SI9300350A - 17(alpha) and 17(beta)alkylketon-3-carboxyaromatic a cyclic analogs of steroidal synthetic compounds - Google Patents

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

17a and 17/3-alkylketone-3-carboxy aromatic A ring analogs of steroid synthetic compounds

The present invention relates to certain novel 17a and 17/3-alkylketone-3-carboxy aromatic A ring steroid compounds, pharmaceutical compositions containing these compounds and methods for using these compounds to inhibit steroid 5-areductase isomer 1 and steroid 5-a -reductase isozyme 2. In the present invention there are also novel intermediates and processes useful in the preparation of these compounds.

A type of steroid hormone known as androgen is responsible for the physical characteristics that differentiate men from women. Of the various organs that produce androgens, these hormones produce the largest amount of testicles. Centers in the brain have primary control over the level of androgen production. Many physical manifestations and disease states occur when ineffective control results in the overproduction of androgen hormones. E.g. common acne, seborrhea, female hirsutism, typical male baldness and prostate diseases such as benign prostatic hypertrophy are associated with increased androgen levels. In addition, a decrease in androgen levels has been shown to have a therapeutic effect on prostate cancer.

Testosterone is the major androgen secreted from the testes and is the primary androgenic steroid in male plasma. Up to now, 5-a-reduced androgen is known to be an effective hormone in some tissues, e.g. prostate and sebaceous glands. Circulating testosterone thus serves as a prohormone for dihydrotestosterone (DHT), its 5-a-reduced analog, in these tissues, but not in others, such as e.g. muscles and testes. Steroid 5-a-reductase is an enzyme dependent on nicotinamide adenine dinucleotide phosphate (NADPH), which converts tes2 toosterone into DHT. The importance of this enzyme in male development is dramatically emphasized by the discovery of a genetic steroid 5-a-reductase deficiency in male pseudohaemaphrodites. Imperato-McGinley, J., et. al., (1979), J. Steroid Biochem. 11: 637-648.

Numerous 3-carboxy-esters 1,3,5 (10) triene 5-a-reductase inhibitors are known in the art. E.g.

1. J. Steroid Biochem., Vol. 34, no. 1-6, p. 571-575 (1989) from M.A. Levy, et al., Describes an interaction mechanism between rat prostatic steroid 5-a reductase and 3-carboxy-17/3-substituted steroids;

2. J. Med. Chem. (1990) Vol. 33, p. 937-942, from D.A. Holt, et al., Describes a novel steroid class of aryl carboxylic acids with A ring;

3. TIPS (December 1989) Vol. 10, p. 491-495, from B. W. Metcalf, et al., Describes the effect of steroidal 5a-reductase inhibitors on benign prostatic hyperplasia, typical male baldness, and acne.

In addition, U.S. Pat. No. 4,954,446 describes a group of 3-carboxy-ester 1,3,5 (10) triene-17/3-substituted compounds which have been shown to be useful inhibitors of stereoid 5-α-reductase. However, none of the references cited or suggested that any of the new 17/3-alkylketone-3-carboxy aromatic A ring steroid compounds of the present invention would be useful as a highly effective inhibitor of both the steroid-5-a-reductase isozyme 1 as well as for steroidal 5-areductase isozyme 2 (dual inhibitors).

The present invention relates to a compound of formula I:

where Z is a or β

Oh

II

-CR in which the RC _{3 2θ is} straight or branched, saturated or unsaturated alkyl and its pharmaceutically acceptable salts, hydrates, solvates and esters.

The present invention also provides a method for simultaneously inhibiting the effectiveness of 5-a-reductase isomer 1 and 5-a-reductase isomer 2 in mammals, including humans, comprising administering to the subject an effective amount of the compounds of the invention that inhibit 5-a- reductase. In a further aspect, the invention provides novel intermediates and novel methods useful in the preparation of the compounds of the invention for the dual inhibition of 5-α-reductase. Also included in the present invention are compositions comprising a pharmaceutical carrier and compounds useful in the processes of the invention. The present invention also includes methods for co-administration of the compounds of the invention for the dual inhibition of 5-α-reductases, with further active ingredients.

The compounds of the invention that inhibit both 5-a-reductase isozyme 1 and 5-areductase isozyme 2 have the following formula (I):

where La or β

Oh

II

-CR in which RC _{1 2θ is} straight or branched, saturated or unsaturated alkyl and their pharmaceutically acceptable salts, hydrates, solvates and esters.

As used herein, such compounds are referred to as dual steroid 5-a-reductase inhibitors.

Preferred among the compounds of the invention are those having formula (II):

(Π) in which RC _{4 2θ is} straight or branched, saturated or unsaturated alkyl and their pharmaceutically acceptable salts, hydrates, solvates and esters.

Preferred among the compounds of the invention of formula II are those of formula III

Oh

in which R ² C _{4 8 is} straight or branched alkyl and their pharmaceutically acceptable salts, hydrates, solvates and esters.

Preferred among the compounds of formula III are those wherein R ^{2 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.

Particularly preferred among the compounds of formula (III) are those in which R ^{2 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.

Particularly preferred among the compounds of formula (III) are:

17 / 3- (Isobutylcarbonyl) -estra-1,3,5 (10) -triene-3-carboxylic acid,

17 _J S- (Octylcarbonyl) -estra-1,3,5 (10) -triene-3-carboxylic acid,

17 / 3- (tert-pentylcarbonyl) -estra-1,3,5 (10) -triene-3-carboxylic acid,

17 / 3- (2,2-dimethylpropylcarbonyl) -estra-1,3,5 (10) -triene-3-carboxylic acid, 17 / 3- (propylcarbonyl) -estra-1,3,5 (10) -triene -3-carboxylic acid, 17 / 3- (methylcarbonyl) -estra-1,3,5 (10) -triene-3-carboxylic acid,

17 / 3- (3,3-dimethylbutylcarbonyl) -estra-1,3,5 (10) -triene-3-carboxylic acid and their pharmaceutically acceptable salts, hydrates, solvates and esters.

The term a as used herein is by standard chemical terminology and means below, respectively, that the corresponding substituent is bound below the plane of the paper.

The term / 3 used herein is according to standard chemical terminology and means above, respectively, that the corresponding substituent is bound to the plane of the paper.

The term alkyl, C _{3 n} alkyl and its derivatives and in all carbon chains as used herein, unless otherwise defined, means a straight or branched carbon chain having 1 to n carbon atoms. Examples of alkyl and its derivatives as used herein include methyl, ethyl, propyl, 3-methylbutyl, isopropyl, n-butyl, isobutyl, 1-methylpropyl, t-butyl, n-pentyl, 1,1-dimethylpropyl, 2. 2-dimethylpropyl, n-octyl, tert-pentyl and 3,3-dimethylbutyl.

The term treatment as used herein means prophylactic or therapeutic therapy.

The term isobutyl as used herein means -CH ₂ CH (CH ₃ ) ₂ .

The term metal-catalyzed coupling reaction as used herein means that the prepared 3-trifluoromethylsulfonate or 3-fluorosulfonate compound reacts in a suitable organic solvent, preferably toluene, dimethylformamide or THF with a base, preferably a tertiary amine base, such as e.g. triethylamine, pyridine or tributylamine, phosphine, such as e.g. bis (diphenylphosphino) alkane, preferably 1,3-bis (diphenylphosphino) propane or tri-o-toliphosphine, or ₆ alkOH, and a metal catalyst, preferably palladium catalysts, such as e.g. palladium (II) acetate, palladium (II) chloride, or bis (triphenylphosphino) palladium II acetate and coupling reagent.

The term coupling reagent as used herein means a compound capable of reacting with an aryl radical to form a carboxylic acid substituent.

Carbon monoxide is a preferred coupling reagent which, when added to a metal-catalyzed coupling reaction as described herein, gives the desired carboxylic acid group.

The compounds of formula (I) and the compounds of formula (IV) are included in the pharmaceutical compositions of the invention and used in the processes of the invention. Where a -COOH group is present, pharmaceutically acceptable esters such as e.g. methyl, ethyl, pivaloyloxymethyl, and the like. and those esters known in the art for modifying solubility or hydrolysis properties, for use in sustained release formulations or prodrug formulations.

