Field of the Invention

This invention relates to pharmaceutical compositions and methods for the treatment of androgen-related diseases, said compositions having novel inhibitors of testosterone 5α-reductase activity. The inhibitors have a good combination of inhibitory effect on 5α-reductase activity, low or no androgenic activity and, in some embodiments, antiandrogenic activity. More particularly, certain embodiments of the invention relate to derivatives of 4-aza-androstanone or 4-aza-androstenone.

Background of the Invention

Prior art inhibitors of 5α-reductase fail to provide an optimal combination of (1) lack of inherent androgenic activity and (2) ability to inhibit both of two different forms of testosterone 5α-reductase ("5α-reductase"). 5α-reductase is an enzyme which catalyzes the conversion of the androgen, testosterone, to the much more potent androgen dihydrotestosterone ("DHT'). DHT is the more active androgen in many target organs (Anderson and Liao. Nature 219:277-279, 1968). The same enzyme catalyzes the conversion of androstenedione into androstanedione. Inhibitors of 5α-reductύse inhibit biosynthesis of the products whose formation is catalyzed by 5α-reductase.

5α-reductase has been studied in different species (Liang et al. Endocrinology 117: 571-579, 1985). Its isolation and structure, and the

SUBSTJTUTE SHEET

expression of cDNA encoding it have been described (Andersson and Russell. Proc Natl. Acad. Sri. 87:3640-3644, 1990).

Recent data have demonstrated the presence of at least two different genes expressing 5α-reductase in humans. Type 15α-reductase (Andersson and Russell, Proc. Natl. Acad. Sά. 87, 3640-3644, 1990) is expressed at a low level in the human prostate while type II 5α-reductase is the predominant enzyme isoform expressed in this tissue (Andersson et al., Nature 354, 159-161, 1991).

The blockade of 5α-reductase has been intensively studied in view o developing pharmaceutical drugs for the therapy of dise ses, such as prostate cancer. In European Patent Appln. No. EP 285383 Ramusson et al. disclose the treatment of prostatic carcinoma with 17β-N-monosubstituted-carbamoyl- 4-aza-5cx-androst-l-en-3-ones). Diseases for which 5α-reductase inhibitors are also being studied include acne, baldness (Rittmaster et al. J. Clin. Endocrinol. Metab.65: 188-193, 1987) and benign prostatic hyperplasia (Metcalf et l., TiPS

10: 91-495, 1989).

The 4-aza-steroid N,N-diethyl-4-methyl-3-oxo-4-aza-5α androstane-17β-carboxamide, 4-MA has proven useful in inhibiting th formation of DHT from testosterone in rat prostate in vitro and in vivo (Brook et al. Endocrinology 109: 830-836, 1981), thus reducing th testosterone-induced increase in ventral prostate weight in these animals Another 4-aza-steroid, MK-906 (PROSCAR), has been found to cause reduction in the intraprostatic concentration of DHT and a 25-30% reductio in prostatic size in men (Imperato-McGinley et ah, Proc. 71st Ann. meet Endocr. Soc, p. 332, abst 1639, 1989). However, Proscar is reported to be potent inhibitor of the type II enzyme but a weak inhibitor of the type enzyme (Andersson et al. _r Nature 354, 159-161, 1991). Such a low inhibitor potency on type I 5cc-reductase probably explains why the highest doses o

Proscar used in men generally fails to reduce serum dihydrotestostero levels below 25 to 35% of control, thus leaving a highly significa concentration of circulating androgens (Vermeulen et al, The Prostate 1 45-53, 1989). The inhibitory effect of the drug on prostatic volume in m remains limited at 25 to 35% over a period of 6 months (Stoner, J. Steroi

Biochem. Mol. Biol. 37, 375-378, 1990). There is thus a need to devel compounds which can efficiently inhibit both type I and type II 5α-reducta and thus cause a more complete inhibition of circulating dihydrotestostero levels. In U.S. Patent Appln. No. 4317,817, Belgian Patent Applr No. S83 0 and British Patent Appln. No. 204 8888, Blohm and Metcalf discuss the u of certain diazo-steroids as steroid 5α-reductase inhibitors. Metcalf et describe the synthesis of related compounds in Tetrahedron Lett. 21, 15-1 1980. In EP Publication No 343 954, EP Publication No 375 347, U.S. Pate

Appln. No 4,882,319, U.S. Patent Appln. No 4,937,237 and J. Med. Chem. 3 937-942, 1990, Holt et al. discuss the use of certain A-ring aryl stero derivatives as steroid 5α-reductase inhibitors.

In EP Publication No 289327 and Publication No 427 434, on one han and in J. Steroid Biochem. 34: 571-575, 1989 and Biochemistry 29: 2815-28

1990, on the other hand, Holt and Levy discuss, respectively, the use androstene- and pregnene-3-carboxylate derivatives as steroid-5α-reducta inhibitors.

In EP Publication No 375 351, Holt et al. discuss the preparation phosphoric acid substituted steroids as testosterone 5α-reductase inhibito

In EP Publication No 271 219, EP Publication No 314 199, and Publication No 155 096, Rasmusson and Reynolds discuss the preparation 17β-substituted-4-aza-5α-androstenones as steroid-5α-reductase inhibitors

Brooks, et al. (Steroid 47: 1-19, 1986; Prostate 9: 65-76, 1986) have reported 5α-reductase inhibiting and androgen-blocking activities for some 4-aza-steroids.

Rasmusson et al. discuss certain aza-steroids as inhibitors of rat prostatic 5α-reductase (in J. Med. Chem. 27: 1690-1701, 1984; idem 29:

2298-2315, 1986 and J. Biol. Chem. 259: 734-739, 1984).

In EP Publication No 277 002, Holt et al. discuss 17β-substituted-4-aza-5α-androstane-3-ones.

In EP Publication No 271 220, Carlin et al. discuss the preparation of 17β-(N-monosubstituted carbamoyl)-4-aza-5α-androstane-3-ones.

In EP Publication No 200 859, Cainelli et al discuss the preparation of certain 4-aza-steroid derivatives which are stated to be steroidal 5α-reductase inhibitors.

In International Publication No WO 91/12261, Panzeri et al. discuss the preparation of 17β-substituted-4-aza-5α-androstan-3-one derivatives.

In U.S.4396,615, Steroids 38: 121-140, 1981 and J. Steroid Biochem. 19: 1491-1502, 1983; Petrow et al discuss certain 6-methylene progesterone derivatives stated to be inhibitors of steroid 5α-reductase.

In U.S. 4377^84 (see e.g., column 13), U.S. 4,220,775 and in EP Publication No. 414 490 and 414 491, Rasmusson et al. discuss certain

17β-substituted-4-aza-5α-androstanones (including acyl amino substitutions) as steroid-5α-reductasc inhibitors.

In EP Publication No 052799, Alig et al discuss the use of certain D-homosteroids as steroid 5α-reductase inhibitors. In U. S . 4,191 ,759, Johnston and Arth discuss

N-substituted-17β-carbamoyl-androst-4-en-3-ones as steroid 5α-reductase inhibitors.

In BE 855 992, Benson and Blohm discuss steroidal inhibitors testosterone 5α-reductase, for treating skin disorders.

In CA 970 692, Voight and Hsia discuss compounds inhibitin 5α-reductase activity. In FR 1 465 544, Jolly and Warnant discuss 4-aza-aromatic steroi derivatives as steroid 5α-reductase inhibitors.

In US 4,087,461, Robinson discuss certain allenic steroids testosterone 5α-reductase inhibitors.

In EP Publication No 414 529, Metcalf discuss certain 17-substitute steroidal acids as testosterone 5oc-reducta.se inhibitors (see e.g. the Abstract

See Also, Holt, et al., EP Publication No 427,434.

In EP Publication No 298 652, Bhattacharya disclose the synthesis 4-aza-Δl -s teroi ds .

In U.S. Patent Appln. No 5,061,803 and 5,061,801, Williams discuss a method for the synthesis of 17β-alkanoyl-3-oxo-4-aza-5α-androst-l -enes an

3-oxo-4-aza-androst-l -ene 17β-ketones.

In U.S. Patent Appln. No 5,061302, Steinberg and Rasmusson discu the preparation of 17β-aminobenzoyl-4-aza-5α-androst-l-en-3-ones as beni prostatic hypertrophy agents. Lan-Hargest et al. discuss the synthesis of bridged A ring steroids

5α-reductase inhibitors (Tetrahedron Lett. 28:6117-6120, 1987).

Weintraub et al (in J. Med. Chem. 28: 831-833, 1985) discuss t preparation of 20-hydroxymethyl-4-methyl-4-aza-2-oxa-5α-pregnan-3-one inhibitors of testosterone 5α-reductase. Kadohama et al. (Cancer Res. 44: 4947-4954, 1984) discuss sodiu

4-methyl-3-oxo-4-aza-5α-pregnane-20 (S) carboxylate inhibition of prosta tumor 5cc-reductase.

Maclndoe et al. in J. Steroid Biochem. 20, 1095-1100, 1984, discuss the 5α-reductase inhibiting effect, in MCF-7 human breast cancer cells and ra prostate, of certain 6-methylene steroids.

Liang et al (J. Biol. Chem. 256:7998-8005, 1981) discus 17β-N,N-diethylcarboxyamoyl-4-methyl-4-aza-5α-androstan-3- one as reversible inhibitor of 5α-reductase.

Salomons and Doorenbos (J. Pharm. Sci.63:19-23, 1974) and Doorenbo et al. (J. Pharm. Sci. 60:1234-1235, 1971; idem 62: 638-640, 1973; Chem and Ind 1322, 1970) discuss synthesis of 17β amino 4-aza- steroids. Nakayama et al. (J. Antibiotics XLJI.T221-1229, 1989; idem, 1230-1234

1989; idem, 1235-1240, 1989) discuss the isolation of WS-9659 fro Streptomyces and its inhibitory activity on testosterone 5α-reductase.

In EP Publication No 294937 and EP Publication No 294035, Nakai e al. discuss the preparation, respectively, of cinnamoyl amide derivatives an ((benzoylamino)phenoxy) butanoic acid derivatives, as inhibitors o

5α-reductase.

