NO172052B - ANALOGY PROCEDURE FOR THE PREPARATION OF STEROID 5-ALFA REDUCTASE INHIBITORS - Google Patents

Description

The present invention relates to an analogue method for the production of therapeutically active compounds with the formula:

where

R<1> is hydrogen or C 1-6 alkyl; and

M is oxygen or sulfur,

R<2> is absent or present as hydrogen or methyl, provided that a 1,10-double bond is present when R<2 >is absent}

X is hydrogen, chlorine, fluorine, bromine, iodine, trifluoromethyl, or C 1-6 alkyl;

Y is hydrogen, trifluoromethyl, fluorine or chlorine, methyl, provided that Y is hydrogen when there is no C5-C6 double bond; and

R<14> is

(1) α-hydrogen, α-hydroxyl or α-acetoxy and

15

R is (a)

where W is a bond or C 1-4 alkyl and R<4> is

(i) hydrogen,

(ii) hydroxyl,

(iii) C 1-6 alkyl,

(iv) hydroxy C 1 -alkyl,

(v) C 1 -C 6 -Alkoxy,

(vi) NR5R<6>, where R<5> and

R<6> are both independently selected from hydrogen, C1-5-alkyl, C3-6-cycloalkyl, phenyl; or

(vii) OR<7>, where R<7> is hydrogen, alkali metal, C1.18-alkyl, benzyl, or (b) /5-Alk-OR<8>, where Alk is

C 1-4 alkyl, and R<8> is

(i) phenyl C 1 -alkylcarbonyl,

(ii) C5-10-cycloalkylcarbonyl,

(iii) benzoyl,

(iv) C 1-6 -Alkoxycarbonyl,

(v) amino- or C 1-6 alkyl-substituted amino, carbonyl,

(vi) hydrogen, or

(vii) C 1-6 alkyl,

(2) =CH-Alk-CO-R<4> or =CH-Alk-OR<8>,

where Alk is present or absent, and R<4> and R<8> have the same meaning as above, and R<8> is also hydrogen or C1-20-alkylcarbonyl; (4) α-hydrogen and /3-NHCOR<9> where R<9> is C1-4-alkyl or /3-NR5R6 where R<5> and R6 have the same meaning as above,

(5) α-hydrogen and /?-cyano.

These compounds can be used to inhibit steroid 5-α-reductase in mammals.

The class of steroid hormones known as androgens is responsible for the physical characteristics that differentiate between the male and female sexes. Of the many organs that produce androgens, it is the testicles that produce these hormones in the greatest quantities. The center of the brain exerts primary control over the level of androgen production. Several physical manifestations and disease states result when poor production control results in an excess of androgen hormone production. E.g. acne vulgaris, seborrhea, female hirsutism and benign prostatic hypertrophy are associated with an elevated androgen level. In addition, male pattern baldness has been linked to high androgen levels.

Testosterone is the main androgen secreted in the testes and is the primary androgenic steroid in plasma in men. It is now known that 5-a-reduced androgens are the active hormones in various tissues such as the prostate and sebaceous glands. Circulating testosterone thus serves as a prohormone for dihydrotestosterone (DHT), its 5-a-reduced analogue, in these tissues, but not in others such as, for example, muscle and testis. Steroid 5-a-reductase is an NADPH-dependent enzyme that converts testosterone to DHT. The importance of this enzyme in male development was dramatically emphasized by the discovery of a genetic deficiency of steroid 5-α-reductase in male pseudohermaphrodites. Imperato-MgGinley, J. et al., (1979), J. Steroid Biochem. 11;637-648.

The recognition of the importance of elevated DHT levels in many disease states has stimulated significant efforts to synthesize inhibitors of this enzyme. The structures of several known steroidal 5-α-reductase inhibitors are shown in Table 1.

The first inhibitor described was 17-β-carboxylic acid (1) by Hsia and Voight in 1973. J. Invest. Dermatologically. 62:224-227. The secosteroid (2) was the next inhibitor to be described, and it has also been shown to be useful as an affinity label for 5-α-reductase. Robaire, B. et al., (1977), J. Steroid Biochem. 8:307-310. The diazoketone (3) has been reported as a potent, time-dependent inhibitor of steroid 5-α-reductase. Blohm, T.R., et al. (1980) Biochem. Biophvs. Res. Comm. 95:273-280; US Patent 4,317,817, March 2, 1982. Compound (4) is an example of a group of 4-aza steroidal inhibitors of steroid 5-a-reductase described in US Patent 4,377,584 issued March 22, 1983, and in Liang, T. et al. (1983), J. Steroid Biochem. 19, 385-390. The 6-methylene steroid (5) has also been shown to be a time-dependent inactivator of steroid 5-α-reductase. Petrow, V., et al. (1981), Steroids 38:121-140.

Other steroidal 5-α-reductase inhibitors have also been described. US Patent 4,361,578 issued June 2, 1986 describes a class of inhibitors of homosteroid enzymes. US Patent 4,191,759 discloses amides of 17/?-carboxy-4-androstene-3-ene which are active as steroidal 5-α-reductase inhibitors. Japanese patents J60146855-A and J60116657-A describe various aniline derivatives with numerous activities, including inhibitory activity for 5-α-reductase. Japanese patent J60142941-A describes phenyl-substituted ketones with inhibitory activity for 5-α-reductase and European patent EP173516-A describes various phenyl-substituted amides with similar activity. Shiseido referred to terpene derivatives that are active inhibitors of steroid 5-a-reductase. Japanese Patent No. J59053417-A.

Palladium-catalyzed carbonylation of substituted androstene derivatives is described. Cacchi, S. et al., (1985), Tet. Letters 26:1109-1112. However, no biological activity for the synthesized compounds has been described.

Preparation of steroidal 3-chloro-3,5-dienes is described by Deghenghi, R. and R. Gaudry, Canadian J. Chem. (1962) 40:818-820.

The use of phosphorus trihalogens to convert steroidal <4->3-ketones into corresponding 3-halo-3,5-dienes is described. Ross, J.A. and M.D. Martz, J. Org. Chem. (1964) 29:2784-2785.

The present invention has its basis in the discovery that steroid 5-a-reductase is inhibited by certain substituted acrylate analogues of synthetic steroid compounds. The compounds are powerful enzyme inhibitors.

Preferred compounds prepared according to the invention, and

which are used in the pharmaceutical preparations are: N,N-diisopropyl-androst-3,5-diene-17/?-carboxamide-3-carboxylic acid,

N-t-Butyl-androst-3,5-diene-17/3-carboxamide-3-carboxylic acid.

As used above and throughout the rest of the specification and claims, the carbon atoms in the steroid core are numbered and the rings named as follows: The compounds are prepared according to the invention by treating a compound with the formula:

where R<2>, R<14>, X and Y are as defined above,

X<1> is bromine, chlorine, fluorine or iodine;

with an alkyllithium reagent, followed by a carboxylating agent such as diethyl carbonate, ethyl chloroformate or preferably carbon dioxide, or optionally with a palladium catalyst in the presence of base and a C 1 alkanol.

Scheme X shows a preferred synthetic method for preparing compounds having double bonds at C3-CA and C5-C6. The starting materials are 4-en-3-one compounds. X<1> is bromine, chlorine, fluorine or iodine. According to the scheme, compounds of formula (i) are treated with a carboxylic acid halide such as acetyl chloride, acetyl bromide, oxalyl chloride, or preferably oxalyl bromide, to give compounds of formula (ii). Alternatively, formula (ii) compounds are prepared by treating formula (i) compounds with a phosphorus trihalide, or phosphorus pentahalide, such as phosphoryl chloride, phosphorus pentachloride, or preferably phosphorus tribromide, in acid, preferably acetic acid. Included in this process may be desired intermediate conversions among the various groups comprising R1A, using standard procedures known to organic chemists, particularly conversion of esters to carboxylic acids, then to acid halides and finally to carboxamides.

Then, compounds of formula (iii), compounds unsaturated in C3-C4 and Cs-C6, are prepared by adding an alkyllithium reagent such as n-butyllithium, sec-butyllithium or t-butyllithium to a compound (ii), followed by treatment with a carbox -silating agent such as diethyl carbonate, ethyl chloroformate, or preferably carbon dioxide. Alternatively, such compounds of formula (iii) are prepared by adding a palladium catalyst, preferably triphenylphosphinepalladium(II) acetate in the presence of a base, preferably triethylamine and a C 1 -alcohol, preferably methanol, under an atmosphere of carbon monoxide.

The form shows the preparation of compounds, where X and Y

is hydrogen. The scheme is used to prepare compounds, where X or Y is different from hydrogen, by replacing the starting materials of formula (i) with suitable substituted alternatives. The compounds are chosen so that they can be converted by known methods into the R<2-> and R<3-> groups in the intended compounds by additional steps in the synthetic process, such as e.g. shown above.

In the scheme above, the starting materials are chosen so that the R<2-> and R" groups in the compounds of formula (a) are the same as R<2->

and the R<3-> groups in the compounds being synthesized. Alternatively, the R<2-> and R<1A-> groups are selected in the compound with formula (a), so that

they can be converted by known methods to the R<2-> and R<3-> groups in the intended compounds by further steps in the synthetic process. E.g. compounds where R<3> is carboxylic acid are converted to the corresponding amides by reaction with amines or substituted amines via the corresponding acid chlorides. Similarly, compounds of formula (Ia) are prepared, where R3 is CH3CHCOOH by oxidation of the corresponding alcohol.

Pharmaceutically acceptable acid addition salts of the compounds of the invention containing a basic group are made when appropriate with strong or relatively strong organic or inorganic acids in the presence of a basic amine by known methods. E.g. the base is reacted with an inorganic or organic acid in a solvent that is miscible with water, such as ethanol, with isolation of the salt by removing the solvent, or in a solvent that is not miscible with water, when the acid is soluble in it, such as e.g. ethyl ether or chloroform, so that the desired salt separates out directly or is isolated by removing the solvent. Examples of the acidic addition salts covered by this invention are maleate, fumarate, lactate, oxalate, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, tartrate, citrate, hydrochloric acid, hydrobromide, sulfate, phosphate and nitrate salts. Pharmaceutically acceptable base addition salts of compounds according to the invention containing an acid group are prepared by known methods from organic and inorganic bases, including non-toxic alkali metal and alkaline earth metal bases, e.g. calcium, sodium and potassium hydroxide; ammonium hydroxide, and non-toxic organic bases such as triethylamine, butylamine, piperazine and (trihydroxymethyl)methylamine.

