OA10122A

OA10122A - 17-Alkylketone steroids useful as 5-alpha reductase inhibitors

Info

Publication number: OA10122A
Application number: OA60599A
Authority: OA
Inventors: Denis Alan Holt; Mark Alan Levy
Original assignee: Smithkline Beecham Corp
Priority date: 1992-06-30
Filing date: 1994-12-29
Publication date: 1996-12-18
Also published as: JPH08500821A; NO945074D0; SK159994A3; BR9306748A; MX9303970A; FI946189A0; WO1994000125A1; ZA934645B; AP9300542A0; BG99313A; EP0651643A4; RU94046378A; IL106158A0; AU4545993A; CA2138956A1; CN1095382A; CZ334694A3; FI946189A; HUT69409A; AP412A

Abstract

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

Description

Ü i 0 I £ 2 - 1 - 17-alkylketone steroids useful as 5-a-reductase inhibitors, HELP QF THE Π<ΪΕΝΊ3ΩΚ

The présent invention relates to certain novel 17a and 17B-alkylketone-3-carboxy aromatic A ring stéroïdal compounds, pharmaceutical compositionscontaining these compounds, and methods for using these compounds to inhibitsteroid 5-a-reductase isozyme 1 and steroid 5-a-reductase isozyme 2. Alsoinvented are novel intermediates and processes useful in preparingthese compounds.

DESCRIPTION OF RELATEPAEI

The class of stéroïdal hormones known as androgens is responsable for thephysical characteristics that differentiate males from females. Of the several organsthaï produce androgens, the testes produce these hormones in the greatest amounts.Centers in the brain exen primary control over the level of androgen production.Numcrous physical manifestations and disease States resuit when incfi'cctivc controlresults in excessive androgen hormone production. For example, acné vulgaris,seborrhea, female hirsutism, male pattern baldness and prostate diseases such asbenign piostatic hypertropy are correlated with elevated androgen levels.Additionally, the réduction of androgen levels has been shown to hâve a therapeuticeffect on prostate cancer.

Testosterone is the principal androgen secreted by the testes and is theprimary androgénie steroid in the plasma of males. It now is known that 5-a-reduced androgens are the active hormones in some tissues such as the prostate andsebaceous gland. Circulating testosterone thus serves as a prohormone fordihydrotestosterone (DHT), its 5-a-reduced analogue, in these tissues but not inothers such as muscle and testes. Steroid 5-a-reductase is a Nicotinamide Adenhedinucleotide Phosphate(NADPH)dependent enzyme that converts testosterone toDHT. The importance of this enzyme in mile development was dramaticallyunderscored by discovery of a genetic steroid 5-a-reductase deficiency in malepseudohermaphrodites. Imperator-McGinley, J., filai.» (1979), J. Steroid Biochem.11:637-648. A number of 3-carboxy-estra 1,3,5(10) triene 5-a-reductase inhibitors are known in the art For example, -2- 0 i ίπ

Levy, et al., describes the interaction mechanism between rat prostatic steroid 5-alpha xeductase and 3-carboxy-17B-substituted steroids; 2.

Vol. 33, pp. 937-942, by D.A. Holt, et al describes a new steroid class of A ring aryl carboxylic acids; 3. UES (Deccmber 1989) Vol. 10, pp. 491-495, by B.W. Metcalf, etal., describes the effect of inhibitors of steroid 5a reductase in benign prostatichyperplasia, male pattern baldness and acné.

In addition U.S. Patent No. 4,954,446 describes a group of 3-cærboxy-estral,3,5(10)triene-17B-substituted compounds which aie disclosed as being useful asinhibitors of steroid 5-a-reductase. However, none of the cited référencés cliscloseor suggest thaï any of the novel 17B-alkylketone-3-carboxy aromatic A ringsteroidal compounds of the présent invention would hâve utility as highly patentinhibitors of both steroid-5-a-ieductase isozyme 1 and steroid 5-a-reducta<;eisozyme 2 (dual inhibitors).

This invention relates to a compound of the formula I:

Z

O (I)

wherein Z is a or B 11

•C-R in which R is Cj.20 linear or branched, satuiated or unsaturated alkyl and.pharmaceudcally acceptable salts, hydrates, solvatés and esters thereof.

The invention also is a rncthod for simultaneously inhibiting 5-a-reductase isozyme 1 and 5-a-reductase isozyme 2 acdvity in mammals, including humans thaï comprises administering to a subject an effective amount of a ptesently invented 5-a-reductase inhibiting compounds. In a further aspect of the invention there aie provided novel intermediates and novel processes useful in preparing tne -3- presently invented dual 5-a-reductase inhibiting compounds. Included in theprésent invention are pharmaceufcal compositions comprising a pharmaceuticalcarrier and compounds useful in the methods of the invention. Also included in theprésent invention are methods of co-administering the presnetly invented dual 5-a- 5 reductase inhibiting compounds with further active ingrédients. DETAILED DESCRIPTION OF THE INVENTIONThe compounds of this invention that inhibit both 5-a-reductase isozyme 1 and 5-a-reductase isozyme 2 haVe the following Formula (I): 10 15

wherein Z is a or BO

II

-C-R in which R is Cj.jO bnear or bfanched, saturated or unsaturated alkyl andpharmaceudcally acceptable safcs, hydrates, solvatés and esters thereof.

As used herein such cotipounds are referred to as dual inhibitors of steroid5-a-reductase.

Preferred among the prlsently invented compounds are those having2.0 FiTrmula (Π): 25

in which R is Cp20 Ibiear or Iranched, saturated or unsaturated alkyl and pharmaceudcally acceptable sâlts, hydrates, solvatés and esters thereof. -4- 0 i 0 1 2

Zw

Preferred among thc presently invented Formula Π compounds arc thosehaving Formula ΙΠ

in which R2 is Cj.g lincar or branched alkyl and pharmaceutically acceptable salts,hydrates solvatés and esters thereof.

Preferred among Formula (HI) compounds are those in which R2 is rnethyl,ethyl, propyl, 3-methylbutyl, isopropyl, n-butyl, isobutyl, 1-methylpropyl, t-butyl,pentyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, octyl or 3,3-dimethylbutyl.

Particularly preferred among Formula (ΙΠ) compounds are those in v/hichR2 is 1-methylpropyl, n-butyl, isopropyl, n-pentyl, 3-methylbutyl, 2,2-dimethyl-propyl, t-butyl, 1,1-dimethylpropyl, isobutyl n-octyl, tert-pentyl, n-propyl, rnethylor 3-3-dimethylbutyl.

Particularly preferred among Formula (ΙΠ) compound are: 17B-(isobutylcarbonyl)-estra-1,3,5(10)-triene-3-carboxylic acid, 17B-(octylcarbonyl)-estra-l ,3,5(10)-triene-3-carboxylic acid, 17S-(tert-pentylcarbonyl)-estra-l ,3,5(10)-triene-3-carboxylic acid, 17B-(2^-dimethylpropylcarbonyl)-estfa-l,3,5(10>triene-3-carlx3xylicacidi 17B-(propylcarbonyl)-estra-l,3,5(10)-ffiene-3-carboxylic acid, 17B-(methylcarbonyl)-estra-l,3,5(10)-triene-3-carboxylic acid and 17B-(3,3-dimethylbutylcarbonyl)-estra-l,3^(10)-triene-3-carboxylic acidand pharmaceutically acceptable salts, hydrates, solvatés and esters thereof .

The term "a", as used herein, follows standard Chemical terminoloj^y andmeans dowri or that the corresponding substituent is attached below the plane of the paper. -5-

The term "β", as used herein, follows standard Chemical terminology andmeans up or that the conesponding substituent is attached above the plane of thepaper.

By the term "alkyl·", Ci_nalkyl and dérivatives thereof and in ail carbonchains as used herein, unies s otherwise defïnedus meant a Cj.n linear or branchedcarbon chain having 1 to n carbons. Examples of "alkyl" and dérivatives thereof asused herein include: rnethyl, ethyl, propyl, 3-raethylbutyl, isopropyl, n-butyl,isobutyl, 1-methylpropyl, t-butyl, n-pentyl, 1,1-dimethylpropyl, 2,2-dimethyl-propyl, n-octyl, tert-pentyl and 3,3-dimethylbutyl.

By the term "treating" as used herein, is meant prophylatic or therapeutictherapy.

By the term "isobutyl" as used herein, is meant -CH2CH(CH3)2·

By the term "rnetal-catalyzed coupling réaction" as used herein is meant thatthe preparcd 3-trifluoromethyl sulfonate or 3-fkiorosulfonate compound is reactedin a suiuble organic solvent, preferably toluent, dimethylformamide or THF with abase, preferably a tertiaryamine base such as txiethylamine, pyridine ortributylamine, a phosphine such as bis(diphen)fiphosphino)alkane, preferably 1,3bis(diphenylphosphino)propane or tri-o-tolyphosphine, or a Cj.galkOH, and amétal catalyst, preferably a palladium catalyst such as palladium (Π) acetate,palladium (Π) chloride ai* bis(triphenylphosphine) palladium Π acetate, and acoupling reagent.

