CZ334694A3 - 17-alkyl ketone steroids usable as inhibitors of 5-alpha-reductase - 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

17-Alkyl ketone steroids useful as 5-alpha-reductase inhibitors

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The present invention relates to certain new 17 from. and 17β-alkylketone-3-carboxy-aromatic A ring-steroid compounds, pharmaceutical compositions containing such compounds, and methods of using such compounds for inhibiting the steroid 5-β-reductase of isozyme 1 and stercidal 5-2-β-isozyme 2. The invention relates to novel intermediates and processes suitable for the preparation of these compounds.

BACKGROUND OF THE INVENTION

The class of steroid hormones known as androgens is responsible for the physical characteristics that distinguish males from females. Of the androgen-producing organs, these hormones produce the most testicles. Mule centers perform primary control of androgen production levels.

Many physical manifestations and disease states arise when ineffective control leads to over androgen hormone production. For example, acne vulgaris, seborrhea, Sava hirsutism, male baldness and prostate diseases such as benign prostatic hypertrophy are associated with elevated androgen levels. Furthermore, the decrease in anemia levels has been found therapeutically effective in the case of cancer.

Testesterone is the primary androgen secreted by the testes and is the primary androgens stercide in mammalian plasma. It is known that 5-alpha-produced androgens are active hormones in some tissues such as the prostate and adipose glands. The circulating testesterone thus serves as prohormone for dihydrotestosterone (DTK), its 5-alpha-reduced analogs, in these tissues but not in others such as muscles and testes. The steroid 5-os-reductase is a nicotinamide adenine dinucleotide phosphate / Nicotinamide Adenine dinucleotide Phosphate (NADPH) dependent enzyme that converts testesterone to DKT. The importance of this enzyme

In the development of males, it has been dramatically emphasized by the discovery of the genetic deficiency of steroid 5 - red reductase in male oseudohermaphrodites. Imperator-McGi.nley, J. et al., (1979), J. Steroid Slechem 11: 527-648.

Numerous 2-carboxy-1,3-aryl-1,3,5 (10) -triene 5-H-reductase inhibitors are known in the art. For example

1. J. Steroid Siochem., Vol. 24, no. 1-5, p. 571-575 (1929),

M. A. Levy et al. Describes a mechanism of interaction between the steroid 5-α-reductase of rat prostate and 3-carboxy-17G-substituted steroids,

2. J. Med.Chem / 1590 / Vol.53, p. 937-942, D. A. Holt et al., Discloses a new sterile class A ring of arylcarboxylic acids,

2. TIPS / December 1239 / Vol., 19, pp. 491-495, by B.W. Hetcalf et al., Describes the effect of phallo-reductase steroid inhibitors on benign prostatic hyperplasia, male baldness and acne.

Further, U.S. Pat. No. 4S54445 discloses a family of 2-carboxy esters of 1,3,5 / 10 / triene-17G-substituted compounds which are said to be useful as steroid 5-ped-peductase inhibitors. However, none of the aforementioned works 02007130: .2 suggest that any of the novel 17G-alkylketone-2-carboxy-aromatic A-ring steroid compounds of the present invention could be useful as potent inhibitors of both steroid-5-6? steroi (-5-ZZ-reductase icozyme 2) (double inhibitors).

The essence of the invention

The invention relates to compounds of formula I

where Z is or 3 π

- 2-3.

is linearly branched, saturated, unsaturated alkyl and pharmaceutically acceptable salts, hydrates, solvates and esters thereof.

The invention also provides a method for the simultaneous inhibition of 5-alpha-reductase isozyme 1 and 5-alpha-isozyme 2 activity by including 5-alpha-reductase inhibiting compounds of the invention.

See £ 2.77. 3 Ξ 70 * -Ό 7 33 OΌ ΌΖ 3 3.3 7 ”7.7. 2 3 Z \ I * 20S '<V taU CV ~ 3VZ'. ”0Ž3Č3 V3 737 VU 777'l not presented to a pair of i-slta-product inhibiting compounds. Included in the present invention are pharmaceutical compositions comprising a pharmaceutical carrier and a compound:

invusible in methods of prayer in the clutch. In the composition fs-r>

Also contemplated by the present invention are methods of the simultaneous non-delivery of the present double 5-alpha-reductase inhibiting compounds with other active ingredients.

The compounds of the present invention which inhibit both 5-alpha-reductase isozyme I and Ξ-alpha-reductase isozyme 2 have the following general formula 1:

% $ *

/ 1 / where Z is or β

II

-CR R ^ is ^not i_20 ^^ ^ ^rn ^ or branched, saturated or unsaturated alkyl and include pharmaceutically acceptable salts, hydrates, solvates and esters thereof.

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

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

wherein R is C 1-4 linear or branched, saturated or unsaturated alkyl, and pharmaceutically acceptable salts, hydrates, solvates and esters thereof.

Of the compounds of formula II, those having formula III are preferred

(111) wherein R is C 1-4 linear or branched alkyl and pharmaceutically acceptable salts, hydrates, solvates and esters thereof.

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

Particularly preferred of the compounds of Formula III 2 are those wherein R is 1-methylpropyl, n-butyl, isopropyl, n-pentyl, 3-methylbutyl, 2,2-dimethylpoly, tert-butyl, 1,1-dimethylpropyl, isobutyl n-octyl, t-pentyl, n-propyl, methyl or 3,3-dimethylbutyl.

Particularly preferred of the compounds of formula III are:

170- (isobutylcarbonyl) -estra-1,3,5 (10) -trien-3-carboxylic acid,

170- (octylcarbonyl) -etra-1,3,5 (10) -trien-3-carboxylic acid,

170- (tert-pentylcarbonyl) -estra-1,3,5 (10) -trien-3-carboxylic acid,

170- (2,2-dimethylpropylcarbonyl) -estra-1,3,5 (10) -trien-3-carboxylic acid,

-617B- (propylcarbonyl) -estra-1,3,5 (10) -trien-3-carboxylic acid,

17Q- (methylcarbonyl) -estra-1,3,5 (10) -trien-3-carboxylic acid a

178- (3,3-dimethylbutylcarbonyl) -estra-1,3,5 (10) -trien-3-carboxylic acid and its pharmaceutically acceptable salts, hydrates, solvates and esters.

As used herein, according to standard chemical terminology, it means down or that the corresponding substituent is attached below the plane of the paper.

The term fi as used herein, according to standard chemical terminology, means up or that the corresponding substituent is attached above the plane of the paper.

The term alkyl ", C ^ _ alkyl and _n and derivatives thereof as used herein in all carbon chains, if not stated otherwise, denotes C _n _ ^ linear or branched carbon chain having 1 to n carbons. Examples of alkyl and its derivatives as used herein mean: methyl, ethyl, propyl, 3-methylbutyl, isopropyl, n-butyl, isobutyl, 1-methylpropyl, tert-butyl, n-pentyl, 1,1-dimethylpropyl, 2,2-dimethylprcoyl, n-octyl, tert-butyl 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 .

