PT100256B - METHOD FOR THE TREATMENT OF BENIGN PROSTATIC HYPERPLASIA - Google Patents

Abstract

The present invention relates to a method for the treatment of benign prostatic hyperplasia in men (BPH). It is characterized by involving combined therapy with a 5α-reductase inhibitor, for example 17β- substituted 4-azasteroids, 17β-substituted non- azasteroids, 17β-acyl-3-carboxy-androst-3,5-dienes, benzoylaminophenoxy butanoic acid derivatives, cinnamoylamide derivatives, condensed benzo(thio)amides, aromatic 1,2-diethers or thioethers, aromatic alkanoic ortho-acylaminophenoxy acids, aromatic ortho- thioalkylacylaminophenoxyalkanoic acids or pharmaceutically acceptable salts or esters thereof, and particularly finasteride in combination with an α1- adrenergic receptor blocker, for example terazosin. The combination provides a therapy at molecular level for the underlying cause of the disease, as well as relief of symptoms. Pharmaceutical compositions that are useful in said method of treatment are also disclosed.

Description

- BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to a new method of treatment for patients, that is, men who have benign prostatic hyperplasia (BPH), involving the combined therapy of administering therapeutically effective amounts of a 5α-reductase inhibitor in combination with an α receptor blocker. -adrenergic.

2. Background to the Invention

Benign prostatic hyperplasia (BPH) affects a substantial number of men over 50 and usually requires surgery in advanced stages for relief.

Testosterone (T) is known to be secreted by the testes and the adrenal glands but can undergo a 5a-reductase-mediated conversion giving rise to dihydrotestosterone (DHT) at peripheral sites including the liver, skin, and prostate. DHT is preferably bound by the nucleus of prostate cells thereby indicating that DHT, instead of T, is a primary androgen required by the prostate for its growth and function. This leads to the hypothesis that, by inhibiting 5a-reductase, DHT formation can be reduced and prostate regression can be successfully achieved.

-3Finasteride, 17β (Nt-butyl) carbamoyl-4-aza-5a-androst-l-en-3-one, was developed as a compound that was discovered to be a 5a-reductase inhibitor and that had effects against benign prostatic hyperplasia . Finasteride is a 4-azasteroid and a competitive enzyme inhibitor. It shows no affinity for the androgen receptor and therefore is not expected to interfere with the binding and action of T in these tissues, such as muscle, which responds to T, and thus does not result in feminizing characteristics.

Typical 4-aza steroid 5a-reductase inhibitors include those developed by Merck. (See US Pat. 4,377,584 by Rasmusson, et al .; US Pat. 4,220,735 by Rasmusson, et al; US Pat. 4,845,104 by Carlin, et al .; US Pat. 4,760,071 by Rasmusson, et al; which reveals finasteride, 17B- (Nt-butyl) carbamoyl-4-aza-5a-androst-l-en-3-one, known by its brand as PROACAR; · US Pat. 4,859,681 by Rasmusson, et al .; EPO Publn. 155 076; EPO Publn. 0 004 949; and EPO Publn. 0314 189.

In many cases, the reversal of the enlarged prostate process is accompanied by symptomatic relief from nicturia, hesitation, and difficulty urinating. However, symptomatic relief does not occur in all cases. When the 5a-reductase inhibitor inhibits the speed of development of the enlarged prostate without the concomitant decrease, symptomatic relief as experienced by patients may not occur.

What is desired in the art is a combination therapy for both the treatment of the underlying cause of BHP as well as the treatment of symptoms of the disease in the short term.

SUMMARY OF THE INVENTION

With this invention, a method of treating benign prostatic hypertrophy is provided, with patients experiencing inadequate symptomatic relief and those in need of such treatment treated with a steroid 5a-reductase 4-aza inhibitor, comprising the stage of administration to such patients. patients in combination of therapeutically effective amounts of a 5a-reductase inhibitor, a 17B-substituted 4-azasteroid, a 17B-substituted non-azasteroid, 17B-acyl-3-carboxyandrost-3,5-diene, benzoylaminophenoxybutanoic acid derivative, benz (thio) condensed amide or cinnamoylamide derivative, 1,2-diethers or aromatic thioethers, aromatic ortho acylaminophenoxy alkanoic acids, ortho thioalkylacylaminophenoxy alkanoic acids, pharmaceutically acceptable salts and their esters, and particularly a α -adrenoceptor blocking agent here ^ referred to as α-blocker.

Thus, the combined effect of a 5a-reductase inhibitor in inhibiting the production of DHT in the prostate and the α-adrenergic receptor blocker, ie terazosin, will result in a greater effect on the growth and symptomatic relief of the enlarged prostate than another agent by itself.

BRIEF DESCRIPTION OF THE INVENTION AND PREFERRED EXECUTIONS

In a preferred aspect, the present invention provides an effective method of treating BHP in patients who need symptomatic relief by administering therapeutically effective amounts of α-blocker in combination with a 5α-reductase inhibitor or a pharmaceutical composition. The active compounds can be administered together or in any order, as will be discussed below.

By the term patients in need of such treatment means male patients with functioning gonads who are being treated with 5a-reductase inhibitor in a therapeutic program designed to combat benign prostatic hyperplasia (BPH) and who reveal the need for symptomatic relief.

The use of therapeutically effective amounts of 5α-reductase inhibitor and α-blocker according to this invention effectively treats adverse symptoms of BPH including nicturia, hesitation, decreased urine flow, and the like.

A-adrenoreceptor stimulation has been shown to contribute to the obstruction of benign prostatic hyperplasia (See M. Caine, et el., Br. J Urol., Vol. 48, pp. 255-263 (1976).

Α-adrenergic receptor blockers generally act as antihypertensive agents by blocking α-adrenergic receptor sites. They relax the stroma of the (smooth) tissue in the bladder, which causes the fibrous tissue to contract when stimulated by norepinephrine and results in a decrease in the amount of urinary flow. In this way, the blocker effect consists of relaxing the fibrous tissue which results in an increase in the amount of urinary flow.

Α-adrenergic blocking agents selectively bind to a class a of adrenergic receptors and thereby interfere with the ability of sympathomimetic amines to initiate actions at these sites.

There are prominent differences in the relative abilities of α-adrenergic blocking agents to antagonize the effects of sympathomimetic amines on the two subtypes of a receptors. Prazosin is known to be much more potent in

block α - receptors (postsynaptic) than receptors a ₂ which, among other effects, regulate the neural release of the transmitter (presynaptic receptors). Phenoxybenzamine is a moderately selective α- ₁ blocking agent, while pentolamine is only three to five times more potent in inhibiting adrenergic receptors than adrenergic receptors. In contrast, yohimbine is a selective _2- blocker and has been shown to avoid the antihypertensive effects of clonidine, an α ₂ agonist ·

However, α-adrenergic blockers are preferred in this invention, which are preferably α _χ blockers and have little or no blocking activity.

Examples of adrenergic receptor blockers are λ terazosin (Abbott-Hytrin) whose chemical name is 1- (4-amino-6,7-dimethoxy-2-quinazolinyl) -4 - [(tetrahydro-2-furanyl) carbonyl] piperazine , as described in German Patent 2,646,186 and Patent. . λ,.

U.S. 4,026,894; doxazosin (Pfízer-Cardura) whose chemical name is

1- (4-amino-6,7-dimethoxy-2-quinazolinyl) -4 - [(2,3-dihydro-1,4-benzododioxin-2-yl) carbonyl] -piperazine, as described in the German Patent «*

2,847,623 and U.S. Patent 4,188,390; prazosin (Pfizer-Minipres) whose chemical name is 1- (4-amino-6,7-dimethoxy-2-quinazolinyl) -4- (2-furanylcarbonyl) piperazine, as described in British Patent 1,156,973, US Patent 3,511,836 and application for Patent. *>

Dutch 7,206,067; bunazosin (Sandoz-Detantol) whose chemical name is 1- (4-amino-6,7-dimethoxy-2-quinazolinyl) hexahydro

4- (1-pxobutyl) -1H-1,4-diazepine, as described in the Belgian Patent

Appln 806,626, U.S. Patent 3,920,636 and Kokai Japanese 75,140,474;

indoramine (Baratol-Wyeth) whose chemical name is N- [1- (2- (1H-indol-3-yl) ethyl] -4-piperidinyl] benzamide, as described in the South Patent

African 68 03204, U.S. Patent 3,527,761; Alfuzosin (Synthelabs) whose chemical name is

-Ί-

Ν— [3— [(4-amino-6,7-dimethoxy-2-quinazolinyl) methylamino] propyl] tetrahydro-2-furancarboxamide, as described in German Patent 2,904,445 and U.S. Patent 4,315,007.

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

on what:

the dotted line represents a double bond when present; 13. _.

R and R are independently hydrogen, methyl or ethyl;

.

R is a hydrocarbon radical selected from straight or branched, substituted or unsubstituted alkyl, cycloalkyl, or aralkyl of 1-12 carbon atoms or mono-cyclic aryl optionally containing 1 or more lower alkyl substituents of from 1-2 carbon atoms and / or 1 or more halogen substituents;

R ^z is hydrogen or methyl;

R ^z 'is hydrogen or β-methyl;

R ^zr 'is hydrogen, α-methyl or β-methyl, and their pharmaceutically acceptable salts or esters.

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

on what

R ¹ is hydrogen, methyl or ethyl, and .11

R is a branched alkyl, cycloalkyl, aralkyl chain of

4-12 carbons, phenyl, optionally substituted by methyl, chlorine or fluorine, substituted or unsubstituted 1-, 2-adamantyl, 1-, 2-adamantyl-methyl, 1-, 2- or 7-norbornanyl, 1-,

2- or 7-norbornanylmethyl.

Representative compounds of the present invention include the following.

175- (N-tert-amylcarbamoyl-4-aza-5a-androst-l-en-3-one,

175- (N-tert-hexylcarbamoyl-4-aza-5a-androst-l-en-3-one,

175- (N-tert-butylcarbamoyl-4-aza-5a-androst-l-en-3-one,

175- (N-tert-isobutylcarbamoyl-4-aza-5a-androst-l-en-3-one,

175- (N-tert-octycarbamoyl-4-aza-5a-androst-l-en-3-one,

175- (N-octylcarbamoyl-4-aza-5a-androst-l-en-3-one,

175- (N-l, l-diethylbutylcarbamoyl-4-aza-5a-androst-l-en-3-one,

175- (N-neopenticarbamoil-4-aza-5a-androst-l-en-3-one,

175- (N-2-adamantylcarbamoyl-4-aza-5a-androst-l-en-3-one,

175- (N-l-adamantylcarbamoyl-4-aza-5a-androst-l-en-3-one,

175- (N-2-norbornylcarbamoil-4-aza-5a-androst-l-en-3-one,

175- (N-l-norbornylcarbamoil-4-aza-5a-androst-l-en-3-one,

175- (N-phenylcarbamoyl-4-aza-4-methyl-5a-androst-l-en-3-one, 17B- (N-benzylcarbamoyl-4-aza-4-methyl-5a-androst-l-en- 3-one,

175- (N-tert-amylcarbamoyl-4-aza-4-methyl-5a-androst-l-en-3-one,

17β- (N-tert-hexylcarbamoyl-4-aza-4-methyl-5a-androst-l-en-3-one,

17β- (N-tert-butylcarbamoyl-4-aza-4-methyl-5a-androst-l-en-3-one,

17β- (N-isobutylcarbamoyl-4-aza-4-methyl-5a-androst-l-en-3-one,

17β- (N-tert-octylcarbamoyl-4-aza-4-methyl-5a-androst-l-en-3-one,

175- (N-1, 1,3,3-tetramethylbutylcarbamoyl-4-aza-5a-androst-l-en-3— one,

175- (N-octylcarbamoyl-4-aza-4-methyl-5a-androst-l-en-3-one,

17β- (Ν-1, l-diethylbutylcarbamoyl-4-aza-4-methyl-5a-androst-l-en-3— one,

17β— (N-neopentylcarbarnoil-4-aza-4-methyl-5a-androst-l-en-3-one,

175- (N-1-adamantylcarbamoyl-4-aza-5a-androstan-3-one,

17β— (N-l-adamantylcarbamoyl-4-methyl-4-aza-5a-androst-l-en-3-one,

175- (N-1-adamantylcarbamoyl-4-methyl-4-aza-5a-androstan-3-one,

175- (N-l-adamantylmethylcarbamoyl-4-aza-5a-androst-l-en-3-one,

17β- (N-2-adamantylcarbamoyl-4-aza-5a-androstan-3-one,

175- (N-methyl-N-2-adamantylcarbamoyl) -4-methyl-4-aza-androstan-3-one,

175- (N-2-adamantylcarbamoyl) -4-methyl-4-aza-5a-androstan-3-one,

175- (Ν-2-adamantylcarbamoyl) -4-methyl-4-aza-5a-androst-l-en-3-one,

17B- (N-metil-N-2-adainant.il) carbamoyl-4-methyl-4-aza-androst-3-one

17β- (N- (3-methyl) -1-adamantyl-carbamoyl) -4-aza-4-methyl-5a-androst-e-an-3-one,

175- (N-exo-2-norbornanylcarbamoyl) -4-aza-4-methyl-5a-androst-l-en-3-one,

17β- (N-exo-2-norbornanylcarbamoyl) -4-aza-5a-androst-l-en-3-one;

17β- (Ν-2-adamantylcarbamoyl) -4-aza-5a-androst-en-3-one,

175- (N-methyl-N-2-adamantylcarbamoyl) -4 ~ aza-4-methyl-androstan-3-one,

175- (Ν-2-adamantylcarbamoyl) -4-methyl-4-aza-5a-androst-en-3-one;

17β- (N-methyl-N-2-adamantyl) carbamoyl) -4-methyl-4-aza-androstan-3-one,

The corresponding compounds of the aforementioned compounds in which the 4-aza substituent is substituted on each of the aforementioned compounds with hydrogen, or a methyl or ethyl radical, form a different N-substituent, where a double bond may optionally be present as indicated by the dashed line in position 1.

The alkyl, cycloalkyl, monocyclic aryl,

1-, 2-adamantyl or 1-, 2-norbornanyl can be substituted with one or more substituents of the following: linear / branched C ₁ -C ₄ alkyl, including methyl, ethyl, isopropyl, n-butyl; nitro; oxo; C-C aralkyl, including benzyl; (CH) n COOR where n is 0-2 and R is H or linear / branched C ₁ -C ₄ alkyl including methyl, ethyl; CH ^ OH; OH; OR where R is linear / branched C 1 -C ₄ alkyl including methyl, ethyl; halo, including fluorine, bromine, iodine; COOH; COOR, where R is ^c 1 ” ^and 4 linear / branched alkyl; -CONH ₂ ; CH ₂ NH ₂ ; CH ₂ NHCOR where R is linear / branched ^C ₁ ^C 4 alkyl including methyl, ethyl; phenene; o, m, p substituted phenyl, including p-nitro, p-amino and p-sulfo; or cyan. The amino group of the adamantyl or norbornanyl moiety can also be substituted as R ¹ with methyl and ethyl, as well as hydrogen.

Also included within the scope of this invention are pharmaceutically acceptable salts or esters, in which a basic or acidic group is present in the substituted alkyl, cycloalkyl, aralkyl, adamantyl or norbornanyl moiety. When the acidic substituent is present, i.e. -COOH, the ammonium, sodium, potassium, calcium, etc. salt can be formed to be used as the dosage form.

Where a basic group is present, i.e., amino acid salts, i.e. hydrochloride, hydrobromide, acetate, pamoate, and the like, can be used as the dosage form.

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

Representative examples included for R (where AD and 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-fluorine-1-AD; 3-fluorine-1-AD; 4-hydroxy-2-AD;

3-phenyl-1-AD; 3- (p-aminophenyl) -1-AD; 3- (p-nitrophenyl) -1-AD;

3-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-iodo2-AD; 4-bromo-2-AD; 4-chloro-2-AD; 1-acetylaminomethyl-2-AD; 1-carboxymethyl-2-AD;

1-methyl-2-AD; 1-aminocarboxymethyl-2-AD; 1-aminocarboxyl-1-AD;

2-cyano-2-AD; 3,5-dimethyl-7-ethyl-1-AD; 4-hydroxy-1-AD; 1-hydroxy-2-AD; 5-carboxy-3-methyl-1-AD; 3-carboxy-1-AD; 3-hydroxy-1-AD; and etc.

. . - 2

Representative examples included for R as substituted norbornanyl moieties are (where 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-ΝΒ; 2,2,3,3,5,5,6,6,7,7-decaflúor-1-NB; 3-hydroxy-2-NB;

3-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; and etc.

Processes for preparing the Formula I compounds useful in this invention, including the above, are well known in the art.

The new compounds of formula I of the present invention can be prepared by a method starting with the known steroid ester (IIIA) of Formula:

IIIA)

-1317Β- (carbomethoxy) -4-aza-5-a-androstan-3 ~ ones which includes the optionally 1) dehydrogenation steps of said starting material to produce the corresponding compound containing a double bond at the 1,2- of ring A, 2) conversion of the 17-carbomethoxy substituent into an N-substituted alkyl substituent, cycloalkyl, aralkyl, monocyclic acyl, or adamantylcarbamoyl and, if desired, 3) alkylation of ring A nitrogen to introduce an N-methyl or N substituent -ethyl no at position 4 of ring A. For the dehydrogenation phase, it is preferable that nitrogen

4-aza is unsubstituted. Alternative paths can consist of one or more discrete chemical phases and, if desired, can take place before step (1) or after 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 175-alkoxycarbonyl-4-aza-5a-androstan-3-ones, compound III, ( prepared in the literature as described in US Patent 4,377,584) with a dehydrogenating agent such as a benzeneselenic anhydride in an inert reflux solvent, for example chlorobenzene, to form a 17B-alkoxycarbonyl-4-aza-5a-androst-l-eno -3-one IV. (alternatively, the Dolling, et al., JACS 1988, VOL. 110, pp. 3318-3319, dichlorodicytobenzoquinone process can be used); (2) the compound formed 5a-androst-1-ene-3-one from Stage 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 alkyl iodide (methyl or ethyl) to form the corresponding 17B-alkoxy-adamantyl-carbamoyl-4-alkyl-4-aza-5a-androst-l-ene-3-one V ; (4) subsequent hydrolyzing of said 17B-alkoxycarbonyl — 4-alkyl-4-aza-5a-androst-l-ene-3-one with a strong base, such as methanolic potassium hydroxide at reflux temperature, followed by acidification and isolation of the resulting steroidal acid to produce

17B-carboxy 4-alkyl-4-aza-5a-androst-1-ene-3-one VI; (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 product 17β- (2-pyridylthiocarbonyl) -4-alkyl-4-aza-5a-androst-1-ene-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 norbornanilamine in an inert solvent for example tetrahydrofuran, to provide the desired 17b-adamantyl-carbamoyl-4-alkyl-4-aza product -5a-androst-l-ene-3-one VIII which can be isolated by chromatography for example on silica gel. When the previous reaction is carried out in the absence of the first formation of the first double bond in position 1, the corresponding 17B- (N-adamantyl-carbamoyl) -4-alkyl-4-aza-5a-androstan-3- is prepared one (or N-norbornanyl carbamoyl compound).

According to the alternative process of our invention the corresponding 17B- (N-adamantyl-carbamoyl) -4-aza-5a-androst-l-en-3-one substituted in Ν, XIV, is readily prepared from 17β- (alkoxycarbonyl) -4-aza-5a-androstone-3-one IV repeating the previous series of reaction phases but omitting the previous alkylation phase 2, that is, treatment of 4-aza-5a-androst-l-eno- 3-one with for example sodium amide followed by methyl or ethyl iodide via intermediates XII and XIII.

According to an alternative process for the preparation of compounds of our invention having only hydrogen as the only substituent on ring A nitrogen, the double bond on ring A is introduced as the last stage of the process. Thus, a 17B-alkoxycarbonyl-4-aza-5a-androstone-3-one III is hydrolyzed to the corresponding steroidal acid IX

17B-carboxy-4-aza-5a-androstone-3-one which in turn is converted to the corresponding pyridylthio ester, 176- (2-pyridylthiocarbonyl) -4-aza-5a-androstone-3-one, X followed of the treatment of the ester with an amine of formula R -NH ₂ where R is previously defined as 1- or 2-adamantium or 1-, 2-, or 7-norbornanyl to form a 17β- (N-adamantyl-carbamoyl) ) -4-aza-5a-androstone-3-one XI which is dehydrogenated as previously described to produce compound XIV, 17β- (N-adamantyl-carbamoyl) -4-aza-androst-l-en-3-one or the corresponding norbornanil derivative.

In another alternative method of introducing the 17β- (N-adamantyl-carbamoyl) substituent into a 17B-carboxy androstane compound of formula VI, XII or IX, each is treated similarly to the process described in Steroids, Vol. 35, 3, March 1980, p. 1-7 with dicyclohexylcarbodiimide and 1-hydroxybenzo-triazole to form ο 17β- (1-benzotriazoloxycarbonyl) -4-aza-5a-androst-l-en-3-one VII, XIII or compound X, where substituent X is a benzotriazoloxy group.

16-methyl derivative in which R 'is methyl are prepared from known 16-methyl-17-acyl-4-methyl-4-aza-5a-androstan-3-ones, for example 4,16B-dimethyl-17fine- acetyl-4-aza-5a-androstan-3-one by known dehydrogenation processes for 4-methyl-4-aza compounds to produce the corresponding 4,16β-dimethyl-175-acetyl-4-aza-5a-androst-l -en-3-one.

The above reactions are shown schematically on the following flow sheet.

-16FLOW SHEET

X and 2-pyridylthio or 1-benzotriazoloxy.

R is 1- or 2-adamantyl or norbornanyl

It is a preferred 4-aza steroid is a 175-acyl-4-aza-5a-androst-l-ene-3-one compound of formula:

where the dashed line represents a double bond when it is present

R is selected from hydrogen, methyl and ethyl;

R is:

(a) a monovalent radical selected from straight or branched chain alkyl, or cycloalkyl, of from 1-12 carbon atoms, which can be substituted by one or more C 1 -C ₂ alkyl or halo;

(b) an aralkyl radical selected from benzyl or phenethyl;

(c) an aromatic polycyclic radical that can be substituted by one or more of: -OH, -OH protected, " ^oc 1" ^and 4 alkyl, C 1 -C 4 alkyl, halo or nitro;

(d) an aromatic monocyclic radical that can be replaced by one or more of:

(1) -OH, “OC ₁ -C ₄ alkyl, alkyl, - (CH ^ OH, - (CH ^,

COOH, including protected hydroxy, where m is 1-4, n is 1-3, provided that C ^ -C ₄ alkyl is only present when a

of the aforementioned oxygen-containing radicals is present;

(2) -SH, -SC -C alkyl, SOC ₁ ~ C ₄ alkyl, -SO ^ -Í ^ alkyl, -S0 ₂ N (C ₁ -C ₄ -alkyl) ₂ , C ^ -C ^ alkyl, - (CH ₂ ) _m SH,

-S- (CH) -O-, COCH ₃ , where m is 1-4, n is 1-3, provided that C ₁ ~ C ₄ alkyl is only present when one of the aforementioned sulfur-containing radicals is present;

. 3 (3) N (R), which can be protected, where R is independently H or ^ 4 alkyl, where the monoaryl ring can also be additionally substituted with C ₄ -C ₄ alkyl; and (4) heterocyclic radical selected from 2 or 4-pyridyl, 2-pyrrolyl, 2-furyl or thiophenyl;

and R ', R' ', R' are each selected from hydrogen and methyl, and their pharmaceutically acceptable salts.

A preferred embodiment of the compounds of the process of our invention is:

the compound of the previous Structure IA where the dashed line is a double bond,

R is hydrogen or methyl, e.g. ·.

R is branched chain alkyl, or 4-10 carbon cycloalkyl, and R and R 'are hydrogen.

Another embodiment of the invention is the foregoing compounds. .

of Structure I where R is phenyl, or phenyl substituted by substituents described above, including where

...

R is phenyl, 2-, 3-, or 4-tolyl, xylyl, 2-bromophenyl,

2-chlorophenyl, 2,6-dichlorophenyl, 2,6-dibromophenyl, aminophenyl, N-alkylaminophenyl, Ν, Ν-dialkylaminophenyl,

4-biphenyl, 3-biphenyl, naphthyl, anthracyl, phenanthryl, thiophenyl, methylthiophenyl, methylsulfinyl, phenyl, methylsulfophenyl, aminosulfophenyl, thioethylphenyl,

acetoxymethylthiophenyl, 175- (4-hydroxyphenyl), 175- (3-hydroxyphenyl), 175- (3,4-dihydroxyphenyl), or 175- (3,5-dimethyl-4-hydroxyphenyl).

Representative compounds of the invention are:

175- (phenylcarbonyl) -4-aza-4-methyl-5a-androst-1-ene-3-one;

175- (2-tolylcarbonyl) -4-aza-4-methyl-5a-androst-1-ene-3-one;

175- (3-tolylcarbonyl) -4-aza-4-methyl-5a-androst-1-ene-3-one;

175- (4-tolylcarbonyl) -4-aza-4-methyl-5a-androst-1-ene-3-one;

175- (2-bromophenylcarbonyl) -4-aza-4-methyl-5a-androst-1-ene-3-one;

175- (2-chlorophenylcarbonyl) -4-aza-4-methyl-5a-androst-1-ene-3-one;

175- (2,6-dichlorophenylcarbonyl) -4-aza-4-methyl-5a-androst-1-ene-3-one;

175- (2,6-dibromophenylcarbonyl) -4-aza-4-methyl-5a-androst-1-ene-3-one;

175- (xylylcarbonyl) -4-aza-4-methyl-5a-androst-1-ene-3-one;

175- (t-butylcarbonyl) -4-aza-5a-androst-1-ene-3-one;

175- (isobutylcarbonyl) -4-aza-5a-androst-1-ene-3-one;

175- (isooctylcarbonyl) -4-aza-5a-androst-1-ene-3-one;

175- (n-octylcarbonyl) -4-aza-5a-androst-1-ene-3-one;

175- (1,1-diethylbutylcarbonyl) -4-aza-5a-androst-1-ene-3-one;

175- (neopentylcarbonyl) -4-aza-5a-androst-1-ene-3-one;

175- (tert-amylcarbonyl) -4-aza-4-5a-androst-1-ene-3-one;

175- (tert-hexylcarbonyl) -4-aza-4-5a-androst-1-ene-3-one;

175- (cyclohexylcarbonyl) -4-aza-5a-androst-1-ene-3-one;

175- (cyclopentylcarbonyl) -4-aza-5a-androst-1-ene-3-one;

175- (benzylcarbonyl) -4-aza-5a-androst-1-ene-3-one;

175- (2-pyridylcarbonyl) -4-aza-5a-androst-1-ene-3-one;

175- (4-pyridylcarbonyl) -4-aza-5a-androst-1-ene-3-one;

175- (2-pyrrolylcarbonyl) -4-aza-5a-androst-1-ene-3-one;

175- (2-furylcarbonyl) -4-aza-5a-androst-1-ene-3-one;

175- (2-thiophenylcarbonyl) -4-aza-5a-androst-1-ene-3-one;

-20—

17β- (2-adamantylcarbonyl) -4-aza-5a-androst-l-ene-3-one;

17β- (phenylcarbonyl) -4-aza-5a-androst-l-ene-3-one;

17B- (2-tolylcarbonyl) -4-aza-5a-androst-1-ene-3-one;

17β- (3-tolylcarbonyl) -4-aza-5a-androst-l-ene-3-one;

17B- (4-tolylcarbonyl) -4-aza-5a-androst-1-ene-3-one;

17B- (2-bromophenylcarbonyl) -4-aza-5a-androst-1-ene-3-one;

17B- (2-chlorophenylcarbonyl) -4-aza-5a-androst-1-ene-3-one;

17B- (2,6-dichlorophenylcarbonyl) -4-aza-5a-androst-1-ene-3-one;

17B- (2,6-dibromophenylcarbonyl) -4-aza-5a-androst-l-ene-3-one;

17β- (xylylcarbonyl) -4-aza-5a-androst-l-ene-3-one;

17B - (phenylethyl) carbonyl-4-aza-5a-androst-1-ene-3-one;

17B- (4-dimethylaminophenylcarbonyl) -4-aza-5a-androst-l-en-3-one;

17B- (3-dimethylaminophenylcarbonyl) -4-aza-5a-androst-l-en-3-one;

17B- (3,4-diethylaminophenylcarbonyl) -4-aza-androst-l-en-3-one;

17B- (3,5-dimethyl-4-diethylaminophenylcarbonyl) -4-aza-5a-androst-1-en-3-one;

17B- (N-4-methylaminomethylphenylcarbonyl) -4-aza-5a-androst-l-en-3-one;

17B- (2-N-ethylamino-4-ethylphenylcarbonyl) -4-aza-5a-androst-l-en-3— one;

17B- (4-phenylbenzoyl) -4-aza-5a-androst-l-en-3-one;

17B- (3-phenylbenzoyl) -4-aza-5a-androst-l-en-3-one;

17B- (4-biphenyl) -4-aza-5a-androst-l-en-3-one;

17B- (3-biphenyl) -4-aza-5a-androst-l-en-3-one;

17B- (1-naphthyl) -4-aza-5a-androst-l-en-3-one;

17B- (2-naphthyl) -4-aza-5a-androst-l-en-3-one;

17B- (1-phenanthryl) -4-aza-5a-androst-l-en-3-one;

17β- (2-phenanthryl) -4-aza-5a-androst-l-en-3-one;

17B- (1-biphenyl) -4-aza-5a-androst-l-en-3-one;

17B- (9-anthracyl) -4-aza-5a-androst-l-en-3-one;

17B- (4-thiophenylcarbonyl) -4-aza-5a-androst-l-en-3-one;

17B- (3-thiophenylcarbonyl) -4-aza-5a-androst-l-en-3-one;

17B- (4-methylthiophenylcarbonyl) -4-aza-5a-androst-l-en-3-one;

17β- (4-methylsulfinylphenylcarbonyl) -4-aza-5a-androst-l-en-3-one; 17β- (4-methylsulfophenylcarbonyl) -4-aza-5a-androst-l-en-3-one;

17β- (3-methylsulfinylphenylcarbonyl) -4-aza-5a-androst-l-en-3-one;

17β- (4-N, N-dimethylaminosulfophenylcarbonyl) -4-aza-5a-androst-1-en-3-one;

17β- (2-ethyl-4-methylthiophenylcarbonyl) -4-aza-5a-androst-l-en-3-one; 17β- (4-thioethylphenylcarbonyl) -4-aza-4-methyl-5a-androst-l-en-3-one; 17B- (4-acetoxymethylthiophenylcarbonyl) -4-aza-4-methyl-5a-androst-1-en-3-one;

17β- (2-methyl-4-methylthiophenylcarbonyl) -4-aza-4-methyl-5a-androst-l-en-3-one;

17β- (2-methyl-4-methylsulfinylphenylcarbonyl) -4-aza-4-methyl-5a-androst-l-en-3-one;

17β- (2-isopropyl-4-methylsulfophenylcarbonyl) -4-aza-4-methyl-5a-androst-l-en-3-one;

17β- (4-methylthiophenylcarbonyl) -4-aza-4-methyl-5a-androstan-3-one;

17β- (4-methylsulfinylphenylcarbonyl) -4-aza-4-methyl-5a-androstan-3— one;

17β- (4-methylsulfophenylcarbonyl) -4-aza-4-methyl-5a-androstan-3-one;

17β- (4-hydroxyphenyl) -4-aza-5a-androst-l-en-3-one;

17β- (3-hydroxyphenyl) -4-aza-5a-androst-l-en-3-one;

17β- (3,4-dihydroxyphenyl) -4-aza-5a-androst-l-en-3-one;

17β- (3,5-dimethyl-4-hydroxyphenyl) -4-aza-5a-androst-l-en-3-one;

17B- (4-hydroxymethylphenyl) -4-aza-5a-androst-l-en-3-one;

17B- (2-hydroxyethylphenylcarbonyl) -4-aza-5a-androst-l-en-3-one;

17β- (4-methoxyphenyl) -4-aza-5a-androst-l-en-3-one;

17β- (4 — carboxymethylphenyl) -4-aza-5a-androst-l-en-3-one;

17β- (4-hydroxyphenyl) -4-aza-4-methyl-5a-androst-l-en-3-one; .

17β- (3-hydroxyphenyl) -4-aza-4-methyl-5a-androst-l-en-3-one;

17β- (3,4-dihydroxyphenyl) -4-aza-4-methyl-5a-androst-l-en-3-one;

17B- (3,5-dimethyl-4-hydroxyphenyl) -4-aza-4-methyl-5a-androst-l-en-3-one;

17β- (4-hydroxymethylphenyl) -4-aza-4-methyl-5a-androst-l-en-3-one;

17Β- (2-hydroxyethylphenylcarbonyl) -4-aza-4-methyl-5a-androst-l-en-3ona;

17β- (4-methoxyphenyl) -4-aza-4-methyl-5a-androst-l-en-3-one;

175- (4-carboxymethylphenyl) -4-aza-4-methyl-5a-androst-1-en-3-one; and

17β- (4-carboxyphenyl) -4-aza-5a-androst-l-en-3-one, and the corresponding compounds in which the 4-hydrogen substituent is replaced in each of the aforementioned compounds by a methyl or ethyl radical .

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

said 17B- (carbomethoxy) -4-aza-5a-androstan-3-one, which includes steps (1) dehydrogenating said starting material to produce the corresponding compound containing a double bond at the 1,2- position of the ring A, (2) conversion of the 17-carbomethoxy substituent to a 17B-acyl substituent and, if desired (3) alkylation of ring A nitrogen to introduce 4-methyl or 4-ethyl substituents into ring A. For the dehydrogenation phase, it is preferable that the 4-aza nitrogen is unsubstituted. The dehydrogenation step can be carried out, for example according to the process of Dolling, et al. involving

dichlorodicianobenzoquinone, JACS (1988), 110, pp. 3318-3319. Phase (2) can consist of one or more chemical phases and, if desired, can take place before phase (1) or after phase (1) or phase (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 III compound with a dehydrogenating agent such as benzeneselenic anhydride in reflux of chlorobenzene to form a 17B-alkoxycarbonyl-4-aza-5a-androst-l-en-3-one (IV) compound, (2) to 5a-androst-l-en-3-one formed in phase (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 iodide (methyl or ethyl) to form the corresponding 17B-alkoxycarbonyl-4-alkyl -4-aza-5a-androst-l-en-3-one (V), (3) subsequent hydrolysation of said 17B-alkoxycarbonyl-4-alkyl-4-aza-5a-androst-l-en-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, 17-carboxy-4-alkyl-4-aza-5a-andr ost-1-en-3-one (VI), (4) said steroidal acid is then converted to its corresponding 2-thiopyridyl ester by refluxing with triphenyl phosphine and 2,2'-dipyridyl disulfide in an inert solvent and the product 17B- (2-pyridylthiocarbonyl) -4-alkyl-4-aza-5a-androst-l-en-3-one (VII) is isolated by chromatography on silica, (5) said pyridylthio ester is then reacted with an R -Li or a compound 2

R MgX (X = C1, Br), such as butylmagnesium chloride in. tetrahydrofuran, to form the desired product, for example, 17B- (sec-butylcarbonyl) -4-alkyl-4-aza-5a-androst-l-en-3-one (VIII) which is isolated by gel chromatography of silica. When the _. . . The previous reaction is carried out using a compound R MgX or a 2

R -Li instead of sec-butylmagnesium chloride, is prepared at

corresponding 17B- (acyl) -4-alkyl-4-aza-5a-androst-1-en-3-one 2 where acyl is R carbonyl.

