Antiglucocorticoid steroids for the treatment of anxiety disorders

The invention relates to the use of antiglucocorticoid steroids for the manufacture of a pharmaceutical composition for the treatment of anxiety disorders.

FIELD OF THE INVENTION 
The invention relates to the use of antiglucocorticoid steroids for the 
manufacture of a pharmaceutical composition for the treatment of anxiety 
disorders. 
BACKGROUND OF THE INVENTION 
Antiglucocorticoid steroids are a well known group of steroids which 
exhibits affinity for the glucocorticoid receptor (GR) and reduce 
completely or to a considerable extent the action of cortisol. For 
example, 11.beta.-substituted steroids having antiglucocorticoid activity 
are disclosed in EP-A-190759 and EP-A-57115. Other steroids having 
antiglucocorticoid activity are 10.beta.-substituted steroids as disclosed 
in EP-A-188396. 
SUMMARY OF THE INVENTION 
It has now been found that antiglucocorticoid steroids also exert 
anxiolytic effects, which make these steroids useful for the treatment of 
anxiety disorders. Anxiety disorder is a rather broad concept including 
for instance general anxiety, panic disorder, and various kinds of 
withdrawal symptoms (see: Diagnostic and Statistical Manual of Mental 
Disorders, 3 RD ED DSM-III, Washington, American Psychiatric Ass., p. 
225-239, 1980). 
The aim of this invention is to provide a pharmaceutical composition which 
can be used for the treatment or prevention of anxiety disorders. 
Steroids that can be used for the treatment of anxiety disorders are known 
from WO 9303732. These steroids, however, have no hormonal effects and 
have no affinity to the glucocorticoid receptor: they activate the GABA 
receptor/chloride ionophore complex instead. No hint or suggestion towards 
the use of antiglucocorticoid steroids for the treatment or prevention of 
anxiety disorders is made in said publication. Antidepressant activity was 
suggested by De Kloet et al. (Neuroendocrinology, 47 (1988), 109-115) and 
by Veldhuis et al. (Eur. J. Pharmacol., 115 (1985)211-217). However, since 
there is no relation between antidepressant and anxiolytic effects, no 
activity of antiglucocorticoid steroids for treating of preventing anxiety 
was suggested. 
Benzodiazepines, such as librium and valium, are the most commonly used 
drugs for the treatment of anxiety disorders. However, these compounds are 
no steroids. 
DETAILED DESCRIPTION OF THE INVENTION 
In a preferred embodiment of the invention the antiglucocorticoid steroids 
according to the invention are 11.beta.- or 10.beta.-sustituted steroids 
having the general formula: 
##STR1## 
wherein: R.sub.1 is H, CH.sub.3, unsubstituted or OH or halogen 
substituted CH.sub.2 .dbd.CH--CH.sub.2 or CH.tbd.C--CH.sub.2, or an aryl, 
arylthio or arylmethyl group, the aryl moieties of which may optionally be 
substituted with (C1-C6) alkyl, (C1-C6) alkoxy, OH, halogen or CF.sub.3, 
or R.sub.1 together with R.sub.7 is a bond; 
R.sub.2 is H, (C1-C6) alkyl or an aryl group optionally substituted with a 
group selected from (C1-C6) acyl, (C1-C6) alkoxy, (C1-C6) thioalkoxy, 
--O--(CH.sub.2).sub.n --O--, n being 1 or 2, and 
##STR2## 
X and Y each being independently H or a group selected from (C1-C6) alkyl 
and (C1-C6) acyl, or R.sub.2 together with R.sub.7 is a bond; 
R.sub.3 is (C1-C6) alkyl; 
R.sub.4 is H, OH, (C1-C6) alkoxy, (C1-C6) acyloxy, a group selected from 
(C1-C6) alkyl, (C1-C6) alkenyl and (C1-C6) alkynyl, each of which group 
may be substituted with hydroxy, oxo, halogen, azido or cyano, or 
--C.tbd.C-phenyl, the phenyl group of which may optionally be substituted 
with --S(O)m--(C1-C6) alkyl, m being 1 or 2, or with 
##STR3## 
X and Y each being independently H or a group selected from (C1-C6) alkyl 
and (C1-C6) acyl, or X and Y together with the nitrogen to which they are 
bonded form a ring; 
R.sub.5 is OH or a group selected from (C1-C6) acyloxy, (C1-C6) alkoxy or 
(C1-C6) acyl, each of which group may optionally be substituted with 
hydroxy, (C1-C6) alkoxy, (C1-C6) acyloxy or halogen; or 
R.sub.4 and R.sub.5 together with the carbon atom to which they are bonded 
form a 5- or 6-membered ring system; 
R.sub.6 is H or methyl optionally substituted with hydroxy or (C1-C6) 
alkoxy; 
R.sub.7 forms a bond with either R.sub.1 or R.sub.2. 
