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Патент USA US3083207

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3,033,197’
ice
aired States
Patented Mar. 26, 1&63
2
1
tri-ol-3,20-dione, 9a-chloro-4-pregnene-17u,21-dio1-3,11,20
3,083,197
trione, 9a-?uoro-4-pregnene-ll?,17a,2letriol - 3,20-dione,
Zi-CARBAMATE DERIVATIVE 0F
QlL-HYDRGXY STEROTDS
Horace D. Brown, Fiain?eld, and Lewis H, Sareit, Prince
.1,4-pregnadiene-1lB,17u,21 - triol - 3,20-dione, 9a.-fluoro
1,4-pregnadiene-11?,17a,21-triol-3,20 - dione, 1,4-pregna
diene-17a,21-diol - 3,11,20 - trione, 9oz - ?uoro-1,4-pregna
ton, NJL, assignors to Merck & Co, Inc, Rahway,
diene-l7a,2l-diol-3,l1,20-trione, 16a-methyl-17u,21-dihy
N1, a corporation of New Jersey
No Drawing. Filed Dec. 1, 1961, Ser. No. 156,476
15 (Iiaims. (ill. 26tl-ZFS5)
droxy-1,4-pregnadiene - 3,11,20‘ - trione, l6ot-methyl-lll8,
17 a,21-trihydroxy-1,4 - pregnadiene-B‘,20-dione, 9a-?uoro
16a-methyl-17a,2‘1-dihydroxy - 1,4 - pregnadiene - 3,11,20
This invention relates to new derivatives of steroid com 10 trione, 9u.-?uoro-16a.-methyl-11,8,17a,21-trihydroxy - 1,4
pounds having cortisone-like activity; more particularly,
pregnadiene-3,20-dione, and the like.
it is concerned with new ZI-carbama-te derivatives of 21
The new 21-(4-methyl-1-piperazinyl) carbarnate de
rivatives, as well as their d-bitartrate salts are conveniently
hydroxy steroids having cortisone-like activity and with
methods of preparing these derivatives.
prepared by reacting the corresponding ZI-hydroxy
Cortisone and certain related steroid compounds have 15 steroid with a 4-methyl-1-piperazinyl carbamyl derivative,
been found to be of inesti-rnable value both locally and
as for example, 4-methyl-1-piperazinyl carbamyl chloride.
systemically in the treatment of rheumatism and arthritis.
This reaction ‘may readily be achieved by contacting the
In particular, these compounds have been found to be
carbamyl chloride with the ZI-hydroxy steroid in an inert
organic solvent, preferably pyridine, although such sol
especially valuable in the treatment of rheumatoid or
osteorithritic joints by intra~articular injection.
20 vents as benzene, toluene and the like may also be em
It is an object of the present invention to provide novel
ployed. The mixture is desirably stirred at room tem
perature for about 24—36 hours, any precipitated excess
derivatives of steroid compounds having pronounced
local cortisone-like activity, but without possessing any
appreciable systemic activity. Another object is to pro
carbamyl salt (as the hydrochloric salt) removed by ?ltra
tion and ‘the desired steroid oarbarnate recovered from
vide processes for the preparation of these new steroid 25 the ?ltrate.
derivatives. A further object is to provide new pharma
The recovery is readily achieved by evaporating the
ceutical compositions containing said novel steroid com~
?ltrate to a thick gum, which, after being (treated with
pounds. Other objects will be apparent from the detailed
potassium carbonate and dried, is then dissolved in a sol—
description of the invention hereinafter provided.
vent such as ethanol and reacted with a solution ‘of d-tar
taric acid dissolved in ethanol. The reaction mixture is
allowed to stand at room temperature for about 3-4 hours,
In accordance with the present invention, it has now
been found that steroid ZI-(N-phenyl) carbam-ates, 21
(4-methyl-1-piperazinyl) carbamates and the dsbitartrate
salts of said piperazinyl derivatives having cortisone-like
activity are valuable new compounds having pronounced
local activity. Thus, these saturated and unsaturated com
pounds of the pregnane series having an oxygen substitu
ent at C11, hydroxy substituents at C17 and C21, keto
whereupon the precipitated steroid 21-(4-methyl-l-piper
azinyl) carbamate-d-bitartrate salt is recovered by ?ltra~
tion. If desired, this product may be further purified by
recrystallization from a suitable solvent ‘such as ethanol,
acetone or the like.
