SOFT STEROIDS HAVING ANTI-INFLAMATORY ACTIVITY

STEROIDES DOUX AYANT DES PROPRIETES ANTI- INFLAMMATOIRES

English Abstract

ABSTRACT OF THE DISCLOSURE
The present invention provides compound having anti-
flammtory activity selected from the group consisting of:
a compound of the formula
<IMG>
wherein R1 is a C1-C10 alkyl; C1-C10 (monohalo or polyhalo)-
alkyl; or -CH2COOR6 wherein R6 is C1-C10 alkyl, or R1 is
-CH2-Y-(lower alkyl) wherein Y is -S-, SO, S02 or -O-, or R1
is -CH2-O?R6 wherein R6 is C1-C10 alkyl or phenyl, R2 is
C1-C10 alkyl, C3-C8 cycloalkyl, phenyl, benzyl or C1-C10
(monohalo or polyhalo)alkyl, R3 is hydrogen, .alpha.-hydroxy,
.beta.-hydroxy, .alpha.-methyl, .beta.-methyl, =CH2, or .alpha.- or .beta.-O?OR2
wherein R2 is identical to R2 as defined hereinabove; R4
is hydrogen, fluoro or chloro; R5 is hydrogen, fluoro, chloro
or methyl; X is -O- or -S- Z is carbonyl or .beta.-hydroxymethyl-
ene; and the dotted line in ring A indicates that the 1,2
linkage is saturated or unsaturated; and a pharmaceutically
acceptable quaternary ammonium salt of the compound represent-
ed by said formlula wherein at least one of Rl and R2 is a
halo- substituted alkyl group.

Claims

THE EMBODIMETNS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for preparing a compound represented
by the formula
<IMG>
wherein R1 is a C1-C10 alkyl; Cl-C10 (monohalo or polyhalo)-
alkyl; or -CH2COOR6 wherein R6 is C1-C10 alkyl, or R1 is
-CH2-Y-(lower alkyl) wherein Y is -S-, SO, SO2 or -O-,
or R1 is -CH2-O?R6 wherein R6 is C1-C10 alkyl or phenyl,
R2 is C1-C10 alkyl, C3-C8 cycloalkyl, phenyl, benzyl or
C1-C10 (monohalo or polyhalo) alkyl, R3 is hydrogen, .alpha.-
hydroxy, .beta.-hydroxy, a-methyl, .beta.-methyl, =CH2, or .alpha.- or .beta.-O?OR2
wherein R2 is identical to R2 as defined hereinabove; R4 is
hydrogen, fluoro or chloro; R5 is hydrogen, fluoro, chloro or
methyl; X is -O- or -S-; Z is carbonyl or .beta.-hydroxymethylene;
and the dotted line in ring A indicates that the 1,2 linkage
is saturated or unsaturated; and a pharmaceutically accep-
table quaternary ammonium salt of the compound represented
by said formula wherein at least one of R1 and R2 is a halo-
substituted alkyl group; comprising the steps of (a) reacting
a compound represented by the formula
<IMG>
125

wherein R2, R3, R4, R5, Z and the dotted line in ring A are
defined as above, and M is alkali metal, alkaline earth metal/2,
thallium or NH4 with a compound represented by the formula
R1W
wherein R1 is defined as above, and wherein R3 is .alpha.- or .beta. -
-O?OR2 and when R3 is required to be hydroxy selectively hydrolyzing
the product obtained, (b)reacting a compound represented by
the formula
<IMG>
wherein R2, R4, R5, Z and the dotted line in ring A are de-
fined as above, and R3" is hydrogen, a-methyl, .beta.-methyl, =CH2
or .alpha.or.beta.- -O?-OR2, with a compound represented by the formula
RlXM'
wherein Rl and X are as defined above, and M' is hydrogen or
M wherein M is as defined above, and wherein R3 is .alpha. or .beta. -
-O?OR2 and when R3 is required to be hydroxy selectively hydrolyzing
th8 product obtained, (c) reacting a compound represented
by the formula
<IMG>
wherein R1, R4, R5, Z and the dotted line in ring A are defined
as above, and R3" is hydrogen, a-methyl, .beta.-methyl, =CH2,
.alpha.-OCOCl or .beta.-OCOCl with a compound represented by the formula
126

R2OM'
wherein R2 is as defined above, and M' is as defined above,
and wherein R3 is .alpha.-or, .beta. -O?OR2 and when R3 is required to be hydroxy
selectively hydrolyzing the product obtained, (d) reacting
a compound represented by the formula
<IMG>
wherein R1, R4, R5, Z and the dotted line in ring A are defined
as above, and R3 is hydrogen, .alpha.-methyl, .beta.-methyl, =CH2, .alpha.-OH or
.beta.-OH with a compound represented by the formula
R2OCOX' or R2O?OR2
wherein R2 is as defined above, and X' is chloro or bromo,
and wherein R3 is .alpha.-or .beta. -O?OR2 and when R3 is required to be
hydroxy selectively hydrolyzing the product obtained, (e)
oxidizing a compound represented by the formula
<IMG>
wherein R1, R2, R3, R4, R5, X, Z and the dotted line in ring A
are as defined above, with the proviso that R1 is a sulfur-
containing group, (f) reducing a compound represented by the
formula
127

<IMG>
wherein R1, R2, R3, R4, R5, X and the dotted line in ring A
are as defined above, or (g) oxidizing a compound represented
by the formula
<IMG>
wherein Rl, R2, R3, R4, R5, X and the dotted line in ring A are
as defined above, and when the quaternary ammonia compound is
required, reacting the compound obtained in which at least one of
R1 and R2 in a halo substituted alkyl group with a
amine or an unsaturated amine.
2. A compound represented by the formula
<IMG>
wherein R1 is C1-C10 alkyl; C1-C10 (monohalo or polyhalo)-
alkyl; or -CH2COOR6 wherein R6 is C1-C10 alkyl or R1 is -CH2-Y-
(lower alkyl) wherein Y is -S-, SO, SO2 or -O-, or R1 is
128

-CH2-O?R6 wherein R6 is C1-C10 alkyl or phenyl, R2 is C1-C10
alkyl, C3-C8 cycloalkyl, phenyl, benzyl or C1-C10 (monohalo or
polyhalo) alkyl, R3 is hydrogen, .alpha.-hydroxy, .beta.-hydroxy, .alpha.-methyl,
.beta.-methyl, =CH2, or .alpha.- or .beta.-O?OR2 wherein R2 is identical to R2
as defined hereinabove; R4 is hydrogen, fluoro or chloro; R5
is hydrogen, fluoro, chloro or methyl; X is -O- or -S-; Z is
carbonyl or .beta.-hydroxymethylene; and the dotted line in ring A
indicates that the 1,2 linkage is saturated or unsaturated;
and a pharmaceutically acceptable quaternary ammonium salt of
the compound represented by said formula wherein at least one of
R1 and R2 is a halo-substituted alkyl group, whenever prepared
by the process or produced by the process as claimed in claim
1, or an obvious chemical equivalent thereof.
3. A process for preparing a compound represented
by the formula:
<IMG>
wherein R1, R2, R3, R4, R5, z and the dotted line in ring A
are as defined in claim 1, a pharmaceutically acceptable
quaternary ammonium salt thereof, comprising reacting a compound
represented by the formula:
<IMG>
129

wherein R2, R3, R4, R5, Z and the dotted line in ring A are
defined as above, and M is alkali metal, alkaline earth metal/2,
thallium or NH4 with a compound represented by the formula
R1W
wherein R1 is defined as above, and W is halogen, and wherein
R3 is .alpha.- or .beta. -O?OR2 and when R3 is required to be hydroxy
selectively hydrolysing the product obtained, and when required
reacting the compound obtained wherein at least one of R1
and R2 is a halo-substituted alkyl group with a tertiary amine
or an unsaturated amine.
4. A compound represented by the formula:
<IMG>
wherein R1 is C1-C10 alkyl; C1-C10 (monohalo or polyhalo)alkyl;
or -CH2COOR6 wherein R6 is C1-C10 alkyl, or R1 is -CH2-Y-
(lower alkyl) wherein Y is -S- or -O-, or R1 is -CH2-O?R6 wherein
R6 is C1-C10 alkyl or phenyl, R2 is C1-C10 alkyl, C3-C8 cyclo-
alkyl, phenyl, benzyl or C1-C10 (monohalo or polyhalo)alkyl, R3
is hydrogen, .alpha.-hydroxy, .beta.-hydroxy, .alpha.-methyl, .beta.-methyl, =CH2,
or .alpha.- or .beta.-O?OR2 wherein R2 is identical to R2 as defined
hereinabove; R4 is hydrogen, fluoro or chloro; R5 is hydrogen,
fluoro, chloro or methyl; Z is carbonyl or .beta.-hydroxymethylene;
and the dotted line in ring A indicates that the 1,2 linkage
is saturated or unsaturated; and a pharmaceutically acceptable
quaternary ammonium salt of the compound represented by said
formula wherein at least one of R1 and R2 as a halo-substituted
alkyl group; whenever prepared or produced by the process as
claimed in claim 3, or an obvious chemical equivalent thereof.
130

5. A process for preparing a compound represented
by the formula:
<IMG>
wherein R1, R2, R3, R4, R5, X, Z and the dotted line in ring
A are as defined in claim 1, and a pharmaceutically acceptable
quaternary ammonium salt thereof, the process comprising reacting
a compound represented by the formula:
<IMG>
wherein R2, R4, R5, Z and the dotted line in ring A are
defined as above and R3" is hydrogen, .alpha.-methyl, .beta.-methyl, =CH2
or .alpha.- or .beta. -OC?-OR2, with a compound represented by the formula:
R1XM'
wherein R1 and X are as defined above, and M' is hydrogen or
M wherein M is as defined in claim 1, and wherein R3 is .alpha.-
or .beta. -O?OR2 and when R3 is required to be hydroxy selectively hydro-
lyzing the product obtained, and, when required, reacting the
compound obtained wherein at least one of R1 and R2 is a
halo-substituted alkyl group with a tertiary amine or an unsat-
urated amine.
131

6. A compound represented by the formula:
<IMG>
wherein R1, R2 R3, R4, R5, X, Z and the dotted line in ring
A are as defined in claim 1,and a pharmaceutically acceptable quaternary
ammonium salt thereof, whenever prepared or produced by the
process as claimed in claim 5, or an obvious chemical equivalent
thereof.
7. A process for preparing a compound represented by
the formula:
<IMG>
wherein R1, R2, R3, R4, R5, X and Z and the dotted line in ring
A are as defined in claim 1, and a pharmaceutically acceptable
quaternary ammonium salt thereof, the process comprising react-
ing a compound represented by the formula
<IMG>
132

wherein R1, R4, R5, Z and the dotted line in ring A are
defined as above, and R3''' is hydrogen, .alpha.-methyl, .beta.-methyl, =CH2
.alpha.-OCOCl or .beta.-OCOCl with a compound represented by the formula:
R2OM'
wherein R2 is as defined above, and M' is hydrogen or M where
M is as defined in claim 1, and wherein R3 is .alpha.-or .beta. -O?OR2 and when
R3 is required to be hydroxy selectively hydrolyzing the product
obtained, and, when required, reacting the compound obtained
above wherein at least one of R1 and R2 is a halo-substituted
alkyl group with a tertiary amine or an unsaturated amine.
8. A compound represented by the formula:
<IMG>
wherein R1, R2, R3, R4, R5, X, Z and the dotted line in ring
A are as defined in claim 1, and a pharmaceutically acceptable
quaternary ammonium salt thereof, whenever prepared or produced
by the process as claimed in claim 7, or an obvious chemical
equivalent thereof.
9. A process for preparing a compound represented
by the formula:
<IMG>
133

wherein R1, R2, R3, R4, R5, Z and the dotted line in ring A are
as defined in claim 1, and a pharmaceutically acceptable quat-
ernary ammonium salt thereof, the process comprising reacting
a compound represented by the formula:
<IMG>
wherein R1, R4, R5, Z and the dotted line in ring A are
defined as above, and R3 is hydrogen, .alpha.-methyl, .beta.-methyl, =CH2
.alpha.-OH or .beta.-OH with a compound represented by the formula:
R2OCOX' or R2O?OR2
wherein R2 is as defined above, and X' is chloro or bromo,
and wherein R3 is .alpha.-or .beta. -O?OR2 and when R3 is required to be hydroxy
selectively hydrolyzing the product obtained, and, when required,
reacting the compound obtained above wherein at least one of
R1 and R2 is a halo-substituted alkyl group with a tertiary
amine or an unsaturated amine.
10. A compound represented by the formula:
<IMG>
wherein R1, R2, R3, R4, R5, Z and the dotted line in ring A are
as defined in claim 1, and a pharmaceutically accpetable quaternary ammonium
salt thereof, whenever prepared or produced by the process as
claimed in claim 9, or an obvious chemical equivalent thereof.
134

11. A process for preparing a compound represented
by the formula:
<IMG>
wherein R1, R2, R3, R4, R5, X, Z and the dotted line in ring
A are as defined in claim 1, with the proviso that R1 is a
sulfinyl- or sulfonyl-containing group, the process comprising
the step of oxidizing a compound represented by the formula:
<IMG>
wherein R1, R2, R3, R4, R5, X, Z and the dotted line in ring
A are as defined above, with the proviso that R1 is a sulfur-
containing group.
12. A compound represented by the formula
<IMG>
135

wherein R1, R2, R3, R4, R5, X, Z and the dotted line in ring
A are as defined in claim 1, with the proviso that R1 is a
sulfinyl- or sulfonyl- containing group, whenever prepared or
produced by the process as claimed in claim 11, or an obvious
chemical eqivalent thereof.
13. A process for preparing a compound represented by
the formula
<IMG>
wherein R1, R2, R3, R4, R5, X and the dotted line in ring A are
as defined in claim 1, and a pharmaceutically acceptable quaternary
ammonium salt thereof, the process comprising reducing a
compound represented by the formula:
<IMG>
wherein R1, R2, R3, R4, R5, X and the dotted line in ring A
are as defined above, and, when required, reacting the compound
obtained above wherein at least one of R1 and R2 is a halo-
substituted alkyl group with a tertiary amine or an unsaturated
amine.
14. A compound represented by the formula:
136

<IMG>
wherein R1, R2, R3, R4, R5, X and the dotted line in ring A
are as defined in claim 1, and a pharmaceutically acceptable
quaternary ammonium salt thereof, whenever prepared or produced
by the process as claimed in claim 13, or an obvious chemical
equivalent thereof.
15. A process for preparing a compound represented
by the formula
<IMG>
wherein R1, R2, R3, R4, R5, X and the dotted line in ring A are
as defined in claim 1, the process comprising the step of oxi-
dizing a compound represented by the formula:
<IMG>
wherein R1, R2, R3, R4, R5, X and the dotted line in ring A are
as defined above.
137

16. A compound represented by the formula;
<IMG>
wherein R1, R2, R3, R4, R5, X and the dotted line in ring A
are as defined in claim 1, whenever prepared or produced by
the process as claimed in claim 15, or an obvious chemical
equivalent thereof.
17. A process as claimed in claim 3, wherein R1 is
C1-C6 alkyl; C1-C6 (monohalo or polyhalo)alkyl; -CH2COOR6"
wherein R6' is C1-C6 alkyl; -CH2-Y-(C1-C6 alkyl) wherein Y
is -S- or -O-; or -CH2-O?R6" wherein R6" is C1-C6 alkyl or
phenyl; R2 is C1-C6 alkyl; C3-C8 cycloalkyl; phenyl, benzyl or
C1-C6 (monohalo or polyhalo)alkyl; R3 is hydrogen; .alpha.-hydroxy;
.alpha.-methyl; .beta.-methyl or .alpha.-O?OR2 wherein R2 is as defined above
R4 is hydrogen or fluoro; and R5 is hydrogen or fluoro.
18. A compound of the formula given in claim 4, or a
pharmaceutically acceptable quaternary ammonium salt thereof,
wherein Z is as in claim 1 and R1, R2, R3, R4 and R5 are as in
claim 17, whenever prepared or produced by the process as claimed
in claim 17, or an obvious chemical equivalent thereof.
19. A process as claimed in claim 17, wherein Z is
.beta.-hydroxymethylene.
20. A compound of the formula given in claim 4,
wherein Z is as in claim 19, and R1, R2, R3, R4 and R5 are as in
claim 17, or a pharmaceutically acceptable quaternary ammonium
salt thereof whenever prepared or produced by the process as
claimed in claim 19, or an obvious chemical equivalent thereof.
138

21. A process as claimed in claim 19, wherein R1 is
C1-C6 (monohalo or polyhalo)alkyl.
22. A compound of the formula given in claim 4, wherein
R2, R3, R4 and R5 are as in claim 17, Z is .beta.-hydroxymethylene
and R1 is as in claim 21, or a pharmaceutically acceptable
quaternary ammonium salt thereof, whenever prepared or produced
by the process as claimed in claim 21, or an obvious chemical
equivalent thereof.
23. A process as claimed in claim 21, wherein R2
is C1-C6 alkyl.
24. A compound of the formula given in claim 4,
wherein R3, R4, and R5 are as in claim 17, Z is .beta.-hydroxymethylene,
R1 is C1-C6 (monohalo or polyhalo)alkyl and R2 is as in claim
23, whenever prepared or produced by the process as claimed in
claim 23, or an obvious chemical equivalent thereof.
25. A process as claimed in claim 21, wherein R2
is C3-C8 cycloalkyl, phenyl, benzyl or C1-C6 (monohalo or poly-
halolalkyl.
26. A compound of the formula given in claim 4, wherein
R3, R4 and R5 are as in claim 17, Z is .beta. -hydroxymethylene,
R1 is C1-C6 (monohalo or polyhalo)alkyl and R2 is as in claim
25, or a pharmaceutically acceptable quaternary ammonium salt
thereof, whenever prepared or produced by the process as claimed
in claim 25, or an obvious chemical equivalent thereof.
27. A process of claim 23, wherein R4 and R5 are
hydrogen.
28. A compound of the formula given in claim 4, wherein
R3 is as in claim 17, Z is .beta.-hydxoxymethylene, R1 is C1-C6
(monohalo or polyhalo)alkyl, R2 is C1-C6 alkyl and R4 and R5
are as in claim 27, or a pharmaceutically acceptable quaternary
ammonium salt thereof, whenever prepared or produced by the
process as claimed in claim 27, or an obvious chemical equivalent
139

thereof.
29. A process of claim 25, wherein R4 and R5 are
hydrogen.
30. A compound of the formula given in claim 4,
wherein R3 is as in claim 17, Z is .beta.-hydroxymethylene, R1
is C1-C6 (monohalo or polyhalo)alkyl, R2 is C3-C8 cycloalkyl,
phenyl, benzyl or C1-C6 (monohalo or polyhalo)alkyl and R4
and R5 are as in claim 29, or a pharmaceutically acceptable
quaternary ammonium salt thereof, whenever prepared or produced
by the process as claimed in claim 29, or an obvious chemical
equivalent thereof.
31. A process as claimed in claim 23, wherein R4
is fluoro and R5 is hydrogen.
32. A compound of the formula given in claim 4,
wherein R3 is as in claim 17, Z is .beta.-hydroxymethylene, R1
is C1-C6 tmonohalo or polyhalo)alkyl, R2 is C1-C6 alkyl and
R4 and R5 are as in claim 31, or a pharmaceutically acceptable
quaternary ammonium salt thereof, whenever prepared or produced
by the process as claimed in claim 31, or an obvious chemical
equivalent thereof.
33. A process as claimed in claim 25, wherein R4
is fluoro and R5 is hydrogen.
34. A compound of the formula given in claim 4,
wherein R3 is as in claim 17, Z is .beta.-hydroxymethylene, R1
is C1-C6 (monohalo or polyhalo)alkyl, R2 is C3-C8 cycloalkyl,
phenyl, benzyl or C1-C6 (monohalo or polyhalo)alkyl and R4
and R5 are as in claim 33, or a pharmaceutically acceptable
quaternary ammonium salt thereof, whenever prepared or produced
by the process as claimed in claim 33, or an obvious chemical
equivalent thereof.
35. A process as claimed in claim 31, wherein R3
is .alpha.-methyl or .beta.-methyl.
140

