PT100388A - METHOD FOR THE COMBINED TREATMENT OF BENIGN PROSTATIC HYPERPLASIA, USING, FOR EXAMPLE, A 17B-SUBSTITUTED STEROID OR AZA-STEROID IN COMBINATION WITH AN AROMATASE INHIBITOR, ESPECIALLY FADRAZOLE - Google Patents

Description

CROSS REFERENCE TO CERTIFIED ORDERS

This application is a continuation-in-part of U.S. application Serial No. 07 / 746,388, (Case 18364IA) filed August 16, 1991, which in turn is a continuation-in-part application of U.S.S.N. 07 / 686,720, (Case 18364) filed April 17, 1991. BACKGROUND OF THE INVENTION 1. Field of the Invention

This invention relates to a novel method of treatment for patients, ie men with benign prostatic hyperplasia (BPH), involving combination therapy by administering therapeutically effective amounts of 5Î ± -reductase inhibitor in combination with an aromatase inhibitor. 2. BACKGROUND OF THE INVENTION Benign prostatic hyperplasia (BPH) affects a substantial number of males over 50 years of age and usually requires surgery at the advanced stages for relieving complaints. It is known that testosterone (T) is secreted by the testis and adrenal glands but can undergo 5α-reductase mediated conversion to dihydrotestosterone (DHT) at peripheral sites including the liver, skin, and prostate. DHT is preferably bound by the nucleus of prostatic cells thus indicating that DHT, instead of T, is the major androgen required by the prostate for its growth and function. This leads to the hypothesis that DHT could be reduced with good prospects for regression of the prostate.

Finasteride, 17β- (N-t-butyl) carbamoyl-4-aza-5α-androst-1-en-3-one, was developed as a compound which was found to inhibit 5α-reductase and which had positive effects against prostatic hyperplasia benign. Finasteride is a 4-azasteroid and a competitive inhibitor of the enzyme. It does not reveal any affinity towards the androgen receptor and thus is not expected to interfere with the binding and action of T on tissues, such as muscle, which responds to T, and thus does not give rise to feminizing characteristics.

Typical inhibitors of the 4-aza steroid 5α-reductase known in the art include those which have been produced by Merck. (See U.S. Patent No. 4,377,584 to Rasmusson, et al., U.S. Patent No. 4,220,735 to Rasmusson et al., U.S. Patent No. 4,845,104 to Carlin, et al .; 4,760,071 by Rasmusson, et al., Which discloses finasteride as being ß7β- (Nt -butyl) carbamoyl-4-aza-5α-androst-1-en-3-one, known by its trade mark as U.S. Patent No. 4,732,897 to Cainelli, et al., U.S. Patent No. 4,859,681 to Rasmusson, et al., EPO Publication 0 155 076, EPO Publication 0,004,949, and EPO Publn. It is also known that small amounts of estrogens, for example oestradiol, can be formed in the testis and prostate by the action of the enzyme, aromatase. It is not clear exactly how these estrogens formed participate biochemically, but they are involved and associated with enlargement of the prostate, i.e. benign prostatic hyperplasia. U.S. Patent No. 4,598,072 to Schering AG describes the combination of that of an aromatase inhibitor and an anti - androgen for the treatment of benign prostatic hyperplasia. However, specific inhibitors of 5-alpha reductase are not suggested or mentioned as suitable anti-androgen agents. What is desired in the art is a combination therapy for both the treatment of the underlying DHT-dependent BPH cause and also to treat the associated cause of estrogen-dependent disease.

SUMMARY OF THE INVENTION

By this invention there is provided a method of treating patients with benign prostatic hyperplasia in need of such treatment comprising administering in combination to such patients therapeutically effective amounts of a 5Î ± -reductase inhibitor, for example a 175, 17β-acyl substituted non azasteroid Carboxyandrost-3,5-diene, benzoylamino-phenoxybutanoic acid derivative, pooled benz (thio) amide or cinnamoylamide derivative, aromatic 1,2-diethers or thioethers, aromatic ortho acylaminophenoxy alkanoic acids, ortho thioalkyl acylaminophenoxy acids alkanoic acids, pharmaceutically acceptable salts and esters thereof, and an aromatase inhibitor. The combined effect of a 5Î ± -reductase inhibitor on the inhibition of DHT production in the prostate and the aromatase inhibitor, i.e., fadrazole, will give rise to a more pronounced effect on growth suppression and symptomatic relief of the enlarged prostate of the prostate. than any agent acting alone.

I 5

SUMMARY DESCRIPTION OF THE

INVENTORY AND PREFERRED EMPLOYMENT

In a preferred aspect, the present invention provides an effective method for treating BPH in patients in need of symptomatic relief by administering therapeutically-effective amounts of the aromatase inhibitor in combination with a 5α-reductase inhibitor or a pharmaceutical composition thereof. The active compounds may be administered together or in any order, as will be described hereinafter. > The term " patients in need of such treatment " means male patients with functioning gonads who are being treated with a 5α-reductase inhibitor in a therapeutic program designed to combat benign prostatic hyperplasia (BPH) and which reveal the need for relief symptomatic. The use of therapeutically effective amounts of the 5Î ± -reductase inhibitor and the aromatase inhibitor according to this invention effectively treats the harmful symptoms of BPH including nocturia, hesitation, decreased urinary flow, etc. Aromatase is an enzyme complex incorporating an NADPH-cytochrome c-reductase and a cytochrome P450 component mediating the conversion of androgens to estrogens, Bellino, J. Steroid Biochem. 17: 261-270 (1982). The reaction is believed to involve three hydroxylation steps, two at the C-19 position (Meyer, Biochem Biophys, Acta 17: 441-442 [1955]; Marato et al., Biochem Biophys. , J. Biol. Chem., 259: 1689-1694 (1984), and Brodie et al., J. Am. Chem. Soc. 91: 1241-348 [1961]) and one in C-2 (Hahn and Fishman, J. Biol. 1242 [1969]) which results in the conversion of the A ring of the androgen molecule into an aromatic ring. Since aromatization consists of a single reaction on steroid biosynthesis, specific inhibitors should not cause deprivation of other essential steroids. Inhibition of the blockade of the conversion of androgens (tetstosterone, androstenedione) to estrogen (estradiol, estrone) results in an accumulation of androgens (testosterone, androstenedione) which may be responsible for participation or through benign prostatic hyperplasia.

An aromatase inhibitor as defined herein is any steroid or non-steroid compound that prevents the conversion of androgens to estrogens. The compounds include analogous substrates of androstenedione, testosterone or other steroidal substances involved in the aromatase pathway, Henderson, J. Steroid Biochem. 27: 905-914 (1987). Non-steroidal compounds which block aromatase activity are also included within the scope of the invention. These non-steroidal compounds include compounds or analogs which can bind to the enzymatic active site of aromatase and which inhibit enzymatic activity. Non-steroidal or steroid compounds also include compounds or analogs which bind to the enzyme at a site far from the enzyme site and which lead to a structural change in the enzyme which leads to a loss of enzyme activity. Aromatase inhibitors further include non-steroidal compounds that interfere with P450 cytochrome mediated hydroxylations such as those described by Brodie, et al., J. Steroid Biochem. 27: 899-903 (1987).

The following compounds are known non-steroidal aromatase inhibitors as indicated by the related reference. The reference will also contain a method for producing the compound or will direct one who wishes to use the compound in a method for producing the compound. Inhibitors of 7

aromatase inhibitors of the present invention known in the art include, but are not limited to, the following compounds: [(1H-imidazol-1-yl) phenylmethyl] -1-methyl-1H-benzotriazole, 6 - [(4- chlorophenyl) (1H-1,2,4-triazol-1-yl) methyl] -1-methyl-1H-benzotriazole as described in EPO Publication No. 293,978, and USP 4,943,574; 2,2- [5- (1H-1,2,4-triazol-1-ylmethyl) -1,3-phenylene] di (2-methylpropionitrile), 2,2- [5- (imidazol- ylmethyl) -1,3-phenylene] -di (2-methylpropiononitrile), 2- [3- (1-hydroxy-1-methylethyl) -5- (1H-1,2,4-triazol-1-ylmethylphenyl) ] -2-methylpropiononitrile, 2,2- [5-di-deuterio- (1H-1,2,4-triazol-1-yl) methyl-1,3-phenylene] di (2-tridecydromethyl- (2-methyl-propiononitrile), and 2,2- [5-dideuterium (1H-1,2,4-triazol-1-ylmethyl-1,3-phenylene) nitrile) as disclosed in European Patent Application, Publication No. 296,749; 1,1-Dimethyl-8- (1H-1,2,4-triazol-1-ylmethyl) -2 (1H) -naphtho [2 , 1 H -1,2,4-triazol-1-ylmethyl) naphtho [2,1-b] furan-1-ylmethyl) -1H-1,2,4- 7-carbonitrile, 1,2-dihydro-1,1-dimethyl-2-oxo-8- (1H-1,2,4-triazol-1-ylmethyl) naphtho [2,1b] furan-7- carboxamide, and 1,2-dihydro-1,1-dimethyl-2-oxo-8- [di (1H-1,2,4-triazol-1-yl) methyl] naphtho [2,1- b] furan -7-carbonitrile as disclosed in European Patent Application, Publication No. 316,097; 2- (4-chlorobenzyl) -2- difluoro-1,3-di (1,2,4-triazol-1-yl) propane, 2-fluoro-2- (2-fluoro-4-chlorobenzyl) -1,3-di 2-fluoro-2- (2-fluoro-4-trifluoromethyl-benzyl) -1,3-di (1,2,4-triazol-1-yl) propane, 3 - (4-chlorophenyl) -1- (1,2,4-triazol-1-yl) -2- (1,2,4-triazol-1-ylmethyl) butan-2-ol, 2- (4- chloro-α-fluorobenzyl) -1,3-di (1,2,4-triazol-1-yl) propan-2-ol, 2-4- (4-chlorobenzyl) -1,3-bis 2,4-triazol-1-yl) propane, 4- (2- (4-chlorophenyl) -1,3-di (1,2,4-triazol-1-ylmethyl) ethoxymethyl] benzonitrile, 1 - (4-fluorobenzyl) -2- (2-fluoro-4-trifluoromethyl-phenyl) -1,3-di (1,2,4-triazol-1-yl) propan- chlorophenyl) -1- (4-fluorophenoxy) -1,3-di (1,2,4-triazol-1-yl) propan-2-ol, 1- (4-cyanobenzyl) -2- ( 2,4-difluorophenyl) -1,3-di (1,2,4-triazol-1-yl) -propan-2-ol, and 2- (4-chlorophenyl) -1- (1,2,4-triazol-1-yl) -propan-2-ol as described in European Patent Application, Publication No. 299,684; 5-bis (4-chlorophenyl) -methylpyrimidine as set forth in U.S. Patent No. 4,762,836; α, α-bis (4-chlorophenyl) -2-pyrazinamethanol as described in U.S. Patent No. 4,764,376; N- (2,4-difluorophenyl) -N-benzyl-3-pyridinemethanamine and N- (2-chlorophenyl-α- (4-fluorophenyl) -3-pyridinemethanamine as disclosed in U.S. Patent No. 4,744,251; 1- (10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5-yl) -1H-imidazole and 1- (9H-fluoren-9-yl) -1H-imidazole as disclosed in U.S. Pat. No. 4,757,082; 3-bis (4-chlorophenyl) -3-methylpyridine and α, α-bis (4-chlorophenyl) -3-pyridinemethanol as disclosed in U.S. Patent No. 4,757,076; 5H- 5- (4-cyanophenyl) -6,7-dihydro-pyrrolo [1,2-c] imidazole and 5H-5- (4-cyanophenyl) -6,7,8,9-tetrahydroimidazo [ 5-a] azepine and are disclosed in U.S. Patent No. 4,728,645; 5 - [(β-imidazol-1-yl) phenylmethyl] -2-methyl-Î ± -benzimidazole and 5- (3-chlorophenyl) -imidazol-1-yl) -methyl] -1H-benzimidazole as disclosed in European Patent Application No. 260,744; (Z) -α- (1,2,4-triazol-1-ylmethyl-stilbene- 4,4'-dicarbonitrile, (Z) -4'-chloro-α- (1,2,4-triazol-1-ylmethyl) -stilbene-4,4'-dicarbonitrile, (Z) -α- 2.4 1-ylmethyl-4 '- (trifluoromethyl) stilbene-4-carbonitrile, (E) -β-fluoro-α- (1,2,4-triazol-1-ylmethyl) stilbene-4,4' (imidazol-1-ylmethyl) -stilbene-4-carbonitrile, (Z) -2 ', 4'-dichloro-α- (imidazol-1-yl) (imidazol-1-ylmethyl) stilbene-4-carbonitrile, (Z) -α- (imidazol-1-ylmethyl) stilbene-4-carbonitrile, (Z) -α- (5-methylimidazol-1-ylmethyl) stilbene-4,4'-dicarbonitrile, and (Z) -2- [2- (4-cyanophenyl) - 3- (1,2,4-triazol-1-yl) propenyl] pyridine-5-carnonitrile as disclosed in European Patent Application No. 299,683; (1R *, 2R *) - 6-fluoro-2- (4-fluorophenyl) -1,2,3,4-tetrahydro-1- (1H-1,2,4-triazol-1-ylmethyl) naphthalene, 9

(1R *, 2E *) - 6-fluoro-2- (4-fluorophenyl) -1,2,3,4-tetrahydro-1- (1H-imidazolylmethyl) -naphthalene, (1R *, 2R *) - and (1R *, 2S *) -2- (4-fluoro-phenyl) -1,2,3,4-tetrahydro-1- (1H-1,2,4-triazol-1-ylmethyl) naphthalen- (1R *, 2E *) and (1R *, 2S *) -2- (4-fluorophenyl) -1,2,3,4-tetrahydro-1- (1H-imidazolylmethyl) naphthalene-6- carbonitrile, (1R *, 2R *) - and (1R *, 2S *) - 1,2,3,4-tetrahydro-1- (1H-1,2,4-triazol-1-ylmethyl) naphthalene-2 (1R *, 2R *) - and (1R *, 12S *) - 1,2,3,4-tetrahydro-1- (1H-imidazol-1-ylmethyl) naphthalene-2,6-dicarbonitrile dicarbonitrile, and (1R *, 2S *) -2- (4-fluorophenyl) -1,2,3,4-tetrahydro-1- (5-methyl-1H-imidazolylmethyl) naphthalene-6-carbonitrile such as are shown in European Patent Application No. 281,283; 8-chloro-5- (4-chlorophenyl) -5H-indeno [1,2-d] pyridine as set forth in U.S. Patent No. 4,769,378; 5-bis (4-chlorophenyl) methylpyrimidine as disclosed in U.S. Patent No. 4,762,836; 10- (2-propynyl) -str-4-ene-3,17-dione as set forth in U.S. Patent No. 4,322,416; 6 - [(4-chlorophenyl) (1H-1,2,4-triazol-1-yl) methyl] -1-methyl-1H-benzotriazole as described in European Patent Application, Publication No. 293,978; 1-methylandrosta 1,4-diene-3,17-dione (Schering AG) as disclosed in U.S. Patent No. 4,591,585; 3-ethyl-3- (4-pyridyl) piperidine-2,6-dione as disclosed in British Patent GB 2,151,266; 4-hydroxyandrostene-3,17-dione as disclosed in U.S. Patent No. 4,500,523; 4- (5,6,7,8-tetrahydroimidazo [1,5-a] pyridin-5-yl) benzonitrile (fadrazole) as disclosed in U.S. Patent No. 4,728,645 and 4- [alpha - (4-cyanophenyl) -1- (1,2,4-triazolyl) methyl] benzonitrile as disclosed in USP 4,978,672, both to Ciba-Geigy; 6-methylene-androsta-1,4-diene-3,17-dione, 4-amino-adrostan-1,4,6-trien-3,17-dione and 4-aminoandrosta-4,6-diene -3,17-dione as disclosed in U.S. Patent No. 4,757,061; 3- (1H-imidazol-1-ylmethyl) -2-methyl-1H-indole-1-propanoic acid as disclosed in U.S. Patent No. 4,273,782; 5- (3-chlorophenyl) (1H-imidazol-1-yl) methyl] -1H-benzimidazole as disclosed in European Patent Application, Publication No. 260,744; 10B-thiandranilestr-4-ene-3,17-dione and 10B-oxiranilestr-4-ene-3,17-dione as set forth in J. Org. Chem. 53: 5947-5951 (1988); 3-ethyl-3- (4-pyridyl) piperidine-2,6-dione as described in U.S. Patent No. 4,668,689; 3- (4-aminophenyl) -3-ethyl-pyrrolidine-2,5-dione as set forth in J. Med. Chem. 29: 520-523 (1986); 1- (7-carboxyheptyl) imidazole as described in U.S. Patent No. 4,320,134; 1,1-dimethyl-8- (1H-1,2,4-tetrazol-1-ylmethyl) -2 (1H) -napht- [2,1-b] furanone (la) as set forth in Request European Patent Publication No. 316,097; 1,3,5-androsatriene-3,17-dione disclosed in Biochem. Pharmac. 31; 2017-2023 (1982) and other compounds well known in the art of aromatase inhibition and cancer therapy such as bis- (p-cyanophenyl) imidazol-1-yl-methane hemisuccinate and derivatives thereof, acid and stereochemically isomeric forms, if appropriate and pharmaceutically acceptable.

Preferred for use in the present invention is ribazole. The invention is also intended to include any biologically active equivalents of an aromatase inhibitor as described above.

Preferred is when the 4-aza steroid has the formula:

Wherein the dashed line represents a double bond when present; R 2 and R 3 are independently hydrogen, methyl or ethyl; R is a hydrocarbon radical selected from substituted or unsubstituted straight or branched alkyl, cycloalkyl or aralkyl of 1-12 carbons or monocyclic aryl optionally containing 1 or more lower alkyl substituents of 1-2 carbon atoms and / or 1 or more halogen substituents; R 'is hydrogen or methyl; R " is hydrogen or B-methyl; R '' 'is hydrogen, α-methyl or β-methyl, and pharmaceutically acceptable salts or esters thereof. )

A preferred embodiment of the compound of formula I applicable in the process of our invention is represented by the formula:

Wherein R 1 is hydrogen, methyl or ethyl, and R 2 is branched chain alkyl, cycloalkyl, aralkyl of 4-12 carbons, phenyl, optionally substituted by methyl, chloro or fluoro, 1, 2-adamantyl , 1-, 2-adamantylmethyl, 1-, 2- or 7-norbornanyl, 1-, 2- or 7-norbornanylmethyl groups.

Representative compounds of the present invention include the following: 17β- (N-tert-amylcarbamoyl) -4-aza-5α-androst-1-en-3-one, 17β- (N-tert -hexylcarbamoyl) -4-aza 17β- (N-tert-butylcarbamoyl) -4-aza-5α-androst-1-en-3-one, 17β- (N-isobutylcarbamoyl) -4-aza- 17β- (N-tert-octylcarbamoyl) -4-aza-5α-androst-1-en-3-one, 17β- (N-octylcarbamoyl) -4-aza- 17β- (N-1,1-diethylcarbamoyl) -4-aza-5α-androst-1-en-3-one, 17β- (N ', 1-neopentylcarbamoyl) -4- 17β- (N-2-adamantylcarbamoyl) -4-aza-5α-androst-1-en-3-one, 17β- (N-adamantylcarbamoyl) -4-aza-5α-androst- 5-androst-1-en-3-one, 17β- (N-2-norbornylcarbamoyl) -4-aza-5α-androst-1-en-3-one, 13

17β- (N-phenylcarbamoyl) -4-aza-4-methyl-5α-androst-1-en-17β- (η-1-norbornylcarbamoyl) -4-aza-5α-androst- 17β- (N-tert-amylcarbamoyl) -4-aza-4-methyl-17β- (N-benzylcarbamoyl) -4-aza-4-methyl-5α-androst- 17β- (N-tert-Hexylcarbamoyl) -4-aza-4-methyl-5Î ± -androst-1-en-3-one, 17β- (N-tert- butylcarbamoyl) -4-aza-4-methyl-5a-androst-1-en-3-one, 17β- (N-isobutylcarbamoyl) -4-aza-4-methyl-5α-androst- , 17β- (N-tert-octylcarbamoyl) -4-aza-4-methyl-5α-androst-1-en-3-one, 17β- (η -1,3,3,3-tetramethylbutylcarbamoyl) -4-aza 17β- (N-1,1-diethylbutylcarbamoyl) -5β-androst-1-en-3-one, 17β- (N-octylcarbamoyl) -4-aza- 17β- (N-neopentylcarbamoyl) -4-aza-4-methyl-5α-androst-1-en-3-one, 17β- 17β- (N-adamantylcarbamoyl) -4-methyl-4-aza-5α-androst-1-en-3-one, 17β- (N α -adamantylcarbamoyl) -4-aza-5α-androstan- N-adamantylcarbamoyl) -4-methyl-4-aza-5α-androstan-3-one, 17β- (N-adamantylmethylca 17β- (η2-adamantylcarbamoyl) -4-aza-5α-androstan-3-one, 17β- (N-methyl-N- 17β- (γ-2-adamantylcarbamoyl) -4-methyl-4-aza-5α-androstan-3-one, 17β- (2-adamantylcarbamoyl) -4-aza-5α-androstan- 17β- (N-methyl-N-2-adamantyl) carbamoyl-4-methyl-4-aza-5α-androst-1-en- androst-1-en-3-one, 17β- (N- (3-methyl) -1-adamantylcarbamoyl) -4-aza-4-methyl-5α-androstan- 2-norbornanylcarbamoyl) -4-aza-4-methyl-5α-androst-1-en-3-one, 17β- (N-exo-2-norbornanylcarbamoyl) -4- 17β- (N-methyl-N-2-adamantylcarbamoyl) -4-aza-5α-androst-en-3-one, 17β- (N-2-adamantylcarbamoyl) -4- 4-methyl-androstan-3-one

17β- (η-2-adamantylcarbamoyl) -4-methyl-4-aza-5α-androstan-3-one; and 17β- (N-methyl-N-2-adamantyl) carbapol-4-methyl-4-aza-androst-1-en-3-one.

The corresponding compounds of the above compounds wherein the 4-aza substituent is substituted in each of the above compounds with a hydrogen, or a methyl or ethyl radical, to form a different N-substituent, and wherein the double bond may optionally be present as indicated by dotted line at position 1.

The alkyl, cycloalkyl, aralkyl, monocyclic aryl, 1-, 2-adamantyl or 1-, 2-norbornanyl moieties may be substituted with one or more of the following substituents: linear or branched, including methyl, ethyl, isopropyl, n-butyl; nitro; oxo; cy "aralkyl, including benzyl; (CH2) n COOR where n is 0-2 and R is H or linear or branched C1 -C4 alkyl including methyl, ethyl; halo, including fluoro, bromo, iodo; COOH; COOR, where R is linear or branched C1 -C4 alkyl; -CONH2; CH2 NH2; Wherein R is linear or branched alkyl including methyl, ethyl; phenyl; phenyl substituted o, m, p including p-nitro, p-amino and p-sulfo; or cyano. The amino group of the adamantyl or norbornanyl moiety may also be substituted as Rx with methyl and ethyl, as well as hydrogen.

Also within the scope of this invention are pharmaceutically acceptable salts or esters wherein a basic or acidic group is present in the substituted alkyl, cycloalkyl, aralkyl, adamantyl or norbornanyl moiety. When an acidic substituent, i.e. -COOH, is present, the ammonium, sodium, potassium, calcium, etc. salts may be formed for use as a dosage form. 15

When a basic group is present; i.e. amino, acidic salts, i.e. hydrochloride, hydrobromide, acetate, pamoate, etc., can be used as the dosage form.

Also, where the -COOH group is present, pharmaceutically acceptable esters, for example acetate, maleate, pivaloyloxymethyl, etc., and esters known in the art may be used for modifying the solubility or hydrolysis characteristics for use as release formulations prolonged or prodrug. . 2

Representative examples include for R (where AD is adamantyl): 3,5,7-trinitro-1-AD; 4-oxo-1-AD; 1-benzyl-1-AD; 4,4-dimethyl-1-Ad; 3,7-dimethyl-5-carboxymethyl-1-AD; 3-carboxymethyl-1-AD; 3-chloro-1-AD; 1,3-dihydroxy-6,6-dimethyl-2-AD; 3-chloro-1-AD; 4-carbethoxy-2-AD; 4-carboxy-2-AD; 3-isopropyl-1-AD; 3-n-butyl-1-AD; 3-propyl-1-AD; 3, 5-diethyl-1-AD; 3-hydroxymethyl-1-AD; 2-carboxy-1-AD; 3-methyl-1-AD; 5-hydroxy-2-AD; 2-hydroxy-1-AD; 1-aminomethyl-1-hydroxy-2-AD; 2-oxo-1-AD; 2-phenyl-2-AD; 1-amino-methyl-2-AD; 1-carboxy-2-AD; 1-aminocarbonyl-2-AD; 3-hydroxy-5,7-dimethyl-1-AD; 4-fluoro-1-AD; 3-fluoro-1-AD; 4-hydroxy-2-AD; 3-phenyl-1-AD; 3- (p-aminophenyl) -1-AD; 3- (p-nitrophenyl) -1-AD; Methyl-5-hydroxymethyl-1-AD; 3,5-dimethyl-4-hydroxy-1-AD; 2-hydroxymethyl-2-AD; 3- (p-sulfophenyl) -1-AD; 3-methyl-5-ethyl-1-AD; 2-carboxy-2-AD; 3,5,7-trimethyl-1-AD; 4-iodo-2-AD; 4-bromo-2-AD; 4-chloro-2-AD; 1-acetylaminomethyl-2-AD; 1-carbomethyl-2-AD; 1-methyl-2-AD; 1-aminocarboxymethyl-2-AD; 1-aminocarbonyl-1-AD; 2-cyano-2-AD; 3,5-dimethyl-7-ethyl-1-AD; 4-hydroxy-1-AD; 1-hydroxy-2-AD; Carboxy-3-methyl-1-AD; 3,5-dimethyl-7-carboxy-1-AD; 3-carboxy-1-AD; 3-hydroxy-1-AD; etc. 2

Representative examples included for R as substituted norbornanyl moieties are (when NB is norbornanyl): 2-NB; 1,7,7-trimethyl-4-phenyl-2-NB; 3-carboxy-2-NB; 3-phenyl-2-carboxy-2-ΝΒ; 2-cyano-3-phenyl-2-NB; 3-hydroxy-4,7,7-trimethyl-2-NB; 6-hydroxymethyl-2-NB; 5-cyano-2-NB; 3-allyl-2-NB; 1-NB; 7,7-dimethyl-1-hydroxymethyl-2-ΝΒ; 3-methoxy-4,7,7-trimethyl-2-NB; 3-aminocarbonyl-2-ΝΒ; 3-ethoxycarbonyl-2-NB; 3,3-dimethyl-2-NB; 7-oxo-1-NB; 3-phenyl-2-NB; 1-carboxymethyl-7,7-dimethyl-2-NB; 1-ethyl-2-ΝΒ; 1-methyl-2-NB; 2,2,3,3,5,5,6,6,7,7-decafluoro-1-NB; 3-hydroxy-2-β-chloro-2-NB; 3- (p-methoxyphenyl) -2-NB; 2,2-dimethyl-3-methylene-7-NB 3-OXO-2-NB; 1-methoxy-2-ΝΒ; 7-NB; 3-isopropyl-2-NB; 2-bromo-1-NB; 3-chloro-1-NB; etc.

Processes for the preparation of compounds of Formula I useful in this invention, including those mentioned above, are well known in the art.

The novel compounds of formula I of the present invention may be prepared by a method starting with the known ester ester (IIIA) of the formula:

COOR

IIIA

O

IHR 17β- (carboxy) -4-aza-5-a-androstan-3-ones which includes the optionally 1) dehydrogenation stages of said starting material to produce the corresponding compound containing a double bond in the 1,2 position of the ring A, 2) converting the 17-carbomethoxy substituent to an N-substituted alkyl, cycloalkyl, aralkyl, monocyclic acyl, or adamantylcarbamoyl substituent and, if desired, 3) alkylating the ring A nitrogen in order to introduce an N-methyl substituent or N-ethyl at the 4-position of ring A. For the dehydrogenation step, it is preferred that the 4-aza nitrogen is unsubstituted. The alternative routes may consist of one or more discrete chemical steps and if desired may take place prior to step (1) or following step (1) or step (3).

According to the process of the present invention (see flow sheet), the products of our invention are formed by optionally: (1) heating 176-alkoxycarbonyl-4-aza-5α-andros-3-ones, compound III ; (prepared in the literature as described in U.S. Patent No. 4,377,584) with a dehydrogenating agent such as benzenesseleninic anhydride in an inert refluxing solvent, for example chlorobenzene, to form a 17β-alkoxycarbonyl-4-aza- 5a-androst-1-ene-3-one IV (alternatively, the dichlorodicyanoobenzoquinone process of Dolling, et al., JACS 1988, Vol. 110, pp. 3318-3319) may be used; (2) the 5α-androst-1-en-3-one compound formed from Step 1 can be reacted with, for example, sodium hydride under anhydrous conditions in a neutral solvent such as dimethylformamide; (3) contacting the resulting reaction mixture with an alkyl (methyl or ethyl) iodide to form the corresponding 17β-alkoxyaminocarbamoyl-4-alkyl-4-aza-5α-androst-1-en-3 -one V; (4) subsequent hydrolysis of said 17B-alkoxycarbonyl-4-alkyl-4-aza-5a-androst-1-en-3-one with a strong base such as aqueous methanolic potassium hydroxide at the reflux temperature, acidification and isolation of steroidal acid 18

resulting to provide 17B-carboxy-4-alkyl-4-aza-5Î ± -androst-1-en-3-one; (5) said steroidal acid can then be converted to its corresponding 2-pyridylthio ester by refluxing with triphenyl phosphine and 2,2'-dipyridyl disulfide in an inert solvent such as toluene and the resulting 17α- (2-pyridylthiocarbonyl) -4-alkyl-4-aza-5α-androst-1-en-3-one VII can be isolated by chromatography on, for example, silica gel; and (6) said pyridylthio ester can then be reacted with 1-adamantyl-, 2-adamantylamine or norbornanylamine in an inert solvent, for example tetrahydrofuran, to form the desired product 176-N-adamantylcarbamoyl-4-alkyl-4- aza-5α-an-drost-1-en-3-one VIII which can be isolated by chromatography, for example on silica gel. When the above reaction is carried out in the absence of first formation of the double bond at position 1, the corresponding 17β- (N-adamantylcarbamoyl) -4-alkyl-4-aza-5α-androstan-3-one ( or N-norbornane-nylcarbamoyl compound).

According to an alternative process of our invention the corresponding N-unsubstituted 17β- (N-adamantyl-carbamoyl) -4-aza-5α-androst-1-en-3-one is prepared rapidly from 17β 4-aza-5α-androstene-3-one by repeating the above repeated series of the reaction steps but omitting the alkylation Step 2 above, i.e. treatment of 4-aza-5-a-androst- 1-en-3-one with, for example, sodium amide followed by methyl or ethyl iodide via intermediates XII and XIII.

According to another alternative process for preparing the compounds of our invention having only hydrogen as the sole substituent on ring A nitrogen, the double bond on ring A is introduced in the last step of the process. Thus, a 17B-alkoxycarbonyl 4-aza-5a-androstan-3-one III is hydrolyzed to give 19

to the corresponding steroidal acid 17Î ± -carboxy-4-aza-5Î ± -androstan-3-one which is converted to the corresponding pyridylthio ester, 17β- (2-pyridylthiocarbonyl) -4-aza-5Î ± - androstane-3-one, X is followed by treatment of the ester with an amine of the formula R 1 -NR 3 wherein R 2 is as hereinbefore defined as 1- or 2-adamantyl or 1-, 2- - or 7-norbornanyl to form a 17B (N-adamantyl-carbamoyl) -4-aza-5a-androstone-3-one which is dehydrogenated as previously described to produce compound XIV, 17β- (N- adamantyl-carbamoyl) -4-aza-an-dost-1-en-3-one or the corresponding norbornanyl derivative.

In another alternative method of introducing 17β- (B-adamantyl-carbamoyl) substituent into a 17β-carboxy androstane compound of formula VI, XII or IX, each is treated in a similar manner to the procedure described in Steroids. Vol. 35, No. 3, March 1980, p. 1-7 with dicyclohexylcarbodiimide and 1-hydroxybenzotriazole to form 17β- (1-benzotriazoloxycarbonyl) -4-aza-5α-androst-1-en-3-one, VII, XIII or compound X, wherein the substituent X is benzotriazoloxy group. The 16-methyl derivative wherein R "" is methyl is prepared from known 16-methyl-17-acyl-4-methyl-4-aza-5α-androstan-3-ones, for example 4,16β-dimethyl -17β-acetyl-4-aza-5α-andros-3-one by known dehydrogenation procedures for 4-methyl-4-aza compounds to yield the corresponding 4,16β-dimethyl-17β-acetyl- aza-5α-androst-1-en-3-one.

The above reactions are shown schematically in the flow sheet below. 20 Flow Sheet

X is 2-pyridylthio or 1-benzotriazoloxy. R 2 is 1- or 2-adamantyl or norbornanyl. 21

Also a preferred 4-azasteroid is a 17β-acyl-4-aza-5α-androst-1-ene-3-one compound of the formula:

W

R 1 '' 1

IA wherein the dotted line represents a double bond when present; R is selected from hydrogen, methyl and ethyl; R 2 is (a) a monovalent radical selected from straight chain or branched alkyl, or cycloalkyl, of 2-12 carbons, which may be substituted by one or more C 1 -C 2 alkyl or halo; (b) an aralkyl radical selected from benzyl or phenethyl; (c) a polycyclic aromatic radical which may be substituted with one or more of: -OH, -CO 2 -C 4 alkyl, C 1 -C 4 alkyl, halo or nitro; (d) a monocyclic aromatic radical which may be substituted with one or more of: (1) -OH, -OC1 -C4 alkyl, -OC4 OH, - (CH2) n / protected hydroxy, where m is 1-4, n is 1-3, providing C 1 -C 4 alkyl is present only when one of the oxygen-containing radicals referred to above is present: (2) -SH, -SC 1 -C 4 alkyl, - (C1-4) alkyl, -SO2 C1-4 alkyl, -30 ((C1 -C4) alkyl, -C2 -C4 alkyl- (CH2) s, -S- (CH2) n -O- Wherein m is 1-4, n is 1-3, providing C 1 -C 4 alkyl is present only when one of the above sulfur containing radicals is present, (3) N (R) 2, which may be protected, where R is independently H or C 1 -C 4 alkyl, wherein the monoaryl ring may also be further substituted with C 1 -C 4 alkyl, and (4) heterocyclic radical selected from 2- or 4-pyridyl, 2-pyrrolyl, 2-furyl or thiophenyl, and R ', R "and R" are each selected from hydrogen and methyl, and pharmaceutically acceptable salts thereof see

A preferred embodiment of the compounds of our process of the invention is: the compound of Structure IA above, wherein the dotted line is a double bond, R is hydrogen or methyl, and R 2 is branched alkyl, or cyclo with 4-10 carbons, and R "and R" are hydrogen. Another embodiment of the invention 2 are the compounds of structure I above wherein R is phenyl, or phenyl substituted by substituents described above, including those wherein R 2 is phenyl, 2-, 3-, or 4-tolyl, xylyl , 2-bromophenyl, 2-chlorophenyl, 2,6-dichlorophenyl, 2,6-dibromophenyl, aminophenyl, N-alkylaminophenyl, Ν-dialkylaminophenyl, 4-biphenyl, 3-biphenyl, naphthyl, anthracyl, phenanthryl , thiophenyl, methylthiophenyl, methylsulfinyl, phenyl, methylsulfophenyl, aminosulfophenyl, thioethylphenyl, acetoxymethylthiophenyl, 17β- (4-hydroxyphenyl), 17β- (3-hydroxyphenyl), 17β- (3,4-dihydroxyphenyl), or 17β- , 5-dimethyl-4-hydroxyphenyl.

Representative compounds of the invention are: 17β- (phenylcarbonyl) -4-aza-4-methyl-5α-androst-1-ene-34-one; 17β- (2-tolylcarbonyl) -4-aza-4-methyl-5α-androst-1-ene-3-one; 17β- (3-tolylcarbonyl) -4-aza-4-methyl-5α-androst-1-ene-3-one; 17β- (4-tolylcarbonyl) -4-aza-4-methyl-5α-androst-1-ene-3-one; 17β- (2-bromophenylcarbonyl) -4-aza-4-methyl-5α-androst-1-ene-3-one; 17β- (2-chlorophenylcarbonyl) -4-aza-4-methyl-5α-androst-1-ene-3-one; 17β- (2,6-dichlorophenylcarbonyl) -4-aza-4-methyl-5α-androst-1-ene-3-one; 17β- (2,6-dibromophenylcarbonyl) -4-aza-4-methyl-5α-androst-1-ene-3-one; 17β- (xylylcarbonyl) -4-aza-4-methyl-5α-androst-1-ene-3-one; 17β- (t-butylcarbonyl) -4-aza-5α-androst-1-ene-3-one; 17β- (isobutylcarbonyl) -4-aza-5α-abdrost-1-ene-3-one; 7β- (isooctylcarbonyl) -4-aza-5α-abdrost-1-ene-3-one; 17β- (n-octylcarbonyl) -4-aza-5α-androst-1-ene-3-one; 17β- (1,1-diethylbutylcarbonyl) -4-aza-5α-androst-1-ene-3-one; 17β- (neopentylcarbonyl) -4-aza-5α-androst-1-ene-3-one; 17β- (tert-amylcarbonyl) -4-aza-4-5a-androst-1-ene-3-one; 17β- (tert-hexylcarbonyl) -4-aza-4-5a-androst-1-ene-3-one; 17β- (cyclohexylcarbonyl) -4-aza-5α-androst-1-en-3-one; 17β- (cyclopentylcarbonyl) -4-aza-5α-androst-1-ene-3-one; 17β- (benzylcarbonyl) -4-aza-5α-androst-1-ene-3-one; 17β- (2-pyridylcarbonyl) -4-aza-5α-androst-1-en-3-one; 17β- (4-pyridylcarbonyl) -4-aza-5α-androst-1-ene-3-one; 17β- (2-pyrrolylcarbonyl) -4-aza-5α-androst-1-ene-3-one; 17β- (2-furylcarbonyl) -4-aza-5Î ± -androst-1-ene-3-one; 17β- (2-thiophenylcarbonyl) -4-aza-5α-androst-1-ene-3-one; 17β- (2-adamantylcarbonyl) -4-aza-5α-androst-1-ene-3-one; 17β- (phenylcarbonyl) -4-aza-5α-androst-1-ene-3-one; 24 - I ι

17β- (2-tolylcarbonyl) -4-aza-5α-androst-1-ene-3-one; 17β- (3-tolylcarbonyl) -4-aza-5α-androst-1-ene-3-one; 17β- (4-tolylcarbonyl) -4-aza-5α-androst-1-ene-3-one; 17β- (2-bromophenylcarbonyl) -4-aza-5α-androst-1-ene-3-one; 17β- (2-chlorophenylcarbonyl) -4-aza-5α-androst-1-ene-3-one; 17β- (2,6-dichlorophenylcarbonyl) -4-aza-5α-androst-1-ene-3-one; 17β- (2,6-dibromophenylcarbonyl) -4-aza-5α-androst-1-ene-3-one; 11S- (xylylcarbonyl) -4-aza-5α-androst-1-ene-3-one; 17β- (phenylethyl) carbonyl-4-aza-5α-androst-1-ene-3-one; 17β- (4-dimethylaminoÂphenylcarbonyl) -4-aza-5α-androst-1-en-3-one; 17β- (3,4-diethylaminophenylcarbonyl) -4-aza-5α-androst-1-en-3-one # 17β- (3,5-dimethyl-4-diethylaminophenylcarbonyl) -4-aza-5α-androst-1-en-3-one; 17β- (4 "N -methylaminomethylphenylcarbonyl) -4-aza-5α-androst-1-en-3-one; or 17β- (2-N-ethylamino-4-ethylphenylcarbonyl) -4-aza-5α-androst-1-en-3-one. 17β- (4-phenylbenzoyl) -4-aza-5α-androst-1-en-3-one; 17β- (3-phenylbenzoyl) -4-aza-5α-androst-1-en-3-one; 17β- (4-biphenyl) -4-aza-5α-androst-1-en-3-one; 17β- (3-biphenyl) -4-aza-5α-androst-1-en-3-one; 17β- (1-naphthyl) -4-aza-5α-androst-1-en-3-one; 17β- (2-naphthyl) -4-aza-5α-androst-1-en-3-one; 17β- (1-phenanthryl) -4-aza-5α-androst-1-en-3-one; 17β- (2-phenanthryl) -4-aza-5α-androst-1-en-3-one; 17β- (1-biphenyl) -4-aza-5α-androst-1-en-3-one; 17β- (9-antracil) -4-aza-5α-androst-1-en-3-one; 17β- (4-thiophenylcarbonyl) -4-aza-5α-androst-1-en-3-one; 17β- (3-thiophenylcarbonyl) -4-aza-5α-androst-1-en-3-one; 17β- (4-methylthiophenylcarbonyl) -4-aza-5α-androst-1-en-3-one; 17β- (4-methylsulfinylphenylcarbonyl) -4-aza-5α-androst-1-en-3-one; 17β- (4-methylsulfophenylcarbonyl) -4-aza-5α-androst-1-en-3-one; 17β- (3-methylsulfinylcarbonyl) -4-aza-5α-androst-1-en-3-one; 17Î ± - (4-N, N-dimethylaminosulfophenylcarbonyl) -4-aza-5Î ± -androst-1-e-η-3-one; 17β- (2-ethyl-4-methylthiophenylcarbonyl) -4-aza-5α-androst-1-en-3-one; 17β- (4-thioethylphenylcarbonyl) -4-aza-4-methyl-5α-androst-1-en-3-one; 17β- (4-acetoxymethylthiophenylcarbonyl) -4-aza-4-methyl-5α-androst-1-en-3-one; 17β- (2-methyl-4-methylthiophenylcarbonyl) -4-aza-4-methyl-5α-androst-1-en-3-one; 17β- (2-methyl-4-methylsulfinylphenylcarbonyl) -4-aza-4-methyl-5α-androst-1-en-3-one; 17β- (2-isopropyl-4-methylsulfophenylcarbonyl) -4-aza-4-methyl-5α-androst-1-en-3-one; 17β- (4-methylthiophenylcarbonyl) -4-aza-4-methyl-5α-androstan-3-one; 17β- (4-methylsulfinylphenylcarbonyl) -4-aza-4-methyl-5α-androstan-3-one; 17β- (4-methylsulfophenylcarbonyl) -4-aza-4-methyl-5α-androstan-3-one; 17β- (4-hydroxyphenyl) -4-aza-5α-androst-1-en-3-one; (3-hydroxyphenyl) -4-aza-5α-androst-1-en-3-one; 17β- (3,4-dihydroxyphenyl) -4-aza-5α-androst-1-en-3-one; 17β- (3,5-dimethyl-4-hydroxyphenyl) -4-aza-5α-androst-1-en-3-one; 17β- (4-hydroxymethylphenyl) -4-aza-5α-androst-1-en-3-one; 17β- (2-hydroxyethylphenylcarbonyl) -4-aza-5α-androst-1-en-3-one; 17β- (4-methoxyphenyl) -4-aza-5α-androst-1-en-3-one; 17β- (4-carboxymethylphenyl) -4-aza-5α-androst-1-en-3-one; 17β- (4-hydroxyphenyl) -4-aza-4-methyl-5α-androst-1-en-3-one; 17β- (3-hydroxyphenyl) -4-aza-4-methyl-5α-androst-1-en-3-one; 17β- (3,4-dihydroxyphenyl) -4-aza-4-methyl-5α-androst-1-en-3-one; Ss7β- (3,5-dimethyl-4-hydroxyphenyl) -4-aza-4-methyl-5α-androst-1-en-3-one; 17β- (4-hydroxymethylphenyl) -4-aza-4-methyl-5α-androst-1-en-3-one; 17β- (2-hydroxyethylphenylcarbonyl) -4-aza-4-methyl-5α-androst-1-en-3-one; 26 176- (4-methoxyphenyl) -4-aza-4-methyl-5Î ± -androst-1-en-3-one; 17- (4-carboxymethylphenyl) -4-aza-4-methyl-5α-androst-1-en-3-one; (4-carboxyphenyl) -4-aza-androst-1-en-3-one and the corresponding compounds in which the 4-hydrogen substituent is substituted in each of the above compounds by a methyl or ethyl radical.