'
The steroid 21-(4-methyl-1-piperazinyl) carbamate-d
groups at C3 and C20, 9, hydrogen or a halo group at C9,
bitartrate salt may conveniently be converted to the cor
and having unsaturation in the A-ring at C4 or C1 and
C4 are found to possess high local cortisone-like activity.
The new carbamate derivatives can be represented by the
responding free base by reaction of the tartrate salt with
a strong base such as sodium hydroxide or potassium hy
droxide, stirring the mixture for about 1 hour and re
partial formula:
covering the precipitated steroid 21-(4-methyl-1-pi-per
azinyl) carbamate by ?ltration. Additionally, the free
611213
base may then be converted to the corresponding acid salt
45 by reaction with a strong mineral acid, preferably hydro
chloric acid, to ‘form the corresponding steroid 21-(4
methyl-l-piperazinyl) carbamate hydrochloride or like
salt.
50
The starting material 4-methyl-l-piperazinyl carbarnyl
chloride is conveniently prepared by reacting N-methyl
piperazine with phosgene to produce 4-rnethyl-1-piper~
azinyl carbamyl chloride as the hydrochloride salt. This
reaction is readily conducted by dissolving the N-methyl
piperazine in an inert organic solvent such as benzene,
toluene, xylene or the like and contacting this solution with
phosgene gas dissolved in toluene for about 1 hour at low
temperature, preferably at approximately 0° C. The re
sulting product may then be recovered by ?ltration and
further puri?ed by conventional means. Trituration of
60 the hydrochloride salt with cold saturated potassium car
P represents a saturated or unsaturated pregnane ring
and
bonate and extraction into ether serves to isolate the
nucleus having an oxygen substituent, such as keto or
4-methyl-l-piperazinyl carbamyl chloride from its hydro
hydroxyl, at C11, hydrogen or a halo substituent at C9, and
chloride salt.
a keto group at C3, and R1 is hydrogen or lower alkyl.
The new phenyl carbarnate derivatives of the present
The terms pregnane compounds ‘or compounds of the 65
invention are readily prepared by reacting the correspond
pregnane series as used herein refers to both saturated
ing 21-hydroxy steroids with phenyl isocyanate. This
pregnanes and unsaturated compounds such as pregnenes
and pregnadienes. Examples of such compounds which
reaction is conveniently effected by intimately contacting
the phenyl isocyanate with the 21-hydroxy steroid in a
are found to possess high local activity that might be men
tioned are the ZI-(N-phenyl) carbamate and 21-(4 70 suitable inert solvent medium such as benzene, toluene,
rnethyl-l-piperazinyl) carhamate derivatives of 4-preg
nene-l7a,2l-diol-3,ll,20 - trione, 4-pregnene-11B,17a,21
xylene, dimethoxyethane, ethyl benzene, and the like.
Thus, the preparation of the phenyl carbamate compound
3,083,197
3
4
is most conveniently carried out by heating the reactionv
mixture consisting of the pregnane alcohol and the phenyl
isocyanate in the inert solvent for sutlicient time to com
plete the formation of the desired phenyl carbamate. In
remove solvent and excess isocyanate. When the residue
is crystallized from acetone-ether, 1,4-pregnadiene-1l?,
17oz.,21-triol-3,20-dione ZI-(N-phenyl) carbamate is ob
tained in crystalline form.
carrying out the reaction, it is desirable to have an excess
of the phenyl isocyanate present over the one mole theoret
In accordance with the foregoing procedure, but start
ing with 1,4'pregnadienel7e,21—diol-3,11,20-trione, there
is obtained the corresponding 1,4-pregnadiene-17a,2l
diol-3,11,20-trione ZI-(N-phenyl) carbamate.
ically required per mole of the steroid alcohol in order
‘to insure completion of the reaction and the recovery of
maximum yields of the desired product. In general, it
EXAMPLE 3
is preferable to carry out the reaction in an essentially 10
dry medium, since under these conditions maximum yields
of desired product are obtained under optimum, condi
tions.
9a-Flu0ro-4-Pregnene-I 1 5,1 7a,21-Tri0l~3,20-Di0ne
21 -(N-Plzenyl) Carbamate
A solution of 1.41 g. of 9u-?uoro-4-pregnene-115.17%
The phenyl carbamates are conveniently recovered from
the resulting reaction mixture by evaporating the solvent 15 2l-triol-3,20-dione in 25 ml. of toluene is dried by dis
tilling oil a few \mls. of solvent. Then 2 ml. of phenyl
and any excess phenyl isocyanate under reduced pressure,
isocyanate is added and the mixture heated under re?ux
and crystallizing the resulting residue containing the de
for three hours.
sired product from a suitable solvent or solvent mixture
and the like.
