Aldehyde metabolite of 17.beta.-N-monosubstituted-carbamoyl-4-aza-5.alpha.- a

17.beta.-N-monosubstituted-carbamoyl-4-aza-5.alpha.-androst-1-en-3-ones of the formula: ##STR1## wherein the dotted line can represent a double bond when present, PA1 R.sup.1 is selected from hydrogen, methyl and ethyl and PA1 R.sup.2 is CONHC(CH.sub.3).sub.2 CHO, and PA1 Ra is methyl, are described as being useful for the treatment of benign prostatic hypertrophy.

BACKGROUND OF THE INVENTION 
The present invention is concerned with side chain aldehydes of 
17.beta.-N-alkyl carbamoyl-4-aza-5.alpha.-androst-1-en-3-one compounds as 
testosterone-5.alpha.-reductase inhibitors for the treatment of benign 
prostatic hypertrophy. 
The art reveals that certain undesirable physiological manifestations, such 
as ache vulgaris, seborrhea, female hirsutism, male pattern baldness and 
benign prostatic hypertrophy, are the result of hyperandrogenic 
stimulation caused by an excessive accumulation of testosterone or similar 
androgenic hormones in the metabolic system. 
It is now known in the art that the principal mediator of androgenic 
activity in some target organs is 5.alpha.-dihydrotestosterone, and that 
it is formed locally in the target organ by the action of 
testosterone-5.alpha.-reductase. It is also known that inhibitors of 
testosterone-5.alpha.-reductase will serve to prevent or lessen symptoms 
of hyperandrogenic stimulation. 
For example, U.S. Pat. Nos 4,377,584, 4,220,775, 4,760,071, 4,859,681 and 
5,049,562 of Rasmusson et al. describe a group of 
4-aza-17.beta.-substituted-5.alpha.-androstan-3-ones which are said to be 
useful in the treatment of hyperandrogenic conditions. Specifically, U.S. 
Pat. No. 4,760,071 describes finasteride, which is 
17.beta.-(N-tert-butylcarbamoyl)-4-aza-androst-1-ene-3-one, also known as 
PROSCAR.RTM., recently approved by the FDA for use in benign prostatic 
hyperplasia therapy. 
U.S. Pat. No. 4,845,104 issued Jul. 4, 1989, to Merck & Co., discloses 
oxidized analogs of 
17.beta.-N-(monosubstituted)carbamoyl-4-aza-5.alpha.-androstan-3-ones 
having utility as highly potent testosterone-5.alpha.-reductase inhibitors 
and being metabolites resulting from in vivo administration of 
7.beta.-(N-t-butylcarbamoyl)-4-aza-5.alpha.-androst-1-en-3-one. 
However, none of the cited references suggest that any of the novel- 
17.beta.-N-(monosubstituted) carbamoyl-4-aza-5.alpha.-androst-1-en-3-ones 
containing an aldehydes-substituted branched alkyl on the 17-position of 
the present invention would also be a metabolite or have utility in 
treating benign prostatic hypertrophy. In many cases, the metabolism of an 
active drug results in deactivation and/or excretion. However, in this 
case the compounds of the present invention maintain a high level of 
bioactivity in treated animals.