During the synthesis of the present compounds, new intermediates with the formula (VI) were also produced: where: The double bonds at X, Y, Z, R<2> and R<1*> in the A, B, C and D rings is as defined in formula (Ia). Because the compounds inhibit the activity of steroid 5-a-reductase, they are used therapeutically for the treatment of diseases and conditions where a reduction of DHT activity produces the desired therapeutic effect. Such diseases and conditions include acne vulgaris, seborrhea, hirsutism in women, prostate diseases such as benign prostatic hypertrophy, and baldness in men. Several compounds according to the invention were tested for their ability to inhibit human steroid 5-α-reductase using tissue from human hyperplastic prostate. To determine the ability to inhibit the human enzyme, the following procedure was used: Frozen human prostate was thawed and cut into small pieces (5 mm<3>). The tissue was homogenized in 3-5 volumes of 20 mM potassium phosphate, pH 6.5, buffer containing 0.33 M sucrose, 1 mM dithiothreitol, and 50 µM NADPH with a Brinkmann Polytron (Sybron Corporation, Westbury, New York) . The solution was sonicated for 3-5 minutes with a Sonifier (Branson Sonic Power Co.), followed by homogenization by hand in a glass-to-glass Dounce homogenizer (Kontes Glass Company, Vineland, New Jersey). Prostate particles were obtained by differential centrifugation at 600 or 1000 g for 20 minutes and 140,000 g for 60 minutes at 4°C. The pellet from the centrifugation at 140,000 g was washed with 5-10 tissue volumes of the buffer described above and centrifuged again at 140,000 g. The resulting pellet was suspended in 20 mM potassium phosphate buffer, pH 6.5, containing 20% glycerol, 1 mM dithiothreitol and 50 ^M NADPH. The solution with the suspended particles was stored at -80°C. ;A constant amount of [ 14 C]-testosterone (52-55 mCi/mmol, New England Nuclear, Boston, MA) in ethanol and varying amounts of the potential inhibitor in ethanol were transferred to test tubes and concentrated to dryness in a SAVANT Speed Vac. To each test tube was added buffer, 20 µl of 10 mM NADPH and an aliquot of the solution with prostate particles to a final volume of 1.0 ml of 50 mM sodium citrate, pH 5.0. After incubating the solution at 37°C for 20-30 minutes, the reaction was suppressed by the addition of 4 ml of ethyl acetate and 0.25 µl of each of testosterone, dihydrotestosterone, androstanediol and androstanedione as carriers. The organic layer was transferred to a second test tube and evaporated to dryness in a Speed Vac. The residue was dissolved in 20-30 µl chloroform, dropped onto an individual strip of a 20 x 20 cm prechannelized silica gel TLC plate (Si 250F-PA, Baker Chemical) and developed twice with acetone:chloroform (1:9). The radiochemical content of the substrate and product bands was determined with a BIOSCAN Imaging Scanner (Bioscan, Inc., Washington, D.C.). The percentage of recovered radiolabel converted to product was calculated, and from this the enzyme activity was determined. All the incubations were carried out so that no more than 12% of the substrate (testosterone) was used. The experimentally obtained data were computer-fitted to a linear function by plotting the inverse of the enzyme activity (1/rate) against the variable inhibitor concentration (Dixon, M, (1953), Biochem. J. 55, 170). Assuming that the steroid inhibitor is a competitive inhibitor against testosterone, a value for the inhibition constant (KA) can be calculated from equation 1: where B is the intersection of the 1/velocity axis, A is the slope of the line, S is the concentration of substrate (testosterone) used in the experiment, and Kn, the Michaelis-Menton constant of the substrate (testosterone) is determined in a separate experiment to be 4.5 ;MM. Table II shows the results of the above testing and shows that the tested compounds produced according to the invention are strong inhibitors of human steroid 5-a-reductase. Certain compounds of the invention were also tested for their in vivo ability to inhibit steroid 5-α-reductase activity. Male rats from Charles River CD, 48 days old, and weighing approximately 200 g, were administered 10 mg/kg of N,N-diisopropyl-androst-3,5-diene-17/3-carboxamide-3-carboxylic acid dissolved in propylene glycol and diluted in normal saline. After coadministration, the animals were sacrificed, the prostate was excised from the abdomen, and the DHT level was measured by the following procedure. ;The prostate tissue was excised, trimmed, weighed, cut into small pieces and washed with phosphate buffer. The tissue was then homogenised in phosphate buffer and extracted by adding ethyl acetate and stirring in an orbital mixer for 45 minutes. The ethyl acetate was evaporated, the residue was reconstituted in ethanol and filtered in a centrifuge with 0.45 µm filter paper. Then the components were separated by reversed phase HPLC to collect the DHT fraction. The fraction was reduced to dryness and reconstituted in standard DHT sample buffer available from Amersham. The DHT level was then measured using standard techniques such as determination of radioactivity (radioimmunoassay). In the co-treated rats, the DHT level in the prostate was reduced by 40% compared to blind test-treated controls four hours after the co-administration. The reduced DHT level was maintained for more than eight hours after administration, and had returned to control levels 24 hours after treatment. A single 10 mg/kg dose of the methyl ester of the above compound reduced DHT levels in the prostate by 48% relative to sham-treated controls after six hours. Thus, although this compound does not inhibit steroid 5-α-reductase in vitro. in vivo administration of this compound produces significant enzyme inhibition. ;N,N-diisopropyl-androst-3,5-diene-17/3-carboxamide-3-carboxylic acid was also tested for its effect on prostate growth. Twice-daily oral administration for 14 days of 0.5-50 mg/kg of this compound to immature rats produced a dose-dependent reduction in prostate growth. Prostate weights from animals in the maximum dose group were 40-50% lower than the controls. Using procedures similar to those described above, the in vivo effects of B 17B-N-t-butylcarboxamide androst-3,5-diene-3-carboxylic acid were also studied. The rats received a single oral dose of blank or 5, 10, 20 or 50 mg/kg of this compound. At all doses, the dihydrotestosterone level in the prostate was significantly reduced to around 50% of the controls, while the testosterone level was not affected. ;The rats also received 10 mg/kg of this compound, and prostate testosterone and dihydrotestosterone levels were measured at several time points over 24 hours. Dihydrotestosterone levels were significantly reduced to approximately 60% of controls at all time points from 2-18 hours after treatment and returned to control values within 24 hours after treatment. Prostate testosterone levels were acceptable with no clear trends. ;In addition, rats were given this compound at doses of 1, 5, 10, 25, or 50 mg/kg twice daily for two weeks to determine whether repeated treatment could cause a reduction in ventral prostate weight. Ventral prostate weight was 90% of control at a dose level of 5 mg/kg and 65% of control at dose levels of 10 and 50 mg/kg. The weight of the seminal vesicles was significantly reduced at all treatment levels. Compounds of formula (Ia) are incorporated into suitable dosage forms such as capsules, tablets or injectable preparations. 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. Likewise, the carrier or diluent may comprise a substance which prolongs the release, such as glyceryl monostearate or glyceryl distearate, alone or with a wax. The amount of solid carrier varies greatly, but will preferably be from about 25 mg to about 1 g per dosage unit. When using a liquid carrier, the preparation will 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 are prepared in accordance with conventional techniques in the pharmaceutical industry, including mixing, granulating and compressing, if necessary, to make tablets, or mixing, filling and dissolving the ingredients as appropriate to provide the desired oral or the parenteral products. The doses of the present compounds in a pharmaceutical dosage unit as described above will be an effective, non-toxic amount selected in the range of 0.1-1000 mg/kg of active compound, preferably 1-100 mg/kg. The selected dose is administered to a human patient who needs inhibition of steroid 5-a-reductase from 1-6 times daily, locally, orally in the rectum by injection, or continuously by infusion. Oral dosage units for human administration preferably contain from 1-500 mg of active compound. Parenteral administration, which uses lower doses, is preferred. However, oral administration can also be used, at higher doses, when it is safe and comfortable for the patient. The method of inhibiting steroid 5-a-reductase activity in mammals, including humans, comprises administering to a subject in need of such inhibition an effective inhibitory amount of steroid 5-a-reductase of a compound of formula (la ). ;The following examples illustrate the preparation of the compounds. Example 1 20-g-(hydroxymethyl)-5-a-pregn-3-ene-3-carboxylic acid (i) 20-g-(hydroxymethyl)-pregn-4-en-3-one Pregn-4-ene -3-one-20-α-carboxaldehyde (16.4 g, 50 mmol) in ethanol (250 mL) and THF (50 mL) was cooled to 0 °C, and a solution of sodium borohydride (NaBH 4 ) in 125 mL of ethanol was added dropwise. The reaction mixture was stirred overnight at 25°C. Acetic acid was added to the reaction mixture until neutral pH, and then the solution was evaporated to remove excess ethanol. The residue was dissolved in trichloromethane and washed with saturated sodium bicarbonate solution, water and saline. The organic layer was then dried over sodium sulfate and evaporated to dryness to give 13.9 g (82%) of 20-α-(hydroxymethyl)-pregn-4-en-3-one. (ii) 20-a-(t-butyldimethylsilyloxyrnethy1-pregn-4-en-3-one; A solution of 2O-a-(hydroxymethyl)-pregn-4-en-3-one (1.2 g, 3 .5 mmol), t-butyldimethylsilyl chloride (627 mg, 4.15 mmol) and imidazole (287 mg, 4.22 mmol) in DMF (40 mL) was stirred overnight at 40° C. The reaction mixture was then poured into ice water , and the emulsion was washed three times with ethyl acetate. The organic layers were combined, washed with cold dilute hydrochloric acid, water, and brine; dried over sodium sulfate and evaporated to dryness. Recrystallization from methanol gave 1.1 g (70%) of 20 -a-(t-Buty1-dimethylsilyloxymethyl)pregn-4-en-3-one.; (iii) 20-a-(t-butyldimethylsiloxymethyl)-3-trifluoromethylenesulfonate)-5-a-pregn-3- Ammonia (200 ml) was doubly distilled into a 3-necked round-bottom flask equipped with a dry ice condenser and argon bubbles. Lithium (Li) wire (120 mg, 17.4 mmol) was dissolved in ammonia (NH 3 ). A solution of 20-α-(t-butyldimethylsiloxymethyl)-pregn-4-en-3-one (3 g, 6.76 mmol) and aniline (49.5 mL, 5.4 mmol) in THF (50 mL) was added dropwise to the Li/NH3 solution. The reaction mixture was stirred at -;78°C for 15 minutes and then pressurized with isoprene until the blue color disappeared. The volatiles were slowly evaporated (to avoid excessive foaming) by gentle heating, and finally at 0.5 mmHg in 1 1/2 h. The residue was redissolved in THF (50 mL) and cooled to 0° C. A solution of N-phenyltrifluoromethylsulfonimide (7 g, 20 mmol) in THF (10 mL) was added to the reaction mixture, and the stirring was continued overnight at 4° C. The solvent was then evaporated, and the residue was chromatographed on silica gel eluting with 3% ethyl acetate in hexane to give 2.24 g (57%) of 20-α-(t-butyldimethylsiloxymethyl )-3-(trifluoromethyl-sulfonate)-5-a-pregn-3-ene. (iv) 20-a-(t-butyldimethylsiloxymethyl)-3-carbomethoxy-5-a-preqn-3-ene; 20-a -(t-butyldimethylsiloxymethyl)-3-(trifluoromethylsulfonate)-5-α-pregn-3-ene (100 mg, 0.173 mmol) was dissolved in methanol (0.5 mL) and DMF (1 mL).Triethylamine (55 µl , 0.386 mmol), triphenylphosphine (9 mg, 0.034 mmol) o g of palladium(II) acetate (3.8 g, 0.017 mmol) was then added to the solution, and CO was bubbled through the solution for 5 min. The reaction mixture was then stirred overnight at 45°C under an atmosphere of CO, diluted with ethyl acetate and washed with water until neutral pH. The organic layer was dried over sodium sulfate and evaporated. The dark oil was purified by chromatography on silica gel eluting with 10% ethyl acetate in hexane to give 52 mg (61%) of the desired product; 20-α-(t-butyldimethylsiloxymethyl)-3-carbomethoxy-5-α-pregn-3-ene. (v) 20-a-(hydroxymethyl)-3carbomethoxy-5-a-preqn-3-ene; 20-a-(t-butyldimethylsiloxymethyl)-3-carbomethoxy-5-a-pregn-3-ene (500 mg , 1.05 mmol) was dissolved in THF (20 mL) and 2 mL of a 1 molar solution of tetrabutylammonium fluoride in THF was added. The reaction mixture was stirred at room temperature for 3.5 hours and then diluted with water. The aqueous mixture was washed very well with dichloromethane. The organic layers were combined, dried over sodium sulfate and evaporated to dryness. Purification by flash chromatography and elution with 20% ethyl acetate in hexane gave 300 mg (78%) of 20-α-hydroxymethyl-3-carbomethoxy-5-α-pregn-3-ene. ;(vi) 20-α-fhydroxymethyl)-5-α-preqn-3-ene-3-carboxylic acid;20-α-(hydroxymethyl)-3-carbomethoxy-5-α-pregn-3-ene (300 mg, 0.802 mmol) was dissolved in THF (15 mL) and methanol (15 mL). Lithium hydroxide (8 mL of a 1 N aqueous solution) was added and the reaction mixture was stirred overnight. The reaction mixture was then diluted with water and evaporated to remove excess methanol and THF. The aqueous solution was acidified with 5% hydrochloric acid and washed several times with ethyl acetate. The organic layers were combined, washed with brine, dried over sodium sulfate and evaporated to dryness. Recrystallization from ethyl acetate and hexane gave 242 mg (84%) of the desired acid; 20-α-(hydroxymethyl)-5-α-pregn-3-ene-3-carboxylic acid, m.p. 197-203°C; Example 2; N. N-diisopropyl-5-a-androst-3-ene-17B-carboxamide-3-carboxylic acid; (i) 17/ 3- (hydroxymethyl-androst-4-ene-3-ol; About 750 ml of dry THF was added to a 3-necked round-bottom flask equipped with a condenser, argon bubbles and mechanical stirrer. The flask was cooled to 0°C and lithium aluminum hydride (LAH) (11.39 g, 0.3 mol) was slowly added. After all the LAH- amount was added, the flask was warmed to room temperature A solution of methylandrost-4-en-3-one-17/3-carboxylate (66 g, 0.2 mol) in 600 mL of THF was added very slowly to the LAH suspension . After the addition of the steroid, the reaction mixture was slowly heated to reflux. After 2 hours, the excess LAH was quenched with 11.4 mL of water, 11.4 mL of 15% sodium hydroxide (NaOH), and 28 mL of water. The salts were removed by filtration and washed with about 1 L warm THF. Concentration of the combined organic solutions gave 63 g (94%) of 17/3-(hydroxymethyl)-androst-4-en-3-ol as a mixture of a and B isomers. ;(i i) 3-oxo-176-(hydroxymethyl)-4-androstene; A solution of 17/3-(hydroxymethyl)-andros-4-en-3-ol (27 g, 0.089 mol) in 1200 ml of trichloromethane was treated with activated manganese dioxide (66 g). After 3 hours, the mixture was filtered. Concentration gave 26 g (96%) of 3-oxo-17/3-(hydroxymethyl)-4-androstene (m.p. 151°C). ;(iii) 3-oxo-17/ 3-( t-butvldimethylsilyloxymethyl)-4-androstene ;To a solution of 3-oxo-17/9-(hydroxymethyl)-4-androstene (15 g, 0.05 mol) in 200 ml of DMF was added 5.8 g (0.085 mol) of imidazole, followed by 9.7 g (0.065 mol) of t-butyldimethylsilyl chloride. The reaction mixture was stirred at room temperature under argon for 2.5 hours. The reaction mixture was then poured into 250 ml of ice water and washed 3 times with ethyl acetate. The combined organic layers were washed twice with cold 5% hydrochloric acid and once each with saturated sodium bicarbonate solution and brine. The organic layer was dried over sodium sulfate and evaporated. Recrystallization from methanol gave 16.9 g (82%) of 3-oxo-17/3-(t-butyldimethylsilyloxymethyl)-4-androstene as a white crystalline solid. ;(iv) 17 B -( t-butyldimethylsilvoxymethyl)- 3-( trifluoromethylsulfonate)- 5- g- androstene- 3- one ;Ammonia (300 ml) was doubly distilled into a 3-necked round-bottomed flask equipped with a dry ice condenser and argon bubbles . 250 mg of Li wire (3 meq) was dissolved in the ammonia and stirred for 15 minutes to ensure dryness. Freshly distilled aniline, 0.53 mL (0.8 meq) was then added. A solution of 3 g (7.2 mmol) * of 3-oxo-17jS-(t-butyldimethylsilyloxymethyl)-4-androstene in 50 m dry THF was added dropwise to the Li/NH 3 solution. An additional 50 mL of dry THF was added to increase solubility. The reaction mixture was stirred at -78°C for 2 hours and then quenched with isoprene until the blue color disappeared. The volatiles were slowly evaporated (to avoid excessive foaming) by slow heating, and finally at 0.5 mmHg for 1.5 hours. The oily residue was redissolved in dry THF (100 mL) and cooled to 0°C. A solution of 7.7 g (3 meq) of N-phenyltrifluoromethylsulfonimide in 50 mL of THF was added, the bottle was tightly sealed, and stirred overnight at 4°C. The mixture was then concentrated to dryness and chromatographed on silica eluting with hexane. Recrystallization from ethyl acetate gave 2.5 g (63%) of 17/3 (t-butyldimethyldilyloxymethyl)-3-(trifluoromethylsulfonate)-5-a-androst-3-ene (m.p. 120-121°C). (v) Methyl 17 B -( t -butyldimethylsilyloxymethyl)-5- g -androst-3-ene-3-carboxylate

