WO1995028413A1

WO1995028413A1 - 17β-SUBSTITUTED 3-CARBOXY STEROIDS THAT INHIBIT 5-α-REDUCTASE

Info

Publication number: WO1995028413A1
Application number: PCT/US1995/004568
Authority: WO
Inventors: Dennis Alan Holt; Dennis Shinji Yamashita; John Gerald Gleason; Michael Gerard Darcy
Original assignee: Smithkline Beecham Corporation
Priority date: 1994-04-15
Filing date: 1995-04-14
Publication date: 1995-10-26

Abstract

Invented are 17β-substituted 3-carboxy steroidal synthetic compounds, pharmaceutical compositions containing these compounds, and methods for using these compounds to inhibit steroid 5-α-reductase.

Description

7/3-SUBST.TUTKD 3-CARBOXY STEROIDS THAT INHIB_T 5-α-REDUCTASE

FIELD OF THE INVENTION The present invention relates to certain novel 17B substituted 3- carboxy steroidal compounds, pharmaceutical compositions containing these compounds, and methods for using these compounds to inhibit steroid 5-α-reductase.

DESCRIPTIONOFRELATEDART

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 control results in excessive androgen hormone production. For example, acne vulgaris, βeborrhea, female hirsutism, male pattern baldness and prostate diseases such as benign prostatic hypertropy are correlated with elevated androgen levels. Additionally, the reduction of androgen levels has been shown to have a therapeutic effect on prostate cancer.

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-α-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-α-reduced analogue, in these tissues but not in others such as muscle and testes. Steroid 5-α-reductase is a Nicotinamide Adenine dinucleotide Phosphate(NADPH)dependent enzyme that converts testosterone to DHT. The importance of this enzyme in male development was dramatically underscored by the discovery of a genetic steroid 5-α-reductase deficiency in male pseudohermaphroditeβ. Imperato-McGinley, J., ≤j. fll., (1979), J. Steroid Biochem.11:637-648.

Recognition of the importance of elevated DHT levels in various disease states has stimulated many efforts to synthesize inhibitors of this enzyme. Among the most potent inhibitors identified to date are 3-carboxy- androsta-3,5-diene steroidal derivatives and 3-carboxy aromatic A ring steroidal derivatives.

A number of 5-α-reductase inhibitors are known in the art. For example,

1. Bioinorganic Chemistry. 17, pp. 372-376 (1986), by B. W. Metcalf, et al. describes the inhibition of human steroid 5α reductase (EC 1.3.1.30) by 3 androstene-3-carboxylic acids;

2. Biochemistry (1990) Vol. 29, pp. 2815-2824, by M. A. Levy, et al, M.A. Levy, et al. describes the mechanism of enzyme inhibitor interaction in the inhibition or rat liver steroid 5α reductase by 3- androstene-3-carboxylic acids;

3. J. Med. Chem. (1990) Vol. 33, pp. 943-950 (1990), by D.A. Holt, et al, describes the inhibition of steroid 5α reductase by unsaturated 3- carboxysteroids;

4. J. Steroid Biochem. Vol. 34, Nos. 1-6, pp. 571-575 (1989), by M. A. Levy, et al, describes the interaction mechanism between rat prostatic steroid 5-alpha reductase and 3-carboxy-17β-substituted steroids;

5. J. Med. Chem. (1990) Vol. 33, pp. 937-942, by D.A. Holt, et al, describes the new steroid class of A ring aryl carboxylic acids;

6. TIPS (December 1989) Vol. 10, pp. 491-495, by B.W. Metcalf, et al, describes the effect of inhibitors of steroid 5α reductase in benign prostatic hyperplasia, male pattern baldness and acne; and

7. EPO Publn. No. 0 289 327. to D.A. Holt, et al. (SmithKline Beckman) describes steroidal 3-carboxylic acid derivatives as useful 5α reductase inhibitors.

8. EPO Publn. No. 0 343 954 A3, to D.A. Holt, et al., (SmithKline Beckman) describes steroidal 3-carboxylic acid derivatives as useful 5-α- reductase inhibitors. 9. EPO Publn. No. 0 465 142 Al. to G.H. Rasmusson, et al,

(Merck & Co. Inc.) describes steroidal 3-carboxylic acid derivatives as useful 5α-reductase inhibitors.

However, none of the above references specifically suggest that any of the novel steroidal 17β-substituted 3-carboxy steroidal compounds of the present invention would have utility as potent testosterone 5-α-reductase inhibitors. SUMMARY OF THE INVENTION This invention relates to compounds of the formula I:

in which: either the A ring is aromatic or the A ring has a C3-C4 double bond and the B ring has a C5-C6 double bond, provided that the B ring does not have a C5-C6 double bond when the A ring is aromatic; pl and P^ are each independently selected from hydrogen and a linear or branched, saturated or unsaturated hydrocarbon chain containing from 1-6 carbon atoms; and

Rl3 is absent when the A ring is aromatic and present as -CH3 when the A ring has a C3-C4 double bond and the B ring has a C5-C6 double bond;

R is absent or present as (1) α H and β-O-Rl where is alkyl, cydoalkyl or aryl, where a) alkyl is a linear or branched, saturated or unsaturated hydrocarbon chain containing from 1-12 carbons, and optionally substituted with one or more substituents selected from the group consisting of: aryloxy, alkoxy, acyloxy, nitro, cyano, oxo, halogen, cydoalkyl, substituted cydoalkyl, CQ-Ci2 ry\, substituted C<g-Ci2aryl, hydroxy and protected hydroxy; b) cydoalkyl is non aromatic, unsaturated or saturated, cyclic or polycyclic Cβ-Cg, optionally containing one or more substituents selected from the group consisting of: aryloxy, aryl, alkyl, alkoxy, acyloxy, cydoalkyl, substituted cydoalkyl, amino, N-acyl amino, nitro, cyano, oxo, hydroxy, halogen substituted aryl, substituted alkyl and protected -OH; and c) aryl is cyclic or polycyclic aromatic C3-C12, optionally containing one or more heteroatoms, provided that when C is 3 the aromatic ring contains at least two heteroatmos and when C is 4 the aromatic ring contains at least one heteroatom, and optionally substituted with one or more substituents selected from the group consisting of: aryloxy, cydoalkyl, substituted cydoalkyl, alkyl, Cg- Ci2^ar l» alkoxy, acyloxy, substituted Cg-C^aryl, amino, N-acylamino, nitro, cyano, halogen, hydroxy, substituted alkyl and protected -OH;

(2)

B-C-R², where B is =A- where A is a linear or branched, saturated or unsaturated hydrocarbon chain containing from 1-8 carbons; and

R2 ig alkyl, cydoalkyl or aryl, where a) alkyl is a linear or branched, saturated or unsaturated hydrocarbon chain containing from 1-12 carbons, and substituted with one or more substituents selected from the group consisting of: aryloxy, acyloxy, N-acylamino, nitro, cyano, oxo, halogen, cydoalkyl, substituted cydoalkyl, Cg-C^ ryl and substituted Cg-Ci2 ryl; b) cydoalkyl is non aromatic, unsaturated or saturated, cyclic or polycyclic C3-C8, optionally containing one or more substituents selected from the group consisting of: aryloxy, aryl, alkyl, alkoxy, acyloxy, cydoalkyl, substituted cydoalkyl, amino, N-acyl amino, nitro, cyano, oxo, hydroxy, halogen substituted aryl, substituted alkyl and protected -OH; and c) aryl is cyclic or polycyclic aromatic C3-C12. optionally containing one or more heteroatoms, provided that when C is 3 the aromatic ring contains at least two heteroatmos and when C is 4 the aromatic ring contains at least one heteroatom, and optionally substituted with one or more substituents selected from the group consisting of: aryloxy, cydoalkyl, substituted cydoalkyl, alkyl, C6-Ci2aryl, alkoxy, acyloxy, substituted Cg-Ci2aryl, amino, N- acylamino, nitro, cyano, halogen, hydroxy, substituted alkyl and protected -OH;

(3) II ₄ ._£ α H and β-O-C-NHR where R⁴ is selected from the group consisting of: hydrogen, Ci-C alkyl, substituted Ci-Cgalkyl, C3-Cgcydoalkyl, substituted C3-C8 cydoalkyl, Cg-Ci2aryl and substituted C -Ci2 aryl;

where Q is O or N-R⁶; wherein R6 is (i) hydrogen, or (ii) a linear or branched, saturated or unsaturated hydrocarbon chain containing from 1-8 carbons, and optionally substituted with one or more substituents selected from the group consisting of: aryloxy, alkoxy, acyloxy, benzyloxy, substituted benzyloxy, N-acylamino, nitro, cyano, oxo, halogen, cydoalkyl, substituted cydoalkyl, Cg-Ci2aryl, substituted Cg-Ci^aryl. hydroxy and protected hydroxy; Rδ is

(i) hydrogen;

(ii) a linear or branched, saturated or unsaturated hydrocarbon chain containing from 1-8 carbons, and optionally substituted with one or more substituents selected from the group consisting of. aryloxy, alkoxy, acyloxy, amino, N-acylamino, nitro, cyano, oxo, halogen, cydoalkyl, substituted cydoalkyl, C -Ci2aryl, substituted Cg-Cj^aryl. hydroxy and protected hydroxy;

(iii) a non aromatic, unsaturated or saturate, cyclic or polycyclic C3-Cg, optionaUy containing one or more substituents selected from the group consisting of: aryloxy, aryl, alkyl, alkoxy, acyloxy, cydoalkyl, substituted cydoalkyl, amino, N-acyl amino, nitro, cyano, oxo, hydroxy, halogen substituted aryl, substituted alkyl and protected -OH; or

(iv) a cyclic or polycyclic aromatic C3-C12. optionally containing one or more heteroatoms, provided that when C is 3 the aromatic ring contains at least two heteroatmos and when C is 4 the aromatic ring contains at least one heteroatom, and optionally substituted with one or more substituents selected from the group consisting of: aryloxy, cydoalkyl, substituted cydoalkyl, alkyl, Cg-Ci2aryl, alkoxy, acyloxy, substituted CQ-CI2^~~Υ*-- amino, N-acylamino, nitro, cyano, halogen, hydroxy, substituted alkyl and protected -OH;

(5) α H and β-D-R? where D is a linear or branched, saturated or unsaturated hydrocarbon chain containing from 1-8 carbons, and

(i) a linear or branched, saturated or unsaturated hydrocarbon chain containing from 1-12 carbons, and optionally substituted with one or more substituents selected from the group consisting of: aryloxy, benzyloxy, substituted benzyloxy, nitro, cyano, oxo, halogen, cydoalkyl, substituted cydoalkyl, Cg-Ci2aryl, substituted C -Ci2 ryl; and N 3R4 where B and R^{4^} are each independently selected from the group consisting of: hydrogen, Cj-Cg alkyl, substituted Cχ-Cgalkyl, C3-Cgcydoalkyl, substituted C3-C cydoalkyl, Cg-Ci2 ryl and substituted C -Cχ2 aryl;

(ii) cydoalkyl is non aromatic, unsaturated or saturated, cyclic or polycyclic C3~Cg, optionally containing one or more substituents selected from the group consisting of: aryloxy, aryl, alkyl, alkoxy, acyloxy, cydoalkyl, substituted cydoalkyl, amino, N-acyl amino, nitro, cyano, oxo, hydroxy, halogen substituted aryl, substituted alkyl and protected -OH;

(iii) aryl is cyclic or polycyclic aromatic C3-C12. optionally containing one or more heteroatoms, provided that when C is 3 the aromatic ring contains at least two heteroatmos and when C is 4 the aromatic ring contains at least one heteroatom, and optionally substituted with one or more substituents selected from the group consisting of: aryloxy, cydoalkyl, substituted cydoalkyl, alkyl, Cg-Ci2aryl, alkoxy, acyloxy, substituted Cg-Ci2 ryl. amino, N- acylamino, nitro, cyano, halogen, hydroxy, substituted alkyl and protected -OH;

(iv) benzyloxy or substituted benzyloxy;

(v) phenoxy or substituted phenoxy; or

(vi) 0-(C₂-C₄alkyl)-Cg-H5.

(6) Y-R8, where Y- is β-N-0- or = N-0- and R8 is a) a linear or branched, saturated or unsaturated hydrocarbon chain containing from 1-12 carbons, and optionally substituted with one or more substituents selected from the group consisting of: aryloxy, alkoxy, acyloxy, amino, N-acylamino, nitro, cyano, oxo, halogen, cydoalkyl, substituted cydoalkyl, C -C ryl, substituted Cg-Ci2βryl, hydroxy and protected hydroxy, b) a non aromatic, unsaturated or saturated, cyclic or polycyclic Ctø-Cg, optionally containing one or more substituents selected from the group consisting of: aryloxy, aryl, alkyl, alkoxy, acyloxy, cydoalkyl, substituted cydoalkyl, amino, N-acyl amino, nitro, cyano, oxo, hydroxy, halogen substituted aryl, substituted alkyl and protected -OH; or c) a cyclic or polycyclic aromatic C3-C12. optionally containing one or more heteroatoms, provided that when C is 3 the aromatic ring contains at least two heteroatmos and when C is 4 the aromatic ring contains at least one heteroatom, and optionally substituted with one or more substituents selected from the group consisting of: aryloxy, cydoalkyl, substituted cydoalkyl, alkyl, Cg-Ci2aryl, alkoxy, acyloxy, substituted Cg-Ci2aryl, amino, N-acylamino, nitro, cyano, halogen, hydroxy, substituted alkyl and protected -OH;

(7) α- 9 and β- lO where ^ is a linear or branched, saturated or unsaturated hydrocarbon chain containing from 1-8 carbons, and optionally substituted with one or more substituents selected from the group consisting of: aryloxy, alkoxy, acyloxy, amino, N-acylamino, nitro, cyano, oxo, halogen, cydoalkyl, substituted cydoalkyl, Cg-Ci2aryl, substituted Cg-Ci2aryl, hydroxy and protected hydroxy; and

RlO is -O- ll where fill is hydrogen or Ci-Cgalkyl;

(9) α H and β-OTBDMS; (10) α H and β-OH;

(11) α H and β-CgH₅;

(12) =CH₂;

O

(13) α H and β-N-C-O-R¹², where ΕL-2 i₈ selected from the group consisting of hydrogen, Ci-Cgalkyl, substituted Ci-Cgalkyl C3-Cgcydoalkyl, substituted C3-Cgcydoalkyl, C -Ci2aryl and substituted Cg-Ci2aryl;

where R^~- is as defined above; or

(15) oxo and pharmaceutically acceptable salts, hydrates, solvates and esters thereof provided that when R is oxo Pi and P^ are not both hydrogen.

The invention also is a method for inhibiting 5-α-reductase activity in mammals, induding humans, that comprises administering to a subject an effective amount of a presently invented 5-α-reductase inhibiting compound. Induded in the present invention are pharmaceutical compositions comprising a pharmaceutical carrier and compounds useful in the methods of the invention. Also included in the present invention are methods of co-administering the presently invented 5-α-reductase inhibiting compounds with further active ingredients.

DETAILED DESCRIPTION OF THE INVENTION The compounds of this invention that inhibit 5-α-reductase have the following Formula (I):

in which: either the A ring is aromatic or the A ring has a C3-C4 double bond and the B zing has a C5-C6 double bond, provided that the B ring does not have a Cs-Cg double bond when the A ring is aromatic; p and p2 are each independently selected from hydrogen and a linear or branched, saturated or unsaturated hydrocarbon chain containing from 1-6 carbon atoms; and

Rl3 ig absent when the A ring is aromatic and present as -CH3 when the A ring has a C3-C4 double bond and the B ring has a C5-C6 double bond;

R is absent or present as (1) α H and β-O-R¹ where R is alkyl, cydoalkyl or aryl, where a) alkyl is a linear or branched, saturated or unsaturated hydrocarbon chain containing from 1-12 carbons, and optionally substituted with one or more substituents selected from the group consisting of: aryloxy, alkoxy, acyloxy, nitro, cyano, oxo, halogen, cydoalkyl, substituted cydoalkyl, Cg-Ci2aryl, substituted Cg-Ci2^aryl_> hydroxy and protected hydroxy; b) cydoalkyl is non aromatic, unsaturated or saturated, cyclic or polycyclic C-3-Cg, optionally containing one or more substituents selected from the group consisting of: aryloxy, aryl, alkyl, alkoxy, acyloxy, cydoalkyl, substituted cydoalkyl, amino, N-acyl amino, nitro, cyano, oxo, hydroxy, halogen substituted aryl, substituted alkyl and protected -OH; and c) aryl is cyclic or polycyclic aromatic C3-C12, optionally containing one or more heteroatoms, provided that when C is 3 the aromatic ring contains at least two heteroatmos and when C is 4 the aromatic ring contains at least one heteroatom, and optionally substituted with one or more substituents selected from the group consisting of: aryloxy, cydoalkyl, substituted cydoalkyl, alkyl, Cg- C-12aryl, alkoxy, acyloxy, substituted Cg-Ci^aryl, amino, N-acylamino, nitro, cyano, halogen, hydroxy, substituted alkyl and protected -OH;

(2)

R2 ig alkyl, cydoalkyl or aryl, where a) alkyl is a linear or branched, saturated or unsaturated hydrocarbon chain containing from 1-12 carbons, and substituted with one or more substituents selected from the group consisting of: aryloxy, acyloxy, N-acylamino, nitro, cyano, oxo, halogen, cydoalkyl, substituted cydoalkyl, Cg-Ci2aryl and substituted Cg-Ci2aryl; b) cydoalkyl is non aromatic, unsaturated or saturated, cyclic or polycyclic Ctø-Cg, optionally containing one or more substituents selected from the group consisting of. aryloxy, aryl, alkyl, alkoxy, acyloxy, cydoalkyl, substituted cydoalkyl, amino, N-acyl amino, nitro, cyano, oxo, hydroxy, halogen substituted aryl, substituted alkyl and protected -OH; and c) aryl is cyclic or polycydic aromatic C3-C12. optionally containing one or more heteroatoms, provided that when C is 3 the aromatic ring contains at least two heteroatmos and when C is 4 the aromatic ring contains at least one heteroatom, and optionally substituted with one or more substituents selected from the group consisting of: aryloxy, cydoalkyl, substituted cydoalkyl, alkyl, Cg-Ci2aryl, alkoxy, acyloxy, substituted Cg-Ci2aryl, amino, N- acylamino, nitro, cyano, halogen, hydroxy, substituted alkyl and protected -OH;

(3)

O α H and β-O-C 11-NHR 4 where R⁴ is selected from the group consisting of: hydrogen, Ci-C alkyl, substituted Ci-Cgalkyl, (-.3-Cgcydoalkyl, substituted C3-C cydoalkyl, C -Ci2aryl and substituted C -Ci2 ryl'.

where Q is O or N-R⁶; wherein R is (i) hydrogen, or

(ii) a linear or branched, saturated or unsaturated hydrocarbon chain containing from 1-8 carbons, and optionally substituted with one or more substituents selected from the group consisting of: aryloxy, alkoxy, acyloxy, benzyloxy, substituted benzyloxy, N-acylamino, nitro, cyano, oxo, halogen, cydoalkyl, substituted cydoalkyl, Ce-Ci2aryl, substituted Cg-Ci2aryl, hydroxy and protected hydroxy, Rδ is

(i) hydrogen;

(ii) a linear or branched, saturated or unsaturated hydrocarbon chain containing from 1-8 carbons, and optionally substituted with one or more substituents selected from the group consisting of: aryloxy, alkoxy, acyloxy, amino, N-acylamino, nitro, cyano, oxo, halogen, cydoalkyl, substituted cydoalkyl, Cg-Ci2aryl, substituted Cg-Ci2aryl, hydroxy and protected hydroxy; (iii) a non aromatic, unsaturated or saturate, cyclic or polycydic

C3~C , optionally containing one or more substituents selected from the group consisting of: aryloxy, aryl, alkyl, alkoxy, acyloxy, cydoalkyl, substituted cydoalkyl, amino, N-acyl amino, nitro, cyano, oxo, hydroxy, halogen substituted aryl, substituted alkyl and protected -OH; or (iv) a cyclic or polycydic aromatic C3-C12. optionally containing one or more heteroatoms, provided that when C is 3 the aromatic ring contains at least two heteroatmos and when C is 4 the aromatic ring contains at least one heteroatom, and optionally substituted with one or more substituents selected from the group consisting of: aryloxy, cydoalkyl, substituted cydoalkyl, alkyl, Cg-Ci2aryl, alkoxy, acyloxy, substituted C -Ci2aryl, amino, N-acylamino, nitro, cyano, halogen, hydroxy, substituted alkyl and protected -OH;

(5) α H and β-D-R⁷ where D is a linear or branched, saturated or unsaturated hydrocarbon chain containing from 1-8 carbons, and

(i) a linear or branched, saturated or unsaturated hydrocarbon chain containing from 1-12 carbons, and optionally substituted with one or more substituents selected from the group consisting of. aryloxy, benzyloxy, substituted benzyloxy, nitro, cyano, oxo, halogen, cydoalkyl, substituted cydoalkyl, C -Ci2 ryl, substituted Cg-Ci2 ryl; and NR^R4 where R3 and R⁴ are each independently selected from the group consisting of: hydrogen, Cj-Cg alkyl, substituted Ci-Cgalkyl, C3~Cgcydoalkyl, substituted C3~Cg cydoalkyl, C -Ci2aryl and substituted Cg-Ci2 aryl;

(ii) cydoalkyl is non aromatic, unsaturated or saturated, cyclic or polycyclic C3-C , optionally containing one or more substituents selected from the group consisting of: aryloxy, aryl, alkyl, alkoxy, acyloxy, cydoalkyl, substituted cydoalkyl, amino, N-acyl amino, nitro, cyano, oxo, hydroxy, halogen substituted aryl, substituted alkyl and protected -OH;

(iii) aryl is cyclic or polycydic aromatic C3-C12. optionally containing one or more heteroatoms, provided that when C is 3 the aromatic ring contains at least two heteroatmos and when C is 4 the aromatic ring contains at least one heteroatom, and optionally substituted with one or more substituents selected from the group consisting of: aryloxy, cydoalkyl, substituted cydoalkyl, alkyl, Cg-Ci2 ryl, alkoxy, acyloxy, substituted Cg-Ci2 ryl. amino, N- acylamino, nitro, cyano, halogen, hydroxy, substituted alkyl and protected -OH;

(iv) benzyloxy or substituted benzyloxy;

(v) phenoxy or substituted phenoxy, or (vi) 0-(C₂-C alkyl)-Cg-H5.

(6) Y-R8, where Y- is β-N-O- or = N-O- and

R8 is a) a linear or branched, saturated or unsaturated hydrocarbon chain containing from 1-12 carbons, and optionally substituted with one or more substituents selected from the group consisting of: aryloxy, alkoxy, acyloxy, amino, N-acylamino, nitro, cyano, oxo, halogen, cydoalkyl, substituted cydoalkyl, C -Ci2aryl, substituted Cg-Ci2 ryl, hydroxy and protected hydroxy; b) a non aromatic, unsaturated or saturated, cyclic or polycyclic C3-Cg, optionally containing one or more substituents selected from the group consisting of: aryloxy, aryl, alkyl, alkoxy, acyloxy, cydoalkyl, substituted cydoalkyl, amino, N-acyl amino, nitro, cyano, oxo, hydroxy, halogen substituted aryl, substituted alkyl and protected -OH; or c) a cyclic or polycyclic aromatic C3-C12, optionally containing one or more heteroatoms, provided that when C is 3 the aromatic ring contains at least two heteroatmos and when C is 4 the aromatic ring contains at least one heteroatom, and optionally substituted with one or more substituents selected from the group consisting of: aryloxy, cydoalkyl, substituted cydoalkyl, alkyl, Cg-C aryl, alkoxy, acyloxy, substituted Cg-Ci2aryl, amino, N-acylamino, nitro, cyano, halogen, hydroxy, substituted alkyl and protected -OH;

(7) α- ^ and β-RlO where R^ is a linear or branched, saturated or unsaturated hydrocarbon chain containing from 1-8 carbons, and optionally substituted with one or more substituents selected from the group consisting of: aryloxy, alkoxy, acyloxy, amino, N-acylamino, nitro, cyano, oxo, halogen, cydoalkyl, substituted cydoalkyl, Cg-Ci2 ryl, substituted Cg-Ci2aryl, hydroxy and protected hydroxy; and Rl° is -O-Rll where l! is hydrogen or Cj-Cgalkyl;

(9) α H and β-OTBDMS;

(10) α H and β-OH;

(11) α H and B-C Hδ; (12) =CH₂;

where R 2 is selected from the group consisting of hydrogen, Ci-Cgalkyl, substituted Ci-Cgalkyl C3-Cgcydoalkyl, substituted C3-Cgcydoalkyl, Cg-Ci2ar l and substituted Cg-Ci2 ryl;

where Rl2 is as defined above; or

(15) oxo and pharmaceutically acceptable salts, hydrates, solvates and esters thereof provided that when R is oxo P¹ and P^ are not both hydrogen.

Preferred among the presently invented Formula I compounds are those in which

R is absent or present as (1) α H and β-O-Rl where R* is a) a linear or branched, saturated or unsaturated hydrocarbon chain ∞ntaining from 1-6 carbons, and optionally substituted with Cg-Ci2aryl or substituted Cg-Ci2aryl;

(2)

O

B-C-R², where B is =A- where A is a linear or branched, saturated or unsaturated hydrocarbon chain containing from 1-4 carbons; and 2 is a) a linear or branched, saturated or unsaturated hydrocarbon chain containing from 1-8 carbons, and optionally substituted with Cg-Ci2aryl or substituted Cg-Ci2aryl; or b) Cg-Ci2aryl or substituted Cg-Ci2aryl;

where R⁴ is selected from the group consisting of: hydrogen, Ci-Cg alkyl, substituted Ci-Cgalkyl, Cg-Ci2aryl, and substituted Cg-Ci2aryl;

where Q is O or N-R⁶; wherein R6 is (i) hydrogen, or

(ii) a linear or branched, saturated or unsaturated hydrocarbon chain containing from 1-4 carbons, and optionally substituted with one or more substituents selected from the group consisting of: aryloxy, benzyloxy and substituted benzyloxy β is

(i) hydrogen;

(ii) a linear or branched, saturated or unsaturated hydrocarbon chain containing from 1-3 carbons, and optionally substituted with Cg- Ci2aryl or substituted Cg-Ci2^aryl. (iii) Cg-Ci2aryl; or

(iv) substituted Cg-C aryl;

(5) α H and β-D-R? where D is a linear or branched, saturated or unsaturated hydrocarbon chain containing from 1-4 carbons, and

R^ is

(i) a linear or branched, saturated or unsaturated hydrocarbon chain containing from 1-12 carbons, and optionally substituted with one or more substituents selected from the group consisting of: aryloxy, benzyloxy, substituted benzyloxy, nitro, cyano, oxo, halogen, cydoalkyl, substituted cydoalkyl, Cg-Ci2aryl, substituted Cg-Cχ2aryl; and NR3R4 where R3 and R⁴ are each independently selected from the group consisting of: hydrogen, Cχ-Cg alkyl, substituted Ci-Cgalkyl, C3-Cgcydoalkyl, substituted C3-Cg cydoalkyl, Cg-Ci2aryl and substituted Cg-Ci2 aryl;

(ii) Cg-Ci2aryl;

(iii) substituted Cg-Ci2aryl; (iv) benzoyloxy or substituted benzyloxy; or

(v) phenoxy or substituted phenoxy;

(6) Y-R⁸, where Y- is β-N-O- or = N-O- and R^β is a) a linear or branched, saturated or unsaturated hydrocarbon chain containing from 1-6 carbons, and optionally substituted with Cg-Ci2aryl or substituted Cg-Ci2aryl; b) Cg-Ci2aryl; or c) substituted Cg-C^aryl;

(7) α-R^ and β-RlO where R^ is a linear or branched, saturated or unsaturated hydrocarbon chain containing from 1-3 carbons, and optionally substituted with Cg-Ci2 ryl or substituted Cg-Ci2aryi; and

RlO is -O-R¹¹ where Rl* is hydrogen or Cι-C3alkyl;

(9) α H and β-OTBDMS;

(10) α H and β-OH;

(11) α H and β-CgH₅;

where 2 is selected from the group consisting of Ci-Cgalkyl and

Cg-Ci2aryl;

where *2 is as defined above; or

(15) oxo and pharmaceutically acceptable salts, hydrates, solvates and esters thereof provided that when R is oxo P¹ and P² are not both hydrogen.

