NZ235818A - 3-halogenated steroid 3,5-dienes - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number £35818 2358 1 Priority Date(s):.£:\ . V* £ .1.. 1 Xr..^.1. 1 Complete Specification BSecf: Class: {5)£Q:i?.\h?r.Cf.AiSfe.<&/f.V.

Gskte,. r.?. & J .te.uyJk.% .<&:fc Publication Date: ... p«Q. Journal, No: r 'JUN1992 fisEL.

NO DRAWINGS Under the o provisions of Re ru- ^tion 23 n; IPC- ,<^?y Divided out of: No.: 224,377 £>ate; 26th April 1988 NEW ZEALAND PATENTS ACT, J 95 3 Gpivcil.caiic.'"; I'-sen to !7.'. 19$L K). AsLa .

Initial COMPLETE SPECIFICATION new zealand patent office j 2 4 OCT 1990 RECEIVED "W "STEROID 5-o(,-REDUCTASE INHIBITORS" P9 We, SMITHKLINE BECKMAN CORPORATION, a corporation organized under the laws of the Commonwealth of Pennsyvania, U.S.A., of One Franklin Plaza, Philadelphia, Pennsylvania 19103, U.S.A., hereby declare the invention for whichxfc/ we pray that a patent may be granted to jusk/us, and the method by which it is to be performed, to be particularly described in and by the following statement:- (Followed by page la) 235 8 18 235318 - 1A -TITLE STEROID 5-oL-REDUCTASE INHIBITORS FIELD OF THE INVENTION This application is divisional to New Zealand Patent Application No. 224,377.

The present invention and that of New Zealand Patent Application No. 224,377 (hereinafter referred to as 'that invention') relate to certain novel substituted acrylate analogues of steroidal synthetic compounds, pharmaceutical compositions containing these compounds, and methods for using these compounds to inhibit mammalian steroid 5-a-reductase.

DESCRIPTION OF RELATED ART The class of steroidal hormones known as androgens is responsible for the physical characteristics that differentiate males from females. Of the several organs that produce androgens, the testes produce these hormones in the greatest amounts. Centers in the brain exert primary control over the level of androgen production. Numerous physical manifestations and disease states result when ineffective production control results in excessive androgen hormone production. For example, acne vulgaris, seborrhea, female hirsutism, and benign 235318 prostatic hypertrophy are correlated with elevated androgen levels. Additionally, the incidence of male pattern baldness has been associated with high androgen levels.

Testosterone is the principal androgen secreted by the testes and is the primary androgenic steroid in the plasma of males. It now is known that 5—a-reduced androgens are the active hormones in some tissues such as the prostate and sebaceous gland. Circulating testosterone thus serves as a prohormone for dihydrotestosterone (DHT), its 5-a-reduced analogue in these tissues but not in others such as muscle and testis. Steroid 5-a-reductase is a NADPH-dependent enzyme that converts testosterone to DHT. The importance 0f this enzyme in male development was dramatically underscored by discovery of a genetic steroid 5-a-reductase deficiency in male pseudohermaphrodites. Imperato-McGinley, J., et al., (1979), J. Steroid Biochem. 11:637-648.

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

Table 1 -a-Reductase Inhibitors (1) t fooh K^l .1x10-6M Hsia and Voight (Reversible) 1973 Table 1 (Continued) 235 8 18 1x10~"6M Robaire, et al. , (Irreversible) 1977 (3) oh 3.5x10 8 Blohm, et al. , (Irreversible) 1980 <4) 5xl0~9M (Reversible) Liang, et al, 1983 (5) 1.25x10 6M Petrow, et al■, (Irreversible) 1981 ZO D J 1 x The first inhibitor described was the 17-B-carboxylic acid (1) by Hsia and Voight in 1973. J. Invest. Dermat. £2:224-227. The secosteroid (2) was the next inhibitor to be described and also has found ^ utility as an affinity label for 5-a-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-a-reductase. Blohm, T. R., et. al. (1980), Biochem. Biophys. Res ■ Comm. £5:273-280; United States Patent 4,317,817, March 2, 1982. Compound (4) is exemplary of a group of 4-aza steroid inhibitors of steroid 5-a-reductase described in United States Patent 4,377,584 which issued March 22, 1983, and in Liang, T., et al. (1983), J. Steroid Biochem. 19, 385-390. The 6-methylene steroid (5) also has been shown to be a time-dependent inactivator of steroid 5-a-reductase. Petrow, V, , et. al. (1981), Steroids 38:121-140.

Other steroid 5-a-reductase inhibitors also have been described. United States Patent 4,361,578 which issued June 2, 1986, describes a class of homosteroid enzyme inhibitors. United States Patent 4,191,759 discloses amides of 17B-carboxy-4-androsten-3-one that are active as steroid 5-a-reductase inhibitors. Japanese Patents J60146855-A and J60116657-A disclose various aniline derivatives having numerous activities including 5-a-reductase inhibiting activity. Japanese Patent I60142941-A discloses phenyl-substituted ketones having 5-a-reductase inhibiting activity and European Patent 3 0 EP173516-A discloses various phenyl-substituted amides having similar activity. Shiseido referenced terpene derivatives that are active inhibitors of steroid 5-a-reductase. Japanese Patent No. J59053417-A. r i .23 f) 818 ~-5- Palladium-catalyzed carbonylation of substituted androstene derivatives has been described. Cacchi, S., et al., (1985), Tet. Letters 26:1109-1112. No biological activity for the synthesized compounds, however, is disclosed.

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

Use of phosphorous tridhalides to convert A steroidal A -3-ketones to corresponding 3-halo-3,5-dienes has been reported. Ross, J.A. and M.D. Martz, J. Org. Chem. (1964) 29:2784-2785.

SUMMARY OF THE INVENTION This and/or that invention resides in the discovery that steroid 5-a-reductase is inhibited by certain substituted acrylate analogues of steroidal synthetic compounds. The compounds are potent enzyme inhibitors.

This invention relates to novel intermediates and processes for preparing them, useful in preparing the 5-ctr reductase inhibiting compounds of the invention of New Zealand Patent Application No. 224,377.

The compounds of this invention are compounds of the formula in which ,1 .= V V ft \ 1 °cr 199j " w ! V X is bromo, chloro, fluoro, or iodo; 2 R is absent or present as H or CH3" f 1 V-\T7 rro \ 235818 - 5a - Xis H, CI, F, Br, I, CF3, or C^aUcyl; and Y is H, CF3, F, or CI, CH3; R14 is (1) a-hydrogen, a-hydroxyl, or acetoxy and/or (a) 0 B-W-tl-R4 where W is a bond or 4 C1_12alkyl, and R is (i) hydrogen, (ii) hydroxyl, (iii) C]L_8alkyl, (iv) hydroxy C1_galkyl, (v) C1_galkoxy, (vi) NR R6, where R5 and R6 are each independently selected from hydrogen, Ci_g-aflkyl, C-^cycloalkyl, 6 phenyl; or R and R taken together with the nitrogen to which they are attached represent a 5-6 membered saturated ring comprising up to one other heteroatom selected from oxygen and nitrogen, or 7 7 (vii) OR , where R is hydrogen, alkali metal, C1_lgalkyl, benzyl, or (b) B-Alk-OR8, where Alk is g C1_12alkyl, and R is (i) phenylC1_galkylcarbonyl, (ii) C5_1Qcycloalkylcarbonyl, (iii) benzoyl, (iv) C1_galkoxycarbonyl, (v) amino, or C^alkyl i '2lQCT]<)r substituted amino, carbonyl, 2 3 5 <j 18 -5b- (vi) hydrogen, or (vii) C1_8alkyl, (2) =CH-Alk-CO-R4 or =CH-Alk-OR8, where Alk is present or absent, and 4 8 R and R have the same meaning as g above and R also is hydrogen or Ci_2Qalkylcarbonyl; (3) o where the dashed bond replaces the 17-a-hydrogen, 9 9 (4) a—hydrogen and B—NHCOR where R is alkyl or B-NR^R6 where 6 R and R have the same meaning as above, (5) a-hydrogen and B-cyano, (6) a-hydrogen and B—tetrazolyl, or (7) keto; or moieties which can be chemically converted to moieties.

£ N f > ' (1) through (7), except compounds in which: 1 14 '-'-J X is CI and R is CH3CO; ofl XI is CI and R14 is ^-OH and \\ 14 MO^'1991 " oi-CH3C02; and •• r „ ^... •( X^" is Br and R^4 is ft -OH and c^-CH3C02.

A preferred compound of this invention is N-t-butyl androst-3,5-diene-3-bromo-17 -carboxamide or N,N-disopropyl-androst-3,5-diene-3-bromo-17 -carboxamide. - 5c - 235818 Presently preferred compounds of the invention and compounds used in the invented pharmaceutical compositions and the invented methods include: 2 0-a-(hydroxymethy1)-5-a-pr egn-3-ene-3-carboxylic acid, N,N-diisopropyl-5-a-androst-3-ene-17G-carboxamide-3-carboxylic acid, N,N-diisopropyl-androst-3,5-diene-17B-carboxamide-3-carboxylic acid, 17B-(N,N-diisopropylcarboxamide)-4-fluoro-5-a-androst-3-ene-3-carboxylic acid, -a-(hydroxymethy1)-4-fluoro-5-a-pregn-3-ene-3-carboxylic acid, -a-(hydroxymethyl)-A-nor-5-a-pregn-l-ene-2-carboxylic acid, :3GH0V?99Q' 2358 18 17fl-N,N-diisopropylcarboxamide-5-a-androst-l,3-diene-3-carboxylic acid, N-t-Butyl Androst-3,5-diene-17B-carboxamide-3-carboxylic acid, N,N-Diisopropyl 5-a-Androst-2-ene-17B-carboxamide-3-carboxylic acid, N,N-Diisopropyl Androst-2,4,-diene-17B-carboxamide-3-carboxylic acid, N,N-Diisopropyl 5-a-Androstane-17B-carboxamide-3B-carboxylic acid, N,N-Diisopropyl Estr-3,5(10)-diene-17B-carboxamide-3-carboxylic acid, N,N-Diisopropyl Estr-3,5-diene-17B-carboxaraide-3-carboxylic acid, 17B-(N,N-Diisopropylcarboxamide)-androst-3,5,11-triene-3-carboxylic acid, 17B-(N,N-Diisopropylcarboxamide)-androst-3,5-dien.e-3-thiocarboxylic acid, 17B-(N-t-Butylcarboxamide)-androst-3,5,ll-triene-3-carboxylic acid, and 176-(N-t-Butylcarboxamide)-androst-3,5-diene-3-thiocarboxylic acid.

In a further aspect of this and/or that invention there are provided novel intermediates and novel processes useful in preparing the presently invented 5-a-reductase inhibiting compounds.

That invention also is a method for inhibiting 5-a-reductase activity in mammals, including humans, that comprises administering to a subject in need thereof an effective amount of a presently invented 5-a-reductase inhibiting compound.

Included in that invention are pharmaceutical compositions comprising a pharmaceutical • carrier and compounds useful in the methods of the invention. 23 5 3 18 ■■ 1 DETAILED DESCRIPTION OF THE INVENTION The compounds of that invention that inhibit -a-reductase have the following Formula (I): .3 (i) in which: The A ring has up to 2 double bonds; The B, C, and D rings have optional double bonds where indicated by the broken lines, provided that the C ring does not have a Cg-C^double 15 bond when the B ring has a C7~Cg double bond; M is O or S; Z is (CH2^n an<^ n 0-2' X is H, CI, F, Br, I, CF3, or C1_galkyl; Y is H, CF3, F, or CI, CH3, provided that Y is H when there is no C--C,. double bond; , 5 6 R is H or Cn Qalkyl; 2 - R is absent or present as H or CH_, provided 2 . .

R is absent when the carbon to which it is attached is double bonded; R10 is absent when there is a C^-C^, Ce-C.., or Cc-C, _ double bond; D6 5 10 or present as an alpha hydrogen, and R3 is (1) a-hydrogen, a-hydroxyl, or a-acetoxy and/or (a) O H 4 B-W-C-R 3 5 and R4 where W is a bond or C^^alkyl is (i) hydrogen, (ii) hydroxyl, 23 5 3 1 (iii) C1_8alkyX, 23 5 8 (iv) hydroxy C-^alkyl, (v) C1_8allcoxy/ (vi) B-NR5R6, where R5 and R6 are each independently selected from hydrogen, C. Q- i. ~*Q alkyl, C3_gcycloalkyl, phenyl; or R5 and R6 taken together with the nitrogen to which they are attached represent a 5-6 membered saturated ring comprising up to one other heteroatom selected from oxygen and nitrogen, or 7 7 (vii) OR , where R is hydrogen, alkali metal, C1_18alkyl, benzyl, or (b) 6-Alk-OR8, where Alk is o C1_12alkyl, and R is (i) • phenylC1_6alkylcarbonyl, (ii) C5_1Qcycloalkylcarbonyl, (iii) benzoyl, (iv) C1_8alkoxycarbonyl, (v) amino, or C1_8alkyl substituted amino, carbonyl, (vi) hydrogen, or (vii) C, nalkyl, 4 8 =CH—W—CO—R or =CH-W-OR , where W 4 is a bond or C1_12alkyl, and R and R8 have the same meaning as o above and R also is hydrogen or Ci_20a.lkylcarbonyl; 23 5 8 18 ^ • 1 (3) where the dashed bond replaces the 17-a-hydrogen, 9 9 (4) a-hydrogen and B-NHCOR where R is C1_12alkyl or B-NR5R6 where R^ and R^ have the same meaning as above, (5) a-hydrogen. and B-cyano, (6) a-hydrogen and B-tetrazolyl, or (7) keto; or a pharmaceutically acceptable salt thereof; except compounds in which: The B ring has C_-C. and Cc-Cc double 3 4.56 bonds, R is CH^, and R is keto; The B ring has C_-C., Cc-Cc, and _. o ^ y b o Clg-C17 double bonds, R is CH3, and R is COOCH_; and . 1 The B ring has a C.--C-. double bond, R is O Do CH3, and RJ is COCH3.

As used herein, unless otherwise specified, C, „,alkyl and C1 ,alk means a straight or branched l—n l—n hydrocarbon chain having 1 to n' carbons and Alk means a straight or branched hydrocarbon chain having 1 to 12 carbons.

Preferred among Formula (I) compounds are those 30 in which Z is -CH2~. 23 5 8 18 Also, preferred among the compounds of that invention are those having Formula (II): 0 X (II) in which: The A ring has up to 2 double bonds; The B and C rings have optional double bonds where indicated by the broken lines; H is O or S; X is H,'or halo, and R1 is H or C1_galkyl; R10 C„-C is absent when there is a C,-Cc, 4 5 or C5~C10 double bond, v6' or present as an alpha hydrogen, and _ 13 • R is (a) (b) 9 0 9 0 C(CH3)CH2OR wherein R^u is H or C1_galkyl, or CONR21R22 wherein R21 and R22 independently are H or C1_galkyl. Particularly preferred are Formula (II) compounds in which the A ring has a C3~C4 double bond.

Also preferred among the compounds of that invention are those having Formula (III): (III). 235318 1 2 13 in which R , R , R , and the B ring broken lines are as in Formula (II) and M is 0 or S.

Additionally, preferred among the compounds of that invention are those having Formula (IV): 3 |v\\ H (IV) 1 2 13 in which R , R , and R are as in Formula (II) and M is as in Formula (I).

■ Compounds of Formula (la) are included in the pharmaceutical compositions of that invention and used in the methods of invention. (la) in which: The A ring has up to 2 double bonds; The B, C, and D rings have optional double bonds where indicated by the broken lines, provided that the C ring does not have a Cg-C^ double bond when the B ring has a C^-CQ double bond; / O M is O or S; 2 is (CH^)n and n is 0-2; 23 5 8 1 8 X is H, CI, F, Br, I, CF3, or Chalky].; Y is H, CF^, F, or CI, CH3, provided that Y is H when there is no C,--C^ double bond; 1 5 6 R is H or C, Qalkyl; 2 .

