SK159994A3 - 17-alkylketone steroids useful as 5-alpha-reductase inhibitors - Google Patents

Abstract

Invented are 17 alpha and 17 beta -alkylketone-3-carboxy aromatic A ring analogues of steroidal synthetic compounds, 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

Technical field

The invention relates to certain novel 17a and 17β-alkyl ketone-3-carboxy A ring steroid compounds, pharmaceutical compositions containing these compounds, and the use of these compounds in inhibiting isozyme 1 steroid 5-a reductase and isozyme 2 steroid 5-a reductase. The invention also relates to novel intermediates and processes for the preparation of these compounds.

BACKGROUND OF THE INVENTION

A class of steroid hormones known as androgens, is responsible for the physical characteristics that distinguish men from women. Of the several organs that produce androgens, they produce the testes in the largest amount. Brain centers show a primary control of androgen production levels. Many physical manifestations and disease states occur when ineffective control results in excess androgen hormone production. For example, acne vulgaris, seborrhea, female hirsutism, signs of male baldness and prostate disease, such as benign prostatic hypertrophy, are associated with elevated levels of androgens.

In addition, a reduction in androgen levels has been shown to be therapeutically useful in prostate cancer.

Testosterone is the major androgen secreted by the testes and is the principal androgenic steroid in male plasma. 5-α-reduced androgens have been shown to be active hormones in some tissues such as the prostate and the gland. Thus, circulating testosterone serves as a prohormone for dihydrotestosterone (DHT), its 5-a-reduced analogue, in these tissues, but not elsewhere than in muscles and testes. The steroid 5-α-reductase is Nicotinamide Adenine Dinucleotide Phosphate (NADPH) dependent enzyme that converts testosterone to DHT. The importance of this enzyme in male development has been greatly noted by the discovery of the genetic deficiency of steroid 5-α-reductase in male pseudodermaphrodism. McGinley.J. et al. (1979), J. Steroid Biochem., 11; 637-648.

A number of (10) 5-α-reductase trenes are known. 1. J. Steroid Biochem.

3-carboxy-estra inhibitors 1,3,5 For example:

Vol. 34, Nos. 1-6, p. 571-575 (1989), M.A. Levy et al. discloses a mechanism of interaction between steroid 5-and reductase in rat prostate and 3-carboxy-17β-substituted steroids;

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

3. TIPS (December 1989) Vol. 10, p. 491-495, B.V. Metcalf et al. describes the effect of steroid 5α-reductase inhibitors in benign prostatic hyperplasia, male baldness and acne.

In addition, U.S. Patent No. 4,954,446 discloses a family of 3-carboxy-estra 1,3,5 (10) triene-17β-substituted compounds known for use as steroid 5-α-reductase inhibitors. However, none of the cited references disclose or suggest that some of the novel 17β-alkylketone-3-carboxy steroid compounds of the aromatic ring A in the present invention could be used as highly potent inhibitors of both isozyme 1 steroid 5-α-reductase and isozyme 2. steroid 5-α-reductase (double inhibitors).

SUMMARY OF THE INVENTION

The present invention provides compounds having an inhibitory activity against 5-.alpha.-reductase isozyme 15 and 5-.alpha.-reductase isozyme of formula I, a method for simultaneously inhibiting 5-.alpha.-reductase isozyme 15 and 5-.alpha.-reductase isozyme in mammals, including humans. comprising administering an effective amount of the 5-α-reductase compounds of the invention. As further aspects of the invention, there are provided novel intermediates and suitable methods for the preparation of the present 5-α-reductase inhibiting double compounds. The invention also includes pharmaceutical compositions together with a pharmaceutical carrier and compounds of the invention. Further, the invention encompasses methods of co-administering the present 5-α-reductase inhibitor double compounds with other active ingredients.

The compounds of the invention having 5-α-reductase isozyme 1 and 5-α-reductase isozyme 1 have the following formula I:

where Z is o or β

R in -COR is C 1-2 alkyl linear or branched, saturated or unsaturated alkyl, and pharmaceutically acceptable salts, hydrates, solvates and esters thereof.

These compounds belong to double steroid 5-α-reductase inhibitors.

Preferred compounds of the invention are compounds of formula II

wherein R is C 1-2 alkyl linear or branched, saturated or unsaturated alkyl, and pharmaceutically acceptable salts, hydrates, solvates and esters thereof.

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

Ο

wherein R ² is C 1-8 linear or branched alkyl and pharmaceutically acceptable salts, hydrates, solvates and esters thereof.

Preferred compounds of formula (III) are those wherein R ² is methyl, ethyl, propyl, 3-methylbutyl, isopropyl, n-butyl, isobutyl, 1-methylpropyl, tert-butyl, pentyl, 1,1-dimethylpropyl, 2,2 -dimethylpropyl, octyl or 3,3-dimethylbutyl.

Particularly preferred among the compounds of formula (III) are those wherein R ² is 1-methylpropyl, n-butyl, isopropyl, n-pentyl, 3-methylbutyl, 2,2-dimethylpropyl, tert-butyl, 1,1-dimethylpropyl, butyl n-octyl, tert-pentyl, n-propyl, methyl or 3,3-dimethylbutyl.

Particularly preferred compounds of formula (III) are:

17β- (isobutylcarbonyl) -estra-1,3,5 (10) -triene-3-carboxylic acid, 17β- (octylcarbonyl) -estra-1,3,5 (10) -triene-3-carboxylic acid, 17β- ( tert-Pentylcarbonyl) -estra-1,3,5 (10) -triene-3-carboxylic acid, 17β- (2,2-dimethylpropylcarbonyl) -estra-1,3,5 (10) triene-3-carboxylic acid, 17β- (propylcarbonyl) -estra-1,3,5 (10) -triene-3-carboxylic acid, 17β- (methylcarbonyl) -estra-1,3,5 (10) -triene-3-carboxylic acid and 17β- (3,3-dimethylbutylcarbonyl) -estra-1,3,5 (10) triene-3-carboxylic acid and pharmaceutically acceptable salts, hydrates, solvates and esters thereof.

The term a, as used herein, is consistent with standard chemical terminology and means that the lower or corresponding substituent is attached below the plane of the paper.

The term β, as used herein, refers to standard chemical terminology and means that the top or corresponding substituent is attached above the plane of the paper.

The term alkyl, C ₁ _ _alkyl chains, and derivatives thereof and in all carbon chains used herein, unless otherwise defined, is meant C ^ _ _n straight or branched carbon chain having 1 to n carbon atoms. Examples of alkyl and its derivatives 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 is a prophylactic or therapeutic treatment.

The term isobutyl, as used herein, represents -C 1 H -CH (CH ₃ ) ₂ .

As used herein, a metal catalyzed coupling reaction is understood to mean that the prepared 3-trifluoromethylsulfonate or 3-fluorosulfonate compound is reacted in a suitable organic solvent, preferably toluene, dimethylformamide or THF with a base, preferably a tertiary amine base such as triethylamine, pyridine or tributylamine. a phosphine such as bis (diphenylphosphine) alkane, preferably 1,3 bis (diphenylphosphine) propane or tri-o-tolylphosphine or C 6-6 alkali and a metal catalyst, preferably palladium such as palladium (II) acetate, palladium (II) chloride or bis (triphenylphosphine) ) - Palladium II acetate and coupling reagent.