The term α-receptor antagonist as used herein refers to a known type of α-andrenergic receptor antagonist compound as described in Lafferty, et al., U.S. Pat. No. 4,963,547 used in the treatment of vascular disorders such as diabetes, cardiovascular disease, benign prostatic hypertrophy and ocular hypertension.

Preferred α-andrenergic receptor antagonists useful in the compositions and methods of the invention include amsulosin, terazosin, doxazosin, alfuzosin, indoramine, prazosin and 7-chloro-2-ethyl-3,4,5,6-tetrahydro-4-methylthieno [4 , 3,2-ef] [3] -benzapine.

The term amsulosin as used herein means a compound of structure

and its salts, hydrates and solvates.

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

Amsulosin is disclosed in U.S. Pat. No. 4,703,063 and protected by U.S. Pat. No. 4,987,125 as useful for treating lower urinary tract dysfunction.

The term terazosin as used herein means a compound of structure

Oh

nh ₂ and its salts, hydrates and solvates.

Chemically, terazosin is designated 1- (4-amino-6,7-dimethoxy-2-quinazolinyl) 4 - [(tetrahydro-2-furoyl) carbonyl] piperazine. Terazosin is shown in U.S. Pat. No. 4,251,532.

The term doxazosin as used herein means a compound of structure

NH ₂ and its salts, hydrates and solvates.

Chemically, doxazosin is designated 1- (4-amino-6,7-dimethoxy-2-quinazolinyl) 4 - [(2,3-dihydro-1,4-benzodioxin-2-yl) carbonyl] -piperazine.

Doxazosin is disclosed in U.S. Pat. No. 4,188,390

The term alfuzosin as used herein means a compound of structure

and its salts, hydrates and solvates.

Chemically, alfuzosin is designated N- [3 - [(4-amino-6,7-dimethoxy-2-quinazolinyl) methylamino] propyl] tetrahydro-2-furancarboxamide.

Alfuzosin is shown in U.S. Pat. No. 4,315,007.

The term indoramine as used herein means a compound of structure

-ch, ch ₂ Ν ^ Λ-NHC— and its salts, hydrates and solvates.

Chemically, indoramine is designated N - [[1- [2- (1H-indol-3-yl) ethyl] -4-piperidinylbenzamine.

Indoramin is disclosed in U.S. Pat. 3,527,761.

The term prazosin as used herein means a compound of structure

and its salts, hydrates and solvates.

Chemically, prazosin is designated 1- (4-amino-6,7-dimethoxy-2-quinazolinyl) -4- (2furanylcarbonyl) piperazine.

Prazosin is shown in U.S. Pat. 3,511,836 th most common

7-Chloro-2-ethyl-3,4,5,6-tetrahydro-4-methylthieno [4,3,2-ef] [3] benzazepine, as used herein, is a compound having the structure of ch ₂ ch ₃ and its salts, hydrates and solvates.

7-Chloro-2-ethyl-3,4,5,6-tetrahydro-4-methylthieno [4,3,2-ef] [3] benzazepine is disclosed in U.S. Pat. No. 5,006,521. Additionally, all compounds disclosed in U.S. Pat. No. 5,006,521 as α-adrenergic receptor antagonists, the preferred α-adrenergic receptor antagonists used herein.

One skilled in the art can readily determine if a compound other than that specifically referenced herein is an α-andrenergic receptor antagonist using the experiment described in Lafferty I. Therefore, all such compounds are included with the term antagonist α-andrenergic receptor as used herein.

The term minoxidil as used herein means a compound of structure

Chemically, minoxidil is designated 2,4-pyrimidinadiamine, 6- (1-piperidinyl) -3-oxide. Minoxidil is an effective ingredient in Rogaine® that is marketed as a topical solution to stimulate hair growth from Upjohn Company, Kalamazoo, Michigan.

The term aromatase inhibitor as used herein refers to a known type of compounds, steroidal and nonsteroidal, which prevent the conversion of androgens to estrogens as described by Gormley et al. in international publication no. WO 92/18132. Aromatase inhibitors are shown by Gormley et al. as useful in the treatment of benign prostatic hyperplasia when used in combination with a 5-a-reductase inhibitor.

A preferred aromatase inhibitor for use in the compositions and methods of the invention is 4- (5,6,7,8-tetrahydroimidazo [1,5-a] pyridin-5-yl) benzonitrile (fadrazole). Fadrazole is disclosed in U.S. Pat. No. 4,728,645. In addition, all the compounds shown by Gormley, et al., International Publication no. WO 92/18132 to have aromatase inhibitory efficiency, preferred aromatase inhibitors as used herein.

As used herein, if a dual 5-α-reductase inhibitor as described herein and a further effective ingredient or ingredients are used together, said inhibitor

5-a-reductase can be co-administered with said further effective ingredient or ingredients.

The term sod and its derivatives as used herein means either the simultaneous administration or any method of separate sequential administration of a 5-a-reductase inhibiting compound as described herein and further effective ingredients or ingredients, such as e.g. other compounds known to treat common acne conditions, seborrhea, female hirsutism, typical male baldness, benign prostatic hypertrophy or prostatic adenocarcinoma, or compounds known to be useful when used in combination with 5-a-reductase inhibitors . Preferably, when the administration is not simultaneous, the compounds are administered very close to each other in time. Furthermore, it is immaterial that the compounds are administered in the same dosage form, e.g. the compound may be administered topically and the other compound may be administered orally.

The new compounds of formula (II) of the present invention can be prepared by the methods shown in Schemes 1-4 below and, in the examples, from the known and readily available estrone of the formula:

or from the estrone analogue 17/3-carboxylic acid, which is known and readily available.

Scheme I

Ο

Ο

II cf ₃ -so

II ο

bis (diphenylphosphino) propane I triethylaryl 'C 1-6 alkyl alcohol palladium (II) acetate

CO (s)?

(g)

Scheme I shows the formation of compounds of formula II. In Scheme I, compound (b) is prepared from compound (a) according to the method of Baldwin, et al., J. Chem. Soc. (c), 1968, 2283-2289.

Compound (b) is then mixed in a suitable organic solvent, preferably methanol with a base, preferably sodium hydroxide, and then acidified to give compound (c). Compound (c) is then treated with a Grignard reagent described after that or lithium reagent in a suitable organic solvent, preferably tetrahydrofuran or diethyl ether, preferably at reflux temperature, to obtain compounds of formula (d).

The compound of formula (d) and a base, preferably 2,5-di-t-butyl-3-methyl-pyridine, is cooled in a suitable organic solvent, preferably dichloromethane at -20 ° C to 20 ° C, preferably 0 ° C and then by reaction with trihaloalkylsulfonic anhydride, preferably trifluoromethanesulfonic anhydride, compounds (e) are formed.

Compounds of formula (f) are prepared by reacting a compound of formula (e) in a metal-catalyzed coupling reaction. The preferred compound of formula (e) is dissolved in dimethylformamide (DMF) in an organic base, preferably triethylamine, phosphine, preferably bis (diphenylphosphino) propane, palladium (II) compound, preferably palladium (II) acetate and C _{x 6} alkyl alcohol (C ^ alkOH ), followed by the addition of carbon monoxide (CO). Subsequently, reaction of compounds (f) with a suitable base, preferably potassium carbonate, and acidification affords compounds (g).

Scheme II

Oh

(d)

Oh

II

co o

(0?

(g)

Scheme II shows the formation of compounds of formula II. The starting materials of Scheme II are the compounds of formula (d) prepared as described in Scheme I.

