CA2541871A1 - Selective androgen receptor modulators and methods of use thereof - Google Patents

Abstract

This invention provides a novel class of androgen receptor targeting agents (ARTA). The agents define a new subclass of compounds which are tissueselective androgen receptor modulators (SARM), which are useful for oral testosterone replacement therapy, male contraception, maintaining sexual desire in women, treating prostate cancer and imaging prostate cancer. These agents have an unexpected in-vivo activity for an androgenic and anabolic activity of a nonsteroidal ligand for the androgen receptor. These agents may be active alone or in combination with progestins or estrogens. The invention further provides a novel class of non-steroidal agonist compounds. The invention further provides compositions containing the selective androgen modulator compounds or the non-steroidal agonist compounds and methods of binding an androgen receptor, modulating spermatogenesis, treating and imaging prostate cancer, and providing hormonal therapy for androgen-dependent conditions.

Description

SELECTIVE ANDROGEN ~tECEPT0~2 MObrtLA~'~RS AND
METHOI1S OF USE TIiEFt>EOF
FIEUb OF 7NVI;NTION
looot] The present i~n'vention relates to a novel class of tissue-selective androgen receptor targeting agents (ABTA) which demonstrate androgenic and anabolic activity .
of a nonsteroidal ligand for the androgen receptoz. The agents define a new subclass of compounds which are tissue-selective androgen receptor modulators (SARM) which are io useful for male hormone therapy such as oral testosterone replacarnent therapy, male contraception, rrtaintaining~ sexual desire in women, treating prostate cancer, and imaging prostate cancer. These agents are also administered to a subject for the treatment of sarcopenia, Lack of sexual libido, osteoporosis, erythropoiesis, and fertility.
The agents may be used alone or in combination with a progestin or estrogen.
is $ACICGROUND OF THE ZNYENT10N
]OOO21 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 known as the male sex ao hormones. However, androgens also play a pivotal tale in female physiology and reproduction. The androgenic hormones are stezoids which are produced in the body by the testis axed the cortex of the adrenal gland, or synthesized in the laboratory.
Androgenic steroids play an important role in many physiologic processes, including the development and maintenance of male sexual characteristics such as muscle and bona as mass, prostate growth, spermatogenesis, and the male hair pattern (Matsumoto, . Endocrinol. Met_ Clip. N. Am. 23:857-75 (1994). The endogenous stezoidal androgens include testosterone and dihydrotestosterone ("1~HT''). Testosterone is the principal steroid secreted by the testes and is the primary circulating androgen found in the plasma of males. Testosterone is converted to DHT by the enzyme 5 alpha-reductase in many 3o peripheral tissues. DHT is thus thought to serve as the intracellular mediator for most androgen actions (Zhou, et al., Molec. Endacrinoi. 9:208-18 (i995))_ Other staroidal androgens include esters of testosterone, such as the cypienata, propionate, phenylpropionate, cyclopentytpropionate, isocarporate, enanthate, and decanoate asters, and other synthetic androgens such as 7-Methyl-hlortestosterone ("M.BNT"') and its acetate ester (Sundaram et al., "7 Alpha-Methyl-Norrestosterone(MBNT): The Optima!
Androgen Bor 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 forms of hormone replacement therapy.
s The AR also regulates female sexual function (i.e., libido), bone formation, and erythropoiesis.
(0049] Worldwide. population growth and social awareness of family planning have stimulated a great deal of research in contraception. Contraception is a difficult subject ~o under any circumstances. Xt 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. Z3espite the availability of suitable contraceptive devices, historically, society has looked to women to be responsible for contraceptive decisions and their consequences. Although health 15 concerns over sexually transmitted diseases have made men more aware of the need to develop safe and responsible sexual habits, ~ovomen still often bear the brunt of conttaceptire choice. Women have a number of choices, from temporary mechanical devices such as sponges and diaphragms to temporary chemical devises such as spermicides. Women also have at their disposal more permanent options, such as 2o physical devices like IUDs and cervical caps as well as more permanent chenuoal treatments, such as birth control pills and subcutaneous implants. hlowever, to date, the only options available for men include the use of condoms or a vasectomy.
Condom use, however is not favored by many men because of the reduced sexual sensitivity, the interruption in sexual spontaneity, and the significant possibility of pregnancy caused by zs breakage or misuse. 'V'asectorniee are also not favored. Zf more convenient rnechods of birth control ware available to men, particularly long term methods that require no preparative activity Immediately prior to a sexual act, such methods could significantly increase the likelihood that men would take more responsibility for contraception.
30 (0004] Adminislratioxt of the male sex steroids (e.g., testosterone and its derivatives) has shown particular promise in this regard due to the combined gonadotropin-suppressing and androgen-substituting properties ofthese cornpouztds (Steinberger et al., "Effect of Chronic Administration of Testosterone Enanthate on Sperm Production and Plasma Testosterone, Follicle Stimulating Idormone, and Luteinizing Homnone Levels:
A Preliminary Evaluation of a Possible Male Contraceptive", Fertility and Sterility 28.1320- 28 (1977)). Chronic administration of high doses of testosterone completely s abolishes sperm production (azoospermia) or reduces it to a very low level {oli.gospetrnia). The degree of spermatogenic suppression necessary to produce infertility is not precisely known. However, a recant report by the world Health Organization showed that weekly intratnuscular injections of testosterone enanthate- result in azoospermia or severe oligospermia (i.e., less than 3 million sperm par ml) and infartiliry o in 98% of men receiving therapy (World Health Organization Task Force on Methods Ar Regulation of Male Fertility, "Contraceptive Efficacy of Testosterone-Induced Azoospermia and Oligosperrnia in Normal Men," Fertility and Sterility 65:82)-(1996)).
~ s 10005) A variety of testosterone esters have been developed that 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 bas been valuable in terms of establishing the feasibility of hormonal agents fox male contraception, it has several drawbacks, including the need for weekly zo injections and the presence of supraphysiologic peak levels of testosterone immediately following intra~uscular injection (Wu, "Effects of Testosterone Enanthate in Normal Men; Experience From a Multicenter Contraceptive Efficacy Study," Fertility and Sterility 65:626-36 (1996)).
zs La006] Steroidal ligands vvhi~h_ 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 clinicahy (Wu 1g88). Although nonsteroidal antiandrogens are in clinical use for hormone-dependent prostate cancer, rionsteroidai androgens have not been reported. For this reason, research on male contraceptives has focused solely on 3o steroidal compounds.

SUM11~IAR~' OF THE 1<NVENT10N
[0oo7j 'this invention provides a novel class of tissue-selective androgen receptor targeting agents (ABTA). The agents define a new subclass of compounds which axe tissue-selective androgen receptor modulators (SARM), which are useful for oral testosterone replacement therapy, male contraception, maintaining sexual desire in women, osteoporosis, treating prostate cancer and imaging prostate cancer.
These agents have art unexpected and tissue-selective in-vivo activity for an androgenic arid anabolic activity of a nonsteroidal ligand for the AR. These agents selectively act as to partial agonists in some tissues, While acting as full agonists in other tissues, providing a a novel and unexpected means for eliciting tissue-selective androgenic or anabolic effects. Those agents may be avtivc alone or in combination with progestins or estrogens. The invention further provides a novel class of non-steroidal agonist compounds. The invention further provides compositions cbntaining the selective androgen modulator compounds or the non-steroidal agonist corr~pounds and methods of binding an A~, modulating spermatogenesis, bone formation and/or resorption, treating arid imaging prostate cancer, and providing hormonal therapy for androgen-dependent conditions.
[oohs) The present invention xelates to a selective aridrc~gen receptor modulator compound having tissue-selective in-vivo andragenic and anabolic activity of a r<onsteroidal ligand for the androgen receptor, the selective androgen receptor modulator compound represented by the structure of formula I:
Z

y NCI X
R~ ~~'T
x wherein 1 is a O, CHz, NH, Se, PR, or NR;
Z is N02, CN, COR, CObH or CONHR;
Y is I, CF3,13r, Cl, or SnRs;
s Q is alkyl, halogen, NRz, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR> NHCSCH3, Nl-iCSCh3, NHCSR NHSOzCH3, NHS02R, OR, CQR, OCQR, OSOzR, SOzR or SR
wherein R is a alkyl, aryl, hydroxy, C~-Ca alkyl, a C,-C4 haloalkyl, phenyl, halo, alkenyl or hydroxyl; .
Io or Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, 8 or C:
NH 0 ~ NH D
I

!5 1~.~ )S Cf~3? CF3, CI~2CHg, Or CI3gCJ"~; and T is OH, OR, -NHCOCH3, orN~COR wherein R is a C~-Cø alkyl, a C,-C.~ haloalkyl, phenyl, halo, allzenyl or hydroxyl.
(OOpsj Xn one embodiment, Q is in the park. position. In another embodiment, X
is O.
za In another embodiment, Q is in the pare position and X is O. Tn yet another embodiment, Q is pare alkyl, halogen, NRz, NHCC~CH~, NF3COC1~3, NHCOR, NHCONHR, NHCOOR, OCOlV'HR, CONHR, NHCSCHs, NHCSCP3, NHCSR
NHSOaCH~, NHSOzR, OR, COR, OCO~, OSO,~JZ, SOzR or SR wherein R is a alkyl, aryl, hydroxy, Cl-C4 alkyl, a Cl-Ca haloalkyl, ph~nyl> halo, alkenyl or hydroxyl.
as [00010] The present invention relates to a selective androgen receptor modulator compound having in-vivo androgenic and anabolic activity of a nonstaroidal Jigand for the androgen receptor, the selective androgen receptor modulator compound represented by the structure of formula TI:

NH ?~
I o ~ 1 Q
y Il S
wherein ~ is a O, CH2, NH, Se, PR, or NR;
Z is a hydrogen bond acceptor, NOz, CN, COR, CONHR;
Y is a lipid soluble group, I, Cla3, Hr, Cl, SnR~;
R is an alkyl or aryl group or OH; and o Q is acetamido-, tri~uroaaetamido-, alkylamiztes, ether, alkyl, N-sulfonyl, O-sulfonyl, alJryfsulfonyi, carbonyl, or a ketone, [ooo~ 1) The present invention also relates to a selective androgen receptor modulator compound having in-vivo androgenic and anabolic activity of a nonsteroidal Jigand for t s the androgen receptor the, selective androgen receptor modulator compound represented by the structure of formula ITI::

NH X.
o w ~ Q
y ITI
urhere X is a O, CHz, NH, $e, PR, or hlR;
z is N02, CN, COR, or CONIdR;
Y is I, CFs> 13r, Cl, or SnT~;
20 R is an alkyl, or aryl group or OH; and Q is acetamido or trifluroacetamido.
[~oD12) Tha present invention also relates to a selective androgen receptor modulator compo>ynd ha'~ing tissue-selective in-vivo androgenic and anabolic activity of a nonsteroidal iigand for the androgen receptor, the selective androgen receptor modulator compound represented by the structure of formula 1V:

p ~ \
CF3 ~ NH O /
H3C .~~~'OH

[O~ol3] The present invention also relates to a selective androgen receptor modulator compound hawing tissue-selective in~vivo androgertic and anabolic activity of a nonsteroidal ligand for the androgen receptor, the selective androgen receptor modulator to compound represented by the structure of formula V:
OzN ~ COCH3 \ I O I /
CF3 NH ,, ~ o H3C~O~Y
V
(00014] The present invention also relates to a selective androgen receptor modulator compound having tissue-selective in-vivo androgenic and , anabolic activity of a 5 nonsteroida~J iigand for the androgen receptor, the selective androgen zeceptor modulator corxipound represented by the structure of formula VI:
02N / O ~ COCF-IZCH~
CF3 \ NH~~O /
H.3 C OH
vl (opo151 The present invention also relates to a selective androgen receptor modulator compound having tissue-selective in vivo androgenic and anabolic activity of a nonsteroidal ligand for the androgen receptor, the selective androgen reeeptar modulator compound represented by the structure of formula VII:
OZN NHCOCI~
/ ~ 0.
CF3 ~ NH~O