In a more preferred embodiment the steroids have above-mentioned formula 
wherein R.sub.1 together with R.sub.7 is a bond, R.sub.2 represents a 
phenyl group which is substituted in the para position with an amino group 
##STR4## 
R.sub.3 is methyl or ethyl, R.sub.4 is prop-1-ynyl, R.sub.5 is hydroxy and 
R.sub.6 is H, hydroxymethyl or methoxymethyl. 
In particular 
11.beta.B-(4-dimethylaminophenyl)-17.beta.-hydroxy-17.alpha.-(prop-1-ynyl) 
-estra-4,9-dien-3-one (RU38486) is a preferred steroid. 
Other preferred steroids are 
(11.beta.,17.alpha.)-11,21-bis4-(dimethylamino)phenyl!-17-hydroxy-19-norp 
regna-4,9-dien-20-yn-3-one, 
(11.beta.,17.alpha.)-11-4-(dimethylamino)phenyl!-17-hydroxy-21-4-(1-pyrr 
olidinyl)phenyl!-19-norpregna-4,9-dien-20-yn-3-one, 
(11.beta.,17.alpha.)-11-(1,3-benzodioxol-5-yl)-21-4-(dimethylamino)phenyl 
!-17-hydroxy-19-norpregna-4,9-dien-20-yn-3-one, and 
(11.beta.,17.alpha.)-11-4-(dimethylamino)phenyl!-17-hydroxy-21-4-(methyl 
sulfonyl)phenyl!-19-norpregna-4,9-dien-20-yn-3-one. 
The aryl group in the definition of R.sub.1 may be derived from benzene, 
naphthalene or a 5- or 6-membered heteroaryl which comprises 1 to 4 hetero 
atoms selected from N, O and S. Preferably the aryl group is phenyl. 
In the definition of R.sub.2 the aryl group may be derived from, for 
example, benzene, biphenyl, naphthalene, anthracene or phenantrene. Phenyl 
is the preferred group. In particular a phenyl group is preferred, which 
is substituted in the para position with the 
##STR5## 
group or in the meta position with OCH.sub.3 or SCH.sub.3. 
The (C1-C6) alkyl group is a branched or unbranched alkyl group having 1-6 
carbon atoms, such as methyl, ethyl, propyl, butyl, isopropyl, pentyl, 
isopentyl, hexyl, tert-butyl and the like. Preferred alkyl groups have 1-4 
carbon atoms; most preferred is the methyl group. 
The (C2-C6) alkenyl group is a branched or unbranched alkenyl group having 
2-6 carbon atoms, such as vinyl, 2-propenyl, 1,3-butadienyl and the like. 
The (C2-C6) alkynyl group is a branched or unbranched alkynyl group having 
2-6 carbon atoms, such as ethynyl, propynyl, butynyl, and the like. Most 
preferred is the prop-1-ynyl group. 
The (C1-C6) alkylidene group is a branched or unbranched alkylidene group 
having 1-6 carbon atoms, such as ethylidene, propylidene, 
2-methylpropylidene and the like. 
The (C1-C6) alkoxy group is an alkoxy group of which the alkyl moiety is 
the (C1-C6) alkyl group as previously defined. 
