DERIVATIVES OF 9-CHLOROPREDNISOLONE

TRADUCTION NON-DISPONIBLE

English Abstract

ABSTRACT OF THE DISCLOSURE
New derivatives of 9-chloroprednisolone of the
formula
(I) ,
<IMG>
in which
R1 represents an alkanoyl group containing 1 to 8
carbon atoms or a benzoyl group and
X represents a fluorine atom, a chlorine atom, a
hydroxyl group, an alkanoyloxy group containing 1 to 8 carbon
atoms or a benzoyloxy group which are systemically almost
inactive, but that in topical use they surprisingly have a
strong anti-inflammatory activity, which generally exceeds that
of the most active commercial corticoids.

Claims

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 compound of
the general formula I
<IMG> (I) ,
in which
R1 represents an alkanoyl group containing 1 to 8
carbon atoms or a benzoyl group and
X represents a fluorine atom, a chlorine atom, a
hydroxyl group, an alkanoyloxy group containing 1 to 8 carbon
atoms or a benzoyloxy group, which comprises
(a) adding HOCl at the .DELTA.9,11-double bond of a compound
of the general formula II
<IMG> (II) ,
in which R1 and X have the meanings given above, or
(b) opening up the epoxide ring of a compound of the
general formula III
<IMG> (III) ,
28

in which R1 and X have the meanings given above, with hydrogen
chloride, or
(c) X represents a hydroxyl group or a fluorine or chlorine
atom, an ortho-ester of the general formula IV
<IMG> (IV) ,
in which R3 represents a hydrogen atom, an alkyl group containing
1 to 7 carbon atoms or a phenyl group and R2 represents an alkyl
group containing 1 to 4 carbon atoms, is hydrolysed or reacted
with trimethylsilyl fluoride or chloride or triphenylmethyl
fluoride or chloride to produce a compound of formula I in
which X represents a hydroxyl group or a fluorine or chlorine
atom or
(d) X represents a chlorine atom, an alkanoyloxy group
or a benzoyloxy group, a 9-chloro-derivative of the general
formula Ia
<IMG> (Ia),
in which R1 has the meaning given above, is chlorinated or
esterified at the 21-position to produce a compound of formula I
in which X represents a chlorine atom, an alkanoyloxy group
or a benzoyloxy group.
2. A compound of the general formula I
29

<IMG> (I)
in which
R1 represents an alkanoyl group containing 1 to 8
carbon atoms or a benzoyl group and
X represents a fluorine atom, a chlorine atom, a
hydroxyl group, an alkanoyloxy group containing 1 to 8 carbon
atoms or a benzoyloxy group when prepared by the process as
claimed in claim 1 or an obvious chemical equivalent thereof.
3. A process as claimed in claim 1, in which in
the reactants R1 is an alkanoyl group having 2 to 6 carbon
atoms.
4. A compound of formula I given in claim 1, wherein
R1 represents an alkanoyl group containing 2 to 6 carbon atoms
when prepared by the process as claimed in claim 3 or an obvious
chemical equivalent thereof.
5. A process as claimed in claim 3, in which in the
reactants X is an alkanoyloxy group having from 2 to 6 carbon
atoms.
6. A process as claimed in claim 1, which comprises
refluxing 17.alpha.,21-(1-ethoxybenzylidenedioxy)-9.alpha.-chloro-11.beta.-
hydroxy-.DELTA.1,4-pregnadiene-3,20-dione in a mixture of methanol,
acetic acid and sodium acetate.
7. 17.alpha.-Benzoyloxy-9.alpha.-chloro-11.beta.,21-dihydroxy-.DELTA.1,4-
pregnadiene-3,20-dione when prepared by the process as claimed
in claim 6 or an obvious chemical equivalent thereof.
8. A process as claimed in claim 6, in which the
17.alpha.-benzoyloxy-9.alpha.-chloro-11.beta.,21-dihydroxy-.DELTA.1,4-pregnadien-3,20-
dione so obtained is treated with formic acid.

9. 17.alpha.-Benzoyloxy-9.alpha.-chloro-21-formyloxy-11.beta.-hydroxy-
.DELTA.1,4-pregnadiene-3,20-dione when prepared by the process as
claimed in claim 8 or an obvious chemical equivalent thereof.
10. A process as claimed in claim 6, in which the
17.alpha.-benzoyloxy-9.alpha.-chloro-11.beta.,21-dihydroxy-.DELTA.1,4-pregnadiene-3,20-
dione so obtained is treated with acetic anhydride in pyridine.
11. 21-Acetoxy-17.alpha.-benzoyloxy-9.alpha.-chloro-11.beta.-hydroxy-
.DELTA.1,4-pregnadiene-3,20-dione when prepared by the process as
claimed in claim 10 or an obvious chemical equivalent thereof.
12. A process as claimed in claim 6, in which the
17.alpha.-benzoyloxy-9.alpha.-chloro-11.beta.,21-dihydroxy-.DELTA.1,4-pregnadiene-3,20-
dione so obtained is treated with propionic anhydride in
pyridine.
13. 17.alpha.-Benzoyloxy-9.alpha.-chloro-11.beta.-hydroxy-21-propionyl-
oxy-.DELTA.1,4-pregnadiene-3,20-dione when prepared by the process
as claimed in claim 12 or an obvious chemical equivalent thereof.
14. A process as claimed in claim 6, in which the
17.alpha.-benzoyloxy-9.alpha.-chloro-11.beta.,21-dihydroxy-.DELTA.1,4-pregnadiene-3,20-
dione so obtained is treated with butyric anhydride in pyridine.
15. 17.alpha.-Benzoyloxy-21-butyryloxy-9.alpha.-chloro-11.beta.-
hydroxy-.DELTA.1,4-pregnadiene-3,20-dione when prepared by the process
as claimed in claim 14 or an obvious chemical equivalent thereof.
16. A process as claimed in claim 6, in which the
17.alpha.-benzoyloxy-9.alpha.-chloro-11.beta.,21-dihydroxy-.DELTA.1,4-pregnadiene-3,20-
dione so obtained is treated with valeric anhydride in pyridine.
17. 17.alpha.-Benzoyloxy-9.alpha.-chloro-11.beta.-hydroxy-21-valeryloxy-
.DELTA.1,4-pregnadiene-3,20-dione when prepared by the process as claimed
in claim 16 or an obvious chemical equivalent thereof.
18. A process as claimed in claim 6, in which the
17.alpha.-benzoyloxy-9.alpha.-chloro-11.beta.,21-dihydroxy-.DELTA.1,4-pregnadiene-3,20-
dione so obtained is treated with trimethyl acetic anhydride in
pyridine.
31

19. 17.alpha.-Benzoyloxy-9.alpha.-chloro-11.beta.-hydroxy-21-trimethyl-
acetoxy-.DELTA.1,4-pregnadiene-3,20-dione when prepared by the process
as claimed in claim 18 or an obvious chemical equivalent thereof.
20. A process as claimed in claim 6, in which the
17.alpha.-benzoyloxy-9.alpha.-chloro-11.beta.,21-dihydroxy-.DELTA.1,4-pregnadiene-3,20-
dione so obtained is treated with isobutyric anhydride in pyridine.
21. 17.alpha.-Benzoyloxy-9.alpha.-chloro-11.beta.-hydroxy-21-isobutyryl-
oxy-.DELTA.1,4-pregnadiene-3,20-dione when prepared by the process
as claimed in claim 20 or an obvious chemical equivalent thereof.
22. A process as claimed in claim 6, in which the
17.alpha.-benzoyloxy-9.alpha.-chloro-11.beta.,21-dihydroxy-.DELTA.1,4-pregnadiene-3,20-
dione so obtained is treated with isovaleric acid chloride in
pyridine.
23. 17.alpha.-Benzoyloxy-9.alpha.-chloro-11.beta.-hydroxy-21-isovaleryl-
oxy-.DELTA.1,4-pregnadiene-3,20-dione when prepared by the process
as claimed in claim 22 or an obvious chemical equivalent thereof.
24. A process as claimed in claim 6, in which the
17.alpha.-benzoyloxy-9.alpha.-chloro-11.beta.,21-dihydroxy-.DELTA.1,4-pregnadiene-3,20-
dione so obtained is treated with oenanthic anhydride in pyridine.
25. 17.alpha.-Benzoyloxy-9.alpha.-chloro-21-heptanoyloxy-11.beta.-
hydroxy-.DELTA.1,4-pregnadiene-3,20-dione when prepared by the process
as claimed in claim 24 or an obvious chemical equivalent thereof.
26. A process as claimed in claim 6, in which the
17.alpha.-benzoyloxy-9.alpha.-chloro-11.beta.,21-dihydroxy-.DELTA.1,4-pregnadiene-3,20-
dione so obtained is treated with benzoyl chloride in pyridine.
27. 17.alpha.,21-Dibenzoyloxy-9.alpha.-chloro-11.beta.-hydroxy-.DELTA.1,4-
pregnadiene-3,20-dione when prepared by the process as claimed
in claim 26 or an obvious chemical equivalent thereof.
28. A process as claimed in claim 1, which comprises
refluxing 17.alpha.,21-(1-ethoxy-ethylidenedioxy)-9.alpha.-chloro-11.beta.-hydroxy-
1,4-pregnadiene-3,20-dione in a mixture of methanol, acetic acid
and sodium acetate.
32