Particularly preferred among Formula (I) compounds are: 17β-17-(benzyloxy)-estra-l,3,5(10)-triene-3-carboxyHc add, 17β-17-(2-propenyloxy)-estra-l,3,5(10)-triene-3-carboxy_ic add,

[17β(E)]-17-[(3-phenyl-2-propenyl)oxy]-estra-l,3,5(10)-triene-3- carboxylic add,

[17β(E)]-17-[(3-ι_henyl-propyl)oxy3-estra-l,3,5(10)-triene-3- carboxylic add, [17β]-17-methoxy-estra-l,3,5(10Mriene-3-carboxylic add,

17β-17-(benzyloxy)-androsta-3,5-diene-3-carboxylic add, 17β-17-[(2-propenyl)oxy]-androsta-3,5-diene-3-carboxylic add, 17B-17-methoxy-androsta-3,5-diene-3-carboxylic add, (20E)-en-(22) phen ethyl -21-one-estra 1,3,5(10) triene -3- carboxylic add,

(20E)-en-(22) phenyl -21-one estra 1,3,5(10) triene -3- carboxylic add,

(20)β methyl -22- phenethyl 21- one estra l,3,5-(10)triene 3- carboxylic add, (20)β methyl -22- phenyl 21-one estra l,3,5-(10)triene 3-carboxylic add,

17(20E)-ene-21-t-butylcarboxamide-estra-l,3,5(10)-triene-3- carboxylic add,

17β-(t-butylacetamido) estra-l,3,5(10)-triene-3-carboxy_ic add, Androsta-3,5-diene-3-carboxylic add, Estra- 1,3,5( 10)- triene-3-carboxylic add,

17β-(3-Oxo-4-phenyl-butyl)-estra-l,3,5(10)-triene-3-carboxylic add, 17β-(5-methyl-3-oxo-l-hexenyl)-estra-l,3,5(10)-3-carboxy_ic add, 17β-(tert- butylamido- ethylenyl) - estra- 1,3,5(10)- triene - 3- carboxylic add,

17β-(3-Oxo-3-phenyl-propyl)-estra-l,3,5(10)-triene-3-c_arboxyUc add, 17β-17-(benzyloxy methyl)- estra-l,3,5(10)-triene-3-carboxy]ic add, 17β(E) -17-(phenyl ethenyl)- estra-l,3,5(10)- triene- 3 -carboxyhc add,

17β(Z) -17-(phenyl ethenyl)- estra-l,3,5(10)- triene- 3 -carboxylic add,

17β-17-(2-phenylethyl)-estra-l,3,5(10)-triene-3-carboxy_ic add, O-benzyl oxime ether of 17-oxo-estra-l,3,5-triene-3-carboxylic add,

O-benzyl oxime ether of 17-oxo- androsta- 3,5- diene- 3 -carboxyhc add,

O-t-butyl oxime ether of 17-oxo- androsta- 3,5- diene- 3 -carboxyhc add, 17β-(Phenyl)estra-l,3,5(10)triene-3-carboxyHc add,

(0-tertbutyloxine)estra-l,3,5(10)-triene-3-carboxylic add, (0-Phenyloxine)eetra-l,3,5(10)-triene-3-carboxyUc add, keto-16,16-diallylestra-l,3,5(10)-triene-3-carboxyKc add, 17β-(N-tertbutoxyam__no)estra-l,3,5(10)-triene-3-c_arboxylic aάd, 17β-(N-Ben__yloxyamino)estra-l,3,5(10-triene-3-carboxyUc add,

17β-[2-(5-Phenyloxazole)]estra-l,3,5(ld0)-triene-3-carboxyUc ^acid» 17β-[2-(N-Benzyloxymethyl) imidazolyl estra-l,3,5(10)-triene-3- carboxylic add,

17β-[2-(5-Phenylimidazole)] estra - 1,3,5 (10) - triene- 3-carboxylic add,

17β-(2-Imidazolyl) estra - 1,3,5 (10)-triene-3-carboxylic add,

17β-(3-Oxo-3-phenyl-l-propenyl>3-hydroxymethyl-estra-l,3,5(10)- triene-3-carboxyhc add,

17β-(3-Oxo-4-phenyl-l-butenyl)-3-hydroxymethyl-estra-l,3,5(10)- triene-3-carboxylic add,

17β-(5-hydroxy,l,l,l,9,9,9 hexafluorononyl)androsta-3,5,diene-3- carboxyhc add, 17β-hydroxy-17α-benzyl-estra-l,3,5(10)-triene-3-carboxyhc add, 17β-(t-butyl dimethyl silyl ether)androsta-3,5-diene-3-carboxylic add, 17β-17-hydroxy-androsta-3,5-diene-3-carboxylic add, 17β- 17-hydroxy-estra- 1,3,5( 10)-triene-3-carboxyHc add, O-phenyl oxime ether of 17-oxo-androsta-3,5-diene-3-carboxylic add,

17β-methoxy-17α-benzyl-estra-l,3,5(10)-triene-3-carboxyUc add, 17β-[O-(N-phenyl<_arbamoyl)]estra-l,3,5(10)-triene-3-carboxyUc add, 17β-[O-(N-tert-butylcarbamoyl)]estra-l,3,5(10)-triene-3-carboxyhc add,

17β-[O-(N-benzylcarbamoyl)]estra-l,3,5(10)-triene-3-carboxyhc add,

17β-[N-(N-tertbutylurea)estra-l,3,5(10)-triene-3-carboxyHc add, 17β-|N-(O-tert-butylcarbamoyl)]estra-l,3,5(10)-triene-3-carboxylic add,

17β-[0-(N-phenylcarbamoyl)] androsta- l,3-diene-3-carboxylic add, 17β-[0-(N-tert-butylcarbamoyl)] androsta- l,3-diene-3-carboxylic add, or 17β-[0-(N-benzylcarbamoyl)] androsta-l,3,diene-3-carboxyUc add.

Preferred among Formula I compounds are those in which the A ring is aromatic and the B ring does not conatin a double bond.

Preferred among Formula I compounds are those in which the A ring has a C3-C4 double bond and the B ring has a CQ-CQ double bond.

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

As used herein C_x-Cγalkyl is meant a linear or branched hydrocarbon chain having from x to y carbons.

As used herein, in Formula (I) compounds when R is absent the 17 position is substituted by two hydrogen atoms. By the term "protected hydroxy" or "protected -OH" as used herein, is meant the alcohoUc or carboxylic-OH groups which can be protected by conventional blocking groups in the art as described in "Protective Groups In Organic Synthesis" by Theodora W. Greene, Wiley-Intersάence, 1981, New York. Preferred are the triorganosilyl groups, e.g. t-butyldimethylsilyl, phenyldimethylsilyl, diphenylmethylsilyl, and the like. By the term "aryl" as used herein, unless otherwise defined, is meant cycUc or polycydic aromatic C3-C12. optionaUy containing one or more heteroatoms, provided that when C is 3 the aromatic ring contains at least two heteroatoms and when C is 4 the aromatic ring contains at least one heteroatom, and optionaUy substituted with one or more substituents selected from the group consisting of: alkyl, Cg-Cχ2 aryl, substituted cydoalkyl, substituted Cg-Ci2aryl, aryloxy, hydroxy, alkoxy, cydoalkyl, acyloxy, amino, N-acylamino, nitro, cyano, halogen, -C(OX)R6, -S(0)nR⁵, protected -OH and alkyl substituted with one or more substituents selected from the group consisting of: alkoxy, acyloxy, Cg-Ci2βryl, substituted Cg-Ci2aryl, amino, N-acylamino, oxo, hydroxy, cydoalkyl, substituted cydoalkyl, -C(0)0R6, -S(0)_nR⁷, aryloxy, nitro, cyano, halogen, and protected -OH, where R is hydrogen or alkyl, n is 0-2, R⁷ is hydrogen or alkyl and B is hydrogen, cydoalkyl, Cg-Ci2aryl, substituted cydoalkyl, substituted Cg-Ci2aryl, alkyl or alkyl substituted with one or more substituents selected from the group consisting of: alkoxy, acyloxy, aryloxy, amino, N-acylamino, oxo, hydroxy, -C(0X)R6, -S(0)_nR⁷, nitro, cyano, cydoalkyl, substituted cydoalkyl, halogen, C -Ci2 ryl, substituted Cg-Cχ2aryl and protected -OH, where R6 is hydrogen or alkyl, n is 0-2 and R⁷ is hydrogen or alkyl.

Examples of aryl and substituted aryl substituents as used herein include: phenyl, naphthyl, furanyl, biphenyl, hydroxyphenyl, pyridyl, fluorophenyl, dihydroxyphenyl, methylenedioxyphenyl, dimethylhydroxyphenyl, methoxyphenyl, trifluoromethylphenyl carboxymethylphenyl, phenoxyphenyl, methylsulfonylphenyl, methylthiophenyl, difluorophenyl, carboxyphenyl, methylsulfoxylphenyl and thiophenyl.

Preferred examples of aryl and substituted aryl substituents as used herein indude: phenyl, 4-fluorophenyl, 2,6-diϋuorophenyl, 1-naphthyl, 4-biphenyl, 4-methoxyphenyl, 4-phenoxyphenyl,

4-trifluoromethylphenyl, 4-methylβulfonylphenyl, 4-methylthiophenyl, 3,5-difluorophenyl, 4-hydroxyphenyl, 4-carboxyphenyl, 2-furanyl, 4- methylsulfoxylphenyl, 3-thiophenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and 3,4-methylenedioxyphenyl.

By the term "Cg-Ci2 aryl" as used herein, unless otherwise defined, is meant phenyl, naphthyl, 3,4-methylenedioxyphenyl, pyridyl, or biphenyl.

By the term "substituted" as used herein, unless otherwise defined, is meant that the subject chemical moiety has one or more substituents selected from the group consisting of: hydroxyalkyl, alkoxy, halogen substituted C3-C cydoalkyl, U3-Cg cydoalkyl, Cg-Ci2aryl, halogen substituted Cg-C^aryl, acyloxy, alkyl, amino, N-acylamino, hydroxy, -(CH2)gC(0)OR6, -S(0)_nR⁷, nitro, cyano, halogen, trifluoromethyl and protected -OH, where g is 0-6, 6 is hydrogen or alkyl, n is 0-2, and R⁷ is hydrogen or alkyl.

By the term "alkoxy" as used herein is meant -Oalkyl where alkyl is as described herein induding -OCH3 and -OC(CH3)2CH3.

The term "cydoalkyl" as used herein unless otherwise defined, is meant a nonaromatic, unsaturated or saturated, cyclic or polycydic C₃-C .

Examples of cydoalkyl and substituted cydoalkyl substituents as used herein include: cydohexyl, 4-hydroxy-cydohexyl,

2-ethylcydohexyl, propyl 4-methoxycydohexyl, 4-methoxycydohexyl, 4-carboxycyclohexyl and cydopentyl.

By the term "acyloxy" as used herein is meant -OC(0)alkyl where alkyl is as described herein. Examples of acyloxy substituents as used herein indude: -OC(0)CH3, -OC(0)CH(CH3)2 and -OC(OXCH₂)3CH₃.

By the term "N-acylamino" as used herein is meant -N(H)C(0)alkyl, where alkyl is as described herein. Examples of N-acylamino substituents as used herein indude: -N(H)C(0)CH3, -N(H)C(0)CH(CH3)2 and -N(H)C(OXCH2)3CH3. By the term "aryloxy" as used herein is meant -OCg-Ci2aryl where Cg-Ci2βryl is phenyl, naphthyl, 3,4-methylenedioxyphenyl, pyridyl or biphenyl optionaUy substituted with one or more substituents selected from the group consisting of: alkyl, hydroxyalkyl, alkoxy, trifuloromethyl, acyloxy, amino, N-acylamino, hydroxy, -(CH2)gC(OjOR⁶, -S(0)_nR⁷, nitro, cyano, halogen and protected -OH, where g is 0-6, 6 is hydrogen or alkyl, n is 0-2 and R⁷ is hydrogen or alkyl. Examples of aryloxy substituents as used herein include: phenoxy, 4-fluorophenyloxy and biphenyloxy.

By the term "heteroatom" as used herein is meant oxygen, nitrogen or sulfur. By the term "halogen" as used herein is meant a substituent selected from bromide, iodide, chloride and fluoride.

By the term "alkyl" and derivatives thereof and in aU carbon chains as used herein is meant a linear or branched, saturated or unsaturated hydrocarbon chain having Cχ-Ci2 carbon atoms. Examples of alkyl substituents as used herein indude: -CH3, -CH2-CH3,

-CH2-CH2-CH3, -CH(CH₃)₂, -C(CH₃)₃, -(CH₂)₃-CH₃, -CH₂-CH(CH₃)2 and -CH(CH₃)-CH2-CH3, -CH=CH₂.

By the term "treating" and derivatives thereof as used herein, is meant prophylatic or therapeutic therapy. By the term "metal-catalyzed coupling reaction" as used herein is meant that the prepared 3-trifluoromethyl sulfonylate or 3-fluoroβulfonylate compound is reacted in a suitable organic solvent; preferably dimethylsulfoxide, toluene, dichloroethane, dimethylformamide or THF; with a base, preferably a tertiaryamine base such as triethylamine, pyridine or tributylamine; a Cχ-Cg alcohol (when an ester is desired) or a Cj-Cg carboxylic add salt, preferably KOAc (when an add is desired) and a phosphine, such as bis(diphenylphosphino)alkane, preferably 1,3 bis(diphenylphosphino)propane, tri-o-tolyphosphine or l,l-bis(diphenylphθ8phino)ferrocene (dppf)) and a metal catalyst, preferably a palladium catalyst such as paUadium (II) acetate or paUadium (II) chloride or bis(triphenylphosphine) paUadium II acetate, thereby forming a metalated complex, and subsequently adding a coupling reagent. By the term "coupling reagent" as used herein is meant a compound which is capable of reacting with said metalated complex to form an ester or a carboxylic add substituent. Carbon monoxide is a preferred coupling reagent which when added to the metal-catalyzed coupling reaction, as described herein, yields the desired ester or carboxylic add group.

Compounds of Formula (I) are induded in the pharmaceutical compositions of the invention and used in the methods of the invention. Where a -COOH or -OH group is present, pharmaceuticaUy acceptable esters can be employed, for example methyl, ethyl, pivaloyloxymethyl, and the like for -COOH, and acetate maleate and the like for -OH, and those esters known in the art for modifying solubility or hydrolysis characteristics for use as sustained release or prodrug formulations.

The term "α-receptor antagonist", as used herein, refers to a known dass of alpha-andrenergic receptor antagonist comounds, such as described in Lafferty, et al. U.S. Patent No. 4,963,547, which are utilized in treating vascular disorders such as diabetes, cardiovascular disease, benign prostatic hypertrophy and ocular hypertension.

Preferred alpha-andrenergic receptor antagonists for use in the compositions and methods of the invention indude amsulosin, terazosin, doxazosin, alfuzosin, indoramin, prazosin, 7-chloro-2-ethyl-3,4,5,6- tetrahydro-4-met_hylthieno[4,3,2-efI[3]-benzazepine and 8-{3-[4-(2-methoxyphenyl)-l-piperazinyl]-propylcarbamoyl}-3-methyl-4- oxo-2-phenyl-4H-l-benzopyran.

By the term "amsulosin" as used herein is meant a compound of the structure

and salts, hydrates and solvates thereof.

ChemicaUy, amsulosin is designated as (-)-(R)-5-[2-[[2-(0- ethoxyphenoxy)etiιyl]ammo]propyl]-2-met_hoxybenzenesulfonamide. Amsulosin is disdosed in U.S. Patent Number 4,703,063 and daimed in U.S. Patent Number 4,987,152 as being useful in treating lower urinary tract dysfunction.

By the term "terazosin" as used herein is meant a compound of the structure

and salts, hydrates and solvates thereof.

Chemically, terazosin is designated as l-(4-amino-6,7-dimethoxy- 2 qt__inazolinyl)-4-[(tet_rahydro-2-_ruroyl)carbonyl]pipera-dne Terazosin is diβdoβed in U.S. Patent Number 4,251,532. By the term doxazosin as used herein is meant a compound of the formula

and salts, hydrates and solvates thereof.

ChemicaUy "doxazosin" is designated as l-(4-amino-6,7- dimethoxy-2-quinazolinyl)-4-[(2,3-dihydro-l,4-benzodioxin-2- yl)carbonyl]-piperazine.

Doxazosin is discolsed in U.S. Patent Number 4,188,390.

By the term "alfuzosin" as used herein is meant a compound of the formula

and salts, hydrates and solvates thereof.

ChemicaUy alfuzosin is designated as N-[3-[(4-amino-6,7- d__methoxy-2-qu__na2θl_lnyl)methylamino]propyl]tetrahydro-2- furancarboxamide. Alfuzosin is disclosed in U.S. Patent Number 4,315,007.

By the term "indoramin" as used herein is meant a compound of the formula

and salts, hy rates and solvates thereof. ChemicaUy indoramin as designated N-[[l-[2-(lH-indol-3- yl)ethyl]-4-piperidinyl]benzamine.

Indoramin is disdosed in U.S. Patent Number 3,527,761.

By the term "prazoβin" as used herein is meant a compound of the formula

and salts, hydrates and solvates thereof.

ChemicaUy prazosin is designated as l-(4-amino-6,7-dimethoxy-2- quinazolinyl)-4-(2-furanylcarbonyl)piperazine.

Prazosin is disdosed in U.S. Patent Number 3,511,836.

"7-chloro-2-ethyl-3,4,5,6-tetrahydro-4-methylthieno[4,3,2-efl- [3]benzazepine" as used herein is meant a compound of the structure

and salts, hydrates and solvates thereof.

7-chloro-2-ethyl-3,4,5,6-tetrahydro-4-methylthieno[4,3,2-efl- [3]benzazepine is disdosed in U.S. Patent No. 5,006,521. Additionally, aU compounds disdosed in U.S. Patent No. 5,006,521 as alpha- adrenergic receptor antagonist are preferred alpha-adrenergic receptor antagonist as used herein.

"8-{3-[4-(2-methoxyphenyl)-l-piperazinyl]-propylcarbamoyl}-3- methyl-4-oxo-2-phenyl-4H-l-benzopyran" as used herein is meant a compound of the structure

and salts, hydrates and solvates thereof.

8-{3-[4-(2-methoxyphenyl)-l-piperazinyl]-propylcarbamoyl}-3- methyl-4-oxo-2-phenyl-4H-l-benzopyran is disdosed in EPO Publn. No. 0558245 Al, to Leonardi, et al., (Recordati S.A.). AdditionaUy aU compopunds disdosed in EPO Publn. No. 0558245

Al, as alpha-adrenergic receptor antagonists are preferred alpha- adrenergic receptor antagonists as used herein.

Persons skiUed in the art can readily determine if a compound other than one specificaUy referred to herein is a alpha-andrenergic receptor antagonist by utilizing the assay described in Lafferty I. Thus, aU such compounds are induded within the scope of the term "alpha- andrenergic receptor antagonist" as used herein.

By the term "minoxidil" as used herein is meant the compound of the formula:

ChemicaUy minoxidil is designated as 2,4-pyrimidineadiamine, 6-(l- piperidinyl)-,3-oxide. Minoxidil is the active ingredient in Rogaine® which is sold as topical solution for stimulating hair growth by the

Upjohn Company, Kalamazoo, Michigan. The term "aromatase inhibitor", as used herein, refers to a known dass of compounds, steroidal and non-steroidal, which prevent the conversion of androgens to estrogens, such as described in Gormley et al. International Publication Number WO 92 18132. Aromatase inhibitors are disdosed in Gormley et al. as having utility in treating benign prostatic hyperplasia when used in combination with a 5-α-reductase inhibitor.

A preferred aromatase inhibitor for use in the compositions and methods of the invention 4-(5,6,7,8-tetrahydroimidazo-[l,5-α]pyridin-5- yDbenzonitrile (fadrazole). Fadrazole is disclosed in U.S. Patent No. 4,728,645. AdditionaUy, aU compounds disclosed in Gormley, et al. International Publication No. WO 92/18132 as having aromatase inhibiting activity are preferred aromatase inhibitors as used herein.

As used herein, when a 5-α-reductase inhibitor, as described herein and a further active ingredient or ingredients are utilized together, said 5-α-reductase inhibitor can be co-administered with said further active ingredient or ingredients.

By the term "co-administering" and derivatives thereof as used herein is meant either simultaneous administration or any manner of separate sequential administration of a 5-α-reductase inhibiting compound, as described herein, and a further active ingredient or ingredients, such as other compounds known to treat the disease states of acne vulgaris, seborrhea, female hirsutism, male pattern baldness, benign prostate hypertrophy or prostatic adenocarcinoma or compounds known to have utility when used in combination with 5-α-reductase inhibitors. Preferably, ifthe administration is not simultaneous, the compounds are administered in a dose time proximity to each other. Furthermore, it does not matter ifthe compounds are administered in the same dosage form, e.g. one compound may be administered topically and another compound may be administered oraUy.

The novel compounds of the Formula (I) of the present invention can be prepared by methods analogous to those described in the Schemes below and in the Examples.

Compounds of Formula (I) in which R is α H and β-O-R^- are prepared by methods analogous to those described in Schemes 1-2.

Scheme 1

a) NaBH4, MeOH; b) NaH, PhCH2Br, TBAI, THF c) K2CO3, MeOH, H 0 The starting ester was obtained from triϋation and subsequent methoxy carbonylation of estrone. Reduction of the ketone can be achieved selectively with a borohydride salt. Alkylation of the alcohol with a suitable alkylating agent (such as benzyl bromide, allyl iodide, methyl iodide, dnnamyl bromide, etc.) and subsequent hydrolysis of the ester under basic conditions (such as potassium carbonate, sodium hydroxide, or lithium hydroxide) provides the desired ether derivatives. Standard functional group manipulation of side chains (such as hydrogenation of an olefin) potentially provide further examples.

Scheme 2

a) Ac2θ, Et3N, CH2CI2; b) Tf₂0, 2,6-dit-butyl-4-methyl pyridine, CH₂C1₂; c) CO, Pd(OAc)₂, DMSO, PPh₃; d) K2CO3, MeOH, H₂0; e) NaH, PhCH2Br, TBAI, THF

The hydroxyl group of testosterone is protected by standard acetylation conditions. Triflation and methoxy carbonylation are carried out using standard conditions. Deprotection of both the acetate and methyl ester can be accompUshed under basic conditions. Final alkylation of the alcohol (without interfering alkylation of the carboxylate) can be achieved using a variety of alkylating reagents (cf. Scheme 1) generating the desired ether derivatrives.

Compounds of the Formula (I) in which R is

O

B-C-R arg prepared by methods analogous to those described in Schemes 3, 4, 7, 8 and 9. Scheme 3

a) NaH, (EtO)2POCH₂CN, THF; H₂, Pd, BaS0 , EtOH, EtOAc for saturated analogs b) Tf2NPh, NaH, THF; c) CO, Pd(OAc)₂, dppp, DMSO, MeOH; d) DIBA1-H, PhMe; e) PhCH2MgCl, THF; f) cat. TPAP, NMO, CH₂C1₂; g) NaC10₂

Estrone was homologated by two carbons with diethylcyanomethyl phophonoacetate and base. Optional catalytic hydrogenation provides the saturated analogs. Triflation and methoxy carbonylation were performed using standard conditions. Reduction of both the nitrile and the ester was accomplished with dϋsobutyl aluminum hydride in toluene. Addition of a Grignard reagent (such as benzyl magnesium chloride, phenyl magnesium chloride, t-butyl magnesium chloride, neopentyl magnesium chloride, etc.) provides an intermediate secondary alcohol, which is oxidized to the desired ketone 3-carboxyUc adds using standard conditions.

Scheme 4

a) H2, Pd, BaS0₄, EtOH, EtOAc for saturated analogs; oxalyl chloride, pyridine; t-butyl amine b) BBr₃, CH2CI2 c) Tf₂NPh, NaH, THF; d) CO, Pd(OAc)₂, dppp, DMSO, MeOH; e) K2CO3, MeOH, H₂0

The amide derivatives were prepared from known 3-methoxy- estra-l,3,5(10) triene-17-(20E)-ene-21 carboxyHc add via the add chloride. (The starting material was reduced with catalytic hydrogenation to prepare the saturated analogs.). Deprotection of the phenol with boron tribromide, triflation, methoxy carbonylation, and hydroylsis of the ester provided the desired 3-carboxylic adds.

As utilized herein corresponding aromatic A ring and 3,5 diene steroidal compounds are interchangably prepared by analogous methods using appropriate starting materials such as described in Schemes 1 and 2

Compounds of the Formula (I) where R is absent (i.e. hydrogen) are prepared by methods described in Schemes 5-6.

Scheme 5

a) Tf2θ, 2,6-di-t-butyl-4-methyl pyridine, CH₂CI2; c) CO, Pd(OAc)₂, DMSO, PPh3,KOAc Starting with the known 17-deshydroxy testosterone, standard triflation and hydroxycarbonylation chemistry provided the desired product.

Scheme 6

a) Tf2θ, 2,6-di-t-butyl-4-methyl pyridine, CH2CI2; b) H₂, Pt0₂, MeOH; c) K2CO3, H₂0, MeOH

Methyl-17-oxo-estra-l,3,5 (10) triene-3-carboxylate is converted to the enol triflate using standard conditions. Reduction of the D-ring to the hydrocarbon is accompUshed using catalytic hydrogenation, and hydrolysis of the ester provides the desired parent steroid-3-carboxyUc add.

Scheme 7

a) PhCH₂COCH₂PO(OMe)2, THF; H₂, Pd/C, EtOAc for the saturated analogs; b) Jones

A Horner-Emmons reagent (such as PhCH₂COCH2PO(OMe)2 or PhCOCH2PO(OMe)2) was used to form enone intermediates from 17β- formyl-estra-l,3,5(10)-3-methanol, (which could also be reduced by catalytic hydrogenation to produce the saturated analogs), then oxidized to the dersired 3-carboxylic adds with an oxidant such as Jones reagent (or in two steps via the aldehyde with oxidants such as TPAP, followed by sodium chlorite).

Scheme 8

a) Ph3PCHCθ2Me ; H₂, Pd/C, EtOAc in the case of the saturated analogs; b) K2CO3, H₂0, MeOH; 2,2'dipyridyl disulfide, CH₂C1₂; c) isobutyl magnesium chloride, THF; e) TPAP, NMO; NaC10₂

An alternate route to the same class of counpounds as described in Scheme 7 can be synthesized via the intermediate 2-pyridyl thioester, followed by addition of a Grignard reagent (such as isobutyl magnesium chloride), followed by oxidation steps as described in Scheme 7.

Scheme 9

a) oxalyl chloride, pyridine; t-butyl amine; b) Jones or TPAP, then NaC102

Acrylamide derivatives can also be produced from the intermediate acryUc add shown in Scheme 8 by standard amino add coupling reactions (such as formation of an acyl chloride with oxalyl chloride, foUowed by addition of t-butyl amine). Deprotection of the alcohol, and oxidation steps as described in Scheme 7 provide the desired 3- carboxylic adds.

Formula (I) where R is β-D-R⁷ and 7 is 0-(C()-C4alkyl)-C H5 are prepared by methods analogous to those described in Scheme 10. Scheme 10

a) NaBH4, MeOH; b) NaH, PhCH₂Br, DMF; c) Jones

Reduction of the previously described 17β-formyl (methyl hydroxy)-estra-l,3,5(10)-triene-3-methyl (t-butyl dimethyl) silyl ether with a borohydride salt (such as sodium borohydride) and alkylation with an alkylating reagent (such as described in Scheme 1), and final oxidation (such as with Jones reagent) provides the desired ether derivatives.

Compounds of the Formula (I) in which R is β-D-R⁷ are prepared by methods analogous to those described in Schemes 11 and 22.

Scheme 11

a) Ph₃PCHPh, NaH, THF; b) Jones ; H₂, Pt/C, MeOH in the case of the saturated analogs Styrene and phenethyl derivatives can be prepared by a Wittig reaction on the known 17b-formyl (methyl hydroxy)-estra-l,3,5(10)- triene-3-methyl (t-butyl dimethyl) silyl ether. Subsequent oxidation with an oxidant such as Jones reagent (removes silyl protective group and oxidizes the 3-position to the carboxylic add), provides the desired compounds. Hydrogenation of the styrene to the saturated analog was also achievable.

The corresponding 3,5-diene steroidal compounds are prepared by analogous methods using starting materials described in Scheme 2.

Compounds of the Formula (I) in which R is Y-R^, where Y is =N-O- are parpared by methods analogous to those described in Schemes 12-13.

Scheme 12

a) Tf₂0, 2,6-di-t-butyl-4-methyl pyridine, CH2CI2, CO, Pd(OAc)2, DMF, dppp, MeOH, EtβN; c) K2CO3, MeOH, H₂0; d) KOAc, PhCH₂ONH₂, EtOH, H₂0

Estrone was triflated, methoxy carbonylated, and hydrolyzed. The desired oxime was formed with either basic conditions (such as potassium acetate and the free hydroxylamine in an alcohoUc, aqueous solvent) or under addic conditions (such as catalytic tosic add, the hydroxylamine hydrochloride, in toluene with azeotropic removal of water).

Scheme 13

a) Jones; b) cat. TsOH, PhCH₂ONH₂ HCl, PhMe Jones oxidation of the previously described alcohol, foUowed by oxime formation as described in Scheme 12 provided the desired compounds.

Compounds of the Formula (I) where R is -C(OHXCH2-CH2-CH2CF3)2 are prepared by methods analogous to those described in Scheme 14.