U.S. Patent 5,026,882 and EP Publication No 375 349 relates to certai steroid-3-phosphinic arid compounds for use as inhibitors of steroi 5α-reductase. These patents also summarize in their description of the relate art, numerous compounds which are stated to be prior art 5α-reductas inhibitors. See, for example, Table I of U.S. Patent 5,026,882 and th discussion in the prior art section of the patent.

EP Publication No. 435 321 relates to A-nor-steroid-3-carboxylic ari derivatives, which reportedly exhibit 5α-reductase inhibition. In International Publication No WO 91/13060 and EP Publication N

458 207, Okada et al. discuss the preparation of Indole derivatives a testosterone 5α-reductase inhibitors.

Salle, et al., "17β-acylurea Derivatives of 4-Azasteroids as Inhibitors o Testosterone 5α-Reductase" relates to studies regarding the effectiveness o 5α-reductase of a new series of 17β-acylurea substituted derivatives.

U.S. Patent 5,053,403 describes the use of certain androgen recepto blocking agents together with certain 5α-reductase enzyme inhibitor in th treatment or prevention of sebaceous gland hypertrophy, hirsutism an male-pattern baldness.

Prior art inhibitors of 5α-reductase are not believed to fully inhibit bot forms of 5α-reductase without exhibiting or causing undesirable androgeni or other hormonal activity.

^' SUMMARY OF THE INVENTION

During treatment of certain diseases whose progress is stimulated by the activation of androgen receptors, it is desirable to reduce activation of those receptors. This may be accomplished by reducing the availability of "agonists", e.g., natural androgens and other compounds capable of activating the receptors or by reducing the availability of receptors and/or by blocking access to the receptors by compounds which would otherwise activate them. The latter function may be achieved by administering an "antagonist", a compound with affinity for a receptor which binds the receptor and blocks access by agonists. In the case of androgen receptors, an androgen antagonist

("an antiandrogen") may desirably bind the androgen receptor without activating the receptor. Its physical presence blocks access to the receptor by natural or other androgens which, given access to the receptor, could bind and activate the receptor. In accordance with the present invention, novel testosterone

5α-reductase inhibitors are used in the treatment of androgen-sensitive diseases whose progress can be slowed by inhibiting activation of androgen receptors. Compounds of the invention inhibit the activity of 5α-reductase which catalyzes the synthesis of the potent androgen, dihydrotestosterone. Thus, availability of dihydrotestosterone to activate androgen receptors is desirably reduced.

It is important to achieve this desirable reduction of 5α-reductase activity without causing adverse effects on the ultimate goal of inhibiting activation of androgen receptors. Hence, even if a compound effectively inhibits 5α-reductase activity, its therapeutic effect is reduced if the inhibitor itself has inherent androgenic properties such that the inhibitor activates the very receptors whose activation it is intended to reduce. Likewise, the inhibitor should resist being converted in vivo into an androgenic compound.

Conversely, however, a 5α-reductase inhibitor having aπfa ^' androgen properties, displays two, rather than one, desirable effect on the treatment androgen-related diseases. First, it inhibits enzymatic conversion testosterone to dihydrotestosterone, thus reducing the amount dihydrotestosterone available to activate androgen receptors. Second, antagonistically blocks androgen receptors, shielding them from activation any available androgens, including any dihydrotestosterone which may ha been synthesized in spite of the inhibitor.

Thus, inhibitors of 5α-reductase activity preferably display combination of desirable qualities, including (A) w ability to effective inhibit 5cc-reductase activity (preferably both types of 5α-reductase); and ( a substantial lack of androgenic activity (and resistance to being converted vivo into an androgen). It is also desirable that the inhibitors ha antiandrogenic properties. In order to eliminate undesirable side effec preferred 5α-reductase inhibitors also substantially lack glucocortico characteristics.

It is, accordingly, an object of the present invention to provi improved 5α-reductase inhibitors which more effectively inhibit 5α-reducta activity, and preferably inhibit the activity of both known types of hum 5α-reductase.

It is another object of the invention to provide pharmaceuti compositions having 5α-τeductase inhibitors possessing little intrin androgenic activity and little propensity to be converted in vivo to anot compound possessing intrinsic androgenic activity. It is another object of the invention to provide methods for t treatment of androgen-related diseases whose progress is aided by activati of androgen receptors. Such diseases include, for example, prostate canc

prostatic hyperplasia and sexual deviance and may be treated by the methods of reducing 5α-reductase activity provide herein.

Methods of treatment are provided which utilize 5α-reductase inhibitors of the invention, either alone or in combination with another active ingredient, e.g., an antiandrogen, as part of a combination therapy.

The foregoing and other objects may be achieved by providing pharmaceutical compositions comprising the 5α-reductase inhibitors disdosed herein together with pharmaceutically acceptable carriers or diluents. These pharmaceutical compositions are administered to a patient afflicted with a disease such as those discussed above, whose progress is aided by activation of androgen receptors.

In one embodiment of the invention, a pharmaceutical composition is provided which comprises a pharmaceutically acceptable diluent or carrier and a testosterone 5α-reductase having the molecular formula:

wherein the dotted line is an optional pi bond; wherein R ⁴ is hydrogen or methyl; wherein R ⁶ is hydrogen or C- _j -C saturated or unsaturated hydrocarbon; wherein R ⁷ is selected from the group consisting of hydrogen, C _I -C ₆ alkyl, C _r C ₆ hydroxyalkyl, C _r C ₆ haloalkyl, C ₂ -C ₆ carbonylalkyl, C ₃ -C _b cydopropylalkyl, C ₃ -C ₆ epoxyalkyl and unsaturated analogs of the foregoing;

PCI7CA

- 11

wherein R ^17α is hydrogen or lower alkyl; and wherein R ¹ ^ is a tertiary amino or amido group.

In another embodiment of the invention, a pharmaceutical compositio is provided which comprises a pharmaceutically acceptable diluent or carri and a therapeutically effective amount of an inhibitor of testosteron 5α-reductase having the molecular formula:

wherein the dotted line is an optional pi bond; wherein R ⁴ is hydrogen or methyl; wherein R is hydrogen or C ₁ -C ₃ saturated or unsaturate hydrocarbon; wherein R ⁷ is selected from the group consisting of hydrogen, C ₁ - alkyl, C^Cg hydroxyalkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ carbonylalkyl, C ₃ - cydopropvlalkyl, C ₃ -C ₆ epoxyalkyl and unsaturated analogs of the foregoin wherein R ^17α is selected from the group consisting of a C- _j -C ₆ alk C- _[ -C ₆ hydroxyalkyl, C-,-C ₆ haloalkyl, C ₂ -C ₆ carbonylalkyl, C ₃ - cyclopropylalkyl, C ₃ -C ₆ epoxyalkyl and unsaturated analogs of the foregoin and wherein R ^17β is hydrogen, hydroxy or a substituent converted in vi to hvdroxv.

In another embodiment of the invention, a pharmaceutical composition is provided comprising a pharmaceutically acceptable diluent or carrier and a therapeutically effective amount of an inhibitor of testosterone 5α-reductase having the molecular formula:

wherein the dotted line is an optional pi bond; wherein R ⁴ is hydrogen or methyl; wherein R ⁶ is C- _J -C ₃ saturated or unsaturated hydrocarbon; wherein R is selected from the group consisting of hydrogen, C- _[ -C ₆ alkyl, C _j -C ₆ hydroxyalky, C C ₆ haloalkyl, C ₂ -C ₆ carbonylalkyl, C ₃ -C ₆ cydopropylalkyl, C ₃ -C ₆ epoxyalkyl and unsaturated analogs of the foregoing; wherein R ^{1 α} is hydrogen or lower alkyl; and wherein R is selected from the group consisting of acyl, carboxamide, tertiary amino and tertiary amido.

In another embodiment, a pharmaceutical composition is provided comprising a pharmaceutically acceptable diluent or carrier and a therapeutically effective amount of an inhibitor of testosterone 5α-reductase having the molecular formula:

wherein the dotted line is an optional pi bond; wherein K ^~ is hydrogen or methyl; wherein R ⁶ is hydrogen or C- _J -C ₃ saturated or unsaturate hydrocarbon; wherein R ⁷ is selected from the group consisting of C ₂ -C ₆ alkyl, C ₂ - hydroxyalkyl, C ₂ -C ₆ haloalkyl, C ₂ -C ₆ carbonylalkyl, C ₃ -C ₆ cyclopropylalk C ₃ -C ₆ epoxyalkyl and unsaturated analogs of the foregoing; wherein R ^17α is hydrogen or lower alkyl; and wherein R is selected from the group consisting of ac carboxamide, tertiary amino and tertiary amido.

In another embodiment, a pharmaceutical composition is provided f the inhibition of testosterone 5α-reductase activity which comprises pharmaceutically acceptable diluent or carrier and a therapeutically effecti amount of a 5α-reductase inhibitor of the formula:

wherein the dotted line is an optional pi bond; wherein R* is hydrogen or methyl; wherein R ⁶ is hydrogen or C _τ -C ₃ saturated or unsaturated hydrocarbon; wherein R ⁷ is selected from the group consisting of hydrogen, C C ₆ alkyl, C _j -C ₆ hydroxyalkyl, C _j -C ₆ haloalkyl, C ₂ -C ₆ carbonylalkyl, C ₃ -C ₆ cydopropylalkyl, C ₃ -C ₆ epoxyalkyl and unsaturated analogs of the foregoing; wherein R _g is selected from the group consisting of lower alkyl, cydoalkyl and a moiety which, together with R _j , and the nitrogen atom depicted at R ^{τ β} , is a 5-7 membered heterocydic ring having a single nitrogen hetero atom; and wherein R _f c is selected from the group consisting of a moiety which, together with R _a and the nitrogen atom depicted at R , is a 5-7 membered heterocydic ring having a single nitrogen hetero atom; -COR -CONR^Rp, -CSNR _C R _D , -SO- _j Rc, -P0 ₃ R _c R _D (R _Q and R _D being hydrogen, lower alkyl or lower haloalkyl).