By the term "coupling reagent" as used herein is meant a compound whichis capable of reacting with an aryl radical to form a carboxylic acid substituent.Carbon monoxide is a preferred coupling reagpet, which when added to the rnetal-catalyzed coupling reaction, as described herein, yields the desired carboxylic acidgroup.

Compounds of Formula (I) and compounds of formula (IV) arc: included inthe pharmaceutical compositions of the invention and used in the methods of theinvention. Where a -COOH group is présent, phannaceutically acceptable esterscan be employed, for example methyl, ethyl, pivaloyloxymethyl, and the like, andthose esters known in the art for modifying sdlubility or hydrolysis characteristicsfor use as sustained release or prodrug formulations.

The term "α-reccptor antagonist", as »sed herein, refers to a known class of alpha-andrenergic receptor antagonist comounds, such as described in Lafferty, et al. U.S. Patent No. 4,963,547, which are utilfeed in treating vascular disorders such -6- as diabètes, cardiovascular disease, benign prostatic hypertrophy and ocularhypertension.

Preferred alpha-andrenergic receptor antagonists for use in the compositionsand methods of the invention include amsulosin, terazosin, doxazosin, alfuzosin,indoramin, prazosin and 7-chloro-2-ethyl-3,4,5,6-tetrahydro-4-methylthieno[4,3,2-ef][3]-benzapine.

By the tenu "amsulosin” as used herein is meant a compound of thestructure

and salts, hydrates and solvatés thereof.

Chemically, amsulosin is designated as (-)-(R)-5-[2-[[2-(O- ethoxyphenoxy)ethyl]amino]propyl]-2-methoxybenzenesulfonamide.

Amsulosin 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 tractdysfonction.

By the term "terazosin" as used herein is meant a compound of the structure:

and salts, hydrates and solvatés thereof.

Chemically, terazosin is designated as l-(4-amino-6,7-dimethoxy-2 quinazolinyl)-4-[(tetrahydro-2-foroyl)caibonyl]piperazine. Terazosin is diisclosecl in U.S. Patent Number 4,251,532.

By the term doxazosin as used herein is meant a compound of the structure

and salts, hydrates and solvatés thereof.

Chemically "doxazosin" is designated as l-(4-amino-6,7-dimethoxy-2- quinazolinyl)-4-[(2,3-dihydro-1,4-benzodioxin-2-yl)carbonyl]-piperazine.Doxazosin is discolsed in U.S. Patent Number 4,188,390.

By the terni "alfuzosin" as used herein is roeant a compound of the structure CH,

and salts, hydrates and solvatés thereof.

Chemically alfuzosin is designated as 14-[3-[(4-amino-6,7-dimethoxy-2- quinazolinyl)methylamino]propyl]tetrahydro-2*furancarixncamide.

Alfuzosin is disclosed in U.S. Patent Number 4,315,007.

By the terni "indoramin" as used herein is meant a compound fo the structure

and salts, hydrates and solvatés thereof.

Chemically indoramin as designated N-[[l-[2-(lH-indol-3-yl)ethyl]-4- piperidinyl]benzamine.

Indoramin is disclosed in U.S. Patent Number 3,527,761.

By the term "prazosin" as used herein is meant a compound of the structure

and salts, hydrates and solvatés thereof. -8- 0 J 0 j λ* 2

Chemically prazosin is designated as l-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-(2’furanyl«irbonyl)piperazine.

Prazosin is disclosed in U.S. Patent Number 3,511,836."7-chloro-2-ethyl-3,4,5,6-tetrahydro-4-raethylthieno[4,3,2-ef]- [3]bcnzazcpinc" as used hercin is meant a compound of the structure

and salts, hydrates and solvatés thereof. 7-chloro-2-ethyl-3„4,5,6-tetrahydro-4-inethylthieno[4,3,2-ef]-[3]ben2azepineis disclosed in U.S. Patent No. 5,006,521. Additionally, ail compounds disdosed inU.S. Patent No. 5,006,521 as alpha-adrenergic receptor antagonist are preferredalpha-adrenergic receptor antagonist as used herein.

Persons skilled in the art can readily détermine if a compound other lhanone spccifically referred to herein is a alpha-andrenergic receptor antagonist byudlizing the assay described in Lafferty I. Thus, ail such compounds aie includedwithin the scope of the tain "alpha-andrenergic receptor antagonist” as used herein.

By the term "minccddil" as used herein is meant the compound of thestructure:

chemically minoxidil is designated as 2,4-pyrimidineadiamine, 6-(l-pipcridinyloxide. Minoxidil is the active ingrédient in Regaine® which is sold as topicalsolution for stimulating hair growth by the Upjohn Company, Kalamazoo,Michigan.

The term "aromatase inhibitor", as used herein, refers to a known class of compounds, steroidal and non-steroidal, which prevent thé conversion of androgens to estnogens, such as described in Gormley et al. International Publication Number WO 92/18132. Aromatase inhibitors arc disdosed in Gormley et al. as having

I -9- utility in trcating bcnign prostatic hypcrplasia when uscd in combination with a 5-α-reductase inhibitor. A prefcrred aromatase inhibitor for use in the compositions and methods ofthe invention 4-(5,6,7,8-tetrahydroimidazo-[l,5-a3pyridin-5-yl)benzonitrile(fadrazole). Fadrazôle is disclosed in U.S. Patent No. 4,728,645. Additionally, ailcompounds disclosed in Gormley, et al. International Publication No. WO92/18132 as having aromatase inhibiting activity are prcfcrred aromatase inhibitorsas used herein.

As used hercin, when a dual inhibitor of 5-a-reductase, as described hereinand a further active ingrédient or ingrédients are utilized together, said 5-a-rcductase inhibitor can be co-administered with said further active ingrédient oringrédients.

By the terrn "co-administering" and dérivatives thereof as used herein ismeant either simultaneous îidministration or any manner of separate sequentialadministration of a 5-a-reductase inhibiting compound, as described hercin, and afurther active ingrédient or ingrédients, such as other compounds known to treat thedisease States of acné vulgaris, seborrhea, femaje hirsutism, male pattern balclness,benign prostate hypertrophy or prostatic adenooarcinoma or compounds known tohâve utility when used in combination with 5-ot-rcductase inhibitors. Preferably, ifthe administration is not simultaneous, the compounds are administered in a closetime proximity to each other. Furthermore, it does not matter if the compounds areadministered in the same dosage form, e.g. one compound may be administeredtopically and another compound may be administered orally.

The novel compounds of Formula (Π) of the présent invention can beprepared by methods outlined in schemes 1-4 below and in the Examples fromknown and readily available estrone which has the formula:

or from the 17B-carboxyïic acid analogue of estrone, which is known and readilyavailable. -10- IH u U 2

SchgmsJ

- 11 - Οί οι 2ί

«D

F

(θ) ?

(g) - 12- 0 I ο ί ζ 2

Scheme I outlines formation of Formula Π compounds. As used in schemeI compound (b) is prepared from compound (a) according to the procedure ofBaldwin, et al., J. Chem. Soc. (c), 1968,2283-2289.

Compound (b) is then stirred in an appropriate organic solvent, preferablymethanol, with a base, preferably sodium hydraxide, and then acidified to yieldcompound (c). Compound (c) is next treated with a Grignard reagent, descriibedhercinbclow, or a lithium reagent in an appropriate organic solvent, preferablytetrahydrofuran or diethylether solvent, preferably at reflux température to yieldformula (d) compounds. A formula (d) compound and a base, preferably 2,5-di-t-butyl-3-methyl-pyridine in an appropriate organic solvent, preferably dichloromethane, is cooled te-20°C to 20°C, preferably 0°C, and reacted with a trihaloalkyî sulfonic anhydride,preferably trifluoromethanesulfonic anhydride to form compounds (e).

Formula (f) compounds are prepared by reacting a formula(e) compound ina métal catalyzed coupling reaction. Preferably a formula (e) compound dissolvedin dimethylformide (DMF) an organic base preferably, triethylamine, a phosphine,preferably bis(diphenylphosphino)propane, a palladium(II) compound, preferably,palladiumOI) acetate, and a Cvgalkyl alcohol (Ci.galkOH), followed by additionof carbon monoxide (CO). Compounds (f) next are reacted with a suitable base,preferably potassium carbonate, and acidified to yield compounds (g).