36. A compound of the formula given in claim 4,
wherein Z is .beta.-hydroxymethylene, R1 is C1-C6 (monohalo or
polyhalo)alkyl, R2 is C1-C6 alkyl, R4 and R5 are as in claim 31,
and R3 is as in claim 35, or a pharmaceutically acceptable
quaternary ammonium salt thereof, whenever prepared or produced
by the process as claimed in claim 35, or an obvious chemical
equivalent thereof.
37. A process as claimed in claim 33, wherein R3
is .alpha.-methyl or .beta.-methyl.
38. A compound of the formula given in claim 4,
wherein Z is B-hydroxymethylene, R1 is C1-C6 (monohalo or
polyhalo)alkyl, R2 is C3-C8 cycloalkyl, phenyl, benzyl or C1-C6
(monohalo or polyhalo)alkyl, R4 and R5 are as in claim 33, and
R3 is as in claim 37, or a pharmaceutically acceptable quaternary
ammonium salt thereof, whenever prepared or produced by the
process as claimed in claim 37, or an obvious chemical equivalent
thereof.
39. A process as claimed in claim 17, wherein Z is
carbonyl.
40. A compound of the formula given in claim 4,
wherein Z is as in claim 39 and R1, R2, R3, R4 and R5 are as
in claim 17, or a pharmaceutically acceptable quaternary ammonium salt
thereof, whenever prepared or produced by the process as claimed
in claim 39, or an obvious chemical equivalent thereof.
41. A process as claimed in claim 1, in which R1
is a C1-C6 alkyl; C1-C6 (monohalo or polyhalo)alkyl; -CH2COOR6
wherein R6 is C1-C6 alkyl; -CH2-Y-(C1-C6 alkyl) wherein Y is
-S-, -SO-, -SO2-, or -O-; or -CH2-O?R6' wherein R6' is C1-C6
alkyl or phenyl; R2 is C1-C6 alkyl, C3-C8 cycloalkyl, phenyl
benzyl or C1-C6 (monohalo or polyhalo)alkyl; R3 is hydrogen,
.alpha.-hydroxy, .alpha.-methyl, .beta.-methyl or .alpha.-OCR2 wherein R2 is identical
to R2 as defined hereinabove; R4 is hydrogen or fluoro; R5
141

is hydrogen or fluoro; Z is .beta.-hydroxymethylene; and X and
the dotted line in ring A are as inclaim 1.
42. A compound of the formula given in claim 4,
or a pharmaceutically acceptable quaternary ammonium salt thereof, wherein R1,
R2, R3, R4, R5, X, Z and the dotted line in ring A are as in claim 41,
whenever prepared or produced by the process as claimed in
claim 41, or an obvious chemical equivalent thereof.
43. A processs as claimed in claim 41, in which X
is oxygen; R2 is C1-C6 alkyl, R1 is C1-C6 alkyl, C1-C6 monohalo
alkyl CH2-Y(C1-C6) alkyl where Y is as in claim 41.
44. A compound of the formula given in claim 4
or a pharmaceutically acceptable quaternary ammonium salt
thereof, wherein X, R1 and R2 are as in calim 43 and R3, R4
and R5 are as in claim 41, whenever prepared or produced by
the process as claimed in claim 43, or an obvious chemical
equivalent thereof.
45. A process as claimed in claim 43, in which R2
is methyl, ethyl, propyl, or isopropyl, and R1 is C1-C6 alkyl
chloromethyl, or CH2Y- methyl where Y is as in claim 43.
46. A compound of the formula given in claim 4
or a pharmaceutically acceptable quaternary ammonium salt
thereof wherein R1 and R2 are as in claim 45, X is oxygen, and
R3, R4 and R5 are as in claim 41, whenever prepared or produced
by the process as claimed in claim 45, or an obvious chemical
equivalent thereof.
47. A process as claimed in claim 3, which comprises reacting
sodium 11.beta.-hydroxy-17.alpha.-methoxycaxbonyloxyandrost-4-en-3-one-
17.alpha.-carboxylate in hexamethyl phosphoramide with chloromethyl
iodide.
48. Chloromethyl 11.beta.-hydroxy-17.alpha.-methoxycarbonyloxyan-
drost-4-en-3-one-17.alpha.-carboxylate, whenever prepared or produced
by the process as claimed in claim 47, or an obvious chemical
142

equivalent thereof.
49. A process as claimed in claim 3, which comprises reacting
sodium 17.alpha.-ethoxycarbonyloxy-11.beta.-hydroxyandrost-4-en-3-one-
17.alpha.-carboxylate in hexamethyl phosphoramide with chloromethyl iodide.
50. Chloromethyl 17.alpha.-ethoxycarbonyloxy-11.beta.-hydroxyand-
rost-4-en-3-one-17.alpha.-carboxylate, whenever prepared or produced
by the process as claimed in claim 49, or an obvious chemical
equivalent thereof.
51. A process as claimed in claim 3, which comprises reacting
sodium 17.alpha.-buoxycarbonoyloxy-11.beta.-hydroxyandrost-4-en-3-one-
17.beta.-carboxylate in hexamethyl phosphoramide with chloromethyl iodide.
52. Chloromethyl 17.alpha.-butoxycarbonyloxy-11.beta.-hydroxy-
androst-4-en-3-one-17.beta.-caxboxylate, whenever prepared or produced
by the process as claimed in claim 51, or an obvious chemical
equivalent thereof.
53. A process as claimed in claim 3, which comprises reacting
sodium 11.beta.-hydroxy-17.alpha.-isopropoxycarbonyloxyandrost-4-en-3-one-
17.beta.-carboxylate in hexamethyl phosphoramide with chloromethyl iodide.
54. Chloromethyl 11.beta.-hydroxy-17.alpha.-isopropoxycarbonyl-
oxyandrost-4-en-3-one-17.beta.-carboxylate, whenever prepared or
produced by the process as claimed in claim 53, or an obvious
chemical equivalent thereof.
55. A process as claimed in claim 3, which comprises acting
sodium 17.alpha.-ethoxycarbonyloxy-11.beta.-hydroxyandrosta-1,4-dien-3-one
17.beta.-carboxylate in hexamethyl phosphoramide with chloromethyl iodide.
56. Chloromethyl 17.alpha.-ethoxycarbonyloxy-11.beta.-hydroxyand-
rosta-1,4-dien-3-one-17.beta.-carboxylate, whenever prepared or
produced by the process as claimed in claim 55, or an obvious
chemical equivalent thereof.
57. A process as claimed in claim 3, which comprises reacting
sodium 11.beta.-hydroxy-17.alpha.-isopropoxycarbonyloxyandrosta-1,4-dien-
3-one-17.beta.-carboxylate in hexamethyl phosphoramide with chloromethyl iodide.
143

58. Chloromethyl 11.beta.-hydroxy-17.alpha.-isopropoxycarbonyl-
oxyandrosta-1,4-dien-3-one-17.beta.-carboxylate, whenever prepared
or produced by the process as claimed in claim 57, or an obvious
chemical equivalent thereof.
59. A process as claimed in claim 3, which comprises reacting
sodium 11.beta.-hydroxy-17.alpha.-isopropoxycarbonyloxyandrosta-1,4-dien-3-one-17.beta.-
carboxylate in hexamethyl phosphoramide with chloromethyl iodide.
60. 1-Chloroethyl 11.beta.-hydroxy-17.alpha.-isopropoxycarbonyl-
oxyandrost-4-en-3-one-17.beta.-carboxylate, whenever prepared or
produced by the process as claimed in claim 59, or an obvious
chemical equivalent thereof.
61. A process as claimed in claim 3, which comprises reacting
sodium 17.alpha.-ethoxycarbonyloxy-9.alpha.-fluoro-11.beta.-hydroxy-16.alpha.-methylandrosta-1,4-
dien-3-one-17.beta.-carboxylate in hexamethyl phosphoramide with chloromethyl iodide.
62. Chloromethyl 17.alpha.-ethoxycarbonyloxy-9.alpha.-fluoro-
11.beta.-hydroxy-16.beta.-methylandrosta-1,4-diene-3-One-17.beta.-carboxylate,
whenever prepared or produced by the process as claimed in claim
61, or an obvious chemical equivalent thereof.
63. A process as claimed in claim 3, which comprises reacting
sodium 9 -fluoro-11 -hydroxy-16 -methyl-17 -propoxycarbonyloxyandrosta-1,4-
dien-3-one-17 -carboxylate in hexamethyl phosphoramide with chloromethyl iodide.
64. Chloromethyl 9.alpha.-fluoro-11.beta.-hydroxy-16.alpha.-methyl-
17.alpha.-propoxycarbonyloxyandrosta-1,4-dien-3-one-17.beta.-carboxylate,
whenever prepared or produced by the process as claimed in
claim 64, or an obvious chemical equivalent thereof.
65. A process as claimed in claim 3, which comprises
reacting sodium 17 -ethoxycarbonyloxy-9 -fluoro-11 -hydroxyandrosta-1,4-dien-
3-one-17 -carboxylate in hexamethyl phosphoramide with chloromethyl iodide.
66. Chloromethyl 17.alpha.-ethoxycarbonyloxy 9.alpha.-fluoro-11.beta.-
hydroxyandrosta-1,4-dien-3-one-17.beta.-carboxylate, whenever prepared
or produced by the process as claimed in claim 65, or an obvious
chemical equivalent thereof.
144

67. A process as claimed in claim 3, which comprises reacting sodium
17.alpha.-ethoxycarbonyloxy-9.alpha.-fluoro-11.beta.-hydroxy-16.alpha.-methylandrosta-1,4-dien-3-one-
17.beta.-carboxylate in hexamethyl phosphoramide with chloromethyl iodide.
68. Chloromethyl 17.alpha.-ethoxycarbonyloxy-9.alpha.-fluoro-11.beta.-
hydroxy-16.alpha.-methylandrosta-1,4-diene-3-one-17.beta.-carboxylate,
whenever prepared or produced by the process as claimed in claim
67, or an obvlous chemical equivalent thereof.
69. A process as claimed in claim 3, which comprises reacting sodium
9.alpha.-fluoro-11.beta.-hydroxy-17.alpha.-isopropoxycarbonyloxy-16.alpha.-methylandrosta-1,4-dien-
3-one-17.beta.-carboxylate in hexamethyl phosphoramide with chloromethyl iodide.
70. Chloromethyl 9.alpha.-fluoro-11.beta.-hydroxy-17.alpha.-isopro-
poxycarbonyloxy-16.alpha.-methylandrosta-1,4-dien-3-one-17.beta.-carboxyl-
ate, whenever prepared or produced by the process as claimed in
claim 69, or an obvious chemical equivalent thereof.
71. A prooess as claimed in claim 3, which comprises reacting sodium
9.alpha.-fluoro-11.beta.-hydroxy-17.alpha.-isopropoxycarbonyloxy-16.alpha.-methylandrosta-1,4 dien-
3-one-17.beta.-carboxylate in hexamethyl phosphoramide with chloromethyl iodide.
72. Chloromethyl 9.alpha.-fluoro-11.beta.-hydroxy-17.alpha.-isopropoxy-
carbonyloxy-16.beta.-methylandrosta-1,4-dien-3-one-17.beta.-carboxylate,
whenever prepared or produced by the process as claimed in
claim 71, or an obvious chemical equivalent thereof.
73. A process as claimed in claim 3, which comprises reacting sodium
9.alpha.-fluoro-11.beta.-hydroxy-17.alpha.-methoxycarbonyloxy-16.alpha.-methylandrosta-1,4-dien-3-
one-17.beta.-carboxylate in hexamethyl phosphoramide with chloromethyl iodide.
74. Chloromethyl 9.alpha.-fluoro-11.beta.-hydroxy-17.alpha.-methoxy-
carbonoyxloxy-1.alpha.-methylandrosta-1,4-dien-3-one-17.beta.-carboxylate,
whenever prepared or produced by the process as claimed in
claim 73, or an obvious chemical equivalent thereof.
75. A process as claimed in claim 3, which comrises reacting sodium
9.alpha.-fluoro-11.beta.-hydroxy-17.alpha.-isopropoxycarbonyloxy-16.beta.-methylandrosta-1,4-dien-
3-one-17.beta.-carboxylate in hexamethyl phosphoramide with .beta.-chloromethyl iodide.
145

76. 1-Chloroethyl 9.alpha.r-fluoro-11.beta.-hydroxy-17.alpha.-iso-
propoxycarbonyloxy-16.beta.-methylandrosta-1,4-dien-3-one-17.beta.-
carboxylate, whenever prepared or produced by the process as
claimed in claim 75, or an obvious chemical equivalent thereof.
77. A process as claimed in claim 3, which comprises reacting sodium
17.alpha.-ethoxycarbonyloxy-9.alpha.-fluoro-11.beta.-hydroxy-16.alpha.-methylandrosta-1,4-dien-3-one-
17.beta.-carboxylate in hexamethyl phosphoramide with fluoromethyl iodide.
78. Fluoromethyl 17.alpha.-ethoxycarbonyloxy-9.alpha.fluoro-11.beta.-
hydroxy-16.alpha.-methylandrosta-1,4-dien-3-one-17.beta.-carboxylate,
whenever prepared or produced by the process as claimed in
claim 77, or an obvious chemical equivalent thereof.
79. A process as claimed in claim 3, which comprises reacting
sodium 17.alpha.-chloroethoxy)carboyloxy-9.alpha.-fluoro-11.beta.-hydroxy-
16.alpha.-methylandrosta-1,4-diene-3-one-17.beta.-carboxylate in hexamethyl
phosphoramide with methyl iodide.
80. Methyl 17.alpha.-(2-chloroethoxy)carbonyloxy-9.alpha.-fluoro-
11.beta.-hydroxy-16.alpha.-methylandrosta-1,4-dien-3-one-17.beta.-carboxylate,
whenever prepared or produced by the process as claimed in
claim 79, or an obvious chemical equivalent thereof.
81. A process as claimed in claim 1, in which R2
is ethyl, R4 is fluorine, z is .beta.-hydroxymethylene, R5 is
hydrogen, R3 is .alpha.-methyl, R1 is chloromethyl, X is oxygen and
the 1,2 linkage is unsaturated.
82. A process as claimed in claim 3, which comprises
reacting sodium 17.alpha.-ethoxycarbonyloxy-9.alpha.-fluoro-11.beta.-hydroxy-16.alpha.-
methylandrosta-1,4-dien-3-one-17.beta.-carboxylate with chloromethyl
iodide.
83. Chloromethyl 17.alpha.-ethoxycarbonyloxy-9.alpha.-fluoro-11.beta.-
hydroxy-16.alpha.-methylandrosta-1,4-dien-3-one-17.beta.-carboxylate,
whenever prepared or produced by the process as claimed in claim
81 or 82, or an obvious chemical equivalent thereof.
146

CLAIMS SUPPORTED BY THE SUPPLEMENTARY DISCLOSURE
84. A process as claimed in claim 3, which comprises reacting sodium
17.alpha.-isopropoxycarbonyloxy-6.alpha.,9.alpha.-difluoro-11.beta.-hydroxy-16.alpha.-methylandrosta,1,4-
dien-3-one-17.beta.-carboxylate in hexamethyl phosphoramide with chloromethyl iodide.
85. Chloromethyl 17.alpha.-isopropoxycarbonyloxy-6.alpha.,9.alpha.-di-
fluoro-11.beta.-hydroxy-16.alpha.-methylandrosta-1,4-dien-3-one-17.beta.-carboxy-
late, whenever prepared or produced by the process as claimed
in claim 84, or an obvious chemical equivalent thereof.
86. A process as claimed in claim 3, which comprises reacting sodium
17 .alpha.-n-propoxycarbonyloxy-6.alpha.,9.alpha.-difluoro-11.beta.-hydroxy-16.alpha.-methylandrosta-1,4-dien-
3-one-17.beta.-carboxylate in hexamethyl phosphoramide with chloromethyl iodide.
87. Chloromethyl 17.alpha.-n-propoxycarbonyloxy-6.alpha.,9.alpha.-
difluoro-11.beta.-hydroxy-16.alpha.-methylandrosta-1,4-dien-3-one-17.beta.-
carboxylate, whenever prepared or produced by the process as
claimed in claim 86, or an obvious chemical equivalent thereof.
88. A process as claimed in claim 3, which comprises reacting sodium
17.alpha.-ethoxycarbonyloxy-6.alpha.-fluoro-11.beta.-hydroxy-16.alpha.-methylandrosta-1,4-dien-3-one
17.beta.-carboxylate in hexamethyl phosphoramide with chloromethyl iodide.
89. Chloromethyl 17.alpha.-ethoxycarbonyloxy-6.alpha.-fluoro-11.beta.-
hydroxy-16.alpha.-methylandrosta-1,4-dien-3-one-17.beta.-carboxylate,
whenever prepared or produced by the process as claimed in
claim 88, or an obvious chemical equivalent thereof.
90. A process as claimed in claim 3, which comprises reacting sodium
17.alpha.-n-propoxycarbonyloxy-6.alpha.-fluoro-11.beta.-hydroxy-16.alpha.-methylandrosta-1,4-dien-3-one-
17-carboxyalte in hexamethyl phosphoramide with chloromethyl iodide.
91. Chloromethyl 17.alpha.-n-propoxycarbonyloxy-6.alpha.-fluoro-
11.beta.-hydroxy-16.alpha.-methylandrosta-1,4-dien-3-one-17.beta.-caxboxylate,
whenever prepared or produced by the process as claimed in claim
90, or an obvious, chemical equivalent thereof.
22. A process as claimed in claim 3, which comprises reacting sodium
17.alpha.-isopropoxycarbonyloxy-6.alpha.-fluoro-11.beta.-hydroxy-16.alpha.-methylandrosta-1,4-dien-3-
one-17.beta. carboxylate in hexamethyl phosphoramide with chloromethyl iodide.
147

93. Chloromethyl 17.alpha.-isopropoxycarbonyl9xy-6a-fluoro-
11.beta.-hydroxy-16.alpha.-methylandrosta-1,4-dien-3-one-17.beta.-carboxylate,
whenever prepared or produced by the process as claimed in claim
92, or an obvious chemical equivalent thereof.
94. A process as claimed in claim 3, which comprises reacting
sodium 17.alpha.-n-propoxycarbonyloxy-11.beta.-hydroxy-androsta-1,4-dien-
3-one-17.beta.-carboxylate in hexamethyl phosphoramide with chloromethyl iodide.
95. Chloromethyl 17.alpha.-n-propoxycarbonyloxy-11.beta.-hydroxy-
androsta-1,4-dien-3-one-17.beta.-carboxylate, whenever prepared or
produced by the process as claimed in claim 94, or an obvious
chemical equivalent thereof.
96. A process as claimed in claim 3, which comprises reacting
sodium 17.alpha.-methoxycarbonyloxy-11.beta.-hydroxy-androsta-1,4-dien-
3-one-17.beta.-carboxylate in hexamethyl phosphoramide with chloromethyl iodide.
97. Chloromethyl 17.alpha.-methoxycarbonyloxy-11.beta.-hydroxy-
androsta-1,4-dien-3-one-17.beta.-carboxylate, whenever prepared or
produced by the process as claimed in claim 96, or an obvious
chemical equivalent thereof.
98. A process as claimed in claim 3, which comprises reacting
sodium 17.alpha.-methoxycarbonyloxy-6.alpha.-fluoro-11.beta.-hydroxy-16.alpha.-methylandrosta-1,4-
dien-3-one-17.beta.-carboxylate in hexamethyl phosphoramide with chloromethyl-iodide.
99. Chloromethyl 17.alpha.-methoxycarbonyloxy-6.alpha.-fluoro-11.beta.-
hydroxy-16.alpha.-methylandrosta 1,4-dien-3-one-17.beta.-carboxylate,
whenever prepared or produced by the process as claimed in
claim 98, or an obvious chemical equivalent thereof.
100. A process as claimed in claim 3, which comprises reacting
sodium 17.alpha.-methoxycarbonyloxy-9.alpha.-fluoro-11.beta.-hydroxy-16.alpha.-methylandrosta-1,4-
dien-3-one-17.beta.-carboxylate in hexamethyl phosphoramide with chloromethyl iodide.
101. Chloromethyl 17.alpha.-methoxycarbonyloxy-9.alpha.-fluoro-11.beta.-
hydxoxy-16.alpha.-methylandrosta-1,4-dien-3-one-17.beta.-carboxylate,
whenever prepared or produced by the process as claimed in claim
100, or an obvious chemical equivalent thereof.
148

102. A process as claimed in claim 3, which comprises reacting sodium
17.alpha.-n-propoxycarbonyloxy-9.alpha.-fluoro-11.beta.-hydroxy-16.alpha.-methylandrosta-1,4-dien-
3-one-17.beta.-carboxylate in hexamethyl phosphoramide with chloromethyl iodide.
103. Chloromethyl 17.alpha.-n-propoxycarbonyloxy-9.alpha.-fluoro-
11.beta.-hydroxy-16.beta.-methylandrosta-1,4-dien-3-on3-17.beta.-carboxylate.
whenever prepared or produced by the process as claimed in claim
102, or an obvious chemical equivalent thereof.
104. A process as claimed in claim 3, which comprises reacting sodium
17.alpha.-n-propoxycarbonyloxy-9.alpha.-fluoro-11.beta.-hydroxy-16.alpha.-methylandrosta-1,4-dien-
3-one-17.beta.-carboxylate in hexamethyl phosphoramide with fluoromethyl iodide.
105. Fluoromethyl 17.alpha.-n-propoxycarbonyloxy-9.alpha.-fluoro-
11.beta.-hydroxy-16.alpha.-methylandrosta-1,4-dien-3-one-17.beta.-carboxylate,
whenever prepared or produced by the process as claimed in
claim 104, or an obvious chemical equivalent thereof.
106. A process as claimed in claim 3, which comprises reacting
sodium 17.alpha.-isopropoxycarbonyloxy-11.beta.-hydroxy-androsta-1,4-dien-3-one
17 -carbaxylate in hexamethyl phosphoramide with .beta.-chloromethyl iodide.
107. 2-Chloroethyl 17.alpha.-isopropoxycarbonyloxy-11.beta.-hydroxy-
androsta-1,4-dien-3-one-16.beta.-carboxylate, whenever prepared or
produced by the process as claimed in claim 106, or an obvious
chemical equivalent thereof.
108. A process as claimed in claim 3, which comprises reacting
sodium 17.alpha.-(2-chloroethoxy)carbonyloxy-9.alpha.-fluoro-11.beta.-hydroxy-
16.alpha.-methylandrosta-1,4-dien-3-one-17.beta.-carboxylate in hexamethyl
phosphoramide with methyl iodide.
109. Methyl 17.alpha.-(2-chloroethoxy)carbonyloxy09.alpha.-fluoro-
11.beta.-hydroxy-16.alpha.-methylandrosta-1,4-dien-3-one-17.beta.-carboxylate,
whenever prepared or produced by the process as claimed in
claim 108, or an obvious chemical equivalent thereof.
149

