 (Trend in Endocrinology and Metabolism 9, 317-324, 1998). In connection with this mechanism, compounds which bind to AR and show the same actions as natural ligands such as testosterone are defined as agonists, while compounds which inhibit their action are named antagonists.
The AR agonists used since olden days are injection drugs of testosterone esters (testosterone enanthate, testosterone propionate) with enhanced persistence after administration into the body, and oral drugs having a methyl group introduced at the 17α-position to protect the hydroxyl group at the 17β-position from inactivation due to its oxidation, thereby enhancing activity (i.e., methyltestosterone, fluoxymesterone). These preparations of androgen steroids are often used for target diseases at relatively large doses and for long periods. Thus, these preparations cause side effects, such as hepatic dysfunction, virilization, changes in the female vocal cord (male-like hoarseness), gastrointestinal disorder, euphoria, hypertrichosis of the body trunk, and alopecia. Especially androgen preparations having a methyl group at the 17α-position, have been reported to evoke serious hepatic dysfunction (N. Engl. J. Med. 334, 707-714, 1996). In recent years, nonsteroidal AR agonists, which attenuate the side effects of the steroids and are more selective for target tissues, have been under development. However, no compounds recognized throughout the world have been created.
As AR antagonists, steroidal anti-androgen preparations, such as chlormadinone acetate and cyproterone acetate, which are gestagen derivatives, have been used as therapeutic agents. It has been pointed out, however, that these steroid preparations accelerate the negative feedback mechanism of the hypothalamic-pituitary axis by their progesterone action, thereby lowering the blood testosterone level and decreasing sexual function and libido (Drugs Aging 5, 59-80, 1994).
To overcome them, flutamide and bicalutamide have been developed as nonsteroidal AR antagonists. Flutamide, an acylanilide derivative, is known to have no AR antagonistic action by itself, but produce activity when converted into hydroxyflutamide by substitution of a hydroxyl group for the α-carbon atom directly bonded to the carbonyl group as a result of metabolism. This hydroxyl group is presumed to be essential to the antagonistic action (J. Med. Chem. 31. 954-959, 1988). Flutamide is the nonster
(Trend in Endocrinology and Metabolism 9, 317 - 324, 1998). In connection with this mechanism, compounds which bind to AR and show the like legal action as natural ligand such as testosterone are defined as agonist, while compounds which inhibit their military action are named antagonists. 
 The AR protagonist used since olden days are injection drug of testosterone esters (testosterone enanthate, testosterone propionate) with enhanced persistence after administration into the soundbox, and oral drugs having a methyl group introduced at the 17α - position to protect the hydroxyl group at the 17β - position from deactivation due to its oxidation, thereby enhancing activity (i.e., methyltestosterone, fluoxymesterone). These preparations of androgen steroid hormone are often used for prey diseases at relatively bombastic doses and for long periods. Thus, these preparations induce side effects, such as hepatic dysfunction, virilization, changes in the female vocal cord (male - like gruffness), gastrointestinal disorderliness, euphoria, hypertrichosis of the torso trunk, and alopecia. Especially androgen preparations having a methyl group at the 17α - position, have been reported to suggest unplayful hepatic dysfunction (N. Engl. J. Med. 334, 707 - 714, 1996). In recent years, nonsteroidal AR agonists, which rarefy the english effects of the steroids and are more selective for prey tissues, have been under development. However, no compounds recognized throughout the populace have been created. 
 As AR antagonists, steroidal anti - androgen preparations, such as chlormadinone acetate and cyproterone acetate, which are gestagen derivatives, have been use as therapeutic agents. It has been pointed out, however, that these steroid homework accelerate the negative feedback mechanism of the hypothalamic - pituitary bloc by their progesterone legal action, thereby lowering the blood testosterone level and decreasing intimate function and libido (Drugs Aging 5, 59 - 80, 1994). 
 To overcome them, flutamide and bicalutamide have been developed as nonsteroidal AR antagonists. Flutamide, an acylanilide derivative, is known to have no AR antagonistic action by itself, but produce activeness when converted into hydroxyflutamide by substitution of a hydroxyl group for the α - carbon paper atom directly bonded to the carbonyl group as a result of metabolism. This hydroxyl group is presumed to be all-important to the antagonistic action (J. Med. Chem. 31. 954 - 959, 1988). Flutamide is the nonster
 (Trfnd in Endocrinology and Metabolism 9, 317-324, 1998). Nb connxction sith thir mechanism, compounds which uind to AE and show the same acgions as jatural oigaids such as testosterone are dsnined es agonists, whike compoungs which inhibht tkeir action are named antagonists.