29. 17.alpha.-Acetoxy-9.alpha.-chloro-11.beta.,21-dihydroxy-.DELTA.1,4-
pregnadien-3,20-dione when prepared by the process as claimed in
claim 28 or an obvious chemical equivalent thereof.
30. A process as claimed in claim 28, in which the
17.alpha.-acetoxy-9.alpha.-chloro-11.beta.,21-dihydroxy-.DELTA.1,4-pregnadiene-3,20-
dione so obtained is treated with acetic anhydride in pyridine.
31. 17.alpha.,21-Diacetoxy-9.alpha.-chloro-11.beta.-hydroxy-.DELTA.1,4-
pregnadiene-3,20-dione when prepared by the process as claimed
in claim 30 or an obvious chemical equivalent thereof.
32. A process as claimed in claim 28, in which the
17.alpha.-acetoxy-9.alpha.-chloro-11.beta.,21-dihydroxy-.DELTA.1,4-pregnadiene-3,20-
dione so obtained is treated with propionic anhydride in
pyridine.
33. 17.alpha.-Acetoxy-9.alpha.-chloro-11.beta.-hydroxy-21-propionyloxy-
.DELTA.1,4-pregnadiene-3,20-dione when prepared by the process as
claimed in claim 32 or an obvious chemical equivalent thereof.
34. A process as claimed in claim 28, in which the
17.alpha.-acetoxy-9.alpha.-chloro-11.beta.,21-dihydroxy-.DELTA.1,4-pregnadiene-3,20-
dione so obtained is treated with valeric anhydride in pyridine.
35. 17.alpha.-Acetoxy-9.alpha.-chloro-11.beta.-hydroxy-21-valeryloxy-
.DELTA.1,4-pregnadiene-3,20-dione when prepared by the process as
claimed in claim 34 or an obvious chemical equivalent thereof.
36. A process as claimed in claim 1, which comprises
refluxing 17.alpha.,21-(1-ethoxy-propylidene-dioxy)-9.alpha.-chloro-11.beta.-
hydroxy-.DELTA.1,4-pregnadiene-3,20-dione in a mixture of methanol, acetic
acid and sodium acetate.
37. 9.alpha.-Chloro-11.alpha.,21-dihydroxy-17.alpha.-propionyloxy-.DELTA.1,4-
pregnadiene-3,20-dione when prepared by the process as claimed
in claim 36 or an obvious chemical equivalent thereof.
38. A process as claimed in claim 36, in which the
9.alpha.-chloro-11.beta.,21-dihydroxy-17.alpha.-propionyloxy-.DELTA.1,4-pregnadiene-3,20-
dione so obtained is treated with formic acid.
33

39. 9.alpha.-Chloro-21-formyloxy-11.beta.-hydroxy-17.alpha.-propionyloxy-
.DELTA.1,4-pregnadiene-3,20-dione when prepared by the process as claimed
in claim 38 or an obvious chemical equivalent thereof.
40. A process as claimed in claim 36, in which the
9.alpha.-chloro-11.beta.,21-dihydroxy-17.alpha.-propionyloxy-.DELTA.1,4-pregnadiene-3,20-
dione so obtained is treated with acetic anhydride in pyridine.
41. 21-Acetoxy-9.alpha.-chloro-11.beta.-hydroxy-17.alpha.-propionyloxy-
.DELTA.1,4-pregnadiene-3,20-dione when prepared by the process as claimed
in claim 40 or an obvious chemical equivalent thereof.
42. A process as claimed in claim 36, in which the
9.alpha.-chloro-11.beta.,21-dihydroxy-17.alpha.-propionyloxy-.DELTA.1,4-pregnadiene-3,20-
dione so obtained is treated with propionic anhydride in pyridine.
43. 9.alpha.-Chloro-11.beta.-hydroxy-17.alpha.,21-dipropionyloxy-.DELTA.1,4-
pregnadiene-3,20-dione when prepared by the process as claimed
in claim 42 or an obvious chemical equivalent thereof.
44. A process as claimed in claim 36, in which the
9.alpha.-chloro-11.beta.,21-dihydroxy-17.alpha.-propionyloxy-.DELTA.1,4-pregnadiene-3,20-
dione so obtained is treated with butyric anhydride in pyridine.
45. 21-Butyryloxy-9.alpha.-chloro-11.beta.-hydroxy-17.alpha.-propionyl-
oxy-.DELTA.1,4-pregnadiene-3,20-dione when prepared by the process
as claimed in claim 44 or an obvious chemical equivalent thereof.
46. A process as claimed in claim 36, in which the
9.alpha.-chloro-11.beta.,21-dihydroxy-17.alpha.-propionyloxy-.DELTA.1,4-pregnadiene-3,20-
dione so obtained is treated with valeric anhydride in pyridine.
47. 9.alpha.-Chloro-11.beta.-hydroxy-17.alpha.-propionyloxy-21-
valeryloxy-.DELTA.1,4-pregnadiene-3,20-dione when prepared by the
process as claimed in claim 46 or an obvious chemical equivalent
thereof.
48. A process as claimed in claim 36, in which the
9.alpha.-chloro-11.beta.,21-dihydroxy-17.alpha.-propionyloxy-.DELTA.1,4-pregnadiene-3,20-
dione so obtained is treated with caproic anhydride in pyridine.
49. 9.alpha.-Chloro-21-hexanoyloxy-11.beta.-hydroxy-17.alpha.-propionyl-
oxy-.DELTA.1,4-pregnadiene-3,20-dione when prepared by the process as
34

claimed in claim 48 or an obvious chemical equivalent thereof.
50. A process as claimed in claim 36, in which the
9.alpha.-chloro-11.beta.,21-dihydroxy-17.alpha.-propionyloxy-.DELTA.1,4-pregnadiene-3,20-
dione so obtained is treated with oenanthic anhydride in pyridine.
51. 9.alpha.-Chloro-21-heptanoyloxy-11.beta.-hydroxy-17.alpha.-
propionyloxy-.DELTA.1,4-pregnadiene-3,20-dione when prepared by the
process as claimed in claim 50 or an obvious chemical equivalent
thereof.
52. A process as claimed in claim 36, in which the
9.alpha.-chloro-11.beta.,21-dihydroxy-17.alpha.-propionyloxy-.DELTA.1,4-pregnadiene-
3,20-dione so obtained is treated with trimethylacetic anhydride
in pyridine.
53. 9.alpha.-Chloro-11.beta.-hydroxy-17.alpha.-propionyloxy-21-trimethyl-
acetoxy-.DELTA.1,4-pregnadiene-3,20-dione when prepared by the process
as claimed in claim 52 or an obvious chemical equivalent thereof.
54. A process as claimed in claim 1, which comprises
treating 21-acetoxy-17.alpha.-butyryloxy-.DELTA.1,4,9(11)-pregnatriene-3,20-
dione in dioxane with N-chloro-succinimide treating the product
obtained with an aqueous solution of perchloric acid and the
mixture so obtained poured into an aqueous solution of sodium
hydrogen sulphate.
55. 21-Acetoxy-17.alpha.-butyryloxy-9.alpha.-chloro-11.beta.-hydroxy-
.DELTA.1,4-pregnadiene-3,20-dione when prepared by the process as
claimed in claim 54 or an obvious chemical equivalent thereof.
56. A process as claimed in claim 1, which comprises
treating 17.alpha.-butyryloxy-21-trimethylacetoxy-.DELTA.1,4,9(11)-pregnatriene-
3,20-dione in dioxane with N-chloro-succinimide treating the
product obtained with an aqueous solution of perchloric acid
and the mixture so obtained poured into an aqueous solution of
sodium hydrogen sulphate.
57. 17.alpha.-Butyryloxy-9.alpha.-chloro-11.beta.-hydroxy-21-trimethyl-
acetoxy-.DELTA.1,4-pregnadiene-3,20-dione when prepared by the process
as claimed in claim 56 or an obvious chemical equivalent thereof.