110. A process as claimed in claim 51, in which the
chloromethyl 11.beta.-hydroxy-17.alpha.-isopropoxycarbonyloxyandrost-4-en-
3-one-17.beta.-carboxylate obtained is reacted in acetonitrile with
silver fluoride at room temperature.
111. Fluoromethyl 11.beta.-hydroxy-17.alpha.-isopropoxy-carbonyl-
oxyandrost-4-en-3-one-17.beta.-carboxylate, whenever prepared or pro-
duced by the process as claimed in claim 110, or an obvious
chemical equivalent thereof.
112. A process as claimed in claim 67, in which the
17.alpha.-ethoxycarbonyloxy-9.alpha.-fluoro-11.beta.-hydroxy-16.alpha.-methylandrosta-
1,4-dien-3-one-17.beta.-carboxylate, obtained is reacted in aceto-
nitrile with silver fluoride at room temperature.
113. Fluoromethyl 17.alpha.-ethoxycarbonyloxy-9.alpha.-fluoro-11.beta.-
hydroxy-16.alpha.-methylandrosta-1,4-dien-3-on3-17.beta.-carboxylate,
whenever prepared or produced by the process as claimed in claim
112, or an obvious chemical equivalent thereof.
114. A process as claimed in claim 63, in which the
17.alpha.-n-propoxycarbonyloxy-9.alpha.-fluoro-11.beta.-hydroxy-16.alpha.-methylandrosta-
1,4-dien-3-one-17.beta.-carboxylate obtained is reacted in aceto -
nitrile with silver fluoride at room temperature.
115. Fluoromethyl 17.alpha.-n-propoxycarbonyloxy-9.alpha.-fluoro-
11.beta.-hydroxy-16.alpha.-methylandrosta-1,4-dien-3-one-17.beta.-carboxylate,
whenever prepared or produced by the process as claimed in
claim 114, or an obvious chemical equivalent thereof.
150

Description

~
1 174667
The invention relates to novel sof t steroids having
anti-inflammatory activity, pharmaceutical compositions con-
taining said soft steroids, novel chemical intermediatesuseful
in the preparation of the steroids, and processes for prepar-
iny said steroids and intermediates.
Successful predictions on a rational basis of the bio-
logical activity of compounds leading to new drugs are the
main objective of drug designers. This has usually been
achieved by considering a known bioactive molecule as the
basis for structural modifications, either by the group or
biofunctional moieties approach or by altering the overall
physical-chemical properties of the molecule. Thus, the main
aim has been to design, synthesize, and test new compounds
structurally analogous to the basic bioactive ~lecule which
have, however, improved therapeutic and/or pharmacokinetic
properties. Although "vulnerable" moieties have been identi-
fied as the ones whose role is the bioinactivation or meta-
bolic elimination of the drug after it has performed its role,
little or no attention has been paid in the drug-design pro-
cess to the rational design of the metabolic disposition of
the drugs. This has been the case despite the fact that the
toxicity of a number of bioactive molecules is due to their
increased elimination half-life, stability, or other factors
introduced during the design of increasing their activity.
Drugs and particularly their metabolic processes contribute
to the various toxic processes by formation of active
,35
- 1 _

1 174667
- 2 -
metabolites. The phenomenon of metabolic activation to
reactive intermediates which covalently bind to tissue
macromolecules is the initial step in cell damage. It is
also clear that the most toxic metabolites will not
survive long enough to be excre~ed and identified; thus,
studies of the stable metabolites may provide misleading
information.
It is clear that, in order to prevent and/or
reduce toxicity problems related to drugs, the metabolic
disposition of the drugs should be considered at an early
stage of the drug-design process. This is true
particularly when one considers that the body can attack
and alter chemically ~uite stable structures and that,
even if a drug is g5% excreted unchanged, the unaccounted
small portion can, and most likely will, cause toxicity.
nSoft drugs" can be defined as biologically
active chemical compounds (drugs) which might structurally
resemble known active drugs (soft analogues) or could be
entirely new types of structures, but which are all
characterized by a predic~able in vivo destruction
(metabolism) to nontoxic moieties, after they achieve
their therapeutic role. The metabolic disposition of the
soft drugs takes place with a controllable rate in a
predictable manner.
The present inventor has found five major classes
of soft drugs. One of the most useful classes was termed
the "inactive metabolite" approach which can be
adyantageously employed to design especially valuable
~soft drugsn. This approach starts with a known inactive
metabolite of a drug or a drug class; followed by
modifying the metabolite to resemble structurally
~isosteric and/or isoelectronic) the active drug (i.e.,
actiyation); and designing the metabolism of the activated
species to lead to the starting inactive metabolite after
achieving the desired therapeutic role, without the
formation of toxic intermediates ~i.e.,

1 174~67
predictable metabolism). The "inactive metabolite"
approach fur~her allows controlling the rate of
metabolism and pharmacokinetic properties by molecllar
manipulation in the activation stage. Also, if no
S useful inactive metabolite is ~nown, one can be designed
by the introduction of transporting groups in noncritical
structural parts.
The present inventor has now applied his
inactive metabolite approach to the case of the natural
and synthetic glucocorticosteroids and has designed the
soft steroidal anti-inflammatory agents of the present
invention, beginning with the known inactive natural
metabolites of the glucocorticosteroids. Thus, for
example, in the case of hydrocortisone, one of its
major, inactive met~bolites, cortienic acid, i.e.,
113,17~-dihydroxyandrost-4-en-3-one-17~-carhoxylic acid,
has been used as a starting point and activated by the
introduction of suitable non-toxic 17a - and
17B -subs.ituents, which activated derivatives will
cleave in vivo, after accomplishment of their
therapeutic role, to the starting inactive metabolite and
other nontoxic moieties.
~ accord with the foregoing, the present
invention provides novel soft steroids having anti-
inflammatory activity, said steroids having the
structural form~la~
.

1 ~ 74667
l -Rl
H C C=O
~ ~ 'R
wherein ~1 is a C1-C10 alkyl; Cl-C10 (monohalo or polyhalo)-
alkyl; or -CH2COOR6 wherein R6 is Cl-C10 alkyl, or R1 is
-CH2-Y-(lower alkyl) wherein Y is -S-, SO, SO2 or -o-, or
1 2 6 wherein R6 is Cl-C10 alkyl or phenyl R
is Cl-C10 alkyl, C3-C8 cycloalkyl, phenyl, benzyl or Cl-C10
(monohalo or polyhalo)alkyl, R3 is hydrogen, a-hydroxy,
~-hydroxy, a--methyl, ~-methyl, =CH2, or a- or ~-OCOR2
wherein R2 is identical to R2 as defined hereinabove; R4 is
hydrogen, fluoro or chloro; R5 is hydrogen, fluoro, chloro or
methyl; X is -O- or -S-; Z is carbonyl or ~-hydroxymethylene;
and the dotted lin in ring A indicates that the 1,2 linkage
is saturated or unsaturated; and a pharm~ceutically accep-
table quaternary ammonium salt of the compound represented
by said formula wherein at least one of Rl and R2 is a halo-
substituted alkyl group.
3Q
C
`:
.,

1 174~6~
A group of preferred compounds of formula (I)
consists of those wherein:
R1 is Cl-C6 alkyl; Cl-C6 (monohalo or polyhalo)-
alkyl; -CH2COOR6 wherein R6 is Cl-C6 alkyl; -CH2-Y-(Cl-C6
alkyl) wherein Y is -S-, -SO-, -SO2- or -O-; or
I
-CH2-OCR6' wherein R6' is Cl-C6 alkyl or phenyl;
R2 is Cl-C6 alkyl, C3-C8 cycloalkyl, phenyl~
benzyl or Cl-C6 (monohalo or polyhalo)alkyl;
R3 is hydrogen, ~-hydroxy, ~-methyl, ~-methyl or
~-OCOR2 wherein R2 is identical to R2 as defined hereinabove;
R4 is hydrogen or fluoro;
R5 is hydrogen or fluoro;
Z is ~-hydroxymethylene;
and X and the dotted line in ring A are defined as
hereinabove.
The invention further provides anti-inflammatory
quaternary ammonium salts of selected compounds of formula
(I), as discussed in further detail below. Novel inter-
mediates to the compounds of formula (I), e.g, the correspond-
ing compounds wherein Rl is hydrogen, are provided also.
The soft steroids of formula (I) and quaternaryammonium salts thereof are extremely potent local anti-
inflammatory agents; however, by virtue of the fact that
their facile ln vivo destruction leads only to the inactive
steroidal metabolite, the present compounds have far less
systemic activity than the known glucocorticosteroids from
whose inactive metabolites they are derived. Indeed, many
of the compounds of the present invention are entirely devoid
of systemic activity. Such minimal -- or non-existent --
systemic activity means that the compounds of the presentinvention can be used in the local (e.g., topical) treat-
ment of inflammatory conditions without the serious

~ 17466~
systemic side effects which attend use of the known glucocor-
ticosteroids.
With respect to the various groups encompassed by the
generic terms used here and throughout this specification,
the following definitions and explanations are applicable:
The alkyl, groupings can be straight or branched-chain
groups containing the aforementioned number of carbon atoms.
Likewise, the alkyl portions of the haloalkyl groupings each
can be straight or branched-chain. The term "lower" used in
conjunction with any of those groupings or in conjunction with
"alkyl" is intended to indicate that each alkyl portion there-
in can contain 1 to 8 carbon atoms.
Specific examples of alkyl radicals encompassed by for-
mula (I), whether as specific values for Rl or R2, or as a
portion of a R1, R2, or R3 group, include methyl, ethyl
propyl, butyl, pentyl, hexyl, heptyl and octyl and their
branched-chain isomers, as well as their straight and branched-
chain higher homologues in the instances where "alkyl" cancontain more than 8 carbon atoms. The alkenyl radicals can
be exemplified by vinyl, propenyl and butenyl. Illustrative
of the cycloalkyl and cycloalkenyl radicals are cyclopentyl,
cyclohexyl, cyclopentyl and cyclohexenyl. The alkylene
moieties are typified by trimethylene, tetramethylene and
the like.
-6-

1 17466~
With respect to the structural variables encompassed
by the group of preferred compounds of formula (I) identified
hereinabove, the term "Cl-C6 alkyl" is used to refer to a
straight or branched-chain alkyl group having 1 to 6 carbon
atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl,
isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl and the
like. In addition, the term "Cl-C6 (monohalo or polyhalo)
alkyl" is used to refer to a straight or branched-chain alkyl
group having 1 to 6 carbon atoms substituted with from 1 to
3 halogen atoms, the term "halogen" as used herein including
a chlorine atom, a bromine atom, an iodine atom or a fluorine
atom. Specific examples of the contemplated
-- 7

l 17466~
monohaloalkyl and polyhaloalkyl groups include chloromethyl,
dichloromethyl, trichloromethyl, bromomethyl, fluoromethyl,
difuloromethyl, trifluoromethyl, l-fluoroethyl, l-chloroethyl,
2-chloroethyl, 2,2,2-trichloroethyl, 2,2,2-trifluoroethyl,
1,2-dichloroethyl, l-chloropropyl, 3-chloropropyl, l-chloro-
butyl~ l-chloropentyl, l-chlorohexyl, 4-chlorobutyl and the
like. Also the term "C3-C8 cycloalkyl" is used to refer to
a cycloalkyl radical having 3 to 8 carbon atoms, such as
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl
and cyclooctyl.
Selected compounds of formula (I), i.e. compounds
wherein Rl is ~-haloalkyl, readily form the corresponding
soft quaternary ammonium salts which are likewise useful as
soft anti-inflammatory agents. Thus, for example, the selec-
ted haloalkyl derivative of formula (I) can simply be reacted
with a tertiary amine ~N) or an unsaturated amine (`"N) to
afford the corresponding quaternary ammonium salt. The re-
actants are
~l - 8 -

1 174667
r
~, ~
generally used in approximately equimolecular
proportions and the reactlon is conducted in the
presence of an inert solvent (e.g., ether, acetonitrile,
C~2C12 or the like), at a temperature of from room
5 temperature to the reflux temperature of the sol~ent,
for approximately 2 to 24 hours. Alternatively, the
reaction can be conducted in the absence of a solvent
by mixing the two reactants together and maintaining
them at room temperature or between 20 to 70C for 2 to
24 hours. In either case, the crystalline salt formed
can be purified by crystallization from an ether-ethanol
mixture, or the like.
The exprèssion "unsaturated amine" used above
denotes N-heterocyclic unsaturated systems having 3 to
15 10 members in the ring, and substituted derivatives
thereof, where the unsaturation corresponds to the
maximum number of non-cumulative double bonds, provided
that the nitrogen atom contains no hydrogen atom as a
substituent~ The following examples will sufficiently
20 illustrate the scope of the defined term:
. . .
C~3
l-Methylazirine ~
~ 3
l-Methylpyrrole
CX3
l-Methylimidazole
l-Methylpyrazole ~3
¢~
Pyridine
.
~', .
.
,~, .
. .
. ~'' .

1 174667
CI ~~
Pyrazine ~0
Pyrimidine
Pyridazine
"6
2-Methylisoindole ~ N--C~3
~ ~ .
. 3~-indole
Quinoline -
Iso~uino1ine
Phthalazine
N
10 Quinazoline ~ i;q
Phenazine

1 17466~
C -~
.
Isot~iazole S~ C~3
~ ,-1
~ ethylphenothiazine
Isoxazole 6~N
o
Furazan N
Substituted derivatives of the unsaturated
amines include groups as shown above containing one or
more alkyl, -COO(alkyl) or -OCO(alkyl) substituents.
With respect to the expression "tertiary amine",
this expression denotes amines wherein the nitrogen atom
has no hydrogen atoms attached thereto and which are not
among the N-heterocyclic unsaturated systems encompassed
by the expression "unsaturated amine" as defined above.
Typically, the term "tertiary amine" includes
trialkylamines, wherein the alkyl groups, which can be
the same or different, each preferably contain 1 to 8
carbon atoms; trialkoxyamines wherein the alkoxy portions
each contain 1 to 8 carbon atoms; tertiary saturated
cyclic amines such as quinuclidine or substituted
quinuclidine (e.g., 3-acetoxyquinuclidine); and
N-substituted derivatives of secondary saturated cyclic
amines [e.g., an ~-substituted derivative of morpholine,
pyrrolidine, imidazolidine, pyrazolidine, piperidine or
piperazine, wherein the N-substituent can be a group
such as (Cl-C8)alkyl], optionally containing additional
substituents such as methyl.
Preferred quaternary ammonium salts include
those derived from 1,2-dimethylpyrrolidine,
3-acetoxyquinuclidine, l-methylpyrrolidine, triethylamine
. . .
:' :
: '

~~
~ 17466~ .
and N-methylimidazole. Especially preferred are the
quaternary ammonium salts de_ived from the reaction of
the aforesaid amines with compounds of for~ula (I)
wherein Z is ~-hydroxymethylene and Rl is chloromethyl,
5 most especially when R2 is lower alkyl.
While all of the compounds encompassed by
for~ula (I) above essentially satis~y the objec'ives of
the present invention, nevertheless certain groups of
compounds re~ain preferred. A "firs." group o~ preferred
compounds of formula (I) has been set forth
hereinabove.
Another preferred group of compcunds consists
of the compounds of formula (I) where-n Z, X, Rl and R2
are defined as hereinabove, and the remainder of the
structural variations are identical to those of
hydrocortisone (i.e., R3, R4 and R5 are each a hydrogen
atom and the 1,2-linkage is saturated) or of prednisolone
(i.e., R3, R4 and R5 are each a hydrogen atom and the
1,2-linkage is unsaturated), most especially when Rl and
R2 are as derined with respect to the "first" group of
preferred compounds set forth hereinabove.
Another preferred group of compounds consists
of the 6~- and/or ga-fluoro and 16a- or 16~-me_hyl
congeners of the compounds indicated in the preceding
paragraph. Within this group, the compounds wherein
Z, X, Rl and R2 are defined as hereinabove and the
remaining structural variables are identical to those
of fludrocortisone, betamethasone and de~amethasone are
particularly prefer~ed, most especially when Rl and R2
are as deined with respect to the n first" group of
preferred compounds set forth here~nabove. Other
compounds of particular interest within this group are
those whe-ein Z, X, Rl and R2 are defined as hereinabove
and the remaining structural variables are identical to
those of triamcinolone, flumethasone, fluprednisolone or
paramethasone, particularly when Rl and R2 are as defined
2 _
.
:
' ' .

1 17466
C '` /3
,~
with respect to the "first" group of preferred
compounds set forth hereinabove. Yet other interesting
compounds are those wherein Z, X, Rl and R2 are defined
as hereinabove, R3 is a-OCOR2, and the remaining
structural variables are identical to those of
triamcinolone, particularly when Rl and R2 are as
defined with respect to the "first" group of preferred
compounds set forth hereinabove.
In each of the groups of compounds indicated
in the three preceding paragraphs, the compounds wherein
X is oxygen are particularly preferred. Most especially
preferred are the compounds encompassed by the groups
indicated above wherein Z is ~-hydroxymethylene, wherein
X is oxygen, wherein R2 is Cl-C6 alkyl (particularly
methyl, ethyl, propyl or isopropyl), and wherein Rl is
Cl-C6 alkyl, Cl-C6 (monohalo)alkyl (particularly chloro-
methyl) or -CH2-Y-(Cl-C6 alkyl) wherein Y is defined as
hereinabove (particularly when the Cl-C6 alkyl group is
methyl).
The compouuds of formula (I) can generally
be prepared by known methods, the method of choice being
dependent on the identity of the various substituents
in the desired final product.
One generally useful method for the preparation
of the compounds of formula (I) wherein Z is ~-hydroxy-
methylene and X is oxygen utilizes steroidal starting
materials of the formula
: .

1 17466~
~, /'f
C` ~
~O ~ ~ ~ - -OE (II)
R3'
R5
wnerein R4, R5 and the dotted line in ring A are defined
as befor2 and R3' is hydrogen, -methyl, B~ yl, -~H, ~-OH
ox -c~2~and which can be conveniently prepared by treatment
of the corresponding 21-hydroxypregnenolones of the
formula
f}I20H
'I
. ~31 f=o
E3 ~ ~ 3
'' ', , ",' , ~ ' :,
- R5
wherein R4, R5, R3' and the dotted line in ring A are
defined as above with ~aIO4 in a suitable organic solvent
at room or elevated temperature.) According to this
process of the invention, a star,ing material of formula
~II) is-reacted with R20COCl or R20COBr (formed by
reacting R20H with COCl2 or COBr2, wherein R2 is
defined as above), under anhydrous conditions,
in an appropriate inert organic solvent such
'.;
: '`'`'
' ' . . ' ,
., ~ ;
! .
.
'

~ - .
1 174667
as dichloromethane, chloroform or tetrahydrofuran,
preferably in the presence of a suitable acid acceptor
(e.g., triethylamine, pyridine, calcium carbonate or
other appropriate base). Tlme and temperature are not
critical factors; however, thé reac'ion is conveniently
carried out at a temperature between 0C and room
temperature, for about 1 to 6 hours. The resultant novel
17B-carboxylic acid 17~-carbonate has the formula
0~
C=O
HO ~ -OCOOR2
n (III)
R5
wherein R2, R4, R5 and the dotted line in the A ring are
defined as above and R3" is H, a-C~3, ~-CH3, a-OCOOR2,
B-ocooR2 or =CH2. When R3' in the starting material of
formula (II) is a-OH or B-oH~ sufficient R2OCOCl or
R2OCOBr is generally employed to ensure formation of the
carbonate grouping at the 16-position as well as at the
I7-position [i.e., when ~3' in formula (II) is OH, R3"
in the resultant intermediate of formula (III) is
a- or B-ocoor~2]-
XI - 15 -
.,
.

117466~ -
. - llo
Af,er the above-desc-ibed introduc_ on or
the 17a-subs~ituent, the resultant novel inte~ediate
or for~ul~ (III) is conve t2~ to its corresponding
metal salt of the for~ula
OM
C=O
~0~ --OCOOR2
wherein R2, R3", R4, R5 and the dotted line in the ring A
are defined as above, and M is a suitable metal, e.g.
alkali metal (such as sodium or potassium), alkaline earth
metal/2, or thallium or MH4. The novel salt of formula (IV)
is typically formed by reacting the steroid of formula (III)
with a hydroxide (MOH) or alkoxide (MOR) in an appropriate
organic solvent, such as ethyl ether or tetrahydrofuran,
at a temperature of 0C to room temperature, for 0.5 to
4 hours. Then, the salt of formula (IV) is reacted with
a compound of the formula Rl-W wherein Rl is defined as
hereinabove and W is halogen, to afford the desired final
product of formula (I). This step of the reaction
sequence can be conveniently conducted at room temperature
for about 1 to 24 hours, or at the boiling of the solvent
(i.e. acetonitrile, THF, etc.) When it is desired to
introduce a halo-substituted Rl grouping into the steroid,
e.g., when a compound of formula (I) wherein Rl is
chloromethyl is desired, it has been found that the
reaction proceeds well using hexamethylphosphoramide as
.