According to the process of our invention, the corresponding 17B- (acyl) -4-aza-5a-androst-l-en-3-one XV is readily prepared from 17β- (alkoxycarbonyl) -4-aza-5a -androsten-3-one (IV) repeating the previous series of reaction phases but

omitting the previous phase 2, that is, treatment of 4-aza-5a- • before drost-l-en -3-one with an sodium amide followed by iodide in methyl or ethyl. According with an alternative alternative process in

preparation of compounds of our invention, having only hydrogen as the single substituent on the nitrogen of ring A, the double bond 1,2- on ring A is introduced as the last stage of the process. Thus, a 17B-alkoxycarbonyl-4-aza-5a-androstan-3-one (III) is hydrolyzed to the corresponding steroidal acid, 17B-carboxy-4-aza-5a-androstan-3-one, (IX) which , in turn, is converted to the corresponding thiopyridyl ester, 17B- (2-pyridylthiocarbonyl) -4-aza-5a-androstan-l-one (X) followed by the ester treatment

2 . 2 . .

with a compound R MgX or R 11 where R e as defined above to form a 17B- (acyl) -4-aza-5a-androstan-3-one (XI) which is dehydrogenated as described above to produce compound XIV , 17B- (acyl) -4-aza-5a-androst-l — en-3-one.

In a further alternative process for making the compounds of Formula I the starting material is an ester, particularly methyl ester as shown in formula III-V in the scheme,. 2 2 the reaction with a Grignard R MgX reagent, gave the ketone, 17B-R CO-, 2 corresponding to the R portion associated with the Grignard reagent.

The 16-methyl derivatives in which R '·· is methyl are prepared from the known

16-methyl-17-acyl-4-methyl-4-aza-5a-androstan-3-ones, for example 4,16B-dimethyl-17B-acetyl-4-aza-5a-androstan-3-one by processes dehydrogenation to 4-methyl-4-aza compounds to produce the corresponding 4,16B-dimethyl-17-acetyl-4-aza-5a-androst-l-en-one.

The previous reactions are schematically represented in the following structural sketch:

X is 2-pyridylthio

-27—

where X is a 2-pyridylthio substituent and R is defined as above.

_. . 2 In the reaction scheme described above, where R is p-hydroxyphenyl, it can be derived starting with an appropriate bromophenylylphenyl, for example p-bromophenylphenol, protecting the phenolic -OH with a conventional blocking group, for example trioganosylyl, ie t -butyldimethylsilyl, carrying out the Grignard reaction and then deblocking the silyl group using, 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 a person skilled in the art from this description.

By the term protected hydroxy as used herein, we designate the -OH alcoholic or carboxylic groups which can be protected by conventional blocking groups in the art as described in Protective Groups In Organic Synthesis by Theodora W. Greene, Wiley-Interscinence, 1981, New York. Preferred are triorganosylyl groups, for example t-butyl-dimethylsilyl, phenyldimethylsilyl, diphenylmethylsilyl, and the like.

The term ^C ₁ ^_ 4 alkyl such with used herein, is meant linear or branched alkyl, including methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl and t-butyl.

When this reaction scheme is carried out using 2 2 2 a compound R MgX or R -Li containing a R substituted with thiophenyl, for example p-methylthiophenyl magnesium chloride, is

the corresponding 175- (substituted thio-benzoyl) -4-al2-kilo-4-aza-5a-androst-l-en-3-one is prepared in which phenyl and R.

Grignard reagent, R MgX, for all species included within the scope of this invention, is available or can be readily produced by a technician. For example,

...

when R is C ₁ -C ₄ alkyl thiophenyl, it can be formed from the appropriate ^c ^ ^"c tiobromobenzeno ₄ alkyl, for example P-metiltiobromobenzeno.

C 1 -C ₄ alkyl thiobenzene formed can be used for further preparation of C ₁ -C ₄ alkyl sulfoxides by oxidation with for example m-chloroperbenzoic acid. The resulting sulfoxide can be further oxidized by using the reaction with m-chloroperbenzoic acid maintained for a longer period of time to form the C 1 -C ₄ alkyl sulfone.

In addition, the sulfoxide can be used in the Pummerer rearrangement to form the corresponding thiol.

. 2 phenyl (R) substituted by -SO ₂ N (C ₁ ~ C ₄ alkyl) ₂ is formed from appropriate bromobenzene, for example pN, N-dimethylaminosulfobromobenzene which is used directly in the Grignard reaction to form the final product.

The thioalkyl groups on the phenyl ring, i.e. - (CH) SH, where m is 1-4, are readily formed via a fourth process step from alkyl phenyl alkoxy bromide, Br-CgH ₄ ~ - (CH ₂ ) _m OCH ₃ . Direct addition of the Grignard reagent prepared from the above bromoalkyl phenyl derivative to the thiopyridyl ester results in the Ceto derivative, i.e. 175- (4-methoxyalkylobenzoyl) -4-aza-5a-androst-l-ene-3-one. This can be readily converted to an analogous uncle via BBr ₃ at -70 ° C to form the

hydroxyalkyl derivative, followed by displacement by halogen, for example, bromine and then converting the halogenated compound by displacement of NaSH to give the final mercapto compound, where in the Reaction Scheme said pyridylthio ester. 2 is reacted with ammophenyl containing compound R-Li or an R MgX (X = C1, Br), such as p-dimethylammophenyl magnesium chloride, this reaction is carried out in tetrahydrofuran to form the desired product 17B- (p-dimethylaminophenyl -carbonyl) -4-alkyl-4-aza-5a-androst-l-en-3-one (VIII) which is isolated by chromatography on silica gel.

. 2 Grignard reagent, R MgX, for all aminophenyl species included within the scope of this invention, is available and can be readily performed by a technician.

When in the process, said Grignard reagent contains a phenolic type R moiety, then said pyridylthio ester. . 2 -2 and reacted with an R -Li or a Grignard R MgX reagent (X = C1, Br), such as p-methoxyphenyl magnesium chloride in tetrahydrofuran to form the desired product, for example 17B- (p-methoxyphenylcarbonyl) -4-alkyl-4-aza-5a-androst-l-en-3-one (VIII) which is isolated by chromatography on silica gel. When this reaction is 2 2.

made using another R MgX or, a compound R -Li instead of p-methoxyphenylmagnesium chloride, the corresponding 17B- (substituted benzoyl) -4-alkyl-4-aza-5a-androst-l-en-3-one is prepared wherein the phenyl and R.

. 2 Grignard reagent, R MgX, for all species included within the scope of this invention, is available and can be produced promptly by a technician.

For example, where R is hydroxyphenyl, it can be derived starting with an appropriate bromophenol, for example

p-bromophenol, protecting the phenolic -OH with a conventional blocking group, for example trioganosilyl, i.e. t-butyldimethylsilyl, carrying out the Grignard reaction and then deblocking the silyl group by using, for example, aqueous tetrabutylammonium fluoride under reflux.

....

When R is hydroxyethylphenyl, the same blocking process can be similarly conducted starting with the appropriate hydroxyalkyl bromophenol, for example p-hydroxymethylbromobenzene, or p-hydroxyethylbromobenzene.

When R is carboxyphenyl, it can be obtained by oxidizing the appropriate hydroxymethylbenzene chromatic acid, for example p-bromohydroxymethylbenzene, formed as described above.

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

Other halogen-substituted benzenes to form the appropriate Grignard reagent used in the present invention will be obvious to a person skilled in the art from this description.

By the term protected hydroxy as used herein, we designate the -OH alcoholic or carboxylic groups which can be protected by conventional blocking groups in the art as described in Protective Groups In Organic Syntesis by Theodora W. Greene, Wiley-Interscience, 1981, New York. Preferred are triorganosylyl groups, for example t-butyldimethylsilyl, phenyldimethylsilyl, diphenylmethylsilyl, and the like.

—31—

Also within the scope of the present invention is the use of IA ketone reduction products, in combination with minoxidyl for the treatment of demarcated alopecia, with secondary alcohols of the formula:

wherein R is selected from hydrogen, methyl and ethyl;

R e:

(a) a monovalent radical selected from straight or branched chain alkyl, or cycloalkyl, of from 1-12 carbon atoms, .. which can be substituted by one or more of C ₁ -C ₂ alkyl or halo;

(b) an aralkyl radical selected from benzyl or phenethyl;

(c) an aromatic polycyclic radical that can be substituted by one or more of: -OH, -OH protected, -0 (^ - 0 alkyl, C4 -C4 alkyl, halo or nitro;

(d) an aromatic monocyclic radical that can be replaced by one or more of:

(1) -OH, -OC ₁ -C ₄ alkyl, 0 _χ -0 ₄ alkyl, - (CH ₂ ) _m 0H, - (CH ₂ ) _n , COOH, including protected hydroxy, where m is 1-4, n is 1-3, provided that C ^ -C ₄ ^to l ⁽ 3 ^u: '-i ^o is only present when a

of the aforementioned oxygen-containing radicals is present;

(2) -SH, -SC -C ₄ alkyl, SOC ^ -C ^ alkyl, “ ^s ° 2 ^C i“ ^C 4 alkyl, -SO ₂ N (C ₁ -C ₄ -alkyl) ₂ , alkyl, - ( CH ^ SH,

-S- (CH ₂ ) -0-, COCH ^, where m is 1-4, n is 1-3, provided that C ₁ -C ₄ alkyl is only present when one of the aforementioned sulfur-containing radicals is present;

. 3 - (3) N (R) ₂ , which can be protected, where R is independently H or alkyl, where the monoaryl ring can 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;

R ', R' ', R' '' are hydrogen or methyl, where the dashed line represents a double bond that may be present, and their pharmaceutically acceptable salts and esters.

These compounds can be made by reducing conventional R-linked carbonyl sodium borohydride without reducing the carbonyl amide in Ring A or the double bond 1,2, if. . 2 is present. If phenyl R contains a carbonyl function, it can be selectively blocked and then regenerated after reduction in borohydride by conventional methods.

The borohydride reduction can be carried out in, for example water or aqueous methanol, at an ambient temperature up to 50 ° C and the product is then isolated and purified by conventional means. The compounds are also active as 5-a reductase inhibitors in the treatment of demarcated alopecia.

The compounds of the present invention, prepared according to the method described above, are, as already described, potent agents in combination with a _1- adrenergic receptor blocker for BPH treatment.

175-substituted steroidal 5a-reductase inhibitors that are non-4-aza steroids are known in the art and include those developed by SmithKline beckmann as disclosed in US Pat. 4,882,319 to Holt, et al .; US Pat. ^and 4,910,226 for 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. 0375 344 now USP 4,937,237; EPO Publn. 0 375 347; now USP 4,970,205; EPO Publn. 0 375 349; now USP 5,026,882.

In the method, steroids not substituted in 175 are of the formula:

on what:

ring A has up to two double bonds;

rings B, C and D have optional double bonds where indicated by dashed lines provided that rings A, B, and C do not have adjacent double bonds and ring D does not have a double bond ^c 16 ^-c 17 when R ₃ represents two substitutes or a divalent substituent;

z is (CH ₂ ) _n and _n is 0 or 2, with the proviso that Z is (CH) _n when adjacent to a double bond;

X is H, Cl, F, Br, I, CF ₃ , or alkyl;

Y is H, CF ₃ , F, Cl, or CH ₃ , with the proviso that Y is H when there is no C-C double bond;

. 3t>

R is H or C alkyl;

°

R is absent or present as H or CH_, with the proviso that ^J is absent when the carbon to which it is attached is unsaturated; and

R ³ is:

(1) α-hydrogen, or a-hydroxy, or a-acetoxy and / or (a) n

-WCR. . 4 where W is a bond or C ^ _ ^ ₂ alkyl ^ l ^ ene, and R e:

(i) hydrogen, (ii) hydroxy, (iii) C ₁ - _g alkyl, (iv) C hydroxy alkyl, ”o (v) ^C i_q alkoxy, (vi) NR x °, where R and R are each independently selected from hydrogen, C_ alkyl, C _oc cycloalkyl, phenyl; or R ° and R taken together with the nitrogen to which they are attached represent a 5- or 6-membered saturated ring,. . 7 7. „.

(vn) OR, where R is hydrogen, alkali metal, C _d

1—8 alkyl, benzyl, or

8 (b) -Alq-OR, where Alq is C _x _ ₁₂ alkylidene, and R is:

(i) phenyl alkylcarbonyl, (ii) ^C 5-iq cycloalkylcarbonyl, (iii) benzoyl, (iv) C. alkoxycarbonyl,

1 — o (v) aminocarbonyl, or aminocarbonyl substituted with C _{1 -g} alkyl, (vi) hydrogen, or

(vii) C ₁ _ ₈ alkyl, (2) = CH-W-CO-R ⁴ or = CH-W-OR ⁸ , where W is a bond of C

8 alkylidene and R and R have the meaning given above and R ⁸ is also hydrogen or C ₁ - _2Q alkylcarbonyl, (3)

where the broken bond replaces 17-a-hydrogen,

9. 5 6 (4) a-hydrogen and NHCOR where R and ^C ^ _- 12 ^to l ^< 3 ^ul l ° / ^{or NR R} has the meaning given above, (5) α-hydrogen and cyano, (6) α-hydrogen and tetrazolyl, or (7) keto;

or a pharmaceutically acceptable salt thereof; except compounds in which:

(ι) ring B has a double bond ^c _{5 &} , R is CH ₃ , and R ³ is keto, methoxycarbonyl, or acetyl; or

(ii) the nor-A ring has a double bond ^C 3-4 θ R ³ is acetoxy or acetyl; (iii) R ¹ is CH ₃ and R ³ is acetoxy or acetyl; or (iv) the nor-A ring has a double bond ^C 3-4 ^and R ¹ is methyl; or (v) ring B. has a double bond ^C 3-4 ^and R ³ is

B-hydroxy.

Representative compounds whose synthesis and properties are disclosed in previous published U.S. patents include the following and their pharmaceutically acceptable salts.

4-Methyl-4-aza-5a-8814) -pregnen-3-ona- (20R) -20-carboxylic acid;

(20R) -hydroxymethyl-4-methyl-4-aza-5a-8 (14) pregnen-3-one;

4-methyl-4-aza-5a-8 (14) -androsten-3-one-17B-N, N-diisopropylcarboxamide;

17B- (Ν, N-diisopropylcarboxamide) -str-1,3,5 (10) -trien-3-phosphonic acid;

17B- (N-tert-butylcarboxamide) -str-1,3,5 (10) -trien-3-phosphonic acid;

17B- (N, N-diisopropylcarboxamide) -str--1,3,5 (10), 16-tetraene-3-phosphonic acid;

17B- (N-tert-butylcarboxamide) -str -1,3,5 (10), 16-tetraene-3-phosphonic acid;

17B- (N, N-diisopropylcarboxamide) -str--1,3,5 (10), 6,8-pentaene-3-phosphonic acid;

17B- (N, N-diisopropylcarboxamide) -2-methyl-estr -1,3,5 (10) -trien-3-phosphonic acid;

17B- (N, N-diisopropylcarboxamide) -4-methyl-estr -1,3,5 (10) -trien-3-phosphonic acid;

17B- (N-N-diisopropylcarboxamide) -str -1,3,5 (10), 6-tetraene-3-phosphonic acid;

17B- (N-N-diisopropylcarboxamide) -2-chloro-estr-1,3,5 (10) -trien-3-phosphonic acid;

17β- (N-N-diisopropylcarboxamide) -4-chloro-est -1,3,5 (10) -trien-3-phosphonic acid;

17B- (N-butylcarboxamide) -str-1,3,5 (10) -trien-3-carboxylic acid;

17B- (N-butylcarboxamide) -str -1,3,5 (10) 16-tetraene-3-carboxylic acid;

17β- (N, N-diisopropylcarboxamide) -str -1,3,5 (10) -trien-3-phosphinoic acid;

17B- (N-tert-butylcarboxamide) -str -1,3,5 (10) -trien-3-phosphonic acid;

17β- (Ν, Ν-diisopropylcarboxamide) -2-methyl-estr -1,3,5 (10) -trien-3-phosphine;

17β- (Ν, Ν-diisopropylcarboxamide) -4-methyl-estr acid

-triene-3-phosphine;

17β- (Ν, Ν-diisopropylcarboxamide) -2-chloro-ester

-triene-3-phosphine;

17β- (Ν, Ν-diisopropylcarboxamide) -4-chloro-ester

-1.3.5 (10) -1.3.5 (10) -1.3.5 (10) -trien-3-phosphine;

17B- (Ν, Ν-diisopropylcarboxamide) -str -1,3,5 (10), 16-tetraene-3-phosphinic acid;

17β- (N-tert-butylcarboxamide) -str -1,3,5 (10), 16-tetraene acid

-3-phosphine;

17β- (Ν, Ν-diisopropylcarboxamide) -estr -1,3,5 (10), 6,8-penta-ene-3-phosphinic acid;

17B- (Ν, Ν-diisopropylcarboxamide) -str-1, 3,5 (10), 6-tetraene-3-phosphonic acid;

17B- (N-N-diisopropylcarboxamide) -str -1,3,5 (10) -trien-3-phosphonic acid;

17β- (N-tert-butylcarboxamide) -str -1,3,5 (10) -trien-3-phosphonic acid;

17β- (Ν, Ν-diisopropylcarboxamide) -str -1,3,5 (10), 16-tetraene-3-phosphonic;

17B- (N-tert-butylcarboxamide) -str -1,3,5 (10), 16-tetraene-3-phosphonic;

17β- (Ν, Ν-diisopropylcarboxamide) -estr -1,3,5 (10), 6,8-pentaene-3-phosphonic acid;

17β- (Ν, Ν-diisopropylcarboxamide) -2-methyl-estr -1,3,5 (10) -trien-3-phosphonic acid;

17β- (Ν, Ν-diisopropylcarboxamide) -4-methyl-est -1,3,5 (10) -trien-3-phosphonic acid;

17β- (Ν, Ν-diisopropylcarboxamide) -estr -1,3,5 (10), 6-tetraene-3-phosphonic acid;

175- (N-N-diisopropylcarboxamide) -2-chloro-est -1,3,5 (10) -trien-3-phosphonic acid;

175- (N-N-diisopropylcarboxamide) -4-chloro-est -1,3,5 (10) -trien-3-phosphonic acid;

175- (N-N-diisopropylcarboxamide) -str -1,3,5 (10) -trien-3-sulfonic acid;

Acid 175- (N-tert-butylcarboxamide) -str -1,3,5 (10) -trien-3

-sulfonic;

175- (Ν, Ν-diisopropylcarboxamide) -str -1,3,5 (10), 16-tetraene-3-sulfonic;

175- (N-tert-butylcarboxamide) -str -1,3,5 (10), 16-tetraene-3-sulfonic;

175- (Ν, Ν-diisopropylcarboxamide) -str -1,3,5 (10), 6,8-pentaene-3-sulfonic acid;

175- (Ν, Ν-diisopropylcarboxamide) -2-methyl-str-trien-3-sulfonic acid;

175- (Ν, Ν-diisopropylcarboxamide) -4-methyl-str-triene-3-sulfonic acid;

175- (N-N-diisopropylcarboxamide) -2-chloro-str-triene-3-sulfonic acid;

175- (N-N-diisopropylcarboxamide) -4-chloroestric acid

-1.3.5 (10) -1.3.5 (10) -1.3.5 (10) -1.3.5 (10) -trien-3-sulfonic;

175- (N-N-diisopropylcarboxamide) -androst-3,5-diene-3-phosphinoic acid;

175- (N-t-butylcarboxamide) -androst-3,5-diene-3-phosphinic acid;

175- (Ν, Ν-diisopropylcarboxamide) -5a-androst-3-ene-3-phosphonic acid;

175- (Ν, Ν-diisopropylcarboxamide) -5a-androst-2-ene-3-phosphonic acid;

175- (Ν, Ν-diisopropylcarboxamide) -androst-2,4-diene-3 acid

-phosphine;

Methyl (175-N, N-diisopropylcarboxamide) -androst-3,5-diene-3-phosphinic acid;

-3920α- (hydroxymethyl) -5a-pregn-3-ene-3-phosphinoic acid;

17β- (Ν, Ν-diisopropylcarboxamide) -4-fluor-5a-androst-3-ene-3-phosphinic acid;

20a- (hydroxymethyl) -4-fluor-5a-pregn-3-ene-3-phosphinic acid;

20a- (hydroxymethyl) -A-nor-5a-pregn-1-ene-2-phosphonic acid;

17B- (Ν, Ν-diisopropylcarboxamide) -5a-androst-1,3-diene-3-phosphinic acid;

17β— (Ν, Ν-diisopropylcarboxamide) -5a-androstane-3B-phosphinoic acid;

17β- (Ν, Ν-diisopropylcarboxamide) -estr -3.5 (10) -diene-3-phosphinic acid;

17B- (Ν, Ν-diisopropylcarboxamide) -str -3,5-diene-3-phosphinoic acid;

17B- (Ν, Ν-diisopropylcarboxamide) -androst-3,5-11-triene-3-phosphonic acid;

20a- (hydroxymethyl) -5a-pregn-3-ene-3-carboxylic acid;

N, N-diisopropyl-5a-androst-3-ene-17B-carboxamide-3-carboxylic acid;

N, N-diisopropyl-androst-3,5-diene 17B-carboxamide-3-carboxylic acid;

17β- (Ν, Ν-diisopropylcarboxamide) -4-fluor-5a-androst-3-ene-3-carboxylic acid;

20a- (hydroxymethyl) -4-fluor-5a-pregn-3-ene-3-carboxylic acid;

20a- (hydroxymethyl) -A-nor-5a-pregn-l-ene-2-carboxylic acid;

17B- (Ν, Ν-diisopropylcarboxamide) -5a-androst-1,3-diene-3-carboxylic acid;

N-t-Butyl Androst-3,5-diene-17B-carboxamide-3-carboxylic acid;

N, N-diisopropyl-5a-androst-2-ene-17B-carboxamide-3-carboxylic acid;

Ν, Ν-diisopropyl Androst-2,4-diene-17B-carboxamide-3-carboxylic acid;

Ν, Ν-diisopropyl 5a-Androstane-17B-carboxamide-carboxylic acid;

Ν, Ν-diisopropyl estr -3.5 (10) -diene-17B-carboxamide-3-carboxylic acid;

Ν, Ν-diisopropyl estr -3,5-diene-17B-carboxamide-3-carboxylic acid;

20a- (hydroxymethyl) -5a-pregn-3-ene-carboxylic acid;

N, N-diisopropyl-5a-androst-3-ene-17B-carboxamide-3-carboxylic acid;

N, N-diisopropyl-androst-3,5-diene-17B-carboxamide-3-carboxylic acid;

17B- (Ν, Ν-diisopropylcarboxamide) -4-fluor-5a-androst-3-diene-3-carboxylic acid;

17β- (Ν, Ν-diisopropylcarboxamide) -androst-3,5,11-triene-3-carboxylic acid;

17B- (Ν, Ν-diisopropylcarboxamide) -androst-3,5-diene-3-thiocarboxylic acid;

17B- (N-t-butylcarboxamide) -androst-3,5,11-triene-3-carboxylic acid;

17B- (N-t-butylcarboxamide) -androst-3,5-diene-3-thiocarboxylic acid;

N-t-butyl-androst-3,5-diene-17B-carboxamide-3-carboxylic acid;

N, N-diisopropyl-androst-3,5-diene-17B-carboxamide-3-carboxylic acid;

20a- (hydroxymethyl) -3a-pregn-3-ene-3-carboxylic acid;

20a- (hydroxymethyl) -4-fluor-5a-pregn-3-ene-3-carboxylic acid;

3-carbomethoxy-N, N-diisopropyl-androst-3,5-diene-17B-carboxamide;

17B-N, N-diisopropylcarboxamide) -5andandrost-1,3-diene-3carboxylic acid;

N, N-diisopropyl-5aandrost-2-ene-17B-carboxamide-3-carboxylic acid;

N, N-diisopropyl-androst-2-4-diene-17B-carboxamide-3-carboxylic acid;

N, N-diisopropyl-5andandrostane-17B-carboxamide-3B-carboxylic acid;

Ν, Ν-diisopropyl-estr -3.5 (10) -diene-17B-carboxamide-3-carboxylic acid;

N, N-diisopropyl-estr-3,5-diene-17B-carboxamide-3-carboxylic acid;

N-t-butyl-androst-3,5-diene-17B-carboxamide-3-carboxylic acid;

'N, N-diisopropyl-androst-3,5-diene-17B-carboxamide-3-carboxylic acid;

20a- (hydroxymethyl) -4-fluor-5a-pregn-3-ene-3-carboxylic acid;

N, N-diisopropyl-5a-androst-3-ene-17B-carboxamide-3-carboxylic acid;

17B- (Ν, Ν-diisopropylcarboxamide) -4-fluor-5a-androst-3-ene-3-carboxylic acid;

17B- (Ν, Ν-diisopropylcarboxamide) -4-fluor-androst-3,5-diene-3-carboxylic acid;

3-carbomethoxy-N, N-diisopropyl-androst-3,5-diene-17B-carboxamide;

17B-N, N-diisopropylcarboxamide-5androst-1,3-diene-3-carboxylic acid;

N, N-diisopropyl-5aandrost-2-ene-17B-carboxamide-3-carboxylic acid;

N, N-diisopropyl-androst-2,4-diene-17B-carboxamide-3-carboxylic acid;

N, N-diisopropyl-5a-androstane-17B-carboxamide-3B-carboxylic acid;

N, N-diisopropyl-estr-3,5 (10) -diene-17B-carboxamide-3-carboxylic acid;

N, N-diisopropyl-estr-3,5-diene-17B-carboxamide-3-carboxylic acid;

17B- (N-t-butylcarboxamide) -androst-3,5-triene-3-carboxylic acid;

17B- (N-t-butylcarboxamide) -androst-3,5-diene-3-thiocarboxylic acid;

N-t-butyl-5a-androst-3-ene-17B-carboxamide-3-carboxylic acid;

-42 17B- (N-t-butylcarboxamide) -6-fluor-5a-androst-3-ene-3-carboxylic acid;

17B- (N-t-butylcarboxamide) -6-fluor-androst-3,5-diene-3-carboxylic acid;

3-Carbomethoxy-N-t-butyl-androst-3,5-diene-17B-carboxamide

17B-N-t-butylcarboxamide-5a-androst-1,3-diene-3-carboxylic acid;

N-t-butyl-5a-androst-2-ene-17B-carboxamide-3-carboxylic acid;

N-t-butyl-androst-2,4-diene-17B-carboxamide-3-carboxylic acid;

N-t-butyl-5a-androstane-17B-carboxamide-3-carboxylic acid;

20a- (hydroxymethyl) -A-nor-5a-pregn-l-ene-2-carboxylic acid;

17B- (N-t-butylcarboxamide) -androst-3,5,11-triene-3-carboxylic acid;

17B- (N-t-butylcarboxamide) -androst-3,5-diene-3-thiocarboxylic acid;

N-t-butyl-5a-androst-3-ene-17B-carboxamide-3-carboxylic acid;

17B- (N-t-butylcarboxamide) -6-fluor-5a-androst-3-ene-3-carboxylic acid;

17B- (N-t-butylcarboxamide) -6-fluor-androst-3,5-diene-3-carboxylic acid;

3-Carbomethoxy-N-t-butyl-androst-3,5-diene-17B-carboxamide;

17B-N-t-butylcarboxamide-5a-androst-1,3-diene-3-carboxylic acid;

N-t-butyl-5a-androst-2-ene-17B-carboxamide-3-carboxylic acid;

N-t-butyl-androst-2,4-diene-17B-carboxamide-3-carboxylic acid;

N-t-butyl-5a-androstane-17B-carboxamide-3-carboxylic acid;

N-t-Butyl-estr-3,5 (10) -diene-17B-carboxamide-3-carboxylic acid

N-t-Butyl-estr-3,5-diene-17B-carboxamide-3-carboxylic acid

N-t-Butyl-estr-3,5 (10) -diene-17B-carboxamide-3-carboxylic acid

N-t-butyl-estr -3,5-diene-17B-carboxamide-3-carboxylic acid 20a- (t-butyldimethylsiloxymethyl) -3- (trifluoromethylsulfonate) -5a-pregn-3-ene;

175- (t-butyldimethylsiloxymethyl) -3- (trifluoromethylsulfonate) -5a-androst-3-ene;

175- (N, N-diisopropylcarboxamide) -3- (trifluoromethylsulfonate) -androst-3,5-diene;

175- (N, N-diisopropylcarboxamide) -3- (trifluoromethylsulfonate) -4-fluor-5a-androst-1,3-diene;

20a- (t-butyldimethylsiloxymethyl) -4-fluor-3- (trifluoromethylsulfonate) -5a-pregn-1,3-diene;

175- (N, N-diisopropylcarboxamide) -3- (trifluoromethylsulfonate) -5a— androst-1,3-diene;

175- (N-t-butylcarboxamide) -3- (trifluoromethylsulfonate) -androst-3,5-diene;

175- (N, N-diisopropylcarboxamide) -3- (trifluoromethylsulfonate) -5a— androst-2-ene;

175- (N, N-diisopropylcarboxamide) -3- (trifluoromethylsulfonate) -androst-2,4-diene;

N-t-butyl-androst-3,5-diene-3-bromo-175-carboxamide, and

N, N-diisopropyl-androst-3,5-diene-3-bromo-175-carboxamide.

175-acyl 3-carboxy-androst-3,5-diene of the formula are also provided:

where R

(a) C ₁ _ ₆ alkyl linear or branched; C ₃ _ ₁₂ cycloalkyl, which can be substituted by C ₄ _ ₄ alkoxy or ^c 1-4 straight or branched alkyl; ^c 6_ ₁₂ ^ar il ° z ^{or C} 7_i3 aralkyl which can be replaced by one or more of: -OH, “ ^0C 1“ ^C 4 alkyl, alkyl, - (CH ₂ ) _m OH, ^- ( ^c H ₂ ) _n , COOH, including protected -OH, where m is 1-4, n is 1-3;

(b) C, _r straight or branched alkyl; C_ cycloalkyl,

1—6 which can be substituted by C ^ -C ₄ al ^alx i ° ^{co co co co C C C C _} 1 1 1 1 1 ^C 1 1 1 1 1 1 linear 1 linear linear linear linear linear linear linear linear linear linear linear linear linear linear linear linear linear linear linear linear linear linear linear linear linear ^c g " ^c 12 aryl, or ^c 7" ^c 13 aralkyl that can be substituted with one or more of: -OH, -OC1-C4 alkyl, 0χ-04 alkyl, - (CH ^ OH, - (CH2) n COOH , including protected -OH, where m is 1-4, n is 1-3 and R ² is selected from COOH, SO3H, PO (OH) ₂ , PH (O) OH.

,. 1

Specifically provided are those where R and t-butyl, cycloalkyl, phenyl, p-hydroxyphenyl, 1-adamantyl, 2-adamantyl, nH-t-butyl, NH-isobutyl, NH-cyclohexyl, NH-phenyl,. . . . 2

NH-p-hydroxy-phenyl, NH-1-adaxmantyl, ΝΗ-2-adamantyl, and R is COOH,

Representative compounds include:

17β (4-hydroxyphenylcarbonyl) -androsta-3,5-diene-3-carboxylic acid;

17B-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;

17B- (4-hydroxymethylphenylcarbamail) -androsta-3,5-diene-3-carboxylic acid;

17B- (2-hydroxyethylphenylcarbonyl) -androsta-3,5-diene-3-carboxylic acid;

17B- (4-methoxyphenylcarbonyl) -androsta-3,5-diene-3-carboxylic acid;

17β- (4-carboxymethylphenylcarbonyl) -androsta-3,5-diene-3-carboxylic acid;

N-t-butyl-androst-3,5-diene-176-carboxamide-3-carboxylic acid; N-phenyl-androst-3,5-diene-17fi-carboxamide-3-carboxylic acid;

N-1-adamantyl-androst-3,5-diene-17fi-carboxamide-3-carboxylic acid;

N-2-adamantyl-androst-3,5-diene-178-carboxamide-3-carboxylic acid;

Also included and known in the art are non-steroidal 5α-reductase inhibitors as developed by 0N0 Pharmaceutical CO., LTD, Osaka, Japan and as described in U.S. patents 4,780,469; 4,847,275; 4,939,141 and EPO Publication Nos

173 516 and EPO 0 291 245, and 4,980,372; and EPO Publn. 291,247 and USP 5,037,852 disclosing certain new condensed benz (thio) amides and benzylaminophenylbutanoic derivatives, respectively.

The benzoylaminophenoxy butanoic acid derivatives are of the formula:

on what:

R 'is hydrogen or alkyl of 1 to 4 carbon atoms; A is an oxygen atom, a sulfur atom or an (SO) 1.1 sulfinyl group; both R are methyl or chlorine or both R and. . 1 the carbon atoms of the benzene ring to which the two R's are attached are cyclopentane, cyclohexane or a benzene ring; and

R represents a group of formula:

where B is oxygen, sulfur or a group of formula NR ¹¹ in 11. . , which R is hydrogen or alkyl of 1 to 4 carbon atoms; R, R, R ³ , R, R ^/ eR 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

-479

R is hydrogen, alkyl of 1 to 5 carbon atoms or a group of formula:

13 14 15 where R, R, R, and R are. independently, hydrogen, alkyl of 1 to 4 carbon atoms, halogen, trifluoromethyl or cyclobutylmethyl, and 1 is an integer from 1 to 4, and 10

R and a group of formula:

13 14 15 where R, R, R, and R are. independently, hydrogen. nio, alkyl of 1 to 4 carbon atoms, halogen, trifluoromethyl or cyclobutylmethyl, and 1 'is an integer from 1 to 4; or its non-toxic salts.

Representative examples of each of these two classes of compounds whose synthesis and properties are disclosed in the aforementioned cited US published patents include the following:

4- [2- (4-benzyloxy-2,3-dimethylbenzoylamino) phenoxybutanoic 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-dimethyl-benzoylamino] phenoxy] butanoic acid;

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-dimethylbenzoylamino] phenoxy] butanoic acid;

4- [2- [4- (4-isobutylbenzyloxy) -5,6,7,8-tetrahydronaphthalene-1-carbonylamino) phenoxybutane 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-dimethylbenzoylamino] phenoxy] butanoic acid;

4- [2- [4 - [bis- (4-propylphenyl) methylthio] -2,3-dimethylbenzoylamino] phenoxy] butanoic acid;

4- [2 - [4 - [Ν, Ν-bis (4-propylphenylmethyl) amino] -2,3-dimethylbenzoylamino] phenoxy] butanoic acid;

4- [2- [4- [Ν, Ν-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) -1,4-benzodioxane;

⁸ ~ (p-pentylbenzoyl) amino-2- (5-tetrazolyl) -6-chloro-1,4-benzodioxane;

8- (m-octylbenzoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane;

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-heptybenzoyl) 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-didecylbenzoyl) 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-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;

8- (N-methyl-N- (p-octinyloxy) benzoyl]) amino-2- (5-tetrazolyl) -1,4-benzodioxane;

8- (p-octyloxybenzoyl) amino-1,4-benzodioxane-2-carboxylic acid and its methyl ester;

8- (p-isoheptyloxybenzoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane;

8- (p- (isooctyloxybenzoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane;

8- [p- (3,7-dimethyloctyloxy) benzoyl] amino-2- (5-tetrazolyl) -1,4-benzodioxane;

8- (p-octyloxybenzoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane; 8- (p-heptyloxybenzoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane-7-carboxylic acid and its methyl ester, etc.