Scheme 14

a) BrMg(CH₂)3CF₃, THF

Ketones (prepared as described in International Application No. PCT/US93/03778, International PubUcation No. WO 93/22333, pubUshed 11 November 1993) ean be reacted with a variety of Grignard reagents (such as 4,4,4-trifluoro butyl magnesium bromide) to produce the desired tertiary alcohol derivatives.

Compounds of the Formula (I) where R is α-R^ and β-R*0 are prepared by methods analogous to those described in Scheme 15.

Scheme 15

a) BrMgCH₂Ph, THF; b) Mel, NaH, THF

A Grignard reagent (such as benzyl magnesium bromide) was added to the ketone at the 17 position and the newly formed hydroxyl group could be alkylated with various alkylating reagents (such as methyl iodide, aUyl iodide, etc.). The corresponding 3,5 diene steroidal compounds are prepared by analogous methods using starting materials as described in Scheme 2.

Compounds of the Formula (I) where R is β-OTBDMS are prepared by methods analogous to those described in Scheme 16.

Scheme 16

a) TBSC1, TEA, CH2CI2, cat. DMAP; b) Tf₂0, 2, 6-di-t-butyl-4-methyl pyridine, CH2CI₂; c) CO, Pd(OAc)₂, Ph3P, DMSO; d) K2CO3, MeOH, H₂0

Formation of a silyl ether, foUowed by the standard triflation, methoxy carbonylation, and hydrolysis conditions produced the desired sflyl protected derivative.

Compounds of the Formula (I) where R is

O

II

O Jxl ζ^~> ^' UD ,1¹2^,ώ are prepared by methods analogous to those described in Scheme 17. Scheme 17

a) NH20H, TsOH; LAH; b) OCNt-butyl; c) Jones

Oxime formation, foUowed by reduction with lithium aluminum hydride produces the amine at the 17 position in addition to reduction of the ester. Selective urea formation with an isocyanate, foUowed by exhaustive oxidation produces the desired 3-carboxyUc adds.

The corresponding 3,5 diene steroidal compounds as prepared by analogous methods using starting materials as described in Scheme 2.

Scheme 18

a) Me₃CCOCl; NaOH b) Jones

Exhaustive acylation followed by selective deacylation of the ester produced the 3-methanol derivative, which in turn was oxidized to the 3- carboxyUc add with Jones reagent.

The corresponding 3,5 diene steroidal compounds are prepared by analogous methods using starting materials as described in Scheme 2.

Compounds of the Formula (I) where R is β-N-C(0)OR¹² are prepared by methods analogous to those described in Scheme 19.

Scheme 19

a) Me3CCOOCOMβ3; b) TPAP, NMO; NaC102

The carbamate was formed by reacting the amine with t-butyl pyrocarbonate, then the 3 position was oxidized to the carboxyUc add.

Compounds of the Formula (I) in which R is Y-R^, where Y is β-N-O- are prepared by methods analogous to those described in Scheme 20.

Scheme 20

a) PhCH₂ONH₂HCl, TsOH, PhMe; b) NaCNBH₃, BF₃ Et₂0; c) K₂C0₃, MeOH, H₂0 Oxime ether was formed under addic conditions from the previously described ketone and a oxygen substituted hydroxyl amine hydrochloride (such as benzyl or t-butyl hydroxyl amine hydrochloride) and azeotropic removal of water. Selective reduction with sodium cyanoborohydride in the presence of boron trifluoride etherate and final hydrolysis of the 3- carboxy methyl gave the desired analogs.

Compounds of the Formula (I) in which pi and P² are Cι-C3alkyl are prepared by methods analogous to those described in Scheme 21.

Scheme 21

a) LDA; allyl iodide; b) K₂C0₃, MeOH, H₂0

The previously described ketone was dialkylated with a base such as lithium diisopropyl amide and an alkylating agent (such as allyl iodide), then was hydrolyzed to the desired analogs.

Scheme 22

a) PhLi, THF; b) Et3SiH, BF₃ Et2θ; c) K₂C0₃, MeOH, H2O Selective addition of an organo lithium or a Grignard reagent (such as phenyl Uthium) to the 17 position of the previously described ketone gave a tertiary alcohol, which was reduced with triethyl silane in the presence of boron trifluoride etherate. Final hydrolysis provided the desired analogs.

Compounds of the Formula (I) where R is

N-⁷ are prepared by methods analogous to those described in

Scheme 23-25.

Scheme 23

a) DIBA1, PhMe; H₂S0 ; b) Jones; c) DCC, HOBt, PhC0CH₂NH₂; d) POCl₃; NaOH; e) PhNTf₂, NaH; CO, Pd(OAc)₂, MeOH, dppf; K₂C0₃, MeOH, H₂0 The known 3-mesylate 17-nitrile was reduced with diisobutyl aluminum hydride to the aldehyde, which was in turn oxidized to the 17- carboxylic add. A standard amino add coupling procedure between the carboxylic add and an alpha amino ketone (such as amino acetophenone was used to form the intermediate amide, which was cyclized to the oxazole with phosphorus trichloride. Deprotection of the mesylate with sodium hydroxide, and standard conversion of the 3-hydroxyl group to the 3-carboxyUc add provided the desired analogs.

Scheme 24

a) (CHO)₂, NH4OH; b) PhCH₂OCH₂Cl; c) NaOH; PhNTf₂, NaH; CO, Pd(OAc)₂, MeOH, dppf; K₂C0₃, MeOH, H₂0; d) H₂, Pd/C An imidazole was formed from the 17-aldehyde with ammonium hydroxide and glyoxaldehyde. Protection of the basic nitrogen, deprotection of the mesylate at the 3 position with sodium hydroxide, standard triflation, carbomethyoxylation, and hydrolysis provided the desired protected imidazole derivative. Final hydrogenation provide the desired parent compound.

Scheme 25

a) PhCOCHO, NH4OH; b) Jones

A substituted imidazole was formed from the previously described aldehyde and a aryl or alkyl keto aldehyde (such as benzoyl aldehyde) and ammonium hydroxide. Oxidation provided the desired 3-carboxylic adds.

Scheme 26

a) NaBH₄, MeOH; b) Ac₂0, DMAP; c) Tf2θ, base; d) CO, Pd(OAc)₂, MeOH, e) K₂CO₃, MeOH, H₂O; f) CH₂N₂₎ Et₂O; g) OCN-t-butyl h) K₂C0 , MeOH, H^ The known bisnorcholenaldehyde was reduced with a borohydride salt (such a sodium borohydride), then was acylated with acetic anhydride, cat. 4-dimethylamino pyridine. Triflation, carbomethoxylation, hydrolysis, and esterification of the 3-carboxy group provided the free alcohol, which was converted to a carbamate with a substituted isocyanate (such as t-butyl isocyanate), and was hydrolyzed to the desired 3-carboxylic add.

By the term "solvent" or "appropriate solvent" as used herein and the in the claims is meant a solvent such as methylene chloride, ethylene chloride, chloroform, ethylene glycol, carbon tetrachloride, tetrahydrofuran (THF), ethyl ether, toluene, ethyl acetate, hexane, dimethylsulfoxide (DMSO), N,N'-dimethyl-N,N'-propylene urea, N- methyl-2-pyrrolidinone, methanol, isopropylalcohol, dimethylformamide (DMF), water, pyridine, quinoline or ethanol.

Pharmaceutically acceptable salts, hydrates and solvates of Formula (I) compounds are formed, where appropriate, by methods well known to those of skill in the art.

Because the presently invented pharmaceutically active compounds inhibit steroid 5-α-reductase activity, they have therapeutic utility in treating diseases and conditions wherein decreases in DHT activity produces the desired therapeutic effect. Such diseases and conditions indude acne vulgaris, seborrhea, female hirsutism, male pattern baldness, prostate diseases such as benign prostatic hypertrophy, and prostatic adenocarάnoma.

In determining potency in inhibiting the human 5α-reductase enzyme, the foUowing procedure was employed:

Preparation of membrane narticulates used as source for recombinant steroid 5α-reductase isozvme 1.

Chinese hamster ovary (CHO) ceUs containing expressed, recombinant human steroid 5α-reductase isoenzyme 1 (Andersson, S., Berman, D.M., Jenkins, E.P., and RusseU, D.W. (1991) Nature 354 159-161) were homogenized in 20 mM potassium phosphate, pH 6.5, buffer containing 0.33 M sucrose, 1 mM dithiothreitol, and 50 uM NADPH (buffer A) using a Dounce glass-to-glass hand homogenizer (Kontes Glass Co., Vineland, N.J.). Membrane particulates were isolated by centrifugation (100,000 x g at 4°C for 60 minutes) and resuspended in 20 mM potassium phosphate, pH 6.5, containing 20% glycerol, 1 mM dithiothreitol, and 50 μM NADPH (buffer B). The suspended particulate solution was stored at -80°C.

Preparation of prostatic membrane particulates used as source for steroid 5α-reductase isozvme 2.

Frozen human prostates were thawed and minced into small pieces ( Brinkmann Polytron (Sybron Corp., Westbury, New York). The solution was sonicated for 3 to 5 minutes with a Sonifier (Branson Sonic Power Co.) foUowed by hand homogenization in a Dounce hand homogenizer. 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 peUet obtained from the 140,000 x g centrifugation was washed with 5 to 10 tissue volumes of the buffer described above and centrifuged at 140,000 x g. The resulting peUet was suspended in buffer B and the particulate suspension was stored at -80°C.

Preparation of membrane particulates used as source for recombinant steroid 5-α-reductase isozvme 2.

Chinese hamster ovary (CHO) cells containing expressed, recombinant human steroid 5-α-reductase isozyme 2 were homogenized in 20 mM potassium phosphate, pH 6.5, buffer containing 0.33 M sucrose, ImM dithiothreitol, and 50 μM NADPH (buffer A) using a Douce hand homogenizer. Membrane particulates containing the recombinant human enzyme were isolated by centrifugation (100,000 x g at 4°C for 60 minutes) and resuspended in 20 mM potassium phosphate, pH 6.5 containing 20% glycerol, ImM dithiothreitol, and 50 μM NADPH (buffer B). The suspended particulate solution was stored at -80°C until used.

Assay for enzvmes activities and inhibitors potency. A constant amount of [ Cjtestosterone (50 to 55 mCi/mmol) in ethanol and varying amounts of potential inhibitor in ethanol were deposited in test tubes and concentrated to dryness in vacuo. To each tube was added buffer, 10 μL (recombinant isoenzyme 1 or isoenzyme 2) or 20 μL (isoenzyme 2 from human prostate tissue) of 10 mM NADPH and an aliquot of a steroid 5α-reductase preparation to a final volume of 0.5 mL. Assays for human steroid 5α-reductase isoenzyme 1 were conducted with a sample of the recombinant protein expressed in CHO ceUs in 50 mM phosphate buffer, pH 7.5 while assays of isoenzyme 2 were conducted with a suspension of human prostatic particulates and/or recombinant protein expressed in CHO ceUs in 50 mM dtrate buffer at pH 5.0.

After incubating the solution at 37°C for 20 or 30 minutes the reaction was quenched by the addition of 4 mL ethyl acetate and 0.25 μmol each of testosterone, 5α-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 40 μL chloroform, spotted on an individual lane of a 20 x 20 cm prechanneUed 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 Imaging Scanner (Bioscan Inc., Washington, D.C.). The percent of recovered radiolabel converted to product was calculated, from which enzyme activity was determined. All incubations were conducted such that no more than 20% of the substrate (testosterone) was consumed.

The experimentally obtained data was computer fit to a Unear fiinction by plotting the redprocal of the enzyme activity ( l/velodty) against the variable inhibitor concentration; apparent inhibition constants (Ki_>app) were determined by the Dixon analysis (Dixon, M. (1953).

The value for the inhibition constant (Ki) was calculated from known procedures (Levy, M. (1989), Biochemistry.22:2815-2824).

The pharmaceutically active compounds within the scope of this invention are useful in inhibiting steroid 5-α-reductase in a mammal, including humans, in need thereof.

Compounds within the scope of this invention have been tested and have shown an activity of from 1600 Ki(nM) to 5 Ki(nM) against isozyme I and an activity of from 330 Ki(nM) to 2 Ki (nM) against isozyme 2. Particularly preferred among the compounds of the invention and the compounds used in the invented pharmaceutical compositions and invented methods are: 17β-17-(benzyloxy)-estra-l,3,5(10)-triene-3-carboxyUc add,

17β-17-(2-propenyloxy)-e8tra-l,3,5(10)-triene-3-carboxyUc add,

[17β(E)]-17-[(3-phenyl-propyl)oxy]-estra-l,3,5(10)-triene-3- carboxyUc add,

[17β]-17-methoxy-estra-l,3,5(10)-triene-3-carboxyUc add,

17β-17-(benzyloxy)-androsta-3,5-diene-3-carboxyUc add,

17β-17-[(2-propenyl)oxy]-androsta-3,5-diene-3-carboxyUc add,

17 β- 17-methoxy-androsta-3 ,5-diene-3-carboxyUc add, (20E en-(22) phen ethyl -21-one-estra 1,3,5(10) triene -3- carboxyUc add,

(20E)-en-(22) phenyl -21-one estra 1,3,5(10) triene -3- carboxyUc add,

(20)β methyl -22- phenethyl 21-one estra l,3,5-(10)triene 3- carboxyUc add,

(20)β methyl -22- phenyl 21-one estra l,3,5-(10)triene 3-carboxyUc add, 17(20E)-ene-21-t-butylcarboxamide-estra-l,3,5(10)-triene-3- carboxylic add,

17β-(t-butylacetamido) estra-l,3,5(10)-triene-3-carboxylic add,

Androsta-3,5-diene-3-carboxyUc add, Estra-l,3,5(10)-triene-3-carboxyUc add,

17β-(3-Oxo-4-phenyl-butyl)-estra-l,3,5(10)-triene-3-carboxyUc add,

17β-(5-methyl-3-oxo- l-hexenyl)-estra- 1,3,5( 10)-3-carboxyUc add,

17β-(tert- butylamido- ethylenyl) - estra-l,3,5(10)- triene - 3- carboxyUc add, 17β-(3-Oxo-3-phenyl-propyl)-estra-l,3,5(10)-triene-3-carboxyUc add,

17β-17-(benzyloxy methyl)- estra-l,3,5(10)-triene-3-carboxyUc add,

17β(E) -17-(phenyl ethenyl)- estra-l,3,5(10)- triene- 3 -carboxyUc add, 17β(Z) -17-(phenyl ethenyl)- estra-l,3,5(10)- triene- 3 -carboxyUc add,

17β-17-(2-phenylethyl)-estra-l,3,5(10)-triene-3-carboxyUc add,

O-benzyl oxime ether of 17-oxo-estra-l,3,5-triene-3-carboxylic add,

O-benzyl oxime ether of 17-oxo- androsta- 3,5- diene- 3 -carboxyUc add,

O-t-butyl oxime ether of 17-oxo- androsta- 3,5- diene- 3 -carboxyUc add,

17β-(Phenyl)estra-l,3,5(10)triene-3-carboxyUc add,

(0-tertbutyloxine)estra-l,3,5(10)-triene-3-carboxyUc add, (0-Phenyloxine)estra-l,3,5(10)-triene-3-carboxyUc add, keto-16,16-diaUylestra-l,3,5(10)-triene-3-carboxyUc add,

17β-(N-tertbutoxyam_lno)est-ra-l,3,5(10 txiene-3-carboxyUc add,

17β-(N-Ben__yloxya__--ino)estra-l,3,5(10-triene-3-carboxyUc add,

17β-[2-(5-Phenyloxazole)]estra-l,3,5(ld0)-triene-3-carboxyUc ^acid» 17β-[2-(N-Benzyloxymethyl) imidazolyl estra-l,3,5(10)-triene-3- carboxyUc add,

17β-[2-(5-Phenylimidazole)] estra - 1,3,5 (10) - triene- 3-carboxyUc add,

17β-(2-Imidazolyl) estra - 1,3,5 (10)-triene-3-carboxyUc add, 17β-(3-Oxo-3-phenyl-l-propenyl)-3-hydroxymethyl-estra-l,3,5(10)- triene-3-carboxyUc add, 17β-(3-Oxo-4-phenyl-l-butenyl)-3-hydroxymethyl-estra-l,3,5(10)- triene-3-carboxylic add,

17^β-(5-hydroxy,l,l, 1,9,9,9 hexafluorononyl)androsta-3,5,diene-3- carboxyUc add, 17^β-hydroxy-17α-benzyl-estra-l,3,5(10)-triene-3-carboxylic add,

17^β-( t-butyl dimethyl sflyl ether)androsta-3,5-diene-3-carboxyUc add, 17β-17-hydroxy-androsta-3,5-diene-3-carboxyUc add, 17β-17-hydroxy-estra-l,3,5(10)-triene-3-carboxyUc add, O-phenyl oxime ether of 17-oxo-androsta-3,5-diene-3-carboxyUc add,

17β-methoxy-17α-benzyl-estra-l,3,5(10)-triene-3-carboxyUc add, 17β-[O-(N-phenylcarbamoyl)]estra-l,3,5(10)-triene-3-carboxylic add,

17β-[O-(N-tert-butylcarbamoyl)]estra-l,3,5(10)-triene-3-carboxylic add,

17β-[O-(N-benzylcarbamoyl)]estra-l,3,5(10)-triene-3-carboxyUc add,

17β-[N-(N-tertbutylurea)estra-l,3,5(10)-triene-3-carboxylic add, 17β-[N-(O-tert-butylcarbamoyl)]estra-l,3,5(10)-triene-3-carboxyUc add,

17β-[0-(N-phenylcarbamoyl)] androsta-l,3-diene-3-carboxyUc add, 17β-[0-(N-tert-butylcarbamoyl)] androsta-l,3-diene-3-carboxyUc add, and

17β-[0-(N-benzylcarbamoyl)] androsta-l,3,diene-3-carboxylic add.

The pharmaceutically active compounds of the present invention are incorporated into convenient dosage forms such as capsules, tablets, or injectable preparations. SoUd or Uquid pharmaceutical carriers are employed. SoUd carriers indude, starch, lactose, caldum sulfate dihydrate, terra alba, sucrose, talc, gelatin, agar, pectin, acada, magnesium stearate, and stearic add. Liquid carriers include syrup, peanut oU, oUve oil, saline, and water. Similarly, the carrier or diluent may indude any prolonged release material, such as glyceryl monostearate or glyceryl distearate, alone or with a wax. The amount of soUd carrier varies widely but, preferably, wiU be from about 25 mg to about 1 g per dosage unit. When a Uquid carrier is used, the preparation wiU be in the form of a syrup, elixir, 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 chemist involving mixing, granulating, and compressing, when necessary, for tablet forms, or mixing, fining and dissolving the ingreidents, as appropriate, to give the desired oral or parenteral products.

Doses of the presently invented pharmaceutically active compounds in a pharmaceutical dosage unit as described above wiU be an efficadous, nontoxic quantity preferably selected from the range of 0.01 - 1000 mg/kg of active compound, preferably 0.1 - 100 mg kg. When treating a human patient in need of steroid 5-α-reductase inhibition, the selected dose is administered preferably from 1-6 times daily, oraUy or parenteraUy. Preferred forms of parenteral administration include topicaUy, rectaUy, transdermally, by injection and continuously by infusion. Oral dosage units for human administration preferably contain from 0.1 to 500 mg of active compound. Oral administration, which uses lower dosages is preferred. Parenteral administration, at high dosages, however, also can be used when safe and convenient for the patient.

The method of this invention of inhibiting steroid 5-α-reductase activity in mammals, including humans, comprises administering to a subject in need of such inhibition an effective steroid 5-α-reductase inhibiting amount of a pharmaceutically active compound of the present invention.

The invention also provides for the use of a compound of Formula (I) in the manufacture of a medicament for use in the inhibition of steroid 5-α-reductase.

The invention also provides for a pharmaceutical composition for use in the treatment of benign prostate hypertrophy which comprises a compound of Formula I and a pharmaceutically acceptable carrier.

The invention also provides for a pharmaceutical composition for use in the treatment of prostatic adenocarcinoma which comprises a compound of Formula I and a pharmaceutically acceptable carrier. The invention also provides for a process for preparing a pharmaceutical composition containing a pharmaceutically acceptable carrier or diluent and a compound of Formula I which comprises Dπngmg ne compound of Formula I into assoάation with the pharmaceutically acceptable carrier or diluent.

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

In addition, the pharmaceutically active compounds of the present invention can be co-administered with further active ingredients, such as other compounds known to treat the disease states of acne vulgaris, seborrhea, female hirsutism, male pattern baldness, benign prostate hypertrophy or prostatic adenocardnoma or compounds known to have utility when used in combination with 5-α-reductase inhibitors.

Particularly preferred is the co-administration of a 5-α-reductase inhibitor, as disclosed herein, and minoxidil for use in the treatment of male pattern baldness. Particularly preferred is the co-administration of a 5α-reductase inhibitor, as disclosed herein, and a α-receptor antagonist for use in the treatment of benign prostatic hypertrophy.

Preferred is the co-administration of a 5-α-reductase inhibitor, as disdosed herein, and an aromatase inhibitor for use in the treatment of benign prostatic hypertrophy. Preferred is the co-administration of a 5- α-reductase inhibitor, as disdosed herein, a α -receptor antagonist and an aromatase inhibitor for use in the treatment of benign prostatic hypertrophy.

Without further elaboration, it is beUeved that one skilled in the art can, using the preceding description, utilize the present invention to its fuUest extent. The foUowing Examples are, therefore, to be construed as merely illustrative and not a limitation of the scope of the present invention in any way.

Example 1

Preparation of 17B-17-.benzvloxv.-estra-1.3.5QQ .-triene-3-carboxylic add a) methyl 17β-17-hydroxy-estra-l,3,5(10)-triene-3-carboxylate Sodium borohydride (100 mg, 2.6 mmol) was added to a solution of methyl 17-oxo-estra-l,3,5(10)-triene 3-carboxylate (200 mg, 0.64 mmol) in EtOH at 0° C and stirred for 0.5 h. The reaction was quenched with pH 7 buffer, extracted with EtOAc, dried (magnesium sulfate), concentrated in vacuo, and flash chromatographed (siUca gel 1:4 EtOAc/ hexanes) to afford a white soUd (190 mg, 95%); H NMR: δ 0.82 (s, 3H), 3.77 (dd, J=8.2, 8.2 Hz, IH), 3.91 (s, 3H), 7.35 (d, J=8.5 Hz, IH), 7.76 (s, IH), 7.80 (d, J=8.5 Hz, IH) b) methyl 17β-17-(benzyloxy)-estra-l,3,5-triene-3-carboxylate Benzyl bromide (30 μl, 0.25 mmol) was added to a mixture of methyl 17β-17-hydroxy- estra-l,3,5(10)- triene- 3 -carboxylate (20 mg, 0.06 mmol), sodium hydride (10 mg, 0.42 mmol), and tetrabutyl ammonium iodide (30 mg, 0.09 mmol) in THF (2.0 ml) and was refluxed for 12 h. The reaction was quenched with pH 7 buffer (10 ml) and extracted with ethyl acetate (20 ml), dried (magnesium sulfate), concentrated in vacuo, and flash chromatographed (silica gel 1:4 EtOAc/ hexanes) to afford the title compound as a white soUd (12 mg, 55%); H NMR: δ 0.88 (s, 3H), 3.53 (dd, J=8.2, 8.2 Hz, IH), 3.91 (s, 3H), 4.58 (s, 2H), 7.30-7.48 (m, 6H), 7.76 (s, IH), 7.79 (d, J=8.5 Hz, IH). c) 17β-17-(benzyloxy)-estra-l,3,5-triene-3-carboxyUc add Potassium carbonate (30 mg, 0.22 mmol) was added to a solution of methyl 17β-17-(phenyl methoxy)-estra-l,3,5(10)-triene-3-carboxylate (10 mg, 0.03 mmol) in MeOH (2.0 ml) and H2O (0.2 ml) and was refluxed for 12 h. The reaction was quenched with pH 4 buffer(10 ml), extracted with EtOAc (20 ml), dried (magnesium sulfate), concentrated in vacuo, and flash chromatographed (silica gel 1:20:80 AcOH/ EtOAc/ hexanes) to afford the title compound as a white soUd (8 mg, 80%); H NMR: δ 0.88 (s, 3H), 3.53 (dd, J=8.2, 8.2 Hz, IH), 4.58 (s, 2H), 7.30-7.36 (m, 5H), 7.42 (d, J=8.5 Hz, IH), 7.84 (s, IH), 7.87 (d, J=8.5 Hz, IH); m/e 391 [M+H]+

F-7røTPPle 2 Preparation of 17β-17-(2-propenyloxy)-estra-1.3.5(10)-triene-3-carboxvlic ϋc a) 17β-17-(2-propenyloxy)-estra-l,3,5(10)-triene-3-carboxylic add

Following the procedure of Example l(a)-(c), except substituting aUyl iodide for benzyl bromide, the title compound was prepared (15 mg, 75%); H NMR (CDCI3, 400 MHz): δ 0.84 (s, 3H), 3.48 (dd, J=8.5, 8.5 Hz, IH), 4.04 (d, J=5.5 Hz, 2H), 5.17(d, 9.0 Hz, IH), 5.30 (d, J=18.9 Hz), 5.95 (ddd,5.5, 9.0, 18.9 Hz,lH), 7.43 (d, J=9.0 Hz, IH), 7.83 (s, IH), 7.87 (d, J=9.0 Hz).