DESCRIPTION OF THE INVENTION 
The present invention is concerned with compounds of the formula I: 
##STR2## 
wherein the dotted line represents a double bond which can be present; 
R.sup.1 is hydrogen, methyl or ethyl, 
R.sup.2 is CONHC(CH.sub.3).sub.2 CHO, 
R' is hydrogen or methyl, 
R" is hydrogen or .beta.-methyl, 
R'" is hydrogen, .alpha.-methyl or .beta.-methyl, 
Ra is methyl. 
A preferred embodiment of the compounds applicable in the process of our 
invention is represented by the formula II: 
##STR3## 
where R.sup.1 is hydrogen or methyl and methyl groups of positions C-18 
and C-19 are present. 
The compounds of formula I of the present invention are prepared by a 
method starting with the known steroid of the formula 1 (See U.S. Pat. No. 
4,845,104, issued Jul. 4, 1989, for its synthesis and properties): 
##STR4## 
See the following Flowsheet which illustrates the stages of: (1) oxidizing 
said starting material 1 with e.g. pyridinium chlorochromate to produce 
the corresponding compound 2 and, if desired; (2) alkylating the A-ring 
nitrogen to introduce an N-methyl or N-ethyl substituent onto the A ring 
by conventional methodology, e.g. methyl iodide and sodium hydride in DMF 
at room temperature to produce 3; and/or (3) reducing the A-ring double 
bond of 2 by catalytic hydrogenation over Pd/C in EtOAc at room 
temperature under a hydrogen atmosphere to produce 4; and then alkylating 
the Ring A nitrogen by the methodology above to produce 5, or 
catalytically hydrogenating the double bond of 3 to produce 5. 
Alternatively, 2 or 4 can be alkylated with ethyl iodide. 
##STR5## 
The compounds of the present invention, prepared in accordance with the 
method described above, are, as already described, potent and selective 
antiandrogens in the treatment of benign prostatic hypertrophy (BPH), by 
virtue of their ability to specifically inhibit 
testosterone-5.alpha.-reductase. 
Accordingly, the present invention is particularly concerned with providing 
a method of treating BPH in human males by systemic or oral administration 
of the novel compounds of the present invention. 
The present invention is thus also concerned with providing suitable 
topical and systemic 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 BPH 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, of by intravenous 
injection. The daily dosage of the products may be varied over a wide 
range varying from 1 to 2,000 mg per person, preferably from 1 to 200 mg. 
and particularly preferred from 10 to 100 mg per person. The compositions 
are preferably provided in the form of scored tablets containing 0.1, 1, 
5, 10, 25, 50, 100, 150, 250, and 500 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 0.01 mg. to about 50 mg./kg. of body weight per day. 
Preferably the range is from about 0.1 mg. to 7 mg./kgs. of body weight 
per day and more preferably from about 0.5 mg to about 20 mg/kg of body 
weight per day. These dosages are well below the toxic dose of the 
product. Capsules containing the product of this invention can be prepared 
by mixing an active compound of the present invention with lactose and 
magnesium stearate, calcium stearate, starch, talc, or other carriers, and 
placing the mixture in gelatin capsule. Tablets may be prepared by mixing 
the active ingredient with conventional tableting ingredients such as 
calcium phosphate, lactose, corn starch or magnesium stearate. The liquid 
forms in suitably flavored suspending or dispersing agents such as the 
synthetic and natural gums, for example, tragacanth, acacia, 
methyl-cellulose and the like. Other dispersing agents which may be 
employed include glycerin, and the like. For parenteral administration, 
sterile suspensions and solutions are desired. Isotonic preparations which 
generally contain suitable preservative are employed when intravenous 
administration is desired. 
The method of preparing the novel compounds of the present invention, 
already described above in general terms, may be further illustrated by 
the following examples. 
EXAMPLE 1 
17.beta.-N-(2-hydroxymethyl-2-propyl) 
carbamoyl-4-aza-5.alpha.-androst-1-en-3-one (1) 
A mixture of 100 mg of 
3-oxo-4-aza-5.alpha.-androst-1-ene-17.beta.-carboxylic acid, 69 mg of 
dicyclohexylcarbodiimide and 77 mg of N-hydroxybenztriazole in 5 ml of 
methylene chloride was stirred at 0.degree. C. for 30 minutes and then at 
24.degree. C. for 16 hours. To the resulting solution of activated ester 
was added 150 .mu.l of 2-amino-2-methylpropanol. After 5 hours the mixture 
was filtered and the solid was rinsed with methylene chloride. The 
combined tiltrates were evaporated and the residue was chromatographed on 
silica coated thin layer plates (4, 1000 .mu..times.20 cm.times.20 cm) 
with 8% methanol in chloroform. The major component was extracted and 
isolated. Recrystallization from acetonitrile-methanol gave 41 mg of the 
product, m.p. 282.degree.-287.degree. C. 
EXAMPLE 2 
17.beta.-[N-(2-oxo-1,1-dimethylethyl)]carboxamido-4-aza-5 
.alpha.-androst-1-en-3-one (2) 
##STR6## 
A suspension of 100 mg of the hydroxy steroid 1 in 4.0 ml of methylene 
chloride was treated with solid pyridinium chlorochromate (130 mg) 
portionwise at room temperature (RT). After stirring for 60 minutes, 
additional chlorochromate reagent was added (75 mg) and the mix was 
stirred for 2 hr more at RT. The supernatant from the reaction mixture was 
chromatographed by applying directly to 4.times.1000 
.mu..times.8".times.8" silica plates and was eluted with 8% 
MeOH/CHCl.sub.3. The major component was isolated (42 mg). The solid was 
recrystallized from EtOAc/MeOH to yield 13 mg, m.p. 
277.degree.-279.degree. C. of product 2. Additional 2 (56 mg) could be 
isolated by treatment of the tarry reaction residue with 5% NaOH solution, 
followed by filtration, aqueous washing and drying.