VII
to [o~W sl The present invention z.lso relates to a method of binding a selective androgen receptor modulator compound to an androgen receptor, which includes contacting the androgen receptor with the selective androgen receptor modulator compound under conditions effective to bind tlxe selective androgen receptor modulator compound to the androgen receptor, xn one embodiment the compound is Compound I. In another t5 embodiment the compound is Compound Ix. In another embodiment the compound is Compound II1. In another embodiment the compound is Compound 1V. In another embodiment the eompou~nd is Compound V. In another embodiment the compound is Compound yI. In another embodiment the compound is Compound VII. (n another embodiment the eompo'und is Compound'V'Y31.
zo (ooplTl Another aspect of the present invention relates to a method of modulating spermatogenesis in a subject, which includes contacting an androgen receptor of the subject with a setecti've androgen receptor modulator compound under conditions effective to increase or decrease Speztti producIion. In one embodiment the compound is 35 Compound X. In another embodiment the compound is Compound II. In another embodiment the compound is Compound III. In another embodiment the compound is Compound fV'. Itt another embodiment the compound is Compound 'V'. !n another embodiment the compound is Compound VI. In another embodiment the compound is Compound VII. In another embodiment the oompound is Compound 'VIII.
[ooa1e] The present invention also relates to a method of bocmone therapy, comprising contacting an ar<drogen receptor of a subject with a selective androgen receptor modulator compound under conditions effective tn bind the selective androgen receptor modulator compound to the lndrogen receptor and effect a change in an androgen-dependent condition, In one embodiment the compound is Compound 1. Yrt another embodiment the compound is Compound II. In another embodiment the compound is to Compound IrI. In another embodirr~ent the compound is Compound IV. In another eznbodirnent the compound is Compound V. In another embodiment the compound is Compound VI. 1n another embodiment the compound is Compound VIZ. In another embodiment the compound is Compound VIII.
Is l0~oZ9] The present invention also relates to $ method of treating a subject having a hormone related condition which comprises contacting an androgen receptor of said subject vc~ith a selective androgen xeceptor modulator compound under conditions effective to bind the selective androgen receptor modulator compound to the androgen receptor and effect a change in an apdrogen-dependent condition. In one embodiment, 20 the selective androgen receptor modulator compound is selective for androgen or testosterone receptor. The present invention also relates to a method of oral administration of the selective androgen receptor modulator compound.
(Ooo2p] The present invention also relates to a method of treating a subject hawing a 25 chronic muscle yvastit~g disease state which comprises contacting an androgen receptor of said subject with a selective androgen receptor modulator compound as described herein under conditions effective to bind the selective androgen receptor modulator compound to the androgen receptor and effect a change iza an androgen-dependent condition. In one ernbodimetzt, the selective androgen receptor modulator compound is 3o selective for androgen or testosterone receptor. The present invention also relates to a method of oral administration of the selective androgen receptor modulator compound.
In one embodiment the compound is Compound I. In another embodiment the compound is Compound II. In another embodiment the coritpound is Compound III.
In another embodiment the cr~mpo~und is Compound IV. In another embodiment the compound is Compound V. In another embodiment the compound is Compound VI. In another embodiment the compound is Compound VII. In another embodiment the s compound is Compound VIII.
(oo02t1 As defined herein, the disease state of "chronic muscl8 wasting" means [00022) The present invention also relates to a method of treating a subject having fo prostate cancer vrhich comprises administering to a subject an effective amount of a selective androgen reoeptor modulator compound. Ixi one embodiment, the selective androgen receptor modulator compound is selective for androgen or testosterone receptor. Iu one embodiment the compound is Compound I. In another embodiment the compound is Compound II. In another embodiment the compound is Compound III.
In ~ 5 another embodiment the compound Is Compound IV. hi another embodiment the compound is Compound V. In another embodimenC the compound is Compeund VI. In another embodiment the compound is Compound VII. In another embodiment the compound is Compound VIII.
zo (00023] The present invention also relates to compositions and a pharmaceutical compositions which comprises a selective androgen receptor modulator alone or in combirxation with a progestin or estrogen and a suitable carrier, diluent or salt. In one embodiment the composition comprises Compound I. In another embodiment the compound is Compound II, xti another embodiment the compound is Compound III.
In as another embodiment the compound is Compound TV. In another embodiment the compound is Compound ~. In another erxtbodiment the compound is Compound Vl.
In another embodiment the compound is Compound VII. In another erxabodiment the compound is Compound VIII.
30 1000241 'The present invention relates to a non-steroidal agonist compound, the non.-steroidal agonist compound represented by the structure of formula V1II:
O
~NH X' R~ T I~
VIII

'uvhereiri X is a O, CHz> NH,. Se, PR, or NR;
R~ is CH3, CP3, CHZCHs, or CFZCF3;
T is OH, OR, -NHCOCH~, or N.~3COR wherein R is a C~-C4 alkyl, a C~-C.~ haloalkyl, phenyl, halo, alkenyl ar hydroxyl;
s A is a 5 oz 6 rnembered saturated, unsaturated or aromatic carbocyclic ox heterocyclic ring represented by the structure;
Z p3._...Az ..AB
As'._ A4 . ,,,rAl-" 4r 2~ ..,,,A7 Y% :; Alo ,, ;
AS..... A6 / 'Ai' ; .
to $ is a 5 oz 6 mexnbered saturated, unsaturated or aromatic carbocyclic or heterocyclic ring represented by the structure:
1\ _.... ~~ . B -_ .. se 9 .
aq~ ~'1- Or QI .
Q3~ i ~, B la QzyC ~ < < ~ I, wherein A1- Al l are each C, O, S orN;
B 1- B" are each C, O, 5 ox N;
Z is N02, CN, COOH CQR, or CONHR;
~'' is I, C~3, $r, Cl, or SnR3; and zo Q1 and Q2 are independently of each other alkyl, halogen, NR,, NHCOCH3, NHCOCF~, NHCOR, NHC4NHR, NHCOOR, OCONHR, CQNHR, NHCSCF~I3, NHCSCF3, NHCSR NHSOzCH3, NI-ISOZR, OR, COR, OCOR, OSOzR, S02R or SR ~vherarn R is a C,-Ca alkyl, a. C,-C~ haloalkyl, phenyl, halo, alkenyl or hydroxyl.
zs [00025] The present inventiozl also relates to a composition and pharmaceuracal composition comprising the non-steroidal agonist compound alone or in combination with a progestin or estrogen and a suitable gamier, diluent or salt, In one embodiment the compound is Compound I. In another embodiment the compound is Compound IT. In another embodiment the compound is Compound III. In another embodiment the compound is Compound IV. Xn another embodiment the compound is Compound V. In another embodiment the compound is Compound VT. rn another embodiment the compound is Compound VII. In another embodiment the compound is Compound VTII, (000261 The present invention also relates to a method of binding a non-steroidal agonist compound to ~.n androgen receptor comprising contacting the androgen receptor with the non-steraidal agonist compound under conditions effective to bind the non-stcroidal agoriist compound to the androgen receptor. In one embodiment the compound is Compound I. In another ernbodimerit the compound is Compound II. In another embodiment the compound is Compouzad III. In another embodiment the compound is Compound IV. In another embodiment the compound is Compound V, In another etnbodixnent the compound is Compound Vr. In another embodiment the compound is Compound VXI. In another embodiment the compound is Compound VIIx.
(0002] The present invention also relates to a method of modulating spermatogenesis in a subject comprising contacting an androgen receptor of the subject with a non-steroidal agonist compound under conditions effactir~e to increase or decrease sperm production. In one embodiment the compound is Compound I. In another embodiment the compound is Compound II. In another embodiment the compound is Compound XT1..
as In anbther embodiment the compound i5 Compound IV. In another embodiment ~e compound is Compound V. In mother embodiment the compound is Compound Vi, In anothex embodiment the compound is Compound VII. xn another embodiment the compound is Compound VIII.
[ooo2e] The present invention also relates to a method of hoxmone therapy carnprising contacting an androgen receptor of a subject with a non-steroidal agonist under conditions effective to bind the non-steroidal agonist compound to the androgen receptor IZ

and effect a change in an androgen-dependent condition. In one embodiment the compound is Compound I. ~ another embodiment the compound is Compound 1I. In another embodiment khe compound is Compound III. In another embodiment the compound is Compound IV. In another embodiment the compound is Compound V. In another embodiment the compound is Compound VI. In another embodiment the compound is Compound VII. Iri another embodiment the compound is Compound VIII.
(ooo2s] The present invention also relates to a method of treating a subjeot having a hormone related condition which comprises contacting an androgen receptor of said io subject with a non-steroidal agonist compound under conditions effective to bind the non-steroidal agonist compound to the androgen receptor and affect a change in an androgen-dependent condition. In one embodiment, the non-steroidal agonist compound is selective for androgen or testosterone receptor. The present invention alsp relates to a method of oral administration of the non-steroidal agonist compound. In one is embodiment the compound is Compound I. In another embodiment the compound is Compound II. In another embodiment the compound is Compound III. In another embodiment the compound is Compound IV. In another embodiment the compound is Compound V. In anothez embodiment the compound is Compound VI_ In anothez embodiment the compound is Compound VII. In another embodiment the compound is as Compound VIII.
[00030] The present invention also relates to a method of treating a subject having prostate cancer which comprises aduzinisttating to a subject an effective amount of a non-steroida! agonist compound, In one embodiment, the non-steroidal agonist zs compound is selective fer androgen or testosterone receptor. In one embodiment the compound is Compound 1'. In another embodiment the compound is Compound II. In another embodiment the corrtpound is Compound .III. In another embodiment the compound is Compound IV. In another ertibodiment the compound is Compound V.
In another embodiment thn compound is Compound VI. Irt another embodiment the 3o compound is Compound VII. In another embodiment the compound is Compound YII1.
[00031] Still another aspect of the present relates to a method of producing s selective !3 androgen receptor modulator or a non- steroidal AR agonist compound of the present inrrention. Tn one embodiment the compound is Compound I. In another embodiment the compound is Compound II. In another embodiment the compound is Compound Illi.
In another embodiment the compound is Compound fV'. In another embodiment the compound is Compound V. In another embodiment the compound is Compound 'VI_ In another arribodiment the compound is Compound VII. In another embodiment the compQUnd is Compound VIII.
i00o321 The present invention further relates to a method of determining the presence of a selective androgen modulator compound and/or a non-steroidal agonist compound of the present invention in a satrtple. 'Y'he method comprises the steps of obtaining the sample, and detecting the compound in the sample, thereby determining the presence of the compound in the sample. In one embodiment, the sample is a blood serum, plasma, urine, or saliva sample. In another ernbodirnent, the detection step comprises measuring the absorbance of the compound. In one embodiment the comppund is Compound I.
Tn another embodiment the compound is Compound II. In another embodiment the compound is Compound III. In another embodiment the compound is Compound N. Xn another embodiment the compound is Compound 'V'. In another embodiment the compound is Gompound VI. In another embodiment the compound is Compound VII.
In 2o another embodiment the compound is Compound VIII.
(00033) The novel selective androgen receptor modulator compounds and the non-steroidal agonist compounds of the present invention, either alone or as a composition, are useful in males and females for tho treatment of a variety of hormone-related conditions, such as hypogonadism, sarcopenia, erythropoiesis, ereotile function, tack of libido, osteoporesis and fertility. blyzther, the selective androgen receptor modulator compounds arid the non- steroidal agorsist compounds are useful for oral testosterone replacement therapy, treating prostate cancer, imaging prostate cancer, and maintaing sexual desire in women. The agents may be used alone or in combination with a ~o pragestin or estrogen. In one embodiment the compound is Compound I. In another embodiment the compound is Compound II. In another embodiment the compound is Compound III. In another emboditrtent the compound is Compo4nd N. 1n another embodiment the compound is Compound V. In another embodiment the compound is Compound VI, In another embodiment the compound is Compound VII. In another embodiment the compound is Compound VIII.
s [00034] The selective androgen receptor modulator compounds and the non-steroidal agonist compounds of the present invention offer a significant advance over steroidal androgen treatment because the selective androgen receptor modulator compounds a.nd the non-steroidal agonist compounds of the present invention hava been shown in-vivo to have a tissue-selective androgenic and anabolic activity of a nonsteroidal ligand for Io the andxogen receptor. Moreover, the selecpve androgen receptorrnodulator compounds and the non-steroidal agonist compound$ of the present invention are not accompanied by serious side effects, labiliry to oxidative metabolism, inconvenient modes of administration, or high cQSts and still have the advantages of oral bioavailability, lack of cross-reactivity wig other steroid receptors, and long biological half lives.
!n one embodiment the compound is Compound I. In another embodiment the compound is Compound II. In another embodiment the compound is Compound III. In anothex embodiment the compound is Compound IV. In another embodiment the compound is Compound 'V, In another embodiment the compound is Compound VI. In another embodiment the compound is Compound VII. In another embodiment the compound is 2o Compound VITI.
BRTE~' DESC~iIPT;<ON OF TT~E DRAWINGS
The presenk invention will be understood and appreciated more fully from the 25 following detailed description taken in conjunction with the appersded drawings in which:
Figure 1: Androgenic and Anabolio activity of (S)-G'I~t-007 in rats, Rats were left untreated (intact contxol), castrated (castrated control), treated with 3o testosterone propionate (TP), or treated with S-GTx-007, and the body weight gain as well as the weight of androgen-responsive tissues (prostate, semimal vesicles and levator ani muscle) was determined.

