Note: Descriptions are shown in the official language in which they were submitted.
`~ 3~
The present invention is concerned with new water-
soluble corticoids and with their manufacture and use.
The present invention provides compounds of the
general formula I
H~OcO(c~3)ncooy
I c=o
HO ~ ~ c~3
t
~ 10 o ~ ~r~ ~I)
`1 F
. ~
J in which n represents 2 or 3, X represents a hydrogen atom, a
fluorine atom or a chlorine atom and Y represents a hydrogen
atom, an alkali metal atom or an N-methylglucamine group.
The new water-soluble corticoids are characterized by
a favourable relation between therapeutic effect and tolerance.
As compared with known water-soluble derivatives of corticoids
of the general formula Il given below ~British Patent Specific-
ation No. 1,286,093) the new corticoids are distinguished by a
substantially more rapid inception of their action.
The therapeutic activity of the new water-soluble
corticoids can be determined, for example, by the known endo-
toxin-shock test, the eosinophilic test or the adjuvant-oedema
test. For determining the undesired systemic side effects, and
therefore the tolerance of the new corticoids, there may be
used, for example, the known thymolysis test, the liver glycogen
test or the sodium-potassium retention test or the tolerance
test.
The present invention accordingly also provides a
pharmaceutical preparation which comprises a compound of the
l~ 2
! general formula I, in admixture or conjunction with a pharma-
. ceutically suitable carrier. The preparation may, if desired,
j be in a form suitable for intravenous administration.
The new water-soluble corticoids of the present
invention may be worked up into pharmaceutical preparations in
the usual manner by converting them, if desired with suitable
additives, carrier substances, solubilizers, stabilizers and
taste correctives, into the desired forms of application, for
k example tablets, dragées, capsules and solutions.
Thus, for example, definite quantities of the water-
soluble corticoids, if desired after the addition of the usual
adjuvants, may be introduced as dry substances into ampoules
S under the conditions conventionally used in galenical pharmacy,
the ampoules preferably each containing a quantity of active
substance within the range of from 10 mg to 500 mg. Before
application the contents of the ampoule are dissolved in sterile
distilled water.
The pharmaceutical preparations may be used preferably
for the treatment of acute threatening states of disease (for
example shock after accident, burns, operations, circulatory
break-downs after poisonings, cardiac infarction, pulmonary
embolism and severe attacks of asthma).
For treatment there may be administered intravenously
to the patients preferably 10 to 1000 mg of active substance
depending on the severity of the state of disease.
The new corticoids may be produced by a type of process
well known to the expert, for example by the process of the
present invention, as defined below.
The present invention accordingly further provides a
process for the manufacture of a compound of the general formula
I, as defined above, wherein a compound of the general formula
II
~34~.~
2 H
C=O
HO - ~ _CH3
F
in which X has the meaning given above, is esterified in the
21-position with succinic anhydride or glutaric anhydride and,
if desired, the resulting compound of the general formula I in
which Y represents a hydrogen atom is converted into an alkali
metal salt or N-methylglucamine salt thereof.
The reaction with the succinic anhydride or glutaric
`~ anhydride may be carried out in the presence of a base, for
example pyridine, lutidine, potassium bicarbonate, sodium car-
bonate, potassium carbonate, sodium hydroxide or potassium hydro-
xide. The optional subsequent conversion into an alkali metal
i 20 salt may be effected by reaction with an alkali metal hydroxide,
-~ alkali metal carbonate, alkali metal bicarbonate or alkali metal
alcoholate.
By the process of the present invention there can be
- produced, for example:
- (6~,9~-difluoro~ hydroxy-16~-methyl-3,20-dioxo-~ ' -pregnadien-
21-yl)-hemiglutarate, also its sodium and potassium salts, and
also (9~-chloro-6~-fluoro-11~-hydroxy-16(1-methyl-3,20-dioxo-Al'4-
pregnadien-21-yl)-hemiglutarate and its sodium and potassium
salts.
d 30 The following Examples illustrate the invention:-
¦ Example 1
(a) 2 Gms of 6~,9~-difluoro~ ,21-dihydroxy-16lY-methyl-
.2
Al'4-pregnadiene-3,20-(lione were dissolved in 10 ml of pyridine,
1 gm of succinic anhydride was added and the whole was heated at
the boil for 30 minutes while gassing with argon. After cooling,
~, the mixture was stirred into ice-water, and acidified with dilute
sulphuric acid, and the precipitated product was filtered off
; with suction, washed until neutral and dried. After recrystal-
lization from acetone-hexane 2.1 gms of (6fl,9fx-difluoro-11~-
hydroxy-16f~-methyl-3,20-dioxo-Al'4-pregnadien-21-yl)-hemisuccinate
melting at 199 - 201C were obtained.
o (b) 700 My of the hemisuccinate i,n 10 ml of absolute
methanol were adjusted with 9.4 ml of a 0.1 normal solution of1
potassium methylate to pl-~ 8 using a pl~-meter. The solution was
concentrated in vacuo and precipitated in 600 ml of ether. The
precipitated potassium salt was filtered off with suction, washed
with ether and dried over phosphorus pentoxide in vacuo. 670 Mg
of potassium (6f~x,9f~-difluoro-llr3-hydroxy-16~t-methyl-3,20-dioxo-
il A '4-pregnadien-21-yl)-succinate melting at 170 - 180C were
obtained. W: fr~238 = 16,600-
(cl 650 Mg of the hemisuccinate were adjusted in 10 ml of
absolute methanol with 11.4 ml of a 0.1 normal sodium methy~ate
solution to pH 8. The solution was concentrated in vacuo, and
stirred into a mixture, cooled to +3~C, of 500 ml of ether and
100 ml of pentane. The precipitated product was filtered off with
suction and dried ln vacuo. 630 M~ of sodium (6f~,9rY-difluoro-
ll~-hydroxy-16fx-methyl-3,20-dioxo-A '4-prff-~nadiell-21-yl)-
succinate melting at 175 - 180C we~re ob'ained. UV: ~ 238 = 16,500.