1
The reaction mixture is then concen
trated under reduced pressure to remove most of the sol
such as acetone, acetone-ether, acetone-petroleum ether,
20
In accordance with another embodiment of this inven
tion, there are provided novel pharmaceutical prepara
tions containing these new carbamate derivatives. Com
positions comprising suspensions ofthese carbamates in
vent and excess isocyanate.
The resulting residue con
taining the 9a-?uoro-4-pregnene-l1p,17u,2‘1-triol-3,20-di
one ZI-(N-phenyl) carbamate is then washed with a few
small portions of ether to remove traces of excess iso
cyanate and the diphenyl urea which forms as a minor
suitable pharmaceutical vehicles and carriers can be pre 25 by-product. Crystallization of the washed residue affords
crystals of substantially pure product.
pared in accordance with methods well known in this art.
In accordance with the foregoing procedure, but start
For example, suitable suspensions in aqueous saline can
ing
with 9a-?uoro-4-pregnene-17a,21-diol-3,11,20-trione,
be prepared pursuant to methods wellrknown in this'art.
there
is obtained the corresponding 9oa-llt10i'O-4-PI‘6gH6I1C
In addition, suspensions of these carbamates in. non
aqueous mediums are likewise prepared ‘in accordance with 30 170;,21rdiol-3,11,20~trione 2l.-(N~phenyl) carbamate.
methods described in this art. Similarly, aqueous solu
EXAMPLE 4
tions of the water soluble salts may be employed.
9m-Flu0ro-1,4-Pregnadiene-11d,]7a,21-Tri0l-3,20-Dione
Although the concentration of the active ingredient in
21~(N—Phenyl) Carbamate
the novel pharmaceutical preparations may be varied
'within wide limits, it is preferred to employ the carbamate 35
When’ 1.4 g. of 9u-?uoro-1,4-pregnadiene-l1p,17a,2lcompounds in an amount ranging from about 0.1% to
triol-3,20-dione is reacted'with 2 ml. of phenyl isocyanate
about 25% by weight of the composition, depending on the
in about 20 ml. of dry toluene at re?ux temperature for
particular pharmaceutical vehicle and the use intended.
about two hours and'the resulting reaction product is re
Vehicles containing from about 1% to 5% of the active
covered as described in Example 3, 9u-?uoro-1,4-pregna
phenyl carbamates have been found to be particularly
diene - l=1/8,17a,21 - triol-3,20-dione 21-(N-phenyl) car
satisfactory and are therefore preferred.
bainiate is obtained.
The following examples illustrate methods of carrying
In accordance with the foregoing procedure, but start
out the present invention but it is to be understood that
ing with 9a-fluoro-1,4-pregnadiene-170¢,21-di0l-3,11,20-tri
these examples are given‘for purposes of illustration and
one, there is obtained the corresponding 9a-?uoro-1,4
not of limitation.
'
45 pregnadiene-17a,21 - diol- 3,11,20-trione 21-(N-phenyl)
carbamate.
EXAMPLE 1
EXAMPLE 5
4-Pregnene-1 1,9,1 7a,2]-Tri0l-3,20-Dione 21 - (N-Pkenyl)
Carbamate
4-Methyl-1-Piperazinylcarbamyl Chloride
A solution of 0.7 g. of 4-pregnene-11e,17<x,21-tri0l-3,20=
Phosgene gas is passed into 460 m1. of ice-cold toluene
50
‘dione in 25 ml. of benzene is dried by distilling oif about
until 200-250 g. (2.02-2.53 moles) are collected. To
5 ml. of benzene. Then 5 ml. of phenyl isocyanate is
this solution at 0° C. is added 17.2 g. N-methyl-piperazine
added to the dried benzene solution, and the resulting re
(0.172 mole) dissolved in 200 ml. of toluene over a one
action mixture is heated under re?ux for four hours. The
half hour period; The mixture is stirred at 0° C. for
mixture is then cooled and concentrated under reduced 55 one hour and then at 25° C. for two hours. The hydro
pressure to remove the benzene and excess isocyanate
chloride salt of the product is ?ltered, washed with toluene
leaving as a solid residue the 4-pregnene-l1/3,17u,21-triol
and then with ether. After removing most of the ether at
3,20-dione ZI-(N-phenyl) carbamate. This residue. is
40° C. under reduced pressure the entire precipitate is
washed with a small amount of acetone to remove impuri
added to a stirred, ice-cold'mixture of 100 ml. saturated
ties and then crystallized from a mixture of acetone-ether 60 potassium carbonate, 120 ml. methylene chloride, and 80
to yield crystals.