The term coupling reagent, as used herein, means a compound that is capable of reacting with an aryl radical to form a carboxylic acid substituent. Preferably, the coupling reagent is carbon monoxide, which upon addition to the metal catalyzed coupling reaction as described herein provides the desired carboxylic acid group.

Compounds of formula (I) and compounds of formula (IV) form part of the pharmaceutical compositions of the invention and are used in the methods of the invention. Where a -COOH group is present, pharmaceutically acceptable esters such as methyl, ethyl, pivaloyloxymethyl and the like can be used. and such esters known to modify solubility or hydrolysis characteristics, for use in sustained release or in prodrug formulations.

The term α-receptor antagonist, as used herein, refers to a known class of alpha-andrenergic receptor antagonist compounds as reported by Lafferty et al., U.S. Pat. U.S. Pat. No. 4,963,547, are used in the treatment of vascular disorders such as diabetes, cardiovascular disease, benign prostate hypertrophy, and ocular hypertension.

Preferred alpha-andrenergic receptor antagonists for use in the compositions and methods of the invention are amsulosin, terazosin, doxazosin, alfuzosin, indoramine, prazosin and 7chlor-2-ethyl-3,4,5,6- (tetrahydro-4-methylthienol [4,3] 2-ef] [3] benzapine.

As used herein, amsulosin is a compound of structure

and salts, hydrates and solvates thereof.

Chemically, amsulosin is expressed as (-) - (R) -5 - [[2- (0-ethoxyphenoxy) ethyl] amino] propyl] -2-methoxybenzenesulfonamide.

Amsulosin is disclosed in U.S. Pat. Patente no. No. 4,703,063 and confirmed in U.S. Pat. Patente no. No. 4,987,125 as useful in the treatment of lower urinary tract dysfunction.

The term terazosin is a compound of the structure

Ί

and salts, hydrates and solvates thereof.

Chemically, terazosin is expressed as 1- (4-amino-6,7-dimethoxy-2-quinazolinyl) -4 - [(tetrahydro-2-furoyl) carbonyl] piperazine. Terazosin is disclosed in U.S. Pat. U.S. Patent No. 5,768,516; 4,251,532.

The term doxazosin, as used herein, represents a compound of the structure

and salts, hydrates and solvates thereof.

Chemically, doxazosin is expressed as 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. U.S. Patent No. 5,768,516; 4,188,390.

The term alfuzosin, as used herein, represents a compound of the structure

CH ₃

nh ₂ and salts, hydrates and solvates thereof.

Chemically, alfuzosin is expressed as N- [3 - [(4-amino-6,7-dimethoxy-2-quinazolinyl) methylamino] propyl] tetrahydro-2-fu rankarboxamide.

Alfuzosin is disclosed in U.S. Pat. Patente no. 4,315,007.

The term indoramine, as used herein, represents a compound of the structure

and salts, hydrates and solvates thereof.

Chemically, indoramine is expressed as N - [[1- [2- (1H-indol-3-yl) ethyl] -4-piperidinyl] benzamine.

Indoramine is disclosed in U.S. Pat. Patente no. 3,527,761.

The term prazosin, as used herein, represents a compound of the structure

and salts, hydrates and solvates thereof.

Chemically, prazosin is expressed as 1- (4-amino-6,7-dimethoxy-2-quinazolinyl) -4- (2-furanylcarbonyl) piperazine. Prazosin is disclosed in U.S. Pat. Patente no. 3,511,836. 7-chloro-2-ethyl-3,4,5,6-tetrahydro-4-methyl-thieno [4,3,2,

-ef] - [3] benzazepine, as used herein, represents a compound of structure

and salts, hydrates and solvates thereof.

7-chloro-2-ethyl-3,4,5,6-tetrahydro-4-methylthieno [4,3,2,9 ef] - [3] benzazepine is disclosed in U.S. Pat. 5,006,521. In addition, all of the compounds disclosed in U.S. Pat. No. 5,006,521 as alpha and / or receptor antagonists are those preferred antagonists as disclosed by the invention.

Those skilled in the art can readily determine whether a compound other than that disclosed herein is an alpha andrenergic receptor antagonist using the assay described by Lafferty I. Thus, all such compounds are included in the term alpha-andrenergic receptor antagonist as used herein.

As used herein, minoxidil means a compound of the formula

FROM

Chemically, minoxidil is expressed as 2,4-pyrimidinediamine, 6- (1-piperidinyl) -, 3-oxide. Minoxidil is an active ingredient in Rogain, which is marketed as a topical solution for hair growth stimulation from Upjohn Company, Kalamazoo, Michigan.

The term aromatase inhibitor as used herein includes a known class of compounds, both steroid and non-steroidal, that prevent the conversion of androgens to estrogens, as described by Gormly et al., Int. Publ.No. VO 92/18132. Aromatase inhibitors as disclosed in Gormley et al. Are useful in the treatment of benign prostatic hyperplasia when used in combination with a 5-α-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. 4,728,645. In addition, all of the compounds listed in Gormley et al., Int. Publ. no. WO 92/18132 with an in10 hibernating aromatase activity are preferred aromatase inhibitors of the present invention.

In this case, when a dual 5-α-reductase inhibitor described herein and another active ingredient or ingredients are used together, the desired 5-α-reductase inhibitor may be administered simultaneously.

The term co-administration and derivatives, as used herein, means or simultaneous administration or any method of sequentially administering a 5-α-reductase inhibitor compound as described herein and another active ingredient or ingredients, such as other compounds known in the treatment. conditions such as acne vulgaris, seborrhea, female hirsutism, male baldness, benign prostate hypertrophy, prostate adenocarcinoma, or compounds known for use with 5-α-reductase inhibitors. Preferably, if administration is not concomitant, the compounds are administered shortly in succession. Further, it is not an obstacle when the compounds are administered in a not the same dosage form, for example one topically and the other orally.

The novel compounds of formula (II) of the invention can be prepared by the methods depicted in Schemes 1-4 below and in the examples from the known and available estrone having the formula:

or an estrone analog of 17β-carboxylic acids, which is known and available.

(C)

Scheme I continued

ABOUT

II

?

(G)

Scheme I illustrates the formation of compounds of Formula II. As shown in Scheme I, the compound of formula (b) is prepared from compound (a) according to the procedure of Baldwin et al. Soc. (c), 1968, 2283-2289.

Compound (b) is then stirred in a suitable organic solvent, preferably methanol, with a base, preferably sodium hydroxide, and then acidified to give compound (c). Compound (c) is further treated with the Grignard reagent described below, or with a 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-tert-butyl-3-methylpyridine in a suitable organic solvent, preferably dichloromethane, are cooled to -20 ° C to 20 ° C, preferably 0 ° C and reacted with trihaloalkylsulfonic anhydride. of an acid, preferably trifluoromethanesulfonic anhydride, to form compounds (e).

Compounds of formula (f) are prepared by reacting a compound of formula (e) with a metal catalyzed coupling agent. Preferably, the compound of formula (e) is dissolved in dimethylformide (DMF), preferably in an organic base, triethylamine, phosphine, preferably bis (diphenylphosphine) propane, a palladium (II) compound, preferably palladium (11) acetate, and C 6-6 alkyl alcohol (C). alkanol), followed by the addition of carbon monoxide (CO). Compounds (f) are then reacted with a suitable base, preferably potassium carbonate, and are acidified to give compounds (g).