F3guse Z: Androgenic arid Anabolic activity of S-GTx;007 in rats. Rats were Ieft untreated (intact control), castrated (castrated control), treated with 0.1, 0.3, 0.5, 0.75 and 1.0 mglday testosterone propionate (Tf), or treated with 0.1, 0.3, s O.S, 0.75 and 1.0 mglday S-GTx-007, and the weight of androgen-responsive tissues (prostate, semimal vesicles and levator ani muscle) was determined.
Figure 3: Andzogenic and Anabolic activity of S-GTx-014 in rats. Rats were left untreated (intact aontxol), castrated (castrated control}, treated with 0.1, 0.3, tp 0.5, 0.7s and 1.0 mglday testosterone propionate (TP), or treated with 0,1, 0.3, O.S, 0.75 and 1,0 mp~day S-GTx-014, and the weight of androgen-responsive tissues (prostate, semimal vesicles and levator ani muscle) w$s determined.
Figure ~: Average plasma concentration-time profiles of S-GTx-007 in beagle dogs i s after 1V administration at 3 and 10 m~.,,lkg.
Figtrr~ 5: Average plasma concentration-time profiles of S-GTx-007 in beagle dogs after PO administration as solution at 10 mglkg.
2o FIg b; Average plasma concentration-time profiles of S-GTx-007 in beagle dogs after fV' administration as capsules at rng/kg.
Figure 7: hffects of GTx-014 and GTx-007 ort LH Levels.
2s .T~lgure 8: Fsffects of GTx-01~ and GTx-007 on FSH Levels.
Figure ~: Synthesis scheme of GTX-007.

DETAILED DESCRIpTIOIV OF ~"FiE Y1~VEIV~TIOIrI
[00035] This invention provides a novel class of androgen reoeptor targeting agents (ABTA). The agents define a new subclass of compounds which are tissue-selective androgen receptor modulators (5A1~M) which are useful for oral testosterone replacement therapy, male contraception, maintaining sexual desire in women, treating prostate cancer and imaging prostate cancer. These agents have an unexpected tissue-selective in-vivb activity for an androgenic and anabolic activity of a nonsteraidal ligand .
for the androgen receptor. These agents may be active alone ar in, combination with to progestins or estrogens, The invention further provides a novel class of non-steroids!
agotust compounds, The invention Filrther provides compositions containing the selective androgen modulator compounds or the non-steroids! aganist compounds and methods of binding an ~.ndrdgen receptor, modulating sperznatagenesis, treating and imaging prostate cancer, and providing hozmonaI therapy for androgen-dependent i5 conditions.
[00036) The compunds described herein, done a new class of selective androgen receptor modulators (SARMS) that demonstrate potent anabolic effects (e.g., muscle growth) with less androgenic activity (e.g,, prostatie growth). This new class of drugs 2o has several advantages over non-selective androgens, °cluding potential therapeutic applications in males arid females for modulation of fertility, erythropoiesis, osteoporosis, sexual libido attd in men with or at high risk for prostate cancez. Ln one embodiment the compound is Compound I. In another embodiment the compound is Compound II. In another embodiment the compound is Compound III. In another 25 embodiment the compound is CQrnpound IV. In another embodiment the compound is Compound V. Tn another embodiment the compound is Compound VI. Xn another embodiment the compound is Compound VII. In another embodiment the compound is Compound VII.
30 (00037] 'purther, in one embodiment the aompunds have tissue specific pharmacologic activity, As demonstaxted in )~igure 7 and 8, CTx-007 does not suppress LH
levels at doses that era capable of eliciting maximal stimulation of levator ant muscle growth and does not suppress 1~SH levels at doses that are capable of eliciting maximal stimulation of levator ani muscle growth, [00038] The present invention relates to a selective androgen receptor modulator s compound having tissue-selective in-vivo androgenic and anabolic activity of a nansteroida! iigand for the androgen receptor selective androgen receptor tnodttlator compound represented by the structyre of formula I:

Nli .~_ .~
R~ .~T

wherein ~C is a O, C~Ix, NH, Se, PR, or NR;
Z is N02, CN, COR, COON or CONHR;
~0 7' is I, CF3, )3r, Cl, or SnR3;
Q is alkyl, halogen, NRz, NHCOCH3, N~COCF3, NHCOR, NHCONHIZ, NHGOOR, OCONHR, CONHR, NHCSCH3, NHCSCI~~, NHCS~. NHS02CH3, NHS02R, OR, COR, OCOR, OS02R, SOzR or SR wherein R is an aryl, C~-C4 alkyl, a Ci-C4 haloalkyl, phenyl, halo, alkenyl or hydroxyl; or Q together with t 5 the benzene ring to which it is attached is a fused ring system represented by structure A, $ or C:

l ~ , A B C

Ri is CH3, CFa, CHzCH3, or CFzCF~; and T is OH, OR, -NHCOC)~3, or NHCOR wherein R is a C,-Gq alkyl, a C,-s Ca haloalkyl, phenyl, halo, alkenyl or hydroxyl.
[OOO3s) In one embodiment, Q is in the para position of the benzene ring to whioh is is attached. In another embodiment, Q is ii1 the para position arid ?C is 0. In t~.tmthsr embodiment, Q is in the para position and is .alkyl, halogen, NR2, NHCOCH3, io NHCOCFa, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCHI, NHCSCP'3, NHGSR NHSO2CH3, NHSO2I2, OR, COR, OCOR, OSOzR, SOzR or SR
wherein R is a, aryl, C,-C4 alkyl, a C~-C4 halaalkyl> phenyl, halo, alkenyl or hydxoxyl.
(00040 The present invention relates to a Selective androgen receptor modulator 1 s compound having in-vivo andragenic and anabolic activity of a nonsteroidal Iigand for the androgen receptor, the selective androgen receptor modulator oorrtpound represented by the structure of formula 11:

NH ' X

Q
II
wherein ~ is a O, CHz, NH, Se, PR, or NR;
2 is a hydrogen bond acceptor, NO2, CN, COR, CONHR;
Y is a 1 ipid soluble group, I, C1~~, Br, Cl, SnR3;
R is an alkyl, or aryl group or OH; and 35 Q is acetamido-, Crifluroacetamido-, alkylamiries, ether, alkyl, N-sulfonyl, O-sulfonyl, alkylsulfanyl, carbonyl, or a ketone.

jopo4la The present invention also relates to a selective androgen receptor modulator compound having inwivo androgenic arid anabolic activity of a rtonsteroidal ligand for the androgen receptor the, selective androgen receptor modulator compound represented by the structure of formula III:
hI3C OH
O \ ~ Q

s where X is a O, CHZ, NH, Se, PR, or NR;
2 is NOx, CN, COR, ~or CONHIt;
Y is T, CF3, Br, C(, or 5nR3;
R is an alkyl or aryl group or OH; 8.nd Q is acetam[do or trifluroacetamido, i0 [OD042j The present invention also relates to a selective androgen receptor modulator compound having tissue-selective in-vivo andro~enic and anabolic activity of a nbnsteroidal ligand for the androgen receptor, the selective androgen receptor modulator compound represented by the structure of formula IV:
OyN y F
/ ~ O
CF3 \ NH~~ Q /
H3C 'OBI
T.Y
ao [0043] Tile present invention also relates to a selective androgen receptor tttodulator compound having tissue-selective in-viva androgenic and anabolic activity of a nonsteroidal ligand fox the androgen receptor, the selective androgen receptor modulator compound represented by the stn.icture of formula 'V:

o~N r o ~ cocH3 C~3 ~ NH O
H3C .~.~~OH
V
(o00a4] The present invention also relates to a selective androgen receptor modulator compound having tissue-selective in-v;ivo androgenic and anabolic activity of a s nonsteroidal ligand for the androgen receptor, tkte selective androgen receptor modulator compound represented by the structure of formula V1;
OzN / O ~ COCHzCI-19 CF3 ~ Nki O
H3C 1~~~'OH
VI
[OOD45j The present invention also relates to a selective androgen receptor modulator compound having tissue-selective in-vivo androgenic and anabolic activity of a 1o nonsteroidal ligand for the androgen receptor, the selective androgen receptor modulator compound represented by the structure of formula VII:
ozN ~ o ~ NHCO~H
I
CF3 ~ NH O
HsC '.'y~'OT~.

[oop46j Then present invention relates to a non-steroidal agotlist compound having the 1 s formula (Cottipound 'VIII):

Q
~NH X
lt~ T
VIII
s wherein ~ is a O, CHx. NH, Se, pR, or NR;
y 15 CH3, CF3, C~I2CH3, or CFzCF3:
T is OH, OR, -NHCOC.H~, or NHCOR wherein wherein R is a C~~Cq alkyl, a Ci-C4 ha]oalkyl, phenyl, halo, a]kenyl or hydroxyl;
A is a 5 or 6 memberad saturated, unsaturated or aromatic earbocyc]ic or to heterocyclic ring represented by the structure:
Z A3__... Aa p9 ,.,.. A$
' z or Ato ~ ~/.Ati.~~
B is a 5 or 6 iriembered saturated, unsaturated or aromatic carbocyclic or heterocyciic ring represented by the structure:
IS
~~...__ as _.>38 B9-~- , or e, Q2 ~ .._._pa, ~lQa~~t~~., ' ?2 wherein At- Any sre each C, O, S or N;
Bt- B,~ axe each C, O, S or N;
Z is NOi, CN, COR, COON, or CONHR;
Y is I> CF3, Br, CI, or SnR3; and and Q2 are independently of each other alkyl, halogen, NRz, NHCOCH3> NbiCOCF3, NHCOR, NHCONHIt, NHCOOR, OCONH.R, CONHR, NHCSCH3, NHCSC>~3, NHCSR NHSOiCH3, NHSO2R, OR, COR, OCOR, to OSOZR, SOzR or SR wherein R is a C,-Ca alkyl, a C~-C4 haloalkyl, phenyl, halo, alkenyl or hydroxyl, .[oa047] The substitutents Z and Y can 6e in any position of the fi~a or 6 membcred ring carrying these substltutenks (hereinafter "A ring"). Similarly, the snbstituent Q can he in ~5 any position of the five or 6 membered ring carrying this substitutent (hereinafter "B
ring"), l;t is understood that when any of the ring members A,- A> > or B ~- B
i ~ are O or S, then these ring members are unsubstituted. It is further understood that when any of the ring members A,- Air or )3t- Big are O or S, then the dotted line betyveen said ring members and other ring members represents a single bond.
ao [ooo4s] In one embodiment, th.e A ring ir~oludes any type of saturated or unsaturated carbocyclic ring. In cne embodiment, the A ring is a 6 membered saturated earbocyclic ring, rwhich may be unsubstituted, monosubstituted or polysubstituted by any of the substitutents described horeinabove. rn one embodiment, the A ring is a S
membered 2s saturated carboeyclic ring, which may be unsubstituted, monosubstituced or polysubstituted by any of the substitutents described hereinabove. In another embodiment, the A ring is a 4 membered carbocyclic ring containing one or more double bonds, which ring may be urisubstituted, monosubstituted or polysubstituted by any of the substitutents described hereinabove, In another embodiment, the A ring is a 5 3o mernbsrad carbocyclic ring containing one or more double bonds, which ring may ba unsubstituted, monosubsti.tuted or polysubstituted by any of the substitutents described hereinabove.

