GB2263403A - N-monosubstituted adamantyl/norbornanyl 17b-carbamides of 3-carboxy-androsta -3,5-dienes as anti-androgenic alopecia agents - Google Patents

Abstract

N-monosubstituted adamantyl/norbornanyl 17 beta -carbamides of 3-carboxy-androsta-3,5-dienes as anti-androgenic alopecia agents of the formula: <IMAGE> wherein R is a hydrocarbon radical selected from substituted or unsubstituted 1-or 2-adamantyl or 1-, 2 or 7-norbornanyl and pharmaceutically acceptable salts or esters thereof. Pharmaceutical formulations of the compounds (1) which are active as testosterone 5 alpha -reductase inhibitors may be topically, orally or parenterally administered.

Description

TITLE OF THE INVENTION N-MONOSUBSTITUTED ADAMANTYL/NORBORNANYL 17ss-CARBAMIDES OF 3-CARBOXY-ANDROSTA-3,5-DIENES AS ANDROGENIC ALOPECIA AGENT BACKGROUND OF THE INVENTION The present invention is concerned with the use of 17ss-N-monosubstituted adamantyl or norbornanyl 3-carboxy-androsta-3,5-dienes compounds in the treatment of male pattern baldness, hereinafter referred to as androgenic alopecia.

DESCRIPTION OF THE PRIOR ART It is known in the art that certain undesirable physiological manifestations, such as acne vulgaris, seborrhea, female hirsutism, and male pattern baldness and benign prostatic hypertrophy, are the result of hyperandrogenic stimulation caused by an excessive accumulation of testosterone or similar androgenic hormones in the metabolic system.

Early attempts to provide a chemotherapeutic agent to counter the undesirable results of'hyperandrogenicity resulted in the discovery of several steroidal antiandrogens having undesirable hormonal activities of their own. The estrogens, for example, not only counteract the effect of the androgens but have a feminizing effect as well. Non-steroidal antiandrogens have also been developed, for example, 4 '-nitro-3 '-trifluoromethylisobutyranilide. See Neri et al., Endo., Vol. 91, No. 2 (1972). However, these products, though devoid of hormonal effects, are peripherally active, competing with the natural androgens for receptor sites, and hence have a tendency to feminize a male host or the male fetus of a female host.

It more recently became known in the art.

that the principal mediator of androgenic activity in some target organs is 5a-dihydrotestosterone, and that it is formed locally in the target organ by the action of testosterone 5a-reductase. It therefore has been postulated and demonstrated that inhibitors of testosterone 5a-reductase will serve to prevent or lessen symptoms of hyperandrogenic stimulation. Nayfeh et al., Steroids, 14, 269 (1969) demonstrated in vitro that methyl 4-androsten-3-one 1713-carboxylate was a testosterone 5a-reductase inhibitor. Then Voigt and Hsia, Endocrinology, 92, 1216 (1973), Canadian Pat. No. 970,692, demonstrated that the above ester and the parent free acid, 4-androsten-3-one-17ss-carboxylic acid are both active inhibitors of testosterone 5a-reductase in vitro.

They further demonstrated that topical application of either testosterone or Sa-dihydrotesterone caused enlargement of the female hamster flank organ, an androgen dependent sebaceous structure. However, concommitant administration of 4-androsten-3-one 1713-carboxylic acid or its methyl ester inhibited the response elicited by testosterone but did not inhibit the response elicited by Sa-dihydrotestosterone.

These results were interpreted as indicating that the compounds were antiandrogenic by virtue of their ability to inhibit testosterone Sa-reductase.

A number of androstene Sa-reductase inhibitors are known in the art. For example: (1) Bioinorpanic Chemistry, 17, pp.

372-376 (1986), by B. W. Metcalf, et al, describes the inhibition of human steroid Sa-reductase (EC 1.3.1.30) by 3-androstene-3-carboxylic acids; (2) Biochemistrv (1990) Vol. 29, pp.

2815-2824, by M. A. Levy, et al, describes the mechanism of enzyme-inhibitor interaction in the inhibition of rat liver steroid Sa-reductase by 3-androstene-3-carboxylic acids; (3) J. Med. Chem. (1990) Vol. 33, pp.