Capsules having the 5α-reductase inhibitors discussed herein may also be utilized. The inhibitors and compositions containing them are utilized in accordance with the invention in methods for reducing 5α-reductase activity, and in the treatment of diseases when progress is aided by activation of androgen receptors, e.g. prostate cancer, benign prostatic hyperplasia, acne, seborrhea, hirsutism, androgenic alopecia and the like.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

In some, but not all, embodiments, an azasteroidal nudeus has a substituent (i.e., other than hydrogen), on at least one of the 4, 6 or 7 positions, e.g 4-methyl and/or 6-lower alkyl and/or 7-lower alkyl. In some embodiments, the R T β substituent is a tertiary amine such as

-N(R ¹⁹ )(R ²⁰ ) where R ¹⁹ is lower alkyl or haloalkyl, and R ²⁰ is lower alkyl. In other embodiments, R ¹ P is a tertiary amido substituent, e.g., acylamino substituents such as -N(R ²⁵ )C(0)R ²⁶ , wherein R ²⁶ is hydrogen or a lower alkyl or and R is a C _j -Cg saturated or unsaturated hydrocarbon such as cydopropyl, cydohexyl, butyl or isobutyl.

As used herein, the terms "tertiary amino" or "tertiary amido" refer to amino or amido substituents wherein the amino or amido nitrogen is not hydrogen substituted. Preferred substituents for the nitrogen indude but are not limited to acyl and lower alkyl. In order to avoid steric interaction between the R ^17α and R ^17β , it is preferred that at least one of these two substituents be hydrogen, hydroxy or a substituent which is converted to hydroxy in vivo (e.g., benzoyloxy, acetoxy).

Hydrocarbon substituents may be saturated or unsaturated. Unsaturated substituents are believed to be especially useful at the R ⁷ and

R ^{1 α} positions. In some embodiments, R ⁷ is a C ₂ -C ₆ alkyl, alkenyl or alkynyl substituent.

In some embodiments, especially when R is hydrogen, hydroxyl (or an ester derivative thereof), R ^17α is C _[ -C ₆ alkyl, C- _j -C ₆ hydroxyalkyl, C _j -C ₈ haloalkyl, C ₂ -C ₆ carbonylalkyl, C ₃ -C ₆ epoxyalkyl or an unsaturated analog of the foregoing. Preferred unsaturated analogs indude, for example, halo or hydroxy alkynyl or alkenyl substituents, especially where the halo or hydroxy group is at the end of the substituent, i.e., farthest from the aza-steroidal

D-ring. An unsaturation at the 1, 2 or 3 position of the 17α substituent is als preferred.

Except where otherwise specified, substituents may have α or stereochemistry. Optional pi bonds denoted by dotted lines in a molecula structure are independent of any other optional bonds appearing in tha structure, the presence of one not being dependent on the presence or absenc of another, unless valence requires interdependence. Compounds discusse herein may be formulated as salts thereof. Atoms of the azasteroidal nudeu for which no substituent is shown may optionally be further substituted (a valence permits) so long as such substitution does not adversely affect th compound's ability to inhibit 5α-reductase activity, and does not render th compound substantially more androgenic.

As used herein, the term "lower" when describing a chemical moiet means a moiety having 8 or fewer atoms. For instance, a "lower alkyl" mea a C- _| to C ₈ alkyl. Any moiety of more than two atoms may be straight- branch-chained unless otherwise specified.

As discussed in more details below, carriers or diluents indude soli and liquids. The novel pharmaceutical compositions of the invention may used in the treatment of androgen-related diseases. When administere systemically by injection, e.g., for treatment of prostate cancer, benig prostatic hyperplasia, and other diseases not primarily effecting the ski conventional diluents or carriers which are known in the art to pharmaceutically acceptable for systemic use are used, e.g., saline, wate aqueous ethanol and oil. When the inhibitors of the invention are utilized f the treatment of androgen related diseases such as acne, seborrhea, hirsutis androgenic alopecia, the inhibitors are preferably administered together wi a conventional topical carrier or diluent such as a mixture of ethanol a propylene glycol. When used topically, it is preferred that the diluent

carrier does not promote transdermal penetration of the active ingredients into the blood stream or other tissues where they might cause unwanted systemic effects. When a composition is prepared other than for immediate use, an art recognized preservative is typically induded (e.g. benzyl alcohol). When the compound is administered in a cutaneous or topical carrier the carrier may be any known carrier in the cosmetic and medical arts, e.g. any gel, cream, lotion, ointment, liquid or non liquid carrier, emulsifier, solvent, liquid diluent or other similar vehide whidi does not exert deleterious effect on the skin or other living animal tissue. Examples of suitable topical carriers indude _. . but are not limited to liquid alcohols, liquid glycols, liquid polyalkylene glycols, water, liquid amides, liquid esters, liquid lanolin and lanolin derivatives and similar materials. Alcohols indude mono and polyhydric alcohols, induding ethanol, glycerol, sorbitol, isopropanol, diethylene glycol, propylene glycol, ethylene glycol, hexylene glycol, mannitol and methoxyethanol. Typical carriers may also indude ethers, e.g. diethyl and dipropyl ether, methoxypolyoxyethylenes, carbowaxes, polyethyleneglycerols, polyoxyethylenes and sorbitols. Usually, the topical carrier indudes both water and alcohol in order to maximize the hydrophylic and lipophylic solubility. A typical carrier will comprise 75% ethanol or isopropanol and 15% water.

The topical carrier may also indude various ingredients commonly used in ointments and lotions and well known in the cosmetic and medical arts. For example, fragrances, antioxidants, perfumes, gelling agents, thickening agents such as carboxymethylcellulose, surfartants, stabilizers emollients, coloring agents and other similar agents may be present.

As illustrated by the examples which follow, the compositions of th present invention may contain well-known and currently used ingredients t form creams, lotions, gels and ointments which are dermatologicall

acceptable and non toxic. The composition may be applied as a gel, a crea an ointment, a lotion or the like.

A dry delivery system, as described in U.S. Patent Nos 3,742,95

3,797,494 or 4368,343 may be used. Solvents or devices as described in U.S. Patent Nos 5,064,654, 5,071,6 or 5,071,657 can also be used to facilitate transdermal penetration whe systemic effects are desired.

The compound can also be administered by the oral route. T compound in the present invention can be typically formulated wi conventional pharmaceutical excipients.. e.g. spray dri lactose an magnesium stearate into tablets or capsules for oral administration. Of cours taste-improving substances can be added in the case of oral administrati forms. When capsules for oral ingestion are desired, any pharmaceutic capsules known in the art may be filled with the 5α-redurtase inhibitors the invention, with or without additional diluents and other additiv discussed herein.

The active substance can be worked into tablets or dragee cores being mixed with solid, pulverulent carrier substances, such as sodium dtra calcium carbonate or dicalαum phosphate, and binders such as polyvin pyrrolidone, gelatin or cellulose derivatives, possibly by adding al lubricants such as magnesium stearate, sodium lauryl sulfate, "Carbowax" polyethylene glycol.

As further forms, one can use plug capsules, e.g. of hard gelatin, well as closed solf-gelatin capsules comprising a softner or plasticizer, e. glycerine. The plug capsules contain the active substance preferably in t form of granulate, e.g. in mixture with fillers, such as lactose, saccharo mannitol, starches, such as potato starch or amylopectin, cellulose derivativ or highly dispersed silicic acids. In solf-gelatin capsules, the active substan

is preferably dissolved or suspended in suitable liquids, such as vegetable oil or liquid polyethylene glycols.

The following non-limiting examples describe the preparation of typical cream, lotion, gel and ointment, respectively. In addition to thes vehides, one skilled in the art may choose other vehides in order to adapt t specific dermatologic needs.

EXAMPLE A. A typical lotion contains (W/W) 5% active compound 15% propylene glycol and 75% ethanol and water 5%.

EXAMPLE B. A typical gel contains (W/W) 5% active compound, 5 propylene glycol, 0.2% Carbomer 940 (available as Carbcpol 940 ^R from B.F

Goodrich), 40% water, 0.2% triethanolamine, 2% PPG-12-Buteh-16 (availabl as Ucon ^R fluid 50 from Union Carbide), 1% hydroxypropyl and 46.8% ethano

(95% ethanol-5% water).

EXAMPLE C. A typical ointment contains (W/W) 5% activ compound, 13% propylene glycol, 79% petrolatum, 2.9% glycerylmonostearat and 0.1% polylparaben.

EXAMPLE D. A typical cream contains (W/W) 5% active compoun 0.2% propylparaben, 5% lanolin oil, 7.5% sesame oil, 5% cetyl alcohol, 2 glyceryl monostearate, 1% triethanolamine, 5% propylene glycol, 0.1 Carbomer 940 ^R and 69.2% water.

The 5α-reductase inhibitors of the invention are preferably formulate into pharmaceutical compositions at conventional concentrations for 5 reductase inhibitors. The attending clinician may elect to modify th concentration and/or dosage in order to adjust the dose to the particul response of each patient.

When 5α-reductase activity inhibitors are administered in accordanc with the invention, they are preferably administered orally or parenterall Dosage preferably ranges from about 1 mg to about 1000 mg of acti

PCI7

- 21

expedient, i.e., 5α-redurtase inhibitor(s), per day per 50 kg of body weig most preferably from about 2.5 mg to about 500 mg per day per 50 kg body weight.

Concentration of active expedient varies in a known manner dependi upon the method of administering the pharmaceutical composition. composition suitable for oral administration may preferably indude at le one inhibitor of 5α-reductase activity wherein the total concentration of such inhibitors in said pharmaceutical composition is from about 1 % to 9 of the composition (by weight), and preferably from about 5% to about 2 The pharmaceutically acceptable diluent is preferably starch or lactose (w or without tartrazine).

When prepared for parental injertion, the inhibitor is preferably ad at a concentration between about 2.0 mg/ml and about 50 mg/ml (prefera about 5.0 mg/ml to about 20 mg/ml) into a carrier preferably selected fr the group consisting of saline, water, aqueous ethanol and oil.

In certain alternative embodiments, the pharmaceutical compositio the invention may be formulated for sustained release in accordance known techniques. The sustained release formulations are prefera prepared in a known manner appropriate for either oral, intramuscular subcutaneous administration.

When the pharmaceutical composition is for topical use, 5α-redurtase inhibitor(s) is preferably formulated together with a car selerted from the group consisting of propylene glycol, ethanol, isopropa and water at a concentration ranging from 0.5% to 10% by total weight of pharmaceutical composition. The composition for topical use may formulated, for example, as an ointment, a gel, a cream or a lotion, to applied to affected areas of the skin in need of treatment twice daily.