- 13-S.CHEMEJI

ο

II

?

te)

Scheme Π outlines formation of Formula Π compounds. The starting materials in Scheme Π are: formula (d) compounds prepared as described in Scheme I. - 14-

0 ϊ Ο 1 2 X

As used in Scheme II, a formula (d) compound and a base, preferably 2,5-di-t-butyl-3-methyl-pyridine in an appropriate organic solvent, preferablydichloromethanc, is cooled to -20°C to 20°C, preferably 0°, and reacted withfluorosulfonic anhydride to form compounds (h). Formula (f) compounds aie 5 prepared by reacting a Formula (h) compound in a metal-catalyzed couplingreaction. Preferably a Formula (h) compound is dissolved in dimethylformide(DMF) an organic base preferably triethylamine, a phosphine preferably bis(diphenylphospine)propane, a palladium(II) compound, preferably, palladium(II)acetate, and a Ci.galkyl alcohol (Cj.galkOH), followed by addition of carbon 10 monoxide (CO). Compounds (f) next are reacted with a suitable base, preferablypotassium carbonate, and acidified to yield compounds (g). - 15- 0 ί Ü i 1 2

Schcmg.gl %

_ COH

5 Scheme ΙΠ outlines formation of Formula H compounds. As used in

Scheme ΠΙ R.1 is CF3O2SO- or FO2SO-. As used in scheme ΠΙ in the alkylationprocess (step C), the pyridylthio ester is reacted with an LiR or an XMgR (X=C1,Br) Grignard reagent (as described hereinbelow), preferably isobutylmagnesiumbromide, n-octylmagnesium chloride, tert-pentylmagnesium chloride or 2,2 10 dimethylpropylmagnesium bromide, preferably in tetrahydrofuran tp form the desired product, preferably 17B-(isobutylcarbpnyl)-estra-l,3,5(10)-triene-3- carboxylic acid, 17B-(oct;dcaibonyl)-estra-l,X5(10)-triene-3-carboxylic acid, 17B- (tert-pentylcarbonyl)-estra-l,3,5(10)-triene-3-carboxylic acid, or 17B-(2,2- - 16- 0 i u i Z 2 dimethylpropylcarbonyl)-estra-l,3,5(10)-triene-3-carboxylic acid respectively inone or two steps.

In Route 1, the 3-hydroxyl acid (i) is converted to the 3-trifluoromethylsulfonylate or 3-fluorosulfonylate dérivative (j) (step A) by treating(i) with trifluoromethylsulfonyl anhydride or fluorosulfonic anhydride and anamine base, such as pyridine, preferably 2,5 di-t-butyl-3-methyl-pyridine, in anappropriate organic solvent, preferably dichloramethane at about -20°C to 20°C,preferably 0e.

The activated ester (k) is produced (step B) by treating (j) with 2,2-dithiopyridyl and triphenylphosphine in an appropriate organic solvent solutionpreferably, tetrahydrofuran/toluene at room température for about 8-14 hours.

The 17-acyl dérivative (1) is produced (step C) by treating (k) with aGrignard reagent, described hereinbelow, in tetrahydrofuran or diethyl cthersolvent, at a température of about -50 to -70°C, for 1-16 hours.

The 3-alkyl ester (f) is produced (step D) by treating (1) under carbonylationconditions, preferably by bubbling carbon monoxide gas through a solution of (1) inan appropriate organic solvent, preferably methanol, containing palladium acetatecatalyst, triphenylphosphine, and a tertiary organic amine preferably triethylamineat about room température for 1-16 hours. Compounds (f) next are reacted with asuitable base, preferably potassium carbonate and acidified to yield compounds (g)

Compounds (g) can also be produced (step G) by treating (1) undercarboxylation conditions, preferably by bubbling carbon monoxide gas through asolution of (1) in an an appropriate non-alcoholic solvent, preferably DMSO,containing a palladium catalyst, preferably palladium (Π) diacetate and 1,1-Bis(diphenylphosphino)ferrocene (DPPF); and a base, preferably potassium acetate,preferably at increased températures.

Route 2 involves converting the starting stéroïdal acid (i) to the 3-trifluoromethylsulfonylate or the 3-fluorosulfonylate dérivative (j) by the above-described step A; carbonylating (j) to (m) by step D; forming the activated 2-pyridylthio ester (n) by step B; forming the 17-acyl compound (f) by step C; andhydrolyzing 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) bythe above-described step B; forming the 17-acyl compound (d) by reacting (o) bythe above described step C; converting (d) to the 3-trifluoromethylsulfonylate or 3-fluorosulfonylate dérivative (1) by the above-described step A; and converting (1) to - 17- 0 1 ο i 2 2 the final producî (g) by thc above dcscribcd step G or by the above-described stepD followed by the above described step F.

<q>

CHO

MR -> (M-MgBr, MgCI, or U)(Grignard Reagent) 10 (r) 18- 0 i (I l λ' 2

5 Scheme IV outlines formation of Formula II compounds.

As used in Schane TV in the alkylation proccss (to préparé compounds ofFormula (s)), the carboxaldehyde is reacted with an Li-R or an XMgR (x=Cl, Br)Grignard reagent (as described hereinbelow), preferably propylmagnesiumbromide, méthylmagnésium bromide or 3,3-dimethylbutyl magnésium cbloride, 10 preferably in tetrahydrofuran to form the desired product, preferably 17B- (propyicarbonyl)-estra-1,3,5(10)-triene-3-cajboxylic acid, 17S-(methylcarbonyl)-estra-l,3,5(10)-triene-3-caiboxylic acid, 17B-(3,3-dimethylbutylcarbonyl)-estra-l,3,5(10)-triene-3-carboxylic acid respecdvely, in one or two steps.

The starting material in Scheme TV is Formula (c) cornpound prepared as in 15 Scheme I.

As used in Scheme TV, a Formula (c) cornpound and a base, preferably 2,5-di-t-butyl-3-methyl-pyridine in an appropriate organic solvent, preferablydichloromethane, is cooled to -20°C to 20°C, preferably 0°C, and reacted with atrihaloalkyl sulfonic anhydride, preferably tsifluoromethanesulfonic anhydride te 20 form compounds (p). _

Formula (q) compounds are prepared by reacting a Formula (p) cornpoundin a métal catalyzed coupling reaction. Prefcrably a Formula (p) cornpounddissolved in dimethylfonnide (DMF) and oqganic base preferably, triethylamine, a - 19- 0 101 Z 2 phosphinc, prefcrably bis(diphenylphosphino)propane, a palladi um(II) comjiound,preferably, palladium(II) acétate, and a Cj-C^llkyl alcohol (CpCgalkOH),followed by addition of carbon monoxide (CO). Formula (q) compounds arereacted with a reducing agent, prefcrably diisobutylaluminum hydride, to yieldFormula (r) compounds.

Formula (s) compounds are produced by treating Formula (r) compoundswith a grignard reagent (as described in Scheme ΙΠ) or a lithium reagent intetrahydrofuran or diethylether solvent, at a température of about -50° to -70°C, for 1-16 hours.

Formula (g) compounds are prepared by oxidation of Formula (s)compounds. Preferably said oxidation will utilize a Jones reagent ortetrapropylamonium penuthenate followed by sodium chlorite.

Grignard reagente of the type, XMgR, (where R is Ci_20 bnear or branchée.,saturated or unsaturated alkyl) for use in preparing ail of the species includcdwithin the scope of this invention, are availabte or can be made readily by oneskilled in the art.

Formula I compounds in which Z is in the a position are prepared C'omcompounds which contain the corresponding β substituent by the General Methodbelow.

General Method A

To a sdrrred solution of a substituted 17β stéroïdal dual 5a-reductaseinhibiting compound of Formula (Π) in an appropriate solvent, preferably ethyleneglycol or dimethyl sulfoxide, is added a base such as a hydroxide or alkoxide base,preferably sodium hydroxide, potassium hydloxide or sodium methoxide, at atempérature over 100°C preferably at reflux températures to yield thecorresponding a epimer, after isolation and work up.

In determining the appropriate solvent for conducting the epimerization,dimethyl sulfoxide or other non-reactive high boiling solvents are preferred whenthe starting 17B dual 5ot-reductase inhibiting steroidal compound contains réactivesubstituents or reactive unsaturated bonds thtt are, for example, subject tonucleophilic attack and ethylene glycol, or other reactive high boiling solvents canbe used when the reacthity of the substituents or any unsaturated bonds of thestarting 17B dual 5a-reductasc inhibiting steroidal compound is not a considération. -20- 0]0122

Also within the scope of the présent invention are the ketone réductionProducts of I, the secondary alcohols of the formula (TV):

wherein Y is a or β

OH

I

—— C—R in which R is Cj_20 linear or branched, saturated or unsaturated alkyl andpharmaceutically acceptable salts, hydrates, solvatés and esters theieof.

Prefened among' the presently inventod ketone réduction products describi^l

above are the secondary alcohols wherein theOH

I — C—R substituent is in the β position.

Particularly prefened among the presently invented ketone réduction productsdescribed above are 17B-(l-hydroxyethyl)-estra-l,3,5(10)-triene-3-carboxylic acidand 17&-(l-hydroxybutyl)-estra-l,3,5(10)-trienc-3-carboyxiic acid.

These compouncls can be made by conventional sodium borohydrideréduction of the carbonyl attached to R without epimerization of the 17 substituentor reducing the carboxy l in Ring A or the aromatic A ring.

The borohydride réduction can be canied out in e.g. water or aqueousmethanol, at a température of room température to 50°C and the product thenisolated and purified by conventional means. The çompounds are also active asdual inhibitors of 5-alpha reductase.