The compounds of the formula IA of the present invention are prepared by a method starting with the known steroid ester of the formula:

(3-chlorophenyl) -4-aza-5α-androstan-3-one, which includes the stages of (1) dehydrogenation of said starting material to produce the corresponding compound containing a double bond (2) conversion of the 17-carbomethoxy substituent to an 17B-acyl substituent and, if desired (3) alkylation of the ring A nitrogen in order to introduce 4-methyl or 4-ethyl substituents on the ring A. For the dehydrogenation step, it is preferred that the 4-aza nitrogen is unsubstituted. The dehydrogenation step can be carried out, for example, according to the procedure of Dolling, et al. involving dichlorodi-cyanobenzoquinone, JACS (1988) Vol. 110, pp. 3318-3319. The stage (2) may consist of one or more chemical steps and if desired may occur before the stage (1) or after the stage (1) or stage (3).

According to the process of the present invention, the products of our invention are formed by (1) heating a 17B-alkoxycarbonyl-4-aza-5a-androstan-3-one compound with a dehydrogenating agent such as benzenesseleninic anhydride in chlorobenzene under reflux to form a 17B-alkoxycarbonyl-4-aza-5a-androst-1-en-3-one (IV), (2) the 5a-androst-1-en-3-one compound formed from step (1) is reacted with sodium hydride and under anhydrous conditions in a neutral solvent such as dimethylformamide, (2) contacting the resulting reaction mixture with an alkyl (methyl or ethyl) iodide to form the corresponding 17β- (3) subsequently hydrolyzing said 17β-alkoxycarbonyl-4-alkyl-4-aza-5α-androst 3-one with a strong base such as aqueous methanolic potassium hydroxide at reflux temperature, followed by acidification and isolation of the resulting steroidal acid, 17B-carboxy-4-alkyl- 4-aza-5Î ± -androst-1-en-3-one (VI), (4) said steroidal acid is then converted to its corresponding 2-thiopyridyl ester by reflux with triphenyl phosphine and disulfide of 2.2 (2-pyridylthiocarbonyl) -4-aza-5a-androst-1-en-3-one (VII) is isolated by chromatography on silica, (5) the said pyridylthio ester is then reacted with a R 1 -L or 2 with a compound MgX (X = Cl, Br), such as sec-butyl magnesium chloride in tetrahydrofuran, to form the desired product, for example , 17B- (sec-butylcarbonyl) -4-alkyl-4-aza-5a-androst-1-en-3-one (VIII) which is isolated by silica gel chromatography. When the above reaction is carried out using a compound 2R MgX or, a compound R -Li instead of sec-butylmagnesium chloride, the corresponding 17β- (acyl) -4-alkyl-4-aza-5α -an-2-drost-1-en-3-one wherein acyl is R-carbonyl. 28

According to the process of our invention, the corresponding 17Î ± -acyl-4-aza-5Î ± -androst-1-en-3-one is prepared rapidly from 17β- (alkoxycarbonyl) -4-aza-5Î ± -androsten- 3-one (IV) by repeating the above series of reactions but omitting step 2 hereinbefore, i.e. the treatment of 4-aza-5α-androst-1-en-3-one with sodium amide followed by iodide methyl or ethyl.

According to a further alternative method of preparing compounds of our invention having only hydrogen as the single substituent on ring A nitrogen, the double bond 1,2 in ring A is introduced in the last step of the process. Thus, 17β-alkoxycarbonyl-4-aza-5α-androstan-3-one (III) is hydrolyzed to the corresponding steroidal acid, 17β-carboxy-4-aza-5α-androstan-3-one, , which in turn is converted to the corresponding thiopyridyl, 17α- (2-pyridylthiocarbonyl) -4-aza-5α-androstan-1-one ester (X) followed by treatment of the ester with 2. 2 - . . a compound R 1 MgX or R 1 Li wherein R 1 is as hereinbefore referred to form a 17D- (acyl) -4-aza-5a-androstan-3-one (XI) which is dehydrogenated as previously described to yield compound XIV, 17D- (acyl) -4-aza-5α-an-dost-1-en-3-one. In a further alternative process for the production of compounds of the formula I when the starting material is an ester, particularly methyl ester as indicated in the formulas. In the scheme, the reaction with a Gngnard R MgX reagent, gives the ketone, 176-R-co, corresponding to the R portion associated with the Grignard reagent. The 16-methyl derivative wherein R 2 '' is methyl is prepared from known 16-methyl-17-acyl-4-methyl-4-aza-5a-androstan-3-ones, for example 29

4-aza-5α-androstan-3-one by known hydrogenation procedures for 4-methyl-4-aza compounds to give the corresponding 4,16β-dimethyl-17β-acetyl-4 5a-an-drost-1-en-3-one.

The foregoing reactions are represented schematically in the following structural outline:

X is 2-pyridylthio

2, wherein X is a 2-pyridylthio substituent and R is defined as hereinbefore defined. 2

In the Reaction Scheme described above, where R is p-hydroxybiphenyl, this may be derived starting with a suitable bromobiphenylphenol, for example p-bromobiphenylphenol, protecting the phenolic -OH with a conventional blocking group, for example trioganosilyl, i.e. t-butyldimethylsilyl, performing the Grignard reaction and then deblocking the silyl group by the use of, for example, aqueous tetrabutylammonium fluoride under reflux.

Other halo-substituted benzenes to form the appropriate Grignard reagent useful in the present invention will be obvious to one skilled in the art from this execution. The term " protected hydroxy " as used herein means the alcoholic or carboxylic -OH groups which may be protected by blocking groups conventional in the art as described in " Protective Groups In Organic Synthesis " by Theodora W. Greene, Wiley-Interscience, 1981, New York. Preferred are triorganosilyl groups, for example t-butyldimethylsilyl, phenyldimethylsilyl, diphenylmethylsilyl, and the like. The term " C 1 -C 4 alkyl " as used herein means straight or branched alkyl including methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl and t-butyl.

When this reaction scheme is carried out using a compound MgX R or R 1 -L containing a substituted thiophenyl R, for example p-methylthiophenyl magnesium chloride, is prepared at 32 ° C.

corresponding 17β- (substituted thio-benzoyl) -4-alkyl-4-aza-25α-androst-1-en-3-one wherein phenyl is R.. The Grignard reagent, R MgX, for all species included within the scope of this invention, is available or can be readily produced by one skilled in the art. For example, when R is C1 -C4 alkylthiophenyl, it may be formed from the appropriate thiobromobenzene C1 -C4 alkyl, for example p-methylthiobromobenzene. The C1 -C4 alkyl thiobenzene formed may be used to further prepare C1 -C4 alkyl sulfoxide by oxidation with for example m-chloroperbenzoic acid. The resulting sulfoxide can be further oxidized by the use of the reaction with m-chloro-perbenzoic acid maintained for a longer period of time to form the C1 -C4 alkyl sulfone.

In addition, the sulfoxide may be used in rearrangement of Pummerer to form the corresponding thiol. Phenyl (R) -substituted by -SO2 N (C1 -C4 alkyl) is formed from the appropriate bromobenzene, for example p-N, N-dimethylaminosulfobromobenzene which is used directly in the Grignard reaction to form the final product.

The thioalkyl groups on the phenyl ring, i.e., - (CHâ,,) SH, â € ƒâ € ƒâ € ƒâ € ƒâ € ƒH1 â € ƒâ € ƒâ € ƒwherein m is 1-4, are rapidly formed by a four step process of an alkyl (CH2) mOCH3. The direct addition of the Grignard reagent prepared from the above bromoalkyl phenyl derivative to the thiopyridyl ester gives the keto derivative, ie 175- (4-methoxyalkylbenzoyl) -4-aza-5α-androst-1-ene-3- one. This can be rapidly converted to the thio analog via BBr 3 at -70 ° C to 33 ° C

to form the hydroxyalkyl derivative, followed by halogen, for example bromine and then conversion of the halogenated compound by NaSH displacement to give the final mercapto compound. When in the reaction scheme o. ^. . Said pyridylthio ester is reacted with a compound R -Li or 2 R MgX (X = Cl, Br) containing aminophenyl, such as p-dimethylaminophenyl magnesium chloride, this reaction is carried out in tetrahydrofuran to form the product 17β- (p-dimethylaminophenylcarbonyl) -4-alkyl-4-aza-5α-androst-1-en-3-one (VIII) which is isolated by chromatography on silica gel. . The Gnnard reagent, R MgX, for all of the aminophenyl species included within the scope of this invention, is available or can be readily produced by one skilled in the art.

When in the process said Grignard reagent 2 contains a R moiety of the phenolic type, then said ester. . . . 2-pyridyl is reacted with a Grignard reagent R -Li or 2R MgX (X = Cl, Br), such as p-methoxyphenylmagnesium chloride in tetrahydrofuran to form the desired product, for example 17β- (p-methoxyphenylcarbonyl ) -4-alkyl-4-aza-5α-androst-1-en-3-one (VIII) which is isolated by silica gel chromatography. 2

When this reaction is carried out using another MgXR or R-Li compound instead of p-methoxyphenylmagnesium chloride, the corresponding 17β- (substituted benzoyl) -4-alkyl-4-aza-5α-anhydrost-1 -en-3-one wherein the phenyl is R3. . 2. The Grignard reagent, R MgX, for all species included within the scope of this invention, is readily available or can be produced by one skilled in the art. 34

2

For example, when R is hydroxyphenyl, it may be derived starting with a suitable bromophenol, for example p-bromophenol, protecting the phenolic -OH with a conventional blocking group, for example trioganosylyl, i.e. t-butyldimethylsilyl, by performing the Grignard reaction and then deblocking the silyl group by the use of, for example, aqueous tetrabutylammonium fluoride under reflux. O

When R is hydroxyethylphenyl, the same blocking process may be similarly conducted starting with the appropriate hydroxy-alkyl bromophenol, for example p-hydroxymethylbromo-benzene, or p-hydroxyethylbromobenzene. O

When R is carboxyphenyl, it may be obtained by the chromic acid oxidation of hydroxymethylbenzene, for example p-bromohydroxymethylbenzene, formed as described above.

When R is -O-C 1 -C 4 alkyl, the appropriate bromo-O-C 1 -C 4 alkyl benzene, for example p-methoxybromobenzene, is used for the Grignard reaction.

Other halo-substituted benzenes to form the appropriate Grignard reagent useful in the present invention will be obvious to one skilled in the art from this execution. The term " protected hydroxy " as used herein means the alcoholic or carboxylic -OH groups which may be protected by blocking groups conventional in the art as described in " Protective Groups In Organic Synthesis " by Theodora W. Greene, Wiley-Interscience, 1981, New York. Preferred are triorganosilyl groups, for example t-butyldimethylsilyl, phenyldimethylsilyl, diphenylmethylsilyl, and the like. 35

Also within the scope of the present invention is the use of AI ketone reduction products in combination with an aromatase inhibitor for treating BPG being secondary alcohols of the formula:

HO R2 CH

wherein R is selected from hydrogen, methyl and ethyl; R is (a) a monovalent radical selected from straight or branched alkyl, or cycloalkyl, of 2-12 carbons, which may be substituted by one or more C1 -C4 alkyl or halo; (b) an aralkyl radical selected from benzyl or phenethyl; (c) a polycyclic aromatic radical which may be substituted with one or more of: -OH, -OC2 -C4 alkyl, C1 -C4 alkyl, halo or nitro; (d) a monocyclic aromatic radical which may be substituted with one or more of: (1) -OH, -CONO, C1-4 alkyl, C1-4 alkyl, - (CH2) m OH, - (CH2) including protected hydroxy, where m is 1-4, n is 1-3, providing C 1 -C 4 alkyl is present only when one of the oxygen-containing radicals referred to above is present; 36

(2) -SH, -SC 1 -C 4 alkyl, -SOC 2 -C 4 -alkyl, -SO 2 C 1 -C 4 alkyl, -SO 2 - (C 1 -C 4 -alkyl) 2, Wherein n is 1-4, n is 1-3, providing Câ, -Câ, ... alkyl is present only when one of the above sulfur containing radicals is present; Wherein R is independently H or C 1 -C 4 alkyl, wherein the monoaryl ring may also be further substituted with C 1 -C 4 alkyl, and (4) heterocyclic radical selected from 2- R 2, R 3 and R 4 are hydrogen or methyl, wherein the dotted line represents a double bond which may be present, and the salts and esters thereof are pharmaceutically acceptable acceptable.

These compounds can be produced by reduction 9

with carbonyl sodium borohydride attached to R without reducing the amido carbonyl in Ring A or the double bond 1,2, 2. if present. If the phenyl R contains a carbonyl function, it may be selectively blocked and then regenerated after reduction with borohydride by conventional methods. The reduction with borohydride can be carried out in, for example, water or aqueous methanol, at a temperature ranging from room temperature to 50øC and the product is then isolated and purified by conventional means. The compounds are also active as 5-alpha reductase inhibitors in the treatment of demarcated alopecia.

The compounds of the present invention, prepared according to the above-described method, are, as already mentioned, agents 37

potent in combination with an aromatase inhibitor for the treatment of BPH.

In this invention, the aromatase inhibitor, and the 5α-reductase inhibitor are administered in combination separately or as a single pharmaceutical composition combined parenterally or orally. Preferably, the aromatase inhibitor and the 5α-reductase inhibitor are administered orally as separate compositions. The amount of each component administered is determined by the attending physician taking into account the etiology and severity of the disease, the condition and age of the patient, the potency of each component and other factors.

The aromatase inhibitory compositions are generally administered in a dosage ranging from about 10 to 400 mg / kg (body weight) per day with 50 to 250 mg per day being preferred in a single dose. the 175-substituted steroid 5a-reductase inhibitors which are non-4-aza steroids are known in the art and include those developed by SmithKline Beckmann as is

filed in U.S. Patent No. 4,882,319 to Holt, et al .; U.S. Patent No. 4,910,226 to Holt, et al .; EPO Publn. 0 289 327 now USP 4,910,226; EPO Publn. 0 277 002 now USP 4,888,336; EPO Publn. 0 343 954; EPO Publn. 0 375 344 now USP 4,937,237; EPO Public 0 375 347; now USP 4,970,205; EPO Publn. 0 375 349; now USP 5,026,882.

In the method the non-aza substituted steroids in 17B are of the formula:

in which: the A ring contains up to 2 double bonds; rings B, C and D have optimal double bonds where indicated by interrupted lines, provided that rings A, B and C do not have adjacent double bonds and ring D does not have a double bond c16 "c17 when R3 represents two substituents or a substituent divalent; z is (CH 2) n and n is 0 or 2, provided that Z is (CH) n when adjacent to a double bond; X is H, Cl, F, Br, I, CF 3, or C 1-4 alkyl; Y is H, CF 3, F, Cl, or CH 3, provided that Y is H when there is no C 5 -C 6 double bond; R 1 is H or C 1-8 alkenyl, R 2 is absent or present as H or CH 3, provided that R is absent when the carbon to which it is attached is unsaturated, and R 3 is (1) α-hydrogen, or Î ± -hydroxy, or Î ± -acetoxy and / or (a) Î ± -WC-R4 where W is a bond or C1-C4 alkylidene, and R4 is (i) hydrogen, (ii) hydroxyl, (iii) alkyl, (iv) hydroxylic alkyl, (v) C alkoxy, nb 56 (vi) NR R, wherein R and R are each independently selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl, phenyl, or R5 and R6 taken together with the nitrogen to which they are attached represent a 5-6 membered saturated ring, (VII) OR, where R is hydrogen, alkali metal, C1-6 alkyl, benzyl, or (b) -Alk-OR8 (iii) benzoyl, (iv) (v) aminocarbonyl, or alkyl substituted aminocarbonyl, (vi) hydrogen, (ii) hydrogen, or (vii) C1-8 alkyl, 1-848 (2) -CH-W-CO-R3 or = CH-W-OR, C5-10 wherein W is a bond of the same meaning as 1-12 above, R 8 is H or C 1-6 alkyl;

alkylidene and R

And R 2 is also hydrogen or (1-4C) alkylcarbonyl (3)

[CX? where the disrupted bond substitutes 17-α-hydrogen, (9) α-hydrogen and NHCOR where R C is C 19 alquilo oualkyl or NR 0 onde where R e and R têm have the same meaning as above, α-hydrogen and cyano, (6) α-hydrogen and tetrazolyl, or (7) keto; or a pharmaceutically acceptable salt thereof; except compounds in which:. . (b) Ring B has a C5-C6 double bond, R3 and CH3, and R5 is keto, methoxycarbonyl, or acetyl; or •. . 3 (ii) the A-nor ring has a C3 -C4 double bond and R is acetoxy or acetyl; (Iii) R3 is CH3 and R3 is acetoxy or acetyl; or (iv) the A-nor ring has a C3 -C4 double bond and is methyl; or (v) ring B has a C3 -C4 double bond and R is B-hydroxy.

Representative compounds whose synthesis and properties are disclosed in the above-referenced US patents include the following compounds and pharmaceutically acceptable salts thereof: 4-methyl-4-aza-5a-8 (14) -pregnen-3-one- (20R ) -20-carboxylic acid; (20R) -hydroxymethyl-4-methyl-4-aza-5a-8 (14) -pregnen-3-one; 41

4-methyl-4-aza-5a-8 (14) -androsten-3-one-17β-N, N-diisopropylcarboxamide; 175- (Ν, Ν-diisopropylcarboxamide) -estr-1,3,5 (10) -triene-3-phosphonic acid; 17β- (N-tert-butylcarboxamide) -estr-1,3,5 (10) -triene-3-phosphonic acid; 17β- (Ν, Ν-diisopropylcarboxamide) -estr-1,3,5 (10), 16-tetraene-3-phosphonic acid; 17β- (N-tert-butylcarboxamide) -estr-1,3,5 (10), 16-tetraene-3-phosphonic acid; 17β- (Ν, Ν-diisopropylcarboxamide) -estr-1,3,5 (10), 6,8-pen-taen-3-phosphonic acid; 17β- (Ν, Ν-diisopropylcarboxamide) -2-methyl-estr-1,3,5- (10) -triene-3-phosphonic acid; 17β- (Ν, Ν-diisopropylcarboxamide) -4-methyl-estr-1,3,5 (10) -triene-3-phosphonic acid; 17B- (N-N-diisopropylcarboxamide) -estr-1,3,5 (10), 6-tetraene-3-phosphonic acid; 17β- (N-N-diisopropylcarboxamide) -2-chloro-estr-1,3,5 (10) -triene-3-phosphonic acid; 17β- (N-N-diisopropylcarboxamide) -4-chloro-estr-1,3,5 (10) -triene-3-phosphonic acid; 17B- (N-butylcarboxamide) -estr-1,3,5 (10) -triene-3-carboxylic acid; 17B- (N-butylcarboxamide) -estr-1,3,5 (10) -16-tetraene-3-carboxylic acid; 17β- (Ν, Ν-diisopropylcarboxamide) -estr-1,3,5 (10) -triene-3-phosphinic acid; 17β- (N-tert-butylcarboxamide) -estr-1,3,5 (10) -triene-3-phosphinic acid; 17β- (Ν, Ν-diisopropylcarboxamide) -2-methyl-estr-1,3,5 (10) -triene-3-phosphinic acid; 42

17β- (Ν, Ν-diisopropylcarboxamide) -4-methyl-estr-1,3,5 (10) -triene-3-phosphinic acid; 17β- (Î ±, β-diisopropylcarboxamide) -2-chloro-estr-1,3,5 (10) -triene-3-phosphinic acid; 17β- (Ν, Ν-diisopropylcarboxamide) -4-chloro-estr-1,3,5 (10) -triene-3-phosphinic acid; 17β- (Î ±, β-diisopropylcarboxamide) -1,3,5 (10), 16-tetraene-3-phosphinic acid; 176- (N-tert-butylcarboxamide) -estr-1,3,5 (10), 16-tetraene-3-phosphinic acid; 17β- (Ν, Ν-diisopropylcarboxamide) -estr-1,3,5 (10), 6,8-pentaen-3-phosphinic acid; 17β- (Ν, Ν-diisopropylcarboxamide) -estr-1,3,5 (10), 6-tetraene-3-phosphinic acid; 176- (Ν, Ν-diisopropylcarboxamide) -estr-1,3,5 (10) -triene-3-phosphonic acid; 176- (N-tert-butylcarboxamide) -estr-1,3,5 (10) -triene-3-phosphonic acid; 176- (Ν, Ν-diisopropylcarboxamide) estr-1,3,5 (10), 616-tetraene-3-phosphonic acid; 176- (N-tert-butylcarboxamide) -estr-1,3,5 (10), 16-tetraene-3-phosphonic acid; 176- (Ν, Ν-diisopropylcarboxamide) -estr-1,3,5 (10), 6,8-pentaen-3-phosphonic acid; 176- (Ν, Ν-diisopropylcarboxamide) -2-methyl-estr-1,3,5 (10) -triene-3-phosphonic acid; 17β- (N, N-diisopropylcarboxamide) -4-methyl-estr-1,3,5 (10) -triene-3-phosphonic acid; 176- (Ν, Ν-diisopropylcarboxamide) -estr-1,3,5 (10), 6-tetraene-3-phosphonic acid); 176- (Ν, Ν-diisopropylcarboxamide) -2-chloro-estr-1,3,5 (10-triene-3-phosphonic acid;

17β- (N, N-diisopropylcarboxamide) -4-chloro-estr-1,3,5 (10) -triene-3-phosphonic acid; 17β- (N, N-diisopropylcarboxamide) -estr-1,3,5 (10) -triene-3-sulfonic acid; 173- (N-tert-butylcarboxamide) -estr-1,3,5 (10) -triene-3-sulfonic acid; 17β- (Ν, N-diisopropylcarboxamide) -estr-1,3,5 (10), 16-tetraene-3-sulfonic acid; 17B- (N-tert-butylcarboxamide) -estr-1,3,5 (10), 16-tetraene-3-sulfonic acid; 17β- (Ν, N-diisopropylcarboxamide) -estr-1,3,5 (10), 6,8-pentaen-3-sulfonic acid; 17β- (Ν, N-diisopropylcarboxamide) -2-methyl-estr-1,3,5 (10) -triene-3-sulfonic acid; 17β- (N, N-diisopropylcarboxamide) -4-methyl-estr-1,3,5 (10) -triene-3-sulfonic acid; 17β- (Ν, N-diisopropylcarboxamide) -2-chloro-estr-1,3,5 (10) -triene-3-sulfonic acid, 17β- (Ν, N-diisopropylcarboxamide) -4-chloro- estr-1,3,5 (10) -triene-3-sulfonic acid); 17β- (N, N-diisopropylcarboxamide) -androst-3,5-diene-3-phosphonic acid; 17β- (N-t-butylcarboxamide) -androst-3,5-diene-3-phosphinic acid; 17β- (N, N-diisopropylcarboxamide) -5α-androst-3-ene-phosphinic acid; 17β- (N, N-diisopropylcarboxamide) -5α-androst-2-ene-3-phosphinic acid; 17β- (N, N-diisopropylcarboxamide) -androst-2,4-diene-3-phosphinic acid; (17β-Ν, N-diisopropylcarboxamide) -androst-3,5-diene-3-phosphinic acid; 20α- (hydroxymethyl) -5α-pregn-3-ene-3-phosphinic acid; 17Î ± - (N, N-Diisopropylcarboxamide) -4-fluoro-5Î ± -androst-3-ene-3-phosphinic acid; 44

20α- (hydroxymethyl) -4-fluoro-5α-pregn-3-ene-3-phosphinic acid; 20α- (hydroxymethyl) -A-nor-5α-pregn-1-ene-2-phosphinic acid; 17β- (Ν, Ν-diisopropylcarboxamide) -5α-androst-1,3-diene-3-phosphinic acid; 17β- (Ν, Ν-diisopropylcarboxamide) -5α-androstane-3E-phosphinic acid; 17β- (Ν, Ν-diisopropylcarboxamide) -estr-3,5 (10) -diene-3-phosphinic acid; 17β- (Ν, Ν-diisopropylcarboxamide) -estr-3,5-diene-3-phosphinic acid; 17β- (Ν, Ν-diisopropylcarboxamide) -androst-3,5-ll-triene-3-phosphinic acid; 20α- (hydroxymethyl) -5α-pregn-3-ene-3-carboxylic acid; N, N-diisopropyl-5Î ± -androst-3-ene-17β-carboxamide-3-carboxylic acid; N, N-diisopropyl-androst-3,5-diene-17β-carboxamide-3-carboxylic acid; 17β- (Ν, Ν-diisopropylcarboxamide) -4-fluoro-5α-androst-3-ene-3-carboxylic acid; 20α- (hydroxymethyl) -4-fluoro-5α-pregn-3-ene-3-carboxylic acid; 20α- (hydroxymethyl) -A-nor-5α-pregn-1-ene-2-carboxylic acid; 17β-N, N-diisopropylcarboxamide-5α-androst-1,3-diene-3-carboxylic acid; N-T-Butyl Androst-3,5-diene-17β-carboxamide-3-carboxylic acid; N, N-Diisopropyl-5α-Androst-2-ene-17-B-carboxamide-3-carboxylic acid; Î ±, β-Diisopropyl Androst-2,4, -diene-17β-carboxamide-3-carboxylic acid; Î ±, β-Diisopropyl-5Î ± -androstane-17β-carboxylic acid; Î ±, β-Diisopropyl Estr-3,5 (10) -diene-17β-carboxamide-3-carboxylic acid; Î ±, β-Diisopropyl Estr-3,5-diene-17β-carboxamide-3-carboxylic acid; i 45

20a (hydroxymethyl) -5a-pregn-3-ene-carboxylic acid; N, N-diisopropyl-5α-androst-3-ene-17β-carboxamide-3-carboxylic acid; N, N-diisopropyl-androst-3,5-diene-17β-carboxamide-3-carboxylic acid; 17β- (Î ±, β-diisopropylcarboxamide) -4-fluoro-5Î ± -androst-3-ene-3-carboxylic acid; 17β- (Ν, Ν-Diisopropylcarboxamide) -androst-3,5,11-triene-3-carboxylic acid; 17β- (Ν, Ν-Diisopropylcarboxamide) -androst-3,5-diene-3-thio-carboxylic acid; 17β- (N-t-Butylcarboxamide) -androst-3,5,11-triene-3-carboxylic acid; 17β- (Nt-Butylcarboxamide) -androst-3,5-diene-3-thiocarboxylic acid, Nt-butyl-androst-3,5-diene-17β-carboxamide-3-carboxylic acid, N, N-diisopropyl 20-α- (hydroxymethyl) -3-a-pregn-3-ene-3-carboxylic acid, 20-α- (hydroxymethyl) 3-carbomethoxy-N, N-diisopropyl-androst-3,5-diene-17β-carboxamide, 17β-N, N-diisopropylcarboxamide- Î ±, β-Diisopropyl-5-Î ± -androst-2-ene-17β-carboxamide-3-carboxylic acid Î ±, β-diisopropyl- androst-2-4-diene-17β-carboxamide-3-carboxylic acid, Î ±, β-diisopropyl-5Î ± -androstene-17β-carboxamide-3β-carboxylic acid, Î ±, β-diisopropyl- 5 (10) -diene-17β-carboxamide-3-carboxylic acid, α, β-diisopropyl estr-3,5-diene-17β-carboxamide-3-carboxylic acid, Nt -butyl-androst- 5-diene-17β-carboxamide-3-carboxylic acid, 46

N-N-diisopropyl-androst-3,5-diene-17β-carboxamide-3-carboxylic acid, 20-α- (hydroxymethyl) 4-fluoro-5-a-pregn-3-ene-3-carboxylic acid , N, N-diisopropyl-5-Î ± -androst-3-ene-17β-carboxamide-3-carboxylic acid, 17β- (Î ±, β-diisopropylcarboxamide) -4-fluoro-5Î ± -adrenergic acid 17β- (Ν, Ν-diisopropylcarboxamide) -4-fluoroandrost-3,5-diene-3-carboxylic acid, 3-carbomethoxy-N, N-diisopropyl-androst- 17β-N, N-diisopropylcarboxamide-5α-androst-1,3-diene-3-carboxylic acid, N, N-Diisopropyl-5-a-androst-2-ene-17β- carboxamide-3-carboxylic acid. N-diisopropyl-5β-androstane-17β-carboxamide-3β-carboxylic acid, N, N-diisopropyl androst-2,4-diene-17β-carboxamide-3-carboxylic acid, N, diisopropyl estr-3,5 (d) -diene-17β-carboxamide-3-carboxylic acid, N, N-diisopropyl estr-3,5-diene-17β-carboxamide-3-carboxylic acid, 17β- (Nt-butylcarboxamide) -androst-3,5-diene-3-thiocarboxylic acid, 17β- (Nt-butylcarboxamide) -androst-3,5-diene-3-carboxylic acid, 5-a-androst-3-ene-17β-carboxamide-3-carboxylic acid, 17β- (Nt -Butylcarboxamide) -6-fluoro-5-a-androst-3-ene-3-carboxylic acid, (Nt-Butylcarboxamide) -6-fluoroandrost-3,5-diene-3-carboxylic acid, 3-Carbomethoxy-Nt-butylandrost-3,5-diene-17β-carboxamide, 17β- 5-a-androst-2-ene-17β-carboxamide-3-carboxylic acid, Nt-Butyl-androst-3-carboxylic acid, Nt-Butyl- 2,4-diene-17β-carboxamide-3-carboxylic acid, Nt-Butyl-5-α-androstane-17β-carboxamide-3-carboxylic acid, and 17β- (Nt-Butylcarboxamide) -androst-3,5-l-triene-3-carboxylic acid, 17β- (Nt -butylcarboxamide) -androst-3,5-a-pregn- 17B- (Nt-Butylcarboxamide) -androst-3,5-diene-3-thiocarboxylic acid, Nt-Butyl-5-a-androst-3-ene-17β-carboxamide-3-carboxylic acid, 17B 17B- (Nt -Butylcarboxamide) -6-fluoro-androst-3,5-diene-3-carboxylic acid, 17B- (Nt -Butylcarboxamide) -6-fluoro-androst- 17β-Nt-Butylcarboxamide-5-Î ± -androst-1,3-diene-3-carboxylic acid, NÎ ± -androst-1,3-diene-3-carboxylic acid, Butyl-5-a-androst-2-ene-17β-carboxamide-3-carboxylic acid, Nt-Butyl-androst-2,4-diene-17β-carboxamide- androstane-17β-carboxamide-3-carboxylic acid, Nt-Butyl-estr-3,5 (10) -diene-17β-carboxamide-3-carboxylic acid, Nt-Butyl-estr-3,5-diene-17β-carboxamide -3-carboxylic acid, N-butyl-estr-3,5 (10) -diene-17β-carboxamide, 3-carboxylic acid, Nt- (T-butyldimethylsilyloxymethyl) -3- (trifluoromethylsulfonate) -5-a-pregn-3-ene, 17β- (t-butyldimethylsilyloxymethyl) -3- (t-butyldimethylsilyloxymethyl) -3- (trifluoromethylsulfonate) -5- -Î ± -androst-3-ene, 17β- (N, N-diisopropylcarboxamide) -3- (trifluoromethylsulfonate) -androst-3,5-diene, 48

17β- (N, N-diisopropylcarboxamide) -3- (trifluoromethylsulfonate) -4-fluoro-5-α-androst-1,3-diene, 20- α- (t-butyldimethylsiloxymethyl) -4- (N, N-diisopropylcarboxamide) -3- (trifluoromethylsulfonate) -5-a-androst-1,3-diene, 17β- (N, N-diisopropylcarboxamide) butylcarboxamide) -3- (trifluoromethylsulfonate) -androst-3, 5-diene, 17S- (N, N-diisopropylcarboxamide) -3- (trifluoromethylsulfonate) -5-a-androst-2-ene, 17b- (N, N-diisopropylcarboxamide) -3- (trifluoromethylsulfonate) -androst-2,4-diene, Nt-butyl-androst-3,5-diene-3-bromo-17β-carboxamide, and N, N-diisopropyl-androst- 3,5-diene-3-bromo-17β-carboxamide. 17B-acyl 3-carboxyandrost-3,5-diene of the formula:

Wherein R is (a) C-C, linear or branched alkyl; C 1 -C 10 cycloalkyl, which may be substituted with C-C. alkoxy or CL-C. Linear / branched alkyl; or C 7 -C 13 aralkyl which may be substituted with one or more of: -OH, -C

alkyl, alkyl, - (CH2) m OH, â € ƒâ € ƒâ € ƒwherein m is 1-4, n is 1-3; (b) straight or branched C1 -C6 alkyl; C3 -C12

cycloalkyl, which may be substituted with C 1 -C 4 alkoxy or C 1 -C 4 linear / branched alkyl; (C 2 -C 12) aryl, or C 7 -C 13 aralkyl which may be substituted with one or more of: -OH, -OC 2 -C 4 alkyl, - (CH 2) m OH, - (CH 2) n COOH, including -OH protected, wherein m is 1-4, n is 1-3, and R2 is selected from COOH, SO3 H, PO (OH) 2, PH (O) OH. Specifically, those in which R is t-butyl, cycloalkyl, phenyl, p-hydroxyphenyl, 1-adamantyl, 2-adamantyl, NH-t-butyl, NH-isobutyl, NH-cyclohexyl, NH-phenyl, NH -p-hydroxy-phenyl, NH-1-adamantyl, β-2-adamantyl, and R2 is COOH,

Representative compounds include: 17β- (4-hydroxyphenylcarbonyl) -androsta-3,5-diene-3-carboxylic acid; 17β-benzoyl-androsta-3,5-diene-3-carboxylic acid; 17B-cyclohexylcarbonyl-androsta-3,5-diene-3-carboxylic acid; 17B-isobutylcarbonyl-androsta-3,5-diene-3-carboxylic acid; 17β- (4-hydroxymethylcarbamyl) -androsta-3,5-diene-3-carboxylic acid; 17β- (2-hydroxyethylphenylcarbonyl) androsta-3,5-diene-3-carboxylic acid; 17B- (4-methoxyphenylcarbonyl) androsta-3,5-diene-3-carboxylic acid; 17B- (4-carboxymethylphenylcarbonyl) androsta-3,5-diene-3-carboxylic acid; N-t-butyl-androst-3,5-diene-17S-carboxamide-3-carboxylic acid; N-phenyl androst-3,5-diene-17S-carboxamide-3-carboxylic acid; 50

N-1-adamantyl androst-3,5-diene-17b-carboxamide-3-carboxylic acid; Γ-2-adamantyl androst-3,5-diene-17β-carboxamide-3-carboxylic acid;

Also included and known in the art are non-steroidal 5Î ± -reductase inhibitors as are produced by Oral Pharmaceutical Co., Ltd., Osaka, Japan and as described in U.S. Patent Nos. 4,780,469; 4,847,275; 4,939,141 and EPO Publication Nos. 0 173 516 and EPO 0 291 245, and USP 4,980,372; and

EPO Publication 291,247 and USP 5,037,852 showing certain novel ben (thio) amides and benzylaminophenylbutanoic derivatives, respectively.

The benzoylaminophenoxy butanoic acid derivatives are of the formula:

wherein R 'is hydrogen or alkyl having 1 to 4 carbon atom (s); A is oxygen atom, sulfur atom or (SO) • sulfinyl group; both R3 are methyl or chlorine, or the two R3 and R5 are the same. 1 carbon atoms of the benzene ring to which the two R are attached together are cyclopentane, cyclohexane or a benzene ring; and R 2 represents a group of the formula:

in which B is oxygen, sulfur or a group of the formula: wherein R is hydrogen or alkyl having 1 to 4 carbon atoms, R 3, R 4, R 5, R 7, R 2 and R 3 are independently hydrogen, alkyl of 1 to 4 carbon atoms, halogen, trifluoromethyl or cyclobutylmethyl, m is 0 or 1, n is an integer from 1 to 5, and R 9 is a hydrogen, alkyl of 1 to 5 carbon atom (s) or a group of the formula:

_1 2

Wherein R 1, R 2, R 3 and R 4 are independently hydrogen, alkyl having 1 to 4 carbon atoms, halogen, trifluoromethyl or cyclobutylmethyl, and 1 is an integer of 1 to 4, and R 10 is a group of the formula:

R, 13C

or 53

12 13 14 15. in which R 1, R 2, R 3 and R 4 are independently hydrogen, alkyl or 1 to 4 carbon atom (s), halogen, trifluoromethyl or cyclobutylmethyl, and 1 'is an integer from 1 to 4; or non-toxic salts thereof.

Representative examples of each of these two classes of compounds the synthesis and properties of which are disclosed in the above-mentioned U.S. patents include the following: 4- [2- (4-benzyloxy-2,3-dimethylbenzoylamino) phenoxy] butanoic acid; 4- [2- [4- (2-methylbenzyloxy) -2,3-dimethylbenzoylamino] butanoic acid; 4- [2- [4- (3-methylbenzyloxy) -2,3-dimethylbenzoylamino] phenoxy] -butanoic acid; 4- [2 - [(4-methylbenzyloxy) -2,3-dimethylbenzoylamino] phenoxy] butanoic acid; 4- [2- [4- (2,6-dimethylbenzyloxy) -2,3-dimethylbenzoylamino] phenoxy] butanoic acid; 4- [2- [4- (4-ethylbenzyloxy) -2,3-dimethylbenzoylamino] phenoxy] -butanoic acid; 4- [2- [4- (4-propylbenzyloxy) -2,3-dimethylbenzoylamino] phenoxy] butanoic acid; 4- [2- [4- (4-isopropylbenzyloxy) -2,3-dimethylbenzoylamino] phenoxy] butanoic acid; 4-2- [4- (4-isobutylbenzyloxy) -2,3-dimethylbenzoylamino] phenoxy] butanoic acid; 4- [2- [4- (4-chlorobenzyloxy) -2,3-dimethylbenzoylamino] phenoxy] -butanoic acid; 4- [2- [4- (4-cyclobutylbenzyloxy) -2,3-dimethylbenzoylamino] phenoxy] butanoic acid; 4- [2- [4- (2-phenylethoxy) -2,3-dimethylneozoylamino] phenoxy] butanoic acid; 54

4- [2- [4- (3-phenylpropoxy) -2,3-dimethylbenzoylamino] phenoxy] butanoic acid; 4- [2- [4- (4-phenylbutoxy) -2,3-dimethylbenzoylamino] phenoxybutanoic acid; 4- [2- [4- (5-phenylpentyloxy) -2,3-dimethylbenzoylamino] phenoxy] -butanoic acid; 4- [2- [4- (1-isobutylphenyl) ethoxy) -2,3-dimethylbenzoylamino] phenoxy] butanoic acid; 4- [2- [4- (4-propylbenzyloxy) -2,3-dimethylbenzoylamino) phenylthio] butanoic acid; 4- [2- [1- (4-isobutylphenyl) ethoxy) -2,3-dimethylbenzoylamino] phenylthio] butanoic acid; 4- [2- [4-propylbenzyloxy) -2,3-dimethylbenzoylamino] phenylsulfinyl) butanoic acid; 4- [2- [4- [N- (4-trifluoromethylphenylmethyl) amino) -2,3-dimethyl-benzoylamino] -phenoxy] -butanoic acid; 4- [2- [4- (4-isobutylbenzyloxy) -5,6,7,8-tetrahydronaphthalene-1-carbonylamino) phenoxybutanoic acid; 4- [2- [4- (4-isobutylbenzyloxy) naphthalene-1-carbonylamino) phenoxy) butanoic acid; 4- [2- [8- (4-isobutylbenzyloxy) -5,6,7,8-tetrahydronaphthalene-1-carbonylamino) phenylthio] butanoic acid; 4- [2- [4- [bis- (4-propylphenyl) methoxy] 2,3-dimethylbenzoylamino) phenoxy] butanoic acid; 4- [2- (4-diphenylmethoxy) -2,3-dimethylbenzoylamino) phenoxy] butanoic acid; 4- [2- [4- [bis (4-propylphenyl) methylamino] -2,3-dimethylbenzo [1-amino] phenoxy] butanoic acid; 4- [2- [4- [bis- (4-propylphenyl) methylthio] -2,3-dimethylbenzoylamino] phenoxy] butanoic acid; 4- [2- [4- [N, N-bis (4-propylphenylmethyl) amino] -2,3-dimethylbenzoylamino] phenoxy] butanoic acid; 55

4- [2- [4- [N, N-bis (4-trifluoromethylphenylmethyl) amino] -2,3-dimethylbenzoylamino] phenoxy] butanoic acid; 4- [2- [4-N-methyl-N- (5,6,7,8-tetrahydronaphth-1-yl] aminomethyl] -2,3-dimethylbenzoylamino] phenoxy] butanoic acid 8- (p-pentylbenzoyl amino-2- (5-tetrazolyl) -6-chloro-1,4-benzodioxane; 8- (m-octylbenzoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane; amino-2- (5-tetrazolyl) -1,4-benzodioxane; 8- (o-pentylbenzoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane; 8- (p-heptylbenzoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane; 8- (p-hexylbenzoyl) amino-2- (5- tetrazolyl) -1,4-benzodioxane; 8- (p-octylbenzoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane; 8- (p-nonylbenzoyl) amino-2- (5-tetrazolyl) -1- 4-benzodioxane; 8- (p-undecylbenzoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane; 8- (p-decylbenzoyl) amino-2- (5-tetrazolyl) -1,4- 8- (p-pentyloxybenzoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane; 8- (p-dideoxybenzoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane; m-pentyloxybenzoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane; 8- (o-pentyloxybenzoyl) amino-2- (5-tetrazole yl) -1,4-benzodioxane; 8- (p-butyloxybenzoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane; 8- (p-nonylbenzoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane; 8- (p-propoxybenzoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane; 8- (p-hexyloxybenzoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane; 8- (p-heptyloxybenzoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane; 8- (p-octyloxybenzoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane; 8- (o-decyloxybenzoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane; 8- (p-isopentyloxybenzoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane; 8- (p-isohexylbenzoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane; 8- [p- (1-methylbutoxy) benzoyl] amino-2- (5-tetrazolyl) -1,4-benzodioxane; 56

8- (p-octyloxybenzoyl) amino-1,4-benzodioxane, 8- (N-methyl- N - (p -ocynyloxy) benzoyl) amino-2- (5-tetrazolyl) -1,4- -2-carboxylic acid and its methyl ester; 8- (p-isoheptyloxybenzyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane; 8- [p- (3,7-dimethyloctyloxy) benzoyl] amino-2- (5-tetrazolyl) -1,4-benzodioxan-8- (p- (isooctyloxybenzoyl) amino-2- (5-tetrazolyl) -1,4- 4-benzodioxane; 8- (p-octyloxybenzoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane; 8- (p-heptyloxybenzoyl) amino-2- (5-tetrazolyl) 4-benzoxane-7-carboxylic acid and its methyl ester, etc.

Also included as a 5α-reductase inhibitor in this invention is a cinnamoyl amide of the following formula:

COOK 2 wherein R 1 and R 2 each independently represent a hydrogen or a methyl group with the proviso that. R 2 is hydrogen and (R 2) n is a member selected from the group consisting of 3-, 4-pentyl, 4-neopentyl, 4- (2-ethylbutyl) and 4- (2-methylpentyl) group, or (ii) when R is hydrogen, R is methyl and (R 1) n is 3-pentyl, or a non-toxic salt thereof.