Ο

ο

HOOC f

(9)

Scheme II illustrates the formation of compounds of Formula II. Starting materials in Scheme II are compounds of formula (d) prepared as described in Scheme I.

As shown in Scheme II, the compound of formula (d) and a base, preferably 2,5-di-t-butyl-3-methyl-pyridine in a suitable organic solvent, preferably dichloromethane, are cooled to -20 ° C to 20 ° C, preferably 0 ° C and treated with fluorosulfonic anhydride to give compounds (h). Compounds of formula (f) are prepared by reacting a compound of formula (h) with a metal-catalyzed coupling agent. Preferably, the compound of formula (h) is dissolved in dimethylformide (DMF) an organic base preferably triethylamine, phosphine preferably bis (diphenylphosphino) propane, a compound of palladium (II), preferably palladium (II) acetate, and a C ₁ _galkylalkohole (C ^ _galkOH ), followed by the addition of carbon monoxide (CO). Compounds (f) are then reacted with a suitable base, preferably potassium carbonate, and are acidified to give compounds (g).

Scheme III

said R ³ is CF ³ O ² SO- or FO 2 SO-. As shown in Scheme III in the alkylation process (step c), the pyridylthioester is reacted with LiR or XMgR (X = Cl, Br), a Grignard reagent (as described below), preferably isobutylmagnesium bromide, n-octylmagnesium chloride, tert-pentylmagnesium chloride or 2,2-dimethylpropylbromide. , preferably in tetrahydrofuran to give the desired compound, preferably 17β- (isobutylcarbonyl) estra-1,3,5 (10) -triene-3-carboxylic acid, 17β- (octylcarbonyl) -estra-1,3,5 (10) ) -triene-3-carboxylic acid, 17β (tert-pentylcarbonyl) -estra-1,3,5 (10) -triene-3-carboxylic acid or 17- / 2,2- (dimethylpropylcarbonyl) -estra-1,3 5 (10) -triene-3-carboxylic acid in one or two steps.

In process 1,3, the 3-hydroxylic acid (i) is converted to a 3-trifluoromethylsulfonylate or 3-fluorosulfonylate derivative (j) (step A) by reaction of (i) trifluoromethylsulfonylanhydride or fluorosulfonic acid anhydride and an amine base such as pyridine, preferably 2.5 di-t-butyl 3-methyl-pyridine, in a suitable organic solvent, preferably in dichloromethane at about -20 ° C to 20 ° C, preferably 0 ° C.

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

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

The 3-alkyl ester (f) is produced (step D) by reaction under carbonylation conditions, preferably by bubbling carbon monoxide gas through solution (1) in a suitable organic solvent, preferably methanol, containing palladium acetate catalyst, triphenylphosphine, and tertiary organic amine, preferably triethylamine at about room temperature for 1 to 16 hours. Compounds (f) are then reacted with a suitable base, preferably potassium carbonate, and are acidified to give compounds (g).

Compounds (g) may also be produced (step G) by reaction under carboxylation conditions, preferably by bubbling carbon monoxide through solution (1) in a suitable non-alcoholic solvent, preferably DMSO, containing a palladium catalyst, preferably palladium (II) diacetate and 1,1- Bis (diphenylphosphine) ferrocene (DPPF); and a base, preferably potassium acetate, preferably at elevated temperature.

Process 2 involves converting the starting steroid acid (i) to a 3-trifluoromethylsulfonylate or 3-fluorosulfonylate (j) derivative as described in Step A above; carbonylating (j) to (m) by step D; creation of activated

2-pyridylthioester (n) by Step B; forming a 17-acyl compound (f) by step C; and hydrolyzing the 3-ester to

3-acid final product (g) using step F.

Process 3 involves converting the starting acid (i) to the activated ester (o) by the above step B; forming the 17-acyl compound (d) by reaction (o) using step C above; converting (d) to a 3-trifluoromethylsulfonylate or 3-fluorosulfonylate derivative (1) by step A above; and converting (1) to the final product (g) using step G or D described above, followed by step F described above.

Scheme IV

(P) trifluoromethanesulfonic anhydride

Bis (diphenylphosphine) propanetriethylamine methanol palladium (11) acetate

-►

WHAT

(D

HO

° C to 20 ° C, preferably 0 trihaloalkylsulfonic acid,

Scheme IV illustrates the formation of compounds of Formula II.

As used in Scheme IV in the alkylation process (to prepare compounds of formula (s)), carboxaldehyde is reacted with LI-R or XMgR (x = Cl, Br), a Grignard reagent (as described below), preferably propylmagnesium bromide or 3.3. -dimethylbutylmagnesium chloride, preferably in tetrahydrofuran, to give the desired compound, preferably 17β- (propylcarbonyl) -estra-1,3,5 (10) -triene-3-carboxylic acid, 17β- (methylcarbonyl) -estra-1,3, 5 (10) -triene-3-carboxylic acid, or 17β- (dimethylbutylcarbonyl) -estra-1,3,5 (10) -triene-3-carboxylic acid, in one or two steps.

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

As shown in Scheme IV, a compound of formula (c) and a base, preferably 2,5-di-t-butyl-3-methyl-pyridine in a suitable organic solvent, preferably dichloromethane, is cooled to -20 ° C and reacted with an acid anhydride. preferably with trifluoromethanesulfonic anhydride to give compounds (p).

Compounds of formula (q) are prepared by reacting a compound of formula (p) in a metal catalyzed coupling reaction. Preferably, the compound of formula (p) is dissolved in dimethylformide (DMF) and an organic base, preferably triethylamine, phosphine, preferably bis (diphenylphosphine) propane, a palladium (II) compound, preferably palladium (II) acetate, and alkyl alcohol (C 1-4 alkyl) , followed by the addition of carbon monoxide (CO). Compounds (q) are then reacted with a reducing agent, preferably diisobutylaluminum hydride, to provide compounds of formula (r).

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

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

Grignard reagents of the XMgR type (where R is C 12q linear or branched, saturated or unsaturated alkyl) for the preparation of all species included in the invention are available or readily prepared by those skilled in the art.

Compounds of formula I wherein Z is in position a are prepared from compounds containing the corresponding substituent β according to the main method below.

Main method

To a stirred solution of a substituted 17β steroid compound of formula II double-inhibiting 5-α-reductase, in a suitable solvent, preferably ethylene glycol or dimethylsulf, is added a base, hydroxide or alkoxide, preferably sodium hydroxide, potassium hydroxide, or sodium methoxide, at a higher temperature. at 100 ° C, preferably at reflux temperature, to recover the corresponding α epimer after isolation and work-up.

Dimethylsulfoxide or other unreactive high boiling solvents are preferred in determining a suitable solvent to effect epimerization when the starting 17β 5-α-reductase inhibiting double steroid compound contains reactive substituents or reactively unsaturated bonds, which are, for example, subjected to nucleophilic attack or ethylene attack; other reactive high boiling solvents, when the reactivity of the substituents and the unsaturated bonds of the starting 17-β steroid double-inhibiting β-α-reductase is irrelevant.

Also included within the scope of the invention are ketone reduction products I, secondary alcohols of formula IV

(IV) wherein Y is α or β OH

-E-R in which R is the OH-CR ^ ι_20 are ^not Árny or branched, saturated or unsaturated alkyl and pharmaceutically acceptable salts, hydrates, solvates and esters thereof.

