CA2138956A1 - 17-alkylketone steroids useful as 5-.alpha.-reductase inhibitors - Google Patents

Abstract

Invented are 17.alpha. and 17.beta.-alkylketone-3-carboxy aromatic A ring analogues of steroidal synthetic compounds, pharma-ceutical compositions containing these compounds, and methods for using these compounds to inhibit steroid 5-.alpha.-reductase iso-zyme 1 and steroid 5-.alpha.-reductase isozyme 2. Also invented are intermediates and processes used in preparing these compounds.

Description

~'~ 94/0012~ 2 1 3 8 9 5 6 -, Pcr/US93/06238 17-alkyL~etone steroids useful as 5-a-reductase inhibitors.

FlF.~ n OF T~F. ~NVENTION
The present invention relates to certain novel 17 and 17B-aLkylketone-3-c~ y aromatic A ring ~,.u;dal cc,~ ounds, ph~~re~ltir~l colll~ositions - cor.~ h-g these colll~ounds, and metho~3s for using these colllpou,lds to inhibit steroid S--~l~ll`t ~;C iSC~L~ and steroid 5-a-reductase isozyme 2. Also invented are novel intermo~tliAt~s _nd proc~sses useful in preparing these compounds.
r)FscRl~rIoN OF ~FT ~TFn ART
The class of steroidal holllloncs known as androgens is responsible for the physical ch~el~.istics that Lrr.,.el,liate males from females. Of the several organs thu pl~luce androgens, the testes produce these hollllo,les in the greatest ~llounts.
15 Centers in the brain exert plilll~ control over the level of androgen production.
Nwl-~,-ous physical ~ nir~ ;onc and disease states result when ineffective control results in e Ace;,~i~e an.l,u~n ho. . . ,onr. pl~duclion. For example, acne vulgaris, se~,lhea, female hil~uLislll, male pattern b~l~ness and ~s~le ~ice~ces such as benign pnDstatic ~ lUp,~ are correlated with elevated andn~gen levels.
20 Additionally, the reduction of andnDgen levels has been shown to have a tll~"~eulic effect on prostate cancer.
Te~losl~,lune is the ~,lin.;iyal andrDgen secreted by the testes and is the primary androgenic steroid in the plasma of males. It now is known that 5-a-l~luced androgens are the active hul~ ncs in some tissues such as the pluà~te and 25 s eb 7 ~ e Duc gland. Circ~ ting tealua~,. one thus serves as a prohormone for dihy~t~ oslel~,i e (DHT), its 5-a-reduced analogue, in these tissues but not in others such as muscle and testes. StenDid S-a-re~lllct~ce is a Nicohn~mide Adenine d;..l~cl~;de Pllo~ hate(NADPH)dependent enzyme that conve~ts te~losl~lune to DHT. The inl~l~nce of this enzyme in male development was dr~m~tic~lly 30 ulld~ d by discovery of a genetic sten~id S--re~uct~ce deftciency in male d~.,. ula~hl~dit~,s. Tmpe~tor-McGinley~ J., et ~ (1979), J. Steroid Biochem.
11:637-648.

A n.~ll.~r of 3-c~l.oAy-estra 1,3,5(10) triene S-a-reduct~ce inhi~itors are 35 knownintheart. For e~ lt, Wo 94/00125 ~ 1 3 8 ~ 5 6 ` Pcr/us93/o62~-1. J. Stemi-l Riochr.m., Vol. 34, Nos. 1-6 pp. 571-575(1989), by M.A.
Lcvy, ct al., des~ihes the int~,lacLion mech~nicm between rat prostatic steroid 5-alpha leduct~ce and 3-carboxy-17~substitut~ steroids;
2. J. Mcd. ('h~,m (1990) Vol. 33, pp. 937-942, by D.A. Holt, et al., S de~ bes a new stcroid class of A ring aryl c~l~ylic acids;

3. ~ (Dcc~ 1989) Vol. 10, pp. 491-495, by B.W. Metcalf, et al., ~s~ihes the effect of inhihitsrs of steroid Sa reAuct~ce in benign prostatic hype~plasia, male pattcrn b~ ness and acne.

In addidon U.S. Patent No. 4,954,446 describes a group of 3-carboxy-estra 1,3,5(10)triene-17B-cubstitl-te~ co~ ou.lds which are rlicclosed as being useful as inhihitors of stcroid 5-a-~uct~ce. However, none of the cited I~Ç~.~nces disclose or suggest that any of the novel 17~aLkyL~etone-3-carboxy a~(JmaLiC A ring steroidal co,ll~ullds of the present invention would have utility as highly potent inh~ ors of both steroid-5-a-reduct~ce isozyme l and steroid 5-a-re~uct~ce isoz~ e 2 (dual inhibitQrs).

SUMl~ARY OF T~F. ~VF.I~TION
This invention relates to a co...l o~nd of the formula I:
z H~C ~ `' (I) w~ eil~ z i {;R
in which R is C1 20 linear or br~nrh~A, satulaled or unsatulaled aLkyl and 25 ~hal~a~eutir~lly ~r~cept~ble salts, hydl~lc,s, solvates and esters thereo The invention also is a metho l for cim~ n~4 -cly inhibiting S-a-re~uc-~ce iSoL~ 1 and 5-a-reduc~ce isoL~Ille 2 activity in .-~ lc, inrh~tling humans, that Colll~JIiSC,S r-l.. ;n ~t~ - ing to a subject an effective amount of a ~I~,sently 30 ii~v~,n~l S-a-re~dnct~ce inhibiting co~l,vuilds. In a further aspect of the invention thcre are provided novel il~te- ,n~ tes and novel processes useful in ~l~aling the ~ 94/00125 2 1 3 8 9 5 ~ PC~r/US93/06238 y~ Iy invcnted dual 5-a-reduct~ce inhibiting colllyollllds. Included in the present invention are yh~ c. " I;c~l cc.. . ~pos;l;ons comrricing a pha, . . .A~e~t~
ca~ier and comrounAc useful in the methods of the invention. Also included in the present invention are ~ l.~c of co-aAminict~ing the yl~"elly invented dual 5-a-S ,~Ju~!~cc inhibiting co.~.l~.J.-As with further active ingreAi~.ntc nFTAn .F.n nF~c~rIoN OF T~. INVENTION
The co...l~ Ac of this invention that inhibit both 5-a-re~uct~ce isozyme 1 and 5-a-re~uct~se iStjZ~I~ 2 have the following Formula (I):

H~C ' ( ~ [ ` ~ (I) wL~ ~;n Z is a or B

_-R
h which R is C1 20 lhear or ~ n~h~d~ Sdlul~ted or nnc~ ated aLkyl and 15 pharmaceutic~lly a~cept~b~e salts, llyd~dtcs, solvates and esters thereo As uscd herein such coll,~unds are refcrred to as dual inhibitors of steroid 5-a-l~ A~e ~ ~ among the p,~scrltly in~r~,nlcd co,~ ,u~ds are those having 20 Fonnula (II):

_~R

H~; S (Il) in which R is C1 20 lhear or ~ r~chrd sal~at~ d or u~ t~ alkyl and pha~ceuti~ y acceprable salts, h~/dlatcs, solvates and esters thereo W O 94/00125 ~ 1 3 8 9 5 6 PC~r/US93/0623 P~Gfe,-~d among the yr~senlly invented Formula II con-yuunds are those having Formula m Il 2 GR

H ~ ~-- ~ (111) S in whieh R2 is Cl 8 linear or l~.~nched aLkyl and pharm~reutir~lly acceptable salts, hrLahs solvates and esters thereof.

F~c~ll~d among Formula (III) colll~unds are those in which R2 is methyl, ethyl, propyl, 3-methylbutyl, isc~lu~ , n-butyl, isobutyl, 1-methylpropyl, t-butyl, 10 pentyl, 1,1 di~ l.ylpropyl, 2,2~imethylpropyl, octyl or 3,3-dimethylbutyl.

Particularly p~r~ d among Formula (m) compounds are those in which R2 is l-methylpropyl, n-butyl, isoyçoy~l, n-pentyl, 3-methylbutyl, 2,2-dimethyl-propyl, t-butyl, l,1-dimethylpropyl, isobutyl n-octyl, tert-pentyl, n-propyl, methyl 15 or 3-3-di-c~l~lbutyl.

Partieularly p-cfel-cd among Formula (III) comyound are:
17~(isobutylcarbonyl)-estra-1,3,5(10)-triene-3-carboxylic acid, 17B-(octylc~bollyl)-estra-1,3,5(10)-triene-3-earboxylie aeid, 17B-(tert-~,c"lylcall,onyl)-estra-1,3,5(10)-triene-3-earboxylie acid, 17~(2,2-dill.clllylpropylearbonyl)-estra-1,3,5(10)-triene-3-earboxylic acid, 17~(propylcarbonyl)-estra-1,3,5(10)-triene-3-carboxylic acid, 17~(methylearbonyl)-estra-1,3,5(10)-triene-3-earboxylie aeid and 17~(3,3-dimethylbutylearbonyl)-estra-1,3,5(10)-triene-3-earboxylie aeid and ph~ eeuticplly aeeeptable salts, hydrates, solvates and esters thereof.

The term "", as used herein, follows s~nda~ chemic~l terminology and means down or that the co.l~,s~nding s~lb~ituent is attaehed belûw the plane of the paper.