PCI7CA93/001

- 22 -

In some embodiments of the invention, the 5α-reductase inhibitors of the invention are used in combination with another active ingredient as part of a combination therapy. For example, the novel inhibitors may be utilized together with a separate antiandrogen which may be incorporated into the same pharmaceutical composition as the 5α-reductase inhibitor, or which may be separately administered. An active compound may possess both antiandrogenic and 5α-reductase inhibiting activity, and may be supplemented with another compound to reinforce either or both of these activities (e.g., another antiandrogen or another inhibitor of 5α-reductase). Combination therapy could also indude treatment with one or more compounds which inhibit the production of testosterone or its precursors.

When antiandrogen is used in a combination therapy in addition to the 5α-redudase inhibitors of the invention, the antiandrogen may be, for example:

Flutamide (systemic) EM 248 (topic)

The antiandrogen is formulated at conventional concentrations a administered at conventional dosages, e.g., at the same concentrations a dosages set forth above for the 5α-redurtase inhibitor.

The antiandrogen Flutamide is commercially available from Scheri Corp. (New Jersey). The antiandrogen EM-248 may be synthesized follows:

r. EM 2 8

Compound b

To a solution of testosterone 1 (288.43 g, 1.0 mole) in glacial acetic arid (3.5 L), ethanedithiol (85 ml, 1.01 mole) and boron trifluoride (800 ml) were added at 10 ^* C. The mixture was stirred at this temperature for 1 hour and poured over ice (2 kg). From this aqueous phase a white solid separated and was collected by filtration, washed with water (2x 2L) and air dried. Crystallization from methanol gave the pure compound b. Yield: 328.28 g (90%).

Compound c A solution of b (182.3 g, 0.5 mole) in dry dichloromethane (1.5 L) was added dropwise to a solution of pyridinium chlorochromate (150 g, 0.7 mole), molecular sieves 3A (200 g) and sodium acetate (25 g) at room temperature with mechanical stirring. After the addition was completed, the mixture was stirred for 16 hours and then diluted with diethyl ether (2 L) and filtered through silica gel in a fritted funnel. The filtrate was concentrated in vacuo and the resulting solid was crytallized from methanol to give the pure compound c. Yield: 158.7 g, (87%).

Compound d

2-(3- Butynyloxy)tetrahydro-2H-pyran (112.5 g, 0.729 mole) was added dropwise to a solution of methyllithium (500 ml of MeLi 1.4M in ether, .70 mole) in 1 L of anhydrous THF at -30 ^* C under argon atmosphere in a 5 L round bottom flask. After the addition was completed, the cooling bath was removed and the solution was allowed to stand at room temperature for 4 hours. The solution was cooled again at -30 'C and a solution of c (75 g, .207 mole) in 2.5 L of anhydrous THF was added dropwise. After the addition, the cooling bath was removed and the mixture was allowed to stand at room

temperature for 16 hours. To this mixture,100 ml of brine was added and t solution was diluted with ethyl acetate washed with brine and dried wi anhydrous MgS0 ₄ . The solvent was evaporated and a solid crystallized aft a short period of time. Hexane was added to complete the precipitation. T solid was then filtered and washed with hexane. The compound was us in the next step without further purification. Yield: 95.8 g (90%).

Compound e

A mixture of compound d (30 g, .058 mole) and methyliodide (65 1 mole) in methanol 96% (750 ml) was heated under reflux for 16 hours. T solvent was then removed in vacuo and the crude mixture was diluted with ethyl acetate (1 L). The organic phase was washed with NaOH 3% (3 500 ml) and dried over MgS0 . After the evaporation of the solvent the sol was washed with diethyl ether, filtered on a fritted funnel and washed aga with diethyl ether. This compound can be used without further purificati in the last step. Yield 65%.

17α-(chlorobutvnyl)-17β-hvdroxy 4-androsten-3-one (f, EM 248) A mixture of compound d (15 g, .04 mole), triphenylphosphine (21 .08 mole) and carbon tetrachloride (9.3, .06 mole) was heated under reflux 1 L of anhydrous dichloromethane for 10 hours. After the evaporation of t solvent the crude mixture was adsorbed on silica gel and chromatographi on silica gel (flash) with diethyl etheπhexane (70:30). The compound w further purified by crystallization in diethyl ether. Yield 85%.

A combination therapy involving 5α-reductase inhibitor a antiandrogen has the beneficial effect of inhibiting activation of androg receptors by two different mechanisms without significantiv reduri testosterone levels, the reduction of which mav cause undesirable side effe

in some patients. In appropriate cases, i.e. where prostate cancer or another androgen related disease is not responding acceptably to treatment, a concurrent therapy designed to decrease testosterone levels may also be utilized (e.g., surgical or chemical castration, for example, by administering a LHRH agonists or antagonists known in the art).

Inhibitors of testosterone 5α-redurtase of the formula:

include but are not limited to those set forth in Tabie I below:

TABLE I

Testosterone 5α-redudase inhibitors of the formula:

are not limited to those set forth in Table II beiow:

TABLE II

- 29

Testosterone 5α-reductase inhibitors of the formula:

indude but are not limited to those set ™+h «„ ,w ^T , „ compounds set forth below in Table m I and H as well as those

TABLE m

SUBSTITUTE SHEET

93/23053

-30-

SUBSTITUTE SHEET

53

-31

SUBSTITUTE SHEET

Except where otherwise indicated, 5α-reductase inhibition is measured by the following method. Plates having 24 dishes per unit are used. Into each dish were placed 100,000 cells from the human carcinoma metastatic prostatic cell line DU 145 (ATCC # HTB 81) in MEM medium containing 2% dextran charcoal-treated calf serum, 1% penicillin, 1% streptomycin and 1% non essential amino a ds. After 24 h, the medium was removed and replaced by 2.5 ml of MEM medium containing 2% dextran charcoal- treated calf serum, 10 nM of tritiated 4-androsten-3,20-dione and 1% of ethanol. Each dish had different concentrations of the 5α-reductase inhibitor being tested. The cells were incubated for 24 h at 37°C under an atmosphere of 5% C0 ₂ saturated with water. The extracellular medium was then removed, centrifuged at 1000 RPM for 10 min., and decanted in test tubes. To these test tubes was added 100 μl of ethanol containing 25 μg of androstanedione, 25 μg of 4-androstenedione, 25 μg of dihydrotestosterone and 25 μg of testosterone. The steroids were then extracted from the mixture by two extractions with 2 ml of diethyl ether. Phase separation was achieved by freezing of the aqueous phase. The organic phase was then evaporated, thus leaving a steroid residue which was dissolved in a few drops of methylene chloride and spotted on TLC plates (Whatman WH 4420222). After developing twice with a mixture of benzene-acetone (9:1), the spots were visualized by U.V. and gaseous iodine, cut, put into separate vials for each steroid and extracted for 15 min with 1 ml of ethanol. After addition of 10 ml of scintillation cocktail (NEN 989), the vials were shaked and counted.

The 5α-reductase activity is the sum of the transformation of 4-androstenedione to androstanedione and of the transformation of testosterone to dihydrotestosterone. Conversion of tπtiated 4-androsten-3,20-dione to other steroids in the presence of different concentrations of inhibitor and a constant concentration of radioactive 4-androstenedione is measured, and IC ₅₀ (i.e. the concentration of inhibitor required to inhibit 50% of 5α-reductase activity) values are then used to calculate Ki values of inhibition for each compound according to Cheng and Prusoff (Biochem. Pharmacol. 22, 3099-3108, 1973).

P

33

Set forth below are non-limiting examples of methods synthesizing 5α-reductase inhibitors for use in the present invention. Tho of skill in the art may readily alter these syntheses by known convention techniques to produce other 5α-reductase inhibitors of the invention.

EXAMPLES OF SYNTHESIS OF PREFERRED INHIBITORS OF STEROI 5α-REDUCTASE ACTIVITY

EXAMPLE 1

Preparation of 17β-(N-n-butyl-N-formamido)-4-methyl-4-az 5α-androstan-3-one (11, R ₁ =C ₄ H ₉ , EM 347)

Synthesis described in scheme 1

Preparation of 17β-hydroxy-5-oxo-A-nor-3,5-secoandrostan-3-oic Acid (1). a stirred mixture of the testosterone acetate (Steraloids Inc. Wilton NH US (200 g, 0.605 mol) in tert-butyl alcohol (2 L) was added a solution of sodiu carbonate (96.3 g, 0.908 mol) in 460 mL of water. The mixture was broug to reflux and a solution of sodium periodate (893.8 g, 4.176 mol) a potassium permanganate (70.8 g, 0.448 mol) in warm water (75 ^* C) was add gradually (1 h) while the reflux temperature was maintained. The reacti was cooled to 30 °C, and after 15 min the solids were removed by filtratio The solid was washed with 800 mL of water, and the combined filtrates we concentrated under reduced pressure to remove most of ter/-butyl alcoh (final volume 1.0 L). The aqueous residue was cooled and acidified to pH with concentrated hydrogen chloride solution. The aqueous solution w

P I

34 -

extracted with methylene chloride (4 X 800 mL) and the combined organic phase was washed with water, dried and concentrated to solid. Thus the solid obtained was subjected to acetate hydrolysis by refluxing with NaOH (34.3 g, 0.857 mol) in methanol (2.0 L) for 12 h. The reaction mixture was concentrated to 400 mL, diluted with water (600 mL) and addified to pH 3. The solid was filtered, washed with water and dried. The filtrate was extracted with methylene chloride (3 X 1.0 ), and the combined organic phases were concentrated to syrup. Both the predpitates and the syrup were swished with boiling EtOAc and cooled at 0 ^* C for overnight to give 125 g (67% yield) of colorless crystals; mp 205-207'C.

Preparation of 17β-hydroxy-4-methyl-4-aza-androst-5-ene-3-one (3). In a

Schlenk tube, MeNH ₂ was bubbled till saturation to a mixture of the seco add 1 (8.0 g, 25.974 mmol) in ethylene glycol (80 mL) at room temperature. The dear yellowish solution was heated gradually (3 ^* C/min) up to 180 °C and held at this temperature for 1 h. The reaction mixture was cooled to 10 °C and water (80 mL) was added with stirring. The solid was filtered, washed with water (20 mL) and dried to give 6.1 g of 3 (81%); mp 181-183 ^* C.