The (C1-C6) thioalkoxy group is an --S-alkyl group of which the alkyl 
moiety is the (C1-C6) alkyl group as previously defined. 
The arylthio and arylmethyl groups, are arylthio and arylmethyl groups the 
aryl moiety of which is derived from benzene, naphthalene or a 5- or 
6-membered heteroaryl which comprises 1 to 4 hetero atoms selected from N, 
O and S. Preferably the aryl moiety is phenyl. 
The (C1-C6) acyl group is a branched or unbranched acyl group having 1-6 
carbon atoms, such as formyl, acetyl, propionyl, butyryl and the like. 
The (C1-C6) acyloxy group is a branched or unbranched acid ester group 
derived from a carboxylic acid having 1-6 carbon atoms, such as the ester 
group derived from formic acid, acetic acid, propionic acid and the like. 
The term halogen means Cl, Br, F, or I. In particular F and Cl are 
preferred halogens. 
When X and Y together with the nitrogen to which they are bonded form a 
ring, this ring is a saturated 5- or 6-membered ring, which may comprise a 
second hetero-atom selected from N, O and S. Examples are pyrrolidinyl, 
piperidinyl, piperazinyl, and morpholinyl. 
When R.sub.4 and R.sub.5 together represent a 5- or 6-membered ring system, 
this ring system can be a homo- or heterocyclic ring system with 5 or 6 
atoms in the ring, the carbon atom at position 17 of the steroid skeleton 
being one of these 5 or 6 atoms. Preferably the ring system comprises at 
least one oxygen atom in the ring which oxygen atom is bonded to the 
carbon atom at position 17 of the steroid skeleton. In particular 
5-membered heterocyclic ring systems having the following structures are 
preferred: 
##STR6## 
wherein the carbon atom which is provided with an * being the carbon atom 
in position 17 of the steroid skeleton, and X is H.sub.2, H,(C1-C6) 
acyloxy!, H,(C1-C6) hydrocarbyl! or oxygen. (C1-C6) hydrocarbyl means a 
hydrocarbon group having 1-6 carbon atoms such as (C1-C6) alkyl, (C1-C6) 
alkenyl, or (C1-C6) alkynyl, as previously defined. 
The antiglucocorticoid steroids according to the invention can be prepared 
by suitable techniques known in the art, for example as described in 
BE-A-862869, DE-OS-3307143, EP-A-188396, EP-A-57115 and J. of Steroid 
Bioch. 31:567-571 (1988), which are incorporated by reference. 
The antiglucocorticoid steroids according to the invention can be 
administered enterally or parentally, and for humans preferably in a daily 
dosage of 0,001-10 mg per kg body weight. Mixed with pharmaceutically 
suitable auxiliaries, e.g. as described in the standard reference, Genarro 
et al., Remington's Pharmaceutical Sciences, (18th ed., Mack Publishing 
Company, 1990, see especially Part 8: Pharmaceutical preparations and 
their manufacture), the steroids may be compressed into solid dosage 
units, such as pills, tablets, or be processed into capsules or 
suppositories. By means of pharmaceutically suitable liquids the steroids 
can also be applied as an injection preparation in the form of a solution, 
suspension, emulsion, or as a spray, e.g. a nasal spray. For making dosage 
units, e.g. tablets, the use of conventional additives such as fillers, 
colorants, polymeric binders and the like is contemplated. In general any 
pharmaceutically acceptable additive which does not interfere with the 
function of the active compounds can be used. Suitable carriers with which 
the compositions can be administered include lactose, starch, cellulose 
derivatives and the like, or mixtures thereof, used in suitable amounts. 
The invention is further illustrated by the following examples without 
being limited thereto.

EXAMPLE 1 
Antagonism of Stress Induced Hyperthermia 
Rectal temperature measurement induces a stress reaction, which results in 
a rise in body temperature. This rise in temperature can be inhibited by 
anxiolytic drugs. The rise in temperature after treatment with a drug, 
expressed as percentage of the rise in temperature after treatment with a 
placebo, is an indication for the anxiolytic effect of the compound. 