1 17466~
the solvent at lower temperatures (0-10C) and employing a
Rl-W reactant wherein W is iodine (e.g., iodochloromethane).
When a non~halogen containing Rl grouping is desired (e.g.,
Rl = alkyl or -CH2COOR6 where R6 is alkyl, etc.), no such
restrictions need be placed on the Rl-W reactant or on the
solvent; thus, W can be any halogen, preferably chloro or
bromo, and the usual organic solvents such as dimethylforma-
mide, dichloromethane, acetonitrile, tetrahydrofuran or
chloroform can, if desired, be used instead of hexamethylphos-
phoramide. When a compound of formula (I) wherein Rl containsa sulfinyl or sulfonyl grouping is desired, such a grouping
is not generally introduced via the Rl-W reaction, but is
subsequently prepared from the corresponding thio steroid,
as described below.
The compounds of formula (I) wherein Rl is a sulfinyl-
or sulfonyl-containing grouping can be prepared by oxidation
of the corresponding thio steroids. Thus, for example, a
compound of formula (I) wherein Rl is -CH2-S-(lower alkyl)
can be reacted with 1 equivalent of m-chloroperoxybenzoic
acid at 0-25C for 1 to 24 hours, in a suitable solvent
such as chloroform, to afford the corresponding compound of
formula (I) wherein Rl is -CH2-SO-(lower alkyl), or with 2
equivalents of _-chloroperoxybenzoic acid to afford the cor-
responding compound of formula (I) wherein Rl is -CH2-SO2)-
(lower alkyl).
~i
- 17 -
,
'
`'''

1 174~67
When the compounds of formula (I) wherein R3 is ~-
or ~-hydroxy are desired, same can be prepared by partial
acid hydrolysis of the corresponding compounds of formula (I)
wherein R3 is ~- or ~-OCOOR2, in a suitable solvent medium.
Use of a mild reagent, e.g., oxalic acid in methanol, is
desirable. Alternatively, hydrolysis of the 16-carbonate
to the 16-hydroxy compound could be carried out at an earlier
stage in any synthetic scheme described herein after the
introduction of the 16,17-carbonate groupings, e.g., selec-
tive hydrolysis of an intermediate of formula (III) having16 and 17 carbonate groupings to the corresponding 16-hydroxy
17-carbonate, followed by conversion to the corresponding
compound of formula (I) as described supra.
~ - 18 -

~ 1 17466~
/q
Another process for the preparation of the
compounds of formula (I) wherein Z is ~-hydroxymethylene
and X is oxygen utilizes the same 17-hydroxy-17~-carboxylic
acid starting materials of formula (II) as are employed in
the synthetic scheme described supra, but involves formation
of the 17 ~-COORl grouping prior to, rather than after,
introduction of the 17~-OCOOR2 substituent. Essentially,
the same non-steroidal reactants, reaction conditions, etc.,
as described above are used for the introduction of each
group. Thus, the starting material of formula (II) is
first reacted with MOH or MOR to form the corresponding
intermediate of the formula
~ f~
o
' ~O~--OEI
. (y
~J ,
I ,
,~ ,
~5
wherein R3', R4, R5 and M and the dotted line in ring A are
defined as above, which is then reacted with RlW wherein
. 15 Rl and W are defined as above, to afford the corresponding
17~-carboxylate of the formula

--~` 117466~
ORl
.. l`
- C=O
HO ~ ~~ (VI
.
wherein Rl, R3', R4, R5 and the dotted line in ring A are
defined as above, which is in turn reacted with R20COCl or
R20COBr wherein R2 is defined as above, to afford the
corresponding 17a-carbonate of formula (I). The various
5 parameters of the process of converting (II) to (V) are the
same as those discussed in detail above with respect to the
conversion of (III) to (IV~. Like~ise, the process parameters
for converting (V) to (VI) parallel those detailed above with
respect to converting (IV) to (I). Similarly, the process
parameters for converting (VI) to (I) are basically the same
as those given above for the conversion of (II) to (III).
Thus, again, when the starting material contains a 16-hydroxy
group, the 16,17-dicarbonate of formula (I) will be formed
which can then be selectively hydrolyzed, if desired, to the
corresponding 16-hydroxy-17-carbonate of formula (I). And,
again, the compounds of formula (I) in which Rl is a
sulfinyl- or sulfonyl-containing grouping can be conveniently
prepared by oxidation of the corresponding thio-containing com-
. pounds of formula (I) as detailed hereinabove. Alternatively,
: 20 the compounds of formula (I) wherein Rl is a sulfinyl-
or sulfonyl-containing group [e.g., when Rl is _CH2-So-
(lower alkyl) or -CH2-SO2-(lower alkyl)] can be prepared
,~ - 20 -
.

~ 17466~
f~ `
by oxidation, preferably with m-chloroperoxybenzoic acid,
of the corresponding compounds of formùla (VI) in which
Rl is a thio-containing group, followed by introduction
of the 17a-OCOOR2 substituent to the resultant sulfinyl
or sulfonyl compound.
Another possible process for the preparation of
the compounds of the present invention, which can be used
to prepare compounds of formula (I) wherein Z is ~-hydroxy-
methylene and X is oxygen or sulfur, utilizes the 17~-
carboxylic acid 17-carbonate intermediates of formula (III)
above. According to this process, an intermediate of formula
(III) is successively treated, first with a mild acyl chloride
forming agent, e.g. such as diethylchlorophosphate or oxalyl
chloride, to form the corresponding novel acid chloride of
the formula
fl
C=O
}~0 ~ ~ ~ ~ `0COOR2
~.R3~
,~1
R5
wherein R2, R3", R4, R5 and the dotted line in ring A are
defined as above, and then with RlXM' wherein Rl and X are
defined as before, and M' is hydrogen or M (M is defined as
above), in an inert solvent (e.g., CHC13, THF, acetonitrile
or DMF), at a temperature between about 0C and the boiling
point of the solvent, for l to 6 hours, to afford the cor-
responding compound of formula (I). When using a compound
of the formula RlXM' wherein M' is hydrogen, an acid scavenger

1 174667
CJ~ ~
such as triethylamine is preferably present in the reaction
system. The two steps of)this process can be very con-
veniently run in the same solvent, without isolating the
acid chloride of formula (VIII) formed in the first step.
This process is of particular value when a compound of
formula (I) wherein X is S is desired.
Yet another desirable process for the preparation
of the compounds of formula (I) wherein Z is ~-hydroxy-
methylene and X is oxygen utilizes the 17 a-hydroxy-17~-
carboxylates of formula (VI) above. According to thisprocess, an intermediate of formula (VI) is reacted with
phosgene, in a suitable organic solvent (e.g., toluene,
benzene, CH2C12 or acetonitrile) at a low temperature
(-20C to room temperature, e.g., 0C), for about 2 hours
(or until the reaction is complete). ~vaporation to remove
solvent and excess phosgene affrods the desired novel 17a-
chlorocarbonyloxy-17~-carboxylate intermediate of the formula
ORl
~_o
(VII)
R
wherein Rl, R4, R5 and the dotted line in ring A are defined
as above, R3"' is hydrogen, a-methyl, ~-methyl, a-OCOCl,
~-OCOCl or =CH2. When R3' in the starting material of formula
(VI) is hydroxy, sufficient phosgene is generally employed
to ensure formation of the chlorocarbonyloxy grouping at
the 16-position as ~ as the 17-position [i.e., when

1 ~ 7 4 6 6 7
- 2~r -
R3' in formula (VI) is a-OH or ~-OH, R3"' in the resultant
intermediate of formula (VII) is a- or ~-OCOCl~. The inter-
mediate of formula (VII) is then reacted with a compound of
the formula R2OM' wherein R2 and M' are defined as above, in
an inert solvent, preferably in the presence of an acid
scavenger (e.g. triethylamine), to afford the corresponding
compound of formula (I). When R20M' is an alcohol of the
formula R2OH, the reaction is conducted under the same
conditions as in the reaction for conversion of compound (II)
to compound (III). On the other hand, if a compound of the
formula R2OM is employed as R2OM', the reaction conditions
are described as above for conversion of compound (VIII) to
compound (I). When R3"' in the formula (~II) is OCOCl,
sufficient R2OM' is generally utilized to ensure conversion
of both the 16- and 17a-substituents to OCOOR2 groupings
in the final product. And, again, the 16-hydroxy and the
sulfinyl- and sulfonyl- containing compounds of formula (I)
are most conveniently formed as a final step in the synthetic
scheme.
As a variation of the process described immediately
above, a steroidal 17a-hydroxy-17~-carboxylic acid starting
material of formula (II) can be reacted with phosgene as
described above, to afford the 17a-chlorocarbonyloxy-17~-
carboxylic acid intermediate of the formula
OIH
1=o
~ '
R5

1 17~667
, _ .
r ~
wherein R3"', R4, R5 and the dotted line in ring A are
defined as above, which can then be reacted with R20M' as
described supra, to afford the corresponding compound of
formula (III) above. The novel intermediate can then be
converted to a corresponding compound of formula (I) as
described supra. Once again, the 16-hydroxy and the
sulfinyl and sulfonyl derivatives are best prepared as a
final step.
Still another process for the preparation of the
compounds of formula (I) wherein Z is ~-hydroxymethylene
and X is oxygen utilizes the 17a-hydroxy-17~-carboxylates
of formula (VI) above. In accord with this method, an
intermediate of formula (VI) is reacted with an excess
o
amount of a carbonate of the formula R20COR2 (which can be
conveniently prepared by reacting phosgene with 2 equivalents
of R20H) in the presence of an acid catalyst, to afford the
corresponding compound of formula (I). Depending on the
o
nature of the R2 grouping, the R20COR2 reactant can also act
as the solvent at the boiling point of the carbonate reactant,
or at the boiling point of the corresponding R20H (which can
conveniently be removed in this way from the reaction mixture,
driving the reaction to completion), or the reactants can be
combined in an appropriate inert organic solvent (e.g., an
aromatic such as benzene or toluene, or a halogenated hydro-
carbon such as dichloromethane or chloroform). And, again,
the 16-hydroxy and the sulfinyl and sulfonyl compounds of
formula (~) can conveniently be prepared as a final step in
the process, although the intermediate of formula (VI) in
which Rl contains a sulfur atom could be first oxidized, and
the resultant sulfinyl of sulfonyl compound of formula (VI)
then reacted with R20COR2.
.

117466
- C
Other procedures for the preparation of
seIected compounds of formula ~I) will be apparent to
those skilled in the art. By way of ~ample, a compound
of formula (I) wherein Rl or ni~is halo-substituted can be
subjected to a halogen e~Ychange~reaction in order to re-
place the halogen with a different halogen according to
the order of reacti~ity Cl<3r<I. For e~ample, reacting
a chloroalkyl 17~ -G~*oxylate of formula (I) with an
alkali metal iodide, e.g., sodium iodide, will afford the
corresponding io~X~l 17~-carboxylate. Similarly, a
bromide salt (e.g., lithium bromide~ can be reacted with
a chloroalkyl 17~-carboxylate to giYe the corresponding
bromoalkyl 17~-carboxylate. A suitable solvent for either
reaction may be selected from the group consisting of
hexamethylphosphoramide, acetone, ethanol, methyl ethyl
ketone, dimethylacetamide, dimethylformamide and acetonitrile.
In like manner, a halogen exchange reaction
based on relative solubilities can be used to convert
a chloroalkyl 17~-carboxylate or an iodoalkyl
17B-carboxylate of formula (I) to the corresponding
fluoroalkyl derivative. Silver fluoride can be
employed in this reaction, which is conducted in a suitable
organic solvent (e.g., acetonitrile), and which is
especially useful in the preparation of the compounds in
which Rl is fluoromethyl or fluoroethyl.
The 21-hydroxypregnenolones from which the
steroidal starting materials of -formula (II) are
preparea can be obtained commercially or prepared by
known methods. Likewise, the non-steroidal starting
materials used in the various processes discussed above
are commercially available or can be prepared by known
chemical procedures.
.

1 17466~
<
C
.`
Also, a starting material of formula (II~ above
can be reacted with a compound of the formula R2OCOCl
or R2OCOBr wherein R2 is as defined above, to af ord an
intzrmediate of the formula o
OCOR2
C=O
~O ~ - OCOOR~
3 (XI)
R5
wherein R2, R3", R4, R5 and the dotted line in rlng A
are defined as above, which can be converted to the
corresponding intermediate of formula ~III) above by
partial hydrolysis, with or without isolation of the
compound of formula (2I). This reaction of a starting
material of formula (II? with R2OCOCl or R2OCOBr-can be
carried out under the same conditions as the reaction of
a compound of formula (II) with R2OCOCl or R2OCOBr as
described hereinabove, except that R2OCOCl or R20COBr is
used in an amount of 2 moles or more to one mole of the
compound of the formula (II). The partial hydrolysis of
the resultant compound of the formula (2I) can be carried
out in an inert solvent in the presence of a catalyst.
~xamples of suitable catalysts include tertiary alkyl
amines such as triethylamine, trimethylamine or the like;
aromatic amines such as pyridine, 4,4-dimethylamino-
pyridine, quinoline or the like; secondary alkyl ~m; nes
such as diethylamine, dimethylamine or the like; and

1 17466~
~1
inorganic bases such as sodium hydroxide, potassium
hydroxide, potassium bicarbonate, or the like.
Preferably, pyridine and potassium
bicarbonate are employed. Examples of suitable inert
solvents for use in the hydrolysis include water;
lower alcohols such as ethanol, methanol or the like;
ethers such as dimethyl ether, diethyl ether,
dimethoxyethane, dioxane, tetrahydrofuran, or the like;
halogenated hydrocarbons such as dichloromethane,
chloroform or the like; tertiary amines such as pyridine,
triethylamine or the like; or a mixture of two or more
of the solvents mentioned above. ~he reaction is usually
carried out a temperature of from about 0 to 100C,
preferably at room temperafure to 50C, for 1 to 48 hours,
preferably for 2 to 5 hours.
In yet another aspect, the present invention
provides novel compounds of the formula
X-Rl
o~_ OCOR2
R3 (IX)
~ 5
wherein Rl, R2, R3,-R4, R5, X and the dotted line in ring
A are as defined with respect to formula (I) above. The
~ eto compounds of formula ~IX) can be prepared by the
procsdures described hereinabove for the preparation of

1 17466~
.
C ~.
~g
the corresponding ll~-hydrc~y compounds o~ formula ~I).
Thus, a starting material correspondins to formula ~II
but having an ll-keto group is reacted with R20COCl or
R20COBr, to afford the corresponding novel intermediate
corresponding to formula ~III] but haYing an ll-keto
group; that intermediate is then converted to its metal
salt, which corresponds to formula ~IV) except for the
presence of an ll-keto instead of an ll~-hydroxy group;
and the metal salt is th~n reacted with RlW to afford the
corresponding compound of form~la ~IX). All reaction
condi,ions are as previol~sly described with respect to
the corresponding processes for preparing the corresponding
compounds of formula ~I). Also, the preparation of the
compounds of formula ~IX) wherein Rl is a sulfinyl- or
sulfonyl- containing grouping or wherein R3 is hydroxy
generally proceeds as a final step in the synthetic scheme
in a manner analogous to that ~sed for the corresponding
compounds of formula (I). ~urther, all of the aboYe-
described alternative processes for the preparation of
the compounds of formula ~I) are eq~lally applicable to the
preparation of the compounds of formula (I~) by simply
substituting the ll-o~o-starting material for the
corresponding ll~-hydro~y steroids used therein, e.g.,
replacing the ll-hydrQxy group in formulas (Y~, (YI),
~VII~, ~VIII), (X) and ~I) with an ll-oxo groLp and
otherwise proceeding as described hereinaboYe for the
reactions (Ti) ~(V) ~YI)~ VIII)~
~ VI) )(VII) ,~I); ~II) i ~X) ~ (I); (YI3 ~ ~),
etc.
Also, the compounds of formula (IX) can be
prepared by reacting the corresponding compounds of
formula (I) with an Qxidizing agent. The Qxidation of a

117~667
~,2q
_ j~
~` J,
compound of formula (I) in order to convert it into the
corresponding compound of formula (IX) is usually
carried out by using an oxidizing agent in an appropriate
solvent. The solvent may be any conventional solvent,
for e~ample, water, an organ~c acid (e.g. formic acid,
acetic acid, t~lI~ucmacetic acid), an alcohol (e.g.
methanol, ethanol),-a halogenatea hydrocarson (e.g.
chloroform, dichloromethane~, or the liXe. The oxidizing
agent may also be any conventional agent which is ef ective
for oxidizing a hydro~y group to a carDonyl group, for
e~ample, pyridinium chlorochromata, chromium trioxide in
pyridine, hydrogen peroxide, dic~romic acid, dichromates
~e.g. sodium dichr~mate, potassium dichromate), permanganic
acid, permznganates ~e.g. sodium permanganate, potassium
permanganate), or the lik~. The ox~dizing agent is usually
used in an amount of 1 mole or more, preferably 1 to 3 mole,
per mole of the compound of formula ~I). The reaction is
usually carried out at a temperature of 0 to 40C, preferably
at around room temperature, for about 6 to 30 hours.
The novel compounds of formula (IX) are useful as
soft steroidal anti-inflammatory agents and also in
vivo or in vitro precursors of the corresponding
hydroxy compounds. Thus, the compounds of formula
(IX) can be reduced in vitro to afford the corresponding
compounds of formula ~I), using a reducing agent known to
be capable of reducing the ll-oxo group to an a ll~-hydroxy
group without modifying the remainder of the steroidal
starting material. Typically, microbiological reduction
- is advantage~us for carrying out the desired conversion,
although chemical reduction also is possible. Further,
the compounds of formula ~IX) may be formulated into
appropriate dosage forms (e.g., retention enemas) for the
.)

1 ~7466
3~
treatment of conditions such as ulcerative colitis. In such
dosage forms, it is thought that the compounds of formula
(IX) are microbiologically reduced by bacteria in the body
(e.g. in the colon) to the highly active ll~-hydroxy
steroids, which elicit the desired anti-inflammatory response.
The preferred compounds of formula (IX) are those
which are precursors of the preferred compounds of formula
(I) wherein Z is ~-hydroxymethylene, namely corresponding
ll-keto compounds of formula (IX). An especially preferred
group of compounds of formula (IX) consists of those
wherein X, Rl and R2 are defined as above with respect to
for~ul~ (I) and the re~aining s.ruc~ral variations are
identical to those of cortisone ~i.e. R3, R4 and R5 are-
each a hydrogen atom and the 1,2-linkage is saturated),
of pre~nisone (i.e. R3, R4 and ~5 are each hydrogen and
the 1,2-linkage is unsat~lrated), or of the 6- and/or
9a-fluoro and the 16a- or 16~-methyl congeners thereof,
particularly when Rl and R2 are as defined with respect
to the "first" group of preferred compounds set forth
hereinabove. Most especially preferred ~f these
derivatives are those wherein X is oxygen, R2 is Cl-C6aIkyl
and Rl is Cl-C6 al~yl, Cl-C6 (monohalo)alkyl [particularly
chloromethyll or -C~2-Y-(Cl-C6 alkyl) [particularly
C~2-Y-cx3 ~
The results of various activity studies of
representative species of the invention, discussed in
detail below, clearly indicate the potent anti-inflammatory
activity and the minimal syste.~ic activity/toxicity of the
soft steroidc of formula (I). In view of this desirable
separation of local and systemic activities, the compounds
of the invention can be used in the treatme~t of topical
or other localized inflammatory conditions without causing
the serious systemic side ef~ects typically exhibited by
the known natural and synthetic glucocorticost2roids such
as cortisone, hydrocortisone, hydrocortisone 17a-butyrate,

1 17466~
betamethasone 17-valerate, triamcinolone, betamethasone
dipropionate and the like.
T~YMUS INVO~UTIO~ TEST
The test animals were female Sprague/Dawley
rats weighing approximately 40-45 grams each. One side
of each ear of each rat was treated with a total of 25
microlite-s of a solution ~ethanol/isopropyl myristate
or acetone/isopropyl myristate, 90/10) containing the
amount of test compound indicated below. Animals which
were treated identically, save for omission of the test
compound, served as controls. After 24 hours, all rats
were sacrificed and weighed, and their thymi were removed
and weighed. The results are tabulated in Table I below,
the weights of the thymi being expressed as mg/100 g of
rat.
.
'
,-

`- 1174667
~ j,~,
-- .3~
C~ ~o+,+, +,
C dP0U~ r~ ~s ~ q
O N N . ~ .
":5 ~ _1 ~ 11~ O O .
~0S ~ ~ er _1 _1 ~o , .
_i ~i ~ O
3 ~ 1~lo u~ D . ~D
C ~ .
O ~ ~ ~ ~ ~ ~_
S-lEl Q ~ ~ ~ . ~
-l ~ CJ ~ . In .
~, ~ ~ q~ . er
C ~ . . .
~ U~ .
.~ ~ ~~ u~ _~ . +~
M a~ ~:, ~ ~r I~ ~ . .
~ O ~ o r~ I~ ~ , o
~a' ~ ~ . ' .
~1: ~ O ~ a~ ~o ~ : ~ . ' '
~c z ~ - ~
~ ~ ~ c ~-- u~ ~ u~
O l r~ r~ . r~
1~ ,~O~ 1. o . ': :
,U- . 1.'
0-~ ,~ ~ _1 C I ~ ~ 1 ~1`
qO C O :~ :~ ~ a I o ~ U
c ~ ~ o ~ ~ X I C C ~
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U 'Z ~ t,~ O ~ ~

- - 1 17466~
,
.....
.,
_ ~ .
The change in weight in the thymi is a measure
of systemic activity and hence of toxicity. The lower the
weight of the thymi, the greate_ the systemic activity.
As can be seen from the above data, even hydrocortisone,
the natural glucocorticoid, causes a significant decrease
in thymus weight compared to the control. The decreases
caused by egual doses of representative species of the
invention are much less significant, indicating those
compounds have much l'ess systemic activity than
hydrocortisone,
BLANC~ING STUDIES
McKenzie-type human blanching studies were
undertaken to study the blancning effects of a represent-
ative test compound of the invention, chloromethyl
17~-ethoxycarbonyloxy-11~-hydroxyandrost-4-en-3-one-17~-
' ' carboxylate. The ability of a compound to cause blanching
,~ in humans has been found to correlate closely with its
anti-inflammatory activity.
The test compound was dissolved in ethanol/
isopropyl myristate ~90/10 or'70/30) at 0.03, 0.01, 0.003,
0.001 and 0.0003 M concentrations. 50 Microliter aliquots
of each solution were applied to separate gauze portions,
' ~of a bandage of the type commonly used for allergy
, testing and the bandage was applied to the forearm. After
6 hours of occlusion, the bandage was removed. After 1 to
5 hours aft^r removal of the bandage, blanching was
observed even at the lowest concentrations of test
compound.
When hydrocortisone was tested according to the
above procedure comparing it directly to the test compound,
blanching was not observed at concentrations of
hydrocortisone below 0.03 M. Further, it was noted that
.. -- . ~
, j ~
j

~ 1 17466~
0.03 M hydrocortisone caused approximately the same
degres of blanching as that resulting from use of
O.001 M cnloromethyl 17a-e~hoxycarbonyloxy-llB-
hydroxyandrost-4-en-3-one-17~-carboxylate.
S EAR EDEMA TEST
The test animals were Sprague/Dawley rats
weighing approximately 150 grams each. In treatment
groups, selected amounts of the test compound were
dissolved in acetone containing 5% croton oil and 50
microliters of the solution were applied to the inner
surface of the right ear of the rats. A control group
was identically treated with vehicle only, i.e. 5%
croton oil in acetone. Six hours after croton oil
challenge, a constant region of each ear was removed by
dissection under anesthesia. Then, 48 hours after
steroid treatment, the animals were sacrificed and the
thymi and adrenals were removed and weighed. The test
results showing the inhibitory effect of topically
applied steroids on the ear swelling induced by croton
oil are summarized in Table II below.
.