(oooG9] In another embodiment, the A ring includes any type of saturated, unsaturated or aromatic heterocyclic ring. )n another embodiment, the A ring is a 6 membered saturated heterocyclic ring, which may be unsubstituted, monosubstituted or polysubstituted by any of the substituents described hereinabove. Tn another embodiment, the A ring is a 5 membered saturated heterocyclic ring, which may be unsubstituted, monosubstituted or polysubstituted by any of the substituextts dascxibed hereinabowe. In another embodiment, the A ring is a 6 membered heterocyclic ring cositaining one or more double bonds, ~cwhich ring may be unsubstituted, monosubstituted or polysubstituted by any of the substitutents described hereinabove. In another embodiment, the A ring is a 5 membered heterocyclic ring containing one or more double bands, which ring may be unsttbstituted, monosubstituted or polysubstituted by any of the substitutents described hareinabove. In another embodiment, the A
ring is a 6 mer~hered heteroaromatic ring which may be unsubstituted, monosubstituted or 1s polysubstituted by any of the substitutents described hereinabove. In another embodiment, the A ring (s a 5 membered heteroaromatic ring which may be unsubstituted, monosubstituted or polysubstituted by any of the substitutents described hersina,bove.
(ooo5al Similarly, the B ring includes any type of saturated or unsaturated carbocyclic ring. In one embodiment, the H ring is a 6 mEmbered saturated carbocyclic ring, which may be unsubstituted, monosubstituted or polysubstituted by any of the substitutents described hereinabove. In one embodiment, the H ring is a 5 membered saturated carbocyclic ring, which may be unsubstituted, monosubstituted or polysubstituted by any ,5 of the substikutents described hereinabove. In another embodiment, the B
ring is a 6 membered carboeyclic ring containing one or zriore double bonds, Whiah ring may be unsubstituted, monosubstiiuted or polysubstituted by any of the substitutents described hereinabowe. In another embodiment, the B ring is a 5 mern6ered cazbocyclic ring containing one or more double bonds, which ring may be unsubstituted, monosubstituted or polysubstituted by any of the substitutents described hereinabove.

(ooo5lj rn another embodiment, the B ring includes any type of saturated, unsaturated or aromatic heterocyclic ring. Iri another embodiment, the B ring is a 6 membered satuzated heterocyclic ring, Nrhich may be unsubstituted, monosubstituted ox polysubstituted by any of the substituents described hereinabove. In another s embodiment, the B ring is a 5 membered saturated t~eterocyclic ring, which may be unsubstituted, monosubsticuted or polysubstituted by any of the substituents described hereinabove. In another embodiment, the B Zing is a 6 membered boteroeyclic ring containing one or more double bonds, which ring may be unsubstituted, ~cnonos'ubstituted or polysubstituted by any of the substitutents described hereinabove. In another to embodiment, the B ring is a 5 membered heterocyclic ring containing one or more double bonds, which ring may be unsubstituted, monosubstituted or polysubstiiuted by any of the substituter<ts described hereinabove. Tn another embodiment, the B
ring is a 6 membered heteroaromatic zing which naay be unsubstituted, monosubstituted or polysubstituted by any of the substitutents described hereinabove. In another 15 embodiment, the ~ ring is a 5 membered heteroaromakic ring which may be unsubstituted, monosubstituted or polysubstituted by any of the substitutents described hexeinabove.
Nonlimiting e~camplas of suitable A rings and/br $ rims era carbocyclic rings such as 2o cyclopentane, eyclopentene, cyclo>;exane, and cyclohexene rings, and heterocycIic rings suci; as pyran, dihydropyrau, tetxahydropyran, pyrrole, dihydropyrrole, tetrahydropyrrole, pyrazine, dihydxopyrazine, tetr~hydropyrazine, pyrimidine, dihydropyrimidine, tetrahydropyrimidone, pyra2ol, dihydropyrazol, tetrahydropyrazol, piperidine, piperazine, pyridine, dihydropyridine, tetra.hydropyridine, morpholine, 25 thiornorpholine, furan, dihydrotiuan, tetrai~ydrofuran, thiophene, dihydrothiophene, tetrahydrothiophene, thiazole, imidazole, isoxazole, and the like.
[ooos2j As used herein, receptors far extracellular signaling molecules are collectively refereed to as "cell signaling receptors". Ivlany cell signaling receptors arc 3o transmembrane proteins on a tell surface; When they bind an extracellular signaling molecule (i.e., a ligand), they become activated so as to generate a cascade of iatraa~Ilular signals that alter the behavior of the cell. In Lontrast, in some cases, the receptors are inside the cell and the signaling ligand has to enter the cell to activate thezh; these signaling moleoulas therefore must lie sufficiently small and hydrophobic to diffuse across the plasma membrane of the call. As used herein, these receptors are collectively roferred to as "ixttracellulax cell signaling receptors", [00053) Steroid hormones are one example of small hydrophobic molecules that diffuse directly across or are transported across the plasma membrane of target cells and bind to intracellular cell signaling receptors. These receptors are structurally related and constitute the intracellular receptor suparfamily (or steroid-hormone receptor superfamily). Steroid hormone receptors include progesterone receptors, estrogen receptors, androgen receptors, glucocorticoid receptors, and mineraloeorticoid, and numerous orphan receptors. The present invention is particularly directed to androgen receptors and all of its isoforms.
is [00054] ln. 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-dimensional structure of the substance fits into a space created by the three-dimensional structure of the receptor in a ball axtd socket configuration.
zo [000551 The better the ball fits into the socket, the more tightly it is held. This phenomenon is called affinity. If the affinity of a substance is su~ciently high, it will compete with the hormone and bind the binding site more frequently. The binding of the ligartd rnay also lead to tissue-selective recruitment of other important proteins to transduce the signal_ These proteins are known as coactivators and carepressor, 2s participate in signal tra.rtsduction, and may be selectively induced or inhibited by ligand binding. Once bound, signals may be sent through the receptor into the cells, causing the cell to respond in some fashion. This is called activation. ~n activation, the activated receptor then directly regulates the trans4ription of specific genes_ But the substance and the receptor znay have cettain attribrltes, other than al:'flxzity, that activate the cell.
so Chemical bonds between atoms of the substance arid the atoms of the receptors may form_ In some cases, this leads to a change in the configuration of the receptor, which is eno4gh to begin th.e activation process (called signal transductian), As a result, substances can be made which bind receptors and activate them (calfed receptor agonists) or inactivate them (palled rec$ptor antagonists), [ooo5s] The present invention is directed to selective androgen receptor modulator compounds which are agonist compounds, and are, therefore, useful in binding to and activating steroida) hormone receptors. The compounds are non-steroidal, Preferably, the agonist compound of the present invention is an agorust that binds the androgen receptor. Preferably, the compound his high afFlniky for the androgen receptor, The compound may bind either reversibly or irreversibly to the androgen receptor.
The o compound of the present invention may contain a functional group (affinity label) that allows allcylation of the androgen receptox (i.e. covalent bond formation).
Thus, in this case, the compound binds izreversibiy to the receptor and, accordingly, cannot be displaced by a steroid, suoh as the endogenous ligands dihydrotestosterone and testosterone. Tt is preferable, however, for the compounds of the present invention to ~ s reversibly bind the androgen receptor.
[000571 According to one aspect of the present invention, a method is provided for binding the selective androgen receptor zr~odulator compounds of the present invention to an androgen receptor by contacting the receptor with a selective androgen receptor zo modul~.tor compound under conditions effective to cause the selective androgen receptor modulator compound to bind the, androgen reoeptor. The binding of the selective androgen receptor modulator compounds to the androgen receptor enables the compounds of the present invention to be useful in males and in females in a number of hormone therapies. The agonist compounds bind to and activate the androgen receptor.
25 F3inding of the agonist compound is either reversible or irreversible, preferably reversible.
(o005s~ According to vne aspect of the present invention, a method is provided for modulating spermatogenesis by contacting an androgen receptor of a patient with a 3o selective androgen receptor modulator compound under conditions effective to bind the selective androgen receptor modulator compound to the androgen receptor and increase or decrease sperm production.