As in Scheme II, the compound of formula (d) and a base, preferably 2-5-di-t-butyl-3-methylpyridine, is cooled in a suitable organic solvent, preferably dichloromethane, at -20 ° C to 20 ° C, preferably 0 ° C, and by reaction with fluorosulfonic anhydride compounds (h) are formed. Compounds of formula (f) are prepared by reacting a compound of formula (h) in a metal-catalyzed coupling reaction. The preferred compound of formula (h) is dissolved in dimethylformamide (DMF), an organic base, preferably triethylamine, phosphine, preferably bis (diphenylphosphino) propane, palladium (II) compound, preferably palladium (II) acetate and _C1-6 alkyl alcohol ( _C1-6 alkOH) followed by the addition of carbon monoxide (CO). Then, by reacting the compounds of formula (f) with a suitable base, preferably potassium carbonate, and acidifying the compounds (g) are obtained.

Scheme III

(g)

Scheme III shows the formation of compounds of formula II. As in Scheme III, R ¹ CF ₃ O ₂ SO- or FO ₂ SO-. As in Scheme III, in the alkylation process (step C), the pyridylthioester reacts with LiR or XMgR (X = C1, Br) Grignard reagent (as described herein), preferably isobutylmagnesium bromide, n-octylmagnesium chloride, tert- pentylmagenzium chloride or 2,2-dimethylpropylmagnesium bromide, preferably in tetrahydrofuran, to give the desired product, preferably 17 / 3- (isobutylcarbonyl) -estra-1,3,5 (10) -triene-3-carboxylic acid, 17/3 (octylcarbonyl) -estra-1,3,5 (10) -triene-3-carboxylic acid, 17 / 3- (tert-pentylcarbonyl) estra-1,3,5 (10) -triene-3-carboxylic acid, resp. . 17 / 3- (2,2-dimethylpropylcarbonyl) -estral, 3,5 (10) -triene-3-carboxylic acid in one or two steps.

Following route 1, 3-hydroxyl acid (i) is converted into 3-trifluoromethylsulfonylate or 3fluorosulfonylate derivative (j) (step A) by treatment (i) with trifluoromethylsulfonyl anhydride or fluorsulfonic anhydride and an amine base such as e.g. pyridine, preferably 2,5-di-t-butyl-3-methyl-pyridine in a suitable organic solvent, preferably dichloromethane at about -20 ° C to 20 ° C, preferably 0 ° C.

The activated ester (k) is prepared (step B) by treating (j) with 2,2-dithiopyridyl and triphenylphosphine in a suitable organic solvent solution, preferably tetrahydrofuran / toluene at room temperature for about 8-14 hours.

The 17-acyl derivative (1) is prepared (step C) by treatment (k) with a Grignard reagent described herein below in solvent tetrahydrofuran or diethyl ether at a temperature of about -50 to -70 ° C for 1-16 hours.

3-Alkyl ester (f) is prepared (step D) by treatment (1) under carbonylation conditions, preferably by introducing carbon monoxide gas bubbles through a solution (1) in a suitable organic solvent, preferably methanol containing a palladium acetate catalyst, triphenylphosphine and tertiary an organic amine, preferably triethylamine, at about room temperature for 1-16 hours. Subsequently, reaction of compounds (f) with a suitable base, preferably potassium carbonate, and acidification affords compounds (g).

Compounds (g) can also be prepared (step G) by treatment (1) under carboxylation conditions, preferably by bubbling carbon monoxide gas through solution (1) in a suitable non-alcoholic solvent, preferably DMSO containing palladium catalyst, preferably palladium (II ) diacetate and 1,1-bis (diphenylphosphino) ferrocene (DPPF); and a base, preferably potassium acetate, preferably at elevated temperatures.

Route 2 involves the conversion of the starting steroid acid (i) into 3-trifluoromethylsulfonylate or 3-flurosulfonylate derivative (j) with step A described above; carbonylation (j) in (m) with grade D; formation of activated B-level 2-pyridylthioester (n); formation of 17-acyl compound (f) with step C; and hydrolyzing the 3-ester into 3 grade F acid product (g).

Route 3 involves the conversion of starting acid (i) into activated ester (o) with step B described above; formation of 17-acyl compound (d) by reaction (o) with step C above; converting (d) to a 3-trifluoromethylsulfonylate or 3-flurosulfonylate derivative (1) with step A above; and converting (1) to the final product (g) with step G above or step D above, followed by step F above.

Scheme IV

(c)

trifluoromethanesulfonic anhydride

-► bis (diphenylphosphino) propane triethylamine methanol palladium (II) acetate

-►

CO., LTD

iBi ^ AlH

-► (q)

(Grignard reagent) (0

(g)

Scheme IV shows the formation of compounds of formula II.

As in Scheme IV, in the alkylation process (for the preparation of compounds of formula (s)), the carboxaldehyde is reacted with Li-R or XMgR (x = Cl, Br) Grignard reagent (as described below), preferably propylmagnesium bromide, methylmagnesium bromide or 3,3-dimethylbutyl magnesium chloride, preferably in tetrahydrofuran, to give the desired product, preferably 17 / 3- (propylcarbonyl) -estral, 3,5 (10) -triene-3-carboxylic acid, 17 / 3- (methylcarbonyl) -estra-1,3,5 (10) -triene-3carboxylic acid or. 17 / 3- (3,3-dimethylbutylcarbonyl) -estra-1,3,5 (10) -triene-3carboxylic acid in one or two steps.

The starting material in Scheme IV is the compound of formula (c) prepared as in Scheme I.

As in Scheme IV, the compound of formula (c) and base, preferably 2,5-di-t-butyl-3-methylpyridine in a suitable organic solvent, preferably dichloromethane, is cooled to -20 ° C to 20 ° C, preferably 0 ° C, and by reaction with trihaloalkylsulfonic anhydride, preferably trifluoromethanesulfonic anhydride, compounds (p) are formed.

Compounds of formula (q) are prepared by reacting a compound of formula (p) in a metal-catalyzed coupling reaction. The preferred compound of formula (p) is dissolved in dimethylformamide (DMF) and organic base, preferably triethylamine, phosphine, preferably bis (diphenylphosphino) propane, palladium (II) compound, preferably palladium (II) acetate and C ₁₆ alkyl alcohol (C ₁₆ alkOH) followed by the addition of carbon monoxide (CO). Compounds of formula (q) are reacted with a reducing agent, preferably diisobutylaluminum hydride, to give compounds of formula (r).

Compounds of formula (s) are prepared by treating compounds of formula (r) with a Grignard reagent (as described in Scheme III) or lithium reagent in solvent tetrahydrofuran or diethyl ether at a temperature of about -50 to -70 ° C for 1-16 hours.

Compounds of formula (g) are prepared by oxidizing compounds of formula (s). Preferably, said oxidation uses a Jones reagent or tetrapropylammonium perrutenate, followed by the addition of sodium chlorite.

Grignard reagents of the XMgR type (wherein R _{2θ is} straight or branched, saturated or unsaturated alkyl) for use in the preparation of all types included in the scope of the present invention are readily available or can be readily prepared by one skilled in the art.

Compounds of formula I in which Z is in position a is prepared from compounds containing the corresponding β substituent by the general procedure below.

General procedure A

To a mixed solution of a substituted steroid 17/3 compound of formula (II), which doubly inhibits 5α-reductase, in a suitable solvent, preferably ethylene glycol or dimethylsulfoxide, is added a base such as e.g. hydroxide or alkoxide base, preferably sodium hydroxide, potassium hydroxide or sodium methoxide at temperatures above 100 ° C, preferably at reflux temperatures, to obtain the corresponding a epimer after isolation and processing.

Dimethyl sulfoxide or other high boiling point non-reactive solvents are preferred in determining the appropriate epimerization solvent when the starting 17/3 steroid compound for the dual 5a-reductase inhibition contains reactive substituents or reactive unsaturated bonds, e.g. the subject of a nucleophilic attack and ethylene glycol or other high boiling point reactive solvents can be used when the reactivity of the sub23 stituents or any unsaturated bonds of the parent 17/3 steroid compound that doubly inhibits 5α-reductase is not significant.

Within the scope of the present invention there are also ketone reduction products of compounds of formula (I), secondary alcohols of formula (IV):

where Y is a or β

OH

I-C-R in which R C _{2 is a} straight or branched saturated or unsaturated alkyl and their pharmaceutically acceptable salts, hydrates, solvates and esters.

