1.alpha.,7.alpha.-dithio-substituted spirolactones, processes for their preparation, and their use as medicines

The disclosure relates to novel 1.alpha.,7.alpha.-dithio-substituted spirolactones of general Formula I ##STR1## wherein R.sup.1 is C.sub.1-3 -alkyl and C.sub.1-3 -acyl and PA0 R.sup.2 is hydrogen, C.sub.1-3 -alkyl and C.sub.1-3 -acyl, to their preparation, and to their use as medicinal agents. The compounds of this invention exhibit anti-aldosterone activity and show the profile of effectiveness of a pro-drug.

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 
solubilizers, such as diisopropyl ether, benzene and heptane, do not 
interfere with the course of the reaction. 
In order to produce compounds of Formula I having an alkylthio group in the 
1.alpha.-position and in the 7.alpha.-position, the starting material of 
Formula II is reacted in a suitable solvent with the corresponding alkyl 
mercaptan. Suitable solvents are, in particular, organic bases, such as 
pyridine, piperidine, collidine and lutidine. The reaction mixture can be 
heated to temperatures above room temperature in case extremely long 
reaction periods are undesirable. 
For preparing compounds of Formula I exhibiting nonidentical substituents 
R.sup.1 and R.sup.2 in the 1.alpha.-position and the 7.alpha.-position, 
the procedure is such that either the 1.alpha.,7.alpha.-disubstituted 
compounds of Formula I are used as the starting materials and these are 
partially cleaved to the corresponding .DELTA..sup.1 -unsaturated 
compounds of Formula II; or that a compound of Formula II is initially 
used as the starting compound which is unsaturated in the 1,2-position and 
is substituted in the 7.alpha.-position by a mercapto, acetylthio or 
methylthio group. 
The partial splitting off of an alkylthio group takes place with an alkali 
metal alcoholate, such as, for example, potassium methylate, at 
temperatures below room temperature. 
The optionally following esterification of the mercapto group is conducted 
according to the processes customary in steroid chemistry for 
esterifications of sterols. Esterification takes place preferably with an 
activated derivative of a lower aliphatic carboxylic acid in the presence 
of pyridine and/or 4-dimethylaminopyridine. Especially suitable 
derivatives are the anhydrides and halogenides of lower carboxylic acids, 
particularly acetic and propionic acid. 
The reaction products of this invention are separated by conventional 
methods, such as precipitation, filtration or extraction, and purified, 
for example, by chromatography and/or recrystallization. 
Insofar as the starting compounds needed for performing the process of this 
invention are unknown, their preparation is described herein. 
Preparation of Starting Material 
A. 
15.beta.,16.beta.-Methylene-7.alpha.-methylthio-3-oxo-17.alpha.-pregna-1,4 
-diene-21 17-carbolactone 
4.0 g of 
15.beta.,16.beta.-methylene-3-oxo-17.alpha.-pregna-4,6-diene-21,17-carbola 
ctone is dissolved in 40 ml of methanol and 4 ml of piperidine. Under ice 
cooling, methanethiol is introduced from a steel bottle into the solution 
over a time period of 30 minutes. Subsequently, the mixture is allowed to 
stand for 15 hours at room temperature, and then the mixture is poured 
into ice water. The thus-precipitated product is filtered off, washed with 
water, dried, and chromatographed on silica gel. With 8.8-10.3% 
acetone-dichloromethane, 2.99 g is eluted and recrystallized from 
hexane-dichloromethane-diisopropyl ether. Yield: 1.80 g of 15.beta., 
16.beta.-methylene-7.alpha.-methylthio-3-oxo-17.alpha.-pregn-4-ene-21,17-c 
arbolactone, mp 269.degree. C. 
UV: .epsilon..sub.236 =16,000 (in methanol). 