Animals are pretreated with reserpine to lower their body temperature and 
make the stress induced temperature rise more apparent. 
1.1 Animals 
Male mice (Crl: CD-1 (ICR) BR, from Charles River, Germany) weighing 20-30 
g were used. They were kept in a temperature controlled room 
(21.degree.-23.degree. C.) under a fixed 12 h light-dark cycle. Food 
pellets and drinking solution were available ad libitum. 
1.2 Measurement of rectal temperature 
The body temperature was measured per rectum using an electrothermometer 
(Ellab TE3, Electrolaboratoriet, Copenhagen, Denmark), lubricated with 
Vaseline grease. The probe was inserted to a depth of approximately 2.5 cm 
and left until the temperature indication was constant. 
1.3 Drugs 
The drugs used were RU38486; 
11.beta.-(4-dimethylaminophenyl)-15.alpha.-hydroxymethyl-17.alpha.-(prop-1 
-ynyl)-17.beta.-hydroxy-estra-4,9-dien-3-one (A); 
11.beta.-(4-dimethylaminophenyl)-15.alpha.-methoxymethyl-17.alpha.-(prop-1 
-ynyl)-17.beta.-hydroxy-estra-4,9-dien-3-one (B); 
(11.beta.,17.alpha.)-11,21-bis4-(dimethylamino)phenyl!-17-hydroxy-19-norp 
regna-4,9-dien-20-yn-3one (C); 
(11.beta.,17.alpha.)-11-4-(dimethylamino)phenyl!-17-hydroxy-21-4-(1-pyrr 
olidinyl)phenyl!-19-norpregna-4,9-dien-20-yn-3-one (D); 
(11.beta.,17.alpha.)-11-(1,3-benzodioxol-5-yl)-21-4-(dimethylamino)phenyl 
!-17-hydroxy-19-norpregna-4,9-dien-20-yn-3-one (E); and 
(11.beta.,17.alpha.)-11-4-(dimethylamino)phenyl!-17-hydroxy-21-4-(methyl 
sulfonyl)phenyl!-19-norpregna-4,9-dien-20-yn-3-one (F). Drugs were used in 
dosages between 0.32 mg/kg and 32 mg/kg. For comparison librium and valium 
were used in dosages of 1 mg/kg, 3.2 mg/kg and 10 mg/kg. The drugs were 
dissolved in mulgophen/NaCl and administered at a volume of 10 ml/kg. 
1.4 Procedure 
The mice were pretreated with 2 mg/kg (s.c.) of reserpine (monoamine 
depletor). The reserpine induced a decrease in body temperature. After 17 
hours the body temperature was measured rectally, which gave the baseline 
value. Thirty minutes after baseline measurement the drugs were 
administered subcutaneously and at t=30, 60, 120, 180, and 240 min the 
temperature was measured. The rise in temperature at t=120 min and at 
t=240 min due to the stress reaction was expressed as percentage of the 
temperature rise of the placebo at t=120 min and t=240 min respectively. 
These percentages are presented in Table 1. 
TABLE 1 
______________________________________ 
Temperature rise in mice after treatment with 
antiglucocorticoid steriods, expressed as percentage of 
the rise in temperature observed after treatment with a 
placebo. The rise in temperature is measured at t = 120 
(between brackets the temperature rise at t = 240 min) 
at various dosages of drugs administered. 
dosage in mg/kg 
0.32 1 3.2 10 32 
______________________________________ 
RU38486 -- -- 70(98) 83(89) 71(74) 
steroid A 
-- -- 42(58) 48(54) 66(71) 
steroid B 
-- -- 63(32) 67(38) 49(37) 
steroid C 
33(50) 57(94) 11(9) -- -- 
steroid D 
102(102) 61(85) 84(109) 
-- -- 
steroid E 
73(97) 59(91) 57(104) 
-- -- 
steroid F 
84(87) 58(43) 115(127) 
-- -- 
librium -- 67(69) 48(87) 33(30) -- 
valium -- 20(3) 7(2) 37(11) -- 
______________________________________ 
As can be seen from the results of Table 1, the antiglucocorticoid steroids 
considerably reduce the rise in temperature. The observed effect on the 
stress reaction is comparable to the effect resulting from treatment with 
librium and valium respectively. 