To a solution of 3 g (5.46 mmol) of 17/3-(t-butyldimethylsilyloxymethyl)-3-(trifluoromethylsulfonate)-5-g-andost-3-ene in 10 ml DMF and 10 ml methanol was added 1.5 ml (2 meq) of triethylamine and 123 mg (0.03 meq) of the catalyst bis(triphenylphosphine) palladium(II) acetate. Carbon monoxide (CO) was bubbled through the solution for 5 min, and the reaction mixture was then stirred at room temperature overnight under 1 atmosphere of CO. The mixture was diluted with ethyl acetate and washed with water to neutral pH. The organic layer was dried over sodium sulfate and evaporated. Chromatography on silica gel and successive elution with 5%, 10% and 20% ethyl acetate in hexane, followed by recrystallization from methanol, gave methyl 176-(t-butyldimethylsilyloxymethyl)-5-a-androst-3-ene-3-carboxylate.

(vi) 3- carbomethoxy- 3- androstene- 176 - carboxylic acid

Methyl 176-(t-butyldimethylsilyloxymethyl)-5-α-androst-3-ene-3-carboxylate (500 mg) was dissolved in 150 mL of acetone. Jones reagent was added until the red color persisted. Isopropanol was then added to suppress excess Jones reagent. Acetone was decanted off, and the remaining chromium salts were then dissolved in water and washed 3 times with dichloromethane. The organic layers were combined and passed through a plug of flurosil and concentrated to give 360 mg (99%) of 3-carbomethoxy-3-androstene-17/3-carboxylic acid.

(vii) 3- carbomethoxy- 3- androstene- 17g- N. N -diisopropylcarboxamide

3-Carbomethoxy-3-androstene-17/?-carboxylic acid (360 mg, 0.78 mmol) was suspended in 10 mL of dry toluene and treated with 0.4 mL of oxalyl chloride for 2 h under argon. The reaction mixture was then evaporated (1 mmHG), and the residue was dissolved in 10 mL of dry THF. A solution of 0.6 mL of diisopropylamine in 2 mL of dry THF was added, and the reaction mixture was stirred for 1 hour. The mixture was diluted with ice water and extracted with dichloromethane. The organic layer was then washed 2 times with cold 5% hydrochloric acid, sodium hydroxide and brine; dried over sodium sulfate and evaporated. Chromatography on silica gel eluting with 20% ethyl acetate in hexane, followed by recrystallization from diethyl ether gave 3-carbomethoxy-3-androstene-17/?-N,N-diisopropylcarboxamide.

(viii) N,N- diisopropyl- 5- Q!- androst- 3- en- 17i8-carboxamide- 3- carboxylic acid

3-Carbomethoxy-3-androstene-17/3-N,N-diisopropylcarboxamide (300 mg, 0.7 mmol) and 300 mg K 2 CO 3 were added to 20 mL of 10:1 methanol:water solution and refluxed under argon for 20 hours.

The mixture was then concentrated to dryness and diluted with water. The aqueous layer was washed with ethyl acetate and acidified. The emulsion was washed several times with dichloromethane. The organic layer was dried over sodium sulfate and evaporated. The product was recrystallized by dissolving in ethyl ether, adding ethyl acetate and concentrating, giving N,N-diisopropyl-5-oe-androst-3-ene-17/3-carboxamide-3-carboxylic acid, m.p. 159-162°C.

Example 3

N. N- diisopropyl- androst- 3 f 5- diene- 17/ 3 carboxamide- 3- carboxylic acid

(i) Androst-4-en-3-one-17β-carboxylic acid Methylandrost-4-en-3-one-17β-carboxylate (20 g, 60 mmol) was dissolved in 700 mL of a 20:1 solution of methanol:water, and potassium hydroxide (7 g) was added, and the solution was refluxed under argon for 24 h. The reaction mixture was then acidified with 5% hydrochloric acid, and 250 ml of water was added. After standing for 1 hour, the solution was filtered and dried to give 18 g (94%) of androst-4-en-3-one-170-carboxylic acid as a white crystalline solid. (ii) Androst-4-ene-3-one-17fi-N.N-diisopropylcarboxamide

A solution of androst-4-en-3-one-17/?-carboxylic acid (18 g, 0.06 mmol) in 350 mL of toluene was dried azeotropically until about 100 mL of distillate was collected. The solution was then cooled to 10°C. Pyridine (6.7 mL, 0.08 mol) was added, followed by careful addition of a solution of oxalyl chloride (7.2 mL, 0.08 mol) in 10 mL toluene. The reaction mixture was stirred at room temperature (under argon) for 2 hours, and then cooled to 0°C. A solution of diisopropylamine (89 mL, 0.6 mol) in 40 mL of toluene was added dropwise so that the temperature did not exceed 40°C. The reaction mixture was stirred for 1 hour and then quenched with 300 mL of ice water. The layers were separated and the the aqueous layer was extracted 4 times with ethyl acetate (800 mL). The organic layers were combined and washed with 5% hydrochloric acid and brine. The organic layer was then dried over sodium sulfate and concentrated to dryness. Recrystallization by dissolving in 10 mL of toluene and adding of 200 ml of hexane gave 16.5 g (69%) of androst-4-en-3-one-17/3-N,N-diisopropylcarboxamide (m.p. 236-239°C).

