Substituted steroid-spiro-oxazolidinone derivatives and a process for the preparation thereof

Compounds of the formula (I) having aldosterone-antagonizing activity are disclosed ##STR1## wherein R.sub.3 and R.sub.4 are each C.sub.1 to C.sub.3 alkyl; and PA1 Z is one of the following groups ##STR2## wherein R.sub.1 is hydrogen or methyl; PA1 R.sub.6 is hydrogen, C.sub.1 to C.sub.3 alkylthio or C.sub.2 to C.sub.4 acylthio; and PA1 X is oxo, hydroximino, C.sub.1 to C.sub.3 alkoxyimino, carboxy-alkoxyimino wherein the alkoxy has 2 to 4 carbon atoms or a salt-converted carboxy-alkoxy-imino wherein the alkoxy has 2 to 4 carbon atoms.

The invention relates to steroid-spiro-oxazolidinone derivatives of the 
formula (I), 
##STR3## 
wherein 
R.sub.1 is hydrogen or methyl, 
R.sub.2 is hydrogen, or 
R.sub.1 and R.sub.2 together form a valence bond, 
R.sub.3 is C.sub.1-3 alkyl, 
R.sub.4 is C.sub.1-3 alkyl or C.sub.2-4 alkenyl, 
R.sub.5 and R.sub.5, are each hydrogen or methyl group with at least one of 
the R.sub.5 and R.sub.5, substituent pairs always representing two methyl 
groups, 
R.sub.6 is hydrogen, C.sub.1-3 alkylthio or C.sub.2-4 acylthio, the dotted 
lines represent additional valence bonds optionally present, and if 
R.sub.5 is methyl, there is a double bond between the carbon atoms in 
positions 4 and 5, and additional double bonds can be between the carbon 
atoms in positions 6 and 7, 9 and 10 (for these compounds R.sub.1 and 
R.sub.2 form together a valence bond) and 11 and 12, and if 
R.sub.5 is hydrogen or methyl and at the same time R.sub.5, is methyl, 
there is a double bond between the carbon atoms in positions 5 and 6, and 
if 
R.sub.6 is C.sub.1-3 alkylthio or C.sub.2-4 acylthio group, only a bond 
lies between the carbon atoms in positions 6 and 7, furthermore 
X is oxygen, hydroxyimino, C.sub.1-3 alkoxyimino, C.sub.2-4 
carboxyalkoxyimino or a salt-converted C.sub.2-4 carboxyalkoxyimino, 
and pharmaceutical compositions containing the same. The invention also 
relates to a process for the preparation of such compounds. 
The compounds of the formula (I) may exist in the form of various 
stereoisomers and isomeric mixtures, all of them being within the scope of 
the invention. 
The compounds of the formula (I) are new and possess valuable biological 
effects. Some representatives of these new compounds exert outstanding 
anti-mineralocorticoid effects. 
It is known that aldosterone, a hormone of the adrenal cortex, causes 
sodium retention and stimulates the excretion of potassium. In certain 
pathological states of the adrenal gland hyperaldosteronism occurs and 
responsible for several oedemas of hepatic, renal and cardial origin. In 
such instances aldosterone always reaches a high concentration in the 
blood. 
Compounds with aldosterone-antagonizing effects are capable of inhibiting 
the harmful effects of the hormone exerted in these pathological states. 
These compounds enhance the excretion of sodium ions through the tubular 
cells of the kidney, thereby evacuating the oedemas. Thus the 
aldosterone-antagonizing agents exert diuretic effects, and represent a 
particularly important group of diuretics. These compounds are used in 
therapy for the treatment of arterial hypertension and cardiac 
insufficiency for example. 
The new steroid derivatives of the formula (I) are prepared according to 
the invention so that a compound of the formula (II) 
##STR4## 
wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4 and the dotted lines are as 
defined above, is reacted with a methyl halide in the presence of an 
alkaline agent, and, if desired, a resulting compound of the formula (I), 
wherein X is oxygen, is converted into a derivative containing one or two 
additional double bonds, and/or, if desired, a C.sub.1-3 alkyl mercaptan 
or a C.sub.2-4 thiocarboxylic acid is coupled by addition on the double 
bond in positions 6 and 7, and/or, if desired, a compound of the formula 
(I), wherein X stands for oxygen, is converted into the respective oxime 
derivative wherein X stands for a hydroxyimino, C.sub.1-3 alkoxyimino or 
C.sub.2-4 carboxyalkoxyimino group, and/or, if desired, a compound of the 
general formula (I), wherein X stands for a carboxyalkoxyimino group is 
converted into its salt. 
The optional conversions listed above can be performed by methods known per 
se. 
According to a preferred method of the invention methyl iodide is used as 
the methyl halide, and an alkali metal alcoholate, such as potassium 
tert.-butoxide, is used as the alkaline agent. Methylation is performed at 
or below room temperature. 