~` ~, 94~nol2s 2 1 3 8 9 5 6 . ~ Pcr/us93/o6238 The term "B", as used herein, follows standard chPrnir~l terminology and means up or that the co~ ontling substituent is ~n~Çhp~d above the plane of the paper.
- By the term "alkyl", Cl naLlcyl and derivatives thereof and in all carbon 5 chains as used herein, unless otherwise definP~ is mean~ a Cl n linear or branched - carbon chain having 1 to n carbons. Examples of "aLtcyl" and derivatives thereof as used herein include: methyl, ethyl, propyl, 3-methylbutyl, isopropyl, n-butyl, isobutyl, l-methylpl~rl, t-butyl, n-pentyl, l,l~hllelllyllJl~y-l, 2,2-dimethyl-propyl, n-octyl, tert-pentyl and 3,3-dimethylbutyl.
By the term "treating" as used herein, is meant prophylatic or therapeutic therapy.
By the term "isobutyl" as used herein, is meant -CH2CH(CH3)2.
By the term "metal-catalyzed coupling reaction" as used herein is meant that the pl~ d 3-trifluc,l~,lllclllyl sulfonate or 3-fluorosulfonate cc.lllpound is reacted 15 in a s~lit~ble organic solvent, preferably toluenp~ dhll~tllylfol .~ ;tle or THF with a base, preferably a tertia,~allul,c base such as triethylamine, pyridine or tributylamine, a phov~ such as bis(diph~n~l~hosyhino)alk~ne~ preferably 1,3 bis(diphenylpho~hino)~l.,pane or tri-o-tol~l.ho~hinç, or a Cl 6alkOH, and a metal catalyst, preferably a p~ linm catalyst such as p~ Ail-m (II) aret~te p~llP~ m(II)chlorideorbis(~ h~nylrho~h;ne)p~ lmII~ret~te anda coupling reagent.
By the term "coupling reagent" as used herein is meant a cGIllpound which is c~p~ble of reacting with an aryl radical to form a carboxylic acid substituçnt Carbon mol o~ide is a p-cfel,~d couplin~ reagnet, which when added to the metal-catalyzed coupling reaction, as ~escribed herein, yields the desired carboxylic acid group.
Compounds of Formula (I) and compounds of formula (IV) are included in the pha~ re~ll;r~l collll)o~ilions of the invention and used in the methoA~ of the invention. Where a -COOH group is present, ph~T7n~r,eutir~lly acceptable esters can be employed, for eY~mple methyl, ethyl, pivaloyloxymethyl, and the like, andthose esters known in dle art for lllodi~ing solubility or hydrolysis characteristics for use as su~ .n~ release or prodrug f~mml~tionc~
The term "a-lec~p~ur ~nt~f~oni~t", as used herein, refers to a known class of alph^ an~l~ .,n~ ~ic l~eplol ~nt~goni~t co,ll.,unds, such as described in Lafferty, et al. U.S. Patent No. 4,963,547, which are udlized in treadng vascular disorders such WO 94/00125 ~ 13 8 9 ~ 6 - pcr/us93/o62?

as ~i~ktes, cardiovascular ~i~e~se, benign prostatic hyp~ .uphy and ocular h~, t~
~ d alpha-&-,d~ncr~ic l~cep~r antagonists for use in the compositions and ...~ of the invention include ~mculo~in~ terazosin, doY~7 )sin, alfuzosin, S indol~ , pr~70sin and 7-chloro-2-ethyl-3,4,5,6-tetrahydro-4-methylthieno[4,3,2-efJ[3]-~ ~inc By the term 'l~mslllosinll as used herein is meant a co.l,poulld of the .;lule CH3~CH2-CNHCH2CH2~

and salt~s, hydrates and ~solvates thereof.
C~hernir~lly, ~msulosin iS designated a~s (-)-(R)-5-[2-[[2-(O-etho~y~,henu~)ethyl]amino]propyl]-2~ ctl.o,.yL~.l.7~.e;,~lfon~mi~le.
~m~ulosin is disclosed in U.S. Patent Number 4,703,063 and claimed in U.S. Patent Number 4,987,125 as being useful in treating lower urinary tract d~r~ ;Q~.
By the term "tc,aLosin" as used herein is meant a compound of the structure ~`N' CH30~N ~N~J

CH30~ N

and salts, hydrates and solvates thereof.
~ 'hemic~lly, te~zosin is ~esigJ-~t~ as 1-(4-amino-6~7-rlimethoxy-2 q~ inyl)-4-[(tetrahydro-2-furoyl)carbonyl]piperazine. Terazosin is disclosed 25 in U.S. Patent Number 4,251,532.
By the term ~o~o:~;n as used herein is meant a compound of the s ~' ~ 94/00125 ~ 1 3 8 9 5 6 ' ` Pcr/us93/o6238 ~N{:O~O~
H3CO~N~NJ ~ ,~J

H3CO~ N

and salts, hydrates and solvates thereof.
~ hernir~lly ''~O~OS;~l'' iS desi~n~t~ as 1-(4-amino-6,7 rlimçthoxy-2-quin~7~1inyl)-4-[(2,3-dihydro- 1 ,4-be n ,~lioxin-2-yl)carbonyl]-piperazine.
Dox~7osin is d;~CQ1~1 in U.S. Patent Number 4,188,390.
By the term "alfuzosin" as used herein is meant a compound of the structure H3CO ~N ~N N

H3CO~ N

and salts, hydrates and solvates thereof.
Ch~rnir~lly alruzosin is design~ as N-r3-[(4-amino-6,7-dimethoxy-2-10 4~l;n~7~linyl)methylamino]propyl]tetrahyd~2-rwal~c~~ ;de Allu20sin is ~isclose~ in U.S. Patent Number 4,315,007.
By the term "indc,l~l~in" as used herein is meant a compound fo the structure 3~ ~ CH2CH2 N~}NHC~

15 and salts, hydrates and solvates thereof.
rhçmi~lly indoramin as desi~n~ted N-[[1-[2-(lH-indol-3-yl)ethyl]-4-piperidinyl]t~l- 7~ . . .i nP
Indola,l~in is disclosed in U.S. Patent Number 3,527,761.
By the term "pr~zosill" as used herein is meant a compound of the structure ~--N~
CH30~,~N ~NJ
I
CH30~ ~ ~`f N

and salts, hydrates and solvates thereo WO 94/00125 Z 13 8 g 5 6 PCr/US93/062?
.

mic~lly ~l~ZOSil~ is ~ sign~ed as 1-(4-amino-6,7-dimethoxy-2-4uh~a2O1inyl)-4-(2-furanylcarbonyl)piperazine.
Prazosin is lisclQsed in U.S. Patent Number 3,511,836.
"7-chloro-2-ethyl-3,4,5,6-tetrahydro-4-methylthieno[4,3 ,2-ef~ - -5 [3]~ ~ p;ne" as used herein is meant a co-ll~und of the structure a~N-CH3 ~< I~
S~CH2CH3 and salts, hydrates and solvates thereof.
7-chloro-2-ethyl-3,4,5,6-tetrahydro-4-methylthieno[4,3,2-ef~-[3]benzazepine is disclosed in U.S. Patent No. 5,006,521. Additionally, all co.llpoul-ds disclosed in 10 U.S. Patent No. 5,006,521 as alpha-a~ .,clgic r~c~tor antagonist are preferred alpha-a~e"llgic .~iceplor antagonist as used herein.

~ lsons skilled in the art can readily dele ..~;ne if a coll~>ound other than onc ~,ecifi,cally l~,r~ ,d to herein is a alpha-anL~n~,ic .~,ce~,lor antagonist by 15 ~ltili7ing the assay described in Lafferty 1. Thus, all such co-l-pounds are included within the scopc of the term "alpha-andl~ne.~ic ..,ceptor antagonist" as used herein.
By the term "minoxidil" as used herein is meant the compound of the structure:
o H2N~N ~NH2 N~J

chem~ y minoxidil is ~esign~t~d as 2,4-pyrimirline~ mine, 6-(1-piperidinyl)-,3-oxide. ~;-lo~ 1 is the active ingredient in Rogaine~9 which is sold as topical solution for stim~ ting hair growth by the Upjohn C`omp~ny, Kalama7oo, ~Sirhigan, The term "aru...-l~oe inhibitr~r", as used herein, refers to a known class of 25 co~ C, steroidal and non-steroidal, which prevent the conversion of androgens to esl,~g~ns, such as ~Psc~ in Gormley et al. Tnt~rn~tion~l Publication Number WO 9V18132. Alo...al; ce inhibitors are ~icclose~ in Gormley et al. as having ' -~ 94/00125 2 1 3 8 g 5 ~ PC~r/US93/06238 g utility in treating benign prostatic hyperplasia when used in cG~.Ibination with a 5-a-l~lu~t~ce inhibitor.
A plcrellcd ar~l,lat~se inhibitor for use in the compositions and methods of the invention 4-(5~6~7~8-tetrahydroimi~7o-[l~s-a]pyridin-s-yl)ben7on;nile S (fadrazole). Fadl~le is ~i~closed in U.S. Patent No. 4,728,645. Additionally, all co.-.l.vu ~Ac tiisclQsed in Gormley, et al. International Publication No. WO
92/18132 as having ar~-..OI~ce inhibiting activity are pl~rell~d ar~ ce inhibitors as used herein.
As used herein, when a dual inhihitor of 5-a-reduct~ce~ as described herein 10 and a further active ingredient or ingredients are utilized together, said 5-a-reAuct~ce inhibjtQr can be co-~dminist~red with said further active ingredient or ingl~;f..-lc~
By the term "co-~dminictering" and derivatives thereof as used herein is meant dther Cim~llt~neous :~lminis~tiQn or any manner of sepa-~le sequential 15 a~lrninic~tion of a 5-a-re~uct~cP inhibiting compouild, as described herein, and a further active in~lic~l or ingl~ c~ such as other compounds known to treat the disease states of acne vulgaris, se~ulll.ea, female hirsutism, male pattern b~l~ness, benign l,lus~l~ h~ ,hy or prostatic adenocar~inc.,na or cc,lllyounds known to have utility when used in cc,...bin3l;Qn with 5-a-re~uct~ce inhibitors. Preferably, if 20 the a~ministratiûn is not cimnlt~neous) the cc,lll~ounds are a~minict~red in a close time ~ru~ y to each other. Furtr,~ .ole, it does not matter if the cc..l.pollnds are ~ d in the same dosage form, e.g. one co-,ll)ound may be a~minictered topically and another coll.poul.d may be a~lminictered orally.
The novel co.l.pou"ds of Formula (II) of the present invention can be 25 l,r~,p~id by methods oullincd in scl.ellles 1-4 below and in the Examples from known and readily available estrone which has the formula:

H~
or from the 17~carboxylic acid analogue of estrone, which is known and readily available.

W O 94/001252 1 3 8 Y 5 6 PC~r/US93/062~

.SchemeI
f`~, HO~J

(a) CN

~[~"~ NaOH
CH~-~O HCI
(b) CN

(m~UgBr, MgCl,or Li) ~~ (Grignard Reagent) HO HCI
(c) "'~ 94/00125 2 1 3 8 9 ~ PC~r/US93/06238 C-R

J ~ triflurjru,-,u~l,anes~llfoni^anhydnde (d) ~CR

0 ~ bis(diphenylphosphino)propane Il ~ triethylamine CF3~0 C1 6alkyl alcohol D palladium(ll)acetate (e) ~R

C,~alkyl ~ ( J ~C03 (~) ~CR

213895~
W O 94/00125 ~ PC~r/US93/062~' SchPm~ I oullines formation of Formula II COu~ ds. As used in scheme I co~ o~Jntl (b) is IJl~al~,d from coulpolu~d (a) according to the procedure of Baldwin, et al., J. Chem. Soc. (c), 1968, 2283-2289.
Cc,lul~ou"d (b) is then stirred in an ap~lo~liate organic solvent, preferably 5 methanol, with a base, preferably sodium hydroxide, and then acidified to yield c~ pou~.d (c). Cc,. . -l~o~ (c) is next treated with a Grignard reagent, described hereinbelow, or a lithium reagent in an a~pl~liate organic solvent, preferably tetraLy~ ru,~n or diethylether solvent, preferably at reflux Ic.llpc,alu~e to yield formula (d) cQ...~ rls A formula (d) cc,-llpo~ d and a base, preferably 2,5-di-t-butyl-3-methyl-pyridine in an applupliate organic solvent, preferably dichloromethane, is cooled to -20C to 20C, preferably 0C, and reacted with a trih~lo~lkyl sulfonic anhydride, preferably trifluor~ nesulfonic anhydride to form compounds (e).
Formula (f) cou,~>ounds are l,l.,pared by reacting a formula(e) colllpound i 15 a metal catalyzed coupling l~iacl;~n Preferably a formula (e) compound dissolved in &l~ hylformide (DMF) an or~anic base preferably, triethylamine, a phosphine, prefe~rably bis(diphenylllhQ~l.;..o)~,u~,~nc, a p~ (lium(II) compound, preferably, p~ iunl(II) ?set~te, and a Cl 6alkyl alcohol (Cl 6aLkOH), followed by addidon of carbon u ono~ide (CO). Cc,...pou -ds (f) next are reacted with a suitable base, 20 preferably pol~ss;.~.. c~l~nale, and ;~ci~lifie~d to yield compounds (g).