943-950 (1990), by D. A. Holt, et al, describes the inhibition of steroid 5-a reductase by unsaturated 3-carboxysteroids; (4) J. Steroid Biochem., Vol. 34, Nos. 1-6, pp. 571-575 (1989), by M. A. Levy, et al, describes the interaction mechanism between rat prostatic steroid 5-alpha reductase and 3-carboxy-17-ss substituted steroids; (5) J. Med. Chem. (1990) Vol. 33, pp.

937-942, by D. A. Holt, et al, describes the new steroid class of A ring aryl carboxylic acids; (6) TIPS (December 1989) Vol. 10, pp.

491-495, by D. W. Metcalf, et al, describes the effect of inhibitors of steroid Sa-reductase in benign prostatic hyperplasia, male pattern baldness and acne; and (7) EPO Publn. No. 0 289 327, to D. A.

Holt, et al, (SmithKline Beckmann) describes steroidal 3-carboxylic acid derivatives as useful 5-a reductase inhibitors.

However, none of the above references specifically suggest that any of the 3-carboxy androsta-3 , 5-diene-17-beta-N-monosubstituted adamantyl I norbornanyl compounds of the present invention would have anti-androgenic alopecia activity.

SUMMARY OF THE INVENTION The present invention relates to N-(monosubstituted) adamantyl and norbornanyl 17ss-carbamides of 3-carboxy-androsta-3,5-diene compounds used as an anti-androgenic alopecia agent and processes for their preparation.

In accordance with this invention, there is-provided a compound of the formula:

wherein R is a hydrocarbon radical selected from substituted or unsubstituted 1- or 2-adamantyl or 1- or 2-norbornanyl, and pharmaceutically acceptable salts or esters thereof.

BRIEF DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS Representative compounds of the present invention include the following: 17ss-(N-l-adamantylcarbamoyl)-3-carboxy-androsta- 3,5-diene; 1713- (N-2-adamantylcarbamoyl )-3-carboxy-androsta- 3,5-diene; 17ss-(N-l-norbornanylcarbamoyl)-3-carboxy-androsta- 3,5-diene; 17ss-(N-2-norbornanylcarbamoyl)-3-carboxy-androsta- 3,5-diene; and pharmaceutically acceptable salts or esters thereof.

The 1-, 2-adamantyl or 1-, 2- or 7-norbornanyl moieties can be substituted with one or more substituents of the following: C1-C4 linear branched alkyl, including methyl, ethyl, isopropyl, n-butyl; nitro; oxo; C7-C9 aralkyl, including benzyl; (CH2)n COOR where n is 0-2 and R is H or C1-C4 linear/branched alkyl including methyl, ethyl; CH20H; OH; OR where R is C1-C4 linear branched alkyl including methyl, ethyl; halo, including fluoro, bromo, iodo; COOH; COOR, where R is linear/branched C1-C4 alkyl; -CONH2; CH2NH2; CH2NHCOR where R is C1-C4 linear/branche & alkyl including methyl, ethyl; phenyl; o, m, p-substituted phenyl including p-nitro, p-amino and p-sulfo; or cyano.

Also included within the scope of this invention are pharmaceutically acceptable salts or esters, where a basic or acidic group is present on the adamantyl or norbornanyl moiety. When an acidic substituent is present, i.e. -COOH, there can be formed the ammonium, sodium, potassium, calcium salt, and the like, for use as the dosage form.

Where a basic substitutent group is present, i.e. amino, acidic salts, i.e. hydrochloride, hydrobromide, acetate, pamoate, and the like, can be used as the dosage form.

Also, in the case of the -COOH or -OH group being present, pharmaceutically acceptable esters can be employed, e.g. acetate, maleate, pivaloyloxymethyl and the like, and those esters known in the art for modifying solubility or hydrolysis characteristics for use as sustained release or prodrug formulations.