By the metal-catalyzed coupling reaction as used herein is meant that the prepared 3-trifluoromethylsulfonate or 3-fluorosulfonate compound is reacted in an organic solvent, preferably toluene, with dihydroxy toluene, di-4-ol in 4

-7-methylformamide or THF with a base, preferably a tertiary amine base such as triethylamine, pyridine or tributylamine, a phosphine such as bis (diphenylphosphino) alkane, preferably 1,3-bis (diphenylphosphino) propane or tri-o-tolylphosphine, or C 1-6 alkanol; a metal catalyst, preferably a palladium catalyst such as palladium acetate, palladium chloride or bis (triphenylphosphine) palladium acetate and a coupling agent.

As used herein, the term coupling agent means a compound that is capable of reacting with an aryl radical to form a carboxylic acid substituent. Carbon monoxide is a preferred coupling agent which, when added to a metal catalyzed coupling reaction as described herein, provides the desired carboxylic acid group.

The compounds of formula (I) and compounds of formula (IV) are included in the pharmaceutical compositions of the invention and are used in the methods of the invention. When a -COOH group is present, pharmaceutically acceptable esters, for example methyl, ethyl, foyoyloxymethyl, and the like, and those esters in the art may be used to modify solubility or hydrolysis characteristics for use in sustained release formulations or prodrugs. .

The term -receptor antagonist as used herein refers to a known class of compounds that are alpha-adrenergic receptor antagonists as described by Lafferty et al., U.S. Patent No. 4,963,547, which are used in the treatment of vascular disorders such as diabetes, cardiovascular diseases, benign prostate hypertrophy and ocular hypertension.

 / '<7 \ 7Ζ'7ιΖΧ ·· <.:?., I javLKV ^ ts. ´ Λ.Ζ ..- V. · -.

-8 Preferred alpha-adrenergic receptor antagonists for use 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-benzazepine.

The term amsulosin as used herein refers to a compound of the formula

and salts, hydrates and solvates thereof.

Chemically, amsulosin is named as (-) - (R) -5- (2-) - 2- (O-ethoxyphenoxy) ethyl / amino / propyl / -2-methoxybenzenesulfonamide.

Amsulosin is described in US Patent No. 4703063 and claimed in US Patent No. 4287125 for the treatment of lower urinary tract dysfunction.

As used herein, terazosin refers to a compound of formula _

1 ·.

-9a salts, hydrates and solvates thereof.

Chemically, terazosin is named 1- (4-amino-6,7 dimethoxy-2-quinazolinyl) -4 - [(tetrahydro-2-furoyl) carbonyl] piperazine. Terazosin is disclosed in U.S. Patent No. 4251532.

By doxazosin as used herein is meant a compound of the formula

and salts, hydrates and solvates thereof.

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

Doxazosin is disclosed in U.S. Patent No. 4,158,330.

As used herein, the term alfuzosin means a compound of the formula

O

And salts, hydrates and solvates thereof.

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

Alfuzosin is described in U.S. Patent No. 4,315,007.

The term indoramine as used herein refers to a compound of the formula

and salts, hydrates and solvates thereof.

Chemically, the indoramine is named N - [1- [2- (1H-indol-3-yl) ethyl] -4-piperidinyl] benzenamide.

indoramine is disclosed in US Patent No. 3327761.

As used herein, prazcsin means a compound of the formula

and salts, hydrates and solvates thereof.

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

Prazosin is described in U.S. Patent No. 3,511,836.

7-Chloro-2-ethyl-3,4,5,6-tetrahydro-4-methylthieno [4]

3,2-ef || 3 [benzazepine as used herein means a compound of the formula and salts, hydrates and solvates thereof.

7-Chloro-2-ethyl-3,4,5,6-tetrahydro-4-methylthieno [4],

3,2-β-benzazepine is described in US Patent No. 5006521. Furthermore, all compounds described in US Patent No. 5006521 are as

Those of ordinary skill in the art will be able to ascertain whether a compound other than the one described herein is an α-adrenergic receptor antagonist using the assay described by Lafferty I. All such compounds are included within the scope of the term alpha-adrenergic receptor antagonist as used herein.

The term minoxidil. As used herein, means a compound of the formula

Chemically, minoxidil is referred to as 2,4-pyrimidinediamine 6- (1-piperidinyl) -3-oxide. Minoxidil is the active ingredient in Rogaine, which is available as a topical hair growth stimulating solution from Upjohn Company, Kalamazoo, Michigan.

The term aromatase inhibitor as used herein refers to a known class of compounds, steroid and non-steroidal, that prevent the conversion of androgens to estrogens, as described in Gormley et al. International Publication No. WO 92/18132. Aromatase inhibitors are described in Gormley et al. as having use in the treatment of benign prostatic hyperplasia when used in combination with a 5-β-reductase inhibitor.

A preferred aromatase inhibitor for use in the compositions and methods of the invention is 4- (5,6,7,3-tetrahydro-imidazo [1,5-b] pyridin-5-yl) -tenzonitrile (fadrazole). Fadrazole is disclosed in US Patent No. 4,728,645. Furthermore, all of the compounds described in Gormley et al., International Publication WO 92/18132 are described as having aromatase inhibition activity, the preferred aromatase inhibitors used herein.

When a dual 5'-reductase inhibitor and another active ingredient (s) are used together as disclosed herein, said 5-reductase inhibitor may be co-administered with said other ingredient (s).

By the term co-administered and its derived terms used herein is meant the simultaneous administration or any mode of separate sequential administration of a compound that inhibits 5-flk-reductase as described herein and other active ingredients or ingredients such as other compounds known to treat acne vulgaris , seborrhea, female hirsutism, male baldness, benign prostatic hypertrophy or prostate adenocarcinoma, or compounds known to be useful in combination with 5 -? - reductase inhibitors. Preferably, if the administration is not simultaneous, the compounds are administered at a certain estimated time of administration. Further, it is not essential that the compounds are administered in the same dosage form, for example, one compound may be administered topically and the other compound may be administered orally.

The novel compounds of formula (II) according to the invention can be prepared by the methods outlined in the following Schemes 1-4 and in the Examples, from known and readily available estrons of formula

-14 or 17β-carboxylic acid analogs of estrone, which are known and readily available.

(C)

, 'V V';. '·' ·. '

-160

II

F

(g) t-xi. Civ íKi'f! Í Í Í: L'.í.

Scheme I represents the formation of compounds of formula II. As shown in Scheme I, compound b was prepared from the compound and following the procedure of Baldwin et al., J. Chem.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 then treated with a Grignard reagent, as described below, or a lithium reagent, in a suitable organic solvent, preferably tetrahydrofuran or diethyl ester as solvent, preferably at reflux temperature, to give compounds d.

The base compounds, 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, preferably trifluoromethanesulfonic anhydride, to give compounds e.

Compounds 6 are prepared by reacting compounds of formula e with a metal-catalyzed coupling reaction. Preferably, the compound of formula (e) is dissolved in dimethyl ammonium in (CN) solution of an organic base, preferably triethylamine, phosphine, preferably bis (diphenylphosphino) propane, a palladium compound, preferably palladium acetate and C1-4alkylalcohol (C1-4alkOH) followed by addition of carbon monoxide /. The compounds f are then reacted with a suitable base, preferably potassium carbonate, and acidified to provide the compounds 6.

