SI9300601A - Pharmaceutical active 17-alpha and 17-beta substituted acyl-3-carboxy-3,5-diene steroidal compounds - Google Patents

Abstract

Invented are 17 alpha and 17 beta -substituted acyl-3-carboxy-3,5-diene analogues of steroidal synthetic compounds, pharmaceutical compositions containing these compounds, and methods for using these compounds to inhibit steroid 5- alpha -reductase. Also invented are intermediates and processes used in preparing these compounds.

Description

Fig. 9300601 (57) We have found 17alpha and 17beta-substituted acyl 3-carboxy-3,5-diene analogues of steroid synthetic compounds, pharmaceutical compositions containing these compounds, and methods for using these compounds to inhibit steroid 5-alpha reductase. We also found intermediates and processes used in the preparation of these compounds.

SmithKline Beecham Corporation

Pharmaceutically active 17a and 17/3 substituted acyl-3-carboxy-3,5-diene steroid compounds

The present invention relates to some novel 17a and 17/3 substituted acyl-3-carboxy-3,5-diene steroid compounds, to pharmaceutical compositions containing these compounds, and to methods of using these compounds to inhibit 5-a-reductase. we are also new intermediates and processes useful in the preparation of these compounds.

A class of steroid hormones, known as androgens, is responsible for the physical characteristics that make men different from women. These hormones are produced by the testicles in large quantities, among the various androgen-producing organs. Centers in the brain carry out primary control of androgen production levels. When the production of androgen hormones is caused by ineffective control, many physical manifestations and illnesses occur. With regard to increased androgen levels, e.g. acne vulgaris, seborrhea, female hirsutism, male pattern baldness and prostate disease, as benign prostatic hypertrophy. In addition, sessions have shown that a decrease in androgen levels has a therapeutic effect on prostate cancer.

Testosterone is the major androgen secreted by the testes and is the primary androgenic steroid in male plasma. 5-a-reduced androgen is now known to be an active hormone in some tissues, such as the prostate and sebaceous glands. Circulating testosterone thus serves as the prohormone for dihydrotestosterone (DHT), its 5-a-reduced analogue, in these tissues, but not in others, such as the muscles and testes. Steroid 5-a-reductase is a nicotinamidadenine dinucleotide phosphate (NADPH) -dependent enzyme that converts testosterone to DHT. The importance of this enzyme in the development of the male has dramatically highlighted the discovery of genetic steroid 5-a-reductase deficiency in male pseudohermaphrodites. Imperato-McGinley, J., et al., (1979), J. Steroid Biochem. 11: 637-648.

The recognition of the importance of elevated DHT levels in various disease states has stimulated a number of efforts to synthesize inhibitors of this enzyme. The most effective inhibitors identified to date are 3-carboxy-androst-3,5diene steroid derivatives.

Many 5-a-reductase inhibitors are known in the art. E.g.

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

2. Biochemistry (1990) Vol. 29, p. 2815-2824, M.A. Levy, et al, M.A. Levy, et al, describes a mechanism of enzymatic inhibitory interaction in inhibiting rat liver steroid 5-α-reductase with 3-androstene-3-carboxylic acids;

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

4. J. Steroid Biochem. Vol. 34, no. 1-6, p. 571-575 (1989), M.A. Levy, et al, describes an interaction mechanism between rat prostatic steroid 5-α-reductase and 3-carboxy-17β-substituted steroids;

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

6. TIPS (December 1989) Vol. 10, p. 491-495, D.W. Metcalf, et al, describes the effect of steroid 5a-reductase inhibitors on benign prostatic hyperplasia, male-type baldness and acne; and

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

8. EPO Publn. No. 0 343 954 A3, D.A. Holt, et al., (SmithKline Beckman), describes steroid derivatives of 3-carboxylic acids as useful 5-α-reductase inhibitors.

9. EPO Publn. No. 0 465 142 Al, G.H. Rasmusson, et al, (Merck & Co. Inc.) describes steroid derivatives of 3-carboxylic acids as useful 5α-reductase inhibitors.

However, none of the above references specifically suggest that any of the novel steroid 17- or 17/3-substituted acyl-3-carboxy-androst-3,5-diene compounds of the present invention would be useful as potent testosterone 5 -areductase inhibitors.

The present invention relates to a compound of formula I

where Z is a or β

Oh

II

-C-A-R wherein A is a straight or branched, saturated or unsaturated hydrocarbon chain containing from 1 to 12 carbon atoms; and R is substituted alkyl, cycloalkyl or aryl, wherein

a) substituted straight or branched alkyl, saturated or unsaturated hydrocarbon chains containing from 1 to 12 carbon atoms, substituted by one or more substituents selected from the group consisting of aryloxy, alkoxy, acyloxy, amino, N-acylamino, nitro , cyano, oxo, halogen, -C (O) OR ⁶ and -S (O) _n R ⁵ where

R ^{6 is} hydrogen or alkyl, n is 0-2 and is

R ^{5 is} hydrogen, cycloalkyl, C 6 -C 12 aryl, substituted cycloalkyl, substituted C 6 -C 12 aryl, alkyl or alkyl substituted with 1 or more substituents selected from the group consisting of alkoxy, acyloxy, amino, N-acylamino, oxo, hydroxy, cycloalkyl, substituted cycloalkyl, aryloxy, -C (O) OR ⁶ , -S (O) nR ⁷ , nitro, cyano, halogen, C ₆ -C ₁₂ aryl, substituted C ₆ -C ₁₂ aryl and protected -OH, where R ^{6 is} hydrogen or alkyl, n is 0-2 and R ^{7 is} hydrogen or alkyl;

b) cycloalkyl non-aromatic, unsaturated or saturated, cyclic or polycyclic C ₃ -C ₁₂ which optionally contains one or more heteroatoms and is optionally substituted by one or more substituents selected from the group consisting of aryloxy, aryl , alkyl, alkoxy, acyloxy, cycloalkyl, substituted cycloalkyl, amino, N-acylamino, nitro, cyano, oxo, hydroxy, halogen, -C (O) OR ⁶ , -S (O) nR ⁵ , protected -OH and alkyl, substituted with one or more substituents selected from the group consisting of: alkoxy, acyloxy, C6-C aryl, substituted C ₆ -C ₁₂ aryl, amino, N-acylamino, oxo, hydroxy, cycloalkyl, substituted cycloalkyl, -C (O ) OR ⁶ , -S (O) _n R ⁷ , aryloxy, nitro, cyano, halogen and protected -OH, where

R ^{6 is} hydrogen or alkyl, n 0-2,

R ⁷ is hydrogen or alkyl and is

R ^{5 is} hydrogen, cycloalkyl, C 6 -C 12 aryl, substituted cycloalkyl, substituted C 6 -C 12 aryl, alkyl or alkyl substituted with one or more substituents selected from the group consisting of alkoxy, acyloxy, cycloalkyl, substituted cycloalkyl, aryloxy, amino, N -acylamino, oxo, hydroxy, -C (O) OR ⁶ , -S (O) nR ⁷ , nitro, cyano, halogen, C ₆ -C ₁₂ aryl, substituted C ₆ -C ₁₂ aryl and protected -OH, where R ^{6 is} hydrogen or alkyl, n is 0-2 and R ^{7 is} hydrogen or alkyl; and

c) aryl is a cyclic or polycyclic aromatic C ₃ -C ₁₂ containing optionally one or more heteroatoms, provided that when C 3 contains an aromatic ring of at least 2 heteroatoms, and when C 4 contains an aromatic ring of at least one heteroatom, and optionally substituted by one or more substituents selected from the group consisting of aryloxy, cycloalkyl, substituted cycloalkyl, alkyl, C ₆ -C ₁₂ aryl, alkoxy, acyloxy, substituted C ₆ -C ₁₂ aryl, amino, N-acylamino, nitro, cyano, halogen, hydroxy, -C (O) OR ⁶ , -S (O) nR ⁵ , protected -OH and alkyl substituted with one or more substituents selected from the group consisting of alkoxy, acyloxy, C ₆ -C ₁₂ aryl, substituted C ₆ -C ₁₂ aryl, amino, N-acylamino, oxo, hydroxy, cycloalkyl, substituted cycloalkyl, -C (O) OR ⁶ , -S (O) _n R ⁷ , aryloxy, nitro, cyano, halogen and protected -OH where it is

R ^{6 is} hydrogen or alkyl, n is 0-2,

R ⁷ is hydrogen or alkyl and is

R ^{5 is} hydrogen, cycloalkyl, C 6 -C 12 aryl, substituted cycloalkyl, substituted C 1 -C 6 aryl, alkyl or alkyl substituted with one or more substituents selected from the group consisting of alkoxy, acyloxy, aryloxy, amino, N-acylamino, oxo, hydroxy, -C (O) OR ⁶ , -S (O) nR ⁷ , nitro, cyano, cycloalkyl, substituted cycloalkyl, halogen, C ₆ -C ₁₂ aryl, substituted C Caryl and protected -OH, where R ⁶ is hydrogen or alkyl, n is 0-2 and ^R7 is hydrogen or alkyl; and to their pharmaceutically acceptable salts, hydrates, solvates and esters.

The invention also provides a method of inhibiting 5-α-reductase activity in a mammal, including a human, comprising administering to an individual an effective amount of a 5-α-reductase inhibitory compound of the invention. A further aspect of the invention is novel intermediates and novel processes useful in the preparation of 5-α-reductase inhibitory compounds of the invention. Within the scope of the present invention, pharmaceutical compositions comprising a pharmaceutical carrier and compounds are useful in the processes of the invention. Also within the scope of the present invention are methods of co-administration of 5-α-reductase inhibitory compounds of the invention with further active ingredients.

The compounds of the present invention that inhibit 5-α-reductase have the following formula (I) /

where Z a ah β

Oh

II

-C-A-R wherein A is a straight ah branched, saturated or unsaturated hydrocarbon chain containing from 1 to 12 carbon atoms; and R is substituted alkyl, cycloalkyl or aryl, wherein

a) substituted straight or branched alkyl, saturated or unsaturated hydrocarbon chains containing from 1 to 12 carbon atoms, substituted by one or more substituents selected from the group consisting of aryloxy, alkoxy, acyloxy, amino, N-acylamino, nitro , cyano, oxo, halogen, -C (O) OR ⁶ and -S (O) _n R ⁵ where

R ^{6 is} hydrogen or alkyl, n is 0-2 and is

R ^{5 is} hydrogen, cycloalkyl, C 6 -C 12 aryl, substituted cycloalkyl, substituted C 6 -C 12 aryl, alkyl or alkyl substituted with 1 or more substituents selected from the group consisting of alkoxy, acyloxy, amino, N-acylamino, oxo, hydroxy, cycloalkyl, substituted cycloalkyl, aryloxy, -C (O) OR ⁶ , -S (O) nR ⁷ , nitro, cyano, halogen, C ₆ -C ₁₂ aryl, substituted C ₆ -C ₁₂ aryl and protected -OH, where R ^{6 is} hydrogen or alkyl, n is 0-2 and R ^{7 is} hydrogen or alkyl;

b) cycloalkyl non-aromatic, unsaturated or saturated, cyclic or polycyclic C ₃ C ₁₂ , which optionally contains one or more heteroatoms, and is optionally substituted by one or more substituents selected from the group consisting of aryloxy, aryl, alkyl, alkoxy, acyloxy, cycloalkyl, substituted cycloalkyl, amino, N-acylamino, nitro, cyano, oxo, hydroxy, halogen, -C (O) OR ⁶ , -S (O) nR ⁵ , protected -OH and alkyl substituted with one or more substituents selected from the group consisting of: alkoxy, acyloxy, C6-C ₁₂ aryl, substituted C ₆ -C ₁₂ aryl, amino, N-acylamino, oxo, hydroxy, cycloalkyl, substituted cycloalkyl, -C (O ) OR ⁶ , -S (O) _n R ⁷ , aryloxy, nitro, cyano, halogen and protected -OH, where

R ^{6 is} hydrogen or alkyl, n 0-2,

R ⁷ is hydrogen or alkyl and is

R ^is hydrogen, cycloalkyl, C6-C12aryl, substituted cycloalkyl, substituted C6-C12aryl, alkyl or alkyl substituted with one or more substituents selected from the group consisting of alkoxy, acyloxy, cycloalkyl, substituted cycloalkyl, aryloxy, amino, N -acylamino, oxo, hydroxy, -C (O) OR ⁶ , -S (O) nR ⁷ , nitro, cyano, halogen, C ₆ -C ₁₂ aryl, substituted C ₆ -C ₁₂ aryl and protected -OH, where R ^{6 is} hydrogen or alkyl, n is 0-2 and R ^{7 is} hydrogen or alkyl; and

c) aryl is cyclic ah polycyclic aromatic C ₃ -C ₁₂ which optionally contains one or more heteroatoms, provided that when C 3 contains an aromatic ring of at least 2 heteroatoms, and when C 4 contains an aromatic ring of at least one heteroatom, and optionally substituted by one or more substituents selected from the group consisting of aryloxy, cycloalkyl, substituted cycloalkyl, alkyl, C ₆ -C ₁₂ aryl, alkoxy, acyloxy, substituted C ₆ -C ₁₂ aryl, amino, N-acylamino, nitro, cyano, halogen, hydroxy, -C (O) OR ⁶ , -S (O) nR ⁵ , protected -OH and alkyl substituted with one or more substituents selected from the group consisting of alkoxy, acyloxy, C ₆ -C ₁₂ aryl, substituted C ₆ -C ₁₂ aryl, amino, N-acylamino, oxo, hydroxy, cycloalkyl, substituted cycloalkyl, -C (O) OR ⁶ , -S (O) _n R ⁷ , aryloxy, nitro, cyano, halogen and protected -OH where it is

R ^{6 is} hydrogen or alkyl, n is 0-2,

R ⁷ is hydrogen or alkyl and is

R ^{5 is} hydrogen, cycloalkyl, C 6 -C 12 aryl, substituted cycloalkyl, substituted C 6 -C 12 aryl, alkyl or alkyl substituted with one or more substituents selected from the group consisting of alkoxy, acyloxy, aryloxy, amino, N-acylamino, oxo, hydroxy , -C (O) OR ⁶ , -S (O) nR ⁷ , nitro, cyano, cycloalkyl, substituted cycloalkyl, halogen, C ₆ -C ₁₂ aryl, substituted C ₆ -C ₁₂ aryl and protected -OH, where R ^{6 is} hydrogen or alkyl, n is 0-2 and R ^{7 is} hydrogen or alkyl, and pharmaceutically acceptable salts, hydrates, solvates and esters thereof.

