound 5. Rats wum le frafad (inct control), cCasrfrd (0 mg/day cain),or heated with 0.1, 0.25, 0.5, 0.75 and 1.0 mg/day of compound 5, and the weight of androgen.esponsjy tissue 2 &rsiat acini vesiales and jevator animnscle) was dtan . [00061] figum 3: Androgeric and Anabolic _acttivty of Compound 6 in at. Rats wee left ureated C t ontro, castrated (castratedcuol), treated with 0.1, 0.3, 0.5, 0.75 and 1.0 mg/day Initou n(e pr tretald with 0.1, 0.3, 0.5, 0.75 2 and 1.0 mg/day Campound V, and the wes sa na esiades and levator ai mscle)was demunrined [oo6] Figure 4: AndwgMiC end Anaboic sctvity of Campound I in zis Ras we left utred (tct o o, cas (castrated control , treated with 0.1,.0.3, 30 0.5, 0.75 and 1.0 mg/day ntoster.,cmTfP or treated with 0.1, 0.3, 0.5, 0.75 and 1.0 mg/day Compound 1, and the weight of androgca-m.pona ti su- (ptat, smma l vedcles and levator ai muscle) was daem ined. 19 gEfi 'at fC mup n I and Cmpond 21 onL L ves, 100641 figure 6: BRnroft lm and 2 mCmpoud21cmPHLavls 5 g0065 Figre 7: Syfheais sehrne of Campojmd21. DETAILED DESCRIPrToN OF THE lNVENTo 10 [Om68] Jn ne also provided is a c]asS of aW2Lkm run e ietg agents (ARTA). The agents denne a new subcas of cwupomds wi& me seleci anrogenM receptir uin (BARM). Severalaft. SARM m m been tbjd to han an luexpcw andogenic and anabolic ativity of a nahAnida iand for the andwgen receptor. Othr SAM compounds haM ben fund to h5e an 5 unapected Ainfrogwid activity of a nonhwt*ibidaj ligmad for the amo ,cptor. The RM pounds, either alone or as a camposkion am usefufor a) mae contrTi b) injwtment of a-vidty of homanBne-- nn condtos, fr rmple canrfitnns auaoniaegd with Androgen Declie in Agng Mae (ADAM suc as ftgue, dq=ssioh dmad bid% sexual dyafmctian, ereotlle dyrnntion, kypgnna 20 ost hair los, aM , obesity sarcopcma, osterEa, osieopais, bign nsznc hyperplasia alftantns in mood and coguifim and prosate c ) fe ocond s is t wIth-An&ogen Decaline in Female (ADIF), sU&h as awmn1 d~ hypogonnnmrn. saopeni, 'Osteopenia, osteapooziaros33 cognii and m6od4 deWauin anmia har loss obesity, 25 bres t oancel, te cancer and ovunan cancer; d) treatment andlor prevention km af R an &or chinic msnlar wasting conditins; e) prevening and/ * teng dry aye caudiinn; 1)orl aMdrsnlm replannent 1mhry; g) deceasing it n of h n ar cmug a g = of prostate canons and/ar h) inducing apopouis in a cancer ce.- [00067] In one embodiment, also provided is a selective androgen receptor modulator (SARM) compound presented by the structure of formula (Ila): S0 Ja whrein X is 0. CF,NH, S. F.R, NO cNR Tis Cm, OR, -NHCOCa. orNHCOR; Z is NO2; CN, COOH, CoR, NHCOR Cr CONER; y iS CF3, ; (r, C, CN CW; ur sn1a; or Z and Y togan:W wite bnze ng to Whirh fiey M "ttahed funn a fused bicycHo curbocychc orhatrcylu i5 QisF,CBrari; Ris' -lky, baloayl, dhioulkyL, fhaloa C , CHFi

CF

3 , CF 2 C0 3 , ayl phenyl F, Cl,'t, l aanyl or OR; and is CH, CH 3 F, CHF2, CF, CEaVS, or CF 2

CF

3 ; wifi ahe pviso at when QisF, Z is tiot N 2 . 20 [00068] In one emnbodmnt, also provided is an analog of 'ite compound of famil (k). aothe embodment-, also provided is a dedvativo of the oompom of "I"ma (a). Inndiw eabimn also provided is a iSmer of ma W of tmula (La). In anothermbodrnemt .also Provided is a 25accehcmpnd Lf fni (o). In ofz eibodin also provided is a phawacendcRWa W&B OieCmondo aya(b.I ~d embolinnt' also provided is a pharmdaut Of fth copoud of foruala (ka). In anyone also provided is a bydlete ofto compound of zmula (ka). 31 8O M eMbodniut, also provided is an N-oddes of the 30 compound Of trmui (I). In another mbodimnta afso provided is. an jgpnty 21 of the compound of fonnula (Ia). In another embodiment, this invention provides a prodrug of the compound of formula (la). In another embodiment, this invention provides a polymorph of the compound of formula (Ia). In another embodiment, this invention provides a crystal of the compound of formula (1a). In another embodiment, 5 this invention provides a combination of any of an analog, derivative, metabolite, isomer, pharmaneutically acceptable salt, pharmaneutical product, hydrate, N-oxide, impurity, prodrug, polymorph or crystal of the compound of formula (Ia). [00069] In one embodiment of formula (Ia), Q is F. In another embodiment of formula 10 (Ia), Q is C1. In another embodiment of formula (1a), Q is Br. In another embodiment of formula (Ia), Q is I. [000701n one embodiment, X in compound (Ia) is 0. In another embodiment, Z in compound (Ia) is NO 2 . In another embodiment, Z in compound (Ia) is CN. In another 15 embodiment, Z in compound (Ia) is NO2, with the proviso that Q is not F. In another embodiment, Y in compound (Ia) is CF 3 . In another embodiment, T in compound (I) is OH. In another embodiment, R 1 in compound (Ia) is CH1 3 . In another embodiment, Q in compound (Ia) is in the para position. In another embodiment, Z in compound (Ia) is in the para position. In another embodiment, Y in compound (Ia) is in the meta position. 20 [00071]In one embodiment, the compound of formula (Ia) is represented by the structure of formula (]Ia):

H

3 C OH y. 25 Ila wherein Z Y and Q are as defined above for formula (Ia). [00072]In another embodiment, the compound of fonnula (Ia) is represented by the structure: 22 0 2 N C1 CF OH [00073]In another embodiment, the compound of formula (a) is represented by the 5 structure: 0 2 N Br 0

CF

3 N O [00074]In another embodiment, the compound of formula (Ia) is represented by the to structure: O

CF

3 . 0

H

3 C O [00075]I another embodiment, the compound of formula (Ia) is represented by the structure: NC F 15 H 3 C 'OH [00076]In another embodiment, the compound of formula (Ta) is represented by the structure: 23 NC ci 0N

CF

3 Iic1. 0 [00077]k another embodiment the conmpoimd of formula ([a) is represented by the 5 structi~c: KC Br

CF

3 3 [00078] In another embodiment, the compound of formula ([a) is represented by the shucture: NC . CF , 0 7c D H 3 C 0O 24 [00079J In another embodiment, also provided is a selective androgen receptor modulator (SAlM) compound represented by the structure of formula (Ib): 0Q whmain . X is O., C14, NH, S.9i, &No or NR; Tis oa, o, -NHCOCs 3 , ac N Ci; .Zis H.FF C%, &-or Yis CFa, JBr, ,C CR7ar. nP Q is ay F, Br; I , , CN CR& Mn, NR& NHCOC, NAooaN NHCoR, NHCON, NHCONBR, NHCONR2, NHOO OCONHR, CONR, NCSCHa, NHOCSCF, NHCSR, NnCWBn. NEMBB, NHCRNp 5 sNBoH2C6 NHBOA OR, COR, OCOR OBO2R, SOA, SR; ar QD Which it is tteeris a fused ig umrep ed bystructure A, B or C: A B C 20 R is ayl, hs oa& dfiaky, fiaoaLk Crjp, CBFa2. 12% 0F 2 0aa, aryi pAMAyl , CS Br,, urkenylor OH ad n C1*3 C&6F,

CHF

2 . CFa 036 or CF 2 CFa.

[00080] In one embodiment, also provided is an analog of the 25 compound of formula (Ib) . In another embodiment, also provided is a derivative of the compound of formula (Ib). In another embodiment, also provided is a metabolite of the compound of formula (Ib). In another embodiment, also provides is a pharmaceutically acceptable 25 salt of the compound of formula (Ib) . In another embodiment, also provided is a pharmaceutical product of the compound of formula (Ib). In another embodiment, also provided is a hydrate of the compound of formula (Ib). In another embodiment, also provided is an N-Oxide of the compound formula (1b). In another embodiment, also provided is an impurity of the compound of the formula (Ib). In another embodiment, also provided is a prodrug of the compound formula (1b). In another embodiment, also provided is a polymorph of the compound of formula (1b). In another embodiment, also provided is a crystal of the compound of formula (Ib). In another 10 embodiment, also provided is a combination of an analog, derivative, metabolite, isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, impurity, prodrug, polymorph or crystal of the compound of formula (Ib). [00081Z In one embodmnt of tmmla ( 1bb, £ is CL In m aoder embomnt of fc-mm 1m5bla (b). £ is R nt ther emboodinnt ofomfula (lb), Z is I (00082] ia one enbodment, X in compound (1b) is 0. In another mbodimn, Y in campoimd 0) is CF 3 . In another embodimm"t T in compound b) is OIL i another 20 Mbodim ntr in Ompound (b) is CH. I other embodimme Q in cOnonnd (1b) is F. In another embodfirm. Q in cmoimnd inb) is CL In anoffi .odmnt, Q in awpon (b)i H. nww=t nodihc i onzm d 1) isar Inasnotiw Mbodi"ent, Q in compound (Yb) is in the pam position. In another embodiment, Z in oampoimd-(1b) is in the papoio. InanoMthrmbomnt. Yin compound0b) is in 25 the meta pos ion.

[00083]In one embodiment, the compound of fonula (Ib) is represented by the structure of formula H1b: HC OH Z NH XaQ y 5 Ilb wheein Z, Y and Q are as defined above for formula (Ib). [00084]In another embodiment, the compound of fonnula (1b) is represented by the structure: C F

CF

3 [00086]In another embodiment, the compound of formula (1b) is represented by the structure: F F 0