[oUO59) According to another aspect of the present invention, a method is provided for hormonal therapy in a patient (i.e., suffering from an androgen- dependent condition) which includes contacting an androgen receptor of a patient with a selective androgen receptor modulator compound under conditions effective to bind the selective androgen receptor modulator compound to the androgen receptor and effect a change in an androgen-dependent condition, Androgen-dependent conditions that may be treated according to the present invention include those conditions associated with aging, such ss hypogonadism, sarcopenia, erythropoiesis, osteoporosis, and any other conditions ~0 later determined to be dependent upon low androgen (e.g., testosterone) IaveJs. In one embodiment, the selective androgen receptor modulator compound is administered alone. In another embodiment, the selective androgen receptor modulator compound is administered in combination with pzogestin. Zn yet another embodiment, the selective androgen receptor modulator compound is administered in combination with estrogen.
~5 [oooso) According to another aspect of the present invention, s method is provided for treating a subject having prostate cancer, The method comprises administrating to a subject an effective amount of a selective androgen receptor modulator compound. In one embodiment, the selective androgen receptor modulator compound is selective foz 20 androgen ortestosterane receptor.
[00061) The present invention also relates to a method of treating a subject hawing a chronic muscle wasting disease state which comprises contacting a.n androgen receptor of said subject with a selective androgen receptor modulator compound under conditions 2s effective to bind the selective androgen receptor modulator compound to the androgen receptor and effect a change in an androgen-dependent condition. In one embodiment, the selective androgen receptor modulator compound is selective fox androgen or testosterone receptor. The present invention also relates to a method of oral administration of the selective androgen receptor modulator compound. In one so embodiment the compound is Compound I. In another embodiment the compound is Compound II. In another embodiment the compound is Compound III. !n another embodiment the compound is Compound IV. In another embodiment the compound is ?8 s Compound V, in anothez embodiment the compound is Compound Vx. In another ezr~bodiznent the compound is Compound 'VII. l:n another embodiment the compound is Compound 'VIII.
[OOO621 According to one aspect of the present invention, a method is provided for binding the non-steroidal aganist compounds of the present invention to an androgen receptor by contacting the receptor with a non-steroidal agonist compound under conditions effective to cause the non-stemidal agonist compound to bind the androgen to receptor. The binding of the non-steroidal agonist compounds to the androgen receptor enables the compounds of the present invention to be useful in males and in females in a number of hormone therapies. The agonist compounds bind to and activate the androgen receptor. Binding of the agonist compound is either reversible or irreversible, preferably reversible.
(OOOS3] According to one aspect of the present invention, a method is provided for modulating spermatogenesis by contacting an androgen receptor of a patient with a non sieroidal agonist compound under conditions effective to bind the selective androgen receptor modulator compound to the androgen receptor and increase or decrease sperm 24 production.
(QOo64] According to another aspect of the present invention, a method is provided for hormonal therapy in a patient (i,e., one suffering from an androgen- dependent condition) which Includes contaoting an androgen receptor of a patient with a non-zs steroidal agonist eompo~xnd under conditions effective to bind the non-steroidal agonist compound to the androgen receptor and effect $ change in an androgen-dependent condition, Androgen-dependant conditions that may be treated according to the present invention include those conditions associated with aging, such as hypogonadism, sarcopenia, erythropoiesis. osteoporosis, lack of seal libido and any other conditions 30 later deterrtmined to be dependent upon low androgen (e.g., testosterone) levels. In one embodiment, the non-sieroidal agonist compound is administered alone. In another embodiment, the non-steroidal agonist compound is administered in combination with progestin. In yet another embodiment, the non-steroidal agonist compound is administered in combination With estrogen.
(ouo65] . According to another aspect of the present invention, a method is provided for treatizlg a subject having prostate cancer, The method comprises administrating to a subject an effective amount of a non-steroidal agonist compound, In onB
embodiment, the non-steroidal agonist compound is selective for androgen oc testosterone receptor.
[ooo6s] The compounds afthe present invention have an assyrnetric center and can be Io the ]2 or S isomer, or a mixture of both. In one embodiment, the compounds racemic mixtures of the R and S enantiomers. Tn another embodiment, the compounds are substantially pure R enantiomers. Xn another embodiment, the compounds are substantially pure S enantiomers. "Substantially pure" is defined herein as groater than about 95% preponderance of one isomer, Where the above-described processes for the is preparation of the compounds of use in the invention give rise to mixtures of stereoisomers, these isomers may be separated by conventional techniques, such as pxeparatiwe chromatography. The compounds may be ptepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis pr by resolution [oooe7] As used hereixt, "pharmaceutical composition" means therapeutically effective amounts of the SARM or the non-steroidal agonlst cQmpourid of the present invention, together with suitable diluents, preservatives, solubilizers, emulsifiers, adjuvant andlor carriers. A. "therapeutically effective amount" as used herein refers to that amount which 2s provides a therapeutic effect for a given condition and administration regimen. Such compositions are liquids or Lyophilized or otherwise dried formulations and include diluents of various buffer conteryt (e.g., Tris-HCI., acetate, phosphate), pH
and ionic strength, additives such as albumin or gelatin to prevent absorption to surfaces, detergents (e.g., Tween 20, T1'Veen S0, Fluronic F68, bile acid salts), solubilizing agents ztf (e.g., glycerol, polyethylene glycerol), anti-oxidants (e.g., ascorbic acid, sodium metabisulfite), preservatives (e.g., Thimerosal, benzyl alcohol, parabens), bulking substances or tonicity modifiers (e.g., lactose, mannitol), covalent attachment of polymers such as polyethylene glycol to the protein, eomplexation ~uvikh metal ions, or incorporation of the material into or onto particulate preparations of polymeric compounds such as polylactic acid, polglycolic acid, hydrogels, etc, pr onto liposomes, microemulsions, micelles, unilamellar or multilamellar vesicles, erythrocyte ghosts, or spheropla9ts. Such compositions will influence the physical ~ state, solubility, stability, rate of iu vivo release, and rate of in vivo clearance_ Controlled or sustained release compositions include formulation in lipophilic depots (e.g., fatty acids, waxes, oils).
Iooo~al Also comprehended by the invention are particulate compositions coated with to polymers (e.g., poloxamers or poloxatniries). Other embodiments of the compositions of the invention incorporate particulate forms, protective coatings, protease inhibitors or permeation enhancers for various routes of administration, including parenteral, pulmonary, nasal and oral. Xn one embodiment the pharrnaeeuti.cal composition is administered parenterally, patacanceraily, transmucosally, tcansdermally, intramuscularly, intravenously, intradetTnally, subcutaneously, intraperitonsaty, intraventxicularly, intracrani$1~y and intratumorally.
10o06sJ Further, as used herein "pharmaceutically acceptable carriers" are well lrnown to those skilled in the art and include, but are not limited to, 0,01-0.1M and preferably zo O.OSM phosphate buffer or 0.$% saline. Additionally, such pharmaceutically acceptable carriers may be aqueous or non-aqueous solutions, suspensions, and emulsions.
Bxamples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive ail, and injectable organic esters such as ethyl oleate.
Aqueous carriers include water, alcoholiclaqueous solutions, emulsions or suspensions, including saline 2s and buffered media.
(00070) Parenterat vehicles include sodium chloride solution, finger's dextrose, dextrose and sodium chloride, lactated Ringer's or fixed oils. Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers such as those based on so Ringer's dextrose, and the like. Preservatives and other additlwes may also be present, such as, for example, antimicrobials, antioxidants, collating agents, inert gases and the like.

[00071] Controlled or sustained rele$se compositions include formulation in lipophilic depots (e.g, fatty acids, waxes, oils). Also comprehended by the invention are particulate compositions coated with polymers (c.g. poloxamers or poloxamines) axtd the compound coupled to antibodies directed against tissue-specific receptors, ligands or antigens or coupled to ligands of tissue-specific receptors.
[000721 Other ernboditrients of the compositions of the invention incorporate particulate forms, protective coatings, protease inhibitors or permeation enhancers for to vaxious routes of administration, including parenteral, pulmonary, nasal and oral.
Io0073j 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, polyvinylpyrrolidone or is polyproline axe known to exhibit substantially longer half lives in blood following intravenous injection than do the corresponding unmodii!ied compounds (Abuchowski et al., 1981; Newmark et al., T~8Z; acrd Katre et al., 198'0. 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 2o immt~uogenicity and reactivity of the compound. As a result, the desired iri vivo biological activity play be achieved by the administration of such polymer-compound abducts lass frequently or in lower doses than with the unmodified compound, [a0074j Tn yet another embodiment, the pharmaceutical composition can be delivered zs iri a controlled release system. 1~or example, the agent may be administered using intravenous infusion, an implantable osmotic ppmp, a transdezmal patch, lipvsomes, or other modes of administration. In one embodiment, a pump rnay be used (see l;anger.
supra; Sefton, CRC Crit. Itef. Bior~aed. Eng. 1~:201 (1987); Buchwald et al"
Surgery $8;507 (1980); Saudek et al., N. $tigl, r. Med. 321:574 (1989). In another embodiment, so polymeric materials can be used. In yet another embodiment, a controlled release system can 6e placed in proximity to the therapeutic target, i.e., the brain, thus requiring only a fiactiot< of the systemic dose (see, e.g., Goodsorl, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138 (198x). Preferably, a controlled release device is intxoduced into a subject in proximity to the site of inappropriate immune activation or a tumor. Other controlled release systems are discussed in the review by banger (Science 249.1527-1533 ( 1990).
[000751 The pharmaceutical preparation can comprise the selective androgen receptor modulator alone, or can further include a pharmaceutically acceptable carrier, and can be in solid or liquid form such as tablets, powders, capsules, pellets, solutions, suspensions, elixirs, emulsions, gels, creams, or suppositories, including rectal and urethral ~ o suppositories. 1?hatmaceutically acceptable carriers include gums, starches, sugars, cellutosic materials, and mixtures thereof. The pharmaceutical preparation containing the selective androgen receptor modulator can be administered to a subject by, for example, subcutaneous implantation of a pellet; in a further embodiment, the pellet provides for controlled release of selective androgen receptor modulator ovex a period of ~5 time. The preparation can also be adrtiinistered by inGcavenous, [ntraarterial, or iz~tramuscular injection of a liquid preparation, oral administration of a liquid or solid preparation, or by topical application. Administration can also be accomplished by use of a rectal suppository or a ureckual suppository.
zo [poo76] The pharmaceutical preparations of the invention can be prepared by known . dissolving, mixing, granulating, or tablet-forming processes. )xor oral adr>iinistration, the selective androgen receptor modulators or their physiologically tolerated derivatives such as salts, esters, N-oxides, and the like are mixed with additives customary for this puxpose, such as vehicles, stabilizers, or inerk diluents, and Converted by customary zs methods into a suitable form for administration, such as tablets, coated tablets, hard or salt gelatin capsules, aqueous, alcoholic or oily solutions. Examples of suitable inert vehicles are conventional tablet bases s~teb as lactose, sucrose, or cornstarch in combination with binders like acacia, cornstarch, gelatin, or with disintegrating agents such as cornstarch, potato starch, alginlc acid, or with x lubricant lik$
steaxic acid or 3o magnesium stearate.
[00077] Examples of suitable oily vehicles or solvents are vegetable or animal oils such as sunflower oil ox fish-liver oil. Preparations can be effeoted both as dry and as wet granules. For parentera.l administration (subcutaneous, intravenous, intraarterial, or intraxnusculax injection), the SARM agents or the non-steroidal agonist agents or their physiologicahy to]crated derivatives such. as s$]ts, esters, N-oxides, and the like are s converted into a solution, suspension, or emulsion, if desired with the substances customary and suitable for this purpose, for example, solubilizers or outer auxiliaries.
Examples are; sterile liquids such as water and oils, with or without the addition of a surfactant and other pharmaceutically acceptable adjuvants. Illustrative oils are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, or ~o mineral oil. In general, water, saline, aqueous dextrose and related sugar solutions, and glycols such as propylene glycols or polyethylene glycol are preferred liquid carriers, particu]arty fox injectable solutions.
[o007s1 The preparation of pharmaceutical compositions which contain an active ~s cot~ponent is well understood in the art. Typically, such compositions are prepared as aerosols of the polypeptide delivered to the nasopharynx or as injectables, either as liquid solutions or suspensions, however, solid forms suitable for solution in, or suspension in, li9uid prior to injection can a]so be prepared. The preparation can also be emulsified, The aotive therapeutic ingredient is often tuixed with excipients that are zo pharmaceutically acceptable and compatible with the active ingredient.
Suitable excipiez~ts are, for example, water, saline, dextrose, g]yceroi, ethanol, or the ]ike aad combinations thereof (ono79] :Ln addition, if desired, the composition can contain minor amounts of auxiliary z5 substances such as wetting or ert~ulsifying agents, pl-T buffering agents, which enhance the effectiveness of the active ingredient.
[000801 An active component can be formulated into the composition as neutralized pharmaceutically acceptable salt forms. Pharmaceutically acceptable salts includt the 3o acid addition salts (formed with the free amino groups of the poiypeptide or antibody molecule), which axe formed with inorganic acids such as, for example, hydrochloric or phosphoric $cids, or such organic acids as acetic, oxalic, tartaric, ntandelic, and the liko.

Salts formed from the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferxic hydroxides, and such organic bases as isoprapylatnine, tcimcthylamine, 2-ethylamino ethanol, histidine, procaine, and the like.
s (Oooe1] For topical administration to body stufaees using, for example, creams, gels, drops, and the like, the SARM agents or the non-agonist steroidal compounds or their physiologically tolerated dexivatives such as salts, esters, ~1-oxides, and the like are prepared and applied as solutions, suspensions, or emulsions in a physiologically to acceptable diluent with or Without a pharmaceutical carrier.
(O~oe2] Tn another embodiment, the active compound caa be delivered in a vesicle, in particular a liposome (see Langer, Science 249:I527-1533 (1990); Treat et al., in laiposomes in the Therapy of infectious Disease and Cancer, Lopez- Becestein and Fidler is (eds.), hiss, New 'York, pp. 353-365 (1989); hopez-Berestein, ibid., pp.
317-327; see generally ibid).
lo0ve3] 1~or use in medicine, the salts of the SARM or the non-steroidal agonist compounds will be pharmaceutioally acceptable salts, Other salts may, however, be zo useful in the preparation of the compounds according to the invention or of their pharmaceutically a.eoeptable salts. Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts, which may, for example, be formed by mixing a solution of the compound according to the invention with a sotution of a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric said, 2s methanesulphonic a~eid, fumario acid, malefic acid, succinic acid, acetic acid, berizeic acid, oxalic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.
(00084] The present invention further relates to a method of determining the presence of a selective androgen modulator compound andlor a non-steroidal agonist compound 30 of the present invention in a sample. The method comprises the steps of obtaining the sample, and detecting the compound in the sample, thereby determining the presence of the cotnpouud in the sample.

joo085] In one embodiment, the sample is a blood serum sample. .In another embodiment, the sample is a plasma sample. In another embodiment, the sample is a urine sample. In another embodiment, the sample is a saliva sample. In another embodiment, the sample is any other tissue sample.
(00086] In one embodiment, the detention step comprises measuring the absorbance of the oompound at a predetermined wavelength. For example, the corttpounds of the present invention absorb in the ultraviolet region of the spectrum, with an absorbency to peak at 270 nm. Thus, in one embodiment of the present invention, the compound is detected by monitoring the W absorbance of the Sample at 270 nm. It should be noted that the present invention is net limited to U'V' absorption, and that any other spectrometric methods of identification are applicable. For example, corupounds can be detected by measuring their infra-red or visible absorbance.
IS
ioooBT] xn another embodiment, the present invention further provides a method of detem~ining the concentration of a selective androgen receptor modulator compound and/or a non-steroidal agonist compound of the present invention in a sample.
The na.ethod comprises the steps of obtaining a sa,xnple; determining the level of the 2o compound in the sar~lple, and caleulatitig the concentration of the compound in the sample by comparing the IeveI with a standard sample containing a known concentration of the compound. Calibration curves of known concentrations of the oompound in the sample, can be obtained, and the concentration of tho compound In the test sample is Calculated therefrom. By "level" it is meant the absorption level of the Compound at the 25 measured vravelength~
jooos8] In another embodiment, the compound is detected in the sample by contacting th.e sample with a binding protein which specifically binds to the compound, and determining the amount of binding protein bound to the oQmpound. The concentration 30 oP the compound can be determined by measuring the amount of binding protein bound to the compound, and comparing that amount to a standard sample containing a known concentration of the compound - binding protein complex.