Preferred of the compounds of formula (I) of the invention are those wherein A is a straight or branched, saturated or unsaturated hydrocarbon chain containing from 2 to 12 atoms

Ί carbon.

Preferred compounds of the invention are those of the following formula (II)

wherein A is a straight or branched, saturated or unsaturated hydrocarbon chain containing from 1 to 12 carbon atoms; and R is substituted alkyl, cycloalkyl or aryl, wherein

a) substituted straight or branched alkyl, saturated or unsaturated hydrocarbon chains containing from 1 to 12 carbon atoms, substituted by one or more substituents selected from the group consisting of aryloxy, alkoxy, acyloxy, amino, N-acylamino, nitro , cyano, oxo, halogen, -C (O) OR ⁶ and -S (O) _n R ⁵ where

R ^{6 is} hydrogen or alkyl, n is 0-2 and is

R ^{5 is} hydrogen, cycloalkyl, C 6 -C 12 aryl, substituted cycloalkyl, substituted C 6 -C 12 aryl, alkyl or alkyl substituted with 1 or more substituents selected from the group consisting of alkoxy, acyloxy, amino, N-acylamino, oxo, hydroxy, cycloalkyl, substituted cycloalkyl, aryloxy, -C (O) OR ⁶ , -S (O) nR ⁷ , nitro, cyano, halogen, C ₆ -C ₁₂ aryl, substituted C ₆ -C ₁₂ aryl and protected -OH, where R ^{6 is} hydrogen or alkyl, n is 0-2 and R ^{7 is} hydrogen or alkyl;

b) cycloalkyl non-aromatic, unsaturated or saturated, cyclic or polycyclic C ₃ -C ₁₂ which optionally contains one or more heteroatoms and is optionally substituted by one or more substituents selected from the group consisting of aryloxy, aryl , alkyl, alkoxy, acyloxy, cycloalkyl, substituted cycloalkyl, amino, N-acylamino, nitro, cyano, oxo, hydroxy, halogen, -C (O) OR ⁶ , -S (O) nR ⁵ , protected -OH and alkyl, substituted with one or more substituents selected from the group consisting of: alkoxy, acyloxy, C6-C ₁₂ aryl, substituted C ₆ -C ₁₂ aryl, amino, N-acylamino, oxo, hydroxy, cycloalkyl, substituted cycloalkyl, -C ( O) OR ⁶ , -S (O) _n R ⁷ , aryloxy, nitro, cyano, halogen and protected -OH, where

R ^{6 is} hydrogen or alkyl, n 0-2,

R ⁷ is hydrogen or alkyl and is

R ^{5 is} hydrogen, cycloalkyl, C 6 -C 12 aryl, substituted cycloalkyl, substituted C 6 -C 12 aryl, alkyl or alkyl substituted with one or more substituents selected from the group consisting of alkoxy, acyloxy, cycloalkyl, substituted cycloalkyl, aryloxy, amino, N -acylamino, oxo, hydroxy, -C (O) OR ⁶ , -S (O) nR ⁷ , nitro, cyano, halogen, C ₆ -C ₁₂ aryl, substituted C ₆ -C ₁₂ aryl and protected -OH, where R ^{6 is} hydrogen or alkyl, n is 0-2 and R ^{7 is} hydrogen or alkyl; and

c) aryl is a cyclic or polycyclic aromatic C ₃ -C ₁₂ containing optionally one or more heteroatoms, provided that when C 3 contains an aromatic ring of at least 2 heteroatoms, and when C 4 contains an aromatic ring of at least one heteroatom, and optionally substituted by one or more substituents selected from the group consisting of aryloxy, cycloalkyl, substituted cycloalkyl, alkyl, C ₆ -C ₁₂ aryl, alkoxy, acyloxy, substituted C ₆ -C ₁₂ aryl, amino, N-acylamino, nitro, cyano, halogen, hydroxy, -C (O) OR ⁶ , -S (O) nR ⁵ , protected -OH and alkyl substituted with one or more substituents selected from the group consisting of alkoxy, acyloxy, C ₆ -C ₁₂ aryl, substituted C ₆ -C ₁₂ aryl, amino, N-acylamino, oxo, hydroxy, cycloalkyl, substituted cycloalkyl, -C (O) OR ⁶ , -S (O) _n R ⁷ , aryloxy, nitro, cyano, halogen and protected -OH where it is

R ^{6 is} hydrogen or alkyl, n is 0-2,

R ⁷ is hydrogen or alkyl and is

R ^{5 is} hydrogen, cycloalkyl, C 6 -C 12 aryl, substituted cycloalkyl, substituted C 6 -C 12 aryl, alkyl or alkyl substituted with one or more substituents selected from the group consisting of alkoxy, acyloxy, aryloxy, amino, N-acylamino, oxo, hydroxy , -C (O) OR ⁶ , -S (O) nR ⁷ , nitro, cyano, cycloalkyl, substituted cycloalkyl, halogen, C ₆ -C ₁₂ aryl, substituted C ₆ C ₁₂ aryl and protected -OH, where R ⁶ is hydrogen or alkyl, n is 0-2 and ^R7 is hydrogen or alkyl, and their pharmaceutically acceptable salts, hydrates, solvates and esters.

Among the compounds of formula II of the invention, preferred are those wherein A is a straight or branched saturated or unsaturated hydrocarbon chain containing 2 to 12 carbon atoms.

Among the compounds of formula II of the invention, preferred are those wherein A is a straight or branched, saturated or unsaturated hydrocarbon chain containing from 1 to 6 carbon atoms, and R

a) straight or branched, saturated or unsaturated hydrocarbon chain containing 1 to 12 carbon atoms substituted with one or more substituents selected from the group consisting of -OC ₆ -C ₁₂ aryl, carboxy, -OC _x -C ₄ alkyl, halogen and -S (O) _n R ⁷ wherein n is 0-2 and R ^{7 is} hydrogen or C 1 -C ₄ alkyl;

b) C ₃ 'Cg non-aromatic, unsaturated or saturated cycloalkyl optionally substituted by one or more substituents selected from the group consisting of -OC ₆ -C ₁₂ aryl, - (CH ₂ ) _m OH, -OCj-C C 1-6 alkyl, C ₆ -C ₁₂ aryl, C 1 -C 6 alkyl, trifluoromethyl, halogen, - (CH ₂ ) _p COOH, -S (O) _n R ⁷ and protected -OH, where m is 0-4, p 0 -3, n 0-2 and R ^{7 is} hydrogen or C 1-6 alkyl; or

c) C ₄ -C ₁₂ aryl, optionally containing one or more heteroatoms, provided that when C 4 contains an aromatic ring, at least one heteroatom, and optionally substituted by one or more substituents selected from the group , in which -OC ₆ -C ₁₂ aryl, - (CH ₂ ) _m OH, C ₆ -C ₁₂ aryl, C 1-6 alkyl, -OC ₁ -C ₆ alkyl, trifluoromethyl, halogen, - (CH 2 COOH, - S (O) _n ^R7 and protected -OH, where m is 0-4, p is 0-3, n is 0-2 and ^R7 is hydrogen or _C1 ^ _t alkyl; and their pharmaceutically acceptable salts, hydrates, solvates and esters.

Of these compounds of formula II, preferred are those wherein A is a straight or branched, saturated or unsaturated hydrocarbon chain containing from 2 to 6 carbon atoms.

Particularly preferred of the compounds of formula II are those wherein A is a straight or branched, saturated or unsaturated hydrocarbon chain containing 1 to 4 carbon atoms and R is

a) a straight or branched hydrocarbon chain containing 1 to 6 carbon atoms substituted by one or more halogens,

b) C ₃ -C _g non-aromatic, unsaturated or saturated cycloalkyl optionally substituted by one or more substituents selected from the group consisting of halogen, thio, methylsulfonyl, methylsulfoxyl, methylthio, carboxy, hydroxy, trifluoromethyl, phenoxy and methoxy , or

c) C ₄ -C ₁₂ aryl, optionally containing one or more heteroatoms, provided that when C 4 contains an aromatic ring, at least one heteroatom, and optionally substituted by one or more substituents selected from the group , which comprises halogen, thio, methylsulfonyl, methylsulfoxyl, methylthio, carboxy, hydroxy, trifluoromethyl, phenoxy and methoxy, and their pharmaceutically acceptable salts, hydrates, solvates and esters.

Of these compounds of formula II, preferred are those wherein A is a straight or branched, saturated or unsaturated hydrocarbon chain containing 2 to 4 carbon atoms.

Particularly preferred of the compounds of formula Ii are those wherein A is a straight or branched, saturated or unsaturated hydrocarbon chain containing from 1 to 4 carbon atoms, and R is

a) CF ₃

b) C ₅ -C ₇ cycloalkyl or

c) C ₄ -C ₁₂ aryl, optionally containing one or more heteroatoms, provided that when C 4 contains an aromatic ring, at least one heteroatom, and optionally substituted by one or more substituents selected from the group , which comprises halogen, thio, methylsulfonyl, methylsulfoxyl, methylthio, carboxy, hydroxy, trifluoromethyl, phenoxy and methoxy, and their pharmaceutically acceptable salts, hydrates, solvates and esters.

Of these compounds of formula II, preferred are those wherein A is a straight or branched, saturated or unsaturated hydrocarbon chain containing 2 to 4 carbon atoms.

Of the compounds of formula II, the following are particularly preferred:

17 / 3- (phenylpropylcarbonyl) -androsta-3,5-diene-3-carboxylic acid,

17 / 3- (Benzylcarbonyl) -androsta-3,5-diene-3-carboxylic acid,

17-8- (cyclohexylethylcarbonyl) -androsta-3,5-diene-3-carboxylic acid,

17 / 3- (phenethylcarbonyl) -androsta-3,5-diene-3-carboxylic acid,

17 / 3- (5,5,5-Trifluoro-1-oxopentyl) -androsta-3,5-diene-3-carboxylic acid, 17 / 3- (2-cyclohexyl-1-oxoethyl) -androsta-3,5 -diene-3-carboxylic acid, 17 / 3- (3-methyl-3-phenyl-1-oxobutyl) -androsta-3,5-diene-3-carboxylic acid, 17 / 3- (3- (4-methoxyphenyl) ) -1-Oxopropyl) -androsta-3,5-diene-3-carboxylic acid, 17 / 3- (3- (4-hydroxyphenyl) -1-oxopropyl) -androsta-3,5-diene-3-carboxylic acid , 17 / 3- (4-fluorophenylcarbonyl) -androsta-3,5-diene-3-carboxylic acid and 17 / 3- (2,6-difluorobenzylcarbonyl) -androsta-3,5-diene-3-carboxylic acid, and their pharmaceutically acceptable salts, hydrates, solvates and esters.

The term a, as used herein, follows standard chemical terminology and means downward or provides a suitable substituent below the plane of the paper.

The term / 3 as used herein follows standard chemical terminology and means pointing upwards or being a suitable substituent above the plane of the paper.

By the term protected hydroxy or protected -OH as used herein are meant alcohol or carboxyl -OH groups which may be protected by conventional blocking groups in the art, as described in Theodora W. Greene Protective Groups In Organic Synthesis, Wiley- Interscience, 1981, New York. Preferred are trior11 ganosilyl groups, e.g. t-butyldimethylsilyl, phenyldimethylsilyl, diphenylmethylsilyl and the like.

As used herein, C _x -C _{y means a} moiety having from x to y carbons.

The term aryl as used herein is intended, unless otherwise defined, to be cyclic or polycyclic aromatic C ₃ -C ₁₂ , optionally containing one or more heteroatoms, provided that when C 3 contains an aromatic ring at least two heteroatoms, and when C 4 contains an aromatic ring of at least one heteroatom and is optionally substituted by one or more substituents selected from the group consisting of alkyl, C ₆ -C ₁₂ aryl, substituted cycloalkyl, substituted C ₆ -C ₁₂ aryl, aryloxy, hydroxy, alkoxy, cycloalkyl, acyloxy, amino, N-acylamino, nitro, cyano, halogen, -C (O) OR ⁶ , -S (O) nR ⁵ , protected -OH and alkyl, substituted with one or more substituents selected from the group consisting of: alkoxy, acyloxy, C6-C ₁₂ aryl, substituted C ₆ -C ₁₂ aryl, amino, Nacilamino, oxo, hydroxy, cycloalkyl, substituted cycloalkyl, -C (O) oR ⁶ , -S (O) nR ⁷ , aryloxy, nitro, cyano, halogen and protected -OH, where R ^{6 is} hydrogen or alkyl, n is 0-2, R ⁷ is hydrogen or alkyl and R ⁵ is hydrogen, cycloalkyl, C6-C ₁₂ aryl, substituted cycloalkyl, substituted C ₆ -C ₁₂ aryl, alkyl aryl alkyl substituted by one or more substituents selected from the group consisting of: alkoxy, acyloxy, aryloxy, amino, N- acylamino, oxo, hydroxy, -C (O) OR ^6, -S (O) n R ^7, nitro, cyano, cycloalkyl, substituted cycloalkyl, halogen, C6-C ₁₂ aryl, substituted C ₆ -C ₁₂ aryl and protected -OH , where R ^{6 is} hydrogen or alkyl, n is 0-2 and R ^{7 is} hydrogen or alkyl.

Examples of aryl and substituted aryl substituents as used herein are: phenyl, naphthyl, furanyl, biphenyl, hydroxyphenyl, pyridyl, fluorophenyl, dihydroxyphenyl, dimethylhydroxyphenyl, methoxyphenyl, phenylphenyl, phenylphenyl, phenylphenyl, phenylphenyl, phenylphenyl, phenylphenyl, phenylphenyl, phenylphenyl, and thiophenyl.