R is absent or present as H or CH_, provided 1 R is absent when the carbon to which it is attached is double bonded; and R10 is absent when there is a C.-C-, 4 3 Cc-C-, or Cc-C._ double bond, 6 5 10 or present as an alpha hydrogen, and R3 is (1) a-hydrogen, a-hydroxyl, or a-acetoxy and/or (a) A 4 B-W-C-R where W is a bond or C1_12alkyl and R4 is (i) hydrogen, (ii) hydroxyl, (iii) C1_galkyl, (iv) hydroxy C1_8alkyl, (v) C1_8alkoxy, (vi) NR5R6, where R5 and R6 are each independently selected from hydrogen, C1_8~ alkyl, C_ -cycloalkyl, 6 phenyl; or R and R taken together with the nitrogen to which they are attached represent a 5—6 membered saturated ring comprising up to one other heteroatom selected from oxygen and nitrogen, or 2558 18 . -13- "7 7 1 (vii) OR , where R is hydrogen, alkali metal, C1_18alkyl, benzyl, or (b) B-Alk-OR8, where Alk is 5 C1_12alkyl, and R8 is (i) phenylC^galkylcarbonyl, (ii) C5_10cycloalkylcarbonyl, (iii) benzoyl, (iv) C1_salkoxycarbonyl, 10 (v) amino, or C1_8alkyl substituted amino, carbonyl, (vi) 'hydrogen, or (vii) C1_3alkyl, (2) =CH—W-CO—R4 or =CH-W-0R8, where W 4 is a bond or C1__12alkyl, and R and R8 have the same meaning as (3) o above and R also is hydrogen or C1_20alkylcarbonyl; where the dashed bond replaces the 25 17-a-hydrogen, 9 9 (4) a-hydrogen and B-NHCOR where R is C ^alkyl or G-NR5R5 where 5 6 R and R have the same meaning as above, (5) a-hydrogen and B-cyano, (6) a-hydrogen and B-tetrazolyl, or (7) keto; or a pharmaceutically acceptable salt thereof. 235 8 18 As used above and throughout the remainder of the specification and claims the carbons of the steriod nucleus are numbered and the rings and lettered as follows: Formula (la) compounds 'are prepared as shown in ,2 Schemes I through X wherein R and X are as defined in 14 3 Formula (la). R is R or moieties which can be chemically converted to those of R by known chemical reactions such as described in 2 J. Fried and J. Edwards, Organic Reactions in Steroid Chemistry, Pub: Van Nostrand Reinhold Company (1972) provided that R14 does not include any such moieties that render inoperative the Schemes I to X processes. As demonstrated in the 1 A *3 following Examples, reactions to convert R to R are performed on products of the synthetic pathways of Schemes I through IX or, where appropriate or preferable, on certain intermediates in these synthetic pathways.

SCHEME I 1) L1/NH3 & 2) rt-phenyltrifluoro-rrethylsulfoniraide (a) •15- cod a i g SCHEME I (Continued) rS-S triethylamine, triphenyIphosphine palladium (II) acetate C]__6alkOH, OD (b) C]__galkO 1) LiOH 2) HC1 (c) (d) 235 8 1 8 Scheme I depicts formation of Formula (la) compounds having a double bond at C^-C^, -X is H, and n is 1. The starting 4-ene-3-one compounds are known and readily available and are synthesized from available precursors using known procedures. According to Scheme I, a solution of a 4-ene-3-one compound (a) and a suitable organic proton donor such as t-butanol, or, preferably aniline in an appropriate organic solvent, preferably tetrahydrofuran (THF) are added to a reducing metal amine, preferably a lithium/ammonia (Li/NH^) solution, to form a reaction mixture. This reaction mixture is stirred at -100°C to -30°C, preferably -78°C, quenched with a lithium scavenger such as dibromoethane, bromobenzene, or, preferably isoprene, and evaporated to form a residue. Formula (b) compounds then are prepared by reacting the residue dissolved in a suitable organic solvent, preferably THF, with.an N-aryltrihaloalkylsulfonimide, preferably N-phenyltrifluoromethylsulfonimide at a temperature of -20°C to 20°C.

Formula (c) compounds are prepared by adding to a formula (b) compound dissolved in a suitable organic solvent such as dimethylformamide (DMF) an organic base such as timethylamine, or, preferably, triethylamine, a phosphine such as bis(diphenylphosphino)propane, or, preferably triphenyl phosphine, a palladium(II) compound such as palladium(II) chloride, or, preferably, palladium(II) acetate, and a C1_6alkyl alcohol (C1_galkOH), followed by addition of carbon monoxide (CO) . Addition of a strong base such as sodium hydroxide, potassium hydroxide, or, preferably, lithium hydroxide to a formula (c) compound dissolved in a suitable organic solvent such as THF and methanol followed by addition of strong acid, preferably, hydrochloric acid yields formula (d) compounds. -17-SCHEME II ^oo a i 8 1) 2,6-di-t-butyl-4-methylpyridine 2) trifluoramethane-sulfonic anhydride (a) y (f) triethvlamine, bis(triphenyl)-phosphine palladium (II) acetate C]__ga_LkOH, CD 23 5 8 1 8 ||P^ SCHEME II (Continued) (g) (h) 205818 Scheme II outlines synthesis of Formula (la) compounds wherein there is a C--C.. double bond and n Z> O is 1. The starting materials are the formula (a) 4-ene-3-one compounds from Scheme I. According to Scheme II, to a formula (a) compound dissolved in an appropriate organic solvent, preferably methylene chloride, is added 2, 6—di—t—butyl-4—methylpyr idine. A trihaloalkyl sulfonic anhydride, preferably trifluoromethane sulfonic anhydride then is added to yield formula (f) compounds. To formula (f) compounds dissolved in a suitable organic solvent such as DMF an organic base such as trimethylamine, or, preferably, triethylamine, a palladium(II) compound such as bis(diphenylphosphino)propane, palladium(II) acetate, or, preferably bis(triphenylphosphine)palladium(II) acetate, and a C1_6alkOH followed by addition of CO to give formula (g) compounds. Salts of formula (h) compounds then are prepared by hydrolyzing with a strong base such as sodium hydroxide, lithium hydroxide, potassium hydroxide, or, preferably, potassium carbonate the formula (g) ester compounds. Formula (h) free acids are prepared by treating the salts with a strong acid such as hydrochloric, sulfuric, or hydrobromic acids.

[THIS SPACE INTENTIONALLY LEFT BLANK] V SCHEME III 235 3 ,14 OI- 1J feBZl^lenvlchloW^ 2) H2O2 H (j) 1) 2) NaOH 0c) 23 5 8 1 $ SCHEME III (Continued) (1) 1) lithium bis (trixnethylsilyl) amide 2) phenyl tr if luorcsmthylsulfonirnide (m) triethylamine, tripheny Iphosphine palladium (II) acetate C_ alKCH, CO 1—6 (o) 2 3 5 8 1 Q ^ SCHEME III (Continued) ^ v W ■ O £d/carbon Hr O F 1) k2oo3 2) H+ (q) Cs) 235 8 18 1 Scheme III illustrates synthesis of Formula (la) compounds in which X is fluoro. The starting compounds are the 4-ene-3-one compounds (a) used in Schemes I and II. According to Scheme III, formula (a) compounds 5 dissolved in a suitable organic solvent such as THF and t-butyl alcohol are added to a metal amine solution, preferably a Li/NH^ solution, to form a reaction mixture which is cooled to -100°C to -30°C, preferably -78°C, and quenched with a lithium scavenger agent such as dibromoethane, bromobenzene, or, preferably, isoprene to ) . form an enolate. This enolate then is treated with a salt of a strong acid and base, preferably ammonium chloride (NH^Cl), to yield a formula (j) compound. Addition of phenylselenyl chloride to a formula (j) compound dissolved in a suitable organic solvent, preferably ethyl acetate, followed by addition of an oxidizing agent, preferably hydrogen peroxide (H202), yields a formula (k) compound. The formula (1) epoxide .compounds next are prepared by addition of an oxidizing agent, preferably 20 H2°2' to a ^orrnu^a (^) compound dissolved in a suitable organic solvent, preferably methanol, cooled to 5°C to 25°C, preferably 15°C, followed by addition of a strong base such as NaOH.

Formula (1) compounds then are dissolved in a ^ 25 suitable organic solvent, preferably THF, and cooled to -20 °C to 0 °C, and a fluorinating agent such as hydrogen fluoride, or, preferably, pyridinium poly(hydrogen fluoride) is added to yield formula (m) compounds in which X is.fluoro. Formula (m) compounds are dissolved in a j 30 suitable organic solvent such as THF followed by addition to a solution of a metalloamide base such as lithium diisopropylamide or, preferably lithium bis(trimethyl-silyl)amide in a suitable organic solvent such as THF. To 235 8 1 a 1 this reaction mixture then is added a triflating agent such as trifluoromethanesulfonic anhydride, or, preferably, N-phenyltrifluoromethanesulfonimide to yield formula (o) compounds.

Formula (p) compounds then are synthesized by adding to a formula (o) compound dissolved in a suitable organic solvent such as DMF an organic base such as timethylamine, or, preferably, triethylamine, a phosphine such as bis(diphenylphosphino)propane, or, preferably 10 tripheny Iphosphine, and a palladium{ II) compound such as palladium(II) chloride, or, preferably, palladium(II) acetate followed by addition of CO. Hydrogenation of formula (p) compounds dissolved in a suitable organic solvent such as ethyl acetate and hexane using an 15 appropriate hydrogenation agent such as platinum dioxide, Raney nickel, or, preferably palladium on carbon (Pd/carbon) yields formula (g) compounds. Hydrolysis of the ester with a base such as sodium hydroxide, potassium hydroxide, lithium hydroxide, or, preferably potassium 20 carbonate dissolved in an aqueous C1_6alkyl alcohol solution, preferably methanol yields a salt of a formula (s) compound. Treatment of the salt with strong acid yields a formula (s) compound.

Formula (s) compounds in which X is other than 25 hydrogen or fluoro are prepared using processes such as exemplified in Examples 23, 24, and 25. -25- 23 5 8 1 8 m 1 SCHEME IV (t) C]_galkO 1) lithium isopropvl cvclohexyl amide 2) phenyl selenv Ibrcmide 3) hydrogen peroxide (u) -26- 23 5 8 1 8 fa SCHEME IV (Continued) (v) t (w) *1 J -27- 23 5 8 1 8 Scheme IV depicts formation of Formula (la) compounds in which n is 0. The starting materials for this formation are formula (j) compounds prepared as described in Scheme III. According to Scheme IV, formula (j) compounds are dispursed in a strong acid, preferably glacial acetic acid, and treated with thallic acetate sesquihydrate to prepare formula (t) compounds. Formula (u) compounds next are prepared by treating formula (t) compounds dispursed in a suitable organic solvent, preferably diethylether, with an alkylating agent such as an alkyl halide and base, for example methyl,iodide and sodium carbonate, ethyl iodide and I,8-diazabicyclo-[5.4.0]undec-7-ene, or diazomethane.

Formula (u) compounds then are dissolved in a suitable organic solvent, preferably THF, cooled to -100°c to —30°C, preferably -78°C, and a metalloamide base, preferably lithium isopropyl cyclohexyl amide, is added. Thereafter phenylselenylbromide is added followed by an oxidizing agent, preferably hydrogen peroxide, to yield formula (v) compounds. Formula (w) compounds then are prepared by processes employed in synthesizing formula (d) compounds in Scheme I.

[THIS SPACE INTENTIONALLY LEFT BLANK] -28-SCHEME V ZSD 8 1 8 (aa) SCHEME V (Continued) 235 8 18 Ci-6 K2°d3 + H (bb) (cc) -so- 23 5 8 fa 1 Scheme V outlines formation of Formula (la) compounds in which A1 is -CH=CH-. The starting materials in Scheme V are formula (m) compounds prepared as described in Scheme III. According to Scheme V, 5 formula (aa) compounds are prepared using the processes used in making formula (f) compounds of Scheme II. Next formula (bb) compounds are prepared by the reactions employed to form formula (c) compounds in Scheme I. Thereafter, treatment of formula (bb) compounds as 10 described in forming formula (s) compounds of Scheme III yields formula (cc) compounds.

[THIS SPACE INTENTIONALLY LEFT BLANK] SCHEKE VI Z35 !6 1 8 »14 1) Dibronantin 2) LiBr 3) Triethylamine/benzenetiiiol 4) -m-chloropertenzoic acid ) Triethylamine 6) K2<X>3 (cfd) 1) butanone 2) Al (iPrO) 3 (ee) 235 3 1 8 SCHEME VI (Continued) 1) Li/NH3 2) NH4C1 (ff) (gg) / Pd/carbon ' H- 1) phenylselenylchloride 2) — (hh) SCHEME VI (Continued) 235 3 (Wc) 235318 Scheme VI shows synthesis of Formula (la) compounds in which there is a Cg-C14 double bond. The formula (dd) starting materials are known and available and can be synthesized from available materials using known methods. Formula (ee) compounds are prepared by first treating formula (dd) compounds in a suitable organic solvent such as hexane with a brominating agent such as N-bromosuccinamide, or, preferably dibromantiri and a mild base, preferably sodium bicarbonate, and heated, preferably at reflux. Thereafter, the mixture is treated with lithium bromide (LiBr), cooled to -20°C to 20°C, preferably 0°C, and treated with triethylamine and benzenethiol. Treatment with an oxidazing agent such as sodium periodate, hydrogen peroxide, or preferably m-chloroperbenzoic acid follows and is followed by heating to 40°C to 100°C, preferably 70°C, and treatment with an organic base such as trimethylamine, or preferably triethylamine. Treatment with a strong base such as sodium hydroxide, potassium hydroxide, lithium hydroxide, or, preferably, potassium carbonate yields formula (ee) compounds.

•Formula (ee) compounds then are dissolved in a suitable organic solvent, preferably toluene, and treated with an alkyl ketone agent such as a cyclohexanone, or, preferably butanone followed by treatment with aluminum isopropoxide and heating, preferably at reflux, to prepare formula (ff) compounds. Reaction of formula (ff) compounds as described in forming Scheme III, formula (j) compounds yields formula (gg) compounds. Hydrogenation of formula (gg) compounds using suitable catalysts such as platinium dioxide, Raney nickel, or, preferably Pd/carbon, yields formula (gg1) compounds. Formula (hh) compounds there are prepared by adding phenylselenyl chloride to a formula (gg') compound dissolved in a suitable organic solvent, preferably ethyl acetate, followed by addition of an oxidzing agent, preferably H202- Substitution of formula (hh) compounds for formula (m) compounds in- Scheme III yields formula (kk) compounds.

SCHEME VII 235 8 18 ) (id ) (run) -3s- 23 5 8 ] 1 Scheme VII outlines formation of Formula (la) 7 compounds m which A and A. are -CH=CH- from Scheme I, formula (a) compounds. Treatment of formula (a) compounds in a suitable solvent such as t-butanol with 5 chloranil, with heating, preferably at reflux, yields formula (11) compounds. Thereafter, substituting formula (11) compounds for formula (a) compounds in the Scheme II process yields formula (mm) compounds.

[THIS SPACE INTENTIONALLY LEFT BLANK] 235 8 1 8 SCHEME VIII \ KOH N-msthylxvitrosourea (a) (nn) > 30 (oo) D 25 j 30 23 5 8 1 1 Scheme VIII shows formation of Formula (la) compounds in which n is 2 from Scheme I, formula (a) compounds. Formula (nn) compounds are prepared by treatment of formula (a) compounds in a suitable organic 5 solvent such as diethyl ether and methanol cooled to -20°C ^ to 20°C, preferably 0°C, with a strong base such as sodium hydroxide, lithium hydroxide, potassium carbonate, or, preferably potassium hydroxide (KOH), followed by treatment with a diazomethane precursor such as 10 N-methyl-N'-nitro-N-nitrosoguanidine, or, preferably ^ N-methylnitrosourea. Substituting formula (nn) compounds for formula (a) compounds in the process of Scheme II yields formula (oo) compounds.

