Dermatics utilizing 17.beta.methyl-18 nor steroids and methods for their use

Dermatics are claimed which are characterized in that they contain as the active compound one or two 17.beta.-methyl-18-nor steroids of general Formula I ##STR1## wherein is a single bond or a double bond, PA0 R.sub.1 is a hydrogen atom or a methyl group, and PA0 R.sub.2 is an alkyl group of maximally 6 carbon atoms, optionally substituted by an alkanoyloxy group containing 2-6 carbon atoms.

The invention relates to the subject matter characterized by the claims. 
Compounds of general Formula I according to claim 1 wherein R.sub.1 means 
hydrogen and R.sub.2 means a methyl group have been disclosed heretofore. 
Also, there are prior-art disclosures to the effect that 
17,17-dimethyl-18-nor-4,13-androstadien-3-one and 
17,17-dimethyl-18-nor-5.alpha.-androst-13-en-3-one exhibit a weak 
antiandrogenic activity upon systemic administration (Steroids 2: 185, 
1963; and Steroids 4: 433, 1964). Furthermore, mention has been made in 
the literature of 17.alpha.-ethyl-17.beta.-methyl-4,13-androstadien-3-one 
(Chem. Ber. 99: 3836, 1966; and Chem. Ber. 100: 1169, 1967) without any 
statements in regard to its pharmacological efficacy. 
It has now been discovered that the aforementioned, previously known 
compounds and the remaining, previously unknown compounds of general 
Formula I as set out in claim 1 possess surprisingly a strong topical 
antiandrogenic activity upon epidermal application. In order to determine 
antiandrogenic efficacy, the influence on androgen-dependent lipogenesis 
by epidermal application of the compounds is analyzed as follows: 
Male, fertile Syrian golden hamsters weighing about 80-100 g are castrated 
and substituted subcutaneously with 0.1 mg daily of testosterone 
propionate. The right ear of each test animal is treated twice daily with 
respectively 0.01 ml of a 1% strength solution of the test compound in 
acetone (or, in case of the control group, only with 0.01 ml of solvent) 
for three weeks. The animals are then sacrificed and in each case a 
defined tissue area of 8 mm diameter is punched out of the treated right 
ear as well as the untreated left ear. 
The ventral and dorsal sides of the punched-out areas are separated along 
the auricular cartilage, transferred immediately into Dulbecco's 
modification of Eagle's medium to which has been added 4 millimoles of 
glutamine and 10% calf serum and which contains, to avoid microbial 
contamination, 100 IU/ml of penicillin, 100 .mu.g/ml of streptomycin, 125 
.mu.g/ml of kanamycin, 25 IU/ml of nystatin, and 10 .mu.g/ml gentamycin, 
and incubated for one hour at 37.degree. C. 
Thereafter, the punched-out tissues are introduced under sterile conditions 
into fresh culture medium containing 1 .mu.Ci/ml of C.sup.14 -tagged 
sodium acetate, and 4 hours at 37.degree. C. Subsequently, the specimens 
are introduced into 2 ml of a proteolysis solution made up of 0.05 mole of 
tris buffer, pH 7.5, 0.01 mole of disodium edetate, 0.5% of sodium dodecyl 
sulfate, and 0.1% of proteinase K (company: E. Merck A.G., Darmstadt, 
Federal Republic of Germany), and incubated for 24 hours at 37.degree. C. 
The thus-obtained specimens are extracted once with 5 ml of chloroform and 
once more with 3 ml of chloroform, the combined chloroform extracts are 
concentrated under vacuum, and their content of radioactively labeled 
lipids is determined in a scintillation counter. The percentage inhibition 
of lipogenesis of the treated control group is calculated by comparison 
with the control group treated solely with solvent. 
The table below shows the results obtained in these tests. 
TABLE 
__________________________________________________________________________ 
Change of 
Lipogenesis 
Concentration 
% 
No. 