- ~17466~
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1 17466~
3 ~
As can be seen from Tahle II akove, the
representative species of the present invention, namely
chloromethyl 17-et.~oxycar~onyloxy~ -hydroxyandrost-
4-en-3-one-17~-carbo.~ylate, s~bs~aniially inhibited the
swelling (and conse uent increased weight) of the ear
caused by c_oton oil, i.e., the com~ound e~nibited
substanti21 anti-inflammatory act-vity. On the other
hand, in contras. to the effect caused by betametasone
17-valerate, the representative compound of the invention
did not significantly decrease ~he thymus weight as
compared to the control, i.e., it did not show a signifi-
cant degreo of syst~mic activi~x.
G ~NULOMA FOR~ION TEST
The test compound was dissolved in acetone and
aliquots of varying concentrations we_e injected into
cotton pellets. The pellets were dried and then one
pellet was implanted beneath the skin of each test rat.
Si~ days later, the animals were sacrificed and the
granulation tissue (granuloma) which formed in and around
the implanted pellet was removed, aried and weighed.
In addition, the thymi and adrenals were removed and
- weighed. The ability of a compound to inhibit granuloma
formulation in this test is a direct indication of local
- anti-inflammatory activity; thus, the lower the weight of
granulation tissue, the better the anti-inflammatory
activity. On the other hand, a significant dec~ease in
thymus weight is indic~tive of significant systemic activity;
conversely, when a test cQmpound does not sig~ific~ntly
decrease thymus weigh~ as compared to the control, such
30 i5 indicative of a lac~ of (or very minimal~ systemic
side effec_s.
The results are tabulated in Tables III, IV and
V-a and V-b below.

1 17466
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~ 174667
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The test data in Tables III, IV and V-a and V-b
above clearly show that the representative compounds of the
present invention exhibited a significant anti-inflammatory
response at lower dosages than did the prior art steroids,
hydrocortisone 17-butyrate and betamethasone 17-valerate.
On the other hand, all of the prior art steroids dramatically
decreased the weight of the thymi and thus showed very potent
systemic activity, while the representative compounds of the
invention either did not significantly decrease the thymi
weights or only minimally decreased the thymi weight. Thus,
the present compounds have a much greater therapeutic index,
i.e., separation of local anti-inflammatory from systemic
activity, than do the prior art steroidal anti-inflammatory
agents.
Also the test data in Table V-b above shows that
the representative compounds of the present invention
exhibited a significant local anti-inflammatory activity.
From the results tabulated in Tables IV and V-b,
the ED40's, ED50's and ED60's and the relative potencies
of representative compounds of the invention were
calculated and are shown in Table VI below. One of the
compounds of the invention, namely chloromethyl 11 -
hydroxy-17 -isopropoxycarbonyloxyandrost-4-en-3-one-17 -
carboxylate, has been assigned a potency value of 1 at each
ED level, and the potencies of the other compounds are
expressed relative thereto. The ED40ls, ED50's and ED60's
are the dosages required to achieve, respectively, 40%, 50%
and 60% reduction in the weight of the granulation tissue.
~,
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1 174667
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..

1 17466~
l~YMUS INHIBI~I~N ~ESTING
Several further studies were undertaken to
determlne the effec~s of selected compounds of the
invention on thymi weights in rats when the drugs were
systemically administered. In each of these studies,
male Sprague-Dawley rats were used. (For average weight of
rats for each study, see the tables which follow.) The
test compounds were suspended in 0.5% G~C
~carboxymethylcellulose) and injected subcutaneously
once daily for three days. On the fifth day (48 hours
following the last $reatmen~, the animals were sacrificed
and the thymi weights were recorded. Body weight gains
were measured 24 hours after the last treatment. The
test results are set forth in Tables VII, VIII and IX
below. The TED40's, TED50's ~thymol~tic effective doses
or doses required to achieve 40% and 50% inhibition of
thymi weight, respectively) and relative potency of
representative compounds of the invention and reference
steroids are shown in Table X below. In Table X, the
TED40 and TED50 for the reference steroid betamethasone
l~-valerate has each been assigned a value of l, and the
- potencies of the other compounds are e~pressed relative
thereto. It is e~ident that the higher the inhibition of
thymus activity at a given dose, the more toxic the
compound is.
.. . . ..
. .

~ 1 74667
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11746
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- 1 17466~
f~ '1
BLANK COTTON PELLET GRANULOMA ASSAY
A further test was undertaken to determine the
thymolytic activity of a representative species of the inven-
tion as compared to betamethasone 17-valerate. In this test,
the drugs were administered intravenously to rats, while
using a blank cotton pellet granuloma assay. Male Sprague-
Dawley rats, each weighing about 185 grams (166-196 grams),
were used. Two cotton pellets, each weighing 30 mg and con-
taining no test compounds, were sterilized and implanted sub-
cutaneously into the back of each test animal. This day wasconsidered day O of implantation. ~Test compounds suspended
in 0.8%~po~yoorbatc 80~were adml~nisJtered intravenously once
daily for 3 consecutive days beginning with day 1. On day 5,
the animals were sacrificed and the two pellets, with their
respective granulomas, were removed, dried overnight in an
oven at 50C and weighed (dry granuloma weight). The thymi
and final body weights were also recorded. The results are
given in Table XI below.
In the foregoing tests, there was determined the
deactivation of the representative species of the present soft
steroids administered intravenously to rats. The ratio
between the potencies of the test steroids and betamethasone
17-valerate against local anti-inflammation was 283:0.7 as seen
from Table VI. This means that the test compounds exhibit a
local anti-inflammatory activity which is approximately 400
times as high as the activity of the betamethasone 17-valerate.
The test compounds were administered intravenously to rats to
` check the test compounds also for systemic anti-inflammatory
activity as compared to betamethasone 17-valerate. The test
compounds were found lower in the inhibition of granulation
tissue formation and also in the thymus involution activity
than betamethasone 17-valerate. From the results of the tests,
it is presumed that the compounds which will not be readily
subjected to metabolism (deactivation) have a systemic anti-
inflammatory activity, as is the case with betamethasone17-valerate.
"
, :

~ 174667
s~
_ ~ o e~ ~ ~ ~ j
q~ ~ _ t~ ~ N r~ ~r W
v e +l +l +l +O +l+l +l +I v
S ~ I ~
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- 1174667
r~ '
~, sY
The ED50's calculated for the local cotton
pellet granuloma assay ¢as shown, for example, in Table
VI above) and the TED40's calc~lated on the basis of
thymus inhibition testing ¢as shown, for example, in
Table X above) were used to arrive at relative potency
and a therapeutic index for representative species of the
invention as compared to prior art steroids. See Table
XII below, which clearly shows the potent anti-
inflammatory activity and minimal systemic toxicity of
the compounds of the present invention.
' , - . ' :
: ~ ' ' . '

1 174667
i! p ~ ~ ,ô~ ~ -I ~
O _I h q~ q.l V 1~
~ J

1 174~67
b
The compounds of formula ~I) can be combined
with suitable non-toxic pharmaceutically acceptable
carriers to provide pharmaceutical compositions for use
in the treatment of topical or other localized
inflammation. Obviously, in vie~ of their lac~ o~
systemic activity, the compounds-of the present invention
are not intended for treatment of conditions where
systemic adrenocortical therapy is indicated, e~g.,
adrenocortical insufficiency. As examples of inflammatory
conditions which can be treated with'pharmaceutical
compositions containing at least one'compound of the
invention and one or more pharmaceutical carriers, the
following can be mentioned: dermatological disorders
such'as atopic dermatitis, acne, psoriasis or contact
dermatitis; allergic states such as bronchial asthma;
' 'ophthalmic and otic diseases involving acute and chronic
allergic and inflammatory reactions; respiratory diseases;
ulcerative cclitis; and anorectal inflammation, pruritus
and pain associated with hemorrhoids, proctitis, cryptitis,
fissures, postoperative pain and pruritus ani. Such
compositions may also be applied locally as a prophylactic
measure against the inflammation and tissue rejection
which arise in connection with transplants.
' Obviously, the choice of carrier~s) and dosage
forms will vary with-the particular condition for which
the'composition is to be administered.
Examples of various types of prepàrations for
topical/local administration include ointments, lotions,
creams, powders, drops, ~e.g. eye or ear drops), sprays,
~e.g. for the nose or throat), suppositories, retention
enemas, chewable or suckable'tablets or pellets ~e.g. for
the'treatment of aphthous ulcers) and aerosols. Ointments
and creams may, for example, be formulated with an aqueous

1 17d~67
~ 5~
_~ _
or oily base with the addition of suitable thickening
and/or gelling agents and/or glycols. Such base may
thus, for example, include water and/or an oil such as
liquid paraffin or a vegetable oil such as arachis oil
or castor oil, or a glycolic sol~ent such as propylene
glycol or 1,3-butanediol. Thic~ening agents which may
be used according to the nature of the base include soft
paraffin, aluminium stearate, cetostearyl alcohol,
polyethylene glycols, woolfat, hydrogenated lanolin and
beeswax and/or glyceryl monostearate and/or non-ionic
emulsifying agents.
The solubility of the steroid in the ointment
or cream may ben enhanced ~y incorporation of an
aromatic alcohol such as benzyl alcohol, phenylethyl
alcohol or phenoxyethyl alcohol.
Lotions may be formulated with an aqueous or
oily base and will in general also include one or more
of the following, namely, emulsifying agents, dispersing
agents, suspending agents, thickening agents, solvents,
coloring agents and perfumes. Powders may be formed with
the aid of any suitable powder base e.g. talc, lactose
or starch. Drops may be formulated with an aqueous base
also comprising one or more dispersing agents,
suspending agents or solubilizing agents, etc. Spray
compositions ~ay, or example, be formulated as ~erosols
with the use of a suitable propellane, e.g.,
dichlorodifluoromethane or trichlorofluoromethane.
The proportion of active ingredient in the
compositions according to the invention will vary with
the precise compound used, the type of formulation
prepared and the particular condition for which the
composition is to be administered. The formulation will
generally contain from about 0.0001 to about 5.0% by
weight of the compound of formula ~I). Topical
.

1 174667
.
s~
preparations will generally cont in ~.0001 to 2.5~,
preferably 0.01 to 0.5%, and will be'administered once
daily, or as ne~ded. Also, generally speaking, the
compounds of the invention can be incorporated into
topical and other local compositIons formulated sub-
stantially as are such'presently available types of
compositlons containing known glucocorticosteroids, at
approximately the same tor in the case'of the most potent
compounds of the invention, at proportionately lower)
dosage levels as compared to known highly active agents
such as methyl prednisolone'acetate''and ~eclomethasone
dipropionate or at considerably lower dosage levels as
compared to less active known agents such'as
hydrocortisone.
Thus, for example, an inhalation formulation
suitable for use in the treatment of asthma can be pre-
pared as a metered-dose aerosol unit containing a
representative species of the'invention such as
chloromethyl 17-ethoxycarbonyloxy-llB-hydro~yandrost-4-
en-3-one-17~-carboxylate, according to procedures well-
known to those skilled in the art of pharmaceutical
formulations. Such an aerosol unit may contain a
microcrystalline suspension of the aforementioned
compound in suitable propellants ~e.'g.,
trichlorofluoromethane'and dichl'orodifluoromethane), with
oleic acid or other suitable'dispersing agent. Each unit
typical~y contains 10 milligrams of the aforesaid active
ingredient, approximately 50 micrograms of which are
released at each actuation. When one'of the more potent
species of the invention,,e.'g. chloromethyl 17-
ethoxycarbonyloxy-9~-fluoro~ -hydroxy-16a-methylandrosta-
1,4-dien-3-one-17~-carboxylate, is employed, each unit
typically contains 1 milligram of the active ingredient
' and Eeleases approximately 5 micrograms at each actuation.

~ ~ 17 466~
s~
Another e~ample of a pharmaceutical com~osition
according to the invention is a foam suitable f,or
trea~ment of a wide variety o' inflammatory anorectal
disorders, to be applied anally or perianally, comprising
0.1% of a compound of formula ~I~ such'as chloromethyl
17a-ethoxycarbonyloxy-11~-hydroxyandr~s.:-4-en-3-one-
17B-,carboxylate, and 1% of a local anaesthe~ic such as
pramoxine hydrochloride, in a mucoadhesive foam base of
propylene glycol, ethoxylated stearyl alcohol,
,10 polyoxyethylene-10-stearyl ether, cetyl alcohol, methyl
paraben, propyl paraben, triethanolamine, and water, with
inert propellents. ~nen a more potent compound of the
invention is employed, less active ingredient generally
is used, e.g. 0.05% of chloromethyl 9a-fluoro~ -hydroxy-
17a-methoxycarbonyloxy-16a-methylandrosta-1,4-dien-3-one-
17~-carboxylate.
Yet another pharmaceutical formulation according
to the invention is a solution or suspension suitable for
use as a retention enema, a single dose of which typically
contains 40 milligrams of a compound o' the invention such
as chloromethy~ 17a-ethoxycarbonyloxy-11~-hydroxyandrost-
4-en-3-one-17~-carboxylate ~or 20 milligrams of a more
potent compound of the invention such as chloromethyl 9a-
fluoro~ -hydroxy-17a~isopropoxycarbonyloxy-16~-
25 ~ethylandrosta~1,4,-dien-3-one-17~-carboxylate or chloro-
methyl'9a-fluoro-11~-hydroxy-16a-methyl-17a-propoxy-
carbonyloxyandrosta-1,4-dien-3-Qn,e-17~-c,arboxy,late) k~
rDlusO~bc~ atr6~ ma~ J
, together with sodium chloride, po~yLorbato 80~and from 1
; to 6 ounces of water (the water being added shortly
before use). The suspension can be administered as a
retention enema or by continuous drip several times weekly
in the treatment of ulcerative colitis.
Other pharmaceutical formulations according to
,

tL 174667
,~
~ 6
,,~
the inYention are illustrated in tne examples which follow.
Without further elaborat~on, it is believed
that one of ordinary skill in the art can, using the
preceding description, utilize the present invention to
its fullest extent. Therefore,~the following eYamples
are to ~e construed as merely illustrative and not
limitative of the remainder of the specification and
clzims in any way whatsoever.
; '
,
.,~ ' ,' ' ~ , ;,

1 174667
, 6l
EX~PLE I
To a solution of hydrocortisone (15 grams, 0.04
mol) in 120 milliliters of tetrahydrofuran and 30
milliliters of methanol at room temperature is added a
warm (approximately 50C) solution of sodium metaperiodate
~25.7 grams, 0.12 mol) in 100 milliliters of water). The
reaction mixture is stirred at room temperature for 2
hours, then is concentrated under reduced pressure to
remove the tetrahydrofuran and methanol. The solid is
triturated with 50 milliliters o~ water, separated by
filtration, washed with water and dried in vacuo at 50C
for 3 hours. The product, 11~,17-dihydroxyandrost-4-
en-3-one-17~-carboxylic acid ~i;e., cortienic acid),
melts at 231-234C, is obtained in approximately 96%
yield (13.76 grams), and can be represented by the
structural formula
OH
C=O
HO ~ - - OH
~ .
,~
EXAMPLE 2
To a cold solution of 1~,17a-
dihydroxyandrost-4-en-3-one-17~-carboxylic acid (5%
weigh~/vo1ume: 1 mol) end triethylamine (4 =ol~ in
.
. ' :

1 174667
6~
'~.i ~
dicholormethane is added a 50~ ~weight/Yolume) solution
of methyl cnloroformat~ ~3.9 mol) in dichloromethane.
The reaction mixture is allowed to warm to room temper-
ature over a 2 hour period. The triethylamine hydro-
chloride precipitate whic~ forms; is removed ~y filtrationand the filtrate is wasned successively with 3~ sodium
bicarbonate, dilute (-1~) hydrochloric acid and water.
The organic layer is separated, dried with magnesium
sulfa.e, and filtered. The filtrate is concentrated in
1~ vac-lo to a foam. The foæm is used in the next step
te.g., E~ample 3 below) or chromatographed and crystal-
lized for analysis. The product, ll~-hydroxy-17a-
methoxycarDonyloxyandrost-4-en-3-one-17~-car~oxylic acid,
melts at 198-204C after chrom2tosraphy and
15crys.allization; ir ~KBr) 3000-2800 ~C-H), 1750, 1735,
1720 ~C-O), 1650, 1640 CC=C-C=O)cm 1, The product
can be represented by the structural formula
OH
~ ~ 3
0~
Substitution of an equi~alent quantity of ethyl
chloroformate for the methyl chIoroformate employed a~ove
and substantial repetition of the for~going procedure
af,ords 17G-ethoxycarbonyloxy-ll~-hydr~Yyandrost-4-en-3-
one-17~-carbo~ylic acid, melting at 192-195C after
chromatography and crystallization; ir tKBr) 3500
(ll~-O_H), 3000-2800 (C-H), 1740(C=O), 1630_

~ 174667
~C=C-C-O)cm l; nmr(C3C13) ~6.4~1, b, CCOH), 5.67(1,s,
~_C~), 4.43 (l,b, C~O~), 4.13 ~2, ~, J=7.5~z, OC~2C~3);
Anal. calcd. for C23~3207: C, 6;.69; ~, 7.67. Found: C,
6;.76; H, 7.74.
In a similar manner, substitution of an
equivalent quantity of butyl chloroformate for the methyl
chloroformate employed in the first paragraph of this
ex2mple and substantial repetition of the procedure there
detailed affords 17-butoxycarbonyloxy-11~-hydroxyandrost-
4-en-3-one-17~-carboxylic acid. The final product, after
crystallization from tetrahydrofuran-hexane, melts at
164-166C.
Similarly, substituting an equivalent amount
of isopropyl chlorofo-rmate f~r the methyl chloroformate
used in the first paragraph of this example and repeating
the procedure there detailed affords ll~-hydroxy-17a-
isopropoxycarbonyloxyandrost-4-en-3-one-17~-carboxylic
acid. The final product, after crystallization from
tetrahydrofuran-hexane, melts at 144.5-146.5C.
EXAM~LE 3
ll~ ydroxy-17a-methoxycarbonyloxyandrost-4-en-
3-one-17B-carboxylic acid is combined with an e~uivalent
amount of lN sodium hydroxide in methanol and that
soiution is diluted to 100 times the original volume with
ethyl ether. The suspension which results is refrigerated
for 1 hour. Then, the crystals which form are removed by
filtration, dried in an evacuated desiccator, and
dissolved in hexamethylphosphoramide ~10~ weight/volume).
A portion of the resultant solution containing 1 mole of
the acid salt, i.e. of sodium 11~-hydroxy-17a-
metho~ycarbonyloxyandrost-4-en-3-one-17B-carbo~ylate, is
combined with 4 moles of chloromethyl iodide. The

1 174667
reaction mixture is maintained at room temperature for
3 hours, then is diluted to 10 times the original ~olume
with ethyl acetate. The diluted reaction mixture is
washed successively with 5% sodium t~iosulfate, 3% sodium
5 bicarbonate, and water. The organic layer is separated,
dried with magnesium sulfate and filtered. The filtrate
is concentrated in vacuo to a foam. The foam is purified
by crystallization from a suitable solvent (ethyl ether
or tetrahydrofuran/hexane). There is thus obtained
10 chloromethyl 11~-hydroxy-17a-methoxycarbonyloxyandrost-4-
en-3-one-17~-car~oxylate, melting at 171-173C after
crystallization; ir(XBr) 3000-2800tC-H), 1760, 1748(C-O),
1650~C=C-C-O)cm l; nmr (CDC13)~ 5.67~s,~1, C=CH), 5.82,
5.62 (ABq, J=5.5Hz, 2, OC~2Cl), 4.47(b, l,:C~OH); Anal.
15 calcd. for C23H31ClO: C, 60.72; H, 6.87; Cl, 7.79.
Found: C, 60.50; H, 7.06; Cl, 7.50. The product is
characterized by the structural formula
OCH2
C=O
~O ~ - -O~O~3
Substitution of an equiYalent quantity of 17a-
20 ethoxycarbonylaxy~ hydroxyandrost-4-en-3-one-17g-
carbo~ylic acid for the steroidal acid employed abo~e and
substantial repetition of the foregoing procedure affords,
as t~e intermediate salt, sodium 17a-ethoxycarbonyloxy-
.; - .