Representative examples include for R2 (where AD is adamantyl): 3, 5, 7-trinitro-1-AD; 4-oxo-l-AD; l-benzyl-l-AD; 4, 4-dimethyl-l-Ad; 3, 7-dimethyl-5-carboxymethyl-l-AD; 3-carboxymethyl-l-AD;. 3-chloro-l-AD; 1,3-dihydroxy6,6-dimethyl-2-AD; 3-chloro-l-AD; 4-carbethoxy-2-AD; 4-carboxy-2-AD; 3-isopropyl-1-AD; 3-n-butyl-l-AD; 3-propyl-l-AD; 3-, 5-diethyl-l-AD; 3-hydroxymethyl 1-AD; 2-carboxy-l-ADi 3-methyl-l-AD; 5-hydroxy-2-AD; 2-hydroxy-l-AD; l-aminomethyl-l-hydroxy-2-AD; 2-oxo1-AD; 2-phenyl-2-AD; l-amino-methyl-2-AD; l-carboxy2-AD; l-aminocarbonyl-2-AD; 3-hydroxy-5,7-dimethyl- 1-AD; 4-fluoro-l-AD; 3-f luoro-1-AD; 4-hydroxy-2-AD; 3-phenyl-1-AD; 3-(p-aminophenyl)-l-AD; 3-(p-nitrophenyl)-l-AD; 3-methyl-5-hydroxymethyl1-AD; 3,5-dimethyl-4-hydroxy-l-AD; 2-hydroxymethyl2-AD; 3-(p-sulfophenyl)-1-AD; 3-methyl-5-ethyl-l-AD; 2-carboxy-2-AD; 3 ,5-7-trimethyl-l-AD; 4-iodo-2-AD; 4-bromo-2-AD; 4-chloro-2-AD; l-acetylaminomethyl 2-AD; l-carboxymethyl-2-AD; l-methyl-2-AD; 1-aminocarboxylmethyl-2-AD; 1-aminocarboxyl-l-AD; 2-cyano-2-AD; 3,5-dimethyl-7-ethyl-1-AD; 4-hydroxy1-AD; l-hydroxy-2-AD; 5-carboxy-3-.methyl-1-AD; 3,5dimethyl-7-carboxy-l-AD; 3-carboxy-l-AD; 3-hydroxy1-AD; and the like.

Representative examples include for R2 as substituted norbornanyl moieties are (where NB is norbornanyl): 2-NB; 1,7,7-trimethyl-4-phenyl-2-NB; 3-carboxy-2-NB; 3-phenyl-2-carboxy-2-NB; 2-cyano-3-phenyl-2-NB; 3-hydroxy-4,7,7-trimethyl-2-NB; 6-hydroxymethyl-2-NB; 5-cyano-2-NB; 3-allyl-2-NB; 1-NB; 7,7-dimethyl-1hydroxymethyl-2-NB; 3-methoxy-4, 7, 7-trimethyl-2-NB; 3-aminocarbonyl-2-NB; 3-ethoxycarbonyl-2-NB; 3,3dimethyl-2-NB; 7-oxo-1-NB; 3-phenyl-2-NB; l-carboxymethyl-7,7-dimethyl-2-NB; l-ethyl-2-NB; l-methyl-2 NB; 2,2,3,3,5,5,6,6,7,7-decafluoro-1-NB; 3-hydroxy2-NB; 3-chloro-2-NB; 3-(p-methoxyphenyl)-2-NB; 2,2dimethyl-3-methylene-7-NB; 3-oxo-2-NB; l-methoxy-2 NB; 7-NB; 3-isopropyl-2-NB; 2-bromo-l-NB; 3-chloro1-NB; and the like.

Procedures for preparing the adamantyl and norbornanyl amines included within the scope of this invention, including the representative examples above, are well known in the art.

The compounds of formula I of the present invention can be prepared by methods starting with the known. steroid acid (II) of the formula:

FLOW SHEET

FLOWSHEET(CON'T)

Referring to the above flowsheet, three routes are described to produce the novel compound I of this invention.

The common feature of the routes is that, unlike the prior art, they involve creating the 17-carbamoyl substitutent by a displacement reaction involving an activated ester, e.g. 2-thiopyridyl.

Common steps are employed in the three procedures, e.g. amine-ester condensation, which are designated by a letter, i.e. Step C, for ease in following the flow chart.

Referring to Route 1, the 3-acyl acid II is converted to the 3-trifluoromethylsulfonyloxy derivative III (Step A) by treating II with trifluoromethylsulfonyl anhydride and a tertiary amine, e.g. lutidine, in e.g. methylenechloride at e.g. room temperature (RT) under dry and anhydrous conditions for e.g. 1-4 hours. Isolation and purification of the product is conventional.