(iii) 17 B -(N.N-diisopropylcarboxamide)-3-(trifluoromethylsulfonate)-androst-3. 5- dien

Androst-4-en-3-one-17j3-N,N-diisopropylcarboxamide (5 g, 12.5 mmol) was dissolved in 50 mL of methylene chloride. 2,6-di-t-butyl-4-methylpyridine (3.08 g, 17.0 mmol) was then added to the steroid solution and stirred at room temperature for 15 minutes. Trifluoromethanesulfonic anhydride (3.5 mL, 19 mmol) was added to the solution and stirring continued for 30 minutes. The reaction mixture was then diluted with 50 ml of methylene chloride and filtered. The organic layer was washed 2 times with 5% hydrochloric acid, saturated sodium bicarbonate and brine. It was then dried over sodium sulfate and evaporated. The triflate was purified by chromatography on silica gel eluting with 20% ethyl acetate in hexane to give 4 g (61%) of 17)3-(N,N-diisopropylcarboxamide)-3-(trifluoromethylsulfonate)-androst-3,5-diene .

(iv) 3- carbomethoxy- androst- 3 , 5- diene- 17/ 8- N. N -diiso<p>ropylcarboxamide

To a solution of 11B-(N,N-diisopropylcarboxamide)-3-(trifluoromethylsulfonate)-androst-3,5-diene (4 g, 7.5 mmol) in 60 mL of a 1:1 solution of methanol in DMF was added bis(triphenylphosphine)-palladium(II) acetate (570 mg) and a large excess (20 ml) of triethylamine. Carbon monoxide was bubbled through the solution for 5 minutes and the reaction was stirred at 65°C overnight under 1 atmosphere of CO. The mixture was then diluted with ethyl acetate and washed with water until neutral pH. The organic layer was dried over sodium sulfate and evaporated to a brown oil. Purification by chromatography on silica gel eluting with 20% ethyl acetate in hexane, followed by recrystallization from ethyl ether and hexane gave 2.1 g (64%) of 3-carbomethoxyandrost-3,5-diene-170-N,N-diisopropylcarboxamide , sp. 159-162°C.

(v) N.N- diisopropvl- androst- 3, 5- diene- 17g-carboxamide- 3- carboxylic acid

3-Carbomethoxy-androst-3,5-diene-17/3-N,N-diisopropylcarboxamide (1.4 g, 3.1 mmol) and 1 g of K 2 CO 3 were added to 88 mL of a 10:1 solution of methanol -water and refluxed under argon for 20 hours. The mixture was then concentrated to dryness and diluted with water. The aqueous layer was washed with ethyl acetate and acidified. The emulsion was washed several times with dichloromethane. The organic

the layer was dried over sodium sulfate and evaporated. The product was recrystallized by dissolution in ethyl ether, addition of ethyl acetate and concentration, and gave N,N-diisopropyl-androst-3,5-diene-17/3-carboxamide-3-carboxylic acid (m.p. 230-234°C).

Example 4

170-(N.N-diisopropylcarboxamide)-4-fluoro-5-α-androst-3-ene-3-carboxylic acid (i) 3-oxo-17lf(hydroxymethyl)-5-α-androstane Ammonia (500 ml) was distilled over ie n 3-neck round-bottom flask equipped with dry ice condenser and argon bubbles. Li wire (3 g) was dissolved in the ammonia and stirred for 15 minutes to ensure dryness. A solution of 3-oxo-17)8-(hydroxymethyl)-4-androstene (prepared as described in Example 2 (ii), 37.5 g, 0.123 mol) in 625 mL of THF and t-butyl alcohol (6.25 mL , 0.8 meq) was added dropwise to the LI/NH3 solution. The reaction was stirred at -78°C for two hours and quenched with isoprene until the blue color disappeared. The resulting enolate was then quenched with ammonium chloride as the ammonia was allowed to evaporate. Acetone was added to the residue and carefully refluxed. The acetone solution was then filtered and evaporated to dryness to give 24.7 g (79%) of 3-oxo-17)3-(hydroxymethyl)-5-α-androstane.

(ii) 3 - ox o- 5- a- androstane- 17 fl- carboxylic acid

Said compound was prepared according to example 2 (vi) by replacing methyl 17B-(t-butyldimethylsilyloxymethyl)-5-a-androst-3-ene-3-carboxylate with 3oxo-17fl-(hydroxymethyl)-5-a-androstane.

(iii) 3-oxo-5-α-androstane-17fl-N,N-diisopropylcarboxamide

3-oxo-5-α-androstane-17/3-carboxylic acid was suspended in toluene (100 mL) and an excess of oxalyl chloride (8 mL) was added. The reaction mixture was stirred for 1 hour at 25°C (under argon). The volatiles were then removed (0.5 mmHg for 2 hours). The residue was resuspended in THF (25 mL), cooled to 0°C, and diisopropylamine (10 mL) was added. The reaction mixture was stirred at 0°C for 2 hours and then diluted with water. The aqueous mixture was extracted with ethyl acetate and evaporated. Purification by chromatography on silica gel and eluting with 20% ethyl acetate in hexane gave 3.15 g (78%) of 3-oxo-5-a-androstane-17/3-N,N-diisopropylcarboxamide.

(iv) 3-oxo-5-g-androst-1-ene-17i8-N.N-diisopropylcarboxamide

To a solution of 3-oxo-5-a-androstane 17Æ-N,N-diisopropylcarboxamide (2.3 g, 5.74 mmol) in 100 ml of ethyl acetate was added phenylselenyl chloride (1.1 g, 5.74 mmol), and the reaction mixture was stirred for 2 hours. The reaction mixture was then washed with 5% sodium bicarbonate solution and brine. The ethyl acetate solution was cooled to 0°C, and 50 mL of THF was added. Hydrogen peroxide (6 ml of a 30% solution) was slowly added and the reaction mixture stirred for 2 hours. The reaction mixture was then washed with 5% sodium bicarbonate solution, brine and evaporated to dryness. Purification by chromatography on silica gel and elution with 20% ethyl acetate in hexane gave 1.3 g (56.5%) of 3-oxo-5-α-androst-1-ene-17/3-N,N-diisopropylcarboxamide.

(v) 3- oxo- 5- Q!- androstane- l. 2- g- epoxvd-17/ 3- N, N- diisopropylcarboxamide

3-oxo-5-α-androst-1-ene-17Æ-N,N-diisopropylcarboxamide (4.6 g, 11.5 mmol) was dissolved in 50 mL of methanol and cooled to 15°C. To the solution was added hydrogen peroxide (0.8 mL of a 30% solution), followed by sodium hydroxide (0.16 mL of a 10% solution in 2 mL methanol. The ice bath was removed, and stirring was continued at room temperature for 1 hour. The reaction mixture was then poured into ice water and washed twice with dichloromethane. The organic layers were combined and washed with water and brine; dried over sodium sulfate and evaporated. Trituration in acetone gave 4.0 g (83.7%) of the desired epoxide; 3-oxo-5-α-androstane-1,2-α-epoxide-17/3-N,N-diisopropylcarboxamide.

(vi) 3- oxo- 4- fluoro- 5- a- androst- l- en- 17) 9-N, N- diisopropylcarboxamide

3-oxo-5-α-androstane-1,2-α-epoxide-17α-N,N-diisopropylcarboxamide (1.7 g, 4 mmol) was dissolved in 25 mL of THF and cooled to 20°C. Pyridine poly(hydrogen fluoride) (10 mL) was slowly added to the solution (under argon). The reaction mixture was warmed to 0°C, stirred for 30 minutes and then warmed to room temperature and

stirred for 15 minutes. The reaction mixture was poured into ice water and washed with ethyl acetate. The organic layer was washed with water, 5% sodium bicarbonate solution and brine; dried over sodium sulfate and evaporated. Purification by chromatography on silica gel and elution with 20% ethyl acetate in hexane gave 750 mg (44%) of the desired 3-oxo-4-fluoro-5-a-androst-1-ene-17Æ-N,N-diisopropylcarboxamide.

(vii) 17/ 3-( N,N-diisopropylcarboxamide)-3-(trifluoromethylsulfonate)-4-fluoro-5-a-androst-1,3-diene

A solution of lithium bis(trimethylsilyl)amide (4.2 mmol, 2.2 eq) in 2 mL of THF was cooled to -78 °C. A solution of 3-oxo-4-fluoro-5-α-androst-1-ene-17Æ-N,N-diisopropylcarboxamide (800 mg, 1.9 mmol) in 10 mL of THF was added, and the reaction mixture was stirred for 1 hour. A solution of N-phenyltrifluoromethanesulfonimide (857 mg, 2.4 mmol) in 8 mL of THF was then added, and the reaction mixture was stirred for 1.5 h at -78°C. The reaction mixture was then evaporated to dryness and chromatographed on silica gel and eluted with 20% ethyl acetate in hexane. Trituration in a hexane and ether solution gave 460 mg (46%) of the desired product, 17)3-(N,N-diisopropylcarboxamide)-3-(trifluoromethylsulfonate)-4-fluoro-5-a-androst-1,3 - the day.

(viii) 3-carbomethoxy-4-fluoro-5-α-androst-1,3-diene-17g-N,N-diisopropvlcarboxamide

The above compound was prepared according to Example 1 (iv) by substituting 20-α-(t-butyldimethylsilyloxymethyl)-3-(trifluoroethylsulfonate)-5-α-pregn-3-ene with 17)3-(N,N- diisopropylcarboxamide) - 3-(trifluoromethylsulfonate)-4-fluoro-5-α-androst-1,3-diene.

(ix) 3-carbomethoxy-4-fluoro-5-a-androst-3-ene-17g-N,N-diisopropylcarboxamide 3-carbomethoxy-4-fluoro-5-a-androst-1,3-diene-17 )3-N,N-diisopropylcarboxamide (120 mg, 0.26 mmol) in 15 mL of a 2:1 solution of ethyl acetate and hexane was hydrogenated at 25°C and 1 atmosphere over 20 mg of 10% palladium on carbon. The solution was filtered to remove the catalyst and concentrated to a white solid (120 mg).Recrystallization from methanol and acetone gave 55 mg (46%) of the desired 3-carbomethoxy-4-fluoro-5-a-androst-3-ene- 17Æ-N,N-diisopropylcarboxamide, mp 171-172°C.

(x) 176 - (N,N-diisopropylcarboxamide)-4-fluoro-5-g-androst-3-ene-3-carboxylic acid

Said compound was prepared according to example 2 (viii) by substituting 3-carbomethoxy-5-a-androst-3-ene-17)3-N,N-diisopropylcarboxamide with 3-carbomethoxy-4-fluoro-5-a-androst -en-17/3-N,N-diisopropylcarboxamide.

Example 5

2 O- a-(hydroxymethyl)-4-fluoro-5-a-preqn- 3- en- 3- carboxylic acid

(i) 20-a-(hydroxymethyl)-5-g-preqnan-3-one

Said compound was prepared according to example 4 (i) by substituting 3-oxo-17Æ-(hydroxymethyl)-4-androstene with 20-g<->(hydroxymethyl)-pregn-4-en-3-one.