EXAMPLE 2 
Anxiety Test 
The (Borsini) anxiety test (Psychopharmacology 98:207-211, 1989) is based 
on the fact that among animals from the same cage, those removed last have 
a higher body temperature as compared to those removed first. This 
phenomenon can also be observed by reversing the order of removal of the 
animals from the cage and can therefore be interpreted as an indication of 
a state of anxiety due to expectation of a (known or unknown) event. The 
observed rise in body temperature can be prevented by the administration 
of anxiolytic drugs. This test is useful in demonstrating the anxiolytic 
effect of compounds. 
2.1 Animals 
Male mice (Crl: CD-1 (ICR) BR, from Charles River, Germany) weighing 20-30 
g were used. They were kept in a temperature controlled room 
(21.degree.-23.degree. C.) under a fixed 12 h light-dark cycle. All 
animals were housed in macrolon cages; 10 animals per cage. Food pellets 
and water were available ad libitum. Prior to the experiments the animals 
were allowed to adapt to the environment for at least 14 days. 
2.2 Temperature measurement 
The body temperature was measured per rectum using an electrothermometer 
(Ellab TE3, Electrolaboriet, Copenhagen, DK), lubricated with Vaseline 
grease. The probe was inserted to a depth of approximately 2.5 cm and left 
until the temperature indication was constant. 
2.3 Drugs 
The used drug was RU38486 in dosages of 3.2, 10, and 32 mg/kg. RU38486 was 
dissolved in mulgophen/NaCl and injected at t=-30 min. The drug was 
administered at a volume of 10 ml/kg. 
2.4 Procedure 
The methodology was similar to that described by Borsini et al 
(Psychopharmacology 98:207-211, 1989). In short, at t=0 min all mice were 
injected subcutaneously. At t=30 min the temperature of the first and the 
last three mice was measured. Mouse 4 to 7 were simply removed. 
Furthermore the behavioural activity of mouse 10 was determined by 
behavioural observations. Effects were evaluated by subtracting the mean 
body temperature of the first three mice from the mean temperature of the 
last three mice. Comparison between placebo and treatment group were made 
by means of Mann Whitney-U tests. 
2.5 Results 
RU38486 in a dosage of 3.2 mg/kg reduced the temperature difference between 
the first and the last three mice significantly. The results are presented 
in FIG. 1. 
EXAMPLE 3 
Antagonism of the Fear Potentiated Startle 
The fear potentiated startle is a well known paradigm to evaluate 
anxiolytic drugs (Davis, Behavioral Neuroscience 100 (1986) 814-824). In 
this paradigm rats are trained to associate a light with the presentation 
of footshocks. Acoustic noise bursts normally elicit a startle reaction; 
this reaction is increased when the noise burst is presented in the 
presence of the light. The fear potentiated startle phenomenon can be 
inhibited by anxiolytics in the non-sedative dose-range. 
3.1 Animals 
Male rats (Wistars, HSD/Cpb: Wu, Harlan Sprague Dawley, Zeist, The 
Netherlands) weighing 275-300 g were used. 
They were housed in groups of 5 (in 40 * 40 * 17 cm cages) at a room 
temperature of 21.degree.-23.degree. C. They were exposed to a normal 12-h 
light-dark cycle (lights on at 6.00 h) and had free access to food and 
water. 
3.2 Measurement of startle reflexes 
The apparatus used was an SRLAB system (San Diego Instruments, San Diego, 
Calif., USA). The system consisted of eight startle boxes, which contained 
each a cylindrical tube resting on a piezoelectric accelerometer for 
detecting total body-activity within the Plexiglas tube. Reflex amplitude 
was measured during the 200 ms interval following the presentation of the 
stimulus. The acoustic noise bursts (120 dB) and background noise (70 dB) 
were presented by a loudspeaker, mounted 24 cm above the animal. For the 
fear potentiated startle session a stainless steel shock grid, which was 
power-supplied by a Coulbourn Animal shocker, was placed into each 
Plexiglas tube. 