Preferred examples of aryl and substituted aryl substituents as used herein are phenyl, 4-fluorophenyl, 2,6-difluorophenyl, 1-naphthyl, 4-biphenyl, 4-methoxyphenyl,

4-phenoxyphenyl, 4-trifluoromethylphenyl, 4-methylsulfonylphenyl, 4-methylthiophenyl, 3,5difluorophenyl, 4-hydroxyphenyl, 4-carboxyphenyl, 2-furanyl, 4-methylsulfoxylphenyl,

3-thiophenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and 3,4-methylenedioxyphenyl.

By the term C ₆ -C ₁₂ aryl as used herein is meant, unless otherwise defined, phenyl, naphthyl, 3,4-methylenedioxyphenyl, pyridyl or biphenyl.

By the term substituted as used herein, unless otherwise indicated, the chemical part in question is meant to have one or more substituents selected from the group consisting of hydroxyalkyl, alkoxy, acyloxy, alkyl, amino, N-acylamino, hydroxy, - ( CH ₂ ) _g C (O) OR ⁶ , -S (O) _n R ⁷ , nitro, cyano, halogen, trifluoromethyl and protected -OH, where g is 0-6, R ⁶ is hydrogen or alkyl, n is 0- 2 and R ^{7 is} hydrogen or alkyl.

By the term alkoxy as used herein is meant -Oalkyl wherein alkyl as described herein includes OCH ₃ and -O ^ CH ^ CH 2.

The term cycloalkyl, as used herein, unless otherwise defined, means non-aromatic, unsaturated or saturated, cyclic or polycyclic C ₃ -C ₁₂ .

Examples of cycloalkyl and substituted cycloalkyl substituents as used herein are cyclohexyl, 4-hydroxy-cyclohexyl, 2-ethylcyclohexyl, propyl4-methoxycyclohexyl, 4-methoxycyclohexyl, 4-carboxycyclohexyl and cyclopentyl.

By the term acyloxy, as used herein, is meant -OC (O) alkyl, where alkyl is as described herein. Examples of acyloxy substituents as used herein are -OC (O) CH ₃ , -OC (O) CH (CH _; ) _2, and -OC (O) (CH ₂ ) ₃ CH. _r

By the term N-acylamino, as used herein, is meant -N (H) C (O) alkyl, where alkyl is as described herein. Examples of N-acylamino substituents as used herein, are -NCHj OjCH ^ ^ N (H) C (O) CH (CH _{3) 2} and -N (H) C (O) (CH _{2) 3} CH _third

By the term aryloxy, as used herein, is meant -OC ₆ -C ₁₂ aryl, wherein C ₆ -C ₁₂ aryl is phenyl, naphthyl, 3,4-methylenedioxyphenyl, pyridyl or biphenyl optionally substituted by one or more substituents selected from the group consisting of alkyl, hydroxyalkyl, alkoxy. trifluoromethyl, acyloxy, amino, N-acylamino, hydroxy, - (CH ₂ ) _g C (O) OR ⁶ , -S (O) _n R ⁷ , nitro, cyano, halogen and protected -OH, where g is 0-6 , R ⁶ is hydrogen or alkyl, n is 0-2 and R ^{7 is} hydrogen or alkyl. Examples of aryloxy substituents as used herein are 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 its derivatives, and in all carbon chains as used herein, a straight or branched, saturated or unsaturated hydrocarbon chain having C _x -C ₁₂ carbon atoms is meant. Examples of alkyl substituents as used herein are -ch ₃ , -ch ₂ -ch ₃ , -CH ₂ -CH ₂ -CH ₃ , -CH (CH ₃ ) ₂ , -C (CH ₃ ) ₃ , - (CH ₂ ) ₃ -CH ₃ , -CH ₂ -CH (CH ₃ ) _2, and -CH (CH ₃ ) -CH ₂ -CH ₃ , -01 = (¾.

By the term treatment and its derivatives as used herein is meant prophylactic or therapeutic therapy.

By the term metal-catalyzed coupling reaction, as used herein, it is meant that the prepared 3-trifluoromethylsulfonylate or 3-fluorosulfonylate compound is reacted in a suitable organic solvent; preferably dimethylsulfoxide, toluene, dichloroethane, dimethylformamide or THF; with a base, preferably a tertiary amine base, such as triethylamine, pyridine or tributylamine; C 1 -C 4 alcohol (when ester is desired) or a C 1 -C 4 carboxylic acid salt, preferably KOAc (when acid is desired), and phosphine, such as bis (diphenylphosphino) alkane, preferably 1,3-bis (diphenylphosphino) propane, three -o-toliphosphine or 1,1-bis (diphenylphosphino) ferrocene (dppf), and metal catalysts, preferably palladium catalysts such as palladium (II) acetate or palladium (II) chloride ah bis (triphenylphosphine) palladium (II) acetate, forming a metal complex and then the coupling reagent is added.

By the term coupling reagent, as used herein, is meant a compound that is capable of reaction with this metallic complex to form an ester or carboxylic acid substituent. A preferred coupling reagent is carbon monoxide which, upon addition to a metal catalyzed coupling reaction as described herein, gives the desired ester or carboxylic acid group.

The compounds of formula (I) and the compounds of formula (V) are included in the pharmaceutical compositions of the invention and are used in the processes of the invention. When a -COOH or -OH group is present, pharmaceutically acceptable esters may be used, e.g. such as methyl, ethyl, pivoloyloxymethyl 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 preparations ah prodrugs.

The term α-receptor antagonist, as used herein, refers to a known class of α-adrenergic receptor antagonist compounds, as described in Laffertv, et al.

U.S. Pat. No. 4,963,547 used in the treatment of vascular disorders such as diabetes, cardiovascular disease, benign prostatic hypertrophy and ocular hypertension.

Preferred α-adrenergic receptor antagonists for use in the compositions and methods of the invention are amzulosin, terazosin, doxazosin, alfuzosin, indoramine, prazosin, 7-chloro-2-ethyl-3,4,5,6-tetrahydro-4-methylthieno [ 4,3,2-ef] [3] benzazepine and

8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -3-methyl-4-oxo-2-phenyl-4H-1-benzopyran.

By the term amzulosin, as used herein, is meant a compound of structure

and its soy, hydrates and solvates.

Chemically, amzulosin is designated (-) - (R) -5- [2 - [[2- (O-ethoxyphenoxy) ethyl] amino] propyl] -2-methoxybenzenesulfonamide.

Amzulosin is described in U.S. Pat. No. 4,703,063 and is required to be protected by U.S. Pat. No. 4,987,152 for use in the treatment of lower urinary tract dysfunction.

By the term terazosine, as used herein, is meant a compound of structure

and its salts, hydrates and solvates.

Chemically, terazosine is designated 1- (4-amino-6,7-dimethoxy-2-quinazolinyl) -4 [(tetrahydro-2-furoyl) carbonyl] piperazine. Terazosine is described in U.S. Pat. No. 4,251,532.

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

and its salts, hydrates and solvates.

Chemically, doxazosin is designated 1- (4-amino-6,7-dimethoxy-2-quinazolinyl) -4 [(2,3-dihydro-1,4-benzodioxin-2-yl) carbonylpiperazine.

Doxazosin is described in U.S. Pat. 4,188,390,

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

and its salts, hydrates and solvates.

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

Alfuzosine is described in U.S. Pat. No. 4,315,007.

By the term indoramine, as used herein, is meant a compound of the formula

H

and its salts, hydrates and solvates.

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

Indoramine is described in U.S. Pat. 3,527,761.

By the term prazosine, as used herein, is meant a compound of formula

and its soy, hydrates and solvates.

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

The blank is described in U.S. Pat. 3,511,836 th most common

7-Chloro-2-ethyl-3,4,5,6-tetrahydro-4-methylthieno [4,3,2-ef | [3] benzazepine, as used herein, is a compound of the structure

7-Chloro-2-ethyl-3,4,5,6-tetrahydro-4-methylthieno [4,3,2-ef] [3] benzazepine is described in U.S. Pat. No. 5,006,521. In addition, all the compounds described in U.S. Pat.

No. 5,006,521 as α-adrenergic receptor antagonists, preferred α-adrenergic receptor antagonists as used herein.

8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -3-methyl-4-oxo-2-phenyl4H-1-benzopyran, as used herein, is a compound having the structure o

and its salts, hydrates and solvates. h

8- {3- [4- (2-Methoxyphenyl) -1-piperazinyl] -propylcarbamoyl} -3-methyl-4-oxo-2-phenyl4H-1-benzopyran is described in EPO Publ. no. 0558245 Al, Leonardi, et al., (Record

SA).

In addition, all the compounds described in EPO Publn no. 0558245 Al as α-adrenergic receptor antagonists, the preferred α-adrenergic receptor antagonist as used herein.

One skilled in the art can readily determine if a compound other than the compound specifically referenced herein is an α-adrenergic receptor antagonist using the assay described in Lafferty I. Thus, all such compounds are included within the scope of the expression α -adrenergic receptor antagonist as used herein.

By the term minoxidil, as used herein, is meant a compound of formula

Ο

chemically, minoxidil is designated 2,4-pyrimidinadiamine, 6- (1-piperidinyl) -, 3oxide. Minoxidil is the active ingredient in Rogain® sold by Upjohn Company, Kalamazoo, Michigan, as a topical solution for stimulating hair growth.

The term aromatase inhibitor, as used herein, refers to a known class of compounds, steroidal and nonsteroidal, which prevent the conversion of androgens to estrogens, as described in Gormley et al., International Publication no. WO 92/18132. Gormley et al. describes that aromatase inhibitors are useful in the treatment of benign prostatic hyperplasia when used in combination with a 5-a-reductase inhibitor.

A preferred aromatase inhibitor for use in the compositions and methods of the invention is 4- (5,6,7,8-tetrahydroimidazo [1,5-a] pyridin-5-yl) benzonitrile (fadrazole). Fadrazole is described in U.S. Pat. No. 4,728,645. In addition, all of the compounds for which Gormley et al., International Publication no. WO 92/18132, described to have aromatase inhibitory activity, 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 used together, this 5-α-reductase inhibitor can be co-administered with this further active ingredient or ingredients.

The term co-administration and derivatives thereof, as used herein, means either the simultaneous administration or by any means of separately sequentially administering a 5-a-reductase inhibitory compound as described herein, and further active ingredients or ingredients such as other compounds, known to treat conditions of acne, seborrhea, female hirsutism, male baldness, benign prostatic hypertrophy or prostatic adenocarcinoma, or a compound known to be useful when used in combination with 5-a-reductase inhibitors. If the administration is not simultaneous, the compounds are preferably administered immediately one after the other. Furthermore, it is not important to administer the compounds in the same dosage form, e.g. one compound may be administered topically and the other compound may be administered orally.

The compounds of formula (II) are prepared as shown in Schemes I, II and III, wherein A is as described in formula (II). As used herein, R ^{8 is} R or moieties which can be converted to moieties of R by chemical reactions well known to those skilled in the art, as described in Derek Barton and UD Ollis, Comprehensive Organic Chemistry: The Svnthesis and Reactions of Organic Compounds , Pub: Pergamon Press (1979), provided that R ⁸ does not include any such proportions that make it impossible to carry out the procedures of Schemes I, II or III. As shown in the following examples, reactions are performed to convert R ⁸ to R on the products of the synthetic routes of Schemes I, II or III, or, where appropriate or preferred, at certain intermediates in these synthesis routes. E.g. methylthio substituents can be converted to methylsulfonyl by oxidation. The methoxy substituents can be converted to hydroxy by treatment with boron tribromide. Hydroxy substituents can be converted to carboxy by reaction with a trihaloalkyl sulfone anhydride such as trifluoromethane sulfone anhydride, followed by a metal catalyzed coupling reaction.

The new compounds of formula (II) of the present invention can be prepared according to the procedures shown in Schemes I-III below and, in the examples, from a known and readily available steroid acid of structure (X)

Scheme I

Oh

(d)

Scheme I shows the formation of compounds of formula II. As used in Scheme I, compound (b) of compound (a) is prepared by treating (a) with the halogen-Vilsmeier reagent described below in a suitable solvent, preferably methylene chloride, followed by quenching with the excess Grignard reagent described below. The 3-cyano derivative (c) is produced by treatment (b) with the cyanide reagent described below, in a suitable solvent, preferably dimethyl formamide. The 17-acyl derivative (c) was saponified as described below to give compounds (d).

Scheme II

G ^ alkO ^ C (i)

R '(0

NC

Scheme II shows the formation of compounds of formula II. As used in Scheme II, A and R ⁸ are as described in Formula IV, R ¹ is CF ₃ O ₂ SO- or FO ₂ SO-. As used in Scheme II in the alkyl process (step C), the pyridylthio ester is reacted with Li-AR ⁸ or XMgAR ⁸ (X = C1, Br) Grignard reagent (as described below), preferably phenylpropylmagnesium bromide, benzylmagnesium chloride, cyclohexylethylmagnesium magnesium , 4-fluorophenethylmagnesium bromide, phenethylmagnesium bromide, 2,2-dimethylphenethylmagnesium bromide, cyclohexylmethylmagnesium bromide, 4,4,4-trifluorobutylmagnesium bromide, 2- (4methoxyphenyl) -ethylmagnesimide-tetrahydrothiazole chloride-azidomersulfonamide , preferably 17/3 (phenylpropylcarbonyl) -androsta-3,5-diene-3-carboxylic acid, 17 / 3- (benzylcarbonyl) androsta-3,5-diene-3-carboxylic acid, 17 / 3- (cyclohexylethylcarbonyl) - 3,5-diene-3-carboxylic acid, 17 / 3- (4-fluorophenylcarbonyl) -androst-3,5-diene-3-carboxylic acid, 17/3-phenethylcarbonyl) -androst-3,5-diene-3-carboxylic acid acid, 17 / 3- (3-methyl-3-phenyl-1-oxobutyl) -androsta-3, 5-Diene-3-carboxylic acid, 17 / 3- (2cyclohexyl-1-oxoethyl) -androsta-3,5-diene-3-carboxylic acid, 17 / 3- (5,5,5-trifluoro-oxopentyl) - androsta-3,5-diene-3-carboxylic acid, 17 / 3- (3- (4-methoxyphenyl) 1-oxopropyl) -androsta-3,5-diene-3-carboxylic acid, resp. 17 / 3- (2,6difluorobenzylcarbonyl) -androsta-3,5-diene-3-carboxylic acid in one or two steps.