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

COOH

3 wherein R and R each independently represent a hydrogen or methyl group with the proviso that o. 3 (1) when R represents a methyl group, R represents hydrogen and (R ¹ ) n represents a member selected from the group consisting of group 3-, 4-pentyl group, 4-neopentyl group, group 4- (2- ethylbutyl) and 4- (2-methylpentyl) group, or. . 2 . . 3 (li) when R represents hydrogen, R represents a methyl group and (R4) n represents a 3-pentyl group, or a non-toxic salt thereof.

Representative compounds include:

4- [2- (4-butylthio-5-methylcinoylamino) phenoxy] butanoic acid 4- [2- (4-cyclobutylmethyl) β-methylcinamoylamino) phenoxy] butanoic acid 4- [2- (4-cyclohexylmethyl) β-methylcinoylamino ) phenoxy] butanoic 4- [2- (4- {4-phenylbutyl) -β-methylcinaminoamino) phenoxybutanoic acid 4- [2- (4-phenoxy-B-methylcinaminoamino) phenoxybutanoic acid

4- [2- (3-pentyl-a-methylcinoylamino) phenoxy] butanoic acid 4- [2- (4-phenethyl-a-methylcinoylamino) phenoxy] butanoic acid 4- [2- (3-pentyl-B-methylcinaminoamino) ) phenoxy] butanoic acid 4- [2- (4-neopentyl] -B-methylcinaminoamino) phenoxy] butanoic acid 4- [2- {4- (2-methylpentyl) -β-methylcinamoylamino) phenoxy] butanoic acid, and 4- [2- (2-fluoro-4-pentyloxy-B-methylcinaminoamino) phenoxy] butanoic.

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

where A represents a single bond or a group of methylene, ethylene, trimethylene, tetramethylene, vinylene, propenylene, butenylene, butadienylene or ethynylene group being optionally substituted by one, two or three linear or branched alkyl group (s) ( s) having from 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 atom (s) selected from the group consisting of oxygen, nitrogen and sulfur atom (s),

-54 wherein said ring may optionally be substituted by group (s) selected from the group (s) oxo, thioxo and / or hydroxy including a ring of the formula:

T represents an oxygen atom or a sulfur atom; 1

R represents a group of the general formula:

Ci)

(ii)

u

-55 (iv) a linear or branched alkyl, alkenyl or alkynyl group having from 1 to 20 carbon atom (s), wherein and R 4 independently represent a hydrogen atom or a halogen atom or an alkyl, alkenyl group or linear or branched alkynyl with 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), atom sulfur (s), halogen atom (s), nitrogen atom (s), benzene ring (s), thiophene ring (s), naphthalene ring (s), carbocyclic ring (s) from 4 to 7 carbon atom (s), carbonyl group (s), carbonyloxy group (s), hydroxy group (s), carboxy group (s), azido group (s) and / or group (s) nitro;

R represents a hydrogen atom or a linear or branched alkyl group having from 1 to 6 carbon atom (s);

R represents a hydrogen atom, a halogen atom, a hydroxy group, a nitro group, a group of the general formula: -COOR, where R represents a hydrogen atom or a linear or branched alkyl group with 1 to 6 atoms (s) carbon, or a lienary or branched alkyl, alkoxy or alkylthio group having from 1 to 6 carbon atom (s);

R represents a group of the general formula:

-U- (CH ₂ ) n-C00R ⁸ ,

N-N

-u- (CH ₂ ) „- 4

NN H - (CH ₂ ) p ^- C °° R ^S > or

N_N

-CCH ₂ ) _q -rf ^Z |

N-N H where U represents an oxygen atom or a sulfur atom, g

R represents a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atom (s), nor does it represent an integer from 1 to 10, respectively, p and q represent zero or an integer from 1 to 10, respectively , or its non-toxic salts.

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- (4-phenylbutoxy) benzoyl] amino-2- (5-tetrazolyl) benzofuran,

7- [p- (2E, 7, -octadienyl) benzoyl] amino-2- (5-tetrazolyl) benzofuran,

7- [p- (6-chlorohexyloxy) benzoyl] amino-2- (5-tetrazolyl) benzofuran,

7- (p-pentylcinamoyl) amino-2- (5-tetrazolyl) benzofuran,

7- (p-hexyloxybenzoyl) amino-2- (5-tetrazolyl) -2,3-dihydro-1-benzofuran,

7- (p-heptybenzoyl) amino-2- (5-tetrazolyl) -2,3-dihydro-1-benzofuran,

7- (p-octyloxybenzoyl) amino-2- (5-tetrazolyl) -2,3-dihydro-1-benzofuran,

7- (p-nonyloxybenzoyl) amino-2- (5-tetrazolyl) -2,3-dihydro-1-benzofuran,

7- (p-pentylcinamoyl) amino-2- (5-tetrazolyl) -2,3-dihydro-1-benzofuran,

8- [p-2E, 7-octadienyloxy) benzoyl] amino-2- (5-tetrazolyl) quinoline,

8- [p- (4-phenylbutoxy) benzoyl] amino-2- (5-tetrazolyl) quinoline,

8- [p— (6-chlorohexyloxy) benzoyl] amino-2- (5-tetrazolyl) quinoline, 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] amino-4-hydroxyquinoline-2-carboxylic acid ,

8- [p- (2E, 7-octadienyloxy) benzoyl] amino-4-hydroxy-2- (tetrazolyl) quinoline,

8- [p ~ [4- (2-phenylbutoxy) benzoyl] amino-4-hydroxy-2- (5-tetrazolyl) quinoline,

8- (p-pentylcinamoyl) amino-4-hydroxy-2- (5-tetrazolyl) quinoline,

4- (p-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-pentylcinamoyl) amino-2- (5-tetrazolyl) -1,3-benzodioxole,

9- [p- (4-phenylbutoxy) benzoyl] amino-2- (5-tetrazolyl) -3,4-dihydro-2H-1,5-benzodioxepine,

9- [ρ- (2Ε, 7-octadienyloxy) benzoyl] amino-2- (5-tetrazolyl) -3,4-dihydro-2H-1,5-benzodioxepine,

9- [p- (7-octenyloxy) benzoyl] amino-2- (5-tetrazolyl) -3,4-dihydro-2H-1,5-benzodioxepine,

8- (p-heptyloxybenzoyl) amino-2- (5-tetrazolyl) -2,3-dihydro-1,4-benzoxazine,

8- [p- (4-phenylbutoxy) benzoyl] amino-2- (5-tetrazolyl) -2,3-dihydro-1,4-benzoxazine,

8- (p-pentylcinamoyl) 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- [p- (4-phenylbutoxy) benzoyl] amino-2- (5-tetrazolyl) -3,4-dihydro-2H-1-benzopyran,

8- [p- (7-octenyloxy) benzoyl] amino-2- (5-tetrazolyl) -3,4-dihydro-2H-1-benzopyran,

8- (p-pentylbenzoyl) amino-2- (5-tetrazolyl) -4-oxo-4H-1-benzopyran, 8- (p-pentylbenzoyl) amino-4-oxo-4H-1-benzopyran-2-carboxylic acid and its ethyl ester,

8- (p-hexylbenzoyl) amino-2- (5-tetrazolyl) -4-oxo-4H-1-benzopyran,

8- (p-heptybenzoyl) amino-2- (5-tetrazolyl) -4-oxo-4H-1-benzopyran,

8- (p-octylbenzoyl) amino-2- (5-tetrazolyl) -4-oxo-4H-1-benzopyran,

8- (p-nonylbenzoyl) amino-2- (5-tetrazolyl-4-oxo-4H-1-benzopyran,

8- (p-butoxybenzoyl) amino-2- (5-tetrazolyl) -4-oxo-4H-1-benzopyran, θ “(p-pentyloxybenzoyl) amino-2- (5-tetrazolyl) -4-oxo-4H- l-benzopyran,

8- (p-hexyloxybenzoyl) amino-2- (5-tetrazolyl) -4-oxo-4H-1-benzopyran,

8- (p-heptyloxybenzoyl) amino-2- (5-tetrazolyl) -4-oxo-4H-1-benzopyran,

8- (p-nonyloxybenzoyl) amino-2- (5-tetrazolyl) -4-oxo-4H-1-benzopyran,

8 “(p-octyloxybenzoyl) amino-2- (5-tetrazolyl) -4-oxo-4H-1-benzopyran,

8- (p-heptyloxybenzoyl) amino-2- (5-tetrazolyl) -6-fluoro-4-oxo-4H-1-benzopyran,

8- (p-octyloxybenzoyl) amino-2- (5-tetrazolyl) -6-methyl-4-oxo-4H-1-benzopyran,

8- (p-heptyloxybenzoyl) amino-2- (5-tetrazolyl) -6-methyl-4-oxo-4H-1-benzopyran,

8- [ρ- (2E, 7-octadienyloxy) benzoyl] amino-2- (5-tetrazolyl) -4-oxo-4H-1-benzopyran,

8 -. (P-geranyloxybenzoyl) amino-2- (5-tetrazolyl) -4-oxo-4H-1-benzopyran,

8- [p- (2E-nonenyloxy) benzoyl] amino-2- (5-tetrazolyl) -4-oxo-4H-1-benzopyran,

8- [p— (2E-octenyloxy) benzoyl] amino-2- (5-tetrazolyl) -4-oxo-4H-1-benzopyran,

8- [p- (7-octenyloxy) 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-oxo-4H-1-benzopyran, ⁸ [ρ- (2E, 7-octadienyloxy) benzoyl] amino-2- ( 5-tetrazolyl) -6-fluoro4-oxo-4H-i-benzopyran, 8- [p- (2E-octenyloxy) benzoyl] amino-2- (5-tetrazolyl) -6-methyl-4-oxo-4H-1 -benzopyran,

8- [ρ- (2E, 7-octadienyloxy) benzoyl] amino-2- (5-tetrazolyl) -6-chloro— 4-oxo-4H-1-benzopyran,

8- [p- (2-octinyloxy) benzoyl] amino-2- (5-tetrazolyl) -4-oxo-4H-1-benzopyran,

8- [p- (4-chlorobutoxy) benzoyl] amino-2- (5-tetrazolyl) -4-oxo-4H-1-benzopyran,

8- [p- (5-chloropentyloxy) benzoyl] 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- (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- [p- (8-chlorooctyloxy) benzoyl] amino-2- (5-tetrazolyl) -6-methyl-4-oxo-4H-1-benzopyran,

8- [p- (7-chloroheptyloxy) benzoyl] amino-2- (5-tetrazolyl) -6-methyl-4— oxo-4H-1-benzopyran,

8- [p- (8-chlorooctyloxy) benzoyl] amino-2- (5-tetrazolyl) -4-ΟΧΟ-4Η-1— benzopyran,

8- [p- (3-phenylpropoxy) benzoyl] amino-2- (5-tetrazolyl) -4-oxo-4H-1-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-oxo-4H-1-benzopyran,

8- [p- (4-phenylbutoxy) benzoyl] amino-2- (5-tetrazolyl) -6-methyl-4-oxo-4H-1-benzopyran,

8— [p— [2- (2-naphthi) 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- (3,4-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-chlorophenyl) butoxy] benzoyl] amino-2- (5-tetrazolyl) -4-oxo-4H-1-benzopyran,

8 ^- [p ~ [3- (p-chlorophenyl) butoxy] benzoyl] amino-6-methyl-2- (5-tetrazolyl) -4-oxo-4H-1-benzopyran,

8- [ρ— [3- (p-chlorophenyl) propoxy] benzoyl] amino-6-methyl-2- (5-tetrazolyl) -4-oxo-4H-1-benzopyran,

8- [p— [4-2-thienyl) butoxy] 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-pentylcinamoyl) amino -4-oxo-4H-1-benzopyran-2-carboxylic acid and its methyl ester,

8- (p-pentylcinamoyl) amino-2- (5-tetrazolyl) -4-oxo-4H-1-benzopyran,

8- (p-pentylcinamoyl) amino-2- (5-tetrazolyl) -6-methyl-4-oxo-4H-1-benzopyran,

8 ^- (p-pentylcinamoyl) amino-2- (5-tetrazolyl) -6-fluoro-4-oxo-4H-1-benzopyran, 8- (p-pentylcinamoyl) amino-6-methyl-4-oxo-4H -l-benzopyran-2-carboxylic acid and its ethyl ester,

8- (p-butylcinamoyl) amino-2- (5-tetrazolyl) -4-oxo-4H-1-benzopyran,

8- (p-hexylcinamoyl) amino-2- (5-tetrazolyl) -4-oxo-4H-1-benzopyran,

8- (p-heptycincinyl) amino-2- (5-tetrazolyl) -4-oxo-4H-1-benzopyran,

8-cinamoylamino-2- (5-tetrazolyl) -4-oxo-4H-1-benzopyran,

8- (p-hexylcyanmoyl) amino-2- (5-tetrazolyl) -4-oxo-4H-1-benzopyran,

8- (p-heptyloxynaminoyl) amino-2- (5-tetrazolyl) -4-oxo-4H-1-benzopyran,

8 “(p-isohexyloxicinamoyl) amino-2- (5-tetrazolyl) -4-oxo-4H-1-benzopyran, 8- [p— (2-octinyloxy) cinamoyl] amino-4-oxo-4H-l- benzopyran-2-carboxylic,

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;

-628- (p-pentylbenzoyl) amino-2- (5-tetrazolyl) -6-chloro-1,4-benzodioxane;

8- (m-octylbenzoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane;

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-heptybenzoyl) 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-octinyloxy) benzoyl]) amino-2- (5-tetrazolyl) -1,4-benzodioxane;

8- (p-octyloxybenzoyl) amino-1,4-benzodioxane-2-carboxylic acid and its methyl ester;

8- (p-isoheptybenzoyl) amino-2- (5 tetrazolyl) -1,4-benzodioxane;

8- (p-isooctyloxybenzoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane;

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,

8- [p- (2E-octyloxybenzoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane,

8- [p— (3-butenyloxy) benzoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane,

8- [p- (3Z-hexenyloxy) benzoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane;

8- [p- (2Z-octenyloxy) benzoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane,

8- [p- (2E-nonenyloxy) benzoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane,

8- [N-methyl-N- [p— (2E-octenyloxy) benzoyl) 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— [p- (2E-decenyloxy) benzoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane,

8- (p-geranyloxy) benzoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane,

8- [ρ- (2E, 7-octadienyloxy) benzoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane,

8- [p- (2E-pentenyloxy) benzoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane,

8— [p— (2E-butenyloxy) benzoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane,

8 “[P“ (3E-octenyloxy) benzoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane,

8- [p- (7-octenyloxy) benzoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane,

8- [ρ- (2E, 4E-octadienyloxy) benzoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane,

8- [p- (2E-octadienyloxy) benzoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane,

8- [p- (2-octinyloxy) benzoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane, 8- [p- (2-octinyloxy) benzoyl] amino-1,4-benzodioxane-2 -carboxylic acid and its methyl ester,

8- [p- (2-isooctinyloxy) benzoyl] amino-2- (5-tetrazolyl) -1,4-benzodioxane,

8- (p-pentylthiobenzoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane,

8- (m-pentylthiovenzoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane,

8- (o-pentylthiobenzoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane and

8- (p-heptylthiobenzoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane,

8- [p- (6-chlorohexyloxy) benzoyl] amino-2- (5-tetrazolyl) -1,4-benzodioxane,

8- [p- (5-chloropentyloxy) benzoyl] amino-2- (5-tetrazolyl) -1,4-benzodioxane,

8- [p— (4-chlorobutoxy) benzoyl] amino-2- (5-tetrazolyl) -1,4-benzodioxane,

8- [p- (7-chloroheptyloxy) benzoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane,

8- [p- (8-chlorooctyloxy) benzoyl] amino-2- (5-tetrazolyl) -1,4-benzodioxane,

8- [p— (9-chlorononyloxy) benzoyl] amino-2- (5-tetrazolyl) -1,4-benzodioxane,

8- [p- (t-bromopentyloxy) benzoyl] amino-2- (5-tetrazolyl) -1,4-benzodioxane-2-carboxylic acid and its methyl ester, 8- [p-hexyloxymethyl) benzoyl] amino-2- (5-tetrazolyl) -1,4-benzodioxane,

8- [p- (cyclohexylmethoxy) benzoyl] amino-2- (5-tetrazolyl) -1,4-benzodioxane,

8- [p- (4-cyclohexylbutoxy) benzoyl] amino-2- (5-tetrazolyl) -1,4-benzodioxane,

8- [p- (2-cyclohexylethoxy) benzoyl]) amino-2- (5-tetrazolyl) -1,4-benzodioxane,

8- [p- (p-butylphenyl) methoxybenoyl] amino-2- (5-tetrazolyl) -1,4-benzodioxane, θ “[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-benzodioxane,

8- [p- (4-phenylbutoxy) benzoyl] amino-2- (5-tetrazolyl) -1,4-benzodioxane,

8- [p- (o-pentylphenyl) methoxybenzoylamino-2- (5-tetrazolyl = -1,4-benzodioxane,

8- [p- (m-butylphenylmethoxybenzoyl] amino-2- (5-tetrazolyl) -1,4-benzodioxane,

8- (p-phenylmethoxybenzoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane, 8- [p- (2-phenylethoxy) benzoyl] amino-2- (5-tetrazolyl) -1,4-benzodioxane ,

8- [ρ-4-phenylbutoxy) benzoyl] amino-2- (5-tetrazolyl) -1,4-benzodioxane,

8— [p— [2. (2-naphthyl) ethoxy] benzoyl]) amino-2- (5-tetrazolyl) -1,4-benzodioxane,

8— [ρ— [3— (p-chlorophenyl) propoxy] benzoyl] amino-2- (5-tetrazolyl) -1,4-benzodioxane,

8- [p- [4- (p-chlorophenyl) butoxy] benzoyl] amino-2- (5-tetrazolyl) -1,4— benzodioxane,

8- [p- (5-methoxycarbonylpentyloxy) benzoyl] amino-2- (5-tetrazolyl) -1,4-benzodioxane,

8- [p- (6-acetyloxyhexyl) benzoyl] amino-2- (5-tetrazolyl) -1,4-benzodioxane,

8- [p- (6-hydroxyhexyloxy) benzoyl] amino-2- (5-tetrazolyl) -1,4-benzodioxane,

8- [p- (2E-octenoyloxy) benzoyl] amino-2- (5-tetrazolyl) -1,4-benzodioxane,

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) benzoyl] amino-2- (5-tetrazolyl) - 1,4-benzodioxane,

8- [p- (2-phenoxyethoxy) benzoyl] amino-2- (5-tetrazolyl) -1,4-benzodioxane,

8- [p- [2- (3-thienyl) ethoxy] benzoyl] amino-2- (5-tetrazolyl) -1,4-benzodioxane,

8- [p- [4- (2-thienyl) butoxy] benzoyl] amino-2- (5-tetrazolyl) -1,4-benzodioxane,

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-benzodioxane, θ ~ [p- (2-azidoethoxy) benzoyl] amino-2- (5-tetrazolyl) -1, 4-benzodioxane,

8- [p- (4-azidobutoxy) benzoyl] amino-2- (5-tetrazolyl) -1,4-benzodioxane,

8- [p— (2-octenoylamino) benzoyl] amino-2- (5-tetrazolyl) -1,4-benzodioxane,

8- (p-pentyloxy-m-methoxybenzoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane,

8- [p- (2E-octenyloxy) -m-chlorobenzoyl] amino-2- (5-tetrazolyl) -1,4-benzodioxane,

8- (2-naphthylcarbonyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane,

8- (p-pentylcinamoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane, 8- (p-pentylcinamoyl) amino-1,4-benzodioxane-2-carboxylic acid and its methyl ester,

8- (p-heptycincinyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane,

8- [N-methyl- [N- (pentylcinamoyl) amino] -2- (5-tetrazolyl) -1,4-benzodioxane,

5- (p-pentylcinamoyl) amino-2- (5-tetrazolyl) -7-chloro-1,4-benzodioxane,

8- (p-pentylcinamoyl) amino-2- (5-tetrazolyl) -6-chloro-1,4-benzodioxane,

8- (p-ethylcinamoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane,

8- (p-propylcinamoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane,

8- (p-butylcinamoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane,

8 ”(p-pentylcinamoyl) amino-2- (5-tetrazolyl) -6-methyl-1,4-benzodioxane,

8- (o-pentylcinamoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane,

8- (m-octyltinamine) amino-2 (5-tetrazolyl) -1,4-benzodioxane,

8- (p-pentylcinamoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane-5-carboxylic acid and its methyl ester, 5- (p-pentylcinamoyl) amino-2 (5-tetrazolyl) -1, 4-benzodioxane-8-carboxylic acid and its methyl ester,

8- (p-hexylcinamoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane,

8- (p-nonylcinamoyl) amino-2 (5-tetrazolyl) -1,4-benzodioxane,

-68acid 8- (p-pentylcinamoyl) amino-2 (5-tetrazolyl) -1,4-benzodioxane-6-carboxylic acid and its methyl ester, 5- (p-pentylcinamoyl) amino-2- (5-tetrazolyl) - 1,4-benzodioxane-7-carboxylic acid and its methyl ester,

8- (p-octycincinoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane,

8- (p-decylcinamoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane,

8- (p-isopropylcinamoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane,

8- (p-isobutylcinamoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane,

8- (p-isopentylcinamoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane,

8- (p-pentyl-2-methylcinamoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane,

8- (p-pentyl-3-methylcinamoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane, θ “(p-pentylcinamoyl) amino-2- (5-tetrazolyl) methyl-1,4-benzodioxane ,

8- (p-pentylcinamoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane,

8- (m-pentylcinamoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane,

8- (o-pentyloxicinamoyl) amino-2- (5-tetrazolyl = -1,4-benzodioxane,

8- (p-propoxicinamoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane,

8- (p-butoxicinamoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane,

8- (p-octyloxynamoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane,

8- (p-hexyloxicinamoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane,

8- (p-heptyloxynaminoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane,

8- (p-isopentyloxynamoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane,

8- (p-isohexyloxicinamoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane,

8- [p- (1-methylbutoxy) cinnamoyl] amino-2- (5-tetrazolyl) -1,4-benzodioxane,

8- (p-isoheptyloxynaminoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane,

8- (p-isooctycinamoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane,

8- (p-isohexyloxy-2-methylcinamoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane,

8- (p-isohexyloxy-2-phenylcinamoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane,

8- [p— (2E-octenyloxy) cinnamoyl] amino-2- (5-tetrazolyl) -1,4-benzodioxane, θ ^- [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- (3 Z-hexenyloxy) cinnamoyl] amino-2- (5-tetrazolyl) -1,4-benzodioxane,

8- [p-2Z-pentenyloxynamoyl] amino-2- (5-tetrazolyl) -1,4-benzodioxane,

8- [p- (2E-nonenyloxy) cinnamoyl] amino-2- (5-tetrazolyl) -1,4-benzodioxane,

8- [p- (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-benzedioxane,

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-benzodioxane,

8— [p— (2 — octinyloxy) cinnamoyl] amino-2- (5-tetrazolyl) -1,4-benzodioxane and

8- [p ~ (2-pentynyloxy) cinnamoyl] amino-2- (5-tetrazolyl) -1,4-benzodioxane,

8- (m-pentylthiocyanmoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane and

8- (o-pentylthiocinamoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane,

8- [p— (6-chlorohexyloxy) cinnamoyl] amino-2- (5-tetrazolyl) -1,4-benzodioxane,

8 [p- (4-chlorobutoxy) cinnamoyl] amino-2- (5-tetrazolyl) -1,4-benzodioxane,

8- [p- (5-chloropentyloxy) cinnamoyl] amino-2- (5-tetrazolyl) -1,4-benzodioxane,

8- [p— (7-chloroheptyloxy) cinnamoyl] amino-2- (5-tetrazolyl) -1,4-benzodioxane,

8- (p-isopentyloxymethyl-cinnamoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane,

8- (p-cyclohexylcinamoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane,

8- (p-cyclohexylmethoxycinnamyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane,

8- [p- (4-cyclohexylbutoxy) cinnamoyl] amino-2- (5-tetrazolyl) -1,4-benzodioxane,

8- [p- (2-cyclohexylethoxy) cinnamoyl] amino-2- (5-tetrazolyl) -1,4-benzodioxane,

8- (p-phenylmethylcinamoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane,

8- (p-phenylmethoxycinnamyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane,

8- [p- (2-phenylethoxy) cinnamoyl] amino-2- (5-tetrazolyl) -1,4-benzodioxane,

8- [p- (4-phenylbutoxy) cinnamoyl] amino-2- (5-tetrazolyl) -1,4-benzodioxane,

8- [p- (5-phenylpentyloxy) cinnamoyl] amino-2- (5-tetrazolyl) -1,4-benzodioxane,

8- [p- (3-phenylpropoxy) cinnamoyl] amino-2- (5-tetrazolyl) -1,4-benzodioxane,

8- [p- (6-acetyloxyhexyl) cinnamoyl] amino-2- (5-tetrazolyl) -1,4-benzodioxane,

8- [p- [2- (2-thienyl) ethoxy) -cinamoyl] -amino-2- (5-tetrazolyl) -1,4-benzodioxane,

8- (m, p-dimethoxycinnamoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane,

8- (m-methoxy-p-pentyloxicinamoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane,

8- (p-pentyloxy-m-chlorokinamoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane,

8- [3- (5-indanyl) acryloyl] amino-2- (5-tetrazolyl) -1,4-benzodioxane,

N- (2-hexadecenoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane,

8- (p.pentylphenylacetyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane and

8- [3- (p-pentylphenyl) propionyl] amino-2- (5-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,

8- [5- (p-butylphenyl) penta-2E, 4E-dienoyl] amino-2- (5-tetrazolyl) -1, -

4-benzodioxane, ^8_ (p-pentylcinamoyl) amino-2- (5-tetrazolyl) -2,3-dihydro-14-dithianaphthalene,

5- (p-pentylcinamoyl) amino-2- (5-tetrazolyl) -2,3-dihydro-1,4-dithianaphthalene and its sodium salts.

1,2-di (thio) aromatic ethers of the formula are also included:

R '

I

on what

A is an aromatic ring disubstituted at 1.2; preferably benzene ring;

on what

X is independently 0, S, S0 or SC>₂;

R is H, ^α _χ -0 ₄ alkyl, phenyl or substituted phenyl, halo, haloalkyl, hydroxy, carboxy, cyano,

C-C. alkoxy,

C _x -C alkylthio,

Cj-C alkylsulfinyl,

C _x -C ₄ alkylsulfonyl, amino, nitro, ^C 1 " ^C 4 mono or di-alkylamino;

R ^z and R '' are independently

H, halo,

0 _χ -0 ₄ alkyl or 0 _χ -0 ₄ alkoxy, amino, or oxo, where CH-R ^Z or CH-R ^Z 'in the formula becomes -C = 0;

y is 1-6;

a z is 6-20; and

on what

R 'R''(CH) _y and (CH) _z can independently represent substituted or unsubstituted alkyl or alkenyl radicals containing at least one alkene bond;

and their pharmaceutically acceptable salts and esters.

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.

The following expressions are used in the description of the formula, which are hereby defined:

X in the aforementioned general formula is 0 or S, preferably when X is 0, and particularly when both X are 0, for example, resulting in the catechol structure.

C1 -C4 alkyl includes linear or branched species, for example methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, t-butyl.

Cj-C 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.

-Ί4-

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-methoxy phenyl; 2,4-dimethoxyphenyl; 2-chloro-4-ethoxyphenyl; 3,5-dimethoxyphenyl; 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, etc.

alkylthio includes alkyl, defined above, substituted with at least one divalent thio (-S-) group including: methylthio, ethylthio, isopropylthio, n-butylthio, etc.

C₁-C₄ alkylsulfinyl includes ^{C] _{_-C4}} alkyl, defined above, substituted with at least one group including -S0-; methylsulfinyl, ethylsulfinyl; isopropylsulfinyl, etc.

C ₁ -C ₄ alkylsulfonyl includes ^c 1 " ^and 4 alkyl, defined above, substituted with at least one sulfonyl group, -SC4 -, including; methylsulfonyl, ethylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, etc.

C ₁ -C ₄ mono or dialkyl amino includes amino, substituted with one or more C-C alkyl groups as defined above, including: methylamino, ethylamino, n-butylamino, t-butylamino, N, N-dimethylamino, Ν , Ν-diethylamino, methyl-t-butylamino, etc.

group or groups R in the benzene ring may be present initially in the process, such as in the starting material I in Flow Sheet A, for example phenyl, methyl, —75—

methoxy, cyano, trifluoromethyl, carbomethoxy, or can be added later by a conventional reaction, for example chlorine, such as by chlorination, nitro by nitration, or created (s) from a functional group starting 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 giving rise to a hydroxy group, and methylation may follow until a methoxy group is obtained. Similarly, a hydroxy group can 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, ES The resulting thiol can be alkylated to an alkylthio, which can 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 radical R shown here.

The expression its pharmaceutically acceptable salts and esters means salts and esters of the acid groups in the final molecule that can be used as part of the drug delivery system to humans and include the salts: sodium, potassium, calcium, ammonium, substituted ammonium , quaternary ammonium, and esters: ethyl ester, aceturate, besylate, edetate, fenpropionate, acetate, pamoate, and esters that serve as prodrug formulations that will hydrolyze in the body at physiological pH in order to regenerate the acid, including pivaloylates, e.g. pivoxetil and pivoxil, and Kanebo esters, etc.

R '(CH) _y where

1-6, preferably 3, can contain i

at least one substituent R 'as defined above, and can 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-;

| | ^{2 2} | ² | ² 2 | 2 CH ₃ CH ₃ Cl OCH ₃ OCH ₂ CH ₃ etc.

An alkene bond can also be present in R ^z (CH) _y -; for example,

-CH ₂ -CH = CH- (CH ₂ ) ₂ ~; etc.

CH ₂ -CH = CH-;

ch ₂ -ch = ch-ch ₂ -;

R ^z '(CH) where z is 6-20, preferably 10-16, can contain z at least one substituent. R ^z 'as defined above, and can be: for example - - (CH ₂ ) _g -, - (CH ₂ ) _2Q -, - (CH ₂ ) _g -CH

CH -CH ₂ -CH- (CH ₂ ) _g -; - (CH ₂ ) ₅ -CH- (CH ₂ ) ₄ - and etc.

F OCH ₃

An alkene bond can also be present in

R ^z ·

I (CH) _z for example, CH ₂ ~ CH = CH- (CH ₂ ) θ-; - (CH ₂ ) ₈ -CH = CH (CH ₂ ) ₂ ~;

- (CH ₂ ) _g -CH = CH_ (CH ₂ ) _g -; (CH ₂ ) ₄ -CH = CH- (CH ₂ ) ₄ -; etc.

R ^z and R can also be -NHCOCH ₃ , which can be hydrolyzed to amino by conventional hydrolysis with acid or base in the final molecule; R ^z and R ^zz can also be oxo, obtained by, for example, adding HBr to an alkene followed by conversion to an alcohol and subsequent oxidation to the ketone.

Preferred is when R ^z or R is H and particularly

- preferred is when both

R '

I (CH) _y e

R '·

I (CH) are alkyl.

ç"

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

R '

_and COOH

CH) _Z COOH

R where X is 0 and R, R ', R' ', y and z are as defined above; and particularly preferred are compounds,

j in what

XéOouSené 10-16.

The compounds of the present invention can be produced by the process indicated in Flow Sheet A-1 below.

/ ..

-79FLOW SHEET A-l

/

As indicated in Flow Sheet A1, Compound I is the starting substrate in the process of the invention and is a 1,2-substituted benzene ring. X can independently be 0 or S and PG 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 PG protecting groups 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 that are known will become obvious to the person skilled in the art to perform 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-benzyloxy-thiophenol,

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-methyl-thiophenol, 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 R is a straight or branched alkyl C portion of the ester, including methyl, ethyl, isopropyl, t-butyl, sec-butyl, etc., and where R and Y are as defined above, but are not limited to:

Br-CH ₂ -COOMe,

C ₁ -CH ₂ CH ₂ CH ₂ COOCH CH ₃ ,

Br-CH ₂ CH ₂ CH ₂ CH ₂ COOMe,

Br-CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ COOEt,

Br-CH ₂ ch ₂ ch ₂ ch ₂ ch ₂ ch ₂ cooch ₂ ch ₂ ch ₂ ch ₃ ,

Br- (CH ₂ ) ₂ CH (CH ₃ ) COOMe,

Br-CH ₂ CH (CH ₃ ) CH ₂ COOEt,

Br-CH ₂ CH ₂ CH ₂ COOMe,

Br-CH ₂ CH (OCH ₃ ) CH ₂ COOCH (CH ₃ ) ₂ , ^C 1-CH2 ^{CH (OCH} 2 ^CH 3> ^CH ₂ ^C00Me '

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

In step (Α) the condensation of I and II to produce III takes place in a non-hydroxylated polar organic solvent, for example, acetone, ethyl acetate, methyl ethyl ketone, dioxane, THF, diethyl ketone, etc. A proton acceptor is also present, 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 to reflux or left to settle for an extended period of time at room temperature. The process is conventional.

In step (Β) the protecting group, PG, is removed catalytically at room temperature under a hydrogen atmosphere, pressurized in an organic solvent to produce IV, being a phenol or thiophenol. Operable catalysts include 5% Pd / C, etc. The organic solvent must be inert under the reaction conditions and includes ethyl acetate, ethanol, methanol, dioxane, etc.

Step (C) involves reacting IV with V to produce VI, the diester. The reaction conditions are similar to those described in Step (A) using an inert organic solvent for the reagents and a proton acceptor.