Example 3

Preparation of ri7B(E)l-17-r(3-phenyl-2-propenvDoxyl-estra-1.3.5(10V triene-3-carbo vli^ς acid a) [17β(E)]-17-[(3-phenyl-2-propenyl)oxy]-estra-l,3,5(10)- triene-3-carboxyUc add FoUowing the procedure of Example l(a)-(c), except substituting dnnamyl bromide for benzyl bromide, the title compound was prepared (5 mg, 50%); ^XH NMR (CDCI3, 400 MHz): δ 0.86 (s, 3H), 3.53 (dd, J=8.5, 8.5 Hz, IH), 4.22 (d, J=5.5 Hz, 2H), 6.27-6.34 (m, IH), 6.64 (d, J=16.5 Hz, IH), 7.25-7.45 (m, 6H), 7.84 (s, IH), 7.87 (d, J=9.0 Hz); MSΦCIZNH3) m/e 341[M+H]+m/e 434 [M+NH41+

E-^gf-mple 4 Preparation of ri7β(E)1-17-r(3-phenvl-propvl)oxv1-estra-1.3.5(10)-triene- 3-carboxvlic add a) [17β(E)]-17-[(3-phenyl-propyl)oxy]-estra-l,3,5(10Mriene-3- carboxylic add

[17β(E)]-17-[(3-phenyl2-propenyl)oxy]-estra-l,3,5-triene-3- carboxyUc add (4 mg, 0.01 mmol) and Pd/C (20 mg) in EtOH (1.0 ml) was stirred under hydrogen (balloon) for 4h, filtered through silica gel (EtOAc), and concentrated in vacuo to afford the title compoxmd as a white soUd (3 mg, 75 %); H NMR (CDCI3, 400 MHz): δ 0.84 (s, 3H), 3.46 (dd, J=8.5, 8.5 Hz, IH), 3.50 (dd, 7.0, 9.0 Hz, 2H), 7.29-7.33 (m, 5H), 7.37 (d, J=8.5 Hz, IH), 7.82 (s, IH), 7.75 (d, 8.5 Hz, IH); MS(DCI/NH3) m/e 419 [M+H]+

Exjipiple ^~ Preparation of T17β .-17-methoxv-estra-1.3.5(10.-triene-3-carboxvlic add a) [17β]-17-methoxy-estra-l,3,5(10)-triene-3-carboxylic add Following the procedure of Example l(a)-(c), except substituting methyl iodide for benzyl bromide, the title compound was prepared (10 mg, 50%);^!H NMIKCDCI3, 400 MHz): δ 0.81 (s, 3H), 3.34(dd, J=8.2, 8.3 Hz, IH), 3.40 (s, 3H), 7.40 (d, J=8.2Hz, IH), 7.83 (s, IH), 7.86(d, 8.2 Hz, IH); MSΦCI/NH3) m/e 315 [M+H]+

Example 6 Preparation of 17β-17-.benzvloxv.-androsta-3.5-diene-3-carhoxvlic add a) 17β-17-benzyloxy-androsta-3,5-diene-3-carboxyUc add

Benzyl bromide (30 μl, 0.25 mmol) was added to a mixture of 17β- 17-hydroxy-androsta-3,5-diene-3-carboxylic add (20 mg, 0.06 mmol), sodium hydride (10 mg, 0.42 mmol), and tetrabutyl ammonium iodide (30 mg, 0.09 mmol) in THF (2.0 ml) and was refluxed for 12 h. The reaction was quenched with pH 4 buffer (10 ml) and extracted with ethyl acetate (20 ml), dried (magnesium sulfate), concentrated in vacuo, and flash chromatographed (siUca gel 1:20:80 AcOH/EtOAc/hexanes) to afford the title compound as a white soUd (12 mg, 55 %); !H NMR: δ 0.88 (s, 3H), 0.94 (s, 3H), 3.45 (dd, J=8.2, 8.2 Hz, IH), 4.57 (s, 2H), 5.86 (d, J=2.0 Hz, IH), 7.16 (s, IH), 7.26-7.37 (m, 5H); m/e 407 [M+H]+

Example 7

Preparation of 17β-17-. (2-propenvl)oxv1-androsta-3.5-diene-3-__arhoxvlic

a) 17β-17-[(2-propenyl)oxy]-androsta-3,5-diene-3-carboxyUc add

FoUowing the procedure of Example 6(a), except substituting aUyl iodide for benzyl bromide, the title compound was prepared (10 mg, 50

%); H NMR (CDCI3, 400 MHz): δ 0.84 (s, 3H), 0.93 (s, 3H), 3.40 (dd, J=8.5, 8.5 Hz, IH), 4.02 (d, J=5.5 Hz, 2H), 5.15(d, 10.4 Hz, IH), 5.27 (d,

J=17.1 Hz), 5.90 (d, J=2.0 Hz, IH) 5.85-5.95 (m,lH), 7.14 (s, IH);

MS(DCI/NH3) m/e 357 [M+H]+

Example 8 Preparation of 17β-17-methoxy-androsta-3.5-diene-3-carboxylic add a) 17β-17-methoxy-androsta-3,5-diene-3-carboxyUc add Following the procedure of Example 6(a), except substituting methyl iodide for benzyl bromide, the title compound was prepared (10 mg, 50%); ;-K NMR (CDCI3, 400 MHz): δ 0.81 (s, 3H), 0.93 (s, 3H) 3.26 (dd, J=8.1, 8.1 Hz, IH), 3.37 (s, 3H), 5.87 (bs, IH), 7.16 (s, IH); MSODCI/NH3) m/e 331 [M+H]⁺

Eynm l 9 Preparation of 17-(20E)-en-(22) nhen ethyl-21-one-estra 1.3.5(10. triene - 3-carboxylic add a) 17-cyanomethylene-3-hydroxy-estra-l,3,5(10)-triene

A solution of diethylcyanomethylphosphonate (52.4g 296 mmole) in 150ml dry THF was added dropwise to sodium amide (11.54g, 296 mmole) in 100ml dry THF. The orange solution was stirred for 2 hours then estrone (20g, 74mmole) was added and refluxed for 4 hours then stirred overnight at room temperature. The resulting solution was evaporated under reduced pressure. Water was added to the residue, addified with dilute HCl and extracted with ethylacetate, dried (MgSθ4) and concentrated to get 36 g of soUd. Flash column chromatographic separation (sUica gel 30:1 CH2Cl2:EtOAc) gave 8.6 lg (46%) pure E isomer and 1.00 g (4 by) of pure z isomer *H NMR (CDCI3, 250 MHz), E isomer: δ 0.88 (s,3H), 5.05 (d, IH J=2.5Hz) 6.57 -6.65 (M,2H), 7.2 (dd IH J=8.2Hz); *H NMR (CDCI3, 250 MHz), Z isomer : δ 0.99(S,3H), 4.77 (S,1H), 5.14 (d, IH, J=2.5 Hz) 6.57-6.65 (m,2H), 7.2 (dd IH, J=8.2 Hz). b) 17-E-cyanomethylene-3-(trifluoromethane sulfonyloxy)- estra-l,3,5(10)-triene

To a solution of 5.82g ( 21.3 m mol) of 17-cyanomethylene-3- hydroxy-estra-l,3,5(10)-triene in 80 ml of dry THF was added sodium hydride (0.96, 40mm) under argon and stirred for 30 minutes. Then N- phenyltriflamide (14.32 g, 40 mmol ) was added and stired overnight The reaction was concentrated under reduced pressure. Water was added and extracted with ethylacetate dried (MgSθ4), the resulting oil was separated on flash column (silica gel (8:2:1 Hexane:EtOAc:CH2Cl₂) to give 6.5g of 17E-cyanomethelene-3-triflate of estrone mp. 136-138 -Η. NMR (CDCI3, 400 MHz): δθ.89 (S,3H), 5.061(m, IH), 6.99 (m,2H), 7.31(dd, IH, J.8.2H₂). c) Methyl-17(20E)-en-21 cyano estra-l,3,5(10)-triene-3- carboxylate A mixture of 3.2g (δmmole) of 17-E-cyanomethylene-3- (trifluoromethane sulfonyloxy)-estra-l,3,5(10)-triene, Pd(OAc)2 (166mg, 0.74mmole), 1,3-bis diphenylphosphino) propane (293mg, 0.71mmole) triethylamine (3.31ml) dichloromethane (14ml) in DMSO (-33ml) and methanol (31) ml under one atm of carbon monoxide was stirred overnight at 70°. Reaction mixture was cooled, dfluted with water, extracted with Ethylacetate, washed with H2O, dried (MgS04) removed of solvent gave solid (2.3g, 85%)mp 153° -Η. NMR (CDCI3, 400 MHz): δ 0.90 (S, 3H), 3.9 (S, 3H), 5.05 (d, IH) 7.35 (d,lH), 7.75 (m,2H). d) 3-Hydroxy methyl estra-l,3,5(10)-triene 17(20E)-ene-21-al.

To a solution of 17 (cyanomethylene) estra 1,3,5 (10) triene-3- carboxyUc add methyl ester (1.9g, 5.67mmole) in 40ml of toluene was added 20ml of 1.0 M solution of DIBAL-H in toluene and stirred ) at room temperature added and stirred for one hour then 60ml of 5% H2SO4 added and stirred another hour, diluted with ethylacetate and washed with cold water, dried (MgSθ4) removal of the solvent gave 1.4g of oil (9%) *H NMR (CDCI3, 400 MHz): δ 0.90 (S,3H), 4.62 (S,2H), 5.8(d, 2H, J=7.98H_Z 7.1-7.3 (m,3H), 9.87 (d, IH, J=7.99 Hz). e) 3-Hydroxymethyl estra l,3,5(10)triene 17-(20E)-en-(22) phenethyl-21-ol

To a solution of benzyl magnasium bromide (2ml, 2M) in 3ml of dry THF under argon was added a solution of 3-hydroxymethyl estra 1,3,5 (10) triene 17 (20 E) -en-al (0.31g lmmole) in 3 ml THF and was stirred for 2 hours. The resulting reaction mixture was quenched with ammonium chloride and extracted with EtOAc, dried (MgSθ4) removal of the solvent gave 0.3g (75%) of oil with was used in the next reaction without purification. f) 3-Formyl estra l,3,5(10)triene 17-(20E)-en-(22)-phenethyl- 21-one To a solution of alcohol (0.3g; 0.75mmole) in 15ml CH2CI2 containing 4A Mol sieves and NMO (0.351g, 2.5 mmole) was added soUd TPAP (53mg, O.lδmmole) and stirred 3 hours at RT. The reaction mixture was put on the silica gel flash column and eluted with 20% EtoAe in hexane to give lOOmg of aldelyde *H NMR (CDCI3, 400 MHz): δ 0.84 (S,3H) 3.76 (S,2H), 6.06 (S, IH) 7.23-7.6 (m, 8H), 9.94 (S, IH). g) 17-(20E)-en-(22) phenethyl-21-one estra l,3,5(10)triene-3- carboxylic add To a stirred solution of aldehyde (50mg, 0.125mmol) t-butylalcohol (2ml) and 2-Me-2-butene (1.5ml) at 0°C was added a solution of NaC102 (117mg, 1.25mmole) and NaH2Pθ4θ H2O (18mg, 1.25 mmole) in water (lml). The resulting solution was warmed up to room temperature and stirred for 3 hours. HO AC (lml) and brine (3ml) added and extracted with EtoAc (3x10 ml), dried (MgS04) and concentrated and purified on a flash column (silica 8.4: 1.5:01 Hexane: EtOAc: HOAc) to give 20mg soUd. M.P. 176-78° *H NMR (CDCI3, 250 MHz): δθ.84 (s,3H) ,3.7 (S,2H) 6.03 (S,1H), 7.2-7.4 (m,6H), 7.82 (m, 2H) m/e 415 [M+H]+; Anal. Calcd for C28H30O3; C.78.15; H,7.44 Found: C,78.07 H.7.21

Example 10 Preparation of 17-(20EVen-(22) phenyl-21-one estra 1.3.5(10) triene-3- carbosylic acid FoUowing the procedure of Example 9 (a)-(f) except substituting phenyl magnesium bromide for benzyl magnesium bromide, the title compound was prepared (40 mg, 30%) m.p.250° ^XH NMR (CDCI3, 250 MHz): δθ.95 (s,3H) , 6.78 (S,1H) 7.44-7.5 (m,5H), 7.85-7.97 (m, 3H) m/e 401 [M+H]+; Anal. Calcd for C27H28O3; C.79.19; H.7.14 Found: C,79.10 H,7.10.

Exam le 11 Preparation of 17-(20EVen-(22) t-butvl-21-one estra 1.3.5(10) triene -3- carboxvlic add FoUowing the procedure of Example 9 (a)-(f) except substituting t- butyl magnesium bromide for benzyl magnesium bromide, the title compound was prepared (64 mg, 30%) m.p.200-202° ⁱH NMR (CDCI3, 250 MHz): δθ.88 (s,3H) ,1.15 (s,9H) 6.3 (S,1H) 7.4 (m,lH), 7.8 (m, 2H) m/e 381 [M+H]+; Anal. Calcd for C25H33O3; C.77.09; H.8.54 Found: C.76.76 H,8.39.

Eyfl 1e 19. Preparation of 17-(20EVen-(22)-methyl (23) t-butvl-21-one estra 1.3.5(10) triene-3-carboxvlic add FoUowing the procedure of Example 9 (a)-(f) except substituting neopentyl magnesium bromide for benzyl magnesium bromide, the title compound was prepared (111 mg, 60%) m.p.218-220° ¹K NMR (CDCI3, 250 MHz): δ 0.86 (s,3H) ,1.02 (s,9H) 65.98 (S,1H) 7.4 (d,lH), 7.8 3 (m, 2H) m/e 395 [M+H]+; Anal. Calcd for C26H34O3; C.77.38; H.8.74 Found: C.77.28 H.8.49

Example 13

Preparation of 17-(20)β methvl-22-phenethvl 21-one estra 1.3.5- (10.triene 3-carboxvlic add a) 17β-(20) cyanomethyl 3-hydroxy-estra-l,3,5(10)-triene To a partial mixture of 17-(20E,Z)-ene-21-cyano 3-hydroxy-estra- l,3,5(10)-triene in 150 ml of 1:1 EtOAc:Ethanol was and added 5%

Pd/BaS04 and subjected to Parr shaker hydrogenation at 50 psi for 2.5 hour. Filtration of the catalyst and concentrating the solvent afforded a white soUd (4g 98%) *H NMR (CDCI3, 250 MHz): dθ.67 (S,3H), 6.56- 6.58(m,2), 7.1 (d, IH, J=8.2Hz); mp 232-4°. b) 17-β-(20)cyanomethyl-3-(trifluoromethane sulfonyloxy)- estra-l,3,5(10)-triene

FoUowing the procedure of Example 9(b), substituting 17 b-(20) cyanomethyl 3-hydroxy-estra-l,3,5(10)-triene for 17-cyanomethylene -3- hydroxy-estra- 1,3,5 -triene, the title compound was prepared (7.00g,77%) iH NMR (CDCI3, 250 MHz): dθ.69 (s, IH) ,6.96- 6.98 (m,lH) ,7.3 (d,lH) c) Methyl-17β(20)methyl-21-cyanoestra-l,3,5(10)-triene-3- carboxylate

FoUowing the procedure of Example 9(c), substituting 17-β-(20) cyanomethyl-3-(trifluoromethane sulfonyloxy)-estra-l,3,5(10)-triene for 17-E-cyanomethylene-3-(trifluoromethane sulfonyloxy)-estra 1,3,5 triene, the title compound was prepared m.p. 155° (4.8g ,80%)!H NMR (CDCI3, 250 MHz): d 0.69 (s, IH) ,6.96- 6.98 (m,lH) ,7.3 (d,lH) d) 3-Hydroxymethyl estra 1,3,5-triene 17-(20)β methyl 21-al FoUowing the procedure of Example 9(d) , substituting methyl -17β (20)methyl-21-cyano estra- l,3,5(10)-triene-3-carboxylate for methyl- 17 (20E)-en-21 cyano estra-l,3,5-(10)triene-3-carboxylate, the title compound was prepared (1.2 g, 80%) !H NMR (CDCI3, 250 MHz): d 0.649 (s, IH) ,6.49- 6.64 (m,2H) ,7.13-7.24 (m,lH) 9.8 (s IH) e) 17-(20)β methyl-22-phenethyl 21-one estra-l,3,5-(10)triene 3-carboxyUc add

FoUowing the procedure of 9 (e)-(g), substituting 3-hydroxymethyl estra l,3,5-(10)triene 17-(20)β methyl 21-al for 3-hydroxy methyl estra 1,3,5 (10) triene 17(20E)-ene-21-al, the title compound was prepared m.p. (150 mg, 60% ) m.p. 188-90° -R NMR (CDCI3, 250 MHz): d 0.58 (s, 3H) 3.3 ( S, 2H) ,7.22-7.34- (m, 6H) ,7.81-(m,2H) m/e 417 [M+H]+ ;

Anal. Calcd for C28 H32O3; C, 79.59; H,7.79 Found C.79.40, H,7.74.

Preparation of 17-(20)B methvl-22-phenvl 21-one estra 1.3.5-( 10.triene

3-carboχylic add

Following the procedure of Example 13(e), substituting phenyl magnesium bromide for benzyl magnesium bromide, the title compound was prepared (140 mg, 60% ) m.p. 210-12° IH NMR (CDCI3, 250 MHz): δθ.741 (s, 3H) 0,7.4-7.65- (m, 4H) ,7.83- 7.95 (m,4H) m/e 403 [M+H]+ ; Anal. Calcd for C27 H3θθ3_; C, 80.12; H,.7.53 Found C,80.25 H.7.78.

Example 15

Preparation of 17-(20)B methyl-22-t-butyl 21-one estra 1.3.5-( 10.triene 3- carboxvlic add

FoUowing the procedure of Example 13(e), substituting t-butyl magnesium bromide for benzyl magnesium bromide, the title compound was prepared m.p. (75 MG. 30%) m.p. 228-30° *H NMR (CDCI3, 250

MHz): δ 0.65 (s, 3H) 1.15 (S, 9H) 0,7.26- (d, IH) ,7.81 (m,2H) m/e 383

[M+H]+ ; Anal. Calcd for C25 H34O3; C, 77.28; H,.8.99 Found C.77.12

H,8.98.

Example 16

Preparation of 17-(20)Bmethvl-22-neopentvl 21-one estra 1.3.5-(10)triene

3-carboxvlic add

FoUowing the procedure of Example 13(e), substituting neopenyl magnesium bromide for benzyl magnesium bromide, the title compound was prepared m.p. (75 MG. 30% ) m.p. 235-37° *H NMR (CDCI3, 250

MHz): δ 0.63 (s, 3H) 1.102 (S, 9H) 0,7.46- (d, IH) ,7.59 (m, 2H) m/e

397 [M+H]+ ; Anal. Calcd for C26 H36O3; C, 77.86; H..9.17 Found

C78.05 H,9.27.

Example 17

Preparation of 17(20E)-ene-21-t-butvlcarboxamide-estra-l ,3.5(10)-triene-

3-carboχylic add. a) N-t-butyl-3-methoxy-estra-l,3,5(10)triene 17-(20E)-ene-21- carboxamide

To a solution of 3-methyoxy-estra-l,3,5(10)triene 17(20E)-ene-21- carboxyUc add (1.0 g, 3 mmol) in 15 ml of toluene was added pyridine (0.47 ml, 6 mmol) and oxalyl chloride (0.76g, 5 mmol) in 3 ml of toluene dropwise and stirred at room temperature for 1 hour, cooled at 0° and 3.0 g of t-buytlamine in 5 ml of toluene was added and stirred overnight. Quenched with water and extracted with ethylacetate, combined organic extracts were washed with 5% NaHCθ3, dried removal of the solvent gave a soUd (l.OOg, 85%). ¹K NMR (CDCI3, 250 MHz): δ 0.83 (S, 3H), 1.38 (S, 9H), 3.77 (S,3H) , 5.32 (S,1H), 6.64 (M, 2H) 7.2 (d, IH, J= 8.2) b) N-t-butyl-3-hydroxyl7(20E)-ene-estra-l,3,5(10Mriene-21-t- butylcarboxamide

To a solution of N-t-butyl-3-methoxy-estra-l,3,5 (10)-triene 17- (20E)-ene-21-carboxamide (0.2g, 5.4mmole) in 10ml CH2CI2 at -78° was added 0.7ml of 1M solution of Boron tribromide in CH2CI2 and stirred at room temperature for 2 hours. Water was added. Organic layer separated and dried, (MgSθ4), removal of the solvent gave soUd (120mg 60%). ⁱH NMR (CDCI3, 250 MHz): δ 0.77 (S, 3H) , 1.25 (S, 9H), 5.59 (S,1H), 6.64 (M, 2H) 7.0 (d, IH, J= 8.2) 7.35 (S, IH) c) 3-(trifluoromethane sulfonyloxy) 17-(20E)-ene-estra- l,3,5(10)-triene21-t- butylcarboxamide

FoUowing the procedure of Example 9(b), substituting N-t-butyl-3- hydroxyl7(20E)-ene-estra-l,3,5(10)-triene-21-t-butylcarboxamide for 17- cyanomethylene -3-hydroxy-estra-l,3,5(10) -triene, the title compound was prepared in 48% yield. d) methyl 17(20E)-ene-21-t-butylcarboxamide-estra 1,3,5- triene-3-carboxylate

FoUowing the procedure Example 9(c), substituting 3- (trifluoromethane sulfonyloxy) 17-(20E)-ene-estra-l,3,5(10)-triene-21-t- butylcarboxamide for 17-E -cyanomethylene -3-(trifluoromethane sulfonyloxy)-estra 1,3,5 triene, the title compound was prepared in 89% yield. e) 17(20E)-ene-21-t-butylcarboxamide-estra-l,3,5(10)-triene-3- carboxyUc add

A solution of methyl 17(20E)-ene-21-t-butylcarboxamide-estra- l,3,5(10)-triene-3-carboxylate (0.3g, 0.73mmole) in 10:1 methanol:H2θ containing K2CO₃ (350mg, 2.1mmole) was refluxed overnight. Concentrated, dissolved in water and aάdified with dilute HCl to get crude solid, purified on flash chromatography (silica gel 30:70:1 EtOAc:Hexane:HOAc) gave soUd (160mg, 55%) mp 163-5°.^ NMR (CDCI3, 250 MHz): δ 0.84 (s, 3H) 1.39 (S, 9H) 5.32 (SIH) , 5.4 ( S, IH) 0,7.35- (m, IH) ,7.83 (d, 2H) m/e 396 [M+H]+ ; Anal. Calcd for C25 H33NO3; C, 74.22; H..8.47, N, 3.46 Found C.73.98 H.8.15 , N. 3.69.

E^τ..mp1 1 Preparation of 17B-.t-bt.tvlacetf,mido) estra-1.3.5(10)-triene-3-carboxvlic add. a) 3-Methoxy-estra-l,3,5(10)-triene(10) 17(20E)-ene 21-methyl carboxylate

To a mixture of 3-methoxy estrone (2.00g, 7.3mmole) and methyl dimethyl phosphonoacetate (4.00g, 21.7mmole) was added at room temperature a solution of sodium ethoxide prepared from δOOmg of sodium and 25ml of ethanol. The mixture was refluxed overnight. The resulting solution was concentrated and diluted with water and extracted with ethylacetate, dried (MgSθ4), removal of the solvent gave crude product, purified by flash column (silica gel 95:5 Hexane:etone) to give soUd (0.75g, 30%) H NMR (CDCI3, 400 MHz): δ 0.90 (S, 3H), 3.77 (S,3H) ,5.58 (S,1H) , 6.62 (S,1H) 6.7 (d,2H) 7.2 (d, IH) b) 3-Methoxy-estra-l,3,5(10)-triene-17β-acetic add methyl ester A solution of 3-methoxy-estra-l,3,5(10)-triene 17(20E)-ene 21- methyl carboxylate (1.2g, 3.5mmole) in 35ml of acetic add containing lOOmg of Ptθ2 was subjected to pair shaker hydrogenation for 2.5 hours at 25 psi. Catalyst filtered off, concenatrating the solvent gave an oil (12g 99% ) H NMR (CDCI3, 250 MHz): Olefinic proton at 5.58 δ disappeared. c) 3-Methoxy-estra, 1,3,5 triene(10)17-acetic add (3) FoUowing the procedure Example 9(c), substituting 3-methoxy- estra-l,3,5(10)-triene-17β-acetic add methyl ester for methyl 17(20E)- ene-21-t-butylcarboxamide-estra-l,3,5(10)-triene-3-carboxylate, the title compound was prepared (0.8g, 66%). d) 3-Methoxy-17(t-butylacetamido)estra-l,3,5(10)-triene Following the procedure Example 17(a), substituting 3-methoxy- estra-l,3,5(10)-triene-17-acetic add for 3-methyoxy-estra-l,3,5(10)triene 17(20E)-ene-21-carboxyUc add, the title compound was prepared (0.80g, 55%). e) 3-Hydroxy-17(t-butylacetamido)estra-l,3,5(10)-triene

FoUowing the procedure Example 17(b), substituting 3-methoxy- 17(t-butylacetamido)estra-l,3,5(10)-triene for 3-methoxy-estra- l,3,5(10)triene 17(20E)-ene-21-carboxyUc add, the title compound was prepared in 90% yield. f) 3-(trifluoromethane sulfonyloxy) 17-(t-butylacetamido) estra- 1,3 ,5( lOHriene

Following the procedure Example 9(b), substituting 3-Hydroxy- 17(t-butylacetamido)estra-l,3,5(10)-triene for estrone, the title compound was prepared in 48% yield. g) methyl-17β-(t-butylacetamido)estra-l,3,5(10)-triene-3- carboxylate

FoUowing the procedure Example 9(c), substituting 3- ( trifluoromethane sulfonyloxy) 17-(t-butylacetamido)-estra-l,3,5(10)- triene for 17-E-cyanomethylene-3-(taifluoromethanesulfonyloxy)-estra- 1,3,5-triene, the title compound was prepared in 89% yield. h) 17β-(t-butylacetamido)estra-l,3,5-triene-3-carboxyUc add

A solution of ester (4) (0.3g, 0.73mmole) in 10:1 methanol:H₂θ containing K2CO3 (350mg, 2.1mmole) was refluxed overnight. Concentrated, dissolved in water and addified with dilute HCl to get crude soUd purified on flash column (silica gel 20:80:1

EtOAc:Hexane:HOAc) gave soUd (160mg, 40%) mp 255-57°.^ NMR (CDCI3, 250 MHz): δ 0.63 (s, 3H) 1.35 (S, 9H) 5.26 (s,lH) , 0,7.39- (d, IH) ,7.83 (m, 2H) m/e 398 [M+H]+ ; Anal. Calcd for C25 H35NO3; C,

74.68; H,.8.90, N, 3.48 Found C,74,81 H.8.89 , N. 3.39.

Example 19 Preparation of Androsta-3.5-diene-3-carboxvlic add a) 3-[[(Trifluoromethyl)sulfonyl]oxy]-androsta-3,5-diene To a solution of 17-des-hydroxy testosterone (0.16g, 0.6 mmol) and 2,6,-di-_:ert-butyl-4-methylpyridine (0.16 g, 0.78 mmol) in CH₂C1₂ (20 mL) was added triflic anhydride (0.15 mL, 0.9 mmol) and the mixture was stirred for 2 h under argon. The mixture was then diluted with CH2CI2 (20 mL), washed with 5% HCl, H2O, 5% NaHCO3, and brine, dried over MgSθ4, and evaporated. The crude triflate was purified by chromatography (hexanes) to yield the title compound as a solid ( 0.2 g, 83%). -U NMR (CDCI3, 400 MHz): δ 0.75 (s, 3H), 0.97 (s, 3H), 5.60 (m, IH), 6.0 (s, IH). b) Androsta-3,5-diene-3-carboxyUc add A mixtureof 3-[[(Trifluoromethyl)sulfonyl]oxy]-androsta-3,5-diene (0.2g, 0.5 mmol), potassium acetate (0.2g, 2 mmol), palladium (II) acetate (5.6 mg, 0.025 mmol), triphenylphosphine (13.1mg, 0.05 mmol) and DMF (3mL) was stirred under 1 atm of carbon monoxide for 3 h at 60 °C. The reaction mixture was dfluted with H₂O, aάdified with 5% HCl and extracted with CH₂Cl₂.The organic extract was washed with H₂O and brine, dried and concentrated. The residue was chromatographed (1:10:90 AcOH EtOAC/hexanes) to yield sUghtly impure product. It was stirred with CH3CN and filtered to give a Ught-yeUow soUd (0.041g, 27%).

Analytical sample was prepared by boiling with MeOH/ acetone, mp 265- 7°C ( softened at 246°C); ^!H NMR (CDCI3, 400 MHz): δ 0.75(s, 3H), 0.92 (s, 3H), 5.88 (m, IH), 7.15 (s, IH); MS (DCI/NH3) m/e 301 [M+H]⁺; Anal. Calcd for C20H28O2; C.79.96 ; H.9.39. Found: C.79.63; H.g.10.

Example 20

Preparation of Estra-1.3.5(10)-triene-3-carboxvlic add a) Methyl 17-[[(trifluoromethyl)sulfonyl]oxy]-estra-l,3,5(10),16- tetraene-3-carboxylate FoUowing the procedure Example 19(a), substituting methyl-17-oxo- estra 1,3,5- triene-3-carboxylate for 17-des-hydroxy testosterone, the title compound was prepared (O.lδg, 71%); H NMR (CDCI3, 400 MHz): d 1.0 (s,3H), 3.9 (s, 3H), 5.62 (m, IH), 7.34 (d, J = 8 Hz, IH), 7.78 (s, IH), 7.80(d, J = 8 Hz, IH). b) Methyl-estra-l,3,5(10)-triene-3-carboxylate

A mixture of methyl 17-[[(trifluoromethyl)sulfonyl]oxy]-estra- l,3,5(10),16-tetraene-3-carboxylate (0.04g, 0.09 mmol), Ptθ2 (20mg) in MeOH (25ml) was stirred under H2 (1 atm) for lh. The mixture was filtered and the filtrate was concentrated. The residue was dissolved in CH2CI2 and washed with H2O and brine, dried and concentrated to an oil which slowly soUdified.This ester was converted to the add without further purification. c) Estra-l,3,5(10)-triene-3-carboxylic add A mixture of the methyl-estra-l,3,5(10)-triene-3-carboxylate (0.020g, 0.067 mmol), K2CO3 (0.03g, 0.2 mmol), H2O (0.5 ml), and MeOH (5ml) was heated at reflux for 3 h. The reaction mixture was concentrated and the residue was addified with 5% HCl, extracted with EtOAC. The organic layer was washsed with H2O and brine, dried and concentrated to a soUd (O.Olδg, 79%). Trituration with MeOH/ acetone provided a white soUd. mp 292-5 °CMi NMR (CDCI3, 400 MHz): δ 0.75 (s,3H),7.40 (d, J = 8 Hz,lH), 7.81 (s,lH), 7.85 (d, J =8 Hz.lH); MS(DC17NH3) m/e 285 [M+H]+; Anal. Calcd for C19H24O2 0.25H2O; C,78.9g; H.8.55. Found: C,79.ig; H,8.42.

Example 21 Preparation of 17β-.3-Oxo-4-phenvl-butvl )-estra-1.3.5(10 riene-3- carboxylic add a) 17β-(3-Oxo-4-phenyl-l-buthenylene)-3-hydroxymethyl-estra- l,3,5(10)-triene

To a stirred suspension of LiCl (0.03 g, 0.7 mmol) in dry CH3CN ( 6 mL ) was added dimethyl-2-oxo-3-phenylpropylphosphonate ( 0.15 g, 0.6 mmol ), DBU ( 0.07 mL, 0.5 mmol ) and 17β-17-(formyl)estra-l,3,5-triene- 3-methanol ( 0.15 g, 0.5 mmol ). After stirring overnight, the reaction mixture was concentrated. The residue was partitioned between H2O and EtOAC. The organic layer was washed with brine and dried, and concentrated. The crude product was chromatographed ( 20 : 80 EtOAc / hexanes ) to provide an oil ( 0.10 g, 50 % ). *H NMR (CDCI3, 400 MHz): δ 0.63 ( s, 3H ), 3.85 (s, 2H), 4.63 (s, 2H), 6.12 (d, J = 15.7 Hz, IH), 6.92 (d,d J = 15.7,15.7 Hz, IH), 7.10 (s, IH), 7.15 (d, J = 8Hz, IH), 7.2-7.35 (m, 6H). b) 17β-(3-Oxo-4-phenyl-butyl)-3-hydroxymethyl-estra-l,3,5(10)- triene A mixture of 17β-(3-Oxo-4-phenyl-l-buthenylene)-3-hydroxymethyl- estra-l,3,5(10)-triene (0.1 g, 0.24 mmol), 5% Pd/C (0.03 g) and EtOAC (5 mL) was stirred under H2 ( 1 atm) for 1 h. The mixture was filtered through a CeUte pad and then concentrated to an oil.(0.08 g, 80%). *H NMR (CDCI3, 400 MHz): δ 0.6 (s, 3H), 3.70 (s, 2H), 4.62 (s, 2H), 7.10-7.34 (m, 8H). c) 17β-(3-Oxo-4-phenyl-butyl)-estra- 1 ,3,5( 10)-triene-3-carboxyUc add Jones reagent was added slowly to acetone (10 mL) solution of 17β- (3-Oxo-4-phenyl-butyl)-3-hydroxymethyl-estra-l,3,5(10)-triene (0.07g, 0.17mmol) After stirring for 4 h. the reaction mixture was concentrated to small volume. The residue was diluted with H2O and extracted with EtOAc. The organic layer was washed with H2O and brine, dried and concentrated.The crude product was chromatographed (1: 20 : 80 AcOH/ EtOAC/ hexanes).: mp 160-3 °C. MS (DCI/NH3) m/e 431 [M+H]+; iH NMR (CDCI3, 400 MHz): o 0.61 (s, 3H),3.70 (s, 2H),7.2-7.4 (m, 6H), 7.81 (s, IH), 7.85 (d, J = 8 Hz, 1Hz).

