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Патент USA US3079309

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3,079,301
Patented Feb. '26, 1963
“
1
2
3,979,301
ates, valerates, isovalerates, as well as ‘the hemi-suc
cinates, malonates and maleates, and ‘also the‘esters of
glycollic, citric, tartaric and aminoacetic acids; and of
9a-HALQ - 1,4,6 - PREGNATRHENES AND THERA
PEUTIC COMPOSHHUNS CGNTAINENG SAME
David H. Gouid, iseenia, and 'Hershel L. Herzog, Moun
tainView, NJ” ass'ignors to Schering Corporation,
Bloom?eld, Ni, a corporation of New Jersey
cycloaliphatic acids,'like cyclopentyl and cyclohexyl car
5 boxylic, acetic and propionic acids and hexahydrophthalic
acid; and of aryl carboxylic acids, like the ben'zoates,
salicylates, veratrates and :phthalates; and the conden
..
No Drawing. Fiied Apr. 25, 1956, Ser.No. $80,137:‘:
12 Claims. (til. 167-477)
sation products of these ke’to-alcohols and keto-esters with
ketone reagents of the'a‘rnine type, including the semi
The present invention relates to a process for the 10 carbazones, thiosemicarbazoneis, hydrazones and oximes;
manufacture of new 1,4,6i‘pregnatri'ene-2l-ol;3,20-diones
and also the S-cycloketal and 3iacetal derivatives, as
and their esters, and to the compounds obtained'there'by.
the ethylene and 1,2-propyléne glycol ketals of the spe
This application is a continuation-in-part'of our co
ci?c trienes named-above, and produced by known meth
pending ‘application Serial No. '5 13,901, ?led June 7, 1955.
ods, and ‘when‘th'e 21-hy'droxyl is free, also the 3,20-bis
The invention relates in particular to the'manufact'ure 15 ketals.
Longer-acting‘ esters ‘of 1,4,6-pregnatriene-17a,2l-diol
‘of 9a-halo-l,4,6 - pregnatriene-l7e,21 - diol-3,20-diones
having a B-hydroxyl or ketonic oxygen ‘at the l-l-position,
‘and of certain derivatives of these compounds. The coin
.pounds of our invention are characterized by adreno
3,11,20-trione, 1,4,6-pregnatriene ‘- ‘11B,17a,21-triol~3,20
dione’and their Qa-halo (i.e., ?uoro, chloro and bromo)
derivatives may be obtained by converting these com
cortical hormone activity, and particularly by an anti 20 pounds into their 21-esters of the following acids; cyclo
in?ammatory glucocorticoid and 'mineralocorticoid ac
hexanecarboxylic acid, 4-methylcyclohexanecarboxylic
tivity which is generally superior to'that of cortisone, so
acid, 3-ethyl-cyclohexylacetic acid, cyclohexylpropionic
that they are useful in the treatment of adrenal de?cien
acid, cyclopentylrpropionic acid, phenylacetic acid, tri
methylacetic acid, tlbutylacetic acid, butoxybutyric acid,
eases. They are suitable also for use as intermediates
ethoxy-caproic acid, methylthiovaleric acid, isopropyl
for the manufacture of known pregnadiene compounds
thioac'etic acid, phenylthioacetic acid, caproic acid, iso
having adrenocortical activity, as will be explained here
butyric acid, enanthic acid, isoaprylic acid, cyclohexyl
inbelow, and of new pregnatetraenes as described and
caproic acid, undecylenic acid, Z-ethylbutyric acid, toluic
claimed in the copending application of Gould, Hersh
acid, ethoxybenzoic acid, phenoxyacetic acid, p-chloro
berg and ‘Shapiro, Serial No. 559,514, ?led January 17, 30 phenoxyacetic} ‘acid, 2,4-dichlorophenoxyacetic acid,
1956, now abandoned in favor of a continuing appli
2,4,5-trichlorophenoxyacetic acid, S-chlorofuroic acid,
cation, now United States Patent No. 2,864,835.
S-methylfubric acid, S-bromofuroic acid, 4-bromophen
The present invention provides a process for introduc
oxyacetic acid, ‘4-methylphenoxyacetic acid, 4-methoxy
ing one, two, or three double bonds into the correspond
phenoxyacetic ,4-t.-butylphenoxyacetic ‘acid, 5-t.-butyl
cies, in?ammatory disorders and certain collagen dis
ing 1,4-pregnadiene, 4-pre‘gnene and saturated pregnane
compounds, respectively, to produce 1,4,6-p'regnatrienes.