When .alpha.,.beta.-unsaturated 3-oxo-steroid-17-spiro-oxazolidinone type 
compounds, which may contain optionally one or more additional conjugated 
double bonds, are methylated according to the invention at low 
temperatures, preferably below -30.degree. C., the respective 2,2-dimethyl 
derivatives or mixtures of the 2,2-dimethyl and 2,2,4,4-tetramethyl 
derivatives are obtained. If methylation is performed at low temperatures, 
it is preferred to conduct the reaction in ether-type solvents, such as 
tetrahydrofuran. 
When .alpha.,.beta.-unsaturated 3-oxo-steroid-17-spiro-oxazolidinones are 
methylated at or near room temperature, the respective 4,4-dimethyl 
derivatives are obtained as main products. In such instances the reaction 
is performed preferably at 0.degree. to +30.degree. C., e.g. in 
tert.-butylalcohol. 
The products obtained in the methylation step can be separated by methods 
known in the art, such as by pouring the reaction mixture into water and 
then extracting the products. The individual compounds can be separated 
from each other e.g. by fractional crystallization or chromatography. 
Optionally one or two additional double bonds may be introduced into the 
compounds obtained by low temperature methylation. Thus e.g. the 
2,2-dimethyl-3-oxo-steroid-4-ene-17-spiro-oxazolidinones can be oxidized 
with a benzoquinone derivative to obtain the respective .DELTA..sup.6(7) 
compounds. It is preferred to use chloranil or 
dichloro-dicyano-benzoquinone as the benzoquinone derivative, and the 
respective 2,2-dimethyl-3-oxo-4-ene-steroid or its enol ether can be used 
as starting substance in the oxidation step. 
When 19-nor-2,2-dimethyl-3-oxo-4-ene-steroids containing double bonds in 
positions 9,10 and 11,12 are to be prepared, the compound to be methylated 
may already contain these double bonds, however, the double bonds can also 
be introduced into the molecule after methylation. Methods well known in 
the steroid chemistry can be used for this purpose [see e.g. Fried, J., 
Edwards, I. A.: Organic Reactions in Steroid Chemistry, Vol. 1, Van 
Nostrand Reinhold Comp., New York, 1972, pages 266 and 314]. Thus e.g. the 
double bond in position 4,5 can be shifted into position 5,10 by enamine 
formation and subsequent hydrolysis under mild acidic conditions, and 
brominating the resulting 2,2-dimethyl-3-oxo-5(10)-ene-spiro-oxazolidinone 
derivative in the presence of pyridine to obtain a 3-oxo-4,9(10)-diene 
structure. Similarly, a 2,2-dimethyl-3-oxo-4,9(10)-diene type 
spiro-oxazolidinone may be subjected to enamine formation and then 
hydrolyzed, and the resulting 3-oxo-5(10),9(11)-diene compound may be 
oxidized with dichlorodicyano-benzoquinone to obtain a 
2,2-dimethyl-3-oxo-4,9(10),11-triene structure. 
The methods discussed above for the introduction of one or two additional 
conjugated double bonds into the methylated compounds are also embraced by 
the scope of the invention. 
If desired, a sulfur-containing substituent can be attached to the carbon 
atom in position 7. These derivatives are prepared preferably from the 
respective 2,2-dimethyl-3-oxo-steroid-4,6-diene-17-spiro-oxazolidinones by 
coupling them with a mercaptan or a thiocarboxylic acid. The addition is 
performed by heating the starting substance in an excess of the reactant. 
When a mercaptan is used as reactant, it is preferred to add a basic 
catalyst, such as piperidine, to the reaction mixture. 
If desired, a methylated spiro-oxazolidinone can be converted into the 
respective oxime by heating the 3-oxo-steroid and the appropriate 
hydroxylamine salt in the presence of an acid binding agent. According to 
a preferred method sodium acetate is applied as acid binding agent and the 
reaction is conducted in aqueous alcohol, or pyridine is applied which 
serves both as acid binding agent and as solvent medium. 
Of the oxime derivatives the 3-carboxyalkoxyiminospiro compounds, prepared 
by applying carboxyalkoxamine salts as reactants, are preferred. These 
compounds are soluble in buffer solutions and can be converted into salts 
by treating them with an equivalent amount of an alkali. Thereby the water 
solubility of the starting substance can be improved, which is an 
essential factor with respect to therapeutical use. 
The compounds of the formula (II) used as starting substances in the 
process of the invention as well as their preparation are described in the 
Belgian Pat. No. 864,689. 
The aldosterone-antagonizing effects of the new compounds according to the 
invention were investigated by two methods. 
The first test series was carried out on rats according to the method of C. 
M. Kagawa [C. M. Kagawa et al.: J. Pharmacology Exp. Ther. 126, 123 
(1959)]. The adrenal gland of the animals was removed 18 hours before 
treatment. The compound under examination was administered together with 
deoxycorticosterone acetate (DOCA), a substance capable of supplementing 
the aldosterone effect, and the sodium and potassium contents of the urine 
were determined by flame photometry. In the comparative test an oral dose 
of 480 .mu.g of spironolactone 
(17.alpha.-carboxyethyl-17.beta.-hydroxy-7.alpha.-acetylthio-androst-4-ene 
-3-one lactone) was administered. The results were evaluated by calculating 
the log (10 Na.sup.+ /K.sup.+) values. The results are summarized in Table 
1. 