Among the ketone reducing products described hereinabove, secondary alcohols are preferred wherein the OHCR substituent is in the β position.

Particularly preferred ketone reduction products described herein are 17β- (1-hydroxyethyl) estra-1,3,5 (10) -triene-3-carboxylic acid, 17β- (1-hydroxybutyl) -estra-1,3, 5 (10) -triene-3-carboxylic acid.

These compounds can be prepared by conventional reduction of carbonyl attached to R without epimerization of substituent 17, sodium borohydride, or reduction of carboxyl in ring A or reduction of aromatic ring A.

The borohydride reduction can be carried out, for example, in water or aqueous methanol, at a temperature from room temperature to 50 ° C, and then the product is isolated and purified in a conventional manner. The compounds are also active as double 5-alpha reductase inhibitors.

The term elevated temperature as used herein and in the claims means a temperature> 25 ° C, preferably reflux temperatures.

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

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

In the preparation of the compounds of formula (I) herein, syn 23 new intermediates of formula V are tattooed

(V) wherein R is a C ₃ _20 straight or branched, saturated or unsaturated alkyl and ^R4 is fluorosulfonyloxy.

Also useful in the synthesis of compounds of formula (I) were the novel intermediates of formula VI

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

A preferred method of preparing the compound of formula II

wherein R is C 1-2 linear or branched, saturated or unsaturated alkyl and its pharmaceutically acceptable salts, hydrates, solvates and esters, comprises reacting a compound of formula

Ο

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

as described above, followed by the reaction of a compound wherein R is, in a metal catalyzed coupling reaction in the presence of a suitable coupling agent, preferably, carbon monoxide followed by any hydrolysis, if any, is formed. a compound of formula (II) and then a pharmaceutically acceptable salt, hydrate, solvate or ester thereof.

Since the pharmaceutical active compounds of the invention disclosed herein are potent dual inhibitors of steroid 5-α-reductase activity, they have therapeutic use in the treatment of diseases and conditions where a decrease in DHT activity induces the desired therapeutic effect. Such diseases include acne vulgaris, seborrhea, female hirsutism, signs of male baldness, prostate diseases such as benign prostatic hypertrophy and prostate adenocarcinoma.

The following methodology was used to determine the potency of inhibition of human 5-α-reductase:

Process for the preparation of membrane particles used as a source for recombinant isozyme I steroid 5-α-reductase.

Chinese hamster ovary (CHO) cells containing expressed, recombinant human isoenzyme 1 steroid 5-α-reductase (Andersson, S., Berman, DM, Jenkins, EP, and Russel, DV (1991) Nature, 354, 159-161) were homogenized in 20 mM potassium phosphate, pH 6.5, in a buffer containing 0.33 M sucrose, 1 mM dithiothritol and 50 μΜ NADPH (buffer A), using a Dounce glass-glass hand homogenizer (Kontes Glass Co., Vineland, NJ). Membrane particles were isolated by centrifugation (100,000 x 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 μΜ NADPH (buffer B). The suspended particulate solution was stored at -80 ° C.

Process for the preparation of prostate membrane particles used as a source for the isozyme 2 steroid 5-α-reductase.

Frozen human prostates were thawed and broken into small particles (Brinkman Polytron (Sybron Corp., Vestbury, New York)).

The solution was sonicated for 3-5 minutes with an ultrasonic apparatus (Branson Sonic Power Co.) followed by manual homogenization in a Dounce hand homogenizer. Prostate particles were obtained by differential centrifugation at 600 or 1000 x g for 20 minutes at 140,000 x g for 60 minutes at 4 ° C. The pellet obtained from the centrifugation of 140,000 x g was washed with 5 to 10 tissue volumes of the buffer described above and was centrifuged at 140,000 x g. The resulting pellet was suspended in buffer B and the particle suspension was stored at -80 ° C.

Process for the preparation of membrane particles used as a source for recombinant isozyme 2 steroid 5-α-reductase.

Chinese Hamster Ovarian (CHO) cells containing expressed, recombinant human isozyme 2 steroid 5-α-reductase were homogenized in 20 mM dra26 sodium phosphate, pH 6.5, buffer containing 0.33 M sucrose, 1 mM dithiothreitol and 50 μΜ NADPH (buffer) A), using a Dounce hand homogenizer. Membrane particles containing recombinant human enzyme were isolated by centrifugation (100,000 x 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 μΜ NADPH (buffer B). The suspended particulate solution was stored at -80 ° C until use.

Determination of enzyme activity and inhibitor potency.

A constant amount of [.alpha.] C testosterone (50-55mCi / mmol) in ethanol and various amounts of the active inhibitor in ethanol were stored in test tubes and concentrated to dryness in vacuo. Buffer, 10 μ každej (recombinant isoenzyme 1) was added to each tube. or isoenzyme 2) or 20μ1 (isoenzyme 2 from human prostate tissue) 10 mM NADPH and the corresponding amount of steroid 5-α-reductase preparation to a final volume of 0.5 ml. Assays for human isoenzyme 1 steroid 5α-reductase were performed with a sample of recombinant protein expressed in CHO cells in 50 mM phosphate buffer, pH 7.5, whereas isoenzyme 2 assays were performed with a suspension of human prostate particles and / or recombinant protein expressed in CHO cells at 50 mM citrate buffer at pH 5.0.

After incubation at 37 ° C for 20 or 30 minutes, the solution was quenched by the addition of 4 ml of ethyl acetate and 0.25 pmol of testosterone, 5-α-dihydrotestosterone, androstanediol and androstanedione as carriers. The organic layer was transferred to a second test tube, evaporated to dryness in a Speed Vac. The residue was dissolved in 40 µl of chloroform, applied to individual strips of 20 x 20 rectified TLC silica gel plates (Si 250F-PA, Baker Chemical) and developed twice with acetone: chloroform (1: 9). Radiochemical content in substrate and product bands was determined using a BIOSCAN imaging scanner (Bioscan Inc., Washington, D. C.). The percentage of recovered radioindex converted to the product from which enzyme activity was determined was calculated.

All incubations were performed so that no more than 20% of the substrate was passed.

The experimentally obtained data were computer-translated to a linear function by graphically showing the relationship of enzyme activity (1 / rate) against the variable-inhibitor concentration; obvious inhibition constants (K i _and pp) were determined by Dixon analysis (Dixon, M. (1953).

The value of the inhibition constant (Ki) was calculated from known procedures (Levy, M. (1989), Biochemistry, 29: 2815-2824).

All compounds of the invention are useful for inhibiting isozyme 1 steroid 5-α-reductase and isozyme 2 steroid 5-α-reductase in mammals, including humans, if desired.

The compounds of the invention were tested and showed activity from 15 Ki (nM) to 180 Ki (nM) against isozyme 1 and activity from 0.5 Ki (nM) to 30 Ki (nM) against isozyme 2. Especially preferred between the compounds of the invention and between the compounds used in the pharmaceutical compositions of the invention and its processes are:

17β- (isobutylcarbonyl) -estra-1,3,5 (10) -triene-3-carboxylic acid, 17β- (octylcarbonyl) -estra-1,3,5 (10) -triene-3-carboxylic acid, 17β- ( tert-Pentylcarbonyl) -estra-1,3,5 (10) -triene-3-carboxylic acid 17β- (2,2- (dimethylpropylcarbonyl) -estra-1,3,5 (10) triene-3-carboxylic acid 17β - (propylcarbonyl) -estra-1,3,5 (10) -triene-3-carboxylic acid, 17β- (methylcarbonyl) -estra-1,3,5 (10) -triene-3-carboxylic acid, 17β- ( 3,3-dimethylbutylcarbonyl) -estra-1,3,5 (10) triene-3-carboxylic acid, 17β- (1-hydroxyethyl) -estra-1,3,5 (10) -triene-3-carboxylic acid and acid 17β- (1-hydroxybutyl) -estra-1,3,5 (10) -triene-3-carboxylic acid.