[THIS SPACE INTENTIONALLY LEFT BLANK] -39- 23 5 8 SCHEME IX (a) Ethylene glycol p-toluene sulfonic acid (PP) a ~40- SCHEME IX (Continued) 235 8 1 $ 1) 2,6-di-t-butyl-4-fnsthylpyridine 2) trifluoranethanesulfonic anhydride -> (rr) O CF3-S-0 Tr iethv lamine bis{triphenyIphosphine)palladium(II) acetate C]_6alKOH CD (ss) cl-6^ (ttj 235 3 1 8 Scheme IX outlines formation of Formula (la) compounds in which Y is chloro or fluoro (Y1) from Scheme I, formula (a) compounds. Formula (pp) compounds are prepared by reacting formula (a) compounds with a suitable keto group protecting agent such as ethylene glycol in the presence of an acid catalyst such as p-toluene sulfonic acid. Treatment of formula (pp) compounds with a suitable oxidizing agent, preferably m-chloroperbenzoic acid in a suitable organic solvent such as dichloromethane yields formula (qq) epoxide compounds.

Formula (rr) compounds then are prepared by adding gaseous hydrogen fluoride or hydrogen chloride to a formula (qq) compound in a suitable organic solvent such as chloroform, or (where Y^ = F) by adding borontrifluoride-etherate to a formula (qq) compound in a suitable organic solvent, prferably benzene:ether followed by treatment with strong acid, preferably hydrogen chloride in glacial acetic acid. Next, 2,6-di-t-butyl-4-methylpyridine followed by trifluoromethanesulfonic anhydride are added to a formula (rr) compound to yield a formula (ss) compound. Reaction of a formula (ss) compound in a suitable organic solvent, preferably dimethylformamide, with triethylamine, a C, calKOH, JL"~ D bis(triphenylphosphine)palladium(II) acetate, and carbon monoxide yields formula (tt) compounds. The free acids of formula (tt) optionally are prepared by processes shown in the preceding schemes. Compounds of Formula (I) in which Y is trifluoromethyl are prepared by processes such as exemplified in Example 26.

Compounds having a double bond at C11 are prepared by modifications of the Schemes I through X by procedures which would be apparent to those skilled in the art and are exemplified in Example 34, below. 235 8 1 m 1 Compounds of Formula (la) wherein M is sulfur are prepared from Formula (la) compounds wherein M is oxygen using known procedures such as shown in Example 35, below.

[THIS SPACE INTENTIONALLY LEFT BLANK] 235 SCHEME X (i) (a) phosphorous tribromide or oxalyl bromide (b) optional step(s) for R' interconversions .14 (ii) 1) Butyllithium 2) Carbon dioxide 3) Acid or Triethylamine, tr ipherylphosphine- J/ palladium (II) acetate, C. ..alkOH, v 1/. JL—o 14 CH-r c0 (iii) ^ 3 0 235 8 1 1 Scheme X shows a preferred synthetic method for preparing Formula (la) compounds having double bonds at C3~C4 and C5~C6. The starting materials are the fomrula (a) 4-ene-3~one compounds from Scheme I. X1 is 5 bromo, or choloro, fluoro, or iodo. According to Scheme X, formula (i) compounds are treated with a carboxylic acid halide such as acetyl chloride, acetyl bromide, oxalyl chloride, or preferably, oxalyl bromide to yield formula (ii) compounds. Alternately, formula (ii) 10 compounds are prepared by treating formula (i) compounds with a phosphorus trihalide;, or phosphorous pentahalide, such as phosphoryl chloride, phosphorous pentachloride or preferably phosphorous tribromide, in acid, preferably acetic acid. Included in this process may be desired , . 1 a interconversions among the various groups comprising R using standard procedures known to organic chemists, especially conversion of esters to carboxylic acids, then to acid halides and then to carboxamides.

. Formula (iii) compounds, Formula (la) compounds unsaturated at C5-Cg, then are prepared by adding an alkyllithium reagent such as n-butyllithium, s-butyllithium or t-butyllithium to a compound (ii) followed by treatment with a carboxylating agent such as 25 diethyl carbonate, ethyl chloroformate, or, preferably, carbon dioxide. Alternatively, such formula (iii) compounds are prepared by adding a palladium catalyst, preferably triphenylphosphine palladium (II) acetate in the presence of a base, preferably triethylamine and a C1_6 alcohol, preferably methanol, under an atmosphere of carbon monoxide. 235 8 1 Scheme X shows preparation of Formula (la) compounds in which X and Y are hydrogen. Scheme X is used to prepare Formula (la) compounds in which X or Y is other than hydrogen by replacing the formula (i) starting materials with appropriately substituted alternates.

Compounds are selected so that they can be converted by 2 3 known procedures to the R and R groups of the target Formula (la) compounds by additional steps in the synthetic process, as stated above, for example.

In the above Schemes, the starting materials are 2 14 selected so that the R and R groups in the formula 2 3 (a) compound are the same as the R and R groups in the Formula (la) compound being synthesized. 2 14 Alternatively, the R and R group of the formula (a) compound are selected so that they can be converted by 2 3 known procedures to the R and R groups of the target Formula (la) compounds by additional steps in the synthetic process. For example, Formula (la) compounds 3 wherein R is carboxylic acid are converted to the corresponding amides by reaction with amines or substituted amines via the corresponding acid chlorides. Similarly, Formula (la) compounds wherein R is CH3CHC00H are prepared by oxidation of the correspanding alcohol.

Pharmaceutically acceptable acid addition salts of the compounds of that invention containing a basic group are formed where appropriate with strong or moderately strong organic or inorganic acids in the presence of a basic amine by methods known to the art. For example, the base is reacted with an inorganic or organic acid in an -4 6- 235 3 1 *\ aqueous miscible solvent such as ethanol with isolation of the salt by removing the solvent or in an aqueous immiscible solvent when the acid is soluble therein, such as ethyl ether or chloroform, with the desired salt separating directly or isolated by removing the solvent. Exemplary of the acid addition salts which are included in this invention are maleate, fumarate, lactate, oxalate, methanesulfonate, ethanesulfonate, benzenesulfonate, tartrate, citrate, hydrochloride, hydrobroraide, sulfate, phosphate and nitrate salts. Pharmaceutically acceptable base addition salts of compounds of that invention containing an acidic group are prepared by known methods from organic and inorganic bases include nontoxic alkali metal and alkaline earth bases, for example, calcium, sodium, and potassium hydroxide; ammonium hydroxide, and nontoxic organic bases such as triethylamine, butylamine, piperazine, and (trihydroxymethyl)methylamine.

In preparing the compounds of Formula <Ia), novel intermediates of the following Formula (V) are synthesized; CF.

(V) in which: The A, B, C, and D ring double bonds, X, Y, Z, R2, R^°, and R'1''4 are as defined in Formula (la). 235 8 1 8 l Also prepared in synthesizing the formula (la) compounds Gf that invention were novel intermediates of this invention, of the formula (VI):^/, -a-reductase activity, they have therapeutic utility in treating diseases and conditions wherein decreases in DHT 15 activity produce the desired therapeutic effect. Such diseases and conditions include acne vulgaris, seborrhea, female hirsutism, prostate diseases such as benign prostatic hypertrophy, and male pattern baldness. The potency of several compounds of that invention was tested 20 for potency in inhibiting human steroid 5-a-reductase using tissue from hyperplastic human prostates. In determining potency in inhibiting the human enzyme, the following procedure was employed: in 3 to 5 volumes of 20 mM potassium phosphate, pH 6.5, buffer containing 0.33 M sucrose, 1 mM dithiothreitol, and 50 \iK NADPH with a Brinkmann Polytron (Sybron subjected to sonication for 3 to 5 minutes with a Sonifier (Branson Sonic Power Co.) followed by hand homogenization in a glass-to-glass Dounce homogenizer (Kontes Glass Company, Vineland, New Jersey).

Frozen human prostates were thawed and minced 25 into small pieces ( 5mm ). The tissue was homogenized Corporation, Westbury, New York). The solution was \ i 235 8 1 8 1 Prostatic particles were obtained by differential centrifugation at 600 or 1000 x g for 20 minutes and 140,000 x g for 60 minutes at 4°C. The pellet obtained from the 140,000 x g centrifugation was washed with 5 to 5 10 tissue volumes of the buffer described above and ' recentrifuged at 140,000 x g. The resulting pellet was suspended in 20 mM potassium phosphate buffer, pH 6.5, containing 20% glycerol, 1 mM dithiothreitol, and 50 \iK NADPH. The suspended particulate solution was stored at _ 10 -80 °C.

A constant amount of [14C]-testosterone (52 to 55 mCi/mmol, New England Nuclear, Boston, MA) in ethanol and varying amounts of the potential inhibitor in ethanol were deposited in test tubes and concentrated to dryness 15 in a SAVANT Speed Vac. To each tube was added buffer, 20 ]il of 10 mM NADPH and an aliquot of prostatic particulate solution 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 to 30 minutes the reaction was quenched by the 20 addition of 4 ml ethyl acetate and 0.25 ymol each of testosterone, dihydrotestosterone, androstanediol, and androstanedione as carriers. The organic layer was removed to a second test tube and evaporated to dryness in a Speed Vac. The residue was dissolved in 20 to 3 0 yl 25 chloroform, spotted on an individual lane of a 20 x 20 cm prechannelled silica gel TLC plate (Si 250F-PA, Baker Chemical) and developed twice with acetone:chloroform (1:9). The radiochemical content in the bands of the substrate and the products was determined with a BIOSCAN ^ 30 Imaging Scanner (Bioscan, Inc., Washington, D.C.). The percent of recovered radiolabel converted to product was 23 5 3 1 ri 1 calculated, from which enzyme activity was determined.

All incubations were conducted such that no more than 12%-of the substrate (testosterone) was consumed.

The experimentally obtained data was computer fitted to a linear function by plotting the reciprocal of the enzyme activity (1/velocity) against the variable inhibitor concentration (Dixon, M. (1953), Biochem. J., 55, 170). Assuming that the steroidal inhibitor is a competitive inhibitor against testosterone, a value for the inhibition constant (K^) can be calculated from equation 1: K. = (B/A)/(S/K + 1) Equation 1 i m where B is the intercept on the 1/velocity axis, A is the slope of the line, S is the concentration of substrate (testosterone) used in the experiment, and Km is the Michaelis-Menton constant of the substrate (testosterone) determined in a separate experiment to be 4.5 jiM.

Table II displays the results of the above testing and shows that the tested compounds of the invention are potent inhibitors of human steroid 5-a-reductase. ^ 30 [THIS SPACE INTENTIONALLY LEFT BLANK] 23 5 3 \ J Table II Inhibition Constants of Human Prostatic Steroid -g-Reduct as e Compound (nM) 5000 2000 J MjC 4000 52 IR> Compound Table II (Continued) 1.^ 23 5 8 1 8 Ki(nM) 26 85 2200 50 32 50 r* i 235 8 1 Table II (Continued) Compound K^(nM) 110 900 35 790 170 110 25 Certain compounds of that invention also were tested for their in vivo potency in inhibiting steroid 5-a-reductase activity. Male Charles River CD rats, 48 days old, weighing approximately 200 gm were administered 30 io mg/kg of N,N-diisopropyl-androst-3,5-diene-17B— carboxamide-3-carboxylic acid dissolved in propylene glycol and diluted in normal saline. Following compound administration the animals were sacrificed, the ventral prostates were excised, and DHT levels were measured by 35 the following procedure. r* 3 0 235 8 1 1 Prostate tissue was excised, trimmed, weighed, minced and washed with phosphate buffer. The tissue then was homogenized in phosphate buffer and extracted by addition of ethyl acetate and mixing on an orbital mixer 5 for forty-five minutes. The ethyl acetate was evaporated, the residue was reconstituted in ethanol, and was centrifuge filtered using 0.45 yM filter paper. The components then were separated using reverse-phase HPLC collecting the DHT fraction. The fraction was reduced to 10 dryness and reconstituted in standard DHT assay buffer available from Amersham. DHT levels then were measured using standard techniques such as radioimmunoassay.

In the compound-treated rats, prostatic DHT levels were decreased forty percent relative to 15 vehicle-treated controls four hours after compound administration. The decreased DHT levels were maintained for greater than eight hours after administration, and had returned to control levels twenty-four hours.after treatment. A single 10 mg/kg dose of the methyl ester of the above compound decreased prostatic DHT levels forty-eight percent relative to vehicle-treated controls after six hours. Thus, even though this compound does not inhibit steroid-5-a-reductase.in vitro, in vivo administration of this compound produces significant enzyme inhibition.

N,N—diisopropyl-androst-3,5-diene—17B-carboxamide-3-carboxylic acid also was tested for its effects on prostatic growth. Twice daily oral administration for fourteen days of 0.5 to 50 mg/kg of this compound to immature rats produced a dose-dependent decrease in prostatic growth. Prostrate weights from animals in the maximum dose group were forty to fifty percent less than controls. 235 8 18 Ci !> 1 Using procedures similar to those described above the in vivo effects of B 17B-N-t- butylcarboxamideandrost-3 ,5-diene-3-carboxylic acid also were studied. Rats received a single oral dose of vehicle 5 or 5, 10, 20 or 50 mg/kg of this compound. At all doses, prostate dihydrotestosterone levels were significantly reduced to approximately, fifty percent of controls while testosterone levels remained unaffected.

Rats also were given lOmg/kg of this compound and 10 prostate testosterone and dihydrotestosterone levels at several points over twenty-four hours.

Dihydrotestosterone levels were significantly depressed to approximately sixty percent of controls at all time poines from two to eighteen hours after treatment, at returned to 15 control values by twenty-four hours post treatment.

Prostate testosterone levels wre viable without consistent trends.

Additionally, rats were given this compound at 1, 5, 10, 25, or 50 mg/kg twice daily for two weeks to 20 determine if repeated treatment caused a reduction in ventral prostate weight. Ventral prostate weight was ninety perccent of control at 5mg/kg dose level and sixty—five percent of control at the 10 and 50mg/kg dose level. Seminal vesicle weights were significantly \) 25 reduced at all treatment levels. f 235 8 1 8 •5 1 The compounds of Formula (la) are incorporated into convenient dosage forms such as capsules, tablets, or injectable preparations. Solid or liquid pharmaceutical carriers are employed. Solid carriers include, starch, 5 lactose, calcium sulfate dihydrate, terra alba, sucrose, "\ 3 talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Liquid carriers include syrup, peanut oil, olive oil, saline, and water. Similarly, the carrier or diluent may include any prolonged release material, 10 such as glyceryl monostearate or glyceryl distearate, alone or with a wax. The amount of solid carrier varies widely but, preferably, will be from about 25 mg to about 1 g per dosage unit. When a liquid carrier is used, the preparation will be in the form of a syrup, elixir, 15 emulsion, soft gelatin capsule, sterile injectable liquid such as an ampoule, or an aqueous or nonaqueous liquid suspension.

The pharmaceutical preparations are made following conventional techniques of a pharmaceutical 20 chemist involving mixing, granulating, and compressing, when necessary, for tablet forms, or mixing, filling and dissolving the ingredients, as appropriate, to give the desired oral or parenteral products.

Doses of the compounds of Formula (la) in y 25 a pharmaceutical dosage unit as described above will be an efficacious, nontoxic quantity selected from 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 in need of steroid 5-a-reductase ^ 30 inhibition from 1-6 times daily, topically, orally, rectally, by injection, or continuously by infusion. Oral dosage units for human administration preferably contain from 1 to 500 mg of active compound. Parenteral administration, which uses lower dosages is preferred. 235 a i r -\ ...j 1 Oral administration, at higher dosages, however, also can be used when safe and convenient for the patient.

The method of that invention of inhibiting steroid 5-a-reductase activity in mammals, including humans, comprises administering to a subject in need of such inhibition an effective steroid 5-a-reductase inhibiting amount of a compound of Formula (la) .

Contemplated equivalents of Formula I compounds 10 are compounds otherwise corresponding thereto wherein substituents have been added to any of the unsubstituted positions of the Formula (la) compounds or the methyl group at C-13 is absent or replaced by C1_4alkyl provided such compounds have the pharmaceutical utility of Formula (la) compounds.

The following examples illustrate preparation.of Formula (la) compounds and pharmaceutical compositions containing these compounds. The examples are not intended to limit the scope of that invention as defined hereinabove.