Preparation of 17β- ydroxy-4-methyl-4-aza-5α-androstan-3-one (5). A solution of the compound 3 (6 g, 20.7 mmol) in acetic add (99.9%, 130 mL) was ydrogenated in the presence of platinium oxide (600 mg) at 45 p.s.i., starting at room temperature and heated to 60 ^* C over 12 h. The reaction mixture was cooled and filtered. The catalyst was washed with acetic add (30 mL), and the combined filtrates were concentrated to a solid (5.5 g, 91%); mp 178-180'C

4-Methyl-4-aza-5α-androstan-3, 17-dione (7). The following method is th representative. To a stirred solution of compound 5 (7.3 g, 25 mmol) i methylene chloride (260 mL) was added pyridinium chlorochromate (8.1 37 mmol) and the mixture was stirred at room temperature for 3 h. Th contents were passed through Florisil (30-60 mesh) to remove the predpitat and the filtrates were washed with water (2 X 200 mL) and dried. Th resulting residue was purified by flash column chromatography to give th dione 7 (4.4 g, 61%); mp 126-128'C.

Preparation of 17β-lN-butyl)-amino-4-methyl-4-aza-5α-androstan-3-onε ( R _j =C ₄ H ₉ ). The following method is representative. To a mixture of dione (0.150 g, 0.495 mmol) and n-butylamine (0.040 g, 0. 54 mmol) i ,2-dichloroethane was added sodium triacetoxyborohydride (0.156 g, 0. mmol) followed by acetic add (0.03 g, 0.49 mmol) under argon at roo temperature. After 16 h, the reartion mixture was diluted with methyle chloride (15 mL) and washed with 1 N aqueous sodium hydroxide (2 X mL), followed by brine (20 mL), dried and solvent removed to give the cru produrt which was purified by flash column chromatography to provide t 17-N-butyl-derivative (0.110 g, 61 % yield).

Preparation of 17β-(N-«-butyl-N-formamido)-4-methyl-4-aza-5α-androsta 3-one (11, R ₁ =C ₄ H ₉ , FM 347). To a solution of formic acid (0.026 g, 0.5 mmol) in chloroform (1.5 mL) was added dropwise dicyclohexylcarbodiimi (DCC) (0.114 g, 0.56 mmol) in chloroform (1.5 mL) at 0°C. After 5 min t above solution was added to the compound 9 (0.10 g, 0.28 mmol) in pvridi (2 mL). The mixture was then stirred for 1 hours at room temperatu Evaporation of solvent was followed by addition of ether ga dicvclohexvlurea which was removed via filtration and the solid was wash

with ether. The combined filtrate was concentrated and purified by flash column chromatography to give the product 11, (EM 347) (0.075 g, 70%); ^~ NMR (CDC1 ₃ ): 80.66 (s,3 H), 0.74-1.42 (m, 11 H), 1.2-2.08 (m, 19 H), 2.37-2.48 (m, 2 H), 2.87 (s, 3 H), 3.04 (dd, 1 H, J=4, 13 Hz), 3.2-3.4 (m, 3H), 8.12 (s, 0.8H), 8.24 (s, 0.2H); ¹³ C NMR (CDCI ₃ ) δ 170.56, 164.54, 162.97, 68.59, 65.62, 51.99, 51.71, 44.11 36.85, 36.40, 34.12, 32.88, 30.64, 29.68, 29.04, 28.96, 25.20, 24.37, 22.86, 20.55, 20.21, 13.77, 12.34: . HRMS: calcd for C ₂₄ H ₄₀ N ₂ O ₂ , 388.3089; found 388.3147.

SCHEME 1

EXAMPLE 2

17β-(N-n-Amyl-N-formamido)-4-methyl-4-aza-5α-androstan- 3-one (11, R ₁ =C ₅ H ₁₁ , EM 401)

This synthesis is described in scheme 1

Preparation of 17β-(N-n amyl)-amino-4-methyl-4-aza-5α-androstan-3-one (9, R ₁ =C ₅ H ₁₁ ). To a mixture of dione 7 (3.4 g , 22.6 mmol) and w-pentylamine (1.07 g, 12.3 mmol) in 1,2-dichloroethane was added sodium triacetoxyborohydride (3.5 g, 16.7 mmol) followed by acetic add (0.68 g, 11.2 mmol) under argon at room temperature. After 16 h, the reaction mixture was diluted with methylene chloride (150 mL) and washed with 1 N aqueous sodium hydroxide (2 X 200 mL), followed by brine (200 mL), dried and solvent removed to give the crude product which was purified by flash column chromatography to provide the 17-N-n-amyl-derivative (2.5 g, 61 % yield).

Preparation of 17β(N-n-Amyl-N-formamido)-4-methyl-4-aza-5α-androstan 3-one (11, R ₁ =C ₅ H ₁₁ , EM 401). To a solution of formic acid (0.504 mL, 13.36 mmol) in chloroform (37 mL) was added dropwise dicydohexylcarbodϋmide (DCC) (2.75 g, 13.36 mmol) in chloroform (37 mL) at O'C. After 5 min., th above solution was added to the compound 9 (2.5 g, 6.68 mmol) in pyridin (20 L). The mixture was then stirred for 1 hours at room temperature Evaporation of solvent was followed by addition of ether gav dicyclohexylurea which was removed via filtration and the solid was washe with ether. The combined filtrate was concentrated and purified by flas column chromatography to give the compound 11, R ₁ =C ₅ H ₁₁ (EM-401) (2.

g, 93%) The NMR spectroscopy analysis gave a (4:1) mixture of t conformers, M. P. 149-151 ^* C; ^! H NMR (CDCI ₃ ): δ 0.67 (s ,3 H), 0.86 (s, 3 0.82-1.19 (m, 6 H), 1.21-1.42 (m, 11 H), 1.56-1.57 (m, 2 H), 1.69-1.91 (m, 4 1.92-1.97 (m, 3 H), 2.38-2.43 (m, 2 H), 2.89 (s, 3 H ), 3.0 (dd, 1 H, /= 3.2, 1 Hz), 3.21-3.28 (m, 3 H), 8.14 (s, 0.8 H), 8.2 (s, 0.2 H); ¹³ C NMR (CDC1 ₃ ): δ 1 .56, 164 8, 162.97, 68.54, 65.58, 61.98, 51.93, 51.66, 51.24, 46.69, 44.28, 37. 36.8, 36.37, 34.07, 32.83, 32.12, 29.64, 29.13, 29.04, 28.8, 28.19, 25.15, 24.33, 23. 22.84, 22.36, 20.51, 13.94, 2.75, 12.32; HRMS: calcd for C ₂₅ H ₄₂ 0 ₂ N ₂ , 402.32 found 402.3242.

EXAMPLE 3

By analogous methods to those described in example 1, the following compounds were synthesized.

EM 316: 17β-(N-methyl-N-foπnamido)-4-methyl-4-aza-5α-androstan-3- one (11, R ₁ =CH ₃ ). The product was prepared in 78% yield and the NMR spectroscopy analysis gave a mixture of two conformers, M.P. 194-196 ^* C; H NMR (CDCI ₃ ): δ 0.74 (s, 2.4 H), 0.75 (s, 0.6 H), 0.88 (s, 0.6 H), 0.89 (s, 2.4 H), 0.75-1.14 (m, 3 H), 1.26-1.47 (m, 6 H ), 1.60-1.90 (m, 7 H), 2.01-2.07 ⁽ m, 2 H), 2.41-2.46 (m, 2 H), 2.90 (s, 3 H), 2.92 (s, 3 H), 3.02-3.07 (dd, 1 H = 12.58, 3.2 Hz), 3.32 (t, 0.8 H, J = 9.6 Hz), 4.21 (t, 0.2 H, J = 10 Hz), 8.15 (s, 0.8 H), 8.18 (s, 0.2 H); ¹³ C NMR (CDCI ₃ ): δ 170.45, 164.20, 163.32, 68.95, 65.43, 61.36, 51.82, 51.37, 51.12, 45.50, 44.21, 37.10, 36.66, 36.26, 33.87, 33.58, 32.70, 29.59, 29.51, 28.92, 28.83, 25.04, 23.03, 22.84, 22.74, 21.49, 20.35, 13.20, 12.61, 12.21; HRMS: calcd for 346.2620; found, 346.2645.

EM 336: 17β-(N-Cydopropyl-N-formamido)-4-methyl-4-aza-5α-androstan - 3-one (11, R _t = cydo C ₃ H ₅ ). The product was prepared in 74% yield and the NMR spectroscopy analysis gave a mixture of two conformers, M.P. 163-165 ^* C; -H NMR (CDC13): δ 0.39-0.44 (m, 0.4 H), 0.61-0.85 (m, 10 H), 0.86-1.17 (m, 2 H), 1.18-1.41 (m, 7 H), 1.42-1.56 (m, 1 H), 1.57-2.06 (m, 6 H), 2.35 (dd, / = 4.5, 9.4 Hz, 2 H), 2.38-2.54 (m, 2 H), 2.85 (s, 3 H), 2.97 (dd, / = 3.4, 12.5 Hz, 1H), 3.24 (t, / = 8.7, 8.9 Hz, 0.4 H), 4.0 (t, / = 9.2, 9.5 Hz, 0.6 H), 8.27 (s, 0.4 H), 8.33 (s, 0.6 H). ¹³ C NMR (CDCI ₃ ): δ 170.6, 165.4, 163.5, 69.9, 65.6, 64.4, 51.9, 51.8, 51.3, 45.7, 44.2, 37.9, 37.5, 36.4, 34.2, 29.7, 29.3, 29.1, 29.0, 28.8, 25.3, 22.2, 20.7, 13.6, 12.3, 9.9, 8.1, 6.4, 6.2. HRMS: calcd for ^H^N.O,, 372.2796; found 372.2820.