The activated ester IV is produced (Step B) by treating III with 2,2-dithiopyridyl (Aldrithiol) and triphenylphosphine in, e.g. THF, toluene at RT under anhydrous conditions for 8-24 hours.

Isolation/purification is accomplished by conventional procedures.

The 17-carbamoyl derivative V is produced (Step C) by treating IV with an adamantyl amine or norbornanyl amine, described hereinabove, in THF or CH2C12 solvent, at room temperature for 1-16 hours. Isolation/purification is by conventional chromatography.

The 3-alkyl ester VI is produced (Step D) by treating V under carbonylation cdnditions by bubbling carbon monoxide gas through a solution of V in e.g.

methanol, containing palladium acetate catalyst, triphenylphosphine, and a tertiary organic amine, e.g. triethylamine, at RT, under anhydrous conditions/N2 for 1-16 hours followed by conventional workup.

The final product I is made (Step E) by treating VI with NaOH or KOH in an alcoholic solvent e.g. methanol, at RT to reflux, for 1-4 hours under air-free conditions. Workup is conventional.

Note that, if R also contains a protected hydroxy group, e.g. with dimethyl-t-butyl-silyl, this may be removed (Step G) by treating with tetrabutylammonium fluoride in e.g. tetrahydrofuran with a.

small amount of added acetic acid, at 0 C-reflux for 1-4 hours, prior to carrying out Step E.

Route &num;2 involves converting the starting steroid acid II to the 3-trifluoromethylsulfonyl ester III by the above-described Step A; carbonylating II to VII by Step D; forming the activated 2-pyridylthioester VIII by Step B; forming the .17-carbamoyl compound VI by Step C; and hydrolyzing the 3-ester to the 3-acid final product I by Step E.

Route &num;3 involves first converting the starting steroid acid II to the 3-alkoxy-derivative IX (Step F) by treating II with, e.g. an alkyl orthoformate, e.g. trimethylorthoformate and a strong sulfonic acid, e.g. 2,4-dinitrobenzenesulfonic acid, in methanol (or ethanol if using triethylorthoformate at e.g. RT, for 0.25-2 hours. Isolation/purification is accomplished by hydrolyzing with base and adding water.

The 3-alkoxy-17-activated ester X is formed from IX by Step B; the 17-carbamoyl derivative XI is formed from X by Step C followed by an acid hydrolysis in the course of the workup by treating the obtained initial product with an acid, e.g. HC1, in MeOH, and stirring overnight at RT; the 3- trifluoromethylsulfonyl ester V is formed from XI by Step A; the 3-alkoxy carbonyl ester VI is formed from V under the carbonylation conditions of Step D; and product I is formed from VI by Step E.

The compounds of the present invention, prepared in accordance with the method described above, are, as already described, potent anti-androgens by virtue of their ability to specifically inhibit testosterone 5a-reductase.

Also included within this invention is a compound of the formula:

wherein R is a hydrocarbon radical selected from substituted or unsubstituted 1-, 2- or 7-adamantyl, 1- or 2-norbornanyl, R2 is C1-C4 linearSbranched alkyl, or trifluoromethylsulfonyloxy, and pharma ceutically acceptable salts or esters thereof. These compounds are useful intermediates in the production of the titled compounds of this invention.

Further included in this invention is a compound of the formula:

wherein R is a hydrocarbon radical selected from substituted or unsubstituted 1- or 2-adamantyl or 1-, 2- or 7-norbornanyl, and pharmaceutically acceptable salts or esters thereof, which are also useful intermediates for producing the title compounds qf this invention Accordingly, the present invention is particularly concerned with providing a method of treating androgenic alopecia conditions by topical, oral or parenteral administration, of the compounds of the present invention.

The present invention is thus also concerned with providing suitable topical, oral and parenteral pharmaceutical formulations for use in the novel methods of treatment of the present invention.

