Compounds of the formula I ##STR1## wherein R.sub.1 hydrogen or methyl; R.sub.2 is methyl; R.sub.3 hydrogen, Alk-R.sub.4, X-Alk, C.sub.1-6 -X-Alk, XCO-Alk, CN, CO-Alk, CO-Ar, CO-O-Alk, CO-NH-Alk, CO-NH-Ar, CO-NH-Het and CO-N(Alk).sub.2 ; Alk is C.sub.1-12 straight or branched alkyl; Ar is phenyl, Het is piperidinyl, piperizinyl, pyrrolidinyl, pyrrolyl, furanyl or thienyl and X is O, N or S. Such compounds are useful in the treatment of pathologic conditions that benefit from blockade of isozymes of 5.alpha.-reductase.

FIELD OF THE INVENTION 
The present invention provides novel compounds, novel compositions, methods 
of their use and methods of their manufacture, where such compounds are 
generally pharmacologically useful as agents in therapies whose mechanism 
of action rely on the selective inhibition of the isozyme 5.dbd.-reductase 
1. 
BACKGROUND OF THE INVENTION 
Certain undesirable physiological manifestations, such as acne vulgaris, 
seborrhea, female hirsutism, male pattern baldness (alopecia) and benign 
prostatic hyperplasia, are the result of hyperandrogenic stimulation 
caused by an excessive accumulation of testosterone or similar androgenic 
hormones in the metabolic system. Early attempts to provide a 
chemotherapeutic agent to counter the undesirable results of 
hyperandrogenicity resulted in the discovery of several steroidal 
antiandrogens having undesirable hormonal activities of their own. The 
estrogens, for example, not only counteract the effect of the androgens 
but have a feminizing effect as well. Non-steroidal antiandrogens have 
also been developed, for example, 
4'-nitro-3'-trifluoromethyl-isobutyranilide. See Neff, et al., Endocrinol. 
1972, 91 (2). However, these products though devoid of hormonal effects, 
compete with all natural androgens for receptor sites, and hence have a 
tendency to feminize a male host or the male fetus of a female host and/or 
initiate feed-back effects which would cause hyperstimulation of the 
testes. 
The principal mediator of androgenic activity in some target organs, e.g. 
the prostate, is 5.alpha.-dihydrotestosterone, formed locally in the 
target organ by the action of testosterone-5.alpha.-reductase. Inhibitors 
of testosterone-5.alpha.-reductase will serve to prevent or lessen 
symptoms of hyperandrogenic stimulation in these organs. It is now known 
that a second 5.alpha.-reductase isozyme exists, which interacts with 
epidermal tissues, especially in scalp tissues. This form is 
conventionally designated as 5.alpha.-reductase 1, while the isozyme that 
principally interacts with the prostatic tissues is designated as 
5.alpha.-reductase 2. Both isozymes are active, to differing extents, in 
the prostatic tissues. In the treatment of hyperandrogenic disease 
conditions e.g. benign prostatic hyperplasia (BPH), it would be desirable 
to have one drug entity which is active against both isozymes in the 
prostate to significantly inhibit dihydrotesterone production, while also 
having another drug entity which is highly selective for inhibiting the 
isozyme 5.alpha.-reductase 1 associated with the scalp, for use in 
treating conditions of the skin and scalp, e.g. acne and alopecia in males 
and hirsutism in females. Additionally, such a selective 
5.alpha.-reductase 1 inhibitor could also be used in combination with 
finasteride (PROSCAR.RTM.), which is highly selective for 
5.alpha.-reductase 2, for combination therapy in the treatment of BPH. 
Therefore, it is an object of this invention to provide compounds that 
have sufficient activity in the inhibition of one or both 
5.alpha.-reductase isozymes. It is an additional object of this invention 
to provide compounds that are useful in the treatment and/or prevention of 
benign prostatic hyperplasia. It is an additional object of this invention 
to provide compounds that are useful in the treatment of female hirsutism, 
male pattern baldness, acne, androgenetic alopecia, prostatic cancer, and 
insufficient plasma levels of high density lipoproteins. The compounds of 
the invention have utility in one or more of the aforementioned areas. 