Particularly preferred among the ketone reduction products of the present invention described above are secondary alcohols wherein

OH

-C-R substituent bound in position β.

Particularly preferred among the ketone reduction products of the invention described above are 17 / 3- (1-hydroxyethyl) -estra-1,3,5 (10) -triene-3-carboxylic acid and 17 / 3- (1-hydroxybutyl) -ester - 1,3,5 (10) -triene-3-carboxylic acid.

These compounds can be prepared by conventional reduction with sodium boron carbonyl bonded to R without epimerization of the 17 substituent or reduction of the carboxyl in ring A or aromatic A ring.

Reduction with borohydride can be carried out in e.g. water or aqueous methanol, at room temperature to 50 ° C, and the product is then isolated and purified by conventional means. The compounds are also effective as dual 5-a-reductase inhibitors.

The expression of elevated temperature as used herein and in the claims means above 25 ° C, preferably at reflux temperatures.

The term solvent or a suitable solvent as used herein and in the claims means a solvent such as e.g. methylene chloride, ethylene chloride, chloroform, ethylene glycol, carbon tetrachloride, tetrahydrofuran (THF), ethyl ether, toluene, ethyl acetate, dimethylsulfoxide (DMSO), N, N'-dimethyl-N, N'-propylene-urea, N-methyl-2-pyrrolidine , isopropyl alcohol, dimethylformamide, (DMF), hexane, water, pyridine, quinoline or ethanol.

Pharmaceutically acceptable salts, hydrates and solvates of the compounds of formula (I) and formula (IV) are formed, where appropriate, by methods well known to those skilled in the art.

In preparing the compounds of formula (I) according to the invention, new intermediates of formula (V) are synthesized

Oh

(V) wherein R _{2θ is} straight or branched, saturated or unsaturated alkyl and R ^{4 is} fluorosulfonyloxy.

Also preferred in the synthesis of the compounds of formula (I) of the invention are novel intermediates of formula (VI)

(VI) wherein R is as described in formula (II).

A preferred process for the preparation of a compound of formula (II)

in which RC ₁ _ _{2θ is} straight or branched, saturated or unsaturated alkyl and its pharmaceutically acceptable salts, hydrates, solvates and esters, comprises reacting a compound of formula

Oh

wherein R is as described above with a fluorosulfonic anhydride and a base, preferably 2,5-t-butyl-3-methyl-pyridine, in a solvent, preferably dichloromethane, to form a compound of formula

Ο

in which R is as described above, and then the reaction of said compound in a metal-catalyzed coupling reaction in the presence of a suitable coupling reagent, preferably carbon monoxide, followed, if appropriate, by a hydrolysis reaction to form compounds of formula (II) and thereafter optionally forming a pharmaceutically acceptable salt, hydrate or solvate thereof.

Because the pharmaceutically effective compounds of the present invention are effective dual inhibitors of steroid 5-a-reductase activity, they have therapeutic utility in the treatment of diseases and conditions where a decrease in the efficacy of DHT produces the desired therapeutic effect. Such diseases and conditions include common acne, seborrhea, female hirsutism, typical male baldness, prostate diseases such as. benign prostatic hypertrophy and prostatic adenocarcinoma.

The following procedures are used to determine the inhibition efficiency of the human 5a-reductase enzyme:

Free Preparation of membrane particles used as a source for recombinant steroid 5areductase isozyme 1 Free

Chinese hamster ovary (CHO) cells containing expressed recombinant human steroid 5a-reductase isoenzyme 1 (Andersson, S., Berman, D.M., Jenkins, E.P., and Russell, D.W. (1991) Nature 354 159-161) are homogenized in 20 mM potassium phosphate, pH 6.5, buffer containing 0.33 M sucrose, 1 mM dithiothreitol and 50 μιη NADPH (buffer A) using a glass-on-glass Dounce manual homogenizer (Kontes Glass Co., Vineland, NJ). The membrane particles were isolated by centrifugation (100,000 g at 4 ° C for 60 minutes) and resuspended in 20 mM potassium phosphate, pH 6.5 containing 20% glycerol, 1 mM dithiothreitol and 50 μηι NADPH (buffer B). The suspended particulate solution is stored at -80 ° C.

Preparation of Prostate Membrane Particles Used as a Source for Steroidal 5areductase Isocim 2

Frozen human prostates are thawed and chopped into small pieces (Brinkmann Polytron (Sybron Corp., Westbury, New York). The solution is sonicated for 3 to 5 minutes with a Branson Sonic Power Co.), followed by manual homogenization in a Dounce handheld homogenizer. Prostatic particles are obtained by differential centrifugation at 600 or 1000 g for 20 minutes and 140,000 g for 60 minutes at 4 ° C. Pellets obtained by 140,000 g centrifugation are washed with 5 to 10 tissue volumes of the buffer described above and centrifuged at 140,000 g The resulting pellets are suspended in buffer B and the particle suspension is stored at -80 ° C.

Preparation of Membrane Particles Used as a Source for Recombinant Steroidal 5areductase Isocim 2

Chinese Hamster Ovary (CHO) cells containing expressed recombinant human steroid 5-a-reductase isocyanate 2 are homogenized in 20 mM potassium phosphate, pH 6.5, buffer containing 0.33 M sucrose, 1 mM dithiothreitol and 50 gm NADPH (buffer A) using a Dounce handheld homogenizer. Membrane particles containing recombinant human enzyme were isolated by centrifugation (100,000 g at 4 ° C for 60 minutes) and resuspended in 20 mM potassium phosphate, pH 6,5 containing 20% glycerol, 1 mM dithiothreitol and 50 gm NADPH (buffer) B). The suspended particulate solution is stored at -80 ° C until used.

An attempt at enzyme activity and inhibitor efficacy

A constant amount of [ ¹⁴ C] testosterone (50 to 55 mCi / mmol) in ethanol and variable amounts of potential inhibitor in ethanol were deposited in test tubes and concentrated to dryness in vacuo. To each tube was added buffer, 10 gl (recombinant isoenzyme 1 or isoenzyme 2) or 20 gl (isoenzyme 2 from human prostate tissue) 10 mM NADPH and an aliquot of the steroid 5a-reductase preparation to a final volume of 0.5 ml. Assays for human steroid 5a-reductase isoenzyme 1 are conducted with a sample of recombinant protein expressed in CHO cells in 50 mM phosphate buffer, pH 7.5, while assays for isoenzyme 2 are conducted with a suspension of human prostatic particles and / or recombinant protein expressed in CHO cells , in 50 mM citrate buffer at pH 5.0.

After incubating the solution at 37 ° C for 20 or 30 minutes, the reaction was quenched by the addition of 4 ml of ethyl acetate and 0.25 μιηοΐ of each testosterone, 5α-dihydrotestosterone, androstanediol and androstanedione as carriers. Remove the organic layer into another test tube and evaporate to dryness in a Speed Vac. The residue was dissolved in 40 μΐ of chloroform, applied to an individual line of 20 × 20 cm silica gel plate for TLC with pre-labeled lines (Si 250F-PA, Baker Chemical) and twice developed with acetonormochloroform (1: 9). The radiochemical content of the substrate and product strips was determined with a BIOSCAN Imaging Scanner (Bioscan Inc., Washington, D.C.). The percentage of recovered radioactive labeling converted to the product is calculated to determine the enzymatic efficiency. All incubations are managed in such a way that no more than 20% of the substrate (testosterone) is consumed.

The experimentally obtained data were computer-tuned to a linear function by drawing the reciprocal of the incima efficiency (1 / speed) against the variable concentration of the inhibitor; apparent inhibition constants (K _japp ) are determined by Dixon analysis (Dixon, M. (1953)).

Values for the inhibition constant (Ki) are calculated from known methods (Levy, M. (1938), Biochemistry, 29: 2815-2824).

All of the compounds of the present invention are useful for inhibiting the steroid 5-areductase isomer 1 and the steroid 5-a-reductase isomer 2 in mammals, including humans, if required.