~, 11~4B6
.. 6~
llB-hydroxyandrost-4-en-3-one-17B-carboxylate, and, as
the final product, chloromethyl 17a-ethoxycarbonylo~y-
llB-hydroxyandrost-4-en-3-one-17B-car~o~ylate, melting at
197-200C after crystallization; ir ~KBr) 3600-3200
~O--d), 3000-2800(C-H), 1763, 1740~C-O), 1650(C=C-C_O)cm l;
S nmr (CDC13)~ 5.7(s, 1, C=C~), 5.81, 5.62 (ABq, J=5~z, 2,
-OCH2Cl); Anal calcd. for C2aH33C1O7: C, 61.46; H,
7.09. Found: C, 61.58; H, 7.08.
In a similar manner, substitution of an
equivalent quantity of 17-butoxycarbonyloxy-llB-
hydroxyandrost-4-en-3-one-17~-carboxylic acid for the
steroidal acid em?loyed in the first paragraph of this
example and subs.antial repetition of the procedure there
detailed affords, as the intermediate salt, sodium 17-
butoxycarbonyloxy-llB-hydroxyandrost-4-en-3-one-17~-
carboxylate, and, as the final product, chloromethyl17~-butoxycarbonyloxy-11~-hydroxyandrost-4-en-3-one-
17B-carboxylate, melting at 98-100C after crystallization;
ir(KBr) 3600-3300 (O-H), 3000-2800 ~C-H~, 1765 (O2C-O),
1735 (OC-O), 1650 (C=C-C=O)cm l; nmr~CDC13)~5.80, ~5.60
~2,ABq, J=4.5Hz, -OCH2Cl), 5.67 (1, s, C=C~), 4.45 ~1, b,
C~O~), 4.08 ~2, t, J=6Hz, O2COC~2-C~2); Anal calcd. for
C26H37ClO7: C, 62.77; H, 7.44; Cl, 7.14. Found: C,
62.88; H, 7.23; Cl, 7.30.
Similarly, substituting an e~uivalent amount of
llg-hydroxy-17a-isopropoxycarbonyloxyandrost-4-en-3-one-
17~-carboxylic acid for the steroidal acid employed in the
first paragraph of this e~ample and substantial repetition
of the procedure there detailed affords, as the
intermediate salt, sodium llB-hydroxy-17a-
isopropoxycarbonyloxyandrost-4-en-3-one-17~-carboxylate,
and, as the final product, chloromethyl ll~-hydroxy-17a-
isopropoxycarbonyloxyandrost-4-en-3-one-17~-carboxylate,
melting at 183.5-184.5C after recrystallization from
tet=ahydrofuran-hexane.
:' .
. .

1 17466~
In a similar manner, an equivalent quantîty of
17~-ethoxycarbonyloxy~ -hydro~yandrost-4-en-3-one-
17B-carboxylic acid is substituted for the steroidal acid
and an equi~alent quantity of ~utyl chloride is
substituted for the chlorGmethyl iodide employed in the
first paragraph of this example; and the procedure there
detailed is substantially repeated, except that the step
of washing with 5~ sodium thiosulfate is eliminated.
Obtained in this manner are the intermediate salt, sodium
17-ethoxycarbonyloxy-llB-hydroxyandrost-4-en-3-one-
17B-carboxylate, and the final product, butyl 17~-
ethoxycarbonyloxy-llB-hydrQxycmdrost-4-en-3-one-17~-
carboxylate. The final product after crystallization
from acetone melts at 148-149C; after chromatography
and crystallization, ir ~Br) 3600-3200~0-H), 3000-
2800 ~C-H), 1750 (2 C-O), 1670 ~C=C-C--O)cm l; nmr
~CDC13) ~5.64(s, 1, -C=CH), 4.46 Ub, l, CHOH),
4.32-4.95 ~m, 4, COOC~2CX3+, COOCH2C~2-); Anal. calcd.
for C27H40O7: C, 67.99; H, 8.39. Found: C, 67.76;
~, 7.74.
EXAMpT~ 4
17-EthQxycarbonyloxy-ll~-hydroxyandrost-4-en-
3-one-17~-carboxy-ic acid ~3 grams, 7.13 mmol) is treated
with 7.13 milliliters of lM methanolic sodium hydroxide
solution, and 500 milliliters of ethyl ether are then
added to effect precipitation. The precipitate is
separated by filtration and dried in an evacuated
dessicator overnight to afford 2.71 grams (6.12 mmol) of
the desired salt, i.e. sodium 17~-etho_ycarbonyloxy-llB-
hydroxyandrost-4-en-3-one-17B-carboxylate, as a yellow
powder. The salt is dissolYed in 40 milliliters of
hexamethylphosphoramide and chloromethyl methyl sulfide
~2.36 grams, 24.5 mmol) is added slowly. A precipitate

1 174667
C. 6f/
of sodium chloride forms in the reaction mixture within 1
minute. The reaction mixture is stirred at room
temperature for 1 hour, then is diluted with ethyl
acetate to a total ~olume of 200 milliliters and washed
successiYely with 3% sodium bicarbonate and water. The
organic layer is separated, dried with magnesium sulfate
and filtered. The filtrate is concentrated in vacuo to
an oil, and the oil is chromatographed from silica gel,
using ethyl acetate, chloroform and acetic acid as
eluants. The chromatographed product is crystallized
from a mixture of ethyl ether and hexane to give white
powdery crystals of methylthiomethyl 17G-
ethoxycarbonyloxy-ll~-hydroxyandrost-4-en-3-one-17~-
carboxylate, melting at 133-136C. That product is
characterized by the structural formula
IC~2SC~3
C=O
~30 ~- -O~OC2115
o~ V
T~ a solution of methylthiome~yl 17a-
ethoxycar~onylo~y-ll~-hydroxyandrost-4-en-3-one-17B-
c-~rboxylato ~0.48 gram,l mmol) in 2 millilite-s of
dichloromethane is added m-chloroperoxybenzoic acid
~0.4 gram o 0~34 gram of peracid, 2 mmol). An exothermic
react~on ensues, ~hich subsides quic~ly. The reaction
mi~ture is stirred at room temperature for 1 hour. The
r '
.

~ 174667
;`.
,. 6g
precipitate which forms is removed by filtration and the
.... .
filtrate is concentrated in vacuo to afford~ as a white
foam, methylsulfonylmethyl 17~-ethoxycarbonyloxy-llg-
hydroxyandrost-4-en-3-one-17~-carboxylate. That product
has the structural formula
~CH2S02CH3
C=O
HO ~ - -O~OC2H5
~ .
0~
NMR ~CDC13): ~5.07 (s, 2, OCH2S02), 2.~7 (s, ~, S02CH3).
Repetition of the procedure described in the
preceding paragraph, but using only 1 mmol of m-
chloroperoxybenzoic acid, affords methylsulfinylmethyl
17~-ethoxycarbonyloxy-11~-hydrQ~yandrost-4-en-3-one-17B-
carboxylate.
ExAMæLE 5A
Substitution of an e~uivalent quantity of one
of the starting materials listed below for the
hydrocortisone used in Example 1 and substantial
repetition of the procedure there detailed affords the
indicated products:
; . ' :

1 17~667
, ' C i 6~
_ ~ _
STARTING MATERIAL PROD~CT
fludrocortisone 9-fl~oro~ ,17~-dihydroxy-
androst-4-en-3-one-17~-
car~oxylic acid,
m.p. 250-253~C
betamethasone 9a-fluoro-11~,17~-dihydroxy-
16~-methylandrosta-1,4-dien-
3-one-173-car~oxylic acid,
m.p. 248-249~C
dexamethasone 9a-fluoro-11~,17-dihydroxy-16a-
methylandrosta-1,4-dien-3-one-
17~-carboxylic acid,
m.p. 275-278~C
EXAMPLE 5B
Substitution of an equivalent quantity of one
of the starting materials listed below for the
hydrocortisone used in Example 1 and s~bstantial
repetition of the procedure there detailed affords the
indicated products:
STARTING MATERIAL PRODUCT
cortisone 17 ~hydroxyandrost-4-en-3,11-
dione-17B-car~oxylic acld
chloroprednisone 6a-chloro-17a-hydroxyandrosta-
1,4-dien-3,11-dione-17~-
` 25 . carboxylic acid
flumethasone 6a~9a-difluoro-ll~ll7a-dihydroxy-
16a-methylandrosta-1,4-dien-3-one-
17~-carboxylic acid
fluprednisolone 6a-fluoro-11~,17a-dihydroxy-
androsta-1,4-dien-3-one-17~-
carboxylic acid
meprednisone 17a-hydroxy-16~-methylandrosta-
1,4-dien-3,11-dione-17~-
; carh~Yylic acid
methyl prednisolone 11~,17a-dihydroxy-6a-methyl-
androsta-1,4-dien-3-one-17~-
carboxylic acid
' " :
., j . ~. - : : ,

- ~ 174~6~
~;
.. ~o
STARTI~& MATERIAL PRODUCT
paramethasone 6a-fluoro-llB,17~-dihydroxy-16a-
methylandrosta-1,4-dien-3-one-
17~-carboxylic acid
prednisolone 11~,17a-dihydroxyandrosta-1,4-
dien-3-one-17~-carboxylic acid
prednisone 17~-hydroxyandrosta-1,4-dien-
3,11-dione-17~-carboxylic acid
triamcinolone 9a-fluoro-llB,16~,17~-trihydroxy-
androsta-1,4-dien-3-one-17~-
carboxylic acid
EXAMPLE 6A
Following the general procedure of Example 2
and substituting therein the appropriate reactants affords
the following novel intermediates of the present
invention:
H
C=O
'~,e= ~COOR~
R5

1 17466~
,i, I ~/
~ ~U~ U~ U ~D
'~1 ~r ~r ~. ~i _i' ~r ~_~ ~ ~_1` ~ . _1'
~1 S PC j\U, \~,~' I \U~ - ~ ~ / lO\~u\F ~F -o\ ,: \u~ ~u~
, ~;1 ~: ss ~ ~ ~ ~ 5 ~, :C : :
: ~t :~ ~ ~ ~ ~ s ~ c ~ ~ ~
~ ~ ~.- ~, ~ ~ ~U` ~ ~u~
i ~ ~ ' ,~ C ~s
.

-
1 17466
1~
.~g
.
~ ~,~ ~,~
~1 ~ x co x x ~ ~ x
~1 u~ ~ ,, ~ I h G~ ~
~ ~ ~ ~ a~
5~1~ 0\~5 ~U~

117466
~3
Compounds 6A-1 to 6A-ls above can be named as
follo~s: .
6A-1: 17~-benzyloxycarbonyloxy~ -hydroxyandrost-4-en-
3-one-17~-carboxylic acid
6A-2: 17a-ethoxycarbonyloxy-9~-fluoro-11~-hydroxyandrost-
4-en-3-one-17B-car~oxylic a-cid
6A-3: 17a-ethoxycarbonyloxv-9a-fluoro-11~-hyaroxy-16~-
methylandrosta-l~4-dien-3-one-l7~-carboxylic acid
6A-4: 17a-ethoxycar~onyloxy-9a-fluoro-ll~-hydroxy-l6a-
methylandrosta-1,4-dien-3-one-17~-carboxylic acid
6A-5: 9a-fluoro-11~-hydroxy-17a-is~propoxycarbonyloxy-
16a-methylandrosta-1,4-dien-3-one-17~-carboxylic
acid
6A-6: 11~-hydroxy-~7a-isobutoxycarbonyloYyandrost-4-en-
3-one-17~-carboxylic acid
6A-7: 9a-fluoro-llB-hydroxy-17a-isopropoxycarbonyloxy-
16~-methylandrosta-1,4-dien-3-one-17~-carboxylic
acid
6A-8: llB-hydroxy-17a-propoxycarbonyloxyandrost-4-en-3-
one-17~5carboxylic acid
6A-9: 9a-fl~oro~ hydroxy-l6a-methyl-l7a-
propoxycarbonyloxyandrosta-1,4-dien-3-one-17~-
carboxylic acid
6A-10: 17a-cyclohexyloxycarbonyloxy-llB-hydroxyandrost-4-
en-3-one-17~-carboxylic acid
6A-11: 9a-fluoro-11~-hydroxy-17~-methoxycarbonyloxy-16-
. . . . . . . methvlanarosta-1,4-dien-3-one-17~-carboxylic acid
6A-12: 17a-n-pentyloxycarbonyloxy-9a-fluoro-11~-hydroxy-16a-
methylandrosta-1,4-dien-3-one-17~carboxylic acid
30 6A-13: 17a-ethoxycarbonyloxy:6,9a-difluoro-11~-hydroxy-16-
methylandrosta-1,4-dien-3-one-17~-carboxylic acid
: 6A-14: :17a-phënoxycarbonyloxy-9a-fluoro-11~-hydroxy-16a-
methylandrosta-1,4-dien-3-one-17~-carboxylic acid
6A-15: 17a-(2-chloroethoxYcarbonyloxY)-9a-fluoro-ll~-hydroxy-
16a-methylandrosta-1,4-dien-3-one-17~-carboxylic acid
EXP~PLE 6B
Following the general procedure of Example 2 and
substituting therein the appropriate reactants affords the
following novel intermediates of the present invention:
.: .
, ~
. . ,

--- 1 174667
... ..
i~
. ~
f
~ ~OOR2
o
R
Com~ound No. R R R R Z
q ~ - 1 ~ ,
6B-l C2H5 ~ - ~ ~ ,C - O 4
6B-2 CH3 H. H H ,C - O 4
6B-3 CH3 H F H ,C~ 4
6B-4. C2H5 ~ -CH3 F F C ~ 1,4
`H
6B-5 C2H5 B H F ,C~ 1,4
6B-Ç C2H5 ~-C~3 ~ . `C - O 1,4
6B-7 CH2CC13 ~ ~ E ,C ~ 4
6B-8 C2~5 -C~3. H F ,C ~ 1,4
OH
; 6B-9. C2H5 H ~ ~ 1,4
6B-lQ C2H5 ~ ~ ~ `C = O 1,4
- ...
'
'
.

J 1 174667
., ~
Compound No. R2 R3 ~4 R5 Z ;~
6B-ll C2H5 a-OCOOC2H5 F H ~C~ 1,4
6B-12 2 a-CH3 F H ~C~OH 1,4
6B-13 CH2CH2Cl -CH3 F H ~C~ 1,4
6B-14 C2H5 H H Cl ~C = O 1,4
~ /OH
6B--15 C6H5 H H H ~C~ 4
6B--16 {¦ H H H ~C 4
`H
6B-17 ~ H H H ~C~ 4
OH
' 6B-18 CH=CH2. H H H ~C~ 4
6B-l9 CH2OCH3 H H H `C~OH 4
OH
6B-20 CH2SCH3 H H H `C~ 4
OH
6B-21 CH2CH2NHCOCH3 H H H ~C~ 4
OH
6B--22 CH2CH2OCOCH3 H H H ~C~, 4
6B--23 C2H5 3 ~ ~H 1,4
OH
6B--24 CH2SO2CH3* H H H ~ ~H 4
OH
6B-25 CH2SOCH3* H H H ,C~ 4
*prepared from 6B-20 by subsequent reaction with m-
chloroperbenzoic acid.

1 174667
r
~,~ rj~?
EXAMP~E 7A
Following the general proc dure of Example 3 and
substituti~g therein the appropriate reactants affords the
following compounds:
IR
,~ OCOOR2
S ~ 3
O
R5

1 174667
. - .7~
_
Ck~nGu~d ~o . . R~ R~ R - . . . z . . . ~ : m.D. .
_- ............... ~ l ~ _
7Ar1 C~2Cl C2~5 ~ F ~ ,C~ 4 228-229C
. , , .. ...... ,... ........ ..... .... .. . .. ~ ..... ~q~
_ _ . _
7A-2 ~Cl c2~B.~ FH ,C~ 1,4 220 - 221C
. ......... .. _ ~I ~
7A-3 C~2Cl C~5a-C~3 FH ~C~ 1, 230 - 235C
_ ~ (~)
7A-4 CH2Cl CzH5 ~ HH ,C~ 1,4 æo .5-223.5C
. ~ ~
CE~
7Ar5 ~Cl iso-C~7 ~ H H C~ 1, 197-198C
. , .......... ,... _ ~ (~IF~xane)
7~6 . C~Cl CzH5 H . . F H C~ 1,41 24S-248C
_ (1~/}~)_
7A-7 ca2cl igo-c3~7 a-C~ F E ~C~ 1, 4 184.5 - 186 C
- 3 ~ (l9F/kY~Y2ne)
7A-8 C~Cl iSo-C~7 B~C~3 F H C ~ 1,4 174-175.5C
. ~ (5~IF)
7A-9 CE~2Cl iso-C Hg H EI H C~ 4 140-141C
4 ~H (~F/i5ap~y
. . . ...... ....... ,. .. . _ ~ e~r)
7A-10 .~Cl ~ H H H ~C~ 4 148-150C
. : .... _ e~
C~I
7A-11 ~2Cl. .~C ~I7 .. .E .. .~ ~I. ~C~... 4 181-182.C
....... . ...... 3 . . ~ . ~. (~/~nc~
7~A--12 ~ C~I2Cl n~ ~ ~I3 F }I ~C~ . . 1,4 ~176--176.5C
. .. ... . . . ............ ~ (qXF/~
-71~13 .. c~ . iso-C3~;~ . H ~ H ~ 4-. ~11"5-213.5C
. .... .3 . . ~ (l~3F/he~et
7Arl4 CE~20C2H~; i5c~-C3~ ~ . H ,~ 4 137--138C
.. .''. ,.'',.' ,.,.. ':.. ' .''.''. '.'. ....... ~;' . :'~F~e~e~'
7~15 ~2Cl . ~ .. ~ . ~. ~I C~ 4 . 182-i83e
. ~' . . _ ~I _ (e~l)
... .
_, ... . .

~ 174667
.
.. . ~iY
_ .~
. ~cmcound No. ~ ~ ~ R~ R Z -- m.p. ,
7~r16* C~3iso-C ~ ~ H H~ 4 181-182.5C
. G~:l . ~ ~I~IF/~)
. .... 1 3 ... ¦ i~o-c ~ . .. ~..... H H ,~ 4 195-200C
,. . .... . ~ 1: . .,. . . . .. I ~ ...... ~
.. 7A D ~2CI~2C2~5-- E U C~ 4 ____
7A-18* 1 3 iso-C ~ ~-C~3 F H ,C~ 1,4 167.5~169C
C~Cl 'H ~IffF/kexane)
c~3 ~ ~a
l iso-C ~ ~-C~3 F H ~ 1,4 163-164C
. ........ '~C~ . .... .. . I ~ .......... (IXF/~ne)
7A-l9 ~ ~-C~3 F H - 1,4 ~00-2 C
. . ... . _ _ _ PrCpyl et~r
7~,20 C~2Cl C2H5 ~-C~3 F H ~ 1,4 138-140C
1 ether
~ _ P~Y
7A-21 a2Cl C~ ~-C~ F H C~ 1,4 260-263C
3 3 . ' ~H (T~F/hexane)
7A-22 C ~ iso-C3H7 H ~ H ,C~c~ 4 2a7.5-210C
. ~a (T~F/h~ ne)
7A-23 C~2Cl n-C ~ o-Ca3 F ~ H - -ca 1,4 176-177C
. ..... _ ~ ~l~F~hexzne) .
7A-24 2 1 C ~ ~ H F C~ 1,4 15~-154
~ I , ~ (q~l?/~ex~ne)
: . ...... ... .. .. C2H
. ~A,25 . . ~ . C2 ~ ~ F H ; ~ 1,4 ~239-240.5C .
................. ...... ~...... ~F~e)
7Ar26 2CCOC~3 C2~ ~ H H ,C~ 4 N~M5.R(6C~s,~)
. OC~2O), 2.01
. ::.. . . . .......... _ ~s-,3~ COC~3)
* ~ias~ ,,

`` 1 174667
t~,
Compourld Rl ~ R2 ~ R3 ¦
\ /OH
7A-27 CH2Cl C2H5 -CH3 F F C 1,4 195-197C
_ / ~H (THF/hexane)
\ /OH
7A-28 CH2CH2Cl C2H5 a-CH3 F H C 1,4 243 245C
/ ~H (THF/hexane)
.';',~; _ \/~ _
I 7A-29 CH C2H5 a-CH3 F H C 1,4 258.5-262.5C
3 _ _ / ~H (THF/hexane)
7A-30 CH2CH2Cl iso-C H H H H C 4 188.5-189.5C
3 7 _ / ~H = (THF/hexane) .