Example 22

Preparation of 17B-(5-methvl-3-oxo-l-hexenvl)-estra-1.3.5(10V3-carboxylic add a) Methyl-3-hydroxymethyl-estra-l,3,5(10)-triene-17β-acrylate A mixture of 17β-17-(formyl)estra-l,3,5-triene-3-methanol (1.6 g,

5.37 mmol) and methyl (triphenylphosphoranyUdene) acetate (2.13 g, 6.37 mmol) in CH2CI2 (80 mL) was refluxed overnight under argon. Additional reagent (0.15 g, 0.45 mmoDwas added. The resulting mixture was refluxed for 3 d and concentrated. The residue was chromatographed (25 : 75 EtOAc/hexanes) to yield a white soUd which was stirred with hexanes and filtered(1.42 g, 75%). IH NMR (CDCI3, 400 MHz): δ 0.69 (s, 3H), 3.74 (s, 3H), 4.63 (s,lH), 5.82 (d, J = 16.0 Hz, IH), 7.0 (d,d J = 16.0, 16.0 Hz, IH), 7.10 (s, IH), 7.12 (d, J = 8 Hz, IH), 7.30 (d, J = 8 Hz, IH). b) 3-Hydroxymethyl-estra-l,3,5(10)-triene-17β-acryUc add FoUowing the procedure Example 20(c), substituting methyl-3- hydroxymethyl-estra-l,3,5(10)-triene-17β-acrylate for methyl-estra- l,3,5(10)-triene-3-carboxylate, the title compound was prepared (0.32 g, 0.9 mmol) and used in the next step without purification and spectral characterization. c) S-(2-Pyridyl)-3-hydroxymethyl-estra-l,3,5(10)-17β-thio- acrylate

A mixture of 3-hydroxymethyl-estra-l,3,5(10)-triene-17β-acryUc add (0.3 g, 0.9 mmol), 2,2'-dipyridyl disulfide (0.4 g,1.8 mmol), taiphenyphosphine (0.47 g,1.8 mmol) and CH2CI2 (20 mL) was stirred at ambient temperature under argon for 6 h. The resulting solution was concentrated and the residue was chromatographed (25 : 75 EtOAc /hexanes) to provide an oil.(0.07 g, 18%). ^XH NMR (CDCI3, 400 MHz): δ 0.70 (s, 3H), 4.60 (s, IH), 6.2 (d, J = 15.7 Hz, IH), 7.05 (d, d. J = 15.7, 15.7 Hz, 1Hz), 7.10 (s, IH), 7.15 (d, J = 8 Hz, 1 H), 7.25-7.3 (m, 2H), 7.62 (d, J = 8 Hz, 1 H), 7.76 (t, IH), 8.62 (m, IH). d) 17β-(3-Oxo-5-methyl- l-hexenyl)-3-hydroxymethyl-estra- l,3,5(10)-triene

Isobutylmagnesium chloride (0.25 mL, 2.0 M in ether) was added slowly to the S-(2-Pyridyl)-3-hydroxymethyl-estra-l,3,5(10)-17β-thio- acrylate ( 0.065 g, 0.15 mmol) in THF (10 mL) at -78°C. after 30 min, the reaction mixture was quenched with saturated aqueous NH4CI and extracted with EtOAC. The organic extract was washed with brine,dried and concentrated. The residue was chromatographed (15 : 85 EtOAC /hexanes) to afford an oil (0.02 g, 35%). -ΕL NMR (CDCI3, 400 MHz): δ 0.70 (s, 3H), 0.95 (d, J = 6.7 Hz, 6H), 4.62 (s, 2H), 6.1 (d, J = 15.7 Hz, IH), 6.82 (d,d J = 15.7,15.7 Hz IH), 7.1(s, IH), 7.15 (d, J = 8 Hz,l H), 7.30 (d, 8.0 Hz, 1 H). e) 17β-(3-Oxo-5-methyl-l-hexenyl)-estra-l,3,5(10)-triene-3- carboxaldehyde

TPAP (1.2 mg, 0.0034 mmol) was added in one portion to a mixture of 17β-<3-Oxo-5-methyl-l-hexenyl)-3-hydroxymethyl-estra-l,3,5(10)-triene (0.002 g, 0.05 mmol), NMO (0.012 g, 0.1 mmol), activated 4 A⁰ molecular sieves (30 mg) and CH2CI2 (95 mL). The resulting mixture was stirred under argon for 1 h and concentrated to smaU volume. The residue was chromatographed (5 : 95 EtOAC /hexanes to 10 : 90 EtOAC /hexanes) to provide a white soUd (0.01 g, 50%) which was used in the next step without spectral characterization. f) 17β-(5-methyl-3-oxo-l-hexenyl)-estra-l,3,5(10)-3-carboxyUc add

A solution of sodium phosphate monobasic monohydrate (36 mg, 0.026 mmol) , sodium chlorite (0.024 g, 0.26 mmol) in H2O ( 1 mL) was added to a solution of 17β-(3-Oxo-5-methyl-l-hexenyl)-estra-l,3,5(10)- triene-3-carboxaldehyde (0.01 g, 0.026 mmol), t BuOH ( 0.25 mL) and 2- methyl-2-butene (1 mL ; 2 M solution in THF) at 0 °C. After stirring for 1 h, saturated NaCl solution (1 mL) and gladal HO Ac (1 mL) were added. This mixture was extracted with EtOAC. The organic extract was washed with brine, dried and concentrated to provided a white soUd which was stirred with CH3CN and filtered to yield 4.5 mg of the pure add (45%). mp 215-7 °C. -Η. NMR (CDCI3, 400 MHz): δ 0.70 (s, 3H), 0.95 (d, J = 6.7 Hz, 6H), 6.10 (d, J = 15.7 Hz, IH), 6.85 (d,d J = 15.7,15.7 Hz, IH), 7.40 (d, J = 8.0 Hz,lH), 7.81 (s, IH), 7.85 (d, J = 8 Hz, 1 H); MS DCI/NH3) m/e 395 [ M+H]+; Anal. Calcd for C26H34O3 0.125 H2O ; C, 78.70; H, 8.70. Found: C78.57; H, 8.57.

Example 23

Preparation of 17β-( t- hnt.v1-.mi.-n- ethvlenvl) - estra-1. .5.10)- triene -

3- carboxylic add a) Methyl-3-(tert-butyldimethylsilyl)oxymethyl-estra-l,3,5(10)- triene-17β-acrylate

A mixture of methyl-3-hydroxymethyl-estra-l,3,5(10)-triene-17β- acrylate (0.95 g, 2.7.mmol), DMAP (0.043 g, 0.35 mmol),Et3N (0.7 mL, 5.5mmlol) and tert-butyldimethylsttyl chloride (0.55 g, 3.65.mmol) and CH2CL2 (10 mL) was stirred overnight. The reaction mixture was washed with H2O and the organic layer was dried,and concentrated. The residue was chromatographed (10 : 90 EtOAC /hexanes) to yield an oil (1.2 g, 100%). b) 3-(tert-Butyldiιnethylsilyl)oxyιnethyl-e8tra-l,3,5(10)-triene- 17β-acryUc add FoUowing the procedure Example 20(c), substituting Methyl-3-(tert- butyld__methylsflyl)oxymethyl-estra-l,3,5(10)-triene acrylate for methyl- estra-l,3,5(10)-triene-3-carboxylate, the title compound was prepared and was used in the next step without purification /spectral characterization. c) 17β-(tert-Butylamido-et_hylenyl)-3-hydroxymethyl-estra- l,3,5(10)-triene

A suspension of 3-(tert-Butyldimethylsilyl)oxymethyl-estra- l,3,5(10)-triene-17β-acryUc add (0.32 g,0.7 mmol) in toluene (50 mL) was azeotropicaUy dried ( 25 mL of distiUate ). Cooled to room temperature. Pyridine ( 0.11 mL, 1.1 mmol) was added foUowed by addition of oxalyl chloride (0.1 mL, 11.6 mmol). The mixture was stirred overnight .Filtered and the filtrate was concentrated.The residue was dissolved in a mixture of toluene (10 mL) and THF (2 mL), treated with t-butylamine ( 0.75 mL, 7 mmol). The thick slurry was stirred overnight, quenched with H2O and extracted with EtOAC. The organic layer was washed brine, dried and concentrated.Theresidue was chromatographed ( 30:70 EtOAC /hexanes) to provide an ofl ( 0.13 g) whose NMR indicated it was a 3-(t- butylamidoxalyDoxy compoxmd. Therefore, it was mixed with K2CO3 ( 0.2 g), MeOH (20mL) and H2O (2 mL). The resulting mixture was refluxed for 2 h and concentrated. The residue was partitioned between H2O and EtOAC and extracted. The organic layer was dried, concentrated to give a foam. Trituration with ether resulted in a white soUd. d) 17β-(tert-Butylamido-ethylenyl)-estra-l,3,5(10>-3- carboxaldehyde

Following the procedure Example 22(e), substituting 17β-(tert- Butylamido-ethylenyl) -3-hydroxymethyl-estra-l,3,5(10)-triene for 17β-(3- Oxo-5-methyl-l-hexenyl)-3-hydroxymethyl-estra-l,3,5(10)-triene, the title compound was prepared and was used in the next step without purification /spectral characterization (0.045 g, 96%). e) 17β-(tert-butylamido-ethylenyl)-estra-l,3,5(10)-triene-3- carboxyUc add

FoUowing the procedure Example 22(f), substituting 17β-(tert- Butylamido-ethylenyD-estra- 1,3,5(10) -3-carboxaldehyde for 17β-(3-Oxo-5- methyl-l-hexenyl)-estra-l,3,5(10)-triene-3-carboxaldehyde, the title compound was prepared (0.003 g, 75%). f) Methyl-3-[(tert-butyldimethylsilyl)oxymethyl]-estra-l,3,5(10)- triene-17β-propionate was prepared foUowing the procedure for 8. Thus, from 0.75 g(1.6 mmol) of 19 there was obtained 0.7 g of an oil ( 0.7 g, 93%).This ester was converted to the add without further purification.

Example 24

Preparation of 17β-(3-Oxo-3-phenvl-propvl)-estra-1.3.5(10)-triene-3- carboxylic add a) 17β-(3-Oxo-3-phenyl-l-propenyl)-3-hydroxymethyl-estra- l,3,5(10)-triene

FoUowing the procedure of Example 21 (a), except substituing dimethyl-2-oxo-3-phenylpropylphosphonate for dimethyl-2-oxo-2- phenylethylphosphonate. Thus, from 0.45 g ( 1.5 mmol) of the aldehyde there was obtained 0.45 g (75%). *H NMR (CDCI3, 400 MHz): ^~ 0.75 (s, 3H), 4.62 (s, 2H), 6.87 (d, J = 16 Hz, IH), 7.05-7.15 (m,3H),7.3 (d, J = 8 Hz lH),7.45-7.57 (m, 3H), 7.95 (d, J = 8Hz, 2H). b) 17β-(3-Oxo-3-phenyl-l-propyl-3-hydroxymethyl-estra- l,3,5(10)-triene

FoUowing the procedure of Example 21(b), except substituting 17β- (3-Oxo-3-phenyl-l-propenyl)-3-hydroxymethyl-estra-l,3,5(10)-triene for 17 β-( 3-Oxo-4-phenyl-l-buthenylene)-3-hydroxymethyl-estra- 1,3,5 (10 )- triene, the title compound was prepared (0.43 g. 98%). *H NMR (CDCI3, 400 MHz): δ 0.68 (s, 3H), 2.9-3.1 (m, 4H), 7.37-8.0 (m, 8H). c) 17β-(3-Oxo-3-phenyl-propyl)-estra-l,3,5(10)-triene-3- carboxyUc add

FoUowing the procedure of Example 21(c), except substituting 17β-

(3-Oxo-3-phenyl-l-propyl-3-hydroxymethyl-estra-l,3,5(10)-triene for 17β-

(3-Oxo-4-phenyl-butyl)-3-hydroxymet_hyl-estra-l,3,5(10)- triene, the title compound was prepared (0.43 g. 92%).mp 230-1 °C; -K NMR (CDCI3, 400 MHz): δ 0.68 (s, 3H),2.9-3.05 ( m, 4H),7.40 (d, J = 8 Hz, IH), 7.5 (t, 2H),

7.57 (d, J =7.4 Hz, 1H),7.81 (s, IH), 7.87(d, J = 8 Hz, IH), 7.97 (d, 7.4 Hz,

1H);MS (DCI/NH3) m/e 417 [M+ H]+; ^Anal- ^{Calcd for C28 H32 03}> ^C> 80.73; H, 7.74. Found: C, 80.53, H, 7.81.

Example 25

Prenaration of 17β-(5-Methvl-3-oxo-hexvl )-estra-1.3.5.10 3-carhoxvlic add a) Met-hyl-3-[(tert-butyld_Lmet_hylsilyl)oxymethyl]-estra-l,3,5(10)- triene-17β-propionate

FoUowing the procedure Example 210b), substituting methyl-3-(tert- butyld__met_hylsilyl)oxymethyl-estra-l,3,5(10)-triene-17β-acrylate for 17β- (3-oxo-4-phenyl-l-buthenylene)-3-hydroxymethyl-estra-l,3,5(10)-triene, the title compoimd was prepared ( 0.7 g, 93%); -K NMR (CDCI3, 400 MHz): δ 0.1 (s, 6H), 0.65 (s, 3H), 0.95 (s, 9H), 3.70 (s, 3H),4.68 (s, 2H),7.02 (s, 1H),7.10 (d, J = 8 Hz, IH), 7.26 (d, J = 8 Hz, IH) b) 3-[(tert-Butyldimethylsilyl)oxymethyl]-estra-l,3,5(10)-triene-

17β-propionic add

FoUowing the procedure Example 20(c), substituting methyl-3- [(tert-butyld__met_hylsUyl)oxymethyl]-estra-l,3,5(10)-triene-17β-propionate for methyl-estra-l,3,5(10)-triene-3-carboxylate, the title compound was prepared (0.5 g, 71%) and was used in the next step without spectral characterization. c) S-(2-Pyridyl)-3-hydroxymethyl-estra-l,3,5(10)-triene-17β- thiopropionate

FoUowing the procedure Example 22(c), substituting 3-[(tert- Butyld__methylsilyl)oxymethyl]-estra-l,3,5(10)-triene-17β - propionic add for 3-hydroxymethyl-estra-l,3,5(10)-triene-17β-acryUc add, the title compound was prepared (0.35 g, 92%) as a Ught-yeUow foam. *H NMR (CDCI3, 400 MHz): δ 0.65 (s, 3H), 4.62 (s, 2H), 7.1 (s, IH), 7.15 (d, J = 8 Hz, IH), 7.25-7.35 (m, 2H), 7.62 (d, J = 8 Hz, 1 H), 7.76 (t, IH), 8.62 (m, IH). d) 3-(Hydroxymethyl)-17β-(5-methyl-3-oxo-hexyl)estra-l,3,5(10)- triene Following the procedure Example 22(d), substituting S-(2-Pyridyl)-

3-hydroxymethyl-estra-l,3,5(10)-triene-17β -thiopropionate for S-(2- Pyridyl)-3-hydroxymethyl-estra-l,3,5(10)-17β-thio-acrylate, the title compound was prepared (0.07 g, 48%) of sUghtly impure product, and was used in the next step without spectral characterization. e) 17β-(5-Methyl-3-oxo-hexyl)-estra-l,3,5(10)-3-carboxyUc add

FoUowing the procedure Example 21(c), substituting 3- (Hydroxymethyl)-17β-(5-methyl-3-oxo-hexyl)estra-l,3,5(10)-triene for 17β- (3-Oxo-4-phenyl-butyl)-3-hydroxymethyl-estra-l,3,5(10)-triene, the title compound was prepared. The crude product was chromatographed (1:20:80 HOAc EtOAC/hexanes) to provide (35 mg, 50%) of sUghtly impure product. It was boiled with CH3CN and filtered off the insoluble material. The filtrate was reduced to small volume to yield a white soUd. MP 192-5 °C. ^!H NMR (CDCI3, 400 MHz): δ 0.65 (s, 3H), 0.93 (d, J = 6.4 Hz, 6H), 7.40 (d, J = 8 Hz, IH), 7.81 (s, IH), 7.85 (d, J = 8 Hz, IH) ;MS (DCI/NH3) m/e 397 [M+H]+; Anal. Calcd for C26H36O3; C, 78.75; H, 9.15. Found : C.78.62: H, 8.98.

Example 26 Preparation of 17β-(tert-Butv1amiHoethyl )-estra-1.3.5(10)-triene-3- carboxylic add a) 17β-(tert-Butylamidoethyl)-3-hydroxymethyl-estra-l,3,5(10)- triene

A mixture of 3-[(tert Butyldi_methylsilyl)oxymethyl]-estra-l,3,5(10)- triene-17β-propionic add, 2-chloro-l-methylpyridinium iodide (0.063 g, 0.25 mmol), t-butylamine (0.026 mL, 0.25 mmol), Et 3N (0.1 mL, 0.75 mmol), DMAP (0.003 g, 0.025 mmol) in CH2CI2 (15 mL) was stirred for 3 h. The reaction mixture was washed with 5% HCl, H2O, brine, dried and concentrated. The residue was chromatographed (30:70 EtOAC/hexanes to 40:60 EtOAC/hexanes) to provide an oil (0.07 g, 70%) which soUdified on cooling. *H NMR (CDCI3, 400 MHz): δ 0.65 (s,3H), 1.35 (s, 9H), 4.62 (s, 2H), 5.28 (br s, IH), 7.1 (s, IH), 7.15 (d, J = 8 Hz, IH), 7.30 (d, J = 8 Hz, IH). b) 17β-(tert-Butylamidoethyl)-estra-l,3,5(10)-triene-3-carboxylic add

FoUowing the procedure Example 21(c), substituting 17β-(tert- Butylamidoethyl)-3-hydroxymethyl-estra-l,3,5(10)-triene for 17β-(3-Oxo-4- phenyl-butyl)-3-hydroxymethyl-estra-l,3,5(10)-triene, the title compom d was prepared. The crude product was chromatographed (1:30:70 HOAc/EtOAC/hexanes) to provide an ofl (0.025 g, 35%) which soUdified on cooling. Analytical sample was prepared by recrystalUzing from MeOH- acetone-CH3CN. mp 138-141 °C. MS (DCI/NH3) m/e 412 [M+H]+; *H NMR (CDCI3, 400 MHz): δ 0.65 (s, 3H), 1.35 (s, 9H), 5.75 (br s, IH), 7.4 (d, J = 8Hz, IH), 7.80 (s, IH), 7.85 (d, J = 8 Hz, IH). Anal. Calcd for C26 H37 NO3 : C, 75.87; H, 9.06; N, 3.40. Found : C,75.75; H,9.04; N, 3.26.

Example 27 Preparation of 17β-17-(benzvloxv methvl)- estra-1.3.5(10)-triene-3- carboxylic add a) 17β-17-(formyl)-estra-l,3,5(10)-triene-3-methyl(t-butyl dimethyl) silyl ether t-Butyl dimethyl silyl chloride (300 mg, 2.0 mmol) was added to a solution of 17β-17-(formyl)estra-l,3,5(10)-triene-3-methanol (295 mg, 1.0 mmol), triethyl amine (278 ml, 2.0 mmol), and CH2CI2 (15 ml) and was stirred at RT overnight. The reaction was quenched with H2O (5 ml), extracted with EtOAc (20 ml), dried (magnesium sulfate), concentrated in vacuo, and flash chromatographed to afford the title compound as a white soUd (190 mg, 49%); mp=207-9°C;¹H NMR: d 0.8 (s, IH), 4.08 (s, 2H), 7.05 (s, IH), 7.20 (d, J=8.7Hz,lH), 7.28 (d, J=8.7Hz,lH). b) 17β-17-(methylhydroxy)-estra-l,3,5(10)-triene-3-methyl(t- butyldimethyl) silyl ether

Sodium borohydride (100 mg, 2.6 mmol) was added to a solution of 17β-17-(phenyl methoxy methyl)- estra- 1,3 ,5(10)- triene- 3 -methyl (t- butyl dimethyl) silyl ether (190 mg, 1.0 mmol) in EtOH (15 ml) at RT for 2.5 h. The reaction was concentrated in vacuo, redissolved in CH2CI2 (10 ml), quenched with H2O (10 ml), washed with brine, dried (magnesium sulfate), filtered, concentrated in vacuo, and flash chromatographed (silica gel, 10% EtOAc/ hexanes) to afford the title compomid as a white soUd (140 mg, 74%); !H NMR:d 0.8 (s,3H), 4.10 (s,2H), 4.25 (d,J=8Hz,2H), 7.05 (s,lH), 7.18 (d,J=8.7Hz,lH), 7.28 (d,J=8.7Hz, IH). c) 17β-17-(phenyl methoxy methyl)-estra-l,3,5(10)-triene-3- methyl(t-butyldimethyl) silyl ether Sodium hydride (24 mg,1.0 mmol) was added to a solution of 17b-

17-(met_hylhydroxy e8t_ra-l,3,5(10)-triene-3-methyl(t butyldimethyl) silyl ether (120 mg, 0.30 mmol) in DMF (1.0 ml), foUowed by benzyl bromide (200 ml, 1.0 mmol) and the reaction was stirred 6h at RT. The reaction was diluted with EtOAc (20 ml), extracted with H2O (10 ml), dried (magnesium sulfate), concentrated in vacuo, and flash chromatographed (silica gel, 30% EtOAc hexanes) to afford the title compomid as a white soUd; mp =217-219°C; H NMR: d 0.8 (s,3H), 4 10 (s,2H), 4.25 (d, J=8Hz,2H), 4.50 (s,2H), 7.05 (s,lH), 7.15-7.35 (m,7H),. d) 17β-17-(phenyl methoxy methyl)-estra-l,3,5(10)-triene-3- carboxyUc add

Jones reagent was added to a solution of 17β-17-(phenyl methoxy methyl)-estra-l,3,5(10)-triene-3-methyl (t-butyl dimethyl) silyl ether (35 mg, 0.06 mmol) in acetone (0.5 ml) and stirred 2h at RT. The reaction was quenched with isopropanol (2 ml), washed with H2O (2 ml), extracted with EtOAc (10 ml), dried (magnesium sulfate), and flash chromatographed (5% MeOH/ CH2CI2) to afford the title compound as a white soUd; mp= 200-202 degrees C; iH NMR d 0.8 (s, 3H), 4.25 (d J=8Hz, 2H), 4.50 (s, 2H), 7.15-7.35 (m,6H),7.70 (s,lH), 7.80 (d, J=8Hz, IH); MS(DC/NH3) m/e 405 [M+H]+;Anal. Calcd for C27H32O3: C,80.16;H,7.99. Found: C.79.77 ,H,7.67.

Example 28 Preparation of 17BTE) -17-(phenvl ethenvlV estra-1.3.5(10V triene- 3 - carboxylic add and!7β(Z) -17-(phenvl ethenvl)- estra-1.3.5(10)- triene- 3 -carboxylic add a) 17β(E)-17-(phenylethenyl)-estra-l,3,5(10)-triene-3-methanol and 17β(Z)-17-(phenylethenyl)-estra-l,3,5(10)-triene-3-methanol n-Butyl lithium (0.3 ml, 1.5 M, 0.45 mmol) in hexanes was added to a solution of diisopropylamine (64ml, 0.45 mmol) in THF (1.0 ml) at 0°C and was stirred for 0.5 h. Then, benzyltriphenyl phosphonium chloride was added at -78°C, and the reaction was stirred for lh. A solution of 17β-17-(formyl) estra-l,3,5(10)-triene- 3-methanol (75 mg, 0.25 mmol) in THF (1.0 ml) was added to the reaction mixture, stirred 0.5 h, then warmed to 0 ° C. The reaction was diluted with Et2θ (20 ml), then quenched with 1% aqueous HCl (10 ml), The organic layer was washed with H2O (10 ml), brine (10 ml), then dried (magnesium sulfate), concentrated in vacuo, and flash chromatographed (1:4 EtOAc/ hexanes) to produce a 1:1 mixture of the title compounds (55 mg, 60%); iH NMR (CDCI3 400MHz): E isomer d 0.76 (s, 3H,), 4.59 (s, 2H), 6.2 (dd, J=12.4,12.4, IH,) 6.38 (d, J=12.4, IH,) 7.05 (s, IH) 7.18 (d, J=8.6, IH) 7.2-7.4 (m, 6H); Z isomer 0.68 (s,3H), 5.64 (dd, J=8.6,8.6 Hz) 6.54 (d, J=8.6) MS(DCIZNH3) m/e 373 {M+HJ+. b) . 17β(E)-17-(phenylethenyl)-estra-l,3,5(10)-triene-3- carboxylic add and

17β(Z)-17-(phenylethenyl)-estra-l,3,5(10)-triene-3-carboxyUc add Jones reagent was added to a mixture of 17b(E)-17- (phenylethenyl)-estra-l,3,5-triene-3-methanol andl7β(Z)-17-(phenyl ethenyl)- estra-l,3,5(10)- triene- 3 - methanol (50 mg, 0.134 mmol) in acetone (2.0 ml) at room temperature until the yeUow color persisted. The reaction was quenched with isopropanol (5 ml), then purified by column chromatography (1:20:80 AcOH/ EtOAc hexanes) to afford a 1:1 mixture of the title compounds (43mg,84%); mp 214-9°C; ^ NMR (CDCL3, 400MHz):d 0.78 (s, 3H), 6.2 (dd, J=12.4, 12.4, IH), 6.38 (d, J=12.4, IH), 7.2-7.4 (m, 6H), 7.8 (s, IH), 7.85 (d, J=8.6,1H), MSΦCIZNH3) m/e 404 [M+NH41+, 387 [M+H]+_; Anal. Calcd for C27H30O2.I/4H2O C,82.93; H,7.84. Found: C,82.92; H.7.39.

Example 29 Preparation of 17β-17-(2-phenvlethvlVestra-1.3.5(10)-triene-3-carboxvlic add a) 17β-17-(2-phenylethyl)-estra-l,3,5(10)-triene-3-carboxyUc add

A mixture ofL7β(E)-17-(2-phenylethenyl)-estra-l,3,5(10)-triene-3- carboxyUc add andl7β(Z)-17-(2-phenylethenyl>estra-l,3,5(10)-triene-3- carboxyUc add (27 mg, 0.073 mmol) was stirred under H2 (baUoon) with Pt C (10 mg) in MeOH (8 ml) for 6h. The reaction was filtered, concentrated in vacuo, and purified by preparative thin layer chromatography (5% MeOH/CH2Cl2) to obtain the title compomid as a white soUd (16 mg, 59%); mp=204-206 ° C H NMR d 0.75 (s, 3H), 7.1-7.4 (m, 6H), 7.8 (s, IH), 7.85 (d, J=8Hz, 1H);MS (DCI/NH3) m/e 406 [M+NH4l⁺,387 [M+H]+ Anal. Calcd for C27H32O2 I/4H2O C,82.50; H, 8.33. Found; C,82.80; H, 8.09.

Example 30

carboxvlic add a) 17-oxo-estra-l,3,5-triene-3-carboxylic add

Potassium carbonate (600 mg, 4.34 mmol) was added to a mixture of methyl 17-oxo-estra- 1, 3, 5- triene-3-carboxylate (600 mg, 1.92 mmol) in MeOH (10 ml) and H2O (1.0 ml) and was refluxed for 12h. The reaction was cooled to room temperature, partitioned between ethyl acetate (100 ml) and 5% aqueous acetic add (100 ml); the organic layer was dried (magnesium sulfate), concentrated in vacuo, and flash chromatographed (silica gel, 1: 20: 80 AcOH/ EtOAc hexanes) to afford the title compound as a white soUd (550 mg, 95%); ^ NMR: δ 0.93 (s, 3H), 2,95-2.gg (m, 2H), 7.41 (d, J=8.5 Hz, IH), 7.85 (s, IH), 7.88 (d, J=8.5 Hz, IH); mp = 278° C (decomp). b) O-benzyl oxime ether of 17-oxo-estra-l,3,5-triene-3- carboxyUc add.