(ii) 20-g-(hydroxymethyl)-5-g-preqn-1-en-3-one

Said compound was prepared according to example 4 (iv) by substituting 3-oxo-5-g<->androstane-17/3-N,N-diisopropylcarboxamide with 20-g<->(hydroxymethyl)-5-g<- >pregnan-3-one.

(iii) 20-g-(hydroxymethyl)-1.2-g-epoxide-5-g-preqnan-3-one

The above compound was prepared according to Example 4 (v) by substituting 3-oxo-5-g<->androst-1-ene-17/3-N,N-diisopropylcarboxamide with 20-g<->(hydroxymethyl)-5 -g<->pregn-l-en-3-one.

(iv) 20-g-(hydroxymethyl)-4-fluoro-5-g-preqn-1-en-3-one

The above compound was prepared according to Example 4 (vi) by substituting 3-oxo-1,2-g<->epoxide-5-g<->androstane-17/3-rN,N-diisopropylcarboxamide with 20-g<- >(hydroxymethyl)-1,2-g<->epoxide-5-a-pregnan-3-one.

(v) 20-g-(t-butyldimethylsilyloxymethyl)-4-fluoro-5-g-preqn-1-en-3-one

Said compound was prepared according to example 1 (ii) by substituting 20-g<->(hydroxymethyl-pregn-4-en-3-one with 20-g<->(hydroxymethyl)-4-fluoro-5-g- pregn-l-en-3-one.

(vi) 20-a-(t- butyldimethylsilyloxymethyl)-4-fluoro-3-(trifluoromethylsulfonate)-5-g-preqn-1,3-diene

The above compound was prepared according to Example 4 (vii) by substituting 3-oxo-4-fluoro-5-a-androst-1-ene-17/3-N,N-diisopropylcarboxamide with 20-g<->(t- buryldimethylsilyloxymethyl)-4-fluoro-5-g<->pregn-l-en-3-one.

(vii) 3-carbomethoxy-20-α-(t-butyldimethyl-syloxymethyl)-4-fluoro-5-α-preqn-1, 3-diene

Said compound was prepared according to Example 4 (viii) by substituting 170-(N,N-diisopropylcarboxamide)-3-(trifluoromethylsulfonate)-4-fluoro-5-a-androst-1,3-diene with 20-a -(t-butyldimethylsilyloxymethyl)-4-fluoro-3-(trifluoromethylsulfonate)-5-a-pregn-1,3-diene.

(viii) 3-carbomethoxy-20-α-(t-butyldimethyl-syloxymethyl)-4-fluoro-5-α-preqn-3-ene

The above compound was prepared according to Example 4 (ix) by substituting 3-carbomethoxy-4-fluoro-5-a-androst-1,3-diene-17/3-N,N-diisopropylcarboxamide with 3-carbomethoxy-20-a -(t-butyldimethylsilyloxymethyl)-4-fluoro-5-a-pregn-1,3-diene.

(ix) 3-carbomethoxy-20-a-(hydroxymethyl)-4-fluoro-5-g-preqn-3-ene

To a solution of 3-carbomethoxy-20-a-(t-butyldimethylsilyloxymethyl)-4-fluoro-5-g<->pregn-3-ene (610 mg, 1.2 mmol) in THF 20 ml was added 2.4 mmol of tetrabutylammonium fluoride, and the reaction mixture was stirred at 25°C for 3.5 hours under argon. The reaction mixture was then poured into ether and washed with water and brine; dried over sodium sulfate and evaporated. Chromatography on silica gel and eluting with 15% ethyl acetate in hexane gave 200 mg (43%) of the desired 3-carbomethoxy-20-g<->(hydroxymethyl)-4-fluoro-5-g<->pregn-3-ene , sp. 177°C.

(x) 20-g-(hydroxymethyl)-4-fluoro-5-g-preqn-3-ene-3-carboxylic acid

Said compound (m.p. 233-236"C from methanol:acetone) was prepared according to Example 1 (vi) by substituting 20-g<->(hydroxymethyl)-3-carbomethoxy-5-g-pregn-3-ene with 3-carbomethoxy-20-g<->(hydroxymethyl)-4-fluoro-5-g<->pregn-3-ene.

Example 6 20-g-(hydroxymethyl-A-nor-5-g preqn-1-ene-2-carboxylic acid

(i) 20-g-(hydroxymethyl)-A-nor-5-a-pregnan-2-g-carboxylic acid

20-g<->(hydroxymethyl)-5-g<->pregnan-3-one (8 g, 24.1 mmol) was suspended in 160 mL of 95% acetic acid, treated with thallium acetate sesquihydrate (30.4 g, 74.5 mmol) and heated to 85°C. After 3

hours, the reaction mixture was cooled and poured into ice water. The precipitate was filtered, redissolved in ethyl acetate, washed with water and brine; dried over sodium sulfate and evaporated. The resulting oil was dissolved in methanol, treated with aqueous KOH (8 g in 50 ml of water), heated to 100°C for 40 minutes and then cooled to room temperature and allowed to stir for 18 hours. The reaction mixture was then diluted with water and washed with ethyl acetate. The aqueous solution was acidified with concentrated hydrochloric acid and washed several times with ethyl acetate. The organic layers were combined, washed with water and brine; dried over sodium sulfate and evaporated. Recrystallization from methanol and acetone gave 4.9 g (58%) of 20-α-(hydroxymethyl)-α-nor-5-α-pregnan-2-α-carboxylic acid.

(ii) 20-α-(hydroxymethyl)-2-α-carbomethoxy-α-nor-5-α-preqnan

20-α-(hydroxymethyl)-α-nor-5-α-pregnan-2-α-carboxylic acid (4.9 g, 13.5 mmol) was suspended in 200 mL of diethyl ether and treated with about 67 mmol of diazomethane in an ether solution , and the reaction mixture was stirred for 6 h. The excess diazomethane and ether were removed in vacuo and recrystallization from methanol gave 3.6 g (72%) of 20-a-(hydroxymethyl)-2-a-carbomethoxy-A-nor-5-a-pregnan.

(iii) 2- as- carbomethoxy- 2 O- a-( t-butyl-dimethylsilvloxymethyl)- A- nor- 5- a-preanane

The above compound was prepared according to Example 1 (ii) by substituting 20-α-(hydroxymethyl)-pregn-4-en-3-one with 20-α-(hydroxymethyl)-2-α-carbomethoxy-A-nor-5 -a-pregnan.

(iv) 2-carbomethoxy-20-a-(t-butyldimethylsilyloxymethyl)-A- nor- 5-a- precm- 2- en 2-a-carbomethoxy-20-a-(t-butyldimethylsilyloxymethyl)-A- nor-5-α-pregnane (960 mg, 2 mmol) was dissolved in 30 mL of THF and cooled to -78°C. Lithium isopropyl cyclohexylamide (5 mL of a 0.72 M solution) was added and the solution was stirred for 30 min at -78°C, warmed to room temperature and stirred for an additional 1 h. The reaction mixture was recooled to -78°C; a soln. of phenyl selenyl bromide (960 mL, 4 mmol) in 6 mL of THF was added and stirred for 30 min. The reaction mixture was then warmed to room temperature and stirred for 1 h; poured into cold saturated NH 4 Cl and washed with ethyl acetate. The organic the layers were combined and washed with cold 5% hydrochloric acid, 5% sodium bicarbonate solution, water, and brine. The ethyl acetate solution was then cooled to 10°C, and hydrogen peroxide (1 mL of a 30% solution) was added. The reaction mixture was then stirred at room temperature for 2 hours, diluted with water and washed with saturated K 2 CO 3 , dilute sodium sulfite and brine, dried over sodium sulfate and evaporated Purification by chromatography on silica gel eluting with 3% ethyl acetate in hexane followed by recrystallization ng of methanol gave 680 mg (72%) of a 5:1 mixture of isomers: 2-carbomethoxy-20-a-(t-butyldimethylsilyloxymethyl)-A-nor-5-a-pregn-1-ene and the desired isomer 2-carbomethoxy-20-a-(t-butyldimethylsilyloxymethyl)-A-nor-5-a-pregn-2-ene. The isomers were separated, so that the yield was 100 mg of the desired compound.

(v) 20-α-(hydroxymethyl)-2-carbomethoxy-α-nor-5-o:-prean-2-ene

Said compound was prepared according to example 1 (v) by substituting 20-α-(t-butyldimethylsilyloxymethyl)-3-carbomethoxy-5-α-pregn-3-ene with 2-carbomethoxy-20-α-(t-butyldimethylsilyloxymethyl) -A-nor-5-a-pregn-2-en.

(vi) 20-α-(hydroxymethyl)-α-nor-5-α-preqn-1-ene-2-carboxylic acid

Said compound (m.p. 235°C from methanol) was prepared according to example 1 (vi) by replacing 20-α-(hydroxymethyl)-3-carbomethoxy-5-α-pregn-3-ene with 20-α-(hydroxymethyl) )-2-carbomethoxy-A-nor-5-a-pregn-2-ene.

Example 7

17/ 3- N. N- diisopropvlcarboxamide- 5- a androst- 1, 3- diene- 3- carboxylic acid (i) 17B -( N. N- diisopropylcarboxamide)-3-( trifluoromethylsulfonate)- 5- a- androst- l , 3-diene Said compound was prepared according to example 4 (vii) by substituting 3-oxo-4-fluoro-5-a-androst-1-ene-17Æ-N,N-diisopropylcarboxamide with 3-oxo-5-a -androst-1-ene-17Æ-N,N-diisopropylcarboxamide. (ii) 3- carbomethoxy- 5- a- androst- 1, 3- diene 170- N. N- diisopropylcarboxamide

Said compound (m.p. 174-176°C) was prepared according to example 1 (iv) by substituting 20-a-(t-butyldimethylsilyloxymethyl)-3-(trifluoromethylsulfonate)-5-a-pregn-3- one with 17/3-(N,N-diisopropylcarboxamide)-3-(trifluoromethylsulfonate)-5-α-androst-1,3-diene.

(iii) 17fl- N, N- diisopropylcarboxamide- 5- a-androst- 1. 3- diene- 3- carboxylic acid

Said compound (m.p. 163°C) was prepared according to example 2 (viii) by substituting 3-carbomethoxy-5-a-androst-3-ene-17Æ-N,N-diisopropylcarboxamide with 3-carbomethoxy-5-a- androst-1,3-diene-17Æ-N,N-diisopropylcarboxamide.

Example 8

N. N- diispropyl androst- 3 , 5, 7- trien- 17/ 3-carboxamide- 3- carboxylic acid

(i) Androst- 4. 6- diene- 3- one- 17/ 3- N, N- diisopropylcarboxamide

Androst-4-en-3-one-17Æ-N,N-diisopropylcarboxamide (12 g, 30 mmol) and chloranil (8.95 g, 36.4 mmol) in 700 ml of t-butanol are heated at reflux for 3.5 hours, and is then cooled and filtered. The filtrate is concentrated and the residue is taken up in 700 ml of trichloromethane and washed in turn with 4 x 150 ml of water, 3 x 150 ml of aqueous bicarbonate, 3 x 150 ml of 5% sodium hydroxide, 3 x 150 ml of saline solution, dried over sodium sulfate and is concentrated to give androst-4,6-dien-3-one-17/3-N,N-diisopropylcarboxamide.