94/00125 ~13 8 9 5l3G PCI`/US93/06238 - SCHF~F, II

fluorosulfonic anhydride (d) O

bis(dl~benylvhosphino)propane FO2SO triethylamine C1 6alkyl alcohol (h) palladium(ll)acetate CO

~R

C,~alkyl O~ J H

(f) ~R
~.
,W~J
HOOC
(9) S~h~mP. II c~u~ es formation of Formula II cc.~ ,ounds. The starting ma~ials in SChçm~ II are formula (d) co,ll~unds ~ d as described in Scheme WO 94/00125 ~ 1 3 8 9 5 ~ Pcr/US93/0623 As used in Sch~-mr II, a formula (d) co,ll~und and a base, preferably 2,5-di-t-butyl-3-methyl-p~l;dil~e in an applo~l;ate organic solvent, preferably dichlo~...~ ne, is cooled to -20C to 20C, preferably 0, and reacted with fluorosulfonic anhydride to form co."pounds (h). Formula (f) compounds are S pl~,"~cd by reacting a Formula (h) cc.~ uund in a metal-catalyzed coupling ;Ql~ Preferably a Formula (h) co,--~u~-~ is dissolved in dil"ethylformide (I)MF) an organic base preferably triethylarnine, a phos~hine preferably bis (di~J~.e~lyl~ho~inc)p,~palle, a p~ m(II) col~pou"d, preferably, p~ ium(II) acetate, and a Cl 6aL~yl alcohol (Cl 6aLlcOH), followed by addition of carbon 10 .~.ol~o,.i~le (CO). Co...po~nds (f) next are reacted with a s~lit~ble base, preferably po!~csiu~.. c~l,onate, and ~irlified to yield compounds (g).

94/0012S 2138 9 5 B ~ i ; Pcr/uss3/o623 SchemP m ~(j) ~ \ RDUTE3 C ~alld~C (m) ~20H \ c5(2-PYr) ~CS~2 Pyr) ~2~r) C

alkO2C (n) (k) r~ CR

G~

~S
H~ (9) Sçhe-mP m outlines formation of Formula II co~ )ounds. As used in SchP-mP m Rl is CF302SO- or F02SO-. As used in scheme III in the alkylation process (step C), the pyridylthio ester is reacted with an LiR or an XMgR (X=Cl,Br) Grignard reagent (as ~lPs~ibe~l hcl~ ~nbclow), preferably isobutylm~..f Si bromide, n-octylm~..e-~ ", ehlori~le, tert-pentylm~nesiom chloride or 2,2 10 dimethyl~lu~ ~es;~ ~. bromide, preferably in tetrahyd~ n to forrn the desired pluducl, preferably 1713 (isobutylca.l~"yl)-estra- 1 ,3,5(10)-triene-3-c~l,ù~ylic acid, 17~(octylca~bu.~yl)-estra-1.3.5(10)-triene-3-carboxylic acid, 17B-(~-pentylcarbonyl)-estra-1,3,5(10)-triene-3-c~l,u~ylic acid, or 17B-(2,2-W O 94/00125 2 1 3 8 9 5 6 `~ - PC~r/US93/0623' dill.~lhylp~up~llcdllJon~l)-estra-1,3,5(10)-triene-3-carboxylic acid l, s~ccL ~rely in one or two steps.
In Route 1, the 3-hydroxyl acid (i) is converted to the 3-triflw.lulne~.ylsulfonylate or 3-fluorosulfonylate derivative (j) (step A) by treating 5 (i) with trifluor~ln~ ylsulfonyl anhydride or fluorosulfonic anhydride and an amine base, such as pyridine, preferably 2,5 di-t-butyl-3-methyl-pyridine, in anal.l,lo~liate organic solvent, preferably dichlc~lu...~ ne at about -20C to 20C, re~ably0.
The activated ester (k) is produced (step B) by treating (j) with 2,2-10 dithiopyridyl and lli?he"ylpho~hinc in an ~l~n,~liate organic solvent sûlutionpreferably, tetrahydlorulan/toluene at roûm te~ ulc for about 8-14 hours.
The 17-acyl derivative (1) is produced (step C) by treating (k) with a Grignard reagent, deccnbed hereinbelow, in tetrahydl~orulan or diethyl ether solvent, at a le~ U1G of about -50 to -70C, for 1-16 hours.
The 3-alkyl ester (f) is ~çoduced (step D) by treating (l) under carbonylation conA;I;Qnc, preferably by bubbling carbon Illono,~ide gas through a solution of (1) in an ap~rop,iate organic solvent, preferably ..~lh~nol, cor.~ining palladium acetate catalyst, tli~hcnyl~.ho~l.;ne, and a tertiary organic amine preferably triethylamine at about room ~ alule for 1-16 hours. Coll-lJounds (f) next are reacted with a 20 sl~it~ble base, preferably l)otAcs;l.... call~nale and ~lifi~A to yield compounds (g).
Colll~unds (g) can also be produced (step G) by treating (I) under call,w~ylation conditions, preferably by bubbling carbon monoxlde gas through a solution of (1) in an an a~lul,liate non-~lcoholic solvent, preferably DMSO, contS~il-i--g a p~ lm catalyst, preferably p~ll3dillm (II) ~ cet~te and 1,1-25 Bis(diphenyll.ho~h;no)r~,.lvc~ne (DPPF); and a base, preferably pot~csium acetate,preferably at ihlcl~ascd ~ul~lalul~,s.
Route 2 involves converting the starting steroidal acid (i) to the 3-trifluulollleullylsulfonylate or the 3-fluorosulfonylate derivative (j) by the above-described step A; c~l~n~lating (j) to (m) by step D; fom~ing the activated 2-30 pyridylthio ester (n) by step B; forming the 17-acyl coul~ound (f) by step C; and hydrolyzing the 3-ester to the 3 acid final product (g) by step F.
Route 3 involves converting the starting acid (i) to the activated ester (o) by the above~es~ibe~ step B; forming the 17-acyl compound (d) by reacting (o) by thc above ~escribe~d step C; converting (d) to the 3-llinuoloulethylsulfonylate or 3-35 nu~:,ulfonylate derivative (1) by the above-describe~ step A; and converting (1) to ~ 94/00125 2 1 3 8 9 5 6 : : PC~r/US93/06238 the ~nal product (g) by the above described step G or by the above-described step D followed by the above described step F.
Sch~mt IV
CN TrifluGro",etl,anesulfonic anhydride ~~ /

(c) _ CN bis(diphenyl,~,hosphino)propane triethylamine ~ methanol CF3~f / p?"A1i~rn (Il) acetate (P) CN

~ ~ iBu2AlH

C, {~6alkylo2 (q) CHO

MR
~J (M=MgBr, MgCI, or Li) (Grignard Reagent) (r) WO 94/00125 2 1 3 8 9 5 6 ~ PCI`/VS93/062.

HO\~R

HO ~ l i Oxidation (s) 0~
~R

Ho2J~J

(9) S Sch~-me IV oull;nes fo~n~tion of Formula II co.l.pounds.
As used in Sçheme IV in the aL~ylation process (to p~ , cc ,llpollnds of Formula (s)), the ca,l)oA~ hyde is reacted with an Li-R or an XMgR (x=Cl, Br) Grignard reagent (as described hereinbelow), preferably propylm~gne-cium bromide, methylm~. e ~ bromide or 3,3-dimethylbutyl m~gnesillm chloride, preferably in tetrahydl~rul~l to form the desired product, preferably 17B-(propylcarbonyl)-estra-1,3,5(10)-triene-3-carboxylic acid, 17~(methylcarbonyl)-estra-1,3,5(10)-triene-3-c&-l~Aylic acid, 17B-(3,3-dimethylbutylcarbonyl)-estra-1,3,5(10)-triene-3-carboxylic acid le;,~ecLi~ely, in one or two steps.
The starting rnaterial in Scheme IV is Formula (c) cc-~-~ound ~ a~cd as in Scheme I.
As used in Scht~m~o- IV, a Formula (c) colll~Jou.ld and a base, preferably 2,5-di-t-butyl-3-methyl-pyridine in an a~l~ç~p~;ate organic solvent, preferably dichlo.u..-~-th~n~., is cooled to -20C to 20C, preferably 0C, and reacted with a lnh~lo~lkyl sulfonic anhydride, preferably trifluulullle~ neslllfonic anhydride to 20 formc~ c (p).
Formula (q) co.npou-lds are ~ d by reacting a Formula (p) compound in a metal catalyzed co~lpling re~tion Preferably a Formula (p) compound dissolved in di l.~tl.ylformide (DMF) and organic base preferably, triethylamine, a ~- ) 94/00125 ~ 1 3 8~ 5 ~ PC~/US93/06238 phosphine7 preferably bis(diphenylphosphino)propane, a p~ um(II) compound, preferably, p~ ium(II) r ~ et~te, and a C1-C6aL~cyl alcohol (Cl-C6aLkOH), followed by s7~ ition of carbon monoxide (CO). Formula (q) colllpounds are reacted with a reducing agent, preferably diisobutyl~lu~.~in~ hydride, to yield S Formula (r) col~ ntlc Formula (s) coulpounds are produced by treating Formula (r) compounds with a ~ignard reagent (as described in Sch~me III) or a lithium reagent in tetrahy~llùrulan or diethylether solvent, at a teull~eialule of about -50 to -70C, for 1-16 hours.
Formula (g) cc~ x~ul ds are p,ep~Gd by oxidation of Formula (s) u.,~ ounds. Preferably said oxi~tion will utilize a Jones reagent or tel~lu~ on;l.~- perruth~ te followed by sodium chlorite.
Grignard reagents of the type, XMgR, (where R is Cl 20 linear or branched, ~tllr~t~ or unsaturated alkyl) for use in ylcp~il~g all of the species included 15 within the scope of this invention, are available or can be made readily by one skilled in the art.
Formula I cc"llpoullds in which Z is in the a position are pl~ucd from co.lll)ounds which contain the cc,ll~ nding ~ substituent by the General Method below.
(~ener~l Me~hod A
To a stirrred solutinn of a sub~ ul~d 17~ steroidal dual 5a-reduct~ce ibiting col..l~l.nrl of Formula (II) in an ap~,lop.iate solvent, preferably ethylene glycol or dilll~ yl sulfoxide, is added a base such as a hydroxide or alkoxide base, 25 preferably sodium hydroxide, pot~ccium hydroxide or sodium methoxide, at a hlll~ alulc over 100C preferably at reflux t~ atulcs to yield the cc~ g a epimer, after icol~tion and work up.
In ~te~ ng the a~l~-iate solvent for conducting the el)illle~ a~ion, dimethyl sulfoxide or other non-reactive high boiling solvents are l~le~l~,d when 30 the starting 17B dual 5a-l~lul~! ce inhibjting steroidal colllpound cor~t~ins reactive cn~c or reactive unsalulated bonds that are, for ex~mple. subject to nu( leophilic attack and ethylene glycol, or other reactive high boiling solvents can be used when the reactivity of the s~bs~ e ~tc or any unsaluu~ted bonds of the star~ng 17B dual Sa~ nhibiting steroidal col.l~und is not a consideration.

