Note: Descriptions are shown in the official language in which they were submitted.
~ Z S~ ~'7~
The present ~nvention relates to 6~-methylprednisolone
derivatives, with a process for their manufacture and with their
use as medicaments.
The present invention provides 6O~-methylprednisolone
derivatives of the general formula I
I H20R2
c=o
~' '~--b~l
oJ ~ ~,J (I)
CH3
in which Rl represents a l-oxoalkyl group containlng 2 to 6
carbon atoms or a benzoyl group and R2 represents a hydrogen
atom, a l-oxoalkyl group containing 2 to 6 carbon atoms or a
benzoyl group.
Each of the l-oxoalkyl groups containing 2 to 6
..... ,~
~zs~
carbon atoms given as possible meanings for the symbols
Rl and R2 may be, for example, an acetyl group, a pro-
pionyl group, a butyryl ~roup, an isobutyryl group, a
valeryl group, a ~-methylbutyryl group, a trimethyl-
acetyl group or a hexanoyl group.
It has been found that the derivati~es of 6a-
methylprednisolone of the general formula I surprising-
ly often have a significantly greater pharmacological
activity when applied topically than the previously
known derivative~ of 6a-methylprednisolone. ~his
activity is often even still significantly greater than
that o~ difluorinated "highly active corticoids" such
as, for example~ 6a,9a-difluorb-11~-hydro~y-16~-methyl-
21-valeryloxy-al'4-pregnadiene-~,20~dione.
When administered systemically, these novel deri-
- vati~es o~ 6a-methylprednisolone are, surprisingly,
often less ac~ive -than the corresponding previously
-- known derivatives of 6~-methylprednisolone.
Accordingly, the novel 6a-methylprednisolone
derivatives of the general formula I of the presen~
invention are suitable, in combination with the carrier~
that are customarily u~ed in, for e~ample~ galenical
pharmacy, for the local treatme~t of contact dermatltls,
eczemas of the most varied kinds, neurodermatoses,
erythrodermia, burns, Pruriti6 vulvae et ani, rosacea~
~r~thematodes cutaneus, psoriasis, ~ichen ruber Planus
et verrucosus and similar skin disorders.
i2~571
The present invention accordingly also provides a
compound o~ the general formula I9 for use as a medica-
ment.
The present invention ~urther provides a pharma-
5 ceutical preparation which compri3es a compound of the
general formula I9 in admixture or conjunction with a
pharmaceutically suitable carrier. The preparation may
contain one or two compounds of the general formula I.
The pharmaceutical preparation may be in a form
suitable, ~or example, for topical application.
The pharmaceutical preparations may be manufactured
in the customary manner by converting the active sub-
stances with suitable additives into the desired forms
of application, ~or example solutions, lotions, oint-
ments, creams or plasters D ~he concentration of activesubstance in the pharmaceutical pre.parations formulated
in this manner depends on the form o~ application. In
the case o~ lotions and ointments, an acti~e substance
concentration within the range of from O.OOl~o to 1~ by
weight is preferably used.
~ urthermore, the no~el compounds of the general
formula I, i~ desirea in combination with the customary
carriers and auxiliaries, are also well suited for the
manufacture of inhalant~, which can be used for the
treatment of allergic disorders of the respiratory
system, for example bronchial asthma or rhinitis.
In addition, the novel corticoids o~ the ~eneral
~S~357~L
formula I are also suitable for the manufacture of
capsule~, tablets or dragées which each preferably con-
tain from lO to 200 mg of active substance and are
admini~tered orally, or for the manufacture of 6U~-
pensions which may be in unit dosage form preferablycontaining from 100 to 500 mg of acti~e substance per
dosage unit and are administered rectally. The novel
corticoids are also suitable for the treatment of
allergic di~orders of the i~testinal tract, for
e~ample aolitis ulcerosa and Colitis ranulomatosa.
The novel 6a methylprea~isolone derivatives o~
the general ~ormula I may be manufactured by the
process of the present invention, as defined below.