By the term "increased températures” as used herein and in the daims ismeant above 25°C, preferably at reflux températures.

By thé terni "solvent" or "appropriait solvent" as used herein and the in ihe daims is meant a solvent such as methylene chloride, ethylene chloride, chloroform, ethylene gïycol, carbon tetrachloride, tetrahydrofuran (THF), ethyl ether, toluene, ethyl acetate, dimethylsulfoxide (DMSO), N,N’-dimethyl-N,N'- -21 010122 propylene urea, N-methyl-2-pyrrolidinone, methanol, isopropylalcohol,dimethylfonnamide (DMF), hexane, water, pyiidine, quinoline or éthanol.

Pharmaceutically acceptable salts, hydrates and solvatés of Formula (I) andFormula (TV) compounds are formed, where appropriate, by methods well known 5 to those of skill in the art

In preparing the presently invented compounds of Formula (I), novelintermediates of the Formula (V) are synthesized;

O 11

10 in which R is Ci_20 Knear or branched, saturated or unsaturated alkyl andis fluorosulfonyloxy.

Also prefeired in synthesising the presently invented formula (I) compound swere novel intermediates of the formula (VI): 15

in which R is as described in formula (Π). A preferred process for preparing a compound of Formula (Π) 20 10 15 -22-

(Π) in which R is C|.2O ünear or branched, saturatod or unsaturated alkyl andpharmaceutically acceptable salts, hydrates, solvatés and esters thereof comprisesrcacting a compound of the formula

O

in which R is as described above with fluorosuifonic anhydride and a base,preferably, 2,5-t-butyl-3-methyl-pyridine, in a solvent, prcferably dichloromethane,to fonn a compound of th e formula

FOfeSO

in which R is as described above and subsequently reacting said compound in ametal-catalyzed coupling réaction in the présence of an approrpirate couplingreagent, prcferably, carbon monoxide followod by an optional, if applicable,hydrolysis reaction to fonn a compound of formula II, and thercafter optionallyforming a pharmaceutically acceptable sait, hydrate, solvaté or ester therecf.

Because the prcsently invented pharmaceutically active compounds are potent dual inhibitors of steroid 5-a-reductase activity, they hâve therapeutic utilii.y in trcating discases and conditions wherein decrcases in DHT activity produces the desircd therapeutic effect Such diseases and conditions include acné vulgaris, -23- 0 hn.2 2. seborrhea, fcraale hirsutism, male pattern baldness, prostate diseases such as benignprostatic hypertrophy, and prostatic adenocarcinoma.

In determining potency in inhibiting the human 5a-reductase enzyme, thefollowing procedure was employed:

Préparation of membrane paniculates used as spuree for recombinant steroid 5a-icductasc isozyme 1,

Chinese hamster ovaiy (CHO) cells containing expressed, recombinanthuman steroid 5a-reductase isoenzyme 1 (Andersson, S., Berman, D.M., Jcnkins, E.P., and Russell, D.W. (1991) Nature 354 159-161) were homogenized in 20 mMpotassium phosphate, pH 6.5, buffer containing 0.33 M sucrose, 1 mMdithiothreitol, and 50 pM NADPH (buffer A) using a Dounce glass-to-glass handhomogenizer (Kontes Glass Co., Vineland, NJ.). Membrane particulates wereisolated by centrifugation (100,000 x g at 4°C for 60 minutes) and resuspended in20 mM potassium phosphate, pH 6.5, containing 20% glycerol, 1 mMdithiothreitol, and 50 pM NADPH (buffer B). The suspended particulate solutionwas stored at -80°C.

Préparation of prostatic membrane particulate^ used as source for steroid 5tt-reductasc isozyme 2-

Prozen human prostates were thawed and minced into small pièces (

Brinkmann Polytron (Sybron Corp., Westbury, New York). The solution wassonicated for 3 to 5 minutes with a Sonifier (Branson Sonic Power Co.) followedby hand homogenizadon in a Dounce hand homogenizer. Prostatic particles wereobtained by differendal centrifugation at 600 or 1000 x g for 20 minutes and140,000 x g for 60 minutes at 4°C. The pellot obtained from the 140,000 x gcentrifugation was washed with 5 to 10 tissus volumes of the buffer describedabove and centrifuged at 140,000 x g. The rssuldng pellet was suspended in bufferB and the particulate suspension was stored at -80°C.

Préparation of membrane particulates used as source for recombinant steroid 5-oc- reductasc isozyme^

Chinese hamster ovary (CHO) cells containing expressed, recombinant human steroid 5-a-reductase isozyme 2 were homogenized in 20 mM potassium phosphate, pH 6.5, buffer containing 0.33 M sucrose, ImM dithiothreitol, and 50 pM NADPH (buffer A) using a Douce hand homogenizer. Membrane particulate s -24- y ι ο 122 containing the recombinânt human enzyme were isolated by centrifugation(100,000 x g at 4°C for 60 minutes) and resuspended in 20 mM potassiumphosphate, pH 6.5 containing 20% glycerol, lmM dithiothreitol, and 50 μΜNADPH (buffer B). The suspended particulate solution was stored at -80°C untilused.

Assay for enzymes activées and inhibitois posngy. A constant amount of [^C]testosterone (50 to 55 mCi/mmol) in éthanoland varying amounts of potential inhibitor in éthanol were deposited in test tubesand concentrated to dryness in vacuo. To each tube was added buffer, 10 jiL(recombinânt isoenzyme 1 or isoenzyme 2) or 20 pL (isoenzyme 2 frotn humanprostate tissue) of 10 mM NADPH and an aliquot of a steroid 5a-reductasepréparation to a final volume of 0.5 mL. Assiys for human steroid 5a-reductaseisoenzyme 1 were conducted with a sample of the recombinant protein expressed inCHO cells in 50 mM phosphate buffer, pH 7.5 while assays of isoenzyme 2 wereconducted with a suspension of human prostate particulates and/or recombinantprotein expressed in CHO cells in 50 mM cioate buffer at pH 5.0.

After incubating the solution at 37°C for 20 or 30 minutes the reaction wasquenched by the addition of 4 mL ethyl acétate and 025 pmol each of testosterone,5a-dihydrotestosterone„ androstanediol, and tndrostanedione as carriers. Theorganic layer was rcmoved to a second test tube and evaporated to dryness in aSpeed Vac. The residue was dissolved in 40 pL chloroform, spotted on artindividual lane of a 20 x 20 cm prechanneUed silica gel TLC plate (Si 250F-PA,Baker Chemical) and developed twice with acetone:chloroform (1:9). Theradiochemical content in die bands of the substrate and the products wasdetermined with à BIOSCAN Imaging Scanner (Bioscan Inc., Washington, D.C.).The percent of recovered radiolabel converted to product was calculated, fromwhich enzyme activity was determined. AU incubations were conducted such tintno more than 20% of the substrate (testosterone) was consumed.

The experimentaUy obtained data was computer fit to a linear function byplotting the reciprocal of the enzyme activity (1/veloçiry) against the variableinhibitor concentration; apparent inhibition constants (Kj^pp) were determined bythe Dixon analysis (Dixon, M. (1953).

The value for die inhibition constant (Ki) was calculated from known procedures (Levy, M. (1989), Biochcmistty. 22:2815-2824). -25- Ü l 0 î Z 2 AU of the compounds within the scope of this invention are useful ininhibiting steroid 5-a-reductase isozyme 1 and steioid 5-a-reductase isozyme 2in a mammal, including humans, in need thereof.

Compounds within the scope of this invention hâve been tested and hâveshown an activity of ftom 15 Ki(nM) to 180 Ki(nM) against isozyme 1 and anactivity of from 0.5 Ki(nM) to 30 Ki(nM) against isozyme 2. Particularly preferredamong the compounds of the invention and the compounds used in the inventedpharmaceutical compositions and invented methods are 17B-(isobutylcarbonyl)-estra-l,3,5(10)-triene-3-carboxylic acid, 17S-(octylcarbony l)-estra-1,3,5 ( 10)-triene-3-carboxylic acid, 17B-(teit-pentylcarbonyl)-estra-1,3,5(10)-triene-3-carboxylic acid, 17U-(2,2-dimethylpropylcarbonyl)-estra-1,3,5(10)-triene-3-carboxylic acid, 17B-(propylcarbonyl)-estra-l,3,5(10)-triene-3-carboxylic acid, 17B-(methylcarbonyl)-estra-1,3,5(10)-triene-3-carboxylic acid, 17B-(3,3-dimethylbutylcarbonyl)-estra-l,3,5(10)-triene-3-carboxylic acid, 17B-(l-hydroxyethyl)-estra-l,3,5(10)-aiene-3-carboxylic acid and 17B-(l-hydroxybutyl)-estra-l,3,5(10)-triene-3-caiboxylic acid.

The pharmaceutically active compounds of the présent invention areincorporated into convenant dosage forms preferably as capsules, tablets, orinjectable préparations. Solid or liquid pharmaceutical carriers are employed.