The compositions containing the compounds of the present invention as the active ingredient for use in the treatment of androgenic alopecia conditions can be administered in a wide variety of therapeutic dosage forms in conventional vehicles for systemic administration, as, for example, by oral administration in the form of tablets, capsules, solutions, or suspensions, of by intravenous injection. The daily dosage of the products may be varied over a wide range varying from 0.1 to 2,000 mg. The compositions are preferably provided in the form of scored tablets containing 5, 10, 25, 50, 100, 150, 250, and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. An effective amount of the drug is ordinarily supplied at a dosage level of from about 0.1 mg. to about 50 mg./kg. of body weight per day.Preferably the range is from about 0.1 mg. to 7 mg./kgs. of body weight per day. These dosages are well below the toxic dose of the product. Capsules containing the product of this invention can be prepared by mixing an active compound of the present invention with lactose and magnesium stearate, calcium stearate, starch, talc, or other carriers, and placing the mixture in gelatin capsule. Tablets may be prepared by mixing the active ingredient with conventional tableting ingredients such as calcium phosphate, lactose, corn starch or magnesium stearate. The liquid forms in suitably flavored suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl-cellulose and the like. Other dispersing agents which may be employed include glycerin and the like. For parenteral administration, sterile suspensions and solutions are desired.Isotonic preparations which generally contain suitable preservative are employed when intravenous administration is desired.

For the treatment of androgenic alopecia conditions, the compounds of the present invention are administered in the formula of pharmaceutical composition comprising the active compound in combination with a pharmacologically acceptable carrier adapted for topical administration.

These topical pharmaceutical compositions may be in the form of a cream, ointment, gel or aerosol formulation adapted for application to the skin. These topical pharmaceutical compositions containing the compounds of the present invention ordinarily include about 0.1% to 15%, preferably about 5%, of the active compound, in admixture with about 95% of vehicle.

The method of preparing the 17ss-N-monosubstituted adamantyl-carbamoyl compounds of the present invention, already described above in general terms, may be further illustrated by the following examples.

EXAMPLE 1 3-(Trifluoromethanesulfonyloxy)3-, 5-androstadiene-1713- carboxylic acid Step A (Route 1) A solution of 3-oxo-4-androstene-17ss- carboxylic acid (4.0 g., 12.5 mmoles), 2,6-di-tert- butyl-4-methyl pyridine (8.304 g., 31 mmoles) and trifluoromethane sulfonic anhydride (9.28 g., 33 mmoles) in 40 ml of methylene chloride was stirred at 22"C for 2 hours and then was kept at 5"C for 16 hours. The organic solvent was evaporated and the residue was dissolved in 200 ml of tetrahydrofuran containing 1.0 ml of water and 4.5 g. of 4-dimethylaminopyridine. This mixture was stirred at 22"C for 20 hours and then acidified with 2N hydrochloric acid.The organic solvent was removed and the residue dissolved in methylene chloride, was applied to a column of 400 g. of silica gel. Elution with a 9:1 mixture of CH2Cl2:- ethyl ether, containing 0.4% of formic acid (88%) afforded 6.2 g. of pure product.. A portion triturated with acetonitrile gave an analytical sample, m.p. 140-150"C with decomposition.

Calcd.: C, 56.24; H, 6.07.

Found: C, 56.71; H, 6.20.

EXAMPLE 2 S-(2-Pyridyl)-3-(trifluoromethanesulfonyloxy)-3, 5- androstadiene-17ss-thiocarboxylate Step B (Route 1) A solution of the steroidal acid (6.2 g., 14.9 mmoles), triphenylphosphine (9.92 g., 38 mmoles) and 2,2'-dipyridyl disulfide (8.68 g., 39.5 mmoles) in 40 ml of toluene was stirred under nitrogen at 24"C for 16 hours. The reaction mixture was eluted directly through 60 g. of silica gel with 3:1 cyclohexane: ethyl acetate. Fractions containing the desired product were combined and concentrated to leave 5.62 g. of the thiopyridyl ester as a glass.

This material had appropriate nmr and mass spectra to confirm the structure and was used directly to make the product of Example 8.