The second test series ("sodium balance" test) was carried out on selected 
male rats weighing 230 to 250 g. The test was performed according to the 
method of Holmann [Arch. Exp. Path. u. Pharmak. 247, 419 (1964)]. 
The rats were loaded with an intravenous infusion of 0.2% sodium chloride 
solution rendered isoosmotic with glucose, and the sodium excreting 
capacity of the kidney was observed for 24 hours. It was found that the 
amount of Na.sup.+ introduced by infusion was in equilibrium with that 
excreted with the urine between the 4th and 13th hours. 
The tests were then performed on the following three groups: 
Group 1--controls 
Group 2--mineralocorticoid group 
Group 3--antagonized mineralocorticoid group 
The animals of the second group received a subcutaneous dose of 6.25 .mu.g 
of deoxycorticosterone acetate (DOCA) simultaneously with the start of 
infusion. By a single dose of the mineralocorticoid hormone of the adrenal 
cortex hyperaldosteroinism was provoked on the animals. The animals of 
Group 3 also received a subcutaneous dose of 6.25 .mu.g of DOCA, and then 
they were treated with 5.5 mg of spironolactone (reference substance) or 
the compound under examination in the 2nd hour of the test period. 
The Na.sup.+ concentration of the urine (expressed in units of 10.sup.-6 
mol/ml) and the amount of Na.sup.+ excreted hourly (expressed in units of 
10.sup.-6 mol/h) were determined, and the extent of sodium retention was 
calculated from the data. Sodium retention, expressed as percent of sodium 
introduced, is given in Table 2. 
The daily dose of the compounds of formula I for adults amounts to 50 to 
400 mg per body weight. 
TABLE 1 
__________________________________________________________________________ 
Examination of antimineralocorticoid effects on rats according to the 
method of Kagawa 
Dose 
.mu.g/animal 
No. of 
Compound tested p.o. animals 
log (10Na.sup.+ /K.sup.+) 
__________________________________________________________________________ 
2,2-Dimethyl-3-oxo-oestr-4-ene-17S-spiro-5'-(2'-oxo- 
3'-methyl-oxazolidine) 480 14 1.08 
2,2-Dimethyl-3-oxo-4-androstene-17S-spiro-5'-(2'-oxo- 
3'-methyl-oxazolidine) 480 8 1.07 
2,2-Dimethyl-3-oxo-androsta-4,6-diene-17S-spiro-5'- 
(2'-oxo-3'-methyl-oxazolidine) 
480 8 1.66 
13.beta.-Ethyl-2,2-dimethyl-3-oxo-gona-4,9(10),11-triene- 
17S-spiro-5'-(2'-oxo-3'-methyl-oxazolidine) 
480 8 1.18 
13.beta.-Ethyl-4,4-dimethyl-3-oxo-gon-5-ene-17S-spiro-5'- 
(2'-oxo-3'-methyl-oxazolidine) 
480 6 1.26 
13.beta.-Ethyl-2,2,4,4-tetramethyl-3-oxo-gon-5-ene-17S- 
spiro-5'-(2'-oxo-3'-methyl-oxazolidine) 
480 8 1.10 
DOCA -- 28 0.78 
Spironolactone 480 21 1.21 
__________________________________________________________________________ 
Remark: DOCA was administered in a subcutaneous dose of 12.5 .mu.g/animal 
TABLE 2 
__________________________________________________________________________ 
Examination of antimineralocorticoid effects on rats according to the 
method of Holmann 
Dose per Sodium 
animal 
No. of 
reten- 
Compound s.c. animals 
tion, % 
__________________________________________________________________________ 
Control -- 6 22.68 
DOCA 6.25 .mu.g 
10 66.55 
DOCA 6.25 .mu.g 
+ Spironolactone + 5.5 9mg 5.36 
DOCA 6.25 .mu.g 
+ 2,2-Dimethyl-3-oxo-androsta-4,6-diene-17S-spiro-5'-(2'-oxo- 
+ 5.5 7mg 4.50 
3'-methyl-oxazolidine) 
DOCA 6.25 .mu.g 
+ 13.beta.-Ethyl-2,2-dimethyl-3-oxo-gona-4,9(10),11-triene-17S-spiro- 
+ 5.5 11g 16.16 
5'-(2'-oxo-3'-methyl-oxazolidine) 
__________________________________________________________________________ 
Some of the compounds strongly inhibit the mineralocorticoid effect of 
DOCA. In this respect the following derivatives proved to be particularly 
preferred: 
2,2-dimethyl-3-oxo-androsta-4,6-diene-17S-spiro-5'-(2'-oxo-3'-methyl-oxazol 
idine), 
13.beta.-ethyl-2,2-dimethyl-3-oxo-gona-4,9(10),11-triene-17S-spiro-5'-(2'-o 
xo-3'-methyl-oxazolidine), and 
13.beta.-ethyl-4,4-dimethyl-3-oxo-gon-5-ene-17S-spiro-5'-(2'-oxo-3'-methyl- 
oxazolidine). 