O-benzyl hydroxylamine (20 mg, 0.162 mmol) was added to a mixture of 17-oxo- estra- 1,3,5- triene-3-carboxyUc add (20 mg, 0.067 mmol), sodium acetate (20 mg, 0.243 mmol) in ethanol (1.0 ml) and H2O (0.2 ml) and was stirred overnight. The readion mixture was partitioned between ethyl acetate (50 ml) and 5% aqueous acetic add (50 ml); the organic layer was dried, filtered, concentrated in vacuo, and flash chromatographed (silica gel, 1: 20: 80 AcOH/ EtOAc/ hexanes) to afford the title compound as a white soUd ( 20 mg, 74%); iH NMR: δ 0.98 (s, 3H), 5.12 (s, 2H), 7.28-7.44 (m, 6H), 7.84 (s, IH), 7.88 (d, J=8.5 Hz, IH); m/e 404 [M+H]+; mp= 198° C (decomp).

Example 31

Preparation of O-benzyl oxime ether of 17-oxo- androsta- 3.5- diene- 3 - carboxylic add a) O-benzyl oxime ether of 17-oxo-androsta-3,5-diene-3- carboxyhc add O-t-benzyl hydroxylamine hydrochloride (20 mg, 0.16 mmol) was added to a mixture of 17-oxo-androsta-3,5-diene-3-carboxyUc add (20 mg, 0.067 mmol), p-toluene sulfonic add (5 mg, 0.03 mmol), and 4 A molecular sieves (50 mg) in toluene (2.0 ml) and was refluxed for 12 h. Flash chromatography (sflica gel, 1: 20: 80 AcOH/ EtOAc/ hexanes) afforded the title compound as white soUd ( 15 mg, 70 %); -Η. NMR: δ 0.95 (s, 3H), 0.96 (s, 3H), 5.08 (s, 2H), 5.88 (d, J=2.0 Hz, IH), 7.15 (s, IH), 7.26-7.37 (m, 5H); MSΦCI/NH3) m/e 420 [M+H]+

Example 32

Preparation of O-t-butvl oxime ether of 17-oxo- androsta- 3.5- diene- 3 - carboxylic acid a) O-t-butyl oxime ether of 17-oxo-androsta-3,5-diene-3- carboxyUc add O-t-butyl hydroxylamine hydrochloride (20 mg, 0.16 mmol) was added to a mixture of 17-oxo-androsta-3,5-diene-3-carboxyUc add (20 mg,

0.067 mmol), p-toluene sulfonic add (5 mg, 0.03 mmol), and 4 A molecular sieves (50 mg) in toluene (2.0 ml) and was refluxed for 12 h.

Flash chromatography (silica gel, 1: 20: 80 AcOH/ EtOAc/ hexanes) afforded the title compound as white soUd (20 mg, 78 %); IH NMR: δ

0.93 (s, 3H), 0.95 (s, 3H), 1.26 (s, 9H), 5.88 (s, IH), 7.16 (bs, IH);

MS(DCI/NH3) m/e 386 [M+H]+

Preparation of 17β-(Phenvl)estra-1.3.5(10)triene-3-carboxvlic add a) Preparation of methyl-17(β-hydroxy-α-phenyl)estra- l,3,5(10)triene-3-carboxylic

PhenylUt_hium(41.5mg, 0.4935 mmol) was added via syringe to a solution of methyl(17 keto)estra-.l,3,5(10)triene-3-carboxylate (146.8mg,

0.47mmol) in freshly distiUed THF (6ml) at -78°C under argon. The mixture is stirred for 75 minutes at 78°C and then warmed to 0°C over 30 minutes at which time the reaction is quenched with saturated ammonium chloride. The reaction was concentrated in vacuo and the residue was dissolved in CHCI3, washed with water and brine, dried (magnesium sulfate), concentrated, and flash chromatographed (siUca gel 100% CHCI3) to afford the title compound as a white soUd (30.3mg, 17%); lA NMR (CDCL3, 400 MH₂): δ 11 (S,3H), 3.88 (S,3H), 7.21 (M, IH), 7.25 (M, IH), 7.35 (M, 2H), 7.42 (M, 2H), 7.75 (M, 2H); MS (DCI/NH3) m/e 408 [M+NH41+. b) Methyl 17β-(Phenyl)estra-l,3,5(10)triene-3-carboxylate

To a solution of methyl 17(β-hydroxy-α-phenyl)estra- l,3,5(10)triene-3-carboxylate (30.0mg, 0.0768mmol) in CH2CI2 (5.0ml was added triethylsilane (10.7mg, 0.092mmol) and BF3.Et2θ (5 drops) at 0°C under argon. The ice bath was removed and the mixture was stirred for 10 minutes at which time the reaction was quenched by careful addition of 10% HCl. The reaction was extracted with CHCL2, washed with H2O, 5% NAHCO3, water, and brine, dried (magnesium sulfate), concentrated, and flash chromatographed (silica gel 100% CHCI3) to afford the title compound as a white soUd (18.6mg, 66%); HNMR (CDCL3, 400 MH_Z): δ 0.51 (Sχ3H), 3.9 (Sχ3H), 7.17-7.37 (M,χ6H), 7.77 (M,2H); MS (ES) m/e 375 [M+H]+. c) 17β-(Phenyl)estra-l,3,5(10)triene-3-carboxyUc add Methyl 17β-(phenyl)estra-l,3,5(10)triene-3-<_arboxyUc (18.5mg, Ommol) was dissolved in 3.0ml of 9:1 MCOH/HCO and to this solution was added K2CO3 (20.7mg, O.lδmmol). The mixture was refluxed overnight, cooled to room temperature, addified with 10% HCl, and concentrated in vacuo. The residue was dissolved in CHCI3, washed with water and brine, dried (magnesium sulfate), concentrated, and flash chromatographed (siUca gel 98:1:1 CHCl3:CH3θH:HOAc) to afford the title compound as a white soUd (11.4mg, 64%); HNMR (CDCI3,

400MHZ): δ 0.54 (S,χ3H), 2.8 (t,lH), 7.20-7.35 (M,δH), 7.4 (d,lH), 7.8δ , (M,2), MS (ES) m/e 361 [M+H]+. Exam le 34

Preparation of 17-(0-tertbutvloxine)estra-1.3.δ(10)-triene-3-carboxvlic δ add a) 17 kete-estra-l,3,5(10)triene-3-carboxyUc add Methyl-17 (keto)estra-l,3,5(10)triene-3-carboxylate (δOOmg, l.βmmol) was dissolved in 10ml of 9:1 CH3θH:H2θ and to this was added U2CO3 (663mg, 4.8mmol). The mixture was refluxed overnight, 0 cooled to room temperature, addified with 10% HCl and concentrated in vacuo. The residue was dissolved in CHCI3, washed with water and brine, dried (sodium sulfate), and concentrated. The residue was triturated with Et θ to afford the title compound as a white soUd (405mg, 85%); IHNM (CDCL₂, 400 MHZ): δ 0.95 (S,3H), 7.4 (d,lH), 5 7.85 (S,1H), 7.87 (d,lH). b) 17-(0-tertbutyloxine)estra-l,3,5(10)triene-3-carboxyUc add 17keto-estra-l,3,δ(10)triene-3-carboxyUc add (28.3mg, 0.09δmmol)

0-tertbutyl hydroxglamine hydrochloride (δ9.7mg, 0.47δmmol), p- toluenesulfonic add monohydrate (4.6mg, 0.024mmol), and 4A°powdered 0 molecular sieves were suspended in 6ml of toluene and refluxed overnight. The reaction was concentrated in vacuo and flash chromatographed (siUdn gel 70:2g:l hexane:EtOAc_AcOH) to afford the title compound as a white soUd (2g.0mg, 83%); IHNMR (CDCL3, 400MHZ): δ 0.94 (S, 3H), 1.3 (S,9H, 7.41 (d,lH), 7.83 (S,1H), 7.87 (d,lH); 5 MS (CI) m/e 370 [M+H]+; Anal. (C23H3INO3) calcd: C, 74.76; H_f 8.46; N 3.79. Found: C, 73.39, H, 818; Nl 3.52. mp 204-206°C (decomp.) -J*

Preparation of 17-(0-Phenvlo_rine)estra-1.3.5(10)-triene-3-carboxvlic add

To a solution of 17 keto-estra-l,3,5(10)triene-3-carboxyUc add (29.4mg, 0.0985mmol) in 6ml of 10:1 EtOH:H2θ was added 0- phenyUiydroxylamine (δOmg, 0.4δ8mmol, freed from the hydrochloride with 5% NaHCθ3) and sodium acetate (8mg, 0.098δmmol) and the mixture was refluxed overnight. The reaction was concentrated and flash chromatographed (siUca gel, 70:29:1 hexans:EtOH. HOAc) to 0 affford the title compound as a reddish powder (δ.4mg, 14%); IHNMR (CDCL3, 400 MHZ): δ l.Oδ (S,13H), 7.0, (t,lH), 7.18 (M,2H), 7.3 (M,2H), 7.42 (M,1H), 7.83 (δ,lH), 7.87 (d,lH); MS (ES) m/e 390 [M+H]+.

Preparation of 17 keto-16.16-diallvlestra-1.3.δ(10Vtriene-3-carboxvlic add a) Methyl 17keto-16,16-diaUylestra-l,3,δ(10)triene-3- carboxylate 0 To a solution of methyl- 17(keto)estra- 1,3, δ(10)triene-3-carboxylate

(200mg, 0.64mmol in freshly distilled THF (10ml) at -78°C under argon was added freshly prepared LDA (343mg, 3.2mmol in THF (4ml). The mixture was stirred for lδ minutes at -78°C at which time a solution of aUyUodide (δ38mg, δ.2mmol) in THF (4ml) was added via syringe. The δ reaction was allowed to warm to room temperature overnight, quenched with 10% HCl, and concentrated. The residue was dissolved in CHCI3, washed with HCl, H2O, saturated Na2S2θ3, H2O, saturated NaCLj dried (magnesium sulfate), concentrated and flash chromatographed (silica gel 8δ:lδ hexanes:EtOAc) to afford the title compound as a colorless oil (40mg, 16%); iHNM (CDCI3, 400MHZ): δ 0.92 (S,3H), 3.9 (S,3H), δ.09 (M,4H), 5.7-5.8δ (M^H), 7.34 (d,lH), 7.78 (S,1H), 7.81 δ (d,lH); MS (DCI/NH3) m/e 393 [M+H]+. b) 17keto-16,16-diaUylestra-l,3,5(10)-triene-3-carboxylic add Methyl 17keto-16,16-diallylestra-l,3,5(10)-triene-3-carboxylate (37mg, 0.094mmol) was dissolved in 5ml of 9:1 MeOH:H2θ and to this was added K2CO3 (39mg, 0.282mmol). The mixture was refluxed 0 overnight, cooled to room temperature, addified with 10% HCl, and concentrated in vacuo. The residue was dissolved in CHCI3, washed with water and brine, dried (sodium sulfate) and concentrated to afford the title compomid as a white soUd (32.3mg, 91% !HNM (CDCI3, 400MHZ): δ 0.95 (S,3H), 5.09 (M,4H), 5.72-5.8δ (m,2H), 7.4 (d,lH), 7.85 5 (S,1H), 7.88 (d,lH); MS (ES) m/e 379 [M+H]+; MP 162-164°C; Anal. (C25H30O3) caled: C, 79.33; H, 7.99. found: C, 78.04; H, 7.72.

Example 37

0

Preparation of 17β-(N-tertbutnyvamino)estra-1.3.5(10)-triene-3- carboxvlic add a) Methyl-17β-(N-tertbutoxyoximo)estra-l,3,δ(10)-triene-3- carboxylate δ To a solution of methyl-17(keto)estra-l,3,δ(10)triene-3-carboxylate

(lOOmg, 0.32mmol) in 6ml of toluene was added 0-tertbutyl hydroxylamine hydrochloride (201mg, l.βmmol), p-toluene-sulfonic add monohydrate (lδ.2mg, 0.08mmol), and some powdered 4 A° molecular sieves and the mixture was heated overnight at 95°C. The reaction was 0 filtered, diluted with Et2θ, washed with l.ON HCl, H2O, brine, dried (magnesium sulfate), concentrated, and flash chromatographed (silica gel 4:1 hexanes.EtOAc) to afford the title compound as a white soUd (61.8mg, 50%); iH M (CDCI3, 400MHZ): δ 0.89 (S,3H), 1.25 (S,9H), 3.g (S,3H), 7.35 (d,lH), 7.74 (S,1H), 7.78 (d,lH; MS (ES) m/e 384 [M+H]+. b) Methyl-17β-(N-tertbutoxyaιnino)estra-l,3,5(10)-triene-3- δ carboxyUc

To a solution of methyl 17β-(N-tertbutoxyoximo)estra-l,3,δ(10)- triene-3- carboxylate (2g mg, 0.07δ6mmol) in freshly distilled THF (4ml) was added sodium cyanoborohydride (47.δmg, 0.7δ6mmol). The mixture was cooled to -δOC°C under argon and BF3 EtO was added (21.δmg,

10 0.1512immol). The reaction was stirred at -4δ°C for l.Ohr. and then aUowed to warm to room temperature overnight. The reaction was concentrated, diluted with water and brought to pHg with 10% NaOH. The mixture was extracted into CHCI3, washed with water and saturated NaCl, dried (magnesium sulfate), concentrated, and flash lδ chromatographed (siUca gel :l hexanes:EtOH) to afford the title compound as a white soUd (13.1mg, 4δ%); iHNM (CDCI3, 400MHZ): δ 0.76 (S,3H), 1.2 (S,9H), 3.0 (t,lH), 3.9 (S,3h), 4.9 (brs, IH), 7.37 (d,lH), 7.7δ (S,1H), 7.78 (d,lH); MS (ES) m/e 386 [M+H]+. c) 17β-(N-tertbutoxyamino)estra-l,3,δ(10)-triene-3- carboxyUc 20 add

Methyl-17β-(N-tertbutoxyamino)estra-l,3,δ(10)-triene-3- carboxylate (12.8mg, 0.0332mmol) was dissolved in 3ml of 9:1 CH3OH and to this was added K2CO3 (13.8mg, O.lmmol). The mixture was refluxed overnight, cooled to room temperature, addified with 10% HCl,

2δ and concentrated in vacuo. The residue was dissolved in CHCI3, washed with water and brine, dried (sodium sulfate), concentrated, and flash chromatographed (silica gel) 5% CH3θH:CHCl3 to afford the title compound as a white soUd (8.2mg, 67%); !HNM (CDCI3, 400MHZ): δ 0.77 (S,H), 1.18 (S,H), 3.0 (t,lH), 7.39 (d,HH), 7.81 (S,1H), 7.85 (d,lH);

30 MS (ES) m/e 372 [M+H]+.

Example 38

Preparation of 17β-(N-Benzvloxvamino)estra-l .3.5(10-triene-3- Carboxvlic Add 5 a) Methyl-17 (N-Benzyloxyoximo)estra-l,3,δ(10)triene-3-

Carboxylate

To a solution of methyl-17(keto)estra-l,3,δ(10)triene-3-carboxylate (200 mg, 0.64 mmol) in 8 ml of toluene was added 0- Benzylhydroxylamine hydrochloride (511 mg, 3.2 mmol), p-

10 toluenesulfonic add monohydrate (122 mg, 0.64 mmol), and some powdered 4A molecular sieves and the mixture was heated overnight at 95°C. The reaction was filtered, diluted with Et2θ, washed with 1.0 NHC1, H2O, brine, dried (magnesium sulfate), concentrated, and flash chromatographed (silica gel 4:1 hexanes:EtOAc) to afford the title lδ compound as a white soUd (20g.8 mg, 7g%); iHNM (CDCI3400 MHz): δ 0.94 (S, 3H), 3.9 (S, 3H), δ.09 (S, 2H), 7.26 - 7.40 (M, 6H), 7.7δ (S, IH), 7.80 (d, IH); MS (DCIZNH3), m/e 418 (M+H]+. b) Met_hyl-17β(N-benzyloxyamino)estra-l,3,δ(10)triene-3- carboxylate

20 To a solution of methyl 17(N-ben__yloxyamino)estra-l,3,5(10)triene-3- carboxylate (206.3mg, 0.494mmol) in freshly distiUed THF (12ml) was added sodium cyanoborohydride (310mg, 4.94mmol). The mixture was cooled to -50°C under argon and BF3 Et2θ was added (142mg, 0.998mmol, 0.123ml). The readion was stirred at -4δ°C for 1.0 hr. and

2δ then aUowed to warm to room temperature overnight. The readion was concentrated, diluted with water and brought to pH9 with 10% NaOH. The mixture was extracted into CHCI3, washed with water and saturated NaCl, dried (magnesium sulfate), concentrated, and flash chromatographed (silica gel 9:1 hexanes:EtoAc) to afford the title

30 compound as a white soUd (δlmg, 25%); HNM (CDCI3, 400MHZ): δ 0.8 (Sχ3H), 3.2 (t,lH) 3.9 (S,3H), 4.72 (S,2H), 5.62 (brs.lH), 7.30-7.40

(M,6H), 7.77 (S,1H), 7.80 (d,lH); MS (DCI/NH) m/e 420 [M+H]+. c) 17β(N-Benzyloxyamino)estra-l,3,5(10)triene-3-carboxyUc add

Methyl-17β(N-benzyloxyamino)estra-l,3,δ(10)triene-3-carboxylate δ (δlmg, 0.122mmol) was dissolved in 8ml of 9:1 CH3OH.H2O and to this was added K2CO3 (δlmg, 0.366mmol). The mixture was refluxed overnight, cooled to room temperature, addified with 10% HCl, and concentrated. The residue was dissolved in CHCI3, washed with water and brine, dried (sodium sulfate), and concentrated in vacuo to afford the 10 title compound as a white soUd (49.0mg, 99%); iHNMR (CDCI3,

400mHZ): δ 0.79 (S,H), 3.2 (t,lH), 4.75 (S,2H, 7.28-7.40 (M,6H), 7.82 (S,1H), 7.85 (d,lH); mp 174-176°C; Anal. (C26H31NO3) calcd. C, 77.01, H 7.7, N, 3.45 found: C, 73.4δ; H, 7.16, N, 3.16.

lδ

Preparation of 17β-(carbonvl-estra-1.3.δ(10)-3-(methvlsulfonvloxv)triene a) 17β-(formyl)-estra-l,3,5(10)-3-(methylsulfonyloxy)triene Methylsulfonyloxy to a suspension of 17β-(cyano)-estra-l,3,5(10)-

20 3-triene (20.0gm, 55.6mmol) in tolene(δδθml) was added Di-isobutyl aluminum hydride (lδ.δgm, 111.2mmol, 111.2 ml of 1.0 molar solution in hexanes) dropwise, with strong under argon. The addition is made over 30 minutes and the mixture is stirred for l.Oh of ambient temperature. The reaction was then poured into 1.0L of 5% H2SO4 and stirred l.Oh at

2δ RT. The organic layer was washed with brine (2Xδ00ml), dried (magnesium sulfate), and concentrated in vacuo to afford the title compound as a white soUd (12.δgm, 62%; HNMR (CDCL3, 400MHz): δ 0.8 (δ,3H), 3.13 (S,3H), 70 (S,1H), 7.0δ (d, IH), 7.3 (d, IH), 9.8 (d, IH). b) 17β-(carbonyl)-estra-l,3,δ(10)-3-(methylsulfonyloxy)triene 30 Jones reagent was added to a solution of 17β-(formyl)-estra- l,3,δ(10)-3-(methylsulfonyloxy)triene (δ.26g, 14.δmmol) at 0°C until an orange color persisted and the reaction was aUowed to warm to room temperature over l.Oh. Isopropanol was added until green color persisted. The reaction mixture was filtered through celite, concentrated in vadio. The residue was dissolved in EtOAc, extracted with 2.δN sodium hydroxide and the aqueas layer is readdified with 1.0 NHCL δ yielding a white ppt. EtOAc was added to dissolve the solid. The layers were separated, and the organic layer was washed with brine, dried (magnesium sulfate), and concentrated in vacuo. The residue was triturated with hexane to afford the titie compound as a yeUow soUd (353gm, 64%); HNMR (CDCL₂, 400MH₂); δ 08(S,3H), 2.5(t, IH), 3.14(S, 0 3H), 70 (2, IH), 70δ (d, 14), 7.3 (d, IH).

⁵ Preparation of 17β-r2-(5-Phenvloxazole)1estra-1.3.5(ld0)-triene-3-carboxvlic add a) 17β-[N-(acetylphenyl)carbamoyl]estra-l,3,5(10)-3- (met_hylsulfonyloxy)triene

To a solution of 17β-carboxyl)-estra-l,3,5(10)-3- 0 (methylsulfonyloxy)triene (l.Olgm, 2.67mmol) in CH2CL2 (100ml) were added 1,3-Dicydo-hexylcarbodicmide (551mg, 2.67mmol), 2- Hydroxybenzotriazole (361mg, 267mmol α-aminoacetaphenone hydrochloride, (458mg, 267mmol), and triethylamine (270mg, 2.67mmol. The reaction was stirred overnight of ambient temperature under argon. δ The reaction was filtered, concentrated in vacuo. and flask chromatographed (siUca gel, 1.1 hexares/EtOAc) to afford the title compound as a slightly yeUow soUd, (730mg, δδ%); iHNML (CDCL3, 400 MHZ): δ 0.74 (S,3H), 3.12 (Sχ3H), 4.71-4.92 (ddd, 2H), 6.4δ (brs, IH, NH), 7.0 (S,1H), 7.0δ (d,lH), 7.32 (d,lH), 7.δ2 (M,2H), 7.63 (M,1H), 8.0 0 (M,2H); MS (DCI/NH3) m/e 496 [M+H]+. b) 17β-[2-(5-Phenyloxazole)]estra-l,3,5(10)- 3(methylsulfonyloxy)triene

A mixture of 17β-[N-(acetylphenyl) carbamoyl]estra-l,3,5(10)-3 (methylsulfonyloxy)triene (702.3mg, 1.417mmol)in phosphorous δ oxychloride (7δml) was heated at 90°C overnight. The mixture was unconcentrated in vacuo and the brown, only residue was dissolved in CHCL3 washed with water and brine, dried (magnesium sulfate) and concentrated. The residue was titurated with hexane and filtered to afford the title compound as a tan soUd (636mg, 94%); iHNMR (COCL3, 0 400MHZ): δ 0.78 (S, 3H), 3.1δ (S,3H), 7.0δ (M,2H), 7.3 (M,1H), 7.δ2 (M,3H), 7.6 (S,1H); 7.68 (M,2H); MS (DCI/NH3) m/e 478 [M+H]+. c) 17β-[2-(δ-Phenyloxazole)]estra-l,3,δ(10)-3(hydroxy)triene To a suspension of 17β-[2-(5-Phenyloxazole)]estra-l,3,δ(10)-

3(methylsuUOnyl)triene(607.8mg, 1.272mmol) in 25ml of 9:1 EtOH:H2θ 5 was added 10% NaOH (1.27g, 31.8mmol, 11.47ml) and the mixture was refluxed for 3.0 hr. The reaction was concentrated in vaςuo and the residue was audified with 1.0 NHCI, extracted into EtOAc, washed with water and brine, (magnesium sulfate), and concentrated. The residue was triturated with acetonitrile and filtered to afford the title compomid 0 as a pale yeUow soUd (329.4mg, 65%); iHNMR (DMSO-d₆410MHZ): δ 0.δl (S,3H), 6.4δ (S,H), 6.δl (M,1H), 7.06 (d,lH), 7.3δ (M,1H), 7.48 (M,2H), 7.57 (S,1H), 7.68 (M.2H), 9.0 (SilHxOH); MS (DCI/NH3) m e 400 [M+H]+. d) 17β-[2-(5)-Phenyloxazole)]estra-l,3,5(10)-3(trifluormethyl δ sulfonyloxy)-triene

To a solution of 17β-[2-(δ-Phenyloxazole)]estra-l,3,δ(10)-3 (hydroxy )triene in freshly distilled DTF (15ml) was added sodium hydride (46.1mg, 1.92mmol, 48.5mg of 95% dispersion) and N- Phenyltrifluoromethane sulfonamide (943mg, 2.64mmol). The mixture 0 was stirred overnight at ambient temperature under Argon. The reaction was concentrated in vacuo and the residue was dissolved in CHI, washed with water and brine, dried (magnesium sulfate, and concentrated. The residue was triturated with hexase and filtered to afford the title compomid as a white powder (354mg, 84%); iHNM δ (CDCL3, 400MHZ): δ 0.65 (S,3H), 7.0 (M,1H), 7.03 (M,1H), 7.35 (M,2H), 7.43 (M,2H), 7.52 (M.1H), 7.6δ (M.2H); MS (DCI/NH3 m/e 532 [M+H]+. e) Methyl 17β-[2-(δ-Phenyloxazole)]estra-l,3,5(10)-triene-3- carboxylate

A mixture of 17β-[2-(5-Phenyloxazole)]estra-l,3,δ(10)- 3(trifluoromethyl sulfonyloxy)-triene (339.2mg, 0.638mmol), paUatium δ (H acetate (39mg, 0.17mmol), 1,3-bis (diphenylphosphino) propane (dppp, 71.9mg, 0.174mmol), triethylamine (129mg, 1.276mmol), methanol (2.0ml), 1,2-dichloroethane (2.0ml), and DMSO (4.0ml) was heated at 80°C under an atmosphere of CO for 16 hrs. The cooled reaction mixture was then diluted with CHCI, washed with H2O 10% 0 aqueous HCL, 10% aqueous NaHCθ3, brine, dried (magnesium sulfate), and concentrated in vacuo. The residue was flush chromotographed (siUca gel 2% CH3OHCHCH3) to afford the title compound a white soUd. (25.7mg, 9.1%); *HNMR (COCL3, 400MHZ: δ 0.66 (S,3H), 3.9 (S,3H), 7.30-7.46 (M,5H), 7.63 (M,2H), 7.78 (M,2H); MS (DCI/NH3) m/e 442 5 [M+H]+. f) 17β-[2-(5-Phenyloxazole)]estra-l,3,δ(10)-triene-3-carboxyUc add

To a suspension of methyl 17β-[2-(δ-Phenyloxazole)]estra- l,3,δ(10)-triene-3-carboxylate (2δ.6mg, 0.0δ8mmol) in 3.0ml of :l EtOH: 0 H2O was added potassium carbonate (32.1mg 0.232mmol) in water (0.5ml) and the mixture was refluxed overnight. The reaction was audified with 1.0 NHCI concentrated in vacuo and the residue was dissolved in EtOAc, washed with water and brine, dried (magnesium sulfate), and concentrated. Flash chromotography (silica gel 5% 5 CH3OH/CNCL3) afforded the titie compomid as a whole soUd (4gmg, 20%); iHNMR (CDCL3, 400 MH₂): δ 0.66 (S,3H), 7.2δ-7.3δ (M,2H), 7.38-7.46 (M,3H), 7.62 (M,2H), 7.83 (S, IH), 7.87 (dlH); MS (ES) m e 428 [M+H]+; Anal. (C28H2gN0₃)calcd: C, 78.66; H, 6.84; N, 3.28. found: C, 76.92; H, 6.73; N, 3.32 0

Preparation of 17β-.2-(N-Benzvloxvmethvl) imidazolvl estra-1.3.5(10)-triene- 5 3-carboxvlic add a) 17β-(2-imidazoly)estra-l,3,δ(10)-3(methylsulfonyloxy)-triene Glyoxaldehyde (0.480g, 8.28mmol, 1.2gm of 40% solution) and ammonium hydroxide (1.408gm, 82.8mmol, 4.7gms of 30% solution) were added to a solution of 17β-(formyl)-estra-l,3,δ(10)-3-(methylsulfonyloxy)-

10 triene (3.0gm, 8.28mmol) in MeOH (100ml) at 0°C. The reaction flash was stoppered and aUowed to warm to room temp, with stirring overnight. The reaction was next concentrated in vacuo and the residue was disolved in EtOAc and extracted into 1.0 NHCL. The aqueous layer is then basified with NaHCθ3 and xtracted into CHCL3, washed with water and brine, lδ dried (magnesium sulfate) and concentrated. The whole, gummy residue was triturated with hexane and filtered to afford the title compound as a white powder (2.4δgm, 74%); iHNMR (CDCL₂, 400MHZ): 5 0.6(S,34), 3.14(S,34), 7.02(M,4H), 7.32 (d,lH); MS (DCI/NH3) m/e 401 [M+H]+. b) 17β-[2-(N-Benzyloxymethyl)imidazole]estra-l,3,5(10)- 20 3(met_hylsulfonyloxy)triene

To a solution of 17β-(2-)estra-l,3,5(10Xmethylsulfonyloxy -triene (1.918gm, 4.79mmol) in DMF was added sodium hydride (126mg, δ.2mmol) and the yeUow solution was stirred for 20 minutes at room temp. The reaction was cooled to 0°C, a DMF solution of benzyloxy chloromethyl ether 25 was added , and the reaction was stirred for 10 minutes at 0°C and then warmed to room temperature for 1.0 hrs. The reaction is quenched by addition of Nartθ3, concentrated in vacuo and the residue was redisolved in EHM, washed in the water, δ%, concentrated. Flash chromatography (siUca gel 100% ETOM) afforded the titie compound (1.106gm, 4δ%); iHNM (CDCL₂ 400MH7): δ 0.7δ (S,3H) 3.11 (S,3H), 4.43 (S,2H), δ.23 (d,lH), δ.45 (d,lH), 6.95-70δ (M,4H), 7.28-7.42 (M,6H); MS (DCI/NH3) m/e δ21 [M+H]+. c) 17β-[2-(N-Benzyloxymethyl) imidazole] estra-l,3,5(10)-3 (hydroxy) triene To a solution of 17β-2-(N-Benzyloxymethyl)in_idazoleestra- l,3,δ(10)-3(methylsulfoxyloxy)triene (1.07 gm, 2.06 mmol) in 3δ mL of 9:1 EtOH H₂0 was added 10% NaOH (2.06 gm, δl.δ mmol, 18.6 mL) and the mixture was refined for 4.0 hr. The reaction was concentrated in vacuo and the residue was addified with 1.0 NHCI, extracted into EtOAc, washed with water and brine, dried (magnesium sulfate) and concentrated. The residue was trituiated with hexane and filtered to afford the title compound as a white soUd (380 mg, 42%); iHNMR (DMSO-de, 400 mHZ): δ 5 0.6 (S,3H), 4.45 (d, 2H), 5.38 (S,2H), 6.42 (SJH), 6.47 (d,lH), 6.48 (S,1H) 70 (d,lH), 7.21 (S,1H), 7.25-7.30 (M,3H), 7.31-7.40 (m,2H); (DCI NH3) m/e 443 [M+H]+. d) 17β-2-(N-Benzyloxymethyl)imidazole]estra-l,3,5(10)-3 (trifluorosulfonyloxy) triene

To a solution of 17B-2-(N-Benzyloxymethyl)estra-l,3,5(10)-3 (hydroxy) triene in freshly distiUed THF (40 mL) was added sodium hydride (49.2 mg, 2.05 mmol, 51.8 mg of 95% dispersion and N-

Phenyltrifluoroxethane sulfonimide (1.00 gm, 2.82 mmol). The mixture was stirred overnight at ambient temperature under ARGON. The reaction was concentrated in vacuo and the residue was dissolved in EtOAc, washed with water and brine, dried (magnesium sulfate), and concentrated. The residue was flash chromatographed (silica gel 1.1 hexaned EtOAc) to afford the title compound as a colorless syrup (401 mg, 82%); iHNMR (CDCI3, 400 MHZ): δ 0.75 (S,3H), 4.45 (S,2H) 5.23(d,lH), 5.31 (S,1H), 5.44 (d.lH), 6.95-7.06 (m,4H), 7.28-7.4 (m,5H); MS (DCI/NH3) m/e δ7δ [[M+H]+. 0 e) Methyl 17β-[2-(N-Benzyloxymethyl) imidazolyl]estra- l,3,5(10)-triene-3-carboxylate

FoUowing the previous described procedure for methyl carboxylation of a phenol, the title compound was prepared as a yellow soUd (172 mg, 32%; iHNMR (CDCI3, 400 NHZ): δ 0.75 (S,34), 3.9 (S,3H), 4.4δ (S,2H), δ δ.2δ (dJH), 5.45 (m,lH), 70 Ls, 2H), 7.06 (S,2H), 7.27-7.40(M,6H); MS (DCI NH3) m/e [M+H]+.