The starting ‘compounds may be, for example, “the 1712,
35
furoic acid, furoicjacid-and phenoxypropionic acid.
By the use of these'esters, ‘the frequency of admin
istration can be greatly reduced while providing adequate
2i-dihydroxy-3,2G-diketo vpregnanes having ‘a keto or
hormone activity.
'
hydroxyl group at'the l'l-carbon or'a 9,11-0Xido group,
The compounds of our invention fall within the fol
and the corresponding 4-pregnenes and 1,4-pre'gnadi'enes, 40 lowing general formula:
‘and the esters ~03": these compounds.
The cortical hormone activity of the pregnatrienes of
our invention is quite surprising in view of the fact that
none of the known steroid adrenal hormones is triply
unsaturated; and, moreover, it is known that 6-dehy 45
drocortisone and G-dehydrocortisol are of a reduced
order or} activity as adrenocortical hormones, whereas
the corresponding 1,4,6-trienes have at least in certain
respects higher activity than cortisone and hydrocortisone,
as will be explained more fully hereinbelow.
50
°=
When not originally produced from the corresponding
known 1,4-dienes, the trienes of our invention can, if
desired, be converted to the dienes by limited and selec
tive reduction at the 6,7-double bond. Thus, 1,4,6
pregnatriene-lhll - diol - 3,11,20-trione and 1,4,6-preg
natriene-l1/3,17u,2l-triol-3,20-dione and their esters can
be reduced to the known highly active 1,4-pregnadiene
17¢,2l-diol73,1'1,2O‘-trione and 1,4-pregnadiene-11p,17u,
ZI-triol-LZO-dione ( l-dehydrocortisone- and‘ 1'-dehydrocor
tisol) and their esters.
The compounds ‘of our invention include 9u-halo
\/
wherein
X is O or
55
.fH
(
‘on
R is H or acyl;
W is F, C1, or Br.
60
With reference to the acyl group at the 21-position,
while the lower alkanoyl groups are generally preferred,
1,4,6-pregnatriene-l15,1'Za,21 - triol-3,20-dione, 9a-halo
any suitable pharmaeeutically acceptable acyl group may
l,4,6¢pregnatriene - 170;,21 - diol-3,l1,20-trione, the halo
be present at such position, such as the acyl groups of
the acids hereinabove named.
group being ?uorine, chlorine or bromine, and also the
ill-esters of all of these trienes esteri?ed or not at the
Our new compounds are prepared by halogenation,
l'l-position (in the case of the ll-hydroxy compounds),
_ including the esters of lower fatty acids, especially the
preferably bromin‘ation, and dehydr'olialdgena‘tion of the
corresponding pregnan'es, 4‘-pr'egne'nes and 1,4-pregnadi
“acetates, but including the formates, propionates, butyr
enes, usually with a'protective ester grouping at the 21
3,079,301
3
In the above equations, Ac stands for an acyl group,
position. The preparation of the compounds is illustrated
by way of example in the following reaction schemes:
speci?cally actyl; and NBS is N-bromosuccinirnide.
(A)
(H), which is then dehydrobrominated to produce (ill).
On reacting the latter with a hydrohalic acid (Equation
B), the 9a-halo-1l/9-OH derivative of the triene (1V) is
obtained. Saponi?cation of (1V) yields the free 2l-alco
hol (Equation C); while oxidation of the ll?-hydroziyl
Procedure A converts (I) to the G-bromo derivative
onto-o 0 OH:
t=°
—--OH
5
<\
l 0 j
/
~
produces the 21-ester of the Qua-halo derivative of 1,6-bis
.
(\
NBS
0:
dehydrocortisone (V, Equation D), which can be saponi
10
-—>
lied to the free 21-a1cohol (Equation E).
While the use of collidine is generally preferred for
(I)
effecting dehydrohalogenation, other organic bases, pref
t‘3Hg0Ae
C=O
erably tertiary bases, can be employed, like pyridine and
bases having a boiling point above that of pyridine, like
|___0H
15 dimethylaniline, diethylaniline, quinaldine, 2,4- and 2,6
f; j
/\
lutidine and quinoline, and mixtures of these bases with
high boiling hydrocarbons, such as xylenes, cumenes, and
//
(
o__
(-HB r)
(H)
V
the like.