These compounds exert the same or even stronger aldosterone inhibiting 
effect as spironolactone, applied as reference substance but, 
surprisingly, they do not have hormonal effects. 
The compounds applied so far in the treatment of hyperaldosteronism, such 
as spironolactone, have the significant disadvantage that they exert 
certain sexualspecific side effects as well, thus, sooner or later, 
certain disturbances may appear during the usual prolonged treatment 
period. 
The disturbances caused by the antiandrogenic and gestagenic effects of the 
known antialdosterone substances are particularly disadvantageous. 
The antiandrogenic effects of the new compounds according to the invention 
were examined by the modified Dorfman method [Dorfman, R. I., Stevens, D. 
F.: Endocrinology 67, 394 (1960)]. 
Infantile castrated male rats, weighing 50 g, were treated for 7 days with 
subcutaneous daily dosages of 50 .mu.g of testosterone propionate. The 
compounds under examination were administered in subcutaneous daily doses 
of 1 mg simultaneously with testosterone propionate. 
On the 8th day of treatment the animals were sacrified, the ventral 
prostatic lobe and the seminal vesicle were removed and weighed on a 
torsion balance. 
It is known that substances with antiandrogenic effects suppress the weight 
gain of accessory sexual glands provoked by testosterone propionate. The 
extent of inhibiting effect can be expressed in percents, regarding the 
weight gain of the glands stimulated by testosterone propionate as 100%. 
According to the above test spironolactone, when administered for 7 days in 
daily doses of 0.5 or 1.0 mg/animal, inhibits the weight gain of ventral 
prostatic lobe by 35% or 45%, respectively, whereas on the seminal vesicle 
an inhibiting effect of 38% or 54%, respectively, can be observed. On the 
contrary, 
2,2-dimethyl-3-oxo-androsta-4,6-diene-17S-spiro-5'-(2'-oxo-3'-methyl-oxazo 
lidine) and 
13.beta.-ethyl-2,2-dimethyl-3-oxo-gona-4,9(10),11-triene-17S-spiro-5'-(2'- 
oxo-3'-methyl-oxazolidine) have no antiandrogenic effects when administered 
in daily doses of 1 mg/animal. 
The gestagenic effects of the new compounds according to the invention were 
examined by the method of C. Clauberg [C. Clauberg: Zentralblatt Gynaekol. 
54, 2757 (1930)]. 
Infantile female New Zealand rabbits were treated for 5 days with 
subcutaneous daily doses of 5 .mu.g of oestradiol. Thereafter the animals 
received subcutaneously the compound under examination for 5 days. Samples 
were taken from both uteral horns at two different heights, the samples 
were processed for histological evaluation and then evaluated according to 
McPhail. 
In this test spironolactone caused a slight gestagenic effect in a dose of 
5.times.1 mg/kg, whereas a significant gestagenic effect appeared after 
treating with 5.times.5 mg/kg of spironolactone (the McPhail indices were 
0.3 and 2.0, respectively). On the contrary, 
2,2-dimethyl-3-oxo-androsta-4,6-diene-17S-spiro-5'-(2'-oxo-3'-methyl-oxazo 
lidine) and 
13.beta.-ethyl-2,2-dimethyl-3-oxo-gona-4,9(10),11-triene-17S-spiro-5'-(2'- 
oxo-3'-methyl-oxazolidine) proved to be inactive in the same doses. 
The compounds of the formula (I) can be converted into pharmaceutical 
compositions for enteral or parenteral administration. These 
pharmaceutical compositions may be solid or liquid preparations (such as 
tablets, coated tablets, capsules, pills, suppositories, emulsions, 
suspensions, injectable solutions, etc.) and can be prepared by 
conventional methods, utilizing pharmaceutically acceptable inert carriers 
(such as talc, lactose, magnesium stearate, starch, water, vegetable oils, 
waxes, etc.) and/or other additives (such as preservatives, stabilizers, 
flavoring agents, surfactants, salts for adjusting the osmotic pressure, 
etc.).

The invention is elucidated in detail with the aid of the following 
non-limiting Examples. 
EXAMPLE 1 
2,2-Dimethyl-3-oxo-4-androstene-17S-spiro-5'-(2'-oxo-3'-methyl-oxazolidine) 
4 g of 3-oxo-4-androstene-17S-spiro-5'-(2'-oxo-3'-methyl-oxazolidine) are 
dissolved in a mixture of 25 ml of tetrahydrofuran and 12.5 ml of methyl 
iodide, and the solution is cooled to -60.degree. C. A suspension of 6 g 
of potassium tert.-butoxide in 30 ml of tetrahydrofuran is added to the 
stirred solution under nitrogen atmosphere at such a rate that the 
temperature does not raise above -60.degree. C. When the addition is 
complete the mixture is stirred at -60.degree. C. for one hour, thereafter 
the reaction mixture is poured into 600 ml of ice water and the product is 
extracted with dichloromethane. The extract is washed with water, dried 
over magnesium sulfate, evaporated, and the residue is recrystallized from 
ethyl acetate. 2.34 g of 
2,2-dimethyl-3-oxo-4-androstene-17S-spiro-5'-(2'-oxo-3'-methyl-oxazolidine 
) are obtained; m.p.: 188.degree.-190.degree. C. 