SUMMARY OF THE INVENTION 
The compounds of the present invention are those of the general structural 
formula I: 
##STR2## 
or a pharmaceutically acceptable salt or ester thereof, wherein 
R.sub.1 is selected from the group consisting of hydrogen and methyl; 
R.sub.2 is methyl; 
R.sub.3 is selected from the group consisting of hydrogen, Alk-R.sub.4, 
X-Alk, C.sub.1-6 -X-Alk, XCO-Alk, CN, CO-Alk, CO-Ar, CO-0-Alk, CO-NH-Alk, 
CO-NH-Ar, CO-NH-Het and CO-N(Alk).sub.2 ; 
Alk is C.sub.1-12 straight or branched alkyl; 
Ar is phenyl 
Het is selected from the group consisting of piperidinyl, piperizinyl, 
pyrrolidinyl, pyrrolyl, furanyl and thienyl; 
X is selected from the group consisting of O, N and S.

DETAILED DESCRIPTION OF THE INVENTION 
Salts encompassed within the term "pharmaceutically acceptable esters and 
salts" refer to non-toxic esters and salts of the compounds of this 
invention which are generally prepared by reacting the free base with a 
suitable organic or inorganic acid. Representative salts and esters 
include the following: 
______________________________________ 
Acetate Lactobionate 
Benzenesulfonate Laurate 
Benzoate Malate 
Bicarbonate Maleate 
Bisulfate Mandelate 
Bitartrate Mesylate 
Borate Methylbromide 
Bromide Methylnitrate 
Calcium Edetate Methylsulfate 
Camsylate Mucate 
Carbonate Napsylate 
Chloride Nitrate 
Clavulanate N-methylglucamine 
Citrate ammonium salt 
Dihydrochloride Oleate 
Edetate Oxalate 
Edisylate Pamoate (Embonate) 
Estolate Palmitate 
Esylate Pantothenate 
Fumarate Phosphate/diphosphate 
Gluceptate Polygalacturonate 
Gluconate Salicylate 
Glutamate Stearate 
Glycollylarsanilate 
Sulfate 
Hexylresorcinate Subacetate 
Hydrabamine Succinate 
Hydrobromide Tannate 
Hydrochloride Tartrate 
Hydroxynaphthoate Teoclate 
Iodide Tosylate 
Isothionate Triethiodide 
Lactate Valerate 
______________________________________ 
The term "pharmacologically effective amount" shall mean that amount of a 
drug or pharmaceutical agent that will elicit the biological or medical 
response of a tissue, system, animal or human that is being sought by a 
researcher or clinician. 
The term "alkyl" shall mean straight or branched chain alkanes of one to 
ten total carbon atoms, or any specified numbers within this range. 
Whenever the term "alkyl" or "aryl" or their prefix root appears in a name 
of a substituent (e.g. aralkoxyaryloxy) it shall be interpreted as 
including those limitations given above for "alkyl" or "aryl". 
The compounds of the present invention can be administered in such oral 
dosage forms as tablets, capsules (each including timed release and 
sustained release formulations), pills, powders, granules, elixers, 
tinctures, suspensions, syrups and emulsions. Likewise, they may also be 
administered in intravenous (both bolus and infusion), intraperitoneal, 
subcutaneous or intramuscular form, all using forms well known to those of 
ordinary skill in the pharmaceutical arts. An effective but non-toxic 
amount of the compound desired can be employed as an antiandrogenic agent. 
The dosage regimen utilizing the compounds of the present invention is 
selected in accordance with a variety of factors including type, species, 
age, weight, sex and medical condition of the patient; the severity of the 
condition to be treated; the route of administration; the renal and 
hepatic function of the patient; and the particular compound or salt 
thereof employed. An ordinarily skilled physician or veterinarian can 
readily determine and prescribe the effective amount of the drug required 
to prevent, counter or arrest the progress of the condition. 