Compound % Right Ear 
Left Ear 
__________________________________________________________________________ 
1 17,17-Dimethyl-18-nor-4,13-androstadien-3-one 
1.0 -48 -17 
0.3 -41 -13 
0.1 -28 -12 
2 17.alpha.-Ethyl-17.beta.-methyl-18-nor-4,13-androstadien- 
1.0 -31 +9 
3-one 0.3 -27 -14 
0.1 -20 0 
3 1.alpha.,17,17-Trimethyl-18-nor-4,13-androstadien- 
1.0 -55 -12 
3-one 0.3 -53 -16 
0.1 -41 -11 
4 1.alpha.,17,17-Trimethyl-18-nor-5.alpha.-androst-13-en-3-one 
1.0 -51 -17 
0.3 -47 -13 
0.1 -30 -7 
5 17.alpha.-Ethyl-1.alpha.,17.beta.-dimethyl-18-nor-5.alpha.-androst- 
1.0 -48 -20 
13-en-3-one 0.3 -40 -9 
6 1.alpha.,17.beta.-Dimethyl-17.alpha.-propionyl-18-nor-5.alpha.-androst- 
1 1.0 -43 +8 
13-en-3-one 
7 17.alpha.-(3-Acetoxypropyl)-17.beta.-methyl-18-nor-4,13- 
1.0 -40 +13 
androstadien-3-one 
8 1.alpha.,17.beta.-Dimethyl-17.alpha.-(3-propionyloxypropyl)- 
1.0 -40 -17 
18-nor-5.alpha.-androst-13-en-3-one 
__________________________________________________________________________ 
When administered subcutaneously, the compounds of general Formula I 
according to claim 1 show an only low systemic antiandrogenic 
effectiveness, or none at all. 
For the production of dermatics, the compounds of general Formula I 
according to claim 1 can be processed with the conventional excipients 
into solutions, gels, ointments, powders, or other preparations. Suitable 
excipients are, for example, water, ethanol, propanol, glycerol, 
methylcellulose, hydroxypropylcellulose, carboxypolymethylene, etc. The 
topically effective antiandrogen is present preferably in a concentration 
of 0.05-5.0% by weight, based on the total weight of preparation. The 
preparations can be utilized for the topical treatment of diseases such as 
acne, seborrhea, alopecia, and hirsutism. 
The compounds of general Formula I according to claim 1 which can carry as 
the substituent R.sub.2, for example, a methyl group, an ethyl group, a 
propyl group, a butyl group, a pentyl group, a hexyl group, an isopropyl 
group, a sec-butyl group, an isobutyl group, or a tert-butyl group--which 
groups can be substituted preferably by, for example, an acetoxy group, by 
a propionyloxy group, a butyryloxy group, a dimethylacetoxy group, a 
trimethylacetoxy group, a valeryloxy group, or a caproyloxy group--can be 
prepared in a conventional way. Suitable production methods are, for 
example, the processes characterized in claims 19 and 20 which can be 
performed under conditions well known to those skilled in the art 
(Steroids 4: 433 et seq., 1964; Chem. Ber. 99: 3836 et seq., 1966; and 
Chem. Ber. 100: 1169, 1967) and which will be described in greater detail 
in the examples below by means of typical representatives.

(A) 
EXAMPLES RELATING TO THE PROCESS OF THIS INVENTION 
EXAMPLE 1 
A solution of 1.5 g of 
17.beta.-hydroxy-1.alpha.-methyl-17.alpha.-propyl-5.alpha.-androstan-3-one 
in 45 ml of ethyl acetate and 6 ml of acetic anhydride is combined with 
0.06 ml of 70% strength perchloric acid and stirred for 15 minutes at room 
temperature. The reaction solution is diluted with pyridine-containing ice 
water; the ethyl acetate phase is separated and washed with water. After 
drying and evaporation, 1.7 g of crude 3-acetoxy 
1.alpha.,17.beta.-dimethyl-17.alpha.-propyl-18-nor-5.alpha.-androsta-2,13- 
diene is obtained. 