As above indicated, the esters are preferably those of
the lower fatty acids; however, other acids or their an
hydrides or chlorides can be employed equally well for
e?eeting esteri?catio-n of the hydroxyl groups at the 11
20
(a) org. base, heat
((2) Ag salty,
Br
organic base, heat
and Zl-positions. As is known, the lie-esters of acetic
CHrOAe 25 acid and its higher homologues are di?icult to form and
/\I
\
also dif?cult to hydrolyze. However, the 11B~formate
10:0
—--OH
I I/O/1
3
can be easily formed and easily hydrolyzed, and, as we
have found, the same is true of the ll?-t-r-i?uoroacctate.
The present invention accordingly provides a process
for the manufacture of therapeutically active preg
natrienes in which, in its broader aspect, derivatives of
0
pregnane, 4-pregnene and 1,4-pregnadiene, all similarly
0:
(B)
(III)
CHzOAC
substituted by the groups 9ot-W-l1-X-l7u-ol-21-OR-3,20
dione, or 9,1l-oxido-l7a-ol-2l-OR-3,20-dione, wherein
35 R, W and X have the signi?cance indicated above, are
reacted with a brominating agent, such as bromine or an
N-bromo saturated aliphatic acid amide, such as N
bromo-acetamide or N-bromo-succinimide, to introduce
bro-mine at least at the 6-position (in the case of the 1,4
=0
40 diene starting compound), or additionally at other posi
tions (in the case of the pregnene and pregnane com
BK
(III)
chhrinated
hydrocarbon or
0 Ac
pounds), followed by dehydrobrornination to introduce
three, two or one double bond, respectively, into the
O:
starting compound to form the pregnatriene. The 9,11
45 oxido-l,4,6-pregnatrienes are additionally reacted with
(C)
hydrogen ?uoride, chloride or bromide, to produce the
9a-halo-l l?-hydroxy compounds.
The 1,4,6-pregnatriene-17a,21-diol-3,l1,20-trione and
1,4,6-pregnatriene-1l?,l7a,21-triol-3,20-dione (and their
50 2l-esters), i.e., the 1,4,6-trienes, corresponding to corti
sapcn
(IV :2)
KH O 05 or
NaOH or
_
NaOMe
(D)
sone and hydrocortisone and their esters, have superior
corticoid activity of the order of that of l-dehydrocor
tisone and l-dehydrocortisol, particularly with respect to
anti-in?ammatory activity, which is 3 to 5 times that of
55 cortisone itself. Anti-in?ammatory corticoids are known
to depress the eosino-phil level in blood and we have
found that 1,4,6-pregn-atriene-1l?a,17a,21-triol-3,20-dione
in a dose only one-fourth that of cortisone, causes cosi
nopenia equal to that of cortisone. It is also known that
60 anti-inflammatory corticoids cause increased deposition
of glycogen in the liver. We have found that 1,4,6-preg
oxidize
(IV)
natriene - 17a,2l-diol-3,11,20-trione, as the 21 - acetate,
causes glycogen deposition to the extent of four times
that of cortisone, a greater ettect than that obtainable
GrO3 or
NB A pyridine, O
t-butanol
(a)
6r
with 1,4-pregnadiene-17a,2l—diol-3,11,20-trione, which
"
only has three times ‘the e?ect of cortisone in this test.
Our pregnatrienes have, therefore, a hormonal and anti
iarthritic e?ect equal to or greater than that of l-dehydro
cortisone and -cortisol. Because of their potent effect on
70 sodium retention, the 9a-halo pregnatrienes are especially
useful in treating Addison’s disease and in maintaining
adrenalectcmized patients.
sapon.
(V 6)
NaH 0 0
son or hiaorre o=
'
I
75
The high order of activity of our new compounds is
all the more surprising when the effect is examined of
introducing a 6,7-double bond into cortisone to obtain
3,079,861
5
.
‘D. 1,4,6-Pregnatriene-1 7u,-21-Di0l-3,11,20-Tri0ne
4,6-pregnadiene-17a,2l-diol-3,11,20-trione. This latter
substance has been known for some time [Mattox and
‘Kendall, J. Biol. Chem., ‘197, 261 (1952)], and study of
‘A sample‘of 10.1 g. of ‘the product of procedure C is
dissolved in 1 ml. of chloroform and 4 ml. of methanol.