2138g56 WO 94/00125 Pcr/us93/0623 Also within the scope of the present invention are the ketone reduction ~ducls of I, the SGCQr~ y alcohols of the forrnula (IV):

11~--H-~C (IV) 5 ~l,~;n Y is ~ or ~
OH
--C--R
in which R is C1 20 linear or br~n~he~, salulated or unsaturated alkyl and phal...q-e~ qlly acceptq-blc salts, hydrates, solvates and esters thereof.

F~c,f~ ,d among the pl~senlly invented ketone reduction products described above are the se~ondary ak,ohol~ ~l,erein the OH
C--R sU~ostitllent iS in the 8 position.

Particularly ç,l~f~,.l~ among the pl.,selllly invented ketone reduction productsdescribed above are 17~(1-hydroxyethyl)-estra-1,3,5(10)-triene-3-carboxylic acidand 17~(1-hydroxybutyl)-estra-1,3,5(10)-triene-3-call,oyAlic acid.
These c~ .po~ can be made by convention-q-l sodium borohydride reductic n of the call~nyl atts~hed to R without eFimeri7~tion of the 17 substituent or reducin~ the carboxyl in Ring A or the aromatic A ring.
The borohydride reductiQn can be ca~ied out in e.g. water or aqueous m.oth~nol at a u,~e.atu~ of room t~...pe ~ture to 50C and the product then isolqtyl and purified by conve~ltion~l means. The colll~unds are also active as dual inhibitors of 5-alpha re(1nct~ce By the tem~ "ir,cl~ased ulllpe~a~ s" as used herein and in the claims is 25 meant above 25C, preferably at reflux u .~p,.~tures.
By the term "solvent" or "a~p~opliate solvent" as used herein and the in the claims is meant a solvent such as methylene chll ride~ ethylene chloride, chlorofc.l~, ethylene glycol, carbon tetrachloride, ~etrahydr~rul~n (1~), ethyl ether, toluene, ethyl q-cetLq-te7 dimethylsulfoxide (OMSO), N,N'-dimethyl-N,N'-" ~ 94/00125 2 1 3 8 9 5 6 : PC~r/US93/06238 propylene urea, N-methyl-2-pyrroli-linor-e7 meth~nol~ isopropylalcohol, di~ hylru~ ff;), h~y~n~, water, pyridine, quinoline or ethanol.
ph~ ;c~lly acceptable salts, hydrates and solvates of Formula (I) and Formula (IV) co..~ n~s are formed, where apl,lol,liate, by methods well known S to those of skill in the ar~
In pl~uing the ~ serlly invented compo~ ds of Formula (I), novel ir,t~ r~ c s of the Pormula (V) are synthesized;

~R

4 ~ ~ (V) 10 in which R is C1 20 linear or bran~h~ sdlLuatcd or unsaturated alkyl and R4 is fluorosulfonyloxy.

Also ~lefe.l.,d in synthecicing the ~l~;st.llly invented formula (I) compounds were novel L~lc....e~ tes of the formula (VI):
O~H

in wbich R is as ~ec~il~l in foqmula (II).

A ~l~çcllcd~Jl~e5s for ~lc~J~ing a cc,lll~uwld of Formula WO 94/00125 2 1 3 8 9 5 6 Pcr/llS93/062~

.
C-R

(II) in which R is C1 20 linear or br~nclled, saturated or unsaturated aLkyl and pharmacentir~lly r~rept~ble salts, hydrates, solvates and esters thereof comprises 5 reacting a compound of the formula o R

HO
in which R is as described above with fluulosulfonic anhydride and a base, l~ere.~bly, 2,5-t-butyl-3-methyl-pyridine, in a solvent, preferably dichlorornethane, to form a co~ vund of the formula o ~R

FO2SO ~----in which R is as described above and subse.luently reacting said coll-pound in ametal-catalyzed coupling reaction in the pl.,sence of an applv~ te coupling reagent, preferably, carbon ll.ono~ e followed by an optional, if applic~ble, hydrolysis reaction to fvllll a colllpou- d of formula II, and thc earlcr optionally 15 folllling a ~,ha~".Ac~.lt;~Ally acceptable salt, hydrate, solvate or ester thereof.
RCC~Il~ the pl~s~ ly invented ph~ .r~ ;c~lly active colllpoullds are potent dual inhibitors of stervid 5--re~ ct~ce activity, they have th~e.l~,c utility in treating ~ ces and conditionc ~l~;n decleases in DHT activity produces the desired lh~a~Lllic effect. Such rlise~es and conditionc include acne vulgaris, ~ ~ 94/00125 2 1 3 ~ ~ 5 ~ PC~r/US93/06238 _ebullhca, female hirsutism, male pattern b~l-lnl-sc~ u~le dise~ces such as benign plU~tiC l,~ lophy, and prûstatic adenocarçinom~
In dete ~ .;ng potency in inhibiting the human 5a-re~luct~ce enzyme, the following ~JlVC~ was employed:

;on of ~n~.ml~n~ tt~s used ~c source for recombinant steroid 5a-~educt~c~. isowme 1.
C~hinese h~ e. ovary (CHO) cells col l~;ni--g c~ ssed, recombinant human steroid 5a-~ el~ce isoenzyme 1 (Andel~son, S., Re~n~n, D.M., Jenkins, 10 E.P., and Russell, D.W. (1991) Nature 354 159-161) were homogeni7~ in 20 mM
pot~csi-lm pho~hate, pH 6.5, buffer co.~ ing 0.33 M sucrose, 1 mM
lith~ h~ ol~ and 50 pM NADPH (buffa A) using a Dounce glass-to-glass hand ho,--oge~-;7f,l (Kontes Glass Co., Vinel~nd N.J.). Membrane par~icul~tes were icols~ted by cer~tl;rugation (100,000 x g at 4C for 60 ,,.il~u~s) and resncpended in 20 mM potAss;-.. phosphate, pH 6.5, c~ in;ng 20% glycerol, 1 mM
lithiû!h.eilol, and 50 yM NADPH (buffer B). The sucpende~ particulate solution was stored at ~0C.

P~ ,..i.t;oll of ~lo~ ;r ~ .nhl~n~ t~c med ~c source for steroid 5a-redurt~c~ icr.~
Frozen human plo~ s were thawed and minced into small pieces ( Brink~n~nn Polytron (Sybron Corp., Westbury, New York). The solution was sonir~te~l for 3 to 5 ~ n~tcs with a Sonifier (Branson Sonic Power Co.) followedby hand homogeni7~tion in a Dounce hand homogenizer. Prostatic particles were ob~ned by difr.,., r,tial cellllirugation at 600 or 1000 x g for 20 minutes and 140,000 x g for 60 ,n;nv~s at 4C. The pellet Gbtained from the 140,000 x g c~ .ifugation was washed with 5 to 10 tissue volumes of the buffer described above and cenl.ifuged at 140,000 x g. The resulting pellet was suspe-n~ed in buffer B and the particulate 5~C~nciol~ was stored at -80C.
.~I ;or of membr~ne p~r~ic~ t~.s used ~c source for recomhin~nt steroid 5-a-r~,.lu~l~c~ "-~ 2.
Chinçse h~ ~t~. ovary (CHO) cdls co~ n;ng eAy~ssed~ recombin~nt - human sterûid 5-a-lcd~ e isoL~llle 2 wae homog"ni7~ in 20 mM pot~csillm pko~yh~ pH 6.5, buffer cQnlain;ng 0.33 M sucrose, lmM lithio~h~Gitûl~ and 50 ,uM NADPH (buffer A) using a Douce hand homogenizer. Membrane particulates WO 94/00125 2 1 3 8 9 5 6 PCr/lJS93/0623 con~ ng the ~cc,.~.h;l-Anl human enzyme were i~l~ted by centlifugation (100,000 x g at 4C for 60 .l~;n~lcs) and lc~ en~ed in 20 mM pot~ccium ~ho:~.hAIe, pH 6.5 co~ n~ 20% glycerol, 1mM ~iithiothreitol, and S0 yM
NADPH (buffer B). The sucpendç~d paniculate solution was stored at -80C until S used.

ACC~Y for ~ ct;nl;es ~n(l inhibitors potency.
A CQ~ mo~ t of [14C]~ s~ one (S0 to SS mCi/mmol) in ethanol and varying A.llolJ~ of pot~ 1 inhibitor in ethanol were deposite~ in test tubes10 and concenl.~t~l to dryness in vacuo. To each tube was added buffer, 10 11L
(lccolllbin&nt isoenz~rllle 1 or isoenzyme 2) or 20 )lL (isoenzyme 2 from human .s~le tissue) of 10 mM NADPH and an aliquot of a steroid Sa-re~uctrce yl~palalion to a final volume of O.S mL. Assays for human steroid Sa-re~uct~ce is~nL~llle 1 were co~ ct~ with a sample of the leco.nb;~-~nt protein eAyl~sied in 15 CHO cells in S0 mM phosph~te buffer, pH 7.5 while assays of isoenzyme 2 were co-~uc~ed with a s,"~ c:~ n of human l,lo~lic par~irul~tes and/or recombinant protein eA~ sed in CHO cells in S0 mM citrate buffer at pH SØ
After incllb~ting the sol~ltion at 37C for 20 ~ ~0 minutes the reaction was ~lu.,nehed by the r dAitior~ of 4 mL ethyl acetate and 025 ,umol each of tÇStO~ un 20 5a dih~ c slQste-~nc, andlusl A np~diol, and andrc,s~ ~nedione as carriers. The organie layer was removed to a seeond test tube and e~pol~ted to dryness in a Speed Vac. The residue was dissolved in 40 pL ehlolufGl-ll, spotted on an individual lane of a 20 x 20 em prechænnPlle~d silica gel TLC plate (Si 250F-PA,BakerChem~ )anddevelopedtwicewith~ ne:chlolofo~ 9). The 25 r~Aioch~mir~l eo~tent in the bands of the subst~ate and the products wac A~,t~ ;n~d with a BIOSCAN Im~in~ Se~nn~- (Biosean Inc., W~chin~on, D.C.).
The ~..,ent of r~u.~l.,d r~ Phel eonverted to product was ealculated, from whieh enzyme aetivity was dlvtel...;n~ All inr~b~tions were conA-let~ such that no more than 20% of the substrate (testosterone) was eonsllmed The e"~,;"--, ~t~lly ob~;n~ data wac coll~ule. fit to a linear function by rlottin~ the lecip,oeal of the enzyme aetivity (1/veloeity) against the variableinhit-itnreo~.cc~.l.alion; app~e. tinhibition cor~ ,app) were dele.mii ~d by the Dixon analysis (Di~con, M. (1953).
The value fc~r the inhi~ition eonst~nt (Ki) was ~ælcul~te~l from known I~lur~s (Levy, M. (1989), Rioehr.~ 2815-2824).