[.alpha.].sub.D.sup.20 =+8.05.degree. (c=0.5%, in chloroform). 
UV .lambda..sub.max..sup.EtOH =239 nm (E=15,000). 
EXAMPLE 2 
2,2-Dimethyl-3-oxo-androsta-4,6-diene-17S-spiro-5'-(2'-oxo-3'-methyl-oxazol 
idine) 
Method "A": 
4.76 g of 
2,2-dimethyl-3-oxo-4-androstene-17S-spiro-5'-(2'-oxo-3'-methyl-oxazolidine 
), prepared as described in Example 1, are dissolved in 90 ml of methanol. 
3.16 g of chloranil and a catalytic amount (about 20 mg) of 
p-toluenesulfonic acid are added to the solution, and the mixture is 
boiled for 15 hours. The reaction mixture is evaporated to one-third of 
its original volume under reduced pressure, the volume of the concentrate 
is readjusted to the original one with water, and the resulting mixture is 
extracted three times with dichloromethane. The dichloromethane solutions 
are combined and washed with 1 n aqueous sodium hydroxide solution 
containing 3% of sodium dithionite until the wash remains colorless. The 
organic phase is washed then with water, dried over magnesium sulfate, 
evaporated, and the 3.74 g of crude crystalline residue are recrystallized 
from ethyl acetate. Pure 
2,2-dimethyl-3-oxo-androsta-4,6-diene-17S-spiro-5'-(2'-oxo-3'-methyl-oxazo 
lidine) is obtained; m.p.: 225.degree.-228.degree. C. 
[.alpha.].sub.D.sup.20 =-31.8.degree. (c=0.5%, in chloroform). 
UV .lambda..sub.max..sup.EtOH =281 nm (E=23,600). 
Method "B": 
3.97 g of 
3-oxo-androsta-4,6-diene-17S-spiro-5'-(2'-oxo-3'-methyl-oxazolidine) are 
dissolved in a mixture of 25 ml of tetrahydrofuran and 12.5 ml of methyl 
iodide, and the solution is cooled to -60.degree. C. A suspension of 6 g 
of potassium tert.-butoxide in 30 ml of tetrahydrofuran is added to the 
stirred solution under nitrogen atmosphere at such a rate that the 
temperature does not rise above -60.degree. C. When the addition is 
complete the mixture is stirred at -60.degree. C. for one hour, thereafter 
the reaction mixture is poured into 600 ml of ice water and the product is 
extracted with dichloromethane. 
The dichloromethane extract is washed with water, dried over magnesium 
sulfate, evaporated, and the crystalline crude product is recrystallized 
from ethyl acetate. 2.72 g of pure 
2,2-dimethyl-3-oxo-androsta-4,6-diene-17S-spiro-5'-(2'-oxo-3'-methyl-oxazo 
lidine) are obtained; the compound is identical with the product obtained 
according to method "A". 
EXAMPLE 3 
2,2-Dimethyl-3-oxo-7.alpha.-acetylthio-4-androstene-17S-spiro-5'-(2'-oxo-3' 
-methyl-oxazolidine) 
A suspension of 2 g of 
2,2-dimethyl-3-oxo-androsta-4,6-diene-17S-spiro-5'-(2'-oxo-3'-methyl-oxazo 
lidine), prepared as described in Example 2, in 2 ml of thioacetic acid is 
heated on a steam bath for 2 hours. The excess of thioacetic acid is 
evaporated under reduced pressure, and the residue is triturated with a 
1:1 mixture of ethyl acetate and isopropyl ether. The crude product is 
filtered off and recrystallized from ethyl acetate. 1.22 g of pure 
2,2-dimethyl-3-oxo-7.alpha.-acetyl-thio-4-androstene-17S-spiro-5'-(2'-oxo- 
3'-methyl-oxazolidine) are obtained; m.p.: 238.degree.-242.degree. C. 
[.alpha.].sub.D.sup.20 =-88.30.degree. (c=0.5%, in chloroform). 
UV .lambda..sub.max..sup.EtOH =237 nm (E=18,900). 