The pharmaceutically active compounds of the invention are formulated in suitable dosage forms, preferably capsules, tablets, or injectables. Solid or liquid pharmaceutical carriers are used. Solid carriers include starch, lactose, calcium sulfate dihydrate, gypsum, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Liquid carriers include syrup, peanut oil, olive oil, saline and water. The carrier or diluent may contain any release-prolonging agent, such as glyceryl monostearate or glyceryl distearate, alone or with paraffin. The amount of solid carrier varies, but preferably from 25 mg to 1 g per dosage unit. When a liquid carrier is used, the preparation will preferably be in the form of a syrup, aromatic alcohol, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampoule, or in the form of an aqueous or non-aqueous liquid suspension.

The pharmaceutical preparations are manufactured by the following conventional pharmaceutical chemistry techniques, such as mixing, granulating and compressing, if necessary for tableted forms, or mixing, filling and dissolving the ingredients, as appropriate, to form oral or parenteral products. Dosages of the present pharmaceutically active compounds in a pharmaceutical dosage form will be effective, nontoxic, in the range of 100 mg / kg, preferably 1 to 100 mg / kg. In human medicine, if desired by inhibiting the steroid 5-α-reductase, the selected dose is preferably administered 1 to 6 times daily, orally or parenterally. Forms of parenteral administration include topical, rectal, transdermal, injection or continuous infusion.

Oral dosage forms for human administration contain 1 to 500 mg of the active compound. Oral administration using lower doses is preferred. However, parenteral administration at high doses can also be used if it is safe and convenient for the patient.

The method of the invention in inhibiting isozyme 1 steroid 5-α-reductase activity and isozyme 2 steroid 5-α-reductase activity in mammals, including humans, comprises administering, if necessary, such an effective amount of a double-acting compound of the present invention. The invention also provides the use of a compound of formula (I) or a compound of formula (IV) in the manufacture of a medicament used in the dual inhibition of steroid 5-α-reductase.

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

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

The 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), which comprises combining a compound of formula I or a compound of formula (IV) with a pharmaceutically acceptable carrier or solvent. No unacceptable toxicological effects are expected with the compounds of the invention when the compounds are administered in accordance with the present invention.

The pharmaceutically active compounds of the invention may be administered together with other active ingredients which are other compounds known in the treatment of disease states in acne vulgaris, seborrhee, female hirsutism, male baldness, benign prostate hypertrophy, adenocarcinoma of the prostate, or with compounds that are useful. in combination with 5-α-reductase inhibitors. Particularly preferred is the simultaneous administration of a dual 5-α-reductase inhibitor as disclosed herein and minoxidil in the treatment of male baldness. Particularly preferred is the simultaneous administration of a double 5-α-reductase inhibitor as described herein and an α-receptor antagonist in the treatment of benign prostatic hypertrophy. It is preferred to co-administer a double 5-α-reductase inhibitor as described herein with an aromatase inhibitor in the treatment of benign prostate hypertrophy. Preferred is the simultaneous administration of a double 5-α-reductase inhibitor as described herein and an α-receptor antagonist and aromatase inhibitor in the treatment of benign prostatic hypertrophy.

Using the foregoing description, one skilled in the art can utilize the invention to its fullest extent, without further processing

The following examples are therefore given for illustration only and in no way to limit the scope of the invention.

DETAILED DESCRIPTION OF THE INVENTION

Example 1- corresponding to Scheme III

17β- (Isobutylcarbonyl) -estra-1,3,5 (10) -triene-3-carboxylic acid (i). S- (2-pyridyl) -3-hydroxy-estra-3,5 (10) -ΐΓΐβη-17βtiokarboxylát

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

(ii) 17β- (Isobutylcarbonyl) -estra-1,3,5 (10) -triene.

To a solution of S- (2-pyridyl) -3-hydroxy-estra-1,3,5 (10) -trien 17β-thiocarboxylate (0.60 g, 1.53 mmol) in tetrahydrofuran was slowly added isobutylmagnesium bromide (2.3 ml; 2M in di31 ethyl ether) at -78 ° C. After 1 hour The mixture was frozen with saturated aqueous NH ₄ Cl and extracted with ethyl acetate. The organic extract was washed with brine, dried, concentrated. The resulting residue was chromatographed (silica gel, washing with 15% ethyl acetate in hexane) to give a foam. Trituration with diethyl ether and hexane gave a white solid (0.27 g).

(iii). 17β- (isobutylcarbonyl) -estra-l, 3,5 (10) -triene-3-trifluoromethylsulfonate.

To a cooled (0 ° C) solution of 17β- (isobutylcarbonyl) -3-hydroxy estra-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 slowly added trifluoromethanesulfonic anhydride (0.23 g, 0.82 mmol). The resulting solution was stirred for 1 hour at 0 ° C and then for 30 minutes at room temperature. The reaction mixture was washed with dilute HCl, water, dilute NaHCO 3, brine, dried and concentrated. The resulting residue was chromatographed (silica gel, washing with 7% ethyl acetate in hexane) to give 0.13 g of an oil.

(Iv). Methyl-17-isobutylcarbonyl-estra-3,5 (10) -triene-3-carboxylate.

A mixture of 17β-isobutylcarbonyl-estra-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 (diphenylphosphine) 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) was heated at 70-75 ° C overnight under a CO atmosphere. Then, the cooled reaction mixture was diluted with dichloromethane, washed with water, dilute HCl, dilute NaHCO 3, brine, dried and concentrated. The residue was chromatographed (silica gel, washing with 10% ethyl acetate in hexane) to give 70 mg of the title compound.

(in). 17β-Isobutylcarbonyl-esΐra-1,3,5 (10) -triene-332 carboxylic acid

A mixture of methyl 17β-isobutylcarbonyl-estra-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) was heated at reflux overnight. The reaction mixture was then concentrated. The residue was diluted with water, acidified with dilute HCl, extracted with ethyl acetate. The organic extract was washed with brine, dried and concentrated. The title compound was purified by HPLC, m.p. Mp 202-206 ° C.

Example 2- corresponding to Scheme III

17β-Isobutylcarbonyl-estra-1,3,5 (10) -triene-3-carboxylic acid (i). 17β-Isobutylcarbonyl-estra-1,3,5 (10) -triene-3-fluoro-sulfonate.

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

(ii). Methyl-17-isobutylcarbonyl-estra-3,5 (10) -triene-3-carboxylate.

A mixture of 17β-isobutylcarbonyl-estra-1,3,5 (10) -triene-3-fluorosulfonate, 1,3-bis (diphenylphosphine) propane, palladium diacetate, triethylamine, methanol, DMSO and 1,2-dichloroethane is heated and stirred vigorously for 5 hours , at 80 ° C under a carbon monoxide atmosphere. After cooling to room temperature, the resulting mixture is diluted with dichloromethane. The organic phase is washed thoroughly with water, dried (MgSO4) and evaporated to dryness. Chromatography on silica gel gives the title compound.