EM 337: 17β-(N-Cyclohexyl-N-formamido)-4-methyl-4-aza-5α-androsta 3-one (11, R ₁ =cycloC ₆ H ₁₁ ). The product was prepared in 52% yield and N spectro-scopy analysis gave a (4:1) mixture of two conformers, M.P. 144-1 °C; ^] H NMR (CDC : δ 0.70 (s, 1.5 H), 0.77 (s, 1.5 H), 0.85 (s, 1.5 H), 0.87 1.5 H), 0.81-1.41 (m, 12 H),1.44-1.83 (m, 13 H), 1.90-2.04 (m, 2 H), 2.40 (dd = 4.6, 9.3 Hz, 2 H), 2.90 (s, 3 H), 2.99 (dd, / = 3.2, 12.4 Hz, 1 H), 3.16 (t, / 9.7, 9.9 Hz, 0.5 H), 3.70-3.82 (m, 0.5 H), 4.28 (t, / = 9.6, 9.9 Hz, 0.5 H), 8.30 0.5 H), 8.38 (s, 0.5 H). ¹³ C NMR (CDCI ₃ ): δ 170.7, 163.5, 163.1, 77.2, 66 65.7, 61.9, 55.4, 54.4, 52.4, 52.1, 51.4 44.7, 43.1, 37.2, 36.8, 36.5, 34.2, 34.1, 33 32.9, 30.9, 30.6, 29.8, 29.7, 29.3, 29.1, 29.0, 27.9, 26.9, 26.2, 26.0, 25.4, 25.3, 23 22.9, 20.: 20.5, 13.0, 12.6, 12.4; HRMS: calcd for C ₂₆ H ₄₂ N ₂ 0 ₂ , 414.3246 fou 414.3270.

EM 402: 17β-(N-n-Hexyl-N-foπnamido)-4-methyl-4-aza-5α-androstan-3 -o (11, R ₂ = C ₆ H ₁₃ ). The product was prepared in 70 % yield. The NMR analy gave a mixture of two conformers, M. P. 101-103 °C, -H NMR (CDCI ₃ ): δ 0. (s, 3 H), 0.86 (s, 3 H), 0.77-1.09 (m, 6 H), 1.22-1.42 (m, 10 H), 1.43-1.57 (m H), 1.60-1.82 (m, 5 H), 1.89-2.03 (m, 4 H), 2.38-2.43 (m, 2 H), 2.89 (s, 3 2.97-3.03 (dd, 1 H, /=12.4, 3.2 Hz), 3.18-3.28 (m, 2.4 H), 4.12 (t, 0.2 H, /=10 H 8.14 (s, 0.8 H), 8.2 (s, 0.2 H); ¹³ C NMR (CDCI ₃ ): δ 170.57, 164.49, 162.97, 68. 65.58, 61.99, 51.95, 51.66, 51.26, 46.72, 45.66, 44.32, 44.22, 37.24, 36.8, 36. 34.07, 32.83, 32.43, 31.32, 29.64, 29.19, 29.04, 28.95, 28.47, 26.64, 26.35, 25. 24.34, 23.23, 22.84, 22.49, 20.51, 13.92, 12.32; HRMS: calcd for C^H^C^ 416.3382, found, 416.3355.

EM 405: 17β-(N-iso-Amyl-N-formamido)-4-methyl-4-aza-5α-androstan-3 - (11, R _j = iso-C _j H _jj ). The product was prepared in 66 % yield. The N analysis gave a (4:1) mixture of two conformers, M.P. 87-89 °C, ^] H N

(CDCI3): δ 0.67 (s, 3 H), 0.77-1.06 (m, 12 H), 1.21-1.57 (m, 10 H), 1.71-1.80 (m, 4 H), 1.82-1.97 (m, 3 H), 2.38-2.43 (m, 2 H), 2.89 (s, 3 H), 2.97-3.01 (dd, 1 H, /= 12.4, 3.2 Hz), 3.20-3.29 (m, 1.8 H), 4.16 (t, 0.2 H, /=10 Hz), 8.13 (s, 0.8 H), 8.2 (s, 0.2 H); ^I3 C NMR (CDCI ₃ ): δ 170.57, 164.46, 162.91, 68.49, 65.58, 51.92, 51.63, 44.19, 42.72, 37.19. 36.80, 36.35, 34.07, 32.81, 29.64, 29.19, 29.04, 28.93, 26.28, 25.92, 25.15, 24.27, 22.84, 22.43, 20.51, 12.77, 12.32; HRMS: calcd for C ₂₅ H ₄₂ 0 ₂ N ₂ , 402.3245, found, 402.3230.

EM 407: 17β-(N-l-EthyIpropyl-N-formamido)-4-methyl-4-aza-5α-andros tan- 3-one (11, R=iso-C ₅ H _1:l ). The product was prepared in 50 % yield and the NMR analysis gave a (2.33:1) mixture of two conformers, M.P. 111-113 °C, ^~ H NMR (CDCI ₃ ): δ 0.74-1.2 (m, 15 H), 1.24-1.84 (m, 17 H), 1.95-2.1 (m, 2 H),2.41-2.42 (m, 2 H), 2.91 (s, 3 H), 2.99-3.1 (m, 1.7 H), 3.95 (t, 0.3 H, / = 10 Hz), 8.24 (s, 0.3 H), 8.48 (s, 0.7 H); ¹³ C NMR (CDCI ₃ ): δ 170.60, 63.88, 163.46, 66.28, 65.74, 65.62, 63.81, 52.85, 52.02, 51.89, 51.77, 44.94, 43.17, 37.24, 36.39, 34.22, 32.89, 29.75, 29.66, 29.07, 29.01, 28.89, 28.56, 28.47, 26.19, 25.32, 25.22,

23.25, 23.05, 22.98, 20, 78, 20.57, 13.25, 13.07, 12.36, 11.79, 11.44, 10.62; HRMS: calcd for C ₂₅ H ₄₂ 0 ₂ N ₂ , 402.3246, found 402.3265.

EM 422: 17β-(N-iso-Butyl-N-foπnamido)-4-methyl-4-aza-5-androstan-3 -one (11, R ₁ =iso-C ₄ H ₉ ). The product was prepared in 90 % yield and the NMR analysis gave a (4:1) mixture of two conformers, M.P. 52-54 ^* C, ^~ H NMR (CDCI ₃ ): δ 0.67 (s, 3 H), 0.85 (s, 3 H), 0.68-1.15 (m, 9 H), 1,21-1.38 (m, 6 H), 1.5-1.79 (m, 6 H), 1.81-1.99 (m, 3 H), 2.38-2.42 (m, 2 H), 2.88 (s, 3 H), 2.94-3.02 (dd, 1 H, / = 12.4, 3.3 Hz), 3.1-3.15 (dd, 0.2 H, /= 13.2, 5.7 Hz), 3.23 (t, 0.8, / =0.8 H), 3.32-3.39 (dd, 0.8 H, / =13.2, 6.6 Hz), 4.05 (t, 0.2 H, / =10 Hz), 8.15 (s, 0.2 H), 8.29 (s, 0.8 H); ^I3 C NMR (CDC1 ₃₎ : δ 170.57, 164.66, 162.82, 69.18, 65.57,

52.26, 51.89, 51.83, 5123, 45.99, 44.25, 37.16, 36.34, 32.81, 29.04, 28.92, 28.03,

27.12, 26.76, 25.12, 24.94, 23.05, 22.81, 20.17, 19.96, 19.78, 12.84, 12.33; HRM calcd for C^H^N^, 388.3089, found, 388.3069.

EM 423: 17β-(N-n-propyl-N-f ormamido)-4-methyl-4-aza-5α-androstan-3-on (11, R _j =C ₃ H ₇ ). The produrt was prepared in 82 % yield and the NM analysis gave a (4.5:1) mixture of two conformers, M.P. 127-129 °C; ¹ H NM (CDCI ₃ ) δ 0.65 (s, 3 H), 0.83 (s, 3 H), 0.69-1.13 (m, 6 H), 1.19-1.81 (m, 13 H 1.86-2.0 (m, 3 H), 2.35-2.4 (m, 2 H), 2.86 (s, 3 H), 2.94-3.0 (dd, 1 H, / = 12.4, 3. Hz), 3.10-3.28 (m, 1.82 H ), 4.1 (t, 0.18 H, / =10 Hz), 8.11 (s, 0.82 H), 8.17 ( 0.18 H); ^I3 C NMR (CDC δ 170.51, 164.43, 162.99, 68.51. 65.52. 51.89, 51.6 48.30, 45.82, 44.17, 36, 32, 34.03, 32,78, 29.58, 28.98, 28.89, 25.11, 24.31, 22.7 21.61, 20,47, 12.27, 11.24; HRMS: calcd for C ₂₃ H ₃₈ θ ₂ N ₂ , 374.2933, foun 374.2903.

EM-436: 17β-(N-Benzyl-N-formamido)-4-methyl-4-aza-5α-androstan-3-o n (11, R ₁ =CH ₂ C ₆ H ₅ ). The product was prepared in 80% yield. The NM analysis gave a mixture of two conformers (4.88:1), m.p. 89-91 °C, IR v cm (KBr): 1640, 1610; ^] H NMR (CDCI ₃ ): δ 0.74 (s, 3 H), 0.85 (s, 3 H), 2.37-2.42 ( 2 H), 2.87 (s, 3 H), 2.95-3.0 (dd, 1 H, J=12.5, 3.4 Hz), 3.28 (t, 0.8 H, J=9.8 Hz 4.18 (t, 0.2 H, J=9.7 Hz), 4.4 (d, 0.8 H _a , J=15.5 Hz), 4.5 (d, 0.4 H, J=3.8 Hz), 4. (d, 0.8 H _b , J=15.5 Hz), 7.1-7.3 ( , 5 H), 8.28 (s, 0.2 H), 8.42 (s, 0.8 H ¹³ C NMR (CDCI ₃ ): δ 170.38, 165.17, 162.93, 138.76, 137.38, 128.55, 128.3 127.27, 126.93, 125.93, 68.01, 65.42, 62.67, 51.80, 51.63, 51.20, 50.36, 47.28, 45.8 44.11, 37.39, 37.06, 36.29, 34.04, 32.75, 29.61, 29.49, 28.87, 25.04, 24.65, 23.2 22.72, 20.54, 12.95, 12.41, 12.23; HRMS: calcd for C ₂₇ H ₃₈ 0 ₂ N ₂ , 422.2933, foun 422.2924.