Representative examples of V useful in the invention are;

Br (CH ₂ ) gCOOMe, Br (CH ₂ ) _? COOMe, Br (CH ₂ ) gCOOMe, Br (CH ₂ ) _g COOMe, Br (CH ₂ ) _lo COOMe,

Br (CH ₂ ) ₁₁ COOMe, Cl (CH ₂ ) COOEt, cl (ch ₂ ) ₁₃ cooch (ch ₃ ) ₂ ,

Cl (CH ₂ ) ₁₄ COOCH ₂ CH ₂ CH ₃ ,

Br- (CH ₂ ) ₁₅ COOMe,

Br- (CH_) _1c COOMe,

1O

Br (CH ₂ ) _lg COOCH ₂ CH ₃ ,

Br (ch ₂ ) _1? cooc (ch ₃ ) ₃ ,

Br (CH ₂ ) ₁₈ COOMe,

Br (CH ₂ ) ₁₉ COOEt,

Br (CH ₂ ) _2Q COOMe,

Br (CH ₂ ) ₂ CH (CH ₃ ) - (CH ₂ ) _χ0 COOMe,

Br-CH ₂ CH (CH ₃ ) (CH ₂ ) ₁₀ COOMe,

Br-CH ₂ CH ₃ CH (CH ₃ ) CH ₂ COOEt,

Br-CH ₂ CH (OCH ₃ ) (CH ₂ ) ₇ COOCH (CH ₃ ) ₂ ,

C1-CH ₂ CH (OCH ₂ CH ₃ ) CH ₂ CH ₂ COOMe,

Br-CH ₂ CH (NHCOCH ₃ ) - (CH ₂ ) ₁₀ -CH ₂ -COOMe,

Cl-CH C- (CH) -COOEt,

U || «^ X X

Br-CH ₂ -CH = CH (CH ₂ ) ₈ -COOEt,

Br-CH ₂ -C- (CH ₂ ) _1Q CH ₂ COOMe, ^CH 2

Br-CH _n - (CH) -CH = CH-COOMe,

7 Z7 etc.

In Step (D), the diester can be de-esterified by means of aqueous basic hydrolysis, for example NaOH in MeOH / H ₂ O to provide diacid VI after acidification.

FLOW SHEET B-l

CO

CO _{+ C} y ---

-85FLOW C-1 SHEET

(THE)

BrCH ₂ CH ₂ CH ₂ CO ₂ Et - ·

2A

(O (W ₊ (5) ---

6Ά (D)

H ₂ (CH ₂ ) ₁₀ COOH ^ CHjCJ ^ COOH

7A

Flow Sheet B-1 illustrates the specific synthesis of 7.

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

A solution of 2 in, for example, ethyl acetate is hydrogenated catalytically at room temperature under for example 40 psig of H ₂ in the presence of a 5% Pd / C catalyst to provide ethyl 4- (2-hydroxyphenoxy) butyrate 4 in Step (B).

Step (C) comprises the reaction of methyl 4. and 12-bromododecanoate 5 with potassium carbonate in acetone as in Step (A) to obtain the monomethyl ester 6.

In Step (D), diester 6 is de-esterified by, for example, 2.5 N NaOH in meOH / H ₂ O to provide the final product, diacid 7, 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 that are involved in Flow Sheet B.

It is also obvious from the aforementioned Flow Sheets that suitable substitution compounds for II and 2 with other substituted and unsubstituted halo alkyl esters known in the art and described herein and that the appropriate substitution of V and 5 with other available bromoesters at

Technical 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-carboxinonadecyloxy) 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-carboxitridecyloxy) phenoxy) butyric acid;

4- (2- (12-carboxidodecyloxy) phenoxy) butyric acid;

4- (2- (11-carboxyundecyloxy) phenoxy) butyric acid;

4- (2- (10-carboxidecyloxy) phenoxy) butyric acid;

4- (2- (9-carboxynonyloxy) phenoxy) butyric acid;

4- (2- (8-carboxycyloxy) 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-carboxynonadecyloxy) 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-carboxitridecyloxy) phenylthio) butyric acid;

4- (2- (12-carboxidodecyloxy) phenylthio) butyric acid;

4- (2- (11-carboxyundecyloxy) phenylthio) butyric acid;

4- (2- (10-carboxidecyloxy) phenylthio) butyric acid;

4- (2- (9-carboxynonyloxy) phenylthio) butyric acid);

4- (2- (8-carboxycyloxy) phenylthio) butyric acid;

4- (2- (7-carboxyheptyloxy) phenylthio) butyric acid;

4- (2- (6-carboxyhexyloxy) phenylthio) butyric acid;

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

4- (2- (19-carboxynonadecylthio) phenoxy) butyric acid;

4- (2- (18-carboxyoctadecylthio) phenoxy) butyric acid;

4- (2- (17-carboxyheptadecylthio) phenoxy) butyric acid;

4- (2- (16-carboxyhexadecylthio) phenoxy) butyric acid;

4- (2- (15-carboxypentadecylthio) phenoxy) butyric acid;

4- (2- (14-carboxytetradecylthio) phenoxy) butyric acid;

4- (2- (13-carboxytridecylthio) phenoxy) butyric acid;

4- (2- (12-carboxidodecylthio) phenoxy) butyric acid;

4- (2- (11-carboxyundecylthio) phenoxy) butyric acid;

4- (2- (10-carboxidecylthio) phenoxy) butyric acid;

4- (2- (9-carboxynonylthio) phenoxy) butyric acid;

4- (2- (8-carboxyctylthio) phenoxy) butyric acid;

4- (2- (7-carboxyheptylthio) phenoxy) butyric acid;

4- (2- (6-carboxyhexylthio) phenoxy) butyric acid;

4- (2- (20-carboxyicosylthio) phenylthio) butyric acid;

4- (2- (19-carboxinonadecylthio) phenylthio) butyric acid;

4- (2- (18-carboxyoctadecylthio) phenylthio) butyric acid;

4- (2- (17-carboxyheptadecylthio) phenylthio) butyric acid;

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

4- (2- (15-carboxypentadecylthio) phenylthio) butyric acid;

4- (2- (14-carboxytetradecylthio) phenylthio) butyric acid;

4- (2- (13-carboxitridecylthio) phenylthio) butyric acid;

4- (2- (12-carboxidodecylthio) phenylthio) butyric acid;

4- (2- (11-carboxyundecylthio) phenylthio) butyric acid;

4- (2- (10-carboxidecylthio) phenylthio) butyric acid;

4- (2- (9-carboxynonylthio) phenylthio) butyric acid;

4- (2- (8-carboxyctylthio) phenylthio) butyric acid;

4- (2- (7-carboxyheptylthio) phenylthio) butyric acid;

4- (2- (6-carboxyethylthio) phenylthio) butyric acid;

—89 -

3- (2- (16-carboxyhexadecyloxy) phenoxy) propionic acid;

3- (2- (15-carboxyisohexadecyloxy) phenoxy) butyric acid;

3- (2- (14-carboxytetradecyloxy) phenoxy) butyric acid;

5- (2- (13-carboxitridecyloxy) phenoxy) valeric acid;

5- (2- (12-carboxidodecyloxy) phenoxy) valeric acid;

5- (2- (11-carboxyisododecyloxy) phenoxy) valeric acid;

4- (2- (11-carboxyundecyloxy) phenoxy) valeric acid;

4- (2- (io-carboxidecyloxy) phenoxy) valeric acid;

4- (2- (9-carboxynonyloxy) phenoxy) valeric acid;

6- (2- (9-carboxynonyloxy) phenoxy) caproic acid;

6- (2- (8-carboxycyloxy) 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-carboxidodecylthio) phenoxy) acetic acid;

2- (2- (11-carboxidecylthio) phenoxy) acetic acid;

2- (2- (10-carboxidecylthio) phenoxy) acetic acid;

3- (2- (9-carboxynonyloxy) phenylthio) propionic acid;

3- (2- (12-carboxidodecyloxy) 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-carboxidodecylthio) phenylthio) butyric acid;

5- (2- (11-carboxyundecylthio) valeric acid;

5- (2- (10-carboxidecyloxy) phenylthio) valeric acid;

5- (2- (9-carboxynonyloxy) phenylthio) valeric acid;

3- (2- (12-carboxidodecyloxy) phenylthio) valeric acid;

3- (2- (11-carboxidecyloxy) phenylthio) valeric acid;

3- (2- (10-carboxidecyloxy) phenylthio) valeric acid;

6- (2- (9-carboxynonylthio) phenylthio) caproic acid;

6- (2- (12-carboxidodecyloxy) phenylthio acid;

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-carboxidodecylthio) phenoxy) enanthic acid;

4- (2- (11-carboxyundecyloxy) -4-methyl-phenoxy) butyric acid;

4- (2- (10-carboxidecyloxy) -3-methylphenoxy) butyric acid;

4- (2- (9-carboxynonyloxy) -5-methylphenoxy) butyric acid;

4- (2- (12-carboxidodecyloxy) -6-methylphenoxy) butyric acid;

4- (2- (12-carboxidodecyloxy) -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-carboxidodecyloxy) -5-ethyl-phenoxy) butyric acid;

4- (2- (11-carboxyundecyloxy) -4-phenylphenoxy) butyric acid;

4— (2- (10-carboxidecyloxy) -3,5-dimethylphenoxy) butyric acid;

4- (2- (9-carboxynonyloxy) -4-fluoro-phenoxy) butyric acid;

4- (2- (12-carboxidodecyloxy) -5- (trifluoromethyl) phenoxy) butyric acid;

4— (2— (12-carboxidodecylthio) -5-nitrophenoxy) butyric acid;

4- (2- (11-carboxyundecylthio) -4-methylphenoxy) valeric acid;

4- (2- (11-carboxyundecylthio) -3,5-di-methylphenoxy) butyric acid;

4- (2- (12-carboxidodecyloxy) -4- (dimethylamino) phenoxy) butyric acid;

4- (2- (11-carboxyundecyloxy) -5- (ethylamino) phenoxy) butyric acid;

2- (2- (9-carboxynonyloxy) phenoxy) propionic acid;

3- (2- (12-carboxidodecyloxy) phenoxy) -3-methylpropionic acid;

4- (2- (10-carboxidecyloxy) 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;

-91 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 5a-reductase inhibitor in this invention is an agent for the treatment of demarcated alopecia in combination with minoxidil which is of the following formula:

on what

A is an aromatic ring disubstituted in 1,2 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 -COOH, -CONH ₂ , -CONHR ^, COOR _fa , SO ₂ OH, SO ₃ (OH), -SO ₂ NH ₂ , -SO ₂ ONa, PH (O) (OH), P ( O) (OH) ₂ ;

i

X is 0, S, SO or S0 ₂ ;

R is H,

C ₁ ~ C ₄ alkyl, phenyl or substituted phenyl, halo, haloalkyl, hydroxy, carboxy, cyano,

C-C. alkoxy,

C ₁ -C ₄ alkylthio,

C ₁ ~ C ₄ alkylsulfinyl,

C - ^ - C alkylsulfonyl, amino, nitro,

C ₁ -C ₄ mono or di-alkylamino;

R 'and R' 'are independently

H, halo, ^c 1 " ^and 4 alkyl or alkoxy, amino, or oxo, where CH-R 'or CH-R in the formula becomes -C = 0;

R4 is H, C.-C. alkyl;

3. J_ 4

R _b is ^a l ⁽ l ^u i ¹⁰ 'phenyl, or phenyl C ₁ -C ₄ alkyl;

y is 1-6;

z is 6-20; and in what

R ^z R ^zz

I (CH) _y and (CH) _z can independently represent substituted or unsubstituted alkyl or alkenyl radicals containing at least one alkene bond;

and their pharmaceutically acceptable salts and esters.

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.

The following expressions are used in the description of the formula, which are hereby defined:

X is preferably 0 or S, and particularly preferred is 0.

C ^ -C ₄ alkyl includes linear or branched species, e.g. methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, t-butyl and i ^{c "C} ₁₂ alkyl includes alkyl having up to 12 carbons including n-octyl, t-decyl, n-dodecyl.

Phenyl C-C ₄ alkyl includes benzyl, 2-phenethyl, etc.

C ^-C ₄ 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 omos atoms, 1 S or 0 atom, or a combination thereof, and includes: pyridine, thiophene, furan, imidazole, 1,3 -thiazole, 1,3-oxazole, 1,2,3-thiadiazole, etc. The limitation here being that the dissubstitution occurs in only the carbon atoms of the heteroatomic ring. Preferred heteroaromatic rings are pyridine, furan and thiophene.

Substituted phenyl includes phenyl substituted by one or more ^c -! _ “ ^C ₄ alkyl, alkoxy, or halo, etc. , as defined above. Representative examples include o-, m-, p-methoxy phenyl; 2,4-dimethoxyphenyl; 2-chloro-4-ethoxyphenyl; 3,5-dimethoxyphenyl; 2,4-dichlorophenyl; 2-bromo-4-methylphenyl, o-fluorophenyl, etc.

Haloalkyl includes C ^-C ^ alkyl, defined above, substituted with one or more halo as defined above and includes: trifluoromethyl, 2,2-dichloroethyl, etc.

C ^ ~ CC ₄ alkylthio includes C ₁ ~C ₄ alkyl, defined above, substituted with at least one divalent thio (-S-) group including: methylthio, ethylthio, isopropylthio, n-butylthio, etc.

C ^-C ^ alkylsulfinyl includes C-C ₄ alkyl, defined above, substituted with at least one -S0- group including; methylsulfinyl, ethylsulfinyl; isopropylsulfinyl, etc.

C ₁ -C ₄ alkylsulfonyl includes ^c -C alkyl, defined above, substituted with at least one sulfonyl group, -S0 -, including; methylsulfonyl, ethylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, etc.

C - ^ - C mono or dialkyl amino includes amino, substituted with one or more C ₁ ~ C ₄ alkyl groups as defined above, including: methylamino, ethylamino, n-butylamino, t-butylamino, dimethylamino, diethylamino, methyl -t-butylamino, etc.

The group or groups R on the benzene ring or on the heteroaromatic ring may be present initially in the process, for example phenyl, methyl, methoxy, cyano, trifluoromethyl, carbomethoxy, (such as o-nitrophenol 1 starting at Flow Sheet A) or can be added later by means of a conventional reaction, for example chlorine, such as by chlorination, nitro by nitration, or created from a functional starting group or added present, for example by converting a later added 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 giving rise to a hydroxy group, and methylation may follow until a methoxy group is obtained. Similarly, a hydroxy group can be converted to a thiol by the analogous procedures described in J. org. Chem. 3.1, pp 3980-3984 (1966) by Newman and Karnes, and

J. Org. Chem. 31, pp 410 (1966) by Kwart, H. and Evans, ES The resulting thiol can be alkylated until an alkylthio is obtained, which can 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 radical R shown here.

The expression its pharmaceutically acceptable salts and esters means salts and esters of the acid groups in the final molecule that can be used as part of the drug delivery system to humans and include the salts: sodium, potassium, calcium, ammonium, substituted ammonium , ammonium —96—

quaternary, and esters: ethyl ester, aceturate, besylate, edetate, fenpropionate, acetate, pamoate, and esters that serve as prodrug formulations that will hydrolyze in the body at physiological pHs in order to regenerate the acid, including pivaloylates, for example pivoxetil and pivoxil, and Kanebo esters, etc.

contain and can be, for example, -CH ₂ -; -CH ₂ -CH ₂ -; -CH ₂ -CH ₂ -CH ₂ -,

-CH-; I -CH-CH -; 1 ² -CH ₂ -CH-; -CH ₂ -CH-CH ₂ -; "CH -CH-CH 1 CH ₃ 1 CH ₃ Cl och ₃ 1 OCH CH z

etc.

An alkene bond can also be present in R ^z

R ^z !

(CH) -; for example, CH -CH = CH-; CH -CH = CH-CH -; -CH ₂ -CH ₂ -CH = CH ^y ; - (CH ₂ ) ₃ ~ CH = CH and etc. ^{2 2}

R ^z '(CH) where z is 6-20, preferably 8-14, can contain z at least one substituent R ^z ' as defined above, and can be: for example - - (CH ₂ ) ₆ -, - (CH ₂ ) _2Q -, - (CH ₂ ) ₉ -CH ^CH 3 -CH ₂ -CH- (CH ₂ ) ₉ -; - (CH ₂ ) ₅ -CH- (CH ₂ ) ₄ - and etc.

F OCH ₃

An alkene bond can also be present in

R ^zz

I (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 ) _g -; (CH ₂ ) ₄ -CH = CH- (CH ₂ ) ₄ -; etc.

-97 is preferred when both

Preferred is when R ^z or R ^z 'is H and particularly

R ^z R ^zz

II (CH) _y and (CH) _z are alkyl.

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

R '

R '

R '

I ___ i, X-CCH) _y D ^ 2 H

NC- (CH) _Z AND TT i

Particularly preferred are. the following compounds:

if

J /s' / X— (CH) _and COOH R — r- 1 | T >; - c-ich) ₂ as II 1 0 P το ’ OC— (CH) _and COOH ' Sj-C ^ CH), P (OH) ₂

H II 1 II

R o

R ’

-100-

Ρ '(CH) _and COOH

SC

Ε

R

where X is O or S and R, R ', R' ', y and z are as defined.

behind

Preferred compounds in this class are:

N — C— (CH ₂ ) _n COOH,

H ||

The —101—

^CH 2) n ^SO 3 ^H

CH ₂ ) ₃ COOH

CH ₂ ) ₃ COOH

R

CH ₂ ) _n SSO ₃ Na

CH ₂ ) ₃ COOH

R

nc- (ch ₂ ^ p (oh3 ₂ h II ^2A - ||

O where X is 0 or S, and n is 8-14.

-102 -

Also preferred compounds belonging to these classes are:

where n is 8-14

COOH ~ CCH ₂ ) _n COOH where n is 8-14.

The compounds of the present invention can be produced by the processes indicated in the following Flow Sheets.

-103-

FLOW SHEET A-2

^^ í ^ zOCHaCHjCHjCOjEC

The II the II

EtOC (CH ₂ ) ₁₀ COEt (C)

O

II

CH ₃ OC (CH ₂ ) 1 ₀ CCOH

CD)

O

II

CH ₃ CCCCH ₂ ) _1O CCC1

CO - ¢ 7)

-104-

FLOW SHEET B-2 (G) l · Il + BrCH ₂ CH ₂ CH ₂ CO ₂ Et ^v -

2

11 + 7

CH)

₂ Et

CO ₂ ? Fe

3

O

105FLOW C-2 SHEET

M

H 25

H

x_ / x_xC Oj E t 'nc (ch ₂ ) ₁₀ co ₂ ch ₃ i

^CH 3 30

-106-

FLOW SHEET D-2

O

NC (CH ₂ ) _g CH ₂ PCOH) ₂

H

O °

—107—

FLOW SHEET E-2

-108

FLOW SHEET F-2

-109-

FLOW SHEET G-2

0 '' CN

NC (0¾), _the CO 2 CH ₃ · Η '

-110

FLOW SHEET H-2

BrCH ₂ CH ₂ CH ₂ CO ₂ Et

-------------------> (9.) (alternative to 9)

As indicated in Flow Sheet A-2, o-nitrophenol

1,4-ethyl bromobutyrate 2 and anhydrous K ₂ CO3 in, for example, dry acetone are heated under reflux or stirred for a prolonged period at room temperature, under a nitrogen atmosphere until the product 4- (2- nitrophenoxy) butyrate 3- _t in Step (a).

A solution of 2 in, for example, ethyl acetate is catalytically hydrogenated at room temperature under for example 40 psig of H ₂ 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 obtain the monomethyl ester 6.

In Step (D) the mono acid mono ester 6. is refluxed with thionyl chloride for about 5 hours in order to produce the mono acid chloride, mono methyl ester 7.

Step (E) comprises the reaction of mono acid chloride

7. with amine 4 at eg 0-10 ° C in eg dry ether in the presence of a hydrogen acceptor eg triethylamine in order to produce amide 8.

In Step (F), the ether-amide diester 8. is de-esterified by, for example, 2.5 N NaOH in MeOH / H ₂ O to provide after acidification the final product, diacid 9 ,.

—111—

Flow Sheet B-2 illustrates the synthesis of the corresponding thio compounds.

Step (G) illustrates the reaction of o-aminobenzenethiol with ethyl 4-bromobutyrate which can be carried out in, for example, dry dimethoxyethane, under dry N ₂ , in the presence of a proton acceptor, for example, K ₂ ^CO 3 ⁱⁿ dry in order to produce 11.

Step (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) illustrates the hydrolysis of the diester to give 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 in Step (A).

Step (K) shows the reduction of the nitro group using, for example, Raney's Ni in ethanol / NH ₃ under 40 psig H ₂ ·

Step (L) shows the trifluoroacetylation of 24 using, for example, trifluoroacetic anhydride in dry ether and dry powdered sodium carbonate.

Step (M) shows the methylation in N that can be carried out using, for example, methyl iodide in dry acetone and dry powder KOH followed by removal of the N-trifluoroacetyl group with MeOH / H ₂ O.

-112-

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 28.benzylation, which can be carried out by, for example, 10% Pd / C in MeOH under an atmosphere of H ₂ .

Step (P) shows O-alkylation of 29 using for example, ethyl 4-bromobutyrate and K ₂ ^CO 3 ⁱⁿ anhydrous acetone.

Step (Q) shows the hydrolysis of diester 30 giving rise to diacid 31 by hydrolysis as, for example, described for Step (F).

Flow Sheet D-2 shows the production of phosphonate-type esters and acids.

Step (R) shows the condensation of 4 with 11-bromoundecanoic acid in anhydrous methylene chloride using N, N'-dicyclohexylcarbodiimide and 4-dimethylaminopyridine in order to produce the important bromine intermediate 32.

Step (S) shows the reaction of 32 with triethyl phosphite at, for example, 180 ° C under N ₂ to produce the phosphonate ester 33.

Step (T) converts 33 by means of bromotrimethylsilane giving rise to monoacid 34 ,.

Step (U) uses hydrolysis conditions similar to those of Step (F) in order to produce the phosphonic carboxylic diacid 35.

-113-

The corresponding phosphonic acids can be produced in an analogous manner from 32 by processes known in the art.

Flow Sheet E-2 illustrates the synthesis of the types of sulfonic acid of the compounds of the invention.

Step (V) shows the reaction of intermediate 32 with thiourea in EtOH / H ₂ O under N ₂ at 90 ° C to provide the isothiouronium salt 36.

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 esters 36 and 37 by means of the showell or Ziegler processes described in Step W in the example provides the corresponding sulfonic acid 38.

The corresponding sulfinic acid can be prepared from 36 by the process of J. M. Sprague and T. B. Johnson, JACS 59, 2440 (1937).

The corresponding sulfonamide can be produced from .38. Sulfonic acid / by protecting, for example, carboxylic acid by means of an ester, converting the sulfonic acid into a sulfonyl chloride, treating the sulfonyl chloride with ammonia and then hydrolyzing the protected carboxylic ester giving rise to the corresponding acid.

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

In Step (X), nitrohydroxy pyridine is alkylated at 0 using first conditions analogous to those in Step (A) in order to produce 40.

Step (Y) shows the reduction of the nitro group in the same way as described for Step (B).

Step (Z) shows the acylation of the amino group in the same way as described for 8. in Step (E) in order to produce diester 42. Hydrolysis produces 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 2 under the conditions of Step (E) in order to produce the N 44-acylated phenol.

In Step (BB), alkylation at 0 of 44 as performed using 4-bromobutyronitrile under conditions similar to those of Step (A), yields 45.

Step (CC) shows the hydrolysis of nitrile to give amide 46 using MnO ₂ in methylene chloride.

Flow Sheet H-2 illustrates an alternative route for 9 starting with o-aminophenol, acylating to produce 44, and then reacting 44 under the conditions of Step (A) to produce 8, and then hydrolysis using Step (F ) to provide 9.

Thus, using the methods described above in the Flow Sheets and the starting materials and reagents for the reaction here

-115described, all compounds described and covered by the claim can be synthesized by any person skilled in the art.

It is obvious that other nitrophenols can substitute 1 in Flow Sheets A-2 and Ç-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-methylphenol

2-nitro-4-methylphenol

2-nitro-3-methylphenol

2-nitro-4-phenylphenol

2-nitro-5-phenylphenol

2-nitro-4-chlorophenol

2-nitro-4-fluorophenol

2-nitro-4-trifluoromethylphenol

2-nitro-4-hydroxyphenol

2-nitro-4-methoxyphenol

2-nitro-6-ethoxyphenol

2-nitro-4-methylthio-phenol

2-nitro-4-methylsulfinylphenol

2-nitro-4-methylsulfonylphenol

4-nitro-3-hydroxypyridine

3-nitro-4-hydroxy-5-methylpyridine

3-nitro-4-hydroxy-6-methylpyridine

2-methyl-3-nitro-4-hydroxypyridine 2-hydroxy-3-nitro-5-phenylpyridine

2-nitro-3-hydroxy-5-phenylpyridine

2-hydroxy-3-nitro-5-chloropyridine

2-nitro-3-hydroxy-5-trifluoromethylpyridine 2-methoxy-4-nitro-5-hydroxypyridine

-116-

3-nitro-4-hydroxy-5-ethoxypyridine

2-methylthio-4-nitro-5-hydroxypyridine

2-nitro-3-hydroxy-thiophene

3-nitro-4-hydroxy-thiophene

3-hydroxy-2-nitro-5-methyl-thiophene

3-hydroxy-2-nitro-4-methyl-thiophene

2-hydroxy-3-nitro-5-phenyl-thiophene

2-nitro-3-hydroxy-4-phenyl-thiophene

2-hydroxy-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 that appropriate substitution of 6 with other diesters, available in this technique, will provide all other ether-amide derivatives within the scope of the claims.

Representative examples of 2 useful in this process of the invention include, but are not limited to:

Br-CH ₂ -COOMe,

C1-CH ₂ CH ₂ ch ₂ cooch (ch),

Br-CH ₂ CH ₂ CH ₂ CH ₂ COOMe,

Br-CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ COOEt,

Br-CH ₂ 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-CH ₂ CH ₂ CH ₂ COOMe, Br-CH ₂ CH (OCH ₃ ) CH ₂ COOCH (CH ₃ ) ₂ , C1-CH ₂ CH (OCH ₂ CH ₃ ) CH ₂ COOMe, Br-CH ₂ CH (F ) CH ₂ COOMe, etc.

-117-

Representative examples of other compounds that can be substituted 6 and useful in the invention are:

H00C (CH ₂ ) ₆ COOMe,

HOOC (CH ₂ ) _? COOMe,

HOOC (CHL) COOMe, the

HOOC (CH _) _ COOMe, z y

HOOC (CH ₂ ) ₁₀ COOMe,

HOOC (CH ₂ ) ₁₁ COOMe,

HOOC (CH ₂ ) ₁₂ COOEt,

HOOC (CH ₂ ) _{χ 3} COOCH (CH ₃ ) ₂ ,

HOOC (CH ₂ ) ₁₄ COOCHCH ₂ CH ₃ ,

HOOC (CH ₂ ) ₁₅ C00 (CH ₂ ) CH ₃ ,

HOOC (CH ₂ ) ₁₆ COOCH ₃ ,

HOOC (CH ₂ ) _1? COOCH ₃ ,

HOOC (CH _) _ _Q COOMe,

Z -Lo

HOOC (CH ₂ ) _ig COOEt,

HOOC (CH ₂ ) _2Q COOPh,

HOOC (CH ₂ ) _1Q COOCH ₂ Ph,

HOOCCH (CH ₃ ). (CH) ₁₀ COOMe,

HOOC-CH ₂ CH- (CH ₃ ) (CH) _1Q COOMe,

HOOC-CH ₂ CH ₃ CH (CH ₃ ) CH ₂ COOEt,

HOOC-CH_ CH CH-CH „COOEt

2 | 2

Cl

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

Representative examples of compounds produced by this process include those listed in the following list.

The nomenclature used here for acid radicals is:

p (O) (OH) ₂ , phosphono;

-118-

-COOH, carboxy;

-CONH ₂ , aminocarbonyl;

-SO ^ H, sulfo;

-SO H, sulfine;

z

-SO4 H, thiosulfate, 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-undzcanoylamino) 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- (19-carboxynonadecanoylamino) phenylthio) butyric acid;

4- (2- (18-carboxyoctadecanoylamino) phenylthio) butyric acid;

4- (2- (17-carboxyheptadecanoyl-N-ethylamino) phenylthio) butyric acid;

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

4- (2- (15-carboxypentadecanoylamino) phenylthio) butyric acid;

4- (2- (14-Carboxytetradecahoylamino) phenylthio) butyramide;

4- (2- (13-carboxitridecanoylamino) phenylthio acid;

4- (2- (12-carboxy-dodecanoylamino) phenylthio) butyric acid;

4- (2- (11-carboxy-undecanoylamino) phenylthio) butyric acid;

4- (2- (10-carboxydecanoylamino) phenylthio) butyric acid;

-119-

4- (2- (9-carboxynonanoylamino) phenylthio) butyric acid;

4- (2- (8-carboxyoctanoylamino) phenylthio) butyric acid;

4- (2- (7-carboxyheptanoylamino) phenylthio) butyric acid;

4- (2- (6-carboxyhexanoylamino) phenylthio) butyric acid;

3- (2- (16-carboxyhexadecanoylamino) phenoxy) propionic acid;

4- (2- (15-carboxysoxadecanoylamino) phenoxy) butyric acid;

4- (2- (14-carboxytetradecanoylamino) phenoxy) butyric acid;

5- (2- (13-carboxitridecanoylamino) phenoxy) valeric acid;

5- (2- (12-carboxidodecanoylamino) phenoxy) valeric acid;

5- (2- (11-carboxyisodecanoylamino) valeric acid;

4- (2- (11-carboxyundecanoylamino) isovaleric acid;

4- (2- (10-carboxydecanoylamino) isovaleric acid;

5- (2- (9-carboxynanoylamino) phenoxy) valeric acid;

6- (2- (9-carboxynonanoylamino) phenoxy) caproic acid;

6- (2- (8-carboxyoctanoylamino) phenoxy) caproic acid;

6- (2- (7-carboxyisooctanoylamino) phenoxy) caproic acid;

7- (2- (7-carboxyheptanoylamino) phenoxy) enanthic acid;

7- (2- (6-carboxyhexanoylamino) phenoxy) enanthic acid;

7- (2- (5-carboxyisohexanoylamino) phenoxy) enanthic acid;

2- (2- (12-carboxidodecanoylamino) phenoxy) acetic acid;

2- (2- (11-carboxyundecanoylamino) phenoxy) acetic acid;

2- (2- (10-carboxydecanoylamino) phenoxy) acetic acid;

3- (2- (9-carboxynonanoylamino) phenoxy) propionic acid;

3- (2- (12-carboxydecanoylamino) phenylthio) propionic acid;

3- (2- (11-carboxyundecanoylamino) phenylthio) propionic acid;

3- (2- (11-carboxyundecanoylamino) phenylthio) isobutyric acid;

4- (2- (11-carboxyundecanoylamino) phenylthio) valeric acid;

5- (2- (10-carboxydecanoylamino) phenylthio) valeric acid;

5- (2- (9-carboxynonanoylamino) phenylthio) valeric acid;

4- (2- (12-carboxydecanoylamino) phenylthio) isovaleric acid;

4- (2- (11-carboxydecanoylamino) phenylthio) isovaleric acid;

4- (2- (10-carboxydecanoylamino) phenylthio) isovaleric acid;

6- (2- (9-carboxynonanoylamino) phenoxy) caproic acid;

-120-

6- (2- (12-carboxydecanoylamino) phenylthio) caproic acid;

6- (2- (11-carboxyundecanoylamino) phenylthio) caproic acid;

7- (2- (11-carboxyundecanoylamino) -3-methylphenylthio) enanthic acid;

7- (2- (11-carboxyundecanoylamino) -4-methylphenylthio) enantico acid;

7- (2- (12-carboxydiodecanoylamino) phenoxy) enanthic acid;

4- (2- (11-carboxyundecanoylamino) -4-methyl-phenoxy) butyric acid;

4- (2- (10-carboxidecanoylamino) -3-methylphenoxy) butyric acid;

4- (2- (9-carboxynonanoylamino) -5-methylphenoxy) butyric acid;

4- (2- (12-carboxidodecanoylamino) -6-methylphenoxy) butyric acid;

4- (2- (11-carboxidecanoylamino) -3-chloro (phenylthio) butyric acid;

4- (2- (10-carboxydecanoylamino) -4-methylphenoxy) butyric acid;

4- (2- (9-carboxynonanoylamino) -5-fluoromethyl) phenylthio) butyric acid;

4- (2- (12-carboxidodecanoylamino) -6-methylphenoxy) butyric acid;

5- (2- (11-carboxyundecanoylamino) -3-methylthio) phenoxy) valeric acid;

4- (2- (11-carboxyundecanoylamino) -3-methylsulfonylphenoxy) butyric acid;

4- (2- (11-carboxyundecanoylamino) -4-methylsulfonyl) phenylthio) butyric acid;

4- (2- (12-carboxidodecanoylamino) -5-ethyl-phenoxy) butyric acid;

4- (2- (11-carboxyundecanoylamino) -4-phenylphenoxy) butyric acid;

4- (2- (10-carboxidecanoylamino) -3,5-dimethylphenoxy) butyric acid;

4- (2- (9-carboxynonanoylamino) -4-fluoro-phenoxy) butyric acid;

4- (2- (12-carboxidodecanoylamino) 5-trifluoromethylphenoxy) butyric acid;

4- (2- (11-carboxyundecanoylamino) -5-hydroxy) phenylthio) butyric acid;

4- (2- (10-carboxydecanoylamino) -4-hydroxy) phenylthio) butyric acid;

4- (2- (9-carboxynonanoylamino) -3,5-dimethoxy-phenylthio) butyric acid;

4- (2- (12-carboxidodecanoylamino) -5-nitrophenoxy) butyric acid;

5- (2- (11-carboxyundecanoylamino) -4-nitrophenoxy) valeric acid;

121-

4- (2- (11-carboxyundecanoylamino) -5-amino-3-methylphenoxy acid)

butyric;

4- (2- (11-carboxyundecanoylamino) -5-amino-4-methylphenylthio) butyric acid;

4- (2- (12-carboxidodecanoylamino) -4-dimethylaminophenoxy) butyric acid;

4- (2- (11-carboxyundecanoylamino) -5-ethylaminophenoxy) butyric acid;

3- (2- (12-carboxidodecanoylamino) phenoxy) -3-methylpropionic acid;

3- (2- (11-carboxidecanoylamino) phenylthio) -2-chloropropionic acid;

4- (2- (10-carboxydecanoylamino) phenylthio) -3-methoxybutyric acid;

4- (2- (9-carboxinonanoylamino) phenylthio) -3-ethoxybutyric acid;

4- (2- (12-carboxidodecanoylamino) -4-methyl-3-pyridyloxy) butyric acid;

4- (2- (11-carboxyundecanoylamino) -4-methyl-3-pyridyloxy) butyric acid;

4- (2- (10-carboxidecanoylamino) -5-methyl-3-pyridyloxy) butyric acid;

4- (2- (9-carboxynonanoylamino) -5-hydroxy-3-pyridyloxy) butyric acid;

4- (2- (12-carboxidodecanoylamino) -6- (dimethylamino) -3-pyridyloxy) butyric acid;

4- (2- (11-carboxidecanoylamino) -3-pyridylthio) butyric acid;

4- (2- (10-carboxidecanoylamino) -6-methylsulfonyl-3-pyridyloxy) butyric acid;

4- (2- (9-carboxynonanoylamino) -5-chloro-3-pyridylthio) butyric acid;

4- (2- (12-carboxidodecanoylamino) -5-methylpyridylthio) butyric acid;

4- (2- (11-carboxyundecanoylamino) -5-methylsulfonyl-3-pyridylthio) butyric acid;