To this are added 0.4 ml. of water and 0.2 m1. of con
"its ‘physiological properties has revealed that, relative to
vcortisone, it has; (1') a decreased eosinopenic effect,
(2) a decreased effect on involution of the thymus gland,
centrated hydrochloric acid at 20° C. The mixture is
diluted vwith water ‘after two days and extracted with
‘chloroform. Evaporation of the ‘chloroform solution
gives the crystalline free-'diol product.
(3) a decreased ability ‘to cause glycogen deposition, and
(4) a decreased anti-in?ammatory action. All of these
"effects‘have‘served as useful indications of the value of
corticoids as anti~arthritic substances, and in each case 10
the 4,6-diene has 1/2 or less of the activity of cortisone.
'A. 2,2,4,o-Tetrabromo-4-Pregnene-I15,17a,2'1-Triol-3,20
Furthermore, we have found that the pregnatrienes of
‘our invention have certain'differenc'e's in ‘physiological ac~
Diana 1‘] -F0rmat-e 21 -Acetate
tion over the known glucofcorticoids which further dis
t-in‘guish them from'tlieknown compounds. In particular,
"it has been observed that cortisone, cortisol, l-dehydro
cortisone and l-dehydrocortisol, ‘all “of the‘ glucocorticoids
EXAMPLE 2
Ten - g. of pregn'ane-ll?,17ot,21-triol-3,20#dione ‘1'1
15 for'rnate 21-acetate (M.P. 209-212° C.) is dissolved -in
50 ml. of methylene chloride and 20 ml. of acetic acid.
presently used for the treatment of arthritis, cause loss of
To'this is added everyone-‘half hourasolution of 7.4 g.
used hormones, but are practically devoid of this undesir
able catabolic action, as they do not cause loss-of pro
tion is Washed thrice withwatendried and evaporated to
a resin. Crystallization from acetone-methanol gives the
‘desired tetr'abromo formate acetate, MZP. ~1>0.0—‘1'10° ‘( de‘c.).
B_ 2,4-D ib ram 0;],4,6_Pregnatrien3e-1 1 {3,1 7a,21 -Trl'0l-3,20
of bromine in 20 ml. of methylene chloride as the solution
proteinaceous colloid from therthyroid gland. ,This is in
decoloriz‘es. Then the reaction is irradiated with a 500
'lirie‘wi'th the known protein 'catabolic‘e?ect of thesehor "20 wattfphoto?ood
lamp, and'over a period of one hour a
mones which is conceded'to be an‘undesirable side-effect.
"solution of _l1.'1 ‘g. of bromide in72'0'rnl. of acetic vacid is
'Our new ‘compounds, ‘on the other hand, surprisingly re
"added. 'Afteriadditional‘irradiation ‘or th'reel'hours’ dura
tain thedesirable>anti~arthritic properties of the presently
tion, the mixture is allowed to stand overnight. The solu
teinaceous colloid from the thyroid gland.
,
Satisfactory procedures for'the preparation of the preg
n'atrienes of our invention are described in detail by way
of illustration in the following’ examples:
EXAMPLE '1
' Dione 1 1 -F0rmaz‘e '21 -A cefate
30
T025 ml. of re?uxing collitlone’are addedS got ‘the
tetrabromo ‘formate acetate and the mixture vis re?uxed
with'stirrin'g for‘ one hour. Theimi'xtureis- cooled, poured
A. 2,6-Dibromo4-Pregnéneé17u,21-Di0l-3,11,20
into excess dilutesulfuric-acid and‘ ice, and the oily sus
Trione 21 -Acetaz‘e
Ten g. of cortisone acetate are'dissolved in 75 ml. of
pension is extracted with methylene chloride, washed with
water and dried. The ‘solution is‘ chromatographed on
methylene chloride and 50 ml. of acetic acid. To this
magnesium silicate ‘and elution ‘with ether separates vthe
stirred solution are added 8.2 g. of bromine 'in 25 ml.
desired dib'romo triene.
of acetic acid, the'bromine solution being added gradually
C. 1,4,6-Pregnatriene-1 15,1 7 a,21 -Tri0l-3,20-Di0ne
_ as the color disappears. After'the addition is completed,
1 I eFormate 21 -A cetate
stirring is continued for thirty minutes, the mixture is 40
concentrated in vacuo and then poured into water. The
Two g. of the product of Example 2B, are dissolved in
separated and dried precipitate is the desired dibromide,
5 ml. of ethylene'chloride and 5 ml.fof acetic acid and
stirred with 2 g. of zinc dust for ‘thirty minutes. The
M.P. 125-130° (dec.), E max. ‘at 242 mp, (00;; +80
(dioxane).