~ o 94/00125 2 13~95 6 . ; Pcr/us93/o6238 All of the compou,lds within the scope of this invention are useful in inhibiting steroid 5-o~-reAuc~e isozyme 1 and steroid 5-o~-reductase isozyme 2 in a ..~qn..l.~l, including h-lm~nc, in need thereof.
Cc,ll,?o~l"ds within the scope of this invention have been tested and have S shown an activity of fr~m 15 Ki(nM) to 180 Ki(nM) against isozyme 1 and an activity of from 0.5 Ki(nM) to 30 Ki(nM) against isozyme 2. Particularly preferred among the cG,l,~ul,ds of the invention and the coml)o~ ds used in the invented pharmaceutical cc~q~ ;o~c and invented m~thlYls are 17B-(isobut,vlcarbonyl)-estra-1,3,5(10)-triene-3-carboxylic acid, 17B-(octylcarbonyl)-estra-1,3,5(10)-triene-3-carboxylic acid, 17~(tert-pentylcarbonyl)-estra-1,3,5(10)-triene-3-carboxylic acid, 17~(2,2-LIllell,~,lpl~?ylcarbonyl)-estra- 1,3,5(10)-triene-3-carboxylic acid, 17B-(propylcalbonyl)-estra-1,3,5(10)-triene-3-carboxylic acid, 17~(methylca,1~nyl)-estra-1,3,5(10)-triene-3-carboxylic acid, 17B-(3,3-dimethylbutylca. bollyl)-estra- 1,3,5(10)-triene-3-carboxylic acid, 17B-(1-hydl~ elllyl)-estra-1,3,5(10)-triene-3-carboxylic acid and 17B-(l-hydl~AybuLyl)-estra-1,3,5(10)-triene-3-carboxylic acid.

The pharmace~ir~tly active c~ of the present invention are 20 in~l~lale~d into cc,l,.,~,n,enl dosage forms preferably as c~ps~lles tablets, or injectable ~l~sla~ons. Solid or liquid pha..n~ctul;r~l carriers are employed.
Solid carriers inclllde, starch, lactose, c~lcillm sulfate dihydrate, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, maE;~es;~ stearate, and stearic acid. Liquid carriers include syrup, peanut oil, olive oil, saline, and water. Similarly, the carrier 25 or diluent may include any prolonged release mqseri~l, such as glyceryl losr~ ~- ale or glyceryl 1i~te~rate~ alone or with a wax. The amount of solid catTier varies widely but, preferably, will be from about 25 mg to about 1 g perdosage unit. When a liquid carrier is used, the plG~)alaLion will peferably be in the form of a syrup, elixir, em~llsion~ soft gelatin capsule, sterile injectable liquid such 30 as an ampoule, or an ~queous or nonaqueous liquid sua~.enaion.
The ph~...A ,eutir~l pl~"p~ ;on~ are made following conventional techniques of a ph~... ~l~e.l~;c~l ch~mi~t i"~lring mixing, gr~n~ tin~, and colllplesaing, when n~css- y, fortablet forms, or mixing, filling and dissolving the ingrei~lent~, as a~ 0~ ;Ztc;, to give the desired oral or pa~1nte.~1 products.
Doses of the pl~,Senll~l invented ph~m~rentir~lly active cc,lnl)ounds in a ~h~ ~ eutir~l dosage unit as described above will be an effiracious, nontoxic wO 94/00125 2 1 3 8 9 5 6 ` Pcr/US93/0623~

4U~I~ly preferably selecte~A from the range of - -0.1 - 1000 mg/lcg of aetive collll,uund, preferably li~0 mg/kg. When treating a human patient in neGd of steroid 5-a-redue~ce inhibi~ion, the sele~ted dose is a 1...;.~ .~l preferably from 1-6 times daily, orally or pdrenlel~lly. P~GÇ~llcdS forms of p~nt~l~l a~minictration inelude topieally, reetally, transdermally, by injeetion and eo~lh~vo~cly by infusion. Oral dosage units for human, lminictration ~ f~ abl~ eontain from 1 to 500 mg of aetive co~ ,ou"d. Oral ~tlminictration~
whieh uses lower ~osqg~s is p.~,f~ d. P~Gnlcl~l a~lminictration~ at high dosages, k~ ,l, also ean be used when safe and eonvenient for the patient.
The ~ ho~l of this invention of inhibiting steroid 5-a-reA~lct~ce isozyme 1 and steroid 5-a-re~ e iS02~llle 2 aetivity in ,..~...,..~lc, ineluding hllm~nc, eomprises ~ln~n;~;ng to a subjeet in need of sueh inhibition an effeetive dual inhibjting amount of a eo...l o~n~ of the present invention.
The invention also provides for the use of a colllpound of Formula (I) or a 15 c~ ovn~ of Forrnula (IV) in the ,~ ,.r~ .G of a m~Aie~ment for use in the dual inhibjtion of ster ~d 5-a-red~let~e The i..~erl~on also provides for a ph~ ;c~l comrosition for use in the t of benign IJlu~tG h~ lophy which comprises a coln~und of Formula I or a eo~ of Formula (IV) and a pharmaeeutirslly r ept~ble carrier.
The invention also provides for a ph~.. ~e~";r~l ec.. pos;l;oll for use in the nl of ylO~IiC r dcnoc~ ~,inollla whieh COIlllJl;SeS a eolllpound of Formula I
or a cc~lll~ui-d of Formula (IV) and a pha,...~^eul;rs~lly aeeeptable earrier.
The invention also provides for a proeess for plepa,il-g a ph~lllace~l~ical eo...l-os;l;on eo.ll~;n;n~ a l,k-- ".seeul;r~lly n ~ r ~le earrier or diluent and a 25 e~...l)o~i-~ of Formula I or a ecnl~uul~d of Formula (IV) whieh eompnces bringing the eolll~und of Formula I or the eom~und of Formula (IV) into association with the pha,...~e~.~l;eslly aeeept~hle earrier or diluent.
No un~r~eptable toxieolegieal effeets are experted when colllpoullds of the invention are ~ lminictered in acco~ance with the present invention.
In r1-1itiQn the pharmaeeu1;rslly aetive colnpounds of the present invention can be eo-adminictered with further aetive ingreAi~ntc, sueh as other col-ll)ounds known to treat the disease states of acne vul~ans, se~ollLca, female hirsutism, male pattern b ~ ness benign prostate h~ u~hy ~r prostatic ~enoc-~.;inoma or ec,lll~unds known to have utility when used in eo...~ t~n with 5-a-reAuet~ce 35 inhibitors. Partieularly pl~fe.l~,d is the eo-a(lminict ation of a dual S-a-reA~uetAce inhi~it~r, as f1i~clQseA herein, and minoxidil for use in the I~ ...f nt of male pattern ~ ~ 94/0012~ 2 1 ~3 8 9 5 ~ ~ PCr/US93/06238 b~l~n~ss Particularly p,efel~d is the co-adminictration of a dual 5a-re~ ct~ce inhibit -r, as l1icclose~l herein, and a -r~cepl~l antagonist for use in the llc~ nt of benign prostatic hy~,h~JlJhy. ~cr~"lcd iS the co-arlmini~tration of a dual 5-a-,~Ju.~-ce inhibitQr, as disclosed herein, and an aromatase inhibitor for use in the 5 ~ t of benign plO~tiC hyl c.llophy. ~cfe~l~d is the co-~dmini~tration of adual 5--reduct~ce inhibitor~ as ~lisclQse~l herein, a a -r~c~ptol antagonist and an alo~ ce inhibitQr for use in the ll~al...~ ~t of benign prostatic hy~ luphy.
Without further elaboration, it is believed that one skilled in the art can, using the plec~ g d~s~..;ption, utilize the present invention to its fullest extent.
10 The following Examples are, ~ rtrorc. to be construed as merely illustrative and not a limit~tion of the scope of the present invention in any way.

FXAMPT .F. 1-co--cs~ondin~ to Scheme IlI
17B-I~obutyll~..l,or,yl-estra-1 ~.~(10)-tnene-3-carboxylic Acid (i). S-(2-pyridyl)-3-hy~y-est~a-1,3,5(10)-triene-17B-thioc~bo~.ylate.
A .. i~lulc of 3-hydroxy-estra-1,3,5(10)-triene-17B-carboxylic acid (0.11 g, 0.37 mmol), 2,2'-diipyridyl tliculfi~e (0.163 g, 0.74 mmol), triphenylphosphine (0.19 g, 0.74 mmol) and dichlc,lo...et~.~n~l (20 ml) was stirred at ambient k~ , under argon for 4 hours. The reslllting solution was concentrated and 20 the residue was cl.lo~c,E;.~hcd (silica gel, eluting with 25 % ethyl acetate in hexane) to provide 0.13 g of the title co..-pound as a white solid, mp 195-196C,~"~ lli7ed from ethyl acetate - m~th~nol).

(ii). 17B-Isobutylcarbonyl-3-hydroxy-estra-1,3,5(10)-triene.
Isobutylm~n~.;l.. bromide (2.3 mL; 2M in diethyl ether) was added slowly to a solutiQn of S-(2-pyridyl)-3-hydroxy-estra-1,3,5(10)-triene-17B-thioca,l~A~late (0.60 g, 1.53 mmol) in tetrah~dluru-~n (20 mL) at -78C. After 1hour, the Illib~lU~ was ~lu~ nch~ with salu.alcd aqueous NH4Cl and extracted with cthyl acetate. The organic extract was washed with brine, dried, and concenl . ~ted.
The r~s~llhng residue was chromato~ hcd (silica gel, eluting with 15% ethyl acetate in hexane) to give a foam. Trituration with diethyl ether and hexane gave a white solid (0.27 g).