·: ..; _{·? Ί.} ·

'1 *

-18Schema II

O

(d)

O

FOjSO

O

HCXX

ÍS)

Scheme II describes the formation of compounds of formula II. The starting material in Scheme II are compounds of formula d, prepared as described in Scheme I.

As shown in Scheme II, a compound of formula d and a base, preferably 2,5-di-tert-butyl-3-methyl-1-pyridine, is cooled to -20 ° C to 20 ° C in a suitable organic solvent, preferably dichloromethane, preferably 0 ° C and reacted with fluorosulfonic anhydride to form compound h. Compounds of formula f are prepared by reacting a compound of formula h with a metal catalyzed coupling reaction. Preferably, the compound of formula (h) is dissolved in dimethylformide (DMF) an organic base, preferably triethylamine, a phosphine preferably bis (diphenylphosphine) propane, a palladium compound, preferably palladium acetate, and C 1-6 alkyl (C 1-6 alkOH), followed by addition of carbon monoxide (CO). Compounds (f) are then reacted with a suitable base, preferably potassium carbonate, and acidified to provide compounds (6).

'V'V. <^; , ií 'λ' / ·! '

-20 □ chema III

Scheme III describes the preparation of compounds of formula II. In Scheme III, CF 4 O 4 O- or FO ₂ SO-. According to Scheme III in the alkylation process (step C), the pyridylthioester is reacted with LiR or XMgR (X = Cl, Br) with a Grignard reagent (as described below), preferably isobutylmagnesium bromide, n-octylmagnesium chloride, tert. pentylmagnesium chloride or 2,2 dimethylpropylmagnesium bromide, preferably in tetrahydrofuran to give the desired product, preferably 17B- (isobutylcarbonyl) -estra-1,3,5 (10) -trien-3-carboxylic acid,

170- (octylcarbonyl) -estra-1,3,5 (10) -trien-3-carboxylic acid, 170- (tert-pentylcarbonyl) -estra-1,3,5 (10) -trien-3-carboxylic acid or 170- (2,2-dimethylpropylcarbonyl) -esta 1,3,5 (10) -trien-3-carboxylic acid in one or two steps.

In Route 1, the 3-hydroxy acid (i) is converted to the 3-trifluoromethylsulfonate or 3-fluorosulfonylate derivative (i) (step A) by treatment (i) with trifluoromethylsulfonylanhydride or fluorosulfonylanhydride and an amine base such as pyridine, preferably 2,5-di-tert. 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 obtained (step B) by treatment with 2,2-dithiopyridylaene and triphenylphosphine in a suitable organic solvent, preferably tetrahydrofuran / zole at room temperature for about 8 to 14 hours.

enu

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

The 3-methyl ester (f) is obtained (step D) by treatment (1) under carbonylation conditions, preferably by bubbling gaseous carbon monoxide solution (1) in a suitable organic solvent, preferably methanol, containing the acetate catalyst preferably triethylamine, at about room temperature for 1. -16 h.

The compounds (f) are then reacted with a suitable base, preferably potassium carbonate, and acidified to give the compounds (g).

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

Route 2 involves the conversion of the starting steroid acid (i) to the 3-trifluoromethylsulfonylate or the 3-fluorosulfonylate derivative (j) by step A above; carbonylation (j) to (m) in step D; formation of the activated 2-pyridylthioester in (n) in step B; formation of the 17-acyl compound (f) in step C; and hydrolysis of the 3-ester to the final product (g) of step F which is 3-acid.

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

-23Schema IV

(C)

MR (M = UgEr, MgCl or Li) (Griqnard reagent) (0

Scheme IV describes the preparation of compounds of formula II.

In the alkylation process of Scheme IV (for preparing compounds of formula (s)), carboxaldehyde is reacted with Li-R or XMgR (X = Cl, Br) by a Grignard reagent (as described herein below), preferably propylmagnesium bromide, methylmagnesium bromide or 3,3-dimethylbutylmagnesium chloride , preferably in tetrahydrofuran, to give the desired product, preferably 172- (propylcarbonyl) -estr α-1,3,5 (10) -trien-2-carboxylic acid, 173- (methylcarbonyl) -estra-1,3,5 (10) -trien-3-carboxylic acid, 172- (3,3-dinethylbutylcarbonyl-O-estra-1,3,5 (10) -trien-3-carboxylic acid, in one or two steps.

The starting material in Scheme IV is a compound of formula c prepared according to Scheme I.

As described in Scheme IV, a compound of formula (c) a base, preferably 2,5-di-tert-butyl-3-methyl-pyridine in a suitable organic solvent, preferably dichloromethane,

It is cooled to -20 ° C to 20 ° C, preferably 0 ° C, and reacted with trihaloalkylsulfonic anhydride, preferably trifluoromethanesulfonic anhydride, to give compounds (p).

Compounds of formula (q) are prepared by reacting a compound of formula (p) with a metal catalyzed coupling reaction. Preferably, the compound of formula (p) is dissolved in dimethylformamide (DMF) and an organic base, preferably triethylamine, phosphine, preferably bis (diphenylphosphino) propane, a palladium compound preferably palladium acetate, and a C 1 -C 6 alkyl alcohol ₍ C 1 -C 6 alkOH) are added. and then carbon monoxide (CO) is added. Compounds of formula (q) are reacted with a reducing agent, preferably diisobutylaluminum hydride, to form compounds of formula (r).

Compounds of formula / s / are obtained by treating compounds of formula / a / with a Grignard reagent / as described in Scheme XII / or a lithium reagent in tetrahydrofuran or diethylether solvent, at ^- a temperature of about -50 ° C to -70 ° C, 1 up to 16 hours.

Compounds of formula (g) are prepared by oxidation of compounds of formula (s). Preferably, Jonas reagents or tetrapropylammonium perrthenate and then sodium hypochlorite are used in the oxidation.

Grignard reagents of the XMgBr type (where R is ^C 2 -C 20 linear or branched saturated or unsaturated alkyl) for use in the preparation of all species included within the scope of the invention are available or can be readily prepared by those skilled in the art.

Compounds of formula I wherein Z is in position are prepared from compounds containing a β substituent by the general method described below.

\ W

General Method

To a stirred solution of 176 steroid, double 5'-reductase inhibiting compound of formula II in a suitable solvent, preferably ethylene glycol or dimethyl sulfoxide, is added a base such as a hydroxide or alkoxide base, preferably sodium hydroxide, potassium hydroxide or sodium methoxide, at a temperature above 100 °. C, preferably reflux temperature and the corresponding epimer is obtained after isolation and work-up.

In determining a suitable solvent for carrying out epimerization, dimethylsulfoxide or other non-reactive high-boiling solvent is preferred if the starting 176 double-O 5 -reductase inhibiting steroid compound contains reactive substituents or reactive unsaturated bonds that are, for example, subject nucleophilic attack and ethylene glycol or other solvents may be used if the reactivity of the substituents or any unsaturated bonds of the starting 176 double-X 5 -reductase inhibiting steroid compounds is not taken into account.

Within the scope of the present invention, the ketone reduction products of formula I are secondary alcohols of formula IV

H-O-C

O

It

/ IV /

-herewhere Y is <or β j

-C-R wherein R is ^C 12 -C 12 linear or branched, saturated or unsaturated alkyls and pharmaceutically acceptable salts, hydrates, solvates and esters thereof.