45
B. 1 ,4,6-PregnYzttriene-J 7oz,21 -Di0l-3,1 1 ,20-1‘rione
21-Acetate 3-Semicarbazone
?ltered solution is evaporated to a resin, and the crude
product is puri?ed by chromatography on magnesium
silicate.
The fraction eluted with ether contains the
desired product.
Ten g. of the dibromide prepared as above are dissolved
vD. I,4,64Pfegriatriene-IIQJ7a,21-Tri0l-3,20-Di0ne
at 60° in 150 ml. of tert.-butyl alcohol and 120 ml. of 50
A sample of 0.5 ‘g. ofthe for-mate acetate of Example
alcohol-free chloroform under an atmosphere of carbon
2C-is dissolved in 10 ml. of methanol and nitrogen is
dioxide. To this are added 4.5 g. of semicarbazide base
bubbled through. The solution is stirred and a solution
and the mixture is stirred two hours at 60°. The solvent
of'0.14'g. of potassium hydroxide in 3 ml. of water is
is then evaporated to remove‘ chloroform and the residual
solution is poured into water. The dried precipitate is 55 added dropwise over three hours. The mixture is'then
stirred overnight at room temperature. The solution is
.the trienetrione semioarbazone, M.P. 185-190" (dec.),
diluted with water, extracted with methylene chloride,
U.V. vIna-x. at 310 my.
C. 1,4,6-Pregnatriene-J7a,21-Di0l-3,11,20-Tri0ne
21 -A cetate
One g. of the trienetrione 'semicarbazone is dissolved
by stirring in 30 ml. of concentrated hydrochloric acid
and'100 ml. of water under a nitrogen atmosphere at
about 20° C. Then 0.275 g. of sodium nitrite in 5 ml.
of water is added over 15 minutes, avoiding excessive
'ebullition. The mixture is stirred one-half hour more
and 1 g. of urea is added and-stirred 15 minutes. The
washed with water, dried and chromatographed on mag
nesium silicate. The fraction eluted with 2% methanol
in, benzene is evaporated and the residue crystallized from
60 dilute acetone to give the‘desired product, M.P. 238—242°
C. (dec.).
EXAMPLE 3_
A sample of 0.5 g. of 9et-?uoro-4-pregnene-11p,17a,21
triol-3,20édirone ZI-acetate (M.P. 230-232") is dissolved
reaction is then'neutralized by» the addition of 10%. so
dium hydroxide solution and ?ltered. The ?lter cake
in 50ml. of chlorobenlzene and 501111. of carbon tetra
and the solution is chromatographed on magnesium sili
cate. The fraction eluted with 5% methylene chloride
water is removed by boiling, the solution is'treated with
0.47 g. of N-bromosuccinimide. and the mixture’is boiled
and mother liquor are extracted with, methylene vchloride, 70 chloride is added'containing 0.2 g. of- pyridine. After
by heating with a 500 watt bulb about 20 min. until a
negative test with starch-iodide paper shows the reagent
on evaporation of the solvent, U.V. max. at 225, 257,
75 is consumed. The cooled'solution is washed'wit'h water,
and 299 my.
in ether contains the desired product which crystallizes
"3,079,301
7
B. 9d,]1p~Oxido-1,4,6-Pregnatriene-17a,2I—Di0l-3,20
dried and evaporated. The residue is crystallized from
benzenehexane to give the desired product.
Dione 21-A cetate
To 15 ml.'of re?uxing dry 'y-collidine is added 0.5 g.
of the product of Example 6A. After 30 minutes’ boil
Dione 21 Acetate
ing, during which solid matter precipitates, the mixture
A sample of 0.3 g. of the product of Example 3A is
is cooled, poured into ice and Water and the pH adjusted
treated with 0.12 g. of 2,4-dinitrophenyl hydrazine and
to 4-6 with dilute hydrochloric acid. The mixture is
0.10 g. of anhydrous sodium acetate and the mixture is
extracted three times with 25 ml. of methylene chloride,
stirred two days at room temperature with 30 ml. of acetic
and the solution is Washed with water, dried, ?ltered and
acid. The mixture is then poured into water and the 10 evaporated
to dryness.
crude diuitrophenyl-hydrazone of the desired product is
The residue is dissolved in a minimum of methylene
?ltered off.