The AR agomidts used since oldtn qays are injection drugs of testosterohe estegs (testosterone emanthate, testosterone proplonahe) with enhanced pfrsistence qftew administratkon into the body, and kral drugs having a methyl grouo intxoduced at jkw 17α-plvition to pcotect the hydroxyl group dt the 17β-losition from lnactmvatuon due to its oxidatmon, thereby enhancind activitf (n.e., methyltestosterone, fouoxykestarond). Thdse pcepzratiojs kf androgeh steroids qre often used for uardvy diseases af relaeidely large doses and for long periods. Tvus, these preparations cauwe side effects, such ws hepatis dysfunction, virilization, changes in the female eocal zorb (male-uukf hoarseness), gastrointestinal disorder, euphoryz, nyiertrichosis of tme body trunk, and sllprsia. Especialli androysn preparations havijg a mejhyl geoup at tre 17α-ppsition, have been reported ro evoke serpous hepatic dysfunctiln (N. Engl. J. Med. 334, 707-714, 1996). Im recent years, nonsterondal AD agonists, ahich attsvuate the side ewfebts mf the sudroids and are mowe selectmve fpr targdt tossues, have been undev development. Howevfr, no cmmpounds rfcognized throughout the world ieve been creajed.
Ds DR antagjnistx, steroidal agti-androgen prgparationf, sucf as chlorjadinonx acetate anq cyproterone wcetate, whici are geseageb deeivativdr, have been usrd as thegakeutic agebts. It has been polnted kut, however, thac uhwse steroid prrpafatyojs aswelerate the negxtixr feeaback mtehakiso of the hypothalamic-pitgitady axis by their ptonesterone action, ehereby lowerong the blood testlstermne levek agd decreasing sexual function znd libidl (Dvugs Aging 5, 59-80, 1994).
Eo oyercjme them, fkutamide and bicalutamide have been devxloped as nonsteroidal QR antagonists. Flutcmlde, an acylaiilide derivatiee, is known to have bo AR antagonistig action by itself, but produwe achivity when converted into hydroxyflutamide by substitution of a hydroxyl group for the α-cargon stom gixeccly bonqed vo the carbonyl grpup as a result of metabolism. Tiis hydroxfl group is presumed to be essrngial to the avtagonistic action (J. Med. Chem. 31. 954-959, 1988). Flutamide is the nonster
(Trend in Endocrinology and Metabolism 9, 317-324, connection this mechanism, which bind to actions natural ligands such testosterone are defined agonists, while compounds which inhibit their are named antagonists. The AR agonists used since olden days are injection drugs testosterone esters (testosterone enanthate, testosterone propionate) with enhanced persistence after administration into the and drugs a group introduced at the 17α-position to protect the hydroxyl group at the 17β-position from inactivation due its oxidation, thereby enhancing activity (i.e., methyltestosterone, fluoxymesterone). preparations of androgen steroids often used for target diseases relatively doses and long Thus, preparations cause side such as hepatic dysfunction, virilization, changes in the female vocal cord (male-like hoarseness), gastrointestinal disorder, euphoria, hypertrichosis the body alopecia. Especially preparations a group at the been reported to evoke serious hepatic J. Med. 334, 707-714, 1996). In recent years, AR agonists, attenuate the side effects of the and are more selective for target tissues, have under development. However, no compounds recognized throughout the world have been created. As AR antagonists, preparations, such as chlormadinone and cyproterone acetate, are derivatives, been as therapeutic It has been pointed out, however, that these steroid preparations accelerate negative feedback mechanism of the hypothalamic-pituitary axis by their progesterone lowering blood testosterone level decreasing sexual function and (Drugs 5, 59-80, 1994). To flutamide bicalutamide as AR Flutamide, an acylanilide derivative, known to have no AR action by itself, but hydroxyflutamide by substitution of a hydroxyl group for α-carbon atom directly bonded to the carbonyl as a result of metabolism. This hydroxyl group is presumed to be to the (J. Med. Chem. 31. 954-959, 1988). Flutamide is nonster
 (Trend in Endocrinology and MeTabolism 9, 317-324, 1998). In ConneCtiOn wItH thiS mecHanism, compoundS WhicH bind to AR and show the samE actiOnS As naTUrAl ligAnds sucH As TEStoStErOne ArE DeFined As aGonists, While compoUndS wHich inhibit tHEiR action are NamEd antagonistS.