Preferred of the ketone reducing products of the invention are secondary alcohols wherein

OH

AND

-C - R is in β position.

Particularly preferred of the ketone reduction products of the invention described above are 17B- (1-hydroxyethyl) -estra-1,3,5 (10) -trien-3-carboxylic acid and 17G-1- (1-hydroxybutyl) -estra-1,3,5 (10) -trien-3-carboxylic acid.

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

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

By elevated temperature as used herein and in the claims is meant a temperature above 25 ° C, preferably a reflux temperature.

The term solvent or suitable solvent in the specification and claims is intended to include a solvent such as methylene chloride, ethylene chloride, chloroform, ethylene glycol,

. · Α · ζΑ «ν.ιί

-28 carbon tetrachloride, tetrahydrofuran (THF), ethyl ether, toluene, ethyl acetate, dimethylsulfoxide (DMSO), N, N'-dimethyl N, N'-propylene urea, N-methyl-2-pyrrolidinone, methanol, 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 prepared, if desired, by methods well known in the art.

In the preparation of compounds of formula I, novel intermediates of formula V were synthesized

wherein R is a ^C] __ 2q linear or branched, saturated or unsaturated alkyl, and R is fluorosulfonyloxy.

Also preferred in the preparation of the compounds of formula I according to the invention are novel intermediates of formula VI

OH

wherein R is as defined in formula II

A preferred method for preparing a compound of Formula II

(11) wherein R is C 1-4 linear or branched, saturated or unsaturated alkyl and their pharmaceutically acceptable salts, hydrates, solvates and esters, comprises reacting a compound of the formula

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

W ’’!

//SALT

-30O

wherein R is as defined above followed by reacting said compound in a metal catalyzed coupling reaction in the presence of a suitable coupling agent, preferably carbon monoxide, followed by, if necessary, hydrolyzing reaction to form a compound of formula II and then optionally forming a pharmaceutically acceptable salt , a hydrate, a solvate or an ester of these compounds.

Since the pharmaceutically active compounds of the present invention are potent double inhibitors of 5-alpha-reductase activity, they have therapeutic utility in the treatment of diseases and conditions where a reduction in DHT activity produces the desired therapeutic effect. Such diseases and conditions include acne vulgaris, seborrhea, female hirsutism, male baldness, prostate diseases such as benign prostatic hypertrophy and prostate adenocarcinoma.

To determine the potency of inhibition of the 5α-reductase enzyme, the following human procedure was used

Preparation of membrane particles used as a source of recombinant steroid 5alpha-reductase isozyme 1

Chinese hamster ovary (CHO) cells containing expressed, recombinant human steroid 5α-reductase isoenzyme 1 / Andersson S., Berman D.M., Jenkins E.P. and Russell DW (1991) (Coat 354 159-161) were homogenized in 20 mm potassium phosphate, pH 6.5, buffer containing 0.32 M sucrose, 1 mM dithicthreitol and 50 µl NAC? R (buffer A) using Dounce glas. a glass homogenizer (Kontes Glass Co., Vineland, NJ). Membrane

The -31 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 dithithreitol and, µM NADPH (buffer B). The suspended particulate solution was stored at -80 ° C.

Preparation of prostate membrane particles used as a source of isozyme 2 steroid 5α-reductase

Frozen human prostates are thawed and chopped into small pieces (Brinkmann Polytron, Sybron Corp., Westbury, New York). The solution is sonicated for 3-5 minutes using a Sinifier / Branson Sonic Power Co./ and then homogenized by manual homogenization in a Dounce hand homogenizer. Prostate particles are obtained by differential centrifugation at 600 or 1000 xg for 20 minutes and 14000 xg for 60 minutes. at 4 ° C. The pellet obtained from centrifugation at 140000 x g is washed with 5-10 volumes of tissue buffer described above and centrifuged at 140000 x g. The resulting pellet is suspended in buffer B and the suspension of particles is stored at -80 ° C.

Preparation of membrane particles used as a source for recombinant steroid salfa-reducase isozyme 2

Chinese hamster ovary (CHO) cells containing expressed, recombinant human steroid 5α-reductase isozyme 2 were homogenized in 20 mM potassium phosphate buffer, pH 6.5 containing 0.33 M sucrose, 1 mM dithiothreitol and 50 µm NADPH / buffer A / using a Dounce hand homogenizer. membrane particles containing recombinant human enzyme were isolated by centrifugation (100,000 xg at 4 ° C for 60 minutes) and resuspended in 20 mM potassium phosphate, pH 6.5, containing 20% glycerol, 1 mM dithiothreitol and 50 µM NADPH / buffer 3 /. The suspended particulate solution was stored at -80 ° C until use.

-32 Assay of enzyme activity and inhibitory potency.

Constant quantity Testosterone (50-55 mCi / mmol) in ethanol and various amounts of potential inhibitor in ethanol were placed in tubes and concentrated to dryness in vacuo. Buffer, 10 µl (recombinant isoenzyme 1 or isoenzyme 2) was added to each tube. 20 / u! (human prostate tissue isoenzyme 2) / 10 mM NADPH and steroid 5α-reductase preparation to 0.5 ml final volume. Human steroid 5alpha-reductase isoenzyme 1 assays were performed with a sample of recombinant protein expressed in CHO cells in 50 mM phosphate buffer, pH 7.5, while isoenzyme 2 assays were performed with a suspension of human prostate 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 minutes or 30 minutes, the reaction is quenched by the addition of 4 ml of ethyl acetate and 0.25 µmol of each of tetstosterone, 5α-dihydrotestosterone, androstanediol and androstanedione as carriers. The organic layer was placed in a second test tube and evaporated to dryness in a Speed Vac. The residue was dissolved in 40 µl of chloroform, applied to an individual lane on a 20 x 20 cm silica gel TLC plate with preformed pathways (Si 250F-PA, Baker Chemical) and developed twice with ethyl acetate (1: 9). The content of radioactive chemicals in the substrate and product bands was determined using a BIOSCAN Imaging Scanner (Bioscan Inc., Washington, D.C./). The percentages of the radiolabel obtained transferred to the product are counted and the enzyme activity determined. All incubations are performed so that no more than 20% of the substrate (testosterone) is consumed.

- '<\ r ΐ · - Λ τ / 1 c' ¹ 1 3 t / ko

The experimentally obtained values were put into linear function by a computer by a graphical representation of the inverted enzyme

-33 apparent inhibition constants (IC _and p ₀ ) were determined by Dixon analysis / Dixon M./1953//:

The value of the inhibition constant (Ki) was calculated by known procedures (Left M./1989), Biochemistry, 29: 28152824). ~ * '

All compounds within the scope of the present invention are useful in inhibiting steroid 5α-reductase isozyme 1 and steroid 5α-reductase isozyme 2 in mammals, including humans, in need thereof.

Compounds within the scope of this 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.