EXAMPLE 3 3-methoxv-35-androstadiene-17ss-carboxylic acid Step F (Route 3) A suspension of 7.0 g. (22 mmoles) of 3-oxo-4-androstene-17ss-carboxylic acid in a mixture of 98 ml. of methanol and 20.3 ml. of trimethyl orthoformate was treated at 24"C with 560 mg. of 2,4-dinitrobenzene sulfonic acid dihydrate. The reaction mixture became momentarily clear and then a precipitate formed. After stirring for 15 minutes, the reaction was neutralized with pyridine (about 1.7 ml). Water was added and the precipatated solid was removed by filtration, washed well with waster and then dried to leave 7 g. of white solid (m.p.

203-208"C). Recrystallization from ethyl acetate gave 4.65 g. of pure title compound as analyzed by thin layer chromatography, and spectral data (nmr and mass spectra).

EXAMPLE 4 S-(2-pyridyl) 3-methoxy-3,5-androstadiene 17ss-thiocarboxylate Step B (Route 3) A solution of 4.1 g. (12.4 mmoles) of the product of Example 3, 5.6 g. (25.5 mmoles) of 2,2'-dipyridyldisulfide and 6.72 g. (25.6 mmoles of triphenylphosphine in 30 ml. of toluene was stirred under nitrogen for 16 hours at 24"C.

The reaction was concentrated to a thick gum which was eluted through 300 g. of silica gel with 9:1 cyclohexane/ethyl acetate. The desired thiopyridyl ester eluted after a bright yellow material and amounted to 3.2 g. of pure material as judged by its nmr spectrum and analysis by thin layer chromatography (4:1 cyclohexane/ethyl acetate, silica gel).

EXAMPLE 5 3-Carbomethoxv-3.5-androstadiene-17ss-carboxylic acid Step D (Route 2) A solution of the product of Example 1 (3.0 g., 6.7 mmoles) in 100 ml. of 1:1 methanol/DMF was reacted with carbon monoxide in the presence of 1.35 g. of triethylamine, 156 mg. of triphenylphosphine and 60 mg. of palladium acetate. The reaction was carried out in a fashion analogously to that of Example 9 with chloroform as the workup solvent. Chromatography on silica gel eluted with 2:1 hexane/ethyl ether containing 0.5% formic acid afforded 700 mg of the title compound which was identified by its nmr and mass spectra. The corresponding diacid and diester were also isolated.

EXAMPLE 6 S-(2-Pyridyl) 3-carbomethoxy-3 , 5-androstadiene-1713- thiocarboxvlate Step B (Route 2) Using an analogous procedure to Example 2, the product of Example 5 was converted to the title compound which was characterized by its nmr and mass spectra.

EXAMPLE 7 N-(2-ådamantvl)-3-oxo-4-androstene-17ss-carboxamide Step C (Route 3) A solution of 1.49 g. (8 mmoles) of 2-adamantamine hydrochloride in methanol was neutralized with 3.68 ml. of 2-.17M sodium methoxide in methanol. The solvent was removed under reduced pressure and the residue was dissolved in 15 ml.

anhydrous tetrahydrofuran. To this solution was added the thiopyridyl steroid from Example 4 (423 mg., 1.0 mmole) with stirring. The resulting solution was stirred for 16 hour at 24"C. The solvent was evaporated and the residue, dissolved in methylene chloride, was washed successively with dilute hydrochloric acid, water, 0.5N sodium hydroxide solution and water. The residue obtained on evaporation was dissolved in 20 ml. of methanol containing 1.0 ml. of 2N hydrochloric acid. After standing for 16 hours the solution was concentrated.

The residue in methylene chloride was washed with aqueous sodium bicarbonate solution and water.

Drying followed by concentration left 500 mg. of a non-crystalline solid. Crystallization from acetonitrile gave the title compound, 330 mg., m.p.

244-2460C.

Anal. Calcd: C, 80.13; H, 9.64; N, 3.12.

Found: C, 79.83; H, 9.62; N, 3.22.

