Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Patent
1986-10-17
1988-12-06
Schenkman, Leonard
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
540 15, A61K 31585, C07J 5300
Patent
active
047896680
DESCRIPTION:
BRIEF SUMMARY
The invention relates to novel 1.alpha.,7.alpha.-disubstituted spirolactones, processes for their production, and pharmaceutical preparations containing same, in accordance with the patent claims.
R.sup.1 in Formula I, when meaning an alkyl residue of 1-3 carbon atoms, represents, for example, a methyl, ethyl, propyl or isopropyl group.
R.sup.1 in Formula I, when meaning an acyl residue of 1-3 carbon atoms, represents, for example, the formyl, acetyl and propionyl group.
The novel compounds of general Formula I have the property of neutralizing or reversing the effect of aldosterone or desoxycorticosterone on the excretion of sodium and potassium. Consequently, the compounds of this invention are suitable for the treatment of certain forms of hypertension, of edemas, e.g. in cardiac insufficiency, of cirrhosis of the liver and nephrotic syndrome, of primary and secondary aldosteronism and other endocrinological disorders caused by aldosterone. They can furthermore be utilized as diuretics.
The active compounds of this invention, as compared with the commercially available spironolactone and its metabolites which contain a mercapto or methylthio group in the 7.alpha.-position in place of the acetylthio group (Steroids 20 : 41 [1972]), exhibit the advantage of higher activity and prolonged duration of effectiveness, the onset of activity also being retarded. This profile of activity indicates that the compounds of this invention involve biologically active compounds which are metabolically activated only within the organism, namely so-called pro-drugs.
Such compounds exhibit the advantage when used medicinally that the content of active agent in the blood plasma is exposed to less extensive fluctuations.
The compounds of this invention are furthermore distinguished by being inactive endocrinologically. For example, they show practically no binding to the androgen receptor.
The compounds according to this invention which contain a thio group in the 1.alpha. as well as 7.alpha.-position prove to be superior in their antialdosterone activity over the known spironolactone in a test model of Hollmann (Naunyn-Schmiedebergs Arch. Exp. Path. Pharmak. 247 : 419 [1964]) and are distinguished over spironolactone by delayed onset of effectiveness.
1.alpha.,7.alpha.-Diacetylthio-15.beta.,16.beta.-methylene-3-oxo-17.alpha.- pregn-4-ene-21,17-carbolactone proved to be especially valuable pharmacologically.
The novel active agents actually can be used in the same way as spironolactone. The dosage of the active agents lies below that for spironolactone. However, on account of the longer-lasting effect, the novel active compounds normally need to be administered only once daily.
The active compounds can be processed according to conventional methods of galenic pharmacy into pharmaceutical preparations, preferably for enteral administration. Particularly suitable for enteral administration are tablets, dragees or capsules containing per dosage unit about 25-200 mg of active ingredient in an inert excipient.
The compounds of this invention corresponding to general Formula I are produced by conventional methods.
Compounds of formula I can be made by reacting a 1,2-unsaturated spirolactone of Formula II, which has the general formula ##STR2## in a conventional manner,
(a) with a thioalkanoic acid in a proton solvent, or
(b) with an alkanethiol in a protonic solvent in the presence of a base and optically esterifiying a free mercapto group with an active acid derivative.
For preparing the compounds of this invention which contain an acylthio group in the 1.alpha.- and 7.alpha.-positions, the .DELTA..sup.1,4,6 -unsaturated 3-ketopregnatriene of Formula II is suitably dissolved in a protonic solvent suited for this purpose, or in a mixture thereof, the desired thioalkanoic acid is added thereto, and the reaction mixture is heated to temperatures above room temperature up to the boiling temperature of the solvent. Suitable solvents and, respectively, mixtures thereof are methanol, acetone and tetrahydrofuran. Optionally employed solu
REFERENCES:
patent: 3013012 (1961-12-01), Cella et al.
Karim et al., "Isolation and Identification of Novel Sulfur-Containing Metabolites of Spironolactone" Stercias, 20:1, pp. 41-62, (1972).
Bittler Dieter
Laurent Henry
Losert Wolfgang
Nickisch Klaus
Wiechert Rudolf
Lipovsky Joseph A.
Schenkman Leonard
Schering Aktiengesellschaft
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