The compounds of the present invention have been tested and have an activity of 15 Ki (nM) to 180 Ki (nM) against isozymes 1 and an activity of 0.5 Ki (nM) to 30 Ki (nM) against isozymes 2. Particularly preferred among the compounds in the terms of the invention and the compounds used in the pharmaceutical compositions and processes of the invention are:

17 / 3- (Isobutylcarbonyl) -estra-1,3,5 (10) -triene-3-carboxylic acid,

17 / 3- (octylcarbonyl) -estra-1,3,5 (10) -triene-3-carboxylic acid,

17 / 3- (tert-pentylcarbonyl) -estra-1,3,5 (10) -triene-3-carboxylic acid,

17 / 3- (2,2-dimethylpropylcarbonyl) -estra-1,3,5 (10) -triene-3-carboxylic acid, 17 / 1- (propylcarbonyl) -estra-1,3,5 (10) -triene -3-carboxylic acid,

17 / 3- (methylcarbonyl) -estra-1,3,5 (10) -triene-3-carboxylic acid,

17 / 3- (3,3-dimethylbutylcarbonyl) -estra-1,3,5 (10) -triene-3-carboxylic acid,

17 / 3- (1-hydroxyethyl) -estra-1,3,5 (10) -triene-3-carboxylic acid and

17 / 3- (1-Hydroxybutyl) -estra-1,3,5 (10) -triene-3-carboxylic acid.

The pharmaceutically effective compounds of the present invention are preferably incorporated into suitable dosage forms, such as e.g. capsules, tablets or injectables. Solid or liquid pharmaceutical carriers are used. Solid carriers include starch, lactose, calcium sulfate dihydrate, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate and stearic acid. Liquid carriers include syrup, peanut oil, olive oil, brine and water. Similarly, carriers or diluents may include any prolonged release material, such as e.g. glyceryl monostearate or glyceryl distearate, alone or with wax. The amount of solid carriers varies widely, but is preferably from about 25 mg to about 1 g per dosage unit. If liquid carriers are used, the compositions are preferably in the form of syrups, elixirs, emulsions, soft gelatin capsules, sterile injectable liquids such as e.g. ampoules or aqueous or non-aqueous liquid suspensions.

The pharmaceutical preparations are prepared according to conventional techniques of pharmaceutical chemists, which include mixing, granulating and compressing, as required for tablet formulations, or mixing, filling and dissolving the ingredients as appropriate to obtain the desired oral or parenteral products.

The dosages of the pharmaceutically effective compounds of the invention in the pharmaceutical dosage units as described above are effective, non-toxic amounts, preferably selected in the range from 0.1 to 1000 mg / kg of the effective compound, preferably 1 to 100 mg / kg. When treating patients in humans requiring steroid 5-a-reductase inhibition, the selected dose is preferably administered 1 to 6 times daily, orally or parenterally. Preferred forms of parenteral administration include topical, rectal, transdermal, injectable and continuous infusion. Oral dosage units for administration to humans preferably contain from 1 to 500 mg of effective compound. Oral administration using lower dosages is preferred. Parenteral administration at higher dosages can, of course, also be used if it is safe and favorable for the patient.

The method of the present invention for inhibiting the efficacy of a steroidal 5-areductase isomer 1 and a steroidal 5-a-reductase isomer 2 in mammals, including humans, comprises administering to the subject in need of such inhibition an effective double inhibitory amount of the compound of the invention.

The present invention also provides the use of a compound of formula (I) or a compound of formula (IV) in the manufacture of a medicament for use in the dual inhibition of steroidal 5 - reductase.

The present invention also provides a pharmaceutical composition for use in the treatment of benign prostatic hypertrophy comprising a compound of formula (I) or a compound of formula (IV) and a pharmaceutically acceptable carrier.

The present invention also provides a pharmaceutical composition for use in the treatment of prostatic adenocarcinoma comprising a compound of formula (I) or a compound of formula (IV) and a pharmaceutically acceptable carrier.

The present invention also provides a process for the preparation of a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound of formula (I) or a compound of formula (IV) comprising combining a compound of formula (I) or a compound of formula (IV) with a pharmaceutical an acceptable carrier or diluent.

No unacceptable toxic effects are to be expected when the compounds of the invention are administered in accordance with the present invention.

Additionally, the pharmaceutically effective compounds of the invention can be co-administered with further effective ingredients such as e.g. other compounds known to treat the disease states of common acne, seborrhea, female hirsutism, typical male baldness, benign prostatic hypertrophy or prostatic adenocarcinoma, or compounds known to be useful when used in combination with 5-a-reductase inhibitors. Particularly preferred is the administration of a dual 5-α-reductase inhibitor as shown herein and minoxidil for use in the treatment of typical male baldness. Particularly preferred is the administration of a dual 5 -? - reductase inhibitor as shown herein and an α-receptor antagonist for use in the treatment of benign prostatic hypertrophy. Preferably, the administration of a dual 5-α-reductase inhibitor as shown herein and an aromatase inhibitor is for use in the treatment of benign prostatic hypertrophy. Preferably, the administration of a dual 5-α-reductase inhibitor, as shown herein, is an? -Receptor and aromatase inhibitor for use in the treatment of benign prostatic hypertrophy.

Without further elaboration, it is believed that a person skilled in the art will be able to take full advantage of the present invention by using the foregoing description. The following examples are therefore drawn up for illustration only and in no way to limit the scope of the present invention.

EXAMPLE 1 - Corresponds to Scheme III

17ff-Isobutylcarbonyl-estra-1,3,5 (10) -triene-3-carboxylic acid (s) S- (2-pyridyl) -3-hydroxy-ester-1,3,5 (10) -triene-17 / 3-Thiocarboxylate

A mixture of 3-hydroxy-ester-1,3,5 (10) -triene-17/3-carboxylic acid (0.11 g, 0.37 mmol), 2,2'-diopyridyl disulfide (0.163 g, 0.74 mmol), triphenylphosphine (0.19 g, 0.74 mmol) and dichloromethane (20 ml) were stirred at room temperature under argon for 4 hours. The resulting solution was concentrated and the residue chromatographed (silica gel, eluting with 25% ethyl acetate in hexane) to give 0.13 g of the title compound as a white solid, m.p. 195 to 196 ° C (recrystallized from ethyl acetate-methanol).

(ii) 17/3-Isobutylcarbonyl-3-hydroxy-ester-1,3,5 (10) -triene

Isobutylmagnesium bromide (2.3 ml; 2M in diethyl ether) was added slowly to a solution of S- (2pyridyl) -3-hydroxy-ester-1,3,5 (10) -triene-17/3-thiocarboxylate (0.60 g , 1.53 mmol) in tetrahydrofuran (20 ml) at -78 ° C. After 1 hour, the mixture was quenched with saturated aqueous NH ₄ Cl and extracted with ethyl acetate. The organic extract was washed with brine, dried and concentrated, and the resulting residue was chromatographed (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) 17/3-Isobutylcarbonyl-ester-1,3,5 (10-triene-3-trifluoromethylsulfonate)

To a cooled (0 ° C) solution of 17/3-isobutylcarbonyl-3-hydroxy-ester-1, 3,5 (10-triene (0.28 g, 0.82 mmol) and 2,6-di-tert.- butyl-4-methylpyridine (0.17 g, 0.83 mmol) in dichloromethane (20 ml) was added slowly trifluoromethane sulfone anhydride (0.23 g, 0.82 mmol) and the resulting solution was stirred at 0 ° C for 1 hour and then at room temperature for 30 minutes The reaction mixture was washed with dilute HCl, water, dilute NaHCO ₃ , brine, dried and concentrated The resulting residue was chromatographed (silica gel, 7% ethyl acetate in hexane) to give 0.13 g of oil.