9δ f) 17β-[2-(N-Benzyloxmethyl)imidazolyl]estra-l,3,5(10)triene-

3-carboxyUc add

FoUowing the previously described procedure for hydrolysis of the 3-methylester, the title compound was prepared as a white soUd (14.6 mg, 22%); IHNME (CDC13, 400 MHZ): δ 0.7δ (S,3H), 4.46 (S,2H), δ.34 (d,lH) δ.4δ (d,lH), 70 (S,1H), 7.2 (S,1H, 7.30-7.42 (m,6H), 7.8δ (m,2H); MS (ES) m/e 471 [M+H]+ ; Anal. (C₃₀ H 34 N₂0₃) calcd:C, 76.57, H,7.28; N, 5.9δ. found.: C.73.28; H,6.91; N,δ.δ9.

Preparation of 17β-r2-(δ-Phenvlimidazole)lestra-1.3.5(10)-triene-3- carboxvlic Add a) 17β-[2-(S-PhenyUmidazole)]estra-l,3,δ(10)- 3(hydroxymethyl) triene

Phenylglyoxal monahydrate (127.5 mg, 0.838 mmol) and ammonium hydroxide (477.0 mg of 30% solution, 8.38 mmol) were added to a solution of 17β-formyl)-estra-l,3,5(10)-3-(Hydroxymethyl) triene (250 mg, 0.838 mmol) in MeOH (10 mL) at 0°C. The reaction was tightly stoppered and aUowed to warm to room temperature with stirring overnight. The reaction was concentrated in vacuos, suspended between EtOAc and 10% HCl, and the observed white soUd predpitate was filtered. The white soUd was then stirred in a flask containing COCI3 and 5% NaHC03 until aU soUd had dissolved. The layers were was separated and the CHCI3 layer was washed with water and brine, dried (magnesium sulfate), and concentrated in vacuo to afford the title compound as a greenish soUd (213.0 mg, 62%); iHNMR (CΔCI3, 400 MHZ): δ 0.6 (S,3H), 4.63 (S,2H), 7.1 (S,1H) 7.12 (m, IH), 7.24 (m,2) 7.26 (m,2H), 7.30 (m, IH), 7.37 (M,2H), 7.72 (brs, IH); MS (DCI/NH3) m/e 413 [M+H]+-

- ge - b) 17β-[2-(5-PhenyUmidazole)]estra-l,3,δ(10)triene-3- carboxylic Add

Jones reagent was added to a solution of 17β-[2-(δ- PhenyUmidazole)]estra-l,3,δ(10)-3(hydroxymethyl) triene in acetone at 0° until an orange color persisted and the reaction was warmed to room temperature overnight. Isopropanol was added until green color persisted and the reaction mixture was filtered through ceUte and concentrated in vacuo to a white soUd. This solid was suspended between δ% NaHC03 and EtOAc and the orange layer was washed with water, brine, dried (sodium sulfate), concentrated in vacuo. and flush chromatographed (siUca gel l:g:90 ACOH/CH3OH/3 to afford the title compound a white soUd (12.2 mg, 24%); IHNME (DMSO-d6, 400 MHZ): δ 0.52 (S,3H), 7.12 (M, IH), 7.40 (M, 3H), 7.45 (M,1H), 7.65 (M,2H), 7.73 (M,2H); MS (ES/NH3) m/e 427 [M+H]+-

Evamplfi 43

Preparation of 17β-(2-Imidazolvl)estra-1.3.5(10)-triene-3-carboxvlic add

10% Pd/C (7.7 mg) was added to a solution of 17β-(2-(N- Benzyloxymethyl) imdidazolyl]estra-l,3,δ(10)triene-3-carboxylic add (7.7 mgs, 0.0164 mmol) in EtOH (3.0 mL and the mixture was placed under an H2 baUon and stirred for 72 hrs. The reaction was filtered through ceUte and concentrated to afford the title compound as an off white soUd (19 mgs, δ3%); iHNMR (CH₃OH-d4, 1400 MHZ δ 0.δ7 (s, 3H), 7.21 (S,2H), 7.3 (d,lH), 7.7 (M,2H); ms (es) m/e 3δ [M+H]+-

Example 44 Preparation of 17B-( 3-Oxo-3-phenvl-l-propenvl)-3-hvdroxvmethvl-estra- 1.3.5(10)-triene-3-carboxvlic add The title compound was prepared following the procedure of Example 21 (a), except βubstituing dimethyl-2-oxo-3- phenylpropylphosphonate for dimethyl-2-oxo-2-phenylethylphosphonate. Thus, from 0.4δ g (1.5 mmol) of the aldehyde there was obtained 0.45 g 5 (75%). *H NMR (CDCI3, 400 MHz): δ 0.75 (s, 3H), 4.62 (s, 2H), 6.87 (d, J = 16 Hz, IH), 7.0δ-7.1δ (m,3H),7.3 (d, J = 8 Hz lH),7.4δ-7.δ7 (m, 3H), 7.9δ (d, J = 8Hz, 2H).

10 Preparation of 17β-(3-Oxo-4-phenvl-l-butenvl )-3-hvdroxvmethvl-estra- 1.3.5(10)-triene-3-carboxvlic add

To a stirred suspension of LiCl (0.03 g, 0.7 mmol) in dry CH3CN ( 6 mL ) was added dimethyl-2-oxo-3-phenylpropylphosphonate ( 0.15 g, 0.6 mmol ), DBU ( 0.07 mL, 0.5 mmol ) and 17b-17-(formyl) estra-1,3,5- lδ triene- 3-methanol ( O.lδ g, O.δ mmol ). After stirring overnight, the reaction mixture was concentrated. The residue was partitioned between H2O and EtOAC. The organic layer was washed with brine and dried, and concentrated. The crude product was chromatographed ( 20 : 80 EtOAc / hexanes ) to provide an oil ( 0.10 g, 60 % ). *H NMR (CDCI3, 400

20 MHz): δ 0.63 ( s, 3H ), 3.8δ (s, 2H), 4.63 (s, 2H), 6.12 (d, J = lδ.7 Hz, IH), 6.92 (d,d J = lδ.7,lδ.7 Hz, IH), 7.10 (s, IH), 7.1δ (d, J = 8Hz, IH), 7.2- 7.3δ (m, 6H).

Example 46

25 Preparation of 17β-(5-hvdroxv.l.l.l.9.9.9 hexafluorononvDandrosta- 3.5.diene-3-carboxvlic add a) 17β-(5-hydroxy,l,l,l,9,9,9 hexafluorononyl)androsta-3,δ,diene- 3-carboxyUc add trifluorobutyl bromide and magnesium in THF, then was added to a solution of 17β-(l-oxo-δ,δ,δ-trifluoro pentyl) androsta-3,5,diene-3-

30 carboxyUc add (40 mg, 0.1 mmol) in THF (2 ml) and the solution was refluxed for 10 minutes, then was quenched with 0.2 N aqueous hydrochloric add (3 ml), and was extracted with EtOAc (10 ml). The combined organic extracts were dried (MgS04), filtered, concentrated in vacuo, and chromatographed (siUca gel, 1:20:80 AcOH EtOAc hexanes) to produce a

35 white soUd (25 mg, 63%); iH NMR (CDCI3, 400 MHz): δ0.67(s,3H), 0.94(s,3H),5.88(s,lH),7.16(bs,lH); MS(DCI/NH3) m/e 5δ0 [M+H]+. Example 47 Preparation of 17β-hvdroxv-17α-benzvl-estra-1.3.5(10)-triene-3-carboxvlic add a) 17^β-hydroxy-17α-benzyl-estra-l,3,δ(10)-triene-3-carboxylic add δ A solution of benzyl magensium bromide in THF (0.3 ml, 2.0 M) was added to a solution of 17-oxo-estra-l,3,δ(10)-triene-3-carboxyUc add (4δ mg, 0.15 mmol) in THF (2 ml) at room temperature, then was stirred for 2 hours, then was quenched with 10% aquesou acetic add (5 ml), then was extracted with EtOAc (10 ml). The combined organic extracts were dried (MgS04), 0 filtered, concentrated in vacul, and chromatographed (silica gel, 1:20:80

AcOH EtOAc hexanes) to produce a white soUd (40 mg, 80%); MS(DCI NH3) m/e 391 [M+H]+.

Example 48 5 Preparation of 17β-(t-butvl dimethyl silvl ether)androsta-3.5-diene-3- carboxylic add a) 17β-(t-butyl dimethyl silyl ether)androsta-3,5-diene Tert-butyl dimethyl silyl chloride (5.7 g, 38.1 mmol) was added to a solution of testosterone (10.0 g 34.7 mmol), triethyl amine (9.7 ml, 69.3 0 mmol), dimethyl amino pyridine (100 mg), in CH2CL2 (50 ml) and was stirred at room temperature for 12 hours. The reaction was quenched with aqueous, saturated ammonium chloride (δO ml), extracted with EtOAc (100 ml), dried (MgS04), filtered, concentrated in vacul, to afford a white soUd (13.5 g, 98%), which was used in the next step without further pruification. 5 TrifiUc anhydride (2.3 ml, 13.7 mmol) was added dropwise to a solution of 17β-(t-butyl dimethyl silyl ether)-andro-4-stene-3-one (3.7 g,9.2 mmol), 2.6-di-t-butyl-4-methyl pyridine (2.6 g, 12.9 mmol) in CH2C12 (37 ml) and was stirred overnight. The reaction was quenched with 0.5 N hydrochloride add, extracted with CH2C12 (100 ml), dried with MgS04, 0 filtered, concentrated in vacuo, and chromatographed (siUca gel, 40%

EtOAc hexanes) to afford a white soUd (2.0 g, 43%); *H NMR (CDC13, 400 MHz): δθ.02 (s, 3H), 0.03 (s,3H), 0.75 (s, 3H) 0.88 (s, 9H), 0.96 (s, 3H), 3.δ8 (dd, J=8.5 Hz, 8.5 Hz), δ.δ8 (s, IH), δ.96 (s, IH). b) A baloon of carbon monoxide was bubbled into a solution of 17^β- δ (t-butyl dimethyl sflyl ether)-3-trifluoromethyl sulfonyloxy-androsta-3,5- diene (1.6 g, 3.2 mmol), triethylamine (0.9 ml, 6.4 mmol), bis(triphenylphosphine)palladium acetate (120 mg, 0.16 mmol), in MeOH (6.4 ml) and DMF (6.4 ml) for 15 minutes, then the reaction was stirred under a baloon of carbon monoxide overnight at 50°C. The reaction was then diluted with EtOAc (20 ml), washed with 2 x 100 ml water, then 100 ml of saturated aqueous ammonium chloride. The combined organic extracts were δ dried with EtOAc/hexanes) to afford a white soUd (0.8 g, 4δ%); iH

NMR(CDC1₃, 400 MHz): δ 0.02 (s, 3H), 0.03 (s, 3H), 0.7δ (s, 3H), 0.88 (s, 9H), 0.92 (s, 3H), 3.δ7 (dd, J=8.δ Hz, 8.δ Hz), 3.76 (s, 3H), δ.80 (s, IH), 7.05 (s, IH). c) 17^β-(t-butyl dimethyl silyl ether androst-3,5-diene-3-carboxyUc

10 add

Potassium carbonate (20 mg, 0.14 mmol) was added to a mixture of methyl 17β-(t-butyl dimethyl silyl ether)-androsta-3,δ-diene-3-carboxylate (20 mg, O.Oδ mmol) in MeOH (2.0 ml) and water (0.2 ml). The reaction was refluxed for 12 hours, then was diluted with 10 ml of water, then was lδ extracted with 10% acetic aάd/EtOAc (20 ml). The combined organic extracts were dried with magnesium sulfate, filtered, concentrated, and chromatographed (sflica gel, 1:20:80 AcOH EtOAc/hexanes) to afford a white soUd (lδ mg, 70%); !H NMR (CDCI3 400 MHz): δθ.02 (s, 3H), 0.03 (s, 3H), 0.75 (s, 3H), 0.88 (s, 9H), 0.92 (s, 3H), 3.57 (dd, J=8.δ Hz), δ.8δ (s, IH), 7.16

20 (s, IH), MS(DC_yNH₃) m/e 431 [M+H]+.

Example 49 Preparation of 17B-17-hvdroxv-androsta-3.5-diene-3-carboxvlic add To a solution of methyl-17β-17-acetoxy-androsta-3,5-diene-3-

25 carboxylate (350 mg, 0.94 mmol) was added potassium carbonate (200 mg, 1.45 mmol) in MeOH (3.0 ml) and H2O (O.δ ml) and was refluxed for 12 h. The reaction was quenched with O.δ N HCl, extracted with EtOAc, dried with MgS04, filtered, concentrated, and chromatographed (1:19:80 AcOH: EtOAc: hexanes) to yield a white soUd (310 mg, 90%); iH NMR: δ 0.82 (s,

30 3H), 0.96 (s, 3H), 3.68 (dd, J=8.2, 8.2 Hz, IH), δ.89 (d, J=2.0 Hz, IH), 7.1δ (s, IH)

Exam e 50

Preparation of 17B-17-hvdroxv-estra-1.3.5(10)-triene-3-carboxvlic add 35 To a solution of 17-oxo-estra-l,3,5(10)-triene3-carboxyUc add (20 mg, 0.07 mmol) was added sodium borohydride (20 mg, 0.5 mmol) in MeOH at 0° C and stirred for 0.5 h. The readion was quenched with pH 7 buffer, extracted with EtOAc, dried (magnesium sulfate), concentrated in vacuo, and flash chromatographed (silica gel 1:19:80 AcOH: EtOAc: hexanes) to afford a white soUd (lδ mg, 75%); H NMR: δ 0.81 (s, 3H), 3.77 (dd, J=8.2, 8.2 Hz, IH), 7.35 (d, J=8.δ Hz, IH), 7.76 (s, IH), 7.80 (d, δ J=8.δ Hz, IH).

Eva p fix

Preparation of O-nhenvl oxime ether of 17-oxo-androsta-3.5-diene-3- carboxvlic add 0 O-phenyl hydroxylamine hydrochloride (20 mg, 0.16 mmol) was added to a mixture of 17-oxo- androsta- 3,5- diene-3-carboxyUc add (20 mg, 0.067 mmol), p-toluene sulfonic add (δ mg, 0.03 mmol), and 4 A molecular sieves (50 mg) in toluene (2.0 ml) and was refluxed for 12 h.

Flash chromatography (siUca gel, 1: 20: 80 AcOH/ EtOAc/ hexanes) 5 afforded the title compomid as white soUd ( lδ mg, 70 %); H NMR: δ

0.9δ (s, 3H), 0.96 (s, 3H), δ.88 (d, J=2.0 Hz, IH), 7.1δ (s, IH), 7.26-7.37

(m, δH); MS(DCI/NH3) m/e 406 [M+H]+

Example 52 0 Preparation of 17β-methoxv-17o-benzvl-estra-1.3.5(10)-triene-3- carboxylic add

Sodium hydride (10 mg, 0.4 mmol) was added to a solution of 17β- hydroxy-17α-benzyl-estra-l,3,δ(10)-triene-3-carboxyUc add (10 mg, 0.026 mmol) in THF (1.0 ml) at RT. Then methyl iodide (lOOul, 1.42 mmol) 5 was added, and the reaction was refluxed for 2h, then was quenched with 1 N HCl (5 ml), then was extracted with EtOAc (10 ml). The combined organic extracts were dried (MgS04), filtered, concentrated in vacuo, and chromatographed (siUca gel, 1:20:80 AcOH/ EtOAc hexanes) to produce a white soUd (4 mg, 40%); -Η. NMR: δ 1.04 (s, 3H), 3.41 (s, 0 3H), 7.23-7.32 (m, δ H), 7.42 (d, J= 8 Hz, IH), 7.84 (s, IH), 7.87 (d., J=8 Hz, IH); MS(DCI/NH3) m/e 40δ [M+H]+

I am le 53

Preparation of 17β-rθ-(N-nhenylcarbamoyl)lestra-1.3.5(10)-triene-3- 5 carboxylic add a) methyl 17β-17hydrbxy-estra-l,3,5(10)-triene-3-carboxylate Sodium borohydride (100 mg, 2.6 mmol) was added to a solution of methyl 17-oxo-estra-l,3,δ(10)-triene-3-carboxylate (200 mg. 0.64 mmol) in EtOH at 0°C and stirred for O.δ h. The reaction was quenched with pH 7 buffer, extracted with EtOAc, dried (magnesium sulfate), δ concentrated in vacuo and flash chromatographed (silica gel 1:4

EtOAc hexane) to afford a white soUd (190 mg, 9δ%). ^XH NMR; δ 0.82 (s, 3H), 3.77 (dd, J=8.2, 8.2 Hz, IH), 3.91 (s, 3H), 7.3δ (d, J=8.δ Hz, IH), 7.76 (s,lH), 7.80 (d, J=8.2 Hz, IH). b) Methyl 17β-[O-(N-phenylcarbamoyl)]estra-l,3,5(10)-triene- 10 3-carboxylate

Phenyl isocyanate (excess) was added to a solution of methyl 17β- 17hydroxy-estra-l,3,δ(10)-triene-3-carboxylate (0.074 mg, 0.234 mmol) in toluene (10 mL) and the reaction was aUowed to stir at reflux for 24h. The mixture was cooled to room temperature and to it was added Et2θ, lδ washed with H2O, dried ( magnesium sulfate), concentrated in vacuo, and flash chromatographed (silica gel 1:4 EtOAc hexane) to afford the title compound as a white soUd (64.8 mg, 64%). !H NMR (CDCI3, 400 MHz): δ 0.88 (s, 3H), 2.92 (m, 2H), 3.gθ (s, 3H), 4.77 (t, IH), 6.60 (br s,lH), 7.07 (t, IH); MS(ES) m/e 434 [M+H]+- 20 c) 17β-[O-(N-phenylcarbamoyl)]estra-l,3,δ(10)-triene-3- carboxyUc add

Potassium carbonate (90 mg, 0.65 mmol) was added to a solution of 17β-[O-(N-phenylcarbamoyl)]estra-l,3,5(10)-triene-3-carboxylate (57 mg, 0.13 mmol) in MeOH (9.0 mL) and H2O (1.0 mL) and the reaction 25 was aUowed to stir at reflux for 24h. The reaction mixture was cooled, then addified with 10% HCl and concentrated in vacuo. The residue was diluted with H2O and extracted with CHCI3, washed with H2O, saturated NaCl, dried (sodium sulfate), concentrated in vacuo, and flash chromatographed (siUca gel 98:2 CHCI3/ CH3OH gradient 97:2:1 30 CHCI3/CH3OH/HOAC) to afford the title compound as a white soUd (13 mg, 24%). iH NMR (CDCI3, 400 MHz): δ 0.89 (s, 3H), 4.76 (t, IH), 6.6δ (br s,lH); MS(ES) m/e 420 [M+H]+.

Example δ4 3δ Preparation of 17β-rθ-(N-tert-butylcarbamoyl)1estra-1.3.5(10)-triene-3- carboxylic add a) Methyl 17β-[O-(N-tert-butylcarbamoyl)]estra-l,3,5(10)- triene-3-carboxylate

Following the procedure of Example 53(aMb), except substituting t-butyl isocyanate for phenyl isocyanate, the title compound was δ prepared as a white soUd (79.0 mg, 60%). !H NMR (CDCI3, 400 MHz): δ 0.82 (s, 3H), 1.33 (s, 9H), 2.g2 (d, 2H), 3.90 (s, 3H), 4.60 (s, 2H), 7.36-7.33 (m, IH), 7.80-7.74 (m, 2H); MS(DCI) m/e 414 [M+H]+- b) 17β-[O-(N-tert-butylcarbamoyl)]estra-l,3,δ(10)-triene-3- carboxylic add

10 FoUowing the procedure of Example δ3(c), the title compound was prepared as a white soUd (32.0 mg, 43%). iH NMR (CDCI3, 400 MHz): δ 0.80 (s, 3H), 1.30 (s, 9H), 4.61 (br s, 2H), 7.38 (d, IH), 7.81 (s, IH), 7.85 (d, IH); MS(ES) m/e 400 [M+H]+-

lδ Example 55

Preparation of 17_ O-(N-benzvlcarbamovl ) .estra-1.3.5(10)-triene-3- carboxvlic add a) Methyl 17β-[O-(N-benzylcarbamoyl)]estra-l,3,5(10)-triene-

3-carboxylate 20 FoUowing the procedure of Example 53(a)-(b), except substituting benzyl isocyanate for phenyl isocyanate, the title compound was prepared as a white soUd (δO mg, 53%). -Η. NMR (CDCI3, 400 MHz): δ

0.80 (s, 3H), 2.90 (m, 2H), 3.90 (s, 3H), 4.46 (m, 2H), 4.67 (t, IH), 4.95 (br s, IH); MS(DCI) m/e 448 [M+H]+. 2δ b) 17β-[O-(N-benzylcarbamoyl)]estra-l,3,δ(10)-triene-3- carboxyUc add

FoUowing the procedure of Example 53(c), the title compound was prepared as a white soUd (31 mg, 64%). iH NMR (CDCI3, 400 MHz): δ

0.80 (s, 3H), 2.92 (m, 2H), 4.39 (m, 2H), 4.70 (t, IH), 5.01 (t, IH); MS(ES) 30 m/e 434 [M+H]+.

xa le 56

Preparation ofl7β-rN-(N-tertbutvlurea)estra-1.3.5(10)-triene-3-carboxvlic add 35 a) Methyl 17-oximo-estra-l,3,5(10)-triene-3-carboxylate

To a solution of methyl 17-oxo-estra-l,3,5(10)-triene-3-carboxylate (2.30 g. 7.37 mmol) in toluene (δO mL) was added hydroxylamine hydrochloride (2.56 g, 36.9 mmol), p-toluenesulfonic add monohydrate (1.4 g, 7.37 mmol) and 4A molecular sieves. The reaction was aUowed to stir at reflux for 24 h. The mixture was cooled, filtered with EtOAc, and the filtrate was concentrated in vacuo and flash chromatographed (siUca gell:4 EtOAc hexane gradient to EtOAc) to afford the title compound as a white soUd (1.76 g, 73%). H NMR (CDCI3, 400 MHz): δ 0.9δ (s, 3H), 2.δ8 (m, 2H), 2.92 (m, 2H), 3.90 (s, 3H). b) 17-β-Amino-estra-l,3,δ(10)-3-(hydroxymethyl)triene

To a 1M solution of LAH in THF (16.0 mL, 16.0 mmol) was added methyl 17-ox__mo-estra-l,3,δ(10)-triene-3-carboxylate (1.74 g, δ.32 mmol) in THF (40 mL) under argon. The reaction was aUowed to stir at reflux for 24 h. The mixture was cooled to room temperature, quenched with H2O (0.61 mL), foUowed by 15% NaOH (0.61 mL), and H2O (1.22 mL). The reaction mixture was filtered, concentrated in vacuo, and flash chromatographed (siUca gel, 9δ:δ CH2Cl2/MeOH- 9δ:4:l

CH2Cl2/MeOH/NH4θH) to afford the title compo id as a white soUd (0.416 g, 27%) iH NMR (CDCI3, 400 MHz): δ 0.68 (s, 3H), 2.7δ (t, IH), 4.60 (s, 2H), 7.0δ (s, IH), 7.15 (d, IH), 7.30 (d, IH); MS(ES) m/e 286 [M+H]+. c) 17M-tertbutylurea]estra-l,3,5(10)-3-(hydroxymethyl)triene

To a solution of 17^-amino-estra-l,3,5(10)-3- (hydroxymethyl)triene (0.090 g, 0.31δ mmol) in CH2CI2 (δ mL) was added a solution of t-butyUsocyanate (0.032 g, 0.31δ mmol) in CH2CI2 (δ mL) and the reaction was aUowed to stir at room temperature for 24 h. The resulting reaction mixture was concentrated in vacuo to afford the title compound as a white soUd (0.121 g, quantitative). iH NMR (CDCI3, 400 MHz): δ 0.66 (s, 3H), 1.33 (s, 9H), 3.63 (m, IH), 4.28 (d, 1H), 4.42 (s, IH), 4.62 (s, 2H), 7.12(d, IH); MS(DCI) m/e 38δ [M+H]+. d) 17β-[N-(N-tertbutylurea)]estra-l,3,δ(10)-triene-3-carboxyUc add

To a solution of 17β-[-tertbutylurea]estra-l,3,δ(10)-3- (hydroxymethyDtriene (0.121 g, 0.315 mmol) in acetone (5 mL) was added Jones reagent at 0°C. The reaction was allowed to stir for 20 minutes at 0°C then at room temperature for 24 h. The mixture was quenched with isopropanol (until the mixture turns green), and the reaction was then aUowed to stir at room temperature for 15 minutes. The mixture was filtered, concentrated in vacuo, and flash chromatographed (siUca gel, 97:2:1 CHCI2/CH3OH HOAC) to afford the title compound as a white soUd (0.060 g, 53%). NMR (CDCI3, 400 MHz): δ 0.76 (s, 3H), 1.38 (s, 9H), 3.5δ (t, IH), 7.36 (d, IH), 7.83 (s, IH), 7.88 (d, IH); MS(ES) m/e 39 [M+H]+; mp: 232-234°C. δ

EYflmp^.fi δ Preparationof l7β-rN-(O-tert-butvlcarbamovl)1estra-1.3.5(10)-triene-3- carboxylic add a) 17β-D^-(O-tert-butylcarbamoyl)]estra-l,3,5(10)-3-(hydroxyl)- 0 triene Tertbutyl-carbonic anhydride (0.18δ g, 0.848 mmol) was added to a suspension of 17β-amino-estra-l,3,δ(10)-3-(hydroxymethyl)triene (0.242 g, 0.848 mmol) of Example 4(b) in CH2CI2 (20 mL) and the reaction was aUowed to stir at room temperature for 24 h. The reaction mixture was washed with H2O, saturated NaCl, dried (magnesium 5 sulfate), concentrated in vacuo, and flash chromatographed ( siUca gel, 6:4 hexane/EtOAc) to afford the title compound as a white foam (0.266 , 81%). iH NMR (CDCI3, 400 MHz): δ 0.70 (s, 3H), 1.47 (s, 9H), 3.64 (m, IH), 4.46 (d, IH), 4.53 (s, 2H), 7.10 (s, IH), 7.16 (d, IH), 7.32 (d, IH); MS(ES) m/e 386 [M+H]+- 0 17β-CN-(O-tert-butylcarbamoyl)]estra-l,3,5(10)-3-(formyl)- triene

To a solution of 17β-[N-(O-tert-butylcarbamoyl)]estra-l,3,5(10)-3- (hydroxylHriene (0.154 g, 0.40 mmol) in CH2CI2 (δ mL) containing 4A molecular sieves and NMO (0.07 g, 0.60 mmol) was added TPAP (0.007 g, 5 0.02 mmol) and the reaction was aUowed to stir at room temperature for 1.5 h. The reaction mixture was flash chromatographed (siUca gel, 2:1 hexane EtOAc) to afford the title compound as a white foam (0.127 g, 83%). iH NMR (CDCI3, 400 MHz): δ 0.73 (s, 3H), 1.47 (s, 9H), 3.66 (m, IH), 4.46 (d, IH), 7.46 (d, IH), 7.60 (s, IH), 7.65 (d, IH), 9.96 (s, IH); 0 MS(ES) m/e 384 [M+H]+- c) 17β-[N-(O-tert-butylcarbamoyl)]estra-l,3,5(10)-triene-3- carboxyUc add

A solution of NaC102 (0.295 g, 3.26 mmol) and NaH2Pθ4-H2θ (0.45 g, 3.26 mmol) in H2O (2.0 mL) was added to a mixture of 17β-[N- δ (O-tert-butylcarbamoyl)]estra-l,3,δ(10)-3-(formyl)-triene (0.12δ g, 0.326 mmol), tert butyl alcohol (6 mL), and 2-methyl -2-butene (0.229 g, 3.26 mmoDat 0°C. The reaction was allowed to stir at room temperature for δ

- lOδ - h. The mixture was then treated with HO Ac (1 m ) and saturated NaCl, extracted with EtOAc, dried (sodium sulfate), concentrated in vacuo, and flash chromatographed (sflica gel, 97:2:1 CHCl3/MeOH/HOAc) to afford the title compound as a white soUd (0.078 g, δδ%). iH NMR (CDCI3, 400 δ MHz): δ 0.73 (s, 3H), 1.47 (s, 9H), 3.68 (m, IH), 4.46 (d, IH), 7.39 (d, IH), 7.83 (s, IH); MS(ES) m/e 400 [M+H]+; mp: 13δ-137°C; Anal. (C2δH33Nθ4.0.7δH2θ) calcd. C, 69.71; H, 8.34; N, 2.04: found C, 69.79; H, 8.42; N, 3.39.