Particularly preferred of the compounds of the invention and the compounds used in the pharmaceutical compositions of the invention are

178- (isobutylcarbonyl) -estra-1,3,5 (10) -trien-3-carboxylic acid

17B- (octylcarbonylQ-estra-1,3,5 (10) -trien-3-carboxylactic acid),

178- (tert-benzylcarbonyl) -estra-1,3,5 (10) -trien-2-carboxylic acid,

178- (2,2-dimethylpropylcarbonyl) -estra-1,3,5 (10) -riene-3-carboxylic acid,

178- (propylcarbonyl) -estra-1,3,5 (10) -trien-3-carboxylic acid,

178- (methylcarbonyl) -estra-1,3,5 (triene) -3-carboxylic acid,

178- (3,3-dimethylbutylcarbonyl) -estra-1,3,5 (10) -trien-3-carboxylic acid,

178- (Ι-hydroxyethyl) -estra-1,3,5 (10) -trien-3-carboxylic acid and

178- (1-hydroxybutyl) -estra-1,3,5 (10) -trien-3-carboxylic acid.

'Α /' Ζ ' ¹

The pharmaceutical active compounds of the present invention are incorporated into conventional dosage forms such as, preferably, 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, saline, and water. Similarly, the carrier or diluent may comprise any sustained release material such as glyceryl monostearate or glyceryl distearate, alone or with a wax. The amount of solid carrier varies over a wide range, but will preferably be from about 25 mg to about 1 g per dosage unit. If a liquid carrier is used, the preparation will preferably be in the form of a syrup, elixir, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampoule or an aqueous or non-aqueous liquid suspension.

The pharmaceutical preparations can be made by conventional pharmaceutical chemistry techniques, including mixing, granulating and compressing, if necessary, for tablet forms, or mixing, filling and dissolving, if desired, to obtain the desired oral or parenteral products.

Dosages of the pharmaceutically active compounds of the present invention in a pharmaceutical dosage unit described above will be effective, nontoxic and in an amount preferably selected from the range of 0.1 to 1000 mg / kg of active compound, preferably 1 to 100 mg / kg. If inhibition of the steroid 5alpha-reductase is required in the treatment of a human patient, the selected dose is preferably administered 1 to 10 times daily, orally or parenterally. Preferred forms of parenteral administration include topical, rectal, transdermal, injection and continuous infusion. Oral dosage units for administration to humans preferably contain 1 to 500 mg of the active compound, oral administration which it utilizes. z s i tav ·; v ^ referenced. Parenteral o;

me, v2 vv:

however, dosages may also be used if necessary for patient safety and convenience.

The method of the invention for inhibiting steroid 5α-reductase isozyme 1 and steroid 5α-reductase isozyme 2 activity in mammals, including humans, comprises administering to a subject in need thereof such an effective double inhibitory amount of a compound of the present invention.

The invention also provides the use of a compound of formula I or a compound of formula IV for the manufacture of a medicament for the double inhibition of steroid 5α-reductase.

The invention also provides a pharmaceutical composition for use in treating 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 use in treating 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 contacting a compound of formula I or a compound of formula IV with a pharmaceutically acceptable carrier or diluent.

No unacceptable toxicological effects are expected when administering the compounds of the invention in accordance with the present invention.

Further, the pharmaceutically active compounds of the present invention may be co-administered with other active ingredients, such as other compounds known for the treatment of disease states such as acne vulgaris, seborrhea, female hirsutism, male baldness, benign hypertro

Known as having utility in their use in combination with 5α-reductase inhibitors. Particularly preferred is the concomitant administration of a dual 5α-reductase inhibitor as described herein and minoxidil for use in the treatment of male baldness. Particularly preferred ^- it is currently administered by a dual 5alpha-reductase inhibitor, as disclosed herein, and alpha-receptor antagonists for use in treating benign prostatic hypertrophy. Preferred is the simultaneous administration of a dual 5α-reductase inhibitor as described herein and an aromatase inhibitor for use in the treatment of benign prostatic hypertrophy. Preferred is the simultaneous administration of a dual 5α-reductase inhibitor as described herein, an alpha-receptor antagonist and an aromatase inhibitor for use in the treatment of benign prostatic hypertrophy.

Without further elaboration, it is believed that one skilled in the art will be able to utilize the present invention to its fullest extent using the foregoing procedure. The following examples are, therefore, to be construed as illustrative and not in any way intended to limit the invention in any way.

DETAILED DESCRIPTION OF THE INVENTION

Example 1 - corresponds to Scheme III

17B-Isobutylcarbonyl-estra-1,3,5 (10) -trien-3-carboxylic acid 1 H- (2-Pyridyl) -3-hydroxy-estra-1,3,5 (10) triene-17B-thiocarboxylate

A mixture of 3-hydroxy-estra-1,3,5 (10) -trien-17B-carboxylic acid (0.11 g, 0.37 mmol), 2,2'-dipyridyldisulfide (0.163 g, 0.74 mmol), triphenylphosphine (0.19 g, 0.74 mmol) and dichloromethane (20 mL) were stirred at room temperature under argon 4 nodines. The resulting solution was concentrated and the residue chromatographed / silica gel, eluting with 25% ethyl acetate in ethyl acetate

Hexane) to give 0.13 g of the title compound as a white solid, m.p. 195-196 ° C (recrystallization from ethyl acetate-methanol).

(ii) 17Q-Isobutylcarbonyl-3-hydroxy-estra-1,3,5 (10) -trien

Isobutylmagnesium bromide (2.3 mL, 2M in diethyl ether) was slowly added to a solution of S- (2-pyridyl) -3-hydroxy-estral, 3,5 (10) -trien-17B-thiocarboxylate (0.60 g, 1). 53 mmol (in tetrahydrofuran (20 mL) at -78 ° C). After 1 h, 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. The 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) 17B-Isobutylcarbonyl-estra-1,3,5 (10) -trien-3-trifluoromethylsulfonate

To the cooled solution (0 ° C) 17B-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 c, 0.83 mmol) in dichloromethane (20 mL) was slowly added trifluoromethanesulfonic anhydride (0.23 c, 0.82 mmol). The resulting solution was stirred at 0 ° C for 1 hour and then at ambient temperature for 30 minutes, the reaction mixture was washed with dilute HCl, water, dilute sodium bicarbonate, brine, dried and concentrated. The resulting residue was chromatographed (silica gel, 7% ethyl acetate in hexane) to give 0.13 g of an oil.

(iv) Methyl 17B-isobutylcarbonyl-estra-1,3,5 (10) -trien-3-carboxylate

A mixture of 17G-isobutylcarbonyl-estra-1,3,5 (10) -trien-3-trifluoromethylsulfonate (0.13 g, 0.28 mmol), papropane acetate (dppp, 7.5 mg, 0.0182 mmol), triechylamine (0). , 08

-38ml), methanol (0.6ml), 1,2-dichloroethane (0.32ml) and DMSO (1ml) were heated at 70-75 ° C under CO atmosphere overnight. The cooled reaction mixture was then diluted with dichloromethane, washed with water, dilute HCl, dilute sodium bicarbonate, 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) 17B-Isobutylcarbonyl-estra-1,3,5 (10) -trien-3-carboxylic acid

A mixture of methyl-17B-isobutylcarbonyl-estra-1,3,5 (10) -trien-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 under reflux overnight. The reaction mixture is 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.

Mp 202-206 ° C.