(ii) N,N-diisopropyl androst-3,5,7-triene-17/3-carboxamide-3-carboxylic acid

Said compound is prepared according to example 3 (iii-v) by substituting androst-4-en-3-one-17Æ-N,N-diisopropylcarboxamide with androst-4,6-dien-3-one-17/3-N, N-diisopropylcarboxamide.

Example 9

A- homo- 5- a- 4- en- 17/ 3- N. N- diisopropylcarboxamide- 4- carboxylic acid

(i) A- homo- 5- a- androstane- 4- one- 17/ 3- N, N-diisopropylcarboxamide

To a 0°C solution of 3-oxo-5-g<->androstane-17/3-N,N-diisopropylcarboxamide (15 g), prepared as in Example 4, and KOH (28 g ) in ether (500 ml ) and methanol (850 ml) are added to 20 g of N-methyl-nitrosourea over 20 minutes. After 5 hours, 300 ml of 10% hydrochloric acid is added, and the mixture is filtered and concentrated to remove the organic solvents. The resulting aqueous suspension is extracted with ether, and the ether solution is dried and concentrated. Chromatography of the residue gives A-homo-5-o:-androstan-4-one-17Æ-N,N-diisopropylcarboxamide.

(ii) A- homo- 5- o:- 4- en- 17g- N, N- diisopropylcarboxamide- 4- carboxylic acid

Using the protocol of Example 3 (iii-v), substitution of androst-4-en-3-one-17jØ-N,N-diisopropylcarboxamide with A-homo-5-a-androstan-4-one- 17Æ-N,N-diisopropylcarboxamide a mixture of 3-ene and 4-ene A-homo-4-carboxylic acids. Chromatography and recrystallization give pure A-homo-5-a-androst-4-ene-17/3-^N-diisopropylcarboxamide^-carboxylic acid.

Example 10

N,N-diisopropyl-4-chloro-androst-3. 5-diene-17<9-carboxamide-3-carboxylic acid

(i) 3-oxo-androstane-4-5-o:-epoxide-17i9-N,N-diisopropvlcarboxamide

Said compound is prepared according to example 4(v) by substituting 3-oxo-5-a-androst-1-en-17Æ-N,N-diisopropylcarboxamide with androst-4-en-3-one-17/3-N, N-diisopropylcarboxamide.

(ii) 3- oxo- 4- chloro- 4- androstene- 17/ 3- N, N -diiso<p>ropylcarboxamide

A stream of hydrogen chloride gas is passed through a chloroform solution of 3-oxo-androstane-4,5-a-epoxide-17Æ-N,N-diisopropylcarboxamide for 2 minutes. The solution is then washed with water, dried (Na 2 SO 4 ) and concentrated to give 3-oxo-4-chloro-4-androstene-17/3-N,N-diisopropylcarboxamide.

(iii) N,N- diisopropyl- 4- chloro- androst- 3. 5- diene-17 B - carboxamide- 3- carboxylic acid

Said compound is prepared according to example 3 (iii-v) by substituting androst-4-en-3-one-17/3-N,N-diisopropylcarboxamide with

3-oxo-4-chloro-4-androstene-17Æ-N,N-diisopropylcarboxamide.

Example 11

N. N- diisopropyl- 4- methyl- 5- o:- androst- 3- en- 17/ 3-carboxamide- 3- carboxylic acid

(i) 3-oxo-17/3-(hydroxymethyl)-4-methyl-4-androstene

A mixture of potassium t-butoxide (5 g) in 100 ml of t-butanol is heated under reflux. A solution of 3-oxo-17/3-(hydroxymethyl)-4-androstene (10 g) in t-butanol is added, followed by a solution of methyl iodide (2.7 g) in t-butanol. The heating is continued for 3 hours. The mixture is then cooled, acidified and extracted with dichloromethane. The dichloromethane solution is washed with saline, dried and concentrated to give 3-oxo-17/3-(hydroxymethyl)-4-methyl-4-androstene.

(ii) N. N- diisopropvl- 4- metvl- 5- g- androst- 3-ene- 17g- carboxamide- 3- carboxylic acid

Said compound is prepared according to example 2 (iii-viii) by substituting 3-oxo-17/3-(hydroxymethyl)-4-androstene with 3-oxo-17/3-(hydroxymethyl)-4-methyl-4-androstene.

Example 12

N. N- diisopropyl- 4- trifluoromethyl- androst- 3, 5-diene- 17i8- carboxamide- 3- carboxylic acid

(i) 3- oxo- 4- trifluoromethyl- 4- androstene- 17/ 3- N, N -diiso<p>ropylcarboxamide

A solution of 3-oxo-4-androstene-17/3-N,N-diisopropylcarboxamide (Ig) in 10 ml of pyridine is cooled to -78°C. Trifluoromethyl iodide gas is condensed in a dry ice-acetone bath and added to the cooled solution of steroid pyridine. The resulting solution is photolyzed using an intermediate pressure 450 watt mercury vapor lamp at room temperature for 18 hours. The reaction mixture is then diluted with ethyl acetate, washed with cold, dilute hydrochloric acid, 5% sodium bisulfite, water, brine, dried over anhydrous sodium sulfate and concentrated to dryness. Purification on a silica gel column and elution with 20% ethyl acetate in hexane gives 3-oxo-4-trifluoromethyl-4-androstene-17/3-N,N-diisopropylcarboxamide.

(ii) N.N-diisopropyl-4-trifluoromethyl-androst-3. 5-diene-17/3-carboxamide-3-carboxylic acid

Said compound is prepared according to example 3 (iii-v) by substituting androst-4-en-3-one-17/3-N,N-diisopropylcarboxamide with 3-oxo-4-trifluoromethyl-4-androstene-17Æ-N, N-diisopropylcarboxamide.

Example 13 N.N-diisopropyl-6-trifluoromethyl-androst-3,5-diene-17/3-carboxamide-3-carboxylic acid

(i) 3-oxo-6-trifluoromethyl-4-androstene-17fi-N,N-diisopropylcarboxamide

17/?-N,N-diisopropylcarboxamide-3-(trifluoromethyl sulfonate)-androst-3,5-diene (1 g) is dissolved in 10 mL of pyridine and photolyzed using a Hanovia medium pressure 450 mercury vapor lamp at room temperature for 18 hours. The reaction solution is diluted with ethyl acetate, which in turn is washed with cold, dilute hydrochloric acid, water, salt solution, dried over anhydrous magnesium sulfate and evaporated to dryness. Chromatography on a silica gel column and elution with 20% ethyl acetate in hexane gives 3-oxo-6-trifluoromethyl-4-androstene-17Æ-N,N-diisopropylcarboxamide.

(ii) N.N-diisopropyl-6-trifluoromethyl-androst-3. 5-diene-17fi-carboxamide-3-carboxylic acid Said compound is prepared according to example 3 (iii-v) by substituting androst-4-en-3-onl7Æ-N,N-diisopropylcarboxamide with 3-oxo-6-trifluoromethyl-4 -androstene-17j-N,N-diisopropylcarboxamide.

Example 14

17<3- N. N- diisopropylcarboxamide- 6- fluoro-androst- 3, 5- diene- 3- carboxylic acid

(i) 17/ ?- N, N- diisopropylcarboxamide- 5- o:-androstene- 3- spiro- 2'- dioxolane

To a solution of 3-oxo-4-androstene-17Æ-N,N-diisopropylcarboxamide (8 g) in 300 ml of benzene was added 30 ml of ethylene glycol and p-toluenesulfonic acid (240 mg). The resulting solution was heated under reflux under argon with water collection and using a Dean Stark trap for 30 hours. The reaction mixture was then allowed to cool to room temperature and diluted with ethyl acetate. The organic layer was washed with 5% sodium bicarbonate, brine, dried over anhydrous magnesium sulfate and evaporated to dryness. The crude product was purified on a silica gel column using 20% ethyl acetate in hexane as eluent to give 7 g of 17/3-N,N-diisopropylcarboxamide-5-α-androstene-3-spiro-2'-dioxolane (80 %).

(ii) 17A- N. N- diisopropylcarboxamide- 5- af 6a-epoxyv- androstane- 3- spiro- 2'- dioxolane

A solution of m -chloroperbenzoic acid (2.8 g) in 40 ml of dichloromethane dropwise through a dropping funnel. After the completion of the addition of the m-chloroperbenzoic acid, the reaction mixture was allowed to warm to room temperature and stirred for an additional 30 minutes. The reaction mixture was then washed with 10% aqueous sodium sulfite solution 4 times, followed by 5% aqueous sodium bicarbonate solution, brine, dried over anhydrous magnesium sulfate and concentrated to a syrup. Column chromatography and elution with 30% ethyl acetate in hexane gave 2.76 g of 17/3-N,N-diisopropylcarboxamide-5-a,6a-epoxy-androstane-3-spiro-2'-dioxolane as a white solid

(61%).

(iii) 3-oxo-6-fluoro-4-androstene-17fl-N,N-diisopropylcarboxamide

17/3-N,N-diisopropylcarboxamide -5-α,6α-epoxy-androstane-3-spiro-2'-dioxolane (2.5 g) was dissolved in a mixture of 50:50 (v/v) benzene and ether. To this solution was added boron trifluoride etherate (2.5 mL) under argon. The reaction solution was stirred at room temperature under argon for 4 hours and then quenched with 5% aqueous sodium carbonate. The organic layer was washed with water, brine, dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure. The residue was then treated with 15 ml of saturated hydrogen chloride in glacial acetic acid. The resulting solution was stirred at room temperature under argon for 1.5 hours and then diluted with ethyl acetate. The ethyl acetate solution was washed with 5% aqueous sodium bicarbonate, water, brine, dried over anhydrous magnesium sulfate and evaporated to dryness. The crude product was purified on a silica gel column and eluted with 25% ethyl acetate in hexane to give 3-oxo-6/3-fluoro-4-androstene-17/3-N,N-diisopropylcarboxamide (675 mg, 30%) and 3 -oxo-6-α-fluoro-4-androstene-17)3-N,N-diisopropylcarboxamide (900 mg, 40%).

(iv) 17/S-N.N-diisopropylcarboxamide-3-(trifluoromethylsulfonate)-6-fluoro-androst-3.5-diene

To a solution of the epimers of 3-oxo-6-fluoro-4-androstene-17)8-N,N-diisopropylcarboxamide (1.4 g) in 50 ml of dry dichloromethane was added 2,6-di-t-butyl- 4-methylpyridine (850 mg), followed by trifluoromethanesulfonic anhydride (0.75 mL) under argon. The resulting solution was stirred at room temperature under argon for 3 hours. The solvent was then removed under reduced pressure. The residue was redissolved in ethyl acetate, which in turn was washed with cold dilute hydrochloric acid, water, brine, dried over anhydrous magnesium sulfate and evaporated to an oil. Column chromatography (silica gel, 10% ethyl acetate in hexane) gave 17Æ-N,N-diisopropylcarboxamide-3-(trifluoromethylsulfonate)-6-fluoro-androst-3,5-diene and 17/3-N,N-diisopropylcarboxamide- 3-(Trifluoromethylsulfonate)-6-Fluoro-androst-2,4-diene.