10 Example 58

Preparation of 17β-. Q-(N-phenvlcarhamovl)1androsta-1.3-diene-3- carboxvlic add a) Methyl 17β-[0-(N-phenylcarbamoyl)]androsta-l,3-diene-3- carboxylate lδ Phenyl isocyanate (excess) was added to a solution of methyl 17β-

17-hydroxy-androsta-l,3-diene-3-carboxylate (lδ8 mg, 0.5 mmol) in toluene (5.0 mL) and the reaction was aUowed to stir at reflux for 24h. The mixture was cooled to room temperature and to it was added Et2θ, washed with Η2O, dried ( magnesium sulfate), concentrated in vacuo,

20 and flash chromatographed (sflica gel 1:4 EtOAc/hexane) to afford the title compound as a white soUd (104 mg, 45%); MS (ES) m/e 450 [M+H]+- b) 17β-[0-(N-phenylcarbamoyl)] androsta-l,3-diene-3- carboxyUc add

Potassium carbonate (90 mg, 0.65 mmol) was added to a solution 25 of methyl 17β-[0-(N-phenylcarbamoyl)] androsta-l,3-diene-3-carboxylate (224 mg, 0.5 mmol) in MeOH (9.0 mL) and H2O (1.0 mL) and the reaction was aUowed to stir at reflux for 24 h. The reaction mixture was cooled, then addified with 10% HCl and concentrated in vacuo. The residue was diluted with H2O and extracted with CHCI3, washed with 30 H2O, saturated NaCl, dried (sodium sulfate), concentrated in vacuo, and flash chromatographed (sflica gel 98:2 CHCI3/ CH3OH gradient 97:2:1 CHCI3/CH3OHZHOAC) to afford the title compomid as a white soUd (121 mg, 56 %); MS(ES) m/e 436 [M+H]+.

35 Eγflmplfi 59

Preparation of 17β-rθ-(N-tert-bύtylcarbamoyl⁾1androsta-1.3-diene-3- carboxvlic add a) 17β-[0-(N-tert-butylcarbamoyl)]androsta-l,3-diene-3- carboxyUc add

Following the procedure of Example δ8(a), (b), except substituting t-butyl isocyanate for phenyl isocyanate, the title compound was prepared as a white solid (δ7 mg, δ9 %); MS(DCI) m/e 416 [M+H]+.

Example 60 Preparation of 17β-rθ-(N-b-.nzv1carbflmovl)1androsta-1.3.diene-3- carboxylic add a) 17β-[0-(N-benzylcarbamoyl)] androsta-l,3,diene-3- carboxyUc add

FoUowing the procedure of Example δ8(a), (b), except substituting benzyl isocyanate for phenyl isocyanate, the title compound was prepared as a white soUd (77 mg, 80 %); MS(DCI) m/e 450 [M+H]+.

Example 61 An oral dosage form for administering Formula I compounds is produced by screening, mixing, and filling into hard gelatin capsules the ingredients in the proportions shown in Table 1, below.

Table I

Ingredients Amounts

17β-(N-benzyloxyamino)estra-l,3,5(10)-triene- δO mg 3-carboxyUc add magnesium stearate δ mg lactose 75 mg

The sucrose, calάum sulfate dihydrate and Formula (I) compound shown in Table II below, are mixed and granulated in the proportions shown with a 10% gelatin solution. The wet granules are screened, dried, mixed with the starch, talc and stearic add, screened and compressed into a tablet.

Table π

Ingredients A oun s

17β-(N-benzyloxyamino)estra-l,3,δ(10)-triene- 100 mg 3-carboxyUc add caldum sulfate dihydrate 150 mg sucrose 20 mg starch 10 mg talc 5 mg stearic add 3 mg

Example 63 17β-(N-Benzyloxyamino)estra-l,3,δ(10)-triene-3-carboxyUc add, 7δ mg, is dispursed in 25 ml of normal saline to prepare an iiyectable preparation.

While the preferred embodiments of the invention are iUustrated by the above, it is to be understood that the invention is not limited to the predse instructions herein disdosed and that the right to aU modifications coming within the scope of the foUowing daims is reserved.

Claims

What is claimed is:

1. A

in which: either the A ring is aromatic or the A ring has a C3-C4 double bond and the B ring has a C5-C6 double bond, provided that the B ring does not have a C5-C-5 double bond when the A ring is aromatic; pl and P² are each independently selected from hydrogen and a linear or branched, saturated or unsaturated hydrocarbon chain containing from 1-6 carbon atoms; and

R 3 is absent when the A ring is aromatic and present as -CH3 when the A ring has a C3-C4 double bond and the B ring has a C5-C6 double bond; R is absent or present as

(1) α H and β-O-R¹ where R* is alkyl, cydoalkyl or aryl, where a) alkyl is a linear or branched, saturated or unsaturated hydrocarbon chain containing from 1-12 carbons, and optionaUy substituted with one or more substituents selected from the group consisting of: aryloxy, alkoxy, acyloxy, nitro, cyano, oxo, halogen, cydoalkyl, substituted cydoalkyl, Cg-Cχ2^ar l- substituted

hydroxy and protected hydroxy; b) cydoalkyl is non aromatic, unsaturated or saturated, cydic or polycydic C3-C8, optionaUy containing one or more substituents selected from the group consisting of: aryloxy, aryl, alkyl, alkoxy, acyloxy, cydoalkyl, substituted cydoalkyl, amino, N-acyl amino, nitro, cyano, oxo, hydroxy, halogen substituted aryl, substituted alkyl and protected -OH; and c) aryl is cydic or polycydic aromatic C3-C12. optionally containing one or more heteroatoms, provided that when C is 3 the aromatic ring contains at least two heteroatmos and when C is 4 the aromatic ring contains at least one heteroatom, and optionaUy substituted with one or more substituents selected from the group consisting of: aryloxy, cydoalkyl, substituted cydoalkyl, alkyl, CQ- Cχ2^aryl» alkoxy, acyloxy, substituted C6-Cχ2 ryl, amino, N-acylamino, nitro, cyano, halogen, hydroxy, substituted alkyl and protected -OH;

(2)

B-C-R², where B is =A- where A is a linear or branched, saturated or unsaturated hydrocarbon chain containing from 1-8 carbons; and R2 is alkyl, cydoalkyl or aryl, where a) alkyl is a linear or branched, saturated or unsaturated hydrocarbon chain containing from 1-12 carbons, and substituted with one or more substituents selected from the group consisting of: aryloxy, acyloxy, N-acylamino, nitro, cyano, oxo, halogen, cydoalkyl, substituted cydoalkyl, Cβ-Cj^ ryl and substituted C6-Cχ2aryl; b) cydoalkyl is non aromatic, unsaturated or saturated, cydic or polycydic C3-C8. optionaUy containing one or more substituents selected from the group consisting of: aryloxy, aryl, alkyl, alkoxy, acyloxy, cydoalkyl, substituted cydoalkyl, amino, N-acyl amino, nitro, cyano, oxo, hydroxy, halogen substituted aryl, substituted alkyl and protected -OH; and c) aryl is cydic or polycydic aromatic C3-C12. optionaUy containing one or more heteroatoms, provided that when C is 3 the aromatic ring contains at least two heteroatmos and when C is 4 the aromatic ring contains at least one heteroatom, and optionally substituted with one or more substituents selected from the group consisting of: aryloxy, cydoalkyl, substituted cydoalkyl, alkyl, Cg-C^ !, alkoxy, acyloxy, substituted C6-Cχ2 τyl, amino, N- acylamino, nitro, cyano, halogen, hydroxy, substituted alkyl and protected -OH;

(3) " 4 α H and B-O-C-NHR where R⁴ is selected from the group consisting of: hydrogen, Ci-Cg alkyl, substituted Ci-Cgalkyl, Cs-Cgcydoalkyl, substituted C3-C8 cydoalkyl, C6-Ci2aryl and substituted Cg-Cχ2 aryl;

(i) hydrogen, or (ii) a linear or branched, saturated or unsaturated hydrocarbon chain containing from 1-8 carbons, and optionaUy substituted with one or more substituents selected from the group consisting of: aryloxy, alkoxy, acyloxy, benzyloxy, substituted benzyloxy, N-acylamino, nitro, cyano, oxo, halogen, cydoalkyl, substituted cydoalkyl, C6-Cχ2aryl, substituted C6-Ci2aryl, hydroxy and protected hydroxy; R5 is

(i) hydrogen;

(ii) a linear or branched, saturated or unsaturated hydrocarbon chain containing from 1-8 carbons, and optionaUy substituted with one or more substituents selected from the group consisting of: aryloxy, alkoxy, acyloxy, amino, N-acylamino, nitro, cyano, oxo, halogen, cydoalkyl, substituted cydoalkyl, Cg-Cχ2aryl» substituted Cg-Cχ2aryl, hydroxy and protected hydroxy;

(iii) a non aromatic, unsaturated or saturate, cydic or polycydic C3-C8, optionaUy containing one or more substituents selected from the group consisting of: aryloxy, aryl, alkyl, alkoxy, acyloxy, cydoalkyl, substituted cydoalkyl, amino, N-acyl amino, nitro, cyano, oxo, hydroxy, halogen substituted aryl, substituted alkyl and protected -OH; or

(iv) a cydic or polycydic aromatic C3-C12. optionaUy containing one or more heteroatoms, provided that when C is 3 the aromatic ring contains at least two heteroatmos and when C is 4 the aromatic ring contains at least one heteroatom, and optionaUy substituted with one or more substituents selected from the group consisting of: aryloxy, cydoalkyl, substituted cydoalkyl, alkyl, Cg-Cχ2aryl, alkoxy, acyloxy, substituted C -Cχ2aryl, amino, N-acylamino, nitro, cyano, halogen, hydroxy, substituted alkyl and protected -OH;

R? is

(i) a linear or branched, saturated or unsaturated hydrocarbon chain containing from 1-12 carbons, and optionaUy substituted with one or more substituents selected from the group consisting of: aryloxy, benzyloxy, substituted benzyloxy, nitro, cyano, oxo, halogen, cydoalkyl, substituted cydoalkyl, Cg-Ci2aryl, substituted Cg-Cχ2aryl; and N 3R4 where 3 and R^ are eadi independently selected from the group consisting of: hydrogen, Cχ-Cg alkyl, substituted Cχ-Cgalkyl, C3-Cgcydoalkyl, substituted C3-C8 cydoalkyl, Cg-Cχ2^aryl and substituted Cg-Cχ2 aryl;

(ii) cydoalkyl is non aromatic, unsaturated or saturated, cydic or polycydic C3-C8, optionaUy containing one or more substituents selected from the group consisting of: aryloxy, aryl, alkyl, alkoxy, acyloxy, cydoalkyl, substituted cydoalkyl, amino, N-acyl amino, nitro, cyano, oxo, hydroxy, halogen substituted aryl, substituted alkyl and protected -OH;

(iii) aryl is cydic or polycydic aromatic C3-C12. optionaUy containing one or more heteroatoms, provided that when C is 3 the aromatic ring contains at least two heteroatmos and when C is 4 the aromatic ring contains at least one heteroatom, and optionaUy substituted with one or more substituents selected from the group consisting of: aryloxy, cydoalkyl, substituted cydoalkyl, alkyl, Cg-Ci2aryl, alkoxy, acyloxy, substituted Cg-Cχ2aryl, amino, N- acylamino, nitro, cyano, halogen, hydroxy, substituted alkyl and protected -OH;

(iv) benzyloxy or substituted benzyloxy;

(v) phenoxy or substituted phenoxy, or

(vi) 0-(C₂-C₄alkyl)-Cg-H5.

(6) Y-R8, where Y- is β-N-0- or = N-0- and R8 is a) a linear or branched, saturated or unsaturated hydrocarbon chain containing from 1-12 carbons, and optionaUy substituted with one or more substituents selected from the group consisting of: aryloxy, alkoxy, acyloxy, amino, N-acylamino, nitro, cyano, oxo, halogen, cydoalkyl, substituted cydoalkyl, Cg-Cχ2aryl, substituted Cg-Cχ2aryl, hydroxy and protected hydroxy; b) a non aromatic, unsaturated or saturated, cydic or polycydic C3~Cg, optionaUy containing one or more substituents selected from the group consisting of: aryloxy, aryl, alkyl, alkoxy, acyloxy, cydoalkyl, substituted cydoalkyl, amino, N-acyl amino, nitro, cyano, oxo, hydroxy, halogen substituted aryl, substituted alkyl and protected -OH; or c) a cydic or polycydic aromatic C3-C12, optionaUy containing one or more heteroatoms, provided that when C is 3 the aromatic ring contains at least two heteroatmos and when C is 4 the aromatic ring contains at least one heteroatom, and optionaUy substituted with one or more substituents selected from the group consisting of: aryloxy, cydoalkyl, substituted cydoalkyl, alkyl, C -Cχ2^aryl. alkoxy, acyloxy, substituted C -Cχ2^aryl. amino, N-acylamino, nitro, cyano, halogen, hydroxy, substituted alkyl and protected -OH;

(7) O R9 and β- *0 where R9 is a linear or branched, saturated or unsaturated hydrocarbon chain containing from 1-8 carbons, and optionaUy substituted with one or more substituents selected from the group consisting of: aryloxy, alkoxy, acyloxy, amino, N-acylamino, nitro, cyano, oxo, halogen, cydoalkyl, substituted cydoalkyl, Cg-C 2aryl. substituted Cg-Ci2aryl, hydroxy and protected hydroxy; and

RlO i_s -O-Rll where

Rll is hydrogen or Ci-Cgalkyl;

(9) α H and β-OTBDMS; (10) α H and β-OH;

(11) α H and β-CgH ;

(12) =CH₂;

where Rⁱ² is selected from the group consisting of hydrogen, Cχ-Cgalkyl, substituted Ci-Cgalkyl C3-Cgcydoalkyl, substituted C3-Cgcydoalkyl, Cg-Cχ2^aryl -nd substituted C -Cχ2aτyl;

; or

(15) oxo and pharmaceuticaUy acceptable salts, hydrates, solvates and esters thereof provided that when R is oxo P¹ and P² are not both hydrogen.

2. A compound of daim 1 in which R is absent or present as

(1) α H and β-O-R¹ where R is a) a linear or branched, saturated or unsaturated hydrocarbon chain ∞ntaining from 1-6 carbons, and optionaUy substituted with

Cg-Cχ2aryl or substituted Cg-Cχ2aryl;

(2)

O

B-C-R², where B is =A- where A is a linear or branched, saturated or unsaturated hydrocarbon chain containing from 1-4 carbons; and R² is a) a linear or branched, saturated or unsaturated hydrocarbon chain containing from 1-8 carbons, and optionaUy substituted with Cg-Cχ2aryl or substituted Cg-Cχ2aryl; or b) Cg-Ci2aryl or substituted Cg-Ci2aryl;

where * is selected from the group consisting of: hydrogen, Cχ-Cg alkyl, substituted Ci-Cgalkyl, Cg-Cχ2aryl, and substituted Cg-Cχ2aryl;

where Q is O or N-R⁶; wherein R is

(i) hydrogen, or

(ii) a linear or branched, saturated or unsaturated hydrocarbon chain containing from 1-4 carbons, and optionaUy substituted with one or more substituents selected from the group consisting of: aryloxy, benzyloxy and substituted benzyloxy; Rδ is

(i) hydrogen;

(ii) a linear or branched, saturated or unsaturated hydrocarbon chain containing from 1-3 carbons, and optionaUy substituted with Cg- Ci2aryl or substituted Cg-Cχ2aryl; (iii) Cg-Cχ2aryl; or (iv) substituted Cg-Cχ2aryl;

(5) α H and β-D-R⁷ where D is a linear or branched, saturated or unsaturated hydrocarbon chain containing from 1-4 carbons, and R^ is

(i) a linear or branched, saturated or unsaturated hydrocarbon chain containing from 1-12 carbons, and optionaUy substituted with one or more substituents selected from the group consisting of: aryloxy, benzyloxy, substituted benzyloxy, nitro, cyano, oxo, halogen, cydoalkyl, substituted cydoalkyl, Cg-Cχ2aryl, substituted Cg-Cχ2aryl; and NR^R⁴ where B? and ^ are each independently selected from the group consisting of: hydrogen, Cχ-Cg alkyl, substituted Cj-Cgalkyl, C3-Cgcydoalkyl, substituted C3-Cg cydoalkyl, Cg-Cχ2aryl and substituted Cg-Cχ2 ^aryl.

(ii) Cg-Cχ2aryl;

(iii) substituted Cg-Cχ2aryl; (iv) benzoyloxy or substituted benzyloxy; or

(v) phenoxy or substituted phenoxy;

(6) Y-R8, where Y- is β-N-0- or = N-0- and Rδ is a) a linear or branched, saturated or unsaturated hydrocarbon chain containing from 1-6 carbons, and optionaUy substituted with Cg-Ci2aryl or substituted Cg-Cχ2aryl; b) Cg-Cχ2aryl; or c) substituted Cg-Ci2aryl;

(7) α-R and β-R*0 where R^ is a linear or branched, saturated or unsaturated hydrocarbon chain containing from 1-3 carbons, and optionaUy substituted with Cg-Cχ2aτyl or substituted Cg-Cχ2aryl; and

RlO is -O-R¹¹ where Rl! is hydrogen or Cι-C3alkyl;

(9) α H and β-OTBDMS;

(10) α H and β-OH;

(11) α H and β-CgH₅;

where R ² is selected from the group consisting of Cχ-Cgalkyl and

Cg-Ci2aryl;

where Rl² is as defined above; or

(15) oxo and pharmaceuticaUy acceptable salts, hydrates, solvates and esters thereof provided that when R is oxo P* and P² are not both hydrogen.

3. A compound of daim 1 that is 17β-17-(benzyloxy)-estra-l,3,5(10)-triene-3-carboxyUc add, 17β-17-(2-propenyloxy)-estra-l,3,5(10)-triene-3-carboxyUc add,

[17β(E)]-17-[(3-phenyl-2-propenyl)oxy]-estra-l,3,5(10)-triene-3- carboxyUc add,

[17β(E)]-17-[(3-phenyl-propyl)oxy]-estra-l,3,5(10)-triene-3- carboxyUc add, [17β]-17-methoxy-estra-l,3,5(10Hriene-3-carboxyUc add,

17β-17-(benzyloxy)-androsta-3,5-diene-3-carboxyUc add, 17β-17-[(2-propenyl)oxy]-androsta-3,5-diene-3-carboxyUc add, 17β-17-methoxy-androsta-3,5-diene-3-carboxyUc add, (20E)-en-(22) phen ethyl -21-one-estra 1,3,5(10) triene -3- carboxyUc add,

(20E)-en-(22) phenyl -21-one estra 1,3,5(10) triene -3- carboxyUc add,

(20)β methyl -22- phenethyl 21-one estra l,3,5-(10)triene 3- carboxyUc add, (20)β methyl -22- phenyl 21-one estra l,3,5-(10)triene 3-carboxylic add,

17(20E)-ene-21-t-butylcarboxamide-estra-l,3,5(10)-triene-3- carboxyUc add,

17β-(t-butylacetamido) estra-l,3,5(10)-triene-3-carboxyUc add, Androsta-3,5-diene-3-carboxyUc add, Estra-l,3,5(10)-triene-3-carboxyUc add,

17β-(3-Oxo-4-phenyl-butyl)-estra-l,3,5(10)-triene-3-carboxyUc add, 17β-(5-methyl-3-oxo-l-hexenyl)-estra-l,3,5(10)-3-carboxyUc add, 17β-(tert- butylamido- ethylenyl) - estra- 1,3, 5(10)- triene - 3- carboxyUc add,

17β-(3-Oxo-3-phenyl-propyD-estra-l,3,5(10)-triene-3-carboxyUc add, 17β-17-(benzyloxy methyl)- estra-l,3,5(10)-triene-3-carboxyUc add, 17β(E) -17-(phenyl ethenyl)- estra-l,3,5(10)- triene- 3 -carboxyUc add,

17β(Z) -17-(phenyl ethenyl)- estra-l,3,5(10)- triene- 3 -carboxyUc add,

17β-17-(2-phenylethyl)-estra-l,3,5(10)-triene-3-carboxyUc add, O-benzyl oxime ether of 17-oxo-estra-l,3,5-triene-3-carboxyUc add,

O-benzyl oxime ether of 17-oxo- androsta- 3,5- diene- 3 -carboxyUc add,

O-t-butyl oxime ether of 17-oxo- androsta- 3,5- diene- 3 -carboxyUc add, 17β-(Phenyl)estra-l,3,5(10)triene-3-carboxyUc add,

(0-tertbutyloxine)estra-l,3,δ(10)-triene-3-carboxyUc add, (0-Phenyloxine)estra-l,3,5(10)-triene-3-carboxyUc add, keto- 16,16-diaUylestra-l,3,5(10)-triene-3-carboxyUc add, 17β-(N-teributoxyam__no)esta^-l,3,5(10)-triene-3-(»rboxylic add, 17β-(N-Ben__yloxyamino)estra-l,3,5(10-triene-3-carboxyUc add,

17β-[2-(5-Phenyloxazole)]estra-l,3,5(ld0)-triene-3-carboxyUc ^acid' 17β-[2-(N-Benzyloxymethyl) imidazolyl estra-l,3,5(10)-triene-3- carboxyUc add,

17β-[2-(5-Phenylimidazole)] estra - 1,3,5 (10) - triene- 3-carboxylic add,

17β-(2-Imidazolyl) estra - 1,3,5 (10)-triene-3-carboxylic add,

17β-(3-Oxo-3-phenyl-l-propenyl)-3-hydroxymethyl-estra-l,3,δ(10)- triene-3-carboxyUc add,

17β-(3-Oxo-4-phenyl-l-butenyl)-3-hydroxymethyl-estra-l,3,δ(10)- triene-3-carboxyUc add,

17β-(5-hydroxy,l,l,l,9,9,9 hexafluorononyl)androsta-3,5,diene-3- carboxyUc add, 17β-hydroxy- 17α-benzyl-estra-l,3,5(10)-triene-3-carboxyUc add, 17β-(t-butyl dimethyl silyl ether)androsta-3,δ-diene-3-carboxylic add, 17β-17-hydroxy-androsta-3,5-diene-3-carboxyUc add, 17β-17-hydroxy-estra-l,3,5(10 triene-3-carboxyUc add, O-phenyl oxime ether of 17-oxo-androsta-3,5-diene-3-carboxyUc add,

17β-methoxy-17α-benzyl-estra-l,3,5(10)-triene-3-carboxyUc add, 17β-[O-(N-phenylcarbamoyl)]estra-l,3,5(10)-triene-3-carboxyUc add, 17β-[O-(N-tert-butylcarbamoyl)]estra-l,3,5(10)-triene-3-carboxyUc add,

17β-[O-(N-benzylcarbamoyl)]estra-l,3,5(10)-triene-3-carboxyUc add,

17β-I^-(N-tertbutylurea)estxa-l,3,5(10Hriene-3-carboxyUc add, 17β-I^-(O-tert-butylcarbamoyl)]estra-l,3,5(10Hriene-3-carboxyUc add,

17β-[0-(N-phenylcarbamoyl)] androsta- l,3-diene-3-carboxyUc add, 17β-[0-(N-tert-butylcarbamoyl)3 androsta- l,3-diene-3-carboxyUc add, or 17β-[0-(N-benzylcarbamoyl)3 androsta-l,3,diene-3-carboxyUc add.

4. A compound according to daim 1 substantiaUy as hereinbefore defined with reference to anyone of the examples.

5. A pharmaceutical composition comprising a compound according to anyone of daims 1 to 3, and a pharmaceuticaUy acceptable carrier.

6. A compomid according to any one of claims 1 to 3 for use in therapy.

7. A compound according to any one of claims 1 to 3 in the manufacture of a medicament for use as a steroid 5-α-reductase inhibitor.

8. A compound according to any one of claims 1 to 3 in the manufacture of a medicament for use in treatment to reduce prostate size.

9. A compound according to any one of claims 1 to 3 in the manufacture of a medicament for use in treatment of prostatic adenocardnoma.

10. A process for preparing a pharmaceutical composition containing a pharmaceuticaUy acceptable carrier or diluent and an effective amount of a compound of the Formula (I) as described in claim 1 and pharmaceuticaUy acceptable salts, hydrates, solvates and esters thereof which process comprises bringing the compomid of the Formula (I) into assodation with the pharmaceuticaUy acceptable carrier or diluent.

11. Use of a compound according to any one of claims 1 to 3 in the manufacture of a medicament for use in inhibiting steroid 5-α- reductase.

12. A method of inhibiting steroid 5-α-reductase in mammals which comprises the administration to a mammal in need such inhibition, an effective amount of a compomid according to any one of daims 1 to 3.

13. The use of a compound according to anyone of daims 1 to 3 and an alpha-receptor antagonist compound as an active therapeutic substance which use consist of separate sequential or simultaneous administration of a compound according to anyone of daims 1 to 3 and an alpha-receptor antagonist compound.

14. The use of a compound according to anyone of daims 1 to 3 and an alpha-receptor antagonist compound in the manufadure of medicament for use in the treatment of benign prostatic hypertrophy which use consist of separate sequential or simultaneous administration of a compound according to anyone of claims 1 to 3 and an alpha-receptor antagonist compound.

15. The use of a compound according to anyone of daims 1 to 3 and minoxidil as an active therapeutic substance which use consist of separate sequential or simultaneous administration of a compound according to anyone of daims 1 to 3 and minoxidil.

16. The use of a compound according to anyone of daims 1 to 3 and minoxidil in the manufadure of a medicament for use in the treatment of male pattern baldness which use consist of separate sequential or simultaneous administration of a compound according to anyone of claims 1 to 3 and minoxidil.