(Iii). Ι7β-Isobutylcarbonyl-estra-1,3,5 (10) -triene-3-carboxylic acid.

A mixture of methyl 17β-isobutylcarbonyl-ester-1,3,5 (10) -triene-3-carboxylate, Κ ₂ ^ 3, water and methanol is heated at reflux for 5 hours. The volatiles were then removed under reduced pressure and the residue was diluted with water, acidified with dilute aqueous HCl and extracted with EtOAc. The organic extract is washed with water and brine, dried and evaporated to give the title compound.

Example 3 corresponding to Scheme III

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

(i) 3- (trifluoromethanesulfonyloxy) -estra-1,3,5 (10) trans-17β-carboxylic acid

A solution of 3-hydroxy-estra-1,3,5 (10) -17β-carboxylic acid, 2,6-di-t-butyl-4-methylpyridine and trifluoromethanesulfonic anhydride in methylene chloride is stirred at 5 ° C for 20 hours. The organic solvent is evaporated and the residue is dissolved in tetrahydrofuran: water (99.5: 0.5) with 4-dimethylaminopyridine, acidified with HCl to give the title compound using an agreed workup.

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

Solution of 3- (trifluoromethanesulfonyloxy) -estra1,3,5 (10) -triene-17β-carboxylic acid, triphenylphosphine and 2,2 ´

-dipyridyldisulfide in toluene is stirred under nitrogen for 20 hours. The reaction mixture is concentrated and the residue is passed directly through silica gel to give the title compound from the appropriate evaporated fractions.

(iii). 17β-isobutylcarbonyl-esΐra-l, 3,5 (10) -triene-3-trifluoromethanesulfonate.

To a solution of S- (2-pyridyl) -3- (trifluoromethanesulfonyloxy) 34 estra-1,3,5 (10) -triene-17β-thiocarboxylate in tetrahydrofuran at about -50 ° C is added isobutylmagnesium bromide. The reaction mixture is warmed to about -10 ammonium chloride flow. After ´C and diluted with saturated custom work-up followed by isolation by column chromatography, the title compound is obtained.

(iv). Methyl-17-isobutylcarbonyl-estra-3,5 (10) -triene-3-carboxylate

A solution of 17β-isobutylcarbonyl-estra-1,3,5 (10) -triene-3-trifluoromethanesulfonate, triphenylphosphine, palladium II acetate, triethylamine, methanol and dimethylformamide is vigorously stirred under a carbon monoxide atmosphere for 20 hours. Conventional isolation followed by column chromatography gave the title compound.

(in) . 17β-Isobutylcarbonyl-estra-1,3,5 (10) -triene-3-carboxylic acid

A mixture of methyl 17β-isobutylcarbonyl-estra-1,3,5 (10) -triene-3-carboxylate, K 2 CO 3, water and methanol was heated at reflux for 5 hours. After acidification, subsequent work-up gives the title compound.

Example 4 corresponding to Scheme III

17β-Isobutylcarbonyl-estra-1,3,5 (10) -triene-3-carboxylic acid (i), 3- (fluorosulfonyloxy) -estra-1,3,5 (10) -trien-17β-carboxylic acid

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

(Ii). S- (2-pyridyl) -3- (fluorosulfonyloxy) estra-1,3,5 (10) -triene-17ss-thiocarboxylate

A solution of 3- (fluorosulfonyloxy) estra-1,3,5 (10) -trien-17β-carboxylic acid, triphenylphosphine and 2,2'-dipyridyldisulfide in toluene is stirred under nitrogen for 20 hours. The reaction mixture is concentrated and the residue is directly passed through silica gel and the title compound is obtained from the appropriate evaporated fractions.

(iii). 17β-isobutylcarbonyl-estra-1,3,5 (10) -triene-3-fluorosulfonate.

To a solution of S- (2-pyridyl) -3- (fluorosulfonyloxy) -estra1,3,5 (10) -trien-17β-thiocarboxylate in tetrahydrofuran at about -50 ° C is added isobutylmagnesium bromide. The reaction mixture is warmed to about -10 ° C and diluted with a saturated aqueous ammonium chloride solution. The usual compound followed by isolation by column chromatography gave the title compound.

(iv). Methyl-17-isobutylcarbonyl-estra-3,5 (10) -triene-3-carboxylate

A solution of 17β-isobutylcarbonyl-estra-1,3,5 (10) -triene-3-fluorosulfonate, triphenylphosphine, Palladium II acetate, triethylamine, methanol and dimethylformamide was stirred vigorously under a carbon monoxide atmosphere for 20 hours. The usual compound followed by isolation by column chromatography gave the title compound.

(in) . 17β-Isobutylcarbonyl-estra-1,3,5 (10) -triene-3-carboxylic acid

A mixture of methyl 17β-isobutylcarbonyl-estra-1,3,5 (10) -triene-3-carboxylate, K 2 CO 3, water and methanol was heated for about 5 hours. in reflux. Acidification followed by conventional technology yields the title compound.

Example 5 corresponding to Scheme III

17β- (octylcarbonyl) -estra-1,3,5 (10) -triene-3-carboxylic acid (i) 17β- (octylcarbonyl) -estra-1,3,5 (10) -triene-3-trifluoromethylsulfonate. The main compound was prepared according to Example 1 (i to iii) by substituting n-octylmagnesium chloride for isobutylmagnesium bromide in step (ii).

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

A mixture of 17β- (octylcarbonyl) -estra-1,3,5 (10) -triene-3-trifluoromethylsulfonate (0.38 g, 0.7 mmol), potassium acetate (0.27 g), Palladium II acetate (0.008) g, 0.036 mmol),

1,1'-bis (diphenylphosphine) ferrocene (dppf; 0.08 g, 0.14 mmol) in DMSO (15 mL) was washed with carbon monoxide for 2 min. The reaction mixture was diluted with water, acidified with 0.5 N HCl and extracted with dichloromethane. The organic layer was washed with water, dried (MgSO 4) and evaporated in vacuo. The residue was chromatographed (silica gel, washing 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- corresponding to Scheme III

17β- (tert-Pentylcarbonyl) -estra-1,3,5 (10) -triene-3-carboxylic acid

Trifluorin-17-beta- (tert-pentylcarbonyl) -estra-1,3,5 (10) -triene 3-sulfonate.

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

(ii) Ι7β- (tert-Pentylcarbonyl) -estra-1,3,5 (10) triene-3-carboxylic acid

The title compound was prepared according to Example 5 (ii) by substituting trifluoromethyl-17β- (tert-pentylcarbonyl) -estra1,3,5 (10) -triene-3-sulfonate, prepared in Example 6 (i), with trifluoromethyl-17β- ( octylcarbonyl) -estra-1,3,5 (10) -triene-3-sulfonate, bt Mp 199-200 ° C.

Example 7 - corresponding to Scheme III

17β-2,2- (dimethylpropylcarbonyl) -estra-1,3,5 (10) triene-3-carboxylic acid (i). Trif1υοπηβΐγ1-17β- (2,2-dimethylpropylcarbonyl) estra-1,3,5 (10) -triene-3-sulfonate.