EXAMPLE 8 N-(2-Adamantyl) 3-(trifluoromethanesulfonyloxy) 3.5-androstadiene-17ss-carboxamide Step A (Route 3) A soluton of the adamantyl amide from Example 7 (350 mg., 0.73 mmole), 2,6-di-tert- butyl-4-methylpyridine (211 mg., 1.03 mmole) and trifluoromethane sulfonic anhydride (416 mg., 1.48 mmole) in 5 ml. of methylene chloride was prepared at 0 C. The mixture warmed to room temperature and was kept at 24"C for 2.5 hours. Additional methylene chloride was added and the solution was washed successively with dilute hydrochloric acid, dilute sodium bicarbonate solution and water. The residue obtained on concentration was eluted on 3-2000 F silica gel plates with 5% acetone in methylene chloride. Starting material and the title compound were isolated.The latter, 376 mg., was identified by its nmr and mass spectra.

EXAMPLE 9 N-(2-Adamantyl)-3-carbomethoxy-3 , 5-androstadiene-1713- carboxamide Step D (Route 3) Into a solution prepared from 350 mg.

(0.623 mmole) of the product of the previous Example, 13.5 mg. (0.024 mmole) of triphenylphosphine, 5.4 mg.

(0.048 mmole) of palladium diacetate and 126 mg. of triethylamine in a 1:1 mixture of methanol and dimethylformamide was bubbled carbon monoxide at 24"C.

The solution was kept under a carbon monoxide atmosphere for 2.5 days. Ethyl acetate was added to the solution followed by water. The layers were mixed and then separated. The organic layer was dried and evaporated. The residue was eluted on 4-1000 > silica plates with 2% acetone in methylene chloride.

The major product, 230 mg., was identified as the title compound by its nmr and mass spectra; EXAMPLE 10 N-(2-Adamantyl)3-carboxy-3 , 5-androstadien-1713- carboxamide Step E (Route 3) A solution of 120 mg. (0.24 mmole) of the product of the previous Example in 25 ml. of'a 10% solution of potassium hydroxide in methanol was heated at reflux for 1.0 hour. The solvent was evaporated and the residue was acidified with dilute hydrochloric acid. The ethyl acetate extract was washed with water, dried and evaporated. The residue was crystallized from acetonitrile to leave 60 mg. of the title compound, m.p. 214-216 C, ymax: 268 (=31,8005 Analysis Calcd. for C31H43NO3 V 0.5 H2O.

C, 76.50; H, 9.11; N, 2.88.

Found: C, 76.58; H, 9.35; N, 2.96.

Claims (10)

WHAT IS CLAIMED IS:

1. A method of treating a patient suffering from androgenic alopecia, which comprises administering to said patient in need of such treatment a therapeutically effective amount of a compound of the formula:

wherein R is a hydrocarbon radical selected from substituted or unsubstituted l- or 2-adamantyl, 1-, 2- or 7-norbornanyl, and pharmaceutically acceptable salts or esters thereof.

2. The method of Claim 1, wherein the 1- or 2-adamantyl or 1-, 2- or 7-norbornanyl moieties are substituted with one or more of: C1-C4 linear or branched alkyl, nitro, oxo, C7-C9 aralkyl, (CH2)n COOR wherein n is 0-2 and R is H or linear/branched C1-C4 alkyl, CH20H, OH, OR where R is C1- C4 linear/branched alkyl, halo, CONH2, CH2NH2, CH2NHCOR wherein R is C1-C4 linear/branched alkyl, phenyl, p-nitrophenyl, p-aminophenyl, p-sulfophenyl or cyano.

3. The method of Claim 1, wherein the 1 or 2-adamantyl or 1-, 2- or 7-norbornanyl moieties are unsubstituted.

4. The method of Claim 1, wherein the compound is 17ss(N-2-adamantylcarbamoyl)-3-carboxy- androsta-3,5-diene.

5. The method of Claim 1, wherein the compound is 17ss(N-l-adamantylcarbamoyl)-3-carboxy- androsta-3,5-diene.

6. A compound of the formula (I) as defined in any of claims 1 to 5 for use as a therapeutic agent.

7. A compound of the formula (I) as defined in any of claims 1 to 5 for use in the preparation of a pharmaceutical composition.

8. A compound of the formula (I) as defined in any of claims 1 to 5 for use in inhibiting testosterone 5a-reductase.

9. A compound of the formula (I) as defined in any of claims 1 to 5 for use in the treatment of male pattern baldness.

10. A pharmaceutical composition comprising a compound of the formula (I) as defined in any of claims to 5 which composition is for use in the treatment of male pattern baldness.