(oo0gs] Protein levels can be determined according to standard techniques, as described in Sambrook et al. Briefly, a sample obtained from a subject is contacted with a binding protein which specifically binds to a specific compound of the present s invention, and the amount of complex formed between the binding protein and the compound is determined. In one embodiment, the binding protein is an antibody which specifically binds to one or more compounds ofthe present invention. In another embodiment, the binding protein has a detectable label bound thereto, and the complex between the binding protein-label compound is determined by visuali2ing the complex.
Io [o0090] As defined herein, "contacting" means that the binding protein is introduced into the sample in a test tetbe, flask, tissue culture, chip, array, plate, microplate, capillary, or the like, and incubated at a temperature and time sufficient to permit the binding component to bind to a cell or a fraction thereof or plasma/serum or a fractiotl ~s thereof containing the target. Methods for contacting the samples with the binding proteins, or other specif]c binding components are known to those skilled in the art and may be selected depending an the type of assay protocol ~to be run. Incubation methods are also standard and are known to those skilled in the art.
zo [oao91] "Visualizing" the complex may be carried out by any means known in the art, including, but not limited to, ELISA, radioimmunoassay, flow cytometry, dot blots, western immunoblotting combined with gel electrophoresis, immunohistochemistry at tight and electron pe levels, HPLC and mass spectrometry.
zs [ooos2] Either monoclonal or polyclonal antibodies (as welt as any recombinant antibodies) specific Per the selective androgen modulator compounds or the non-steroidal agonist compounds of the present invention can be used iu the various immunbassays. The antibodies rrlay be delectably labeled, utilizing conventional labeling techniques wall-Imown to the art, As used herein, the term "label"
refers to a 3o molecule, vvhieh may be conjugated or otherwise attached (i.e., covalently or non-covalently) to a binding protein as defined herein. Labels are known to those skilled in the azt. Thus, the antibodies may be labeled with radioactive isotopes, non-radioactive isotopic labels, fluorescent labels, enzyme labels, chemiluminescent labels, biolutrtinescent labels, free radical.labels, or bacteriophage labels, using techniques known in the art. Examples of radioisotopic labels are ³ ~I, ¹²⁵ I, t 31 I, ³⁵ S, ,sup.I4 C, etc. Examples of non-radioactive isotopic labels are ⁵⁵ Mn, s ,sup.56 Fe, etc. Exaxaples of fluorescence labels are fluorescent labels which are directly labeled with the preferred fluorescence label, or fluorescent labels which are indirectly labeled with the preferred fluorescence label. !n the last case, the preferred fluoxescence label is conjugated to a secondary antibody, which is directed against the first antibody, such as an anti species Ig antibody. Typical fluorescent labels include, but 1o are not limited to a fluorescein label, an isothiocyanate label, a rhodamine label, a phycoerythrin label, etc" for example fluorescein isothi.ocyattate (FITC, International Biological Supplies, Melbourne, FL), rhodamine, phycoerythrin (P.~., Coulter Corp., Hialeah, FL)" phycocyanin, alophycocyanin, phycoerythrin-cyanin dye 5 (PECyS, Coulter), label, a phycoeyanin label, an allophycocyanin label, an O-phthaldehyde label, 1 s a tluorescarnine and Texas Red.
[o0os3a Examples of enzyme labels include alkaline phosphatase, beta-galactosidase, glucose-6-phosphate dehydrogenase, tnaleate dehydrogenase, and peroxidase, Two principal types of enzyme immunoassay are the enzyme-linked 2o immunosorbent assay (ELISA), and the homogeneous enzyme immunoassay, also knovcrn as enzyme-multiplied imrrtunoassay (EMT.T, Syva Corporation, Palo Alto, CA).
In the ELISA system, separation may be achieved, for example, by the use of antibodies coupled to a solid phase. The EMIT system depends oil deactivation Qf the etaayma iri the tracer-antibody complex; the acti'~ity can thus be measured without the need for a 25 separation step.
iooos4) Particularly suitable labels include those, which permit analysis by flow cytometry, e.g" fluoYoohromes. Qther suitable detectable labels include those useful in coloritnetric enzyme systems, e. g" horseradish peroxidase (HRF'} and slkalir~e 3o phosphatase (AP). Other proximal enzyme systems are known to those of skilt in the an, including hexokinase in conjunction with glucose-6-phosphate dehydrogeriase, (00095] Additionally, chemiluminesoent compounds rnay he used as labels.
Chemiluminescent labels, such as green fluorescent proteins, blue fluorescent proteins, and variants thereof are mown. Also bioluminescence or chemiluminescence can be detected using, respectively, NAD oxidoreductase with luciferase and substrates NADH
s and FN)N or peroxidase'with luminol and substrate peroxide, Typioal chemiluminescent compounds include luminal, isoluminol, aromatic acridlnium esters, irnidazoles, acridinium salts, and oxalate esters. Similarly, biolumitlescent compounds rr~ay be utilized for labelling, the bioluminescent compounds including luciferin, luciferase, and aequotin. Once labeled, the antibody may be employed to identify and quantify to ~ inununologie counterparts (antibody or antigenic polypeptide) utilizing techniques well-known to the art.
[ooos67 The following examples are presented in order to more fully illustrate the 1 s preferred embodiments ef the invention. They should in no way be oonsm.~ed, however, as limiting the broad scope of the invention.
EXPERTMENTAIr DETAItLS SECT)(fJN
zo EXAMPLE I
Nonsteroidat Llgsnds wzth Androgelnic and Anabolic Activity z5 100p9i1 The SAZ2.M compounds provided herein wens designed, synthesized and evaluated for in-vitro and in-vivo phatmacologlc activity. The in-vitto androgen receptor binding affinity and ability to maintain androgen dependent tissue growth in castrated animals was studied. Androgenic activity was monitored as the ability of the SARM compounds to maintain and~or stinnulatB the growth of the prostate and seminal 3o vesicles, as measured by weight. Anabolic activity was monitored as the ability of the SAlZIt~ compounds to maintain and/or stimulate the gowth of the levator ani muscle, as measured 6y weight, S~rnthetic Praaedures of Carnaounds I-VrY>(:
(ooosa] (2R)-1-Metttacryloylpyrrolfdin-2-F~rboxylic Acid (R-1z9), D-proline (R-128, 14.93 g, 0. I3 mol) was dissolved in 71 mI. of 2 N NaOH and cooled in an ice bath;
s the resulting alkaline solution was diluted with acetone ('71 mL). An acetone solution (71 mL) of metacryloly chloride 1z7 (I3.56 g, 0.13 mol) and 2N NaOH solution (71 m~.) were simultaneously added over 40 min to the aqueous solution of D-proiine in an ice bath. The pH ofthe mixture was kept at 10-11°C during the addition of the metacryloly chloride. After stirring (3 h, room temperature), the mixture was evaporated in vaauo at 1o a temperature at 35-45 °C to remove acetone. The resulting solution was washed with ethyl ether arid was acidified to pH 2 with concentrated HCI. The acidic mixture was saturated with NaCI and was extracted with EtOAc (100 mL x 3). The combined extracts were dried over Naa504, filtered through Celite, and evaporated in vacuo to give the crude product as a colorless oil. Recrystallization of the oil from ethyl ether and hexanes ~ s affoxded 16.2 (68%) of the desired compound as colorless crystals: mp 102-103 °C (lit.
[214 mp 102.5-103,5 °C); the NMIt spectzum of this compound demonstrated the existence of two rotamers of the title compound. tH NIvIR (300 MHz, DMSO-ds} 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 Cl'lz), 4.48-4.44 for the first rotatner, 4.24-4.20 (m) far the 24 second rotamer (totally Il-T for both rotamers, CH at the chiral eantex), 3.57-3.38 (tn, 2H, CHz), 2.27-2.I2 (IH, CH)> I.97-1.72 (m, 6H, C~:f"~CH, Me); t3C NMR (7S MHz, DMSO-ds) & for major rotarrier 173.3, 169.1, 140.9, 116.4, 58.3, 48,7, 28.9, 24.7, 19.5:
for minor rotarner 174.0, 170.0, I4I-6, 115.2, 60.3, 45.9, 31.0, 22.3, 19.7;
IR (KBr) 3437 (OH), 1737 (C=O), 1647 (CQ, COOH), 1584, 15p8, 1459, 1369, 1348, 1178 cm'';
as [oc]p 6 +80.8° (c - 1, MeOH); Anal. Calcd, for C9H~sNO3: C 59.00, H
?,15, N 7.65.
Found; C 59.13, H 7.19, N 7.61.
(Opp99j (3R,$aR)-3-Rromotnethyl-3-tnetltyl-tetrahydro-pyrrolo[2,y-c](1,4]pxazine-1,4-dione (R, R-X30). A solution of NHS (23.Sg, O.I32 mot) in I00 mlr 30 of DMF was added dropwise to a stirred solution ofcompound R-129 (l6.Ig, 88 mmol) in 70 mL of hMF 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 was suspended in vJater, stirred overnight at room temperature, filtered, and dried to give i 8.6 (81%) (smalier weight when dried ~ 34%) of the title compound as a yellow solid: mp i52-154 °C (lit. [214] mp 107-109 °C for the S-isomex);'$ NMR (300 MI3z, DMSO-db) s 4.69 (dd, I = 9.6 Hz, J = 5.7 Hz, 1H, Cli at the chiral center), 4.02 (d, J = 11.4 Hz, 1 H, CHI°), 3.86 (d, J = 11.4 Hz, 1 H, CH1~lb), 3.53-3.24 (m, 4H, CHZ), 2.30-2.20 (m, IH, CH), 2,04-1.72 (m, 3H, CHi and CH), 1.56 (s, 2pT, Me);'3CNMR
(75 MHz, DMSQ-ds) b 167.3, 163.1, 83.9, 57.2, 45.4, 37.8, 29.0, 22.9, 21.6; IR
(T~Br) 3474, 1745 (C=O), 1687 (C=O), 1448, 1377, 1360, 1308, 1227, 1159, 1062crri ~;
[a]pz6+124.5 ° (C = 1.3, chloroform); Anal. Caltd. for CyH~2HrN03: C 41.24, H 4.6I, N 5.34. Found:
C 41.46, H 4.64, N 5.32.
[OOO1oo) {2R)-3-Brpmo-2-hy'droxy-2-methylpropsnoic Acid (R-131). A mixture of bromolactone R-13p (lB.Sg, 71 mmol) in 300 mL of 24% HEr was heated at reflex for I
h. The resulting solution was diluted with brine {200 rnL), and was extracted with ethyl acetate (I00 mL x 4). The combined extracts were washed with saturated Nal-1C03 (100 mL x 4). The aqueous solution was ecidif~ed with concentrated HCl to pH~ = 1, which, in tum, was extracted with ethyl acetate ( 100 ml; x 4). The combined organic solution ~cvas dried over Na~Spa,~ filtered khrough Celite, and evaporated in vacuo to dryness.
Recry'stallizatiori from toluene afforded 10.2 g (86%) of the desired compound as zo colorless crystals: top 107-109 °C (lit, [214] mp 109-113 °C
for the S-isomer);'H NMR
(300 MHz, DMSO-d6) b 3.63 (d, J = 10.1 Hz, 1H, CHHg), 3.52 (d, J = 10.1 Hz, IH, CHHb), 1.35 (s, 3H, Me); rR (KBr) 3434 (OH), 3300-2500 (COOK), 1730 (C=O}, I449, 1421, 1380, 1292, 1193, 1085 cnri'; [a]p'6 +10,5° (c ~ 2.6, MeOH);
Arial. Calcd. fox C4H~Bz03: C 26.25, H 3.86. Found: C 26.28, H 3,75_ zs i0oo101j N-(4-Nitro-3-(trifluoromethyl]phenyl)-(2R)-3-6romo-Z-hydrOxy-2-triett~yipropanasnide (R.-13Z}. Thionyl chloride (8.6 g, 72 ntmol) was added dropwise under argon to a solution of bromoacid R-13x (11.0 g, 60 mrnol) in 70 mL of DMA at 5 to --10 °C. The resulting mixture was stirred for 2 h under the same conditions. A
solution of 4-vitro-3-trifluvrornechyl-aniline (12.4 g, 60 mmol) in 80 mL of DMA was added dropwise to the above solution, and the resulting mixture was stirred overnight at room tenxpatature. The solvent was removed on Rotavapor using high vacuum oil pump;