In route 1, one acid (a) is converted to 3-trifluoromethylsulfonylate or 3-fluorosulfonylate derivative (e) (step A) by treatment (a) with trifluoromethylsulfonyl anhydride ah with fluorosulfonic anhydride and an amine base such as pyridine, preferably 2,5-diridine tbutyl-3-methyl-pyridine, in a suitable organic solvent, preferably dichloromethane, at about -20 ° C to 20 ° C, preferably 0 °.

The activated ester (f) is produced (step B) by treatment (e) with 2,2-dithiopyridyl and triphenylphosphine in a suitable solution of an organic solvent, preferably tetrahydrofuran / toluene, at room temperature for about 8 to 14 hours.

The 17-acyl derivative (g) is produced (step C) by treatment (f) with the Grignard reagent described below in solvent tetrahydrofuran or diethyl ether at a temperature of about -50 to -70 ° for 1 to 16 hours.

3-alkyl ester (j) is produced (step D) by treatment (g) under carbonylation conditions, preferably by bubbling gas carbon monoxide through a solution (g) in a suitable organic solvent, preferably methanol containing a palladium acetate catalyst, triphenylphosphine and a tert.organic amine, preferably triethylamine, at about room temperature for 1 to 16 hours. Compound (j) is then reacted with a primed base, preferably potassium carbonate, and acidified (step F) to give compounds (d).

Compounds (d) can also be produced (step H) by treatment (g) under carbonylation conditions, preferably by bubbling gas carbon monoxide through solution (d) in a suitable non-alcoholic solvent, preferably DMF containing a palladium catalyst, preferably bis (triphenylphosphine) ) palladium II diacetate, and a carboxylate salt, preferably potassium acetate, preferably at elevated temperatures.

It should be appreciated that if R ^{8 is an} aroyl which also contains a protected hydroxy group, e.g. with dimethyl-t-butylsilyl, which can be removed by treatment with tetrabutylammonium fluoride in a suitable organic solvent, preferably tetrahydrofuran, with a small amount of acetic acid added from 0 ° C to reflux for 1 to 4 hours before performing step F.

Route 2 involves the conversion of the starting steroid acid (a) into 3-trifluoromethylsulfonylate or 3-fluorosulfonylate derivative (e) with step A described above; carbonylation (e) in (h) with grade D; formation of activated B-level 2-pyridylthio ester (i); formation of a 17-acyl compound (j) with stage C; and hydrolysis of the 3-ester into the 3-acid end product (d) by step

F.

Route 3 involves the conversion of the starting steroid acid (a) into 3-trifluoromethylsulfonylate or

3-Fluorosulfonylate derivative (s) with step A described above The 3-cyano derivative (k) is produced (step E) by treatment (s) with a cyanide agent (as described below) in a suitable solvent, preferably dimethylformamide. The activated 2-pyridylthio derivative (L) is prepared from (k) with step B. The formation of 17-acyl compound (c) involves the metabolism (1) with step C. The 17-acyl derivative (c) is soaped (step G) (as here described) to give compounds (d).

Scheme III

(d)

Scheme III shows the formation of compounds of formula II.

As used in Scheme III, compound (1) is prepared from compound (k) by treatment with phosphorus oxychloride in toluene, followed by treatment with methanol.

Compounds of formula (1) are reacted with a reducing agent, preferably diisobutyl aluminum hydride, to give compounds of formula (m).

The compounds of formula (n) are prepared by treating the compounds of formula (m) with Grignard reagent (as described in Scheme II) in solvent tetrahydrofuran ah diethyl ether at a temperature of about -50 ° C to -70 ° C for 1-16 hours.

The compounds of formula (o) are prepared by oxidizing compounds of formula (n). Preferably, tetrapropylammonium perutenate or Jone's reagent will be used for this oxidation.

Compounds of formula (d) are prepared by oxidizing compounds of formula (o). Preferably, sodium chlorite will be used in this oxidation.

As used herein, Grignard reagents of the XMgAR ⁸ type are available for all compounds within the scope of the present invention or can be provided by one skilled in the art.

E.g. when AR ^{8 is} hydroxyphenyl, it can be obtained starting with suitable bromophenol, e.g. p-bromophenol, with the protection of phenolic -OH with a conventional blocking group, e.g. triiorganosilyl, i.e. t-butyldimethylsilyl, performing the Grignard reaction and then unblocking the silyl group using e.g. of refluxing aqueous tetrabutylammonium fluoride.

For AR ⁸ , when hydroxyethyl is phenyl, the same blocking procedure can be performed analogously, starting with a suitable hydroxyalkyl bromophenol, e.g. p-hydroxymethylbromobenzene or p-hydroxymethylbromobenzene or p-hydroxyethylbromobenzene.

When AR ^{8 is} carboxyphenyl, it can be obtained by oxidation of suitable hydroxymethylbenzene, e.g. p-Bromo-hydroxymethylbenzene obtained as described above with chromic acid.

Where AR is ⁸ -O alkyl, a suitable bromo27 is used for the Grignard reaction

Oalkylbenzene e.g. p-methoxybromobenzene.

Other halogen substituted benzenes for the formation of a suitable Grignard reagent useful in the present invention will be apparent to those skilled in the art from the present description.

Compounds of formula I wherein Z is in position a is prepared from compounds containing the corresponding β-substituent following the general procedure below.

General procedure A

To a mixed solution of substituted 17/3-steroidal, 5α-reductase inhibiting compound of formula (II) in a suitable solvent, preferably ethylene glycol or dimethylsulfoxide, is added a base such as hydroxide or alkoxide base, preferably sodium hydroxide, potassium hydroxide or sodium methoxide, at a temperature of above 100 ° C, preferably at reflux temperatures, to obtain the corresponding α-epimer after isolation and completion.

Dimethylsulfoxide or other high boiling point nonreactive solvents are preferred in determining the appropriate epimerization solvent if the starting 17/3, 5a-reductase inhibitory steroid compound contains reactive substituents or reactive unsaturated bonds, eg subjected to nucleophilic attack, and ethylene glycol other high boiling point reactive solvents may be used when the reactivity of the substituents or any unsaturated bonds of the parent 17/3, 5α-reductase inhibiting steroid compound need not be considered.

Also within the scope of the present invention are ketone reducing products of compounds of formula (I), second alcohols of formula

where Y is a or β

OH ί

-C-A-R wherein A is a straight or branched, saturated or unsaturated hydrocarbon chain containing from 1 to 12 carbon atoms; and R is substituted alkyl, cycloalkyl or aryl, wherein

a) substituted straight or branched alkyl, saturated or unsaturated hydrocarbon chains containing from 1 to 12 carbon atoms substituted with one or more substituents selected from the group consisting of aryloxy, alkoxy, acyloxy, amino, N-acylamino, nitro, cyano, oxo, halogen, -C (O) OR ⁶ and -S (O) _n R ⁵ where

R ^{6 is} hydrogen or alkyl, n is 0-2 and is

R ^{5 is} hydrogen, cycloalkyl, C 6 -C 12 aryl, substituted cycloalkyl, substituted C 6 -C 12 aryl, alkyl or alkyl substituted with 1 or more substituents selected from the group consisting of alkoxy, acyloxy, amino, N-acylamino, oxo, hydroxy, cycloalkyl, substituted cycloalkyl, aryloxy, -C (O) OR ⁶ , -S (O) nR ⁷ , nitro, cyano, halogen, C ₆ -C ₁₂ aryl, substituted C ₆ -C ₁₂ aryl and protected -OH, where R ^{6 is} hydrogen or alkyl, n is 0-2 and R ^{7 is} hydrogen or alkyl;

b) cycloalkyl non-aromatic, unsaturated or saturated, cyclic or polycyclic C ₃ -C ₁₂ , and optionally containing one or more heteroatoms which is optionally substituted by one or more substituents selected from the group consisting of aryloxy, aryl , alkyl, alkoxy, acyloxy, cycloalkyl, substituted cycloalkyl, amino, N-acylamino, nitro, cyano, oxo, hydroxy, halogen, -C (O) OR ⁶ , -S (O) nR ⁵ , protected -OH and alkyl, substituted with one or more substituents selected from the group consisting of: alkoxy, acyloxy, C6-C ₁₂ aryl, substituted C ₆ -C ₁₂ aryl, amino, N-acilamirio, oxo, hydroxy, cycloalkyl, substituted cycloalkyl, -C ( O) OR ⁶ , -S (O) _n R ⁷ , aryloxy, nitro, cyano, halogen and protected -OH, where

R ^{6 is} hydrogen or alkyl, n 0-2,

R ⁷ is hydrogen or alkyl and is

R ^{5 is} hydrogen, cycloalkyl, C 6 -C 12 aryl, substituted cycloalkyl, substituted C 6 -C 12 aryl, alkyl or alkyl substituted with one or more substituents selected from the group consisting of: alkoxy, acyloxy, cycloalkyl, substituted cycloalkyl, aryloxy, amino, N-acylamino, oxo, hydroxy, -C (O) OR ⁶ , -S (O) nR ⁷ , nitro, cyano, halogen, C ₆ -C ₁₂ aryl, substituted C ₆ -C ₁₂ aryl and protected -OH, where R ^{6 is} hydrogen or alkyl, n is 0-2 and R ^{7 is} hydrogen or alkyl; and

c) aryl is a cyclic or polycyclic aromatic C ₃ -C ₁₂ containing optionally one or more heteroatoms, provided that when C 3 contains an aromatic ring of at least 2 heteroatoms, and when C 4 contains an aromatic ring of at least one heteroatom, and optionally substituted by one or more substituents selected from the group consisting of aryloxy, cycloalkyl, substituted cycloalkyl, alkyl, C ₆ -C ₁₂ aryl, alkoxy, acyloxy, substituted C ₆ -C ₁₂ aryl, amino, N-acylamino, nitro, cyano, halogen, hydroxy, -C (O) OR ⁶ , -S (O) nR ⁵ , protected -OH and alkyl substituted with one or more substituents selected from the group consisting of alkoxy, acyloxy, C6-C ₁₂ aryl, substituted C ₆ -C _J2 aryl, amino, N-acylamino, oxo, hydroxy, cycloalkyl, substituted cycloalkyl, -C (O) OR ^6, -S (O) _n R ^7, aryloxy, nitro, cyano, halogen and protected -OH where it is

R ^{6 is} hydrogen or alkyl, n is 0-2,

R ⁷ is hydrogen or alkyl and is

R ^{5 is} hydrogen, cycloalkyl, C ₆ -C ₁₂ aryl, substituted cycloalkyl, substituted C ₆ -C ₁₂ aryl, alkyl or alkyl substituted with one or more substituents selected from the group consisting of alkoxy, acyloxy, aryloxy, amino, N-acylamino, oxo, hydroxy, -C (O) OR ^6, -S (O) n R ^7, nitro, cyano, cycloalkyl, substituted cycloalkyl, halogen, C6-C ₁₂ aryl, substituted C ₆ -C ₁₂ aryl and protected -OH, where R ^{6 is} hydrogen ah alkyl, n is 0-2 and R ^{7 is} hydrogen or alkyl, and pharmaceutically acceptable salts, hydrates, solvates and esters thereof.

Of the ketone reduction products of the invention described above, those where A is a straight or branched saturated or unsaturated hydrocarbon chain containing 2 to 12 carbon atoms are preferred.

Among the ketone reduction products of the invention described above, alcohols are particularly preferred, and Iger is 17

OH

I

I

-C-A-R substituent bound in position β.

These compounds can be prepared by conventional reduction of carbonyl bound to A without epimerization or reduction of the carboxyl in ring A or 3,5-double bonds, with sodium borohydride. If the R substituent contains a carbonyl function, it can be selectively blocked and subsequently regenerated after reduction with borohydride by conventional methods.

Reduction with borohydride can be carried out e.g. in water or aqueous methanol at room temperature to 50 ° C and the product is then isolated and purified in the usual way. The compounds are also active as 5-reductase inhibitors.

By the term halogen-Wilsmeie reagent, as used herein, is meant a halogenated disubstituted formamide reagent having the structure

wherein R ⁹ and R ^{10 are} independently selected from an alkyl, aryl or arylalkyl group; X is Br or I; y is an amphoteric ion prepared by z

a) reaction, preferably at reduced temperatures, of a chloride source, such as oxalyl chloride or thionyl chloride, with a disubstituted formamide reagent, such as a dialkyl substituted formamide reagent, preferably dimethylformamide, in a suitable solvent, preferably methylene chloride, to give chloro-ethyl reagent, the chloro-Vilsmeier reagent is reacted in situ, preferably at reduced temperatures, with a bromide or iodide source, preferably with a gas bromide, or

b) reaction, preferably at reduced temperatures, of a bromide or iodide source, preferably oxalyl bromide, with a disubstituted formamide reagent, such as a dialkyl substituted formamide reagent, preferably dimethyl formamide in a suitable solvent, preferably methylene chloride.

By the term reduced temperature as used herein is meant below 25 ° C, preferably between -15 and 15 ° C, most preferably between 0 and 10 ° C.

By the term cyanate reagent as used herein, and the claims, a compound is meant ah reagents capable of reacting with a halogenated moiety to form a cyanoyl moiety, under suitable conditions.

Preferably, this cyanide moiety is prepared by reacting a suitable halogenated moiety with a cyanide agent in a suitable solvent such as N, N-dimethyl-N, N-propylene urea (DMPU), Ν, Ν-dimethylformamide (DMF) or N-methyl-2- pyrrolidinone (NMP), preferably DMF, at elevated temperatures.

The term saponifiers and derivatives thereof, as used herein and in the claims, means ah reagent ah a type of reagent capable of reaction with nitrile to form a carboxylic acid substituted moiety under suitable conditions. Preferably, the carboxylic acid substituted moiety is prepared by reacting the corresponding cyanoated moiety with a hydroxide base, preferably aqueous sodium hydroxide, in a suitable solvent such as ethylene glycol, isopropyl alcohol or ethanol, preferably ethanol, at elevated temperatures with subsequent acidification.