7~67
- c
The foregoing compounds can be named as follows:
7A-l: chloromethyl 17a-ethoxycarbonylQxy-9a-fluoro-llB-
hydroxyandrost-4-en-3-one-17B-carboxylate
7A-2: chloromethyl 17a-ethoxycarbonylQxy-9a-fluoro~
hydroxy-16~-methylandrosta-1,4-dien-3-one-17~-
carboxylate
7A-3: chlom methyl 17a-ethoxycarbonyloxy-9a-fluoro-11~-
hydroxy-16a-methylandrosta-1,4-dien-3-one-17~-
carboxylate
10 7A-4: chloromethyl 17a-ethoxycarbonyloxy-11~-hydroxy-
androsta-1,4-dien-3-one-17~-carboxylate
7A-5: chloromethyl 11~-hydroxy-17a-isopropoxycarbonyloxy-
androsta-1,4-dien-3-one-17~-carboxylate
7A-6: chloromethyl 17a-ethoxycarbonyloxy-9a-fluoro-11~-
hydroxyandrosta-1,4-dien-3-one-17~-carboxylate
7A-7: chloromethyl 9a-fluoro-11~-hydroxy-17a-
isopropoxycarbonyloxy-16a-methylandrosta-1,4-dien-
3-one-17~-carboxylate
7A-8: chloromethyl 9a-fluoro-11~-hydroxy-17a-isopropoxy-
carbonyloXy-16~-methylandrosta-1,4-dien--3-one-17~-
carboxylate
7A-9: chloromethyl 11~-hydroxy-17a-isobutoxycarbonyloxy-
androst-4-en-3-one-17~-carboxylate
7A-10: chloromethyl 17a-cyclohexyloxycarbonyloxy-11~-
hydroxyandrost-4-en-3-one-17~-carboxylate
7A-ll: chloromethyl ll~-hydroxy-17a-propoxycarbonyloxy-
androst-4-en-3-one-17~-carboxylate
7A-12: chloromethyl 9a-fluoro-ll~-hydroxy-l6a-methyl-l7a
propoxycarbonyloxyandrosta-1,4-dien-3-one-17~-
carboxylate
7A-13: methyl 11~-hydroxy-17a-isopropoxycarbonyloxyandrost-
4-en-3-one-1.7~-.~arbo~ylate
7A-14: ethoxymethyl 11~-hydro~y-17a-
isopropoxycarbonyloxyandrost-4-en-3-one-17~-
carboxylate
7A-15: chloromethyl 17-benzyloxycarbonyloxy-llB-
hydroxyandrost-4-en-3-one-17~-carboxylate
7A-16: l-chloroethyl 11~-hydroxy-17a-isopropoxycarbonyloxy-
: androst-4-en-3-one-17B-carboxylate
7A-17: ethoxycarbonylmethyl 11~-hydro~y-17a-isopropoxy-
carbonylQxyandrost-4-en-3-one-17~-carboxylate

1 17~667
7A-18: l-chloroethyl 9a-fluoro-11~-hydroxv-17a-
isopropo~ycarbonyloxy-16B-methylandrosta-1,4 -
dien-3-one-17B-carbQxylate
7A-~l9: chloromethyl 9a-fluoro-17a-isopropoxycarbonyloxy-
16~-methylandrosta-1,4~dien-3,11-dione-17 -
carboxylate
7A-20: chloromethyl 9a-fluoro-17a-isopropoxycarbonyloxy-
16~-methylandrosta-1,4-dlen-3,11-dione-17 -
carboxylate
10 7A-21: chloromethyl 9a-fluoro-11~-hydroxy-17a-
methoxycarbonylo~y-16a-methylandrosta-1,4-dien-
3-one-17~-carboxylate
7A-22: fluoromethyl llB-hydroxy-17a-isopropoxycarbonyl-
oxyandrost-4-en-3-one-17~-carboxylate
15 7A-23: chloromethyl 9a-fluoro-llB-hydroxy-16a-methyl-
17a-pentyloxycarbonylo~yandros~a-1,4-dien-3-one-
17~-carboxylate
7A-24: chloromethyl 16a,17-di~ethoxycarbonyloxy)-6a-
fluoro-ll~-hydroxyandrosta-1,4-dien-3-one-17B-
carboxylate
7A-25: fluoromethyl 17a-ethoxycarbonyloxy-9a-fluoro- 11~-
hydroxy-16a-methylandrosta-1,4-dien-3-one-17B-
carboxylate
7A-26: acetoxymethyi 17a-ethoxycarbonyloxy-11~-hydroxy-
androst-4-en-3-one-17B-carboxylate
7A-27: chloromethyl 17a-ethoxycarbonyloxy-6,9a-difluoro-
llB-hydroxy-16a-methylandrosta-1,4-dien-3-one-17~-
carboxylate
7A-28: 2-chloroethyl 17a-ethoxycarbonyloxy-ga-fluoro-llB
hydroxy-l6a-methylandrosta-l~4-dien-3-one-l7B
carboxylate
7A-29: methyl 17a-ethoxycarbonyloxy-9a-fluoro-11~-hydroxy-
16a-methylandrosta-1,4-dien-3-one-17~-carboxylate
7A-30: 2-chloroethyl 17a-isopropoxycarbonyloxy-11~-hydroxy-
androst-4-en-3-one-17~-carboxylate

f~ ` 1 1746~7`
EXAMPLE 7B
, Following the gene~al procPdure of ExamDles 3 or
4 and subs~ituting therein the appropriate reactants
affords the following compounds:
OR
I
H3C f -
~ OCOOR2
~ R3

.. .. . ... , . , _ . .. .. . ... . . ....
.. . . . .. ... ....

1 17466~ .
.. ~3
,~ _
- R~ R; _ ~-- ~H ~--
. 7B-1 C2H5 2 5 H H . `~ 4 .
7B-2 C4H9 CHzC6H5 H H H ~C~ 4
7B-3CH2~CC2.L.; CzH5 H H H ,C~ 4
7B-4 CH2~3 C2H5 H R H `~C ~{H 4
7B-5 CH2Cl C6H5 . H H H ~--C~H 4
/ . ~OEI _
7E~6CE12U ~1 _ ~1 . H ~C~ 4
7B-7 CH2Cl C6ZS ~3 _ a H ~C~ ~H 4
7B-8 C4Hg CZH5 _ 3 H ,C = O 4
7B gCH2Cl Cl}3 _ _ H ,C = O 4
C132CL CZH5 iI 3 H ,C = O 4
7B-llC~2SC63 C2E~5 }~ ~ ~! X = O 4
7B-12CE12SO. 2CH. 3 . C2~5 N 11 H `C = O 4
~13C~.2SC~3 C2~5 H _ H `C-- O 4
.. . 7B-14 ~2CL C~3 _ H ,C~ 4
7B-15~2SCH3 . C.2H.5- . ~ --- F EI : ,C~ ~ 4
. .

1 174667
~,,., ~_
~mDol~nd Nb. R~ R_ R~ R R_ z
1 ~ _ ~
7B~16 CH2S32CH3 C2~ H F H `,C ~ 4
" .............. .... : : , . '
7B-17 CH2SCH3 C2H5 B-C~3 F H ,C ~ 1,4-
. .......................... . . - . H
7B-18 CH2SO2CH3 C2H5 3 F H ,C~ ~1,4 .
7B~l9 CH2Cl C2H5 H H Cl ,C = O ¦1,4 .
7B-20 2 3 C2H5 H H Cl ~C = O I .1,4 .. : . .
7B-2L CH2902CH3 C2H5 H H Cl ,C = O L,4
. OH
7B-22 CH2SCH3 ~ 5 F H ,C~ 1,4
7B-23 CHzS02CH3 C2H5 1 3 F H ~ ~ ~ 1,4
7B-24 CH2Cl C2H5 I--C~3 F F ~C ~ 1,4
7B-25 CH2SCH3 C2H5 I-C;33 F F ,C~ 1,4
7B~26 2 2 3 C2H5 1 3 F F ,C ~ 1,4.
7D~n CHzCl CZ 5 3 H F ~ ~ 3 L,4 .
7B-28 CH2SCH3 C2H5 H H F ,C~ 1,4
7E-29 CH2S02CH3 C2 5 H F ~C ~ 1,4
... ....... .. .. . .... .... . . ...... . . . H ..
7B-30 CH2Cl C H ~-CH3 H H ,C = O 1,4
.. . . . ... 2.5 ........ .._ .
7B-31....... C~2CCH3 ... C2H5 ~ 3 H .. H ,C = O . 1,4 .
_
7B~32 . CzH B-CH H H ~ _ o 1,4 ... . .
- 2.. . ~ 3. I l
. ~ , , .

-- 117466~
~al~ound No. . R R, ~ -
. . _ _ ~ ~OH
7.~33 C~2Cl C2~i ~ E~ C~3 ,C~ 1,4
.. .. ~H
7B-34 CH2SCH3 . C. 2H5 H H C~3 . ~ ~ 1, 4
7B-35 CH2502CH3 C2H5 H H C~3 ,C~ 1,4
_ _ ~
7B-36 CH2Cl ~5 ~CH3 H F ,C 1,4
7~37 CH2SCH3C2H5 ~CH3 H F ~ ~ 1, 4
7B 38 CH2S02C~I3 CZH5 ~CH3 H F ~(YI 1, 4
7B-39 CH2SCE~3C2H5 H H ~C-~H 1, 4
7B-40 CH2S02CH3 C2H5 H H `C~. 1, 4
7B-41 CH2Cl C2H5 H H 1~ ,C = O 1, 4
7B-42 CH2SCH3C2H5 H H ,C = O 1,4
7B-43 CH2S02CH3 C2H5 H H H ,C = O 1,4
7B-44 CH2Cl C2H5 ~ C2H5 F li ,C ~li 1, 4
7B-45 C~,12SCH 3 C~5 ~2H5 F II ,C~ 1,4
. 7B-46 CH2S02CH3C2H5 ~-CCCCC2H5 F H ,C~HH 1, 4
. .7B..4?.. . c--~--c~5 - .l~ _ F ,C,~ON 1,4
7B-48 C~2Cl ~ a-CH3 F H ,,C~ 1,1
.... .... . .... .. . ....... . ~H
.i _ ~.
~49 CH2ClCH2CH2Cl-CX, F H c~i 1 4
~, . : .: .. .... .. _ ~H
~50 C~13 CH2Cq ........ - F _ `,C~ 1, 4
'
.~ .
.

1 17i~667
. Ccm~ound No. Rl I R~ R, R~ R, Z _
~ ~OH
7E-51 C4Hg CH2CC13 H H H ~C~H 4
OH
7E-52 CH2OON(CZH5)2 C2H5 H H H ,C~ 4
__ _ O~I
7B-53 CH2CON CH3 H _ H ,C~ 4 .
. 7B~54 C6H5 C2H5 H H H ~C ~ 4
. _ OH _ .
7B-55 CH2C6H5 CH3 H H H ~C~H 4
S OE~ .
7B~56 ~ C2H5 H H H `,C~ H 4
OH
7B-57 CH2Cl' ~ H H _ ~C ~ 4
7B~58 CH2Cl CH=CH2 H H H `C ~HH 4
OH
7B-59 CH2Cl CH2CCH3 HH H ~ ~H 4
. . - OH
7B-60 CH2Cl CH2CH2NHCocH3 H H H ,C ~ 4
OH
7B~61 CH2ClCH2cH2ococH3 H H H ,C ~H 4
. _ OH
¦ 7B~62 j 2 3 C2H5 H H H ,C~' 4
'. 1
. .

- ` (~ ` ~ 17466
g7
I a3~ound No ~ j _ _ ~ Z ~
2C~ c 2502C~3 1~ ~ ~¦
7B--64 l CE2Cl CH2~X~3* I ~ H ¦~ ¦ ~C~
* prepared from Example 6B-24 and 6B~25 respectively by
reaction with ClC~2I, or from Example 7B-7 by reaction with
m-chloroperbenzoic acid.

74667
. .
8~ _
EXAMPLE 8
An equivalent quantity of 11~,17-dihydroxy-
androst-4-en-3-one-17B-carboxylic acid is s~bstit1lted for
the ll~-hydroxy-17a-methoxycarbonyloxyandrost-4-~n-3-one-
17~-carboxylic acid starting material employed in Example
3, and the procedure of the first paragraph of that example
is substantially repeated. There are thus obtained, as the
intermediate salt, sodium llB,17a-dihydroxyandrost-4-en-
3-one-17B-carboxylate, and, as the final product,
chloromethyl 11~,17a-dihydroxyandrost-4-en-3-one-17~-
carboxylate, melting at 184-186C ~recrystallization from
tetrahydrofuran-ether-hexane).
EXAMPLE 9
An equivalent quantity of llB,17a-dihydro~y-
androst-4-en-3-one-17B-carboxylic acid is substituted for
the 17a-ethoxycarbonyloxy~ -hydrQxyandrost-4-en-3-one-
17B-carboxylic acid starting material employed in Example
4, and the procedure of the first paragraph of that example
is substantially repeated. There are thus obtained, as the
intermediate salt, soaium 11~,17a-dihydroxyandrost-4-en-
3-one-17B-carboxylate, and,as the final product,
methylthiomethyl llB,17a-dihydroxyandrost-4-en-3-one-
17~-carboxylate.
Substitution of an equi~alent quantity of
methylthiomethyl llB,17a-dihydroxyandrost-4-en-3-one-17B-
carboxylate for the methylthiomethyl 17a-ethoxycarbonyloxy-
ilB-hydroxyandrost-4-en-3-one-17B-carboxylate used in the
second paragraph of Example 4 and substantial repetition
of the procedure there detailed affords methylsulfonylmethyl
llB,17a-dihydroxyanarost-4-en-3-one-17B-carbo~ylate.

- -" 1 174667
., ~
EXA~D?LE lOA
The procedure of each paragraph of Example 2 is
substantially repeated, substituting an equiYalent quantity
of each of the following starting materials for the steroids
5 employed therein: chloromethyl 11~ ,17~-dihydroxyandrost-
4-en-3-one-17~-carboxylate; and methylthiomethyl 11~, 17~-
dihydroxyandrost-4-en-3-one-17 ~carboxylate. The following
soft anti-inflammatory agents of formula ~I) are obtained:
0~
~R2
~5~ "
10o~d No. R, I m.p.
lOA-l CH2Cl CH3 171-173C
10A-2 C~I2Cl C2H5 197-200C~l~/h~ane)
, . .
10A-3 C~2SCH3 C2H5 137.5-138C(etherh~re)
-4 ~ jC4H9 I 99.5-102C(l~F/h~e) i
1aA-5 CE~2Cl 13 7 183.5-184.5C(~IF/h~e)
, _ .
j 10A-6 * CH2Cl iso C~g 1140-141C~?/isopropyl ether)
*utilizing isobutyl chloroformate as the alkyl
chloroformate reactant
........ ~ .. _ _ . .. _ _ .. . . . . .
.
,

I 17466~
C ,9~
EXAMPLE lOB
_ _
The procedure of each paragraph of Example 2
is substantially repeated, substituting an equivalent
quantity of each of the following starting materials for
the steroids employed therein: methylthiomethyl 11~,17a-
dihydroxyandrost-4-en-3-one-17~-carboxylate; and
methylsulfonylmethyl 11~,17-dihydroxyandrost-4-en-3-one-
17~-carboxylate. The following soft anti-inflammatory
agents of formula (I) are obtained.
~Rl
HO ~ - OCOR2
H3C l O
~/
0~ J
Co pound No. R~_
lOB-l CH2SCH3 CH3
lOB-2 CH2SCH3 C4Hg
_
lOB-3 CH2SCH3 3 7
. ,
lOB-4 - CH2SO2CH3 CH3
. ._
lOB-5 CH2SO2CH3 C2H5
.
lOB-6 CH2SO2CH3 C4Hg
_ .___ ._
. lQB-7 CH2502CH3 i-C3H7

- ~ j 1 17466~
ql
Other representatiye speci.es, e.g. compounds
of Examples 7A and 7B, can likewise be prepared according
to the procedures of Examples 8 throl~gh l0.
EXAMPLE 11
The products of Example 2 and Example 6A-4 are
each allowed to react, first with. diethylchlorophosphate
and then with C~3SNa in chloroform for approximately 6
hours. The following intermediates are obtained in the
first step: . 71
10 ~J~,`D`3
R~ R3 R~ ___~ _
CH3 H . H 4
_ _ _
C2H5 H ~ 4
. . _
i C4Hg H _ 4
i-C3H7 H .~ 4
. . a-CH3 F 1,4

1 17~667
,~
and the ollo~ing compounds of formula ¢I) are obtained
in the second step:
SCH3
H ~ R3~R2
0~
R~ R3 R1 .
CH3 H H 4
C2H5 H H 4
C4Hg H H 4
i-C3H7 H 4
~ _ ~-CH3 F 1,4
; 5 When the remaining products of Example 6A
and those of Example 6B are treated according to the
above procedure, the corresponding compounds of the
formula
.
~ .
~'.',,
,
,
,

1 17466~
' .1 ~ ~
.. . I
IC~3
~3C f=o
~ OCOOR2
o~
wherein the various structural parameters represented by
R2, R3, R4, R5, Z and the dotted line are identical to
those of compounds 6Al-6A3, 6A5-6All, and..6B]..-6B25 of
Examples 6A and 6B are obtained.
EXAMPLE 12
Chloromethyl 11~, 17-dihydroxyandrost-4-en-
3-one-17~-carboxylate (3.01 mol) is dissolved in toluene
(100 milliliters) and the solution is cooled to
approximately 0C. Phosgene is then bubbled into the
solution, while maintaining the reaction mixture at low
temperature, until the reaction is complete
~approximately 2 hours). The solvent and excess phosgene
are removed by evaporation to leave the crude 17~-
chlorocarbonyloxy compound of the formula
OC~2Cl
I
C
O
. . _ .
.

- 1 17466~
C
9~f
,~ _
The intermediate (0.01 mol) obtained above is
then combined with ethanol (0.02 mol) containing 2,6 -
dimethylpyridine (0.01 mol) and allowed to react at
room temperature for 6 hours. At the end of that time,
the desired chloromethyl 17~-ethoxycarbonyloxy-11~-
hydroxyandrost-4-en-3-one-17~-carboxylate is isolated
from the reaction mixture. The compound melts at 197-
200C, after crystallization.
Substitution of an equivalent quantity of
10 methylthiomethyl 11~,17a-dihydroxyandrost-4-en-3-one-17~-
carboxylate for the chloromethyl 11~,17a-dihydroxyandrost-
4-en-3-one-17~-carboxylate used above and substantial
repetition of the foregoing procedure affords methylthio-
methyl 17~-ethoxycarbonyloxy-llB-hydroxyandrost-4-en-3-
15 one-17~-carboxylate, melting at 133-136C, after
crystallization. That compound can then, if desired,
be converted to the corresponding sulfonyl or sulfinyl
compound as described in Example 4.
Other representative species, e.g., the compounds
20 of Example 3, paragraphs 1, 3, 4 and 5, and the compounds
of Examples 7A and 7B can be prepared in li~e manner from
reaction of the corresponding 17a-hydroxy 17~-carboxylates
with the appropriate alcohols, including, when appropriate,
subsequent treatment with m-chloroperoxybenzoic acid as
in Example 4.
EXAMPLE 13
The procedure of the first paragraph of Example
12 is repeated, except that an equivalent quantity of
11~,17~-dihydroxyandrost-4-en-3-one-17B-carboxylic acid
is used in place of the chloromethyl llB,17a-
dihydroxyandrost-4-en-3-one-17B-carboxylate. The crude
intermediate thus obtained has the formula
, . . .
.
~' . .
. .
.,
:
:
.: '
..... . .

` `- 1 17466~
~s
9,~ _
OH
I
C=o
~ _ollcl
That intermediate is then subjected to the
procedure of the second paragraph of Example 12, to
afford 17a-ethoxycarbonyloxy-11~-hydroxyandrost-4-en-3-
one-17B-carboxylic acid, identical to the product of
Example 2, paragraph 2.
The other compounds of Examples 2, 6~and ~æ can
be prepared using the same general procedure.
EXAMPLE 14
Chloromethyl 1~17a-dihydroXyandrOSt-4-en-3-one-
17~-carboxylate (0.02 mol) is combined with
diethylcarbonate (0.2 mol) containing 20 mg of p-
toluenesulfonic acid. The reaction mixture is maintained
at room temperature for 4 hours, then h-eated to about
80 to 85C; the remaining ethanol which forms is removed
by distillation under reduced pressure. Obtained as the
residue is crude chloromethyl 17a-ethoxycarbonyloxy-llg-
hydroxyandrost-4-en-3-one-17B-carboxylate, melting at 197-
200C, after crystallization.
Substitution of an equivalent quantity of
methylthiomethyl llg,17~-dihydroxyandrost-4-en-3-one-17~-
carboxylate for the chloromethyl 11~,17a-dihydroxyandrost-
4-en-3-one-17g-carboxylate used above and substantial
repetition of the foregoing procedure affords
methylthiomethyl 17a-ethoxycarbonyloxy-11~-hydroxyandrost-
. . .
, ' ' ' ' . .
:. , ' .,
,'; ' '' ' '
:, . . .
.`, , ~, . .. .
~, ~

1 17466~
4-en-3-one-17~-carboxylate, melting at 133-136C. That
compound can then, if desired, be converted to the cor-
responding sulfonyl or sulfinyl compound as described in
Example 4.
Other representative species, e.g., the com-
pounds of Example 3, paragraphs 1, 3; 4 and 5, and the
compounds of Examples 7A and 7B, can be prepared in like
manner from reaction of the corresponding 17~-hydroxy-
17~-carboxylates with the appropriate carbonates of the
type R20~0R2 (including, when appropriate, subsequent
treatment with m-chloroperoxybenzoic acid as in Example
4).
EXAMPLE 15
. _
To a solution of 8.7 grams of 11~,17~-dihydroxy-
androst-4-en-3-one-17~-carboxylic acid and 9.6 milliliters
of triethylamine in 100 milliliters of dry
dichloromethane, is added 10 grams ofethyl chloroformate,
dropwise at 0 to 5C. The reaction mixture is gradually
allowed to warm to room temperature and the insoluble
material is removed by filtration. The filtrate is
washed successively with 3% aqueous sodium bicarbonate, 1~
-hydrochloric acid, and water, then is dried over anhydrous
magnesium sulfate. The solvent is concentrated under
reduced pressure and the residue is crystallized to give
10.5 grams of ethoxycarbonyl 17~-ethoxycarbonyloxy-11~-
hydroxyandrost-4-en-3-one-17~-carboxylate, melting at
158-159C.
EXAMPLE 16
Following the general method described in
Example 15 and substituting therein the appropriate
reactants affords the following additional compounds:
:
.