(iii). 17~Isobutylca,l~n~l-estra-1.3.5(10)-triene-3-trifluo.~ hylsulfonate.
To a cooled (0C) solution of 17~Isobutylc&-l~nyl-3-hydroxy-estra-1,3,5(10~triene (0.28 g, 0.82 mmol) and 2,6-di-tert-butyl-~methylpyridine (0.17 WO 94/00125 2 1 3 8 9 5 6 I PCI/US93/0623~

g,0.83 mmol) in dichlc"~ hqne (20 ml) was slowly added trifluolo~ lhqne sulfonic anhydride (0.23 g, 0.82 mmol). The res~llting so!lltion was stirred at 0C
for 1 hour and then at ambient ~In~e.alule of 30 .n;~ es The reaction ~h~lulc was washed with dilute HCl, water, dilute ~aHC03, brine dried and conccrlllalcd.5 The res~lhing residue was chrf u~alc,~hed (silica gel, 7% ethyl acetate in hexane) to pl~ide 0.13 g of oil.

(iv). Methyl-17~isobutylca~1~nyl-estra-1,3,5(10)-triene-3-carboxylate.
A u~lulc of 17~isobulylc~l~llyl-estra-1,3,5(10)-triene-3-10 hinuo~uuu~ "rlsulfonate (0.13 g 0.28 mmol), pqllq~illm (II) acetate (4.2 mg, 0.0187 mmûl), 1,3-bis(diphe,n~ .hosI-hino)l,lù~ e (dppp, 7.5 mg, 0.0182 mmol), h;cll~yla"~il c (0.08 rnL), m~th~nol (0.6 mL), 1,2-dichloroethane (0.32 mL), andDMSO (1 mL) was heated at 70-75C under an ~l . ,.o~h.,. c of CO overnight. The cooled reaction u~lulc was then diluted with dichlol~,!..f,tl.~ne, washed with water, 15 dilute HCl, dilute NaHC03 brine, dried and co~ c~.l.ated. The residue was Chl. ~ "-t~ ~hed (silica gel, eluting with 10% ethyl acetate in hexane) to provide 70 mg of the title Co...~ d (v). 17~Iso~ t~lc&l~uyl-cstra-1,3,5(I0)-triene-3~l~cylic acid.
A u~lulc of methyl-17~isobutylca,l,onyl-estra-1,3,5(10)-triene-3-c~ul.u~ylate (70 mg, 0.18 mmol), K2C03 (0.12 g, 0.87 mmol), water (1.5 mL) and meth~nol (10 mL) was heated at reflux overnight. The reaction .,~ u,c was then co~-c~ tl. The residue was diluted with water, ~lified with dilute HCI and e~l,~t~,d with ethyl acetate. The organic extract was washed with brine, dried, and cone~ alcd. The title co.. l~~ d purified by HPLC. mp 202-206C.

F.X~l~P~.F 2-co"~on~i~ to Scheme m 17~Icobutylr~rbonyl~ctra-1 ~ ~(10)-triene-3~ ylic Acid (i). 17~Isobutylc~ul~i yl-cstra-1,3,5(10)-triene-3-fluolosulfonate.
A solution of 17~ isobulylcall,on~l-estra-1,3,5(10)-trien-3-ol, pre~d acco~ing to F~ nrle 1 (i-ii), in dichl~,r~ n~ at 0C is treated with 2,5-di-t-butyl-3-methyl-p~fldine followed after 10 min with fluorosulfonic anhydride. Theresllltin~ ~lul., is stirred for 2 h and then diluted with dichl("o...~ ne The organic layer is washed with S~uld~ aqueous NaHCO3 and brine, dried over 35 MgSO4, and e~a~ t~,d to ~L~ness. Chrc~ dlo~hy on silica gel yields the title J~

" ~ 94/00125 2 1 3 8 9 56 PC~r/US93/06238 (ii). Methyl 17~Isobutylcall~nyl-estra- 1 ,3,5(10)-triene-3-carboxylate.
A uliAlult of 17~isobutylcarbonyl-estra-1,3,5(10)-triene-3-fluorosulfonate 1,3-bis(diphenylphosphino)y,oya~le, p~ m ~ et~te, triethylamine, methanol, 5 DMSO and 1,2-dichlo.~~ n~ is heated and vigorously stirred for 5 h at 80C
under an a~ o~h~"., of carbon monolcide After cooling to ambient tcu~y~ ~tUl~;, the reslllting U~AIUlC is diluted with dichlolc ..~et~.~nf The organic phase is thoroughly washed with water, dried (MgSO4) and evaporated to dryness.
ChIVI~aLU~aY1IY on silica gel yields the title c~ uund.
(iii). 17,B Isobutylcarbonyl-estra-1,3,5(10)-triene-3-carboxylic Acid.
A Illixlure of methyl 17~isobutylcarbonyl-estra-1,3,5(10)-triene-3-carboxylate, K2CO3, water and mf th~nol is heated at reflux for 5 h. The volatiles are then removed at reduced lJlCS~UlC and the residue is diluted with water, aci~lified 15 with dilute aqueous HCl, and eAIl~C~ed with EtOAc. The organic extract is washed with water and brine, dried, and e~ul~tcd to yield the title compound.

FX~ F. 3-cc,.l.~ n-1;,~ to Schemf n~
17~I~obutyl~.l,on~l-es~-l.~(lO)-triene-3-r~rboxyli~ acid 20 (i). 3-(1lilluuro~..elh~neslllfonyloxy)-estra-1,3,5(10)-triene-17~c~l~Aylicacid A solution of 3-h~d~c,Ay-estra-1,3,5(10)-17~carboxylic acid, 2,~di-t-butyl-4-methyl pyridine and trifulc,lo...f th~ne sulfonic anhydride in methylene chloride is stirred at 5C for 20 hours. The organic solvent is e~a~l~t~d and the residue isdissolved in tetral~ c ru.~n water (99.5:0.5) with ~dimethyl~.inoy)rridine which25 upon a~lific~tion with hydlochloric acid followed by conventional WOI~uy yields title cc,lll~und.

(ii). S-(2-pyridyl)-3-(triflulw..~e~ nes~llfonyloxy)-estra-1,3,5(10)-triene-17B-thioc~ul,uAylate A s~lution of 3-(llifluolu---~ Ih~ne~ fonyloxy)-estra-l~3~5(lo)-triene-l7B
C~ UAY1iC acid, triphenylphosyhin~ and, 2,2'-dipyridyl ~ic~lf~e in toluene is stirred under niL,og~,n for 20 hours. The reaction ~iAlure is concer.~ated and the residue is passed .lilcclly tluough silica gel and apyloyliate fractions e~pol~lcd to yield title cc.n~o~,~nd.
(iii). 17B-Isobutylc~l~onyl-estra-1,3,5(10)-triene-3-trifluolu...~,lh~ne sulfonate WO 94/00125 2 13~ 95 6 - Pcr/US93/0623~' To a solution of S-(2-pyridyl)-3-(llinuulu~le~ nçsll1fonyloxy)-estra-1,3,5(10)-triene-17B-Ihioc~ul.o~ylate in tetrahydl~ n at about -50C is added isobutylmq~--r-s;~ - bq~mide. The reaction ll~L~Lur~, iS wall~lCd to about -10C, and diluted with a S ~ tç~ aqueous ~.. O~ .. chloride solution Conventional S WOII~U~J with ~ubs~u~l~t iCol~tiQn by column chl.,lllatography yields title CQI~ ~l'OU~

(iv). Methyl 17B-Isobul~lc~l,onyl-estra-1,3,5(10)-triene-3-carboxylate A s~lutior~ of 17~isobulylcal1~nyl-estra-1,3,5(10)-triene-3-10 tlillu~lv...e~ ne sulfonate, ~ henyl pho~hinç, p~ illm II acetate, triethylamine, meth~nol and dill~lhyl fo....~.u;~P is stirred vigorously under a carbon monoxide ~tmosphP e for 20 hours. Convention~l wo~l~ul) with subsequent isolation by column ch~omatography yields title co,l,po-lnd.

(v). 17B-Isobutylcarbonyl-estra-1,3,5(10)-triene-3-carboxylic acid A ll,i,~lul~ of methyl 17B-isobutylcarbonyl-estra-1,3,5(10)-triene-3-c&l~Alate, K2C03, water and mçth~m~l is heated at reflux for about 5 hours.
Ac~lific~tion~ followed by convention~l WOI~UIJ yields title colllpound.

FX~ .F. 4-cc"l~on~ to S~hPme m 17B-Isobutyll~.bol~l-cstr-l.~ ~(10)-triene-3-~rboxylic acid (i). 3-(fluorosulfonyloxy)-cstra-1,3,5(10)-triene-17B-carboxylic acid A solution of 3-h~d~Ay-cstra-1,3,5(10)-17B-carboxylic acid, 2,6-di-t-butyl-~methyl pyridine and fluoros~llfonic anhydride in methylene chloride is stirred at 5C for 20 hours. The reaction ~ luue is washed with aqueous hydrochloric acid and water. The organic phase is concenl . alcd and the res.llting residue is purified by column cl~ ato~hy to yield the title colll~und.

(ii). S-(2-pyridyl)-3-(fluolosulfonyloxy)-estra-1,3,5(10)-triene-17B-thiocarboxylate A solution of 3-(fluorosulfonyloxy)estra-1,3,5(10)-triene-17B-carboxylic acid, I,ipheny1l)hos~ r and, 2,2'-dipyridyl ~ fi~e in toluene is stirred under rlil~ùgen for 20 hours. The reaction ,l,i~lul~ is COI cenl~i.ted and the residue is passed di.~;ll~ through silica gel and a~plu~liate fractions evaporated to yield title c~ ou--~

(iii). 17~Isobutylc~ul~n~l-estra-1,3,5(10)-triene-3-fluorosulfonate ~--') 94/0012~ ~ ~ 3 8 9 S 6 Pcr/US93/06238 To a solution of S-(2-pyridyl)-3-(fluorosulfonyloxy)-estra-1,3,5(10)-triene-17B-thiocall,uAylate in tet~hy~llorulan at about -50C is added isobutylmi ~nesjum bromidc. The reaction ll iAIUU~ is ~ cd to about -10C and diluted with a s~u,~ aqueous ~.. ~r.;~.. chloride soluti~n Convention~l workup with S ~ubs~uel~t icQl~ti~n by column c~u.l,alography yields title cc,.ll~uund.

(iv). Methyll7B-isobutylcul~nyl-estra-1,3,5(10)-triene-3-carboxylate A solu~io~ of 17B-isobutylcarbonyl-estra-1,3,5(10)-triene-3-fluorosulfonate, Llip}lc.i~yl ~hQ~l~hine, palladium II acetate, triethylamine, methi nol and dimethyl f . . .Iq~. .;de is stirred vigorously under a carbon monoxitl~ atmosphere for 20 hours.
ConvPntion_l WUl~ul) with subse~uent icol~tion by column chromatography yields title co,l,~uul~d.

(v). 17B-Isobutylcarbonyl-estra- 1,3,5(10)-triene-3-carboxylic acid A ~lul~ of methyl 17B-isobutylcarbonyl-estra-1,3,5(10)-triene-3-carboxylate, K2CO3, water and meth~nQl is heated at reflux for about 5 hours.
Ardifir?tiQn followed by Con~enl;Qn~l WUII~U~ yields title colllpound.