Representative compounds include: 4- [2- (4-Cyclobutylmethyl) β-methylcinnamoylamino) phenoxy] buta-noic acid 4- [2- (4-Amino- 4- [2- (4- (4-phenylbutyl) -β-methylcinnamoylamino) phenoxy] butanoic acid 4- [2- (4-phenoxy-B-methylcinnamoylamino) phenoxy] butanoic acid 4- [2- (4-Phenethyl-Î ± -methylcinnamoylamino) phenoxy] butanoic acid 4- [2- (3-pentyl-β-methyl-cinnamoylamino] -acetic acid 4- [2- (3-pentyl-Î ± -methylcinnamoylamino) ) phenoxy] butanoic acid 4- [2- (4-neopentyl] -B-methylcinnamoylamino) phenoxy] butanoic acid 4- [2- {4- (2-ethylbutyl) -β-methylcinnamoylamino) phenoxy] butanoic acid. 4- [2- (4- (2-methylpentyl) -β-methylcinnamoylamino) phenoxybutanoic acid, and 4- [2- (2-fluoro-4-pentyloxy-β-methyl-cinnamoylamino) -phenoxy] -butanoic acid.

Also included in this invention are fused benz (thio) amides of the formula:

wherein A represents a single bond or a methylene, ethylene, trimethylene, tetramethylene, vinylene, propenylene, butenylene, butadienylene or ethynylene group being optionally substituted by one, two or three line (s) alkyl group (s) or branched (s) with 1 to 10 carbon atom (s) and / or phenyl group (s); B represents a 4- to 8-membered heterocyclic ring containing one, two or three hetero atoms selected from the group consisting of oxygen, nitrogen and sulfur atom (s), wherein said ring is optionally substituted by the group (s) selected from oxo, thioxo and / or hydroxy group (s) including a ring of the formula:

T represents an oxygen atom or a sulfur atom; R 2 represents a group of the general formula:

Ci)

(iv) a linear or branched alkyl, alkenyl or alkynyl group having from 1 to 20 carbon atom (s), wherein R5 and R6 independently represent a hydrogen atom or a halogen atom or a linear alkyl, alkenyl or alkynyl group or branched alkyl groups having from 1 to 20 carbon atoms being unsubstituted or substituted by one, two, three, four or five optional carbon atom (s), per oxygen atom (s), atom (s) sulfur atom (s), nitrogen atom (s), benzene ring (rings), thiophene ring (rings), naphthalene ring (rings), carbocyclic ring (rings) of 4 to 7 atom carbonyl group (s), carbonyl group (s), carbonyloxy group (s), hydroxy group (s), carboxy group (s), azido group (s) and / or nitro group (s); R represents a hydrogen atom or a linear or branched alkyl group having from 1 to 6 carbon atom (s); R 3 represents a hydrogen atom, a halogen atom, a. Hydroxy group, a nitro group, a group of the general formula: -COOR, 60

Wherein R represents a hydrogen atom or a linear or branched alkyl group having from 1 to 6 carbon atom (s), or a linear or branched alkyl, alkoxy or alkylthio group having from 1 to 6 carbon atom (s) ; R 4 represents a group of the general formula: -U- (CH 2) n -C00 R 8, -U- (CH 2)

N-N H -CCH2) p-COOR8, or -C2),

: wherein R represents a hydrogen atom or a linear or branched alkyl group having from 1 to 6 carbon atom (s), nor represents an integer of 1 to 10 respectively, p and q represent zero or an integer of 1 to 10, respectively, or non-toxic salts thereof. Representative compounds include: 7- (p-hexyloxybenzoyl) amino-2- (5-tetrazolyl) benzofuran, 7- (p-octyloxybenzoyl) amino-2- (5-tetrazolyl) benzofuran, 7- (p- heptyloxybenzoyl) amino-2- - (5-tetrazolyl) benzofuran, 7- (p-nonyloxybenzoyl) amino-2) -5-tetrazolyl) benzofuran,

7- [p- (2E, 7, -octadienyl) benzoyl] amino-2- (5-tetrazolyl) benzofuran, 7- [2- (5-tetrazolyl) benzofuran, amino-2- (5-tetrazolyl) benzofuran, 7- (p-hexyloxybenzoyl) amino-2- (5-tetrazolyl) benzofuran, and 7- (p- (6-chlorohexyloxy) benzoylamino- 7- (p-heptylbenzoyl) amino-2- (5-tetrazolyl) -2,3-dihydro-1-benzofuranone, 7- (5-tetrazolyl) -2,3-dihydro- - (p-octyloxybenzoyl) amino-2- (5-tetrazolyl) -2,3-dihydro-1-benzofuran, 7- (p-nonyloxybenzoyl) amino-2- (5-tetrazolyl) -2,3- benzofuran, 8- [p-2E, 7-octadienyloxy) benzoyl] amino-1- (p-pentylcinnamoyl) amino-2- (5-tetrazolyl) -2,3-dihydro- 8- [p- (6-chlorohexyloxy) benzoyl] amino-2- (5-tetrazolyl) quinoline, 8- [p- (4-phenylbutoxy) benzoyl] amino- 8- [p- (2E, 7-octadienyloxy) benzoyl] amino-4-hydroxy-quinoline-2-carboxylic acid, 8- [p- (4-phenylbutoxy) benzoyl] amino- 4-hydroxyquinoline-2-carboxylic acid, 8- [p- [4- (2-thienyl) butoxy) benzoyl] ] -8- [p- (2E, 7-octadienyloxy) benzoyl] amino-4-hydroxy-2- (tetrazolyl) -quinoline, 8- [ 2-phenylbutoxy) benzoyl] amino-4-hydroxy-2- (5-tetrazolyl) -quinoline, and 8- (p-pentylcinnamoyl) amino-4-hydroxy-2- (5-tetrazolyl) quinoline, and 4- ( heptyloxybenzoyl) amino-2- (5-tetrazolyl) -1,3-benzodioxole, 4- (p-hexyloxybenzoyl) amino-2- (5-tetrazolyl) -1,3-benzodioxole, 4- [p- [4- - (phenylbutoxy) benzoyl] amino-2- (5-tetrazolyl) -1,3-benzodioxole, 4- (p-pentylcinnamoyl) amino-2- (5-tetrazolyl) -1,3-benzodioxole, 62

9- [p- (2E, 7-octadienyloxy) benzoyl] -9- [p- (4-phenylbutoxy) benzoyl] amino-2- (5-tetrazolyl) -3,4-dihydro- amino-2- (5-tetrazolyl) -3,4-dihydro-2H-1,5-benzodioxepine, 9- [p- (7-octenyloxy) benzoyl] amino-2- (5-tetrazolyl) 4-dihydro-2H-1,5-benzodioxepine, 8- (p-heptyloxybenzoyl) amino-2- (5-tetrazolyl) -2,3-dihydro-1,4-benzoxazine, 8- [ 4-phenylbutoxy) benzoyl] amino-2- (5-tetrazolyl) -2,3-dihydro-l, 4-benzoxazine and 8- (p-pentylcinnamoyl) amino-2- (5-tetrazolyl) -2,3- dihydro-1,4-benzoxazine, 8- [p- (4-phenylbutoxy) benzoyl] amino-2- (5-tetrazolyl) -4-oxo-4H-1-benzothiopyran, 8- [ phenylbutoxy) benzoyl] amino-2- (5-tetrazolyl) -3,4-dihydro-2-H -benzopyran, 8- [p- (7-octenyloxy) benzoyl] amino-2- (5-tetrazolyl) 4-dihydro-2H-1-benzopyran, S- (p-pentylbenzoyl) amino-2- (5-tetrazolyl) -4-oxo-4H-1-benzopyran, 8- (p- 4-oxo-4H-1-benzopyran, 8- (p-hexylbenzoyl) amino-2- (5-tetrazolyl) -4-oxo-4H-1-benzopyran, 8- (p- -heptylbenzoyl) amino-2- (5- (p-octylbenzoyl) amino-2- (5-tetrazolyl) -4-oxo-4H-1-benzopyran and 8- (p-nonylbenzoyl) amino- 2- (5-Tetrazolyl) -4-oxo-4H-1-benzopyran, 8- (p-butoxybenzoyl) amino-2- (5-tetrazolyl) -4-oxo-4H-1-benzopyran, 8- (p- amino-2- (5-tetrazolyl) -4-oxo-4H-1-benzopyrie, 8- (pheyloxybenzoyl) amino-2- (5-tetrazolyl) -4- pyran, 8- (p-heptyloxybenzoyl) amino-2- (5-tetrazolyl) -4-oxo-4H-1-benzopyran, 8- (p-nonyloxybenzoyl) amino-2- (5-tetrazolyl) -4- oxo-4H-1-benzo-pyran, 63

(P-octyloxybenzoyl) amino-2- (5-tetrazolyl) -4-oxo-4H-1-benzopyran, 8- (p-heptyloxybenzoyl) amino-2- (5-tetrazolyl) -6-fluoro- 4-oxo-4H-1β-benzopyran, and 8- (p-heptyloxybenzoyl) amino-4-oxo-4H-1-benzopyran, 8- (p-octyloxybenzoyl) amino-2- (5-tetrazolyl) -6- 4-oxo-4H-1-benzopyran and 8- [p- (2E, 7-octadienyloxy) benzoyl] amino-2- (5-tetrazolyl) -4-oxo -4-oxo-4H-1-benzopyran, 8- [P "(2E-nonenyloxy) benzoyl) amino] -4-oxo-4H-1-benzopyran, 8- (p-geranyloxybenzoyl) amino-2- (5-tetrazolyl) (2-tetrazolyl) -4-oxo-4H-1-benzoylamino, 2- benzoyl] amino-2- (5-tetrazolyl) -4-oxo-4H-1-benzopyran, 8- [p- (2E-heptenyloxy) benzoyl] amino-2- (5-tetrazolyl) -4-oxo-4H-1-benzopyran, 8- [p- (2E-hexenyloxy) benzoyl] amino-2- (5-tetrazolyl) -4- 8-β-benzoyl] amino-2- (5-tetrazolyl) -6-fluoro-4-oxo-4H-1-benzopyran, 8- [p- ( 2E-octenyloxy) benzoyl] amino-2- (5-tetra-furyl) -6-methyl-4-oxo-4- H-1-benzopyran-8- [p- (2E, 7-octadienyloxy) benzoyl] amino-2- (5-tetrazolyl) -6-chloro-4-oxo-4H-1-benzopyran, 8- [ (4-chlorobutoxy) benzoyl] amino-2- (5-tetrazolyl) -4-oxo-4H-1-benzopyran, -oxo-4H-1-benzopyran, 8- [p- (5-chloropentyloxy) benzoyl] amino-2- (5-tetrazolyl) -4-oxo-4H-1-benzopyran, 64

Amino-2- (5-tetrazolyl) -4-oxo-4H-1-benzopyran, 8- [p- (6-chlorohexyloxy) benzoyl] amino-2- (5-tetrazolyl) -4-oxo-4H-1-benzopyran, 8- [p- (7-chloroheptyloxy) benzoyl] amino-2- (5-tetrazolyl) -4-oxo-4H-1-benzopyran, 8 benzoyl] amino-2- (5-tetrazolyl) -6-methyl-4-oxo-4H-1-benzopyran, 8-CP- (7-chloroheptyloxy) benzoyl] amino- 8- [p- (8-chlorooctyloxy) benzoyl] amino-2- (5-tetrazolyl) -4-oxo-4H-pyrazole-2- benzoyl] amino-2- (5-tetrazolyl) -4-oxo-4 H -benzopyran, 8- [p- (3-phenyl-2E-propenyloxy) benzoyl] amino-2- (5-tetrazolyl) -4-oxo-4H-1-benzopyran, 8- [p- (4-phenylbutoxy) benzoyl] amino-2- (5-tetrazolyl) -4- 4-oxo-4H-1-benzopyran, 8β- [N- (4-phenylbutoxy) benzoyl] amino-2- (5-tetrazolyl) -6- [2- (2-naphthyl) ethoxy) benzoyl] amino-2- (5-tetrazolyl) -4-oxo-4H-1-benzopyran, 8- [p- [2- (2-naphthyl) ethoxy] benzoyl] amino-2- (5-tetrazolyl) -6-methyl-4-oxo-4H-1-benzopyran, 8- [p- [3- Dichlorophenyl) propoxy] benzoyl] amino-2- (5-tetrazolyl) -4-oxo-4H-1-benzopyran, 8- [p- [3- (3,4-dichlorophenyl) propoxy] benzoyl] amino-2- (5-tetrazolyl) -4-oxo-4H-1-benzopyran, 8- [p- [3- (p-odororophenyl) butoxy] benzoyl] amino- oxo-4H-1-benzopyran, 8- [p- [3- (p-chlorophenyl) butoxy] benzoyl] amino-6-methyl-2- (5-tetrazolyl) -4-oxo-4H-1-benzopyran , 65

8- [β- [3- (p-chlorophenyl) propoxy] benzoyl] amino-6-methyl-2- (5-tetrazol-4-yl) -4-oxo-4H-1-benzopyran, 8- [ Benzoyl] amino-2- (5-tetrazolyl) -4-oxo-4H-1-benzopyran, 8- [p- [4- (2-thienyl) butoxy] benzoyl] amino-2- (5-tetrazolyl) -6-methyl-4-oxo-4H-1-benzopyran, 8- (p-pentylcinnamoyl) amino-4-oxo-4H-1-benzopyran-2-carboxylic acid and its methyl ester, Amino-2- (5-tetrazolyl) -4-oxo-4H-1-benzopyran-8- (p-pentylcinnamoyl) amino-2- (5-tetrazolyl) -6-methyl- 4-oxo-4H-1-benzopyran, 8- (p-pentylcinnamoyl) amino-2- (5-tetrazolyl) -6-fluoro-4-oxo-4H- ) 4-oxo-4H-1-benzopyran-2-carboxylic acid and its ethyl ester, 8- (p-butylcinnamoyl) amino-2- (5-tetrazolyl) -4-oxo-4H-1 4-oxo-4H-1-benzopyran, 8- (p-heptylcinnamoyl) amino-2- (5-tetrazolyl) -4-oxo-2- (5-tetrazolyl) -4-oxo-4H-1-benzopyran, 8- (p-hexylcyanmoyl) amino-2- (5-tetrazolyl) -4-benzopyranyl, 8-cinnamoylamino-2- (5-tetrazolyl) oxo-4H-1-ben 2- (5-Tetrazolyl) -4-oxo-4H-1-benzopyran, 8- (p-isohexyloxycinnamoyl) amino-2- (5-tetrazolyl) -4- 8- [p- (2-octynyloxy) cinnamoyl] amino-4-oxo-4H-1-benzopyran-2-carboxylic acid, 8- [p- (5-chloropentyloxy) cinnamoyl] amino-2- (5-tetrazolyl) -4-oxo-4H-1-benzopyran, 8- [p- (6-chlorohexyloxy) cinnamoyl] amino-2- (5-tetrazolyl) -4-oxo-4H- 1-benzopyran, 8- (p-pentylbenzoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane; 66

8- (p-pentylbenzoyl) amino-2- (5-tetrazolyl) -6-chloro-1,4-benzodioxane; 8- (o-pentylbenzoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxan; 8- (o-pentylbenzoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane; 8- (p-butylbenzoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane; 8- (p-hexylbenzoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane; 8- (p-heptylbenzoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane; 8- (p-octylbenzoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane; 8- (p-nonylbenzoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane; 8- (p-decylbenzoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane; 8- (p-undecylbenzoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane; 8- (p-dodecylbenzoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane; 8- (p-pentyloxybenzoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane; 8- (m-pentyloxybenzoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane; 8- (o-pentyloxybenzoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane; 8- (p-butyloxybenzoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane; 8- (p-nonyloxybenzoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane; 8- (p-propoxybenzoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane; 8- (p-hexyloxybenzoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane; 8- (p-heptyloxybenzoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane; 8- (p-octyloxybenzoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane; 8- (o-decyloxybenzoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane; 8- (p-isopentyloxybenzoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane; 8- (p-isohexyloxybenzoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane; 8- [p- (1-methylbutoxy) benzoyl] amino-2- (5-tetrazolyl) -1,4-benzodioxane; 8- (N-methyl-N- (p -ocynyloxy) benzoyl]) amino-2- (5-tetrazolyl) -1,4-benzodioxane; 8- (p-octyloxybenzoyl) amino-1,4-benzodioxane-2-carboxylic acid and its methyl ester; 8- (p-isoheptylbenzoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane; 8- (p-isooctyloxybenzoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane; 67

8- [ρ- (3,7-dimethyloctyloxy) benzoyl] amino-2- (5-tetrazolyl) -1,4-benzodioxane; 8- (p-octyloxybenzoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane-7-carboxylic acid, 8- [p- (2E-octyloxybenzoyl) amino-2- (5-tetrazolyl) -1- 4-benzodioxane, 8- [β- (3Z-hexenyloxy) benzoyl) amino] -2- (3-butenyloxy) benzoyl) amino-2- (5-tetrazolyl) -1,4- - (5-tetrazolyl) -1,4-benzodiox-ano; 8- [p- (2E-nonenyloxy) benzoyl) amino] -2- (5-methoxyphenyl) benzoyl) amino-2- (5-tetrazolyl) -1,4- 8- [N-methyl-N- [p- (2E-octenyloxy) benzyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane, 8- - [p- (2E-hexenyloxy) benzoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane, 8- [p- (3E -heptenyloxy) benzoyl) amino-2- (5-tetrazolyl) -1- , 4-benzodioxane; 8- [p- (2E-octenyloxy) benzoyl) amino-1,4-benzodioxane-2-carboxylic acid and its methyl ester, 8- [p- (2E-heptenyloxy) benzoyl) amino-2- (5- tetrazolyl) -1,4-benzodioxane, 8- [p- (4-pentenyloxy (benzoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane, 8- [2 '- (2E-decenyloxy) benzoyl] amino-2- (5-tetrazolyl) -1,4-benzodioxane, 8- (p-geranyloxy) benzoyl) amino-2- (5-tetrazolyl) -1,4- (2E, 7-octadienyloxy) benzoyl) amino-2- (5-tetrazolyl) -1,4-benzdioxane, 8 "[P" (2E Pentenyl) benzoyl) amino-2- (5-tetrazolyl) 1,4-benzodioxane, 68

8- [p- (3E-octenyloxy) benzoyl) amino-2- (5-tetrazolyl) amino] -2- (5-tetrazolyl) -1,4-benzodiox- ) -1,4-benzodioxane, 8- [p- (2-octenyloxy) benzoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane, 8- [ octadienyloxy) benzoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxan and 8- [p- (2E-octadienyloxy) benzoyl) amino-2- (5-tetrazolyl) -1,4- 8- [p- (2-octynyloxy) benzoyl] amino-1,4-benzodioxanecarboxylic acid, 8- [p- (2-octynyloxy) benzoyl) amino-2- (5-tetrazolyl) -1,4- 2-carboxylic acid methyl ester and 8- [p- (2-isooctyloxy) benzoyl] amino-2- (5-tetrazolyl) -1,4-benzodioxane, 8- (p-pentylthiobenzoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane, 8- (o-pentylthiobenzoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane, (5-tetrazolyl) -1,4-benzodioxane and 8- (p-heptylthiobenzoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane, 8- [p- (6-chlorohexyloxy) benzoyl] amino-2- - (5-chloropentyloxy) benzoyl] amino-2- (5-tetrazolyl) -1,4-benzodioxane, 8- [p- (5-chloropentyloxy) benzoyl] Benzoyl] amino-2- (5-tetrazolyl) -1,4-benzodioxane, 8- [p- (7-chloroheptyloxy) benzoyl) amino-2- (5-tetrazolyl) -1,4- benzodioxane, 8- [p- (9-chlorononyloxy) benzoyl] amino-2- (5-tetrazolyl) benzoyl] amino-2- (5-tetrazolyl) -1,4- ) -1,4-benzodioxane and 69

8- [p- (t-bromopentyloxy) benzoyl] amino-2- (5-tetrazolyl) -1,4-benzodioxane-2-carboxylic acid and its methyl ester, 8- [p-hexyloxyinethyl) benzoyl] amino 8- [p- (cyclohexylmethoxy) benzoyl] amino-2- (5 "-tetrazolyl) -1,4-benzodioxane, 8- [p- (4-cyclohexylbutoxy ) benzoyl] amino-2- (5-tetrazolyl) -1,4-benzodioxane, and 8- [p- (2-cyclohexylethoxy) benzoyl]) amino-2- (5-tetrazolyl) -1,4-benzodioxane, and 8- [p- (p-butylphenyl) methoxybenzoyl] amino-2- (5-tetrazolyl) -1,4-benzodioxane, 8- [p- (5-phenylpentyloxy) benzoyl] amino-2- (5-tetrazolyl) - 1,4-benzodioxane, 8- [p- (3-phenylpropoxy) benzoyl]) amino-2- (5-tetrazolyl) -1,4-benzodioxane, 8- [p- (p-propylphenyl) methoxybenzoyl] ] amino-2- (5-tetrazolyl) -1,4-benzodioxane, 8- [p- (3-phenyl-2-propenyloxy) benzoyl] amino-2- (5-tetrazolyl) -1,4-b-enzodioxane , 8- [β- (Î ± -pentylphenyl) methoxybenzoylamino-2- (5-tetrazolyl)] - 1 - [(p- (4-phenylbutoxy) benzoyl] amino-2- (5-tetrazolyl) -1,4-benzodioxane, , 4-benzodioxane, 8- [p- (m-butylphenylmethoxybenzoyl) amino-2- (5-tetrazolyl) -1,4-benzo-di (p-phenylmethoxybenzoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane, 8- [p- (2-phenylethoxy) benzoyl] amino-2- (5-tetrazolyl) -1,4- benzoyl] amino-2- (5-tetrazolyl) -1,4-benzodioxane, 8- [p- [2- (2-naphthyl) ethoxy] benzoyl]) amino- 8 - [[3- [3- (P-chlorophenyl) propoxy] benzoyl] amino-2- (5-tetrazolyl) -1,4-benzodioxane and 8- [p- [4- (p-chlorophenyl) butoxy] benzoyl] amino-2- (5-tetrazolyl) -1,4-benzodioxane, 8 "[P" (5 "Ethoxycarbonylpentyloxy) benzoyl] amino- 8- [p- (6-acetyloxyhexyl) benzoyl] amino-2- (5-tetrazolyl) -1,4-benzodioxane, 8- [p- (6-hydroxyethoxyhexyloxy) ) benzoyl] amino-2- (5-tetrazolyl) -1,4-benzodioxane, 8- [p- (2E-octenoyloxy) benzoyl] amino-2- (5-tetrazolyl) -1,4-benzodioxane and 8- ( p-octanoylbenzoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane, 8- [p- (3-phenylthiopropoxy) benzoyl] amino-2- (5-tetrazolyl) -1,4-benzodioxane, 8- [p- (3-phenoxypropoxy) benzoyl] amino-2- (5-tetrazolyl) -1,4-benzodioxane, 8- [p- (2-phenylthioethoxy) ben benzoyl] amino-2- (5-tetrazolyl) -1,4-benzodioxane, 8- [p- (2-phenoxyethoxy) benzoyl] amino-2- (5-tetrazolyl) -1,4- - [2- (3-thienyl) ethoxy] benzoyl] amino-2- (5-tetrazolyl) -1,4-benzodioxane and 8- [p- [4- (2-thienyl) butoxy] benzoyl] amino- 8- [P- (5-azidophenyloxy) benzoyl] amino-2- (5-tetrazolyl) -1,4-benzodioxane, 8- [p- ( 5-dimethylaminopentyloxy) benzoyl] amino-2- (5-tetrazolyl) -1,4-benzodioxane, 8- [p- (4-nitrobutoxy) benzoylamino-2- (5-tetrazolyl) -1,4- , 8- [p- (2-azidoethoxy) benzoyl] amino-2- (5-tetrazolyl) -1,4-benzodioxane,

8- [p- (2-octenoylamino) benzoyl] amino-2- (5-tetrazolyl) -8- [p- (4-azidobutoxy) benzoyl] amino-2- (5-tetrazolyl) -1,4-benzodioxane, 1,4-benzodioxane, 8- (p-pentyloxy-m-methoxybenzoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane, 8- [p- (2E-octenyloxy) chlorobenzoyl] amino-2- (5-tetrazolyl) -1,4-b-endoxodioxane, 8- (2-naphthylcarbonyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane, 8- (p- amino-2- (5-tetrazolyl) -1,4-benzodioxane, 8- (p-pentylcinnamoyl) amino-1,4-benzodioxane-2-carboxylic acid and its methyl ester, 8- (p- heptylcinnamoyl) amino-2- - (5-tetrazolyl) -1,4-benzodioxane, 8- [N-methyl- [N- (pentylcinnamoyl) amino] -2- (5-tetrazolyl) -1,4-benzodioxane, 5- (p-pentylcinnamoyl) amino-2- (5-tetrazolyl) -7-chloro-1,4-benzodioxane, 8- (p-pentylcinnamoyl) amino-2- (5-tetrazolyl) -6-chloro-1,4- - (p-ethylcinnamoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane, 8- (p-propylcinnamoyl) amino-2- (5-tetrazolyl) -1,4- butylcinnamoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane, 8- (p-pentylcinnamoyl) amino-2- (5-tetrazolyl) -6- methyl-1,4-benzodioxane, 8- (o-pentylcinnamoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane, 8- (m-octylcinnamoyl) amino-2- (5-tetrazolyl) -1- , 4-benzodioxane, 8- (p-pentylcinnamoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane-5-carboxylic acid and its methyl ester, 5- (p-pentylcinnamoyl) amino- 5-tetrazolyl) -1,4-benzodioxane-8-carboxylic acid and its methyl ester, 8- (p-hexylcinnamoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane, 8- (p- amino-2- (5-tetrazolyl) -1,4-benzodioxane, 72

8- (p-pentylcinnamoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane-6-carboxylic acid and its methyl ester, 5- (p-pentylcinnamoyl) amino-2- (5-tetrazolyl) - 1,4-benzodioxane-7-carboxylic acid and its methyl ester, 8- (p-octylcinnamoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane, 8- (p-decylcinnamoyl) amino-2- ( (P-isobutylcinnamoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane, 8- (p-isobutylcinnamoyl) amino-2- (5-tetrazolyl) -1,4- (P-pentyl-2-methylcinnamoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane, 8- (p-isopentylcinnamoyl) amino-2- (5-tetrazolyl) -1,4-benzodiox-8- (p-pentyl-3-methylcinnamoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxan and 8- (p-pentylcinnamoyl) amino-2- ( 5-tetrazolyl) methyl-1,4-benzodioxane, 8- (p-pentylcinnamoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane, 8- (m-pentylcinnamoyl) amino-2- (5-tetrazolyl ) -1,4-benzodioxane, 8- (o-pentyloxycinnamoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane, 8- (p-propoxycinnamoyl) amino-2- (5-tetrazolyl) 4-benzodioxane, 8- (p-butoxycinnamoyl) a (p-hexyloxycinnamoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane, 8- (p-octyloxycinnamoyl) amino-2- (5-tetrazolyl) -1,4- (P-heptyloxycinnamoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane, 8- (p-isopentyloxycinnamoyl) amino-2- (5-tetrazolyl) -1,4- ) -1,4-benzodioxan-8- (p-isohexyloxycinnamoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane, 8- [p- (1-methylbutoxy) cinnamoyl] amino-2- ( (P-isooctylcinnamoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxan-8- (p-isooctylcinnamoyl) amino-2- (5-tetrazolyl) -1,4- tetrazolyl) -1,4-benzodioxane, 8- (p-isohexyloxy-2-methylcinnamoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane and 73

8- [p- (2E-octenyloxy) cinnamoyl] amino-2- (5-tetrazolyl) -8- (p-isohexyloxy-2-phenylcinnamoyl) amino-2- (5-tetrazolyl) -1,4- -1,4-benzodioxane, 8- [p- (2-propenyloxy) cinnamoyl] amino-2- (5-tetrazolyl) -1,4-benzodioxane, 8- [p- (3-butenyloxy) cinnamoyl] ] amino-2- (5-tetrazolyl) -1,4-benzodioxane, 8- [p- (3Z-hexenyloxy) cinnamoyl] amino-2- (5-tetrazolyl) -1,4-benzodioxane, 8- - [p-2Z-pentenyloxycinnamoyl] amino-2- (5-tetrazolyl) -1,4-benzodioxanediol, 8- [p- (2E-nonenyloxy) cinnamoyl] amino-2- (5-tetrazolyl) 4-benzodioxane, 8- [β- (3E-heptenyloxy) cinnamoyl] amino-2- (5-tetrazolyl) -1,4-benzodioxane, 8- [p- (2E-heptenyloxy) cinnamoyl] ] amino-2- (5-tetrazolyl) -1,4-benzodioxane, 8- [p- (2E-hexenyloxy) cinnamoyl] amino-2- (5-tetrazolyl) -1,4-benzenedioxane, 8- - [p- (2E-pentenyloxy) cinnamoyl] amino-2- (5-tetrazolyl) -1,4-benzodioxane, 8- [p- (4-pentenyloxy) cinnamoyl] amino-2- (5-tetrazolyl) - 1,4-benzodioxane, 8- [p- (2E-butenyloxy) cinnamoyl] amino-2- (5-tetrazolyl) -1,4-benzodioxane and 8- [p- (2E-decenyloxy) cinnamoyl] amino-2- (5-tetrazolyl) -1,4-benzodio- 8- [p- (2-pentynyloxy) cinnamoyl] amino-2- (5-methoxyphenyl) amino-2- (5-tetrazolyl) -tetrazolyl) -1,4-benzodioxane, 8- (m-pentylthiomethylamino) amino-2- (5-tetrazolyl) -1,4-benzodioxane and 74

8- [P "(6-chlorohexyloxy) cinnamoyl] amino-2- (5-tetrazolyl) -1,4-benzodioate 8- (o-pentylthioquininyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane, 8- [p- (5-chloropentyloxy) cinnamoyl] amino-2- (5-chloropentyloxy) amino-2- (5-tetrazolyl) -1,4-benzodioxane, 8- [p- (7-chloroheptyloxy) cinnamoyl] amino-2- (5-tetrazolyl) -1,4-benzo-dioxane, 8- (p-isopentyloxymethyl- cinnamoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane, 8- (p-cyclohexylcinnamoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane, 8- (p- cyclohexylmethoxycinnamoyl) amino- 8- [p- (4-cyclohexylbutoxy) cinnamoyl] amino-2- (5-tetrazolyl) -1,4-benzodioxane and 8- [p- (2-tetrazolyl) cyclohexylethoxy) cinnamoyl] amino-2- (5-tetrazolyl) -1,4-benzdioxane, 8- (p-phenylmethylcinnamoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane, 8- (p- phenylmethoxycinnamoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane, 8- [p- (2-phenylethoxy) cinnamoyl] amino-2- (5-tetrazolyl) -1,4-benzodioxane, 8- [ - (4-phenylbutoxy) cinnamoyl] amino-2- (5-tetrazolyl) -1,4-benzodioxane, 8- [ 5-phenylpentyloxy) cinnamoyl] amino-2- (5-tetrazolyl) -1,4-benzodioxane and 8- [p- (3-phenylpropoxy) cinnamoyl] amino-2- (5-tetrazolyl) -1,4- oxane, 8- [p- (6-acetyloxyhexyl) cinnamoyl] amino-2- (5-tetrazolyl) -1,4-benzodioxane, 8- [p- [2- (2-thienyl) ethoxy) -cinnamoyl] amino -2- (5-tetrazolyl) -1,4-benzodioxane, 8- (m, p-dimethoxycinnamoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane, 75

8- (p-pentyloxy-m-chlorocinnamoyl) amino-2- (5-tetrazolyl) -1- (m-methoxy-p-pentyloxycinnamoyl) amino-2- (5-tetrazolyl) -1,4- (5-indanyl) acryloyl] amino-2- (5-tetrazolyl) -1,4-benzodioxane, N- (2-hexadecenoyl) amino-2- (5-tetrazolyl) ) -l-4-benzodioxane, and 8- [3- (p-pentylphenyl) propionyl] amino-2- (5-trifluoromethylphenyl) amino-2- (5-tetrazolyl) tetrazolyl) -1,4-benzodioxane, 8- (p-hexylphenylpropionyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane, 8- [5- (p-propoxyphenyl) penta-2E, 4E- dienoyl] amino-2- (5-tetrazolyl) -1,4-benzodioxane and 8- [5- (p-butylphenyl) penta-2E, 4E-dienoyl] amino-2- (5-tetrazolyl) -1,4- benzodioxane, 8- (p-pentylcinnamoyl) amino-2- (5-tetrazolyl) -2,3-dihydro-14-dithiananthalene and 5- (p-pentylcinnamoyl) amino-2- (5-tetrazolyl) -2 , 3-dihydro-1,4-dithia-naphthalene and its sodium salts. Also included are 1,2-di (thio) aromatic ethers of the formula:

R 'I

in which 76

A is an aromatic ring disubstituted at 1.2; preferably a benzene ring; wherein X is independently O, S, SO or SO; R1 is H, C1 -C4 alkyl, phenyl or substituted phenyl, halo, haloalkyl, hydroxy, carboxy, cyano, C1 -C4 alkoxy, C1 -C4 alkylthio, C1 -C4 alkylsulfinyl, C1 -C4 alkylsulfonyl, amino, nitro, C 1 -C 4 mono or di-alkylamino; R 'and R " are independently H, halo, C1 -C4 or C1 -C4 alkoxy, amino, or oxo, wherein CH-R 'or CH-R "in the formula becomes -C = O; y is 1-6; z is 6-20; and wherein 77

R '

I (CH) y and R "

I

(CH) Z may independently represent substituted or unsubstituted alkyl or alkenyl radicals containing at least one alkene linkage; and pharmaceutically acceptable salts and esters thereof.

The compounds of the present invention are inhibitors of the human enzyme testosterone-5α-reductase. The scope of the compounds of the present invention is described by the formula described above.

In the description of the formula the following expressions are used which are hereby defined: X in the above general formula is O or S, preferably when X is O, and particularly when both X are O, for example, resulting in catechol structure. " C1-4 alkyl " includes linear or branched species, for example methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, t-butyl. " C1-C4 alkoxy " includes linear or branched species, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy. " Halo " includes fluorine, chlorine, bromine or iodine. 78

" Substituted Phenyl " includes phenyl substituted by one or more C1 -C4 alkyl, C1 -C4 alkoxy, or halo, etc., as defined above. Representative examples include o-, m-, p-methoxyphenyl; 2,4-dimethoxyphenyl; 2-chloro-4-ethoxyphenyl; 3,5-dimethoxy-phenyl; 2,4-dichlorophenyl; 2-bromo-4-methylphenyl, o-fluorophenyl, etc. " Haloalkyl " includes C 1 -C 4 alkyl, defined above, substituted with one or more " halo " as defined above and includes: trifluoromethyl, 2,2-dichloroethyl, and the like. " C 1 -C 4 alkylthio " includes C 1 -C 4 alkyl, defined above, substituted with at least one divalent thio (-S-) moiety including: methylthio, ethylthio, isopropylthio, n-butylthio, and the like. " C? -C? alkylsulfinyl " includes C 1 -C 4 alkyl, defined above, substituted with at least one -COOH group including; methylsulfinyl, ethylsulfinyl; isopropylsulfinyl, etc. " C1-C4 alkylsulfonyl " includes C 1 -C 4 alkyl, defined above, substituted with at least one sulfonyl group, -SO 2 -, including; methylsulfonyl, ethylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, etc. " C1-C4 mono or dialkylamino " includes amino substituted with one or more C 1 -C 4 alkyl groups as defined hereinbefore, including: methylamino, ethylamino, n-butylamino, t-butylamino, N, N-dimethylamino, Ν-diethylamino, t-butylamino, etc. the group (s) R on the benzene ring may be present initially in the process, such as in starting material I in Flow Sheet A, for example phenyl, methyl,

methoxy, cyano, trifluoromethyl, carbomethoxy, or may be added subsequently by a conventional reaction, for example chlorine, such as by chlorination, nitro by nitration, or created from a group functional starting material or added present, for example by converting a nitro group to an amino group by catalytic reduction, and then alkylating until a mono or dialkylamine is obtained. An amino group can be subjected to diazotization to give a hydroxy group, and methylation can then be followed until a methoxy group is obtained. Similarly, a hydroxy group may be converted to a thiol by the analogous procedures described in J. Org. Chem. 31, pp 3980-3984 (1966) by Newman and Karnes, and J. Org. Chem. 31, pp 410 (1966) by Kwart, H. and Evans, E.S. the resulting thiol can be alkylated to an alkylthio, which may be oxidized to the corresponding sulfoxide or sulfone. Preferred substituents are H, C1 -C4 alkyl, C1 -C4 alkoxy and phenyl. These reactions and sequences are conventional in the art for modifying the benzene ring in order to arrive at a R radical shown herein. The phrase " its pharmaceutically acceptable salts and esters " means, salts and esters of the acid groups in the final molecule which may be used as part of the human drug delivery system and include the sodium, potassium, calcium, ammonium, substituted ammonium, quaternary ammonium, and esters: ester ethyl acetate, aceturate, besylate, edetate, phenpropionate, acetate, pamoate, and esters which serve as formulations of " prodrug " which will hydrolyse the organism at physiological pHs in order to regenerate the acid, including pivaloylates, for example pivoxethyl and pivoxyl, and Kanebo esters, etc. R '

I (CH) y wherein y is 1-6, preferably 3, may contain 80

at least one R 'substituent as defined above, and may be, for example, -CH 2 -; -CH 2 -CH 2 -; -CH 2 -CH 2 -CH 2 -, -CH-; -CH-CH-CH-CH-; -CH "-CH-CH-; -CH-CH-CH-; | | Δ Z | ú | ú Δ | Δ CH 3 CH 3 Cl OCH 3 OCH 2 CH 3 etc.

An alkene linkage may also be present in R '(CH) y-; for example, CH 2 -CH = CH-; CH 2 -CH = CH-CH 2 -; -CH 2 -CH = CH- (CH 2) 2 -; etc. (CH) where z is 6-20, preferably 10-16, may contain

Li

at least one R "substituent as defined above, and may be: for example - (CH 2) 6 -, - (CH 2) 20 -, - (CH 2) g -CH

CH-CH 2 -CH- (CH 2) 9 -; - (CH 2) 5-CH- (CH 2) 4 - and the like. 3

F och3

An alkene linkage may also be present in R "

For example, CH 2 -CH = CH- (CH 2) 2 -, - (CH 2) 8 -CH = CH (CH 2) 2 -; - (CH 2) 9 -CH = CH (CH 2) 9 -; (CH 2) 4-CH = CH- (CH 2) 4 -; etc. R 'and R "may also be -NHCOCH 3, which may be hydrolyzed to the amino by conventional hydrolysis with acid or base in the final molecule; R 'and R "may also be oxo, obtained by, for example, adding HBr to an alkene followed by conversion into an alcohol and subsequent oxidation to the ketone.

Preferred is when R7 or R " is H and in particular R 'R " Preferred is when both (CH3) 4 and (CH3) Z are alkyl. indicated

Preferred compounds of the present invention are by the following formulas:

in which defined; an X is O and R, R ', R ", y and z are as defined above. Particularly preferred are the compounds,

CH2) 3 COOH

0-CCH2) nC00H where X is O or S is 10-16. 82 i

The compounds of the present invention may be produced by the process indicated in Flow Sheet A-1 which follows. 83

FLOW SHEET A-1

R 'i

VII 84

As is indicated in Flow Sheet A-1, Compound I is the starting substrate in the process of the invention and is a benzene ring substituted in 1.2. X may be independently 0 or S and iipgn represents a protected hydroxy or thio group which is inactive during Step (A) but may be subsequently removed by, for example, palladium on carbon catalyst in ethanol under a pressurized H2 atmosphere.

Examples of protecting groups " PG " that are conventional and known in the art (See " Protective Groups in Organic Synthesis " by Theodora W-Greene - 1981 - John Wiley - Chapter 2, " Protection for the Hydroxyl Group, Including 1,2- and 1,3-Diols " pp. 16-87 and Chapter 6 " Protection for the Thiol Group " pp. 193-218).

Representative examples of " PG " include: benzyl, p-methoxybenzyl, p-halobenzyl; including p-chlorobenzyl, p-fluorobenzyl, etc. Other protecting groups which are known will become apparent to the person skilled in the art in carrying out the function of Step (A).

Representative examples of compounds useful as I in the present invention include, but are not limited to, the following: 2- (benzyloxy) phenol, 2-benzyloxythiophenol, 2- (benzylthio) phenol, 2- (benzylthio) thiophenol 3-methoxy-2-benzyloxyphenol, 2-benzyloxy-4-methoxyphenol, 3-methyl-2-benzyloxyphenol, 2-benzyloxy-5-methylphenol, 2-benzyloxy-4-methylphenol, 2-benzyloxy-5-methylphenol, 2 benzyloxy-3,5-diisopropylphenol, 2-benzyloxy-3,5-di-t-butylphenol, 2-benzyloxy-4-t-butylphenol, 2-benzyloxy-3-ethylphenol, 2-benzyloxy-5-phenylphenol, 2- benzyloxy-4-methyl-1-thiophenol, 2-benzyloxy-5-trifluoromethyl-1-thiophenol, 2-benzyloxy-6-methoxy-1-thiophenol, 2-benzylthio-4-methylthiophenol, 2-benzylthio-5- -methylsulfonyl-phenol, etc.

Representative examples of II useful in the process of the invention where L is a leaving group, for example, halogen, including bromine, chlorine, or sulfonate, etc., and Ra is a C.C. linear or branched alkyl of the ester, including methyl, ethyl, isopropyl, t-butyl, sec-butyl, etc., and wherein R and Y are as defined above, but are not limited to:

Br-CH2 COOMe, c1-ch2ch2ch2cooch2ch3,

Br-CH 2 CH 2 CH 2 CH 2 COOMe,

Br-CH 2 CH 2 CH 2 CH 2 COOEt,

Br-CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2,

Br- (CH 2) 2 CH (CH 3) COOMe,

Br-CH 2 CH (CH 3) CH 2 COOEt,

Br-CH2 CH2 CH2 COOMe,

Br-CH 2 CH (OCH 3) CH 2 COOCH (CH 3),

Cl-CH 2 CH (OCH 2 CH 3) CH 2 COOMe '

Br-CH 2 CH (F) CH 2 COOMe, Cl-CH 2 CH 2 COOEt, etc.

In step (A) the condensation of I and II to produce II takes place in an unhydroxylated polar organic solvent, for example, acetone, ethyl acetate, methyl ethyl ketone, dioxane, THF, diethyl ketone, etc. Also provided is a proton acceptor, for example potassium carbonate, sodium bicarbonate, pyridine, triethylamine, etc. Generally, the reaction is carried out under an inert atmosphere, for example dry nitrogen, and heated under reflux or allowed to settle for an extended period of time at ambient temperature. The process is conventional.

In step (B) the protecting group " PG " is catalytically removed at ambient temperature under an atmosphere of hydrogen, pressurized in an organic solvent to yield IV, being a phenol or thiophenol. Operatable catalysts include 5% Pd / C, etc. the organic solvent should be inert under the reaction conditions and include ethyl acetate, ethanol, methanol, dioxane, etc. Step (C) involves the reaction of IV with V to afford VI, the diester. The reaction conditions are similar to those described in Step (A) using an organic solvent inert to the reactants and a proton acceptor.