ml. petroleum ether. The organic layer (upper layer)
In accordance with the foregoing procedure, but start?
ing with 4-pregnene-17a,21-diol-3,11,20-trione, there is
is removed, washed with 50 ml. Water and dried over
sodium sulfate. After removing the solvents at room
temperature under reduced pressure, an. oily residue of
obtained the corresponding 4-pregnene-17u,2l~diol—3,11,
4-methyl-l-piperazinylcarbamyl chloride is obtained.
20-trione 21-(N~phenyl) carbarnate.
65
EXAMPLE 2
' 1,4-Pregnadiene-1L6J 70:,21 -Triol-3,20-Di0ne
21 -(N-Phenyl) Carbamaze
To a dry solution of 1.44 g. of 1,4-pregnadiene-11B,17a, 70
2l-triol-3,20-dione in about 20 ml. of dimethoxy ethane
is added 0.62 g. of phenyl isocyanate. The resulting re
action mixture is heated to re?ux temperature for about
EXAMPLE 6
9oz - Fluoro-l 6a-Metlzyl-11B,I7ot,21-Trihydr0xy-1,4-Preg
nadiene - 3,20 - Dione 21 - (4-Methyl-I-Pz'perazinyl)
Carbamate-d-Bitartrate Salt
9a-fluoro-l6a-methyl—l 1B,17a,21-trihydroxy-1,4 - preg
nadiene-3,20~dione (15.35 g., 0.0391 mole) is added to a
solution of 19.0 g. (0.117 mole) freshly prepared 4
one and one-half hours. The reaction mixture is then
.methyl-l-piperazinylcarbamyl chloride in 138 ml. of dry
concentrated to a dry solid under reduced pressure to 75 pyridine. The mixture is stirred at 25° C. for 24 hours
3,083,197
6
5
during which time ‘a ?ne crystalline precipitate of 4-meth
there is obtained the corresponding
yl - 1 - piperazinylcarbamyl chloride hydrochloride is
90: - ?uoro-lGet-methyl-1706,21-dihydroxy-1,4-pregnadiene
formed. The precipitate is removed by suction ?ltration
3,11,20-trione 21-(4-methyl-1-piperazinyl) carbamate,
16a-methyl-17u,21—dihydroxy-1,4-pregnadiene-3, 1 1,20-tri
and washed with pyridine. The combined ?ltrates are
evaporated under reduced pressure to a thick gum and the
one 2l-(4-methyl-1-piperazinyl) carbamate,
residue triturated with 100 ml. 10% potassium carbamate
with stirring. The solidi?ed product is collected by suc
tion ?ltration, washed with water, and dried at 50° C.
16a-methyl-11B,17¢x,21-trihydroxy-1,4-pregnadiene-3,20
dione 21-(4-methyl-1-piperazinyl) carbamate,
9a-?uoro-1 1B,17a,21-trihydroXy-1,4-pregnadiene-3,20-di
under reduced pressure. This product is dissolved in 210
ml. absolute ethanol and a solution of 21 g. of d-tartaric 10
acid dissolved in 100 ml. absolute ethanol is added. After
standing at room temperature for three hours the pre
cipitated crude tartrate salt is ?ltered, washed with ethanol,
and dried at 50° C. The crude product is recrystallized
from 1500 ml. 90% ethanol, the hot solution being treated 15
one 21~(4-methyl-1-piperazinyl) carbamate, or
1 16, 17a,21-trihydroXy-1,4-pregnadiene-3,20-dione 21-(4
methyl-l-piperazinyl) carbamate.