Oral dosages of the present invention, when used for the indicated effects, 
will range between about 0.05 to 1000 mg/day orally. The compositions are 
preferably provided in the form of scored tablets containing 0.5, 1.0, 
2.5, 5.0, 10.0, 15.0, 25.0 and 50.0 mg of active ingredient. Effective 
plasma levels of the compounds of the present invention range from 0.002 
mg to 50 mg per kg of body weight per day. Advantageously, compounds of 
the present invention may be administered in a single daily dose, or the 
total daily dosage may be administered in divided doses of two, three or 
four times daily. Furthermore, preferred compounds for the present 
invention can be administered in intranasal form via topical use of 
suitable intranasal vehicles, or via transdermal routes, using those forms 
of transdermal skin patches well known to those of ordinary skill in that 
art. To be administered in the form of a transdermal delivery system, the 
dosage administration will, of course, be continuous rather than 
intermittant throughout the dosage regimen. Other preferred topical 
preparations include creams, ointments, lotions, aerosol sprays and gels, 
wherein the concentration of active ingredient would range from 0.1% to 
15%, w/w or w/v. 
In the methods of the present invention, the compounds herein described in 
detail can form the active ingredient, and are typically administered in 
admixture with suitable pharmaceutical diluents, excipients or carders 
(collectively referred to herein as "carrier" materials) suitably selected 
with respect to the intended form of administration, that is, oral 
tablets, capsules, elixirs, syrups and the like, and consistent with 
conventional pharmaceutical practices. 
For instance, for oral administration in the form of a tablet or capsule, 
the active drug component can be combined with an oral, non-toxic 
pharmaceutically acceptable inert carder such as ethanol, glycerol, water 
and the like. Moreover, when desired or necessary, suitable binders, 
lubricants, disintegrating agents and coloring agents can also be 
incorporated into the mixture. Suitable binders include starch, gelatin, 
natural sugars such as glucose or beta-lactose, corn sweeteners, natural 
and synthetic gums such as acacia, tragacanth or sodium alginate, 
carboxymethylcellulose, polyethylene glycol, waxes and the like. 
Lubricants used in these dosage forms include sodium oleate, sodium 
stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium 
chloride and the like. Disintegrators include, without limitation, starch, 
methyl cellulose, agar, bentonite, zanthan gum and the like. 
The compounds of the present invention can also be administered in the form 
of liposome delivery systems, such as small unilamellar vesicles, large 
unilamellar vesicles and multilamellar vesicles. Liposomes can be formed 
from a variety of phospholipids, containing cholesterol, stearylamine or 
phosphatidylcholines. 
Compounds of the present invention may also be delivered by the use of 
monoclonal antibodies as individual carders to which the compound 
molecules are coupled. The compounds of the present invention may also be 
coupled with soluble polymers as targetable drug carders. Such polymers 
can include polyvinylpyrrolidone, pyran copolymer, 
polyhydroxypropyl-methacrylamide-phenol, 
polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysine 
substituted with palmitoyl residues. Furthermore, the compounds of the 
present invention may be coupled to a class of biodegradable polymers 
useful in achieving controlled release of a drug, for example, polylactic 
acid, polyepsilon caprolactone, polyhydroxy butyfic acid, polyorthoesters, 
polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or 
amphipathic block copolymers of hydrogels. 
The compounds of the present invention can be prepared readily according to 
the following reaction Schemes and Examples or modifications thereof using 
readily available starting materials, reagents and conventional synthesis 
procedures. In these reactions, it is also possible to make use of 
variants which are themselves known to those of ordinary skill in this 
art, but are not mentioned in greater detail. 
##STR3## 
The most preferred compounds of the invention are any or all of those 
specifically set forth in these examples. These compounds are not, 
however, to be construed as forming the only genus that is considered as 
the invention, and any combination of the compounds or their moieties may 
itself form a genus. The following examples further illustrate details for 
the preparation of the compounds of the present invention. Those skilled 
in the art will readily understand that known variations of the conditions 
and processes of the following preparative procedures can be used to 
prepare these compounds. All temperatures are degrees Celsius unless noted 
otherwise. 