CF

3 NH.,a

H

3 C O [00086]In another embodiment, the compound of formula (Ib) is represented by the structure: 2 F

CF

3 'C* 0 H, "OH p000871n another embodiment the compound of formula (Ib) is represented by the structure: 27 Br CF3 0 O 'a S IMM",h cal2poun mbfi M Of frrMMI (1b) is repnioned by ih CF2L [000OJnI another embodhnwnt, he cnqomd of frma (D) is by Urn Drr [0009O0gfn anohe anubodrnet hecozouAftna(l)sbyr srutn 10 [00091] In another embodiment, also provided is a selective androgen receptor modulator (SARM) compound represented by the structure of formula (Ic). 28 Ila wAmein 5 Xis 0. Cih 4 ,PR, No or Tis OH, OR -NHcoca, or NHCOR- Zis NO 2 , CN, COOH. COR, NHCR or CONER QisF, CZ,& ar1; 10 It ~~is ak bala~k ayl ah4 zlzlsrACSPCH 2 CZa, CF2CFs, mry- phA, P, CL W,, 4e a&M or ON- and Ra z, GbF, CHF2, CF 3 , QCEa, or CF 2 CF3 [00092] In one embodiment, also provided is an analog of the is compound of formula (Ic) . In another embodiment, also provided is a derivative of the compound of formula (Ic). In another embodiment, also provided is an isomer of the compound of formula (Ic). In another embodiment, also provided is a metabolite of the compound of formula (Ic). In another embodiment, also provided is a pharmaceutically acceptable salt of the compound of formula (Ic). 20 In another embodiment, also provided is a pharmaceutical product of the compound of the formula (Ic). In another embodiment, also provided is a hydrate of the compound of formula (Ic). In another embodiment, also provided is an N-oxide of the compound of formula (Ic) . In another embodiment, also provided is an impurity of the compound of formula (Ic). In another embodiment, also provided is a -25 prodrug of the formula (Ic). In another embodiment also provided is a polymorph of the compound of formula (Ic) . In another embodiment, also provided is a crystal of the compound of formula (Ic). In another embodiment, also provided is a combination of any of an analog, derivative, metabolite, isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, impurity, prodrug, 30 polymorph or crystal of the compound of formula (Ic). 29 [00093] In one embodiment of fonnula (Ic), Y is F. In another embodiment of formula (Ic), Y is Cl. In another embodiment of formula (Ic), Y is Br. In another embodiment of formula (Ic), Y is L In another embodiment of formula (Ic), Q is F. In another 5 embodiment of formula (Ic), Q is Cl. In another embodiment of formula (Ic), Q is Br. In another embodiment of formula (Ic), Q is I. [00094] In one embodiment of formula (Ic), Y is F and Z is F. In one embodiment of formula (Ic), Y is F and Z is CL In one embodiment of formula (Ic), Y is F and Z is Br. 1o In one embodiment of formula (Ic), Y is F and Z is L 1000951 In one embodiment of formula (1c), Y is Cl and Z is F. In one embodiment of fonnula (Ic), Y is Cand Z is C In one embodiment of formula (Ic), Y is CIand Z is Br. In one embodiment of formula (Ic), Y is CI and Z is L 15 [00096] In one embodiment of formula (Ic), Y is Br and Z is F. In one embodiment of formula (Ic), Y is Br and Z is Cl. In one embodiment of formula (Ic), Y is Br and Z is Br. In one embodiment offormula (Ic), Y is Br and Z is I. .0 [00097] In one embodiment of formula (Ic), Y is I and Z is F. In one embodiment of formula (Ic), Y is'I and Z is CL In one embodiment of formula (Ic), Y is I and Z is Br. In one embodiment of formula (Ic), Y is I and Z is I. [00098]In one embodiment, X in compound (Ic) is 0. In another embodiment, Z in 25 compound (Ic) is NO 2 . In another embodiment Z in compound (1c) is CN. In another embodiment, T in compound (Ic) is OH. In another embodiment, R 1 in compound (Ic) is

CH

3 . In another embodiment, Q in compound (Ic) is in the para position. In another embodiment, Z in compound (Ic) is in the para position. In another embodiment, Y in compound (Ic) is in the meta position. 30 30 [00099] In one embodiment, the compound of fomula (Ic) is represented by the structure of formula (He):

H

3 C OH NEI Z Q y s Hc wherein Z, Y and Q are as defined above for formula (Ic). [000100] In another embodiment the compound of formula (Ic) is represented by the structure: 10 NC F [000101] In another embodiment, the compound of formula (Ic) is represented by the structure: 31 HC rfllOF [0001021 In one embodiment, also provided is a selective androgen receptor modulator (SARM) compound represented by the structure of formula (Id). Whemei 10 x is, Q CUN Se.,PR, NaorNM T is Of, OR, -NHCoc orNHCOR Z isH F C, C NO, Cq COOH COR, NHCORor CON3R; Y isCzdTPa zcC is Or Z and YmetDdW j the bezsne ring to) whic fiay are .: affache d A=m a fused biyoic carbocyclc orhemocyclicng Q SX F-, I Br, CL C,,C NR, NHCOC3, NlCoCF NHCO, MCO , NECOER, 20 BNHCQNR, NHCOo OCONHR, CONMB NCSCE16 NRCSCF NCSR, NHCsN, NaCmR, NH R, RCO, OCOR osoa S02, SR; r 32t is aahed is a fused ' M AYkM BP=nkdby afruture A, B or C: 32 Ris altyL halkyL talmalkyL daloalkyi CS6F. CRP 3 C32 3,LA phen F C B Ay -and "a4 IS C%6 CR.W, a, C.CH2,6 Or C&2CF. [000103] In one embodiment, also provided is an analog of the compound of formula (Td). In another embodiment, also Provided is a derivative if the compound of formula (Id). In another embodiment, also Provided is an isomer of the compound of formula (Id). In 10 another embodiment, also provided is a metabolite of the Compound Of formula (Id). In another embodiment, also provided is a Pharmaceutically acceptable salt of the compound of formula (1d). In another embodiment also provided is a pharmaceutical product of h Cydt of f(Id). In another embodiment, also provided is a hydrate of the compound of formula (Id). In another 15 embodiment, also provided is an N-oxide of the compound of formula (Id). In another embodiment, also provided is an impurity of the compound of formula (Id). In another embodiment, also Provided is a prodrug Of the compound of formula (Id). In another embodiment, also provided is a crystal of the cn fother (Idimen another embodiment, also providedudoffrua .d.i analo, deriat alo pod is a combination of any of an nsalt, Pharmaceutical prto t, isomer, pharmaceutically acceptable l product hydrate, N-oxide, impurity, prodrug, R.YMOrh or crystal. of the compound of formula (Id). looo0 w cne ambodin"" X in onmpond (Ed)is 0. In another embodhnnn z 25 i cam d 0d)b i02. Inz aothe embomZ in i h a m m. In AtW Mbodhmt Z in c ompom n nd ) is Br. b mano gem Zi cmonl(1d) is p Iflfw dcnbod~hm Zj inCMMd >sL Inazmtwi emohm YinCM03d" sC3 nM~=WDM3 Y in Cunpoudf) is 3D C In anoi - a embodimnt, Yin aMpound (Td) is Br. n noter embodimmn, y in omponud (14) is F. In fnnthr compound g) M r anohe) imn . IenotYin camoun cad)m is* F. In anothen-Y 6mbor -aoi Qi Q in canpound (d) is NCocnw. In dothar cnboinmen, Q in 33 o wnjMp . in a r Qi hlnqoni (mboILmarrt Q I- no MeQ, (ncmpudM .f; CL I anOfb Q in-caonna dM is Br. In nmflwembodmt Q in compound M) I. h anofl."Mz l T n caoa is o n r c0nomd (() is C3%. 5 [00015 In another embodiment, also provided is a selective androgen receptor modulator (SARM) compound represented by the structure of formula (lid): aC -oE NE 10 d whemiA'Y~ Q Ras pee~ abov fr campond (10). [000106] In one embodiment, also provided is an analog of the compound of formula (lid). In another embodiment, also provided is 15 a derivative if the compound of formula (lid). In another embodiment also provided is an isomer of the compound of formula (lid). In another embodiment, also provided is a metabolite of the compound of formula (lid). In another embodiment, also provided is a pharmaceutically acceptable salt of the compound of formula (lid). In another embodiment, also provided is a pharmaceutical 2 product of the compound of formula (lid). In another embodiment, also provided is a hydrate of the compound of formula (lid). In another embodiment, also provided is an N-oxide of the compound of formula (lid). In another embodiment also provided is an impurity of the compound of formula (lid). In another embodiment, also provided is a prodrug of the compound of formula (lid). In another 25 embodiment, also provided is a crystal of the compound of formula (lid). In another embodiment, also provided is a combination of any of an analog, derivative, metabolite isomer, pharmaceuticals acceptable salt, pharmaceutical product, 34 hydrate, N-oxide, impurity, prodmg, polymorph or crystal of the compound of fomrula (]Id). [000107] In one embodiment, X in compound (IId) is 0. In another embodiment, Z 5 in compound (I) is NO 2 . In another embodiment, Z in compound (iRd) is CN. In another embodiment, Z in compound (Id) is a In another embodiment, Z in compound (fid) is Cl. In another embodiment Z in compound (Ild) is Br. In another embodiment, Z in compound (Id) is F. In another embodiment, Z in compound (lId) is L In another embodiment, Y in compound (Ild) is CF 3 . In another embodiment, Y in compound (1) is 10 Cl. In another embodiment, Y in compound (iRd) is Br. In another embodiment, Y in compound (lid) is F. In another embodiment, Y in compound (]Id) is I. In another embodiment, Q in compound (Id) is NHCOCH 3 . In. another embodiment, Q in compound (Hd) is F. In another embodiment, Q in compound (Id) is Cl. In another embodiment, Q in compound (iRd) is Br. In another embodiment, Q in compound (iHd) is 15 1. In another embodiment, T in compound (Ild) is OH. In another embodiment, R 1 in compound (Ild) is CH 3 . [000108] The substituents Z and Y can be in any position of the ring carrying these 20 substituents (hereinafter "A ring"). In one embodiment, the substituent Z is in the para position of the A ring. In another embodiment, the substituent Y is in the meta position of the A ring. In another embodiment, the substituent Z is in the para position of the A ring and substituent Y is in the meta position of the A ring. In another embodiment, the substitutAent Z is NO2 and is in the para position of the A ring. In another embodiment, 25 the substitutent Z is CN and is in the para position of the A ring. In another embodiment the substitutent Z is F and is in the para position of the A ring. In another embodiment, the substitutent Z is Cl and is in the para position of the A ring. In another embodiment, the substitutent Z is Br and is in the para position of the A ring. In another embodiment, the substitAuent Z is I and is in the para position of the A ring. In another embodiment, 30 the substitutent Z is L In another embodiment, the substitutent Y is CF 3 and is in the meta position of the A ring. In another embodment, the substitutent Y is F and is in the meta position of the A ring. In another embodiment, the substitutent Yis Cl and is in the 35 meta position of the A ring. In another embodiment, the substitutent Yis Br and is in the meta position of the A ring. In another embodiment, the substitutent Y is I and is in the metLaposition of the A ring. 5 [000109]. In another embodiment, one of Z or Y together with the benzene ring to which it is attached is a fused bicyclic carbocyclic or heterocyclic ring system, such as, but not being limited to: nalphthyl, quinaizolyl, pyrinidiny, and the like. [000110] The substituent Q can be in any position of the ring carrying these io substiients (hereinafter "B ring"). In one embodiment the substitutent Q is in the para position of the B ring. In another embodiment, Q is F and is in the para position of the B ring. In another embodiment, Q is C1 and is in the para position of the B ring. In another embodiment, Q is Br and is in the para position of the B ring. In another embodiment, Q is I and is in the para position of the B ring. In another embodiment, Q 15 is NHCOCH 3 and is in the para position of the B ring. [000111] The substituent R is defined herein as an alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CBF2, CF 3 , CF 2