A solution of 1.5 g of 
3-acetoxy-1.alpha.,17.beta.-dimethyl-17.alpha.-propyl-18-nor-5.alpha.-andr 
osta-2,13-diene in 30 ml of methanol and 15 ml tetrahydrofuran is stirred 
with 4.5 ml of concentrated hydrochloric acid for 17 minutes at room 
temperature. The reaction solution is diluted with diethyl ether, washed 
neutral with water, dried, and evaporared. The residue is chromatographed 
on silica gel. Yield: 1.04 g of 
1.alpha.17.beta.-dimethyl-17.alpha.-propyl-18-nor-5.alpha.-androst-13-en-3 
-one, mp 88.degree.-90.degree. C. 
EXAMPLE 2 
A solution of 700 mg of 
17.beta.-hydroxy-1.alpha.,17.alpha.-dimethyl-5.alpha.-androstan-3-one in 5 
ml of 99% strength formic acid is stirred for 5 minutes at 100.degree. C. 
The reaction solution is subsequently stirred into ice water; the 
thus-obtained precipitate is filtered off, washed with water, and taken up 
in dichloromethane. After drying and evaporation, the residue is 
recrystallized from methanol, yielding 350 mg of 
1.alpha.17,17-trimethyl-18-nor-5.alpha.-androst-13-en-3-one, mp 
135.7.degree. C. 
EXAMPLE 3 
A solution of 6.5 g of 
17.alpha.-ethyl-3,3-ethylene-dioxy-1.alpha.-methyl-5.alpha.-androstan-17.b 
eta.-ol in 65 ml of 99% strength formic acid is stirred for 15 minutes at 
100.degree. C. and worked up as described in Example 2. Recrystallization 
from methanol yields 4.05 g of 
17.alpha.-ethyl-1.alpha.,17.beta.-dimethyl-18-nor-5.alpha.-androst-13-en-3 
-one, mp 1226.degree. C. 
EXAMPLE 4 
Under the conditions described in Example 2, 4.5 g of 
17.alpha.-butyl-17.beta.-hydroxy-1.alpha.-methyl-5.alpha.-androstan-3-one 
is reacted and worked up. After chromatography on silica gel, 2.17 g of 
17.alpha.-butyl-1.alpha.,17.beta.-dimethyl-18-nor-5.alpha.-androst-13-en-3 
-one is obtained as a viscous oil. 
EXAMPLE 5 
A solution of 1.0 g of 
17.beta.-hydroxy-17.alpha.-(3-hydroxypropyl)-1.alpha.-methyl-5.alpha.-andr 
ostan-3-one in 10 ml of propionic acid is combined with 10 ml of 
concentrated hydrochloric acid and agitated at room temperature for 45 
minutes. The reaction solution is diluted with diethyl ether, washed with 
water and sodium bicarbonate solution, dried, and evaporated. The residue 
is chromatographed on silica gel, thus producing 780 mg of 
1.alpha.,17.beta.-dimethyl-17.alpha.-(3-propionyloxypropyl)-18-nor-5.alpha 
.-androst-13-en-3-one as a viscous oil. 
EXAMPLE 6 
Under the conditions set forth in Example 5, 1.0 g of 
17.beta.-hydroxy-17.alpha.-(4-hydroxybutyl)-1.alpha.-methyl-5.alpha.-andro 
stan-3-one is reacted and worked up. After chromatography on silica gel, 
810 mg of 
1.alpha.,17.beta.-dimethyl-17.alpha.-(4-propionyloxybutyl)-18-nor-5.alpha. 
-androst-13-en-3-one is obtained as a viscous oil. 
EXAMPLE 7 
A solution of 790 mg of 
17.beta.-hydroxy-1.alpha.,17.alpha.-dimethyl-4-androsten-3-one in 30 ml of 
concentrated formic acid is heated for 10 minutes to 100.degree. C. The 
reaction mixture is diluted with water and extracted with diethyl ether. 
The extract is washed with water, dried, and concentrated under vacuum. 
The residue is chromatographed. The fractions eluted with 9-19% diethyl 
ether-pentane contain 500 mg which, recrystallized from pentane, yields 
190 mg of 1.alpha.,17,17-trimethyl-18-nor-4,13-androstadien-3-one, mp 
69.5.degree. C. 