58. A process as claimed in claim 1, which comprises
treating 17.alpha.-butyryloxy-21-heptanoyloxy-.DELTA.1,4,9(11)-pregnatriene-
3,20-dione in dioxane with N-chloro-succinimide treating the
product obtained with an aqueous solution of perchloric acid and
the mixture so obtained poured into an aqueous solution of sodium
hydrogen sulphate.
59. 17.alpha.-Butyryloxy-9.alpha.-chloro-21-heptanoyloxy-11.beta.-
hydroxy-.DELTA.1,4-pregnadiene-3,20-dione when prepared by the process
as claimed in claim 58 or an obvious chemical equivalent thereof.
60. A process as claimed in claim 1, which comprises
treating 21-propionyloxy-l7.alpha.-valeryloxy-.DELTA.1,4,9(11)-pregnatriene-
3,20-dione in dioxane with N-chloro-succinimide treating the
product obtained with an aqueous solution of perchloric acid
and the mixture so obtained poured into an aqueous solution of
sodium hydrogen sulphate.
61. 9.alpha.-Chloro-11.beta.-hydroxy-21-propionyloxy-17.alpha.-
valeryloxy-.DELTA.1,4-pregnadiene-3,20-dione when prepared by the process
as claimed in claim 60 or an obvious chemical equivalent thereof.
62. A process as claimed in claim 1, which comprises
treating 17.alpha.,21-divaleryloxy-.DELTA.1,4,9(11)-pregnatriene-3,20-
dione in dioxane with N-chloro-succinimlde treating the
product obtained with an aqueous solution ofperchloric acid
and the mixture so obtained poured into an aqueous solution of
sodium hydrogen sulphate.
63. 9.alpha.-Chloro-11.beta.-hydroxy-17.alpha.,21-divaleryloxy-.DELTA.1,4-
pregnadiene-3,20-dione when prepared by the process as claimed
in claim 62 or an obvious chemical equivalent thereof.
64. A process as claimed in claim 28 in which the
17.alpha.-acetoxy-9.alpha.-chloro-11.beta.,21-dihydroxy-.DELTA.1,4-pregnadien-3,20-
dione so obtained is treated with a mixture of hexamethyl
phosphoric acid triamide and thionyl chloride.
36

65. 17.alpha.-Acetoxy-9.alpha.,21-dichloro-11.beta.-hydroxy-.DELTA.1,4-
pregnadiene-3,20-dione when prepared by the process as claimed
in claim 64 or an obvious chemical equivalent thereof.
66. A process as claimed in claim 36, in which the
9.alpha.-chloro-11.beta.,21-dihydroxy-17.alpha.-propionyloxy-.DELTA.1,4-pregnadiene-
3,20-dione so obtained is treated with a mixture of hexamethyl
phosphoric acid triamide and thionyl chloride.
67. 9.alpha.,21-Dichloro-11.beta.-hydroxy-17.alpha.-propionyloxy-.DELTA.1,4-
pregnadien-3,20-dione when prepared by the process as claimed in
claim 66 or an obvious chemical equivalent thereof.
68. A process as claimed in claim 6, in which the
17.alpha.-benzoyloxy-9.alpha.-chloro-11.beta.,21-dihydroxy-.DELTA.1,4-pregnadiene-3,20-
dione so obtained is treated with a mixture of hexamethyl
phosphoric acid triamide and thionyl chloride.
69. 17.alpha.-Benzoyloxy-9.alpha.,21-dichloro-11.beta.-hydroxy-.DELTA.1,4-
pregnadiene-3,20-dione when prepared by the process as claimed
in claim 68 or an obvious chemical equivalent thereof.
70. A process as claimed in claim 1, which comprises
treating 17.alpha.-acetoxy-21-fluoro-.DELTA.1,4,9(11)-pregnatriene-3,20-
dione in dioxane with N-chlorosuccinimide and the product
obtained treated with perchloric acid and then sodium hydrogen
sulphate.
71. 17.alpha.-Acetoxy-9.alpha.-chloro-21-fluoro-11.beta.-hydroxy-.DELTA.1,4-
pregnadiene-3,20-dione when prepared by the process as claimed
in claim 70 or an obvious chemical equivalent thereof.
72. A process as claimed in claim 1, which comprises
treating 21-fluoro-17.alpha.-propionyloxy-.DELTA.1,4,9(11)-pregnatriene-
3,20-dione in dioxane with N-chlorosuccinimide and the product
obtained treated with perchloric acid and then sodium hydrogen
sulphate.
73. 9.alpha.-Chloro-21-fluoro-11.beta.-hydroxy-17.alpha.-propionyloxy-
.DELTA.1,4-pregnadiene-3,20-dione when prepared by the process as claimed
in claim 72 or an obvious chemical equivalent thereof.
37

74. A process as claimed in claim 1, which comprises
treating 17.alpha.-butyryloxy-21-fluoro-.DELTA.1,4,9(11)-pregnatriene-3,20-
dione in dioxane with N-chlorosuccinimide and the product
obtained treated with perchloric acid and then sodium hydrogen
sulphate.
75. 17.alpha.-Butyryloxy-9.alpha.-chloro-21-fluoro-11.beta.-hydroxy-
.DELTA.1,4-pregnadiene-3,20-dione when prepared by the process as claimed
in claim 74 or an obvious chemical equivalent thereof.
76. A process as claimed in claim 1, which comprises
reacting 17.alpha.,21-(1-ethoxy-benzylidenedioxy)-9.alpha.-chloro-11.beta.-hydroxy-
.DELTA.1,4-pregnadiene-3,20-dione with trimethyl silyl fluoride in
dimethyl formamide.
77. 17.alpha.-Benzoyloxy-9.alpha.-chloro-21-fluoro-11.beta.-hydroxy-
.DELTA.1,4-pregnadiene-3,20-dione when prepared by the process as claimed
in claim 76 or an obvious chemical equivalent thereof.
78. A process as claimed in claim 1, which comprises
treating 21-fluoro-17.alpha.-isobutyryloxy-.DELTA.1,4,9(11)-pregnatriene-
3,20-dione in dioxane with N-chlorosuccinimide and the
product obtained treated with perchloric acid and then sodium
hydrogen sulphate.
79. 9.alpha.-Chloro-21-fluoro-11.beta.-hydroxy-17.alpha.-isobutyryloxy-
.DELTA.1,4-pregnadiene-3,20-dione when prepared by the process as
claimed in claim 78 or an obvious chemical equivalent thereof.
38

Description

~ 0~3
The present inyention is concerned with new derivatives
of 9-chloroprednisolone, with a process for their manufacture
and with pharmaceutical preparations containing these active
substances.
9-Chloroprednisolone (9~-chloro-11~,17a,21-trihydroxy-
' -pregnadiene-3,20-dione) has been kno~n for a long time
~J. Amer. Chem. Soc. 77, 1955, 4181) This corticoid is
unsuitable as an active substance in pharmacuetical preparations
that are to be used for the topical treatment of infla~matory
disorders, as it has very s-trong syste~ic effects.
It has no~ been found that hitherto unknown derivatives
of 9-chloroprednisolone are systemically almost inactive,
but that in topical use they surprisingly have a strong anti-
inflammatory activity, which generally exceeds that of the most
active commercial corticoids.
The present invention accordingly provides derivatives
of 9-chloroprednisolone of the general Eormula I ~ -
~[~ .
b~
E0 ~ ~ ~o ~ ~ ~
~ '~' "' : ~
in which Rl represents an alkanoyl group containing l to 8
carbon atoms or a benzoyl group and X represents a fluorine atom,
a chlorine atom, a hydroxyl group, an alkanoyloxy group containing
l to 8 carbon atoms or a benzoyloxy group.
As an alkanoyl group represented by Rl containing 1 to
8 carbon atoms and an alkanoyloxy group represented by X
containing l to 8 carbon atoms there is to be understood in each
case a group that is derived from a straight-chained or branched
~ -2 ~ ~

09~3
fatty acid, for example formic acid, acetic acid, propionic acid,
butyric acid, isobutyric acid, valeric acld, isovaleric acid,
trimethylacetic acid, caproic acid, tert. butylacetic acid or
caprylic acid.
Especially preferred alkanoyl groups represented by Rl
and alkanoylQxy groups represented by X are those deri~ed fro~ :
alkane carboxylic acids containing 2 to 6 carbon atoms.
9-chloroprednisolone derivatives of the general f~rmula
I in which X represents a chlortne atom or a fluorine atom
are, ~or example those listed in the following Table:
Table l
17a-Acetoxy-9a,21-dichloro~ hydroxy-hl'4-pregnad.iene-3,20-dione,
9a,21-dichloro-11~-hydroxy-17~-propionyloxy-hl'4-pregnadiene-
3,20-dione,
17a-butyryloxy--9a~21-dichloro-11~-hydroxy-hl~4-pregnadiene-3,20-
dione,
9a,21-dichloro=11~-hydroxy-17-isobutyryloxy-h '4-pre~nadiene- .
3,20-dione, . .
17a-acetoxy-9a-chloro-21-fluoro~ hydroxy-hl'4-pregnadiene-
3,20-dione,
9a-chloro-21-fluoro-11~-hydroxy-17a-propionyloxy-hl'4-pregnadiene-
3,20-dione,
17a-butyryloxy-9a-chloro-21-fluoro-11~-hydroxy-hl'4-pregnadiene-
3,20-dione,
17~-benzoyloxy-9a-chloro-21-fluoro-11~-hydroxy-hl'4-pre~andiene-
3,20-dione,
9a-chloro-21-fluoro-11~-hydroxy-17a isobutyryloxy-hl'4-pregnadiene- ~-
3,20-dione,
9a,21.dichloro-ll~-hydroxy-17a-valeryloxy~hl'4-pregnadiene-3,20-
dione,
17~-benzoyloxy-9~,21~dichloro~ -hydroxy-hl'4-pregnadienc-3,20-
dIone .
~ -3-