Representative V-forms useful in the invention are:

Br (CH 2) 6 COOMe,

Br (CH 2) 7 COOMe,

Br (CH 2) g COOMe,

Br (CH 2) g COOMe,

Br (CH 2) 1 () COOMe,

Br (CH 2) 1; LCOOMe, Cl (CH 2) 12 COOEt, Cl (CH 2) χ 3 COOCH (CH 3) 2, ci (ch 2)

Br- (CH 2) 15 COOMe,

Br- (CH 2) 16 COOMe,

Br (CH 2) 16 COOCH 2 CH 3, Br (CH 2) 17cooc (CH 3) 3,

Br (CH 2) 18 COOMe,

Br (CH 2) 1 COOEt,

Br (CH 2) 20 COOMe,

Br (CH2) 2 CH (CH3) - (CH2) 10COOMe, Br-CH2CH (CH3) (CH2) 10COOMef Br-CH2 CH3 CH (CH3) CH2 COOEt,

CH-CH 2 CH (OCH 3) (CH 2) 2 - (CH 2) 1 - (CH 2) -COOMe, --CH 2 CH 3 - (CH 3) L-cooEt, 0

Br-CH 2 -CH = CH (CH 2) g -COOEt,

Br-CH2-C- (CH2) 10CH2COOMe, CH2

Br-CH 2 - (CH 2) -CH = CH-COOMe, etc.

In Step (D) the diester can be de-esterified by aqueous basic hydrolysis, for example NaOH in MeOH / H2 O to provide the diacid VI after acidification. FLOW SHEET B-1

+ BrCH2CH2CH2C02Et, Ph2O2CE2CE2CO2E2 (C4) + C5) (C2) (J2C2CH2CU2CQ2Et) k4 X'ocH2 (CH2), OCO2CH3 CD) ^^ jdce2 ch2ch2cooh

Of OCH2C ch2) λ 0cooh 7 89

FLOW SHEET C-1

CC) (4A) + (5) -

CD)

CH 2 CH 2 CH 2 COOH OCH 2 (CH 2) 10 COOH

7 to 90

Flow Sheet B-1 illustrates the specific synthesis of τ_ ·

As can be seen, ethyl 2-benzyloxyphenol 1,4-bromo-butyrate 2 and anhydrous CO 2 in eg dry acetone are heated under reflux or stirred for an extended period of time at ambient temperature under an atmosphere of nitrogen to give the ethyl 4- (2-benzyloxyphenoxy) butyrate product 3 in Step (A).

A solution of 3 in, for example, ethyl acetate is catatically hydrogenated at room temperature under for example 40 psig H2 in the presence of a 5% Pd / C catalyst to provide ethyl 4- (2-hydroxyphenoxy) butyrate 4 in Step (B). Step (C) comprises reacting methyl 4 and 12-bromododeca-naphthate 5 with potassium carbonate in acetone as in Step (A) to give the monomethyl ester 6.

In Step (D), the diester 6 is de-esterified by, for example, 2.5 N NaOH in MeOH / H2 O to provide the final product, diacid 1, after acidification. Flow Sheet C-1 illustrates the synthesis of the sulfur analog of 7 as 7A. This analogous process uses substantially the same steps as are involved in Flow Sheet B. It is also obvious from the above Flow Sheets that suitable substituent compounds for II and 2 with other substituted and unsubstituted halo alkyl esters known in the described herein and that the appropriate substitution of V and 5 with other bromo esters available from the

and also described above will provide all compounds within the scope of the present claims.

Representative examples of compounds produced by this process include:

4- (2- (20-Carboxyicosyloxy) phenoxy) butyric acid;

4- (2- (19-Carboxyldecyloxy) phenoxy) butyric acid; 4- (2- (18-carboxyoctadecyloxy) phenoxy) butyric acid; 4- (2- (17-Carboxyhepotadecyloxy) phenoxy) butyric acid; 4- (2- (16-carboxyhexadecyloxy) phenoxy) butyric acid; 4- (2- (15-carboxypentadecyloxy) phenoxy) butyric acid; 4- (2- (14-Carboxytetradecyloxy) phenoxy) butyric acid; 4- (2- (13-carboxytridecyloxy) phenoxy) butyric acid; 4- (2- (12-carboxydecyloxy) phenoxy) butyric acid; 4- (2- (11-carboxyundecyloxy) phenoxy) butyric acid; 4- (2- (10-Carboxyidyloxy) phenoxy) butyric acid; 4- (2- (9-Carboxynonyloxy) phenoxy) butyric acid; 4- (2- (8-carboxyoctyloxy) phenoxy) butyric acid; 4- (2- (7-Carboxyheptyloxy) phenoxy) butyric acid; 4- (2- (6-Carboxyhexyloxy) phenoxy) butyric acid; 4- (2- (20-Carboxyicosyloxy) phenylthio) butyric acid; 4- (2- (19-Carboxyldecyloxy) phenylthio) butyric acid; 4- (2- (18-carboxyoctadecyloxy) phenylthio) butyric acid; 4- (2- (17-Carboxyheptadecyloxy) phenylthio) butyric acid; 4- (2- (16-carboxyhexadecyloxy) phenylthio) butyric acid; 4- (2- (15-carboxypentadecyloxy) phenylthio) butyric acid; 4- (2- (14-Carboxytetradecyloxy) phenylthio) butyric acid; 4- (2- (13-Carboxytdecyloxy) phenylthio) butyric acid; 4- (2- (12-Carboxydodecyloxy) phenylthio) butyric acid; 4- (2- (11-carboxyundecyloxy) phenylthio) butyric acid; 4- (2- (10-Carboxyidyloxy) phenylthio) butyric acid; 4- (2- (9-Carboxynonyloxy) phenylthio) butyric acid); 92 92 4-Acid 4-Acid 4-Acid 4-Acid 4-Acid 4-Acid 4-Acid 4-Acid 4-Acid 4-Acid 4- Acid 4-Acid 4-Acid 4-Acid 4-Acid 4-Acid 4-Acid 4-Acid 4-Acid 4-Acid 4-Acid 4-Acid 4-Acid 4-Acid 4-Acid 4-Acid 4-Acid 4-Acid 4 - (2- (8-carboxyoctyloxy) phenylthio) butyric acid; (2- (7-carboxyheptyloxy) phenylthio) butyric acid; (2- (6-carboxyhexyloxy) phenylthio) butyric acid; (2- (20-carboxyicosylthio) phenoxy) butyric acid; (2- (19-carboxynonidecylthio) phenoxy) butyric acid; (2- (18-carboxyoctadecylthio) phenoxy) butyric acid; (2- (17-carboxyheptadecylthio) phenoxy) butyric acid; (2- (16-carboxyhexadecylthio) phenoxy) butyric acid; (2- (15-carboxypentadecylthio) phenoxy) butyric acid; (2- (14-carboxytetradecylthio) phenoxy) butyric acid; (2- (13-carboxy trietylthio) phenoxy) butyric acid; (2- (12-carboxydodecylthio) phenoxy) butyric acid; (2- (11-carboxyundecylthio) phenoxy) butyric acid; (2- (10-carboxidecylthio) phenoxy) butyric acid; (2- (9-carboxynonylthio) phenoxy) butyric acid; (2- (8-carboxyoctylthio) phenoxy) butyric acid; (2- (7-carboxyheptylthio) phenoxy) butyric acid; (2- (6-carboxyhexylthio) phenoxy) butyric acid; (2- (20-carboxyhexylthio) phenylthio) butyric acid; (2- (19-carboxynonidecylthio) phenylthio) butyric acid; (2- (18-carboxyoctadecylthio) phenylthio) butyric acid; (2- (17-carboxyheptadecylthio) phenyl) butyric acid; (2- (16-carboxyhexadecylthio) phenylthio) butyric acid; (2- (15-carboxypentadecylthio) phenylthio) butyric acid; (2- (14-carboxytetradecylthio) phenylthio) butyric acid; (2- (13-carboxy trietylthio) phenylthio) butyric acid; (2- (12-carboxydodecylthio) phenylthio) butyric acid; (2- (11-carboxyundecylthio) phenylthio) butyric acid; (2- (10-carboxidecylthio) phenylthio) butyric acid; (2- (9-carboxynonylthio) phenylthio) butyric acid; (2- (8-carboxyoctylthio) phenylthio) butyric acid; (2- (7-carboxyheptylthio) phenylthio) butyric acid; (2- (6-carboxyethylthio) phenylthio) butyric acid; 3- (2- (16-carboxyhexadecyloxy) phenoxy) propionic acid; 3- (2- (15-carboxyisohexadecyloxy) phenoxy) butyric acid; 3- (2- (14-carboxytetradecyloxy) phenoxy) butyric acid; 5- (2- (3-Carboxytdecyloxy) phenoxy) valeric acid; 5- (2- (12-carboxydecyloxy) phenoxy) valeric acid; 5- (2- (11-carboxyisododecyloxy) phenoxy) valeric acid; 4- (2- (11-carboxyundecyloxy) phenoxy) valeric acid; 4- (2- (10-Carboxyidyloxy) phenoxy) valeric acid; 4- (2- (9-Carboxynonyloxy) phenoxy) valeric acid; 6- (2- (9-Carboxynonyloxy) phenoxy) caproic acid; 6- (2- (8-carboxyoctyloxy) phenoxy) caproic acid; 6- (2- (7-Carboxyisooctyloxy) phenoxy) caproic acid; 7- (2- (7-carboxyheptyloxy) phenoxy) enanthic acid; 7- (2- (8-carboxyhexyloxy) phenoxy) enanthic acid; 7- (2- (5-carboxyisohexyloxy) phenoxy) enanthic acid; 2- (2- (12-Carboxyidodecylthio) phenoxy) acetic acid; 2- (2- (11-Carboxyidithio) phenoxy) acetic acid; 2- (2- (10-Carboxyidithio) phenoxy) acetic acid; 3- (2- (9-Carboxynonyloxy) phenylthio) propionic acid; 3- (2- (12-carboxydecyloxy) phenylthio) propionic acid; 3- (2- (11-carboxyundecyloxy) phenylthio) propionic acid; 3- (2- (11-carboxyundecyloxy) phenylthio) butyric acid; 3- (2- (11-Carboxyundecylthio) -4-methyl-phenylthio) butyric acid 3- (2- (12-Carboxyidodecylthio) phenylthio) butyric acid; 5- (2- (9-Carboxynonyloxy) phenylthio) valeric acid 5- (2- (10-Carboxydecyloxy) phenylthio) valeric acid 3- (2- (2- 12-carboxydecyloxy) phenylthio) valeric acid 3- (2- (11-carboxydecyloxy) phenylthio) valeric acid 3- (2- (10-Carboxydecyloxy) phenylthio) ) caproic acid 6- (2- (12-carboxydecyloxy) phenylthio) 6- (2- (11-carboxyundecyloxy) phenylthio) caproic acid;

6- (2- (11-carboxyundecyloxy) -3-methylphenylthio) enanthic acid; 7- (2- (11-carboxyundecyloxy) -4-methylphenylthio) enanthic acid; 7- (2- (12-carboxydodecylthio) phenoxy) enanthic acid; 4- (2- (11-carboxyundecyloxy) -4-methyl-phenoxy) butyric acid; 4- (2- (10-Carboxyidyloxy) -3-methylphenoxy) butyric acid; 4- (2- (9-Carboxynonyloxy) -5-methylphenoxy) butyric acid; 4- (2- (12-carboxydecyloxy) -6-methylphenoxy) butyric acid; 4- (2- (12-carboxydecyloxy) -6-methylphenoxy) butyric acid; 4- (2- (11-carboxyundecylthio) -3- (methylthio) phenoxy) valeric acid; 4- (2- (11-carboxyundecylthio) -3- (methylsulfonyl) phenoxy) butyric acid; 4- (2- (11-carboxyundecyloxy) -4- (methylsulfonyl) phenoxy) butyric acid; 4- (2- (12-carboxydecyloxy) -5-ethyl-phenoxy) butyric acid; 4- (2- (11-carboxyundecyloxy) -4-phenylphenoxy) butyric acid; 4- (2- (10-Carboxyidyloxy) -3,5-dimethylphenoxy) butyric acid; 4- (2- (9-Carboxynonyloxy) -4-fluoro-phenoxy) butyric acid; 4- (2- (12-carboxydecyloxy) -5- (trifluoromethyl) phenoxy) butyric acid; 4- (2- (12-Carboxyidodecylthio) -5-nitrophenoxy) butyric acid; 4- (2- (11-carboxyundecylthio) -4-methylphenoxy) valeric acid; 4- (2- (11-carboxyundecylthio) -3,5-dimethylphenoxy) butyric acid; 4- (2- (12-carboxydecyloxy) -4- (dimethylamino) phenoxy) butyric acid; 4- (2- (11-carboxyundecyloxy) -5- (ethylamino) phenoxy) butyric acid; 2- (2- (9-Carboxynonyloxy) phenoxy) propionic acid; 3- (2- (12-carboxydecyloxy) phenoxy) -3-methylpropionic acid; 4- (2- (10-Carboxyidyloxy) phenylthio) -3-methoxy-butyric acid; 4- (2- (9-Carboxynonyloxy) phenylthio) -3-ethoxy-butyric acid; 4- (2- (11-carboxyundecyloxy) phenoxy) but-2-enoic acid; 4- (2- (9-Carboxynonyloxy) phenoxy) -2-butenoic acid; 4- (2- (11-Carboxy-2-methylundecyloxy) phenoxy) butyric acid; 4- (2- (11-Carboxyundecyl-7-ene-oxy) phenoxy) butyric acid; 95

4- (2- (13-Carboxy-2-methylene-tri-decyloxy) phenoxy) butyric acid; 4- (2- (11-carboxyundecyloxy) phenylsulfonyl) butyric acid; 4- (2- (11-carboxyundecyloxy) phenylsulfinyl) butyric acid; 4- (2- (11-carboxyundecylsulfinyl) phenoxy) butyric acid; 4- (2- (11-carboxyundecylsulfonyl) phenoxy) butyric acid; 4- (2- (11-carboxyundecylsulfinyl) phenylsulfinyl) butyric acid; 4- (2- (11-carboxyundecylsulfonyl) phenylsulfonyl) butyric acid, etc.

Also included as a 5α-reductase inhibitor in this invention is an agent for the treatment of alopecia demarcated in combination with minoxidil which is of the following formula:

wherein A is an aromatic 1,2-disubstituted ring selected from (a) benzene; naphthalene disubstituted in 1.2: (b) 5-6 membered heteroaromatic ring containing 1-2 N atoms, 1 S or 0 atom, or a combination thereof; D and E are independently -CONH, -CONH2, -CONHR3, COOR4, SO2 H, SO3 (OH), -SO2 NH2, -SO2 NOa, PH (O) (OH), P (O) (OH) 2; X is o, s, so or sc >2; R¹ is H, 96

C 1 -C 4 alkyl, phenyl or substituted phenyl, halo, haloalkyl, hydroxy, carboxy, cyano, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, C 1 -C 4 alkylsulfinyl, C 1 -C 4 alkylsulfonyl, amino, nitro C 1 -C 4 mono- or di-alkylamino; R 'and R "are independently H, halo, C1 -C4 alkyl or C1 -C4 alkoxy, amino, or oxo, where CH-R' or CH-R" in the formula becomes -C = O;

Ra is H, C1-4 alkyl;

Rfa is alkyl, phenyl, or phenyl C1 -C4 alkyl; y is 1-6; z is 6-20; and wherein R '< eH, y and 97

R "

I

(CH) Z may independently represent substituted or unsubstituted alkyl or alkenyl radicals containing at least one alkene linkage; and pharmaceutically acceptable salts and esters thereof.

The compounds of the present invention are inhibitors of the human enzyme testosterone-5α-reductase. The scope of the compounds of the present invention is described by the formula described above.

In the description of the formula the following expressions are used which are hereby defined: X is preferably 0 or S, and particularly preferred is 0. " includes straight or branched species, for example methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, t-butyl and C 1 -C 12 alkyl; includes alkyl of up to 12 carbons including n-octyl, t-decyl, n-dodecyl. " C 1 -C 4 alkyl phenyl " includes benzyl, 2-phenethyl, etc. " C1-C4 alkoxy " includes linear or branched species, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy. " Halo " includes fluoro, chloro, bromo or iodo. The term " heteroatomic ring " as used herein means a 5-6 membered ring containing 1-2 N, 1 or S atom, or a combination thereof, and includes: pyridine, thiophene, furan, imidazole, 1,3-thiazole, 1 , 3-oxazole, 1,2,3-thiadiazole, and the like. Here the limitation is constituted by the fact that disubstitution occurs on only the ring carbon atoms of the heteroatom ring. Preferred heteroaromatic rings are pyridine, furan and thiophene. " Substituted Phenyl " includes phenyl substituted by one or more C 1 -C 4 alkyl, C 1 -C 4 alkoxy, or halo, etc., as defined above. Representative examples include o-, m-, p-methoxyphenyl; 2,4-dimethoxyphenyl; 2-chloro-4-ethoxyphenyl; 3,5-dimethoxy-phenyl; 2,4-dichlorophenyl; 2-bromo-4-methylphenyl, o-fluorophenyl, etc. " Haloalkyl " includes C 1 -C 4 alkyl, defined above, substituted with one or more " halo " as defined above and includes: trifluoromethyl, 2,2-dichloroethyl, and the like. " C 1 -C 4 alkylthio " includes above defined C1-4 alkyl substituted with at least one divalent thio (-S-) moiety including: methylthio, ethylthio, isopropylthio, n-butylthio, and the like. " C1-C4 alkylsulfinyl " includes C 1 -C 4 alkyl, defined above, substituted with at least one -COOH group including; methylsulfinyl, ethylsulfinyl; isopropylsulfinyl, etc. " C1 -C4 alkylsulfonyl " includes C 1 -C 4 alkyl, defined above, substituted with at least one sulfonyl group, -SO 2 -, including; methylsulfonyl, ethylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, etc. 99

" C? -C? mono or dialkylamino " includes amino, substituted with one or more C 1 -C 4 alkyl groups as defined hereinbefore, including: methylamino, ethylamino, n-butylamino, t-butylamino, dimethylamino, diethylamino, methyl-t-butylamino, and the like. The group (s) R on the benzene ring or the heteroaromatic ring may be present initially in the process, for example phenyl, methyl, methoxy, cyano, trifluoromethyl, carbomethoxy, (such as o-nitrophenol 1 in Flow Sheet A) or may be added thereafter by a conventional reaction, for example chlorine, such as by chlorination, nitro by nitration, or created from a group functional starting material or added present, for example by converting a nitro group subsequently added to an amino group by catalytic reduction, and then alkylating until a mono or dialkylamine is obtained. An amino group may be subjected to diazotization to give a hydroxy group, and methylation may be followed until a methoxy group is obtained. Similarly, a hydroxy group may be converted to a thiol by the analogous procedures described in J. Org. Chem. 31, pp 3980-3984 (1966) by Newman and Karnes, and J. Org. Chem. 31, pp 410 (1966) by Kwart, H. and Evans, E.S. The resulting thiol can be alkylated to an alkylthio, which may be oxidized to the corresponding sulfoxide or sulfone. Preferred substituents are H, C 1 -C 4 alkyl, C 1 -C 4 alkoxy and phenyl. These reactions and sequences are conventional in the art for modifying the benzene ring in order to arrive at a R radical shown herein. The phrase " its pharmaceutically acceptable salts and esters " means, salts and esters of the acid groups in the final molecule which may be used as part of the human drug delivery system and include the sodium, potassium, calcium, ammonium, substituted ammonium, quaternary ammonium, and esters: ester ethyl acetate, aceturate, besylate, edetate, phenpropionate, acetate, pamoate, and esters which serve as formulations of " prodrug " which will hydrolyse the organism at physiological pHs in order to regenerate the acid, including pivaloylates, for example pivoxethyl and pivoxyl, and Kanebo esters, etc. R '

And wherein y is 1-6, preferably 3, may contain at least one substituent R 'as defined above, and may be, for example, -CH 2 -; -CH 2 -CH 2 -; -CH 2 -CH 2 -CH 2 -, -CH-; -CH-CH-; -CH-CH-; -CH-CH-CH-CH-CH-CH-;

| j Z Z | Z Z Z Z Z CH 3 CH 3 Cl OCH 3 OCH 2 CH 3 etc.

An alkene linkage may also be present in R 'R' (CH) -; for example, CH 2 -CH = CH-; CH 2 -CH = CH-CH -x: H 2 -CH 2 -CH = CH 2; - (CH 2) 3 -CH = CH and the like. z R " (CH) where z is 6-20, preferably 8-14, may contain z

at least one R'1 substituent as defined above, and may be: for example, - (CH2) g -, (CH2) 20 CH2 CH2 CH

CH

-CH 2 -CH- (CH 2) g -; F - (CH 2) 5-CH- (CH 2) 4 - and the like. 3 och3

An alkene linkage may also be present at R " (CH) z for example, CH 2 -CH = CH- (CH 2) g-; - (CH 2) 8-CH = CH (CH 2) 2 -; - (CH 2) 9 -CH = CH (CH 2) 9 -; (CH 2) 4-CH = CH- (CH 2) 4 -; etc. 101

Preferred is when R 'or R " is H and in particular R 'R "

Preferred is when both (CH) and (CH) are alkyl. And z

Representative compounds of the present invention of the above general formula are indicated by the following structures:

I

R

i-X- (CH) and D-O-

" N-C- (CH) z H and R 1

r-4

VX- (CH) and Dnf or C-CCH5ZE H R " 5 102 R- R '

> X- (CH) & D

The N-C- (CH) H 'R "

i

Particularly preferred are the following compounds: R '

(CH) COOH

(C-CCH) 2 COOH ... H || [- The R " R '

v / X- (CH) COOH

H

(OH) 2, or R 2, R 3,

R '

f / X / X-CC1 and CONH2

R

the K " Wherein X is O or S and R, R ', R ", y and z are as defined above.

Preferred compounds in this class are

Preferred compounds in this class are

CH2) 3 COOH

R

0

CH2) nCOOH 3

CH2) 3 COOH

R

C (CH 2) n SO 3 H 5 O

R

ch2) 3cooh CH2) nSS03Na 5

CH2) 3 COOH (CH2) n PC OH) 2 or 105

where X is O, S is 8-14.

Also preferred compounds belonging to these classes are:

(CH2) 3 COOH

O

CH2) nC00H where n is 8-14.

CH2) 3 COOH

CH2) n COOH II where n is 8-14. 106

The compounds of the present invention may be produced by the processes indicated in the Flow Sheets that follow. 1 FLOW SHEET A-2 OC ·

BrCH2CH2CH2CO2Et

(CH 2), aCOEt or II CH 3 OCC CH 2) 10 COOH (CD) o

CH3OC (CH2) 10COCl7 (4) + (7) CE): DCH2CH2CH2CO2Et

CCH2), OCO2CH3 CF), OCH2 CH2 CH2 COOH (CH3), CH3), 10cooh

Ho 9 FLOW SHEET B-2 h BrCH2CH2CH2CO2Et 2 (G)

(H) -CH 2 CH 2 CH 2 CO 2 Et (CH 2)

/>nxsch2ch2ch2co2hCC.M

T the

<CH 2) 10 CO 2 H 1 3 FLOW SHEET C-2

CH3 30

(CH 2) 10 CO 2 CH 3 31

NH, FLOW SHEET D-2 • C02Et

E • C02Et -NOCCH2) 9CH2Br HM ° 32

C02Et NCCCH2) gCH2PCOEt) 2 HM &quot;

O ° 33

U

• C02Et NC (CH2) gCH2PC OH) 2 H &quot; &quot; (CH2) gCH2P (OH) 2 HM &quot; O ° 35 34 FLOW SHEET E-2 32

W

• C02Et NC (CH2) gCH2SS03Na Η &quot; O 37

O

&quot; C02H

NC (CH 2) g CH 2 SO 3 H H 11 -

THE F-2 FLOW SHEET

(ccncch2) 10co2h H &quot; or 43 113

FLOW SHEET G-2 10

CN

(CH 2) 10 CO 2 CH 3 HL I O 45 46 FLOW SHEET H-2

BrCH2CH2CH2CO2Et 44 - &gt; (9.) (alternative to 9.)

As indicated in Flow Sheet A-2, o-nitrophenol ethyl 1,4-bromobutyrate 2 and K 2 CO 3 in example, dry acetone are heated under reflux or stirred for a period of time protonated at room temperature under a nitrogen atmosphere until ethyl 4- (2-nitrophenoxy) butyrate product 3 was obtained in Step (A).

A solution of 3 in, for example, ethyl acetate is catalytically hydrogenated at room temperature under for example 40 psig H2 in the presence of a 5% Pd / C catalyst to provide ethyl 4- (2-aminophenoxy) butyrate 4 in Step (B). Step (C) comprises reacting diethyl dodecanoate 5 with barium hydroxide octahydrate in methanol at room temperature to give the monomethyl ester 6.

In Step (D) the mono-ester mono-acid 6 is refluxed with thionyl chloride for about 5 hours to afford the mono acid chloride, mono methyl ester 7. Step (E) comprises reacting the mono acid chloride 7 with the amine 4a for example, 0-10 ° C in e.g. dry ether in the presence of a hydrogen acceptor for example triethylamine to give the amide 8. 115

In Step (F), the ether amide diester 8 is deesterified by e.g. 2.5 N NaOH in MeOH / H 2 O to provide the acidic end product 9 after acidification. Flow Sheet B-2 illustrates the synthesis of the corresponding thio compounds. Step (G) shows the reaction of o-aminobenzenethiol with ethyl 4-bromobutyrate which may be carried out in for example dry dimethoxyethane under dry N2 in the presence of a proton acceptor, eg K2CC> 3 dry powder (H) illustrates the acylation of the amino group of 11 with ethyl 11-bromoundecanoate in a dry solvent, for example dry ether, at 0 ° C in the presence of an acid acceptor, for example , pyridine. Step (I) shows the hydrolysis of the diester giving the final diacid 13, which can be carried out with, for example, NaOH / MeOH.

As indicated in Flow Sheet C-2, o-nitrophenol is benzylated under the same conditions as Step (A). Step (K) shows the reduction of the nitro group using, for example, Raney's Ni in ethanol / NH4 under 40 psig H2. Step (L) shows the trifluoroacetylation of 24 using, for example, trifluoroacetic anhydride in dry ether and carbonate of dry powdered sodium. Step (M) shows the N-methylation which can be carried out using, for example, methyl iodide in dry acetone and KOH in dry powder followed by removal of the N-trifluoroacetyl group with MeOH / H2O. Step (N) shows the N-acylation of 27. using an acid chloride, for example 7, in, for example, dry methylene chloride and pyridine at 0 ° C. Step (O) shows the debenzylation of 28, which may be carried out by, for example, 10% Pd / C in MeOH under an atmosphere of K2. Step (P) shows the alkylation in 0 of 29 using, for example, ethyl 4-bromobutyrate and K2 CO3 in anhydrous acetone. Step (Q) shows the hydrolysis of the diester 30 to give diacid 31 by hydrolysis as, for example, described for Step (F). Flow Sheet D-2 shows the production of phosphonate and acid esters. Step (R) shows the condensation of 4 with 11-bromomoundecanoic acid in anhydrous methylene chloride using Î ±, Î'-dicyclohexylcarbodiimide and 4-dimethylaminopyridine to give the important bromo intermediate 32. Step (S ) shows the reaction of 32 with triethyl phosphite at, for example, 180 ° C under N 2 to give the phosphonate ester 33 Step (T) converts 33 by means of bromotrimethylsilane to the monoacid 34, 117

Step (U) uses the hydrolysis conditions similar to those of Step (F) to afford the phosphonicocarboxylic diacid 35.

The corresponding phosphinic acids can be produced in an analogous manner from 32 by methods known in the art. Flow Sheet E-2 illustrates the synthesis of the sulfonic acid types of the compounds of the invention. Step (V) shows the reaction of intermediate 32 with thiourea in EtOH / H2 O under 90 ° C to provide the isothiouronium salt. Step (W) shows the reaction of 32 with sodium thiosulfate under the conditions of Step (V) to provide the thiosulfate ester 37,

Further oxidation of the esters 36 and 37 by the procedures of Showell or Ziegler described in Step W in the examples provides the corresponding sulfonic acid 38. The corresponding sulfinic acid can be prepared from 36 by the procedure of JM Sprague and TB Johnson, JACS 59, 2440 (1937). The corresponding sulfonamide can be produced from sulphonic acid 38 by protecting the carboxylic acid by means of an ester, converting the sulfonic acid to a sulfonyl chloride, treating the sulfonyl chloride with ammonia and then hydrolyzing the ester protected carboxylic acid yielding the corresponding acid. 118

Flow Sheet F-2 shows the corresponding synthesis of the pyridine analogues of 8 and 9.

In Step (X), the nitrohydroxy pyridine is alkylated at 0 using first conditions analogous to those of Step (A) to afford 40. Step (Y) shows the reduction of the nitro group in the same manner as described for Step (X). B). Step (Z) shows the acylation of the amino group in the same manner as described for 8 in Step (E) to afford the diester 42. The hydrolysis yields diacid 43. Flow Sheet G-2 shows the production of some amides 46 of the invention.

In Step (AA), o-aminophenol is reacted directly with 7 under the conditions of Step (E) to yield the N-acylated phenol 44.

In Step (BB), the alkylation at 0 of 44 as carried out using 4-bromobutyronitrile under conditions similar to those of Step (A) affords 45. Step (CC) shows the hydrolysis of the nitrile giving the amide 46 using MnC &gt;; 2 in methylene chloride. Flow Sheet H-2 illustrates an alternative route to starting with o-aminophenol, acylating to afford 44, and then reacting 44 under the conditions of Step (A) to afford 8, and then hydrolyzing using Step (F ) to provide 9.

Thus, using the methods described above in the Flow Sheets and the starting materials and reaction reagents described herein, all of the compounds described and encompassed by the claim can be synthesized by one of ordinary skill in the art. It is obvious that other nitrophenoids may substitute 1 in Flow Sheets A-2 and--2 to provide the scope of the compounds covered by this invention and include the following: 2-nitrophenol 2-nitro-6-methylphenol 2-nitro- 5-phenylphenol 2-nitro-4-chlorophenol 2-nitro-4-fluorophenol 2-nitro-4-methylphenol 2-nitro-4-methylphenol 2-nitro-4-methylphenylphenol 2-nitro-4-methylphenol 2-nitro-4-methoxyphenol 2-nitro-6-ethoxyphenol 2-nitro-4-methylthiophenol 2-nitro- 3-nitro-4-hydroxypyridine 2-nitro-4-hydroxypyridine 2-nitro-4-hydroxypyridine 3-nitro-4-hydroxypyridine 3-nitro-4- -3-hydroxy-5-phenylpyridine 2-hydroxy-3-nitro-5-chloropyridine

2-nitro-3-hydroxy-5-trifluoromethylpyridine 2-methoxy-4-nitro-5-hydroxypyridine 3-nitro-4-hydroxy-5-ethoxypyridine 2-methylthio- hydroxy-2-nitro-5-methyl-thiophene 3-hydroxy-2-nitro-4-methylthiophene 2-hydroxy-3-nitro-5-phenyl- thiophene 2-nitro-3-nitro-4-chlorothiophene 2-hydroxy-3-nitro-4-fluorothiophene, etc. It is obvious that substitution compounds suitable for 2 with other halo alkyl esters known in the art, and which appropriate substitution of 6 with other diesters available in the art, will provide all other ether amide derivatives within the scope of the claims.

Representative examples of useful in this process of the invention include, but are not limited to:

Br-CH2-COOMe, ci-ch2ch2ch2cooch (ch3),

Br-CH2 CH2 CH2 CH2 COOMe,

Br-CH 2 CH 2 CH 2 CH 2 CH 2 COOEt,

Br-cH2 ch2 ch2 ch2 ch2 ch2 cooch2 ch2 ch2 ch3,

Br-CH 2 CH (CH 3) COOMe,

Br-CH2 CH (CH3) CH2 COOEt,

Br-CH2 CH2 CH2 COOMe,

Br-CH2CH (OCH3) CH2C00CH (CH3),

Cl-CH 2 CH (OCH 2 CH 3) CH 2 COOMe, 121

Br-CH 2 CH (F) CH 2 COOMe, etc. can

Representative examples of other compounds which substitute and are useful in the invention are: HOOC (CH3) COOMe, HOOC (CH2) 7COOMe / HOOC (CH3) COOMe, HOOC (CH) COOMe, and HOOC (CH2) (CH3) 2, HOOC (CH2) 14 COOCHCH2 CH3, HOOC (CH2) 15 COO (CH2) CH3, HOOC (CH2) 16 COOCH3, HOOC (CH2) 17 COOCH3, HOOC (CH2) 12 COOEt, (CH 3) (CH 2) 10 COOMe, HOOC-CH 2, CH 2 CHO CH 2, CHOC CH 2 CH 2 CHO, CH3 CH (CH3) CH2 COOEt, HOOC-CH0 CH_CH-CH0COOEt CΔJa

HOOC-CH 2 CH (OCH 3) (CH 2) 7 COOCH (CH 3) 2, where Ph is phenyl, etc.

Representative examples of compounds produced by this process include those listed below. 122

The nomenclature used herein for the acid radicals is: p (O) (OH) 2 I phosphono; -COOH, carboxy; -CONH 2, aminocarbonyl; -SO2 H, sulfo; -SO2 H, sulfino; -SO 2 H, thiosulfate, such as the sodium salt. 4- (2- (20-carboxyicosanoylamino) phenoxy) butyric acid; 4- (2- (19-Carboxynonadecanoylamino) phenoxy) butyric acid; 4- (2- (18-carboxyoctadecanoylamino) phenoxy) butyric acid; 4- (2- (17-Carboxyheptadecanoylamino) phenoxy) butyric acid); 4- (2- (16-Carboxyhexadecanoyl-N-methylamino) phenoxy) butyric acid; 4- (2- (15-Carboxypentadecanoylamino) phenoxy) butyramide; 4- (2- (14-Carboxytetradecanoylamino) phenoxy) butyric acid; 4- (2- (13-Carboxyl-tridecanoylamino) phenoxy) butyric acid; 4- (2- (12-Carboxy-dodecanoylamino) phenoxy) butyric acid; 4- (2- (11-Carboxy-undecanoylamino) phenoxy) butyric acid; 4- (2- (10-Carboxy-decanoylamino) phenoxy) butyric acid; 4- (2- (9-Carboxy-nonanoylamino) phenoxy) butyric acid;

4- (2- (8-carboxyoctanoylamino) phenoxy) butyric acid; 4- (2- (7-Carboxyheptanoylamino) phenoxy) butyric acid; 4- (2- (6-carboxyhexanoylamino) butyric acid 4- (2- (20-Carboxyicosanoylamino) phenylthio) butyric acid 4- (2- (6-Carboxynonadecanoylamino) phenylthio) butyric acid 4- 18-carboxyoctadecanoylamino) phenylthio) butyric acid 4- (2- (17-Carboxyheptadecanoyl-N-ethylamino) phenylthio) butyric acid 4- (2- (16-Carboxyhexadecanoylamino) phenylthio) butyric acid; 4- (2- (12-carboxy-dodecanoylamino) phenylthio) butyric acid 4- (2- (14-Carboxytetradecanoylamino) phenylthio) butyramide 4- (2- (13-carboxytridecanoylamino) phenylthio) ; 4- (2- (9-Carboxynonanoylamino) phenylthio) butyric acid, 4- (2- (10-Carboxyidecanoylamino) phenylthio) butyric acid; - (2- (8-carboxyoctanoylamino) phenylthio) butyric acid 4- (2- (7-Carboxyheptanoylamino) phenylthio) butyric acid 4- (2- (6-Carboxyhexanoylamino) 16-carboxyhexadecanoylamino) phenoxy) propionic acid; 4- (2- (15-ca (phenoxy) butyric acid 4- (2- (14-carboxytetradecanoylamino) phenoxy) butyric acid; 5- (2- (13-Carboxytridecanoylamino) phenoxy) valeric acid; 5- (2- (12-Carboxydodecanoylamino) phenoxy) valeric acid; 5- (2- (9-Carboxynanoylamino) -hexanoic acid) 4- (2- (11-Carboxyisodecanoylamino) phenoxy) caproic acid; 6- (2- (9-Carboxyanooylamino) phenoxy) caproic acid; 6- (2- (8-Carboxyoctanoylamino) phenoxy) caproic acid; 7- (2- (7-carboxyheptanoylamino) phenoxy) enanthic acid; 7- (2- (6-Carboxyhexanoylamino) phenoxy) (12-carboxydodecanoylamino) phenoxy) acetic acid 2- (2-Carboxyundecanoylamino) phenoxy) acetic acid 2- (2- (10-carboxydecanoylamino) phenoxy) acetic acid 3- phenoxy) propionic acid 3- (2- (12-carboxydodecanoylamino) phenylthio) propionic acid 3- (2- (11-carboxyundecanoylamino) phenylthio) propionic acid 3- - (2- (11-carboxyundecanoylamino) phenylthio) valeric acid; 5- (2- (10-carboxydecanoylamino) phenylthio) valeric acid; 5- (2- (9-Carboxynonanoylamino) phenylthio) valeric acid; 4- (2- (12-carboxydodecanoylamino) phenylthio) isovaleric acid 4- (2- (11-carboxydecanoylamino) phenylthio) isovaleric acid; 124

4- (2- (10-carboxidecanoylamino) phenylthio) isovaleric acid; 6- (2- (9-Carboxynonanoylamino) phenoxy) caproic acid; 6- (2- (12-carboxydodecanoylamino) phenylthio) caproic acid; 6- (2- (11-carboxyundecanoylamino) phenylthio) caproic acid; 7- (2- (11-carboxyundecanoylamino) -3-methylphenylthio) enanthic acid; 7- (2- (11-carboxyundecanoylamino) -4-methylphenylthio) enanthic acid; 7- (2- (12-carboxydiodecanoylamino) phenoxy) enanic acid; 4- (2- (11-Carboxyundecanoylamino) -4-methyl-phenoxy) butyric acid; 4- (2- (10-Carboxyidecanoylamino) -3-methylphenoxy) butyric acid; 4- (2- (9-Carboxynonanoylamino) -5-methylphenoxy) butyric acid; 4- (2- (12-Carboxydodecanoylamino) -6-methylphenoxy) butyric acid; 4- (2- (9-Carboxynonanoylamino) -propionic acid) 4- (2- (10-Carboxyidecanoylamino) -4-methylphenoxy) butyric acid 4- (2- (11-Carboxydecanoylamino) -3-chloro (phenylthio) butyric acid; 5-fluoromethyl) phenylthio) butyric acid; 4- (2- (12-Carboxydodecanoylamino) -6-methylphenoxy) butyric acid; 5- (2- (11-carboxyundecanoylamino) -3-methylthio) phenoxy) valeriσο; 4- (2- (11-Carboxyundecanoylamino) -3-methylsulfonylphenoxy) butyric acid; 4- (2- (11-carboxyundecanoylamino) -4-methylsulfonyl) phenylthio) butyric acid; 4- (2- (12-Carboxydodecanoylamino) -5-ethyl-phenoxy) butyric acid; 4- (2- (11-carboxyundecanoylamino) -4-phenylphenoxy) butyric acid; 4- (2- (10-Carboxyidecanoylamino) -3,5-dimethylphenoxy) butyric acid; 4- (2- (9-Carboxynonanoylamino) -4-fluoro-phenoxy) butyric acid; 4- (2- (12-Carboxydodecanoylamino) -5-trifluoromethylphenoxy) butyric acid; 4- (2- (11-carboxyundecanoylamino) -5-hydroxy) phenylthio) butyric acid; 4- (2- (10-Carboxyidecanoylamino) -4-hydroxy) phenylthio) butyric acid; 4- (2- (9-Carboxynonanoylamino) -3,5-dimethoxy-phenylthio) butyric acid; 125

4- (2- (12-Carboxydodecanoylamino) -5-nitrophenoxy) butyric acid; 5- (2- (11-Carboxyundecanoylamino) -4-nitrophenoxy) valeric acid; 4- (2- (11-carboxyundecanoylamino) -5-amino-3-methylphenoxy) butyric acid; 4- (2- (11-carboxyundecanoylamino) -5-amino-4-methylphenylthio) butyric acid; 4- (2- (12-Carboxydodecanoylamino) -4-dimethylaminophenoxy) butyric acid; 4- (2- (11-carboxyundecanoylamino) -5-ethylaminophenoxy) butyric acid; 3- (2- (12-Carboxydodecanoylamino) phenoxy) -3-methylpropionic acid; 3- (2- (11-carboxidecanoylamino) phenylthio) -2-chloropropionic acid; 4- (2- (10-Carboxyidecanoylamino) phenylthio) -3-methoxybutyriocoic acid; 4- (2- (9-Carboxynonanoylamino) phenylthio) -3-ethoxybutyric acid; 4- (2- (12-Carboxydodecanoylamino) -4-methyl-3-pyridyloxy) butyric acid; 4- (2- (11-Carboxyundecanoylamino) -4-methyl-3-pyridyloxy) butyric acid; 4- (2- (10-Carboxyidecanoylamino) -5-methyl-3-pyridyloxy) butyric acid; 4- (2- (9-Carboxynonanoylamino) -5-hydroxy-3-pyridyloxy) butyric acid; 4- (2- (12-Carboxydodecanoylamino) -6- (dimethylamino) -3-pyridyloxy) butyric acid; 4- (2- (11-Carboxyidecanoylamino) -3-pyridylthio) butyric acid; 4- (2- (10-Carboxyidecanoylamino) -6-methylsulfonyl-3-pyridyloxy) butyric acid; 4- (2- (9-Carboxynonanoylamino) -5-chloro-3-pyridylthio) butyric acid; 4- (2- (12-Carboxydodecanoylamino) -5-methylpyridylthio) butyric acid; 4- (2- (11-Carboxyundecanoylamino) -5-methylsulfonyl-3-pyridylthio) butyric acid; 126

4- (2- (1-carboxyundecanoylamino) -6-methyl-3-pyridylthio) butyric acid; 4- (2- (N-carboxyundecanoylamino) -4,6-dimethyl-3-pyridyloxy) butyric acid; 4- (2- (12-Carboxydodecanoylamino) -5-methylthio-3-pyridyloxy) butyric acid; 4- (2- (11-carboxyundecanoylamino) pyridyloxy) butyric acid; 4- (2- (10-Carboxyidecanoylamino) -5-methoxy-3-pyridyloxy) butyric acid; 4- (2- (9-Carboxynonanoylamino) -4-fluoro-6-methyl-3-pyridyloxy) butyric acid; 4- (2- (12-Carboxydodecanoylamino) -5-methylamino-3-pyridyloxy) butyric acid; 4- (2- (11-carboxyundecanoylamino) -4-phenyl-3-pyridylthio) butyric acid; 4- (2- (ω-carboxidecanoylamino) -5-methyl-3-pyridylthio) butyric acid; 4- (2- (9-Carboxynonanylamino) -6-methoxy-3-pyridylthio) butyric acid; 4- (2- (12-Carboxydodecanoylamino) -6-trifluoromethyl-3-pyridyloxy) butyric acid; 5- (2- (11-Carboxyundecanoylamino) -4-methyl-3-thienyloxy) valeric acid; 4- (2- (11-Carboxyundecanoylamino) -4-methyl-3-thienyloxy) butyric acid; 4- (2- (11-Carboxyundecanoylamino) -4-methyl) -3-thienylthio) butyric acid; 4- (2- (12-Carboxydodecanoylamino) -5-methyl-3-thienylthio) butyric acid; 4- (2- (11-carboxyundecanoylamino) -4-methyl-3-thienylthio) butyric acid; 4- (2- (10-Carboxyidecanoylamino) -5-methyl-3-thienylthio) butyric acid; 127