4- (2- (11-carboxyundecanoylamino) -6-methyl-3-pyridylthio) butyric acid;

4- (2- (11-carboxyundecanoylamino) -4,6-dimethyl-3-pyridyloxy) butyric acid;

-122-

4- (2- (12-carboxidodecanoylamino) -5-methylthio-3-pyridyloxy) butyric acid;

4- (2- (11-Carboxyundecanoylamino) pyridyloxy) butyric acid;

4- (2- (10-carboxidecanoylamino) -5-methoxy-3-pyridyloxy) butyric acid;

4- (2- (9-carboxynonanoylamino) -4-fluoro-6-methyl-3-pyridyloxy) butyric acid;

4- (2- (12-carboxidodecanoylamino) -5-methylamino-3-pyridyloxy) butyric acid;

4- (2- (11-Carboxyundecanoylamino) -4-phenyl-3-pyridylthio) butyric acid;

4- (2- (10-carboxydecanoylamino) -5-methyl-3-pyridylthio) butyric acid;

4- (2- (9-carboxynonanilamino) -6-methoxy-3-pyridylthio) butyric acid;

4- (2- (12-carboxidodecanoylamino) -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-carboxidodecanoylamino) -5-methyl-3-thienylthio) butyric acid;

4- (2- (11-Carboxyundecanoylamino) -4-methyl-3-thienylthio) butyric acid;

4- (2- (10-carboxydecanoylamino) -5-methyl-3-thienylthio) butyric acid;

4- (2- (9-carboxynonanoylamino) -4-hydroxy-3-thienyloxy) butyric acid;

4- (2- (12-carboxidecanoylamino) -4-methylthio-3-thienyloxy) butyric acid;

4- (2- (11-carboxidecanoylamino) -4-methylthio-3-thienyloxy) butyric acid;

i

4- (2- (10-carboxydecanoylamino) -4-methylsulfonyl-3-thienyloxy) butyric acid;

4- (2- (9-carboxynonanoylamino) -4-methylsulfonyl-3-thienyloxy) butyric acid;

4- (2- (12-carboxidodecanoylamino) -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-carboxidodecanoylamino) -5-dimethylamino-3-thienyloxy) butyric acid;

4- (2- (11-carboxyundecanoylamino) -3-thienyloxy) butyric acid;

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

4- (2- (19-phosphononadecanoylamino) 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-sulfododecanoylamino) phenoxy) butyric acid;

4- (2- (11-Sulfoundecanoylamino) phenoxy) butyric acid;

4- (2- (10-sulfinodecanoylamino) phenoxy) butyric acid;

4- (2- (9-thiosulfatononanoylamino) phenoxy) butyric acid, sodium salt;

4- (2- (8-thiosulfateoctanoylamino) phenoxy) butyric acid, sodium salt;

4- (2- (7-sulfinoheptanoylamino) phenoxy) butyric acid;

4- (2- (6-Phosphonohexanoylamino) butyric acid;

4- (2- (19-sulfononadecanoylamino) phenylthio) butyric acid;

4- (2- (18-sulfinooctadecanoylamino) phenylthio) butyric acid;

-124-

4- (2- (17-thiosulfate-heptadecanoyl-N-ethylamino) phenylthio) butyric acid;

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

4- (2- (14-sulfotetradecanoylamino) phenylthio) butyric acid;

4- (2- (13-sulfinotridecanoylamino) butyric acid;

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

4- (2- (11-phosphononoundecanoylamino) phenylthio) butyric acid;

4- (2- (10-sulfinodecanoylamino) phenylthio) butyric acid;

4- (2- (9-carboxynonanoylamino) phenylthio) butanesulfonic acid;

4- (2- (8-carboxyoctanoylamino) phenylthio) butanesulfinic acid;

4- (2- (7-carboxyheptanoylamino) phenylthio) butanothiosulfonic acid;

4- (2- (20-carboxyicosanoylamino) thio) phenoxy) butanophosphonic acid;

4- (2- (19-carboxynonadecanoylamino) phenoxy) butanesulfonic acid;

4- (2- (18-carboethoxyoctadecanoyl-N-butylamino) phenoxy) butanesulfinic acid;

4- (2- (17-carboxyheptadecanoylamino) phenoxy) butanothiosulfonic acid;

4- (2- (15-carboxypentadecanoylamino) phenoxy) butanophosphonic acid;

4- (2- (14-carboxytetradecanoylamino) phenoxy) butanesulfonic acid;

4- (2- (13-n-carboxytridecanoylamino) phenoxy) butanesulfinic acid;

4- (2- (12-carboxydecanoylamino) phenoxy) butanothiosulfonic acid, sodium salt;

4- (2- (10-carboxydecanoylamino) phenoxy) butanophosphonic acid;

4- (2- (9-carboxynonanoylamino) phenoxy) butanesulfonic acid;

4- (2- (8-carboxyoctanoylamino) phenoxy) butanesulfinic acid;

4- (2- (7-carboxyheptanoylamino) phenoxy) butanothiosulfonic acid, sodium salt;

4- (2- (20-carboxyicosanoylamino) phenylthio) butanophosphonic acid;

4- (2- (19-carboxynonadecanoyl-N-methylamino) phenylthio) butanesulfonic acid;

-125-

4- (2- (18-carboxyoctadecanoylamino) phenylthio) butanesulfonic acid;

4- (2- (17-carboxyheptadecanoylamino) phenylthio) butanesulfinic acid;

4- (2- (16-carboxyhexadecanoylamino) phenylthio) butanothiosulfonic acid, sodium salt;

4- (2- (14-carboxytetradecanoyl-N-propylamino) phenylthio) butanophosphonic acid;

4- (2- (13-carboxytridecanoylamino) phenylthio) butanesulfonic acid;

4- (2- (12-carboxydecanoylamino) phenylthio) butanesulfinic acid;

4- (2- (11-carboxyundecanoylamino) phenylthio) butanothiosulfonic acid, sodium salt;

4- (2- (9-carboxynonanoylamino) phenylthio) butanophosphonic acid;

4- (2- (8-carboxyoctanoylamino) phenylthio) butanesulfonic acid;

4- (2- (7-carboxyheptanoylamino) phenylthio) butanesulfinic acid;

4- (2- (6-carboxyhexanoylamino) phenylthio) butanothiosulfonic acid, sodium salt;

3- (2- (15-carboxyisohexadecanoylamino) phenoxy) isobutanophosphonic acid;

3- (2- (14-carboxytetradecanoylamino) phenoxy) isobutanoic acid;

5- (2- (13-carboxytridecanoylamino) phenoxy) pentanesulfinic acid;

5- (2- (12-phosphonododecanoylamino) phenoxy) valeramide;

5- (2- (11-sulfoundecanoylamino) valeric acid;

5- (2- (10-sulfinodecanoyl-N-methylamino) phenoxy valeric acid;

5- (2- (9-thiosulfatononanoylamino) phenoxy) valeric acid, sodium salt;

6— (2— (9 — phosphonononanoylamino) phenoxy) caproic acid;

6- (2- (7-sulfoisooctanoyl-N-methylamino) phenoxy) caproic acid;

7- (2- (7-sulfinoheptanoyl-N-ethylamino) phenoxy) enanthic acid;

7- (2- (6-thiosulfatehexanoylamino) phenoxy) enantamide, sodium salt,

7- (2- (5-phosphonoisohexanoylamino) phenoxy) enanthic acid;

2- (2- (11-sulfoundecanoylamino) phenoxy) acetic acid;

2- (2- (10-sulfodecanoyl — N-propylamino) phenoxy) acetic acid;

3- (2- (9-sulfinononanoylamino) phenoxypropionic acid;

—126—

3- (2- (12-thiosulfatoddodecanoylamino) phenylthio) propionamide, sodium salt;

3- (2- (11-phosphonoundecanoylamino) phenylthio) propionic acid;

3- (2- (11-sulfoundecanoylamino) -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-phosphonododecanoylamino) phenylthio) pentanesulfonic acid;

5- (2- (11-carboxidecanoylamino) phenylthio) pentane sulfonic acid;

5- (2- (10-phosphonodecanoylamino) phenylthio) pentanothiosulfonic acid;

6- (2- (12-phosphonododecanoylamino) phenylthio) hexanophosphonic acid;

4- (2- (11-sulfinoundecanoylamino) -4-methyl-phenoxy) butane-thiosulfonic acid, sodium salt;

4- (2- (12-sulfododecanoylamino) -6-methylphenoxy) butane acid;

4- (2- (11-sulfodecanoylamino) -3-chloro) phenylthio) butanesulfinic acid;

4- (2- (10-sulfodecanoylamino) -4-methylphenoxy) butanothiosulfonic acid, sodium salt;

4- (2- (12-sulfododecanoylamino) -6-methylphenoxy) butane-phosphonic acid;

5- (2- (11-sulfinoundecanoylamino) -3-methylphenylthio) pentanesulfonic acid;

4- (2- (11-sulfinoundecanoylamino) -3-methylsulfonylphenoxy) butane sulfinic 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;

-127-

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-phosphonododecanoylamino) -4-dimethyl-aminophenoxy) butyric acid;

4— (2— (10-sulfodecanoylamino) -phenoxy) butyric acid;

3- (2- (9-sulfinononanoylamino) phenoxy) propionic acid;

3- (2- (12-thiosulfatododecanoylamino) phenoxy) -3-methylpropionic acid, sodium salt;

3- (2- (11-phosphonodecanoylamino) thienyloxy) -2-chloropropionic acid;

4- (2- (9-sulfononanoylamino) thienyloxy-3-ethoxy-butyric acid;

4- (2- (12-sulfinododecanoylamino) phenoxy) -2-fluoro-butyric acid;

7- (2- (11-thiosulfatoundecanoylamino) phenoxy) -6-amino-enanthic acid, sodium salt;

5- (2- (11-phosphonoundecanoylamino) -3-methylphenoxy) -4-oxo-valeric acid;

4- (2-12-sulfododecanoylamino) phenoxy) but-2-enoic acid;

4- (2- (11-sulfinodecanoylamino) phenoxy) but-2-enoic acid;

4- (2- (10-thiosulfatodecanoylamino) phenoxy) -4-methylene 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-sulfino-3-chlorobutanoylamino) thienyloxy) butyric acid;

-128-

4- (2- (9-thiosulfate-2-methoxyynonanoylamino) thienyloxy) butyric acid, sodium salt;

4- (2-phosphono-2-ethoxybutanoylamino) phenoxy) butyric acid;

4- (2- (14-sulfο-14-fluoro-2-acetamidotetradecanoylamino) -3-methylphenoxy) butyric acid;

4- (2-13-sulfino-2-oxotridecanoylamino) -4-methylthio) phenyloxy) 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-thiosulfatoundecanoylamine) -4-methyl-3-pyridyloxy) butyric acid;

4- (2- (10-phosphonodecanoylamino) -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-sulfoundecanoylamino) -5-methylsulfonyl-3-pyridylthio) butyric acid;

4- (2- (11-sulfinoundecanoylamino) -6-methyl-3-pyridylthio) butyric acid;

4- (2- (11-thiosulfatoundecanoylamino) -4,6-dimethyl-3-pyridyloxy) butyric acid, sodium salt;

4- (2- (12-phosphonododecanoylamino) -5- (methylthio) -3-pyridyloxy) butyric acid;

4- (2- (10-sulfodecanoylamino) -5-methoxy-3-pyridyloxy) butyric acid;

4- (2- (9-sulfinononanoylamino) -4-fluoro-6-methyl-3-pyridyloxy) butyric acid;

-129-

4- (2- (12-thiosulfamododecanoylami.no) -5- (methylamino) -3-pyridyloxy) butyric acid, sodium salt;

4- (2- (11-Phosphonoundecanoylamino) -4-phenyl-3-pyridylthio) butyric acid;

4- (2- (9-sulfounonanoylamino) -6-methoxy-3-pyridylthio) butyric acid;

4- (2- (12-sulfinododecanoylamino) -6-trifluoromethyl-3-pyridyloxy) butyric acid;

5- (2- (11-thiosulfatoundecanoylamino) -4-methyl-3-thiophenyloxy) valeric acid, sodium salt;

4- (2- (11-phosphonoundecanoylamino) -4-methyl-3-thiophenyloxy) butyric acid;

4- (2- (12-sulfododecanoylamino) -5-methyl-3-thiophenylthio) butyric acid;

4- (2- (11-sulfinoundecanoylamino) -4-methyl-3-thiophenylthio) butyric acid;

4- (2- (10-thiosulfatodecanoylamino) -5-methyl-3-thienylthio) butyric acid, sodium salt;

4- (2- (9-phosphonononanoylamino) -4-hydroxy-3-thienyloxy) butyric acid;

4- (2- (11-sulfodecanoylamino) -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-phosphonododecanoylamino) -5-trifluoromethyl-3-thienyloxy) butyric acid;

4- (2- (11-sulfoundecanoylamino) -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-thienyloxy) butyric acid, sodium salt;

-130-

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- (11-carboxyundecanoylamino) phenylthio) butyric acid, 4- (2- (9-carboxynonanoylamino) phenoxy) butyric acid, 4- (2 - (10-carboxidecanoylamino) phenoxy) butyric, 4- (2- (12-carboxydecanoylamino) phenoxy) butyric acid, 4- (2- (13-carboxytridecanoylamino) phenoxy) butyric acid, 4- (2- (15-carboxy pentadecanoylamino acid) ) phenoxy) butyric, 4- (2- (11-carboxyundecanoylamino) -4-methylphenoxy) butyric acid, 4- (2- (11-carboxyundecanoylamino) -5-methylphenoxy) butyric acid.

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

on what

A is an aromatic ring disubstituted by 1,2, preferably a benzene ring;

-131-

D is OH, NH, NHR, OR;

C C

X is O; S, SO or SO ₂ ;

R ê H,

C ₁ ~ C ₄ alkyl, phenyl or substituted phenyl, halo, haloalkyl, hydroxy, carboxy, cyano,

C -C. alkoxy,

C ^ -C ^ alkylthio,

C ₁ ~ C alkylsulfinyl,

C ^-C alkylsulfonyl, nitro, amino,

C-C ₄ mono or dialkylamino;

R 'and R' 'are independently

H, halo,

C ₄ -C ₄ alkyl or C ₄ -C ₄ alkoxy, amino, or oxo, where CH-R 'or CH-R in the formula becomes -C = 0;

R _a is H,--C alkyl;

R ^, R _c are independently, C ^-CC. Alkyl, phenyl, phenyl-C ^-C ^ alkyl;

n is 0-2;

y is 1-6;

-132-

z is 6-20; and in what

R 'R''(CH) _y and (CH) _z can independently represent substituted or unsubstituted alkyl radicals or alkenyl radicals containing at least one alkene bond;

and their pharmaceutically acceptable salts and esters.

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.

In the description of the formula, the following expressions are used, which are hereby defined:

X may be 0 or S, preferably an X being 0, and particularly preferably when both Xs are 0, that is, the catechol structure.

C ^-C ^ alkyl includes linear 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 having ⁰ to 12 carbon atoms including n-octyl, t-decyl, n-dodecyl.

Phenyl C _x -C ₄ alkyl includes benzyl, 2-phenethyl, etc .;

-133 -

C ₁ -C ₄ 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;

Substituted phenyl includes phenyl substituted by one or more of C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, or halo, etc., as defined above; representative examples include o-, m-, p-methoxy phenyl; 2,4-dimethoxyphenyl; 2-chloro-4-ethoxyphenyl; 3,5-dimethoxyphenyl; 2,4-dichlorophenyl; 2-bromo-4-methylphenyl; o-fluorophenium, 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, etc.

C ₁ -C ₄ alkylthio includes C ₁ ~ C ₄ alkyl, defined above, substituted with at least one divalent thio (-S-) group including: methylthio, ethylthio, isopropylthio, n-butylthio, etc.

^C ₁ -C ₄ alkylsulfinyl includes ^C ₁ -C ₄ alkyl, defined above, substituted with at least one -S0- group including; methylsulfinyl, ethylsulfinyl; isopropylsulfinyl, etc.

C ^-C ₄ alkylsulfonyl includes ^c ^ “ ^and ₄ alkyl, defined above, substituted with at least one sulfonyl group, -S0 ₂ -, including; methylsulfonyl, ethylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, ate .;

C ₄ -C ₄ mono or dialkyl amino includes amino, substituted with one or more C ₄ -C ₄ alkyl groups as defined herein above, including: methylamino, ethylamino, n-butylamino,

-134t-butylamino, dimethylamino, Ν, Ν-diethylamino, methyl-t-butylamino, etc.

The group or groups R on the benzene ring may be present initially in the process, for example phenyl, methyl, methoxy, cyano, carbomethoxy, trifluoromethyl, (present as in the starting 6-nitrophenol 1 in the Flow Sheet A) or be added later by a conventional reaction, for example chlorine, such as chlorination, nitro by nitration, or created from a functional group present from the start or added, for example by converting an added nitro later to an amino group by catalytic reduction, and then alkylating giving rise to a mono or dialkylamine. An amino group can be subjected to diazotization giving rise to a hydroxy group, which can be followed by methylation giving rise to a methoxy group. Similarly, a hydroxy group can 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, ES The resulting thiol can be alkylated to give alkylthio, which can be oxidized to give the corresponding sulfoxide or sulfone. Preferred substituents are H, ^C ₁ ^_C 4 alkyl, ^C i ^-C 4 alkoxy and phenyl. These reactions and sequences are conventional in this technique and will be obvious to anyone skilled in the art in order to modify the benzene ring to arrive at a radical R presented here.

The expression its pharmaceutically acceptable salts and esters means salts and esters of the acid groups in the final molecule that can be used as part of the drug delivery system to humans 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 that serve as formulations —135—

of prodrug ”and which will hydrolyze in the body at a physiological pH in order to regenerate the acid, including pivaloylates, for example pivoxetil and pivoxil, and Kanebo esters, etc.

R '(CH) y where y is 1-6, preferably 3, can contain at least one substituent R' as defined above, and can be, for example, -CH -; -CH ₂ “CH ₂ -; -CH ₂ -CH ₂ ~ CH ₂ -,

-CH-; -CH-CH -; -CH-CH-; -CH -CH-CH -; -CH -CH-CH -;

| | ^{2 2} | ² | ² 2 | 2 ch ₃ ch ₃ ci och ₃ och ₂ ch ₃

CH ₂ CH ₂ -CHF etc.

An alkene bond can also be present in

R '

I (CH) y-; for example, CH ₂ -CH = CH-; CH ₂ -CH = CH-CH ₂ -; -CH ₂ -CH = CH-; - (CH ₂ ) ₃ -CH = CH and etc.

R ^z '

I (CH) where z is 6-20, preferably 8-14, can contain z at least one substituent R '' as defined above, and can be completely alkyl: for example, (CH ₂ ) _n COOH, where n is preferably 8 to 14 and the like.

An alkene bond can also be present in

R ''

I (CH) _z for example, (CH ₂ ) ₄ -CH = CH- (CH ₂ ) ₄ ~; etc.

Preferred is when R 'or R is H and particularly preferred is when both

R '. R

II (CH) ^ and (CH) _z are alkyl.

indicated

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

R CCH) _and COOH —C CCH) ζ $ ίθ) n ^ b H 11 I ⁰ R

where R, R ', R' ',

Y, Z, R ^ are defined above;

and particularly preferred are:

137-

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

The compounds of the present invention can be produced by the processes indicated in the following Flow Sheets.

-138-

FLOW SHEET A-3

O

II

BrCH ₂ CCH ₂ ) ₁₀ COH

------ CCH ₃ ) ₂ CHSCH ₂ CCH ₂ ) ₁₀ COOH (C)

139-

FLOW SHEET A-3 (CONT.)

-140

FLOW SHEET B-3

CO ₂ Et ch ₃

ÇCCH ₂ ) _b CH ₂ S- <

II ^ch 3 o

'COOH

CH ₃ çC ch ₂ ) _b ch ₂ s ~ 7.

II ^lw 3 ⁰ 13

-141FLOW C-3 SHEET

O

CO ₂ H

O O

V

C (CH ₂ ) gCH ₂ SCH ₂ CH ₃ II

O )

-142-

As shown in Flow Sheet A-3, o-nitrophenol JL, ethyl 4-bromobutyrate 2 θ ^ 2 ^C0 3 ^an ^ - ^ro ^ P ^{or in} eg, dry acetone are heated at reflux for 12-100 hours , or stirred for an extended period of time at room temperature, under a nitrogen atmosphere to produce ethyl 4- (2-nitrophenoxy) butyrate in Step (A).

A solution of 3. in eg ethyl acetate is catalytically hydrogenated at room temperature under, for example, 40 psig H ₂ in the presence of a 5% Pd / ca catalyst to provide ethyl 4- (2-aminophenoxy) butyrate in 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 obtain acid 6.

In Step (D) the mono acid .6 is and N ', Ν'-dicyclohexylcarbodiimide (DCC) a for example,. ambient temperature in, for example, dry methylene chloride, in the presence of producing amide 7.

reacted with the amine at 4-dimethylaminopyridine tempefaculfim,

In Step (E), for example, 2.5 N final NaOH, monoacid 8 ,.

ether-amide 7.

in MeOH / H ₂ O to provide the is de-esterified by monoacid product 8 in water) to produce the corresponding sulfoxide 8a. being treated can be treated with NaO ₄ in an environment for (4-24 hours) at

Additionally, with meta-chlorobenzoic acid in (CH „C1) Ct Cr (acetofin of can to a —143 -

temperature varying between about 0 and 25 ° C for (1-24 hours) to produce the corresponding sulfone 8b.

In Step (F) ester 7 is treated with ammonia in (methanol) at room temperature for, for example, 1-7 days in order to produce amide 9.

Flow Sheet B-3 illustrates the synthesis of 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 in order to produce 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 in order to produce the acylated ester 12.

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

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

Similarly, 14 can be converted to the sulfone ester 17, which can then be hydrolyzed in a manner analogous to the conditions in Step I to give the corresponding acid 18.

-144-

Alternatively, the sulfur in o-nitrobenzene thiol as a separate starting material analogous to JL, can be coupled to provide the 3-alkylthio ester compound which can be oxidized to the corresponding sulfoxide or sulfone, followed by reduction of the nitro group giving rise to the amino and then coupling with an appropriate reagent, for example 6, to provide the linear amide containing unoxidized sulfur analogs giving rise to Ί_. A further modification exists when the sulfuracylation agent is first oxidized to the corresponding sulfoxide or sulfone, and is then coupled with the amino group of, for example, 11 to provide, for example, 13 containing only an oxidized sulfur in the amide chain.

It is obvious that other nitrophenols can 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-nitro-4-methylphenol 2-nitro-3-methylphenol 2-nitro-4-phenylphenol 2-nitro-5-phenylphenol 2-nitro-4-chlorophenol 2 -nitro-4- (trifluoromethyl) phenol 2-nitro-4-methoxyphenol

2-nitro-6-ethoxyphenol, etc.

Starting materials for Flow Sheets B-3 and C-3 in addition to 10 are commercially available and are produced quickly through technical processes

-145-

above and include all of the above compounds where -SH replaces -OH, ortho position relative to the nitro group.

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

Br-CH ₂ -COOMe, ci-ch ₂ ch ₂ ch ₂ COOCH (ch ₃ ) ₃ ,

Br-CH ₂ CH ₂ CH ₂ CH ₂ COOMe,

Br-CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ COOEt, βγ-οη ₂ 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-CH ₂ CH ₂ CH ₂ COOMe,

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 acid 6 to produce the acid for acylation of the amino group at 4. or 11 include the following:

MeS- (CH „)„ COOH,

Z O

MeS_ (CH ₂ ) ₇ COOH, (CH ₃ ) ₂ CHS- (CH ₂ ) gCOOH,

EtS- (CH_) _Q COOH, δ y

CH ₃ CH ₂ CH ₂ S (CH ₂ ) ₁₀ COOH, (CH ₃ ) ₂ CHS (CH ₂ ) ₁₁ COOH,

MeS- (CH ₂ ) ₁₂ COOH,

EtS_ (CH ₂ ) ₁₃ COOH,

CH ₃ CH ₂ CH ₂ S- (CH ₂ ) ₁₄ COOH, _o (CH ₃ ) ₂ chs- (ch ₂ ) ₁₅ cooh, —146—

ch ₃ (ch ₂ ) ₃ s- (ch ₂ ) ₁₆ cooh, (CH) ₂ CH-CH ₂ S- (CH ₂ ) ₁₇ COOH,

CH ₃ -CH ₂ -CH ₂ -S- (CH ₂ ) ₁₈ cooh, (ch ₃ ) ₂ chs- (ch ₂ ) ₁₉ cooh,

Ets- (CH ₂ ) ₂₀ COOH,

MeS-CH (CH ₃ ) - (CH ₂ ) _1q COOH, (CH ₃ ) ₂ CHS-CH ₂ Ch ₂ CH (CH ₃ ) CH ₂ COOH, MeS-CH_ CH CH-CH COOH

Z Z | z

Cl

EtS-CH ₂ CH (OCH ₃ ) (CH ₂ ) ₇ COOH,

CH ₃ CH ₂ CH ₂ S-CH ₂ CH (OCH ₂ CH ₃ ) CH ₂ CH ₂ COOH, CH ₃ (CH ₂ ) ₇ -S-CH ₂ -COOH, (CH ₃ ) ₂ CH (CH ₂ ) ₅ - S-CH ₂ -COOH,

CH ₃ (CH ₂ ) ₉ -S-CH ₂ -COOH,

CH ₃ (CH ₂ ) ₁₁ S-CH ₂ COOH, etc.

Representative compounds of the present invention include, but are not limited to:

4- (2- (20-isopropylthioeicosanoylamino) 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-methylsulfinyl-tetradecaboylamino) phenoxy) butyric acid; 4- (2- (13-n-propylthiotridecanoylamino) phenoxy) butyric acid;

4- (2- (12-n-butylsulfinyldodecanoylamino) phenoxy) butyric acid;

4- (2- (11-sec-butylthioundecanoylamino) phenoxy) butyric acid;

4- (2- (10-phenyliodecanoylamino) phenoxy) butyric acid;

4- (2- (10-benzyltiodecanoylamino) phenoxy) butyric acid;

4- (2- (10-iso-butylsulfonyldecanoylamino) phenoxy) butyric acid;

4- (2- (9-t-butylthiononanoylamino) phenoxy) butyric acid;

-147-

4- (2- (8-ethylsulfonyloctanoamino) phenoxy) butyric acid;

4- (2- (7-isopropylthioheptanoylamino) phenoxy) butyric acid;

4- (2- (6-methylthiohexanoylamino) butyric acid;

4- (2- (20-ethylsulfonylicosanoylamino) phenylthio) butyric acid;

4- (2- (19-isopropyltiononadecanoylamino) phenylthio) butyric acid;

4- (2- (18-methylthiooctadecanoylamino) phenylthio) butyric acid;

4- (2- (17-ethylthioheptadecanoylamino) phenylthio) butyric acid;

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

4- (2- (15-methylthiopentadecanoylamino) phenylthio) butyric acid;

4- (2- (14-methylsulfinyl tetradecanoylamino) phenylthio) butyric acid;

4- (2- (13-methylsulfonyltridecanoylamino) butyric acid;

4- (2- (12-n-propyliododecanoylamino) phenylthio) butyric acid;

4- (2- (II-n-butylsulfinylundecanoylamino) phenylthio) butyric acid;

4- (2- (10-sec-butyldiodecanoylamino) phenylthio) butyric acid;

4- (2- (10-phenyliodecanoylamino) phenylthio) butyric acid;

4- (2- (10-benzyltiodecanoylamino) phenylthio) butyric acid;

4- (2- (9-iso-butylsulfonylnonanoylamino) phenylthio) butyric acid;

4- (2- (8-t-butylthiooctanoylamino) phenylthio) butyric acid;

4- (2- (7-Ethylsulfinylheptanoylamino) phenylthio butyric acid;

4- (2- (6-isopropylthiohexanoylamino) phenyl butyric acid;

3- (2- (16-methylsulfinylhexadecanoylamino) phenoxy) propionic acid;

4— (2— (15 — methylsulfonylisohexadecanoylamino) phenoxy) butyric acid;

3- (2- (14-n-propylthietradecanoylamino) phenoxy) isobutyric acid;

5- (2- (13-n-butylsulfinyltridecanoylamino) phenoxy) valeric acid;

5- (2- (12-sec-butyl-diodecanoylamino) phenoxy) valeric acid;

5- (2- (11-iso-butylsulfonylisododecanoylamino) valeric acid;

5- (2- (II-t-butylthioundecanoylamino) valeric acid;

5- (2- (10-Ethylsulfinyldecanoylamino) valeric acid;

5- (2- (9-isopropyltiononanoylamino) phenoxy) valeric acid;

6- (2- (9-methylthiononanoylamine) caproic acid;

6- (2- (8-Ethylthiooctanoylamino) phenoxy) caproic acid;

6- (2- (7-Isopropylthioisooctanoylamino) phenoxy) caproic acid;

7- (2- (7-methylheptanoylamino) phenoxy) enanthic acid;

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7- (2- (6-methylsulfinylhexanoylamino) phenoxy) enanthic acid;

7- (2- (5-methylsulfonylisohexanoylamino) phenoxy) enanthic acid;

2- (2- (12-n-propyl diodecanoylamino) phenoxy)) acetic acid;

2- (2- (11-n-butylsulfinylundecanoylamino) phenoxy) acetic acid;

2- (2- (10-sec-butyldiodecanoamino) phenoxy) acetic acid;

3- (2- (9-iso-butylsulfonylnonanoylamino) propionic acid;

3- (2- (12-t-butyl-diodecanoylamino) phenylthio) propionic acid;

3- (2- (11-ethylsulfinylundecanoylamino) phenylthio) propionic acid;

4- (2- (11-isopropylthioundecanoylamino) phenylthio) butyric acid;

4- (2- (11-methylthioundecanoylamino) -4-methylthiophenoxy) butyric acid;

4- (2- (12-Ethyliododecanoylamino) phenylthio) butyric acid;

5- (2- (11-isopropylthioundecanoylamino) phenylthio) valeric acid;

5- (2- (10-methylthiodecanoylamino) phenylthio) valeric acid;

5- (2- (9-methylsulfinylnonanoylamino) phenylthio) valeric acid;

5- (2- (12-methylsulfonyldodecanoylamino) phenylthio) valeric acid;

5- (2- (11-n-propyliodecanoylamino) phenylthio) valeric acid;

5- (2- (10-n-butylsulphinylldecanoylamino) phenylthio) valeric acid;

6- (2- (9-sec-butylthiononanoylamino) phenoxy) caproic acid;

6- (2- (12-iso-butylsulfonyldodecanoylamino) phenylthio) caproic acid;

6- (2- (11-t-butylthioundecanoylamino) phenylthio) caproic acid;

7- (2- (11-ethylsulfinylundecanoylamino) -3-methylphenylthio) enanthic acid;

7- (2- (11-isopropylthioundecanoylamino) -4-methylphenylthio) enanthic acid;

7- (2- (12-methylthiododecanoylamino) phenoxy) enanthic acid;

4- (2- (11-phenylthioundecanoylamino) -4-methyl-phenoxy) butyric acid;

4- (2- (10-benzyltiodecanoylamino) -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;

4- (2- (10-n-propyliodecanoylamino) -4-methylphenoxy) butyric acid;

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4- (2- (9-n-butylsulfinylnonanoylamino) -5-fluoromethylphenylthio) butyric acid;

4- (2- (12-sec-butyl-diodecanoylamino) -6-methylphenoxy) butyric acid;

5- (2- (11-iso-butylsulfonylundecanoylamino) -3-methylphenylthio) valeric acid;

4- (2- (11-t-butylthioundecanoylamino) -3-methylsulfonylphenoxy) butyric acid;

4- (2- (11-ethylsulfinylundecanoylamino) -4-methylsulfonylthio) butyric acid;

4- (2- (12-isopropyl diodecanoylamino) -5-ethylphenoxy) butyric acid;

4- (2- (11-methylthioundecanoylamino) -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-isopropylthio) undecanoylamino) phenoxy) butyric acid,

4- (2- (11-Ethylthio) undecanoylamino) phenylthio) butyric acid,

4- (2- (9-isopropylthio) nonanoylamino) phenoxy) butyric acid,

4- (2- (10-isopropylthio) decanoylamino) phenoxy) butyric acid,

4- (2- (12-isopropylthio) dodecanoylamino) phenoxy) butyric acid,

4- (2- (13-butylthio) tridecanoylamino) phenoxy) butyric acid,

4- (2- (15-t-butylthio) pentadecanoylamino) phenoxy) butyric acid,

5- (2- (11-Isopropylthio) undecanoylamino) phenoxy) valeric 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 already described, can be used to treat BPH in combination with a

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adrenergic blocker, by oral administration., parenteral or topical.

In this invention, the α-adrenergic receptor blocker, and the 5α-reductase inhibitor are administered in combination separately or as a single combined pharmaceutical composition by parenteral and oral routes. Preferably , the _blocking-1 and 5a-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.

A-blocker ₁ compositions are generally administered according to the current Physitian's Desk Reference (PDR) published by Medicai Economics Co. Inc. of Oradell, NJ 07649. The dosage ranges administered are from PDR 44 (edition, 1990) . For example, terazosin is administered in a dosage range of about 1 to 10 mg once (qd) per person per day while prazosin is administered twice daily.

The 5a-reductase inhibitor compositions are generally administered in a dosage range of about 5 mg per day per person once per day (q.d.).

In the preferred aspect of this invention, the α-blocker is terazosin which is administered orally at a daily dose to a male human of about 5-10 mg and the 5a-reductase inhibitor is finasteride, which is administered orally at a daily dose of about 5 mg.

“Ιδί-

The α-blocker and the 5α-reductase inhibitor can be compounded in a simple dosage form for oral or parenteral administration. A tablet or capsule is a particularly convenient form 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, can be made into tablet or dragee cores by mixing with powdery, solid carrier substances, such as sodium citrate, calcium carbonate or dicalcium phosphate, and agents binding agents such as polyvinyl pyrrolidone, gelatin or cellulose derivatives, possibly also adding lubricants such as magnesium stearate, sodium lauryl sulfate, Carbowax or polyethylene glycols. Of course, substances that improve the taste can be added in the case of oral administration forms.

As other forms of administration, buffered capsules, for example hard gelatin capsules, as well as closed gelatin capsules comprising a softening or plasticizing agent, for example glycerin, can be used. The buffered capsules preferably contain the active substance 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 mol gelatin capsules, the active substance is preferably dissolved or suspended in suitable liquids, such as vegetable oils or liquid polyethylene glycols.

The active ingredient components used in accordance with the present invention can also be formulated into a composition for administration once a day or for even longer release, by means of conventional techniques well known in the art.

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

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

To help determine the effect of prostate treatment, blood plasma concentrations of tetstosterone (T), dihydrotetstosterone (DHT), and prostate acid phosphatase (PAP) as well as prostate volume are measured. Lower concentrations of DHT and prostatic PAP, a reduction in prostate volume are indicative of successful treatment. The concentrations of the above components in plasma are measured by standardized 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 staining and E-Nieschlay and DL Loriaux, Z. Klin, Chem, Klin, Biochem (1972), 4, 164 for radioimmunoassay T determinations).