.
chloride and chromatographed on activated magnesium
The hydrazone is then treated as in Example 1C with
silicate, using hexane to develop the column. The frac
110 mg. of sodium nitrite and dilute hydrochloric acid.
tion
eluted with 70% ether in hexane is the desired
The desired product is isolated by chromatography as in
95,116 - Oxido - 1,4,6 - pregnatriene - 170:,21 - diol - 3,20
Example 1C, eluting with 2% methanol in methylene
dione 21 acetate, which may be crystallized further from
chloride.
acetone-hexane. The ultraviolet spectrum has
C. 9o:-Flll0f0-1 ,4,6-Pregnatriene-1l 5,1 711,21 -Tri0l-3,20
7 max.=223, 255, 297 mp.
Dione
B. Qm-FluOrO-I,4,6-Pregnatriene-11B,1 704,21-Tfi0l-3,20
A sample of 0.1 g. of the product of Example 313 is
hydrolyzed as in Example 1D. Chromotography yields
the desired product which is crystallized from dilute
acetone.
EXAMPLE 4
A. 2,6-Dibr0m0-9ot-Flu0r0-4-Pregnene-I7a,21-Di0l-3,11,
20
C. 9a-Fluor0-1,4,6-Pregnatriene-1 1,8,1 711,21 -Tri0l-3,20
Dione 21 ~Acetate
A sample of 0.2 g. of the product of Example 6B is
dissolved in 10 ml. of alcohol-free chloroform, chilled
25 to 0° and treated with 0.1 g. of anhydrous hydrogen
?uoride. The solution is maintained at 0° for 5 hours,
and washed with dilute sodium bicarbonate and water
till neutral. The dried solution is ?ltered and evaporated
ZO-Trione 21 Acetate
to a residue which is crystallized from methylene chloride
A sample of l g. of 9a-?uoro-4-pregnene-l7u,21-diol 30 hexane to give 9a-?uoro-1,4,6-pregnatriene-l l,8,17a,21
4,11,20-trione 21-acetate is treated, as in Example 1A, with
triol-3,20-dione ZI-acetate. The ultraviolet absorption
0.40 g. of bromine to give the 2,6-dibromo-derivative.
maxima are at 222, 254, 298 mu.
B. 9a-FluOrO-Z ,4, o-Pregnatriene-I 7 04,21 -Di0l-3,1 1-20
EXAMPLE 7
Trione 21 -A cetate
9ot-Bromo-L4?-Pregnatriene-I 113,1 7ot,21 —Triol-3,20
A sample of 1 g. of the product of Example 4A is de
hydrobrorninated as in Example 2B in 15 ml. of boiling
collidine. Chromatography separates the desired product
which is eluted with ether.
'
Example 6C is repeated using hydrogen bromide in
place of hydrogen ?uoride. The product obtained on
crystallization of the residue from acetone-hexane is 91x
C. 9a-Flu0ro-1,4,6-Pregnatriene-1 704,21 -Di0l-3,]1,20
bromo - 1,4,6 - pregnatriene - 11/3,l7a,21 - triol - 3,20
Trione
dione 21-acctate.
EXAMPLE 8
A sample of 0.1 g. of the last-named product (Example
413) is saponi?ed as in Example 2D with 50 mg. of po
tassium bicarbonate. The residue is crystallized from
acetone to give the desired product.
9a-Chlor0-1,4,6-Pregnatriene-I 113,1 70:,21 -Trial-3,20
Dione 21 -Acetate
Example 6C is repeated using hydrogen chloride in
stead of hydrogen ?uoride. The product obtained on
crystallization of the residue from acetone-hexane is 9o:
EXAMPLE 5
Pct-FluOra-1,4-Pregnadiene-1 15,1 7(1,21 -Tri0l-3,20—DiOne
A sample of 0.2 g. of the material obtained as in Ex
Dione 21 -A cetate
bromo - 1,4,6 - pregnatriene - 1lB,17oc,21 - triol — 3,20
50 dione 21-acetate.