~ i 9 1 1 17466~
~ .
f-~}-OR2
C=O o
~3~
HO ~ - - OCOR2
i3
G~ouna No. R~ _ R~ _ ~ ~Elting point
16-A -C~2C~3 HF H 4 llO-111C (T~F-
isopr~Fyl ethe~)
_ _ _ .
16-B i~C ~ H H H 4 200-203C
_ . .
16-C -CH2C~2C~3 H _ H 4 142-143~C (TffF) .
.... .. .. . . .
EXAMPLE 17
To a solution of 9.8 grams of ethoxycarbonyl 17~
ethoxycarbonyloxy-11~-hydroxyandrost-4-en-3-one-17~-carboxylate
in 100 milliliters of tetrahydrofuran and l20 milliliters of
ethanol are added 42 milliliters of 5% aqueous sodium
bicarbonate. The mixture is stirred at room temperature for
about 30 hours and adjusted to pH 2 to 3 by adding lN hydro-
chloric acid. The insoluble material is isolated by filtra-
tion. Recrystallization from a mixture of tetrahydrofuran
and n-hexane gives 6 grams of 17a-ethoxycarbonyloxy-11~-
hydroxyandrost-4-en-3-one-17B-carboxylic acid having a melting
point of 192-195C.
The compound obtained in Example 2, first
paragraph, and the compounds of Example 6A can be prepared,
; following the same procedure as above and substituting therein
appropriate reactants.

1 17466
qg
_, 5~
ExAMæLE 18
Following the general method described in
Example 17 and substituting therein the appropriate
reactants affords the following compounds:
H- ~00~
O~OR
~,J '
5 Compound No. _ R -~ melting point
18-A C~3 144.5-146.5C (T~F/hexane)
. .
18-B (C 2)~3 164-166-C (T~F/hexane)
. :'
. EXAMPLE 19
To a solution of 8.7 grams of 11-~,17~.~
dihydroxyandrost-4-en-3-one-17~-carboxylic acid and 10
: grams of triethylamine in 100 milliliters of
dichloromethane, a solution of 13.2 grams of n-propyl
chloroformate in 20 milliliters of dichloromethane is
added dropwise over l-l.S hours with ice-cooling. The
reaction mixture is allowed to warm to room temperature
over a 2 hour period, then is washed successively with
15 3S aqueous 60dium bicarbonate, lN hydrochloric acid, and
water and dried over anhydrous sodium sulfate. The
sol~ent is concentrated under reduced pressure.
Crystallization ~rom a mixture of ether and n-hexane
.. . ..
.
- . ~' ' ' ' ' ~
.

4~67
- ~
gives 10.; grams of propoxycarbonyl 11~-hydroxy-17a-
propoxycarbonyloxyandrost-4-en-3-one-17~-carboxylate,
which is dissolved in 40 milliliters of pyridine'. To
that solution, 300 milliliters of water are added
dropwise over a 1 to 1.5 hour period. The mixture is
stirred for one hour and adjusted to pH 2 to 2.5 by adding
concentrated ~ydrochloric acid with ice-cooling. The
mixture is then extracted with chloroform, washed
successively with lN hydrochloric acid and water, and
then dried over sodium sulfate. The solvent is
concentrated under reduced pressure, and the residue is
recrystallized from a mixture of acetone and tetrahydra-
furan to give 7.7 grams of 11~-hydroxy-17~-
propoxycarbonyloxyandrost-4-en-3-ene-17~-carDoxylic acid,
melting at 1~6-157C.
EXAMPLE 20
Following the general procedure detailed in
Exam le 19, but utilizing the appropriate starting
materials and reaction conditions, affords the remaining
compounds of Example 6A.
EXAMPLæ 21
Chloromethyl 17a-ethOxycarbonyloxy-9a-fluoro-
ll~-hydroxy-16a-methylandrosta-1,4-dien-3-one-17~-
carboxylate (2 grams) is dissolved .n anhydrous
dichloromethane [200 millil'iters) and pyri~;n;um ~ Qnx~x~ '
mate (3.5 grams) is added at room'temperature, with
stirring. ~he resultant mixture is ~tirred for 24 hours,
then the solvent is conc~ntrated under reducod pressure
at about 10 to 20~C. The residue is subjected to column
chromatography on silica gel ~Riesel gel 60), using
chloroform as an eluting solvent, followed by
recrystallization from a mixture of tetrahydrofuran and

1 1746~
...~.., ~0
isopropyl ether to give chlorome~hyl 17a-
ethoxycarbonyloxy-9a-fluoro-16a-methylandrosta-1,4-dien-
3,11-dione-L7~-carboxylate, in the yield of 1.7 gr~ms,
melting at 138-140C.
EXAMPLE 22
By a method similar to that described in
Example 21, there is obtained chloromethyl 9-fluoro-
17a-isopropoxycarbonyloxy-16~-methylandrosta-1,4-dien-
3,11-dione-17B-carboxylate, melting at 200-201C.
EXAMPLE 23
Utilizing the general procedure of Example 3,
but substituting the appropriate reactantsA therein, affords
methyl 17a-~2-chloroethoxyjcarbonyloxy-9a-fluoro-llB-
hydroxy-16a-methylandrosta-1,4-dien-3-one-17~-
carboxylate. That product, after recrystallization from
isopropanol, melts at 223-227C.
EXAMPLE 24
In the same general manner as in Example 3, there
is obtained 2-chloroethyl 17a-ethoxycarbonyloxy-9~-
fluoro-11~-hydroxy-16~-methylandrosta-1,4-dien-3-one-
17B-carboxylate. That product, after recrystallization
from tetrahydrofuraa-hexane, mel~s at 243-245C.
.
.
.
. ~ ,
.~ ' ' '' ' ''

~ 1 ~4 ~6 7
EXAMPLE 25
Chloromethyl 17a-ethoxycarbonyloxy~
hydrQxyandrost-4-en-3-one-17~-car~oxylate ~0.01 mol) and
1,2-dimethylpyrrolidine ~0.01 1) are dissolved in
acetonitrile (80 milliliters), and heated to the reflux
temperature. The reaction mixture is maintained at that
temperature, with stirring, for approximately 4 hours.
About 65 ml of acetonitrile are removed; then, the
mixture is cooled to room temperature and excess ethyl
ether is added to cause precipitation. The precipitate
is separated by filtration, washed, and dried in vacuo,
thus afford~ng the desired quaternary ammonium salt of
the formula
~-0 ~ 3
~`~
. '
~
..... .
_ .
In analogous fashion, use of the appropriate
steroidal and ~mj ne starting-materials in the foregoing
general procsdure affords the following additional
quaternary ammonium salts of the ~nvention
- OC~2~ ~ C~-
'CsO
EEO ~ OR2
'~

l 17466~
o ~
--`~3 --
N '
C~3 ~3~ ~ 3
i-C3~7 N(C2~5)3
C
C2~5 . H3C~
C2115 N~OCOC~3
C2~5 N(C2~5)3
' . C2~5 ' . ~
EXAMPL2 26
.: - .
- Ointment
Compound of formula (I), 0.2% w/w
e.g. chloromethyl 17-
ethoxycar~onyloxy-ll~-
: hydroxyandrost-4-en-
3-one-17~-car~oxylate or
chloromethyl 11 ~hydroxy-
l-.~..isopropoxycar~onyl-
oxyandrost-4-en-3-one-
17~-carboxylate
Liquid paraffin 10.0% ~/w
~hite soft paraffin89.8% w/w
~ . .
.. _ .. . . . _ _ __ . . ,_ . _ __ . __ .. ... _ .. _ . . . _ . . .. . . . . .. . .
... . . .
.

1 17~6
-;
~V~ .
~_
APhthous Ulcer Pellet
-
Compound of formula (I), . 0.25 mg
as above
Lactose 69.90 mg
Acacia 3.00 mg
Magnesium stearate 0.75 mg
Retention Enema
Compound of formula (I), 0.001% w/v
as above
Tween 80 0.05% w/v
Ethanol 0.015% w/v
Propylparaben ~ 0.02~ w/v
Methylparaben ~ 0.08% w/v
Distilled water q.s. 100 volumes
Eye Drops
Compound of formula (I), 0.1% w/v
as above
~ .
~ Tween 80 ~ 2.5% w/v
Ethanol 0.75% w/v
Benzalkonium chloride 0.02% w/v
Phenyl ethanol 0.25% w/v
Sodium chloride 0.60% w/v
20 . Water for injection q.s. 100 volumes
~ ( a ~ mcll k)
; "' '

1 17466~ -
C,, ~tS~
EXAMPLE 27
Ointment
Compound of formula ~I), 0.025% w/w
e.g. chloromethyl 17-
ethoxycarbonyloxy-ga-
fluoro-llB-hydroxy-16a-
methylandrosta-1,4-dien-
3-one-17B-carboxylate or
chloromethyl 9a-fluoro-
llB-hydroxy-17a-
methoxycarbonyloxy-16o_
methylandrosta-1,4-dien-
. 3-one-17B-carboxylate
Liquid paraffin~ 10.175% w/w
S White soft paraffin89.8% w/w
Aphthous Ulcer Pellet
Compound of formula (I),
e.g. chloromethyl 9a-fluoro-
ll~-hydroxy-17a-
isopropoxycarbonyloxy-16B-
. methylandrosta-1,4-dien-3-
one-17B-carboxylate or
chloromethyl 17a-
ethoxycarbonyloxy-9o-fluoro- -
llB-hydroxy-16-
methylandrosta-1,4-dien-3-
~ one-l? ~-carboxylate0.1 mg
Lactose 69.90 mg
Acacia . 3.00 mg
Magnesium stearate0.75 mg
. .
; ~ '
.
'
....
.. ..
. . ~
. . ,
:
:.
~ . ~
,

~ 17466~
I S
Retention Enema
Compound of formula (I), 0.001% w/v
e.g. chloromethyl llB-
hydroxy-17a-
isopropoxycarbonyloxy-
androsta-1,4-dien-3-one-
17~-carboxylate or
chloromethyl 9a-fluoro-
llB-hydroxy-17a- ~-
isopropoxycarbonyloxy-
16B-methylandrosta-1,4-
dien-3-one-17B-carboxylate
Tween 80 ~ 0.05~ w/v
Ethanol 0.015% w/v
Propylparaben ~ 0.02% w/v
Methylparaben 0.08~ w/v
Distilled water q.s. 100 volumes
.
Eye Drops
Compound of formula ~I), 0.025% w/v
e.g. chloromethyl 9a-
fluoro-ll~-hydroxy-16a-
methyl-17a-propoxy-
carbonyloxyandrosta-1,4-
dien-3-one-I7B-carboxylate
or chloromethyl 9a-fluoro-
llB-hydroxy-17a-methoxy-
carbonyloxy-16a-methyl-
androsta-1,4-dien-3-one-
17B-carboxylate
Tween 80 2.5% w/v
Ethanol 0.75% w/v
Benzalkonium chloride 0.02% w/v
Phqnyl ethanol 0.25% w/v
Sodium chloride 0.60% w/v
Water for injection q.s. 100 volumes
:
a ~rade ~r7a~ k

1 17466~
From the foregoing description, one of ordinary
skill in the art can readily ascertain the essential
characteristics of the present invention and, without
departing from the spirit and scope thereof, can make
various changes in and/or modifications of the invention
to adapt it to various usages and conditions. As such,
these changes and/or modifications are properly,
equitably and intended to be within the full range of
equivalence of the following claims.

r --~ 117466~
SUPPLEMENTARY DISCLOSURE
. E~AMæLE 6C
Following the ge~eral procedure or Example 2
and substituting therei~ the appropriate reactants
af_ords the following novel intermediates of the
present invention:.
OE~
C=O ' .
Z~OC00~2
~ ~ 3
o~ ' ' . ' - .
R5
,.~
,~.1 C

~ 174687
~ t,= ~ t~ ~
C~l X C~ o ,,
. ~ ~ o o ~ o
U~ C ~ C
E ,~ c~ u~ 0 ~4 0
t`~ 9 - S
~ ~ ~ ' . ~
'~
.
,. , ~; . '
'., ' :
.'', ' .
., ' ' ~, ' '. ',

1 1746~
C C C C ~x ~x'
. O ~ O a) O ~ O ~ O ~ O a.a:~ ~~ c~l~ ~.- O ~ ! ~O
. o, U~ ~ ~, CO ~ 0, U~ ~E ~ c ~ c ,~ c , , ~ c
U~ ~ o ~ C~ _ ~ ~ C~l
~ ~ E~ ~ E~ ~ E~ ~ E~ ~ E~
_ ~ ~ r_ _ _ ~ C _ _ ~
C~l /~;~ o~,~ o~"~ /~\ o~,~ /~'\
. . .~ .
~ -~ ~5~ ~ 5~
..
. ' ,

1 174667
8--¦ ¦ o K
~ r ~ C
~o = ~ =
S= o_
o
~ ~ ' :' ,
.
`
. ~

r~~
~ 17~667
The foregoing compounds can be named as follows:
6C-1: 17a-allyloxycarbonyloxy-9a-fluoro-11~-hydroxy-
16a-methylandrosta-1,4-dien-3-one-17~-
carboxylic acid
6C-2: 17a-n-propoxycarbonyloxy-6a,9a_difluoro-11~-
hydroxy-16a-methylandrosta-1,4-dien-3-one-
17~-carboxylic acid
6C-3: 17a-isopropoxycarbonyloxy-6a,9a-difluoro-11~-
hydroxy-16a-methylandrosta-1,4-dien-3-one-
17~-carboxylic acid
///
.~
~t

466~
6C-4: 17a-ethoxycarbonyloxy-6a-fluoro-llB-hydroxy-16a-
methylandrosta-1,4-dien-3-one-17B-carboxylic acid
6C-5: 17a-n-propoxycarbonyloxy-6a-fluoro-llB-hydroxy-16a-
methylandrosta-1,4-dien-3-one-17~-carboxylic acid
6C-6: 17a-isopropoxycarbonyloxy-6a-fluoro-11~-hydroxy-16a-
methylandrosta-1,4-dien-3-one-17~-carboxylic acid
6C-7: 17a-methoxycarbonyloxy-llB-hydroxy-androsta-1,4-
dien-3-one-17g-carboxylic acid
6C-8: 17a-methoxycarbonyloxy-6a-rluoro-11~-nyaroxy-16a-
methylandrosta-1,4-dien-3-one-17~-carboxylic acid
6C-9: 17a-ethoxycarbonyloxy-llB-hydroxy-androsta-1,4-
dien-3-one-17~-carboxylic acid
_ ~ _
J~
C. 1~
.: .

' 1~7~667
6C-10: 17a-methoxycar~onyloxy-9G-flouro-ll~-hydroxy-16~-
. methylandrosta-1,4-dien-3-one-17~-carboxylic acid
6C-11: 17G-n-propoxycarbonyloxy-9~-fluoro-11~-hydroxy-16~-
methvlandrost~-1,4-dien-3-one-17B-carboxylic acid
_ "~ _
i 7 ~ 3
." i
.

~ ~7~667`
E2A~E 7C
Following the general proceduIe of E~zm~le 3
and cUbstituti~g therein the appropriate reactants
ar ords the ~ollowing compounds:
. IRl
C=O
: R5
-- ,La~ --
r~ .,
,

1 17466~
"c ~C U~ U~c "
~ ,~ ~ ~ ~ ~ 0 1~ ~a
C~l X ~ X ~o X X X C~
'~ ' ~ ' ~ '~ ~ o
U~ = U~ ~ U~ ~ U~
E~ E~ ~ E~ . ~ ~ ~
C~- o- ,,_ oo-- C~i-
~ ~ ,
- _ _ 3: _ _ _ = _ ~
C~ _~" _~" _,~" _,c,", _~,
~ ' ~ a ~ ~ U _ ~ ¦
~ ~ ~ 5~ 0~ ~
. C~c~
~:~ ~ ~ ~ ~C~
C~ ~ C~
_ .~ _

1 ~7~667
C~- . ,7_ _ ~_
o ~ U U o ~ ~ o ~
U~ C . C' U " U U~ C C U~ C
~ X u~ ~ ~D ~ ~ X ~ X u~ X
u~ ~ ~ c~ c~ a~ ~ o ~ .
_~5 a~ ~a ~ 5 _1 ~ c c~ -
U~ C U~ ~ U~ U~ ~: C`J C U~ C
~r~ r-. S ~ 5 o ~ u~ ~ `* ~
~~ a~ u c~ co _. ~ ~ _ ~
. ~ ' a~ ~ ~ ~ ~ E~ c~ c`l E~
~ -o~ _ _ _ _ o~- o _ 0~"~
~ ~ ~ ~ _ .~ k
~5 _ r~ _ _ 5 5
C~
_ "~ ~ 5
. ~ '~ '~'`1 3'`' ~,~ C5~ 'c~
~ ,~i /~6
....
;
- . .: .
:

1 174667
~.; ~ //~
~,cJ I "
.
'`, ' ' ~' ~ ."` .
' ~ , ` ' ,
.. '
,: : ' ,
'~.' ~ , ' ' : `

-
~ 17466~
The foregoing compounds can be named as follows:
7C-l: chloromethyl 17a-isopropoxycarbonyloxy-6a~9a-
difluoro-llB-hydroxy-16-methylandrosta-1,4-
dien-3-one-17g-carboxylate
7C-2: chloromethyl 17a-n-propoxycarbonyloxy-6a,9a-
difluoro-ll~-hydroxy-16a-methylandrosta-1,4-
dien-3-one-17B-carboxylate
7C-3: fluoromethyl 17a-n-propoxycarbonyloxy-9a-fluoro-
llB-hydroxy-16a-methylandrosta-1,4-dien-3-one-
17B-carboxylate
7C-4: 2-chloroethyl 17a-isopropoxycarbonyloxy-11~-hydroxy-
androsta-1,4-dien-3-one-17B-carboxylate
7C-5: methyl 17a-(2-chloroethoxy)carbonyloxy-9a-fluoro-
ll~-hydroxy-16a-methylandrosta-1,4-dien-3-one-17B-
carboxylate
-- ,a~ --
/~
C, '~` "` '
.
'
. ' ~ . .

~ 174~67
7C-6: chloromethyl 17a-ethoxycarbonyloxy-6a-fluoro-llB-
hydroxy-16a-methylandrosta-1,4-dien-3-one-17~-
carboxylate
7C-7: chloromethyl 17a-n-propoxycarbonyloxy-6a-fluoro-
113-hydroxy-16a-methylandrosta-1,4-dien-3-one-17
-carboxylate
7C-8: chloromethyl 17a-isopropoxycarbonyloxy-6a-fluoro-
llB-hydroxy-16a-methylandrosta-1,4-dien-3-one-
17~-carboxylate
7C-9: chloromethyl 17a-n-propoxycarbonyloxy-11~-hydroxy-
androsta-1,4-dien-3-one-17~-carboxylate
7C-10: chloromethyl 17a-methoxycarbonyloxy-llB-hydroxy-
androsta-1,4-dien-3-one-17B-carboxylate
7C-ll: chloromethyl 17a-methoxycarbonyloxy-6a-fluoro-
ll~-hydroxy-16a-methylandrosta-1,4-dien-3-one-
17~-carboxylate
'
_ ~ _
'
. : :

1 ~7466~
7C-12: Chloromethyl 17a-methoxycarbonyloxy-9a-flouro-11~-
hydroxy-16~-methylandrosta-1,4-dien-3-one-17~-
carboxylate
7C-13: Chloromethyl 17a-n-propoxycarbonyloxy-ga-cluoro-
ll~-hydroxy-16~-methylandrosta-1,4-dien-3-one-17B-
carboxylate
C Y~ a
. . ~ .. . ~
.~
:. , ' ' . : . . . ' '

1 17466~
Exam~le 28
To a solution of 3 grams of chloromethyl 113-hydroxy-
17a-isopropoxycarbonyloxyandrost-4-en-3-one-l7B-carboxylate
in 100 ml of acetonitrile, 7.9 grams (10 times moles) of AgF
is added, and the mixture is stirred at room temperature for
12 days while shading the reaction syste~ from light~
Thereafter the reaction mixture is filtered, and the solid on
the filter is fully washed with ethyl acetate. The filtrate
and the ethyl acetate solution are combined, and the mix~ure
is washed with water and a saturated sodium chloride aqueous
solution, and dried over anhydrous sodium sulfate. The solvents
are distilled off, giving 2 grams of crude crystalline product.
The product is subjected to preparative thin-layer chromatography
~Silica Gel 60F254, Merc~), using a mix~ure of chloroform and
methanol (15:1) as an eluting solvent. Then the product is
recrystallized from a mixture of tetrahydrofuran and n-hexane
to give 180 mg of fluoromethyl l~ -hydroxy-17~-isopropoxy-
carbonyloxyandrost-4-en-3-one-17~-carboxylate as colorless
needles, melting at 207.5-210C.
_ ~_
/0~/
;
. ......
... .

1 i7-1~67
Exam~le 29
Following the general procedure of Example 28 and
substituting ~herein the appropriate reactants afrords the
followqng compounds:
IORl
C=O
¦ OCOOR~
R5
~ .
.'` ' ' ' .
~, .

1 174~67.
~,~, C~
C~
c~
/~ / \
.
.
. .
.. `.. - . ~ . . .
.` :

``` l 17466~
The foregoing compounds can be named as follows:
¢ /L~
C 29-1: fluoromethyl 17a-ethoxycarbonyloxy-9- louro--ll~-
hydroxy-16-methylandrosta-1,4-dien-3-one-17~-
carboxylate
29-2: fluoromethyl 17a-n-propoxycarbonyloxy-9-fluoro-11~-
hydroxy-16-methylandrosta-1,4-dien-3-one-17~-
carboxylate
_ ,~
: a~
; , . . ~
.~ .