Example 2 - corresponds to Scheme III

178-isobutylcarbonyl-estra-1,3,5 (10) -trien-3-carboxylic acid [i] 17B-Isobutylcarbonyl-es tra-1,3,5 (19) -trien-2-fluorosulfate

A solution of 172-isobutylcarbobyl-estra -1,3,5 (10) -trien-3-ol, prepared as described in Example 1 (i), in dichloromethane at 0 ° C was treated with 2,5-di-tert-butyl-3-methyl-pyriaine and then for 10 min with fluorosulfonic anhydride. The resulting mixture was stirred for 2 hours and then diluted with dichloromethane. The organic layer was washed with saturated fragrant HCl, and brine, dried over magnesium sulfate, and evaporated to dryness. ddro.o n ^ she; The title compound is obtained on a silica gel.

(ii) Methyl 17β-isobutylcarbonyl-estra-1,3,5 (10) trien-3-carboxylate

A mixture of 17β-isobutylcarbonyl-estra-1,3,5 (10) -trien-3-fluorosulfonate, 1,3-bis (diphenylphosphino) propane; palladium (II) acetate, triethylamine, methanol, DMSO and 1,2-dichloroethane were heated and stirred vigorously at 80 ° C for 5 h under a carbon monoxide atmosphere. After cooling to ambient temperature, the resulting mixture was diluted with dichloromethane. The organic phase is then carefully washed with water, dried (magnesium sulfate) and evaporated to dryness. Silica gel chromatography gave the title compound.

(iii) 176-Isobutylcarbonyl-estra-1,3,5 (10) triene-3-carboxylic acid

A mixture of methyl-176-isobutylcarbonyl-estra-1,3,5 (10) trien-3-carboxylate, potassium carbonate, water and methanol was heated under reflux for 5 h. The volatiles were then removed under reduced pressure and the residue diluted with water, acidified with dilute aqueous HCl and extracted 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

170-Isobutylcarbonyl-estra-1,3,5 (10) -trien-3-carboxylic acid (i) 3- (Trifluoromethanesulfonyloxy) -estra1,3,5 (10) -trien-170-carboxylic acid

A solution of 3-hydroxy-estra-1,3,5 (10) -176-carboxylic acid, 2,5-di-tert, butyl-4-methylpyridine and trifluoromethanesulfonic anhydride in methylene chloride is stirred at 5 ° C for 20 hours . Organic solvent

The residue was dissolved in tetrahydrofuran-water (99.5: 0.5) with 4-dimethylaminopyridine and acidified with hydrochloric acid followed by usual work-up to give the title compound.

(ii) S- (2-Pyridyl) -3- (trifluoromethanesulfonyloxy) -estra 1,3,3 (10) -trien-17B-thiocarboxylate

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

(iii) 17B-Isobutylcarbonyl-estra-1,3,5 (10) -trien-3-trifluoromethanesulfonate

To a solution of S- (2-pyridyl) -3- (trifluoromethanesulfonyloxy) -estra-1,3,5 (10) -trien-17B-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. Conventional work-up followed by isolation by column chromatography affords the title compound.

(iv) ethyl 17B-isobutylcarbonyl-estra-1,3,5 (10) -trien-3-carboxylate

A solution of 17β-isobutylcarbonyl-estra-1,3,5 (10) -trien-3-trifluoromethanesulfonate, triphenylphosphine, palladium acetate, triethylamine, methanol and dimethylformamide was stirred vigorously under carbon monoxide for 20 hours. Conventional work-up followed by isolation by column chromatography affords the title compound.

-41 / v / 17B-Isobutylcarbonyl-estra-1,3,5 (10) -trien-3-carboxylic acid

A mixture of methyl 17β-isobutylcarbonyl-estra-1,3,5 (10) trien-3-carboxylate, K ₂ CO ₃ , water and methanol is heated to reflux for about 5 hours. Acidification followed by usual work-up yields the title compound.

Example 4 - corresponds to Scheme III

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

A solution of 3-hydroxy-estra-1,3,5 (10) -17H-carboxylic acid, 2,6-di-tert-butyl-4-methylpyridine 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- (fluorosulfonyl) -estra-1,2,5 (10) triene-17B-thiocarbonyloxylate

A solution of 3- (fluorosulfonyloxy) -estra-1,3,5 (10) trien-17B-carboxylic acid, triphenylphosphine and 2,2'-dipyridyldisulfide in toluene was stirred under nitrogen for 20 hours, the reaction mixture was concentrated and the residue was left Pass directly through silica gel and evaporate the appropriate fractions to give the title compound.

(iii) 17B-Isobutylcarbonyl-estra-1,3,5 (10) -trien-3-fluorosulfonate

To a solution of S- (2-pyridyl) -2- (fluorosulfonyloxy) -estra

V / J. ·. .1.1 '.6. '. . ·. · ', 1. r ‘,. ·. <-, í Z 11! ii \ -. 'r-. . . .. ‘. &Gt; 1 &lt; 6 &gt;

-421,3,5 (10) -trien-17B-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. Conventional work-up followed by isolation by column chromatography affords the title compound. (iv) Methyl 17B-isobutylcarbonyl-estra-1,3,5 (10) -trien-3-carboxylate

A solution of 17B-isobutylcarbonyl-estra-1,3,5 (10) -trien-3-fluorosulfonate, triphenylphosphine, palladium (II) acetate, triethylamine, methanol and dimethylformamide was stirred vigorously under carbon monoxide for 20 hours. Conventional work-up followed by column chromatography isolation affords the title compound.

(v) 17B-Isbutylcarbonyl-estra-1,3,5 (10) -trien-3-carboxylic acid

A mixture of methyl 17B-isobutylcarbonyl-estra-1,3,5 (10) trien-3-carboxylate, potassium carbonate, water and methanol was heated to reflux for about 5 hours. Acidification and subsequent usual work-up gives the title compound.

Example 5 - corresponds to Scheme III

17β- (octylcarbonyl) -estra-1,3,5 (10) -trien-3-carboxylic acid 17β- (octylcarbonyl) -estra-1,3,5 (10) -trien-3-trifluoromethylsulfonate

The title compound was prepared according to Example 1 (iiii) by replacing isobutylmagnesium bromide with n-octylmagnesium bromide in broth (Li).

-43 (ii) 172- (octylcarbonyl) -estra-1,3,5 (10) trien-3-carboxylic acid

A mixture of 172- (octylcarbonyl) -estra-1,3,5 (10) -trien-3-trifluoromethylsulfonate (0.38 g, 0.77 mmol), potassium acetate (0.27 g), palladium (II) diacetate (0.008 g),

0.036 mmol / 1,1,1-bis (diphenylphosphino) ferrocene / dppf,

0.08 g (0.14 mmol) in DMSO (15 mL) was bubbled through carbon monoxide for 2 minutes and stirred with a CO balloon 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) and the obtained solid was triturated with methanol-acetonitrile to give the title compound - 0.22 g (73%) m.p. 175 ° C.