A solution of 600 mg of 
15.beta.,16.beta.-methylene-7.alpha.-methylthio-3-oxo-17.alpha.-pregn-4-en 
e-21,17-carbolactone in 12 ml of dioxane is combined with 660 mg of 
2,3-dichloro-5,6-dicyano-1,4-benzoquinone and stirred for 17 hours at 
100.degree. C. The reaction mixture is diluted with diethyl ether, washed 
with sodium bicarbonate solution and water, dried, and evaporated. The 
residue is chromatographed on silica gel. After trituration with 
diisopropyl ether, 145 mg of 
15.beta.,16.beta.-methylene-7.alpha.-methylthio-3-oxo-17.alpha.-pregna-1,4 
-diene-21,17-carbolactone is obtained, mp 265.3.degree. C. 
UV: .epsilon..sub.244 =15,400 (in methanol). 
B. 
7.alpha.-Mercapto-15.beta.,16.beta.-methylene-3-oxo-17.alpha.-pregna-1,4-d 
iene-21,17-carbolactone 
277 mg of potassium ethylate in 7 ml of methanol is added dropwise to a 
suspension, cooled to 0.degree. C., of 640 mg of 
7.alpha.-acetylthio-15.beta.,16.beta.-methylene-3-oxo-17.alpha.-pregna-1,4 
-diene-21,17-carbolactone (EPO 099 853) in 5 ml of methanol and 8 ml of 
tetrahydrofuran, and the mixture is stirred for one hour. The mixture is 
worked up by diluting with dichloromethane, washing with dilute sulfuric 
acid and water, drying over magnesium sulfate, and concentration under 
vacuum. The resultant crude product is purified by column chromatography, 
thus obtaining 296 mg of 
7.alpha.-mercapto-15.beta.,16.beta.-methylene-3-oxo-17.alpha.-pregna-1,4-d 
iene-21,17-carbolactone, mp 258.7.degree. C. 
[.alpha.].sub.D =+17.degree. (in chloroform).

The examples set forth below are to describe the invention in detail. 
EXAMPLE 1 
A solution of 1.5 g of 
15.beta.,16.beta.-methylene-3-oxo-17.alpha.-pregna-1,4,6-triene-21,17-carb 
olactone in 30 ml of methanol and 6 ml of water is combined with 2.1 ml of 
thioacetic acid and allowed to stand for 16 hours at room temperature. The 
mixture is worked up by diluting with diethyl ether, washing with sodium 
bicarbonate solution and water, drying over sodium sulfate, and 
evaporation under vacuum. The residue is chromatographed on silica gel; 
elution yields 570 mg of 
1.alpha.,7.alpha.-diacetylthio-15.beta.,16.beta.-methylene-3-oxo-17.alpha. 
-pregn-4-ene-21,17-carbolactone. 
UV: .epsilon..sub.234 =16,400 (in methanol). 
[.alpha.].sub.D =-28.degree. (in chloroform). 
EXAMPLE 2 
Methanethiol is introduced almost up to the saturation point into a 
solution of 8.6 g of 
15.beta.,16.beta.-methylene-3-oxo-17.alpha.-pregna-1,4,6-triene-21,17-carb 
olactone in 86 ml of methanol and 1.72 ml of piperidine. The reaction 
mixture is then allowed to stand at room temperature for 16 hours. For 
working-up purposes, the mixture is diluted with methylene chloride, 
washed with water, dried over sodium sulfate, and evaporated under vacuum. 
The residue is chromatographed on silica gel. Trituration with diisopropyl 
ether yields 6.9 g of 
15.beta.,16.beta.-methylene-1.alpha.,7.alpha.-dimethylthio-3-oxo-17.alpha. 
-pregn-4-ene-21,17-carbolactone, mp 129.1.degree. C. 
UV: .epsilon..sub.240 =12,000 (in methanol). 
[.alpha.].sub.D =+12.degree. (in chloroform). 
EXAMPLE 3 
(a) An ice-cooled solution of 6.0 g of 
15.beta.,16.beta.-methylene-1.alpha.,7.alpha.-dimethylthio-3-oxo-17.alpha. 