The term "elevated temperature" as used herein and in the claims is meant above 25 ° C, preferably at reflux temperatures.

Preferably, cyanide complexes are used as cyanide reagents for use in the methods described herein, as described in Richard C.Larock. Comprehensive Organic Transformations: A. A Guide to Functional Group Preparations. Pub: VCH Publishers, Inc. (1989) P. 861. An example of a cyanide complex as used herein is the in situ co-mixture of KCN, NiBr ₂ (PPh ₃ ) ₂ , Zn, PPh ₃ . Other examples are Co (CN) ³ '4; K4Ni2 (CH) 6, KCN; KCN, floor Pd (PPh3) 4; Co (CN) ³ 5; CuCN and NaCu (CN) ₂ . As used herein, the term NaCu (CN) ₂ refers to the reagent obtained by co-mixing CuCN and NaCN in situ.

Of the above cyanir complexes, CuCN and NaCu (CN) ₂ are preferred.

Of the above cyanide complexes, NaCu (CN) ₂ is particularly preferred.

This NaCu (CN) ₂ complex is preferably prepared by the addition of 1 molar equivalent of sodium cyanide to copper (I) cyanide in situ.

By the term solvent or a suitable solvent, as used herein and 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 the compounds of formula (I) and formula (V) are formed, where appropriate, by methods known to those skilled in the art.

In preparing the compounds of formula (I) of the invention, new intermediates of the following formula (III) are synthesized.

(III) wherein R ^{2 is} 2-thiopyridylcarbonyl and R ^{3 is} fluorosulfonyloxy or cyano.

In the synthesis of the compounds of formula (I) of the invention, new intermediates of formula (IV) have also been prepared

Oh

wherein A is defined as in Formula (II) and R ^{8 is} R as defined in Formula (II), or moieties which can be converted to those of R by known reactions, as described in DerekBarton and US Ollis, Comprehensive Organic Chemistry: The Synthesis and Reactions of Organic Compounds, Pub: Pergamon Press (1979), and R ^{4 is} fluorosulfonyloxy, halogen, cyano or -CHO.

When synthesizing the compounds of formula I of the invention, new intermediates of structure (VI) have also been prepared

When synthesizing the compounds of formula (I) of the invention, new intermediates of formula (VII) were also prepared

(VII) wherein A and R ⁸ are as defined in formula (IV).

A preferred process for the preparation of a compound of formula (II)

(II) wherein A is a straight or branched, saturated or unsaturated hydrocarbon containing from 1 to 12 carbon atoms; and R, as defined in formula (II) above, and pharmaceutically acceptable salts, hydrates, solvates and esters thereof, comprises reacting a compound of formula O

CAR (VIII) wherein A and R ⁸ are as defined in formula (IV) with a fluorosulfonic anhydride and a base, preferably 2,5-t-butyl-3-methyl-pyridine, in a solvent, preferably dichloromethane, to give the compound with the formula

Oh

wherein A and R ⁸ as described above and then the reaction of this compound in a metal-catalyzed coupling reaction in the presence of a suitable coupling reagent, preferably carbon monoxide, followed by a facultative, if appropriate, hydrolysis reaction and, if appropriate, if appropriate, converting R ⁸ to R to give the compound of formula (II) and then optionally forming a pharmaceutically acceptable salt, hydrate or solvate thereof.

The compounds of formula (VIII) above are prepared first by activating a carboxylic acid substituent in the 17 position of compounds of structure (X) as described herein, preferably with an acid chloride such as thionyl chloride, or by forming a thiopyridyl ester by reaction with 2,2dithiopyridyl, and then by treatment with Grignard reagent as described herein.

A preferred process for the preparation of a compound of formula (II)

wherein A and R, as defined above, and pharmaceutically acceptable salts, hydrates, solvates and esters thereof, comprise the reaction of a compound of formula

at reduced temperature in the presence of halogen-Vilsmeie reagent and solvent, then quenched with Grignard reagent to give the compound of formula

Halogen

where A and R ⁸ are as described in formula (IV) and then the reaction of this compound in a suitable solvent with a cyanate reagent to give the compound of formula

wherein A and R ⁸ are as defined above, followed by saponification of this compound, and optionally converting R ⁸ to R to give the compound of formula II, and then optionally forming a pharmaceutically acceptable salt, hydrate but solvate.

A process for preparing a compound of formula

where A and R are as defined in formula (II);

and the pharmaceutically acceptable salts, hydrates, solvates and esters thereof

where A and R ⁸ are as defined in formula (IV), ah (ii) the reaction of a compound of formula (XI)

(XI) wherein A and R ⁸ , as described above, are in a metal-catalyzed coupling reaction in the presence of a suitable coupling reagent, preferably carbon monoxide, followed by a facultative, if appropriate, hydrolysis reaction, or

wherein A and R ⁸ are as described above and, optionally, converting R ⁸ to R and, if appropriate, forming a pharmaceutically acceptable salt, hydrate or solvate thereof.

Because the pharmaceutically active compounds of the invention inhibit steroid 5-a-reductase activity, they are therapeutically useful in the treatment of diseases and conditions where reductions in DHT activity produce the desired therapeutic effect. Such diseases and conditions are acne vulgaris, seborrhea, female hirsutism, male pattern baldness, prostate diseases, such as benign prostatic hypertrophy and prostatic adenocarcinoma.

The following procedure was used to determine the inhibitory activity of the human 5α-reductase enzyme.

Free Preparation of membrane particles used as a source for recombinant steroidal 5reductase isozyme 1 Free

Chinese hamster ovary (CHO) cells containing recombinant human steroid 5a-reductase isoenzyme 1 (Andersson, S., Berman, D.M., Jenkins, E.P., and Russell, D.W. (1991) Nature 354 159-161) are homogenized in 20 mM. potassium phosphate buffer, pH 6.5 containing 0.33 M sucrose, 1 mM dithiothreitol and 50 μΜ NADPH (buffer A) using a Dounce hand-on-glass homogenizer (Kontes Glass Co., Vineland, NJ) . The membrane particles were isolated by centrifugation (100,000 x g for 60 minutes at 4 ° C) and resuspended in 20 mM potassium phosphate, pH 6.5 containing 20% glycerol, 1 mM dithiothreitol, and 50 μΜ NADPH (buffer B). The suspended particulate solution is stored at -80 ° C.

Preparation of Prostate Membrane Particles Used as a Source for Steroidal 5areductase Isocim 2

Frozen human prostates are thawed and ground into small pieces (Brinkmann Polytron (Sybron Corp., Westbury, New York), sonicated for 3 to 5 minutes with a sonicator (Branson Sonic Power Co.), followed by manual homogenization in Dounce's manual Prostate particles are obtained by differential centrifugation at 600 or 1000 xg for 20 minutes and 140000 xg for 60 minutes at 4 ° C. The pellet obtained from 140000 xg centrifugation is washed with 5 to 10 tissue volumes of buffer described above and centrifuged at 140000 x g. The resulting pellet is suspended in buffer B and the particle suspension is kept at -80 ° C.

Preparation of membrane fragments used as a source for recombinant steroid 5-areductase isozyme 2

Chinese hamster ovary (CHO) cells containing expressed recombinant human steroid 5-reductase isocyme 2 were homogenized in 20 mM potassium phosphate, buffer, pH 6.5 containing 0.33 M sucrose, 1 mM dithiothreitol and 50 μΜ NADPH (buffer A) using a Douce handheld homogenizer. Membrane fragments containing recombinant human enzyme were isolated by centrifugation (100,000 xg at 4 ° C for 60 minutes) and resuspended in 20 mM potassium phosphate, pH 6.5 containing 20% glycerol, 1 mM dithiothreitol and 50 μΜ NADPH (buffer) B). The suspended particulate solution was stored at -80 ° C until use.

Test for enzyme activities and inhibitor efficacy

A constant amount of [ ¹⁴ C] testosterone (50 to 55 mCi / mmol) in ethanol and varying amounts of potential inhibitor in ethanol were placed in tubes and concentrated to dryness in vacuo. To each tube was added a buffer, 10 μ iz (recombinant isoenzyme 1 or isoenzyme 2) or 20 μ \ (isoenzyme 2 from human prostate tissue) 10 mM NADPH and an aliquot of the steroid 5a-reductase preparation to a final volume of 0.5 ml. Assays for human steroid 5a-reductase isoenzyme 1 are performed with a sample of recombinant protein experimented in CHO cells in 50 mM phosphate buffer pH 7.5 while isoenzyme 2 assays are performed with suspension of human prostate particles and / or recombinant protein expressed in CHO cells 50 mM citrate buffer at pH 5.0.

After incubating the solution for 20 or 30 minutes at 37 ° C, the reaction was quenched by the addition of 4 ml of ethyl acetate and 0.25 μπιοίον of testosterone, 5α-dihydrotestosterone, androstandiol and androstandion as carriers. Transfer the organic layer to another tube and evaporate to dryness in a Speed Vac. The residue was dissolved in 40 μΐ of chloroform, stained on a single line of 20 × 20 cm silica gel TLC plate with pre-made channels (Si 250F-PA, Baker Chemical), and developed 2 times with acetone: chloroform (1: 9). The radiochemical content of the substrate and product strips was determined with a BIOSCAN Imaging Scanner (Bioscan Inc., Washington, D.C.). The percentage of recovered radiomarking converted to the product from which the enzyme activity is determined is calculated. All incubations are performed in such a way that no more than 20% of the substrate (testosterone) is consumed.

The experimentally obtained data were computer-tuned to a linear function by plotting the reciprocal value of enzyme activity (1 / speed) against the variable inhibitory concentration; apparent inhibition constants (K _iapp ) were determined by Dixon analysis (Dixon, M. (1953).

The value for the inhibition constant (Ki) was calculated according to known procedures (Levy, M. (1989), Biochemistry, 29: 2815-28241.

The pharmaceutically active compounds of the present invention are useful in inhibiting steroid 5-a-reductase in mammals, including humans, in need thereof.

Compounds within the scope of the present invention have been tested and have shown activity from 85 Ki (nM) to 2 Ki (nM) against isozymes 1 and activity from 7 Ki (nM) to 0.2 Ki (nM) against isozymes 2. Particularly preferred of the compounds of the invention and the compounds used in the pharmaceutical compositions of the invention and the processes of the invention are ΙΊβ (phenylpropylcarbonyl) -androst-3,5-diene-3-carboxylic acid, 17 / 3- (benzylcarbonyl) androst-3,5 -diene-3-carboxylic acid, 17 / 3- (cyclohexylethylcarbonyl) -androsta 3,5,5-diene-3-carboxylic acid, 17 / 3- (5,5,5-trifluoro-1-oxopentyl) -urosta-3,5 -diene-3-carboxylic acid, 17 / 3- (2-cyclohexyl-1-oxoethyl) -androst-3,5-diene-3-carboxylic acid, 17 / 3- (3-methyl-3-phenyl-1-oxobutyl) -androst-3,5-diene-3-carboxylic acid, 17 / 3- (phenethylcarbonyl) -androst-3,5-diene-3-carboxylic acid, 17 / 3- (3- (4-methoxy phenyl) -1 -oxopropyl) -androsta-3,5-diene-3-carboxylic acid, 17 / 3- (3- (4-hydroxyphenyl) -1-oxopropyl) -androsta-3,5-diene-3-carboxylic acid, 17 / 3- (4-11 uorophenethylcarbon) il) -androsta-3,5-diene-3-carboxylic acid and 17 / 3- (2,6-difluorobenzylcarbonyl) androsta-3,5-diene-3-carboxylic acid.

The pharmaceutically active compounds of the present invention are incorporated into advantageous dosage forms, such as capsules, tablets or injectables. Solid or liquid pharmaceutical carriers are used. Solid carriers include starch, lactose, calcium sulfate dihydrate, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate and stearic acid. Liquid carriers include syrup, peanut oil, olive oil, saline soh and water. Similarly, the carrier or diluent may include any sustained release material, such as glyceryl monostearate or glyceryldistearate, alone or with wax. The amount of solid carrier varies widely, but will preferably be from about 25 mg to about 1 g per dosage unit. When a liquid carrier is used, the preparation will be in the form of a syrup, elixir, emulsion, soft gelatin capsule, sterile injectable fluid such as ampoules, or aqueous or non-aqueous liquid suspensions.

The pharmaceutical compositions are made according to conventional pharmaceutical chemist techniques, comprising mixing, granulating and compressing as needed for tablet forms or mixing, filling and dissolving ingredients as appropriate to obtain the desired oral or parenteral products.

The dosages of the pharmaceutically active compounds of the present invention in the pharmaceutical dosage unit as described above will be an effective non-toxic amount, preferably selected from 0.01 to 1000 mg / kg of active compound, preferably 0.1 to 100 mg / kg. . When treating a human patient who requires inhibition of steroid 5-α-reductase, the selected dose is preferably administered 1 to 6 times daily orally or parenterally. The preferred forms of parenteral administration are topical, rectal, transdermal, injectable, and continuous infusion. Oral dosage units for human administration preferably contain from 0.1 to 500 mg of active compound. Oral administration with lower dosages is preferred. However, parenteral administration at high dosages can also be used when it is safe and favorable for the patient.

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

The invention also relates to the use of a compound of formula (I) or a compound of formula (V) in the preparation of a medicament for use in inhibiting steroid 5-a-reductase. ,

The invention also provides a pharmaceutical composition for use in the treatment of benign prostatic hypertrophy comprising a compound of formula I or a compound of formula (V) and a pharmaceutically acceptable carrier.

The invention also provides a pharmaceutical composition for use in the treatment of prostatic adenocarcinoma comprising a compound of formula (I) or a compound of formula (V) and a pharmaceutically acceptable carrier.

The invention also provides a process for the preparation of a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound of formula (I) or a compound of formula (V), wherein the compound of formula (I) or the compound of formula (V) is taken together with a pharmaceutically acceptable carrier or diluent.