EXAMPLE 1 
A solution of the known bis-acetate A (available from Sigma Chemical 
Company, Milwauke, Wis.), methylethyl ketone, n-hydroxyphthalimide (1.1 
eq), benzoyl peroxide (5 mol %) is warmed to 60.degree. C. while a stream 
of air is slowly bubbled through the yellow reaction mixture. After 5 
hours the reaction is cooled and concentrated. The concentrate is slurried 
in dichloromethane and filtered. The filtrate is then concentrated, 
disolved in pyridine and chilled to 0.degree. C. Acetic anhydride is added 
and the resulting solution stirred overnight at room temperature. The 
reaction is concentrated, slurried with methanol, warmed to 50.degree. C. 
for 20 minutes, cooled and filtered to yield 1. 
EXAMPLE 2 
The enone product of Example 1 is taken into anhydrous THF and cooled to 
0.degree. C. Methyllithium (6.5 eq, 1.5M in ether) is added dropwise and 
the resulting mixture stirred for 1 hour at 0.degree. C. The reaction is 
quenched with 1M ammonium chloride and extracted with dichloromethane. 
Drying over anhydrous sodium sulfate and removal of solvent affords 2. 
EXAMPLE 3 
The carbinol product of Example 2 is dissolved in toluene and the resulting 
solution is treated with cyclohexanone and aluminum triisopropoxide and 
warmed to 120.degree. C. for 15 hours. The reaction is then cooled to 
ambient temperature and quenched with water. Extraction with 
dichloromethane, drying over anhydrous sodium sulfate and removal of 
volatiles gives 3. 
EXAMPLE 4 
The dienone product of Example 3 is taken into a -50.degree. C. mixture of 
ammonia:THF:toluene (5:1:1) and treated with excess lithium metal for two 
hours. The excess lithium is then decomposed with 1,2-dibromoethane and 
the enolate quenched with ammonium chloride. The reaction is warmed to 
room temperature to remove the ammonia and diluted with more toluene. This 
mixture is washed with water then brine, and dried over anhydrous sodium 
sulfate. Removal of solvent gives the olefin 4. 
EXAMPLE 5 
The olefin product of Example 4 is dissolved in ethyl acetate and cooled to 
-20.degree. C. and ozone is bubbled through the solution for 3 hours. The 
blue solution is warmed to room temperature and treated with excess 30% 
hydrogen peroxide and vigorously stirred for 48 hours longer. The reaction 
is washed with water and concentrated to remove the ethyl acetate. The 
residue is partitioned between ether and 2N sodium hydroxide. The ether is 
extracted with 2N sodium hydroxide once more and the basic extracts 
combined. Dichloromethane is added to the aqueous base and the biphasic 
mixture cooled to 0.degree. C. and acidified to pH 2 with 2N sulfuric 
acid. The phases are separated and the aqueous extracted twice more with 
dichloromethane. After washing with brine, the combined organic extracts 
are dried over anhydrous sodium sulfate and concentrated to afford the 
acid 5. 
EXAMPLE 6 
The acid product of Example 5 is dissolved in anhydrous acetone and 
diisopropylethylamine (1.5 eq) is added. The solution is cooled to 
0.degree. C. and treated with ethyl chloroformate (1 eq) dropwise. After 
stirring for 2 hours the mixture is treated, dropwise, with sodium azide 
(2 eq) dissolved in a minimal amount of water. After stirring an 
additional hour, the reaction is quenched with ice water and extracted 
with toluene (.times.6), dried over anhydrous sodium sulfate and 
concentrated to 1/4 original volume. This concentrate is added to a 
100.degree. C. solution of benzyl alcohol (5 eq) in toluene and stirred 
for 15 min. or until gas evolution ceases. The reaction temperature is 
raised to reflux and stirring is continued for an additional 3 hours. The 
reaction is cooled and concentrated to afford the benzyl carbamate 6. 