Example 8
Fifty-eight mg. (l-milli-mole) of 9u-?uoro-l6a-methyl
11,8,17a,21 - trihydroxy-1,4-pregnadiene-3,20-dione 21-(4
methyl-l-piperazinyl) carbamate is dissolved in 5 ml. of
dry ethanol. To this is added 1 ml. of absolute ethanol
for one hour prior to ?ltration of the product. After
containing 10% anhydrous hydrogen chloride. This so
drying at 50° C. under reduced pressure there is obtained
9u—?uoro - 16a-methyl-l1,8,17a,21-trihydroXy-1.4-pregna 20 lution is then triturated with dry ethyl ether to induce
with 2 g. nuclear C 1000 N. The clear ?ltrate is stirred
over night at room temperature and then stirred at 10° C.
precipitation of the hydrochloride salt of 9zx-?l1or0-l6a
diene-3,20-dione 21-1-(4-methyl-1-piperazinyl) carbamate
methyl - 11B,17u,21 - trihydroxy - 1,4 - pregnadiene-3,20
d~bitartrate salt.
dione 21-(4-methyl-1-piperazinyl) carbamate. Ethyl ace
In accordance with the foregoing procedure, but start
tate solutions (freshly prepared) of hydrogen chloride
ing with 9a-?uoro-l6u-methyl-17a,21-dihydroxy-1,4-preg
nadiene - 3,11,20—trione, 16u~methyl-17a,21-dihydroXy-1, 25 may be substituted for the alcoholic HCl.
Various changes and modi?cations may be made in
4 - pregnadiene-3,l1,20atri0ne, 16a-methyl-11B,17u,21-tri
hydroXy - 1,4 - pregnadiene-3,20-dione, 9a-?uoro-'1=1,8,17oc,
carrying out the present invention without departing from
the spirit and scope thereof. Insofar as these changes
21 - trihydroxy - 1,4 - pregnadiene-3,20-dione, or l1/3,l7a,
21 - trihydroxy ~ 1,4 - pregnadiene-3,20-dione, there are
and modi?cations are within the purview of the annexed
obtained the corresponding 9a-?uoro-16a-methyl—17a,21 30 claims, they are to be considered as part of our invention.
We claim:
1. A compound selected from the group consisting of
21-(4-methyl-1-piperazinyl) carbamate of an ll-oxygen
dihydroxy - 1,4 _ pregnadiene - 3,11,20—trione 21-(4ameth
yl - 1 - piperazinyl) carbarrrate-d-bitartrate salt, 16a-meth
yl-17a,21 - dihydroxy - 1,4-pregnadiene-3,11,20-trione
21 _ (4 - methyl-l-piperazinyl) carbamate-d-Ibitartrate
salt, 16m - methyl-11B,17<x,21-trihydroxy-1,4-pregnadiene
ated-16-methyl-17a,21 - dihydroXy-3,20-diketo compound
35 of the pregnane series and the d~bitartrate salts thereof.
2. 9a~?uoro - 16 - methyl-11B,17a,21-trihydroxy-1,4
3,20 - dione 21 - (4-methyl-1-piperazinyl) carbamate-d
‘bitartrate salt, 90: _ ?uoro - 11?,17a,21-trihydroXy-1,4
pregnadiene-3,20-dione 21-(4-methyl-1-piperazinyl) car
barnate-d-bitartrate salt.
pregnadiene - 3,20 - dione 21 - (4~methyl-1-pipenazinyl)
3. 9a-?uoro-16-methyl-17oz,21-dihydroxy - 1,4 - pregna
carbamate - d - bitartrate salt, or 11;8,17o¢,21-trihydroxy
1,4 - pregnadiene - 3,20 - dione 21-(4-methy1-1-piper
diene-3,11,20-trione 21-(4-methyl-1-piperazinyl) carba
azinyl) carbamate-d-bitartrate salt.
mate-d-bitartrate salt.
4. 16-methyl-17a,2l-dihydroxy - 1,4 - pregnadiene-3,11,
EXAMPLE 7
20-trione 21-(4-methy1-1-piperazinyl) carbamate-d-bitar
trate salt.
9m - Fluor0-16u-Methyl-116J70:,21-Trihydr0xy-1,4-Preg
nadiene-3,20-Di0ne 2] -(4-Methyl-1-Piperazinyl) Carbu 45
mate
.
5. 16-methyl-11?,17a,21-trihydroXy - 1,4 - pregnadiene
3,20-dime 21-(4-methyl-1-piperazinyl) carbamate-d-bi
tartrate salt.