UV: .epsilon..sub.241 =12,800. 
EXAMPLE 8 
Under the conditions described in Example 7, 1.0 g of 
17.beta.-hydroxy-1.alpha.-methyl-17.alpha.-pentyl-4-androsten-3-one is 
reacted. The crude product is chromatographed. The fractions eluted with 
22-34% diethyl ether-pentane contain 1.08 g which, recrystallized from 
pentane, yields 460 mg of 
1.alpha.,17.beta.-dimethyl-17.alpha.-pentyl-18-nor-4,13-androstadien-3-one 
, mp 59.1.degree. C. 
UV: .epsilon..sub.240 =13,500. 
EXAMPLE 9 
Under the conditions described in Example 7, 1.0 g of 
17.alpha.-(4-acetoxybutyl)-17.beta.-hydroxy-1.alpha.-methyl-4-androsten-3- 
one is reacted. The crude product is chromatographed. With 38-44% diethyl 
ether-pentane, 356 mg of 
17.alpha.-(4-acetoxybutyl)-1.alpha.,17.beta.-dimethyl-18-nor-4,13-androsta 
dien-3-one is eluted in the form of a viscous oil. 
UV: .epsilon..sub.241 =12,600. 
EXAMPLE 10 
A solution of 20.0 g of 17.beta.-hydroxy-17.alpha.-methyl-4-androsten-3-one 
in 76 ml of concentrated formic acid is heated for 10 minutes to 
100.degree. C. The reaction solution is diluted with water and extracted 
with diethyl ether. The extract is washed with water, dried, and 
concentrated under vacuum. The residue is chromatographed, thus obtaining 
15.80 g of 17,17-dimethyl-18-nor-4,13-androstadien-3-one in the shape of 
an oil which solidifies in crystalline form after some time. Melting point 
68.degree. C. 
UV: .epsilon..sub.238 =16,200. 
EXAMPLE 11 
Under the conditions set forth in Example 10, 2.0 g of 
17.beta.-hydroxy-17.alpha.-methyl-5.alpha.-androstan-3-one is converted 
into 17,17-dimethyl-18-nor-5.alpha.-androst-13-en-3-one. Yield: 1.68 g, mp 
139.0.degree. C. 
EXAMPLE 12 
3.0 g of 17.alpha.-ethyl-17.beta.-hydroxy-4-androsten-3-one is reacted 
under the conditions disclosed in Example 10. The crude product is 
chromatographed. The fractions eluted with 39-44% diethyl ether-pentane 
contain 2.45 g of oily 
17.alpha.-ethyl-17.beta.-methyl-18-nor-4,13-androstadien-3-one which, 
after having been allowed to stand, solidifies in crystalline form. 
Melting point 56.2.degree. C. 
UV: .epsilon..sub.238 =16,100. 
EXAMPLE 13 
A solution of 1.0 g of 17.beta.-hydroxy-17.alpha.-propyl-4-androsten-3-one 
in 2 ml of acetic acid and 2 ml of concentrated hydrochloric acid is 
stirred for 40 minutes at room temperature. The reaction mixture is 
diluted with water and extracted with dichloromethane. The organic phase 
is washed neutral with water, dried, and evaporated under vacuum. The 
crude product is purified by chromatography, thus obtaining 666 mg of 
17.beta.-methyl-17.alpha.-propyl-18-nor-4,13-androstadien-3-one as a 
viscous oil which, after some time, solidifies in crystalline form. 
Melting point 80.3.degree. C. 
UV: .epsilon..sub.240 =16,300. 
EXAMPLE 14 
Under the conditions set forth in Example 13, 1.0 g of 
17.alpha.-(3-acetoxypropyl)-17.beta.-hydroxy-4-androsten-3-one is 
converted into 
17.alpha.-(3-acetoxypropyl)-17.beta.-methyl-18-nor-4,13-androstadien-3-one 
. Yield: 670 mg (oily). 
UV: .epsilon..sub.240 =16,300. 