(iv) Methyl-17/3-isobutylcarbonyl-ester-1,3,5 (10) -triene-3-carboxylate

A mixture of 17/3-isobutylcarbonyl-ester-1,3,5 (10) -triene-3-trifluoromethylsulfonate (0.13 g, 0.28 mmol), palladium (II) acetate (4.2 mg, 0.0187 mmol) ), 1,3-bis (diphenylphosphonium) propane (dppp, 7.5 mg, 0.0182 mmol), triethylamine (0.08 ml), methanol (0.6 ml), 1,2-dichloroethane (0. 32 ml) and DMSO (1 ml) were heated at 70 to 75 ° C under a CO atmosphere overnight. The cooled reaction mixture was then diluted with dichloromethane, washed with water, diluted HCl, diluted NaHCO ₃ , brine, dried and concentrated. The residue was chromatographed (silica gel, eluting with 10% ethyl acetate in hexane) to give 70 mg of the title compound.

(v) 17/3-Isobutylcarbonyl-ester-1,3,5 (10) -triene-3-carboxylic acid

Mixture of methyl-17/3-isobutylcarbonyl-ester-1,3,5 (10) -triene-3-carboxylate (70 mg, 0.18 mmol), K ₂ CO ₃ (0.12 g, 0.87 mmol) , water (1.5 ml) and methanol (10 ml) are heated at reflux overnight. The reaction mixture was then concentrated. The residue was diluted with water, acidified with dilute HCl and extracted with ethyl acetate. The organic extract was washed with brine, dried and concentrated. The title compound was purified by HPLC, m.p. 202 to 206 ° C.

EXAMPLE 2 - Corresponds to Scheme III

17/3-Isobutylcarbonyl-estra-1,3,5 (10) -triene-3-carboxylic acid (s) 17/3-isobutylcarbonyl-estra-1,3,5 (10) -triene-3-fluorosulfonate

A solution of 17/3-isobutylcarbonyl-ester-1,3,5 (10) -trien-3-ol prepared according to Example I (i-ii) in dichloromethane at 0 ° C was treated with 2,5-di-t-butyl -3-methyl-pyridine followed by treatment with fluorosulfonic anhydride after 10 minutes. The resulting mixture was stirred for 2 h and then diluted with dichloromethane. The organic layer was washed with saturated aqueous NaHCO ₃ and brine, dried over MgSO ₄ and evaporated to dryness. Silica gel chromatography afforded the title compound.

(ii) Methyl 17/3-isobutylcarbonyl-ester-1,3,5 (10) -triene-3-carboxylate

A mixture of 17/3-isobutylcarbonyl ester-1,3,5 (10) -triene-3-fluorosulfonate, 1,3-bis (diphenylphosphino) propane, palladium diacetate, triethylamine, methanol, DMSO and 1,2 dichloroethane was heated and stirred vigorously 5 h at 80 ° C under an atmosphere of carbon monoxide. After cooling to room temperature, the resulting mixture was diluted with dichloromethane. The organic phase was washed thoroughly with water, dried (MgSOJ and evaporated to dryness. Chromatography on silica gel gave the title compound.

(iii) 17/3-Isobutylcarbonyl-ester-1,3,5 (10) -triene-3-carboxylic acid

A mixture of methyl 17/3-isobutylcarbonyl ester-1,3,5 (10_triene-3-carboxylate, K2CO3 water and methanol was refluxed for 5 h. The solubles were then removed under reduced pressure and the residue was diluted with water, acidified with dilute aqueous HCl and extract with EtOAc The organic extract was washed with water and brine, dried and evaporated to give the title compound.

EXAMPLE 3 - Corresponds to Scheme III

N7,3-Isobutylcarbonyl ester-1,3,5 (10) -triene-3-carboxylic acid (i) 3- (trifluoromethanesulfonyloxy) -estra-1,3,5 (10) -triene-17 / S-carboxylic acid acid

A solution of 3-hydroxy-ester-1,3,5 (10) -17 / 3-carboxylic acid, 2,6-di-t-butyl-4-methyl pyridine and trifluoromethane sulfonic anhydride in methylene chloride was stirred at 5 ° C 20 ur. The organic solvent was evaporated and the residue was dissolved in tetrahydrofuran-water (99.5: 0.5) with 4-dimethylaminopyridine, after acidification with hydrochloric acid followed by the usual treatment to give the title compound.

(ii) S- (2-pyridyl) -3- (trifluoromethanesulfonyloxy) -estra-1,3,5 (10) -triene-17/3-thiocarboxylate

A solution of 3- (trifluoromethanesulfonyloxy) -estra-1,3,5 (10) -triene-17/3-carboxylic acid, triphenylphosphine and 2,2'-dipyridyl disulfide in toluene was stirred under nitrogen for 20 hours. The reaction mixture was concentrated and the residue was passed directly through silica gel and the appropriate fractions were evaporated to give the title compound.

(iii) 17/3-Isobutylcarbonyl-estra-1,3,5 (10) -triene-3-trifluoromethane sulfonate

Isobutylmagnesium bromide was added to a solution of S- (2-pyridyl) -3- (trifluoromethane] phyloxy) -estra-1,3,5 (10) -triene-17/3-thiocarboxylate in tetrahydrofuran at approximately -50 ° C. The reaction mixture was warmed to about -10 ° C and diluted with saturated aqueous ammonium chloride solution. Normal treatment with the following isolation by column chromatography afforded the title compound.

(iv) Methyl 17) 3-isobutylcarbonyl ester-1,3,5 (10) -triene-3-carboxylate

A solution of 17/3-isobutylcarbonyl-ester-1,3,5 (10) -triene-3-trifluoromethane sulfonate, triphenyl phosphine, palladium (II) acetate, triethylamine, methanol and dimethyl formamide was stirred vigorously under carbon monoxide for 20 hours. Normal treatment with the following isolation by column chromatography afforded the title compound.

(v) 17/3-Isobutylcarbonyl-ester-1,3,5 (10) -triene-3-carboxylic acid

A mixture of methyl 17/3-isobutylcarbonyl-ester-1,3,5 (10) -triene-3-carboxylate, B ^ CC ^, water and methanol was refluxed for about 5 hours. Acidification, followed by normal treatment, yields the title compound.

EXAMPLE 4 - Corresponds to Scheme III

17,8-Isobutylcarbonyl ester-1,3,5 (10) -triene-3-carboxylic acid (i) 3- (fluorosulfonyloxy) -estra-1,3,5 (10) -triene-17/3-carboxylic acid

A solution of 3-hydroxy-ester-1,3,5 (10) -17 / 3-carboxylic acid, 2,6-di-t-butyl-4-methyl pyridine and fluorosulfonic anhydride in methylene chloride was stirred at 5 ° C for 20 hours . The reaction mixture was washed with aqueous hydrochloric acid and water. The organic phase was concentrated and the resulting residue was purified by column chromatography to give the title compound.

(ii) S- (2-pyridyl) -3- (fluorosulfonyloxy) -estra-1,3,5 (10) -triene-17/3-thiocarboxylate

A solution of 3- (fluorosulfonyloxy) ester-1,3,5 (10) -triene-17/3-carboxylic acid, triphenylphosphine and 2,2'-dipyridyl disulfide in toluene was stirred under nitrogen for 20 hours. The reaction mixture was concentrated and the residue was passed directly through silica gel and the appropriate fractions were evaporated to give the title compound.

(iii) 17/3-isobutylcarbonyl ester-1,3,5 (10) -triene-3-fluorosulfonate

To a solution of S- (2-pyridyl) -3- (fluorosulfonyloxy) -estra-1,3,5 (10) -triene-17/3-thiocarboxylate in tetrahydrofuran at about - 50 ° C was added isobutylmagnesium bromide. The reaction mixture was heated to about -10 ° C and diluted with saturated aqueous ammonium chloride solution. Normal treatment with the following isolation by column chromatography afforded the title compound.

(iv) Methyl 17/3-isobutylcarbonyl ester-1,3,5 (10) -triene-3-carboxylate

A solution of 17/3-isobutylcarbonyl-ester-1,3,5 (10-triene-3-fluorosulfonate, triphenyl phosphine, palladium (II) acetate, triethylamine, methanol and dimethyl formamide was stirred vigorously under carbon monoxide for 20 hours. isolation by column chromatography afforded the title compound.