CF

3 ; aryl, phenyl, F, Cl, Br, I, alkeny], or hydroxyl (OH). [000112] An "alkyl" group refers to a saturated aliphatic hydrocarbon, including straight chain, branched-chain 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 25 has 1-4 carbons. The alkyl group may be unsubstituted or substituted by one or more groups selected from halogen (e.g. F, Cl, Br, I), hydroxy, alkoxy carbonyl, amido, alkylamido, dialkylamido, nitro, amino, alkyainmino, dialkylamino, carboxyl, thio and thioalkyl. 30 [000113] A "haloalkyl" group refers to an alkyl group as defined above, which is substituted by one or more halogen atoms, e.g. by F, CL, Br or L A "halogen" refers to elements of Group VII or the periodic table, e.g. F, CL, Br or L 36 [000114] An "aryl" group refers to an aromatic group having at least one carbocyclic aromatic group or heterocyclic aromatic group, which may be unsubstituted or substituted by one or more groups selected from halogen (e.g. F, CL, Br, 1), haloalkyl, 5 hydroxy, alkoxy carbonyl, amido, alkylamido, dialkylamido, nitro, amin, alkylamino, dialkylamino, carboxy or thio or thioalkyl. Nonlimiting examples of aryl rings are phenyl, naphthyl, pyranyl, pyrrolyl, pyrazinyl, pyriMidinyl, pyrazolyl, pyridinyl, furanyl, thiophenyl, thiazolyl, imidazolyl, isoxazolyl, and the like. 10 [000115] A "hydroxyl" group refers to an OH group. An "alkenyr group refers to a group having at least one carbon to carbon double bond. [000116] An "arylalkyl" group refers to an alkyl bound to an aryl, wherein alkyl and aryl are as defined above. An example of an aralkyl group is a benzyl group. 15 [ooo 17] As contemplated herein, the present invention relates to the use of a SARM compound and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, prodrug, polymorph or crystal or combinations thereof. In one embodiment, the invention relates to the use of an analog 20 of the SARM compound. In another embodiment the invention relates to the use of a derivative of the SARM compound. In another embodiment, the invention relates to the use of an isomer of the SARM compound. In another embodiment, the invention relates to the use of a metabolite of the SARM compound. In another embodiment, the invention relates to the use of a pharmaceutically acceptable salt of the SARM 25 compound. In another embodiment, the invention relates to the use of a pharmaceutical product of the SARM compound. In another embodiment, the invention relates to the use of a hydrate of the SARM compound. In another embodiment, the invention relates to the use of an N-oxide of the SARM compound. In another embodiment, the invention. relates to the use of a prodrug of the SARM compound. In another embodiment, the 30 invention relates to the use of a polymorph of the SARM compound. In another embodiment, the invention relates to the use of a crystal of the SARM compound. In another embodiment, the invention relates to the use of any of a combination of an 37 analog, derivative, isomer, metabohlte, phanmaceutically acceptable salt, pharmaceutical product, hydrate, or N-oxide, prodrug, polymorph or crystal of the SARM compounds of the present invention. 5 [000118] As. defined herein, the teon "isomer" includes, but is not limited to, optical isomers and analogs, structural isomers and analogs, conformational isomers and analogs, and the like. [000119] In one embodiment, this invention encompasses the use of various optical LO isomers of the SARM compounds. It will be appreciated by those sldlled in the art that the SARM compounds of the present invention contain at least one chiral center. Accordingly, the SARM compounds used in the methods of the present invention may exist in, and be isolated in, optically-active or racemic fonns. Some compounds may also exhibit polymorphism. It is to be understood that the present invention 5 encompasses any racemic, optically-active, polymorphic, or stereroisomeric form, or mixtures thereof, which fonn possesses properties useful in the methods as described herein. In one embodiment, the SARM compounds are the pure (R)-isomers. In another embodiment, the SARM compounds are the pure (S)-isomers. In another embodiment, the SARM compounds are a mixture of the (R) and the (S) isomers. In another 0 embodiment, the SARM compounds are a racemic mixture comprising an equal amount of the (R) and the (S) isomers. It is well known in the art how to prepare optically-active fonns (for example, by resolution of the racemic form by recrystallimtion techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase). 1.5 [0001201 The invention includes pharmaceutically acceptable salts of amino-substituted compounds with organic and inorganic acids, for example, citric acid and hydrochloric acid. The invention also includes N-oxides of the aminn substitnents of the compounds described herein. Pharmaceutically acceptable salts can also be prepared from the o phenolic compounds by treatment with inorganic bases, for example, sodium hydroxide. Also, esters of the phenolic compounds can be made with aliphatic and aromatic carboxylic acids, for example, acetic acid and benzoic acid esters. 38 [000121] This invention further includes derivatives of the SARM compounds. The term "derivatives" includes but is not limited to ether derivatives, acid derivatives, amide derivatives, ester derivatives and the like. In addition, this invention further includes 5 hydrates of the SARM compounds. The term '"hydrate" includes but is not limited to hemihydrate, monohydrate, dihydrate, trihydrate and the like. [000122] This invention further includes metabolites of the SARM compounds. The term "metabolite" means any substance produced from another substance by metabolism or a 10 metabolic process. [000123] This invention further includes pharmaceutical products of the SARM compounds. The term "pharmaceutical product" means a composition suitable for pharmaceutical use (pharmaceutical composition), as defined herein. 15 [000124] This invention further includes prodrugs of the SARM compounds. The term "prodrug" means a substance which can be converted in-vivo into a biologically active agent by such reactions as hydrolysis, esterification, desteification, activation, salt formation and the like. 20 [000125] This invention further includes crystals of the SARM compounds. Furthermore, this invention provides polymorphs of the SARM compounds. The term "crystal" means a substance in a crystalline state. The term "polymorph" refers to a particular crystalline state of a substance, having particular physical properties such as 25 X-ray diffraction, IR spectra, melting point and the like. BIOLOGICAL ACIVIT OF SELECTIVE ANDROGEN RECEPTOR MODULATOR COMPOUNDS 30 [000126] Selective androgen receptor modulator (SARM) compounds are a novel class of androgen receptor targeting agents ("ARTA"), that have previously been shown to be useful for a) male contraception; b) treatment of a variety of homone-related 39 conditions, for example conditions associated with Androgen Decline in Aging Male (ADAM), such as fatigue, depression, decreased libido, sexual dysfimciion, erectile dysfunction, hypogonadisn, osteoporosis, hair loss, anemia, obesity, sarcopenia, osteopenia, osteoporosis, benign prostate hyperplasin. alterations in mood and cognition 5 and prostate cancer, c) treatment of conditions associated with Androgen Decline in Female (ADIF), such as sexual dysfinction, decreased sexual libido, hypogonadimn, sarcopenia, osteopenia, osteoporosis, alterations in cognition and mood, depression, anemia, hair loss, obesity, endometriosis, breast cancer, uterine cancer and ovarian cancer; d) treatment and/or prevention of acute and/or chronic muscular wasting 10 conditions; e) preventing and/or treating dry eye conditions; f) oral androgen replacement therapy; g) decreasing the incidence of, halting or causing a regression of prostate cancer; and/or h) inducing apoptosis in a cancer cell. 10001274 As used herein, receptors for extracellular signaling molecules are 15 collectively referred to as "cell signaling receptori. Many-cell signaling receptors are transmembrane proteins on a cell surface; when they bind an extracellular signaling molecule (i.e., a ligand), they become activated so as to generate a cascade of intracellular signals that alter the behavior of the celL In contrast, in some cases, the receptors are inside the cell and the signaling ligand has to enter the cell to activate 20 them; these signaling molecules therefore must be sufficiently small and hydrophobic to diffuse across the plasma membrane of the cell. [000128] Steroid honnones are one example of small hydrophobic molecules that .. diffuse directly across the plasma membrane of target cells and bind to intracellular cell 25 signaling receptors. These receptors are structurally related and constitute the intracellular receptor supefamily (or steroid-hormone receptor superiamily). Steroid hormone receptors include progesterone receptors, estrogen receptors, androgen receptors, glueocorticoid receptors, and mineralocorticoid receptors. The present invention is particularly directed to androgen receptors. 30 [000129] In addition to ligand binding to the receptors, the receptors can be blocked to prevent ligand binding. When a substance binds to a receptor, the three 40 dhneuaol sirtUrt Of the substance flug inb a9 Bpaoe d by *tnohesm tutuw Of the rcepftr in a bal and soettca gmann dt iet; 2cmgaudight its im This phanan is nalIad Of aL ststan s greater than Sie -nriginai knruna it w mpee w& ft 5 and bindte binig sie rn fiuquseyOnce'oct Bins my be nbt ehrugh *e reptor ito te cel, caning due cali to respond in Dome &nahMn. This i cled activate" On activatinnhe aud receptor than detly regnlatm tk Of specific. gem&s. Bt te substance and te recepinr may have ccRim atu 0han uf ,fir l ianoer n activate The eL. -Chinal -band between atom of the 10 substance and the atomn ofthe eltn may Mw In some cans, this led to a chag ite o af the recepfor which is enough to begin the actvad prcs . (flf sgnainiocin). mmi:OOIS f onW nibodrmnnt, I also provided is dieftd to selectiv 15 androgon -eceptor modular compou& wh wt agonist compounds A reeor agonist is a substance which binds recptor and acta ftm Thus, i Om embodim e SA oo of te paOsetinventin re m fAin bnng to and acBivtinghsteroidaj hnonn recepors.-n one t agi com d oft pi= inimm is an agonist which binds 1e androgen receptor. In another 20 emboim empod hs hi sfnky for the fhog= racqtb. eh antw nothe agonist compumd also has sabolic activity. In anoherd also provided is sselecye andrge mooduto compoud which have agonisti and mnabolic actviy.of a ncmstAu Conqiond for t androgeceptor. 25 [00131D. In anoffier cnborinnt also provided is dfectud tr androgen zeceptor mnodnintor cmon~wihm ."p o~t . ~ k~ 6M Mn which are aningnist campound. A recep u ""i" 28 a substance widc binds mcepor and inatvalus them. Us, in oe th AM o~omnd offheirpsiveto am usfu in ending to and km r tgsedal hmn e receptis In one mbodhmt he antgonist compound 30 of the p Meren irz nim is I *~ffi.jj bind te fndngmn rc tmr hI aod= embodr'"tthe campnd bas high affiity fm e androgen ep 41 [000132] In yet another embodiment, the SARM compounds can be classified as partial AT agonist/antagonists- The SARMS are AR agonistg in some tissues, to cause increased transcription of AR responsive genes (e.g. muscle anabolic effect). In other tissues, these compounds serve as inhibitors at the AR to prevent agonistic effects of the native androgens. [000133] Assays to determine whether the compounds are AR agonists or antagonists are well known to a person skilled in the art. For j0 example, AR agonistic activity can be determine by monitoring the ability of SAn compounds to maintain and/or timl tgo of AR containing tissue such as prostate and seminal vehicles, as measured by weight. AR antagonistic activity can be determined by monitoring the ability of SARM compounds to inhibit the growth of AR containing tissue. 25 [000134] The compounds bind either reversible or irreversibly to an androgen receptor. In one embodiment, the androgen receptor is an androgen receptor of a mammal. In another embodiment, the androgen receptor is an androgen receptor in a human. In one embodiment, the SARK compounds bind reversible to the androgen 20 receptor of a mammal, for example a human. Reversible binding of a compound to a receptor means that a compound can detach from the receptor after binding. [000135M ]i mioffies t o BAlM coxpounas hid tr mly to the audgm receptor of a mawnna fm am.plie a Inn -. a Tuione a 25 coupmnds Of the peswt hvnin may contain a fmctonaj gWp (eg. affiny lab) that aw. a;t Of the dgen mcepktr .e. covalat bond Irmaion). Th% in tis cawe. the cOnnpon& am aflkaenng im wbioh bind intvribly to me reCptor =d. acodigy cannot be displaced by a snA such as te endoganona linns DET and twfostcrone. An '"hy~flating gaajfrls dCfinWd herein a an agmet which alkylat 30 (fDw a covalent bom) wit a cellular esoh as DR&. RNA r eoynn Ais a hih MyCtiVe chsM g ini frdUf :aDL$ randia intD inigay acdve 42 molecu lmad &=eby PrWV01 9[Wr yuper hMclisaing& Th allkafig OL oiet EMa Wekuhfk MUP & hm t WIfh =WniaPhilic mainti in MeUler na1mnnene [000136] According to an embodiment a method is provided for 5 binding the SARM compounds of the present invention to an androgen receptor by contacting the receptor with a SARM compound and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, prodrug, polymorph, crystal or any combination thereof, under conditions effective to cause the selective androgen receptor modulator compound to bind 10 the androgen receptor. The binding of the selective androgen reepto com-the androgen receptor enables the compounds of the present invention to be useful as a male contraceptive and in a number of hormone therapies. The agonist compounds bind to activate the androgen receptor. Binding of the agonist or antagonist compounds is either reversible or 15 :irreversible. [000137] According to one embodiment a method is provided for suppressing spermatogenesis in a subject by contacting an androgen receptor of the subject with a SAR compound and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, 20 pharmaceutical product, hydrate, N-oxide, prodrug, polymorph, crystal or any combination thereof, in an amount effective to bind the selective androgen receptor modulator compound to the androgen receptor and suppress spermatogenesiso [000138] In another embodiment, also provided is a method of 25 contraception in a male subject, comprising the step of administering to the subject a SARm compound of the present invention, and/or its analog, derivative, isomer, metabolite pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, prodrug, Polymorph, crystal or any combination thereof, in an amount effective to suppress sperm production in the subject, 30 thereby effecting contraception in the subject. 