EXAMPLE 1 20-g-(Hydroxymethyl)-5-a-pregn-3-ene-3-carboxylic acid _ _ \J 20-a-(Hydroxymethyl )-pregn-4-ene-3-one Pregn-4-ene-3-one-2 0-a-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 (NaBH4) in 125 ml ethanol was added j 3° dropwise. The reaction mixture was stirred overnight at °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 235 8 1 bicarbonate solution, water and brine. The organic layer was then dried over sodium sulfate and evaporated to dryness to yield 13.9 g (82%) of 20-a-(hydroxymethyl)-pregn-4-ene-3-one. ( ii) 2Q-a-( t-Butyldimethylsilyloxymethyl )-pregm-4-ene-3-one A solution of 20-a-(hydroxymethyl)-pregn-4-ene-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 afforded 1.1 g (70%) of 20-a-(t-butyldimethylsilyl oxymethy 1 )pregn-4-ene-3 -one . (iii) 20-a-(t-Butyldimethylsiloxymethyl)-3-trifluoromethylsulfonate)-5-a-pregn-3-ene Ammonia (200 ml) was double distilled into a 3—neck roundbottom flask equipped with a dry ice condenser and argon bubbler. Lithium (Li) wire (120 mg, 17.4 mmol) was dissolved in ammonia (NH^). A solution of 20-a-(t-butyldimethylsiloxymethyl)-pregn-4-ene-3-one (3 g, 6.7 6 mmol) and aniline (49.5 1, 5.4 mmol) in THF (50 ml) was added dropwise to the Li/NH^ solution. The reaction mixture was stirred at -78°C for 15 minutes and then quenched with isoprene until the blue color disappeared. The volatiles were slowly evaporated (to avoid excess foaming) by slow warming, and eventually at 0.5 mmHg for 1 and 1/2 hours. The residue was redissolved in THF (50 ml) and cooled to 0°C. A solution of N-phenyltrifluoromethylsulfonimide (7 g, 20 mmol) in 235 8 1 r) 1 THF (10 ml) was added to the reaction mixture, and stirring was continued overnight at 4°C. The solvent was then evaporated and the residue was chroraatographed on silica gel eluting with 3% ethyl acetate in hexane to 5 yield 2.24 g (57%) of the 20-a-(t-butyldimethyl-Ni siloxymethyl)-3-( trif luoromethylsulfonate)-5-a-pregn- 3-ene. (iv) 2 0-a-(t-Butyldimethyls iloxymethyl)-3-carbomethoxy-5-a-pregn-3-ene -a-( t-Butyldimethylsiloxymethyl) -3-(trifluoromethylsulfonate)-5-a-pregn-3-ene (100 mg, 0.173 mmol) was dissolved in methanol (0.5 ml) and DMF (1 ml). Triethylamine (55 yl, 0.386 mmol), triphenyl-phosphine (9 mg, 0.034 mmol) and palladium(II) acetate (3.8 g, 0.017 mmol) were then added to the solution and CO was bubbled through the solution for 5 minutes. The reaction mixture was then stirred overnight at 45°C under 1 atmosphere of CO, diluted with ethyl acetate and washed with water until neutral pH. The organic layer was dried 20 over sodium sulfate and evaporated. The dark oil was purified by chromatography on silica gel eluting with 10% ethyl acetate in hexane to yield 52 mg (61%) of the desired product; 20-a-(t-butyldimethylsiloxymethyl)-3-carbomethoxy-5-a-pregn-3-ene. •^) 25 (v) 2 0-a- (Hydroxymethyl) -3 -carbomethoxy- -g-precrn-3-ene -a-( t-Butyldirnethyl si loxymethyl) -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 / 30 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 thoroughly with dichloromethane. The organic layers were combined, dried over sodium sulfate and 235 8 1 1 evaporated to dryness. Purification by flash chromatography eluting with 20%- ethyl acetate in hexane afforded 300 mg (78%) of 20-a-hydroxymethyl-3-carbomethoxy-5-a-pregn-3-ene. (vi) 20-a-(Hydroxymethyl )-5-a-preqn-3-ene-3-carboxylic acid 2 0-a-(Hydr oxymethy 1)-3-car bo- methoxy-5-a-pregn-3-ene (300 mg, 0.802 mmol) was dissolved in THF (15 ml) and methanol (15 ml). Lithium 10 hydroxide (8 ml of a IN 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 15 times with ethyl acetate. The organic layers were combined, washed with brine, dried over sodium sulfate, and evaporated to dryness. Recrystalli2:ation from ethyl acetate and hexane afforded 242 mg (84%) of the desired acid; 20-a-(hydroxymethyl)-5-a-pregn-3-ene-3- • 20 carboxylic acid, m.p. 197-203°C. added to a 3-neck round bottom flask equipped with a condenser, argon bubbler and mechanical stirrer. The flask was cooled to 0°C and lithium aluminum hydride (LAH) 30 (11.39 g, 0.3 mol) was slowly added. After all of the LAH was added, the flask was warmed to room temperature. A solution of methyl androst-4-ene-3-one-17B-carboxylate (66 g, 0.2 mol) in 600 ml of THF was very slowly added to the LAH slurry. After the addition of the steroid, the EXAMPLE 2 N,N—Diisopropyl-5-g-androst-3-ene-17B—carboxamide-3-carboxvlic acid (i) 17B-(Hydroxymethyl)—androst-4-ene-3-ol Approximately 750 ml of dry THF was 235 8 1 1 reaction mixture was slowly warmed to reflux. After 2 hours the excess LAH was quenched with 11.4 ml water, 11.4 ml 15% sodium hydroxide (NaOH) and 28 ml water. The salts were removed by filtration and washed with 5 approximately 1 liter of warm THF. Concentration of the ^ combined organic solutions afforded 63 g (94%) of 17B-(hydroxymethyl)-androst-4-ene-3-ol as mixture of a and B isomers. (ii) 3-Oxo-l7B-(hydroxymethyl)-4-androstene 10 A solution of 17B-(hydroxymethyl)- androst-4-ene-3-ol (27 g, 0.089 mol) in 1200 ml trichloromethane was treated with activated manganese dioxide (66 g). After 3 hours the mixture was filtered. Concentration afforded 26 g (96%) of 3-oxo-17B-15 (hydroxymethyl)-4-androstene (m.p. 151°C). (iii) 3-Oxo-170-(t-buty ldimethyls ilyloxymethy1)-4-androstene To a solution of 3-oxo-17B-(hydroxymethyl)-4-androstene (15 g, 0.05 mol) in 200 ml 20 DMF was added 5.8 g (0.085 mol) imidazole followed by 9.7 g (0.065 mol) 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 ice water and washed 3 times with ethyl •n ) 25 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 afforded J 30 16.9 g (82%) of 3-oxo-17B-(t-butyldimethylsilyloxy- methyl)-4-androstene as a white crystalline solid. (17B-(t-Butyldimethylsilyloxymethyl)-3-(trifluoromethylsulfonate)-5-a-androst-3-ene Ammonia (300 ml) was double distilled into a 3-neck round bottom flask equipped with a dry ice 23 5 8 1 8 1 condenser and argon bubbler. Li wire, 250 mg (3 eq), was dissolved in the ammonia and stirred for 15 minutes to ensure dryness. Freshly distilled aniline, 0.53 ml (0.8 eq), was then added. A solution of 3 g (7.2 mmol) of 5 3—oxo—17B—(t—butyldimethylsilyloxymethyl) —4—androstene in ^ 50 ml of dry THF was added dropwise to the Li/NH^ solution. An additional 50 ml dry THF was added to aid in solubility. The reaction mixture was stirred at -78*0 for 2 hours and then quenched with isoprene until the blue 10 color disappeared. The volatiles were slowly evaporated (to avoid excess foaming) by slow warming, and eventually at 0.5 mrnHg 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 eq) of N-phenyltrifluoromethyl-15 sulfonimide in 50 ml THF was added, the flask 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 yielded 2.5 g (63%) of 176-(t-butyldimethyl-silyloxymethyl)-3-( tr if luoromethyl sulfonate )-5-a-androst-3-ene (m.p. 120-121°C). (v) Methyl 17B-(t-butyldimethylsilyloxymethy1)-5-<x-androst-3-ene—3-carboxylate To a solution of 3 g (5.46 mmol) of 17B-( t-butyldimethylsilyloxymethyl)-3-(tr if luoromethyl-sulfonate)-5-a-androst-3-ene in 10 ml DMF and 10 ml methanol was added 1.5 ml (2 eq) triethylamine and 123 mg (0.03 eq) of the catalyst bis(triphenylphosphine)-palladium(II) acetate. Carbon monoxide (CO) was bubbled 30 through the solution for 5 minutes and the reaction mixture- was then stirred at room temperature overnight under 1 atmosphere of CO. The mixture was diluted with *N 25 235 ethyl acetate and washed with water until neutral pH. The organic layer was dried over sodium sulfate and evaporated. Chromatography on silica gel eluting successively with 5%, 10%, and 20% ethyl acetate in hexane followed by recrystallization from methanol afforded methyl 17G-(t-butyldimethylsilyloxymethyl)-5-a-androst-3-ene-3-carboxylate. (vi) 3-Carbomethoxy-3-androstene-176-carboxylic acid Methyl 17B-(t-butyldimethylsilyloxymethyl )-5-a-androst-3-ene-3-carboxyl ate (500 mg), was dissolved in 150 ml acetone. Jones reagent was added until a red color persisted. Isopropanol was then added to quench excess Jones reagent. The acetone was decanted off and the residual chromium salts were then dissolved in water and washed 3 times with dichloromethane. The organic layers were combined and passed through a plug of florosil and concentrated to give 360 mg (99%) of 3-carbomethoxy-3-androstene-17G-carboxylic acid. (vii) 3-Carbomethoxy-3-androstene-17B-N,N-diisopropylcarboxamide 3-Carbomethoxy-3-androstene-17B-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 hours under argon. The reaction mixture 0 was then evaporated ( 1 mm Hg) and the residue was dissolved in 10 ml dry THF. A solution of 0.6 ml diisopropylamine in 2 ml dry THF was added and the reaction mixture stirred for 1 hour. The mixture was diluted with ice water and extracted with dichlorome-thane. The organic layer was then washed twice 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 "S 235 8 1 1 followed by recrystallization from diethyl ether afforded 3-carbomethoxy-3-androstene-17C-N,N-diisopropylcarboxamide. (viii) N,N-Diisopropyl-5-a-androst-3-ene-17B~ 5 carboxamide~3-carboxylic acid 3—C arbomethoxy-3-andro s t ene-17 B-N, N-diisopropylcarboxamide (300 mg, 0.7 mmol) and 300 mg of K^CO^ 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 rinsed 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 15 dissolving in ethyl ether, adding ethyl acetate and concentration■to afford N,N-diisopropyl-5-a-androst-3-ene-17B-carboxamide-3-carboxylic acid, m.p. 159-162 °C.

EXAMPLE 3 N,N-Diisopropyl-androst-3,5-diene-I7B-carboxamide-3-carboxylic acid (i) Androst-4-ene-3-one-176-carboxylic acid Methyl androst-4-ene-3-one-17B-y 25 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 hours. The reaction mixture was then acidified with 5% hydrochloric acid and 250 ml water was added. > 30 After aging for 1 hour, the mixture was filtered and dried to yield 18 g (94%) of androst-4-ene-3-one-17B-carboxylic acid as a white crystalline solid. ( i i) Androst-4-ene-3-one-1713-N,N-diisopropyl-carboxamide A solution of androst-4-ene-3-one-17B- carboxylic acid (18 g, 0.06 mol) in 350 ml of toluene was 235818 1 azeotropically dried until approximately 100 ml distillate was collected. The solution was then cooled to 10°C. Pyridine (6.7 ml, 0.08 mol) was added, followed by slow addition of a solution of oxalyl chloride (7.2 ml, 5 0.08 mol) in 10 ml of 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 toluene was added dropwise such that the temperature did not exceed 40°C. The reaction 10 mixture was stirred for 1 hour and then quenched with 300 ml ice water. The layers were separated and 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 15 dried over sodium sulfate and concentrated to dryness. Recrystallization by dissolving in 10 ml toluene and adding 200 ml hexane afforded 16.5 g (69%) of androst-4-ene-3-one-17G-N,N-diisopropylcarboxamide (m.p. 236—239 °C). 20 (iii) 170-(N,N-Diisopropylcarboxamide)-3- (trifluoromethylsulfonate)-androst-3,5-diene Androst-4-ene-3-one-17B-N,N-diisopropylcarboxamide (5 g, 12.5 mmol) was dissolved into 25 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. Trifluoromethane sulfonic anhydride (3.5 ml, 19 mmol) was added to the solution and stirring continued J* 30 for 30 minutes. The reaction mixture was then diluted with 50 ml methylene chloride and filtered. The organic layer was washed twice with 5% hydrochloric acid, 235818 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 yield 4 g (61%) of 17B-(N,N-diisopropylcarboxamide)-3-(trifluoromethyl-sulfonate)~androst-3,5-diene. (iv) 3-Carbomethoxy-androst-3,5-diene-1713-N,N-diisopropylcarboxamide To a solution of 17B-(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(triphenyl-phosphine)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 afforded 2.1 g (64%) of 3-carbomethoxy-androst-3,5-diene-178-N,N-diisopropylcarboxamide, m.p. 159-162°C. (v) N,N-Diisopropyl-androst-3,5-diene-17B-carboxamide-3-carboxylic acid 3-Carbomethoxy-androst-3,5-diene-17B-N,N-diisopropylcarboxamide (1.4 g, 3.17 mmol) and 1 g of K2C03 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 rinsed with ethyl acetate and acidified. The emulsion was washed several times with dichloromethane. The organic layer was dried over sodium 235818 a 1 sulfate and evaporated. The product was recrystallized by dissolving in ethyl ether, adding ethyl- acetate and concentration to afford N,N-diisopropyl-androst-3,5-diene-17B-carboxamide-3-carboxylic acid (m.p. 230~234°C).