(v) 17jS-Isobutylcarbonyl ester-1,3,5 (10) -triene-3-carboxylic acid

A mixture of methyl 17/3-isobutylcarbonyl-ester-1,3,5 (10) -triene-3-carboxylate, N, N, N-water and methanol was refluxed for about 5 hours. Acidification, followed by normal treatment, yields the title compound.

EXAMPLE 5 - Corresponds to Scheme III

17 / 3- (octylcarbonyl) -estra-1,3,5 (10) -triene-3-carboxylic acid (s) 17 / 3- (octylcarbonyl) -estra-1,3,5 (10) -triene-3 -trifluoromethylsulfonate

The title compound was prepared according to Example 1 (i-iii) by substituting n-octylmagnesium chloride for isobutylmagnesium bromide in step (ii).

(ii) 17 / 3- (octylcarbonyl) -estra-1,3,5 (10) -triene-3-carboxylic acid

A mixture of 17 / 3- (octylcarbonyl) -estra-1,3,5 (10) -triene-3-trifluoromethylsulfonate (0.38 g, 0.7 mmol), potassium acetate (0.27 g), palladium (II) diacetate (0.008 g, 0.036 mmol), 1,1'-bis (diphenylphosphino) ferrocene (dppf; 0.08 g, 0.14 mmol) in DMSO (15 ml) was purified by carbon monoxide for 2 minutes and stirred in a balloon with CO at 60 ° C overnight.

The reaction mixture was diluted with water, acidified with 0.5N hydrochloric acid and extracted with dichloromethane. The organic layer was washed with water, dried (MgSO ₄ ) and evaporated in vacuo. The residue was chromatographed (silica gel, eluting with 20% ethyl acetate, 1% acetic acid in hexane) to give a solid triturated with methanol-acetonitrile to give the title compound 0.22 g (73%), m.p. 175 ° C.

EXAMPLE 6 - Corresponds to Scheme III

17 / 3- (tert-pentylcarbonyl) -estra-1,3,5 (10) -triene-3-carboxylic acid (i) Trifluoromethyl-17 / 3- (tert-pentylcarbonyl) -estra-1,3. 5 (10) -triene-3-sulfonate

The title compound was prepared according to Example 1 (i-iii) by substituting tert-pentylmagnesium chloride for isobutylmagnesium bromide in step (ii).

(ii) 17 / 3- (tert-pentylcarbonyl) -estra-1,3,5 (10) -triene-3-carboxylic acid

The title compound was prepared according to Example 5 (ii) by substitution of trifluoromethyl-17/3 (tert-pentylcarbonyl) -estra-1,3,5 (10) -triene-3-sulfonate as prepared in Example 6 (i), for trifluoromethyl-17 / 3- (octylcarbonyl) -estra-1,3,5 (10) -triene-3-sulfonate. Tal. 199 to 200 ° C.

EXAMPLE 7 - Corresponds to Scheme III

17 / 3- (2,2-dimethylpropylcarbonyl) -estra-1,3,5 (10) -triene-3-carboxylic acid (i) Trifluoromethyl-17 / 3- (2,2-dimethylpropylcarbonyl) -estra-1, 3,5 (10) -triene-3-sulfonate

The title compound was prepared according to Example 1 (i-iii) by substituting 2,2-dimethylpropylmagnesium bromide for isobutylmagnesium bromide in step (ii).

(ii) 17 / 3- (2,2-dimethylpropylcarbonyl) -estra-1,3,5 (10) -triene-3-carboxylic acid

The title compound was prepared according to Example 5 (ii) by substituting trifluoromethyl-17 / 3- (2,2dimethylpropylcarbonyl) -estra-1,3,5 (10) -triene-3-sulfonate as prepared for example 7 (i), for trifluoromethyl-17 / 3- (octylcarbonyl) -estra-1,3,5 (10) -triene-3-sulfonate. Tal. 210 ° C.

EXAMPLE 8 - Corresponds to Scheme IV

17 / 3- (propylcarbonyl) -estra-1,3,5 (10) -triene-3-carboxylic acid (s) 17/3-cyano-ester-1,3,5 (10) -triene-3-methanesulfonate

The title compound is known and is prepared from estrone by the method of: Baldwin et al., J. Chem. Soc. (C) 1968, 2283-2289.

(ii) 17? - cyano-ester-1,3,5 (10) -trien-3-ol the title compound of 17/3-cyano-ester-1,3,5 (10) -triene-3-methanesulfonate ( 10 g) in methanol (100 ml) was added dropwise a solution of NaOH (42 ml, 20% solution in MeOH 1: 1). The resulting mixture was heated at 40 ° C for 24 h, then cooled to 0 ° C, diluted with water (350 ml) and acidified with dilute HCl. The resulting white precipitate was isolated by vacuum filtration, washed with water and dried under vacuum. Recrystallization from acetonitrile gave the title compound, m.p. 249 to 250 ° C dec.

(iii) 17/3-cyano-ester-1,3,5 (10) -triene-3-trifluoromethanesulfonate

17/3-cyano-ester-1,3,5 (10) -trien-3-ol (4.2 g) and 2,6-di-t-butyl-4-methylpyrid (3.6 g) were dissolved in 50 ml of methylene chloride. The mixture was stirred at room temperature for 30 minutes. Trifluoromethanesulfonic acid anhydride (4.2 ml) was added and the mixture stirred for a further 40 minutes, diluted with 50 ml CH ₂ Cl ₂ , filtered, concentrated and chromatographed on silica gel. Elution with 20% ethyl acetate in hexane gave 5.3 g (87%) of the title compound, m.p. 115 to 117 ° C.

(iv) Methyl 17/3-cyano-ester-1,3,5 (10) -triene-3-carboxylate

To a solution of 17/3-cyano-ester-1,3,5 (10) trien-3-ol (10 g) in 77 ml of DMSO and 50 ml of MeOH was added 7 ml of triethylamine, 0.35 g of palladium acetate, 0.64 g of bis (diphenylphosphino) propane and 1,2-dichloroethane (26 ml). Carbon monoxide is introduced through the bubble solution and the reaction mixture is then stirred at 75 ° C overnight at a CO pressure of 1.01 x 10 ^s Pa (balloon). The mixture was diluted with EtOAc and washed with water (3 times), dried and concentrated. The residue was chromatographed (silica gel, eluting with 10% EtOAc in hexane) to give 4.5 g of the title compound, m.p. 161 to 163 ° C.

(v) 3-hydroxymethyl-ester-1,3,5 (10) -triene-17/3-carboxaldehyde

Methyl-17/3-cyano-ester-1,3,5 (10) -triene-3-carboxylate (0.8 g) was dissolved in 30 ml of toluene and treated with diisobutylaluminum hydride (DIBAL) (6 ml, IM). The mixture was stirred at room temperature under argon for 2.5 hours. The mixture was then poured into 50 ml of 5% H ₂ SO ₄ and stirred for 1 hour, filtered, dried and concentrated. The residue was chromatographed (silica gel, eluting with 20% EtOAc in hexane) to give 424 mg of the title compound, m.p. 146-150 ° C.

(vi) 17 / 3- (1-hydroxybutyl) -estra-1,3,5 (10) -triene-3-hydroxymethyl

A solution of 3-hydroxymethyl ester, 1,3,5 (10) -triene-17/3-carboxaldehyde (75 mg in 2 ml of THF) was slowly added to a solution of propyl magnesium bromide (2 ml, 1.6 M). The mixture was stirred at room temperature for 2 hours.

The mixture was quenched with saturated aqueous NH ₄ Cl and extracted with CH ₂ Cl ₂ . The organic extract was washed with brine, dried and concentrated. The resulting residue was chromatographed (silica gel, eluting with 30% ethyl acetate in hexane) to give 57 mg of the title compound.