Example 6 - corresponds to Scheme III

172- (tert-pentylcarbonyl) -estra-1,3,5 (10) trien-3-carboxylic acid / Trifluoromethyl-172- (tert-pentylcarbonyl) -estra1,3,5 (10) -trien-3- sulfonate

The title compound was prepared according to Example (i-iii) by replacing t-pentylmagnesium chloride with butylmagnesium bromide in step (ii).

lade I for iso (ii) 172- (tert-pentylcarbonyl) -estra-1,3,5 (10) trien-3-carboxylic acid

The title compound was prepared according to Example 5 (ii) by replacing trifluoromethyl-177- (octylcarbonyl) -estra1,3,5 (10) -trien-3-sulfonate with trifluoromethyl-177- (tert-pentene).

-44 -tyloxycarbonyl) -estra-1,3,5 (10) -trien-3-sulfonate, m.p.

Mp 199-200 ° C.

Example 7 - corresponds to Scheme III

17B- (2,2-Dimethylpropylcarbonyl) -estra-1,3,5 (10) triene-3-carboxylic acid (1) Trifluoromethyl-17B- (2,2-dimethylpropylcarbonyl) estra-1,375 (10) -trien-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) 17B- (2,2-Dimethylpropylcarbonyl) -estra1,3,5 (10) -trien-3-carboxylic acid

The title compound was prepared according to Example 5 (ii) by replacing trifluoromethyl-17B- (2,2-dimethylpropylcarbonyl) estra-1,3,5 (10) -trien-3-sulfonate as prepared in Example 7 (i), trifluoromethyl-17B- (octylcarbonyl) estra-1,3,5 (10) -trien-3-sulfonate, mp 210 ° C.

Example 8 - corresponds to Scheme IV

17β- (Propylcarbonyl) -estra-1,3,5 (10) -trien-3-carboxylic acid 17β-Cyano-estra-1,3,5 (10) -trien-3-methanesulfonate

The title compound is known and is prepared from estrone according to the procedure of Baldwin et al., J. Chem. Soc./C/, 1968, 2283-2289.

(ii) 17B-Cyano-estra-1,3,5 (10) -trien-3-ol

The title compound 17B-cyano-estra-1,3,5 (10) trien-3-methanesulfonate (10 g) in methanol (100 ml) was added to the target. . · Άύ <Π / t Z i i

-45MeOH-water /. The resulting mixture was heated to 40 ° C for 24 hours and 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, mp '_; 249 DEG-250 DEG C., dec.

(iii) 17B-Cyano-estra-1,3,5 (10) -trien-3-trifluoromethanesulfonate

17B-Cyano-1,3,5 (10) -trien-3-ol (4.2 g) and 2,6-di-tert. butyl-4-methylpyridine (3.6 g) was dissolved in 50 ml of methylene chloride. The mixture was stirred at room temperature for 30 min. Triflic anhydride was added. / 4.2 ml / and the mixture stirred for 40 minutes, diluted with 50 ml CH ₂ Cl ₂ r filtered, concentrated and chromatographed on silica gel. Elution with 20% ethyl acetate in hexane gave 5.3 g (87%) of the title compound, mp 115-117 ° C.

(iv) Methyl 17B-cyano-estra-1,3,5 (10) -trien-3-carboxylate

To a solution of 17B-cyano-estra-1,3,5 (10) -trien-3-ol (10 g) in 77 ml DMSO and 50 ml MeOH was added 7 ml triethylamine, 35 g palladium acetate, 0.54 c. bid (diphenylphosphino) 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 under 1 atm of CO (balloon). The mixture was diluted with EtOAc and washed with water (3x), dried, and concentrated.

The residue was chromatographed / silica gel, eluting with 10% EtOAc in hexanes to give 4.5 g of the title compound, m.p. Mp 161-163 ° C.

(v) 3-Hydroxymethyl-estra-1,3,5 (10) -triene-17B-carboxaldehyde

Methyl 17B-cyano-estra-1,3,5 (10) -trien-3-carboxylate

-46 (0.8 g) was dissolved in 30 ml of toluene and treated with DIBAL (6 ml, 1M). The mixture was stirred at room temperature under argon for 2.5 hours. The mixture is then poured into 50 ml of 5%

The mixture was 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. Mp 146-150 ° C.

(vi) 178- (1-Hydroxybutyl) -estra-1,3,5 (10) -trien-3-hydroxymethyl

A solution of 3-hydroxymethyl-estra-1,3,5 (10) -trien-17β-carboxaldehyde (75 mg in 2 mL THF) was slowly added to a solution of propylmagnesium bromide (2 mL, 1.6 M). The mixture was stirred at room temperature for 2 hours.

Quench the mixture with saturated aqueous NH 4 Cl and extract with CH 2 Cl 2. The organic extract is 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) 17B- (Propylcarbonyl) -astra-1,3,5 (10) trien-3-carbonyl acid

178- (1-Hydroxybutyl) -estra-1,3,5 (10) -trien-3-hydroxyethyl (57 g) was dissolved in acetone (5 mL) and treated with Jones reagent. The mixture was stirred for 1 hour and then quenched with 2-propanol, extracted with CH ₂ Cl 2 and purified by chromatography / silica gel, eluting with 30% ethyl acetate in hexane with 0.5% HOAc / 47 mg of the title compound, mp 211-213 Deň: 32 ° C.

-47Example 9 - corresponds to Scheme IV

170- (Methylcarbonyl) -estra-1,3,5 (10) -trien-3-carboxylic acid

The title compound was prepared according to Example 8 (III) (III) by replacing methyl magnesium bromide with propyl magnesium bromide in step (vi), m.p. Mp 199-202 ° C.

Example 10 - corresponds to Scheme IV

170- (3,3-Dimethylbutylcarbonyl) -estra-1,3,5- (10) triene-3-carboxylic acid

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

Example 11 - corresponds to Scheme IV

170- [1- (R, S) -Hydroxyethyl] -estra-1,3,5 (10) trien-3-carboxylic acid (i) 173- (methylcarbonyl) -estra 1,3,3,5 (10) - triene-3-carboxylic acid (6 mg) - prepared according to Example 9 - in methanol was treated with NaBH4 (0) (7 mg).

Heat the mixture to 45 ° C and stir 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 separation techniques that are readily available and known to those skilled in the art.

Example 12 - corresponds to Scheme IV

170- [1- (R, S) -Hydroxybutyl] -estra-1,3,5 (10) triene-3-carboxylic acid

(48) (i) The title compound was prepared according to Example 11 by substituting 17fl- (propylcarbonyl) -estra-1,3,5 (10) trien-3-carboxylic acid, prepared according to Example 8 (i) (vii), with 17fl acid. - (methylcarbonyl) -estra-1,5,5 (10) triene-3-carboxylic acid Mp 208-211 ° C.

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

Example 13

An oral dosage form for administration of compounds of Formula I is prepared by sieving, mixing and filling the ingredients into hard gelatin capsules in the amounts set forth in Table I of Table I below.

Ingredient amount 17β-isobutylcarbonyl- 50 mg estra-1,3,5 (10) -trien-3-carboxylic acid magnesium stearate 5 mg lactose 75 mg

Example 14

Table II

Ingredients Amounts of 170-isobutylcarbonyl-100 mg estra-1,3,5 (10) -trien-3-carboxylic acid calcium sulfate dihydrate

150 mg

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

-49Table II / continued / sucrose starch talc stearic acid mg 10 mg mg 3 mg

Example 15

17β-Isobutylcarbonyl-estra-1,3,5 (10) -trien-3-carboxylic acid is dispersed in 25 ml of normal saline for injection preparation.