43 [000139] According to another embodiment, also provided is a method for hormonal therapy in a patient (i.e., one auf fering from an androgen-dependent condition) which includes contacting an androgen receptor of a patient with SARM compound of the present invention and/or its analog, derivative, isomer, metabolite, Pharmaceutically acceptable salt, pharmaceutical product, hydrate, K-xie,-p.rodr_g__-]..iymrph_, _gry,,tal I _w-r nY-cQ~-Lx-i-thexep -in~ an amount effective to bind the selective androgen receptor modulator compound to the androgen receptor and effect a change in an androgen-dependent condition. [000140] According to another embodiment, also provided is a method for hormonal replacement therapy in a patient which includes contacting an androgen receptor of a patient with SARM compound of the present invention and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, prodrug, polymorph, crystal or any combination thereof, in an amount effective to bind the selective androgen receptor modulator compound to the androgen receptor and effect a change in an androgen-dependent condition. [000141] According to another embodiment, also provided is a method for treating a subject having a hormone related condition which includes administering to the subject a SARM compound of the present invention and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, prodrug, polymorph, crystal or any combination thereof, in an amount effective to bind the SAn compound to the androgen receptor and effect a change in an androgen-dependent condition. [000142] Androgen-dependent conditions which may be treated include those conditions which are associated with aging, such as 226WS47V (G3HUag.) 44 hypogonadism, sarcopenia, erythropoiesis, osteoporosis, and any other conditions determined to be dependent upon low androgen (e.g., testosterone) levels. (0001431 According to another embodiment a method is provided for treating a subject suffering from prostate cancer, comprising the --- "ep---_adminiJs tPering--o-thie-amubdacet._a-SARM--compound-otzelcsn, invention and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, prodrug, polymorph, crystal or any combination thereof, in an amount effective to treat prostate cancer in the subject. [000144] According to another embodiment a method is provided for preventing prostate cancer in a subject, comprising the step of administering to the subject a SARM compound of the present invention and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, prodrug, polymorph, crystal or any combination thereof, in an amount effective to treat prostate cancer in the subject. [000145] According to another embodiment a method is provided for delaying the progression of prostate cancer in a subject suffering from prostate cancer, comprising the step of administering to the subject a SARM compound of the present invention and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, prodrug, polymorph, crystal or any combination thereof, in an amount effective to delay the progression of prostate cancer. [000146] According to another embodiment a method is provided for preventing the recurrence of prostate cancer in a subject suffering from prostate cancer, comprising the step of administering to the subject a SANM compound of the present invention and/or its analog, fl~s~l (~kb~rs~45 derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, prodrug, polymorph, crystal or any combination thereof, in an amount effective to prevent the recurrence of prostate cancer in the subject. [000147] According to another embodiment a method is provided for treat ing thexecurrence . of po aaicna~n- batfi ~ from prostate cancer, comprising the step of administering to the subject a SARM compound of the present invention and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, prodrug, polymorph, crystal or any combination thereof, in an amount effective to treat the recurrence of prostate cancer in the subject. Ri4nl A tism af the Andlrogn Rarepgn srmwnn tho podctnof ta and ims th iAflI compounds of te pmsent invuion may be used to rst 4 eye onnaitrmas -. t00f0=o oRcg to ano&w mboa Of te parent nvrntbm a method is pivi&do for fI.w a dy y Offldi a a bject S"ff"ing"f"m" ryh se gAf nnrtm i n 's'oaid uIbmje t saeetive androgen reeptor modunton compound of te present ivann and/or its =naog dwivaiveM fisoinw metblIftmpa ix -~x MgnctL ydatq, N-nrZa Xprdrgm&*=i M (w MW-C Me &M'f nM amoDBa efocfivm to tret dry eyes in the sbjc. [000149] According to another embodiment a method is provided for preventing a dry eye condition in a subject, comprising the step of administering to said subject the selective androgen receptor modulator compound of the present invention and/or its analog, derivative, isomer, metabolite, pharmaceuticaiiy acceptable salt, pharmaceutical product, hydrate , N-oxide, prodrug, polymorpi, crystal or any combination thereof, in an amount effective to prevent dry eyes in the subject. 22845471 1-ibtor) 46 [000150] In another embodiment also provided is a method of inducing apoptosis in a cancer cell, comprising the step of contracting the cell with the selective androgen receptor modulator compound of the present invention and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, prodrug, polymorph, _ crystal or any comintion thereof, in an_ amount_effective to induce apoptosis in said cancer cell. 228"4j Ha2) 46A [000151] As defined herein, "contacting" means that the SARM compound of the present invention is introduced into a sample containing the enzyme in a test tube, flask, tissue cultureor Chip, aray, plate, microplate, capillary, or the like, and incubated at a temperature and time sufficient to pennit binding of the SARM to the enzyme. Methods 5 for contacting the samples with the SARM or other specific binding components are known to those skilled in the art and may be selected depending on the type of assay protocol to be run. Incubation methods are also standard and are known to-those skilled in the art. 10 [000152] In another embodiment, the term "contacting" means that the SARM compound of the present invention is introduced into a subject receiving treatment, and the SARM compound is allowed to come in contact with the androgen receptor in ivo. [000153] The tmm "libido, as used herein, means sexual desire. 15 [000154] The term "erectile", as used herein, means capable of being erected. An erettile tissue is a tissue, which is capable of being greatly dilated and made rigid by the distension of the numerous blood vessels which it contains. 20 [000155] "Hypogonadism" is a condition resulting from or characterised by abnormally decreased functional activity of the gonads, with retardation of growth and sexual development "Osteopenia" refers to decreased calcification or density of bone. This is a term which encompasses all skeletal systems in which such a condition is noted. 25 [000156] "Osteoporosis" refers to a thinning of the bones with reduction in bone mass due to depletion of calcium and bone protein. Osteoporosis predisposes a person to fractures, which are often slow to heal and heal poorly. Unchecked osteoporosis can lead to changes in posture, physical abnormality, and decreased mobility. 30 [000157] "BPH (benign prostate hyperplasia)" is a nonmalignant enlargement of the prostate gland, and is the most common non-malignant proliferative abnonnality 47 found in any internal organ and the major cause of morbidity in the adult male. BPH occurs in over 75% of men over 50 years of age, reaching 88% prevalence by the ninth decade. BPH frequently results in a gradual squeezing of the portion of the urethra which traverses the prostate (prostatic urethra). This causes patients to experience a 5 frequent urge to urinate because of incomplete emptying of the bladder and urgency of urination. The obstruction of urinary flow can also lead to a general lack of control over urination, including difficulty initiating urination when desired, as well as difficulty in preventing urinary flow because of the inability to empty tirne from the bladder, a condition known as overflow urinary incontinence, which can lead to urinary obstruction 10 and to urinary failure. [000158] "Cognition" refers to the process of knowing, specifically the process of being aware, knowing, thinking, learning and judging. Cognition is related to the fields .of psychology, linguisdcs, computer science, neuroscience, mathematics, ethology and 15 philosophy. The tem "mood" refers to a temper or state of the mind. As contemplated herein, alterations means any change for the positive or negative, in cognition and/or mood. [000159] The tem "depression" refers to an illness that involves the body, mood 20 and thoughts, that affects the way a person eats, sleeps and the way one feels about oneself and thinks about things. The signs and symptoms of depression include loss of interest in activities, loss of appetite or overeating, loss of emotional expression, an empty mood, feelings of hopelessness, pessimism, guilt or helplessness, social withdrawal, fatigue, sleep disturbances, trouble concentrating, remembering, or making 25 decisions, restlessness, irritability, headaches, digestive disorders or chronic pain. [000160] The term "hair loss", medically known as alopecia, refers to baldness as in the very common type of male-pattem baldness. Baldness typically begins with patch hair loss on the scalp and sometimes progresses to complete baldness and even loss of 30 body hair. Hair loss affects both males and females. 48 [000161] "Anemia" refers to the condition of having less than the nonnal number of red blood cells or less than the normal quantity of hemoglobin in the blood. The oxygen-carrying capacity of the blood is, therefore, decreased. Persons with anemia may feel tired and fatigue easily, appear pale, develop palpitations and become usually 5 short of breath. Anemia is caused by four basic factors: a) hemorrhage (bleeding); b) hemolysis (excessive destruction of red blood cells); c) underproduction of red blood cells; and d) not enough normal hemoglobin. There are many fons of anemia, including aplastic anemia, benizene poisoning, Fanconi anemia, hemolytic disease of the newborn, hereditary spherocytosis, iron deficiency anemia, osteopetrosis, pernicious 10 anemia, sickle cell disease, thalasseinia, myelodysplastic syndrome, and a variety of bone marrow diseases. As contemplated herein, the SARM compounds of the present invention are useful in preventing and/or treating any one or more of the above-listed forms of anemia. 15 [000162] "Obesity" refers to the state of being well above one's normal weight. Traditionally, a person is considered to be obese if they are more than 20 percent over their ideal weight. Obesity has been more precisely defined by the National Institute of Health (NIH) as a Body to Mass Index (BMI) of 30 or above. Obesity is often multifactorial, based on both genetic and behavioral factors. Overweight due to obesity 20 is a significant contributor to health problems. It increases the risk of developing a number of diseases including: Type 2 (adult-onset) diabetes; high blood pressure (hypertension); stroke (cerebrovascular accident or CVA); heart attack (myocardial infarction or MI); heart failure (congestive heart failure); cancer (certain farms such as cancer of the prostate and cancer of the colon and rectum); gallstones-and gallbladder 25 disease (cholecystitis); Gout and gouty arthritis; osteoarthritis (degenerative arthritis) of the knees, hips, and the lower back; sleep apnea (failure to breath normally during sleep, lowering blood oxygen); and Pickwickian syndrome (obesity, red face, underventilation and drowsiness). As contemplated herein, the term "obesity" includes any one of the above-listed obesity-related conditions and diseases. Thus the SARM compounds of the 30 present invention are useful in preventing and/or treating obesity and any one or more of the above-listed obesity-related conditions and diseases. 49 [000163] "Prostate cancer" is one of the most frequently occurring cancers among men in the United States, with hundreds of thousands of new cases diagnosed each year. Over sixty percent of newly diagnosed cases of prostate cancer are found to be pathologically advanced, with no cure and a dismal prognosis. One third of all men over 5 5Q years of age have a latnt form of prostate cancer that may be activated into the life threatening clinical prostate cancer form. The frequency of latent prostatic tumors has been shown to increase substantially with each decade of life from the 50s (5.3-14%) to the 90s (40-80%). The number of people with latent prostate cancer is the same across all cultures, ethnic groups, and races, yet the frequency of clinically aggressive cancer is 10 markedly different. This suggests that environmental factors may play a role in activating latent prostate cancer. PHARMACEUTICAL COMPOSITIONS 15 [000164] The treatment methods of. the present invention comprise, m one embodiment, administering a pharmaceutical preparation comprising the SARM compound and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, prodrug, polymorpb, crystal or any combination thereof; and a pharmaceutically acceptable cancer. 20 [000165] As used herein, "pharmaceutical composition" means a composition comprising an "effective amount" of the active ingredient, i.e. the SARM compound, together with a pharmanceutically acceptable carrier or diluent 25 [0001661 An "effective amount" as used herein refers to that amount which provides a therapeutic effect for a given condition and administration regimen. An "effective amount" of the SARM compounds as used herein can be in the range of 1-500 mg/day. In one embodiment the dosage is in the range of 1-100 mg/day. In another embodiment the dosage is in the range of 100-500 mg/day. Jn another embodiment the 30 dosage is in a range of 45-60 mg/day. In another embodiment the dosage is in the range of 15-25 mg/day. In another embodiment the dosage is in the range of 55-65 mg/day. In another embodiment the dosage is in the range of 45-60 mg/day. The SARM 50 compounds can be administered daily, in single dosage fams containing the entire amount of daily dose, or can be administered daily in multiple doses such as twice daily or three times daily. The SARM compounds can also be administered intemittently, for example every other day, 3 days a week, four days a week, five days a week and the 5 like. (000167] As used herein, the term "treating" includes preventative as well as disorder remitative treatment. As used herein, the temns "reducing", "suppressing" and 'nbibiting" have their commonly understood meaning of lessening or decreasing. As 10 used herein, the term "facilitating" is giving its commonly understood meaning of increasing the rate. As used herein, the tern "promoting" is given its commonly understood meaning of increasing. As used herein, the term "progression" means increasing in scope or severity, advancing, growing or becoming worse. 