The present invention further provides a process
for the manufacture of a compound o~ the general
formula I, wherein hydrogen bromide is split off from
a corticoid of the general formula II
, .
fH20R2
C=O
H0 ~ -- ORl
(II3,
' . 0~
CH~
~S~57~L
in which Rl and R2 have the meanings given above.
The process of the present invention may be carried
out in a manner known ~ e, for example under the
condition3 desoribed in German Patent ApplicationsNos.
26 45 104, 26 45 105, 2~ 40 591 and 19 58 549, in
United States Patent ~pecification No. 3,383,~94 or in
the publication J. Amer~ Chem. SocO, 791 1957, 1515.
The following Example~ illustrate the invention:
~am~le 1
~ ~ suspension of 34~0 g of 21-acetoxy-9a-bromo-
11~,17a-dihydroxy-6~-methyl-al'4-pregnadiene-~,20-
dione in 1.36 1 of methanol and 120 ml of 70~ perchlor-
ic acid was stirred for 20 hours at room temperature~
A~er precipitation with ice-water, the precipitate
was filtered off with suction, washed until neutral
with water and dried in a vacuum drying chamber.
28.3 g o~ 9a-bromo-11~,17a,21-trihydroxy-6a-methyl~
~1'4-pregnadiene-3,20-dione were obtained. M.p. 159-
160C
B) ~rom a solution of 403 g o~ 9~-bromo~ ,17a,21-
trihydro~y-6a-methyl ~1t4-pregnadiene-3,20-dione and
430 mg of pyridinium tosylate in 34.5 ml of dimethyl-
formamide and ~00 ml of benzenep 129 ml of benzene
were distilled off at 130C using a water separator
10.3 ml of orthobut~ric acid trimethyl ester were
~2S~57~L
6 -- .
added dropwise to the hot reaction solution and then
further benzene and other readily volatile reaction
oomponents were distilled off~ 5 ml of pyridine were
then added and the whole was concentrated to dryness
in vacuo. 9a-Bromo~ hydroxy 17a,21-(1-methoxy~
butylidenedioxy)-6a-methyl-~1'4-pregnadiene-3,20-dione
was isolated in the form o~ an oil.
a) The crude 9a-bromo~ -hydro~y-17a,21-(l methoxy-
butyliderledio~y)-6~-methyl~ '4-pregr}adiene-3920-dione
was dissolved in 129 ml of methanol and the solution
waa stirred for 1 hour at a bath temperature of 80C
~ith a mixture of 46.4 ml o~ 0.lN aqueous acetic acid
and 5~2 ml o~ a O.IM aqueous 60dium acetate solutionO
- The solution wa~ concentrated to 1/3 o* lts volume,
added to water and extracted with eth~l acetate. The
ethyl acetate extracts were washed until neutral wi-th
water ~ter drying and concentrating9 the crude
product was puri~ied o~er 200 g of silica gel using
a hexane/acetone gradie~t (0-60% acetone~. 3.7 g o~
9a-bromo-17a-butyryloxy-11~,21-dihydroxy 6~-methyl-
~l94-pregnadiene-3,20-dione were isolated. M.p. 158-
159C.
D3 A suspension of 3~0 g of 9a-bromo-17-butyryloxy-
11~,21-dihydro~y-6a-methyl~ 4-pregnadiene-3,20-dione
2~ in 60 ml of hexamethylphosphoric acid triamide was
stlrred for 1 hour at a bath temperature of 80C with
lZ~)5~1
~DO g of lithium chloride. After precipitation with
ice-water, the re~idue ~as filtered off and washed with
water, a~d the resulting crude product was purified
over 105 g of silica gel U9i~g a methylene chloride/
acetone gradient (0-2~% acetone)~ 9~8 Mg of 17~
butyryloxy-ll~ t 21-dihydroxy-6~-methyl-~1'4~8-pregna-
triene ~,20-dione were isolated in the form of a foam.