Solid carriers include, starch, lactose, calcium sulfate dihydrate, terra alba, sucrose,talc, gelatin, agar, pectin, acacia, magnésium stéarate, and stearic acid. Liquidcarriers include syrup, peanut oU, olive oil, saline, and water. Similarly, the; carrieror diluent may include any prolonged release material, such as glycerylmonostearate or glyceryl distearate, alone or with a wax. The amount of solidcamer varies widely but, preferably, will be from about 25 mg to about 1 g perdosage unit. When a liquid carrier is used, the préparation will peferably be in theform of a syrup, élixir, émulsion, soft gelatin capsule, stérile injectable liquid suchas an ampoule, or an aqueous or nonaqueous liquid suspension.

The pharmaceutical preparaüons are Otade following conventionaltechniques of a pharmaceutical chemist involving mixing, granulating, andcompressing, when necessary, foriablet forms, or mixing, fUling and dissolving theingreidents, as appropriate, to give the desired oral or parentéral products.

Doses of the piesentiy invented phanaaceutically active compounds in a pharmaceutical dosage unit as described above will be an efficacious, nontoxic -26- 0 I 0 i, 2 2 quantity preferably selecttd from the range of 0.1 -1000 mg/kgof active compound, preferably 1 - 100 mg/kg. When treating ahuman patient in need of stcroid 5-a-reductase inhibition, the selected dose isadministtred preferably from 1-6 tunes daily, orally or parentcrally. Preferredforms of parentéral administration include topioally, rectally, transdermally, byinjection and continuously by infusion. Oral dosage units for human administrationpreferably contain from 1 to 500 mg of active compound. Oral administration,which uses lower dosages is preferred. Parentéral administration, at high dosages,however, also can be used when safe and convonient for the patient

The method of this invention of inhibiting stcroid 5-a~reductasc isoz.yme 1and steroid 5-a-reductase isozymé 2 activity in mammals, including humans,comprises administering to a subject in need of such inhibition an effective dual.nhibiting amount of a compound of the présent invention.

The invention also provides for the use of a compound of Formula (I) or acompound of Formula (TV) in the manufacture of a médicament for use in the dualinhibition of steroid 5-a-reductase.

The invention also provides fora pharmaceutical composition for use in thetreatment of benign prostate hypcrtrophy whioh comprises a compound of FormulaI or a compound of Formula (IV) and a phannaceutically acceptable carrier.

The invention also provides for a pharmaceutical composition for use in thetreatment of prostatic adr ocarcinoma which comprises a compound of Formula Ior a compound of Formula (TV) and a phannaceutically acceptable carrier.

The invention also provides for a process for preparing a pharmaceuticalcomposition containing a phannaceutically acceptable carrier or diluent and acompound of Formula I or a compound of Formula (IV) which comprises bringingthe compound of Formula I or the compound of Formula (TV) into association withthe phannaceutically acceptable carrier or diluent.

No unacceptable toxicological effects are expected when compounds of theinvention are administered in accordance with the présent invention.

In addition, the phannaceutically active compounds of the présent inventioncan be co-administered with further active ingrédients, such as other comj>oundsknown to treat the diseuse States of acné vulgaris, seborrhea, female hirsutism, malepattern baldness, benign prostate hyperirophy or prostatic adenocarcinoma orcompounds known to hâve ütility when used in combination with 5-a-reductaseinhibitors. Particularly preferred is the co-administration of a dual 5-a-reductaseinhibitor, as disclosed herein, and minoxidil for use in the treatment of male pattern -27- baldness. Parücularly preferred is the co-administradon of a dual 5a-reductaseinhibitor, as disclosed herein, and a α-receptor antagonist for use in the veannent ofbenign prostatic hypertrophy. Preferred is the ao-administration of a dual 5-îx-rcductase inhibitor, as disclosed herein, and an aromatase inhibitor for use in thetreatment of benign prostadc hypertrophy. Prefexred is the co-administradon of adual 5-ct-reductase inhibitor, as disclosed hereia, a a -receptor antagonist and anaromatase inhibitor for use in the treatment of benign prostadc hypertrophy.

Without further élaboration, it is believad that one skilled in the art can,using the preceding description, utilize the présent invention to its fullest extent.

The following Examples arc, therefore, to be construed as merely illustrative: andnot a limitation of the scope of the présent invention in any way. EX AMPLE 1-correspondipg to Scheme III17B-Isobufylcarbonvl-estra-l-3.5flQfr-triene-3-carboxvlic Acid (i) . S-(2-pyridyl)-3-hydroxy-estra-l,3,5(10)-triene- 17B-thiocarboxylate. A mixture of 3-hyclroxy-estra-l,3,5(10)-triene-17B-carboxylic acid (0.11 g,0.37 mmol), 2,2’-diipyridyl disulfide (0.163 g, 0.74 mmol), triphenylphosphine(0.19 g, 0.74 mmol) and dichloromethand (20 ml) was stirred at ambienttempérature under argon for 4 hours. The restdting solution was concentraüid andthe residue was chromatographed (silica gel, eluting with 25 % ethyl acetate: inhexane) to provide 0.13 g of the title compound as a white solid, mp 195-196°C(recrystallized ffom ethyl acetate - methanol). (ii) . 17B-Isobutylcarbonyl-3-hydroxy-estra-13»5(10)-triene.

Isobutylmagnesium bromide (2.3 mL; 2M in diethyl ether) was addedslowly to a solution of S-(2-pyridyl)-3-hydroxy-estra-l,3,5(10)-triene-17B~thiocarboxylate (0.60 g, 1.53 mmol) in tetrahydrofuran (20 mL) at -78°C. After 1hour, the mixture was quenched with saturated aqueous NH4CI and extractcd withethyl acetate. The organic extract was washed with brine, dried, and concentrated.The resulting residue was chromatographed (silica gel, eluting with 15% ethylacetate in hexane) to givc a foam. Trituration with diethyl ether and hexane gave awhite solid (0.27 g). (iii) . 17B-Isobutylcarbonyl-estra-l,33(10)-triene-3-trifluoromethylsulfonaxe.

To a cooled (0°C) solution of 17B-Isobutylcarbonyl-3-hydroxy-esaa- l,3,5(10)-triene (0.28 g, 0.82 mmol) and 2,6«di-tert-butyl-4-methylpyridine (0.17 0 ί υ 1 ζ 2 -28- g,0.83 mmol) in dichloromethane (20 ml) was slowly added trifluoromethanesulfonic anhydride (023 g, 0.82 mmol). The resuldng solution was stirred at 0°Cfor 1 hour and then at ambient température of 30 minutes. The reaction mixturewas washedwith dilute HCl.water, dilute NaHCC>3, brine dried and concentrated.The resulting residue was chromatographed (silica gel, 7% ethyl acetate in hexane)to provide 0.13 g of oil. (iv) . Methyl-17B-isobuüdcarbonyl-estra-l,3,5(10)-triene-3-carboxylate.

Amixtureofl7B-isobutylcarbonyl-es»a-l,3,5(10)-triene-3-trifluoromethylsulfonate (0.13 g 0.28 mmol), palladium (Π) acetate (4.2 mg, 0.0187mmol), l,3-bis(dipheriylphdsphiho)propane (dppp, 7.5 mg, 0.0182 mmol),triethylamine (0.08 mL)„ methanol (0.6 mL), 1,2-dichloroethane (0.32 mL), andDMSO (1 mL) was heated at 70-75°C under an atmosphère of CO ovemight. Thecooled réaction mixture was then diluted with dichloromethane, washed wi th water,dilute HQ, dilute NariCOj brine, dried and concentrated. The residue waschromatographed (silica gel, eluting with 10% ethyl acetate in hexane) to provide70 mg of the title compound. (v) . 17B-IsobutyIcarbonyl<stra-l,3,5(10)-triene-3-caxboxylic acid. A mixture of methyl-17B-isobutylcarbonyI-estra-1,3,5( 10)-tricne-3-carboxylate (70 mg, 0.18 mmol), K2CO3 (0.12 g, 0.87 mmol), water (1.5 mL) andmethanol (10 mL) was heated at reflux ovemdght. The reaction mixture was thenconcentrated. The residue was diluted with water, acidified with dilute HCl andextracted with ethyl acetate. The organic exaract was washed with brine, dried, andconcentrated. Thé ride compound purified by HPLC. mp202-206°C.