The startle boxes were sound-tight and isolated from each other. Between 
test sessions, the cages were cleaned thoroughly using water and 
non-perfumed soap. 
3.3 Drugs 
The drug used was RU38486 in a dosages of 3.2 mg/kg. RU38486 was dissolved 
in mulgophen/NaCl and administered at a volume of 5 ml/kg. 
3.4 Procedure 
For two days, rats were placed in the startle boxes in which the shock 
grids were installed. They were conditioned using a session of 15 trials, 
in which a signal of 3 seconds light was linked to a 1 mA shock during 0.5 
s. 
On day 3 the animals were injected with the compound or placebo and were 
placed in the startle boxes 90 min later. They were, after an 
acclimatisation period of 5 min (background noise only) confronted with 60 
acoustic noise bursts (25 ms duration). Bursts were separated by an 
interval of 15 s. Data were averaged over blocks of 5 trials. 
3.5 Results 
RU38486 (3.2 mg/kg) reduced the amplitude of the fear potentiated startle. 
The results are presented in FIG. 2. 
EXAMPLE 4 
A pharmaceutical composition based on RU38486 for the treatment of anxiety 
disorders was prepared and comprises 50 mg of RU38486 and additives (talc, 
polyvinylpyrrolidone and magnesium stearate) up to a total weight of 120 
mg. 
EXAMPLE 5 
(11.beta.,17.alpha.)-11,21-Bis4-(dimethylamino)phenyl!-17-hydroxy-19-norpr 
egna-4,9,dien-20-yn-3-one 
a) 27 g (100 mmol) of estra-4,9-diene-3,17-dione, dissolved in 270 ml of 
tetrahydrofuran (THF) and 270 ml of methanol, were cooled to -10.degree. 
C. and treated with 2.27 g (60 mmol) of sodium borohydride. The solution 
was stirred for 30 min at -10.degree. C. Work-up was accomplished by 
dropwise addition of 8 ml of 50% acetic acid. The mixture was extracted 
with ethyl acetate, the organic layers were washed with brine, dried on 
anhydrous magnesium sulfate, filtered and evaporated to dryness resulting 
in 27.2 g of 17.beta.-hydroxy-estr-4,9-diene-3-one. 
b) 25 g of the obtained material were dissolved in 375 ml of 
dichloromethane; 125 ml of ethylene glycol, 75 ml of trimethylorthoformate 
and 250 mg of p-toluenesulfonic acid were added and the mixture was 
refluxed for 20 min. After cooling, 200 ml of a saturated sodium hydrogen 
carbonate solution were added and the resulting mixture was extracted with 
dichloromethane. Evaporation in vacuo followed by purification of the 
resulting oil by column chromatography using silicagel, provided 19.9 g of 
17.alpha.-hydroxy-estra-5(10),9(11)-diene-3-one 3-(cyclic 1,2-ethanediyl 
acetal) as an oil. 
c) 19.9 g (62.9 mmol) of 17.alpha.-hydroxy-estra-5(10),9(11)-diene-3-one 
3-(cyclic 1,2-ethanediyl acetal) were dissolved in 400 ml of 
dichloromethane. 27.6 g (336 mmol) of sodium acetate were added followed 
by 36.2 (168 mmol) of pyridinium chlorochromate and the mixture was 
stirred at ambient temperature. After 2 hours, 43.5 ml of 2-propanol were 
added and stirring was continued for 1 hour. The mixture was filtered over 
celite, evaporated and partitioned between ethyl acetate (1350 ml) and 
water (675 ml). The organic layer was separated, washed with brine, dried 
with anhydrous magnesium sulfate and filtered. Evaporation followed by 
purification by column chromatography using silicagel provided 10.9 g of 
estra-5(10),9(11)-diene-3,17-dione 3-(cyclic 1,2-ethanediyl acetal). 