Preferred embodiments of the invention are illustrated above, and the invention is to be understood not to be limited by the precise instructions described herein, and that all modifications that fall within the scope of the following claims are also protected.

Represented by:

-50 <£ r * C ·> 2 V - - <C -4 -4, 1 2> Ζ ->

q <°

ΓΗ *

N cn

LD cn σ

ο ·

Ο

Claims (36)

PATENT CLAIMS 1. The 17-alkylketonsteroids of formula I Wherein Z is Λ or β -C-R 1 wherein R is C 1-2 linear or branched, saturated or unsaturated alkyl and pharmaceutically acceptable salts, hydrates, solvates and esters thereof. 2. A compound according to claim 1 wherein R is ^C 12-12 linear or branched, saturated or unsaturated alkyl, and pharmaceutically acceptable salts, hydrates, solvates and esters thereof. -513. Compound according to claim 2 of the general formula III / 111 wherein R is C 1-8 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, tert-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, tert-butyl, 1,1-dimethylpropyl, isobutyl, n-butyl, tert-pentyl, n-propyl, methyl or 3,3-dimethylbutyl and pharmaceutically acceptable salts, hydrates, solvates and esters thereof. 6. 17B- (Isobutylcarbonyl) -estra-1,3,5 (10) triene-3-carboxylic acid. 17. 17B- (Octylcarbonyl) -estra-1,3,5 (10) -trien-3-carboxylic acid. 17. 17B- (tert-Pentylcarbonyl) -estra-1,3,5 (10) triene-3-carboxylic acid. -529. 17β- (2,2-Dimethylpropylcarbonyl) -estra 1,3,5 (10) -trien-3-carboxylic acid. 10. 17β- (Propylcarbonyl) -estra-1,3,5 (10) triene-3-carboxylic acid. . .. _____.... ... _ 11. 176-? (Methylcarbonyl, -estra-1,3,5 (10) trien-3-carboxylic acid). 12. 17β- (3,3-Dimethylbutylcarbonyl) -estra1,3,5 (10) -trien-3-carboxylic acid. A compound according to claim 1 of the general formula wherein R is C _1-2 linear or branched, saturated or unsaturated alkyl and pharmaceutically acceptable salts, hydrates, solvates and esters thereof. 14. A compound of formula wherein Y is -CR alpha or B / wherein R is a ^C-20 JL ^^ ^non ^ ^rn ^ or branched, saturated or unsaturated alkyl and pharmaceutically acceptable salts, hydrates, solvates and esters thereof. The compound of claim 14, wherein Y is in the B position. The compound of claim 14, wherein Y is in the alpha position. 17. 17β- (1-Hydroxyethyl) -estra-1,3,5 (10) triene-3-carboxylic acid. 18. 17B- (1-Hydroxybutyl) -estra-1,3,5 (10) triene-3-carboxylic acid. The compound of claim 1 substantially as defined herein by reference to any of the examples. 20. 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. -5422. A compound according to any one of claims 1 to 18 for the manufacture of a medicament for use as a 5α-reductase inhibitor. A compound according to any one of claims 1 to 18 for the manufacture of a medicament for use in the treatment of prostate size reduction. A compound according to any one of claims 1 to 18 for the manufacture of a medicament for use in the treatment of prostate adenocarcinoma. _O A process for the preparation of a compound of formula (II), wherein R is C _1-2 linear or branched, saturated or unsaturated alkyl, and pharmaceutically acceptable salts, hydrates, solvates and esters thereof, i) oxidizing a compound of formula wherein R 1 or (ii) reacting a compound of the formula wherein R is as defined above by a metal catalyzed coupling reaction with a suitable coupling reagent, preferably an oxide, followed by, if appropriate, hydrolyzing or carbon black reactions, (iii) hydrolyzing a compound of the formula Wherein R is as defined above, and then optionally, a pharmaceutically acceptable salt, hydrate, solvate or ester thereof is prepared. 26. A process for the preparation of a compound of formula (II) comprising: wherein R is O, _{2, 2,} linear or branched, saturated or unsaturated alkyl and pharmaceutically acceptable salts, hydrates, solvates and esters thereof, characterized in that the reaction of a compound of formula Where R is as defined above, with fluorosulfonic anhydride and a base, preferably 2,5-di-tert-butyl-3-methyl-pyridine in a solvent, preferably dichloromethane, to give a compound of formula Wherein R is as defined above, and the reaction is followed by a compound in a metal catalyzed coupling reaction in the presence of a suitable coupling agent, preferably carbon monoxide, and optionally followed, if desired, by a hydrolysis reaction, to form a compound of formula II and then optionally forming a pharmaceutically acceptable salt, hydrate, solvate or ester thereof. 27 Mar: A process for the preparation of a compound of the general formula wherein R is C 1-2 linear or branched, saturated or unsaturated alkyl and pharmaceutically acceptable salts, hydrates, solvates and esters thereof, comprising epimerizing a compound of formula (II): wherein R is as defined above, and then optionally a pharmaceutically acceptable salt, hydrate, solvate or ester thereof is prepared. A method of preparing a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and an effective amount of a compound of Formula I η wherein Z is alpha or O -CR wherein R is or a branched, saturated or unsaturated alkyl and pharmaceutically acceptable salts, hydrates, solvates and esters thereof, comprising providing a compound of formula I or a pharmaceutically acceptable salt, hydrate thereof or an ester, in association with a pharmaceutically acceptable carrier or diluent. A compound of formula V wherein R is C _1-2 linear or branched, saturated or unsaturated alkyl and R ⁴ 'is fluorosulfonyloxy. Compound of Formula VI 30. ry X5 rc σ O CZ). wherein R is C 1-2 linear or branched, saturated or unsaturated alkyl. Use of a compound according to any one of the claims 1 to 18, in the manufacture of a medicament for use in inhibiting a steroid. 5alpha-reductase. «* Use of a steroid according to any one of claims 1 to 13 and a compound which is an alpha-receptor antagonist for the manufacture of pharmaceutical compositions. The use of the steroid of any one of claims 1 to 18 and a compound that is an alpha-receptor antagonist in the manufacture of a pharmaceutical composition for use in the treatment of benign prostatic hypertrophy. Use of the steroid according to any one of claims 1 to 18 and an aromatase inhibiting compound for the manufacture of a pharmaceutical composition. Use of the steroid according to any one of claims 1 to 18 and an atomatase inhibiting compound in the manufacture of a pharmaceutical drug. ,? j. ’Ά ^ · - 61 Use of a steroid according to any one of claims 1 to 18 and minoxidil for the manufacture of a pharmaceutical composition. Use of the steroids according to any one of claims 1 to 18 and minoxidil in the manufacture of a pharmaceutical composition for use in the treatment of baldness. Use of the steroid according to any one of claims 1 to 18 and an atomatase inhibiting compound and an alpha receptor agonist compound for the manufacture of a pharmaceutical composition. Use of a steroid according to any one of claims 1 to 18 and an aromatase inhibiting compound and an alpha receptor antagonist compound in the manufacture of a pharmaceutical composition for use in the treatment of benign prostatic hypertrophy.