~Y, m~l?le S - Cc".~;~...line to Scheme m 17~octy1r-.l,on~l)-estra-1.~ ~(10)-triene-3-carboxylic acid (i) 17~(octylc~bonyl)-estra-1,3,5(10)-triene-3-1lifluo,ul.,~,~hylsulfonate.
The title coll,puu,~d was ~ ipal~d according to Example 1 (i-iii) by sub~l;lul;n~ n-octylmq~;..G~ .. chloride for isobutylm~..cs;l.... bromide in step (ii).

(u) 17~(octylc~ubon~1)-estra-1,3,5(10)-triene-3-ca,bo~ylic acid.
A ~ u~ of 17~(octylca,l~nyl~estra-1,3,5(10)-triene-3-hi~luo,û~etllylsulfonate (0.38 g, 0.7 mmol), ~li cs;~.. acetate (0.27 g), pqllq~ ^et~te (0.008 g, 0.036 mmol), 1,1'-bis(diphenylphGs~.h;no)fe"ocene(dppf; 0.08 g, 0.14 mmol), in DMSO (15 ml) was 30 purged with carbon --on~ e for 2 ~in~l(es and stirred under a CO balloon at 60C
ovçrnight The ~chûn ~ Ul~; was diluted with water, qc idifie~d with O.5N
hydrochloric acid and extracted with dichlof~ nc The organic layer was washed with water, dried (MgSO4), and e~a~ùlat~ under vacuum. The residue was chlu...~ .~hcd (silica gd, duting with 20% ethylacetate, 1% acetic acid in 35 hexane) to give solid ~.;t...~ted with ...- ti.~nol-~celoh;l~;le to yield the title cc....l ûun~ 0.22 g (73%) mp 175C.

Wo 94/00125 PCr/US93/0623~
213895~ 32-FY~ le 6 - C~ vont~ E to Schem~- m 17~(tert-~ntylr-.l~Q~I)-~ctra-1~ ~(10)-triene-3-r~rboxylic acid (i) Tlinuulu~lclllyl- 17~(tert-pentylcarbonyl)-estra- 1,3,5(10)-triene-3-sulfonate.
The title cc,.-.ro---.d was yle~p~d according to Example 1 (i-iii) by s~ g tert-yc~ es~ chloride for isobutylm~;.. esi,.. bromide in step (ii).

(ii) 17~(tert-pentylcarbonyl)-estra-1,3,5(10)-triene-3-carboxylic acid.
The title co~..pou~d was yl~yal~d according to Example 5 (ii) by substinlting ll;nuûloll-c~lyl-17~(tert-pentylcarbonyl)-estra-1,3,5(10)-triene-3-sulfonate, asyleyal~d in F.x~mrle 6 (i), for trifluolom~ yl-17~(octylcarbonyl)-estra-1.3.5(10)-triene-3-sulfonate. mp 199-200C.
r~AU~le 7 - Cu~ vondin~ to Scheme nT
17~ limrtl~ lr~rbonyl)~tra-1~ (10)-tnene-3-r~rboxylic acid (i) Trifluc lulnctll~l- 17~(2,2-dimethylpropylcallrûnyl)-estra- 1,3,5(10)-triene-3-sulfonate.
The title co.. ~,o.~-d was yl~iy~cd according to Example 1 (i-iii) by su~s~ 2,2-dimethylyloyyl~.. a~.. esi.~.. bromide for isobuty1m~g.. e~;u.. ~ bromide in step (ii).

(ii) 17~(2,2-dim~ ly~pylcall~nyl)-estra- 1 ~3~5(10)-triene-3-carboxylic acid.
The title compound was yl~ pal~d accor~ing to Example S (ii) by su~ ul;ng Il in uon~me II-yl -17 ~ (2,2-dimethylpropylcarbonyl )-estra- 1,3,5 (10)-triene - 3 -sulfonate, as yl~pal~d in Example 7 (i), for llinuuron~ 1-17~(octylcarbonyl)-estra-1,3,5(10)-triene-3-sulfonate. mp210C.

FY:~1e 8 - Cû~l~s~onding to Scheme IV
17~(propylr~rbonyl)-es~a-1 ~ ~(10)-triene-3-carboxylir acid (i) 17~cyano-estra-1,3,5(10)-triene-3-m~-th~neslllfonate.
The title comrolln~ is known and is yleyal~d from estrone according to the yn~ul~i of Baldwin et al., J. Chem. Soc. (C), 1968, 2283-2289.
(ii)17,~Cyano-estra-1,3,5(10)-triene-3-ol.

'- ~ 94/00125 ~ 13~6 ;~j; ; PC~r/US93/06238 The title comyound of 17~cyano-estra-1,3,5(10)-triene-3-m~th~nesulfonate (10 g) in m~thqno] (100 rnL) is added dropwise a solution of NaOH (42 mL of a 20% sOl~ltiOrl in 1:1 MeOH-water). The reslllting lllixlul~ is heated to 40C for 24 h after which time the ~lul~ is cooled to 0C, diluted with water (350 mL), and acidified with dilute HCl. The reslll*ng white yre~ip~ e is i~l~ted by vacuum filtration, washed with wate~r, and dried under vacuum. Recrystq-lli7~tion from acetols;t.;le provides the title comyound mp 249-250C Dec (iii) 17~cyano-estra-1~3,5(10)-triene-3-LIinuolvl.~f ~ e~ulfonate.
17,B cyano-estra-1,3,5(10)-triene-3-ol (4.2 g) and 2,6-di-t-butyl-4-lll~ lhyly~l;de (3.6 g) was dissolved in 50 ml of methylene chloride. The Il~ixlule was stirred at ~om te"lyel~dlule for 30 min. Triflic anhydride (4.2 ml) was added and the lluAlu e was stirred another 40 mins, diluted with 50 ml CH2Cl2, filtered, cQnc~ ~I.ated, and c~ atoE;layhed on silica gel. Elution with 20% ethyl acetate in hexane gave 5.3 g (87%) of the title cGlllyound~ mp 115-117C.

(iv) Methyl 17~cyano-estra-1,3,5(10)-triene-3-carboxylate.
To a solution of 17~cyano-estra-1,3,5(10)triene-3-ol (10 g) in 77 ml of DMSO and 50 ml of MeOH was added 7 ml of triethylamine, 0.35 g of p~llq~ m --~tqte 0.64 g of bis(diyhellylphosrhino)ylYJyane and 1,2-dichlol{,etllane (26 ml).
Carbon lllono,-ide was bubbled through the solution and the reaction Illi~lule was then stirred at 75C overnight under 1 atrn of CO (balloon). The ~u~clul~ was diluted with EtOAc and washed with water (3x), dried, and concentrated. The residue was c~uulnalûglayhed (silica gel, eluting with 10% EtOAc in hexane) to provide 4.5 g of the title co~ u~ d~ mp 161-163C.

(v) 3-Hydlo~ clhyl-estra-l~3~s(lo)-triene-l7~ Jorq-ldehyde~
Methyl-17~cyano-estra-1,3,5(10)-triene-3-call,u~ylate (0.8 g) was dissolved in 30 ml of toluene and treated with DIBAL (6 ml, lM). The mixture was stirred at room temp under argon for 2.5 hours. The mi~lule was then poured into 50 ml of 5% H2S04 and the uu,~lul~, was stirred for 1 hou;, filited, dried, and concen~rated.
The residue was cluo~tc.E~aphed (silica gel, eluting with 20% EtOAc in hexane) to provide 424 mg of the title coul~ulld~ mp 146-150C.

( n) 17 ~(l-hyJlu~y~ulyl)-estra-l~3~5(lo)-triene-3-hydLuxyul~lyl.

WO 94/00125 2 ~3~ ~ 5 6 Pcr/US93/062~

A solutiQn of 3-hydl~xylllelllyl-estra, 1,3,5(10)-triene-17~carboxaldehyde (75 mg in 2 ml of THF) was added slowly to a solution of propylm~gnçsium bromide (2 ml, 1.6 M). The llfiAlu.c was stirred at room temp for 2 hours.
The llliAlUl., was 4~el~c!~rd with salulat~ aqueous NH4Cl and extracted 5 with CH2C12. The organic extract was washed with brine, dried, and concentrated.
The res~l1ting residue was c~uol~log~pahed (silica gel, eluting with 30% ethyl acetate in hexane) to give 57 mg of title co-l~ound.

(vii) 17~(propylc~1,unyl)-estra-1,3,5(10)-triene-3-carboxylic acid.
17~(1-hydloAybutyl)-estra-1,3,5(10)-triene-3-hydroxymethyl (57 mg) was dissolved in ncetor e (5 ml) and treated wi~h Jones reagent. The l~ixlul~, was stirred for 1 hour and then quc nr~ with 2-propanol, eAIlacled with CH2CL2 and purified by c~ ography (silica gel, eluting with 30% etase in hexane with 0.5% HOAc added) to give 47 mg of the title col--pulJ~ mp 211-213C.
F.x~ ?le 9 - Co,lc~ondin~ to Scheme IV
17~ tl~ylr~rbor~yl)-~tra- 1 ~ ~(10)-triene-3-c~rboxylic acid The title co~ ol~n~l was plepal~,d acco~illg to Example 8 (i)-(vii) by s~lb~ ul;ng ..-clh~/l...agl.~s;.~l. bromide for propylm~ P~hl~l~ bron~ide in step (vi).
20 mp 199-202C.

F.Y~ e 10 - Co"~ondin~ to Scheme IV
17~(3 ~ ylbutylci~ l~n~l)-estra-l ~(10)-triene-3-carboY~ylic acid The title co.--l,uu-~d was p~cyalcd ac~ing to Example 8 (i)-(vii) by 25 sub~ ul; .~g 3,3-~li---elll~lbutylm~gnesinm chloride for propylm~ c si~., bromide in step (vi). mp 252-255C.

FY~n~le 11 - Collc~vondi-~ to Scheme IV
17~rl-(~ ydroxy~th~yll-estra-l~ ~(10~-triene-3-carboxylic acid (i) A solutinn of 17~(methylcarbonyl)-estra-1,3,5(10)-triene-3-carboxylic acid (6 mg) - ~lepa.cd acco,dil.g to Example 9 - in meth~nol was treated with NaBH~
(0.7 mg). The l~ ixlule was wanl~ed to 45C and stirTed overnight. The solvent was .._n.o~d by rotary evaporation and the residue was dissolved in dichlc~lo...~,!h~ne and filtered. The title co ll~ound (1.6 mg) was purified by pic~ re thin layer 35 cl~uu.at~aphy, mp 202-204C.