Melting point: 152.degree. C. 
d) A mixture of 13 g (116.2 mmol) of potassium tert. butoxide, 55 ml of THF 
and 18.7 ml of tert. butanol was cooled to 0.degree.-5.degree. C. under 
inert atmosphere. Acetylene was bubbled through the mixture for one hour; 
then 9.43 g (30 mmol) of estra-5(10),9(11)-diene-3,17-dione 3-(cyclic 
1,2-ethanediyl acetal), dissolved in 50 ml of THF were added. Stirring was 
continued for 1.5 hrs at 0.degree.-5.degree. C. under acetylene 
atmosphere. Work-up was accomplished by pouring the mixture into a 
saturated aqueous ammonium chloride solution, followed by ethyl acetate 
extraction. The organic layers were washed with brine, dried with 
anhydrous magnesium sulfate, filtered and evaporated to give 10.4 g of 
17.alpha.-ethynyl-17.beta.-hydroxy-estra-5(10),9(11)-diene-3-one 3-(cyclic 
1,2-ethanediyl acetal). 
e) 10 g (29.4 mmol) of 
17.alpha.-ethynyl-17.beta.-hydroxy-estra-5(10),9(11)-diene-3-one 3-(cyclic 
1,2-ethanediyl acetal) were dissolved in 150 ml of dichloromethane. 
Subsequently 0.91 ml of pyridine, 2.84 ml of trifluoroacetophenone and 
18.8 ml of 30% hydrogen peroxide were added and the resulting two-phase 
system was vigorously stirred at room-temperature for 36 hrs. The mixture 
was poured into water and the organic layer was washed twice with a 
saturated sodium thiosulfate solution. Drying with anhydrous magnesium 
sulfate, filtering and evaporation provided a semi-solid mass consisting 
of a mixture of epoxides. Trituration with toluene afforded 4.22 g of 
5.alpha.,10.alpha.-epoxy-17.alpha.-ethynyl-17.beta.-hydroxy-estr-9(11)-ene 
-3-one 3-(cyclic 1,2-ethanediyl acetal). 
f) 158 mg of CuCl were added at 0.degree.-5.degree. C. to a solution of 
p-dimethylaminophenylmagnesium bromide in THF, prepared from 1.49 g of 
magnesium (61 mmol), 30 ml of THF and 11.8 g (58.9 mmol) of 
4-bromo-N,N-dimethylaniline. After stirring for 30 min at 
0.degree.-5.degree. C., 4.2 g of 
5.alpha.,10.alpha.-epoxy-17.alpha.-ethynyl-17.beta.-hydroxy-estr-9(11)-ene 
-3-one 3-(cyclic 1,2-ethanediyl acetal) in 42 ml of THF were added 
dropwise. After being stirred for 2.5 hrs at ambient temperature, the 
solution was poured into a saturated ammonium chloride solution and 
extracted with ethyl acetate. The organic layers were washed until 
neutral, dried with anhydrous magnesium sulfate, filtered and evaporated 
in vacuo and the residue was chromatographed using silicagel. This 
provided after crystallization from ether/heptane 3.2 g of pure 
5.alpha.,17.beta.-dihydroxy-11.beta.-4-(N,N-dimethylamino)phenyl!-17.alph 
a.-ethynyl-estr-9-ene-3-one 3-(cyclic 1,2-ethanediyl acetal). Melting 
point: 198.degree. C. 
g) 3.0 g (6.3 mmol) of 
5.alpha.,17.beta.-dihydroxy-11.beta.-4-(N,N-dimethylamino)phenyl!-17.alph 
a.-ethynyl-estr-9-ene-3-one 3(cyclic 1,2-ethanediyl acetal) were dissolved 
in 39 ml of pyrrolidine. Subsequently 1.26 g of 
4-bromo-N,N-dimethylaniline (6.3 mmol), 33 mg of palladium(II) acetate, 33 
mg of copper(I) iodide and 99 mg of triphenylphosphine were added and the 
mixture was refluxed for one hour under inert atmosphere. After cooling, 
the mixture was poured into a 50% aqueous ammonium chloride solution and 
extracted with ethyl acetate. The organic layers were washed with brine, 
dried with anhydrous magnesium sulfate, filtered and evaporated to 
dryness, yielding a crystalline mass. Trituration with diethyl ether 
provided 2.45 g of pure 
11,21-bis(dimethylamino)phenyl-!5.alpha.,17.beta.-dihydroxy-pregn-9-ene-2 
0-yn-3-one (cyclic 1,2-ethanediyl acetal). Melting point: 150.degree. C. 