4- (2- (9-Carboxynonanoylamino) -4-hydroxy-3-thienyloxy) butyric acid; 4- (2- (12-Carboxyidecanoylamino) -4-methylthio-3-thienyloxy) butyric acid; 4- (2- (11-Carboxyidecanoylamino) -4-methylthio-3-thienyloxy) butyric acid; 4- (2- (10-Carboxyidecanoylamino) -4-methylsulfonyl-3-thienyloxy) butyric acid; 4- (2- (9-Carboxynonanoylamino) -4-methylsulfonyl-3-thienyloxy) butyric acid; 4- (2- (12-Carboxydodecanoylamino) -5-trifluoromethyl-3-thienyloxy) butyric acid; 5- (2- (11-Carboxyundecanoylamino) -5-chloro-3-thienyloxy) valeric acid; 4- (2- (11-Carboxyundecanoylamino) -4-methyl-5-phenyl-3-thienyloxy) butyric acid; 4- (2- (11-carboxyundecanoylamino) -5-methylamino-3-thienyloxy) butyric acid; 4- (2- (12-Carboxydodecanoylamino) -5-dimethylamino-3-thienyloxy) butyric acid; 4- (2- (11-carboxyundecanoylamino) -3-thienyloxy) butyric acid; 4- (2- (20-Phosphonoeicosanoylamino) phenoxy) butyric acid; 4- (2- (19-Phosphonononadecanoylamino) phenoxy) butyric acid; 4- (2- (17-Sulfoheptadecanoylamino) phenoxy) butyric acid; 4- (2- (16-sulfinohexadecanoyl-N-methylamino) phenoxy) butyric acid; 4- (2- (15-Thiosulfatopentadecanoylamino) phenoxy) butyramide, sodium salt; 4- (2- (14-Phosphonotetradecanoyl-N-methylamino) phenoxy) butyric acid; 4- (2- (12-Sulphododecanoylamino) phenoxy) butyric acid; 4- (2- (11-Sulphoundecanoylamino) phenoxy) butyric acid; 4- (2- (10-Sulfinodecanoylamino) phenoxy) butyric acid; 4- (2- (9-Thiosulfatononanoylamino) phenoxy) butyric acid, sodium salt; 128

4- (2- (8-Thiosulfatooctanoylamino) phenoxy) butyric acid, sodium salt; 4- (2- (7-sulfinoheptanoylamino) phenoxy) butyric acid; 4- (2- (6-Phenohexanoylamino) butyric acid 4- (2- (19-sulfononadecanoylamino) phenylthio) butyric acid 4- (2- (6-Phenohexanoylamino) (17-thiosulfatoheptadecanoyl-N-ethylamino) phenylthio) butyric acid;

4- (2- (16-Phosphonohexadecanoylamino) phenylthio) butyric acid;

4- (2- (14-Sulfotetradecanoylamino) phenylthio) butyric acid; 4- (2- (13-Sulfinothridecanoylamino) butyric acid;

4- (2- (12-Thiosulfatododecanoylamino) phenylthio) butyric acid, sodium salt;

4- (2- (11-Phosphononoundecanoylamino) phenylthio) butyric acid; 4- (2- (lo-sulfinodecanoylamino) phenylthio) butyric acid; 4- (2- (9-Carboxynonanoylamino) phenylthio) butanesulfonic acid; 4- (2- (8-carboxyoctanoylamino) phenylthio) butanesulfonic acid; 4- (2- (7-Carboxyheptanoylamino) phenylthio) butane thiosulfonic acid; 4- (2- (20-Carboxyicosanoylamino) thio) phenoxy) butanephosphonic acid; 4- (2- (19-Carboxynonadecanoylamino) phenoxy) butanesulfonic acid; 4- (2- (18-Carboethoxyoctadecanoyl-N-butylamino) phenoxy) butane-sulfinic acid; 4- (2- (17-Carboxyheptadecanoylamino) phenoxy) butane thiosulfonic acid;

4- (2- (15-carboxypentadecanoylamino) phenoxy) butanephosphonic acid; 4- (2- (14-Carboxytetradecanoylamino) phenoxy) butanesulfonic acid; 4- (2- (13-n-carboxytridecanoylamino) phenoxy) butanesulfonic acid; 4- (2- (12-Carboxydodecanoylamino) phenoxy) butane thiosulfonic acid, sodium salt;

4- (2- (10-Carboxyidecanoylamino) phenoxy) butanephosphinic acid;

4- (2- (9-Carboxynonanoylamino) phenoxy) butanesulfonic acid; 4- (2- (8-carboxyoctanoylamino) phenoxy) butanesulfonic acid; 129

4- (2- (7-Carboxyheptanoylamino) phenoxy) butane thiosulfonic acid, sodium salt; 4- (2- (20-carboxyicosanoylamino) phenylthio) butanephosphonic acid; 4- (2- (19-Carboxynonadecanoyl-N-methylamino) phenylthio) butanesulfonic acid; 4- (2- (18-carboxyoctadecanoylamino) phenylthio) butanesulfonic acid; 4- (2- (17-Carboxyheptadecanoylamino) phenylthio) butanesulfonic acid; 4- (2- (16-carboxyhexadecanoylamino) phenylthio) butane thiosulfonic acid, sodium salt; 4- (2- (14-Carboxytetradecanoyl-N-propylamino) phenylthio) butanephosphonic acid; 4- (2- (13-Carboxytridecanoylamino) phenylthio) butanesulfonic acid; 4- (2- (12-carboxydodecanoylamino) phenylthio) butanesulfonic acid; 4- (2- (11-carboxyundecanoylamino) phenylthio) butane thiosulfonic acid, sodium salt; 4- (2- (9-Carboxynonanoylamino) phenylthio) butanephosphonic acid; 4- (2- (S-carboxyoctanoylamino) phenylthio) butanesulfonic acid; 4- (2- (7-Carboxyheptanoylamino) phenylthio) butanemulfinic acid; 4- (2- (6-Carboxyhexanoylamino) phenylthio) butane thiosulfonic acid, sodium salt; 3- (2- (15-Carboxyisohexadecanoylamino) phenoxy) isobutanephosphonic acid; 3- (2- (14-carboxytetradecanoylamino) phenoxy) isobutanoic acid; 5- (2- (13-Carboxytridecanoylamino) phenoxy) pentanesulfonic acid; 5- (2- (12-phosphonomododecanoylamino) phenoxy) valeramide; 5- (2- (9-Thiosulfatononanoylamino) phenoxy) valeric acid, 5- (2- (10-sulfinodecanoyl-N-methylamino) phenoxy) valeric acid; 6- (2- (7-Sulfoisooctanoyl-N-methylamino) phenoxy) caproic acid;

7- (2- (7-sulfinoheptanoyl-N-ethylamino) phenoxy) enanic acid; 7- (2- (6-thiosulfatohexanoylamino) phenoxy) enanthamide, sodium salt, 7- (2- (5-phosphonoisohexanoylamino) phenoxy) enanthic acid; 2- (2- (11-Sulphoundecanoylamino) phenoxy) acetic acid; 2- (2- (Iso-sulfodecanoyl-N-propylamino) phenoxy) acetic acid; 3- (2- (9-Sulfinononanoylamino) phenoxy) propionic acid; 3- (2- (12-thiosulfatodododecanoylamino) phenylthio) propionamide, sodium salt; 3- (2- (11-Phosphonoundecanoylamino) phenylthio) propionic acid; 3- (2- (11-Sulphoundecanoylamino) -4-methyl-phenylthio) isobutyric acid; 3- (2- (12-sulfinododecanoylamino) phenylthio) isobutyramide; 5- (2- (11-Thiosulfoundecanoyl-N-butylamino) phenylthio) valeric acid, sodium salt; 5- (2- (10-Phosphonodecanoylamino) phenylthio) valeric acid; 5- (2- (12-Phosphodododecanoylamino) phenylthio) pentane sulfonic acid; 5- (2- (11-Carboxyidecanoylamino) phenylthio) pentane sulfinic acid; 5- (2- (10-Phosphonodecanoylamino) phenylthio) pentane thiosulfonic acid; 6- (2- (12-Phosphodododecanoylamino) phenylthio) hexanephosphonic acid; 4- (2- (11-Sulfinoundecanoylamino) -4-methyl-phenoxy) butane-thio-sulfonic acid, sodium salt; 4- (2- (12-Sulphododecanoylamino) -6-methylphenoxy) butane sulfonic acid; 4- (2- (11-Sulphodecanoylamino) -3-chloro) phenylthio) butane-sulfonic acid; 4- (2- (10-Sulphodecanoylamino) -4-methylphenoxy) butane thiosulfonic acid, sodium salt; 4- (2- (12-Sulphododecanoylamino) -6-methylphenoxy) butane-phosphonic acid; 5- (2- (11-Sulfinoundecanoylamino) -3-methylphenylthio) pentanesulfonic acid; 131

4- (2- (11-Sulfinoundecanoylamino) -3-methylsulfonylphenoxy) butane-sulfonic acid; 4- (2- (11-sulfinoundecanoylamino) -4-methylsulfonyl) phenylthio) butanesulfonic acid; 4- (2- (12-Sulfinododecanoylamino) -5-ethyl-phenoxy) butane-phosphonic acid; 4- (2- (10-Sulfinodecanoylamino) -3,5-dimethylphenoxy) butane sulfonic acid; 4- (2- (9-Thiosulfatononanoylamino) -4-fluoro-phenoxy) butane-sulfinic acid, sodium salt; 4- (2- (12-Thiosulfatododecanoylamino) -5-trifluoromethylphenoxy) butane-thiosulfonic acid, sodium salt; 4- (2- (10-Thiosulfatododecanoylamino) -4-hydroxy-phenylthio) butane-phosphonic acid, sodium salt; 4- (2- (9-Phosphonononanoylamino) -3,5-dimethoxyphenylthio) butyric acid; 5- (2- (11-sulfoundecanoylamino) -4-nitrophenoxy) valeric acid; 4- (2- (11-Sulfinoundecanoylamino) -5-amino-3-methylphenoxy) butyric acid; 4- (2- (11-Thiosulfatoundecanoylamino) -5-amino-4-methylphenylthio) butyric acid, sodium salt; 4- (2- (12-Phosphodododecanoylamino) -4-dimethylamphophenoxy) butyric acid; 4- (2- (10-Sulphodecanoylamino) phenoxy) butyric acid; 3- (2- (9-Sulfinononanoylamino) phenoxy) propionic acid; 3- (2- (12-Thiosulfatododecanoylamino) phenoxy) -3-methylpropionic acid, sodium salt; 3- (2- (11-phosphonomodecanoylamino) thienyloxy) -2-chloropropionic acid; 7- (2- (11-Thiosulfatoundecanoylamino) -7- (2- (12-sulfinododecanoylamino) phenoxy) -2-fluoro-butyric acid 4- (2- (9-Sulphononanoylamino) thienyloxy- phenoxy) -6-amino-enanti-co, sodium salt;

5- (2- (11-Phosphonoundecanoylamino) -3-methylphenoxy) -4-oxo-valeric acid; 4- (2-12-Sulphododecanoylamino) phenoxy) but-2-enoic acid; 4- (2- (11-Sulfinodecanoylamino) phenoxy) but-2-enoic acid; 4- (2- (10-Thiosulfatodecanoylamino) phenoxy) -4-methylene valeric acid, sodium salt; 4- (2- (9-Phosphonononanoylamino) phenoxy) -4-fluoro-2-butenoic acid; 4- (2- (11-Sulfo-3-methylbutanoylamino) thienyloxy) butyric acid; 4- (2- (4-Sulfo-3-chlorobutanoylamino) thienyloxy) butyric acid; 4- (2- (9-Thiosulfato-2-methoxynonanoylamino) thienyloxy) butyric acid, sodium salt; 4- (2-Phosphono-2-ethoxybutanoylamino) phenoxy) butyric acid; 4- (2- (14-Sulfo-14-fluoro-2-acetamidotetradecanoylamino) -3-methylphenoxy) butyric acid; 4- (2-Bromo-2-oxotridecanoylamino) -4-methylthio) phenyl-xy) butyric acid; 4- (2- (12-Thiosulfatododecanoyl-3-en-amino) phenoxy) butyric acid; 4- (2- (11-Phosphonoundecanoyl-7-ene-amino) phenoxy) butyric acid; 4- (2-Sulfo-2-fluoro-2-butenoylamino) phenoxy) butyric acid; 4- (2- (12-Sulfinododecanoylamino) -4-methyl-3-pyridyloxy) butyric acid; 4- (2- (11-Thiosulfatoundecanoylamino) -4-methyl-3-pyridyloxy) butyric acid; 4- (2- (10-Phosphono-decanoylamino) -5-methyl-3-pyridyloxy) butyric acid; 4- (2- (11-Sulfinodecanoylamino) -4-nitro-3-pyridylthio) butyric acid; 4- (2- (10-Thiosulfatodecanoylamino) -6-methylsulfonyl-3-pyridyloxy) butyric acid, sodium salt; 4- (2- (9-Phosphonononanoylamino) -5-chloro-3-pyridylthio) butyric acid; 4- (2- (11-Sulphoundecanoylamino) -5-methylsulfonyl-3-pyridylthio) butyric acid; 133

4- (2- (11-Sulfinoundecanoylamino) -6-methyl-3-pyridylthio) butylacetic acid; 4- (2- (11-Thiosulfatoundecanoylamino) -4,6-dimethyl-3-pyridyloxy) butyric acid, sodium salt; 4- (2- (12-Phosphodododecanoylamino) -5- (methylthio) -3-pyridyloxy) butyric acid; 4- (2- (10-Sulphodecanoylamino) -5-methoxy-3-pyridyloxy) butyric acid; 4- (2- (9-Sulfinononanoylamino) -4-fluoro-6-methyl-3-pyridyloxy) butyric acid; 4- (2- (12-Thiosulfatododecanoylamino) -5- (methylamino) -3-pyridyloxy) butyric acid, sodium salt; 4- (2- (11-Phosphonoundecanoylamino) -4-phenyl-3-pyridylthio) butyric acid; 4- (2- (9-Sulphononanoylamino) -6-methoxy-3-pyridylthio) butyric acid; 4- (2- (12-Sulfinododecanoylamino) -6-trifluoromethyl-3-pyridyloxy) butyric acid; 5- (2- (11-Thiosulfatoundecanoylamino) -4-methyl-3-thiophenyl-xi) valeric acid, sodium salt; 4- (2- (11-Phosphonoundecanoylamino) -4-methyl-3-thiophenyloxy) butyric acid; 4- (2- (12-Sulphododecanoylamino) -5-methyl-3-thiophenylthio) butyric acid; 4- (2- (11-Sulfinoundecanoylamino) -4-methyl-3-thiophenylthio) butyric acid; 4- (2- (10-Thiosulfatoethoxyaminoamino) -5-methyl-3-thienylthio) butyric acid, sodium salt; 4- (2- (9-Phosphonononanoylamino) -4-hydroxy-3-thienyloxy) butyric acid; 4- (2- (11-Sulphodecanoylamino) -4-methylthio-3-thienyloxy) butyric acid; 4- (2- (10-Sulfinodecanoylamino) -4-methylsulfonyl-3-thienyloxy) butyric acid; 4- (2- (9-Thiosulfatononanoylamino) -4-methylsulfonyl-3-thienyloxy) butyric acid, sodium salt; 4- (2- (12-Phosphodododecanoylamino) -5-trifluoromethyl-3-thienyloxy) butyric acid; 4- (2- (11-Sulphoundecanoylamino) -4-methyl-5-phenyl-3-thienyloxy) butyric acid; 4- (2- (11-Sulfinoundecanoylamino) -5-methylamino-3-thienyloxy) butyric acid; 4- (2- (12-Thiosulfatododecanoylamino) -5-dimethylamino-3-thia-xyloxy) butyric acid, sodium salt; 4- (2- (11-Phosphonoundecanoylamino) -4-amino-3-thienyloxy) butyric acid;

Preferred compounds in the invention include: 4- (2- (11-Carboxyundecanoylamino) phenoxy) butyric acid, 4- (2- (9-Carboxyundecanoylamino) phenylthio) butyric acid, 4- (2- (9-Carboxynonanoylamino) phenoxy) butyric acid , 4- (2- (10-Carboxyidecanoylamino) phenoxy) butyric acid, 4- (2- (12-Carboxydodecanoylamino) phenoxy) butyric acid, 4- (2- (10- 2- (11-carboxyundecanoylamino) -4-methylphenoxy) butyric acid, 4- (2- (11-Carboxyundecanoylamino) -5-methylphenoxy) butyric acid.

Also included as a 5α-reductase inhibitor in this invention is an agent of the following formula:

I

wherein A is an aromatic ring disubstituted at 1.2, preferably a benzene ring; D is OH, NH-, NHR, OR; 2 and X is 0; S, SO or SO2; R 2 is H, C 1 -C 4 alkyl, phenyl or substituted phenyl, halo, haloalkyl, hydroxy, carboxy, cyano, C 1 -C 4 -alkyl. alkoxy, C1 -C4 alkylthio,

C1 -C4 alkylsulfinyl, C1 -C4 alkylsulfonyl, nitro, amino, C1 -C4 mono- or dialkylamino; 136

R 'and R "are independently H, halo, C1 -C4 alkyl or C1 -C4 alkoxy, amino, or oxo, wherein CH-R' or CH-R" in the formula becomes -C = O; R is H, C-C? alkyl; cl 1 4

Rb, Rc are independently C1 -C12 alkyl, phenyl, phenyl-C1 -C12 alkyl; n is 0-2; y is 1-6; z is 6-20; and wherein R '

(CH) and R (y) may independently represent substituted or unsubstituted alkyl or z radicals containing at least one alkene linkage; and pharmaceutically acceptable salts and esters thereof.

The compounds of the present invention are inhibitors of the human testosterone 5α-reductase enzyme. The scope of the compounds of the present invention is described by the formula described above. 137

In the description of the formula the following expressions are used which are hereby defined: X may be O or S, preferably an X being O, and particularly preferably when both Xs are O, i.e. the catechol structure . &quot; C? -C? alkyl &quot; includes linear or branched species, for example methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, t-butyl; and &quot; c1-c12 &lt; 3u &quot; includes alkyl of up to 12 carbon atoms including n-octyl, t-decyl, n-dodecyl. &quot; C1-C4 alkyl phenyl &quot; includes benzyl, 2-phenethyl, etc .; &quot; C1-C4 alkoxy &quot; includes straight or branched species, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy; &quot; Halo &quot; includes fluorine, chlorine, bromine or iodine; &quot; Substituted Phenyl &quot; includes phenyl substituted by one or more of C1 -C4 alkyl, C1 -C4 alkoxy, or halo, etc., as defined above; representative examples include o-, m-, p-methoxyphenyl; 2,4-dimethoxyphenyl; 2-chloro-4-ethoxyphenyl; 3,5-dimethoxyphenyl; 2,4-dichlorophenyl; 2-bromo-4-methylphenyl; o-fluorophenyl, etc. &quot; Haloalkyl &quot; includes C 1 -C 4 alkyl, defined above, substituted with one or more &quot; halo &quot; as defined above and includes: trifluoromethyl, 2,2-dichloroethyl, and the like. 138

C1 -C4 alkylthio &quot; includes C 1 -C 4 alkyl, defined above, substituted with at least one divalent thio (-S-) moiety including: methylthio, ethylthio, isopropylthio, n-butylthio, and the like. &quot; C? -C? alkylsulfinyl &quot; includes alkyl, defined above, substituted with at least one -COOH group including; methylsulfinyl, ethylsulfinyl; isopropylsulfinyl, etc. &quot; C? -C? alkylsulfonyl &quot; includes C 2 -C 10 alkoxycarbonyl, which is substituted with at least one sulfonyl group, -SO 2 -, including methylsulfonyl, ethylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, C 1 -C 4 mono or dialkyl amino "includes amino substituted with one or more C -C-C alquilo alkyl groups as defined hereinbefore, including: methylamino, ethylamino, n-butylamino, t-butylamino, dimethylamino, Ν, diethylamino, methyl-t-butylamino, etc. The group (s) R in the benzene ring may be present initially in the process, for example phenyl, methyl, methoxy, cyano, carbomethoxy, trifluoromethyl, (such as 6- nitrophenol 1 in Flow Sheet A) or may be added later by a conventional reaction, for example chlorine, such as by chlorination, nitrile by nitration, or created from a starting group functional group or added, for example by converting a nitro added later to an amino group by catalytic reduction, and then alkylating giving rise to a mono or dialkylamine. An amino group may be subjected to diazotization to give a hydroxy group, which may be followed by methylation to give a methoxy group. Similarly, a hydroxy group may be converted to a thiol by the analogous procedures described in J. Org, Chem. 31, pp 3980-3984 (1966) by Newman and Karnes, and J.Org. Chem. 31, pp 410 139

(I.e.

(1966) by Kwart, H. and Evans, E.S. The resulting thiol may be alkylated to give the alkylthio, which may be oxidized to the corresponding sulfoxide or sulphone. Preferred substituents are H, C 1 -C 4 alkyl, C 1 -C 4 alkoxy and phenyl. These reactions and sequences are conventional in this art and will be obvious to one skilled in the art in order to modify the benzene ring to arrive at a R radical shown herein. The phrase &quot; its pharmaceutically acceptable salts and esters &quot; means salts and esters of the acid groups in the final molecule which may be used as part of the drug delivery system to the human and include the salts of: sodium, potassium, calcium, ammonium, substituted ammonium, quaternary ammonium, and esters; ethyl ester, aceturate, besylate, edetate, fenpropionate, acetate, pamoate, and esters which serve as formulations of &quot; prodrug &quot; and which will hydrolyse the organism at physiological pH in order to regenerate the acid, including pivaloylates, for example pivoxethyl and pivoxyl, and Kanebo esters, etc. R '(CH) y wherein y is 1-6, preferably 3, may contain at least one substituent R' as defined above, and may be, for example, -CH2 -; -CH 2 -CH 2 -; -Câ, "-

-CH-; -CH-CH-; -CH2-CH-; -CH-CH-CH-; -CH.-CH-CH

| | 2 »Á \ ώ I is Δ | A -CH 3 CH 3 Cl-OCH 3 -CH 2 CH 3 -CH "-CH 3 -CH-; etc. Δ &amp; |

F

An alkene linkage may also be present in R '

I -CH 2 -CH = CH-; (CH) y-; for example, CH 2 -CH = CH-; CH 2 -CH = CH-CH 2 -; - (CH 2) 3 -CH = CH-, and the like. R ''

I (CH) where z is 6-20,

Z at least one R77 substituent may be completely alkyl; is preferably 8-14, etc. preferably 8-14, may contain as defined above, and for example, (CH 2) n -COOH, where n

An alkene linkage may also be present at R &quot;

I (CH) for example, (CH 2) 2 -CH = CH- (CH 2) 3 -; etc. Z Z 4 Z 4

Preferred is when R7 or R &quot; Preferred H R 'R' 'is when both (CH) and (CH)

Preferred compounds of the present invention are the following formulas; and particularly alkyl. invention are indicated

(C) (c) (c) (2)

And R '

in which R 1, R 2, R 3, Y, Z, R 2 are as hereinbefore defined; and particularly preferred are:

C H 2) 3 COOH uc

(CH2) n SR2,

O

where n is 8-14, and R4 is methyl, ethyl, cyclopropyl, n-propyl, t-butyl, phenyl or benzyl. isopropyl,

142 I)

The compounds of the present invention may be produced by the processes indicated in the Flow Sheets that follow. FLOW SHEET A-3

O

II

BrCH2CCH2) 10CGH -►CCH332CHSCH2CCH2) 10COOH (c)

FLOW SHEET A-3 (CONT.

CH 2 CH 2 CH 2 CONH 2,

II

O

(CH2Cl2CH2COOH) CH2 Cl2) 10CI% SCHCCI%) 2 1

H2CH2CH2COOH 10CH2SCH3] 2o or 145FLOW FLOW B-3

'C02Et CH3acWn, s- <

I

C (CH 2) 8 CH 2 S (CH 3) 13 12 146 FLUX SHEET C-3

(CH2) s CH3 SCH2 CH3

As indicated in Flow Sheet A-3, o-nitrophenol ethyl 1,4-bromobutyrate 2 and anhydrous K2 CO3 in, for example, dry acetone are heated under reflux for 12-100 hours, or stirred for an extended period of time at room temperature under a nitrogen atmosphere to afford ethyl 4- (2-nitrofexy) butyrate 3. in Step (A).

A solution of 3. in, for example, ethyl acetate is catalytically hydrogenated at room temperature under, for example, 40 psig H2 in the presence of a 5% Pd / ca catalyst to afford ethyl 4- (2-aminophenoxy) butyrate 4 in the Step (B). Step (C) comprises reacting 12-bromo-dodecanoic acid 5 with isopropyl mercaptan in an appropriate solvent, for example dimethoxyethane, at about 80-85 ° C to provide the acid 6.

In Step (D) the mono acid 6 is reacted with the amine 4 and Ν ', Ν'-dicyclohexylcarbodiimide (DCC) at, for example, at room temperature in, for example, dry methylene chloride, optionally in the presence of 4-dimethylaminopyridine , in order to produce the amide 7.

In Step (E), the ether amide 7 is de-esterified by, for example, 2.5 N NaOH in MeOH / H2 O to afford the final product, monoacid 8. The monoacid 8 can be treated with NaIO4 in (acetone / water) at room temperature for (4-24 hours) to afford the corresponding sulfoxide 8a. In addition, 8 may be treated with meta-chlorobenzoic acid in (CH 2 Cl 2)

temperature ranging from about 0 ° to 25 ° t! (1-24 hours) to yield the corresponding sulfone 8b.

In Step (F) ester 7 is treated with ammonia in (methanol) at ambient temperature for, for example, 1-7 days to produce amide 9. Flow Sheet B-3 illustrates the synthesis of the sulfur analogs of the compounds of the invention.

In Step G, the orthoaminothiophenol is reacted with bromoester 2 under conditions similar to those of Step A to afford the thioether 11.

In Step (Η), the thioether 11 is reacted with an alkylthioalkanoic acid under similar conditions using DCC in a manner analogous to that of Step D to afford the acylated ester 12.

In Step I, the ester 12 is hydrolyzed to yield the free acid thio 13, which has the 5-Î ± -reductase activity described herein.

As shown in Flow Sheet C-3, the compound 13 can be further oxidized to the sulfoxide in Step J, starting with the compound thio 14 to produce the sulfoxide 15, which can be hydrolyzed, in a manner analogous to conditions in Step I to produce the active acid 16.

Similarly, 14 may be converted to the sulfone-ester 17, which may then be hydrolyzed in a manner analogous to the conditions in Step I giving the corresponding acid 18 149

Alternatively, the sulfur in o-nitrobenzene thiol as a separate starting material analogous to 1, may be coupled to provide the alkylthio ester compound corresponding to 3 which may be oxidized to the corresponding sulfoxide or sulfone, followed by reduction of the nitro group yielding the amino and then coupling with an appropriate reagent, for example 6, to provide the linear amide containing un oxidized sulfur analogues to give 7. A further modification exists when the sulfuracil agent is first oxidized to the corresponding sulfoxide or sulfone, then coupled with the amino group of for example 11 to provide for example 13 containing only one oxidized sulfur in the amide chain. It is obvious that other nitrophenoids may substitute 1 in Flow Sheet A-3 to provide the scope of the compounds covered by this invention and include the following: 2-nitrophenol 2-nitro-6-methylphenol 2-nitro-5-methylphenol 2 3-methylphenol 2-nitro-4-phenylphenol 2-nitro-5-phenylphenol 2-nitro-4-chlorophenol 2-nitro-4- (trifluoromethyl) phenol 2-nitro- methoxyphenol 2-nitro-6-ethoxyphenol, etc.

Starting materials for Flow Sheets B-3 and C-3 in addition to 3L0 are commercially available and are produced rapidly by prior art processes and include all of the above compounds where -SH replaces -OH, position ortho to the nitro group.

Other starting materials for 2 in both Flow Sheets A-3 and B-3 include the following:

Br-CH2-COOMe,

Cl-CH 2 CH 2 CH 2 COOCH (CH 3) 3,

Br-CH2 CH2 CH2 CH2 COOMe,

Br-CH 2 CH 2 CH 2 CH 2 COOEt,

Br-CH 2 CH 2 CH 2 CH 2 CH 2 COOCH 2 CH 2 CH 2 CH 3,

Br-CH 2 CH (CH 3) COOMe,

Br-CH 2 CH (CH 3) CH 2 COOEt,

Br-CH2CH2CH2COOMe,

Br-CH 2 CH (OCH 3) CH 2 COOCH (CH 3) 2,

Cl-CH 2 CH (OCH 2 CH 3) CH 2 COOMe,

Br-CH 2 CH (F) CH 2 COOMe, etc.

Other starting materials for the acid 6 to produce the acid for acylation of the 4 or 11 amino group include the following:

MeS- (CH2) 6COOH, MeS_ (CH2) 7COOH, (ch3) 2chs- (CH2) 8cooh,

(CH3) 2 CHS-CH2 CH2 COOH, EtS- (CH2) gC00H, ch3ch2ch2s (ch2) 1qcooh, (CH3) 2CHS (CH2) (CH2) 15 -COOH, 151

ch3 (ch2) 3s- (ch2) 16cooh, (ch3) 2ch-ch2s- (ch2) 17cooh, ch3-ch2-ch2-s- (ch2) 18cooh, (ch3) 2chs- (ch2) 19cooh,

EtS - (CH2) 20 COOH,

MeS-CH (CH 3) - (CH 2) 10 COOH, (CH 3) 2 CHS-CH 2 CH 2 CH (CH 3)

CH 2 CH 2

Cl

(CH 2) 2 CH (CH 2) 7-s-ch 2 -COOH, CH 3 (CH 2) 2 CH (CH 2) 9-S-CH 2 -COOH, CH 3 (CH 2) 1, S-CH 2 COOH, etc.

Representative compounds of the present invention include, but are not limited to: 4- (2- (20-Isopropylthiooicosanoylamino) phenoxy) butyric acid; 4- (2- (19-methylthiononadecanoylamino) phenoxy) butyric acid; 4- (2- (18-Ethylthiooctadecanoylamino) phenoxy) butyric acid; 4- (2- (17-Isopropylthioheptadecanoylamino) phenoxy) butyric acid; (2- (16-methylthiohexadecanoylamino) phenoxy) butyric acid; 4- (2- (15-Methylsulfinylpentadecanoylamino) phenoxy) butyric acid; 4- (2- (14-methylsulfinyltetradecaboylamino) phenoxy) butyric acid; 4- (2- (13-n-propylthiotridecanoylamino) phenoxy) butyric acid; 4- (2- (12-n-butylsulfinyldodecanoylamino) phenoxy) butyric acid; 4- (2- (11-sec-butylthiotreanoylamino) phenoxy) butyric acid; 4- (2- (10-Phenylthiodecanoylamino) phenoxy) butyric acid; 4- (2- (10-Benzylthiodecanoylamino) phenoxy) butyric acid; 4- (2- (10-iso-butylsulfonyldecanoylamino) phenoxy) butyric acid; 4- (2- (9-t-Butylthionanoylamino) phenoxy) butyric acid; 4- (2- (8-Ethylsulfonyloctanoamino) phenoxy) butyric acid; 4- (2- (7-Isopropylthioheptanoylamino) phenoxy) butyric acid; 4- (2- (6-Isopropyltiononadecanoylamino) phenylthio) butyric acid 4- (2- (20-ethylsulfonyleicosanoylamino) phenylthio) butyric acid 4- (2- (16-isopropylhexadecanoylamino) phenylthio) butyric acid 4- (2- (15-methylthiopentadecanoylamino) phenylthio) butyric acid 4- (2- (17-ethylthioheptadecanoylamino) phenylthio) butyric acid 4- phenylthio) butyric acid 4- (2- (14-methylsulfinyltetradecanoylamino) phenylthio) butyric acid 4- (2- (13-methylsulfonyltridecanoylamino) butyric acid; - (2- (10-sec-butylthiodecanoylamino) phenylthio) butyric acid 4- (2- (10-phenylthiodecanoylamino) phenylthio) butyric acid 4- (2- (8-t-butylthiooctanoylamino) phenylthio) butyric acid 4- (2- (9-isobutylsulfonylnonanoylamino) phenylthio) butyric acid 4- (2- (10-benzylthiodecanoylamino) phenylthio) butyric acid 4- (2- 2 - (7-ethylsulfinylheptanoylamino) phenylthio butyric acid; 4- (2- (15-Methylsulfonylisohexadecanoylamino) phenoxy) butyric acid 3- (2- (6-Methylsulfinylhexadecanoylamino) phenoxy) propionic acid 4- (2- (6-Isopropylthiohexanoylamino) 14-n-propylthiotetradecanoylamino) phenoxy) isobutyric acid 5- (2- (13-n-butylsulfinyltridecanoylamino) phenoxy) valeric acid 5- (2- (12- sec-butylthiododecanoylamino) phenoxy) 5- (2- (9-isopropyltiononanoylamino) phenoxy) acetic acid, 5- (2- (4-isopropylidonanoylamino) 6- (2- (8-ethylthiooctanoylamino) phenoxy) caproic acid; 6- (2- (7-Isopropylthioisooctanoylamino) phenoxy) caproic acid; - (7-methylheptanoylamino) phenoxy) enanthate;

7- (2- (6-methylsulfinylhexanoylamino) phenoxy) enanthic acid; '7- (2- (5-Methylsulfonylisohexanoylamino) phenoxy) enanthic acid; 2- (2- (12-n-propylthiododecanoylamino) phenoxy) acetic acid; 2- (2- (11-n-Butylsulfinylundecanoylamino) phenoxy) acetic acid; 2- (2- (10-sec-butylthiodecanoylamino) phenoxy) acetic acid; 3- (2- (12-t-butylthiododecanoylamino) phenylthio) propionic acid 3- (2- (9-isobutylsulfonylnonanoylamino) propionic acid 3- 4- (2- (12-ethylthiododecanoylamino) phenylthio) butyric acid, 4- (2- (11-Methylthioethaneanoylamino) -4-methylthiophenoxy) butyric acid 4- (2- (11-Isopropylthiooundecanoylamino) phenylthio) butyric acid; (2- (9-methylsulfinylnonanoylamino) phenylthio) valeric acid 5- (2- (10-methylthiodecanoylamino) phenylthio) valeric acid 5- (2- (11-isopropylthio) 5- (2- (10-n-butylsulfinyldecanoylamino) phenylthio) valeric acid; 6- (2- (9-N-propylthio) sec-butylthionanoylamino) phenoxy) caproic acid; 6- (2- (12-Isobutylsulfonyldodecanoylamino) phenylthio) caproic acid, 6- (2- (11-t-butylthiotreanoylamino) phenylthio) caproic acid; ethylsulfinylundecanoylamino) -3-methylphenyl 7- (2- (11-isopropylthiotreanoylamino) -4-methylphenylthio) enanothioic acid; 7- (2- (12-methylthiododecanoylamino) phenoxy) enanthic acid; 4- (2- (11-Phenylthiotrianoylamino) -4-methyl-phenoxy) butyric acid; 4- (2- (10-Benzylthiodecanoylamino) -3-methylphenoxy) butyric acid; 4- (2- (9-methylthiononanoylamino) -5-methylphenoxy) butyric acid; 4- (2- (12-Methylsulfinyldodecanoylamino) -6-methylphenoxy) butyric acid; 4- (2- (11-Methylsulfonyldecanoylamino) -3-phenylthio) butyric acid; 154

\

4- (2- (10-n-propylthiodecanoylamino) -4-methylphenoxy) butyric acid; 4- (2- (9-n-butylsulfinylnonanoylamino) -5-fluoromethylphenylthio) butyric acid; 4- (2- (12-sec-butylthiododecanoylamino) -6-methylphenoxy) butyric acid; 5- (2- (11-Iso-butylsulfonylundecanoylamino) -3-methylphenylthio) valeric acid; 4- (2- (11-t-Butylthioctanoecanoylamino) -3-methylsulfonylphenoxy) butyric acid; 4- (2- (11-ethylsulfinylundecanoylamino) -4-methylsulfonylthio) butyric acid; 4- (2- (12-Isopropylthiododecanoylamino) -5-ethylphenoxy) butyric acid; 4- (2- (11-Methylthiotreanoylamino) -4-phenylphenoxy) butyric acid; 4- (2- (10-Ethylthiodecanoylamino) -3,5-dimethylphenoxy) butyric acid; 4- (2- (9-Isopropyltiononanoylamino) -4-fluoro-phenoxy) butyric acid; 4- (2- (12-Methylthiododecanoylamino) -5-trifluoromethylphenoxy) butyric acid; 4- (2- (11-Ethylthio) undecanoylamino) phenylthio) butyric acid, 4- (2- (9-Isopropylthio) nonanoylamino) phenoxy) butyric Acid 4- (2- (11-isopropylthio) undecanoylamino) phenoxy) , 4- (2- (12-Isopropylthio) dodecanoylamino) phenoxy) butyric acid, 4- (2- (10-Isopropylthio) phenoxy) butyric acid, 4- (2- (15-t-Butylthio) pentadecanoylamino) phenoxy) butyric acid, 4- (2- (11-Ethylsulfinyl) undecanoylamino ) phenoxy) butyric acid, 4- (2- (11-Isopropylsulfonyl) undecanoylamino) -4-methylphenoxy) butyric acid, 4- (2- (11-Ethylsulfinyl) undecanoylamino) -5-methylphenoxy) butyric acid.

All of the compounds described above in the present invention, prepared according to the methods described above, as described above, may be used to treat BPH in combination with an aromatase inhibitor, by oral, parenteral or topical administration.

In this invention, the aromatase inhibitor, and the 5α-reductase inhibitor are administered in combination separately or as a single combined pharmaceutical composition by the parenteral and oral routes. Preferably the aromatase inhibitor and the 5α-reductase inhibitor are administered orally as separate compositions. The amount of each component administered is determined by the attending physician taking into account the etiology and severity of the disease, the condition and age of the patient, the potency of each component and other factors.

Aromatase inhibitor compositions are generally administered in a dosage range of about 10 to 400 mg / kg (body weight) per day with a single dose of 50 to 250 mg per day being preferred.

The 5Î ± -reductase inhibitor compositions are generally administered in a dose ranging from about 0.01 to 1.0 mg / kg (body weight) per day with one being preferred at 70 mg per day in a total daily dose.

In the preferred aspect of this invention, the aromatase inhibitor is fadrazole which is administered orally at a daily dose of about 100 mg / kg and the 5α-reductase inhibitor is finasteride, which is administered orally at a daily dose of about 10 mg / kg . 156

The aromatase inhibitor and the 5α-reductase inhibitor may be compounded in a single dosage form for oral or parenteral administration. A tablet or capsule or caplets are particularly convenient forms for oral administration. Such compositions useful in the present invention are typically formulated with conventional pharmaceutical excipients, for example, spray-dried lactose and magnesium stearate in tablets or capsules for oral administration. One or more of the active substances, with or without additional types of active agents, may be converted into tablets or dragee cores by mixing with solid powdery carrier substances such as sodium citrate, calcium carbonate or dicalcium phosphate, and such as polyvinyl pyrrolidone, gelatin or cellulose derivatives, possibly also by adding lubricants such as magnesium stearate, sodium lauryl sulfate, &quot; Carbowax &quot; or polyethylene glycols. Of course, flavor enhancing substances may be added in the case of oral dosage forms.

As other forms of administration, buffered capsules, for example hard gelatin capsules, as well as closed soft gelatin capsules comprising a softening or plasticizing agent, for example glycerin, may be used. The buffered capsules contain the active substance preferably in the form of a granulate, for example in mixtures with fillers such as lactose, sucrose, mannitol, starches such as potato starch or amylopectin, cellulose derivatives or highly dispersed silicic acids . In soft gelatin capsules, the active substance is preferably dissolved or suspended in suitable liquids, such as vegetable oils or liquid polyethylene glycols. 157

The active ingredient components used in accordance with the present invention may also be formulated into a composition for once-daily administration or for further sustained release by conventional techniques well known in the art.

Instead of oral administration, the active compounds may be administered parenterally. In that case, a solution of the active substance may be used, for example in sesame oil or olive oil.

Following the above treatment using the described regimen, symptoms of BPH including increased prostate volume, nocturia, increased hesitation, decreased urinary flow, are inhibited, in some cases avoided when treating androgen dependent diseases such as benign prostatic hypertrophy with this invention.

To help determine the effect of prostatic treatment, the blood plasma concentration of testosterone (T), dihydrotestosterone (DHT), estradiol and prostate acid phosphatase (PAP) as well as prostate volume, flow rate urination, hesitation and nocturia. Decreased concentrations of DHT, estradiol, prostatic PAP, and reduced prostate volume are indicative of successful treatment. The concentrations of the above components in plasma are measured by standard methods well known to those skilled in the art (See, for example, R. Neri and M. Monahan, Invest Urology (1972), 10, 123-130 for prostatic P E-Nieschlay and DL Loriaux, Z. Klin. Chem. Klin. Biochem (1972), 4, 164 for radioimmunoassay determinations of T). 158

Prostate volume is measured by rectal examination and / or by transrectal ultrasonography. The objective evaluation of the effect of the treatment is also measured by physical methods well known to those skilled in the art of nuclear magnetic resonance analysis as well as by physical examination.

Using a protocol similar to the one described above, clinical trials on the effect of the combination of finasteride and fadrazole will have an even greater effect on the relief of BPH symptoms in patients who will outweigh the effect obtained with each of the agents used alone. The method for preparing the compounds of the present invention, already described above in general terms, may be further illustrated by the following examples which are not to be construed as limiting the scope of the spirit of the present invention. CHAPTER 1 EXAMPLE 1 Methyl 3-oxo-4-aza-5Î ± -androst-1-ene-17β-carboxylate

A suspension of 83.7 g of methyl 3-oxo-4-aza-5α-androstane-17-carboxylate and 126.5 g of benzenesselenic anhydride in 2.09 L of chlorobenzene was heated under reflux for 2 hours. hours. The reflux condenser was connected to a distillation head and the mixture slowly distilled to remove water which had formed in the reaction (2 hours). The solution was evaporated to give 198 g of wet residue. The residue as a dichloromethane solution was washed with a saturated aqueous NaHCO3 solution and a saturated NaCl solution, then dried and evaporated to give 172.4 g. This material was chromatographed on 2.56 kg of silica gel

eluting first with dichloromethane (5 L) and then with 4: 1 dichloromethane acetone. The desired product eluted after 8 1 and provided an amount of 53.4 g. It was washed with diethyl ether and dried to give 49.5 g of the title compound, m.p. 278-280 ° C. In a similar manner the following compounds were converted to their corresponding 1,2-unsaturated derivatives: C12 NH-2

Federal Police.

the R = CONHC (CH 3) 3 252-254 ° C lb = CONHC (CH 3) 2 CH 2 C (CH 3) 3 224-226 ° * Rasmusson Johnston and Arth.

U.S. Pat. No. 4,377,584, March 22, 1983. EXAMPLE 2 Methyl 4-methyl-3-oxo-4-aza-5Î ± -androst-1-ene-17β-carboxylate

A suspension of 25 g of the product of Example 1 and 2.25 g of sodium hydride in 500 ml of dry dimethylformamide was stirred under nitrogen for 15 minutes. Methyl iodide (15 ml) was added dropwise and the mixture was stirred for 30 minutes at room temperature. Methyl iodide (5 ml) was added and the mixture was heated at 50 ° C for 2 hours. After cooling the mixture was diluted with water to a volume of 2 liters. The solid was separated after cooling to the amount of 25.4 g, m.p. 159-161 ° C.

In a similar manner the following compounds were converted to the corresponding 4-methyl derivatives:

H

2a R-CONHC (CH 3) 2 CH 2 C (CH 3) 3, androstane 2b = CONHC (CH 3) 3; 1-androstene 2C = CONHC (CH 3) 2 CH 2 C (CH 3) 3 Δ-1-androstene

148-150 ° C 153-155 ° 168-170 ° EXAMPLE 3 4-Methyl-3-oxo-4-aza-5α-androst-1-ene-17α-thiocarboxylate S- (2-pyridyl)

A 25 g suspension of the product of Example 2 in 125 ml of methanol was treated with a solution of KOH (12.5 g) in 12.5 ml of water. After refluxing for 4 hours, the solution was acidified with 6N HCl and then diluted with water. The crude acid (23.32 g) was separated, dried and had a m.p. 300 ° C. The dried, crude (23 g), triphenylphosphine (36.45 g) and 2,2'-dipyridyl disulfide (30.4 g) were suspended in 138 ml of toluene with stirring for 3 hours at room temperature. The reaction mixture was directly chromatographed on a 4.5 kh silica gel column eluting with 9: 1 ethyl acetate-acetone to give 20.4 g of the desired product, mp 218-220ø W. Further elution with acetone afforded 5.2 g of the methanol addition product, S- (2-hydroxy-4-methyl-3-oxo-4-aza-5Î ± -androstan-17β-thiocarboxylate, pyridyl), mp 221-223 ° C as a by-product. 3A. In a similar manner the product of Example 1 was converted to S- (2-pyridyl) 3-oxo-4-aza-5Î ± -androst-1-ene-17β-thiocarboxylate, m.p. 230-232 ° C. 3B. methyl 3-oxo-4-aza-5Î ± -androstane-17β-carboxylate was converted to S- (2-pyridyl) 3-oxo-4-aza-5Î ± -androstane-17β-thiocarboxylate , mp 232-234 ° C. EXAMPLE 4 Anhydrous N-t-butyl-t-butylamine 4-methyl-3-oxo-4-aza-5Î ± -androst-1-ene-17β-carboxylate was added to a suspension of 162

2.5 g of the pyridylthiol ester of Example 3 in 70 ml of tetrahydrofuran. After 60 minutes of exposure, the resulting solution was evaporated and the residue was chromatographed on 125 g of silica gel. Elution with 20: 1 ethyl acetate dichloromethane afforded 1.5 g of product, mp 152-154 ° C.