EXAMPLE 4 
2,2-Dimethyl-3-oxo-7.alpha.-ethylthio-4-androstene-17S-spiro-5'-(2'-oxo-3'- 
methyl-oxazolidine) 
2.4 g of 
2,2-dimethyl-3-oxo-androsta-4,6-diene-17S-spiro-5'-(2'-oxo-3'-methyl-oxazo 
lidine), prepared as described in Example 2, are suspended in 15 ml of 
ethyl mercaptan, and 1.5 ml of piperidine are added. The reaction mixture 
is heated on a steam bath for 10 hours, then cooled and allowed to stand 
in a refrigerator. The separated crystalline crude product is filtered off 
and recrystallized from ethanol. 1.44 g of pure 
2,2-dimethyl-3-oxo-7.alpha.-ethylthio-4-androstene-17S-spiro-5'-(2'-oxo-3' 
-methyl-oxazolidine) are obtained; m.p.: 262.degree.-263.degree. C. 
[.alpha.].sub.D.sup.20 =-78.3.degree. (c=0.5%, in chloroform). 
UV .lambda..sub.max..sup.EtOH =239 nm (E=16,100). 
EXAMPLE 5 
2,2-Dimethyl-3-oxo-oestr-4-ene-17S-spiro-5'-(2'-oxo-3'-methyl-oxazolidine) 
and 
2,2,4,4-tetramethyl-3-oxo-oestr-5-ene-17S-spiro-5'-(2'-oxo-3'-methyl-oxazo 
lidine) 
A solution of 3.43 g of 
3-oxo-oestr-4-ene-17S-spiro-5'-(2'-oxo-3'-methyl-oxazolidine) in a mixture 
of 30 ml of tetrahydrofuran and 10 ml of methyl iodide is cooled to 
-60.degree. C., and a suspension of 5.0 g of potassium tert.-butoxide in 
10 ml of tetrahydrofuran, previously cooled to -30.degree. C., is added to 
the stirred solution under nitrogen atmosphere. The reaction mixture is 
stirred at -60.degree. C. for 5 hours and then poured into 600 ml of 
water. The product is extracted with ethyl acetate. The ethyl acetate 
solution is washed with water and then with 5% aqueous sodium chloride 
solution until neutral, dried and evaporated. The oily residue is 
subjected to chromatography on 300 g of silica gel, using a 3:1 mixture of 
chloroform and ethyl acetate as eluting agent. 
The pure effluent fractions which contain the first eluted substance are 
combined and evaporated. 0.66 g of crude crystalline 
2,2,4,4-tetramethyl-3-oxo-oestr-5-ene-17S-spiro-5'-(2'-oxo-3'-methyl-oxazo 
lidine) are obtained; this compound melts at 184.degree.-185.degree. C. 
after recrystallization from ethyl acetate. (The UV spectrum of the 
compound contains no absorption band between 220 and 300 nm). 
The pure effluent fractions which contain the second eluted substance are 
combined and evaporated. 1.00 g of crystalline 
2,2-dimethyl-3-oxo-oestr-4-ene-17S-spiro-5'-(2'-oxo-3'-methyl-oxazolidine) 
is obtained. This compound melts at 221.degree.-223.degree. C. after 
recrystallization from ethyl acetate. 
[.alpha.].sub.D.sup.20 =-13.1.degree. (c=0.5%, in chloroform). 
UV .lambda..sub.max..sup.EtOH= 238 nm (E=16,500). 
EXAMPLE 6 
3-Oxo-4,4-dimethyl-oestr-5-ene-17S-spiro-5'-(2'-oxo-3'-methyl-oxazolidine) 
2.44 g of potassium tert.-butoxide are dissolved in 24 ml of tert.-butanol, 
the solution is cooled to 8.degree. C., and 1.85 g of 
3-oxo-oestr-4-ene-17S-spiro-5'-(2'-oxo-3'-methyl-oxazolidine) are 
introduced under stirring. The reaction mixture turns yellow. After 10 
minutes a solution of 1.40 ml of methyl iodide in 5 ml of tetrahydrofuran 
is added dropwise to the mixture within about 10 minutes. Stirring is 
continued for 4 hours at 8.degree. C. and then the reaction mixture is 
poured into 1 liter of ice water. 
The product is extracted thrice with 200 ml of ethyl acetate, each, the 
extracts are combined, washed with water until neutral, dried and 
evaporated. The crystalline crude product is dissolved in 100 ml of 
ethanol under heating, and the solution is concentrated to a final volume 
of about 30 ml. 0.69 g of pure 
3-oxo-4,4-dimethyl-oestr-5-ene-17S-spiro-5'-(2'-oxo-3'-methyl-oxazolidine) 
separate from the solution; m.p.: 217.degree.-218.degree. C. 
[.alpha.].sub.D.sup.20 =-61.7.degree. (c=1%, in chloroform). 
EXAMPLE 7 
13.beta.-Ethyl-2,2-dimethyl-3-oxo-gon-4-ene-17S-spiro-5'-(2'-oxo-3'-methyl- 
oxazolidine) and 
13.beta.-ethyl-2,2,4,4-tetra-methyl-3-oxo-gon-5-ene-17S-spiro-5'-(2'-oxo-3 
'-methyl-oxazolidine) 
A solution of 5.0 g of 
13.beta.-ethyl-3-oxo-gon-4-ene-17S-spiro-5'-(2'-oxo-3'-methyl-oxazolidine) 
in a mixture of 40 ml of tetrahydrofuran and 20 ml of methyl iodide is 
cooled to -70.degree. C., and a suspension of 10 g of potassium 
tert.-butoxide in 50 ml of tetrahydrofuran is added to the stirred 
solution under nitrogen atmosphere. The addition requires 10 minutes. 