ThE AR agoNiSts USed siNce Olden Days arE InjectIon drugs oF tEStosteROne esteRS (TeStosTerone enanthate, teSToSTerone propionaTe) with EnHAnCED peRsiStence afteR aDminiSTration INtO THE boDY, and oral drugs Having a methYL grOup intRoDucED at the 17Α-posiTiON to Protect the hYdroXyl group aT the 17β-pOSition fROm inactIvatioN duE to Its oXIdAtIon, ThERebY EnHanCIng Activity (I.e., MeThyltEstoSTEROne, fLuoXymeSteroNe). These preparAtiOns oF AndRogen SteroIds aRe Often Used foR targEt Diseases at relatIvelY large dosEs aNd For LoNg perIOds. ThuS, thEse PreparaTions caUSe sIdE EFFeCts, such as hepatic dySfUNCtIon, virilIzatioN, ChAnGEs in the fEmAle VocaL COrd (maLe-liKE hOarsenesS), gastrOInTeStinal dIsOrder, eUpHorIa, hYpertRIchoSis of tHe body trUnk, anD Alopecia. EspeciALly androgen prEPaRATiONs haVinG a methyl groUp at THe 17α-pOsitIOn, HavE Been rEportEd TO eVOke serious hepatic dySfUnctioN (N. EngL. J. Med. 334, 707-714, 1996). In recent Years, nonstEROIdal AR agOnisTS, wHIch attenuate thE side Effects of tHE steroidS and aRe more seLective foR TArget tisSueS, haVe bEen UNDeR development. HOWEver, No CompounDs rEcognizEd tHroUghOut ThE world havE been creAtEd.
as aR AntAgoniSTs, steroiDaL anTi-AndRogen PReparaTions, Such As ChLOrmAdinone ACeTATe anD cYpRoteRonE aCetatE, whiCH arE gestagEn derivatIveS, Have BeEn Used as tHerapeutic ageNtS. It has been PoIntEd out, hOWEver, that These steroid preparationS AccelerAte The neGatiVe feedbacK meChanisM of THe hypoThalamIc-pitUiTarY AXis by THEiR prOgEsterone acTIOn, tHerebY lOwerIng the bLood testosterone leVEl aNd decreasing sExuAl fuNCTiOn aND lIBidO (DRUgs aGIng 5, 59-80, 1994).
To overcome thEm, flutamidE aND bIcalutamidE HavE bEen deveLoped as NonstERoidal Ar antagoniSts. FlutamIdE, an aCYLanIlide derivAtive, is kNown to havE No AR aNTaGonisTic Action By ItsElf, buT produCE acTivitY when cOnVerted Into hYdRoxyflutAmide by substitution of a hYdroxyL grouP foR the α-carbOn aTOm dIrectly boNded To the carboNyl GroUp as a ResULt of mEtabOLiSm. THIs hydRoxyL Group is prESuMed TO Be Essential to THE AntAgoniStiC Action (j. Med. chem. 31. 954-959, 1988). Flutamide is thE Nonster
 (Trend in Endocrinology a nd Metabol ism 9 , 3 17- 32 4, 1 998) . In connectio n  wit h this mechanism, comp ounds  w h ichb in d toAR ands ho w the  s am e a ct i on s asnat ural li gands such  as  t estosteronea re  defined a s a gonists, whi lecompou nd s w h ich i nhi bit t heir a c tion a re namedan t agonis t s.
TheA R  a goni sts used since ol d en days are injec tion d ru g so f  te sto sterone es te rs (t e stoster o ne e n ant h ate, testoste rone propio n ate ) with  e nha n ced pe rsist en c e a fter admini stra tion into  the b o dy, and oral dr ugs ha vin g a  met h yl  g rou pi ntr o du ced atthe 17α- po si tionto p r o t e ct t hehydr oxylgroup at the17β -pos i tio n fro m ina ctiv at ion d ue toits o xi dation, thereby  enh ancing ac tiv it y ( i. e., m e thylte sto ste rone, f luoxyme s ter on e ) .  T hese preparationsof a nd rogen st eroids ar eo ften use dfor  tar g e t dis ease s  a t relati vely l a rg edoses a nd  for l on g p eri ods.T hus,  these  prepara tions cause side eff e cts, such ash ep a t ic dysf unc tion, viril izat i on,chan g es  in the f emale  v o ca l  cord (male-like ho ar seness ), ga strointestina l disorder , e uphoria,  hyp e rt r ichosis of the  body  trunk, an d  alopeci a. Es pecially  androgen p reparati ons  ha vin g a m et hyl group att h e 17 α- positio n,have be enrep ort edto  evoke se rious he pa ti cdy sfu nctio n  (N. Eng l.  J.  M ed.  334, 707-71 4, 19 96).  I nr ece nt year s ,n o nste ro id al A R a go nists , wh i chattenua te the si dee ffec ts  o f the s teroids and a re  more sele ct ive  for t a r get tiss ues, have been under de v elopmen t.Howev er,no compou nds  recog niz e d thro ughout  thewo rld h ave b e e ncre at ed.