15 [000168] As used herein, the term "administering" refers to bringing a subject in contact with a SARM compound of the present invention. As used herein, administration can be accomplished in vitro, ie. in a test tube, or in vivo, iLe. in cells or tissues of living organisms, for example human. In one embodiment, the present invention encompasses administering the compounds of the present invention to a subject. In one embodiment, 20. the subject is a mammalian subject In another embodiment, the subject is ahuan. [000169] The pharmaceutical compositions containing the SARM agent can be administered to a subject by any method known to a person skilled in the art, such as parenterally, paracancerally, transmucosally, transdermally, intramusculaly, 25 intravenously, intradermally, subcutaneously, intraperitonealy, intraventricularly, intraranially, infravaginally or intratumorally. [000170] In one embodiment, the pharmaceutical compositions are administered orally, and are thus formulated in a form suitable for oral administration, i.e. as a solid or 30 a liquid preparation. Suitable solid oral furmulations include tablets, capsules, pills, granules, pellets and the like. Suitable liquid oral fomulations include solutians, suspensions, dispersions, emulstions, oils and the like. In one embodiment of the 51 present invention, the SARM compounds are fonnulated in a capsule. In accordance with this embodiment, the compositions of the present invention comprise in addition to the SARM active compound and the inert carrier or diluent, a hard ge]Ating capsule. 5 (000171] Further, in another embodiment, the pharmaceutical compositions are administered by intravenous, intraarbinal, or intramuscular injection of a liquid preparation. Suitable liquid formulations include solutions, suspensions, dispersions, emulsions, oils and the like. In one embodiment, the pharmaceutical compositions are administered intravenously, and are thus fonnulated in a form suitable for intravenous 10 administration. i another embodiment, the pharmaceutical compositions are administered intraarterially, and are thus formulated in a form suitable for intraarterial administration. In another embodiment, the pharmaceutical compositions are administered intramuscularly, and are thus formulated in a form suitable for intramuscular administration 15 [000172] Further, in another embodiment, the pharmaceutical compositions are administered topically to body surfaces, and are thus formulated in a fom suitable for topical administration. Suitable topical formulations include gels, ointments, creams, lotions, drops and the like. For topical administration, the SARM agents or their 20 physiologically tolerated derivatives such as salts, esters, N-oxides, and the like are prepared and applied as solutions, suspensions, or emulsions in a physiologically acceptable diluent with or without a pharmaceutical cancer. [000173] Further, in another embodiment, the pharmaceutical compositions are 25 administered as a suppository, for example a rectal suppository or a urethial suppository. Further, in another embodiment, the phamanutical compositions are administered by subcutaneous implantation of a pellet In a further embodiment, the pellet provides for controlled release of SARM agent over a period of time. 30 [000174] In another embodiment, the active compound can be delivered in a vesicle, in particular a liposome (see Langer, Science 249:1527-1533 (1990); Treat et al., in Liposomes in the Therapy of Infectious Disease and Cancer, Lopez- Berestein and 52 Fidler (eds.), Liss, New York, pp. 353-365 (1989); Lopez-Berestein, ibid., pp. 317-327; see generally ibid). [000175] As used herein "phanmaceutically acceptable carriers or diluents" are well 5 known to those skilled in the art. The carrier or diluent may be a solid carrier or diluent for solid fonnuations, a liquid carrier or diluent for liquid fornulations, or. mixtures thereof. [000176] Solid carriers/diluents include, but are not limited to, a gum, a starch (e.g. 10 corn starch, pregeletanized starch), a sugar (e.g., lactose, mannitol, sucrose, dextrose), a cellulosic material (e.g. microcrystalline cellulose), an acrylate (e.g. polymethylacrylate), calcium carbonate, magnesium oxide, tale, or mixtures thereof. [00O177] ... For liquid formulations, pharmaceutically acceptable carders may be 15 aqueous or non-aqueous solutions, suspensions, emulsions or oils. Examples of non aqueous solvents are propylene glycol, polyethylene glycol, and injectable organic esters such as ethyl oleate. Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media. Examples of oils are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, 20 soybean oil, mineral oil, olive oil, sunflower oil, and fish-liver oil. [000178] Parenteral vehicles (for subcutaneous, intravenous, intraarterial, or intramuscular injection) include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's and fixed oils. Intravenous vehicles include-fuid 25 and nutrient replenishers, electrolyte repleninhers such as those based on Ringer's dextrose, and the like. Examples are stedle liquids such as water and oils, with or without the addition of a surfactant and other pharmaceutically acceptable adjuvants. In general, water, saline, aqueous deadrose and related sugar solutions, and glycols such as propylene glycols or polyethylene glycol are preferred liquid carriers, particularly for 30 injectable solutions. Examples of oils are those of petroleum, animal vegetable, or synthetic origin, for temple, peauut oil, soybean oil, mineral oil, olive oil, sunflower oil, and fish-liver oil. 53 [000179] In addition, the compositions may further comprise binders (e.g. acacia, cornstarch, gelatin, carbomer, ethyl cellulose, guar gum, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, povidone), disintegrating agents (e.g. cornstarch, potato 5 starch, alginic acid, silicon dioxide, croscarmelose sodium, crospovidone, guar gum, sodium starch glycolate), buffers (e.g., Tris-HCI., acetate, phosphate) of various pH and ionic strength, additives such as albumin or gelafin to prevent absorption to surfaces, detergents (e.g., Tween 20, Tween 80, Pluronic F68, bile acid salts), protease inhibitors, surfactants (e.g. sodium lauryl sulfate), permeation enhancers, solubilizing agents (e.g., 10 glycerol, polyethylene glycerol), anti-oxidants (e.g., ascorbic acid, sodium metabisulfite, butylated hydroxyanisole), stabilizers (e.g. hydroxypropyl cellulose, hyroxypropylmethyl cellulose), viscosity increasing agents(e.g. carbomer, colloidal silicon dioxide, ethyl cellulose, guar gum), sweetners (e.g. aspartame, citric acid), preservatives (e.g., Thimeosal, benzyl alcohol,parabens), lubricants (e.g. stearic acid, 15 magnesium stearate, polyethylene glycol, sodium lauryl sulfate), flow-aids (e.g. colloidal silicon dioxide), plasticizers (e.g. diethyl phthalate, triethyl citrate), emulsifiers (e.g. carbomer, hydroxypropyl cellulose, sodium lauryl sulfate), polymer coatings (e.g., poloxamers or poloxamines), coating and film forming agents (e.g. ethyl cellulose, acrylates, polymethacrylates) and/or adjuvants. 20 [000180] In one embodiment, the pharmaceutical compositions provided herein are controlled release compositions, i.e. compositions in which the SARM compound is released over a period of time after administration. Controlled or sustained release compositions include formulation-in-lipophilic depots-(e.g. fatty acids, waxes, oils). In 25 another embodiment, the composition is an immediate release composition, i.e. a composition in which all of the SARM compound is released immediately after administration. [000181] In yet another embodiment, the pharmaceutical composition can be 30 delivered in a controlled release system. For example, the agent may be administered using itravenous infusion, an implantable osmotic pump, a transderimal patch, liposomes, or other modes of administration. In one embodiment, a pump may be used 54 (see Langer, supra; Sefton, CRC Crit. Ref. Biomed. Eng. 14:201 (1987); Buchwald et al., Surgery 88:507 (1980); Saudek et al., N. Engl. J. Med. 321:574 (1989). In another embodiment, polymeric materials can be used. In yet another embodiment, a controlled release system can be placed in proximity to the therapeutic target, ie., the brain, thus 5 requiring only a fraction of. the systemic dose (see, e.g., Goodson, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138 (1984). Other controlled release systems are discussed in the review by Langer (Science 249:1527-1533 (1990). [000182] The compositions may also include incorporation of the active material 10 into or onto particulate preparations of polymeric compounds such as polylactic acid, polglycolic acid, hydrogels, etc, or onto liposomes, microemulsions, micelles, umilamellar or multilamellar vesicles, erythrocyte ghosts, or spheroplasts.) Such compositions will influence the physical state, solubility, stability, rate of in vivo release, .ad rate.of.in vivo clearance. 15 [00D183] Also comprehended by the invention are particulate compositions coated with polymers (e.g. poloxamers or poloxamines) and the compound coupled to antibodies directed against tissue-specific receptors, ligands or antigens or coupled to ligands of tissue-specific receptors. 20 [000184] Also comprehended by the invention are compounds modified by the covalent attachment of water-soluble polymers such as polyethylene glycol, copolymers of polyethylene glycol and polypropylene glycol, carboxymethyl cellulose, dextran, polyvinyl alcohol polyvinylpyirolidone or polyproline. The modified compounds 'are 25 known to exhibit substantially longer half-lives in blood following intravenous injection than do the corresponding unmodified compounds (Abuchowski et al., 1981; Newmark et al., 1982; and Katre et al., 1987). Such modifications may also increase the compound's solubility in aqueous solution, eliminate aggregation, enhance the physical and chemical stability of the compound, and greatly reduce the immunogenicity and 30 reactivity of the compound. As a result, the desired in vivo biological activity may be achieved by the administration of such polymer-compound abducts less frequently or in lower doses than with the unmodified compound. 55 [000185] The preparation of phannaneutical compositions which contain an active component is well understood in the art, for ammple by mixing, granulating, or tablet forming processes. The active therapeutic ingredient is often mixed with excipients 5 which are pharaceutically acceptable and compatible with the active ingredient For oral administration, the SARM agents or their physiologically tolerated derivatives such as salts, esters, N-oxides, and the like are mixed with additives customary for this purpose, such as vehicles, stabilizers, or inert diluents, and converted by customary methods into suitable forms for administration, such as tablets, coated tablets, hard or 10 soft gelatin capsules, aqueous, alcoholic or oily solutions. For parentaral administration, the SARM agents or their physiologically tolerated derivatives such as salts, esters, N oxides, and the like are converted into a solution, suspension, or emulsion, if desired with the substances customary and suitable for this purpose, for example, solubilizers or .. other. 15 [000186] An active component can be formulated into the composition as neutralized pharmaceutically acceptable salt fonns. Pharmaceutically acceptable salts include the acid addition salts (formed with the free amino groups of the polypeptide or antibody. molecule), which are formed with inorganic acids such as, for example, 20. .hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric, mandelic, and the like. Salts fored from the free carboxyl-groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, 2 ethylamino ethanol, histidine, procaine, and the like. 25 [000187] For use in medicine, the salts of the SARM will be pharmneutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds according to the invention or of their pharmaeutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of this invention include 30 acid addition salts which may, for example, be formed by mixing a solution of the compound according to the invention with a solution of a pharmaneutically acceptable acid such as hydrochloric acid, sulphuric acid, methanesulphonic acid, fumnaric acid, 56 maleic acd suocic a acec cd beoia: acd, o cd. Gci aCd tadr acd, arboncacid rphosphric acid. [000188] In one embodiment, the methods of the present invention comprise administering a SARM compound as the sole active 5 ingredient. However, also provided are methods encompassed within the scope of the present invention are methods of a) male counmnpozjn; b) trament Of a vanity of hcrwaje-abd confkons, hr auwl coni&= ofwth Aadzgen Decline in Aging Male (ADAM); c) tmen of ccndit aooird ht Andrgen Decline in Female (ADIF); d) tm and/or 10 pcvd " of acute and/or chronic mu lar wat cni ns ; q) pw i ano& dry~i eye c~ canditions; O) ond andregen r~aemthm g)dcein t .nidence of, hating or coming a ze n" of pute oannr; andr I) finding apoPtDsis in a cancr cell as disciosedaeai, Wid c.mn dmithe BAM 15 but aE not iMAed to:I aWlogs, revamible antiandm m ia anfifcawj -Mgs, 5-alha reduitase kihhitom, frnmfane inhbi s pogass o agent acting trough other nndear hmm rqtO [000189] Thus, also provided are compositions 20 and phacmniat canpoii in combinsan with an LHRH naiog. in anon embdmu th prent m n prod campositions ad phajnfml an osifin canprising a slten androgen mpt nodtor cnpound, in combination wih a reveiible Mnut nrhgen. anof nbei embomde-m M 2comPOSitin compsing a selective androgen receptor modulator scmpeondr oin cetr n t cmainoniaion&a attn ccwomd = 0m~x~fan ~han mAsbngen. b another embormInat the pa~ 30 ph nanj nd pa enial ,compositionaneip a Scpotive androg ten a S-at red inhibin.I another dg. p res the emboamt pesen invenian provide cmposi~fins d 30 ph~murar ntic1 c a- S m andrgen recoin modnfntnr campund, m cennh nation wifh a anrenAm inhhfnr- u noMxd' e md-t thePm~ fic~d pmFvide GodIfinn and phannacendWcal &fi 57 comprising a selective androgen receptor modulator compound, in combination with an aromatase inhibitor. In another embodiment, the present invention provides compositions and pharnnaceutical compositions comprising a selective androgen receptor modulator compound, in combination with a progestin. In another embodiment, the 5 present invention provides compositions and pharmaceutical compositions comprising a selective androgen receptor modulator compound, in combination with an agent acting through other nuclear hormone receptors. 10 [000190] The following examples are presented in order to more fully illustrate the pmferred embodiments of the invention. They should in no way be construed, however, 15 as limiting the broad scope of the invention. EXPERIMENTAL DETAILS SECIlON EXAMPLE 1 20 AN"ROGENIC AND ANABOLIC ACTIVITY OF COMPOUNDS 1-4 0001q91] Binding affinities of select B-ring F, Cl, Br, Iated SARMS were determined and are represented in Table 1: 25 TABLE 1: Name Structure MW RBA(/) Ki I N2N F 402.3 26.4 2.3±0.0.06 C OH 58 2 0 2 N C1 419 7.6 8.6t 12 CF3 3 0 2 N Br 462 5.3 12.6 1.8 4 0 2 N 0 I 510 2.7 23 11.6