[aJD25 = -53.8 (chloroform).
Example 2
A) In a manner analogous to that described in
Example lB), 17.4 g o~ 9a-bromo~ ,17a~21-trihydroxy-
6a-methyl ~1'4-pregnadiene-3,20-dione were reacted with
42.0 ml of orthobenzoic acid triethyl ester and worked
up. 9a-bromo-17,21-(a~etho~ybenzylidenedioxy~-11~-
hydroxy-6a-methyl-~1'4~pregnadiene-~,20-dione was ieo-
lated in the ~orm o~ an oil.
~) The crude 9a-bromo-17a,21-(a-ethoxybenzylidene-
dioxy)~ -hydroxy-6a-methyl-~1'4-pregnadie~e-3,20
dione was hydrolysed and worked up under the conditions
described in Example lC). ~he crude product wa~ puri-
~ied o~er 1 kg of silica gel using a hexane/acetone
gradient (0~50% acetone). Yield: 12047 g of 17a-
benzoyloxy-9a-bromo-11@,21-dihydroxy-6a-methyl-~1'4-
pregnadiene-~,20-dione. M.p. 159C.
C) A solution of 2.0 g of 17a-benzoyloxy-9a-bromo-
~Z~ 7~
11~,21-dihydroxy-6~-methyl-~1'4-pregnadiene-~,20-dione
was reacted with 2.0 g of lithium chloride znd worked
up ln a manner analogous to that described in ~xample
lD). ~he crude product was purified over 10~ g of
silica gel using a methylene chloride/acetone gradient
(0.20~ acetone). Yield: 1~2 g of 17a-benzoylo~y-
11~,21-dihydroxy-6a-methyl-~1'4'8-pregnatriene-3,20-
dione D M.p. 206-208C.
xample ~
~) 3.0 g o~ 17-benzoyloxy-9~-bromo~ ,21-dihydroxy-
6a-methyl-~l94-pregnadiene-3,20-dione were stirred for
3 hours at room temperature in 30 ml o~ pyridine with
15 ml o~ acetic anhydride~ After working up in a
customary manner, ~.2 g of 21-acetoxy-17a-benzoyloxy-
9a-bromo~ -hydroxy-6a-methyl-~1'4-pregnadiene-3,20-
dio~e were obtained. M.p. 172-173C.
.
~) 3.~ g of 21-acetoxy-17a-benzoyloxy-9a-bromo-
~ hydroxy-6a-methyl-~1'4-pregnadiene-3 9 20-dione
were reacted with 303 g o~ lithium chloride and worked
up in a manner analogous to that described in E~ample
lD). The crude product ~Ta~ puri~ied over 200 g of
silica gel using a methylene chloride/acetone gradient
(0-15~o acetone). Yield: 1.78 g of 21-acetoxy 17a-
beD~loxy~ hydroxy_6a_methyl~ 4 ~8_p~eg~latriene_
3.20-dione. M.p~ 229-2~0C.
~S~71
. g _
Exam~le 4
~) In a manner analogous to that described in
~ample 3A), 3.0 g o~ 17a-benzoyloxy-9~-bromo~ ,21-
dihydroxy-6~-methyl-~1'4-pregnadiene-~,20-dione were
reacted with propionic acid anhydride ~d worked up.
3.1 g of 17a-benzoyloxy-9a-bromo~ -hvlro~y-6a-methyl-
21-propionyloxy-~1'4~pregnadiene-3,20-~ione were
obtained. M.p. 155-156Co
~) Under the conditions described in ~xample lD) 9
~2 g of 17a-benzoyloxy-9x bromo-11~-hycroxy-6a-methyl-
21-propionyloxy-hl'4-pregnadiene-3,20-~ione were
reacted with lithium chloride, worked up and purified.
1.96 g o~ 17a-ben~oyloxy 11~-hydroxy-6a-methyl-21-
propionylogy-~1~4'8-pregnatriene~,20-dione were i~o-
lated. M.p. 225-226C.