EXAMPLE 4 17B-(N,N-Diisopropylcarboxamide)-4-fluoro-5-a-androst-3-ene-3-carboxylic Acid (i) 3-Qxo-17B-(hydroxymethyl)-5-a-androstane 10 Ammonia (500 ml) was distilled into a 3-neck roundbottom flask equipped with a dry ice condenser and argon bubbler. Li wire (3 g) was dissolved in the ammonia and stirred for 15 minutes to ensure dryness. A solution of 3-oxo—17B-(hydroxymethyl)-4-androstene 15 (prepared as described in Example 2 (ii)/ 37.5 g, 0.123 mol) in 625 ml THF and t-butyl alcohol (6.25 ml, 0.8 eq) was added dropwise to the Li/NH3 solution. The reaction was stirred at -78°C for 2 hours and quenched with isoprene until the blue color disappeared. The 20 resulting enolate was then quenched with ammonium chloride and the ammonia was allowed to evaporate. Acetone was added to the residue and gently refluxed. The acetone solution was then filtered and evaporated to dryness to yield 24.7 g (79%) of 3-oxo-17G-(hydroxymethyl)-5-) 25 a-androstane. (ii) 3-Oxo-5-a-androstane-17B-carboxylic Acid The title compound was prepared according to Example 2 (vi) by replacing 3-oxo-17B-(hydroxymethyl)—5-a-androstane for methyl 17B-(t-J 3 0 butyldimethylsilyloxymethyl)-5-a-androst-3-ene-3- carboxylate. (iii) 3-Oxo-5-a-androstane-17B-N,N-diisopropylcarboxamide 3-Oxo-5-a-androstane-17B-carboxylic 35 acid was suspended in toluene (100 ml) and an excess of A 235 8 18 1 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 5 diisopropyl amine (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 eluting with 20% ethyl acetate in hexane 10 afforded 3.15 g (78%) of 3-oxo-5-a-androstane-17£-N,N-diisopropylcarboxarnide. (iv) 3-Oxo-5-a-androst-l-ene-17B-N,N-di isopropylcarboxamide To a solution of 3-oxo-5-a-15 androstane-17B-N,N-diisopropylcarboxamide (2.3 g, .74 mmol) in 100 ml ethyl acetate was added phenylselenylchloride (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 20 acetate solution was cooled to 0°C and 50 ml THF was added. Hydrogen peroxide (6 ml of a 3 0% 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 ) 25 dryness. Purification by chromatography on silica gel eluting with 20% ethyl acetate in hexane afforded 1.3 g (56.5%) of 3-oxo-5-a-androst-l-ene-17B-N,N-diisopropylcarboxamide. (v) 3-Oxo-5-a-androstane-l,2-alpha-epoxide-^ 30 17B-N ,N-diisopropylcarboxamide 3-Oxo-5-g-androst-l-ene-178-N,N-diisopropylcarboxamide (4.6 g, 11.5 mmol) was dissolved in 50 ml methanol and cooled to 15°C. To the solution was added hydrogen peroxide (0.8 ml of a 30% solution) 235 8 i 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 afforded 4.0 g (83.7%) of the desired epoxide; 3-oxo-5-g-androstane-l,2-g-epoxide-17B-N,N-diisopropylcarboxamide. (vi) 3-Oxo-4-fluoro-5-g-androst-l-ene-17B-N,N-diisopropylcarboxamide 3-Oxo-5-a-androstane-l,2-a-epoxide—17B-N,N-diisopropylcarboxamide (1.7 g, 4 mmol) was dissolved in 25 ml THF and cooled to -20°C. Pyridinium poly(hydrogen fluoride) (10 ml) was slowly added to the • solution (under argon). The reaction mixture was warmed to 0°C, stirred 3 0 minutes 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 eluting with 20% ethyl acetate in hexane yielded 750 mg (44%) of the desired 3-oxo-4-fluoro-5-a-androst-l-ene-17B-N,N-diisopropylcarboxamide. (vii) 17B-(N,N-Diisopropylcarboxamide)-3- (trifluoromethylsulfonate)-4-fluoro-5-a-androst-l,3-diene A solution of lithium bis(trimethyl-silyl)amide (4.2 mmol, 2.2 eq) in 2 ml THF was cooled to —78°C. A solution of 3-oxo-4-fluoro-5-a-androst-l-ene-17B-N,N-diiso'propylcarboxamide (800 mg,.1.9 mmol) in 10 ml THF was added and the reaction mixture was stirred for l -ss- 235 8 1 1 hour. A solution of N-phenyltrifluoromethanesulfonimide (857 mg, 2.4 mmol) in 8 ml THF was then added and ths reaction mixture was stirred for 1.5 hours at -78°C. The reaction mixture was then evaporated to dryness and 5 chromatographed on silica gel eluting with 20% ethyl f: ' • acetate in hexane. Trituration in a hexane and ether solution afforded 460 mg (46%) of the desired product, 17B-(N,N-diisopropylcarboxamide)-3-(trifluoromethyl-sulfonate)-4-fluoro-5-a-androst-l,3-diene. 10 (viii) 3-Carbomethoxy-4-fluoro-5-a-androst-l,3- diene-17B-N,N-diisopropylcarboxamide' The title compound was prepared according to Example 1 (iv) by substituting 17B-(N,N-diisopropylcarboxamide)-3-(trifluoromethylsulfonate)-4-15 fluoro-5-a-androst-l,3-diene for 20-a-(t-butyldimethyl-sily loxymethyl)-3-(trifluoromethylsulfonate)-5-a-pregn-3-ene. (ix) 3-Carbomethoxy-4-fluoro-5-<x-androst-3-ene—17B-N,N-diisopropylcarboxamide 20 3-Carbomethoxy-4-fluoro-5-a- androst-1,3-diene-17B-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 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 afforded 55 mg (46%) of the desired 3-carbornethoxy-4-fluoro-5-a-androst-3-ene-17B-N,N-diisopropylcarboxamide, m.p. 171—172 °C. ~ 30 (x) 17fi-(N,N-Diisopropylcarboxamide)-4-fluoro-5- g-androst-3-ene-3-carboxylic Acid The title compound was prepared according to Example 2 (viii) by substituting 3-carbomethoxy-4-fluoro-5-a-androst-3-ene-17B-. 235 S -70- ~ ~ w 1 1 diisopropylcarboxamide for 3-carbomethoxy-5-g-androst-3-ene-17B-N,N-diisopropylcarboxamide.

EXAMPLE 5 20-g-(Hydroxymethyl)-4-fluoro-5-g- ^ preqn-3-ene-3-carboxylic Acid (i) 20-g-(Hydroxymethyl)-5-g-preqnan—3-one The title compound was prepared 10 according to Example 4 (i) by substituting 20-g-(hydroxymethyl)-pregn-4-ene-3-one for 3-oxo-17B-(hydroxymethyl)-4-androstene. (ii) 20-g-(Hydroxymethy1)-5-g-pregn-l-ene-3-one The title compound was prepared according to Example 4 (iv) by substituting. 20-g-(hydroxymethyl)-5-g-pregnane-3-one for 3-oxo-5-a-androstane-17B-N,N-diisopropylcarboxamide. (iii) 20-g-(Hydroxymethyl)-l,2-g-epoxide-20 5-g-precrnan-3-one The title compound was prepared according to Example 4 (v) by substituting 20-g-(hydroxymethyl)-5-g-pregn-l-ene-3-one for 3-oxo—5-a—androst-l-ene—17B-N,N-diisopropylcarboxamide. 0 25 (iv) 20—g—(Hydroxymethyl)-4—fluoro-5-g- pr egn-l-ene-3-one The title compound was prepared according to Example 4 (vi) by substituting 20-g-(hydroxymethyl)-l,2-g-epoxide-5-a-pregnane-3-one for J 30 3-oxo-l,2-g-epoxide-5-g-androstane-17B-N,N- diisopropylcarboxamide. (v) 2 0-g- (t-Buty ldimethy Is i lyloxymethy 1) -4-fluoro—5-g—pregn-l-ene—3-one The title compound was prepared 35 according to Example 1 (ii) by substituting 20-g- 23 5 8 -71-/ (hydroxymethyl)-4-£luoro-5-g-pregn-l-ene-3-one for 20—a-(hydroxymethyl)-pregn-4-ene—3-one. (vi) 2Q-a-(t-Butyldimethylsilyloxymethvl)-4-fluoro-3-(trifluoromethylsulfonate)-5-g-pregn-1,3-diene The title compound was prepared according to Example 4 (vii) by substituting 20-a-(t-butyldimethylsilvloxymethyl)-4-fluoro-5-a-pregn-l-ene-3-one for 3-oxo-4-fluoro-5-g-androst-l-ene-17B-N,N-diisopropylcarboxamide. (vii) 3-Carbomethoxy-2 0-g-(t-butyId imethyl-s.ily loxymethyl) -4-fluoro-5-a-pregn- 1> 3-diene The ritle compound was prepared according to Example 4 (viii) by substituting 20-a-(t-butyldimethylsilyoxymethyl)-4-fluoro-3-(trifluoromethyl-sulfonate)-5-g-pregn-l,3-diene for 17B-(N,N-diisopropylcarboxamide)-3-(trifluoromethylsulfonate)-4-fluoro-5-a-androst-l,3-diene. (viii) 3-Carbomethoxy-20-g-(t-buty1dimethyl- si lyl oxymethy 1)-4-f luoro-5-g-precrn-3-ene The title compound was prepared according to Example 4 (ix) by substituting 3-carbomethoxy-20-g-(t-butyldimethyIsilyloxymethy1)-4-fluoro-5-a-pregn-1,3-diene for 3-carbomethoxy-4-fluoro-5-a-androst-1,3-diene-17B-N,N-diisopropylcarboxamide. (ix) 3-Carbomethoxy-2Q-g-(hydroxymethyl)-4-fluoro-5-g-pr egn-3-ene To a solution of 3-carbomethoxy-2 0~ g-(t-butyldimethylsilyloxymethyl)-4-fluoro-5-g-pregn-3-ene (610 mg, 1.2 mmol) in THF 20 ml was added 2.4 mmol tetrabutylammonium fluoride and the reaction 23 5 8 i 1 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 eluting with 15% 5 ethyl acetate in hexane yielded 200 mg.(43%) of the \ desired 3-carbomethoxy-20-a-(hydroxymethyl)-4-fluoro-5- a-pregn-3-ene, m.p. 177°C. (x) 20-a-(Hydroxymethyl)-4-fluoro-5-a-pregn-3-ene-3-carboxylic acid 1° The title compound (m.p. 233-236°C ) from methanol:acetone) was prepared according to Example 1 (vi) by substituting 3-carbomethoxy-20-a-(hydroxy-methyl)-4-fluoro-5-a-pregn-3-ene for 20-a-(hydroxymethyl )-3-carbomethoxy-5-a-pregn-3-ene.

EXAMPLE 6 -a-( Hydr oxymethy 1) -A-no r-5-a-preqn-i-ene-2-carboxylic acid (i) 20-a-(Hydroxymethyl)-A-nor-5-a— 20 pregnan-2-a-carboxylic acid -a-(Hydroxymethyl)-5-a-pregnane-3-one (8 g, 24.1 mmol) was suspended in 160 ml of 95% acetic acid, treated with thallic acetate sesquihydrate (30.4 g, 74.5 mmol), and warmed to 85°C. 25 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 30 50 ml water), warmed to 100°C for 40 minutes and then cooled to room temperature and allowed to stir 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 235 8 1 1 1 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 afforded 4.9 g (58%) of 20—g-(hydroxymethyl)-5 A-nor-5-a-pregnan-2-a-carboxylic acid. ^ (i i) 20-g-(Hydroxymethyl)-2-g- carbomethoxy-A-nor-5-g-preqnane 2 0-g-(Hydr oxymethy1)-A-no r-5-a-pregnan-2-g-carboxylic acid (4.9 g, 13.5 mmol) was 10 suspended in 20 0 ml diethylether and treated with approximately 67 mmol of diazomethane in an ethereal solution and the reaction mixture was stirred for 6 . hours. The excess diazomethane and ether was removed in vacuo and recrystallization from methanol afforded 3.6 g 15 (72%) of 20-g-(hydroxymethyl)-2-g-carbomethoxy-A-nor-5-g-pregnane. (iii) 2-g-Carbomethoxy-2 0-g-(t-buty1-dimethylsilyloxymethyl)-A-nor-5-g-pregnane The title compound was prepared according to Example 1 (ii) by substituting 20-g-(hydr oxymethyl)-2-g-carbomethoxy-A-nor-5-g-pregnane for 20-g-(hydroxymethyl)-pregn-4-ene-3-one. (iv) 2-Carbomethoxy-20-g-(t-butyldimethyl-J 25 silyloxymethyl)-A-nor-5-g-pregn-2-ene 2-g-Carbomethoxy-2 0-g-(t-butyldimethylsi lyloxymethyl )-A-nor-5-a-pregnane (960 mg, 2 mmol) was dissolved in 30 ml THF and cooled to -78°C. Lithium isopropylcyclohexylamide (5 ml of a 0.72 M J 3 0 solution) was added and the solution was stirred for 30 minutes at -78°C, warmed to room temperature and stirred an additional 1 hour. The reaction mixture was again cooled to -78°C; a solution of phenylselenylbromide (96 0 ml, 4 mmol) in 6 ml THF was added and stirred for 30 235 8 1 1 minutes. The reaction mixture was then warmed to room temperature and stirred 1 hour; poured into- cold saturated NH^Cl and washed with ethyl acetate. The organic layers were combined and washed with cold 5% hydrochloric acid, _ 5 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 ^ 10 K^CO^, 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 from methanol afforded 680 mg (72%) of a 5:1 mixture o£ isomers: 15 2-carbomethoxy-20-g-( t-buty ldimethyls i lyloxymethyl )-A-nor-5-a-pregn-l-ene and the desired isomer 2-carbomethoxy-2 0-a-(t-buty ldimethy Is i lyloxymethyl )-A-nor-5-a-pregn-2-ene. The isomers were separated to yield 100 mg of the desired title compound. 20 (v) 20-g-(Hydroxymethyl )-2-carbomethoxy-A- nor-5-g-pregn-2-ene The title compound was prepared according to Example 1 (v) by substituting 2-carbomethoxy-^ 20-g-(t-butyldimethylsilyloxymethyl)-A-nor-5-a- J 25 pregn-2-ene for 20-g-(t-butyldimethylsilyloxymethyl)-3- carbomethoxy-5-g-pregn-3-ene. (vi) 20-g-(Hydroxymethyl)-A-nor-5-a-preqn-l-ene-2-carboxylic acid The title compound (m.p. 235°C from ** 30 methanol) was prepared according to Example 1 (vi) by replacing 20-g-(hydroxymethyl )-2-carbomethoxy-A-nor-5-g-pregn-2-ene for 20-g-(hydroxymethyl)-3-carbomethoxy-5-g-pregn-3-ene. 23 5 8 18 EXAMPLE 7 17B-N,N-Dii sopropyl ca rboxamide-5-<x-androst-1,3-diene-3-carboxvlic acid ( i) 1713-(N,N-Dii sopropyl carboxamide) -3-(trif luoromethylsulf onate)-5~a.-androst-1,3-diene The title compound was prepared according tc Example 4 (vii) by substituting 3-oxo-5-<x-androst~l-ene-17B-N,N-diisopropylcarboxamide for 3-oxo-4-fluoro-5-a-androst-l-ene-17B-N,N-diisopropylcarboxamide. (ii) 3-Carbomethoxy-5-a-androst-I,3-diene-17B-N/N-diisopropylcarboxamide The title compound (m.p. 174=-176°C) was prepared according to Example 1 (iv) by substituting 17B-(N,N-diisopropylcarboxamide)-3-(trifluoromethylsulf onate) -5-a-androst-l, 3-diene for 20-a-(t- butyldimethy1silyloxymethyl)-3-(trifluoromethylsulfonate)-5-a-p regn-3-ene. (iii) 17B-N/N-Diisopropylcarboxamide-5-o:-androst-1^-diene-S-carboxylic acid The title compound (m.p. 163°C) was prepared according to Example 2 (viii) by substituting 3-carbomethoxy-5-a-androst-l,3-diene-17fl-N,N-diisopropylcarboxamide for 3-carbomethoxy-5-a-androst-3-ene-17B-N,N-diisopropylcarboxamide.

EXAMPLE 8 19-Nor-5-a-androst-3-ene-17B-ol-3-carboxylic acid The title compound is prepared according to Example 1 (ii through vi) by substituting 19-nor-testosterone for 20-a-(hydroxymethyl)-pregn-4-ene-3-one.

EXAMPLE 9 235 1 5-q-Pregn-3-ene-(20R)-3,20-dicarboxylic acid ( i) 3-Carbomethoxy-5-a-pregn-3-ene-(20R)-20-carboxylic acid To a solution of 2 0-g-(hydroxy-5 methyl)-3-carbomethoxy-5-g-pregn-3-ene, prepared as in. Example 1, (374 mg, 1.0 mmol) in 25 ml acetone is added Jones reagent dropwise until a red color persists. Isopropanol is then added to quench the excess oxidant. The solution is decanted from the gummy chromium salts, - 10 concentrated, and partioned between dichloromethane and water. The salts are dissolved in water and extracted with dichloromethane. The combined organic layers are then washed with brine, dried over sodium sulfate, and concentrated to yield 3-carbomethoxy-5-a-pregn-3-ene-15 (20R)-20-carboxylic acid. (ii) 5—a—Pregn—3-ene-(20R)-3,20-dicarboxylic acid The title compound is prepared according to Example 1 (vi) by substituting 3-carbomethoxy 20 5-g-pregn-3-ene-(20R)-20-carboxylic acid for 20-g-(hydroxymethyl)-3-carbomethoxy-5-g-pregn-3-ene.