After 25 minutes a suspension of additional 7 g of potassium 
tert.-butoxide in 30 ml of tetrahydrofuran is introduced, and the mixture 
is stirred then at -60.degree. C. for 15 minutes. Thereafter the reaction 
mixture is decomposed with 30 ml of a 1:1 mixture of concentrated 
hydrochloric acid and water, and the mixture is poured into 400 ml of 
water. 
The product is extracted thrice with 150 ml of ethyl acetate, each. The 
extracts are combined, washed thrice with 100 ml of water, each, twice 
with 50 ml of 2% aqueous sodium thiosulfate solution, each, and then again 
with 50 ml of water, dried and evaporated. The resulting oily residue, 
weighing 6.0 g, is subjected to chromatography on 480 g of silica gel, 
using a 3:1 mixture of chloroform and ethyl acetate as eluting agent. 
The pure effluent fractions which contain the first eluted substance are 
combined and evaporated. An oily substance is obtained which crystallizes 
when triturated with isopropyl ether. The resulting 1.56 g of crude 
13.beta.-ethyl-2,2,4,4-tetra-methyl-3-oxo-gon-5-ene-17S-spiro-5'-(2'-oxo-3 
'-methyl-oxazolidine) are recrystallized from ethanol; m.p.: 
191.degree.-192.degree. C. 
[.alpha.].sub.D.sup.20 =-7.6.degree. (c=0.5%, in chloroform). 
Elution is continued, the pure fractions which contain a more polar 
substance are combined, and the solution is evaporated. The crystalline 
residue is washed with isopropyl ether, and the resulting 1.81 g of 
13.beta.-ethyl-2,2-dimethyl-3-oxo-gon-4-ene-17S-spiro-5'-(2'-oxo-3'-methyl 
-oxazolidine) are recrystallized from 6 ml of ethanol. 1.29 g of the pure 
substance are obtained; m.p.: 223.degree.-225.degree. C. 
[.alpha.].sub.D.sup.20 =-9.6.degree. (c=0.5%, in chloroform). 
UV .lambda..sub.max..sup.EtOH =238 nm (E=15,600). 
EXAMPLE 8 
13.beta.-Ethyl-4,4-dimethyl-3-oxo-gon-5-ene-17S-spiro-5'-(2'-oxo-3'-methyl- 
oxazolidine) 
1.22 g of potassium tert.-butoxide are dissolved in 14 ml of tert.-butanol, 
and 1.0 g of 
13.beta.-ethyl-3-oxo-gon-4-ene-17S-spiro-5'-(2'-oxo-3'-methyl-oxazolidine) 
is added to the stirred solution at 10.degree. C. After 10 minutes 1.35 ml 
of methyl iodide are added dropwise to the mixture. The reaction mixture 
is stirred for 4 hours and then concentrated to the half of its original 
volume under reduced pressure. The concentrate is diluted with water and 
the product is extracted with ethyl acetate. The ethyl acetate solution is 
washed with water until neutral, dried and then evaporated. The oily 
residue is subjected to chromatography on 40 g of silica gel, using a 3:1 
mixture of chloroform and ethyl acetate as eluting agent. The fractions 
which contain the main product are combined and evaporated, and the 
resulting 0.58 g of crude product is crystallized from isopropyl ether. 
The product, 
13.beta.-ethyl-4,4-dimethyl-3-oxo-gon-5-ene-17S-spiro-5'-(2'-oxo-3'-methyl 
-oxazolidine), melts at 168.degree.-170.degree. C. 
[.alpha.].sub.D.sup.20 =-56.6.degree. (c=0.5%, in chloroform). 
EXAMPLE 9 
13.beta.-Ethyl-2,2-dimethyl-3-oxo-gona-4,9(10),11-triene-17S-spiro-5'-(2'-o 
xo-3'-methyl-oxazolidine) 
2.77 g of 
13.beta.-ethyl-3-oxo-gona-4,9(10),11-triene-17S-spiro-5'-(2'-oxo-3'-methyl 
-oxazolidine) are dissolved in a mixture of 50 ml of tetrahydrofuran and 6 
ml of methyl iodide, and the solution is cooled to -70.degree. C. A 
suspension of 4.1 g of potassium tert.-butoxide in 25 ml of 
tetrahydrofuran, cooled to -40.degree. C., are added dropwise to the 
stirred solution within about 10 minutes. After a reaction time of 1.5 
hours the mixture is poured into 800 ml of saturated aqueous ammonium 
chloride solution, and the product is extracted with four portions of 100 
ml of ethyl acetate, each. The extracts are combined, washed twice with 40 
ml of water, each, and then with 20 ml of a 2% aqueous sodium thiosulfate 
solution, dried and evaporated. The oily residue is subjected to 
chromatography on 400 g of silica gel, using a 3:1 mixture of chloroform 
and ethyl acetate as eluting agent. The pure fractions which contain the 
product are combined and evaporated. The resulting 1.67 g of crystalline 
substance are recrystallized from ethyl acetate to obtain 
13.beta.-ethyl-2,2-di-methyl-3-oxo-gona-4,9(10),11-triene-17S-spiro-5'-(2' 
-oxo-3'-methyl-oxazolidine) melting at 176.degree.-179.degree. C. 