EXAMPLE 9
ample 3C is hydrogenated by dissolving it in 40 ml. of
ethylacetate and shaking with 0.10 g. of 10% palladium
9ot-Flu0r0-1,4,6-Pregnatriene-11?,17a,21-Triol-3,20
on carbon in a hydrogen atmosphere until 10.5 cc. of
-
Dione
hydrogen have been absorbed. Crystallization of the 55 A sample of 0.1 g. of the product of Example 60 is
residue from aqueous methanol gives the diene product,
saponi?ed under nitrogen using 26 mg. of potassium
MP. 247-250“.
bicarbonate in 5 ml. of 95% methanol for eighteen hours.
The water-precipitated product is further crystallized
EXAMPLE 6
A. 6-Bromo-9BJJ,B-Oxido-J,4-Pregnaziiene-1701,21
from aqueous methanol to give 9oz-?uoro-1,4,6-pregnatri
60
Dz'0l-3,2U-Di0ne ZJ-Acetate
Two g. of 95,1l?-oxido-1,4-pregnadiene-17u,21-diol
3,20-dione 21-acetate (see I. Fried et al., J. Am. Chem.
Soc. 77, 4181 (1955)), is dissolved by boiling in 100 65
ml. of chlorobenzene and 50 ml. of carbon tetrachloride
and the solution is dried by distilling oif 5 ml. of solvent.
ene-l 1,8,17a,21-triol-3,20-dione.
EXAMPLE l0
9a-Flu0r0-1,4,6—Pregnatrienc-l 7 (1,21 -D fol-3,1 1,20
Trione 2] -A cetate
A sample of 0.2 g. of the product of Example 6C is
dissolved in 5 ml. of acetic acid, stirred and treated with
a soiution of 32 mg. of chromic anhydride in 0.1 cc. of
To the solution is added 0.93 g. of N-bromosuccinimide
water to which 0.4 cc. of acetic acid is added. The solu
and the mixture is irradiated with a 300-watt photo?ood
lamp while re?uxing for 15 minutes as succinimide crys 70 tion is stirred 15 minutes, treated with methanol, stirred
30 minutes longer, and poured into water. The pre
tallizes out. The mixture is cooled and Washed with
water, and the organic solution is dried, ?ltered and
evaporated in vacuo to a residue of 6-bromo—9e,11p
oxido-1,4-pregnadiene-17a,21-diol-3,2'0-dione 21 - acetate.
The ultraviolet spectrum has A maX.=249 mu.
cipitate is collected, dried and recrystallized from acetone
hexane to give 9u-?uoro-1,4,6-pregnatriene-17a,21-diol
3,11,20~trione 21-acetate. The ultraviolet spectrum has
75 A max.=222, 255, 296 mu.
.7
3,079,301
9
10
EXAMPLE 11 -
an atomic number less than that of iodine, said pregnenes
having a keto group at the 3- and 20-pcsitions, a hydroxy
Qa-Bromo-JA,6-Pregnatriene-1 7oc,2]-DiOl-3,11,20
group at the Net-position, a member of the group con
Trz'one 21 -A cetate
sisting of hydroxyl and aliphatic acyloxy having up to
The product from Example 7 (0.1 g.) is treated as in
Example 10 with 15 mg. of chromic anhydride in 0.2‘
ml. of 75% acetic acid. The precipitate is crystallized
12 carbon atoms at the 21-position and characterized by
the presence of a double bond in each of the 1- and 6
positions.
from methylene chloride-hexane to give 9a-bromo-1,4,6
2. 9a-halo-l,4,6 - pregnatriene -11?,17a,21 - triol - 3,20
pregnatriene-17a,21-diol-3,11,20-trione 21-acetate.
EXAMPLE l2
dione wherein the halo group is a halogen atom having
10 an atomic number lower than that of iodine.
3. 9u-halo-1,4,?-pregnatriene-170:,21-di0l-3,11,20-trione
9a-Chlor0-J,4,6-Pregnatriene-1 7a,21-Di0l-3,11,20
wherein the halo group is a halogen atom having an
Trione 21 -Acetate
atomic number lower than that of iodine.
4. A 2l-aliphatic acyl ester of a compound of claim 2
treated as in Example 10 with 31 mg. of chromic an 15 wherein the aliphatic acyl group has up to 12 carbon
atoms.
hydride in 0.5 ml. of 80% acetic acid. The product is
5. A 21-aliphatic acyl ester of a compound of claim 3
crystallized from aqueous acetone to give 9a-Chl01‘0-1,4,6
wherein the aliphatic acyl group has up to 12 carbon
pregnatriene-l7ot,2l-diol-3,11,20-trione 2l-acetate.
