DERIVES DE 6.alpha.-METHYLPREDNISOLONE; PREPARATION ET UTILISATION

6 -METHYLPREDNISOLONE DERIVATIVES AND THEIR MANUFACTURE AND USE

Abrégé anglais

ABSTRACT OF THE DISCLOSURE
Novel 6?-methylprednisolone derivatives of the general
formula I
<IMG>
(I)
in which R1 represents C2-C6-1-oxoalkyl or benzoyl and R2
represents H, C2-C6-1-oxoalkyl or benzoyl and a process for their
manufacture. The novel compounds are pharmacologically active
substances and may accordingly be made up with suitable carriers
into pharmaceutical preparations.

Revendications

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the manufacture of a 6.alpha.-methyl-
prednisolone derivative of the general formula I
<IMG> (I)
in which R1 represents a 1-oxoalkyl group containing 2 to 6
carbon atoms or a benzoyl group and R2 represents a hydrogen
atom, a 1-oxoalkyl group containing 2 to 6 carbon atoms or
a benzoyl group, wherein hydrogen bromide is split off from
a corticoid of the general formula II
<IMG> (II),

in which R1 and R2 have the meanings given above.
2. A 6?-methylprednisolone derivative of the general
formula I
<IMG> (I)
in which R1 represents a 1-oxoalkyl group containing 2 to 6
carbon atoms or a benzoyl group and R2 represents a hydrogen
atom, a 1-oxoalkyl group containing 2 to 6 carbon atoms or a
benzoyl group.
3. A process as claimed in claim 1, wherein R1
represents an acetyl, propionyl, butyryl, isobutyryl, valeryl, 3-
methylbutyryl, trimethylacetyl or hexanoyl group.
4. A process as claimed in claim 3, wherein R2
represents an acetyl, propionyl, butyryl, isobutyryl, valeryl, 3-
methylbutyryl, trimethylacetyl or hexanoyl group.
5. A compound of formula I given in claim 1, wherein
R2 is as in claim 1 and R1 is as in claim 3.
6. A compound of formula I given in claim 1, wherein
R2 is as in claim 4 and R1 is as in claim 3.
7. A process as claimed in claim 1, in which R1 is
benzoyl and R2 is propionyl.
8. A process as claimed in claim 1, which comprises
11

reacting 17.alpha.-benzoyloxy-9 .alpha.-bromo-11 .beta.-hydroxy-6.alpha.-methyl-21-
propionyloxy- .DELTA.1,4-pregnadiene-3,20-dione with lithium chloride
in hexamethylphosphoric acid triamide at elevated temperature.
9. 17 .alpha.-benzoyloxy-11.beta.-hydroxy-6.alpha.-methyl-21-
propionyloxy- .DELTA.1,4,8-pregnatriene-3,20-dione.
10. A process as claimed in claim 1, in which R1 is
butyryl and R2 is hydrogen.
11. A process as claimed in claim 1, which comprises
reacting 9.alpha.-bromo-l7.alpha.-butyryloxy-11.beta.,21-dihydroxy-6.alpha.-methyl-
.DELTA.1,4-pregnadiene-3,20-dione with lithium chloride in
hexamethylphosphoric acid triamide at elevated temperature.
12. 17.alpha.-butyryloxy-11.beta.,21-dihydroxy-6.alpha.-methyl-
.DELTA.1,4,8-pregnatriene-3,20-dione.
13. A process as claimed in claim 1, in which R2 is
acetyl and R1 is benzoyl.
14. A process as claimed in claim 1, which comprises
reacting 21-acetoxy-17.alpha.-benzoyloxy-9.alpha.-bromo-11.beta.-hydroxy-6.alpha.-
methyl-.DELTA.,1,4-pregnadiene-3,20-dione with lithium chloride in
hexamethylphosphoric acid triamide at elevated temperature.
15. 21-acetoxy-17.alpha.-benzoyloxy-11.beta.-hydroxy-6.alpha.-methyl-
.DELTA.1,4,8-pregnatriene-3,20-dione.
16. A process as claimed in claim 1, in which R1
benzoyl and R2 is hydrogen.
17. A process as claimed in claim 1, which comprises
reacting 17.alpha.-benzoyloxy-9.alpha.-bromo-11.beta.,21-dihydroxy-6.alpha.-methyl-
.DELTA.,1,4-pregnadiene-3,20-dione with lithium chloride in
hexamethylphosphoric acid triamide at elevated temperature.
12

18. 17?-benzoyloxy-11.beta.,21-dihydroxy-6?methyl-
.DELTA.1,4,8-pregnatriene-3,20-dione.
13

Description

~ 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.