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

(ii) 17β-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-17β- (2,2-dimethylpropylcarbonyl) estra-1,3,5 (10) -triene-3-sulfonate, prepared in Example 7 (i), with trifluoromethyl- 17β- (octylcarbonyl) -estra-1,3,5 (10) triene-3-sulfonate; b. t. 210 ° C.

Example 8 corresponding to Scheme 4

17β- (Propylcarbonyl) -estra-1,3,5 (10) -triene-3-carboxylic acid

17β-cyano-estra-3,5 (10) -triene-3-methanesulfonate.

The main compound is known and is prepared from estrone according to the procedure of Baldwin et al., J. Chem. Soc. (C) 1968,

2283-2289.

(11). 17β-cyano-estra-1,3,5 (10) -trien-3-ol.

To the title compound 17β-cyano-estra-1,3,5 (10) -triene-338 methanesulfonate (10 g) in methanol (100 mL) was added dropwise a solution of NaOH (42 mL of a 20% solution in 1: 1 MeOH- Water) . The resulting mixture is heated at 40 ° C for 24 hours, then cooled to 0 ° C, diluted with water (350 mL) and acidified with dilute HCl. The resulting white precipitate is isolated by vacuum filtration, washed with water and dried under vacuum. Recrystallization from acetonitrile gave the title compound, m.p. 249-250 C. C.

(iii) 17β-Cyano-estra-1,3,5 (10) -triene-3-trifluoromethanesulfonate.

17β-Cyano-estra-1,3,5 (10) -trien-3-ol (4.2 g) and 2,6-di-butyl-4-methylpyridine (3.6 g) were dissolved in 50 mL of methylene chloride. The mixture was stirred at room temperature for 30 minutes. Trifluorohydride (4.2 mL) was added and the mixture was stirred for an additional 40 minutes, diluted with 50 mL of CH 2 Cl 2, filtered, concentrated and chromatographed on silica gel. Washing with 20% ethyl acetate in hexane gave 5.3 g (87%) of the title compound, m.p. 115 to 117 ’C.

(iv) Methyl 17β-cyano-estra-1,3,5 (10) -triene-3-carboxylate.

To a solution of 17β-cyano-estra-1,3,5 (10) -trien-3-ol (10 g) in 77 mL DMSO and 50 mL MeOH was added 7 mL triethylamine, 0.35 g palladium acetate, 0.64 g bis (diphenylphosphine) propane and 1,2-dichloroethane (26 mL). Carbon monoxide was bubbled through the solution and the reaction mixture was then stirred at 75 ° C overnight at 0.1 MPa CO (round vessel). The mixture was diluted with EtOAc and washed with water (3x), dried and concentrated. The residue was chromatographed (silica gel, washing with 10% EtOAc in hexane) to give the title compound, 4.5 g, m.p. 161 to 163 ’C.

(v) 3-hydroxymethyl-estra-1,3,5 (10) -triene-17β-carboxaldehyde.

Methyl 17β-cyano-estra-1,3,5 (10) -triene-3-carboxylate (0.8 g) was dissolved in 30 mL of toluene and treated with DIBAL (6 mL, 1 M). 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, washing with 10% EtOAc in hexane) to give the title compound, 424 mg, m.p. 146 to 150 ’C.

(vi) 17β (3-hydroxybutyl-estra-1,3,5 (10) -triene-3-hydroxymethyl 3-hydroxymethyl-estra-1,3,5 (10) -ΐΓΪβη-17β-carboxaldehyde solution (75 mg in 2 mL of THF) was added slowly to a solution of propylmagnesium bromide (2 mL, 1.6 M), stirred at room temperature for 2 hours, 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, washing with 30% ethyl acetate in hexane) to give 57 mg of the title compound.

(Vii). β7β- (Propylcarbonyl) -estra-1,3,5 (10) -triene-3-carboxylic acid

17β- (1-hydroxybutyl-estra-1,3,5 (10) -triene-3-hydroxymethyl (57 mg) was dissolved in acetone (5 mL) and treated with Jones reagent. cooled with 2-propanol, extracted with CH 2 Cl 2 and purified by chromatography (silica gel, washing with 30% in hexane with 0.5% HOAc) to give 47 mg of the title compound, mp 211-113 ° C.

Example 9-Corresponding to Scheme IV

17β- (Methylcarbonyl) -estra-1,3,5 (10) -triene-3-carboxylic acid.

The title compound was prepared according to Example 8 (i) to (vii) by substituting methyl magnesium bromide for propyl magnesium bromide in step (vi), m.p. 199 to 202 ’C.

Example 10 - corresponding to Scheme IV

17β- (3,3-Dimethylbutylcarbonyl) -estra-1,3,5 (10) triene-3-carboxylic acid

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

Example 11 - corresponding to Scheme IV

17β- [1- (R, S) -Hydroxyethyl] -estra-1,3,5 (10) -triene-3-carboxylic acid

A solution of 17β- (methylcarbonyl) -estra-1,3,5 (10) triene-3-carboxylic acid (6 mg) - prepared according to Example 9 - in methanol was treated with NaBH 4 (0.7 mg). The mixture was warmed 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. Mp 202-204 ° C.

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

Example 12 - corresponding to Scheme IV

17β- [1- (R, S) -Hydroxybutyl] -estra-1,3,5 (10) -triene-3-carboxylic acid (i) The main compound was prepared according to Example 11 by substituting 17β- (propylcarbonyl) -estra acid, 3,5 (10) -triene-3-carboxylic acid prepared according to Example 8 (i) to (vii) for 17β- (methylcarbonyl) -estra-1,3,5 (10) -triene-3-carboxylic acid, bt 208-211 ’C. (ii) Pure (R) and (S) forms are obtained by a separation technique readily available and known to those skilled in the art.

Example 13

The oral dosage form for administration of the compounds of Formula I is manufactured by sieving, mixing, and filling the ingredients into solid gelatin capsules in proportions as shown in Table 1 below.

Table I

Ingredients Quantities 17β-isobutyl-carbonyl-estra-50 mg

1,3,5 (10) -triene-3-carboxylic acid 5 mg magnesium stearate 5 mg lactose 75 mg

Example 14

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

Table II

Ingredients Quantities

17β-Isobutyl-carbonyl-estra- 100 mg 1,3,5 (10) -triene-3-carboxylic acid calcium sulfate dihydrate 150 mg sucrose 20 mg starch 10 mg talc 5 mg stearic acid 3 mg

Example 15

17β-Isobutylcarbonyl-estra-1,3,5 (10) -triene-3-carboxylic acid, 75 mg, is dispersed in 25 ml of physiological saline for injection preparations.

While preferred embodiments of the invention are described above, it is to be understood that the invention is not limited to the foregoing instructions herein and the right to all modifications in accordance with the following claims is reserved.