EXAMPLE 7 
The carbamate product of Example 6 is dissolved in ethanol and palladium 
hydroxide (10 wt %) is added. The resulting black suspension is stirred 
under a hydrogen balloon for 24 hours, filtered to remove the catalyst and 
concentrated. The residue is dissolved in benzene and crushed 3 angstrom 
sieves are added. Stirring is continued for 16 hours and the mixture is 
filtered and concentrated to afford the vinylogous amide 7. 
EXAMPLE 8 
The vinylogous amide product of Example 7 is taken into dichloromethane and 
powdered 4 angstrom sieves (500 mg/g 7), N-methylmorpholine-N-oxide (1.5 
eq) and TPAP (5 mol %). The green mixture is stirred for 30 minutes during 
which time the reaction becomes black colored. The mixture is then 
filtered through a small pad of silica gel eluting with ethyl acetate to 
yield the ketone 8. 
EXAMPLE 9 
The ketone product of Example 8 is dissolved in anhydrous dichloromethane 
chilled to 0.degree. C. and treated with triflic anhydride (2.2 eq). After 
stirring for 2 hours the reaction is diluted with water and extracted with 
more dichloromethane. After washing with brine and drying over anhydrous 
sodium sulfate, the solvent is removed to afford triflate 9. 
EXAMPLE 10 
A solution of the triflate product of Example 9, triethylamine (2 eq), 
palladium acetate (0.03 eq), triphenylphosphine (0.06 eq), t-butylamine 
(40 eq) and DMF is purged with carbon monoxide for 5 minutes and then 
stirred under a balloon of CO for 24 hours. Ethyl acetate and water is 
added to the reaction, the phases separated and the water extracted once 
more with ethyl acetate. The combined organic solutions are washed with 
brine, dried over anhydrous sodium sulfate and concentrated to yield the 
amide 10. 
EXAMPLE 11 
The amide product of Example 10 is dissolved in ethanol and palladium 
hydroxide (10 mol %) is added. The resulting black suspension is stirred 
under a hydrogen balloon for 20 hours. The mixture is filtered and 
concentrated to give 11. 
BIOLOGICAL ASSAYS 
5.alpha.-reductase assay. 
The reaction mixture contained in a final volume of 100 .mu.l is: 40 mM 
buffer (human scalp, potassium phosphate, pH 6.5; human prostatic 
5.alpha.-reductase, sodium citrate, pH 5.5), 0.3-10 .mu.M.sup.14 C-T (or 
.sup.3 H-T), 1 mM DTT, and 500 .mu.M NADPH. Typically, the assay is 
initiated by the addition of 50-100 .mu.g prostatic homogenate or 75-200 
.mu.g scalp homogenate and incubated at 37.degree. C. After 10-50 min the 
reaction is quenched by extraction with 250 .mu.l of a mixture of 70% 
cyclohexane: 30% ethyl acetate containing 10 .mu.g each DHT and T. The 
aqueous and organic layers are separated by centrifugation at 14,000 rpm 
in an Eppendorf microfuge. The organic layer is subjected to normal phase 
HPLC (10 cm Whatman partisil 5 silica column equilibrated in 1 ml/min 70 % 
cyclohexane: 30 % ethyl acetate; retention times DHT, 6.8- 7.2 min; 
androstanediol, 7.6-8.0; T, 9.1-9.7 min). The HPLC system consists of a 
Waters Model 680 Gradient System equipped with a Hitachi Model 655A 
autosampler, Applied Biosystems Model 757 variable UV detector, and a 
Radiomatic Model A120 radio-activity analyzer. The conversion of T to DHT 
is monitored using the radioactivity flow detector by mixing the HPLC 
effluent with one volume of Flo Scint 1 (Radiomatic). Under the conditions 
described, the production of DHT is linear for at least 25 min. The only 
steroids observed with the human prostate and scalp preparations were T, 
DHT and androstanediol. 