EXAMPLE 2-corrc5PQHding to Schcme HI 17B-Isobutvlcarhonvl-cstra-1.3.5(J0)-triene-3-carboxvlic Acid (i). 17p-Isobutylcàrbonyl-estra-l,3^(10)-ttiene-3-fluorosulfonate. A solution of 17i3-isobutylcarbonyl-estra-l,3,5(10)-trien-3-ol, preparedaccording to Example 1 (i ; . in dichloromethane at 0°C is treated with 2,5-di-t-butyl-3-methyl-pyridine fouowed after 10 min with fluorosulfqnic anhydride. Theresulting mixture is stined for 2 h and then diluted with dichloromethane. Theorganic layer is washed with saturittèd aqueàus NaHCQs and brine, dried overMgSCU, and evapééâted to dryness? Chromatography on silica gel yields the titecompound. -29- 0 I 22 (ü). Methyl 17P-Isobutylcaibonyl-estra-l,3,5(10)-triene-3-carboxylate. A mixture of 17J3-isobutylcarbonyl-estra-1,3,5( 10)-triene-3-fluorosuIfonate l,3-bis(diphenylphosphino)propane, palladium diacetate, triethylamine, methanol,DMSO and 1,2-dichlorocüiane is heated and vigorously stirred for 5 h at 80°Cunder an atmosphère of carbon monoxide. After cooling to ambient température,the rcsulüng mixture is diluted with dichloromethane. The organic phase isthoroughly washed with water, dried (MgSÛ4) and evaporated to dryness.Chromatography on silica gel yields the title compound. (iii). 17|3-Isobutylcarbonyl-estra-l,3,5(10)-triene-3-carboxylic Acid. A mixture of methyl 17{i-isobutylcarbonyl-estra-l,3,5(10)-triene-3-carboxyiate, K2CO3, water and methanol is heated at reflux for 5 h. The volatilesare then removed at reduced pressure and the residue is diluted with water, acidifiaiwith dilute aqueous HCl, and extracted with EtOAc. The organic extract is washedwith water and brine, dried, and evaporated to yield the title compound. EXAMPLE 3-conc5pandin& ifl..SchcmcHI17felsflbattlcaibonyl^sff-.l .3.5( lOrgicnsJ-carbgxylic acid (i) . 3-(trifluoromethanesulfonyloxy)-estra-l,3,5(10)-triene-17û-carboxylic acid A solution of 3-hydroxy-estra-l,3,5(10)-17B-carboxylic acid, 2,6-di-t-butyl- 4-methyl pyridine and trifuloromethane sulfonic anhydride in methylene chloride isstirred at 5°C for 20 hours. The organic solvent is evaporated and the residue isdissolved in tetrahydrofuran water (99.5:0.5) with 4-dimethylaminopyridine whichupon acidification with hydrpchloric acid followed by convenüonal workup yieldstitle compound. (ii) . S-(2-pyridyl)-3-(triflurormethanesulfonyloxy)-estra-1,3,5(10)-triene- 17B-thiocarboxylate A solution of 3-(trifluoromethanesulfbnyloxy)-estra-l,3^(10)-triene-17B-carboxylic acid, triphenylphosphine and, 2,2-dipyridyl disulfide in toluene isstirred under nitrogen for 20 hours. The reaction mixture is concentrated and theresidue is passed directly through silica gel and appropriate fractions evaporated toyield. title comopund. (iii) . 17B-Isobutylcarbonyl-estra-1,3,5 (10)-triene-3-trifluoromethane sulfonate -30- 0 10122 Το a solution of S-(2-pyridyl)-3-(trifluofomethanesulfonyloxy)-estra·l,3,5(10)-triene-17B-thiocarboxylate in tetrahydrofuran at about -50°C is addedisobutylmâgnesium bromidc. The reaction mixture is warmed to about -10°C, anddiluted with a saturated aqueous ammonium chloride solution. Conventionalworkup with subséquent isolation by column chromatography yields titlecompound. (iv) . Methyl 17B-Isobutylcarbonyl-estra-l,3*S(10)-triene-3-carboxylate A solution of 17B-ïsobutylcarbonyl-estra-l,3,5(10)-triene-3-trifluoromethane sulfonate, triphenyl phosphine, palladium Π acetate, triethylamine,methanol and dimethyl fonnamide is stirrcd vigorously under a carbon monoxideatmosphère for 20 hours. Conventional workup with subséquent isolation bycolumn chromatography yields title compound. (v) . 17,B-Isobutylcarbonyl-estra-l,3,5(10)-triene-3-carboxylic acid A mixture of methyl 17B-isobutylcarbonyl-estra-l,3,5(lQ)-trienc-3-carboyxlate, K2CO3, water and methanol is heated at reflux for about 5 hours.Acidifications followed by conventional workup yields title compound. EXAMPLE 4-coirespondpi g to Scheme ΙΏ17B-Isobutylcarbonyl-estr-1.3.5f l(p-triene-3-carboxylic acid (i) . 3-(fluorosulfonyloxy)-estra-l,3,5(10)-trieae-17B-carboxylic acid A solution of 3-hydroxy-estra-l,3,5(lQ)-17B-carboxylic acid, 2,6-di t-butyl - 4-methyl pyridine and fluorosulfonic anhydride in methylene chloride is stirrcd at5°C for 20 hours. The réaction mixture is washed with aqueous hydrochloric acidand water. The organic phase is concentrated and the resulting residue is purifiedby column chromatography to yield the title compound. (ii) . S-(2-pyridyl)-3-(fluorosulfonyloxy)-esti>-l,3,5(10)-triene-17B-thiocarboxylare A solution of 3-(Huorosulfonyloxy)estra-l,3,5(10)-triene-17B-carboxylicacid, triphenylphosphine and, 2,2'-dipyridyl disulfide in toluene is stirrcd undernitrogen for 20 hours. The réaction mixture is concentrated and the residue ispassed directly through silica gel and appropriate fractions eyaporated to yield titlecompound. (iii) . 17B-Isobutylcarbonyl-estra-l,3,5(10)-triene-3-fluorosulfonate -31 - Το a solution of S-(2-pyndyl)-3-(fluor»suifonyloxy)-estra-l,3,5(10)-lriene-I7B-thiocarboxyiate in tctrahydrofuran at about -50°C is added isobutylmagnesiumbromide. The reaction mixture is warmed to about - 10°C and diluted with asaturated aqueous ammonium chloride solution. Conventional workup with 5 subséquent isolation by eolumn chromatography yields title compound. (iv). Methyl 17B-iso butylcarbonyl-estra-1,3,5( 10)-triene-3-carboxylate À solution of 17ll-isobutylcarbonyl-csara-l,3»5(10)-triene-3-fluorosulfonate,rriphenyl phosphine, palladium II acetate, triethylamine, methanol and dîmethyl 10 formamide is stirred vigorously under a carbon monoxide atmosphère for 20 hours.Conventional workup with subséquent isolation by eolumn chromatography yieldstitle compound. (v). 17B-Isobutylcarboriyl-estra-l,3,5(lO)-triene-3-carboxylic acid15 A mixture of methyl î7B-isobutylcarbonyl-estra-l,3t5(10)-trienc-3- carboxyiate. K-jCOg, water and methanol is beated at reflux for about 5 hours.Acidificanon i toweti by conventional workup yields title compound. ing to Scligme.ni 20 .2 y. '.•jcarbonyn-estra-î.3.5f|0,>-triene-3-cgrboxylic acid (i) 17ii-''.crcarbonyî)-estra-l^,5(ÎO)-tB.cne-3-trifluoromcthylsulfonate.

The ritle compound was prepared accortiing to Example 1 (i-iii) bysubstitutniK .i-cctyunagnesium chloride for isobutylmagnesium bromide in step (ii), 25 (ii) I7^-iûctyicarbonyl)-estra-l,3,5(10)-uiene-3-carboxylic acid. A mixture of 17^-(octylcarbonyl)-estra-l^,5(10)-triene-3- tntluoromethyisuifonaie (0.38 g, 0.7 mmol), potassium acetate (0.27 g),palladiumAI) diacetate (0.008 g, 0.036 mmol), 1,1-

bis(diDhenv!phosphino)ferrocene(dppf; 0.08 g, 0.14 mmol), in DMSO (15 ml) was30 purged with carbon monoxide for 2 minutes and stirred under a CO balloori at 60°C ovemight. The reaction mixture was diluted with water, acidifled with. 0.5Nhydrochlcric acid and extracted with dichioromethane. The organic layer was•vsshed ντ± vaisr, dried (MgSO4), and evaporated under vacuum. The residue wascnromatcçranned fsiLica gel, eiuting with 20% ethylacetate, 1% acetic acid in 55 hexaix; :z .^::2 rond triturated with methanol-acetonitrile to yield the titleccmocu::·’ "22 g <73%) mn 175’C. -32- 0 ( 0 I Z 2

Example 6 : Cwresponding.ip SchcmcJIll?&-ftcrt-P6niylcarfapnylhgaia-1.3J(.Whgicng-3rcarbpxylig acid (i) Trifluoromcthyl-17P>-(tcrt-pcntylcarbonyl>-cstra-l,3»5(10)-tricnc-3-sulfonate.

The title compound was prcparcd according to Example 1 (i-iii) bysubstituting tert-pentylmagnesium chloride for isobutylmagnesium bromide in step (ii) . (ii) 17fi-(teit-pentylcarbonyl)-estra-l,3,5(10)-triene-3-carboxyIic acid.