(v) Etyl 17/3-N,N-diisopropvlcarboxamide-6-fluoro-androst-3,5-diene-3-carboxylate

A mixture of 17/S-N,N-diisopropylcarboxamide-3-(trifluoromethylsulfonate)-6-fluoro-androst-3,5-diene (250 mg), triethylamine (0.12 mL), ethanol (1.5 ml), N,N-dimethylformamide (2 ml) and bis(triphenylphosphine)palladium(II) acetate (25 mg) were purified by flowing through with carbon monoxide for 10 minutes. The reaction mixture was stirred under 1 atmosphere of carbon monoxide at room temperature overnight and then diluted with ethyl acetate. The ethyl acetate solution was then washed with cold dilute hydrochloric acid, water, brine, dried over anhydrous magnesium sulfate and concentrated to dryness. Silica gel column chromatography and elution with 10% ethyl acetate in hexane gave 108 mg of ethyl 17Æ-N,N-diisopropylcarboxamide-6-fluoro-androst-3,5-diene-3-carboxylate (55%).

(vi) 17/ 3-N,N-diisopropylcarboxamide-6-fluoroandrost-3,5-diene-3-carboxylic acid

Said compound was prepared according to example 2 (viii) by substituting 3-carbomethoxy-3-androstene-17Æ-N,N-diisopropylcarboxamide with ethyl 17Æ-N,N-diisopropylcarboxamide-6-fluoro-androst-3,5-diene- 3-carboxylate. The product had a melting point of 225-226°C (recrystallized from acetonitrile).

Example 15

N- t- butyl androst- 3. 5- diene- 17/ 3-carboxamide- 3- carboxylic acid

(i) Androst-4-en-3-one-17/3-N-t-butyl-carboxamide

Said compound was prepared according to example 3 (ii) by using tert-butylamine instead of diisopropylamine.

(ii) ' 17/ 3-( N- t-butylcarboxamide)-3-( trifluoromethylsulfonate)- androst- 3 r 5-diene

Said compound was prepared in 45% yield in accordance with Example 3 (iii) by using androst-4-en-3-one-17/3-N-t-butylcarboxamide instead of androst 4-en-3-one- 17/3-N,N-diisopropylcarboxamide .

(iii) 3-carbomethoxyandrost-3,5-diene-17/3-N-t-butylcarboxamide

Said compound was prepared according to Example 3 (iv) by using 175-(N-t-butylcarboxamide)-3-(trifluoromethylsulfonate)-androst-3,5-diene instead of 17/3-(N,N-diisopropylcarboxamide)-3 -(trifluoromethylsulfonate)-androst-3,5-diene.

(iv) N-t-butyl androst-3.5-diene-17/3-carboxamide-3-carboxylic acid

Said compound was prepared according to example 3 (v) by using 3-carbomethoxyandrost-3,5-diene-17Æ-N-t-butylcarboxamide in place of 3-carbomethoxyandrost-3,5-diene-17/3-N,N -diisopropylcarboxamide. Said compound was recrystallized from acetonitrile, m.p. 247-250°C.

Example 15A

N- t-butvl androst- 3. 5- diene- 17fl-carboxamide- 3- carboxylic acid

(i) N-t-butyl androst-3,5-diene-3-bromo-17/3-carboxamide

To an ice-cooled solution of 3-oxo-androst-4-ene-17-carboxylic acid (10 g, 30 mmol) in toluene (100 mL) was added a solution of oxalyl bromide (24.2 g, 11 mL, 112 mmol) in toluene (100 ml). The reaction mixture was warmed to room temperature until gas evolution stopped.

Excess oxalys bromide was evaporated at room temperature, and the remaining androst-3,5-diene-3-bromo-17/?-acid bromide in toluene solution was cooled with ice. T-butylamine (40 mL) in toluene (70 mL) was added slowly and the mixture was stirred for 19 h.

The reaction mixture was diluted with water (200 mL) and toluene (100 mL). The organically soluble material was separated and washed with water (2 x 250 mL), dried over magnesium sulfate and evaporated. The oil/solid residue was flash chromatographed on silica gel, flash grade, eluting with 5:1 hexane:ethyl acetate to give 5.5 g of a white solid, m.p. 174-77°C (40.3%).

(ii) N- t- butyl- androst- 3. 5- diene-17/ 3- carboxamide- 3- carboxylic acid

N-butyllithium (2.5 M in hexane, 90 mL, 225 mmol) was added over 20 minutes to a solution of androst-3,5-diene-3-bromo-17/3-N-t-butylcarboxamide (25 g, 57 .7 mmol) in dry tetrahydrofuran (650 ml) cooled to -64°C. After 2.5 h, the reaction mixture was quenched with dry CO for 1 h, diluted with toluene (500 mL), 10% hydrochloric acid solution (100 mL) and water (500 mL). The organically soluble extract was separated from, washed with water (2 x 300 ml), dried over magnesium sulfate and evaporated. The crude, off-white solid was recrystallized from ethyl acetate to give 3.5 g of a white solid, m.p. 242-49°C.

Example 15B

N- t-butvl androst- 3, 5- diene- 3- bromo- 17/ 3-carboxamide- 3- carboxylic acid

(i) Methyl androst-3,5-diene-3-bromo-17fl-carboxylate

Methyl androst-4-ene-17/3-carboxylate (100 g, 316 mmol) was dissolved in glacial acetic acid (500 mL), and phosphorus tribromide (119 g, 80 mL, 440 mmol) was added over 15 minutes. After stirring at room temperature for 2 hours, the yellow precipitate formed was filtered off, washed with methanol (400 mL) and dried in vacuo to give 97.6 g (81.4%) of a white solid, m.p. 178-180°C.

(ii) Androst- 3, 5- diene- 3- bromo- 17/ 3- carboxylic acid

A solution of potassium hydroxide (50 g, 890 mmol) in 9:1 methanol:water (500 mL) was added to a slurry of methyl androst-3,5-diene-3-bromo-17Æ-carboxylate. After refluxing for 41 hours, the resulting yellow solution was cooled and brought to pH 4 using 10% hydrochloric acid solution. The white solid that formed was filtered off and washed with water. After drying in vacuum at 40°C, 49 g (100%) of the product were obtained, m.p. 248-250°C.

(iii) N-t-butyl androst-3.5-diene-3-bromo-17B-carboxamide

Oxalyl chloride (17 mL, 190 mmol) was added to a cooled mixture of androst-3,5-dien-3-bromo-175-carboxylic acid (30 g, 79 mmol) in dry toluene (300 mL) over 14 min. The reaction mixture was stirred at room temperature until gas evolution stopped (approximately 1.5 hours).

Excess oxalyl chloride was removed by concentration in vacuo at room temperature. The reaction mixture was cooled with ice and t-butylamine (102 mL, 954 mmol) was added over 10 minutes. The reaction mixture was stirred at room temperature for 1.5 hours.

The mixture was diluted with water (300 ml) and toluene (50 ml). The organic layer was separated, washed with water (2 x 300 ml), dried over magnesium sulfate and evaporated. The resulting pale yellow solid was stirred to a slurry first in methanol:water (7:3, 200 mL) then in acetonitrile:water (39:11, 300 mL). After filtration and drying in vacuo, 33.2 g (77.5%) of a white solid product was obtained.

(iv) N-t-butvl androst-3.5-diene-17fl-carboxamide-3- carboxylic acid

N-butyllithium (2.5 M in hexane, 90 mL, 225 mmol) was added

over 20 minutes to a solution of androst-3,5-dien-3-bromo-17-N-t-butylcarboxamide (25 g, 57.7 mmol) in dry tetrahydrofuran (650 mL) cooled to -64°C. After 2.5 hours, the reaction mixture was quenched with dry CO for one hour, diluted with toluene (500 mL), 10% hydrochloric acid solution (100 mL) and water (500 mL). The organically soluble extract was separated, washed with water (2 x 300 ml), dried over magnesium sulfate and evaporated. The crude, off-white solid was recrystallized from ethyl acetate to give 3.5 g of a white solid, m.p. 242-49°C.

Example 15C

N, N- diisopropvl- androst- 3, 5- diene 17/ 3- carboxamide- 3- carboxylic acid

Said compound was prepared by substituting t-butylamine in the procedure in Example 28B with diisopropylamine.

Example 15D

Androst- 3, 5-diene- 3- methoxycarbonyl-17/ 3- t-butylcarboxamide

A mixture of N-t-butyl androst-3,5-dien-3-bromo-17Æ-carboxamide (42 mg), prepared as in Example 28B, palladium(II) acetate (20 mg), triphenylphosphine (40 mg), methanol (5 ml), dimethylformamide (5 ml) and triethylamide (3 ml) were heated at 85-95°C under a carbon monoxide atmosphere until the starting material had disappeared. Said compound was isolated by flash chromatography on silica gel with 6:1 hexane:ethyl acetate.

Example 15E

Androst- 3, 5-diene- 3- methoxycarbonyl-170- N, N- diisopropylcarboxamide

Said compound is prepared according to example 28D by substituting N-t-butylamine with N,N-diisopropylamine.

Example 16

N,N-diisopropvl-5-a-androst-2-ene

17fl- carboxamide- 3- carboxylic acid

(i) 176 -( N.N- diisopropylcarboxamide)- 3-( tri-fluoromethylsulfonate)- 5a- androst- 2- one

Said compound was prepared according to example 4 (vii) by using 3-oxo-5a-androstane-17/3-N,N-diisopropylcarboxamide instead of 3-oxo-4-fluoro-5a-androst-1-ene- 17/3-N,N-diisopropylcarboxamide .

(ii) 3- carbomethoxy- 5a- androst- 2- en- 17fl- N, N-diisopropvlcarboxamide

Said compound was prepared according to Example 3 (iv) by using 17/3-(N,N-diisopropylcarboxamide)-3-(trifluoromethylsulfonate)-5a-androst-2-ene in place of 17/3-(N, N-diisopropylcarboxamide)-3-(trifluoromethylsulfonate)androst-3,5-diene.

(iii) N. N- diisopropvl 5a- androst- 2- en- 17fi carboxamide- 3- carboxylic acid

Said compound was prepared according to Example 3 (v) by using 3-carbomethoxy-5a-androst-2-ene-17/3-N,N-diisopropylcarboxamide in place of 3-carbomethoxyandrost-3,5-diene-17/3 -N,N-diisopropylcarboxamide. Said compound was recrystallized from acetonitrile; sp. 203-205°C.

Example 17

N. N- diisopropvl androst- 2. 4- diene- 17fl-carboxamide- 3- carboxylic acid (i) 17 B -( N, N- diisopropylcarboxamide)- 3-( trifluoromethylsulfonate) androst- 2. 4- diene The said compound was prepared according to example 4 (vii) by using 3-oxoandrost-4-ene-17/3-N,N-diisopropylcarboxamide instead of 3-oxo-4-fluoro-5-a-androst-1-ene-17Æ-N ,N-diisopropylcarboxamide. Said compound was recrystallized from methanol; sp. 165-168°C. (ii) 3- carbomethoxyandrost- 2. 4- diene- 17fl- N. N-diisopropvlcarboxamide

Said compound was prepared according to Example 3 (iv) by using 175-(N,N-diisopropylcarboxamide)-3-(trifluoromethylsulfonate)-androst-2,4-diene in place of 11B-(N,N-diisopropylcarboxamide)-3 -(trifluoromethylsulfonate)-androst-3,5-diene. Said compound had a melting point of 162°C after trituration with methanol.