;)V9~3
9-Chloroprednisolone derivatives of the gener~l formula
I in which X represents a hydroxyl ~roup are, for exa~ple, those
listed in the following Table: -
Table 2
17~-Acetoxy-9~chloro~ ,21~dihydroxy-Al'4-pregnadiene-3,20-
dione,
9a-chloro-11~,21-dihydroxy-17~-propion~loxy-Al'4-pregnadiene-
3,20-dione,
17~-butyryloxy-9~-chloro~ 21~dihydroxy-a ' -pre~nadiene-
3,20-dione,
9~-chloro~ ,21-dihydroxy-17~-isobutyryloxy-~1'4-pregnadiene-
3,20-dione,
9a-chloro-11,B, 21-dihydroxy-17c~-valeryloxy-~1 ' 4-pregnadiene-
3,20-dione and
17a-benzoyloxy-9~-chloro-11~,21-dihydroxy-~1'4-pregnadiene-
3,20-dione.
These compounds ~n which X of the general ~ormula I
represents a hydroxyl group are of importance not only as
pharmacologically active substances. They can also be used as
intermediates for the production of 9-chloroprednisolone
derivatives of the general formula I in which X represents a
chlorine atom, an alkanoyloxy group or a benzoyloxy group.
As 9-chloroprednisolone derivatives of the general
formula I in which X represents ~n alkanoyloxy group or a
benzoyloxy ~roup there are preferred those in which the groups
represented by Rl and X together contain 3 to 14 carbon atoms. --
Such chloroprednisolone derivatives are, for example, those
listed in the followin~ Table;
Table 3
17~,21-Diacetoxy-9u-chloro~ hydroxy-al'4-pregnadiene-3,20-
dione,
17~-acetoxy-9~-chloro-11~-hydroxy-21-propionyloxy-al'4-pregnadiene-
3,20-dione,
~,= -4-

)g~3
21-ace-toxy-9~-chloro~ hydroxy-l7a-propionyloxy-Q '4-pregna-
diene-3,20~dione,
17a-acetoxy-21-butyryloxy-9~chloro~ -hydroxy-~1~4-pregnadiene-
3,20-dione,
21-ace~oxy-17a-butyryloxy-9~-chloro-ll~-hydroxy~ pregnadiene-
3,20-dione,
17a-acetoxy-9a-chloro-11~-hydroxy-21-isobutyryloxy-Q ' -pregna-
diene-3,20~dione, . -
21-acetoxy-9~-chloro-ll~-h~droxy~17~-isobutyryloxy~ 4-pre~na
diene-3,20-dione~
17~-acetoxy-9~-chloro-11~-hydroxy-21-valeryloxy-Ql'4-pregnadiene-
3,20-dione, ~: ~
21-acetoxy-9~-chloro-11~-hydroxy-17~-valeryloxy-~1'4-pregnadiene- ~ -
3,20-dione,
17~-acetoxy-21-benzoyloxy-9~-chloro-11~-hydroxy-~ '4~pregnadiene- ~
3,20-dione, ~ :
21-acetoxy-17a-benzoyloxy-9~-chloro~ -hydroxy-~1'4-pregnadiene-
3,20-aione,
9a-chloro~ hydroxy-17a,21-dipropionyloxy-~1'4-pregnadiene-
3,20-dione,
17a-butyryloxy-ga-chloro-1-1~-hydroxy-21-propionyloxy-~ '4-
pregnadiene-3,20-dione,
21-butyryloxy-9a-chloro~ -hydroxy-17~-propionyloxy-~l/4
pregnadiene-3,20-dione,
9a-chloro~ B-hydroxy-17a-isobutyryloxy=21-propionyloxy-~1'4-
pregnadiene-3,20-dione, . . :
9a-chloro-ll~hydroxy-21-isobutyryloxy-17a-propionyloxy;~l~4
pregnadiene-3~20-dione,
9a-chloro-11~-hydroxy-17a~propionyloxy=21-valeryloxy-~ '4-
pregnadiene-3,20-dione,
9a-chloro-11~-hydroxy-21-propionyloxy-17~valeryloxy~l'4-
pregnadiene=3 ! 20-dione,

lL~00~43
17~-benzo~loxy-9~-chloro~ hydroxy-21-propionyloxy-Al'4-
pregnadiene-3,20-dione,
21-benzoyloxy-9a-chloro-ll~-hydroxy-l7~-propionyloxy~Ql~4
pregnadiene 3,20-dione,
17~,21-dibutyryloxy-9a-chloro-11~-hydroxy ~1'4-pre~nadiene-
3,20-dione,
17~-butyryloxy-9~-chloro-ll~-hydroxy-2l-isobutyryloxy~ 4
pregnadiene-3,20-dione,
21-butyryloxy-9c~-chloro-ll,~-hyd:roxy~17~-isobutyryloxy-~114_
pregnadiene-3,20-dione,
17~-butyryloxy-9a-chloro-11~-hydroxy-21-valeryloxy-~'4- ~ -
pregnadiene-3,20-dione,
21-butyrylQxy-9~-chloro-11~-hydroxy-17~-valeryloxy-~1'4
pregnadiene-3,20-dione,
17~-benzoyloxy-21-butyryloxy-9a-chloro-11~-hydroxy-~
pregnadiene-3,20-dione,
2l-benzoyloxy~l7~-bu~yryloxy-9a-chloro-ll,g-hydroxy ~1~4
pregnadiene=3,20~dione, ~ ;
9~-chloro-11~-hydroxy-17,21-aitsobutyryloxy-~1'4-pregnadiene- ~-
3,20-dione, and ~-
9a-chloro~ hydroxy-17a,21-divaleryloxy-~ '4-pregnadiene-
3,20-dione. ~.
The new 9-chloroprednisolone derivatives may be
prepared by the process of the present invention, as defined below.
The present invention accordingly also provides a
process for the manufacture of a compound of the general formula
I, wherein
(a) HOCl is added on ~t the ~9'11-double bond of a compound
of the general formula II :
.
:., :: :, -

L00943
1 2
C~
OE~
. O
.in which ~1 and X have the meanings given above, or
(b) the epox.ide ring of a compound of the general formula III
1 2
.- ~0
OX
~
~;, f .f' ` ' -, ~
in which Rl and X have the meanings given above, is opened up
with hydrogen chloride, or tc) when X represents a hydroxyl
group or a fluorine or chlorine atom, an ortho-ester o~ the
general formula I~ ;
a-o / \ ~ ~
.1 ~i ,.
in which R3 represents a hydrogen atom, an alkyl group containing
~ -7-

9~3
l to 7 carbon atoms or a phenyl group and R2 represents an alkyl
group containin~ 1 to 4 carbon atoms, is hydrolysed or reacted
with trimethylsilyl fluoride or chloride or triphenylmethyl
fluoride or chlorlde, or (d) when X represents a chlorine atom,
an alkanoyloxy group or a benzoyloxy group, a 9-chloro-derivative
of the general formula Ia
a~2o~ ,
C-O
~ (Ja),
,
f
in which Rl has the meaning gi~en above, is chlorinated or
esterified at the 21-position. -
Each of the variants of the process of the presentinvention may be carried out in a manner known per se. The
process ~ariants (a), (b) and (d) may be carried out under the
conditions descrlbed in United States Patent Specification Nos.
3,678,034, 3,718,671 and 3,828,083. The process of the
present invention in accordance with process variant (c) may be
carried out under the conditions described in United States ~ ;
Patent No. 3,152,154 and in ~erman Offenlegungsschriften Nos.
26 13 875 and 24 36 747.
The starting compounds for the process of the present
invention can be preparea, as ls known, ln a simple manner and
in high yields from prednisolone, which ltself can be synthesized
relatively easily from diosgenin. The consequence of this is that
the compounds of the present invention can be prepared from
diosgenin with relatively lTttle expenditure in a total yield of
about 15%. On the other hand, the syntheses of known highly
~ -8-

~vg43
active corticoids from dios~enin are considerably more expensive
- and the total yields obtained are si~nificantl~v smaller (about
0.5 to 5%). This is not without importance in view of the
increastng difficulties in procuring suf~icient quantities of
starting materials suitable for the syntheses of corticoids,
and having regard to the hi~h costs of the active substances with
which medicinal specialties containing corticoids are encumbered.
The compounds o~ the present invention possess, as has
~lready been stated, a strong anti inflammatory activity in
topical applicatlon, but they are only very weakly active in
systemic appllca-tion.
The pharmacological properties of the compounds have
been determined by the following tests: -
(A) The inflammation-inhibiting activity in local application
to the ears of rats:
The substance to be tested was dissolved in an irritant
ronsisting of 4 parts of pyridine, 1 part of-distilled water,
5 parts o~ ether and 10 parts of an ethereal soluti~n of 4~
strength of croton oil Str;ps of felt, which were attached to
the inner sides of a microscope slide forceps, were impregnated
with this test solution, and were pressed with light pressure for
15 seconds on the right ear of male rats wei~hing 100 to 160
grams. The left ear remained untreated and served for comparison.
Three hours after the application tha animals were killed and
-discs having a size of 9 mm were stamped out of their ears. The
difference in weight between the discs of the right and that of
the left ear w~s a measure of ~he pedema formed.
The dose of test substance was determined at which after
three h~urs a 50~ inhibitlon ~f the f~rmatlon of oedema was
observed.
(B) The inflammatlon-inhibiting activity ln subcutaneous
application to the pa~ of rats:
_.
_g_ ~