Human Dermal Papilla Cell Assay 
The dermal papilla is a small group of cells at the base of each hair 
follicle, and it is presently thought that these cells are stem cells that 
form the basis for hair growth. These cells have been shown to have 5 
alpha reductase activity, and it is therefore possible to test inhibitors 
of 5 alpha reductase in these cell culture systems. 
Isolated and cultured dermal papilla cells are prepared according to the 
methods of Messenger, A. G., The Culture of Dermal Papilla Cells From 
Human Hair Follicles, Br. J. Dermatol. 110:685-689, 1984 and Itami, S. et. 
al., 5.alpha.-Reductase Activity In Cultured Human Dermal Papilla Cells 
From Beard Compared With Reticular Dermal Fibroblasts, J. Invest. 
Dermatol. 94:150-152, 1990. Beard dermal papilla cells and occipital scalp 
hair of two different individuals are used throughout the study. All 
experiments are performed at confluency after the fourth to sixth 
subculture. Confluent monolayers are rinsed twice with phosphate-buffered 
saline, scraped from dishes by rubber policemen, and collected into a 
centrifuge tube. The cell suspensions are centrifuged at 1,500 rpm for 10 
min at 4.degree. C. The pellets are resuspended in 20 mM Tris-HCl buffer, 
pH 7.5, at 4.degree. C., containing 250 mM sucrose, 1 mM MgCl.sub.2, and 2 
mM CaCl.sub.2, by vortexing and 10 passes through a 25-gauge needle., The 
crude homogenate is further homogenized by a teflon-glass homogenizer, and 
is used as the cell homogenate. For the study of subcellular localization 
of 5.alpha.-reductase, the cell homogenate is centrifuged at 800.times.g 
for 10 min to yield a crude nuclear pellet. The resultant supernatant is 
centrifuged at 10,000.times.g for 15 min to produce a crude mitochondrial 
pellet. The supernatant is centrifuged at 100,000.times.g for 60 min to 
yield a microsomal pellet and cytosol. Each particulate fraction is washed 
twice and resuspended in the buffer. 
A standard incubation mixture will consist-of 50 nM [.sup.3 
H]-testosterone, 1 mM NADPH, 100 mM sodium citrate, pH 5.5 or 100 mM 
Tris-HCl, pH 7.5, and 50 .mu.l of the cell homogenate, in a final volume 
of 100 .mu.l. Each tube contains 50-100 .mu.g of cellular protein. 
Incubation is carried out at 37.degree. C. for 30 min. During this 
incubation, the reaction is proportional to the time. For the study of 
optimum pH, citrate buffer is used at pH 4.5-6.5, and the Tris HCl buffer 
at pH 7.0-9.0. The protein content is determined by the method of Lowry, 
et. al., Protein Measurement With The Folin Phenol Reagen.t J. Biol. Chem. 
193:265-275, 1951. 
After incubation, the reaction is stopped by adding 4 times volume of 
chloroform-methanol (2/I:V/V) containing 110 .mu.g each of carder 
steroids. The extracted steroids are analyzed by thin-layer 
chromatographyl as previously described by Gomez, et. al., In Vitro 
Metabloism Of Testosterone-4-.sup.14 C and .alpha.-androstene-3, 
17-dione-4-.sup.14 C In Human Skin. Biochem. 7:24-32, 1968, and the purity 
of each steroid is determined by the recrystallization method. The 
activity of 5.alpha.-reductase is expressed by the sum of 
dihydrotestosterone, androstanediol and androstanedione formed. 
[1,2-.sup.3 H]-testosterone (55.2 Ci/mmol) is obtainable from New England 
Nuclear Corporation (Boston, Mass.) and unlabeled steroids can be 
purchased from Sigma Chemical Company (St. Louis, Mo.). Fetal calf serum 
is obtainable from Hazleton (Lenaxa, Kans.). All other chemicals are of 
reagent grade. 
