Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Patent
1986-12-17
1989-08-22
Robinson, Douglas W.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
2603973, A61K 3156, C07J 100
Patent
active
048596590
DESCRIPTION:
BRIEF SUMMARY
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)
REFERENCES:
Pelc et al., Journal of the Chemical Society, Perkin Transactions, 1972, pp. 1219-1220.
Bittler Dieter
Laurent Henry
Nickisch Klaus
Rach Petra
Lipovsky Joseph A.
Robinson Douglas W.
Schering Aktiengesellschaft
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