EXAMPLE 4

Preparation of 17β-(N-methyl-N-foπnamido)-4-methyl-4-aza-5α-androst- l-ene-3-one (17)

Preparation described in scheme 2

Preparation of 17β-(N-methyl-N-foπnamido)-4-methyl-4-aza-5α-androst-l- ene-3-one (17, R ₁ =CH ₃ , EM 314). The following method is representative. Bi≤(trimerhylsiiyi)trifiuoroacetamide (0.305 g, 1.185 mmol) was added to the mixture of formamide 11, R^CH _j (EM 316) (0.10 g, 0.289 mmol) and 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (0.066 g, 0.289 mmol) in dioxane (4 L) under nitrogen. After 4 h at 25 "C, the contents were heated at 110 "C for 24 h. The resulting dark red solution was pour into the stirred mixture of methylene chloride (6 mL) and 1% aqueous sodium bisulphite solution (1.8 mL). The heterogeneous mixture was filtered. The dark red organic layer was washed with 2 mL of 2N HC1 followed by brine, dried and concentrated. The crude mixture was purified by column chromatography to give 41 mg of the product 17 R _T =CH ₃ (EM 314) (41%); ^~ H NMR (CDCI ₃ ): δ 0.72 (s, 3H (78%)), 0.74 (s, 3H(22%)), 0.86-2.15 (m, 15H), 0.89 (s, 3H(22%)), 0.91 (s, 3H(78%)), 2.89 (s, 3H), 2.93 (s, 3H), 3.27-3.36 (m, 2H), 5.82-5.85(m, 3 H), 6,65 (d, 1H, J=ll Hz), 8.14-8.24 (m, 1H); HRMS: calcd for C ₂₁ H ₃₂ N ₂ 0 ₂ , 344.2463; found 344.2426.

SCHEME 2

EXAMPLE 5

By analogous methods to those described in example 4, the compounds 16 (i.e. EM 346), 18 and 19 (i.e. EM 420) were synthesized using the formamide 10 or the ureas 12 and 13 as starting material.

EXAMPLE 6

Preparation of 17β-N-(lN-cydopropyl-2N-phenylurea)-4-methyl 4-aza-5α-androstan-3-one (13, R _j ^H _g , R^CgHg, EM 374 )

Preparation described in scheme 1

Preparation of 17β-N-(lN-cyclopropyl-2N-phenylurea)-4-methyl-4-aza-5 androstan-3-one (13, R ₁₌ cydo C _j H^ ₂ =C ₆ H ₅ , EM 374). The followin method is representative. To a solution of compound 9 (Ri. cyclo C ₃ H ₅ ) (22 mg, 0.64 mmol) in THF (100 mL) was added N-methylmorpholine (0.107 m 0.975 mmol) followed by phenylisocyanate (0.1 mL, 0.9 mmol) at 0"C und argon. The mixture was stirred overnight at 0"C to room temperature. Th mixture was diluted with ethyl acetate and washed twice with 2N HCI, drie and solvent removed to give the crude product which was purified b column to give the pure product 13 (EM 374) (210 mg, 73%); ^] H NM (CDC1 ₃ ): δ 0.74-1.11 (m, 6H), 0.8 (s, 3 H), 0.86 (s, 3 H), 1.23-2.06 (m, 14H 2.34-2.65 (m, 4H), 2.9 (s, 3 H), 2.99 (dd, 1 H, J=4, 13 Hz), 4.06 (t, IH, J= 9. Hz), 7.0-7.42 ( , 5H); ¹³ C NMR (CDCI3): δ 170.72, 157.19, 139.09, 128.8 122.77, 119.49, 65.63, 52.04, 51.10, 45.57, 38.08, 36.35, 34.22, 32.79, 29.70, 29.0 27.79, 25.244, 23.43, 23.05, 20.72, 13.73, 12.35, 12.01, 9.96.

EXAMPLE 7

By analogous methods to those described in example 6, the following compounds were synthesized.

EM 373: 17β-N-(lN-cyclopropyl-2N-methylurea)-4-methyl-4-aza-5α- androstan-3-one (13, R _j =cydo ^H _g , R ₂ =CH ₃ ). The product was prepared in 68% yield, *H NMR (CDClg): δ 0.71 (s, 3 H), 0.82 (s, 3 H), 1.94-198 (dd, 1 H, / = 12.6, 3.4 Hz), 2.28-233 (m, 1 HO, 2.35-2.40 (dd, 2 H, / = 9.5, 4.8 Hz), 2.5-2.53 (q, 1 H, / = iθ.36 Hz), 2.76 (d, 3 H, / = 4.8 Hz), 2.87 (s, 3 H), 2.95-3.01 (dd, 1 H, / = 12.5, 3.4 Hz), 3.9 (t, 1 H, / = 10 Hz), 5.29 (q, 1 H, J=5 Hz); ¹³ C NMR (CDCI ₃ ): δ 170.66, 160.86, 67.74, 65.58, 52.01, 51.05, 45.16, 37.98, 36.31, 34.16, 32.75, 29.66, 28.96, 27.37, 25.21, 23.32, 22.94, 20.68, 13.61, 12,29, 11.43, 9.51; MS: m e (% rel. int.) 344 (M ⁺ -57).

EM 392: 17β-N-(lN-cyclopropyl-2N-ethylurea)-4-methyl-4-aza-5α-andr ostan- 3-one (13, R ₁ =cydo-C ₃ H ₅ , R ₂ =C ₂ H ₅ ). The product was prepared in 78% yield, ^~ H NMR (CDCI ₃ ): δ 0.70 (s, 3 H), 0.81 (s, 3 H), 1.08 (t, 3 H, / = 7 Hz), 1.94 (dd, 1 H, / = 12.4, 3.2 Hz), 2.25-2.31 (m, IH), 2.36 (dd, 1 H, / = 9.5, 4.8 Hz), 2.42-2.57 (q, 1 H, / =1 0 Hz), 2.86 (s, 3 H), 2.95-3.19 (dd, 1 H, / = 12.5, 3.4 Hz), 3.20-3.23 (m, 2 H), 3.9 (t, 1 H, / = 10 Hz), 5.27 (t, 1 H, / = 5 Hz); ¹³ C NMR (CDCI ₃ ) δ 170.60, 160.03, 67.50, 65.55, 51.95, 50.96, 45.31, 37.95, 36.26, 35.27, 34.10, 32.70, 29.61, 28.92, 27.18, 25.17, 2328, 22.90, 20.64, 15.47, 13.58, 12.26, 11.64, 9.57; HRMS: calcd for C^H^NgO^ 415.319, found, 415.318.

EM 408: 17β-N-(lN-methyl-2N-phenylurea)-4-methyl-4-aza-5α-androsta n- 3-one (13, R-^Oi,, R ₂ = C ₆ H ₅ ). The product was obtained in 87 % yield, ^T H NMR (CDCI ₃ ): δ 0.73 (s, 3 H), 0.86(s, 3 H), 2.4 (dd, 2 H, / = 9.5, 4.7 Hz), 2.90

(s, 3 H), 2.96 (s, 3 H), 2.96-3.0 (dd, 1 H, / = 12.5, 3.4 Hz), 4.24 (t, 1 H, / = 1 Hz), 6.53 (s, 1 H), 6.98 (t, 1 H, / = 7 Hz), 7.24 (t, 2 H, / = 7 Hz), 7.36 (d, 2 H / = 7 Hz); ¹³ C NMR (CDC . δ 170.66, 156.37, 139.24, 128.69, 122.70, 119.79 65,55, 63.96, 51.92, 51.17, 44.91, 37.35, 36.34, 33.92, 32.75, 31.58, 29.66, 29.03 28.95, 25.19, 23.11, 20.50, 13.10, 12.30; HRMS: calcd for C ₂₇ H ₃₉ N ₃ 0 ₂ , 437.2804 found, 437.2823.

EXAMPLE 8

Preparation of 17β-N-(lN-cydopropyl-2N-methylthiourea)-4-methyl-4-aza- 5α-androstan-3-one (15, EM 379)

The preparation is analogous to the preparation of compounds 13 in example 6 (see scheme 1), but using phenylisothiocyanate as reagent in the step converting compound 9 to compound 15.

EXAMPLE 9

Preparation of 17α-allyl-17β-hydroxy-4-methyl-4-aza-5α-androstan-3-one (2 R ₃ =C ₃ H ₅ , EM 322).

Preparation described in scheme 3

Preparation of 17α-allyH7β-hydroxy-4-methyl-4-aza-5α-androstan-3-one (2 R ₃ SC ₃ H ₅ , EM 322). The following method is representative. To a solution compound 7 (see scheme 1) (0.1 g, 0.328 mmol) in THF (10 mL) was adde allylmagnesium bromide (394 μL, 0.394 mmol) at -78 ^* C. After addition th contents were stirred for 1 h and workup as usual to provide the crud product which was purified by column chromatography to give the pur product EM 322 (77 mg, 67 %); ^~ H NMR (CDCI ₃ ): δ 0.68-1.0 (m, 2 H), 0.84 ( 6 H), 1.14-1.66 (m, 11 H), 1.77-2.06 (m, 5 H), 2.14-2.2 (m, 1 H), 2.28-2.36 ( 1 H), 2.42-2.48 (m, 2 H), 2.86 (s, 3 H), 2.94-2.99 (dd, 1 H, J=4, 13 Hz), 5.14 (d 1 H, J=17, 2 Hz), 5.2 (dd, 1 H, 13, 2 Hz), 5.91-6.06 (m, 1 H); ¹³ C NMR (CDC1 ₃ δ 170.70, 134.85, 118.99, 82.13, 65.70, 51.91, 50.13, 46.33, 41.75, 36.45, 35.1 34.78, 32.94, 31.63, 29.95, 29.03, 25.31, 23.55, 20.77, 14.55, 12.37; HRMS: calc for C ₂₂ H ₃₅ N0 ₂ , 345.2668; found, 345.2658.

SCHEME3

EXAMPLE 10

Preparation of 17α-propyl-17β-hydroxy-4-methyl-4-aza-5α-androstan-3-o (21, R ₃ =C ₃ H ₇ , EM 378). Same preparation as the preparation of compoun 21 in example 9, but using propylmagnesium bromide instead allylmagnesium bromide as reagent.

EXAMPLE 11

Preparation of 17α-allyl-17β-hydroxy-4-aza-5α-androstan-3-one (20, R^C _j EM 441)

Same preparation than the preparation of compounds 21 in example 9 using the compound 6 as starting material .