To a stirred solution of 3.05 g. of 9a-?uoro-16a-methyl
6. 9a-?uoro-11B,17a,21-trihydroxy - 1,4 - pregnadiene
1113,17a,21 - trihydroxy-l,4-pregnadiene-3,20-dione 21-(4
3,20-dione 21-(4-methy1-1-piperazinyl) carbamate-d-bi
methyl-l-piperazinyl) carbamate-d-bitartrate salt in 300 50 tartrate salt.
ml. of water is slowly added 4 ml. 2.5 N sodium hydrox
7. 11,B,17a,21-trihydroXy - 1,4 - pregnadiene-3,20-dione
ide. The ?nal pH of the mixture is about 11. The mix
21-(4~methyl-1-piperazinyl) carbamate-d-bitartrate salt.
ture is stirred for ?fteen minutes and the white product
8. .9oc-?tl0f0 - 16 - methyl-11,3,17u,21-trihydroXy-1,4
is removed by suction ?ltration and washed with water.
pregnadiene-3,20-dione 21-(4-methyl-1-piperazinyl) car
After drying at 50° C. under reduced pressure, there is 55 barnate.
-
obtained 9oz-?1l0IO-l6oc-In6thYl-l 1,3,17a,21-trihydroxy-1,4
9. 9a-?uoro~16~methyl-17a,21-dihydroXy - 1,4- - pregna
pregnadiene-3,-20-dione 21-(4-methyl-1-piperazinyl) car
diene-3,11,20-trione 21-(4-methy1-1-piperazinyl) carba
bamate.
mate.
In accordance with the foregoing procedure, but start
ing with
9a-?uoro-16a-methyl-17a,21 - dihydroxy-1,4-pregnadiene
3,11,20-trione 21-(4-methyl-1-piperazinyl) carbamate-d
bitartrate salt,
10. 16 - methyl-lh?l-dihydroxy - 1,4 - pregnadiene
60
3,11,20-trione 21-(4-methyl-1-piperazinyl) carbamate.
11. 16-methyl-11B,17u,21 - trihydroxy-1,4-pregnadiene
3,20-dione 21-(4-methyl-1-piperaziny1) carbamate.
12. 9oc-?IlOl‘O-l l/3,l7oc,2l - trihydroXy-l,4-pregnadiene
3,20-(hone 21-(4-methyl-1-piperazinyl) carbamate.
16u-methyl-17a,21-dihydroxy - 1,4 - pregnadiene-3,11,20 65
13. 1l?,l7oc,21 -trihydroxy-1,4-pregnadiene-3,20-dione
trione 21-(4-methyl-1-piperazinyl) carbamate-d-bitar
21-(4-methyl-1-piperazinyl) carbamate.
trate salt,
16a~methyl-1113,17a,21 - trihydroxy-1,4-pregnadiene-3,20
:dione 21-(4-methyl-1-piperazinyl) carbamate-d-bitar
trate salt,
9a—?uoro-11?,17a,21-trihydroxy - 1,4 - pregnadiene-3,20
dione 21-(4-methyl-1-piperazinyl) carbamate-d-bitar
trate salt, or
11p,17a,21 - trihydroxy-1,4-pregnadiene-3,ZO-d-ione 21-(4
methyl-l-piperazinyl) carbamate-d-bitartrate salt,
14. ‘The process which comprises reacting an ll-oxy
genated-l7a,21-dihydroXy-3,20-diketo steroid compound
of the pregnane series with a 4-methyl-1-piperazinyl salt,
70 thereby forming the corresponding 21-(4-methyl-1~piper
azinyl) carbamate, contacting said carbamate compound
with d-tartaric acid to produce the corresponding 21-(4
methyl-l-piperazinyl) carbamate-d-bitartrate salt, and
heating said salt with a strong base to yield the free
75 steroid 21-(4-methyl-1-piperazinyl) carbamate compound.
3,083,197
7
,
15. The process according to claim 14 wherein the
pregnane compound is 9a-?uoro-16oz-methyl-11;8,17a,—21tr-ihydroxy-1,4-p-regnadier1e-3,ZO-dione.
'
'
8
Korman et a1 __________ __ Feb. 10, 1959
Hogg __'____2_'_________ .. Feb. 2, 1960
-
'
References cued m the ?le of thls Patent
UNITED STATES PATENTS
2,s73,271
2,873,285
2,923,722
Korrnan et a1 _____ __'_____ Feb. 10, 1959
OTHER REFERENCES
5
Royals: Advanced Organic Chemistry, page 609, Pren
tice-Hall, Inc., Englewood Cliffs, NJ., 1954 edition, sec
0nd Prmfmg ‘
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