EXAMPLE 10 N,N-Diisopropyl-5-g-preqn-3-ene-(20R)-2 0-25 carboxamide-3-carboxylic acid The title compound was prepared according to Example 2 (vii-viii) by substituting 3-carbomethoxy-5-a-pregn-3-ene-(20R)-20-carboxylic acid, prepared as in 3* Example 9, for 3-carbomethoxy-3-androstene-17C-carboxylic acid. 235818 EXAMPLE 11 -a-3-Ene-17B-carboxaldehyde-3-carboxylic acid (i) 3-Carbomethoxy-5-g-androst-3-ene-17B-carboxychloride A solution of 3-carbomethoxy-3-androstene-17B-carboxylic acid (462 mg, 1.0 mmol) is suspended in 10 ml toluene and treated with 0.5 ml of oxalyl chloride for 2 hours.. The volatile materials are then removed at 1 mmHg leaving a residue of 3-carbomethoxy-5-a—androst-3-ene-17S-carboxylchloride. (ii) 3-Carbomethoxy-5-g-androst-3-ene-176-carboxaldehyde A solution of 3-carbomethoxy-5-a-androst-3-ene-17B-carboxylchloride (480 mg, 1.0 mmol) in 10 ml tetrahydrofuran is treated with lithium tri-t-butoxyaluminum hydride (254 mg, 1.0 mmol) at 0°C for one hour to yield, after aqueous workup, 3-carbomethoxy-5-a-androst-3-ene-17B-carboxaldehyde. (iii) 5-a-3-Androst-3-ene-17B-carboxaldehyde-3-carboxylic acid The title compound is prepared according to Example 2 (viii) by substituting 3-carbomethoxy-5-g-androst-3-ene-17B-carboxaldehyde for 3-carbomethoxy-3-androstene-17B-N,N-diisopropylcarboxamide.

EXAMPLE 12 -a-Androst-3-ene-17B-(l-oxobuty1)-3-carboxy1ic acid (i) 3-Carbomethoxy-17B-(1-oxobutyl)-5-g-androst-3-ene A solution of 3-carbomethoxy-5-g-androst-3-ene-17B-carboxylchloride (480 mg, 1 mmol), prepared as in Example 11, in 10 ml THF is treated with 1.0 mmol of di-n-butyl copperlithium at -78°C. The reaction is qu.enched with aqueous ammonium chloride. 235 \ ; Extraction with dichloromethane followed by concentration 1 of the organic extracts and chromatography of the residue yields 3-carbomethoxy-17G-(l-oxobutyl)-5-a-androst-3-ene. (ii) 5-a-Androst-3-ene-170-(1-oxobutyl)-3-carboxylic acid 5 The title compound is prepared according to Example 1 (vi) by substituting 3-carbomethoxy 17G—(1-oxobutyl)-5-a-androst-3-ene for 20-a-(hydroxymethyl )-3-c arbomethoxy-5-a-pregn-3-ene.

EXAMPLE 13 Androst-3,5-diene-17I3-ol-3-carboxylic acid The title compound is prepared according to Example 3 (iii through v) by substituting commercially available testosterone acetate for androst-4-ene-3-one-1713 15 N,N—diisopropylcarboxamide.

EXAMPLE 14 Androst-3,5-diene-17-one-3-carboxylic acid The title compound is prepared according to 20 Example 9 (i) by substituting androst-3,5-diene-17B-ol-3-carboxylic acid (Example 13) for 20-a-( hydroxymethyl )-3-carbomethoxy-5-a-pregn-3-ene.

EXAMPLE 15 Ethyl pregn-3,5,17(20)-triene-3-carboxy-21-oate A solution of sodium ethoxide (680 mg, 10 mmol) in 5 ml ethanol is added to a mixture of androst-3, 5-diene-17-one-3-carboxylic acid (942 mg, 3 mmol) prepared as in Example 14, and methyl diethylphosphonoacetate 30 (2.12 g, 10 mmol) and the resulting mixture heated at reflux for 4 hours. The mixture is cooled, concentrated, diluted with dilute acetic acid and washed with ether. The combined ethereal extracts are washed with water and 2358 N • -79- t V/ J (J brine, and concentrated to yield ethyl pregn-3,5,17(20)-1 triene-3-carboxy-2l-oate.

EXAMPLE 16 Androst-3,5,16-triene~17-N,N-diisopropyl-5 carboxarnide-3-carboxylic acid (i) Androst-3,5,16-triene-17~(trifluoromethylsulf onate)-3-carboxylic acid To a solution of androst-3,5-diene-17-one-3-carboxylic acid (314 mg, 1 mmol), prepared as in 10 Example 14, in 10 ml methylene chloride is added 2,6—di—t—butyl-4—methylpyridine (272 mg, 1.5 mmol) and trif luoromethanesulfonic anhydride (0-.3 ml, 1.6 mmol) and the solution is stirred for 4 hours. The reaction mixture is then diluted with methylene chloride, washed with 10% 15 hydrochloric acid, brine, and concentrated to yield crude androst-3,5,16-triene-17-(trifluoromethylsulfonate)-3-carboxylic acid. (ii) Androst-3, 5,16-triene-17-N'yN-diisopropyl-carboxamide-3-carboxyIic acid A mixture of androst-3,5,16-triene-17- (trifluoromethylsulfonate)-3-carboxylic acid (447 mg, 1 mmol), triethylamine (200 mg, 2 mmol), diisopropylamine (4 g, 40 mmol), and bis(triphenylphosphine)palladium(II) acetate (22 mg, 0.03 mmol) in 4 ml DMF is stirred under an ' 25 atmosphere of carbon monoxide for 4 hours. The mixture is then diluted with 10% hydrochloric acid and thoroughly washed with dichloromethane. The dichloromethane solution is washed with brine, dried and concentrated, and the residue is recrystallized (diethylether) to yield ^ 30 androst-3,5,16-triene-17-N,N-diisopropylcarboxamide-3- carboxylic acid.

EXAMPLE 17 23 5 8 18 1 2 ' ,3 ' -a-Tetrahydro£urari-2 ' -spiro-17-( 3 , 5- androstadiene-3-carboxylic acid The title compound is prepared according to Example 3 (iii through v) by substituting 2',3'-g-5 tetrahydrofuran-2'-spiro-17-(androst-4-ene-3-one) for androst-4-ene-3-one-l7B-N,N-di isopropylcarboxamide.

EXAMPLE 18 3-Carbomethoxy-17B-acetamido-3,5-androstadiene 10 The title compound is prepared according to Example 3 (iii-iv) by substituting 17B-acetamido-4-androsten-3-one for androst-4-ene-3-one-17B-N,N-diisopropylcarboxamide.

EXAMPLE 19 Androst-3,5-diene-17-g-ol-3,1713-dicarboxylic acid (i) 17B-Cyano-17-g-acetoxyandrost-4-ene-3-one 4-Androsten-3,17-dione (20 g) is dissolved by gentle warming in acetone cyanohydrin 20 (30 ml). The crystals which form after several minutes are filtered, washed with pentane, and then dissolved-in a mixture of pyridine (50 ml) and acetic anhydride (50 ml). After 48 hours the volatiles are removed under reduced pressure. The residue is then dissolved in ether and J 25 washed successively with 5% hydrochloric acid and aqueous sodium bicarbonate. The organic solution is dried and concentrated to afford a mixture of C-17 epimers of 17-cyano-17-acetoxyandrost-4-ene-3-one. Chromatography affords 17S-cyano-17-g-acetoxyandrost-4-ene-3-one. ^ 30 (ii) 3-Carbomethoxy-17B-cyano-l7-g-acetoxy- androst-3,5-diene The title compound is prepared according to Example 3 (iii-iv) by substituting 235 8 1 """N .) 17-cyano-17-acetoxyandrost-4-ene-3-one for androst-4-ene-1 3-one-17B-N,N-diisopropylcarboxamide. (iii) Androst-3 ,5-diene-17-g-ol-3 ,17(3-dicarboxylic acid A solution of 3-carbomethoxy-178-5 cyano-17-g-acetoxyandrost-3,5-diene in methanol is 1 cooled to 15°C. Dry hydrochloric acid is bubbled into the solution and the mixture allowed to stand at room temperature for 2 hours. Solvent is then removed under reduced pressure. A mixture of 1:1 THF-water is added 10 followed by excess sodium hydroxide and the mixture is stirred for 2 hours. The reaction mixture then is acidified and extracted with chloroform. Concentration of the organic solution affords androst-3,5-diene-17-g-ol-3,17B-dicarboxylic acid which is recrystallized from 15 methanol.

EXAMPLE 20 -a-Androst-3,8(14)-diene-17B-ol-3-carboxylic acid (i) Androst-5,7-diene-3B,17B-diol 20 A mixture of androst-5-ene-3fl,17B-diol diacetate (3.75 g, 10 mmol), dibromantin (2.03 g, 7 mmol), and sodium bicarbonate (4.54 g, 54 mmol) in hexane (200 ml) is heated under reflux for 0.5 hours. The mixture is then cooled and filtered and the filtrate D 25 evaporated to dryness. The residue is dissolved in 50 ml toluene and treated with lithium bromide (2 g) in 5 ml of acetone. The mixture is stirred at 0°C for 2 hours and then treated with 2 ml triethylamine and 1.5 ml benzenethiol. After stirring at room temperature for 1.5 v 30 hours, 100 ml ethyl acetate is added and the organic solution is washed with 1 N hydrochloric acid and water. The organic phase is dried and concentrated. The residue is then redissolved in 75 ml ethyl acetate, cooled to 0°C 235818 /" ' and treated with 2.6 g of m-chloroperbenzoic acid for 2 1 hours. The mixture is washed with 10% sodium bicarbonate solution and then concentrated. The residue is dissolved in 100 ml toluene, treated with triethylamine (3.6 ml), heated at 70°C for 24 hours, cooled, and washed with water. The organic solution was concentrated and chromatographed to yield androst-5,7-diene-3S,l7Q-diol diacetate. The diacetate is treated with K2C03 in a 10:1 methanol:water solution overnight to yield, after extractive workup, androst-5,7-diene-3B,17G-diol. (ii) Androst-4,7-diene-3,17-dione A solution of androst-5,7-diene-3G,17G—diol (2.9 g, 10 mmol) in 150 ml toluene is azeotropically dried for one hour. Butanone (15 ml) is added followed by aluminum isopropoxide (1.7 g, 8 mmol) and the mixture is heated at reflux for 2.5 hours. The solution is then concentrated to a volume of 25 ml, diluted with trichloromethane, and washed with 5% hydrochloric acid, aqueous sodium bicarbonate, and brine. Concentration and chromatography affords androst-4,7- 2 0 diene-3,17-dione. (iii) 5-a-Androst-7-ene-3-one-17B-ol The title compound is prepared according to the procedure of Example 4 (i) by substituting androst-4,7-diene-3,17-dione for 3-oxo-17B-y 25 (hydroxymethyl)-4-androstene. (iv) 5-a,-Androst-8 (14) -ene-3-one-17Q-ol A solution of 5-cc-androst-7-ene-3—one-17B-ol in ethyl acetate is hydrogenated at room temperature and 1 atmosphere over 10% palladium on carbon J 30 for 8 hours. Filtration to remove the catalyst and concentration affords 5-a-androst-8(14)-ene-3-one-17B-ol. 235 8 1 8 .""N (v) 5-g-Androst-l , 8( 14)-diene-3-one-17B-o 1 1 The title compound is prepared according to Example 5 (ii) by substituting 5-g-androst-8(14)-ene-3-one-17B-ol for 20-g-(hydroxymethyl)-5—a-pregnan-3-one. (vi) 5-g-Androst-3, 8(14)-diene-17B-ol-3- carboxylic acid The title compound is prepared according to Example 5 (v through x) by substituting 5-g-androst-l,8(14)-diene-3-one-17B-ol for 20-g-10 (hydroxymethyl)-pregn-4-ene-3-one.

EXAMPLE 21 N,N-Diisopropyl androst-3 , 51 7-triene-17B-carboxamide-3-carboxylic acid 15 (i) Androst-4,6-diene-3-one-17B-N,N-diisopropyl- carboxamide Androstr-4-ene-3-one-17B-N,N-diisopropyl-carboxamide (12 g, 30 mmol) and chloranil (8.95 g, 36.4 mmol) in 700 ml t-butanol is heated at reflux for 3.5 20 hours then cooled and filtered. The filtrate is concentrated and the residue taken up in 700 ml trichloromethane and washed successively with 4 x 150 ml water, 3 x 150 ml aqueous sodium bicarbonate, 3 x 150 ml 5% sodium hydroxide, 3 x 150 ml brine, dried over sodium ^ 25 sulfate and concentrated to yield androst-4,6-diene-3- one-17B-N,N-diisopropylcarboxamide. (ii) N,N-Diisopropyl androst-3,5,7-triene-176-carboxamide-3—carboxylic acid ^ The title compound is prepared according to Example 3 (iii-v) by substituting androst-4,6-diene-3-one-17B-N,N-diisopropylcarboxamide for androst-4-ene—3—one-17B—N, N—di i sopropy lcar boxamide.

EXAMPLE 22 235 8 1 1 A-Homo-5-g-4-ene-17B-N,N-diisopropyl- carboxamide-4-carboxylic acid < i) A-Homo-5-g-androstan-4-one-l 7B-N,N-diisopropylcarboxamide 5 To a 0°C solution of 3-oxo-5-g- } androstane-17B-N",N-diisopropylcarboxamide (15 g), prepared as in Example 4, and KOH (28 g) in ether (500 ml) and methanol (850 ml) is added 20 g of N-methylnitrosourea over 20 minutes. After 5 hours, 300 ml of 10% 10 hydrochloric acid is added and the mixture is filtered and ) concentrated to remove the organic solvents. The resulting aqueous suspension is extracted vith ether and the ethereal solution is dried and concentrated. Chromatography of the residue yields A-homo-5-g-15 androstane-4-one-17B-N,N-diisopropylcarboxamide. (ii) A—Homo-5-g-4-ene-l 7B-N, N-di isopr opy 1 -carboxamide-4-carboxylic acid Utilizing the protocol of Example 3 (iii-v), substitution of androst-4-ene-3-one-17B-N,N-20 diisopropylcarboxamide with A-homo-5-g-androstane-4- one-17B-N,N-diisopropylcarboxamide yields a mixture of 3-ene, and 4-ene A-homo-4-carboxylic acids. Chromatography and recrystallization yields pure A-homo-5-g— androst-4-ene-17B-N,N-diisopropylcarboxamide-4-carboxylic 25 acid.

EXAMPLE 23 N,N-Diisopropyl-4-chloro-androst-3,5-diene-17B-carboxamide-3-carboxylic acid (i) 3-Oxo-and r o s t ane-4-5-g-epox i de-17 B-N,N-30 diisopropylcarboxamide The title compound is prepared according to Example 4 (v) by substituting androst-4-ene-3 one-17B-N,N-diisopropylcarboxamide for 3-oxo-5-a-androst-l-ene-17B-N,N-di i sopropylcarboxamide. 235 8 1 (ii) 3-Oxo~4-chloro-4-androstene-17B~N,N- 1 diisopropylcarboxamide A stream- of hydrogen chloride gas is passed through a chloroform solution of 3-oxo-androstane-4,5—a—epoxide—17B—N,N-di isopropylcarboxamide for 2 minutes. The solution is then washed with water, dried ) (Na^SO^), and concentrated to yield 3-oxo-4- chloro—4-androstene-1713—N,N-diisopropylcarboxamide . (iii) N,N~Diisopropyl-4-chloro-androst-3,5-diene-17B-carboxamide-3-carboxylic acid The title compound is prepared ") according to Example 3 (iii through v) by substituting 3-oxo~4-chloro-4-androstene-17B—N, N-di isopropyl carboxamide for androst-4-ene-3-one-17B-N,N-diisopropylcarboxamide.

EXAMPLE 24 N,N-Diisopropyl-4-methyl-5-<x-androst-3-ene-17B-carboxamide-3-carboxylic acid (i) 3-Oxo-17fi-(hydroxymethyl)-4-methyl-4-androstene A mixture of potassium-t-butoxide (5 g) in 100 ml t-butanol is heated to reflux. A solution of 3-oxo-17B-(hydroxymethyl)-4-androstene (10 g) in t-butanol is added followed by a solution of methyl iodide (2.7 g) in t-butanol. Heating is continued for 3 hours. } .25 The mixture is then cooled, acidified, and extracted with dichloromethane. The dichloromethane solution is washed with brine, dried, and concentrated to yield 3-oxo-17B-(hydroxymethyl)-4-methyl-4-androstene. (ii) N,N-Diisopropyl-4-methyl-5-a-androst-3-^ 3 0 ene-17B-carboxamide-3-carboxylie acid The title compound is prepared according to Example 2 (iii through viii) by substituting 235 8 18 i 3-oxo-17B-(hydroxymethyl)-4-methyl-4-androstene for 1 3-oxo—17B-(hydroxymethyl)-4-androstene.