43
SPF-Rats weighing 130 to 150 grams were injec-ted in the
right rear paw for ~roaucing a source of inflammation with 0.1
ml of a suspension of 0.56 strength of ~ycobacterium butyricu~
(obtainable from the American f~rm Di~ko). Before the injection
the paw yolumes of the rats were measured, 24 Hours after the
injection the paw volume was again measured to determine the
extent of the oedema. The rats were then injected subcutaneously
with various quantities of the te$t s~stance dissolved in a
mixture of 29% of benzyl benzoate and 71~ of castor oil. After
a further 24 hour~ the paw volume was again determined. ~'
Contxol anilnals were treated in the same manner with
the difference that they were injected with a mixture of benzyl ~ ~;
benzoate and castor oil free from the test substance.
Fro~ the paw ~olumes so obtained was determined in the
usual manner the quantities of test substance which was required
to produce a 50% healing of the paw oedema.
(C) The thymolytic effect after ora-l applicationO ;~
SP~-Rats weighing 70 to 110 grams were adrenalectomized
under narcosis produced by ether. E~ery 6 animals formed a
test group, each of which received over 3 days a definite
quantity of test substance applied -per os. On the fourth
day the animals were killed and the weight of their thymus'
was determined. Control animals were treated in the same manner,
but received a mixture of benzyl benzoate and castor oil without
the test substance. From the weights of the thymus so obtained '~
was determined in the usual manner the quantity of test substances
at which a 50% thy~olysis was observed.
As sub,st,a,nces for comparison there were used in these
tests the structurally analo~ous 9-chloroprednisolone and its
21-acetate and also ~eclomethasone-17,21-dipropionate (9~-
chloro-ll~-hydroxy-l6~-methyl-l7~2l-dipropionyloxy-~l~4-pregna
diene-3,20-dione).
--10--

943 : ^
The xesults obtained in these tests are given in the ~:
following Table;
N ~ _ . ~ _ `
~ ~ ~D O U~ ~ a;
10 ` c~ ' o, o ~ .
~a _ _~ _ _~ ~ `:
C ,¢ o ~) ~ o A o o Is`) o A .
o r~ ~ ~ _ ~ ~:
~+) ~r' u~' ~, ~, u~ ~' u~ ~
' ~_ .-1 o o o ~
. .. ,: : . : .
x ~ r ~ o ~: o ~ x ~ ~
~ X c F Y ~c c 2 C I ~D ~ ~r
r h ` ~ rD o r~ ~ r~ o ~ N h h h
O ~ 5~ ` ~ ~ ~ 'I O I ~ Q~ I ~i .
~ 1 ~ ~ ~ I~r ~: ~ z~ I ~:
CQ ~ I .Q) ~ X . ~ rl ~ ~ I a 1--à X O
0 v ~ O ~ ~ u I O N ~ N ~ N
. :S ~ ~1 ,la. ~ ~ ~5 ~,i ;~ ,~
_ ~
Z H H H H ~ H H H
i 1 1

~L~00943
Similar results are obtained when the pharmacological
activity of the 9-chloroprednisolone derivatives of the present ~
invention is determined by means of the known vasoconstriction ~ -
test or the known sodium~potassium retention test.
The new compounds of the present invention are suitable
in combination with the carrier substances customarily used in,
for example, galenical pharmacy for the local treatment of
contact dermatitis, eczemas of a very wide variety of types,
neurodermatoses, erythrodermia, burns, Pruritis vulvae et ani,
Rosacea, ErythematQdes cutaneus, Psoriasis, Lichen ruber planus
~t verrucosus and similar skin diseases.
The present invention accordingly further provides a
pharmaceutical preparation which comprises a compound of the
general formula I, in admixture of conjunction with a pharmaceu-
tically suitab~e carrier. The preparation is advantageously
in a form suitable for the topical trçatment of inflammations.
The manufacture of the pharamceutical preparations
may be carried out in the usual mannex by converting the active
substances with suitable additives into the desired form of
application, for example solutions, lotions, salves, creams
or plasters. The concentration of active substance in the
pharmaceutical preparations so formulated depends on the form
of application. In the case of lotions and salves there is
preferably used a concentration of active substance within the
ran~e of from 0.001% to 1% by weight.
~ -12-

)943
Furt}len~ore, tne new compounds of the gene~al formula I
are also well suited for the production of inhalant preparations,
if desire~ in combination witil the usual carrier substances and
auxiliary substanc~s, wllich preparations can be used for tlle
thera~y of allergic disorders of the respiratory system, for
example broncllial asthma or rhinitis.
The following Examples illustrate tlle invention. Examples
`1 to 3~ illustrate t.he manufacture of compounds of tlle general
formula I and Examples 40 and 41 illustrate pharmaceutical
preparations contailling such compounds.
Example 1
.
(a) 5.0 gms of 9~-chloro~ , 17~, 21-trihydroxy-~ pregnaaiene-
3,20-dione were mixea with 500 ml of benzene, 40 ml of dimethyl-
formamide and 500 my of absolute pyridine tosylate. The mixture
- was heated, 50 ml of the solvent were distilled off at a bath
temperature of 130C, 60 ml of ortho-benzoic acid trietllyl ester
were aadea and tlle residual benzene was distilled off during the
course of 2 1/2 hours. 2.4 ml of pyriaine were added to the
residue, tlle mixture was concentrated in vacuo and 17~,21-(1-
ethoxy-~enzylidenedioxy)-9~-chloro-11~-hydroxy-Al'4-pregnadiene-
3,20-dione was o~tained in tlle form of an oily crude product.
(~, The crude product so obtained was mixed with 150 nl of
methanol, 54 ml of O.lN-aqueous acetic acid and 6 ml of an O.lN-
aqueous solution of sodium acetate and the mixture was heated under
refl:~x for 90 minutes. The reaction mixture was then concentrated
in vacuo, water was added to the residue and the mixture was
extracted with eth~l acetate. The organic phase was washed with
water, concentrated in vacuo, the residue was purified by
chromatography over a column of silica gel and recrystallized from
acetone-hexane and there were obtained 3.7 gms of 17~-benzoyloxy-
9Q-chloro-ll~ aihydroxy-~1'4-pregnadient-3,20-dione melting
at 216C (with aecomposition).
- 13 -
,~ ;,. .

09~3
Example 2
0.~ gm of 17a-bellzoyloxy-9a-chloro-11~,21~dihydroxy-
~1'4-pregnadiene-3,20-dione was stirred for 24 hours at room
temperature with 10 ml of formic acid. The reaction mixture was
then poured into ice-water and extracted witll dicllloromethane,
tlle organic phase was washed, dried over sodium sulphate and
concentrated _ vacuo and there were obtained 400 mg of 17a-
l)enzoyloxy-9a-chloro-21-formyloxy-11~ ydroxy-~1'4-pregnadieiie-
3,2~-dione that solidified in tlle form of a ylassy mass.
1~ la~2~ 58 (chloroform).
Example 3
1.5 gms of 17a-benzoyloxy-9a-chloro~ ,21-dillydroxy- ~
' -pregnadiene-3,20-dione were mixed wlth 17 ml of pyridine and -;
8.0 ml of acetic anhydride and the w~lole was stirred for one hour -~
at 0C. The reaction mixture was poured into ice-water, the `~
product that separated was filtered off and dissolved in the
dicllloromethane, and the organic phase was washed, dried with
sodium sulphate and concentrated ln v~acuo. The residue was
chromatographed over a column of silica gel with methyl~ne chloride-
~0 acetone gradients and recrystallized from acetone-hexane and 1.2 ~-
yms of 21-acetoxy-17a-benzoyloxy-9a-cllloro-11~-hydroxy-~1'4- ~ -
prenadiene-3,20-dione melting at 221C (with decomposition) were -
obtained.
Example 4
1.5 gms of 17a-benzoyloxy-9N-chloro-ll~-dihydroxy-~1'4-
pregnadiene-3,20-dione were mixed witll 17 ml of pyridine and
8.0 ml of propionic anhydride and the whole was stirred for one
hour at 0C. The reaction mixture was worked up as described in
Example 3-and there were obtained 960 mg of 17a-benzoyloxy-9a-
chloro-11~ ydroxy-21-propionyloxy-~ '4-pregnadiene-3,20-dione
melting at 226~C (Witrl decomposition).
- 14 -