No unacceptable toxicological effects are expected when the 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 acne vulgaris, seborrhea, female hirsutism, male baldness, benign prostatic hypertrophy or prostatic adenocarcinoma, or a compound which are known to be useful when used in combination with

5-α-reductase inhibitors. Particularly preferred is co-administration of a 5-α-reductase inhibitor as described herein and minoxidil for use in the treatment of male pattern baldness. Particularly preferred is co-administration of a 5-α-reductase inhibitor as described herein and a? -Receptor antagonist for use in the treatment of benign prostatic hypertrophy. Preferably, co-administration of a 5-α-reductase inhibitor as described herein and an aromatase inhibitor for use in the treatment of benign prostatic hypertrophy. Preferably, co-administration of a 5-α-reductase inhibitor as described herein is a? -Receptor antagonist and an aromatase inhibitor for use in the treatment of benign prostatic hypertrophy.

Without further ado, we believe that the person skilled in the art can use the present invention to its fullest extent using the foregoing description. Therefore, the following examples should be considered as illustrative only and not as limiting the scope of the present invention in any way.

EXAMPLE 1 - Corresponding to Scheme I

17j3- (Phenethylcarbonyl) -androsta-3,5-diene-3-carboxylic acid (s) 17 / 3- (phenethylcarbonyl) -androsta-3-bromo-3,5-diene

100 ml of methylene chloride and 6.12 ml (2.5 molar equivalents) of dimethylformamide are added to the flask under a nitrogen atmosphere. The solution was cooled to 0 to 5 ° C and treated with 6.9 ml (2.5 molar equivalents) of oxalyl chloride while maintaining the temperature between 0 and 10 ° C. A white precipitate forms. After stirring for 1 hour, it is bubbled through the solution

50.1 g (19.6 molar equivalents) of gas bromide, maintaining the temperature between 0 and 10 ° C. The suspension becomes a clear colorless solution. The solution is degassed by reducing the volume of the solution to about 1/2 by vacuum distillation and restoring it to its original volume with methylene chloride. We repeat this concentration / refill process. To the resulting white suspension was added 10.0 g (1 molar equivalent) of androst-4-en-3-one-17b-carboxylic acid, the mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was poured into a container containing 100 ml of methylene chloride and 1 molar equivalent of phenethyl magnesium bromide while maintaining the temperature between 0 and 10 ° C. The mixture was stirred for 30 minutes. About 100 ml of water is added and the biphasic mixture is filtered through a pad of celite. The organic phase is separated and reduced to about half its volume by vacuum distillation. Reconstitute the solution to its original volume with acetone. Repeat this concentration / charge procedure 2 more times. The resulting acetone solution (about 300 ml) was heated to about 50 ° C and treated with about 100 ml of water to precipitate the product. The suspension was cooled and the product, 17 / 3- (phenethylcarbonyl) -androsta-3-bromo-3,5-diene, was isolated by filtration and dried.

(ii) 17 / 3- (phenethylcarbonyl) -androsta-3-cyano-3,5-diene

A mixed mixture of 17 / 3- (phenethylcarbonyl) -androsta-3-bromo-3,5-diene (50 g, 1 molar equivalent), copper (I) cyanide (11.0 g, 1 molar equivalent) and dimethylformamide (200 ml ) is heated to reflux for 3.5 hours. The reaction mixture was cooled to 90-100 ° C and poured while stirring into a solution of 100 ml of concentrated aqueous ammonia and 200 ml of water. Wash the reaction flask with 25 ml of dimethylformamide, which is also added to the fused solution. The resulting suspension was extracted twice with 200 ml portions of methylene chloride and the organic extracts filtered through a pad of celite. The organic phase is washed with three 200 ml portions of 50/50 v / v concentrated aqueous ammonia / water, followed by two 200 ml portions of water. The organic phase was concentrated in vacuo to 150 ml and 250 ml of ethanol were added. The solution was again concentrated in vacuo to 150 ml and 250 ml of ethanol were added. The solution was concentrated in vacuo to 300 ml and 30 ml of water was added to initiate crystallization. At the same time, the suspension was cooled for 2 hours at 0 to 5 ° C. The solid was collected by filtration and dried at 65 ° C in vacuo to give 17 / 3- (phenethylcarbonyl) -androsta-3cyano-3,5-diene.

(iii) 17β- (phenethylcarbonyl) -androsta-3,5-diene-3-carboxylic acid

A mixture of 17 / 3- (phenethylcarbonyl) -androsta-3-cyano-3,5-diene (20.0 g, 1 molar equivalent), 50% aqueous sodium hydroxide (80 ml, 30 molar equivalents) and ethanol (200 ml) is heated to reflux for 18 hours. The reaction suspension was cooled to 50 ° C and added to a mixture of 6 N hydrochloric acid (300 ml) and methylene chloride (200 ml). The final pH of the aqueous phase is 1.5 to 2.0. The organic phase was separated and the aqueous phase was re-extracted with 250 ml of methylene chloride. The combined organic phases are stirred with 2 g of decolorized charcoal for 1 hour and filtered through a pad of celite. The organic phase was concentrated in vacuo to 120 ml and 200 ml of ethyl acetate were added. The suspension was again concentrated in vacuo to 120 ml and 200 ml of ethyl acetate were added. The resulting suspension was concentrated in vacuo to a final volume of 120 ml and heated at reflux for 2 hours. The suspension was cooled to 0 to 5 ° C for 2 hours and filtered. The solid was dried in vacuo at 65 ° C to give 17 / 3- (phenethylcarbonyl) -androsta-3,5-diene-3-carboxylic acid.

EXAMPLE 2 - Corresponding to Scheme II

17 / 3- (phenethylcarbonyl) -androsta-3,5-diene-3-carboxylic acid (s) 3- (trifluoromethanesulfonyloxy) -androst-3,5-diene-17/3-carboxylic acid

A solution of androst-4-en-3-one-17/3-carboxylic acid (8.0 g; 25 mmol), 2,6-di-butyl-4-methylpyridine (16.6 g; 62 mmol) and trifluoromethanesulfonic anhydride (11 ml; 66 mmol) in methylene chloride. Stirred for 20 hours at 5 ° C. The organic solvent was evaporated and the residue was dissolved in tetrahydrofuran / water (99.5: 0.5) with 4-dimethylaminopyridine (9.0 g) from which, after acidification with hydrochloric acid, followed by conventional treatment, 13 g of the title compound were obtained (yield 92 %). Tal. 182 ° C.

(ii) S- (2-pyridyl) -3- (trifluoromethanesulfonyloxy) -androsta-3,5-diene-17/3-thiocarboxylate

Solution of 3- (trifluoromethanesulfonyloxy) -androst-3,5-diene-17/8-carboxylic acid (6.2 g; 14.9 mmol), triphenylphosphine (9.92 g; 38 mmol) and 2,2'-dipyridyldisulfide (8.68 g; 39.5 mmol) in (50 ml) was stirred for 20 hours under nitrogen. The reaction mixture was concentrated, the residue was taken directly through silica gel and the appropriate fractions were evaporated to give 4.0 g of the title compound (50% yield). 120 to 122 ° C.

(iii) 17 / 3- (phenethylcarbonyl) -androsta-3,5-diene-3-trifluoromethanesulfonate

To a solution of S- (2-pyridyl) -3- (trifluoromethanesulfonyloxy) -androst-3,5-diene17 / 3-thiocarboxylate (0.3 g; 0.56 mmol) in tetrahydrofuran (20 ml) at about -50 ° C phenethylmagnesium bromide (1.6 mmol) was added. The reaction mixture was warmed to about -10 ° C and diluted with saturated aqueous ammonium chloride solution. Normal treatment by subsequent isolation by column chromatography gave 166 mg of the title compound (60% yield), m.p. 98 to 99 ° C.

(iv) 17 / 8- (Phenethylcarbonyl) -androsta-3,5-diene-3-carboxylic acid

A mixture of 17 / 3- (phenethylcarbonyl) -androsta-3,5-diene-3-trifluoromethanesulfonate (0.125 g; 0.23 mmol) of potassium acetate (0.130 g; 1.32 mmol) and bis (triphenylphosphine) palladium (II) diacetate (0.015 g; 0.02 mmol) in DMF (3 ml) was rinsed with carbon monoxide for 2 minutes and stirred under a CO 2 balloon for 60 hours at 60 ° C. The reaction mixture was diluted with water; acidified with 0.5 N HCl, extracted with ethyl acetate, and the ethyl acetate extracts were washed with water, dried (MgSO ₄ ) and evaporated in vacuo. The residue was chromatographed on a silica gel column eluting with hexane: ethyl acetate: acetic acid 70: 30: 1. The resulting solid was recrystallized from acetonitrile to give 17 mg (17%) of a white solid. Tal. 218-220 ° C.

EXAMPLE 3 - Corresponding to Scheme II

17 / 3- (4-fluorophenylcarbonyl) -androsta-3,5-diene-3-carboxylic acid

The title compound was prepared according to Example 2 (i-iv) by replacing the phenethylmagnesium bromide in step iii with 4-fluorophenethylmagnesium bromide.

EXAMPLE 4 - Corresponding to Scheme II

17ff- (Phenylpropylcarbonyl) -androsta-3,5-diene-3-carboxylic acid

The title compound was prepared according to Example 2 (i-iv) by replacing the phenethylmagnesium bromide in step iii with phenylpropylmagnesium bromide. Tal. Mp 208-210 ° C.

EXAMPLE 5 - Corresponding to Scheme II

17g- (Benzylcarbonyl) -androsta-3,5-diene-3-carboxylic acid

The title compound was prepared according to Example 2 (i-iv) by replacing the phenethylmagnesium bromide in step iii with benzylmagnesium chloride. 258 ° C.

EXAMPLE 6 - Corresponding to Scheme II

17 / 3- (cyclohexylethylcarbonyl) -androsta-3,5-diene-3-carboxylic acid

The title compound was prepared according to Example 2 (i-iv) by replacing the phenethylmagnesium bromide in step iii with cyclohexylethylmagnesium bromide. Tal. 247 ° C.

EXAMPLE 7 - Corresponding to Scheme ΠΙ

17.3- (2,6-Difluorobenzylcarbonyl) -androsta-3,5-diene-3-carboxylic acid

The title compound was prepared according to Example 10 (i-iv) by replacing 4,4,4-trifluorobutylmagnesium bromide in step iii with 2,6-difluorobenzylmagnesium bromide.

EXAMPLE 8 - Corresponding to Scheme II

17 / 3- (Phenethylcarbonyl) -androsta-3,5-diene-3-carboxylic acid (s) 3- (fluorosulfonyloxy) -androsta-3,5-diene-17/3-carboxylic acid

A solution of androst-4-en-3-one-17/3-carboxylic acid, 2,6-di-t-butyl 4-methylpyridine and fluorosulfonic anhydride in methylene chloride was stirred for 20 hours at 5 ° C. The reaction mixture was washed with aqueous hydrochloric acid and water. The organic phase was concentrated and the resulting residue was purified by column chromatography to give the title compound.

(ii) S- (2-pyridyl) -3- (fluorosulfonyloxy) -androsta-3,5-diene-17/3-thiocarboxylate

A solution of 3- (fluorosulfonyloxy) -androsta-3,5-diene-17/3-carboxylic acid, triphenylphosphine and 2,2'-dipyridyldisulfide in toluene was stirred for 20 hours under nitrogen. The reaction mixture was concentrated, the residue was taken directly through silica gel, and the appropriate fractions were evaporated to give the title compound.

(iii) 17 / 3- (phenethylcarbonyl) -androsta-3,5-diene-3-fluorosulfonate

To a solution of S- (2-pyridyl) -3- (fluorosulfonyloxy) -androst-3,5-diene-17/3-thiocarboxylate in tetrahydrofuran was added at about -50 ° C phenethylmagnesium bromide. The reaction mixture was warmed to about -10 ° C and diluted with saturated aqueous ammonium chloride solution. Normal treatment with the following isolation by column chromatography afforded the title compound.

(iv) Methyl-17β- (phenethylcarbonyl) -androsta-3,5-diene-3-carboxylate

A solution of 17 / 3- (phenethylcarbonyl) -androsta-3,5-diene-3-fluorosulfonate, triphenylphosphine, palladium (II) acetate, triethylamine, methanol and dimethylformamide was stirred vigorously for 20 hours under a carbon monoxide atmosphere. By conventional treatment by the following isolation by column chromatography the title compound is obtained.

(v) 17 / 3- (phenethylcarbonyl) -androsta-3,5-diene-3-carboxylic acid

A mixture of methyl-17 / 3- (phenethylcarbonyl) -androsta-3,5-diene-3-carboxylate, K ^ CO ^ water and methanol was heated at reflux for about 5 hours. Acidification followed by conventional finishing gives the title compound.

EXAMPLE 9 - Corresponding to Scheme II

17j8- (Phenethylcarbonyl) -androst-3,5-diene-3-carboxylic acid (s) 3- (fluorosulfonyloxy) -androst-3,5-diene-17j8-carboxylic k + kna

The title compound was prepared according to Example 8 (i).

(ii) 3-cyano-androsta-3,5-diene-17/3-carboxylic acid

A solution of 3- (fluorosulfonyloxy) -androst-3,5-diene-17/3-carboxylic acid in dimethylformamide is treated with excess copper (I) cyanide at reflux. The reaction solution was poured into aqueous ammonia and filtered. The filtered solids were dissolved in methylene chloride / hydrochloric acid. Conventional completion and isolation by column chromatography afforded the title compound.

(iii) S- (2-pyridyl) -3-cyano-androsta-3,5-diene-17/3-thiocarboxylate

The title compound was prepared according to Example 2 (ii) by substituting 3- (trifluoromethanesulfonyloxy) -androst-3,5-diene-17/3-carboxylic acid with 3-cyano-androsta-3,5-diene17 / 3-carboxylic acid, prepared as in Example 9 (ii).

(iv) 3-cyano-17 / 3- (phenethylcarbonyl) -androsta-3,5-diene

The title compound was prepared according to Example 2 (iii) by substituting S- (2-pyridyl) -3 (trifluoromethanesulfonyloxy) -androst-3,5-diene-17/3-thiocarboxylate with S- (2-pyridyl) 3-cyano-androst -3,5-diene-17/3-thiocarboxylate as prepared in Example 9 (iii).