-pregn-4-ene-21,17-carbolactone in 187 ml of ethanol is combined with 2.27 
g of potassium ethylate and stirred for 45 minutes under cooling and while 
passing argon over the mixture. The latter is poured into ice water for 
working-up purposes. The thus-obtained precipitate is suctioned off, 
washed with water, and dried. Chromatography on silica gel and 
crystallization from acetone yield 3.1 g of 
15.beta.,16.beta.-methylene-7.alpha.-methylthio-3-oxo-17.alpha.-pregna-1,4 
-diene-21,17-carbolactone, mp 267.4.degree. C. 
(b) Under the conditions described in Example 1, 1.0 g of 
15.beta.,16.beta.-methylene-7.alpha.-methylthio-3-oxo-17.alpha.-pregna-1,4 
-diene-21,17-carbolactone is reacted and worked up. After chromatography on 
silica gel and trituration with diisopropyl ether, 960 mg of 
1.alpha.-acetylthio-15.beta.,16.beta.-methylene-7.alpha.-methylthio-3-oxo- 
17.alpha.-pregn-4-ene-21,17-carbolactone is obtained, mp 192.3.degree. C. 
UV: .epsilon..sub.239 =15,950 (in methanol). 
[.alpha.].sub.D =+15.degree. (in chloroform). 
EXAMPLE 4 
Under the conditions disclosed in Example 1, 50 mg of 
7.alpha.-mercapto-15.beta.,16.beta.-methylene-3-oxo-17.alpha.-pregna-1,4-d 
iene-21,17-carbolactone is reacted and worked up. After layer 
chromatography, 45 mg of 
1.alpha.-acetylthio-7.alpha.-mercapto-15.beta.,16.beta.-methylene-3-oxo-17 
.alpha.-pregna-4-ene-21,17-carbolactone is obtained. 
UV: .epsilon..sub.236 =11,600 (in methanol). 
[.alpha.].sub.D =+36.5.degree. (in chloroform). 
EXAMPLE 5 
Methanethiol is introduced almost to saturation into a solution, cooled to 
-20.degree. C., of 720 mg of 
7.alpha.-mercapto-15.beta.,16.beta.-methylene-3-oxo-17.alpha.-pregna-1,4-d 
iene-21,17-carbolactone in 28 ml of tetrahydrofuran. Then the reaction 
mixture is combined with 192 mg of potassium tert-butylate and stirred at 
the above temperature for 30 minutes. The mixture is worked up by pouring 
into ice water and neutralizing with acetic acid. The resultant 
precipitate is suctioned off, washed with water, and dried. Trituration 
with diisopropyl ether yields 760 mg of 
7.alpha.-mercapto-15.beta.,16.beta.-methylene-1.alpha.-methylthio-3-oxo-17 
.alpha.-pregn-4-ene-21,17-carbolactone, mp 252.3.degree. C. 
UV: .epsilon..sub.237 =11,100 (in methanol). 
[.alpha.].sub.D =+62.degree. (in chloroform). 
EXAMPLE 6 
A solution of 500 mg of 
7.alpha.-mercapto-15.beta.,16.beta.-methylene-1.alpha.-methylthio-3-oxo-17 
.alpha.-pregn-4-ene-21,17-carbolactone in 2 ml of pyridine is combined with 
1 ml of acetic anhydride and allowed to stand at room temperature for 3 
hours. After ice water precipitation, the filtered-off and dried 
precipitate is recrystallized from diisopropyl ether/acetone, thus 
obtaining 440 mg of 
7.alpha.-acetylthio-15.beta.,16.beta.-methylene-1.alpha.-methylthio-3-oxo- 
17.alpha.-pregn-4-ene-21,17-carbolactone, mp 251.8.degree. C. 
UV: .epsilon..sub.236 =16,100 (in methanol). 
[.alpha.].sub.D =-19.degree. (in chloroform).