C

3 OH EXPERIMENTAL METHODS [000192] Animals. Immature male Sprague-Dawley rats, weighing 90 to 100g, .5 were purchased from Harlan Biosciences (Indianapolis, IN). The animals were maintained on a 12-hour light-dark cycle with food and water available ad libitum. The animal protocol was reviewed and approved by the Institutional Laboratory Animal Care and Use Committee. 10 [000193] Study Design. Rats were randomly distributed into treatment groups groups. One day prior to the start of drug treatment animals were individually removed from the cage, weighed and anesthetized with an intraperitoneal dose of keanmine/xylazine (87/13 mg/kg; approximately I mL per kg). When appropriately anesthetized (i.e., no response to toe pinch), the animais'- ears were marked for 15 identification purposes. Animals were then placed on a sterile pad and their abdomen and scrotum washed with betadine and 70% alcohol. The testes were removed via a midline scrotal incision, with sterile suture being used to ligate supra-testicular tissue prior to surgical removal of each testis. The surgical wound site was closed with sterile stainless steel wound clips, and the site cleaned with betadine. The animals were allowed 20 to recover on a sterile pad (until able to stand) and then retumed to their cage. [000194] Twenty-four hours later, animals were re-anesthetized with ketamine/xylazine, and an Alzet osmotic pump(s) (model 2002) was placed subcutaneouly in the scapular region. In this instance, the scapular region was shaved 59 and cleaned (betadine and alcohol) and a small incision (1 cm) made using a sterile scalpel. The osmolic pump was inserted and the wound closed with a sterile stainless steel wound clip. Animals were allowed to recover and were retumed to their cage. Osmotic pumps contained the appropriate treatment dissolved in polyethylene glycol 5 300 (PEG300). Osmotic pumps were fled with the appropriate solution one day prior to implantation. Animals were monitored daily for signs of acute toxicity to drug treatment (e.g., lethargy, rough coat). [000195] After 14 days of drug treatment, rats were anesthetized with 10 ketamine/xylazine. Animals were then sacrificed by exsanguinations under anesthesia. A blood sample was collected by-venipuncture of the abdominal aorta, and submitted for complete blood cell analysis. A portion of the blood was placed in a separate tube, centrifuged at 12,000g for 1 minute, and the plasma layer removed and frozen at -20"C. The ventral prostates, seminal vesicles, levator ani muscle, liver, kidneys, spleen, lungs, 15 and heart were removed, cleared of extraneous tissue, weighed, and placed in vials containing 10% neutral buffered formalin. Preserved tissues were sent to GTx, Inc. for histopathological analysis. [000196] For data analysis, the weights of all organs were normalized to body 20 weight, and analyzed for any statistical significant difference by single-factor ANOVA. Te weights of prostate and seminal vesicle were used as indexes for evaluation of androgenic activity, and the levator ani muscle weight was used to evaluate the anabolic activity. 25 RESULTS [000197] The androgenic and anabolic activities of compounds 1-4 were examined in a castrated rat model after 14 days of administration. The results are shown in Figure I A-D as a percent of the Intact Contol (not castrated, untreated). 0mg/day denotes 30 Castrated Controls (castrated, untreated). 60 [000198] As shown in Figure 1, the weights of prostate, seminal vesicle, and levator ani muscle in castrated rats decreased significantly, due to the ablation of endogenous androgen production. Treatment with increasing dosages of compounds 1-4 (Figure 1 A-D respectively) resulted in a tissue-selective increase in levator ani muscle 5 weights, with little or no stimulation of prostate and seminal vesicle growth (i.e. the prostate and seminal vesicle weights were less than 40% of that observed in intact animals for compound 2, and less than 20% for compounds 1, 3 and 4). Thus these compounds showed little potency and intrinsic activity in increasing the weights of prostate and seminal vesicle, but a great potency and intrinsic activity in increasing the 10 weight of levator ani muscle. Particularly, compound 2 was able to maintain the levator ani muscle weight of castrated animals in the same level as that of intact animals. Thus, compounds 1-4 are potent nonsteroidal anabolic agents. This is a significant improvement over previous compounds, in that these compound selectively stimulate muscle growth and other.anabolic.,effects while havingfess effect on the prostate and 15 seminal vesicles. This may be particularly relevant in aging men with concems related to the development or progression of prostate cancer. EXAMPLE 2 ANDROGENIC AND ANABOLIC ACTIVITY OF COMPOUND 5 20 [000199] The binding afinitiy of select compound 5 is represented in Table 2: TABLE 2: 25 Name Struature MW Ki 5 NC F 382.3 3.310.08 CF36 61 [000200] The androgenic and anabolic activities of compound 5 was exanmined in a castrated rat model after 14 days of administration, using the method outlined in Example 1 above. 5 [000201] As shown in Table 3 and in Figure 2, compound 5 demonstrated tissue selective pharmanological effects in castrated male rats, with higher efficacy in anabolic tissues (i.e. levator ani) as compared to androgenic tissues (i.e. prostate and seminal vesicles). Compound 5 demonstrated little pharmacologic activity in the prostate (8.7± 1.39% of intact at 1.0 mg/day dose) and sminal vesicles (10.7 0.91% of intact at 1.0 10 mg/day dose), suggesting that it acts as a weak partial agonist in these tissues. Importantly, compound 5 demonstrates highly efficacious anabolic activity at 1.0 mg/day dose, returning the levator ani muscle to 75.2+ 9.5 1% of that observed in intact animas. .15 TABLE 3. Average (Mean i S.D.) Organ Weights Prostate Levator Ani Seminal Vesicles Intact Control 100 11.28 100 12.12 100± 2.48 Castrated Control 7.6 ± 0.68 45.9+ 10.84 8.4± 1.05 0.10 mg/day 6.4 +0.82 54.9+5.77 8.8± 1.18 0.25 mg/day 5.7+0.61 61.0 5.23 7.6* 1.37 .0.50 mg/day 6.2+0.56 55.0 +9.23 9.3 1.57 0.75 mg/day 7.6 L 0.74 68.9 A 8.46 9.8 A 3.65 1.00 mg/day 8.7+1.39 75.2 9.51 10.7+ 0.91 EXAMPLE3 ANDROGENIC AND ANABOLIC ACTIVITY OF COMPOUND 6 20 [000202] The binding affinity of select compound 6 is represented in Table 4: TABLE 4: 25 Name Structure MW Ki 62 6 NC CI 398.8 3.4 t0.08

CF

3 N. HC [000203] The androgenic and anabolic activities of compound 6 was examined in a 5 castrated rat model after 14 days of administration, using the method outlined in Example 1 above. [000204] As shown in Figure 3, the weights of prostate, seminal vesicle, and levator ani muscle in castmted, vehicle-treated rats decreased significantly, due to the 10 ablation of endogenous androgen production. Exogenous administration of testosterone propionate,. an androgenic and anabolic steroid, increased the weights of prostate, seminal vesicle, and levator ani muscle in castrated rats in a dose-dependent manner. Treatment with compound 6 resulted in dose-dependent increases in prostate, seminal vesicle and levator ani muscle weights. Compared with testosterone propionate, 15 compound 6 showed lower potency and intrinsic activity in increasing the weights of prostate and seminal vesicle, but a greater potency and intrinsic activity in increasing the weight of levator ani muscle. Particularly, compound V, at a dose as low as 0.3 mg/day, was able to maintain the levator ani muscle weight of castrated animals in the same level as that of intact animals. Thus, compound 6 is a potent nonsteroidal anabolic agent with 20 less androgenic activity but more anabolic activity than testosterone propionate. As in compounds 1-5 above, this is a significant improvement in that this compound selectively stimulates muscle growth and other anabolic effects while having less effect on the prostate and seminal vesicles. 25 30 63 EXAMPLE 4 Binding Afnties of Selective Androgen Receptor Modulators [000205] The in-vitro androgen receptor binding affinity of other SARM 5 compounds was studied and the results are presented in Table 5. TABLE 5 Name Structure MW Ki 7 NC F 348.1 4.5±0.11 C1 NHO H C OFI 8 N / - O NHCOCH 3 421.4 12.7±0.03 9 C 360.6 22.2 L0.17

CF

3 Br 10 C F 391.7 14.5-0.18 0 .N

CF

3 0 11 F F 3'>5.3 32.6 ±0.1

CF

3 N O

H

3 OF 64 13 Br Ci 452.7 52.0 +0.13 CIF3 NH Or~ HC 'OH 14 *Br Br 436.2 25.9+0.04 0 F

CF

3

H

3 C OH. 15 0F 357.3 62.0 +0.05

OF

3 "ON 16 NC F 440.2 3.5 0.13 IH3 C 17 0 2 N F 376.3 >1800 0 N

H

3 C -10H 0-N 18 Br F 436.2 ND CF3 N 13C \"OH 19 s 458.41 ND 20 0 2 0 ce, 20 CN2N N 17.00.64 CF N If ND - Not Determined Average DHT Ki value: 0.360.15 65 EXAMPLE 5 Nonsteroidal Ligands with Androgenic and Anabolic ActivitV 5 [000206] The in-vivo efficacy and acute toxicity of four nonstmoidal androgens (compounds 1, 21, 22 and 23) in rats was examined. In-vitro assays established that these compounds bind the androgen receptor with very high affinity. The structures and names of the four compounds are presented below: 0 2 N R

CF

3 )