9~3
Example 5
2.3 gms of 17~-benzoyloxy-9~-chloro-11~-dinydroxy-A ' -
pregnadiene-3,~0-dione were mixed with 50 ml of pyridine and 25
ml of butyric anllydride and tl~e whole was stirred for 16 hours
at room temperature. Tne reaction mixture was worked up as
described in Example 3 and 2.0 gms of 17~-benzoyloxy-21-bu~-
yryloxy-9~-c~lloro~ nydrox~ 1'4-prenadiene-3,20-dione melting
at 22~C ~(with decomposition) were obtained.
Example 6
1~ 2.3 ~ms of 17a-benæoyloxy-9~-chloro-11~,21-dihydroxy-
'4 prenadiene-3,20-dione wer~ mixed with 50 ml of pyridine and
25 ml of valeric anhydride and the wllole was stirred for 16 hours
at room temperature. The reaction mixture was worked up as
described in ~xample 3 and there were obtained 1.63 ~ms of 17a-
benzoyloxy-9~-chloro-11~-hydroxy-21-valeryloxy-~1'4 pregnadiene-3,
20-dione melting at 208C. `
Example 7
2.3 gms of 17~-benzoyloxy-9~-chloro~ ,21-dihydroxy- -
~ '4-pregnadiene-3,20-dione were mixed with 50 ml of pyridine and
25 ml of trimekhylacetic anhydride and the whole was stirred for
16 hours at room temperature. ~he reaction mixture was worked up
as described in Example 3 and there were obtained 1.72 ~ms of
17c~-benzoyloxy-9a~chloro-11~-hydroxy-21-trimethylacetoxy~~ ' - '-
prenadiene-3,20-dione melting at 236C.
Example 8
2.3 gms of 17~-benzoyloxy-9~-chloro-11~,21-dihydrox~-
~1'4-pregnaaiene-3,20-dione were mixed with 50 ml of pyridine and
25 ml of isobutyric anhydride and the ~.~hole was stirred for 16
nours at room temperature. The reaction mixture was wor~ed up
as described in Example 3 and 2.1 gms of 17~-benzoyloxy-9~-chloro~
ll~-ilydroxy-21-isobutyryloxy-~1'4-pregnadiene-3,20-dione were
obtained in the form of a ylassy mass. [~]25 = ~68 (chloroform).
-- 1~ --
... ....

" 11()~943
Example 9 -
:
2.3 ~ms of 17c~-~enzoyloxy-9c~-chloro-11~,21~dillydroxy-
Q ' - pregnadiene-3,2ù-dione were mixed with 5û ml of pyridine
and 2û ml of isovaleric acid chloride and the w~ole was stirred
for 2 hours at 0C. The reaction mixture was worked up as des-
cribed in Example 3 and 2.1 gms of 17c~-benzoyloxy-9~-chloro-
ll~-hydroxy-21-isovaleryloxy-~1'4-pregnadiene-3,2û-dione melting
at 197C were obtained.
Example 10
lQ 2.3 gms of 17a-benzoyloxy-9c~ chloro~ ,21-dihydroxy-
Ql'4-pregnadiene-3,20-dione were mixed with 50 ml of pyridine and
30 ml of oenanthic anliydride and the whole was stirred for 16
hours at room temperature. The reaction mixture was poured into
ice-water and heated and the excess of oenanthic acid was removed ;~
by steam distillation. The mixture was extracted with dichloro-
methane, the organic phase was worl~ed up as described in Example
3 and 2.03 gms of 17~-benzoyloxy-9o~-chlorc~21 he~tanoyloxy~
hydroxy-~l' -pregriadiene-3~20-dione were obtained in the form
of an oily product.
la]D = ~64 (Ch1OrOfOrm~ ;
Example 11
2.3 gms of 17c~-benzoyloxy-9a-chloro-ll,B,21-dlllydroxy-
Q '4-pregnadiene-3,2()-dione were stirred with 45 ml of pyridine
and 1 ml of benzoyl chloride for one hour at room temperature.
The reaction mixture was worked up as descri}~ed in Example 3 and
there were obtained 2.5 gms of 17~,21-dibenzoyloxy-9~-chloro-11
hydroxy-Ql'4-pregnadiene-3,20-dione melting at 221C.
Example 12
(a) Under tlle conditions described in Example l(a) 7.5 gms
of 9~-chloro~ ,17 a,21-trillydroxy-â '4-pregnadiene-3,20-dione
, -16~
,,~

)0~43
were reacted with ortho-acetic acid triethyl es-ter and worked
up. There was obtained 17~,21-(1-ethoxy-ethylidenedioxy)-9~-
chloro~ hydroxy-~l'4-pregnadiene-3,20-dione in the form of
an oily crude product.
(b) The crude product so obtained was reacted under the con-
ditions described in Example l(b) and worked up, and 5.2 gms
of 17a-acetoxy-9~-chloro-11~,21-dihydroxy-~1~4-pregnadiene-3,20-
dione melting at 205C (with decomposition) were obtained.
Example 13
1.0 gm of 17a-acetoxy-9a-chloro-11~,21-dil1ydroxy-~l'4-
pregnadiene-3,20-dione was mixed with 20 ml of pyridine and 5 ml
o~ acetic anllydride and the whole was stirred for one hour at
room temperature. The reaction mixture was then poured into ice-
water, the product that separated was filtered off with suction
and dissolved in dichloromethane and the organic phase was washed
and concentrated _ vacuo. The residue was recrystallized from
acetone-hexane and there were obtained 860 mg of 17~,21-diacetoxy-
9a-chloro~ -hydroxy-~1'4-pregnadiene-3,20-dione melting at 222C
(with decomposition).
Example 14
Under the conditions described in Example 4, 1.0 gms of
17a-acetoxy-9~-chloro-11~,21-dihydroxy-~1'4-pregnadiene-3,20-
dione was reacted with propionic anhydride and worked up, and
there were obtained 940 mg of 17a-acetoxy-9a-chloro-11~-hydroxy-
21-~ropionyloxy-~1'4-pregnadiene-3,20-dione melting at 219C ~ -
(with decomposition).
Example 15
Under the conditions described in Example 6, 1.0 gm
of 17~-acetoxy-9a-chloro-11~,21-dihyroxy-~1'4-pregnadiene-3,20-
dione was reacted with valeric anhydride and worked up, and therewere obtained 660 mg of 17a-acetoxy-9~-chloro-11~-hydroxy-21
valeryloxy-~l'4-pregnadiene-3,20-dione melting at 220C (with
- 17 -
, , , .- , .
-.-, ,

1~00943
decomposition).
Example 16
(a) Under the conditions described in Example l(a) 7 gms of
9~-chloro~ ,17~,21-trihydroxy-~1'4-pregnadiene-3,20-dione were
reacted with ortno-propionic acid trietilyl ester and worked up,
and 17~,21-(1-ethoxy-propylidenedioxy)-9~-chloro~ -hydroxy-
'4-pregnadiene-3,20-dione was obtained in the form of a crude
product.
(b) The crude ~roduct so ohtained was react~d under the con-
ditions described in Example l(b) and worked up, and there were
obtained 2.9 gms of 9a-chloro-11~,21-dihydroxy-17a-propionyloxy-
~ '4-pregnadiene-3,20-dione melting at 181C (with decomposition).
Example 17
Under the conditions described in Example 2, 1.2 gms
of 9~-cnloro-11~,21-dihydroxy-17a-propionyloxy-Al'4-pregnadiene-
3,20-dione were reacted with formic acid and worked up, and there
were obtained 400 mg of oily 9u-chloro-21-formyloxy-11~-hydroxy-
17~-propionyloxy~l'4-pregnadiene-3,20-dione. [~]~5 = +67
(chloroform).
Example 18
700 mg of 9a-chloro-11~,21-dihydroxy-17~-propionyloxy-
~ '4-pregnadiene-3,20-dione were reacted with acetic anhydride as
aescribed in Example 3 and worked up and there were obtained 320
mg of 21-acetoxy-9~-chloro~ -hydroxy-li~-propionyloxy-~
pregnadiene-3,20-dione meltins at 210C (with decomposition).
Example 19
700 mg of 9a-chloro~ ,21-dihydroxy-17a propionyloxy-
~1~ -pregnadiene-3,20-dione were reacted with propionic anhydride
under the conditions described in Example 4 and worked up, and
there were obtained 420 mg of 9~-chloro-11~-hydroxy-17a,21-
dipropionyloxy-~l'4-pregnadiene-3,20-dione melting at 215C
(with decomposition).