The title compound was préparai according to Example 5 (ii) by substitutingtrifluoromethyl-17|3-(tert-pentylcarbonyl)-estra-l,3»5(10)-triene-3-sulfonate, aspréparai in Example 6 (i)„ for trifluoromethyl-17|3-(octylcarbonyl)-estra-1,3,5(10)-triene-3-sulfonate. mp 199-200°C.

Example 7- Carrcspondigg to Schcmg-ΠΙI7^-,(2,2-dimcthylprûpylgaibonyl)-c5tra-U3^(10)-tngng.-3-garbQxylic acid (i) Trifluoromethyl-17j3-(2,2-dimethylpropylcarbonyl)-estra-l,3,5(10)-triene-3sulfonate.

The title compound was préparai accoading to Example 1 (i-iii) bysubstituting 2,2-dimethylpropylmagnesium bromide for isobutylmagnesium bromidein step (ii). (ii) 17J3-(2,2-dimethylpropylcarbonyl)-estra-l,3,5(10)-triene-3-carboxyIic acid.

The title compound was préparai according to Example 5 (ii) by substituting trifluoromethyl-17fï-(2,2-dimethylpiopylcarb©nyl)-estra-l,3»5(10)-triene-3-sulfonate, as prcparcd in Example 7 (i), for trifluoromethyl-17p-(octylcarbonyl)-estra-l,3,5(10)-trienc-3-sulfonate. mp 210°C.

Example 8 - Correspondine to Scheme IV17S-fpronvlcarbonvn-estra-1.3.5il01-triene-3-carbQxvlicacid (i) 17fJ-cyano-estra-1,3,5(10)-tricnc-3-methanesulfonatc.

The title compound is known and is prepared firom estrone according to theprocedure of Baldwin et al., J. Chèm. Soc. (C), 1968,2283-2289. (ii) 17fi-Cyano-estra-l,3,5(10)-triene-3-ol. -33- < J i 0 î 2 2

The tille compound of 17J3-cyano-estra-l,3,5(10)-triene-3-methanesu].fonate(10 g) in methanol (100 ml.) is added dropwise a solution of NaOH (42 mL of a20% solution in 1:1 MeOH-water). The resulting mixture is heated to 40°C for 24 h .*· - ... i after which time the mixture is cooled to 0°C, diluted with water (350 mL), andacidified with dilute HCl. The resulting white piecipitate is isolated by vacuumfiltration, washed with water, and dried under vacuum. Recrystallization frornacetonitrile provides the title compound mp 249-250°C Dec.. (iii) 17P-cyano-estra-l,3,5(10)-triene-3-trifluoromethanesulfonate. 17|3-cyano-estra-l,3,5(10)-triene-3-ol (4.2 g) and 2,6-di-t-butyl-4- methylpyride (3.6 g) was dissolved in 50 ml of methylene chloride. The mixturewas stirred at room température for 30 min. Triflic anhydride (4.2 ml) was addedand the mixture was stirred another 40 mins, diluted with 50 ml CH2CI2, filtered,concentrated, and chromatographed on silica gel. Elution with 20% ethyl acetate inhexane gave 5.3 g (87%) of the title compound, mp 115-117°C. (iv) Methyl 17^-cyano-estra-l,3,5(10)-triene-3-carboxylate.

To a solution of 17|3-cyano-cstra-l,3,5(10)triene-3-ol (10 g) in 77 ml ofDMSO and 50 ml of MeOH was added 7 ml of triethylamine, 0.35 g of palladiumacetate, 0.64 g of bis(diphenylphosphino)propane and 1,2-dichloroethane (26 ml).Carbon monoxide was bubbled through the solution and the reaction mixture: wasthen stirred at 75°C ovemight under 1 atm of CO (balloon). The mixture wasdiluted with EtOAc and washed with water (3x), dried, and concentrated. Theresidue was chromatographed (silica gel, elutiog with 10% EtOAc in hexane) toprovide 4.5 g of the title compound, mp 161-163°C. (v) 3-Hydroxymethyl-estra-1,3,5( 10)-triene- 17^-carboxaldehydc.

Methyl-17fJ-cyano-estra-l,3,5(10)-trieae-3-carboxylate (0.8 g) was dissolved in 30 ml of toluene and treated with DIB AL (6 ml, IM). The mixture was stirred atroom temp under argon for 2.5 hours. The mixture was then poured into 50 ml of5% H2SO4 and the mixture was stirred for 1 hour, filited, dried, and concentrated.The residue was chromatographed (silica gel, eluting with 20% EtOAc in hexane) 1:0provide 424 mg of the tille compound, mp 146-150°C. (vi) 17{3-(l-hydroxybutyl)-estra-l,3,5(10)-triene-3-hydroxymethyl. 010 12 2 -34- A solution of 3-hydroxymethyl-estra, l,3,5(10)-triene-17^arboxaldchyde(75 mg in 2 ml of THF) was àdded slowly to a solution of propylmagnesiumbromide (2 ml, 1.6 M). The'mixture was stirred at room temp for 2 hours.

The mixture was quenched with saturated aqueous NH4CI and extracitedwith CH2CI2. The organic extract was washed with brine, dried, and concentrated.The resulting residue was chromatogipahed (silica gel, eluting with 30% ethylacetate in hexane) to give 57 mg of title compound. (vii) 17^-(propylcarbonyl)-estra~l,3,5(10)-triene-3-carboxylic acid. 17£-(l-hydroxybuiyl)-estra-l,3,5(10)-triene-3-hydroxymethyl (57 mg) wasdissolved in acetone (5 ml) and treated with Jones reagent The mixture was stirredfor 1 hour and then quenched with 2-propanol, extracted with CH2CL2 and purifiedby chromatography (silica gel, eluting with 30% etase in hexane with 0.5% HOAcadded) to give 47 mg of the title compound, mp 211-213°C.

Exainris.9Correspondes io. Schème JY17&-(mcthylcarbQnyl)-çstra-1 .g^iWl-tticnc^garboxylig acid

The title compoiind was prepared according to Example 8 (i)-(vli) b}'substituting méthylmagnésium bromide for propylmagnesium bromide in step (vi).mp 199-202°C. 17&?f3.3:dimcttiÿlbüCdgaifeanyl)-g5ffa- llt3^(10)-.ttiene-3.-carbQxylic acid

The title compound was prepared according to Example 8 (i)-(vii) bysubstituting 3,3-dimethylbutylmagnesium chlaride for propylmagnesium bromide instep (vi). mp 252-255°C.

Example 11 - Correspon^ngtoSchemelV 17Β-Π-fR.SVhvdroxvethvn-estra-l.33f 101-triene-3-c;irboxvlic acid(i) A solution of 17£l-(methylcarbonyl)-estra-l,3,5(10)-triene-3-carboxylic acid(6 mg) - prepared according to Example 9 - in methanol was treated with NaBH4(0.7 mg). Thé mixture was warmed to 45°C and stirred ovemighL The solvent wasremoved by rotary évaporation and the residue was dissolved in dichloromethaneand filtered. The title compound (1.6 mg) was purified by préparative thin layerchromatography, mp 202-204°C. -35- il UH Z < (ii) Pure (R) and (S) faims are obtained by séparation techniques readily available and known ta those of skill in the art

Example 12 - Correspondipp to Scheme IV 1?β-ί 1 -fR.Sl-hydK)xybutyn-estra-L3.y lOl-trienc-3-carboxvlic..acid (i) The title compound was prepared according to Example 11 by substiniting17£-(propylcarbonyl)-estra-l,3,5(10)-triene-3-earboxylic acid, prepared accordingto Example 8 (i)-(vii) for 17|3-(methylcarbonyl)-estra-l,3,5(10)-triene-3-carboxylicacid, mp 208-211°C. (ii) Pure (R) and (S) forms are obtained by séparation techniques readilyavailable and known to th ose of skill in the art

Example. 13

An oral dosage form for administering Formula I comounds is produced byscreening, mixing, and fîlling into hard gelatin capsules the ingrédients in theproportions shown in Table 1, below.

Table I

Ingrédients Amonnis nB-Isobutylcîirionyl-estra-l, 3,5(10)- 50 mg triene-3-caiboxylic acid magnésium stéarate 5 mg lactose 75 mg EXAMPUE.1.4

The sucrose, calcium sulfate dihydratt and Formula (I) compound shown inTable Π below, are mixed and granulated in die proportions shown with a 10%gelatin solution. The wet granules are screened, dried, mixed with the starch, talcand steaiic acid, screened and compressed into a tablet. -36- 0 ί U 1 2 2

Tablc.II

IngsdifiDis Amounis 17B-Isobutylcarbonyl-estra-1,3,5(10)- 100 mg triene-3-cartooxylic acid calcium sulfate dihydrate ISO mg sucrose 20 mg starch 10 mg talc 5 mg stearic acid 3 mg

ExawlLU 17B-lsobutylcart»nyl-estra-l,3,5(10)-triene-3-carboxylic acid, 75 mg, is5 dispursed in 25 ml of normal saline to préparé an injectable préparation.