H

3 C OH Compound 1 R= F Compound 21 R=NHCOCH 3 Compound 22 R=COCH 3 10 Compound23

R=COC

2 H5 EXPERIMENTAL METHODS 15 [000207] Materials. The S-isomers of 1, 21, 22 and 23 and R-isomer of compound 1 were synthesized in accordance with the scheme as set forth in Figure 7. Testosterone propionate (TP), polyethylene glycol 300 (PEG3 00, reagent grade) and neutral buffeed formalin (10% w/v) were purchased from Sigma Chemical Company (St Louis, MO). 20 Alzet osmotic pumps (model 2002) were purchased from Alza Corp. (Palo Alto, CA). [000208] Animals. Tmmature male Sprague-Dawley ras, weighing 90 to 100g, were purchased from Harlan Biosciences (Indianapolis, IN). The animals were maintained on a 12-hour light-dak cycle with food and water available ad libitum. The 25 animal protocol was reviewed and approved by the Institutional Laboratory Animal Care and Use Committee. 66 [000209] &udy Design Rafs were randomly distributed into twenty-nine (29) groups, with 5 animals per group. Treatment groups are described in Table 6. One day prior to the start of drug treament, animals in groups 2 through 29 were individually 5 removed from the cage, weighed and anesthetized with an intraperitoneal dose of ketamine/xylazine (87/13 mg/kg approximately 1 mL per kg). When appropdately anesthetized (i.e., no response to toe pinch), the animals' ears were marked for identification purposes. Animals were then placed on a sterile pad and their abdomen and scrotum washed with betadine and 70% alcohol. The testes were removed via a 10 midline scrotal incision, with sterile suture being used to ligate supra-testicular tissue prior to surgical removal of each testis. The surgical wound site was closed with sterile stainless steel wound clips, and the site cleaned with betadine. The animals wtre allowed to recover on a sterile pad (until able to stand) and then returned to their cage. 15 [000210] Twenty-four hours later, animals in groups 2 through 29 were re anesthetized with ketaminerylazine, and an Alzet osmotic pump(s) (model 2002) was placed subcutaneouly in the scapular region. In this instance, the scapular region was shaved and cleaned (betadine and alcohol) and a small incision (1 cm) made using a sterile scalpel. The osmotic pump was inserted and the wound closed with a sterile 20 stainless steel wound clip. Animals were allowed to recover and were returned to their cage. Osmotic pumps contained the appropriate treatment (designated in Table 1) dissolved in polyethylene glycol 300 (PEG300). Osmotic pumps were filled with the appropriate solution one day prior to implantation. Animals were monitored daily for signs of acute toxicity to drug treatment (e.g., lethargy, rough coat). 25 [000211] After 14 days of drug treatment, rats were anesthetized with ketamine/xylazine. Animals were then sacrificed by exsanguinations under anesthesia. A blood sample was collected by venipuncture of the abdominal aorta, and submitted for complete blood cell analysis. A portion of the blood was placed in a separate tube, 30 centrifuged at 1 2,000g for 1 minute, and the plasma layer removed and frozen at -20"C. The ventral prostates, seminal vesicles, levator ani muscle, liver, kidneys, spleen, lungs, and heart were removed, cleared of extraneous tissue, weighed, and placed in vials 67 containing 10% neutral buffered formalin. Preserved tissues were sent to GTx, Inc. for histopathological analysis. [000212] For data analysis, the weights of all organs were nonnalized to body 5 weight, and analyzed for any statistical significant difference by single-factor ANOVA. The weights of prostate and seminal vesicle were used as indexes for evaluation of androgenic activity, and the levator ani muscle weight was used to evaluate the anabolic activity. 10 RESULTS [000213] The androgenic and anabolic activities the S isomers of compounds 1, 21, 22 and 23, and the R isomer of compound 1 were examined in a castrated rat model after 14 day of administration. Testosterone propionate, at increasing doses, was used as the 1-5 positive control of anabolic and androgenic effects. [000214] As shown in Figure 4, the weights of prostate, seminal vesicle, and levator ani muscle in castrated, vehicle-treated rats decreased significantly, due to the ablation of endogenous androgen production. Exogenous administration of testosterone 20 propionate, an androgenic and anabolic steroid, increased the weights of prostate, seminal vesicle, and levator ani muscle in castrated rats in a dose-dependent manner. The R-isomer of compound 1, and S-isomers of compounds 22 and 23 showed no effect on the weights of prostate, seminal vesicle, and levator ani muscle in castrated animals (data not shown). The S-isomer of compound 1 (Figure 4) resulted in dose-dependent 25 increases in prostate, seminal vesicle and levator ani muscle weights. [000215] Compound 1 but showed great tissue selectivity. Compound 1 significantly increased levator ai muscle weights, but showed little to no ability to stimulate prostate and seminal vesicle growth (i.e., the prostate and seminal vesicle 30 weights were less than 20% of that observed in intact animals or in animals treated with testosterone propionate). 68 [000216] In summary, Compound 1 showed selective anabolic activity in comparison with testosterone propionate, an androgenic and anabolic steroid. The tissue selective activity is actually one of the advantages of nonsteroidal androgens in terms of anabolic-related applications. 5 [000217] None of the examined compounds produced significant effect on body weight or the weights of other organs (i.e., liver, kidneys, spleen, lungs and heart). Nor did any compound produce any signs of acute toxicity, as gauged by diagnostic hematology tests and visual examination of animals receiving trealnents. Importantly, 10 compound 21 did not suppress the production of luteinizing hormone (LH) or follicle stimulating hormone (FSH) at a dose of 0.3 mg/day (i.e., a dose that exhibited maximal anabolic effects). [000218] These studies show the.discovery of compound 1 is a member of a class 15 of selective androgen receptor modulators (SARMS) that demonstrates potent anabolic effects (e.g., muscle growth) with less androgenic activity (e.g., prostatic growth). This new class of drugs has several advantages over non-selective androgens, including potential therapeutic applications in males and females for modulation of fertility, erythropoiesis, osteoporosis, sexual libido and in men with or at high risk for prostate 20 cancer. [000219] Further, Figures 5 and 6 demonstrate the effects of compound 1 and compound 21 on LH and FSH levels in rats. These results further demonstrate the riovelty of these SARMs, due to-their differential effects on these reproductive 25 hormones, thus demonstrating the tissue-specific pharmannlogic activity. In Figure 5, LH levels in castrated animals treated with TP and compound 1 were significantly lower than those of untreated animals (ie., castrated controls) at doses greater than or equal to 0.3 mg/day. However, higher doses (i.e., 0.5 mg/day or higher) of compound 21 were required before significant decreases in LH levels were observed. Thus, compound 21 30 does not suppress LH levels at doses that are capable of eliciting maximal stimulation of levator ani muscle growth. In Figure 6, FSH levels in castrated animals treated with compound 1 were significantly lower than those of untreated animals (i.e., castrated 69 controls) at doses of 0.5 mg/day or higher. Similarly, lower FSH levels were observed in animis treated with TP. However, only this difference was only significant at a dose of 0.75 mg/day. FSH levels in animals treated with compound 21 were not significantly different from those of untreated animals at any dose level tested. Thus, compound 21 5 does not suppress FSH levels at doses that are capable of eliciting maximal stimulation of levator ani muscle growth. [000220] Table 6. Animals Groups and Experimental Design 10 Grup # Castrated? Drug Dose # of animals 1 No None None 5 2 Yes None Vehicle only 5 3 Yes Testosterone 0.1 mg/day 5 4 Yes Testosterone 0.3 mg/day 5 5 Yes Testosterone 0.5-g/day 5 6 Yes Testosterone 0.75 mg/day 5 7 Yes Testosterone 1.0 mg/day 5 8 Yes R- 1.0 mg/day 5 9 Yes S- 1 mg/day 5 10 Yes S-1 0.3 mg/day 5 11 Yes S-1 0.5 mg/day 5 .12 Yes S-1 0.75 mg/day 5 13 Yes S-1 1.0 m/d5 14 Yes S-1 0.1mg/day 5 15 Yes S-21 0.3 mg/day 5 16 Yes S-21 0.5 mg/day 5 17 Yes -21 0.75 mg/day 5 18 Yes S-21 1.0 mg/day 5 19 Yes S-22 0.1 mg/day 5 20 Yes S-23 0.3 mg/day 5 21 Yes S-23 0.5 mg/day 5 22 Yes S-23 0.75 mg/day 5 23 Yes S-23 1.0 mg y 5 24 Yes S-21 0.1 mg/day 5 25 Yes S-21 0.3 mg/day 5 26 Yes S-21 0.5 mg/day 5 27 Yes S-21 0.75 mg/day 5 28 Yes S-21 1.0 mg/day 5 29 Yes None Vehicle only 5 70 EXAMPLE 6 - SYNTHETIC PROCEDURES [000221] (2R)-1-Methacryloylpyrrolidin-2-carboxylic Acid (R-129). D-Proline (R-128, 14.93 g, 0.13 mol) was dissolved in 71 mL of 2 N NaOH and cooled in an ice 5 bath, the resulting alkaline solution was diluted with acetone (71 mL). An acetone solution (71 mL) of metacryloly chloride 127 (13.56 g, 0.13 mol) and 2N NaOH solution (71 mL) were simultaneously added over 40 min to the aqueous solution of D-proline in an ice bath. The pH of the mixture was kept at 10-1OC during the addition of the metacryloly chloride. After stirring (3 h, room temperature), the mixture was evaporated 10 in vacuo at a temperature at 35-45 "C to remove acetone. The resulting solution was washed with ethyl ether and was acidified to pH 2 with concentrated HCL The acidic mixture was saturated with NaCl and was extracted with EtOAc (100 mL x 3). The combined extracts were dried over Na 2 S04, filtered through Celite, and evaporated in vacuo to give the crude product as a colorless oil. Ferys zation of the oil from ethyl 15 ether and hexanes afforded 16.2 (68%) of the desired compound as colorless crystals: mp 102-103 "C (lit. [214] mp 102.5-103.5 "C); the NMR spectrum of this compound demonstrated the existence of two rotamers of the title compound. 'H NMR (300 MHz, DMSO-d) 8 5.28 (s) and 5.15 (s) for the first rotamer, 5.15 (s) and 5.03 (s) for the second rotamer (totally 2H for both rotamers, vinyl CH 2 ), 4.48-4.44 for the first rotamer, 20 4.24-4.20 (m) for the second rotamer (totally 1H for both rotamers, CH at the chiral canter), 3.57-3.38 (m, 2H, CH 2 ), 2.27-2.12 (1H, CH), 1.97-1.72 (m, 6H, CH2, CH, Me); 1 3 C NMR (75 MHz, DMSO-d) 8 for major rotamer 173.3, 169.1, 140.9, 116.4, 58.3, 48.7, 28.9, 24.7, 19.5: for minor rotamer 174.0, 170.0, 141.6, 115.2, 60.3, 45.9, 31.0, 22.3, 19.7; IR (KBr) 3437 (OH), 1737 (C=0), 1647 (CO, COOH), 1584, 1508, 1459, 2:5 1369, 1348, 1178 cm'; [a]D 26 +80.8" (c = 1, MeOH); Anal. Calcd. for C 9 HuNOs: C 59.00, H 7.15, N 7.65. Found: C 59.13, H 7.19, N 7.61. [000222] (3R,8aR)-3-Bromomethyl-3-methyl-tetrahydro-pyrrolo2,1c] [1,4] oxazine-1,4-dione (R, R-130). A solution of NBS (23.5g, 0.132 mol) in 100 mL of 30 DMF was added dropwise to a stirred solution of compound R-129 (16.1g, 88 mmol) in 70 mL of DMF under argon at room temperature, and the resulting mixture was stirred 3 days. The solvent was removed in vacuo, and a yellow solid was precipitated. The solid 71 was suspended in water, stirred overnight at room temperature, filtered, and dried to give 18.6 (81%) (smaller weight when dried ~ 34%) of the title compound as a yellow solid: mp 152-154 *C (lit. [214] mp 107-109 *C for the S-isomer); IH NMR (300 MHz, DMSO-) 8 4.69 (dd, J= 9.6 Hz, J= 6.7 Hz, 1H, CH at the chiral center), 4.02 (d, J= 5 11.4 Hz 1, CHIL), 3.86 (d, J1= 11.4 Hz, 1H, CHb), 3.53-3.24 (m, 4H, CHI), 2.30 2.20 (m, 1H, CH), 2.04-1.72 (m, 31, CH 2 and CR), 1.56 (s, 2H, Me); ' 3 C NMR (75 MHz, DMSO-d) 8 167.3, 163.1, 83.9, 57.2, 45.4, 37.8, 29.0, 22.9, 21.6; IR (KBr) 3474, 1745 (C=O), 1687 (0=0), 1448, 1377, 1360, 1308, 1227, 1159, 1062cnf; [x.] 2 6 +124.5 * (c = 1.3, chloroform); Anal. Calcd. for C 9 HuBrNO3: C 41.24, H 4.61, N 5.34. Found: 10 C 41.46, H 4.64, N 5.32. [0002231 ( 2