9~3
Example 20
650 mg of 9a-chloro~ ,21-dihydroxy-17~-propionyloxy-
~ ' -pre~nadiene-3,20-dione were reacted with butyric anhydride
under the conditions described in Example 5 and worked up, and
there were obtained 360 mg of 21-butyryloxy-9~-chloro-11~-
hydroxy-17a-propionyloxy-~1'4-pregnadiene-3,20-dione melting at
208C twith decomposition~.
Example 21
Under the conditions described in Example 6, 700 mg
of 9~-chloro-11~,21-dihydroxy-17a-propionyloxy-~1'4-pregnadiene-
3,20-dione were reacted with valeric anhydride and ~orked up, and
there were obtained 520 mg of 9a-chloro-11~-hydroxy-17a-propiony-
loxy-21-valeryloxy-~1'4-pregnadiene-3,20-dione melting at 210C
(with decomposition).
Example 22
3.0 gms of 9~-chloro~ ,21-dihydroxy-17a-propionyloxy-
' -pregnadiene-3,20-dione were mixed with 30 ml of pyridine and
15 ml of caproic anhydride and the whole was stirred for 90
minutes at room temperature. The reaction mixture was worked up
as described in Example 3 and there were obtained 2.6 gms of 9a-
chloro-21;hexanoyloxy~ hydroxy-17a-propionyloxy-~1'4-preg-
nadiene-3,20-dione. ;
Example 23
UndQr the conditions described in Example 10, 2.1 gms
of 9~-chloro-11~,21-dihydroxy-17~-propionyloxy-~ '4-pregnadiene-
3,20-dione were reacted with oenanthic anhydride and worked up,
and there were obtained 1.02 gms of 9a-chloro-21-lleptanoyloxy-
ll~-hydroxy-17~-propionyloxy-~1'4-pregnadiene-3,20-dione.
Example 24
Under the conditions described in Example 7, 1.4 gms of
9a-chloro-11~,21-dihydroxy-17a-propionyloxy-~ '4-pregnadiene-
3,20-dione were reacted with trimethylacetic anhydride and worked
f: 19
, , ,

`943
up, and 670 mg of 9~-chloro-11~-hydroxy-17~-propionyloxy-21-
trimethylacetoxy-~l'4-pregnadiene-3,20-dione were o~tained.
~xample 25
(a) Under the conditions described in Example 20, 25 gms of 11~-
17~,21-trihydroxy-~1'4-pregnadiene-3,20-dione were reacted with
butyric anhydride and worked up, and 23.1 gms of 21-butyryloxy-
11~,17 ~dihydroxy-~1'4-pregnadiene-3,20dione were obtained.
tb) Into a suspension of 24 gms of cooper-(l) chloride in 480
ml of absolute tetrahydrofuran were introduced dropwise under
1~ argon at 0C 100 ml of an ethereal solution of 5~ strength of
lithium methyl. The mixture was then cooled to -30C and a
solution of 22.3 gms of 21-butyryloxy-11~,17~-dillydroxy-~1'4-
pregrandiene-3,20-dione was added. The mixture was stirred for
4 hours until the primarily formed ll~-hydroxy 17a,21-(1-
hydroxy-butylidenedioxy)_~l'4-pregnadiene-3,20-dione had been
rearranged. An a~ueous solution of ammonium chloride was then
added to the reaction mixture, extraction was carried out with
methylene chloride, the organic phase was washed and concentrated
in vacuo and 20.3 gms of 17a-butryrloxy-11~21-dillydroxy-~ '4-
pregnadiene-3,20-dione were obtained in the form of a crude
product.
(c) Under the conditions described in Example 3, 20 gms of the
crude product so obtained were reacted with acetic anhydride and
worked up, and there were obtained 14.2 gms of 21-acetoxy-17~- -
butyryloxy-ll~ ydroxy-~l'4-pregnadiene-3,20-dione.
(d) 5.4 ml of metllane sulphonic acid chloride were introduced
dropwise at room temperature into a solution of 10 gms of 21-
acetoxy-17a-butyryloxy-11~-hydroxy-~1' -pregnadiene-3,20-dione
in 50 ml of dimethylformamide and 11 ml of pyridine. The reaction
mixture was stirred for two hours at 85C, poured, after cooling,
into ice-water and wor~ed up as described in Example 3, and 6.5
gms of 2l-acetoxy-l7~-butyryloxy-~l~4~9(ll)
~ - 20 -
, . , ~ . - .

1~L()~9~3
dione were obtained in the form of a crude product.
(e) 6 gms of the crude product so obtained were suspended in 80
ml of dioxane and 5.6 gms of N-chlorosuccinimide were added.
There were then introduced dropwise into the mixture during the
course of 10 minutes at 20C, 42 ml of an a~ueous solution of
ld~ strength of perchloric acid, and the mixture was stirred
for 3 hours at 20C and was then poured into a solution of 2.5
gms of sodium hydrogen sulphlte in 400 ml of water. The product
that separated was filtered off with suction and worked up as
described in Example 3, and 3.1 gms of 21-acetoxy-17a~butyryloxy-
9~-chloro-11~-hydroxy-~1'4-pregnadiene-3,2-dione melting at 215C
were obtained.
Example 26
(a) 9.5 gms of 17~-butyryloxy~ ,21-dihydroxy-~1'4-pregnadiene-
3,20-dione prepared as a crude product in accordance with Example
25~b) were reacted under the conditions described in Example 7
with trimethylacetic anhydride and worked up, and 6.3 gms of
i7~-~utyryloxy-11~-hydroxy-21-trimethylacetoxy-~1'4- pregnadiene
3,20-dione were obtained.
(b) 6.0 gms of 17a-butyryloxy-11~-hydroxy-21-trimethylacetoxy-
~ ' -pregnadiene-3,20--dione were reacted with methane sulphonic
acid chloride under the conditions described in Example 25(d) and ~-~
wor~ed up, and there were obtained 3.4 gms of 17a-butyryloxy- -
21~trimethylacetoxy-~1'4-pregnatrienen-3,20-dione in the form of
- a crude product.
(c) 3.0 gms of ~he crude product so obtained were reacted under
the conditions described in Example 25(e) and worked up, and there
were obtained l.i gms o~ 17~-butyryloxy-9~-chloro-11~-hydroxy-21-
trimeth~lacetoxy-~l'4-pregnadiene-3,20-dione melting at 259C.
Example 27
(a) 14.1 gms of 17~-butyryloxy-11~,21-dihydroxy-~1'4-pregnadiene-
3,20-dione, prepared as a crude product in accordancP with ~xample
- 21
-

~l~()094~3
25(b), were reacted under the conditions described in Example 10
with oenanthic anhydride and worked up, and there were obtained
8.2 gms of 17a-butyryloxy-21-heptanoyloxy-11~-hydroxy~
pre~nadiene-3,20-dione.
(b) 7.6 gms of 17a-butyryloxy-21-heptanoyloxy-11~ ydroxy-
~pregnadiene-3,20-dione were reacted under the conditions described
in Example 25(d) and worked up, and 3.9 gms of 17a-bu~yryloxy-
21-heptanoyloxy-~1'4-pre~natriene-3,20-dione were obtained as
a crude product.
(c) 3 gms of tne crude product so obtained were reacted with
N-chlorosuccinimide under tl~e conditions described in Example 25
(e) and worked up, and 950 mg of 17a-butyryloxy-9a-chloro-21-
heptanoyloxy-ll~-hydroxy-~l'4-pregnadiene-3,20-dione were obtained.
~xample 28
.
(a) Under the conditions described in ~xample 25(b) 20 gms of
11~,17a-dihydroxy-21-valeryloxy-Ql'4-pregnadiene-3,20-dione were
reacted with lithium dimethyl cuprate and worked up, and 18.6
gms of 11~,21-dihydroxy-17a-valeryloxy-~1'4-pre~nadiene-3,20-
dione were obtained in the form of a crude product.
(b) 18 gms of the crude product so obtained were reacted with
propionic anhydride under the conditions described in Example 4
and worked up, and 10.8 gms of 11~-hydroxy-21-propionyloxy-17a-
valeryloxy-~l'4-pregnadiene-3,20-dione were obtained.
(c) 9 gms of 11~-hydroxy-21-propionyloxy-17a-valeryloxy-~1'4-
pregnadiene-3,20-dione were reacted with methane sulphonic acid
chloride under the conditions described in Example 25(d) and
worked up, and 4.9 gms of 21-propionyloxy-17~-valeryloxy-~1'4'9(11)-
pregnatriene-3,20-dione were obtained in the form of a crude
product.
(d) 4.0 gms of the crude product so obtained were reacted under
the conditions described in Example 25(e) and worked up, and 1.4
gms of 9a-chloro-11~-hydroxy-21-propionyloxy-17a-valeryloxy-~ ' -
22 ... !
,~ " ~ : .