Fuzzy Rat Acne Model 
Adult fuzzy rats are a variety of rat that has stunted hair growth, brown 
colored seborrhea coveting their entire back skin and abnormally increased 
sebum production after puberty that has been demonstrataed to be due to 
circulating androgens. 0.1, 0.05 and 0,025% solutions of a selected 
5.alpha.-reductase inhibitor of interest are prepared in a vehicle of 
propylene glycol, isopropanol, isopropyl myristate and water 
(50/30/2/18%), and is topically applied onto the backs of adult male fuzzy 
rats, 0.2 ml per animal daily for 4 weeks. Controls receive the vehicle 
alone and 5 of them are castrated. After 2 weeks seborrhea will be 
dose-dependently depleted and after 4 weeks bromodeoxyuridine (BrdU, 
200mg/kg) is intraperitoneally injected 2 hours before sacriice. The skin 
tissues are incubated with EDTA (20 mM) in phosphate buffer, 1.5 hours at 
37.degree. C. The pilo-sebaceous unit attached to the epidermis is striped 
from the dermis and fixed with formalin for immuno-staining of BrdU. DNA 
synthesis cells showing a BrdU-positive nucleus are located in the outer 
glandular border. The number of S-phase cells per lobe is determined with 
a micro-image apparatus. Using formalin fixed skin, frozen serial sections 
are stained with 1% osmium and the size of the lobes is measured. A 
positive inhibitor of skin 5.alpha.-reductrase will induce suppression of 
sebum production by inhibiting the rate of glandular cell turnover, and 
showing reduced lobular size. 
The present invention has the objective of providing suitable topical, oral 
and parenteral pharmaceutical formulations for use in the novel methods of 
treatment of the present invention. 
The compositions containing the compounds of the present invention as the 
active ingredient for use in the treatment of e.g., benign prostatic 
hypertrophy, prostatitis, and treatment and prevention of prostatic 
carcinoma, hyperandrogenic conditions, can be administered in a wide 
variety of therapeutic dosage forms in conventional vehicles for systemic 
administration, as, for example, by oral administration in the form of 
tablets, capsules, solutions, or suspensions, or by injection. The daily 
dosage of the products may be varied over a wide range varying from 0.5 to 
1,000 mg per adult human/per day. The compositions are preferably provided 
in the form of scored tablets containing 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 
25.0, and 50.0 milligrams of the active ingredient for the symptomatic 
adjustment of the dosage to the patient to be treated. An effective amount 
of the drug is ordinarily supplied at a dosage level of from about 0.002 
mg. to about 50 mg./kg. of body weight per day. Preferably the range is 
from about 0.01 mg. to 7 mg./kgs. of body weight per day. These dosages 
are well below the toxic dose of the product. For the treatment of 
androgenic alopecia, acne vulgaris, seborrhea, female hirsutism, the 
compounds of the present invention are administered in a pharmaceutical 
composition comprising the active compound in combination with a 
pharmacologically acceptable carder adapted for topical, oral or 
parenteral administration. 
These topical pharmaceutical compositions may be in the form of a cream, 
ointment, gel or aerosol formulation adapted for application to the skin. 
These topical pharmaceutical compositions containing the compounds of the 
present invention ordinarily include about 0.1% to 15%, preferably about 
5%, of the active compound, in admixture with about 95% of vehicle. 
The compounds of the present invention can be administered in such oral 
dosage forms as tablets, capsules (each including timed release and 
sustained release formulations), pills, powders, granules, elixers, 
tinctures, suspensions, syrups and emulsions. Likewise, they may also be 
administered in intravenous (both bolus and infusion), intraperitoneal, 
subcutaneous or intramuscular form, all using forms well known to those of 
ordinary skill in the pharmaceutical arts. An effective but non-toxic 
amount of the compound desired can be employed as a 5.alpha.-reductase 
agent. 
The dosage regimen utilizing the compounds of the present invention is 
selected in accordance with a variety of factors including type, species, 
age, weight, sex and medical condition of the patient; the severity of the 
condition to be treated; the route of administration; the renal and 
hepatic function of the patient; and the particular compound thereof 
employed. An ordinarily skilled physician or veterinarian can readily 
determine and prescribe the effective amount of the drug required to 
prevent, counter or arrest the progress of the condition. Optimal 
precision in achieving concentration of drug within the range that yields 
efficacy without toxicity requires a regimen based on the kinetics of the 
drug's availability to target sites. This involves a consideration of the 
distribution, equilibrium, and elimination of a drug. 
