Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Patent
1988-02-05
1989-09-19
Robinson, Douglas W.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
540 8, 540 11, A61K 3158, C07J 2100, C07J 1900
Patent
active
048681660
DESCRIPTION:
BRIEF SUMMARY
The invention relates to 2,2;6,6-diethylene-3-oxo-17alpha-pregn-4-ene-21,17alpha-carbolactones of general formula I, process for their production and pharmaceutical preparations containing them as mentioned in the claims.
For the treatment of certain forms of hypertension, edemas, primary aldosteronism and other endocrinological disorders caused by aldosterone and as diuretics, substances are used which reverse the effect of aldosterone or desoxycorticosterone on the sodium and potassium salt elimination and whose best known representative is spironolactone long available as a commercial product. But in the treatment with spironolactone undesirable endocrine side effects often occur, which are caused by the antiandrogen and gestagen activity of spironolactone. Thus in the case of prolonged continuous treatment of male patients with spironolactone the occurrence of gynecomastia (Smith, W. G., The Lancet 1962, p. 886; Mann, N. M., JAMA 1963, p. 778; Clark, E., JAMA 1965, p. 157; Greenblatt, D. J., JAMA 1973, p. 82) and impotence (Greenblatt, D. J., JAMA 1973, p. 82), is observed which is ascribed to the antiandrogen side effect of this active ingredient (Steelman, S. L. et al, Steroids 1963, p. 449; Schane, H. P., J. of Clinical Endocrinology and Metabolism 1978, p. 691).
On the other hand, side effects such as amenorrhea and menstrual irregularities occurring in women being treated with spironolactone are blamed on the gestagen side effect of spironolactone. Both side effects can be proven both in animal tests and in vitro by the receptor binding test with the androgen or gestagen receptor. Spirorenone, superior to spironolactoe in its antialdosterone effect, also binds relatively strongly to the gestagen receptor.
The object of this invention was to make available compounds which are superior to spirorenone in antialdosterone effect but have a greatly reduced gestagen side effect.
6,6-ethylene-15,16-methylene-3-oxo-17alpha-pregn-4-ene-21,17-carbolactones, which have both an aldosterone antagonist and a gestagen effect, are known from German laid-open specification No. 34 02 329.
The new compounds of general formula I exhibit a marked increase of the antimineral corticoid effect. The affinity of the new compounds for the gestagen receptor is considerably reduced by the additional cyclopropyl ring in the 2 position (the competition factor is greater than 20). In comparison with spirorenone the new compounds prove to be suitable antimineral corticoids with up to 50% better aldosterone antagonist effect and up to 10 times less affinity for the gestagen receptor (in comparison with dihydrospirorenone, the active metabolite of spirorenone).
The relative values of the strength of action of antialdosterone and the competition factors in the gestagen receptor test (KG) of spirorenone (A) and the compounds according to the invention in the example of 2,2;6,6-diethylene-18-methyl-15beta,16beta-methylene-3-oxo-19-nor-17alpha- pregn-4-ene-21,17-carbolactone (B) are compiled in the following table.
Formulation of the pharmaceutical preparations on the basis of the new compounds takes place in a way known in the art by processing the active ingredient with vehicles, diluents, optionally taste corrigents, etc., usual in galenics and transforming them into the desired application form.
Especially tablets, dragees, capsules, pills, suspensions or solutions are suitable for the preferred oral application.
Especially oily solutions, such as, for example, solutions in sesame oil, castor oil and cottonseed oil are suitable for parenteral application. Solubilizing agents such as, for example, benzyl benzoate or benzyl alcohol, can be used to increase solubility.
Production of the compounds of general formula I according to the invention takes place according to claim 6.
First the delta.sup.4 -3-ketone is transformed with a secondary base into the corresponding delta.sup.3,5 -3-amine.
Diethylamine, aniline, pyrrolidine and morpholine, for example, are suitable as secondary bases.
For introduction of the hydroxymethyl groups in th
REFERENCES:
patent: 3422097 (1969-01-01), Kerwin
patent: 4584288 (1986-04-01), Nickish et al.
Chemical Abstracts, vol. 103 (1985) #215646w; Sandor et al.
Bittler Dieter
Haberey Martin
Laurent Henry
Nickisch Klaus
Wiechert Rudolf
Lipovsky Joseph A.
Robinson Douglas W.
Schering Aktiengesellschaft
LandOfFree
2,2:6,6-diethylen-3-oxo-17alpha-pregn-4-ene-21,17alpha-carbolact does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with 2,2:6,6-diethylen-3-oxo-17alpha-pregn-4-ene-21,17alpha-carbolact, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and 2,2:6,6-diethylen-3-oxo-17alpha-pregn-4-ene-21,17alpha-carbolact will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-368778