The volume of the prostate is measured by rectal examination and / or by transrectal ultrasound. The objective assessment of the effect of

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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 terazosin will have an even greater effect on the relief of symptoms of BPH in patients that will be greater than the effect obtained with each of the agents used alone.

The method for preparing the compounds of the present invention, already described in general terms, can be further illustrated by the following examples which are not to be elaborated as being limiting the scope of the spirit of the present invention.

CHAPTER 1

EXAMPLE 1

Methyl 3-0xo-4-aza-5a-androst-l-ene-17fi-carboxylate

A suspension of 83.7 g of methyl 3-oxo-4-aza-5a-androstane-17-carboxylate * and 126.5 g of benzeneselenin 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 was slowly distilled in order to remove water that had formed in the reaction (2 hours). The solution was evaporated to give 198 g of wet residue. The residue in the form of a solution in dichloromethane was washed with a saturated aqueous solution of NaHCO ₃ and a saturated solution of NaCl, then being dried and evaporated to give 172.4 g. This material was chromatographed on 2.56 kg of silica gel, eluting first with dichloromethane (51) and then with 4: 1 dichloromethane. The desired product eluted

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after 8 1 and had an amount of 53.4'g. It was washed with diethyl ether and dried to give 49.5 g of the title compound, mp 278-280 ° C. Similarly, the following compounds were converted to their corresponding unsaturated derivatives in 1.2 corresponding:

la lb

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

U.S. Patent No. 4,377, .584, March 22, 1983.

EXAMPLE 2

Methyl 4-methyl-3-oxo-4-aza-5a-androst-l-ene-175-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 to 50 ° C for 2 hours. After

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On cooling the mixture was diluted with water until a volume of 2 liters was obtained. The solid was separated after cooling in an amount of 25.4 g, mp 159-161 ° C.

Similarly, the following compounds were converted to their corresponding 4-methyl derivatives:

Federal Police.

2a R = CONHC (CH ₃ ) ₂ CH ₂ C (CH ₃ ) ₃ , 148-150 ° C androstane

2b = CONHC (CH ₃ ) 3; delta-l-androstene 153-155 ° 2C = CONHC (CH ₃ ) ₂ CH ₂ C (CH ₃ ) ₃ 168-170 ° delta-l-androstene

EXAMPLE 3

4- Methyl-3-oxo-4-aza-5a-androst-l-ene-17B-thiocarboxylate ____

5- (2-pyridyl)

A suspension of 25 g 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 reflux for 4 hours, the solution was

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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.

dry, crude acid (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 chromatographed directly on a 4.5 kh column of silica gel eluting with 9: 1 ethyl acetate-acetone to give 20.4 g of the desired product, mp 218-220 ° Ç.

Continued elution with acetone gave 5.2 g of the methanol addition product, S- (2-pyridyl) la-methoxy-4-methyl-3-oxo-4-aza-5a-androstane-17B-thiocarboxylate , mp 221-223 ° C as a by-product.

3A. Similarly, the product of Example 1 was converted to S- (2-pyridyl) 3-oxo-4-aza-5a-androst-1-ene-17B-thiocarboxylate, m.p. 230-232 ° C.

3B. similarly methyl 3-oxo-4-aza-5a-androstane-17B-carboxylate was converted to S- (2-pyridyl) 3-oxo-4-aza-5a-androstane-17B-thiocarboxylate, mp 232 -234 ° C.

EXAMPLE 4

Anhydrous N-t-butyl 4-Methyl-3-oxo-4-aza-5a-androst-l-ene-17B-carboxylate t-Butylamine was added to a suspension of

2.5 g of the pyridylthioester 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 gel of

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silica. Elution with 20: 1 ethyl acetate dichloromethane gave 1.5 g of the product, mp 152-154 ° C.

When the example is repeated using an appropriate amine and an appropriate pyridylthioester, the following products are obtained:

4b: N-t-butyl 3-oxo-4-aza-5a-androstane-17B-carboxamide,

mp 275-276 ° C.

4c: 4-methyl-3-oxo-4-aza — 5a-androst-l-ene-17B-carboxamide

N- (2,4,4-trimethyl-2-pentyl), mp 168-170 ° C.

EXAMPLE 5

5 — oxo — 3,5-secaetian-3,20-dioic acid

To a solution of 200 g of 3-oxo-4-etien-17B-oic acid in 3.5 l of 80 ° t-butanol was added a solution of 198.4 g of sodium carbonate in 474 ml of water. A hot solution (65 ° C) 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 80 ° C. 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 that 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, saturated sodium chloride solution, then 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, mp 189-192 ° C.

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3-Oxo-4-aza-5-etien-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 was 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 dried in air to give 57.5 g of the product, m.p. 310 ° C

EXAMPLE 5C

3-Oxo-4-aza-5a-etian-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 60 ° C in the presence of platinum catalyst (from 16.32 g of PtO 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 well with 3 l of water and then filtered and air dried to give 125 g of white solid, mp 310 ° C.

This material is also obtained by saponification of methyl 3-oxo-4-aza-5a-androstane-17B-carboxylate (3-oxo-4-aza-5a-etien-17B-oate) in 7% methanolic potassium hydroxide followed by acidic treatment.

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EXAMPLE 5D

N-f2,4,4-trimethyl-2-pentyl) -3-oxo-4-aza-5a-androstane-17B-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 room temperature overnight. The solid was filtered off and the filtrate was treated with 2,4,4-trimethyl-2-pentylamine (t-octylamine). This solution remained at room 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 concentrating the crude product was eluted through 240 g of silica gel with 3: 7 acetone-dichloromethane to give 5.5 g of the product, mp 250-251 ° C.

EXAMPLE 5E

Example 5D is repeated using t-butylamine instead of 2,2,4-trimethyl-2-p.thylamine to obtain Nt-butyl 3-oxo-4-aza-5a-androstane-17B-carboxamide, mp 274 -276 ° C.

EXAMPLE 6

Synthesis of 17β (N-l-adamantyl-carbamoyl) -4-aza-5a-androst-l-en-3-one

100 mg of 17-methyl ester (0.305 mmoles) from Example 1 were suspended in 3.0 ml of THF (dried over 3A molecular sieves), then adding 183.0 mg of 1-adamantanamine (1.2 mmoles) ). The suspension was cooled to 5-10 ° C τ '

then adding 590 μΐ of a 2.0 M EtMgBr solution in THF. The resulting mixture was left to stir for 10 minutes, then refluxed for 1-2 hours under Ν ₂ · The mixture was cooled to 0 ° C and then quenched with saturated NH ^Cl solution (about 10 ml). The organic layer was separated and the aqueous layer was extracted with three volumes of CH ₂ C1 ₂ ·

The organic layers were combined, washed 2 times with H ₂ O, twice with saturated sodium chloride, and dried over MgSO ₄ , filtered and evaporated to dryness in vacuo. Crystallization from EtOAc gave 75.0 mg of product. Recrystallization from MeOH and drying at 110 ° C for 2 hours / 0.1 mm gave the product, mp 305-306 ° C. Molecular weight (by FAB) revealed M ⁺ = 451: Calculated = 451.

Anal. Shut, for ^C ₂ 9 ^H 42 ^N 2 ° 2 ^:

C, 77.28; H, 9.40; N, 6.21. Found: C, 76.84; H, 9.73; N, 5.93.

EXAMPLE 7

Synthesis of 17B (Ν-2-adamantyl-carbamoyl) -4-aza-5a-androst-l-en-3-one

Following the general process described above in Example 6 but using 2-adamantamine (prepared by aqueous hydrochloride neutralization and extraction with EtOAc and isolation) instead of 1-adamantamine, and refluxing for 7 hours instead of 1-2 hours , the title compound, mp 284-285 ° C, is prepared.

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EXAMPLE 8

Synthesis of 17β (N-l-adamantylcarbamoyl) -4-aza-5a-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 was added and the mixture was hydrogenated for 6.0 hours at 40 psi RT. The mixture was filtered through celite, the mass was washed with THF (3 times) and the solvent was evaporated in vacuo to provide 97.0 mg of the aforementioned title product. NMR revealed absence of olefins. The crude material was placed on a column of 15.0 g of silica gel, and was eluted with 1: 1 (CH2 Cl2: acetone).

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

Anal. Shut, for ^C 29 ^H 44 ^O 2 ^N 2 ^H 2 ^0:

C, 76.18; H, 9.81; N, 6.13. Found: C, 75.91; H, 9.97; N, 6.06.

EXAMPLE 9

Synthesis of 17fi (N-l-adamantylcarbamoyl) -4-methyl-4-aza-5a-androst-l-en-3-one

120 mg of thiopyridyl ester from Example 3 were suspended in 20 ml of dry THF, and to the suspension were added 175.0 mg of 1-adamantanamine under Ν ₂ · The reaction was carried out at RT for 16 hours under Ν ₂ · The reaction was monitored by TLC on silica gel using 1: 1 acetone: hexane. The product has been separated

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in TLC 20 cm x 20 cm, 1,000 μπ of silica gel plate, eluted with (acetone / hexane) 1: 1.

The product was crystallized from ethyl acetate to give 50.0 mg of pure material, mp 202-205 ° C. The Molecular Weight (FAB) revealed a value of 465; Calc.:465. Recrystallization gave 19.14 mg of the aforementioned title product, mp 202-202.5 ° C.

Analysis Cale, for ^C 30 ^h 44 ^N 2 ° 2 · Η ₂ Ο:

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-5Qi-androstane-17B-carboxylate

The 17B-androstane carboxylate starting material of Example 1 was hydrolyzed with 7% KOH in isopropanol or aqueous 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-5a: -androstane-17B-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 room temperature overnight. The solid was filtered off and the filtrate was treated with 1-adamantamine. This solution remained at room temperature for 64 hours, then it was filtered, and the solution was washed successively with 10% hydrochloric acid and saturated aqueous sodium chloride. After drying with MgS0 ₄ ,

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filtered and concentrated. The crude product was eluted through 240 g of silica gel with 3: 7 (acetone: dichloromethane) to give 5.5 g of the aforementioned title product, mp 323-324 ° C.

EXAMPLE 12

Synthesis of Benztriazol-1-yl-3-oxo-4-methyl-4-aza-5a-androstan-17fi-carboxylate

An 83.7 g suspension of methyl 3-oxo-4-methyl-4-aza-5a-androstane-17B-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 17B-carboxylic acid.

The acid was quickly converted to benzotriazil-1-yl-3-oxo-4-methyl-4-aza-5a-androstane-17B-carboxylate as described in Example 13. The activated ester (the benzotriazolyl derivative) was purified by TLC (4 plates, 20 cm x 20 cm x 20 cm x 1,000 μπι of silica gel) eluting with 4:96 (MeOH-CHCl ₃ ). The isolated product was washed with ether to give the active ester mp 198-200 ° C with decomposition.

EXAMPLE 13

Synthesis of 17β (N-1-adamantylcarbamoyl) -4-methyl-4-aza-5a-androstan-3-one

100.0 mg of the 4-methyl-4-aza-benzotriazole derivative prepared as described in Example 12, were dissolved in 20.0 ml of CH ₂ C1 ₂ · To make the solution clear 127 mg of 1-adamantamine were added . The reaction mixture was stirred overnight at RT / N ₂ ·

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

Anal. Shut, for C _O „H. · 1.5 H„ O:

^r 30 46 2 2 2

C, 73.58; H, 9.68; N, 5.62;

Found: C, 73.15; H, 9.30; N, 5.67.

EXAMPLE 14

Diastereomeric Synthesis of 175 (N-exo-2-norbornylcarbamoyl) -4-aza-5a-androst ~ l-en-3-one)

100.0 mg of the corresponding 4-H thiopyridyl ester of Example 3, prepared by the process of Example 3, but using the 4-H methyl ester product 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, 477 μΐ (±) of racemic exo-2-aminonorbornane were added. The reaction was allowed to continue for 16 hours at RT / NO. 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 MgSO ₄ , 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 µm / silica gel) eluted with (CHCl ₃ : acetone) 70:30 to provide 43.4 mg of the title product above

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referred to. Recrystallization from EtOAc gave 30 mg of product, mp 245-245.9 ° C.

NMR (CDC1 ₃ ) confirmed the aforementioned structure.

Mass spectrum FAB calc. for ° 26 ^Η 3θ ° 2 ^Ν 2 ^{: m} / ^{e 411} 'Found: 441.

Anal. Calc. for ^C 26 ^H 38 ° 2 ^N 2 · Η20:

C, 72.82; H, 9.40; N, 6.58. Found: C, 73.21; H, 9.20; N, 6.25.

EXAMPLE 15

Synthesis of 17B (N-1-adamantylmethylcarbamoyl) -4-aza-5a-androst-l-en-3-one

200.0 mg of steroid thiopyridyl aza 4-H, used in Example 14, was suspended in 2.0 ml of dry THF.

400 μΐ of 1-aminomethylene adamantane was added to the suspension using a syringe at TA / N ₂ · After several minutes, a clear yellow solution resulted and after 1/2 hour, precipitation occurred. The reaction was allowed to continue overnight / N ₂ · It was diluted with CH ₂ C _{1 2} , washed with 10% NaOH, twice, then with H ₂ O twice, followed by 10% HCl (twice) , HO (twice), and finally twice with saturated NaCl solution 2.

The organic layer was dried over MgSO ₄ , filtered, concentrated in vacuo to obtain the product, as indicated by NMR, recrystallized from EtOAc, to provide 149.0 mg of product, mp 255-257 ° C with decomposition .

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

-166—

EXAMPLE 16

Synthesis of 17B- (Ν-2-adamantylcarbamoyl) -4-aza-5a-androstan-3-one

A mixture of 1.09 grams of 17B- (Ν-2-adamantylcarbamoyl) -4-aza-5a-androst-l-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 elution on a 200 ml silica gel column with 40:60 acetone / methylene chloride eluant to provide 1.0 g of solid, m.p. 294-296 ° C.

Anal. Shut, for ^C 29 ^H 44 ^N 2 ° 2 '°' ^2H 2 °

Cal .: C, 76.33; H, 9.80; N, 6.14

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

Mass Spectrum Analysis by electron impact revealed 452 MW.

EXAMPLE 17

Synthesis of 17β- (Ν-2-adamantylcarbamoyl) -4-aza-4-methyl-5o! -Androst-l-en-3-one

A 500 mg suspension of 17β- (Ν-2-adamantylcarbamoyl) -4-aza-5a-androst-l-en-3-one, as prepared in Example 16, 10 ml DMF sieve, 140 mg NaH solution, 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 maintained 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 of CH ₂ C1 ₂ · The organic layers were combined, washed with saline, dried and evaporated to provide a white crystalline residue. Recrystallization from ethyl acetate / CH ₂ Cl ₂ gave a pure white solid, mp 246-248 ° C.

Analysis calculated for C_ _H. .N_0 · 0,3H_, 0

44 2 2 2

Shut up. C, 76.65; H, 9.56; N, 5.95

Found: C, 76.50; H, 9.75; N, 5.84

Mass spectrography revealed a molecular weight of 464.

EXAMPLE 18

Synthesis of 17β- (Ν-2-adamantylcarbamoyl) -3-oxo-4-methyl-4-aza-5a-androstane

17β- (Ν-2-adamantylcarbamoyl) -4-methyl-4-aza-androsten-l-en-3-one, (200 mg) as prepared in Example 17, was placed in 25 ml of absolute ethanol with catalyst of hydrogenation 200 mg of Pd / C at 30%. 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 hot ethyl acetate to give a white crystalline solid, mp 113-115 ° C. Stop, for C ₃₂ H ₅ ON ₂ O ₃ · 0.5 EtOAc

Shut up. C, 75.25; H, 9.86; N, 5.48

Found: C, 75.07; H, 9.52; N, 5.28

Mass spectroscopy indicated a molecular weight of 466 for the unsolvated molecule.

-168-

EXAMPLE 19

Synthesis of 17fi- (N-methyl-N-2-adamantyl) carbamoyl-4-methyl-4-aza-androst-l-en-3-one

17B- (Ν-2-adamantyl) carbamoyl-4-aza-androst-l-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 was added dropwise and left 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 C _{1 2} (3 x 100 ml), the organic extracts were combined, washed with H ₂ O, brine, then evaporated to dryness to provide crude product. The crude product was eluted on an HPLC column (silica gel) with acetone / CH ₂ C1 ₂ 10/1 to provide 2 peaks having retention times of 3 CV (B) and 3.8 CV (A). Peak (A) was analyzed against the product of the 4-methylaza title from Example 15. The second product (B) was analyzed as the analogue 4-methylaza-17B- (N-methyl-N-2-adamantyl (carbamoyl, this is the title compound, mp 163-165 ° C.

Shut up, for σ _οι Η. ^ Ν_0_

46 2 2

Shut up. ç, 77.77; H, 9.68; N, 5.85 Found: ç, 77.29; H, 9.79; N, 5.77

Mass spectrometry revealed a molecular weight of 478.

—169 -

EXAMPLE 20

Synthesis of 17B- (N-methyl-N-2-adamantylcarbamoyl) -4-aza-4-methyl-androstan-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 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 C ^ CC ^ / diethyl ether / hexane to provide 800 mg of the pure monomethyl androstane compound of Example 16, mp 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. Shut, for ^C 31 ^H 48 ^N ₂ ^O 2

Shut up. 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

N-t-butyl androst-3,5-diene-17B-carboxamide-3-carboxylic acid (a) N-t-butyl androst-3,5-diene-3-bromo-17B-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 dried sieve toluene was added over a period of one hour 1 g ( 0.003 mol) of androst-4-ene-3-one 17B-carboxylic acid. The reaction

170-

it was stirred at room temperature for 2 hours and then it was concentrated in vacuo. The excess oxalyl bromide was removed by azeotropy 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 were added dropwise over 15 minutes. Once the addition was 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 and was then stirred at 25 ° C for one hour. The volatiles were removed under vacuum. The residue was partitioned between chloroform / water, the layers were stirred together and separated and then the aqueous phase was extracted again twice with chloroform. The combined organic extracts were washed with water (2x) and then dried over 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.

(b) N-t-butyl androst-3,5-diene-17-carboxamide-3-carboxylic acid

To a solution of Nt-butyl androst-3,5-diene-3-bromo-17B-carboxamide (0.5 g, 0.00115 mol) in 5 ml of tetrahydrofuran, cooled to -78 ° C (ice bath dry / acetone) under argon, 1.5 ml (0.00375 mol) of a 2.5 M solution of n-butyl lithium in hexane was added dropwise. The reaction mixture was stirred at this temperature for one hour and then carbon dioxide was bubbled into the reaction for 45 minutes, using a concentrated sulfuric acid tower. The reaction mixture was allowed to warm to room temperature and was then diluted with water, aqueous HCI solution and chloroform. The layers were shaken together and separated, with the

171-

aqueous phase extracted again with chloroform (2x). The combined organic extracts were washed with water (2x), and brine (1x) and then dried with 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-5a-androst-l-ene-17e-carboxylate

A suspension of 83.7 g of methyl 3-oxo-aza-5a-androstane-17-carboxylate * and 126.5 g of benzeneselenin 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 was distilled slowly in order to remove the water that had formed in the reaction (2 hours). The solution was evaporated to give 198 g of wet residue. The residue as a solution in dichloromethane was washed with saturated aqueous NaHCO3 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 aforementioned 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 aforementioned title product, mp 278-280 ° C.

-172-

* Rasmussori Johnston and Arth. U.S. Patent No. 4,377-584, March, 1983.

EXAMPLE 2

5- (2-Pyridyl) -3-oxo-4-aza-5a-androst-1-ene-173-thiocarboxylate

A 25.0 g suspension of the aforementioned product from Example 1 was saponified with 12.5 g of KOH in 150.0 ml of CH ₃ OH-H ₂ O 5: 1 under reflux conditions for 4 hours / N ₂ · 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.

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 stirred at 24 ° C overnight / N ₂ · The reaction mixture was placed on a silica gel column (1.3 kg) and eluted with 1: 1 (acetone (CH ₂ C 1 ₂ ). The desired thioester was eluted slowly, and after washing with ether, provided 36.8 g of the aforementioned title product, mp 232-235 ° C.

173-

EXAMPLE 3

22-Methyl-4-aza-21-nor-5a-col-1-ene-3,20-dione

To a solution of 7.2 g of S- (2-pyridyl) -3-oxo-4-aza-5a-androst-1-ene-17B-thiocarboxylate in 288 ml of tetrahydrofuran were added at -78 ° C 33, 6 ml of 1.3M S-butylmagnesium chloride. After 30 minutes at -78 ° C the solution rose to room temperature and was treated with a saturated aqueous solution of NaCl. The product was extracted into dichloromethane and was 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 9: 1 dichloromethane-acetone to give

4.5 g of the product, mp 246-249 ° C.

When the process is repeated using the following reagents, the indicated product is obtained.

174-

Material of

Match Reagent Product S- (2-pyridyl) 3- 2- chloride 17B- (2-pyrrolyl- oxo-4-aza-5a- pirrolil mag- carbonyl) -4-aza- androst-l-eno- nesium 5a-androst-l-eno- 17B-thiocarboxylate 3-one mp 294-296 ° C S- (2-pyridyl) 3- sec- 4.22-dimethyl-4- oxo-4-methyl-5a- butyl magnesium aza-21-nor-5a- androst-l-eno-17B- col-l-ene-3,20-dione thiocarboxylate mp 134—136 ° C S- (2-pyridyl) 3- 2- chloride 4-methyl-17B- (2- oxo-4-methyl-4- pirrolil mag- pyrrolylcarbonyl) - aza-5a-androst- nesium 4-aza-5a-androst l-ene-17B-uncle- l-eno-3-one carboxylate mp 234-238 ° C S- (2-pyridyl) 3- chloride 23-methyl-4-aza- oxo-4-aza-5a- isobutyl mag- 21-nor-5a- androst-eno-17B- nesium colano-3,20- thiocarboxylate diona mp 220-222 ° C

175-

EXAMPLE 4

22-Methyl-4-aza-21-nor-5a-col-1-ene-3,20-dione

A solution of 21 g of 22-methyl-4-aza-21-nor-5a-colano-3,20-dione and 29.49 g of benzeneselenin 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 the product, mp 248-251 ° C.

When the process is repeated using 23-methyl-4-raza-21-nor-5a-choline-3,20-dione as starting material, the product obtained is 23-methyl-4-aza-21-nor-5a- col-1-ene-3,20-dione, mp 283-286 ° C.

-176-

EXAMPLE 5

175- (phenylcarbonyl) -4-aza-5a-androst-l-ene-3-one

To a stirred suspension of 43 g of S- (pyridyl) -3-oxo-4-aza-5-alpha-androst-1-ene-17-beta-thiocarboxylate in 500 ml of anhydrous tetrahydrofuran (THF) was added to - 78 ° C a solution in 157 ml of 2N phenylmagnesium chloride in 157 ml for 60 minutes. After stirring at -78 ° C for 60 minutes, the mixture was brought to 30 ° C and was quenched by the addition of 10% HCl while maintaining the temperature below -20 ° C. After heating to 0 ° C, the mixture was diluted with 2,000 ml of water and extracted with 4,000 ml of didoromethane fractionally. The organic layer was washed sequentially with water, 1N sodium hydroxide, water and saturated sodium chloride solution. Drying with MgSO ₄ 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).

Federal Police. 290-291 ° C. Shut up Found N 3.61 3.56 ç 77.48 77.16 H 8.26 8.19

EXAMPLE 6

17-beta-4-fluorophenylcarbonyl-4-aza-5-alpha-androst-l-ene-3-one

The process 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.

—177 -

EXAMPLE 7

17β- (cyclohexylcarbonyl) -4-aza-5o! -Androst-l-eno-3-one

To a suspension of 34.8 g of the thiopyridyl ester of Example 2 in 700 ml of anhydrous THF was added at -65 ° C 130 ml of a solution in 2 M ether of cyclohexyl magnesium chloride over a period of 20 minutes. After stirring at -70 ⁰ C for 60 minutes the solution was heated and stirred at -10 ⁰ C for 60 minutes. The mixture was diluted with 500 ml of dichloromethane and then dropwise with dichloromethane, the phases were separated and the organic layer was treated sequentially with water, 1 N sodium hydroxide, water and saturated sodium chloride solution. The organic solution was decolorized with charcoal, filtered and concentrated until a residue was obtained which was crystallized from ethyl acetate to give 28.2 of the title compound, mp 271.5-277 ° C.

EXAMPLE 8 The title compound of Example 7 was also prepared by the following process.

To a mixture of 150 g of methyl 3-oxo-4-aza-5-alpha-androst-1-ene-17-beta-carboxylate in 2,800 ml of anhydrous THF were added with stirring at less than ⁰ ° C temperature 678 ml of a 2 N solution of cyclohexyl magnesium chloride in ether. The solution was then refluxed for 6 hours. The cooled reaction mixture (less than 10 ° C) was acidified with a 10% HCl solution and extracted with dichloromethane. The organic layer was washed sequentially with water, saturated NaHCC solution> ₃ and saturated NaCl solution. Drying (MgSO ₄ ) and evaporation gave 163 g of ketone

-178-

raw cyclohexyl. Recrystallization from dichloromethane / ethyl acetate gave 131 g of the pure material.

mp 269-270 ° C.

% Shut up. Found

3,613.61

77.3777,37

9.7410,13

EXAMPLE 9

17-beta- (cyclopentylcarbonyl) -4-aza-5-alpha-androst-l-ene-3-one

When the procedure of Example 7 or 8 was repeated using cyclopentylmagnesium chloride, the title compound was obtained: mp 272-273 ⁰ C.

Shut up Found N 3.66 3.78 Ç 75.25 74.89 H 9.60 9.54

EXAMPLE 10

17-beta- (cyclobutylcarbonyl) -4-aza-5-alpha-androst-l-ene-3-one

When the process of Example 7 or 8 was repeated using cyclobutylmagnesium chloride, the title compound was obtained:

mp 288-289 ⁰ C.

-179-

% Calc Found N 3.94 3.87 Ç 77.71 78.06 H 9.36 9.61

EXAMPLE 11

Synthesis of 17-β- (4-phenylbenzoyl) -4-aza-5a-androst-l-en-3-one

To a suspension of 258.0 mg of dry activated magnesium chips in 5.0 ml of dry THF was added 932.0 mg of 4-bromobiphenyl in 5.0 ml of dry THF under N ₂ · The reaction was carried out in a bath ultrasonic with a temperature range of 24-30 ° C. To the well-stirred mixture, 30 ml of 1,2-dibromoethane / N ₂ was added dropwise. The reaction was allowed to continue for 1-1 1/2 hours at 28 ° C / N ₂ · The concentration of Grignard's reagent was 4.0 mmoles in 10.0 ml of dry THF.

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 Grignard's reagent were added via a syringe to the steroidal suspension for 5-10 minutes / N ₂ · The reaction was allowed to continue for 1 hour at -80 ° C / N ₂ and then at -10 ° C for an additional hour / N. The solution was diluted with 10.0 ml of methylene chloride and quenched with saturated aqueous NH 4 Cl solution until pH = 4. The organic layers were separated, washed 3 times with water, 3 times with saturated sodium chloride, dried over MgSO4, filtered and evaporated in vacuo to provide 156.2 mg of crude product. Crystallization from EtOAc gave the title product mentioned above at 98.58 mg, mp 290 ° C-290.5 ° C, i

-180-

Anal. Calc. for ^C 3 _X ^H 35 ^NO 2 ^:

C, 82.08; H, 7.78; N, 3.09;

Found: C, 81.84; H, 8.01; N, 3.06.

FAB: Calc. for ^C ₃₁ ^H 35 ^NO 2 ^{: 453} 'Found: 453.

EXAMPLE 12

17-B- (3-Phenylbenzoyl) -4-aza-5a-androst-l-en-3-one

To a suspension of 258.0 mg of dry activated magnesium chips in 8.0 ml of dry THF was added 932.0 mg of 3-bromobiphenyl in 2.0 ml of dry THF under Ν ₂ · The reaction was carried out in a bath ultrasonic with a temperature range of 24-30 ° C. To the well-stirred mixture, 30 microliters of 1,2-dibromoethane / N ₂ were added dropwise. The concentration of Grignard's reagent was 4 mmoles in 10.0 ml of dry THF.

steroid of Example 2, 205.0 mg (0.5 mmoles) was suspended in 2.0 ml of dry THF, cooled to -80 ° C and the Grignard reagent prepared above, 3.80 ml, was added via a syringe to the steroidal suspension for 5-10 minutes / N. The reaction was allowed to continue for 1 hour at -80 ° C / N and then 2 at -10 ° C for an additional hour / N ₂ . The solution was diluted with 10.0 ml of methylene chloride and quenched with a saturated aqueous solution of NH ₄ C1 to a 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 gave 122.84 mg of product. The material was purified on a 20.0 g column of silica gel using 70:30 (CHClg-acetone) as eluent, to give 117.0 mg of a single spot material of the aforementioned title compound, mp 184-185 ° C.

-181-

Anal. Calc, for C ₃ H ₃₅ NO ₂ ^;

C, 82.08; H, 7.78; N, 3.09; Found: C, 82.28; H, 8.04; N, 2.98.

FAB: Shut up, for ^C 31 ^H 35 ^NO ₂ ^{: 453} <Found: 453.

EXAMPLE 13

Synthesis of 17-B- (4-methylthiobenzoyl) -4-aza-5-a-androst-l-en-3-one

To a suspension of 250.0 mg of dry activated magnesium chips 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 N ₂ . The reaction was carried out in an ultrasonic bath at a temperature ranging between 24-30 ° C. To the well stirred mixture were added 40 μΐ of 1,2-dibromoethane / N ₂ dropwise. The reaction was allowed to continue for 11/2 hours at 28 ° C / N ₂ · The concentration of Grignard's reagent was 4.0 mmoles in 10 ml of dry THF.

The steroid of Example 2, that is, 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 in 5-10 minutes / N. The reaction was allowed to continue for 1 hour at -80 ° C / N ₂ and then at -10 ° C for an additional hour / N ₂ . The solution was diluted with 10.0 ml of methylene chloride, and quenched with saturated aqueous solution of NH ₄ C1 until 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 105.0 mg of crude product.

The crude product was chromatographed on TLC (a plate, 20 cm x 20 cm x 20 cm x 1,000 gm of silica gel) eluted with 80:20 (CH ₂ C1 ₂ -acetone) to provide 66.0 mg of

-182-

a single spot. Crystallization from EtOAc provided 45.0 mg of the aforementioned title compound, mp 286-287 ° C. FAB for ^C ₂ 6 ^H 33 ^NO 2 ^S (Cal.) 424; Found 424.

EXAMPLE 14

Synthesis of 17-β- (4-methylsulfinylbenzoyl) and - (4-methylsulfonyl) -4-aza-5a-androst-l-en-3-one

19.91 mg of the methylthio product from Example 13 were dissolved in 2.5 ml of CH ₂ C1 ₂ , cooled to 0 - (- 2) ° C and treated with a solution of 9.6 mg of m- chloroperbenzoic in 1.0 ml of CH ₂ C1 ₂ over a period of 4 minutes. After stirring for 1 hour at 0 - (- 2) ° C, the reaction was diluted with 10 ml. of CH ₂ C1 ₂ . The layers were subsequently washed with 2.5% NaHCO ₃ , H ₂ 0 and saturated NaCl solutions. The organic layer was dried over MgSO ₄ overnight, filtered and evaporated in vacuo to provide 17 mg of product. Crystallization from EtOAc gave 11.8 mg of the aforementioned title compound, a solid, mp 313-313.5 ° C (with decomposition). Anal. Shut, for C „ _r H__N0 _o S · 1 / 4H_O:

z o 3 3 3 z

C, 70.31; H, 7.60; N, 3.15; Found: C, 70.47; H, 7.70; N, 3.00.

FAB for C _{n /} _H__NO_S (Cal. 440); Found 440.

Jj 3

Sulfona

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,

-183-

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

Anal, for ^C 26 ^H 33 ^NO 4 ^S · 0.25 H., 0

Calc: C, 67.87; H, 7.28; N, 3.04.

Found: C, 67.96; H, 6.72; N, 2.95.

EXAMPLE 15

Synthesis of 17-B- (4-acetoxymethylthiobenzoyl) -4-aza-5a-androst-l-en-3-one

Trifluoroacetic anhydride (165 μΐ) was dissolved in 780 μΐ of acetic anhydride and kept for 5 hours at room temperature (RT).

To 300 μΐ of the aforementioned mixed anhydride solution was added 34.15 mg of pure sulfoxide from Example 14 with stirring. A few minutes later 54.0 μΐ of 2,6-lutidine was added and the reaction was allowed to stir at RT / N for 17 hours.

The liquid anhydrides were removed under reduced pressure and the remaining residue The CHCl ₃ extracts were diluted; NaHCO ₃ solution and finally with NaCl solution was extracted (4 times with CHCl ₃ ). subsequently washed with 5% HCl, 3 times; 3 times with H ₂ O; and saturated, and then dried over

Filtered MgSO ₄ and the solution was evaporated to dryness in vacuo to provide 42.1 mg of crude product.

crude product from Step A was purified by chromatography on silica gel using 95: 5 (CHCl ₃ ~ acetone) as eluent and then the solid obtained from EtOAc was crystallized

-184-

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

Anal. Shut, for C _2g H ₃₅ O ₄ NS · 1/4 H ₂ 0:

C, 68.57; H, 7.40; N, 2.86;

Found: C, 69.02; H, 7.39; N, 2.73.

FAB for C ₂₈ H ₂₈ O ₄ NS calc .: 482; Found 482.

NMR (protonic) was in accordance with the indicated product structure.

EXAMPLE 16

Synthesis of 17B (4-mercaptobenzoyl) -4-aza-5a-androst-l-en-3-one

40.0 mg of the acetoxy-methylthio 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 aforementioned mixture, 40.0 mg of K ₂ ^CO 3 ^{in 2 '00} ^ and water (without oxygen) were added by means of a syringe, and the reaction temperature was allowed to rise to 80 ° C 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. It was taken to RT, cooled to 0-5 ° C and quenched with 2.5 HC HCl acid (Ν ₂ · The reaction mixture was extracted 4 times with CH ₂ C _{1 2 <} The organic layer was washed with H ₂ 0 4 times 3 times with saturated saline, and finally dried over MgSO ₄ · Filtered and evaporated to dryness in vacuo to provide 36.9 mg of crude product The crude product was dissolved in 2.0 ml of CHCl ₃ , filtered through of Teflon (Acrodisc CR) and purified by preparative HPLC on silica gel and eluted with 60:40 (CH Cl -acetone) 60. Crystallization from EtOAc provided a single spot material, 20.7 mg of the title compound above mentioned, mp 285-286 ° C.

-185-

Anal. Shut, to ^c 25 ^H 3i ° 2 ^NS '1/2 H20:

C, 72.19; H, 7.69; N, 3.24; Found: C, 71.82; H, 7.43; N, 3.26.

FAB: Shut, for C_ _and H_.O_NS: 410; Found: 410.