While the prefened embodiments of the invention are illustratcd by theabove, it is to be understood that the invention is not limited to the préciséinstructions heiein disclosed and that the right to ail modifications commirg within 10 the soope of the following daims is reserved.

Claims

- 37 - 0ΙΟΙ 22 What is claimed is:

1. A compound represented by the formula:

(I) wherein Z is a or BO II -C-R in which R is Ci_20 ^near or branched, saturated or unsaturated alkyl andpharmaceutically acceptable salts, hydrates, solvatés and esters thereof.
2. A compound of claim 1 of the Formula:

(Π) in which R is (4 „20 Onear or branched, saturatcd or unsaturated alkyl andpharmaceutically acceptable salts, hydrates, solvatés and esters thereof
3. A compound of claim 2 having the following formula:

(ΙΠ) in which R^ is Cj.g linear or branched alkyl and pharmaceutically acceptable sait:», hydrates solvatés and esters thereof - 38 -
4. A compound of claim 3 wherein is methyl, cthyl, propyl, 3-mcthylbutyl, isopropyl, n-butyl, isobutyl, 1-methylpropyl, t-butyl, pentyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, octyl or 3,3-dimethylbutyl andpharmaceutically acceptable salts, hydrates, solvatés and esters thereof.
5. A compound of claim 4 wherein 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 andpharmaceutically acceptable salts, hydrates, solvatés and esters thereof. 6. 17B-(isobutylcaibonyl)-estra-l,3,5(10)-triene-3-carboxylic acid. 7. 17B-(octylcarbonyl)-estra-l,3,5(10)-triene-3-carboxylic: acicl. 8. 17B-(tert-pentylcarbonyl)-estra-l,3,5(10)-triene-3-carboxylic acid. 9. 17B-(2,2-climethylpropylcarbonyl)-estra-1,3,5(10)-triene-3-carboxylic acid. 10. 17B-(propylcarbonyl)-estra-l,3,5(10)-triene-3-carboxylic acid. 11. 17B-(methylcarbonyl)-estra-l,3,5(10)-triene-3-carboxylic acid. 12. 17B-(3,3 -dimethylbutylcarbonyl)-estra-1,3,5( 10)-triene-3-carboxyl ic acid.
13. A compound of claim 1 of the Formula ff

- 39 - 0 1 0 I Z 2 in which R is Cj_20 bnear or branched, saturated or unsaturated alkyl andpharmaceutically acceptable salts, hydrates, solvatés and esters thereof.
14. A compound of the formula

wherein Y is a or β OH — C—R in which R is Cp20 bnear or branched, saturated or unsaturated alkyl andpharmaceutically acceptable salts, hydrates, solvatés and esters thereof.
15. A compound of claim 14 in which Y is in the β position.
16. A compound of claim 14 in which Y is in the a position. 17. 17B-(l-hydroxyethyl)-estra-l,3,5(10)-triene-3-caiboxylic acid. 18. 17B-(l-hydroxybutyl)-estra-l,3,5(10)-triene-3-carboxylic acid.
19. A compound according to claim 1 substantially as hereinbeforedefined with référencé to anyone of the examples.
20. A pharmaceutical composition comprising a compound according toanyone of daims 1 to 18 and a pharmaceutically acceptable carrier.
21. A compound according to any one of daims 1 to 18 for use intherapy.
22. A compound according to any one of daims 1 to 18 in themanufacture of a médicament for use as a steroid 5-a-reductase inhibitor. - 40 - 010122
23. A compound according to any onc of daims 1 to 18 in themanufacture of a médicament for use in treatment to reduce prostate size.
24. A compound accotding to any oae of daims 1 to 18 in the 5 manufacture of a médicament for use in treatment of prostatic adenocarcinoina.
25. A process for the préparation of a compound of the Formula (Π)

10 in which R is C|.2O linear or branchcd, saturaied or unsaturated alkyl andpharmaceutically acceptable salts, hydrates, solvatés and esters thereof whichcomprises either i) oxidation of a compound of the Formula 15

in which R is as described above, or 20 (ii) reacting a compound of the Formula - 41 -

in which R is as described above in a metal-catalyzed coupling reaction in thepresence of an appropriate coupling reagent, preferably, carbon monoxide followedby an opdonal, if applicable, hydrolysis reaction, or (iii) hydrolyzing a compound of the Formula C^alkyl

10 in which R is as described above and thereafter optionally forming apharmaceutically acceptable sait, hydrate, solvaté or ester thereof.
26. A process for the préparation of a compound of the formula (Π)

(Π) in which R is Cp20 bneaT or branched, saturated or unsaturated alkyî and pharmaceutically acceptable salte, hydrates, solvatés and esters thereof which comprises reacting a compound of the formula 15 - 42 -

in which R is as described above with fluorosulfonic anhydride and a baseprefcrably, 2,5-di-t-butyl-3-methyï-pÿridine, in a solvent, preferably,dichloromethane to form a compound of the formula

in which R is as described above and subsequently reacting said compouncl in ametal-catalyzed coupling reaction in the présence of an appropriate couplingreagent, preferably, carbon monoxide, followed by an optional, if applicable,hydrolysis reaction to fonn a compound of formula (Π) and thereafter optionallyforming a pharmaceutically acceptable sait, hydrate, solvaté or ester thereof.
27. A process for preparing a compound of the Formula

in which R is Cj_20 hnt;ar or branched, satupted or unsaturated alkyl and ·«#··... pharmaceutically acceptable salts, hydrates, solvatés and esters thereofwhich comprises epimerization of a compound of Formula (Π) 1 - 43 -

010122 pharrnaceutically acceptable sait, hydrate, solvaté or ester thereof.
28. A process for preparing a pharmaceutical composition conuining apharrnaceutically acceptable carrier or diluent and an effective amount of a

in which Z is a or BO II -C-R in which R is Ci_20 linear or branched, saturated or unsaturated alkyl andpharrnaceutically acceptable salts, hydrates, solvatés and esters thereofwhich process comprises bringing the compound of the Formula (I) or apharrnaceutically acceptable sait, hydrate, solvaté or ester thereof, into associationwith the pharrnaceutically acceptable carrier or diluent.
29. A compound of the formula (V): O II

in which R is Ci_20 linear or branched, saturated or unsaturated alkyl and - 44 - is fluorosulfonyloxy.
30. A compound of the Formula (VI) 010122

in which R is C}_20 ^ncar or branched, saturaied or unsaturated alkyl.
31. Use of a compound according to any one of daims 1 to 18 in themanufacture of a médicament for use in inhibiting steroid 5-a-reductase. 10
32. A method of inhibiting steroid 5-a-reductase in mammals whichcomprises the administration to a mammal in need such inhibition, an effectiveamount of a compound according to any one of daims 1 to 18.
33. The use of a compound according to anyone of daims 1 to 18 and an aipha-receptor antagonist compound as an active therapeutic substance which useconsist of separate sequential or simultaneous administration of a compoundaccording to anyone of daims 1 to 18 and an aipha-receptor antagonist compound.
34. The use of a compound according to anyone of daims 1 to 18 and an aipha-receptor antagonist compound in the manufacture of médicament for use inthe treatment of benign prostatic hypertrophy which use consist of separatesequential or simultaneous administration of a compound according to anyone ofdaims 1 to 18 and an aipha-receptor antagonist compound. 2.5
35. The use of a compound according to anyone of daims 1 to 18 and anaromatase inhibiting compound as an active therapeutic substance which useconsists of separate sequential or simultaneous administration of a compoundaccording to anyone of daims 1 to 18 and aa aromatase inhibiting compound. 30
36. The use of a compound according to anyone of daims 1 to 18 anci anaromatase inhibiting compound in the manufacture of a médicament for use in tte - 45 - OUI 122 treatment of benign prostatic hypertrophy which use consist of separate sequentialor simultaneous administration of a compound according to anyone of daims 1 to18 and an aromatase inhibiting compound.
37. The use of a compound according to anyone of daims 1 to 18 andminoxidil as an active therapeutic substance which use consist of separate sequentialor simultaneous administration of a compound according to anyone of daims 1 to18 and minoxidil.
38. The use of a compound according to anyone of daims 1 to 18 andminoxidil in the manufacture of a médicament for use in the treatment of malepattern baldness which use consist of separate sequential or simultaneousadministration of a compound according to anyone of daims 1 to 18 and minoxidil.
39. The use of a compound according to anyone of daims 1 to 18 and anaromatase inhibiting comjxjund and an alpha-receptor antagonist compound as anactive therapeutic substance which use consiste of separate sequential orsimultaneous administration of a compound according to anyone of daims 1 to 18and an aromatase inhibiting compound and an alpha-receptor antagonist compound.
40. The use of a compound according to anyone of daims 1 to 18 and anaromatase inhibiting compound and an alpha receptor antagonist compound in themanufacture of a médicament for use in the treatment of benign prostatichypertrophy which use consist of separate sequential or simultaneous administrationof a compound according to anyone of daims 1 to 18 and an aromatase inhibitingcompound and an alpha-receptor antagonist compound.