(iii) N. N- diisopropvl androst- 2. 4- diene- 17fl-carboxamide- 3- carboxylic acid

Said compound was prepared according to example 3 (v) by using 3-carbomethoxy-androst-2,4-diene-17/3-N,N-diisopropylcarboxamide in place of 3-carbomethoxy-androst-3,5-diene-17 /3-N,N-diisopropylcarboxamide. Said compound was recrystallized from methanol-acetone; sp. 227°C.

Example 18

N,N- diisopropyl 5- o:- androstane- 17g-carboxamide- 3lf- carboxylic acid

(i) 3/ 3- carbomethoxysv- 5o;- androstane- 17g- N. N-di isopropylcarboxamide

3-Carbomethoxy-5-α-androst-2-ene-17Æ-N,N-diisopropylcarboxamide (87 mg, 0.19 mmol) (Example 29 (ii)) in 15 ml of a 10:1 solution of ethyl acetate and acetic acid was hydrogenated at 25°C and 1 atm over 20 mg of 10% Pd on carbon. The solution was filtered to remove the catalyst and concentrated to yield 77 mg (88%) of the title compound.

(ii) N,N-diisopropyl 5-a-androstane-17i8-carboxamide-3B-carboxylic acid

Said compound was prepared according to example 3 (v) by using 3Æ-carbomethoxy-5-a-androstane-17Æ-N,N-diisopropylcarboxamide in place of 3-carbomethoxyandrost-3,5-diene-17/3-N,N -diisopropylcarboxamide. The title compound was recrystallized from acetonitrile; sp. 142-144°C.

Example 19

N, N- diisopropyl ester- 3, 5( 10)- diene-17/ 3- carboxamide- 3- carboxylic acid

(i) 3- methoxy- ester- l. 3. 5( 10), 16- tetraene- 17-N, N- diisopropylcarboxamide

Said compound was prepared according to the two steps in example 3 (iii, iv) by using methylestrone instead of androst-4-en-3-one-17Æ-N,N-diisopropylcarboxamide and diisopropylamine instead of methanol.

(ii) 3-Methoxy-estr-1. 3, 5(10)-triene-17/3-N.N-diisopropylcarboxamide

3-Methoxy-ester-1,3,5(10),16-tetraene-17-N,N-diisopropylcarboxamide (4.45 g, 11.3 mmol) in 100 mL of a 3:1 solution of ethyl acetate and ethanol was hydrogenated at 25°C and 1 atm. over PtO 2 (350 mg) for 6 h. The solution was filtered to remove the catalyst and concentrated to give 4.36 g (98%) of the title compound.

(iii) 3-oxo-ester-5(10)-ene-17fl-N,N-diisopropylcarboxamide

To a solution of 3-methoxyestr-1,3,5(10)-triene-17/3-N,N-diisopropylcarboxamide (1.4 g, 3.5 mmol) in liquid ammonia (25 mL), THF (10 ml) and t-butanol (10 ml) at -33°C was added 0.5 g of lithium wire. The solution was stirred for 5 h, and then methanol (10 mL) was slowly added. The ammonia was allowed to evaporate and the residue was then partitioned between water and chloroform. The organic phase was concentrated to a white solid which was suspended in a methanol/water mixture and then treated with 1.4 F oxalic acid for 1.5 hours. The reaction mixture was then diluted with water and extracted with ethyl acetate. The organic phase was concentrated and the residue chromatographed (silica, 1:9 ethyl acetate-hexane), so that the result was 0.4 g of the mentioned compound.

(iv) N,N-diisopropyl ester-3,5(10)-diene 17jS-carboxamide-3-carboxylic acid

Said compound was prepared according to example 29 (i-iii) by using 3-oxoestr-5(10)-ene-17Æ-N,N-diisopropylcarboxamide in place of 3-oxo-5-a-androstane-17Æ-N, N-diisopropylcarboxamide. The title compound was recrystallized from acetonitrile; sp. 250-253°C.

Example 20

N. N- diisopropyl ester- 3. 5- diene- 17fi- carboxamide- 3- carboxylic acid (i) 3- oxoestr- 4- ene- 17if- N, N- diisopropyl carboxamide 3-oxoestr-5(10)-ene- 175-N,N-diisopropylcarboxamide (Example 29 (iii)) was dissolved in methanol and 10% aqueous HCl (2:1) and heated at 65°C for 1 hour, cooled and extensively extracted with chloroform. The organic extracts were concentrated to give the title compound as a white solid.

(ii) N.N-diisopropyl ester-3.5-diene-17/3-carboxamide-3-carboxylic acid

Said compound was prepared according to example 3 (iii-v) by using 3-oxo-estr-4-ene-17/3-N,N-diisopropylcarboxamide instead of androst-4-en-3-one-17Æ-N ,N-diisopropylcarboxamide. The said compound had a melting point of 215°C

Example 21

17/ 3- ( N. N- diisopropylcarboxamide) - androst-3. 5. ll-triene-lf-carboxylic acid

(i) Androst-4-en-3-one-11-ol-117/3-carboxylic acid

Corticosterone is dissolved in methanol and treated with an aqueous solution of periodic acid at room temperature for 18 hours. The solution is then diluted with water, so that androst-4-en-3-one-11-ol-17/3-carboxylic acid precipitates out and is collected by filtration.

(ii) Androst- 4- en- 3 . ll- dione- 17j3- carboxylic acid

Jones reagent is added dropwise to a solution of androst-4-en-3-one-11-ol-17fi-carboxylic acid in acetone until the red color remains. Isopropanol is then added to suppress the excess of oxidizing agent. The solution is decanted, and the resulting chromium salts are washed thoroughly with acetone. The combined organic solutions are then filtered through magnesium sulfate and concentrated to give androst-4-ene-3,11-dione-17/3-carboxylic acid.

(iii) Androst-4-ene-3,11-dione-17/3-N,N-diisopropylcarboxamide

The aforementioned compound is prepared according to example 3 (ii) by substituting androst-4-en-3-one-17/3-carboxylic acid with androst-4-ene-3,11-dione-17/3-carboxylic acid.

(iv) 170- fN. N-diisopropylcarboxamide)-3-(trifluoromethylsulfonate)-11-oxo-androst-3f5-diene

The aforementioned compound is prepared according to example 3 (iii) by substituting androst-4-en-3-one-17Æ-(N,N-diisopropylcarboxamide) with androst-4-en-3,11-dione-17Æ-(N,N -diisopropylcarboxamide).

(v) 3-carbomethoxy-ll-oxo-androst-3.5-diene 170-(N.N-diisopropvlcarboxamide)

The aforementioned compound is prepared according to example 3 (iv) by substituting 170-(N,N-diisopropylcarboxamide)-3-(trifluoromethylsulfonate)-androst-3,5-diene with 170-(N,N-diisopropylcarboxamide) - 3-(Trifluoromethylsulfonate)-11-oxo-androst-3,5-diene.

(vi) 3- carbomethoxy- 11- f trifluoromethyl-sulfonate)- androst- 3, 5. ll- triene- 170-( N. N- diisopropylcarboxamide)

The aforementioned compound is prepared according to example 4 (vi) by substituting 3-oxo-4-fluoro-5a-androst-1-ene-170-(N,N-diisopropylcarboxamide) with 3-carbomethoxy-11-oxo-androst-3 ,5-diene-17fl-(N,N-diisopropylcarboxamide) .

(vii) 3- carbomethoxy- androst- 3. 5. 11- triene 170-( N, N- diisopropylcarboxamide)

The aforementioned compound is prepared according to the method of Cacchi ( Tet. Lett. 25 (42) 4821-4824 (1984) by substituting 170-acetoxyandrosta-3,5-dien-3-yl triflate with 3-carbomethoxy-1-(trifluoromethylsulf onate)-androst-3,5,11-triene-170-(N,N-diisopropylcarboxamide) .

(viii) 170-(N,N-diisopropylcarboxamide)-androst-3.5.ll-triene-3-carboxylic acid

The aforementioned compound is prepared according to example 3 (v) by substituting 3-carbomethoxy-androst-3,5-diene-170-(N,N-diisopropylcarboxamide) with 3-carbomethoxy-androst-3,5,11-trien-170 -(N,N-diisopropylcarboxamide).

Examples 22 and 23

The following compound is prepared by substituting diisopropylamine for t-butylamine using the procedure in Examples 2, 3, 4, 7, 14, 16, 17, 18, 19 and 20 respectively:

N-t-butyl-5-α-androst-3-ene-170-carboxamide-3-carboxylic acid;

Claims (2)

1. Analogy method for the preparation of therapeutically active compounds of the formula: where R<1> is hydrogen or C1-8 alkyl; and M is oxygen or sulfur, R<2> is missing or present as hydrogen or methyl, provided that a 1,10-double bond is present when R2 is missing. X is hydrogen, chlorine, fluorine, bromine, iodine, trifluoromethyl, or C 1-6 alkyl; Y is hydrogen, trifluoromethyl, fluorine or chlorine, methyl, provided that Y is hydrogen when there is no C5-C6 double bond; and R<14> is (1) α-hydrogen, α-hydroxyl or α-acetoxy and 15 R is (a) where W is a bond or C1-12 alkyl and R<4> is (i) hydrogen, (ii) hydroxyl, (iii) C1-6 alkyl, (iv) hydroxy C1-6 alkyl, (v) C1- s-Alkoxy, (vi) NR5R<6>, where R<5> and R<6> are both independently selected from hydrogen, C1-6-alkyl, C3-6-cycloalkyl, phenyl; or (vii) OR<7>, where R<7> is hydrogen, alkali metal, C1-10-alkyl, benzyl, or (b) Æ-Alk-OR8, where Alk is C1-12-alkyl, and R<8 > is (i) phenyl C 1-8 -alkylcarbonyl, (ii) C 5-10 -cycloalkylcarbonyl, (iii) benzoyl, (iv) C 1-8 -alkylcarbonyl, (v) amino- or C 1-8 -alkyl-substituted amino, carbonyl , (vi) hydrogen, or (vii) C 1-6 alkyl, (2) =CH-Alk-CO-R<4> or =CH-Alk-OR<8>, where Alk is present or absent, and R <4> and R<8> have the same meaning as above, and R<8> is also hydrogen or C 10 -alkylcarbonyl; (4) a-hydrogen and fi-NHCOR9 where R<9> is C^^-alkyl or Æ-NR5R6 where R<5> and R<6> have the same meaning as above, (5) a-hydrogen and Ø- cyano, characterized by treating a compound with the formula: where R2, R1<4>, X and Y are as defined above, X<1> is bromine, chlorine, fluorine or iodine; with an alkyllithium reagent, followed by a carboxylating agent such as diethyl carbonate, ethyl chloroformate or preferably carbon dioxide, or optionally with a palladium catalyst in the presence of base and a C 1 alkanol. 2. Method according to claim 1, in the preparation of N-t-butyl-androst-3,5-diene-17/3-carboxamide-3-carboxylic acid or N,N-diisopropyl-androst-3,5-diene-17Æ-carboxamide- 3-carboxylic acid, characterized by using correspondingly substituted starting materials.