EXAMPLE 25 N,N-Diisopropyl-4-trifluoromethyl-androst-3,5-5 diene-17B-carboxamide-3-carboxylic acid (i) 3-Qxo-4-trifluoromethy1-4-androstene-17B-N,N-diisopropylcarboxamide A solution of 3-oxo-4-androstene-17I3-N,N-diisopropylcarboxamide (1 g) in 10 ml of pyridine is 1° cooled to —78°C. Trifluoromethyl iodide gas is condensed in a dry ice-acetone bath and added to the steroid-pyridine cooled solution. The resulting solution is photolyzed using a medium pressure 450 watt mercury vapor lamp at room temperature for 18 hours. The reaction 15 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 eluting with 20% ethyl acetate in hexane yields 20 3-oxo-4-trifluoromethyl-4-androstene-17B-N,N--diisopropylcarboxamide. (ii) N,N-Diisopropyl-4-trifluoromethyl—androst- 3,5-diene-17B-carboxamide-3-carboxylic acid The title compound is prepared Ls 25 according to Example 3 (iii through v) by substituting 3-oxo-4-trifluoromethyl-4-androstene-17G-N,N-diisopropyl-carboxamide for androst-4-ene-3-one-17B-N,N-diisopropyl-carboxamide.

EXAMPLE 26 N,N-Diisopropyl-6-trifluoromethyl-androst-3,5-diene-17B—carboxamide-3-carboxylic acid (i) 3-Oxo—6-trifluoromethyl—4-androstene-17B-N,N-diisopropylcarboxamide 35 17B-N,N-diisopropylcarboxamide-3- (trifluoromethylsulfonate)-androst-3,5-diene (1 g) is n 235 dissolved in 10 ml of pyridine and is photolyzed using a 1 Hanovia medium pressure 450 watt 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, brine, dried over 5 anhydrous magnesium sulfate, and evaporated to dryness. Silica gel column chromatography eluting with 20% ethyl acetate in hexane affords 3-oxo-6-trifluoromethyl-4-androsten-17B-N,N-diisopropylcarboxamide. (ii) N,N-Diisopropyl-6-trifluoromethy1-androst-—^ ^ 3,5-diene-17G-carboxaraide-3-carboxylic acid The title compound is prepared according to Example 3 (iii through v) by substituting 3-oxo-6-trifluoromethy 1-4-androstene-17S-N,N-diisopropyl-carboxamide for androst-4-ene-3-one-17B-N,N-15 diisopropylcarboxamide.

EXAMPLE 27 17B—N,N-Di isopropylcarboxamide—6-fluoro-androst-3,5-diene-3—carboxylic acid 20 (i) 17B—Piisopropylcarboxamide-5-a- androstene—3—spiro-2'-dioxolane To a solution of 3-oxo-4-androstene-17B-N,N-diisopropylcarboxamide (8 g) in 300 ml of benzene was added 30 ml of ethylene glycol and p-toluenesulfonic i > acid (240 mg). The resulting solution was refluxed under argon with water collection 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, 3 0 235 brine, dried over anhydrous magnesium sulfate, and 1 evaporated to dryness. The crude material was purified on a silica gel column using 20% ethyl acetate in hexane as the eluting solvent to afford 7 g of 17B-N,N-diisopropyl-carboxamide-5-a-androstene-3-spiro-2'-dioxolane (80%) . 5 (ii) 17B-N,N-Diisopropylcarboxamide-5-a,6-a- 3 epoxy-androstane-3-spiro-2'-dioxolane To a solution of 17B-N,N-diisopropyl-carboxamide-5-androstene-3-spiro-2'-dioxolane (4.43 g, 10 mmol) in 100 ml of dry dichloromethane at 0°C was added 10 a solution of m-chloroperbenzoic acid (2.8 g) in 40 ml of dichloromethane dropwise through a dropping funnel. After completion of addition of m-chloroperbenzoic acid, the reaction mixture was allowed to warm to room temperature and stirred for another 30 minutes. The reaction mixture 15 was then washed with 10% aqueous sodium sulfite solution four times followed by 5% aqueous sodium bicarbonate solution, brine, dried over anhydrous magnesium sulfate, and concentrated to a syrup. Column chromotography, eluting with 30% ethyl acetate in hexane, yielded 2.76 g 20 of 17B-N,N-diisopropylcarboxamide-5-a, 6-a-epoxy- androstane-3-spiro-2'-dioxolane as a white solid (61%). (iii) 3-Oxo-6-fluoro-4-androstene-17fi-N,N-diisopropylcarboxamide 17B-N,N-diisopropylcarboxamide-5-a, ^ 25 6-a-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 borontrifluoride-etherate (2.5 ml) under argon. The reaction solution was stirred at room temperature under argon for four hours and then s 30 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 235 8 1 saturated hydrogen chloride in glacial acetic acid. The 1 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 5 magnesium sulfate, and evaporated to dryness. The crude material was purified on a silica gel column eluting with 25% ethyl acetate in hexane to yield 3-oxo-6B-fluoro-4-androstene-17G-N,N-diisopropylcarboxamide (675 mg, 30%) and 3-oxo-6-a-fluoro-4-androstene-17B-N,N-10 diisopropylcarboxamide (900 mg, 40%). (iv) 17B-N, N-Diisopropylcarboxamide-3-(trifluoromethylsulfonate)-6-fluoro-androst-3,5-diene To a solution of the epimers of 15 3-oxo-6-fluoro-4-androstene-17B-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 20 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 25 chromatography (silica gel, 10% ethyl acetate in hexane) yielded 17B-N,N-diisopropylcarboxamide-3-(trifluor omethy1— sulfonate)-6-fluoro-androst-3,5-diene and 17S-N,N-diisopropylcarboxamide-3-(trifluoromethylsulfonate)-6-f luoro-androst-2, 4-diene. (v) Ethyl 17B-N,N-di i sopropylcarboxamide—6- fluoro-androst—3,5-diene-3-carboxylate A mixture of 17B-N,N-diisopropyl-carboxamide-3-(trif luoromethylsulf onate) -6-f luoro-andros t- 235 8 18 3,5-diene (250 mg) , triethylamine (0.12 ml), ethanol (1.5 ml), N,N-dimethylformamide (2 ml) and bis(triphenyl-phosphine)palladium(II) acetate (25 mg) was purged with carbon monoxide for 10 minutes. The reaction mixture was stirred under one 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 eluting with 10% ethyl acetate in hexane yielded 108 mg of ethyl 17B-N,N-diisopropylcarboxamide-6-fluoro-androst-3,5-diene-3-carboxylate (55%). (vi) 1713-N, N-Di isopropyl carboxamide-6-f luoro-androst-3 ,5-diene-3-carboxylic Acid The title compound was prepared according to Example 2 (viii) by substituting ethyl 17G-N,N-diisopropylcarboxamide-6-fluoro-androst-3,5-diene-3-carboxylate for 3-carbomethoxy-3-androstene-1713-N,N-diisopropylcarboxamide. The product had a melting point of 225—226°C (recrystallized from acetonitrile).

EXAMPLE 28 N-t-Butyl Androst-3,5-diene-17l3-carboxamide-3-Carboxylic Acid (i ) Andr ost-4-ene-3-one- 17fl-N-t-Butyl Carboxamide The title compound was prepared according to Example 3(ii) by using tert-butylamine in place of diisopropylamine. ( ii) 17 B- (N-t-buty 1c arboxamide) -3- (trif luo r omethy 1 sulfonate)-androst-3,5-diene The title compound was prepared in 4 5% yield according to Example 3(iii) by using androst-4-ene— 3-one-17B-N-t-butylcarboxamide in place of androst-4-ene- 235818 3 -one- 1713-N, N-di isopropyl carboit amide. (iii) 3-Carbomethoxyandrost-3,5-diene-l butylcarboxamide The title compound was prepared according to Example 3(iv) by using 17S-(N-t-butylcarboxa-mide)-3-(trifluoromethylsulfonate)-androst-3,5-diene in place of 17B-(N,N-diisopropylcarboxamide)- 3-(trifluoromethylsulf onate)-androst-3 ,5-diene. (iv) N-t-Butyl Androst-3,5-diene-17B-carboxamide-3-carboxylic Acid The title compound was prepared according to Example 3(v) by using 3-carbomethoxy-androst-3,5-diene-17C-N-t-butylcarboxamide in place of 3-carbomethoxyandrost-3,5-diene-17B-N,N-diisopropyl-carboxamide. The title compound was recrystallized from acetonitrile, m.p. 247-250°.

EXAMPLE 28A N-t-Butyl Androst-3,5-diene-17B-carboxamide-3-carboxylic Acid (i) N-t-Butyl Androst-3,5-diene-3-bromo-17B-carboxamide To an ice cooled solution of 3-oxo—androst-4-ene—17-carboxylic acid (10g, 30 mmol) in toluene (100 mL) was added a solution of oxalyl bromide (24.2g, 11 mL, 112 mmol) in toluene (lQOmL). The reaction mixture was warmed to room temperature until gas evolution ceased.

Excess oxalyl bromide was evaporated at room temperature and the residual androst-3,5-diene-3-bromo-17S-acid bromide in toluene solution was ice cooled. T-butyl amine (40 mL) in toluene (70 mL) was slowly added and the mixture was stirred 19 hours. 23 5 8 The reaction mixture was diluted with water 1 (2Q0mL) and toluene (lOOmL). The organic soluble material was separated and washed with water (2 x 250mL), dried over magnesium sulfate, and evaporated. The oil/solid residue was flash chromotographed using silica gel, flash 5 grad, eluting with 5:1 hexane:ethyl acetate to give 5.5 g of white solid, mp 174-77°C(40.3%). (ii) N-t-Butyl Androst-3,5-diene 17B-carboxamide-3-carboxylic Acid N-Butyl lithium (2.5M in hexane, 9'OmL, 225 mmol) 10 was added over 20 minutes to a solution of androst-3,5-diene-3-bromo-17B-N-t-butylcarboxamide (25g, 57.7mmol) in dry tetrahydrofuran (650mL) cooled to -64 C. After 2.5 hours the reaction mixture was quenched with dry CO for hour, diluted with toluene (500 mL), 10% 15 hydrochloric acid solution (100 mL), and water (500 mL). The organic soluble extract was separated, washed with water (2x 300 mL), dried over magnesium sulfate and evaporated. The crude off-white solid was recrystallized from ethyl acetate to give 3.5 g of white solid, 20 mp 242-49 °C D 25 J 3 0 -93-' EXAMPLE 28B 235 8 1 N-t-Butyl Androst-3,5-diene-3-bromo-17B-carboxamide-3-carboxylic Acid (i) Methyl Androst-3,5-diene-3-bromo-17B- 1 carboxylate Methyl androst-4-ene-170-carboxylate (lOOg, 316(mmol) was dissolved in glacial acetic acid (500 mL), 10 and phosphorous tribromide (119 g, 80ml, 440mmol) was added over 15 minutes. After stirring at room temperature for 2 hours, the yellow precipitate that formed was filtered, washed with methanol (400 mL), and dried in vacuo to give 97.6 g (81.4%) of white solid, mp 178-180°C. (ii) Androst-3,5-diene-3-bromo-17B-carboxylic .

Acid A solution of potassium hydroxide (50g, 890 20 nunol) in 9:1 methanol: water (500 mL) was added to a slurry of methyl androst-3,5-diene-3-bromo-17B-carboxylate. After refluxing 41 hours, the resultant yellow solution was cooled and brought to pH4 using 10% ^ hydrochloric acid solution. The white solid that formed was filtered and washed with water. After drying in vacuo at 40°C, 49g (100%) of product, mp 248-250°C was obtained. > 25 > 30 (iii) N-tButyl Androst-3 ,5-diene-3-bromo-17B-carboxamide Oxalyl chloride (17ITIL, 190 mmol) was added to a cooled mixture of androst-3/5-diene-3-bromo-17B— carboxylic acid (30g,, 79 mmol) in dry toluene (300mL) over 14 minutes. The reaction mixture was stirred at room 35 temperature until gas evolution ceased (about 1.5 hours). 235 8 1 D Excess oxalyl chloride was removed by 1 concentration in vacuo at room temperature. The reaction mixture was ice cooled and t-butylamine (102 mL, 9 54 mmol) was added over 10 minutes. The reaction mixture was stirred at room temperature for 1.5 hours. 5 The mixture was diluted with water (300mL) and toluene (50mL). The organic layer was separated, washed with water (2x300 mL), dried over magnesium sulfate and evaporated. The resultant pale yellow solid was slurried first methanol:water (7.3, 200mL) then acetonitrile:water 10 (39:11, 300mL). After filtration and drying in vacuo, 33.2 (77.5%) of white solid product was obtained. (iv) N-t-Butyl Androst-3,5-diene-17fi-carboxamide-3-carboxylic Acid N—Butyl lithium (2.5M in hexane, 90mL, 225 mmol) was aded over 20 minutes to a solution of androst-3,5-diene~3-bromo-17-N-t-butylcarboxamide (25g 57.7mmol) in dry tetrahydrofuran (650mL) cooled to -64°C. After 2.5 20 hours the reaction mixture ws quenched with dry CO for one hour, diluted with toluene (500 mL), '10% hydrochloric acid solution (100 mL), and water (500 mL). The organic soluble extract was separated, washed with water (2x 3 00 mL), dried over magnesium sulfate and evaporated. The J 25 crude off-white solid was recrystallized from ethyl acetate to give 3.5 g of white solid, mp 242-49°C.

EXAMPLE 28C J 3 0 N,N-Diisopropyl-androst-3,5-diene- 17B-carboxamide-3-carboxylic Acid The title compound was prepared by substituting di isopropyl amine for t-butylamine in the process of Example 28B. r> l D -95-EXAMPLE 28D 235 8 1 Androst-3,5-diene-3-methoxycarbonyl-17ft-t-butylcarboxamide A mixture of N-t-butyl "■■S. . * androst-3,5-diene-3-bromo-17B-carboxamide (42 mg), prepared as in Example 28B, palladuim (II) acetate (20mg), triphenyIphosphine (40mg), methanol (5mL), dimethyl formamide (5mL), and triethylamine (3mL) was heated at 85-95°C under a carbon monoxide atmosphere until the starting material disappeared. The title compound was isolated by flash chromatography on silica gel with 6:1 hexane:ethyl acetate.

EXAMPLE 28E Androst-3,5-diene-3-Methoxycarbonyl-17fl-N,N-diisopropylcarboxamide The title compound is prepared according to Example 28D, substituting N,N-diisopropylamine for N-t—butylamine.

EXAMPLE 29 N,N-Diisopropyl 5-a-Androst-2-ene-178-carboxamide-3-carboxylic Acid (i) 17fi-(N,N-Diisopropylcarboxamide)-3-(tri-fluoromethylsulfonate)-5<x-androst-2-ene 30 The title compound was prepared according to Example 4(vii) by using 3-oxo-5a-androstane— 17B-N,N,-diisopropylcarboxamide in place of 3—oxo—4-f luor o—5a—androst-l—ene—7B—N,N—diisopropylcarboxamide . 235 8 18 ' • (i i) 3-Carbomethoxy-5a-Androst-2-ene-17Q-N, N- 1 diisopropylcarboxamide The title compound was prepared according to Example 3(iv) by using 17G-(N,N-diisopropyl-carboxamide)-3-(trifluoromethylsulfonate)-5a-androst-2-5 ene in place of 17B-(N,N-diisopropylcarboxamide)-3-... 1 (trif luoromethylsulf onate) androst-3, 5 ,-diene . (iii) N,N-Diisopropyl 5a-Androst-2-ene-170-carboxamide-3-carboxylic Acid The title compound was prepared according 10 to Example 3(v) by using 3-carbomethoxy-5a-androst-2-ene-17G-N,N-diisopropylcarboxamide in place of 3-carbomethoxyandrost-3,5-diene-17G-N,N-diisopropylcarbox-amide. The title compound was recrystallized from acetonitrile; m.p. 203-205°.