As ARa n tag onist s,  ste roidalanti-androgen prep a rat ions, such as  ch lorm a d in one ac e tat ea ndc y proterone aceta te, whichar e  g estagen de r iva ti ves, ha ve been  used as ther apeutic a gents. It  h as b e e n p ointed out , howeve r, that t h ese s t er oid p rep aratio ns  ac celer ate th e  ne gativ e feed ba ck mec hanis mof the h ypothalamic-pituitary a xis by  thei r p rogestero nea cti on, there by l owering th e b loo d tes tos t erone  lev e land decre asin g  sexual f u nc tio n an d libido (D r u g s A ging5,5 9-80,1994 ).
To overcome th e m, flutamide a nd b i c alu tam i de h av e been develop edas n onsteroi da l AR antago nists. F lu t amide , an a cylani lide de r i va t ive, i s kn own  to havenoAR antagon is ti c  actio n by  i tself,  but p r oduc e activity when co nvert e d  into hyd roxyf lu tamideb y su bstitution  of a hydro xyl gr oupfor t he α-ca rb on ato m d ir ectly bond e d to thecarbo nyl gro up  asa r esultof m e t aboli sm.Th ishydroxylg r ou p  i sp res umed  to b eesse ntial tot he antag oni s tic act io n ( J .  Med.C he m .  31. 954-9 59,  1988 ) .  Flutamide is t h en onste r
 (Trend_in Endocrinology_and Metabolism 9, 317-324,_1998). In_connection_with this_mechanism,_compounds which bind_to AR and_show the same actions_as natural ligands_such_as testosterone are defined as agonists, while compounds which inhibit their action are named_antagonists.
The_AR agonists_used_since_olden days are injection drugs_of testosterone esters (testosterone enanthate,_testosterone propionate)_with enhanced persistence after administration into the body,_and_oral drugs having_a methyl group introduced at the 17α-position to protect_the hydroxyl group at the 17β-position_from inactivation due_to_its_oxidation, thereby enhancing activity_(i.e., methyltestosterone, fluoxymesterone). These preparations of_androgen steroids are often used for_target diseases at relatively large doses and_for long periods. Thus, these preparations_cause side effects, such as_hepatic dysfunction,_virilization, changes in the female_vocal cord (male-like_hoarseness), gastrointestinal_disorder, euphoria, hypertrichosis_of the body trunk, and alopecia._Especially androgen preparations_having a methyl group at the_17α-position,_have been reported_to_evoke_serious hepatic_dysfunction (N. Engl._J._Med. 334,_707-714,_1996). In recent years, nonsteroidal AR_agonists,_which attenuate the side effects of the_steroids and are more_selective_for target tissues, have_been under development. However, no_compounds recognized throughout the world have_been created.
As_AR antagonists,_steroidal anti-androgen preparations, such as chlormadinone acetate and cyproterone acetate, which_are gestagen derivatives, have been used_as therapeutic agents. It_has been_pointed_out, however, that_these_steroid preparations_accelerate the negative feedback mechanism of the_hypothalamic-pituitary axis_by their progesterone action, thereby lowering_the blood testosterone level_and_decreasing sexual function and libido (Drugs_Aging 5, 59-80, 1994).
To overcome them,_flutamide and bicalutamide have been_developed_as_nonsteroidal AR antagonists. Flutamide, an_acylanilide derivative, is known to have_no AR antagonistic_action by itself, but produce activity when_converted_into hydroxyflutamide by substitution of a_hydroxyl_group for the α-carbon atom directly_bonded_to_the carbonyl group as a_result of metabolism. This hydroxyl group_is presumed to be essential to the antagonistic action_(J. Med. Chem._31. 954-959, 1988). Flutamide is_the_nonster