the residue was diluted with saturated NaHCO~ solution, and extracted with ethyl ether (I04 mL x 3). Combined extracts were dried over anllydxous NazSOa, filtered through Celite, and ptltified by flash chromatography on silica gel, using methylene chloride as etuent to afford 18.0 g (80%) of the desired compound: mp 98-100 °C
(Rr= 0.2 , silica gel, CHzClz);'H NN1R (300 MH2, DMSO-d6) 8 I0.54 (s, IH, NH), 8.54 (d, J = 2.1 Hz, 1H, Arl~, 8.34 (dd, J = 9.0 Hz, J = 2.1 Hz, 1H, ArH), 8.18 (d, J ~ 9.0 Hz, 1H, ArH), 6,37 (s, 1H, OH), 3.82, (d, J = 10.4 Hz, IH, CHHa), 3.58 (d, J ~ 10.4 Hz, 1H, CHHr), J .48 (s, 3H, Me); "C NMR (?5 MHz, DMSO-ds) S 173.6 (C=O), 143.0, 127.2, 123.2, 122.6 (q, J = 33.0 Hz), I22.0 (q, J = 271.5 Hz), 118.3 (q, J = 6.0 HZ), 74.4, 41.4, ? 4.9;1R
(KBr) 3344 (OH), 1680 (C=O), 1599, 1548 (C= C, Ar), 1427, 1363, 1161 cm''; MS
(~51~: m!z 370.8 (M)+; Anal. Calcd. for C~~H~oBrly~204: C 35.60, H 2.'72, N

7.55, pound:
C 35.68, H Z.72, N 7.49.
(ooo1D21 N-j4-nitro-3-fr9fluoromethyl)phe~yl~-(2S)-3-j4-(acetylamino)phenoxy]-~ s )aydroxy-2-msthylpropanamide (5..147). The title compound was prepared from compound R-13Z (0.37 g, L0 mmol)> 4-acetamidoplaenol (0.23 ~g, I.S mmol) ~.aC03 (0.28 g, 2.0 mmol), and 10% of ben2yltribt~tylammortium chloride as a phase rxansfer catalyst in 20 mL of methyl ethyl ketone vvas heated at rehux overnight under argon.
The reaction was followed by TLC, the resulting mixture was filtered through Celite, 2o and concentrated in vaceto to dryness. Purification by flash column chromatography o~
silica gel (hexanes-ethyl acetate, 3:1) yielded 0.38 g ($6%) (Rf = 0.18 hexanes-ethyl .
acetate, 3:1) of the desired compound as a light yellow pov~rder: mp 70-74 °C; The solid can be recrystalixed from ethyl acetate and hexane); ~H NMR (3DD MHz, DMSO-ds) S
10.62 (s, 1H, NH), 9.75 (s, 1H, NH), 8.56 (d, J = 1.9 I3~z, 1H, ArH), 8.36 (dd, J = 9.1 Hz, z5 J = 1.9 Hz, 1H, ArH), 8.18 (d, r = 9.1 Hz, 1H, ArH), 7.45-7.42 (m, 2pI, ArH), 6.85-6.82 (m, 2H, ArH), 6.25 (s, 1H, OH), 4.17 (d, J ~ 9.5 Hz, 113, CHHa), 3.94 (d, J =
9.5 Hz, 1H, CliHb), 1.98 (s, 3H, Me), 1.43 (s, 3H, M.e); tsC NMR (75 MHz, DMSO-ds) 8 I74.6 (C=Q), 167.7, 154.2, 143.3, 141.6, 132.5, 127.4, 123.0, 122.7 (g, J = 33.0 Hz), 122.1 (q, T = 271.5 Hz), 120,1, 118.3 (q,1= 6.b Hx), 114.6, 74.9, 73.8, 23.8, 23.0; IR
(fix) 3364 3a (OH), 1668 (C=O), 1599, 1512 (C=C, Ar), 1457, 1415, I351, 1323, 1239, 1154 cui ~; MS (BSr): rnlz 464.1 (MfNa)+; Anal. Calcd. for C~gH,eF3N3Os: C 51.71, H
4.11, N 9.52. Fouled: C 52.33, H 4.40, N 9.01.

[puane insert]
[000103] The in-vitro activity of the SARM compounds, specifically compound 'VII, ~o demonsfxated high androgen receptor ,binding affinity (Ki = 7,5 nNi).
Animal studies with the SARM compounds, specifically compound V, demonstrated that it is a potent androgenic and anabolic nonsteroidal agent. Four groups of rats were used for these studies: (1) intact controls, (2) castrated controls, (3) castrated animals treated with testosterone propionate (lOD p.g/day), and (4) castrated animals treated with compound 1 s V (1 ODD ~c~day). Testosterone and compound VII were delivered at a constant rate for 14 days via suhcutaneous osmotic pumps.
[000104] The results of these studies are shown in Figure 1. Castration significantly reduced the weight ofandroge~aic (e.g., prostate and seminal vesicles) aTad anabolic (e.g., zo levator alai muscle) tissues, but had little effect on animal body weight (B'VV). Treatment of castrated animals With testosterone propionate of compound VxI maintained the weight of androgenic tissues to the same degree. Compound VII had similar attdrogenic activity as testosterone propionate (i.e., the prostate and seminal vesicle weights were the sarlle), but m~tGh greater efficacy &s an anabolic agent. Compound VII
showed zs greater anabolic activity than testosterone propionate at the doses tested (i.e., the levator ani muscle maintained the same weight as intact control animals and was greater than that observed for testosterone). The experiments presented herein are the first in-vivo results which demonstrate tissue-selective androgenic and anabolio activity (i.e., differing androgenic and anabolic potency) of a nonsteroidal ligand for the androgen ,t so receptor, EXAMPLE Z
Nonsteroidal T.igands with A~droge~nie and Ansbolic Activity (00o1o5j The in-vivo efficacy and acute toxicity of four novel rlonsteroidal androgens (compounds fV~, Y, V); and VIA in rats was examined. In-vitro essays established that these compounds bind the androgen receptor with very high affinity. The structures and names of the four compounds are presented below:

OzN ~ R
O ~ /
C);3 NH ~.~~, ,O

GTx-014 k~= F
OTx-015 R=COCkI~
GTx-a16 R=coC2~s GTx-017 R~NIiCOCH3 EXPERrMENTAL METHODS
1000106] Materials. The S-isomers of compounds GTx-014 (compound ~, GTx-015 z5 (compound V), GTx-OIb (compound VI) and G'px-007 (compotuid VII rwherein R
is N.~TCOCH3) and the R-isomer of GTx-014 were synthesized in accordance with the scheme as set forth in Figure 9, Testosterone propionate (TP), polyethylene glycol 3Qa (PEG300, reagent grade) and neutral buffered formaiin (IO% w/w) were purchased from Sigma Chemical Company (St Louis, lvZO). Alzet osmotic pumps (model 2002} were purchased fxom AJ2a Core. (Palo Alto, CA).
100010?] ~tnirr~c~ls, Immature male Spxague-pawley rats, weighing 90 to IOOg, were purchased from Harlan J~iosciences (7.ndianapolis, IN). The animals were maintained on a 12-hour light-dark cycle with food and water available ad libiturn.. The animal pxotocol was reviewed and approved by the rnstiiutional Laboratory Anirnal Care and U'se Camtnittee.
to [ooo~0sl Str~dyDesigri. Rats were randomly distributed into twenty-nine (291 groups, with S animals per group. Treatment goups are described in Table 1, One day prior to the start of drug treatment, animals ~ groups 2 through 29 were individually removed from the cage, weighed and anesthetized with an intraparitoneal dose o~
ketaminelxylazine (g7/13 mg/kg; approximately I mL per leg). Where appropriately 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 midline scrotal incisioxt, with sterile suture being used to legate supra-testicular tissue prior to surgical removal of each testis. The surgical wound site was olosed with sterile stainless steel wound clips, and 24 the site cleaned with betadine. The animals were allowed to recover on a stexiJe pad (until able to stand) and then returned to theix cage.
(oo01 os] Twenty-four hours later, animals in groups Z through 29 were re-anesthetized with ketamineJxylazine, and an Alzet osmotic pumps) (model 2002) was placed 2s subcutaneouly in the scapular region. Xn this instance, the scapular region was shaved and cleaned (betadine and alcohol) and a small incision (I cm) made using a sterile scalpel. The osmotic pump was inserted and the wound closed with a sterile stainless steel wound clip. Animals were allowed to recover and were returned to their cage.
Osmotic pumps contained the appropriate treatrdent (designated in Table I) dissolved in 3o polyethylene glycol 300 (PEG300). Osmotic pumps were filled with the appropriate solution one day prior to implantation. Animals were mox~itoxed daily for signs of acute toxicity' to drug treatment (e.g., lethargy, rough coat).

(000110] After 14 days of drug treatment, rats were aneskhBtized with ketaminelxylazine. Animals were then sacrificed by exsanguinations under anesthesia.
A blood sample was collected byvenipuncture ofthe abdominal aorta, and submitted for complete blood cell analysis. A. portion of the blood was placed in a separate tube, s centrifuged at 12,OOOg 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 containing 10% neutral buffered formalin. preserved tissues were sent to GTx, Tnc. for histopathological analysis.
io (ooottt] For data analysis, the weights of all organs were normalized to body weight, and analyzed for any statistical significant difference by single-factor ANO'V'A, The weights of prostate and seminal vesicle were used as indexes for evaluation of androgeuit activity, and the levator ani muscle weight was used to evaluate the anabolio ~s activity.