Claims (40)

PATENT CLAIMS A compound of formula I r r '(077 (I), wherein Z is a or β H -C-R R in -COR is C ₁₂ linear or branched, saturated or unsaturated alkyl and pharmaceutically acceptable salts, hydrates, solvates and esters thereof. A compound according to claim 1 of formula II wherein R is C ₁ - ₂ q linear or branched, saturated or unsaturated alkyl, and pharmaceutically acceptable salts, hydrates, solvates and esters thereof. A compound according to claim 2 of formula III O Wherein C 1-6 is a linear or branched alkyl and pharmaceutically acceptable salts, hydrates, solvates and esters thereof. A compound according to claim 3, wherein R 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 according to claim 4, wherein R is 1-methylpropyl, n-butyl, isopropyl, n-pentyl, 3-methylbutyl, 2,2-dimethylpropyl, t-butyl, 1,1-dimethylpropyl, isobutyl n-octyl, tert-butyl. pentyl, n-propyl, methyl or 3,3-dimethylbutyl and pharmaceutically acceptable salts, hydrates, solvates and esters thereof. 6. 17β- (Isobutylcarbonyl) -estra-1,3,5 (10) -triene-3-carboxylic acid, 7. 17β- (octylcarbonyl) -estra-1,3,5 (10) -triene-3-carboxylic acid, 8. 17β- (tert-Pentylcarbonyl) -estra-1,3,5 (10) triene-3-carboxylic acid; 9. 17β- (2,2-Dimethylpropylcarbonyl) -estra-1,3, 5 (10) -triene-3-carboxylic acid, 10. 17β- (Propylcarbonyl) -estra-1,3,5 (10) -triene-3-carboxylic acid 11. 17β- (Methylcarbonyl) -estra-1,3,5 (10) -triene-3-carboxylic acid 12. 17β- (3,3-Dimethylbutylcarbonyl) -estra-1,3,5 (10) -triene-3-carboxylic acid A compound according to claim 1 of formula f wherein R is C ₁₂ linear or branched, saturated or unsaturated alkyl, and pharmaceutically acceptable salts, hydrates, solvates and esters thereof. A compound of the formula wherein Y is a or β OH I -C-R R -COHR of the C ₂ _ ₃ Q a linear or branched, saturated or unsaturated alkyl and pharmaceutically acceptable salts, hydrates, solvates and esters thereof. The compound of claim 14, wherein Y is at position β. The compound of claim 14, wherein Y is at position a. 17. 17β- (1-Hydroxyethyl) -estra-1,3,5 (10) -triene-3-carboxylic acid. 18. 17β- (1-Hydroxybutyl) -estra-1,3,5 (10) -triene-3-carboxylic acid. A compound according to claim 1 essentially as defined above with reference to any of the examples. A pharmaceutical composition comprising a compound according to any one of claims 1 to 18 and a pharmaceutically acceptable carrier. A compound according to any one of claims 1 to 18 for use in therapy. A compound according to any one of claims 1 to 18 for the manufacture of a medicament for use as a steroid-5α-reductase inhibitor. A compound according to any one of claims 1 to 18 for the manufacture of a medicament for use in a therapy for reducing prostate size. A compound according to any one of claims 1 to 18 for the manufacture of a medicament for use in the treatment of adenocarcinoma of the prostate. A process for the preparation of a compound of formula II wherein R is C 1-2 alkyl linear or branched, saturated or unsaturated alkyl, and pharmaceutically acceptable salts, hydrates, solvates and esters thereof, comprising: i) oxidizing a compound of formula ii) reacting a compound of formula wherein R is as described above in a metal-catalysed coupling reaction in the presence of a coupling agent, preferably carbon monoxide, followed by a hydrolytic reaction, if applicable, or iii) hydrolyzing a compound of formula wherein R is as described above, and then forming a pharmaceutically acceptable salt, hydrate, solvate or ester thereof. A process for the preparation of a compound of formula II (II), wherein R is C 1-12 linear or branched, saturated or unsaturated alkyl, and pharmaceutically acceptable salts, hydrates, solvates and esters thereof, which comprises reacting a compound of formula Wherein R is as described above sulfonic and with a base, preferably a din, in a solvent, preferably a compound of the formula with fluoro-2,5-di-t-butyl-3-methylpyridichloromethane to form wherein R is as as described above and the subsequently reacting desired compound in a metal catalyzed coupling reaction, in the presence of a suitable coupling agent, preferably carbon monoxide, is followed by any hydrolytic reaction, if permissible to give the compound of formula (II) and then any pharmaceutically acceptable salt thereof. , solvate. A process for preparing a compound of formula wherein R is linear or branched, saturated or unsaturated alkyl and pharmaceutically acceptable salts, hydrates, solvates and esters thereof, which comprises epimerizing a compound of formula (II), wherein: R is as described above and subsequently forms a pharmaceutically acceptable salt, hydrate, solvate thereof. A process for preparing a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and an effective amount of a compound of formula I wherein: Z is a or β h -C-R R in -COR is C 1-8 linear or branched, saturated or unsaturated alkyl and pharmaceutically acceptable salts, hydrates, solvates and esters thereof, characterized in that it comprises a compound of formula (I) or a pharmaceutically acceptable salt, hydrate , a solvate or an ester is associated with a pharmaceutically acceptable carrier or diluent. A compound of formula V O (V), where R is t is C 12q linear or branched, saturated or unsaturated alkyl and R ⁴ is fluorosulfonyloxy. A compound of formula VI (VI) wherein R is C 1-20 linear or branched, saturated or unsaturated alkyl. Use of a compound according to any one of claims 1 to 18 for the manufacture of a medicament for use as a steroid-5-α-reductase inhibitor. A method of inhibiting a steroid 5-α-reductase in a mammal which comprises administering to a mammal in need of such inhibition an effective amount of a compound of any one of claims 1 to 18. The use of a compound according to any one of claims 1 to 18 and an α-receptor antagonist compound as a therapeutic substance, the use of which comprises the separate, sequential or simultaneous administration of a compound according to any one of claims 1 to 18 and an α-receptor antagonist compound. Use of a compound according to any one of claims 1 to 18 and an α-receptor antagonist compound in the manufacture of a medicament for use in the treatment of benign prostatic hypertrophy, which consists of administering a compound according to any one of claims 1 to 18 and a compound having antagonistic activity alone, sequentially or simultaneously. towards the α-receptor. Use of a compound according to any one of claims 1 to 18 and an aromatase inhibiting compound as an active therapeutic substance, the use of which consists in the separate, sequential or simultaneous administration of a compound according to any one of claims 1 to 18 and an aromatase inhibiting compound. Use of a compound according to any one of claims 1 to 18 and an aromatase inhibiting compound in the manufacture of a medicament for use in the treatment of benign prostatic hypertrophy, which consists of administering a compound according to any one of claims 1 to 18 and an aromatase inhibiting compound alone, sequentially or concurrently. Use of a compound according to any one of claims 1 to 18 and minoxidil as an active therapeutic substance, which consists of separate, sequential or simultaneous administration of a compound according to any one of claims 1 to 18 minoxidil. Use of a compound according to any one of claims 1 to 18 and minoxidil in the manufacture of a medicament for use in the treatment of male baldness, consisting of separate, sequential or simultaneous administration of a compound according to any one of claims 1 to 18 and minoxidil. Use of a compound according to any one of claims 1 to 18 and an aromatase inhibiting compound and an α-receptor antagonist compound as an active therapeutic substance, consisting of separate, sequential or simultaneous administration of a compound according to any one of claims 1 to 18 and an aromatase inhibiting compound and an antagonist compound. α-receptor activity. Use of a compound according to any one of claims 1 to 18 and an aromatase inhibiting compound and an α-receptor antagonist compound in the manufacture of a medicament for use in the treatment of benign prostate hypertrophy which consists of a single, subsequent or any one of the claims> aromatase and and a receptor. concomitant administration of compounds 1 to 18 and compounds inhibiting antagonistic activity against