(v) 17 / 3- (phenethylcarbonyl) -androsta-3,5-diene-3-carboxylic acid

A mixture of 3-cyano-17 S- (phenethylcarbonyl) -androsta-3,5-diene, excess sodium hydrochloride and ethanol was heated at reflux. The resulting mixture was quenched with aqueous hydrochloric acid and extracted with methylene chloride. Conventional completion and isolation by column chromatography afforded the title compound.

EXAMPLE 10 - Corresponding to Scheme III

17 / 3- (5,5,5-Trifluoro-1-oxopentyl) -androsta-3,5-diene-3-carboxylic acid (s) Methyl-17/3-cyano-androsta-3,5-diene-3 -carboxylate

Phosphorus oxychloride (40 ml, 429 mmol) was added to a solution of (17/3) -17-Nt-butyl carboxamidyl androst-3,5-diene-3-carboxylic acid (15.5 g, 39 mmol) in benzene (500 ml) ) and heated to reflux. After 12 hours, the reaction mixture was treated with MeOH (10 ml), then with aqueous NaHCO ₃ , extracted with CH ₂ Cl ₂ , dried (MgSO ₄ ), filtered, concentrated, chromatographed (silica gel, 20% EtOAc / hexanes) and recrystallized (EtOAc / hexane) to give the title compound as a yellow solid.

ii) 17/3-carboxaldehyde-androsta-3,5-diene-3-methanol

Diisobutyl aluminum hydride (1.0 M in toluene, 60 ml, 60 mmol) was added to a solution of methyl- (17/3) -17-cyano-androst-3,5-diene-3-carboxylate (10 g, 29 mmol) in toluene (200 ml) at room temperature. After 3.5 hours, the reaction mixture was quenched with aqueous H ₂ SO ₄ (700 ml) and stirred for 2 hours. The organic layer was washed with brine, H ₂ O, then dried (MgSO ₄ ), filtered, concentrated and chromatographed (20% EtOAc / hexanes) to give the title compound as a yellow solid.

iii) 17 / 3- (5,5,5-trifluoro-1-hydroxypentyl) -androsta-3,5-diene-3-methanol

4,4,4-Trifluorobutyl magnesium bromide (0.25 M in THF, 4.0 ml, 1.0 mmol) was added to a solution of (17/3) -17-carboxaldehyde-androsta-3,5-diene-3- of methanol (50 mg, 0.16 mmol) in THF at 0 ° C. After 0.5 hours, the reaction mixture was quenched with aqueous ammonium chloride, the aqueous layer was extracted with EtOAc, the combined organic extracts dried (MgSO ₄ ), filtered, concentrated and chromatographed (silica gel 20% EtOAc) to give the title compound.

iv) 17 / 3- (5,5,5-trifluoro-1-oxopentyl) -androsta-3,5-diene-3-carboxaldehyde

Tetrapropylammonium perutenate (10 mg, 0.028 mmol) was added to a solution of (17/3) 17- (5,5,5-trifluoro-1-hydroxypentyl) -androst-3,5-diene-3-methanol (65 mg, 0, 15 mmol) and 4-methylmorpholine-N-oxide (80 mg, 0.68 mmol) in CH ₂ Cl ₂ (2.0 ml) at room temperature. After 1 hour, the reaction mixture was flash chromatographed (silica gel, 20% EtOAc / 80% hexanes) to give the title compound.

v) 17 / 3- (5,5,5-Trifluoro-1-oxopentyl) -androsta-3,5-diene-3-carboxylic acid

Sodium chlorite (53 mg, 0.6 mmol) was added to a mixture of 17 / 3- (5,5,5-trifluoro-loxopentyl) -androsta-3,5-diene-3-carboxaldehyde (50 mg, 0.12 mmol) , sodium phosphate, monobasic monohydrate (140 mg, 1.18 mmol) in 2-methyl-2-butene in

THF (2.0 M, 3.0 ml), H ₂ O (0.5 ml) and t-butanol (0.5 ml) at room temperature. After 6 hours, acetic acid (3.0 ml) was added, then the aqueous layer was extracted with EtOAc (10 ml), the combined organic extracts dried (MgSO ₄ ), filtered, concentrated and flash chromatographed (silica gel, 1% AcOH / 19% EtOAc / 80% hexanes) to give the title compound as a white waxy solid. ESMS m / e 439 [M + H] ⁺

EXAMPLE 11 - Corresponding to Scheme III

17g- (2-cyclohexyl-1-oxoethyl) -androsta-3,5-diene-3-carboxylic acid

i) 17 / 3- (2-Cyclohexyl-1-oxoethyl) -androsta-3,5-diene-3-carboxylic acid

Following the procedure of Example 10 (i) - (v), except that the 4,4,4-trifluorobutylmagnesium bromide in step iii is replaced by cyclohexylmethyl magnesium bromide, the title compound is prepared as a white solid, m.p. 257 ° C (dec). MS (DCI / NH ₃ ) m / e 425 [M + H] ⁺ .

EXAMPLE 12 - Corresponding to Scheme III

17.3- (3-Methyl-3-phenyl-1-oxobutyl) -androsta-3,5-diene-3-carboxylic acid

i) 17.3- (3-Methyl-3-phenyl-1-oxobutyl) -androsta-3,5-diene-3-carboxylic acid

Following the procedure of Example 10 (i) - (v), except that the 4,4,4-trifluorobutyl magnesium bromide in step iii is replaced by 2-methyl-2-phenyl propyl magnesium bromide, the title compound is prepared as a white solid, m.p. 192 ° C, dec. MS (DCI / NFL) m / e 461 [M + H] ⁺ .

EXAMPLE 13 - Corresponding to Scheme III

17 / 3- (3- (4-Methoxyphenyl) -1-oxopropyl) -androsta-3,5-diene-3-carboxylic acid

i) 17 / 3- (3- (4-Methoxy phenyl) -1-oxopropyl) -androsta-3,5-diene-3-carboxylic acid

According to the procedure of Example 10 (i) - (v), except that 4,4,4-trifluorobuts! magnesium bromide in step iii is replaced by 2- (4-methoxy phenyl) ethyl magnesium chloride, preparing the title compound as a white solid MS (DCI / NH ₃ ) m / e 463 [M + H] ⁺ .

EXAMPLE 14 - Exchange of the functional group of Example 13

17 / 3- (3- (4-hydroxyphenyl) -1-oxopropyl) -androsta-3,5-diene-3-carboxylic acid

Boron tribromide (0.4 ml, 0.4 mmol, 1.0 M in CHfdf) was added dropwise to a solution of 17 / 3- (3- (4-methoxy phenyl) -1-oxopropyl) -androst-3,5- of diene-3-carboxylic acid (60 mg, 0.129 mmol) in CH ₂ Cl ₂ (2.0 ml) at 0 ° C and stirred for 0.5 hours, then warmed to room temperature and stirred for another 2.5 hours. The reaction mixture was quenched with 0.5 N HCl (5.0 mL), then extracted with CH ₂ Cl ₂ (2x10 mL). The combined organic extracts were dried (MgSO ₄ ), filtered, concentrated in vacuo and chromatographed (silica gel, 1% AcOH / 19% EtOAc / 80% hexanes) to give the title compound as a yellow solid, MS (DCI / NH ₃ ) m / e. e 449 [M + H] ⁺ .

EXAMPLE 15 - Corresponding to General Procedure A

17- (Phenethylcarbonyl) -androsta-3,5-diene-3-carboxylic acid

17 / 3- (Phenethylcarbonyl) -androsta 3,5,5-diene-3-carboxylic acid and excess sodium hydroxide are added to a 250 ml round-bottomed flask. Dimethylsulfoxide is added to the flask as a solvent. The mixture was heated to reflux for 3 hours. With standard finishing followed by isolation by preparative HPLC, the title compound is obtained.

EXAMPLE 16

17 / 3- [3-fluoro-phenyl-1-oxopropyl] -3'5-androsta-diene-3-carboxylic acid (s) S- (2-pyridyl) -androst-4-en-3-one-17 / 3-Thiocarboxylate

Mixture of 3-oxo-4-androstene-17/3-carboxylic acid (0.95 g, 3 mmol), triphenylphosphine (1.6 g, 6 mmol), 2,2'-dipyridyldisulfide (1.32 g, 6 mmol) ) and toluene (250 ml) were stirred at room temperature overnight under argon. The resulting homogeneous solution was concentrated in vacuo and chromatographed (silica gel, 30% EtOAc in hexanes) to give 0.87 g (71%) of a white solid.

(ii) 17 / 3- [3- (4-fluorophenyl) -1-oxopropyl] -androst-4-en-3-one p-fluorophenylethylmagnesium bromide (5 mmol in 10 ml THF) was added slowly to a solution of S- (2 -pyridyl) -1-androst-4-en-3-one-17/3-thiocarboxylate (1.2 g, 3 mmol) in THF (30 ml) at -78 ° C. After 30 minutes, the mixture was quenched with saturated NH ₄ Cl and extracted with EtOAc. The organic extract was washed with brine, dried (MgSO ₄ ), filtered, concentrated in vacuo and chromatographed (silica gel, 15% EtOAc in hexanes - * 20% EtOAc in hexanes) to give an oil, 0.78 g (62%).

(iii) Trifluoromethyl-17 / 3- [3- (4-fluorophenyl) -1-oxopropyl] -androsta-3,5-diene-3 sulfonate

To a solution of 17 / 3- [3- (4-fluorophenyl) -1-oxopropyl] -androst-4-en-3-one (0.77 g, 1.8 mmol) and 2,6-di-tert-butyl -4-methylpyridine (0.51 g, 2.5 mmol) in CH ₂ Cl ₂ (20 ml) was slowly added trifluoromethanesulfonic anhydride (0.75 g, 2.7 mmol). After stirring for 2 hours at room temperature, the reaction mixture was washed with dilute HCl, water, dilute NaHCO ₃ , brine, dried (MgSO ₄ ), filtered, concentrated in vacuo and chromatographed (silica gel, hexanes - EtOAc in hexanes) to give 0. 44 g of white solid (44% yield).

(iv) 17-3- [3- (4-fluorophenyl) -1-oxopropyl] -3,5-androsta-diene-3-carboxylic acid

A mixture of trifluoromethyl-1 H- [3- (4-fluorophenyl) -1-oxopropyl] -androstane-3,5-diene-3 sulfonate (0.28 g, 0.5 mmol), palladium (II) acetate (5, 6 mg, 0.025 mmol), triphenylphosphine (13 mg, 0.05 mmol), potassium acetate (0.19 g, 2 mmol) and.DMF (6 ml) was heated at 60 ° C for 2.5 hours in a CO atmosphere. The cooled mixture was diluted with ice water, acidified with dilute HCl and extracted with CH ₂ Cl ₂ . The organic extract was washed with water, brine, dried (MgSO ₄ ), filtered, concentrated in vacuo and chromatographed (silica gel, 1% AcOH / 19% EtOAc / 80% hexanes) to give the title compound 0.12 g (53%). Recrystallized from methanol-acetone, m.p. 220-220 ° C.

Analysis for C ₂₉ H ₃₅ FO ₃ 0.25 H ₂ O (455.1) calculated:

76.54

7.86 found:

76,61

7.88

MS (DCI / NH ₃ ) m / e 451 [M + H] +

EXAMPLE 17

17g-fl (R) -hydroxy-3-phenylpropyl1-androsta-3,5-diene-3-carboxylic acid and 17g- [1 (S) -hydroxy-3-phenylpropyl-androsta-3,5-diene-3- carboxylic acid (i) Solution 17) S- (phenethylcarbonyl) -androsta-3,5-diene-3-carboxylic acid (50 mg in 10 ml MeOH and 1 ml H ₂ O) prepared according to Example 2 (i-iv) , treated with 2 LiBH ₄ equivalents. The mixture was heated to 40 ° C and stirred overnight. EtOAc was added and the mixture was filtered, dried and concentrated. Chromatography (silica gel, eluting 30% EtOAc in hexane with 0.5% HOAc) afforded the title compounds with an undetermined C-20 stereochemistry.

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

EXAMPLE 18

An oral dosage form for the administration of compounds of formula I is prepared by seeding, mixing and stuffing the ingredients into hard gelatin capsules in the portions shown in Table 1 below.

TABLE I

Ingridients

17 / 3- (phenethylcarbonyl) androsta-3,5-diene-3-carboxylic acid magnesium stearate lactose

Quantities mg mg 75 mg

EXAMPLE 19

Sucrose, calcium sulphate dihydrate and the compound of formula (I) shown in Table II below are mixed and granulated in portions shown with 10% gelatin solution. The wet granules are sieved, dried, mixed with starch, talc and stearic acid, sieved and squeezed into a tablet.

TABELAH

Ingridients

Quantities

17 / 3- (phenethylcarbonyl) androst-3,5-diene-3-carboxylic acid calcium sulfate dihydrate sucrose starch talc stearic acid

100 mg

150 mg 20 mg 10 mg 5 mg 3 mg

EXAMPLE 20

17 / 3- (Phenethylcarbonyl) -androsta-3,5-diene-3-carboxylic acid, 75 mg was dispersed in 25 ml of normal saline solution to prepare the injection.

While preferred embodiments of the invention are shown above, it should be understood that the invention is not limited to the precise instructions described herein and that we reserve the right to make any modifications to the extent of the following claims.