~L~V0~43
pr~gnadiene-3,20-dione were obtained. Melting point: 242C.
Lxar.lpl_ 2
(a) 17.2 gms of 11~,21-dihydroxy-17a-valeryloxy-~1'4-pregnadiene-
3,20-dione, crude product, were reacted with valeric anhydride
under the conditions descri~ed in Example 6 and worked up, and
there were obtained 9.7 gms of 11~-hydroxy-17~,21-divaleryloxy-
~1, -pregnadiene-3,20-dione.
(b) 8 gms of 11~-hydroxy-17~,21-diva~eryloxy-~1'4-pregnadiene-
3,20-dione were reacted with methan sulphonic acid chloride
under the conditions described in Example 25(d) and worked up,
and 4.6 gms of 17~,21-divaleryloxy-~1'4'9(11)-pregnatriene-3,20-
dione were obtained in the form of a crude product.
(c) 4.5 gms of the crude product so obtained were reacted under
the conditions described in Example 25(e) and worked up, and
1,8 gms of 9~-chloro-11~-hydroxy-17~,21-divaleryloxy-~ ' -preg~
nadiene-3,20-dione were obtained. Melting point: 254~C.
Example 30
To 10 ml of hexamethyl-phosphoric acid triamide were
added at 0C 1.3 ml of thionyl chloride and the whole was stirred
for 30 minutes. 800 mg of 17~-acetoxy-9~-chloro-11~,21-dihydroxy~
~1'4-pregnadiene-3,20--dione were then added to the mixture and
the whole was stirred for a further 5 1/2 hours at 0C.
The reaction mixture was worked up as described in
Example 3 and 540 r.lg of 17a-acetoxy-9a,21-dichloro-11~ y~roxy-
~ '4-pregnadiene-3,20-dione melting at 222QC (with decomposition)
were obtained. --
Example 31
Under the conditions described in Example 30, 1.2
gms of 9~-chloro-11~,21-dihydroxy-17 ~propionyloxy-~l' -preg-
nadiene-3,20-dione were reacted with thionyl chloride and worked
up and 860 mg of 9~,21-dichloro-11~-hydroxy-17~-propionyloxy-
~1'4-pregnadiene-3,20-dione melting at 232C were obtained.

94~
E~ample 32
Under the conditions described in Example 30, 8.5 gms
of 17~-~enzoyloxy-9~-chlQro-11~,21-dihydroxy-Ql'4-pregnadiene-
3,20-dione were reacted and worked up, and 4.1 gms of 17a-ben-
zoyloxy-9~,21-dichloro~ ydroxy-Ql'4-pregnadiene-3,20-dione
melting at 220C were obtained.
Example 33
(a~ A suspension of S.~ gms of 21-fluoro-17a~hydroxy-Ql'4'9(11)-
pregnatriene-3,20-dione in 80 ml of dietl~ylene glycol dimethyl
etller was stirred wlth 10 gms of N,N-dimethylamino~pyridine and
6.4 ml o~ acetic anhydride for 6.5 hours at 80C. The reaction
mixture was diluted with methylene chloride and washed with 2N-
hydrocl~loric acid. After steam distillation extraction was
carried out with methylene chloride, the mixture was dried over
sodium sulphate and, after evaporation, 6.7 gms of 17a-acetoxy-
21-fluoro-~1'4'9(11)-pregnatriene-3,20-dione were isolated.
(b) 2 gms of the above crude product was dissolved in 20 ml of
dioxan and treated with N-chlorosuccinimide in a manner analogous
to tllat described in Example 25~e). Purification of the reaction -
product was carried out over 220 gms of silica ael with a methlenechloride-acetone gradient (0-10% of acetone). The yield was
1.3 gms of 17 ~acetoxy-9~-chloro-21-fluoro-11~-hydroxy-al'4-
pregnadiene-3,20-dione. Melting point: 232C (with decomposition).
[~I2s= +52 (chloroform) UV: ~239 = 15,100 (methanol)
Example 34
2 gms of 21-fluoro-17a-propionyloxy-Ql'4'9~11)- ;
pregnatriene-3,20-dione, prepared in a manner analogous to that
described in Example 33(a) from 21-fluoro-17a-hydroxy-~ ~4~9(11)_
pregnatriene-3,20-dione and propionic anhydride, ~ere reacted with
N-chloro-succinimide under the conditions described in Example
25(e). The crude product was purified over 220 gms of silica
yel with a methylene chloride-acetone gradient (0-10% of acetone).
- ~4 -
~ ;-
:

943
The yield was 1.24 gms of 9~-chloro-21-fluoro~ ydroxy-17~-
propionyloxy-~ '4-pregnadiene-3,20-dione. Melting point 221C.
(with decomposition). [~]25 = +48~ (cllloroform).
UV: 239 = 15,500 (methanol)
Example 35
1.5 gms of 17~-butyryloxy-21-fluoro-~ i ~ ( )-preg-
natriene-3,20-dione, prepared from 21-fluoro-17~-hydroxy-A ,4,9(11)
pregnatriene-3,20-dione and butyric anhydride in a manner analo-
gous to that described in Example 33(a), were treated with N-
clllorosuccinimide in a manner analogous to that described inExample 25(ej. Purification of the crude product was carried
out over 1~0 gms of silica gel with a methylene chloride-acetone
gradient (60-10~ of acetone). The yield was 840 mg of 17~-
~utyryloxy-9o-chloro-21-fluoro-11~- hydroxy-~l'4-pregnadiene- -
3,20-dione.
~xample 36
1 gm of 17~,21-(1-ethoxy-benzylidenedioxy)-9~-chloro-
ll~-hydroxy-~l'4-pregnadiene-3,20 dione prepared in a manner
analogous to that described in Example l(a) was stirred in 40
ml of dimet}lylformamide with 4 ml of trimethylsilyl fluoride
for 2 hours at room temperature. After precipitation in ice-
water and the usual workiny up, evaporation in vacuo was carried
out. Tile crude product was purified over 120 gms of silica gel
with a methylene chloride-acetone gradient (0-10~ of acetone).
The yield was 240 mg of 17~-benzoyloxy-9~-cllloro-21-fluoro-
~ hydroxy-~l'4-pregnadiene-3,20-dione.
Example 37
In a manner analogous to that described in Example 33(a)
tllere were prepared from 5 gms of 21-fluoro-17~-hydroxy-~1'4'9(11)-
3V pregnatriene-3,20-dione and iso~utyric anhydride 4.8 gms of 21-
fluoro-17~-isobutyryloxy-~1'4'9~11)-pregnatriene--3,20-dione,
which were reacted with N-chlorosuccinimide under the conditions
, _

9~3
descri~ed in Example 25(e). The crude product was purified over
350 gms of silica gel with a methylene chloride-acetone gradient
(0-10~ of acetone). The yield was 3.5 gms of 9~chloro-21-
fluoro~ hydroxy-17a-isobutyryloxy-~1'4-pregnadiene-3,20-dione.
Example 38
5 gms of crude 17~,21-(1-ethoxy-ethylidenedioxy)-9a-
chloro-ll~- hydroxy-~l'4-pregnadiene-3,20-dione, prepared from
~ -chloroprednisolone and ortho-acetic acid triethyl ester in
a manner analogous to that described in Example l(a), were
refluxed under nitrogen for one hour in 30 ml of methylene
chloride with 3 gm~ of triphenyl-metllyl chloride. The solvent
was distilled off and the residue was purified over 350 gms o~
silica gel with a methylene chloride-acetone gradient (0-15
of acetone)O The yield was 1.3 gms of 17a-acetoxy-9~,21-
dichloro-ll~-hydroxy-A '4-pregnadiene-3,20-dione. Melting
point: 222C (with decomposition). [~]25 = +124
,
(pyridine). UV: E239 = 15,200 (methanol).
Example ~9
2 gms of crude 17a,21-(1-ethoxypropylidenedioxy)-9~ -~
chloro-11~-hydroxy-~1'4~pregnadiene-3,20-dione, prepared from
9 -chloroprednisolone and ortho-propionic acid triethyl ester in
a manner analogous to that described in Example l(a), were
stirred in 50 ml of dimethylformamide with 5 ml of trimethylsilyl
chloride for 2-hours at room temperature. After precipitation in --
ice-water and the usual working up, 1.4 gms of 9a,21-dichloro-
ll~-hydroxy-17~-propionyloxy-~1'4-pregnadiene-3,20-dione were
isolated, which was purified by recrystalli~ation from acetone/
hexane. Melting point: 232C. [~]D = +78 (chloroform)
UV:~239 = 15,200 (methanol).
Example 40
The composition of a salve.
: .
- 2~ -
, ,

~ ILOV943
O.Q3~ of 21-acetoxy-9a-chloro~ -hydroxy-17~-propionyloxy-
~l~4-pregnadiene-3l2o-dione
2.50% of Allereur hexaehlorophenate, micronized, particle size
about 8~ (Allercur = Registered Trade Mark for l-para-
chloro-benzyl-2-pyrrolidyl-methyl-benzimidazole)
6.00% of Hostaphat KW 340(R) (tertiary ester of O~phosphoric
acid and wax alcohol tetra-ylycol ether)
0.10% of sorbic aeid
10.00% of neutral oil (Migloyol 8.2(R))
3.50% of stearyl aleohol
1.50% of wool fat, anhydrou~ DAB 6
76.36% of desalted water.
"DAB 6" is an abbreviation for Deutsches Arzneibuch,
6th edition. -
Example 41
The manufacture of an inhalant preparation.
1.000 gms of micronized 21-acetoxy-9a-ehloro-11~ ydroxy-
17a-propionyloxy-~1' -pregnadiene-3,20-dione (average partiele ~ ;
size smaller than 7~) and 39.000 gms of ground lactose were mixed
together. A dose of 20 mg of inhalant preparation, per inhalation
is used.
~ - G7 -