(vii) 17 / 3- (propylcarbonyl) -estra-1,3,5 (10) -triene-3-carboxylic acid

17 / 3- (1-Hydroxybutyl) -estra-1,3,5 (10) -triene-3-hydroxymethyl (57 mg) was dissolved in acetone (5 ml) and treated with Jones's reagent. The mixture was stirred for 1 hour and then quenched with 2-propanol, extracted with CH ₂ C1 ₂ and purified by chromatography (silica gel, eluting with 30% ethyl acetate in hexane with 0.5% HOAc added) to give 47 mg of the title compound, m.p. . 211 to 213 ° C.

EXAMPLE 9 - Corresponds to Scheme IV

17 N - (methylcarbonyl) -estra-1,3,5 (10) -triene-3-carboxylic acid

The title compound was prepared according to Example 8 (i) - (vii) by substituting methylmagnesium bromide for propylmagnesium bromide in step (vi), m.p. 199 to 202 ° C.

EXAMPLE 10 - Corresponds to Scheme IV

17 / 3- (3,3-dimethylbutylcarbonyl) -estra-1,3,5 (10) -triene-3-carboxylic acid

The title compound was prepared according to Example 8 (i) - (vii) by substitution of 3,3 dimethylbutylmagnesium chloride for propylmagnesium bromide in step (vi), m.p. 252 to 255 ° C.

EXAMPLE 11 - Corresponds to Scheme IV

17 / 3- [1- (R, S) -hydroxyethyl] estra-1,3,5 (10) -triene-3-carboxylic acid (i) Solution 17 / 3- (methylcarbonyl) -estra-1,3. 5 (10) -triene-3-carboxylic acid (6 mg) - prepared according to Example 9 - was treated with NaBH ₄ (0.7 mg) in methanol. The mixture was heated to 45 ° C and stirred overnight. The solvent was removed by rotary evaporation and the residue was dissolved in dichloromethane and filtered. The title compound (1.6 mg) was purified by preparative thin layer chromatography, m.p. 202 to 204 ° C.

(ii) Pure (R) and (S) forms are obtained by separation techniques that are readily available and known to those skilled in the art.

EXAMPLE 12 - Corresponds to Scheme IV

17 / 3- [1- (R, S) -Hydroxybutyl-ester-1,3,5 (10) -triene-3-carboxylic acid (i) The title compound was prepared according to Example 11 by substitution 17 / 3- (propylcarbonyl) -estra-1,3,5 (10) -triene-3-carboxylic acids prepared according to Example 8 (i) (vii) for 17 / 3- (methylcarbonyl) -estra-1,3,5 (10) -triene -3-carboxylic acid, m.p. 208 to 211 ° C.

(ii) Pure (R) and (S) forms are obtained by separation techniques that are readily available and known to those skilled in the art.

EXAMPLE 13

An oral dosage form for the administration of compounds of formula I is produced by screening, mixing and filling into hard gelatin capsules, the ingredients in portions shown in Table 1 below.

Table I

Ingredients Quantities

17/3-Isobutylcarbonyl-ester-1,3,5 (10) - 50 mg triene-3-carboxylic acid magnesium stearate 5 mg lactose 75 mg

EXAMPLE 14

Sucrose, calcium sulfate dihydrate and the compound of formula (I) shown in Table II below are mixed and granulated in portions shown with 10% gelatin solution. The wet granules are screened, dried, mixed with starch, talc and stearic acid, screened and compressed into tablets.

Table II

Ingredients Quantities

17/3-Isobutylcarbonyl-ester-1,3,5 (10) - 100 mg triene-3-carboxylic acid calcium sulfate dihydrate 150 mg sucrose 20 mg starch 10 mg talc 5 mg stearic acid 3 mg

EXAMPLE 15 mg of 17/3-isobutylcarbonyl-ester-1,3,5 (10) -triene-3-carboxylic acid was dispersed in 25 ml of normal brine to prepare the injection.

While the preferred embodiments of the present invention are illustrated above, it should be understood that the invention is not limited to the precise instructions shown here and we reserve the right to make any modifications within the scope of the following claims.

Claims (16)

PATENT APPLICATIONS A compound represented by the formula wherein La is or β Oh II -CR in which the RC _is straight or branched, saturated or unsaturated alkyl, and pharmaceutically acceptable salts, hydrates, solvates and esters thereof. Compound according to claim 1, characterized in that it has the following formula: O (ΠΙ) in which R ² C _{g is} straight or branched alkyl, and pharmaceutically acceptable salts, hydrates, solvates and esters thereof. Compound according to claim 2, wherein R ^{2 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. A compound of formula wherein Y is a or β OH I-C-R in which RC _{120 is} straight or branched, saturated or unsaturated alkyl, and pharmaceutically acceptable salts, hydrates, solvates and esters thereof. 5. A compound selected from the group consisting of: 17 / 3- (isobutylcarbonyl) -estra-1,3,5 (10) -triene-3-carboxylic acid, 17 / 3- (octylcarbonyl) -estra-1,3,5 (10) -triene-3-carboxylic acid acid, 17 / 3- (tert-pentylcarbonyl) -estra-1,3,5 (10) -triene-3-carboxylic acid, 17 / 3- (2,2-dimethylpropylcarbonyl) -estra-1,3,5 (10) -Triene-3-carboxylic acid, 17 / 3- (propylcarbonyl) -estra-1,3, 3,5 (10) -triene-3-carboxylic acid, 17 / 3- (methylcarbonyl) -estra-1,3 , 5 (10) -triene-3-carboxylic acid, 17 / 3- (3,3-dimethylbutylcarbonyl) -estra-1,3,5 (10) -triene-3-carboxylic acid, 17 / 3- (hydroxyethyl) -estra-1,3,5 (10) -triene -3-carboxylic acid and 17 / 3- (1-hydroxybutyl) -estra-1,3,5 (10) -triene-3-carboxylic acid. Pharmaceutical composition comprising a compound according to any one of claims 1 to 5 and a pharmaceutically acceptable carrier. A compound according to any one of claims 1 to 5 for use in therapy. A compound according to any one of claims 1 to 5 for the manufacture of a medicament for use as a steroid 5-a-reductase inhibitor. A compound according to any one of claims 1 to 5 for the manufacture of a medicament for use in treatment for reducing prostate size. A compound according to any one of claims 1 to 5 for the manufacture of a medicament for use in the treatment of prostatic adenocarcinoma. 11. An intermediate characterized in that it has the formula: O (V) in which RC _{b θ is} straight or branched, saturated or unsaturated alkyl and R ^{4 is} fluorosulfonyloxy. Use of a compound according to any one of claims 1 to 5 and an antagonist compound "receptor" in the manufacture of a medicament for use in the treatment of benign prostatic hypertrophy, the use of which consists in the separate sequential or simultaneous administration of the compound according to any one of claims 1 to 5 and the antagonist compound «-Receptor. Use of a compound according to any one of claims 1 to 5 and minoxidil in the manufacture of a medicament for use in the treatment of typical male baldness, the use consisting of separate sequential or simultaneous administration of the compound according to any one of claims 1 to 5 and minoxidil. 14. Intermediate having the formula OH HO (VI) in which RC _{120 is} straight or branched, saturated or unsaturated alkyl. 15. A process for the preparation of a compound of formula (II) OR H-0-0 (II) in which RC _{b is} straight or branched, saturated or unsaturated alkyl, and pharmaceutically acceptable salts, hydrates, solvates and esters thereof, characterized in that it comprises either (i) oxidation of a compound of the formula wherein R is as described above, or (ii) the reaction of a compound of the formula wherein R, as described above, is in a metal-catalyzed coupling reaction in the presence of a suitable coupling reagent, preferably carbon monoxide, followed, if appropriate, as appropriate , a hydrolysis reaction, or (iii) hydrolysis of a compound of formula C ₁ ^ alkyl, in which R is as described above, or (iv) reacting a compound of formula Oh II in which R, as described above, is in a metal-catalyzed coupling reaction in the presence of a suitable coupling reagent, preferably carbon monoxide, followed, if appropriate, by a hydrolysis reaction and then optionally the formation of a pharmaceutically acceptable salt, hydrate thereof , solvate or ester. Use of a compound according to any one of claims 1 to 5 in the manufacture of a medicament for use for inhibiting steroid 5-α-reductase.