A sample of 0.2 g. of the product of Example 8 is
EXAMPLE 13
atoms.
20
9a-Fluor0-1,4,6-Pregnatriene-Z 7a,21-Dz‘0l
3,11,20-Tri0ne
A sample of 0.1 g. of the product of Example 10 is
saponi?ed as in Example 9. The product is puri?ed
by crystallization from aqueous acetone to give 9a-?uoro
1,4, 6-pregnatriene-17a,2l-diol-S,11,20-trione.
The therapeutically active pregnatrienes may be ad
ministered by mouth in the form of tablets containing,
for example, from 1 to about 50 or more mg. per tablet
mixed with a solid non-toxic pharmaceutical carrier con
taining one or more of the usual ingredients, such as
starches, sugars, gums, gelatins, soaps, clays, calcium and
magnesium carbonates, aluminum hydroxide, and the like.
They may, however, be also administered by subcutaneous
or intramuscular injection, dissolved or suspended in a
suitable non-toxic liquid vehicle; or they can be admin
6. 9a-fluoro-1,4,6-pregnatriene-1116,17a,21 - triol - 3,20
dione 21-acetate.
dione 21-acetate.
8. 9ot-chloro-1,4,6-pregnatriene-1113,17a,21-triol - 3,20
dione 21-acetate.
9. 90¢ - ?uoro-1,4,6 - pregnatriene-l113,17a,21-triol-3,20~
dione.
10. 9a-chloro~l,4,6-pregnatriene-17ot,2l-diol-3,11,20-tri
one 2l-acetate.
11. A therapeutic composition comprising a pregna
triene compound as de?ned in claim 1, mixed with a
non-toxic pharmaceutical carrier.
12. A therapeutic composition as defined in claim 11
in unit dosage form, wherein each dosage unit contains
from 1 mg. to about 50 mg. of the pregnatriene.
References Cited in the ?le of this patent
UNITED STATES PATENTS
istered in the solid form by subcutaneous implantation,
or in the form of suppositories dissolved or suspended
in a fatty or Waxy vehicle which melts at approximately 40
body temperature. They can also be administered topi
cally in the form of an ointment or cream in which they
are dissolved or suspended in an unguent or cream base
of known composition; and they may also be employed
in the form of ointments and aqueous suspensions for
ophthalmic use. The compounds in microcrystalline form
in aqueous suspensions can be used for intra-articular
injection and also as nasal sprays; while infusions can be
prepared for intravenous use.
Because of their anti-inflammatory or glucocorticoid 50
activity, all of our compounds are especially useful in
the form of lotions, ointments, and the like, in the topical
treatment of skin irritations and rashes, such as pruritis
of the mucosal surfaces, allergic dermatoses and similar
diseases.
55
We claim:
1. A composition of matter selected from the group
consisting of ll-keto and 1lp-hydroxy-9a-halo-A4-preg
nenes wherein the halo group is a halogen atom having
-
7. 9a - bromo -l,4,6-pregnatriene-1118,17a,21-trio1-3,20
2,341,250
2,563,247
2,590,978
2,602,804
2,606,913
2,684,376
2,705,237
2,730,525
2,736,734
2,752,339
2,763,671
2,768,189
2,768,191
2,783,226
2,788,353
2,788,354
2,789,117
Wallis et al. __________ __ Feb. 8,
Kendall et al. ________ __ Aug. 7,
Kendall et al. ________ __ Apr. 1,
Kendall ______________ __ July 8,
Levin et al ___________ __ Aug. 12,
Oliveto et al. ________ __ July 20,
Djerassi et al. _______ __ Mar. 29,
Hogg et al. __________ __ Jan. 10,
Sarett ______________ __ Feb. 28,
Julian et al. _________ __ June 26,
Fried et al ___________ __ Sept. 18,
Nomine et al. ________ __ Oct. 23,
Watnant et al. ________ __ Oct. 23,
Gould et al. ________ .. Feb. 26,
Djerassi et al. ________ __ Apr. 9,
Agnello et al. ________ __ Apr. 9,
Sarett ______________ __ Apr. 16,
1944
1951
1952
1952
1952
1954
1955
1956
1956
1956
1956
1956
1956
1957
1957
1957
1957
OTHER REFERENCES
Jour. Am. Chem. Soc., vol. 72, pages 4531—4539
(1950).
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