h) 2.45 g (4.0 mmol) of 
11,21-bis(dimethylamino)phenyl!-5.alpha.,17.beta.-dihydroxy-pregn-9-ene-2 
0-yn-3-one (cyclic 1,2-ethanediyl acetal) were dissolved in 123 ml of 
acetone and with stirring 4.9 ml 6N HCl were added. After stirring for 30 
min at ambient temperature, the mixture was neutralized with sodium 
hydrogen carbonate, followed by extraction with ethyl acetate. The organic 
layer was washed until neutral, dried with anhydrous magnesium sulfate, 
filtered and evaporated in vacuo. The residue was purified by column 
chromatography using silicagel. This afforded 1.2 g of pure 
(11.beta.,17.alpha.)-11,21-bis4-(dimethylamino)phenyl!-17-hydroxy-19-norp 
regna-4,9-dien-20-yn-3-one. .alpha.!.sup.20.sub.D =-12.degree. (c=1, 
chloroform). 
EXAMPLE 6 
The following products were prepared from 
5.alpha.,17.beta.-dihydroxy-11.beta.-4-(N,N-dimethylamino)phenyl!-17.alph 
a.-ethynyl-estr-9-ene-3-one 3-(cyclic 1,2-ethanediyl acetal) (see example 
5f) by using the appropriate starting material for the Heck coupling 
reaction (according to the procedure of example 5g), followed by the 
acidic dehydration and deprotection as described in example 5h: 
A using 4-bromo-(1-pyrrolidinyl)benzene the reaction resulted in 
(11.beta.,17.alpha.)-11-4-(dimethylamino)phenyl!-17-hydroxy-21-4-(1-pyrr 
olidinyl)phenyl-19-norpregna-4,9-dien-20-yn-3-one having a specific 
rotation of .alpha.!.sup.20.sub.D =-19.degree. (c=1, chloroform). 
B using 4-bromo-(methylsulfonyl)benzene the reaction resulted in 
(11.beta.,17.alpha.)-11-4-(dimethylamino)phenyl!-17-hydroxy-21-4-(methyl 
sulfonyl)phenyl-19-norpregna-4,9-dien-20-yn-3-one having a specific 
rotation of .alpha.!.sup.20.sub.D =-23.degree. (c=0.5, dioxane). 
EXAMPLE 7 
According to the procedure described in example 5f, the Cu-catalyzed 
Grignard reaction of 3,4-methylenedioxophenylmagnesium bromide with 
5.alpha.,10.alpha.-epoxy-17.alpha.-ethynyl-17.beta.-hydroxy-estr-9(11)-ene 
-3-one 3-(cyclic 1,2-ethanediyl acetal) provided 
5.alpha.,17.beta.-dihydroxy-17.alpha.-ethynyl-11.beta.-(1,3-benzodioxol-5- 
yl)-estr-9-ene-3-one 3-(cyclic 1,2-ethanediyl acetal). Melting point: 
155.degree. C. 
By using 4-bromo-N,N,-dimethylaniline for the Heck coupling reaction 
(according to the procedure of example 5g), followed by the acidic 
dehydration and deprotection as described in example 5h was prepared 
(11.beta.,17.alpha.)-11-(1,3-benzodioxol-5-yl)-21-4-(dimethylamino)phenyl 
!-17-hydroxy-19-norpregna-4,9-dien-20-yn-3-one; .alpha.!.sup.20.sub.D 
=-63.degree. (c=1, chloroform).