SmithKline Beecham Corporation:

rri ¹

Claims (16)

A compound of formula H-O-C Z? (I) where Z is a or β Oh -C-A-R wherein A is a straight or branched, saturated or unsaturated hydrocarbon chain containing from 1 to 12 carbon atoms; and R is substituted alkyl, cycloalkyl or aryl, wherein a) substituted straight or branched alkyl, saturated or unsaturated hydrocarbon chains containing from 1 to 12 carbon atoms, substituted by one or more substituents selected from the group consisting of aryloxy, alkoxy, acyloxy, amino, N-acylamino, nitro , cyano, oxo, halogen, -C (O) OR ⁶ and -S (O) _n R ⁵ where R ^{6 is} hydrogen or alkyl, n is 0-2 and is R ^{5 is} hydrogen, cycloalkyl, C 6 -C 12 aryl, substituted cycloalkyl, substituted C 6 -C 12 aryl, alkyl or alkyl substituted with 1 or more substituents selected from the group consisting of alkoxy, acyloxy, amino, N-acylamino, oxo, hydroxy, cycloalkyl, substituted cycloalkyl, aryloxy, -C (O) OR ⁶ , -S (O) nR ⁷ , nitro, cyano, halogen, C ₆ -C ₁₂ aryl, substituted C ₆ -C ₁₂ aryl and protected -OH, where R ^{6 is} hydrogen or alkyl, n is 0-2 and R ^{7 is} hydrogen or alkyl; b) cycloalkyl non-aromatic, unsaturated or saturated, cyclic or polycyclic C ₃ -C ₁₂ which optionally contains one or more heteroatoms and is optionally substituted by one or more substituents selected from the group consisting of aryloxy, aryl , alkyl, alkoxy, acyloxy, cycloalkyl, substituted cycloalkyl, amino, N-acylamino, nitro, cyano, oxo, hydroxy, halogen, -C (O) OR ⁶ , -S (O) _n R ⁵ , protected -OH and alkyl substituted with one or more substituents selected from the group consisting of alkoxy, acyloxy, C ₆ -C ₁₂ aryl, substituted C ₆ -C ₁₂ aryl, amino, N-acylamino, oxo, hydroxy, cycloalkyl, substituted cycloalkyl, - C (O) OR ⁶ , -S (O) _n R ⁷ , aryloxy, nitro, cyano, halogen and protected -OH, where R ^{6 is} hydrogen or alkyl, n 0-2, R ⁷ is hydrogen or alkyl and is R ^{5 is} hydrogen, cycloalkyl, C 6 -C 12 aryl, substituted cycloalkyl, substituted C 6 -C 12 aryl, alkyl or alkyl substituted with one or more substituents selected from the group consisting of alkoxy, acyloxy, cycloalkyl, substituted cycloalkyl, aryloxy, amino, N -acylamino, oxo, hydroxy, -C (O) OR ⁶ , -S (O) nR ⁷ , nitro, cyano, halogen, C ₆ -C ₁₂ aryl, substituted C ₆ -C ₁₂ aryl and protected -OH, where R ^{6 is} hydrogen ah alkyl, n is 0-2 and R ^{7 is} hydrogen ah alkyl; and c) aryl is a cyclic or polycyclic aromatic C ₃ -C ₁₂ containing optionally one or more heteroatoms, provided that when C 3 contains an aromatic ring of at least 2 heteroatoms, and when C 4 contains an aromatic ring of at least one heteroatom, and is optionally substituted by one or more substituents selected from the group consisting of aryloxy, cycloalkyl, substituted cycloalkyl, alkyl, C ₆ -C ₁₂ aryl, alkoxy, acyloxy, substituted C ₆ -C ₁₂ aryl, amino, N-acylamino, nitro, cyano, halogen, hydroxy, -C (O) OR ⁶ , -S (O) nR ⁵ , protected -OH and alkyl substituted with one or more substituents selected from the group consisting of alkoxy, acyloxy, C ₆ -C ₁₂ aryl, substituted C ₆ -C ₁₂ aryl, amino, N-acylamino, oxo, hydroxy, cycloalkyl, substituted cycloalkyl, -C (O) OR ⁶ , -S (O) _n R ⁷ , aryloxy, nitro, cyano, halogen and protected -OH where it is R ^{6 is} hydrogen or alkyl, n is 0-2, R ⁷ is hydrogen or alkyl and is R ^{5 is} hydrogen, cycloalkyl, C 6 -C 12 aryl, substituted cycloalkyl, substituted C 6 -C 12 aryl, alkyl or alkyl substituted with one or more substituents selected from the group consisting of alkoxy, acyloxy, aryloxy, amino, N-acylamino, oxo, hydroxy , -C (O) OR ⁶ , -S (O) nR ⁷ , nitro, cyano, cycloalkyl, substituted cycloalkyl, halogen, C ₆ -C ₁₂ aryl, substituted C ₆ C ₁₂ aryl and protected -OH, where R ⁶ hydrogen or alkyl, n is 0-2 and ^R7 is hydrogen or alkyl, and the pharmaceutically acceptable salts, hydrates, solvates and esters thereof. A compound according to claim 1 of formula II (ID characterized in that A and R are as defined in claim 1; and the pharmaceutically acceptable co-formulants, hydrates, solvates and esters thereof. A compound according to claim 1 or 2, characterized in that A is a straight or branched, saturated or unsaturated hydrocarbon chain containing 1 to 4 carbon atoms and R is a) straight or branched, saturated or unsaturated hydrocarbon chain containing from 1 to 6 carbon atoms substituted by one or more halogens, b) C ₃ -C _g non-aromatic, unsaturated or saturated cycloalkyl optionally substituted by one or more substituents selected from the group consisting of halogen, thio, methylsulfonyl, methylsulfoxite, methylthio, carboxy, hydroxy, trifluoromethyl, phenoxy and methoxy , or c) C ₄ -C ₁₂ aryl, optionally containing one or more heteroatoms, provided that when C 4 contains an aromatic ring, at least one heteroatom, and optionally substituted by one or more substituents selected from the group , which comprises halogen, thio, methylsulfonyl, methylsulfoxyl, methylthio, carboxy, hydroxy, trifluoromethyl, phenoxy and methoxy, and pharmaceutically acceptable salts, hydrates, solvates and esters thereof. A compound of the formula wherein Ύ a or / 3 OH I -C-A-R wherein A and R are as defined in claim 1; and pharmaceutically acceptable salts, hydrates, solvates and esters thereof. 5. A compound selected from the group in which they are 17 / 3- (phenylpropylcarbonyl) -androsta-3,5-diene-3-carboxylic acid, 17 / 3- (Benzylcarbonyl) -androsta-3,5-diene-3-carboxylic acid, 17 / 3- (cyclohexylethylcarbonyl) -androsta-3,5-diene-3-carboxylic acid, 17 / 3- (4-fluorophenylcarbonyl) -androsta-3,5-diene-3-carboxylic acid, 17 / 3- (Phenethylcarbonyl) -androsta-3,5-diene-3-carboxylic acid 17 / 3- (5,5,5-Trifluoro-1-oxopentyl) -androsta-3,5-diene-3-carboxylic acid, 17 / 3- (2-cyclohexyl-1-oxoethyl) -androsta-3,5 -diene-3-carboxylic acid, 17 / 3- (3-methyl-3-phenyl-1-oxobutyl) -androsta-3,5-diene-3-carboxylic acid, 17 / 3- (3- (4 -methoxyphenyl) -1-oxopropyl) -androsta-3,5-diene-3-carboxylic acid, 17 / 3- (3- (4-hydroxyphenyl) -1-oxopropyl) -androsta-3,5-diene-3- carboxylic acid and 17 / 3- (2,6-difluorobenzylcarbonyl) -androsta-3,5-diene-3-carboxylic acid. Pharmaceutical composition comprising a compound according to any one of claims 1 to 5 and a pharmaceutically acceptable carrier. A compound according to any one of claims 1 to 5 for use in therapy. A compound according to any one of claims 1 to 5 for the manufacture of a medicament for use as a steroidal 5-reductase inhibitor. A compound according to any one of claims 1 to 5 for the manufacture of a medicament for use in treatment for reducing prostate size. A compound according to any one of claims 1 to 5 in the manufacture of a medicament for use in the treatment of prostatic adenocarcinoma. 11. An intermediate of the formula where is R ^{2 is} 2-thiopyridylcarbonyl and R ^{3 is} fluorosulfonyloxy or cyano. 12. An intermediate of formula O where A is a straight or branched, saturated or unsaturated hydrocarbon chain containing from 1 to 12 carbon atoms; and R ^{8 is} substituted alkyl, cycloalkyl or aryl, wherein a) substituted straight or branched alkyl, saturated or unsaturated hydrocarbon chains containing from 1 to 12 carbon atoms, substituted by one or more substituents selected from the group consisting of aryloxy, alkoxy, acyloxy, amino, N-acylamino, nitro , cyano, oxo, halogen, -C (O) OR ⁶ and -S (O) _n R ⁵ where R ^{6 is} hydrogen or alkyl, n is 0-2 and is R ⁵ is hydrogen, cycloalkyl, C ₆ -C _r aryl, substituted cycloalkyl. substituted C ₆ -C aryl. alkyl ah alkyl substituted with 1 or more substituents selected from the group consisting of alkoxy, acyloxy, amino, N-acylamino, oxo, hydroxy, cycloalkyl, substituted cycloalkyl, aryloxy, -C (O) OR ⁶ , -S ( O) nR ⁷ , nitro, cyano, halogen, C ₆ -C ₁₂ aryl, substituted C ₆ -C ₁₂ aryl and protected -OH, where R ^{6 is} hydrogen or alkyl, n is 0-2 and R ^{7 is} hydrogen or alkyl; b) cycloalkyl non-aromatic, unsaturated or saturated, cyclic or polycyclic C ₃ -C ₁₂ which optionally contains one or more heteroatoms and is optionally substituted by one or more substituents selected from the group consisting of aryloxy, aryl , alkyl, alkoxy, acyloxy, cycloalkyl, substituted cycloalkyl, amino, N-acylamino, nitro, cyano, oxo, hydroxy, halogen, -C (O) OR ⁶ , -S (O) nR ⁵ , protected -OH and alkyl, substituted with one or more substituents selected from the group consisting of: alkoxy, acyloxy, C6-C ₁₂ aryl, substituted C ₆ -C ₁₂ aryl, amino, N-acylamino, oxo, hydroxy, cycloalkyl, substituted cycloalkyl, -C ( O) OR ⁶ , -S (O) _n R ⁷ , aryloxy, nitro, cyano, halogen and protected -OH, where R ^{6 is} hydrogen or alkyl, n 0-2, R ⁷ is hydrogen or alkyl and is R ^{5 is} hydrogen, cycloalkyl, C ₆ -C ₁₂ aryl, substituted cycloalkyl, substituted C ₆ -C ₁₂ aryl, alkyl or alkyl substituted with one or more substituents selected from the group consisting of alkoxy, acyloxy, cycloalkyl, substituted cycloalkyl , aryloxy, amino, N-acylamino, oxo, hydroxy, -C (O) OR ^6, -S (O) n R ^7, nitro, cyano, halogen, C6-C ₁₂ aryl, substituted C ₆ -C ₁₂ aryl and protected -OH, where R ^{6 is} hydrogen or alkyl, n is 0-2 and R ^{7 is} hydrogen or alkyl; and c) aryl is a cyclic or polycyclic aromatic C ₃ -C ₁₂ containing optionally one or more heteroatoms, provided that when C 3 contains an aromatic ring of at least 2 heteroatoms, and when C 4 contains an aromatic ring of at least one heteroatom, and optionally substituted by one or more substituents selected from the group consisting of aryloxy, cycloalkyl, substituted cycloalkyl, alkyl, C ₆ -C ₁₂ aryl, alkoxy, 'acyloxy, substituted C ₆ -C ₁₂ aryl , amino, N-acylamino, nitro, cyano, halogen, hydroxy, -C (O) OR ⁶ , -S (O) nR ⁵ , protected -OH and alkyl substituted with one or more substituents selected from the group consisting of are alkoxy, acyloxy, C ₆ -C ₁₂ aryl, substituted C ₆ -C ₁₂ aryl, amino, N-acylamino, oxo, hydroxy, cycloalkyl, substituted cycloalkyl, -C (O) OR ⁶ , -S (O) _n R ⁷ , aryloxy, nitro, cyano, halogen and protected -OH where it is R ^{6 is} hydrogen or alkyl, n is 0-2, R ⁷ is hydrogen or alkyl and is R ^{5 is} hydrogen, cycloalkyl, C ₆ -C ₁₂ aryl, substituted cycloalkyl, substituted C ₆ -C ₁₂ aryl, alkyl or alkyl substituted with one or more substituents selected from the group consisting of alkoxy, acyloxy, aryloxy, amino, N-acylamino, oxo, hydroxy, -C (O) OR ⁶ , -S (O) nR ⁷ , nitro, cyano, cycloalkyl, substituted cycloalkyl, halogen, C 6 -C ₁₂ aryl, substituted C ₆ C ₁₂ aryl and protected - OH, where R ^{6 is} hydrogen or alkyl, n is 0-2 and R ^{7 is} hydrogen or alkyl, or moieties which can be chemically converted to moieties a, b or c; and is R ^{4 is} fluorosulfonyloxy, halogen, cyano or -CHO. 13. Intermediate with structure 14. An intermediate of formula wherein A and R ⁸ are as defined in claim 12. A process for the preparation of compounds according to claim 2, characterized in that either OHC i) oxidize a compound of formula (VII) wherein A and R ⁸ are as defined in claim 12, or (ii) metabolize a compound of formula (XI) wherein A and R ⁸ , as described above, are in the coupling reaction, metal catalyzed in the presence of a suitable coupling reagent, preferably carbon monoxide, followed by a facultative, if appropriate, hydrolysis reaction, or (iii) hydrolyzing a compound of formula (XII) in which A and R ⁸ are as described above, or (iv) reacting the compound of formula o wherein A and R ⁸ as described above are in a metal-catalyzed coupling reaction in the presence of a suitable coupling reagent, preferably carbon monoxide, followed by a facultative, if appropriate, hydrolysis reaction, or (v) the compound is reduced at reduced temperature with the formula in the presence of a halogen-Wilsmer reagent and a solvent, then quenched with a Grignard reagent to give a compound of the formula where A and R ⁸ as defined above, and then in a suitable solvent, react this compound with a cyanate reagent to give the compound with of formula wherein A and R ⁸ are as defined above and subsequently saponifying this compound; and optionally converting R ⁸ to R and then optionally forming a pharmaceutically acceptable salt, hydrate or solvate thereof. Use of a compound according to any one of claims 1 to 5 and a? -Receptor antagonist compound in the manufacture of a medicament for use in the treatment of benign pros63-hypertrophy.