EXAMPLE 30 N,N-Diisopropyl Androst-2,4-diene-17B-carboxamide—3—carboxylic Acid (i) 17B-(NyN-Piisopropylcarboxamide):-3- trifluoromethylsulfonate)androst-2,4-diene The title compound was prepared according to Example 4(vii) by using 3-oxoandrost-4-ene—17G-N,N-diisopropylcarboxamide in place of 3-oxo-4-fluoro-5-a-androst-l-ene-17fi~N,N- f-s diisopropylcarboxamide. The title compound was recrystallized from methanol; m.p. 165-168°. (ii) 3-Carbomethoxyandrost-2,4-diene-l7B-N,N-diisopropylcarboxamide 3 0 The title compound was prepared according to Example 3(iv) by using 17B-(N,N-diisopropylcarboxamide)-3-(trifluoromethylsulfonate)-androst-2,4-diene in place of 17B-(N,N-diisopropylcarbox-amide)-3-(trifluoromethylsulfonate)-androst-3,5-diene.

The title compound had a melting point of 162° after trituration with methanol. -9 7- 235 8 i \ (iii) N,N-Di isopropyl Androst-2,4-diene-170- 1 carboxamide-3-carboxylic Acid The title compound was prepared according to Example 3(v) by using 3-carbomethoxy-androst-2,4-diene-17B,N,N-diisopropylcarboxamide in place of 3-carbomethoxy-5 androst-3,5-diene-17B-N,N-diisopropylcarboxamide. The title compound was recrystallized from methanol-acetone; m.p. 227°.

EXAMPLE 31 N,N—Diisopropyl 5-a-Androstane-17B— carboxamide-3B-carboxylic Acid (i) 3B-Carbomethoxy-5ct-androstane-17B-N fN-di isopropylcarboxamide 3-Carbomethoxy-5-a-androst-2-ene-17f3- 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° and 1 atm over 20 mg 10% Pd on carbon. The solution was filtered to remove the 20 catalyst and concentrated to yield 77 mg (88%) of the title compound. (ii) N,N—Diisopropyl 5-a-Androstane-17B-carboxamide-3B-carboxylic Acid The title compound was prepared ^ 25 according to Example 3(v) by using 3B-carbomethoxy- -a—androstane-17B-N,N-diisopropylcarboxamide in place of 3-carbomethoxyandrost-3,5-diene-17B-N,N-diisopropylcarboxamide. The title compound was recrystallized from acetonitrile; m.p. 142-144°. % y 30 235 8 1 g 1 EXAMPLE 32 N,N-Diisopropyl Estr-3,5(10)-diene-17fl-carboxamide-3-carboxylic Acid (i) 3-Methoxy-estr-1,3,5(10),16-tetr aene-17-5 N,N-diisopropylcarboxamide The title compound was prepared according to the two steps of Example 3(iii, iv) by using methyl estrone in place of androst-4-ene-3-one-17S-N,N-diisopropylcarboxamide and diisopropylamine in place **s 1° of methanol. (ii) 3-Methoxy-estr-l, 3 ,5 (10 )-triene-1713-N,N-diisopropylcarboxamide 3-Methoxy-estr-l,3,5(10),16-tetraene-17-N,N-diisopropylcarboxamide (4.45g, 11.3 mmol) in 100 ml of 15 a 3:1 solution of ethyl acetate and ethanol was hydrogenated at 25° and 1 atm. over PtC^ (350 mg) for 6 hours. The solution was filtered to remove the catalyst and concentrated to afford 4.36g (98%) of the title compound. . (iii) 3-Oxo-estr-5( 10 J-ene-^B-N.N- diisopropylcarboxamide To a solution of 3-methoxyestr-l,3,5(10)-triene-17B-N,N-diisopropylcarboxamide (1.4 g, 3.5 mmol) in liquid ammonia (25 ml), THF (10 ml), and 25 t-butanol (10 ml) at -33°C was added 0.5 g of lithium wire. The solution was stirred for 5 hours 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 30 concentrated to a white solid which was suspended in a methanol-water mixture and then treated with 1.4g 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 35 (silica, 1:9 ethyl acetate-hexane) to yield 0.4g of the title compound.

D 235818 (iv) N,N-Diisopropyl Estr-3,5(10)-diene-17B-carboxaniide-3-carboxYlic Acid The title compound was prepared according to Example 29, (i-iii), by using 3-oxoestr-5(10 )-ene-17B-N,N-diisopropylcarboxamide for 3-oxo— 5-a-androstane-17B-N,N-diisopropylcarboxamide. The title compound was recrystallized from acetonitrile; m.p. 250-253°.

EXAMPLE 33 N,N-Diisopropyl Estr-3,5-diene-17B-carboxamide-3-carboxylic Acid (i) 3-Oxoestr-4-ene-17B-N,N-diisopropyl-carboxamide 3-Oxoestr-5(10)-ene-17B-N,N-diisopropylcarboxamide (Example 29, (iii)) was dissolved in methanol and 10% aqueous HC1 (2:1) and heated at 6 5° for 1 hour, cooled, and thoroughly extracted with chloroform. The organic extracts were concentrated to yield the title compound as a white solid. (ii) N,N-Diisopropyl Estr-3,5-diene-17B-carboxamide-3-carboxylic Acid The title compound was prepared according to Example 3(iii-v) by using 3-oxo-estr-4-ene-17B-N,N-diisopropylcarboxamine in place of andr ost-4-ene-3-one-17B-N, N-di isopropylcarboxamide. The title compound had a melting point of 215°.

EXAMPLE 34 17B-(N,N-Diisopropy1carboxamide)-Androst- . 3,5,11-triene—B—carboxylic Acid (i) Androst-4-ene-3-one-ll-o1-17B-carboxylic Acid Corticosterone is dissolved in methanol and treated with an aqueous solution of periodic n.

A v ■100- 235 8 18 1 acid at room temperature for 18 hours. The solution is then diluted with water -to induce precipitation of androst-4-ene-3-one-ll-ol-17I3-carboxylic acid which is collected by filtration. 5 (ii) Androst-4-ene-3,ll-dione-17B-carboxylic Acid To a solution of androst-4-ene-3-one-ll-ol-17B-carboxylic acid in acetone is added Jones Reagent dropwise until a red color persists. Isopropanol 10 is then added to quench the excess oxidant. The solution is decanted and the residual chromium salts are thoroughly washed with acetone. The combined organic solutions are then filtered through magnesium sulfate and concentrated to yield androst-4-ene-3,ll-dione-17B-carboxylic acid. 15 (iii) Androst-4-ene-3,ll-dione-17B-(N,N- diisopropyl-carboxamide) .

The title compound is prepared according to Example 3(ii) by substituting androst-4-ene-3/ll-dione-17B-carboxylic acid for androst-4-ene-20 3-one-17B-carboxylic acid. (iv) 17B-(N,N-Diisopropylcarboxamide)-3-(trifluor omethy 1 sul f onate) -11 -oxo-androst-3,5-diene.

The title compound is prepared according to Example 3 (iii) by substituting androst-4-ene-3, ll-dione-17B-(N,N-diisopropylcarboxamide) "fo r and androst-4-ene-3-one-17B-(N,N-diisopropyl-carboxamide). (v) 3— Carbomethoxy-ll-oxo-androst-3 , 5-diene 3 0 17fi-(N,N-diisopropylcarboxamide).

The title compound is prepared according to Example 3 (iv) by substituting 17B-(N,N-diisopropylcarboxamide)-3-( trif luoromethylsulf onate)-11-oxo-androst-3,5-diene for 17B-(N,N-diisopropyl-35 carboxamide)-3-( trif luoromethylsulfonate)-androst-3 , 5-diene . -loi- 23 5 8 1 8 (vi) 3-Carbomethoxy-ll-(trifluoromethyl- sulfonate)-androst-3,5,11-triene—17Q-(N,N-diisopropylcarboxamide).

The title compound is prepared according to Example 4(vi) by substituting 3-carbomethoxy-ll-oxo-androst-3,5-diene-17B~(N,N-diisopropylcarboxamide) for 3-oxo-4-fluoro-5<x-androst~l-ene-17B-(N,N-diisopropyl-carboxamide). (vii) 3-Carbomethoxy-androst-3,5,11-triene- 17B—(N,N-diisopropylcarboxamide). The title compound is prepared according to .the procedure of Cacchi (Tet. Lett. 25 (42) 4821-4824 (1984)) by substituting 3-carbomethoxy-ll-(trifluoromethylsulfonate)-androst-3,5,ll-triene-17B-(N,N-diisopropylcarboxamide) for 17B-acetoxyandrosta-3,5-diene-3-yl triflate. (viii) 17B—(N,N-Di isopropylcarboxamide)-androst-3,5,ll-triene-3-carboxylic Acid.

The title compound is prepared according Example 3 (v) by substituting 3-carbomethoxy-androst-3,5,ll-triene-17B-(N,N-diisopropylcarboxamide) for 3-carbomethoxy-androst-3,5-diene-17B-(N,N-diisopropylcarboxamide) .

EXAMPLE 3 5 17B-(N—t-Butylcarboxamide)-androst-3,5,ll-triene-3-carboxylic Acid The process of Example 3 5 wherein N-t-butyl amine is used in place of diisopropylamine yields 17B-(N-t-Butylcarboxamide)-androst~3,5,ll-triene-3-carboxylic Acid. 235818 EXAMPLE 36 17B-(N,N-diisopropylcarboxamide)-androst-3,5-diene-3-thiocarboxylic Acid A solution of 17B-(N,N-diisopropylcarboxamide) -androst-3,5-diene-3-carboxylic acid (1 mmol) is suspended in 10 mL toluene and treated with 0.5 mL of oxalyl chloride for two hours. The resulting solution is then slowly added to a solution of THF and hydrogen sulfide through which hydrogen sulfide is bubbled. The mixture is then diluted with ethyl acetate, washed with water, dried and concentrated the residue is recrystallized from acetonitrile to yield the title compound.

EXAMPLE 37 17B-(N-t-Butylcarboxamide)-androst-3,5-diene-3-thiocarboxylic Acid The process of Example 36 wherein 17B-(N,N-di isopropyl carboxamide)-androst-3,5-diene-3-carboxylic acid is replaced by 17B-(N-t-Butylcarboxamide)-androst-3,5-diene-3-carboxylic acid yields 17B-(N-t-Butylcarboxamide)-androst-3 , 5-diene~3-thiocarboxylic Acid.

EXAMPLE 38-47 The following compounds are preared by substituting diisopropylamine for t-butylamine using the procedures of examples 2, 3, 4, 7, 27, 29, 30, 31, 32, and 33, respectively: N-t-Butyl-5-a-androst-3-ene-17B-carboxamide-3-carboxylic acid; 17B-(N-t-Butylcarboxamide)-6-fluoro-5-a-androst-3-ene-3-carboxylic acid; 17B—(N-t-Butylcarboxamide)-6-fluoro—androst-3,5-diene-3-carboxylic acid; 3-Carbomethoxy-N-t-butyl-androst-3,5-diene-17B-carboxamide, 0 235 8 1 ~103" r, 1 17B-N-t-Butylcarboxamide-5~a-androst-l,3-diene-3- carboxylic acid; N-t-Butyl-5--a-androst--2-ene-17B-carboxamide-3-carboxylic acid; 5 N-t-Butyl-androst-2,4-diene-17B-carboxamide-3- carboxylic acid; N-t-Butyl-5-a-androstane-17B-carboxamide-3-carboxylic acid; N-t-Butyl-estr-3,5(10)-diene-17B-carboxamide-3-^ 10 carboxylic acid; and N-t-Butyl-estr-3,5-diene-17B-carboxamide-3-carboxylic acid.

EXAMPLE 4 8 An oral dosage form for administering Formula 15 (la) compounds is produced by screening, mixing, and filling into hard gelatin capsules the ingredients in the proportions shown in Table V, below.

Table V Ingredients Amounts -a-(Hydroxymethyl)-5-a-pregn-3- 50 mg ene-3-carboxylic acid magnesium stearate 5 mg lactose 75 mg •s ^ 30 EXAMPLE 49 The sucrose, calcium sulfate dihydrate and Formula (la) compound shown in Table VI below, are mixed and granulated in the proportions shown with a 10% gelatin solution. The wet granules are screened, dried, mixed 35 with the starch, talc and stearic acid, screened and compressed into a tablet. 235818 Table VI Ingredients Amounts N,N-Diisopropyl-5-a-androst-3-ene- 100 mg 17J3-carboxamide-3-carboxylic acid calcium sulfate dihydrate 150 mg sucrose 20 mg starch 10 mg talc 5 mg stearic acid 3 mg EXAMPLE 50 —a— (Hydroxymethyl) -4-f luor o-5-a-pregn-3-ene-3-carboxylic acid, 75 mg, is dispursed in 25 ml of normal saline to prepare an injectable preparation.

While the preferred embodiments of the invention are illustrated by the above, it is to be "understood that the invention is not limited to the precise instructions herein disclosed and that the right to all modifications coming within the scope of the following claims is reserved. c J - 105 -

Claims (6)

1. WHAT WE CLAIM IS: 1. A compound of the formula in which X1 is bromo, .chloro, fluoro, or iodo; _2 . R is present as H or CH3* X is H, CI, F, Br, I, CF3, or C1_galicyl and Y is H, CF3, F, or Cl, CH3; _ 14 . R IS (1) a-hydrogen, a-hydroxyl, or ^t-acetoxy and/or - 106 - 235810 o b-W-!:-R4 where W is a bond or 4 C^^alkyl, and R is (i) hydrogen, (ii) hydroxyl, (iii) C1_8alkyl, (iv) hydroxy C1_galkyl, (v) C1_Ralkoxy, (vi) NR R , where R and 6 R are each independently selected from hydrogen, C1_8-alkyl, ,-cycloalkyl, 5 6 phenyl; or R and R taken together with the nitrogen to which they are attached represent a 5-6 membered saturated ring comprising up to one other heteroatom selected from oxygen arid nitrogen, or (vii) OR7, where R7 is hydrogen, alkali metal, Ci_i8alkyl, benzyl, or B-Alk-OR8, where Alk is C1_12alkyl, and R® is (i) phenylC1_6alkylcarbonyl, (ii) C5_10cycloalkylcarbonyl, (iii) benzoyl, (iv) C1_8alkoxycarbonyl, (v) amino, or C]L_8alkyl substituted amino, carbonyl, - 107 - ? 3 5 81 8 2_ (vi) hydrogen, or (vii) C1_8alkyl, (2) =CH-Alk-CO-R4 or =CH-Alk-OR8, where Alk is present or absent, and X 4 8 tJ 5 R and R have the same meaning as 10 20 O above and R also is hydrogen or Ci_2Qalkylcarbonyl; (3) where the dashed bond replaces the 17-a-hydrogen, 9 9 2_5 (4) a-hydrogen and B-NHCOR where R is C, alkyl or B-NR5R6 where 5 6 R and R have the same meaning as above, (5) a-hydrogen and B-cyano, (6) a-hydrogen and B-tetrazolyl, or (7) keto; or moieties which can be chemically converted to moieties (1) through (7), except compounds in which: X1 is CI and R14 is CH3CO.
2. 2- A compound of Claim 1 that is N-t-butyl androst-3,5-diene-
3. 3-bromo-17B-carboxamide or N,N-diisopropyl-androst-3,5-diene-3-bromo-17B-carboxamide. 3. formula: r u J - 108 - A process for preparing compounds of the in which X* is bromo, chloro, fluoro, or iodo; present as H or CH^; _2 - R is X is H, CI, F, Br, I, CF_, or C, calkyl; o I—b Y is H, CF3, F, or Cl, CH3; and 14 R is as defined in claim 1, except compounds in which: X*" is ,C1 and R^"4 is CH^COj that comprises treating with a carboxylic acid halide or phosphorous polyhalide a compound of the formula: o 1 J X Y O 1 A in which R , R , x and Y are as defined above. - 109 - 235 3
4. 4. The process of Claim 3 wherein the compound prepared is N-t-butyl-androst-3,
5. 5-diene-3-bromo-17fi-carboxamide or N,N-diisopropyl-androst-3,5-diene-3—bromo-17B-carboxamide. 5. A compound as claimed in claim 1 or 2 substantially as hereinbefore described with reference to any example thereof.
6. 6. A process as claimed in claim 3 or 4 when performed substantially as hereinbefore described with reference to any example thereof. zealand f, ; -\!i c?r-:ci 240CT1990