When the example is repeated using an appropriate amine and an appropriate pyridylthioester, the following products are obtained: N -butyl 4b: 3-oxo-4-aza-5a-androstane-178-carboxamide, mp 275-276øC . 4-methyl-3-oxo-4-aza-5Î ± -androst-1-ene-17β-carboxamide of N- (2,4,4-trimethyl-2-pentyl), m.p. 168-170 ° C. To a solution of 200 g of 3-oxo-4-ethyl-17β-oic acid in 3.5 L of t-butanol at 80 ° was added A solution of 198.4 g of sodium carbonate in 474 ml of water was added. A warm (65øC) solution of 948.5 g of sodium metaperiodate and 6.95 g of permanganate in 3.5 l of water was added at such a rate that the reaction mixture was maintained at 80øC. After the addition the mixture was heated under reflux for one hour. The mixture remained at room temperature overnight. The inorganic salts were removed by filtration and the mass was washed with 225 ml of water. A 5% aqueous sodium bisulfite solution was added in order to reduce the iodine which was present. The t-butanol was removed under reduced pressure and the aqueous residue was acidified with concentrated hydrochloric acid. The separated gum was extracted into dichloromethane and washed with 5% aqueous sodium bisulfite, brine, and dried and concentrated to an off-white residue (214 g). The crystalline material was obtained by suspending the residue in ether and diluting with hexane to give 152 g, m.p. 189-192 ° C.

EXAMPLE 5B 3-Oxo-4-aza-5-ethen-20-oic acid

A suspension of 64.7 g of the dioic acid from Step 5 in 350 ml of ethylene glycol was treated with 80 ml of ammonia. The resulting solution was heated at a rate of 3 ° / min to 180 ° C and maintained at that temperature for 15 minutes. After cooling, 1 liter of water was added and the mixture was acidified with 10% hydrochloric acid to a pH of 1.5. The product was removed and washed with water, then air dried to give 57.5 g of product, m.p. 310Â ° C

EXAMPLE 5C 3-Oxo-4-aza-5α-ethan-20-oic acid

A solution of 136 g of the 5-acid of Example 5B in 16.32 ml of acetic acid was hydrogenated at 60øC in the presence of platinum catalyst (from 16.32 g of PtC &gt; 2) at 40 psig for 3 hours , the catalyst was removed and the solution was concentrated to give 128.2 g of the crude product. The material was washed thoroughly with 3 L of water and then filtered and air dried to give 125 g of the white solid, m.p. 310 ° C.

This material is also obtained by saponification of methyl 3-oxo-4-aza-5α-androstane-17β-carboxylate (3-oxo-4-aza-5α-ethen-175-oate) in 7% methanolic potassium hydroxide % following an acidic treatment.

EXAMPLE 5D N- (2,4,4-trimethyl-2-pentyl) -3-oxo-4-aza-5Î ± -androstane-17β-carboxamide

A solution of 5.0 g of the product of Example 5C, 3.35 g of dicyclohexylcarbodiimide and 3.18 g of 1-hydroxybenztriazole in 500 ml of dichloromethane was stirred at ambient temperature overnight. The solid was filtered off and the filtrate treated with 2,4,4-trimethyl-2-pentylamine (t-octylamine). This solution remained at ambient temperature for 64 hours. A small portion of solid was removed and the solution was washed successively with 10% aqueous sodium hydroxide, water, 10% hydrochloric acid and saturated aqueous sodium chloride. After drying and concentration the crude product was eluted through 240 g of silica gel with acetone-dichloromethane 3: 7 to give 5.5 g of the product, m.p. 250-251 ° C.

EXAMPLE 5E Example 5D is repeated using t-butylamine instead of 2,2,4-trimethyl-2-pentylamine to yield Nt -butyl 3-oxo-4-aza-5a-androstane-17β-carboxamide, mp 274-276 ° C. EXAMPLE 6 Synthesis of 17β-N-1-adamantylcarbamoyl) -4-aza-5Î ± -androst-1-en-3-one

100 mg of 17-methyl ester (0.305 mmol) from Example 1 were suspended in 3.0 mL of THF (dried over 3A molecular sieves), then 183.0 mg of 1-adamantanamine (1, 2 mmol). The suspension was cooled to 5-10 ° C.

then 590 μΐ of a 2.0M solution of EtMgBr in THF was added. The resulting mixture was allowed to stir for 10 minutes, then refluxed for 1-2 hours under Ν 2. The mixture was cooled to 0 ° C then quenched with saturated NH 4 Cl solution (ca. 10 ml). The organic layer was separated and the aqueous layer was extracted with three volumes of CH2 Cl2 ·

The organic layers were combined, washed 2 times with H2 O, twice with saturated sodium chloride, and dried over MgSO4, filtered and evaporated to dryness in vacuo. Crystallization from EtOAc provided 75.0 mg of product. Recrystallization from MeOH and drying at 110 ° C for 2 hours / 0.1 mm gave the product, m.p. 305-306 ° C. Molecular weight (by FAB) showed M + = 451: Calculated = 451.

Anal. Calc. for C 29 H 42 N 2 O 2: C, 77.28; H, 9.40; N, 6.21.

Found: C, 76.84; H, 9.73; N, 5.93. EXAMPLE 7 Synthesis of 17β- (N-2-adamantylcarbamoyl) -4-aza-5α-androst-1-en-3-one

Following the general procedure described above from Example 6 but using 2-adamantanamine (prepared by aqueous neutralization of the hydrochloride and extraction with EtOAc and isolation) instead of 1-adamantamine, and refluxing for 7 hours instead of 1-2 hours, the title compound is prepared, mp 284-285 ° C. EXAMPLE 8 Synthesis of 17β-N-1-adamantylcarbamoyl-4-aza-5α-androstane-3-one 100.0 mg of adamantyl derivative produced in Example 6 were dissolved in 5.0 mL of dry THF. 300 mg of 5% Pd / C were added and the mixture was hydrogenated for 6.0 hours at RT at 40 psi. The mixture was filtered through celite, the slurry was washed with THF (3 times) and the solvent was evaporated under vacuum to provide 97.0 mg of the above title product crude. NMR showed absence of olefins. The crude material was placed on a 15.0 g silica gel column, and eluted with 1: 1 (CHCl3: acetone). CD*

The fractions collected provided a single spot material by TLC weighing 77.98 mg. NMR showed excellent agreement with the proposed structure. Recrystallization from EtOAc to provide 65.59 mg of the title product, m.p. 323-324 ° C.

Anal. Calc. for α 294 4402 Ν 2 1/4 Η 20 C C, 76.18; H, 9.81; N, 6.13.

Found: C, 75.91; H, 9.97; N, 6.06. EXAMPLE 9 Synthesis of 17S (N-Adamantylcarbamoyl) -4-methyl-4-aza-5a-androst-1-en-3-one 120 mg of thiopyridyl ester of Example 3 were suspended in 20 ml of dry THF, suspension was added 175.0 mg of 1-adamantanamine under Ν2. The reaction was run at RT for 16 hours under Ν2. The reaction was monitored by TLC on silica gel using 1: 1 acetone: hexane. The product was separated 167

in TLC 20 cm x 20 cm, 1000 μκι of gas plate! of silica, eluted with 1: 1 (acetone / hexane). the product was crystallized from ethyl acetate to give 50.0 mg of pure material, m.p. 202-205 ° C. Molecular Weight (FAB) showed a value of 465; Calc.:465. Recrystallization provided 19.14 mg of the title product, m.p. 202-202.5 ° C.

Calc'd. for C 30 H 44 N 2 O 2 • H 2 O: C, 76.64; H, 9.60; N, 5.80.

Found: C, 74.32; H, 9.47; N, 5.89. EXAMPLE 10

Hydrolysis of methyl 3-oxo-4-aza-5α-androstane-17β-carboxylate The 17β-androstane carboxylate starting material of Example 1 was hydrolyzed with 7% KOH in aqueous isopropanol or methanol followed by an acidic treatment to give 17B-carboxylic acid which was used in Example 11. EXAMPLE 11 N- (1-Adamantyl) -3-oxo-4-aza-5α-androstane-17β-carboxamide

A solution of 5.0 g of the product of Example 10, 3.35 g of dicyclohexylcarbodiimide and 3.18 g of 1-hydroxybenztriazole in 500 ml of dichloromethane was stirred at ambient temperature overnight, the solid was filtered off and The filtrate was treated with 1-adamantamine. This solution remained at ambient temperature for 64 hours, then filtered, and the solution was washed successively with 10% hydrochloric acid and saturated aqueous sodium chloride. After drying with MgSO 4, 168

filtered and concentrated. The crude product was eluid &quot; through 240 g of silica gel with 3: 7 (acetone: dichloromethane) to give 5.5 g of the title product, m.p. 323-324 ° C. EXAMPLE 12 Synthesis of Benztriazol-1-yl-3-oxo-4-methyl-4-aza-5Î ± -androstan-17β-carboxylate

A suspension of 83.7 g of methyl 3-oxo-4-methyl-4-aza-5Î ± -androstane-17β-carboxylate (See Rasmusson, et al., J. Med. Chem., 29, 2298-2315 , 1986) was hydrolyzed with 7% KOH in aqueous methanol, followed by an acidic treatment to give the corresponding 17S-carboxylic acid. The acid was rapidly converted to benzotriazol-1-yl-3-oxo-4-methyl-4-aza-5α-androstane-17β-carboxylate as described in Example 13. The activated ester (the benzotriazole derivative) was purified by TLC (4 plates, 20 cm x 20 cm x 20 cm x 1,000æ silica gel) eluting with (MeOH-CHCl 3) 4:96. The isolated product was washed with ether to give the active ester m.p. 198-200 ° C with decomposition. EXAMPLE 13 Synthesis of 4-Methyl-4-aza-benzotriazole derivative prepared as described in Example 1 Example 12, were dissolved in 20.0 ml of CH2 Cl2. To make the solution clear, 127 mg of 1-adamantanamine was added. The reaction mixture was stirred overnight at R.A./N2 169 169

Crystallization from EtOAc after filtration of the solution through Teflon Acrodisc CR provided 26.32 mg, m.p. 210-217 ° C. The product was subsequently purified on a column of 1.0 g of silica gel (silica gel EM) with (acetone-hexane) 1: 1 as eluent to give after recrystallization (ethyl acetate) at 21.75 mg of white needles of the above title product, mp 203-205 ° C.

Anal. Calc. Calc'd for C 18 H 18: 2: C, 73.58; H, 9.68; N, 5.62;

Found: C, 73.15; H, 9.30; N, 5.67. 17B (N-exo-2-norbornylcarbamoyl) -4-aza-5a-androst-1-en-3-one) 100.0 mg of the corresponding thiopyridyl ester 4-H of Example 3, prepared by The title compound was prepared according to the procedure of Example 3, but using the product 4-H methyl ester of Example 1 (See Rasmusson et al., J. Med. Chem. Vol. 29, pp. 2298-2315 (1986)), were dissolved in 3.0 ml of dry THF under N 2. To the clear solution was added 477 μΐ (±) racemic exo-2-aminonorbornane. The reaction was allowed to proceed for 16 hours at ΤΑ / / Ν2. The reaction mixture was evaporated to dryness in vacuo. The residue was dissolved in chloroform. The organic layer was washed with 2.5 N HCl acid (3 times); 3 times with water; 3 times with saturated NaCl solution, dried over MgSO4, filtered and evaporated to dryness in vacuo to provide 56.3 mg of a racemic diastereomeric mixture. The crude product was chromatographed by TLC (2 plates, 20 cm x 20 cm x 500 μ silica gel) eluted with (CHCl 3: acetone) 70:30 to provide 43.4 mg of the title product above. Recrystallization from EtOAc afforded 30 mg of product, m.p. 245-245.9Â ° C. NMR (CDCl 3) confirmed the above structure.

FAB mass spectrum calc. Calc'd for C 26 H 38 N 2 O 2: m / e 411.

Anal. Calc. Calc'd for C 26 H 12 N 2 O • 20: C, 72.82; H, 9.40; N, 6.58.

Found: C, 73.21; H, 9.20; N, 6.25. EXAMPLE 15 Synthesis of 17β- (N-Adamantylmethylcarbamoyl) -4-aza-5α-androst-1-en-3-one 200.0 mg dp steroid thiopyridyl aza 4-H, used in Example 14, was suspended in 2.0 ml of dry THF. To the suspension 400 μΐ 1-aminomethylene adamantane was added by means of a syringe to T.A./N2. After several minutes, a clear yellow solution resulted and after 1/2 hour, precipitation occurred. The reaction was allowed to proceed overnight / N 2 · It was diluted with CH 2 Cl 2, washed with 10% NaOH, twice, then with CH 2 twice, followed by 10% (twice) HCl, H 2 O ( twice), and finally twice with saturated NaCl solution. The organic layer was dried over MgSO4, filtered, concentrated in vacuo to afford the product as indicated by NMR, recrystallized from EtOAc, to afford 149.0 mg of product, mp 255-257øC with decomposition.

Mass Spectrum FAB, Calc .: m / e 464 + 1 = 465:

Found 465. EXAMPLE 16 Synthesis of 17β- (γ-2-adamantylcarbamoyl) -4-aza-5α-androstan-3-one

A mixture of 1.09 grams of 17β- (γ-2-adamantylcarbamoyl) -4-aza-5α-androst-1-en-3-one (See Example 10 for preparation), 150 ml of ethanol, and 1 , 0 g of 30% Pd / C was hydrogenated overnight with stirring under a pressure of 45 psig. of hydrogen. The suspension was filtered to remove the catalyst, and evaporated to dryness to provide a gray residue. This was chromatographed by eluting on a 200 ml silica gel column with 40:60 acetone / methylene chloride eluent to give 1.0 g solid, m.p. 294-296 ° C.

Anal. Calc. Calc'd for C 21 H 44 N 2 O • 0.2H 2 O. Calc .: C, 76.33; H, 9.80; N, 6.14

Found: C, 76.23; H, 9.86; N, 5.92

Analysis of Mass Spectrum by electron impact revealed MW of 452. EXAMPLE 17 Synthesis of 17β- (β-2-adamantylcarbamoyl) -4-aza-4-methyl-5α-androst-1-en-3-one

A suspension of 500 mg of 17β- (N-2-adamantylcarbamoyl) -4-aza-5Î ± -androst-1-en-3-one, as prepared in Example 16, 10 ml of screen dried DMF, 140 NaH, was heated and stirred at 70 ° C under a nitrogen atmosphere for 18 hours. The suspension was cooled to room temperature and then 0.4 ml of methyl iodide was added dropwise with stirring which was held at 50 ° C for 3 hours. The reaction mixture was then treated by cooling to room temperature, followed by the addition of 15 ml of water. The mixture was extracted with 3 x 20 mL CH2 Cl2. The organic layers were combined, washed with brine, dried and evaporated to give a white crystalline residue. Recrystallization from ethyl acetate / CH 2 Cl 2 provided a pure white solid, m.p. 246-248 ° C.

Calc'd for C 30 H 44 N 2 O 2 • 0.3H 2 O

Calc. C, 76.65; H, 9.56; N, 5.95

Found: C, 76.50; H, 9.75; N, 5.84 Mass spectrometry revealed a molecular weight of 464. EXAMPLE 18 Synthesis of 17β- (β-2-adamantylcarbamoyl) -3-oxo-4-methyl-4-aza-5Î ± -androstane 2-adamantylcarbamoyl) -4-methyl-4-aza-androsten-1-en-3-one (200 mg) as prepared in Example 17 was placed in 25 ml of absolute ethanol with hydrogen The suspension was oscillated overnight under a pressure of 40 psig of hydrogen The suspension was filtered, and the filtrate was evaporated to dryness The residue was recrystallized from ethyl acetate to give a white crystalline solid, mp 113-115 ° C Calc'd for C 20 H 15 NO 4 · 0.5 EtOAc Calc'd: C, 75.25; H, 9.86; N, 48

Found: C, 75.07; H, 9.52; N, 5.28 Mass spectroscopy indicated a molecular weight of 466 for the unsolvated molecule. 173

EXAMPLE 19 Synthesis of 17β- (γ-2-adamantyl) carbamoyl-4-methyl-4-aza-anhydrost-1-en- aza-androst-1-en-3-one (5.0 g) and 1.5 g of sodium hydride in 100 ml of dry DMF were stirred under dry nitrogen for 3 hours at 40 ° C. The reaction was cooled to room temperature and about 4 ml of methyl iodide were added dropwise and allowed to stir at room temperature for one hour. The reaction was cooled in an ice bath and a large excess of about 250 ml of water was added. The aqueous mixture was extracted with CH 2 Cl 2 (3 x 100 mL), the organic extracts were combined, washed with H 2 O, brine, and then evaporated to dryness to give crude product. The crude product was eluted on an HPLC (silica gel) column with acetone / CH 2 Cl 2 10/1 to afford 2 peaks having retention times of 3 CV (B) and 3.8 CV (A). Peak (A) was analyzed for the title product 4-methylaza of Example 15. The second product (B) was analyzed as the 4-methylaza-17β- (N-methyl-N-2-adamantyl (carbamoyl , i.e. the title compound, mp 163-165 ° C. calc'd for C 31 H 46 N 2 O 2

Calc. C, 77.77; H, 9.68; N, 5.85

Found: C, 77.29; H, 9.79; N, 5.77 Mass spectrometry revealed a molecular weight of 478. EXAMPLE 20 Synthesis of 17β- (N-methyl-N-2-adamantylcarbamoyl) -4-aza-4-methyl-anandrostan-3-one The crude reaction mixture from Example 19 (4.6 g) was dissolved in 200 ml of ethanol and together with 1.0 g of 30% Pd / C was hydrogenated under an atmosphere of 40-45 Psig of hydrogen at at room temperature overnight. The mixture was filtered, the residue was washed with ethanol. The ethanol solution was evaporated to dryness to provide a crude mixture. Recrystallization from CH 2 Cl 2 / diethyl ether / hexane to provide 800 mg of the pure monomethyl androstane compound of Example 16, m.p. 113-115 ° C. The second and third crops were combined with the mother liquor and treated by HPLC as in Example 17 to provide the dimethylated title compound, m.p. 180-182 ° C.

Anal. Calc. for C31 H48 N2 O2

Calc. C, 77.45; H, 10.06; N, 5.83

Found: C, 77.26; H, 9.87; N, 5.82

Mass spectrometry revealed a molecular weight of 480. EXAMPLE 21 Nt -butyl androst-3,5-diene-17E-carboxamide-3-carboxylic acid (a) Nt -butylndrost-3,5-diene-3-bromo-17β- carboxamide To a solution of oxalic acid (0.0011 mol, 0.1 g) and oxalyl bromide (0.0211 mol, 3 ml) in 15 ml of screen dried toluene was added over a period of one hour 1 g (0.003 175

mol) of androst-4-ene-3-one. The reaction was stirred at room temperature for 2 hours and then concentrated in vacuo. Excess oxalyl bromide was azeotroped with toluene. The resulting brown oil was redissolved in toluene, cooled to 0 ° C and then 10 ml of t-butylamine (7.0 g) in 30 ml of toluene was added dropwise over 15 minutes. Once the addition complete, the reaction was stirred at 0 ° C for 15 minutes and then maintained at -20 ° C for 19 hours. The reaction mixture was allowed to warm to room temperature then stirred at 25 ° C for one hour. The volatiles were removed under vacuum. The residue was partitioned between chloroform / water, the layers were shaken together and separated, and then the aqueous phase was extracted twice more with chloroform. The combined organic extracts were washed with water (2x) then dried with anhydrous magnesium sulfate. The crude product was purified by flash chromatography on silica, eluting with 20% ethyl acetate in hexane, to give 1.06 g of the title compound, a white solid. To a solution of Nt -butyl androst-3,5-diene-3-bromo-1'-carboxamide (0.25 g) in dichloromethane 5 g, 0.00115 mol) in 5 ml of tetrahydrofuran cooled to -78 ° C (dry ice / acetone bath) under argon was added dropwise 1.5 ml (0.00375 mol) of a 2.5 M solution of n-butyllithium in hexane. The reaction mixture was stirred at this temperature for one hour and then carbon dioxide was bubbled through the reaction for 45 minutes by means of a concentrated sulfuric acid tower. The reaction mixture was allowed to warm to room temperature then was diluted with water, aqueous HCl solution and chloroform. As 176

The layers were shaken together and separated, the aqueous phase being extracted again with chloroform (2x). The combined organic extracts were washed with water (2x), brine (1x) and then dried over anhydrous magnesium sulfate. The solvents were removed under reduced pressure to give 0.6 g of a crude solid. This material was slurried with hexane and a white solid (0.43 g) was isolated. The title compound was recrystallized from acetonitrile, m.p. 247-250 ° C. CHAPTER 2 EXAMPLE 1 Methyl 3-oxo-4-aza-5Î ± -androst-1-ene-17β-carboxylate

A suspension of 83.7 g of methyl 3-oxo-aza-5α-androstane-17-carboxylate and 126.5 g of benzenesseleninic anhydride in 2.09 L of chlorobenzene was heated under reflux for 2 hours. The reflux condenser was connected to a distillation head and the mixture slowly distilled to remove the water which had formed in the reaction (2 hours). The solution was evaporated to give 198 g of wet residue. The residue as a dichloromethane solution was washed with saturated aqueous NaHCO 3 solution and saturated NaCl solution, then dried and evaporated to give 172.4 g. This material was chromatographed on 2.56 kg of silica gel eluting first with dichloromethane (5 liters) and then with dichloromethane-acetone 4: 1. The desired product was eluted with 8 liters of the above mixed solvent and evaporated to dryness in vacuo to provide 53.4 g of solid. This was washed with diethyl ether and dried to give 49.5 g of the title product, m.p. 278-280 ° C. * Rasmusson Johnston and Arth. U.S. Patent No. 4,377-584, March 22, 1983. EXAMPLE 2 S- (2-Pyridyl) -3-oxo-4-aza-5Î ± -androst-1-ene-17β-thiocarboxylate

A suspension of 25.0 g of the above product from Example 1 was saponified with 12.5 g of KOH in 150.0 ml of 5: 1 CH3 OH-H2 O under reflux conditions for 4 hours / N . The mixture was cooled to 25 ° C and acidified to pH <2. Water (175 ml) was added gradually with stirring to give a crystalline precipitate which was collected and washed with water.

After drying, the product had an amount of 25 g, m.p. 313-315 ° C with decomposition. The crude dry acid (23.0 g) was suspended in 210 ml of toluene, and triphenylphosphine (56.0 g) and 2,2'-dipyridyl disulfide (48.3 g) were added to the suspension, and the mixture was The reaction mixture was placed on a silica gel column (1.3 kg) and eluted with 1: 1 acetone (CH 2 Cl 2). The desired thioester was slowly eluted, and the reaction mixture was allowed to warm to room temperature. after washing with ether gave 36.8 g of the above title product, mp 232-235øC. EXAMPLE 3 22-Methyl-4-aza-21-nor-5α-οο1-1ββ- dione

To a solution of 7.2 g of S- (2-pyridyl) -3-oxo-4-aza-5α-androst-1-ene-17β-thiocarboxylate in 288 ml of tetrahydrofuran were added at -78ø C 33.6 ml of 1.3M S-butylmagnesium chloride. After 30 minutes at -78øC the solution rose to room temperature and was treated with a saturated aqueous NaCl solution. The product was extracted into dichloromethane and washed with saturated aqueous NaCl solution and 10% aqueous NaOH solution, then dried and concentrated. The residue was eluted through 430 g of silica gel with dichloromethane-acetone 9: 1 to give 4.5 g of product, mp 246-249 ° C. 179

When the process is repeated using the following reagents, the indicated product is obtained. Starting material S- (2-pyridyl) 3-oxo-4-aza-5α-androst-1-ene-17β-carboxylate Reaction of 2- (2-pyridyl) carbonyl) -4-aza-5α-androst-1-ene-3-one mp 294-296øC S- (2-pyridyl) -3-oxo-4-methyl-5α -androst-1-ene-17β-thiocarboxylate sec-butyl magnesium chloride 4,22-dimethyl-4-aza-21-nor-5a-chol-1-ene-3,20-dione mp 134-136 ° C 2-pyrrolyl magnesium chloride 4-methyl-17β- (2-pyrrolylcarbonyl) -4- (2-pyridyl) -3-oxo-4-methyl-4-aza-5α-androst-1-ene-17β- 2-pyridyl) -3-oxo-4-aza-5a-androstene-17β-thiocarboxylate 23-methyl-isobutyl magnesium chloride -4-aza-21-nor-5α-colane-3,20-dione

m.p. 220-222 ° C. EXAMPLE 4 22-Methyl-4-aza-21-nor-5a-chol-1-ene-3,20-dione

via alternative

A solution of 21 g of 22-methyl-4-aza-21-nor-5α-colane-3,20-dione and 29.49 g of benzenesseleninic anhydride in 552 ml of chlorobenzene was refluxed with water separation for 4 hours. The mixture was concentrated and the residue was redissolved in dichloromethane. After washing with 10% aqueous sodium hydroxide, then with 10% hydrochloric acid and saturated aqueous sodium chloride the solution was dried and concentrated to 45 g of yellow residue. This was chromatographed on 1.5 kg of silica gel packed in dichloromethane and eluted with ethyl acetate to give 10.6 g of product, mp 248-251 ° C.

When the procedure is repeated using 23-methyl-4-aza-21-nor-5a-cholane-3,20-dione as the starting material the obtained product is 23-methyl-4-aza-21- EXAMPLE 5 17β-Phenylcarbonyl) -4-aza-5α-androst-1-ene-3-one To a stirred suspension of 43 g of S- (pyridyl) -3- 5-alpha-androst-1-ene-17-beta-thiocarboxylate in 500 ml of anhydrous tetrahydrofuran (THF) was added at -78 ° C a THF solution of 157 ml of phenylmagnesium chloride 2N for 60 minutes. After stirring at -78 ° C for 60 minutes, the mixture was brought to -30 ° C and quenched by the addition of 10% HCl while maintaining the temperature below -20 ° C. After heating to 0øC, the mixture was diluted with 2000 ml of water and extracted with 4000 ml of dichloromethane in portions. The organic layer was washed sequentially with water, 1N sodium hydroxide, water and brine. Drying with MgSO4 and concentration provided 37.5 g of the crude product. Recrystallization from dichloromethane / ethyl acetate gave the title phenyl ketone (30.4 g, 77% yield). m.p. 290-291 ° C.

Calc'd. N 3.61 3.56 C and 77.16 H 8.26 8.19 EXAMPLE 6 17-beta-4-fluorophenylcarbonyl-4-aza-5-alpha-androst-1-ene-3-one of Example 5 was repeated except that p-fluorophenylmagnesium bromide was used as the Grignard reagent and the title compound was obtained, mp 315-315.5 ° C. To a suspension of 34.8 g of the thiopyridyl ester of Example 2 in 700 mL of anhydrous THF was added at -65 degrees Celsius C 130 ml of a 2 M solution of cyclohexyl magnesium chloride over a period of 20 minutes After stirring at -70 ° C for 60 minutes the solution was warmed and stirred at -10 ° C for 60 minutes. diluted with 500 ml of dichloromethane and then dropwise with dichloromethane, the layers were separated and the organic layer was treated sequentially with water, 1N sodium hydroxide, water and saturated sodium chloride solution.The organic solution was decolorized with charcoal, filtered and concentrated to a residue which was crystallized from ethyl acetate to give 28.2% of the title compound, mp 271.5-277 degrees C. EXAMPLE 80 The title compound of Example 7 was also prepared by the following procedure. of 150 g of methyl 3-oxo-4-aza-5-alpha-androst-1-ene-17-beta-carboxylate in 2800 ml of anhydrous THF was added with stirring at less than 0 degrees C of internal temperature 678 ml of a 2 N solution of cyclohexyl magnesium chloride. The solution was then refluxed for 6 hours. The cooled reaction mixture (less than 10 degrees C) was acidified with a 10% HCl solution and extracted with dichloromethane. The organic layer was washed sequentially with water, saturated NaHCO 3 solution and saturated NaCl solution. Drying (MgSO4) and evaporation gave 163 g of 183

cyclohexyl ketone. Recrystallization from dichloromethane / ethyl acetate gave 131 g of the pure material. m.p. 269-270 ° C. Calc'd. Found: N 3.61 3.61 C 77.37 77.37 H 9.74 10.13 EXAMPLE 9 17β- (Cyclopentylcarbonyl) -4-aza-5-alpha-androst-1-en-3-one

When the procedure of Example 7 or 8 was repeated using cyclopentylmagnesium chloride, the title compound was obtained: m.p. 272-273 ° C.

Calc'd. N 3.66 3.78 C 75.25 74.89 H 9.60 9.54 EXAMPLE 10 17-beta- (cyclobutylcarbonyl) -4-aza-5-alpha-androst-1-ene-3-one

When the procedure of Example 7 or 8 was repeated using cyclobutylmagnesium chloride, the title compound was obtained: m.p. 288-289 degrees C.

% Calc Found N 3.94 3.87 C 77.71 78.06 H 9.36 9.61 EXAMPLE 11 Synthesis of 17β- (4-phenylbenzoyl) -4-aza-5α-androst-1-en- 3 To a suspension of 258.0 mg of dried activated magnesium turnings in 5.0 ml of dry THF was added 932.0 mg of 4-bromobiphenyl in 5.0 ml of dry THF under Ν2. The reaction was run in a bath with a temperature range of 24-30 ° C. To the well stirred mixture was added dropwise 30 ml of 1,2-dibromoethane / N2. The reaction was allowed to continue for 1-1 / 2 hours at 28 ° C / N2. The Grignard reagent concentration was 4.0 mmol in 10.0 mL dry THF. The steroid of Example 2 (205.0 mg, 0.5 mmol of thiopyridyl ester) was suspended in 2.0 mL of dry THF, cooled to -80 ° C and 3.80 mL of the Grignard reagent were added via a syringe to the steroidal suspension for 5-10 minutes / N2. The reaction was allowed to proceed for 1 hour at -80øC / N2 and then at -10øC for an additional 1 hour / N2. The solution was diluted with 10.0 ml of methylene chloride and quenched with saturated aqueous NH 4 Cl to pH = 4. The organic layers were separated, washed 3 times with water, 3 times with saturated sodium chloride, dried over MgSO4, filtered and evaporated under vacuum to provide 156.2 mg of crude product. Crystallization from EtOAc gave the title product above in 98.58 mg, m.p. 290Â ° C-290.5Â ° C.

Anal. Calc. for C 31 H 35 NO 2:

Found: C, FAB: Calc'd. Calc'd for C 82.08; H, 7.78, 81.84; H, 8.01; H 35 NO 2: 453%; N, 3.09; ; N, 3.06. Found:

453. EXAMPLE 12 17-B- (3-Phenylbenzoyl) -4-aza-5a-androst-1-en-3-one To a suspension of 258.0 mg of activated magnesium turnings dried in 8.0 mL of THF 932.0 mg of 3-bromobiphenyl in 2.0 ml of dry THF was added under N2. The reaction was

4U carried out in an ultrasonic bath with a temperature range of 24-30 ° C. To the well stirred mixture were added dropwise 30 microliters of 1,2-dibromoethane / N2. The Grignard reagent concentration was 4 mmol in 10.0 mL dry THF. the steroid of Example 2, 205.0 mg (0.5 mmol) was suspended in 2.0 mL of dry THF, cooled to -80 ° C and the above prepared Grignard reagent, 3.80 mL, was added via from a syringe to the steroidal suspension for 5-10 minutes / N. The reaction was allowed to proceed for 1 hour at -80øC / N2 and then at -10øC for an additional hour / The solution was diluted with 10.0 mL of methylene chloride and quenched with a saturated aqueous NH4 Cl2 solution at pH = 4. The organic layers were separated, washed 3 times with water, 3 times with saturated sodium chloride, dried over MgSO 4, filtered and evaporated in vacuo. Crystallization from ethyl acetate afforded 122.84 mg of product. The material was purified on a 20.0 g silica gel column using (CHCl 3 -acetone) 70:30 as eluent to give 117.0 mg of single-spot material of the above-mentioned title compound , mp 184-185 ° C.

Anal. Calc. Calc'd for C 12 H 12 N 3 O 3: C, 82.08; H, 7.78; N, 3.09; Found: C, 82.28; H, 8.04; N, 2.98. FAB: Calc. for C3] _H35N02! 453 Found: 453. Synthesis of 17-5- (4-methylthiobenzoyl) -4-aza-5-a-androst-1-en-3-one To a suspension of 250.0 mg of activated magnesium turnings dried in 8.0 mL of dry THF was added 812.0 mg of p-bromophenyl methyl sulfide in 3.0 mL of dry THF under Ν 2. The reaction was run in an ultrasonic bath at a temperature ranging from 24-30 ° C . To the well stirred mixture were added dropwise 40 μΐ of 1,2-dibromoethane / N 2. The reaction was allowed to proceed for 1 1/2 hours at 28 ° C / N2. The concentration of the Grignard reagent was 4.0 mols in 10 ml of dry THF. The steroid of Example 2, i.e. the pyridylthio ester, 205 mg, was suspended in 2.0 mL of dry THF, cooled to -80 ° C and the Grignard reagent prepared above was added via syringe to the steroidal suspension at 5 ° C. The reaction was allowed to proceed for 1 hour at -80øC / N2 and then at -10øC for an additional hour / N2. The solution was diluted with 10.0 ml of methylene, and quenched with saturated aqueous NH 4 Cl to pH = 4. The organic layers were separated, washed 3 times with water; 3 times with saturated sodium chloride, dried over MgSO 4, filtered and evaporated under vacuum to provide 105.0 mg of crude product. The crude product was chromatographed on TLC (one 20 cm x 20 cm x 20 cm x 1000 μ sil silica gel slurry) eluted with (CH2 Cl2 -acetone) 80:20 to provide 66.0 mg of a single spot material. Crystallization from EtOAc provided 45.0 mg of the title compound, m.p. 286-287 ° C. FAB for C26H33NC> 2S (Calc.) 424; EXAMPLE 14 Synthesis of 17β- (4-methylsulfinylbenzoyl) and - (4-methylsulfonyl) -4-aza-5α-androst-1-en-3-one 19.91 mg of the methylthio product from Example 13 were dissolved in 2.5 ml CHCl, cooled to 0 - (- 2) ° C and treated with a solution of 9.6 mg of m-chloroperbenzoic acid in 1.0 ml CHCl 3 period of 4 minutes.

After stirring for 1 hour at 0 - (- 2) ° C, the reaction was diluted with 10 ml. of CH 2 Cl 2. The layers were subsequently washed with 2.5% NaHCO 3, H2 O and saturated NaCl solutions. The organic layer was dried over MgSO4 overnight, filtered and evaporated under vacuum to provide 17 mg of product. Crystallization from EtOAc gave 11.8 mg of the title compound, a solid, m.p. 313-313.5Â ° C (with decomposition).

Anal. Calc. for, N0., S-1 / 4H2 O:

ZO JJ J Z C, 70.31; H, 7.60; N, 3.15;

Found: C, 70.47; H, 7.70; N, 3.00. FAB for C26 H33 N3 O3 S (Calc 440); Found: 440.

Sulfone

Fifteen percent (15%) of the corresponding sulfone, 17B- (4-methylsulfonyl benzoyl) derivative was isolated by chromatography from the reaction as a by-product. Recrystallization from EtOAc to provide a solid, 188

m.p. 279-279.5 ° C. Molecular weight by FAB revealed 456; calculated 456.

Anal. Calc'd for Câ, â, † Hâ,,â, "Nâ," Oâ, ": 0.25 H2 O Calc'd: C, 67.87; H, 7.28; N, 3.04 Found: C, 67.96; H, 6.72; N, 2.95 EXAMPLE 15 Synthesis of 17β- (4-acetoxymethylthiobenzoyl) -4-aza-5α-androst-1-en-3-one

Trifluoroacetic anhydride (165 μΐ) was dissolved in 780 μΐ acetic anhydride and maintained for 5 hours at room temperature (RT). To 300 μΐ of the above solution of mixed anhydrides were added 34.15 mg of pure sulfoxide from Example 14 with stirring. A few minutes later 54.0 μΐ of 2,6-lutidine were added and the reaction was allowed to stir at RT / N2 for 17 hours.

The liquid anhydrides were removed under reduced pressure and the remaining residue was extracted (4 times with CHCl 3). The extracts of CHCl3 were washed subsequently with dilute HCl; 5% NaHCO 3 solution 3 times; 3 times with H2 0; and finally with saturated NaCl solution, and then dried over MgSO 4, and the solution was evaporated to dryness in vacuo to provide 42.1 mg of crude product. The crude product from Step A was purified by chromatography on silica gel using 95: 5 (CHCl3 -acetone) as the eluent and then crystallizing the solid obtained from EtOAc.

to provide 17.8 mg of the above title compound as crystals, m.p. 235-236 ° C (dec.).

Anal. Calc. for H2 O: C, 68.57; H, 7.40; N, 2.86;

Found: C, 69.02; H, 7.39; N, 2.73. FAB calc'd for CoHH0ONSS: 482; Found: 482. 1 H NMR (proton) was according to the structure of the indicated product. EXAMPLE 16 Synthesis of 17β- (4-mercaptobenzoyl) -4-aza-5α-androst-1-en-3-one 40.0 mg of the acetoxy-methyl thio derivative of Example 15 were suspended in 3.0 ml of isopropanol. The reaction mixture was flushed several times with N 2 and under vacuum and the system was maintained under a nitrogen atmosphere. To the above mixture was added 40.0 mg of K 2 CO 3 in 2.00 ml of water (without oxygen) by means of and the reaction temperature was allowed to rise to 80øC under gentle reflux under slight vacuum for 10 minutes, and then under N 2 for 1 hour.After 1 hour, the reaction mixture was a clear yellow solution. cooled to 0-5 ° C and quenched with 2.5% HCl acid (Ν 2). The reaction mixture was extracted 4 times with CH 2 Cl 2. The organic layer was washed with H 2 O 4 times 3 times with saturated saline , and finally dried over MgSO 4 · Filtered and evaporated to dryness in vacuo to afford 36.9 mg of crude product cr The crude product was dissolved in 2.0 ml CHCl3, filtered through Teflon (Acrodisc CR) and purified by preparative HPLC on silica gel and eluted with (CH 2 Cl 2 -acetone) 60:40. Crystallization from EtOAc provided a single spot material, 20.7 mg of the title compound, m.p. 285-286 ° C. 190

Anal. Calc. Calc'd for C 25 H 312 N 2 N 2 úH 2 O: C, 72.19; H, 7.69; N, 3.24; Found: C, 71.82; H, 7.43; N, 3.26. FAB: Calc. for C25 H31 N2 OS: 410; EXAMPLE 17 Synthesis of 17-BM-dimethylaminobenzoyl) -4-aza-5-a-androst-1-en-3-one To a suspension of 291.0 mg of activated magnesium turnings dried at 8, 0 ml of dry THF was added 800.0 mg of 4-bromo-N, N-dimethylaniline in 2.0 ml of dry THF under Ν 2. The reaction was run in an ultrasonic bath with a temperature range of 24-30 ° C . To the well stirred mixture was added dropwise 30 ml of 1,2-dibromoethane / N2. The reaction was allowed to continue for 11/2 hours at 28 ° C / N2. The Grignard reagent concentration was 4.0 mmol in 10.0 mL dry THF. The steroid of Example 2 (205 mg of pyridyl thioester) was suspended in 2.0 ml of dry THF, cooled to -80 ° C and 3.8 ml of the above Grignard reagent (3 equivalents) were added via a syringe to the steroidal suspension for 5-10 minutes / N2. The reaction was allowed to proceed for 1 hour at -80øC / N and then at -10øC for an additional 1 hour / N2. The solution was diluted with 10 , 0 ml of methylene chloride and quenched with a saturated aqueous solution of NH 4 Cl to pH = 4. The organic layers were separated, washed 3 times with water, 3 times with saturated sodium chloride, dried over MgSO 4, filtered, and evaporated in vacuo to provide 151.3 mg of crude product. Crystallization from ethyl acetate gave 124.5 mg of the title compound, m.p. 268.5-269 ° C. FAB: Calc. Î »0: 421; Found; 421. 27 36 2 2 191

NMR (protonic in CDCl3) confirmed the indicated structure. EXAMPLE 18

General Process for Preparing Protected Silyl Derivatives 1.0 mole of phenol or its derivatives, or 1 mole of alcohol is treated with 1.5 liters of dry methylene chloride. 3.0 mol of imidazole / N 2 is added to the clear solution. The clear solution is cooled to 0øC / N 2, and 2.0 moles of t-butyl are added dropwise at 0øC / N 2 dimethyl chlorosilane in 300.0 ml of dry methylene chloride. At the end of the addition, precipitation occurs, the ice bath is removed, and the reaction is allowed to proceed overnight at RT / N2. Filtrate, wash the mass with cold CH 2 Cl 2 solution, and the solvent is evaporated under vacuum to provide the crude product. The crude product was purified rapidly by filtration through a silica gel column. (1 g of crude product per 100 g of silica gel, using CH 2 Cl 2 as eluent). This method gives about 99% pure silyl derivatives of phenols and alcohols. EXAMPLE 19 Synthesis of 17-B- (4-Hydroxybenzoyl) -4-aza-5-O-androst-1-ene-3-one A. Gricnard Reaction To a suspension of 1.22 g of active magnesium After drying in 20.0 ml of dry THF was added 5.6 g of 1-bromo-4- (butyl tertiary dimethylsilyloxy) benzene (prepared from p-bromophenol by the general procedure described in detail above) 0 ml THF under Ν2. The reaction was run in an ultrasonic bath at a temperature ranging from 24-30 ° C. À 192

150 μl of 200 μl of 1,2-dibromoethane / N2 was added dropwise. The reaction was allowed to continue for 1-1 / 2 hours at 28 ° C / N2. The concentration of the Grignard reagent formed was of 19.5 mmol in 30.0 mL of dry THF. The steroid from Example 2 (1.02 g, 2.49 mmol) was suspended in 20.0 mL of dry THF, cooled to -80 ° C and the above prepared Grignard reagent (11.5 mL) was added by syringe to the steroidal suspension in 5-10 minutes / N 2. The reaction was allowed to proceed for 1 hour at -80øC / N2, and then at -10øC for an additional hour / N2. The reaction solution was diluted with 10.0 mL of methylene chloride and quenched with saturated aqueous NH4 Cl solution to pH = 4. The organic layers were separated, washed 3 times with H 2 O, 3 times with saturated sodium chloride, dried over MgSO 4, filtered, and evaporated in vacuo to a yellow solid. Crystallization from ethyl acetate provided 607 mg of product, m.p. 248-249 ° C.