~j Example 2
(a) 5 Gms of 6(~-fluoro-llB,21-dihydroxy-16~-methyl ~
pregnadiene-3,20-dione in 25 ml of pyridine were reacted with
5 gms of succinic anhydride in a manner anllo(lous to that
described in Example l(a? and worked up. ~fter recrystallization
from ethyl acetate 5.2 ~ms of (6fY-t~luoI-o-ll~i-hydroxy-16(Y-methyl-
~ ~ ~ 3L~ ~
3,20-dioxo-~1'4-pregnadien-21-yl)-hemisuccinate melting at 210 -
212C were obtained.
(b) 10 Gms of the hemisuccinate in 400 ml of absolute
methanol were adjusted with 17.3 ml of a 0.1 normal solution of
sodium methylate to Ph 8 and precipitated as described in Example
~ l(c). 9.6 Gms of sodium (6~-fluoro-11~-hydroxy-16~-methyl-3,20-
j dioxo-Al'4-pregnadien-21-yl)-succinate were obtained. W : E242 =
16,100. Melting point: 163 - 170C (with decomposition).
Example 3
~ 10 (a) 5 Gms of 6~-fluoro-llr~,21-dihydroxy-16~-methyl-~ ' -
1 pregnadiene-3,20-dione in 20 ml of pyridine were heated at the
boil with 2 gms of glutaric anhydride for 45 minutes while
gassing with argon. After cooling, the mixture was stirred into
ice-water, and acidified with dilute sulphuric acid, and the
J precipitated product was filtered off with suction, washed until
neutral and dried. The crude product was dissolved in ethyl
acetate and extracted by agitation with a sodium carbonate
solution of 5% strength. The separated aqueous phase was acidi-
fied with hydrochloric acid, and extracted with ethyl acetate,
and the ethyl acetate extract was washed until neutral and
evaporated in vacuo. 5.2 Gms of (6~-fluoro-llr~-hydroxy-16~-
methyl-3,20-dioxo-~1'4-pregnadien-21-yl)-hemiglutarate were
obtained. Melting point: 171 - 173C.
(b) 2.5 Gms of the hemiglutarate were converted into the
sodium salt in a manner analogous to that described in Example
l(c). 2.4 Gms of sodium (6r~-fluoro-llr'-hydroxy-16~-methyl-3,20-
dioxo-~1'4-pregnadiene-21-yl)-glutarate were obtained. UV: 241 =
16,000. Melting point: 167C (with decomposition).
Example 4
..
(a) 1 Gm of 9~-chloro-6~-fluoro-11~',21-dihydroxy-16~-
methyl-A '4-~regnadiene-3,20-dione in 5 ml of pyridine was heated
at the boil with 0.5 gm of succinic anhydride for 30 minutes while
~ i
l~i;3 4~;~
gassing with argon. After working up as described in Example
I l(a) and recrystallization from acetone-ethyl acetate 1.23 gms
j of (9~-chloro-6~-fluoro-11~-hydroxy-16a-methyl-3,20-dioxo-~ '4-
; pregnadien-21-yl)-hemisuccinate melting at 249C (with decomposit-
ion) were obtained.
(b) 700 Mg of the hemisuccinate in 15 ml of methanol were
converted with a 0.1 normal solution of sodium methylate into
the sodium salt. 570 Mg of sodium (9~-chloro-6~-fluoro-11~-
1 4
hydroxy-16~-methyl-3,20-dioxo-A ' -pregnadien-21-yl)-succinate
were obtained. Melting point: 165C (with decomposition).
~ Example 5
.,, ~ - .
, In a manner analogous to that described in Example 3
. ' ~ 9(x-chloro-6~-fluoro-1113,21-dihydroxy-16(x-methyl-Al'4-pregnadiene-
" i
; s 3,20-dione was converted into (9~-chloro-6~-fluoro-11~-hydroxy-
~! 16a-methyl-3,20-dioxo-~1'4-pregnadien-21-yl)-hemiglutarate
. . ..
(melting at 182 - 183.5C with decomposition) and the latter was
3 further reacted to form sodium (9~-chloro-6~-fluoro-11~-hydroxy-
16~-methyl-3,20-dioxo-Al'4-pregnadien-21-yl)-glutarate. Melting
point: 124C (with decomposition).
Example 6
1.5 Gms of (6~-fluoro-11~-hydroxy-16~-methyl-,3,20-
dioxo-al'4-pregnadien-21-yl)-hemisuccinate and 0.646 gm of
- N-methyl-glucamine were dissolved in 30 ml of bidistilled water
and the clear solution was freeze-dried for 24 hours. 2.07 Gms
- of amorphous N-methylglucamine ~6~-fluoro~ hydroxy-16~-methyl-
3,20-dioxo-A ' -pregnadien-21-yl)-succinate were obtained.
-- 6