Oral dosages of the present invention, when used for the indicated effects, 
will range from about 0.01 mg. to 50 mg./kgs. of body weight per day. 
Advantageously, compounds of the present invention may be administered in 
a single daily dose, or the total daily dosage may be administered in 
divided doses of two, three or four times daily. Furthermore, preferred 
compounds for the present invention can be administered in intranasal form 
via topical use of suitable intranasal vehicles, or via transdermal 
routes, using those forms of transdermal skin patches well known to those 
of ordinary skill in that art. To be administered in the form of a 
transdermal delivery system, the dosage administration will, of course, be 
continuous rather than intermittant throughout the dosage regimen. 
In the methods of the present invention, the compounds herein described in 
detail can form the active ingredient, and are typically administered in 
admixture with suitable pharmaceutical diluents, excipients or carders 
(collectively referred to herein as "carrier" materials) suitably selected 
with respect to the intended form of administration, that is, oral 
tablets, capsules, elixirs, syrups and the like, and consistent with 
conventional pharmaceutical practices. 
For instance, for oral administration in the form of a tablet or capsule, 
the active drug component can be combined with an oral, non-toxic 
pharmaceutically acceptable inert carder such as ethanol, glycerol, water 
and the like. Moreover, when desired or necessary, suitable binders, 
lubricants, disintegrating agents and coloring agents can also be 
incorporated into the mixture. Suitable binders include starch, gelatin, 
natural sugars such as glucose or beta-lactose, corn sweeteners, natural 
and synthetic gums such as acacia, tragacanth or sodium alginate, 
carboxymethylcellulose, polyethylene glycol, waxes and the like. 
Lubricants used in these dosage forms include sodium oleate, sodium 
stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium 
chloride and the like. Disintegrators include, without limitation, starch, 
methyl cellulose, agar, bentonite, zanthan gum and the like. 
The compounds of the present invention can also be administered in the form 
of liposome delivery systems, such as small unilamellar vesicles, large 
unilamellar vesicles and multilamellar vesicles. Liposomes can be formed 
from a variety of phospholipids, such as cholesterol, stearylamine or 
phosphatidylcholines. 
Compounds of the present invention may also be delivered by the use of 
monoclonal antibodies as individual carriers to which the compound 
molecules are coupled. The compounds of the present invention may also be 
coupled with soluble polymers as targetable drug carders. Such polymers 
can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropyl- 
methacrylamide-phenol, polyhydroxyethylaspartamidephenol, or 
polyethyleneoxidepolylysine substituted with palmitoyl residues. 
Furthermore, the compounds of the present invention may be coupled to a 
class of biodegradable polymers useful in achieving controlled release of 
a drug, for example, polylactic acid, polyepsilon caprolactone, 
polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, 
polycyanoacrylates and cross-linked or amphipathic block copolymers of 
hydrogels. 
While the invention has been described and illustrated with reference to 
certain preferred embodiments thereof, those skilled in the art will 
appreciate that various changes, modifications and substitutions can be 
made therein without departing from the spirit and scope of the invention. 
For example, effective dosages other than the preferred dosages as set 
forth herein above may be applicable as a consequence of variations in the 
responsiveness of the mammal being treated for any of the indications for 
the compounds of the invention indicated above. Likewise, the specific 
pharmacological responses observed may vary according to and depending 
upon the particular active compound selected or whether there are present 
pharmaceutical carders, as well as the type of formulation and mode of 
administration employed, and such expected variations or differences in 
the results are contemplated in accordance with the objects and practices 
of the present invention. It is intended, therefore, that the invention be 
limited only by the scope of the claims which follow and that such claims 
be interpreted as broadly as is reasonable.