Anal. Calc. Calc'd for C 20 H 30 N 3 O 3. H, 8.93; N, 2.75

Found: C, 73.27; H, 8.99; N, 2.75. FAB: Found 508; Cale 508. B. De-silting

1.3 g of product from the above-mentioned step A were dissolved in 20.0 ml of dry THF. Cooled to -5 ° C and 437 μl of glacial acetic acid / N2 was added. To the cold solution at -5 ° C was added via syringe 3.0 ml of

tetra-n-butylammonium bromide dropwise under an atmosphere of N. The reaction was allowed to continue under stirring for 11/2 to 2 hours at 0Â ° to -5Â ° C / N2. The reaction mixture was poured into a

A mixture of 2 layers of a saturated solution of ethyl acetate / sodium bicarbonate at 0 ° C. The water layer was separated and further extracted with EtOAc 3 times and with CH2 Cl2 (3 times).

The organic layers were combined, washed 3 times with H 2 O, 1 with saturated sodium chloride solution, and dried over MgSO 4, filtered and evaporated to dryness in vacuo. The crude product was crystallized from ethyl acetate to afford 977.9 mg, and was subsequently recrystallized from methanol to provide 842.3 mg of the title product, m.p. 296-297 ° C.

Anal. Calc. Calc'd for C 25 H 31 N 3 O 3 · 1 - 3 H 2 O: C, 75.15; H, 7.98; N, 3.51.

Found: C, 75.13; H, 7.76; N, 3.54. (Specific mass) FAB: Found 394; Calc. 394. EXAMPLE 20 17β- (3,5-dimethyl-4-hydroxybenzoyl) -4-aza-5α-androst-1-ene-3-one A. Preparation of Griqnard Reagent To a suspension of 260.0 mg of activated magnesium chloride in 6.0 ml dry THF was added 628.0 mg of 1-bromo-3,5-dimethyl-4-tertiarybutyl-dimethylsilyloxybenzene (prepared from 4-bromo-2,6-dimethylphenol by The reaction was conducted in an ultrasonic bath at a temperature ranging from 24 DEG-30 DEG C. To the well-stirred mixture was added dropwise 40 ml of 1,2- The concentration of the Grignard reagent thus formed was 2 mmoles in 10.0 ml of dry THF The steroid of Example 2 (205.0 mg (0.5 mmoles) was suspended in 3.0 mL of dry THF, cooled to -80 ° C, and 7.5 mL (1.50 milieq.) of the above prepared Grignard reagent were introduced through a syringe into the steroidal suspension for one period of 5 The reaction was allowed to proceed for 1 hour at -80øC / N2 and then at -10øC for a further one hour / N2. The reaction was quenched with 1N HCl, then diluted with chloroform. The organic layers were combined, washed 3 times with H2 O, 3 times with saturated sodium chloride and dried over MgSO4, filtered and concentrated under vacuum. The crude residue was washed with ether to provide 121.7 mg of product. The crude product was dissolved in 70:30 (CHCl3 -acetone), filtered through Teflon (Acrodisc CR) and purified by preparative HPLC (Waters Prep-pak) on silica gel eluting with (CHCl3 -acetone) 70 : 30. The major component was recrystallized from ethyl acetate to give 52.0 mg of product, m.p. 245-245.5 ° C.

Anal. Calc. for CH OH NSNO:: C, 73.96; H, 9.23; N, 2.61; Found: C, 74.06; H, 9.33; N, 2.64 (Mass Spectrum) FAB: Found: 536; Calc .: 536 B. Unblocking the Silyl Derivative

54.0 mg of the previous product were dissolved from A in dry THF (1.3 ml). The clear solution was cooled to 0 ° C, and 29 μl of glacial HOAc was added via syringe / N2. To the above solution was added dropwise 195

%

172 μl of tetra-n-butylammonium fluoride at 0 ° C was added dropwise via syringe / N 2. The reaction was allowed to proceed at 0 ° C / N 2 for 1 1/2 hours. The reaction mixture was poured into ice / saturated NaHCO 3 solution and EtOAc, and stirred for several minutes. The layers were allowed to separate, and the H2 O layer was extracted 3 times with EtOAc and 3 times with CHCl3.

The organic layers were combined and washed 3 times with H 2 O, then 3 times with saturated NaCl, then dried over MgSO 4, filtered and evaporated to dryness in vacuo to provide 52.2 mg. The product was crystallized from EtOAc to give 22.5 mg of the title product above, m.p. 305-306 ° C.

Calc. Calc'd for C 27 H 30 N 3 O • H 2 O: C, 73.77; H, 8.49; N, 3.10 Found: C, 73.62; H, 7.90; N, 3.44. (Mass Spectrum) FAB: Calc. 422; EXAMPLE 21 Synthesis of 17β- (4-methoxybenzoyl) -4-aza-5-a-androst-1-en-3-one A. Grianard Reaction To a suspension of 258.0 mg of activated Mg dried in 8.0 mL of THF / N 2 was added 748.0 mg of p-bromo-anisole in 2.0 mL of dry THF. The reaction was run in an ultrasonic bath at a temperature ranging from 24-30 ° C. To the well stirred mixture were added dropwise 30.0 μ of 1,2-dibromoethane as a catalyst. The reaction was allowed to proceed for 1-2 hours at 28 ° C. The formed Grignard reagent had a concentration of 4 mmol in 10.0 μΐ dry THF. The steroid of Example 2 (205.0 mg (0.50 mmol) was suspended in 2.0 mL of THF, cooled to -78 ° C and the above Grignard reagent (3.75 mL, 14 mol. Equivalent) was added by syringe to the steroidal suspension for 5-10 minutes / N 2 and then at -10 ° C for an additional 1 hour / N 2. The resulting reaction mixture was a clear solution, which was cooled to 0-5 ° The organic layers were separated, washed with H 2 O 2, then saturated NaCl solution, dried over MgSO 4, filtered and evaporated under vacuum. The crude product was dried over sodium sulfate and evaporated under vacuum. washed with ether, and crystallized from EtOAc to give 110 mg of product, mp 305-306 ° C.

Further purification was performed by chromatographic isolation on a TLC plate (20 cm x 20 cm x 1000 mm), using as eluent, (CHCl 3): 70:30. The above product, mp 305-306 ° C (dec.) (Mass Spectrum) FAB: Calc .: 408: Found 408. EXAMPLE 22 Synthesis of 17β- (3-hydroxybenzoyl) -4-aza-5α-androst -1-ene-3-one A. Preparation of Grignard Reagent To a suspension of 230.0 mg of activated Mg shavings dried in 2.0 ml of dry THF was added 722.4 mg of 1-bromo- 3-tert-butyl dimethylsilyloxybenzene (prepared from 3-bromophenol by General Procedure above) in 8.0 ml dry THF / N2. The reaction was run in an ultrasonic bath at a temperature ranging from 24-300C / N2. To the well stirred mixture were added dropwise 20.0 μl of 1,2-dibromoethane / N2. The reaction was allowed to proceed for 2-1 / 2 hours at 280 ° C. The Grignard reagent formed had a concentration of 2.52 mmol in 10.0 mL of dry THF. The steroid of Example 2 (205.0 mg (0.5 mmol) was suspended in 2.0 mL of THF, cooled to -78 ° C and the above Grignard reagent (6.0 mL, (1.5 ' milliequivalents) was added via syringe to the steroidal suspension for 5-10 minutes / N 2 and then stirred for an additional hour at -10 ° C / N 2. The clear reaction mixture was quenched from 0 to 5 The combined organic layers were washed 3 times with H 2 O, 3 times with saturated NaCl, then dried over MgSO 4, filtered and concentrated in vacuo to provide the crude product. The product was purified on a silica gel column and eluted with (CHCl3 -acetone) 70:30. The desired product had an amount of 58.0 mg, as the silyl derivative, 178- (3-tertiary butyl 4-methyl-4-aza-5Î ± -androst-1-en-3-one B.Blocking 57.6 mg of the above silyl derivative were d dissolved in 3.0 mL of dry THF. The solution was cooled to 0 ° C, and 20 μΐ glacial acetic acid was introduced through a syringe. To the clear solution was added 130.0 μΐ of (n-butyl) N, NF by syringe, and the reaction was allowed to continue for 1 hour / N at 0 ° C. The reaction mixture was poured into a saturated solution EtOAc / NaHC03 @ 0 ° C. Layer 198

The aqueous phase was separated, extracted 3 times with EtOAc, and then 3 times with chloroform. The organic layers were combined and washed 3 times with H 2 O, 3 times with saturated NaCl solution, dried over MgSO 4, filtered and evaporated in vacuo to give 57.11 mg of crude product. The crude product was TLC chromatographed (one 20 cm x 20 cm x 250 μl silica gel plate), eluted with (CHCl3 -acetone) 70:30 to provide 44.5 mg of the title product above. Recrystallization from EtOAc gave 29.30 mg, m.p. 279-280 ° C.

Anal. Calc. Calc'd for C 25 H 31 N 3 &gt; 3: 8: 20: C, 73.60; H, 8.06; N, 3.43.

Found: C, 73.26; H, 8.22; N, 3.28. (Mass spectrum) FAB: Calc .: 394; Found 394. Synthesis of 17β- (4-hydroxymethyl-benzoyl) -4-aza-5α-androst-1-en-3-one A. Preparation of Griqnard solution To a suspension of 100.0 mg (4 mmol) of dried activated Mg shavings in 5.0 mL dry THF / N 2 was added 753.0 mg (2.5 mmol) of 1-bromo-4-tertiarybutyl dimethylsilyloxy methyl benzene The reaction was conducted in an ultrasonic bath at a temperature ranging from 24-30 ° C / N 2. To the well stirred mixture was added 20 μl of 1,2-dibromoethane / N 2. The reaction was allowed to proceed for 2 hours at 28 ° C / N 2. The concentration of Grignard reagent formed was 2.5 mmol in 5.0 mL of dry THF.

Β. Gricmard reaction &quot; '&quot; The steroid of Example 2 (205.0 mg (0.5 mmol) was suspended in 2.0 mL of THF, cooled to -78 ° C, and the Grignard reagent prepared above (3.0 mL, 3.75 milliequivalents) was introduced via a syringe into the steroidal suspension for 5-10 minutes / N 2. The reaction was allowed to proceed for 1 hour at -80 ° C / N 2, and then an additional hour at -10 ° C / N 2. The clear reaction solution was quenched with saturated NH4 Cl at 0 ° to -5 ° C and then diluted with CH2 Cl2. The organic layers were separated and washed 3 times with water, 3 times with saturated NaCl, dried over MgSO 4. The crude product was crystallized from EtOAc to give 137.8 mg of silyl product. (Mass Spectrum) FAB: Calc'd for C 31 H 41 N 3 O 3: 521.75 Found: 522 The product of the above-mentioned Step B (23.67 mg) was dissolved in 0.5 ml of THF and 0.5 ml of MeOH and cooled to -78øC. tea 0 ° C / N. To the cold solution was added 10 μl of concentrated sulfuric acid (98%). The reaction was stirred for 45 minutes at 0 ° C / N2. To the cold solution at 0 ° C was slowly added a saturated solution of NaHCO 3 and chloroform. Extraction 3 times with CHCl 3 · The organic layers were washed 3 times with water, 3 times with saturated NaCl, the solution was dried over MgSO 4, filtered and evaporated to dryness in vacuo to provide 10.18 mg. After chromatography on a TLC plate (elution with 1: 1 CHCl:: acetone) the crude product was crystallized from EtOAc to give 6.0 mg of the title product, m.p. 318-320 ° C.

Anal. Calc. for CO (CH3 OH) 1 / 3H-O:

Z D J or J Z C, 75.41; H, 7.94; N, 3.38. Found: C, 75.61; H, 7.84; N, 3.12. (Mass spectrum) FAB: Calc'd; 408; EXAMPLE 24 Synthesis of 17-B- (4-carboxybenzoyl) -4-aza-5a-androst-1-en-3-one A. Oxidation 90.2 mg of the product of Example 23 were dissolved in 2.63 ml of glacial acetic acid and to make the solution clear 69.0 mg of Cr03 (previously dried over Ρ2.5 at RT for 2 days under vacuum) was added. After stirring overnight, the reaction mixture was diluted with water and left The reaction mixture was filtered and the mother liquor and washings were extracted overnight using a liquid-liquid extractor, (O-EtOAc) under reflux conditions. The organic layer was dried over The residue was dissolved in hot MeOH, filtered and evaporated in vacuo to provide a product weighing 32.0 mg FAB: Calc'd for C 26 H 30 N 4 N 4: 422 /

Found: 422. B. Purification The above free acid was purified by dissolving the above product in 1N sodium hydroxide solution. The clear solution was extracted 3 times with EtOAc. The basic aqueous solution was cooled and acidified with 1N HCl dropwise to pH = 4 with stirring. The reaction mixture was

allowed to age for 1 hour at 0 ° C. It was filtered and the residue was washed with cold water and dried overnight at 100 ° C under vacuum pressure &lt; 0.2 mm. The free acid yield of the above-mentioned title was 9.85 mg. FAB: Calc. for C25H3104N: 422; Found 422. NMR analysis indicated the product was an acid. C. Acid Acid Sodium Salt Referred to 4.9 mg of the above acid product B were dissolved in 2.0 ml of hot methanol. To the clear solution, 11.6 μl of NaHN (aqueous) was added. To the solution after evaporation of methanol under vacuum, water was added to reach a pH of 7.21. The aqueous solution was freeze-dried to give 6.3 mg of the sodium salt of the title product above. EXAMPLE 25 Synthesis of 17β- (4-hydroxyethylbenzoyl) -4-aza-5α-androst-1-en-3-one A. Griqnard Reagent To a suspension of 252 mg of activated Mg shavings dried in 10 , Tert -butyl dimethylsilyloxyethyl benzene (prepared from 2- (p-bromophenyl) ethanol by the general procedure described above) was added to 0 ml of dry THF and 1.26 g (4 mmol) of 1-bromo-4- The reaction mixture was vigorously shaken using an ultrasonic / N 2 vibrator. To the well stirred mixture was added 40 μl of 1,2-dibromoethane to catalyze the above reaction The reaction was allowed to proceed for 3-1 / 2-4 hours / N2 · 202

The concentration of the Grignard reagent formed was 4 mmol in 10 mL of THF. B. Grignard Reaction 205.0 mg (0.5 mmol) aza-steroid from Example 2 were suspended in 2.0 ml dry THF / N 2, cooled to -80 ° C, and the above prepared Grignard reagent (3, 75 ml, 1.5 milliequivalents) by syringe was introduced into the steroidal suspension for 5-10 minutes / N2. The reaction was carried out at -80 ° C for 1 hour / N and then for an additional hour at -10 ° C. The reaction was quenched with saturated NH4 Cl solution at 0-5 ° C and diluted with 10.0 mL of CH2 Cl2. The organic layers were washed with water (3 times), saturated NaCl solution (3 times), dried with MgSO 4, filtered and evaporated in vacuo to dryness. The crude product was crystallized from EtOAc overnight to give 152.0 mg of product m.p. 233-234 ° C. Anal. Calc. for C 19 H 13 N 3 O 4 N 4: 1 H 4 O: o J 4 and J Δ C, 73.55; H, 9.18; N, 2.59.

Found: C, 73.45; H, 8.94; N, 3.21 FAB: Calc. 536; Found: 536 C. Desalting 70.8 mg of product from Step B were dissolved in 1.45 ml of methanol and 1.45 ml of THF. The solution was cooled to 0-5 ° C and 29 μl of concentrated H2 SO4 was added via syringe under N2. The reaction was allowed to cool at 0 ° C with saturated NaHCO 3 solution and extracted 3 times with CH 2 Cl 2. The organic layers were separated, washed with water (3 times ), and then with NaCl solution, dried over MgSO 4, filtered and evaporated in vacuo to give 43.0 mg of 203

product. The crude product was placed on a silica gel column and eluted with 1: 1 acetone-CH₂Cl₂. The isolated product was crystallized from anhydrous methanol to provide 20.0 mg of the title product, m.p. 292-293 ° C with decomposition.

Anal. Calc. for C27H3503N.1 / 4C, 75.31; H, 8.25; N, 3.25.

Found: C, 75.49; H, 8.29; N, 3.45. FAB: Calc. 422; Found: 422. Synthesis of 17β- (4-carboxymethylbenzoyl) -4-aza-5α-acrost-1-en-3-one A. Oxidation 13.0 mg of the product of Example 25 were dissolved in 1 ml of glacial acetic acid. To the clear solution was added 10.0 mg of CrCl 3 (previously dried over P2 O5, v / v) and the reaction allowed to proceed overnight at RT, then at 0 ° C for 48 hours. The crude product was isolated, washed with cold water and dried under vacuum at 110 ° C under a pressure below 1 mm. The dried crude product was dissolved in water The organic layers were separated, and the basic aqueous solution was cooled and acidified with 1.5N hydrochloric acid.The precipitate was filtered, washed with water and dried at 110 ° C under vacuum under a pressure of 0.1 mm.

Yield of above titled product = 7.0 mg. FAB Calc. C27 H33 NO4: 436; Found: 436. Synthesis of 17β- (3,4-dihydrobenzoyl) -4-aza-5α-androst-1-en-3-one A. Grignard To a suspension of 258.5 mg of dry activated magnesium turnings in 10.0 ml of dry THF was added 482 mg. of 4-bromo-1,2-methylenedioxybenzene / N2. (The starting material is commercially available from Aldrich Chemical). The reaction was conducted in an ultrasonic water bath at a temperature ranging from 24 ° -30 ° C. To the well-stirred mixture 40 μΐ of 1,2-dibromoethane was added as a catalyst, the reaction was allowed to proceed for 1 1/2 hours at 28 ° C / N 2. The concentration of the Grignard reagent formed was 3.75 mmol in 10 mL dry THF. The steroid of Example 2 (410 mg, 1 mmol) was suspended in 4.0 mL of dry THF / N2 and cooled to -80 ° C and 8.0 mL of the above prepared Grignard reagent (3.04 milliequivalents) were added via from a syringe to the sterile / N2 suspension over a period of 5-10 minutes. The reaction was allowed to proceed for 1 hour at -80 ° C, and then at -10 ° C for a further 1 hour / N2. The reaction mixture was diluted with CH2 Cl2, then cooled with 1N HCl at -5 ° C.

The organic layers were collected and washed with water three times, saturated NaCl solution 3 times, dried over MgSO 4, filtered and evaporated in vacuo to dryness. A 205

purification of the crude product was performed on 50.0 g of silica gel using 1: 1 as eluant (CH 2 Cl 2 -acetone) to give 347.0 mg. FAB revealed 422; Calc. 422. 62.4 mg of the above product was crystallized from EtOAc to afford 11.39 mg of product, m.p. 324-325 ° C.

Anal. Calc. for C .. OH₂O: N 3/4H 0O:

Z O 4, C, 71.78; H, 7.53; N, 3.22.

Found: C, 71.90; H, 7.54; N, 3.25. FAB for C 20 H 13 N 2 O: N: 422; Calc .: 422. Z 4 B. Cleavage of the Methylene Group Dioxylan 70.0 mg of the product of Step A were dissolved in 25.0 ml of dry 1,2-dichloroethane at ΤΑ / / Ν 2. The solution was cooled to -10 ° C, and 1.03 ml BBr 3 (1.0M solution in dichloromethane) were added dropwise under N 2

The reaction was allowed to proceed at RT for 3-1 / 2-4 hours / N2. After 4 hours / N2, the reaction was cooled to -10 ° C and quenched with 10.0 ml of methanol for 10 minutes at 0 ° C ° C, and then gradually the temperature was allowed to rise to Τ.Α / Ν 2 · A

The reaction mixture was evaporated in vacuo to dryness. The residue was extracted 3 times with EtOAc. The organic layers were washed with water 3 times, 2 times with saturated NaHCO 3 solution, 3 times with water and finally with a saturated NaCl solution. The organic layers were dried over magnesium sulfate, filtered and concentrated under vacuum. The crude material was chromatographed on 2 plates of silica gel (20 cm x 20 cm x 20 cm x 250 mm) eluting with (acetone-methylene chloride). Recrystallization from EtOAc provided 5.0 mg of the title product, m.p. 222-222.5Â ° C.

Anal. Calc. Calc'd for C25 H31 N4 Nâ € ¢ 1/2 H 2 Oâ € ¢ C, 71.78; H, 7.66; N, 3.35 Found: C, 71.71; H, 7.71; N, 3.33 FAB: Calc'd. for C25 H31 N4 O4: 410. Found: 410. A. Synthesis of 17β- (2-methoxybenzoyl) -4-aza-5Î ± -androst-1-ene-3-one A. Griconard To a suspension of 258.0 mg of dried activated magnesium turnings in 8.0 mL of dry THF was added 771.0 mg of o-bromoanisole in 2.0 mL of dry THF / N. The reaction was conducted in an ultrasonic water bath with a temperature range of 24-30 ° C. To the well stirred mixture was added 30μl of 1,2-di-bromoethane / N2, and the reaction was allowed to proceed for 2 hours at 28 ° C / N2. The concentration of the Grignard reagent formed was 4 mmol in 10.0 mL of dry THF. The steroid of Example 2 (205 mg, 0.5 mmol) was suspended in 2.0 mL of dry THF / N2, cooled to -79 ° C, and 4.0 mL of the above prepared Grignard reagent (1.6 milliequivalents) were added by syringe to the sterile / N2 suspension over a period of 5-10 minutes. The reaction mixture was allowed to proceed for 1 hour at -80 ° C, then at 0-2 ° C for an additional 1/2 hour. The reaction mixture was diluted with CH 2 Cl 2 and then quenched with 1N HCl solution at 0 ° C.

The organic layers were combined, washed 3 times with water, 3 times with saturated NaCl solution; and dried over MgSO4. They were filtered and evaporated in vacuo to dryness. The crude material was crystallized from EtOAc to give 124.5 mg of product m.p. 228-230 ° C. Purification of the silica gel column using (CHCl 3 -acetone) 70:30 gave a single spot of material in a yield of 83.0 mg, m.p. 241-241.5.

Anal. Calc. Calc'd for C 26 H 33 N 3: C, 76.91; H, 8.19; N, 3.45 Found: C, 76.36; H, 8.26; N, 3.35. FAB calc. for C 26 H 33 N 3: 406; Found: 406. B: Methoxy group cleavage 12.7 mg (0.03 mmol) of the product of Step A were dissolved in 5.0 ml of dry methylene chloride / N2. To the clear solution at -79 ° C / 50 μΐ of 1 mmol / ml BBr 3 in CH 2 Cl 2 was added via syringe dropwise. The reaction was allowed to continue at RT overnight / N2 with rapid stirring. The next day a clear yellow solution was obtained. The reaction mixture was cooled to 0-2 ° C and quenched with water to hydrolyze excess BBr 3. The organic phase was washed three times with dilute sodium hydoxide, 3 times with water, 3 times with dilute HCl, 3 times with water, 3 times with saturated NaCl solution, and the organic layer was dried over MgSO 4. This layer was filtered, concentrated in vacuo to dryness. The crude product crystallized from EtOAc to provide 7.0 mg of a single spot material consisting of 17β- (2-hydroxymethyl-benzoyl) -4-aza-5-androst-1-en -3-one. FAB for C 25 H 31 N 2 O 2: Calc'd 394; Found: 394. EXAMPLE 29 17β- (α-hydroxybenzyl) -4-aza-5α-androst-1-ene-3-one 570 milligrams of 17β-benzoyl-4-aza-5α-androst- (prepared from the thiopyridyl ester of Example 2 and commercially available phenyl magnesium bromide, analogously by the procedure of Example 5, to yield the 17-benzoyl derivative, mp 295-296 ° C crystallized from EtOAc) were suspended in 80 ml of anhydrous isopropanol. To the suspension was added 500.0 mg NaBH 4 in 5 portions. Once all the hydride was added, 20.0 ml of dry THF was carefully added, so that the reaction mixture became a clear solution. The reaction was allowed to proceed to T.A./N2 overnight. The reaction was quenched cautiously with 1N HCl and allowed to stir under N 2 for one additional hour at RT. The reaction was then diluted with water and extracted three times with CHCl 3. The organic layers were combined, washed 3 times with H2 O; 3 times with saturated NaCl solution, and dried over MgSO 4 &gt; They were filtered and evaporated to a white solid weighing 495.0 mg. The crude material was recrystallized from EtOAc to provide 349.5 mg of material. Subsequent purification on a silica gel column using 70:30 eluent (CHCl 3 -acetone) gave single spot material of the title compound, m.p. 296-297Â ° C.

Anal. Calc'd for C 18 H 13 NO 2: C 25.32 C, 79.17; H, 8.78; N, 3.70.

Found: C, 79.24; H, 8.85; N, 3.48. FAB Calc. for C 25 H 33 NO 2 380. Found: 380. Found: 380. EXAMPLE 30 17β-Hydroxymethyl-4-aza-5α-androst-1-ene-3-one 500.0 mg of 209

S-2-pyridyl-3-oxo-4-aza-5Î ± -androst-1-ene-3-one (Example 2) were dissolved in 40.0 ml of dry THF at r.t./Ng. The solution was cooled to -78 ° C / N2 and 5.5 ml of 1 M dibutyl aluminum hydride in THF was added slowly via a syringe to the rapidly stirred solution. The reaction was allowed to continue at -76 ° C and -78 ° C for 1/2 hour under Ν2. The temperature was brought to RT until the reaction mixture was maintained for 2-1 / 2 hours / N2. then quenched at 0 ° C with 2N HCl acid, then diluted with CHCl3. The organic layers were separated, washed with H 2 O 3 times, then saturated NaCl solution, and finally dried over MgSO 4. The filtrate was filtered and the organic phase was evaporated in vacuo to give 216.0 mg of crude product. The crude product was chromatographed on 20.0 g of E.M. silica gel column using (CHCl3 -acetone) 70:30) as the eluent. The yield of the single-spot material was 126.3 mg of the title compound, m.p. 271-271.5 ° C. Calc. Found: 304. NMR in CDCl3 confirmed the above structure. EXAMPLE 31 17β-Formyl-4-aza-5Î ± -androst-1-ene-3-one

In a dry flask of 100.0 ml were placed 1.3 ml of oxalyl chloride (2M in CH2 Cl2) with 50.0 ml of dry CH2 Cl2 / N2> The above solution was cooled to -78 ° C and 338 μl of DMSO were added dropwise via syringe. The mixture was stirred at -78 ° C / N 2 for 30 minutes, and a solution of the alcohol above prepared from Example 15, i.e. 17β-hydroxymethyl-4-aza-5α-androst-l-ene-3- one (256.9 mg in 15.0 ml dry CH 2 Cl 2 / N 2 was added via syringe) The reaction was allowed to proceed for one hour at -78øC / N 2 After one hour at -78øC, was added 1 ml of dry triethylamine at a rapid rate.The reaction temperature was slowly raised to RT / N2 with stirring, whereupon the resulting yellow solution was poured into 50.0 ml of cold water.The organic layers were washed with dried over MgSO4, the solvent evaporated under vacuum to give 172.4 mg of crude product The crude product was chromatographed on a column of 60% NaCl, 0 g of silica gel using (CHCl 3 -acetone) 70:30 to give a single spot material. Crystallization from EtOAc affords or the title compound, 37.7 mg, m.p. 258-259 ° C. EXAMPLE 32 Synthesis of diastereoisomeric 17β- (4-hydroxybenzyl) -4-aza-5α-androst-1-ene-3-ones 26.3 g of the formyl derivative prepared above (from Example 31) were dissolved in 7.0 ml of dry THF / N 2. The solution was cooled to -78 ° C / N 2, and 131 μl of phenyl magnesium bromide (Aldrich's reagent) (0.393 milliequivalents) in dry THF was added dropwise via syringe / N2. The reaction was allowed to proceed for 1 hour / N2 at -78 ° C and then at RT for an additional hour / N2. The reaction was quenched at 0-5 ° C with 2.5N HCl, then diluted with CHCl3. The organic layers were separated, washed 3 times with water; 3 times with saturated NaCl solution, dried over MgSO 4. Filtered and evaporated in vacuo to dryness to provide 28.6 mg of crude product. Analysis of the NMR spectra and peak heights from HPLC indicated that this product was a 1: 1 mixture of diastereoisomers. The crude product was filtered through a 1 æl Teflon filter and purified by HPLC on a Whitman Portisil 10 column using (CHCl 3, Î ± -acetone) 70:30. The FAB mass spectrum indicated the same M +1 for both isomers, being units of mass 380. The isomer eluting more rapidly, mp 289-289.5 ° C, was crystallized from EtOAc and revealed a single material spot on TLC.

Anal. calc. for C25H33NC> 2 * 1/4 H2O; C, 78.39; H, 8.81; N, 3.65.

Found: C, 78.11; H, 8.65; N, 3.58. The isomer eluting more slowly, m.p. 300-301Â ° C revealed a single spot material on TLC. The faster isomer was found by NMR (CDCl3): CH3 to C-18 was deprotected # (0.895) compared to a slower isomer CH3 to C-18 to (0.695). The benzylic proton for the faster isomer was also deprotected (4.55) versus (4.955). The C-1 olefinic proton revealed deprotection effects for the faster isomer from (6.815) to (6.625). From the previous data, the two isomers revealed distinctly different physical properties. CHAPTER 3 EXAMPLE 1

Preparation of 4- (2-f] -carboxyundecanoylamino) phenoxy) butyric acid

Step A: Ethyl 4- (2-nitrophenoxy) butyrate (3) To a stirred solution of 2-nitrophenol (1.4 g, 10 mM) and 212

4-bromobutyrate (2.1 g, 1.57 ml, 11 mM) in 35 ml of dry acetone was added 2 g (14.5 mM) of anhydrous milled potassium carbonate. The resulting colored mixture is then heated under a nitrogen atmosphere under gentle reflux until the color due to the phenol anion dissipates and a yellow mixture remains. Concentration of the cooled and filtered mixture affords an oil which by flash chromatography (silica gel, ethyl acetate / hexane or methylene chloride as eluant) affords 2.4 g (96% yield) of the title compound (3) in the form of an oily liquid. When substituted ortho-nitro-phenools are used in place of 2-nitrophenol in the above example, the corresponding substituted 2-nitrophenoxybutyrate is obtained. Similarly, when ethyl 4-bromobutyrate is substituted by other halo esters the corresponding 2-nitrophenoxyalkanoate is obtained.

Step B: Ethyl 4- (2-aminophenoxy) butyrate (4)

A solution of 3 (1.27 g, 5.0 mM) in 15 mL of ethyl acetate containing 200 mg of 5% palladium on carbon is reacted under a hydrogen atmosphere (40 psig) at room temperature until liberation ceases of hydrogen. The mixture is then filtered and concentrated in vacuo to provide 1.0 g of (4) as a low melting point oil / solid.

Step C: 12- (Isopropylthio) dodecanoic acid (6)

A mixture of 12-bromododecanoic acid (5) (0.558 g, 2.0 mM) and sodium isopropylthiolate (1.1 g, 11.2 mM) in 1,2-dimethoxyethane (50 ml) was deaerated (N2 ), heated to 85 ° C (bath temperature), and held at this temperature for 72 hours. The cooled mixture was filtered, the collected solid was dissolved in water and filtered. The stirred solution was acidified with dilute hydrochloric acid, aged, filtered, the solid washed well with water and dried. The product 6 (0.54 g) was obtained as a white solid.

When other haloacids are used in place of 12-bromododecanoic acid in the above example, the corresponding acid (isopropylthio) is obtained.

Similarly, where other mercaptan salts are used in place of sodium isopropylthiolate in the previous example, the corresponding (alkylthio) alkanoic acids are obtained.

Representative of, but not limited to, the acids obtained by this process are: 8- (isopropylthio) octanoic acid 10- (isopropylthio) decanoic acid 10- (ethylthio) decanoic acid 11- (t-butylthio) undecanoic acid 14- (n-propylthio) tetradecanoic acid 9- (methylthio) nonanoic acid

To a solution of ethyl (4) (0.25 g, 1.14 mM) and (6) (DMSO-tetrazolylmethyl) 0.274 g, 1.0 mM) in dry methylene chloride (10 ml) at ambient temperature was added 4-dimethylaminopyridine (0.122 g, 1.0 mM) followed by a solution of N, N'- dicyclohexylcarbodiimide (0.22 g, 1.06 mM) in methylene chloride (1 ml), 3X1 ml washes with methylene chloride. After 2 days, the filtered mixture was concentrated in vacuo and the residue flash chromatographed on silica gel using 15-20% ethyl acetate in hexane as eluant to give product 7 (0.22 g) under argon. form of an oil which solidified rapidly in a short time.

Step E: 4- (2- (12- (isononylthio) dodecanoylaminolfenoxyl) butyric acid (8)

A stirred solution of ester (7) (0.124 g, 0.258 mM) in methanol (10 mL) was treated at ambient temperature under a nitrogen atmosphere with 2.5 N sodium hydroxide solution (0.6 mL). Methanol (2X2) was used to make the mixture transparent, and the reaction was allowed to continue until TLC analysis showed no ester remained. The filtered mixture was concentrated in vacuo and the obtained residue was stirred with water (30 mL). After aging, the mixture was filtered (the filter cake is the sodium salt of the product) (100 mg), and the stirred filtrate is acidified with dilute hydrochloric acid, aged, filtered, washed with water and dried to give product 8 (0.02 g) as a white solid. Mp 82-84 ° C, with softening from 66 ° C.

Treatment of 8 with NaIC> 4 as in Step Ja will yield the corresponding sulfoxide, and treatment of 8 with m-chloroperbenzoic acid with Step will yield the corresponding sulfone.

Step F: 4- (2- (12- (Isopropylthio) dodecanoylamino) phenoxy) butyramide (9)

To a stirred solution of (7) (20 mg, 0.041 mM) in methanol (10 ml) is added methanol saturated with ammonia (5 ml) and the capped mixture is allowed to stir at room temperature until TLC analysis reveals that it remained little or no (D). Concentration of the reaction mixture followed by preparative plate chromatography (silica gel, 3% methanol / methylene chloride as eluant) affords product 9 (11 mg) as a waxy solid.

Step G; Ethyl 4- (2-aminophenylthio) butyrate (11) To a stirred (N2) deacetylated solution of 2-aminothiopholol (10) (1.25 g, 10mM) and ethyl (2, 1 g, 1mM) in 40 ml of dry 1,2-dimethoxyethane is added 8.3 g of solid ground anhydrous potassium carbonate, the resulting mixture being deaerated 3X under nitrogen and allowed to stir at room temperature until TLC The filtrate was then concentrated and the residue flash chromatographed on silica gel (85 g) using 15% ethyl acetate / hexane as eluant to give 1.8 g of (11) as a light-colored oil.

Step H; Ethyl 4- (2- (10- (isopropylthio) decanoylamino) phenylthio) butyrate (12)

When (11) and 10- (Isopropylthio) decanoic are reacted together in a manner analogous to the conditions indicated in the above Step (D), the title compound 12 is obtained.

Step I; 4- (2- (10- (Isopropylthio) decanoylamino) phenylthio) butyric acid (13)

When (12) is hydrolyzed as under the conditions of Step (E), compound 13 is obtained.

Step J: 4- (2- (11- (ethylsulfinyl) undecanoylamino) phenoxy) butyric acid '

When the indicated esters or acids are treated with sodium metaperiodate (Step J &amp;) in a suitable solvent (eg acetone / water) the corresponding sulfoxides are obtained, treatment with meta-chloroperbenzoic acid (Step Jfa) affords the corresponding sulfones . For example, with ethyl 4- (2- (11- (ethylthio) undecanoylamino) phenoxy) butyrate 14 (0.045 g, 0.1 mM) in acetone (10 ml) is reacted with sodium metaperiodate (0.072 g, 0.33 mM) in water (2 ml) at room temperature the corresponding sulfoxide 15 is obtained. Hydrolysis as in Step (E) affords product 16 as an off-white solid. In addition, treatment of 14 with m-chloroperbenzoic acid will produce the sulfone 17. which provides the acid after hydrolysis using the hydrolysis conditions of Step E. The method for preparing the novel compounds of the present invention, already described above in terms can be further illustrated by the following examples which are not to be construed as limiting the scope or spirit of the present invention. EXAMPLE 2 Synthesis of Ethyl 4- (2- (11-carboxyundecyloxy) phenoxy) butyric acid (7) (Cn 2) 3 COOn- (ck 2) 11ccoh 7 217 - A. Ethyl 4 - [(2-benzyloxyphenoxy) To a stirred solution of 2-benzyloxyphenol (1) (4.0 g, 20 nM) and ethyl 4-bromobutyrate (2) (5.6 g, 28.7 mM) in dry acetone (100 ml) was added carbonate of anhydrous milled potassium (6.0 g, 44 mM) and the resulting mixture was heated under reflux under nitrogen until TLC analysis revealed the absence of the starting phenol. Flash chromatography (silica gel, 15% ethyl acetate / hexane as eluent) of the filtered and concentrated mixture afforded 3.0 g of product (2) as a clear oil.

When the ethyl 4-bromobutyrate is replaced by halo esters in the previous example, the corresponding ether ester is obtained. Similarly, when the above phenol is substituted by other substituted 2-benzyloxyphenois, the corresponding 2-substituted ethers are obtained. Substitution of 2-benzyloxyphenol by 2-benzyloxy or by 2-benzylthio-thiophenol provides the corresponding thioether. B. Ethyl 4- (2-hydroxyphenoxy) butyrate (A)

A mixture of (3.) (11.5 g, 5.0 mM), ethanol (50 ml), glacial acetic acid (7 drops) and 10% palladium on carbon (0.7 g) was reacted in an atmosphere of hydrogen (40 psi) at room temperature until hydrogen evolution ceases. Concentration of the filtered mixture afforded product (4) as an oil. C. Ethyl 4- (2-1- (carbomethoxy) undecyloxyphenoxy) butyrate (6)

When (4) (0.224 g, 1.0 mM) and 218-bromododecanoate

methyl (5) (0.32 g, 1.1 mM) were reacted with potassium carbonate in acetone as in Example (A), the product (6) (0.3 g) was obtained as a colorless oil.

When methyl 12-bromododecanoate is substituted by other halo esters in the above example, the corresponding diester is obtained. D. To a stirred solution of (6) (0.102 g, 0.23 mM) in methanol (4 mL) and water (3 drops) was added a solution of 4- (2-fluoro- 1.5 N sodium hydroxide solution (0.55 mL, 1.37 mM) dropwise, and the resulting mixture was made transparent with additional methanol (2 mL). When TLC analysis (2% methanol in methylene chloride (10 ml) containing glacial acetic acid (4 drops)) indicated no mono- or diester remained, the methanol was removed in vacuo. the residue was stirred with water (10 ml), and the solution was filtered and acidified with 2N hydrochloric acid. Filtration of the resulting precipitate followed by washing with water and drying afforded product 7 (88 mg) as a white solid; M.p. softens at 95 ° C, complete melting at 105 ° C (uncorrected; A.O. Spencer Hot stage).

Calc'd for C 22 H 34 O 6: C, 66.98; H, 8.69.

Found: C, 67.32; H, 8.45.

Compounds (1) - (7) all had NMR and Mass spectral data consistent with their indicated molecular formulas. 4- (2- (11-Carboxyundecetyloxy) phenylsulfinylbutyric acid (7B)

When the thioethers shown, for example, Compound 7A in Flow Sheet C, as ester or acid, are treated with sodium metaperiodate in an appropriate solvent (eg acetone / water) the corresponding sulfoxides are obtained. Similarly, the reaction of the thioethers shown with m-chloroperbenzoic acid provides the corresponding sulfones. For example, when 4- (2- (11-carboxyundecyloxy) phenylthio butyric acid 7A (0.41 g, 1.0 mM) in acetone (25 mM) is reacted with sodium metaperiodate (0.72 g, 3 mM) in water at room temperature, the title sulfoxide 7B is obtained. When the same starting material in methylene chloride is reacted with excess m-chlorobenzoic acid, the corresponding sulfone is obtained.

Compounds (3) - (16) all showed NMR and Mass Spectrum data consistent with their indicated molecular structures. EXAMPLE 3

Preparation of 4- (2-Carboxyundecanoylamino) phenoxy) butyric acid

Step A: Ethyl 4- (2-nitrophenoxy) butyrate To a stirred solution of 2-nitrophenol (1) (1.4 g, 10 mM) and ethyl 4-bromobutyrate (2.1 g, 1.57 ml, 11 mM) in 35 ml of dry acetone is added 2 g (14.5 mM) of anhydrous milled potassium carbonate. The resulting colored mixture is then heated under a nitrogen atmosphere with gentle reflux until the color due to the phenol anion has dissipated and a yellow mixture remains. Concentration of the cooled and filtered mixture affords an oil which by flash chromatography (silica gel, ethyl acetate / hexane or methylene chloride as eluant) affords 2.4 g (96% yield) of the title compound (3.) in the form of an oily liquid.

Step B; 4-f2-Aminophenoxy) butyrate m

A solution of (3.) (1/27 g, 5.0 mM) in 15 mL of ethyl acetate containing 200 mg of 5% palladium on carbon is reacted under a hydrogen atmosphere (40 psig) at room temperature until hydrogen evolution ceases. The mixture is then filtered and concentrated in vacuo to provide 1.0 g of (4.) as a low melting point oil / solid.

Step C: Dodecanedioic acid. mono methyl ester (6)

Diethyl dodecanedioate (5) (34.4 g, 0.12 M) is reacted with barium hydroxide octahydrate (19.2 g, 0.06 M) in methanol (240 ml) as in the analogous procedure of Ora. Svn. Coll. Vol. III. n. 635 to provide 24.8 g of (6.) as a white solid.

Step D: Dodecanedioic acid. mono methyl ester mono-acid chloride (7)

A mixture of mono acid ((5) (10.0 g, 0.041 M) and thionyl chloride (12.1 ml, 0.166 M) is refluxed for 5 hours, excess thionyl chloride being removed in vacuo. and the residual acid chloride being repeatedly dissolved in dry benzene and concentrated until no thionyl chloride remained to provide 10.8 g of the title compound (7) as a waxy solid.

Step E: Ethyl 4- (2- (11-carbomethoxyundecanoylamino) phenoxy) butyrate (8) To a stirred, ice-cooled solution of 0.89 g (4.0 mM) amine (4) and dry triethylamine (1.2 ml) in dry ether (40 ml) is added dropwise over about 4 minutes a solution of acid chloride (7) (1.04 g, 4.6 mM) in 20 ml of dry ether. The resulting mixture is allowed to stir cold for 20 minutes, and then at room temperature overnight. After filtration of the triethylamine hydrochloride, the ether filtrate is concentrated in vacuo and the residue is chromatographed on a column of 82 g of silica gel using 20% ethyl acetate / hexane as eluant to give 1, 49 g (85%) of (8.) as a waxy solid. The ether / triethylamine in the above reaction may be replaced by methylene chloride / pyridine with similar results. The same compound can also be prepared by direct coupling of acid (6) with the same amine using common coupling reagents, such as dicyclohexylcarbodiimide / N, N-dimethylaminopyridine, etc.

Step F: 4- (2- (11-Carboxyundecanoylamino) phenoxy) butyric acid To a stirred solution of (8) (1.0 g, 2.22 mM) in methanol (100 mL) is added 1 mL of water followed by dropwise addition of 2.5 N sodium hydroxide solution (4.0 ml). The walls of the reaction flask are washed with 10 ml of methanol and the mixture is stirred under a nitrogen atmosphere until TLC analysis does not show the permanence of any mono- or di-). The methanol is removed in vacuo. the residue is mixed with 100 ml of water, stirred for solution, filtered (20 ml of washings with water), and the stirred filtrate is acidified dropwise with 2N hydrochloric acid. Filtration of the resulting precipitate followed by copious washing with water and drying gave 0.87 g (96%) of (9) as a white, chalky solid. The compound was a component by TLC (silica gel, the eluent consisted of 10 ml of 2% methanol in methylene chloride containing 4 drops of glacial acetic acid). m.p. 128.5-130 ° C, uncorrected.

Microanalysis: Calc .: C, 64.84; H, 8.16; N, 3.44.

Found: C, 64.90; H, 8.34; N, 3.33.