EXAMPLE 15 
Under the conditions of Example 13, but using propionic acid in place of 
acetic acid, 1.0 g of 
17.beta.-hydroxy-17.alpha.-(4-propionyloxybutyl)-4-androsten-3-one is 
converted into 
17.beta.-methyl-17.alpha.-(4-propionyloxybutyl)-18-nor-4,13-androstadien-3 
-one. Yield: 667 mg (oily). 
UV: .epsilon..sub.241 =16,100. 
(B) 
EXAMPLES RELATING TO PHARMACEUTICAL PREATIONS 
EXAMPLE 1 
(a) Preparation of the Oil/Water Emulsion 
10.00 g of disodium edetate and 10.00 g of chlorquinaldol are dissolved in 
300.00 g of purified, demineralized water and combined with 10.00 g of 
"Carbopol". 
This mixture is introduced under vigorous agitation into a melt of 80.00 g 
of "Vaseline" (DAB 8)--DAB being the abbreviation for "Deutsches 
Arzneibuch" [German Pharmacopoeia], official issue, 8th edition, 
1978--40.00 g of stearyl alcohol, 30.00 g of "MYRJ", and 50.00 g of jojoba 
oil. The mixture is stirred until an emulsion is produced having a 
particle size of 20-70 .mu.m. 
(b) Preparation of the Water/Oil Emulsion 
230.00 g of purified, demineralized water is introduced under vigorous 
agitation into a melt of 220.00 g of "Vaseline" (DAB 8), 10.00 g of 
"Dehymuls" and 10.00 g of cera alba. The mixture is stirred until an 
emulsion is produced having a particle size of 20-70 .mu.m. 
(c) Production of a Cream 
The water/oil emulsion is introduced under vigorous agitation under a 
vacuum of 10 torr into the oil/water emulsion. Stirring is continued until 
a dispersion is formed having a particle size of 10-50 .mu.m, and the 
vacuum is lifted. 
Under agitation, 5.000 g of 
17.alpha.,17.beta.-dimethyl-18-nor-4,13-androstadien-3-one--micronized; 
particle size predominantly 1-20 .mu.m--is added into 95.000 g of this 
ointment base, and the agitation is continued until the active agent has 
been uniformly distributed in the ointment base. 
EXAMPLE 2 
97.000 g of the ointment base produced accordi to Example 1(c) is combined 
with 8.000 g of 
1.alpha.,17,17-trimethyl-18-nor-5.alpha.-androst-13-en-3-one--micronized; 
particle size predominantly 1-20 .mu.m--and the mixture is stirred until 
the active agent has been uniformly distributed in the ointment base. 
EXAMPLE 3 
95.000 g of the ointment base prepared according to Example 1(c) is 
combined with 5.000 g of 
17.alpha.-ethyl-1.alpha.,17.beta.-dimethyl-18-nor-5.alpha.-androst-13-en-3 
-one--micronized; particle size predominantly 1-20 .mu.m--and the mixture 
is stirred until the active ingredient has been uniformly distributed in 
the ointment base. 
EXAMPLE 4 
95.000 g of the ointment base produced as described in Example 1(c) is 
combined with 5.000 g of 
17.alpha.-(3-acetoxypropyl)-17.beta.-methyl-18-nor-4,13-androstadien-3-one 
and the mixture is stirred until the active compound has been uniformly 
distributed in the ointment base. 
EXAMPLE 5 
45.000 g of "Vaseline" (DAB 8), 19.600 g of paraffin oil, 5.000 g of cetyl 
alcohol, 5.000 g of beeswax, and 5.000 g of sorbitan sesquinolate are 
melted together, combined with a solution of 0.2000 g of p-hydroxybenzoic 
acid ester in 15.2 g of demineralized water and emulsified at 50.degree. 
C. The emulsion is then allowed to cool down, combined with 5.000 g of 
1.alpha.,17,17-trimethyl-18-nor-4,13-androstadien-3-one--micronized; 
particle size predominantly 1-20 .mu.m--and stirred until the active agent 
has been uniformly distributed in the ointment base.