R)-

3 -Bromo-2-hydroxy-2-methylpropanoic Acid (R-131). A mixture of bromolactone R-130 (18.5g, 71 mmol) in 300 mL of 24% HBr was heated at reflux for 1 h. The resulting solution was diluted with brine (200 mL), and was extracted with 15 ethyl acetate (100 mL x 4). The combined extracts were washed with saturated NaHCO 3 (100 mL x 4). The aqueous solution was acidified with concentrated HC1 to pH = 1, which, in turn, was extradted with ethyl acetate (100 mL x 4). The combined organic solution was dried over Na 2 S04, fltered through Celite, and evaporated in vacuo to dryness. Recrystallization from toluene afforded 10.2 g (86%) of the desired compound 20 as colorless crystals: mp 107-109 *C (lit [214] mp 109-113 *C for the S-isomer); 1 H NIVMR (300 MHz, DMSO-d 6 ) 5 3.63 (d, J = 10.1 Hz, 1H, CHH), 3.52 (d, J = 10.1 Hz, 11, CHib), 1.35 (s, 3H, Me); IR (KBr) 3434 (OH), 3300-2500 (COOH), 1730 (C=0), 1449, 1421, 1380, 1292, 1193, 1085 m- 1 ; [%V 2 6 +10.5" (c = 2.6, MeOH); Anal. Calod. for C 4

H

7 BrO 3 : C 26.25, H 3.86. Found: C 26.28, H 3.75. 25 [000224] N-[ 4 -Nxtro-3-(trfnoromethyl)pheny]-(2R)-3-bromo-2.hydroxy-2 methylpropanamide (R-132). Tbionyl chloride (8.6 g, 72 mmol) was added dropwise under argon to a solution of bromoacid R-131 (11.0 g, 60 mmol) in 70 mL of DMA at 5 to -10 "C. The resulting mixture was stirred for 2 h under the same conditions. A 30 solution of 4-nitro-3-trifluoromethyl-aniline (12.4 g, 60 mmol) in 80 mL of DMA was added dropwise to the above solution, and the resulting mixture was stirred ovemnigt at room temperature. The solvent was removed on Rotavapor using high vacuum oil pump; 72 the residue was diluted with saturated NaHCO 3 solution, and extracted with ethyl ether (100 mL x 3). Combined extracts were dried over anhydrous Na 2

SO

4 , filtered through Celite, and purified by flash chromatography on silica gel, using methylene chloride as eluent to afford 18.0 g (80%) of the desired compound: mp 98-100 "C (Rf= 0.2 , silica 5 gel, CH 2 Cl 2 ); 'H NMR (300 MHz, DMSO-d4) 5 10.54 (s, 1H, NH), 8.54 (d, J= 2.1 Hz, 1H, AtH), 8.34 (dd, J= 9.0 Hz, J = 2.1 Hz, 1H, ArH), 8.18 (d, J= 9.0 Hz, Il, Ai), 6.37 (s, 1H, OH), 3.82 (d, J = 10.4 Hz, 1H, CHH.), 3.58 (d, J= 10.4 Hz, 11, CH.), 1.48 (s, 3H, Me); "C NMR (75 MHz, DMSO-d) 8 173.6 (C=0), 143.0, 127.2, 123.2, 122.6 (q, J = 33.0 Hz), 122.0 (q, J = 271.5 Hz), 118.3 (q, J = 6.0 Hz), 74.4,41.4,24.9; 1R 10 (KBr) 3344 (OH), 1680 (C=0), 1599, 1548 (C=C, Ar), 1427, 1363, 1161 cm'; MS (ESI): in/z 370.8 (M); Anal. Calcd. for Cu 1 HioBrN 2 0 4 : C 35.60, H 2.72, N 7.55. Found: C 35.68, H 2.72, N 7.49. [0002261- N-[ 4 -nitro- 3 -trfluoromethyl)pheny]-(2)-3-[4-(acetylamino) phen 15 oxy]-2-hydroxy-2-methylpropanamide (S-147, Compound 21). The title compound was prepared from compound R-132 (0.37 g 1.0 mmol), 4-acetamidophenol (0.23 g, 1.5 mmol) K 2

CO

3 (0.28 g, 2.0 mmol), and 10% of benzyltributylammonium chloride as a phase transfer catalyst in 20 mL of methyl ethyl ketone was heated at reflux overnight under argon. The reaction was followed by TLC, the resulting mixture was filtered 20 through Celite, and concentrated in vacuo to dryness. Purification by flash column chromatography on silica gel (hOexanes-ethyl acetate, 3:1) yielded 0.38 g (86%) (Rf = 0.18 hexanes-ethyl acetate, 3:1) of the desired compound as a light yellow powder: rap 70-74 "C; The solid can. be recrystalized from ethyl acetate and hexane); 1H NMR (300 MHz, DMSO-d 6 ) 6 10.62 (s, 1M, NH), 9.75 (s, 1H, NH), 8.56 (d, J = 1.9 Hz, 1H, ArH), 25 8.36 (dd, J= 9.1 Hz, J= 1.9 Hz, 1H, ArH9), 8.18 (d, J= 9.1 Hz, 1H, ArH), 7.45-7.42 (m, 21H, ArH), 6.85-6.82 (in, 21, ArHl), 6.25 (s, 1H, OH), 4.17 (d, J= 9.5 Hz, 1H, CBH.), 3.94 (d, J= 9.5 Hz, 1HE, CHH 1 ), 1.98 (s, 3H, Me), 1.43 (s, 3H, Me); ' 3 C NMR (75 MHz, DMSO-d 6 ) 8 174.6 (C=O), 167.7, 154.2, 143.3, 141.6, 132.8, 127.4, 123.0, 122.7 (q, J= 33.0 Hz), 122.1 (q, J=271.5 Hz), 120.1, 118.3 (q, J= 6.0 Hz), 114.6, 74.9, 73.8, 23.8, 30 23.0; JR (KBr) 3364 (OH), 1668 (C=0), 1599, 1512 (C=C, Ar), 1457,1415,1351, 1323, 1239, 1150 1046 cm4i; MS (ESI): ma/z 464.1 (M+Na)+; Anal. Caled. for CiWHIF 3

N

3 0 6 : C 51.71, H 4.11, N9.52. Found: C 52.33, H 4.40, N9.01. 73 [000226] The synthesis of the various ether analogs of Compound 21, such as, but not limited to, compounds 1-4, 22 and 23 provided herein, utilizes the common intermediate that is the final.reaction step. Bromo-intermediates are used which allow 5 various phenolic compounds to displace the bromide to give the desired ether product. Bromohydrin was converted to an epoxide and to open the epoxide to give the same desired ether product. [000227] It will be appreciated by a person skilled in the art that the present 10 invention is not limited by what has been particularly shown and described heminabove. Rather, the scope of the invention is defined by the claims that follow: 74 - 75 [000228] In the claims which follow and in the preceding description of the invention, except where the context requires otherwise due to express language or necessary implication, the word "comprise" or variations 5, such as "comprises" or "comprising" is used in an inclusive sense, ie. to specify the presence of the stated features but not to preclude the presence or addition of further features in various embodiments of the invention. [000229] It is to be clearly understood that 10 although prior art publication(s) are referred to herein, this reference does not constitute an admission that any of these documents forms part of the common general knowledge in the art in Australia or in any other country. H:\MaraR\Keep\Speci\P60042.doc 23/02/U0

Claims (15)

1. A method of treatment of conditions associated with Androgen Decline in Female (ADIF) in a subject, the method comprising administering to said subject a selective androgen receptor modulator (SARM) compound represented by the structure of formula (Ila): Z NO -- ------ x H lIla wherein X is O; Z is CN; Y is CF 3 , I, Br, Cl, CN, C(R) 3 or Sn(R) 3 ; Q is F, Cl, Br or 1; and R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, phenyl, F, Cl, Br, 1, alkenyl or OH; wherein said conditions associated with Androgen Decline in Female (ADIF) comprises sexual dysfunction, decreased sexual libido, hypogonadism, sarcopenia, osteopenia, osteoporosis, alterations in cognition and mood, depression, anemia, endometriosis, breast cancer, uterine cancer or ovarian cancer.

2. The method of claim 1, wherein said selective androgen receptor modulator (SARM) compound is represented by the following structure: NCp CF NH O0F H 3 C OH

3. The method of claim 1, wherein said selective androgen receptor modulator (SARM) compound is represented by the following structure: fl2dS47-l (GNUbb) 76 NC Cl CF0 O C1 CF 3 N H 3 O

4. The method of claim 1, wherein said selective androgen receptor modulator (SARM) compound is represented by the following structure: NC CF 3 H 3 C 'OH

5. The method of claim 1, wherein said selective androgen receptor modulator (SARM) compound is represented by the following structure: NC CF 3 ): N- 0N YHf N0X

6. A method of treatment of conditions associated with Androgen Decline in Female (ADEF) in a subject, the method comprising administering to said subject a selective androgen receptor modulator (SARM) compound represented by the structure of formula (l1b): z H - bNH Ilb wherein X is 0; Z is H, F, CI, Br or 1; Y is CF 3 , I, Br, Cl, CN, C(R) 3 or Sn(R) 3 ; Q is alkyl, F. I, Br, CI, CF 3 , CN, C(R) 3 , Sn(R) 3 , N(R) 2 , NHCOCH 3 , NHCOCF 3 , NHCOR, NHCONH 2 , NHCONHR, NHCONR 2 ,-NHCOOR, OCONHR, CONHR, NHCSCH, NHCSCF, NHCSR, NHCSNH 2 , NHCSNHR, NHCSN(R) 2 , 77 NHSO 2 CH 3 , NHSO 2 R, OR, COR, OCOR, OSO2R, SO 2 R, SR; or Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C: NH 0NH 0H - - C and R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, phenyl, F, Cl, Br, I, alkenyl or OH.

7. The method of claim 6, wherein said selective androgen receptor modulator (SARM) compound is represented by the following structure: ClF 11 1 CF 3 NH O H- 3 C'O

8. The method of claim 6, wherein said selective androgen receptor modulator (SARM) compound is represented by the following structure: F 0 CF 3 NHO F H 3 C

9. The method of claim 6, wherein said selective androgen receptor modulator (SARM) compound is represented by the following structure: CF 3 N NH 0 * O F H 3 C 'OH

10. The method of claim 6, wherein said selective androgen receptor modulator (SARM) compound is represented by the following structure: 2284547_1 PH~t)78 Cr Cl CF 3 H 3 C ~OH

11. The method of claim 6, wherein said selective androgen receptor modulator (SARM) compound is represented by the following structure: - - - - B r-- 0 CF 3 NH O H 3 C OH

12. The method of claim 6, wherein said selective androgen receptor modulator (SARM) compound is represented by the following structure: Br F CF 3 r NH O H 3 C 'OH

13. A method of treatment of conditions associated with Androgen Decline in Female (ADIF) in a subject, the method comprising administering to said subject a a selective androgen receptor modulator (SARM) compound represented by the structure: NC F N I NH . 0 H 3 C 'OH

14. A method of treatment of conditions associated with Androgen Decline in Female (ADIF) in a subject, the method comprising administering to said subject a a selective androgen receptor modulator (SARM) compound represented by the structure: NC CI N NH O F H 3 C 'OH

15. The method of claim 10, wherein said conditions associated with Androgen Decline in Female (ADIF) comprises sexual dysfunction, decreased sexual libido, hypogonadism, sarcopenia, 2 _,L M ,t 79 osteopenia, osteoporosis, alterations in cognition and mood, depression, anemia, hair loss, obesity, endometriosis, breast cancer, uterine cancer or ovarian cancer. (G2ffiIIorsg ) 80