Step G: Ethyl 4- (2-Amino-3-methylphenylthio) butyrate To a stirred (N 2) deoxyated solution of 2-aminothiophene (10) (1.25 g, 10 mM) and 4-bromobutyrate (2.14 g, 11 mM) in 40 ml of dry 1,2-dimethoxyethane is added 8.3 g of solid ground anhydrous potassium carbonate, the resulting mixture is deaerated 3X under nitrogen and allowed to stir at room temperature. at room temperature until TLC analysis indicated that the reaction was complete. The filtered mixture is then concentrated and the residue flash chromatographed on silica gel (85 g) using 15% ethyl acetate / hexane as eluant to give 1.8 g of (11) as a Light-colored oil.

Step H: 4- (2- (11-carboxyundecanoylamino) phenylthio) butyric acid (13).

When the amine (11) is acylated with acid chloride (7) as in the procedure of Step (E), and the resulting diester 4- (2- (11-carbomethoxyundecanoylamino) phenylthio) butyrate 12 is hydrolyzed in Step I as in process (F), the title compound, 13, mp 113.5-115 ° C is obtained.

Representative compounds which follow in this series were additionally produced by the above procedures: 14) 4- (2- (9-carboxynonanoylamino) phenoxy) butyric acid, m.p. 121.5-124.5 ° C. 15) 4- (2- (10-carboxydecanoylamino) phenoxy) butyric acid, m.p. 110-111.5 ° C. 16) 4- (2- (12-carboxydodecanoylamino) phenoxy) butyric acid, m.p. 116-119 ° C. 17) 4- (2- (13-carboxytridecanoylamino) phenoxy) butyric acid, m.p. 128-129.5 ° C. 18) 4- (2- (15-carboxypentadecanoylamino) phenoxy) butyric acid, m.p. 121-125 ° C. 19) 5- (2- (11-carboxyundecanoylamino) phenoxy) valeric acid, m.p. 112-113.5 ° C. 20) 4- (2- (11-carboxyundecanoylamino) -3-methylphenoxy) butyric acid, m.p. 134.5-136.5 ° C. 21) 4- (2- (11-carboxyundecanoylamino) -4-methylphenoxy) butyric acid, m.p. 99.5-100.5 ° C. 22) 4- (2- (11-carboxyundecanoylamino) -5-methylphenoxy) butyric acid, m.p. 109.5-113 ° C.

Step J: 2-Nitrophenyl Benzyl ether (231

When 2-nitrophenol (1) is reacted with 224 bromide

benzyl chloride under the conditions of Step A gives the title ether (23) as a gold oil.

Step K: 2-Aminophenyl Benzyl ether (24)

A solution of 2-nitrophenyl benzyl ether (23) (1/15 g, 5.0 mM) in ethanol (25 mL) saturated with anhydrous ammonia is stirred under an atmosphere of hydrogen (40 psi) with Raney Nickel (2 g .) until TLC analysis indicated the absence of starting nitro compound. The filtered mixture is freed from excess ammonia by bubbling on anhydrous nitrogen. Removal of ethanol by distillation under vacuum at room temperature affords 1.0 g of title compound (24) as an intense colorless crust, which was used as in the next reaction. This compound can also be obtained by careful reduction in ethanol or ethyl acetate using palladium on carbon as the catalyst, but may be accompanied by slight excess reduction if not monitored.

To a quasi-stirred solution of amine (24.) (5.0 mM) in dry diethyl ether (30 ml) is added anhydrous sodium carbonate (6.0 g) in dichloromethane 57 mM), and the resulting mixture is cooled in an ice-water bath. Trifluoroacetic anhydride (1.5 ml, 10.6 mM) is added dropwise to this cold mixture for 2 minutes, changing the color to a yellowish red. After 2 hours the cooling bath is removed and the mixture is allowed to stir at room temperature overnight. After filtration, the filtrate is concentrated, in vacuo and is then pumped to provide 1.3 g of the title compound (25) as a light colored crust (with some reddish brown color at the edges). 225

Step Μ: N-Methyl-2-Benzyloxyaniline (27)

A well stirred solution of (25) (0.295 g, 1.0 mM), methyl iodide (0.25 ml, 4.0 mM) and anhydrous acetone (5.0 ml) is placed in a previously heated oil bath to 59øC, and held for 2 minutes. Anhydrous powdered potassium hydroxide (0.225 g, 4.0 mM) is added all at once, and the bath temperature is allowed to rise to 65øC. A certain amount of KOH is observed. After an additional 15 minutes, the reaction mixture is removed from the bath, allowed to cool, and the volatiles are removed. Methanol (7 ml) is added with stirring to the obtained N-Methyl-N-trifluoroacetyl-2-benzyloxyaniline residue (26), followed by water (1 ml), and methanol (2 ml) (for side washing) . After stirring overnight at room temperature, the methanol is removed in vacuo. the residue is partitioned between ether and water, the organic layer is washed with additional water, brine, and dried over sodium sulfate. Concentration of the filtered ether solution gives the title compound (27) (0.212 g) as an oil. NMR, MS and TLC indicate little or no dimethyl compound.

Step N: N- (11- (Carbomethoxy) undecanoyl) -N-Methyl-2-Benzyloxyaniline (28) To a stirred, ice-cooled solution of (27) (0.21 g, 1.0 mM ) in dry methylene chloride (10 ml) containing anhydrous pyridine (0.3 ml) is added (7) (0.27 g, 1.03 mM), dissolved in methylene chloride (5 ml), dropwise drop for 1 minute (some methylene chloride used for washing). After stirring in the cold for 30 minutes, the mixture is allowed to stir at room temperature for completion of the reaction. The reaction mixture is washed with 1 N HCl, dried (Na2 SO4) and filtered. Flash chromatography (silica gel, 20% 226 acetate

ethyl acetate / hexane as eluent) of the obtained residue gives the title compound (28) (0.33 g) as a colorless oil.

Step 0: N- (11- (Carbomethoxyl undecanoyl) -N-Methyl-2-Hydroxyaniline (29)

A solution of (28) (0.11 g, 0.25 mM) in methanol (11 mL) containing 10% palladium on carbon (30 mg) is stirred in an atmosphere of 40 p.s.i. of hydrogen until there is no (V) (TLC analysis). The filtered solution was then concentrated in vacuo to give the title compound (29), used immediately in step P.

Step P; Ethyl 4- (2-N- (11-Carbomethoxyundecanoyl) -N-methyl) amino) phenybutyrate (30) To a stirred solution of (29) (0.087 g, 0.25 mM) and 4- bromobutyrate (0.115 ml, 0.80 mM) in anhydrous acetone (10 ml) is added anhydrous ground potassium carbonate (0.45 g, 3.2 mM) and the resulting mixture is heated under gentle reflux under an atmosphere of nitrogen for 24 hours. The mixture is cooled, filtered, and concentrated, and the residue is flash chromatographed (silica gel: 20% ethyl acetate / hexane as eluant) to give 80 mg of the title compound (30) as a white solid. a colorless oil.

Step 0: 4- (2-N- (11-Carboxyundecanoyl) -N- (methyl) amino) -phenoxybutyric acid (31)

When (30) (0.055 g, 0.118 mM) is hydrolyzed as for its N-demethyl analogue (Step F, above), and the resulting oil obtained after acidification is extracted with methylene chloride, the compound of title (31); (51 mg.) As a colorless oil.

Step R: Ethyl 4- (2- (11-bromoundecanoylamino) phenoxy) butyrate (32). To a solution of (4) (2.60 g, 11 mM) and 11-bromomoundecanoic acid (2.65 g, 10 mM) in anhydrous methylene chloride (90 ml) is added 4- (dimethylamino) ) pyridine (1.22 g, 10 mM) followed by N, N'-dicyclohexylcarbodiimide (2.3 g, 11 mM) (4 x 5 ml washes with methylene chloride). Precipitation of dicyclohexylurea (DCU) begins within 4 minutes. When TLC analysis indicates that the reaction is complete, the mixture is filtered, the filtrate is concentrated in vacuo and the residue is extracted with ether. The combined ether extracts are washed with 1N hydrochloric acid, 1N with saturated sodium chloride solution, dried (Na 2 SO 4) and concentrated to a residue which is stirred, filtered, and concentrated alternately with ether and methylene chloride to yield removed the entire DCU. Concentration of the final solution affords the title product (32) (2.35 g) as an oil which is rapidly converted to a waxy solid. Attempting to purify a previous product by column chromatography (silica gel, 20% ethyl acetate / hexane as eluant) gave a crude product in very low yield.

Step S: Diethyl 10- (N- (2- (3-Carboethoxypropyloxy) phenyl) carboxamido) diethylcyclophosphonate (331

A stirred mixture of (32) (0.235 g, 0.5 mM) and triethyl phosphite (TEP) (0.3 ml) is heated at 180 ° C (bath temperature) under a nitrogen atmosphere for 8 hours , 228

cooled, excess TEP is removed in vacuo. and the residue is flash chromatographed (Silica gel: ethyl acetate as eluent) to provide 32 (0.13 g) as a colorless clear oil.

Step T; Cleavage of the phosphonate ester (32) using bromotrimethylsilane (procedure of JCS Chem. Comm. P.739 (1979) provides 10- (N - ((2- (3- (carboethoxy) propyloxy) phenyl) carboxamido ) decylphosphonic acid (34).

Passed on;

Subsequent hydrolysis of (21) using the procedure of Example (F) above gives the corresponding 10- (N - ((2- (3-Carboxy) propyloxy) phenyl) carboxamido) decylphosphonic acid di

Step V: 10- (N - ((2- (3-Carboethoxy) propyloxy) phenyl) carboxamido) decaneisothiouronium bromide (36)

A stirred solution of (32) (0.047 g, 0.1 mM) in ethanol (2 ml) is reacted with thiourea (0.010 g, 0.13 mM) under the same conditions as in Step W. The concentration of The reaction mixture affords the title compound (2α) (contaminated with a small amount of thiourea) which slowly solidifies in resting crystalline circles. Stirring with dry chloroform followed by filtration and concentration gives the product as a thick wax. 229

Step W: To a stirred solution of (32) (0.047 g, 0.1 mM) in ethanol (2 ml) was added sodium bicarbonate , 0 ml) is added water (10 drops, slowly) followed by sodium thiosulfate (0.035 g, 0.14 mM), and the reaction mixture is heated in an oil bath (bath temperature about 90øC ) under a nitrogen atmosphere until TLC analysis indicated no bromine compound was present. The cooled mixture was then concentrated to remove the ethanol and water to give a white crysta, extracting this crustacea with chloroform, followed by filtration at The oxidation of (36) or (37) in the presence of an inorganic element gives the product (37) (49 mg) in a glassy form which is converted over time into a waxy solid. as in the analogous processes in JS Showell et al., J. Org. Chem. 27 (1962) 2853 or C. Ziegler et al J. Org. Chem. (1951) 621) provides the corresponding sulphonic acid (38).

Step X: Ethyl 4- (2-Nitropyrid-3-yloxy) butyrate (40)

This compound was prepared from ethyl 4-bromobutyrate 2 and 2-nitro-3-pyridinol (39) by the procedure of Step (A), above. After flash chromatography (silica gel, 1.5% methanol / methylene chloride as eluent) of a dilute sodium bicarbonate wash product of an ether solution of the product, it was necessary to remove traces of the starting phenol. The product (40) was obtained in 76% yield as a light yellow oil. 230

Step Y: Ethyl 4- (2-aminopyrid-3-yloxy) butyrate (41)

This compound was prepared by reduction of (40) as in the procedure of Step (B), above. The amine (41) was obtained as a waxy solid.

Step Z: Ethyl 4- (2- (11-Carbomethoxyundecanoylamino) pyrid-3-yloxy) butyrate (42)

When (41) and (7) are reacted as in the aforementioned Step (E), the title compound (42) is obtained. The hydrolysis will provide the corresponding 4- (2- (11-carboxyundecanoylamino) pyrid-3-yloxy) butyric acid di-acid (43).

Step AA; To a quasi-stirred solution of 2-aminophenol (0.24 g, 2.2 mM) in anhydrous methylene chloride (25 ml) was added dry pyridine (0.01 g, 66 ml) and the mixture was cooled in an ice water bath. A solution of (7) (0.525 g, 2.0 mM) in methylene chloride (2 ml) was added over 1 minute (washings with 2X1.5 ml of methylene chloride), and the mixture was allowed to stir cold. After 30 minutes the bath was removed. After stirring overnight at ambient temperatures, the mixture was filtered, the solvents were removed in vacuo. and the residue was pumped to remove all traces of pyridine. The product, (44) was used as in the subsequent steps.

Step BB: 4- (2- (11-Carbomethoxyundecanoylamino) phenoxy) butyronitrile (45)

When (44) and 4-bromobutyronitrile are reacted under the conditions of Step (A), above, (4) is obtained as a waxy solid. In contrast, reacting (44) with ethyl 4-bromobutyrate as in Step (A) gives (8).

To a stirred solution of (45) (11 mg, 0.027 mM) in methylene chloride (3 ml) is added manganese dioxide (100 ml) mg) and the resulting suspension is allowed to stir covered at room temperature After some days some additional methylene chloride and manganese dioxide (100 mg) are added and the solution is allowed to continue. by TLC indicates that no nitrile remains, the mixture is filtered, the catalyst is washed well with fresh methylene chloride, and the filtrate is concentrated to afford the title product (46) as a waxy solid.

The purified new compounds, isolated, had NMR and Mass spectral data consistent with their indicated chemical structures. All melting points were recorded in a warm A.O. Spencer and are uncorrected. EXAMPLE 1 17-Benzoyl-Androst-3,5-diene-3-carboxylic Acid The title compound is produced by reacting 176-carbomethoxy-androst-3,5-diene-3-protected carboxylic acid in, for example, THF , with phenyl magnesium bromide under conditions of 232

Grignard standards. The standard production procedure provides the title compound, m.p. 222-225 ° C. EXAMPLE 1 Synthesis of 4- (4-isobutylbenzyloxy) -2,3-dimethylbenzaldehyde

I

HO

A mixture of 4-hydroxy-2,3-dimethylbenzaldehyde (220 mg), 4-isobutylbenzyl bromide (341 mg), potassium carbonate (1.38 g) and methyl ethyl ketone (10 ml) was refluxed for 6 hours. hours. After cooling, the reaction mixture was diluted with ethyl acetate, the solution was washed with dilute hydrochloric acid, water, successively, dried and evaporated. The residue was purified by silica gel column chromatography (hexane: EtOAc = 1: 1) to give the title compound (383 mg) having the following physical data: TLC: Rf 0.48 (hexane: EtOAc = 5: 1); NMR (CDCl 3): δ 7.64 (1H, d), 7.32 (1H, d), 7.16 (1H, d), 5.12 (2H, s) (2H, d), 2.24 (3H, s), 1.94-1.80 (1H, m), 0.90 (6H, d). REFERENCE EXAMPLE 2 Synthesis of 4- (4-isobutylbenzyloxy) -2,3-dimethylbenzoic acid

A solution of the aldehyde prepared in Reference Example 1 (380 mg) in acetone (5 ml) was cooled with ice. To the solution, Jones reagent (2.67 N, 2 mL) was added dropwise and allowed to stand. The solution was stirred for 1.5 hours at room temperature. The reaction was quenched by the addition of isopropyl alcohol. The deposited crystals were washed with hexane, dried and purified by silica gel column chromatography (hexane-EtOAc) to give the title compound (328 mg) having the following physical data: TLC: Rf 0.36 ( hexane: EtOAc = 2: 1); NMR (CDCl 3): δ 7.80 (1H, d), 7.33 (1H, d), 7.15 (1H, d), 6.90 (1H, d) 58 (3H, s), 2.48 (8H, d), 2.26 (3H, s), 0.91 (6H, d). 234 234

EXAMPLE PEEEPANCE_3 Synthesis of 4- [2- [4- (4-isobutylbenzyloxy) -2,3-dimethylbenzoylaminophenyl] butanoic acid ethyl ester

Oxalyl chloride (2 ml) was added dropwise to a solution of carboxylic acid prepared in reference example 2 (325 mg) in methylene chloride (2 ml). The solution was stirred for 1 hour and evaporated. To an ice-cooled mixture of ethyl 4- (2-aminophenoxy) butanoate (232 mg), pyridine (1 ml) and methylene chloride (15 ml), the above solution was added dropwise. The mixture was stirred for 30 minutes at the same temperature and for 1 hour at room temperature. The reaction solution was washed with water, dried and evaporated. The residue was purified by silica gel column chromatography (hexane: EtOAc = 5: 1) to give the title compound (383 mg) having the following physical data: TLC: Rf 0.5 (hexane: EtOAc = 3: 1); NMR: δ 8.58-8.48 (1H, m), 8.05 (1H, s), 7.34 (1H, d), 7.16 (1H, d), 7.08-6.96 (2H, m), 6.90-6.80 (2H, m), 5.07 (2H, s), 4.14-3.96 (4H, m), 2.49 (2H, d), 2.44 (3H, s), 1.18 (3H, t), 0.91 (6H, d).

I

EXAMPLE 4 Synthesis of 4- (2-4-4-Methyl isothiocarbonyloxy) -2,3-dimethylbenzoylamino-1-phenoxybutanoic acid

Aqueous solution of lithium hydroxide (3 ml) was added to a solution of the ester prepared in Reference Example 3 (380 mg) in dimethoxyethane (8 ml). The mixture was stirred for 30 minutes at 50 ° C. After the reaction, the solution was neutralized with dilute hydrochloric acid and extracted with ethyl acetate. The extract was dried and evaporated. The obtained residue was recrystallized from hexane to give the title compound (317 mg) having the following physical data: TLC: Rf 0.26 (hexanor EtOAc = 1: 1): mp 143 ° C. EXAMPLE REFERENCE 5

By a procedure similar to reference examples 1, 2, 3 and 4, the following compound, 4- [2- [4- [1- (4-isobutylphenyl) ethoxy) -2,3- dimethylbenzoylamino] phenoxy] butanoic acid, having the structural formula:

in which the Rf value is 0.37 (hexane: EtOAc = 1: 1), and the mass spectrum had m / z values of 503, 345. EYPMPT. REFERENCE 6 (-) - 4- [2- ( The compound prepared above in reference example 5, (403 mg) and cinchonidine (2.36 g) were dissolved in acetone (70 ml) under heating. The solution was allowed to stand to give white crystals. The crystals were collected by filtration and purified by recrystallization from acetone four times. The white crystals obtained were dissolved in chloroform. The solution was washed with dilute hydrochloric acid. The oily layer was washed with water, dried and evaporated to give the title compound having the following physical data:

Appearance: white crystal;

Optical rotation angle: [Î ±] D-39.6Â ° (C = 1, CHCl3) EXAMPLE REFERENCE 7

(-0-4- [2- (4-Isopropylphenyl) ethoxy] -2,3-dimethylbenzoylamino) phenoxylbutanoic acid sodium salt The compound prepared in Reference Example 6 was dissolved in methanol. aqueous sodium hydroxide solution was added and evaporated to give the title compound having the following data: IR: # 3050, 1750, 1580, 1560, 1510, 1445, 1260, 1090, 1020, 740 cm -1.

FORMULATION EXAMPLE The following components are mixed by a conventional method and punctured to yield 100 tablets each containing 50 mg of active ingredient. 238

4- [2- [4- [1- (4-isobutylphenyl) -5-ethoxy) butanoic acid

Cellulose calcium gluconate 0.2 g (disintegrating agent)

Magnesium stearate 0.1 g (lubricating agent)

Microcrystalline cellulose 4.7 g

Lisbon, April 15, 1992

J. PEREIRA DA CRUZ Official Property Agent Industriai RUA VtCTOR GORDON, 10.- A 3.® 1200 LISBOA

Claims (3)

* I. A method for the treatment of benign prostatic hyperplasia in patients in need of such treatment comprising the step of administering to such patients therapeutically effective amounts of a 5α-reductase inhibitor selected from non-aza- 17? -acyl-3-carboxyandrosta-3,5-dienes, benzoylaminophenoxybutanoic acid derivatives, cinnamoylamides, condensed benzene (thio) amides, aromatic 1,2-diethers or thioethers, ortho-acylaminophenoxy-alkanoic acids, ortho-thioalkyl-acylamphophenoxy-alkanoic acids, or the pharmaceutically acceptable esters or salts thereof in combination with an aromatase inhibitor. 2â. 3. A method according to claim 1, wherein said 5α-reductase inhibitor is an 17β-substituted 4-aza-iso-roid of the formula: 2 2 wherein: the dashed line represents a double bond when present; R1 and R2 are independently hydrogen, methyl or ethyl; R 2 is a hydrocarbon radical selected from straight or branched chain alkyl, cycloalkyl or aralkyl of 1-12 carbons, substituted or unsubstituted, or monocyclic aryl optionally containing 1 or more lower alkyl substituents with 1-2 carbon atoms and / or 1 or more halogen substituents; R 'is hydrogen or methyl; R "is hydrogen or β-methyl; R &quot; ' is hydrogen, α-methyl or β-methyl, and pharmaceutically acceptable salts or esters thereof. &gt; 3a. 2. A method according to claim 1, wherein said 5α-reductase inhibitor is a 4-aza-isooride of the formula: wherein: the dashed line represents a double bond when present and R is selected from hydrogen, methyl and ethyl; and (a) a monovalent radical selected from straight or branched chain alkyl, or cycloalkyl, of 1-12 carbons which may be substituted by one or more of alkyl or halo; (b) an aralkyl radical selected from benzyl or phenethyl; (c) a polycyclic aromatic radical which may be substituted with one or more of: protected -OH, protected -OH, -OC3 -C4 alkyl, C1 -C4 alkyl, halo or nitro; (d) a monocyclic aromatic radical which may be substituted with one or more of: (1) -OH, -CONH2, -C4 alkyl, - (CH2) m OH, - (CH2) n COOH , including protected hydroxy, wherein m 4 is 1-4, n is 1-3, provided that C 1 -C 4 alkyl is only present when one of the oxygen-containing radicals referred to above is present; (2) -SH, -SC 1 -C 4 alkyl, -SOC 2 -C 4 alkyl, -SO 2 C 4 -C 4 alkyl, -SO 2 N (C 1 -C 4 alkyl) 2, -C 1 -C 4 alkyl- (CH 2) -S- (CH-) -O-COCH-, where m is 1-4 and n is 1-3, provided that C 1 -C 4 alkyl is only present when one of the above sulfur containing radicals is present; 3. (3) N (R) 2, which may be protected, wherein R is independently H or C1 -C4 alkyl, wherein the monoaryl ring may also be further substituted with C1 -C4 alkyl; and (e) heterocyclic radical selected from 2- or 4-pyridyl, 2-pyrrolyl, 2-furyl or thiophenyl; R ', R', R "'are each selected from hydrogen and methyl; and pharmaceutically acceptable salts thereof. 43. A method according to claim 1, wherein said 5α-reductase inhibitor is a 17-substituted non-aza-esteroid of the formula: wherein: the A-ring is up to 2 doublets connections; rings B, C and D have optimum double bonds where indicated by interrupted lines, provided that rings A, B and C do not have adjacent double bonds and ring D does not have a double bond when R 3 represents two substituents or a divalent substituent; Z is (CH 2) 2 and n is 0 or 2, provided that Z is (CH) n when adjacent to a double bond; X is H, Cl, F, Br, I, CF 3, or C 1-4 alkyl; Y is H, CF 2, or CH 3; provided that .Y is H when there is no C5-C6 double bond; R 2 is H or C 1-4 alkyl; R 2 is absent or present as H or CH 2, provided that R 2 is absent when the carbon to which it is attached is unsaturated; and 6 3. - · &quot; (1) α-hydrogen, or α-hydroxyl, or α-acetoxy and / or (a) wherein W is a bond or C alc to C alc to C alc to C alc to C alc to C alc to C alc to C alc to C alc to C alc to C alc to C alc to C alc to C alc to C alc to C alc to C alc to C alc to C alc to C alc to C alc to C (ii) hydroxyl, (iii) C 1-8 alkyl, (iv) hydroxylic alkyl, (v) C 1-4 alkoxy, (Vi) where R1 and R2 are each independently selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl, phenyl; or R5 and R6 taken together with the nitrogen to which they are attached represent a 5-6 membered saturated ring. . (B) -Alk-OR, where Alk is al <3uylidene, and R is (i) phenyl C1-6 alkoxycarbonyl, alkylcarbonyl, (ii) C5-8 cycloalkylcarbonyl, (iii) benzoyl, (iv) C1-6 alkoxycarbonyl, 1 '' (o) aminocarbonyl, or C1-4 alkyl substituted aminocarbonyl, (vi) hydrogen, or (vii) C (2) -CH-W-CO-R 4 or = CH-W-OR 1 2 3 4, wherein W is a bond of C 1-4 alkylidene and R 1 and R 2 have the same meaning as above and R3 is also hydrogen or C1-2 alkylcarbonyl, (3) where the disrupted bond substitutes 17-α-hydrogen, (4) α-hydrogen and NHCOR where R3 is C1-4 alkyl or NR6, , Wherein R and R have the same meaning as above, (5) α-hydrogen and cyano, 4 (6) α-hydrogen and tetrazolyl, or δ (7) keto; or a pharmaceutically acceptable salt thereof; except compounds in which: (1) Ring B has a C -C-C dupla double bond, R ê is CH₂, and R ce is keto, methoxycarbonyl, or acetyl; or (O) the ring A-nor has a C-C2 double bond and R is O-acetoxy or acetyl; ... 1 3 (m) R is CH3 and R is acetoxy or acetyl; or (iv) the A-nor ring has a C3-C4 double bond and R1 is methyl; or (v) ring B has a C3 -C4 double bond and R is β-hydroxy. 5â. The method of claim 4, wherein said 17β-acyl-3-carboxy-androsta-3,5-diene has the formula: in which 1. . R 'is (a) straight or branched alkyl group; C3 -C12 cycloalkyl, which may be substituted with C1 -C4 alkoxy or linear or branched C1 -C4 alkyl; Cg-C12. aryl, or C7 -C13 aralkyl which may be substituted with one or more of: -OH, -OCC4 alkyl, C1 -C4 alkyl, - (CH2) m OH, - (CH2) n COOH, including -OH protected, where m is 1-4, n is 1-3; (b) C 1 -C 5 linear or branched alkyl; ε 3 -cycloalkyl which may be substituted with C 1 -C 4 alkoxy or straight-chain branched alkyl; Or aralkyl which may be substituted with one or more of: -OH, -OC 1 -C 4 alkyl, C 1 -C 4 alkyl, - (CH 2) m OH ,  € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒ (OH) 2, â € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒ (OH) . 6â. 4. A method according to claim 1, characterized in that the benzoylaminophenoxy-butanoic acid derivatives are the formula: wherein R 'is hydrogen or alkyl having 1 to 4 carbon atom (s); 10 10 A is oxygen, sulfur atom or sulfinyl group (SO); Both R 's' are methyl or chlorine, or the two R' s and the carbon atoms of the benzene ring to which the two Rs are attached together are cyclopentane, cyclohexane or a benzene ring; and R 2 represents a group of the formula: wherein R is hydrogen or alkyl of 1 to 4 carbon atoms, R 3, R 4, R 5, R 6, R 7, and R 8 are independently selected from the group consisting of hydrogen, independently, hydrogen, alkyl having 1 to 4 carbon atom (s), halogen, trifluoromethyl or cyclobutylmethyl, 11 R 1 is hydrogen or C 1 -C 5 alkyl, C 1 -C 4 alkoxy, C 1 -C 5 alkoxy, C 1 -C 5 alkoxy, C 1 -C 5 alkoxy, wherein R 1, R 2, R 3 and R 4 are independently hydrogen, alkyl of 1 to 4 carbon atom (s), halogen, trifluoromethyl or cyclobutylmethyl, and 1 is an integer from 1 to 4 , and R 10 is a group of the formula: R12 is H2 H2 - and wherein R 1, R 2, R 3 and R 4 are independently hydrogen, alkyl or carbon atom (s), halogen, trifluoromethyl or cyclobutylmethyl, and 1 'is an integer of 1 to 4; or non-toxic salts thereof. 7â. 8. A method according to claim 1, wherein said cyanamideamide is of the formula: 13 in which 2 3.. R 2 and R 3 each independently represent a hydrogen or a methyl group with the proviso that when R 2 is methyl, R 2 is hydrogen and (R 2 n is a member selected from the group consisting of 3-pentyl group, 4-pentyl group, 4-neopentyl group, 4- (2-ethylbutyl) group and 4- (2-methylpentyl) group, or (ii) when R is hydrogen, R is methyl and A compound according to claim 1, wherein said condensed benz (thio) amide is of the formula: wherein A represents a single bond or a methylene, ethylene, trimethylene, tetramethylene, vinylene, propenylene, butenylene, butadienylene or ethynylene group being optionally substituted by one, two or three linear alkyl group (s) ) or branched (s) with the carbon atom (s) and / or the phenyl group (s); B represents a 4- to 8-membered heterocyclic ring containing one, two or three hetero atoms selected from the group consisting of oxygen, nitrogen and sulfur atom (s), wherein said ring is optionally (s) selected from oxo, thioxo and / or hydroxy group (s) including a ring of the formula: T represents an oxygen atom or a sulfur atom; R1 represents a group of the general formula: (i) R 3 (Iv) a linear or branched alkyl, alkenyl or alkynyl group having from 1 to 20 carbon atom (s), wherein R 1, R 6 R5 and R6 independently represent a hydrogen atom or a halogen atom or a linear or branched alkyl, alkenyl or alkynyl group having from 1 to 20 carbon atom (s) being unsubstituted or substituted by one, two, three, four or five optional carbon atom (s), per oxygen atom (s), sulfur atom (s), halogen atom (s), nitrogen atom (s), benzene ring, thiophene ring (rings), naphthalene ring (rings), carbocyclic ring (rings) of 4 to 7 carbon atom (s), carbonyl group (s), carbonyloxy group (s), ) of 16 hydroxy, carboxy group (s). azido group (s) and / or nitro group (s); 2 . R represents a hydrogen atom or a linear or branched alkyl group having from 1 to 6 carbon atom (s); R 2 represents a hydrogen atom, a halogen atom, a hydroxy group, a nitro group, a group of the general formula: -COOR, wherein R 7 represents a hydrogen atom; a linear or branched alkyl group having from 1 to 6 carbon atom (s), or an alkyl, alkoxy or alkylthio group. or branched with 1 to 6 carbon atom (s); R 4 represents a group of the general formula: wherein U represents an atom of (C 1 -C 4) alkyl, oxygen or a sulfur atom, R q represents a hydrogen atom or a linear or branched alkyl group having from 1 to 6 carbon atoms, nor represents an integer from 1 to 10, respectively, and q represents zero or an integer from 1 to 10, respectively, or nontoxic salts thereof. ga. 2. A method according to claim 1, wherein the ortho-acylaminophenoxy-alkanoic acid is of the structure: wherein A is an aromatic 1,2-disubstituted ring selected from (a) benzene; (b) 5-6 membered heteroaromatic ring containing 1-2 N, 1, or 0 atoms, or a combination thereof; o 18 τ Of E and are independently -COOH, -CONH 2, -CONHR 3, SO 2 OH, -SO 2 NH 2, -CO 2 R b, -SO 2 NaN, SO 0 H, P (O) (OH) 2; X is O, S, SO or SO2; R 2 is H, C 1 -C 4 alkyl, phenyl or substituted phenyl, halo, haloalkyl, hydroxy, carboxy, cyano, C 1 -C 4 -alkyl. alkoxy, C1 -C4 alkylthio, C1 -C4 alkylsulfinyl, C1 -C4 alkylsulfonyl, amino, nitro, C1 -C4 mono- or di-alkylamino; R 'and R "are independently H, halo, C1 -C6 alkyl. alkyl or C.-C. alkoxy, 14-14 'amino, or oxo, wherein CH-R' or CH-R " in the formula becomes -C = O; R & is H, C1 -C4 alkyl; R b is C 1 -C 12 alkyl, phenyl, or phenyl C 1 -C 4 alkyl; y is 1-6; z is 6-20; and wherein (CH) z and R "(CH) Z may independently represent substituted or unsubstituted alkyl or alkenyl radicals containing at least one alkene linkage; and pharmaceutically acceptable salts and esters thereof. 10â. 2. A method according to claim 1, wherein said ortho-thioalkyl acylaminophenoxy-alkanoic acid is of the structure: Wherein A is a substituted aromatic ring in 1, 2, 3, 4, 5; D is OH, NH2, NHRc, ORc; 20 X is O, S, SO, OR SO2; ; R 1 is H, C 1 -C 4 alkyl, phenyl or substituted phenyl, halo, halobutyl, hydroxy, carboxy, cyano, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, C 1 -C 4 alkylsulfinyl, C 1 -C 4 alkylsulfonyl, nitro, amino, -C4 mono or di-alkylamino; R 'and R "are independently H, halo, C1 -C4 alkyl or C1 -C4 alkoxy, amino, or oxo, when CH-R' or CH-R" in the formula become -C = O; Ra is H, C 1 -C 4 alkyl; R 2, R 3 are independently C 1-4 alkyl, phenyl, phenyl-C 1-4 alkyl; n is 0-2; y is 1-6; 2 z is 6-20; and . wherein R 1 is (CH) Z and R &quot; 1 (cn) z may independently represent substituted or unsubstituted alkyl or alkenyl radicals containing at least one alkene linkage; and pharmaceutically acceptable salts and esters thereof. 11-. 2. A method according to claim 1, wherein said aromatic diether or thioether is a compound of the structure: wherein: R 1 is selected from the group consisting of: A is a 1,2-substituted aromatic ring; D is OH, NH2, NHR, OR; X is O, S, SO, or SO2; R1 is H, C1 -C4 alkyl, phenyl or substituted phenyl, halo, halobutyl, hydroxy, carboxy, cyano, C1 -C4 alkoxy, C1 -C4 alkylthio, C1 -C4 alkylsulfinyl, alkylsulfonyl, nitro, amino, C 1 -C 4 mono or di-alkylamino; R 'and R "are independently H, halo, C1 -C4 alkyl or C1 -C4 alkoxy, amino, or oxo, where CH-R' or CH-R" in the formula become -C = O; R is H, C-C alkyl; c-X-phenyl-C-C. R1, R2 and R3 are independently C1 -C6 alkyl, phenyl, alkyl; n is 0-2; 23 y is 1-6; z is 6-20; and wherein R 'is (CH) Z e. R '' (ck) z may independently represent substituted or unsubstituted alkyl or alkenyl radicals containing at least one alkene linkage; and pharmaceutically acceptable salts and esters thereof. 12â. 2. A method according to claim 1, wherein said aromatase inhibitor is a steroid substrate analog or a non-steroidal analog that binds to and inactivates aromatase or is a compound that inhibits the cytochrome P component of the aromatase complex. 13a. A method according to claim 12, wherein said aromatase inhibitor is selected from the group consisting of: 6 - [(1H-imidazol-1-yl) phenylmethyl] -1-methyl-1H benzotriazole, 6 - [(4-chlorophenyl) (1H-1,2,4-triazol-1-yl) methyl] -1-methyl-1H-benzo-triazole; 24 - 2,2- [5- (1-1,2,4-triazol-1-ylmethyl) -1,3-phenylene] di (2-methylpropiononitrile), 2,2- [5- (imidazol-1-ylmethyl) -1- , 3-phenylene] -di (2-methylpropiononitrile), 2- [3- (1-hydroxy-1-methylethyl) -5- (1H-1,2,4-triazol-1-ylmethylphenyl] - 1,2-triazol-1-yl) methyl-1,3-phenylene] di (2-trideoxyethyl) -3,3,3-dihydroxy-2-methylpropionitrile, (triduter-propiononitrile), 2,2- [5-dideuterio (1H-1,2,4-triazol-1-ylmethyl-1,3-phenylene) di (2-methylpropiononitrile), 1,1-dimethyl-8- (1H-1,2,4-triazol-1-ylmethyl) -2 (1H) -naphtho [2,1-b] furanone, 1,2-dihydro-1,1-dimethyl-2-oxo-8 - (1 H -1,2,4-triazol-1-ylmethyl) naphtho [2,1-b] furan-7-carbonitrile, 1,2-dihydro-1,1-dimethyl-2-oxo-8 1,2-dihydro-1,1-dimethyl-2-oxo-8 (1H) -one, - [(1 H -1,2,4-triazol-1-yl) methyl] naphtho [2,1-b] furan-7-carbonitrile, 2- (4-chlorobenzyl) -2-fluoro- 3-di (1,2,4-triazol-1-yl) propane, 2-fluoro-2- (2-fluoro-4-chlorobenzyl) yl) -propane, 25 2-fluoro-2- (2-fluoro-4-trifluoromethylbenzyl) -1,3-di (1,2,4-triazol-1-yl) propane, 3- (4-chlorophenyl) -1- (1,2 1,2-triazol-1-ylmethyl) butan-2-ol, 2- (4-chloro-α-fluorobenzyl) -1,3-di (1,2,4-triazol-1-yl) propan-2-ol, 2-4- (4-chlorobenzyl) -1,3-bis (1,2,4-triazol-1-yl) propane, 4 - [2- (4-chlorophenyl) -1,3-di (1,2,4-triazol-1-ylmethyl) ethoxymethyl] benzonitrile, 1- (4-fluorobenzyl) -2- (2-fluoro-4- (4-fluorophenyl) -1,3-di- (1,2,4-triazol-1-yl) propan-2-ol, 2- (4-chlorophenyl) 1,3-di (1,2,4-triazol-1-yl) propan-2-ol, 1- (4-cyanobenzyl) -2- (2,4-difluorophenyl) -1,3- Triazol-1-yl) -propan-2-ol, 2- (4-chlorophenyl) -1-phenyl-1,3-di (1,2,4-triazol- 2-ol; 5-bis (4-chlorophenyl) methylpyrimidine; α, α-bis (4-chlorophenyl) -2-pyrazinemethanol; N- (2,4-difluorophenyl) -N-benzyl-3-pyridinemethanamine, N- (2-chlorophenyl) -α- (4-fluorophenyl) -3-pyridineethanethanamine, 1- (10,11- 5H-dibenzo [a, d] cyclohepten-5-yl) -1H-imidazole, 26 1 - (9H-fluoren-9-yl) -β-imidazole, 3-bis (4-chlorophenyl) -3-methylpyridine (4-cyanophenyl) -6,7-dihydro-pyrrolo [1,2-c] imidazole, 5H-5- (4-chlorophenyl) 5-yl) -6,7,8,9-tetrahydroimidazo [1,5-a] azepine; 5 - [(1H-imidazol-1-yl) phenylmethyl] -2-methyl-1H-benzimidazole; - (3-chlorophenyl) (1H-imidazol-1-yl) methyl] -1H-benzimidazole; (Z) -α- (1,2,4-triazol-1-yl-ethyl-stilbene-4,4'-dicarbonitrile , (Z) -4'-chloro-α- (1 (R) -1- (1,2,3-triazol-1-ylmethyl) stilbene-4,4'-dicarbonitrile , 4-carbonitrile, (Z) -4'-chloro-α- (1,2,4-triazol-1-ylmethyl) stilbene-4-carbonitrile, (Z) (trifluoromethyl) stilbene-4-carbonitrile, (E) -β-fluoro-α- (1,2,4-triazol-1-yl) ylmethyl) stilbene-4,4'-dicarbonitrile, (Z) -4'-f (Z) -2 ', 4'-dichloro-α- (imidazol-1-ylmethyl) stilbene-4-carbonitrile, (Ζ) -4- (Ζ) -α- (imidazol-1-ylmethyl) stilbene-4,4'-dicarbonitrile, (Ζ) -α (imidazol-1-ylmethyl) stilbene-4-carbonitrile, (Ζ) -2- [2- (4-cyanophenyl) -3- (1,2,4-triazol-1-yl) propenyl] pyridine-5-carnonitrile; (1R *, 2R *) - 6-fluoro-2- (4-fluorophenyl) -1,2,3,4-tetrahydro-1- (1H-1,2,4-triazol-1-ylmethyl) naphthalene, (1R *, 2R *) - 6-fluoro-2- (4-fluorophenyl) -1,2,3,4-tetrahydro-1- (1H-imidazolylmethyl) -naphthalene, (1R *, 2S *) - 2- (4-fluorophenyl) -1,2,3,4-tetrahydro-1- (1H-1,2,4-triazol-1-ylmethyl) naphthalene-6-carbonitrile, 2R *))) and (1R *, 2S *) -2- (4-fluorophenyl) -1,2,3,4-tetrahydro-1- (1H-imidazolylmethyl) naphthalene-6-carbonitrile, *, 2R *) - and (1R *, 2S *) - 1,2,3,4-tetrahydro-1- (1H-1,2,4-triazol-1-ylmethyl) naphthalene-2,6 (1R *, 2S *) - 1,2,3,4-tetrahydro-1- (1H-imidazol-1-ylmethyl) naphthalene-2,6-dicarbonitrile (4-fluorophenyl) -1,2,3,4-tetrahydro-1- (5-methyl-1H-imidazolylmethyl) naphthalene-6-carbonitrile; 8-chloro-5- (4-chlorophenyl) -5H-inden- [1,2-d] pyrimidine; 5-bis (4-chlorophenyl) methylpyrimidine; 28 10- (2-propynyl) -str-4-ene-3,17-dione; [(4-chlorophenyl) (1H-1,2,4-triazol-1-yl) methyl] -1-methyl-1H-benzotriazole; 1-methylandrosta-1,4-diene-3,17-dione; 3-ethyl-3- (4-pyridyl) piperidine-2,6-dione; 4-hydroxyandrostene-3,17-dione; 4- (5,6,7,8-tetrahydro-pyrazido [1,5-a] pyridin-5-yl) -benzonitrile; 4- [alpha- (4-cyanophenyl) -1- (1,2,4-triazolyl) methyl] benzonitrile; 6-methylene-androsta-1,4-diene-3,17-dione, 4-amino-adrostan-1,4,6-triene-3,17-dione, 4-aminoandrosta-4,6-diene-3 , 17-dione; 3- (ΙΗ-Triazolazol-1-ylmethyl) -2-methyl-1H-indole-1-propanoic acid; 5- [3-chlorophenyl) (1H-imidazol-1-yl) methyl] -1H-benzyloxyazo; 105-thiandanilestr-4-ene-3,17-dione, 10α-oxiranilestr-4-ene-3,17-dione; 3-ethyl-3- (4-pyridyl) piperidine-2,6-dione; 3- (4-aminophenyl) -3-ethyl-pyrrolidine-2,5-dione; 29 1- (7-carboxyheptyl) imidazole; 1,1-dimethyl-8- (1 H -1,2,4-tetrazol-1-ylmethyl) -2 (1H) -naphtho [2,1-b] furanone (la); 1 5- (p-cyanophenyl) -5,6,7,8-tetrahydroimidazo [1,5-a] -pyridine hydrochloride; 1,4,6-androst-1-ene-3,17-dione; and bis (p-cyanophenyl) imidazo-1-yl-methane hemisuccinate; and pharmaceutically acceptable derivatives, their acid addition salts. 14a. A method according to claim 12, characterized in that said aromatase inhibitor is 4- (5,6,7,8-tetrahydroimidazo [1,5-a] pyridin-5-yl) benzonitrile hydrochloride ( fadrazole). 15. A method according to claim 9, wherein said aromatase inhibitor is 1,4,6-androsta-triene-3,17-dione. 16. A method according to claim 1, wherein said 5α-reductase inhibitor is finasteride and said aromatase inhibitor is fadrazole. 17. A pharmaceutical composition for the treatment of benign prostatic hyperplasia, characterized in that it comprises therapeutically effective amounts of a 5Î ± -reductase inhibitor selected from 17β-substituted 4-aza-steroids, 17β-substituted non-aza-steroids, 17, 3-acyl-3-carboxyandrosta-3,5-dienes, benzoylaminophenoxy-butanoic acid derivatives, cinnamoylamides, condensed benz (thio) amides, aromatic 1,2-diethers or thioethers, ortho-thioalkylacylaminophenoxy-alkanoic acids , or pharmaceutically acceptable esters or salts thereof, and an aromatase inhibitor in a pharmaceutically acceptable carrier therefor. Lisbon, April 15, 1992 J. PEREIRA DA CRUZ Official Industrial Property Agent RUA N / tCTOR CORDON, 10-A 3.® 1200 LISBOA