Zo 31 2

EXAMPLE 17

Synthesis of 17-β- (4-dimethylaminobenzoyl) -4-aza-5-a-androst-l-en-3-one

To a suspension of 291.0 mg of dry activated magnesium chips in 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 N ₂ . The reaction was carried out in an ultrasonic bath with a temperature range of 24-30 ° C. To the well stirred mixture, 30 ml of 1,2-dibromoethane / N ₂ was added dropwise. The reaction was allowed to continue for 1 1/2 hours at 28 ° C / N ₂ · The concentration of Grignard's reagent was 4.0 mmoles in 10.0 ml of 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 aforementioned Grignard reagent (3 equivalents) were added via of a syringe to the steroidal suspension for 5-10 minutes / N ₂ · The reaction was allowed to continue for 1 hour at -80 ° C / N and then at -10 ° C for an additional hour / N ₂ · The solution was diluted with 10.0 ml of methylene chloride and quenched with a saturated aqueous solution of NH ^Cl until pH = 4. The organic layers were separated, washed 3 times with water, 3 times with saturated sodium chloride, dried over MgSO4, filtered, and evaporated in vacuo to provide 151.3 mg of crude product. Crystallization from ethyl acetate gave 124.5 mg of the aforementioned title compound, mp 268.5-269 ° C.

FAB: Shut up. C__H_ ^ N _n 0 _o : 421; Found; 421.

36 2 2 '

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NMR (proton in CDC1 ₃ ) confirmed the indicated structure. EXAMPLE 18

General Process for Preparing Protected Silyl Derivatives

1.0 mol of phenol or its derivatives, or 1 mol of alcohol is treated with 1.5 liters of dry methylene chloride. To the clear solution, 3.0 moles of imidazole / N „are added dry. The clear solution is cooled to 0 ° C / N ₂ , and 2.0 moles of t-butyl dimethyl chlorosilane in 300.0 ml of dry methylene chloride are added dropwise to 0 ° C / N ₂ . At the end of the addition, precipitation occurs. The ice bath is removed, and the reaction is. allowed to continue overnight at RT / N ₂ · Filter, wash the dough with cold CH ₂ C1 _{2 solution} , and the solvent is evaporated in vacuo to provide the crude product. The crude product was rapidly purified by filtration through a silica gel column. (1 g. Of crude product per 100 g of silica gel, using CH ₂ C _{1 2} as eluent). This method gives about 99% of pure silyl derivatives of phenols and alcohols.

EXAMPLE 19

Synthesis of 17-5- (4-Hydroxybenzoyl) -4-aza-5-o: -androst-l-ene-3-one

A. Grignard reaction

IA a suspension of 1.22 g of dry magnesium chips. Activated in 20.0 ml of dry THF, 5.6 g of 1-bromo-4- (tertiary butyl dimethyl silyloxy) benzene (prepared from p- bromophenol by the General Procedure described in detail above) in 10.0 ml of THF under Ν ₂ · The reaction was carried out in an ultrasonic bath at a temperature ranging between 24-30 ° C.

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To the well-stirred mixture, 150 μ1-200 μΐ of 1,2-dibromoethane / N ₂ were added dropwise. The reaction was allowed to continue for 1-1 1/2 hours at 28 ° C / N ₂ · The concentration of the Grignard reagent formed was 19.5 mmoles in 30.0 ml of dry THF.

The steroid from Example 2 (1.02 g, 2.49 mmoles) was suspended in 20.0 ml of dry THF, cooled to -80 ° C and the Grignard reagent prepared above (11.5 ml) was added using a syringe to the steroidal suspension in 5-10 minutes / N ₂ · The reaction was allowed to continue for 1 hour at -80 ° C / N ₂ , and then at -10 ° C for an additional hour / N ₂ . The reaction solution was diluted with 10.0 ml of methylene chloride and cooled rapidly with a saturated aqueous solution of NH 4 Cl to a 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 until a yellow solid was obtained.

Crystallization from ethyl acetate gave 607 mg of product, mp 248-249 ° C.

Anal. Shut, for CH 0f3 ^NSi:

C, 73.32; H, 8.93; N, 2.75

Found: C, 73.27; H, 8.99; N, 2.75.

FAB: 508 found; Shut 508.

B. Desilation

1.3 g of product from step A above was dissolved in 20.0 ml of dry THF. It was cooled to -5 ° C and 437 μacial of glacial acetic acid / N _{2 was added} . To the cold solution at -5 ° C, 3.0 ml of tetra-n-butylammonium fluoride was added dropwise to a syringe. drop under an atmosphere of N „. The reaction was allowed to continue stirring for 1 1 / 2-2 hours at 0 ° to -5 ° C / N ₂ · The reaction mixture was poured into a

188

mixture of 2 layers of a saturated solution of ethyl acetate / sodium bicarbonate at 0 ° C. The water layer was separated and subsequently extracted with EtOAc 3 times and with CH ₂ C _{1 2} (3 times).

The organic layers were combined, washed 3 times with H ₂ ^{O / 1 times 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 provide 977.9 mg, and was later recrystallized from methanol to provide 842.3 mg of the aforementioned title product, mp 296-297 ° C.

Anal. Shut, for ^c 25 ^H 3i ^NO 3.1 / 3 H20:

C, 75.15; H, 7.98; N, 3.51.

Found: C, 75.13; H, 7.76; N, 3.54.

(Specific mass) FAB: 394 found; Shut up. 394.

EXAMPLE 20

17-β- (3,5-dimethyl-4-hydroxybenzoyl) -4-aza-5a-androst-l-ene-3-one

A. Preparation of Grignard Reagent

To a suspension of 260.0 mg of dry activated magnesium chips in 6.0 ml of dry THF, 628.0 mg of 1-bromo-3,5-dimethyl-4-tertiary-butyl-dimethylsilyloxybenzene (prepared from of 4-bromo-2,6-dimethylphenol by the General procedure described above) in 4.0 ml of THF / N ₂ · The reaction was conducted in an ultrasonic bath at a temperature ranging from 24 ° -30 ° C. To the well stirred mixture were added 40 μΐ of 1,2-dibromoethane / N ₂ dropwise. The reaction was allowed to continue for 2 hours / N ₂ . The concentration of the Grignard reagent thus formed was 2 mmoles in 10.0 ml of dry THF.

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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 millieq.) of Grignard reagent above prepared were introduced by syringe to the steroidal suspension over a period of 5-10 minutes / N ₂ · The reaction was allowed to continue for 1 hour at -80 ° C / N ₂ and then at -10 ° C for another additional hour / N ₂ .

The reaction was quenched with 1N HCl, then diluted with chloroform. The organic layers were combined, washed 3 times with H ₂ O, 3 times with saturated sodium chloride and dried over MgSO ₄ , filtered and concentrated in vacuo. The crude residue was washed with ether to provide 121.7 mg of product.

crude product was dissolved in (CHC1 ₃ -acetone) 70:30, filtered through Teflon (Acrodisc CR) and purified by preparative HPLC '(Waters Prep-pak) on silica gel eluting with (CHCl ₃ ~ acetone ) 70:30.

main component was recrystallized from ethyl acetate to give 52.0 mg of product, mp 245-245.5 ° C.

Anal. Shut, for C ₃₃ H _4g O ₃ NSi:

C, 73.96; H, 9.23; N, 2.61;

Found: C, 74.06; H, 9.33; N, 2.64 (Mass Spectrum) FAB: Found: 536; Cal .: 536

B. Unlocking the Sililo Derivative

54.0 mg of the previous product from A was dissolved in dry THF (1.3 ml). The clear solution was cooled to 0 ° C, and 29 μΐ of glacial HOAc was added via a syringe / N ₂ · To the previous solution were added dropwise

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172 μΐ of tetra-n-butylammonium fluoride at 0 ° c dropwise via syringe / N ₂ · The reaction was allowed to continue at 0 ° C / N ₂ for 11/2 hours. The reaction mixture was poured into ice / saturated NaHCC solution> ₃ and EtOAc, and stirred for several minutes. The layers were allowed to separate, and the H ₂ O layer was extracted 3 times with EtOAc and 3 times with CHCl ₃ .

The organic layers were combined and washed 3 times with HO, then three times with saturated NaCl, then dried over MgSO4, 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 indicated above, m.p. 305-306 ° C.

Shut, for C ₂₇ H ₃₅ O ₃ NH ₂ O:

C, 73.77; H, 8.49; N, 3.10 Found: C, 73.62; H, 7.90; N, 3.44.

(Mass Spectrum) FAB: Shut up. 422; Found: 422

EXAMPLE 21

Synthesis of 17-B-f4-methoxybenzoyl) -4-aza-5-a-androst-l-ene-3-one

A. Griqnard reaction

To a suspension of 258.0 mg of dry activated Mg chips in 8.0 ml of THF / N ₂ was added 748.0 mg of p-bromoanisole in 2.0 ml of dry THF. The reaction was carried out in an ultrasonic bath at a temperature ranging from 24-30 ° C. To the well stirred mixture, 30.0 μΐ of 1,2-dibromoethane was added dropwise as a catalyst. The reaction was allowed to progress for 1-2

191-

hours at 28 ° C. The Grignard reagent formed had a concentration of 4 mmoles in 10.0 μΐ of dry THF.

The steroid of Example 2 (205.0 mg (0.50 mml)) was suspended in 2.0 ml of THF, cooled to -78 ° C and the aforementioned Grignard reagent (3.75 ml; 14 moliequivalents) was added using a syringe to the steroidal suspension for 5-10 minutes / N ₂ and then at -10 ° C for an additional hour / N. The resulting reaction mixture was a clear solution, which was cooled to 0-5 ° C , diluted with chloroform and quenched with 1N HCl acid The organic layers were separated, washed with 2 O 2 times, then with saturated NaCl solution, dried over MgSO ₄ , filtered and evaporated in vacuo. 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 1,000 / xm), using as eluent, (CHCl _{3r; acetone) 70:30} . _{Recrlstallization} from EtOAc provided 78.56 mg of the above product, mp 305-306 ° C (dec.).

(Mass Spectrum) FAB: Cal., 408; Found 408.

EXAMPLE 22

Synthesis of 17-β- (3-hydroxybenzoyl) -4-aza-5oi-androst-l-eno-3-one

A. Preparation of Grignard Reagent

To a suspension of 230.0 mg of dried activated Mg shavings in 2.0 ml of dry THF was added 722.4 mg of 1-bromo-3-tertiary-butyl dimethyl-silyloxybenzene (prepared from 3-bromophenol by General process described above) at 8.0

-192-

ml of dry THF / N ₂ · The reaction was carried out in an ultrasonic bath at a temperature ranging between 24-30 ° C / stirred N ₂ - Â 20.0 μΐ of mixture was added dropwise well

1,2-dibromoethane / N ₂ · The reaction was allowed to progress for 2 1/2 hours at 28 ° C / N ₂ · The Grignard reagent formed had a concentration of 2.52 mmoles in 10.0 ml of dry THF .

steroid of Example 2 (205.0 mg (0.5 mmoles) was suspended in 2.0 ml of THF, cooled to -78 ° C and the Grignard reagent prepared above (6.0 ml, (1.5 milliequivalents) was added via syringe to the steroidal suspension for 5-10 minutes / N, then stirring for an additional hour at -10 ° C / N ₂ · The clear reaction mixture was quenched to 0 to 5 ° C with IN HCl for 10.0 minutes and diluted with CHCl 1 _3. 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 70:30 (CHCl ₃ -acetone) The desired product was 58.0 mg in the form of the silyl derivative, 17B- ( 3-tertiary-butyl-dimethylsilyloxybenzoyl) 4-methyl-4-aza-5a-androst-l-en-3-one.

B. Deblogging

57.6 mg of the aforementioned silyl derivative was dissolved in 3.0 ml of dry THF. The solution was cooled to 0 ° C, and 20 μΐ of glacial acetic acid were introduced through a syringe. 130.0 μΐ of (n-butyl) ₄ NF was added to the clear solution by means of a syringe, and the reaction was allowed to continue for 1 hour / N ₂ at 0 ° C. The reaction mixture was poured into a saturated EtOAc / NaHCO ₃ solution at 0 ° C. The aqueous layer was separated, extracted 3 times with EtOAc and then 3

-193-

times with chloroform. The organic layers were combined and washed 3 times with ^H 2 ° ^{r 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 chromatographed by TLC (a plate, 20 cm x 20 cm x 250 μπι of silica gel), eluted with 70:30 (CHCl ₃ -acetone) to provide 44.5 mg of the title product mentioned above. Recrystallization from EtOAc gave 29.30 mg, mp 279-280 ° C.

Anal. Shut up, for ^C 25 ^H 3i ^NO 3 ^{: 8H} 2 ^O:

C, 73.60; H, 8.06; N, 3.43.

Found: C, 73.26; H, 8.22; N, 3.28.

(Mass spectrum) FAB: Cal .: 394; Found 394.

EXAMPLE 23

Synthesis of 17-β- (4-hydroxymethyl-benzoyl) -4-aza-5a-androst-l-en-3-one

A. Preparation of Griqnard's solution

To a suspension of 100.0 mg (4 mmoles) of dry activated Mg chips in 5.0 ml of dry THF / N ₂ , 753.0 mg (2.5 mmoles) of 1-bromo-4-tertiary were added -butyl dimethyl silyloxy methyl benzene (prepared from 4-bromobenzyl alcohol by the General Process described above). The reaction was conducted in an ultrasonic bath at a temperature ranging from 24-30 ° C / N ₂ · To the well-stirred mixture, 20 μΐ of 1,2-dibromoethane / N _{2 was added} . The reaction was allowed to progress for 2 hours at 28 ° C / N ₂ · The concentration of Grignard reagent formed was 2.5 mmoles in 5.0 ml of dry THF.

194B. Grignard reaction

steroid of Example 2 (205.0 mg (0.5 mmoles) 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 by syringe into the steroidal suspension for 5-10 minutes / N ₂ · The reaction was allowed to progress for 1 hour at -80 ° C / N ₂ , and then an additional hour at -10 ^o C / N ₂ · The clear reaction solution was quenched with NH Cl saturated at 0 ° to -5 ° C, then diluted with CH Cl. The organic layers were separated and washed 3 times with water, 3 times with NaCl saturated, dried over MgSO ₄ , filtered and evaporated in vacuo to dryness. The crude product was crystallized from EtOAc to give 137.8 mg of silyl product. (Mass Spectrum) FAB: Calc. to C ₃₀ H ₄₁ O ₃ NSi: 521.75 Found: 522.0.

C. Unlocking of Silyl Derivative

The product from Step B above (23.67 mg) was dissolved in 0.5 ml THF and 0.5 ml MeOH and cooled to 0 ° C / N ₂ . 10 μΐ of concentrated sulfuric acid (98%) was added to the cold solution. The reaction was stirred for 45 minutes at 0 ° C / N ₂ · To the cold solution at 0 ° C, a saturated solution of NaHCO ₃ and chloroform was slowly added. Extraction 3 times with CHC1 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 CHC1 ₂ : acetone 1: 1) the crude product was crystallized from EtOAc to give 6.0 mg of the aforementioned title product, mp 318-320 ° C.

195—

Anal. Shut, for ^C 26 ^H 33 ° 3 ^N · 1 / 3H ₂ O:

C, 75.41; H, 7.94; N, 3.38.

Found: C, 75.61; H, 7.84; N, 3.12.

(Mass spectrum) FAB: Calc .; 408; Found: 408

EXAMPLE 24

Synthesis of 17-β- (4-carboxybenzoyl) -4-aza-5a-androst-l-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 transparent, 69.0 mg of CrO ^ (previously dried over P-Ο, - to RT for 2 days under vacuum) were added. After stirring overnight, the reaction mixture aged overnight (was not filtered and the mother liquor and overnight liquid using one day under vacuum).

was diluted with water and refrigerator. The mixture of washing products were extractor to

extra-liquid-liquid reaction, (H ₂ O-EtOAc) under reflux conditions. The organic layer was dried over residue was dissolved to provide

MgSO4, filtered and evaporated in vacuo. O in hot MeOH, filtered and evaporated in vacuo to a product weighing 32.0 mg.

FAB: Shut up, for C _nr H ... N: 422.0; 26 3104

Found: 422.

B. Free acid purification referred to above was purified by dissolving the aforementioned 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

196-

allowed to age for 1 hour at 0 ° C. It was filtered and the residue was washed with cold water, being dried overnight at 100 ° C under vacuum pressure <0.2 mm.

The yield of the aforementioned free acid was 9.85 mg.

FAB: Calc, for C4 HO ₄ N: 422; Found 422.

NMR analysis indicated that the product was an acid.

C. Sodium Salt of the Acid Behind Referenced

4.9 mg of the above mentioned acid B product were dissolved in 2.0 ml of methanol. To the clear solution, 11.6 μΐ of NaH IN (aqueous) were 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 aforementioned title product.

EXAMPLE 25

Synthesis of

-3-one

17-β- (4-hydroxyethylbenzoyl) -4-aza-5a-androst-l-en-

A. Grignard reagent

To a suspension of 252 mg of dry activated Mg shavings in 10.0 ml of dry THF were added 1.26 g (4 mmol) of tertiary 1-bromo-4-butyl dimethyl silyloxy ethyl benzene (prepared from 2- (p-bromophenyl) ethanol by the General Process described above). The reaction mixture was stirred vigorously using an ultrasonic / N vibrator. To the well stirred mixture, 40 μΐ of 1,2-dibromoethane was added to catalyze the aforementioned reaction. The reaction was allowed to progress for 3 1 / 2-4 hours / N ₂ ·

-197-

The concentration of the Grignard reagent formed was 4 mmoles in ml of THF.

B. Grignard reaction

205.0 mg (0.5 mmoles) of aza-steroid of Example 2 were suspended in 2.0 ml of dry THF / N ₂ , cooled to -80 ° C, and the Grignard reagent prepared above (3.75 ml, 1 , 5 milliequivalents) using a syringe was introduced into the steroidal suspension for 5-10 minutes / N ₂ . The reaction was carried out at -80 ° C for 1 hour / N ₂ and then for an additional hour at -10 ° C. The reaction was quenched with saturated NH 5 Cl solution at 0-5 ° C and diluted with 10.0 ml CR 4 Cl 2. The organic layers were washed with water (3 times), saturated NaCl solution (3 times), dried over MgSO ₄ , filtered and evaporated in vacuo to dryness. The crude product was crystallized from EtOAc overnight to give 152.0 mg of product mp 233-234 ° C.

Anal. Calc. for ^c ₃₃ H _4g O ₃ NSi: 1/4 H ₂ 0:

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. Desiccation

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 29μ1 of concentrated H ₂ SO _{4 was added} via syringe under Ν ₂ · The reaction was allowed to continue for 45 minutes / N ₂ · The reaction was carefully quenched at 0 ° C with a saturated solution of NaHCO, and extracted 3 times with CH Cl. At

2 organic layers were separated, washed with water (3 times), and then with NaCl solution, dried over MgSC> ₄ , filtered and evaporated in vacuo to give 43.0 mg of crude product. The crude product was placed on a silica gel column and was eluted with acetone-CH ₂ Cl ₂ 1: 1. The isolated product was crystallized from anhydrous methanol to provide 20.0 mg of the aforementioned title product, mp 292-293 ° C with decomposition.

Anal. Shut, for C ₂₇ H ₃₅ 0 ₃ N.1 / 4 H ₂ :

C, 75.31; H, 8.25; N, 3.25. Found: C, 75.49; H, 8.29; N, 3.45. FAB: Shut up. 422; Found 422.

EXAMPLE 26

Synthesis of 17-β- (4-carboxymethylbenzoyl) -4-aza-5a-açdrost-l-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 _CrO3 (previously dried over ^P ₂ ° 5 ^ ^v ^ ^{are vacuo} at RT) .The reaction was allowed to proceed overnight at RT and then at 0 ° C for 48 hours . The addition of 7.0 ml of water caused the product to crystallize overnight in a refrigerator. The crude product was isolated, washed with cold water and dried under vacuum at 110 ° C under a pressure below 1 mm.

dry crude product was dissolved in 1N sodium hydroxide and the basic solution was extracted 3 times with methylene chloride. (The organic layers were separated, and the aqueous basic 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.

—199 -

Yield of the aforementioned title product = 7.0 mg.

FAB Cale. CH 0 ₄ N: 436; Found 436.

EXAMPLE 27

Synthesis of 17-B- (3,4-dihydrobenzoyl) -4-aza-5a-androst-l-en-3-one

A. Grignard

To a suspension of 258.5 mg of dry activated magnesium chips in 10.0 ml of dry THF, 482 mg was added. of 4-bromo-1,2-methylenedioxybenzene / N ₂ . (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-mixed mixture were added 40 μΐ of 1,2-dibromoethane in the form of a catalyst / N ₂ , the reaction was allowed to progress for 1 1/2 hours at 28 ° C / N ₂ · The concentration of the Grignard reagent formed was 3.75 mmoles in 10 ml of dry THF.

steroid of Example 2 (410 mg, 1 mmol) was suspended in 4.0 ml of dry THF / N ₂ and cooled to -80 ° C and 8.0 ml of the Grignard reagent prepared above (3.04 milliequivalents) were added using a syringe to the steroidal suspension / N ₂ over a period of 5-10 minutes. The reaction was allowed to continue for 1 hour at -80 ° C, and then at -10 ° C for an additional hour / N _{2 <} The reaction mixture was diluted with _CH ₂ C1 ₂ , 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. THE

-200-

Purification of the crude product was carried out on 50.0 g of silica gel using 1: 1 as eluent (CH ₂ Cl ₂ -acetone) to give 347.0 mg.

FAB revealed 422; Shut up. 422.

62.4 mg of the aforementioned product was crystallized from EtOAc to provide 11.39 mg of product, mp 324-325 ° C.

Anal. Shut, for C „.0.N · 3/4 H„ O:

U 31 4 2

C, 71.78; H, 7.53; N, 3.22.

Found: C, 71.90; H, 7.54; N, 3.25.

FAB for ^c ₂ 6 ^H 3i ° 4 ^N revealed 422; Cal .: 422.

B. Cleavage of Gruno Methylene Dioxilan

70.0 mg of the product from Step A were dissolved in dry 25.0 ml of 1,2-dichloroethane at Τ.Α. / Ν ₂ · The solution was allowed to cool to -10 ° C, and 1.03 ml of BBr ^ (1.0 M solution in dichloromethane) were added dropwise under N _o. The reaction was allowed to continue at RT for 3 1 / 2-4 hours / N _2> After 4 hours / N ₂ , the reaction was cooled to (-10 ° C) and quenched with 10.0 ml of methanol for 10 minutes at 0 ° C, and then the temperature was gradually allowed to rise to RT / N. 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 in vacuo. The raw material was chromatographed on 2 silica gel plates, (20 cm x 20 cm x 20 cm x 250 μπι) eluting with (acetone-methylene chloride). Recrystallization from EtOAc provided 5.0 mg of the aforementioned title product mp 222-222.5 ° C.

-201-

Anal. Shut up. for C O J- 1/2 H ₂ 0: C, 71.78; H, 7.66; N, 3.35. Found : C, 71.71; H, 7.71; N, 3.33.

FAB: Shut, for CHO ₄ N: 410; Found 410.

EXAMPLE 28

Synthesis of 17-B-(2-methoxybenzoyl) -4-aza-5a-androst-l-ene-3-one

A. Grignard

To a suspension of 258.0 mg of dry activated magnesium chips in 8.0 ml of dry THF was added 771.0 mg of o-bromoanisole in 2.0 ml of dry THF / N ₂ , The reaction was conducted in a bath of ultrasonic water with a temperature range of 24-30 ° C. To the well stirred mixture, 30μ1 of 1,2-dibromoethane / N _{2 was added} , and the reaction was allowed to continue for 2 hours at 28 ° C / N ₂ · The concentration of the formed Grignard reagent 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 / N ₂ , cooled to -79 ° C, and 4.0 ml of the Grignard reagent prepared above (1.6 milliequivalents) were added via syringe to the steroidal suspension / N ₂ over a period of 5-10 minutes. The reaction mixture was allowed to continue for 1 hour at -80 ° C, and then at 0-2 ° C for an additional hour / N ₂ . The reaction mixture was diluted with CH ₂ C _{1 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 MgSO ₄ · They were filtered and evaporated in vacuo to dryness. O

-202-

raw material was crystallized from EtOAc to give rise to

124.5 mg of product mp 228-230 ° C. Purification of the silica gel column using 70:30 (CHCl ₃ -acetone) 70:30 gave rise to a single patch of material with a yield of 83.0 mg, mp 241-241.5. Anal. shut, for ^C 26 ^H 33 ^O 3 ^N:

C, 76.91; H, 8.19; N, 3.45

Found: C, 76.36; H, 8.26; N, 3.35.

FAB calc. for C_ ^ H._O_N: 406; Found: 406.

Z b 3 3 3

B Cleavage of the Methoxy Group

12.7 mg (0.03 mmoles) of the product from Step A were dissolved in 5.0 ml of dry methylene chloride / N ₂ · To the transparent solution at -79 ° C / N, 50 μΐ of 1 mmole / ml of BBr ₃ in CH ₂ C1 ₂ using a syringe dropwise. The reaction was allowed to continue at RT overnight / N ₂ 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 in order to hydrolyze the excess BBr ₃ . The organic phase was washed three times with diluted sodium hydroxide, 3 times with water, 3 times with diluted 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 17-B- (2-hydroxymethyl-benzoyl) -4-aza-5-a-androst-l-en-3 -one. FAB for ^C 25 ^H 31 ^NO ₂ ^: Calc .; 394; Found: 394.

EXAMPLE 29

17B- (g-hydroxybenzyl) -4-aza-5a-androst-l-ene-3-one

570 milligrams of

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175-benzoyl-4-aza-5a-androst-l-ene-3-one (prepared from commercially available thiopyridyl ester of Example 2 and phenyl magnesium bromide, analogously by the process of Example 5, to produce the derivative 17-benzoyl, mp 295-296 ° C crystallized from EtOAc) were suspended in 80 ml of anhydrous isopropanol. To the suspension, 500.0 mg of NaBH4 was added in 5 portions. Once all the hydride was added, 20.0 ml of dry THF were carefully added, so that the reaction mixture became a clear solution. The reaction was allowed to continue at RT / N ₂ overnight. The reaction was quenched carefully with 1N HCl, and allowed to stir under N ₂ for an 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 H ₂ O; 3 times with saturated NaCl solution, and dried over MgSO _4. They were filtered and evaporated until a white solid weighing 495.0 mg was obtained.

raw material was recrystallized from EtOAc to provide 349.5 mg of material. Subsequent purification on a silica gel column, using 70:30 as eluent (CHCl ₃ -acetone) 70:30 gave rise to a single stain material, of the title compound mentioned above, mp 296-297 ° C.

Anal. Shut down to C ₂₅ H ₃₃ NO ₂ :

C, 79.17; H, 8.78; N, 3.70.

Found: C, 79.24; H, 8.85; N, 3.48.

FAB Cale, for C ^ H ^ NO ^ · Found: 380.

EXAMPLE 30

17B-hydroxymethyl-4-aza-5a-androst-l-ene-3-one

500.0 mg of

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S-2-pyridyl-3-oxo-4-aza-5a-androst-1-ene-3-one (Example 2) were dissolved in 40.0 ml of dry THF at RT / N2. The solution was cooled to -78 ° C / N ₂ and 5.5 ml of 1 M dibutyl aluminum hydride in THF was added slowly via syringe to the solution with rapid stirring. The reaction was allowed to continue at -76 ° C to -78 ° C for half an hour under N _{2 <} The temperature was gradually brought to RT and the reaction mixture was maintained over 2-1 / 2 hours / N ₂ · The reaction was then quenched at 0 ° C with 2N HCl acid, then diluted with CHCl ₃ . The organic layers were separated, washed with H ₂ O 3 times, then with saturated NaCl solution, and finally dried over MgSO4. They were filtered, and the organic phase was evaporated in vacuo to give 216.0 mg of crude product.

crude product was chromatographed on 20.0 g of MS silica gel column, using 70:30 (CHCl ₃ -acetone) 70 as eluant.

yield of a single stain material was

126.3 mg of the aforementioned title compound, mp 271-271.5 ° C. Shut, for C Η ON: FAB 304; Found 304. CDC1 ₃ NMR confirmed the aforementioned structure.

. EXAMPLE 31

17B-Formyl-4-aza-5a-androst-l-ene-3-one

In a 100.0 ml dry flask 1.3 ml of oxalyl chloride (2 M in CH ₂ C1 ₂ ) with 50.0 ml of dry / N ₂ · were placed

The above solution was cooled to -78 ° C and 338 μΐ of DMSO was added dropwise via syringe. The mixture was stirred at -78 ° C / N ₂ for 30 minutes, and a solution of the above alcohol prepared from Example 15, i.e.

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175-hydroxymethyl-4-aza-5a-androst-l-ene-3-one (256.9 mg in 15.0 ml dry CH ₂ C _{1 2} / N ₂ was added via syringe. The reaction was left continue for one hour at -78 ° C / N ₂ · After one hour at -78 ° C, 1 ml of dry triethylamine was added at a rapid rate.The reaction temperature was slowly raised to RT / N with stirring, the resulting yellow solution was then poured into 50.0 ml of cold water. The organic layers were washed with a saturated solution of NaHCO ₃ , and then with a saturated solution of NaCl. They were dried over MgSO ₄ , the solvent being evaporated under vacuum to give 172.4 mg of crude product The crude product was chromatographed on a 60.0 g column of silica gel using 70:30 (CHCl ₃ ~ acetone) to give a single stain material Crystallization from EtOAc gave the aforementioned title compound, 37.7 mg, mp 258-259 ° C.

EXAMPLE 32

Synthesis of diastereoisomeric 175 (α-hydroxybenzyl) -4-aza-5oi-androst-l-ene-3-ones

26.3 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 μΐ of phenyl magnesium bromide (Aldrich reagent) (0.393 milliequivalents) in dry THF were added dropwise via syringe / N ₂ · The reaction was allowed to continue for 1 hour / N ₂ at -78 ° C and then at RT for one hour. additional hour / N ₂ .

The reaction was quenched to 0-5 ° C with 2.5N HCl, then diluted with CHCl ₃ · 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 —206—

to dryness to provide 28.6 mg of crude product. Analysis of 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 μια Teflon filter and purified by HPLC on a Whitman Portisil 10 column using 70:30 (CHC1 -acetone). The FAB mass spectrum indicated the same M +1 for both isomers, being units of mass 380. The more rapidly eluting isomer, mp 289-289.5 ° C, was crystallized from EtOAc and revealed a single material stain on CCF.

Anal. calc. for ^C 25 ^H 33 ^NO 2 · 1/4 H2O;

Found: C, 78.11; H, 8.65; N, 3.58.

The isomer eluting more slowly, mp 300-301 ° C revealed a single spot material in TLC. The fastest isomer revealed by NMR (CDCl ₃ ); CH ₃ to C-18 was deprotected (0.895) compared to a slower CH ₃ to C-18 a isomer (0.695). The benzyl proton for the faster isomer was also deprotected (4.55) versus (4.955). The olefinic proton in Cl showed 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- (11-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

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Ethyl 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, ground potassium carbonate. The resulting colored mixture is then heated under an atmosphere of nitrogen under gentle reflux to. color due to the phenol anion dissipates and remains a yellow mixture. Concentration of the cooled and filtered mixture provides an oil which by flash chromatography (silica gel, ethyl acetate / hexane or methylene chloride as eluent) provides 2.4 g (96% yield) of the title compound (3) in the form of an oily liquid. When substituted ortho-nitrophenols are used instead of 2-nitrophenol in the above example, the corresponding substituted 2-nitrophenoxybutyrate is obtained. Similarly, when ethyl 4-bromobutyrate is replaced 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 in a hydrogen atmosphere (40. psig) at room temperature until hydrogen release. The mixture is then filtered and concentrated in vacuo to provide 1.0+ g of (4) as a low melting 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 de-aerated (N ), heated to 85 ° C (bath temperature), and maintained 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

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diluted hydrochloric acid, aged, filtered, the solid was washed well with water and dried. Product 6, (0.54 g), was obtained as a white solid.

When other halo acids are used instead of acid

12-bromododecanoic in the above example, the corresponding acid- (isopropylthio) is obtained.

Similarly, when other mercaptan salts are used instead of sodium isopropylthiolate in the previous example, the corresponding alkanoic acids (alkylthio) 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- 9- (methylthio) nonanoic acid (n-propylthio) tetradecanoic acid

Step D: Ethyl 4- (2- (12- (Isoproothyl)) dodecanoylamino) -phenoxy) -butyrate (7)

To a solution of (4) (0.25 g, 1.14 mM) and (6) (0.274 g,

1.0 mM) in dry methylene chloride (10 ml) at room temperature, 4-dimethylaminopyridine (0.122 g, 1.0 mM) was added, followed by a N, N'-dicyclohexylcarbodiimide solution within one minute (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 was subjected to flash chromatography on silica gel using 15-20%

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ethyl acetate in hexane as an eluent to give product 7 (0.22 g) as an oil which solidified rapidly in a short time.

Step E:

4- (2- (12- (Isopropylthio) dodecanoylamino) phenoxy acid)

-butyric (8)

A stirred solution of ester (7) (0.124 g, 0.258 mM) in methanol (10 ml) was treated at room 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 that no ester remained. The filtered mixture was concentrated in vacuo and the residue obtained was stirred with water (30 ml). After aging, the mixture was filtered (the mass is the product's sodium salt) (100 mg), and the stirred filtrate is acidified with diluted hydrochloric acid, aged, filtered, washed with water and dried to give the product 8. (0.02 g) as a white solid. 82-84 ° C, with softening starting at 66 ° C.

Treatment of 8 with NalO. as in Step J will - 4 produce the corresponding sulfoxide, and treatment of 8. with m-chloroperbenzoic acid with Step will produce 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 remains little or none (D). THE

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concentration of the reaction mixture followed by preparative plate chromatography (silica gel; 3% methanol / methylene chloride as eluent) provides product 9 (11 mg) as a waxy solid.

Step G:

Ethyl 4- (2-Amino-phenylthio) butyrate (11)

To a de-aerated stirred solution (N2) of 2-aminothiophenol (10) (1.25 g., 10 mM) and ethyl 4-bromobutyrate (2.1 g, 11 mM) in 40 ml of dry 1,2-dimethoxyethane add 8.3 g of solid ground anhydrous potassium carbonate, the resulting mixture being de-aerated 3X under nitrogen and allowed to stir at room temperature until TLC analysis indicates that the reaction is complete. The filtered mixture is then concentrated and the residue is subjected to flash chromatography on silica gel (85 g.) Using 15% ethyl acetate / hexane as the eluent to give (11) as a light-colored oil.

1.8 g of

Step H: ethyl

4- (2- (10- (Isopropylthio) decanoylamino) phenylthio) butyrate

021

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

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

When (12) is hydrolyzed as in the conditions of the

Step (E) compound 13 is obtained.

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

When the esters or acids indicated are treated with sodium metaperiodate (Step J) in an appropriate solvent (for example acetone / water) the corresponding sulfoxides are obtained. Treatment with meta-chloroperbenzoic acid (Step J4) provides the corresponding sulfones. For example, when 4- (2- (11- (ethylthio) undecanoylamino) phenoxy) ethyl 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) provides product 16 as an off-white solid. In addition, treatment of 14 with m-chloroperbenzoic acid will produce sulfone 17, which provides acid 18 after hydrolysis using the hydrolysis conditions of Step

AND.