- `~ 94/00125 ~ 1 3 8 9 ~ 6 ~` . Ci Pcr/US93/06238 (ii) Pure f~R) and (S) fo~ns are obtahled by se~ ~,on techniques readily available and known to those of skill in the ar~

FYan~le 12 - Col~c~o~ ~ to Scheme IV
17~rl-fI~ y.l.u.~ybutyll-ectra-l ~.~flO)-triene-3-~-~rboxy]ic acid (i) The title co..~ ..d was ylc~1ar~d according to Fyamrle 11 by sub~ l;ng 17~f~propylcarbonyl)-estra-1,3,5(10)-triene-3-carboxylic acid, ~"e~ar~d according to FY~rle 8 (i)-(vii) for 17~(methylcarbonyl)-estra-1,3,5(10)-triene-3-carboxylic acid. mp 208-211C.
(ii) Pure (R) and (S) forms are obt~in~d by separation techniques readily available and known to those of skill in the art.

FYam~ e 13 An oral dosage form for ~rlminictering Formula I co.. ou~ c is produced by sc,cc~ning~ mixing, and filling into hard gelatin carsules the ingredients in the plUI)Ul lions shown in Table 1, below.

Table I

Tru~ientc Amountc 17~Isobulylcarbonyl-estra-1,3,5(10)- 50 mg triene-3-carboxylic acid ma~,,.cs;l.. stearate 5 mg lactose 75 mg FXAMP!.F. 14 'Ihe sucrose, calcium sulfate dihydrate and Formula (I) collll)uund shown in Table II below, are mixed and gran~llated in the ~,rùpul~ions shown with a 10%
gelatin solution. The wet granules are scl~ned, dried, mixed with the starch, talc 25 and stearic acid, scl~ncd and col~ressed into a tablet.

WO 94/00125 2 1 3 8 g 5 6 PCr/US93/062~

Table II

~Ai~ntc Amounts 17~Isobutylcarbonyl-estra-1,3,5(10)- 100 mg triene-3~&.l~Aylic acid c~l~inn- sulfate dihydrate 150 mg sucrose 20 mg starch 10 mg talc 5 mg stearic acid 3 mg FY~rrU~Ie 15 17~Isobutylcarbonyl-estra-1,3,5(10)-triene-3-carboxylic acid, 75 mg, is S di~u.~ed in 25 ml of normal saline to ~ e an inject~hle pl~palaLion.

While the ~.leÇe.l~d elllbo~ of the invention are illusLIat~ by the above, it is to be understood that the invention is not limited to the precise in~l~uc~ons herein liCrlQ~d and that the right to all motlific~tio~s comming within 10 the scope of the following claims is reserved.

Claims (40)

What is claimed is:

1. A compound represented by the formula:

(I) wherein Z is .alpha. or .beta.
in which R is C1-20 linear or branched, saturated or unsaturated alkyl and pharmaceutically acceptable salts, hydrates, solvates and esters thereof.

2. A compound of claim 1 of the Formula:

(II) in which R is C1-20 linear or branched, saturated or unsaturated alkyl and pharmaceutically acceptable salts, hydrates, solvates and esters thereof.

3. A compound of claim 2 having the following formula:

(III) in which R2 is C1-8 linear or branched alkyl and pharmaceutically acceptable salts, hydrates solvates and esters thereof.

4. A compound of claim 3 wherein R2 is methyl, ethyl, propyl, 3-methylbutyl, isopropyl, n-butyl, isobutyl, 1-methylpropyl, t-butyl, pentyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, octyl or 3,3-dimethylbutyl and pharmaceutically acceptable salts, hydrates, solvates and esters thereof.

5. A compound of claim 4 wherein R2 is 1-methylpropyl, n-butyl, isopropyl, n-pentyl, 3-methylbutyl, 2,2-dimethylpropyl, t-butyl, 1,1-dimethylpropyl, isobutyl, n-octyl, tert-pentyl, n-propyl, methyl or 3,3-dimethylbutyl and pharmaceutically acceptable salts, hydrates, solvates and esters thereof.

6. 17.beta.-(isobutylcarbonyl)-estra-1,3,5(10)-triene-3-carboxylic acid.

7. 17.beta.-(octylcarbonyl)-estra-1,3,5(10)-triene-3-carboxylic acid.

8. 17.beta.-(tert-pentylcarbonyl)-estra-1,3,5(10)-triene-3-carboxylic acid.

9. 17.beta.-(2,2-dimethylpropylcarbonyl)-estra-1,3,5(10)-triene-3-carboxylic acid.

10. 17.beta.-(propylcarbonyl)-estra-1,3,5(10)-triene-3-carboxylic acid.

11. 17.beta.-(methylcarbonyl)-estra-1,3,5(10)-triene-3-carboxylic acid.

12. 17.beta.-(3,3-dimethylbutylcarbonyl)-estra-1,3,5(10)-triene-3-carboxylic acid.

13. A compound of claim 1 of the Formula in which R is C1-20 linear or branched, saturated or unsaturated alkyl and pharmaceutically acceptable salts, hydrates, solvates and esters thereof.

14. A compound of the formula wherein Y is a or .beta.
in which R is C1-20 linear or branched, saturated or unsaturated alkyl and pharmaceutically acceptable salts, hydrates, solvates and esters thereof.

15. A compound of claim 14 in which Y is in the .beta. position.

16. A compound of claim 14 in which Y is in the .alpha. position.

17. 17.beta.-(1-hydroxyethyl)-estra-1,3,5(10)-triene-3-carboxylic acid.

18. 17.beta.-(1-hydroxybutyl)-estra-1,3,5(10)-triene-3-carboxylic acid.

19. A compound according to claim 1 substantially as hereinbefore defined with reference to anyone of the examples.

20. A pharmaceutical composition comprising a compound according to anyone of claims 1 to 18 and a pharmaceutically acceptable carrier.

21. A compound according to any one of claims 1 to 18 for use in therapy.

22. A compound according to any one of claims 1 to 18 in the manufacture of a medicament for use as a steroid 5-.alpha.-reductase inhibitor.

23. A compound according to any one of claims 1 to 18 in the manufacture of a medicament for use in treatment to reduce prostate size.

24. A compound according to any one of claims 1 to 18 in the manufacture of a medicament for use in treatment of prostatic adenocarcinoma.

25. A process for the preparation of a compound of the Formula (II) (II) in which R is C1-20 linear or branched, saturated or unsaturated alkyl and pharmaceutically acceptable salts, hydrates, solvates and esters thereof which comprises either i) oxidation of a compound of the Formula in which R is as described above, or (ii) reacting a compound of the Formula in which R is as described above in a metal-catalyzed coupling reaction in the presence of an appropriate coupling reagent, preferably, carbon monoxide followed by an optional, if applicable, hydrolysis reaction, or (iii) hydrolyzing a compound of the Formula in which R is as described above and thereafter optionally forming a pharmaceutically acceptable salt, hydrate, solvate or ester thereof.

26. A process for the preparation of a compound of the formula (II) (II) in which R is C1-20 linear or branched, saturated or unsaturated alkyl and pharmaceutically acceptable salte, hydrates, solvates and esters thereof which comprises reacting a compound of the formula in which R is as described above with fluorosulfonic anhydride and a base preferably, 2,5-di-t-butyl-3-methyl-pyridine, in a solvent, preferably, dichloromethane to form a compound of the formula in which R is as described above and subsequently reacting said compound in a metal-catalyzed coupling reaction in the presence of an appropriate coupling reagent, preferably, carbon monoxide, followed by an optional, if applicable, hydrolysis reaction to form a compound of formula (II) and thereafter optionallyforming a pharmaceutically acceptable salt, hydrate, solvate or ester thereof.

27. A process for preparing a compound of the Formula in which R is C1-20 linear or branched, saturated or unsaturated alkyl and pharmaceutically acceptable salts, hydrates, solvates and esters thereof which comprises epimerization of a compound of Formula (II) (II) in which R is as described above, and thereafter optionally forming a pharmaceutically acceptable salt, hydrate, solvate or ester thereof.

28. A process for preparing a pharmaceutical composition containing a pharmaceutically acceptable carrier or diluent and an effective amount of a compound of the Formula (I) (I) in which Z is a or .beta.
in which R is C1-20 linear or branched, saturated or unsaturated alkyl and pharmaceutically acceptable salts, hydrates, solvates and esters thereof which process comprises bringing the compound of the Formula (I) or a pharmaceutically acceptable salt, hydrate, solvate or ester thereof, into association with the pharmaceutically acceptable carrier or diluent.

29. A compound of the formula (V):

(V) in which R is C1-20 linear or branched, saturated or unsaturated alkyl and R4 is fluorosulfonyloxy.

30. A compound of the Formula (VI) (VI) in which R is C1-20 linear or branched, saturated or unsaturated alkyl.

31. Use of a compound according to any one of claims 1 to 18 in the manufacture of a medicament for use in inhibiting steroid 5-.alpha.-reductase.

32. A method of inhibiting steroid 5-.alpha.-reductase in mammals which comprises the administration to a mammal in need such inhibition, an effective amount of a compound according to any one of claims 1 to 18.

33. The use of a compound according to anyone of claims 1 to 18 and an alpha-receptor antagonist compound as an active therapeutic substance which use consist of separate sequential or simultaneous administration of a compound according to anyone of claims 1 to 18 and an alpha-receptor antagonist compound.

34. The use of a compound according to anyone of claims 1 to 18 and an alpha-receptor antagonist compound in the manufacture of medicament for use in the treatment of benign prostatic hypertrophy which use consist of separate sequential or simultaneous administration of a compound according to anyone of claims 1 to 18 and an alpha-receptor antagonist compound.

35. The use of a compound according to anyone of claims 1 to 18 and an aromatase inhibiting compound as an active therapeutic substance which use consists of separate sequential or simultaneous administration of a compound according to anyone of claims 1 to 18 and an aromatase inhibiting compound.

36. The use of a compound according to anyone of claims 1 to 18 and an aromatase inhibiting compound in the manufacture of a medicament for use in the treatment of benign prostatic hypertrophy which use consist of separate sequential or simultaneous administration of a compound according to anyone of claims 1 to 18 and an aromatase inhibiting compound.

37. The use of a compound according to anyone of claims 1 to 18 and minoxidil as an active therapeutical substance which use consist of separate sequential or simultaneous administration of a compound according to anyone of claims 1 to 18 and minoxidil.

38. The use of a compound according to anyone of claims 1 to 18 and minoxidil in the manufacture of a medicament for use in the treatment of male pattern baldness which use consist of separate sequential or simultaneous administration of a compound according to anyone of claims 1 to 18 and minoxidil.

39. The use of a compound according to anyone of claims 1 to 18 and an aromatase inhibiting compound and an alpha-receptor antagonist compound as an active therapeutic substance which use consists of separate sequential or simultaneous administration of a compound according to anyone of claims 1 to 18 and an aromatase inhibiting compound and an alpha-receptor antagonist compound.

40. The use of a compound according to anyone of claims 1 to 18 and an aromatase inhibiting compound and an alpha receptor antagonist compound in the manufacture of a medicament for use in the treatment of benign prostatic hypertrophy which use consist of separate sequential or simultaneous administration of a compound according to anyone of claims 1 to 18 and an aromatase inhibiting compound and an alpha-receptor antagonist compound.