EXAMPLE 12

Synthesis of 17α-(4-bromo-butynyl)-17β-hydroxy-4-aza-5α-androstane-3-o ne (24, x=2, P=Br, EM 465) (scheme 4)

Preparation described in scheme 1 and scheme 4

Preparation of 17β-hydroxy-4-aza-androst-5-ene-3-one (2). Referring first to sheme 1, in a pressure apparatus , NH ₃ was bubbled till saturation to a mixture of the seco acid 1 (6.0 g, 18 mmol) in ethylene glycol (60 mL) at room temperature. The dear yellowish solution was heated gradually (3 "C/min) up to 180 ^* C and held at this temperature for 1 h. The reaction mixture was cooled to 10 ^* C and water (80 mL) was added with stirring. The solid was filtered, washed with water (20 mL) and dried to give 4.5 g of 2.

Preparation of 4-aza-5α-androstan-3,17-dione (6). A solution of the compound 2 (160 g, 0.5 mol) in acetic add (500mL) was hydrogenated at 60 psi using Pt02 (15 g) as catalyst at 60 ^* C for 60 min After cooling and filtering, the catalyst was washed with acetic add and the solvent removed. The residue dissolved in methylene chloride was washed with IN sulfuric add, brine, saturated sodium bicarbonate, and brine. The organic phase was dried, filtered, and evaporated. The residue was chromatographed on silica gel. Elution with ethyl acetate/hexane gave crystalline compound which was treated with 3% methanolic sodium hydroxide solution at reflux for 90 min. After usual work up the obtained residue was dissolved in acetone (500 mL) cooled to O'C and Jones' reagent was added (8N-chromic add solution, 65 mL). After 15 min., isopropanol was added and the mixture was concentrated

under vacuo. Water was added and the mixture was extracted with ethy acetate. The organic layers were washed with brine, dried and evaporated t dryness. The chromatography on silica-gel of the residue with ethyl acetat / hexane as eluent gave the aza-ketone 6 (152 g) of which structure wa determined by spectroscopic mean.

17α-(4-tetrahydropyranyloxy-butynyl)-17β-hydroxy-4-aza- 5α-androstan-3-on (22, x=2). Referring now to scheme 4, to anhydrous THF (140 mL) at -60 ° was added methyl lithium (1.4 M, 100 mL) and a solution o 4-tetrahydropyranyloxybutyne (21.6 g, 140 mmol).To this mixture warmed u to room temperature, stirred for 2h, and cooled to -60 °C was added dropwis a solution of above aza-ketone 6 (9.6 g, 30 mmol) in THF (350 mL), and th mixture was warmed up to room temperature and stirred for 16h. After usua work up, the compound 22 (x=2) was purified by silica-gel chromatograph and its structure determined by spectroscopic mean. In a similar fashio 17α-(4-tetrahydropyranyloxybutynyl)-17β-hydroxy-4-methyl-4 -aza-5α androstan-3-one (23, x=2) was prepared.

17α-(4-bromo-butynyl)-17β-hydroxy-4-aza-5α-androstane- 3-one (24, P=B x=2, EM 465). To a solution of aza-diol 24, (P=OH) (179 mg, 0 mmol obtained by addic hydrolysis of the compound 22, and triphenylphosphin (262 mg, 1 mmol) in methylene chloride (15 mL) at 0°C was added CBr ₄ (24 mg, 1 mmoDand the mixture was stirred for 2h at room temperature, th solvent was removed and the compound 24 (P=Br, x=2 EM 465) was purifie by flash silica-gel chromatography and this structure determined b spectroscopic mean. In a similar fashion, 17α-(4-bromo-butvnyl

17β-hydroxy-4-methyl-4-aza-5α-androstane-3-one (25, x=2, P=Br, EM 321) was prepared.

Preparation of 17α-(4-iodobutynyl)-17β-hydroxy-4-methyl-4-aza-5α- androstan-3-one (25, x=2, P=I, EM 320). To a mixture of 17α-(4- bromobutynyl)-17β-hydro3^-4-methyl-4-aza-5α-androstan-3-on e (25, x=2, P=B _j , EM 321) (200 mg, 0.471 mmol) in acetone (16 mL) was added sodium iodide (92 mg, 0.6132 mmol) and the mixture was refluxed for 12 h. Removal of acetone and usual workup provided the crude product which was purified by u iumn chromatography to give the pure produrt (EM 320) (137 mg.60%); ^] H NMR (CDClg): δ 0.83 (s, 3 H), 0.88 (s, 3 H), 2.41-2.46 (m, 2 H), 2.83 (t, 2 H, J=6.84 Hz), 2.91 (s, 3 H), 3.0-3.06 (dd, 1 H, J=3.4, 12.5 Hz), 3.24 (t, 2 H, J=7.1 Hz); HRMS: calcd for C^^INC^, 483.1635; found, 483.1634.

SCHEME 4

25 R=CH ₃

EXAMPLE 13

In a similar fashion, to Example 12, the following compounds described in Table IV are prepared using different tetrahydropyranyloxy-alkynes and different carbon tetrahalides.

TABLE IV

EXAMPLE 14

Preparation of 17β-(N-«-butyl-N-formamido)-4, 6-dimethyl-4-az 5α-androstan-3-one (31, EM 548)

Preparation described in Scheme 5.

Preparation of 17β-acetoxy-6α-methyl -4-androsten-3-one (30). Testostero (50 g) (Schering A.G. Germany) was treated in an apparatus equipped wi a Dean-Stark, distillation apparatus, by die.thylene glycol in toluene in t presence of a catalytic amount of p-toluenesulfonic add at reflux for 16h. T resulting ketal 26 was oxidized by monoperoxyphtalic add, magnesium s (Aldrich Chem. Comp, Inc. Milwaukee Wis USA ) in iso-propanol at 50 °C f lh. After removal of the solvent and crystallization the mixture of epoxy 27 was heated at reflux with large excess methyl magnesium iodide tetrahydrofuran for 18h. The 6β-methyl ketal 28 was deprotected standing overnight at room temperature with a mixture of acetone / wa (9 : 1 ). The hydroxy ketone 29 thus obtained was mono dehydrated heating in a mixture of 0.1 N sodium hydroxide in methanol and t 17β-hydroxyl was acetylated by usual manner (acetic anhydride pyridine).The 6-methyl enone 30 was thus obtained (27 g) and characteriz by spectroscopy.

17β-(N-n-butyl-N-formamido)-4, 6-dimethyl-4-aza-5α-androstan-3-one ( EM 548). The 6-methyl enone 30 is transformed into 17β-(N-n-butyl- formamido)-4, 6-dimethyl-4-aza-5α-androstan-3-one (31, EM 548) by a proc analogous to the process described in the example 1 for conversion compound testosterone acetate to compound 11.

SCHEME5

31

EXAMPLE 15

Preparation of 17β-(N-alkyl-N- ormamido)-4-methyl-7α-hydroxyalkyl-4-a 5α-androstan-3-one (34)

Synthesis is described in scheme 6

The following method is representative. The commerdal 17β-acetoxy 6-androstadien-3-one 32 (Steraloids Inc. Wilton, NH, USA) is treated by an excess of TBDMSO(CH ₂ ) _r Cu(CN)Li (prepared from TBDMSO(CH ₂ ) _x I ,t-B and CuCN) in ether and tetrahydrofuran in presence of trimethylsilyl chlori at -78 °C. The mixture is heated to room temperature and usual work up made. The resulting compound 33 is transformed into 17β-(N-alkyl- formamido)-4-methyl-7α-hydroxyalkyl-4-aza-5α-androstan-3-o ne (34) by process similar to the process described in the example 1. The last step is t deprotection of the silyl group.

SCHEME 6

34

EXAMPLE 16

Preparation of alkylamide, alkylsulfamide and alkylphosphite derivative of 17β-N-alkyl-4-methyl-4-aza-5α-androstan-3-one

Synthesis is described in scheme 7

The compounds 8 or 9 prepared in accordance with scheme 1 are treated room temperature by acyl chloride in tetrahydrofuran using a 2 fold exces of K ₂ C0 ₃ powder as base. After usual work up, the compounds 35 or 36 ar obtained. The use of sulfonyl chloride instead of acyl chloride gives in th same conditions respectively the compounds 37 or 38 , and the use of dialk chloro phosphate gives respectively the compounds 39 or 40.

EM 424: 17β-(N-n-butyl-N-acetamido)-4-methyl-4-aza-5α-androstan-3- on

The product was prepared in 85 % yield. The NMR analysis gave a (1.85: mixture of two conformers, M.P. 152-154 °C, ^] H NMR (CDC1 ₃ ): δ 0.67 (s, 1.9 H), 0.74 (s, 1.05 H), 0.80-1.0 (m, 9 H), 1.07-1.69 (m, 12 H), 1.71-1.91 (m, 5 H 1.99-2.07 (m, 1 H), 2.12 (s, 1.05 H), 2.14 (s, 1.95 H), 2.42-2.45 (m, 2 H), 2.84-3. (m, 0.35 H), 2.91 (s, 3 H), 3.0-3.05 (dd, 1 H, /= 12.3, 3.2 Hz), 3.11-3.18 (m, 0. H), 2.24-2.29 (m, 0.65 H), 3.68-3.71 (m, 0.7 H), 4.49 ( , 0.65 H, / = 9.9 Hz); ¹³ NMR (CDC1 ₃ ): δ 171.43, 171.14, 170.54, 67.29, 65.53, 62.27, 51,05, 46, 36, 45.5 44.55, 44.34, 37.10,36.31, 33.96, 33.01, 32.75, 30.87, 29.67, 29.22, 28.98, 28.9 25.18, 24.59, 23.65, 23.17, 22.70, 22.33, 20.49, 20.34, 20.04, 13.66, 12.94, 12.7 12.29; HRMS: calcd for C ₂₅ H ₄₂ N ₂ 0 ₂ , 402.3246, found, 402.3234.

SCHEME 7

Additional examples of pharmaceutical compositions are set forth below:

EXAMPLE 17 - Composition suitable for injection

EXAMPLE 18 - Topical lotion

PCI7CA93/00192

- 66 -

EXAMPLE 19 - A tablet

The terms and descriptions used herein are preferred embodiments set forth by way of illustration only, and are not intended as limitations on the many variations which those of skill in the art will recognize to be possible in practicing the present invention as defined by the daims.