[ooo1~z] The androgenic and anabolic activities the S isomers cf compol~tds GTx-0x4, GTx-015, GTx-016 and G'15c-007, and the R isomer of GTx-014 'overe examined in a zo castrated rat model after 14 days of administration. Testosterone propionate, at increasing doses, was used as the positive control of anabolic and androgenic effects.
[ooo1t31 As shown in Figures 2 and 3, the weights of prostate, seminal vesicle, and levator ani muscle in casaated, vehicle-treated rats decreased significantly, due tv the as ablation of endogencus androgen production. Exogenous administration of testosterone prapionate, an androgenio , and anabolic steroid, increased the weights of prostate, seminal vesicle, and levatar ani muscle in castrated rats irt a dose-dependent manner.
The R-isomer of GTx-014, attd S-isomers of GTx-015 and G'I~t-016 showed no effect on the weights of prostate, seminal vesicle, and levator ar~i muscle in castrated animals 3U (data not shown). The S-isomers of GTx-007 (Figure 2: S-GTx-007) and GTx-(Figure 3: S-GTx-014) resulted in dose-dependent increases in prostate, seminal vesicle and levator ani muscle weights. compared with testosterone propionate, S-(',uTx-007 ~#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 levatox ani muscle. Particularly, S-GTx-007, at a dose as low as 0.3 mp.,,lday, was able to maintain the levator ani muscle weight of castrated animals in the same level as that of intact animals. Thus, S-GTx-ODD is a potent nonsteroidal anabolic agent with less androgenic activity but more anabolic activity than testosterone propionate.
This is a significant improvement over previous clairixs, in that this compound selectively stimulates muscle growth and other anabolic effects white having less effect on the prostate and seminal vesicles_ This may be partieularly relevant in aging men with I o concerns related to the development or progression of prostate cancer.
(opo114] GTx-014 was less potent than GTx-007, but showed greater tissu~
selectivity (compare effects on the prostate and seminal vesicles in Figures 2 and 3). GTx-significantly increased levator ani muscle weights, but showed little to no ability to 1s stimulate prostate and seminal vesicle growth (i.e_, the prostate and seminal vesicle tx~eights were less than 20% of that observed in intact animals or in animals treated with testosterone propionate), (OOO115] results showed that none of the examined compounds produced significant Zo effect on body weight or the weights of outer organs (i.e., liver, kidneys, spleen, Jungs and heart). Nor did any compound produce any signs of acute toxicity, as gauged by diagnostic hernatolagy tests and visual examination of animals receiving treatments.
Importantly, GTx-Ob7 did not suppress the production of luteinizang hormone (L'f-I) or follicle stimulating hormone (FSH) at a dose of 0.3 mglday (i.e" a dose that exhibited 2s maxima( anabolic effects).
(ooolls] In summary, S-GTx-D07 exhibited exceptional anabolic activity in animals by maintaining the weight of levator aril muscle after removal of endogenous androgen.
This discovery represents m~jox progress towards the development of therapeutically 3o useful nonsteroidal androgens, and a major improvement (i.e., tissue selectivity and potency) fiver previous drugs in this class. S-GTx-O1~ and S-GTx-007 showed selective anabolic activity in comparison with testosterone propionate, an andragenic and anabolic steroid. The tissue-selective activity is actually one of the advantages of nonsteroidal androgens in terms of anabolic-related applications.
(000117) Despite similarities in structure and in-vitro functional activity, the S-isomers s of compounds GTx-014, GTx-015, GTx-016, and GTx-007 exhibited profound differences in terms of their in-vivo activixy, GTX-007 the most efficacious androgenic and anabolic activity in animals, with the anabolic activity greater than that of testosterone propionate. GTx-014 showed a small degree of androgenic activity, but an anabolic activity comparable to testosterone propionate, In contrast, GTx-015 and GTx-to OI6 failed to produce any androgenic or anabolic activity in-vivo, [0001181 These studies show the discovery of two rr~emhers (GTx-014 and GTx-007, compounds, compounds IX attd Y respectively) of a new class of selective .
androgen receptor modulators (SARMS) that demonstrate potent anabolic effects (e.g., nnuscle 15 growth) with less attdrogenic 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 cancer.
:0 [0001191 Fwther, Figures 7 axtd 8 demonstrate the effects of GTx-014 and GTx-007 on LH and FSH Levels in rats. Those restalts further demonstrate the novelty of these SARMs, due to their difFerential effects on these xeproductlve hormones, thus demonstrating the tissue-specific phaxmacologic activity. In Fire 7, LH levels in castrated animals treated r.vith TP and GTx-014 were significantly lo~cwer than those of zs untreated animals (i.e., castrated controls) at doses greater than or equal to 0.3 mglday.
However, higher doses (i.e., O.S mg/day or higher) of GTx-007 were required before significant decreases in LH levels were observed. Thus, GTx-007 does not suppress ~,I-I
levels at doses that are capable of eliciting maximal stimulation of levator ani muscle growth, In 1 figure 8, FSH levels in castrated animals created with GTx-014 were 3o significantly lower than those of untreated animals (i,e" castrated controls) at doses of 0.5 xnglday or higher. Similarly, lower FSH levels were observed in animals treated with TP. Ilowever, only this difference was only significant at a dose of 0.75 mg/day. 1~Sfl levels in animals treated with GTx-007 wexe not significantly different from those of untreated animals at any dose level tested. Thus, G1k~007 does not suppress FSH levels at doses that are capable of eliciting maximal stimulation of levator ani muscle growth.
Table 1. Animals Groups and Experimental Design Grpup # CastratedhDrug Dpse # o~ animals 1 No None None ,5 2 Yes None Vehicle 5 only 3 Yes Testosterone0.1 mg/day5 4 Yes Testosterone.3 rng/day5 Yes Testosterone0.5 mg/day5 6 Yes Testosterone0.'15 mg/day5 ? Yes Testosterone1.0 mg/day5 8 Yes It-OTx-OI4 1.0 mg/dayS

9 Yes S-GTx-014 0.1 mg/day5 'f'es S-GTx-014 0.3 mglday5 11 Yes S-GTx-014 0.5 mg/day5 2 Yes -GTx-014 D.7S mg/day5 13 Yes S-GTx-014 1.0 mglday5 14 Yes S-CrTx-015 0.1 mg/dayS

I S Yes S-GTac-015 D. mg/day 5 16 Yes S-GTx-015 0.5 m~day 5 I7 Yes S-GTx-015 0.75 mg/day5 18 Yes S-GTx-0i5 1.0 mglday5 19 Yes s-GTx-o16 a.! mg/day5 Yes S- Tx-016 0.3 rng/day5 zI es s-GTx-o1s o.s m~/d$y5 22 Yes S-Gxx-016 0.75 mg/day5 23 Yes S-GTx-O1 1.0 mglday5 24 Yes S-GTx 047 0.1 m~day 5 Yes S- Tx-007 4,3 m /day5 26 Yes S-GTx-007 0.5 mglday5 27 Yes S- Tx-007 0.75 mg/day5 i 2$ Yes S-GTx-0 1.0 mg/day5 29 Yes None Ve icle 5 only ~o Pharxnacoltinetics of GTx-007 in Dogs ~o 10001201 The pharmacokinetics of S-~xTx-007, s. novel selective androgen receptor modulator (SARM), weze characterized in beagle dogs. A. four-treatment, foux-period crossover design was utilized in the study, which involved a total of six beagle dogs, three of each gender. Each animal received a 3 mg~kg IV dose, a.10 m~kg N
dose, a 10 m~kg PO dose in solution, arid a 10 mglkg p0 dose in capsule, ixr a randomly assigned i S order. There was an one-week washout period between treatments. Plasma samples were collected for up to 72 hr offer drug administration. plasma S-Gfx-007 concentrations were analyzed by a. validated HP1.C method. The cIearanae (CL), volume of distribution (Vss), half life (T~ia), and other pharmacokinetic parameters were determined by noncompartmental methods. R$sults showed that S-GTx-007 was cleared from dog zo plasma. with a tennibal T~~ of about ~ hr and a CL of 4.4 mL/min/kg a$er rY
administration. Figures 4, 5, and 6 show the plasma aflnoentration-time prol:iles of S-GTx-007 after administration of an intravenous sotutiori, oral solution, and oral capsule, respectively. The pharmacokinetics were dose. and gender-independent. The oral bioavailability of S-G'Ik-007 varied with the dosage form, and averaged 3$%
and 19%
z5 for solution and capsule, respectively. Thus, S-GTx-007 demonstrated modexate half Iife, slow clearance and moderate bioavailabiiity in beagle dogs, identifying it as the first of a new class of orally bioavailable tissue.selactive androgen receptor mvduiators.
ExaMpL~ a GTx-U0T Analyses bY PLC
10o0121J A reversed phase high pressuxe liquid chromatograph (~iP?;C) assay was SO

developed to quantitate GTx-007 concentrations in dog plasma. Dog blood simples were obtained by venipuncture and centrifuged at I OOOg for 15 minutes. Samples were stored frozen at -20°C until analysis. Individual samples wexe rapidly thawed and an aliquot (0.5 ml) was spiked with intezrtal standard (20 ul of a 200 p.g/ml aqueous solution of CM-u-87). An aliquot of 1 ml of acetonitrile was added to the samples to precipitate plasma proteins. The samples were vortexed and then centrifuged at 10008 for minutes. The supernatant was decanted into glass extraction tubes and 7.5 mi of ethyl acetate was added, The e~;traction mixture was left at room temperature for 20 minutes, and vortexed several times during this interval. The samples were then centrifuged at to 10008 for 10 minutes, and the organic phase was removed and placed in conical-bottomed glass tubes. The organic phase was evaporated under nitrogen, The samples were reconstituted in 200 wl of rnobilG phase (35:65 acetonitrile:water) and transferred to an autosampler vial for HPLC injection (Waters 717 plus autosampler, Watexs Carp., Ivlilford, MA). The isoeratic mobile phase of 35% (v/v) acetoriitrile in water was ~ s puruped at a flow rate of 1 ml/min (Model 510, Waters Corp.). The stationary phase was a C18 reversed phase column (N'ovapak C18, 3.9 x 150 mm). Analytes were monitored with UV detection at 270 nm (Model 486 absorbance detector, Waters Corp.).
Retention times for GTx-007 and CM-rI-87 were 11-1 and 16.9 minutes, respectively.
Chromatography data was collected and analyzed using Millennium software.
Plasma 24 concentrations of GTx-D07 in each sample were determined by comparison to calibration curves. Calibration curves were constructed by adding known amounts of CrTx-007 to dog plasma. Final O~'x-007 concentrations in dog plasma samples used in the calibration ourves were 0.08, 0.2, 0.4, 2, 4, 10, and 20 ~g/rnl.
Calibration curves were linear over this concentration range and exhibited correlation eaefficients (r2) of 25 0.9935 or greater. Infra- and inter-day coeflaacients of variation for the standards ranged from 6.4% for 0,08 ~glrnl to 7.9% for 20 pg/ml.
1000'122) Melting points were dBtermined on a Thomas-Hoover capillary melting point apparatus and are uncorrected. Infrared spectra were recorded on a Perkin Elmer System 30 2000 >~T-IR. Optical rotations were determined on an Autopol°° TII Automatic polarimeter (Rudolph Research Made1 ~-589-10, p'airfield, New Jersey). Proton and carbon-13 magnetic resonance spectra were obtained on a l3ruker AX 300 spectrometer (300 and 75 MEIz for tTd and ~aC, respe~tivel~r). Chemical shift values were reported as parts per million (b) relative to tetramcthylsilat~e (TMS), Spectral data were consistent with assigned structures. Mass spectra were determined on a Broker-~1P Esquire LC
System. ~lement2G1 atzalyses were performed by Atlantic Microlnb Inc, (Norcross, GA), s and found values were within 0.4 % of the theoretical values. )Zoutine thin-layer chromatography (TLC) vv~.s performed on silica gel on aluminum plates (silica gel 60 F
254, 24 x 20 cm, AldriCh Chemical Company Inc., Milwaukee, WT). Flash chromatography was performed on silica gel (Merck, grade 60, 230-400 mesh, 60).
Tetrahydrofuran (THp) was dried by distillation over sodium metal.
Acetonitrile Io (MeCI~ and methylene chloride (CH2C12) were dried by distillation tom PzCs.

Claims (5)

1. A selective androgen receptor modulator compound having in-vivo androgenic and anabolic activity of a nonsteroidal ligand for the androgen receptor, the selective androgen receptor modulator compound represented by the structure of formula II below, Wherein X is O
Z is a hydrogen bond acceptor, NO2 CN, COR, CONHR;
Y is a lipid soluble group, I, CF3, Br, Cl, SnR3;
R is an alkyl or aryl group or HO; and Q is acetamido, trifluoracetamido, alkylamines, ether, alkyl, N-sulfonyl, O-sulfonyl, alkylsulfonyl, carbonyl or a ketone.

2. The selective androgen receptor modulator compound of O, Z is NO2, Y lipid soluble, and Q is acetamido.

3. Use of the compound of claim 1 or 2 for the preparation of a medicament for use in hormone therapy in a subject.

4. Use of the compound of claim 1 or 2 for the preparation of a medicament for use in treating a hormone-dependent condition in a subject.

5. Use of the compound of claim 1 or 2 for the preparation of a medicament for use in treating prostate cancer in a subject.