[.alpha.].sub.D.sup.20 =+95.1.degree. (c=0.5%, in chloroform). 
UV .lambda..sub.max..sup.EtOH =234 nm (E=6000), 335 nm (E=30,000). 
EXAMPLE 10 
2,2-Dimethyl-3-oximino-androsta-4,6-diene-17S-spiro-5'-(2'-oxo-3'-methyl-ox 
azolidine) 
1.2 g of 
2,2-dimethyl-3-oxo-androsta-4,6-diene-17S-spiro-5'-(2'-oxo-3'-methyl-oxazo 
lidine), prepared as disclosed in Example 2, are suspended in 12 ml of 
ethanol, and a solution of 0.3 g of hydroxylamine hydrochloride and 0.38 g 
of sodium acetate in 2 ml of water is added to the suspension. The 
reaction mixture is stirred and boiled for 2 hours, then the solvent is 
evaporated under reduced pressure. The residue is triturated with water, 
the precipitate is filtered off, washed with water and dried. The crude 
product is recrystallized from methanol to obtain 0.83 g (66%) of 
2,2-dimethyl-3-oximino-androsta-4,6-diene-17S-spiro-5'-(2'-oxo-3'-methyl-o 
xazolidine); m.p.: 267.degree.-272.degree. C. 
UV .lambda..sub.max..sup.EtOH= 277 nm (E=24,000). 
EXAMPLE 11 
2,2-Dimethyl-3-carboxymethoxyimino-androsta-4,6-di-ene-17S-spiro-5'-(2'-oxo 
-3'-methyl-oxazolidine) 
3 g of 
2,2-dimethyl-3-oxo-androsta-4,6-diene-17S-spiro-5'-(2'-oxo-3'-methyl-oxazo 
lidine), prepared as described in Example 2, are dissolved in 30 ml of 
pyridine. 1.2 g of aminoxyacetic acid hemihydrochloride are added to the 
solution, and the mixture is heated on a steam bath for 3 hours. The 
reaction mixture is cooled and poured into 600 ml of water containing 40 
ml of concentrated hydrochloric acid. After one hour of standing the 
separated precipitate is filtered off and washed with water until neutral. 
The resulting 3.21 g (89%) of 
2,2-dimethyl-3-carboxymethoxyimino-androsta-4,6-diene-17S-spiro-5'-(2'-oxo 
-3'-methyl-oxazolidine) are triturated with isopropyl ether and washed on 
the filter. The product melts at 210.degree.-213.degree. C. 
UV .lambda..sub.max..sup.EtOH =281 nm (E=23,200). 
EXAMPLE 12 
3-Oxo-4,4-dimethyl-5-androstene-17S-spiro-5'-(2'-oxo-3'-methyl-oxazolidine) 
3.15 g of potassium tert.-butoxide are dissolved in 30 ml of tert.-butanol, 
and 2.6 g of 
3-oxo-4-androstene-17S-spiro-5'-(2'-oxo-3'-methyl-oxazolidine) are added 
to the solution at 10.degree. C. under stirring. After 10 minutes 3.5 ml 
of methyl iodide are added dropwise to the mixture. The reaction mixture 
is stirred for 2 hours, then concentrated under reduced pressure, and the 
residue is triturated with water. The crude product is filtered off, dried 
and then subjected to chromatography on 100 g of silica gel, using a 3:1 
mixture of chloroform and ethyl acetate as eluting agent. The fractions 
which contain the main product are combined, evaporated, and the resulting 
1.33 g of crude product are recrystallized from dioxane. 
3-Oxo-4,4-dimethyl-5-androstene-17S-spiro-5'-(2'-oxo-3'-methyl-oxazolidine 
) are obtained; m.p.: 194.degree.-198.degree. C. 
[.alpha.].sub.D.sup.20 =-69.1.degree. (c=0.5%, in chloroform). 
EXAMPLE 13 
Preparation of pharmaceutical compositions 
Tablets for oral administration, containing 25 mg of active agent, are 
prepared from the following components: 
______________________________________ 
2,2-dimethyl-3-oxo-androsta-4,6-diene-17S-spiro- 
5'-(2'-oxo-3'-methyl-oxazolidine) 
25 mg 
maize starch 128 mg 
polyethylene glycol 6000 40 mg 
talc 6 mg 
magnesium stearate 1 mg 
average weight: 200 mg 
______________________________________ 
The tablets are provided with a film coating or sugar coating.