The method for preparing the new compounds of the present invention, already described in general terms, can be further illustrated by the following examples which should not be elaborated in such a way as to limit the scope or spirit of the present invention.

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EXAMPLE 2

Synthesis of 4- (2- (11-carboxyundecyloxy) phenoxy) butyric acid (7)

A. Ethyl 4- (2-Benzyloxyphenoxy) -butyrate (3)

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 anhydrous ground potassium carbonate (6.0 g, 44 mM) and the resulting mixture was heated under reflux under nitrogen until CCF 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 (3.) 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 previous phenol is replaced with other 2-benzyloxyphenols substituted, the corresponding 2-substituted ethers are obtained.

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replacement of 2-benzyloxyphenol with 2-benzyloxy or with 2-benzylthio-thiophenol provides the corresponding ester-thioether.

B. ethyl 4- (2-hydroxyphenoxy) -butyrate (4)

A mixture of (3.) (1.57 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 the hydrogen release ceases. Concentration of the filtered mixture gave the product (4) as an oil.

C. ethyl 4- (2-11- (Carbomethoxy) undecyloxyphenoxy) butyrate (6)

When (4) (0.224 g, 1.0 mM) and methyl 12-bromododecanoate (5) (0.32 g, 1.1 mM) were reacted with potassium carbonate in acetone as in Example (A), it obtained The product (.6) (0.3 g) is taken up as a colorless oil. <

When methyl 12-bromododecanoate is replaced by other halo esters in the above example, the corresponding diester is obtained.

D. 4— (2— (11 — carboxyundecyloxy) phenoxy) butyric acid (7)

To a stirred solution of (Ç) (0.102 g, 0.23 mM) in methanol (4 ml) and water (3 drops) was added a 1.5 N sodium hydroxide solution (0.55 ml, 1.37 mM) dropwise, and the resulting mixture was made clear with additional methanol (2 ml). When the TLC analysis (2% methanol in methylene chloride (10 ml) containing glacial acetic acid (4 drops)) indicated that there was no mono- or diester left, the methanol was removed in vacuo, the residue was stirred with water (10 ml), and the solution was

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filtered and acidified with 2N hydrochloric acid. Filtration of the resulting precipitate followed by washing with water and drying gave product 7 (88 mg) as a white solid;

Softens at 95 ° C, complete melting at 105 ° C (uncorrected; A.O. Spencer Hot Stage).

Calculated for C ^ H ^ CL ·:

^c 22 34 6

C, 66.98; H, 8.69.

Found: C, 67.32; H, 8.45.

Compounds (1) - (7) all had NMR and Mass spectrum data consistent with their indicated molecular formulas.

4- (2- (11-carboxyundecyloxy) phenylsulfinyl) butyric acid (7B)

When the thioethers presented, for example, Compound 7A on Flow Sheet C, in the form of an ester or acid, are treated with sodium metaperiodate in an appropriate solvent (for example, acetone / water) the corresponding sulfoxides are obtained. Similarly, the reaction of the presented thioethers 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, 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 had NMR and Mass Spectrum data consistent with their indicated molecular structures.

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EXAMPLE 3

Preparation of 4- (2- (11-carboxyundecanoylamino) phenoxy) butyric acid

Step A: Ethyl 4- (2-Nitrophenoxy) butyrate (3)

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, ground potassium carbonate. The resulting colored mixture is then heated under a nitrogen atmosphere with a gentle reflux until the color due to the phenol anion has dissipated and a yellow mixture remains. Concentration of the cooled and filtered mixture provides an oil which by flash chromatography (silica gel, ethyl acetate / hexane or methylene chloride as eluent) provides 2.4 g (96% yield) of the title compound (2) under the form of an oily liquid.

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

A solution of (2) (1.27 g, 5.0 mM) in 15 ml of ethyl acetate containing 200 mg of 5% palladium on carbon is reacted in a hydrogen atmosphere (40 psig.) At room temperature until it ceases the release of hydrogen. The mixture is then filtered and concentrated in vacuo to provide 1.0+ g of (4.) as a low melting 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 process of Org. Svn. Coll.

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Vol. III, ρ. 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 (6.) (10.0 g, 0.041 M) and thionyl chloride (12.1 ml, 0.166 M) is refluxed for 5 hours, with the excess of thionyl chloride removed in vacuo, and the residual acid chloride being repeatedly dissolved in dry benzene and concentrated until no thionyl chloride remains 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 chilled solution of 0.89 g (4.0 mM) of 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 left to stir cold for 20 minutes, and then at room temperature overnight. After filtration separation of the triethylamine hydrochloride, the ether filtrate is concentrated in vacuo and the residue is chromatographed on an 82 g column of silica gel using 20% ethyl acetate / hexane as eluent to give 1.49 g ( 85%) of (8.) as a waxy solid.

The ether / triethylamine in the above reaction can be replaced with methylene chloride / pyridine with similar results. The same compound can also be prepared by direct coupling of acid (6) with the same amine using

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common coupling reagents, such as dicyclohexylcarbodiimide / N, N-dimethylaminopyridine, etc.

Step F; 4- (2- (11-carboxyundecanoylamino) phenoxy)-butyric acid W.

To a stirred solution of (8.) (1.0 g, 2.22 mM) in methanol (100 ml) is added 1 ml of water followed by the 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 water washes), and the stirred filtrate is acidified dropwise with 2% hydrochloric acid. Filtration of the resulting precipitate followed by copious washing with water and drying gave 0.87 g (96%) of (9.) as a chalk-like white 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), mp 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 (11)

To a stirred solution (N ₂ ) stirred of 2-aminothiophenol (10) (1.25 g., 10 mM) and ethyl 4-bromobutyrate (2.14 g., 11 mM) in 40 ml of 1,2- dry dimethoxyethane 8.3 g of solid ground anhydrous potassium carbonate are added, the resulting mixture being de-aerated 3X under nitrogen and left to stir at

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at room temperature until TLC analysis indicates that the reaction is complete. The filtered mixture is then concentrated and the residue is subjected to flash chromatography on silica gel (85 g.) Using 15% ethyl acetate / hexane as the eluent 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 process of Step (E), and the resulting diester 4- (2- (11-carbomethoxyundecanoylamino) phenylthio) ethyl butyrate 12 is hydrolyzed in Step I as in process (F), the title compound, 13., mp 113.5-115 ° C, is obtained.

The following representative compounds in this series were additionally produced by the processes indicated above:

14) 4- (2- (9-carboxynonanoylamino) phenoxy) butyric acid, m.p.

121.5-124.5 ° C.

15) 4- (2- (10-carboxydecanoylamino) phenoxy) butyric acid, mp 110-111.5 ° C.

16) 4- (2- (12-carboxydecanoylamino) phenoxy) butyric acid, mp 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.

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19) 5- (2- (11-carboxyundecanoylamino) phenoxy) valeric acid, m.p.

112-113.5 ° C.

20) 4- (2- (11-carboxyundecanoylamino) -3-methylphenoxy) -butyric acid, mp 134.5-136.5 ° C.

21) 4- (2- (11-carboxyundecanoylamino) -4-methylphenoxy) butyric acid, mp 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 (23)

When 2-nitrophenol (1) is reacted with benzyl bromide under the conditions of Step A, the title ether (23) is obtained as a golden 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 the CCF analysis indicates the absence of starting nitro compound. The filtered mixture is released from excess ammonia by bubbling anhydrous nitrogen. Removal of ethanol by vacuum distillation at room temperature provides 1.0 g of the title compound (24) as one. intense color crust, which was used as it was in the next reaction. This compound can also be obtained by careful reduction in ethanol or ethyl acetate using palladium on carbon as a catalyst, but it can be accompanied by a slight excess of reduction if not monitored.

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Step L: Ν-Trifluoroacetill 2-Benzyloxyaniline (25)

To an almost stirred solution of amine (24) (5.0 mM) in dry diethyl ether (30 ml) is added anhydrous sodium carbonate (6.0 g, 57 mM) and the resulting mixture is cooled in a cold water bath. Trifluoroacetic anhydride (1.5 ml, 10.6 mM) is added dropwise to this cold mixture over 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 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).

Step M: 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 up to 59 ° C, and maintained for 2 minutes. Powdered anhydrous potassium hydroxide (0.225 g, 4.0 mM) is added all at once, and the bath temperature is allowed to rise to 65 ° C. A certain amount of KOH is seen piling up. 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 residue of N-Methyl-N-trifluoroacetyl-2-benzyloxyaniline (26) obtained, followed by water (1 ml), and methanol (2 ml) (for washing on the sides ). After stirring overnight at room temperature, methanol is removed in vacuo, the residue is partitioned between ether and water, separated, the organic layer is washed with additional water, saturated sodium chloride solution, and dried over sodium sulfate. The concentration of the filtered ether solution gives rise to

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title compound (27) (0.212 g) as an oil. NMR, MS and CCF indicate little or no dimethyl compound.

Step Ν: 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 over 1 minute (some methylene chloride used for washing). After cold stirring for 30 minutes, the mixture is left to stir at room temperature so that the reaction is complete. The reaction mixture is washed IX with 1N HCl, dried (Na SO) and

Filtered Z. Flash chromatography (silica gel, 20% ethyl acetate / hexane as eluent) of the residue obtained gives the title compound (28) (0.33 g) as a colorless oil.

Step 0: N- (11- (Carbomethoxy) undecanoyl) -N-Methyl-2-Hydroxy aniline (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 no more remains (V) (CCF 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-Ν- (11-Carbomethoxyundecane i1) -N- (methyl) -amino) phenoxybutyrate (30)

To a stirred solution of (29.) (0.087 g., 0.25 mM) and

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Ethyl 4-bromobutyrate (0.115 ml, 0.80 mM) in anhydrous acetone (10 ml) is added anhydrous potassium carbonate (0.45 g, 3.2 mM) and the resulting mixture is heated under gentle reflux under a nitrogen atmosphere for 24 hours. The mixture is cooled, filtered, and concentrated, and the residue is subjected to flash chromatography (silica gel: 20% ethyl acetate / hexane as eluent) to give 80 mg of the title compound (30) as 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-desmethyl analog (Step F, above), and the resulting oil obtained after acidification is extracted with methylene chloride, the title compound (31), (51 mg.), as a colorless oil.

Step R: Ethyl 4- (2- (11-Bromoundecanoylamino) phenoxy) -butyrate

To a solution of (4) (2.60 g., 11 mM) and 11-bromoundecanoic 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). The precipitation of dicyclohexylurea (DCU) begins within 4 minutes. When the 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 IX with 1N hydrochloric acid, IX with saturated sodium chloride solution, dried (Na ₂ SO ₄ ) and concentrated until a residue is obtained which is stirred, filtered, and alternatively concentrated with ether and sodium chloride.

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methylene until all the DCU is removed. Concentration of the final solution provides the title product (32) (2.35 g.) In the form of an oil which rapidly changes to a waxy solid.

The attempt to purify a previous product by means of column chromatography (silica gel; 20% ethyl acetate / hexane as eluent) gave rise to an impure product with very low yield.

Step S: 10- (N - ((2- (3-Carboethoxy) propyloxy) phenyl) carboxamido) diethyl decylphosphonate (33)

A stirred mixture of (32) (0.235 g., 0.5 mM) and triethyl phosphite (TEP) (0.3 ml) is heated to 180 ° C (bath temperature) under a nitrogen atmosphere for 8 hours, cooled, excess TEP is removed in vacuo, and the residue is subjected to flash chromatography (silica gel; ethyl acetate as eluent) to provide 33 (0.13 g.) as a clear colorless oil.

Step T:

Cleavage of the phosphonate ester (33.) using bromotrimethylsilane (JCS Chem. Comm. P. 739 process (1979) provides 10- (N - ((2- (3- (carbethoxy) propyloxy) phenyl) carboxamido) decylphosphonic acid (34).

Passed on;

Subsequent hydrolysis of (34) using the process of Example (F) above provides the corresponding di-acid, 10- (N - ((2- (3-Carboxy) propyloxy) phenyl) carboxamido) -decylphosphonic acid (35).

224-

Step V: 10- (N - ((2- (3-Carboethoxy) propyloxy) phenyl) carboxamido) decanoisothiouronium 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 reaction mixture provides the title compound (36) (contaminated with a small amount of thiourea) which slowly solidifies in crystalline circles at rest. Stirring with dry chloroform followed by filtration and concentration provides the product * in the form of a thick wax.

Step W: 10- (N - ((2- (3-Carboethoxy) propyloxy) phenyl) carboxamido) decanothiosulfate (37)

To a stirred solution of (32) (0.047 g., 0.1 mM) in ethanol (2.0 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 90 ° C) under a nitrogen atmosphere until TLC analysis indicates no bromine compound. The cooled mixture was then concentrated to remove ethanol and water, providing a white crust. Extraction of this crust with chloroform, followed by filtration from inorganic elements, provides the product (37) (49 mg) in a glassy form which over time turns into a waxy solid. This product has an appreciable solubility in water.

The oxidation of (36) or (32) as in the analogous processes in J.S. Showell et al., J. Org. Chem. 27 (1962) 2853 or C. Ziegler et al J. Org. Chem. (1951) 621) provides the corresponding sulfonic acid (.38).

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

This compound was prepared from ethyl 4-bromobutyrate 2 and 2-nitro-3-pyridinol (22) by the process of Step (A), mentioned above. After flash chromatography (silica gel; 1.5% methanol / methylene chloride as eluent) of a sodium bicarbonate wash product diluted with 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.

Step Y: 4— (2 — Aminopyrid — 3 — iloxy) ethyl butyrate (41)

This compound was prepared by reducing (40) as in the process of Step (B), mentioned 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 process of Step (E), mentioned above, the title compound (42) is obtained. Hydrolysis will provide the corresponding 4- (2- (11-carboxyundecanoylamino) pyrid-3-yloxy) butyric acid (43).

Step AA: N- (11-Carbomethoxyundecanoyl) -2-hydroxyaniline (44)

To an almost stirred solution of 2-aminophenol (0.24 g, 2.2 mM) in anhydrous methylene chloride (25 ml) was added dry pyridine (0.66 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 (washes with

-226-

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 room 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), referred to above, (45) is obtained as a waxy solid. On the contrary, reacting (44) with ethyl 4-bromobutyrate as in Step (A) gives (8).

Step CC: 4- (2- (11-Carbomethoxyundecanoylamino) phenoxy) -butyramide 1461

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

The new purified compounds, isolated, presented NMR and Mass spectrum data consistent with their indicated chemical structures. All melting points were recorded in a hot O.O phase. Spencer and are not corrected.

-227-

CHAPTER 4

EXAMPLE 1

17B-Benzoi-Androst-3,5-diene-3-carboxylic acid compound of the title is produced by reacting 17B-carbomethoxy-androst-3,5-diene-3-protected carboxylic acid in, for example, THF, with phenyl bromide magnesium in standard Grignard conditions. The standard production process provides the title compound, mp 222-225 ° C.

REFERENCE EXAMPLE 1

Synthesis of 4- (4-isobutylbenzyloxy) -2,3-dimethylbenzaldehyde

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. After cooling, the reaction mixture was diluted with ethyl acetate, the solution was washed with dilute hydrochloric acid, water, successively dried and evaporated. The —228 -

The residue was purified by column chromatography on silica gel (hexane: EtOAc = 1 =: 1) to give the title compound (383 mg) giving the following physical data: TLC: Rf 0.48 (hexane: EtOAc = 5.: L); NMR: 6 7.64 (IH, d), 7.32 (IH, d), 7.16 (IH, d), 5.12 (2H, S), 2.60 (3H, s), 2, 48 (2H, d), 2.24 (3H, s), 1.94-1.80 (IH, m), 0.90 (6H, d).

REFERENCE EXAMPLE 2

Synthesis of 4- (4-isobutylbenzyloxy) -2,3-dimethylbenzoic acid

OOH

A solution of the aldehyde prepared in the example of reference 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 stopped by the addition of isopropyl alcohol. The deposited crystals were washed with hexane, dried and purified by column chromatography on silica gel (hexane-EtOAc) to give the title compound (328 mg) showing the following physical data: TLC: Rf 0.36 ( hexane: EtOAc = 2: 1); NMR: δ 7.80 (IH, d), 7.33 (IH, d), 7.15

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(1Η, d), 6.90 (1H, d), 5.09 (2H, s), 2.58 (3H, s), 2.48 82H, d),

2.26 (3H, s), 0.91 (6H, d).

REFERENCE EXAMPLE 3

Synthesis of 4-Γ2-Γ4- (4-isobutylbenzyloxy) -2,3-dimethylbenzoylaminophenoxybutanoic 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 column chromatography on silica gel (hexane: EtOAc = 5: 1) to give the title compound / 383 mg) with 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 (H, 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).

-230-

REFERENCE EXAMPLE 4

Synthesis of 4-Γ2-Γ4- (4-isobutylbenzyloxy) -2,3-dimethylbenzoylaminophenoxyIbutanoic acid

1N aqueous lithium hydroxide solution (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 was extracted with ethyl acetate. The extract was dried and evaporated. The residue obtained was recrystallized from hexane to give the title compound (317 mg) with the following physical data:

TLC: RF 0.26 (hexane: EtOAc = 1: 1): mp 143 ° C.

EXAMPLE REFERENCE 5 «

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

-231-

where R ^ ®

where the Rf value is 0.37 (hexane: EtOAc = 1: 1), and the mass spectrum showed m / z values of 503, 345.

EXAMPLE REFERENCE 6

(-) - 4-r2- (4-ri- (4-isobutylphenyl) ethoxy) -2,3-dimethylbenzoylamino phenoxy1butanoic compound prepared above in reference example 5,

-232-

(403 mg) and cinchonidine (2.36 g) were dissolved in acetone (70 ml) with heating. The solution was left 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 with the following physical data:

Appearance: white crystal;

Optical rotation angle: [a] _D -39.6 ° (c = l, CHCip

REFERENCE EXAMPLE 7

(-) - 4-Γ2- (4-Γ1- (4-isobutylphenyl) ethoxy-2,3-dimethylbenzoylamino) phenoxybutanoic acid sodium salt

The compound prepared in Reference Example 6 was dissolved in methanol. The molar equivalent of an aqueous sodium hydroxide solution was added and evaporated to give the title compound with the following data:

IR: nu 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 obtain 100 tablets each containing 50 mg of active ingredient.

-233 4- [2- [4- [1- (4-isobutylphenyl) ethoxy) butanoic acid

Calcium gluconate cellulose (disintegrating agent)

Magnesium stearate (lubricating agent)

Microcrystalline cellulose g

0.2 g

0.1 g

4.7 g

Lisbon, March 18, 1992

J. PEREIRA DA CRUZ Official Industrial Property Agent RUA VICTOR CORDON, 10-A 3 «1200 LISBOA

Claims (2)

CLAIMS ia - Method for the treatment of benign prostatic hyperplasia in patients in need of such treatment characterized by comprising the stage of administration to such patients of therapeutically effective amounts of a 5a-reductase inhibitor selected from 17B-substituted, non-azaesteroids 4-azaestteroids 17B-substituted, 17B-acyl-3-carboxy-androst-3,5-dienes, benzoylamino butanoic acid derivatives, cinnamoylamides, condensed benzo (thio) amides, aromatic 1,2-diethers or thioethers, aromatic orthoacylaminophenoxy alkanoic acids, alkanoic ortho-thioalkylacylaminophenoxy or its pharmaceutically acceptable salts or esters, in combination with an α-adrenergic receptor blocker. 2. The method of claim 1 wherein said 5a-reductase inhibitor is a 4-azasteroid 17B-substituted formula. The where: the dotted line represents a double bond when present; 13_ R and R are independently hydrogen, methyl or ethyl; R is a hydrocarbon radical selected from straight or branched, substituted or unsubstituted alkyl, cycloalkyl, or aralkyl of 1-12 carbon atoms or mono-cyclic aryl optionally containing 1 or more lower alkyl substituents of from 1-2 carbon atoms and / or 1 or more halogen substituents; R 'is hydrogen or methyl; R '' is hydrogen or β-methyl; R ^z '' is hydrogen, α-methyl or β-methyl, and pharmaceutically acceptable salts or esters. 33. The method of claim 1 wherein said 5a-reductase inhibitor is a 4-aza steroid of formula wherein the dotted line represents a double bond when present; R is selected from hydrogen, methyl and ethyl; and .X (a) a monovalent radical selected from straight or branched chain alkyl, or cycloalkyl, of from 1-12 carbon atoms, which can be substituted by one or more C1 -C4 alkyl or halo; (b) an aralkyl radical selected from benzyl or phenethyl; (c) an aromatic polycyclic radical that can be substituted by one or more of: -OH, -OH protected, “OC -C ₄ alkyl, C ₄ -C ₄ alkyl, halo or nitro; (d) an aromatic monocyclic radical that can be replaced by one or more of: (1) -OH, “OC ₁ -C ₄ alkyl, alkyl, - (CH ₂ ) _m 0H, - (CH ^, COOH, including protected hydroxy, where m is 1-4, n is 1-3, provided that C ^-C ^ alkyl is only present when one of the antteriormént referred to as oxygen-containing radicals is present; (2).-SH, -SC ^ -C ₄ alkyl, SOC ^ -C ^ alkyl, -SO ₂ C ₁ ~ C ₄ alkyl, -SO ₂ N (C ₁ -C ₄ ~ alkyl) ₂ , ^C 1 ~ ^C 4 alkyl, - (CH ₂ ) _m SH, -S- (CH ₂ ) -0-, COCH ₃ , where m is 1-4, n is 1-3, provided that C ₁ ~ C ₄ alkyl is only present when one of the aforementioned sulfur-containing radicals is present; 3, 3 (3) N (R), which can be protected, where R is independently H or C - alkyl, where the monoaryl ring can also be additionally substituted with ^c 1 " ^and 4 alkyl; and (e) heterocyclic radical selected from 2 or 4-pyridyl, 2-pyrrolyl, 2-furyl or thiophenyl; R ^z , R, R '''are each selected from hydrogen and methyl, and their pharmaceutically acceptable salts. Method according to claim 1, characterized in that said 17B-substituted 5a-reductase inhibitor is non-azaesteroid of the formula: on what: ring A has up to two double bonds; rings B, C and D have optional double bonds where indicated by dashed lines counting that rings A, B, and C do not have adjacent double bonds and ring D does not have a double bond ^c 16 “ ^c 17 when R ₃ represents two substituents or a divalent substituent; Z is (CH ₂ ) _n and _n is 0 or 2, with the proviso that Z is (CH) when adjacent to a double bond; X is H, Cl, F, Br, I, CF_, or C_ _and alkyl; 3 _L “O Y is H, CF ₃ , F, Cl, or CH ₃ , with the proviso that Y is H when there is no C-C double bond; R ^x is H or C alkyl; 2 ¹⁸ R is absent or present as H or CH „, with the condition of 2. ⁸ that R is absent when the carbon to which it is attached is unsaturated; and R ³ is: (1) α-hydrogen, or a-hydroxy, or a-acetoxy and / or (a) II -WCR where W is a bond or C ₁ _ alkylidene, and R ⁴ is: (i) hydrogen, (ii) hydroxyl, (iii) ^c ₁ _ ₈ alkyl, (iv) C „hydroxy alkyl, χ - o (v) and alkoxy, (vi) NkR, where R and R ° are each independently selected from hydrogen, C alkyl, C_. cycle- 5 63-6 alkyl, phenyl; or R and R taken together with the nitrogen to which they are attached represent a 5- or 6-membered saturated ring, (vii) OR, where R is hydrogen, alkali metal, C J_ - alkyl, benzyl, or S8 (b) -Alq-OR, where Alq is C. ^. ^ Alkylidene, and R is: (i) phenyl C _n _ alkylcarbonyl, ± - Ό (ii) 5- ^C ₁₀ cycloalkylcarbonyl, (iii) benzoyl, (iv) alkoxycarbonyl CL, χ-O (v) aminocarbonyl, or aminocarbonyl substituted with C ₁ _ ₈ alkyl, (vi) hydrogen, or (vii) CL alkyl, J.-M (2) = CH-W-CO-R , or = CH-W-OR, where W is a CL connection ___. . 48 .... ¹ alkylidene and R and R have the meaning given above and R is also hydrogen or C ₁ _ _2Q alkylcarbonyl, (3) where the broken bond replaces 17-a-hydrogen, 9 9 5 6 (4) α-hydrogen and NHCOR wherein R is iq ^u ^ ith / ^or NR R has the meaning given above, (5) α-hydrogen and cyano, (6) α-hydrogen and tetrazolyl, or (7) keto; or a pharmaceutically acceptable salt thereof; except compounds in which: (i) ring B has a double bond c _{5 g} , R ¹ is CH ₃ , and R ³ is keto, methoxycarbonyl, or acetyl; or (ii) the nor-A ring has a C ₃ _ ₄ β R double bond and acetoxy or acetyl; 13 (ii) R is CH and R is acetoxy or acetyl; or (iv) the nor-A ring has a ^c ₃ _ ₄ double bond ^and R ^and methyl; or. 3 (v) ring B has a double bond ^c ₃ _ ₄ θ R θ β-hydroxy. 5 - Method according to claim 1, characterized in that the 17-B-acyl-3-carboxy-androst-3,5-diene has the formula Hi where R ¹ is: (a) C ₁ _ ₆ alkyl linear or branched; ^and 3_12 cycloalkyl, which can be substituted by C 1 4 alkoxy or 4 straight or branched alkyl; ^c g_12 ^ar il ° ' ^{or c} 7 13 aralkyl which can be replaced by one or more of: -OH, -OC1-C4 alkyl, 0χ-04 alkyl, - (CH2) mOH, “( ^CH 2) _n ^{/ C00H} 'including protected -OH, where m is 1-4, n is 1-3; (b) _{C and} straight or branched alkyl; C „cycloalkyl, _L - b 3” _L z which can be replaced by C-C ₄ alkoxy or C ”C ₄ linear or branched alkyl; C _g -C ₁₂ ° z yl ^{air or C} 7 ^-C i3 aralkyl which may be substituted with one or more of: -OH, -OCX -C4 alkyl, 0χ-04 alkyl, - (CH ^ OH, - (CH2) n COOH, including protected -OH, where m is 1-4, n is 1-3 and R ² is selected from COOH, SO3H, PO (OH) ₂ , PH (O) OH. 6 - Method according to claim 1, characterized in that the benzoylaminophenoxy butanoic acid derivatives have the formula: on what: R 'is hydrogen or alkyl of 1 to 4 carbon atoms; A is an oxygen atom, a sulfur atom or a (SO) sulfinyl group; both R ¹ are methyl or chlorine or both R ¹ and the carbon atoms of the benzene ring to which the two R ¹ are attached are cyclopentane, cyclohexane or a benzene ring; and R represents a group of formula: where B is oxygen, sulfur or a group of formula NR at 11. . that R is hydrogen or alkyl of 1 to 4 carbon atoms; R, R, R, R4, R and R ° 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 g R is hydrogen, alkyl of 1 to 5 carbon atoms or a group of formula: 12 13 14 15 _. where R, R, R, and R are. independently, hydrogen, alkyl of 1 to 4 carbon atoms, halogen, trifluoromethyl or cyclobutylmethyl, and 1 is an integer from 1 to 4, and rIQ is a group of formula: OR I -1012 13 14 15. - < where R, R, R, and R are. independently, hydrogen, alkyl of 1 to 4 carbon atoms, halogen, trifluoromethyl or cyclobutylmethyl, and 1 'is an integer from 1 to 4; or its non-toxic salts. X Method according to claim 1, characterized in that said cinnamoylamide has the formula: COOH 2 3.. . wherein R and R each independently represent hydrogen or a methyl group with the proviso that: 2 . 3 (1) when R represents a methyl group, R represents hydrogen and ( ^R ' ¹ ') _n represents a member selected from the group consisting of a 3-pentyl, 4-pentyl group, a 4-neopentyl group, a 4- group (2-ethylbutyl) and 4- (2-methylpentyl), or 2 .... 3 (ii) when R represents hydrogen, R represents one. 1 methyl group and (R) represents a 3-pentyl group, or its non-toxic salts. Method according to claim 1, characterized in that the condensed benzo (thio) amide is of the formula: -li- where: A represents a single bond or a methylene, ethylene, trimethylene, tetramethylene, vinylene, propenylene, butenylene, butadienylene or ethinylene group optionally substituted by one, two or three linear or branched alkyl groups of 1 to 10 carbon atoms and / or group ( s) phenyl; B represents a 4- to 8-membered heterocyclic ring containing one, two or three heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur atoms, wherein said ring can be optionally substituted by group (s) selected from group (s) ) oxo, thioxo and / or hydroxy including a ring of formula: T represents an oxygen atom or a sulfur atom; —12 - R ¹ represents a group of general formula: (iv) a linear or branched alkyl, an alkenyl or alkynyl group of 1 to 20 carbon atoms, wherein R ⁵ and R ⁶ independently represent a hydrogen atom or a halogen atom or a linear or branched alkyl, an alkenyl group or alkynyl of 1 to 20 carbon atoms, 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 (s), thiophene ring (s), naphthalene ring (s), carbocyclic ring (s) from 4 to 7 atoms, carbonyl group (s), group (s) carbonyloxy, hydroxy group (s), carboxy group (s), azido group (s) and / or nitro group (s); 2 . . R represents a hydrogen atom or a linear or branched alkyl group of 1 to 6 carbon atoms; 3. . „. R represents a hydrogen atom, a halogen atom, a hydroxy group, a nitro group, a group of the general formula —COOR, where R represents a hydrogen atom, a linear or branched alkyl group of 1 to 6 carbon atoms or an alkoxy, alkylthio group of 1 to 6 carbon atoms; R represents a group of general formula: -U- (CH2) n-C00R ⁸ , N-N -U-CCH ₂ ) _m - / ^/ NN H —CCH ₂ ) _p -COOR ^S , or N_N - (CH ₂ ) _to - N-N H where U represents an oxygen atom, or an atom of Sulfur, R represents hydrogen or a linear or branched alkyl group of 1 to 6 carbon atoms, nor does it represent an integer from 1 to 10, respectively, p and q represents zero or an integer from 1 to 10, respectively, or their salts non-toxic. Method according to claim 1, characterized in that said orthoacylaminophenoxy alkanoic acid has a structure: R 'where: A is a 1,2-di-substituted aromatic ring selected from: (a) benzene; (b) 5-6 membered heteroaromatic ring containing 1-2 N atoms, an S or O atom, or a combination thereof; D and E are independently -COOH, -CONH, -CONHR,, SO OH, Z ÍJ Ct -SO ₂ NH ₂ , -CO ₂ R _b , -SSO ₂ ONa, SO ₃ OH, P (O) (OH) ₂ ; X is O, S, SO or SO ₂ ; D: H C ^ -C ^ alkyl, phenyl or substituted phenyl, halo, haloalkyl, hydroxy, carboxy, cyano, C-C. alkoxy, C _x -C alkylthio, 0 _χ -0 ₄ alkylsulfinyl, ^c 1 " ^and 4 alkylsulfonyl, amino, nitro, C-C mono or di-alkylamino; R 'and R' 'are independently: H, halo, C ₁ -C alkyl or C-C ₄ alkoxy, amino, or oxo, where CH-R 'or CH-R in the formula represents -C = O; R _a is H, C-C ₄ alkyl; R1 is ^C4 -C alkyl, y is 1-6; phenyl, or C1-4 alkyl phenyl; z is 6-20; and on what R ' (U _y and R '' | (CH) _z can independently represent substituted alkyl or unsubstituted or alkenyl radicals substituted or unsubstituted containing at least one alkane bond; and their pharmaceutically acceptable salts and esters. Method according to claim 1, characterized in that said ortho-thioalkylacylaminophenoxy alkanoic acid has the structure in which: A is a 1,2-substituted aromatic ring; D is OH, NH_, NHR, OR; 2 c 'c' x is o, s, so, or so ^; R is H, phenyl or substituted phenyl, halo, haloalkyl, hydroxy, carboxy, cyano, ^c 1 ” ^and 4 alkoxy, C - ^ - C alkylthio, C ₁ ~ C ₄ alkylsulfinyl, C-jy-C alkylsulfonyl, nitro, amino, C - ^ - C mono or dialkylamino; R 'and R' are independently H, halo, 17C ^ -C ^ alkyl or ^c -C alkoxy, amino, or oxo, where CH-R 'or CH-R''in the formula represents -C = 0; R is H, C.-C. alkyl; to 14 R _b , R _c are independently, ^C i ^-C ₁₂ alkyl, phenyl, phenyl-C ^-C ^ alkyl; n is 0-2; y is 1-6; z is 6-20; and on what R '(CH) and y represent alkyl radicals R '’ I (CH) _z can independently or substituted alkenyl or substituted insubstitutes containing at least one alkene bond; and their pharmaceutically acceptable salts or esters. 113 - Method according to claim 1, characterized in that the aromatic diether or thioether is a compound of structure: on what: A is a 1,2-di-substituted aromatic ring; D is OH, NH, NHR, OR; c c X is O, S, SO, or S0 ₂ ; R is H, Cj-C ^ alkyl phenyl or substituted phenyl, halo, haloalkyl, hydroxy, carboxy, cyano, C-C. alkoxy, 1 4 ' Cj — alkylthio, Cj-C alkylsulfinyl, ^C 1 ^-C alkylsulfonyl, nitro, amino, ^C 1 ^-C 4 ^{mono or} dialkylamino; R 'and R' are independently H, halo, C ₁ ~ C ₄ alkyl or C ₁ ~ C ₄ alkoxy, amino, or oxo, where CH-R 'or CH-R''in the formula represents -C = 0; R _& is H, ^c j " ^and ₄ alkyl; R ^, _Rc are independently, ^C I ^-C j2 alkyl, phenyl, phenyl-C₁-C₄ alkyl; n is 0-2; y is 1-6; z is 6—20; and on what R ' I ( ^CH ) _y R '' (CH) _Z can independently -19represents substituted or unsubstituted alkyl or alkenyl radicals containing at least one alkene bond; and their pharmaceutically acceptable salts or esters. 12. The method of claim 1 wherein said α-adrenergic receptor blocker is selected from terazosin, doxazosin, prazosin, bunazosin, indoramine or alfuzosin. 13. The method of claim 8 wherein said _x -adrenergic receptor blocker is terazosin. 14. A method according to claim 1, characterized in that said 5α-reductase inhibitor is finasteroid and said α-adrenergic receptor blocker is terazosin. 15 ^ - Pharmaceutical composition for the treatment of benign prostatic hyperplasia characterized by comprising therapeutically effective amounts of 17b-substituted, 17b-substituted, 17b-acyl-3-carboxy-androst- 4-azaesteroides inhibitor 3,5-dienes, benzoylamino-phenoxy butanoic acid derivatives, cinnamoylamides, condensed benzo (thio) amides, aromatic 1,2-diethers or thioethers, aromatic ortho-acylaminophenoxy alkanoic acids, aromatic orthoalkylacylaminophenoxy-alkanoic acids or their aromatic or aromatic acids pharmaceutically acceptable esters and a α-adrenergic receptor blocker in a pharmaceutically acceptable vehicle.